WO2024097394A1 - Formes solides et co-cristallines d'un composé de pyrimidine triazole - Google Patents

Formes solides et co-cristallines d'un composé de pyrimidine triazole Download PDF

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WO2024097394A1
WO2024097394A1 PCT/US2023/036758 US2023036758W WO2024097394A1 WO 2024097394 A1 WO2024097394 A1 WO 2024097394A1 US 2023036758 W US2023036758 W US 2023036758W WO 2024097394 A1 WO2024097394 A1 WO 2024097394A1
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acid
compound
polymorph
crystalline
triazol
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Katrien Brak
Anantha Sudhakar
Travis Remarchuk
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Denali Therapeutics Inc.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/122—Propionic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/12—Glutaric acid
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    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
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    • C07C55/14—Adipic acid
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/14—Monocyclic dicarboxylic acids
    • C07C63/15—Monocyclic dicarboxylic acids all carboxyl groups bound to carbon atoms of the six-membered aromatic ring
    • C07C63/26—1,4 - Benzenedicarboxylic acid
    • C07C63/28—Salts thereof
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
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    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings

Definitions

  • FIELD The present disclosure relates to crystalline polymorph and amorphous forms of N 2 -(3- (2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5- (trifluoromethyl)pyrimidine-2,4-diamine and cocrystals thereof for use in the treatment of peripheral and neurodegenerative diseases, including Parkinson’s disease.
  • DESCRIPTION Combined genetic and biochemical evidence implicates certain kinase function in the pathogenesis of neurodegenerative disorders (Christensen, K.V. (2017) Progress in medicinal chemistry 56:37-80; Fuji, R.N.
  • X-ray powder diffraction is a powerful tool in identifying different crystal phases by their unique diffraction patterns.
  • Other techniques such as solid-state Nuclear Magnetic resonance NMR spectroscopy, RAMAN spectroscopy, DSC (differential scanning calorimetry) are useful as well.
  • the pharmaceutical industry is often confronted with the phenomenon of multiple 1 ME1 46604090v.1 137485-01120 polymorphs of the same crystalline chemical entity. Polymorphism is often characterized as the ability of a drug substance, i.e. Active Pharmaceutical Ingredient (API), to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattices giving the crystals different physicochemical properties.
  • API Active Pharmaceutical Ingredient
  • Synchrotron X-ray powder diffraction is a useful technique. In such situations the crystal structure can be solved from X-ray powder diffraction data obtained by measurements at ambient conditions and/or at variable temperature or humidity. There is a need to develop new polymorph forms and cocrystals of drug substances, and methods of preparing them.
  • the present disclosure relates to crystalline, amorphous, and cocrystal forms of a LRRK2 inhibitor N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)- N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, referred to herein as the Formula I compound and having the structure:
  • a crystalline compound of Formula I selected from: 2 ME1 46604090v.1 137485-01120 a Form A polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6; and a Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.
  • a Form A polymorph of Formula I exhibiting an X- ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6.
  • the Form A polymorph further comprises peaks at approximately 5.4 and 7.4 degrees 2-theta.
  • the Form A polymorph has a differential scanning calorimetry DSC shows a melting endotherm at about 107.1 °C onset.
  • the Form A polymorph is an anhydrate.
  • the Form A polymorph is characterized by the X-ray powder diffraction pattern shown in Figure 2.
  • a Form B polymorph of Formula I that exhibits an X- ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.0, 9.9, 16.1, 19.9, and 23.2.
  • a crystalline compound of Formula I in substantially pure form In other embodiments, provided is a cocrystal thereof of Formula I in substantially pure form.
  • a pharmaceutical composition comprising a crystalline polymorph of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
  • the crystalline polymorph is Form A.
  • a pharmaceutical composition comprising an amorphous compound of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, 3 ME1 46604090v.1 137485-01120 or excipient.
  • a cocrystal comprising N 2 -(3-(2-(2H-1,2,3-triazol-2- yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4- diamine and a coformer, and hydrates thereof.
  • a pharmaceutical composition comprising the cocrystal of Formula I and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
  • a process for preparing a cocrystal of any one of Formula I comprising contacting N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol- 5-yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine with the coformer.
  • the coformer is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconitic acid, adipic acid, benzoic acid, butyric acid, cholic acid, gallic acid, glutaric acid, fumaric acid, 4-hydroxybenzoic acid, isobutyric acid, malonic acid, D,L- mandelic acid, propionic acid, salicylic acid, succinic acid, terephthalic acid, and vanillic acid.
  • BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the inter-conversion relationships between Formula I compound polymorph Forms A and B and amorphous form C in a schematic diagram.
  • Figure 2 shows the XRPD pattern of Form A polymorph.
  • Figure 3 shows an overlay of the XRPD patterns of Formula I compound polymorph Forms A and B.
  • Figure 4 shows TGA and DSC data of Form A polymorph.
  • Figure 5 shows the thermal ellipsoid drawing of an asymmetric unit molecule from the single crystal X-ray structure of Form A polymorph.
  • Figure 6 shows XRPD Diffractogram of amorphous Form C.
  • Figure 7 shows PLM image of the Form A single crystal.
  • Figure 8 shows XRPD overlay comparing Form A after 6 months storage at 40 oC/75%RH and 25 oC/60%RH.
  • Figure 9 shows XRPD overlay comparing Form A after 48 months storage at 25 oC/60%RH.
  • the term "about” or “approximately” when used in reference to X-ray powder diffraction pattern peak positions refers to the inherent variability of the peaks depending on, for example, the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material and the like, depending on the instrumentation used. In this case the measure variability of the instrument was about plus/minus understand the use of "about” or “approximately” in this context unless specified otherwise (e.g. ⁇ 0.05 degrees 2-theta).
  • Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate. Hydrates/solvates may exist as polymorphs for compounds with the same solvent content but different lattice packing or conformation. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, morphology, density, flowability, compactibility and/or X-ray diffraction peaks. The solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles.
  • XRPD means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component with a display of the X- Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. Materials with similar unit cells will give X-ray diffraction patterns that are isostructural or isomorphous solvates.
  • the intensity of the reflections varies according to the electron density causing diffraction as well as sample, sample preparation, and instrument parameters.
  • Analysis of XRPD data is based upon the general appearance of the measured powder pattern(s) with respect to the known response of the X-ray diffraction system used to collect the data.
  • diffraction peaks that may be present in the powder pattern
  • their positions, shapes, widths, and relative intensity distributions can be used to characterize the type of solid state order in the powder sample.
  • the position, shape, and intensity of any broad diffuse scatter (halos) on top of the instrumental background can be used to characterize the level and type of solid state disorder.
  • the combined interpretation of the solid state order and disorder present in a powder sample provides a qualitative measure of the macro-structure of the sample.
  • cocrystal refers to a crystalline molecular complex composed of two or more different molecular compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.
  • the cocrystal consists of a hydrogen-bonded complex with a “pharmaceutically acceptable” coformer (Aitipamula, S. et al (2012) Cryst. Growth Des.12(5):2147–2152).
  • Coformers include, but are not limited to, acetylsalicylic acid, trans-acontic acid, adipic acid, L- ascorbic acid, benzoic acid, citric acid, fructose, fumaric acid, gallic acid, glucose, glutaric acid, hippuric acid, 4-hydroxybenzoic acid, maleic acid, malonic acid, mannitol, nicotinamide, nicotinic acid, phenylalanine, riboflavin, salicylic acid, succinic acid, and vanillic acid.
  • hydrate refers to the complex where the solvent molecule is water.
  • RH refers to Relative Humidity 6 ME1 46604090v.1 137485-01120 FORMULA I COMPOUND
  • the present disclosure includes polymorphs, cocrystal, and amorphous forms of Formula I compound, (CAS Registry Number 2170179-24-3), having the structure: and named as: N 2 -(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5- yl)-N 4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (WO 2017/218843, US 9932325, each of which are incorporated by reference).
  • Form A was found to be a stable crystalline form and can be converted to a mixture of Forms A and B by crystallization from cyclohexane and methyl isobutyl ketone (MIBK). The mixture reverts back to Form A after one month at room temperature. Heating Form A to 110 o C followed by cooling to – 20 o C forms amorphous Form C, which converts back to Form A on warming to room temperature. The 24 hours solubility evaluation showed that the solubility of Form A in water at was 29.9 ⁇ g/mL. DVS (dynamic vapor sorption) results indicated Form A is non-hygroscopic, as defined by less than 0.2% reversible water intake (Table 1). Table 1.
  • POLYMER INDUCED CRYSTALLIZATION Polymer induced crystallization experiments were performed with two sets of polymer mixtures in four different solvent systems. Approximate 20 mg of Formula I compound was dissolved in 1.0-2.0 mL of appropriate solvent in a 3-mL glass vial containing about 2 mg of polymer mixture. Clear solutions were transferred to evaporate at room temperature. The obtained solids were collected for XRPD characterization. Results summarized in Table 7B below shows that only Form A was generated. Table 7B.
  • Polymer mixture A polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylchloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methyl cellulose (MC) (mass ratio of 1:1:1:1:1:1).
  • Polymer mixtureB polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA) sodium alginate (SA), and hydroxyethyl cellulose (HEC) (mass ratio of 1:1:1:1:1).
  • PCL polycaprolactone
  • PEG polyethylene glycol
  • PMMA poly(methyl methacrylate)
  • SA poly(methyl methacrylate)
  • HEC hydroxyethyl cellulose
  • the X-ray source was a Cu tube that was operated at 45 kV and 40 mA.
  • the scan mode was continuous and the divergence slit automatic.
  • Each sample was analyzed from 3° to 40° 2- theta with a step size of 0.0167° 2-theta and 18 sec scan step time.
  • Parameters for XRPD test DSC/TGA DSC analysis was conducted on a TA Instruments Q2000 DSC. The DSC cell was kept under a nitrogen purge. The sample was placed in an aluminum crimped pan and was heated from 25 °C to 300 °C at a rate of 10 °C /min.
  • TGA data was collected using a TA Q500/Q5000 TGA from TA Instruments.
  • the TGA was performed using nitrogen purge gas.
  • Each sample was placed in an open aluminum pan and heated from room temperature to 350 °C at a rate of 10 °C /min.
  • DSC analysis was conducted on a TA Instruments Q200/Q2000 DSC. The DSC cell was kept under a nitrogen purge.
  • the sample was placed in an aluminum crimped pan and was heated from 25 °C to 300 °C at a rate of 10 °C /min.
  • Table 9 Parameters for TGA and DSC test 15 ME1 46604090v.1 137485-01120 DVS DVS analysis was carried out using a SMS (Surface Measurement Systems) DVS Intrinsic analyzer.
  • the relative humidity at 25 oC was calibrated against the deliquescence point of LiCl, Mg(NO3)2, and KCl. Approximately 15-20 mg of sample was loaded into a pan for analysis. A nitrogen gas flow rate of 200 mL/min was used. The sample was analyzed at 25 oC in a range of 0 to 95% relative humidity (RH), with 10% RH steps from 0 to 90% RH and a 5% RH step from 90 to 95% RH. The progression from one step to the next occurred either after satisfying the equilibrium criterion of 0.002 %/min weight change (dm/dt), or if the equilibrium criterion was not met, after 180 min. The minimum dm/dt stability duration of each step was 10 min.
  • FORM A CHARACTERIZATION Form A was characterized by XRPD, TGA, DSC, DVS, and polarized light microscopy (PLM).
  • XRPD Figure 2, Table 10
  • TGA indicated low weight loss
  • DSC indicated a single sharp melt at around 107 oC ( Figure 4).
  • DVS showed that Form A is non-hygroscopic with no form change after exposure to humidity. Examination of the PLM indicates irregular plate-like particles. Based on the characterization results, Form A is an anhydrate form. Table 10.
  • Form A Pos. [°2Th.] Height [cts] FWHM Left [°2Th.] d-spacing [ ⁇ ] Rel. Int.
  • Form A was demonstrated to be physically and chemically stable for up to 6 months at 40 oC/75%RH and for up to 48 months at 25 oC/60%RH. Samples were analyzed for appearance, HPLC purity, and polymorphic form. No form change was detected by XRPD and no changes in purity by HPLC were observed. Table 11.
  • Form C was characterized by XRPD and DSC.
  • the XRPD trace revealed a characteristic amorphous halo with no significant diffraction peaks ( Figure 6).
  • SINGLE CRYSTAL DETERMINATION OF FORM A Form A SXRPD Characterization A suitable single crystal was selected from block-like crystals and analyzed by a single- crystal X-ray diffractometer (SCXRD). The structure of the single crystal was determined successfully.
  • Crystal Growth Procedure The block-like single crystals of Form A used for single-crystal X-ray diffractometry (SCXRD) characterization were obtained via liquid vapor diffusion from a DMSO and H2O solvent system at room temperature. PLM image of the Form A single crystals is shown in 19 ME1 46604090v.1 137485-01120 Figure 7. Data Collection A colorless block-like single crystal selected from the Form A single crystals sample was mounted in a random orientation and immersed in a stream of nitrogen at 150 K.
  • a semi-empirical absorption correction was made (multi-scan method) using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Transmission coefficients ranged from 0.95582 to 1.00000. Intensities of equivalent reflections were averaged. The agreement factor for the averaging was 1.65% based on intensity.
  • Single Crystal Structure Solution and Refinement The structure was solved with the Superflip structure solution program using Charge Flipping and refined with ShelXL (Version 2014/7) refinement package using full-matrix least- squares on F2 contained in OLEX2. Hydrogen atoms were refined as riding model on the atom to which they are bonded.
  • XRPD Calculated X-ray Powder Diffraction
  • the calculated XRPD pattern was generated for Cu radiation using Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M. & van de Streek, J. J. Appl. Cryst.2006, 39, 453–457) program and the atomic coordinates, space group, and unit cell parameters from the single crystal structure.
  • the calculated XRPD pattern generated from the Form A single crystal structure is in agreement with the experimental XRPD 20 ME1 46604090v.1 137485-01120 pattern.
  • Anisotropic displacement parameters ( ⁇ 2 ⁇ 10 3 ) for Freebase Type A single crystal (810014-28-A6) 25 ME1 46604090v.1 137485-01120 2[h 2 a* 2 U 11 + 2hka*b*U 12 26 ME1 46604090v.1 137485-01120 Table 17. Bond lengths for Freebase Type A single crystal 27 ME1 46604090v.1 137485-01120 Table 18. Bond angles for Freebase Type A single crystal 28 ME1 46604090v.1 137485-01120 Table 19.
  • Table 21 below shows melting points as characterized by DSC analysis of select cocrystals that were formed.
  • Table 21 GENERAL METHODS FOR CO-CRYSTAL ANALYSES DSC analysis was conducted on a TA Instruments Q2500 Discovery Series instrument. The instrument calibration was performed using Indium. The DSC cell was kept under a nitrogen purge of ⁇ 50 mL per minute during each analysis. The sample was placed in an 39 ME1 46604090v.1 137485-01120 aluminum crimped pan and was heated from approximately 25 °C to 350 °C at a rate of 10 °C per minute.
  • a polymorph form of Formula I may be formulated in accordance with standard pharmaceutical practice and according to procedures of Example 9, for use in therapeutic treatment (including prophylactic treatment) in mammals including humans.
  • the present disclosure provides a pharmaceutical composition comprising the Formula I compound in association with one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient.
  • Suitable carriers, diluents, glidants, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), blister packaging, sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container.
  • the label may also include appropriate warnings.
  • Pharmaceutical formulations of a polymorph form of Formula I compound may be prepared for various routes and types of administration with pharmaceutically acceptable diluents, carriers, excipients, glidants or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
  • the pharmaceutical formulation can be sterile.
  • formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.
  • the pharmaceutical formulation ordinarily can be stored as a solid composition, a tablet, a pill, a capsule, a lyophilized formulation or as an aqueous solution.
  • the pharmaceutical formulations of the invention will be dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, ethanol, or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • macroemulsions for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Such techniques are disclosed in Remington's Pharmaceutical Sciences 18th edition, (1995) Mack Publ. Co., Easton, PA.
  • Other examples of drug formulations can be found in Liberman, H. A.
  • Tablets may comprise of one or more pharmaceutically acceptable excipient such as a 41 ME1 46604090v.1 137485-01120 carrier, glidant, diluent, binder, disintegrant, or lubricant.
  • Pharmaceutically acceptable diluents maybe selected from microcrystalline cellulose, lactose, sodium starch glycolate, calcium carbonate, corn starch, sugar alcohols such as sorbitol, xylitol, mannitol, and combinations thereof.
  • glidants may be selected from silicon dioxide, powdered cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium silicate, magnesium carbonate, asbestos free talc, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.
  • Pharmaceutically acceptable binders may be selected from corn starch and pregelatinized starch, carboxymethylcellulose sodium, carmellose sodium, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellose calcium, PEG (Polyethylene Glycol) povidone, compressible sugar, and combinations thereof.
  • Pharmaceutically acceptable disintegrants may be selected from microcrystalline cellulose, powdered cellulose, carmellose sodium, carboxymethylcellulose calcium, sodium starch glycolate, crospovidone, and combinations thereof.
  • Pharmaceutically acceptable lubricants may be selected from magnesium stearate, stearic acid, calcium stearate, sodium stearic fumarate, polyethylene glycols, colloidal silicon dioxide, talc, beeswax, hydrogenated vegetable oil, and combinations thereof.
  • the pharmaceutical formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences 18 th Ed.
  • compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may be a solution or a suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared from a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol or prepared from a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride 42 ME1 46604090v.1 137485-01120 solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the present disclosure relates to a method of treating a disease or condition mediated, at least in part, by leucine-rich repeat kinase 2 (LRRK2).
  • LRRK2 leucine-rich repeat kinase 2
  • the disclosure provides methods for preventing or treating a disorder associated with LRRK2 in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of a compound provided herein.
  • the disease or condition mediated, at least in part, by LRRK2 is a neurodegenerative disease, for example, a central nervous system (CNS) disorder, such as Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and cascular dementia), amyotrophic lateral sclerosis (ALS), age related memory dysfunction, mild cognitive impairment (e.g., including the transition from mild cognitive impairment to Alzheimer’s disease), argyrophilic grain disease, lysosomal disorders (for example, Niemann-PickType C disease, Gaucher disease) corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD), and HIV- associated dementia (HAD).
  • CNS central nervous system
  • PD central nervous system
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • dementia
  • the disorder is an ischemic disease of organs including but not limited to brain, heart, kidney, and liver.
  • the disease or condition mediated, at least in part, by LRRK2 is cancer.
  • the cancer is thyroid, renal (including papillary renal), breast, lung, blood, and prostate cancers (e.g. solid tumor), leukemias (including acute myelogenous leukemia (AML)), or lymphomas.
  • the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, or multiple myeloma.
  • the presently disclosed compounds are used in methods for treatment of inflammatory disorders.
  • the disorder is an inflammatory disease of the intestines, such as Crohn’s disease or ulcerative colitis (both generally known together as inflammatory bowel disease).
  • the inflammatory disease is leprosy, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
  • the inflammatory disease is leprosy, Crohn’s disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
  • the presently disclosed compounds are used in methods for 43 ME1 46604090v.1 137485-01120 treatment of multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus, Sjogren’s syndrome, Devic’s disease, and inflammatory myopathies.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines et amorphes de N2 -(3-(2-(2H-l,2,3-triazol-2-yl)propan-2-yl)-l-cyclopropyl-l//-pyrazol-5- yl)-/V7-éthyl-5-(trifluorométhyl)pyrimidine-2,4-diamine (composé de formule I), des co-cristaux, des compositions pharmaceutiques et des préparations de ceux-ci.
PCT/US2023/036758 2022-11-03 2023-11-03 Formes solides et co-cristallines d'un composé de pyrimidine triazole WO2024097394A1 (fr)

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