WO2023249989A1 - Solid forms of deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors - Google Patents
Solid forms of deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors Download PDFInfo
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- WO2023249989A1 WO2023249989A1 PCT/US2023/025826 US2023025826W WO2023249989A1 WO 2023249989 A1 WO2023249989 A1 WO 2023249989A1 US 2023025826 W US2023025826 W US 2023025826W WO 2023249989 A1 WO2023249989 A1 WO 2023249989A1
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- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- a primary concern for the large-scale manufacture of pharmaceutical compounds is that the active substance should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, crystal morphology may change during manufacture and/or storage, resulting in quality control problems and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions. In this regard, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which can improve its physical and chemical stability gives a significant advantage over less stable forms of the same drug.
- polymorphism When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as “polymorphism.” Each of the crystal forms is a “polymorph.” Although polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal shape, morphology, particle size, compaction behavior, flow properties, and/or solid-state stability. The difference in the physical properties of different polymorphic forms results from different orientation and interm olecular interactions of adjacent molecules in the solid. Polymorphic forms of a compound can be distinguished, in particular, by X-ray diffraction.
- compositions comprising the solid forms of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin- 6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/ disclosed herein and a pharmaceutically acceptable carrier.
- Still further disclosed herein is a method of treating a disease and condition mediated by CSF-1R in a patient in need thereof, comprising administering to the patient an effective amount of the solid forms of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3Z7-imidazo[4,5-Z>]pyridine-2-t/ disclosed herein.
- the present disclosure also relates to the solid forms of 3-(((25,35)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/- imidazo[4,5-Z>]pyridine-2-t/ disclosed herein for use in treating a disease and condition mediated by CSF-1R in a patient in need thereof.
- the present disclosure further relates to use of the disclosed solid forms of 3- (((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/ in the manufacture of a medicament for treating a disease involving mediation of CSF-1R.
- FIG. 1 shows an XRPD pattern of Compound (I) Form A.
- FIG. 2 shows a PLM image of Compound (I) Form A.
- FIG. 3 shows a TGA (top pattern)/DSC (bottom pattern) overlay of Compound (I) Form A.
- FIGS. 4A and 4B show NMR spectrum of Compound (I) a) initial starting material and b) NMR spectrum of Compound (I) Form A.
- FIG. 6 shows an XRPD pattern of Compound (I) a) Form I b) Form A, c) Form II dioxane solvate, d) Form III acetic acid solvate, and e) Form IV ACN solvate.
- FIG. 7 shows DSC/TGA of Form I.
- FIG. 8 shows DSC/TGA of Form A.
- FIG. 9 shows DSC/TGA of Form II, dioxane solvate.
- FIG. 10 shows DSC/TGA of Form III, acetic acid solvate.
- FIG. 11 shows DSC/TGA of Form IV, ACN solvate.
- FIG. 12 shows XRPD pattern of Compound (I) a) Scaled up Form I and b) Form I (Reference).
- FIG. 13 shows XRPD pattern of Compound (I) a) Form A (Reference), b) Acetone @ 25 °C, c) EtOAc @ 25 °C, d) Acetone @ 50 °C, e) EtOAc @ 50 °C and f) Form I (Reference).
- FIGS. 14A-14D show LC-MS a) Chromatogram of Form I, b) Chromatogram of Form A, c) MS-Spectra of Form I and d) MS-Spectra of Form A.
- FIG. 15 shows DVS plot of Form A.
- FIG. 16 shows XRPD pattern of Form A a) before DVS and b) after DVS.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- crystalline refers to a solid form which is substantially free of any amorphous solid-state form, e.g., any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with more or less sharp peaks.
- the crystalline solid form is a single solid-state form, e.g. crystalline Form A.
- Crystalline forms can be identified and distinguished from each other by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and/or thermogravimetric analysis (TGA).
- XRPD X-ray powder diffraction
- DSC differential scanning calorimetry
- DVS dynamic vapor sorption
- TGA thermogravimetric analysis
- DSC refers to the analytical method of differential scanning calorimetry.
- CSF-1R inhibitors colony stimulating factor-1 receptor inhibitors
- CNS central nervous system
- This disclosure also relates to pharmaceutical formulations comprising CSF-1R inhibitors and to the use of CSF-1R inhibitors and pharmaceutical compositions comprising CSF-1R inhibitors to treat disease.
- diseases include immune-mediated diseases, including multiple sclerosis, lupus nephritis, rheumatoid arthritis, and neurological diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
- ALS amyotrophic lateral sclerosis
- Solid forms of Compound (I) disclosed herein may be at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.
- Example 1-3 Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3- methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine
- Tri n-butyl phosphine (11.99 ml; 48.60 mmol; 2.10 eq.) was added dropwise over 10 min with a slight exotherm. The resulting brown solution was stirred at 45-50 °C for 1.5 h.
- sodium hydroxide solution (15 wt%, 40 mL, 6.5 eq.) and the mixture was stirred at 45 °C for 0.5-1 h.
- the reaction was cooled to room temperature. The layers were separated. The aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to a wet-solid.
- the solid was stirred in methyl t-butyl ether (60 mL) for 2 h, filtered and dried under vacuum.
- the off-white solid was dissolved in ethanol (55 mL) at elevated temperature. The solution was stirred at room temperature with seeding and cooling to 0-5 °C.
- Example 1-4 Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3- methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2- ⁇ /
- the suspension was washed with aqueous 10% w/w ammonium chloride (400 mL).
- the organic layer was separated, diluted with ethyl acetate (200 mL) and washed with water (3 x 100 mL) followed by i saturated sodium chloride solution (100 mL).
- the organic layer was dried (sodium sulfate), filtered and concentrated to a solid.
- the solid was dried by azeotroping with toluene (2 x 100 mL).
- the solid was dissolved in 2-methyl tetrahydrofuran (560 mL) at 80 °C.
- the reaction solution was cooled to 75 °C, seeded with the compound of Example 1-3 (200 mg).
- the mixture was stirred while the temperature was cooled to 22 °C and kept for 1 h.
- the mixture was stirred at 0-5 °C for 1 h.
- the compounds described herein are formulated into pharmaceuticalcompositions.
- Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- a summary of pharmaceutical compositions described herein isfound, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
- the compounds described herein are administered either alone or incombination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
- Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action.
- compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should bein dosages suitable for such administration.
- the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
- concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations ofactive compound doses.
- compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
- a pharmaceutical composition comprising a crystalline form of the Compound of Formula (I) and a pharmaceutically acceptable carrier.
- said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I).
- said crystalline form is at least 90 percent by weight of all forms.
- Normalizing according to the patient's body weight is particularly useful when adjusting dosages between patients of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human patient such as dog to a dosage suitable for a human patient.
- the daily dosage may also be described as a total amount of a compound disclosed herein administered per dose or per day.
- Daily dosage of a compound disclosed herein may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
- a method of treating a disease and condition mediated by CSF-1R in a patient in need thereof comprising administering to the patient an effective amount of a crystalline form of the Compound of Formula (I).
- said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I).
- said crystalline form is at least 90 percent by weight of all forms.
- said crystalline form is Form A.
- a crystalline form of the Compound of Formula (I) for use as a medicine, for use as an inhibitor CSF-1R receptor, and for use in the treatment of various diseases wherein CSF-1R is involved.
- said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I).
- said crystalline form is at least 90 percent by weight of all forms.
- said crystalline form is Form A.
- kits and articles of manufacture for use withone or more methods described herein.
- additional component of the kit comprises a package or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
- Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes.
- the containers are formed from a variety of materials such as glass or plastic.
- the articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for a selected formulation and intended mode of use.
- the container(s) include one or more of the compounds described herein.
- kits optionally include an identifying description or label or instructions relating to its use inthe methods described herein.
- a label is on or associated with the container.
- alabel is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is presentwithin a receptacle or carrier that also holds the container, e.g., as a package insert.
- a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
- FaSSIF fasted state simulated intestinal fluid
- polymorph screening was performed to identify a stable crystal form suitable for pharmaceutical development. Based on the approximate solubility of the starting material in 20 different solvent systems, an extensive approach was used to setup 102 polymorph screening experiments using anti-solvent addition, solid vapor diffusion, liquid vapor diffusion, slurry at RT and 50 °C, slow evaporation at RT and 50 °C, slow cooling, and polymer induced crystallization. A total of five crystalline solid forms were observed, out of which Form A and Form I were anhydrate, whereas Form II was a 1,4 dioxane solvate, Form III was an acetic acid solvate and Form IV was an ACN solvate.
- Competitive slurry experiments were performed to determine the relative stability of anhydrates and Form A was determined to be a thermodynamically more stable form. Characterization summary of Form I and Form A is provided in Table 1-1.
- Form I was scaled-up at -300 mg to evaluate the production feasibility and to generate enough sample for further evaluation. Further evaluation includes relative stability studies via competitive slurry experiments as well as hygroscopicity studies. The re-production procedures are provided in Table 1-4.
- Form I was successfully re-produced as a pure Form I at -300 mg scale as evidenced by the XRPD comparison in Figure 12. Table 1-4. Procedure for preparation of Form I
- Anti-solvent addition experimental procedure - -15 mg Free Base was dissolved in solvent to create a saturated solution and anti-solvent was added up to 10 volume ratio, the obtained solids were characterized by XRPD.
- Form I (poorly crystalline pattern) obtained may be a result of re-crystallization or desolvation product of a MEK solvate
Abstract
Described herein are solid forms of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d, process of preparing the forms, pharmaceutical compositions, and methods of use thereof.
Description
SOLID FORMS OF DEUTERATED COLONY STIMULATING FACTOR-1 RECEPTOR (CSF-1R) INHIBITORS
[0001] Described herein are solid forms of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3- yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, the process of preparing the forms, pharmaceutical compositions, and methods of use thereof.
BACKGROUND OF THE DISCLOSURE
[0002] Enzymes in living organisms, such as aldehyde oxidase, can lead to unwanted metabolic degradation. Aldehyde oxidase (AO) is a cytosolic molybdenum-containing enzyme involved in the biotransformation of numerous drugs. The challenge represented by AO-mediated metabolism is driven by several overlapping factors, including the complex biology of the enzyme and the widespread use of structural motifs that are AO substrates (e.g., azaheterocycles and amides.) See, e.g., Manevski, N. et al, Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery, J. Med. Chem. 2019, 62, 10955-10994. Furthermore, differences in AO-mediated metabolism, not only between species, but also between individuals, contribute to variability in exposure and complicate human dose selection.
[0003] It was surprisingly found that Colony Stimulating Factor-1 (“CSF-1R”) inhibitor compounds substituted with deuterium as set forth in PCT/US2021/064831 have improved ADME properties, e.g., such CSF-1R inhibitor compounds substituted with deuterium at specific positions have improved ADME properties, in particular, significant resistance to AO degradation, thus potentially improving the drug efficacy and the exposure of the drug in vivo. These CSF-1R inhibitors are small molecule compounds that are capable of penetrating the blood-brain barrier to reach the central nervous system (CNS.) Because these compounds are advantageously able to penetrate the blood-brain barrier (a highly desirable property in neurological indications), the compounds need to be able to exhibit sufficient absorption, metabolism, distribution, and excretion (ADME) properties in order to ensure proper dosing. Metabolism issues can include rapid metabolism as well as metabolic degradation, both of which can lead to toxicities and/or suboptimal dosing of the active agent.
[0004] One factor in assessing the suitability of a compound as a therapeutic agent is whether the compound as a therapeutic agent can be administered in a form that is easily absorbed by the body and also shelf-stable. The pharmaceutically active substance used to prepare the
treatment should be as pure as possible and its stability on long-term storage should be guaranteed under various environmental conditions. These properties are useful to prevent the appearance of unintended degradation products in pharmaceutical compositions, which degradation products may be potentially toxic or result simply in reducing the potency and/or efficacy of the composition.
[0005] A primary concern for the large-scale manufacture of pharmaceutical compounds is that the active substance should have a stable crystalline morphology to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, crystal morphology may change during manufacture and/or storage, resulting in quality control problems and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions. In this regard, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which can improve its physical and chemical stability gives a significant advantage over less stable forms of the same drug.
[0006] When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as “polymorphism.” Each of the crystal forms is a “polymorph.” Although polymorphs of a given substance have the same chemical composition, they may differ from each other with respect to one or more physical properties, such as solubility, dissociation, true density, dissolution, melting point, crystal shape, morphology, particle size, compaction behavior, flow properties, and/or solid-state stability. The difference in the physical properties of different polymorphic forms results from different orientation and interm olecular interactions of adjacent molecules in the solid. Polymorphic forms of a compound can be distinguished, in particular, by X-ray diffraction.
[0007] Although it is known that the preparation of crystalline forms may improve the physical or pharmaceutical properties of a pharmaceutically active compound, it is not possible to predict whether a compound exists in crystalline form(s) or which crystalline form(s) may possess advantages for a particular purpose prior to the actual preparation and characterization of the crystalline form. In particular, such advantages, in a non-limiting manner could include better processability, solubility or shelf-life stability, just to name a few. Other advantages may also include biological properties such as improved bioavailability, reduced adverse reactions at the GI tract (for example irritation of the GI
tract, partial degradation of the compound, etc.), or better deliverability of the drug to the intended target site among other advantages.
BRIEF SUMMARY OF THE DISCLOSURE
[0008] This disclosure relates to various solid state forms of the deuterated CSF-1R inhibitor 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin- 6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), the process of preparing the forms, and pharmaceutical compositions and methods of use to treat disease. These solid state forms of the compound of formula (I) can meet at least one of the important features mentioned above.
[0009] Disclosed herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as an anhydrate which is in a crystalline Form A.
[0010] Also disclosed herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as an anhydrate which is in a crystalline Form I.
[0011] Also disclosed herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as a solvate which is in a crystalline Form II.
[0012] Also disclosed herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as a solvate which is in a crystalline Form III.
[0013] Also disclosed herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-
2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as a solvate which is in a crystalline Form IV.
[0014] Also disclosed herein are pharmaceutical compositions comprising the solid forms of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin- 6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/ disclosed herein and a pharmaceutically acceptable carrier.
[0015] Still further disclosed herein is a method of treating a disease and condition mediated by CSF-1R in a patient in need thereof, comprising administering to the patient an effective
amount of the solid forms of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3Z7-imidazo[4,5-Z>]pyridine-2-t/ disclosed herein.
[0016] The present disclosure also relates to the solid forms of 3-(((25,35)-8-methoxy-2-(6- methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/- imidazo[4,5-Z>]pyridine-2-t/ disclosed herein for use in treating a disease and condition mediated by CSF-1R in a patient in need thereof.
[0017] The present disclosure further relates to use of the disclosed solid forms of 3- (((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/ in the manufacture of a medicament for treating a disease involving mediation of CSF-1R.
[0018] The compound of formula (I), depicted below, is a CSF-1R inhibitor compound improved ADME properties, particularly, significant resistance to AO degradation. The compound of formula (I) is a small molecule compound capable of penetrating the bloodbrain barrier to reach the central nervous system (CNS.) It may be used for treating, e.g., neurological diseases, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and Huntington’s disease. This compound is forth in PCT/US2021/064831 :
[0019] Provided herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, hereafter designated as compound of formula (I), as an anhydrate which is in a crystalline Form A, characterized by having an X-ray powder diffraction pattern derived using Cu (Ka) radiation comprising three, four, five, six or more peaks, in term of 2-theta degrees, chosen from: 7.6, 11.9, 16.6, 17.2, 18.6, 19.6, 22.4 ± 0.2 degrees, optionally further characterized by a powder X-ray diffractogram as substantially illustrated in Figure 1.
[0020] Provided herein is 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3Z7-imidazo[4,5-Z>]pyridine-2-t/, hereafter
designated as compound of formula (I), as an anhydrate which is in a crystalline Form I, characterized by having an X-ray powder diffraction pattern derived using Cu (Ka) radiation comprising three, four, five, six or more peaks, in term of 2-theta degrees, chosen from: 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3 ± 0.2 degrees, optionally further characterized by a powder X- ray diffractogram as substantially illustrated in Figure 12.
[0021] As used herein, the term “substantially pure” means that the crystalline form contains at least 90 percent, for example, at least 95 percent, such as at least 97 percent, and for instance at least 99 percent by weight of the indicated crystalline form. Alternatively, it will be understood that “substantially pure” means that the crystalline form contains less than 10 percent, for example less than 5 percent, such as less than 3 percent, and for instance, less than 1 percent by weight of impurities, including other polymorphic, solvated or amorphous forms.
BRIEF DESCRIPTION OF THE FIGURES
[0022] FIG. 1 shows an XRPD pattern of Compound (I) Form A.
[0023] FIG. 2 shows a PLM image of Compound (I) Form A.
[0024] FIG. 3 shows a TGA (top pattern)/DSC (bottom pattern) overlay of Compound (I) Form A.
[0025] FIGS. 4A and 4B show NMR spectrum of Compound (I) a) initial starting material and b) NMR spectrum of Compound (I) Form A.
[0026] FIG. 5 shows an HPLC trace of Compound (I) Form A.
[0027] FIG. 6 shows an XRPD pattern of Compound (I) a) Form I b) Form A, c) Form II dioxane solvate, d) Form III acetic acid solvate, and e) Form IV ACN solvate.
[0028] FIG. 7 shows DSC/TGA of Form I.
[0029] FIG. 8 shows DSC/TGA of Form A.
[0030] FIG. 9 shows DSC/TGA of Form II, dioxane solvate.
[0031] FIG. 10 shows DSC/TGA of Form III, acetic acid solvate.
[0032] FIG. 11 shows DSC/TGA of Form IV, ACN solvate.
[0033] FIG. 12 shows XRPD pattern of Compound (I) a) Scaled up Form I and b) Form I (Reference).
[0034] FIG. 13 shows XRPD pattern of Compound (I) a) Form A (Reference), b) Acetone @ 25 °C, c) EtOAc @ 25 °C, d) Acetone @ 50 °C, e) EtOAc @ 50 °C and f) Form I (Reference).
[0035] FIGS. 14A-14D show LC-MS a) Chromatogram of Form I, b) Chromatogram of Form A, c) MS-Spectra of Form I and d) MS-Spectra of Form A.
[0036] FIG. 15 shows DVS plot of Form A.
[0037] FIG. 16 shows XRPD pattern of Form A a) before DVS and b) after DVS.
[0038] FIG. 17 shows DVS Plot of Form I.
[0039] FIG. 18 shows XRPD pattern of Form I a) Before DVS and b) After DVS.
[0040] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. While the disclosure provides illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the disclosure as defined by the appended claims.
[0041] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.
[0042] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings.
TERMS
[0043] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
[0044] The term “about” or “substantially as shown in” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%.
[0045] The term "and/or" is used in this disclosure to mean either “and” or “or” unless indicated otherwise.
[0046] The terms “article of manufacture” and “kit” are used as synonyms.
[0047] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
[0048] The term “crystalline” or “crystalline solid form,” refers to a solid form which is substantially free of any amorphous solid-state form, e.g., any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with more or less sharp peaks. In some embodiments, the crystalline solid form is a single solid-state form, e.g. crystalline Form A.
[0049] The terms “polymorph,” “crystal form,” “crystalline form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and/or thermogravimetric analysis (TGA). Accordingly, the term “crystalline Form [X] of Compound (I)” refers to a unique crystalline form that can be identified and distinguished from other forms by at least one characterization technique including, e.g., X- ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and/or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are
characterized by an X-ray powder diffractogram having at least one signal at least one specified two-theta value (° 29).
[0050] “Anhydrate” refers to a crystal form of a substance with no water in its structure. By extension, “anhydrate” usually refers to a crystal form of a substance with no water and/or solvent in its structure.
[0051] Characterizations (XRPD, DSC and DVS) and some properties of the herein described different anhydrate and solvate forms are detailed below.
[0052] “DSC” refers to the analytical method of differential scanning calorimetry.
[0053] “ TGA” refers to the analytical method of thermo gravimetric (also referred to as thermogravimetric) analysis.
[0054] “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.
[0055] The expression “almost complete evaporation” of a solvent means that the evaporation is not carried out in full, that is to say that the amount of solvent which is evaporated is decreased but nevertheless still present in a very low content. In other terms, the evaporation must not be carried out dry.
[0056] “Ambient temperature” or “room temperature” refers to a temperature ranging from 18°C to 25°C unless specified differently.
[0057] In some embodiments, “substantially free” means less than about 10 % w/w, less than about 9 % w/w, less than about 8 % w/w, less than about 7 % w/w, less than about 6 % w/w, less than about 5 % w/w, less than about 4 % w/w, less than about 3 % w/w, less than about 2.5 % w/w, less than about 2 % w/w, less than about 1.5 % w/w, less than about 1 % w/w, less than about 0.75 % w/w, less than about 0.50 % w/w, less than about 0.25 % w/w, less than about 0.10 % w/w, or less than about 0.05 % w/w of other crystalline forms of the compound and the amorphous compound. In some embodiments, “substantially free” means an undetectable amount of other crystalline forms of the compound and the amorphous compound.
[0058] “Substantially pure” means that the crystalline form contains at least 90 percent, for example at least 95 percent, such as at least 97 percent, and for instance at least 99 percent by
weight of the indicated crystalline form compared to the total weight of the compound of all forms.
[0059] Alternatively, it will be understood that “substantially pure” means that the crystalline form contains less than 10 percent, for example less than 5 percent, such as less than 3 percent, and for instance less than 1 percent by weight of impurities, including other polymorphic, solvated or amorphous forms compared to the total weight of the compound of all forms.
[0060] Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0061] This disclosure relates to colony stimulating factor-1 receptor inhibitors (“CSF-1R inhibitors”) that are small molecules capable of penetrating the blood-brain barrier to reach the central nervous system (CNS). This disclosure also relates to pharmaceutical formulations comprising CSF-1R inhibitors and to the use of CSF-1R inhibitors and pharmaceutical compositions comprising CSF-1R inhibitors to treat disease. Such diseases include immune-mediated diseases, including multiple sclerosis, lupus nephritis, rheumatoid arthritis, and neurological diseases, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease.
[0062] Solid forms of Compound (I) disclosed herein may be at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.
PREPARATION OF COMPOUND OF FORMULA (I) [0063] Compound (I) may be made as follows.
[0064] Example 1-1: Preparation of 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2- (benzyloxy)-3-methoxyphenoxy)-l-(6-methoxypyridin-3-yl)propan-l-one
[0065] A mixture of 2-bromo-l -(6-methoxypyri din-3 -yl)propan-l -one (21.2 g, 87 mmol, 1 eq, CAS 1391089-35-2), 5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3- methoxyphenol (32.9 g. 91.3 mmol, 1.05 eq) (WO2017015267 Example 1-193) and potassium carbonate (30 g, 218 mmol, 2.5 eq) in acetonitrile (330 mL) was stirred at room temperature for 4 h. HPLC analysis showed complete consumption of 2-bromo-l-(6- methoxypyridin-3-yl)propan-l-one. Methyl t-butyl ether (330 mL) was added to the slurry and the mixture was filtered and the solids washed with methyl t-butyl ether. The filtrate was washed with dilute sodium hydroxide solution (350 mL) and saturated sodium chloride solution (300 mL). The solvent was swapped with methanol. The methanol solution was stirred at room temperature with seeding (20 mg). After stirring at room temperature for 16 h, the crystallized product was isolated by filtration, washed with methanol and dried to afford 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)- l-(6-methoxypyridin-3-yl)propan-l-one (35.9 g of 85% yield) as an off-white, crystalline solid, m.p. 72 °C; ’H NMR (400 MHz, CDCh) 6 8.83 (dd, J= 2.4, 0.7 Hz, 1H), 8.39 (dd, J= 4.8, 1.4 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.96 (s, 1H), 7.48 - 7.41 (m, 2H), 7.36 - 7.21 (m, 4H), 6.69 (dd, J= 8.8, 0.8 Hz, 1H), 6.55 (d, J= 1.9 Hz, 1H), 6.44 (d, J= 2.0 Hz, 1H), 5.32 (s, 2H), 5.29 (q, J= 6.8, 1H), 4.99 (s, 2H), 3.98 (s, 3H), 3.74 (s, 3H), 1.60 (d, J= 6.8 Hz, 3H)ppm; (M+l) = 525.
[0066] Example 1-2: Preparation of 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2- (((lS,2S)-l-hydroxy-l-(6-methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol
[0067] 2-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(benzyloxy)-3-methoxyphenoxy)-l-
(6-methoxypyridin-3-yl)propan-l-one (14 g, 25.2 mmol), potassium t-butoxide (1.35 g, 12.01
mmol, 0.48 eq.) and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN] (CAS 220114-01-2, 0.33 g, 0.27 mmol, 0.01 eq.) were dissolved in isopropyl alcohol (230 mL) and charged into a hydrogenation reactor. The reactor was purged with nitrogen and charged with hydrogen to 70 psi. After stirring at 70 psi hydrogen pressure at 22 °C for 5 h, HPLC analysis showed the complete consumption of the starting material. Hydrogenolysis was carried out by charging Pd/C (4.8 g, 34 wt%, 5% Pd on active carbon, 50% wet) into the reactor. The Parr reactor was purged with nitrogen and charged with hydrogen to 70 psi. After stirring at 70 psi hydrogen pressure at 22 °C for 48 h, HPLC analysis showed the reaction was essentially completed. The reaction mixture was filtered through a celite pad, washed with isopropanol and methanol. The filtrate was concentrated to a clear yellow oil. The oil was dissolved in ethyl acetate (250 mL) and washed with aqueous ammonium chloride (130 mL). The aqueous layer was back extracted with ethyl acetate (30 mL). The combined organic layers was washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated to obtain 4-((3H-imidazo [4,5-b] pyridin-3-yl)methyl)-2-(((l S,2S)-l-hydroxy- l-(6-methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol as a light yellow hard foam (10.1 g, 23.1 mmol, 92% yield.) The product is approximately a 84: 16 ratio of the 1S,2S to 1R,2S diastereomers (by XH NMR); >98% ee (by chiral HPLC) XH NMR (400 MHz, CDCk) 8 8.43 (d, J= 4.6 Hz, 1H), 8.13-8.05 (m, 2H), 8.02 (d, J= 1.7 Hz, 1H), 7.68 and 7.61 (2 br d, J= 8.7Hz, 1H), 7.31-7.23 (m, 2H), 6.77-6.67 (m, 2H), 6.66 (d, J= 2.7 Hz, 1H), 5.36 (s, 2H), 4.82 and 4.71 (br s and d, J= 8.3 Hz, 1H), 4.13 (m, 1H), 3.94 (br s, 3H), 3.83 (br s, 3H), 1.18-1.07 (d, J= 6.4Hz, 3H)ppm; (M+l) = 437.
[0068] Example 1-3: Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3- methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine
[0069] A solution of 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(((lS,2S)-l-hydroxy-l-(6- methoxypyridin-3-yl)propan-2-yl)oxy)-6-methoxyphenol (10.10 g; 23.14 mmol; 84: 16 mixture of diastereomers; 1.00 eq.) in ethyl acetate (90 mL), with diisopropylethylamine (16.02 ml; 92.56 mmol; 4.00 eq.) and CCI4 (5.58 ml; 57.85 mmol; 2.50 eq.) was stirred at 45- 50 °C. Tri n-butyl phosphine (11.99 ml; 48.60 mmol; 2.10 eq.) was added dropwise over 10 min with a slight exotherm. The resulting brown solution was stirred at 45-50 °C for 1.5 h.
To the reaction was added sodium hydroxide solution (15 wt%, 40 mL, 6.5 eq.) and the mixture was stirred at 45 °C for 0.5-1 h. The reaction was cooled to room temperature. The layers were separated. The aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated to a wet-solid. The solid was stirred in methyl t-butyl ether (60 mL) for 2 h, filtered and dried under vacuum. The off-white solid was dissolved in ethanol (55 mL) at elevated temperature. The solution was stirred at room temperature with seeding and cooling to 0-5 °C. The resulting solid was filtered and dried to afford 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine as off-white solid powder (6.16 g, 63.6%) 99 A% (by HPLC), 98% ee, Pd: 1 ppm; Ru: 225 ppm. m.p.164.9 °C. ’H NMR (400 MHz, CDC13) 8 8.45 (dd, J= 4.8, 1.5 Hz, 1H), 8.16 (d, J= 2.4 Hz, 1H), 8.13- 8.03 (m, 2H), 7.56 (dd, J= 8.6, 2.5 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 6.78 (d, J= 8.6 Hz, 1H), 6.53 (br s, 2H), 5.38 (s, 2H), 4.62 (d, J= 7.8 Hz, 1H), 4.13 (m, 1H) 3.94 (s, 3H), 3.79 (s, 3H), 1.17 (d, J= 6.4 Hz, 3H)ppm. (M+l) = 419.
[0070] Example 1-4: Preparation of 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3- methyl-2,3-dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-</
[0071] 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (20 g; 47.80 mmol) was dissolved in 2-methyl tetrahydrofuran (400 mL) at 60 °C. Methanol-d (20 mL; 1 V, 99 % D) was added followed by solid potassium t-butoxide (5.36 g; 47.80 mmol; 1 eq). The solution was heated for 2 h. LCMS showed 87% D. The reaction solution was cooled to 22°C. The suspension was washed with aqueous 10% w/w ammonium chloride (400 mL). The organic layer was separated, diluted with ethyl acetate (200 mL) and washed with water (3 x 100 mL) followed by i saturated sodium chloride solution (100 mL). The organic layer was dried (sodium sulfate), filtered and concentrated to a solid. The solid was dried by azeotroping with toluene (2 x 100 mL). The resulting tan solid was dissolved in 2-methyl tetrahydrofuran (500 mL) at 60 °C and methanol-d (40 mL; 2V) was added followed by solid potassium t- butoxide (1.1 g; 9.80 mmol; 0.2 eq). The solution was heated for 3 h at 60 °C. LCMS
showed 96-97% D after 3 h. The reaction solution was cooled to room temperature washed with aqueous 10% w/w ammonium chloride solution (200 mL; 10 V). The organic layer was separated and washed 3 times with water (200 mL each). The organic solution was filtered, concentrated and azeotropically dried with toluene. The solid was dissolved in 2-methyl tetrahydrofuran (560 mL) at 80 °C. The reaction solution was cooled to 75 °C, seeded with the compound of Example 1-3 (200 mg). The mixture was stirred while the temperature was cooled to 22 °C and kept for 1 h. The mixture was stirred at 0-5 °C for 1 h. The resulting solid was filtered, washed with cold 2-methyl tetrahydrofuran and dried in vacuum oven to obtain 3-(((2S,3S)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[b][l,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-2-d as an off white powder, (100 A% (by HPLC), chiral purity: 99.5% ; 96.1% D (by LCMS); Pd 1 ppm; Ru 20 ppm, 84% yield) 'H N R (400 MHz, DMSO-d6) 6 8.57 (s, residual un deuterated, 0.02H), 8.40 (dd, J= 4.8, 1.5 Hz, 1H), 8.22 (d, J= 2.3 Hz, 1H), 8.10 (dd, J= 8.0,1.5, 1H), 7.72 (dd, J= 8.6, 2.4 Hz, 1H), 7.36 (dd, J= 8.0, 4.8, 1H), 6.88 (d, J= 8.6 Hz, 1H), 6.76 (d, J= 1.9, 1H), 6.50 (d, J= 1.9, 1H), 5.40 (s, 2H), 4.72 (d, J= 7.8 Hz, 1H), 4.26-4.29 (m, 1H), 3.87 (s, 3H), 3.70 (s, 3H), 1.03 (d, J= 6.3 Hz, 3H)ppm. (M+l) = 420.
PHARMACEUTICAL COMPOSITIONS
[0072] In some embodiments, the compounds described herein are formulated into pharmaceuticalcompositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein isfound, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.
[0073] In some embodiments, the compounds described herein are administered either alone or incombination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described
herein can be affected by any method that enables delivery of the compounds to the site of action.
[0074] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[0075] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
[0076] In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should bein dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations ofactive compound doses.
[0077] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents
conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
[0078] Herein is also provided a pharmaceutical composition comprising a crystalline form of the Compound of Formula (I) and a pharmaceutically acceptable carrier. In one aspect, in said pharmaceutical composition, said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I). In another aspect, in said pharmaceutical composition, said crystalline form is at least 90 percent by weight of all forms.
METHODS OF DOSING AND TREATMENT REGIMENS
[0079] The specific dose level of a compound of the present application for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the patient's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In certain embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the patient's body weight is particularly useful when adjusting dosages between patients of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human patient such as dog to a dosage suitable for a human patient.
[0080] The daily dosage may also be described as a total amount of a compound disclosed herein administered per dose or per day. Daily dosage of a compound disclosed herein may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.
[0081] When administered orally, the total daily dosage for a human patient may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.
[0082] In certain embodiments, the method comprises administering to the patient an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.
[0083] Herein is also provided a method of treating a disease and condition mediated by CSF-1R in a patient in need thereof, comprising administering to the patient an effective amount of a crystalline form of the Compound of Formula (I). In one aspect, in said method, said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I). In another aspect, in said pharmaceutical composition, said crystalline form is at least 90 percent by weight of all forms. In yet another aspect, said crystalline form is Form A.
[0084] Herein is also provided a crystalline form of the Compound of Formula (I) for use as a medicine, for use as an inhibitor CSF-1R receptor, and for use in the treatment of various diseases wherein CSF-1R is involved. In one aspect, said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I). In another aspect, said crystalline form is at least 90 percent by weight of all forms. In yet another aspect, said crystalline form is Form A.
[0085] Herein is also provided use of a crystalline form of the Compound of Formula (I) for the manufacture of a medicament for treating a disease involving inhibition of CSF-1R. In one aspect, said crystalline form is substantially pure and substantially free of other crystalline forms of the Compound of Formula (I). In another aspect, said crystalline form is at least 90 percent by weight of all forms. In yet another aspect, said crystalline form is Form A.
ARTICLES OF MANUFACTURE AND KITS
[0086] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use withone or more methods described herein. In some embodiments, additional component of the kit comprises a package or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.
[0087] The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for a selected formulation and intended mode of use.
[0088] For example, the container(s) include one or more of the compounds described herein. Such kits optionally include an identifying description or label or instructions relating to its use inthe methods described herein.
[0089] A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
[0090] In one embodiment, a label is on or associated with the container. In one embodiment, alabel is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is presentwithin a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
ABBREVIATIONS
[0091] The following abbreviations may be relevant for this application.
FaSSIF: fasted state simulated intestinal fluid;
[0092] The following examples are provided for illustrative purposes only and not to limit thescope of the claims provided herein.
EXAMPLE 2 - CHARACTERIZATION OF STARTING MATERIAL
[0093] Compound (I), made according to Example 1-4, was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC) prior to undergoing polymorph screening. The characterization results indicated that the starting material was highly crystalline, defined as free base Form A, and the crystal form was further identified to be anhydrate.
[0094] As set forth in greater detail below, polymorph screening was performed to identify a stable crystal form suitable for pharmaceutical development. Based on the approximate solubility of the starting material in 20 different solvent systems, an extensive approach was used to setup 102 polymorph screening experiments using anti-solvent addition, solid vapor diffusion, liquid vapor diffusion, slurry at RT and 50 °C, slow evaporation at RT and 50 °C, slow cooling, and polymer induced crystallization. A total of five crystalline solid forms were observed, out of which Form A and Form I were anhydrate, whereas Form II was a 1,4 dioxane solvate, Form III was an acetic acid solvate and Form IV was an ACN solvate. Competitive slurry experiments were performed to determine the relative stability of anhydrates and Form A was determined to be a thermodynamically more stable form. Characterization summary of Form I and Form A is provided in Table 1-1.
EXAMPLE 3 - INITIAL CHARACTERIZATION OF STARTING MATERIAL [0095] Compound (I), made according to Example 1-4, was characterized by XRPD, PLM, DSC, TGA, 1H-NMR and HPLC. The results are summarized in Table 1-2, indicating the starting material is a crystalline anhydrate.
EXAMPLE 4 - POLYMORPH SCREEN SUMMARY
[0096] Based on the approximate solubility of this starting material (see Table 2-1, below), a total of 102 polymorph screening experiments were conducted using different screening techniques that include anti-solvent addition (14 experiments, Table 1-6), solid vapor diffusion (14 experiments, Table 1-7), liquid vapor diffusion (9 experiments, Table 1-8), slurry at RT (22 experiments, Table 1-9), slurry at 50 °C (16 experiments, Table 1-10), slow evaporation at RT and 50 °C (10 experiments, Table 1-11) and slow cooling (9 experiments, Table 1-12) and polymer induced crystallization (9 experiments, Table 1-13). Specifically, about 20 mg Form A was used per experiment. The different solid forms are summarized in Table 3 with XRPD results (Figure 5) and DSC/TGA (Figure 6, Figure 7, Figure 8, Figure 9
and Figure 10). Solid forms identified which were Form A and Form I were anhydrates, whereas Form II was a dioxane solvate, Form III was an acetic acid solvate and Form IV was an ACN solvate.
EXAMPLE 5 - SCALE UP OF FORM I
[0097] Considering the preliminary solid-state properties, Form I was scaled-up at -300 mg to evaluate the production feasibility and to generate enough sample for further evaluation. Further evaluation includes relative stability studies via competitive slurry experiments as well as hygroscopicity studies. The re-production procedures are provided in Table 1-4.
Form I was successfully re-produced as a pure Form I at -300 mg scale as evidenced by the XRPD comparison in Figure 12.
Table 1-4. Procedure for preparation of Form I
Form Procedure
1. Weigh -300 mg free base Form A and dissolve it in 4 mL of acetone to obtain a clear solution.
2. Gradually add 14 mL heptane to be the solution prepared in step 1 with
Free Base continuous magnetic stirring at 400 rpm.
Form I 3. Immediately, the solution showed turbidity.
4. Continue stirring for 2 h, until a dense slurry solution was observed.
5. Isolate the solids via vacuum filtration and subject the wet cake to dry overnight at 40 °C under vacuum.
6. The isolated solids weight was found to be 159 mg with a yield of 53.1 %.
7. Dried sample was analyzed by XRPD (Figure 12.)
COMPETITIVE SLURRY EXPERIMENTS OF ANHYDRATE FORMS
[0098] Slurry conversion experiments between Form I and Form A were conducted to determine the relative stability using acetone and ethyl acetate as solvents. At the end of the study, the Form I converted to Form A at RT and 50 °C in both acetone as well as ethyl acetate (Figure 13). Therefore, Form A is a thermodynamically more stable form at RT and 50 °C. The lower melting form I converts to the higher melting Form A by slurry at 25 °C and 50 °C in two different solvents, suggesting these two forms are monotropic which is further confirmed by the melting points and enthalpy of fusion for Form I and Form A reported in Table 1-5.
Table 1-1. Comparison of melting point and enthalpy of fusion for Form I and Form A
EXAMPLE 5 - CONFIRMATORY TEST FOR DEUTERIUM IN FORM I AND
FORM A BY LC-MS
[0099] Form I and Form A tested by LC-MS eluted at the retention time of 5.37s and 5.38s respectively (Figures 14A-14D). These respective peaks were used to calculate the mass of each moiety at the respective retention times. The mass spectra were found to be identical and consistent with the molecule weight for both Form I and Form A (Figures 14A-14D), suggesting the deuterium atoms in Form I and Form A are still intact.
EXAMPLE 6 - HYGROSCOPICITY
[00100] To understand the hygroscopicity of Form I and Form A, dynamic vapor sorption (DVS) was employed to measure the mass change as a function of relative humidity at 25 °C. Anhydrate Form I and Form A were equilibrated at 0%RH to remove the adsorbed moisture or residual solvent before analysis.
[00101] The results indicated, 1) Form A showed a water uptake of 0.09% at 25 °C/80%RH (Figure 15), suggesting Form A is non-hygroscopic. No form change was observed for sample after DVS evaluation (Figure 16). 2) Form I showed a water uptake of -2.8% at 25 °C/80%RH (Figure 17), suggesting it to be hygroscopic. No form change was observed for sample after DVS evaluation (Figure 18). The DVS data suggested the possible formation of a metastable hydrate at high humidity that could convert back to Form I during desorption.
EXAMPLE 7 - POLYMORPH SCREEN RESULTS IN ALL EXPERIMENTS
[00102] Anti-solvent addition experimental procedure - -15 mg Free Base was dissolved in solvent to create a saturated solution and anti-solvent was added up to 10 volume ratio, the obtained solids were characterized by XRPD.
[00103] Solid vapor diffusion experimental procedure - ~15 mg Free Base was kept in a 2 mL HPLC vial, the vial was placed in 20 mL glass vial containing solvent. The solids were characterized by XRPD after 10 days.
[00104] Liquid vapor diffusion experimental procedure - ~15 mg Free Base was dissolved in solvent to create a saturated solution in a 2 mL HPLC vial, the vial was placed in 20 mL glass vial containing anti-solvent. The obtained solids were characterized by XRPD after 10 days.
[00105] Slurry at RT experimental procedure - ~15 mg Free Base was slurried in different solvents in a 2 mL HPLC vial using magnetic stirrer at RT. The solids in slurry were characterized by XRPD after 7 days.
* -120 mg solids were added to 0.5 mL MEK solvent yielding a thin slurry, therefore, Form I (poorly crystalline pattern) obtained may be a result of re-crystallization or desolvation product of a MEK solvate
[00106] Slurry at 50 °C experimental procedure — 15 mg Free Base was slurried in different solvents in a 2 mL HPLC vial using mechanical at 50 °C. The solids in slurry were characterized by XRPD after 3-5 days.
[00107] Slow evaporation at RT and 50 °C experimental procedure - ~15 mg Free Base was dissolved in solvent to create a saturated solution in 2mL HPLC vial. The vial was covered with paraffin film and 3-5 holes were created. The obtained solids were characterized by XRPD.
[00108] Slow cooling experimental procedure - ~15 mg Free Base was dissolved in solvent to create a saturated solution in 4mL glass vial. The vial was placed in a mechanical shaker and the five temperature steps were ran, 35 °C for 2 hours, 30 °C for 2 hours, 20 °C
for 2 hours, 10 °C for 2 hours and 5 °C for 2 hours. The obtained solids were characterized by XRPD.
[00109] Polymer induced crystallization experimental procedure - ~15 mg Free Base was dissolved in solvent to create a saturated solution. PVP or HPMC was added to saturated solution to induce heteronucleation.
1.1 X-Ray Powder Diffraction
Instrument: Panalytical Empyrean Powder Diffractometer
Parameters: X-Ray tube Cu (Ka); tube voltage 45 kV; tube current 40 mA
Scan from 2 to 40 degrees 2-theta; 0.013 degrees/step; scan rate 6 degrees/min
1.2 Thermogravimetric Analysis
Instrument: TA Instruments Discovery TGA Q5500
Parameters: Ramp 10 °C per minute, ambient temperature to 250/300 °C, 50 mL/min N2 sweep
1.3 Differential Scanning Calorimetry
Instrument: TA Instruments Discovery DSC
Parameters: Ramp 10 °C per minute from ambient temperature to 250/300 °C with 50 mL/min N2 sweep
1.4 Polarized Light Microscopy
Instrument: Nikon Eclipse Ci Pol
Camera: Nikon
Software: NIS-Elements image software
Samples were dispersed on a microscope slide as slurries or if dry, samples were dispersed with silicone oil and examined under transmitted polarized light .5 Determination of Approximate Solubility for Polymorph screening
Procedure:
1) Weigh ~ 5mg of material into a 4.0ml vial
) Initially, add solvent at 25 °C in following increment while observe the visual change from turbid solution to clear solution o Up to 2.0 mL at an increment of 50 pL (twice), 100 pL (four times), 250 pL (twice) and 500 pL (twice) ) The approximate solubility was reported between low concentration (still slurry) and high concentration (clear solution)
Claims
1. A solid Form I of 3-(((25,35)-8-methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)methyl)-3J/-imidazo[4,5-Z>]pyridine-2-t/, having an X-ray powder diffraction pattern derived using Cu (Ka) radiation comprising three, four, five, six, or more peaks, in term of 2-theta degrees, chosen from: 3.6, 6.3, 9.6, 12.6, 15.9, 21.2, 25.3 ± 0.2 degrees.
2. The solid Form I of claim 1, which is at least 50% crystalline form, such as at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% crystalline.
3. The solid Form I of claim 1, having an X-ray powder diffraction pattern that is substantially in accordance with that shown in Figure 12.
4. The solid Form I of claim 1, characterized by a differential scanning calorimetry (DSC) curve with an onset at about 134.55 °C and an endothermic peak at 158.52°C.
5. The solid Form I of claim 1, characterized by a Thermogravimetric Analysis (TGA) profile with a negligible w/w loss observed before 150 °C.
6. The solid Form I of claim 1, characterized by a DSC/TGA profile substantially in accordance with that shown in Figure 7.
7. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 and/or a pharmaceutically acceptable salt thereof.
8. A method for treating an immune-mediated disease in a subject in need thereof comprising administering a compound according to any of claims 1 to 6, or a composition of of claim 7, to the subject in a therapeutically effective amount.
9. A method for treating multiple sclerosis in a subject in need thereof comprising administering a compound according to any of claims 1 to 6, or a composition of of claim 7, to the subject in a therapeutically effective amount.
10. A method for treating lupus nephritis in a subject in need thereof comprising administering a compound according to any of claims 1 to 6, or a composition of of claim 7, to the subject in a therapeutically effective amount.
11. A method for treating a neurological disease in a subject in need thereof comprising administering a compound according to any of claims 1 to 6, or a composition of of claim 7, to the subject in a therapeutically effective amount.
12. The method of claim 11, wherein the neurological disease is ALS.
13. The method of claim 11, wherein the neurological disease is PSP.
14. The method of claim 11, wherein the neurological disease is MSA.
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Citations (2)
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WO2017015267A1 (en) | 2015-07-20 | 2017-01-26 | Genzyme Corporation | Colony stimulating factor-1 receptor (csf-1r) inhibitors |
WO2022140528A1 (en) * | 2020-12-23 | 2022-06-30 | Genzyme Corporation | Deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors |
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WO2017015267A1 (en) | 2015-07-20 | 2017-01-26 | Genzyme Corporation | Colony stimulating factor-1 receptor (csf-1r) inhibitors |
WO2022140528A1 (en) * | 2020-12-23 | 2022-06-30 | Genzyme Corporation | Deuterated colony stimulating factor-1 receptor (csf-1r) inhibitors |
Non-Patent Citations (8)
Title |
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"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS |
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER, NEW YORK |
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY |
A.B. FOSTER: "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design", ADVANCES IN DRUG RESEARCH, vol. 14, 1985, Academic Press, London, GB, pages 1 - 40, XP009086953, ISSN: 0065-2490 * |
CAS , no. 1391089-35-2 |
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MANEVSKI, N ET AL.: "Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery", J. MED. CHEM., vol. 62, 2019, pages 10955 - 10994 |
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