EA041321B1 - CRYSTALLINE FORMS 3-IL)-1H-IMIDAZOLE-2-CARBOXAMIDE - Google Patents

Description

Technical field

The present invention relates to crystalline forms of 4-cyano-X-(2-(4,4dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl) pyridin-3-yl)-III-imidazole-2-carboxamide.

Prerequisites for the creation of the invention

Protein kinases are enzymes that act as key components of signal transduction pathways by catalyzing the transfer of the terminal phosphate group of the adenosine 5'-triphosphate (ATP) molecule to the hydroxyl group of tyrosine, serine, and threonine residues in proteins. Therefore, protein kinase-based inhibitors and substrates are important tools for evaluating the physiological consequences of protein kinase activation. Studies have shown that overexpression and inappropriate expression of normal or mutant protein kinases in mammals play a significant role in the development of many diseases, including cancer and diabetes.

Protein kinases can be divided into two classes: preferably phosphorylating tyrosine residues (protein tyrosine kinases) and preferably phosphorylating serine and/or threonine residues (serine/threonine protein kinases). Protein tyrosine kinases perform a variety of functions, from stimulating cell growth and differentiation to blocking cell proliferation. They can be classified either as receptor protein tyrosine kinases or as intracellular protein tyrosine kinases. Receptor protein tyrosine kinases, which contain an extracellular ligand-binding domain and an intracellular catalytic domain with intrinsic tyrosine kinase activity, are divided into 20 subfamilies.

McDonough's feline sarcoma (FMS) is a cellular receptor tyrosine kinase response to colony stimulating factor-1 (CSF-1). CSF-1 is the main growth factor of the macrophage/osteoclast lineage. FMS kinase inhibitors reduce macrophage survival in tissues and osteoclastogenesis in bone. Accordingly, examples of pathogenic conditions associated with abnormal protein tyrosine kinase activity are diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, rheumatoid arthritis, cardiovascular disease, and cancer.

4-Cyano-X-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4yl)pyridin-3-yl) -1H-imidazole-2-carboxamide exhibits inhibitory activity against FMS in the treatment of diseases in which macrophages and osteoclasts are pathogenic, namely rheumatoid arthritis and cancer with bone metastases.

There is a need to create alternative forms of 4-cyano-X-[2-(4,4-dimethylcyclohex-1en-1 -yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridine -3-yl] - 1H-imidazole-2-carboxamide.

Statement of the Invention

Provided herein are the crystalline forms of 4-cyano-X-(2-(4,4-dimethylcyclohex1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl) pyridin-3-yl)-1H-imidazole-2-carboxamide. Pharmaceutical compositions containing these crystalline forms and methods of using these crystalline forms to inhibit colony stimulating factor-1 receptor are also described.

Brief description of graphic materials

The summary of the invention, as well as the following detailed description, will be better understood when viewed in conjunction with the accompanying drawings. For the purpose of illustrating the invention, the drawings present exemplary embodiments of the invention; however, the invention is not limited to the specific methods, compositions and devices described. In addition, the graphics are not necessarily to scale and show the following:

in fig. 1 is an X-ray powder diffraction pattern (XRPD) of Compound A, Form I, FIG. 2 is an XRPD pattern of Compound A, Form II, FIG. 3 is an XRPD pattern of Compound A, Form IIA, FIG. 4 is an XRPD pattern of Compound A, Form IIB, FIG. 5 is an XRPD pattern of Compound A, Form III, FIG. 6 is an XRPD pattern of Compound A, Form IV, FIG. 7 is an XRPD pattern of Compound A, Form V, FIG. 8 is an XRPD pattern of Compound A, Form VI.

in fig. 9A is a differential scanning calorimetry (DSC) thermogram of Compound A, Form I, FIG. 9B is a DSC thermogram of Compound A, Form II, FIG. 9C is a DSC thermogram of Compound A, Form III, FIG. 9D is a DSC thermogram of Compound A, Form IV, FIG. 9E is a DSC thermogram of Compound A, Form V, FIG. 10 is an XRPD pattern of Compound A, Form I obtained by suspending the HCl salt of Compound A in water, FIG. 11 is a DSC thermogram of Compound A, Form I, obtained by suspending the HCl salt of Compound A in water,

- 1 041321 in FIG. 12 is a thermogravimetric analysis (TGA) spectrum of Compound A, Form I prepared by suspending the HCl salt of Compound A in water, FIG. 13 is a Dynamic Vapor Sorption (VVAS) spectrum of Compound A, Form I obtained by suspending the HCl salt of Compound A in water, showing two adsorption/desorption cycles, FIG. 14 shows a comparison of the XRPD pattern of a representative sample of Compound A, Form I, prior to EAF (lower panel) and the XRPD pattern of a representative sample of material isolated after EAF (upper panel);

Also showing a diagram corresponding to Compound A Form I in FIG. 15 is an XPRD diffraction pattern of the HCl salt of Compound A, FIG. 16 is a DSC thermogram of the HCl salt of Compound A, FIG. 17 shows the TGA spectrum of the HCl salt of Compound A, FIG. 18 is a DSP spectrum of the HCl salt of Compound A showing two adsorption/desorption cycles.

Detailed Description of Illustrative Embodiments

The disclosure of the invention can be appreciated more fully by referring to the following description, including the following definitions of terms and final examples. It should be understood that certain elements of the described compositions and methods, presented for clarity in the context of separate aspects, may also be given in combination in one aspect. In contrast, certain elements of the described compositions and methods, presented for brevity in the context of one aspect, may also be given individually or in any subcombination.

The terms form and polymorph form are interchangeable and refer to the solid phase crystalline forms of Compound A. Forms I, II, IIA, IIB, III, IV, V, and VI each represent different crystalline forms of the polymorphs.

The term subject includes people. In this document, the terms human, patient, and subject are used interchangeably.

Treatment of any disease or disorder refers, in one embodiment, to alleviating the disease or disorder (ie stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, the treatment refers to the alleviation of at least one physical parameter that may not be recognized by the subject. In yet another embodiment, treatment refers to modulating a disease or disorder, either physically (eg, stabilizing a recognizable symptom) or physiologically (eg, stabilizing a physical parameter) or both. In yet another embodiment, treatment refers to delaying the onset of a disease or disorder.

Some quantitative expressions given in this document are not qualified using the term about. It is understood that whether or not the term about is used explicitly, each numerical value given herein is intended to refer to an actual given value and is intended to refer to an approximation to such a given value that can reasonably be estimated. one of ordinary skill in the art, including approximations associated with the conditions of experimentation and/or measurement for such a given value.

Pharmaceutically acceptable means approved or subject to approval by a legislative agency of the federal or state government or an appropriate agency in countries other than the United States, or listed in the USP or other generally accepted pharmacopoeias for use in animals, and in particular in humans.

A pharmaceutically acceptable carrier medium refers to a diluent, adjuvant, excipient or carrier with which a compound is administered as described. A pharmaceutically acceptable excipient means a substance that is non-toxic, biologically tolerable, and otherwise biologically acceptable for administration to a subject, such as an inert substance added to a pharmacological composition or otherwise used as a carrier, carrier, or diluent to facilitate administration of the agent and compatible with it. . Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

In addition, some quantitative expressions herein are specified as a range from about X to about Y. It is understood that when a range is indicated, it is not limited to the indicated upper and lower limits, but includes the entire range of values from about X to about X. around the Y amount, or any value or range in between.

This document describes novel crystalline forms of 4-cyano-L-[2-(4,4dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl )pyridin-3-yl]-1H-imidazole-2-carboxamide having the following structure and referred to herein as Compound A. In some embodiments, Compound A is a free base.

- 2 041321

Compound A

In the development of pharmaceutical preparations, in particular drugs delivered orally, advantage is often given to new crystalline forms of these drugs, which have improved physical properties, such as increased water solubility and stability. The crystalline forms of Compound A described herein have improved properties over previously described solid forms of Compound A.

Compound A (as the free base) and Compound A as the corresponding hydrochloride salt can be prepared, for example, as described in US Pat. No. 8,497,376 and US Pat. also using the procedures described in Example 1. In some embodiments, Compound A is prepared from its hydrochloride salt. In other embodiments, Compound A is prepared from its hydrochloride salt as described in Example 1.

Various crystalline forms of Compound A are described and characterized herein. The crystalline forms described herein include Forms I, II, IIA, IIB, III, IV, V, and VI. In some embodiments, crystalline Compound A, Form I is provided. Compound A, Form I produces an X-ray powder diffraction pattern containing peaks at 6.1, 9.2, 9.4, 12.7, 15.1, 15.7, and 18.4° 2θ ±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 14.6, 16.4, or 19.0° 2θ±0.2° 2θ. Compound A, Form I can also be characterized by a differential scanning calorimetry thermogram having an initial temperature of 187.5°C and/or a peak endothermic reaction temperature of 204.6°C. Compound A Form I may further be characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1 or 10 and/or a differential scanning calorimetry thermogram essentially as shown in FIG. 9A or 11. Compound A, form I, may further be characterized by a powder x-ray diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks listed in table. 3A. Compound A, form I, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%.

In other embodiments, Compound A, Form II is provided. Compound A, form II, gives an x-ray powder diffraction pattern containing peaks at 6.3, 7.3, 11.5, 17.0 and 18.3° 2θ theta±0.2° 2θ. The X-ray powder diffraction pattern for Compound A, Form II, may further contain one or more peaks at 14.0, 14.6, 18.8, or 23.0° two theta±0.2° 2θ. Compound A Form II may further be characterized by a differential scanning calorimetry thermogram having an initial temperature of about 177.0°C and/or a peak endothermic reaction temperature of about 199.1°C. Compound A Form II may also have an X-ray powder diffraction pattern essentially as shown in FIG. 2 and/or a differential scanning calorimetry thermogram essentially as shown in FIG. 9B. Compound A, Form II, may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks shown in Table 1. 3b. Compound A, form II, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%.

In additional embodiments, Compound A, Form IIA is provided. Compound A, form IIA, gives an x-ray powder diffraction pattern containing peaks at 6.4, 14.1, 14.6, 17.1, 18.3, 18.9, 19.3 and 23.0° two theta ±0 ,2° 2θ. The powder x-ray diffraction pattern may further contain one or more peaks at 5.9, 7.3, 7.4, 11.5, 12.6, 18.3, 18.9, 20.2, 25.3, or 29.3 ° 2θ ±0.2° 2θ. Compound A Form IIA may also have an X-ray powder diffraction pattern essentially as shown in FIG. 3. Compound A, form IIA, may further be characterized by a powder x-ray diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks listed in table. 3C. Compound A, form IIA, may further be characterized by a powder x-ray diffraction pattern containing the peaks listed in table. 3A, with the relative intensity of the peaks being greater than about 2%,

- 3 041321 preferably more than about 5%, more preferably more than about 10%.

In other embodiments, Compound A, Form IIB is provided. Compound A, form IIB, gives an x-ray powder diffraction pattern containing peaks at 6.3 and 18.9° 2θ theta±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 12.6, 14.0, or 25.2° 2θ±0.2° 2θ. Compound A Form IIB can also have an X-ray powder diffraction pattern essentially as shown in FIG. 4. Compound A, form IIB, may further be characterized by a powder x-ray diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks listed in table. 3D. Compound A, form IIB, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%.

In other additional embodiments, Compound A, Form III is provided. Compound A Form III gives an X-ray powder diffraction pattern containing peaks at 4.6, 6.3, 6.8, 9.1, 17.1 and 28.5° 2θ±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 7.4, 11.7, 12.6, 18.1, or 23.0° 2θ±0.2° 2θ. Compound A Form III can also be characterized by a differential scanning calorimetry thermogram having an initial temperature of about 155.4°C and/or a peak endothermic reaction temperature of about 182.9°C. Compound A Form III may further have an X-ray powder diffraction pattern substantially as shown in FIG. 5 and/or a differential scanning calorimetry thermogram essentially as shown in FIG. 9C. Compound A, form III, may further be characterized by a powder x-ray diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks listed in table. 3E. Compound A, form III, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 5%, preferably greater than about 10%, more preferably greater than about 15%.

In other embodiments, Compound A, Form IV is provided. Compound A, form IV, gives an x-ray powder diffraction pattern containing peaks at 6.3, 6.6, 6.9, 7.3, 11.7, 17.1 and 18.3° 2θ±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 3.5, 14.6, 18.9, 20.2, or 23.0° 2θ±0.2° 2θ. Compound A, Form IV can be further characterized by a differential scanning calorimetry thermogram having an initial temperature of about 195.4°C and/or a peak endothermic reaction temperature of about 207.5°C. Compound A Form IV may also have an X-ray powder diffraction pattern essentially as shown in FIG. 6 and/or a differential scanning calorimetry thermogram essentially as shown in FIG. 9D. Compound A, form IV, may further be characterized by a powder x-ray diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks listed in table. 3F. Compound A, form IV, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%.

In further embodiments, Compound A, Form V is provided. Compound A, Form V produces an X-ray powder diffraction pattern containing peaks at 6.3, 7.4, 11.5, 11.7, 17.0, 18.3, and 23 .0° 2θ ±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 5.3, 12.6, 13.3, 14.0, 14.7, 18.3, 19.2, 20.2, or 22.1° 2θ ± 0.2° 2θ. Compound A, Form V can further be characterized by a differential scanning calorimetry thermogram having an initial temperature of about 174.6°C and/or a peak endothermic reaction temperature of about 188.6°C. Compound A Form V can also have an X-ray powder diffraction pattern essentially as shown in FIG. 7 and/or a differential scanning calorimetry thermogram essentially as shown in FIG. 9E. Compound A, Form V, may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks shown in Table 1. 3g. Compound A, form V, may further be characterized by a powder x-ray diffraction pattern containing the peaks shown in table. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%.

In other embodiments, Compound A, Form VI is provided. Compound A, form VI, gives an x-ray powder diffraction pattern containing peaks at 5.7, 10.8, 11.4 and 17.1° 2θ±0.2° 2θ. The powder x-ray diffraction pattern may further comprise one or more peaks at 7.3, 13.2, 14.0, 15.7, 18.0, or 19.2° 2θ±0.2° 2θ. Compound A Form VI can also have an X-ray powder diffraction pattern essentially as shown in FIG. 8.

Compound A, Form VI, may further be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine or more peaks selected from the peaks shown in Table 1. 3H. Compound A, form VI, can be further characterized by an X-ray powder diffraction pattern containing the peaks shown in Table 1. 3A, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%.

In the methods of treatment as described, an effective amount of a pharmaceutical agent as described is administered to a subject suffering from or having such a diagnosed disease, disorder or condition. An effective amount means an amount or dosage that is sufficient to achieve a substantially desired therapeutic effect for a patient in need of such treatment for a specified disease, disorder or condition. Effective amounts or doses of compounds of the present disclosure may be confirmed by conventional means, such as modeling, dose escalation studies, or clinical trials, and taking into account conventional factors such as the regimen or route of drug administration or delivery, compound pharmacokinetics, severity, and the course of the disease, disorder, or condition; the subject's previous or current treatment; the subject's medical condition and response to the drug; and the judgment of the attending physician. An exemplary dosage is in the range of about 0.001 to about 200 mg of the compound per kg of the subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day in single or divided doses. (e.g. twice/day, three times/day, four times/day). For a 70 kg human, an exemplary acceptable dosage range is from about 0.05 to about 7 g/day. or from about 0.2 to about 2.5 g/day.

In addition, the compounds may be used in combination with additional active ingredients for the treatment of the aforementioned conditions. Additional active ingredients may be administered separately for co-administration with a compound as described, or may be included in a pharmaceutical composition as described. The combination can be used to improve efficacy (eg, by including in the combination a compound that increases the potency or efficacy of the compound), reduce one or more side effects, or reduce the required dose of the compound.

The compounds can be used alone or in combination with one or more additional active ingredients to prepare pharmaceutical compositions as described. The pharmaceutical composition according to the description contains:

(a) an effective amount of at least one compound as described; and (b) a pharmaceutically acceptable excipient.

Delivery forms of pharmaceutical compositions containing one or more dosage units of the compounds can be prepared using acceptable pharmaceutical excipients and preparation techniques currently known or available to those skilled in the art in the future. The compositions can be administered using methods having the features of the invention, suitable delivery route, for example orally, parenterally, rectally, topically, through the eyes or by inhalation. The delivery method includes immediate release, timed release, and sustained release.

The preparation may be presented in the form of tablets, caplets, gelatin capsules, capsules, lozenges, sachets, dragees, powders, granules, lozenges, reconstitution powders, liquid preparations or suppositories. In some embodiments, the compositions are formulated for intravenous infusion, topical application, or oral administration.

For oral administration, the compounds described herein may be provided in the form of tablets or capsules, or as a solution, elixir, emulsion or suspension. A total daily dose of from about 5 mg to 5 g per day, preferably from about 10 to about 1000 mg per day, more preferably from about 50 to about 500 mg per day can be provided by dosing once, twice, three or four times per day.

Tablets for oral administration may include one or more of the compounds as described in admixture with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, suspending agents, coloring agents and preservative agents. . Acceptable excipients include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Liquid excipients for oral administration may include ethanol, glycerol, water, and the like. Suitable disintegrating agents are starch, polyvinylpyrrolidone, sodium starch glycolate, microcrystalline cellulose and alginic acid. Binding agents may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or they may be enteric coated.

Capsules for oral administration may include hard and soft gelatin capsules. To prepare hard gelatin capsules, the compounds described herein may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be obtained by

- 5 041321 mixing a compound as described with water, an oil such as peanut or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.

Liquids for oral administration may be presented in the form of suspensions, solutions, emulsions or syrups, or they may be lyophilized or presented dry for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous carrier vehicles such as oil (eg almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and optionally flavoring or coloring agents.

The compounds can also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous, the compounds of the present invention may be provided as sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonicity, or as a suitable parenteral oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride solution. Such forms will be presented in unit dose form such as ampoules, auto-injectors or disposable injection devices, in multiple dose forms such as vials from which the appropriate dose can be withdrawn, or in solid form or in the form of a primary concentrate, which can be used to prepare formulations for injection. Exemplary infusion doses may range from about 1 to 1000 μg/kg/min of the compound admixed with a pharmaceutical carrier over a period of several minutes to several days. Other routes of administration include, without limitation, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal, and/or perispinal routes.

For topical use, the compounds may be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% of the drug in vehicle. In another route of administration, the compounds described herein may be used as a patch with a transdermal delivery formulation.

The compounds described herein may alternatively be administered by the methods of this description by inhalation through the nose or mouth, for example with a spray formulation also containing a suitable carrier such as an aerosol or liquid spray.

Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI alone or in combination with each other, respectively, is used to inhibit colony stimulating factor 1 receptor. In some embodiments, Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI are used in methods of treating a disease that is at least one of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, failed prosthetics, osteolytic sarcoma, myeloma, or tumor metastasis to bone . In some embodiments, the disease is rheumatoid arthritis or cancer, such as cancer metastasis to bone. In other embodiments, Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI. used to treat a disease that is glomerulonephritis, inflammatory bowel disease, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia or Alzheimer's disease. In further embodiments, Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI is used to treat pain, including bone pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, or neurogenic pain. In other embodiments, Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI is used to treat a disease that is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer. colon, stomach cancer, or hairy cell leukemia. In other additional embodiments, Compound A, Forms I, II, IIA, IIB, III, IV, V, or VI is used to treat or prevent metastasis of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer. colon, stomach cancer, or hairy cell leukemia. In other embodiments, Compound A, Forms I, II, IIB, IIB, III, IV, V, or VI is used to treat an autoimmune disease that is at least one of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis or uveitis.

The following examples help to understand the present invention and in no way imply and should not be construed as limiting the invention as set forth in the following claims.

- 6 041321

Examples

X-ray powder diffraction (XRPD) was performed using an X-ray diffractometer (Philips Model X'Pert PRO PW3040) equipped with an X'Celerator detector and a calibrated X-ray multilayer parabolic mirror. The sample was scanned from 3° to 40° with a step of 0.0165° 2θ and a time per step of 48.260 s. The voltage and current parameters on the X-ray tube were 45 kV and 40 mA, respectively. The sample was mounted on a holder with zero background and scanned at room temperature and relative humidity.

One skilled in the art will appreciate that the diffraction patterns and peak positions are generally substantially independent of the diffractometer used and whether any particular calibration method was used. Typically, peak positions may differ by about ±0.2° 2θ or less. The intensities (and relative intensities) of any particular diffraction peak may also vary depending on various factors, including, without limitation, particle size, orientation, sample purity, and the like. However, one skilled in the art will be able to distinguish between Forms I, II, IIA, IIB, III, IV, V, and VI of Compound A.

Thermal analyzes were performed using a TA DSC instrument, model Q1000. The sample was processed in an open aluminum bowl. An empty aluminum bowl was used as a reference. The sample was scanned from 25 to 300°C with a programmed heating rate of 10°C/min. The total weight loss of the sample was obtained using a TGA instrument manufactured by TA, model Q5000. The sample was placed in a tared aluminum bowl, automatically weighed, and placed in a TGA oven. The sample was scanned from 25 to 300° C. at a heating rate of 10° C./min with a 25 ml/min nitrogen purge of the sample and a trim nitrogen purge of 10 ml/min.

Moisture absorption analysis was performed using the Hiden Isochema system, model IGAsorp. The sample was processed in a stainless steel mesh crucible. The sample was initially dried at 60°C for 30 min and subsequently the moisture profile was assessed by monitoring vapor adsorption/desorption over a relative humidity range of 0 to 90% at 25°C. The moisture profile consisted of 2 vapor adsorption/desorption cycles.

Example 1 Synthesis of form I of compound A

The hydrochloride salt of Compound A was prepared as described in US Pat. No. 8,497,376. Water (150 ml) was added to the hydrochloride salt of Compound A (about 10 g). The resulting solution was stirred with a stirrer. After a few days, the solution was filtered under vacuum using a Buchner glass filter until most of the water was removed. Next, a stream of N ₂ gas was applied to the surface of the precipitate for about 1 h to achieve complete removal of the solvent. The glass filter was weighed before and after filtration and the net weight was recorded.

A portion of the precipitate was analyzed using XRD and the results confirmed the conversion of the salt to the free base, form I of Compound A. The glass filter was placed in a vacuum oven at 60° C. overnight to achieve complete drying until constant weight was obtained. The isolated solid (form I of Compound A as the free base) was characterized using XRPD, DSC, TGA and DSP.

The isolated solid (compound A as free base) was a white crystalline solid, hygroscopic and insoluble in water, as determined by USP methods. The isolated solid exhibited an XRPD spectrum corresponding to Compound A, Form I, having sharp and intense reflections indicative of crystalline form (as shown in FIG. 10). The XRD for form I of Compound A was different from the XRD of the HCl salt sample of Compound A (eg, FIG. 15). The DSC spectrum of the isolated solid (Compound A, Form I) showed a broad endothermic peak up to 110°C due to loss of water from the surface, followed by melting with initial and peak temperatures of 187.5 and 204.6°C, respectively, and heat melting point 56.2 J/g (as shown in Fig. 11). This spectrum also differed from the DSC spectrum of the HCl salt of Compound A, as shown in FIG. 16. Thermogravimetric analysis of the isolated solid (Compound A, Form I) showed a two-stage weight loss of 0.9% from room temperature (RT, about 20°C) to 182°C (equivalent to 0.23 mol water) due to loss of water from the surface, and 0.5% between 182 and 219°C due to melting/decomposition (as shown in Fig. 12). This spectrum also differed from the TGA spectrum of the HCl salt of Compound A (eg Fig. 17).

The DSP of the isolated solid (Compound A, Form I) showed hygroscopicity with a moisture adsorption of 41.8% at relative humidity (RH) up to 90%. The isolated solid (Compound A, Form I) also showed little hysteresis and retained 1.8% moisture (equivalent to 0.47 mol water, hemihydrate form) at the end of the second moisture sorption/desorption cycle (as shown in FIG. 13). Comparison of the XRPD analysis of the isolated solid (before EAF) and the solid residue after EAF showed a substantially similar diffraction pattern with only one additional peak at 6.729 (FIG. 14), and this indicates that the crystalline form in moisture cycling tests didn't change. The DSP spectrum differed from the DSP spectrum of the HCl salt of compound A, as shown

- 7 041321 in FIG. 18.

Example 2 Synthesis of Forms II, PA, PV, III, IV, V and VI of Compound A

Automated selection of solid state forms of Compound A was performed using a binary solvent system. Screening experiments included a set of 13 solvents (water, methanol, ethanol, acetone, acetonitrile, isopropyl alcohol, ethyl acetate, toluene, tetrahydrofuran (THF), dichloromethane, 2-butanone (MEK), 1-butanol, and heptane) under slow evaporation conditions to crystallization. Specifically, saturated solutions of Compound A (prepared as described in Example 1 above) in 13 different solvents were prepared by adding solid powder of Compound A, Form I (50 mg, prepared as described in Example 1 above) and the selected solvent in vials of 20 ml. The resulting solutions were stirred and heated to 40°C. All drugs dissolved quickly, except for dissolution in water, toluene and heptane. In table. 1 is a summary of the apparent solubility of Compound A, Form I in the indicated solvents.

Table 1

Solvent systems Volume solvent (ml) Solubility (mg/ml) Apparent solubility Water 10 N/A Suspension methanol 10 > 5 Dissolution ethanol 10 > 5 Dissolution Acetone 10 > 5 Dissolution Acetonitrile 10 > 5 Dissolution IPA 10 > 5 Dissolution ethyl acetate 10 > 5 Dissolution Toluene 10 N/A Suspension THF 10 > 5 Dissolution dichloromethane 10 > 5 Dissolution Methyl ethyl ketone (IEC) 10 > 5 Dissolution Heptane 10 N/A Suspension 1-butanol 10 > 5 Dissolution

Subsequently, the solutions were filtered through a 0.2 µm PTFE filter cartridge and dispensed into 91 wells of a 96-well plate with 1 ml glass vials, for a total volume of 900 µl (50:50) using the Gilson Liquid Handling System and allowed to settle in a closed sight during the night at room conditions. The next day, the lid was removed and the solution was allowed to evaporate overnight. After evaporation, all solid residues were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

In table. 2 provides a summary of the contents of each of the 91 wells (5 wells were blank) and the crystalline form of Compound A for each isolated residue.

________________________________________ Table 2

# Solvent 1 Solvent 2 The crystalline form of the isolated residue 1 Water Water N/A 2 Water methanol I 3 Water ethanol I 4 Water Acetone I 5 Water Acetonitrile I 6 Water IPA I 7 Water ethyl acetate IV 8 Water Toluene IIB 9 Water THF II 10 Water dichloromethane I eleven Water IEC II 12 Water 1-butanol I 13 Water Heptane n/a 14 methanol methanol III 15 methanol ethanol II 16 methanol Acetone II 17 methanol Acetonitrile III 18 methanol IPA III 19 methanol ethyl acetate IV 20 methanol Toluene ON 21 methanol THF IV

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22 methanol dichloromethane I 23 methanol IEC II 24 methanol 1-butanol I 25 methanol Heptane III 26 ethanol ethanol chk 27 ethanol Acetone II 28 ethanol Acetonitrile III 29 ethanol IPA I thirty ethanol ethyl acetate III 31 ethanol Toluene III 32 ethanol THF III 33 ethanol dichloromethane I 34 ethanol IEC II 35 ethanol 1-butanol I 36 ethanol Heptane ON 37 Acetone Acetone ON 38 Acetone Acetonitrile ON 39 Acetone IPA II 40 Acetone ethyl acetate II 41 Acetone Toluene ON 42 Acetone THF ON 43 Acetone dichloromethane II 44 Acetone IEC II 45 Acetone 1-butanol ON 46 Acetone Heptane ON 47 Acetonitrile Acetonitrile II 48 Acetonitrile IPA ON 49 Acetonitrile ethyl acetate II 50 Acetonitrile Toluene HB 51 Acetonitrile THF ON 52 Acetonitrile dichloromethane HB 53 Acetonitrile IEC II 54 Acetonitrile 1-butanol I 55 Acetonitrile Heptane II 56 IPA IPA V 57 IPA ethyl acetate II 58 IPA Toluene II 59 IPA THF II 60 IPA dichloromethane V 61 IPA IEC II 62 IPA 1-butanol I 63 IPA Heptane IV 64 ethyl acetate ethyl acetate II 65 ethyl acetate Toluene II 66 ethyl acetate THF II 67 ethyl acetate dichloromethane IV 68 ethyl acetate IEC II 69 ethyl acetate 1-butanol I 70 ethyl acetate Heptane HB 71 Toluene Toluene HB 72 Toluene THF HB 73 Toluene dichloromethane HB 74 Toluene IEC II 75 Toluene 1-butanol II 76 Toluene Heptane II 77 THF THF II 78 THF dichloromethane II 79 THF IEC II 80 THF 1-butanol I 81 THF Heptane HB 82 dichloromethane dichloromethane II 83 dichloromethane IEC II 84 dichloromethane 1-butanol I 85 dichloromethane Heptane HB 86 IEC IEC VI 87 IEC 1-butanol I 88 IEC Heptane ON 89 1-butanol 1-butanol n/a 90 1-butanol Heptane n/a 91 Heptane Heptane n/a

N/A=not applicable

CC=partially crystalline

In table. 3A is a listing of the XRPD peaks for Compound A, Form I (see also FIG. 1).

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Table 3A

Position [°2θ] Relative intensity [%] 6, 1 100.0 9, 2 53, 6 9, 4 16.5 10.2 2.0 12.7 18.4 14.6 7.8 15, 1 28.0 15, 7 10.4 16, 2 4, 1 16, 4 8.5 17, 6 4.8 17.8 4.9 18.4 13.4 19.0 5, 4 19, 9 2.1 20.3 2, 6

21.2 2.4 22.0 3.4 24.5 5, 1 25.0 2.1 25, 4 3.2 26, 3 3.0 27.2 2.1

In table. 3B is a listing of the XRPD peaks for Compound A, Form II (see also FIG. 2).

_____________________ Table 3 B

Position [°2θ] Relative intensity [%] 6, 3 100.0 7.3 5, 9 11.5 6.0 12.6 thirty 14.0 2.5 14.6 2.3 17.0 12.4 18.3 5, 6 18.8 3, 9 22.1 2.2 23.0 4.7 28.5 2.7

In table. 3C is a listing of the XRPD peaks for Compound A, Form IIA (see also FIG. 3).

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Table 3C

Relative Position [°2θ] intensity [%] 5, 7 50 5, 9 9, 8 6, 4 100.0 7.3 7b 7.4 6, 7 11.5 7.2 12.6 thirty 14.1 10.2 14.6 7.7 17, 1 31.6 18.3 10, 9 18, 9 14.6 19, 3 7, 6 20.2 3.3 22.1 thirty 23.0 19, 8 25, 3 3, 5 29, 3 4.2

In table. 3D is a listing of the XRPD peaks for Compound A, Form IIB (see also FIG. 4).

Table 3D

In table. 3E is a listing of the XRPD peaks for Compound A, Form III (see also FIG. 5).

Table 3E

In table. 3F is a listing of the XRPD peaks for Compound A, Form IV (see also FIG. 6).

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Table 3F

In table. 3G is a listing of the XRPD peaks for Compound A, Form V (see also FIG. 7).

_________________ Table 3G

Position [°20] Relative intensity [%] 5, 3 50 6, 3 100.0 7.4 13.5 11.5 8.0 11.7 8.7 12.6 3.5 13, 3 thirty 14.0 3.3 14.7 4, 6 17.0 17, 6 18.3 9, 7 18, 9 4.2 19.2 2.7 20.2 5, 5 22, 1 3.2 23.0 7.3

In table. 3H is a listing of the XRPD peaks for Compound A, Form VI (see also FIG. 8).

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Position [°2θ] Relative intensity [%] 5, 7 100.0 b, 3 1.9 b, 7 3, 5 7.3 7.7 8.8 4.1 10, 8 11, 8 11.4 17.4 13.2 8.1 14.0 b, b 15, 4 3.0 15, 7 5.2 16, 1 2.4 17.1 13.5 17.5 2.1 18.0 4.9 18.4 2.2 19, 2 8.8 20, 8 2.4 24.7 2.3 25.5 1.9

Table 3H

Example 3 Suspension Studies

Small amounts of saturated solutions of Compound A, Form I (prepared as described in Example 1 above) in the organic solvents of Example 2 other than water, toluene and heptane were prepared as described below. Compound A, Form I (5-10 mg) was placed in 2 ml HPLC vials and the selected solvent (50 μl) was added. The resulting suspensions were stirred at 300 rpm up to 1 day. At 1 hour and 1 day, a sample of each suspension was placed in an XRPD sample holder and the solvent was evaporated at room conditions to isolate a solid residue, which was subsequently analyzed by X-ray powder diffraction. In table. 4 shows suspension conditions and isolated crystal forms as determined by XRPD.

Table 4

Suspension systems Saturated Concentrate (mg/ml) XRPD Form After 1 hour and 1 day methanol 80 I ethanol 110 I Acetone 130 I Acetonitrile 80 I ΙΡΑ (isopropyl acetate) 95 I ethyl acetate 120 I THF (tetrahydrofuran) 420 II DXM (dichloromethane) 210 III 1-butanol 90 I

These results show that analysis of the solids isolated from all suspensions with solvents other than THF and DCM by powder X-ray diffraction shows an XRPD pattern corresponding to Form I. The results show that the crystal form did not change after 1 hour of suspension in all solvents except THF and DXM as indicated by XRPD. XRPD analysis of the THF suspension solids showed a pattern similar to Form II, and this pattern did not change after 1 day. XRPD analysis of the solid residues of the suspension in dichloromethane showed a pattern that was not similar to any of the forms of the free bases and did not change after 1 day.

Example 4

Comparative suspension studies of Compound A, Forms II, IIA, IIB, III, IV, V and VI, were performed at RT (room temperature, about 20°C) and at 50°C in water. The suspension was monitored at room temperature over an extended period of time using XRPD (suspension was withdrawn at selected time points, sample was placed on the XRPD sample holder, the solvent was allowed to evaporate at room conditions to isolate the residue, and XRPD was performed on this residue) and observed

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Claims (12)

complete conversion to form I, which occurred after 3 days. After 2 days, a small portion of the suspension was transferred to 50°C conditions and analyzed using X-ray powder diffraction after being suspended at 50°C for 2 h (a sample of the suspension was placed on the XRPD sample holder, the solvent was allowed to evaporate at room conditions to isolate the residue and carried out XRPD for this balance). Within 2 h of heating, complete transformation into form I occurred. Based on these results, Form I is believed to be the most thermodynamically stable polymorph as indicated by comparative suspension data. The descriptions of each patent, patent application, and publication cited or described in this document are incorporated herein by reference in their entirety. Those skilled in the art will appreciate that the preferred embodiments of the present invention are susceptible to many changes and modifications, and that such changes and modifications may be made without departing from the spirit of the invention. Thus, the appended claims are intended to include all such equivalent variations as fall within the true spirit and scope of the present invention. CLAIM 1. Crystalline form of 4-cyano-X-(2-(4,4-dimethylcyclohex-1-en-1-yl)-6-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl) pyridin-3-yl)-1 H-imidazole-2-carboxamide (compound A) Compound A, wherein the crystalline form is Compound A, Form I, which is characterized by an X-ray powder diffraction pattern containing peaks at the following 2Θ±0.2° 2θ values: 6.1, 9.2, 9.4, 12.7, 15 .1, 15.7 and 18.4°. 2. The crystalline form according to claim 1, which is Compound A, Form I, wherein the powder X-ray diffraction pattern further contains one or more peaks at the following 2θ±0.2° 2θ values: 14.6, 16.4, or 19.0. 3. A crystalline form according to any one of claims 1 or 2, which is Compound A, Form I, further characterized by a differential scanning calorimetry thermogram having a peak endothermic reaction temperature of about 204.6°C. 4. A crystalline form according to any one of claims 1 to 3, which is Compound A, Form I, further characterized by an X-ray powder diffraction pattern as shown in FIG. 1. 5. A pharmaceutical composition comprising a crystalline form according to any one of the preceding claims and at least one pharmaceutically acceptable excipient. 6. A method for inhibiting colony stimulating factor-1 receptor in a subject, comprising administering to said subject a crystalline form according to any one of claims 1-4. 7. A method of treating a disease that is at least one of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, failed prosthetics, osteolytic sarcoma, myeloma, or tumor metastasis to bone in a subject, comprising administering to said subject a therapeutically effective amount crystalline form according to any one of claims 1 to 4. 8. The method of claim 7 wherein said disease is rheumatoid arthritis or cancer. 9. The method of claim 7 or 8, wherein said disease is cancer metastasis to bone. 10. A method of treating a disease that is at least one of glomerulonephritis, inflammatory bowel disease, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, psoriasis, diabetes associated with tumor angiogenesis, age-related macular degeneration , diabetic retinopathy, restenosis, schizophrenia, and Alzheimer's disease in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of claims 1-4. 11. A method of treating pain, including bone pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, or neurogenic pain in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of claims 1-4. 12. A method for treating a disease that is ovarian cancer, uterine cancer, breast cancer -