RU2803145C2 - Crystalline pyrimidinyl-3,8-diazabicyclo[3.2.1]octanylmethanone and its applications - Google Patents

Abstract

FIELD: chemical industry.

SUBSTANCE: invention relates to a method for obtaining a crystalline form ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone (Form 1), which is characterized by an x-ray powder diffraction pattern including peaks expressed in angles 2θ, at 5.0, 9.4, 9.9, 14.8, 16.8 and 18.7° 2θ± 0.2° 2θ, where the method includes the introduction of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone into ethanol/water and heating to form a solution followed by cooling to form crystals. The invention also relates to a method for obtaining a crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone (Form 1), which is characterized by an X-ray powder diffraction pattern including peaks expressed in angles 2θ at 5.0, 9.4, 9.9, 14.8, 16.8 and 18.7° 2θ±0.2° 2θ, where the method includes the introduction of a free base ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone to methylisobutylketone and heating, followed by the addition of n-heptane to form a solution, seeding the solution by introducing a free base ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-yl)methanone followed by cooling to ambient temperature to form crystals.

EFFECT: obtaining a crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone.

8 cl, 4 dwg, 4 tbl, 4 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone. The present invention also relates to pharmaceutical compositions containing crystalline forms and methods for preparing such forms. The present invention also relates to the use of the crystalline form for the treatment of various diseases and methods for its preparation.

BACKGROUND OF THE ART

((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octan-8-yl)methanone has the chemical formula C ₁₈ H ₂₁ F ₂ N ₇ O and the following structural formula:

Synthesis of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8-yl)methanone is described in co-assigned patent application US9663526, the contents of which are incorporated herein by reference in their entirety. Crystalline form of the free base ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone is useful as an inhibitor of protein kinases such as the enzyme Janus kinase (JAK), and is itself useful in therapy as an immunosuppressive agent in organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease (IBD), psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease , leukemia and other indications when immunosuppression is desired. The present invention relates to a new solid form of the free base which has improved characteristics for use in the preparation of a pharmaceutical dosage form.

Based on chemical structure, it is not possible to predict with any certainty whether a compound will crystallize, under what conditions it will crystallize, how many crystalline solid forms of a compound may exist, or to predict the solid phase structure of any of these forms. The key characteristics of any crystalline drug is the polymorphic behavior of such a substance. In general, crystalline forms of drugs are preferred over non-crystalline forms of drugs, particularly due to their superior stability. For example, in many cases, a non-crystalline drug during storage is converted to a crystalline form of the drug. Since non-crystalline and crystalline forms of a drug typically have different physical characteristics and chemical characteristics, such interconversion may be undesirable for safety reasons for pharmaceutical use. The different physical characteristics of different solid forms of a pharmaceutical compound can affect important pharmaceutical parameters such as storage, compressibility, density (important in product formulation and preparation), and dissolution rates (important in determining bioavailability). Differences in stability may be due to changes in chemical reactivity (eg, different hydrolysis or oxidation parameters such that a dosage form containing a polymorph may discolor more quickly than a dosage form containing another polymorph), mechanical changes (eg, tablets may crumble when storage, as the kinetically more favorable crystalline form is converted to a thermodynamically more stable crystalline form) or both (for example, tablets of one polymorph may be more prone to disintegration under high humidity).

Differences in solubility of polymorphs in extreme situations can lead to transitions to crystalline forms that are inactive. In addition, the physical characteristics of the crystalline form may also be important for pharmaceutical processing. For example, a particular crystalline form may form solvates more easily or be more difficult to filter or wash away impurities than other crystalline forms (i.e., the shape and particle size distribution may be different for different crystalline forms).

There is usually no ideal physical form of a drug because different physical forms provide different benefits. Finding the most stable form is difficult and the result is unpredictable. Thus, it is important to find multiple forms of a particular drug, such as salts, polymorphs, non-crystalline forms that can be used in different formulations. To select a drug form for a particular drug or therapeutic application, consideration of various characteristics is necessary, and the best form for a particular application may be one that has one particular good characteristic, while other characteristics may be acceptable or minimally acceptable.

For a drug to be successfully developed, it must meet certain general requirements to provide a therapeutically effective treatment for patients. These requirements fall into two categories: (1) requirements for successful manufacture of dosage forms and (2) requirements for successful delivery and distribution of the drug after administration of the drug product to the patient.

Different crystalline solid forms of the same compound often have different solid-state characteristics, such as melting point, solubility, dissolution rate, hygroscopicity, powder flowability, mechanical properties, chemical stability, and physical stability. These solid-phase characteristics can provide benefits in filtration, drying, and dosage form unit operations. Thus, once different crystalline solid forms of the same compound have been identified, the optimal crystalline solid form for a given set of preparation and processing conditions can be determined, as well as the different solid phase characteristics of each crystalline solid form.

Polymorphs of a molecule can be obtained using a variety of techniques known in the art. Such techniques include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, flash evaporation, flash cooling, slow cooling, vapor diffusion and sublimation. Polymorphs can be detected, identified, classified and characterized by well-known techniques such as, but not limited to, differential scanning calorimetry (DSC), thermogravimetry (TGA), X-ray powder diffraction (XRPD), single crystal x-ray diffraction, solid phase nuclear magnetic resonance (NMR) ), infrared (IR) spectroscopy, Raman spectroscopy and high temperature optical microscopy.

The present invention relates to the crystalline form of the free base ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. The present invention also relates to compositions, including pharmaceutical compositions, containing the crystalline free base ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazole-4- yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. The present invention also relates to methods for preparing crystalline ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine free base -4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone.

As drug formulations characterized by, for example, improved bioavailability or stability are continually sought, new or purer polymorphic forms of drug molecules are constantly needed. Polymorph ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3, The 8-diazabicyclo[3.2.1]octan-8-yl)methanone described in the present invention helps to solve these and other problems.

SUMMARY OF THE INVENTION

The present invention relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone.

One aspect of the present invention is the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, having one or more characteristics selected from the group consisting of the following:

I) X-ray powder diffraction pattern including: (a) one, two, three, four, five or more peaks selected from the group consisting of the peaks given in Table 1, expressed by °2θ±0.2°2θ; (b) one, two, three, four, five or more than five characteristic peaks selected from the group consisting of the peaks shown in Table 1, expressed in °2θ±0.2°2θ; or (c) peaks at 2θ values, generally as shown in FIG. 1;

II) a Raman spectrum comprising: (a) one, two, three, four, five or more wavenumber values (cm ^-1 ) selected from the group consisting of the values given in Table 2, expressed in cm ^-1 ±2 cm ^-1 ; (b) one, two, three, four, five or more than five wavenumber values (cm ^-1 ) selected from the group consisting of the characteristic values given in Table 2, expressed in cm ^-1 ±2 cm ^-1 ; or (c) wavenumber values (cm ^-1 ), generally as shown in FIG. 2;

III) ¹³ C solid phase NMR spectrum (ppm) comprising: (a) one, two, three, four, five or more than five resonance values (ppm) selected from the group consisting of values shown in Table 3, expressed in ppm ±0.2 ppm; (b) one, two, three, four, five or more than five resonance values (ppm) selected from the group consisting of the characteristic values given in Table 3, expressed in ppm ±0.2 ppm; or (c) resonance values (ppm), generally as shown in FIG. 3;

IV) solid phase ¹⁹ F spectrum (ppm) comprising: (a) one, two or three resonance values (ppm) selected from the group consisting of the values given in Table 4, expressed in ppm. /million±0.2 ppm; (b) the characteristic values given in Table 3, expressed in ppm ± 0.2 ppm; or (c) resonance values (ppm), generally as shown in FIG. 3; And

V) a combination of any two, three or four of the preceding embodiments (I)(a)-(c), (II)(a)-(c), (III)(a)-(c) or (IV)( a)-(c), provided that they are not inconsistent with each other.

Another object of the present invention is a crystalline form according to any of the embodiments described in the present invention, crystallized from a solvent system, which could include acetone, methyl isobutyl ketone, 2-propanol, methanol, ethanol, water or tetrahydrofuran.

Another object of the present invention is also a pharmaceutical composition containing crystalline ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, a pharmaceutically acceptable carrier or excipient.

Another aspect of the present invention is also a method of treating a disease in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of crystalline ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl -1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo-[3.2.1]octan-8-yl)-methanone or a pharmaceutically acceptable salt or pharmaceutical composition thereof according to any one of the embodiments described in the present invention, said disease is selected from the group consisting of rheumatoid arthritis, lupus, psoriasis, psoriatic arthritis, atopic dermatitis and inflammatory bowel disease.

BRIEF DESCRIPTION OF THE DRAWINGS

In fig. Figure 1 shows a powder X-ray diffraction pattern of the crystalline form ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone.

In fig. Figure 2 shows the Raman spectrum of the crystalline form ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone.

In fig. Figure 3 shows the solid-phase ¹³ C nuclear magnetic resonance spectrum of the crystalline form ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. Side rotation bands are marked with an asterisk.

In fig. Figure 4 shows the solid-phase ¹⁹ F nuclear magnetic resonance spectrum of the crystalline form ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. Side rotation bands are marked with an asterisk.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. The present invention also relates to pharmaceutical compositions containing crystalline forms and methods for preparing such forms. The present invention also relates to the use of the crystalline form for the treatment of various diseases.

There are a number of analytical techniques that a person with general training in solid state chemistry can use to analyze solid forms. The term "analysis" as used in the present invention means obtaining information about the solid phase structure of solid forms. For example, powder X-ray diffraction is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, distinguishing between crystalline forms, and for characterizing and identifying crystalline solid forms of a compound. Powder x-ray diffraction is also suitable for quantifying the content of crystalline solid form (or forms) in a mixture. In powder radiography, x-rays are directed at a powder containing crystals, and the intensity of the diffracted x-rays is measured as a function of the angle between the x-ray source and the beam diffracted by the sample. The intensity of this diffracted x-ray can be represented graphically as peaks, where the x-axis represents twice the angle (also known as the "2θ" angle) between the x-ray source and the diffracted x-ray and the y-axis represents the intensity of the diffracted x-ray. This graph is called a powder X-ray diffraction pattern. Different crystalline solid forms have different X-ray powder diffraction patterns because the x-axis position of the peaks is a characteristic of the solid structure of the crystal.

Such X-ray powder patterns, or portions thereof, can be used as signatures of the crystalline solid form. Thus, it is possible to take an X-ray powder pattern of an unknown sample and compare that X-ray powder pattern to a reference X-ray powder pattern. An exact match means that the unknown sample is the same crystalline solid as the reference. It is also possible to analyze an unknown sample containing a mixture of solid forms by adding and subtracting X-ray powder diffraction patterns of known compounds.

When selecting peaks in an x-ray powder diffraction pattern to characterize a crystalline solid form, or when using a reference x-ray powder diffraction pattern to identify a shape, a peak or set of peaks of one shape are identified that are not contained in the x-ray powder diffraction patterns of other solid forms.

The term "characterize" as used in the present invention means selecting a suitable set of data capable of distinguishing one solid form from another. This X-ray powder diffraction data set consists of the positions of one or more peaks. The selection of peaks in a powder X-ray diffraction pattern that define a particular shape is a specified characterization of that shape.

The term "identification" as used in the present invention means selecting characteristic data for a solid form and using this data to determine whether that form is contained in the sample. In powder radiography, this data is the x-axis position of one or more peaks characterizing the shape in question, as discussed above. For example, once it has been determined that a number of X-ray diffraction peaks are representative of a particular solid form, these peaks can be used to determine whether that form is present in the sample.

When characterizing and/or identifying crystalline solid forms of the same chemical compound using powder X-ray diffraction, it is often not necessary to use the entire X-ray powder diffraction pattern. A smaller portion of the entire X-ray powder diffraction pattern can often be used to perform characterization and/or identification. By selecting a set of peaks that distinguish a crystalline solid form from other crystalline solid forms of a compound, these peaks can be used to characterize the form and to identify the form, for example, in an unknown mixture. Additional data can be added, such as data from another analytical technique or additional X-ray powder diffraction peaks to characterize and/or form identify, such as additional polymorphs identified later.

Due to differences in instrumentation and sample preparation, peak values are sometimes given with the word "about" in front of the peak values. This is common practice in solid state chemistry because these changes are inherent in the peak values. Typical accuracy of the 2θ value for the x-axis peak in an X-ray powder diffraction pattern is on the order of ±0.2° 2θ. Thus, a peak in a powder X-ray diffraction pattern that is at "about 9.2° 2θ" means that the peak can be in the range of 9.0° 2θ to 9.4° 2θ when determined by most X-ray diffractometers under most conditions . The variability in peak intensities is a consequence of what the orientation of the individual crystals in the sample container is relative to the external x-ray source (known as the "preferred orientation"). This orientation effect does not provide information about the crystal structure. Powder X-ray diffraction is just one of various techniques that can be used to characterize and/or identify crystalline solid forms. Spectroscopic techniques such as Raman spectroscopy (including microscopic Raman spectroscopy), infrared and solid phase NMR spectroscopy can be used to characterize and/or identify crystalline solid forms. These techniques can also be used to determine the amount of one or more crystalline solid forms in a mixture, and peak values can also be reported with the word "about" preceding the peak values. Typical variations in peak values when examined by FT-Raman spectroscopy and FT-infrared spectroscopy are on the order of ±2 cm ^-1 . Typical variations in values for the ¹³ C or ¹⁹ F chemical shift peaks for a crystalline material are on the order of ±0.2 ppm. Typical variations in the start temperature value in differential scanning calorimetry are on the order of ±5°C.

The term "room temperature" as used in the present invention means a temperature in the range of 20°C to 23°C.

The first object of the present invention is the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, having one or more characteristics selected from the group consisting of the following:

I) X-ray powder diffraction pattern containing the following 2θ values measured using Cu K _α1 radiation (λ=1.54056 Å): 2θ , at 5.0, 9.9 and 15.3° 2θ±0.2° 2θ.

ii) X-ray powder diffraction pattern containing the following 2θ values measured using Cu K _α1 radiation (λ=1.54056 Å): 5.0, 9.9, 15.3 and 19.7° 2θ±0.2° 2θ.

III) X-ray powder diffraction containing the following 2θ values measured using Cu K _α1 radiation (λ=1.54056 Å): 5.0, 9.9, 15.3, 16.8 and 19.7° 2θ±0, 2° 2θ.

Accordingly, the present invention relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, having a powder X-ray diffraction pattern including peaks expressed in 2θ angles at 5.0, 9.9 and 15.3° 2θ ±0.2° 2θ. The present invention also relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, having a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3 and 19.7° 2θ±0.2 °2θ. The present invention also relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, having a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3, 16.8 and 19.7° 2θ±0.2° 2θ. In addition, the present invention relates to a pharmaceutical composition containing a crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl) amino)pyrimidin-4-yl)-3,8-diazabicyclo-[3.2.1]octan-8-yl)-methanone; and a pharmaceutically acceptable carrier. In some embodiments, the present invention relates to said pharmaceutical composition, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9 and 15.3° 2θ±0.2° 2θ. In other embodiments, the present invention relates to said pharmaceutical composition, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3 and 19.7° 2θ±0.2° 2θ. In other embodiments, the present invention relates to said pharmaceutical composition, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3, 16.8 and 19.7° 2θ±0.2° 2θ .

The present invention also relates to a pharmaceutical composition of the specified crystalline form according to any of the embodiments described in the present invention, comprising a topical preparation selected from the group consisting of cream, transdermal patch, ointment, eye drops, lotion and gel. In some embodiments, the present invention provides said pharmaceutical composition wherein the topical preparation contains from about 0.1% to about 5.0% (w/v) crystalline ((S)-2,2-difluorocyclopropyl)(( 1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone .

Furthermore, the present invention provides a method of treating a disease in a mammal, comprising administering to the mammal in need thereof a therapeutically effective amount of a crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, where the disease is selected from a group that includes lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis and atopic dermatitis. In some embodiments, the present invention relates to said method, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9 and 15.3° 2θ±0.2° 2θ. In some other embodiments, the present invention provides said crystalline form that has a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3 and 19.7° 2θ ± 0.2° 2θ. In other embodiments, the present invention provides said crystalline form that has an X-ray powder diffraction pattern including peaks expressed in 2θ angles at 5.0, 9.9, 15.3, 16.8 and 19.7° 2θ±0, 2° 2θ.

The present invention also provides a method of topical treatment of a disease in a mammal, comprising locally administering to a mammal in need thereof a therapeutically effective amount of a crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-( (1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the disease is selected from the group consisting of vitiligo, alopecia, psoriasis and atopic dermatitis. In some embodiments, the present invention relates to said method, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9 and 15.3° 2θ±0.2° 2θ. In some other embodiments, the present invention relates to said method, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3 and 19.7° 2θ±0.2° 2θ. In some other embodiments, the present invention relates to said method, wherein said crystalline form has a powder X-ray diffraction pattern including peaks at 5.0, 9.9, 15.3, 16.8 and 19.7° 2θ±0.2° 2θ .

Instrument and analysis methods:

Calculated X-ray powder patterns: X-ray powder patterns were calculated from single crystal X-ray data using SHELXTL software including XFOG (SHELXTL, Bruker AXS, XFOG, Version 5.100, 1997) and XPOW (SHELXTL, Bruker AXS, XPOW, Version 5.102, 1997-2000) . The appropriate wavelength required for graphics overlay was added using the XCH file exchange program (SHELXTL, Bruker AXS, XCH, Version 5.0.4, 1995-2001).

Powder radiography:

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Advance diffractometer equipped with a Cu light source equipped with a Goebel mirror. Diffracted radiation was detected by a LYNXEYE_EX detector with electrically driven slits. Soller slits 2.5 were used for the primary and secondary beams. The voltage and current on the X-ray tube were set to 40 kV and 40 mA, respectively. Data were acquired using a theta-theta goniometer in a theta-two-theta scan at Cu K-alpha wavelengths from 3.0 to 40.0 degrees 2-theta using 1204 steps and a scan rate of 0.50 s per step . Samples were prepared by placing them in a low-background silicon holder and rotating them while collecting data. Data were collected using Bruker DIFFRAC Plus software. The analysis was carried out using EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in EVA software, peaks with a threshold value of 1 were used to pre-assign peaks. To ensure correct assignment, assignments were done manually; The results of automatic assignment were checked visually and the positions of the peaks were established based on the peak maxima. Typically, peaks with relative intensities ≥ 2% were selected. Unresolved peaks and peaks consistent with noise were not selected. Typical PXRD peak position uncertainty in USP is set to +/- 0.2° 2-Theta (USP-941).

PXRD reflection assignments: Eva Application 9.0 software was used to visualize and analyze PXRD spectra. The peak positions were referred to the maximum intensity of a given reflection. All reflections having a relative intensity greater than 10% are included in the following tables.

Solid-Phase NMR: Solid-phase NMR (ssNMR) analysis was performed using a CPMAS probe located in a Bruker-BioSpin Avance III™ 500 MHz ( ¹ H frequency) NMR spectrometer. The material was placed in a 4 mm rotor, sealed using a standard head attachment. Using magic angle rotation at 15.0 kHz. During the accumulation of spectra, an 80-90 kHz proton decoupling field with phase modulation was applied. The ¹³ C ssNMR spectrum was collected in cross-polarization magic angle spinning with proton decoupling (CPMAS) experiments. The cross polarization contact time is set to 3 ms and the repeat latency is set to 60 s. The number of scans was adjusted and an adequate signal-to-noise ratio was obtained using 768 scans for API (active pharmaceutical ingredient) and more scans, typically ≥4096, for drug products. The ¹³ C chemical shift scale was established using a ¹³ C CPMAS experiment with crystalline adamantane as an internal standard, setting its high field resonance to 29.5 ppm.

The ¹⁹ F ssNMR spectrum was accumulated in magic angle spinning (MAS) experiments with proton decoupling. The repetition timeout is set to 60 s. The number of scans was adjusted and an adequate signal-to-noise ratio was obtained using 64 scans for the API and a larger number of scans, typically ≥256, for the drug product. The ¹⁹ F chemical shift scale was established using a ¹⁹ F MAS proton decoupling experiment with a 50/50 (v/v) trifluoroacetic acid/water external standard, setting its resonance to -76.54 ppm.

Automatic peak selection was performed using Bruker-BioSpin TopSpin version 3.5 software. Typically, a relative intensity threshold of 5% was used for peak preselection. The results of automatic peak extraction were visually assessed to ensure reliability and, if necessary, assignments were made manually. Although the present invention provides specific values for solid phase NMR peaks, there is a range in the values for these peaks due to differences in instrumentation, samples, and sample preparation. The solid phase NMR peak heights given in the present invention are relative intensities. In solid-phase NMR, intensities can vary depending on the actual established experimental CPMAS parameters and the thermal history of the sample.

The present invention relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, which can be identified using one or more solid phase analytical techniques. A list of PXRD peaks for the crystalline form at 23°C is given in Table 1.

Table 1: List of PXRD peaks for Form 1 ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone obtained in Example 4. The asterisked peaks are representative of Form 1, the anhydrous free base.

Angle (2θ) Relative intensity (%) Angle (2θ) Relative intensity (%) 5.0* 47.8 20.8 65.1 9.4 30.3 21.3 4.6 9.9* 29.1 22.8 20.4 12.1 6.4 23.4 21.8 12.7 9.7 23.7 15.4 14.8 26.4 24.2 12.5 15.3* 13 24.7 18 16.0 10.7 27.5 16.7 16.8* 77.8 27.9 5.2 18.3 14.7 28.2 3.8 18.7 68.2 29.8 4 19.0 100 19.3 thirty 19.7* 18.5 20.3 12.5 20.7 65.8

Intensities may vary depending on the actual CPMAS experimental parameters set and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

The Raman peaks for the crystalline form are given in Table 2.

Table 2: Complete list of Raman peaks for Form 1 ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino )pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. Characteristic peaks for Form 1 are marked with an asterisk (S=strong, M=medium, W=weak).

Raman peak position /cm ^-1 Normalized intensity 111 S 145 M 165 M 178 M 203 W 244 W 280 W 304 W 336 W 356 W 367 W 384 W 413 W 459 W 486 W 513 W 543 W 588 W 616 W 642 W 649 W 681 W 714 W 735 W 768 W 780 W 792 W 814 W 836 W 847 W 868 W 886 M 906 W 915 W 950 W 975* S 987 M 1011 W 1022 M 1032 W 1054 W 1077 W 1091 W 1115* M 1152 W 1169 W 1198 W 1220 W 1243 W 1259 W 1280 W 1297 W 1322 W 1346 M 1358 M 1366 M 1375 M 1387 M 1415 W 1443 W 1455 W 1481 W 1538 W 1566* M 1578* M 1605* M 1638 W 1944 W 1022 M 1032 W 1054 W 1077 W 1091 W 1115* M 1152 W 1169 W 1198 W 1220 W 1243 W 1259 W 1280 W 1297 W 1322 W 1346 M 1358 M 1366 M 1375 M 1387 M 1415 W 1443 W 1455 W 1481 W 1538 W 1566* M 1578* M 1605* M 1638 W 1944 W 2487 W 2705 W 2746 W 2857 W 2872 W 2897 W 2956 M 2969 M 2987 M 3021 S 3095 M 3107 W 3187 W 3238 W

The lists of peaks in the solid phase ¹³ C and solid phase ¹⁹ F NMR spectrum for the crystalline form are given in Tables 3 and 4, respectively.

Table 3: List of peaks in the ¹³ C solid-phase spectrum for form 1 ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. Peaks marked with asterisks are characteristic of form 1.

¹³ C Chemical shifts [ppm] Relative intensity, % 13.4 25 16.3 28 24.5 35 26.7 43 27.5 63 28.0 92 38.6* 85 49.4 36 50.4 51 51.0 100 51.5 87 54.6* 84 93.3 55 93.4 55 110.4 8 114.0 9 123.5 66 124.9* 67 129.8* 60 156.2 51 159.6 77 160.8 32 165.3* 54

Table 4: List of peaks in the solid phase ¹⁹ F NMR spectrum for form 1 ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4- yl)-amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone. Peaks marked with asterisks are characteristic of form 11.

¹⁹ F Chemical shift (ppm) Relative intensity, % -141.2* 100 -128.1 68 -126.5 70

Accordingly, the present invention relates to pharmaceutical compositions including crystalline form, and methods for preparing such forms, as well as pharmaceutical compositions for use in medicine and for use in the treatment of diseases such as lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis, psoriatic arthritis and atopic dermatitis. The present invention also relates to the use of such pharmaceutical compositions for the preparation of a medicament for the treatment of diseases such as lupus, rheumatoid arthritis, IBD, ulcerative colitis, Crohn's disease, vitiligo, alopecia, psoriasis and atopic dermatitis.

The present invention also relates to the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone, obtained by recrystallization of ((2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl- 1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone) from a suitable solvent.

The present invention also relates to a topical preparation ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone, obtained by combining its crystalline form with excipients suitable for transdermal administration.

Methods for treating diseases and syndromes provided herein are to be understood as including administering to an individual in need of such treatment a therapeutically effective amount of a polymorph of the present invention, or a composition containing the same. As used herein, the term “treating” in relation to a disease means preventing, suppressing and/or ameliorating the disease.

When used in the present invention, the term "individual" or "patient", used interchangeably, means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, goats, horses or primates and most preferably humans. As used herein, the expression "therapeutically effective amount" means an amount of active compound or pharmaceutical agent that produces a biological or medical response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician or health care provider. assistance, or to an individual, which includes one or more of the following:

(1) disease prevention; for example, preventing a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder, but who does not experience or exhibit disease pathology or symptoms;

(2) disease suppression; for example, suppressing a disease, condition or disorder in an individual who experiences or exhibits the pathology or symptoms of the disease, condition or disorder (ie, stopping or slowing further development of the pathology and/or symptoms); And

(3) improvement of the course of the disease; for example, ameliorating a disease, condition, or disorder in an individual who experiences or exhibits pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and/or symptoms).

Doses and drug

The present invention also includes pharmaceutical compositions that use one or more of the provided crystalline forms together with one or more of the following: pharmaceutically acceptable carriers, excipients, diluents, and the like.

The crystalline form provided by the present invention is administered in an amount effective to treat the pathological condition described in the present invention, and may be administered as the crystalline compound itself , or, alternatively, as a pharmaceutically acceptable salt. For administration and dosage purposes, the crystalline compound itself or a pharmaceutically acceptable salt thereof is simply referred to as the compounds of the present invention.

The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted for such route, at a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally or topically.

The compounds of the present invention can be administered orally. Oral administration may involve ingestion so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used whereby the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the present invention can also be administered directly into the bloodstream, into a muscle or into an internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, epigastric, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion devices.

In another embodiment, the compounds of the present invention can also be administered topically to the skin or mucous membrane, ie, cutaneously or transdermally. In another embodiment, the compounds proposed in the present invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention can be administered rectally or vaginally. In another embodiment, the compounds of the present invention can also be administered directly into the eye or ear.

The dosage regimen of the compounds of the present invention and/or compositions containing these compounds is based on a variety of factors, including the type, age, weight, gender and health status of the patient; severity of the pathological condition; route of administration; and the activity of the particular compound used. Thus, the dosage regimen may vary significantly. In one embodiment, the total daily dose of a compound of the present invention is typically from about 0.01 to about 100 mg/kg (i.e., the number of milligrams of the compound of the present invention per kg of body weight) for the treatment of these pathological conditions considered in the present invention. In another embodiment, the total daily dose of a compound of the present invention is from about 0.1 to about 50 mg/kg and in another embodiment from about 0.5 to about 30 mg/kg.

For oral administration, the compositions can be used in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0 , 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 mg of the active ingredient for symptomatic dose adjustment for the patient. The drug typically contains from about 0.01 mg to about 500 mg of active ingredient, or in another embodiment from about 1 mg to about 100 mg of active ingredient. Intravenous doses may range from about 0.01 to about 10 mg/kg/minute at a constant infusion rate.

Suitable subjects in the context of the present invention include mammals. Mammals suitable for the present invention include canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, and the like, and include mammals in utero. In one embodiment, suitable subjects are humans. People can be of any gender and at any stage of development.

As used herein, a “pharmaceutically acceptable carrier” includes any and all solvents, dispersing media, coatings, antibacterial and fungicidal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of the following: water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., as well as combinations thereof, and may contain in the composition isotonic agents, for example, sugars, chloride sodium or polyols such as mannitol or sorbitol. Pharmaceutically acceptable substances, such as wetting agents or small amounts of excipients, such as wetting or emulsifying agents, preservatives or buffers, which increase the duration of action or effectiveness of antibodies or antibody fragments.

The compositions proposed in the present invention may be in different forms. These include, for example, liquid, semi-liquid and solid dosage forms such as liquid solutions (eg, injections and infusions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended route of administration and therapeutic use.

Typical compositions are in the form of solutions for injection or infusion, such as compositions similar to those used for passive general immunization of humans with antibodies. One route of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibodies are administered by intravenous infusion or injection. In yet another embodiment, the antibodies are administered by intramuscular or subcutaneous injection.

The oral solid dosage form may, for example, be presented in unit portions such as hard or soft capsules, pills, wafers, lozenges or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in the form of a powder or granule. In another embodiment, the oral dosage form is sublingual, such as, for example, a lozenge. In such solid dosage forms, the crystalline compound is typically combined with one or more excipients. Such capsules or tablets may be a controlled release formulation. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents or be formulated with enteric coatings.

In another embodiment, oral administration may be via a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also contain auxiliary agents such as wetting, emulsifying, suspending, flavoring (eg, sweetening) and/or flavoring agents.

In another embodiment, the present invention relates to a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, epigastric injections and infusion. Injectable preparations (ie, sterile aqueous or oleaginous injectable suspensions) can be prepared in accordance with the prior art using suitable dispersing, wetting and/or suspending agents.

In another embodiment, the present invention relates to a dosage form for topical use. "Local administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. The topical formulation may include a crystalline compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas. When the crystalline compound of the present invention is administered via a transdermal device, administration is carried out using a reservoir and porous membrane type patch, or various solid matrices. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, dressings and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Permeation enhancers may be included - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

Accordingly, topical preparations prepared from the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, can be administered in the form of such preparations, including all the usual routes of administration through the body surface and internal lining passages of the body, including epithelial tissues and mucous membranes, including transdermal, epidermal, buccal, pulmonary, ocular, intranasal, vaginal and rectal routes of administration. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Such topical preparations can be prepared in combination with additional pharmaceutically acceptable excipients. An excipient that may be important for clinical effectiveness is one or more permeation enhancers, such as one or more saturated or cis-unsaturated C10-C18 fatty alcohols. Such fatty alcohols include C16-C18 fatty alcohols, and most preferred is a C18 fatty alcohol. Examples of cis-unsaturated C16-C18 fatty alcohols include oleyl alcohol, linoleyl alcohol, γ-linolenyl alcohol and linolenyl alcohol. Saturated C10-C18 fatty alcohols useful as penetration enhancers include decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol and stearyl alcohol. Alternatively, other permeation enhancers that can be used to prepare topical formulations include C10-C18 fatty acids, which, if saturated, may include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid . Alternatively, the permeation enhancer may preferably be a cis-unsaturated fatty acid such as palmitoleic acid (cis-9-hexadecenoic acid), oleic acid (cis-9-octadecenoic acid), cis-vaccenic acid (cis-11-octadecenoic acid). acid), linoleic acid (cis-9,12-octadecadienoic acid), γ-linolenic acid (cis-6,9,12-octadecatrienoic acid), linolenic acid (cis-9,12,15-octadecatrienoic acid) and arachidonic acid (cis-5,8,11,14-eicosatetraenoic acid). Penetration agents, for example selected from C10-C18 fatty alcohols, are used in amounts ranging from about 0.1 to about 5% (w/v), more preferably from 1 to about 4%, even more preferably from 1 to about 3% (w/v).

Preparations for topical use containing ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone in therapeutically effective amounts can be administered to patients in need once or twice daily. These amounts range from about 0.1% to about 5.0% (w/v), more preferably from about 0.1% to about 3.0% (w/v). Other excipients that increase the stability of these drugs include aldehyde scavengers such as glycerin and propylene glycol, and antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbic acid (vitamin C), polyphenols, tocopherols ( vitamin E) and their derivatives.

Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present invention is dissolved or suspended in a suitable carrier. A typical formulation suitable for administration to the eyes or ears may be in the form of drops of a micronized suspension or solution in isotonic, pH adjusted sterile saline. Other preparations suitable for administration to the eyes or ears include ointments, biodegradable (i.e., gel-absorbent sponges, collagen) and nonbiodegradable (i.e., silicone) implants, wafers, lenses, and crushed or vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a polymeric heteropolysaccharide such as gellan gum may be included along with a preservative such as benzalkonium chloride. Such drugs can also be delivered using iontophoresis.

For intranasal or inhalation administration, the crystalline compound of the present invention is typically delivered in the form of a solution or suspension from a spray pump container that is squeezed or pumped by the patient, or an aerosol spray system from a pressurized container or nebulizer using a suitable propellant. Drugs suitable for intranasal administration are usually administered in the form of a dry powder (pure, as a mixture, for example, a dry mixture with lactose, or mixed particulate components, for example, in a mixture with phospholipids such as phosphatidylcholine) from a dry powder inhaler or by nebulization aerosol from a pressurized container, by means of a pump, atomizer, atomizer (preferably an atomizer using an electrodynamic device to produce a fine mist), or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1, 1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive agent, such as chitosan or cyclodextrin.

In another embodiment, the present invention relates to a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is the traditional suppository base, but various alternatives can be used if they are suitable.

Other carrier materials and routes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention can be prepared by any of the well known pharmaceutical techniques, such as efficient preparation and administration procedures. The above considerations regarding effective drugs and administration techniques are well known in the art and are described in standard textbooks. Drug formulation is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

The crystalline compound of the present invention can be used alone or in combination with other therapeutic agents. The present invention relates to any of the uses, methods or compositions defined herein, wherein a crystalline compound of the present invention, or a pharmaceutically acceptable solvate of the compound, is used in combination with one or more other therapeutic agents contemplated by the present invention.

Administering two or more compounds "in combination" means that all compounds are administered at similar times such that the presence of one agent may alter the biological effects of the other compound(s). Two or more compounds can be administered simultaneously, together or sequentially. In addition, simultaneous administration can be accomplished by mixing the compounds prior to administration or by administering the compounds at the same time point but in separate dosage forms at the same or different administration sites.

The expressions "simultaneous administration", "co-administration", "simultaneous administration" and "simultaneous administration" mean that the compounds are administered in combination.

In another embodiment, the present invention provides methods of treatment that include administering a crystalline compound of the present invention in combination with one or more other pharmaceutical agents, wherein the one or more other pharmaceutical agents may be selected from those discussed herein. invention.

These agents and the crystalline compound of the present invention can be combined with pharmaceutically acceptable diluents such as saline, Ringer's solution, dextrose solution, etc. The specific mode of administration, i.e., dose, time and number of repetitions, depends on the individual and the individual's medical history.

Suitable carriers, excipients or stabilizers are non-toxic to the recipient at the doses and concentrations used and may contain buffers such as phosphate, citrate and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; pyrocatechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium ions; metal complexes (eg Zn-protein complexes); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Liposomes containing these agents and/or compounds of the present invention are prepared by methods known in the art, such as those described in U.S. patents. Nos. 4485045 and 4544545. Extended circulation time liposomes are disclosed in U.S. Pat. No. 5013556. Particularly useful liposomes can be prepared by a reverse phase evaporation technique using a lipid composition containing phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through filters with a specific opening size to obtain liposomes of the desired diameter.

These agents and/or compounds proposed in the present invention can also be placed in microcapsules obtained, for example, by coacervation or interfacial polymerization techniques, for example, hydroxymethylcellulose, or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, for colloidal drug delivery systems agents (eg liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or included in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

Extended-release preparations can be used. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the antibodies/compound of the present invention, and these matrices are in the form of molded articles, such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (eg, poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, nondegradable copolymers ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOT™ (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3 -hydroxybutyric acid.

Preparations for use for intravenous administration must be sterile. This can easily be achieved, for example, by sterile membrane filtration. A crystalline or non-crystalline form of n-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide prepared by the method provided herein invention is typically placed in a container containing a sterile inlet, such as an intravenous solution bag or vial with a stopper pierced by a hypodermic syringe needle.

Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient can be dissolved in a premixed emulsion composition or, alternatively, it can be dissolved in an oil (such as soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and the emulsion formed after mixing with a phospholipid (such such as egg phospholipids, soy phospholipids or soy lecithin) and water. It should be understood that other ingredients, such as glycerin or glucose, can be added to adjust the tonicity of the emulsion. Suitable emulsions typically contain up to 20% oil, for example 5 to 20%. The fat emulsion may contain fat droplets ranging in size from 0.1 to 1.0 microns, preferably from 0.1 to 0.5 microns, and have a pH ranging from 5.5 to 8.0.

The compounds of the present invention can be prepared by methods known in the art. The reagents used to prepare the compounds of the present invention can be purchased or can be prepared using standard procedures described in the literature. For example, the compounds of the present invention can be prepared according to the procedures described in the following examples.

In describing the present invention, various abbreviations are used that are well known to those skilled in the art, including the following:

CH ₃ CN: Acetonitrile

DCM: Dichloromethane

DMF: N,N-Dimethylformamide

DMSO: Dimethyl sulfoxide

EtOAc: Ethyl acetate

EtOH: Ethanol

FT-IR: Fourier transform infrared spectroscopy

HOAc: Acetic acid

MeOH: Methanol

PXRD: powder radiography

ss ¹³ C NMR: solid phase ¹³ C nuclear magnetic resonance

THF: Tetrahydrofuran

TLC: Thin Layer Chromatography

EXAMPLES

The following non-limiting examples are provided only to illustrate the present invention. One of ordinary skill in the art will understand that there are numerous equivalents and variations, not shown by way of example, which are still part of the present invention.

Example 1

Preparation of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8-yl)methanone

The title compound was prepared in accordance with Example 2 of US Patent No. 9663526. The crude material was heated in 10 volumes (100 mg/ml) of a 2:1 EtOH/water mixture at 80°C (until complete dissolution) and then filtered and cooled slowly until the product crystallized . After filtering, the substance was dried in vacuum at 45-55°C.

Example 2

Preparation of Form I ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8-yl)methanone

One molar aqueous solution of sodium hydroxide (1.2 eq.) and p-toluenesulfonate ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazole-4 -yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (1.0 eq.) was combined in methyl isobutyl ketone (MIBK) (8 ml/g). After dissolving the solids and neutralizing the salt, the two liquid sloates were allowed to separate. The aqueous layer was extracted with MIBK (5 ml/g) and the combined organic layers were washed with water (3 ml/g). The washed organic solution was filtered through a fine filter and concentrated to remove water. The concentrate was diluted with MIBK (total volume=6.8 ml/g based on free base ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H -pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone), heated at 75°C, then further diluted with n-heptane (3 .2 ml/g in terms of (S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone to obtain a solution of the free base in a 2:1 v/v ratio. MIBK:n-heptane. The solution was slightly cooled to 65°C and the warm solution was seeded with 0.02 mol.% free base form 1 ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone) (0.02 eq.). The API free base was allowed to crystallize at 65°C for ~1 h, the resulting suspension was cooled to ambient temperature (~20°C at 0.1°C/min) and maintained at this temperature for 14 h to complete crystallization. Free base ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8-yl)-methanone) was collected by filtration, washed with a 3:7 v/v mixture. MIBK/n-heptane (0.7 ml/g) and dried on a filter or optionally in a vacuum oven at 45°C.

Example 3

Preparation of the free base (S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octan-8-yl)methanone:

Amorphous free base ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3 ,8-diazabicyclo[3.2.1]octan-8-yl)methanone) (100 mg) and ethyl acetate (EtOAc) (1 ml) were placed in a solution vessel and heated at 60°C. Heptane was added until a precipitate appeared, then EtOAc was added again until the precipitate redissolved. The solution was cooled to room temperature (RT) and stirred at RT overnight. Drops of clear oil appeared at the bottom of the vessel, the mixture was heated at 60°C, then it was allowed to cool to ambient temperature. Racemate crystals obtained in accordance with US patent No. 9663526 were added and the mixture was stirred at RT overnight. The mixture (the racemate seed is not yet dissolved, but precipitation no longer occurs) was heated at 35°C for ~64 h. The resulting precipitate was filtered off as crystalline free base Form 1 ((S)-2,2-difluorocyclopropyl)((1R, 5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone) 1.

Example 4

Preparation of the racemate: ((2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octan-8-yl)methanone)

1 and 0.72 mmol of racemate ((2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1]octan-8-yl)methanone), 1 mol (S)-2,2-difluorocyclopropane-1-carboxylic acid, 2.06 mol HATU (1-[bis(dimethylamino)methylene ]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidohexafluorophosphate, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridinium- 1-ylmethylene]-N-methylmethanamminium hexafluorophosphate-N-oxide) and 8 ml of dichloromethane were added to the flask at RT, then 6.88 mmol of DIEA (N,N-diisopropylethylamine) was added. The reaction mixture was stirred at RT for 6 hours. The solvent was removed and the resulting crude reaction product was purified by silica gel chromatography and eluted with a mixture of 30% ethyl acetate and 70% heptane to 100% ethyl acetate. It was further purified by silica gel chromatography using 8% methanol (MeOH) and 92% dichloromethane (DCM). The sample was dissolved in DCM and washed three times with water saturated with ammonium chloride (NH ₄ Cl). The organic layer was concentrated into a resin. The residue was placed in a flask and 3 ml of EtOAc was added and heated at 60°C, then heptane was added until a precipitate appeared, then EtOAc was added again until the precipitate redissolved. The solution was cooled to RT and stirred overnight at RT. The resulting precipitate was processed using a temperature cycle with the following parameters: holding at 60°C for 2 hours, then cooling to 20°C and holding for another 18 hours. The solid was filtered and dried in vacuum. PXRD showed that the solid was crystalline.

Variations, modifications and other implementations of what is described in the present invention will be apparent to those skilled in the art without departing from the spirit and essential characteristics of the present invention. Accordingly, the scope of the present invention is to be determined not by the preceding illustrative description but by the appended claims, and all modifications within the spirit and range of equivalence of the claims are intended to be included within the scope of the present invention.

Each of the printed publications, including, but not limited to, patents, patent applications, books, technical documents, trade publications and journal articles, which are described or referenced herein are incorporated in their entirety by the present invention. as a reference for all objects.

Claims (10)

1. Method for obtaining the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone (form 1), which is characterized by an X-ray powder diffraction pattern including peaks expressed in 2θ angles at 5.0, 9.4, 9.9 , 14.8, 16.8 and 18.7° 2θ±0.2° 2θ, where the method includes the introduction of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone into ethanol/water and heating to form a solution followed by cooling to form crystals. 2. The method according to claim 1, in which the solution is heated to a temperature of 80°C. 3. The method according to claim 1, in which the solution is filtered after cooling. 4. The method according to claim 1, in which after the formation of crystals the solution is dried in vacuum. 5. The method according to claim 4, in which the solution is dried in vacuum at a temperature from 45°C to 55°C. 6. Method for obtaining the crystalline form of ((S)-2,2-difluorocyclopropyl)((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl )-3,8-diazabicyclo[3.2.1]octan-8-yl)-methanone (form 1), which is characterized by an X-ray powder diffraction pattern including peaks expressed in 2θ angles at 5.0, 9.4, 9.9, 14.8, 16.8 and 18.7° 2θ±0.2° 2θ, where the method includes the introduction of the free base ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4 -yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone into methyl isobutyl ketone and heating followed by the addition of n-heptane to form a solution, seeding the solution by introducing the free base ((S)-2,2-difluorocyclopropyl )-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -yl)methanone followed by cooling to ambient temperature to form crystals. 7. The method according to claim 6, in which the solution is heated to 75°C. 8. The method according to claim 6, in which the solution is filtered after cooling.

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