JAK inhibitors with a specific particle size distribution

Abstract

The present disclosure provides compositions of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile having specific assay values ​​and / or particle size distributions, pharmaceutical compositions containing same, methods of using same, and processes for making same.

Description

[Technical Field]

[0001] This disclosure relates to 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution, pharmaceutical compositions and processes for preparing the same, and methods for using the same, for example, for the treatment of skin conditions. [Background technology]

[0002] International Patent Publication No. 2009 / 114512 discloses certain JAK inhibitors, including the compound 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, as a trifluoroacetate, and preparations thereof as a phosphate. [Overview of the project]

[0003] There is a need for 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution that can be used effectively, safely, and reproducibly, and for methods of preparation and purification that can be used on a large scale, efficiently, and reproducibly for industrial production. In particular, there is a need for crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution that can be used effectively, safely, and reproducibly, and for methods of preparation and purification that can be used on a large scale, efficiently, and reproducibly for industrial production. More specifically, there is a need for substantially polymorphic, pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile that can be used effectively, safely, and reproducibly, and for methods for its preparation and purification that can be used on a large scale, efficiently, and reproducibly for industrial production.

[0004] In certain embodiments, the disclosure provides a substantially polymorphic pure crystalline form I of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution, and a process for producing the same. In certain preferred embodiments, the disclosure provides a substantially polymorphic pure crystalline form II of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution, and a process for producing the same. In certain embodiments, the disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution, and a process for producing the same.

[0005] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a pharmaceutical composition comprising a substantially polymorphically pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a pharmaceutical composition comprising a substantially polymorphically pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution and a pharmaceutically acceptable excipient.

[0006] In certain embodiments, the Disclosure provides a method for treating a skin condition, comprising administering to a non-human mammal in need of such treatment an effective amount of substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution. In certain preferred embodiments, the Disclosure provides a method for treating a skin condition, comprising administering to a non-human mammal in need of such treatment an effective amount of substantially polymorphically pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution. In certain embodiments, the present disclosure provides a method for treating a skin condition, comprising administering to a non-human mammal in need thereof an effective amount of substantially polymorphically pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific particle size distribution.

[0007] This disclosure provides tablets containing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile as described herein, the tablets having a specific determination value such as about 5 or less.

[0008] This disclosure provides a process for producing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having specific particle size distributions such as d50 (15-30 μm), d90 (50-80 μm), dv90 (80 μm or less), and dv50 (30 μm or less). Detailed description of the invention

[0009] This disclosure relates to a compound having a specific particle size distribution, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, its polymorphs identified herein as form I, form II, and form III, and pharmaceutical compositions thereof, as well as methods of using its polymorphs for, for example, the treatment of skin conditions, methods for producing the polymorphs, and methods for producing the compound and its intermediates.

[0010] Crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile having a specific PSD (particle size distribution) and / or a specific AV (amount value) can provide various processing advantages (e.g., good flow properties, e.g., to provide uniformity of tablet weight and content) or therapeutic advantages (e.g., a preferred PK in vivo). More specifically, the Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile described herein can provide various processing advantages (e.g., good flow properties), product advantages (e.g., to provide weight and / or content uniformity of tablets), or therapeutic advantages (e.g., a preferred PK in the in vivo profile).

[0011] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. In case of any conflict, this specification, including its definitions, shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0012] The terms “comprise(s),” “include(s),” “have,” “possess,” “can have,” and “contain,” and their variations, when used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an,” and “the” include multiple references unless the context otherwise explicitly indicates. This disclosure also contemplates other embodiments that “include,” “consist of,” and “essentially consist of,” the embodiments or elements presented herein, whether expressly described or not.

[0013] When used in relation to a measurable numerical variable, the term "approximately" refers to the given value of the variable and all values ​​of the variable that are within the experimental error of the given value or within ±10 percent of the given value (whichever is greater).

[0014] The term "acceptable excipients" typically refers to excipients used in the preparation of veterinary and pharmaceutical compositions, which should be pure and non-toxic in the amounts used. Acceptable excipients are generally solid, semi-solid, or liquid substances in which aggregates can serve as a vehicle or medium for the active ingredient. Some examples of acceptable excipients can be found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, sweeteners, flavorings, gel bases, sustained-release matrices, stabilizers, preservatives, solvents, suspenders, buffers, emulsifiers, dyes, propellants, coatings, etc.

[0015] The term "aromatic solvent" refers to benzene optionally substituted with one or two substituents selected from the group consisting of methyl, chloro, bromo, cyano, nitro, and aceto. Specifically, the term "aromatic solvent" includes nitrobenzene, chlorobenzene, toluene, xylene, and acetophenone.

[0016] 「C 1-5 The term "C alcohol" refers to straight-chain or branched-chain alkanols having 1 to 5 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, 1-butanol, ethylene glycol, 1,3-propanediol, etc.

[0017] The term "C1-C4 alkyl" refers to straight-chain or branched-chain alkyl chains having 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, etc.

[0018] 「C 2-8 The term "C alkyl ether" refers to straight-chain, branched-chain, or cyclic alkyl ethers having a total of 2 to 8 carbon atoms, such as dimethyl ether, diethyl ether, methyl t-butyl ether, THF, 2-methyl THF, dioxane, etc.

[0019] 「C 3-8 The term "C alkyl acetate" refers to straight-chain or branched-chain alkyl esters of acetic acid having a total of 3 to 8 carbons, such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, etc.

[0020] 「C 2-5 The term "C alkyl cyanide" refers to straight-chain or branched-chain alkyl cyanides having a total of 2 to 5 carbon atoms, such as acetonitrile, propionitrile, and butyronitrile.

[0021] 「C 3-9 The term "C alkyl ketone" refers to straight-chain, branched-chain, or cyclic alkyl groups having an oxo group and a total of 3 to 9 carbon atoms, such as acetone, methyl ethyl ketone, and cyclohexanone.

[0022] 「C 5-8The term "hydrocarbon" refers to linear, branched, or cyclic saturated alkyl hydrocarbons, such as pentane, hexane, heptane, octane, cyclopentane, cyclohexane, and methylcyclohexane.

[0023] The term "5-6 member heterocycle" refers to a 5-6 member monocyclic saturated ring containing oxygen atoms bonded to R1 and R2, and boron atoms bonded to those oxygen atoms.

[0024] The terms "crystallize," "crystallizing," and "crystallization" refer to precipitation and slurry processes that occur after complete dissolution, without complete dissolution. Slurry processes include those that encompass the continuation of the crystallization process following precipitation after complete dissolution.

[0025] The term "d50" or "dv50" is known as the median diameter or median of the particle size distribution, representing the particle size at 50% of the cumulative distribution. It is measured by light scattering methods, such as a Sympatec Malvern Mastersizer or Helos laser diffractometer. For example, if d50 = 10 μm, then 50% of the particles in the sample are larger than 10 μm, and 50% are smaller than 10 μm.

[0026] The terms "d90" or "dv90" refer to the particle size value at 90% of the cumulative distribution, measured by light scattering methods such as a Sympatec Malvern Mastersizer or Helos laser diffractometer. For example, if d90 = 10 μm, 90% of the particles in the sample are smaller than 10 μm.

[0027] The term "skin condition" includes skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, skin hypersensitivity (e.g., contact dermatitis or allergic contact dermatitis), pruritus including itching associated with allergic dermatitis, and allergic reactions.

[0028] The term "effective dose" refers to the amount or dose of the compound of the present invention, or a pharmaceutically acceptable amount or dose of its salt, that, when administered to a patient once or multiple times, produces the desired effect in a patient undergoing diagnosis or treatment. The effective dose can be readily determined by a person skilled in the art by the use of known techniques and by observing results obtained under similar circumstances. When determining the effective dose for a patient, several factors will be considered by the attending physician, including, but are not limited to, the patient's species, non-human mammal, size, age, and general health status, the specific disease or disorder involved, the degree or involvement or severity of the disease or disorder, the individual patient's response, the specific compound administered, the mode of administration, the bioavailability characteristics of the administered preparation, the dose regimen chosen, the use of concomitant medications, and other relevant circumstances.

[0029] "Patient," "subject," and "non-human mammal" refer to warm-blooded animals, such as dogs, cats, mice, rats, guinea pigs, rabbits, cattle, horses, sheep, goats, and pigs. Certain non-human mammals are dogs and cats, as well as pet or companion animals such as mice, guinea pigs, and rabbits. Preferred non-human mammals are dogs and cats. Preferably, the non-human mammal is a dog. Particularly preferred non-human mammal is a dog.

[0030] The term "salt" refers to salts of veterinary or pharmaceutically acceptable organic acids and bases, or inorganic acids and bases. Such salts are well known in the art and include those described in the Journal of Pharmaceutical Science, 66, 2-19 (1977). One example is hydrochloride salts. The term used herein expressly excludes trifluoroacetate salts and phosphate salts.

[0031] The term "substantially polymorphically pure" refers to a polymorphic purity of more than 90%, preferably more than 97%, more preferably more than 99%, and even more preferably more than 99.5%.

[0032] The terms “treating” or “to treat” include suppressing, slowing, halting, or reversing the progression or severity of an existing condition or disease.

[0033] The term "water activity" is expressed in terms of p / p * This is equal to the equation, where p is the partial vapor pressure of water in solution and p* is the partial vapor pressure of pure water at the same temperature.

[0034] For the purposes of enumerating numerical ranges as defined herein, each number intervening between them is explicitly intended with the same degree of precision. For example, for the range 92 to 97, in addition to 92 and 97, the digits 93, 94, 95 and 96 are intended, and the digits 92.1, 92.2, 92.3, 92.4, 92.5, 92.6, etc., to 97.0 are intended as the range.

[0035] This disclosure refers to specific embodiments or aspects. However, within the scope of this disclosure, various characteristics of embodiments and / or aspects may be combined with any characteristics disclosed in the remainder of this specification, the examples, the claims, etc.

[0036] 2.Compound Examples of compounds of the present invention include crystalline forms I, II, and III of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. The crystalline forms of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile are desired to provide pharmaceutical compositions with efficient and reproducible manufacturing of pharmaceutical formulations, as well as suitable stability.

[0037] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is also known as 2-[1-cyclopropylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile and 2-(1-cyclopropylsulfonyl-3-pyrazole-1-yl-(4-(7H-pyrrolo[2,3-d]pyrimidine azetidine-3-yl)acetrill, and is clarified by the compound of the following formula (I): [ka]

[0038] In preferred embodiments, the compound of the present invention is crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile as described herein. Crystallized form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is an anhydrous.

[0039] In another preferred embodiment, the compound of the present invention is crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile as described herein. Crystallized form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is also an anhydride.

[0040] In another preferred embodiment, the compound of the present invention is crystalline form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile as described herein. Crystallized form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is in a hydrated form.

[0041] Forms I, II, and III, as well as other polymorphic forms of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, can be characterized by X-ray diffraction. Peaks were measured using a powder diffractometer equipped with a copper source, primary beam monochromator, and position-sensing detector. The incident beam was collimated using a 1° divergence slit. The source was operated at 40 kV and 40 mA. X-ray powder diffraction data were collected from 2.5° to 50° using a step width of 0.02° and a step time of 37 sec. Alternatively, peaks were measured using a powder diffractometer equipped with a copper source, primary beam monochromator, and position-sensing detector. The incident beam was collimated using a 1° divergence slit. The source was operated at 40 kV and 40 mA. X-ray powder diffraction data were collected from 1.5° to 50° using a step width of 0.02° and a step time of 12 seconds.

[0042] It is recognized that the relative intensity of X-ray powder diffraction peaks may depend on other factors such as preferred orientation and particle size and sample preparation. While the peak intensity may change when the effects of preferred orientation and / or particle size are present, the characteristic peak positions of the polymorphs remain unchanged. See, for example, The United States Pharmacopoeia #24, National Formulary #19, pages 1843-1844 (2000). Therefore, samples of Form I, Form II, or Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile may require treatment to mitigate such factors, such as grinding the sample with agate mortar and pestle or other measures. It is understood that differences in the relative intensity of diffraction peaks do not prevent the acquired pattern from matching morphology I, morphology II, or morphology III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0043] Furthermore, it is well known in the field of crystallography that the angular peak positions can vary slightly for any given crystal morphology. For example, peak positions may change due to sample displacement or changes in temperature or relative humidity during analysis. In this case, a peak position variation of ±0.2° at 2θ will take these potential variations into account without hindering the clear identification of the crystal morphology of this disclosure.

[0044] Forms I, II, or III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile can also be characterized by differential scanning calorimetry. DSC can be performed in a closed (sealed) gold crucible or an aluminum pan with a pinhole, with the sample filled under ambient conditions or N2 flow (3-10 minutes), at a heating rate of 10°C / min from -50°C to 300°C.

[0045] Form I The crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile has the following characteristic peaks at a degree 2θ (°2θ) with a relative intensity (I / I%) exceeding about 10% of the maximum peak: 12.72° (43.1%), 14.04° (61.3%), 17.56° (20.8%), 20.33° (87.4%), 24.50° (100%), and 25.83° (94.9%) (±0.2°2θ). o / I 100 %) and was found to have the following characteristic peaks at a degree 2θ (°2θ): 12.72° (43.1%), 14.04° (61.3%), 17.56° (20.8%), 20.33° (87.4%), 24.50° (100%), and 25.83° (94.9%) (±0.2°2θ).

[0046] The present disclosure provides a substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern comprising peaks at 12.72°, 14.04°, 17.56°, 20.33°, 24.50°, or 25.83° 2θ (±0.2°2θ). More specifically, the present disclosure provides a substantially polymorphically pure form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern comprising peaks at 12.72° and 24.50° (±0.2°2θ), or at 20.33° and 24.50° (±0.2°2θ), or at 12.72° and 20.33° (±0.2°2θ).

[0047] As used herein, the term "Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile" includes the term "substantially polymorphic pure Form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile".

[0048] Style II Crystal form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (relative intensity exceeding approximately 10% of the maximum peak, I o / I 100 At degrees 2θ (°2θ) with a %) value, the following characteristic peaks were found: 5.34° (16.2%), 10.68° (26.2%), 14.26° (20.8%), 16.06° (13.5%), 16.39° (17.9%), 16.48° (18.6%), 18.26° (19.5%), 18.65° (43.4%), 19.03° (100.0%), 21.05° (10.2%), 21.15° (9.9%). %), 21.45°(9.0%), 21.76°(20.5%), 22.45°(9.6%), 22.68°(22.5%), 23.23°(11.1%), 23.7 2°(12.3%), 24.90°(11.7%), 25.08°(9.2%), 26.75°(30.7%), 31.18°(10.1%), (±0.2°2θ).

[0049] This disclosure provides a substantially polymorphically pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 19.03°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2°²θ). More specifically, the present disclosure provides substantially polymorphically pure form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, characterized by an X-ray powder diffraction pattern containing peaks at 18.65° and 10.68° (±0.2°²θ), or at 18.65° and 21.76° (±0.1°²θ), or at 26.75° and 21.76° (±0.2°²θ).

[0050] As used herein, the term "Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile" includes the term "substantially polymorphic pure Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile".

[0051] Form III Crystal form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (relative intensity exceeding approximately 10% of the maximum peak, I o / I 100At degrees 2θ (°2θ) with a %) value, the following characteristic peaks were found: 11.08° (62.3%), 12.32° (15.9%), 13.28° (13.7%), 14.06° (15.3%), 14.73° (32.8%), 17.86° (16.9%), 18.06° (46.4%), 18.27° (18.1%), 18.51° (35.2%), 18.91° (10.9%), 20.3 6°(15.8%), 21.48°(12.7%), 22.24°(26.9%), 22.69°(100%), 23.40°(10.2%), 24.76°( 18.8%), 25.48°(55.4%), 25.97°(12.6%), 26.70°(12.5%), 28.04°(12.8%), (±0.2°2θ)

[0052] This disclosure provides a substantially polymorphically pure form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile characterized by an X-ray powder diffraction pattern containing peaks at 11.08°, 14.73°, 18.06°, 18.27°, 18.51°, 22.24°, 22.69°, 24.76°, 25.48°, or 28.04° (±0.2°²θ). More specifically, the present disclosure provides substantially polymorphically pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, characterized by an X-ray powder diffraction pattern containing peaks at 11.08° and 22.69° (±0.2°2θ), 14.73° and 22.69° (±0.2°2θ), 22.69° and 25.48° (±0.2°2θ), 11.08° and 18.06° (±0.2°2θ), or 11.08° and 25.48° (±0.2°2θ).

[0053] As used herein, the term "Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile" includes the term "substantially polymorphic pure Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile".

[0054] Those skilled in the art will understand that compounds can exist as tautomers. All tautomer forms of the compounds of the present invention are intended to be within the scope of this disclosure.

[0055] The compounds of the present invention also include all isotopic changes in which at least one atom of the dominant atomic mass is replaced by an atom having the same atomic number but a different atomic mass from the dominant atomic mass. Isotope changes (e.g., deuterium, 2 The use of H) may provide greater metabolic stability. In addition, certain isotopic changes of the compounds of the present invention may be useful in drug and / or substrate tissue distribution studies of radioisotopes (e.g., tritium). 3 H, or 14 You may incorporate C). 11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 12N may be useful in positron emission topography (PET) studies.

[0056] 3. Process for creating crystal forms Morphology I process Crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile can be prepared by crystallization under controlled conditions. The disclosure also provides a process for producing substantially polymorphic pure crystalline form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, which includes crystallization from a mixture of acetone and heptane as an antisolvent. In a preferred embodiment, form I 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile can also be obtained by dehydrating the form III sample, which is typically heated under vacuum at a temperature of about 40°C to about 80°C.

[0057] Morphological II process Crystallized form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile can be prepared by crystallization from a solvent or a mixture of solvents under controlled conditions. The disclosure also provides a process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, the process comprising crystallization from a solvent, or a mixture of solvents further containing water and having a water activity of less than 0.7. In practice, preferred solvents are C 1-5 Alcohol, C 2-8 Alkyl ether, C 2-8 Alkyl acetate, C 2-5 Alkyl cyanide, C 3-9 Selected from the group consisting of alkyl ketones and aromatic solvents, each having a water activity of less than approximately 0.7.

[0058] In a preferred embodiment, the disclosure also provides a process for producing substantially polymorphic pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from a solvent, or a mixture of solvents further containing water and having a water activity of less than 0.5.

[0059] The use of an antisolvent may be advantageous. In this context, "antisolvent" refers to a solvent in which 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is significantly less soluble compared to the selected solvent. Preferably, when using an antisolvent, it is miscible with the selected solvent. While an antisolvent may be used, care must be taken to ensure that the selected antisolvent does not increase the water activity beyond the desired level.

[0060] The water activity of the substantially polymorphic, pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is understood to be temperature-dependent. Higher temperatures in the final crystallization state can tolerate higher water activity. Thus, a water activity of about 0.7 is effective at temperatures above about 40°C in the final crystallization state.

[0061] Since recovery rates may be high at low temperatures, in preferred embodiments, the disclosure also provides a process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from a solvent or a mixture of solvents having a water activity of less than 0.5. Typically, a water activity of about 0.5 is effective at a final crystallization temperature of less than about 25°C.

[0062] A preferred solvent is C 1-5 Alcohol and C 2-5 A solvent is selected from the group consisting of alkyl cyanides, each having a water activity of less than approximately 0.7. A more preferred solvent is C 1-5 Alcohol and C 2-5 Selected from the group consisting of alkyl cyanides, each having a water activity of less than approximately 0.5.

[0063] In one embodiment, the disclosure provides a process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from acetonitrile further containing water having a water activity of less than 0.7.

[0064] In another embodiment, the present disclosure provides a process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from acetonitrile further containing water having a water activity of less than 0.5.

[0065] This disclosure provides a process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from acetonitrile further containing water. Care must be taken to avoid the formation of undesirable hydrated crystalline forms. Therefore, preferred embodiments for crystallization from acetonitrile further containing water utilize a v / v ratio of 92-97 acetonitrile to 8-3 water, and more preferably crystallize from acetonitrile further containing water at a v / v ratio of 95-97 acetonitrile to 5-3 water. The use of 96:4 (v / v) acetonitrile / water has been found to have the most preferred volumetric efficiency at temperatures below about 20°C.

[0066] Therefore, a more preferred process for producing substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is to crystallize from acetonitrile further containing water in a v / v ratio of about 96 acetonitriles to about 4 waters.

[0067] Optionally, crystallization may be seeded with form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0068] Crystallization by precipitation from solutions and slurrying techniques is intended to be within the scope of this process. When crystallization involves complete dissolution, slow cooling at a rate of 0.2°C / min to 0.02°C / min is preferable. Crystallization to yield Form II does not require complete dissolution. A slurry process can be used. The slurry can be formed by processing without complete dissolution, or by processing after complete dissolution and initial precipitation. In the slurry process, the volume must be sufficient to provide a readily flowable slurry. The volume of solvent is not critical, but should be kept to a minimum for convenience. The water activity of the solvent used must take into account water, including water that may be released from the hydrated starting material. Optionally, the slurry crystallization process may be seeded with Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0069] In one embodiment, non-form II containing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is crystallized by slurry at a temperature of about 50°C or higher, and optionally cooled to recover the final product. In another embodiment, non-form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is crystallized by slurry from a solvent at a temperature of about room temperature. Optionally, crystallization may be seeded with form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. Such a slurry process generally requires 2 to 14 days.

[0070] Morphological III process Crystallized form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile can be prepared by crystallization from a solvent or a mixture of solvents under controlled conditions. The disclosure also provides a process for producing substantially polymorphically pure crystalline form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, comprising crystallization from a solvent, or a mixture of solvents further containing water and having a water activity greater than 0.9. In practice, preferred solvents are water, C 1-5 Alcohol, C 2-8 Alkyl acetate, C 2-5 Alkyl cyanide, and C 3-9 Selected from the group consisting of alkyl ketones, each possessing a water activity greater than approximately 0.9.

[0071] The use of an antisolvent may be advantageous. In this context, “antisolvent” refers to a solvent in which 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is significantly less soluble than the selected solvent(s). Preferably, when using an antisolvent, it is miscible with the selected solvent.

[0072] An antisolvent may be used, but care must be taken not to let the selected antisolvent reduce the water activity below the desired level.

[0073] A preferred solvent is C with a water activity greater than approximately 0.9. 1-5 It is selected from the group consisting of alcohols.

[0074] Crystallization from solutions and slurry techniques is intended to be within the scope of this process. When crystallization involves complete dissolution, slow cooling at a rate of 0.2°C / min to 0.02°C / min is preferable. Crystallization to yield Form III does not require complete dissolution. A slurry process can be used. The slurry can be formed by processing without complete dissolution, or by processing after complete dissolution and initial precipitation. In the slurry process, the volume must be sufficient to provide a readily flowable slurry. The volume of solvent is not important, but should be kept to a minimum for convenience. Optionally, the slurry crystallization process may be seeded with Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0075] In one embodiment, non-form III containing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is crystallized by a slurry from a solvent having a water activity greater than 0.9 at a temperature of about room temperature. Optionally, crystallization may be seeded with form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. Such a slurry process generally requires 2 to 10 days.

[0076] When drying Form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, care must be taken to avoid conversion to Form I, and the drying is preferably carried out under vacuum at a temperature below 20°C.

[0077] 4.Synthesis method This disclosure provides a process for producing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile as shown in Scheme A. [ka]

[0078] In Scheme A, Step 1, the compound of formula (1) is reacted with the compound of formula (2) in the presence of a suitable catalyst to obtain the compound of formula (3). The compound of formula (1) is a compound in which X is selected from the group consisting of tosylic acid, triflate, chloro, bromo, and iodine, and Pg is a protecting group. In practice, the compound of formula (1) in which X is bromo or chloro is preferred, and chloro is more preferred. Various protecting groups are suitable. The selection of an appropriate protecting group can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999). For example, t-BOC, 2-(trimethylsilyl)ethoxymethyl, and N-pivaloyloxymethyl are useful, to name just a few examples. In practice, the t-BOC group is preferred. The compound of formula (2) is one in which R1 and R2 are hydrogen and C 1-6 R1 and R2 are independently selected from the group consisting of alkyl groups, or together with the oxygen and boron atoms to which they are bonded, they form a 5-6 membered heterocycle, which has 1, 2, 3, or 4 carbon atoms. 1-4It is optionally substituted with an alkyl group. As will be understood by those skilled in the art, the reaction shown in step 1 is the well-known Suzuki reaction. A variety of suitable catalysts are available. Both nickel and palladium catalysts are useful, but palladium catalysts are preferred. Several suitable palladium(O) and palladium(II) catalysts are known in the art. For example, tetrakis(triphenylphosphine)palladium(O), tetrakis(triphenylphosphine)palladium(II) chloride, 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, and dichloromethane[1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (1:1).

[0079] The reaction is typically carried out in solvents containing a wide variety of organic solvents. These solvents may contain water. For example, suitable solvents include 1,4-dioxane, THF, 1-butanol, 1,2-dimethoxyethane (DME), 2-propanol, toluene, or ethanol, or combinations thereof. A typical palladium catalyst is used in amounts of approximately 0.01 to 0.1 equivalents.

[0080] The reaction is carried out in the presence of a base. Both organic and inorganic bases can be used, for example, alkali metal carbonates and alkali metal bicarbonates, as well as bases such as cesium carbonate. The reaction is typically carried out at a temperature of about 40°C to about 100°C and generally requires 1 to 18 hours.

[0081] The desired particle size for the filtered and dried compound (I) from step 2 of scheme A may be achieved, for example, using a loop-style jet mill. The jet mill may be carried out under nitrogen with, for example, a venturi-mill differential pressure of 10 psi and a material feed rate of 9.0-9.6 kg / hour.

[0082] 5. Composition This disclosure provides a composition comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof. The composition may contain particles of the compound, the particles in the composition having a specific particle size distribution.

[0083] This compound provides therapeutic benefits even at low doses. Distributing small amounts of the compound uniformly in unit dose form is problematic. This is particularly problematic when the unit dose form may be further divided, for example, when treating smaller animals. It has been surprisingly found that this compound can be effectively dispersed within unit dose form by methods described herein, such as controlling PSD.

[0084] The uniformity of the dosage unit is consistent with the United States Pharmacopeia. <905> It can be evaluated according to the following. The result is expressed as an AV (Auditory Value). This disclosure provides oral unit dose forms, such as tablets, containing the compound. The tablets may contain other substances outlined herein. The tablets may be coated as described herein. The tablets have AVs of about 5 or less, about 4.5 or less, about 4 or less, about 3.5 or less, and about 3 or less.

[0085] These tablets can be assayed via UHPLC-UV by isocratic elution for the purpose of calculating AV according to the following method. The materials and equipment listed are examples only; similar quality materials can be used. [Table 1] [Table 2] *Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile The following equipment is an example. Equipment of similar quality from other suppliers may also be used. [Table 3] As long as the concentration is maintained, all solutions can be prepared. 1. Mobile phase buffer: 0.1% phosphate, pH 3.0 2. Mobile phase: 20% acetonitrile in mobile phase buffer. 3. Diluent: 90% acetonitrile in water 4. Prepare a working standard solution for content uniformity – a solution of 6.0 μg / mL of Form II reference substance in mobile phase buffer. Sample solution Prepare 10 units. 1. Select the flask size according to Table A. [Table 4] 2.1 Place the tablets into the flask. 3. Add approximately 10% of the volume of water to the flask. Sonicate until the tablet is completely disintegrated. 4. Add 70% more acetonitrile and sonicated material. 5. After cooling to room temperature, dilute by volume with acetonitrile. 6. Transfer 1.0 mL of this stock sample solution to a volumetric flask of the appropriate size (see Table A) and dilute it to volume with mobile phase buffer. 7. Filter the aliquots into an HPLC vial (working sample solution). 8. Inject into the HPLC system. [Table 5] calculation The content of Form II will be evaluated as a percentage of the published content. USP for 10 individuals <905> The uniformity of content is calculated using the method described above.

[0086] This disclosure provides a composition comprising particles of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof, wherein the particles in the composition have a particle size distribution characterized by d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less.

[0087] A composition comprising particles of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof, wherein the particles in the composition have a specific particle size distribution and can be prepared by methods known in the art (for example, size reduction or micronization of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof can be performed using any of the conventional mills, such as wet milling, jet mills, ball mills, colloidal mills, grinding mills, roller mills, impact mills, cryomills, or preferably wet milling and jet mills). In certain embodiments, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof may be wet-ground in any suitable aqueous, non-aqueous, or organic solvent (e.g., oil). In certain embodiments, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof may be dry-ground. In certain embodiments, 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof may be jet-milled.

[0088] 6. Pharmaceutical Compositions In practice, the compound is usually administered in the form of a composition, i.e., a mixture with at least one acceptable excipient. The proportion and nature of any acceptable excipient are determined by the properties of the selected compound, the selected route of administration, and the standard practice in the fields of veterinary medicine and pharmacy.

[0089] This disclosure provides a pharmaceutical composition comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof and an acceptable excipient. The composition may contain particles of the compound having a particle size distribution of d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. In a preferred embodiment, the present disclosure provides a pharmaceutical composition comprising particles of crystalline form I, form II, or form III 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and an acceptable excipient, wherein the particles in the composition have a particle size distribution of d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. In another preferred embodiment, the present disclosure provides a pharmaceutical composition comprising particles of crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and at least one acceptable excipient, wherein the particles in the composition have a particle size distribution of d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. In another preferred embodiment, the present disclosure provides a pharmaceutical composition comprising substantially polymorphically pure crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile and particles of at least one acceptable excipient, wherein the particles in the composition have a particle size distribution of d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less.

[0090] The composition may also be in the form of tablets containing 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof. The tablets may have an AV of 5 or less, 4.5 or less, 4 or less, 3.5 or less, or 3 or less for 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof.

[0091] When administering treatment to subjects requiring such treatment, the composition may be administered in any form and via any route that makes the compound bioavailable.

[0092] This composition can be administered orally, particularly by various routes including tablets and capsules. Other routes of administration include parenteral routes, more specifically inhalation, subcutaneous, intramuscular, intravenous, intra-arterial, percutaneous, intranasal, intrarectal, intravaginal, intraocular, topical, sublingual, and oral cavity, intraperitoneal, intrafat, intrathecal, and topical delivery, such as by catheter or stent.

[0093] Those skilled in the art can easily select an appropriate dosage form and route of administration depending on the specific characteristics of the selected composition, the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions described herein may be administered to a patient in the form of, for example, tablets, capsules, pouches (cachet), paper, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, injections, and suspensions.

[0094] In one embodiment, the composition is adapted for oral administration, such as in tablets. In one embodiment, the composition is adapted for oral administration, such as in a chewable formulation adapted for oral administration.

[0095] The composition is prepared in a manner well known in the fields of veterinary medicine and pharmacy and contains at least one of the compounds present as an active ingredient. The amount of the compound of the disclosure in the composition may vary depending on its particular form and may conveniently be 1% to about 50% of the weight of the unit dose form. The composition is preferably formulated in unit dose forms, each dose typically containing about 0.25 mg to about 20 mg of the compound of the present invention. For example, about 1 mg to about 20 mg, about 2 mg to about 17 mg, and about 2.4 mg to about 15 mg. It may be in the form of one or more unit dose forms to affect the therapeutic dose.

[0096] This composition may also be in oral dosage form. Preferably, it contains 2.4 mg, 3.6 mg, 4.8 mg, 5.4 mg, 6.4 mg, 8.5 mg, 15 mg, or 16 mg of the compound. Oral dosage forms containing 4.8 mg, 6.4 mg, 8.5 mg, or 15 mg of the compound having a specific AV and / or PSD are preferred.

[0097] The oral dosage form may be a tablet. The tablet is preferably coated. For example, the coating may be selected from commercially available coating mixtures acceptable for the intended use herein. One preferred coating mixture is Opadry®, available from Colorcon GmbH, Buchwiese 18D-65510 Idstein, Germany.

[0098] The composition preferably comprises microcrystalline cellulose, pregelatinized starch, calcium phosphate dibasic dihydrate, povidone, magnesium stearate, a coating, or any combination thereof. The composition preferably comprises pregelatinized starch.

[0099] 7.How to use This disclosure provides a method for treating a skin condition, comprising administering an effective amount of the compound or composition to a non-human mammal in need thereof.

[0100] This disclosure provides a method for treating skin conditions (e.g., psoriasis (e.g., skin disorders, e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, skin hypersensitivity (e.g., contact dermatitis or allergic contact dermatitis), itching including itching associated with allergic dermatitis, and allergic reactions) comprising administering an effective amount of the composition disclosed herein to a non-human mammal in need thereof. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months of age, or at least 12 months of age.

[0101] In a preferred embodiment, the present disclosure provides a method for treating atopic dermatitis, comprising administering an effective amount of the composition disclosed herein to a non-human mammal in need thereof. The preferred non-human mammal is a dog. In a particular embodiment, the dog is at least 9 months of age, or at least 12 months of age.

[0102] In a preferred embodiment, the present disclosure provides a method for treating pruritus associated with allergic dermatitis, comprising administering an effective amount of the composition disclosed herein to a non-human mammal in need thereof. The preferred non-human mammal is a dog. In a particular embodiment, the dog is at least 9 months of age, or at least 12 months of age.

[0103] In certain embodiments, the Disclosure provides a method for treating skin conditions (e.g., skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, skin hypersensitivity (e.g., contact dermatitis or allergic contact dermatitis), pruritus including itching associated with allergic dermatitis, and allergic reactions) to a non-human mammal in need thereof, comprising administering an effective amount of a composition disclosed herein, comprising 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile or a salt thereof. The composition comprises particles of the compound having a particle size distribution of d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. The composition may have AV as described herein. A preferred non-human mammal is a dog. In certain embodiments, the dog is at least 9 months old, or at least 12 months old.

[0104] The effective dose of the compound of the present invention may be in the range of 0.25 mg to 100 mg. The specific amount can be determined by those skilled in the art. These doses are based on subjects with a mass of about 0.5 kg to about 80 kg, but a diagnostician may determine an appropriate dose for subjects whose mass falls outside this weight range. Effective doses may be in the range of, for example, 0.2 mg to 1.2 mg / kg for patients, 0.4 mg to 1.0 mg / kg for patients, 0.6 mg to 0.9 mg / kg for patients, and 0.8 mg / kg for patients. The dosing regimen may be once daily, twice daily, once weekly, or once monthly. 8. Examples The following examples are provided to illustrate the present invention and are not intended to limit it in any way.

[0105] Example 1 2-[1-(cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile 850 g of 2-(1-cyclopropylsulfonylazetidine-3-ylidene)acetonitrile and 874 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were combined in 2.6 L of acetonitrile. 65 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and the mixture was heated to 70°C. After 2.5 hours, the reaction mixture was cooled to ambient temperature over approximately 2 hours. 5.2 L of water was slowly added to the mixture over approximately 1 hour, and the mixture was stirred over approximately 3 hours. The formed solid was collected by filtration and dried in a vacuum at 45°C for approximately 24 hours to obtain 2-[1-(cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile.

[0106] Example 2 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile

[0107] Potassium phosphate (829 g) was mixed with water (1 L) and cooled to ambient temperature. THF (2 L) was added. 4-chloropyrrolo[2,3-d]pyrimidine (200 g) was added, followed by di-tert-butyl dicarbonate (344 g). The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was sparged with nitrogen gas for 60 minutes. 562 g of 2-[1-(cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile and 6.6 g of Pd-134 were added, and the reaction temperature was raised to 60°C. After about 2 hours, the aqueous layer was separated, 40 g of silicathiol was added, and the reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was filtered at 60°C, and the filtrate was stirred and cooled to 10-20°C to obtain a solid. This solid was collected by filtration, rinsed with cold THF, and dried under vacuum at 40-50°C for 2 hours to obtain tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (540 g).

[0108] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate obtained above (540 g) was mixed with n-butanol (3 L) and water (770 mL) and heated to 90°C. After 6 hours, the reaction mixture was cooled to 80°C within 30 minutes, then stirred at 80°C for 30 minutes, cooled to 20°C over 6 hours, and stirred at 10-20°C for 16 hours to obtain a solid, which was filtered to obtain 460 g of the title compound (as a wet cake).

[0109] Example 3 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile

[0110] Potassium phosphate (829 g) was mixed with water (1 L) and cooled to ambient temperature. THF (2 L) was added. 4-chloropyrrolo[2,3-d]pyrimidine (200 g) was added, followed by di-tert-butyl dicarbonate (344 g). The reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was sparged with nitrogen gas for 60 minutes. 562 g of 2-[1-(cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile and 6.6 g of Pd-134 were added, and the reaction temperature was raised to 60°C. After about 2 hours, the aqueous layer was separated, 40 g of silicathiol was added, and the reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was filtered at 60°C, and the filtrate was stirred and cooled to 10-20°C to obtain a solid. The solid was collected by filtration, rinsed with cold THF, and dried under vacuum at 40-50°C for 2 hours to obtain tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (525 g).

[0111] The tert-butyl 4-[1-[3-(cyanomethyl)-1-cyclopropylsulfonyl-azetidine-3-yl]pyrazole-4-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate obtained above (540 g) was mixed with n-butanol (3 L) and water (770 mL) and heated to 90°C. After 6 hours, the reaction mixture was cooled to 80°C within 30 minutes, then stirred at 80°C for 30 minutes, cooled to 20°C over 6 hours, and stirred at 10-20°C for 16 hours to obtain a solid, which was filtered to obtain 454 g of the title compound (as a wet cake).

[0112] Example 4 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0113] The moist cakes (approximately 907 g) from Examples 2 and 3 were mixed in acetonitrile (4 L) and stirred at 60°C for 2 hours. The reaction mixture was cooled to 20°C over 6 hours, and then stirred at 20°C for 12 hours. The solid was collected by filtration, rinsed with acetonitrile, and dried under vacuum at 50-60°C for 24 hours to obtain the title compound (695 g).

[0114] Example 5 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form I

[0115] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (104.1 mg) was mixed with acetone (8 mL) and heated to 55°C. After 30 minutes, the reaction mixture was cooled to 30°C at a rate of 0.02°C / min, then to 5°C at a rate of 0.1°C / min, while simultaneously adding heptane (12 mL) at a rate of 2.94 mL / hour to obtain a solid. This solid was collected by filtration and dried to obtain the title compound (79.5 mg).

[0116] Example 6 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0117] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (152.4 mg) was mixed with acetonitrile (8.1 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled to 5°C at a rate of 0.05°C / min to obtain a solid. The solid was collected by filtration and dried to obtain the title compound (93.4 mg).

[0118] Example 7 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0119] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (157.8 mg) was mixed with acetonitrile / water 96:4 (v / v) (4.2 mL) and heated to 80°C. After 30 minutes, the reaction mixture was cooled to 5°C at a rate of 0.05°C / min to obtain a solid. The solid was collected by filtration and dried to obtain the title compound (89.4 mg).

[0120] Example 8 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0121] 5 g of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was mixed with acetonitrile / water 96:4 (v / v) (100 mL) and heated to 80°C. After about 75 minutes, the reaction mixture was cooled to 70°C at a rate of 0.20°C / min, then seeds (two portions of 0.25 g) were added, and cooling was continued to 8°C at a rate of 0.05°C / min to obtain a solid. After about 6 hours, the solid was collected by filtration and dried to obtain the title compound (4.88 g).

[0122] Example 9 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0123] (2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (20.6 mg) was mixed with 4:1 (v / v) methanol / water (0.3 mL) having a water activity of approximately 0.5, stirred at 25°C for 4 days, then 4:1 (v / v) methanol / water (0.5 mL) was added, and stirring continued at 25°C for 6 days. The solid was then collected by filtration centrifugation (3 minutes, 5000 rpm, 0.2 μm PVDF membrane) to obtain the title compound.

[0124] Example 10 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0125] 10 g of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was mixed with 250 mL of acetonitrile / water 96:4 (v / v) and heated to 72°C. After about 60 minutes, the reaction mixture was cooled to 65°C at a rate of 0.20°C / min, then 0.10 g of seeds were added, and the mixture was cooled to 35°C at a rate of 0.035°C / min to obtain a solid, and then cooled to 5°C at a rate of 0.125°C / min to obtain a solid. After about 3 hours, the solid was collected by filtration and dried to obtain the title compound (8.51 g).

[0126] Example 11 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0127] 70.3 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was combined with 0.2 mL of 9:1 (v / v) acetone / water and heated to 60°C with stirring. An additional 1.6 mL of 9:1 (v / v) acetone / water was gradually added. After maintaining the temperature at 60°C for 1.5 hours, the mixture was cooled to 10°C at a rate of 0.05°C / min and held at 10°C for 2 hours and 45 minutes to obtain a solid. The solid was collected by filtration centrifugation (2 minutes, 5000 rpm) to obtain the title compound.

[0128] Example 12 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0129] 149.8 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was combined with 8.0 mL of acetonitrile and heated to 80°C. After 30 minutes, the reaction mixture was cooled to 55°C at a rate of 0.02°C / min. The reaction mixture was then cooled at a rate of 0.1°C / min over a range of 55°C to 5°C, while simultaneously adding a total of 12 mL of isopropyl acetate at a rate of 1.44 mL / hour over the same period as the cooling gradient from 55°C to 5°C to obtain a solid, which was collected by filtration and dried to obtain the title compound (94.2 mg).

[0130] Example 13 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0131] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (208.5 mg) was combined with 0.2 mL of 3:1 (v / v) methanol / water and heated to 60°C with stirring. An additional 23.2 mL of 3:1 (v / v) methanol / water was gradually added. After maintaining the temperature at 60°C for 30 minutes, the mixture was cooled to 10°C at a rate of 0.05°C / min and held at 10°C for 20 minutes to obtain a solid. The solid was collected by filtration to obtain the title compound.

[0132] Example 14 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0133] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60 mg) was mixed with 5:1(v / v)1-butanol / water having a water activity of approximately 0.9, stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0134] Example 15 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0135] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (33 mg) was mixed with 0.4 mL of 3:2 (v / v) methanol / water having a water activity of approximately 0.7, stirred at approximately 20°C for 14 days, and then the solid was collected by filtration centrifugation (2 minutes, 4400 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0136] Example 16 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0137] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.4 mg) was mixed with acetophenone (1 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0138] Example 17 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0139] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (59.9 mg) was mixed with butyronitrile (2 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0140] Example 18 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0141] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.3 mg) was mixed with cyclohexanone (1.5 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0142] Example 19 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0143] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.9 mg) was mixed with dioxane (2 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0144] Example 20 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0145] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.0 mg) was mixed with ethyl formate (1.5 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0146] Example 21 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0147] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (59.4 mg) was mixed with methyl acetate (1.5 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0148] Example 22 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0149] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.5 mg) was mixed with nitrobenzene (2 mL), stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0150] Example 23 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0151] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.5 mg) was mixed with anisole (0.6 mL), stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0152] Example 24 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0153] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (59.8 mg) was mixed with ethyl formate (0.6 mL), stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.22 μm PVDF membrane) to obtain the title compound.

[0154] Example 25 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0155] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.5 mg) was mixed with isopropyl acetate (0.6 mL), stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.22 μm PVDF membrane) to obtain the title compound.

[0156] Example 26 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0157] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.4 mg) was mixed with isopentanol (1 mL), stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0158] Example 27 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0159] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.4 mg) was mixed with methyl isobutyl ketone (1 mL), stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.22 μm PTFE membrane) to obtain the title compound.

[0160] Example 28 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0161] 60.6 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was mixed with approximately 0.7 (0.9 mL) of 3:1 (v / v) ethanol / water having a water activity, stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 2 μm PVDF membrane) to obtain the title compound.

[0162] Example 29 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0163] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (69.7 mg) was mixed with 1-propanol (10.8 mL) and heated to 60°C with stirring. Dimethyl sulfoxide (2 mL) was slowly added to the mixture of 1-propanol / DMSO in a ratio of approximately 85:15 (v / v). The temperature was maintained at 60°C for approximately 1.5 hours, then the mixture was cooled to 10°C at a rate of 0.05°C / min, maintained at 10°C for 7.5 hours, then 1-propanol (5 mL) was added, and the mixture was stirred at 5°C for 10 days to obtain the title compound, which was collected by filtration.

[0164] Example 30 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0165] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (70.6 mg) was mixed with ethyl acetate saturated with water (0.2 mL), heated to 60°C with stirring, then ethyl acetate (7.2 mL) was added, and the mixture was stirred at 60°C for about 1.5 hours. The mixture was then cooled to 10°C at a rate of 0.05°C / min, and the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0166] Example 31 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0167] 199.6 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was mixed with ethyl acetate saturated with water (2.0 mL), stirred at room temperature for 2 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0168] Example 32 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form I

[0169] By drying under vacuum at 60°C for approximately 69 hours, the title compound was obtained, which is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III obtained from the material of Example 31.

[0170] Example 33 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0171] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.3 mg) was mixed with ethanol (1 mL), stirred at 5°C for 7 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0172] Example 34 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0173] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.4 mg) was mixed with methanol (1 mL), stirred at 5°C for 7 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0174] Example 35 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0175] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.0 mg) was mixed with isopropanol (1 mL), stirred at 5°C for 7 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0176] Example 36 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0177] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.3 mg) was mixed with 1-butanol (2 mL), stirred at 5°C for 7 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0178] Example 37 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0179] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (59.6 mg) was combined with ethanol (1 mL), stirred at 60°C for 5 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0180] Example 38 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0181] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (59.9 mg) was mixed with methanol (1 mL), stirred at 60°C for 5 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0182] Example 39 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0183] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.1 mg) was mixed with isopropanol (1.5 mL), stirred at 60°C for 5 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0184] Example 40 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0185] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.6 mg) was mixed with 1-butanol (1.5 mL), stirred at 60°C for 5 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.45 μm PVDF membrane) to obtain the title compound.

[0186] Example 41 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0187] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (10.4 mg) was mixed with acetonitrile (0.5 mL), stirred at 20°C for 1 day, and then the solid was collected by filtration centrifugation (1 minute, 4500 g rcf, 0.2 μm PTFE membrane) to obtain the title compound.

[0188] Example 42 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0189] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (10.3 mg) was mixed with acetone (0.5 mL), stirred at 20°C for 1 day, and then the solid was collected by filtration centrifugation (2 minutes, 4000 g rcf, 0.2 μm PTFE membrane) to obtain the title compound.

[0190] Example 43 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0191] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (20.6 mg) was mixed with approximately 0.5 (0.4 mL) of 4:1 (v / v) methanol / water having a water activity, stirred at 25°C for 4 days, then 0.5 mL of 4:1 (v / v) methanol / water was added, stirred at 25°C for 6 days, and the solid was collected by filter centrifugation (3 minutes, 5000 rpm, 0.2 μm PVDF membrane) to obtain the title compound.

[0192] Example 44 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0193] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (539.9 mg) was mixed with 1:1 (v / v) ethanol / acetone (18 mL), stirred at 60°C for 45 minutes, then cooled to 5°C at a rate of 0.05°C / min, collected by filtration, and dried under vacuum at 40°C to obtain the title compound.

[0194] Example 45 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form II

[0195] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (256.1 mg) was mixed with 7:3 (v / v) acetone / isopropyl acetate (13.5 mL), stirred at 60°C for 1 hour, then cooled to 5°C at a rate of 0.02°C / min, collected by filtration, and dried under vacuum at 40°C to obtain the title compound.

[0196] Example 46 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0197] 60 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile was mixed with 2 mL of 5:1(v / v)1-butanol / water having a water activity of approximately 0.9, stirred at room temperature for 10 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0198] Example 47 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile form III

[0199] 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (60.1 mg) was mixed with approximately 0.9 mL of 1:1 (v / v) acetonitrile / water having a water activity, stirred at 40°C for 6 days, and then the solid was collected by filtration centrifugation (2 minutes, 5000 rpm, 0.2 μm PTFE membrane) to obtain the title compound.

[0200] Example 48 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile [ka]

[0201] 4-chloropyrrolo[2,3-d]pyrimidine (100g) and THF (890g) were packed into reactor 2. The mixture was stirred at 20-30°C until all solids were dissolved. Pre-melted Boc2O (248.7g) and THF (534g) were packed into reactor 1. Then, KOtBu (11.0g) was slowly added to reactor 1 at 17-27°C and rinsed with THF (89g). The mixture in reactor 1 was stirred at 17-27°C for 10-20 minutes. The solution in reactor 2 was transferred to reactor 1 over 1-2 hours at 17-27°C. Reactor 2 was rinsed with THF (89g) and the washing solution was transferred to reactor 1. The mixture in reactor 1 was stirred at 17-27°C for 1-3 hours until the reaction was complete. After degassing with N2 for 30-60 minutes, H2O (500g) and K3PO4·3H2O (433.5g) were packed into reactor 1 at 17-27°C. The reaction mixture was degassed with 2-[1-(cyclopropylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-yl]azetidine-3-yl]acetonitrile (263.1 g), and PdCl2-Xtranphos (2.46 g) was added to reactor 1 under N2 protection. The resulting mixture was changed with N2 three times and then stirred at 50-60°C for 1-3 hours until the reaction was complete. After standing at 50-60°C for 20-40 minutes, the aqueous phase was separated and discarded. The reaction mixture was washed once with 10% KCl solution (640 g) and then twice with water (500 g). The organic layer was concentrated to 12-13V by atmospheric distillation at ≤75°C. The reaction was carried out as follows: Acetonitrile (1943g) was added to reactor 1, and the organic layer was concentrated to 20-30V by atmospheric distillation at ≤85°C. Acetonitrile (1476g) was added to reactor 1, and the organic layer was concentrated to 20-30V by atmospheric distillation at ≤85°C. The residual THF was checked and confirmed to have reached the judgment level of ≤1%. Water (300g) and silicathiol (20.0g) were added to reactor 1, and the reaction mixture was heated to 70-80°C. The mixture was stirred at 70-80°C for 18-24 minutes until the reaction was complete. The reaction mixture was cooled to 60-70°C and filtered into reactor 3 through a diatomaceous earth (20g) bed. Reactor 1 was rinsed with acetonitrile (540g), and the washing solution was filtered into reactor 3.The mixture in reactor 3 was concentrated to 31-33V by atmospheric distillation at 70-85°C. Acetonitrile (1554g) was added to reactor 3 by continuous atmospheric distillation at 70-85°C. Seed (0.5g) was packed in and stirred at 70-85°C for 30-60 minutes. Optional acetonitrile (389g) was packed into reactor 3 by continuous atmospheric distillation at 70-85°C to ensure KF ≤ 4.0%. The reaction mixture was cooled to 15-25°C over 5-7 hours, and then aged for a further 2-4 hours to obtain a filtered solid, which was washed with acetonitrile (311g). The moist cake was dried under vacuum at 45-55°C for 20-24 hours to obtain the title compound (227g). Note: The amount of material used in Example 48 is the nominal amount of a batch containing 9.0 kg of 4-chloropyrrolo[2,3-d]pyrimidine as the input limiting reagent.

[0202] Example 49 Control of pruritus and skin lesions associated with allergic dermatitis in dogs.

[0203] This study evaluated 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile for controlling pruritus and skin lesions associated with allergic dermatitis in dogs.

[0204] Oral tablets containing Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile were prepared as follows: An oral tablet blend containing crystalline Form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate dihydrate, oxide pigment, and magnesium stearate was prepared. The tablet blend was pressed to obtain tablet cores containing 2.4 mg, 3.6 mg, 5.4 mg, and 16 mg of crystalline form II 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, as well as a placebo core. The tablet cores were coated with a mixture containing water and Opadry 20A150011 Red, thereby obtaining the final oral tablets for this study. [Table 6]

[0205] A four-group, blinded, randomized, placebo-controlled trial was conducted to evaluate the efficacy of daily administration of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile for the control of pruritus and skin lesions associated with allergic dermatitis in dogs. Subjects were randomly assigned to one of the following treatment groups: API-containing tablets 0.25–0.40 mg / kg body weight, API-containing tablets 0.40–0.60 mg / kg body weight, API-containing tablets 0.60–0.80 mg / kg body weight, and placebo tablets 0.0 mg / kg body weight.

[0206] Dogs enrolled in the study received treatment once daily for approximately 28 days. Baseline data (clinical history, combination therapy, body weight, physical examination, and assessment of pruritus and atopic dermatitis) were collected for each dog at enrollment (day 0). Additional health assessments, physical examinations, body weight measurements, assessments of pruritus and atopic dermatitis, and collection of blood samples for hematological, serological, and pharmacokinetic (PK) analysis were performed in accordance with the standard study protocol.

[0207] The primary efficacy variable was treatment success. Treatment success was defined as a reduction of at least two units from baseline in the pruritus visual analog scale (VAS), as assessed by the owner, for at least 70% of the first seven days of treatment (i.e., at least five days of the first seven days of treatment). Dogs that withdrew from the study within the first seven days of treatment due to perceived lack of efficacy were considered treatment failures. The minimum effective dose was defined in the protocol as the dose at which treatment success was achieved in at least 50% of the dogs.

[0208] Table 2 shows that the response rate for the highest dose of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile (0.60-0.80 mg / kg) was 0.7188 (95% confidence interval 0.5331, 0.8512), which is statistically significantly higher than the placebo response rate of 0.2935 (0.1571, 0.4808), with a p-value (on the logit scale) of 0.0006. Therefore, the highest dose group (0.6-0.8 mg / kg) achieved the primary endpoint for treatment success. Furthermore, once-daily administration of 0.6-0.8 mg / kg showed a significant improvement in pruritus from the first dose, and the group showed a significant improvement in lesion scores on day 28 of the study. The estimated limit mean response rates for both low-dose (0.24–0.4 mg / kg) and medium-dose (0.4–0.6 mg / kg) were also higher than the placebo rate. These results are based on a generalized linear mixed model with a fixed-effect condition for treatment and a VAS score on day 0. Random effects were fitted to site and site treatment with variance component covariance structures, while composite symmetric covariance structures were fitted to individual dogs. [Table 7] Example 50 Micronization was performed using a feed rate of 9.6 kg / hour, starting with a short "setup" run of approximately 300 grams. The venturi / mill differential pressure was 10 psi. The sample drawn from this run (sample "I") had a dv10 value of 4, a dv50 value of 20, and a dv90 value of 53.

[0209] Example 51 A method for determining the particle size distribution of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

[0210] Method: Disperse 150-175 mg of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile sample into a paste in a beaker with 1 ml of Tween 20 / water mixture (10 / 90 v / v%). Next, transfer the entire paste to a measuring cuvette (rinse the beaker with water for complete sample transfer) and disperse in 300 ml of water. Set the pump speed to 600 rpm to homogenize the suspension in the measuring cuvette. Stir the sample for 30 seconds before measurement. The optical density should be in the range of approximately 15-20%, but the value strongly depends on the particle size distribution in the sample. If the range of 15-20% is not reached, more sample paste should be added or the sample should be diluted with water.

[0211] Instrument: A Sympatec Helos laser diffractometer was used. Suspensions were measured using a Quixel cell. Dry measurements were performed using a Rodos unit. Evaluation was performed using Paqxos software. Using this PSD method, the manufactured and ground material as in Example 50 was analyzed, and the results were a dv10 value of 4, a dv50 value of 20, and a dv90 value of 51. [Table 8] The present invention includes the following embodiments. [1] A tablet comprising polymorphically pure crystals of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, wherein the tablet has a determination value of 5 or less. [2] The tablet according to [1], wherein the tablet has a judgment value of 3.5 or less. [3] The tablet according to [1], wherein the substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2°²θ). [4] The tablet according to [1], wherein the tablet is coated. [5] The tablet according to [1], wherein the substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is in the form of particles having a particle size distribution characterized by d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. [6] The tablet according to [1], comprising 1 mg to 20 mg of substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. [7] The tablet according to [1], wherein the tablet contains 4.8 mg, 6.4 mg, 8.5 mg, or 15 mg of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile. [8] A composition comprising substantially polymorphic pure crystalline particles of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, wherein the particles have a particle size distribution characterized by d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less. [9] The composition according to [8], wherein the substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2°²θ).

[10] The composition according to [8], further comprising microcrystalline cellulose, pregelatinized starch, calcium phosphate dibasic dihydrate, povidone, magnesium stearate, a coating, or any combination thereof.

[11] The composition according to [8], wherein the composition is in oral dosage form.

[12] The composition according to

[11] , wherein the oral dosage form comprises 1 mg to 20 mg of substantially polymorphically pure crystals of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, having a particle size distribution characterized by d50 of 15 to 30 μm, d90 of 50 to 80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less.

[13] The composition according to

[11] , wherein the oral dosage form comprises 4.8 mg, 6.4 mg, 8.5 mg, or 15 mg of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, having a particle size distribution characterized by d50 of 15-30 μm, d90 of 50-80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less.

[14] A method for treating a skin condition, comprising administering an effective amount of the tablet described in [1] or the composition described in [8] to a non-human mammal in need thereof.

[15] The method according to

[14] , wherein the skin condition is atopic dermatitis or pruritus.

[16] The method according to

[14] , wherein the non-human mammal is a dog.

Claims

1. A composition comprising substantially polymorphic pure crystalline particles of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, wherein the particles have a particle size distribution characterized by d50 of 15 to 30 μm, d90 of 50 to 80 μm, dv90 of 80 μm or less, and dv50 of 30 μm or less.

2. The composition according to claim 1, wherein the substantially polymorphic pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern containing peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2°²θ).

3. The composition according to claim 1 or 2, wherein the composition further comprises microcrystalline cellulose, pregelatinized starch, calcium phosphate dibasic dihydrate, povidone, magnesium stearate, a coating, or any combination thereof.

4. The composition according to claim 1 or 2, wherein the composition is in oral dosage form.

5. The composition according to claim 4, wherein the oral dosage form contains 1 mg to 20 mg of substantially polymorphically pure crystals of 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, having a particle size distribution characterized by a d50 of 15 to 30 μm, a d90 of 50 to 80 μm, a dv90 of 80 μm or less, and a dv50 of 30 μm or less.

6. The composition according to claim 4, wherein the oral dosage form contains 4.8 mg, 6.4 mg, 8.5 mg, or 15 mg of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile, having a particle size distribution characterized by a d50 of 15 to 30 μm, a d90 of 50 to 80 μm, a dv90 of 80 μm or less, and a dv50 of 30 μm or less.

7. A method for treating a skin condition, comprising administering an effective amount of the composition according to claim 1 to a non-human mammal in need thereof.

8. The method according to claim 7, wherein the skin condition is atopic dermatitis or itching.

9. The method according to claim 7, wherein the skin condition is a skin disorder associated with allergic dermatitis.

10. The method according to claim 7, wherein the non-human mammal is a dog.

11. The composition according to claim 4, wherein the oral dosage form is a tablet having a determination value of 5 or less.

12. The composition according to claim 11, wherein the tablet is coated.

13. The composition according to claim 11, wherein the tablet contains 1 mg to 20 mg of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

14. The composition according to claim 11, wherein the tablet contains 4.8 mg, 6.4 mg, 8.5 mg, or 15 mg of substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile.

15. The composition according to claim 11, wherein the substantially polymorphically pure crystalline 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-1H-pyrazole-1-yl)-1-(cyclopropylsulfonyl)azetidine-3-yl)acetonitrile is characterized by an X-ray powder diffraction pattern including peaks at 5.34°, 10.68°, 14.26°, 16.06°, 16.39°, 16.48°, 18.26°, 18.65°, 21.05°, 21.76°, 22.68°, or 26.75° (±0.2°²θ).

Images