Cocrystals of n-{cis-3-[methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide

Abstract

The present invention relates to cocrystals of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1-sulfonamide, to a method for obtaining said cocrystals, and to pharmaceutical compositions comprising said cocrystals, and to the medical uses thereof, particularly for the treatment or prevention of diseases that are known to improve by inhibiting the Janus kinase 1 enzyme.

Description

[0001] DESCRIPTION

[0002] Cocrystals of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide

[0003] Field of the Invention

[0004] The present invention relates to novel cocrystals of N-{cis-3-[methyl(7 / 7-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide, which is a selective Janus kinase 1 (JAK1) enzyme inhibitor. Said cocrystals are useful for the treatment or prevention of diseases that are known to improve by inhibiting the Janus kinase 1 enzyme.

[0005] Background of the Invention

[0006] Selective Janus kinase 1 enzyme inhibitors have been proposed for the treatment of cancer and inflammatory diseases such as rheumatoid arthritis and various skin conditions.

[0007] N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide, with the international non-proprietary name abrocitinib, is a selective Janus kinase 1 enzyme inhibitor that has been approved by the EMA and the FDA under the name Cibinqo® for the treatment of atopic dermatitis.

[0008] Specifically, patent application WO 2014 / 128591 A1 discloses pyrrolo[2,3-d]pyrimidine derivatives as Janus kinase inhibitors useful in the treatment of various immune disorders. Said patent application discloses N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1-sulfonamide the structure of which is shown below:

[0009] Abrocitinib

[0010] Patent application WO 2020 / 008391 A1 discloses obtaining a crystalline form of abrocitinib (also referred to as PF-04965842), as well as different crystalline forms of abrocitinib hydrochloride, as well as different salts in crystalline form of abrocitinib with sulfuric, methylsulfonic, and p-toluenesulfonic acids. The crystalline form of abrocitinib is an anhydrous form known as Form I, which is used in the formulation of the medicinal product Cibinqo®, marketed by Pfizer. Patent application EP 4 144 737 A1 describes five novel crystalline forms (Forms B-F) of abrocitinib, as well as the preparation of the crystalline form referred to as form A, which matches the crystalline form disclosed in WO 2020 / 008391 A1.

[0011] None of the aforementioned documents discloses cocrystals of N-{cis-3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide derivatives.

[0012] Although N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide has shown suitable pharmacological activity, there seems to be room for improvement in terms of the physical and / or pharmacological properties of said compound, particularly its hygroscopicity and solubility. The improvement of said properties would help in further pharmaceutical development for medicinal product formulation.

[0013] Therefore, there is a need in the art to provide a method for improving the hygroscopicity and / or solubility of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide.

[0014] Therefore, it is highly desirable to develop pharmaceutically acceptable, soluble, and stable forms of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide with improved hygroscopicity and / or solubility. The present invention addresses such problems.

[0015] Cocrystals can be differentiated from salts because, unlike salts, the components that coexist in the crystal lattice of the cocrystal with a defined stoichiometry interact in a non-ionic manner. Generally, it is considered that when an active pharmaceutical ingredient (API) and its cocrystal-forming compound (coformer) have a ApKa (ApKa= pKa (conjugate acid of base) - pKa (acid)) < 1 , there will be a less than substantial proton transfer. If this criterion is met, the API-coformer entity should be classified as a cocrystal (Regulatory Classification of Pharmaceutical Cocrystals Guidance for Industry, February 2018, http: / / www.fda.gov / Drugs / GuidanceComplianceRegulatorylnformation / Guidances / default.htm )■

[0016] Several properties can be altered by means of cocrystal formation, such as melting point, considered one of the first physicochemical properties to be taken into account, storage stability, solubility, dissolution rate, hygroscopicity, and bioavailability, among others (Izutsu, K et al., Characterization and Quality Control of Pharmaceutical Cocrystals, Chem. Pharm. Bull. 64, 1421-1430 (2016)).

[0017] Given the availability of a large number of pharmaceutically acceptable coformers and the lack of correlation between the nature of a pharmaceutically acceptable coformer and the final properties of the corresponding cocrystal, finding suitable cocrystals is a complicated method, and its results cannot be predicted a priori.

[0018] There is a need to provide cocrystals that improve the physicochemical and pharmaceutical properties of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide, particularly cocrystals that improve the hygroscopicity and / or solubility of the active compound which allow obtaining an improvement in the production, handling, storage, and the pharmaceutical properties of said compound.

[0019] Summary of the Invention

[0020] The present invention provides cocrystals of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1-sulfonamide.

[0021] Following the attempt to obtain cocrystals of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide with a large number of possible crystal-forming compounds, the inventors have surprisingly found that hydroxylated derivatives of benzoic acid, and specifically 4-hydroxybenzoic and 3,4-dihydroxybenzoic acids, have particularly good hygroscopicity and solubility properties, with respect to the compound in the form of free base. Improvement in the aforementioned properties represents an advantage for the methods of producing, handling, and storing said compound, as well as for the pharmaceutical characteristics of said product. Specifically, a significant improvement in solubility has been shown by means of the cocrystals object of the present invention.

[0022] In terms of the subject matter of the present invention, there is no disclosure in the state of the art concerning the preparation and use of a cocrystal of N-{cis-3-[methyl(7 / 7-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide, let alone cocrystals of N-{cis-3- [methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide, with 4- hydroxybenzoic acid or 3,4-dihydroxybenzoic acid.

[0023] Therefore, in a first aspect, the present invention relates to cocrystals of N-{cis-3-[methyl(7 / - / - pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide with a cocrystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid.

[0024] In a second aspect, the present invention relates to a method for preparing the cocrystal defined in the first aspect, which comprises: a) contacting N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide and a cocrystal-forming compound selected from the group consisting of 4- hydroxybenzoic acid and 3,4-dihydroxybenzoic acid, and b) isolating the resulting cocrystal.

[0025] In a third aspect, the present invention relates to a pharmaceutical composition comprising the cocrystal according to the first aspect and a pharmaceutically acceptable excipient.

[0026] In a fourth aspect, the present invention relates to the cocrystal according to the first aspect or to the pharmaceutical composition according to the third aspect, for use as a medicament.

[0027] In a fifth aspect, the present invention relates to the cocrystal according to the first aspect or to the pharmaceutical composition according to the third aspect, for use thereof in the treatment and / or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme.

[0028] In a sixth aspect, the present invention relates to the use of a cocrystal according to the first aspect or a pharmaceutical composition according to the third aspect the manufacture of a medicament.

[0029] In a seventh aspect, the present invention relates to the use of a cocrystal according to the first aspect or a pharmaceutical composition according to the third aspect the manufacture of a medicament for the treatment and / or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme.

[0030] In an eight aspect, the present invention relates to a method for treatment of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme by administering to a subject in need thereof a cocrystal according to the first aspect or a pharmaceutical composition according the third aspect.

[0031] Brief Description of the Drawings

[0032] Figure 1 illustrates the XRPD pattern of the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide and 4-hydroxybenzoic acid of Example 1.

[0033] Figure 2 illustrates the XRPD pattern of the cocrystal of N-{cis-3-[methyl(7 / 7-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide and 3,4-dihydroxybenzoic acid of Example 2.

[0034] Figure 3 illustrates the kinetic solubility profile of the cocrystals obtained by means of the methodologies described in Examples 1 and 2 and of the crystalline form of N-[cis-3- [methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) disclosed in patent application WO 2020 / 008391 A1 at a pH of 4.5.

[0035] Figure 4 illustrates the kinetic solubility profile of the cocrystals obtained by means of the methodologies described in Examples 1 and 2 and of the crystalline form of N-[cis-3- [methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) disclosed in patent application WO 2020 / 008391 A1 at a pH of 1.2.

[0036] Detailed Description of the Invention

[0037] The present patent application discloses several cocrystals of N-{cis-3-[methyl(7 / 7-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide. The following cocrystals have been obtained from N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide and a cocrystal-forming compound selected from the group consisting of 4- hydroxybenzoic acid and 3,4-dihydroxybenzoic acid. All these cocrystals have shown improved physicochemical and pharmacokinetic properties with respect to the free base.

[0038] Cocrystal with 4-hydroxybenzoic acid

[0039] The inventors have surprisingly found that the cocrystal of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide and 4-hydroxybenzoic acid has the following advantageous properties:

[0040] 1) Hygroscopicity: it shows a lower hygroscopicity than the free base, particularly in usual drug storage conditions (RH<95%).

[0041] 2) Solubility: improvement in the solubility of the cocrystal with 4-hydroxybenzoic acid was surprising compared to the free base, particularly at pH that are below 4.5.

[0042] Therefore, said cocrystal with 4-hydroxybenzoic acid provides advantages for the preparation of solid dosage forms, which contain the pharmacologically active compound, facilitating its handling and allowing an improved dosing regimen. Furthermore, the cocrystal with 4- hydroxybenzoic acid object of the present invention is a stable solid, even under forced stability conditions. This cocrystal is less hygroscopic than the free base, particularly up to 95% RH, as can be seen in the examples when comparing the variation in the moisture content reached by the cocrystal with 4-hydroxybenzoic acid (no significant change occurs in relative humidity conditions between 0 and 95%) with that of crystalline form 1 of the free base (0.34% weight increase at 95% RH). acid The cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide with 3,4-dihydroxybenzoic acid was also prepared and it was found that this cocrystal had each and every one of the following advantages:

[0043] 1) Hygroscopicity: it shows a hygroscopicity very similar to the one of the free base, but has the advantage that, once humidity has been absorbed, it is released more easily when the ambient relative humidity is lowered than in the case of the free base.

[0044] 3) Solubility: improvement in the solubility of the cocrystal with 3,4-dihydroxybenzoic acid was surprising compared to the free base, particularly at pH that are below 4.5.

[0045] Therefore, said cocrystal with 3,4-dihydroxybenzoic acid provides advantages for the preparation of solid dosage forms, which contain the pharmacologically active compound, facilitating its handling and allowing improved dosing regimen. Furthermore, the cocrystal with 3,4-dihydroxybenzoic acid object of the present invention is a stable solid, even under forced stability conditions. This cocrystal is less hygroscopic than the free base, particularly up to 95% RH, as can be seen in the examples when comparing the variation in the moisture content reached by the cocrystal with 3,4-dihydroxybenzoic acid (0.26% at 95% RH) with that of the free base (0.34% at 95% RH). Additionally the absorption and desorption profiles are essentially superimposed, which indicates that the moisture is absorbed on the surface of the material unlike the case of the free base in which difficulties are observed in removing the absorbed water, most likely due to the fact that said free base has a solid structure with micropores.

[0046] Therefore, in a first aspect, the present invention relates to cocrystals of N-{cis-3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide with a cocrystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid.

[0047] In the context of the present invention, the term “cocrystal” is used to designate a crystalline material made up of two or more different molecules in a defined stoichiometric ratio within the same crystal lattice, which interact through non-ionic and non-covalent bonds. Generally, cocrystals are made up of an API moiety such as N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclobutyl}propane-1 -sulfonamide and a cocrystal-forming compound (coformer, cocrystal former, guest molecule).

[0048] In the context of the present invention, the term “cocrystal-forming compound” or “coformer” is used to designate a component that is typically solid at room temperature and that interacts in a non-ionic manner with the API in the crystal lattice. In the context of the present invention, a liquid is any substance which is liquid at room temperature, for example, at 25°C, preferably a class 1 , class 2, or class 3 solvent according to ICH guideline Q3C (R6), preferably being selected from the group consisting of alkanols, ethers, ketones, esters, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, water, and mixtures thereof, preferably water, acetonitrile, methanol, isopropanol, ethyl acetate, acetone, methyl isobutyl ketone, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichloromethane, and mixtures thereof, preferably acetonitrile.

[0049] In a preferred embodiment, the cocrystal is a cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide and 4-hydroxybenzoic acid.

[0050] In a more preferred embodiment, the molar ratio of N-{cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide with respect to 4-hydroxybenzoic acid in said cocrystal is comprised between 1.9 and 2.1 , preferably 2:1.

[0051] In a more preferred embodiment, the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclobutyl}propane-1-sulfonamide and 4-hydroxybenzoic acid, with a molar ratio of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide with respect to 4-hydroxybenzoic acid comprised between 1.9 and 2.1, preferably 2:1 , is characterized by showing an X-ray powder diffraction pattern comprising 20° peaks at XRPD: 10.3° 20, 13.2° 20, 17.5° 20, 19.4° 20, 20.8° 20, and 22.0° 20, all of them with a margin of error of ± 0.2° 20, wherein the X-ray diffraction pattern is measured using CuKa radiation. In a more preferred embodiment, the X-ray diffraction pattern comprises 20° peaks at 9.1° 20, 10.3° 20, 13.2° 20, 14.2° 20, 14.4° 20, 17.2° 20, 17.5° 20, 19.4° 20, 20.8° 20, 22.0° 20, 23.0° 20, and 23.2° 20, all of them with a margin of error of ± 0.2° 20°.

[0052] The crystalline structure of the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide and 4-hydroxybenzoic acid of the invention was determined by means of electron diffraction analysis at a temperature of about 25°C of a product sample and characterized by a triclinic system into the P-1 spatial symmetry group with cell parameters A = 9.1560 (11) A, B = 10.1612 (13) A, C = 11.4536 (14) A, a = 71.466° (11), = 69.478° (12), y = 86.963° (10), V= 944.2 A3(2). Particularly, the distances found for the bonds between C and O atoms in the carboxylic group of the 4-hydroxybenzoic acid molecule were 1.22 and 1.35 A, which can be interpreted as distances typical of C-OH and C=O bonds, respectively, and not as distances of a carboxylate group, since in this second case the distances would have been the same, i.e., about 1.26 A, reflecting the electron resonance of the possible anion. Therefore, a cocrystal, and not a crystalline salt, model would correspond with the compound of the invention. In a preferred embodiment, the cocrystal is a cocrystal of N-{cis-3-[methyl(7 / - / -pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide and 3,4-dihydroxybenzoic acid.

[0053] In a more preferred embodiment, the molar ratio of N-{cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide with respect to 3,4- dihydroxybenzoic acid in said cocrystal is comprised between 0.9 and 1.1 , preferably 1 :1.

[0054] In a more preferred embodiment, the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclobutyl}propane-1 -sulfonamide and 3,4-dihydroxybenzoic acid is characterized by showing an X-ray powder diffraction pattern comprising 20° peaks at 12.1° 20, 13.4° 20, 13.9° 20, 16.7° 20, 19.9° 20, 24.0° 20, and 24.2° 20, all of them with a margin of error of ± 0.2° 20, wherein the X-ray diffraction pattern is measured using CuKa radiation. In a more preferred embodiment, the X-ray diffraction pattern comprises 20° peaks at 4.6° 20, 12.1° 20, 13.4° 20, 13.9° 20, 14.1° 20, 16.7° 20, 19.9° 20, 21.9° 20, 24.0° 20, 24.2° 20, 25.9° 20, and 26.6° 20, all of them with a margin of error of ± 0.2°.

[0055] The crystalline structure of the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide and 3,4-dihydroxybenzoic acid of the invention was determined by means of electron diffraction analysis at a temperature of about 25°C of a product sample and characterized by a monoclinic system into the P-21 / c spatial symmetry group with cell parameters A = 20.6097 (16) A, B = 8.9368 (8) A, C = 13.1686 (11) A, a = 90°, P = 109.853° (7), y = 90°, V= 2281.3 A3(3). Particularly, the distances found for the bonds between C and O atoms in the carboxylic group of the 4-hydroxybenzoic acid molecule were 1.22 and 1.28 A, which can be interpreted as distances typical of C-OH and C=O bonds, respectively, and not as distances of a carboxylate group, since in this second case the distances would have been the same, i.e., about 1.26 A, reflecting the electron resonance of the possible anion. Therefore, a cocrystal, and not a crystalline salt, model would correspond with the compound of the invention.

[0056] In the present invention, N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1-sulfonamide has a pKa of 5.3. The ApKa between the free acid and the selected cocrystal-forming compounds is < 1 , as shown in Table 1 below.

[0057] Table 1 General method for preparing cocrystals of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- i-1-sulfonamide

[0058] In another aspect, the present invention relates to a method for preparing cocrystals of N-{cis- 3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide object of the present invention, which comprises: a) contacting N-{cis-3-[methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane- 1 -sulfonamide and a crystal-forming compound selected from the group consisting of 4- hydroxybenzoic acid and 3,4-dihydroxybenzoic acid in the presence of a liquid, and b) isolating the cocrystal of N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1-sulfonamide and coformer.

[0059] Step a) comprises contacting N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide and the crystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4-dihydroxybenzoic acid in the presence of a liquid. In one embodiment, contacting the two starting compounds can be performed by mixing them. In one embodiment, the mixture resulting from step a) can be seeded with small crystals of the desired cocrystal compound to facilitate precipitation, although this is not essential to obtain the cocrystals.

[0060] N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide is prepared using the methods disclosed in patent application WO 2014 / 128591 A1 , incorporated by reference herein.

[0061] In a particular embodiment, when the cocrystal-forming compound is 4-hydroxybenzoic acid, in step a), N-{cis-3-[methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide and 4-hydroxybenzoic acid are used in a molar ratio of 1 :0.8 to 1 :1.8, preferably 1 :1 to 1 :1.4, more preferably 1 :1.

[0062] In another particular embodiment, when the cocrystal-forming compound is 3,4- dihydroxybenzoic acid, in step a), N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide and 3,4-dihydroxybenzoic acid are used in a molar ratio of 1 : 1 to 1:2, preferably 1 : 1.4 to 1 : 1 .8, most preferably 1 :1.6.

[0063] Contacting the two starting compounds can be performed by mixing them. Both compounds can be mixed, for example, by means of magnetic stirring. The mixture can be a solution or a suspension. Preferably, step a) comprises preparing the mixture of N-{cis-3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide and a crystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid at a temperature comprised between 0°C and the reflux temperature of the liquid that is part of the solution or suspension. In a particular embodiment, the mixture is preferably kept at a temperature of 20°C ± 5°C, preferably at 20°C and under stirring, for between 30 minutes and 24 hours, more preferably between 3 hours and 22 hours, even more preferably between 10 hours and 20 hours.

[0064] The liquid can be any suitable liquid that does not react with N-{cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide or with the crystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid. Preferably, the liquid is selected from the group consisting of alkanols, ethers, ketones, esters, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, water and mixtures thereof, preferably water, acetonitrile, methanol, isopropanol, ethyl acetate, acetone, methyl isobutyl ketone, methyl tert-butyl ether, tetrahydrofuran, dioxane, dichloromethane, and mixtures thereof, preferably acetonitrile.

[0065] In another particular embodiment, a solution of the cocrystal-forming compound (4- hydroxybenzoic acid or 3,4-dihydroxybenzoic acid) in acetonitrile is slowly added to N-{cis-3- [methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide at a temperature between 0 and 40°C, preferably between 10 and 30°C, more preferably between 15 and 25°C, more preferably at 20°C, with stirring being maintained for at least 0.5 hours, more preferably for at least 2 hours, more preferably at least 5 hours, more preferably 20 hours.

[0066] As it is used herein, the term alkyl includes linear or branched hydrocarbon chains having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, and having no unsaturation. When the term alkyl is accompanied by an expression indicating the number of carbon atoms, such as C1-C3, it means that said alkyl has the indicated number of carbon atoms, such as from 1 to 3 carbon atoms.

[0067] As it is used herein, the term alkanol includes linear or branched alkyl chains, as defined above, attached to a hydroxyl group (OH). Preferred alkanols are isopropanol, propanol, ethanol, methanol, butanol, tert-butanol, isobutanol, and mixtures thereof, more preferably isopropanol.

[0068] As it is used herein, the term ether refers to compounds of formula R-O-R’, wherein R and R' are selected from: (a) alkyl chains as defined above, (b) wherein R and R’ together form an alkylene chain -(CH2)m, with m being an integer selected from 4 to 6, optionally substituted with a C1-C3 alkyl group, or (c) wherein R and R’ together form a -(CH2)n-O-(CH2)P- group, with n and p being integers selected independently from 1 to 3. Examples of ether are diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof, among others.

[0069] As it is used herein, the term ketone refers to compounds of formula R-C(=O)-R’, wherein R and R’ are selected independently from an alkyl radical, as defined above. Examples of ketones are acetone and methyl isobutyl ketone and mixtures thereof, among others.

[0070] As it is used herein, the term ester refers to an R-COOR’ group, wherein R and R’ are independently an alkyl radical, as defined above. Examples of esters are ethyl acetate and isobutyl acetate and mixtures thereof.

[0071] The skilled person can determine the volume of the liquid to be used in step a) of the method of forming cocrystals. Preferably, a volume is used such that the liquid-to-mass ratio (expressed in ml / g) of the compound N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl}propane-1 -sulfonamide is comprised between 1 and 20, preferably between 5 and 15, more preferably between 8 and 12.

[0072] The skilled person can determine, through routine methods, when the cocrystal of N-{cis-3- [methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1 -sulfonamide has been formed, for example, by filtering the solid of a sample from the reaction mass, drying it, and performing an XRPD to check for coincidence in the pattern obtained.

[0073] Once said cocrystal is formed, step b), i.e., isolating the resulting cocrystal through conventional methods in the field of the invention, for example, by means of filtration, is carried out.

[0074] Preferably, step b) may further comprise steps of washing the resulting cocrystal to remove impurities and to dry said cocrystal. Washing is preferably carried out with the same liquid as that used in step a). Drying is preferably carried out in an air oven and at a temperature comprised between 30 and 60°C.

[0075] Furthermore, the invention also encompasses pharmaceutical compositions comprising the cocrystal as defined above and a pharmaceutically acceptable excipient. In particular, the cocrystal is in a therapeutically effective amount.

[0076] An “effective amount” or a "therapeutically effective amount” of a drug or pharmacologically active agent means a non-toxic but sufficient amount of the drug or agent to provide the desired effect. The amount that is “effective” will vary from one subject to another, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Therefore, it is not always possible to specify an exact “effective amount”. However, the skilled person can determine a suitable “effective” amount in any individual case using routine experimentation.

[0077] The term “pharmaceutically acceptable excipient” refers to a carrier, diluent, or adjuvant which is administered with the active ingredient. Such pharmaceutical excipients may be sterile liquids, such as water and oils, including excipients derived from petroleum, excipients of animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water or aqueous cocrystal solutions and aqueous solutions of dextrose and glycerol, particularly for injectable solutions, are preferably used as carriers.

[0078] Examples of pharmaceutically acceptable excipients for oral dosage pharmaceutical compositions of the invention are conventional excipients known in the art such as binding agents, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, mannitol, xylitol, sorbitol, sucrose, corn starch, calcium phosphate, sorbitol, glycine, dextrose, maltodextrin, dextran, dextrin, modified starches; glidants and lubricants for tablets, for example magnesium stearate, calcium stearate, stearic acid, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, colloidal silicon dioxide, silicon dioxide, anhydrous colloidal silicon, glycerin, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate or talc; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, microcrystalline cellulose, hydroxypropyl cellulose or sorbitan fatty acid esters; pharmaceutically acceptable wetting agents such as sodium lauryl sulfate; water solubilizing aids such as urea, betaine monohydrate, potassium sulfate, potassium acetate, mannitol; alkalinizing agents such as potassium carbonate, sodium carbonate, sodium bicarbonate, trisodium phosphate, tripotassium phosphate, trisodium citrate, tripotassium citrate; sweeteners such as saccharin sodium, sodium cyclamate, and aspartame; flavoring agents such as menthol and peppermint oil.

[0079] The pharmaceutical compositions of the invention may be administered parenterally, orally, or topically, preferably orally.

[0080] In a preferred embodiment, the pharmaceutical compositions are in a dosage form suitable for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in the form of a suitable dosage unit. Suitable excipients such as fillers, buffering agents, or surfactants can be used.

[0081] The pharmaceutical compositions can also be in solid or liquid oral form . Suitable dosage forms for oral administration can be tablets, capsules, syrups, or powder solutions for dissolution or oral suspension, granules, sachets. Preferably, the dosage form is selected from the group consisting of tablets and capsules.

[0082] The preceding formulations will be prepared using conventional methods such as those described or contemplated in the Spanish and United States pharmacopeias and similar reference texts.

[0083] Medical uses

[0084] The cocrystals object of the present invention have / maintain a potent Janus kinase enzyme inhibitory activity.

[0085] Therefore, the invention also relates to the cocrystal as described above or to a pharmaceutical composition as defined above for use thereof as a medicinal product. This constitutes the fourth aspect of the invention.

[0086] This aspect can also be formulated as the use of the cocrystal of the invention as described above or of the pharmaceutical composition as defined above for the manufacture of a medicament. This constitutes the sixth aspect of the invention.

[0087] Another aspect of the invention relates to the cocrystal of the invention as described above or to a pharmaceutical composition as defined above, for use thereof in the treatment and / or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme. This constitutes the fifth aspect of the invention.

[0088] This aspect can also be formulated as the use of the cocrystal of the invention as described above or a pharmaceutical composition as defined above, for the manufacture of a medicament for the treatment and / or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme. This constitutes the seventh aspect of the invention.

[0089] This aspect can also be formulated as a method for the treatment and / or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme, which comprises administering to a subject in need of such treatment the cocrystal of the invention as described above or a pharmaceutical composition as defined above. This constitutes the eight aspect of the invention.

[0090] The disease or condition susceptible of improvement by inhibiting the Janus kinase 1 enzyme is selected from the group consisting of cancer and inflammatory diseases such as rheumatoid arthritis and various skin conditions, particularly atopic dermatitis. The terms "treat” and “treatment”, as they are used herein, mean reversing, alleviating, inhibiting the progression of the disease or condition to which this term is applied, or of one or more symptoms of said disease or condition.

[0091] The terms "prevent” and “prevention”, as they are used herein, mean inhibiting the onset of the disease or condition to which this term is applied, or of one or more symptoms of such disease or condition.

[0092] In the use according to the invention, the cocrystal of the invention, the combination product, or the pharmaceutical composition can be administered 1 , 2, 3, 4, or 5 times / day. In the use, the cocrystal of the invention, the combination product, or the pharmaceutical composition can be administered until reversing, alleviating, or inhibiting the progression of the symptoms of the disease or condition to be treated.

[0093] The following non-limiting examples seek to illustrate the present invention and must not be considered as limiting the scope thereof.

[0094] Examples

[0095] General

[0096] Differential scanning calorimetry (DSC)

[0097] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a ramp of 10°C / min and an N2 flow of 50 mL / min. The measurement is taken with a closed perforated capsule.

[0098] Purity

[0099] The purity of the obtained products was analyzed by means of the ultra-high resolution liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. An Acquity HSS C18 column (100 x 2.1 mm; 1.8 pm) and mobile phases A (30 mM of ammonium formate, pH 4.8), B (methanol), and C (acetonitrile) were used with the following analysis conditions:

[0100] Flow rate: 0.3 mL / min

[0101] Column temperature: 40°C

[0102] Wavelength: 290 nm

[0103] Injection volume: 1 pL

[0104] Diluent: Water / Methanol (2:3) Gradient (for the analysis of the cocrystal of abrocitinib and 4-hydroxybenzoic acid):

[0105] Gradient (for the analysis of the cocrystal of abrocitinib and 3,4-dihydroxybenzoic acid):

[0106] X-ray crystallography

[0107] XRPD analysis was performed using a Malvern PANalytical X’Pert PRO X-ray powder diffractometer with a radius of 240 mm and equipped with a copper anode. The radiation used is CuKa with a wavelength of 1 .54 A. The following scan parameters were used: 3-40 degrees 20, continuous scan, ratio: 0.328 degrees / minute.

[0108] Nuclear magnetic resonance

[0109] Proton nuclear magnetic resonance (1H-NMR) analysis was performed in a Varian Mercury 400 MHz spectrometer. The chemical shifts were referenced to the DMSO-d6 signal (2.49 PPm).

[0110] Hygroscopicity analysis

[0111] The hygroscopicity of the compounds was determined in a TA Instruments Q5000 sorption analyzer apparatus. The samples were not dried previously but kept exposed to 0% RH until stable weight before starting the cycles. The sorption and desorption values were determined at the temperature of 25°C over a range of 0-95% RH. Increases in RH level were performed when the variation in sample weight was below 0.01% after 20 min or after a time limit of 500 minutes.

[0112] Example 1. Synthesis of the 2:1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 4- hydroxybenzoic acid

[0113] A previously prepared solution of 59.8 g (432.9 mmol) of 4-hydroxybenzoic acid in 1400 ml of acetonitrile was slowly added to 140.85 g (432.9 mmol) of N-[cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) at the temperature of about 20°C. The resulting reaction mass was kept under stirring for 20 hours at said temperature.

[0114] Thereafter, the resulting solid was filtered, washed successively with three fractions of 210 ml of acetonitrile each, and dried in an air oven at the temperature of about 45°C to obtain 166.5 g (98.1% yield and 99.93% purity by means of HPLC) of a white solid corresponding to the 2:1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1- sulfonamide (abrocitinib) and 4-hydroxybenzoic acid.

[0115] XRPD: 9.1° 20, 10.3° 20, 13.2° 20, 14.2° 20, 14.4° 20, 17.2° 20, 17.5° 20, 19.4° 20, 20.8° 20, 22.0° 20, 23.0° 20, and 23.2° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 1.

[0116] The differential scanning calorimetry (DSC) diagram of the compound obtained has an endothermal peak with a threshold temperature of about 181.9°C.

[0117] 1H-NMR (DMSO-d6, 400 MHz) 6(ppm): 11.62 (s, 1 H), 8.10 (s, 1 H), 7.78 (d, J = 8.6 Hz, 1 H), 7.48 (d, J = 9.2 Hz, 1 H), 7.17-7.10 (m, 1 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.63 (dd, J = 3.4, 1.6 Hz, 1 H), 4.97-4.82 (m, 1H), 3.64-3.49 (m, 1H), 3.25 (s, 3H), 2.98-2.87 (m, 2H), 2.59 (ddd, J = 16.0, 7.5, 2.8 Hz, 2H), 2.22 (ddd, J = 18.6, 9.2, 2.7 Hz, 2H), 1.75-1.60 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). The chemical shift values in bold correspond with protons of the abrocitinib molecule. The rest of the chemical shift values correspond with protons of the 4-hydroxybenzoic acid molecule. Integration of the signals observed in the NMR spectrum is consistent with the structure of the 2:1 cocrystal of abrocitinib and 4-hydroxybenzoic acid, without observing any signals corresponding to degradation products.

[0118] Example 2. Synthesis of the 1 :1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 3,4- dihydroxybenzoic acid A previously prepared solution of 76.24 g (494.7 mmol) of 3,4-dihydroxybenzoic acid in 1400 ml of acetonitrile was slowly added to 100 g (309.2 mmol) of N-[cis-3-[methyl(7 / 7- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) at the temperature of about 20°C. The resulting reaction mass was kept under stirring for 20 hours at said temperature.

[0119] Thereafter, the resulting solid was filtered, washed successively with a fraction of 50 ml of acetonitrile, and dried in an air oven at the temperature of about 45°C to obtain 144.5 g (97.8% yield and 99.93% purity by means of HPLC) of a white solid corresponding to the 1 :1 cocrystal of N-[cis-3-[methyl( / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) and 3,4-dihydroxybenzoic acid.

[0120] XRPD: 4.6° 29, 12.1° 29, 13.4° 29, 13.9° 29, 14.1° 29, 16.7° 29, 19.9° 29, 21.9° 29, 24.0° 29, 24.2° 29, 25.9° 29, and 26.6° 29, all of them with a margin of error of ± 0.2° 29. The X-ray powder diffractogram of the compound is shown in Figure 2.

[0121] The differential scanning calorimetry (DSC) diagram of the compound obtained has an endothermal peak with a threshold temperature of about 151.0°C.

[0122] 1H-NMR (DMSO-d6, 400 MHz) 6(ppm): 12.31 (s, 1 H), 11.63 (s, 1H), 9.67 (s, 1H), 9.28 (s, 1H), 8.10 (s, 1 H), 7.49 (d, J = 9.2 Hz, 1 H), 7.33 (d, J = 1.9 Hz, 1 H), 7.28 (dd, J = 8.2, 1.9 Hz, 1 H), 7.17-7.10 (m, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 6.69-6.59 (m, J = 1.6 Hz, 1 H), 4.96-4.84 (m, 1 H), 3.56 (dd, J = 16.1 , 7.9 Hz, 1 H), 3.25 (s, 3H), 3.00-2.86 (m, 2H), 2.64-2.54 (m, 2H), 2.22 (q, J = 9.5 Hz, 2H), 1.77-1.60 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). The chemical shift values in bold correspond with protons of the abrocitinib molecule. The rest of the chemical shift values correspond with protons of the 3,4-dihydroxybenzoic acid molecule. Integration of the signals observed in the NMR spectrum is consistent with the structure of the 1 :1 cocrystal of abrocitinib and 3,4-dihydroxybenzoic acid, without observing any signals corresponding to degradation products.

[0123] Example 3. Hygroscopicity study

[0124] A comparative hygroscopicity study was performed on the cocrystals obtained by means of the methodologies described in Examples 1 and 2 from the crystalline form of N-[cis-3- [methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) disclosed in patent application WO 2020 / 008391 A1. Hygroscopicity was determined by means of a DVS (Dynamic Vapor Sorption) study in which the amount of water absorbed and desorbed by a sample is measured at different RH (relative humidity) values. The results obtained are listed in Table 2. Table 2

[0125] Example 4. Solubility testing

[0126] A comparative kinetic solubility study was performed on the cocrystals obtained by means of the methodologies described in Examples 1 and 2 and on the crystalline form of N-[cis-3- [methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) disclosed in patent application WO 2020 / 008391 A1. The study was performed in aqueous solutions with two different buffers: acetate buffer at pH 4.5 and KCI / HCI at pH 1.2.

[0127] The study was performed by generating a suspension of the 2:1 cocrystal of N-[cis-3- [methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) and 4-hydroxybenzoic acid and the 1 :1 cocrystal of N-[cis-3-[methyl(7 / 7-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 3,4- dihydroxybenzoic acid and the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1. The relative solubility of abrocitinib was obtained directly by means of comparing the peak area observed by means of HPLC corresponding to abrocitinib of the aliquots resulting from the experiments (previously filtered and analyzed in duplicate) analyzed at different times (30 min, 60 min, 120 min, 180 min, and 24 hours) to obtain the corresponding kinetic solubility profiles.

[0128] The following conditions were used to perform the study:

[0129] • for pH 4.5: 24 ml of a 0.05 M buffer solution and 200 mg of each of the three solids were stirred under the same conditions and in the same type of container

[0130] • for pH 1.2: 16 ml of a 0.540 M buffer solution and the corresponding amount of each of the three solids to generate abrocitinib oversaturation were stirred under the same conditions and in the same type of container.

[0131] The amounts used were 165 mg of the 2:1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 4-hydroxybenzoic acid, 200 mg of the 1 :1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) and 3,4-dihydroxybenzoic acid, and 136 mg of the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1 (in the assays performed at pH 1 .2, the initial formation of a solution was observed, followed by the precipitation of the abrocitinib hydrochloride salt generated in situ in the buffer solution. Therefore, the amounts used were adjusted to generate the same abrocitinib oversaturation for each of the compounds in order to compare the precipitation rates of the abrocitinib hydrochloride salt).

[0132] In both cases, a Kinetex C18 column (50 x 4.6 mm; 2.6 m) and mobile phase A (10 mM ammonium carbonate, pH 8) and mobile phase B (acetonitrile) were used in HPLC analysis with the following analysis conditions:

[0133] Flow rate: 1 mL / min

[0134] Column temperature: 40°C

[0135] Wavelength: 290 nm

[0136] Injection volume: 5 pL (for the study at pH 4.5) and 0.5 pL (for the study at pH 1 .2) Gradient: A / B (95:5) - 0.5 min - A / B (95:5) - 3 min A / B (0:100).

[0137] Figure 3 shows the depiction of the mean area values obtained by means of HPLC analysis in relation to the sampling time for the 2:1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 4-hydroxybenzoic acid (line with square point markers), the 1:1 cocrystal of N-[cis-3-[methyl(7 / - / -pyrrolo[2,3- d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide (abrocitinib) and 3,4- dihydroxybenzoic acid (line with round point markers), and the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1 (line with triangle point markers) for the study performed at pH 4.5.

[0138] It can be deduced from Figure 3 that the solubility of both cocrystals is higher than the solubility of the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1, with the best results being observed for the 1 :1 cocrystal of abrocitinib with 3,4-dihydroxybenzoic acid.

[0139] Figure 4 shows the depiction of the mean area values obtained by means of HPLC analysis in relation to sampling time for the 2:1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) and 4-hydroxybenzoic acid (line with square point markers), the 1 :1 cocrystal of N-[cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl]-propane-1-sulfonamide (abrocitinib) and 3,4-dihydroxybenzoic acid (line with round point markers), and the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1 (line with triangle point markers) for the study performed at pH 1 .2.

[0140] At pH 1 .2, a complete dissolution of the three forms studied was immediately observed due to the in situ formation of the abrocitinib hydrochloride salt. This first dissolution is followed by the crystallization of a solid which, upon filtering the aliquots obtained, corresponded to crystalline form E of the abrocitinib hydrochloride salt disclosed in patent application WO 2020 / 008391 A1. Based the results depicted in Figure 4, it can be deduced that the solubility of the two cocrystals is higher than the solubility of the crystalline form of abrocitinib disclosed in patent application WO 2020 / 008391 A1 due to the slower crystallization of crystalline form E of the abrocitinib hydrochloride salt when coformers (4-hydroxybenzoic acid and 3,4- dihydroxybenzoic acid) are present in the respective media in which the assays are performed.

Claims

CLAIMS1. Cocrystal comprising: a) N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1- sulfonamide, and b) a cocrystal-forming compound selected from the group consisting of 4- hydroxybenzoic acid and 3,4-dihydroxybenzoic acid.

2. Cocrystal according to claim 1 , wherein the cocrystal-forming compound is 4- hydroxybenzoic acid.

3. Cocrystal according to claim 2, wherein the molar ratio of N-{cis-3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide with respect to 4- hydroxybenzoic acid in said cocrystal is comprised between 1.9:2 and 2.1:1 and is preferably 2:1.

4. Cocrystal according to any one of claims 2 to 3, wherein the cocrystal is characterized by showing an X-ray powder diffraction pattern comprising 20° peaks at 10.3° 20, 13.2° 20, 17.5° 20, 19.4° 20, 20.8° 20, and 22.0° 20 ± 0.2020°, wherein the X-ray diffraction is measured using CuKa radiation.

5. Cocrystal according to claim 1 , wherein the cocrystal-forming compound is 3,4- dihydroxybenzoic acid.

6. Cocrystal according to claim 5, wherein the molar ratio of N-{cis-3-[methyl(7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide with respect to 3,4-dihydroxybenzoic acid in said cocrystal is comprised between 0.9:1 and 1.1:1 and is preferably 1 :1.

7. Cocrystal according to any one of claims 5 to 6, wherein the cocrystal is characterized by showing an X-ray powder diffraction pattern comprising 20° peaks at 4.6° 20, 12.1° 20, 13.4° 20, 13.9° 20, 14.1° 20, 16.7° 20, 19.9° 20, 21.9° 20, 24.0° 20, 24.2° 20, 25.9° 20, and 26.6° 20 ± 0.20 20°, wherein the X-ray diffraction is measured using CuKa radiation.

8. Method for preparing a cocrystal according to any one of claims 1 to 7, which comprises: a) contacting N-{cis-3-[methyl(7 / - / -pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl} propane-1 -sulfonamide and a crystal-forming compound selected from the group consisting of 4-hydroxybenzoic acid and 3,4-dihydroxybenzoic acid in the presence of a liquid, and b) isolating said cocrystal.

9. Method according to claim 8, wherein the liquid is selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, i-butyl acetate, propan-2-one (acetone), methyl isobutyl ketone (MIBK), tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), diethyl ether, methyl tert-butyl ether (MTBE), and mixtures thereof.

10. Method according to claim 9, wherein the liquid is acetonitrile.

11. Pharmaceutical composition comprising a cocrystal according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

12. Cocrystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 11 , for use thereof as a medicinal product.

13. Cocrystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 12, for use thereof in the treatment or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme.

14. Cocrystal or pharmaceutical composition for use thereof according to claim 13, wherein the disease that is known to improve by inhibiting the Janus kinase 1 enzyme is selected from the group consisting of cancer and inflammatory diseases such as rheumatoid arthritis and various skin conditions, particularly atopic dermatitis.

15. Use of a cocrystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 11 for the manufacture of a medicament.

16. Use of a cocrystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment or prevention of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme.

17. Use of a cocrystal or a pharmaceutical composition according to claim 16, wherein the disease that is known to improve by inhibiting the Janus kinase 1 enzyme is selected from the group consisting of cancer and inflammatory diseases such as rheumatoid arthritis and various skin conditions, particularly atopic dermatitis.

18. Method for treatment of a disease that is known to improve by inhibiting the Janus kinase 1 enzyme by administering to a subject in need thereof a cocrystal according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 11 .

19. Method according to claim 18 wherein the disease that is known to improve by inhibiting the Janus kinase 1 enzyme is selected from the group consisting of cancer and inflammatory diseases such as rheumatoid arthritis and various skin conditions, particularly atopic dermatitis.

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