Cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid

Abstract

The present invention relates to co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, processes for obtaining said co-crystals, combination products and pharmaceutical compositions comprising said co-crystals, and their medical uses, especially for the treatment or prevention of diseases known to be ameliorated by A1 adenosine receptor antagonism.

Description

[Technical Field]

[0001] The present invention relates to a novel co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, an A1 adenosine receptor antagonist, which is useful for the treatment or prevention of diseases known to be ameliorated by A1 adenosine receptor antagonism. [Background technology]

[0002] Adenosine A1 receptor antagonists are useful for the treatment or prevention of a variety of diseases, including hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma, and autoimmune diseases such as multiple sclerosis (Hocher, B, Adenosine A1 receptor antagonists in clinical research and development, Kidney International (2010) 78, 438-445; Hasko, G et al, Adenosine receptors: therapeutic aspects for inflammatory and immune diseases, Nature Reviews, volume 7, September 2008, 759).

[0003] Specifically, patent application WO2009 / 044250 A1 discloses 5-cyano-1,3-thiazole derivatives, which are potent A1 adenosine receptor antagonists and are useful for the treatment of the above-mentioned diseases. The patent application also discloses 3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, particularly the (1R,3S) stereoisomer, the structure of which is shown below. [ka]

[0004] Co-crystals of 5-cyano-1,3-thiazole derivatives are not described in the cited documents or in other documents known to the applicant.

[0005] Although (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid has shown favorable pharmacological activity, it appears that there is room for improvement in the physical and / or pharmacological properties of the compound, particularly its hygroscopicity and bioavailability. Improvement of these properties would aid in the further pharmaceutical development of the drug.

[0006] Therefore, there is a need in the art to provide methods for improving the hygroscopicity and / or bioavailability of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

[0007] Therefore, the development of a soluble, stable, pharmaceutically acceptable form of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with improved hygroscopicity and / or bioavailability is highly desirable. The present invention addresses these problems.

[0008] Cocrystals are distinguished from salts because, unlike salts, the components coexisting in a cocrystal lattice in a defined stoichiometric ratio interact nonionically. Generally, if an active pharmaceutical ingredient (API) and its cocrystal-forming compound (coformer) have a ΔpKa (ΔpKa = pKa (conjugate acid of base) - pKa (acid)) < 1, substantial proton transfer is considered to be low. If this criterion is met, the API-coformer entity should be classified as a cocrystal (Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, February 2018, http: / / www.fda.gov / Drugs / GuidanceComplianceRegulatoryInformation / Guidances / default.htm).

[0009] Several properties, especially melting point (considered to be one of the important physicochemical properties to consider), storage stability, solubility, dissolution rate, hygroscopicity, and bioavailability, may be altered by cocrystal formation (Izutsu, K et al, Characterization and Quality Control of Pharmaceutical Cocrystals, Chem. Pharm. Bull. 64, 1421-1430 (2016)).

[0010] Given the availability of numerous pharmaceutically acceptable coformers and the lack of correlation between the pharmaceutically acceptable coformers and the final properties of the corresponding cocrystals, the discovery of suitable cocrystals is a challenging process, the outcome of which cannot be predicted a priori.

[0011] There is a need to provide cocrystals that improve the pharmacological and pharmaceutical properties of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, particularly those that improve its hygroscopicity without adversely affecting other important parameters such as the crystallinity or bioavailability of the active compound. To obtain improvements in the manufacture, handling, storage, and drug properties of the acid, there is a need to reduce the hygroscopicity of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid while simultaneously ensuring a good level of its stability and solubility under typical drug storage conditions (<75% RH). Summary of the Invention

[0012] The present invention provides a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

[0013] After attempting to obtain co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a number of potential crystal-forming compounds, the present inventors unexpectedly found that gentisic acid, urea, and nicotinamide exhibit particularly favorable hygroscopicity and bioavailability properties, as well as higher melting points, compared to the free acid forms of the compounds. The improved properties provide advantages to the manufacturing process, handling, and storage of the compounds, as well as to the pharmaceutical properties of the products. Specifically, the co-crystals of the present invention exhibit significantly improved oral bioavailability, which allows for the administration of significantly lower doses of the compounds to achieve desired therapeutic levels.

[0014] With respect to the subject matter of the present invention, there are no known disclosures in the state of the art regarding the preparation and use of any cocrystals of compounds belonging to the series of compounds disclosed in patent application WO2009 / 044250 A1 (much less cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and even less cocrystals with gentisic acid, urea and nicotinamide).

[0015] Thus, in a first aspect, the present invention relates to a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal former selected from the group consisting of gentisic acid, urea and nicotinamide.

[0016] In a second aspect, the present invention provides a method for preparing a co-crystal as defined in the first aspect, comprising the steps of: a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a co-crystal former selected from the group consisting of gentisic acid, urea, and nicotinamide in the presence of a liquid; and b) Isolating the resulting co-crystal The present invention relates to a method, comprising:

[0017] In a third aspect, the present invention relates to a combination product comprising a cocrystal according to the first aspect and one or more therapeutic agents selected from the group consisting of angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers, statins, beta-blockers, calcium channel blockers and diuretics.

[0018] In a fourth aspect, the present invention relates to a pharmaceutical composition comprising a co-crystal according to the first aspect or a combination product according to the third aspect and a pharmaceutically acceptable excipient.

[0019] In a fifth aspect, the present invention relates to a co-crystal according to the first aspect, a combination product according to the third aspect or a pharmaceutical composition according to the fourth aspect for use as a medicament.

[0020] In a sixth aspect, the present invention relates to a co-crystal according to the first aspect, a combination product according to the third aspect or a pharmaceutical composition according to the fourth aspect for use in the treatment and / or prevention of a disease known to be ameliorated by A1 adenosine receptor antagonism. [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 shows the H-NMR spectrum of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid. [Figure 2] FIG. 2 shows the XRPD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid. [Figure 3] FIG. 3 depicts the DSC pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, showing an endothermic event beginning at 179.59° C., which corresponds to the melting point of this compound. [Figure 4] FIG. 4 shows the H-NMR spectrum of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2. [Figure 5] FIG. 5 shows the XRPD pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2. [Figure 6]FIG. 6 shows the DSC pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2, which shows an endothermic event with an onset at 181.69° C., which corresponds to the melting point of the co-crystal. [Figure 7] FIG. 7 shows the H-NMR spectrum of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea of ​​Example 3. [Figure 8] FIG. 8 shows the XRPD pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea of ​​Example 3. [Figure 9] FIG. 9 shows the DSC pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea co-crystal of Example 3, which shows an endothermic event beginning at 197.7° C., which corresponds to the melting point of the co-crystal. [Figure 10] FIG. 10 shows the H-NMR spectrum of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide of Example 4. [Figure 11] FIG. 11 shows the XRPD pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide of Example 4. [Figure 12] FIG. 12 depicts the DSC pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide from Example 4, showing an endothermic event with an onset at 189.55° C., which corresponds to the melting point of the co-crystal. [Figure 13]FIG. 13 depicts the DVS pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid from Example 2, showing the weight change (%) of the co-crystal as a function of relative humidity (RH). [Figure 14] FIG. 14 depicts the DVS pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea from Example 3, showing the weight change (%) of the co-crystal as a function of relative humidity (RH). [Figure 15] FIG. 15 depicts the DVS pattern of the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide from Example 4, showing the weight change (%) of the co-crystal as a function of relative humidity (RH). [Figure 16] FIG. 16 shows a comparison of the DVS patterns of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with the different cocrystals obtained in Examples 2, 3 and 4. DETAILED DESCRIPTION OF THE INVENTION

[0022] This patent application discloses several co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid. The following co-crystals were obtained from (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal former selected from the group consisting of gentisic acid, urea, and nicotinamide. All of them showed improved pharmacological and pharmacokinetic properties compared to the free acid.

[0023] Gentisic Acid Cocrystal The present inventors have surprisingly found that a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid has the following advantageous properties: 1) Stability under forced conditions (1 week) and in a 4-week stability test: The obtained cocrystals showed no change in crystallinity, color or any other aspect. 2) Hygroscopicity: It exhibits lower hygroscopicity than the free acid, especially under normal drug storage conditions (<75% RH). 3) Bioavailability: Unexpectedly, gentisic acid cocrystals showed improved oral exposure and bioavailability compared to the free acid.

[0024] Therefore, the gentisic acid cocrystal is advantageous for the production of solid dosage forms containing pharmacologically active compounds, which facilitates their handling and allows for better dosing regimens. In addition, the gentisic acid cocrystal that is the subject of the present invention is a stable solid, even under forced stability conditions. This cocrystal is less hygroscopic than the free acid, especially up to 75% RH, as can be seen in the examples where the variation in water content achieved by the gentisic acid cocrystal (0.10% at 75% RH) is compared to that of the free acid (0.43% at 75% RH).

[0025] urea cocrystal Co-crystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with urea have also been prepared and found to have all of the following advantages: 1) Stability under forced conditions (1 week) and in a 4-week stability test: The obtained cocrystals showed no change in crystallinity, color or any other aspect. 2) Hygroscopicity: It exhibits lower hygroscopicity than the free acid, especially under normal drug storage conditions (<75% RH). 3) Bioavailability: Unexpectedly, the urea cocrystal showed improved oral exposure and bioavailability compared to the free acid.

[0026] Thus, the urea cocrystal is advantageous for the production of solid dosage forms containing pharmacologically active compounds, allowing for easier manipulation and better dosing regimens. Additionally, the urea cocrystal that is the subject of the present invention is a stable solid, even under forced stability conditions. The cocrystal is less hygroscopic than the free acid, especially up to 75% RH, as can be seen in the examples comparing the variation in water content achieved with the urea cocrystal (0.08% at 75% RH) to that of the free acid (0.43% at 75% RH).

[0027] Nicotinamide Cocrystal The present inventors have surprisingly found that a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide has all of the following advantages: 1) Stability under forced conditions (1 week) and 4-week stability study: The resulting co-crystals showed no change in crystallinity, color or any other aspect during both stability assays. 2) Hygroscopicity: It exhibits lower hygroscopicity than the free acid, especially in the range of 5 to 70% RH. 3) Bioavailability: Unexpectedly, nicotinamide cocrystals showed improved oral exposure and bioavailability compared to the free acid.

[0028] Therefore, the nicotinamide cocrystals are advantageous for the production of solid dosage forms containing pharmacologically active compounds, allowing for easier handling and better dosing regimens. Additionally, the nicotinamide cocrystals that are the subject of the present invention are stable solids, even under forced stability conditions. The cocrystals are less hygroscopic than the free acid, especially in the range of 5-70% RH, as can be seen in the examples when compared to the variations in water content achieved with nicotinamide cocrystals.

[0029] As shown in Examples 5-8, the resulting co-crystals exhibit improved melting point, hygroscopicity and bioavailability properties compared to the free acid.

[0030] Accordingly, a first aspect of the present invention relates to a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal former selected from the group consisting of gentisic acid, urea and nicotinamide.

[0031] In the context of the present invention, the term "cocrystal" is used to refer to a crystalline material composed of two or more molecules in a defined stoichiometric ratio within the same crystal lattice, interacting through nonionic and noncovalent bonds. Generally, a cocrystal is composed of an API moiety, e.g., (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, and a co-crystal-forming compound (coformer, co-crystallite, guest molecule).

[0032] In the context of the present invention, the term "co-crystal former" or "coformer" is used to refer to a component that is typically solid at room temperature and that interacts non-ionically with the API within the crystalline lattice.

[0033] In the context of the present invention, a liquid is any substance that 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 selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, isobutyl acetate, propan-2-one (acetone), methyl-isobuthyl-cetone (MIBK), tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), p-xylene, ethyl ether, methyl tert-butyl ether (TMBE) and heptane.

[0034] In a preferred embodiment, the co-crystal is a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid.

[0035] In a more preferred embodiment, the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to gentisic acid in the cocrystal is 0.9 to 1.1, and preferably 1:1.

[0036] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 181.69°C.

[0037] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid is characterized by exhibiting a powder X-ray diffraction pattern comprising 2θ peaks at 6.99, 13.29, 13.42, 14.02, and 17.82 degrees 2θ (all of which are ±0.20 degrees 2θ), wherein the X-ray diffraction pattern is measured using CuKα radiation. In a more preferred embodiment, the X-ray diffraction pattern comprises 2θ peaks at 6.99, 13.29, 13.42, 14.02, 17.82, 18.71, 21.09, 26.34, 26.58, 27.28, 28.24, and 31.56 degrees 2θ (all of which are ±0.20 degrees 2θ).

[0038] In another preferred embodiment, the co-crystal is a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea.

[0039] In a more preferred embodiment, the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to urea in the cocrystal is 0.9 to 1.1, and preferably 1:1.

[0040] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 197.7°C.

[0041] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid is characterized by exhibiting an X-ray powder diffraction pattern comprising 2θ° peaks at 8.32, 8.82, 13.86, 15.60, 16.47, 24.86 (all ±0.20) 2θ°, wherein said X-ray diffraction pattern is measured using CuKα radiation. In a more preferred embodiment, the X-ray diffraction pattern comprises 2θ° peaks at 7.77, 8.32, 8.82, 13.86, 15.60, 16.47, 18.23, 18.94, 19.38, 19.86, 20.05, 20.71, 21.38, 21.84, 22.76, 23.02, 24.86, 26.10, 27.28, 28.40 (all of which are ±0.20) 2θ°.

[0042] In a preferred embodiment, the co-crystal is a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide.

[0043] The molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to the nicotinamide cocrystal is 0.9 to 1.1, and preferably 1:1.

[0044] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 189.55°C.

[0045] In a more preferred embodiment, the co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide is characterized by exhibiting an X-ray powder diffraction pattern comprising 2θ° peaks at 6.40, 8.54, 11.75, 17.29, 20.88, 23.66 (all ±0.20) 2θ°, wherein said X-ray diffraction pattern is measured using CuKα radiation. In a more preferred embodiment, the X-ray diffraction pattern comprises 2θ° peaks at 6.40, 8.54, 11.28, 11.75, 13.02, 17.29, 18.33, 19.56, 20.11, 20.55, 20.88, 21.36, 21.62, 22.73, 22.96, 23.66, 24.26, 24.46, 25.12, 26.17, 26.46, 27.53, 28.81, 29.36, 30.28, 32.96 (all of which are ±0.20) 2θ°.

[0046] In the present invention, (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid has a pKa of 4.3. The ΔpKa between the free acid and selected co-crystal formers is <1, as shown in Table 1 below.

[0047] [Table 1]

[0048] General method for the preparation of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid cocrystals In another aspect, the present invention provides a method for preparing the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid cocrystal that is the subject of the present invention, comprising the steps of: a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a crystal-forming compound in the presence of a liquid; and b) Isolating the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid-coformer cocrystal The present invention relates to a method, comprising:

[0049] Step a) comprises contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a crystal-forming compound selected from gentisic acid, urea, and nicotinamide in the presence of a liquid. In some embodiments, contacting the two starting materials can be achieved by stirring them. In some embodiments, the mixture resulting from stirring step a) may be seeded with small crystals of the desired co-crystal compound to promote precipitation, although this is not required to obtain a co-crystal.

[0050] (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid is prepared using the method disclosed in patent application WO2009 / 044250 A1, which is incorporated herein by reference.

[0051] In certain embodiments, when the co-crystal-forming compound is gentisic acid, in step a), (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid are present in a molar ratio of 0:9 to 1:1.5, preferably 1:1 to 1:1.5, and preferably 1:1 to 1:1.2. Contacting the two starting materials can be achieved by stirring them. Mixing of both compounds can be achieved, for example, by magnetic stirring. The mixture can be a solution or a suspension. Preferably, step a) comprises bringing the mixture of acid and gentisic acid to the reflux temperature of a liquid forming part of the solution or suspension, preferably until a solution is obtained. In certain embodiments, the mixture is maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, and even more preferably 10 hours to 15 hours.

[0052] The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or with gentisic acid. Preferably, the liquid is selected from the group consisting of alkanols, aliphatic hydrocarbons, aromatic hydrocarbons, 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, xylene, heptane, and mixtures thereof.

[0053] In another particular embodiment, when the co-crystal former is urea, in step a), (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea are present in a molar ratio of 0.9:1 to 1:1.5, preferably 1:1 to 1:1.5, and preferably 1:1 to 1:1.2. Bringing the two starting materials into contact can be achieved by stirring them. Mixing of both compounds can be carried out, for example, by magnetic stirring. The mixture can be a solution or a suspension. Preferably, step a) comprises bringing the mixture of acid and urea to the reflux temperature of the liquid forming part of the solution or suspension, preferably until a solution is obtained. In a particular embodiment, the mixture is maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, and even more preferably 10 hours to 15 hours.

[0054] The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or with urea. Preferably, the liquid is selected from the group consisting of alkanols, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ketones, esters, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, water, and mixtures thereof, preferably acetonitrile, methanol, isopropanol, isobutyl acetate, acetone, methyl isobutyl ketone, dichloromethane, xylene, heptane, and mixtures thereof.

[0055] In certain embodiments, when the co-crystal former is nicotinamide, in step a), (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide are present in a molar ratio of 0:9 to 1:1.5, preferably 1:1 to 1:1.5, and preferably 1:1 to 1:1.2. Contacting the two starting materials can be achieved by stirring them. Mixing of both compounds can be achieved, for example, by magnetic stirring. The mixture can be a solution or a suspension. Preferably, step a) comprises bringing the mixture of acid and nicotinamide to the reflux temperature of a liquid forming part of the solution or suspension, preferably until a solution is obtained. In certain embodiments, the mixture is maintained at reflux temperature with stirring for 30 minutes to 24 hours, more preferably 5 hours to 18 hours, and even more preferably 10 hours to 15 hours.

[0056] The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or with nicotinamide. Preferably, the liquid is selected from the group consisting of alkanols, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, ketones, esters, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile, water, and mixtures thereof, preferably acetonitrile, acetone, methyl isobutyl ketone, and mixtures thereof.

[0057] As used herein, the term alkyl includes straight or branched hydrocarbon chains having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and no unsaturation. When the term alkyl is accompanied by a term indicating the number of carbon atoms, such as C1-C3, it means that the alkyl has the specified number of carbon atoms, such as 1 to 3 carbon atoms.

[0058] As used herein, the term alkanol includes a straight or branched alkyl chain, as previously defined, linked to a hydroxyl group (OH). Preferred alkanols are isopropanol, propanol, ethanol, methanol, butanol, tert-butanol, isobutanol, and mixtures thereof, more preferably isopropanol, propanol, ethanol, methanol, and mixtures thereof.

[0059] As used herein, the term aliphatic hydrocarbon refers to a compound consisting of linear, branched, or cyclic carbon and hydrogen atoms, preferably 5 to 12 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 6 or 7 carbon atoms, saturated or having one or more unsaturations (double or triple bonds), e.g., 1, 2, or 3 unsaturations. Examples of aliphatic hydrocarbons are, inter alia, pentane, hexane, heptane, cyclopentane, cyclohexane, and mixtures thereof; preferably, heptane and cyclohexane, and mixtures thereof.

[0060] As used herein, the term aromatic hydrocarbon refers to a cyclic compound consisting of carbon and hydrogen atoms, unsaturated, according to Hückel's rule, preferably having six carbon atoms in the ring, optionally substituted with one, two or three C1-C3 alkyl groups, which may be the same or different. Examples of aromatic hydrocarbons are toluene and xylene and mixtures thereof.

[0061] As used herein, the term ether means a compound of formula R—O—R′, where R and R′ are selected from: (a) an alkyl chain as previously defined; (b) R and R′ together form an alkylene chain —(CH) m (m is an integer from 4 to 6), optionally substituted with a C1-C3 alkyl group, or (c) R and R' together form -(CH2) n -O-(CH2) p- group, where n and p are integers independently selected from 1 to 3. Examples of ethers are, among others, diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, methyltetrahydrofuran, and mixtures thereof.

[0062] As used herein, the term ketone means a compound of formula RC(=O)-R', where R and R' are independently selected from alkyl groups as previously defined. Examples of ketones are, among others, acetone and methyl isobutyl ketone and mixtures thereof.

[0063] As used herein, the term ester refers to the group R-COOR', where R and R' are independently selected from alkyl groups as previously defined. Examples of esters are ethyl acetate and isobutyl acetate and mixtures thereof.

[0064] As used herein, the term gentisic acid is used herein to refer to the compound with the IUPAC name 2,5-dihydroxybenzoic acid.

[0065] As used herein, the term urea is used herein to refer to a compound having the formula (NH2)2-C=O.

[0066] As used herein, the term nicotinamide is used herein to refer to the compound with the IUPAC name 3-pyridinecarboxamide.

[0067] According to one embodiment of the invention, the liquid in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, isobutyl acetate, propan-2-one (acetone), methyl isobutyl ketone (MIBK), tetrahydrofuran (THF), 1,4-dioxane, dichloromethane (DCM), p-xylenediethyl ether, methyl tert-butyl ether (TMBE) and heptane, and mixtures thereof.

[0068] The volume of the liquid used in this method can be determined by one skilled in the art, and is preferably 1 to 50 times, more preferably 1 to 10 times the molar amount of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (ml).

[0069] One skilled in the art can routinely determine when the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid co-crystal has formed using, for example, thin layer chromatography, nuclear magnetic resonance, or high performance liquid chromatography.

[0070] Once said co-crystals have been formed, step b) is carried out, ie the isolation of the co-crystals obtained by methods conventional in the field of the invention, for example by filtration.

[0071] Preferably, step b) may further comprise washing the obtained co-crystal to remove impurities and drying the co-crystal. Washing is preferably carried out with the same liquid as used in step a). Drying is preferably carried out under vacuum at room temperature.

[0072] Combinations and Pharmaceutical Compositions The present invention further provides combination products comprising a cocrystal of the invention and one or more therapeutic agents selected from a) angiotensin-converting enzyme inhibitors (ACE inhibitors), b) angiotensin receptor antagonists, c) statins, d) beta-blockers, e) calcium channel blockers, and f) diuretics.

[0073] Examples of ACE inhibitors are, for example, captopril, enalapril, and benazepril, among others.

[0074] Examples of angiotensin receptor antagonists are, for example, losartan, azilsartan, irbesartan, and eprosartan, among others.

[0075] Examples of statins are, for example, atorvastatin, fluvastatin, simvastatin, and lovastatin, among others.

[0076] Examples of beta-blockers are, for example, atenolol, betaxolol, carvedilol, and propanolol, among others.

[0077] Examples of calcium antagonists are, for example, amlodipine, verapamil, bidipine, and isradipine, among others.

[0078] Examples of diuretics are, for example, chlorothiazide, chlorthalidone, furosemide, and spironolactone, among others.

[0079] The combination product can be a pharmaceutical composition comprising the cocrystal and one or more therapeutic agents. Alternatively, in the combination product, the cocrystal and one or more therapeutic agents are different compositions.

[0080] Furthermore, the present invention also encompasses pharmaceutical compositions comprising a cocrystal as defined above or a combination as defined above and a pharmaceutically acceptable excipient. In particular, the cocrystal is in a therapeutically effective amount. The therapeutic agent, if present, is also preferably in a therapeutically effective amount.

[0081] An "effective amount" or "therapeutically effective amount" of a drug or pharmacologically active agent means a sufficient, but non-toxic, amount of the drug or agent to provide the desired effect. An "effective" amount will vary from subject to subject, depending on the individual's age and genetic condition, the particular active agent, and the like. Thus, it is not always possible to specify an exact "effective amount." However, in any individual case, one of ordinary skill in the art can determine an appropriate "effective" amount using routine testing.

[0082] The cocrystal of the present invention and one or more therapeutic agents as defined above may be administered simultaneously, sequentially, or separately.

[0083] Simultaneous administration may be carried out, for example, in the form of a composition comprising a cocrystal of the invention and one or more therapeutic agents as defined above, or by simultaneous administration, i.e., administration at the same time, of a cocrystal of the invention and one or more therapeutic agents as defined above formulated separately (i.e., when they are not part of the same composition).

[0084] Sequential administration preferably means administering a cocrystal of the invention at one time point and one or more therapeutic agents as defined above at different alternating times.

[0085] Separate administration preferably means that the cocrystal of the present invention and one or more therapeutic agents as defined above are administered independently of each other at different times.

[0086] The term "pharmaceutically acceptable excipient" refers to a carrier, diluent, or adjuvant with which an active ingredient is administered. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water or aqueous cocrystal solutions, and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as carriers.

[0087] Examples of pharmaceutically acceptable excipients for the orally administered pharmaceutical compositions of the present invention include conventional excipients known in the art, such as binders, e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth gum or polyvinylpyrrolidone; fillers, e.g., lactose, mannitol, xylitol, sorbitol, sucrose, corn starch, calcium phosphate, sorbitol, glycine, dextrose, maltodextrin, dextran, dextrin, modified starch; glidants and tablet lubricants, e.g., 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 such as starch, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, microcrystalline cellulose, hydroxypropyl cellulose or sorbitan fatty acid esters; pharmaceutically acceptable humectants such as sodium lauryl sulfate; water solubilizing aids such as urea, betaine monohydrate, potassium sulfate, potassium acetate, mannitol; alkalizing agents such as potassium carbonate, sodium carbonate, sodium bicarbonate, trisodium phosphate, tripotassium phosphate, trisodium citrate, tripotassium citrate; sweeteners such as sodium saccharin, sodium cyclamate and aspartame; flavoring agents such as menthol and peppermint oil.

[0088] The pharmaceutical compositions of the present invention may be administered parenterally, orally or topically, preferably by the oral route.

[0089] In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for parenteral administration, such as a sterile solution, suspension, or lyophilized product in the form of a suitable dosage unit. Suitable excipients, such as bulking agents, buffers, or surfactants, can also be used.

[0090] The pharmaceutical composition may also be in the form of an oral formulation, either solid or liquid. Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions or powder solutions for oral suspension, granules, sachets. Preferably, the dosage form is selected from the group consisting of tablets and capsules.

[0091] The above formulations are prepared using standard methods such as those described or contemplated in the Spanish and US Pharmacopoeias and similar reference texts.

[0092] medical use The co-crystals that are the subject of the present invention exhibit / maintain potent antagonist activity at the A1 adenosine receptor.

[0093] Thus, the present invention is also directed to the use of a co-crystal as defined above, a combination product of a co-crystal of the invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition such as defined above, for use as a medicament.

[0094] This embodiment may also be formulated as a co-crystal of the invention as defined above, a combination product of a co-crystal of the invention with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above to prepare a medicament.

[0095] Another aspect of the present invention relates to a cocrystal as defined above, a combination product of a cocrystal of the invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition such as defined above, for use in the treatment and / or prevention of diseases known to be ameliorated by A1 adenosine receptor antagonism.

[0096] This embodiment may also be formulated as the use of a cocrystal of the invention as defined above, a combination product of a cocrystal of the invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition as previously defined, in the manufacture of a medicament for the treatment and / or prevention of a disease known to be ameliorated by A1 adenosine receptor antagonism.

[0097] This embodiment may also be formulated as a method for treating and / or preventing diseases known to be ameliorated by A1 adenosine receptor antagonism, comprising administering to a subject in need of such treatment a cocrystal of the invention as defined above, a combination product of a cocrystal of the invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above.

[0098] The disease or condition that can be improved by adenosine A1 receptor antagonism is selected from the group consisting of hypertension, heart failure, ischemia, supraventricular arrhythmia, acute renal failure, or any other disease caused by fluid retention, myocardial reperfusion injury, asthma, allergic reactions, including, but not limited to, hypertension, heart failure, ischemia, supraventricular arrhythmia, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions (including rhinitis and urticaria), autoimmune diseases such as scleroderma and multiple sclerosis, etc. In a preferred embodiment, the disease or condition that can be improved by adenosine A1 receptor antagonism is selected from the group consisting of heart failure, acute renal failure, asthma, arterial hypertension, and dialysis hypotension.

[0099] The terms "treat" and "treatment" as used herein mean to reverse, alleviate, or inhibit the progression of a disease or condition to which said term or one or more symptoms of said disease or condition apply.

[0100] The terms "prevent" and "prevention," as used herein, mean the inhibition of the occurrence of the disease or condition to which the term applies or one or more symptoms of such disease or condition.

[0101] In use according to the invention, the cocrystal, combination product or pharmaceutical composition of the invention may be administered 1, 2, 3, 4 or 5 times per day. In use, the cocrystal, combination product or pharmaceutical composition of the invention may be administered until the symptoms of the disease or condition being treated are reversed, alleviated or inhibited in their progression.

[0102] The following non-limiting examples are intended to illustrate the present invention and should not be considered as limiting the scope of the invention. [Example]

[0103] General 1 H-NMR analysis. Nuclear magnetic resonance analyses were recorded on a Varian Mercury 400 MHz spectrometer equipped with a 5 mm broadband probe ATB 1H / 19F / X using DMSO-d6. Spectra were acquired by dissolving 5–10 mg of sample in 0.7 mL of deuterated solvent.

[0104] XRPD Analysis. Diffraction measurements of the starting material and samples from the screening were performed under ambient conditions on a PANalytical X'Pert PRO θ-θ diffractometer equipped with CuKα radiation and a PIXcel detector, with a 240 mm radius reflection geometry, operated at 45 kV and 40 mA. Each sample was mounted on a zero-background silicon sample holder and rotated at 0.25 rev / s during data acquisition. The measurement angle range was 3.0-40.0° (2θ) with a step size of 0.013°. The scan rate was 0.082° / s (40.80 s / step) for the starting material and 0.328° / s (10.20 s / step) for the samples generated during testing.

[0105] DSC analyses were recorded using a Mettler Toledo DSC2. Samples were weighed into 40 μl aluminum crucibles with pinhole lids and heated under nitrogen (50 ml / min) from 25 to 300 °C at a rate of 10 °C / min.

[0106] Crystal stability tests were performed under accelerated stability conditions (40°C, 75±5%RH) for one week. Samples of each form stored on XRPD silicon holders were exposed in a climate chamber. It is not worthwhile to make these conditions too harsh, as the high surface area exposed to these storage conditions could accelerate possible crystalline transformations. Samples were analyzed periodically by XRPD to observe any changes that may have occurred.

[0107] Additional crystal stability studies were performed under accelerated stability conditions (40°C, 75% RH ± 5%). Co-crystal vials were stored in open vials and exposed in a climate chamber maintained at precisely the conditions (40°C, 75% RH ± 5%). These samples were analyzed weekly for one month.

[0108] Hygroscopicity Testing. The hygroscopicity of the cocrystals was determined by DVS (Dynamic Vapor Sorption) using a Q5000 (TA Instruments). This is a gravimetric technique that measures the amount of water adsorbed or desorbed by a sample at different relative humidity (RH). At each RH level, the sample mass must reach (or exceed) gravimetric equilibrium before proceeding to the next humidity level. Adsorption and desorption isotherms were generated at 25 °C over the range of 0 to 95% RH. Samples were not pre-dried but were exposed to 0% RH until a constant weight was reached before starting the DVS cycle. This equilibration step allowed for the removal of any adsorbed moisture from the atmosphere. Relative humidity (RH) was controlled by a mixture of humid and dry nitrogen flows. RH was held constant until equilibrium was achieved (constant weight) or a maximum time was reached, after which RH was changed to the next level.

[0109] Example 1 Synthesis of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid The synthesis of the compound (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid is described in patent application WO2009 / 044250 A1, which is incorporated herein by reference. 1H-NMR (300 MHz, DMSO-d6): δ = 1.88 (m, 4H), 1.99 (m, 1H), 2.22 (m, 1H), 2.79 (m, 1H), 3.06 (m, 1H), 7.57 (m, 3H), 7.99 (m, 2H), 12.37 (s, 1H), 12.89 (s, 1H).

[0110] FIG. 1 shows the structure of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid. 1 The H-NMR spectrum is shown.

[0111] FIG. 2 shows the XRPD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

[0112] FIG. 3 depicts the DSC pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, showing an endothermic event beginning at 179.59° C., which corresponds to the melting point of this compound.

[0113] Example 2 Preparation of cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid To a round-bottom flask equipped with a magnetic stir bar and containing a mixture of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (300 mg, 0.88 mmol) and gentisic acid (169 mg, 1.10 mmol, 1.25 equiv.), TBME (3 mL) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sintered filter flask (porosity: No. 3) and washed with TBME (2 × 0.2 mL). After drying under vacuum at room temperature, a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid was obtained as a white solid.

[0114] FIG. 4 shows the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid in Example 2. 1 The H-NMR pattern spectrum confirms a 1:1 molar ratio.

[0115] The co-crystal of Example 2 was also characterized by XRPD. Figure 5 shows the corresponding pattern and Table 2 lists the major peaks.

[0116] [Table 2]

[0117] FIG. 6 depicts the DSC pattern of the co-crystal of Example 2, showing an endothermic event with an onset at 181.69° C., corresponding to the melting point of the co-crystal.

[0118] Example 3 Preparation of cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with urea To a round-bottom flask equipped with a magnetic stir bar and containing a mixture of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (260 mg, 0.77 mmol, 1.3 equiv.) and urea (35.2 mg, 0.59 mmol), ACN (2 mL) was added. The resulting mixture was stirred at room temperature for 15 h. The suspension was then filtered through a sintered filter flask (porosity: No. 3) and washed with ACN (2 × 0.2 mL). After drying under vacuum at room temperature, the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea was obtained as a white solid.

[0119] Figure 7 shows the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea. 1 The H-NMR pattern spectrum confirms a 1:1 molar ratio.

[0120] The co-crystal of Example 3 was also characterized by XRPD. Figure 8 shows the corresponding pattern and Table 3 lists the major peaks.

[0121] [Table 3]

[0122] FIG. 9 depicts the DSC pattern of the co-crystal of Example 3, showing an endothermic event beginning at 197.72° C., which corresponds to the melting point of this co-crystal.

[0123] Example 4 Preparation of cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide To a round-bottom flask equipped with a magnetic stir bar and containing a mixture of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (400 mg, 1.17 mmol, 2 equiv.) and nicotinamide (71.5 mg, 0.59 mmol), MIBK (4 mL) was added. The resulting mixture was stirred at room temperature for 15 h. The suspension was then filtered through a sintered filter flask (porosity: No. 3) and washed with MIBK (3 × 0.2 mL). After drying under vacuum at room temperature, a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide was obtained as a white solid.

[0124] FIG. 10 shows the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide. 1The H-NMR pattern spectrum confirms a 1:1 molar ratio.

[0125] The co-crystal of Example 4 was also characterized by XRPD. Figure 11 shows the corresponding pattern and Table 4 lists the major peaks.

[0126] [Table 4]

[0127] FIG. 12 depicts the DSC pattern of the co-crystal of Example 4, showing an endothermic event with an onset at 189.55° C., corresponding to the melting point of this co-crystal.

[0128] Example 5 Stability testing The stability of the co-crystalline form of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid was tested under accelerated storage conditions (40°C, 75±5% RH) for 1-4 weeks. See results in Table 5.

[0129] [Table 5]

[0130] After the exposure time, the co-crystal remained stable according to XRPD analysis: no amorphization or appearance of crystalline form was detected within the detection limits of the analytical conditions.

[0131] Example 6 Moisture absorption test The table below (Table 6) shows the water content of the parent carboxylic acid and the co-crystal in the hygroscopicity test.

[0132] [Table 6]

[0133] As can be seen from the table above, the co-crystal with gentisic acid and the co-crystal with urea are less hygroscopic than the free acid, especially up to 75% RH. See Figures 13-16.

[0134] Example 7 Oral bioavailability assay The objective of this study was to investigate the plasma pharmacokinetics of various cocrystals derived from (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid after single intravenous (IV) and oral (PO) administration in male SD rats.

[0135] Animals were divided into two groups: Group 1 (IV: 1 mg / kg) and Group 2 (PO: 5 mg / kg). Animals in Groups 1 and 2 received solutions of various cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid in saline. Blood samples were collected from sets of three rats per time point into labeled microcentrifuge tubes containing K2EDTA solution as an anticoagulant at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (IV) and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours (PO). Plasma samples were separated by centrifugation of whole blood and stored at temperatures below -70 ± 10 °C until bioanalysis. All samples were processed for analysis by protein precipitation with acetonitrile and analyzed by a qualified LC-MS / MS method (LLOQ = 1.00 ng / ml). Pharmacokinetic parameters were calculated using the non-compartmental analysis tool in Phoenix WinNonlin® (version 6.3).

[0136] The main pharmacokinetic parameters obtained from Examples 1 to 4 are shown in Table 7 below.

[0137] [Table 7]

[0138] Cmax means the maximum plasma drug concentration obtained after drug administration between the time of administration and the last observation time point.

[0139] AUC last means the area under the curve from the time of administration to the last observation greater than the limit of quantitation.

[0140] Clearance refers to a measurement of the body's ability to remove a drug from the plasma and is calculated from an intravenous dose.

[0141] F% means bioavailability. The systemic availability of a compound after oral administration is calculated using the following formula: F(%)=(AUC last PO x dose IV / AUC last IV x dose PO) x 100

[0142] As can be seen from the table above, the co-crystals of gentisic acid, urea and nicotinamide show increased bioavailability compared to the free acid.

[0143] Example 8 Comparative bioavailability assay in healthy volunteers The healthy volunteers in this study were males aged 18 years or older to assess the comparative bioavailability of the compound of Example 2 and the compound of Example 1 under fasting conditions and to study the effects of a high-fat, high-calorie diet. The compounds of Example 1 (5 mg) and Example 2 (7.3 mg) were administered orally as a single dose. The study was conducted in a randomized, open-label, four-fold crossover design.

[0144] To determine comparative bioavailability, AUC 0―t (AUC 0―t : area under the plasma concentration-time curve from time 0 to the final measurable concentration) and C max (C max The maximum observed plasma concentration (peak exposure) is determined after each dose.

[0145] result There were 16 volunteers in this study. Baseline samples from all volunteers showed no presence of the compound of Example 1. Therefore, all data were included in all pharmacokinetic measurements and calculations without any correction. See Table 8.

[0146] [Table 8]

[0147] AUC 0―t = area under the curve of plasma concentration with respect to time up to the last quantifiable sample (time t), calculated by the trapezoidal method. AUC 0―∞ : Area under the curve with respect to time, extrapolated to infinity, calculated as follows: AUC 0―∞ =AUC 0―t +C t / ke (In the formula, C t is the concentration determined at time t, and k is the elimination rate constant. The latter is calculated using linear regression analysis during the final monoexponential phase of elimination (Phoenix WinNonLin). In all cases, at least three plasma concentration values ​​are used to define this phase.

[0148] C max :Maximum concentration t max =C max Time to reach

[0149] The bioavailability of Example 1 was similar to that of Example 2, with an AUC 0―t and C max and AUC under fed conditions 0―t In this case, the 90% confidence limit is within the range of the bioequivalence acceptance limit (80.00% to 125.00%). max was slightly higher when administered after a high-fat meal.

Claims

1. A co-crystal consisting of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal-forming compound which is gentisic acid, 1. The co-crystal, wherein the co-crystal exhibits a powder X-ray diffraction pattern comprising 2θ° peaks at 6.99, 13.29, 13.42, 14.02, 17.82±0.20 2θ°, wherein the X-ray diffraction is measured using CuKα radiation.

2. 2. The co-crystal according to claim 1, wherein the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to gentisic acid in the co-crystal is 1:

1.

3. 2. The co-crystal of claim 1, wherein the co-crystal has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at 181.69°C.

4. A co-crystal consisting of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal forming compound which is urea, 1. The co-crystal, wherein the co-crystal exhibits a powder X-ray diffraction pattern comprising 2θ° peaks at 8.32, 8.82, 13.86, 15.60, 16.47, 24.86±0.20 2θ°, wherein the X-ray diffraction is measured using CuKα radiation.

5. 5. The cocrystal according to claim 4, wherein the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to urea in the cocrystal is 1:

1.

6. 5. The co-crystal of claim 4, wherein the co-crystal has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at 197.7°C.

7. A co-crystal consisting of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a co-crystal-forming compound that is nicotinamide, 10. The co-crystal, wherein the co-crystal exhibits a powder X-ray diffraction pattern comprising 2θ° peaks at 6.40, 8.54, 11.75, 17.29, 20.88, 23.66±0.20 2θ°, wherein the X-ray diffraction is measured using CuKα radiation.

8. 8. The co-crystal according to claim 7, wherein the molar ratio of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to nicotinamide in the co-crystal is 1:

1.

9. 8. The co-crystal of claim 7, wherein the co-crystal has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at 189.55°C.

10. A method for producing the cocrystal according to any one of claims 1 to 3, comprising: a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with gentisic acid in the presence of methyl tert-butyl ether; and b) isolating the co-crystal. A method for producing a cocrystal, comprising:

11. A method for producing the cocrystal according to any one of claims 4 to 6, comprising: a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with urea in the presence of acetonitrile; and b) isolating the co-crystal. A method for producing a cocrystal, comprising:

12. A method for producing the cocrystal according to any one of claims 7 to 9, comprising: a) contacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with nicotinamide in the presence of methyl isobutyl ketone; and b) isolating the co-crystal. A method for producing a cocrystal, comprising:

13. 10. A combination product comprising the cocrystal of any one of claims 1 to 9 and one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, statins, beta-blockers, calcium channel blockers, and diuretics.

14. A pharmaceutical composition comprising the cocrystal of any one of claims 1 to 9 and a pharmaceutically acceptable excipient.

15. 10. A pharmaceutical composition comprising the cocrystal of any one of claims 1 to 9, one or more therapeutic agents selected from the group consisting of angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, statins, beta-blockers, calcium channel blockers, and diuretics, and a pharmaceutically acceptable excipient.

16. A, comprising a cocrystal according to any one of claims 1 to 9, a combination product according to claim 13 or a pharmaceutical composition according to claim 14 or 15. １ A drug for treating or preventing a disease known to be improved by adenosine receptor antagonism.

17. A １ 17. The compound according to claim 16, wherein the disease known to be improved by adenosine receptor antagonism is selected from the group consisting of hypertension, heart failure, ischemia, supraventricular arrhythmia, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma, and autoimmune diseases. １ A drug for treating or preventing a disease known to be improved by adenosine receptor antagonism.

18. A １ 16. Use of a co-crystal according to any one of claims 1 to 9, a combination product according to claim 13 or a pharmaceutical composition according to claim 14 or 15 for the manufacture of a medicament for the treatment or prevention of a disease known to be ameliorated by adenosine receptor antagonism.

19. A １ 19. The use according to claim 18, wherein the disease known to be improved by adenosine receptor antagonism is selected from the group consisting of hypertension, heart failure, ischemia, supraventricular arrhythmias, acute renal failure, myocardial reperfusion injury, asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases.

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