EA045045B1 - CO-CRYSTALS OF (1R,3S)-3-(5-CYANO-4-PHENYL-1,3-THIAZOL-2-YLCARBAMOYL)CYCLOOPENTANCARBOXYLIC ACID - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to novel cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid, which is an adenosine receptor antagonist

A _b These cocrystals are useful for the treatment or prevention of diseases that are known to improve with antagonism of the adenosine A ₁ receptor.

State of the art

Adenosine A1 receptor antagonists are useful for the treatment or prevention of various diseases, including hypertension, heart failure, ischemia, supraventricular arrhythmia, 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; Hask0, G et al, Adenosine receptors: therapeutic aspects for inflammatory and immune diseases, Nature Reviews, volume 7, September 2008, 759).

In particular, patent application WO 2009/044250 A1 discloses 5-cyano-1,3-thiazole derivatives which are active antagonists of the adenosine A ₁ receptor and which are useful for the treatment of the above diseases. This patent application discloses a 3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic, specifically a (1R,3S) stereoisomer, the structure of which is given below:

Cocrystals of 5-cyano-1,3-thiazole derivatives are not indicated either in the cited document or in other documents known to the applicant.

Although (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid has been shown to have suitable pharmacological activity, there appears to be room for improvement in the physical and/or pharmacological properties of said compound, in particular its hygroscopicity and its bioavailability. Improving these characteristics should contribute to additional pharmaceutical development with the production of a drug.

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

Therefore, the development of soluble and stable pharmaceutically acceptable forms of the said (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 is aimed at solving such problems.

Cocrystals differ from salts because, unlike salts, components that coexist in a joint crystal lattice with a specific stoichiometry interact nonionically. It is generally believed that if the active pharmaceutical ingredient (API) and its cocrystal compound (coformer) have a ΔpKa (ΔpKa= pKa (conjugate acid to base) - pKa (acid)) < 1, less than significant proton transfer occurs. If this criterion is met, the API coformer should be classified as a cocrystal. (Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, February 2018, http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/default.htm).

During the formation of a cocrystal, certain characteristics may change, in particular, such as melting point, which is considered one of the first physicochemical characteristics taken into account, storage stability, solubility, dissolution rate, hygroscopicity and bioavailability. (Izutsu, K et al., Characterization and Quality Control of Pharmaceutical Cocrystals, Chem. Pharm. Bull. 64, 1421-1430 (2016)).

Due to the availability of a large number of pharmaceutically acceptable coformers and the lack of correlation between the nature of the pharmaceutically acceptable coformer and the final characteristics of the corresponding cocrystal, the search for suitable cocrystals is difficult and the results are a priori unpredictable.

It is necessary to obtain cocrystals that improve the physicochemical and pharmaceutical characteristics of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, in particular cocrystals that improve hygroscopicity without adverse effects on other important parameters such as crystallinity or bioavailability of the active compound. In particular, it is necessary to reduce the hygroscopicity of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid under normal drug storage conditions (<75% RH) and at the same time ensure good levels of their stability and solubility and provide improvement in the production, use, storage and pharmaceutical characteristics of the said acid.

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The essence of the invention

The present invention relates to cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid.

After attempting to prepare cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid with a large number of potential crystal-forming compounds, the present inventors unexpectedly found that gentisic acid, urea and nicotinamide have particularly good hygroscopicity and bioavailability characteristics and higher melting points compared to the free acid form of the compound. Improving the above characteristics means improving the production, use and storage of the specified compound, as well as the pharmaceutical characteristics of the specified product. In particular, the cocrystals of the present invention show significant improvement in oral bioavailability, allowing significantly lower doses of the compound to be administered to achieve desired therapeutic levels.

In connection with the subject matter of the present invention, there is no disclosure in the prior art relating to the preparation and use of any co-crystal of a compound belonging to the family of compounds disclosed in patent application WO 2009/044250 A1, much less co-crystals (1R,3S)- 3(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and even fewer cocrystals with gentisic acid, urea and nicotinamide.

Thus, the first object of the present invention is cocrystals of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a cocrystal-forming compound selected from the group consisting of the following: gentisic acid, urea and nicotinamide.

A second aspect of the present invention is a method for producing a cocrystal as defined in the first aspect, comprising:

a) reacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a cocrystal-forming compound selected from the group consisting of: gentisic acid, urea and nicotinamide, in the presence of liquid and

b) isolating the resulting cocrystal.

A third aspect of the present invention is a combination product comprising a cocrystal corresponding to the first aspect and one or more therapeutic agents selected from the group consisting of the following: angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor antagonists, statins, beta blockers, antagonists calcium and diuretics.

A fourth aspect of the present invention is 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.

A fifth aspect of the present invention is a cocrystal 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 drug.

A sixth aspect of the present invention is a cocrystal in accordance with the first aspect, a combination product in accordance with the third aspect, or a pharmaceutical composition in accordance with the fourth aspect, for use in the treatment and/or prevention of a disease known to be ameliorated by antagonism of the adenosine A1 receptor.

Brief description of drawings

In fig. Figure 1 shows the 1H NMR spectrum of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

In fig. Figure 2 shows the XRPD XRD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid.

In fig. Figure 3 shows the DSC diagram of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, which has an endothermic event starting at 179.59°C, which corresponds to melting point of this compound.

In fig. Figure 4 shows the 1H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2.

In fig. Figure 5 shows the XRPD XRD pattern of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2.

In fig. 6 shows the DSC diagram of the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2, which has an endothermic event starting at 181.69° C, which corresponds to the melting temperature of this cocrystal.

In fig. Figure 7 shows the 1H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and urea of Example 3.

In fig. Figure 8 shows the XRPD XRD pattern of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-2045045 ylcarbamoyl)cyclopentanecarboxylic acid and urea of Example 3.

In fig. 9 is a DSC diagram of the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid-urea cocrystal of Example 3, which has an endothermic event starting at 197.7° C, which corresponds to the melting temperature of this cocrystal.

In fig. 10 shows the 1H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide of Example 4.

In fig. 11 shows the XRPD XRD pattern of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide of Example 4.

In fig. 12 is a DSC diagram of the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid-nicotinamide co-crystal of Example 4, which exhibits an endothermic event starting at 189.55°C , which corresponds to the melting temperature of this cocrystal.

In fig. 13 is a DVS diagram of the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid-gentisic acid co-crystal of Example 2, showing the weight change (in %) of the said co-crystal in depending on relative humidity (RH).

In fig. 14 is a DVS diagram of the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid-urea co-crystal of Example 3, which shows the change in mass (in %) of the specified co-crystal depending on on relative humidity (RH).

In fig. 15 is a DVS diagram of the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid-nicotinamide co-crystal of Example 4, which shows the change in mass (in %) of the specified co-crystal depending on on relative humidity (RH).

In fig. 16 compares the DVS diagrams of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and various cocrystals obtained in examples 2, 3 and 4.

Detailed Description of the Invention

This patent application discloses various cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid. The following cocrystals are prepared from (1R,3S)3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a cocrystal-forming compound selected from the group consisting of gentisic acid, urea and nicotinamide All of them have improved physicochemical and pharmacokinetic characteristics compared to the free acid.

Gentisic acid cocrystal

The present inventors have surprisingly found that a cocrystal of (1R,3S)-3-(5-cyano-4phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid has the following beneficial characteristics:

1) Stability under harsh conditions (one week) and according to a 4-week stability study: no change in crystallinity, color or any other change in aspect ratio was detected in the resulting co-crystal.

2) Hygroscopicity: It is less hygroscopic than free acid under normal drug storage conditions (<75% RH).

3) Bioavailability: The improvement for the gentisic acid cocrystal in oral exposure and bioavailability compared to the free acid was unexpected.

Therefore, this gentisic acid co-crystal provides advantages in the preparation of solid dosage forms containing the pharmacologically active compound, facilitating operations and providing a better mode of administration. Moreover, the gentisic acid cocrystal of the present invention is a stable solid even under stringent stability testing conditions. This cocrystal is less hygroscopic than the free acid, in particular up to 75% RH, as can be seen in the examples by comparing the moisture change achieved in the gentisic acid cocrystal (0.10% at 75% RH) with that for the free acid ( 0.43% at 75% RH).

Urea cocrystal

A cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with urea was also prepared and found to have all of the following advantages:

1) Stability under harsh conditions (one week) and according to a 4-week stability study: no change in crystallinity, color or any other change in aspect ratio was detected in the resulting co-crystal.

2) Hygroscopicity: It is less hygroscopic than free acid under normal drug storage conditions (<75% RH).

3) Bioavailability: The improvement for the urea cocrystal in oral exposure and bioavailability compared to the free acid was unexpected.

Therefore, said urea co-crystal provides advantages in the preparation of solid dosage forms containing the pharmacologically active compound, facilitating operations and providing a better mode of administration. Moreover, the urea cocrystal of the present invention is a stable solid even under stringent stability test conditions. This co-crystal is less hygroscopic than the free acid, in particular up to 75% RH, as can be seen in the examples by comparing the moisture change achieved in the urea co-crystal (0.08% at 75% RH) with that for the free acid (0 .43% at 75% RH).

Nicotinamide cocrystal

The present inventors have surprisingly found that a cocrystal of (1R,3S)-3-(5-cyano-4phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with nicotinamide has all of the following advantages:

1) stability under harsh conditions (one week) and in a 4-week stability study: the resulting cocrystal showed no change in crystallinity, color or any other change in aspect ratio during both stability studies;

2) hygroscopicity: it is less hygroscopic than free acid in the range of 5-70% RH;

3) Bioavailability: The improvement for the nicotinamide cocrystal in oral exposure and bioavailability compared to the free acid was unexpected.

Therefore, this nicotinamide co-crystal provides advantages in the preparation of solid dosage forms containing the pharmacologically active compound, facilitating operations and providing a better mode of administration. Moreover, the nicotinamide cocrystal of the present invention is a stable solid even under stringent stability testing conditions. This cocrystal is less hygroscopic than the free acid, particularly in the range of 5-70% RH, as can be seen in the examples by comparing the humidity change achieved in the nicotinamide cocrystal.

As shown in Examples 5-8, the resulting cocrystals exhibit improved melting point, hygroscopicity, and bioavailability characteristics compared to the free acid.

Therefore, the first object of the present invention is cocrystals of (1R,3S)-3-(5-cyano-4phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid with a cocrystal-forming compound selected from the group consisting of: gentisic acid, urea and nicotinamide.

In the context of the present invention, the term cocrystal is used to refer to a crystalline material consisting of two or more different molecules in a specific stoichiometric ratio in the same crystal lattice, which interact through nonionic and noncovalent bonds. Typically, cocrystals consist of an API moiety, such as (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, and a cocrystal-forming compound (coformer, cocrystal-forming substance , guest molecule).

In the context of the present invention, the term cocrystal-forming compound or coformer is used to refer to a component that is typically solid at room temperature and that interacts nonionically with the API crystal lattice.

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 Q3C (R6) guideline, preferably selected from the group consisting of the following : water, methanol, ethanol, isopropanol, propanol, butanol, acetonitrile, ethyl acetate, isobutyl acetate, propan-2-one (acetone), methyl isobutyl ketone (MIBK), tetrahydrofuran (THF), 1,4dioxane, dichloromethane (DCM), p-xylene , ethyl ether, methyl tert-butyl ether (TMBE) and heptane.

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

In a more preferred embodiment, the ratio of moles of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to moles of gentisic acid in said cocrystal is from 0.9 to 1 ,1, preferably 1:1.

In a more preferred embodiment, a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 181.69°C.

In a more preferred embodiment, a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid is characterized by an X-ray powder diffraction pattern including 2θ° peaks at 6.99, 13 ,29, 13.42, 14.02, 17.82 (all ± 0.20) 2θ° where X-ray diffraction is examined using CuKa radiation. In a more preferred embodiment, the x-ray diffraction pattern contains 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, 31.56 (all ± 0.20) 2θ°.

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

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In a more preferred embodiment, the ratio of the number of moles of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to the number of moles of urea in said co-crystal is from 0.9 to 1, 1, preferably 1:1.

In a more preferred embodiment, the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 197 .7°C.

In a more preferred embodiment, the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea is characterized by an X-ray powder diffraction pattern including 2θ° peaks at 8.32, 8. 82, 13.86, 15.60, 16.47, 24.86 (all ± 0.20) 2θ°, where X-ray diffraction is examined using CuKa radiation. In a more preferred embodiment, the x-ray diffraction pattern contains 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 ± 0.20) 2θ°.

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

In a more preferred embodiment, the ratio of moles of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid to moles of nicotinamide in the cocrystal is from 0.9 to 1.1 , preferably 1:1.

In a more preferred embodiment, the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 189 .55°C.

In a more preferred embodiment, the cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide is characterized by an X-ray powder diffraction pattern including 2θ° peaks at 6.40, 8. 54, 11.75, 17.29, 20.88, 23.66 (all ± 0.20) 2θ°, where X-ray diffraction is examined using CuKa radiation. In a more preferred embodiment, the x-ray diffraction pattern contains 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 ± 0.20) 2θ°.

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 value of the free acid and cocrystal-forming compounds is < 1, as shown in the following table. 1.

Table 1

Compound pKa of the conjugate base Arch Gentisic acid Not main - Urea Not main - Nicotinamide 3.4 0.9

General method for the preparation of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid cocrystals

Another object of the present invention is a method for preparing co-crystals of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, which is the object of the present invention, comprising:

a) reacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and a crystal-forming compound in the presence of liquid and

b) isolating the (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid coformer cocrystal.

Step a) involves reacting (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and a crystal-forming compound selected from the group consisting of: gentisic acid, urea and nicotinamide in the presence of liquid. In one embodiment, bringing two parent compounds into contact can be accomplished by mixing them. In one embodiment, the mixture obtained in step a) may be seeded with fine crystals of the desired co-crystal of the compound to facilitate precipitation, although not necessary, to form co-crystals.

(1R,3S)-3-(5-Cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid is prepared according to the procedures disclosed in patent application WO 2009/044250A1, which is incorporated herein as links.

In a preferred embodiment, when the cocrystal-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 in a molar ratio from 0:9 to 1:1.5, preferably from 1:1 to 1:1.5, preferably from 1:1 to 1:1.2. The interaction of these two starting compounds can be done by mixing them. Mixing both compounds

- 5 045045 can be carried out, for example, by magnetic stirring. The mixture may be a solution or a suspension. Preferably, step a) involves mixing the acid and gentisic acid at the boiling point of the liquid forming part of the solution or suspension, preferably to form a solution. In a preferred embodiment, the mixture is kept, preferably at reflux and stirring, for 30 minutes to 24 hours, more preferably 5 to 18 hours, even more preferably 10 to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or gentisic acid. Preferably, the liquid is selected from the group consisting of the following: 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.

In another preferred embodiment, when the cocrystal-forming compound is urea, in step a) (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea are in molar ratio from 0.9:1 to 1:1.5, preferably from 1:1 to 1:1.5, preferably from 1:1 to 1:1.2. The interaction of these two starting compounds can be done by mixing them. Mixing of both compounds can be carried out, for example, by magnetic stirring. The mixture may be a solution or a suspension. Preferably, step a) involves mixing the acid and urea at the boiling point of the liquid forming part of the solution or suspension, preferably until a solution is obtained. In a preferred embodiment, the mixture is kept, preferably at reflux and stirring, for 30 minutes to 24 hours, more preferably 5 to 18 hours, even more preferably 10 to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or urea. Preferably, the liquid is selected from the group consisting of the following: 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.

In a preferred embodiment, when the cocrystal-forming compound is nicotinamide, in step a) (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide are in molar ratio from 0:9 to 1:1.5, preferably from 1:1 to 1:1.5, preferably from 1:1 to 1:1.2. The interaction of these two starting compounds can be done by mixing them. Mixing of both compounds can be carried out, for example, by magnetic stirring. The mixture may be a solution or a suspension. Preferably, step a) involves mixing the acid and nicotinamide at the boiling point of the liquid forming part of the solution or suspension, preferably to form a solution. In a preferred embodiment, the mixture is kept, preferably at reflux and stirring, for 30 minutes to 24 hours, more preferably 5 to 18 hours, even more preferably 10 to 15 hours.

The liquid may be any suitable liquid that does not react with (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid or nicotinamide. Preferably, the liquid is selected from the group consisting of the following: 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 .

As used herein, the term alkyl includes straight or branched hydrocarbon chains containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, and not containing multiple bonds. If the term alkyl contains an expression that indicates the number of carbon atoms, such as C1- _C3 , it means that the specified alkyl contains the specified number of carbon atoms, such as from 1 to 3 carbon atoms.

As used herein, the term alkanol includes straight or branched alkyl chains as defined above linked to a hydroxy 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.

As used herein, the term aliphatic hydrocarbons means compounds consisting of carbon and hydrogen atoms, saturated or containing one or more multiple bonds (double or triple bonds), for example, one, two or three multiple bonds, linear, branched or cyclic; preferably containing 5 to 12 carbon atoms, more preferably 5 to 8 carbon atoms, and even more preferably 6 or 7 carbon atoms. Examples of aliphatic hydrocarbons include, but are not limited to, pentane, hexane, heptane, cyclopentane,

- 6 045045 cyclohexane and mixtures thereof, preferably heptane and cyclohexane and mixtures thereof.

As used in the present invention, the term aromatic hydrocarbons means cyclic compounds consisting of carbon and hydrogen atoms, unsaturated and according to Hückel's rule, preferably containing 6 carbon atoms in the ring, optionally substituted with one, two or three C ₁ -C ₃ alkyl groups, which may be the same or different. Examples of aromatic hydrocarbons are toluene and xylene and mixtures thereof.

As used herein, the term ether means compounds of the formula RO-R', in which R and R' are selected from the following: (a) alkyl chains as defined above, (b) in which R and R' together form an alkylene chain - (CH ₂ ) _m where m is an integer selected from 4 to 6, optionally substituted with a C1-C3 alkyl group, or (c) in which R and R' together form a -(CH ₂ ) _n - group O-(CH ₂ )p-, n and p are integers independently selected from 1 to 3. Examples of ether include, but are not limited to, diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, methyltetrahydrofuran and their mixtures.

As used herein, the term ketone means compounds of the formula RC(=O)-R', wherein R and R' are independently selected from alkyl radicals as defined above. Examples of ketones are, in particular, acetone and methyl isobutyl ketone and mixtures thereof.

As used in the present invention, the term ester means the group R-COOR', in which R and R' independently represent an alkyl radical as defined above. Examples of esters are ethyl acetate and isobutyl acetate and mixtures thereof.

The term gentisic acid is used herein to refer to the compound whose IUPAC name is 2,5-dihydroxybenzoic acid.

The term urea is used herein to refer to a compound whose formula is (NH ₂ ) ₂ -C=O.

The term nicotinamide is used herein to refer to the compound whose IUPAC name is 3-pyridinecarboxamide.

In one embodiment of the present invention, the liquid in step a) is selected from the group consisting of the following: 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-xylene diethyl ether, methyl tert-butyl ether (TMBE) and heptane, and mixtures thereof.

The volume of liquid used in the method can be determined by one skilled in the art. Preferably, a volume (in milliliters) of 1 to 50 times the volume of 1 mole of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid is used, more preferably 1-10 times.

One skilled in the art can determine when a (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid cocrystal is formed, for example, using standard procedures such as thin layer chromatography, nuclear magnetic resonance or high performance liquid chromatography.

After the formation of said co-crystal, step b) is carried out, i.e. isolating the resulting cocrystal by conventional techniques used in the field of technology to which the present invention relates, for example, by filtration.

Preferably, step b) may further include the steps of washing the resulting co-crystal to remove impurities and drying said co-crystal. The washing is preferably carried out with the same liquid as used in step a). Drying is preferably carried out in vacuum and at room temperature.

Combinations and pharmaceutical compositions

The present invention also provides a combination product containing a cocrystal of the present invention and one or more therapeutic agents selected from the following: a) angiotensin converting enzyme inhibitors (ACE inhibitors), b) angiotensin receptor antagonists, c) statins, d ) beta blockers, e) calcium antagonists and f) diuretics.

Examples of ACE inhibitors include, but are not limited to, captopril, enalapril and benazepril.

Examples of angiotensin receptor antagonists include, for example, losartan, azilsartan, irbesartan and eprosartan.

Examples of statins include, but are not limited to, atorvastatin, fluvastatin, simvastatin and lovastatin.

Examples of beta blockers include, but are not limited to, acebutol, atenolol, betaxolol, carvedilol and propanolol.

Examples of calcium antagonists are, for example, amlodipine, verapamil, vidipine and isradipine.

Examples of diuretics include, but are not limited to, chlorothiazide, chlorthalidone, furosemide and

- 7 045045 spironolactone.

Said combination product may be a pharmaceutical composition containing a co-crystal and one or more therapeutic agents. Alternatively, in a combination product, the cocrystal and one or more therapeutic agents are in different compositions.

In addition, the present invention also relates to pharmaceutical compositions containing a co-crystal as defined above, or a combination as defined above, and a pharmaceutically acceptable excipient. In particular, the cocrystal is present in a therapeutically effective amount. The therapeutic agent, if contained, is also preferably contained in a therapeutically effective amount.

An effective amount or 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 varies from subject to subject depending on the age and general health of the individual, the particular active agent or agents, and the like. Therefore, it is not always possible to determine the exact effective amount. However, the appropriate effective amount for any particular case can be determined by one skilled in the art through standard experimentation.

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

Co-administration can, for example, be carried out in the form of a composition containing a co-crystal according to the present invention and one or more therapeutic agents as defined above, or by simultaneous administration, i.e. administering at the same time the cocrystal of the present invention and one or more therapeutic agents as defined above, which are formulated independently, i.e., when they are not part of the same composition.

Sequential administration preferably means administering a cocrystal of the present invention at one point in time and one or more therapeutic agents as defined above at another point in time, alternately.

Separate administration preferably means the administration of a cocrystal according to the present invention and one or more therapeutic agents as defined above, independently of each other at different points in time.

The term pharmaceutically acceptable excipient means a carrier, diluent or excipient that is administered with the active ingredient. Such pharmaceutical excipients can be sterile liquids such as water and oils, including petroleum, animal or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solutions of the cocrystal and aqueous solutions of dextrose and glycerol are preferably used as carriers, especially for injection solutions.

Examples of pharmaceutically acceptable excipients for oral administration of the pharmaceutical compositions of the present invention include conventional excipients known in the art, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone; fillers, eg lactose, mannitol, xylitol, sorbitol, sucrose, corn starch, calcium phosphate, sorbitol, glycine, dextrose, maltodextrin, dextran, dextrin, modified starches; Tablet glidants and lubricants, e.g. magnesium stearate, calcium stearate, stearic acid, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, colloidal silica, silica, anhydrous colloidal silica, 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, hydroxypropylcellulose or sorbitan fatty acid esters; pharmaceutically acceptable wetting agents such as sodium lauryl sulfate; solubilizing agents in water 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 sodium saccharinate, sodium cyclamate and aspartame; flavoring agents such as menthol and peppermint oil.

The pharmaceutical compositions of the present invention can be administered parenterally, orally or topically, preferably by the oral route.

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

Pharmaceutical compositions may also be in oral form, solid or liquid. Suitable dosage forms for oral administration may be tablets, capsules, syrups or powders for solution or oral suspensions, granules, sachets. Preferably, the dosage form is selected from the group consisting of tablets and capsules.

The above preparations are prepared according to standard methods, such as those described or suggested in the Spanish and US Pharmacopoeias and similar reference books.

Application in medicine

The cocrystals that are the object of the present invention have/retain high antagonistic activity towards the A ₁ adenosine receptor.

Thus, the present invention also relates to the use of a cocrystal as described above, a combination product of a cocrystal as provided herein, together with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above, as a drug.

This subject matter may also be formulated as a cocrystal of the present invention described above, a combination product of a cocrystal of the present invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above for the preparation of a medicament. .

Another aspect of the present invention is the cocrystal of the present invention described above, a combination product of the cocrystal of the present invention together with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above for use in the treatment of and/or prevention of a disease that is known to improve with antagonism of the adenosine A ₁ receptor.

This subject matter may also be stated as the use of a cocrystal of the present invention as described above, a combination product of the cocrystal of the present invention, together with one or more therapeutic agents as defined above, or a pharmaceutical composition as defined above, for the preparation of a medicinal product. agents for the treatment and/or prevention of a disease that is known to improve with antagonism to the adenosine receptor Ai.

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

A disease or pathological condition that is ameliorated by antagonism of the adenosine _Ai receptor, selected from the group consisting of the following: hypertension, heart failure, ischemia, supraventricular arrhythmia, acute renal failure or any other disease caused by fluid retention, myocardial reperfusion injury , asthma, allergic reactions including rhinitis and urticaria, scleroderma and autoimmune diseases such as multiple sclerosis. In a preferred embodiment, the disease or condition ameliorated by adenosine A1 receptor antagonism is selected from the group consisting of heart failure, acute renal failure, asthma, hypertension, and intradialytic hypotension.

The terms treat and treat as used herein mean reversing, alleviating, inhibiting the progression of the disease or condition to which the term refers, or one or more symptoms of the disease or condition.

The terms prevent and prevent as used in the present invention mean suppressing the occurrence of a disease or condition to which the term refers, or one or more symptoms of such a disease or condition.

For the use of the present invention, the cocrystal of the present invention, combination product or pharmaceutical composition can be administered 1, 2, 3, 4 or 5 times per day. For use, the cocrystal of the present invention, combination product, or pharmaceutical composition can be administered until the symptoms of the disease or condition being treated are reversed, alleviated, or suppressed.

The following non-limiting examples are intended to illustrate the present invention and should not be construed as limiting its scope.

- 9 045045

Examples

General provisions

Analysis by Ή-NMR.

Nuclear magnetic resonance analysis was performed in DMSO-d ₆ on a Varian Mercury 400 MHz spectrometer equipped with a 5 mm ATB 1H/19F/X broadband probe. Spectra were recorded with 5-10 mg of sample dissolved in 0.7 ml of deuterated solvent.

Analysis using XRPD.

Diffraction studies of the starting material and screening samples were carried out under ambient conditions on a PANalytical X'Pert PRO θ-θ diffractometer with a radius of 240 mm in reflection mode, equipped with a Cu Ka radiation source and a PIXcel detector operating at 45 kV and 40 mA. Each sample was mounted in a silicon holder with zero background and allowed to rotate at 0.25 rpm during data acquisition. Measurements were carried out in the angle range of 3.0-40.0° (2θ) in increments of 0.013°. The scanning speed during the study was 0.082°/s (40.80 s/step) for the original substances and 0.328°/s (10.20 s/step) for the deuterated samples.

DSC analysis was performed on a Mettler Toledo DSC2 instrument. The sample was weighed into a 40 ml aluminum crucible with a micro-hole lid and heated from 25 to 300°C at a rate of 10°C/min under a nitrogen atmosphere (50 ml/min).

The crystal stability study was carried out under accelerated conditions (40°C, 75 ± 5 RH%) for one week. A sample of each shape, placed in a silicon XRPD holder, was exposed to conditions in an environmental chamber. It should be noted that these conditions are very stringent, since the large surface area exposed under storage conditions can contribute to the possible transformation of crystals. Samples were periodically analyzed by XRPD to detect possible transformations.

An additional study of crystal stability was carried out under accelerated conditions (40°C, 75 ± 5 RH%). Cocrystal samples were kept in an open dish and exposed in a climate chamber, maintaining conditions to the following precision (40°C - 75% RH ± 5 RH). These samples were analyzed weekly for 1 month.

Hygroscopicity study.

The hygroscopicity of the cocrystals was determined using DVS (dynamic vapor sorption) on a Q5000 TA instrument. It is a gravimetric technique that measures the amount of water adsorbed to and desorbed from the sample at different relative humidity (RH) values. At each RH value, the sample mass was allowed to reach gravimetric equilibrium (or held for a limited time) and then moved to the next moisture value. Sorption and desorption isotherms were obtained at 25°C in the range of 0-95%RH. The sample is not pre-dried, but is kept at 0% RH to constant weight before running the DVS cycle. This equilibration step ensures that any water adsorbed from the atmosphere is removed. Relative humidity (RH) is controlled by a mixture of dry and wet nitrogen flow. RH is kept constant until equilibrium (constant mass) is established or time elapses until the next RH value is established.

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 detail in patent application WO 2009/044250 A1, which is included in the present invention as links.

Ή-NMR (300 MHz, DMSO-d ₆ ): 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).

In fig. Figure 1 shows the 1H NMR spectrum of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

In fig. Figure 2 shows the XRPD XRD pattern of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid.

In fig. Figure 3 shows the DSC diagram of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid, which has an endothermic event starting at 179.59°C, which corresponds to melting point of this compound.

Example 2. Preparation of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid

In a round bottom flask equipped with a magnetic stirrer and containing a mixture of (1R,3S)-3-(5-cyano4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (300 mg, 0.88 mmol) and gentisic acid ( 169 mg, 1.10 mmol, 1.25 eq.), TBME (3 ml) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sintered glass filter (porosity no. 3) and washed with TBME (2x0.2 ml). After drying under vacuum at RT, a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and gene-tisinic acid was obtained as a white solid.

In fig. Figure 4 shows the 1H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid of Example 2, confirming the molar ratio of 1:1.

The cocrystal of Example 2 was also characterized by XRPD. In fig. 5 shows the corresponding diagram and table. Figure 2 shows the main peaks.

table 2

Positions [°2-theta ± 0.2] Relative intensity [%] 6.99 100 13.29 6.2 13.42 6.3 14.02 5.6 17.82 4.2 18.71 2.7 21.09 3 26.34 1.8 26.58 1.1 27.28 1.5 28.24 2.5 31.56 1.1

In fig. 6 is a DSC diagram of the cocrystal of Example 2, which shows an endothermic event starting at 181.69° C., which corresponds to the melting point of the cocrystal.

Example 3. Preparation of co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea

In a round bottom flask equipped with a magnetic stirrer and containing a mixture of (1R,3S)-3-(5-cyano4-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 hours. The suspension was then filtered through a sintered glass filter (porosity no. 3) and washed with ACN (2x0.2 ml). After drying under vacuum at RT, the cocrystal of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and urea was obtained as a white solid.

In fig. Figure 7 shows the ¹ H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and urea, confirming the molar ratio of 1:1.

The cocrystal of Example 3 was also characterized by XRPD. In fig. 8 shows the corresponding diagram and table. Figure 3 shows the main peaks.

- 11 045045

Table 3

Positions [°2-theta ± 0.2] Relative intensity [%] 7.77 7 8.32 27 8.82 100 31 15.60 19 16.47 18 18.23 17 18.94 6 19.38 14 19.86 16 20.05 15 20.71 10 21.38 7 21.84 5 22.76 7 23.02 eleven 24.86 19 26.10 6 27.28 16 28.40 6

In fig. 9 is a DSC diagram of the cocrystal of Example 3, which has an endothermic event starting at 197.72°C, which corresponds to the melting point of this cocrystal.

Example 4. Preparation of a co-crystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide

In a round bottom flask equipped with a magnetic stirrer containing a mixture of (1R,3S)-3-(5-cyano4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid (400 mg, 1.17 mmol, 2 eq.) and nicotinamide (71.5 mg, 0.59 mmol), MIBK (4 ml) was added. The resulting mixture was stirred at room temperature for 15 hours. The suspension was then filtered through a sintered glass filter (porosity no. 3) and washed with MIBK (3x0.2 ml). After drying under vacuum at RT, the cocrystal of (1R,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide was obtained as a white solid.

In fig. 10 shows the 1H NMR spectrum of a cocrystal of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide, confirming the molar ratio of 1:1.

The cocrystal of Example 4 was also characterized by XRPD. In fig. 11 shows the corresponding diagram and table. Figure 4 shows the main peaks.

- 12 045045

Table 4

Positions [°2-theta ± 0.2] Relative intensity [%] 6.40 100 8.54 55 11.28 AND 11.75 64 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 20 70 24 32 15 eleven 41 12 13 19 29 44 12 23 19 13 I 7 12 8 15 5

In fig. 12 is a DSC diagram of the cocrystal of Example 4, which has an endothermic event starting at 189.55° C., which corresponds to the melting point of this cocrystal.

Example 5: Stability Study

The stability of cocrystalline forms of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid was studied under accelerated storage conditions (40°C, 75 ± 5 RH%) for from 1 to 4 weeks. See results in table. 5.

Table 5

Compound 1 Week 2 weeks 3 weeks 4 weeks Example 2: Co-crystal of (lR,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid stable stable stable stable Example 3: Co-crystal of (lR,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and urea stable stable stable stable Example 4: Co-crystal of (lR,3S)-3-(5cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide stable stable stable stable

After exposure, the cocrystals remained stable as determined by XRPD analysis. No amorphization or appearance of crystalline forms was detected within the detection limits under the analytical conditions.

Example 6: Hygroscopicity Study

The table below (Table 6) shows the moisture content of the original carboxylic acid and cocrystals according to the hygroscopicity study.

- 13 045045

Table 6

Compound 15% RH 35% RH 55% RH 75% RH Example 1: (III,38)-3-(5-cyano-4-phenyl-1,3thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid 0.0168 0.1842 0.3008 0.4369 Example 2: Cocrystal (III,38)-3-(5-cyano4-phenyl-1,3-thiazol-2- ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid 0.0079 0.0175 0.0398 0.1035 Example 3: Co-crystal of (III,38)-3-(5-cyano4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and urea 0.015 0.0339 0.0545 0.0895 Example 4: Co-crystal of (III,38)-3-(5-cyano4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide 0.029 0.066 0.165 0.4584

As can be seen from the table above, the gentisic acid co-crystal and the urea co-crystal are less hygroscopic than the free acid, particularly up to 75% RH. See fig. 13-16.

Example 7: Oral Bioavailability Studies

The objective of this study was to investigate the plasma pharmacokinetics of different cocrystals derived from (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentαnecarboxylic acid after one intravenous (IV) and oral (PO) administration to male SD rats.

Animals were divided into two groups: group 1 (IV: 1 mg/kg) and group 2 (PO: 5 mg/kg). Animals of groups 1 and 2 were injected with solutions of different cocrystals of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid in normal saline. Blood samples were collected from a set of three rats at each time point in a labeled microcentrifuge tube containing K2EDTA solution as an anticoagulant at a dose of Pre, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h ( IV) and at dose, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours (PO). Plasma samples were isolated by centrifugation of whole blood and stored at temperatures below −70 ± 10°C until biological analysis. All samples were treated with acetonitrile for protein precipitation analysis and analyzed using fit-for-purpose LC-MS/MS (LLOQ=1.00 ng/mL). Pharmacokinetic parameters were calculated using Phoenix WinNonlin® non-block analysis software (Version 6.3).

The main pharmacokinetic parameters obtained for examples 1-4 are given below in table. 7.

Table 7

Compound Path Dose (mg/kg) Spach (ng/ml) AUCiast (ng/ml*h) Clearance (ml/min/kg) F% Example 1: (lR,3S)-3-(5cyano-4-phenyl-1,3- iv 1 - 2204.38 6.3 - ro 5 2012 5200.71 - 47

- 14 045045

thiazol-2- ylcarbamoyl)cyclopentanecarboxylic acid Example 2: Co-crystal of (1K,38)-3-(5-cyano-4phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and gentisic acid acids iv 1 - 3304.55 5.03 - ro 5 8642.28 16502.48 100 Example 3: Co-crystal of (1H38)-3-(5-cyano-4phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and urea iv 1 - 3441.71 4.82 - Ro 5 12028.35 21456.11 100 Example 4: Co-crystal of (1C.38)-3-(5-cyano-4phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid and nicotinamide iv 1 - 2714.55 6.12 - Ρθ 5 10227.47 19238.03 100

po: oral administration (per os) iv: intravenous administration

Cmax means the maximum plasma drug concentration obtained after oral administration of the drug during the period from the time of administration to the final follow-up.

AUC _last means the area under the curve from the time of administration to the final observation that is greater than the limit of quantitation.

Clearance refers to the body's ability to remove a drug from the plasma and is calculated for intravenous administration.

F% means bioavailability. Systemic availability of a compound after oral administration is calculated using the following equation:

F (%)=(AUC _last POx dose IV/AUC _last IVx dose PO)x100

As can be seen from the table above, cocrystals with gentisic acid, urea and niacinamide have greater bioavailability than the free acid.

Example 8: Comparative Bioavailability Study in Healthy Volunteers

In this study, healthy volunteers were males 18 years of age or older and examined the bioavailability of Example 2 compared to Example 1 under fasting conditions and examined the effects of a high-fat, high-calorie meal. The compounds of Example 1 (5 mg) and Example 2 (7.3 mg) were administered orally in a single dose. The study was randomized, open-label, 4-fold crossover.

To determine comparative bioavailability, AUC _0-t (AUC _0-t : area under the plasma concentration-time curve from time 0 to the last measurable concentration) and Cmax ( _Cmax : observed maximum plasma concentration (peak exposure)) were determined after each administration.

results

The study included 16 volunteers. For all volunteers, the starting samples did not contain the compound of Example 1. Therefore, all data were included in the pharmacokinetic measurements without correction. See table. 8.

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Claims (12)

Table 8 Parameter Example 1 mean ± SD (geometric mean) Example 2 mean ± SD (geometric mean) Example 1 mean ± SD (geometric mean) Example 2 mean ± SD (geometric mean) On an empty stomach On an empty stomach After meal After meal AUC0-t (ng/ml ^x h) 1155.0 ± 567.8 (1052.8) 1138.5 ± 451.1 (1071.4) 588.1 ± 160.9 (567.9) 599.1 ± 132.1 (585.9) AUCO-co (ng/ml reagent grade) 1257.2 ± 661.9 (1132.2) 1216.5 ± 483.3 (1141.7) 657.9 ± 191.4 (632.7) 675.0 ± 158.8 (659.1) Stach (ng/ml) 186.7 ± 71.6 (175.9) 173.7 ± 60.7 (165.8) 68.0 ± 18.6 (65.6) 73.6 ± 25.1 (69.8) tmax (h)* 2.5 (1.5-4.0) 2.25(1.5-5.0) 7.0 (5.0-7.0) 7.0 (5.0-7.0) *: median and range AUC _0-t : Area under the plasma concentration-time curve until the last sample quantified (time t), calculated using the trapezoidal method. AUC _0-a : Area under the plasma concentration-time curve extrapolated to infinity, calculated as follows: AUC0.AUC0t.Ctke, where C _t is the quantified concentration at time t and ke is the elimination constant. The latter was calculated using linear regression analysis during the last monoexponential phase of elimination (Phoenix WinNonLin). In all cases, at least three plasma concentrations were used to determine this phase. _Cmax : maximum concentration. t _max = settling time C _max . The bioavailability of the compound of Example 1 was similar to the value for the compound of Example 2 with 90% confidence intervals being within the acceptable limits for bioequivalence (80.00125.00%) for AUC _0-t and C _max in the fasting state and for AUC _0-t after food. The _Cmax for Example 2 was slightly greater when administered after a high-fat meal. CLAIM 1. Co-crystal including: a) (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2-ylcarbamoyl)cyclopentanecarboxylic acid and b) a co-crystal forming compound selected from the group consisting of the following: gentisic acid, urea and nicotinamide. 2. The cocrystal according to claim 1, wherein the compound forming the cocrystal is gentisic acid. 3. The cocrystal according to claim 2, where the ratio of the number of moles of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid to the number of moles of gentisic acid in said cocrystal is from 0 .9:1 to 1.1:1 and is preferably 1:1. 4. The cocrystal according to any one of claims 2, 3, wherein the cocrystal has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 181.69°C. 5. Co-crystal according to any one of claims 2-4, where the co-crystal is characterized by a powder X-ray diffraction pattern including 2θ° peaks at 6.99, 13.29, 13.42, 14.02, 17.82 ± 0.20 2θ°, where X-ray diffraction is studied using CuKa radiation. 6. The co-crystal according to claim 1, wherein the compound forming the co-crystal is urea. 7. A co-crystal according to claim 6, where the ratio of the number of moles of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid to the number of moles of urea in said co-crystal is from 0. 9:1 to 1.1:1 and preferably 1:1. 8. The cocrystal according to any one of claims 6, 7, wherein the cocrystal has a differential scanning calorimetry (DSC) thermogram containing an endothermic peak at approximately 197.7°C. 9. Co-crystal according to any one of claims 6 to 8, wherein the co-crystal is characterized by an X-ray powder diffraction pattern including 2θ° peaks at 8.32, 8.82, 13.86, 15.60, 16.47, 24.86 ± 0.20 2θ°, where X-ray diffraction is examined using CuKa radiation. 10. The co-crystal according to claim 1, wherein the compound forming the co-crystal is nicotinamide. 11. Co-crystal according to claim 10, where the ratio of the number of moles of (1R,3S)-3-(5-cyano-4-phenyl-1,3-thiazol-2ylcarbamoyl)cyclopentanecarboxylic acid to the number of moles of nicotinamide in said cocrystal is from 0. 9:1 to 1.1:1 and preferably 1:1. 12. Co-crystal according to any one of claims 10, 11, where the co-crystal has a differential thermogram -