Crystalline forms of par4 inhibitor

Abstract

The present invention relates to co-crystals of a compound of formula (I) in which the co-former molecule is succinic acid or citric acid, processes for preparing the co-crystals, pharmaceutical compositions thereof, and methods of treating or preventing thromboembolic disorders using the co-crystals.

Description

[0001] This application is a continuation-in-part of the application filed on December 20, 2019, having application number 201980085324.0 (International Application Number PCT / US2019 / 067717), entitled “CRYSTALLINE FORMS OF PAR4 INHIBITORS.”

[0002] Cross Reference to Related Applications

[0003] This application is entitled to the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 783,223, filed December 21, 2018, which is incorporated herein in its entirety. TECHNICAL FIELD

[0004] The present invention relates to a co-crystal of the protease-activated receptor-4 (PAR4) antagonist 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide. The present invention also relates to methods of manufacture, pharmaceutical compositions, and methods of using the co-crystal of the present invention. BACKGROUND

[0005] Despite the availability of anticoagulants such as warfarin Heparin, low molecular weight heparin (LMWH), synthetic pentasaccharide, and antiplatelet agents such as aspirin and clopidogrel Thromboembolic disorders, however, remain a major cause of death in developed countries.

[0006] Current antiplatelet therapy has limitations, including increased risk of bleeding and partial efficacy (relative cardiovascular risk reduction in the range of 20% to 30%). Thus, the discovery and development of safe and effective oral or parenteral antithrombotic drugs for the prevention and treatment of a wide range of thromboembolic disorders remains an important goal.

[0007] Alpha-thrombin is the most potent known activator of platelet aggregation and degranulation. Activation of platelets is causally related to atherothrombotic vascular occlusion. Thrombin activates platelets by cleaving G-protein coupled receptors known as protease-activated receptors (PARs). PARs provide their own cryptic ligands present in the N-terminal extracellular domain that are unmasked by proteolytic cleavage, followed by intramolecular binding to the receptor molecule to induce signaling (tethered ligand mechanism; Coughlin, S.R., Nature, 407:258-264 (2000)). Synthetic peptides that mimic the sequence of the newly formed N-terminus after proteolytic activation can induce signaling independent of receptor cleavage. Platelets are key players in atherothrombotic events. Human platelets express at least two thrombin receptors, commonly referred to as PAR1 and PAR4. Inhibitors of PAR1 have been extensively studied, and several compounds including vorapaxar and atopaxar have entered late stage clinical trials. Recently, vorapaxar did not significantly reduce cardiovascular events but significantly increased the risk of major bleeding in the TRACER phase III trial in ACS patients (Tricoci, P. et al., N. Eng. J. Med., 366(1):20-33 (2012)). Thus, there remains a need to discover new anti-platelet agents with increased efficacy and reduced bleeding side effects.

[0008] The compound 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,l-b][l,3,4]thiadiazol-6- yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide (Compound (I)) of formula (I) is a PAR4 inhibitor and its synthesis, and preparation as a free form solid material, and uses are described in WO 2013 / 163279.

[0009] SUMMARY

[0010] The present invention relates to a co-crystal comprising a compound of formula (I),

[0011]

[0012] and succinic acid or citric acid, pharmaceutical compositions comprising them, and the treatment or prevention of thromboembolic disorders by administering to a patient or mammal in need thereof an effective amount of said co-crystal. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1Simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns are shown for the succinic acid co-crystal of the compound of formula (I).

[0014] Figure 2 DSC is shown for the succinic acid co-crystal of the compound of formula (I).

[0015] Figure 3 TGA is shown for the succinic acid co-crystal of the compound of formula (I).

[0016] Figure 4 FT-Raman spectra are shown for the succinic acid co-crystal of the compound of formula (I).

[0017] Figure 5 FT-IR spectra are shown for the succinic acid co-crystal of the compound of formula (I).

[0018] Figure 6 Simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns are shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0019] Figure 7 DSC is shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0020] Figure 8 TGA is shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0021] Figure 9 FT-Raman is shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0022] Figure 10 C-13 CPMAS SSNMR is shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0023] Figure 11 FT-IR is shown for the N-1 form of the citric acid co-crystal of the compound of formula (I).

[0024] Figure 12 Simulated (bottom, calculated from atomic coordinates generated at room temperature) and experimental (top) PXRD patterns are shown for the N-2 form of the citric acid co-crystal of the compound of formula (I).

[0025] Figure 13 DSC is shown for the N-2 form of the citric acid co-crystal of the compound of formula (I).

[0026] Figure 14 TGA is shown for the N-2 form of the citric acid co-crystal of the compound of formula (I).

[0027] Figure 15 The dissolution of the citric acid co-crystal and the succinic acid co-crystal of the compound of formula (I) is shown in comparison to the dissolution of the free form of the compound of formula (I).

[0028] Figure 16 The pharmacokinetic (PK) profile of the citric acid co-crystal and the succinic acid co-crystal of the compound of formula (I) in dogs is shown. DETAILED DESCRIPTION

[0029] In one embodiment of the application is a co-crystal of the compound of formula (I) and a coformer, wherein the coformer is citric acid or succinic acid

[0030]

[0031] In another embodiment of the application the coformer is succinic acid.

[0032] In another embodiment the co-crystal of the compound of formula (I) and succinic acid is characterized by one or more of:

[0033] a) a single crystal structure having unit cell parameters substantially equal to:

[0034]

[0035] wherein the measurement of the single crystal structure is at room temperature;

[0036] b) an observed PXRD pattern substantially as shown in Figure 1 ;

[0037] c) a PXRD pattern comprising 4 or more 2theta values selected from the group consisting of 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, and 25.9 ± 0.2 (obtained at room temperature and

[0038] d) an infrared spectrum substantially as shown in Figure 5 ; and / or

[0039] e) an FT-Raman spectrum substantially as shown in Figure 6 .

[0040] In another embodiment the co-crystal of the compound of formula (I) and succinic acid has a ratio of the compound of formula (I) to succinic acid of 1 :0.5.

[0041] In another embodiment of the application the coformer is citric acid.

[0042] In another embodiment, the co-crystal of the compound of formula (I) and citric acid is in Form N-1 and is characterized by one or more of the following:

[0043] a) a single crystal structure having unit cell parameters substantially equal to:

[0044]

[0045] b) a PXRD pattern substantially as shown in Figure 6 ; and / or

[0046] c) an x-ray powder diffraction pattern comprising four or more 2Θ values (at room temperature ) selected from 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.2.

[0047] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid has a ratio of 1 : 1.

[0048] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid consists essentially of Form N-1.

[0049] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid comprises Form N-1.

[0050] In another embodiment, the co-crystal of the compound of formula (I) and citric acid is in Form N-2 and is characterized by one or more of the following:

[0051] a) a single crystal structure having unit cell parameters substantially equal to:

[0052]

[0053] b) a PXRD pattern substantially as shown in Figure 12 ; and / or

[0054] c) an x-ray powder diffraction pattern comprising four or more 2Θ values (at room temperature ) selected from 4.6 ± 0.2, 5.5 ± 0.2, 8.4 ± 0.2, 11.3 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2.

[0055] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid has a ratio of 1 : 1.

[0056] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid in Form N-2 has a ratio of 1 : 1.

[0057] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid consists essentially of Form N-2.

[0058] In another embodiment of the present application, the co-crystal of the compound of formula (I) and citric acid comprises Form N-2.

[0059] In another embodiment of the present application, the present application is directed to any one of the co-crystals in substantially pure form.

[0060] In another embodiment of the present application, the succinic acid co-crystal is characterized by a PXRD having 4 or more, 5 or more, or 6 or more 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, and 25.9 ± 0.2 (at room temperature ).

[0061] In another embodiment of the present application, the succinic acid co-crystal is characterized by a PXRD having at least one or more 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, and 25.9 ± 0.2 (at room temperature ).

[0062] In another embodiment of the present application, the succinic acid co-crystal is characterized by a PXRD having 4 or more, or 5 or more 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, and 25.9 ± 0.2 (at room temperature ).

[0063] In another embodiment of the present application, the succinic acid co-crystal is characterized by a PXRD having 4 or more, or 5 or more, or 6 or more 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, and 25.9 ± 0.2 (at room temperature ).

[0064] In another embodiment of the present application, the succinic acid co-crystal has a single crystal structure having unit cell parameters substantially equal to:

[0065]

[0066] In another embodiment, the succinic acid co-crystal is characterized by a FT-IR substantially in accordance with Figure 5 In another embodiment, the succinic acid co-crystal is characterized by a FT-IR substantially in accordance with -1 FT-IR spectrum having peaks at 1627.9, 1704.4, and 3102.1 cm -1 ).

[0067] In another embodiment, the succinic acid co-crystal is characterized by a FT-Raman substantially in accordance with Figure 4 In another embodiment, the succinic acid co-crystal is characterized by a FT-Raman substantially in accordance with -1 FT-Raman spectrum having peaks at 975.3, 1185.0, 1242.9, 1455.6, and 3104.4 cm -1 ).

[0068] In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD substantially in accordance with Figure 6 In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD having 4 or more, or 5 or more, or 6 or more 2-theta values selected from the group consisting of 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.2 (at room temperature ). In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD having at least one or more 2-theta values selected from the group consisting of 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.2 (at room temperature ). In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD comprising 2-theta values selected from the group consisting of 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, and 26.6 ± 0.2 (at room temperature ).

[0069] In another embodiment, the N-1 form of the citric acid co-crystal has a single crystal structure having unit cell parameters substantially equal to a single crystal structure having unit cell parameters substantially equal to:

[0070]

[0071] In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR substantially in accordance with Figure 11 In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR substantially in accordance with -1 In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR spectrum having peaks at 1585.7, 1725.9, and 3150.5 cm -1 ) ± 0.4 cm -1 ) ± 0.3 cm -1 .

[0072] In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR substantially in accordance with Figure 9 In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR substantially in accordance with -1 In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a FT-IR spectrum having peaks at 1585.7, 1725.9, and 3150.5 cm -1 ) ± 0.4 cm -1 ) ± 0.3 cm -1 .

[0073] In another embodiment, the N-2 form of the citric acid co-crystal is characterized by a PXRD substantially in accordance with Figure 12 In another embodiment, the N-2 form of the citric acid co-crystal is characterized by a PXRD having 4 or more, or 5 or more, or 6 or more 2-theta values selected from the group consisting of: 4.6 ± 0.2, 5.5 ± 0.2, 8.4 ± 0.2, 11.3 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2. In another embodiment, the N-2 form of the citric acid co-crystal is characterized by a PXRD having at least one or more 2-theta values selected from the group consisting of: 4.6 ± 0.2, 5.5 ± 0.2, 8.4 ± 0.2, 11.3 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2. In another embodiment, the N-1 form of the citric acid co-crystal is characterized by a PXRD comprising 2-theta values selected from the group consisting of 4 or more, or 5 or more 2-theta values selected from the group consisting of: 4.6 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, and 25.2 ± 0.2. (at room temperature ).

[0074] In another embodiment, the N-2 form of the citric acid co-crystal has a single crystal structure having unit cell parameters substantially equal to:

[0075]

[0076] In another embodiment, the present application describes a pharmaceutical composition comprising a therapeutically effective amount of at least one co-crystal form of a compound of Formula (I) and a pharmaceutically acceptable carrier.

[0077] In another embodiment, the present application describes a method for treating a thromboembolic disorder, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one co-crystal form of a compound of Formula (1).

[0078] In some embodiments, the present application provides a pharmaceutical composition further comprising another therapeutic agent or agents. In preferred embodiments, the present application provides a pharmaceutical composition wherein the other therapeutic agent or agents is an antiplatelet agent or a combination thereof. Preferably, the antiplatelet agent or agents is a P2Y12 antagonist and / or aspirin. Preferably, the P2Y12 antagonist is clopidogrel, ticagrelor, or prasugrel. In another preferred embodiment, the present application provides a pharmaceutical composition wherein the other therapeutic agent or agents is an anticoagulant or a combination thereof. Preferably, the anticoagulant or agents is a FXa inhibitor or a thrombin inhibitor. Preferably, the FXa inhibitor is apixaban or rivaroxaban. Preferably, the thrombin inhibitor is dabigatran.

[0079] In some embodiments, the present application provides a method for treating or preventing a thromboembolic disorder, comprising the step of administering to a subject (e.g., a human) in need of such treatment or prevention a therapeutically effective amount of at least one co-crystal form of a compound of Formula (I) disclosed herein (e.g., succinate co-crystal, citrate co-crystal, citrate co-crystal N-l, or citrate co-crystal N-2).

[0080] In some embodiments, the present application provides a method for treating a thromboembolic disorder or primary or secondary prevention of a thromboembolic disorder, comprising the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one co-crystal form of a compound of Formula (I) disclosed herein (e.g., succinate co-crystal, citrate co-crystal, citrate co-crystal N-l, or citrate co-crystal N-2), wherein the thromboembolic disorder is selected from the group consisting of an arterial cardiovascular thromboembolic disorder, a venous cardiovascular thromboembolic disorder, a cerebrovascular thromboembolic disorder, and a thromboembolic disorder in a heart chamber or in the peripheral circulation.

[0081] In some embodiments, the present application provides a method for treating or primary or secondary prevention of a thromboembolic disorder, the method comprising the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the co-crystal forms of the compound of Formula (I) disclosed herein (e.g., the succinate co-crystal, the citrate co-crystal, the citrate co-crystal N-l, or the citrate co-crystal N-2), wherein the thromboembolic disorder is selected from acute coronary syndrome, unstable angina, stable angina, ST-elevated myocardial infarction, non-ST-elevated myocardial infarction, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral arterial disease, venous thrombosis, deep vein thrombosis, thrombotic phlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, cancer-related thrombosis, and thrombosis resulting from medical implants, devices, and procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0082] In some embodiments, the present application provides a method for treating or primary or secondary prevention of a thromboembolic disorder, the method comprising the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the co-crystal forms of the compound of Formula (I) disclosed herein (e.g., the succinate co-crystal, the citrate co-crystal, the citrate co-crystal N-l, or the citrate co-crystal N-2), wherein the thromboembolic disorder is selected from acute coronary syndrome, unstable angina, stable angina, ST-elevated myocardial infarction, and non-ST-elevated myocardial infarction.

[0083] In some embodiments, the present application provides a method for treating or primary or secondary prevention of a thromboembolic disorder, the method comprising the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the co-crystal forms of the compound of Formula (I) disclosed herein (e.g., the succinate co-crystal, the citrate co-crystal, the citrate co-crystal N-l, or the citrate co-crystal N-2), wherein the thromboembolic disorder is selected from transient ischemic attack and stroke.

[0084] In some embodiments, the present application provides a method for treating or primary or secondary prevention of a thromboembolic disorder, the method comprising the step of administering to a patient (e.g., a human) in need thereof a therapeutically effective amount of one of the co-crystal forms of the compound of Formula (I) disclosed herein (e.g., the succinate co-crystal, the citrate co-crystal, the citrate co-crystal N-l, or the citrate co-crystal N-2), wherein the thromboembolic disorder is peripheral arterial disease.

[0085] In another embodiment, the present application includes the methods as described above, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombotic phlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices or surgery in which blood is exposed to artificial surfaces that promote thrombosis.

[0086] In some embodiments, the present application includes a method of inhibiting or preventing platelet aggregation comprising the step of administering to a subject (such as a human) in need thereof a therapeutically effective amount of one of the co-crystal forms of the compound of formula (I) disclosed herein (e.g., the succinate co-crystal, the citrate co-crystal, the citrate co-crystal N-l, or the citrate co-crystal N-2).

[0087] In still yet even further embodiments, each of the co-crystal forms of Compound (I) is substantially pure.

[0088] In still yet another embodiment, each of the co-crystal forms of Compound (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.% of Compound (I), based on the weight of each of the co-crystal forms of Compound (I).

[0089] In another embodiment, the compound of formula (I) can have a mixture of the co-crystals described herein.

[0090] The present application includes the use of the co-crystals of the compound of formula (I) in therapy.

[0091] The present application relates to the use of the co-crystals of the compound of formula (I) in the manufacture of a medicament for the treatment or prevention of a thromboembolic disorder.

[0092] In the manufacture of pharmaceutical compositions, a balance of the form of the active ingredient is sought that has the desired properties, such as, for example, dissolution rate, solubility, bioavailability, and / or storage stability. For example, a form of the active ingredient is sought that has sufficient solubility, bioavailability, and storage stability to prevent the conversion of the sufficiently soluble and bioavailable form to another form having undesirable solubility and / or bioavailability characteristics during storage.

[0093] The present application provides at least one co-crystal form of Compound (I) that surprisingly provides a balance of the properties sought in a pharmaceutical composition. The present application is also directed to other important aspects.

[0094] The present application also encompasses all combinations of the alternative aspects of the present application referred to herein. It is to be understood that any and all embodiments of the present application can be used in combination with any other embodiment to describe yet further embodiments of the present application. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0095] Definitions

[0096] The features and advantages of the present application can be better understood after a review of the following detailed description together with the drawings, in which like numerals refer to like features throughout. It is to be understood that certain features of the application that are, for clarity, described above and below in the context of separate embodiments can also be combined to form additional embodiments. Conversely, various features of the application that are, for brevity, described in the context of a single embodiment can also be combined or removed in other embodiments.

[0097] The names used herein to characterize particular forms, e.g., "N-1", and the like, are merely identifiers to be interpreted in light of the characterization information provided herein and should not be construed to be limiting to exclude any other substance having similar or identical physical and chemical characteristics.

[0098] The definitions set forth herein are prior to any definitions set forth in any patent, patent application and / or patent application publication incorporated by reference herein.

[0099] All numbers expressing quantities of ingredients, weight percentages, temperatures, etc. as used in the specification and claims are to be understood as approximations rather than exact specific values preferred ranges to invoke the equivalency of such subtleties in material quantity, consistency, etc. Accordingly, unless indicated to the contrary with respect to any specific numerical parameter, the numerical parameters set forth in the specification and claims are approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0100] All measurements are affected by experimental error and are within the spirit of the present application.

[0101] As used herein, "co-crystal" means a crystalline material in the solid state, which is composed of two or more molecules in the same crystal lattice, the molecules being in a neutral state, interacting via non-ionic interactions, and being a solid as individual components at room temperature.

[0102] As used herein, "polymorph" refers to a crystal form having the same chemical structure but different spatial arrangements of the molecules and / or ions forming the crystal.

[0103] As used herein, "solvate" refers to a crystalline form of molecules, atoms, and / or ions that further includes the molecules of one or more solvents, interposed in the crystal lattice structure. When the solvent is water, the form is referred to as a "hydrate." The solvent molecules in a solvate can be present in a regular arrangement and / or in a disordered arrangement. A solvate can include a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules can result from partial loss of solvent from a solvate. Solvates can exist as dimers or oligomers that include more than one molecule of the compound of Formula (I) or co-crystal in the crystal lattice structure.

[0104] As used herein, "amorphous" refers to a non-crystalline solid form of molecules, atoms, and / or ions. An amorphous solid does not exhibit a defined X-ray diffraction pattern.

[0105] As used herein, "substantially pure" when used in reference to a co-crystal form means a compound having a purity greater than 90% by weight, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% by weight, and also including equal to about 100% by weight of the co-crystal of compound (I), based on the weight of the compound. The remaining material includes one or more other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a co-crystal form of compound (I) can be considered substantially pure because it has a purity greater than 90% by weight, as measured by means known and generally accepted in the art at the time, wherein the remaining less than 10% by weight material includes other one or more forms of compound (I) and / or reaction impurities and / or processing impurities.

[0106] When dissolved, a co-crystal form of a compound of Formula (I) loses its crystal structure and is therefore referred to as a solution of a compound of Formula (I). However, all forms of the present application can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, co-crystal forms of a compound of Formula (I) can be incorporated into solid formulations.

[0107] As used herein, an XRPD (x-ray powder diffraction) or PXRD (powder x-ray diffraction) pattern "comprising" or having a plurality of peaks selected from a specified peak group is intended to include a PXRD pattern having additional peaks not included in the specified peak group. For example, a PXRD pattern comprising at least one or more, four or more, five or more, or six or more 2-theta values selected from A, B, C, D, E, F, G, and H is intended to include a PXRD pattern having: (a) at least one or more, four or more, five or more, six or more 2-theta values selected from A, B, C, D, E, F, G, and H; and (b) zero or more peaks that are not any of the A, B, C, D, E, F, G, and H peaks.

[0108] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis. The term "IR" refers to infrared spectroscopy. The abbreviation "FT" stands for Fourier Transform.

[0109] The term "room temperature" generally means about 22°C, but can vary up or down by 7°C.

[0110] When the term "substantially in accordance with" is used in reference to an XRPD or PXRD pattern, it is understood that measurements of peak positions for a given crystalline form of the same compound will vary within a range of error. It is also understood that the intensity of a peak can vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of different peaks are not intended to limit the comparison of different PXRD scans.

[0111] A "therapeutically effective amount" is intended to include an amount of a compound of the present application effective to inhibit and / or antagonize PAR4 and / or to prevent or treat a disorder listed herein when administered alone or in combination. When applied to combination therapy, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, regardless of whether the combination is administered together in a single dosage form, administered sequentially, or administered simultaneously in separate dosage forms.

[0112] As used herein, the term "thrombosis" refers to the formation or presence of a blood clot within a blood vessel that can cause ischemia or infarction of the tissue supplied by the blood vessel. As used herein, the term "embolism" refers to the sudden blocking of an artery by a clot or foreign material carried to its site of deposition by the bloodstream. As used herein, the term "thromboembolic disorder" includes both "thrombotic" and "embolic" disorders (as defined above).

[0113] The term "thromboembolic disorder" as used herein includes arterial cardiovascular, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in cardiac chambers or in the peripheral circulation. The term "thromboembolic disorder" as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndrome, atrial fibrillation, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombotic phlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices or surgery in which blood is exposed to artificial surfaces that promote thrombosis. Medical implants or devices include, but are not limited to, prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices and artificial hearts or heart chambers, and vascular grafts. Surgery includes, but is not limited to, cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term "thromboembolic disorder" includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.

[0114] In some embodiments, the therapeutically effective amount of the PAR4 compound is preferably less than about 100 mg / kg, 50 mg / kg, 10 mg / kg, 5 mg / kg, 1 mg / kg, or less than 1 mg / kg. In another embodiment, the therapeutically effective amount of the PAR4 compound is less than 5 mg / kg. In another embodiment, the therapeutically effective amount of the PAR4 compound is less than 1 mg / kg. In another embodiment, the dose is 8 mg to 48 mg. As recognized by one skilled in the art, the effective dose varies according to the route of administration and the excipient used.

[0115] The co-crystal form is typically administered in admixture with a suitable pharmaceutical diluent, excipient or carrier (collectively referred to herein as a pharmaceutical carrier) suitably selected with respect to the intended form of administration (oral tablets, capsules, elixirs, syrups, and the like) and consistent with conventional pharmaceutical practices.

[0116] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, calcium lactose, mannitol, sorbitol and the like; for oral administration in liquid form, the drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0117] The co-crystals of the present application can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0118] The co-crystals of the present application can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyethylene glycol, pyran co-polymers, polyhydroxyethylmethacrylate-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present application can be coupled to a class of biodegradable polymers such as polylactide, polyglycolide, copolymer of polylactide and polyglycolide, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0119] Each dosage unit for administration (pharmaceutical composition) can contain from about 1 milligram to about 100 milligrams of the active ingredient. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5%-95% by weight based on the total weight of the composition.

[0120] Gelatin capsules can contain the active ingredient in admixture with a powder or granule carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare the tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of the drug over a period of several hours. Tablets and capsules can also be prepared with coating materials such as gelatin or

[0121] Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

[0122] Generally, water, suitable oils, saline, aqueous dextrose (d-glucose), and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration can contain water-soluble salts, suitable stabilizing agents, and buffering agents (if needed) for the active ingredient. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, individually or in combination, are suitable stabilizing agents. Citric acid and its salts and EDTA sodium are also used. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.

[0123] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, which is a standard reference in the field.

[0124] Representative useful pharmaceutical dosage form for administration of the compounds of the present application can be illustrated as follows:

[0125] Capsules

[0126] A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules, each having 100 mg of the active ingredient in powdered form, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

[0127] Soft gelatin capsules

[0128] Mixtures of the active ingredient in edible oils, such as soybean oil, cottonseed oil, or olive oil, can be prepared, and the mixture is injected, for example, by a positive displacement pump, into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

[0129] Tablets

[0130] Tablets can be prepared by a conventional procedure such that the dosage unit is 100 mg of the active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Suitable coatings can be applied to increase palatability or to delay absorption.

[0131] Dispersion

[0132] Spray-dried dispersions for oral administration can be prepared by methods known to those skilled in the art.

[0133] Injectables

[0134] Parenteral compositions suitable for injectable use are prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0135] Suspensions

[0136] Aqueous suspensions can be prepared for oral administration so that each 5 mL contains 100 mg of finely divided active ingredient, 200 mg sodium carboxymethyl cellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (U.S.P.), and 0.025 mL vanillin.

[0137] When two or more of the foregoing second therapeutic agents are administered with a co-crystal of a compound of Formula I, typically, the amount of each component in the typical daily dose and the typical dosage form can be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

[0138] There is a potential for chemical interaction between the active ingredients of the combination, particularly when provided as a single dosage unit. For this reason, when a co-crystal form of Compound (I) and a second therapeutic agent are combined in a single dosage unit, they are formulated such that physical contact between the active ingredients is minimized, if not eliminated, despite the fact that the active ingredients are combined in a single dosage unit. For example, one of the active ingredients can be enteric coated. By enteric coating one of the active ingredients, not only can the contact between the active ingredients of the combination be minimized, but the release of one of the components in the gastrointestinal tract can also be controlled, such that one of the components is not released in the stomach, but rather in the intestine. It is also possible to coat one of the active ingredients with a material that achieves sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the active ingredients of the combination. Furthermore, the sustained release component can be additionally enteric coated such that release of this component only occurs in the intestine. Yet another approach involves formulating the combination product wherein one component is coated with a sustained release and / or enteric release polymer and the other component is also coated with a polymer, such as low viscosity grade hydroxypropyl methylcellulose (HPMC), or other appropriate material known in the art, to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0139] These and other ways of minimizing contact between the components of the combination products of the present application once bound to the present disclosure, whether administered in a single dosage form or administered in separate form, but administered at the same time in the same manner, will be readily apparent to those skilled in the art.

[0140] As discussed above, the compounds of the present application, including co-crystal forms of compounds of Formula I, can be administered orally, intravenously, or both.

[0141] Embodiments

[0142] Co-crystal forms can be prepared by a variety of methods including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and spray- drying. Techniques for crystallizing or recrystallizing co-crystal forms from solvent mixtures include, for example, evaporation of a solvent, lowering the temperature of a solvent mixture, seeding a supersaturated solution of a molecule and / or salt with crystals, freeze-drying a solvent mixture, and adding an antisolvent (anti-solvent) to a solvent mixture.

[0143] For crystallization techniques that use solvents, the choice of solvent(s) is generally dependent on one or more factors such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used, for example, a compound can be dissolved in a first solvent to provide a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and provide for the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

[0144] In one method of preparing crystals, a compound is suspended and / or agitated in a suitable solvent to provide a slurry, which can be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of a compound, which can also contain an additional amount of the compound to provide a heterogeneous mixture of the compound and solvent at a given temperature.

[0145] Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding can be employed to control the growth of a particular polymorph or to control the particle size distribution of the crystalline product. Thus, the calculation of the amount of seed required depends on the availability of seed and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small size seeds are required to effectively control the growth of crystals in a batch. Small size seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. It should be noted that grinding or micronizing of crystals does not result in any change in crystalline form (i.e., to amorphous or another polymorph) compared to the desired crystal form.

[0146] The cooled crystallization mixture can be filtered under vacuum, and the isolated solid can be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to provide the desired crystalline form. The isolated solid can be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, and the like, to ensure that the preferred crystalline form of the product is formed. The resulting crystalline form is typically produced in an isolated yield of greater than about 70% by weight, preferably greater than 90% by weight, based on the weight of the compound initially used in the crystallization procedure. If desired, the product can be co-milled or passed through a mesh screen to de-lump the product.

[0147] The presence of more than one polymorph in a sample can be determined by techniques such as powder x-ray diffraction (PXRD) or by Raman or IR spectroscopy solid state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks when comparing an experimentally measured PXRD pattern to a simulated PXRD pattern can indicate more than one polymorph in the sample. Simulated PXRDs can be calculated from single crystal x-ray data. See Smith, D. K., “A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0148] Co-crystal forms of the compounds of Formula (I) according to the present application can be characterized using a variety of techniques, the operation of which is well known to those of ordinary skill in the art. The forms can be characterized and distinguished using single crystal x-ray diffraction, based on unit cell measurements of a single crystal of the form at a fixed analysis temperature. A detailed description of unit cells is provided in Stout and Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the unique arrangement of atoms in the spatial relationships within the crystal lattice can be characterized in terms of observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder x-ray diffraction analysis (where the diffraction pattern is compared to a simulated pattern representative of a pure powdered material, both run at the same analysis temperature) and measurement of the subject form (characterized as a series of 2-theta values, typically four or more).

[0149] Other means of characterizing the forms can be used, such as solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermal analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the subject forms. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined by other suitable analytical methods.

[0150] Example 1

[0151] 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide: succinate co-crystal (1 :0.5)

[0152] To a 250 mL glass reactor was added the compound of formula (I) in free form (2 g, 3.561 mmol), dichloromethane (100 mL) and methanol (20 mL). The reaction mass was heated to 39 °C until complete dissolution. Succinic acid (0.45 g, 3.8 mmol) was then added in one portion. After 3 days, 50 mL of the solution mass was distilled off until a slurry form. Ethyl acetate (70 mL) was added. The volatiles were removed to dryness and ethyl acetate (100 mL) was charged to the reaction mixture and the reaction mass was stirred for 12 h. The resulting slurry was then filtered and the resulting solid was washed with ethyl acetate (10 mL). The solid was dried in a vacuum oven for 24 h (30 mmHg, 50 °C) to give the succinate co-crystal of the compound of formula (I). The product was obtained as a white solid (1.8 g, 41% yield) with a purity of 99.4% by HPLC. 1 H NMR (400 MHz, DMSO-d6) d 8.37 (s, 2H), 8.03 (s, 2H), 8.01 (s, 2H), 7.94 (s, 2H), 7.54 (d, J = 7.8 Hz, 4H), 7.03 (s, 2H), 6.85 (dd, J = 1.8, 0.8 Hz, 2H), 6.65 (d, J = 1.8 Hz, 2H), 5.39 (s, 4H), 4.20 (s, 6H), 3.90 - 3.77 (m, 6H), 3.31 (s, 5H), 3.00 (br s, 6H), 2.94 (br s, 6H), 2.43 - 2.41 (m, 4H).

[0153] The succinate co-crystal has a stoichiometry of one molecule of the compound of formula (I) to 0.5 molecules of succinic acid or hemi-succinate of the compound of formula (I).

[0154] The succinate co-crystal of the compound of formula (I) was obtained Figure 1 the PXRD pattern shown, Figure 2Differential scanning calorimetry (DSC) as shown, and Figure 3 Thermogravimetric analysis (TGA) as shown.

[0155] The PXRD of the succinic acid co-crystal of the compound of Formula (I) has selected 2-theta peaks at 4.5, 9.5, 14.6, 16.3, 17.6, 21.4, 22.4, and 25.9 (all peaks at degrees 2-theta ± 0.2). The PXRD was obtained at room temperature and the diffraction peak positions (degrees 2-theta ± 0.2) are based on high quality patterns collected with a diffractometer (Cu Ka) with a rotating capillary, where 2-theta is calibrated with NIST other appropriate standards.

[0156] The succinic acid co-crystal is further characterized by a PXRD having at least one or more, or 4 or more, 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, and 25.9 ± 0.2.

[0157] The succinic acid co-crystal is further characterized by a PXRD having 4 or more 2-theta values selected from 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, and 25.9 ± 0.2.

[0158] A single crystal X-ray of the succinic acid co-crystal of the compound of Formula (I) was obtained and yielded the following results:

[0159]

[0160] The atomic coordinates for the single crystal X-ray of the succinic acid co-crystal are shown in Table 1.

[0161] Table 1. Atomic coordinates of the succinic acid co-crystal

[0162]

[0163]

[0164] The DSC of the succinic acid co-crystal shows a variable endotherm at about 182 °C, which indicates that the melt has decomposition. The TGA of the succinic acid co-crystal shows negligible weight loss up to 150 °C.

[0165] FT-IR and FT-Raman are shown in Figure 4 and Figure 5 and show characteristic peaks in the range of 1700 to 3500 cm -1

[0166] ​FT-Raman spectrum for succinic acid co-crystal had characteristic peaks at 975.3, 1185.0, 1242.9, 1455.6, and 3104.4 cm -1 (±0.3 cm -1 ).

[0167] FT-IR spectrum for succinic acid co-crystal had characteristic peaks at 1627.9, 1704.4, and 3102.1 cm -1 (±0.4 cm -1 ).

[0168] Example 2

[0169] 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide: citric acid co-crystal (1:1), Form N-1.

[0170] A mixture of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide (6.1 g, 11 mmol, 1.0 equiv) and citric acid (3.3 g, 18 mmol, 1.6 equiv) in ethyl acetate (210 mL) was heated to 76 °C for 10 h and then slowly cooled to room temperature and allowed to stir for 16 h. The slurry was filtered and washed with EtOAc (80 mL), then the filter cake was dried under vacuum in an oven at 55 °C for 1 day to give 8.0 g (98% yield) of N-1 form of citric acid co-crystal as a white solid.

[0171] Alternative procedure

[0172] To citric acid (222.5 g, 1,16 mol, 1.3 eq) was added EtOAc (17 L) and heated to 55 °C for 2 h to give a clear solution. 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1- b][1,3,4]thiadiazol-6-yl)benzofuran-4-yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide (500.00 g, 0.89 mol, 1.0 eq) was added followed by EtOAc (1 L). The mixture was heated to 76 °C over 1 h. 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide citric acid co-crystal (1.0 g, 0.2% wt) in EtOAc (15 mL) was added as seed. The mixture was heated for another 30 min and then slowly cooled to room temperature over 2 h and allowed to stir for 5 h. The slurry was filtered and washed twice with EtOAc (3 L) and then the filter cake was dried under vacuum in an oven at 50 °C for 3 days to give 663.7 g (99% yield) of the N-1 form of the citric acid co-crystal of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide as a white solid with 99.8 AP purity.

[0173] The N-1 form of the citric acid co-crystal of the compound of Formula (I) has a stoichiometry of 1 molecule of the compound of Formula (I) to every molecule of citric acid (1:1).

[0174] The N-1 form of the citric acid co-crystal of the compound of Formula (I) gives a PXRD with selected 2-theta peaks at 6.4, 12.7, 14.4, 17.1, 23.9, 25.0, and 26.6 (all peaks at degrees 2-theta ± 0.2). Figure 6 Figure 7 The DSC shown for the N-1 form of the citric acid co-crystal of the compound of Formula (I), Figure 8 The TGA shown for the N-1 form of the citric acid co-crystal of the compound of Formula (I).

[0175] The N-1 form of the citric acid co-crystal of the compound of Formula (I) has a PXRD with selected 2-theta peaks at 6.4, 12.7, 14.4, 17.1, 23.9, 25.0, and 26.6 (all peaks at degrees 2-theta ± 0.2). The PXRD was obtained at room temperature and the diffraction peak positions (degrees 2-theta ± 0.2) are based on high quality patterns collected with a diffractometer (Cu Ka) with rotating capillary, where 2-theta is calibrated with NIST or other suitable standards.

[0176] The N-1 form of the citric acid co-crystal of the compound of Formula (I) has a PXRD with selected 2-theta peaks at 6.4, 12.7, 14.4, 17.1, 23.9, 25.0, and 26.6 (all peaks at degrees 2-theta ± 0.2). The PXRD was obtained at room temperature and the diffraction peak positions (degrees 2-theta ± 0.2) are based on high quality patterns collected with a diffractometer (Cu Ka) with rotating capillary, where 2-theta is calibrated with NIST or other suitable standards.​

[0177] The N-1 form of the citric acid co-crystal of the compound of formula (I) is further characterized by having one or more, or four or more, PXRD 2Θ values selected from 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.2.

[0178] The N-1 form of the citric acid co-crystal of the compound of formula (I) is further characterized by having four or more PXRD 2Θ values selected from 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, and 26.6 ± 0.2.

[0179] A single crystal X-ray of the N-1 form of the citric acid co-crystal of the compound of formula (I) was obtained and yielded the following results:

[0180]

[0181]

[0182] The atomic coordinates for the single crystal X-ray of the N-1 form of the citric acid co-crystal are shown in Table 3.

[0183] Table 3

[0184]

[0185]

[0186] The DSC of the N-1 form of the citric acid co-crystal showed a variable endotherm at about 185-190 °C, which indicates that the melt has decomposition. The TGA of the N-1 form of the citric acid co-crystal showed negligible weight loss up to 150 °C.

[0187] The C-13 solid state NMR (C-13 SSNMR) of the citric acid co-crystal exhibited peaks as shown in Table 4. The C-13 SSNMR is consistent with Z = 2.

[0188] Table 4: N-1 citric acid co-crystal C-13 chemical shifts

[0189]

[0190]

[0191] The IR and Raman spectroscopy of the N-1 form of the citric acid co-crystal exhibited peaks as shown in Figure 9 and Figure 11 The spectra exhibited characteristic peaks shown in the range from 1700 to 3500 cm-1.

[0192] FT-Raman spectrum of N-1 citric acid co-crystal of has characteristic peaks at 755.3, 807.7, 982.1, 1191.2, 1367.8, 1450.6, and 2978.9 cm -1 (±0.3 cm -1 ).

[0193] FT-IR spectrum of N-1 citric acid co-crystal of has characteristic peaks at 1585.7, 1725.9, and 3150.5 cm -1 (±0.4 cm -1 ).

[0194] Example 3

[0195] 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide: citric acid co-crystal (1:1), Form N-2.

[0196] A mixture of 4-(4-(((6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4- yl)oxy)methyl)thiazol-2-yl)-N,N-dimethylbenzamide (5.00 g, 8.9 mmol, 1 equiv) and citric acid (2.50 g, 13.4 mmol, 1.5 equiv) in 200 mL EtOAc was heated to 74 °C for 18 h. The mixture was slowly cooled to room temperature and allowed to stir for 3 h. The slurry was filtered and washed twice with EtOAc (20 mL) and then the filter cake was dried under vacuum in an oven at 55 °C for 1 day to give 6.5 g (97% yield) of citric acid co-crystal Form N-2 as a white needle-like solid.

[0197] The N-2 form of the citric acid co-crystal of the compound of Formula (I) contains 1 molecule of the compound of Formula (I) for every molecule of citric acid (1:1).

[0198] The N-2 form of the citric acid co-crystal of the compound of Formula (I) gave the PXRD pattern shown, Figure 12 the DSC shown, and Figure 13 the TGA shown. Figure 14

[0199] ​The N-2 form of the citric acid co-crystal of the compound of Formula (I) has a PXRD with selected 2-theta (all peaks are at degrees 2-theta ± 0.2) at 4.6, 14.6, 16.4, 21.0, and 25.2. The PXRD is obtained at room temperature and the diffraction peak positions (degrees 2-theta ± 0.2) are based on high quality patterns collected with a diffractometer (Cu Ka) with rotating capillary, where 2-theta is calibrated with NIST appropriate standards.

[0200] The N-2 form of the citric acid co-crystal of the compound of Formula (I) has a PXRD with selected 2-theta (all peaks are at degrees 2-theta ± 0.2) at 4.6, 5.5, 8.4, 11.3, 14.6, 16.4, 21.0, 24.2, and 25.2. The PXRD is obtained at room temperature and the diffraction peak positions (degrees 2-theta ± 0.2) are based on high quality patterns collected with a diffractometer (Cu Ka) with rotating capillary, where 2-theta is calibrated with NIST appropriate standards.

[0201] The N-2 form of the citric acid co-crystal is further characterized by a PXRD with one or more, or 4 or more, 2-theta values selected from: 4.6 ± 0.2, 5.5 ± 0.2, 8.4 ± 0.2, 11.3 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2.

[0202] The N-2 form of the citric acid co-crystal is further characterized by a PXRD with 4 or more 2-theta values selected from: 4.6 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 21.0 ± 0.2, and 25.2 ± 0.2.

[0203] A single crystal X-ray of the N-2 form of the citric acid co-crystal of the compound of Formula (I) was obtained and yielded the following results:

[0204]

[0205] The atomic coordinates for the single crystal X-ray of the N-2 form of the citric acid co-crystal are shown in Table 5.

[0206] Table 5

[0207]

[0208]

[0209]

[0210]

[0211] The N⁻² form of citric acid eutectic DSC exhibits variable endothermic activity at approximately 180 °C, indicating that the variable melt undergoes decomposition. The TGA of succinic acid eutectic shows negligible weight loss up to 150 °C.

[0212] The analytical data for each eutectic described in this article were obtained using the following procedure.

[0213] Single crystal data

[0214] For the citric acid eutectic form disclosed in this paper, a monochromatic Cu Kα radiation was used. A Bruker X8APEX IICCD diffractometer with a MICROSTAR-H micro-focusing rotating anode X-ray generator was used to collect diffraction data at room temperature. For the succinic acid eutectic form, a monochromatic Cu Kα radiation system was used. Diffraction data at room temperature were collected using a Bruker X8 Prospector Ultra diffractometer with an 1μS micro-focused X-ray source and an APEX II detector. The measured intensity data were indexed and processed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, Wisconsin 53711, USA). The final unit cell parameters were determined using the complete dataset. The structure was solved using direct methods and refined using the SHELXTL software package (GMSheldrick, SHELXTL v6.14, Bruker AXS, Madison, Wisconsin, USA) via a full-matrix least squares method. The structure refinement involved minimizing ∑w(|F o |-|F c |) 2 The defined function, where w is a suitable weighting factor based on the observed intensity error, F o It is based on the measured structure factor of reflection, and F c It is a calculation-based reflection structure factor. This is achieved by using the residual factor R = ∑||F o |-|F c || / ∑|F o | and wR=[∑w(|F o |-|F c |) 2 / ∑w|F o |] 1 / 2The consistency between the refined crystal structure model and experimental X-ray diffraction data was evaluated. Difference Fourier plots were examined at all stages of the refinement process. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were calculated using an idealized geometry, isotropically refined, and included in the structure factor calculation with fixed parameters. A few exceptions exist where hydrogen atoms are located from the difference Fourier plot and isotropically refined, such as the acidic hydrogen atoms of succinic acid in a eutectic structure.

[0215] PXRD

[0216] PXRD data were obtained using a Bruker C2 GADDS (Universal Zone Detector Diffraction System). The radiation was CuKα (40 kV, 40 mA). The sample-detector distance was 15 cm. The sample was placed in a sealed glass capillary with a diameter ≤ 1 mm. The capillary was rotated during data acquisition. Transmission data were collected for approximately 2 ≤ 2θ ≤ 32°, with a sample exposure time of at least 1000 seconds. The resulting two-dimensional diffraction arc was integrated to construct a conventional one-dimensional PXRD pattern with a step size of 0.05 degrees 2θ within an approximate range of 2 to 32 degrees 2θ.

[0217] DSC

[0218] Use TA DSC data is generated using models Q2000, Q1000, or 2920. Measurements are performed using a standard TA instrument sealed disc. Measurements are taken in a nitrogen atmosphere at a heating rate of 10°C / min from room temperature to 300°C, with a sample size of approximately 2-10 mg. DSC plots are generated, showing the endothermic peak pointing downwards.

[0219] TGA

[0220] Use TA TGA data are generated using models Q5000, Q500, or 2950. Measurements are performed using a standard TA instrument with a platinum disk. Measurements are taken in a nitrogen atmosphere at a heating rate of 10°C / min from room temperature to 300°C, with sample amounts of approximately 10–30 mg.

[0221] Solid-state nuclear magnetic resonance (SSNMR)

[0222] All solid state C-13 NMR measurements were performed with a Bruker DSX-400, 400 MHz NMR spectrophotometer. High resolution spectra were obtained using high power proton decoupling and the TPPM pulse sequence and ramped amplitude cross polarization (RAMP-CP) with magic angle spinning (MAS) at approximately 12 kHz (A. E. Bennett et al., J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A,. 1994, 110, 219-227). Approximately 70 mg of sample loaded into a zirconia rotor designed for the tank was used for each experiment. The chemical shift (δ) reference was set to the high frequency resonance of external adamantane at 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).

[0223] Raman spectroscopy

[0224] Raman spectra were obtained using an IS50 FT-Raman spectrophotometer with co-added 64 scans at a resolution of 4 cm -1 -1. The wavelength of the laser excitation was 1064 nm. A CaF2 beamsplitter and a high sensitivity InGaS detector were used.

[0225] IR spectroscopy

[0226] Infrared spectra were obtained using an IS50 FT-IR spectrophotometer, coupled with a KBr beamsplitter and a DTGS detector, with co-added 64 scans at a resolution of 4 cm -1 -1. Sample preparation was performed via attenuated total reflectance (ATR) using a single bounce diamond ATR sampling accessory. An ATR correction step was included to correct for path length.

[0227] Dissolution data:

[0228] The dissolution of the citric acid co-crystal of the compound of formula (I) and the succinic acid co-crystal of the compound of formula (I) was tested against the dissolution of the free form of the compound of formula (I). The dissolution characteristics, rate and extent were tested in FaSSIF (fasted state simulated intestinal fluid); and peak solubility.

[0229] This experiment was performed on a pION Microdissolution Profiler TM TM ​is an API sparing low volume dissolution instrument with UV fiber optic (UVFO) probe to measure real time dissolution profiles in biorelevant media. Experiments were run under the following conditions:

[0230] Instrument: pIon Microdissolution Analyzer

[0231] Medium: FaSSIF, pH 6.5

[0232] Volume: 15 mL at 37 °C

[0233] Stir: 150 rpm with small stir bar

[0234] Dose: API powder at 0.2 mg / mL or 3 mg / vial

[0235] Study Duration: 180 min

[0236] Time Points: Capture initial dissolution rate and several time points throughout 180 min (typical time for absorption)

[0237] Results were analyzed using UVFO Analysis: standard curve range 0-3 pg / mL; 10 mm path length probe window; detection wavelength 315 nm; slope ~ 17 pg / mL / AU; R 2 = 0.99.

[0238] Results are shown in Figure 15 and Table 6 below.

[0239] Dissolution of both succinic acid and citric acid co-crystals in FaSSIF was better than the free form. Dissolution rate, AUC (extent of dissolution) and peak solubility of citric acid co-crystal was 3-4 times that of succinic acid co-crystal.

[0240] In vivo performance:

[0241] To demonstrate the ability of the co-crystals to be absorbed, a pharmacokinetic study was performed in a canine model. The co-crystals were tested using the following formulations:

[0242] 1. Succinic acid co-crystal capsules (5 mg dose) - fasted dogs pretreated with pentagastrin

[0243] 2. Citric acid co-crystal capsules (5 mg dose) - fasted dogs pretreated with pentagastrin Study design was as follows:

[0244] Cross-over in 4 fasted male dogs (approximately 10 kg); dose 5 mg / dog; flushed with 50 mL water; 2 week washout between treatments; 8 blood sampling points per treatment.

[0245] Results are shown in Table 7 and Figure 16 Table 8.

[0246] The citric acid co-crystal and succinic acid co-crystal exhibited measurable systemic absorption in the canine model at the relevant doses. Bioavailability ranged from 32-55% relative to the well absorbed reference formulation.

[0247] The PK variability (%CV) for both co-crystal capsules was high, primarily due to one dog showing very low / non-detectable blood levels.

[0248] Many modifications and variations of this application are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the application can be practiced otherwise than as specifically described.

[0249]

[0250] The present application also relates to embodiments of:

[0251] 1. A compound of formula (1)

[0252]

[0253] and a coformer, wherein the coformer is succinic acid or citric acid.

[0254] 2. The co-crystal according to item 1, wherein the coformer is succinic acid.

[0255] 3. The co-crystal according to item 2, wherein the co-crystal is characterized by one or more of the following:

[0256] a) a single crystal structure having unit cell parameters substantially equal to:

[0257]

[0258] wherein the measurement of the single crystal structure is at room temperature;

[0259] b) an observed PXRD pattern substantially as shown in Figure 1 ;

[0260] c) a PXRD pattern comprising 4 or more 2-theta values selected from the group consisting of: 4.5 ± 0.2, 9.5 ± 0.2, 14.6 ± 0.2, 16.3 ± 0.2, 17.6 ± 0.2, 21.4 ± 0.2, 22.4 ± 0.2, and 25.9 ± 0.2 (obtained at room temperature and

[0261] d) an infrared spectrum substantially as shown in Figure 5 ; and / or

[0262] e) FT-Raman spectrum substantially as shown in Figure 17. Figure 6

[0263] 4. The co-crystal of items 1-3, wherein the ratio of the compound of Formula (I) to succinic acid is 1 :0.5.

[0264] 5. The co-crystal of item 1, wherein the co-former is citric acid.

[0265] 6. The co-crystal of item 5, wherein the co-crystal is in Form N-1 and is characterized by one or more of the following:

[0266] a) a single crystal structure having unit cell parameters substantially equal to:

[0267]

[0268]

[0269] b) a PXRD pattern substantially as shown in Figure 18; and / or Figure 6

[0270] c) a PXRD pattern comprising four or more 2-theta values (at room temperature ) selected from 6.4 ± 0.2, 12.7 ± 0.2, 14.4 ± 0.2, 17.1 ± 0.2, 23.9 ± 0.2, 25.0 ± 0.2, and 26.6 ± 0.2.

[0271] 7. The co-crystal of items 5-6, wherein the ratio of the compound of Formula (I) to citric acid is 1 : 1.

[0272] 8. The co-crystal of items 5-7, consisting essentially of Form N-1.

[0273] 9. The co-crystal of item 5, wherein the co-crystal is in Form N-2 and is characterized by one or more of the following:

[0274] a) a single crystal structure having unit cell parameters substantially equal to:

[0275]

[0276] wherein the measurement of the single crystal structure is at room temperature;

[0277] b) a PXRD pattern substantially as shown in Figure 19; and / or Figure 12

[0278] c) a PXRD pattern comprising four or more 2-theta values (at room temperature ​​​PXRD pattern of Form N-2: 4.6 ± 0.2, 5.5 ± 0.2, 8.4 ± 0.2, 11.3 ± 0.2, 14.6 ± 0.2, 16.4 ± 0.2, 18.3 ± 0.2, 19.2 ± 0.2, 20.2 ± 0.2, 21.1 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2.

[0279] 21.1 ± 0.2, 24.2 ± 0.2, and 25.2 ± 0.2.

[0280] 10. The co-crystal of item 9, wherein the ratio of the compound of Formula (I) to citric acid is 1 : 1.

[0281] 11. The co-crystal of item 9, consisting essentially of Form N-2.

[0282] 12. The co-crystal of items 1-11, in substantially pure form.

[0283] 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, alone or in combination with another therapeutic agent, and a co-crystal according to items 1-12.

Claims

1. A compound of formula (1) The co-formed substance is a eutectic of succinic acid or citric acid.

2. The eutectic according to claim 1, wherein the eutectic is succinic acid.

3. The eutectic according to claim 2, wherein the eutectic is characterized by one or more of the following: a) A single-crystal structure having unit cell parameters substantially equal to the following: The measurements of the single crystal structure were performed at room temperature; b) The observed PXRD pattern is basically as shown in Figure 1; c) PXRD plots containing four or more 2θ values ​​selected from the following: 4.5±0.2, 9.5±0.2, 14.6±0.2, 16.3±0.2, 17.6±0.2, 21.4±0.2, 22.4±0.2, and 25.9±0.2 (obtained at room temperature and (CuKα) ); d) The infrared spectrum is essentially as shown in Figure 5; and / or e) Basically, the FT-Raman spectrum is shown in Figure 6.

4. The eutectic according to claims 1-3, wherein the ratio of the compound of formula (I) to succinic acid is 1:0.

5.

5. The eutectic according to claim 1, wherein the eutectic is citric acid.

6. The eutectic according to claim 5, wherein the eutectic is in the form of N-1 and is characterized by one or more of the following: a) A single-crystal structure having unit cell parameters substantially equal to the following: b) A PXRD plot essentially as shown in Figure 6; and / or c) Contains four or more 2θ values ​​selected from the following (CuKα at room temperature) PXRD values ​​for: 6.4±0.2, 12.7±0.2, 14.4±0.2, 17.1±0.2, 23.9±0.2, 25.0±0.2, and 26.6±0.

2.

7. The eutectic according to claims 5-6, wherein the ratio of the compound of formula (I) to citric acid is 1:

1.

8. The eutectic according to claims 5-7, which is substantially composed of form N-1.

9. The eutectic according to claim 5, wherein the eutectic is in the form of N-2 and is characterized by one or more of the following: a) A single-crystal structure having unit cell parameters substantially equal to the following: The measurements of the single crystal structure were performed at room temperature; b) A PXRD plot essentially as shown in Figure 12; and / or c) Contains four or more 2θ values ​​selected from the following (CuKα at room temperature) PXRD values ​​for: 4.6±0.2, 5.5±0.2, 8.4±0.2, 11.3±0.2, 14.6±0.2, 16.4±0.2, 21.1±0.2, 24.2±0.2, and 25.2±0.

2.

10. The eutectic according to claim 9, wherein the ratio of the compound of formula (I) to citric acid is 1:1.

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