Salts and crystalline forms of an apoptosis-inducing agent

[0001] Reference is also made, without reserving the benefit of priority or prior art status, to the following U.S. application under consideration, covering the subject matter associated with this application: serial number 12 / 787,682 (published as US 2010/0305122), entitled "Measures inducing apoptosis for the treatment of cancer and immunological and autoimmune diseases ".

FIELD OF THE INVENTION [0002] The present invention relates to salts and crystal forms of an apoptosis-inducing agent, pharmaceutical dosage forms containing such salts and crystal forms, methods for preparing salts and crystal forms, and such salts and crystal forms for use in methods of treating diseases characterized by antiapoptotic overexpression proteins from the Bcl-2 family.

BACKGROUND OF THE INVENTION [0003] Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical effect, disease progression, overall prognosis or their combination in various cancers and disorders of the immune system.

[0004] Avoiding apoptosis is a hallmark of cancer (Hanahan and Weinberg (2000) Cell 100: 5770). Cancer cells must overcome the constant bombardment by cellular stress reactions such as DNA damage, oncogen activation, abnormal cell cycle progression and an acute microenvironment that would cause apoptosis of normal cells. One of the main ways that cancer cells avoid apoptosis is upregulation of antiapoptotic proteins from the Bcl-2 family.

[0005] A particular type of cancer for which improved therapies are needed is non-Hodgkin's lymphoma (NHL). NHL is the sixth most common type of new cancer in the US and occurs mainly in patients aged 60-70. NHL is not a single disease, but a family of related diseases that are classified based on several features, including clinical features and histology.

[0006] According to one classification method, the different histological subtypes are divided into two main categories based on the natural course of the disease, i.e., depending on whether the disease is mild or aggressive. In general, mild subtypes develop slowly and are generally incurable, while aggressive subtypes develop rapidly and are potentially treatable. Follicular lymphomas are the most common benign subtype, and multiple large cell lymphomas are the most common aggressive subtype. Bcl-2 oncoprotein was originally described in non-Hodgkin's B cell lymphoma.

[0007] Treatment of follicular lymphoma usually involves biological or combination chemotherapy. Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is routinely used, as is combination therapy with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). Single agent therapy with rituximab (CD20 targeting, phosphoprotein evenly expressed on B cell surface) or fludarabine is also used. Adding rituximab to chemotherapy regimens can provide an improvement in response rates and an increase in progression-free survival.

[0008] Radioimmunotherapeutic agents, high-dose chemotherapy and stem cell transplants can be used to treat refractory or relapsed NHL. There is currently no approved treatment regimen that causes healing, and current guidelines recommend that patients be treated in the context of a clinical trial, even under first-line treatment.

[0009] First-line treatment of patients with aggressive large B-cell lymphoma usually consists of the administration of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or the administration of adjusted doses of etoposide, prednisone, vincristine, cyclophosfamide, and rituxuxx DA-EPOCH-R).

[0010] Most lymphomas initially respond to any of these therapies, but tumors usually recur and eventually become refractory. The greater the number of schedules that patients undergo, the more the disease becomes more resistant to chemotherapy. The average response to first-line therapy is approximately 75%, 60% for second-line therapy, 50% for third-line therapy, and approximately 35-40% for fourth-line therapy. Response rates close to 20% for a single agent in the treatment of multiple relapses are considered positive and require further study.

[0011] Other cancers for which improved therapies are needed include leukemia such as chronic lymphocytic leukemia (such as NHL, B-lymphoma) and acute lymphocytic leukemia. [0012] Chronic lymphocytic leukemia (CLL) is the most common type of leukemia. CLL is primarily a disease of adults, more than 75% of people with newly diagnosed disease are over 50 years old, but in rare cases it also occurs in children. The main treatments are combination chemotherapy, for example fludarabine with cyclophosphamide and / or rituximab, or more complex combinations such as CHOP or R-CHOP.

[0013] Acute lymphocytic leukemia, also known as acute lymphoblastic leukemia (ALL), is primarily a childhood disease, once with essentially zero survival, but now with a survival rate of up to 75% due to combination chemotherapies similar to those mentioned above. New therapies are still needed to ensure further improvement of survival rates.

[0014] Modern chemotherapeutic agents elicit their anti-tumor response by inducing apoptosis by various mechanisms. However, many cancers eventually become resistant to these factors. For Bcl-2 and Bcl-XL, they have been shown to induce resistance to chemotherapy in short-term survival tests in vitro and, more recently, in vivo. This suggests that if it were possible to develop improved therapies to suppress Bcl-2 and Bcl-XL function, such resistance to chemotherapy could be successfully overcome.

[0015] Bcl-2 protein involvement in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, CLL, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T cell lymphoma cancers or B cells, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell carcinoma

EP 2643322 B1, lung cancer, small cell lung cancer, spleen cancer and the like are described in international patent applications WO 2005/024636 and WO 2005/049593.

[0016] The involvement of Bcl-2 proteins in immune and autoimmune diseases are described, for example, in Puck and Zhu (2003) Current Allergy and Asthma Reports 3: 378-384; Shimazaki et al. (2000) British Journal of Hematology 110 (3): 584-590; Rengan et al. (2000) Blood 95 (4): 12831292; and Holzelova et al. (2004) New England Journal of Medicine 351 (14): 1409-1418. The involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in US Patent Application Publication No. US 2008/0182845.

[0017] Compounds that occupy the binding site on Bcl-2 proteins are known. In order for them to be therapeutically useful after oral administration, such compounds require high binding affinity, e.g. Ki <1 nM, preferably <0.1 nM, more preferably <0.01 nM, for proteins of the Bcl-2 family, specifically Bcl -2, Bcl-XL and Bcl-w. In addition, it is desirable that they be formulated in a manner that provides high systemic exposure after oral administration. A typical measure of systemic exposure after oral administration of a compound is the area under the curve (AUC) resulting from the plot of the compound concentration in plasma versus time after oral administration.

[0018] US 2010/0184750 A1 and WO 2010/065824 A2 disclose N- (phenylsulfonyl) benzamide derivatives that inhibit the activity of anti-apoptotic Bcl-2 proteins.

[0019] Apoptosis-inducing drugs targeting the Bcl-2 family of proteins, such as Bcl-2 and Bcl-XL, are best administered according to a regimen that provides continuous, e.g. daily, plasma concentration supplementation to maintain therapeutically effective concentration range. This can be achieved by daily parenteral administration, e.g. intravenous (iv) or intraperitoneal (ip) administration. However, daily parenteral administration is often not practical in clinical settings, especially for outpatient patients. In order to increase the clinical utility of an apoptosis-inducing agent, for example as a chemotherapeutic agent in cancer patients, a dosage form with acceptable oral bioavailability would be highly desirable. Such a dosage form and oral administration regimen would be an important advance in the treatment of many types of cancers, including NHL, CLL and ALL, and would easily enable combination therapies with other chemotherapeutic agents.

[0020] Different crystal forms of the apoptosis-inducing agent may provide different properties in terms of stability, solubility, release rate, hardness, compressibility and melting point, as well as other physical and mechanical properties. Because the ease of manufacture, formulation, storage and transport of an apoptosis-inducing agent depends on at least some of these properties, there is a need in the field of chemistry and therapy to identify new salts and crystalline forms of apoptosis-inducing agents, and methods for the repeated production of such salts and forms crystalline.

SUMMARY OF THE INVENTION [0021] The present disclosure relates to the salts and crystalline forms of an apoptosis-inducing agent, referred to herein as "Compound 1", whose systematic name is 4- (4 - {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-ene -1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-43

Ylmethyl) amino] phenyl} sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzamide, which can be represented by the formula:

<img file="PL2643322T3_D0001.tif" />

[0022] After the synthesis of Compound 1, as described herein, the product can be isolated as a powder in amorphous form. The amorphous form of Compound 1 may not be suitable for use as an active pharmaceutical ingredient (API) for various types of subsequent formulations. In particular, the amorphous form of Compound 1 can be difficult and therefore expensive to purify and can create problems in process control.

[0023] The present disclosure provides a series of new salts and crystalline forms of Compound 1 suitable for use as API in a wide variety of formulation types, including those in which the API is in particulate form with excipients, for example in tablets or capsules for oral administration. The salts and crystal forms of Compound 1 may also be useful when the crystalline form is converted to a non-crystalline form (e.g. solution or amorphous form) in the formulation process. Also included within the scope of the invention are methods for preparing the salts and crystal forms of Compound 1. The salts and crystalline forms of Compound 1 can be used to modulate and / or improve the physicochemical properties of API, including solid state (e.g. crystallinity, hygroscopicity, melting point, hydration capacity, polymorphism, etc.), pharmaceutical properties (e.g. solubility / release rate, stability, compatibility, etc.) and crystallization characteristics (e.g. purity, performance, morphology, etc.) as non-limiting examples.

[0024] In some embodiments, the salts or crystalline form of Compound 1 includes the anhydrous free base of Compound 1 having an XRPD A image, the anhydrous free base of Compound 1 having an XRPD B image, Compound 1 free base hydrate having an XRPD C image, Compound 1 free base hydrate having an XRPD D image, solvate of the free base of Compound 1 with dichloromethane having an XRPD E image, Compound 1 ethyl acetate free base solvate having an XRPD F image, Compound 1 ethyl acetate free base solvate having an XRPD G image, solvate of the free base compound 1 with acetonitrile having an XRPD H image, solvate of the free base compound 1 with acetonitrile having an XRPD I image, solvate of the free base compound 1 with acetone having an XRPD J image, Compound 1 hydrochloride having an XRPD K image, Compound 1 hydrochloride hydrate having an XRPD L image, Compound 1 sulfate having an XRPD M image, each of which has an appropriate X-ray powder diffraction pattern, as described here. Compound 1 tetrahydrofuran (THF) free base solvate of XRPD N image was also described as described herein.

[0025] In some embodiments, the crystalline forms of Compound 1 free base solvate with dichloromethane, Compound 1 free base solvate with acetonitrile, Compound 1 hydrochloride have

EP 2643322 B1 corresponding crystal lattice parameters as described herein. Compound 1 tetrahydrofuran free base solvate with crystal lattice characteristics has also been described as described herein.

[0026] In another embodiment, the hydrochloride of Compound 1 is provided.

[0027] In another embodiment, Compound 1 sulfate is provided.

[0028] In some embodiments, an API composition is provided comprising Compound 1 as an API in which at least a portion, for example at least about 10%, of Compound 1 in the composition is present in the form of a salt or crystal form. In some embodiments, more than 95% or substantially 100% of the API in such a composition is in the salt or crystalline form of Compound 1.

[0029] In some embodiments, a pharmaceutical composition is provided that comprises a salt or crystalline form of Compound 1, as described herein, and one or more pharmaceutically acceptable excipients.

[0030] In some embodiments, a method of preparing a pharmaceutical solution composition of Compound 1 is provided, the method comprising dissolving a salt or crystalline form of Compound 1, as described herein, together with a pharmaceutically acceptable solvent or mixture of solvents.

[0031] Compound 1 can be used in a method of treating a disease characterized by apoptotic dysfunction and / or overexpression of an antiapoptotic protein of the Bcl-2 family, wherein the method comprises administering to a subject suffering from said disease a therapeutically effective amount of (a) a salt or crystalline form of Compound 1, as described here, or (b) a pharmaceutical composition comprising the salt or crystalline form of Compound 1, as described here, and one or more pharmaceutically acceptable excipients.

[0032] Compound 1 can be used in a method of treatment of a disease characterized by apoptotic dysfunction and / or overexpression of an antiapoptotic protein of the Bcl-2 family, wherein the method comprises preparing a solution or dispersion of the salt or crystal form of compound 1, described in this document, in a pharmaceutically acceptable solvent or mixture of solvents and administering the resulting solution or dispersion in a therapeutically effective amount to a subject suffering from the disease.

[0033] Additional embodiments of the invention, including specific aspects of those set forth above, will be described or become apparent from the following detailed description.

BRIEF DESCRIPTION OF THE FIGURES [0034]

Fig. 1 is an XRPD scan of anhydrous Compound 1 designated as image A.

Fig. 2 is an XRPD scan of anhydrous Compound 1 designated as image B Fig. 3 is an XRPD scan of Compound 1 hydrate designated as image C.

Fig. 4 is an XRPD scan of Compound 1 hydrate designated as image D.

Fig. 5 is a calculated XRPD image of a compound 1 solvate with dichloromethane designated as E.

Fig. 6 is an XRPD scan of the compound 1 with ethyl acetate solvate designated as F.

Fig. 7 is an XRPD scan of Compound 1 ethyl acetate solvate designated as G.

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Fig. 8 is a calculated XRPD image of a Compound 1 acetonitrile solvate designated as H.

Fig. 9 is an XRPD scan of the solvate of Compound 1 with acetonitrile designated as image I.

Fig. 10 is an XRPD scan of the solvate of Compound 1 with acetone, designated as image J.

Fig. 11 is a calculated XRPD image of Compound 1 hydrochloride designated as K.

Fig. 12 is a PXRD scan of compound 1 hydrochloride hydrate designated by formula L.

Fig. 13 is an XRPD scan of Compound 1 sulfate designated as M.

Fig. 14 is an XRPD scan of the solvate of Compound 1 with tetrahydrofuran designated as image N.

DETAILED DESCRIPTION [0035] The term "free base" is used herein for convenience in relation to the parent compound Compound 1, to distinguish it from any salt thereof, it being understood that the parent compound, strictly speaking, is under neutral conditions with a zwitterion, and therefore, it does not always behave like a real rule.

[0036] The apoptosis inducing agent, referred to herein as Compound 1, has the systematic name for 4- (4 {[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-en-1-yl] methyl} piperazin-1 yl) -N - ({3-nitro-4 - [(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzamide and can be represented by the following formula:

<img file="PL2643322T3_D0002.tif" />

[0037] In various embodiments, the salts and crystalline forms of Compound 1 are provided. The crystalline forms include solvates, hydrates, anhydrous forms and salts of Compound 1.

[0038] In contrast to the amorphous form of Compound 1 free base and the amorphous form of Compound 1 salt, the crystalline form is characterized by the presence of observable peaks in the X-ray Powder Diffraction (XRPD), measured for the crystalline form. In the case of crystalline forms obtained in order to obtain monocrystals of an appropriate size, the crystalline form may be further characterized by experimental determination of unit cell parameters, identification of the crystallographic space group to which the monocrystalline belongs, or by both methods. After knowing the unit cell parameters, the position of the diffraction peaks can be calculated, and in particular the 2θ angle values ​​for the XRPD peaks to further characterize the crystal form. Of course, the XRPD image can also be measured experimentally for such crystal forms. If not only cell parameters are known, but also the three-dimensional structure of the single crystal, then further characterizing the crystalline form, you can calculate not only the location, but also the intensity of the peaks in the diffraction pattern.

[0039] XRPD images measured or calculated for the salts and crystal forms described herein constitute a "fingerprint" which can be compared with other experimentally designated images to find a match. The identity of the respective crystal forms is determined by superimposing or matching the experimentally defined XRPD image with the XRPD image of the crystal forms described herein. In various embodiments, the salts and crystal forms are characterized in that they exhibit at least one of the XRPD peaks listed herein. Thus, in various embodiments, the salt or crystalline form is characterized by matching two or more peaks, matching 3 or more peaks, 4 or more peaks, or 5 or more peaks, and so on, from corresponding XRPD images.

[0040] An embodiment of the synthesis of Compound 1 (free base) and representative intermediates is provided below. Exemplary compounds were named using ACD / ChemSketch version 5.06 (June 5, 2001, Advanced Chemistry Development Inc., Toronto, Ontario), ACD / ChemSketch version 12.01 (May 13, 2009, Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw ® ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates were named using the ChemDraw® program ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

Synthesis of Compound 1

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4- [(tetrahydro -2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzamide

Relationship A

3-nitro-4 - ((tetrahydro-2H-pyran-4-yl) methylamino) benzenesulfonamide [0041] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), 1- (tetrahydropyran-4-yl) methylamine ( 1.14 g) and triethylamine (1 g) in tetrahydrofuran (30 ml) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to give the title compound.

Compound B

4,4-Dimethyl-2- (trifluoromethylsulfonyloxy) cyclohex-1-enocarboxylate 38.5 g). After stirring for 30 minutes, the mixture was cooled to -78 ° C and trifluoroacetic anhydride (40 ml) was added. The reaction mixture was warmed to room temperature and stirred for 24 hours. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to give the product.

Compound C

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Methyl 2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enocarboxylate Compound B (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and tetrakis (triphenylphosphine) ) palladium (0) (2 g) in dimethoxyethane / methanol 2: 1 (600 ml) was heated at 70 ° C for 24 hours. The mixture was concentrated. Ether (4x 200 mL) was added and the mixture was filtered. The combined ether solution was concentrated to give the product.

Compound D (2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methanol [0044] To a mixture of LiBH4 (13g), Compound C (53.8 g) and ether (400 ml) slowly methanol ( 25 ml) using a syringe. The mixture was stirred at room temperature for 24 hours. The reaction was quenched with 1N HCl while cooling with ice. The mixture was diluted with water and extracted with ether (3 x 100 mL). The extracts were dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica gel with 0-30% ethyl acetate / hexanes.

Relationship E

Tert-butyl 4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazine-1-carboxylate [0045] Mesyl chloride (7.5 mL) was added using Compound D syringe (29.3 g) and triethylamine (30 mL) in CH 2 Cl 2 (500 mL) at 0 ° C and the mixture was stirred for 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at room temperature for 24 hours. The suspension was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica gel using 10-20% ethyl acetate / hexanes.

Relationship F

1 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazine Compound E (200 mg) and triethylsilane (1 ml) were stirred in dichloromethane (15 ml) and trifluoroacetic acid (15 ml) for 1 hour. The mixture was concentrated, taken up in ethyl acetate, washed twice with NaH2PO4, brine, and dried (Na2SO4), filtered and concentrated.

Compound G

5-bromo-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridine [0047] To a mixture of 5-bromo-1H-pyrrolo [2,3-b] pyridine (15.4 g) in tetrahydrofuran ( 250 ml) 1 M lithium hexamethyldisilazide in tetrahydrofuran (86 ml) was added, and after 10 minutes TIPS-Cl (triisopropylchlorosilane) (18.2 ml). The mixture was stirred at room temperature for 24 hours.

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The reaction mixture was diluted with ether and the resulting solution was washed twice with water. The extracts were dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica gel using 10% ethyl acetate / hexanes.

Compound H.

1- (triisopropylsilyl) -1H-pyrrolo [2,3-b] pyridin-5-ol [0048] To a mixture of Compound G (24.3 g) in tetrahydrofuran (500 mL) at -78 ° C was added 2.5 M BuLi (30.3 ml). After 2 minutes, trimethyl borate (11.5 mL) was added and the mixture was allowed to warm to room temperature over 1 hour. The reaction mixture was poured into water, extracted three times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was dissolved in tetrahydrofuran (200 mL) at 0 ° C and 1 M NaOH (69 mL) was added, followed by 30% H 2 O 2 (8.43 mL), and the solution was stirred for 1 hour. Na2S2O3 (10 g) was added and the pH was adjusted to 4-5 with concentrated HCl and solid NaH2PO4. The solution was extracted twice with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica gel using 5-25% ethyl acetate / hexanes.

Relationship

Methyl 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4-fluorobenzoate A mixture of Compound H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g) and K3PO4 (9.32 g) in diglyme (40 ml) was stirred at 115 ° C for 24 hours. The reaction mixture was cooled, diluted with ether (600 mL), and washed twice with water and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate / hexanes.

Union J

2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-enyl) methyl) piperazin-1-yl ) methyl benzoate [0050] A mixture of Compound I (1.55 g), compound F (2.42 g) and HK2PO4 (1.4 2 g) in dimethyl sulfoxide (20 mL) was stirred at 135 ° C for 24 hours. The reaction mixture was cooled, diluted with ether (400 mL), washed with 3x 1 M NaOH and brine, and concentrated. The crude product was chromatographed on silica gel with 10-50% ethyl acetate / hexanes.

Compound K 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid

[0051] Compound J (200 mg) in dioxane (10 mL) and 1M NaOH (6 mL) was stirred for 24 hours at 50 ° C. The reaction mixture was cooled, added to NaH2PO4 solution and extracted times with ethyl acetate. The combined extracts were washed with brine and concentrated to give a pure product.

Compound L (Compound 1 as a free rule)

4- (4 - {[2- (4-chlorophenyl) -4,4-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-1-yl) -N - ({3-nitro-4- [(tetrahydro -2H-pyran-4-ylmethyl) amino] phenyl} sulfonyl) -2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzamide [0052] Compound K (3.39 g), Compound A (1.87 g), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (2.39 g) and 4-dimethylaminopyridine (1.09 g) was stirred in CH 2 Cl 2 (40 ml) for 24 hours. The reaction mixture was cooled and chromatographed on silica gel with 25-100% ethyl acetate / hexanes, then 10% methanol / ethyl acetate with 1% acetic acid to give the product (1.62 g, 32%) as a solid. ¹H NMR (300 MHz, dimethyl sulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.51 (m, 3H), 7.33 (d, 2H), 7.08 (m, 1H). 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (d, 1H), 6.19 (d, 1H), 3.84 (m, 1H), 3.30 (m , 4H), 3.07 (m, 4H), 2.73 (m, 2H), 2.18 (m, 6H), 1.95 (m, 2H), 1.61 (dd, 2H), 1 , 38 (m, 2H), 1.24 (m, 4H), 0.92 (s, 6H).

[0053] The preparation of the free base of Compound 1 is also described in Example 5 of US Application No. serial 12 / 787,682 (published as US 2010/0305122) entitled "Agents that induce apoptosis for the treatment of cancer and immune and autoimmune diseases". A solid can be prepared from the chromatographic eluate; for example by means of lyophilization, precipitation or evaporation techniques. The product of this process may be a solid that is amorphous.

[0054] The salts and crystal forms of Compound 1 were prepared as described in the following examples.

Anhydrous free base of Compound 1 (XRPD A Image) [0055] The following two routes can give this crystalline form, wherein drying at ambient conditions involves leaving solid material at room temperature and exposure to air overnight. The solvent can be evaporated, for example.

[0056] Example 1: Solvate of Compound 1 free base with dichloromethane having an E image (see below) was dried at ambient conditions.

[0057] Example 2: Compound 1 ethyl acetate free base solvate having an F image (see below) was dried at ambient conditions.

[0058] The X-ray powder diffraction pattern and list of peaks are shown in Figure 1 and Table 1, respectively.

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Table 1: List of Peaks for Image A of the Anhydrous Free Rule 1

Piku location (° 2θ)

6.3

7.1

9.0

9.5

12.5

14.5

14.7

15.9

16.9

18.9

Anhydrous Free Base of Compound 1 (XRPD B Image) [0059] Example 3: Solvate of Compound 1 free base with acetonitrile having an H image was dried at ambient conditions.

[0060] The X-ray powder diffraction pattern and list of peaks are shown in Figure 2 and Table 2, respectively.

Table 2: List of Peaks for Image B of Anhydrous Free Rule 1

<td>Piku location (° 2θ)</td>

<td>5.8</td>

<td>7.7</td>

<td>8.3</td>

<td>9.9</td>

<td>13.0</td>

<td>13.3</td>

<td>14.2</td>

<td>15.3</td>

<td>16.6</td>

<td>17.9</td>

<td>18.3</td>

<td>19.8</td>

<td>20.7</td>

<td>21.2</td>

<td>21.9</td>

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<img file="PL2643322T3_D0003.tif" />

Compound 1 Free Base Hydrate (XRPD C Image) [0061] The free base hydrate characterized by the C image can be prepared in three ways.

[0062] Example 4: Solvate of Compound 1 free base with methanol was dried at ambient conditions. [0063] Example 5: Solvate of Compound 1 free base with ethanol was dried at ambient conditions.

[0064] Example 6: Solvate of Compound 1 free base with 2-propanol was dried at ambient conditions. [0065] The X-ray powder diffraction pattern and the list of peaks are shown in Figure 3 and Table 3, respectively.

Table 3: List of Peaks for Image C of Hydrate of Free Base Compound 1

<td>Peak location (° 2θ)</td>

<td>5.8</td>

<td>7.6</td>

<td>7.9</td>

<td>10.7</td>

<td>11.7</td>

<td>14.0</td>

<td>15.3</td>

<td>15.8</td>

<td>17.4</td>

<td>18.3</td>

<td>19.9</td>

<td>20.4</td>

<td>20.7</td>

<td>22.5</td>

<td>24.9</td>

<td>25.8</td>

<td>26.7</td>

Compound 1 Free Base Hydrate (XRPD D Image) [0066] Example 7: Compound 1 Free Acetate with an ethyl acetate solvate having a G image was dried at ambient conditions.

[0067] The X-ray powder diffraction pattern and list of peaks are shown in Figure 4 and Table 4, respectively.

Table 4: List of Peaks for the Hydrate Image of Compound 1's Free Base

<td>Piku location (° 2θ)</td>

<td>3.3</td>

<td>6.4</td>

<td>7.1</td>

<td>7.3</td>

<td>10.1</td>

<td>11.4</td>

<td>13.2</td>

<td>14.4</td>

<td>14.6</td>

<td>15.1</td>

<td>15.8</td>

<td>16.2</td>

<td>17.2</td>

<td>17.6</td>

<td>18.0</td>

<td>18.6</td>

<td>19.0</td>

<td>19.5</td>

<td>19.8</td>

<td>20.2</td>

<td>20.7</td>

<td>21.0</td>

<td>22.5</td>

<td>23.0</td>

<td>26.0</td>

<td>28.9</td>

<td>29.2</td>

Solvate of the Free Base of Compound 1 with Dichloromethane (Image XRPD E)

[0068] Example 8: The solid free base of Compound 1 was suspended in dichloromethane at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0069] The X-ray powder diffraction pattern and list of peaks are shown in Figure 5 and Table 5A, respectively. Crystallographic data are given in Table 5B.

Table 5A: List of Peaks for the Calculated XRPD for Image E of the Solvate Free Base Compound 1 with

dichloromethane

<img file="PL2643322T3_D0004.tif" />

Table 5B: Structural Information for the Single Crystal Solvate of the Free Base of Compound 1 with

with dichloromethane

<td>Crystal Form</td><td>Solvate of the Free Base Compound 1 with Dichloromethane</td>

<td>Network Type</td><td>monoclinic</td>

<td>Space Group</td><td>P21 / n</td>

<td>a (A)</td><td>13.873</td>

<td>b (A)</td><td>12.349</td>

<td>c (A)</td><td>29.996</td>

<td>α (°)</td><td>90,00</td>

<td>β (°)</td><td>92.259</td>

<td>Y (°)</td><td>90,00</td>

<td>Volume (A³)</td><td>5,134.85</td>

<td>WITH</td><td>4</td>

Compound 1 Free Ethyl Acetate Solvate (XRPD F Image) [0070] Example 9: Solid free base Compound 1 was suspended in ethyl acetate at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0071] The X-ray powder diffraction pattern and list of peaks are shown in Figure 6 and Table 6, respectively.

Table 6: List of XRPD Peaks for the Solvate F Image of the Free Base Compound 1 with Ethyl Acetate

<td>Piku location (° 2θ)</td>

<td>5.8</td>

<td>7.1</td>

<td>9.5</td>

<td>9.9</td>

<td>10.6</td>

<td>11.6</td>

<td>13.1</td>

<td>13.8</td>

<td>14.8</td>

<td>16.0</td>

<td>17.9</td>

<td>20.2</td>

<td>21.2</td>

<td>23.2</td>

<td>24.4</td>

<td>26.4</td>

Compound 1 Free Ethyl Acetate Solvate (XRPD G Image) [0072] Example 10: Solid free base Compound 1 was suspended in ethyl acetate at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0073] The X-ray powder diffraction pattern and list of peaks are shown in Figure 7 and Table 7, respectively.

Table 7: List of XRPD Peaks for Image G of Solvate Free Base Compound 1 with Ethyl Acetate

<img file="PL2643322T3_D0005.tif" />

EP 2643322 B1

<td>Piku location (° 2θ)</td>

<td>11.2</td>

<td>11.4</td>

<td>11.9</td>

<td>12.9</td>

<td>14.4</td>

<td>14.9</td>

<td>15.8</td>

<td>16.2</td>

<td>17.2</td>

<td>17.4</td>

<td>17.8</td>

<td>18.5</td>

<td>18.9</td>

<td>19.4</td>

<td>20.1</td>

<td>20.7</td>

<td>20.9</td>

<td>22.0</td>

<td>22.7</td>

<td>23.4</td>

<td>23.8</td>

<td>24.7</td>

<td>25.9</td>

<td>27.0</td>

<td>28.9</td>

Compound 1 Free Acetonitrile Solvate (XRPD H Image) [0074] Example 11: Solid free Compound 1 base was suspended in acetonitrile at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0075] The X-ray powder diffraction pattern and the list of peaks are shown in Figure 8 and Table 8A, respectively. Crystallographic data are given in Table 8B.

EP 2643322 B1

Table 8A: List of Peaks for the Calculated XRPD for Image H of the Solvate Free Base Compound 1 with

acetonitrile

<td>Piku location (° 2θ)</td>

<td>5.8</td>

<td>7.4</td>

<td>7.6</td>

<td>10.2</td>

<td>13.0</td>

<td>13.6</td>

<td>14.9</td>

<td>16.4</td>

<td>17.0</td>

<td>17.5</td>

<td>18.2</td>

<td>19.4</td>

<td>19.7</td>

<td>20.4</td>

<td>21.0</td>

<td>21.2</td>

<td>21.8</td>

<td>22.4</td>

<td>22.9</td>

<td>24.2</td>

<td>24.3</td>

<td>26.1</td>

<td>29.2</td>

Table 8B: Structural information for the Single Crystal Solvate H of the Free Principle of Compound 1 with

acetonitrile

<td>Crystal Form</td><td>Solvate A of the Free Base Compound 1 with Acetonitrile</td>

<td>Network Type</td><td>triclinic</td>

<td>Space Group</td><td>P1</td>

<td>a (A)</td><td>12.836</td>

<td>b (A)</td><td>13.144</td>

<td>c (A)</td><td>15.411</td>

<td>α (°)</td><td>92.746</td>

<td>β (°)</td><td>95.941</td>

EP 2643322 B1

<td>Crystal Form</td><td>Solvate A of the Free Base Compound 1 with Acetonitrile</td>

<td>γ (°)</td><td>113.833</td>

<td>Volume (A³)</td><td>2,354.06</td>

<td>WITH</td><td>2</td>

Acetonitrile Free Base Solvate of Compound 1 (XRPD I Image) [0076] Example 12: For 2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -4- (4 - ((2- ( (4-chlorophenyl) 4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl) benzoic acid (16 g, 28 mmol) and 3-nitro-4 ((tetrahydro-2H-pyran-4-yl) methylamino ) benzenesulfonamide (8.83 g, 28 mmol) in DCM (300 mL) EDCI (10.74 g, 56 mmol) and DMAP (6.85 g, 56 mmol) were added. The mixture was stirred at rt. through the night. LC / MS analysis showed the expected product as a single peak. The mixture was diluted with DCM (500 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. The solvent evaporation residue was dissolved in DCM and applied to the column, then eluted with 30% ethyl acetate in DCM followed by 1 to 2% MeOH in DCM to give 24.5 g of pure product (95% purity) which was dissolved in DMSO and MeOH (1: 1) and TFA (2 equivalents) and applied to a 330 g C18 column (6 g once) to give 13.5 g of pure (&gt; 99.7% purity) product (55% yield). The API was extracted with dichloromethane and then the solvent was removed by rotary evaporation. The resulting solid was suspended in acetonitrile at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0077] The X-ray powder diffraction pattern and list of peaks are shown in Figure 9 and Table 9, respectively.

Table 9: List of XRPD Peaks for Image and Solvate of Free Base Compound 1 with Acetonitrile

<td>Piku location (° 2θ)</td>

<td>6.4</td>

<td>6.9</td>

<td>7.7</td>

<td>8.8</td>

<td>9.4</td>

<td>11.1</td>

<td>12.3</td>

<td>12.8</td>

<td>16.5</td>

<td>17.0</td>

<td>17.4</td>

<td>18.3</td>

<td>18.6</td>

EP 2643322 B1

Piku location (° 2θ)

19.0

19.2

20.3

21.6

22.3

22.9

23.7

Acetone Compound 1 Free Base Solvate (XRPD Image J) [0078] Example 13: The resulting solid was suspended in acetone at ambient temperature to obtain its solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0079] The X-ray powder diffraction pattern and the list of peaks are shown in Figure 10 and Table 10, respectively.

Table 10: List of XRPD Peaks for Image J of Solvate Free Base Compound 1 with Acetone

<td>Piku location (° 2θ)</td>

<td>6.0</td>

<td>6.8</td>

<td>8.0</td>

<td>9.0</td>

<td>9.7</td>

<td>11.2</td>

<td>11.9</td>

<td>12.6</td>

<td>14.7</td>

<td>15.0</td>

<td>15.2</td>

<td>15.8</td>

<td>16.4</td>

<td>16.6</td>

<td>17.6</td>

<td>17.8</td>

<td>17.9</td>

<td>18.7</td>

EP 2643322 B1

<td>Piku location (° 2θ)</td>

<td>20.2</td>

<td>20.8</td>

<td>21.6</td>

<td>22.2</td>

<td>22.6</td>

<td>23.3</td>

<td>23.8</td>

<td>24.0</td>

<td>24.4</td>

<td>26.8</td>

<td>27.1</td>

<td>28.0</td>

<td>28.2</td>

Compound 1 hydrochloride (XRPD K image) Example 14: Solid free base Compound 1 (16 mg, 0.018 mmol) was suspended in 0.5 mL of acetonitrile. Hydrochloric acid (1M, 25 μθ was added to the suspension while stirring (molar ratio Compound 1: acid = 1: 1.4). Compound 1 reacted quickly with hydrochloric acid and formed a clear solution. Yellowish solids which later crystallized were confirmed. from the solution is Compound 1 hydrochloride in a stoichiometric ratio of 1: 1 free base to HCl.

[0081] The X-ray powder diffraction pattern and list of peaks are shown in Figure 11 and Table 11A, respectively. Crystallographic data are given in Table 11B.

Table 11A: Peak List for Calculated XRPD for Image K of Compound 1 Hydrochloride

<td>Piku location (° 2θ)</td>

<td>5.1</td>

<td>5.9</td>

<td>7.7</td>

<td>9.9</td>

<td>10.2</td>

<td>10.8</td>

<td>13.6</td>

<td>14.0</td>

<td>15.4</td>

<td>15.9</td>

<td>16.2</td>

EP 2643322 B1

<td>Piku location (° 2θ)</td>

<td>17.6</td>

<td>18.3</td>

<td>18.7</td>

<td>19.7</td>

<td>19.9</td>

<td>20.1</td>

<td>20.4</td>

<td>20.7</td>

<td>20.9</td>

<td>22.9</td>

<td>26.2</td>

Table 11B: Structural information for Compound 1 Hydrochloride

<td>Crystal Form</td><td>Compound 1 hydrochloride</td>

<td>Network Type</td><td>triclinic</td>

<td>Space Group</td><td>P1</td>

<td>a (A)</td><td>10.804</td>

<td>b (A)</td><td>12.372</td>

<td>c (A)</td><td>19.333</td>

<td>α (°)</td><td>76.540</td>

<td>β (°)</td><td>87.159</td>

<td>Y (°)</td><td>70.074</td>

<td>Volume (A³)</td><td>2361.5</td>

<td>WITH</td><td>2</td>

Compound 1 Hydrochloride Hydrate (XRPD L Image) [0082] Example 15: Compound 1 Solid Hydrochloride (having image K) was exposed to ambient air and the formation of Compound 1 hydrochloride hydrate was confirmed.

[0083] The X-ray powder diffraction pattern and list of peaks can be seen in Figure 12 and Table 12, respectively.

Table 12: List of XRPD Peaks for Image L of Hydrochloride Compound 1

Piku location (° 2θ)

4.6

8.7

EP 2643322 B1

<td>Piku location (° 2θ)</td>

<td>9.6</td>

<td>9.9</td>

<td>12.3</td>

<td>14.9</td>

<td>15.7</td>

<td>17.6</td>

<td>18.1</td>

<td>18.4</td>

<td>19.3</td>

<td>19.6</td>

<td>21.0</td>

<td>23.3</td>

<td>23.9</td>

<td>24.8</td>

<td>26.5</td>

<td>27.2</td>

<td>27.4</td>

<td>29.0</td>

Compound 1 Sulphate (XRPD M Image) [0084] Example 16: Solid free Compound 1 base (16 mg, 0.018 mmol) was suspended in 0.5 mL of 2-propanol at 70 ° C. Sulfuric acid (1M, 25 μ!) Was added to the suspension with stirring (molar ratio Compound 1: acid = 1: 1.4). Compound 1 dissolved quickly by reacting with sulfuric acid. A yellowish solid crystallized from solution immediately after dissolution. Using ion chromatography it was confirmed that the crystalline solid was Compound 1 sulfate with 1: 1 stoichiometry.

[0085] The X-ray powder diffraction pattern and list of peaks can be seen in Figure 13 and Table 13, respectively.

Table 13: List of XRPD Peaks for Image M of Compound 1 Sulfate

<img file="PL2643322T3_D0006.tif" />

EP 2643322 B1

<td>Piku location (° 2θ)</td>

<td>12.6</td>

<td>14.5</td>

<td>15.4</td>

<td>17.4</td>

<td>17.9</td>

<td>18.4</td>

<td>19.1</td>

<td>19.5</td>

<td>21.0</td>

<td>22.4</td>

<td>23.3</td>

<td>23.9</td>

<td>25.1</td>

<td>26.8</td>

Compound 1 Free Tetrahydrofuran Solvate (XRPD N Image) (not according to claims) [0086] Example 17: Solid free base Compound 1 was suspended in tetrahydrofuran (THF) at ambient temperature to obtain solubility. After reaching equilibrium, the solids were isolated at ambient temperature.

[0087] The X-ray powder diffraction pattern and list of peaks are shown in Figure 14 and Table 14, respectively.

Table 14: List of XRPD Peaks for Image N of Solvate Free Base Compound 1 with Tetrahydrofuran

<td>Piku location (° 2θ)</td>

<td>4.0</td>

<td>4.6</td>

<td>8.0</td>

<td>8.5</td>

<td>9.4</td>

<td>14.6</td>

<td>17.1</td>

<td>17.4</td>

<td>17.8</td>

<td>18.1</td>

<td>19.2</td>

EP 2643322 B1

<img file="PL2643322T3_D0007.tif" />

[0088] XRPD data was collected using a G3000 diffractometer (Inel Corp., Artenay, France) equipped with a bent position detector and parallel beam optics. The diffractometer worked with a copper anode lamp (precise focusing 1.5 kW) at 40 kV and 30 mA. Germanium monochrome with the incident beam provided monochrome Cu-Κα radiation, which has a wavelength of 1.54178 A. The diffractometer was calibrated using a weakened direct beam at one-stage intervals. The calibration was checked using a reference standard for the silicon powder line position (NIST 640c). The apparatus was computer controlled using Symphonix software (Inel Corp., Artenay, France) and the data was analyzed using Jade software (version 6.5, Materials Data, Inc., Livermore, CA). The sample was mounted in an aluminum sample holder and aligned with a glass plate. XRPD peak position measurement typically has an accuracy of ± 0.2 degrees two theta (° 2θ).

[0089] In some embodiments, the percentage of crystallinity of any salt or crystal form of Compound 1 as described herein may vary with respect to the total amount of Compound 1. In particular, some embodiments provide a crystallinity salt or crystalline Compound 1 percentage of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60% at least 70%, at least 80%, at least 90%, at least 95% or at least 99%. In some embodiments, the percentage of crystallinity can be substantially 100%, where substantially 100% indicates that all of Compound 1 appears to be crystalline, as best determined by methods known in the art. Accordingly, the pharmaceutical compositions and therapeutically effective amounts of Compound 1 may contain amounts that differ in crystallinity. This applies to cases in which Compound 1 is used as an API in various formulations and solid forms, including those in which the amount of Compound 1 in solid form is then dissolved, partially dissolved, or suspended or dispersed in a liquid.

[0090] As noted, in some embodiments, API compositions are provided that comprise Compound 1, wherein at least a portion of Compound1 in the API composition is present in one of the salts or crystal forms. For example, the API composition containing Compound 1 has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at at least 90%, at least 95%, or at least 99% of the compound of the composition in the form of one of the salts or crystalline forms. In some embodiments, substantially 100% of Compound 1 in the API formulation is in the form of a salt or crystal form, as described herein.

[0091] Any of the crystalline forms of Compound 1, including salts and solvated forms, may be useful as the active pharmaceutical ingredient (API) for the preparation of pharmaceutical compositions. However, solvent-free forms are generally preferred for this purpose. In this context, the hydrate is considered to be solvent free. The solvated forms may be, as indicated above,

EP 2643322 B1 useful as intermediates for the preparation of solvent-free forms. The salts and crystalline forms of Compound 1 can be used to prepare pharmaceutical compositions suitable for various routes of administration, including oral, to a subject in need thereof. Thus, in some embodiments, a pharmaceutical composition is provided comprising the crystalline form of Compound 1 and one or more pharmaceutically acceptable excipients. Such compositions can be prepared using various methods known in pharmacy.

[0092] In some embodiments, the salt or crystalline form of Compound 1 includes the anhydrous free base of Compound 1 having the XRPD A image, the anhydrous free base of Compound 1 having an XRPD B image, Compound 1 free base hydrate having an XRPD C image, Compound 1 free base hydrate having an XRPD D image, solvate of the free base of Compound 1 with dichloromethane having an XRPD E image, Compound 1 ethyl acetate free base solvate having an XRPD F image, Compound 1 ethyl acetate free base solvate having an XRPD G image, solvate of Compound 1 free acetonitrile having an XRPD H image, solvate of Compound 1 free acetonitrile having XRPD I image, solvate of Compound 1 free acetone with XRPD J image, Compound 1 hydrochloride having an XRPD K image, Compound 1 hydrochloride hydrate having an XRPD L image, Compound 1 sulfate having an XRPD M image, each of which has appropriate X-ray powder diffraction images, as described here. Compound 1 tetrahydrofuran (THF) free base solvate having an XRPD N image as described herein has also been described.

[0093] According to any of these embodiments, the composition may be delivered, for example, by the oral route. Other routes of administration include, without limitation, parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, ear, rectal, vaginal, intragastric, intracranial, intrasynovial and intra-articular routes.

[0094] Where it is desired to provide the free base or salt of Compound 1 in the form of a solution, for example in a liquid formulation for oral or parenteral administration, the free base or salt of Compound 1 will obviously not be present in such a formulation in crystalline form; in fact, the presence of crystals is generally undesirable in such a formulation. However, the crystalline free form of Compound 1 may be important as an API in the preparation of such a formulation. Thus, the present disclosure further provides a method of preparing a pharmaceutical solution composition of Compound 1, comprising dissolving the crystalline salt or crystalline form of the free base of Compound 1 in a pharmaceutically acceptable solvent or mixture of solvents. Even when the desired formulation contains the free base of Compound 1 in amorphous form, for example a solid alloy formulation, the crystalline form of the free base of Compound 1 may still be useful as an API in the process of making such a formulation.

[0095] As API, the crystalline form of Compound 1 free base or mixtures thereof may have an advantage over the amorphous form. For example, purifying the API to the high degree of purity required by most registration authorities may be more efficient and therefore less costly when the API is in crystalline rather than amorphous form. Physical and chemical stability, and therefore stability of solid API, may also be better for crystalline forms than for amorphous ones. Compared to the amorphous form, ease of handling can be improved as the amorphous form can be oily or sticky. Drying may be simpler and easier to control for crystalline material that may have a well-defined drying or desolvation temperature than for amorphous material which may have a higher affinity for organic solvents and not have

EP 2643322 B1 has a specific drying temperature. Subsequent processing of the crystalline API may additionally allow better process control. In the preparation of a liquid formulation, for example a solution in a lipid carrier, the crystalline Compound 1 may dissolve faster and may have a lower tendency to form a gel during dissolution. These advantages are illustrative and not limiting.

[0096] Pharmaceutical compositions containing the crystalline free base of Compound 1 or prepared using the crystalline free base of Compound 1 or a salt of Compound 1 as an API, contain Compound 1 in an amount that can be therapeutically effective when the composition is administered to a subject in need thereof in accordance with the appropriate scheme. Dose amounts are expressed here as equivalent amounts of the free base, unless the context requires a different interpretation. Typically, a unit dose (one-time dose) that can be administered at an appropriate frequency, e.g., twice daily once a week, is about 10 to about 1000 mg. When the frequency of administration is once daily (qd), the unit dose and daily dose are the same. For example, a unit dose of Compound 1 in the composition of the invention may be from about 25 to about 1000 mg, more typically from about 50 to about 500 mg, for example about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450 or about 500 mg. When the composition is prepared in the form of a separate dosage form, such as a tablet or capsule, the unit dosage may be provided in the form of a single dose or in a small number of dosage forms, usually from 1 to about 10 dosage forms.

[0097] The higher the unit dose, the more desirable it will be to select excipients that allow relatively high contents of API (in this case the free base or salt of Compound 1) in the formulation. Typically, the concentration of Compound 1 in the formulation prepared according to the present disclosure is at least about 1%, e.g., from about 1% to about 25% by weight, but lower and higher concentrations may be acceptable or achievable in specific cases. For example, the equivalent concentration of Compound 1 free base in various embodiments is at least about 2%, e.g., from about 2% to about 20% by weight, for example about 5%, about 10% or about 15% by weight of the formulation.

[0098] The composition made according to the invention contains, in addition to API, one or more pharmaceutically acceptable excipients. If the composition is to be prepared in solid form for oral administration, for example as a tablet or capsule, it usually contains at least one or more solid diluents and one or more solid disintegrants. Optionally, the excipients further include one or more binders, wetting agents and / or anti-friction agents (lubricants, release agents and / or glidants). Many excipients have two or more functions in the pharmaceutical composition. The characterization in the present description of a particular excipient as having a specific function, e.g., diluent, disintegrant, binder, etc., should not be construed as limited to that function. Further information on excipients can be found in standard reference works such as Handbook of Pharmaceutical Excipients, ed. 3. (Kibbe, ed. (2000), Washington: American Pharmaceutical Association).

[0099] Suitable diluents for example include, alone or in combination, lactose, including anhydrous lactose and lactose monohydrate; lactitol; maltitol; mannitol; sorbitol; xylitol; dextrose and dextrose monohydrate; fructose; sucrose and sucrose-based diluents such as compressible sugar,

EP 2643322 B1 confectionery sugar and sugar balls; maltose; inositol; hydrolyzed solid cereal products; starches (e.g. Corn starch wheat starch, rice starch potato starch tapioca starch, e.t.c.), starch ingredients, such as amylose and dextrose, and modified or processed starches, such as pregelatinized starch; dextrins; cellulose, including powdered cellulose, microcrystalline cellulose, silica microcrystalline cellulose, food sources of α- and amorphous cellulose and powdered cellulose and cellulose acetate; calcium salts, including calcium carbonate, tribasic calcium phosphate, dibasic calcium phosphate dihydrate, monobasic calcium sulfate monohydrate, calcium sulfate and granulated calcium lactate trihydrate; magnesium carbonate; magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Such diluents, if present, typically comprise from about 5% to about 95% in total, for example from about 20% to about 90%, or from about 50% to about 85%, based on the weight of the composition. The diluent or diluents selected preferably show suitable flow properties and, if tablets are desired, compressibility.

[0100] Microcrystalline cellulose and silica microcrystalline cellulose are particularly useful diluents and are optionally used in combination with a water-soluble diluent such as mannitol. For example, a suitable weight ratio of microcrystalline cellulose or silica microcrystalline cellulose to mannitol is from about 10: 1 to about 1: 1, but ratios outside this range may be useful in special circumstances.

[0101] Suitable disintegrants include, individually or in combination, starches, including pregelatinized starch and sodium starch glycolate; clays; magnesium aluminum silicate; cellulose based disintegrants, such as powdered cellulose, microcrystalline cellulose, methylcellulose, low substituted hydroxypropyl cellulose, carmellose, calcium caramel carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; potassium polacrylin; gums such as agar gum, guar gum, Locust beans karaya pectin and tragacanth; colloidal silicon dioxide; and the like. One or more disintegrants, if present, typically together comprise from about 0.2% to about 30%, for example from about 0.5% to about 20%, or from about 1% to about 10% by weight of the composition.

[0102] Sodium starch glycolate is a particularly useful disintegrant and typically constitutes a total of from about 1% to about 20%, for example from about 2% to about 15%, or from about 5% to about 10% by weight of the composition.

[0103] Binders or binders are useful excipients, especially when the composition is in the form of a tablet. Such binders and binders should provide sufficient cohesiveness to the tabletting blend to allow normal processing operations such as screening, lubrication, compression and packaging, but still allow tablet to disintegrate and absorb the composition after ingestion. Suitable binders and binders include, individually or in combination, acacia; tragacanth; glucose; polydextrose; starch, including pregelatinized starch; gelatin; modified celluloses including methyl cellulose, sodium caramelose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose; dextrins including maltodextrin; zein; alginic acid and alginic acid salts, for example, sodium alginate; magnesium aluminosilicate; bentonite; polyethylene glycol (PEG); poly (ethylene oxide); guar gum; polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), for example povidone K-15, K-30 and K-29/32; polyacrylic acids (carbomers); polymethacrylates; and the like. One or more binding agents and / or

Binders, if present, typically together comprise from about 0.5% to about 25%, for example from about 1% to about 15%, or from about 1.5% to about 10% by weight of the composition.

[0104] Povidone and hydroxypropyl cellulose, alone or in combination, are particularly useful binders in tablet formulations and, if present, typically comprise from about 0.5% to about 15%, for example from about 1% to about 10%, or from about 2% to about 8% by weight of the composition. [0105] Wetting agents, if present, are usually selected to keep the drug in close contact with water, under conditions that may improve the bioavailability of the composition. Non-limiting examples of surfactants, which can be used as wetting agents include, individually or in combination, quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride; dioctyl sodium sulfosuccinate; alkylphenyl polyoxyethylene alkyl ethers, for example nonoxynol 9, Nonoxynol 10 and Octoxynol 9; poloxamers (block copolymers of polyoxyethylene and polyoxypropylene); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic / capric mono and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4 laureth-23 oleth-2 oleth10, Oleth-20 steareth-2 steareth-10 steareth-20 steareth-100 and polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, for example polyoxyethylene (20) stearate, polyoxyethylene (40) stearate and polyoxyethylene (100) stearate; sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate; polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80; esters of propylene glycol and fatty acids, for example propylene glycol laurate; sodium lauryl sulfate; fatty acids and their salts, for example oleic acid, sodium oleate and triethanolamine oleate; glycerol and fatty acid esters, for example glyceryl monooleate, glyceryl monostearate and glyceryl palmitostearate; tyloxapol; and the like. The one or more wetting agents, if present, typically together comprise from about 0.1% to about 15%, for example from about 0.2% to about 10%, or about 0.5% to about 7% by weight of the composition.

[0106] Nonionic surfactants, in particular poloxamers, are examples of wetting agents that may be useful in the invention. For example, a poloxamer, such as Pluronic ™ F127, if present, may constitute from about 0.1% to about 10%, for example from about 0.2% to about 7%, or from about 0.5% to about 5 % by weight of the composition.

[0107] Lubricants reduce friction between the tableting compound and the tabletting instrumentation when compressing the formulation into tablets. Suitable lubricants include, alone or in combination, glyceryl behenate; stearic acid and its salts, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEG (e.g., PEG 4000 and PEG 6000); poloxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and the like. One or more lubricants, if present, typically together comprise from about 0.05% to about 10%, for example from about 0.1% to about 5%, or from about 0.2% to about 2% by weight of the composition . Sodium stearyl fumarate is a particularly useful lubricant.

[0108] Release agents reduce the adherence of tableting formulations to tooling surfaces. Suitable release agents include, alone or in combination, talc, colloidal silicon dioxide, starch, DL-leucine, sodium lauryl sulfate and metal stearates. One or

The greater number of release agents, if present, typically comprises from about 0.05% to about 10%, for example from about 0.1% to about 7%, or from about 0.2% to about 5% by weight of the composition. Colloidal silicon dioxide is a particularly useful release agent.

[0109] Glidants improve flow properties and reduce electrostatic charges in the tablet mixture. Suitable lubricants include, alone or in combination, colloidal silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate and metal stearates. One or more lubricants, if present, typically comprise from about 0.05% to about 10%, for example from about 0.1% to about 7%, or from about 0.2% to about 5% by weight of the composition . Colloidal silicon dioxide is a particularly useful lubricant.

[0110] Other excipients such as buffering agents, stabilizers, antioxidants, antimicrobials, dyes, flavors and sweeteners are known in the pharmaceutical art and can be used in the compositions of the present invention. The tablets may be uncoated or may contain a core that is coated, e.g., a non-functional release-modifying coating or coating, or an enteric coating. The capsules must be hard or soft and contain, for example, gelatin (in the form of hard gelatin capsules or soft flexible gelatin capsules), starch, carrageenan and / or HPMC, optionally together with one or more plasticizers.

[0111] The solid oral composition of the present invention is not limited by any method used to prepare it. Any suitable process known in the art may be used, including dry blending with or without direct compression, and wet or dry granulation.

[0112] If the composition is to be prepared in liquid form (including as an encapsulated liquid), then the API (e.g. for example, the crystalline free base or salt of Compound 1) can be dissolved in a suitable carrier, usually containing a lipid solvent for API. The higher the unit dose, the more desirable it will be to choose a carrier which allows for a relatively high concentration of the drug in solution. Typically, the equivalent concentration of API free base in the vehicle is at least about 10 mg / mL, e.g. from about 10 to about 500 mg / ml, but lower and higher concentrations may be acceptable or achievable in specific cases. For example, the drug concentration in various embodiments is at least about 10 mg / mL, e.g., from about 10 to about 250 mg / mL, or at least about 20 mg / mL, e.g., from about 20 to about 200 mg / ml, for example about 20, about 25, about 30, about 40, about 50, about 75, about 100 or about 150 mg / ml.

[0113] The carrier may be substantially non-aqueous, i.e., contain no water or contain an amount of water that is small enough to be, practically speaking, substantially harmless to the composition or properties. Typically, the carrier comprises from 0 to less than about 5% by weight of water. It will be understood that some components useful in the invention may bind small amounts of water to or within their supramolecular molecules or structures; such bound water, if present, does not affect the "substantially non-aqueous" nature of the carrier as defined herein.

[0114] In some embodiments, the carrier comprises one or more glyceride materials. Suitable glyceride materials include, but are not limited to, medium to long chain mono-, di- and triglycerides. The term "medium chain" as used herein refers to hydrocarbon chains having individually not less than about 6 and less than about 12

EP 2643322 B1 carbon atoms, including for example C8 to C10 chains. Thus, glyceride materials containing caprylic and capric chains, e.g., mono-, di- and / or caprylic / capric triglycerides are examples of "medium chain" glyceride materials. The term "long chain" as used herein refers to hydrocarbon chains individually having at least about 12, for example from about 12 to about 18 carbon atoms, including, for example, lauryl, myristyl, cetyl, stearyl, oleyl, linoleic and linolenyl. Medium to long chain hydrocarbon groups in glyceride materials can be saturated, mono- or polyunsaturated.

[0115] In one embodiment, the carrier comprises medium chain and / or long chain triglyceride material. A suitable example of a medium chain triglyceride material is a caprylic / capric triglyceride product, such as, for example, Captex 355 EP ™ from Abitec Corp. and products essentially equivalent to it. Suitable examples of long chain triglycerides include any pharmaceutically acceptable vegetable oil, for example rapeseed, coconut, corn, cotton, linseed, olive, palm, peanut, safflower, sesame, soybean and sunflower oil and mixtures of such oils. Animal oils may also be used, in particular those derived from marine animals, including, for example, fish oil.

[0116] In some embodiments, the carrier comprises a phospholipid and a pharmaceutically acceptable phospholipid solubilizing agent. It will be understood that the singular reference to a certain (or specific) phospholipid, solubilizing agent or other formulation component includes the plural; in this connection, combinations of, for example, mixtures of more than one phospholipid or more than one solubilizing agent are expressly included herein. The solubilizing agent or combination of solubilizing agent and phospholipid also solubilize the drug, although other carrier components, such as a surfactant or alcohol such as ethanol, optionally present in the carrier, may under certain circumstances provide increased drug solubility.

[0117] Any pharmaceutically acceptable phospholipid or mixture of phospholipids can be used. Generally, such phospholipids are phosphoric acid esters that result in hydrolysis of phosphoric acid, fatty acid (fatty acids), alcohol and alkaline nitrogen bases. Pharmaceutically acceptable phospholipids may include, without limitation, phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine. In one embodiment, the composition comprises phosphatidylcholine, obtained, for example, from natural lecithin. Any source of lecithin can be used, including animal sources such as egg yolk, but plant sources are generally preferred. Soy is a particularly rich source of lecithin that can provide phosphatidylcholine for use in the present invention.

[0118] For example, a suitable amount of phospholipid is from about 15% to about 75%, for example from about 30% to about 60% by weight of the carrier, although larger and smaller amounts may be useful in special situations.

[0119] Ingredients useful as components of the solubilizing agent are not particularly limited and will depend to some extent on the desired drug and phospholipid concentration. In one embodiment, the solubilizing agent comprises one or more glycols and / or one or more glyceride materials.

[0120] Suitable glycols include propylene glycol and polyethylene glycols (PEG) with a molecular weight of from about 200 to about 1000 g / mol, e.g., PEG-400, which has an average molecular weight of about 400 g / mol. Such glycols can provide relatively high drug solubility; however,

The risk of oxidative degradation of a drug may be increased for a solution in a carrier containing such glycols, for example due to the tendency of glycols to form superoxides, peroxides and / or free hydroxyl radicals. The higher the glycol content in the carrier, the greater the tendency to degrade the chemically labile drug may be. In one embodiment, therefore, one or more glycols are present in a total glycol amount of at least about 1%, but less than about 50%, e.g., less than about 30%, less than about 20%, less than about 15% or less than about 10% by weight of the carrier. In another embodiment, the carrier is substantially free of glycol.

[0121] Suitable glyceride materials for use with a phospholipid include, without limitation, those mentioned above. When one or more glyceride materials are present as the main component of the solubilizing agent, the corresponding total amount of glycerides is an effective amount for solubilizing the phospholipid and, in combination with the other carrier components, effective in keeping the drug and antioxidant in solution. For example, glyceride materials, such as medium chain and / or long chain triglycerides, may be present in the total amount of glycerides from about 5% to about 70%, for example from about 15% to about 60% or from about 25% to about 50% by weight of carrier. [0122] Additional solubilizing agents that are other than glycols or glyceride materials may be included if desired. Such agents, for example N-substituted amide solvents, such as dimethylformamide (DMF) and N, N-dimethylacetamide (DMA), may, in certain cases, help increase the solubility limit of a drug in a carrier, thereby allowing an increase in the amount of drug contained. However, N-substituted amides, including DMF and DMA, can create registration and / or toxicological problems that limit the amount of such solvents that can be used in the formulation. In addition, the carriers useful herein generally ensure adequate solubility of the small molecule drugs of interest without such additional agents. [0123] Even if the presence of sufficient glycol or glyceride material is ensured for the solubilization of the phospholipid, the resulting carrier solution and / or carrier / drug system may be rather viscous and difficult or inconvenient to handle. In such cases, it may be desirable to include in the carrier a viscosity reducing agent in an effective amount to provide an acceptable low viscosity. An example of such an agent is alcohol, in particular ethanol, which is preferably introduced in a substantially water-free form, e.g. as 99% ethanol, USP dehydrated alcohol or absolute ethanol. However, generally too high ethanol levels should be avoided. This is especially important when, for example, the carrier / drug system is to be administered in a gelatin capsule, due to the tendency of high ethanol concentrations to cause mechanical damage to the capsule. In general, suitable amounts of ethanol are from 0% to about 25%, for example from about 1% to about 20%, or from about 3% to about 15% by weight of the carrier.

[0124] Optionally, the carrier further comprises a pharmaceutically acceptable non-phospholipid surfactant. One skilled in the art will be able to choose the appropriate surfactant for use in the composition of the invention. For example, a surfactant such as polysorbate 80 may be present in an amount of from 0% to about 5%, for example from 0% to about 2%, or from 0% to about 1% by weight of the carrier.

[0125] Conveniently, pre-mixed products are available containing a suitable combination of phospholipid + solubilizing agent for use in the compositions of the present invention. Pre-mixed phospholipid + solubilizing products may be beneficial in improving the ease of preparation of the present compositions.

[0126] An illustrative example of a pre-mixed phospholipid + solubilizing product is Phosal 50 PG ™, available from Phospholipid GmbH, Germany, which contains not less than 50% phosphatidylcholine by weight, not more than 6% lysophosphatidylcholine, about 35% glycol propylene, about 3% mono- and diglycerides from sunflower oil, about 2% soy fatty acids, about 2% ethanol and about 0.2% ascorbyl palmitate.

[0127] Another illustrative example is Phosal 53 MCT ™, also available from Phospholipid GmbH, which contains, by weight, not less than 53% phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 29% medium chain triglycerides, 3-6% (typically about 5%) ethanol, about 3% mono- and diglycerides from sunflower oil, about 2% oleic acid and about 0.2% ascorbyl palmitate (reference composition). A product with the above or substantially equivalent composition, whether sold under the name Phosal 53 MCT ™ or another name, is generally referred to as "phosphatidylcholine + 53/29 medium chain triglycerides". A product with a "substantially equivalent composition" in the present context means that it has a composition sufficiently similar to the reference composition in terms of the list of ingredients and the relative amounts of ingredients so as not to show any practical difference in properties with respect to the utility of the product in the present invention. [0128] Still another illustrative example is Phosal 50 SA + ™, also available from Phospholipid GmbH, which contains, by weight, not less than 50% phosphatidylcholine and not more than 6% lysophosphatidylcholine in a solubilizing system containing safflower oil and other ingredients.

[0129] The phosphatidylcholine component of each of these pre-mixed products may be derived from soy lecithin. Products with a substantially equivalent composition can be obtained from other suppliers. [0130] A pre-mixed product, such as Phosal 50 PG ™, Phosal 53 MCT ™ or Phosal 50 SA + ™, may in some embodiments be essentially the entire carrier system. In other embodiments, additional ingredients are present, e.g., ethanol (additional to that which may be present in the premixed product), a non-phospholipid surfactant, such as polysorbate 80, polyethylene glycol and / or other ingredients. Such additional ingredients, if present, are usually contained only in small amounts. For example, phosphatidylcholine + medium chain 53/29 triglycerides can be contained in the carrier in an amount from about 50% to 100%, for example from about 80% to 100%, by weight of the carrier.

[0131] Without being bound by theory, it is believed that the therapeutic efficacy of Compound 1 is at least partly due to its ability to bind a Bcl-2 family protein, such as Bcl-2, Bcl-XL or Bcl-in a manner that inhibits the action antiapoptotic of this protein, for example by occupying the BH3 binding groove of the protein.

[0132] Compound 1 can be used in a method of treating a disease characterized by apoptotic dysfunction and / or overexpression of an antiapoptotic Bcl-2 family protein, comprising administering to a subject suffering from such a disease a therapeutically effective amount of a crystalline free base of Compound 1 or a pharmaceutical composition comprising a salt or form crystalline free base of Compound 1 and one or more pharmaceutically acceptable excipients.

[0133] Compound 1 may be used in a method of treating a disease characterized by apoptotic dysfunction and / or overexpression of an antiapoptotic protein of the Bcl-2 family, the method comprising preparing a solution or dispersion of a salt or crystalline form of Compound 1 as described herein in a pharmaceutically acceptable solvent or solvent mixture and administration

Of the resulting solution or dispersion in a therapeutically effective amount to an individual suffering from this disease.

[0134] The subject may be human or may be non-human (e.g. a breeding animal, a zoo animal, an animal used for work or an accompanying animal, or a laboratory animal, used as a model), but in a significant embodiment the individual is a person in need of a drug, e.g. for the treatment of a disease characterized by apoptotic dysfunction and / or overexpression of anti-apoptotic protein from the Bcl-2 family. The human subject may be a man or woman of all ages, but usually an adult.

[0135] The composition is usually administered in an amount that provides a therapeutically effective daily dose of the drug. The term "daily dose" here means the amount of drug administered per day, regardless of the frequency of administration. For example, if you receive a unit dose of 150 mg twice daily, the daily dose is 300 mg. The use of the term "daily dose" will be understood as not suggesting that the specific dose is necessarily administered once daily. However, in a specific embodiment, the dosing frequency is once daily (qd) and the daily dose and unit dose are in this embodiment the same.

[0136] What constitutes a therapeutically effective dose depends on the bioavailability of the formulation, the individual (including the species and body weight of the individual), the disease (e.g., a particular type of cancer) to be treated, the degree and / or severity of the disease, the individual the individual's tolerance of the compound, whether the compound is administered alone or in combination with one or more other drugs, e.g., other chemotherapeutic agents, for the treatment of cancer and other agents. Thus, the daily dose may vary within wide limits, for example from about 10 to about 1000 mg. Higher or lower daily doses may be appropriate in certain situations. It should be understood that listing the "therapeutically effective" dose herein does not necessarily require that the drug be therapeutically effective if only one such dose is administered; typically, therapeutic efficacy depends on a composition administered repeatedly according to a regimen comprising the appropriate frequency and duration of administration. It is very beneficial if, although the daily dose selected is sufficient to provide a benefit in the treatment of cancer, it should not be sufficient to cause an unacceptable or unacceptable side effect. A suitable therapeutically effective dose can be selected by a physician of ordinary skill without undue experimentation based on the present disclosure and publications cited herein, taking into account factors such as those mentioned above. Your doctor may, for example, start therapy for a cancer patient with a relatively low daily dose and increase the dose over days or weeks to reduce the risk of side effects.

[0137] For example, suitable doses of Compound 1 are generally from about 25 to about 1000 mg / day or from about 50 to about 1000 mg / day, more often from about 50 to about 500 mg / day or from about 200 to about 400 mg / day, for example about 50, about 100, about 150, around 200, about 250, about 300, about 350, about 400, about 450, about 500, about 750 or about 1000 mg / day, administered in an average interval between doses from about 3 hours to about 7 days, for example from about 8 hours to about 3 days, or from about 12 hours to about 2 days. In most cases, once daily dosing (qd) is appropriate.

[0138] The "average dose interval" herein is defined as the period of time, e.g. one day or one week, divided by the number of unit doses administered in

EP 2643322 B1 during this time. For example, when the drug is given three times a day, around 8am, around noon and around 6pm, the average dose interval is 8 hours (24-hour interval divided by 3). If the drug is formulated as a separate dosage form, such as a tablet or capsule, many (e.g., 2 to about 10) single-dose dosage forms are considered to be unit dose to determine the average dose interval.

[0139] The compositions prepared according to the present invention are suitable for use in monotherapy or in combination therapy, for example with other chemotherapeutics or with ionizing radiation. A particular advantage of the present invention is that it allows oral administration once a day, a treatment regimen convenient for a patient who is undergoing treatment with other oral drugs on a once daily basis. Oral administration is easy to be carried out by the patient alone or by a carer at the patient's home; it is also a convenient route of administration for patients in a hospital or care center.

[0140] Combination therapies, for example, include administering a composition comprising (or prepared using API) one or more crystalline forms of Compound 1 (including crystalline salt forms) simultaneously with one or more of bortezomib, carboplatin, cisplatin, cyclophosphamide, dacarbazine, deksametazony, docetaxel, doxorubicin, etoposide, fludarabine, hydroxydoxorubicin, irinotecan, paclitaxel, rapamycin, rituximab, vincristine and the like, for example with polytherapy, such as CHOP (cyclophosphamide + hydroxydoxorubicin + vincristine + prednisone), RCVP (rituximab + cyclophosphamide + vincristine + prednisone), R-CHOP (rituximab + CHOP) or DA-EPOCH-R (adjusted dose of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab).

[0141] The Compound 1 composition may be administered in combination therapy with one or more therapeutic agents that include, but are not limited to, angiogenesis inhibitors, antiproliferative agents, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl- inhibitors 1), death receptor pathway activators, BiTE antibodies bi-specific T-cell engager), double variable domain binding (DVD) proteins, protein inhibitors of apoptosis (IAP), microRNA, inhibitors of kinases activated by mitogens regulated by extracellular signal, multivalent binding proteins, poly-ADP- (adenosine diphosphate) -ribose (PARP) polymerase inhibitors, small inhibitory ribonucleic acids (siRNA), kinase inhibitors receptor tyrosine kinase inhibitors, Aurora kinase inhibitors polo-like kinase inhibitors, bcr-abl kinase inhibitors growth factor inhibitors, COX-2 inhibitors nonsteroidal anti-inflammatory drugs (NSAIDs), antimitotic agents, alkylating agents, anti-metabolites, intercalating antibiotics, platinum-containing chemotherapeutic agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, immunological drugs, antibodies, hormonal therapies, retinoids, deltoidy, plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors, purine analogues, pyrimidine analogues, MEK inhibitors CDK inhibitors ErbB2 receptor inhibitors, mTOR inhibitors, as well as other anti-cancer agents.

[0142] Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, metalloproteinase matrix 9 (MMP-9) inhibitors and thrombospondin analogs.

[0143] Examples of EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, cetuximab, EMD7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusion protein, EGF vaccine, anti-EGFR immunoliposomes and lapatinib.

[0144] Examples of PDGFR inhibitors include, but are not limited to, CP-673451 and CP-868596.

[0145] Examples of VEGFR inhibitors include bevacizumab, sunitinib, sorafenib, CP-547632, axitinib, vandetanib, AEE788, AZD-2171, VEGF trap, vatalanib, pegaptanib, IM862, pazopanib, ABT-869 and angiozyme.

[0146] Bcl-2 family protein inhibitors other than Compound 1 include, but are not limited to , ABT-263, AT-101 ((-) gossypol), an antisense oligonucleotide targeted to Bcl-2 Genasense ™ (G3139 or oblimersen), IPI-194, IPI-565, N- (4- (4 - ((4'-chloro (1,1'-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4 (((( 1R) -3- (dimethylamino) -1 - ((phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT737), GX-070 (obatoclax) and the like.

[0147] Death receptor pathway activators include, but are not limited to, TRAIL, antibodies or other agents directed to death receptors (e.g., DR4 and DR5) such as apomab, conatumumab, ETR2ST01, GDC0145 (lexatumumab), HGS-1029, LBY -135, PRO-1762 and trastuzumab.

[0148] Examples of thrombospondin analogs include, but are not limited to, TSP-1, ABT-510, ABT-567 and ABT-898.

[0149] Examples of Aurora kinase inhibitors include, but are not limited to, VX-680, AZD-1152 and MLN-8054. [0150] An example of a polo-like kinase inhibitor includes, but is not limited to, BI-2536.

[0151] Examples of bcr-abl kinase inhibitors include, but are not limited to, imatinib and dasatinib.

[0152] Examples of platinum-containing agents include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin.

[0153] Examples of mTOR inhibitors include, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001 and AP-23573.

[0154] Examples of HSP-90 inhibitors include, but are not limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS-683664, efungumab, CNF-2024, PU3, PU24FCl, VER-49009, IPI-504, SNX-2112 and STA-9090.

[0155] Examples of HDAC inhibitors include, but are not limited to, suberoilanil hydroxyamic acid (SAHA), MS-275, valproic acid, TSA, LAQ-824, trapoxin and depsipeptide.

[0156] Examples of MEK inhibitors include, but are not limited to, PD-325901, ARRY-142886, ARRY438162 and PD-98059.

[0157] Examples of CDK inhibitors include, but are not limited to flavopiridol, MCS-5A, CVT-2584, seliciclib ZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438 . [0158] Examples of COX-2 inhibitors include, but are not limited to, celecoxib, parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS 57067, NS-398, valdecoxib, rofecoxib, SD8381, 4-methyl-2 - (3,4-dimethylphenyl) -1- (4-sulfamoyl-phenyl-1H-pyrrole, T-614, JTE-522, S-2474, SVT2016, CT-3 and SC-58125.

[0159] Examples of NSAIDs include, but are not limited to, salsalate, diflunizal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac and oxaprosine.

[0160] Examples of ErbB2 receptor inhibitors include, but are not limited to, CP-724714, canertinib, trastuzumab, pertuzumab, TAK-165, ionafamib, GW-282974, EKB-569, PI-166, dHER2, APC-8024,

EP 2643322 B1 dual specificity antibody against HER / 2neu, B7.her2IgG3, trifunctional dual specificity antibodies against HER2, mAB AR-209 and mAB 2B-1.

[0161] Examples of alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, trophosphamide, chlorambucil, melphalan, busulfan, mitobronitol, carbocon, thiotepa, ranimustine, nimustine, Cloretazine ™ (laromustine3), AMD-47 altretamine, AP-5280, apazicwon, brostalicin, bendamustine, carmustine, estramustine, photemustine, glufosfamide, KW-2170, mafosphamide, mitolactol, lomustine, treosulfan, dacarbazine and temozolomide.

[0162] Examples of anti-metabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, Cytarabine Ocophosphate enokitabinę, S-1 pemetrexed, gemcitabine, fludarabine, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, etenylocytydynę, cytosine arabinoside, hydroxyurea, TS-1 melphalan, nelarabine, nolatreks, pemetrexed disodium, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, widearabinę, Mycophenolic acid ocfosfate, pentostatin, tiazofurin, ribavirin, EICAR hydroxyurea and deferoxamine.

[0163] Examples of antibiotics include, but are not limited to, intercalating antibiotics, aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, (including liposomicinicin, pepsomicomicinicin, , pirarubicin, rebecamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.

[0164] Examples of topoisomerase inhibiting agents include, but are not limited to, aclarubicin, ammonaphide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, amsacrine, dexrazoxane, diflomotecan, irinotecan, etecicekecine, edecotecan lurtotecan, oratecin, BN-80915, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.

[0165] Examples of antibodies include, but are not limited to, rituximab, cetuximab, bevacizumab, trastuzumab, CD40 specific antibodies and IGF1R specific antibodies, chTNT-1 / B, denosumab, edrecolomab, WX G250, zanolimumab, lintuzumab and ticilimum.

[0166] Examples of hormone therapies include, but are not limited to, sevelamer carbonate, rilostan, luteinizing hormone releasing hormone, modrastan, exemestane, Leuprolide Acetate buserelin, cetrorelix, deslorelin, histrelin, anastrozole, fosrelinę, goserelin, degarelix, doksercalcyferol, fadrozol, formestane, tamoxifen, arzoksyfen, bicalutamide, abarelix, triptorelin, finasteride, fulvestrant, toremifene, raloxifene, trilostane, lasofoxifene, letrozole, flutamide, megestrol, mifepristone, nilutamide, dexamethasone, prednisone and other glucocorticoids.

[0167] Examples of retinoids or deltoids include, but are not limited to, seocalcitol, lecalacitol, fenretinide, alitretinoin, tretinoin, bexarotene and LGD-1550.

[0168] Examples of plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine.

[0169] Examples of proteasome inhibitors include, but are not limited to, bortezomib, MG-132, NPI-0052 and PR-171.

[0170] Examples of immunological agents include, but are not limited to, interferons and many other resistance enhancers. Interferons include interferon alfa, interferon alfa-2a, interferon

Alpha-2b, interferon beta, interferongamma-Ia, interferon gamma-1b, interferon gamma-n1 and combinations thereof. Other measures include filgrastim. lentinan, sizofilan, BCG live ubenimex, WF-10 (tetrachlorodecoxide or TCDO), aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, diftitox, gemtuzumab ozogamycin, ibritumomab, imiquimod, lenograstim, Melanoma vaccine molgramostim, sargramostim, tasonermin, tekleukinę, thymalfasin, tositumomab, Virulizin ™ immunological drug from Lorus Pharmaceuticals, Z-100 (specific substance Maruyama or SSM), Zevalin ™ (90Y-ibritumomab thiuksetan), epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge ™ (sipuleucel-T), tekeleukinę, Therocys ™ (Bacillus Calmette-Guerin), cytotoxic lymphocyte antigen4 (CTLA4) and agents capable of blocking CTLA4, such as MDX-010.

[0171] Examples of biological response modulators are agents that modify the defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to anti-tumor activity. Such agents include, but are not limited to, crestin, lentinan, sisophiran, picibanil, PF-3512676 and ubenimex.

[0172] Examples of pyrimidine analogs include, but are not limited to, 5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine, cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine and gemcitabine.

[0173] Examples of purine analogs include, but are not limited to, mercaptopurine and thioguanine.

[0174] Examples of antimitotic agents include, but are not limited to, N- (2 - ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batabulin, ixabepilone , patupilon, XRP-9881, vinflunine and ZK-EPO (synthetic epothilone).

[0175] Examples of radiotherapy include, but are not limited to, external beam radiotherapy (XBRT), teletherapy, brachytherapy, closed source radiotherapy and non-closed source radiotherapy.

[0176] BiTE antibodies are dual specificity antibodies that direct T cells to attack cancer cells by simultaneously binding two cells. The T cell then attacks the target cancer cell. Examples of BiTE antibodies include, but are not limited to, adecatumumab (Micromet MT201), blinatumomab (Micromet MT103), and the like. Without being bound by theory, one of the mechanisms by which T cells induce apoptosis of the target cancer cell is exocytosis of cytolytic granular components, which include perforin and B-granzyme. In this context, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could potentiate T cell-induced cytotoxic effects when directed against cancer cells (Sutton et al. (1997) J. Immunol. 158: 5783-5790).

[0177] SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. Modifications do not abolish cellular activity, but rather confer increased stability and / or increased cellular activity. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3 containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl carbonucleotides, combinations thereof, and the like. SiRNAs can have varying lengths (e.g., 10-200 bp) and structures (e.g., hairpins, single / double-stranded, bulges, notches / gaps, mismatches) and are processed in cells, causing active gene silencing. Double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetrical ends (overhangs). A overhang of 1-2 nucleotides may be present on the sense and / or strand

Antisense as well as present at the 5 'and / or 3' ends of the given strand. For example, siRNAs directed at Mcl-1 have been shown to increase ABT-263 activity (Tse et al. (2008) Cancer Res. 68: 3421-3428 and references therein).

[0178] Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are designed to have three or more antigen binding sites, and are generally not naturally occurring antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Double variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two DVD heavy polypeptide chains and two DVD light polypeptide chains are referred to as DVD immunoglobulins. Each of the DVD immunoglobulin halves comprises a DVD heavy polypeptide chain, a DVD light polypeptide chain, and two antigen binding sites. Each binding site includes a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per one antigen binding site.

[0179] PARP inhibitors include, but are not limited to, ABT-888, olaparib, KU-59436, AZD-2281, AG014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

[0180] Additionally or alternatively, the composition of the present invention may be administered in combination therapy with one or more anti-cancer agents selected from ABT-100, N-acetylokolchinolo-O-phosphate, acitretin, AE-941, protopanoxadiol aglykon, arglabiny, arsenic trioxide, HPV vaccine adsorbed on AS04 adjuvant, L-asparaginase atamestanu, atrasentanu, AVE-8062, bosentan, canfosfamidu, Canvaxin ™, catumaxomab, CeaVac ™, celmoleucyny, combrestatin A4P, contusugene ladenovec, Cotara ™, cyproterone deoksykoformycyny, dexrazoxane, N, N-diethyl-2- (4- (phenylmethyl) phenoxy) ethanamine. 5,6-dimethylxanthenone-4-acetic acid, docosahexaenoic acid / paclitaxel, dyskodermolidu, efaproksiralu, enzastauryny, epothilone B, etynylouracylu, eksysulindu, falimarewu, Gastrimmune ™, GMK vaccines, GVAX ™, halofuginone, histamine, hydroksykarbamidu, ibandronic acid ibritumomab tiuxetan, IL-13-PE38, inalimarewu, interleukins 4, KSB-311, lanreotide, lenalidomide, lonafarnibu, lovastatin, 5,10-methylenetetrahydrofolate. mifamurtide, miltefozyny, moteksafiny, oblimersenu, OncoVAX ™, Osidem ™, albumin stabilized paclitaxel nanoparticles, paclitaxel polyglumex, pamidronate, panitumumab, peginterferon alfa, pegaspargazy, fenoksodiolu, poly (I) poly (C12U) procarbazine ranpirnazy, rebimastatu, recombinant tetravalent HPV vaccine, Squalamine, staurosporine, STn-KLH vaccines, T4 endonuclease V, tazarotene, 6,6 ', 7,12-tetramethoxy-2,2'-dimethyl-1β-berbamanu. thalidomide, TNFerade ™, ¹³¹I-tosytumomab, trabectedin, triazone, tumor necrosis factor, Ukrain ™, vaccinia vaccine MUC1, L-valine-L-boroproline, Vitaxin ™, witespene, zoledronic acid and zorubicin.

[0181] A composition comprising (or prepared using API) one or more crystalline forms of Compound 1 (including crystalline salts) may be administered in a therapeutically effective amount to a subject in need thereof for the treatment of a disease in which one or more antiapoptotic is overexpressed Bcl-2 protein, anti-apoptotic Bcl-XL protein and anti-apoptotic Bcl-w protein.

[0182] A composition comprising (or prepared using API) one or more crystalline forms of Compound 1 (including crystal salts) can be administered in a therapeutically effective amount to a subject in need thereof for the treatment of a disease of abnormal cell growth and / or dysregulated apoptosis .

[0183] Examples of such diseases include, but not only cancer, mesothelioma, bladder cancer pancreatic cancer skin cancer head or neck cancer skin or eyeball melanoma, ovarian cancer breast cancer uterine cancer fallopian tube cancer endometrial cancer cervical cancer vaginal cancer vulvar cancer bone cancer colon cancer rectal cancer anal cancer stomach cancer cancer of the gastrointestinal tract (stomach, large intestine and / or duodenum), chronic lymphocytic leukemia, esophageal cancer small intestine cancer endocrine cancer thyroid cancer parathyroid gland cancer adrenal cancer soft tissue sarcoma, urethral cancer penile cancer testicular cancer hepatocellular carcinoma (hepatic and / or biliary tract), primary or secondary tumor of the central nervous system, primary or secondary brain tumor Hodgkin's disease chronic or acute leukemia, chronic myelogenous leukemia, lymphoma lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphatic neoplasms from T or B cells, melanoma, multiple myeloma, oral cancer non-small cell lung cancer prostate cancer small cell lung cancer kidney and / or ureter cancer renal cell carcinoma renal pelvis cancer central nervous system cancers, primary lymphoma of the central nervous system, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma pituitary adenoma, adrenal cortex cancer gallbladder cancer spleen cancer bile duct cancer fibrosarcoma, neuroblastoma, retinoblastoma or combinations thereof.

[0184] A composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including crystalline salts) can be administered in a therapeutically effective amount to a subject in need thereof for the treatment of bladder cancer, brain cancer breast cancer bone marrow cancer cervical cancer chronic lymphocytic leukemia, colorectal cancer esophageal cancer hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoma cancers, melanoma, myeloid leukemia myeloma, oral cancer ovarian cancer non-small cell lung cancer prostate cancer small cell lung cancer or spleen cancer. [0185] The composition may be administered in combination therapy with one or more additional therapeutic agents.

[0186] For example, method of treating mesothelioma, bladder cancer pancreatic cancer skin cancer head or neck cancer skin or eyeball melanoma, ovarian cancer breast cancer uterine cancer fallopian tube cancer endometrial cancer cervical cancer vaginal cancer vulvar cancer bone cancer colon cancer rectal cancer anal cancer stomach cancer cancer of the gastrointestinal tract (stomach, large intestine and / or duodenum), chronic lymphocytic leukemia, esophageal cancer small intestine cancer endocrine cancer thyroid cancer parathyroid gland cancer adrenal cancer soft tissue sarcoma, urethral cancer penile cancer testicular cancer hepatocellular carcinoma (hepatic and / or biliary tract), primary or secondary tumor of the central nervous system, primary or secondary brain tumor Hodgkin's disease chronic or acute leukemia, chronic myelogenous leukemia, lymphoma lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphatic neoplasms from T or B cells, melanoma, multiple myeloma, oral cancer non-small cell lung cancer prostate cancer small cell lung cancer kidney cancer and / or

EP 2643322 B1 ureter, renal cell carcinoma renal pelvis cancer central nervous system cancers, primary lymphoma of the central nervous system, non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma pituitary adenoma, adrenal cortex cancer gallbladder cancer spleen cancer bile duct cancer fibrosarcoma, neuroblastoma, retinoblastoma or a combination of them, the subject comprising administering to the subject a therapeutically effective amount of (a) a composition comprising (or obtained using as API) the crystalline free base of Compound 1 and (b) one or more of etoposide, vincristine, CHOP rituximab, rapamycin, R-CHOP. RCVP, DA-EPOCH-R or bortezomib.

[0187] A composition comprising (or prepared using API) the crystalline free base of Compound 1 can be administered in a therapeutically effective amount to a subject in need thereof in combination therapy with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DAEPOCH-R or bortezomib in a therapeutically effective amount to treat lymphatic neoplasms such as B-cell lymphoma or non-Hodgkin's lymphoma.

[0188] The composition of the invention may be administered in a therapeutically effective amount to a subject in need thereof for the treatment of an immune or autoimmune disorder. Such disorders include acquired immune deficiency syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia inflammatory diseases, thrombocytopenia, acute or chronic immune disease associated with organ transplantation, Addison's disease allergic diseases alopecia, alopecia areata, atherosclerotic disease / atherosclerosis, atherosclerosis arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis Lyme disease, psoriatic arthritis and reactive arthritis), autoimmune pemphigus abetalipoprotemię, diseases associated with acquired immunodeficiency, acute immune disease associated with organ transplantation, Acrocyanosis acquired acute and chronic parasitic or infectious processes, acute pancreatitis acute renal failure acute rheumatic fever acute transverse myelitis, adenocarcinomas, extra-sinus cramps, respiratory distress syndrome in adults (acute), AIDS-related dementia, alcoholic cirrhosis, Liver damage caused by alcohol alcohol-induced hepatitis allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis allergy and asthma allograft rejection, alpha-1-antitrypsin deficiency, Alzheimer's disease amyotrophic lateral sclerosis, anemia, angina pectoris, ankylosing spondylitis associated with lung disease degeneration of anterior horn cells cytotoxicity with antibodies, antiphospholipid syndrome, hypersensitivity reactions against receptors, aortic and peripheral aneurysms, aortic rupture hypertension, atherosclerosis arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy atrial fibrillation (persistent or paroxysmal) atrial flutter atrioventricular block, atrophic autoimmune thyroid hypoplasia, autoimmune hemolytic anemia, autoimmune hepatitis autoimmune hepatitis 1 (classic autoimmune or lupus hepatitis), hypoglycemia involving an autoimmune reaction, autoimmune neutrophil deficiency, autoimmune thrombocytopenia, autoimmune thyroid disease B-cell lymphoma, bone transplant rejection bone marrow transplant rejection (BMT) obliterative inflammation

EP 2643322 B1 bronchioles, atrioventricular bundle block (Hisa), Burns, cachexia, arrhythmia arrhythmias heart tumors cardiomyopathy, inflammatory response to cardiopulmonary bypass, rejection of cartilage transplant, degeneration of the cerebral cortex brain disorders chaotic or multifocal atrial tachycardia, chemotherapy related disorders, chlamydia, cholestasis, chronic alcoholism, chronic active hepatitis, chronic fatigue syndrome, chronic immune disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucosal and skin candidiasis, chronic obstructive pulmonary disease (COPD), chronic salicylate poisoning, colorectal primary immunodeficiency (primary blood gamma globulin deficiency), conjunctivitis, connective tissue disease associated with interstitial lung disease, contact dermatitis, haemolytic anemia positive Coombs, pulmonary heart Creutzfeldt-Jakob disease, autoimmune cryptogenic hepatitis, fibrotic cryptogenic folliculitis, sepsis with negative culture results, cystic fibrosis, disorders related to cytokine therapy, Crohn's disease boxing dementia, demyelinating diseases, Dengue hemorrhagic fever skin infection, scleroderma, dermatological conditions, dermatomyositis / polymyositis associated with lung disease, diabetes, diabetic atherosclerosis, diabetes, dementia with Lewy bodies, dilated cardiomyopathy, dilatation-dilated cardiomyopathy, thyroid lupus erythematosus, disorders of the basal ganglia, disseminated intravascular coagulation, middle-age Down syndrome, drug-induced interstitial lung disease, drug-induced hepatitis, drug-induced movement disorders caused by drugs, which block dopamine receptors in the CNS, drug sensitivity eczema, encephalomyelitis endocarditis, endocrinopathies, enteropathic synovitis, epiglottitis Epstein-Barr virus infection painful erythema of the extremities, extrapyramidal and cerebellar disorders, familial hematophagocytic lymphohistiocytosis, fetal thymus rejection, Friedreich's ataxia, functional disorders of peripheral arteries, female type infertility, fibrosis, pulmonary fibrosis fungal septicemia, gas gangrene, stomach ulcer, giant cell temporal inflammation, glomerulonephritis, glomerulonephritis, Goodpasture syndrome, gouty autoimmune hypoplasia of the parathyroid glands (Hashimoto's disease), gouty arthritis, rejection of any organ or tissue transplant, graft versus host disease, negative septicemia, I play positive sepsis granulomas caused by intracellular microorganisms, Group B streptococcal infection (GBS), Graves disease pulmonary disease associated with hemosiderosis, hairy cell leukemia, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto's thyroiditis hay fever, rejection of a heart transplant hemochromatosis, hematologic malignancies (leukemia and lymphoma), hemolytic anemia haemorrhagic syndrome / thrombolytic thrombotic purpura, haemorrhage, Henoch-Schonlein disease, hepatitis A, hepatitis B, hepatitis C HIV infection / HIV related neuropathy Hodgkin's disease hypoparathyroidism Huntington's chorea, hyperkinetic movement disorders, hypersensitivity reactions pneumonia associated with hypersensitivity, hyperthyroidism, hypokinetic movement disorders, assessment of the hypothalamic-pituitary-adrenal axis idiopathic Addison's disease, idiopathic leukopenia idiopathic pulmonary fibrosis, idiopathic thrombocytopenia idiosyncratic liver disease childhood spinal muscular atrophy, infectious diseases, aortitis inflammatory bowel disease diabetes

Insulin-dependent EP 2643322 B1, interstitial pneumonia, iritis and vitreous humor / uveitis / optic nerve, ischemia-reperfusion injury, ischemic stroke Juvenile Pernicious Anemia juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma, Kawasaki disease kidney transplant rejection Legionella infection leishmaniasis, leprosy, lesions of the cortico-spinal system, linear IgA disease, hyperlipidemia, liver transplant rejection Lyme disease, lymphoedema lymphocytic infiltrating lung disease, malaria, male idiopathic or other unspecified infertility, malignant histiocytosis, malignant melanoma, meningitis, meningococcal infection inflammation of the small vessels of the kidney, migraine headaches multi-system mitochondrial disorder, mixed connective tissue disease, pneumonia associated with mixed connective tissue disease, monoclonal gammopathy, multiple myeloma, multi-system degenerations (Mencel Dejerine-Thomas Shi-Drager and MachadoJoseph), chronic fatigue syndrome / Royal Free disease, myasthenia gravis, inflammation of the small kidney vessels non-tuberculosis infection (Lady Windermere syndrome), Mycobacterium tuberculosis infection myelodysplastic syndrome, myocardial infarction ischemic heart disorder, nasopharyngeal cancer chronic lung disease in newborns, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic and muscular atrophy, Febrile neutropenia non-alcohol fatty liver, closure of the abdominal aorta and its branches, occlusive arterial disorders organ transplant rejection, orchitis / epididymitis orchitis / vasectomy reversing procedures, abnormal organ enlargement ruffian guy, osteoporosis, ovarian failure rejection of a pancreas transplant parasitic diseases, rejection of parathyroid transplant Parkinson's disease Pelvic inflammatory disease pemphigus vulgaris pemphigus pemphigoid, perennial rhinitis, pericardial disease peripheral atherosclerosis, peripheral vascular disorders peritonitis, pernicious anemia glaucoma uveitis pneumonia caused by Pneumocystis carinii, pneumonia, POEMS syndrome (syndrome involving polyneuropathy, organomegaly, endocrinopathies, monoclonal gammopathy and skin lesions), post-perfusion syndrome, assembly after connecting the pump, post-cardiotomy syndrome after a heart attack, interstitial pneumonia after infection, premature ovarian failure primary biliary cirrhosis, primary sclerosing hepatitis, primary myxedema, primary pulmonary hypertension primary sclerosing cholangitis, primary vasculitis progressive spinal palsy, psoriasis, type 1 psoriasis, type 2 psoriasis, psoriatic arthritis secondary pulmonary hypertension after connective tissue disease, pulmonary symptom of nodular arteritis, post-inflammatory interstitial lung disease, radiation fibrosis, radiotherapy, Raynaud's syndrome and disease Raynaud's disease Refsum's disease regular tachycardia with narrow QRS, Reiter's disease kidney disease not otherwise specified Renovascular hypertension reperfusion injury, limiting cardiomyopathy, rheumatoid arthritis associated with interstitial lung disease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome, scleroderma, senile chorea, senile dementia with Lewy bodies, sepsis syndrome, septic shock seronegative arthropathies, shock, sickle cell anemia Sjogren's disease associated with lung disease Sjorgren's syndrome, skin allograft rejection, skin lesions syndrome, rejection of a small intestine transplant, production of antibodies against your own semen, multiple sclerosis (all subtypes), spinal ataxia degeneration of the spinal cord and cerebellum, arthritis involving the joints of the spine, arthritis involving the joints of the spine, sporadic shortages

Glandular gland type I, sporadic type II glandular deficiencies, Still's disease streptococcal myocarditis, stroke, pathological changes in the cerebellum, subacute sclerosing encephalitis, sympathetic choroiditis, fainting, cardiovascular syphilis, systemic anaphylaxis systemic inflammatory response syndrome, systemic rheumatoid arthritis from adolescence, systemic lupus erythematosus, lung disease associated with systemic lupus erythematosus, systemic sclerosis interstitial lung disease associated with systemic sclerosis, diseases involving T lymphocytes or FAB ALL, Takayasu disease / arteritis, telangiectasia, Th2 and Th1 type diseases, thromboangiitis obliterans, thrombocytopenia, thyroiditis toxicity, toxic shock syndrome, transplants, trauma / hemorrhage, autoimmune hepatitis 2 (hepatitis with anti-LKM antibodies), type B insulin resistance with dark keratosis, type III hypersensitivity reactions, Type IV hypersensitivity ulcerative colitis with arthritis, ulcerative colitis, unstable angina, uremia, diuretic septicemia, urticaria, uveitis, heart valve disease varicose veins, vasculitis interstitial lung disease with vasculitis, vein diseases vein thrombosis ventricular fibrosis, albinism acquired in acute liver disease, viral and fungal infections, viral encephalitis / aseptic meningitis, viral hemocyte syndrome, Wegener's granulomatosis, Wernicke-Korsakow syndrome, Wilson's disease xenograft rejection of any organ or tissue, arthropathy associated with Yersinia and Salmonella infection, and the like.

[0189] The pharmaceutical composition described herein can be used in a method of maintaining a human patient in the bloodstream, having a therapeutically effective plasma concentration of Compound 1 and / or one or more of its metabolites suffering from cancer, comprising administering to the subject the pharmaceutical composition described herein, at a dose equivalent to about 50 to about 500 mg of Compound 1 per day, with an average interval between doses of from about 3 hours to about 7 days.

[0190] What constitutes a therapeutically effective plasma concentration depends, inter alia, on the particular tumor present in the patient, the stage, severity and aggressiveness of the tumor and the expected result (e.g., stabilization, slowing of tumor growth, tumor contraction, reduction of the risk of metastasis, e.t.c.). It is very preferred, although the plasma concentration is sufficient to provide benefits in the context of cancer treatment, so that it is not sufficient to cause an unacceptable or unacceptable side effect.

[0191] In the treatment of cancer in general and lymphatic system cancer, such as non-Hodgkin's lymphoma, the plasma concentration of Compound 1 should in most cases be maintained in the range of about 0.5 to about 10 μg / ml. Thus, during Compound 1 therapy, the steady-state Cmax should generally not exceed about 10 μg / ml, and the steady-state Cmin should generally not fall below about 0.5 μg / ml. It has further been found that it is desirable to select, within the ranges given above, a daily dose and average effective dose to provide a Cmax / Cmin ratio of not more than about 5, for example not more than about 3, in a steady state. It should be understood that longer dose intervals will tend to increase the Cmax / Cmin ratio. For example, at steady state for Compound 1, the method of the invention may have a Cmax of from about 3 to about 8 μg / mL, and a Cmin of from about 1 to about 5 μg / mL.

[0192] A daily dose effective to maintain a therapeutically effective plasma level of Compound 1 is, according to the present embodiment, from about 50 to about 1000 mg. In most cases, a suitable daily dose is from about 200 to about 400 mg. For example, a daily dose may be, for example, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 750 or about 1000 mg.

[0193] The average interval between doses effective to maintain a therapeutically effective plasma level of Compound 1 is, according to the present embodiment, from about 3 hours to about 7 days. In most cases, a suitable average dose interval is from about 8 hours to about 3 days, or from about 12 hours to about 2 days. A once-daily (qd) schedule is often appropriate.

[0194] As in other embodiments, administration according to the present embodiment can be carried out with or without food, i.e. in an unhealthy or fasted state. It is generally preferred to administer the present compositions to a patient who has not fasted.

[0195] When incorporating elements of the present disclosure or its preferred embodiments, "certain", "said" and "said" are intended to mean one or more elements. The terms "comprising", "including" and "having" are intended to mean "inclusive", i.e., additional elements other than the listed elements may be present.

EP 2643322 B1