HUE034804T2

Salts and crystalline forms of an apoptosis-inducing agent

Abstract

This record has no abstract on file.

HUE034804T2, drawing sheet 1 — Sheet 1 of 11

Term

No projected expiry on record.

35 claims: 5 independent, 30 dependent

1
Claims 1. A compound having the systematic name 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-(1 H-pyrrolo[2,3-b]pyridin-5yloxyjbenzamide (Compound 1) or a salt thereof in a crystalline form. ΕΡ 2 643 322 Β1
15
9, 16.2, 17.6, 18.3, 18.7, 19.7, 19.9, 20.1, 20.4, 20.7, 20.9, 22.9, and 26.2 degrees 2θ (Pattern K), each peak being ± 0.2 degrees 2θ, when measured at about 25°C with Cu K a radiation at 1.54178 Á. 15. The salt of Claim 1, wherein the crystalline form is Compound 1 hydrochloride, characterized by a triclinic lattice type and P1 space group having unit cell lengths for the three axes of about (a) 10.804 Á, (b) 12.372 Á, (c) 19.333 Á and the three unit cell angles of about (a) 76.540°, (β) 87.159°, and (γ) 70.074°.
18
4, 19.1, 19.5, 21.0, 22.4, 23.3, 23.9, 25.1, and 26.8 degrees 2θ (pattern M), each peak being ± 0.2 degrees 2θ, when measured at about 25°C with Cu K a radiation at 1.54178 Á. 18. A pharmaceutical composition comprising the compound or salt of any one of Claims 1 to 17 and one or more pharmaceutically acceptable excipients.
19
A proeess for preparing a pharmaceutical solution of Compound 1 or a salt thereof comprising dissolving the compound or salt of any one of Claims 1 to 17 in a pharmaceutically acceptable solvent or mixture of solvents.
20
The compound or salt of any one of Claims 1 to 17, or a pharmaceutical composition comprising the compound or salt of any one of Claims 1 to 17 and one or more pharmaceutically acceptable excipients, for use in a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein wherein the disease is a neoplastic, immuné, or autoimmune disease.
27
A dispersion of the compound or salt of any one of Claims 1 to 17 for use in a method for treating a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein, wherein the disease is a neoplastic, immuné, or autoimmune disease.

Independent claims6

538 paragraphs in 1 section, as filed

(56) References cited:

WO-A2-2010/065824 WO-A2-2010/138588 US-A1- 2010 184 750 US-A1- 2010 305 122 • CAIRAM R: CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS, TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198,1 January 1998 (1998-01-01), pages 163-208, XP001156954, ISSN: 0340-1022, DÓI: 10.1007/3-540-69178-2_5 ISBN:

978-3-540-36760-4 • BERGE S M ETAL: PHARMACEUTICALS SALTS, JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 66, no. 1, 1 January 1977 (1977-01-01), pages 1-19, XP000562636, ISSN: 0022-3549, DÓI:

10.1002/JPS.2600660104

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Note: Within nine months ofthe publication ofthe mention ofthe grant ofthe European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall nőt be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

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Description [0001] Cross-reference is alsó made, without claim to benefit of priority or admission as to prior art status, to the following pending U.S. application containing subject matter related to the present application: Serial No. 12/787,682 (published as U.S. 2010/0305122) titled Apoptosis-inducing Agents for the Treatment of Cancer and Immuné and Autoimmune Diseases.

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

BACKGROUND OF THE INVENTION [0003] Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders ofthe immuné system.

[0004] Evasion of apoptosis is a hallmark of cancer (Hanahan &Weinberg (2000) Cell 100:57-70). Cancer cells must overcome a continual bombardment by cellular stresses such as DNA damage, oncogene activation, aberrant cell cycle progression and harsh microenvironments that would cause normál cells to undergo apoptosis. One of the primary means by which cancer cells évadé apoptosis is by up-regulation of anti-apoptotic proteins of the Bcl-2 family.

[0005] A particular type of neoplastic disease for which improved therapies are needed is non-Hodgkin’s lymphoma (NHL). NHL is the sixth most prevalent type of new cancer in the U.S. and occurs primarily in patients 60-70 years of age. NHL is nőt a single disease bút a family of related diseases, which are classified on the basis of several characteristics including clinical attributes and histology.

[0006] One method of classification places different histological subtypes intő two major categories based on natural history of the disease, i.e., whether the disease is indolent or aggressive. In generál, indolent subtypes grow slowly and are generally incurable, whereas aggressive subtypes grow rapidly and are potentiaily curable. Follicular lymphomas are the most common indolent subtype, and diffuse large-cell lymphomas constitute the most common aggressive subtype. The oncoprotein Bcl-2 was originally described in non-Hodgkin’s B-cell lymphoma.

[0007] Treatment of follicular lymphoma typically consists of biologically-based 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 (targeting CD20, a phosphoprotein uniformly expressed on the surface of B-cells) or fludarabine is alsó used. Addition of rituximab to chemotherapy regimens can provide improved response rate and increased progressionfree survival.

[0008] Radioimmunotherapy agents, high-dose chemotherapy and stem cell transplants can be used to treat refractory or relapsed NHL. Currently, there is nőt an approved treatment régimén that produces a cure, and current guidelines recommend that patients be treated in the context ofa clinical trial, even in a first-line setting.

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

[0010] Most lymphomas respond initially to any one of these therapies, bút tumors typically recur and eventually become refractory. As the number of regimens patients récéivé increases, the more chemotherapy-resistant the disease becomes. Average response to first-line therapy is approximately 75%, 60% to second-line, 50% to third-line, and about 35-40% to fourth-line therapy. Response rates approaching 20% with a single agent in a multiple relapsed setting are considered positive and warrant further study.

[0011] Other neoplastic diseases for which improved therapies are needed include leukémiás such as chronic lymphocytic leukémia (like NHL, a B-cell lymphoma) and acute lymphocyctic leukémia.

[0012] Chronic lymphoid leukémia (CLL) is the most common type of leukémia. CLL is primarily a disease of adults, more than 75% of people newly diagnosed being over the age of 50, bút in rare cases it is alsó found in children. Combination chemotherapies are the prevalent treatment, for example fludarabine with cyclophosphamide and/or rituximab, or more complex combinations such as CHOP or R-CHOP.

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

[0014] Current chemotherapeutic agents elicit their antitumor response by inducing apoptosis through a variety of

ΕΡ 2 643 322 Β1 mechanisms. However, many tumors ultimately become resistant to these agents. Bcl-2 and Bcl-XL have been shown to confer chemotherapy resistance in short-term survival assays in vitro and, more recently, in vivő. This suggests that if improved therapies aimed at suppressing the function of Bcl-2 and Bcl-XL can be developed, such chemotherapyresistance could be successfully overcome.

[0015] Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, boné marrow cancer, cervical cancer, CLL, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukémia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukémia, myeloma, órai cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer and the like is described in International Patent Publication Nos. WO 2005/024636 and WO 2005/049593.

[0016] Involvement of Bcl-2 proteins in immuné and autoimmune diseases is described, for example, by Puck & Zhu (2003) Current Allergy and Asthma Reports 3:378-384; Shimazaki et al. (2000) British Journal of Haematology 110(3):584-590; Rengan et al. (2000) Blood 95(4):1283-1292; and Holzelova et al. (2004) New England Journal of Medicine 351(14):1409-1418. Involvement of Bcl-2 proteins in boné marrow transplant rejection is disclosed in United States Patent Application Publication No. US 2008/0182845.

[0017] Compounds that occupy a binding site on Bcl-2 proteins are known. To be therapeutically useful by órai administration, such compounds desirably have high binding affinity, exhibiting for example Kj <1 nM, preferably <0.1 nM, more preferably <0.01 nM, to proteins ofthe Bcl-2 family, specifically Bcl-2, Bcl-XL and Bcl-w. It is further desirable that they be formulated in a manner that provides high systemic exposure after órai administration. A typical measure of systemic exposure after órai administration of a compound is the area under the curve (AUC) resulting from graphing plasma concentration ofthe compound versus time from órai administration.

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

[0019] Apoptosis-inducing drugs that target Bcl-2 family proteins such as Bcl-2 and Bcl-XL are best administered according to a régimén that provides continual, forexample daily, replenishment ofthe plasma concentration, to maintain the concentration in a therapeutically effective rangé. This can be achieved by daily parenteral, e.g., intravenous (i.v.) or intraperitoneal (i.p.) administration. However, daily parenteral administration is often nőt practical in a clinical setting, particularly for outpatients. To enhance clinical utility of an apoptosis-inducing agent, forexample as a chemotherapeutic in cancer patients, a dosage form with acceptable órai bioavailability would be highly desirable. Such a dosage form, and a régimén for órai administration thereof, would represent an important advance in treatment of many types of cancer, including NHL, CLL and ALL, and would more readily enable combination therapies with other chemotherapeutics. [0020] Different crystalline forms ofan apoptosis-inducing agent can provide different properties with respect to stability, solubility, dissolution rate, hardness, compressibility and melting point, among other physical and mechanical properties. Because ease of manufacture, formulation, storage and transport of an apoptosis-inducing agent is dependent on at least somé of these properties, there is a need in the Chemical and therapeutic árts for identification of new salts and crystalline forms of apoptosis-inducing agents and ways for reproducibly generating such salts and crystalline forms.

SUMMARY OF THE INVENTION [0021] The present disclosure relates to salts and crystalline forms of an apoptosis-inducing agent, referred to herein as Compound 1, which has the systematic name 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-5yloxy)benzamide, and which can be depicted by the formula:

[0022] Following synthesis of Compound 1, as described herein, the product may be recovered as a powder in an amorphous state. An amorphous form of Compound 1 may nőt be well suited for use as an active pharmaceutical

EP 2 643 322 Β1 ingredient (API) for various types of downstream formulations. More particularly, an amorphous form of Compound 1 can be difficult and therefore expensive to purify and can present process control problems.

[0023] The present disclosure provides a series of növel salts and crystalline forms of Compound 1 suitable for use as API in a wide variety of formulation types, including those where the API is present in particulate form together with excipients, for example in orally deliverable tablets or capsules. The salts and crystalline forms of Compound 1 may alsó be useful where the crystalline form is converted to a non-crystalline form (e.g., solution or amorphous form) when formulated. Alsó included are ways to prepare the salts and crystalline forms of Compound 1. Salt and crystalline forms of Compound 1 can be used to modulate and/or improve the physicochemical properties ofthe API, including solid state properties (e.g., crystallinity, hygroscopicity, melting point, hydration potential, polymorphism, etc.), pharmaceutical properties (e.g., solubility/dissolution rate, stability, compatibility, etc.), and crystallization characteristics (e.g., purity, yield, morphology, etc.), as non-limiting examples.

[0024] In somé embodiments, the salt or crystalline form of Compound 1 includes those of Compound 1 free base anhydrate having PXRD pattern A, Compound 1 free base anhydrate having PXRD pattern B, Compound 1 free base hydrate having PXRD pattern C, Compound 1 free base hydrate having PXRD pattern D, Compound 1 free base dichloromethane solvate having pattern E, Compound 1 free base ethyl acetate solvate having PXRD pattern F, Compound 1 free base ethyl acetate solvate having PXRD pattern G, Compound 1 free base acetonitrile solvate having PXRD pattern H, Compound 1 free base acetonitrile solvate having PXRD pattern I, Compound 1 free base acetone solvate having PXRD pattern J, Compound 1 hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydrate having PXRD pattern L, Compound 1 sulfate having PXRD pattern M, each having the respective powderX-ray diffraction patterns as described herein. Alsó described is Compound 1 free base tetrahydrofuran (THF) solvate having PXRD pattern N as described herein.

[0025] In somé embodiments, the crystalline forms of Compound 1 free base dichloromethane solvate, Compound 1 free base acetonitrile solvate, Compound 1 hydrochloride have the respective crystal lattice parameters as described herein. Alsó described is Compound 1 free base tetrahydrofuran solvate having the crystal lattice parameters as described herein.

[0026] In anotherembodiment, Compound 1 hydrochloride is provided.

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

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

[0029] In somé 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 somé embodiments, a process for preparing a pharmaceutical solution composition of Compound 1 is provided, where the process comprises dissolving a salt or crystalline form of Compound 1 as described herein with a pharmaceutically acceptable solvent or mixture of solvents.

[0031] Compound 1 may be used in a method for treating a disease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, where the method comprises administering to a subject having the disease a therapeutically effective amount of (a) a salt or crystalline form of Compound 1 as described herein or (b) a pharmaceutical composition comprising a salt or crystalline form of Compound 1 as described herein and one or more pharmaceutically acceptable excipients.

[0032] Compound 1 may be used in a method for treating a disease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein, where the method comprises preparing a solution or dispersion of a salt or crystalline form of Compound 1 described herein in a pharmaceutically acceptable solvent or mixture of solvents, and administering the resulting solution or dispersion in a therapeutically effective amount to a subject having the disease.

[0033] Additional embodiments of the invention, including particular aspects of those provided above, will be found in, orwill be evident from, the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS [0034]

Fig. 1 is a PXRD scan of Compound 1 anhydrate designated pattern A.

Fig. 2 is a PXRD scan of Compound 1 anhydrate designated pattern B.

Fig. 3 is a PXRD scan of Compound 1 hydrate designated pattern C.

Fig. 4 is a PXRD scan of Compound 1 hydrate designated pattern D.

Fig. 5 is a calculated PXRD pattern of Compound 1 dichloromethane solvate designated pattern E.

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Fig. 6 is a PXRD scan of Compound 1 ethyl acetate solvate designated pattern F.

Fig. 7 is a PXRD scan of Compound 1 ethyl acetate solvate designated pattern G.

Fig. 8 is a calculated PXRD pattern of Compound 1 acetonitrile solvate designated pattern H.

Fig. 9 is a PXRD scan of Compound 1 acetonitrile solvate designated pattern I.

Fig. 10 is a PXRD scan of Compound 1 acetone solvate designated pattern J.

Fig. 11 is a calculated PXRD pattern of Compound 1 hydrochloride designated pattern K.

Fig. 12 is a PXRD scan of Compound 1 hydrochloride hydrate designated pattern L.

Fig. 13 is a PXRD scan of Compound 1 sulfate designated pattern M.

Fig. 14 is a PXRD scan of Compound 1 tetrahydrofuran solvate designated pattern N.

DETAILED DESCRIPTION [0035] The term free base is used fór convenience herein to refer to Compound 1 parent compound as distinct from any salt thereof, while recognizing that the parent compound, strictly speaking, is zwitterionic at neutral conditions and thus does nőt aiways behave as a true base.

[0036] An apoptosis-inducing agent, referred to herein as Compound 1, has the systematic name 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 depicted by the formula:

O [0037] In various embodiments, salts and crystalline forms of Compound 1 are provided. Crystalline forms include solvates, hydrates, anhydrates, and salts of Compound 1.

[0038] In confrast to an amorphous form of Compound 1 free base and an amorphous form of a Compound 1 salt, a crystalline form is characterized by the presence of observable peaks in a powder x-ray diffraction (PXRD) pattern measured on the crystalline form. Fór crystalline forms prepared to yield suitably sízed single-crystals, the crystalline form can be further characterized through an experimental determination of the unit cell parameters, the identification of the crystallographic space group to which a single crystal belongs, or both of these. Once the unit cell parameters are known, the location ofthe diffraction peaks, and in particular the 2θ values ofthe peaks in a PXRD pattern can be calculated, to further characterize the crystalline form. Of course, the PXRD pattern can alsó be measured experimentally fór such crystalline forms. If nőt only the cell parameters bút a three dimensional single crystal structure is known, then nőt only the positions bút alsó the intensity ofthe peaks in the diffraction pattern can be calculated in further characterization ofthe crystalline form.

[0039] The PXRD patterns measured or calculated fór the salts and crystalline forms reported herein represent a fingerprint that can be compared to other experimentally determined patterns to find a match. Identity ofthe respective crystalline forms is established by overlap or match of an experimentally determined PXRD pattern with the PXRD pattern ofthe crystalline forms reported herein. In various embodiments, the salts and crystalline forms are characterized by exhibiting at least one of the PXRD peaks reported here. Thus, in various embodiments, a salt or crystalline form is characterized by a match of two or more peaks, a match of 3 or more peaks, 4 or more peaks, or 5 or more peaks, and so on, from the respective PXRD patterns.

[0040] An embodiment of the synthesis of Compound 1 (free base) and representative intermediate compounds is presented below. The exemplified compounds are named using ACD/ChemSketch Version 5.06 (05 June 2001, Advanced Chemistry Development Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13 May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA). Intermediates are named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, MA).

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Synthesis of Compound 1

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

Compound 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 HCI and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound.

Compound B methyl 4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate [0042] To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL) was added 5,5-dimethyl-2methoxycarbonylcyclohexanone (38.5 g) dropwise at 0°C. After stirring fór 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 fór 24 hours. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated to give the product.

Compound C methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate [0043] Compound B (62.15g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2g) in 2:1 dimethoxyethane /methanol (600 mL) were heated to 70°C fór 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), was added methanol (25 mL) slowly by syringe. The mixture was stirred at room temperature fór 24 hours. The reaction was quenched with 1N HCI with icecooling. The mixture was diluted with water and extracted with ether (3x 100 mL). The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gél with 0-30% ethyl acetate/hexanes.

Compound E tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate [0045] Mesyl Chloride (7.5 mL) was added via syringe to Compound D (29.3 g) and triethylamine (30 mL) in CH2CI2 (500 mL) at 0°C, and the mixture was stirred fór 1 minute. N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was stirred at room temperature fór 24 hours. The suspension was washed with brine, dried, (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gél with 10-20% ethyl acetate/hexanes.

Compound F

1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine [0046] Compound E (200 mg) and triethylsilane (1 mL) were stirred in dichloromethane (15 mL) and trifluoroacetic acid (15 mL) fór 1 hour. The mixture was concentrated, taken up in ethyl acetate, washed twice with NaH2PO4, and brine, and dried (Na2SO4), filtered and concentrated.

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Compound G

5-bromo-1-(triisopropylsilyl)-1 H-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) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and after 10 minutes, TIPS-CI (tnisopropylchlorosilane) (18.2 mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction 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 gél with 10% ethyl acetate/hexanes.

Compound H

1- (triisopropylsilyl)-1H-pyrrolo[2,3-b]pyndin-5-ol [0048] To a mixture of Compound G (24.3 g) in tetrahydrofuran (500 mL) at -78°C was added 2.5M BuLi (30.3 mL). After 2 minutes, trimethylborate (11.5 mL) was added, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was poured intő water, extracted thee times with ethyl acetate, and the combined extracts were washed with brine and concentrated. The crude product was taken up in tetrahydrofuran (200 mL) at 0°C, and 1M NaOH (69 mL) was added, followed by 30% H2O2 (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 HCI 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 gél with 5-25% ethyl acetate/hexanes.

Compound I methyl 2-(1 H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate [0049] A mixture of Compound H (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115°C was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gél with 2-50% ethyl acetate/hexanes.

Compound J methyl 2-(1 H-pyrrolo[2,3-b]pyndin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1yljbenzoate [0050] A mixture of Compound I (1.55 g), Compound F (2.42 g), and HK2PO4 (1.42 g) in dimethylsulfoxide (20 mL) at 135°C was stirred for 24 hours. The reaction was cooled, diluted with ether (400 mL), and washed with 3x 1M NaOH, and brine, and concentrated. The crude product was chromatographed on silica gél with 10-50% ethyl acetate/hexanes.

Compound K

2- (1 H-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) at 50°C was stirred for 24 hours. The reaction was cooled, added to NaH2PO4 solution, and extracted thee times with ethyl acetate. The combined extracts were washed with brine, and concentrated to give the pure product.

Compound L (Compound 1 free base)

4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1 H-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) were stirred in CH2CI2 (40 mL) for 24 hours. The reaction was cooled and chromatographed on silica gél 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 (300MHz, dimethylsulfoxide-d6) 11.65 (brs, 1H), 8.55 (br s,

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Η), 8.04 (d, 1 Η), 7.89 (dd, 1 Η), 7.51 (m, 3Η), 7.33 (d, 2Η), 7.08 (m, 1 Η), 7.04 (d, 2Η), 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] Preparation of Compound 1 free base is alsó described in Example 5 of U.S. Application Serial No. 12/787,682 (published as U.S. 2010/0305122) titled Apoptosis-inducing agents forthe treatment of cancer and immuné and autoimmune diseases. A solid can be prepared from the chromatography eluate; for example, by using freeze-drying, precipitation, or rotary evaporation techniques. The product ofthis process can be a solid that is amorphous in character. [0054] Salts and crystal forms of Compound 1 have been prepared as described in the following examples.

Compound 1 Free Base Anhydrate (PXRD Pattern A) [0055] The following two routes can prepare this crystalline form, where drying at ambient conditions involves leaving the solid rnaterial at room temperature and exposed to air overnight. For example, solvent can be allowed to evaporate. [0056] Example 1: Compound 1 free base dichloromethane solvate having pattern E (see below) was dried at ambient conditions.

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

[0058] Powder X-ray diffraction pattern and peak listing are shown in Figure 1 and Table 1, respectively.

Table 1: Peak Listing for Compound 1 Free Base Anhydrate Pattern A

Compound 1 Free Base Anhydrate (PXRD Pattern B) [0059] Example 3: Compound 1 free base acetonitrile solvate pattern H was dried at ambient conditions. [0060] Powder X-ray diffraction pattern and peak listing are shown in Figure 2 and Table 2, respectively.

Table 2: Peak Listing for Compound 1 Free Base Anhydrate Pattern B

ΕΡ 2 643 322 Β1 (continued)

Compound 1 Free Base Hydrate (PXRD Pattern C) [0061] The free base hydrate, characterized by Pattern C, can be prepared in three ways.

[0062] Example 4: Compound 1 free base methanol solvate was dried at ambient conditions.

[0063] Example 5: Compound 1 free base ethanol solvate was dried at ambient conditions.

[0064] Example 6: Compound 1 free base 2-propanol solvate was dried at ambient conditions.

[0065] Powder X-ray diffraction pattern and peak listing are shown in Figure 3 and Table 3, respectively.

Table 3: Peak Listing for Compound 1 Free Base Hydrate Pattern C

<td> Peak Position (° 2θ)</td>

Compound 1 Free Base Hydrate (PXRD Pattern D) [0066] Example 7: Compound 1 free base ethyl acetate solvate pattern G was dried at ambient conditions. [0067] Powder X-ray diffraction pattern and peak listing are shown in Figure 4 and Table 4, respectively.

EP 2 643 322 Β1

Table4: Peak Listing for Compound 1 Free Base Hydrate Pattern D

<td> Peak Position (° 2θ)</td>

Compound 1 Free Base Dichloromethane Solvate (PXRD Pattern E) [0068] Example 8: Compound 1 free base solid was suspended in dichloromethane at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0069] PowderX-ray diffraction pattern and peak listing are shown in Figure 5 and Table 5A, respectively. Crystallographic information is listed in Table 5B.

Table 5A: Calculated PXRD Peak Listing for Compound 1 Free Base Dichloromethane Solvate Pattern E

EP 2 643 322 Β1 (continued)

Table 5B: Structural Information for Compound 1 Free Base Dichloromethane Solvate Single Crystal

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

<td> Lattice Type</td><td> Monoclinic</td>

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

<td> Volume (Á3)</td><td> 5134.85</td>

Compound 1 Free Base Ethyl Acetate Solvate (PXRD Pattern F) [0070] Example 9: Compound 1 free base solid was suspended in ethyl acetate at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0071] PowderX-ray diffraction pattern and peak listing are shown in Figure 6 and Table 6, respectively.

Table 6: PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate Solvate Pattern F

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1 (continued)

Compound 1 Free Base Ethyl Acetate Solvate (PXRD Pattern G) [0072] Example 10: Compound 1 free base solid was suspended in ethyl acetate saturated with water at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0073] Powder X-ray diffraction pattern and peak listing shown in Figure 7 and Table 7, respectively.

Table 7: PXRD Peak Listing for Compound 1 Free Base Ethyl Acetate Solvate Pattern G

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1 (continued)

Compound 1 Free Base Acetonitrile Solvate (PXRD Pattern H) [0074] Example 11: Compound 1 free base solid was suspended in acetonitrile at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0075] Powder X-ray diffraction pattern and peak listing are shown in Figure 8 and Table 8A, respectively. Crystallographic information is listed in Table 8B.

Table 8A: Calculated PXRD Peak Listing for Compound 1 Free Base Acetonitrile Solvate Pattern H

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1

Table 8Β: Structural informationforCompound 1 Free Base Acetonitrile Solvate H Single Crystal

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

<td> Lattice Type</td><td> Triclinic</td>

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

<td> Volume (Á3)</td><td> 2354.06</td>

Compound 1 Free Base Acetonitrile Solvate (PXRD Pattern I) [0076] Example 12: To a solution of 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(16g, 28mmol) and 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide(8.83g, 28mmol) in DCM(300mL) was added EDCI(10.74g, 56mmol) and DMAP(6.85g, 56mmol). The mixture was stirred at r.t. overnight. LC/MS showed the expected product as a single peak. The mixture was diluted with DCM(500ml) and washed with aq. NaHC03, water, brine and dried over Na2S04. The residue after evaporation of solvent was dissolved in DCM and loaded on a column and eluted with 30% ethyl acetate in DCM followed by 1 to 2% MeOH in DCM to give 24.5g pure product(95% purity) which was dissolved in DMSO and MeOH(1:1) and TFA(2eq) and loaded on a 330g C18 column (6g a time)to give 13.5g pure(>99.7% purity) product(55%yield). The API was extracted using dichloromethane and then, the solvent was removed using rotary evaporator. The resulting solid was suspended in acetonitrile at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0077] Powder X-ray diffraction pattern and peak listing are shown in Figure 9 and Table 9, respectively.

Table 9: PXRD Peak Listing forCompound 1 Free Base Acetonitrile Solvate Pattern I

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1 (continued)

Compound 1 Free Base Acetone Solvate (PXRD Pattern J) [0078] Example 13: Compound 1 free base solid was suspended in acetone at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0079] Powder X-ray diffraction pattern and peak listing are shown in Figure 10 and Table 10, respectively.

Table 10: PXRD Peak Listing for Compound 1 Free Base Acetone Solvate Pattern J

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1 (continued)

Compound 1 Hydrochloride (PXRD Pattern K) [0080] Example 14: Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of acetonitrile. Hydrochloric acid (1M, 25 μί) was added to the suspension while stirring (molar ratio of Compound 1:acid = 1:1.4). Compound 1 quickly reacted with hydrochloric acid and formed a clear solution. Yellowish solids, which later crystallized from the solution, were confirmed to be Compound 1 hydrochloride in a 1:1 stoichiometric ratio of free base to HCI. [0081] Powder X-ray diffraction pattern and peak listing can be seen in Figure 11, and Table 11A, respectively. Crystallographic inforrnation is listed in Table 11B.

Table 11A: Calculated PXRD Peak Listing of Compound 1 Hydrochloride Pattern K

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1

Table 11 Β: Structural information fór Compound 1 Hydrochloride

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

<td> Lattice Type</td><td> Triclinic</td>

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

<td> Volume (Á3)</td><td> 2361.5</td>

Compound 1 Hydrochloride Hydrate (PXRD Pattern L) [0082] Example 15: Compound 1 hydrochloride solid (having pattern K) was exposed to the air under ambient conditions, and was confirmed to be Compound 1 hydrochloride hydrate.

[0083] Powder X-ray diffraction pattern and peak listing can be seen in Figure 12, and Table 12, respectively.

Table 12: PXRD Peak ListingforCompound 1 Hydrochloride Hydrate Pattern L

<td> Peak Position (° 2θ)</td>

ΕΡ 2 643 322 Β1 (continued)

Peak Position (° 2θ) 30.1

Compound 1 Sulfate (PXRD Pattern M) [0084] Example 16: Compound 1 free base solid (16 mg, 0.018 mmol) was suspended in 0.5 mL of 2-propanol at 70°C. Sulfuric acid (1M, 25 μι) was added to the suspension while stirring (molar ratio of Compound 1:acid = 1:1.4). Compound 1 quickly dissolved by reacting with sulfuric acid. Yellowish solids crystallized from the solution immediately after the dissolution occurred. The crystalline solid was confirmed to be Compound 1 sulfate with a stoichiometry of 1:1 using ion chromatography.

[0085] Powder X-ray diffraction pattern and peak listing can be seen in Figure 13, and Table 13, respectively.

Table 13: PXRD Peak Listing for Compound 1 Sulfate Pattern M

<td> Peak Position (° 2θ)</td>

Compound 1 Free Base THF Solvate (PXRD Pattern N) (nőt according to the claims) [0086] Example 17: Compound 1 free base solid was suspended in tetrahydrofuran (THF) at ambient temperatures to reach its solubility. After equilibrating, the solids were isolated at ambient temperature.

[0087] Powder X-ray diffraction pattern and peak listing are shown in Figure 14 and Table 14, respectively.

Table 14: PXRD Peak Listing for Compound 1 Free Base THF Solvate Pattern N Peak Position (° 2θ)

4.0

ΕΡ 2 643 322 Β1 (continued)

<td> Peak Position (° 29)</td>

[0088] PXRD data were collected using a G3000 diffractometer (Inéi Corp., Artenay, Francé) equipped with a curved position-sensitive detector and parallel-beam optics. The diffractometer was operated with a copper anode tűbe (1.5 kW fine focus) at 40 kV and 30 mA. An incident-beam germanium monochromator provided monochromatic radiation Cu-Ka radiation, which has a wavelength of 1.54178 Á. The diffractometer was calibrated using the attenuated direct beam at one-degree intervals. Calibration was checked using a Silicon powder line position reference standard (NIST 640c). The instrument was computer-controlled using Symphonix software (Inéi Corp., Artenay, Francé) and the data were analyzed using Jade software (version 6.5, Materials Data, Inc., Livermore, CA). The sample was loaded onto an aluminum sample holder and leveled with a glass síidé. PXRD peak position measurements are typically ± 0.2 degrees two-theta (° 29).

[0089] In somé embodiments, the percent crystallinity of any of the salt or crystalline forms of Compound 1 described herein can vary with respect to the totál amount of Compound 1. In particular, certain embodiments provide for the percent crystallinity of a salt or crystalline form of Compound 1 being 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 somé embodiments, the percent crystallinity can be substantially 100%, where substantially 100% indicates that the entire amount of Compound 1 appears to be crystalline as best can be determined using methods known in the art. Accordingly, pharmaceutical compositions and therapeutically effective amounts of Compound 1 can include amounts that vary in crystallinity. These include instances where Compound 1 is used as API in various formulations and solid forms, including where an amount of Compound 1 in a solid form is subsequently dissolved, partially dissolved, or suspended or dispersed in a liquid.

[0090] As noted, in somé embodiments API compositions are provided that comprise Compound 1, wherein at least a portion of the Compound 1 in the API composition is in one of the salt or crystalline forms. For example, an 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 least 90%, at least 95% or at least 99% ofthe compound ofthe composition in one ofthe salt or crystalline forms. In somé embodiments, essentially 100% ofthe Compound 1 ofan API formulation is in a salt or crystalline form as described herein.

[0091] Any of the crystalline forms of Compound 1, including salts and solvated forms, can be useful as an active pharmaceutical ingredient (API) for preparation of pharmaceutical compositions. However, solvent-free forms are generally preferred for this purpose. A hydrate is considered solvent-free for this purpose. Solvated forms can be, as indicated above, useful as process intermediates in preparation of solvent-free forms. Compound 1 salts and crystalline forms can be used in preparation of pharmaceutical compositions suitable for various routes of administration, including órai, to a subject in need thereof. Thus, in somé embodiments, a pharmaceutical composition is provided, comprising a crystalline form of Compound 1 and one or more pharmaceutically acceptable excipients. Such compositions can be

ΕΡ 2 643 322 Β1 prepared using various known processes of pharmacy.

[0092] In somé embodiments, the salt or crystalline form of Compound 1 includes those of Compound 1 free base anhydrate having PXRD pattern A, Compound 1 free base anhydrate having PXRD pattern B, Compound 1 free base hydrate having PXRD pattern C, Compound 1 free base hydrate having PXRD pattern D, Compound 1 free base dichloromethane solvate having pattern E, Compound 1 free base ethyl acetate solvate having PXRD pattern F, Compound 1 free base ethyl acetate solvate having PXRD pattern G, Compound 1 free base acetonitrile solvate having PXRD pattern H, Compound 1 free base acetonitrile solvate having PXRD pattern I, Compound 1 free base acetone solvate having PXRD pattern J, Compound 1 hydrochloride having PXRD pattern K, Compound 1 hydrochloride hydrate having PXRD pattern L, Compound 1 sulfate having PXRD pattern M, each having the respective powderX-ray diffraction patterns as described herein. Alsó described is Compound 1 free base tetrahydrofuran (THF) solvate having PXRD pattern N as described herein.

[0093] According to any of these embodiments, the composition can be deliverable, for example, by the órai route. Other routes of administration include without limitation parenteral, sublingual, buccal, intranasal, pulmonary, topical, transdermal, intradermal, ocular, otic, rectal, vaginái, intragastric, intracranial, intrasynovial and intra-articular routes. [0094] Where it is desired to provide Compound 1 free base or salt in solution form, for example in a liquid formulation for órai or parenteral administration, the Compound 1 free base or salt will nőt, ofcourse, be present in such a formulation in crystalline form; indeed, the presence of crystals is generally undesired in such a formulation. However, a crystalline form of Compound 1 free base can nonetheless be important as API in a process for preparing such a formulation. Thus, the present disclosure further provides a process for preparing a pharmaceutical solution composition of Compound 1 comprising dissolving a crystalline salt or a crystalline form of Compound 1 free base in a pharmaceutically acceptable solvent or mixture of solvents. Even where the desired formulation is one containing Compound 1 free base in amorphous form, for example a solid melt formulation, a crystalline form of Compound 1 free base can still be useful as API in a process for preparing such a formulation.

[0095] As API, a crystalline form of Compound 1 free baseor mixtures thereof can have advantages over an amorphous form. For example, purification of API to the high degree of purity required by most regulatory authorities can be more efficient and therefore cost less where the API is in crystalline form asopposed to amorphous form. Physical and Chemical stability, and therefore shelf-life ofthe API solid, can alsó be better for crystal line than amorphous forms. Ease of hand ling can be improved over the amorphous form, which can be oily or sticky. Drying can be more straightforward and more easily controlled in the case ofthe crystalline rnaterial, which can have a well-defined drying ordesolvation temperature, than in the case of the amorphous rnaterial, which can have greater affinity for organic solvents and no well-defined drying temperature. Downstream processing using crystalline API can further permit enhanced process control. In preparing a liquid formulation, for example a solution in a lipid carrier, crystalline Compound 1 can dissolve faster and can have a reduced tendency to form a gél during dissolution. These advantages are illustrative and non-limiting.

[0096] Pharmaceutical compositions comprising crystalline Compound 1 free base, or prepared using crystalline Compound 1 free base or salts of Compound 1 as API, contain Compound 1 in an amount that can be therapeutically effective when the composition is administered to a subject in need thereof according to an appropriate régimén. Dosage amounts are expressed herein as free base equivalent amounts unless the context requires otherwise. Typically, a unit dose (the amount administered at a single time), which can be administered at an appropriate frequency, e.g., twice daily to once weekly, is about 10 to about 1,000 mg. Where frequency of administration is once daily (q.d.), unit dose and daily dose are the same. I llustratively, the unit dose of Compound 1 in a composition ofthe invention can be about 25 to about 1,000 mg, more typically 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. Where the composition is prepared as a discrete dosage form such as a tablet or eapsuie, a unit dose can be deliverable in a single dosage form or a small plurality of dosage forms, most typically 1 to about 10 dosage forms.

[0097] The higher the unit dose, the more desirable it becomes to select excipients that permit a relatively high loading of API (in this case Compound 1 free base orsalt) in the formulation. Typically, the concentration of Compound 1 in a formulation prepared according to the present disclosure is at least about 1 %, e.g., about 1 % to about 25%, by weight, bút lower and higher concentrations can be acceptable or achievable in specific cases. Illustratively, the Compound 1 free base equivalent concentration in various embodiments is at least about 2%, e.g., about 2% to about 20%, by weight, for example about 5%, about 10% or about 15%, by weight ofthe formulation.

[0098] A composition prepared according to the invention comprises, in addition to the API, one or more pharmaceutically acceptable excipients. If the composition is to be prepared in solid form for órai administration, for example as a tablet or eapsuie, it typically includes at least one or more solid diluents and one or more solid disintegrants. Optionally, the excipients further include one or more binding agents, wetting agents and/or antifrictional agents (lubricants, antiadherents and/or glidants). Many excipients have two or more functions in a pharmaceutical composition. Characterization herein of a particular excipient as having a certain function, e.g., diluent, disintegrant, binding agent, etc., should nőt be read as limiting to that function. Further information on excipients can be found in standard reference works such as Handbook of Pharmaceutical Excipients, 3rd ed. (Kibbe, ed. (2000), Washington: American Pharmaceutical Associ20

EP 2 643 322 Β1 ation).

[0099] Suitable diluents illustratively include, either individually 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 sugár, confectioner’s sugár and sugár spheres; maltose; inositol; hydrolyzed cereal solids; starches (e.g., corn starch, wheat starch, rice starch, potato starch, tapioca starch, etc.), starch components such as amylose and dextrates, and modified or processed starches such as pregelatinized starch; dextrins; celluloses including powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, food grade sources ofa- 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 granular calcium lactate trihydrate; magnesium carbonate; magnesium oxide; bentonite; kaolin; sodium chloride; and the like. Such diluents, if present, typically constitute in totál about 5% to about 95%, for example about 20% to about 90%, or about 50% to about 85%, by weight of the composition. The diluent or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.

[0100] Microcrystalline cellulose and silicified microcrystalline cellulose are particularly useful diluents, and are optionally used in combination with a water-soluble diluent such as mannitol. Illustratively, a suitable weight ratio of microcrystalline cellulose or silicified microcrystalline cellulose to mannitol is about 10:1 to about 1:1, bút ratios outside this rangé can be useful in particular circumstances.

[0101] Suitable disintegrants include, either 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 hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums; colloidal Silicon dioxide; and the like. One or more disintegrants, if present, typically constitute in totál about 0.2% to about 30%, for example about 0.5% to about 20%, or about 1% to about 10%, by weight ofthe composition.

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

[0103] Binding agents or adhesives are useful excipients, particularly where the composition is in the form of a tablet. Such binding agents and adhesives should impart sufficient cohesion to the blend being tableted to allow for normál Processing operations such as sizing, lubrication, compression and packaging, bút still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, carmellose sodium, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, hydroxyethylcellulose and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and salts of alginic acid, for example sodium alginate; magnesium aluminum silicate; bentonite; polyethylene glycol (PEG); polyethylene 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 adhesives, if present, typically constitute in totál about 0.5% to about 25%, for example about 1 % to about 15%, or about 1.5% to about 10%, by weight of the composition.

[0104] Povidone and hydroxypropylcellulose, either individually or in combination, are particularly useful binding agents for tablet formulations, and, if present, typically constitute about 0.5% to about 15%, for example about 1% to about 10%, or about 2% to about 8%, by weight of the composition.

[0105] Wetting agents, if present, are normally selected to maintain the drug in close association with water, a condition that can improve bioavailability ofthe composition. Non-limiting examples of surfactants that can be used as wetting agents include, either individually or in combination, quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride; dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers); polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric monoand diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castoroil; polyoxyethylene alkyl ethers, for example ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20, steareth-2, steareth-10, steareth20, 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; propylene glycol fatty acid esters, for example propylene glycol laurate; sodium lauryl sulfate; fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate; glyceryl fatty acid esters, for example glyceryl monooleate, glyceryl monostearate and glyceryl palmitostearate; tyloxapol; and the like. One or more wetting agents, if present, typically constitute in totál about 0.1 % to about 15%, for example about 0.2% to about 10%, or about 0.5% to about 7%, by weight ofthe composition.

[0106] Nonionic surfactants, more particularly poloxamers, are examples of wetting agents that can be useful herein.

ΕΡ 2 643 322 Β1 lllustratively, a poloxamer such as Pluronic™ F127, if present, can constitute about 0.1% to about 10%, for example about 0.2% to about 7%, or about 0.5% to about 5%, by weight of the composition.

[0107] Lubricants reduce friction between a tableting mixture and tableting equipment during compression of tablet formulations. Suitable lubricants include, either individually or in combination, glyceryl behenate; stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils; glyceryl palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (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 constitute in totál about 0.05% to about 10%, for example about 0.1% to about 5%, or about 0.2% to about 2%, by weight ofthe composition. Sodium stearyl fumarate is a particularly useful lubricant.

[0108] Anti-adherents reduce sticking of a tablet formulation to equipment surfaces. Suitable anti-adherents include, either individually or in combination, talc, colloidal Silicon dioxide, starch, DL-leucine, sodium lauryl sulfate and metallic stearates. One or more anti-adherents, if present, typically constitute in totál about 0.05% to about 10%, for example about 0.1 % to about 7%, or about 0.2% to about 5%, by weight ofthe composition. Colloidal Silicon dioxide is a particularly useful anti-adherent.

[0109] Glidants improve flow properties and reduce static in a tableting mixture. Suitable glidants include, either individually or in combination, colloidal Silicon dioxide, starch, powdered cellulose, sodium laurylsulfate, magnesium trisilicate and metallic stearates. One or more glidants, if present, typically constitute in totál about 0.05% to about 10%, forexample about 0.1 % to about 7%, or about 0.2% to about 5%, by weight ofthe composition. Colloidal Silicon dioxide is a particularly useful glidant.

[0110] Other excipients such as buffering agents, stabilizers, antioxidants, antimicrobials, colorants, flavors and sweeteners are known in the pharmaceutical art and can be used in compositions ofthe present invention. Tablets can be uncoated or can comprise a core that is coated, for example with a nonfunctional film or a release-modifying or enteric coating. Capsules can have hard or soft shells comprising, for example, gelatin (in the form of hard gelatin capsules or soft elastic gelatin capsules), starch, carrageenan and/or HPMC, optionally together with one or more plasticizers. [0111] A solid orally deliverable composition ofthe present invention is nőt limited by any proeess used to prepare it. Any suitable proeess of pharmacy can 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 (including encapsulated liquid) form, the API (e.g., crystalline Compound 1 free base orsalt) can be, forexample, dissolved in a suitable carrier, typically one comprising a lipid solvent for the API. The higher the unit dose, the more desirable it becomes to select a carrier that permits a relatively high concentration ofthe drug in solution therein. Typically, the free base equivalent concentration of API in the carrier is at least about 10 mg/mi, e.g., about 10 to about 500 mg/mi, bút lower and higher concentrations can be acceptable or achievable in specific cases. lllustratively, the drug concentration in various embodiments is at least about 10 mg/mi, e.g., about 10 to about 250 mg/mi, or at least about 20 mg/mi, e.g., about 20 to about 200 mg/mi, for example about 20, about 25, about 30, about 40, about 50, about 75, about 100 or about 150 mg/mi.

[0113] The carrier can be substantially non-aqueous, i.e., having no water, or having an amount ofwater that is small enough to be, in practical terms, essentially non-deleterious to performance or properties ofthe composition. Typically, the carrier comprises zero to less than about 5% by weight water. It will be understood that certain ingredients useful herein can bind small amounts of water on or within their molecules or supramolecular structures; such bound water if present does nőt affect the substantially non-aqueous character of a carrier as defined herein.

[0114] In somé embodiments, the carrier comprises one or more glyceride materials. Suitable glyceride materials include, without limitation, médium to long chain mono-, di- and triglycerides. The term médium chain herein refers to hydrocarbyl chains individually having no less than about 6 and less than about 12 carbon atoms, including for example C8 to C10 chains. Thus glyceride materials comprising caprylyl and capryl chains, e.g., caprylic/capric mono-, di- and/or triglycerides, are examples of médium chain glyceride materials herein. The term long chain herein refers to hydrocarbyl chains individually having at least about 12, forexample about 12 to about 18, carbon atoms, including forexample lauryl, myristyl, cetyl, stearyl, oleyl, linoleyl and linolenyl chains. Médium to long chain hydrocarbyl groups in the glyceride materials can be saturated, mono- or polyunsaturated.

[0115] In one embodiment the carrier comprises a médium chain and/or a long chain triglyceride matéria!. A suitable example of a médium chain triglyceride matéria! is a caprylic/capric triglyceride product such as, for example, Captex 355 EP™ of Abitec Corp. and products substantially equivalent thereto. Suitable examples of long chain triglycerides include any pharmaceutically acceptable vegetable oil, for example canola, coconut, corn, cottonseed, flaxseed, olive, palm, peanut, safflower, sesame, soy and sunflower oils, and mixtures ofsuch oils. Oils of animal, particularly maríné animal, origin can alsó be used, including for example fish oil.

[0116] In somé embodiments the carrier comprises a phospholipid and a pharmaceutically acceptable solubilizing agent for the phospholipid. It will be understood that reference in the singular to a (or the) phospholipid, solubilizing agent or other formulation ingredient herein includes the plural; thus combinations, for example mixtures, of more than

ΕΡ 2 643 322 Β1 one phospholipid, or more than one solubilizing agent, are expressly contemplated herein. The solubilizing agent, orthe combination of solubilizing agent and phospholipid, alsó solubilizes the drug, although other carrier ingredients, such as a surfactant or an aleohoi such as ethanol, optionally present in the carrier can in somé circumstances provide enhanced solubilization ofthe drug.

[0117] Any pharmaceutically acceptable phospholipid or mixture of phospholipids can be used. In generál such phospholipids are phosphoric acid esters that yield on hydrolysis phosphoric acid, fatty acid(s), an aleohoi and a nitrogenous base. Pharmaceutically acceptable phospholipids can include without limitation phosphatidylcholines, phosphatidylserines and phosphatidylethanolamines. In one embodiment the composition comprises phosphatidylcholine, derived for example from natural lecithin. Any source of lecithin can be used, including animal sources such as egg yolk, bút plánt sources are generally preferred. Soy is a particularly rich source of lecithin that can provide phosphatidylcholine for use in the present invention.

[0118] lllustratively, a suitable amount of phospholipid is about 15% to about 75%, for example about 30% to about 60%, by weight of the carrier, although greater and lesser amounts can be useful in particular situations.

[0119] Ingredients useful as components ofthe solubilizing agent are nőt particularly limited and will depend to somé extent on the desired concentration of drug and of phospholipid. In one embodiment, the solubilizing agent comprises one or more glyeols and/or one or more glyceride materials.

[0120] Suitable glyeols include propylene glycoi and polyethylene glyeols (PEGs) having molecular weight of about 200 to about 1,000 g/mol, e.g., PEG-400, which has an average molecular weight of about 400 g/mol. Such glyeols can provide relatively high solubility ofthe drug; however the potential for oxidative degradation ofthe drug can be increased when in solution in a carrier comprising such glyeols, for example because ofthe tendency of glyeols to produce superoxides, peroxides and/or free hydroxyl radicals. The higher the glycoi content of the carrier, the greater may be the tendency for degradation of a chemically unstable drug. In one embodiment, therefore, one or more glyeols are present in a totál glycoi amount of at least about 1 % bút less than about 50%, for example less than about 30%, less than about 20%, less than about 15% or less than about 10% by weight ofthe carrier. In another embodiment, the carrier comprises substantially no glycoi.

[0121] Suitable glyceride materials for use together with a phospholipid include, without limitation, those mentioned above. Where one or more glyceride materials are present as a major component ofthe solubilizing agent, a suitable totál amount ofglycerides is an amount effective to solubilize the phospholipid and, in combination with other components ofthe carrier, effective to maintain the drug and antioxidant in solution. Forexample, glyceride materials such as médium chain and/or long chain triglycerides can be present in a totál glyceride amount of about 5% to about 70%, for example about 15% to about 60% or about 25% to about 50%, by weight ofthe carrier.

[0122] Additional solubilizing agents that are other than glyeols orglyceride materials can be included if desired. Such agents, forexample N-substituted amidé solvents such as dimethylformamide (DMF) and N,N-dimethylacetamide(DMA), can, in specific cases, assist in raising the limit of solubility ofthe drug in the carrier, thereby permitting increased drug loading. However, N-substituted amides including DMF and DMA can present regulatory and/or toxicological issuesthat restrict the amount of such solvents that can be used in a formulation. Furthermore, the carriers useful herein generally provide adequate solubility of small-molecule drugs of interest herein without such additional agents.

[0123] Even when a sufficient amount of a glycoi or glyceride matéria! is present to solubilize the phospholipid, the resulting carrier solution and/or the drug-carrier system may be rather viscous and difficult or inconvenient to handle. In such cases it may be found desirable to include in the carrier a viscosity reducing agent in an amount effective to provide acceptably low viscosity. An example of such an agent is an aleohoi, more particularly ethanol, which is preferably introduced in a form that is substantially free of water, for example 99% ethanol, dehydrated aleohoi USP or absolute ethanol. Excessively high concentrations of ethanol should, however, generally be avoided. This is particularly true where, for example, the drug-carrier system is to be administered in a gelatin capsule, because of the tendency of high ethanol concentrations to result in mechanical failure of the capsule. In generál, suitable amounts of ethanol are 0% to about 25%, for example about 1% to about 20% or about 3% to about 15%, by weight ofthe carrier.

[0124] Optionally, the carrier further comprises a pharmaceutically acceptable non-phospholipid surfactant. One of skill in the art will be able to select a suitable surfactantfor use in a composition ofthe invention. lllustratively, a surfactant such as polysorbate 80 can be included in an amount of 0% to about 5%, for example 0% to about 2% or 0% to about 1 %, by weight of the carrier.

[0125] Conveniently, pre-blended products are available containing a suitable phospholipid + solubilizing agent combination for use in compositions ofthe present invention. Pre-blended phospholipid + solubilizing agent products can be advantageous in improving ease of preparation ofthe present compositions.

[0126] An illustrative example ofa pre-blended phospholipid + solubilizing agent product is Phosal 50 PG™, available from Phospholipid GmbH, Germany, which comprises, by weight, nőt less than 50% phosphatidylcholine, nőt more than 6% lysophosphatidylcholine, about 35% propylene glycoi, 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™, alsó available from Phospholipid GmbH, which contains, by

ΕΡ 2 643 322 Β1 weight, nőt less than 53% phosphatidylcholine, nőt more than 6% lysophosphatidylcholine, about 29% médium 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 having the above or substantially equivalent composition, whether sold under the Phosal 53 MCT™ brand or otherwise, is generically referred to herein as phosphatidylcholine + médium chain triglycerides 53/29. A product having substantially equivalent composition in the present context means having a composition sufficiently similar to the reference composition in its ingredient list and relatíve amounts of ingredients to exhibit no practícai difference in properties with respect to utilization of the product herein.

[0128] Yet another illustrative example is Phosal 50 SA+™, alsó available from Phospholipid GmbH, which contains, by weight, nőt less than 50% phosphatidylcholine and nőt more than 6% lysophosphatidylcholine in a solubilizing system comprising safflower oil and other ingredients.

[0129] The phosphatidylcholine component of each of these pre-blended products can be derived from soy lecithin. Products of substantially equivalent composition may be obtainable from other suppliers.

[0130] A pre-blended product such as Phosal 50 PG™, Phosal 53 MCT™ or Phosal 50 SA+™ can, in somé embodiments, constitute substantially the entire carrier system. In other embodiments, additional ingredients are present, fór example ethanol (additional to any that may be present in the pre-blended product), non-phospholipid surfactant such as polysorbate 80, polyethylene glycol and/or other ingredients. Such additional ingredients, if present, are typically included in only minor amounts. Illustratively, phosphatidylcholine + médium chain triglycerides 53/29 can be included in the carrier in an amount of about 50% to 100%, fór example 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 due at least in part to its ability to bind to a Bcl-2 family protein such as Bcl-2, Bcl-XL or Bcl-w in a way that inhibits the anti-apoptotic action of the protein, fór example by occupying the BH3 binding groove of the protein.

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

[0133] Compound 1 may be used in a method fór treating a disease characterized by apoptotic dysfunction and/or overexpression ofan anti-apoptotic Bcl-2 family protein is provided, where the method comprises preparing a solution or dispersion of a salt or crystalline form of Compound 1 described herein in a pharmaceutically acceptable solvent or mixture of solvents, and administering the resulting solution or dispersion in a therapeutically effective amount to a subject having the disease.

[0134] The subject can be humán or non-human (e.g., a farm, zoo, work or companion animal, or a laboratory animal used as a model) bút in an important embodiment the subject is a humán patient in need of the drug, fór example to treat a disease characterized by apoptotic dysfunction and/or overexpression of an anti-apoptotic Bcl-2 family protein. A humán subject can be male or female and of any age, bút is typically an aduit.

[0135] The composition is normally administered in an amount providing a therapeutically effective daily dose ofthe drug. The term daily dose herein means the amount of drug administered per day, regardless of the frequency of administration. Fór example, if the subject receives a unit dose of 150 mg twice daily, the daily dose is 300 mg. Use of the term daily dose will be understood nőt to imply that the specified dosage amount is necessarily administered once daily. However, in a particular embodiment the dosing frequency is once daily (q.d.), and the daily dose and unit dose are in this embodiment the same thing.

[0136] What constitutes a therapeutically effective dose depends on the bioavailability ofthe particular formulation, the subject (including species and body weight of the subject), the disease (e.g., the particular type of cancer) to be treated, the stage and/or severity ofthe disease, the individual subject’s tolerance ofthe compound, whether the compound is administered in monotherapy or in combination with one or more other drugs, e.g., other chemotherapeutics fór treatment of cancer, and other factors. Thus, the daily dose can vary within wide margins, fór example from about 10 to about 1,000 mg. Greater or lesser daily doses can be appropriate in specific situations. It will be understood that recitation herein of a therapeutically effective dose herein does nőt necessarily require that the drug be therapeutically effective if only a single such dose is administered; typically therapeutic efficacy depends on the composition being administered repeatedly according to a régimén involving appropriate frequency and duration of administration. It is strongly preferred that, while the daily dose selected is sufficient to provide benefit in terms of treating the cancer, it should nőt be sufficient to provoke an adverse side-effect to an unacceptable or intolerable degree. A suitable therapeutically effective dose can be selected by the physician of ordinary skill without undue experimentation based on the disclosure herein and on art cited herein, taking intő account factors such as those mentioned above. The physician may, fór example, start a cancer patient on a course of therapy with a relatively low daily dose and titrate the dose upwards over a period of days or weeks, to reduce risk of adverse side-effects.

[0137] lllustratively, suitable doses of Compound 1 are generally about 25 to about 1000 mg/day or about 50 to about 1000 mg/day, more typically about 50 to about 500 mg/day or about 200 to about 400 mg/day, fór example about 50,

ΕΡ 2 643 322 Β1 about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 750 or about 1000 mg/day, administered at an average dosage interval of about 3 hours to about 7 days, forexample about 8 hours to about 3 days, or about 12 hours to about 2 days. In most cases a once-daily (q.d.) administration régimén is suitable. [0138] An average dosage interval herein is defined as a span of time, fór example one day or one week, divided by the number of unit doses administered over that span oftime. Fór example, where a drug is administered three times a day, around 8 am, around noon and around 6 pm, the average dosage interval is 8 hours (a 24-hourtime span divided by 3). If the drug is formulated as a discrete dosage form such as a tablet or capsule, a plurality (e.g., 2 to about 10) of dosage forms administered at one time is considered a unit dose fór the purpose of defining the average dosage interval. [0139] Compositions prepared according to the present invention are suitable fór use in monotherapy or in combination therapy, fór example with other chemotherapeutics or with ionizing radiation. A particular advantage of the present invention is that it permits once-daily órai administration, a régimén which is convenient fór the patient who is undergoing treatment with other orally administered drugs on a once-daily régimén. Órai administration is easily accomplished by the patient him/herself or by a caregiver in the patient’s home; it is alsó a convenient route of administration fór patients in a hospital or residential care setting.

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

[0141] A Compound 1 composition can be administered in combination therapy with one or more therapeutic agents that include, bút are nőt limited to, angiogenesis inhibitors, antiproliferative agents, other apoptosis promoters (fór example, Bcl-xL, Bcl-w and Bfl-1 inhibitors), activators of a death receptor pathway, BiTE (bi-specific T-cell engager) antibodies, dual variable domain binding proteins (DVDs), inhibitors of apoptosis proteins (lAPs), microRNAs, mitogenactivated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, small inhibitory ribonucleic acids (siRNAs), kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum-containing chemotherapeutic agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids, deltoids, plánt alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors as well as other antitumor agents.

[0142] Angiogenesis inhibitors include, bút are nőt limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, mátrix metalloproteinase 2 (MMP-2) inhibitors, mátrix metalloproteinase 9 (MMP-9) inhibitors and thrombospondin analogs.

[0143] Examples of EGFR inhibitors include, bút are nőt limited to, gefitinib, erlotinib, cetuximab, EMD-7200, ABXEGF, HR3, lgAantibodies,TP-38(IVAX), EGFRfusion protein, EGF-vaccine, anti-EGFRimmunoliposomesand lapatinib. [0144] Examples of PDGFR inhibitors include, bút are nőt limited to, CP-673451 and CP-868596.

[0145] Examples of VEGFR inhibitors include, bút are nőt limited to, 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, bút are nőt limited to, ABT-263, AT-101 ((-)gossypol), Genasense™ Bcl-2-targeting antisense oligonucleotide (G3139 or oblimersen), IPI-194, IPI-565, N-(4-(4-((4’chloro(1,1’-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1 R)-3-(dimethylamino)-1-((phenylsulfanyl) methyl)propyl)amino)-3-nitrobenzenesulfonamide) (ABT-737), GX-070 (obatoclax) and the like.

[0147] Activators of a death receptor pathway include, bút are nőt limited to, TRAIL, antibodies or other agents that target death receptors (e.g., DR4 and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

[0148] Examples of thrombospondin analogs include, bút are nőt limited to, TSP-1, ABT-510, ABT-567 and ABT-898. [0149] Examples of aurora kinase inhibitors include, bút are nőt limited to, VX-680, AZD-1152 and MLN-8054.

[0150] An example of a polo-like kinase inhibitor includes, bút is nőt limited to, BI-2536.

[0151] Examples of bcr-abl kinase inhibitors include, bút are nőt limited to, imatinib and dasatinib.

[0152] Examples of platinum-containing agents include, bút are nőt limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin.

[0153] Examples of mTOR inhibitors include, bút are nőt limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001 and AP-23573.

[0154] Examples of HSP-90 inhibitors include, bút are nőt limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 1725

ΕΡ 2 643 322 Β1

DMAG, CNF-101, CNF-1010,17-AAG-nab, NCS-683664, efungumab, CNF-2024, PU3, PU24FCI, VER-49009, IPI-504, SNX-2112 and STA-9090.

[0155] Examples of HDAC inhibitors include, bút are nőt limited to, suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA, LAQ-824, trapoxin and depsipeptide.

[0156] Examples of MEK inhibitors include, bút are nőt limited to, PD-325901, ARRY-142886, ARRY-438162 and PD98059.

[0157] ExamplesofCDK inhibitors include, bút are nőt limited to.flavopiridol, MCS-5A, CVT-2584, seliciclibZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438.

[0158] Examples of COX-2 inhibitors include, bút are nőt limited to, celecoxib, parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS 57067, NS-398, valdecoxib, rofecoxib, SD-8381,4-methyl-2-(3,4-dimethylphenyl)1-(4-sulfamoyl-phenyl-1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3 and SC-58125.

[0159] Examples of NSAIDs include, bút are nőt limited to, salsalate, diflunisal, ibuprofen, ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, ketorolac and oxaprozin.

[0160] Examples of ErbB2 receptor inhibitors include, bút are nőt limited to, CP-724714, canertinib, trastuzumab, pertuzumab, TAK-165, ionafamib, GW-282974, EKB-569, PI-166, dHER2, APC-8024, anti-HER/2neu bispecificantibody B7.her2lgG3 and HER2 trifunctional bispecific antibodies mAB AR-209 and mAB 2B-1.

[0161] Examples of alkylating agents include, bút are nőt limited to, nitrogén mustard N-oxide, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, Cloretazine™ (laromustine), AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2170, mafosfamide, mitolactol, lomustine, treosulfan, dacarbazine and temozolomide.

[0162] Examples of antimetabolites include, bút are nőt limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, pemetrexed, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethenylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, disodium pemetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, mycophenolic acid, ocfosfate, pentostatin, tiazofurin, ribavirin, EICAR, hydroxyurea and deferoxamine.

[0163] Examples of antibiotics include, bút are nőt limited to, intercalating antibiotics, aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin (including liposomal doxorubicin), elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.

[0164] Examples of topoisomerase inhibiting agents include, bút are nőt limited to, aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-amino-camptothecin, amsacrine, dexrazoxane, diflomotecan, irinotecan HCI, edotecarin, epirubicin, etoposide, exatecan, becatecarin, gimatecan, lurtotecan, orathecin, BN-80915, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.

[0165] Examples of antibodies include, bút are nőt limited to, rituximab, cetuximab, bevacizumab, trastuzumab, CD40specific antibodies and IGF1 R-specific antibodies, chTNT-1/Β, denosumab, edrecolomab, WX G250, zanolimumab, lintuzumab and ticilimumab.

[0166] Examples of hormonal therapies include, bút are nőt limited to, sevelamer carbonate, rilostane, luteinizing hormoné releasing hormoné, modrastane, exemestane, leuprolide acetate, buserelin, cetrorelix, deslorelin, histrelin, anastrozole, fosrelin, goserelin, degarelix, doxercalciferol, fadrozole, formestane, tamoxifen, arzoxifene, bicalutamide, abarelix, triptorelin,finasteride,fulvestrant, toremifene, raloxifene, trilostane, lasofoxifene, letrozole.flutamide, megestrol, mifepristone, nilutamide, dexamethasone, prednisone and other glucocorticoids.

[0167] Examples of retinoids ordeltoids include, bút are nőt limited to, seocalcitol, lexacalcitol, fenretinide, alitretinoin, tretinoin, bexarotene and LGD-1550.

[0168] Examples of plánt alkaloids include, bút are nőt limited to, vincristine, vinblastine, vindesine and vinorelbine. [0169] Examples of proteasome inhibitors include, bút are nőt limited to, bortezomib, MG-132, NPI-0052 and PR-171. [0170] Examples of immunologicals include, bút are nőt limited to, interferons and numerous other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon béta, interferon gammala, interferon gamma-lb, interferon gamma-n1 and combinations thereof. Other agents include filgrastim, lentinan, sizofilan, BCG live, ubenimex, WF-10 (tetrachlorodecaoxide orTCDO), aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, melanoma vaccine, molgramostim, sargramostim, tasonermin, tecleukin, thymalfasin, tositumomab, Virulizin™ immunotherapeutic of Lorus Pharmaceuticals, Z-100 (specific substance of Maruyama or SSM), Zevalin™ (90Y-ibritumomab tiuxetan), epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge™ (sipuleucel-T), teceleukin, Therocys™ (Bacillus Calmette-Guerin), cytotoxic lymphocyte antigén 4 (CTLA4) antibodies and agents capable of blocking CTLA4 such as MDX-010. [0171] Examples of biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.

ΕΡ 2 643 322 Β1

Such agents include, bút are nőt limited to, krestin, lentinan, sizofiran, picibanil, PF-3512676 and ubenimex.

[0172] Examplesof pyrimidine analogs include, bút are nőt limited to, 5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine, cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine and gemcitabine.

[0173] Examples of purine analogs include, bút are nőt limited to, mercaptopurine and thioguanine.

[0174] Examples of antimitotic agents include, bút are nőt limited to, N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4methoxybenzenesulfonamide, paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batabulin, ixabepilone, patupilone, XRP-9881, vinflunine and ZK-EPO (synthetic epothilone).

[0175] Examples of radiotherapy include, bút are nőt limited to, external beam radiotherapy (XBRT), teletherapy, brachytherapy, sealed-source radiotherapy and unsealed-source radiotherapy.

[0176] BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell. Examples of BiTE antibodies include, bút are nőt limited to, adecatumumab (Micromet MT201), blinatumomab (Micromet MT 103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B. In this regard, 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 enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (Sutton et al. (1997) J. Immunoi. 158:5783-5790).

[0177] SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do nőt abolish cellular activity, bút rather impart increased stability and/or increased cellular potency. Examples of Chemical modifications include phosphorothioate groups, 2’-deoxynucleotide, 2’-OCH3-containing ribonucleotides, 2’F-ribonucleotides, 2’-methoxyethyl ribonucleotides, combinations thereof and the like. The SÍRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded SÍRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5’- and/ or the 3’-ends of a given strand. For example, siRNAs targeting Mcl-1 have been shown to enhance the activity of the apoptosis-promoting agent ABT263 (Tse et al. (2008) Cancer Rés. 68:3421-3428 and references therein).

[0178] Multivalent binding proteins are binding proteins comprising two or more antigén binding sites. Multivalent binding proteins are engineered to have the three or more antigén binding sites and are generally nőt naturally occurring antibodies. The term multispecific binding protein means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigén binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigén) or multispecific (i.e., capable of binding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light-chain DVD polypeptides are referred to as DVD Ig’s. Each half of a DVD lg comprises a heavy-chain DVD polypeptide, a light-chain DVD polypeptide, and two antigén binding sites. Each binding site comprises a heavy -chain variable domain and a light-chain variable domain with a totál of 6 CDRs involved in antigén binding per antigén binding site.

[0179] PARP inhibitors include, bút are nőt limited to, ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

[0180] Additionally or alternatively, a composition ofthe present invention can be administered in combination therapy with one or more antitumor agents selected from ABT-100, N-acetylcolchinol-O-phosphate, acitretin, AE-941, aglycon protopanaxadiol, arglabin, arsenic trioxide, AS04 adjuvant-adsorbed HPV vaccine, L-asparaginase, atamestane, atrasentan, AVE-8062, bosentan, canfosfamide, Canvaxin™, catumaxomab, CeaVac™, celmoleukin, combrestatin A4P, contusugene ladenovec, Cotara™, cyproterone, deoxycoformycin, dexrazoxane, N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine, 5,6-dimethylxanthenone-4-acetic acid, docosahexaenoic acid/paclitaxel, discodermolide, efaproxiral, enzastaurin, epothilone B, ethynyluracil, exisulind, falimarev, Gastrimmune™, GMK vaccine, GVAX™, halofuginone, histamine, hydroxycarbamide, ibandronic acid, ibritumomab tiuxetan, IL-13-PE38, inalimarev, interleukin 4, KSB-311, lanreotide, lenalidomide, lonafarnib, lovastatin, 5,10-methylenetetrahydrofolate, mifamurtide, miltefosine, motexafin, oblimersen, OncoVAX™, Osidem™, paclitaxel albumin-stabilized nanoparticle, paclitaxel poliglumex, pamidronate, panitumumab, peginterferon alfa, pegaspargase, phenoxodiol, poly(l)-poly(C12U), procarbazine, ranpirnase, rebimastat, recombinant quadrivalent HPV vaccine, squalamine, staurosporine, STn-KLH vaccine, T4 endonuclase V, tazarotene, 6,6’,7,12-tetramethoxy-2,2’-dimethyl-1 β-berbaman, thalidomide, TNFerade™, 131l-tositumomab, trabectedin, triazone, tumor necrosis factor, Ukrain™, vaccinia-MUC-1 vaccine, L-valine-L-boroproline, Vitaxin™, vitespen, zoledronic acid and zorubicin.

[0181] 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 to treat a disease during which is overexpressed one or more of antiapoptotic Bcl-2 protein, antiapoptotic Bcl-XL protein and antiapoptotic Bcl-w protein.

[0182] A composition comprising (or prepared using as API) one or more crystalline forms of Compound 1 (including

ΕΡ 2 643 322 Β1 crystalline salts) can be administered in a therapeutically effective amount to a subject in need thereof to treat a disease of abnormal cell growth and/or dysregulated apoptosis.

[0183] Examples of such diseases include, bút are nőt limited to, cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma ofthe fallopian tubes, carcinoma ofthe endometrium, carcinoma ofthe cervix, carcinoma of the vagina, carcinoma ofthe vulva, boné cancer, colon cancer, rectal cancer, cancer ofthe anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duódénál) cancer, chronic lymphocytic leukémia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or seeondary Central nervous system tumor, primary or seeondary brain tumor, Hodgkin’s disease, chronic or acute leukémia, chronic myeloid leukémia, lymphocytic lymphoma, lymphoblastic leukémia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, órai cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer ofthe kidney and/or ureter, renal cell carcinoma, carcinoma ofthe renal pelvis, neoplasms ofthe Central nervous system, primary Central nervous system lymphoma, non Hodgkin’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer ofthe spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma óra combination 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 to treat bladder cancer, brain cancer, breast cancer, boné marrow cancer, cervical cancer, chronic lymphocytic leukémia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukémia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukémia, myeloma, órai cancer, ovarian cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer or spleen cancer.

[0185] The composition can be administered in combination therapy with one or more additional therapeutic agents. [0186] For example, a method for treating mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma ofthe fallopian tubes, carcinoma ofthe endometrium, carcinoma ofthe cervix, carcinoma ofthe vagina, carcinoma ofthe vulva, boné cancer, colon cancer, rectal cancer, cancer ofthe anal region, stomach cancer, gastrointestinal (gastric, colorectal and/or duódénál) cancer, chronic lymphocytic leukémia, esophageal cancer, cancer ofthe small intestine, cancer ofthe endocrine system, cancer ofthe thyroid gland, cancer ofthe parathyroid gland, cancer ofthe adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or seeondary Central nervous system tumor, primary or seeondary brain tumor, Hodgkin’s disease, chronic or acute leukémia, chronic myeloid leukémia, lymphocytic lymphoma, lymphoblastic leukémia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, órai cancer, non-small-cell lung cancer, prostate cancer, small-cell lung cancer, cancer ofthe kidney and/or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms ofthe Central nervous system, primary Central nervous system lymphoma, non Hodgkin’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer ofthe spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma óra combination thereof in a subject comprises administering to the subject therapeutically effective amounts of (a) a composition comprising (or prepared using as API) crystalline Compound 1 free base 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 as API) crystalline Compound 1 free base 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, DA-EPOCH-R or bortezomib in a therapeutically effective amount, for treatment of a lymphoid malignancy such as B-cell lymphoma or non-Hodgkin’s lymphoma.

[0188] A composition of the invention can be administered in a therapeutically effective amount to a subject in need thereof to treat an immuné or autoimmune disorder. Such disorders include acquired immunodeficiency disease syndrome (AIDS), autoimmune lymphoproliferative syndrome, hemolytic anémia, inflammatory diseases, thrombocytopenia, acute and chronic immuné diseases associated with organ transplantation, Addison’s disease, allergic diseases, alopecia, alopecia areata, atheromatous disease/arteriosclerosis, atherosclerosis, arthritis (including osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme arthritis, psoriatic arthritis and reactive arthritis), autoimmune bullous disease, abetalipoprotemia, acquired immunodeficiency-related diseases, acute immuné disease associated with organ transplantation, acquired acrocyanosis, acute and chronic parasitic or infectious processes, acute pancreatitis, acute renal failure, acute rheumatiefever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats, aduit (acute) respiratory distress syndrome, AIDS dementia complex, alcoholic cirrhosis, alcohol-induced liver injury, alcohol-induced hepatitis, allergic conjunctivitis, allergic contact dermatitis, allergic rhinitis, allergy and asthma, allograft rejection, alpha-1-antitrypsin deficiency, Alzheimer’s disease, amyotrophic lateral selerosis, anémia, angina pectoris, ankylosing spondylitisassociated lung disease, anterior horn cell degeneration, antibody mediated cytotoxicity, antiphospholipid syndrome,

ΕΡ 2 643 322 Β1 anti-receptor hypersensitivity reactions, aortic and peripheral aneurysms, aortic dissection, artéria! hypertension, arteriosclerosis, arteriovenous fistula, arthropathy, asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustained or paroxysmal), atrialflutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolyticanaemia, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid hepatitis), autoimmune mediated hypoglycemia, autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune thyroid disease, B-cell lymphoma, boné graft rejection, boné marrow transplant (BMT) rejection, bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation response, cartilage transplant rejection, cerebellar cortical degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia, chemotherapy-associated disorders, chlamydia, choleosatatis, chronic alcoholism, chronic active hepatitis, chronicfatigue syndrome, chronic immuné disease associated with organ transplantation, chronic eosinophilic pneumonia, chronic inflammatory pathologies, chronic mucocutaneous candidiasis, chronic obstructive pulmonary disease (COPD), chronic salicylate intoxication, colorectal common varied immunodeficiency (common variable hypogammaglobulinemia), conjunctivitis, connective tissue disease-associated interstitial lung disease, contact dermatitis, Coombs-positive hemolytic anémia, cor pulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis, culture-negative sepsis, cystic fibrosis, cytokine therapy-associated disorders, Crohn’s disease, dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma, dermatologic conditions, dermatomyositis/ polymyositis-associated lung disease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus, diffuse Lewy body disease, dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupus erythematosus, disorders ofthe basal ganglia, disseminated intravascular coagulation, Down’s Syndrome in middle age, drug-induced interstitial lung disease, drug-induced hepatitis, drug-induced movement disorders induced by drugs which block CNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis, Epstein-Barr vírus infection, erythromelalgia, extrapyramidal and cerebellar disorders, famíliái hematophagocytic lymphohistiocytosis, fetal thymus implant rejection, Friedreich’s ataxia, functional peripheral artéria! disorders, female infertility, fibrosis, fibrotic lung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis, glomerular nephritis, glomerulonephritides, Goodpasture’s syndrome, goitrous autoimmune hypothyroidism (Hashimoto’s disease), gouty arthritis, graft rejection of any organ or tissue, graft versus hőst disease, gram-negative sepsis, gram-positive sepsis, granulomas due to intracellular organisms, group B streptococci (GBS) infection, Graves’ disease, hemosiderosis-associated lung disease, hairy cell leukémia, Hallerrorden-Spatz disease, Hashimoto’s thyroiditis, hay fever, heart transplant rejection, hemachromatosis, hematopoietic malignancies (leukémia and lymphoma), hemolytic anémia, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpura, hepatitis A, hepatitis B, hepatitis C, HÍV infection/HIV neuropathy, Hodgkin’s disease, hypoparathyroidism, Huntington’s chorea, hyperkinetic movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis, hyperthyroidism, hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison’s disease, idiopathic leucopenia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia, idiosyncratic liver disease, infantile spinal muscular atrophy, infectious diseases, inflammation of the aorta, inflammatory bowel disease, insulin dependent diabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury, ischemic stroke, juvenile pernicious anémia, juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi’s sarcoma, Kawasaki’s disease, kidney transplant rejection, legionella, leishmaniasis, leprosy, lesions ofthe corticospinal system, linear IgAdisease, lipidema, liver transplant rejection, Lyme disease, lymphederma, lymphocytic infiltrative lung disease, malaria, male infertility idiopathic or NOS, malignant histiocytosis, malignant melanoma, meningitis, meningococcemia, microscopic vasculitis ofthe kidneys, migraine headache, mitochondrial multisystem disorder, mixed connective tissue disease, mixed connective tissue disease-associated lung disease, monoclonal gammopathy, multiple myeloma, multiple systems degenerations (Mencel, Dejerine-Thomas, Shy-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease, myasthenia gravis, microscopic vasculitis ofthe kidneys, mycobacterium avium intracellulare, mycobacterium tuberculosis, myelodyplastic syndrome, myocardial infarction, myocardial ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis, nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic I muscular atrophies, neutropenicfever, non-alcoholic steatohepatitis, occlusion ofthe abdominal aorta and its branches, occlusive artéria! disorders, organ transplant rejection, orchitis/epidydimitis, orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian failure, pancreas transplant rejection, parasitic diseases, parathyroid transplant rejection, Parkinson’s disease, pelvic inflammatory disease, pemphigus vulgáris, pemphigus foliaceus, pemphigoid, perennial rhinitis, pericardial disease, peripheral atherlosclerotic disease, peripheral vasculardisorders, peritonitis, pernicious anémia, phacogenic uveitis, pneumocystis carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), post-perfusion syndrome, post-pump syndrome, post-MI cardiotomy syndrome, postinfectious interstitial lung disease, premature ovarian failure, primary biliary cirrhosis, primary sclerosing hepatitis, primary myxoedema, primary pulmonary hypertension, primary sclerosing cholangitis, primary vasculitis, Progressive supranuclear palsy, psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy, pulmonary hypertension secondary to connective tissue disease, pulmonary manifestation of polyarteritis nodosa, post-inflammatory interstitial lung disease, radiation fibrosis, radiation therapy,

ΕΡ 2 643 322 Β1

Raynaud’s phenomenon and disease, Raynoud’s disease, Refsum’s disease, regular narrow QRS tachycardia, Reiter’s disease, renal disease NOS, renovascular hypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoid arthritis-associated interstitial lung disease, rheumatoid spondylitis, sarcoidosis, Schmidt’s syndrome, seleroderma, senile chorea, senile dementia of Lewy body type, sepsis syndrome, septic shock, seronegative arthropathies, shock, sickle cell anémia, Sjögren’s disease-associated lung disease, Sjögren’s syndrome, skin allograft rejection, skin changes syndrome, small bowel transplant rejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinal ataxia, spinocerebellardegenerations, spondyloarthropathy, sporadicpolyglandulardeficiencytype I, sporadicpolyglandulardeficiency type II, Still’s disease, streptococcal myositis, stroke, structural lesions ofthe cerebellum, subacute selerosing panencephalitis, sympathetic ophthalmia, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, systemic onset juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic lupus erythematosus-associated lung disease, systemic sclerosis, system icsclerosis-associated interstitial lung disease, T-cell or FAB ALL, Takayasu’s disease/arteritis, telangiectasia, Th2-type and Th1-type mediated diseases, thromboangitis obliterans, thrombocytopenia, thyroiditis, toxicity, toxic shock syndrome, transplants, trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), type B insulin resistance with acanthosis nigricans, type Ili hypersensitivity reactions, type IV hypersensitivity, ulcerative colitic arthropathy, ulcerative colitis, unstable angina, uremia, urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins, vasculitis, vasculitic diffuse lung disease, venous diseases, venous thrombosis, ventricularfibrillation, vitiligo acute liverdisease, viral and fungal infections, vitai encephalitis/aseptic meningitis, vital-associated hemaphagocytic syndrome, Wegener’s granulomatosis, Wernicke-Korsakoff syndrome, Wilson’s disease, xenograft rejection of any organ or tissue, yersinia and salmonella-associated arthropathy and the like.

[0189] A pharmaceutical composition as described herein can be used in a method for maintaining in bloodstream of a humán cancer patient a therapeutically effective plasma concentration of Compound 1 and/or one or more metabolites thereof, comprising administering to the subject a pharmaceutical composition as described herein, in a dosage amount equivalent to about 50 to about 500 mg Compound 1 per day, at an average dosage interval of about 3 hours to about 7 days.

[0190] What constitutes a therapeutically effective plasma concentration depends inter alia on the particular cancer present in the patient, the stage, severity and aggressiveness ofthe cancer, and the outcome sought (e.g., stabilization, reduction in tumor growth, tumor shrinkage, reduced risk of metastasis, etc.). It is strongly preferred that, while the plasma concentration is sufficient to provide benefit in terms of treating the cancer, it should nőt be sufficient to provoke an adverse side-effect to an unacceptable or intolerable degree.

[0191] Fortreatmentofcancerin generál and ofa lymphoid malignancy such as non-Hodgkin’s lymphoma in particular, the plasma concentration of Compound 1 should in most cases be maintained in a rangé of about 0.5 to about 10 μg/ml. Thus, during a course of Compound 1 therapy, the steady-state Cmax should in generál nőt exceed about 10 μg/ml, and the steady-state Cmin should in generál nőt fali below about 0.5 μg/ml. It will further be found desirable to select, within the ranges provided above, a daily dosage amount and average dosage interval effective to provide a Cmax/Cmin ratio nőt greater than about 5, for example nőt greater than about 3, at steady-state. It will be understood that longer dosage intervals will tend to result in greater Cmax/Cmin ratios. 11lustratively, at steady-state, an Compound 1 Cmax of about 3 to about 8 μg/ml and Cmin of about 1 to about 5 μg/ml can be targeted by the present method.

[0192] A daily dosage amount effective to maintain a therapeutically effective Compound 1 plasma level is, according to the present embodiment, about 50 to about 1000 mg. In most cases a suitable daily dosage amount is about 200 to about 400 mg. Illustratively, the daily dosage amount can 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] An average dosage interval effective to maintain a therapeutically effective Compound 1 plasma level is, according to the present embodiment, about 3 hours to about 7 days. In most cases, a suitable average dosage interval is about 8 hours to about 3 days, or about 12 hours to about 2 days. A once-daily (q.d.) administration régimén is often suitable.

[0194] As in other embodiments, administration according to the present embodiment can be with or without food, i.e., in a non-fasting orfasting condition. It is generally preferred to administerthe present compositions to a non-fasting patient. [0195] When introducing elements ofthe present disclosure or the preferred embodiments(s) thereof, the articles a, an, the and said are intended to mean that there are one or more ofthe elements. The terms comprising, including and having are intended to be inclusive and mean that there may be additional elements other than the listed elements.

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41665610	United States of America	P	2010-11-23

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CA2817629A1	Canada	A1	2012-05-31
WO2012071336A1	World Intellectual Property Organization (WIPO)	A1	2012-05-31
US2012157470A1	United States of America	A1	2012-06-21
TW201305154A	Taiwan Province of China	A	2013-02-01
AU2011332043A1	Australia	A1	2013-05-30
SG190361A1	Singapore	A1	2013-06-28
MX2013005851A	Mexico	A	2013-07-05
IL226489D0	Israel	D0	2013-07-31
CN103328474A	China	A	2013-09-25
EP2643322A1	European Patent Office (EPO)	A1	2013-10-02
JP2013543894A	Japan	A	2013-12-09
KR20140009265A	Republic of Korea	A	2014-01-22
US8722657B2	United States of America	B2	2014-05-13
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RU2013128612A	Russian Federation	A	2014-12-27
ZA201303586B	South Africa	B	2015-01-28
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US9238649B2	United States of America	B2	2016-01-19
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AU2011332043B2	Australia	B2	2016-08-11
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JP6141188B2	Japan	B2	2017-06-07
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EP2643322B1	European Patent Office (EPO)	B1	2017-08-30
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US2025340550A1	United States of America	A1	2025-11-06

Salts and crystalline forms of an apoptosis-inducing agent

Abstract

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10.1002/JPS.2600660104

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