CXCR4 inhibitor compositions and methods of making and using

文档序号：589428 发布日期：2021-05-25 浏览：10次中文

阅读说明：本技术 Cxcr4抑制剂组合物以及制备和使用的方法 (CXCR4 inhibitor compositions and methods of making and using ) 是由 K·M·J·布兰兹于 2019-08-30 设计创作，主要内容包括：本发明提供了用于治疗、预防或改善与趋化因子受体(例如CXCR4)有关的疾病、病症或病状的组合物和使用方法。(The present invention provides compositions and methods of use for treating, preventing, or ameliorating a disease, disorder, or condition associated with a chemokine receptor (e.g., CXCR 4).)

1. An X4P-001 composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and a detectable amount of at least one of the following compounds:

or a pharmaceutically acceptable salt thereof; and wherein the X4P-001 composition does not include a detectable amount of the following compound:

or a pharmaceutically acceptable salt thereof.

2. The X4P-001 composition of claim 1, wherein the X4P-001 composition comprises at least a detectable amount of each of I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

3. The X4P-001 composition of claim 1 or 2, wherein the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w/w of the X4P-001 composition.

4. The X4P-001 composition of any one of claims 1-3, wherein the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

5. The X4P-001 composition of any one of claims 1-4, wherein the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

6. The X4P-001 composition of any one of claims 1-5, wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

7. The X4P-001 composition of any one of claims 1-6, wherein the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w/w of the X4P-001 composition.

8. The X4P-001 composition of claim 3, wherein the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w/w of the X4P-001 composition.

9. The X4P-001 composition of claim 4, wherein the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

10. The X4P-001 composition of claim 5, wherein the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

11. The X4P-001 composition of claim 6, wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

12. The X4P-001 composition of claim 7, wherein the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w/w of the X4P-001 composition.

13. The X4P-001 composition of claim 1, wherein:

(a) the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w/w of the X4P-001 composition;

(b) the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition;

(c) the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition;

(d) wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition; and is

(e) The amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w/w of the X4P-001 composition.

14. The X4P-001 composition of claim 1, wherein:

(a) the amount of I-2 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.3% w/w of the X4P-001 composition;

(b) the amount of I-3 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition;

(c) the amount of I-5 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition;

(d) the amount of I-6 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition; and is

(e) The amount of I-7 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.25% w/w of the X4P-001 composition.

15. The X4P-001 composition of claim 1, wherein:

(a) the amount of I-2 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(b) the amount of I-3 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(c) the amount of I-5 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(d) the amount of I-6 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition; and is

(e) The amount of I-7 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.25% w/w of the X4P-001 composition.

16. The X4P-001 composition of any one of claims 13-15, optionally further comprising the following compound:

or an isomeric form thereof; or a pharmaceutically acceptable salt thereof, in an amount of from about 0.02 to about 0.5% w/w of the X4P-001 composition.

17. A pharmaceutical composition comprising the X4P-001 composition of any one of claims 1-16 and a pharmaceutically acceptable excipient, adjuvant, carrier, or vehicle.

18. The pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable adjuvant comprises at least one diluent, disintegrant, lubricant, and glidant.

19. A unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

(a) about 10-20%, by weight of the composition, of the X4P-001 composition of any one of claims 1-16;

(b) from about 70% to about 85%, by weight of the composition, of microcrystalline cellulose;

(d) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate; and

(e) from about 0.1% to about 1.0% by weight of the composition of colloidal silica.

20. A unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

(a) about 10-20%, by weight of the composition, of the X4P-001 composition of any one of claims 1-16;

(b) from about 70% to about 85%, by weight of the composition, of microcrystalline cellulose;

(d) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate; and

(e) from about 0.1% to about 1.0% by weight of the composition of colloidal silica.

21. A unit dosage form comprising a pharmaceutical composition, the pharmaceutical composition comprising:

(a) from about 35-75%, by weight of the composition, of the X4P-001 composition of any one of claims 1-16;

(b) from about 5% to about 28%, by weight of the composition, of microcrystalline cellulose;

(d) from about 2% to about 10%, by weight of the composition, of croscarmellose sodium;

(e) from about 0.3% to about 2.5%, by weight of the composition, of sodium stearyl fumarate;

(f) from about 0.05% to about 1.2%, by weight of the composition, of colloidal silica; and

(g) from about 0.2% to about 1.2%, by weight of the composition, of sodium lauryl sulfate.

22. A method of treating a disease, disorder or condition associated with CXCR4 in a subject in need thereof, comprising administering to the subject an effective amount of the X4P-001 composition of any one of claims 1-16.

23. The method of claim 22, wherein the disease, disorder, or condition is a cancer selected from: renal cell carcinoma, RCC, or renal cancer; hepatocellular carcinoma HCC or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal carcinoma; colon cancer; rectal cancer; anal cancer; non-small cell lung cancer NSCLC; small cell lung cancer SCLC; epithelial carcinoma of the ovary; ovarian cancer; fallopian tube cancer; papillary serosa adenocarcinoma or uterine papillary serous carcinoma UPSC; prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary cancer; soft tissue sarcoma and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; ewing's sarcoma; undifferentiated thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma; pancreatic cancer; gastrointestinal/gastric GIST cancer; lymphoma; squamous cell carcinoma of the head and neck SCCHN; salivary gland cancer; glioma or brain cancer; neurofibroma-1 associated malignant peripheral nerve sheath tumor MPNST; waldenstrom's macroglobulinemia; or neural tube blastoma.

24. The method of claim 22, wherein the disease, disorder, or condition is a cancer selected from: advanced renal cell carcinoma, clear cell renal carcinoma ccRCC, papillary renal carcinoma, metastatic melanoma, or waldenstrom's macroglobulinemia.

25. The method of claim 22, wherein the disease, disorder, or condition is primary immunodeficiency.

26. The method of claim 22, wherein the disease, disorder or condition is selected from warts, hypogammaglobulinemia, infection, myeloagranulocytosis (WHIM) syndrome, severe congenital neutropenia SCN, GATA2 deficiency (single MAC syndrome), idiopathic CD4+ T lymphopenia ICL, or westkott-aldrich syndrome.

27. The method of claim 22, wherein the disease, disorder, or condition is WHIM syndrome.

28. The method of claim 22, wherein the disease, disorder, or condition is SCN.

Technical Field

The present invention relates to compounds that inhibit the type 4C-X-C receptor (CXCR 4). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional patent application No. 62,726,010 filed on 31/8/2018 and the priority of U.S. patent application No. 16/215,963 filed on 11/12/2018, each of which is incorporated herein by reference in its entirety.

Background

The type 4C-X-C chemokine receptor (CXCR4), also known as fusin or clade 184(CD184), is a seven-transmembrane G-protein coupled receptor (GPCR) belonging to the class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 plays multiple roles and is expressed primarily in the hematopoietic and immune systems. CXCR4 was initially found to be one of the co-receptors involved in the entry of Human Immunodeficiency Virus (HIV) into cells. Subsequent studies have shown that it is expressed in many tissues, including brain, thymus, lymphoid tissues, spleen, stomach, and small intestine, as well as in specific cell types, such as Hematopoietic Stem Cells (HSCs), mature lymphocytes, and fibroblasts. CXCL12, previously referred to as SDF-1 α, is the only known CXCR4 ligand. CXCR4 mediates stem cell migration during embryonic development and as a response to injury and inflammation. CXCR4 has been demonstrated to play multiple roles in human disease (e.g., cell proliferative disorder, Alzheimer's disease, HIV, rheumatoid arthritis, pulmonary fibrosis, etc.). For example, expression of CXCR4 and CXCL12 has been noted in several tumor types. CXCL12 is expressed by cancer-associated fibroblasts (CAF) and is often present at high levels in the Tumor Microenvironment (TME). In clinical studies of a wide variety of tumor types, including breast, ovarian, renal, lung and melanoma, expression of CXCR4/CXCL12 has been associated with poor prognosis and with increased risk of metastasis to lymph nodes, lung, liver and brain (CXCL12 expression site). CXCR4 is frequently expressed on melanoma cells, particularly on the CD133+ population considered to represent melanoma stem cells; CXCL12 has been shown to be chemotactic for such cells in vitro and in murine models.

In addition, there is evidence that the CXCL12/CXCR4 axis causes loss or loss of tumor response to angiogenesis inhibitors (also referred to as "angiogenesis evasion"). In animal cancer models, interference with CXCR4 function has been shown to alter TME and sensitize tumors to immune attack by multiple mechanisms (e.g., elimination of tumor revascularization and increased ratio of CD8+ T cells to Treg cells). These effects lead to a significant reduction in tumor burden and to an extension of the overall survival of xenograft, syngeneic and transgenic cancer models. See Wanhan nan Tower (Vanharantana) et al (2013) Nature & medicine (Nat Med) 19: 50-56; gal (Gale) and McColl (1999) bioanalysis (BioEssays) 21: 17-28; haifeil (Highfill) et al (2014) science transformation medicine (Sci Transl Med) 6: ra 67; facciabene et al (2011) Nature 475: 226-230.

These data highlight the unmet significant need for CXCR4 inhibitors for the treatment of a variety of diseases and conditions mediated by aberrant or undesired receptor expression (e.g., cell proliferative disorders).

Disclosure of Invention

It has now been found that the presently disclosed X4P-001 compositions and pharmaceutically acceptable compositions thereof are effective as inhibitors of CXC receptor type 4 (CXCR 4). In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

or a pharmaceutically acceptable salt thereof.

The X4P-001 compositions and pharmaceutically acceptable compositions thereof of the invention are useful for treating a variety of diseases, disorders, or conditions associated with CXCR4, such as hyperproliferative conditions, including a variety of cancers. Such diseases, disorders or conditions include those described herein.

Drawings

FIG. 1 shows a detailed summary of the manufacturing process of a capsule (unit dosage form) containing a solid pharmaceutical formulation of X4P-001.

FIG. 2 shows the flow of the original synthetic process (version 2 or Process 2) for the preparation of X4P-001 for clinical trials.

FIG. 3 shows a comparison of Process 3 (modified current synthesis) to Process 2 (original process) for the preparation of X4P-001.

Figure 4 shows a detailed comparison between the version 2 process and the version 3 process in terms of downstream continuous operations with respect to API processing and separation.

Figure 5 shows HPLC and MS data for X4P-001(PTL/ST/0511, batch 3-1 (prepared using process 2), 25 ℃/60% RH, t3 months). HPLC condition 1 (described in detail below); 1mg/mL in methanol, injection volume 100 u L.

Figure 6 shows HPLC and MS data for X4P-001(PTL/ST/0511, batch 3-1 (prepared using process 2), 25 ℃/60% RH, t3 months). HPLC condition 2 (described in detail below); 1mg/mL in methanol, injection volume 100 u L.

Figure 7 shows HPLC and MS data for X4P-001(PTL/ST/0511, batch 3-1 (prepared using process 2), 25 ℃/60% RH, t3 months). HPLC condition 2 (described in detail below); the sample concentration was 10mg/mL in methanol and 100. mu.L was injected.

Figure 8 shows HPLC and MS data for X4P-001 (degraded sample, 80 ℃/80% RH, t ═ 1 day). HPLC condition 2 (described in detail below); the sample concentration was 10mg/mL in methanol, 100. mu.L injection volume.

Figure 9 shows HPLC and MS data for X4P-001 (degraded sample, 80 ℃/80% RH, t ═ 7 days). HPLC condition 2 (described in detail below); the sample concentration was 10mg/mL in methanol, 100. mu.L injection volume.

Figure 10 shows HPLC and MS data for X4P-001(PTL/ST/0511, batch 3-1 (prepared using process 2), 25 ℃/60% RH, t3 months). HPLC condition 3 (described in detail below); the sample concentration was 10mg/mL in methanol, 100. mu.L injection volume.

Detailed Description

1.General description of certain aspects of the invention

In one aspect, the invention provides compounds and compositions thereof useful for treating, preventing, and/or reducing the risk of a disease, disorder, or condition in which CXCR4 is implicated. In some embodiments, such compounds include those of the formulae described herein or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides compositions, including formulations and unit dosage forms, comprising X4P-001 (i.e., a compound of formula I, the structure of which is shown below), or a pharmaceutically acceptable salt thereof, wherein such compositions exhibit an improved purity profile. In some embodiments, the disclosed X4P-001 composition has a reduced level of known impurities (e.g., those described herein) and/or a reduced level of unknown impurities as compared to a similar composition prepared in a conventional manner.

In another aspect, the invention provides a composition of X4P-001 comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

or a pharmaceutically acceptable salt thereof.

2.Definition of

The compounds of the present invention include those compounds described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to CAS version of the periodic Table of the elements (Handbook of Chemistry and Physics, 75 th edition). In addition, the general principles of Organic Chemistry are described in "Organic Chemistry" (Organic Chemistry), "Thomas Sorrell", University Science Books (University Science Books), Shaoshi (Sausaltito): 1999, and "March's Advanced Organic Chemistry" (5 th edition, ed., Smith M.B (Smith, M.B.) and March J. (March, J.), John Wiley parent-Press (John Wiley & Sons), New York: 2001, the entire contents of each of which are incorporated herein by reference.

As used herein, the term "X4P-001 composition" or "disclosed X4P-001 composition" refers to a composition comprising a compound of formula I (i.e., X4P-001) or a pharmaceutically acceptable salt thereof in combination with at least one other compound selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7. For clarity, the "pharmaceutical composition" of the disclosed X4P-001 composition refers to a composition comprising a compound of formula I (i.e., X4P-001) or a pharmaceutically acceptable salt thereof in combination with at least one other compound selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, and a pharmaceutically acceptable excipient, such as an adjuvant, filler, binder, carrier, or vehicle.

For the sake of clarity, and without wishing to be bound by theory, it is believed that compound I-1 exists at least partially in isomeric (e.g., tautomeric) forms; for example, it is believed that Compound I-1 undergoes the following interconversion to become the compound of structure I-1 a:

thus, it is understood that the single isomers of I-1 and I-1a as well as tautomers and other isomeric forms are within the scope of the invention.

Other known or unknown impurities may be present in the disclosed X4P-001 composition. As used herein, the term "impurities" includes one or more degradation products produced during the storage of X4P-001 and/or one or more byproducts formed in the chemical reaction used to make X4P-001. In some embodiments, the impurities result from oxidation, photoinitiated decomposition, reaction with residual solvents (e.g., water or isopropyl acetate), side reactions that occur during the process used to prepare X4P-001, or reaction of X4P-001 with excipients present in the X4P-001 pharmaceutical composition.

The term "inhibitor" as used herein is defined as a compound that binds to and/or inhibits CXCR4 with a measurable affinity. In certain embodiments, the inhibitor has an IC of less than about 100 μ M, less than about 50 μ M, less than about 1 μ M, less than about 500nM, less than about 100nM, less than about 10nM, or less than about 1nM₅₀And/or binding constants.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s.m. berge (s.m. berge) et al, in journal of medical science (j.pharmaceutical Sciences), 1977,66,1-19, describe in detail pharmaceutically acceptable salts, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of basic groups (e.g., amino groups) with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, besylate, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, laurates, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N⁺(C_1-4Alkyl radical)₄And (3) salt. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Other pharmaceutically acceptable salts include, where appropriate, those using, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, (C)_1-6Alkyl) sulfonates and arylsulfonates, and the like.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) isomer mixtures of the compounds of the present invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, "therapeutically effective amount" or "effective amount" means the amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and/or delay the onset of a disease, condition, or disorder when administered as part of a dosing regimen to a subject suffering from or susceptible to the disease, condition, or disorder. As will be appreciated by those skilled in the art, the effective amount of a substance may vary depending on factors such as the desired biological indicator, the substance to be delivered, the target cell or tissue, and the like. For example, an effective amount of a compound in a formulation for treating a disease, condition, or disorder is an amount that alleviates, ameliorates, alleviates, inhibits, prevents, delays onset, reduces the severity of, and/or reduces the incidence of one or more symptoms or features of the disease, condition, or disorder. In some embodiments, a "therapeutically effective amount" is at least the minimum amount of a compound or composition containing a compound sufficient to treat one or more symptoms of a disease or disorder.

As used herein, the terms "treat", "treating" and "treating" refer to partially or completely alleviating, inhibiting, delaying the onset of, preventing, ameliorating and/or alleviating a disease or disorder or one or more symptoms of a disease or disorder as described herein. In some embodiments, the treatment may be administered after one or more symptoms have occurred. In some embodiments, the term "treating" includes preventing or halting the progression of the disease or disorder. In other embodiments, the treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, e.g., to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence or recurrence of a disease or disorder.

As used herein, the term "CXCR 4 mediated" when referring to a disorder, disease, and/or condition means any disease, disorder, or condition for which CXCR4 or a mutant thereof is known to play a role. Thus, another embodiment of the invention relates to treating or lessening the severity of one or more diseases for which CXCR4 or a mutant thereof is known to play a role. "CXCR 4 mediated" also includes diseases, disorders, and conditions involving the CXCR4/CXCL12 axis.

As used herein, the term "unit dosage form" refers to a physically discrete unit of a therapeutic formulation suitable for the individual to be treated. It will be appreciated, however, that the total daily amount of the X4P-001 composition of the invention will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular individual or organism will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active agent employed; the particular composition employed; age, weight, general health, sex, and diet of the individual; the time of administration and rate of excretion of the particular active agent employed; the duration of treatment; drugs and/or other therapies used in combination or concomitantly with the particular compound employed, and similar factors well known in the medical arts.

3.Description of exemplary Compounds

It has now been found that the compounds of the present invention and compositions thereof are useful for treating, preventing and/or reducing the risk of diseases, disorders or conditions associated with CXCR4 or CXCR4 and its pathogenesis.

In one aspect, the present invention provides a composition comprising X4P-001 having a purity of at least 98.5%, or a pharmaceutically acceptable salt thereof. In some embodiments, X4P-001 in the composition has at least 98.5% purity and contains less than 1.5% w/w impurities. In some embodiments, the composition comprises X4P-001 or a pharmaceutically acceptable salt thereof in at least 98.6%, 98.7%, 98.8%, 98.9%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% purity.

In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and a detectable amount of at least one of the following compounds:

or a pharmaceutically acceptable salt thereof; and wherein the X4P-001 composition does not include a detectable amount of the following compound:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w/w of the X4P-001 composition.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w/w of the X4P-001 composition.

In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is from about 0.02 to about 0.5% w/w of the X4P-001 composition.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w/w of the X4P-001 composition.

In one aspect, the invention provides a pharmaceutical composition comprising the disclosed X4P-001 composition and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

In some embodiments, the pharmaceutically acceptable adjuvant comprises at least one diluent, disintegrant, lubricant, and glidant.

In another aspect, the invention provides an X4P-001 composition or a pharmaceutical composition thereof, wherein:

(a) the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w/w of the X4P-001 composition;

(b) the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w/w of the X4P-001 composition;

(c) the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition;

(d) the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition;

(e) wherein the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition; and is

(f) The amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w/w of the X4P-001 composition.

In one aspect, the invention provides an X4P-001 composition or a pharmaceutical composition thereof, wherein:

(a) the amount of I-1 or a pharmaceutically acceptable salt thereof is from about 0.02 to about 0.5% w/w of the X4P-001 composition;

(b) the amount of I-2 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.3% w/w of the X4P-001 composition;

(c) the amount of I-3 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition;

(d) the amount of I-5 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition;

(e) the amount of I-6 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition; and is

(f) The amount of I-7 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.25% w/w of the X4P-001 composition.

In one aspect, the present invention provides an X4P-001 composition, wherein:

(a) the amount of I-2 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(b) the amount of I-3 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(c) the amount of I-5 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.2% w/w of the X4P-001 composition;

(d) the amount of I-6 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.4% w/w of the X4P-001 composition; and is

(e) The amount of I-7 or a pharmaceutically acceptable salt thereof is from about 0.01 to about 0.25% w/w of the X4P-001 composition.

In some embodiments, the X4P-001 composition optionally further comprises I-1 or a pharmaceutically acceptable salt thereof in an amount of about 0.02 to about 0.5% w/w of the X4P-001 composition.

In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:

(a) from about 10% to about 20%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 70% to about 85%, by weight of the composition, of microcrystalline cellulose;

(d) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate; and

(e) from about 0.1% to about 1.0% by weight of the composition of colloidal silica.

In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:

(a) from about 35% to about 75%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 5% to about 28%, by weight of the composition, of microcrystalline cellulose;

(d) from about 2% to about 10%, by weight of the composition, of croscarmellose sodium;

(e) from about 0.3% to about 2.5%, by weight of the composition, of sodium stearyl fumarate;

(f) from about 0.05% to about 1.2%, by weight of the composition, of colloidal silica; and

(g) from about 0.2% to about 1.2%, by weight of the composition, of sodium lauryl sulfate.

In one aspect, the invention provides a method of treating, preventing, or reducing the risk of a disease, disorder, or condition associated with CXCR4 in an individual in need thereof, comprising administering to the individual an effective amount of a disclosed X4P-001 composition.

In some embodiments, the disease, disorder, or condition is a cancer selected from renal cancer, renal tumor, renal cancer, ovarian cancer, or melanoma.

In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a composition of X4P-001 comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and at least one compound selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and a compound of the structure:

or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of I-6 and any additional impurities present comprises no more than about 0.8% w/w in the X4P-001 composition.

In some embodiments, the X4P-001 composition comprises at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises two, three, or four compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of two, three, or four compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises three compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of three compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of each of I-1, I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and a detectable amount of at least one of the following compounds:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition does not include a detectable amount of the following compounds:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition does not include a detectable amount of the following compounds:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the total amount of I-6 or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% w/w of the X4P-001 composition, relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises no more than 0.15% w/w of I-6 relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

In some embodiments, the total amount of I-6 or a pharmaceutically acceptable salt thereof comprises no more than about 0.2% w/w of the X4P-001 composition, relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises no more than 0.15% w/w of I-6 relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the X4P-001 composition comprises at least a detectable amount of I-6 or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, together comprise less than about 3.0% w/w of the X4P-001 composition, relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, is present in the X4P-001 composition in at least a detectable amount. In some embodiments, the X4P-001 composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise the compound of formula I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In some embodiments, one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, together comprise less than about 3.0% w/w of the X4P-001 composition, relative to the total weight of the X4P-001 composition of a compound of formula I and one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, is present in the X4P-001 composition in at least a detectable amount. In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise any of compounds I-1 or I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In some embodiments, total organic impurities (including one or more compounds selected from I-2, I-3, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof) comprise less than about 4.0% w/w of the X4P-001 composition.

In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is less than about 0.5% w/w of the X4P-001 composition.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

In some embodiments, the X4P-001 composition does not include a detectable amount of I-4 or a pharmaceutically acceptable salt thereof.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.07% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is less than about 0.25% w/w of the X4P-001 composition.

In some embodiments, I-1, I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, is present in the X4P-001 composition in at least a detectable amount.

In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is from about 0.02 to about 0.5% w/w of the X4P-001 composition.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.3% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.07% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.4% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7 or a pharmaceutically acceptable salt thereof is about 0.01 to about 0.25% w/w of the X4P-001 composition.

In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof in at least 99.3% purity (by HPLC) and comprises less than 0.7% (as measured by HPLC) of the total additional compounds selected from I-1, I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional compounds are present in at least a detectable amount.

In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof in at least 99.3% purity (by HPLC) and comprises less than 0.7% (as measured by HPLC) of the total additional compounds selected from I-2, I-3, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more additional compounds are present in at least a detectable amount. In some embodiments, each of I-2, I-3, I-5, I-6, and I-7, or a pharmaceutically acceptable salt thereof, is present in at least a detectable amount (as measured by HPLC).

In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, and one or more compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.3% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w/w of the X4P-001 composition; or

Or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.25% w/w of the X4P-001 composition; wherein each% w/w is measured relative to the total weight of the X4P-001 composition of the compound of formula I and one or more compounds selected from I-1, I-2, I-3, I-5, I-6 or I-7. In some embodiments, the X4P-001 composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise the compound of formula I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In one aspect, the present invention provides X4P-001 compositions comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, and one or more compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.3% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.5% w/w of the X4P-001 composition;

or a pharmaceutically acceptable salt thereof, in an amount not exceeding about 0.4% w/w of the X4P-001 composition; or

In some embodiments, the chiral purity of the X4P-001 composition is at least about 97% enantiomeric excess (% ee).

In some embodiments, the X4P-001 composition comprises 7000, 6000, 5000, 4500, 4000, 3500, 3000, 2500, 2000, 1750, 1700, 1650, 1600, 1550, 1500, 1450, 1400, or 1350ppm or less of toluene.

In some embodiments, toluene is used as the crystallization solvent for the separation of X4P-001. In certain embodiments, the specification for residual toluene in the X4P-001 free base is that the X4P-001 composition comprises no more than 4500 ppm. In other embodiments, the X4P-001 composition comprises no more than 4000ppm, 3500ppm, 3000ppm, 2500ppm, 2000ppm, 1750ppm, 1700ppm, 1650ppm, 1600ppm, 1550ppm, 1500ppm, 1450ppm, 1400ppm, or 1350ppm of toluene. In some embodiments, a Permissible Daily Exposure (PDE) method is used. The term allowable daily exposure (PDE) is defined as the pharmaceutically acceptable uptake of residual solvent in the drug. See, for example, the Department of Health and Human Services (Department of Health and Human Services), Food and Drug Administration (FDA) published "guide to industry: impurity Q3C: residual solvent (guidelines for Industry: Q3 samples: Residual Solvents).

In some embodiments, the% purity of the X4P-001 composition decreases by less than 1% when the X4P-001 composition is stored at 25 ℃/60% relative humidity for three months as measured by HPLC.

In some embodiments, the X4P-001 composition further comprises one or more of the following:

and wherein compounds I-8, I-9, I-10, and/or I-11 are present in an amount of less than about 25 parts per million (ppm) of the X4P-001 composition.

In some embodiments, compounds I-8, I-9, I-10, and/or I-11 are present in an amount less than about 50, 40, 30, 20, 15, 10, 5, 4,3, 2, or 1ppm of the X4P-001 composition. In some embodiments, compounds I-8, I-9, I-10, and/or I-11 are each independently present in an amount between about 1ppm and about 25ppm or between about 100 parts per billion (ppb) and 4 ppm. In some embodiments, the X4P-001 composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise the compound of formula I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In one aspect, the invention provides a pharmaceutical composition comprising the disclosed X4P-001 composition and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

In one aspect, the invention provides a solid unit dosage form for oral formulation comprising the disclosed X4P-001 composition or pharmaceutical composition.

In some embodiments, the present invention provides a combination of the disclosed X4P-001 composition with another therapeutic agent.

In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:

(a) from about 10% to about 20%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 70% to about 85%, by weight of the composition, of microcrystalline cellulose;

(d) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate; and

(e) from about 0.1% to about 1.0% by weight of the composition of colloidal silica.

In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:

(a) from about 30% to about 40%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 20% to about 25%, by weight of the composition, of microcrystalline cellulose;

(d) from about 5% to about 10%, by weight of the composition, of croscarmellose sodium;

(e) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate;

(f) from about 0.1% to about 1.0%, by weight of the composition, of colloidal silica; and

(g) from about 0.1% to about 1.0%, by weight of the composition, of sodium lauryl sulfate.

In another aspect, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising:

(a) from about 35% to about 75%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 5% to about 28%, by weight of the composition, of microcrystalline cellulose;

(d) from about 2% to about 10%, by weight of the composition, of croscarmellose sodium;

(e) from about 0.3% to about 2.5%, by weight of the composition, of sodium stearyl fumarate;

(f) from about 0.05% to about 1.2%, by weight of the composition, of colloidal silica; and

(g) from about 0.2% to about 1.2%, by weight of the composition, of sodium lauryl sulfate.

In some embodiments, the unit dosage form is in the form of a capsule.

In some embodiments, the capsule comprises about 25mg, about 100mg, or about 200mg of X4P-001, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of treating, preventing, or reducing the risk of a disease, disorder, or condition associated with CXCR4 in a subject in need thereof, comprising administering to the subject the disclosed X4P-001 composition.

In some embodiments, the disease, disorder, or condition is cancer.

In some embodiments, the cancer is selected from renal cancer, renal tumor, renal cancer (including clear cell carcinoma and papillary renal cancer), ovarian cancer, or melanoma.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and one additional compound selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and two other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and three additional compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and four other compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise the compound of formula I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In some embodiments, the one or more additional compounds are present in at least a detectable amount.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and each of I-1, I-2, I-3, I-4, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and one additional compound selected from I-2, I-3, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and two other compounds selected from I-2, I-3, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and three additional compounds selected from I-2, I-3, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and four other compounds selected from I-2, I-3, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and does not comprise a compound of formulae I-1 and I-4 or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In some embodiments, the one or more additional compounds are present in at least a detectable amount.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and each of I-2, I-3, I-5, I-6, and I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition includes a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-2, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-3, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-4, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-5, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-6, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and I-7, or a pharmaceutically acceptable salt thereof.

In some embodiments, the X4P-001 composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof; and I-1, I-2, I-3, I-4, I-5, I-6 and I-7; or a pharmaceutically acceptable salt thereof.

In some embodiments, the% w/w amount of a compound in the disclosed X4P-001 composition is measured by comparing the area percent of the compound in an HPLC chromatogram to any other compound present in the X4P-001 composition. For example, if measured in this manner, the presence of 0.2% w/w of compound I-6 in a composition of X4P-001 comprising I-6 and a compound of formula I means that the composition contains 0.2% (peak area%) of I-6 and 99.8% (peak area%) of a compound of formula I according to HPLC. In other embodiments, the% w/w is measured using another means known to one of ordinary skill in the art (such as those described herein).

In one aspect, the present invention provides a method of making the disclosed X4P-001 composition, wherein the composition is prepared substantially as described in the examples and figures herein.

In another aspect, the present invention provides a compound selected from those depicted in table 1 below.

Table 1: representative Compounds of the invention

In some embodiments, the present invention provides a compound depicted in table 1 above, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one compound depicted in table 1 above, or a pharmaceutically acceptable salt thereof. The composition may comprise 1, 2,3, 4,5, 6 or 7 of said compounds. In some embodiments, the composition does not comprise a detectable amount of compound I-4. In some embodiments, the composition does not comprise a detectable amount of compound I-1. In some embodiments, the composition does not contain a detectable amount of compounds I-1 and I-4.

In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, is present in an X4P-001 composition in an amount of at least about 96, 97, 97.5, 98, 98.5, 98.7, 98.9, 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.75, 99.8, 99.85, 99.9, 99.95, 99.97, or 99.999 weight percent, wherein the percentages are based on the total weight of the free base of the compound and the X4P-001 composition. In other embodiments, the X4P-001 composition contains no more than about 2.0 area% HPLC total organic impurities, or in other embodiments, no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1, 0.75, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area% HPLC total organic impurities, relative to the total area of the HPLC chromatogram.

In other embodiments, the X4P-001 composition contains no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1, 0.75, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area% (as measured by HPLC) of compounds I-1, I-2, I-3, I-4, I-5, I-6, and I-7 relative to the total area of the HPLC chromatogram.

In other embodiments, the X4P-001 composition comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more additional compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7; or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the X4P-001 composition contains a compound of formula I, or a pharmaceutically acceptable salt thereof, in an amount from about 1% to about 99% by weight, wherein the percentages are based on the free base of the compound and the total weight of the X4P-001 composition. In other embodiments, the X4P-001 composition contains no more than about 2.0 area% HPLC total organic impurities, or in other embodiments, no more than about 5.0, 4.0, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.25, 1.1, 1.05, 1, 0.95, 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.25, 0.2, 0.1, 0.01, 0.005, or 0.001 area% HPLC total organic impurities, relative to the total area of the HPLC chromatogram.

In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, collectively or individually, comprise about 0.01 to 0.20 area% of the HPLC chromatogram with respect to a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, collectively or individually, comprise about 0.02 to 0.18, 0.03 to 0.16, 0.05 to 0.15, 0.075 to 0.13, 0.09 to 0.1, 0.1 to 0.2, or 0.15 to 0.2 area% of the HPLC chromatogram relative to a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the above area percentages of the HPLC chromatogram are measured relative to the total area of the HPLC chromatogram, and not relative to the peak area of the compound of formula I, or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, collectively or individually, comprise less than about 5.0 weight percent (% w/w) or about 0.01-5.0% w/w relative to a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or a pharmaceutically acceptable salt thereof, collectively or individually comprise less than about 3.0% w/w of the X4P-001 composition; or about 0.02-4.0, 0.03-3.5, 0.05-3.1, 0.05-2.9, 0.05-2.5, 0.05-2.0, 0.05-1.8, 0.05-1.6, 0.05-1.5, 0.05-1.4, 0.05-1.2, 0.05-1.1, 0.05-1.0, 0.05-0.9, 0.05-0.8, 0.05-0.7, 0.05-0.6, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1, or about 0.1-0.5% w/w of the X4P-001 composition.

In some embodiments, total organic impurities (including one or more compounds selected from I-1, I-2, I-3, I-4, I-5, I-6, or I-7, or pharmaceutically acceptable salts thereof) comprise less than about 0.05% w/w, about 0.1, 0.5, 1.0, 2.0, 3.0, or about 4.0% w/w or less of the X4P-001 composition. In some embodiments, the total organic impurities comprise about 0.02-4.0, 0.03-3.5, 0.05-3.1, 0.05-2.9, 0.05-2.5, 0.05-2.0, 0.05-1.8, 0.05-1.6, 0.05-1.5, 0.05-1.4, 0.05-1.2, 0.05-1.1, 0.05-1.0, 0.05-0.9, 0.05-0.8, 0.05-0.7, 0.05-0.6, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1, or about 0.1-0.5% w/w of the X4P-001 composition.

In some embodiments, the amount of I-1, or a pharmaceutically acceptable salt thereof, is less than about 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P001 composition. In some embodiments, I-1 or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is less than about 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is less than about 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition.

In some embodiments, the amount of I-4 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition. In some embodiments, I-4 or a pharmaceutically acceptable salt thereof is undetectable.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7, or a pharmaceutically acceptable salt thereof, is less than about 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% w/w of the X4P-001 composition.

In some embodiments, the amount of I-1 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 1.1%, from about 0.01 to about 0.8%, from 0.01 to about 0.7%, from about 0.01 to about 0.6%, from 0.01 to about 0.5%, from 0.01 to about 0.4%, from 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-2 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 0.3%, from about 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-3 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 0.4%, from about 0.01 to about 0.4%, from 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-4 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 0.5%, from about 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-5 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 0.5%, from about 0.01 to about 0.5%, from 0.01 to about 0.4%, from 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-6 or a pharmaceutically acceptable salt thereof is from about 0.001 to about 0.5%, from about 0.01 to about 0.4%, from about 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of I-7, or a pharmaceutically acceptable salt thereof, is from about 0.001 to about 0.5%, from about 0.01 to about 0.4%, from about 0.01 to about 0.3%, from 0.01 to about 0.2%, from 0.01 to about 0.1%, from 0.01 to about 0.09%, from 0.01 to about 0.08%, from 0.01 to about 0.07%, from 0.01 to about 0.06%, from 0.01 to about 0.05%, from 0.01 to about 0.03%, or from 0.01 to about 0.02% w/w of the X4P-001 composition.

In some embodiments, the amount of any additional or unknown impurity in the X4P-001 composition is from about 0.01 to about 0.2% w/w of the composition.

In some embodiments, the amount of parahydroxybenzoic acid present in the X4P-001 composition is from about 0.01 to about 0.5% w/w of the composition. In some embodiments, the composition is substantially free of parahydroxybenzoic acid. In some embodiments, no detectable amount of parahydroxybenzoic acid is present in the composition. In some embodiments, the X4P-001 composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, and does not comprise the compound of formula I-4, or a pharmaceutically acceptable salt thereof, in terms of detectable amounts.

In some embodiments, the chiral purity of the X4P-001 composition is at least about 97% enantiomeric excess (% ee). In some embodiments, the chiral purity of the compound of formula I is at least 97% ee. In some embodiments, the chiral purity of the compound of formula I is at least 98% ee. In some embodiments, the chiral purity of the compound of formula I is at least 99% ee. In some embodiments, the chiral purity of the compound of formula I is at least 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% ee.

In some embodiments, the present invention provides isolated forms of any of the compounds described above and herein. The term "sequestered" as used herein means to provide a compound in a form that is separated from other components that may be present in the common environment of the compound. In certain embodiments, the isolated compound is in solid form. In some embodiments, the isolated compound has at least about 50% purity, as determined by a suitable HPLC method. In certain embodiments, the isolated compound has at least about 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.95%, 99.99%, or 99.999% purity as determined by a suitable HPLC method. Percent purity can be measured as weight percent of the desired compound (w/w%), as area% relative to the total area of the HPLC chromatogram, or by other methods known in the art.

Methods for the preparation and analysis of certain compounds suitable for use in the present invention are disclosed in US7,354,934, WO 00/56729, USSN60/232,891 and USSN 60/234,510 and ann H. (An, H.); king T. (Wang, T.); mohan, V.); griffey r.h. (r.h.); cook P.D (Cook, P.D.) 1998,54, 3999-4012; each of which is incorporated herein by reference in its entirety.

The disclosed compounds can be purified by any means known in the art. Such means include, for example, silica gel column chromatography; medium Pressure Liquid Chromatography (MPLC); high Pressure Liquid Chromatography (HPLC); preparative HPLC (prep-HPLC); flash Chromatography (FC); liquid Chromatography (LC); supercritical Fluid Chromatography (SFC); thin Layer Chromatography (TLC); preparative TLC (prep-TLC); liquid chromatography-mass spectrometry (LC-MS, LCMS or LC/MS); recrystallizing; precipitating; grinding; distilling; derivatization; acid-base extraction, and the like.

For compounds, the terms "purified", "purified form" or "isolated and purified form" refer to the physical state of the compound after isolation from a synthetic process (e.g., from a reaction mixture) or natural source, or a combination thereof. Thus, for a compound, the terms "purified," "purified form," or "isolated and purified form" refer to the physical state of the compound (or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of the compound, the stereoisomer, or the tautomer) after having been obtained from a purification process or a process described herein or well known to those skilled in the art (e.g., chromatography, recrystallization, etc.), the compound having sufficient purity to be suitable for in vivo or pharmaceutical use and/or being characterizable by standard analytical techniques described herein or well known to those skilled in the art.

As used herein, the term "detectable amount" means that a component present in a sample (e.g., a sample of the disclosed X4P-001 composition) is present in an amount that is at least detectable by analytical means known in the art. For example, in some embodiments, a "detectable amount" is an amount that is detectable at least by HPLC, LC-MS, mass spectrometry, NMR, or other analytical methods known to those skilled in the art or described herein.

Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting mixtures of enantiomers into mixtures of diastereomers with appropriate optically active compounds, for example chiral adjuvants, such as chiral alcohols or Mosher's acid chloride, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

4.Use, formulation and administration

Pharmaceutically acceptable compositions

In one aspect, the invention provides an X4P-001 composition comprising a disclosed compound, a pharmaceutically acceptable salt, or a pharmaceutically acceptable derivative; or the disclosed X4P-001 composition; and a pharmaceutically acceptable excipient, carrier, adjuvant or vehicle. The amount of compound in the compositions of the invention is effective to produce a measurable inhibition of CXCR4 or a mutant thereof in a biological sample or patient. In certain embodiments, the amount of compound in the compositions of the invention is effective to produce a measurable inhibition of CXCR4 or a mutant thereof in a biological sample or patient. In certain embodiments, the compositions of the present invention are formulated for administration to a patient in need of such compositions. In some embodiments, the compositions of the present invention are formulated for oral administration to a patient.

As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat.

By "pharmaceutically acceptable derivative" is meant any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof having inhibitory activity.

As used herein, the term "metabolites or residues thereof having inhibitory activity" means metabolites or residues thereof which are also inhibitors of CXCR4 or mutants thereof.

The compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (e.g., oleic acid and its glyceride derivatives) are suitable for the preparation of injectables, as are pharmaceutically-acceptable natural oils (e.g., olive oil or castor oil, especially in their polyoxyethylated versions). These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. The materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical administration, including diseases of the eye, skin or lower intestinal tract. Topical formulations suitable for each of these areas or organs are readily prepared.

Topical administration to the lower intestinal tract may be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical transdermal patches may also be used.

For topical administration, the provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in pH adjusted isotonic sterile saline or, preferably, as solutions in pH adjusted isotonic sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The pharmaceutically acceptable compositions of the present invention are most preferably formulated for oral administration. Such formulations may be administered in the presence or absence of a food product. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the absence of food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the presence of food.

The amount of a compound of the invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dose of between 0.01-100 mg/kg body weight/day of inhibitor can be administered to a patient receiving these compositions.

It will also be understood that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease undergoing therapy. The amount of the compound of the present invention in the composition will also depend on the particular compound in the composition.

The compounds and compositions according to the methods of the invention can be administered in any amount and by any route of administration effective to treat or reduce the severity of cancer, an autoimmune disorder, a primary immunodeficiency, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, a liver disease, or a cardiac disorder. The exact amount required will vary from individual to individual, depending on the species, age, and general condition of the individual, the severity of the infection, the particular agent, its mode of administration, and the like. In some embodiments, the compounds of the present invention are formulated in unit dosage forms that are easy to administer and are uniform in dosage.

As used herein, the term "patient" or "individual" means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, orally, or nasally, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally, one or more times a day, at dosage levels of from about 0.01 mg to about 50mg, or for example from about 1mg to about 25mg, per kg of body weight of the individual per day, to achieve the desired therapeutic effect.

Oral liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable vehicles and solvents that can be employed are water, ringer's solution (u.s.p.), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (e.g., cocoa butter, polyethylene glycol); or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with: at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retarders, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. It may optionally contain an opacifying agent and may also have a composition such that it releases only or preferentially the active ingredient, optionally in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). Such dosage forms may also contain, as is normal practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. It may optionally contain an opacifying agent and may also have a composition such that it releases only or preferentially the active ingredient, optionally in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. The dosage form may be manufactured by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

In certain embodiments, the composition is formulated for oral administration in the form of a tablet or capsule. In some embodiments, the composition comprising X4P-001 is formulated for oral administration in capsule form.

In certain embodiments, the provided methods comprise administering to a patient one or more capsules comprising 10mg to 1200mg of X4P-001 active ingredient and one or more pharmaceutically acceptable excipients. In certain embodiments, the capsule comprises hard gelatin.

In certain embodiments, the present invention provides a pharmaceutical composition comprising an X4P-001 composition, one or more diluents, disintegrants, lubricants, glidants, and wetting agents. In some embodiments, the present invention provides a pharmaceutical composition comprising 10mg to 1200mg of X4P-001 composition, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate. In some embodiments, the present invention provides a unit dosage form, wherein the unit dosage form comprises a pharmaceutical composition comprising 10-200mg X4P-001 composition, microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide, and sodium lauryl sulfate. In certain embodiments, the present invention provides a unit dosage form comprising a pharmaceutical composition comprising X4P-001 present in an amount of about 10mg, about 20mg, about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 400mg, about 450mg, about 500mg, about 600mg, about 700mg, about 750mg, about 800mg, about 900mg, about 1000mg, about 1100mg, or about 1200 mg. In some embodiments, a provided composition (or unit dosage form) is administered to a patient once a day, twice a day, three times a day, or four times a day. In some embodiments, a provided composition (or unit dosage form) is administered to a patient once a day or twice a day.

In some embodiments, the present invention provides a pharmaceutical composition comprising:

(a) from about 30% to about 40%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 20% to about 25%, by weight of the composition, of microcrystalline cellulose;

(d) from about 5% to about 10%, by weight of the composition, of croscarmellose sodium;

(e) from about 0.5% to about 2%, by weight of the composition, of sodium stearyl fumarate;

(f) from about 0.1% to about 1.0%, by weight of the composition, of colloidal silica; and

(g) from about 0.1% to about 1.0%, by weight of the composition, of sodium lauryl sulfate.

In some embodiments, the present invention provides a pharmaceutical composition comprising:

(a) from about 8% to about 25%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 65% to about 85%, by weight of the composition, of microcrystalline cellulose;

(d) from about 0.1% to about 3%, by weight of the composition, of sodium stearyl fumarate; and

(e) from about 0.05% to about 0.7%, by weight of the composition, of colloidal silica.

In some embodiments, the present invention provides a pharmaceutical composition comprising:

(a) from about 25% to 45%, by weight of the composition, of the disclosed X4P-001 composition;

(b) from about 10% to about 35%, by weight of the composition, of microcrystalline cellulose;