VLA4 inhibitor and its use

Abstract

The present disclosure provides therapeutic agents comprising VLA-4 (α4β1) and α4β? inhibitors as defined herein. Methods of using the therapeutic agents are also provided. The present disclosure further provides combinations of VLA-4 inhibitors with one or more agents that interact with one or more chemokine receptors, and methods of using the same. In some embodiments, the disclosed combinations can be used in methods of mobilizing hematopoietic stem cells. In some embodiments, the disclosed methods can be used in the treatment of conditions that require collection of hematopoietic stem cells for transfusion or in chemotherapy. The present disclosure further provides methods of treating a patient comprising administering an agent that interacts with a chemokine, such as G-CSF, plerixafor, BL-8040 (motixafortide), or Crop and a VLA-4 inhibitor.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 353,947, filed on June 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] Statement Regarding Federally Sponsored Research or Development Not applicable.

[0003] Materials Incorporated by Reference Not applicable.

[0004] This disclosure relates to the fields of medicine, medical science, and cell biology. More specifically, it relates to pharmaceuticals that are useful as antagonists (i.e., inhibitors) of one or more integrins, such as integrin α4β1 (VLA - 4), which, when used alone or in combination with other known agents, can mobilize hematopoietic stem cells (HSCs) into the peripheral blood to enhance the collection of hematopoietic stem cells from donors.

Background Art

[0005] Hematopoietic stem cell transplantation (HSCT) is a major curative therapy available for many blood diseases, including blood cancers, and more recently, is available in gene therapy for blood - borne diseases caused by genetic mutations such as sickle cell disease. In this technique, HSCT promotes the repopulation of healthy bone marrow and immune system cells after high - dose chemotherapy treatment of cancers, including but not limited to Hodgkin lymphoma and non - Hodgkin lymphoma, multiple myeloma, and leukemia, or, in the case of gene therapy, is used to repopulate with ex vivo genetically modified cells that correct disease gene deficiencies. To facilitate transplantation when cells are needed, hematopoietic stem cell / progenitor cells (HSPCs) are collected, recovered, frozen from the patient's blood, and then stored while the patient is undergoing high - dose chemotherapy and / or radiation therapy. For a successful transplantation, often a minimum of 2×10 6Intravenous injection of 6 CD34+ stem cells per kg body weight is required. However, for early and long-term multi-lineage engraftment, a dose of 5×10

[0006] CD34+ cells / kg is considered preferable.Currently, stem cells for hematopoietic stem cell transplantation are often collected from peripheral blood. Since the amount of these cells in circulating peripheral blood is low, the stem cells often have to be stimulated to increase their amount in the peripheral blood. This is a process that can take nearly a week using current therapeutic agents. Still, the collection is carried out over several days to achieve a sufficient concentration of stem cells for transplantation. This significantly increases the cost of transplantation and places a great burden on the patient or donor. Currently, cytokines such as granulocyte colony-stimulating factor (G-CSF) and immunostimulants such as plerixafor are used to increase the amount of hematopoietic stem cells in peripheral blood, but single agents often result in insufficient mobilization of stem cells. Additional methods for collecting hematopoietic stem cells have been developed, which involve combining G-CSF with multiple other agents such as plerixafor or another cytokine. Unfortunately, this treatment regimen can take 5 to 8 days if G-CSF is administered daily, and even with these combination therapies, even with these multiple days of apheresis, in many patients, the concentration cannot be increased to a sufficient level for transplantation. This results in excessive costs and time-consuming constraints. Furthermore, G-CSF often has undesirable side effects and is contraindicated in some individuals such as those with sickle cell disease. Therefore, there is still a need for a better method for collecting hematopoietic stem cells, preferably a method that can rapidly mobilize these stem cells and has the ability to collect a sufficient amount within 6 to 8 hours in one day after administering a single dose of a mobilizing agent. Additionally, gene editing using techniques such as CRISPR also requires sufficient hematopoietic stem cells to perform gene editing before injecting them into the patient as a means to treat and potentially cure blood diseases caused by genetic mutations. A more efficient and timely method for mobilizing and collecting these stem cells for such gene therapies would be desirable. And, as mentioned above, some pathologies suitable for gene therapies such as sickle cell disease cannot use G-CSG as a mobilizing agent, thereby necessitating the need for new powerful and suitable drugs to address these procedures.

[0007] Small molecule inhibitors of integrin α4β1 (VLA-4) have been shown to rapidly mobilize HSCs in mice after single administration (Christopher et al., Blood. 2009;114(7):1331-9; Ramirez et al. Blood. 2009;114(7):1340-3). This mobilizing effect has also been shown to be synergistic when administered in combination with CXCR4 inhibitors such as plerixafor (Ramirez et al. Blood. 2009;114(7):1340-3). Previous small molecule inhibitors of VLA-4 reported in the literature have been shown to be highly insoluble, lack sufficient inhibition of VLA-4, and / or have poor pharmacokinetic properties in mice, resulting in a significant but short-term effect on HSPC mobilization. Most more potent VLA-4 inhibitors provided rapid and significant HSPC mobilization that peaked at 2 hours after administration, but the mobilization returned to baseline at 4 hours, not long enough to collect a sufficient number of HSPCs. Therefore, it is desirable to have a potent mobilizing agent that rapidly mobilizes and can extend this mobilization beyond 4 hours after single administration. Such an agent with these long-term mobilizing properties would enable collection of a sufficient number of HSPCs from a donor within one day.

[0008] Potent VLA-4 inhibitors that are readily soluble in saline, have desirable pharmacokinetic properties, and result in significant and long-term mobilization of HSPCs that persists for at least 6 hours after single-dose administration have now been identified and are disclosed herein. Furthermore, this HSPC mobilizing effect is synergistic when co-administered with a single dose of a CXCR4 inhibitor, such as, but not limited to, plerixafor or motixafortide, and / or a CXCR2 chemokine agonist. The ability of these novel inhibitors to achieve sufficient mobilization and collection of HSPCs from a donor within one day will greatly contribute to a more efficient and cost-effective method for collecting HSPCs for stem cell transplantation and gene therapy. SUMMARY OF THE INVENTION

[0009] Among various aspects of the present disclosure, there is provided a novel VLA-4 composition, a combination therapy using a chemokine interaction agent, or a method of using the same. The present disclosure provides a compound, a pharmaceutical composition, a method for producing them, or a method of using them, which is an a4b1 (VLA-4) or a4b7 antagonist (i.e., inhibitor). The present disclosure provides a method of using a compound that is a VLA-4 antagonist in combination with an agent that inhibits the CXCR4 receptor and / or a CXCR2 agonist or a similar cytokine agent (including methods of using them or treatment methods using them). Also provided herein are compositions containing these novel a4b1 (VLA-4) or a4b7 antagonists. The present disclosure provides a method of using a compound containing a VLA-4 antagonist in combination with a first or second agent that interacts with a chemokine (such as a CXCR2 agonist or a CXCR4 inhibitor) (including methods of using them or treatment methods using them). Also provided herein are compositions containing these compounds.

[0010] Aspects of the present disclosure are of the formula:

Chemical formula

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Chemical Formula

Chemical Formula

Chemical formula

Chemical formula

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Chemical formula

[0011] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description, examples, and the supporting biological data, particularly from the unexpected ability of the compounds described herein to enable long-term mobilization of HSPC after a single administration. However, it should be understood that various changes and modifications within the spirit and scope of the present disclosure will be apparent to those skilled in the art from the detailed description, and thus this detailed description and specific examples are presented by way of illustration only and not limitation. It should be noted that simply because a particular compound is assigned to one particular general formula does not mean that the compound cannot also belong to another general formula.

[0012] Those skilled in the art will understand that the drawings described below are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

Brief Description of the Drawings

[0013]

Figure 1A

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Mode for Carrying Out the Invention

[0014] The present disclosure is based, at least in part, on the unexpected and surprising discovery that a defined length of polyethylene glycol (PEG) units covalently and specifically bound to the disclosed chemical structures (as shown in Examples 1-19, for example, see Table 1) provides excellent and significantly extended mobilization of hematopoietic stem cells into the peripheral blood after administration of a single subcutaneous dose, compared to similar chemical structures (as shown in Comparative Compounds 1-22, for example, see Table 2) that do not have such specific structural attributes. Further, these specific PEG compounds disclosed herein maintain high potency as inhibitors of VLA4 (α4β1) and α4β7, and also provide excellent solubility in pure saline.

[0015] The present disclosure involves two main core structures, the "dichlorophenylsulfonamide core" represented by Example 1 and the "dichlorobenzoic acid core" represented by Example 9. The PEG groups of different lengths mentioned above are covalently bonded to each core via a linker at specific attachment points on the terminal phenyl group, as shown in Examples 1 and 9. As shown in and described in detail in the HSPC mobilization section of Exemplary Embodiment 2 (see, for example, FIGS. 11 - 25), simply attaching PEG chains of any type or length to these core structures is not sufficient to achieve the desired long-term mobilization of HSPC at high levels for more than 4 hours. In the case of the "dichlorophenylsulfonamide core", as represented in Examples 1, 2, 4, 5, 6, 7, and 8, at least 24 PEG units of m-PEG chains are required for excellent rapid and long-term mobilization for at least 6 hours after a single-dose administration. This is in contrast to non-PEG chains or PEG chains of less than 24 PEG units, as represented by Comparative Compounds C5 - 8, C12 - 14, and C16. As demonstrated, PEG lengths of 4, 8, 12, and 16 PEG units do not extend mobilization for more than 4 hours compared to the claimed patent objects having a PEG length of 24 PEG units or more. Based on this data, it is clear that more than 16 PEG units are required for long-term mobilization. Due to the limited availability of reagents with specific PEG units required for the synthesis of these compounds, specific PEG lengths of 17 - 23 PEG units were not readily available. Therefore, clear and long-term HSPC mobilization is somewhere between 16 - 24 PEG units such that it directly correlates with a specific PEG length. However, the claimed minimum of 24 PEG units required for robust and reproducible long-term HSPC mobilization for the "dichlorophenylsulfonamide core" (represented as n = 19 - 1000 in the formula section) can be assumed as a reasonable minimum PEG length to achieve the desired long-term HSPC mobilization effect for this core. Furthermore, as demonstrated by Comparative Compounds C15 and C21, attaching any PEG functional group, even if more than 24 PEG units, does not guarantee long-term or more significant mobilization, emphasizing the non-obvious nature of the claims and examples disclosed herein.This non-obviousness is further illustrated by the bis “dichlorophenylsulfonamide core” separated by the 10KD PEG linker of Example 11. This, quite surprisingly and unexpectedly, extends mobilization up to 24 hours. To further emphasize the non-obvious nature of the disclosed claims, the context in which the PEG chains are attached to the core structure is demonstrated by Example 3 and Comparative Compounds C9 and C10. Example 3 utilizes the facile synthesis enabled by “click” chemistry to attach an azide chain of 24 PEG units to an acetylene functional group on the core structure, forming a triazole of 24 PEG units coupled to the “dichlorophenylsulfonamide core” via a 3-unit PEG linker. Example 3 provides a long-term mobilization of over 4 hours. In contrast, C9, which has the same 24 PEG unit triazole attached to the “dichlorophenylsulfonamide core” via a linker shorter than that of Example 3, and C10, which has a 36 PEG unit triazole, demonstrate inferior mobilization at 4 hours compared to Example 3, as shown in Figure 4 of the mobilization data section. Further, C11, which is a 24 PEG unit attached to a cleaved “dichlorophenylsulfonamide core”, provides no mobilization at any time point, and the long PEG chain itself does not mobilize HSPCs, demonstrating that the excellent long-term mobilization of HSPCs depends on the entire structure of the disclosed materials consisting of a core structure covalently bonded to a PEG group, as defined and described in the claims.

[0016] To further illustrate the non-obviousness of the claimed subject matter of the disclosed technology, as in Example 1, the minimum PEG chain length required for long-term mobilization attached to a "dichlorophenylsulfonamide core" does not correlate with the minimum PEG chain length required for long-term mobilization when attached to a "dichlorobenzoic acid core". Even 24 PEG units (Comparative Compound C17), 2KD PEG (Comparative Compound C19), and 5KD PEG (Comparative Compound C20) attached to a "dichlorobenzoic acid core" do not provide long-term mobilization. In the case of the "dichlorobenzoic acid core", as shown in FIGS. 18, 24, and 25, 10KD PEG (Example 12), 20KD PEG (Example 9), and 40KD PEG (Example 10) are required for long-term mobilization, all providing excellent mobilization exceeding 6 hours and, in Examples 9 and 10, up to 24 hours of mobilization. Similar to the "dichlorophenylsulfonamide core", due to the limited availability of reagents of specific PEG lengths, from the disclosed data represented by Examples 9, 10, and 12, and Comparative Compounds 17, 19, and 20, robust and long-term HSPC mobilization for the "dichlorobenzoic acid core" requires a PEG length greater than 5KD MW (about 110 PEG units, Comparative Compound 20), reasonably either within 5 - 10KD, but at least 10KD (corresponding to n = 222 - 1000 PEG units in the formula section of the "dichlorobenzoic acid core") can be assumed as a reasonable minimum PEG length to achieve the desired robust and long-term HSPC mobilization effect for this core.

[0017] As shown herein, these new VLA-4 inhibitors are superior with respect to providing more and longer-term mobilization of hematopoietic stem cells in mice compared to previously generated molecules (see, e.g., U.S. Application No. 16 / 401,950, which is hereby incorporated by reference in its entirety).

[0018] New compounds and compositions having integrin receptor antagonist properties, methods for their manufacture, and methods of their use including methods for the treatment and / or prevention of diseases are disclosed herein.

[0019] Compound and Synthesis Method The compounds provided by the present disclosure can be prepared using the methods outlined below and further described in the Examples section. General synthetic sequences for preparing the compounds useful in the present disclosure are outlined in Schemes I-XVII. Where appropriate, both the description of the various aspects of the present disclosure and the actual procedures are explained. The following schemes, methods, descriptions, and exemplary embodiments are intended to merely illustrate the present disclosure and are not intended to limit its scope or spirit. Those skilled in the art will readily understand that known variations of the conditions and processes described in the schemes and exemplary embodiments can be used to synthesize the compounds of the present disclosure. The starting materials and equipment used were either commercially available, prepared by previously reported methods, or readily reproducible by those skilled in the art. For purposes of illustration, as described herein, X1 is often shown as a methyl ester throughout the following schemes, but it should be understood that in practice, it is not necessary to limit to this ester, and other esters or acid derivatives suitable for the reaction conditions or reagent availability or other specific selections can equally be utilized.

[0020] Scheme I

Chemical Structure

Chemical Structure

[0021] Briefly, an appropriate 4-bromo 、3,5 - Dialkoxy (R1 and R2 as defined herein) benzyl alcohol is converted to the corresponding benzyl bromide, or to other suitable electrophilic leaving groups such as tosylate, mesylate, or iodide, using reagents generally known to those skilled in the art. The benzyl bromide is then reacted with a suitable PEG alcohol under conditions known in the art such as NaH in anhydrous DMF, or using alternative substitution conditions and reagents, to obtain intermediate (A).

[0022] In the simplest and most straightforward example, X3 is oxygen, R3 is methoxy or another group defined in the general claims, and m and n are also defined as in the general claims. If X3 is oxygen and R3 is not methoxy, a larger alkoxy, or another simple functional group, but it is necessary to add or couple a second functional group to the R3 terminus of the PEG alcohol, for example, in the case of forming a group such as a PEGylated sulfide or amine at the R3 position, such a reaction can be carried out after the penultimate intermediate (A) has been formed. Examples showing such additional modifications can be exemplified herein as follows:

[0023] Scheme I - A

Chemical formula

[0024] In Scheme I-A, the penultimate (A) example consists of a terminal hydroxyl group protected by a suitable protecting group such as a silyl protecting group. The PEG group is attached to the R1, R2-bromobenzyl group as described and shown in the main Scheme I using a suitable PEG alcohol having a protected alcohol on the terminal side of the reagent. After removing the hydroxyl protecting group using a reagent specific for the removal of the protecting group utilized, the hydroxyl is converted to another leaving group such as bromide or mesylate or tosylate. This can then be reacted with the desired mercaptan or amine as shown in the scheme for forming intermediate (A).

[0025] These intermediates (A) having the conjugate R3 functional group can here be reacted with intermediate (B) from the main Scheme I and the reaction sequence can be continued as shown in the main Scheme I to form the desired product of the present disclosure.

[0026] As mentioned above, these exemplary schemes are not intended to be limiting and those skilled in the art can perform similar such reactions using appropriate reagents and reaction conditions to understand that other such product derivatives can be formed with R3 as defined herein.

[0027] Alternatively, as described and illustrated above, further functionalization at R3, if feasible, can be done using appropriate protecting groups at the end of the entire reaction sequence of Scheme I, rather than adding it to the penultimate intermediate (A), before the Suzuki coupling of the resulting intermediate (A) and intermediate (B).

[0028] This alternative method can be shown as in the following general example of Scheme I-B:

[0029] Scheme I-B

Chemical formula

[0030] Briefly, intermediate (E) is formed via an initial reaction of a suitable PEG diol having a hydroxyl protecting group at one end with a suitable 4-bromo, 3,5-dialkoxy (R1 and R2) benzyl bromide in the first step of Main Scheme I. Continuing the reaction sequence, intermediate (E) of Scheme I-B above is obtained, which includes a terminal hydroxyl group protected with a suitable protecting group (e.g., a suitable silyl group, etc.) that can withstand all of the reaction conditions encountered throughout the sequence from the overview of Main Scheme I. The protecting group is then removed under conditions specific to such protecting groups. This will be known to those skilled in the art. The free alcohol is then converted to Br, Cl, iodine, or a mesylate or tosylate using standard conversion reagents and conditions. In the example above, it is converted to bromide using PBr3. This bromide (or other electrophile) is then reacted with a suitable mercaptan (in this case, PEG mercaptan) to obtain a newly functionalized intermediate (E) having z and R 11 as defined herein, as shown in the above scheme. The desired product of the present disclosure (in this case, the terminal sulfide product) is then obtained by hydrolysis of the ester.

[0031] The example shown in Scheme I-B is not inherently limiting and can further be envisioned to be applicable to other functional groups defined by R3 by substituting a suitably protected terminal group that can be deprotected and functionalized to provide the desired group defined by R3 other than the terminal sulfide of Scheme I-B, such as an amine, sulfone, etc.

[0032] When X3 is other than oxygen and is sulfur, amino, or amide as defined for X3 in the claims, the formation of intermediate (A) can be synthesized stepwise as in the following example.

[0033] Scheme I-C

Chem.

[0034] In its simplest form, R3 is methoxy or a larger alkoxy. If R3 is not methoxy, a larger alkoxy, or other simple functional groups, but consists of a group that forms, for example, an amide, sulfonamide, etc. at the R3 position and requires addition or coupling of a second functional group to the R3 terminus of the PEG alcohol, then as in Schemes I-A and I-B, when X2 is oxygen, such reactions can occur as described and shown above.

[0035] Scheme I-D

Chem.

[0036] Scheme I-E

Chemical Structure

[0037] Separate from the formation of intermediate (A) and the penultimate intermediate (A) in main scheme I (general examples of which are shown in schemes I-A, B, C, D, and E), the boronic acid pinacol ester of intermediate B is formed from 4-bromophenylalanine methyl ester after adding a Boc protecting group to the amine. Intermediate B is formed via a Suzuki coupling reaction of Boc-protected 4-bromophenylalanine methyl ester with bis(pinacolato)diboron.

[0038] Next, intermediate B is reacted with intermediate A from the above via another Suzuki coupling to form intermediate C after acidic deprotection of the Boc amine. These Suzuki coupling reactions can be carried out using various reagents and experimental conditions known to those skilled in the art, such as the palladium catalysts and reagents shown in scheme I.

[0039] Alternatively, the prolyl sulfonamide intermediate D is formed by reaction of a suitable R4 and R5 (as defined herein) containing a sulfonyl chloride with a suitable prolyl ester, followed by hydrolysis to the free acid.

[0040] Intermediate D is then reacted with intermediate C using standard amide-forming coupling reagents and experimental procedures known to those skilled in the art, such as HOBt, EDCI in DMF, or DMA containing a base such as DIEA. This reaction results in ester intermediate E.

[0041] Finally, hydrolysis of intermediate E results in the formation of the desired integrin inhibitor claimed within this disclosure.

[0042] Scheme II

Chemical formula

[0043] Scheme III

Chemical formula

[0044] Scheme IV

Chemical formula

[0045] Scheme V [Chemical formula] Scheme V shows a general method for the synthesis of the compounds of the present disclosure as an alternative to the methods described in Schemes I-IV above. In this general method, intermediate (D) of Scheme V can function as a common intermediate useful for the addition of a plurality of PEG "tail" groups defined in the general claims without going through a plurality of steps after the addition of each new PEG tail group, as shown in Schemes I-IV. The method of Scheme V will consist of one or a minimal number of steps once the common intermediate (D) is synthesized and the desired product of the present disclosure is reached. Such synthetic efficiency can be understood by those skilled in the art.

[0046] Briefly, the methods, reagents, and reaction conditions utilized to synthesize intermediates (A), (B), (C), and ultimately the common intermediate (D) are shown in the descriptions and overviews of Schemes I-IV. Once intermediate (D) is obtained, it can be reacted with an appropriate PEG alcohol represented by intermediate (E) and InCl3 at high temperature to obtain the desired product or ester. This can be hydrolyzed to the free acid using reagents and conditions known to those skilled in the art. In many cases, the reaction of (D) and (E) with InCl3 at high temperature is simultaneously converted to the free acid and no additional steps are required.

[0047] This general reaction scheme is intended to provide examples of alternative steps and conditions for Schemes I-IV, but is not intended to be limiting in nature. One of ordinary skill in the art will understand that similar and related methods and conditions for reaching the products described in detail in the general claims of the present disclosure can be envisioned (R 1-6 , X3, m, and n are as defined within these claims).

[0048] Scheme VI

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[0049] Scheme VII

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[0050] Scheme VIII

Chem.

[0051] Scheme IX

Chem.

[0052] Scheme X

Chem.

[0053] Scheme XI

Chem.

[0054] Scheme XI(A)

Chem.

[0055] Scheme XII

Chemical formula

Chemical formula

[0056] Briefly, the appropriately substituted benzoic acid is reacted with 4-bromophenylalanine methyl ester using coupling reagents and reaction conditions known to those skilled in the art to form the amide (A) shown in Step 1 above. Y, R7, and R8 are as defined herein. In this Scheme XII, Y is either shown as a precursor or protected with an appropriate protecting group as necessary such that all reactions in this scheme are successfully completed and then, finally, deprotected or modified using reagents and methods known in the art and then the Y as defined herein is obtained. Then, (A) is reacted with bis(pinacolato)diboron in 1,4-dioxane, [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride, and potassium acetate to obtain the boronic ester (B). Then, (B) is reacted with benzyl alcohol (C) using generally used Suzuki palladium coupling methods and reagents known to those skilled in the art to form the intermediate (D). If X2 in the final product is oxygen, (D) is reacted directly with the appropriate PEG alcohol shown as reagent (F) using the InCl3 method described in the scheme above. If X2 is sulfur, the intermediate (D) is first converted to benzyl bromide (E) by reaction of benzyl alcohol with PBr3 under conditions and methods known to those skilled in the art. Then, the intermediate (E) is reacted with the appropriate PEG mercaptan shown as reagent (F) and K2CO3 or other suitable base. The product from this step is hydrolyzed to the desired product as the free acid with LiOH or other ester hydrolysis base with X2 as oxygen or sulfur and as a methyl ester and then acidified with HCl or another suitable acid to obtain the desired product (R1, R2, R3, R7, R8, X2, Y, m, and n are as defined herein).

[0057] Scheme XIII [Chemical formula] Scheme XIII shows a general method for the synthesis of a preferred embodiment included in this disclosure. In the formula, Z is [Chemical formula] wherein X2 is sulfur, R1, R2 and R3 are methoxy, m and n are as defined herein, and the (S) stereochemistry is preferred, as shown in Scheme XIII above.

[0058] Briefly, 4-bromo-2,6-dichlorobenzoic acid (13.3 mmol) and cesium carbonate (23.2 mmol) are suspended in acetonitrile (50 mL) at 0 °C, and then benzyl bromide (13.93 mmol) is added dropwise. As shown in Step 1, the reaction mixture is heated at 60 °C for 4 hours to obtain the benzyl ester. Then, this benzyl ester (4.17 mmol) is added to a 20 mL microwave vial together with palladium acetate (0.208 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.417 mmol), 4-dimethylaminopyridine (16.7 mmol), dicobalt octacarbonyl (3.33 mmol), and toluene / methanol (2:1, 15 mL). The vial is crimped closed and irradiated using a microwave at 90 °C for 30 minutes. The reaction mixture is diluted with ethyl acetate, filtered through Celite®, and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with 10% citric acid solution and then brine. The ethyl acetate layer is dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography using ethyl acetate / hexane as the eluent as shown in Step 2 to obtain Intermediate (A). To a solution of Intermediate (A) (6.78 mmol) in ethyl acetate (20 mL) is added 10% palladium on carbon (0.34 mmol), and the mixture is stirred at room temperature under a hydrogen atmosphere at ambient pressure for 1.5 hours. The reaction mixture is filtered through Celite®, concentrated in vacuo, and Intermediate (B) is obtained as shown in Step 3. Intermediate (B) (8.38 mmol), benzotriazol-1-ol (1.59 mmol), 3-[bis(dimethylamino)-methylurumyl]-3H-benzotriazol-1-oxide hexafluorophosphate (8.77 mmol), and DMSO (15 mL) are added to a round-bottom flask. Then, N,N-diisopropylethylamine (23.93 mmol) is added, and the reaction mixture is stirred at room temperature for 40 minutes. Then, methyl (S)-2-amino-3-(4-bromophenyl)propanoate hydrochloride (7.98 mmol) of Intermediate (C) is added, and the reaction mixture is stirred at room temperature overnight.The reactants are diluted with water (50 mL) and stirred for 20 minutes, then extracted using ethyl acetate (100 mL). The ethyl acetate layer is washed with additional water, dried using sodium sulfate, and concentrated in vacuo. The resulting oil is purified on silica gel using ethyl acetate and hexane as eluents to obtain Intermediate (D) as shown in Step 4. In a 20 mL microwave vial, add Intermediate (D) (2.04 mmol), bis(pinacolato)diboron (2.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride (0.123 mmol), potassium acetate (6.13 mmol), and 1,4-dioxane (10 mL). Crimp and close the vial, sparge with nitrogen gas for 10 minutes, and then heat at 80 °C overnight. Cool the reaction mixture to room temperature, filter through Celite®, and rinse with ethyl acetate. Wash the ethyl acetate layer with additional water, dry using sodium sulfate, and concentrate in vacuo. Purify the resulting oil on silica gel using ethyl acetate and hexane as eluents to obtain Intermediate (E) as shown in Step 5. The benzyl alcohol of Intermediate (F) is synthesized by dropwise addition of dimethylsulfide borane complex (2 M, 7.6 mL in tetrahydrofuran, 15.3 mmol) at room temperature to an oven-dried round-bottom flask containing 4-bromo-3,5-dimethoxybenzoic acid (7.66 mmol) and anhydrous tetrahydrofuran (24 mL). Heat the reaction mixture at 40 °C overnight, then quench with hydrochloric acid (1 N) and partition between ethyl acetate and water. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate in vacuo to obtain Intermediate (F). In a microwave vial, add Intermediate (E) (0.186 mmol), Intermediate (F) (0.28 mmol, 1.5 equiv), tetrakis(triphenylphosphine)palladium(0) (0.009 mmol), and cesium acetate (0.559 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL). Crimp and close the vial, sparge with nitrogen for 10 minutes, and then heat at 115 °C overnight.The reactants are partitioned between ethyl acetate and water, the layers are separated, the ethyl acetate layer is dried using sodium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel using ethyl acetate and hexane as eluents to obtain Intermediate (G) as shown in Step 6. The benzyl alcohol of Intermediate (G) is converted to benzyl bromide of Intermediate (H) using PBr3 under conditions readily known to those skilled in the art as shown in Step 7. In Step 8, Intermediate (H) is then reacted with a suitable PEG mercaptan represented by Intermediate (I) and potassium carbonate or another suitable base in DMF or another suitable solvent to obtain the desired precursor product as a dimethyl ester, which is then hydrolyzed to the desired product as the free acid using LiOH or another suitable base for hydrolyzing the methyl ester precursor.

[0059] Scheme XIV

Chemical formula

Chemical formula

[0060] Briefly, the methyl ester of 4-bromophenylalanine HCl is converted to the Boc-protected compound as shown in Step 1 using reagents and methods known to those skilled in the art. This is then converted to the boronic acid ester of intermediate (A) as shown in Step 2 and as follows. To a solution of the Boc intermediate (74.2 mmol) in dioxane (250 mL) and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (111 mmol), Pd(dppf)Cl2 (7.43 mmol) and KOAc (222 mmol) are added. The mixture is stirred at 90 °C for 12 h under a N2 atmosphere. The reaction mixture is then filtered and concentrated under vacuum to obtain the desired intermediate (A) as a yellow oil, which is purified by column chromatography (SiO2, petroleum ether / ethyl acetate). Then, as shown in Step 3 and as follows, intermediate (A) is converted to intermediate (C) by reacting it with intermediate (B). A solution of intermediate (A) (23.7 mmol), intermediate (B) (28.4 mmol), Pd(dppf)Cl2 (2.37 mmol), and K3PO4 (71.2 mmol) in dioxane (50.0 mL) and H2O (10.0 mL) is stirred at 80 °C for 12 h. The reaction mixture is filtered. The filtrate is poured into water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers are washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to obtain intermediate (C) as a pale yellow oil. This is purified by column chromatography and further purified by preparative HPLC. The Boc group from intermediate (C) is removed with HCl / dioxane as shown in Step 4 to obtain intermediate (D) as the HCl salt. Then, a solution of intermediate (E) (6.78 mmol, 1.00 equivalent) in DMF (30.0 mL) is taken and intermediate (D) is coupled with the benzoic acid intermediate (E) by adding DIEA (33.9 mmol, 5.00 equivalents), HATU (10.1 mmol, 1.50 equivalents), and HOBt (2.03 mmol, 0.300 equivalents). The mixture is stirred at 25 °C for 0.5 h. Then, intermediate (D) (6.78 mmol, 1.00 equivalent) is added.The mixture is stirred at 25 °C for 12 h. The reaction mixture is poured into water (50.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers are washed with brine (80.0 mL), dried over Na2SO4, filtered, and concentrated. The crude product is purified by preparative HPLC as the intermediate (F) as shown in Step 5. The benzyl alcohol of the intermediate (F) is converted to the benzyl bromide of the intermediate (G) as shown in Step 6 using PBr3 and reaction conditions readily known to those skilled in the art. The intermediate (G) is then reacted in DMF with a suitable PEG mercaptan, the intermediate (H), and potassium carbonate or other suitable base to afford the intermediate (I) as shown in Step 7.

[0061] A mixture of the intermediate (I) (51.5 μmol, 1.00 equiv) in MeOH (20.0 mL), TEA (206 μmol, 28.6 μL, 4.00 equiv), and Pd(dppf)Cl2 (5.15 μmol, 0.10 equiv) is heated at 80 °C for 16 h under a CO atmosphere (50 psi). The reaction mixture is filtered and the filtrate is concentrated in vacuo to afford the penultimate product. This is hydrolyzed with LiOH in THF / H2O as shown in Step 8 to afford the desired product (where m and n are as defined herein) as the diacid.

[0062] Scheme XV

Chemical formula

[0063] Further functionalization of the products synthesized via Scheme XV with R3 can be envisioned from the methods and examples illustrated in the previous scheme and also as defined by R3 herein. Scheme XV is meant to be an example showing the efficiency enabled by using "click chemistry" as shown, and it is not meant to be limiting in nature as those skilled in the art can envision additional methods, reagents, and conditions for deriving the triazole-linked PEG products defined in the general claims of the present disclosure.

[0064] Scheme XVI

Chemical Structure

[0065] Scheme XVII

Chemical formula

[0066] By incorporating previous schemes and methods that would be recognized by those skilled in the art, Z =

Chemical formula

[0067] In some embodiments, the compounds of the present disclosure include the compounds described in the exemplary embodiments and claims listed below. Further, these compounds are listed in Table 1 below.

Table 1-1

Table 1-2

Table 1-3

[0068] Compounds having similar structural identities (some of which are described in the prior art) are described herein to demonstrate the novelty of the compounds of the present disclosure when compared to these compounds having structural similarity with respect to the mobilization of long-term hematopoietic stem cells after single administration. These are referred to as comparative compounds and are listed in Table 2 below.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0069] Mobilization of hematopoietic stem cells The mobilization of hematopoietic stem cells from the bone marrow to the peripheral blood is an important procedure for stem cell transplantation in the treatment of blood cancers. The current mobilizing agent in clinical use is a protein called granulocyte colony-stimulating factor (G-CSF). Patients or donors must come to the hospital daily for G-CSF injections for up to one week or more in order to mobilize a sufficient number of blood stem cells for a safe stem cell transplantation. Furthermore, G-CSF does not effectively mobilize a sufficient number or quality of stem cells in all donors and can cause undesirable side effects in some individuals. Additionally, when HSPC mobilization is utilized for gene editing in sickle cell disease patients, G-CSF is actually contraindicated in sickle cell anemia patients because of its ability to induce life-threatening acute chest syndrome and life-threatening vaso-occlusive episodes. Therefore, it is desirable to identify a safe, rapid, and cost-effective alternative treatment and thus make this procedure more inclusive across all patient populations.

[0070] The novel VLA4 inhibitors of the present disclosure achieve the same degree of mobilization after a single injection, particularly in combination with other agents such as inhibitors of CXCR4, and can be harvested over a period of 4 - 6 hours, after which the patient or donor can go home. This provides a more efficient donor HSPC harvest as compared to the current protocol using G-CSF which requires daily hospital visits for up to one week or more. This will not only be more convenient but will dramatically reduce the cost of the mobilization procedure.

[0071] The clinical uses of these new compositions can be for hematopoietic stem cell transplantation and other uses. The disclosed compositions can mobilize donor stem cells and collect them for patients in need. The disclosed compositions can mobilize the cells of patients (e.g., having leukemia, multiple myeloma) to make chemotherapy, radiotherapy, and other cancer therapies more efficient. For example, the disclosed compositions can be administered to a subject having sickle cell anemia or other blood-borne genetic diseases for mobilization and collection of their own hematopoietic stem cells. These compositions are then subjected to gene editing to correct the mutant disease gene, and then the corrected hematopoietic stem cells are reinfused as a means to cure the disease. Due to the mechanism of these new compositions as inhibitors of integrin VLA4 (α4β1) and α4β7, in addition to mobilization of hematopoietic cells, other envisioned uses are for the treatment of graft-versus-host disease (GvHD), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, multiple sclerosis, spinal cord injury, neurological diseases, and other inflammatory pathologies related to this mechanism.

[0072] Hematopoietic stem / progenitor cell (HSPC) cell therapy Hematopoietic stem / progenitor cells (HSPCs) (wild-type or engineered) generated according to the methods described herein can be used in cell therapy. Cell therapy (also called cellular therapy, cell transplantation, or cytotherapy) can be a therapy in which living cells are injected, grafted, or implanted into a patient to provide a pharmaceutical or therapeutic benefit. For example, injecting or transplanting hematopoietic stem / progenitor cells (HSPCs) can treat, prevent, or enhance the effectiveness of cancer therapy for a disease, disorder, or condition.

[0073] Stem cell and cell transplantation have gathered great interest from researchers as potential new treatment strategies for a wide range of diseases, particularly proliferative, degenerative, and immunogenic pathologies.

[0074] Allogeneic cell therapy or allotransplantation uses donor cells from a subject different from the recipient of the cells. The advantage of the allogeneic strategy is that unparalleled allogeneic cell therapies can form the basis of "off-the-shelf" products.

[0075] Autologous cell therapy or autotransplantation uses cells derived from the subject's own tissue. It can also involve the isolation of mature cells from diseased tissue so that they can be re-implanted later into the same or adjacent tissue. The advantage of the autologous strategy is that concerns about immunogenic responses or transplant rejection are limited.

[0076] Xenogeneic cell therapy or xenotransplantation uses cells from another species. For example, pig-derived cells can be transplanted into humans. Xenogeneic cell therapy can involve the transplantation of human cells into experimental animal models for efficacy and safety evaluation, or enable xenogeneic strategies in humans.

[0077] Hematopoietic stem cell transplantation (HSCT) is a major curative therapy available for many blood diseases, including blood cancers. In this technique, HSCT is used to promote the repopulation of healthy bone marrow and immune system cells after high-dose chemotherapy treatment of cancers including, but not limited to, Hodgkin lymphoma and non-Hodgkin lymphoma, multiple myeloma, or leukemia. To facilitate transplantation when cells are needed, hematopoietic stem / progenitor cells (HSPCs) are collected from the patient's blood, recovered, frozen, and then stored while the patient is undergoing high-dose chemotherapy and / or radiation therapy.

[0078] The amount of hematopoietic stem / progenitor cells (HSPCs) collected for use in a subject can be any amount that is therapeutically effective for the subject. For example, for a successful transplant, often an intravenous infusion of a minimum of 2×10 6 CD34+ stem cells / kg body weight is required. However, for early and long-term multilineage engraftment in humans, 5×10 6A dose of [[number]] CD34+ cells / kg is considered preferable. Thus, generally, at least 2 million CD34+ stem cells per kilogram of human recipient body weight are required to proceed with transplantation and ensure multi-lineage engraftment in the recipient. If possible, it is preferable to transplant 5 million CD34+ cells per kilogram of recipient body weight, as this can result in more consistent neutrophil and platelet engraftment.

[0079] Currently, stem cells for hematopoietic stem cell transplantation are often collected from peripheral blood. Since the amount of these cells in circulating peripheral blood is low, the stem cells often have to be stimulated to increase their amount in the peripheral blood (a process that can take almost a week). Even so, the collection is carried out over several days to achieve a sufficient concentration of stem cells for transplantation. This significantly increases the cost of transplantation and places a great burden on the patient. Currently, cytokines such as granulocyte colony-stimulating factor (G-CSF) and immunostimulants such as plerixafor are used to increase the amount of hematopoietic stem cells in the peripheral blood, but single agents often result in insufficient mobilization of stem cells. Additional methods for collecting hematopoietic stem cells have been developed, which involve combining G-CSF with multiple other agents such as plerixafor or another cytokine. Unfortunately, even these combination therapies often cannot increase the concentration to sufficient levels for transplantation in many patients, even with multiple days of apheresis. Furthermore, some of these agents such as plerixafor are very expensive, adding costs of over $25,000 per patient compared to using G-CSF alone. Thus, a better method for collecting hematopoietic stem cells is still needed.

[0080] VLA-4 inhibitor or antagonist The present disclosure provides compounds that are VLA-4 antagonists (i.e., inhibitors), pharmaceutical compositions, methods for their manufacture, and methods for their use.

[0081] Disclosed herein are new compounds and compositions, pharmaceutical compositions, methods for their manufacture, and methods of their use, including the treatment and / or prevention of diseases, that act as antagonists (i.e., inhibitors) of, for example, α4β1 integrin (VLA-4) and α4b7 integrin. In some embodiments, these compounds can be used to improve the collection of hematopoietic stem cells or progenitor cells or to enhance anti-cancer therapy.

[0082] The VLA-4 inhibitors disclosed herein represent a novel composition of matter with respect to the utility of significantly mobilizing hematopoietic stem cells / progenitor cells from bone marrow to peripheral blood over a long period of time as compared to previously disclosed molecules.

[0083] PEG Disclosed herein is that by increasing the length of polyethylene glycol (PEG) covalently attached to a specific chemical structure, the inhibitor of integrin VLA-4 is actually improved for the excellent long-term mobilization of hematopoietic stem cells, and that the nature of PEG itself and the minimum length of PEG required for such improvement depend on the nature of the specific chemical core structure to which PEG is attached. The multiple direct comparison compounds provided herein demonstrate the non-obvious nature of the disclosed compositions and support the novelty of the claimed subject matter presented.

[0084] Thus, it has been shown that it is not the length of PEG itself, but the molecule as a whole that increases the mobilization time and cell mobilization. The triazole linker analogs described herein provide convenient and facile synthetic utility by utilizing the "click chemistry" reaction of appropriate acetylene precursors reacted with PEG azides of the desired composition and molecular weight. One of ordinary skill in the art can recognize the potential utility of such analogs in various biological processes and functional outcomes. However, as shown herein, the placement of the triazole linker in relation to the core inhibitor structure determines whether long-term mobilization occurs and further supports the non-obvious nature of the disclosed technology.

[0085] As shown herein, these new VLA-4 inhibitors are superior to previously generated molecules (see, e.g., U.S. Application No. 16 / 401,950, which is incorporated herein by reference in its entirety) with respect to providing more long-term mobilization of hematopoietic stem cells in mice.

[0086] The present disclosure provides for the covalent addition of polyethylene glycol (PEG) units of defined length to specific attachment points on the core VLA-4 inhibitor structure. This provides solubility in saline and rapid, long-term, and significant mobilization after single dosing while retaining unexpectedly high (sub-nM) potency (inhibition) against VLA-4 compared to analogs lacking the disclosed minimum PEG chain length. Further, the minimum chain length required to achieve these properties varies depending on the specific core structure. This emphasizes the fact that attaching the minimum PEG length to one core structure to achieve long-term mobilization is not applicable to different core structures, thereby rendering the disclosed compounds non-obvious compared to the prior art. To further emphasize this point, herein, such long-term HSPC mobilization is achieved only with the minimum PEG length disclosed in the general claims, and numerous comparative compounds are provided to demonstrate that this minimum PEG length is specific to the core structures recited in the claims' definitions. Multiple bound PEG length analogs below the required minimum are highlighted within the described comparative compounds along with mobilization data showing the lack of long-term mobilization by such comparative compounds. Also, conventionally, when long PEG groups are attached to drug molecules to improve pharmacokinetic properties such as plasma half-life, the potency of the drug decreases in proportion to the length of the PEG chain. Unexpectedly, the novel compositions disclosed herein demonstrate that attaching a long PEG length to specific attachment points on the core structures disclosed herein does not reduce potency in relation to VLA-4 inhibition, but rather retains high potency even up to 40KD regardless of the PEG chain length. Further, comparative compounds (Comparative Compounds C11 and C18) composed of truncated core structures with long PEG chains provide no mobilization, demonstrating that the long PEG groups themselves do not exhibit HSPC mobilization.

[0087] Additional properties of the compositions disclosed herein are that they inhibit integrin α4β7 in addition to VLA-4 (α4β1). This dual inhibition, as further described herein, confers upon the compounds of the technology the ability to act as therapeutics for diseases and pathologies such as multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, graft-versus-host disease (GvHD), neurodegeneration, spinal cord injury, and other inflammatory diseases, in addition to HSPC mobilization. From the fact that the examples disclosed herein include the conjugation of 20KD and 40KD PEG and still retain sub-nM potency against VLA4, an extension of the plasma half-life of the drug after a single subcutaneous injection can be achieved, making them suitable candidates as therapies for diseases that would require more chronic plasma exposure such as multiple sclerosis.

[0088] In some embodiments, the composition can include a linker group. The linker group can be linked to the VLA-4 inhibitor or can connect two VLA-4 inhibitors. In some embodiments, the linker can be PEG, a triazole, a chemical linker, an enzyme linker, a bond, or an electrostatic linker.

[0089] Polyethylene glycol (PEG) is a polyether compound derived from petroleum and has many uses from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE) depending on its molecular weight. The structure of PEG is generally represented as H-(O-CH2-CH2)n-OH. PEG, PEO, and POE refer to oligomers or polymers of ethylene oxide. The three names are chemically synonymous, but conventionally, PEG is preferred in the biomedical field while PEO is more common in the field of polymer chemistry. PEG can be prepared by the polymerization of ethylene oxide and is commercially available over a wide range of molecular weights from 300 g / mol (300 Da) to 10,000,000 g / mol (10,000 kDa).

[0090] PEG and PEO can be liquids or low-melting solids depending on their molecular weight. PEGs and PEOs with different molecular weights are used in different applications and have different physical properties (e.g., viscosity) due to the chain length effect, but their chemical properties are nearly identical. Different forms of PEG are also available depending on the initiator used in the polymerization process, and the most common initiator is monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated mPEG. Low molecular weight PEGs are also available as purer oligomers, referred to as monodisperse, uniform, or discrete. Very high purity PEGs have recently been shown to be crystalline, and their crystal structures can be determined by X-ray crystallography. Since the purification and separation of pure oligomers can be difficult, the price of this type of quality is often 10 to 1000 times that of polydisperse PEG.

[0091] Different shaped PEGs are also available. Branched PEGs can have 3 to 10 PEG chains emanating from a central core group. Star PEGs can have 10 to 100 PEG chains emanating from a central core group. Comb PEGs can usually have multiple PEG chains grafted onto a polymer backbone.

[0092] The numbers often included in the name of PEGs indicate their average molecular weight (e.g., PEG with n = 9 has an average molecular weight of about 400 Daltons and is labeled PEG400). Some PEGs contain molecules with a distribution of molecular weights (i.e., they are polydisperse). The size distribution can be statistically characterized by its weight average molecular weight (M w ) and its number average molecular weight (M n ), and the ratio is called the polydispersity index (D M ). M w and M n can be measured by mass spectrometry.

[0093] PEGylation is the act of covalently bonding a PEG structure to another, larger molecule (e.g., a VLA4 inhibitor, which may be referred to as a PEGylated VLA4 inhibitor). PEG is soluble in water, methanol, ethanol, acetonitrile, benzene, and dichloromethane and insoluble in diethyl ether and hexane.

[0094] PEG and methoxypolyethylene glycol are manufactured by Dow Chemical under the trade name Carbowax for industrial use and under the trade name Carbowax Sentry for food and pharmaceutical use. They vary in consistency from liquid to solid depending on their molecular weight, as indicated by the number following the name. They are commercially used in a number of applications including food, cosmetics, pharmaceuticals, biopharmaceuticals, dispersants, solvents, ointments, suppository bases, tablets, excipients, and laxatives. Some specific groups are lauromacrogol, nonoxynol, octoxynol, and poloxamer. Macrogol, MiraLax, GoLytely, Colace are in the form of polyethylene glycol. The number representing the average molecular weight (e.g., macrogol 3350, macrogol 4000, macrogol 6000) may follow the name.

[0095] The PEG described in this specification can be from about 1 kDa to 100 kDa. The PEG lengths described in this specification are about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 6 kDa, about 7 kDa, about 8 kDa, about 9 kDa, about 10 kDa, about 11 kDa, about 12 kDa, about 13 kDa, about 14 kDa, about 15 kDa, about 16 kDa, about 17 kDa, about 18 kDa, about 19 kDa, about 20 kDa, about 21 kDa, about 22 kDa, about 23 kDa, about 24 kDa, about 25 kDa, about 26 kDa, about 27 kDa, about 28 kDa, about 29 kDa, about 30 kDa, about 31 kDa, about 32 kDa, about 33 kDa, about 34 kDa, about 35 kDa, about 36 kDa, about 37 kDa, about 38 kDa, about 39 kDa, about 40 kDa, about 41 kDa, about 42 kDa, about 43 kDa, about 44 kDa, about 45 kDa, about 46 kDa, about 47 kDa, about 48 kDa, about 49 kDa, about 50 kDa, about 51 kDa, about 52 kDa, about 53 kDa, about 54 kDa, about 55 kDa, about 56 kDa, about 57 kDa, about 58 kDa, about 59 kDa, about 60 kDa, about 61 kDa, about 62 kDa, about 63 kDa, about 64 kDa, about 65 kDa, about 66 kDa, about 67 kDa, about 68 kDa, about 69 kDa, about 70 kDa, about 71 kDa, about 72 kDa, about 73 kDa, about 74 kDa, about 75 kDa, about 76 kDa, about 77 kDa, about 78 kDa, about 79 kDa, about 80 kDa, about 81 kDa, about 82 kDa, about 83 kDa, about 84 kDa, about 85 kDa, about 86 kDa, about 87 kDa, about 88 kDa, about 89 kDa, about 90 kDa, about 91 kDa, about 92 kDa, about 93 kDa, about 94 kDa, about 95 kDa, about 96 kDa, about 97 kDa, about 98 kDa, about 99 kDa, or about 100 kDa. Each enumeration of these discrete values is understood to include the range between each value. Each enumeration of a range is understood to include the discrete values within the range. Each enumeration of these discrete values is understood to include being greater than, less than, and / or equal to a discrete value or range.

[0096] The PEG described in this specification can have a length of 1 - 3, 16 - 24, 222 - 1000, 19 - 1000, 19 - 32, or 100 - 900 (e.g., n, m, W). For example, the PEG length may exceed 16. As another example, the PEG length can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 110, about 111, about 112, about 113, about 114, about 115, about 116, about 117, about 118, about 119, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, about 130, about 131, about 132, about 133, about 134, about 135, about 136, about 137, about 138, about 139, about 140, about 141, about 142, about 143, about 144, about 145, about 146, about 147, about 148, about 149, about 150, about 151, about 152, about 153, about 154, about 155, about 156, about 157, about 158, about 159, about 160, about 161, about 162, about 163, about 164, about 165, about 166, about 167, about 168, about 169, about 170, about 171, about 172, about 173, about 174, about 175, about 176, about 177, about 178, about 179, about 180, about 181, about 182, about 183, about 184, about 185, about 186, about 187, about 188, about 189, about 190, about 191, about 192, about 193, about 194, about 195, about 196, about 197, about 198, about 199,about 200, about 201, about 202, about 203, about 204, about 205, about 206, about 207, about 208, about 209, about 210, about 211, about 212, about 213, about 214, about 215, about 216, about 217, about 218, about 219, about 220, about 221, about 222, about 223, about 224, about 225, about 226, about 227, about 228, about 229, about 230, about 231, about 232, about 233, about 234, about 235, about 236, about 237, about 238, about 239, about 240, about 241, about 242, about 243, about 244, about 245, about 246, about 247, about 248, about 249, about 250, about 251, about 252, about 253, about 254, about 255, about 256, about 257, about 258, about 259, about 260, about 261, about 262, about 263, about 264, about 265, about 266, about 267, about 268, about 269, about 270, about 271, about 272, about 273, about 274, about 275, about 276, about 277, about 278, about 279, about 280, about 281, about 282, about 283, about 284, about 285, about 286, about 287, about 288, about 289, about 290, about 291, about 292, about 293, about 294, about 295, about 296, about 297, about 298, about 299, about 300, about 301, about 302, about 303, about 304, about 305, about 306, about 307, about 308, about 309, about 310, about 311, about 312, about 313, about 314, about 315, about 316, about 317, about 318, about 319, about 320, about 321, about 322, about 323, about 324, about 325, about 326, about 327, about 328, about 329, about 330, about 331, about 332, about 333, about 334, about 335, about 336, about 337, about 338, about 339, about 340, about 341, about 342, about 343, about 344, about 345, about 346, about 347, about 348, about 349, about 350, about 351, about 352, about 353, about 354, about 355, about 356, about 357, about 358, about 359, about 360, about 361, about 362, about 363, about 364, about 365, about 366, about 367, about 368, about 369, about 370, about 371, about 372, about 373, about 374, about 375, about 376, about 377, about 378, about 379, about 380, about 381, about 382, about 383, about 384, about 385, about 386, about 387, about 388, about 389, about 390, about 391, about 392, about 393, about 394, about 395, about 396, about 397, about 398, about 399about 400, about 401, about 402, about 403, about 404, about 405, about 406, about 407, about 408, about 409, about 410, about 411, about 412, about 413, about 414, about 415, about 416, about 417, about 418, about 419, about 420, about 421, about 422, about 423, about 424, about 425, about 426, about 427, about 428, about 429, about 430, about 431, about 432, about 433, about 434, about 435, about 436, about 437, about 438, about 439, about 440, about 441, about 442, about 443, about 444, about 445, about 446, about 447, about 448, about 449, about 450, about 451, about 452, about 453, about 454, about 455, about 456, about 457, about 458, about 459, about 460, about 461, about 462, about 463, about 464, about 465, about 466, about 467, about 468, about 469, about 470, about 471, about 472, about 473, about 474, about 475, about 476, about 477, about 478, about 479, about 480, about 481, about 482, about 483, about 484, about 485, about 486, about 487, about 488, about 489, about 490, about 491, about 492, about 493, about 494, about 495, about 496, about 497, about 498, about 499, about 500, about 501, about 502, about 503, about 504, about 505, about 506, about 507, about 508, about 509, about 510, about 511, about 512, about 513, about 514, about 515, about 516, about 517, about 518, about 519, about 520, about 521, about 522, about 523, about 524, about 525, about 526, about 527, about 528, about 529, about 530, about 531, about 532, about 533, about 534, about 535, about 536, about 537, about 538, about 539, about 540, about 541, about 542, about 543, about 544, about 545, about 546, about 547, about 548, about 549, about 550, about 551, about 552, about 553, about 554, about 555, about 556, about 557, about 558, about 559, about 560, about 561, about 562, about 563, about 564, about 565, about 566, about 567, about 568, about 569, about 570, about 571, about 572, about 573, about 574, about 575, about 576, about 577, about 578, about 579, about 580, about 581, about 582, about 583, about 584, about 585, about 586, about 587, about 588, about 589, about 590, about 591, about 592, about 593, about 594, about 595, about 596, about 597, about 598, about 599about 600, about 601, about 602, about 603, about 604, about 605, about 606, about 607, about 608, about 609, about 610, about 611, about 612, about 613, about 614, about 615, about 616, about 617, about 618, about 619, about 620, about 621, about 622, about 623, about 624, about 625, about 626, about 627, about 628, about 629, about 630, about 631, about 632, about 633, about 634, about 635, about 636, about 637, about 638, about 639, about 640, about 641, about 642, about 643, about 644, about 645, about 646, about 647, about 648, about 649, about 650, about 651, about 652, about 653, about 654, about 655, about 656, about 657, about 658, about 659, about 660, about 661, about 662, about 663, about 664, about 665, about 666, about 667, about 668, about 669, about 670, about 671, about 672, about 673, about 674, about 675, about 676, about 677, about 678, about 679, about 680, about 681, about 682, about 683, about 684, about 685, about 686, about 687, about 688, about 689, about 690, about 691, about 692, about 693, about 694, about 695, about 696, about 697, about 698, about 699, about 700, about 701, about 702, about 703, about 704, about 705, about 706, about 707, about 708, about 709, about 710, about 711, about 712, about 713, about 714, about 715, about 716, about 717, about 718, about 719, about 720, about 721, about 722, about 723, about 724, about 725, about 726, about 727, about 728, about 729, about 730, about 731, about 732, about 733, about 734, about 735, about 736, about 737, about 738, about 739, about 740, about 741, about 742, about 743, about 744, about 745, about 746, about 747, about 748, about 749, about 750, about 751, about 752, about 753, about 754, about 755, about 756, about 757, about 758, about 759, about 760, about 761, about 762, about 763, about 764, about 765, about 766, about 767, about 768, about 769, about 770, about 771, about 772, about 773, about 774, about 775, about 776, about 777, about 778, about 779, about 780, about 781, about 782, about 783, about 784, about 785, about 786, about 787, about 788, about 789, about 790, about 791, about 792, about 793, about 794, about 795, about 796, about 797, about 798, about 799about 800, about 801, about 802, about 803, about 804, about 805, about 806, about 807, about 808, about 809, about 810, about 811, about 812, about 813, about 814, about 815, about 816, about 817, about 818, about 819, about 820, about 821, about 822, about 823, about 824, about 825, about 826, about 827, about 828, about 829, about 830, about 831, about 832, about 833, about 834, about 835, about 836, about 837, about 838, about 839, about 840, about 841, about 842, about 843, about 844, about 845, about 846, about 847, about 848, about 849, about 850, about 851, about 852, about 853, about 854, about 855, about 856, about 857, about 858, about 859, about 860, about 861, about 862, about 863, about 864, about 865, about 866, about 867, about 868, about 869, about 870, about 871, about 872, about 873, about 874, about 875, about 876, about 877, about 878, about 879, about 880, about 881, about 882, about 883, about 884, about 885, about 886, about 887, about 888, about 889, about 890, about 891, about 892, about 893, about 894, about 895, about 896, about 897, about 898, about 899, about 900, about 901, about 902, about 903, about 904, about 905, about 906, about 907, about 908, about 909, about 910, about 911, about 912, about 913, about 914, about 915, about 916, about 917, about 918, about 919, about 920, about 921, about 922, about 923, about 924, about 925, about 926, about 927, about 928, about 929, about 930, about 931, about 932, about 933, about 934, about 935, about 936, about 937, about 938, about 939, about 940, about 941, about 942, about 943, about 944, about 945, about 946, about 947, about 948, about 949, about 950, about 951, about 952, about 953, about 954, about 955, about 956, about 957, about 958, about 959, about 960, about 961, about 962, about 963, about 964, about 965, about 966, about 967, about 968, about 969, about 970, about 971, about 972, about 973, about 974, about 975, about 976, about 977, about 978, about 979, about 980, about 981, about 982, about 983, about 984, about 985, about 986, about 987, about 988, about 989, about 990, about 991, about 992, about 993, about 994, about 995, about 996, about 997, about 998, about 999Or it can be about 1000. The enumeration of each of these distinct values is understood to include the range between each value. The enumeration of each range is understood to include the distinct values within the range. The enumeration of each of these distinct values is understood to include values greater than, less than, and / or equal to the distinct values or ranges.

[0097] Formula In some embodiments, the present disclosure provides compounds of the following formula:

Chemical formula

[0098] In some embodiments, Z =

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0099] In some embodiments, the disclosure provides a compound of the following formula:

Chemical formula

[0100] In some embodiments, m = 1 to 3, n = 19 to 1000, and R3 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) , haloalkyl, aryl, substituted aryl, -CH2-CH2-SO 2- alkyl (C≦8) , -CH2-CH2-N(R9)(R 10 )(wherein R9 and R 10 are each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), -(CH2) g -CH2-CO2R9 (wherein g is 0 or 1 and R9 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), or R3 may represent a biomarker tag for in vitro or in vivo utility, an antibody targeting a specific protein or receptor, or another entity (which, when attached to the core molecule, increases the biological effect of the combined entity and all are attached to the core molecule by R3), or when m = 1, n = 19 to 32, and X3 is oxygen, R3 may also be

Chemical formula

Chemical formula

[0101] In some embodiments, the present disclosure provides compounds of the following formula:

Chemical formula

[0102] In some embodiments, m = 1 to 3, n = 19 to 1000, X2 is oxygen or sulfur, or X3 is oxygen, sulfur, -NH(C=O)-, -(C=O)NH-, -N(R 12 ), (wherein R 12 is alkyl (C≦6) , substituted alkyl (C≦6) ), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog or bis-derivative thereof.

[0103] In some embodiments, the present disclosure provides compounds of the following formula:

Chemical formula

[0104] In some embodiments, n = 19, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog or bis-derivative thereof.

[0105] In some embodiments, the present disclosure provides compounds of the following formula: [Chemical formula] (IV).

[0106] In some embodiments, n = 31, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis derivative thereof.

[0107] In some embodiments, the present disclosure provides compounds of the following formula: [Chemical formula] (V).

[0108] In some embodiments, n = 19 - 1000, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis derivative thereof.

[0109] In some embodiments, the present disclosure provides compounds of the following formula: [Chemical formula] (VI).

[0110] In some embodiments, n = 19 - 1000, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof.

[0111] In some embodiments, the present disclosure provides compounds of the following formula: [Chemical formula] (VII).

[0112] In some embodiments, n = 222 to 1000, and X2 is oxygen or sulfur, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis derivative thereof.

[0113] In some aspects, the present disclosure provides a compound of the following formula: [Chemical formula] (VIII).

[0114] In some embodiments, n = 222 to 1000, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis derivative thereof.

[0115] In some aspects, the present disclosure provides a compound of the following formula: [Chemical formula] (IX).

[0116] In some embodiments, m = 1 to 3, n = 19 to 1000, X1 is hydroxy, alkoxy (C≦8) , substituted alkoxy (C≦8) , cycloalkoxy (C≦8) , substituted cycloalkoxy (C≦8) , alkenyloxy (C≦8) , substituted alkenyloxy (C≦8) , aryloxy (C≦8) , substituted aryloxy (C≦8) , aralkyloxy (C≦8) , substituted aralkyloxy (C≦8) , or a substituent convertible to hydroxy in vivo, or a pharmaceutically acceptable salt thereof, X2 is oxygen or sulfur, and R1 or R2 is each independently hydroxyl, alkoxy (C≦8) , or substituted alkoxy (C≦8)and R3 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) , haloalkyl, aryl, substituted aryl, -CH2-CH2-SO 2- alkyl (C≦8) , -CH2-CH2-N(R9)(R 10 )(wherein R9 or R 10 is each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), -(CH2) g -CH2-CO2R9 (wherein g is 0 or 1 and R9 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), or R3 represents a biomarker tag for in vitro or in vivo utility, an antibody targeting a specific protein or receptor, or another entity which, when attached to the core molecule, increases the biological effect of the combined entity and all are attached to the core molecule by R3, or when m = 1 and n = 19 - 32, R3 may also be

Chemical formula

[0117] In some embodiments, the disclosure provides a compound of the following formula:

Chemical formula

[0118] In some embodiments, m = 1 - 3, n = 222 - 1000, X1, X2, R1, R2, and R3 are as defined above, and R7 and R8 are each independently hydrogen, halo, haloalkyl (C≦8) and Y is hydrogen, cyano, halo, haloalkyl, hydroxy, or -C(O)X4, where X4 is amino, hydroxy, alkoxy (C≦8) substituted alkoxy (C≦8) cycloalkoxy (C≦8) substituted cycloalkoxy (C≦8) alkenyloxy (C≦8) substituted alkenyloxy (C≦8) aryloxy (C≦8) substituted aryloxy (C≦8) aralkyloxy (C≦8) substituted aralkyloxy (C≦8) alkylamino (C≦8) substituted alkylamino (C≦8) dialkylamino (C≦8) substituted dialkylamino (C≦8) cycloalkylamino (C≦8) substituted cycloalkylamino (C≦8) alkenylamino (C≦8) substituted alkenylamino (C≦8) arylamino (C≦8) substituted arylamino (C≦8) aralkylamino (C≦8) substituted aralkylamino (C≦8)), or a substituent convertible to hydroxy in vivo, or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis derivative thereof.

[0119] In some embodiments, the present disclosure provides compounds of the following formula:

Chemical formula

[0120] In some embodiments, m = 1 to 3, n = 19 to 1000, X2 is oxygen or sulfur, and R3 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) , haloalkyl, aryl, substituted aryl, -CH2-CH2-SO 2- alkyl (C≦8) , -CH2-CH2-N(R9)(R 10 )(wherein R9 or R 10 is each independently hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), -(CH2) g -CH2-CO2R9 (wherein g is 0 or 1 and R9 is hydrogen, alkyl (C≦6) , substituted alkyl (C≦6) ), or R3 may represent a biomarker tag for in vitro or in vivo utility, an antibody targeting a specific protein or receptor, or another entity (which, when attached to the core molecule, increases the biological effect of the combined entity, all being attached to the core molecule by R3), and when m = 1 or n = 19 to 32, R3 may also be

Chemical formula

[0121] In some embodiments, the present disclosure provides a compound of the following formula:

Chemical formula

[0122] In some embodiments, n = 19 to 1000, and X2 is oxygen or sulfur, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis-derivative thereof.

[0123] In some embodiments, the present disclosure provides a compound of the following formula:

Chemical formula

[0124] In some embodiments, n = 222 to 1000, and X2 is oxygen or sulfur, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog thereof or a bis-derivative thereof.

[0125] In some embodiments, the present disclosure provides a compound of the following formula:

Chemical formula

[0126] Bis-derivative As described herein, bis-derivatives or bis-analogs of VLA-4 inhibitors may be useful in the methods described herein. Bis-analogs use a "dichlorosulfonamide" core (see, for example, Example 11). As another example, the bis-analog or bis-derivative may have a "dichlorobenzoic acid" core.

[0127] Chemical substance definition Any of R1 to R of the R group is independently hydroxyl, C 12 alkylhydroxyl, amine, C 1-10 carboxylic acid, C 1-10 carboxyl, linear or branched C optionally containing unsaturation 1-10 alkyl, C optionally containing unsaturation or one oxygen or nitrogen atom 1-10 cycloalkyl, linear or branched C 2-10 alkylamine, heterocyclyl, heterocyclic amine, and aryl including phenyl, heteroaryl containing 1 to 4 N, O, or S atoms, unsubstituted phenyl ring, substituted phenyl ring, unsubstituted heterocyclyl, and substituted heterocyclyl may be optionally substituted or functionalized with one or more groups selected from the group consisting of, and the unsubstituted phenyl ring or substituted phenyl ring is independently hydroxyl, C 1-10 alkylhydroxyl, amine, C 1-10 carboxylic acid, C 1-10 carboxyl, linear or branched C optionally containing unsaturation 1-10 alkyl, linear or branched C optionally containing unsaturation 1-10 alkylamine, linear or branched C optionally containing unsaturation or one oxygen or nitrogen atom 1-10 cycloalkyl, linear or branched C 2-10 alkylamine, heterocyclyl, heterocyclic amine, aryl including phenyl, and heteroaryl containing 1 to 4 N, O, or S atoms may be optionally substituted with one or more groups selected from the group consisting of, and the unsubstituted heterocyclyl or substituted heterocyclyl is independently hydroxyl, C 1-10 alkylhydroxyl, amine, C 1-10 carboxylic acid, C 1-10 carboxyl, linear or branched C optionally containing unsaturation 1-10Carboxyl, a linear or branched C optionally containing unsaturation 1-10 Alkyl, a linear or branched C optionally containing unsaturation 1-10 Alkylamine, a C optionally containing unsaturation or one oxygen or nitrogen atom 2-10 Cycloalkyl, a linear or branched C 1-10 Alkylamine, heterocyclic amine, and heteroaryl containing 1 to 4 N, O, or S atoms, and may be optionally substituted with one or more groups selected from the group consisting of. Any of the above may be further optionally substituted.

[0128] As used herein, the terms "imine" or "imino" can include a functional group or compound containing a carbon-nitrogen double bond, unless otherwise indicated. As used herein, the expression "imino compound" refers to a compound containing an "imine" or "imino" group as defined herein, unless otherwise indicated. The "imine" or "imino" group may be optionally substituted.

[0129] As used herein, the term "hydroxyl" can include -OH, unless otherwise indicated. "Hydroxyl" may be optionally substituted.

[0130] As used herein, the terms "halogen" and "halo" include chlorine, chloro, Cl; fluorine, fluoro, F; bromine, bromo, Br; or iodine, iodo, or I, unless otherwise indicated.

[0131] The term "acetamide" as used herein is an organic compound having the formula CH3CONH2. "Acetamide" may be optionally substituted.

[0132] As used herein, the term "aryl" includes a carbocyclic aromatic group, unless otherwise indicated. Examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, or anthracenyl. "Aryl" may be optionally substituted.

[0133] As used herein, the terms "amine" and "amino", unless otherwise indicated, include a nitrogen atom having a lone pair of electrons and include, but are not limited to, functional groups in which one or more hydrogen atoms are replaced by substituents such as alkyl or aryl groups. The "amine" or "amino" group may be optionally substituted.

[0134] As used herein, the term "alkyl", unless otherwise indicated, includes, but is not limited to, saturated monovalent hydrocarbon radicals having straight or branched chain moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl groups, etc. Representative straight-chain lower alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl, while branched-chain lower alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, and unsaturated C 1-10 Alkyl includes, but is not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, -ethynyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, or -3-methyl-1-butynyl. Alkyl can be saturated, partially saturated, or unsaturated. "Alkyl" may be optionally substituted.

[0135] The term "alkyl" can refer to a monovalent saturated aliphatic group that has a carbon atom as a bonding point, has a linear or branched acyclic structure, and has no atoms other than carbon and hydrogen. -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH3)2 (i-Pr, i Pr or isopropyl), -CH2CH2CH2CH3 (n-Bu), -CH(CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl, t-butyl, t-Bu or tThe groups -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, and -CH2C(CH3)3 (neo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" can refer to a divalent saturated aliphatic group having one or two saturated carbon atoms as the bond point(s), having a straight-chain or branched acyclic structure, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylidene" can refer to a divalent group =CRR', where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" refers to a class of compounds having the formula H~R, where R is alkyl as defined above. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "haloalkyl" is a subset of substituted alkyl where the hydrogen atom replacement is limited to halo (i.e., -F, -Cl, -Br, or -I) such that no other atoms other than carbon, hydrogen, and halogen are present. The group -CH2Cl is a non-limiting example of a haloalkyl.The term "fluoroalkyl" is a subset of substituted alkyl in which the hydrogen atom replacement is limited to fluoro so that no other atoms other than carbon, hydrogen, and fluorine are present. The groups -CH2F, -CF3, and -CH2CF3 are non-limiting examples of fluoroalkyl groups.

[0136] As used herein, the term "carboxyl" can include a functional group consisting of a carbon atom double-bonded to an oxygen atom and single-bonded to a hydroxyl group (-COOH), unless otherwise indicated. "Carboxyl" can be optionally substituted.

[0137] As used herein, the term "alkenyl" can include an alkyl moiety having at least one carbon-carbon double bond, unless otherwise indicated, where the alkyl is as defined above, and includes the E and Z isomers of the alkenyl moiety. The alkenyl can be partially saturated or unsaturated. "Alkenyl" can be optionally substituted.

[0138] The term "alkenyl" can refer to a monovalent unsaturated aliphatic group that has a carbon atom as a bonding point, has a straight-chain or branched acyclic structure, has at least one non-aromatic carbon-carbon double bond, has no carbon-carbon triple bond, and has no atoms other than carbon and hydrogen. Non-limiting examples include -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenediyl" can refer to a divalent unsaturated aliphatic group that has two carbon atoms as bonding points, has a straight-chain or branched, straight-chain or branched acyclic structure, has at least one non-aromatic carbon-carbon double bond, has no carbon-carbon triple bond, and has no atoms other than carbon and hydrogen. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It should be noted that although the alkenediyl group is aliphatic, when connected at both ends, it is not precluded from forming part of an aromatic structure. The terms "alkene" and "olefin" are synonymous and refer to a class of compounds having the formula H~R, where R is an alkenyl as defined above. Similarly, the terms "terminal alkene" and "α-olefin" are synonymous and refer to an alkene having only one carbon-carbon double bond, where this bond is part of a vinyl group at the end of the molecule. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -CH=CHF, -CH=CHCl, and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

[0139] As used herein, the term "alkynyl" can include, unless otherwise indicated, an alkyl moiety having at least one carbon-carbon triple bond, where alkyl is as defined above. Alkynyl can be partially saturated or unsaturated. "Alkynyl" can be optionally substituted.

[0140] As used herein, the term "acyl" can include, unless otherwise indicated, a functional group derived from an aliphatic carboxylic acid by removal of a hydroxyl (-OH) group. "Acyl" can be optionally substituted.

[0141] As used herein, the term "alkoxyl" can include an O-alkyl group, where alkyl is as defined above and O represents oxygen, unless otherwise indicated.Representative alkoxyls include, but are not limited to, -O-methyl, -O-ethyl, -O-n-propyl, -O-n-butyl, -O-n-pentyl, -O-n-hexyl, -O-n-heptyl, -O-n-octyl, -O-isopropyl, -O-sec-butyl, -O-isobutyl, -O-tert-butyl, -O-isopentyl, -O-2-methylbutyl, -O-2-methylpentyl, -O-3-methylpentyl, -O-2,2-dimethylbutyl, -O-2,3-dimethylbutyl, -O-2,2-dimethylpentyl, -O-2,3-dimethylpentyl, -O-3,3-dimethylpentyl, -O-2,3,4-trimethylpentyl, -O-3-methylhexyl, -O-2,2-dimethylhexyl, -O-2,4-dimethylhexyl, -O-2,5-dimethylhexyl, -O-3,5-dimethylhexyl, -O-2,4-dimethylpentyl, -O-2-methylheptyl, -O-3-methylheptyl, -O-vinyl, -O-allyl, -O-1-butenyl, -O-2-butenyl, -O-isobutenyl, -O-1-pentenyl, -O-2-pentenyl, -O-3-methyl-1-butenyl, -O-2-methyl-2-butenyl, -O-2,3-dimethyl-2-butenyl, -O-1-hexenyl, -O-2-hexenyl, -O-3-hexenyl, -O-ethynyl, -O-propynyl, -O-1-butynyl, -O-2-butynyl, -O-1-pentynyl, -O-2-pentynyl, and -O-3-methyl-1-butynyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-cycloheptyl, -O-cyclooctyl, -O-cyclononyl, and -O-cyclodecyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH2-cyclopentyl, -O-CH2-cyclohexyl, -O-CH2-cycloheptyl, -O-CH2-cyclooctyl, -O-CH2-cyclononyl, -O-CH2-cyclodecyl, -O-(CH2)2-cyclopropyl, -O-(CH2)2-cyclobutyl, -O-(CH2)2-cyclopentyl, -O-(CH2)2-cyclohexyl, -O-(CH2)2-cycloheptyl, -O-(CH2)2-cyclooctyl, -O-(CH2)2-cyclononyl, or -O-(CH2)2-cyclodecyl.The alkoxyl can be saturated, partially saturated, or unsaturated. The "alkoxyl" can be optionally substituted.

[0142] As used herein, the term "cycloalkyl", unless otherwise indicated, includes aromatic, non-aromatic, saturated, partially saturated, or unsaturated, monocyclic or fused, spiro or non-fused bicyclic or tricyclic hydrocarbons having a total of 1 to 10 carbon atoms (e.g., 1 or 2 carbon atoms if other heteroatoms are present in the ring), preferably 3 to 8 ring carbon atoms. Examples of cycloalkyl include, but are not limited to, C 3-10 cycloalkyl groups (-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl). The term "cycloalkyl" can also include -lower alkyl-cycloalkyl, where lower alkyl and cycloalkyl are as defined herein. Examples of -lower alkyl-cycloalkyl groups include, but are not limited to, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclopentadienyl, -CH2-cyclohexyl, -CH2-cycloheptyl, or -CH2-cyclooctyl. The "cycloalkyl" can be optionally substituted. As used herein, "cycloheteroalkyl" can include any of the above having carbon substituted with a heteroatom (e.g., O, S, N), unless otherwise indicated.

[0143] The term "cycloalkyl" can refer to a monovalent saturated aliphatic group having carbon atoms as attachment points, where said carbon atoms form part of one or more non-aromatic ring structures, having no carbon-carbon double or triple bonds and no atoms other than carbon and hydrogen. Non-limiting examples include -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). The term "cycloalkanediyl" can refer to a divalent saturated aliphatic group having two carbon atoms as attachment points, having no carbon-carbon double or triple bonds and no atoms other than carbon and hydrogen. The group

Chem.

[0144] As used herein, the term "heterocyclic" or "heteroaryl", unless otherwise indicated, can include aromatic or non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. Representative examples of heterocycles include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, (1,4)-dioxane, (1,3)-dioxolane, 4,5-dihydro-1H-imidazolidyl, or tetrazolyl. The heterocycle can be substituted or unsubstituted. The heterocycle can also be attached by any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). The heterocyclic can be saturated, partially saturated, or unsaturated. "Heterocyclic" can be optionally substituted.

[0145] As used herein, the term "indole" is an aromatic heterocyclic organic compound having the formula C8H7N. It has a bicyclic structure consisting of a 6-membered benzene ring fused to a 5-membered nitrogen-containing pyrrole ring. "Indole" can be optionally substituted.

[0146] As used herein, the term "cyano", unless otherwise indicated, can include a -CN group. "Cyano" can be optionally substituted.

[0147] The terms "alkylsulfonyl" and "alkylsulfinyl" can each refer to -S(O)2R and -S(O)R groups, respectively, where R is alkyl (as defined above). The terms "cycloalkylsulfonyl", "alkenylsulfonyl", "alkynylsulfonyl", "arylsulfonyl", "aralkylsulfonyl", "heteroarylsulfonyl", and "heterocycloalkylsulfonyl" are defined in a similar manner. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0148] When used in the context of chemical groups: "hydrogen" means -H, "hydroxy" means -OH, "oxo" means =O, "carbonyl" means -C(=O)-, "carboxy" means -C(=O)OH (also denoted as -COOH or -CO2H), "halo" independently means -F, -Cl, -Br, or -I, "amino" means -NH2, "hydroxyamino" means -NHOH, "nitro" means -NO2, imino means =NH, "cyano" means -CN, "isocyanate" means -N=C=O, "azide" means -N3, in a monovalent context "phosphate" means -OP(O)(OH)2 or its deprotonated form, in a divalent context "phosphate" means -OP(O)(OH)O- or its deprotonated form, "mercapto" means -SH, "thio" means =S, "sulfonyl" means -S(O)2-, and "sulfinyl" means -S(O)-.

[0149] In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. The symbol

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemistry

[0150] The group “R” is a ring system, e.g., the following formula:

Chemistry

Chemistry

[0151] For chemical groups and compound classes, the number of carbon atoms within the group or class is indicated as follows. "Cn" defines the exact number (n) of carbon atoms within the group / class. "C≦n" defines the smallest possible minimum number for the group / class in question, along with the maximum number (n) of carbon atoms that can be present in the group / class. For example, for the group "alkenyl" (C≦8) " or the class "alkene" (C≦8) ", it is understood that the minimum number of carbon atoms is 2. Compare with "alkoxy" (C≦10) ", which represents an alkoxy group having 1 to 10 carbon atoms. "Cn-n'" defines both the minimum number (n) and the maximum number (n') of carbon atoms within the group. Thus, "alkyl" (C2-10) " indicates an alkyl group having 2 to 10 carbon atoms. These carbon number indicators can be before or after the chemical group or class that they modify, and they may or may not be enclosed in parentheses without indicating a change in meaning. Thus, the terms "C5 olefin", "C5-olefin", "olefin" (C5) ", and "olefin" C5 " are all synonymous. If any of the chemical groups or compound classes defined herein are modified by the term "substituted", any carbon atom(s) in the moiety replacing the hydrogen atom(s) is not counted. Thus, methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl (C1-6) .

[0152] When used to modify a compound or chemical group, the term "saturated" means that, except as described below, the compound or chemical group has no carbon-carbon double bonds and no carbon-carbon triple bonds. When this term is used to modify an atom, this means that the atom is not part of a double or triple bond. In the case of substituted versions of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. When such bonds are present, carbon-carbon double bonds that may arise as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, this means that the substance can no longer dissolve in this solution.

[0153] The term "aliphatic" can be used to indicate that the compound or chemical group thus modified is an acyclic or cyclic compound or group, but is a non-aromatic hydrocarbon compound or group. Within an aliphatic compound / group, carbon atoms can be linked together in a straight chain, a branched chain, or a non-aromatic ring (alicyclic). An aliphatic compound / group can be saturated, linked by carbon-carbon single bonds (alkanes / alkyls), or can be unsaturated, linked by one or more carbon-carbon double bonds (alkenes / alkenyls) or one or more carbon-carbon triple bonds (alkynes / alkynyls).

[0154] The term "aromatic", when used to modify a compound or chemical group, refers to a planar unsaturated ring of atoms having 4n + 2 electrons in a fully conjugated cyclic π-system.

[0155] The term "aryl" can refer to a monovalent unsaturated aromatic group that has an aromatic carbon atom as a point of attachment, where the carbon atom forms part of one or more 6-membered aromatic ring structures, all of the ring atoms are carbon, and the group contains no atoms other than carbon and hydrogen. When two or more rings are present, the rings may be fused or unfused. As used herein, the term "aryl" does not exclude the presence of one or more alkyl or aralkyl groups (within the allowable carbon number limits) attached to the first aromatic ring or any additional aromatic rings present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl. The term "arenediyl" can refer to a divalent aromatic group that has two aromatic carbon atoms as points of attachment, where the carbon atoms form part of one or more 6-membered aromatic ring structures, all of the ring atoms are carbon, and the monovalent group consists of no atoms other than carbon and hydrogen. As used herein, the term "aryl" does not exclude the presence of one or more alkyl, aryl, or alkyl groups (within the allowable carbon number limits) attached to the first aromatic ring or any additional aromatic rings present. When two or more rings are present, the rings may be fused or unfused. Unfused rings may be connected via one or more of a covalent bond, an alkanediyl, or an alkenediyl group (when carbon number restrictions allow). Non-limiting examples of arenediyl groups include the following:

Chemical formula

[0156] "Arene" refers to a class of compounds having the formula H~R, where R is aryl as defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms is used with the "substituted" modifier, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0157] The term "aralkyl" can refer to a monovalent group -alkanediyl-aryl, where the terms alkanediyl and aryl are used in a manner consistent with the definitions provided above. Non-limiting examples are phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier, one or more hydrogen atoms from the alkanediyl group and / or the aryl group are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. Non-limiting examples of substituted aralkyl are (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl.

[0158] The term "acyl" can refer to a group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, or aryl as defined above. Groups -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, and -C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, except that the oxygen atom of the group -C(O)R is replaced by a sulfur atom -C(S)R. The term "aldehyde" corresponds to an alkyl group as defined above attached to a -CHO group. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms (including, if present, hydrogen atoms directly bonded to the carbon atom of a carbonyl or thiocarbonyl group) are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. Groups -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methyl carboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups.

[0159] The term "alkoxy" can refer to a group -OR, where R is an alkyl as defined above. Non - limiting examples include -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), -OC(CH3)3 (tert - butoxy), -OCH(CH2)2, -O - cyclopentyl, and -O - cyclohexyl. The terms "cycloalkoxy", "alkenyloxy", "aryloxy", "aralkoxy", and "acyloxy" can refer to groups defined as -OR, where R is cycloalkyl, alkenyl, aryl, aralkyl, and acyl, respectively. The terms "alkylthio" and "acylthio" can refer to groups -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, where at least one of the hydrogen atoms is replaced by a hydroxy group. The term "ether" corresponds to an alkane as defined above, where at least one of the hydrogen atoms is replaced by an alkoxy group. When any of these terms is used with a "substituted" modifier, one or more hydrogen atoms are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2.

[0160] The term "alkylamino" can refer to a group -NHR, where R is an alkyl as defined above. Non - limiting examples include -NHCH3 and -NHCH2CH3. The term "dialkylamino" can refer to a group -NRR', where R and R' can be the same or different alkyl groups, or R and R' can together represent an alkanediyl. Non - limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)(CH2CH3). The terms "cycloalkylamino", "alkenylamino", "arylamino", "aralkylamino", "alkoxyamino", and "alkylsulfonylamino" can refer to groups defined as -NHR, where R is cycloalkyl, alkenyl, aryl, aralkyl, alkoxy, and alkylsulfonyl, respectively. A non - limiting example of an arylamino group is -NHC6H5. The term "amide" (acylamino) can refer to a group -NHR, where R is an acyl as defined above. A non - limiting example of an amide group is -NHC(O)CH3. The term "alkylimino" can refer to a divalent group =NR, where R is an alkyl as defined above. When any of these terms are used with a "substituted" modifier, one or more hydrogen atoms bonded to a carbon atom are independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are non - limiting examples of substituted amide groups.

[0161] The methods and compositions used herein may include one or more VLA-4 inhibitors or VLA-4 antagonists. The terms VLA-4 inhibitor and VLA-4 antagonist are used interchangeably in this disclosure. Some non-limiting examples of VLA-4 inhibitors that may be used in the compositions and methods described herein include antibodies such as the humanized monoclonal antibody natalizumab (Antegren®) against α4, and small molecules such as those described in U.S. Patent No. 5,510,332, WO06 / 023396, WO97 / 03094, WO97 / 02289, WO96 / 40781, WO96 / 22966, WO96 / 20216, WO96 / 01644, WO96 / 06108, WO95 / 15973, WO96 / 31206, WO06 / 010054, WO05 / 087760, WO01 / 12186, WO99 / 37605, WO01 / 51487, WO03 / 011288, WO02 / 14272, WO01 / 32610, and EP0842943, the entire contents of which are incorporated herein by reference. An example of a VLA-4 inhibitor that may be used herein is BIO5192 (also known as AMD15057) disclosed in PCT Publication No. WO01 / 12186, which is incorporated herein by reference. Alternatively, analogs of BIO5192 such as BIO1211 may be used. In other embodiments, the VLA-4 inhibitor is filgrastim or a pharmaceutically acceptable salt thereof.

[0162] As used herein, the term "alcohol" can include compounds in which a hydroxyl functional group (-OH) is bonded to a carbon atom, unless otherwise indicated. In particular, this carbon center is saturated and must be singly bonded to three other atoms. "Alcohol" may be optionally substituted.

[0163] The term "solvate" is intended to mean a solvated form of a designated compound that retains the effectiveness of such compound. Examples of solvates include, for example, compounds of the present technology combined with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, or ethanolamine.

[0164] As used herein, the term "mmol" is intended to mean millimolar concentration. As used herein, the term "equiv" is intended to mean equivalent. As used herein, the term "mL" is intended to mean milliliter. As used herein, the term "g" is intended to mean gram. As used herein, the term "kg" is intended to mean kilogram. As used herein, the term "μg" is intended to mean microgram. As used herein, the term "h" is intended to mean hour. As used herein, the term "min" is intended to mean minute. As used herein, the term "M" is intended to mean molar concentration. As used herein, the term "μL" is intended to mean microliter. As used herein, the term "μM" is intended to mean micromolar. As used herein, the term "nM" is intended to mean nanomolar concentration. As used herein, the term "N" is intended to mean normal concentration. As used herein, the term "amu" is intended to mean atomic mass unit. As used herein, the term "℃" is intended to mean Celsius temperature. As used herein, the term "wt / wt" is intended to mean weight / weight. As used herein, the term "v / v" is intended to mean volume / volume. As used herein, the term "MS" is intended to mean mass spectrometry. As used herein, the term "HPLC" is intended to mean high performance liquid chromatography. As used herein, the term "RT" is intended to mean room temperature. As used herein, the term "e.g." is intended to mean for example. As used herein, the term "N / A" is intended to mean not tested.

[0165] As used herein, the expression "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present disclosure. Preferred salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Further, pharmaceutically acceptable salts may have two or more charged atoms in their structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, the salt may have multiple counterions. Thus, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counterions. As used herein, the expression "pharmaceutically acceptable solvate" refers to the association of one or more solvent molecules with the compounds of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. As used herein, the expression "pharmaceutically acceptable hydrate" refers to the compounds of the present disclosure or salts thereof that may further include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0166] In some embodiments, the compounds used in the compositions of the present disclosure include the compounds described in the examples and claims listed below. All of the above synthetic methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by those skilled in the art. Such principles and techniques are taught, for example, in March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2007) (incorporated herein by reference).

[0167] The compounds used in the methods of the present disclosure may contain one or more asymmetrically substituted carbon atoms or nitrogen atoms and may be isolated in optically active forms or racemic forms. Accordingly, unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic, epimeric forms, and all geometric isomeric forms of the structure are intended. Compounds can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 recommendations. For example, mixtures of stereoisomers can be separated using the techniques taught in the following examples section, as well as modifications thereof. Tautomers, as well as pharmaceutically acceptable salts of such isomers and tautomers are also included.

[0168] The atoms that make up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. The compounds of the present disclosure include those having one or more atoms that are isotopically modified or enriched, particularly those having pharmaceutically acceptable isotopes, or those useful in pharmaceutical research. As used herein, an isotope includes atoms having the same number of atoms but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium, and isotopes of carbon are 13 C and 14It contains C. Similarly, it is contemplated that one or more carbon atoms of the compounds of the present disclosure may be replaced with silicon atom(s). Further, it is contemplated that one or more oxygen atoms of the compounds of the present disclosure may be replaced with sulfur or selenium atom(s).

[0169] The compounds of the present disclosure may also exist in prodrug form. Since prodrugs are known to enhance many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), the compounds used in some of the methods of the present disclosure may be delivered in prodrug form if desired. Accordingly, the present disclosure contemplates prodrugs of the compounds of the present disclosure and methods of delivering the prodrugs. Prodrugs of the compounds used in the present disclosure can be prepared by modifying the functional groups present in the compounds in such a manner that the modification is cleaved to the parent compound either by routine manipulation or in vivo. Thus, prodrugs include, for example, compounds as described herein in which a hydroxy, amino, or carboxy group is bonded to any group that is cleaved to form a hydroxy, amino, or carboxylic acid, respectively, when the prodrug is administered to a subject. Further details regarding prodrugs are described in Smith and Williams, 1988 (the entire content of which is incorporated herein by reference). Smith and Williams Introduction to the Principles of Drug Design, Smith, H.J.; Wright, 2nd ed., London (1988) (the content of which is incorporated herein by reference).

[0170] It should be appreciated that the specific anion or cation forming part of any salt of the present disclosure is not critical so long as the overall salt is pharmacologically acceptable. The compounds useful in the present disclosure (which are amines) can be administered or prepared in the form of their acid addition salts or metal complexes thereof. Suitable acid addition salts include salts of biocompatible inorganic acids such as HCl, HBr, sulfuric acid, phosphoric acid, etc., as well as organic acids such as acetic acid, propionic acid, butyric acid, etc., and acids containing two or more carboxyl groups such as oxalic acid, glutaric acid, adipic acid, etc. Compounds useful in the present disclosure that are carboxylic acids or otherwise acidic can be administered or prepared in the form of salts formed from physiologically compatible inorganic or organic bases. Thus, these compounds may, if desired, be prepared in the form of their sodium, potassium, calcium, or magnesium salts, or may be salts with organic bases such as caffeine or ethylamine. These compounds may also be in the form of metal complexes. Further examples of pharmaceutically acceptable salts, as well as methods for their preparation and use, are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002) (incorporated herein by reference).

[0171] It should be further recognized that the compounds of the present disclosure include those that are further modified to contain substituents convertible to hydrogen in vivo. This includes groups that can be convertible to hydrogen atoms by enzymatic or chemical means, including but not limited to hydrolysis and hydrogenolysis. Examples include hydrolyzable groups such as groups having an acyl group, an oxycarbonyl group, an amino acid residue, a peptide residue, o-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, tert-butoxycarbonyl (-C(O)OC(CH3)3, Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like. Suitable amino acid residues include, but are not limited to, Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn (ornithine), and β-Ala. Examples of suitable amino acid residues also include amino acid residues protected with a protecting group. Examples of suitable protecting groups include groups typically used in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonyl groups (-C(O)OC(CH3)3, Boc), and the like. Suitable peptide residues include peptide residues containing 2 to 5 amino acid residues. These residues of amino acids or peptides can exist in a stereochemical configuration of D-type, L-type, or a mixture thereof.In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having an asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr, and Tyr. Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Examples of suitable amino acid protecting groups include groups typically used in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert-butoxycarbonyl group (-C(O)OC(CH3)3), and the like. Other examples of "substituents convertible to hydrogen in vivo" include hydrolysable groups removable by reduction. Examples of suitable hydrolysable groups removable by reduction include arylsulfonyl groups (such as o-toluenesulfonyl), methyl groups substituted with phenyl or benzyloxy (such as benzyl, trityl, and benzyloxymethyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl), and haloethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl and β-iodoethoxycarbonyl), but are not limited thereto.

[0172] Regardless of whether the compounds of the present disclosure are used in the indications described herein, they are more effective, less toxic, act longer, are more potent, have fewer side effects, are more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than compounds known in the prior art, and / or may have other useful pharmacological, physical or chemical properties.

[0173] Agents that interact with chemokine receptors As used herein, a "drug that interacts with a chemokine receptor" can include a chemokine, cytokine, chemokine receptor, or a drug that modulates the activity of these molecules, such as a fragment, antibody, or small organic molecule.

[0174] In some embodiments, the drug that interacts with a chemokine receptor is a drug that interacts with a CXC chemokine receptor. In one embodiment, the present disclosure relates to a composition that modulates the activity of a CXC chemokine receptor such as CXCR2 or CXCR4. In some embodiments, the method and composition comprise at least one CXCR2 agonist or CXCR4 antagonist. In some embodiments, the method and composition comprise at least one CXCR2 ligand or CXCR4 ligand. The ligand may be an agonist or an antagonist.

[0175] As used herein, "interacts with" means that the drug binds to a chemokine in a manner that modulates the activity of the chemokine, such as by reducing, inhibiting, increasing, or activating the activity of the chemokine. In one embodiment, the present disclosure relates to a composition that modulates the activity of a CXC chemokine receptor such as CXCR2 or CXCR4. In some embodiments, the method and composition comprise at least two drugs that interact with a chemokine. In some embodiments, the method and composition comprise a first drug comprising a CXCR2 agonist and a second drug comprising a CXCR4 inhibitor. In a preferred embodiment, the method and composition comprise a VLA-4 inhibitor or VLA-4 antagonist, a CXCR4 inhibitor, and / or a CXCR2 agonist disclosed herein. In certain embodiments, the method and composition comprise a VLA-4 inhibitor or VLA-4 antagonist, AMD3100 (plerixafor) or BL-8040 (motixafortide), and / or Groβ disclosed herein.

[0176] In some embodiments, the agent is a CXCR2 agonist. In some embodiments, the agent is Groβ or a derivative of Groβ. In some embodiments, the derivative of Groβ is truncated Groβ (tGroβ). In some embodiments, the truncated Groβ is SB-251353.

[0177] CXCR2 agonists include any molecule that activates the CXCR2 receptor. Such molecules include chemokines, cytokines, agonist antibodies or biologically active fragments thereof, or small organic molecules. Some non-limiting examples of chemokines that act via the CXCR2 receptor include, but are not limited to, Groβ, Groα, Groγ, GCP-2 (granulocyte chemoattractant protein 2), IL-8, NAP-2 (neutrophil activating peptide 2), ENA-78 (epithelial cell-derived neutrophil activating protein 78), and MGSA.

[0178] The CXCR2 receptor agonist that can be used in the compositions and methods described herein is SB-251353, a basic heparin-binding protein having a molecular weight of about 7500 Da (King et al., 2000, Hepburn et al., 2001). In some embodiments, the CXCR2 agonist used in the methods and compositions described herein is Groβ and modified forms thereof. King et al., 2001 demonstrated that the recombinant N-terminal 4-amino acid truncated form of human chemokine Groβ (also known as SB-251353 or garnocestm or Groβt or tGroβ) can mobilize progenitor cells after administration of SB-251353 in combination with G-CSF. This combination resulted in the mobilization of neutrophils and platelets during these studies. Chemokines such as SB-251353, Groα, Groβ, and Groγ are further discussed in WO94 / 29341, WO97 / 15594, WO97 / 15595, WO99 / 26645, WO02 / 02132, U.S. Patent No. 6,080,398, U.S. Patent No. 6,399,053, and U.S. Patent No. 6,447,766, which are incorporated herein by reference.

[0179] The "Groβ", "Groβ protein", or "Groβ chemokine" class includes Groβ itself, as well as modified forms of Groβ. These modified forms include, but are not limited to, modifications by cleavage, multimerization, amino acid substitution, amino acid deletion and / or insertion, or combinations thereof. "Modified forms of Groβ" include cleavage forms such as those described in U.S. Patent Nos. 6,447,766, 6,399,053, 6,080,398, PCT Publication No. 99 / 26645, PCT Publication No. WO97 / 15595, PCT Publication No. WO02 / 02132, PCT Publication No. WO97 / 1594, and PCT Publication No. WO94 / 29341 (which are incorporated herein by reference). "Modified forms of Groβ" are multimeric forms of Groβ such as dimers, trimers, tetramers, or other versions containing multiple proteins or modified proteins. Some non-limiting examples of "modified forms" include cleavage of 2 to about 8 amino acids at the amino terminus of the mature protein, cleavage of about 2 to about 10 amino acids at the carboxy terminus of the mature protein, or modified forms of Groβ having multimeric forms (e.g., dimers, trimers, tetramers, and other aggregated forms) of modified and / or cleaved proteins. Some non-limiting examples of cleavage forms of Groβ include SB-251353 consisting of amino acids 5 - 73 and its form in which amino acid 69 is deamidated.

[0180] Another specific CXCR2 receptor agonist that can be used in the compositions and methods described herein is SB-251353, a basic heparin-binding protein having a molecular weight of about 7500 Da (King et al., J Immunol 2000;164:3774 - 3782, Hepburn et al., Journal of Pharmacology and Experimental Therapeutics 2001;298:886 - 893).

[0181] The compositions and methods described herein may include one or more CXCR4 inhibitors. Some non-limiting examples of CXCR4 inhibitors include AMD3100 (plerixafor), BL-8040 (motixafortide), AMD3465, CTCE-0214, CTCE-9908, CP-1221 (linear peptides, cyclic peptides, natural amino acids, unnatural amino acids, and peptidomimetic compounds), T140 and analogs, 4F-benzoyl-TN24003, KRH-1120, KRH-1636, KRH-2731, polyphemusin analogs, ALX40-4C, or CXCR4 inhibitors (described in WO01 / 85196, WO99 / 50461, WO01 / 94420, WO03 / 090512, US2005 / 0059702, US2005 / 027767, US2003 / 9229341, US5021409, US6001826, and US5583131. Each of these is incorporated herein by reference).

[0182] The compositions and methods described herein may include one or more CXCR4 inhibitors (e.g., antagonists). In some embodiments, the agent is a CXCR4 antagonist. In some embodiments, the agent is plerixafor or BL-8040 (motixafortide), or a derivative thereof.

[0183] Some non-limiting examples of CXCR4 inhibitors include AMD3100 (Plerixafor), BL-8040 (Motixafortide), AMD3465, CTCE-0214, CTCE-9908, CP-1221 (linear peptides, cyclic peptides, natural amino acids, unnatural amino acids, and peptidomimetic compounds), T140 and analogs, 4F-benzoyl-TN24003, KRH-1120, KRH-1636, KRH-2731, polyphemusin analogs, ALX40-4C, or CXCR4 inhibitors (described in WO01 / 85196, WO99 / 50461, WO01 / 94420, WO03 / 090512, US2005 / 0059702, US2005 / 027767, US2003 / 9229341, US5021409, US6001826, and US5583131. Each of these is incorporated herein by reference).

[0184] The compositions or methods described herein can include G-CSF. It is contemplated that any suitable source of G-CSF can be used. In some embodiments, the composition further comprises an inhibitor of integrin α9β1, G-CSF, a derivative of G-CSF, or a combination thereof. In some embodiments, the derivative of G-CSF is PEGylated G-CSF. In some embodiments, the inhibitor of integrin α9β1 is (N-benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl) tyrosine (BOP). In some embodiments, the G-CSF used in the present composition or method may be recombinant or purified using known techniques. This includes, but is not limited to, Neupogen® filgrastim (Amgen), Neutrogin® / Granocyte® lenograstim (Chugai Pharmaceuticals), and Neulasta® PEGylated filgrastim (Amgen). Additionally, biologically active fragments, variants, derivatives, or fusion proteins may also be used if these agents retain the ability to mobilize progenitor or stem cells.

[0185] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compositions disclosed herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration, intraarterial administration, intraperitoneal administration, intravenous administration, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for administration via intravenous infusion. In other embodiments, the pharmaceutical composition is formulated for administration via subcutaneous injection. In some embodiments, the composition consists essentially of an agent that interacts with one or more chemokine receptors, a VLA-4 inhibitor, and a pharmaceutically acceptable excipient. In some embodiments, the composition consists essentially of an agent that interacts with one or more chemokine receptors, a VLA-4 inhibitor, and a pharmaceutically acceptable excipient.

[0186] Disclosed herein are methods comprising chemokine receptor interacting agents such as CXCR2 agonists and CXCR4 antagonists, and compounds that act as integrin antagonists or inhibitors such as α4β1 integrin (VLA-4) antagonists, and pharmaceutical compositions thereof. These pharmaceutical compositions can effect mobilization of progenitor and / or stem cells from the bone marrow to the peripheral circulation. Further provided herein are methods for treating and / or preventing a disease by combining these two therapeutic agents. These compositions described herein can be used to stimulate progenitor and / or stem cells (e.g., hematopoietic stem cells such as CD34+ hematopoietic stem cells) and effect such stimulation in a shorter time compared to either the agent alone or any other known agent or combination. These compositions also effect a greater number of mobilizations, initiate mobilization over a shorter or longer period of time, or have the additional advantage of mobilizing an increased number of early progenitor and / or stem cells, LSK-SLAM cells, CFU-C cells, or other progenitor and / or stem cells that can result in successful engraftment in a patient. In some embodiments, these compositions can be used to improve the collection of hematopoietic stem cells or progenitor cells. These methods, compositions, or uses are described in more detail below.

[0187] A VLA-4 inhibitor in combination with an agent that interacts with a chemokine receptor The present disclosure provides methods of using a compound that is a VLA-4 antagonist in combination with an agent that interacts with a chemokine receptor. The chemokine receptor may be CXCR2 (e.g., tGroβ) and / or CXCR4 (e.g., AMD3100 (plerixafor), BL-8040 (motixafortide)), and includes these methods of use and methods of treatment. Also provided herein are compositions comprising these drugs. For example, the VLA-4 inhibitor compositions described herein have been shown to increase the amount or number of mobilized cells in combination with a chemokine interacting agent such as plerixafor (AMD3100) or BL-8040 (motixafortide) and / or tGroβ.

[0188] In some aspects, the present disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor. In some embodiments, the disease or disorder is related to integrin α4β1. In some embodiments, the disease or disorder is related to hematopoietic stem cells. In some embodiments, the hematopoietic stem cells are LSK-SLAM cells. In some embodiments, the disease or disorder is cancer, or a reduction in blood cell count such as a reduction in blood cell count resulting from cancer therapy. In some embodiments, the disease or disorder is a reduction in blood cell count resulting from cancer therapy such as chemotherapy or radiation therapy. In some embodiments, the disease or disorder is cancer. In some embodiments, the patient is also administered chemotherapy or radiation therapy. In some embodiments, an effective combined dose of the agent that interacts with a chemokine receptor and the VLA-4 inhibitor results in an improvement in the effectiveness of chemotherapy or radiation therapy. In some embodiments, the therapeutically effective amount is a therapeutically effective combined dose.

[0189] In some aspects, the present disclosure provides a method of inducing mobilization of hematopoietic stem cells or progenitor cells, the method comprising contacting the hematopoietic stem cells with an agent that interacts with a chemokine receptor in an effective combined amount and a VLA-4 inhibitor. In some embodiments, the method is ex vivo. In other embodiments, the method is in vitro. In still other embodiments, the method is in vivo.

[0190] In some aspects, the present disclosure provides a method of harvesting hematopoietic stem cells or progenitor cells from a patient, the method comprising administering to the patient an agent that interacts with a chemokine receptor disclosed herein and a VLA-4 inhibitor in an amount sufficient to mobilize the hematopoietic stem cells or progenitor cells into the patient's peripheral blood, and then collecting peripheral blood from the patient to harvest the hematopoietic stem cells or progenitor cells.

[0191] In some aspects, the present disclosure provides a method of harvesting hematopoietic stem cells or progenitor cells from a patient administered an agent that interacts with a chemokine receptor and a VLA-4 inhibitor in an amount sufficient to mobilize the hematopoietic stem cells or progenitor cells into the patient's peripheral blood, the method comprising then collecting peripheral blood from the patient to harvest the hematopoietic stem cells or progenitor cells.

[0192] In some aspects, the present disclosure provides a method of improving the harvesting of hematopoietic stem cells or progenitor cells, the method comprising administering to the patient a therapeutically effective combined amount of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor. In some aspects, the present disclosure provides a method of transplanting hematopoietic stem cells or progenitor cells, the method comprising administering to a first patient a therapeutically effective combined amount of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor, harvesting hematopoietic stem cells or progenitor cells from the first patient, and transplanting the hematopoietic stem cells or progenitor cells into a second patient. In some embodiments, the hematopoietic stem cells are harvested from the patient prior to an event that results in a reduction in the amount of hematopoietic stem cells or progenitor cells of the first patient. In some embodiments, the first patient is a compatible hematopoietic stem cell donor.

[0193] In some aspects, the present disclosure provides a method of transplanting hematopoietic stem cells or progenitor cells, comprising transplanting into a second patient hematopoietic stem cells or progenitor cells obtained from a first patient administered a therapeutically effective combination dose of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor. In some embodiments, the hematopoietic stem cells are obtained from the patient prior to an event that results in a reduction in the amount of hematopoietic stem cells or progenitor cells of the first patient. In some embodiments, the first patient is a matched hematopoietic stem cell donor.

[0194] In some aspects, the present disclosure provides a method of transplanting hematopoietic stem cells or progenitor cells, comprising administering to a patient a therapeutically effective combination dose of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor, obtaining hematopoietic stem cells or progenitor cells from the patient, and transplanting the hematopoietic stem cells or progenitor cells into the patient. In some embodiments, the hematopoietic stem cells or progenitor cells are transplanted after an event that results in a reduction in the amount of hematopoietic stem cells or progenitor cells of the patient.

[0195] In some aspects, the present disclosure provides a method of transplanting hematopoietic stem cells or progenitor cells into a patient, comprising transplanting hematopoietic stem cells or progenitor cells obtained from a patient administered a therapeutically effective combination dose of an agent that interacts with a chemokine receptor and a VLA-4 inhibitor. In some embodiments, the hematopoietic stem cells or progenitor cells are transplanted after an event that results in a reduction in the amount of hematopoietic stem cells or progenitor cells of the patient.

[0196] In some embodiments, the present disclosure provides a method of improving the effectiveness of cancer treatment in a patient administered chemotherapy or radiation therapy, the method comprising administering to the patient a chemokine receptor-interacting agent and a VLA-4 inhibitor in a therapeutically effective combined amount, and administering chemotherapy or radiation therapy to the patient. In some embodiments, the chemotherapy or radiation therapy is administered concurrently with the chemokine receptor-interacting agent and the VLA-4 inhibitor. In some embodiments, the chemotherapy or radiation therapy is administered prior to the chemokine receptor-interacting agent and the VLA-4 inhibitor. In other embodiments, the chemotherapy or radiation therapy is administered subsequent to the chemokine receptor-interacting agent and the VLA-4 inhibitor.

[0197] In some embodiments, the present disclosure provides a method of improving the effectiveness of cancer treatment in a patient who has been or is to be administered chemotherapy or radiation therapy, and a chemokine receptor-interacting agent and a VLA-4 inhibitor in a therapeutically effective combined amount. In some embodiments, the chemotherapy or radiation therapy is administered concurrently with the chemokine receptor-interacting agent and the VLA-4 inhibitor. In some embodiments, the chemotherapy or radiation therapy is administered prior to the chemokine receptor-interacting agent and the VLA-4 inhibitor. In other embodiments, the chemotherapy or radiation therapy is administered subsequent to the chemokine receptor-interacting agent and the VLA-4 inhibitor.

[0198] In some embodiments, the method comprises administering the chemokine receptor-interacting agent once. In other embodiments, the method comprises administering the chemokine receptor-interacting agent two or more times.

[0199] In some embodiments, the method comprises administering the VLA-4 inhibitor once. In other embodiments, the method comprises administering the VLA-4 inhibitor two or more times.

[0200] In some embodiments, the VLA-4 inhibitor and the agent that interacts with the chemokine receptor are administered simultaneously. In further embodiments, the method comprises administering a composition comprising an agent that interacts with the chemokine receptor and a VLA-4 inhibitor. In other embodiments, the method comprises administering an agent that interacts with the chemokine receptor before administering the VLA-4 inhibitor. In some embodiments, the agent that interacts with the chemokine receptor is administered 15 minutes to 0 minutes before the VLA-4 inhibitor. In other embodiments, the method comprises administering an agent that interacts with the chemokine receptor after administering the VLA-4 inhibitor.

[0201] In some embodiments, the agent that interacts with the chemokine receptor is administered subcutaneously and the VLA-4 inhibitor is administered intravenously. In other embodiments, both the agent that interacts with the chemokine receptor and the VLA-4 inhibitor are administered subcutaneously.

[0202] In some embodiments, the method produces an effect corresponding to the sum of the effects of each of the agent that interacts with the chemokine receptor or the VLA-4 inhibitor when administered independently. In other embodiments, the method produces a synergistic effect as compared to the effects of each of the agent that interacts with the chemokine receptor or the VLA-4 inhibitor when administered independently.

[0203] In some embodiments, the hematopoietic stem cells or progenitor cells are LSK-SLAM cells.

[0204] In some embodiments, the agent that interacts with the chemokine receptor is selected from preleukisophor, Groβ, or a derivative of Groβ. In some embodiments, the derivative of Groβ is a truncated version of Groβ. In some embodiments, the truncated version of Groβ is SB-251353.

[0205] In some embodiments, the method further comprises administering an inhibitor of integrin α9β1, G-CSF, a derivative of G-CSF, or a combination thereof. In some embodiments, the inhibitor of integrin α9β1 is (N-benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl) tyrosine (BOP).

[0206] Compositions and methods are disclosed herein that include a first agent that interacts with a chemokine such as a CXCR2 agonist, a second agent that interacts with a chemokine such as a CXCR4 inhibitor, and a compound that acts as an integrin antagonist or inhibitor such as an α4β1 integrin (VLA-4) antagonist, and compositions thereof. These compositions can effect mobilization of progenitor cells and / or stem cells from bone marrow to the peripheral circulation. Further, methods are provided herein for treating and / or preventing a disease by combining these two therapeutic agents. These compositions described herein can be used to stimulate progenitor cells and / or stem cells and effect such stimulation in a shorter period of time compared to either the agent alone or other known agents or combinations. These compositions also provide the additional advantage of effecting a greater number of mobilizations, initiating mobilization over a shorter or longer period, or mobilizing an increased number of early progenitor cells and / or stem cells, LSK-SLAM cells, CFU-C cells, or other progenitor cells and / or stem cells that can successfully engraft in a patient. In some embodiments, these compositions can be used to improve the collection of hematopoietic stem cells or progenitor cells. These methods, compositions, or uses are described in more detail below.

[0207] Pharmaceutical Formulations and Routes of Administration In some embodiments, the present disclosure relates to a composition comprising one or more VLA-4 inhibitors and one or more agents that interact with chemokines such as a CXCR2 agonist, a CXCR4 inhibitor, or G-CSF. In some embodiments, the present disclosure relates to a composition comprising one or more VLA-4 inhibitors and at least two agents that interact with chemokines. In some embodiments, the present disclosure relates to a composition comprising one or more VLA-4 inhibitors, at least one CXCR4 inhibitor, and at least one CXCR2 agonist. These compositions may further comprise excipients such as solvents or diluents that render the composition suitable for administration by injection. In some embodiments, the components of these compositions may be independently formulated and then administered to a patient simultaneously. In other embodiments, these compositions are formulated with additional therapeutic agents or excipients. In other embodiments, these compositions consist essentially of, consist of, or comprise one or more VLA-4 inhibitors, one or more agents that interact with chemokines, and one or more excipients. Each of the compositions described herein comprises a pharmaceutically effective amount of each of these combined agents. In particular, the composition may comprise a pharmaceutically effective combination amount of a VLA-4 inhibitor, a CXCR4 inhibitor, and a CXCR2 agonist. A pharmaceutically effective combination amount is obtained when each agent is present in an amount such that the combined effect results in an increase in activity as compared to the same amount of the single agent. In some embodiments, the combined effect results in an additive increase in activity. In some embodiments, the combined effect results in synergistic activity.

[0208] For administration to a subject in need of such treatment, a therapeutically effective amount of the compound is usually combined with one or more excipients appropriate for the indicated route of administration. The compounds of the present disclosure are intended to be formulated in a manner suitable for the treatment of veterinary and human patients. In some embodiments, the veterinary patient can be a bird such as a chicken, turkey, or duck, a companion animal such as a cat or dog, a livestock animal such as a cow, horse, pig, or goat, a zoo animal, and a wild animal. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and can be tableted or encapsulated for ease of administration. Alternatively, the compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffer solutions. Other excipients and modes of administration are well and widely known in the pharmaceutical art and can be adapted to the type of animal being treated. Explanation of potential routes of administration that can be used to formulate the compositions described herein can include those taught in Remington’s Pharmaceutical Sciences (incorporated herein by reference).

[0209] The pharmaceutical compositions useful in the present disclosure may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional pharmaceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, buffering agents, etc.

[0210] The compounds of the present disclosure can be administered by various methods, such as orally or by injection (e.g., subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the active compounds can be coated with materials to protect the compounds from the action of acids and other natural conditions that can inactivate the compounds. They can also be administered by continuous perfusion / infusion of the disease.

[0211] In order to administer a therapeutic compound by a method other than parenteral administration, it may be necessary to coat the compound with a material to prevent inactivation of the compound, or to co-administer the compound with this material. For example, a therapeutic compound may be administered to a patient in a suitable carrier, such as a liposome, or in a diluent. Pharmaceutically acceptable diluents include physiological saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0212] A therapeutic compound may also be administered parenterally, intraperitoneally, intramuscularly, intraarterially, intraspinally, or intracerebrally. The dispersion can be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof, and in oils. Under normal storage and use conditions, these preparations may contain a preservative to prevent the growth of microorganisms.

[0213] A pharmaceutical composition suitable for use in injection may include (in the case of water-soluble) a sterile aqueous solution, or a dispersion for the immediate preparation of a sterile injectable solution or dispersion, and sterile powder. In all cases, the composition must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it may be useful to include in the composition an isotonic agent, such as sugar, sodium chloride, or a polyhydric alcohol such as mannitol and sorbitol. Prolonged absorption of an injectable composition can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin.

[0214] For intravenous or parenteral administration, the compound is formulated in a suitable liquid form, optionally with excipients. The composition may include liposomes or other suitable carriers. For intravenous injection, the solution is made isotonic using standard preparations such as Hank's solution or other isotonic solutions.

[0215] Sterile injectable solutions can be prepared by incorporating the required amount of the therapeutic compound into a suitable solvent containing, optionally, one or a combination of the ingredients listed above, followed by filter sterilization. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile carrier containing a basic dispersion medium and the other required ingredients from those listed above. In the case of sterile powders for preparing sterile injectable solutions, the preparation methods include vacuum drying and freeze drying, from which powders of the active ingredient (i.e., the therapeutic compound) and any additional desired ingredients are obtained from a previously sterile filtered solution.

[0216] The therapeutic compound can be administered orally, for example, with an inert diluent or an absorbable edible carrier. The therapeutic compound and other ingredients may also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the subject's food or drink. For oral therapeutic administration, the therapeutic compound is incorporated with excipients and can be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. The proportion of the therapeutic compound in the composition and preparation can, of course, vary. The amount of the therapeutically useful therapeutic compound in such pharmaceutical formulations is an amount such that a suitable dosage is obtained.

[0217] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the parenteral composition in unit dosage form. As used herein, unit dosage form refers to physically discrete units suitable as unit doses for the subject to be treated, each unit containing a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specifications for the unit dosage forms of the present disclosure are defined by and directly depend on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such therapeutic compounds for the treatment of the selected condition of the patient.

[0218] The therapeutic compound can also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lung is desired, the therapeutic compound can be administered by inhalation in a dry powder or aerosol formulation. Alternatively, the therapeutic agent may be administered transdermally.

[0219] The active compound is administered in a therapeutically effective dosage sufficient to treat the condition associated with the patient's disease state. For example, the effectiveness of the compound can be evaluated in an animal model system (e.g., the model systems shown in the Examples and Drawings) that can predict effectiveness in the treatment of diseases in humans or other animals.

[0220] The effective dosage range of the therapeutic agent can be extrapolated from the effective dosages determined in animal studies for various different animals. Generally, the human equivalent dose (HED) in mg / kg can be calculated according to the following formula (see, for example, Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, incorporated herein by reference). HED (mg / kg) = animal dose (mg / kg) × (animal K m / human K m )

[0221] The use of the K m coefficient in the conversion results in a more accurate HED value based on body surface area (BSA) rather than based solely on body mass. The K mThe values are well-known. For example, for a human with an average weight of 60 kg (BSA is 1.6 m 2 ), the K m is 37, while for a 20 kg child (BSA is 0.8 m 2 ), the K m is 25. The K m for some related animal models is also well-known, which is 3 for a mouse (assuming a weight of 0.02 kg and a BSA of 0.007), m 5 for a hamster (assuming a weight of 0.08 kg and a BSA of 0.02), m 6 for a rat (assuming a weight of 0.15 kg and a BSA of 0.025), m and 12 for a monkey (assuming a weight of 3 kg and a BSA of 0.24). m

[0222] The exact amount of the therapeutic composition depends on the judgment of the physician and is specific to each individual. However, the calculated HED dose provides a general guide. Other factors that affect the dose include the patient's physical and clinical condition, the route of administration, the intended goal of the treatment, and the potency, stability, and toxicity of the specific therapeutic formulation.

[0223] The actual dosage of the compound of the present disclosure or a composition comprising the compound of the present disclosure administered to a subject can be determined by physical and physiological factors such as the type of animal being treated, age, sex, weight, severity of the condition, type of disease being treated, previous or concurrent therapeutic interventions, idiosyncrasy of the subject, and the route of administration. These factors can be determined by those skilled in the art. The physician responsible for administration typically determines the concentration of the active ingredient(s) in the composition and the appropriate dosage(s) for the individual subject. The dosage can be adjusted by the individual physician in the event of any complications.

[0224] ​In one aspect, the method or composition can be administered such that the VLA-4 inhibitor is administered intravenously and the agent (e.g., the first and / or second agent) that interacts with the chemokine receptor is administered subcutaneously. Alternatively, both the VLA-4 inhibitor and the agent that interacts with the chemokine receptor may be administered subcutaneously. In yet another embodiment, both the VLA-4 inhibitor and the agent that interacts with the chemokine receptor are administered subcutaneously in a single formulation. In some embodiments, the VLA-4 inhibitor and the agent that interacts with the chemokine receptor are administered subcutaneously or intravenously as a single formulation. The protocol for administration to a particular patient can be further optimized by a skilled physician.

[0225] The effective amount typically varies from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.001 mg / kg to about 50 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, from about 10.0 mg / kg to about 150 mg / kg, or from about 1.0 mg / kg to about 15 mg / kg, with administration once or more per day for one day or several days (depending, of course, on the mode of administration and the factors discussed above). Other suitable dosage ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some particular embodiments, the amount is less than 10,000 mg per day and is in the range of 750 mg to 9,000 mg per day.

[0226] In some embodiments, the VLA-4 antagonist (i.e., inhibitor) can be administered in an amount of about 1 mg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg, or about 1 mg / kg to about 15 mg / kg, or about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg, or about 3 mg / kg. In some embodiments, a specific VLA-4 inhibitor such as a compound of formula I can be administered in the range of about 1 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 100 mg / kg, or about 75 mg / kg to about 100 mg / kg, or about 100 mg / kg.

[0227] In some embodiments, an agent that interacts with a chemokine receptor can be administered in an amount of about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg, or about 2.5 mg / kg. The agent that interacts with the chemokine receptor can be Groβ or a derivative thereof. Similarly, the VLA-4 inhibitor can be administered in an amount of about 1 mg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg, or about 1 mg / kg to about 15 mg / kg, or about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg, or about 3 mg / kg. In some embodiments, a specific VLA-4 inhibitor such as a compound of formula I or a specific compound described in the examples (e.g., filategrast) or a compound of the VLA-4 inhibitor described herein (e.g., the compounds listed in Table 1) can be administered in the range of about 1 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 100 mg / kg, or about 75 mg / kg to about 100 mg / kg, or about 100 mg / kg.

[0228] The effective amount of the inhibitor or agent can be less than 1 mg / kg / day, less than 500 mg / kg / day, less than 250 mg / kg / day, less than 100 mg / kg / day, less than 50 mg / kg / day, less than 25 mg / kg / day, or less than 10 mg / kg / day. Alternatively, it can be in the range of 1 mg / kg / day to 200 mg / kg / day.

[0229] In other non-limiting examples, the dosage can be, per administration, about 1 microgram / kg / body weight, about 5 micrograms / kg / body weight, about 10 micrograms / kg / body weight, about 50 micrograms / kg / body weight, about 100 micrograms / kg / body weight, about 200 micrograms / kg / body weight, about 350 micrograms / kg / body weight, about 500 micrograms / kg / body weight, about 1 milligram / kg / body weight, about 5 milligrams / kg / body weight, about 10 milligrams / kg / body weight, about 50 milligrams / kg / body weight, about 100 milligrams / kg / body weight, about 200 milligrams / kg / body weight, about 350 milligrams / kg / body weight, about 500 milligrams / kg / body weight, up to about 1000 mg / kg / body weight or more, and can include any range derived therefrom. In non-limiting examples of ranges derived from the numerical values listed herein, based on the above numerical values, ranges such as about 5 mg / kg / body weight to about 100 mg / kg / body weight, about 5 micrograms / kg / body weight to about 500 milligrams / kg / body weight can be administered.

[0230] In certain embodiments, the pharmaceutical composition of the present disclosure can contain, for example, at least about 0.1% of the compound of the present disclosure. In other embodiments, the compound of the present disclosure can be included in an amount of about 1% to about 75% by unit weight, or, for example, about 25% to about 60%, and any range derived therefrom.

[0231] Single or multiple doses of the agent are contemplated. The desired time interval for multiple-dose delivery can be determined by one of ordinary skill in the art using only routine experimentation. By way of example, a subject can be administered two doses per day at an interval of about 12 hours. In some embodiments, the agent is administered once a day.

[0232] The agent(s) can be administered according to a conventional schedule. As used herein, a conventional schedule refers to a predetermined specified period. The conventional schedule can include periods of the same or different lengths as long as the schedule is a predetermined schedule. For example, the conventional schedule can involve administration twice a day, daily, every two days, every three days, every four days, every five days, every six days, on a weekly basis, on a monthly basis, or with any set number of days or weeks in between. Alternatively, a given conventional schedule can include administering twice a day for the first week and then daily for several months, etc. In other embodiments, the disclosure provides that the agent(s) may be orally ingested, and the timing may or may not depend on food intake. Thus, for example, the agent can be ingested every morning and / or every night regardless of when the subject ate or will eat.

[0233] An "active ingredient" (AI) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or therapeutic compound) is a component in a pharmaceutical or pesticidal agent that is biologically active. Similar terms such as active pharmaceutical ingredient (API) and bulk active are also used in pharmaceuticals, and the term active substance can be used in the formulation of pesticidal agents.

[0234] A "stable" formulation or composition can refer to a composition having sufficient stability to allow storage for a commercially reasonable period, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years, for example, at a convenient temperature between about 0°C and about 60°C.

[0235] The formulation must be compatible with the mode of administration. The agents used in conjunction with the present disclosure can be formulated by known methods for administration to a subject using several routes including, but not limited to, parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., by aerosol), implantation, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intraventricular, subcutaneous, intranasal, epidural, intrathecal, intraocular, transdermal, buccal, and rectal. Individual agents can be administered in combination with one or more additional agents or together with other biologically active or biologically inactive agents. Such biologically active or inactive agents may be in fluid or mechanical communication with the agent(s) or may be bound to the agent(s) by ionic, covalent, van der Waals, hydrophobic, hydrophilic, or other physical forces.

[0236] The compositions and methods described herein may include one or more additional agents that are therapeutically or nutritionally useful, such as antibiotics, vitamins, herbal extracts, anti-inflammatory agents, glucose, antipyretics, analgesics, cyclophosphamide, recombinant stem cell factor (Stemgen®), granulocyte-macrophage colony-stimulating factor (GM-CSF) (such as Leukine® and Leucomax®), ETRX-101, TLK199 / TILENTRA™, interleukin-1 (IL-1), interleukin-3 (IL-3), interleukin-8 (IL-8), PIXY-321 (GM-CSF / IL-3 fusion protein), macrophage inflammatory protein, thrombopoietin, or similar agents. Additionally, the composition may include one or more agents that prevent the growth of microorganisms and increase the shelf life of the composition. Such agents can be anti-parasitic, anti-fungal, antibiotic, or antiviral agents. Further, the composition may further include one or more chemotherapeutic agents.

[0237] Controlled release (or sustained release) preparations can be formulated to extend the activity of the drug(s) and reduce the frequency of administration. Controlled release preparations can be used to affect other properties such as the onset time of action or the blood level of the drug, and as a result, can affect the occurrence of side effects. Controlled release preparations can be designed to first release an amount of the drug(s) that produces the desired therapeutic effect and then gradually and continuously release other amounts of the drug over a long period of time to maintain the level of the therapeutic effect. To maintain a nearly constant level of the drug in the body, the drug can be released from the dosage form at a rate that replaces the amount of drug that is metabolized or excreted from the body. The controlled release of the drug can be stimulated by various inducing factors, such as changes in pH, temperature, enzymes, water, or other physiological conditions or molecules.

[0238] The drugs or compositions described herein can also be used in combination with other treatment modalities as further described below. Thus, in addition to the therapies described herein, other therapies known to be effective in the treatment of a disease, disorder, or condition can also be provided.

[0239] The drugs and compositions described herein can be administered by a variety of means known in the art according to the methods described herein. The drugs and compositions can be used for treatment as either an exogenous or an endogenous substance. An exogenous drug is one that is produced or manufactured outside the body and administered to the body. An endogenous drug is one that is produced or manufactured in the body by some type of (biological or other) device for delivery within or to other organs in the body.

[0240] As described above, administration can be parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., by aerosol), implantation, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intraventricular, subcutaneous, intranasal, epidural, intrathecal, intraocular, transdermal, buccal, and rectal.

[0241] The agents and compositions described herein can be administered by a variety of methods well known in the art. Administration can be, for example, oral ingestion, direct injection (e.g., systemic or localized), transplantation of cells engineered to secrete the factor of interest, drug-eluting biomaterials, polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, implantable matrix devices, mini-osmotic pumps, implantable pumps, injectable gels and hydrogels, liposomes, micelles (e.g., up to 30 μm), nanospheres (e.g., less than 1 μm), microspheres (e.g., 1 - 100 μm), reservoir devices, any combination of the foregoing, or other suitable delivery vehicles that provide the desired release profile at various rates. Other methods of controlled release delivery of the agent or composition are known to those skilled in the art and are within the scope of the present disclosure.

[0242] Delivery systems can include, for example, infusion pumps that can be used to administer the agent or composition in a manner similar to that used to deliver insulin or chemotherapy to a particular organ or tumor. Typically, using such a system, the agent or composition can be administered in combination with a biodegradable biocompatible polymer implant that releases the agent over a controlled period at a selected site. Examples of polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyvinyl acetate, and copolymers, and combinations thereof. In addition, the controlled release system can be placed in proximity to the therapeutic target and thus requires only a small fraction of the systemic dose.

[0243] The agent can be encapsulated and administered in various carrier delivery systems. Examples of carrier delivery systems include microspheres, hydrogels, polymeric implants, smart polymer carriers, and liposomes (see generally, Uchegbu and Schatzlein, eds. (2006) Polymers in Drug Delivery, CRC, ISBN-10:0849325331). Carrier-based systems for molecular or biomolecular agent delivery provide intracellular delivery, regulate the release rate of the biomolecule / agent, increase the proportion of the biomolecule reaching its site of action, improve the transport of the drug to its site of action, enable co-localized deposition with other agents or excipients, improve the stability of the agent in vivo, extend the residence time of the agent at its site of action by reducing clearance, reduce non-specific delivery of the agent to non-target tissues, reduce the irritation caused by the agent, reduce the toxicity resulting from high initial doses of the agent, alter the immunogenicity of the agent, reduce the frequency of administration, improve the taste of the product, or improve the shelf life of the product.

[0244] Diseases, disorders, or conditions treatable with wild-type or genetically engineered hematopoietic stem / progenitor cells The compositions described herein can be used to mobilize hematopoietic stem / progenitor cells for treating or preventing a number of diseases, disorders, or conditions. The diseases, disorders, or conditions can be related to high-dose chemotherapy, radiation therapy, such as for treating blood cancers or genetic abnormalities, impairment of the production of hematopoietic progenitor cells and / or stem cells due to another therapeutic agent. The diseases, disorders, or conditions can be a reduction in blood cell counts due to cancer therapies such as chemotherapy or radiation therapy. The diseases, disorders, or conditions can be related to cell adhesion-mediated inflammatory pathways, including but not limited to asthma, multiple sclerosis, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, neuroinflammation, neurodegeneration, spinal cord injury, neurological diseases, or other inflammatory pathologies related to this mechanism.

[0245] The disease, disorder, or condition can be cancer, blood cancer, or a genetic abnormality. The disease, disorder, or condition can be a blood-borne disease (e.g., sickle cell disease). The disease, disorder, or condition can be a blood disease such as blood cancer. Blood cancers can include Hodgkin lymphoma and non-Hodgkin lymphoma, multiple myeloma, or leukemia. The disease, disorder, or condition can be a hematopoietic malignancy (e.g., leukemia such as multiple myeloma or acute myeloid leukemia, lymphoma, or myeloma).

[0246] Treatment method These compositions can be used in various indications such as mobilization of hematopoietic stem cells or progenitor cells. These indications include increasing the number of progenitor cells and / or stem cells circulating in the patient, particularly increasing the number of these cells in the patient's peripheral blood. Alternatively, these compositions can be used to treat patients with cancer, which includes treatment of hematopoietic cancers such as leukemia, myeloma, or lymphoma, or sensitizing the patient to chemotherapy and / or radiotherapy for collection of hematopoietic progenitor cells and / or stem cells, or collecting hematopoietic progenitor cells and / or stem cells that can be transplanted into patients with impaired production of hematopoietic progenitor cells and / or stem cells. The patient can have impaired production of hematopoietic progenitor cells and / or stem cells or a genetic abnormality due to high-dose chemotherapy, radiotherapy, or another therapeutic agent. Alternatively, the compositions described herein can be used to mobilize pre-cancerous cells or cancerous cells from the bone marrow to the peripheral blood. In some embodiments, the mobilization of pre-cancerous cells or cancerous cells from the bone marrow is used to enhance or increase the effect of standard cancer therapies such as chemotherapy and / or radiotherapy. Further, each of these compositions can be used in the manufacture of a medicament for these indications.

[0247] The present disclosure relates to the fields of medicine, medical science, and cell biology. In another aspect, the present disclosure provides methods for inhibiting or antagonizing VLA-4 and α4β7 using one or more of the compounds disclosed herein, and pharmaceutical compositions thereof. In some aspects of the present disclosure, the compounds provided herein can be used in various biological, prophylactic, or therapeutic areas that include regions where VLA-4 and / or α4β7 play a role.

[0248] In one aspect, the present disclosure provides methods for inhibiting or antagonizing VLA-4 and α4β7 using one or more of the compounds disclosed herein in the presence of one or more agents that interact with chemokines such as Groβ, G-CSF, or derivatives thereof, and pharmaceutical compositions thereof that include one or more VLA-4 and α4β7 antagonists. The treatment methods described herein can be used to enhance or increase the circulation of hematopoietic progenitor cells and / or stem cells. These treatment methods can be used for stem cell transplantation, to improve tissue repair, to improve the effectiveness of cancer treatment, or in other situations where in vivo stimulation of hematopoiesis is desirable. A VLA-4 inhibitor and an agent that interacts with a chemokine receptor act synergistically to induce rapid mobilization of progenitor cells and stem cells, the compositions or methods described herein. For example, when these combination therapeutic agents are used, peak mobilization can occur at about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours after administration of the combination drug. In one embodiment, these compositions or methods result in a composition that acts synergistically to induce rapid mobilization of progenitor cells and stem cells by peak mobilization at about 15 minutes after administration of the combination drug. In contrast, this mobilization is significantly shorter than the 4 to 5 days required to achieve maximal mobilization using G-CSF.

[0249] In one aspect, the compounds and compositions described herein can be used to increase the collection of HSPCs for a variety of different applications. These compounds and compositions can be used to treat patients in need of transplantation. Alternatively, the compounds and compositions can be used to treat patients who do not require transplantation. Patients in need of HSPC transplantation require either allogeneic, autologous, or tandem transplantation of HSPCs. In some embodiments, the HSPCs can be used in either an allogeneic or autologous transplantation. In another aspect, the compounds and compositions described herein can be used to improve the circulation of cells to tissues in need of repair. An increase in the circulation of HSPCs can be used to improve the repair of the target tissue in a patient.

[0250] When HSPCs are collected, these cells may be returned to the donor patient (autologous transplantation), or provided to another patient who is sufficiently matched to prevent rejection (allogeneic transplantation). One non-limiting application of autologous transplantation is in combination with radiotherapy or chemotherapy in patients with tumors because the methods of radiotherapy or chemotherapy deplete the patient's normal cells. In the present application, the patient's cells can be collected before or during treatment, fractionated if necessary, cultured, optionally expanded, and then returned to the patient to restore the damaged immune system depleted by the therapy. An allogeneic recipient may receive the cells for the same purpose, or may have a condition in which they can benefit by enhancing the hematopoietic system. In typical protocols for these types of transplantation, the mobilized cells are collected from the donor, for example, by apheresis, and then stored / cultured / expanded / fractionated as desired. In some embodiments, the compounds and compositions described herein can result in the elimination of the need for apheresis.

[0251] In some embodiments, the compounds, compositions, and methods described herein can be used to increase the circulation of pre-cancerous or cancerous cells from the bone marrow to the peripheral blood. Without being bound by any theory, increasing the circulation of pre-cancerous or cancerous cells from the bone marrow is thought to potentially increase the effectiveness of anti-cancer therapy. In particular, these compounds and compositions can be used to treat patients having or at risk of having hematopoietic malignancies such as lymphoma, myeloma, or leukemia. The compounds and compositions described herein can be administered or used before, during, or after anti-cancer therapy. Two non-limiting examples of anti-cancer therapies that can be used in the methods described herein or in combination with the compounds and compositions described herein are chemotherapeutic agents or radiation therapy.

[0252] In another embodiment, the compounds, compositions, and methods described herein can be used to reduce inflammation that can increase tissue repair. Accordingly, the compounds and compositions described herein can be used to treat graft-versus-host disease. Further, these compounds and compositions can be used to treat diseases or disorders associated with cell adhesion-mediated inflammatory pathways. Some non-limiting examples of cell adhesion-mediated inflammatory pathologies include asthma, multiple sclerosis, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, neuroinflammation, neurodegeneration, and spinal cord injury.

[0253] In some aspects, the present disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the disease or disorder is related to integrin α4β1. In other embodiments, the disease or disorder is related to inflammation. In still other embodiments, the disease or disorder is an autoimmune disorder. In still other embodiments, the disease or disorder is related to hematopoietic stem cells such as LSK-SLAM cells. In still other embodiments, the disease or disorder is a reduction in blood cell count, such as a reduction in blood cell count resulting from the treatment of cancer or a reduction in blood cell count resulting from cancer therapy such as chemotherapy or radiation therapy. In some embodiments, the disease or disorder is a reduction in blood cell count resulting from cancer therapy such as chemotherapy or radiation therapy. In other embodiments, the disease or disorder is cancer. In some embodiments, the compound or composition results in an improvement in the effectiveness of chemotherapy or radiation therapy.

[0254] Such pharmaceutical compositions can further comprise one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials), and, if desired, other active ingredients. These methods can be used to treat blood diseases or disorders such as sickle cell anemia or as part of a hematopoietic stem cell therapy to promote the generation of stem cells. In some embodiments, the compounds are administered as part of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In some embodiments, the compounds and / or their pharmaceutical compositions may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. As used herein, the term parenteral includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques, or intraperitoneal. In some embodiments, the composition is formulated for administration by oral, intra-adipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intramembranous, intraperitoneal, intrathoracic, intraprostatic, rectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracystic, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, transbuccal, transdermal, vaginal, in creams, in lipid compositions, via catheter, via lavage, via continuous infusion, via infusion, via inhalation, via injection, via localized delivery, or via regional perfusion. In some embodiments, the compounds of the disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a therapeutically effective dose for the intended treatment. The therapeutically effective dose of the compounds necessary to prevent or arrest or treat the progression of a medical condition is readily ascertainable by one of ordinary skill in the art using preclinical and clinical approaches well known in the medical arts.

[0255] In some aspects, the disclosure provides a method of inducing mobilization of hematopoietic stem cells or progenitor cells, the method comprising contacting the hematopoietic stem cells or progenitor cells with an effective amount of a compound or composition disclosed herein. In some embodiments, the method is ex vivo or in vitro. In some embodiments, the method is in vivo.

[0256] In some embodiments, the present disclosure provides a method for collecting hematopoietic stem cells or progenitor cells from a patient, comprising: (A) administering to the patient a compound or composition disclosed herein in an amount sufficient to mobilize hematopoietic stem cells or progenitor cells into the patient's peripheral blood; and (B) subsequently collecting peripheral blood from the patient to collect hematopoietic stem cells or progenitor cells.

[0257] In some embodiments, the present disclosure provides a method for collecting hematopoietic stem cells or progenitor cells from a patient who has been administered a compound or composition disclosed herein in an amount sufficient to mobilize hematopoietic stem cells or progenitor cells into the patient's peripheral blood, comprising subsequently collecting peripheral blood from the patient to collect hematopoietic stem cells or progenitor cells.

[0258] In other embodiments, the present disclosure provides a method for improving the collection of hematopoietic stem cells or progenitor cells, comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein.

[0259] In yet other embodiments, the present disclosure provides a method for transplanting hematopoietic stem cells or progenitor cells into a patient, comprising: (A) administering to the patient a compound or composition disclosed herein; (B) collecting hematopoietic stem cells or progenitor cells from the patient; and (C) transplanting the hematopoietic stem cells or progenitor cells into the patient.

[0260] In some embodiments, the present disclosure provides a method for transplanting hematopoietic stem cells or progenitor cells into a patient, comprising transplanting hematopoietic stem cells or progenitor cells collected from a patient who has been administered a therapeutically effective amount of a compound or composition disclosed herein.

[0261] In some embodiments, the present disclosure provides a method for transplanting hematopoietic stem cells or progenitor cells, comprising: (A) Administering a compound or composition described herein to a first patient, (B) Collecting hematopoietic stem cells or progenitor cells from the first patient, (C) Transplanting the hematopoietic stem cells or progenitor cells into a second patient, and providing a method comprising the same.

[0262] In some embodiments, the present disclosure provides a method of transplanting hematopoietic stem cells or progenitor cells, comprising transplanting hematopoietic stem cells or progenitor cells collected from a first patient administered a therapeutically effective amount of a compound or composition disclosed herein into a second patient.

[0263] In some embodiments, the hematopoietic stem cells are collected from a patient prior to an event that results in a reduction in the amount of the patient's hematopoietic stem cells or progenitor cells. In some embodiments, the hematopoietic stem cells or progenitor cells are transplanted after an event that results in a reduction in the amount of the patient's hematopoietic stem cells or progenitor cells. In some embodiments, the first patient is a compatible hematopoietic stem cell donor. In some embodiments, the hematopoietic stem cells or progenitor cells are LSK-SLAM cells.

[0264] In some embodiments, the present disclosure provides a method of improving the effectiveness of cancer treatment in a patient administered chemotherapy or radiation therapy, comprising: (A) Administering to the patient a therapeutically effective amount of a compound or composition disclosed herein, (B) Administering chemotherapy or radiation therapy to the patient, and providing a method comprising the same.

[0265] In some embodiments, the present disclosure provides a method of improving the effectiveness of cancer treatment in a patient administered chemotherapy or radiation therapy and a compound or composition disclosed herein.

[0266] Based on standard experimental techniques and procedures well-known and understood by those skilled in the art, and comparison with compounds having known utility, the above compounds can be used for the treatment of patients suffering from the above pathological conditions. Those skilled in the art will recognize that the selection of the most appropriate compounds of the present disclosure is within the ability of those skilled in the art and depends on various factors including the evaluation of results obtained in standard assays and animal models.

[0267] The amounts of the compositions described herein that can be combined with pharmaceutically acceptable carriers to produce single dosage forms will vary depending on the subject or host to be treated and the particular mode of administration. Since the required therapeutically effective amount can be achieved by administration of multiple individual doses, those skilled in the art will understand that the unit content of the agent contained in the individual dose of each dosage form need not itself constitute a therapeutically effective amount.

[0268] The toxicity and therapeutic efficacy described herein can be measured, for example, by standard pharmaceutical procedures in cell cultures or experimental animals for determining LD 50 (the dose lethal to 50% of the population), and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which can be expressed as the LD 50 / ED 50 ratio, and a larger therapeutic index is generally understood to be optimal in the art.

[0269] The specific therapeutically effective dosage level for any particular subject will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition being used; the duration of the treatment; drugs used in combination with or concurrently with the specific compound being used, and like factors well known in the medical arts (see, for example, Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453, Winter (2003) Basic Clinical Pharmacokinetics, 4th ed., Lippincott Williams & Wilkins, ISBN 0781741475, Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start the dosage of the composition at a level lower than that required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dosage can be divided into multiple dosages for purposes of administration. Consequently, a single dose composition can contain such an amount or an approximation thereof to constitute a daily dosage. However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.

[0270] In addition, each of the conditions, diseases, disorders, and pathologies described herein, and others, can benefit from the compositions and methods described herein. Generally, treating a condition, disease, disorder, or pathology includes reversing or delaying the onset of clinical symptoms in a mammal that is at risk of developing or is susceptible to that condition, disease, disorder, or pathology, but has not yet experienced or manifested its clinical or subclinical symptoms. Treatment can also include inhibiting a condition, disease, disorder, or pathology, for example, preventing or reducing the onset of a disease or at least one of its clinical or subclinical symptoms. Further, treatment can include alleviating a disease, for example, causing regression of at least one of a condition, disease, disorder, or pathology, or its clinical or subclinical symptoms. The benefit to the subject being treated can be statistically significant or at least perceptible to the subject or the physician.

[0271] Combination therapy The present disclosure can relate to one or more agents used in combination with a VLA-4 antagonist. The present disclosure describes combinations of VLA-4 antagonists with other treatment modalities as combination therapies for increasing the mobilization of hematopoietic stem cells.

[0272] To increase the mobilization of hematopoietic stem cells using the methods and compositions of the present disclosure, generally, a subject will be administered with a VLA-4 antagonist and at least one other therapy. These therapies will be provided in combination amounts effective to achieve increased activity. This process can include contacting the cell / subject with both agents / therapies simultaneously, for example, using a pharmacological formulation that includes a single composition or both agents, or contacting the cell / subject simultaneously with two different compositions or formulations, where one composition includes the VLA-4 antagonist and the other composition includes the other agent.

[0273] Alternatively, the individual compounds in the compositions described herein may precede or follow treatment with other compounds at time intervals ranging from seconds to days. Generally, sufficient time should not elapse between each delivery such that the treatment still exerts an advantageous combined effect on the cells / subject. In such cases, it is contemplated that two or more modalities are administered to each other within about 12 - 24 hours, within about 6 - 12 hours of each other, or with a delay time of only about 1 - 2 hours or less than 1 hour. Further, an agent that interacts with a chemokine can be administered about 10 - 15 minutes before, about 5 - 10 minutes before, or about 0 - 5 minutes before administration of the VLA-4 inhibitor. For example, an agent that interacts with a chemokine can be administered about 15 minutes before, about 14 minutes before, about 13 minutes before, about 12 minutes before, about 11 minutes before, about 10 minutes before, about 9 minutes before, about 8 minutes before, about 7 minutes before, about 6 minutes before, about 5 minutes before, about 4 minutes before, about 3 minutes before, about 2 minutes before, about 1 minute before, or any range derivable therefrom, or and up to and including 1 minute before administration of the VLA-4 inhibitor. Alternatively, the components can be administered simultaneously.

[0274] The compositions and combinations of agents used in the methods described herein can be administered as a single bolus dose, a dose over time such as by infusion, by intravenous, subcutaneous, or transdermal administration, or as multiple doses. If infusion is used, the combination can be infused for about 15 minutes to about 6 hours. In one embodiment, the infusion can be performed during the period of apheresis. Further, the composition or combination can be administered once a day for multiple days (including 1 - 4 days).

[0275] Further, the composition or combination can be administered to the patient for 1 day or less than 1 day, and then HSPC isolated from the patient can be administered. The compositions or combinations described herein can be administered, and then the HSPC can be isolated about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours after administration.

[0276] It is also contemplated that more than one administration of either the compound or another therapy may be desired. As exemplified below, when the compound of the present disclosure is "A" and another compound or therapy is "B", various combinations can be used: A / B / A, B / A / B, B / B / A, A / A / B, B / A / A, A / B / B, B / B / B / A, B / B / A / B, A / A / B / B, A / B / A / B, A / B / B / A, B / B / A / A, B / A / B / A, B / A / A / B, B / B / B / A, A / A / A / B, B / A / A / A, A / B / A / A, A / A / B / A, A / B / B / B, B / A / B / B, B / B / A / B.

[0277] Other combinations are also contemplated. In some aspects of the present disclosure, the agent can be a CXC chemokine, a CXC chemokine receptor, or a derivative thereof. Some non-limiting examples of agents include Groβ, truncated Groβ (Groβt), plerixafor (AMD3100), granulocyte colony-stimulating factor (G-CSF) (e.g., filgrastim, PEG-filgrastim, or lenograstim), or an inhibitor of integrin α9β1 (e.g., BOP (N-benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl) tyrosine).

[0278] In other embodiments, the compositions or methods used herein can be administered in conjunction with an anti-cancer therapy such as those described below. The methods or compositions described herein can be used in combination with standard methods or variations thereof practiced by those skilled in the art. These anti-cancer agents can be administered before and / or simultaneously with the compositions or methods described herein. Some non-limiting examples of anti-cancer therapies that can be used herein include carmustine, etoposide, cytarabine, melphalan, cyclophosphamide, busulfan, thiotepa, bleomycin, platinum (cisplatin), cytarabine, cyclophosphamide, busid, daunorubicin, doxorubicin, the agent ara-C, cyclosporine, Rituxan®, thalidomide, clofarabine, Velcade®, Antegren®, Ontak®, Revlimid® (a thalidomide analog), Prochymal®, Genasense® (oblimersen sodium), Gleevec®, Glivec® (imatinib), tamibarotene, nelarabine, gallium nitrate, PT-100, Bexxar®, Zevalin®, pixantrone, Onco-TCS, and agents that are topoisomerase inhibitors, or another specific anti-cancer therapy.

[0279] Chemotherapy The term "chemotherapy" refers to the use of drugs to treat cancer. The term "chemotherapeutic agent" is used to mean a compound or composition administered in the treatment of cancer. These agents or drugs are classified by their mode of action within the cell, e.g., whether they affect the cell cycle and at which stage. Alternatively, the agents may be characterized based on their ability to induce chromosomal and mitotic abnormalities by directly cross-linking DNA, intercalating into DNA, or affecting nucleic acid synthesis. Most chemotherapeutic agents are classified as alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.

[0280] Examples of chemotherapeutic agents include alkylating agents (e.g., thiotepa and cyclophosphamide), alkyl sulfonates (e.g., busulfan, improsulfan, and piposulfan), aziridines (e.g., benzodopa, carboquone, meturedopa, and uredopa), ethyleneimines and methylamelamines (e.g., altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine), acetogenins (particularly, bullatacin and bullatacinone), camptothecin (including the synthetic analogue topotecan), bryostatin, calistatin, CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogues), cryptophycins (particularly, cryptophycin 1 and cryptophycin 8), dolastatin, duocarmycin (including the synthetic analogues KW-2189 and CB1-TM1), erythrobins, pancratistatin, sarcodictyin, spongistatin, nitrogen mustards (e.g., chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trofosfamide, uracil mustard), nitrosoureas (e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine), enediyne antibiotics (e.g., calicheamicin, particularly, calicheamicin γ1 and calicheamicin ω1), dynemicin (including dynemicin A), ansiamycins and their derivatives, bisphosphonates (e.g., clodronate), esperamicin, and neocarzinostatin chromophore and related pigment protein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, calminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin), epirubicin, esorubicin,Idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, or zorubicin, antimetabolites (e.g., methotrexate and 5-fluorouracil (5-FU)), folic acid analogs (e.g., denopterin, methotrexate, pteropterin, trimetrexate), purine analogs (e.g., fludarabine, 6-mercaptopurine, thiampurine, thioguanine), pyrimidine analogs (e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, floxuridine), androgens (e.g., calusterone, drostanolone propionate, epithiostanol, mepitiostane, testolactone), antiadrenal drugs (e.g., aminoglutethimide, mitotane, trilostane), folic acid supplements (e.g., folic acid), aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, dexamethasone, diacozine, efronitine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidamine, maytansinoids (e.g., maytansine and ansamitocin), mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, PSK polysaccharide complex), razoxane, lysoxine, sizofiran, spirogermanium, tenuazonic acid, triazocine, 2,2’,2’’-trichloroethylamine, trichothecene (especially, T-2 toxin, verracurin A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside (“Ara-C”), cyclophosphamide, thiotepa, taxoids (e.g., paclitaxel and docetaxel), chlorambucil, gemcitabine, 6-thioguanine,Mercaptopurine, methotrexate, platinum coordination complexes (e.g., cisplatin, oxaliplatin, and carboplatin), vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, mitoxantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, irinotecan (e.g., CPT-11), topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids (e.g., retinoic acid), capecitabine, cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosourea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binders, paclitaxel, docetaxel, gemcitabine, vinorelbine, farnesyl protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine, and methotrexate, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0281] Radiation therapy Radiation therapy (also called radiotherapy) is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation accumulates energy and damages genetic material, damaging or destroying the cells in the treated area and making it impossible for these cells to continue growing. Radiation damages both cancer cells and normal cells, but the latter can repair themselves and function properly.

[0282] Radiation therapies used in accordance with the present disclosure may include, but are not limited to, the use of gamma rays, X-rays, and / or the direct delivery of radioisotopes to tumor cells. Other forms of DNA damaging agents such as microwaves and UV irradiation are also contemplated. All of these agents are most likely to induce a wide range of DNA damage to DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. The dose range of X-rays is in the range from 12.9 to 51.6 mC / kg per day for a long period (3 to 4 weeks) to 0.516 to 1.55 C / kg in a single dose. The dose range of radioisotopes varies widely and depends on the half-life of the isotope, the intensity and type of the emitted radiation, and the uptake by tumor cells.

[0283] Radiation therapy may include using radiolabeled antibodies to directly irradiate a cancer site (radiation immunotherapy). Antibodies are very specific proteins made by the body in response to the presence of an antigen (a substance recognized as foreign by the immune system). Some tumor cells contain specific antigens that induce the production of tumor-specific antibodies. These antibodies can be produced in large quantities in the laboratory and can be conjugated to radioactive substances (a process known as radiolabeling). When injected into the body, the antibodies actively seek out cancer cells, and the cancer cells are destroyed by the cell-killing (cytotoxic) action of the radiation. This approach can minimize the risk of radiation damage to healthy cells.

[0284] Conformal radiation therapy uses a radiation therapy device that is the same linear accelerator as conventional radiation therapy, but a metal block is placed in the path of the X-ray beam and its shape is changed to match the shape of the cancer. This ensures that a higher radiation dose is delivered to the tumor. Healthy surrounding cells and nearby structures receive a lower dose of radiation, reducing the potential for side effects. A device called a multi-leaf collimator has been developed and can be used as an alternative to the metal block. The multi-leaf collimator consists of several metal plates fixed to the linear accelerator. Each layer can be adjusted so that the radiation therapy beam can be shaped to the treatment area without the need for a metal block. The precise positioning of the radiation therapy device is very important for conformal radiation therapy treatment, and a special scanning device can be used to confirm the position of the internal organs at the start of each treatment.

[0285] High-resolution intensity-modulated radiation therapy also uses a multi-leaf collimator. During this treatment, the layers of the multi-leaf collimator move while the treatment is being performed. This method has a high potential to achieve a more precise shaping of the treatment beam and can make the radiation therapy dose uniform across the treatment area.

[0286] Studies have shown that conformal radiation therapy and intensity-modulated radiation therapy may reduce the side effects of radiation therapy treatment, but precisely shaping the treatment area may prevent the destruction of microscopic cancer cells just outside the treatment area. This means that using these special radiation therapy techniques may increase the risk of cancer recurrence in the future.

[0287] Scientists are also exploring ways to enhance the effectiveness of radiation therapy. Two types of investigational drugs are being studied for their effects on cells receiving radiation. Radiation sensitizers make tumor cells more vulnerable to damage, and radiation protectors protect normal tissues from the effects of radiation. Hyperthermia, which uses heat, is also being studied for its effect of increasing the sensitivity of tissues to radiation.

[0288] Immunotherapy In the context of cancer treatment, immunotherapeutic agents generally rely on the use of immune effector cells and molecules to target and destroy cancer cells. Trastuzumab (Herceptin™) is such an example. The immune effector can be, for example, an antibody specific for some markers on the surface of tumor cells. The antibody may function as the effector of the therapy in some cases, or may recruit other cells to actually cause cell killing in other cases. The antibody can also be conjugated to a drug or toxin (chemotherapeutic agent, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and can function simply as a targeting agent. Alternatively, the effector can be a lymphocyte carrying surface molecules that interact directly or indirectly with the tumor cell target. Various effector cells include cytotoxic T cells and NK cells. The combination of treatment modalities, namely, direct cytotoxic activity and inhibition or reduction of ErbB2, will provide a therapeutic benefit in the treatment of cancers overexpressing ErbB2.

[0289] In one aspect of immunotherapy, tumor cells must have some markers suitable for targeting, i.e., markers that do not exist in most other cells. There are many tumor markers, and any of these may be suitable for targeting in the context of the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate-specific antigen, urinary tumor-associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, sialyl Lewis antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B, and p155. An alternative aspect of immunotherapy is to combine an anti-cancer effect with an immune-stimulating effect. Immune-stimulating molecules also include cytokines such as IL-2, IL-4, IL-12, GM-CSF, γ-IFN, chemokines such as MIP-1, MCP-1, IL-8, and growth factors such as FLT3 ligand. It has been shown that the anti-tumor effect is enhanced by combining immune-stimulating molecules, either as proteins or using gene delivery, in combination with tumor suppressors (Ju et al., 2000). Furthermore, antibodies against any of these compounds can be used to target the anti-cancer agents discussed herein.

[0290] Examples of immunotherapies currently under investigation or in use are immune adjuvants such as Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene, and aromatic compounds (U.S. Pat. Nos. 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al., 1998), cytokine therapies such as interferon α, β, and γ; IL-1, GM-CSF, and TNF (Bukowski et al., 1998; Davidson et al., 1998; Hellstrand et al., 1998), gene therapies such as TNF, IL-1, IL-2, p53 (Qin et al. 1998; Austin-Ward and Villaseca, 1998; U.S. Pat. Nos. 5,830,880 and 5,846,945), and monoclonal antibodies such as anti-ganglioside GM2, anti-HER-2, anti-p185 (Pietras et al., 1998; Hanibuchi et al., 1998; U.S. Pat. No. 5,824,311). It is contemplated that one or more anti-cancer therapies may be used in conjunction with the gene silencing therapy described herein.

[0291] In active immunotherapy, antigenic peptides, polypeptides or proteins, or autologous or allogeneic tumor cell compositions or "vaccines" are generally administered with different bacterial adjuvants (Ravindranath and Morton, 1991; Morton et al., 1992; Mitchell et al., 1990; Mitchell et al., 1993).

[0292] In adoptive immunotherapy, a patient's circulating lymphocytes or tumor infiltrating lymphocytes are isolated in vitro, activated by lymphokines such as IL-2, or transduced with a gene for tumor necrosis and re-administered (Rosenberg et al., 1988; 1989).

[0293] Biological activity Another object of the present disclosure is to provide a pharmaceutical composition comprising the above compounds. These compounds and pharmaceutical compositions can be used to improve the collection of hematopoietic stem cells or progenitor cells. Further, the compounds or compositions can increase the circulation of hematopoietic progenitor cells and / or stem cells, improve the collection of hematopoietic stem cells or progenitor cells for transfusion, increase the sensitization to anti-cancer therapies such as chemotherapy or radiotherapy, or mobilize pre-cancerous or cancerous cells (which can increase the sensitivity to anti-cancer therapies) into the peripheral blood.

[0294] Hematopoietic stem cell transplantation (HSCT) is used to facilitate the repopulation of healthy bone marrow cells and immune system cells after high-dose chemotherapy treatment of cancers such as Hodgkin lymphoma and non-Hodgkin lymphoma, multiple myeloma, and leukemia. In HSCT, hematopoietic stem cell / progenitor cells (HSPCs) are collected from a patient's blood, recovered, frozen, and then stored while the patient is undergoing high-dose chemotherapy and / or radiotherapy. To succeed in HSCT, an intravenous infusion of a minimum of 2 × 10 6 CD34+ stem cells / kg body weight is required. However, for early and long-term multi-lineage engraftment, a dose of 5 × 10 6 CD34+ cells / kg is considered preferable.

[0295] Stem cells collected from peripheral blood are the most commonly used graft source in HSCT. Granulocyte colony-stimulating factor (G-CSF) is the most frequently used agent for stem cell mobilization, but the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients. Plerixafor (AMD3100), a small molecule CXCR4 antagonist, in combination with G-CSF, increases total CD34+ HSPCs compared to G-CSF alone and has received FDA approval for stem cell mobilization in non-Hodgkin lymphoma and multiple myeloma. However, a major drawback of plerixafor is that it incurs an additional cost of $25,567 per patient compared to G-CSF alone. Further, up to 24% of patients administered plerixafor and G-CSF still have < 2 × 10 6It is not possible to collect [[X]] CD34+ cells / kg. Recent economic analysis has shown that shortening apheresis by one day could potentially reduce healthcare costs by $6,600. Therefore, improved / alternative mobilization agents and strategies are needed.

[0296] The compositions or methods disclosed herein may have the additional advantage of mobilizing an increased number of early progenitor cells and / or stem cells, LSK-SLAM cells, CFU-C cells, or other progenitor cells and / or stem cells such that the composition or method results in a greater number of mobilizations, initiates mobilization over a shorter period, over a longer period, or successfully engrafts into a patient. For example, the number of progenitor cells and / or stem cells mobilized when using the combinations or methods described herein may be at least about 1.2-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5-fold, at least about 7-fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, at least about 11-fold, at least about 12-fold, at least about 13-fold, at least about 14-fold, or at least about 15-fold greater than when using a single agent alone. Specifically, the number of early progenitor cells and / or stem cells (e.g., LSK-SLAM cells) mobilized when using a combination of at least one VLA-4 inhibitor and at least one CXCR2 agonist may be at least about 1.2-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, at least about 6-fold, at least about 6.5-fold, at least about 7-fold, at least about 7.5-fold, at least about 8-fold, at least about 8.5-fold, at least about 9-fold, at least about 9.5-fold, at least about 10-fold, at least about 11-fold, at least about 12-fold, at least about 13-fold, at least about 14-fold, at least about 15-fold, at least about 16-fold, at least about 17-fold, at least about 18-fold, at least about 19-fold, at least about 20-fold, at least about 21-fold, at least about 22-fold, at least about 23-fold, at least about 24-fold, or at least about 25-fold greater than when using a single agent alone.

[0297] The compositions and methods described herein that utilize molecular biology protocols can follow various standard techniques known in the art (see, e.g., Sambrook and Russel (2006) Condensed Protocols from Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ISBN-10: 0879697717; Ausubel et al. (2002) Short Protocols in Molecular Biology, 5th ed., Current Protocols, ISBN-10: 0471250929; Sambrook and Russel (2001) Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Laboratory Press, ISBN-10: 0879695773; Elhai, J. and Wolk, C. P. 1988. Methods in Enzymology 167, 747-754; Studier (2005) Protein Expr Purif. 41(1), 207-234; Gellissen, ed. (2005) Production of Recombinant Proteins: Novel Microbial and Eukaryotic Expression Systems, Wiley-VCH, ISBN-10: 3527310363; Baneyx (2004) Protein Expression Technologies, Taylor & Francis, ISBN-10: 0954523253).

[0298] The definitions and methods described herein are provided to better define the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. Unless otherwise noted, terms should be understood according to their conventional usage by one of ordinary skill in the relevant art.

[0299] In some embodiments, numerical values representing properties such as amounts of components, molecular weights, and reaction conditions, used to describe and claim certain embodiments of the present disclosure, are to be understood as being modified in some cases by the term "about." In an exemplary embodiment, the term "about" is used to indicate that a value includes ±10% of that value. In some embodiments, the term "about" is used to indicate that a value includes the average standard deviation of ±1 of the device or method used to determine the value. In some embodiments, the numerical parameters set forth in this specification and the appended claims are approximations that may vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practically possible. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective test measurements. The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited herein. The recitation of separate values is understood to include the ranges between each value.

[0300] In some embodiments, the terms "a," "an," and "the," and similar references used in the context of describing a particular embodiment (in particular, in a particular context of the following claims) may be construed to include both the singular and the plural forms unless specifically stated otherwise. In some embodiments, the term "or" used in this specification including the claims is used to mean "and / or" unless explicitly indicated to refer only to alternatives or when the alternatives are mutually exclusive.

[0301] The terms "comprise", "have", and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises", "comprising", "has", "having", "includes", and "including", is also open-ended. For example, a method that "comprises", "has", or "includes" one or more steps is not limited to having only those one or more steps, and may also include other unrecited steps. For example, a composition or device that "comprises", "has", or "includes" one or more features is not limited to having only those one or more features, and also includes other unrecited features.

[0302] All of the methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly inconsistent with the context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein with respect to a particular embodiment is merely intended to better illustrate the disclosure and is not intended to impose a limitation on the scope of the disclosure as otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0303] The grouping of alternative elements or embodiments of the present disclosure disclosed herein should not be construed as limiting. Each element of a group may be referred to and claimed individually, or in any combination with other elements of the group or other elements found herein. One or more elements of a group may be included in or deleted from the group for reasons of convenience or patentability. If any such inclusion or deletion occurs, the specification is considered to include the group as modified so as to meet the written description of all Markush groups used in the appended claims herein.

[0304] All publications, patents, patent applications, and other references cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference were specifically and individually indicated to be incorporated by reference for all purposes. The citation of a reference herein should not be construed as an admission that it is prior art to the present disclosure.

[0305] Although the present disclosure has been described in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing from the scope of the present disclosure as defined in the appended claims. Further, it is to be understood that all examples of the present disclosure are provided as non-limiting examples.

[0306] Exemplary Embodiments To further illustrate the present disclosure, the following non-limiting exemplary embodiments are provided. Those skilled in the art will understand that the techniques disclosed in the following exemplary embodiments represent approaches that the inventors have found to function well in the practice of the present disclosure and, accordingly, can be considered to constitute examples of modes of practice. However, those skilled in the art should understand that, in light of the present disclosure, many changes can be made to the specific embodiments disclosed and still obtain similar or analogous results without departing from the spirit and scope of the invention.

[0307] Exemplary Embodiment 1: VLA-4 Compounds, Comparative Compounds, and Synthetic Methods The following exemplary embodiments describe instrumentation and general methods, compound preparation, and comparative compounds.

[0308] Instrumentation and General Methods Unless otherwise specified, commercially available reagents and solvents were used without further purification. LC-MS analysis was performed on an Agilent 1100 or 1200 HPLC / MSD electrospray mass spectrometer in positive ion mode with a scan range of 100 - 1000 d. Preparative normal phase chromatography was performed on a CombiFlash Rf+ (Teledyne Isco) using a prepacked RediSep Rf silica gel cartridge. Preparative reverse phase HPLC was performed on a CombiFlash Rf+ (Teledyne Isco) equipped with a RediSep Rf Gold prepacked C18 cartridge and an acetonitrile / water / 0.05% TFA gradient. The purity of the test compounds was ≧95% as determined by HPLC analysis performed on an Agilent 1100 or 1260 system using a reverse phase C18 column equipped with a diode array detector, unless otherwise specified. NMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. Signals from deuterated solvents were used as internal references. Chemical shifts (δ) are reported in ppm and are referenced to residual solvent signals that are not completely deuterated. Coupling constants (J) are reported in Hz.

[0309] Compound Preparation Example 1 (2S)-2-[[(2S)-1-(3,5-dichlorophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[2,6-dimethoxy-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoic acid Preparation

Chem.

[0310] The synthesis of Example 1 is shown in Scheme A: Scheme A 1:

Chem.

Chem.

Chem.

[0311] Step 1. Preparation of (S)-methyl 1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxylate

Chem.

[0312] Step 2. Preparation of (S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxylic acid

Chemical formula

[0313] Step 3. Preparation of (S)-methyl 3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0314] Step 4. Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

Chemical formula

[0315] Step 5. Preparation of 2-bromo-5-(bromomethyl)-1,3-dimethoxybenzene

Chemical formula

[0316] Step 6. Preparation of 1-(4-bromo-3,5-dimethoxyphenyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74-pentacosaooxapentaoheptacontane

Chemical formula

[0317] Step 7. Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2’,6’-dimethoxy-4’-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74-pentacosaoxapentaoctacontyl)-[1,1’-biphenyl]-4-yl)propanoate

Chemical formula

[0318] Step 8. Preparation of (S)-Methyl 2-Amino-3-(2’,6’-Dimethoxy-4’-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74-Pentacosaoxapentacontyl)-[1,1’-Biphenyl]-4-yl)Propanoate [Chemical Formula] A solution of methyl (2S)-2-(tert-Butoxycarbonylamino)-3-[4-[2,6-Dimethoxy-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]phenyl]propanoate (1.4 g, 923.00 μmol, 1 equiv) in MeOH (5 mL) was added to HCl / dioxane (4 M, 10 mL, 43.34 equiv), and the solution was stirred at 20 °C for 1 h. The solution was concentrated in vacuo to give the crude product methyl (2S)-2-amino-3-[4-[2,6-Dimethoxy-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]phenyl]propanoate (1.34 g, crude, HCl) as a brown gum and used in the next step without further purification.

[0319] Step 9. Preparation of (S)-methyl 2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(2’,6’-dimethoxy-4’-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74-pentacosaoxapentaoctacontyl)-[1,1’-biphenyl]-4-yl)propanoate

Chemical formula

[0320] Step 10. Preparation of (S)-2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamide)-3-(2’,6’-dimethoxy-4’-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74-pentacosaoxapentaoctacontyl)-[1,1’-biphenyl]-4-yl)propanoic acid

Chemical formula

[0321] 11H NMR (400 MHz, CD3OD): δ 7.84 (d, J = 2.0 Hz, 2H), 7.82 - 7.79 (m, 1H), 7.30 - 7.25 (m, 2H), 7.23 - 7.18 (m, 2H), 6.74 (s, 2H), 4.78 (dd, J = 5.2, 8.4 Hz, 1H), 4.61 (s, 2H), 4.24 (t, J = 6.4 Hz, 1H), 3.72 - 3.61 (m, 101H), 3.57 - 3.53 (m, 2H), 3.48 - 3.44 (m, 1H), 3.37 (s, 3H), 3.30 - 3.24 (m, 1H), 3.16 - 3.11 (m, 1H), 1.93 - 1.82 (m, 2H), 1.79 - 1.60 (m, 2H). HRMS (ESI), C 78 H 128 Cl2N2O 32 Calculated mass for S 1706.7548, measured m / z 1707.7508 [M + H]+.

[0322] The desired product was confirmed by QTOF - MS and had a mass of 1706.7565.

[0323] Example 2 (2S)-2 - [[(2S)-1-(3,5 - dichlorophenyl)sulfonylpyrrolidine - 2 - carbonyl]amino]-3-[4-[2,6 - dimethoxy - 4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2 - methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoic acid preparation

Chemical Structure

[0324] The synthesis of Example 2 is shown in Scheme B: Scheme B

Chemical formula

[0325] Step 1. Preparation of (S)-methyl 3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate

Chemical formula

[0326] Step 2. Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

Chemical formula

[0327] Step 3. Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4’-(hydroxymethyl)-2’,6’-dimethoxy-[1,1’-biphenyl]-4-yl)propanoate

Chemical formula

[0328] Step 4. Preparation of (S)-methyl 2-amino-3-(4'-(hydroxymethyl)-2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate

Chemical formula

[0329] Step 5. Preparation of (S)-methyl 1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxylate

Chemical formula

[0330] Step 6. Preparation of (S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxylic acid

Chemical formula

[0331] Step 7. Preparation of (S)-methyl 2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4'-(hydroxymethyl)-2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate

Chemical Structure

[0332] Step 8. Preparation of methyl (2S)-2-[[(2S)-1-(3,5-dichlorophenyl)sulfonylpyrrolidin-2-carbonyl]amino]-3-[4-[2,6-dimethoxy-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoate

Chem.

[0333] Step 9. Preparation of (2S)-2-[[(2S)-1-(3,5-dichlorophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[2,6-dimethoxy-4-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoic acid (Example 2)

Chemical formula

[0334] The desired product was confirmed by QTOF - MS and had a mass of 2233.0753.

[0335] Example 2 can also be synthesized according to the method described for the synthesis of Example 1 above by replacing m - PEG24 - alcohol (BroadPharm) with an equal amount of m - PEG36 - alcohol (BroadPharm) in Step 6.

[0336] Example 3 (2S)-2 - [[(2S)-1-(3,5 - dichlorophenyl)sulfonylpyrrolidine - 2 - carbonyl]amino]-3 - [4 - [2,6 - dimethoxy - 4 - [2 - [2 - [[1 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - [2 - (2 - methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol - 4 - yl]methoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoic acid Preparation

Chemical Structure

[0337] The synthesis of Example 3 is shown in Scheme C: Scheme C

Chemical formula

[0338] Step 1. Preparation of (S)-2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(2’,6’-dimethoxy-4’-((2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)methyl)-[1,1’-biphenyl]-4-yl)propanoic acid

Chemical formula

[0339] Step 2. Preparation of (2S)-2-[[(2S)-1-(3,5-dichlorophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[2,6-dimethoxy-4-[2-[2-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methoxy]ethoxy]ethoxymethyl]phenyl]phenyl]propanoic acid [Chemical formula] A solution of (S)-2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamide)-3-(2’,6’-dimethoxy-4’-((2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)methyl)-[1,1’-biphenyl]-4-yl)propanoic acid (71.0 mg, 89.7 μmol, 131 mL), m-PEG24-azide (BroadPharm) (100 mg, 89.7 μmol), CuSO4 (14.3 mg, 89.7 μmol, 13.7 μL), and sodium ascorbate (17.7 mg, 89.7 μmol) in H2O (400 μL) and THF (2.00 mL) was stirred at 100 °C for 12 h. LCMS indicated that the reaction was complete. The reaction mixture was diluted with acetonitrile (4.00 mL) and filtered to give the desired product (51.0 mg, 30.1% yield) as a yellow gum, which was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10um, mobile phase: [water (0.225% FA)-ACN], B%: 36% - 66%, 10 min). 11H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 2.0 Hz, 2H), 7.70 (s, 1H), 7.61 (t, J = 1.8 Hz, 1H), 7.17 - 7.27 (m, 5H), 6.65 (d, J = 16.0 Hz, 2H), 4.92 (d, J = 6.0 Hz, 1H), 4.69 (d, J = 30.0 Hz, 4H), 4.51 (t, J = 5.2 Hz, 2H), 4.34 - 4.36 (m, 2H), 4.11 (d, J = 5.6 Hz, 1H), 3.86 (t, J = 5.2 Hz, 2H), 3.65 (s, 105H), 3.38 (s, 5H), 3.08 - 3.13 (m, 2H), 2.03 - 2.08 (m, 1H), 1.59 - 1.61 (m, 2H).

[0340] The desired product was confirmed by QTOF - MS and had a mass of 1875.8408.

[0341] Example 4 (2S)-2-[[(2S)-1-(3,5-dichlorophenyl)sulfonylpyrrolidine-2-carbonyl]amino]-3-[4-[2,6-dimethoxy-4-[5K MW PEG-thiomethyl]phenyl]phenyl]propanoic acid preparation

Chemical formula

[0342] Step 1. Preparation of (S)-methyl 2-((S)-1-((3,5-dichlorophenyl)sulfonyl)pyrrolidine-2-carboxamido)-3-(4'-(bromomethyl)-2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)propanoate

Chemical formula

Claims

1. A VLA-4 inhibitor of the following formula (I), 【Chemistry 1】 (I) During the ceremony, Z = 【Chemistry 2】 And, m = 1 to 3, Z = 【Transformation 3】 If so, n = 19 to 1000, or Z = 【Chemistry 4】 If this is the case, then n = 222 to 1000, R １ and R ２ These are, independently, hydroxyl and alkoxy compounds. （Ｃ≦８） , or substituted alkoxy （Ｃ≦８） And, R ３ is hydrogen, alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） haloalkyl, aryl, substituted aryl, -CH ２ -CH ２ -SO ２－ alkyl （Ｃ≦８） -CH ２ -CH ２ -N(R ９ )(R １０ )(wherein R ９ and R １０ are each independently hydrogen, alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） ), -(CH ２ ) ｇ -CH ２ -CO ２ R ９ (wherein g is 0 or 1 and R ９ is hydrogen, alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） ), or R ３ This includes biomarker tags for in vitro or in vivo utility, antibodies targeting specific proteins or receptors, or other entities (which, when bound to formula (I), enhance the biological effect of the combined entity, and all are R in formula (I)). ３ It can represent (which are joined by) m = 1, n = 19 to 32, X ３ If R is oxygen, ３ Also, 【Transformation 5】 (In the formula, w = 100 to 900, and / or R １１ R ３ (As defined above) and / or, X ３ If is oxygen, m=1, and n=19-1000, then R ３ Also, 【Transformation 6】 (In the formula, R １ , R ２ , X １ , and Z can be as defined above, R ４ and R ５ These are, independently, hydrogen and alkyl. （Ｃ≦８） alkoxy （Ｃ≦８） , halo, haloalkyl （Ｃ≦８） , substituted haloalkyl （Ｃ≦８） , or -C(O)X ５ (In the formula, X ５ These are amino, hydroxy, and alkoxy compounds. （Ｃ≦８） substituted alkoxy （Ｃ≦８） , alkylamino （Ｃ≦８） substituted alkylamino （Ｃ≦８） , dialkylamino （Ｃ≦８） substituted dialkylamino （Ｃ≦８） cycloalkylamino （Ｃ≦８） substituted cycloalkylamino （Ｃ≦８） (or substituents that can be converted to hydroxyl in vivo, or pharmaceutically acceptable salts thereof) R ６ hydrogen, alkyl （Ｃ≦６） , or substituted alkyl （Ｃ≦６） And, R ７ and R ８ These are, independently, hydrogen, halo, and haloalkyl. （Ｃ≦８） And, Y is hydrogen, cyano, halo, haloalkyl, hydroxy, or -C(O)X ４ (In the formula, X ４ These are amino, hydroxy, and alkoxy compounds. （Ｃ≦８） substituted alkoxy （Ｃ≦８） cycloalkoxy （Ｃ≦８） , substituted cycloalkoxy （Ｃ≦８） alkenyloxy （Ｃ≦８） , substituted alkenyloxy （Ｃ≦８） aryloxy （Ｃ≦８） substituted aryloxy （Ｃ≦８） , Aalkyloxy （Ｃ≦８） , substituted aralkyloxy （Ｃ≦８） , alkylamino （Ｃ≦８） substituted alkylamino （Ｃ≦８） , dialkylamino （Ｃ≦８） substituted dialkylamino （Ｃ≦８） cycloalkylamino （Ｃ≦８） substituted cycloalkylamino （Ｃ≦８） alkenylamino （Ｃ≦８） , substituted alkenylamino （Ｃ≦８） arylamino （Ｃ≦８） substituted arylamino （Ｃ≦８） , aralkylamino （Ｃ≦８） , substituted aralkylamino （Ｃ≦８） (or substituents that can be converted to hydroxyl in vivo, or pharmaceutically acceptable salts thereof) X １ is hydroxy, alkoxy （Ｃ≦８） , substituted alkoxy （Ｃ≦８） , cycloalkoxy （Ｃ≦８） , substituted cycloalkoxy （Ｃ≦８） , alkenyloxy （Ｃ≦８） , substituted alkenyloxy （Ｃ≦８） , aryloxy （Ｃ≦８） , substituted aryloxy （Ｃ≦８） , aralkyloxy （Ｃ≦８） , substituted aralkyloxy （Ｃ≦８） , or a substituent convertible to hydroxy in vivo, or a pharmaceutically acceptable salt thereof, X ２ It is oxygen or sulfur, X ３ is oxygen, sulfur, -NH(C=O)-, -(C=O)NH-, -N(R １２ )- (In the formula, R １２ is alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） VLA-4 inhibitors are, A composition comprising a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog or bis derivative thereof.

2. The composition according to Claim 1, A VLA-4 inhibitor having the structure of formula (II) below, 【Transformation 7】 (II) During the ceremony, m = 1 to 3, n = 19 to 1000, R ３ hydrogen, alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） Haloalkyl, aryl, substituted aryl, -CH ２ -CH ２ -SO ２－ Alkyl （Ｃ≦８） ien-CH ２ -CH ２ -N(R) ９ ) (Caution １０ ) (wherein, R ９ or R １０ These are, independently, hydrogen and alkyl. （Ｃ≦６） substituted alkyl （Ｃ≦６） (is) - (CH ２ ) ｇ -CH ２ -CO ２ R ９ (In the formula, g is 0 or 1, R ９ hydrogen, alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） ) or R ３ This includes biomarker tags for in vitro or in vivo utility, antibodies targeting specific proteins or receptors, or other entities (which, when bound to formula (II), enhance the biological effect of the combined entity, and all are R in formula (II)). ３ It can represent (which are joined by) or m = 1, n = 19 to 32, X ３ If R is oxygen, ３ Also, 【Transformation 8】 (In the formula, w = 100 to 900, and / or R １１ R ３ (As defined above) and / or, X ３ If is oxygen, m=1, and n=19-1000, then R ３ Also, 【Chemistry 9】 (In the formula, R １ , R ２ , X １ , and Z can be as defined above, X ２ is oxygen or sulfur, or X ３ These are oxygen, sulfur, -NH(C=O)-, -(C=O)NH-, -N(R １２ )-(wherein, R １２ is alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） VLA-4 inhibitors are or including its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, prodrugs, analogs, or stereoisomers, or optionally substituted analogs or bis derivatives thereof, Or, A VLA-4 inhibitor having the structure of the following formula (III), 【Chemistry 10】 (III) During the ceremony, m = 1 to 3, n = 19 to 1000, X ２ is oxygen or sulfur, or X ３ These are oxygen, sulfur, -NH(C=O)-, -(C=O)NH-, -N(R １２ )-(wherein, R １２ is alkyl （Ｃ≦６） substituted alkyl （Ｃ≦６） VLA-4 inhibitors are or including its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, prodrugs, analogs, or stereoisomers, or optionally substituted analogs or bis derivatives thereof, Or, A VLA-4 inhibitor having the structure of the following formula (IV), 【Chemistry 11】 (IV) During the ceremony, VLA-4 inhibitors, n = 19 or 31 or including its pharmaceutically acceptable salts, solvates, polymorphs, tautomers, prodrugs, analogs, or stereoisomers, or optionally substituted analogs or bis derivatives thereof, Or, A VLA-4 inhibitor having the structure of the following formula (V), 【Chemistry 12】 (V) During the ceremony, n = 19 to 1000, VLA-4 inhibitors, A composition comprising, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog or bis derivative thereof.

3. The composition according to Claim 1, A VLA-4 inhibitor having the structure of the following formula (VII), 【Chemistry 13】 (VII) During the ceremony, n = 222 to 1000, X ２ VLA-4 inhibitors are oxygen or sulfur. A composition comprising, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, analog, or stereoisomer thereof, or an optionally substituted analog or bis derivative thereof.

4. The composition according to claim 1, The following formula: 【Chemistry 24】 【change】 【change】 A composition comprising a formula selected from any one of the following, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition, a) The composition according to any one of claims 1 to 4, b) Excipients, and / or c) A pharmaceutical composition comprising physiological saline.

6. A composition, A VLA-4 inhibitor according to any one of claims 1 to 4, One or more drugs that interact with one or more chemokine receptors or chemokines, Includes, A composition in which one or more agents that interact with the chemokine receptor or chemokine are a C-X-C chemokine or an agent that interacts with the C-X-C chemokine receptor, or a CXCR4 inhibitor or a CXCR2 agonist.

7. A pharmaceutical composition comprising the composition according to claim 6, wherein the pharmaceutical composition comprising a combination of a VLA4 inhibitor and a drug that interacts with one or more chemokines according to any one of the prior claims is formulated and administered as a unit dose, or is formulated and administered independently of each other.

8. A composition according to any one of claims 1 to 4, used to treat a patient or donor to enhance the mobilization and / or collection of a sufficient amount of hematopoietic stem cells / progenitor cells into the peripheral blood of the patient or donor, for administration to the patient or donor in an amount sufficient to mobilize and / or collect a sufficient amount of hematopoietic stem cells / progenitor cells into the peripheral blood.

9. A composition according to any one of claims 1 to 4, used for treating a patient who requires treatment for cancer, wherein the cancer is a hematopoietic malignant tumor, and the hematopoietic malignant tumor is multiple myeloma or acute myeloid leukemia.

10. A composition according to claim 9, which is administered or used in combination with a bispecific antibody or other immunotumor agent for the treatment of a patient having multiple myeloma or acute myeloid leukemia.

11. A pharmaceutical composition according to claim 5, which is used to treat a disease, disorder, or condition related to a cell adhesion-mediated inflammatory pathway.

12. The pharmaceutical composition according to claim 11, wherein the disease, disorder, or pathological condition is asthma, multiple sclerosis, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, neuroinflammation, neurodegeneration, or spinal cord injury.

13. A composition according to any one of claims 1 to 4, used for inhibiting integrin binding.

14. A pharmaceutical composition comprising the composition described in any one of claims 1 to 4, which provides remarkable and prolonged mobilization of hematopoietic stem cells / progenitor cells into the peripheral blood of a patient or donor, lasting for more than 4 hours or 24 hours after a single dose.

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