LENALIDOMIDE PRODRUGS, POLYMERIC CONJUGATES, AND FORMULATIONS THEREOF, AND THEIR USES FOR THE TREATMENT OF MULTIPLE MYELOMA

Abstract

Compounds of formula I and II:

##STR00001##

or a pharmaceutically acceptable salt thereof, and their compositions including polymer encapsulated micro/nano particle compositions are provided, wherein: R.sup.1 is —CH.sub.2—, a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; R.sup.2 is hydrogen or —(C═O)R.sup.3 wherein R.sup.3 is a C2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; and R.sup.4 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that R.sup.1 is linked to the polymer chain through an ester, carbonate or carbamate bond including the oxygen atom linking R.sup.1 and R.sup.4.

The compositions are useful for treatment of multiple myeloma, mantle cell lymphoma, and transfusion-dependent anemia due to myelodysplastic syndromes.

Claims

1. A compound of formula: ##STR00005## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is —CH.sub.2—, a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; and R.sup.2 is hydrogen or —(C=0)R.sup.3 wherein R.sup.3 is a C2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof.

2. A compound of formula II: ##STR00006## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is —CH2-, a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; R.sup.2 is hydrogen or —(C=0)R.sup.3 wherein R.sup.3 is a C2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; and R.sup.4 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain such that R.sup.1 is linked to the polymer chain through an ester, carbonate or carbamate bond including the oxygen atom linking R.sup.1 and R.sup.4.

3. A compound of formula III: ##STR00007## or a pharmaceutically acceptable salt thereof, wherein; R.sup.1 is —CH.sub.2—; a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; R.sup.2 is hydrogen or —(C=0)R.sup.3 wherein R.sup.3 is a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; R.sup.5 is a linker selected from —(C=0)R.sup.7—(C=0)0-; —(C=0)R.sup.7—(C=0)N—; —(C=0)R.sup.7-0(C=0)0-; —(C═O) R.sup.7-0 (C=0)NH—; —(C=0)R.sup.7—NH(C=0)0-; —(C=0)0R.sup.7—(C=0)0-; —(C=0)0R.sup.7—(C=0)N—; —(C=0)0R.sup.7-0(C=0)0-; —(C=0)0R.sup.7-0(C=0)NH—; —(C=0)0R.sup.7—NH(C=0)0-; —(C=0)NHR.sup.7—(C=0)0-; —(C=0)NHR.sup.7—(C=0)N—; —(C=0)NHR.sup.7-0(C=0)0-; —(C=0)NHR.sup.7-0(C=0)NH—; —(C=0)NHR.sup.7—NH(C=0)0-; R.sup.7 is —CH.sub.2—, a C.sub.2-6 straight or branched chain alkylene, alkenylene or alkynylene group or a short chain polyethylene glycol group having 2-6 monomers, or a combination thereof; and R.sup.6 is a pharmaceutically acceptable polymeric moiety comprising a pharmaceutically acceptable polymer chain.

4. The compound of claim 2, wherein the pharmaceutically acceptable polymer chain comprising the polymeric moiety R.sup.4 is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialic acid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine) dendrimers, and mixtures, combinations and copolymers thereof.

5. The compound of claim 3, wherein the pharmaceutically acceptable polymeric moiety R.sup.6 is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialic acid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine) dendrimers, and mixtures, combinations and copolymers thereof.

6. A composition comprising a pharmaceutically effective amount of the compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

7. The composition of claim 6, wherein the composition is injectable or topical.

8. (canceled)

9. The composition according to claim 6, wherein the pharmaceutically acceptable carrier is castor oil or a derivative thereof.

10. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1, wherein the composition comprises micro or nano particles comprising: the compound of formula I; and a second pharmaceutically acceptable polymer, wherein the compound of formula I is encapsulated in the second pharmaceutically acceptable polymer.

11. The pharmaceutical composition according to claim 10, wherein the second pharmaceutically acceptable polymer is selected from the group consisting of polyethylene glycol, poly(glycolide), poly(lactide), poly(caprolactone), poly(lactide-co-caprolactone), poly(lactide-co-glycolide), and poly(lactic acid)-butanol, poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(ethyleneimine), poly(malic acid), poly(L-lysine), poly(L-glutamic acid), and poly ((N-hydroxyalkyl)glutamine), dextrins, hydroxyethylstarch, polysialic acid, polyacetals, N-(2-hydroxypropyl)methacrylamide copolymer, poly(amido amine) dendrimers, and mixtures, combinations and copolymers thereof.

12. The pharmaceutical composition according to claim 10, wherein the composition further comprises one or more pharmaceutically acceptable carriers or excipients.

13. The composition of claim 12, wherein the composition is injectable or topical.

14. A method for the treatment of multiple myeloma, mantle cell lymphoma, or transfusion-dependent anemia due to myelodysplastic syndromes in a subject in need thereof comprising administering a composition according to claim 6 to the subject.

15. The method according to claim 14, wherein the composition is administered intravenously, intramuscularly, intraperitoneally, or subcutaneously.

16. The method according to claim 15, wherein the composition is administered once monthly, biweekly, once weekly, or at most twice weekly.

17. (canceled)

18. (canceled)

19. (canceled)

20. A method for the treatment of multiple myeloma, mantle cell lymphoma, or transfusion-dependent anemia due to myelodysplastic syndromes in a subject in need thereof comprising administering a composition according to claim 12 to the subject.

21. The method according to claim 20, wherein the composition is administered intravenously, intramuscularly, intraperitoneally, or subcutaneously.

22. The method according to claim 21, wherein the composition is administered once monthly, biweekly, once weekly, or at most twice weekly.

23. (canceled)

24. (canceled)

25. (canceled)

26. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 2, wherein the composition comprises micro or nano particles comprising: the compound of formula II; and a second pharmaceutically acceptable polymer, wherein the compound of formula II is encapsulated in the second pharmaceutically acceptable polymer.

27. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 3, wherein the composition comprises micro or nano particles comprising: the compound of formula III; and a second pharmaceutically acceptable polymer, wherein the compound of formula III is encapsulated in the second pharmaceutically acceptable polymer.

Description

DETAILED DESCRIPTION

[0023] Pharmaceutically acceptable polymers used in the present invention may be non-toxic, non-immunogenic, non-antigenic, highly soluble in water and FDA (The Food and Drug Administration) approved. The polymer conjugate compounds of the invention and polymer-encapsulated compounds of the invention have several advantages: a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. The covalent attachment of polymer to a drug can increase its hydrodynamic size (size in solution), which prolongs its circulatory time by reducing renal clearance (Knop et al., Angew. Chemie Int. Ed. 2010; 49(36):6288-6308; Veronese et al., Drug Discov Today. 2005; 10(21):1451-1458; and Harris et al., Nat Rev Drug Discov. 2003; 2(3):214-221). Advantages of pharmaceutical compositions disclosed herein include, for example: increased bioavailability at lower doses; predictable drug-release profile over a defined period of time following each administration; better patient compliance; ease of application; improved systemic availability by avoidance of first-pass metabolism; reduced dosing frequency without compromising the effectiveness of the treatment; decreased incidence of side effects; and overall cost reduction of medical care.

[0024] In some embodiments, R.sup.1 is —CH.sub.2—, R.sup.2 is hydrogen in the compound of formula I. In other embodiments, R.sup.1 is —CH.sub.2—, R.sup.2 is hydrogen, and R.sup.4 is a pharmaceutically acceptable polymeric moiety comprising straight, branched or globular chain polyethylene glycol in the compound of formula II.

[0025] Polymer conjugates of formula II and III may be prepared by methods known in the art, for example, Sk U H et al., Biomacromolecules. 2013; 14(3):801-10. Polymer-encapsulated micro/nano particles may be prepared by methods known in the art. For example, Han et al., Front Pharmacol. 2016; 7:185; Qutachi O et al., Acta Biomater. 2014; 10(12):5090-5098.

[0026] In some embodiments, the pharmaceutically acceptable polymer in compounds of formula II or III comprises 15-75 monomer units, 20-70 monomer units, or 25-65 monomer units. In other embodiments, the polymer has a molecular weight in the range of 1 kDa to 75 kDa, 2 kDa to 60 kDa, or 3 kDa to 50 kDa.

[0027] In certain other embodiments, the pharmaceutically acceptable polymer in compounds of formula II or III is a branched chain PEG comprising 4-120 monomer units, 4-75 monomer units, 4-50 monomer units, or 4-30 monomer units. In certain other embodiments, the polymer is a straight or branched chain PEG comprising 12-120 monomer units, 12-75 monomer units, 12-75 monomer units, or 12-30 monomer units. In some other embodiments, the polymer is a straight or branched chain PEG comprising 11-20 monomer units, 26-42 monomer units, 49-64 monomer units, or 72-111 monomer units. In certain other embodiments, the polymer is a straight or branched chain PEG having a molecular weight in the range of 0.4 kDa to 50 kDa, 0.5 kDa to 50 kDa, 0.8 kDa to 50 kDa, or 1 kDa to 50 kDa.

[0028] The term “encapsulated” in the context of the present invention means coated by, covered by, or surrounded by, such that about 20% to about 80% of the compound of formula I or II is enclosed/covered/coated by the polymer.

[0029] In some embodiments, PLGA and mixture of PLGA with other polymers, such as PLA and PVA, in different ratios are used to encapsulate compounds of the invention to form microparticles. PLGA, is a pharmaceutically acceptable widely used biodegradable material use for encapsulation of a broad range of therapeutic agents including hydrophilic and hydrophobic small molecule drugs, DNA, and proteins, due to its excellent biocompatibility. Other additives can be used to enhance the drug loading and efficiency in PLGA microparticles, such as PEG, poly(orthoesters), chitosan, alginate, caffeic acid, hyaluronic acid etc. PLGA can be a varying composition of PLA and PGA with a ratio from 20 to 80% PGA in PLA and vice versa.

[0030] In some embodiments, the amount of compound of formula I, II or III in the compositions of the invention is in the range of 1 mg to 50 mg equivalent of lenalidomide. In some other embodiments, the amount of compounds compound of formula I or II in the compositions of the invention is in the range of 2.5 mg to 25 mg equivalent of lenalidomide.

[0031] In some embodiments, dosage forms of the composition of the invention are adapted for administration to a patient parenterally, including subcutaneous, intramuscular, intraperitoneal, intravenous or intradermal injections. In other embodiments, the composition may be administered as a depot.

[0032] Upon parenteral injection of lenalidomide-polymer conjugates of formula II or III, enzymatic cleavage may occur generating the compound of formula I, and the respective polymer used in the conjugation. A water-mediated hydrolysis may convert compound of formula I to the active form, lenalidomide, and formaldehyde. When R.sup.2 is —(C═O)R.sup.3′ enzymatic hydrolysis may occur simultaneously to generate lenalidomide, and a carboxylic acid R.sup.3COOH.

[0033] In some embodiment, the compositions of the invention further comprise one or more pharmaceutically effective carriers or excipients. Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0034] The compositions may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Examples

[0035] a) Preparation of N-hydroxymethyl lenalidomide

[0036] Dissolve lenalidomide in DMF (dimethyl formamide) and stir the reaction under nitrogen atmosphere for 10 minutes. Add thiethylamine followed by formaldehyde in DMF and stir the reaction mixture at 80° C. for 24 hours. After completion of the reaction, evaporate all solvents and purify the crude mixture using column chromatography. Characterize the resulting N-hydroxymethyl lenalidomide using reverse-phase HPLC, proton NMR and mass spectroscopic techniques.

[0037] b) Preparation of Lenalidomide-polymer conjugates

[0038] Dissolve carboxylate functionalized linear/branched PEG or any other carboxylate functionalized globular polymer in anhydrous DMF under nitrogen atmosphere. Add EDC and DMAP to the reaction mixture and dissolve in DMF. Stir the reaction mixture for 30 minutes. Add a calculated amount of N-hydroxymethyl lenalidomide dissolved in DMF to the reaction mixture and stir the reaction mixture for 2 days under nitrogen atmosphere. Evaporate the solvent and dialyze the resulting reaction mixture for 24 h with water using dialysis membrane (MWCO 1 kDa). Lyophilize the resulting water to get the final lenalidomide-polymer conjugates. Check the purity of the conjugate by Reverse-phase HPLC and characterize/calculate the loading of the polymeric conjugate by proton NMR, and MALDI-TOF mass spectroscopy.

[0039] c) Preparation of Lenalidomide Microparticle

[0040] Nanoprecipitation technique is used for the preparation of the lenalidomide microparticles. Briefly, lenalidomide and polymer (e.g., PLGA) are dissolved in a suitable solvent (e.g., dichlromethane) in different ratios, the mixture being subjected to sonication for 5-10 minutes to achieve dissolution, if required. Dissolve a hydrophilic non-ionic surfactant (for example a triblock copolymer), such as Pluronic F127, in 50 mL of deionized water and add the lenalidomide/PLGA solution dropwise using a syringe with a flow rate of 1 mL/10 min with stirring at varying speed. Centrifuge, and lyophilize the obtained nanosuspension with cryoprotectant (e.g., 2% sucrose). Characterize the microparticle with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-Ray diffraction (XRD).

[0041] Other compound of formula I, II and III may be prepared by similar procedures using conventional methods known in the art. Lenalidomide may be prepared by methods known in the art or obtained from commercial sources.