WO2018222572A1

WO2018222572A1 - Non-covalent derivatives and methods of treatment

Info

Publication number: WO2018222572A1
Application number: PCT/US2018/034846
Authority: WO
Inventors: Carmen M. Baldino; Laura MUOLLO; John C. Warner
Original assignee: Warner Babcock Institute For Green Chemistry, Llc
Priority date: 2017-06-01
Filing date: 2018-05-29
Publication date: 2018-12-06

Abstract

The present application discloses compositions that are NCDs of histone deacetylase inhibitors.

Description

NON-COVALENT DERIVATIVES AND METHODS OF TREATMENT

BACKGROUND

Histone deacetylases (HDACs) are a class of proteins with an important role in the regulation of gene expression responsible for the removal of the acetyl group from histones. Acetylated histones are involved in the increase of transcription while deacetylated histones are involved in gene repression. HDACs are also a key player in epigenetic mechanisms that have been demonstrated to cause a number of human diseases including cancer, neurological diseases, and immune disorders. The HDACs have received significant attention from the pharmaceutical industry for the development of HDAC inhibitors for the treatment of cancer. This approach has been validated by the FDA approval of HDAC inhibitors such as vorinostat for the treatment of cancer.

SUMMARY OF THE APPLICATION

[0001] There is a continuing need for novel and effective agents that provide treatment options for cancer patients. HDAC inhibitors comprise an important and diversified class of drugs with multiple utilities in the treatment of various cancers. HDAC inhibitors in general suffer from limited pharmaceutical properties that decrease the potential of these drugs to provide an optimal solution for the neediest of patients. The following embodiments, aspects and variations thereof are exemplary and illustrative are not intended to be limiting in scope.

[0002] The present invention is based on the discovery that non-covalent derivatives (NCDs) of certain HDAC inhibitors (HDACi's) are effective in delivering active drug and may be used in the treatment of conditions which can be prevented, treated or ameliorated by HDACi's. In particular, these NCDs are found to be effective in delivering HDACi's to a biological system with enhanced aqueous solubility, permeability, chemical stability, metabolic stability, oral bioavailability and/or pharmeocokinetic/pharmacodynamic profiles.

[0003] In a first embodiment, the present application discloses a non-covalent derivative (NCD) of an HDACi with a Ligand. In one aspect of the NCD, the HDACi is selected from the group consisting of vorinostat, belinostat, pabinostat, mocetinostat, abexinostat, chidamide, pracinostat, entinostat, tacedinaline, resminostat, M344, BML-210, quisinostat, givinostat, dacinostat and ricolinostat. [0004] In another embodiment, the application discloses a method for the treatment or prophylaxis of a condition in a mammal in which HDACi delivery can prevent, alleviate or ameliorate the condition comprising administering to the mammal a therapeutically effective amount of an NCD or a pharmaceutical composition thereof of any one of the above

embodiments, aspect and variations. In one variation of the above method, the condition is selected from the group consisting of cancer (including solid tumors and hematological malignancies), inflammatory diseases (including systemic inflammation, inflammatory bowel disease, and arthritis), autoimmune diseases, cardiac diseases and heart failure, diseases of the brain and neurological system, diabetes, fibrotic diseases, muscular dystrophy, and HIV infection.

[0005] In still another embodiment, the application discloses a solid state synthetic method for the production of an NCD, the method comprising the steps of (a) a step selected from the group consisting of mechanical milling, jet milling, microfluidization, manual or automated grinding, evaporation, crystallization, melting, co-solvent techniques, anti-solvent techniques, spray drying, liquid assisted grinding, sonication, extrusion, and twin screw extrusion of an HDACi with a ligand, so as to form a solid phase NCD; and (b) isolating the NCD.

BRIEF DESCRIPTION OF THE FIGURES

[0006] Figures 1 and 2 show the solubility of a batch of vorinostat L-arginine NCD in H₂0.

[0007] Figure 3 displays the solubilities of certain vorinostat NCDs with enhanced aqueous solubility.

DETAILED DESCRIPTION

Definitions

[0008] Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic synthesis and pharmaceutical sciences. Exemplary embodiments, aspects and variations are illustrated in the figures and drawings, and it is intended that the embodiments, aspects and variations, and the figures and drawings disclosed herein are to be considered illustrative and not limiting.

[0009] As used herein, the term "unsubstituted" means that there is no substituent or that the only substituents are hydrogen. [0010] The term "optionally substituted" as used throughout the specification denotes that the group may or may not be further substituted or fused, with one or more substituent groups. The substituent groups may be one or more groups independently selected from the group consisting of halogen, =0, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, phenoxy, benzyloxy and arylalkyl.

[0011] "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, such as a C1-C14 alkyl (or Ci-14 alkyl), C1-C10 alkyl or Ci-C₆ alkyl, unless otherwise noted. Examples of straight and branched Ci-C₆ alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.

[0012] "Acyl" means an alkyl-CO- or HC(O)- group in which the alkyl group is as described herein. Examples of acyl include acetyl and benzoyl. The alkyl group is preferably a Ci-C₆ alkyl group.

[0013] "Alkenyl" as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched having 2-14 carbon atoms, 2-12 carbon atoms or 2-6 carbon atoms in the normal chain. The group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.

[0014] "Alkoxy" refers to an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a Ci-Ojalkoxy. Examples include, but are not limited to methoxy and ethoxy.

[0015] "Alkynyl" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain. Exemplary structures include, but are not limited to, ethynyl and propynyl.

[0016] "Amino Acids" means the standard amino acids compounds that possess both an amino group and a carboxy function bonded to the same carbon, and include natural and unnatural amino acids, including alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine,

phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine; and as disclosed herein. [0017] "Aryl" as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) and may have from 5 to 12 atoms per ring. Examples of aryl groups include phenyl, naphthyl, and the like.

[0018] "Cycloalkyl" means saturated or partially unsaturated cyclic hydrocarbon radical having from three to twelve carbon atoms. Cycloalkyl may include 5-6 membered cycloalkyl groups, C3-C6 cycloalkyl groups, a 5 -membered cycloalkyl or a 6 membered cycloalkyl group. The term "cycloalkyl" includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl ring fused to a saturated, partially unsaturated or aromatic cycloalkyl or heterocyclic ring. The cycloalkyl may be optionally substituted independently with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cyclooctyl, decalin and adamantane.

[0019] "Heteroalkyl" refers to a straight- or branched-chain alkyl group may have from 2 to 14 carbons or 2 to 10 atoms in the chain, one or more of which is a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like.

[0020] "Heteroaryl" means an aromatic ring system including at least one N, O, S or P.

"Heteroaryl" either alone or part of a group refers to groups containing an aromatic ring (such as a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur. Examples of heteroaryl include but are not limited to thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazol, pyridyl, dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl and pyrrolyl.

[0021] A "Heterocycle" or "heterocyclyl" or "heterocycloalkyl" group means a saturated or partially unsaturated carbocyclic radical of 3 to 8 ring atoms in which at least one ring atom is a heteroatom independently selected from N, O and S, with the remaining ring atoms being C, where one or more ring atoms may be optionally substituted independently with one or more substituents described herein. In one embodiment, the heterocycle is a 4-6 membered heterocycle, a 5-6 membered heterocycle, a 5-membered heterocycle or a 6-membered heterocycle. Examples of heterocyclyl groups include, but are not limited to, pyrrolidyl, tetrahydrothiofuranyl, morphilino, 1 ,3 -diazapane, 1 ,4-diazapane, 1 ,4-oxazepane,

1 ,4-oxathiapane, aziridinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, piperazinyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl and imidazolidinyl.

[0022] The term "histone deacetylase inhibitor" or "HDACi" refers to a small molecule that inhibits the activity of all or some of the isoforms of the histone deacetyase (HDAC) enzymes. Structurally, HDACi's generally have a linker with a hydroxamide or aromatic or heteroaromatic diamine at one end of the linker and a substituted aromatic or heroaromatic group at the other end of the linker.

[0023] The term "ligand" refers to a co-additive, co-former, coordinating moiety, or an organic compound, as defined herein. Preferably the organic compound has a molecular weight of less than 500.

[0024] The term "non-covalent derivative" ("NCD") means a eutectic or co-crystal derived from an HDACi and a ligand (a co-additive, co-former, coordinating moiety, compound, or co- crystal former) that results in a compound, complex or derivative in which the HDACi and the ligand are coordinated by noncovalent intermolecular interactions that result in the stabilization of the non-covalent derivative. Such interactions are often associated with the stabilization of proteins, drug-enzyme complexes, DNA and protein complexes etc ... See for example, Meyer, Emmanuel A. et al, Angewandte Chemie, International Edition (2003), 42(11), 1210-1250; 1433-7851. English. As depicted herein, the product or result from the combination of the HDACi with a Ligand is an NCD (a co-crystal or eutectic composition) that is stabilized by non- covalent intermolecular interactions when compared to derivatives or admixtures lacking non- covalent intermolecular interactions. Such NCDs have significantly different physical properties (such as solubility, activity, etc.) and electronic properties than a combination of two or more compounds that do not form NCDs. Representative NCDs are disclosed in Warner JC. In:

Anastas P, Williamson T, editors. Green chemistry: frontiers in benign chemical synthesis and processes. London: Oxford University Press; 1998. p. 336- 46. NCDs of the present application may be depicted generally, for example, as "X:Y" which means that it is an NCD of X with Y. [0025] "Optionally substituted" means a molecule may be unsubstituted or may be further substituted by a substituent as defined herein.

[0026] The term "patient" as used herein refers to any animal having a disease or condition which requires treatment or prophylaxis with a biologically-active agent. The patient may be a mammal, such as a human, or may be a non-human primate or non-primates such as used in animal model testing. While the compounds are suitable for use in medical treatment of humans, it is also applicable to veterinary treatment.

[0027] The phrase "pharmaceutically acceptable" means that the compound, substance or composition is compatible chemically and/or toxicologically with the other ingredients comprising a formulation, and/or with the patient being treated.

[0028] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

[0029] Generally, the terms "treatment" and "prophylaxis" mean affecting a subject, tissue, or cell to obtain a desired pharmacological and/or physiological effect and include: (a) preventing the condition from occurring in a subject that may be predisposed to the condition, but has not yet been diagnosed as having it; (b) inhibiting the condition, i.e., arresting its development; or (c) relieving or ameliorating the effects of the condition, i.e., cause regression of the effects of the condition.

[0030] "Substituted" group, as in "substituted or unsubstituted alkyl" for example, means that the alkyl goup may be unsubstituted, or substituted (where one or more hydrogens on the atom or group is replaced with one or more group) with a group selected from the group consisting of halo (F-, C1-, Br- or I-), -CN, -N0₂, -OH, -SH, -OCH₃, Ci-Ce alkyl (e.g., Methyl, ethyl, propyl, etc ...) or phenyl.

HP AC inhibitors

[0031] The histone deacetylase inhibitors (HDACi's) used herein are a class of compounds that inhibit the function of the histone deacetylase enzyme. Known HDACi's include:

[0032] The HDACi can also be an acid addition salt or base addition salt of any of the above- listed compounds. Suitable pharmaceutically acceptable salts of compounds include acid addition salts, such as those formed with mineral acids such as hydrochloric acid and

hydrobromic acid, and also those formed with organic acids such as maleic acid. For example, acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic,

ethanesulfonic, benzenesulfonic, lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate,

dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Where the compounds carry one or more acidic moieties, pharmaceutically acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically acceptable base. Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides and carbonates of alkali metals such as sodium, potassium, and lithium; alkaline earth metal such as calcium and magnesium; and other metals, such as aluminum and zinc. Suitable bases also include ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines, such as N,N-dimethyl-N- (2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. Ligands

[0033] The ligands of the application are partners (such as co-formers) of the HDACi in forming the NCD. Suitable ligands are amino acids, esters of amino acids, dipeptides, carboxylic acids, guanidine derivatives, mono- or di-saccharides, or other organic compounds.

[0034] Suitable amino acid ligands are D- or L- isomers (or racemic mixtures) of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0035] Suitable amino acid ester ligands are methyl, ethyl, propyl or /-butyl esters of an amino acid such as the D- and L-isomers (or racemic mixtures) of alanine, arginine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine.

[0036] Suitable dipeptide ligands are dipeptides comprising two D- or L-amino acids;

[0037] Suitable carboxylic acid ligands are an organic carboxylic acid, dicarboxylic acid or polycarboxylic acid (and, where applicable, the D- and L-isomers and racemic mixtures thereof) such as citric acid, thiodipropionic acid, 3,3 '-dithiopropionic acid, gluconic acid, glucuronic acid, ascorbic acid, citric acid, succinic acid, lactic acid, 3-phenyllactic acid, mandelic acid, vanillomandelic acid, 2,5-dihydroxybenzoic acid, diphenic acid, cinnamic acid, 4- hydroxycinnamic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, vanillic acid, 4- aminobenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, ellagic acid, tannic acid, malic acid, adipic acid, iram-aconitic acid, benzoic acid, caprylic acid, uric acid, cholic acid, tartaric acid, linoleic acid, nicotinic acid, oleic acid, pectinic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, tropic acid, fumaric acid, cyclamic acid, and maleic acid.

[0038] Suitable guanidine derivative ligands include 4-guanidinobutyric acid, 3- guanidinopropionic acid, 4-aminobutyric acid, 5 -amino valeric acid, and creatine.

[0039] Suitable mono- or disaccharide ligands include monosaccharides or disaccharides that are D- or L-isomers (or racemic mixtures) of glucose, lactose, maltose, sucrose, fructose, mannitol, sorbitol, ribose, and sorbose.

[0040] Other suitable organic compound ligands are 2-pyrrolidinone, caffeine,

epigallocatechin gallate, saccharin, Ν,Ν,Ν',Ν'-tetrabutylterephthalamide, Ν,Ν,Ν',Ν'- tetraethylterephthalamide, Ν,Ν,Ν',Ν'-tetrapropylterephthalamide, urea, propylene glycol, niacinamide (nicotinamide), pyridoxine, riboflavin, thiamin (thiamine), alpha-tocopherol acetate (Vitamin E acetate), quinine, D-trehalose, myo-inositol, meso-erythritol, vanillin, resorcinol, green tea extract, 4-hexylresorcinol, catechol, 2-naphthol, hydroquinone, t-butyl hydroquinone, acetaminophen, aspartame, epigallocatechin gallate, methyl vanillate, and vanillyl alcohol.

NCDs and Methods of Making

[0041] NCDs are compounds, compositions or complexes as defined above. As disclosed in the present application, the NCDs are represented or depicted, for example, as a 1 : 1

stoichiometry simply to represent the NCDs irrespective of the stoichiometry. That is, the NCDs may be formed or prepared irrespective of the stoichiometry. For example, the NCDs may be formed from the HDACi with 1 , 2 or 3 ligands, depending on the nature of the HDACi and the relative stoichiometry of the added reagents to form the NCD.

[0042] NCDs can be prepared using a variety of processes, including but are not limited to the following: cocrystalization; cooling crystallization; slurry formation; slow or rapid solvent evaporation; solid-state grinding (with or without solvent assistance); mortar-and-pestle;

automated grinders; ball mills; speed mixers and spray milling; spray-drying techniques; and hot melt extrusion. Descriptions of these techniques are found in Staler, E. et al, Molecules (2015) 20:14833-48, the contents of which are incorporated herein in their entirety.

[0043] The present application discloses the use of NCDs of HDACi's that are capable of delivering increased levels of HDACi's to biological sites, tissues or cells where needed. The properties of the HDACi's are typically retained on dissolution of the HDACi-NCDs, including but not limited to cellular uptake, bioavailability, ability to cross the blood-brain-barrier, redox potential, or therapeutic efficacy. In one aspect, the HDACi-NCD may be administered as a solid or a solid dispersed in water, without the need for additional formulation.

Methods of Treatment. Ameliorating and/or Prophylaxis

[0044] The NCD's of the present application are effective as HDAC inhibitors. They may be used in the treatment or prophylaxis of a number of conditions in which HDAC inhibition can prevent, alleviate or ameliorate the condition. Such conditions include (but are not limited to) cancer of a system selected from the group consisting of the hematopoietic system, immune system, endocrine system, pulmonary system, gastrointestinal system, musculoskeletal system, reproductive system, central nervous system, and urologic system. In one embodiment, the cancer is a cancer of the myeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues, lung tissues, colon tissues, rectal tissues, anal tissues, liver tissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues, breast, prostate, testicular tissues, brain, brainstem, meningeal tissues, kidney or bladder. In another embodiment the cancer is selected from the group consisting of breast cancer, colon cancer, multiple myeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, hematologic malignancy, renal cell carcinoma, renal cancer, malignant melanoma, pancreatic cancer, lung cancer, colorectal carcinoma, brain cancer, head and neck cancer, bladder cancer, thyroid cancer, ovarian cancer, cervical cancer, myelodysplastic syndrome, leukemia, multiple myeloma, and other hematologic malignancies. HDACi's may also be useful to treat systemic inflammation, inflammatory bowel disease, arthritis, immune system diseases, heart failure, diabetes, neurological diseases, fibrotic diseases, HIV infection, and muscular dystrophy.

[0045] In one aspect, the NCDs may be administered via oral or non-oral methods, to a mammal without requiring the formulation with excipients, solubilizers and the like that are not acceptable for human use.

Administration of NCD

[0046] Administration of the NCD to humans can be performed by any of the accepted modes of administration well known in the art. For example they may be administered by enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion. The NCD is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the subject a therapeutically effective dose.

[0047] The NCD may be administered in any form or mode which makes the complex bio- available. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the selected HDACi, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. See Remingtons Pharmaceutical Sciences, 19^th edition, Mack Publishing Co. (1995). In one aspect, the NCD can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

[0048] Pharmaceutical compositions of the NCD for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. These compositions comprising the NCD may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.

[0049] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active complex is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,

polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

EXAMPLES

Preparation of the NCDs

[0050] The complexes of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art for each of the individual step/reactions and using starting materials that are readily available. The synthesis of non-exemplified complexes may be performed by modifications apparent to those skilled in the art. Suitable protecting groups can be found in T.W. Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 1981.

Example 1

Preparation of Vorinostat NCD' s

[0051] NCDs of vorinostat were generated using solid state methods (including ball milling, microfluidization, grinding, and co-crystallization). In the standard NCD preparation, equimolar amounts of vorinostat and the conformer molecule were combined to achieve a total mass of 300 mg (1 :1 molar ratio) in a plastic ball-milling vial with a single milling sphere and cap. The vial was milled using a Spex Amalgamator for 60 min. The NCD was then transferred to a glass 1 dram vial for storage at room temperature.

[0052] The vorinostat NCDs were then characterized by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), and/or X-ray Powder Diffraction (XRPD). The results from the solid-state preparation and characterization of the vorinostat NCDs is summarized in the following tables providing the data for each vorinostat-coformer NCD. Shifts in the FTIR stretches (cm-1) and/or in the DSC melts (°C) demonstrates the formation of an NCD between vorinostat and the coformer.

Example 2

Aqueous Solubility of vorinostat NCDs

[0053] The vorinostat NCDs prepared in Example 1 are evaluated for enhanced aqueous solubility according to the following standard protocol.

[0054] A stock solution of vorinostat is made in DMSO at 10 mg/mL. The solution is then diluted in acetonitrile +0.05% trifluoroacetic acid (ACN-TFA) to 50 μg/mL to observe behavior in LC-MS-UV. [0055] Conditions for the chromatographic mobile phase are optimized such that there is a distinction between the retention time of the compound and the column void volume. (This may require diluting the API in a different solvent, e.g. water, DMSO, etc., to obtain appropriate separation. Conditions for the mass spec Atmospheric Pressure Chemical Ionization (APCI) (e.g. fragmentation, drying gas volume and temperature, nebulizer pressure & vaporizer temperature) are also optimized, using the single ion method (SIM) of detection to achieve the greatest sensitivity. A calibration curve in ACN-TFA is run to determine the limits of detection by both UV and MS, and then used to calculate the concentration of vorinostat in solution.

[0056] A general amount of vorinostat in H₂0, PBS or 0.1M HC1 that will result in a saturated solution with solids left in tube after shaking (based on literature values) is determined. A saturated solution of vorinostat, milled vorinostat and each NCD in water, PBS (IX &/or lOx) & HC1 is made and shaken for 2 hours and 24 hours at 25 °C as appropriate.

[0057] It is determined whether samples can be centrifuged or filtered, including type of filter to use, to separate undissolved particles to reduce the chance of false positives. The solution is stabilized by adding 10%(v/v) DMSO to help prevent any soluble compound from precipitating and causing a false negative, then assay using optimized LC-MS-UV conditions.

[0058] The retention time of the co-former's elutions are checked for difference from vorinostat to check for chromatographic interference. LC-MS-UV conditions are re-optimized if necessary and samples re-assayed.

[0059] The chromato grams are integrated and the peak area determined for all samples. The solution concentration ^g/mL) is determined for all runs. The concentration of the "As

Received" vorinostat to the milled vorinostat and each NCD is measured, and percent change (positive or negative) is determined. Samples displaying >20% change (positive or negative) are validated through repeat analyses.

[0060] The resulting solubility of the vorinostat NCD made with L-arginine showed a consistent increase of over 300% versus the As Received vorinostat, as shown in Figures 1 to 3.

[0061] While a number of exemplary embodiments, aspects and variations have been provided herein, those of skill in the art will recognize certain modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations. It is intended that the following claims are interpreted to include all such

modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations are within their scope. The entire disclosures of all documents cited throughout this application are incorporated herein by reference.

Claims

What is claimed is:

1. A non-covalent derivative (NCD) comprising a histone deacetylase inhibitor (HDACi) and a ligand.

2. The NCD of claim 1 wherein the HDACi is selected from the group consisting of vorinostat, belinostat, pabinostat, mocetinostat, abexinostat, chidamide, pracinostat, entinostat, tacedinaline, resminostat, M344, BML-210, quisinostat, givinostat, dacinostat and ricolinostat.

3. The NCD of claim 2 wherein the HDACi is vorinostat.

4. The NCD of claim 2 wherein the HDACi is ricolinostat.

5. The NCD of claim 2 wherein the HDACi is entinostat.

6. The NCD of claim 1 wherein the ligand is: a) an amino acid selected from the group consisting of D- and L- isomers (or racemic mixtures) of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine; b) a methyl, ethyl, propyl or f -butyl ester of an amino acid selected from the group consisting of the D- and L-isomers (or racemic mixtures) of alanine, arginine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tyrosine, tryptophan, and valine; c) a dipeptide comprising two D- or L-amino acids; d) an organic carboxylic acid, dicarboxylic acid or polycarboxylic acid (and, where applicable, the D- and L-isomers and racemic mixtures thereof) selected from the group consisting of citric acid, thiodipropionic acid, 3,3 '-dithiopropionic acid, gluconic acid, glucuronic acid, ascorbic acid, citric acid, succinic acid, lactic acid, 3-phenyllactic acid, mandelic acid, vanillomandelic acid, 2,5-dihydroxybenzoic acid, diphenic acid, cinnamic acid, 4-hydroxycinnamic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, vanillic acid, 4-aminobenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, ellagic acid, tannic acid, malic acid, adipic acid, fraws-aconitic acid, benzoic acid, caprylic acid, uric acid, cholic acid, tartaric acid, linoleic acid, nicotinic acid, oleic acid, pectinic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, tropic acid, fumaric acid, cyclamic acid, and maleic acid; e) a guanidine derivative selected from the group consisting of 4-guanidinobutyric acid, 3- guanidinopropionic acid, 4-aminobutyric acid, 5-aminovaleric acid, and creatine; f) a monosaccharide or a disaccharide selected from the group consisting of D- or L-isomers (or racemic mixtures) of glucose, lactose, maltose, sucrose, fructose, mannitol, sorbitol, ribose, and sorbose; or g) an organic compound selected from the group consisting of 2-pyrrolidinone, caffeine, saccharin, Ν,Ν,Ν' ,Ν' -tetrabutylterephthalamide, Ν,Ν,Ν',Ν' -tetraethy lterephthalamide,

Ν,Ν,Ν',Ν'-tetrapropylterephthalamide, urea, propylene glycol, niacinamide (nicotinamide), pyridoxine, riboflavin, thiamin (thiamine), alpha-tocopherol acetate (Vitamin E acetate), quinine, D-trehalose, myoinositol, meso-erythritol, vanillin, resorcinol, green tea extract, 4-hexylresorcinol, catechol, 2-naphthol, hydroquinone, t-butyl hydroquinone, acetaminophen, aspartame, epigallocatechin gallate, methyl vanillate, and vanillyl alcohol.

7. The NCD of claim 1 which is a eutectic.

8. The NCD of claim 1 which is a co-crystal.

9. The NCD of claim 1 which is not explicitly identified as a co-crystal or eutectic but is included in a pharmaceutical formulation and the ligand is considered an excipient or component of the pharmaceutical formulation providing an improvement of certain pharmaceutical properties.

10. A solid state synthetic method of making the NCD of claim 1, the method comprising a step selected from the group consisting of: mechanical milling, jet milling, microfluidization, manual or automated grinding, evaporation, crystallization, melting, co-solvent techniques, anti-solvent techniques, spray drying, liquid assisted grinding, sonication, extrusion, and twin screw extrusion.