PARP inhibitor pharmaceutical compositions

Abstract

The invention provides a pharmaceutical composition comprising (a) a pharmaceutically acceptable excipient of vitamin E derivatives, specifically TPGS (tocopheryl polyethylene glycol succinate) derivatives / homologs, and (b) a PARP inhibitor such as olaparib, rucaparib, niraparib, talazoparib, veliparib, saruparib, [6-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-l- ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester, or a pharmaceutically acceptable salt thereof, and a combination thereof. The inventive pharmaceutical compositions inhibit one or more proteins comprising PARP and / or tubulin, and therefore have the potential to treat diseases in which these proteins are associated.

Description

PATENT Atorney Docket No.: ATLA-002WOPARP INHIBITOR PHARMACEUTICAL COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATION

[0001] Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing date of United States Provisional Patent Application Serial No. 63 / 737,258 filed December 20, 2024, the disclosure of which is herein incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] There is a need for new pharmaceutical compositions for the treatment of diseases such as cancer. There is also a need for new pharmaceutical compositions for PARP inhibitors (e.g. [6-]2-fluoro-5-(4-oxo-3.4-dihydro-phthalazin-l-ylmethyl- phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester, or a salt thereof). The present invention addresses these and other needs.SUMMARY OF THE INVENTION

[0003] The invention provides pharmaceutical compositions of PARP inhibitors (e.g. [6-]2-fluoro-5-(4-oxo-3.4-dihydro-phthalazin- 1 -ylmethyl-phenyl]- 1 H-benzoimidazol- 2-yl)-carbamic acid ethyl ester).DETAILED DESCRIPTION OF THE INVENTIONI. Definitions and Abbreviations

[0004] In order that the application may be more completely understood, several definitions are set forth below. Such definitions are meant to encompass grammatical equivalents.

[0005] The term “about” in relation to a reference numerical value can include the numerical value itself and a range of values plus or minus 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 9 to 11. For example, the term “about” in relation to a reference numerical value can alsoinclude a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1 % from that value.

[0006] Specific embodiments disclosed herein can be further limited in the claims using “consisting of’ or “consisting essentially of’ language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the disclosure so claimed are inherently or expressly described and enabled herein.

[0007] The terms “a,” “an,” “the” and similar referents used in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0008] The following abbreviations have been used: Ac is acetyl; AcOH is acetic acid; ACTBr is cetyl tri methylammonium bromide; A1BN is azobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Ar is aryl; B2pin2 is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS)2 is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; BOC2O is di-tert-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl; CS2CO3 is cesium carbonate; CSA is camphor sulfonic acid; CT AB is cetyltrimethylammonium bromide; Cy is cyclohexyl; DABCO is 1,4- diazabicyclo[2.2.2]octane; DCM is dichloromethane or methylene chloride; DHP is dihydropyran; DIAD is diisopropyl azodicarboxylate; DIEA or DIPEA is N,N- diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is 1,2- dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate; EtOH is ethanol; Et2O is diethyl ether; EDCI is W(3-dimethylaminopropyl)-7V'-ethylcarbodiimide hydrochloride; ELS is evaporative light scattering; equiv or eq is equivalent; h is hours; HATU is O-(7- azabenzotriazol-l-yl)-N,N,N’,N'-tetramethyluronium hexafluorophosphate; HOBt is A-hydroxybenzotriazole; HC1 is hydrochloric acid; HPLC is high performance liquid chromatography; ISCO Companion is automated flash chromatography equipmentwith fraction analysis by UV absorption available from Presearch; KO Ac or AcOK is potassium acetate; K2CO3 is potassium carbonate; Li AIH4 or LAH is lithium aluminum hydride; LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl) amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methyl cyanide or cyanomethane or ethanenitrile or acetonitrile which are all names for the same compound; MeOH is methanol; MgSCL is magnesium sulfate; mins or min is minutes; Mp or MP is melting point; NaCNBHs is sodium cyanoborohydride; NaOH is sodium hydroxide; Na^SCft is sodium sulfate; NBS is N-bromosuccinimide; NH4CI is ammonium chloride; NIS is N-iodosuccinimide; N2 is nitrogen; NMM is N- methylmorpholine; n-BuLi is n-butyllithium; O / N is overnight; PdCh(pddf) is 1,1'- Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd / C is the catalyst known as palladium on carbon; Pd2(dba)s is an organometallic catalyst known as tris(dibenzylideneacetone) dipalladium(O); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is 1 -propanol; iPrOH is 2-propanol; POCI3 is phosphorus chloride oxide; PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used herein means pyridine; RT or rt or r.t. is room temperature; sat. is saturated; Si- amine or Si-NFE is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et3N is triethylamine; TFA is trifluoroacetic acid; TfzO is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H2O is water; diNCFPhSChCl is dinitrophenyl sulfonyl chloride; 3-F-4-NO2-PhSO2Cl is 3-fluoro-4-nitrophenylsulfonyl chloride; 2-MeO-4- NO2-PI1SO2CI is 2-methoxy-4-nitrophenylsulfonyl chloride; and (EtOftPOCFECOOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.

[0009] "Pharmaceutical composition of the invention," as used herein refers to the pharmaceutical compositions discussed herein, and salts (e.g. pharmaceutically acceptable salts), thereof of Compound 1.

[0010] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left, e.g., -CH2O- is intended to also recite -OCH2-.

[0011] The term "poly" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valency of at least 2.

[0012] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.

[0013] The symbol ' / wv' , whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.

[0014] The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

[0015] The symbol "R" is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.

[0016] By “effective” amount of a drug, pharmaceutical composition, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A “Topically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.

[0017] The term "pharmaceutically acceptable salt" is meant to include a salt of a compound of the invention which is prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, or 1-lysine), or magnesium salt, ora similar salt. When compounds of the invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, perchloric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. In an exemplary embodiment, the PARP inhibitor, or a pharmaceutically acceptable salt thereof, is a salt thereof, wherein the salt of the PARP inhibitor is aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, histidine, lithium, lysine, magnesium, meglumine, potassium, procaine, sodium, triethylamine, or zinc, or a combination thereof.

[0018] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0019] Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amoiphous forms.

[0020] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention. The graphicrepresentations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.

[0021] Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and transisomers, (-)- and (-i-)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0022] Optically active ( / ?)- and (S)-isomers and d and I isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0023] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (123I) or carbon-14 (14C). All isotopic variations ofthe compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

[0024] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle” refers to any pharmaceutical composition or carrier medium that provides the appropriate delivery of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently nontoxic to the subject. Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. The pharmaceutical composition is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.

[0025] The term “excipients” is conventionally known to mean carriers, diluents and / or vehicles used in formulating drug compositions effective for the desired use.

[0026] The terms “effective amount” or a “therapeutically effective amount” of a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to provide the desired effect. In the oral dosage forms of the present disclosure, an “effective amount” of one active of the combinatilon is the amount of that active that is effective to provide the desired effect when used in combination with the other active of the combination. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0027] The phrases “active ingredient”, “therapeutic agent”, “active”, or “active agent” mean a chemical entity which can be effective in treating a targeted disorder, disease or condition.

[0028] The phrase “pharmaceutically acceptable” means moieties or compounds that are, within the scope of medical judgment, suitable for use in humans without causingundesirable biological effects such as undue toxicity, irritation, allergic response, and the like, for example.

[0029] "Biological medium," as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro "biological media" include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.

[0030] "Inhibiting" and "blocking," are used interchangeably herein to refer to the partial or full blockade of an enzyme, such as PARP and / or tubulin.

[0031] Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof.IL Introduction

[0032] The invention provides pharmaceutical compositions and methods of using same to treat diseases, such as cancer.III. Pharmaceutical Composition

[0033] In one aspect the invention provides a pharmaceutical composition comprising: (a) a pharmaceutically acceptable excipient; and (b) a PARP inhibitor. In an exemplary embodiment, the pharmaceutical composition is described herein. In an exemplary embodiment, the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, saruparib, [6-]2-fhroro-5-(4-oxo-3,4-dihydro-phthalazin-l -ylmethyl-phenyl]- lH-benzoimidazol-2-yl)-carbamic acid ethyl ester, a pharmaceutically acceptable salt thereof, and a combination thereof. In an exemplary embodiment, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is rucaparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is talazoparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is veliparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is saruparib or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is [6-]2-fluoro-5-(4-oxo-3,4- dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethylester (sometimes mentioned as Compound 1 herein) or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the PARP inhibitor is an HC1 salt of [6-]2- fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)- carbamic acid ethyl ester or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, perchloric, sulfuric, and phosphoric. In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is sulfonic (such as methanesulfonic, ethanesulfonic, p-toluenesulfonic). In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is monocarboxylic (such as formic, acetic, propionic, butyric, valeric, caproic, acrylic, pyruvic, benzoic, hydroxybenzoic, dihydroxybenzoic). In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is dicarboxylic (such as oxalic, maleic, malonic, fumaric). In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is hydroxy -dicarboxylic (such as tartaric). In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is hydroxy-tricarboxylic (such as citric). In an exemplary embodiment, the salt of the pharmaceutically acceptable salt of the PARP inhibitor is uronic (such as glucuronic acid, galacturonic acid, iduronic acid, N-acetyl-neuraminic acid (sialic acid), gluconic acid).

[0034] In an exemplary embodiment, the pharmaceutically acceptable excipients listed herein may be combined in a pharmaceutical composition described herein. In an exemplary embodiment, the pharmaceutically acceptable excipient is selected from vitamin E, saturated fat, unsaturated fat, monoglyceride, diglyceride, triglyceride, polyalkylene glycol, polyoxylglyceride, alcohol, mannitol, lactose, maltodextrin, microcrystalline cellulose, starch, citric acid, potassium hydroxide, glycerin, gelatin, or a combination thereof. In an exemplary embodiment, the pharmaceutically acceptable excipient is olive oil. In an exemplary embodiment, the saturated fat is palmitic acid, ricinoleic acid, or stearic acid. In an exemplary embodiment, the monounsaturated fat is oleic acid or palmitoleic acid. In an exemplary embodiment, the polyunsaturated fat is linoleic acid or a-linoleic acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is medium chain triglycerides (MCT). In an exemplary embodiment, the MCT comprises a fatty acid having an aliphatic tail from 6 to 12carbon atoms. In an exemplary embodiment, the monoglyceride comprises a member selected from caproate, caprylate, caprate, and laurate. In an exemplary embodiment, the diglyceride comprises a member selected from caproate, caprylate, caprate, and laurate. In an exemplary embodiment, the triglyceride comprises a member selected from caproate, caprylate, caprate, and laurate. In an exemplary embodiment, the pharmaceutically acceptable excipient is a glyceryl monoester of caprylic acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is a glyceryl monoester of capric acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is a glyceryl diester of caprylic and capric acids. In an exemplary embodiment, the pharmaceutically acceptable excipient is glyceryl mono and dicaprylocaprate. In an exemplary embodiment, the monoglyceride, diglyceride, or triglyceride comprises an oleate. In an exemplary embodiment, the pharmaceutically acceptable excipient is hard gelatin or soft gelatin. In an exemplary embodiment, the pharmaceutically acceptable excipient is gelatin, type B. In an exemplary embodiment, the pharmaceutically acceptable excipient is glycerin. In an exemplary embodiment, the pharmaceutically acceptable excipient is starch. In an exemplary embodiment, the starch is gelatinized starch. In an exemplary embodiment, the gelatinized starch is partially gelatinized starch. In an exemplary embodiment, the pharmaceutically acceptable excipient is a mono-, di-, or triglyceride comprising a ricinoleate. In an exemplary embodiment, the pharmaceutically acceptable excipient is a glyceride. In an exemplary embodiment, the glyceride is a member selected from the group consisting of glyceryl monocaprylocaprate, glyceryl dicaprylocaprate, medium chain triglycerides, and a combination thereof.

[0035] In an exemplary embodiment, the pharmaceutically acceptable excipient is selected from vitamin E, Miglyol, Lauroglycol, Labrafac, Labrafil, Labrasol, Capryol, Maisine, Gelucire, Kolliphor, or Transcutol. In an exemplary embodiment, the pharmaceutically acceptable excipient is selected from Miglyol 812N, Miglyol 840, Lauroglycol 90, Lauroglycol FCC, Labrafac MC60, Labrafac CC MB, Labrafac N MB, Labrafac PG, Labrafac Lipophile WL 1349, Labrafil M2125CS, Labrafil M2130CS, Labrafil M1944 CS, Labrasol, Labrasol ALF, Capryol 90, Capryol PGMC, Maisine CC, Maisine, Gelucire 44 / 14, Gelucire 48 / 16, Gelucire 50 / 13, Gelucire 59 / 14, Kolliphor CS 12, Kolliphor CS 20, Kolliphor CS A, Kolliphor CSL, Kolliphor CSS, Kolliphor EL, Kolliphor ELP, Kolliphor HS 15, Kolliphor P 188 Bio, Kolliphor P 188Geismar, Kolliphor P 188 micro Geismar, Kolliphor P 338 Geismar, Kolliphor P 407 Geismar, Kolliphor P 407 micro Geismar, Kolliphor PS 20, Kolliphor PS 60, Kolliphor PS 80, Kolliphor RH 40, Kolliphor SLS, Kolliphor SLS Fine, Kolliphor SML 20, Transcutol V, Transcutol CG, Transcutol HP, Transcutol P, or a combination thereof. In an exemplary embodiment, the pharmaceutically acceptable excipient is selected from Miglyol 812N, Lauroglycol FCC, Labrafac MC60, Labrafil M2125CS, Labrasol ALF, Capryol 90, Maisine CC, Gelucire 44 / 14, Kolliphor EL, Kolliphor RH 40, Transcutol HP, or a combination thereof. In an exemplary embodiment, the alcohol is ethanol or benzyl alcohol. In an exemplary embodiment, the polyalkylene glycol is polyethylene glycol. In an exemplary embodiment, the polyalkylene glycol is polypropylene glycol. In an exemplary embodiment, the polyethylene glycol is from PEG50 to PEG2000, from PEG100 to PEG1500, from PEG200 to PEG1000, from PEG250 to PEG750, or from PEG300 to PEG500. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG + potassium hydroxide. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG400 + potassium hydroxide. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG + 5% potassium hydroxide. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG400 + 5% potassium hydroxide. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG + citric acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG400 + citric acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG + 5% citric acid. In an exemplary embodiment, the pharmaceutically acceptable excipient is PEG400 + 5% citric acid.

[0036] In an exemplary embodiment, the pharmaceutically acceptable excipient is vitamin E, diethylene glycol monoethyl ether, lauroyl PEG-32 glyceride, glycerol polyethylene glycol oxystearate, fatty acid glycerol polyglycol ester, macrogolglycerol ricinoleate, polyoxyl 35 castor oil, glyceryl monolinoleate, propylene glycol monocaprylate, PEG-8 caprylic / capric glyceride, com oil PEG-6 esters, glycerol monocaprylocaprate (type I), glycerol monocaprylocaprate (type II), propylene glycol monolaurate (type I), propylene glycol monolaurate (type II), or triglyceride ester of saturated coconut / palm kernel oil derived caprylic and capric fatty acids.

[0037] In one aspect the invention provides a pharmaceutical composition comprising:wherein R1, R2, R3, R4, R5, and R6are each independently H or C1-3 alkyl; each dashed line ( — ) is independently a single or double bond; n is an integer from 1 to 5000; m and q each independently are 0, 1, 2, or 3; p is an integer from 1 to 20; z is an integer from 1 to 10; and (b) a PARP inhibitor. In an exemplary embodiment, in the vitamin E, R1, R2, R3, R4, R5, and R6are each independently H or CH3. In an exemplaryembodiment, n is from about 600 to about 1400, from about 700 to about 1300, from about 800 to about 1200, from about 900 to about 1100, or from about 950 to about1050. In an exemplary embodiment, n is about 1000. In an exemplary embodiment, n is from about 1 to about 100, from about 5 to about 90, from about 5 to about 50, from about 10 to about 40, from about 20 to about 40, from about 25 to about 37, or from about 30 to about 35. In an exemplary embodiment, n is about 33.

[0038] In an exemplary embodiment, the pharmaceutical composition consists essentially of:wherein n is an integer from 950 to 1050; a HC1 salt of [6-]2-fhioro-5-(4-oxo-3,4-dihydro-phthalazin- l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester; and glyceryl monocaprylocaprate.

[0039] In an exemplary embodiment, the pharmaceutical composition comprises:CHs wherein n is an integer from950 to 1050; a HC1 salt of [6-]2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl- phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester; and medium chain triglycerides. In an exemplary embodiment, the pharmaceutical composition comprises:wherein n is an integer from 950 to 1050; a HC1 salt of [6-]2-fhioro-5-(4-oxo-3,4-dihydro-phthalazin- l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester; and glyceryl monocaprylocaprate and medium chain triglycerides.

[0040] In another aspect, the invention is a pharmaceutical composition comprising: (a) a pharmaceutically acceptable excipient; and (b) Compound 1 ([6-]2-fluoro-5-(4- oxo-3.4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester), or a salt thereof. In another aspect, the invention is a pharmaceutical composition comprising: (a) a pharmaceutically acceptable excipient; and (b) a compound which is [6-]2-fhioro-5-(4-oxo-3.4-dihydro-phthalazin-l-yhnethyl-phenyl]- lH-benzoimidazol-2-yl)-carbamic acid ethyl ester, or a salt thereof. In an exemplary embodiment, the compound, or a salt thereof, is a HC1 salt of [6-]2-fluoro-5-(4-oxo- 3.4-dihydro-phthalazin- 1 -y Imethyl-phenyl] - 1 H-benzoimidazol-2-yl)-carbamic acid ethyl ester. In an exemplary embodiment, the pharmaceutically acceptable excipient is a diluent. In another aspect, the invention provides a pharmaceutical compositioncomprising: (a) a diluent which is mannitol, lactose, maltodextrin, microcrystalline cellulose, or starch; and (b) a compound which is [6-]2-fluoro-5-(4-oxo-3.4-dihydro- phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester, or a salt thereof. In an exemplary embodiment, the compound, or a salt thereof, is a HC1 salt of [6-]2-fhioro-5-(4-oxo-3.4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH- benzoimidazol-2-yl)-carbamic acid ethyl ester. In an exemplary embodiment, the diluent is mannitol. In an exemplary' embodiment, the diluent is mannitol and the compound, or a salt thereof, is a HC1 salt of [6-]2-fluoro-5-(4-oxo-3.4-dihydro- phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester.

[0041] In an exemplary embodiment, the pharmaceutical composition is an oral pharmaceutical composition. In an exemplary embodiment, the oral pharmaceutical composition is a capsule. In an exemplary embodiment, the oral pharmaceutical composition is a hard gelatin capsule. In an exemplary embodiment, the oral pharmaceutical composition is a soft gelatin capsule.

[0042] In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to between about 5 mg to about 120 mg of the free base of the PARP inhibitor. In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to between about 4.5 mg and about 5.5 mg, or about 9.5 mg and about 10.5 mg, or about 19.5 mg and about 20.5 mg, or about 39.5 mg and about 40.5 mg, or about 59.5 mg and about 60.5 mg, or about 119.5 mg and about 120.5 mg, of the free base of the PARP inhibitor. In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to between about 4.5 mg and about 5.5 mg, or about 9.5 mg and about 10.5 mg, or about 19.5 mg and about 20.5 mg, or about 39.5 mg and about 40.5 mg, or about 59.5 mg and about 60.5 mg, or about 119.5 mg and about 120.5 mg, of the free base of the PARP inhibitor. In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to from about 50 mg to about 300 mg of the free base of the PARP inhibitor. In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to from about 180 mg to about 240 mg of the free base of the PARP inhibitor. In an exemplary embodiment, the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to from about 1% (weight of free base of PARP inhibitor / weight ofpharmaceutical composition) to about 50% (w / w), from about 5% (w / w) to about 30% (w / w), from about 15% (w / w) to about 25% (w / w), or from about 19% (w / w) to about 21% (w / w). In an exemplary embodiment, the PARP inhibitor is a HC1 salt of [6-J2- fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)- carbamic acid ethyl ester, and is present in the pharmaceutical composition in an amount equivalent to from about 180 mg to about 240 mg of the free base of the PARP inhibitor.

[0043] In an exemplary embodiment, the vitamin E is present in the pharmaceutical composition in an amount equivalent to from about 5% (weight of vitamin E / weight of pharmaceutical composition) to about 95% (w / w), from about 40% (w / w) to about 90% (w / w), from about 75% (w / w) to about 85% (w / w), from about 15% (w / w) to about 25% (w / w), or from about 16% (w / w) to about 20% (w / w).

[0044] In an exemplary embodiment, the glyceryl mono and dicaprylocaprate is present in the pharmaceutical composition in an amount equivalent to from about 10% (weight of glyceryl mono and dicaprylocaprate / weight of pharmaceutical composition) to about 90% (w / w), from about 40% (w / w) to about 90% (w / w), from about 75% (w / w) to about 85% (w / w), from about 25% (w / w) to about 35% (w / w), or from about 27% (w / w) to about 31% (w / w).

[0045] In an exemplary embodiment, the medium chain triglycerides are present in the pharmaceutical composition in an amount equivalent to from about 10% (weight of medium chain triglycerides / weight of pharmaceutical composition) to about 50% (w / w), from about 20% (w / w) to about 40% (w / w), from about 30% (w / w) to about 36% (w / w), or from about 32% (w / w) to about 34% (w / w).

[0046] In an exemplary embodiment, the saturated fat, unsaturated fat, monoglyceride, diglyceride, and / or triglyceride are present in the pharmaceutical composition in an amount equivalent to from about 10% (weight of medium chain triglycerides / weight of pharmaceutical composition) to about 50% (w / w), from about 20% (w / w) to about 40% (w / w), from about 30% (w / w) to about 36% (w / w), or from about 32% (w / w) to about 34% (w / w).IV. Methods of Inhibiting PARP and / or tubulin

[0047] The pharmaceutical compositions of the invention inhibit one or more proteins, and said one or more proteins are PARP and / or tubulin, and therefore have thepotential to treat diseases in which these proteins are associated. The pharmaceutical compositions of the invention inhibit tubulin, and therefore have the potential to treat diseases in which tubulin is associated. The pharmaceutical compositions of the invention inhibit PARP, and therefore have the potential to treat diseases in which PARP is associated. In an exemplary embodiment, the PARP is PARP1. In an exemplary embodiment, the PARP is PARP2. In an exemplary embodiment, the pharmaceutical compositions of the invention inhibit one or more proteins, and said one or more proteins are PARP1 and / or PARP2 and / or tubulin, and therefore have the potential to treat diseases in which these proteins are associated.

[0048] In a further aspect, the invention provides a method of inhibiting PARP and / or tubulin, said method comprising: contacting said PARP and / or tubulin with an effective amount of a pharmaceutical composition of the invention, thereby inhibiting said PARP and / or tubulin. In a further aspect, the invention provides a method of inhibiting PARP, said method comprising: contacting said PARP with an effective amount of a pharmaceutical composition of the invention, thereby inhibiting said PARP. In a further aspect, the invention provides a method of inhibiting tubulin, said method comprising: contacting said tubulin with an effective amount of a pharmaceutical composition of the invention, thereby inhibiting said tubulin. In a further aspect, the invention provides a method of inhibiting PARP1 and / or PARP2 and / or tubulin, said method comprising: contacting said PARP1 and / or PARP2 and / or tubulin with an effective amount of a pharmaceutical composition of the invention, thereby inhibiting said PARP1 and / or PARP2 and / or tubulin. In an exemplary embodiment, the one or more proteins is one protein which is PARP1. In an exemplary embodiment, the one or more proteins is one protein which is PARP2. In an exemplary embodiment, the one or more proteins is one protein which is tubulin. In an exemplary embodiment, the one or more proteins are two proteins which are PARP1 and tubulin. In an exemplary embodiment, the one or more proteins are two proteins which are PARP2 and tubulin. In an exemplary embodiment, the one or more proteins are two proteins which are PARP1 and PARP2. In an exemplary embodiment, the invention provides a method of inhibiting PARP1 and / or PARP2 and / or tubulin, comprising: contacting said PARP1 and / or PARP2 and / or tubulin with an effective amount of the pharmaceutical composition of the invention, thereby inhibiting said PARP1 and / or PARP2 and / or tubulin.V. Methods of Treatins Disease

[0049] The pharmaceutical compositions of the invention exhibit potency against disease, such as cancer, and therefore have the potential to achieve therapeutic efficacy in the animals described herein.

[0050] In an exemplary embodiment, the invention provides a method of treating a disease. The method includes administering to the animal a therapeutically effective amount of the pharmaceutical composition of the invention, sufficient to treat the disease. In an exemplary embodiment, the invention provides a method of treating a disease in an animal comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of the invention, wherein the animal is in need of treatment, sufficient to treat the disease. In another aspect, the invention provides a method of treating a disease in an animal comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of the invention, wherein the animal is not otherwise in need of treatment with the pharmaceutical composition of the invention, sufficient to treat the disease. In an exemplary embodiment, the disease is a tumor. In an exemplary embodiment, the disease is a tumor, and the tumor is benign, or non-cancerous. In an exemplary embodiment, the disease is a tumor, and the tumor is malignant, or cancerous. In an exemplary embodiment, the disease is a tumor, and the tumor is benign (non- cancerous). In an exemplary embodiment, the disease is cancer. In an exemplary embodiment, the disease is cancer. In an exemplary embodiment, the term “cancer” defines any malignant cancerous growth. In an exemplary embodiment, the disease is a sarcoma, adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, a central nervous system (CNS) cancer, a peripheral nervous system (PNS) cancer, Castleman’s Disease, cervical cancer, colon cancer, rectum cancer, endometrial cancer, esophagus cancer, Ewing’s family of tumors (e.g. Ewing’s sarcoma), eye cancer, gallbladder cancer, a gastrointestinal carcinoid tumor, a gastrointestinal stromal tumor, gestational trophoblastic disease, hairy cell leukemia, Hodgkin’s disease, kidney cancer, laryngeal cancer, a hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children’s leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, a lung carcinoid tumor, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, a nasal cavity cancer, a paranasal cancer, nasopharyngeal cancer, neuroblastoma, an oral cavitycancer, an oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, an adult soft tissue cancer, melanoma skin cancer, nonmelanoma skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g. uterine sarcoma), vaginal cancer, vulvar cancer, or Waldenstrom’ s macroglobulinemia.

[0051] In an exemplary embodiment, the disease is a cancer of the blood, such as leukemia, cancer of the skin, such as melanoma, cancer of the colon, cancer of the lung, cancer of the ovary, cancer of the uterus, cancer of the breast, cancer of the prostate, cancer of the pancreas. In an exemplary embodiment, the disease is a cancer of the central nervous system, or a cancer of the renal system. In an exemplary embodiment, the disease is a soft tissue cancer. In an exemplary embodiment, the disease is multiple myeloma. In an exemplary embodiment, the cancer is ovarian cancer. In an exemplary embodiment, the cancer is uterine cancer. In an exemplary embodiment, the cancer is pancreatic cancer. In an exemplary embodiment, the cancer is lung cancer. In an exemplary embodiment, the cancer is brain cancer. In an exemplary embodiment, the cancer is skin cancer. In some embodiments, the cancer is colon cancer. In an exemplary embodiment, the cancer is derived from cancer stem cells.

[0052] In an exemplary embodiment, the cancer is breast cancer. In an exemplary embodiment, the breast cancer is negative for one or more of Estrogen Receptor (ER), Progesterone Receptor (PR), or Human Epidermal Growth Factor Receptor 2 (HER2). In an exemplary embodiment, the breast cancer is negative for one or more of ER, PR or HER2; and wherein the breast cancer is positive for one or more of ER, PR or HER2. In an exemplary embodiment, the breast cancer is negative for two of ER, PR or HER2. In an exemplary embodiment, the breast cancer is ER negative and PR- negative.

[0053] In an exemplary embodiment, the breast cancer is ER-negative and HER2- negative. In an exemplary embodiment, the breast cancer is PR-negative and HER2- negative. In an exemplary embodiment, the breast cancer is an ER -negative breast cancer. In an exemplary embodiment, the breast cancer is an HER2 -negative breast cancer.

[0054] In an exemplary embodiment, a pharmaceutical composition of the invention treats a disease in an animal, by inhibiting tubulin polymerization and / or PARP activity. The present invention thus provides a method for treating a disease by inhibiting either or both tubulin polymerization and PARP activity comprising the step of administering pharmaceutical compositions of the invention to a patient in need thereof.

[0055] In an exemplary embodiment, a pharmaceutical composition of the invention is used at an early stage of a disease, or before early onset, or after significant progression, including metastasis in case of cancer. The term “treatment” or “treating” applied to tumor can refer to a reduction of the burden in a patient, such as a reduction in cell proliferation rate, a destruction of diseased proliferative cells, a reduction of tumor mass or tumor size, a delaying of tumor progression, or a complete tumor suppression.

[0056] In an exemplary embodiment, a pharmaceutical composition of the invention can be used in treatment of cancers deficient in Homologous Recombination (HR) dependent DNA double strand repair (DSB), which consist or comprise one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway.

[0057] In an exemplary embodiment, a pharmaceutical composition of the invention can be used in any disease state for which either or both tubulin polymerisation and PARP play a role.

[0058] In an exemplary embodiment, the disease is a bacterial infection. In an exemplary embodiment, the disease is a bacterial ulcer infection. In an exemplary embodiment, the disease is a viral infection. In an exemplary embodiment, the disease is a herpes simplex infection. In an exemplary embodiment, the disease is an Acquired Immune Deficiency Syndrome (AIDS) infection. In an exemplary embodiment, the disease is a protozoal infection. In an exemplary embodiment, the disease is a flagellated parasite infection. In an exemplary embodiment, the disease is a Chagas' disease. In an exemplary embodiment, the disease is Leishmania.

[0059] In an exemplary embodiment, the disease is vascular neointimal hyperplasia.

[0060] In an exemplary embodiment, the invention provides a use of a pharmaceutical composition of an invention in the manufacture of a medicament for the treatment of a disease described herein.

[0061] In an exemplary embodiment, a pharmaceutical composition of the invention may be dosed at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject.

[0062] In an exemplary embodiment, a pharmaceutical composition of the invention may be administered in a single dose or a series of doses.

[0063] In another exemplary embodiment, the animal is a eukaryote. In another exemplary embodiment, the animal is a vertebrate animal. In another exemplary embodiment, the animal is a mammal. In another exemplary embodiment, the animal is a rodent. In another exemplary embodiment, the animal is a mouse. In another exemplary embodiment, the animal is a horse. In another exemplary embodiment, the animal is a primate or a simian. In another exemplary embodiment, the animal is a monkey or an ape. In another exemplary embodiment, the animal is a human or a farm animal or a companion animal. In another exemplary embodiment, the animal is a human. In another exemplary embodiment, the animal is a goat or pig or sheep or horse or cow or bull. In another exemplary embodiment, the animal is a cat. Tn another exemplary embodiment, the animal is a dog. In another exemplary embodiment, the animal is a rabbit.

[0064] In an exemplary embodiment, the disease is treated through oral administration of the pharmaceutical composition of the invention. In an exemplary embodiment, the pharmaceutical composition is administered in an orally effective amount.

[0065] The invention is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.EXAMPLES

[0066] The following Examples illustrate the synthesis of representative compounds used in the invention and the following Reference Examples illustrate the synthesis of intermediates in their preparation. These examples are not intended, nor are they to beconstrued, as limiting the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.

[0067] In the examples below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma- Aldrich Chemical Company, and may be used without further purification unless otherwise indicated. Reagents may also be prepared following standard literature procedures known to those skilled in the art. Solvents may be purchased from Sigma-Aldrich in Sure-Seal bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated. The reactions set forth below were run generally at ambient temperature, unless otherwise indicated. The reaction vessels were fitted with rubber septa for introduction of substrates and reagents via syringe. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel precoated plates (Amalec TLC Uniplates™ with fluorescent indicator) and eluted with appropriate solvent ratios (v / v). Reactions were assayed by TLC or LC / MS, and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 nm wavelength) or with an appropriate TLC visualizing solvent, such as basic aqueous KMnCU solution, ninhydrin, cerium molybdate, or phosphomolybdic acid, activated with heat. Flash column chromatography (W. C. Still et al., J. Org. Chem., 43, 1978, 2923-2925) was performed using Biotage Isolera Prime automated flash purification system (220 and 254 nm wavelength) with ZIP Sphere-spherical Silica or KP Silica cartridges or various preparative HPLC systems. The compound structures in the examples below were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy, mass spectrometry, and melting point. Proton magnetic resonance ('HNMR) spectra were recorded using an NMR spectrometers operating at 300, 400 or 500 MHz field strength. Chemical shifts are reported in the form of delta (5) values given in parts per million (ppm) relative to an internal standard, such as tetramethylsilane (TMS). Alternatively, ’HNMR spectra were referenced to signals from residual protons in deuterated solvents as follows: CDCh = 7.25 ppm; DMSO-de = 2.49 ppm; CD3OD = 3.30 ppm. Peak multiplicities are designated as follows: s,singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectrometric (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.

[0068] Starting materials used were either available from commercial sources or prepared according to literature procedures and had experimental data in accordance with those reported.EXAMPLE 1Pharmaceutical Composition A of HCl salt of Compound 1

[0069] The following pharmaceutical compositions are immediate release capsules containing micronized HCl salts of Compound 1 ([6-]2-fluoro-5-(4-oxo-3.4-dihydro- phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acid ethyl ester) and mannitol. The pharmaceutical compositions were manufactured by wet granulation followed by capsule filling.

[0070] Strengths of the HCl salt of Compound 1 in these pharmaceutical compositions range from 5 mg to 120 mg. The quantitative compositions of Compound 1, 5 mg and 10 mg capsules are listed in Table 1, the 20 mg, 40 mg, and 60 mg capsules are provided in Table 2. and the 120 mg strength is listed in Table 3. Compound 1 capsules contain the equivalent of their corresponding nominal strength of Compound 1 free base. The white capsule shells are composed of hypromellose with a small amount of titanium dioxide as an opacifier. The clear capsule shells are composed of hypromellose (no titanium dioxide). The capsule sizes range from Size 3 to Size 00.Table 1: Compositions of Compound 1 Capsules, 5 mg and 10 mg StrengthsaActual amount may be different depending on adjustment for the Compound 1 HCl purity and water content.hEquivalent to 5 mg of Compound 1 free base.cEquivalent to 10 mg of Compound 1 free base.Table 2: Compositions of Compound 1 Capsules, 20 mg, 40 mg, & 60 mg StrengthsActual amount may be different depending on adjustment for the Compound 1 HC1 purity and water content.bEquivalent to 20 mg of Compound 1 free base.cEquivalent to 40 mg of Compound 1 free base.dEquivalent to 60 mg of Compound 1 free base.eEither white opaque or clear capsule shells may be used.Table 3: Compositions of Compound 1 Capsules, 120 mg StrengthaActual amount may be different depending on adjustment for the Compound 1 HC1 purity and water content.bEquivalent to 120 mg of Compound 1 free base.

[0071] Compound 1 capsules were packaged in high density polyethylene (HDPE) bottles with a foil seal and polypropylene child-resistant closure. A silica gel desiccant was included in each bottle.EXAMPLE 2Components and preparation of Pharmaceutical Composition AHCl salt of Compound 1

[0072] The HCl salt of Compound 1 was obtained as described in PCT Pat App No PCT / US2017 / 039119 (PCT Pub No WO 2017 / 223516) and US Pat App No 16 / 526,620 (US Pat No 10,640,493) The HCl salt of Compound 1 was a stable crystalline solid which was micronized by jet-milling before formulation.Mannitol

[0073] Mannitol is a commonly used excipient in pharmaceutical solid dosage forms. It is also a permissible food additive up to 20 g daily. Mannitol is used in thepharmaceutical composition as a diluent and constitutes 96.3% of the granulation. At approximately 289 mg per 10 mg capsule, the level of mannitol in the pharmaceutical composition is well below the highest amount in approved products listed on the FDA’s inactive ingredient database (IID). The highest amount on the IID is 1197 mg per dose unit.Hypromellose Capsules

[0074] The capsule shells used to contain the pharmaceutical composition are Size 3 to Size 00, white opaque or clear HPMC capsules. The white capsules are made of hypromellose, with added titanium dioxide for color and opacity. The clear capsules are made of hypromellose as the only ingredient. Hypromellose is a commonly used excipient in solid and liquid oral dosage forms. The amount of hypromellose intake per Size 00 capsule is less than 121 mg. The highest amount of the excipient listed on the IID is 679 mg.

[0075] Titanium dioxide, the minor component in the white capsule shell, is a common coloring and opacifying agent used in oral pharmaceutical compositions. It is present in the white opaque capsule shell at approximately 2%, which is less than 1 mg / capsule. The highest amount of titanium dioxide in an FDA-approved oral product is 129.7 mg per dose unit.Water

[0076] Water is used as a granulation fluid to aid in uniformly distributing Compound 1 in the pharmaceutical composition. Water is removed during processing by drying the pharmaceutical composition.Pharmaceutical Composition A

[0077] The HC1 salt of Compound 1 was produced by jet-milling to reduce the particle size to a target range of < 10 pm. The milled HC1 salt of Compound 1 was granulated with mannitol using an aqueous wet granulation process. The granulation was dried and filled into capsules.

[0078] Compound 1 strengths ranging from 5 mg to 120 mg were produced from wetgranulation pharmaceutical compositions. 5 mg strength Compound 1 capsules were initially produced. 10 mg strength Compound 1 capsules were later made using the same pharmaceutical composition filled at a proportionally larger fill weight to produce the higher strength. To develop higher strengths of Compound 1 capsules, Compound 1 concentration in the granulation was increased to approximately 15%.This increased Compound 1 drug load allowed for filling capsules at 20 mg, 40 mg, and 60 mg strengths using a common blend. The Compound 1 drug load was further increased to 30% to produce a 120 mg strength.EXAMPLE 3Pharmaceutical Composition B of HCl salt of Compound 1

[0079] The following pharmaceutical composition B is an immediate release gelatin capsule containing a suspension of micronized HCl salts of Compound 1 ([6-]2-fluoro- 5-(4-oxo-3 ,4-dihydro-phthalazin- 1 -ylmethyl -phenyl] - 1 H-benzoimidazol-2-yl)- carbamic acid ethyl ester) in a non-aqueous liquid vehicle.

[0080] The drug product is supplied at 200 mg strength, on a free-base basis. The quantitative compositions of the HCl salt of Compound 1. 200 mg capsules is listed in Table 4. The HCl salt of Compound 1 was produced as described herein. The soft gelatin capsule shells are composed of gelatin and contain glycerin as plasticizer and titanium dioxide as opacifier. The capsule size is 22.Table 4: Compositions of Compound 1 Capsules, 200 mg Strengthsa Equivalent to 200 mg of Compound 1 free base. Will be adjusted for water content and purity. b Actual amount may be different depending on adjustment for the API purity and water content.

[0081] Pharmaceutical Composition B includes Vitamin E TPGS, glyceryl mono and dicaprylocaprate, and medium chain triglycerides. Tn addition, the soft gelatin capsule shell contains gelatin (main ingredient) and small amounts of glycerin and titanium dioxide. A brief discussion of each excipient is provided below.Vitamin E TPGS

[0082] Tocopherol polyethylene glycol succinate, also known as vitamin E polyethylene glycol succinate, TPGS, or Vitamin E TPGS, is a water-soluble synthetic derivative of vitamin E that is used as an emulsifying agent, solubilizer and a component of lipid vehicles with the aim of enhancing the bioavailability ofpharmaceutical compounds. TPGS contains from about 25.0% (by weight) of d-alpha tocopherol (Vitamin E). Each soft-gelatin capsule contains 194.4 mg of TPGS, which is equivalent to not less than (NLT) 48.5 mg of Vitamin E. The highest maximum daily exposure from an oral approved pharmaceutical product containing TPGS is 3000 mg / day, equivalent to NLT 750 mg of Vitamin E.Glyceryl Mono and Dicayrylocayrate

[0083] Glyceryl mono and dicaprylocaprate is a mixture of glyceryl mono- and diesters of caprylic and capric acids acid. It is used in oral and topical pharmaceutical products as a solubilizer and emulsifier. This excipient is present in the soft-gelatin capsules at 313.3 mg / capsule. The highest daily exposure in oral approved products listed in the FDA’s inactive ingredients database is 13,770 mg.Medium-Chain Triglycerides

[0084] Medium-chain triglycerides is a GRAS excipient derived from edible oils. It is used as a lipid vehicle in various pharmaceutical products. The highest daily exposure from an approved oral product (per the FDA’s inactive ingredients database) is 10,170 mg. The content of medium-chain triglycerides in the soft-gelatin capsules is 356.4 mg.Gelatin, Tyye B

[0085] Gelatin, a GRAS excipient, is the main component of the soft-gelatin capsule shell. The amount of gelatin per capsule is approximately 297 mg.Glycerin

[0086] Glycerin is a GRAS excipient derived from oils and fats and is widely used in pharmaceutical and personal care products. In the capsules, glycerin is used as a plasticizer in the capsule shell formulation. Each soft-gelatin capsule contains approximately 132 mg of glycerin. The highest daily exposure from oral approved products on the inactive ingredients database is 32,400 mg / day.Titanium Dioxide

[0087] Titanium dioxide, the minor component in the white soft-gelatin capsule shell, is a common coloring and opacifying agent used in oral drug products. It is present in the white opaque capsule shell at approximately 3.4 mg / capsule. The highest amount of titanium dioxide in an FDA-approved oral product is 129.7 mg per dose unit, and the highest listed daily exposure is 297 mg / day.Purified Water

[0088] Purified water is used in the manufacture of the soft gelatin capsule shells. Most of it is removed during drying.Manufacturing Pharmaceutical Composition B

[0089] TPGS was melted at approximately 60°C followed by mixing with mono- and dicaprylocaprate and a portion of the medium-chain triglycerides at a target product temperature of approximately 45°C. Micronized Compound 1 and the rest of the medium chain triglycerides were added and mixed at a target product temperature of approximately 40°C. The soft-gelatin capsule shells were formed, filled with the resulting mixture and sealed.Type of Container and Closure

[0090] Pharmaceutical Composition B capsules were packaged in high density polyethylene (HDPE) bottles with a foil seal and polypropylene child-resistant closure.EXAMPLE 4Dog PK Studies with Pharmaceutical Composition B of HCl salt of Compound 1

[0091] Eight male beagle dogs were each administered Pharmaceutical Composition A and Pharmaceutical Composition B and the pharmacokinetics were assessed. The animals were fasted overnight. Food was returned after the collection of the 4-hour samples. Water was provided ad libitum. A washout period of 7-days was allowed between sessions. Oral capsule doses for all Groups were administered by hand, followed by 10 mL of water to assist with swallowing. The dose administered ranged from 13.8 mg / kg to 18.9 mg / kg.

[0092] Serial blood samples (~0.5 mL per sample) were collected from each animal prior to dosing and at 0.5, 1, 2, 4, 8, 12, 18, 24, 36 and 48 hours post dose. Samples were collected, via direct puncture of a cephalic vein, into tubes containing K2EDTA. Blood samples were stored on wet ice until processed to plasma by centrifugation (3500 rpm at 5°C for 10 minutes) within 30 minutes of collection. Plasma samples were transferred into 96-well plates and then stored in a -70°C freezer. During dosing and at each sample collection, animals were observed for any clinically relevant abnormalities. Plasma samples were analyzed for Compound 1 using an LC-MS / MS method. Non-compartmental pharmacokinetic parameter estimates were calculated from the individual animal Compound 1 concentration-time data using PhoenixWinNonlin (Pharsight) using nominal times. The single-dose pharmacokinetic parameters assessed include, as appropriate: maximum concentration (Cmax); time of maximum observed concentration (Tmax); terminal half-life (T1 / ?); area under the concentration-time curve from time zero to the last quantifiable concentration (AUClast); and area under a concentration-time curve from time zero extrapolated to infinity (AUCinf).

[0093] The AUClast for Pharmaceutical Composition B was about 2.7 fold greater than the AUClast for Pharmaceutical Composition A. This large increase in AUClast indicates that the HC1 salt of Compound 1 is more bioavailable to the subject when administered as part of Pharmaceutical Composition B than Pharmaceutical Composition A.EXAMPLE 5

[0094] A Phase I / II, open-label, multi-center, non-randomized trial in adult human participants with advanced malignancies was conducted. The adult human participants received treatment with Pharmaceutical Composition A or Pharmaceutical Composition B. Pharmaceutical Composition A or Pharmaceutical Composition B was administered BID on a continuous basis, i.e., 7 days each week for 28-day cycles.Pharmacokinetic (PK) Assessment

[0095] Concentrations of Pharmaceutical Composition A or Pharmaceutical Composition B in plasma samples at different time points were measured. PK derived parameters including Cmax, Tmax, T1 / 2, AUC0-24, CL / F, and Vd / F, as described in the Table below, were calculated. Further details will be elaborated in a PK Statistical Analysis Plan (PK-SAP).Pharmacokinetic ParametersPharmacokinetic Sampling

[0096] Blood samples (4 mL) for assessment of Pharmaceutical Composition A or Pharmaceutical Composition B plasma levels were drawn on all participants on the following days: Cycle 1 Day 1, Day 2, and Day 25 (Day 24 permitted) and Cycle 2 Day 1 and Day 25 (Day 24 permitted).

[0097] All participants in the Dose Escalation Phase had additional PK samples drawn on Cycle 2 Day 1.Blood Sample Collection for Plasma PK Analysis

[0098] Blood samples (4 mL whole blood collected with K2EDTA anticoagulant) to provide approximately 2 mL of plasma for measurement of PharmaceuticalComposition A or Pharmaceutical Composition B concentrations were collected from participants in appropriately labeled tubes at times specified in the following table.

[0099] The PK sample collection time -points were relative to the beginning of the oral administration of Pharmaceutical Composition A or Pharmaceutical Composition B.Pharmacokinetic Sampling Time PointsResults:

[0100] The following PK results are from Cycle 1 D25. Pharmaceutical Composition A or Pharmaceutical Composition B was administered orally twice daily (BID), with food, a minimum of 8 hours apart, as a single agent, for cycle durations of 28 days. Treatment was administered BID continuously, i.e., 7 days each week.

[0101] For Pharmaceutical Composition A:AUCO-24 (ng*h / mL) =14205 ± 3835 (N=3) Cmax (ng / mL): 1110 + 300 (N=3)

[0102] For Pharmaceutical Composition B:AUCO-24 (ng*h / mL) = 33072 ± 3492 (N=3)Cmax (ng / mL): 2573 ± 591 (N=3)

[0103] The Results demonstrate that both AUC0-24 and Cmax for Pharmaceutical Composition B were approximately 2.4-fold higher than the corresponding AUC0-24 and Cmax values observed with Pharmaceutical Composition A.

[0104] This substantial increase in AUC0-24 and Cmax indicates that Pharmaceutical Composition B exhibits significantly improved bioavailability compared with Pharmaceutical Composition A when administered to subjects. Importantly, these findings are consistent with the dog study results described in Example 4.

[0105] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0106] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0107] Recitation of ranges 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 into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element essential to the practice of the disclosure.

[0108] Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0109] Certain embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof are encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0110] It is to be understood that the embodiments of the disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that can be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure can be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described.

[0111] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the disclosure being indicated by the following claims. All references,patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS;1. A pharmaceutical composition comprising:(a) a compound having a structure which is:wherein R1, R2, R3, R4, R5, and R6are each independently H or C1-3 alkyl; each dashed line ( - ) is independently a single or double bond; n is an integer from 1 to 5000; m and q each independently are 0, 1, 2, or 3; p is an integer from 1 to 20; z is an integer from 1 to 10; and(b) a PARP inhibitor.

2. The pharmaceutical composition of claim 1, wherein R1, R2, R3, R4, R\ and R6are each independently H or CH3.

3. The pharmaceutical composition of claim 1 or 2, wherein (a) is4. The pharmaceutical composition of a preceding claim, wherein (a) is5. The pharmaceutical composition of a preceding claim, wherein (a) is6. The pharmaceutical composition of claim 1, wherein n is from about 600 to about 1400.

7. The pharmaceutical composition of claim 1, wherein n is from about 950 to about 1050.

8. The pharmaceutical composition of claim 1, further comprising a glyceride.

9. The pharmaceutical composition of claim 8, wherein the glyceride is a member selected from the group consisting of glyceryl monocaprylocaprate, glyceryl dicaprylocaprate, medium chain triglycerides, and a combination thereof.

10. The pharmaceutical composition of a preceding claim, wherein the PARP inhibitor is olaparib, rucaparib, niraparib, talazoparib, veliparib, saruparib, [6-J2- fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)- carbamic acid ethyl ester, a pharmaceutically acceptable salt thereof, and a combination thereof.

11. The pharmaceutical composition of claim 10, wherein the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 10, wherein the PARP inhibitor is [6- ]2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2- yl)-carbamic acid ethyl ester or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 1, wherein the PARP inhibitor is a HC1 salt of [6-]2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH- benzoimidazol-2-yl)-carbamic acid ethyl ester.

14. The pharmaceutical composition of claim 1, wherein (a) has a structure which is:wherein n is an integer from 950 to 1050; (b) is a HC1 salt of [6-]2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH-benzoimidazol-2-yl)-carbamic acidethyl ester; and the pharmaceutical composition further comprises glyceryl monocaprylocaprate and medium chain triglycerides.

15. The pharmaceutical composition of a preceding claim, wherein the pharmaceutical composition is an oral pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein the oral pharmaceutical composition is a capsule.

17. The pharmaceutical composition of claim 1, wherein the PARP inhibitor is present in the pharmaceutical composition in an amount equivalent to from about 50 mg to about 300 mg of the free base of the PARP inhibitor.

18. The pharmaceutical composition of claim 1, wherein the PARP inhibitor is a HC1 salt of [6-]2-fhioro-5-(4-oxo-3,4-dihydro-phthalazin-l-ylmethyl-phenyl]-lH- benzoimidazol-2-yl)-carbamic acid ethyl ester, and is present in the pharmaceutical composition in an amount equivalent to from about 180 mg to about 240 mg of the free base of the PARP inhibitor.

19. A method of inhibiting PARP, comprising contacting an inhibitory amount of the pharmaceutical composition of a preceding claim with PARP, thereby inhibiting PARP.

20. A method of treating a PARP-associated disease in a subject, the method comprising administering to a subject not otherwise in need of treatment thereof, a therapeutically effective amount of the pharmaceutical composition of claims 1-18, thereby treating the PARP-associated disease in the subject.

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