WO2011130317A2 - Therapeutic agents having reduced toxicity - Google Patents

Abstract

Therapeutic hybrid compounds having an active moiety and a toxicity reducing moiety are provided, as are methods of use of such compounds, methods of preparation of such compounds, and compositions containing such compounds. In some embodiments, the hybrid compounds have lower toxicity (such as lower neurotoxicity) compared with the non-hybridized active moiety.

Description

Therapeutic Agents Having Reduced Toxicity

Cross Reference to Related Applications

[0001] This application claims priority under 35 U.S.C. § 119(e)(1) to United States

Provisional Patent Application Serial Nos. 61/323,820, filed April 13, 2010, and 61/324,211, filed April 14, 2010, the contents of which are incorporated herein by reference.

Background

[0002] Chemically induced peripheral neuropathy (CIPN) is an undesirable condition that compromises the use of a number of clinically important therapeutics including paclitaxel, docetaxel, cisplatin, vincristine, and interferon-alpha. Numbness and pain generally appear first in the extremities, followed by more extreme muscle cramps, aching, weakness, and even respiratory dysfunction. The taxanes paclitaxel and docetaxel are mainstay therapeutics for breast cancer and ovarian cancer, and docetaxel is also commonly used to treat androgen refractory prostate cancer. Docetaxel is sold as Taxotere by Sanofi- Aventis and has projected sales of over $1.65 billion in 2010.

[0003] Unfortunately, toxicity often limits dosing courses for taxanes and precludes patient compliance: 33% of patients receiving paclitaxel at 250 mg/m2 experience Grade 3 or 4 neuropathy. CIPN is the most common, non-hematological toxicity for patients undergoing taxane chemotherapy. In spite of various approaches to lowering PNP including coadministering additional therapeutics such as gabapentin and glutamine, altering drug vehicles, changing infusion times, or searching for less neurotoxic taxane derivatives, CIPN remains an important problem for patients undergoing chemotherapy.

[0004] For taxanes, CIPN is the most common cause of dose-limiting toxicity, apart from neutropenia. A patient's inability to maintain a therapeutic regimen due to toxicity limits optimal treatment for taxanes. Neurotoxicity is evident in a number of other important therapeutics (bortezomib, vinblastine, gemcitabine, e.g.). For many years, it was

hypothesized that the solvent CremophorEL was primarily responsible for dose-limiting neurotoxicity in treatment regimens including paclitaxel. However, newer paclitaxel formulations which do not include CremophorEL such as Abraxane, as well as the chemically related docetaxel, also exhibit chemically induced peripheral neuropathy (CIPN). Although a vast number of taxane derivatives have been synthesized and tested, no FDA-approved taxanes have significantly reduced CIPN. Accordingly, there remains a need in the art to develop new anticancer pharmaceuticals (and other pharmaceuticals) that lack or have substantially reduced neurotoxicity.

[0005] In addition to the problem of neurotoxicity of known anti-cancer

pharmaceuticals, some anticancer agents are difficult to prepare, are expensive to obtain, have a poor pharmacokinetic profile (which may be reflected in a shorter than desirable half- life), and/or have significant adverse side effects; all of these drawbacks may result in lower patient compliance and/or less effective treatment.

Summary

[0006] In one aspect, there is provided herein a method for lowering the neurotoxic effects of a neurotoxicity producing therapeutic active moiety upon administration to a host, the method comprising: administering to the host an effective amount of a hybrid compound of less than about 15000 Daltons comprising the therapeutic active moiety or an active derivative, fragment or analog thereof and a neurotoxicity lowering moiety, wherein the neurotoxicity lowering moiety binds to at least one neurotoxicity lowering biomoiety and substantially reduces at least one neurotoxicity symptom.

[0007] In another aspect there is provided herein a method for reducing the neurotoxicity of a taxane compound, the method comprising covalently bonding the taxane to a neurotoxicity-lowering moiety either directly or through an optional linking moiety to form a hybrid compound.

[0008] In yet another aspect, there is provided herein a compound comprising a taxane moiety covalently attached either directly or through an optional linking moiety to a neurotoxicity lowering moiety. For example, in some embodiments of this aspect, there is provided compounds having the structure of formula (I)

wherein the variables A¹, A² , A³ , and A⁴ are as described herein.

[0009] These and other aspects of interest are described in more detail below.

Brief Description of the Figures

[00010] Figure 1 provides blood permeability data showing a comparison between non-hybridized paclitaxel and a hybrid paclitaxel-ligand.

[00011] Figure 2 provides metabolic stability data, and also shows a comparison between non-hybridized paclitaxel and a hybrid paclitaxel-ligand.

[00012] Figure 3 provides tumor volume measurement data over a 46 day period, and compares non-hybridized paclitaxel and a hybrid paclitaxel-ligand.

[00013] Figure 4 provides total neurite outgrowth measurement data for a paclitaxel- ligand hybrid, and compares the data to paclitaxel and control data.

[00014] Figure 5 provides images of primary cortical neuron (PCN) growth after exposure to a paclitaxel-ligand hybrid, and compares the data to paclitaxel data.

[00015] Figure 6 provides cell number data, which were recorded for PCNs untreated

(first column) or PCNs treated with: (i) CremophorEL vehicle; (ii) paclitaxel; (iii) a paclitaxel-ligand hybrid; (iv) free FK506; (v) a paclitaxel-FK506 hybrid.

[00016] Figure 7 provides cytotoxicity data for Paclitaxel and Compound (2) (a compound prepared according to the disclosure) against SKOV3 cells.

[00017] Figure 8 provides average neurite outgrowth for samples treated with

Compound (2) and compares the data with paclitaxel and control samples.

[00018] Figure 9 provides cell counts for viable cells after treatment with Compound

(2), and compares the data with paclitaxel and control samples.

[00019] Figure 10 provides data for an in vivo study using Compound (1).

Definitions

[00020] Unless otherwise indicated, the disclosure is not limited to specific procedures, starting materials, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. [00021] As used in the specification and the appended claims, the singular forms "a,"

"an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a reactant" includes not only a single reactant but also a combination or mixture of two or more different reactant, reference to "a substituent" includes a single substituent as well as two or more substituents, and the like.

[00022] In describing and claiming the present invention, certain terminology will be used in accordance with the definitions set out below. It will be appreciated that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall within the definition of more than one term.

[00023] As used herein, the phrases "for example," "for instance," "such as," or

"including" are meant to introduce examples that further clarify more general subject matter. These examples are provided only as an aid for understanding the disclosure, and are not meant to be limiting in any fashion.

[00024] As used herein, the phrase "having the formula" or "having the structure" is not intended to be limiting and is used in the same way that the term "comprising" is commonly used. The term "independently selected from" is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different.

[00025] As used herein, the terms "may," "optional," "optionally," or "may optionally" mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.

[00026] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group (i.e., a mono-radical) typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, i-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although not necessarily, alkyl groups herein may contain 1 to about 18 carbon atoms, and such groups may contain 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of 1 to 6 carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and this includes instances wherein two hydrogen atoms from the same carbon atom in an alkyl substituent are replaced, such as in a carbonyl group (i.e., a substituted alkyl group may include a -C(=0)- moiety). The terms "heteroatom-containing alkyl" and "heteroalkyl" refer to an alkyl substituent in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively.

[00027] The term "alkenyl" as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, w-propenyl, isopropenyl, w-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Generally, although again not necessarily, alkenyl groups herein may contain 2 to about 18 carbon atoms, and for example may contain 2 to 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of 2 to 6 carbon atoms. The term "substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkenyl" and "lower alkenyl" include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.

[00028] The term "alkynyl" as used herein refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms. The term "lower alkynyl" intends an alkynyl group of 2 to 6 carbon atoms. The term "substituted alkynyl" refers to alkynyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms "alkynyl" and "lower alkynyl" include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.

[00029] The term "alkoxy" as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, w-propoxy, isopropoxy, t- butyloxy, etc. Substituents identified as "Ci-C6 alkoxy" or "lower alkoxy" herein may, for example, may contain 1 to 3 carbon atoms, and as a further example, such substituents may contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy). [00030] The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent generally, although not necessarily, containing 5 to 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Aryl groups may, for example, contain 5 to 20 carbon atoms, and as a further example, aryl groups may contain 5 to 12 carbon atoms. For example, aryl groups may contain one aromatic ring or two or more fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc.). Examples include phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term "aryl" includes unsubstituted, substituted, and/or heteroatom- containing aromatic substituents.

[00031] The term "aralkyl" refers to an alkyl group with an aryl substituent, and the term "alkaryl" refers to an aryl group with an alkyl substituent, wherein "alkyl" and "aryl" are as defined above. In general, aralkyl and alkaryl groups herein contain 6 to 30 carbon atoms. Aralkyl and alkaryl groups may, for example, contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.

[00032] The term "alkylene" as used herein refers to a di-radical alkyl group. Unless otherwise indicated, such groups include saturated hydrocarbon chains containing from 1 to 24 carbon atoms, which may be substituted or unsubstituted, may contain one or more alicyclic groups, and may be heteroatom-containing. "Lower alkylene" refers to alkylene linkages containing from 1 to 6 carbon atoms. Examples include, methylene (— CH₂— ), ethylene (~CH₂CH₂~), propylene (-CH₂CH₂CH2-), 2-methylpropylene (~CH₂~CH(CH₃)~ CH₂-), hexylene (-(CH₂)₆-) and the like.

[00033] Similarly, the terms "alkenylene," "alkynylene," "arylene," "aralkylene," and

"alkarylene" as used herein refer to di-radical alkenyl, alkynyl, aryl, aralkyl, and alkaryl groups, respectively.

[00034] The term "amino" is used herein to refer to the group -NZ 1 Z2 wherein Z 1 and

Z are hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and/or heteroatom-containing variants thereof. [00035] The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.

[00036] The term "heteroatom-containing" as in a "heteroatom-containing alkyl group"

(also termed a "heteroalkyl" group) or a "heteroatom-containing aryl group" (also termed a "heteroaryl" group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the term "heterocyclic" refers to a cyclic substituent that is heteroatom-containing, the terms "heteroaryl" and "heteroaromatic" respectively refer to "aryl" and "aromatic" substituents that are heteroatom-containing, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl, etc.

[00037] "Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about

30 carbon atoms, including 1 to about 24 carbon atoms, further including 1 to about 18 carbon atoms, and further including about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the term "heteroatom-containing hydrocarbyl" refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term "hydrocarbyl" is to be interpreted as including substituted and/or heteroatom- containing hydrocarbyl moieties.

[00038] By "substituted" as in "substituted hydrocarbyl," "substituted alkyl,"

"substituted aryl," and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.

Examples of such substituents include, without limitation, functional groups, and the hydrocarbyl moieties Ci-C24 alkyl (including C C^ alkyl, further including Ci-C^ alkyl, and further including C C₆ alkyl), C₂-C₂₄ alkenyl (including C₂-Q8 alkenyl, further including C₂- Cn alkenyl, and further including C₂-C₆ alkenyl), C₂-C₂₄ alkynyl (including C₂-Q8 alkynyl, further including C₂-Q₂ alkynyl, and further including C₂-C₆ alkynyl), C₅-C₃₀ aryl (including C₅-C₂₀ aryl, and further including Cs-C^ aryl), and C₆-C₃₀ aralkyl (including C₆-C₂₀ aralkyl, and further including C₆-C₁₂ aralkyl). The above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.

[00039] By the term "functional groups" is meant chemical groups such as halo, hydroxyl, sulfhydryl, C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₀ aryloxy, acyl (including C₂-C₂₄ alkylcarbonyl (-CO-alkyl) and C₆-C₂o arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C₂-C₂₄ alkoxycarbonyl (-(CO)-O-alkyl), C₆-C₂₀ aryloxycarbonyl (-(CO)- O-aryl), halocarbonyl (-CO)-X where X is halo), C₂-C₂₄ alkylcarbonato (-O-(CO)-O-alkyl), C₆-C₂₀ arylcarbonato (-O-(CO)-O-aryl), carboxy (-COOH), carboxylato (-COO^" ), carbamoyl (-(CO)-NH₂), mono-substituted Ci-C₂₄ alkylcarbamoyl (-(CO)-NH(Ci-C₂₄ alkyl)), di- substituted alkylcarbamoyl (-(CO)-N(C₁-C₂₄ alkyl)₂), mono-substituted arylcarbamoyl (-(CO)-NH-aryl), thiocarbamoyl (-(CS)-NH₂), carbamido (-NH-(CO)-NH₂), cyano (-C≡N), isocyano (-N⁺≡ ), cyanato (-0-C≡N), isocyanato (-0-N⁺≡ ), isothiocyanato (-S-C≡N), azido (-N=N⁺=N^"), formyl (-(CO)-H), thioformyl (-(CS)-H), amino (-NH₂), mono- and di- (Ci-C₂₄ alkyl)-substituted amino, mono- and di-(Cs-C₂o aryl)- substituted amino, C₂-C₂₄ alkylamido (-NH-(CO)-alkyl), C₅-C₂₀ arylamido (-NH-(CO)-aryl), imino (-CR=NH where R = hydrogen, Ci-C₂₄ alkyl, C₅-C₂₀ aryl, C₆-C₂o alkaryl, C₆-C₂o aralkyl, etc.), alkylimino (-CR=N(alkyl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), arylimino (-CR=N(aryl), where R = hydrogen, alkyl, aryl, alkaryl, etc.), nitro (-N0₂), nitroso (-NO), sulfo (-S0₂-OH), sulfonato (-S0₂-0^~), Ci-C₂₄ alkylsulfanyl (-S-alkyl; also termed "alkylthio"), arylsulfanyl (-S-aryl; also termed "arylthio"), Ci-C₂₄ alkylsulfinyl (-(SO)-alkyl), C₅-C₂₀ arylsulfinyl (-(SO)-aryl), Ci-C₂₄ alkylsulfonyl (-S0₂-alkyl), C₅-C₂₀ arylsulfonyl (-S0₂-aryl), phosphono (-P(0)(OH)₂), phosphonato (-P(0)(0^")₂), phosphinato (-P(0)(0^~)), phospho (-P0₂), and phosphino (-PH₂), mono- and di-(C₁-C₂₄ alkyl) -substituted phosphino, mono- and di-(Cs-C₂o aryl) -substituted phosphine. In addition, the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.

[00040] By "linking" or "linker" as in "linking group," "linker moiety," etc., is meant a bivalent radical moiety. Examples of such linking groups include alkylene, alkenylene, alkynylene, arylene, alkarylene, aralkylene, and linking moieties containing functional groups including, without limitation: amido (-NH-CO-), ureylene (-NH-CO-NH-), imide

(-CO-NH-CO-) , epoxy (-0-), epithio (-S-), epidioxy (-O-O-), carbonyldioxy (-O-CO-O-), alkyldioxy (-0-(CH₂)_n-0-), epoxyimino (-0-ΝΗ-), epimino (-NH-), carbonyl (-CO-), etc. [00041] When the term "substituted" appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase "substituted alkyl and aryl" is to be interpreted as "substituted alkyl and substituted aryl."

[00042] Unless otherwise specified, reference to an atom is meant to include isotopes of that atom. For example, reference to H is meant to include 1 H, 2 H (i.e., D) and 3 H (i.e., T), and reference to C is meant to include 12 C and all isotopes of carbon (such as 13 C).

[00043] The term "hybrid compound" as used herein refers to a drug moiety (also referred to herein as a "first active moiety") and neurotoxicity lowering moiety (also referred to herein as a "second active moiety") that are linked by covalent bonds. The covalent linkage may be via a linking moiety or via a direct covalent bond between the two moieties.

[00044] Unless otherwise indicated, the terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. Thus, the terms include prophylactic use of active agents. "Preventing" a disorder or unwanted physiological event in a patient refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the patient may or may not exhibit heightened susceptibility to the disorder or event.

[00045] By the term "effective amount" of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide a desirable effect.

[00046] As used herein, and unless specifically stated otherwise, an "effective amount" of a beneficial refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts.

[00047] As used herein, a "therapeutically effective amount" of an active agent refers to an amount that is effective to achieve a desirable therapeutic result, and a "prophylactically effective amount" of an active agent refers to an amount that is effective to prevent or lessen the severity of an unwanted physiological condition.

[00048] By a "pharmaceutically acceptable" component is meant a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the disclosure and administered to a patient as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term "pharmaceutically acceptable" is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[00049] The term "pharmacologically active" (or simply "active"), as in a

"pharmacologically active" derivative or analog, refers to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

[00050] The term "controlled release" refers to a formulation, dosage form, or region thereof from which release of a beneficial agent is not immediate, i.e., with a "controlled release" dosage form, administration does not result in immediate release of the beneficial agent in an absorption pool. The term is used interchangeably with "nonimmediate release" as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995). In general, the term "controlled release" as used herein includes sustained release and delayed release formulations.

[00051] The term "sustained release" (synonymous with "extended release") is used in its conventional sense to refer to a formulation, dosage form, or region thereof that provides for gradual release of a beneficial agent over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of the agent over an extended time period.

[00052] The term "neurotoxicity lowering biomoiety" may refer to proteins, nucleic acids, carbohydrates, lipid, or any naturally occurring moiety in an organism that interacts with the neurotoxicity lowering moiety to produce a neurotoxicity lowering effect.

[00053] The term "naturally occurring" refers to a compound or composition that occurs in nature, regardless of whether the compound or composition has been isolated from a natural source or chemically synthesized.

Detailed Description

[00054] In some embodiments, then, there is disclosed herein hybrid compounds comprising an active moiety and a toxicity reducing moiety. The two moieties are covalently linked, wherein such linkage may be a direct bond or may be via an optional linker moiety that is covalently bonded to each of the active moiety and the toxicity reducing moiety. For example, the active moiety is an anticancer moiety, and the toxicity lowering moiety is a neurotoxicity lowering moiety. Also for example, the toxicity reducing moiety is a neurotoxicity lowering moiety and is a neurotrophic ligand. In some embodiments, the neurotrophic ligand specifically targets neurotoxicity lowering biomoieties including FKBP proteins such as FKBP52 and FKBP38, or heat shock proteins.

[00055] In some embodiments, the hybrids compounds (also referred to herein as

"conjugates," "hybrid compounds," "hybrids," or simply as "compounds") of interest are at least equipotent with the active moiety in non-hybridized form. In addition to being at least equipotent, the compounds of interest are also substantially less neurotoxic compared with the active moiety in non-hybridized form. For example, a paclitaxel-neurotrophic ligand hybrid compound according to the disclosure is at least equipotent with paclitaxel alone, but exhibits substantially reduced neurotoxicity when administered to a patient.

[00056] Although equipotency is preferred, in some embodiments the compounds of the invention exhibit somewhat reduced potency compared with the active moiety in non- hybridized form. In some embodiments, such reduced potency is no more than 10% reduced, or 20% reduced, or 25% reduced, or 30% reduced, or 40% reduced, or 50% reduced.

[00057] The compounds of interest have reduced toxicity compared with the non- hybridized active compound. For example, by one method of measure, a compound of interest is substantially less neurotoxic than the native (non-hybridized) active moiety, wherein "substantially less neurotoxic" occurs when a statistically significant portion of patients receiving treatment with the hybridized compound exhibit reduced symptoms of a neurologic side effect (such as CIPN). By "reduced symptoms" is meant that the symptoms may be reduced by at least 10%, reduced by at least 20%, reduced by at least 25%, reduced by at least 30%, reduced by at least 40%, reduced by at least 50%, reduced by at least 75%, or reduced by 100% (i.e., the patient exhibits no neurotoxic symptoms).

[00058] In some embodiments, the compounds of interest are conjugates of an anticancer moiety and a neurotoxicity lowering moiety, both of which are covalently bound either directly to each other or via an optional linker moiety. In some such embodiments, the neurotoxicity lowering moiety has a dissociation constant of less than 10 μΜ, or less than 9000 nM, or less than 8000 nM, or less than 7000 nM, or less than 6000 nM, or less than 5000 nM, or less than 4000 nM, or less than 3000 nM, or less than 2000 nM, or less than 1000 nM with an FKBP protein (such as, for example, FKBP52 or FKBP38) or a heat shock protein. In some such embodiments, the neurotoxicity lowering moiety's dissociation constant for FKBP52 divided by the neurotoxicity lowering moiety's dissociation constant for

FKBP12 is greater than 0.1, or greater than 0.2, or greater than 0.3, or greater than 0.4, or greater than 0.5. [00059] In some embodiments, the compounds of the invention achieve reduced neurotoxicity (e.g., reduced CINP) by incorporating into a single compound both a neurotrophic moiety having nanomolar affinity for one or more FKBP proteins and an active moiety such as a taxane moiety. In some embodiments, the toxicity-reducing moiety is a neuroimmunophilin moiety.

[00060] In some embodiments, the disclosure provides compounds having two or three components: a first active moiety, a second active moiety, and an optional linker moiety that links the first active moiety with the second active moiety. In some embodiments the three components are linked via covalent bonds. In other words, the first and second active moieties are each linked to the linking moiety via one (or more) covalent bond(s). In some embodiments, the linker moiety is absent, such that the first and second active moieties are directly connected via a covalent bond. As described herein, in some embodiments the linkage between the first and second active moieties may be labile such that the moieties are only transiently linked.

[00061] In some embodiments, the compounds have a total molecular weight of less than about 15000 D, or less than about 12500 D, or less than about 10000 D, or less than about 7500 D, or less than about 5000 D, or less than about 4000 D, or less than about 3000 D, or less than about 2000 D, or less than about 1500 D, or less than about 1000 D.

[00062] In some embodiments, the first active moiety is a therapeutically active moiety, derivative, fragment, or analog thereof (collectively referred to herein as a

"therapeutically active moiety" or "therapeutic"), wherein such therapeutically active moiety is useful in the treatment of an undesirable medical condition in a patient. For example, in some embodiments, the first active moiety is an anti-cancer moiety, derivative, fragment, or analog thereof (collectively referred to herein as an "anti-cancer moiety"). More specifically, in some embodiments, the first active moiety is a taxane moiety, or a derivative, fragment, or analog thereof (collectively referred to herein as a "taxane moiety"). Examples of suitable taxane moieties include paclitaxel, docetaxel, and cabazitaxel. It will be appreciated that, for the moiety used as the first active moiety, at least one of the atoms (e.g. a hydrogen atom) will be replaced to accommodate a covalent linkage between the first active moiety and the linking moiety or the second active moiety. For example, when the first active moiety is said herein to be "paclitaxel," it will be appreciated that the moiety is in fact the paclitaxel structure having at least one atom replaced with a covalent bond to the linking compound or second active moiety. In other words, the "paclitaxel" moiety used as the first active moiety is not, in fact, the complete paclitaxel structure, but rather is the paclitaxel structure modified (by replacement of at least one atom) to accommodate a covalent linkage to the linking moiety or second active moiety. This convention applies throughout the instant disclosure wherever a molecule, moiety, or fragment is described as being covalently attached to another molecule, moiety, or fragment.

[00063] Where the first active moiety is a taxane moiety, it may connect to the second active moiety or the linker moiety through any of the oxygen groups at the C-2', C-7, or C-10 positions (taxane structures typically have hydroxyl groups at the C-2' and C-7 positions, and an acetyloxy group at the C-10 position - see the structure and numbering scheme of Paclitaxel below).

Pac!smxsl

[00064] In some embodiments, the acetyloxy group at the C-10 position is not present, as described and shown in the structures below.

[00065] Although the C-2', C-7, and C-10 positions are specifically mentioned here, it will be appreciated that connections through other positions of the taxane moiety are within the scope of interest.

[00066] Some examples of first active moieties, wherein the stars indicate their points of attachment to the linker moiety or the second active moiety, are shown below:

- 14-

[00067] In some embodiments, the first active moiety is attached to a linker in two locations, such that the linker and first active moiety create a cyclic structure. For example, the linker may attach to the first active moiety at two positions selected from the C-2', C-7, and C-10 positions. In such embodiments, the linker comprises a branch point where the second active moiety attaches. For example, in some embodiments the second active moiety attaches to a position on an aryl ring of the linking moiety.

[00068] The second active moiety is a toxicity lowering moiety, and in some embodiments, the second active moiety is a neurotoxicity lowering moiety. In some embodiments, the second active moiety is a ligand for FKBP protein. In some embodiments, the second active moiety is a ligand for FKBP52 or FKBP38. In some embodiments, the second active moiety is a ligand for a heat shock protein. For example, in some embodiments, the neurotoxicity lowering moiety has a dissociation constant of less than 10 μΜ with an FKBP protein, or less than 9000 nm with an FKBP protein (e.g. FKBP52 or FKBP38). In some such embodiments, the neurotoxicity lowering moiety has a dissociation constant of less than 10 μΜ with a heat shock protein, or less than 9000 nm with a heat shock protein. In some embodiments, the second active moiety is a neuroimmunophilin ligand. Examples of suitable second active moieties are provided in the following paragraphs as well as the examples provided herein.

[00069] The second active moiety may be selected from Units A, B, C, D, E, and F:

Unit D Unit E Unit F

[00070] wherein:

[00071] p represents an integer from 0 to 2;

[00072] R^a is selected from hydrocarbyl groups; and

[00073] the stars represent the point of connection to the first active moiety or, when present, the linking moiety as described herein.

[00074] For example, in some embodiments, R^a is an alkyl group such as a methyl, ethyl, or propyl group. For example, R^a is methyl.

[00075] The linker component is an optional moiety that, when present, covalently links the two active moieties. Thus, in some embodiments, the linking moiety links the therapeutic active moiety with the neurotoxicity lowering moiety. When the linker is not present, the two active moieties may be linked via a direct covalent bond. Some embodiments of the linker affect the potency of the overall compound and/or can also be used to optimize solubility of the overall compound. The linker can also be varied in order to modify the pharmacological and/or chemical properties of the conjugate compound.

[00076] Some examples of linking moieties include alkylene linkers, amides, ureas, sulfoxides, sulfonamides, amines (including polyamines), carbonyls, ethers (including polyethers), and combinations thereof. For example, some combinations include amide/urea combinations, amide/amide combinations, sulfoxide/ether combinations, amide/ether combinations, amine/ether combinations, amide/amine combinations, carbonyl/amide combinations, and other combinations as appropriate. Such linkers may include unsaturated or saturated segments. Some examples of linking moieties include the following structures:

wherein L^a is a linking moieties selected from hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl.

[00077] Further exam les of linking moieties include the structures shown below.

[00078] wherein:

[00079] R, R², and R³ are selected from H, hydrocarbyl, and functional groups;

[00080] the stars (which may be alternatively and equivalently represented herein by wavy lines) represent attachment points to the remainder of the compound; and

[00081] m, n, and q represent independently selected integers.

[00082] For example, the integer values for m, n, and q may, for example, be 0, 1, 2, 3,

4, 5, 6, 7, 8, 9, 10, or greater than 10.

[00083] Also for example, R, R², and R³ may be selected from alkyl, aryl, substituted alkyl, substituted aryl, heteroatom containing alkyl, heteroaryl, and functional groups such as hydroxyl, amino, carboxyl, and the like as defined above.

[00084] Protected versions of any of the abovementioned linkers (e.g. a linker having a hydroxyl group protected by a protecting group) are also within the scope of the linkers of interest. Furthermore, it will be appreciated that the linkers may be attached to the first and second active moieties in either "direction" (i.e. as written above or in reverse orientation).

[00085] In some embodiments, the linking moiety is a flexible polymeric linker. By

"polymeric" is meant that the linker contains a unit that is repeated two or more times. For example, a polyalkylene oxide or polyethyleneamine linker provides increased water solubility and increased flexibility between the first and second moieties. In some

embodiments, the flexible polymeric unit results in a slight decrease in efficacy of the first active moiety (i.e. relative to the parent, non-hybridized active compound). In some embodiments, however, the hybrid compound retains some efficacy, and in some

embodiments, the hybrid compound is equipotent compared with the parent non-hybridized compound. In some embodiments, the polymeric linker does not affect cell permeability of the hybrid compound, and in some embodiments the polymeric linker reduces cell permeability slightly but not to the point that the hybrid compound loses all efficacy.

[00086] In some embodiments, the linker comprises a polyethylene oxide moiety having 2, 3, 4, 5, 6, or more ethylene oxide repeat units. Such linkers may further contain alkylene portions and/or functional groups (e.g., amide groups, amine groups, carbonyl groups, ester groups, additional ether groups, and combinations thereof) between the polyethylene oxide moiety and the first and/or second active moieties.

[00087] The linker moiety may be, in some embodiments, a labile moiety such that the first and second active moieties are only transiently linked. Thus, in some embodiments, the linker moiety is labile in vivo such that, when administered to the patient, the compound degrades to produce a neurotoxicity-reducing moiety and an active moiety (e.g., an anticancer moiety) that are no longer linked. It will be appreciated that such degradation can be designed to occur under desirable conditions (e.g., when the compound reaches cancerous cells). For example, the compound may be administered as a formulation wherein the compound is contained within a liposome, and the compound degrades when it leaves the liposome environment.

[00088] In some embodiments, the disclosure provides compounds having the structure of formula (I)

[00089] wherein:

[00090] A² is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom- containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, provided that A 2' optionally comprises the moiety A ;

[00091] A^3' is selected from -O-A³ and -A³;

[00092] one of A¹, A², A³, and A⁴ is selected from -U and -L-U, and the others are selected from H, and alkyl, provided that A 4 may be taken together with A 2 to form a cycle;

[00093] L is a linking moiety; and [00094] U is a toxicity lowering moiety.

[00095] For example, in various embodiments, L is selected from any of the linking moieties described herein, and U is selected from any of the second active moieties described herein.

[00096] Also for example, in some embodiments, A¹ is selected from -U, -L-U, acetyl, methyl, and H. In some embodiments, A¹ is selected from H or methyl.

[00097] Also for example, in some embodiments, A² is a carbonyl-containing moiety that further contains the moiety A 2. For example, A 2' is an acetyl moiety. In some

embodiments, A 2' is an isoserine residue such as a phenylisoserine residue or a derivative thereof.

[00098] Also for example, in some embodiments, A² is selected from -U, -L-U, acetyl, methyl, and H. In some embodiments, A is H.

[00099] Also for example, in some embodiments, A³ is selected from -U, -L-U, acetyl, methyl, and H. In some embodiments, A3 is -L-U or acetyl.

[000100] In certain embodiments, the disclosure provides compounds having the structure of formula (la)

[000101] wherein:

[000102] R is selected from hydrocarbyl, substituted hydrocarbyl, heteroatom- containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl; and

[000103] A¹, A², and A³ are as defined above for formula (I).

[000104] For example, in some embodiments, R is selected from alkyl, alkoxy, aryl, and aryloxy. In some embodiments, R is phenyl, and in other embodiments, R is tert-butoxyl.

[000105] Some embodiments include compounds having the structure of formula (I), wherein the core structure is that of paclitaxel, docetaxel, or carbazitaxel except that one of A¹, A², or A³ is -U or -L-U. [000106] In some embodiments, the neurotoxicity of the compound when administered to a patient is lower than the neurotoxicity of a compound having the same structure but lacking a -U or -L-U moiety (e.g. having H or alkyl in place of -U or -L-U).

[000107] As described herein in the examples and accompanying disclosure, the relative toxicity of the compounds of interest compared with the parent (non-hybridized) anti-cancer compound may be measured by the normal methods for measuring toxicity of such compounds. In some embodiments, the compounds of interest produce fewer and/or less intense symptoms of chemically induced peripheral neuropathy (CIPN) in patients receiving the compound as compared with patients receiving the parent (non-hybridized) anti-cancer compound.

[000108] It will be appreciated that, for a compound comprising a first active moiety and a second active moiety, the "parent anti-cancer compound" refers to the first active moiety without having been hybridized by linking to the second active moiety. For example, for a paclitaxel-FK506 hybrid compound, the parent anti-cancer compound is non-hybridized paclitaxel.

[000109] A selection of example compounds of interest is shown in the Schemes and Figures set forth herein.

[000110] Any of the compounds of the disclosure may be administered in the form of a salt, ester, amide, prodrug, active metabolite, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite or analog is pharmaceutically acceptable and

pharmacologically active in the present context. Salts, esters, amides, prodrugs, active metabolites, analogs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Ed. (New York: Wiley- Interscience, 2001). Furthermore, where appropriate, functional groups on the compounds of the disclosure may be protected from undesired reactions during preparation or administration using protecting group chemistry. Suitable protecting groups are described, for example, in Green, Protective Groups in Organic Synthesis, 3rd Ed. (New York: Wiley- Interscience, 1999). [000111] For example, where appropriate, any of the compounds described herein may be in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or combinations thereof. The acid or base used to prepare the salt may be naturally occurring.

[000112] Suitable organic acids for preparing acid addition salts include, e.g., C -C alkyl and C6-C₁₂ aryl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, and terephthalic acid, and aryl and alkyl sulfonic acids such as methanesulfonic acid, ethane sulfonic acid, and p-toluenesulfonic acid, and the like. Suitable inorganic acids for preparing acid addition salts include, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base.

[000113] Suitable organic bases for preparing basic addition salts include, e.g., primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amines such as caffeine, N- ethylmorpholine, N-ethylpiperidine, and purine, and salts of amines such as betaine, choline, and procaine, and the like. Suitable inorganic bases for preparing basic addition salts include, e.g., salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate, and the like. A basic addition salt may be reconverted to the free acid by treatment with a suitable acid.

[000114] Preparation of esters involves transformation of a carboxylic acid group via a conventional esterification reaction involving nucleophilic attack of an RO^~ moiety at the carbonyl carbon. Esterification may also be carried out by reaction of a hydroxyl group with an esterification reagent such as an acid chloride. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs and active metabolites may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.

[000115] Other derivatives and analogs of the active agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature. In addition, chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers.

[000116] Any of the compounds of the disclosure may be the active agent in a formulation as described herein. Formulations containing the compounds of the disclosure may include 1, 2, 3 or more of the compounds described herein, and may also include one or more additional active agents such as analgesics and other antibiotics.

[000117] The amount of active agent in the formulation typically ranges from about 0.05 wt to about 95 wt based on the total weight of the formulation. For example, the amount of active agent may range from about 0.05 wt to about 50 wt%, or from about 0.1 wt to about 25 wt . Alternatively, the amount of active agent in the formulation may be measured so as to achieve a desired dose.

[000118] Formulations containing the compounds of the disclosure may be presented in unit dose form or in multi-dose containers with an optional preservative to increase shelf life.

[000119] The compositions of the disclosure may be administered to the patient by any appropriate method. In general, both systemic and localized methods of administration are acceptable. It will be obvious to those skilled in the art that the selection of a method of administration will be influenced by a number of factors, such as the condition being treated, frequency of administration, dosage level, and the wants and needs of the patient. For example, certain methods may be better suited for rapid delivery of high doses of active agent, while other methods may be better suited for slow, steady delivery of active agent. Examples of methods of administration that are suitable for delivery of the compounds of the disclosure include parental and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery via these methods are well known in the art.

[000120] For example, formulations containing the compounds of the disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and/or continuous infusion. Generally, parenteral administration employs liquid formulations.

[000121] The compositions may also be administered via the digestive tract, including orally and rectally. Examples of formulations that are appropriate for administration via the digestive tract include tablets, capsules, pastilles, chewing gum, aqueous solutions, and suppositories.

[000122] The formulations may also be administered via transmucosal administration. Transmucosal delivery includes delivery via the oral (including buccal and sublingual), nasal, vaginal, and rectal mucosal membranes. Formulations suitable for transmucosal deliver are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes.

[000123] The formulations may also be administered transdermally. Transdermal delivery may be accomplished using, for example, topically applied creams, liquids, pastes, gels and the like as well as what is often referred to as transdermal "patches."

[000124] The formulations may also be administered via the respiratory tract.

Pulmonary delivery may be accomplished via oral or nasal inhalation, using aerosols, dry powders, liquid formulations, or the like. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.

[000125] Liquid formulations include solutions, suspensions, and emulsions. For example, solutions may be aqueous solutions of the active agent and may include one or more of propylene glycol, polyethylene glycol, and the like. Aqueous suspensions can be made by dispersing the finely divided active agent in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents. Also included are formulations of solid form which are intended to be converted, shortly before use, to liquid form.

[000126] Tablets and lozenges may comprise, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth and an effective amount of an active agent. Pastilles generally comprise the active agent in an inert base such as gelatin and glycerine or sucrose and acacia. Mouthwashes generally comprise the active agent in a suitable liquid carrier.

[000127] For topical administration to the epidermis the chemical compound according to the disclosure may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. [000128] Transdermal patches typically comprise: (1) a impermeable backing layer which may be made up of any of a wide variety of plastics or resins, e.g. aluminized polyester or polyester alone or other impermeable films; and (2) a reservoir layer comprising, for example, a compound of the disclosure in combination with mineral oil, polyisobutylene, and alcohols gelled with USP hydroxymethylcellulose. As another example, the reservoir layer may comprise acrylic -based polymer adhesives with resinous crosslinking agents which provide for diffusion of the active agent from the reservoir layer to the surface of the skin. The transdermal patch may also have a delivery rate-controlling membrane such as a microporous polypropylene disposed between the reservoir and the skin. Ethylene- vinyl acetate copolymers and other microporous membranes may also be used. Typically, an adhesive layer is provided which may comprise an adhesive formulation such as mineral oil and polyisobutylene combined with the active agent.

[000129] Other typical transdermal patches may comprise three layers: (1) an outer layer comprising a laminated polyester film; (2) a middle layer containing a rate-controlling adhesive, a structural non-woven material and the active agent; and (3) a disposable liner that must be removed prior to use. Transdermal delivery systems may also involve incorporation of highly lipid soluble carrier compounds such as dimethyl sulfoxide (DMSO), to facilitate penetration of the skin. Other carrier compounds include lanolin and glycerin.

[000130] Rectal or vaginal suppositories comprise, for example, an active agent in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids. Another example of a suppository formulation includes ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter in combination with an effective amount of an active agent.

[000131] Nasal spray formulations may comprise a solution of active agent in physiologic saline or other pharmaceutically suitable carder liquids. Nasal spray compression pumps are also well known in the art and can be calibrated to deliver a predetermined dose of the solution.

[000132] Aerosol formulations suitable for pulmonary administration include, for example, formulations wherein the active agent is provided in a pressurized pack with a suitable propellant. Suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. The aerosol may also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve. [000133] Dry powder suitable for pulmonary administration include, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. Unit doses for dry powder formulations may be, for example, in the form of capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[000134] In addition to the foregoing components, it may be necessary or desirable in some cases (depending, for instance, on the particular composition or method of

administration) to incorporate any of a variety of additives, e.g., components that improve drug delivery, shelf-life, patient acceptance, etc. Suitable additives include acids,

antioxidants, antimicrobials, buffers, colorants, crystal growth inhibitors, defoaming agents, diluents, emollients, fillers, flavorings, gelling agents, fragrances, lubricants, propellants, thickeners, salts, solvents, surfactants, other chemical stabilizers, or mixtures thereof.

Examples of these additives can be found, for example, in M. Ash and I. Ash, Handbook of Pharmaceutical Additives (Hampshire, England: Gower Publishing, 1995), the contents of which are herein incorporated by reference.

[000135] In some embodiments of the invention, the compounds of the invention are administered in the form of a composition comprising one or more additives. In some embodiments, the composition does not comprise CremophorEL (i.e., the polyethoxylated caster oil produced by BASF®). In some such embodiments, the composition consists essentially of a compound of the invention and a pharmaceutically acceptable carrier that is not CremophorEL. In other such embodiments, the compositions consist essentially of a compound of the invention and one or more pharmaceutically acceptable additives that are not CremophorEL.

[000136] In some embodiments, the compounds of the invention are administered in the form of a composition that further comprises a nonionic surfactant other than CremophorEL. In some embodiments, the compositions according to the invention comprise albumin.

[000137] In some embodiments, the compounds of the invention are administered in the form of a composition, wherein the composition comprises liposomes containing one or more of the compounds of the invention. Formation of liposomes for encapsulation of the compounds of the invention may be accomplished in the normal way.

[000138] Appropriate dose and regimen schedules will be apparent based on the present disclosure and on information generally available to the skilled artisan. Administration may be carried out over weeks, months, or years. In some embodiments, controlled, low-level dosages are provided over a long period of time, whereas in some embodiments, higher level dosages are administered for a short period of time. Other dosage regimens, including less frequent or one-time administration of high-intensity dosages, are also within the scope of the disclosure.

[000139] The amount of active agent in formulations that contain the compounds of the disclosure may be calculated to achieve a specific dose (i.e., unit weight of active agent per unit weight of patient) of active agent. Furthermore, the treatment regimen may be designed to sustain a predetermined systemic level of active agent. For example, formulations and treatment regimen may be designed to provide an amount of active agent that ranges from about 0.001 mg/kg/day to about 100 mg/kg/day for an adult. As a further example, the amount of active agent may range from about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, or about 1 mg/kg/day to about 10 mg/kg/day. One of skill in the art will appreciate that dosages may vary depending on a variety of factors, including method and frequency of administration, and physical characteristics of the patient.

[000140] The compounds of the disclosure may be prepared using standard procedures that are known to those skilled in the art of synthetic organic chemistry and used for the preparation of analogous compounds. Appropriate synthetic procedures may be found, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Edition (New York: Wiley- Interscience, 2001). Syntheses of representative compounds are detailed in the Examples below.

[000141] Accordingly, in some embodiments the compounds of interest find utility in treating cancer. In some embodiments, this disclosure provides a method for treating a patient suffering from cancer, the method comprising administering to the patient an effective amount of any of the compounds disclosed herein. This disclosure also provides a method for inhibiting the spread of a cancer (e.g. a cancerous cell or tumor), the method comprising contacting a cancerous cell with an effective amount of any of the compounds disclosed herein. The disclosure also provides a method for inhibiting the spread of a cancer, the method comprising contacting a tissue containing cancerous cells with an effective amount of any of the compounds disclosed herein. As described in more detail herein, in any of the aforementioned methods, the compound may be administered in a composition comprising one or more active agents and one or more additives (such as, for example, a

pharmaceutically acceptable carrier).

[000142] In some embodiments, the compounds of interest are used to treat any types of cancer that are normally treated with taxane compounds. Such cancers include, for example, lung (e.g. non-small cell lung), ovarian, breast cancer, head and neck cancer, and Kaposi's sarcoma. Additionally, such cancers include cancers that may be vulnerable to FKBP inhibition, including chronic lymphocytic leukemia, hepatoma, prostate cancer, glioma, acute lymphoblastic leukemia, melanoma, and glioma. Furthermore, in some embodiments the compounds of interest may be used to treat cancer cells and tumors that have displayed resistance toward unmodified taxanes (e.g. paclitaxel or docetaxel).

[000143] In some embodiments, the disclosure provides a method for lowering the neurotoxic effects of a neurotoxicity producing therapeutic active moiety upon administration to a host. The method includes the step of administering to the host an effective amount of a hybrid compound comprising the therapeutic active moiety, a neurotoxicity lowering moiety, and an optional linker moiety. The hybrid compound has a molecular weight less than about 15,000 Daltons. The neurotoxicity lowering moiety binds to at least one neurotoxicity lowering biomoiety and substantially reduces neurotoxicity symptoms in the host. In this way, the hybrid compound reduces neurotoxicity by activating endogenous neuroprotective pathways (rather than merely preventing or reducing the amount of active agent reaching neurons). In some embodiments, the hybrid compound is administered as a pharmaceutical formulation. In some such embodiments, the pharmaceutical formulation does not contain CremophorEL, and the hybrid compound is not co-administered with CremophorEL. In some embodiments, the pharmaceutical formulations contains albumin. In some embodiments, the hybrid compound is administered in a liposome. In some embodiments, the therapeutic active moiety is an anticancer therapeutic moiety. In some such embodiments, the anticancer therapeutic moiety is a taxane. Examples of taxanes include paclitaxel, docetaxel, and carbazitaxel. In some embodiments, the anticancer therapeutic moiety contains platinum. In some embodiments, the neurotoxicity symptom is chemically induced peripheral neuropathy (CIPN).

[000144] In some embodiments, the disclosure provides a method for preparing a hybrid compound having reduced toxicity, the method comprising covalently bonding an active compound to a toxicity lowering moiety either via a direct covalent bond or via a linking moiety. The hybrid has toxicity that is reduced compared with the active compound in non- hybridized form. In some embodiments, the compound has reduced neurotoxicity. In some embodiments, the active compound is a taxane compound. In some embodiments, the linker is a flexible linker. In some embodiments, the linker is a hydrophilic linker.

[000145] In some embodiments, the disclosure provides compounds comprising a taxane moiety covalently attached either directly or through an optional linking moiety to a neurotoxicity lowering moiety. In some embodiments, the neurotoxicity lowering moiety is a neurotrophic ligand. In some embodiments, the neurotoxicity lowering moiety targets an FKBP protein (such as FKBP52 or FKBP38) or a heat shock protein. In some embodiments the taxane moiety is selected from paclitaxel, docetaxel, and cabazitaxel. In some

embodiments, the taxane moiety is covalently linked through the oxygen at the C-2', C-7, or C-10 position to the neurotoxicity lowering moiety or, when present, to the linking moiety.

[000146] All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entireties. However, where a patent, patent application, or publication containing express definitions is incorporated by reference, those express definitions should be understood to apply to the incorporated patent, patent application, or publication in which they are found, and not to the remainder of the text of this application, in particular the claims of this application.

[000147] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description and the examples that follow are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains.

Examples

Example 1

[000148] Paclitaxel-ligand hybrid compounds of interest were prepared according to the disclosure, and the following observations were noticed:

[000149] 1) Paclitaxel-ligand hybrids achieved high intracellular concentrations;

[000150] 2) Paclitaxel-ligand hybrids were at least equipotent with the parent taxane in vitro in slowing the growth of tumor cell lines;

[000151] 3) Paclitaxel-ligand hybrids had good pharmacokinetic properties in vitro and in vivo with good metabolic stability;

[000152] 4) Paclitaxel-ligand hybrids were just as efficacious as the parent taxane in reducing tumor size in a xenograft cancer model in mice;

[000153] 5) Paclitaxel-ligand hybrids when administered to mice over a period of 46 days did not produce any greater observable toxicity effects relative to the parent taxane;

[000154] 6) A paclitaxel-ligand hybrid exhibited no detectable neurotoxicity when compared with paclitaxel in a primary cortical neuron outgrowth assay.

[000155] In addition to these observations, Compound (1), having paclitaxel (linked at the 2' position) and an FKBP52 ligand linked to a linker moiety, was prepared as shown below in Scheme 1. An FKBP52 ligand was employed for this study, as well as unmodified paclitaxel, which is commercially available. An activated succinimidyl ester was created on the FKBP52 ligand and was coupled to the 2' hydroxyl on paclitaxel as shown. The synthesis had a 58% yield after purification by HPLC. The structure was verified by proton NMR and LC-MS.

[000156] The resulting paclitaxel-ligand hybrid ("TNL") from Scheme 1 was assessed for its solubility and also permeability into cells. A number of different solvent systems were appropriate for working with the compound, including 0.01% PEG-400 as well as 10% 1- Methyl-2 Pyrrolidinone/30%Labrasol/60%water. Data provided in FIG. 1 shows that the paclitaxel-ligand hybrid is somewhat more permeable into blood cells relative to non- hybridized paclitaxel. To obtain the data in FIG. 1, the paclitaxel-ligand hybrid or paclitaxel were added to a pooled blood sample of human blood and incubated with gentle rocking at 37°C for one hour. Next, samples were centrifuged to separate blood cells and plasma, and then these compounds were subject to organic extraction, and quantities were measured using liquid chromatography- mass spectroscopy employing a standard curve. This data addressed concerns that the larger hybrid might have lower permeability into cells which would lower efficacy since paclitaxel stabilizes tubulin inside cells.

[000157] The paclitaxel-ligand also displayed better metabolic stability compared with paclitaxel in a pharmacokinetic study performed in mice as shown in FIG. 2. To obtain the data in FIG. 2, the paclitaxel-ligand hybrid was injected into mice as shown (4 mice per data point) and the concentration assessed by LC-MS at the time points shown. The area under the curve for the paclitaxel ligand-hybrid was increased relative to paclitaxel, illustrating that it was more stable in the circulation. CremophorEL/Ethanol was used as a solvent (diluted into normal saline) for both compounds to eliminate pk differences caused by different solvents. Importantly, the paclitaxel-ligand hybrid had comparable potency compared with paclitaxel both in vitro and in vivo.

[000158] After verifying comparable in vitro activity (data not shown), an in vivo study was performed as shown in FIG. 3. The tumor xenograft study established that the paclitaxel- ligand hybrid was equally effective as the parent paclitaxel in vivo. Observations of weight loss and behavior showed no increase in toxicity for the hybrid vs. paclitaxel (data not shown). To obtain the data in FIG. 3, an MDA-MB-435 breast cancer cell line was implanted in female athymic Nu/Nu mice. Both compounds and vehicle were dosed every other day at 20 mg/kg. As of day 39, one animal in the Paclitaxel-ligand group had no detectable tumor (N=3) for the remainder of the study.

[000159] FIG. 4 and FIG. 5 show lower axonal injury in primary cortical neurons (PCN) for the paclitaxel-ligand hybrid relative to paclitaxel. Mechanistically, paclitaxel exposure to PCN results in unusual patterns of microtubule assembly which leads to apoptosis.

Intriguingly, the exposure of PCN to the paclitaxel-ligand hybrid exhibited no detectable injury to PCN neurons in this assay performed as described. To obtain the data in FIG. 4, primary cortical neurons derived from day 17 Wistar rat fetuses were prepared accordingly to a previously published protocol (Grimaldi, M. Proc. Natl. Acad. Sci. 1998, 95, 8268-8273). The neurons were plated in poly-lysine coated 12 well plates and allowed to settle for 48 hours. After that the cells were exposed to PBS, 0.0035% CremophorEL:ethanol (1: 1) as vehicle for the other agents, Paclitaxel, and Paclitaxel-ligand. After 72 hours the cells were washed and loaded with the vital staining Calcein-AM for 20 min. Cells were observed under an inverted epifluorescence microscope equipped with a computer operated acquisition system to measure cell size, neurite outgrowth, cell branching, and other parameters as indicators of neurotoxicity. "Ligand" is a neurotoxicity lowering moiety that binds to FKBP52.

[000160] With reference to FIG. 5, images of PCN growth are provided. Images of (i) paclitaxel treated PCN's revealed fewer cell numbers and more morphological abnormalities including sparse, thick, and non-connected prolongments compared with (iv) untreated cells or (v) CremophorEL vehicle. In contrast, PCN's treated with a (iii) free FKBP52 ligand or the (ii) paclitaxel-ligand hybrid or (vi) paclitaxel with a non-bound FKBP52 ligand exhibited comparable cell numbers compared with untreated cells or vehicle treated cells and healthy morphology characterized by well interconnected neurite networks between cells and healthy neurite morphology. [000161] FIG. 6 shows lower neurotoxicity of the paclitaxel-ligand hybrid compared with paclitaxel as measured by cell number. Cell number data were recorded for PCNs untreated (first column) or PCNs treated with: (i) CremophorEL vehicle; (ii) paclitaxel; (iii) a paclitaxel-ligand hybrid; (iv) free FK506; (v) a paclitaxel-FK506 hybrid. PAC=paclitaxel. PAC-ligand is paclitaxel bound to a neurotoxicity lowering moiety (NLM). The cell numbers were normal for PAC-ligand and low for PAC, indicating protection from neurotoxicity conferred by the ligand, an NLM. The presence of ** indicated P<0.001 for the statistical significance of PAC vs. PAC-ligand data.

[000162] As mentioned herein, taxane moieties allow modification (i.e., connection of the second active moiety via a linker, when present) at the C-2, C-7, or C-10 positions.

Examples of compounds having a taxane moiety linked at the C-2 position, as well as examples linked at the C-7 position were prepared according to the disclosure, and both were shown to allow good efficacy. Examples having a linkage at the C-10 position were also prepared and are described in Example 5 below.

Example 2

Synthesis of conjugates

[000163] Docetaxel and docetaxel/palictaxel-related derivates conjugated to known FK506 mimics may be prepared. In one example, a conjugate of docetaxel and Unit A is prepared as shown below (Scheme 2). In the example, docetaxel and Unit A are linked via a tartaric acid linking moiety.

Scheme 2. Synthesis of docetaxel-tartaric acid-Unit A conjugate

[000164] Other neurotoxicity reducing moieties may be used in this chemistry to prepare additional conjugates. Employing the tartaric acid linker moiety is designed to improve the overall solubility of the conjugates, but other linkers as described herein may be used.

[000165] Other docetaxel and docetaxel/palictaxel-related derivates conjugated to known FK506 mimics may also be prepared through the use of solubilizing amino-acid linkers. Examples are shown below in Schemes 3 and 4.

Scheme 3. Synthesis of paclitaxel-amino acid-Unit A conjugate

Scheme 4. Synthesis of paclitaxel-amino acid-Unit A conjugate Example 3

Synthesis of coniugates

Further conjugates may be prepared as shown in the following Schemes.

paclitaxel, Et₃N, DMF

Scheme 5. Synthesis of paclitaxel conjugate

Scheme 6. Synthesis of docetaxel conjugate

docetaxel

(

Scheme 7. Synthesis of docetaxel conjugate

Scheme 8. Synthesis of taxane conjugates

Scheme 9. Synthesis of taxane conjugates

Example 4

Synthesis and efficacy of conjugates

[000167] Further conjugates were prepared and subjected to tests of efficacy. Scheme 10 shows a synthetic route used to prepare one such compound.

Scheme 10. Synthesis of paclitaxel conjugate

Example 5

Efficacy of conjugates

[000168] Further conjugates were prepared and subjected to tests of efficacy. One such taxane derivative, compound (2), showed remarkable potency and low neurotoxicity in a cell model. The structure of (2), shown below in Scheme 11, uses a taxane modified at the 10' position.

Compound (2)

Scheme 11.

[000169] This compound represents a departure from prior taxanes in the literature and poses some challenging features. Notable, a very polar linker has been attached to help improve solubility of this notoriously insoluble class of compounds. It would be expected that a bulky, soluble linker would also compromise efficacy due to decreased permeability across cell membranes. Moreover, the large moiety attached to the taxane, an analogue of FK506, would also be expected to pose a challenge in hindering the taxane moiety from interacting with tubulin, the intracellular target.

[000170] Surprisingly, the bulky FK506 analogue and polar linker did not hinder the ability of (2) to inhibit the growth of three different cancer cell lines compared to paclitaxel. Data shown in FIG. 7 are a comparison of (2) vs. paclitaxel. As can be seen, the activities of paclitaxel and (2) are the same vs. the SKOV3 ovarian cancer cell line. The IC₅₀ value for Paclitaxel and for (2) were both found to be 1 nM. Similar results were obtained from both a lung cancer cell line, PC3, and a breast cancer cell line, MCF7. (Data was obtained by treating cells at the concentrations shown and then assessing viability).

[000171] In contrast with the high potency against this cancer cell line, the observed toxicity when (2) is used to treat primary cortical neurons is similar to untreated cells, as shown in FIG. 8. Primary cortical neurons were obtained from fetal rats. Cells were either untreated, exposed to cremophor (vehicle), or treated with 10 nM paclitaxel, 20 nM compound (2), 20 nM paclitaxel, or 10 nM FK506 for three days prior to assessing neurite outgrowth via optical methods or cell viability using a viability fluorescent stain. The data show that at 20 nM compound (2), the neurite outgrowth is equivalent to untreated cells or cells treated with vehicle. However, paclitaxel severely lowers the average neurite outgrowth.

[000172] Similar results are obtained when viable cells are measured, as shown in FIG. 9. Cells were treated with compounds as described above with reference to FIG. 8, and viable cells were counted after treatment with a cell viability stain. The number of viable cells treated with (2) is similar to untreated cells. However, the cell number of paclitaxel treated cells is 10-fold lower relative to (2)-treated cells.

Example 6

In vivo study

[000173] A test compound, "paclitaxel-ligand" (which has the structure of Compound (1)), showed evidence of producing significantly less neuropathic pain (NP) in vivo in a rat model. Compounds were injected i.p. and animals were evaluated using von Frey filaments for allodynia and heat for thermal hyperalgesia (not shown). The dosage used is at the known LD so for i.p. injected paclitaxel in rats. For the data shown in FIG. 10, *** and ** indicate p<.001 and p< .01, respectively, for the Bonferroni post- test following RM two-way

ANOVA between paclitaxel and vehicle control. Kruskal Wallis analysis between paclitaxel and paclitaxel-ligand gave p< .005. The study was perfomed in male Wistar rats and the evaluations used the "up-down" methodology (Chaplan, S. et al. J Neurosci Methods 1994; 53: 55-63) employing 10 animals per group.

Claims

Claims What is claimed is

1. A method for lowering the neurotoxic effects of a neurotoxicity producing therapeutic active moiety upon administration to a host, the method comprising:

administering to the host an effective amount of a hybrid compound of less than about 15,000 Daltons comprising the therapeutic active moiety or an active derivative, fragment or analog thereof and a neurotoxicity lowering moiety,

wherein the neurotoxicity lowering moiety binds to at least one neurotoxicity lowering biomoiety and substantially reduces at least one neurotoxicity symptom.

2. The method according to claim 1, wherein the compound is administered as a pharmaceutical formulation, and wherein the pharmaceutical formulation does not contain CremophorEL.

3. The method of claim 1, wherein the therapeutic active moiety is an anticancer therapeutic moiety.

4. The method according to claim 3 where the anticancer therapeutic moiety is a taxane analog.

5. The method according to claim 1, wherein the neurotoxicity symptom is chemically induced peripheral neuropathy.

6. The method according to claim 1, wherein the neurotoxicity lowering moiety has a dissociation constant of less than 10 μΜ with an FKBP protein or with a heat shock protein.

7. The method according to claim 1, wherein the compound further comprises a linking moiety that forms a covalent bond with the therapeutic active moiety and a covalent bond with the neurotoxicity lowering moiety.

8. A compound comprising a taxane moiety covalently attached either directly or through an optional linking moiety to a neurotoxicity lowering moiety.

9. The compound of claim 8, wherein the neurotoxicity lowering moiety is a neurotrophic ligand and targets an FKBP protein or a heat shock protein.

10. The compound of claim 8, wherein the taxane moiety is covalently linked through the oxygen at the C2, C7, or CIO position to the neurotoxicity lowering moiety or, when present, to the linking moiety.

11. The compound of claim 8, wherein the compound has the structure of formula (I)

A 2' is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, provided that A 2' optionally comprises the moiety A ;

A³ is selected from -O-A³ and -A³;

one of A¹, A², A³, and A⁴ is selected from -U and -L-U, and the others are selected from H, and alkyl, provided that A 4 may be taken together with A 2 to form a cycle;

L is the linking moiety; and

U is the neurotoxicity lowering moiety.

12. The compound of claim 11, wherein R is selected from alkyl, alkoxy, aryl, and aryloxy.

13. The compound of claim 11, wherein A 1 is selected from H and methyl, A 2 is H, and A⁴ is H.

14. The compound of claim 11, wherein U is selected from Units A, B, C, D, E, and

F:

Unit D Unit E Unit F wherein:

p represents an integer from 0 to 2;

R^a is selected from hydrocarbyl groups; and

the stars represent the point of connection to the first active moiety or, when present, the linking moiety.

15. The compound of claim 11, wherein L is selected from alkylene, amides, ureas, sulfoxides, sulfonamides, amines, carbonyls, ethers, amide/urea combinations, amide/amide combinations, sulfoxide/ether combinations, amide/ether combinations, amine/ether combinations, amide/amine combinations, and carbonyl/amide combinations, any of which may include unsaturated or saturated segments.

16. The compound of claim 11, wherein the compound has the structure of formula

(la)

wherein

R is selected from hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;

one of A 1 , A2 , and A 3 is selected from -U and -L-U, and the others are selected from H, and alkyl.

17. A method for reducing the neurotoxicity of a taxane compound, the method comprising covalently bonding the taxane to a neurotoxicity-lowering moiety either directly or through an optional linking moiety to form a hybrid compound.

18. The method of claim 17, wherein the taxane is selected from paclitaxel, docetaxel, and cabazitaxel.

19. The method of claim 18, wherein the optional linker is present and comprises a polyether moiety.

20. The method of claim 17, wherein the hybrid compound exhibits a lower incidence of chemically-induced peripheral neuropathy compared with the taxane compound when administered to a human host.

21. A method for treating cancer in a patient, the method comprising administering to the patient an effective amount of a compound comprising a taxane moiety covalently attached either directly or through an optional linking moiety to a neurotoxicity lowering moiety.

22. The method of claim 21, wherein the cancer is selected from lung, ovarian, breast cancer, head and neck cancer, Kaposi's sarcoma, chronic lymphocytic leukemia, hepatoma, prostate cancer, glioma, acute lymphoblastic leukemia, melanoma, and glioma.

23. The method of claim 22, wherein the cancer is resistant to one or more taxane compounds.