WO2011133385A2 - Novel ether-based compounds and their use - Google Patents

Abstract

This invention relates to compounds having the structure herein X, Y, A, B, and L are further described herein.

Description

NOVEL ETHER-BASED COMPOUNDS AND THEIR USE This application claims priority of U.S. Provisional Application No. 61/325,197, filed April 16, 2010, the contents of which are hereby incorporated by reference.

Throughout this application, certain publications are referenced in brackets. Full citations for these publications may be found immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention relates.

Background of the Invention

Inflammation, a key component of immunity, functions in both defense and pathophysiological events to maintain the homeostasis of tissues, organs and individual cells. Although rheumatological diseases have long been the prototypical inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, and cancer are now appreciated as having inflammation as a unifying component of their pathogenesis. In cancer, chronic inflammation often acts as a tumor promoter, resulting in aggressive cancerous growth and spread. Many of the same inflammatory factors that promote tumor growth also are responsible for cancer cachexia/anorexia, pain, debilitation, and shortened survival. A compelling case has been made even for attacking inflammation at initial diagnosis to improving patient quality of life and survival.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used anti-inflammatory compounds, with aspirin, the prototypical NSAID, still being one of the oldest and most extensively used medications in the world [1, 2]. NSAIDs have a significant antineoplastic effect, which should be viewed, at least in part, in the context of the increasingly appreciated role of inflammation in cancer. Aspirin is formally documented to be a chemopreventive agent against colon cancer. For other NSAIDs, the evidence on their antineoplastic properties is quite strong but still it is based mainly on epidemiological studies [3-5]. For example, a recent meta-analysis of 91 epidemiological studies showed a significant exponential decline with increasing intake of NSAID luding the four major types: colon, breast, lung, and prostate cancer [6, 7].

NSAIDs prevent cancer likely through pleiotropic effects. [8, 9] It is, however, clear that conventional NSAIDs do not meet two important criteria for their wide application as chemopreventive agents against cancer, i.e. safety and high efficacy, as NSAIDs are associated with a considerable number of side effects, and their efficacy is rather limited, not exceeding 50% [8]. Statins, a frequently used class of agents for the treatment of dyslipidemia, have been considered to have anti-cancer prperties. Although not uniformely accepted, there is strong evidence that this is the case based on epidemiological and preclinical data. For example, in a large randomized control study (RCT), Alsheikh-Ali et al. reported that there was a significant inverse association between patients treated with statins for LDL-C (low-density lipoprotein cholesterol) and cancer incidence [10]. This evidence was supported by epidemiologic data, which observed an inverse relationship between serum cholesterol levels and cancer incidence [11].

Other meta-analyses of RCTs on statins, however, suggest a neutral relationship between statin treatment and cancer incidence [12-14]. Preclincial data show a favorable cytokintec effect on cancer cells and strong anticancer efefcts in animal models of cancer. Nevertheless, the uncertiantly on statins' effect on cancer persists, and it may reflect, as in the case of NSAIDs, limited anti-cancer efficacy by statins.

Thus, there is a need to develop compounds with improved efficacy and safety profiles for the treatment of cancer and other inflammation-related diseases, such as neurodegenerative, rheumatological, and cardiovascular diseases.

Summary of the Invention

This invention provides a compound having the structure:

wherein

X is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic; Y is -O-, -NH-, or -S-;

A and B are each, independently, alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene,

L is -ONO₂, -OSO2R1, -OS0₂0Ri, -OPO(OR,)₂, -OB(OR,)₂, -N₂ ⁺, -O(R₁)₂ ⁺, S(R₁)2⁺, N(R₁)₃ ⁺, or halogen,

wherein each instance of R| is, independently, H, alkyl, or aryl; n and m are each, independently, an integer greater than or equal to 1; wherein when A is alkylene and -(CH₂)_n- and n is 2, L is -OPO(OR₁)₂, - OB(OR|>₂, -N₂ ⁺, -O(R₁)2⁺, -S(R₁)₂ ⁺, or halogen; wherein each instance of alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkylene is branched or unbranched, substituted or unsubstituted; and wherein each instance of cycloalkyl, aryl, heterocyclic, heteroaryl, and heteroarylene is substituted or unsubstituted; or an enantiomer, a diaste le salt thereof.

Detailed Description of the Inv

This invention provides a compound having the structure:

wherein

X is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic; Y is -Ο-, -NH-, or -S-;

A and B are each, independently, alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene,

L is -ONO₂, -OSO₂R₁, -OSO₂OR₁, -OPO(OR₁)₂, -OB(OR,)2, -N₂ ⁺, -O(R₁)₂ ⁺ S(R₁)2⁺, N(R₁)₃ ⁺, or halogen,

wherein each instance of R₁ is, independently, H, alkyl, or aryl; n and m are each, independently, an integer greater than or equal to 1; wherein when A is alkylene and -(CH₂)_n- and n is 2, L is -OPO(OR₁)₂, - OB(OR₁)₂, -N₂ ⁺, -O(R₁)₂ ⁺, -S(R₁)₂ ⁺, or halogen; wherein each instance of alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkylene is branched or unbranched, substituted or unsubstituted; and wherein each instance of cycloalkyl, aryl, heterocyclic, heteroaryl, and heteroarylene is substituted or unsubstituted; or an enantiomer p y acceptable salt thereof.

In an embodiment,

X is ~(CR;R i)j R->.

wherein

a is an integer from 1 to 10;

each instance of K and Rj are each, independently, H, OH, (% (^",,. alkyl, C₂- alkynyl, or aryl substituted with C1-C5 alkyl;

wherein

Rs is H, C1-C₁0 alkyl, ⁽ Y^{( "}i,, alkenyl, or C₂-Cio alkynyl;

R₆ and R₇ are each, independently, H, Ci~C]₀ alkyl, C2-C₁0 alkenyl, C₂- C[() alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic;

a is present or absent;

or

wherein

R_g, Rg, Rio, Ri i, and R₁₂ are each, independently, H, OH, halogen, -CN, -NO?, C,-C[o alkyl, C₂-Ci₀ alkenyl, C₂-C₁₀ alkynyl, -(C=0)-R_{l 3}, or -0-(C=0)-R,₃, wherein R,₃ is H, -OH, -OR, , -NR 14R 15, Ci-C,₀ alkyl, C₂-C_{l 0} alkenyl, or C2-C₁0 alkynyl,

wherein and Ris are, each, independently, H, C,-Cio alkyl, Ci-Cio alkenyl, or C₂-C|₀ alkynyl;

pharmaceutically acceptable salt thereof. In another embodiment,

X is -(CH₂)-(CHOH)-(CH₂)-(CHOH)-R₄,

wherei

wherein

Rs is H, CpCio alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;

Re and R? are each, independently, H, C1 -C10 alkyl, C2-C10 alkenyl, C:

C,o alkynyl,

wherein |₆ is H, C₁-C₁0 alkyl, C2-C₁0 alkenyl, C2-C10 alkynyl, or -

(C=0)-R₂2,

wherein R₂₂ is H, -OH, -OR₂₃, -NR23R24, C,-C_l0 alkyl, C₂-C|₀ alkenyl, or C2~C io alkynyl,

wherein R23 and R2 are, each, independently, H, Ci-Qo alkyl, ⁽.^'-( 'H alkenyl, or C₂-Cio alkynyl;

Ri7, Ris, Ri<), R20, and R21 are each, independently, H, -OH, halogen, - CN, -NO2, C I -CIO alkyl, C2-C10 alkenyl, C₂-C₁₀ alkynyl, -(C=0)-R₂₅, - 0-(C=0)-R2s, or aryl substituted by halogen, wherein R25 is H, -OH, -OR26, R R.: -'. Ci-Cio alkyl, C₂-Ci₀ alkenyl, or C2-C10 alkynyl,

wherein R₂6 and R27 are, each, independently, H, C₁-C₁0 alkyl, C2-C10 alkenyl, or C₂-Cio alkynyl;

a is present or absent;

pharmaceutically acceptable salt thereof. In a further embodiment,

X is -(CH₂)-(CHOH)-(CH₂)-(CHOH)-R4,

wherein

wherein

R₅ is H;

R₆ and R₇ are each, independently,

wherein R| is Ci-Cio alkyl;

R i7, R] 8, R]<), R20, and R21 are each, independently, H or aryl substituted with halogen;

or a pharmaceutically acceptable salt thereof.

In an embodiment,

X i

or a pharmaceutically acceptable salt thereof. In another embodiment,

X is -CR2R3-R4,

wherein

each instance of and R3 are each, independently, C I-C IO alkyl or aryl substituted with C_rC₅ alkyl;

R4 is H, or a pharmaceutically acceptable salt thereof. In a further embodiment,

wherein

each instance of R? and R₃ are each, independently, methyl, propyl, or aryl substituted with isobutyl;

R4 is H, or a pharmaceutically acceptable salt thereof.

In an embodiment.

or a pharmaceutically acceptable salt thereof.

In another embodiment,

wherein

Re, Rio, R11, and R|₂ are each, independently, H, OH, halogen, -CN, -NO₂, C1-C0 alkyl, C₂-C|₀ alkenyl, C₂-Ci₀ alkynyl, -(C=0)-Ri₃, or -0-(C=0)-R,₃, wherein R,₃ is H, -OH, -OR₁₄, -NR₁₄Ri₅, C_rCi₀ alkyl, C Ci₀ alkenyl, or C₂-C₁₀ alkynyl,

wherein R_i4 and are, each, independently, H, C|-Cio alkyl, C₂-C|o alkenyl, or -C1₀ alkynyl; or a pharmaceutically acc

In an embodiment,

wherein

Re, Re, Rio, Ri i, and R₁2 are each, independently, H or -0-(C=0)-R n. wherein Ro is H, -OH. -OR |₄. -NR|₄R_l5, Ci-C|₀ alkyl, C2-C 10 alkenyl, or C2-C10 alkynyl,

wherein R_i4 and R15 are, each, independently, H, Ci-Cio alkyl,

C2-C₁Q alkenyl, or CI-CKJ alkynyl; or a pharmaceutically acceptable salt thereof. a further embodiment,

wherein

R«, Ri), Rio, R, and R,_: are each, independently, H or -0-(C=0)-CH₃; or a pharmaceutically acceptable salt tliereof. In an embodiment,

or a pharmaceutically acceptable salt thereof.

In an embodiment of the compound.

X is a pharmaceutically active agent;

Y is -0-, -NH-. or -S-;

2-, -(CH₂)„-.

wherein

n is an integer from 1 to 20,

m is an integer from 1 to 200;

L is -ON0₂, -OS0₂R,, -OSO₂OR₁, -OPO(OR,)₂, -OB(OR,)₂, -N₂ ⁺, -0(R,)₂ ⁺, S(R,)₂ ⁺, N(R,)₃ ⁺, or halogen,

wherein each instance of Ri is, independently, H, alkyl, or aryl; wherein when A is -(CH₂)„- and n is 2, L is ~OPO(OR,)₂, -OB(ORi) 0(R|)₂ ⁺, -S(R,)₂ ⁺, or halogen: wherein each instance of alkyl, alkenyl, and alkynyi is branched or unbranched, substituted or unsubstituted; and wherein each instance of cycloalkyl, aryl, heterocyclic, and heteroaryl is substituted or unsubstituted; or an enantiomer, cceptable salt thereof.

In an embodiment.

wherein A is -O- or -NH-,

R₄ is H, -(C=0)CH₃, or aryl,

R Ri, R7, and Rg are each, independently, alkyl or aryl;

R9, and Ro are each, independently, halogen, alkyl, aryloxy, or heterocyclic;

is heteroaryl or cycloalkyl, and

bond a is present or absent; wherein each instance of alkyl is unbranched or branched, substituted or unsubstituted, and each instance of aryl is substituted or unsubstituted.

In another embodiment,

X is -CH(CH₂CH₂C

In an embodiment, Y is O,

In another embodiment, Y is N or S.

In some embodiments,

, or -(CH₂)_n-0~(CH₂CH₂0)_mCH₂CH .

In some embodiments, L is -OPO(OCH₂C¾)₂.

Y is O;

, or -(CH₂CH₂0)_mCH₂CH ; and

L is -OPO(OCH₂CH₃)₂;

or a pharmaceutically acceptable salt thereof.

In further embodiments, the compound has the structure

or a pharmaceutically acceptable salt thereof.

This invention provides methods of preventing or treating cancer in a subject comprising administering to the subject compounds and compositions of the present invention so as to prevent or treat cancer in the subject.

This invention further provides methods of treating diseases characterized by inflammation in a subject comprising administering to the subject compounds and compositions of the present invention so as to treat the disease characterized by inflammation in the subject. Diseases characterized by inflammation include, but are not limited to rheumatological disease, neurodegenerative disease, and cardiovascular disease.

This invention further provides methods of treating pain and/or fever in a subject comprising administering to the subject compounds and compositions of the present invention so as to treat pain and/or fever in the subject.

The compounds of the present invention include hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469—1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautome , each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. When the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C- 13 and C- 14.

It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as ^l2C, ^l3C, or ^l C. Furthermore, any compounds containing ^l3C or ^l C may specifically have the structure of any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as Ή, ²H, or ³H. Furthermore, any compounds containing ²H or ¾ may specifically have the structure of any of the compounds disclosed herein.

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non- labeled reagents employed. As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, Ci-C„ as in "C|-C„ alkyl" is defined to include groups having 1, 2 n- 1 or n carbons in a linear or branched arrangement. For example, Ci-Ct, as in "Ci-Ce alkyl" is defined to include groups having 1, 2, 3, 4, S, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl. As used herein, "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least t carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, "C2-C<j alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, and butenyl.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, "C2-C6 alkynyl" means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or S carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. "Alkylene", "alkenylene" and "alkynylene" shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted. As used herein, the term "heteroalkyl" refers to a straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quate nized. The heteroatom(s) O, N and S may be placed at any interior position of the het H2-CH2-O-CH3, -C¾- CH2-NH-CH3, -CH2-CH₂-N(CH₃)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH_3> -CH₂-CH₂- S(0)₂-CH3, -CH=CH-O-CH₃, -CH₂-CH=N-OCH₃, and -CH=CH-N(CH₃)-CH₃. Similarly, the term "heteroalkylene" means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2-CH2-, -CH2-S-CH2-CH2-NH-CH2-, -(CH2CH20)_mCH₂-, and -(CitCItOJmCHzCHk-, where m is an integer from 1 to 200. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

As used herein, the term "arylene" refers to divalent aromatic groups having in the range of 6 up to 14 carbon atoms. As used herein, the term "heteroarylene" means a divalent radical derived from heteroaryl.

A "heteroalkyl", "heteroalkylene", "arylene", and "heteroarylene" may be unsubstituted or substituted with one or more substituents set forth herein. As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system, which may be saturated or partially saturated, i.e. possesses one or more double bonds. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Bicyclic fused ring systems are exemplified by a cycloalkyl ring fused to another cycloalkyl ring. Examples of bicyclic fused ring systems include, but are not limited to, decalin, l,2,3,7,8,8a-hexahydro-naphthalene, and the like. Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system fused to an additional cycloalkyl group.

As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the y y g is non-aromatic, it is understood that attachment is via the aromatic ring.

The term "arylalkyl" refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an "arylalkyl" group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p- trifluoromethylbenzyl (4-trifluoromethylphenylmethyI), 1-phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and the like.

The term '¾eteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatorns selected from the group consisting of O, N and S. Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl. pyrrazolyl, indolyl, benzotriazo y y y xazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

The term "heterocycle", "heterocyclyl", or "heterocyclic" refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathioIane, and the like.

The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.

In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

The term "substituted" refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non- carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described above, and, in particu g ( ) alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

The term "acid" refers to acids under both the Bronsted-Lowry and the Lewis definitions of acids. Under the Bronsted-Lowry definition, acids are defined as proton (H*) donors. Examples of Bronsted-Lowry acids include, but are not limited to, inorganic acids such as hydrofluoric, hydrochloric, hydrobromic, hydroiodic, perchloric, hypochlorous, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric, nitrous, and the like; and organic acids such as formic, acetic, trifluoroacetic, p-toluenesulfonic, camphorsulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Under the Lewis definition, an acid is an electron acceptor capable of accepting electron density by virtue of possessing unoccupied orbitals. Examples of Lewis acids include, but are not limited to, metal salts such as A1C¾, FeCl₃, FeCl₃'SiC>2, CrCl₂, HgCl₂, CuCl, TiCL», Yb(OTf₃), InOTf, TiChfOiPrfe, and Ti(OiPr)4; organometallic species such as trimethylaluminum and dimethylaluminum chloride; and p ( ) BF3, BFj-OEti, ΒΒΓ3, B(OMe)₃, and B(OiPr)₃.

Examples of bases include, but are not limited to, alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert- butoxide, potassium tert-butoxide, lithium methoxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal bicarbonates and carbonates, such as sodium bicarbonate, sodium carbonate, lithium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and cesium bicarbonate; organolithium bases, such as methyllithium, n-butyllithium, s-butyllithium, tert-butyllithium, isobutyllithium, phenyllithium, ethyllithium, n-hexyllithium, and isopropyllithium; amide bases, such as lithium amide, sodium amide, potassium amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, and lithium 2,2,6,6-tetramethylpiperidide; and amine bases, such as pyridine, 4-(dimethylamino)pyridine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), and the like. As used herein, the term "leaving group" refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage, for example, in nucleophilic substitution. Upon heterolytic bond cleavage, leaving groups can be anions or neutral molecules. Examples of leaving groups include, but are not limited to, nitrates (-ONO₂), sulfates (-OSO2OR), sulfonates (-OSO2R), phosphates (-OPO(OH)₂), phosphate esters (-OPO(OR 2), boronic esters (-OB(OR>2), diazonium (-N₂ ⁺), halides, -OR₂ ⁺, -OH₂ ⁺, -SR₂ ⁺, -NR₃ ⁺, and the like. Examples of sulfonate leaving groups include, but are not limited, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, and the like. Examples of phosphate ester leaving groups include, but are not limited to, -OPC OMe , -OPO(OEt)₂, -OPO(OiPr)₂, and the like.

As used herein, the term "pharmaceutically active agent" means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject. Pharmaceutically active agents include, but are not limited to, substances and compounds des y ence (PDR Network, LLC; 64th edition; November 15, 2009) and "Approved Drug Products with Therapeutic Equivalence Evaluations" (U.S. Department Of Health And Human Services, 30^th edition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent's biological activity or effect. Classes of pharmaceutically active agents include, but are not limited to, anticancer agents, NSAEDs, and statins. The term "anticancer agents" refer to compounds useful for the treatment of various types of cancer. Examples of anticancer agents include, but are not limited to, alitretinoin, all-trans retinoic acid, chlorambucil, methotrexate, doxorubicin hydrochloride, fluorouracil, imiquimod, pemetrexed disodium, aminolevulinic acid, anastrozole, exemestane, nelarabine, azacitidine, bendamustine hydrochloride, bexarotene, bortezomib, bleomycin, irinotecan hydrochloride, capecitabine, carboplatin, daunorubicin hydrochloride, cisplatin, cyclophosphamide, clofarabine, cytarabine, dacarbazine, decitabine, dasatinib, dexrazoxane hydrochloride, docetaxel, doxorubicin hydrochloride, leuprolide acetate, epirubicin hydrochloride, oxaliplatin, erlotinib hydrochloride, etoposide phosphate, raloxifene hydrochloride, fulvestrant, toremifene, letrozole, pralatrexate, fludarabine phosphate, gefitinib, gemcitabine hydrochloride, imatinib mesylate, topotecan hydrochloride, romidepsin, ixabepilone, lapatinib ditosylate, lenalidomide, leucovorin calcium, temozolomide, plerixafor, paclitaxel, sorafenib tosylate, nilotinib, tamoxifen citrate, pazopanib hydrochloride, sunitinib malate, thalidomide, vincristine sulfate, vinblastine, melphalan, zoledronic acid, suberoylanilide hydroxamic acid, valproic acid, and the like.

The term "NSAIDs" as used herein refers to non-steroidal anti-inflammatory drugs. NSAIDs comprise a structurally and, to a large extent, functionally diverse group of compounds approved for the treatment of patients with a variety of inflammatory diseases. They all have analgesic, antipyretic and anti-inflammatory effects. Broadly, NSAIDs can be categorized into the following chemical g p y y s (e.g. sulindac), 2- arylpropionic acids (profens), N-arylanthranilic acids (fenamic acids), pyrazolidine derivatives, oxicams, and sulphonanilides. Most of the available NSAIDs are amenable to derivatization as described herein using methods readily available and known to those ordinarily skilled in the art. Examples of NSAIDS include, but are not limited to, acetaminophen, aspirin, ibuprofert, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenprofen calcium, fluiobiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like.

The term "statin" as used herein refer to compounds that inhibit HMG-CoA reductase (or 3- hydroxy-3-methyl-glutaryI-CoA reductase). Most of the statins possess a free carboxylic acid group or lactone that is amenable to derivatization as described herein using methods readily available and known to those having ordinary skill in the art. Examples of statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, pravastatin, pravastatin, rosuvastatin, lovastatin, simvastatin, and the like. As used herein, abbreviations are defined as follows:

Ac = acetyl

4-DMAP = 4-(dimethylamino)pyridine

DMF = AW-dimemylformamide

EDC = JV-emyl-A^-(3-dimemylaminopropyl)carbodiimide

TB AF = tetra-n-butylammonium fluoride

TBS = fert-butyldimethylsilyl

TMS = trimethylsilyl

Tf = trifluoromethanesulfonyl

KHMDS = potassium bis(trimethylsilyl)amide or potassium hexamethyldisilazide

AIBN = 1,1 '-azobisisobutyronitrile

9-BBN = 9-borabicyclo[3.3.1]nonane

DIB A = diisobutylaluminum

THF = tetrahydrofuran

MeOH = methanol DCE = 1,2-dichloroethane

Ph = phenyl

Me = methyl

Et = ethyl

iPr = isopropyl

n-Bu = n-butyl

i-Bu = isobutyl

s-Bu = sec-butyl

t-Bu = iert-butyl

Ms = methanesulfonyl

Ts = p-toluenesulfonyl

SET = single electron transfer

In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. Ri, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.

The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.

The compounds of the instant invention may be in a salt form. As used herein, a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used for treatment of cancer, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately react g p p ion in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et at. (1977) "Pharmaceutical Salts", / Pharm. Set 66:1-19).

As used herein, "treating" means slowing, stopping or reversing the progression of a disease. An embodiment of "treating cancer" is inhibition of proliferation of tumor cells.

The compositions of this invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.

The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds may comprise a single compound or mixtures thereof with anti-cancer compounds, or tumor growth inhibiting compounds, or with other compounds also used to treat neurite damag in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules.

Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 197S. Techniques and compositions for making dosage forms useful in the present inv eferences: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. The compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral ad g flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The compounds of the instant invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject. Below, compounds of the present invention are synthesized according to the general procedures shown in the following synthetic schemes. The "R" groups shown in the following schemes denote any number of generic substituents, such as those described hereinabove, "n" refers to any integer greater than or equal to 1. Preferably, "n" is an integer from 1-20, inclusive, "m" refers to any integer greater than or equal to 1. Preferably, "m" is an integer from 1-200, inclusive.

In general scheme 1, compounds having the structure of compound c are synthesized via ester or amide formation between a compound capable of forming an ester bond, such as compound a, and compound b. "Y" refers to a nucleophilic moiety, including, but not limited to, O, NH, and S.

Ester formation is achieved by any number of esterification reactions known to those having ordinary skill in the art. For example, coupling reagents including, but not limited to, 1,3- diisopropylcarbodiimide (DIC) and Ν,Ν'-dicyclohexylcarbodiimide (DCC) can be used in the presence of a suitable base.

The resulting ester, compound c, is conjugated to an ether-containing moiety as shown in scheme 2 through a nucleophilic substitution reaction. Examples of ether-containing moieties include, but are not limited to, polyethylene glycol, polyethylene glycol hydroxymethyl monoether, para-hydroxyalkyl benzaldehyde, polyalkylene glycols, and the like. One of ordinary skill in the art of chemical synthesis will appreciate that the free nucleophilic atoms of the ether-containing moieties may be O, N, or S.

The pendant hydroxyl group of d to a leaving group. Any method known to those of ordinary skill in the art for conversion of hydroxyl groups to functional groups may be used. For example, the conversion of hydroxyl groups to diethyl phosphate functional groups is shown in scheme 3.

La general scheme 4, the aldehyde in compound f is first reduced to an alcohol by the action of a reducing agent, for example, sodium cyanoborohydride, before conversion to a functional group.

Alternatively, the compounds of the present invention may be synthesized by formation of an ester linkage between compound a and an ether-containing moiety wherein the free nucleophilic atoms may be O, N, or S. Various ether-containing moieties are shown in schemes 5, 6, and 7.

a

Those having ordinary skill in the art of organic synthesis will appreciate that modifications to the general procedures shown in the schemes above can be made to yield structurally diverse compounds. For example, where aryl rings are present, all positional isomers are contemplated and may be synthesized using standard aromatic substitution chemistry. The number and types of substituents may also vary around the aryl rings. Furthermore, where alkyl groups are present, the chain length may be modified using methods well known to those of ordinary skill in the art. Where ester formation is contemplated, lactones may be used wherein the lactone ring is opened by reaction with a nucleophile, such as an ether- containing moiety described hereinabove. Suitable organic transformations are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (Wiley- Interscience; 6^th edition, 2007), the content of which is hereby incoporated by reference.

The compounds and compositions of the present invention are useful for the prevention and treatment of cancer and other inflammation-related diseases, such as neurodegenerative, rheumatological, and cardiovascular diseases.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Experimental Details

Example 1. Synthesis of Ether-based Compound 3

Synthetic steps:

Step A. 1 eq. of valproic acid and 1 eq. p-hydroxybenzylbromide are dissolved in dichloromethane (DCM), with the addition of 1 eq. N, N'-dic clohexylcarbodiimide (DCC), 4-(dimethyIamino)pyridine (DMAP) as the catalyst. The mixture is stirred for 3 h at room temperature. Acetone is added to precipitate DCC. After the solvent is removed by vacuum, the product is purified by flash column chromatography to give compound 1. Step B. A suspension of 1 eq. of ethylene diol and 1 eq. of dibutyltin oxide in chloroform- methanol is refluxed for 3 h to give a clear solution. After the solvents are removed under reduced pressure to give a white solid, 2 eq. of cesium fluoride are added. After the solid mixture is dried overnight under high vacuum, the mixture is suspended in DMF. To the suspension is added a solution of 1 eq. of compound 1 in DMF, and the mixture is stirred for 24 h at room temperature. After the mixed solvent of ethyl acetate and water are added, the mixture is stirred vigorously for 30 min and then filtered through a pad of silica gel to remove dibutyltin oxide. The filtrate is washed with water and then with brine. Removal of the solvents gives a residue that is purified by column chromatography on silica gel to give compound 2. Step C. 1 eq. of compound 2 an re dissolved in DCM and stirred for 3 h at room temperature. After the solvent is removed by vacuum, the product is purified by flash column chromatography to give compound 3. Proton chemical shifts are expressed in parts per million (ppm, 5 scale) and are referenced to residual protium in the NMR solvent (CDC1₃, δ 7.26; CD₃OD, δ 3.30; DMSO, δ 2.49). Data for Ή NMR are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, bs = broad singlet), and coupling constant in Hertz (Hz). Ή NMR (400 Mhz, CDC1₃): δ 7.30 (d, 2H), 7.05 (d, 2H), 5.04 (d, 2H), 4.09 (m, 6H), 2.60 (m, 1H), 1.71 (m, 2H), 1.20-1.60 (m, 14H), 0.90 (t, 6H).

Derivatives of compound 3 are synthesized using the above method where valproic acid is replaced by aspirin, ibuprofen, or fluvastatin.

References

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2. Rinsema T J. One hundred years of aspirin. Med Hist 1999; 43:502-7.

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4. Jacobs E J, Rodriguez C, Mondul A M, Connell C J, Henley S J, Calle E E, et al. A large cohort study of aspirin and other nonsteroidal anti-inflammatory drugs and prostate cancer incidence. J Natl Cancer Inst 2005; 97:975-80.

5. Thun M J, Henley S J, Gansler T Inflammation and cancer: an epidemiological perspective. Novartis Foundation symposium 2004; 256:6-21; discussion 2-8, 49-52, 266-9.

6. Harris R E, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncology reports 2005; 13:559-83.

7. Ratliff T L. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). The Journal of urology 2005; 174:787-8.

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9. Shiff S J, Rigas B. Aspirin for cancer. Nat Med 1999; 5:1348-9.

10. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007 Jul 31; 50(5):409-18. 11. Jacobs et al. 1992

12. Bierre et al. 2001

13. Baigent et al. 2005

14. Dale et al. 2006

Claims

Claims

What is claimed is:

1. A compound having the structure:

wherein

X is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic; Y is -O-, -NH-, or -S-;

A and B are each, independently, alkylene, alkenylene, alkynylene, heteroalkylene, arylene, heteroarylene.

L is -ONO2, -OSO2R1, -OSO₂OR1, -OPO(OR₁)2, -OB(OR₁)2, -N₂ ⁺, -O(R₁)₂ ⁺, - S(R₁)₂ ⁺, N(R|)₃ ⁺, or halogen,

wherein each instance of R| is, independently, H, alkyl, or aryl; n and m are each, independently, an integer greater than or equal to 1; wherein when A is alkylene and -((¾)„- and n is 2, L is -OPO(OR|)₂, - OB(OR₁)2, -N₂ ⁺. -O(R₁)₂ ⁺, -S(R₁)₂ ⁺, or halogen; wherein each instance of alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heteroalkylene is branched or unbranched, substituted or unsubstituted; and wherein each instance of cycloalkyl, aryl, heterocyclic, heteroaryl, and heteroarylene is substituted or unsubstituted; or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

X is -(CR2 3V 4,

wherein

a is an integer from 1 to 10;

each instance of R2 and R3 are each, independently, H, OH, C1-C10 alkyl, C₂- Cio alkenyl, C2-C10 alkynyl, or aryl substituted with Ci-Cs alkyl;

R4 is H or

wherein

R₅ is H, C1-C10 alkyl, C2-C10 alkenyl, or C₂-Ci₀ alkynyl;

Re and R7 are each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2- Cio alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclic;

a is present or absent;

wherein

Re, R9, Rio, Rii, and R12 are each, independently, H, OH, halogen, -CN, -NO2, Ct-Cio alkyl, C2-C10 alkenyl, C₂-C₁₀ alkynyl, -(C=0)-Ri3, or -O-(C=0)-R|₃, wherein R13 is H, -OH, -OR|₄, -NR14R15, Ci-Cio alkyl, C₂-Cu> alkenyl, or C2-C10 alkynyl,

wherein R14 and R15 are, each, independently, H, C|-Cio alkyl, C2-C10 alkenyl, or C2-C10 alkynyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein

X is -(CH₂HCHOH)-(CH₂)-(CHOH)-R4,

wherein

wherein

R₅ is H, C1-C10 alkyl, C₂-Ci₀ alkenyl, or C2-C10 alkynyl;

Ri and R7 are each, independently, H, C 1-C10 alkyl, C2-C10 alkenyl, C₂-

C10 alkynyl, or "21

wherein Rie is H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or -

(C=0)-R22,

wherein R22 is H, -OH, -OR23, -NR23R24, Ci-Cio alkyl, C₂-C|₀ alkenyl, or C₂-Cio alkynyl,

wherein R₂3 and 2 are, each, independently, H, CI-CIO alkyl, C₂-C₁₀ alkenyl, or C₂-Ci₀ alkynyl;

Ri7, Ri8. Ri9. R20. and R21 are each, independently, H, -OH, halogen, - CN, -NO2, CI-CIO alkyl, C₂-C|₀ alkenyl, C₂-Cio alkynyl, -(C=0)-R25, - 0-(C=0)-R25, or aryl substituted by halogen,

wherein R25 is H, -OH, -OR₂₆, -NR26R27, Ci-Cio alkyl, C₂-Cio alkenyl, or C -C10 alkynyl, wherein I¾6 and 27 are, each, independently, H, C|-Ci₀ alkyl, C2-C10 alkenyl, or C.-C10 alkynyl;

a is present or absent;

or a pharmaceutically acceptable salt thereof. ompound of claim 3, wherein

X is -(CH2)-(CHOH)-(CH₂)-(CHOH)-R4,

wherein

R4 is

wherein

Rs is H;

Re and R7 are each, independently, H o

r

wherein R½ is Ci-Cio alkyl;

R17, Rig, Rig, R20, and R21 are each, independently, H or substituted with halogen;

or a pharmaceutically acceptable salt thereof. ompound of claim 4, wherein X is

or a pharmaceutically acceptable salt thereof. compound of claim 2, wherein

X is -CR2 3-R4,

wherein

each instance of R2 and Rs are each, independently, C1-C10 alkyl or aryl substituted with C1-C5 alkyl;

R4 IS H, or a pharmaceutically acceptable salt thereof. compound of claim 6, wherein

X is -CR2R3-R4,

wherein

each instance of R2 and R3 are each, independently, methyl, propyl, or aryl substituted with isobutyl;

R is H, or a pharmaceutically acceptable salt thereof. ompound of claim 7, wherein

X is -C(CH₂CH₂CH3)2,

or a pharmaceutically acceptable salt thereof. ompound of claim 2, wherein

X is

wherein

Re, R«, Rto, R11, and R^ are each, independently, H, OH, halogen, -CN, -N(½, Ci-Cio alkyl, C2-C10 alkenyl, C C|₀ alkynyl, -(C=0)-R_f3, or -O-(C=0)-R,₃, wherein R|₃ is H, -OH, -OR14, -NR14R15, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl,

wherein R14 and R15 are, each, independently, H, Ci-Qo alkyl, C2-C10 alkenyl, or C2-C10 alkynyl; or a pharmaceutically acceptable salt thereof. compound of claim 9, wherein

X is

wherein

Re, R9, Rio, R11 , and R12 are each, independently, H or -O-(C=0)-Ri₃,

wherein R_!3 is H, -OH, -OR14, - R14R15, Ci-Qo alkyl, C2-C10 alkenyl, or C2-C10 alkynyl,

wherein R14 and R15 are, each, independently, H, C1-C10 alkyl,

C2-C10 alkenyl, or C₂-Cio alkynyl; or a pharmaceutically acceptable salt thereof. compound of claim 10, wherein

X is

wherein

Rg, R», Rio. Rii. and R12 are each, independently, H or -O-(C=0)-CH3; or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11, wherein

X is

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1,

wherein

X is a pharmaceutically active agent; Y is -O-, -NH-, or -S-;

A is -(CH₂)„- or

; and

B is -(CH₂CH₂0)_mCH₂-, -(CH₂CH₂0)_mCH₂CH₂-, -((¾)„-,

wherein n is an integer from 1 to 20,

m is an integer from 1 to 200;

L is -ONO2, -OSO2 1, -OSO2OR1, -OPO(OR₁)₂, -OB(OR|)₂, -N₂ ⁺, -0(Ri - S(R₁)₂ ⁺, N(R₁)₃ ⁺, or halogen,

wherein each instance of Ri is, independently, H, alkyl, or aryl; wherein when A is -(CH₂)„- and n is 2, L is -OPO(OR₁)₂, -OB(OR₁)₂, -N₂ ⁺, - 0(R₁)₂ ⁺, -S(R₁)₂ ⁺, or halogen; wherein each instance of alkyl, alkenyl, and alkynyl is branched or unbranched, substituted or unsubstituted; and wherein each instance of cycloalkyl, aryl, heterocyclic, and heteroaryl is substituted or unsubstituted; or an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof. e compound of claim 13,

wherein A is -O- or -ΝΉ-,

R4 is H, -(C=0)CH₃, or aryl,

R5, Re, R7, and Rg are each, independently, alkyl or aryl; Rg, Rio, RI I, Ri2, and 13 are each, independently, halogen, alkyl, aryloxy, or heterocyclic;

Ri4 is heteroaryl or cycloalkyl, and

bond a is present or absent; wherein each instance of alkyl is unbranched or branched, substituted or unsubstituted, and each instance of aryl is substituted or unsubstituted.

compound of claim 14, wherein X is -CHiCHjCHbCHsk,

compound of any one of claims 1-15, wherein Y is O. compound of any one of claims 1-15, wherein Y is N or S. compound of any one of claims 1-15, wherein Z is

19. The compound of any one of claims 1-15, wherein L is -ΟΡΟ(< Η₂α¾)2.

20. The compound of claim 1, 2, or 13, wherein

X is -CH(CH₂CH₂CH₃)_,

L is -OPO(OCH₂CH₃)₂;

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, 2, or 13 having the structure:

or a pharmaceutically acceptable salt thereof.