BACKGROUND Tschnical.Field

The present disclosure relates generally to compounds and methods to enhance the oral availability of giycomimetics. A glycomimetic is modified, for example by replacement of one or more substituents on the glycomimetic or by covalently linking the glycomimetic to a molecule that is transported on its own across a biological membrane, in order to increase absorption of the glycomimetic by the Gi tract.

Description of the Related Art

A variety of potential routes exist for the administration of a therapeutic agent. The routes include intravenous and non-intravenous administration, Examples of non- intravenous routes include oral, rectal, transdermal, subcutaneous, or sublingual

administration. A number of therapies require the therapeutic agent to be administered to a patient intravenously. This is often the result of the agent either being not absorbed or poorly absorbed from the gastrointestinal (Gi) tract, or being rendered inactive by the Gi tract milieu, following non-intravenous administration of the agent.

Furthermore, even where absorption of an agent from the patient's Gi tract is sufficient, the bioavailability of the agent (or an active metabolite thereof) may be too low to have a proper therapeutic effect. Bioavailability is how much and how fast a therapeutic agent (or active metabolite thereof) enters systemic circulation. Low therapeutic agent bioavailability will be the result of a single cause or a combination of causes. Such causes may be due to the general nature, or specific composition, of the therapeutic agent; or the particular patient; or both.

A general cause of low bioavailability of a therapeutic agent is, for example, insufficient time for absorption in the Gi tract. Examples of causes specific to a particular therapeutic agent include the inability of an agent to dissolve readily or to penetrate the epithelial membrane. The latter may be due, for example, to the agent being highly ionized or polar. Another example of a cause that can be specific to a particular therapeutic agent is any chemical reaction (such as hydrolysis by gastric acid or digestive enzymes) that, reduces absorption and therefore may decrease bioavailability. Factors that can affect the therapeutic- agent's bioavailability in a particular patient include age, sex, physical activity, genetic phenoiype, stress, disorders (e.g., achlorhydria or malabsorption syndromes), and previous Gl surgery (e.g. , bariatric surgery).

An example of a non-intravenous route of administration (of a therapeutic agent) that can result in low bioavailability is oral administration. Many therapeutic agents may be metabolized before adequate plasma concentrations are reached. Orally administered drugs must pass through common sites of metabolism (e.g., the intestinal wail and the portal circulation to the liver) that occur prior to an agent reaching systemic circulation.

Therapeutic- agents, which when in oral dosage forms are poorly water-soluble and slowly absorbed, are the most common candidates for low bioavailability.

Accordingly, there is a need in the art for enhancing the oral availability of therapeutic agents, such as giycomimeiic therapeutic agents. The present disclosure fulfills this need and further provides other related advantages.

BRIEF SUMMARY

These and other aspects of the present disclosure will become apparent upon reference to the following detailed description and attached drawing. The present disclosure includes the following compounds and compositions.

m an embodiment, a compound has formula (i):

or an isomer, polymorph, prodrug or solvate thereof, and a pharmaceutically acceptable ^, salt of any of the foregoing,

wherein:

n is any single integer from 1 to 1 1 ;

R ¹ is Ci-Cg aikyl, C ₂ -Cs aikenyl, C Cg alkynyl, Cj-Cs haloalkyl, C ₂ -Cs haloaikenyl or C ₂ -C ₃ haloalkynyl; R ² is H, -L'-CrCg alkyl, -L'-C ₂ -Cg alkenyl -L ^! -C ₂ -C ₈ aikynyi, -L'-Cj-Cg haioalkyl, -L'-CrCg haloaikenyl, -L* -C ₂ ~Cg haloalkynyi or -L ^] ~M;

R ³ is -OH, C| -Cg alkoxy, C _r Cg cycloalkylalkoxy,

alkyl, -OC(=0)C ₃ -C ₆ cycloalkyi, -OC(=0)aryl, -NHC(-0)aryl, or -NHC(=0)R ¹² ;

R ⁴ is -OR ¹³ , -NHOR , -NHN(R ¹ )(R ¹⁵ ), -NHS0 ₂ R ¹² , -NHS0 ₂ aryI, heieroaryi, -NH-heterocyc!yl, -NH-heteroaryL or -N(R ^{! 4} )(R ¹⁵ );

R ³ is -OH, Cj-Cg hydroxyalkyl, Cj-Cg hydroxyalkenyl, CpCg hydroxyaikynyl or C3-C.6 cycloa!kyl;

R ⁶ and R ⁿ are each independently -OH, -N¾, halo, Ci-Cg alkyl, C ₂ ~C _g alkenyl, C ₂ -C ₈ aikynyi, Q-Cs haioalkyl, C ₂ -Cg haloaikenyl or C ₂ ~Cg haloalkynyi;

R ⁷ is -CH ₂ OH, -CH ₂ NH ₂ , Ci-C ₈ alkyl, Q-C ₈ alkenyl, C ₂ ~C _S aikynyi, C Cg haioalkyl, C ₂ -Cg haloaikenyl or C ₂ -Cg haloalkynyi;

R ⁸ and R ⁵² are each independently Q-Cg alkyl, C ₂ -C8 alkenyl, C ₂ -C ₃ aikynyi, Ci-Cg haioalkyl, C ₂ -Cg haloaikenyl or C ₂ ~Cg haloalkynyi;

R' ^y and R'° are each -OH;

R ¹³ is H, Cj-Cg alkyl, C ₂ -C ₈ alkenyl, C ₂ -Cg aikynyi, Ci-Cg haioalkyl, C ₂ -Cg haloaikenyl or C ₂ -C* haloalkynyi;

R' ⁴ and R ⁵⁵ are each independently H, Cj-Cg alkyl, C ₂ -Cg alkenyl, C ₂ -Cg aikynyi C _¾ -C ₈ haioalkyl, C ₂ -Cg haloaikenyl or C ₂ -C ₃ haloalkynyi;

L ³ is an optional linker; and

with the provisos that the compound does not possess the combination of R ¹ and R ⁹ are both CH ₃ , R ² is H, R ⁸ is CH ₂ OH, all of R ³ , R ⁵ , R ⁷ , R ^!0 , R ^{1 1} and R ^{i 2} are OH, and n is 2; or the combination of R ¹ and R ⁹ are both CH ₃ , R ² is H, R ⁵ is NHCH ₃ , R ⁸ is CH ₂ OH, ail of R ³ , R ⁷ , R ⁱ⁰ , R ^H and R ¹² are OH, and n is 2; or the combination of R ⁵ and R ⁹ are both C¾ ₅ R ² is H, R ⁵ is NHBn, R ⁸ is CH ₂ OH, all of R ³ , R ⁷ , R ⁱ⁰ , R ⁿ and R ^{1 2} are OH, and n is 2.

Other embodiments include embodiments (a), (b), (e), and (d) and (e) as follows:

(a) R ⁵ is ΝΙ-Ϊ ₂ , N(CH ₃ ) ₂ , or NRR' where R and R ^f are independently selected from H and C Cg alkyl;

(b) R ⁵ is NHCH ₃ ;

(c) R ^! is Ci-Cg alkyl;

(d) R ^! is CH ₃ or CH ₃ CH ₂ ; and

(e) R ³ is OBz or NHAc, In an embodiment, a composition comprises a compound of formula (I) above, and a pharmaceutically acceptable carrier, diluent or exeipient.

In an embodiment, a method for treating a cancer in an individual, comprises administering to the individual a compound having the formula (I) above, or a composition as described above, in an amount effective to treat the cancer.

In an embodiment, a method for treating a cancer in an individual, comprising administering to the individual (a) a compound having the formula (I) above, or a

composition as described above, and (b) at least one of (i) chemotherapy and (ii)

radiotherapy, in an amount effective to treat the cancer.

In an embodiment, a method for decreasing the likelihood of occurrence of thrombus formation in an individual, comprising administering to the individual a compound having the formula (I) above, or a composition as described above, in an amount effective to decrease the likelihood of occurrence of thrombus formation,

In an embodiment, a method for decreasing inflammation in an individual, comprising administering to the individual a compound having the formula (1) above, or a composition as described above, in an amount effective to decrease inflammation.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a diagram of the synthesis of a compound of formula (I) herein.

DETAILED DESCRIPTION

The present invention in one aspect provides compounds and methods to enhance the oral availability of glycornimetics. The term "giycomimetic" refers to any naturally occurring or non-natural ly occurring carbohydrate compound in which one or more substituents has been replaced, or one or more rings has been modified (e.g. , substitution of carbon for a ring oxygen), to yield a compound that is not fully carbohydrate.

As set forth herein, the oral availability of a giycomimetic may be enhanced by one of several different embodiments. Additionally, each embodiment may be combined in any way, so as to utilize the resultant combination of any two, any three, or all four embodiments.

In an embodiment, oral availability of a giycomimetic is enhanced by increasing its hydrophobicity (i.e., decreasing the polar surface area) and increasing its log D, For example, a hydroxyl group is replaced with hydrogen or an aliphatic carbon chain. A general rule used to approximate whether a compound is sufficiently non-polar to he reasonably likely to be orally active is "Lipinski's Rule" (C.A. Lipinski et al., Adv. Drug Deliv. Review 25:3-25 (1997).

In an embodiment, oral availability of a glyeoraimetic is enhanced by targeting the g!yeomimetic to an active transport system that provides transport across a biological membrane (e.g., lipid bilayer). For example, the bile acid active transport system may be used. An example of a bile acid active transport system is the cholic acid active transport system. Tn an embodiment, cholic acid is covaiently attached to a glycomimetic.

n an embodiment, oral availability of a glycomimetic is enhanced by adding a lipid "tail" to the glycomimetic so as to increase its hydrophobicity for passive transport across a biological membrane (e.g., lipid bilayer), For example, a lipid (or Hpid-iike) aliphatic chain is added to a glycomimetic.

In an embodiment oral availability of a glycomimetic is achieved by enhancing passive transport of the glycomimetic. Passive transport is enhanced by forming a facile amphiphile by covaiently attaching the glycomimetic to a molecule that is passively transported across a biologicai membrane (e.g. , lipid bilayer) when not conjugated (attached) to the glycomimetic. An example of such a facile amphiphile is one that is formed with a glycomimetic and cholic acid (or a derivative thereof). The glycomimetic may be covaiently attached to a passive transport molecule via a linker th t contains a labile bond. The labile bond is cleaved once the conjugate is transported across a biological membrane, or once in the biood system. For example, by use of an activated ester in the linker of the conjugate, an esterase residing in the blood system can cleave the labile bond. Alternatively, the facile amphiphile may be a glycomimetic itself, or a prodrug form of a glycomimetic.

in an embodiment of a compound useful to enhance oral availability, a compound has the formula (I):

(I) or ars isomer, polymorph, prodrug, or solvate thereof, and a pharmaceutically acceptable salt of any of the foregoing, wherein:

n is any single integer from i to 1 1 ;

R ^! is Ci-Cg alkyl, C ₂ -Cg aikenyi, C ₂ -Cg alkynyl, CpC ₈ haloalkyl, C ₂ -Cg haloalkenyl or C ₂ -C ₈ ha!oalkynyi;

R ² is H, -L ^J -Ci-C ₈ alkyl, -L ¹ -C ₂ -C ₈ a!kenyi, -L ^l -C ₂ -C$ alkynyl, -L ^] -C,-C ₈ haloalkyl, ~L ^] -C ₂ -C _S haloalkenyl, -L ¹ -C ₂ -C ₈ haloalkyny! or ~L ^! -M;

R ³ is -OH, Ci-Cs alkoxy, CpC ₈ cycloalkylalkoxy, -OC(-0)CpC« alkyl, -OC(=0)C ₃ -C ₆ cycloalkyl, -0C(=O)aryl, -NHC(=0)aryl, or -NHC(=0)R ¹² ;

R ⁴ is -OR ¹³ , -NHOR ¹⁴ , -NHN(R ¹⁴ )(R ^!5 ), -NHS0 ₂ R ¹² , -NHS0 ₂ aryl, heteroaryl, -NH-heterocyclyL -NH-heteroary!, or -N(R ⁱ )(R ^{f 5} );

R ⁵ is -OH, Ci-Cg hydroxy alkyl, CpCg hydroxyalkenyl, Cj-Cg hydroxyalkynyl or C3-C5 cycloalkyl;

& and R ^{1 1} are each independently -OH, -Nl¾, halo, CpCg alkyl, C ₂ -Cg aikenyi, Oy-Cs alkynyl, Ci-Cg haloalkyl, C ₂ -Cg haloalkenyl or C ₂ -Cg haSoalkynyl;

R ⁷ is -CH ₂ OH, ~CH ₂ N1¾ ₅ Ci-Cg alkyl, C ₂ -C _G aikenyi, C ₂ ~C _¾ alkynyl, CpCg haloalkyl, C ₂ -Cg haloalkenyl or CT-CS haioalkynyi;

R ^S and R ⁵² are each independently Cj-Cg alkyl, C ₂ -Cg aikenyi, C ₂ -Cg alkynyl, CpCg haloalkyl, C ₂ -Cs haloalkenyl or C ₂ -Cg haioalkynyi;

R ⁹ and R ^{! 0} are each -OH;

R ³³ is H, CpCg alkyl, C ₂ -C ₈ aikenyi, C ₂ -Cg alkynyl, C _r C ₈ haloalkyl, C ₂ -C ₈ haloalkenyl or C ₂ -C _S haioalkynyi;

R ¹⁴ and R ^{I S} are each independently H, Ci-Cg alkyl, C ₂ -Cg aikenyi, C ₂ -C ₈ alkynyl, C Cg haloalkyl, C ₂ -Cg haloalkenyl or C ₂ -C ₈ haioalkynyi;

L ⁵ is an optional linker; and

with the provisos that the compound does not possess the combination of R ¹ and R* are both CH.3, R ² is H, R ⁸ is CH ₂ OH, all of R ³ , R ⁵ , R ⁷ , R ¹⁰ , R ^U and R ¹² are OH, and n is 2; or the combination of R ^S and R ⁹ are both CH _3> R ² Is H, R ⁵ is NHCH3, R ⁸ is CH ₂ OH, all of R ³ , R ⁷ , R/ , R ¹¹ and R ¹² are OH, and n is 2; or the combination of R ^! and R ⁹ are both CH _? „ R ² is H, R ^s is HBn, R ⁸ is C¾OH, ail of R ³ , R ⁷ , R ¹⁰ , R ^{1 1} and R ¹² are OH, and n is 2. In an embodiment, the compound has the formula;

Compounds of formula (I) include ail isomers, physiologically acceptable salts (i.e., pharmaceutically acceptable salts), hydrates, solvates, polymorphs, metabolites and prodrugs of any. Examples of isomers are stereoisomers (e.g., enantiomers and race-mates) and tautomers.

Also provided herein are pharmaceutical compositions that comprise one or more of the compounds of formula (I), substructures and specific structures thereof, and a pharmaceutically acceptable excipient. A compound of formula (I) or a pharmaceutical composition comprising the compound may be used in one or more therapeutic methods in need of a therapeutic agent with increased oral availability. A number of therapeutic agents used in treatment, for example of cancer or inflammation, can be administered only intravenously.

In an embodiment, a method is provided for treating a cancer in an individual by administering a compound of formula (Ϊ), or a composition comprising the compound, to the individual. The compound (or composition comprising the compound) may be administered in conjunction with (i.e., as an adjunct therapy, which is also called adjunctive therapy) with chemotherapy or radiation or both. The chemotherapy or radiation therapy or combination of both may be referred to as the primary anti-tumor or anti-cancer therapy that is being administered to the individual to treat the particular cancer. A giyeomimetie compound of formula (1), or a composition comprising the compound, may be used for treating any one or more of the diseases or conditions described herein, or for the preparation or manufacture of a medicament for use in treating any one or more of the diseases or conditions described herein. Each of these methods and uses are described in greater detail herein. Definitions

The terms below, as used herein, have the following meanings, unless indicated otherwise, Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group, A chemical group recited herein may be referred to by an abbreviation that is customary in the art. Examples of such an abbreviation are "Ac" for acetyl, "Ph" for phenyl, "Bn" for benzyl, and "Bz." for benzoyl.

As used herein, "n is any single integer from 1 to 11" means that "n" can be 1 ,

2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, as well as any range of these numbers, for example, n is 1-2, l-

3, 1-4, etc.

As used herein, a "Cj-Cs alkanyl" refers to an aikane substituent with one to eight carbon atoms and may be straight chain, branched, or cyclic (e.g., cycloalkanyi).

Examples are methyl ("Me"), ethyl ("Et"), prop l, isopropyl, butyl and t— butyl. A "Ci-Cg halo alkanyl" refers to a Cr-Cg alkanyl substituted with at least one halogen (halo), When more than one halogen is present, the halogens present may be the same or different or both (if at least three present). A "C ₂ -C8 aikenyl" refers to an alkene substituent with two to eight carbon atoms, at least one carbon-carbon double bond, and may be straight chain, branched or cyclic (c-ycloalkenyl). Examples are similar to "Cr-Cg alkanyl" examples except the aikenyl has at least one carbon-carbon double bond. A "Ci-Cs haloalkenyl" refers to a C ₂ - Cg aikenyl substituted with at least one halogen (halo). When more than one halogen is present, the halogens present may be the same or different or both (if at ieast three present). A "C -Cg alkynyi" refers to an alkyne substituent with two to eight carbon atoms, at ieast one carbon-carbon triple bond, and may be straight chain, branched, or cyclic (e.g.,

cyeloaikynyl). Examples are similar to Cj-Cs alkanyl examples except the alkanyl has at least one carbon-carbon triple bond, A "Cj-Cs haloalkynyi" refers to a "C ₂ -Q alkynyl" substituted with at least one halogen (halo), When more than one halogen is present, the halogens present may be the same or different or both (if at least three present).

"Halo" (or "halogen" or "haiide") is fluoro (F), chloro (CI), bromo (Br), or iodo (I) radical,

"Ary!" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryi radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, aryi radicals derived from the hydrocarbon ring systems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, os-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenyiene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

"Aralkyl" refers to a radical of the formula -R _b -Rc where R _b is an alkylene chain as defined above and R _c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl, trityl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

"Heierocyclyl" "heterocycle" or "heterocyclic ring" refers to a stable 3- to 24-membered non-aromatic ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoras selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, the heterocyclyl radical is a 5-10 membered heterocycle that comprises 3-9 carbon atoms and from 1-3 heteroatoms. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; nitrogen, carbon or sulfur atom(s) in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated, Examples of such heterocyclyl radicals include dioxolanyl, thienyi[ l,3]dithianyL

decahydroisoquinolyl, imidazolmyi, irmdazolidinyi, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyi, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4~piperidonyl ₃ pyrrolidinyl, pyrazolidinyl, quinuclidiny!, thiazoiidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorphoiinyi, l-oxo-ihiomorpho!inyl, Ι, ί -dioxo-thiomorpholinyl, 12- crown-4, 15-crown-5, 18-crown-6, 21-crown~7„ aza-18-crown-6, diaza-18-crown-6, aza-21- crown-7, and diaza-21-crown-7. Unless stated otherwise specifically in the specification, a heterocyclyl group may be optionally substituted.

"Heterocyclylaikyl" refers to a radical of the formula -R _b -Rc where R¾ is an alkylene chain as defined above and R _c is one or more heterocyclyl radicals as defined above, for example, tetrahydrofurany!-methyl, tetrahydropyranyl-raethyl and the like. A 6- membered heterocyclylaikyl refers to a heterocyclylaikyl, wherein the heterocyclyl moiety has 6 atoms in the ring. Unless stated otherwise specifically in the specification, a heterocycialkyl group may he optionally substituted. "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. In certain embodiments, the heteroaryl radical is a 5-10 membered heteroaryl that comprises 3-9 carbon atoms and from 1 -3 heteroatoms. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyciic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyi, benzodioxolyl,

benzofuranyi, benzooxazolyl, benzothiazolyl benzothiadiazolyl, benzo[6][l ,4]dioxepinyl, 1 ,4-benzodioxanyI, benzonaphthofuranyl, benzoxazoiyl, benzodioxolyl, benzodioxinyl, benzopyranyl, henzopyranonyl, benzofuranyi, benzofuranonyl, benzothienyl

(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyi, carbazoiyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyi, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindo!yl, indolinyl, isoindolinyi, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazoiyl, 2-oxoazepinyl, oxazoly!, oxiranyl, 1 -oxidopyridinyl, i-oxidopyrimidinyl, 1-oxidopyrazinyl, i-oxidopyridazinyi, 1 -phenyl-IH-pyrrolyl.

phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyi, purinyi, pyrroiyl, pyrazolyl, pyridmyi, pyrazinyi, pyrimidinyi. pyridazinyi, quinazolinyl, quinoxalinyl, quinoiinyl, quinuciidinyl, isoquinolinyi. tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyi). Unless stated otherwise specifically in the specification, a heteroaryl group ma be optionally substituted.

"Heteroaryialkyl" refers to a radical of the formula -R _b -R _c where ¾ is an aikylcne chain as defined above and R _c is one or more heteroaryl radicals as defined above, for example, furanyl-methyi, pyridyi-methy! and the like. A 6-membered heteroarylaikyl refers to a heteroarylaikyl, wherein the heteroaryl moiety has 6 atoms in the ring. Unless stated otherwise specifically in the specification, a heteroarylaikyl group may be optionally substituted.

The compounds described herein may generally be used as the free acid or free base. Alternatively, the compounds may be used in a salt, for example, an acid or base addition salt. Acid addition salts of the free base amino compounds may be prepared according to methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic. methanesulfontc, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelie, cinnamic, aspartic, stearic, palmitic, glycol ic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobroniic, sulfuric, phosphoric, and nitric acids. Base addition saits of the free acid compounds of the compounds described herein may also be prepared by methods well known in the art, and may be formed from organic and inorganic bases. Suitable inorganic bases included the hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and organic bases such as substituted ammonium salts. Thus, the term "pharmaceutically acceptable salt" (or physiologically suitable salt) of compounds of formula (I) and substructures thereof, as well as any and all substructures and specific compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.

A compound of formula (I), substructures thereof and specific structures thereof, may sometimes be depicted as an anionic species. One of ordinary skill in the art will recognize that the compound exists with an equimoiar ratio of cation. For instance, the compounds described herein can exist in the fully protonated form, or in the form of a salt such as sodium, potassium, ammonium or in combination with any inorganic base as described above. When more than one anionic species is depicted, each anionic species may independently exist as either the protonated species or as the salt species. In some specific embodiments, the compounds described herein exist as the sodium salt.

Furthermore, some of the crystalline forms of any compound described herein may exist as polymorphs, which are also included and contemplated by the present disclosure. In addition, some of the compounds may form solvates with water or other solvents. Such solvates are similarly included within the scope of compounds and compositions described herein.

With regard to the term "isomer" as used herein, a compound of formula (I) as well as any substructure or specific structure described herein, may have one or more ehJral (or asymmetric) centers, and may thus give rise to stereoisomers including enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( ?)- or (S)~. When a compound described herein contains an olefinie double bond(s) or another center of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers (e.g., cis or trans). Likewise, unless otherwise specified, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. It is therefore contemplated that various stereoisomers and mixtures thereof include "enantiomers," which refers to two stereoisomers whose molecules are nonsuperiraposeable mirror images of one another. Thus, a compound of formula (Ϊ) may occur in any isomeric form, including racemates, racemic mixtures, and as individual enantiomers or diastereomers. A tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule,

"Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a metabolic precursor of a compound described herein that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound as described herein. Prodrugs are typically rapidly transformed in vivo to yield the parent compound described herein, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in SHiguchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound as described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein may be prepared by modifying a functional group(s) present in the compound described herein in such a way that the modification(s) is cleaved, either in routine manipulation or in vivo, to yield a parent compound described herein as a compound of formula (I). Prodrugs include a compound described herein wherein, for example, a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound is administered to a mammalian subject, it is cleaved to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include an ester or amide derivative of hydroxy, carboxy, mercapto or amino functional groups in a compound described herein and the like. Compound Synthesis Procedures

Synthesis of a compound of formula (1), a substructure, and a specific compound thereof may be performed as described herein, including the disclosure within Example 1 , using techniques familiar to a person skilled in the art, A synthesis scheme for preparing an exemplary compound of formula (I) is described in Example 1. The methods may be used for synthesis of a compound of formula (I) by using appropriate reactants for preparation of the specific compound using the techniques and methods described herein, and that are routinely practiced in the art or available in the technical literature. By way of further example, Figure 1 provides a schematic of a synthesis scheme for an exemplary compound disclosed herein.

Specific and analogous reactants may also be identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known, but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply- houses (e.g., those listed herein) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is P. H. Stahi & C. G. Wermuth "Handbook of Pharmaceutical Salts," Veriag Helvetica Chimica Acta, Zurich, 2002.

In general, the compounds used in the reactions described herein may be made according to organic synthesis techniques known to one of ordinary skill in this art, starting from one or more commercially available chemicals or from one or more compounds described in the chemical literature, "Commercially available chemicals" may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich

Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chems rvice Inc. (West Chester PA). Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher

Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co, (Rockford IL), Riede! de Haen AG (Hanover, Germany), Spectrum Quality Product, inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockvilie MD), and Wako Chemicals USA, Inc. (Richmond VA).

Methods known to one of ordinary skill in the art may be identified through various reference hooks, articles and databases. Suitable reference books and treatise that detail the synthesis of reaetants useful in the preparation of compounds of the present disclosure, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S. R. Sandler et ah, "Organic Functionai Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A, Benjamin, Inc. Mcnlo Park, Calif. 1972: T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiiey-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reaetants useful in the preparation of compounds of the present disclosure, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471 -29031 -4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471 -60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functionai Groups" (1992) Interscience ISBN: 0-471 -93022-9; Quin, L.D. et al. "A Guide to Organophosphorus Chemistry" (2000) Wiiey-Interscience, ISBN: 0-471-31824- 8: Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471 -19095-0; Stoweil, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiiey- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ulimann's Encyclopedia" ( 1999) John Wiley & Sons, ISBN: 3-527-29645- X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

A kit with a unit dose of one or more of the compounds of formula (I), or a composition containing at least one such compound, are provided for oral administration. Such a kit may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the therapeutic in treating the pathological condition of interest, and optionally an appliance or device for delivery of the composition,

EJCAMPLES EXAMPLE 1

SYNTHESIS OF A COMPOUND OF FORMULA (1)

Synthesis of 2 ^ND compound: 2-Aminogalactose is suspended in a mixture of toluene and saturated aqueous sodium bicarbonate, Benzyloxycarbonyl chloride is added and the mixture is stirred vigorously for 3 hours at room temperature. The reaction mixture is transferred to a separatory funnel and the phases are separated. The organic phase is dried over sodium sulfate, filtered, and concentrated. The residue is dissolved in pyridine. Acetic anhydride is added and the reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 2 times with saturated aqueous sodium bicarbonate and 2 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford the desired compound.

Synthesis of the 3 ^RD compound: The above product is dissolved in DMF and hydrazine hydrate is added. The reaction mixture is stirred overnight at room temperature. The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 3 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford the anomeric hydroxy! as a mixture of anomers.

This mixture is dissolved in dichioromethane at room temperature.

Trichloroacetonitrile is added followed by powdered potassium carbonate. The reaction mixture is stirred 5 hours at room temperature then filtered and concentrated. The mixture is separated by column chromatography to afford the trichloroacetimidate as a mixture of anomers.

This mixture is dissolved in dichioromethane and cooled on an ice bath. Ethyl sulfide is added followed by BF3 ^' OEt ₂ . The reaction mixture is stirred 3 hours on the ice bath then quenched by addition of saturated aqueous sodium bicarbonate. The reaction mixture is transferred to a separatory funnel and the phases separated. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column

chromatography to afford the anomeric ethyl sulfide as the β anomer,

The sulfide is dissolved in methanol at room temperature. A solution of 25% sodium methoxide in methanol is added and the reaction mixture stirred overnight. The solvent is removed and the product filtered through silica to afford the triol.

This material is dissolved in dry pyridine and treated with trityl chloride. The reaction mixture is stirred at room temperature for 2 days then diluted with ethyl acetate and transferred to a separator)' funnel and washed 3 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford the 3 ^rd compound.

Synthesis rf the 4 ^t! ' compound: The above compound is dissolved in methanol, treated with dibutyltin oxide, and refluxed for 4 hours. The solvent is removed and the residue rotovapped 3 times from toluene. The residue is dissolved in DMF and treated with 4-benzyloxy-2-trifluoromethanesulfonyloxy-butyric acid dimethyl amide and cesium fluoride. The reaction mixture is stirred overnight at room temperature, The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 3 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is dissolved in pyridine and treated with acetic anhydride and stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 3 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford 4 ^th compound.

Synthesis of the 5' ^h compound : The above compound is combined with the fucosylcyclohexyl alcohol in dichioromethane and cooled on an ice bath. Tert- butyldimethylsilyl in flate is added and the reaction mixture is stirred tor 3 hours. The reaction mixture is transferred to a separatory funnel and washed 2 times with saturated aqueous sodium bicarbonate and 2 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford the desired compound.

Synthesis of the final compound: The above compound is dissolved in ethyl acetate in a Paar bottle and palladium on carbon is added, The reaction mixture is hydrogenated on a Paar apparatus at SOpsi hydrogen pressure until hydrogen uptake ceases. The reaction mixture is filtered through Celite and concentrated. The residue is dissolved in pyridine and treated with acetic anhydride. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, transferred to a separatory funnel and washed 3 times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is separated by column chromatography to afford peracetylated material

This material is dissolved in methanol at room temperature. A solution of 25% sodium methoxide in methanol is added and the reaction mixture stirred overnight. The solvent is removed and the product filtered through silica to afford the desired product (the last compound structure depicted above).

EXAMPLE 2

E-SELECTIN ACTIVITY - BINDING ASSAY

The inhibition assay to screen a glycomimetic antagonist of E-seiectin is a competitive binding assay, which allows the determination of IC ₅₀ values. E-selectin/Ig chimera is immobilized in 96 well microliter plates by incubation at 37°C for 2 hours. To reduce nonspecific binding, bovine serum albumin is added to each well and incubated at room temperature for 2 hours. The plate is washed and serial dilutions of the test compounds are added to the wells in the presence of conjugates of biotinylated, sLe ^a polyaerylamide with streptavidin/horseradish peroxidase and incubated for 2 hours at room temperature.

To determine the amount of sLe ^a bound to immobilized E-selectin after washing, the peroxidase substrate, 3,3\5,5' tetramethylbenzidine (TMB) is added. After 3 minutes, the enzyme reaction is stopped by the addition of H ₃ PO ₄ . and the absorbance of light at a wavelength of 450 nm is determined. The concentration of test compound required to inhibit binding by 50% is determined and reported as the IC50 value.

In addition to reporting the absolute [C50 value as measured above, relative IC50 values are determined by a ratio of the IC50 measured for the test compound to that of an internal control (reference) stated for each assay,

The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent

applications, non-U. S, patents, non-U. S. patent applications, and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.