Novel lipid-based small molecule integrin receptor-ligand agonist adjuvant carrier compositions, integrin agonist adjuvant pharmaceutical compositions thereof, and methods of making and using same

Abstract

Pharmaceutical compositions comprise a drug carrier system of a small molecule drug, such as one or more small molecule integrin agonist adjuvants, having low water solubility in a substantially non-aqueous carrier composition comprising at least one phospholipid, at least one neutral lipid, and at least one pharmaceutically acceptable solubilizer. When mixed with an aqueous phase, the drug carrier system typically forms a non-gelled, substantially non-transparent liquid dispersion. The composition is suitable for administration to a subject in need thereof by a suitable route (e.g., oral administration).

Description

[0001] Inventor: Upendra K. Marathi

[0002] Assignee: 7 HILLS PHARMA LLC

[0003] Related Applications

[0004] This application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 348,852 filed on 06 / 03 / 2022 (June 3, 2022) and U.S. Provisional Patent Application Serial No. 63 / 337,960 filed on 05 / 03 / 2022 (May 3, 2022).

[0005] U.S. patent applications and patents are incorporated by reference via the concluding paragraphs: U.S. patent application serial number 14 / 621,112 filed on 2 / 12 / 2015; U.S. patent application serial number 14 / 754,931 filed on 6 / 30 / 2015; U.S. patent application serial number 16 / 516,978 filed on 7 / 19 / 2019; and U.S. patent application serial number 17 / 471,922 filed on 9 / 10 / 2021; U.S. published application number 20150250883; U.S. published application number 20160000 755; U.S. Published Application No. 20160000755; and U.S. Published Application No. 20200054600; and U.S. Patent No. 10342866 published on 7 / 9 / 2019; U.S. Patent No. 10,709,781 published on 7 / 13 / 2020; U.S. Patent No. 10,716,849 published on 7 / 20 / 2020; U.S. Patent No. 10,709,780 published on 7 / 13 / 2020, and U.S. Patent No. 11,311,619 published on 4 / 26 / 2022. Background Art 1. Technical Field

[0007] Embodiments of the present invention relate to carrier compositions for poorly water-soluble pharmaceutical agents, poorly water-soluble pharmaceutical agent compositions derived therefrom, and methods of making and using the same.

[0008] More particularly, embodiments of the present invention relate to carrier compositions for water-poorly soluble small molecule integrin agonist adjuvant pharmaceutical agents, their water-poorly soluble small molecule integrin agonist adjuvant pharmaceutical agent compositions, and methods of preparing and using them, wherein the integrin agonist adjuvant carrier composition comprises one or more zwitterionic surfactants, one or more nonionic surfactants, one or more neutral lipids, and one or more polar organic co-solvents or solubilizers.

[0009] 2. Description of related fields

[0010] Integrin agonists are agents that increase integrin activation and promote interactions between cells with integrins and cells with integrin-associated ligands. These interactions have been found to be important in many pharmaceutical applications.

[0011] Although a large number of drug carriers are known in the art, there is still a need in the art for carrier compositions for improving the oral bioavailability of integrin agonists for enhancing vaccine efficacy, antigen presentation efficacy, immune response efficacy and other treatments involving integrin activation. SUMMARY OF THE INVENTION

[0013] The embodiment of the present disclosure provides a carrier composition for applying a water-insoluble pharmaceutical agent in the form of a lipid-based delivery system, wherein the carrier composition comprises one or more zwitterionic surfactants such as one or more phospholipids, one or more neutral lipids and one or more cosolvents or solubilizing agents. The lipid-based delivery system can be used to prepare an oral water-insoluble pharmaceutical agent solution, which can be encapsulated or filled in a soft gel capsule or a hard gel capsule, and when mixed with water, a non-gelled substantially opaque liquid dispersion or emulsion is usually formed. In a specific embodiment, one or more neutral lipids comprise a neutral lipid or a phospholipid containing a fatty acid group (i.e., >C 14) with more than 14 carbon atoms. 14 Fatty acids), which are believed to enhance the distribution of the composition into the lymphatic circulation and reduce the extent of gastrointestinal mucosal and liver CYP450 enzymes. Thus, lipid-based drug delivery systems will increase the solubility and oral bioavailability of poorly soluble integrin agonists with LogP values ​​greater than 5 (i.e., LogP>5).

[0014] Embodiments of the present disclosure provide integrin agonist vector compositions comprising one or more zwitterionic surfactants, one or more neutral lipids, and one or more organic solvents.

[0015] Embodiments of the present disclosure provide integrin agonist pharmaceutical compositions comprising an integrin agonist carrier composition and an effective amount of one or more integrin agonists capable of enhancing cell-to-cell interactions between cells with surface integrins and cells with surface-associated ligands. In specific embodiments, the surface integrins targeted by these agonists include, but are not limited to, α4β1, α4β7, α5β1, αLβ2, and / or αVβ3, promoting interactions with ligands including, but not limited to, VCAM-1, fibronectin, MAdCAM-1, ICAM-1, ICAM-2, and / or vitronectin. In specific embodiments, the integrin agonist is a small molecule integrin agonist having a molecular weight of about 300 g / mole to about 2000 g / mole, about 300 g / mole to 1,500 g / mole, or about 300 g / mole to 1,000 g / mole. In other embodiments, the integrin agonist contains a linker comprising at least one protonatable group, at least one aromatic or non-aromatic cyclic ring, at least one aromatic or non-aromatic heterocyclic group, at least one alkylene group (i.e., -C n H 2n - group, n = 1 to about 10), at least one oxyalkylene group (ie, -C n H 2n OC m H 2m -, n and m = 1 to about 10) or any combination of these linkers. In other embodiments, the terminal group comprises an aryl group, an aromatic or non-aromatic heterocyclic group, an alkaryl group, an alkyl-substituted aromatic or non-aromatic heteroaryl group, or any combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The present disclosure may be better understood with reference to the following detailed description and the accompanying illustrative drawings, wherein like elements are numbered alike:

[0018] Definitions used in this invention

[0019] In addition to their customary and ordinary meanings, the following definitions apply where the context permits in the specification and claims:

[0020] The term "integrin agonist pharmaceutical composition" refers to one or more integrin agonists contained in the integrin agonist vector composition of the present disclosure, which is used for administration to a mammal as a pharmaceutical.

[0021] The term "cell-based therapy" refers to a pharmaceutical composition comprising one or more cell types, one or more integrin agonists, or other chemical substances or agents for administration as a pharmaceutical to a mammal.

[0022] The term "therapeutically effective amount" refers to the amount of the administered agent that will alleviate, at least to some extent, one or more symptoms of the disorder being treated. For example, an amount of the compound that is effective to prevent, alleviate or ameliorate disease symptoms or prolong the survival of the subject being treated.

[0023] With respect to a disease or condition, the term "treat" or "treatment" means to prevent, protect against the occurrence of the disease or condition, arrest, reverse or alleviate the symptoms or side effects of the disease or condition, and / or prolong the survival of the subject being treated.

[0024] As used herein, the term "alkyl" alone or in combination refers to a C1-C 12 A straight or branched, substituted or unsubstituted saturated chain radical derived from a saturated hydrocarbon by removing one hydrogen atom. Representative examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0025] The term "alkenyl", alone or in combination, refers to a substituted or unsubstituted straight chain alkenyl group or a substituted or unsubstituted branched chain alkenyl group containing 2 to 10 carbon atoms. Examples of such groups include, but are not limited to, vinyl, E- and Z-pentenyl, decenyl, and the like.

[0026] The term "alkynyl", alone or in combination, refers to a substituted or unsubstituted straight chain alkynyl group or a substituted or unsubstituted branched chain alkynyl group containing 2 to 10 carbon atoms. Examples of such groups include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl, etc.

[0027] The term "lower" modifying "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a C1-C6 unit for a particular functional group. For example, lower alkyl means a C1-C6 alkyl.

[0028] The term "cycloalkyl" as used herein alone or in combination refers to a substituted or unsubstituted aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl and adamantyl, etc. Cycloalkyl can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxyl, halogen, sulfhydryl, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl and carboxamide. The term is meant to cover cycloalkenyl and cycloalkynyl. "Cycloalkyl" includes cis or trans forms. In addition, the substituent can be in an inner position or an outer position in a bridged bicyclic system.

[0029] As used herein, the term "cycloalkenyl" alone or in combination refers to a cyclic carbocyclic ring containing 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

[0030] The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group attached to a lower alkyl group, including but not limited to cyclohexylmethyl.

[0031] As used herein, the term "halo" or "halogen" refers to I, Br, Cl or F.

[0032] The term "haloalkyl" as used herein refers to a lower alkyl group to which is attached at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl, pentafluoroethyl and the like.

[0033] The term "alkoxy", alone or in combination, refers to an alkyl ether group, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0034] The term "alkenyloxy", alone or in combination, refers to a group of the formula alkenyl-O-, with the proviso that the group is not an enol ether, wherein the term "alkenyl" is as defined above. Examples of suitable alkenyloxy groups include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenyloxy, and the like.

[0035] The term "alkynyloxy", alone or in combination, refers to a radical of the formula alkynyl-O-, with the proviso that the radical is not -alkynol ether. Examples of suitable alkynyloxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy, and the like.

[0036] The term "carboxyl" as used herein refers to -CO2H.

[0037] The term "thioalkoxy" refers to a thioether group of the formula alkyl-S-, wherein "alkyl" is as defined above.

[0038] As used herein, the term "carboxaldehyde" refers to -C(O)R, wherein R is hydrogen.

[0039] As used herein, the term "carboxamide" refers to -C(O)NR2, wherein R is hydrogen, alkyl or any other suitable substituent.

[0040] As used herein, the term "alkoxyalkoxy" refers to R b OR c O-, where R b is lower alkyl as defined above, and R c is an alkylene group, wherein the alkylene group is -(CH2) n' -, wherein n' is an integer from 1 to 6. Representative examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, tert-butoxymethoxy and the like.

[0041] As used herein, the term "alkylamino" refers to d NH-, where R d It is a lower alkyl group, such as ethylamino, butylamino and the like.

[0042] The term "alkenylamino", alone or in combination, refers to a radical of the formula alkenyl-NH-- or (alkenyl)2N-, wherein the term "alkenyl" is as defined above, with the proviso that the radical is not an enamine. An example of such an alkenylamino radical is an allylamino radical.

[0043] The term "alkynylamino", alone or in combination, refers to a radical of the formula alkynyl-NH-- or (alkynyl)2-, wherein the term "alkynyl" is as defined above, with the proviso that the radical is not an amine. An example of such an alkynylamino radical is a propargylamino radical.

[0044] As used herein, the term "dialkylamino" refers to e R f N-, where R e and R f Independently selected from lower alkyl groups, such as diethylamino and methylpropylamino, and the like.

[0045] As used herein, the term "amino" refers to H2N-.

[0046] The term "alkoxycarbonyl" as used herein refers to an alkoxy group as defined above attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.

[0047]

[0013] The term "aryl" or "aromatic" as used herein, alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms, such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furanyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, dihydroindolyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]phenylthio, 1H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl, and the like. "Arylalkyl" and "alkylaryl" use the term "alkyl" as defined above. The ring may be substituted. The aromatic ring may be a fused ring system including other aromatic rings or non-aromatic rings to form a multicyclic ring, and is also included in the term "aromatic" as used herein.

[0048] The term "aralkyl", alone or in combination, refers to an alkyl group substituted with an aryl group, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl groups include, but are not limited to, phenylmethyl, phenylethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, thienylpropyl, and the like.

[0049] The term "aralkenyl", alone or in combination, refers to an aryl substituted alkenyl group, wherein the terms "aryl" and "alkenyl" are as defined above.

[0050] The term "arylamino", alone or in combination, refers to a radical of the formula aryl-NRg-, wherein "aryl" is as defined above. Rg can be selected from the group consisting of H, lower alkyl, aryl and aralkyl, etc. Examples of arylamino radicals include, but are not limited to, phenylamino (anilido), naphthylamino, 2-pyridylamino, 3-pyridylamino and 4-pyridylamino, etc.

[0051] The term "biaryl", alone or in combination, refers to a radical of the formula aryl-aryl, wherein the term "aryl" is as defined above.

[0052] The term "thioaryl", alone or in combination, refers to a radical of the formula aryl-S-- wherein the term "aryl" is as defined above. An example of a thioaryl radical is a phenylthio radical.

[0053] The term "aroyl", alone or in combination, refers to a radical of the formula aryl-CO--, wherein the term "aryl" is as defined above. Examples of suitable aromatic acyl groups include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl, and the like.

[0054] The term "heterocyclyl", alone or in combination, refers to a non-aromatic 3 to 10 membered ring containing at least one endocyclic N, O or S atom. The heterocycle may optionally be aryl-fused. The heterocycle may also optionally be substituted with at least one substituent independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, alkoxycarbonyl, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl, etc.

[0055] The term "alkylheterocyclyl" as used herein refers to an alkyl group, as defined above, attached to the parent molecular moiety through a heterocyclyl group.

[0056] The term "heterocyclylalkyl" as used herein, refers to a heterocyclyl group as defined above attached to the parent molecular moiety through an alkyl group.

[0057] As used herein, the term "aminal" refers to a hemiacetal having the structure RCH(NH2)(OH).

[0058] The term "electron-withdrawing" or "electron-donating" refers to the ability of a substituent to withdraw or donate electrons relative to hydrogen if hydrogen occupies the same position in a molecule. Those skilled in the art fully understand these terms, and they have the meaning described in J. March's Advanced Organic Chemistry, 1985, pp. 16-18 (incorporated herein by reference). Electron-withdrawing groups include halogen, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl and aryl lower alkanoyl, etc. Electron-donating groups include groups such as hydroxyl, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, sulfhydryl, lower alkylthio, lower alkylthio and disulfide. Those skilled in the art will appreciate that substituents can have electron-donating or electron-withdrawing properties under different chemical conditions. In addition, the present invention contemplates any combination of substituents selected from the above-mentioned determined groups.

[0059] The most preferred electron donating or electron withdrawing substituents are halogen, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine, lower alkylthio, mercaptoalkyl, alkylthio and alkyldisulfide.

[0060] The use of the above-mentioned terms means to cover replacement and unsubstituted parts.Replacement can be by one or more groups, such as alcohol, ether, ester, amide, sulfone, sulfide, hydroxyl, nitro, cyano, carboxyl, amine, heteroatoms, low alkyl, low alkoxy, low alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, alkoxycarbonyl (carboalkoxy), carboxylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical, alkylheterocyclic radical, heterocyclic radicalalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl, or any substituent in the aforementioned paragraph, or any substituent directly or by any of those substituents attached by suitable joints.Joints are typically short chains of 1-3 atoms, including-C-,-C (O)-,-NH-,-S-,-S (O)-,-O-,-C (O) O- or-S (O) O- in any combination. The ring may be substituted.

[0061] The term "mammal" includes humans and other animals.

[0062] The term "heteroatom" as used herein encompasses nitrogen, sulfur and oxygen.

[0063] The term "α (alpha)" as used herein refers to a position immediately adjacent to a stated position.

[0064] The term "LogP" means the ratio of the concentrations of a substance in two heterogeneous phases in equilibrium with each other. Typically, the organic solvent is n-octanol, but n-hexane; toluene; chlorobenzene; methylene chloride; methyl tert-butyl ether; isopropyl acetate; benzyl alcohol; cyclohexanol; or n-butanol may also be used.

[0065] As used herein, the term "inactive ingredient" means an innocuous drug that may be used as an inactive ingredient (such as a colorant, emulsifier, excipient, flavoring agent, lubricant, preservative, or solvent) in the preparation of another drug and is exempt from section 502(f)(1) of the act (21 CFR 201.117).

[0066] The term "gelatin" means a collection of peptides and proteins produced by partial hydrolysis of collagen extracted from the skin, bones and connective tissue of animals such as livestock cattle, chickens, pigs and fish. During the hydrolysis process, some bonds between and within the protein components are broken. In many ways, its chemical composition is very similar to its parent collagen. Photographic and pharmaceutical grade gelatin are derived from cattle bones and pig skin. Gelatin is classified as a hydrogel.

[0067] As used herein, the term "excipient" or "adjuvant" means any substance, other than an active drug or product, that has been appropriately evaluated for safety and is included in a drug delivery system to aid in the processing of the drug delivery system during its manufacture; to protect, support or enhance stability, bioavailability or patient acceptability; to assist in product identification; or any other attribute that enhances the overall safety and effectiveness of the drug delivery system during storage or use (40 CFR 63.1251).

[0068] The term "effector cell" as used herein means a cell that has been activated by its cognate tumor antigen and participates in the elimination of cancer cells. Effector cell types may include: 1) Tumor infiltrating lymphocytes (TILs) are lymphocytes isolated from tumors and expanded in vitro, which have cell surface markers (including but not limited to CD8 or CD4); 2) T cell clones reactive to one or more tumor antigens, which have cell surface markers (including but not limited to CD8 or CD4); 3) T cells genetically engineered with tumor-specific T cell receptors or chimeric antigen receptors, which have cell surface markers (including but not limited to CD8 or CD4); 4) Natural killer cells reactive to specific or multiple tumor antigens.

[0069] The term "adoptive T cells" refers to effector cells derived from naive T cells or activated T cells with effector function.

[0070] The term "solid tumor" as used herein means an abnormal mass of tissue that does not usually contain cysts or fluid areas. Solid tumors can be benign (non-cancer), or malignant (cancer). Solid tumors are named after the cell types present in the solid tumor. Examples of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas.

[0071] The term "small molecule agonist" as used herein is not a conventional ligand, but is synonymous with a stabilizer of a cognate ligand-receptor interaction.

[0072] The term "linker" means a part that connects two parts of a molecular system together. In the present disclosure, a linker is a molecular part that is connected to the terminal group of a small molecule integrin agonist, for example, terminal group 1-linker-terminal group 2. In the integrin agonist of formula (I), the linker is connected to the terminal group of the small molecule integrin agonist through -M 3 -M 4 -M 5 -M 6 - defined, and the terminal group 1 is connected by R 1 -M 1 -N(R 2 )-M 2 - defined, and the terminal group 2 is defined by -R 3 Definition. In the integrin agonist of formula (II), the linker is connected by -R a -ZR b - defined, and the terminal group 1 is connected by Q 1 - defined, and the terminal group 2 is defined by -Q 2 definition.

[0073] The terms "at least one", "one or more" or "one or more" mean one or two or more, and the three terms can be used interchangeably herein. For example, at least one device, one or more devices, or one or more devices means one device or two devices or many devices, up to some finite number such as the number 20, but higher and lower values ​​can be used.

[0074] The term "one or more" means one item or a plurality of items.

[0075] The term "about" means that the value of a given amount is within ±10% of the stated value. In other embodiments, the value is within ±5% of the stated value. In other embodiments, the value is within ±2.5% of the stated value. In other embodiments, the value is within ±1% of the stated value.

[0076] The term "substantially" or "essentially" means that the value of a given amount is within ±5% of the stated value. In other embodiments, the value is within ±2.5% of the stated value. In other embodiments, the value is within ±2% of the stated value. In other embodiments, the value is within ±1% of the stated value. In other embodiments, the value is within ±0.5% of the stated value. In other embodiments, the value is within ±0.1% of the stated value.

[0077] The term "substantially free" or "substantially free" means that the value of a given amount is ≤ 5%. In other embodiments, the value is ≤ 2.5%. In other embodiments, the value is ≤ 2%. In other embodiments, the value is ≤ 1%. In other embodiments, the value is ≤ 0.5%. In other embodiments, the value is ≤ 0.1%.

[0078] All ranges include endpoint values ​​and any subranges thereof. All individual values ​​include all lower values. For example, the term about 25 includes all values ​​greater than zero up to 25.

[0079] Abbreviations used in this invention

[0080] The following abbreviations are used herein: Ac is acetyl, AcOH is acetic acid, 6-Ahx-OH is 6-aminohexanoic acid, Bn is benzyl, Boe is tert-butyloxycarbonyl, nBu is n-butyl, nBuLi is n-butyllithium (1.6 M in hexanes unless otherwise specified), CBz is benzyloxycarbonyl, CDI is N,N'-carbonyldiimidazole, COMU is (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholinyl -carbenium hexafluorophosphate, Dab is 2,4-diaminobutyryl, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, DCE is 1,2-dichloroethane, DCHA is dicyclohexylamine, DCM is dichloromethane (methylene chloride), dioxane is 1,4-dioxane, DIPEA is N,N-diisopropylethylamine, DMED is N,N'-dimethylethylenediamine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, Et is ethyl, EtOH is ethanol, Fmoc is 9H-fluoren-9-ylmethoxycarbonyl, Glu is glutamic acid, Gly is glycine, HBTU is O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HMDS is hexamethyldisilazane, iPr is isopropyl, KHMDS is potassium bis(trimethylsilyl)amide, Lys is lysine, LHMDS is bis(trimethylsilyl)amide )amide, Me is methyl, MeOH is methanol, Nle is norleucine, NMM is 4-methylmorpholine, NSMC is N-succinimidyl-N-methylcarbamate, OAc is acetate, Orn is ornithine, pTsOH is p-toluenesulfonic acid, Ph is phenyl, RT is room temperature, tBu is tert-butyl, TEA is triethylamine, Tfa is trifluoroacetyl, THF is tetrahydrofuran, Tol is toluene, Tyr is tyrosine, and Z is benzyloxycarbonyl. DETAILED DESCRIPTION OF THE INVENTION

[0082] The inventors have discovered that integrin agonist carrier compositions can be formulated to improve the bioavailability of integrin agonists. Integrin agonist carrier compositions can be used to formulate integrin agonist pharmaceutical compositions for administration to animals or humans. In addition, the inventors have discovered methods for preparing and using integrin agonist carrier compositions and integrin agonist pharmaceutical compositions. Integrin agonist carrier compositions comprise one or more zwitterionic surfactants, one or more neutral lipids, and one or more polar organic solvents.

[0083] The present inventors have found that integrin agonists that enhance integrin-mediated cell-cell adhesion can be beneficial in a variety of therapies, particularly therapies known or suspected to involve integrin-mediated binding of cells with specific integrins to cells with integrin-associated ligands. Integrins targeted by integrin agonists include, but are not limited to, α4β1 (very late antigen-4 (VLA-4)), α4β7, α5β1, αLβ2 (lymphocyte function-associated antigen 1 (LFA-1)), and / or αVβ3, and corresponding ligands include, but are not limited to, VCAM-1, fibronectin, MAdCAM-1, ICAM-1, ICAM-2, and / or vitronectin.

[0084] Disclosed herein are small molecules, poorly water-soluble drug integrin agonist adjuvant reagents and immunogenic compositions thereof, as well as methods of using them to induce an immune response in a subject. Small molecules, poorly water-soluble drug integrin agonist adjuvant reagents include one or more compounds that promote the interaction of integrins α4β1, α4β7, α5β1 and / or αLβ2 with their cognate ligands. The above-mentioned integrin adjuvant reagents can be used to strengthen and enhance the immune effects of active agents, including vaccine antigens derived from various pathogens, toxins and / or tumors. The actual and preferred route of administration of these integrin agonist adjuvant reagents is through the oral route in the form of capsules, tablets, solutions or suspensions.

[0085] Ethane-1,2-diylbis(oxy)bis(ethane-2,1-diyl)bis(bis(thiophen-2-ylmethyl)carbamate (C1) is a representative small molecule, poorly water-soluble drug integrin agonist adjuvant agent with desirable pharmacological properties. However, C1 is limited by its aqueous solubility and oral bioavailability. To improve oral absorption, lipid-based carrier compositions have been formulated, as well as methods for preparing oral formulations to achieve optimal pharmacokinetic exposure.

[0086] Drug integrin agonist adjuvant agents with low water solubility, such as those classified as "practically insoluble" or "insoluble" according to the United States Pharmacopeia (USP) 24 (2000), page 10, i.e., having a solubility of less than about 1 part per 10,000 parts of water (less than about 100 ug / ml), are obviously difficult to formulate for oral delivery. Among other problems, the bioavailability of such drugs is often very low when administered by the oral route. Oral bioavailability is further complicated by the fact that these molecules have a molecular weight of >500, have no ionizable groups, and are metabolized by gastrointestinal mucosal and liver CYP450 enzymes.

[0087] C1 is a small molecule integrin agonist adjuvant agent with low water solubility, which is disclosed and used in U.S. Patent Nos. 9512109, 10071980, 10035784, 10287264, 10342866, 10709780, 10709781, 10716849 and 11311619 and foreign counterparts. The relevant properties of 7HP349 are listed in Table 1.

[0088] Table 1

[0089] Small molecule integrin agonist adjuvant reagent 7HP349, description and properties

[0090]

[0091] Another specific illustrative small molecule drug with low water solubility is the compound 3-oxo-l-(2-thienyl)-2-(2-thienylmethyl)-4,7-dioxa-2-azanonan-9-ylbis(2-thienylmethyl)carbamate or 1,13-bis(2-thienyl)-2-12-bis(2-thienylmethyl)-3,11-dioxo-4,7,10-trioxa-2,12-diazatridecane (7HP577), which is an integrin agonist adjuvant disclosed in U.S. Pat. Nos. 9512109, 10071980, 10035784, 10287264, 10342866, 10709780, 10709781, 10716849 and 11311619 and foreign counterparts. The neutral compound had a molecular weight of 576.78 g / mol and a LogP value of 6.58.

[0092] US20070104780 of Lipari et al. discloses a pharmaceutical composition comprising a drug-carrier system having a low water-soluble small molecule drug in a solution in a substantially non-aqueous carrier, such as N-4-(3-amino-1H-indazole-4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea (ABT-869) and (+)-1-(5-tert-butyl-1-yl)-3-(1H-indazole-4-yl)-urea (ABT-102), wherein the substantially non-aqueous carrier comprises at least one phospholipid and a pharmaceutically acceptable solubilizing agent. When mixed with water, the drug carrier system typically forms a non-gelled substantially opaque liquid dispersion. The composition is suitable for being administered to a subject in need thereof by a suitable route (e.g., oral administration).

[0093] Caliph et al., J. Pharm Sci , 98, 1073, 2000 discloses the use of a carrier comprising a neutral lipid, wherein the neutral lipid contains a carrier having more than 10 carbon atoms (i.e., >C 10 The fatty acid side chain of the fatty acid preferably contains at least 18 carbon atoms (i.e., ≥ C 18 Neutral lipids with fatty acid side chains of 1,2-dihydro-1,4 ... Int J Nanomedicine , 2013; 8: 2733-2744 discloses that such lipid-based formulations can reduce first-pass metabolic losses.

[0094] There remains a need in the pharmaceutical art for novel liquid formulations of poorly water-soluble small molecule drugs such as 7HP349 and 7HP577 suitable for oral administration. More particularly and without limitation, there is a need for such formulations having at least one of the following features, advantages, or benefits: an acceptably high concentration of integrin agonists such as 7HP349 and 7HP577 (e.g., at least about 5% w / w); and an acceptable bioavailability upon oral administration (e.g., at least about 5%).

[0095] Range of lipid-based carrier compositions

[0096] The lipid-based carrier compositions of the present disclosure comprise one or more zwitterionic surfactants, one or more neutral lipids and one or more polar organic cosolvents or solubilizers. In a specific embodiment, the one or more zwitterionic surfactants comprise one or more phospholipids. Tables 2 and 3 list the ranges of the three major components of the lipid-based carrier compositions.

[0097] Table 2

[0098] Composition Ranges of Type 1 Lipid-Based Carrier Compositions

[0099]

[0100] All ranges are inclusive.

[0101] Table 3

[0102] Composition Ranges of Lipid-Based Carrier Compositions

[0103]

[0104] All ranges are inclusive.

[0105] The lipid-based carrier composition may also include up to 10% by weight of other adjuvants and / or excipients, wherein the other weight % is adjusted so that the composition increases to 100% by weight. In other embodiments, the other ingredients include up to 5% by weight. In other embodiments, the other ingredients include up to 2.5% by weight. In other embodiments, the other ingredients include up to 1% by weight.

[0106] Lipid-based carrier drug composition range

[0107] The lipid-based pharmaceutical composition of the present disclosure comprises one or more zwitterionic surfactants, one or more neutral lipids, one or more polar organic cosolvents or solubilizers and one or more small molecules, water-poorly soluble drug integrin agonist adjuvant agents. In a specific embodiment, the one or more zwitterionic surfactants comprise one or more phospholipids. Table 4 below lists the ranges of the four main components of the lipid-based carrier composition.

[0108] Table 4

[0109] Composition Ranges of Lipid-Based Carrier Compositions

[0110]

[0111] All ranges are inclusive.

[0112] The lipid-based pharmaceutical composition may also include up to 10% by weight of other adjuvants and / or excipients, wherein the other weight % is adjusted so that the composition increases to 100% by weight. In other embodiments, the other ingredients include up to 5% by weight. In other embodiments, the other ingredients include up to 2.5% by weight. In other embodiments, the other ingredients include up to 1% by weight.

[0113] Dosage and effective amount

[0114] In specific embodiments, the dosage effective amount of the poorly water-soluble pharmaceutical agent of the present disclosure (such as an integrin agonist) in a lipid-based delivery system is from about 1 milligram (mg) to about 500 mg, or any subrange, such as from about 1 mg to about 250 mg, from about 1 mg to about 200 mg, from about 1 mg to about 150 mg, from about 1 mg to about 100 mg, from about 1 mg to about 75 mg, from about 1 mg to about 50 mg, from about 1 mg and about 25 mg, from about 5 mg to about 150 mg, from about 5 mg to about 100 nM, from about 5 mg to about 75 mg, from about 5 mg to about 50 mg, from about 5 mg to about 25 mg, or any other subrange thereof.

[0115] In specific embodiments, the therapeutically effective amount of a poorly water-soluble pharmaceutical agent of the present disclosure (such as an integrin agonist) is from about 1 femtomolar (fM) to about 300 micromolar (μM) or any subrange, such as from about 1 fM to about 200 μM, from about 1 fM to about 100 μM, from about 1 fM to about 50 μM, from about 1 fM to about 25 μM, from about 1 fM to about 20 μM, from about 1 fM to about 15 μM, from about 1 fM to about 5 μM, from about 1 fM to about 1 μM, from about 1 fM to about 100 nanomolar (nM), from about 1 fM to about 75 nM, from about 1 fM to about 50 nM, from about 1 fM to about 25 nM, or any other subrange thereof, at the administration portion.

[0116] In specific embodiments, the plasma concentration of a poorly water-soluble pharmaceutical agent of the present disclosure, such as an integrin agonist, in nanograms per milliliter (ng / mL) is from about 1 ng / mL to about 25 ng / mL, or any subrange, such as from about 1 ng / mL to about 20 ng / mL, from about 1 ng / mL to about 15 ng / mL, from about 1 ng / mL to about 5 ng / mL, from about 1 ng / mL to about 1 ng / mL, from about 1 ng / mL to about 100 ng / mL, from about 1 ng / mL to about 75 ng / mL, from about 1 ng / mL to about 50 ng / mL, from about 1 ng / kg to about 25 ng / mL, or any other subrange thereof.

[0117] Water-insoluble pharmaceutical reagents

[0118] The lipid-based carrier compositions of the present disclosure can be used to deliver any poorly water-soluble pharmaceutical agent or mixture thereof to an animal or human. In a specific embodiment, the poorly water-soluble pharmaceutical agent includes a poorly water-soluble integrin-activating pharmaceutical agent or mixture thereof. Such agents are characterized by a Log P value greater than 5.0 (>5.0), greater than or equal to 5.25 (≥5.25), greater than or equal to 5.5 (≥5.5), greater than or equal to 5.75 (≥5.75), or greater than or equal to 6.0 (≥6.0).

[0119] General Types of Integrin Activating Pharmacological Agents

[0120] In a particular embodiment, the integrin activating pharmaceutical agent is given by a compound of formula (I):

[0121] R 1 -M 1 - N(R 2 ) - M 2 -M 3 -M 4 -M 5 -M 6 -R 3 (I)

[0122] The first type of compounds of formula (I) are defined as follows:

[0123] R 1 is selected from the group consisting of aryl and aralkyl,

[0124] R 2 is an alkyl group, an aryl group or an aralkyl group,

[0125] M 1 It is CH2,

[0126] M 2 It is CO.

[0127] M 3 O, S or NR 6 ,

[0128] When present, R 6 is hydrogen or lower alkyl,

[0129] M 4 Does not exist, or is CH2,

[0130] M 5 Yes (CR 11 R 12 ),

[0131] R 11 It is hydrogen,

[0132] R 12 Selected from the group consisting of: hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 S02R 24 NR 21 COOR 24 ,OCOR 24 , OR 24 、O(CH2CH2O) s R 24 、COOR 24 , alkyl and hydroxyalkyl,

[0133] s is an integer from 1 to 6,

[0134] When present, R 21 and R 22 are independently selected from the group consisting of hydrogen or lower alkyl,

[0135] When present, R 23 is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl,

[0136] The condition is that when M 3 YesNR 6 And M 4 If it does not exist, then R 23 is not 1-(1,3-benzodioxol-5-yl)-3-ethoxy-3-oxopropyl,

[0137] When present, R 24 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl, and mixtures thereof,

[0138] M 6 Yes (CH2) q ,

[0139] q is an integer from 0 to 6,

[0140] R 3 Selected from the group consisting of: hydrogen, CONR 13 R 14 NR 15 COOR 16 NR 15 COR 16 NR 15 CONR 13 R 14 NR15 S02R 16 ,OCOR 16 、COOR 16 , OR 16 , SR 16 , heterocyclic, hydroxy, hydroxyalkyl, guanadino, alkyl and aryl,

[0141] When present, R 13 and R 15 are independently hydrogen or lower alkyl,

[0142] When present, R 14 and R 16 independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl and heterocyclylalkyl,

[0143] When present, R 1 , R 2 , R 3 , R 12 , R 14 , R 16 , R 23 and R 24 may be independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halogen, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO2(alkyl), -NHSO2(aryl), -NHSO2(aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino), and mixtures thereof;

[0144] or

[0145] The second class of compounds of formula (I) is defined by:

[0146] R 1 is an aryl group or an aralkyl group,

[0147] R 2 is an alkyl group or an aralkyl group,

[0148] M 1 It is CH2,

[0149] M 2 It is CO.

[0150] M 3 Does not exist, or is O or CH2,

[0151] M 4 Does not exist, or is CH2,

[0152] M 5 Not present, or O or (CR 11 R 12 ),

[0153] R 11 It is hydrogen,

[0154] R 12 Selected from the group consisting of: hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 S02R 24 and NR 21 COOR 24 ,

[0155] When present, R 21 and R 22 Each of is independently selected from the group consisting of hydrogen and lower alkyl,

[0156] When present, R 23 and R 24 each of which is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl,

[0157] M 6 Selected from the group consisting of: (CH2) q 、(CH2) q -CH=CH-(CH2) r 、(CH2) q -Arylene-(CH2) r and (CH2CH2O) q ,in

[0158] q and r are independently integers from 0 to 6,

[0159] R 3 It is CONR 13 R 14 ,

[0160] When present, R 13 and R 14Each of is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, and

[0161] When present, R 1 , R 2 , R 13 , R 14 , R 23 and R 24 are independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halogen, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO2(alkyl), -NHSO2(aryl), -NHSO2(aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino), and mixtures thereof;

[0162] or

[0163] The third class of compounds of formula (I) is defined as follows:

[0164] R 1 is an aryl group or an aralkyl group,

[0165] R 2 is an alkyl group or an aralkyl group,

[0166] M 1 It is CH2,

[0167] M 2 It is SO2 or CO,

[0168] M 3 Does not exist, or is CH2,

[0169] M 4 Does not exist, or is CH2,

[0170] M 5 Does not exist, or (CR 11 R 12 ),

[0171] When present, R 11 It is hydrogen,

[0172] When present, R 12 Selected from the group consisting of: hydrogen, alkyl, NR21 CONR 22 R 23 NR 21 COR 24 NR 21 S02R 24 and NR 21 COOR 24 ,

[0173] When present, R 21 and R 22 Each of is independently selected from the group consisting of hydrogen, lower alkyl and aralkyl,

[0174] When present, R 23 and R 24 each of which is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl,

[0175] M 6 Yes (CH2) q or NR 34 (CH2) q ,

[0176] q is an integer from 0 to 6,

[0177] When present, R 34 Selected from alkyl, aralkyl, COR 35 and SO2R 35 The group composed of

[0178] When present, R 35 is selected from the group consisting of alkyl, aryl and aralkyl, and

[0179] R 3 Selected from the group consisting of: CONR 13 R 14 、SO2NR 13 R 14 NR 15 COOR 16 NR 15 COR 16 NR 15 CONR 13 R 14 and NR 15 S02R 16 ,

[0180] When present, R 13 and R 14 each of which is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl,

[0181] When present, R 15 and R 16 Each of is independently selected from the group consisting of hydrogen, lower alkyl and aralkyl,

[0182] When present, R 1 , R 2 , R 13 , R 14 , R 15 , R 16 , R 23 , R 24 , R 34 and R 35 is unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halogen, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO2(alkyl), -NHSO2(aryl), -NHSO2(aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino) and -OCO(dialkylamino),

[0183] The condition is that when M 2 When it is CO, then M 6 YesNR 34 (CH2) q ,

[0184] Where q is not 0;

[0185] or

[0186] The fourth class of compounds of formula (I) is defined as follows:

[0187] R 1 is an alkyl group, an aryl group or an aralkyl group,

[0188] R 2 is selected from the group consisting of aralkyl and alkyl,

[0189] The condition is that when R 1 When it is an alkyl group, R 2 is an aralkyl group,

[0190] M 1 is CO or SO2,

[0191] The condition is that when M 1 is SO2 and R1 When it is phenyl, 4-methylphenyl or 2,4,6-trimethylphenyl, R 2 is not alkyl, 2-phenylethyl, benzyl or 2-methoxy-2-oxyethyl, and when M 1 is CO and R 1 When R is 2-furanyl, 4-pyridyl or 3,5-dinitrophenyl, 2 is not alkyl, benzyl or 2-(1H-indol-2-yl)ethyl,

[0192] M 2 Does not exist, or is CH2,

[0193] M 3 and M 4 does not exist,

[0194] M 5 Yes (CR 11 R 12 ),

[0195] R 11 It is hydrogen,

[0196] R 12 Selected from the group consisting of: hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 S02R 24 NR 21 COOR 24 ,CONR 22 R 23 、COOR 24 、O(CH2CH2O) s R 24 , hydroxyalkyl and alkoxyalkyl,

[0197] When present, R 21 and R 22 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, and

[0198] When present, R 23 and R 24 Each of is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, and

[0199] s is an integer from 1 to 6,

[0200] M 6 Yes (CH2) q ,

[0201] q is an integer from 0 to 6,

[0202] R 3 Selected from the group consisting of: NR 15 COOR 16 NR 15 COR 16 NR 15 CONR 13 R 14 and NR 15 S02R 16 ,and

[0203] When present, R 13 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, and

[0204] When present, R 14 , R 15 and R 16 Each of is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, and aralkyl, and

[0205] When present, R 1 , R 2 , R 3 , R 12 , R 14 , R 15 , R 16 , R 23 and R 24 are independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, haloalkoxy, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halogen, haloalkyl, haloaryl, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO2(alkyl), -NHSO2(aryl), -NHSO2(aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino) and -OCO(dialkylamino),

[0206] or

[0207] Its pharmaceutical salts,

[0208] or

[0209] A mixture thereof.

[0210] In some embodiments, a chemical compound having the general formula (I) is provided, wherein R 1 is an aryl group or an aralkyl group, R 2 is an alkyl group, an aryl group or an aralkyl group, M 1 It is CH2, M 2 It is CO, M 3 Does not exist, M 4 Not present or CH2, M 5 Yes (CR 11 R 12 ), M 6 Yes (CH2) q , where q is an integer from 0 to 6, R 11 is hydrogen, and R 12 Selected from the group consisting of: hydrogen, NR 21 CONR 22 R 23 NR 21 COR 24 NR 21 S02R 24 NR 21 COOR 24 ,OCOR 24 , OR 24 SCOR 24 , SR 24 , N3, CN and O(CH2CH2O) s R 24 , where s is an integer from 1 to 6, and when present, R 21 and R 22 is independently selected from the group consisting of hydrogen, lower alkyl or aralkyl, and when present R 23 is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, alkyl, aryl, aralkyl and alkoxycarbonylalkyl, and when present, R 24 is selected from the group consisting of alkyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkylalkyl and heterocyclylalkyl, provided that when M 3 and M 4 When it does not exist, R 12 Not the following:

[0211]

[0212] wherein A is selected from -O-, -S- and -NR 26 -, E is selected from -CH2-, -O-, -S- and -NR 27 -, J is selected from -O-, -S- and -NR 28 -, T is selected from the group consisting of CO and (CH2) bThe group consisting of, wherein b is an integer from zero to three, L is selected from --(CH2)--, --O--, --S-- and --NR 29 --a group consisting of, wherein n is an integer from zero to three, and M is selected from CR 30 R 31 and (CH2) u u, wherein u is an integer of zero or one, and X is selected from CO2B, PO3H2, SO3H, OPO3H2, CONHCOR 32 、CONHSO2R 33 , oxazolyl, tetrazolyl and hydrogen, B, R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 and R 33 independently selected from the group consisting of hydrogen, haloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, thioalkoxy, aliphatic acyl, --CF3, nitro, amino, cyano, N(C1-C3 alkyl)CO(C1-C3 alkyl), C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, CO2(C1-C3 alkylamino), CONH(C1-C3 alkylamino), CH=NOH, PO3H2, OPO3H2, CON(C1-C3 alkyl)2, haloalkyl, alkyl, alkoxycarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, arylalkyl, alkylheterocyclyl, heterocycloalkyl, sulfonyl, sulfonamide, carbamate, aryloxyalkyl, carboxyl, and CONH (benzyl), wherein B, X, R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 and R 32 is unsubstituted or substituted with at least one electron withdrawing or electron donating group, R 3 Selected from the group consisting of: hydrogen, NR 15 COOR 16 NR 15 COR 16 NR 15 CONR13 R 14 NR 15 S02R 16 ,OCOR 16 、COOR 16 、alkyl、SR 16 , heterocyclyl, hydroxy, hydroxyalkyl, guanadino and aryl, wherein when present, R 13 and R 15 is independently hydrogen, lower alkyl or aralkyl, and when present R 14 and R 16 independently selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, provided that when R 3 When R is hydrogen, alkyl or aryl, 12 is not hydrogen, and if R 1 When it is phenyl, R 3 is benzyloxycarbonylamino, and R 12 is hydrogen, R 2 is not 2-methoxybenzyl, and when present R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 16 , R 21 , R 22 , R 23 and R 24 and may be independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylaryl, hydroxy, alkoxy, azido, hydroxyalkyl, aryloxy, hydroxyaryl, alkoxyaryl, halogen, haloalkyl, haloaryl, haloalkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, -NHCO(alkyl), -NHCO(aryl), -NHCO(aralkyl), -NHCO(haloalkyl), -NHSO2(alkyl), -NHSO2(aryl), -NHSO2(aralkyl), alkoxycarbonyl, alkoxycarbonylalkyl, -OCO(alkylamino), -OCO(dialkylamino).

[0213] In other embodiments, the integrin activating pharmaceutical agent is defined by a compound of formula (II):

[0214] Q 1 -R a -Z -R b -Q2 (II)

[0215] in:

[0216] Q 1 and Q 2 The groups may independently be R 1 R 2 N-group, R 1 R 2 NC(=O)-group, R 1 R 2 NC(=O)N(R 3 )-group, R 1 R 2 NC(=O)O-group or R 1 R 2 NSO2-group,

[0217] R 1 and R 2 The groups may independently be a hydrocarbyl group, a heterohydrocarbyl group, a hydrocarbyl group containing an aryl group, a hydrocarbyl group containing a heteroaryl group, a heterohydrocarbyl group containing an aryl group, a heterohydrocarbyl group containing a heteroaryl group, a fused heterocyclic ring group, or any combination thereof, and

[0218] R 3 The group may be a hydrocarbyl group or a heterohydrocarbyl group;

[0219] R a and R b The groups may independently be hydrocarbenyl linking groups in which one or more carbon atoms may be substituted with oxygen atoms, for example, alkyleneoxide linking groups such as linking groups containing oxymethylene or linking groups containing oxyethylene; and

[0220] The Z group may be a hydrocarbenyl linking group or a heterocarbenyl linking group and contain one or more protonatable moieties.

[0221] In certain embodiments, the one or more protonatable moieties become protonated and / or are protonated at biological pH and include a pharmaceutically acceptable counterion.

[0222] In a specific embodiment, R 1 and R 2 The group is selected from the group consisting of 2-thienylalkyl, 3-alkoxybenzyl, 4-alkoxybenzyl, pyridin-2-ylalkyl, pyridin-4-ylalkyl, pyridin-4-ylalkyl, 4-dialkylaminobenzyl, 3-dialkylaminobenzyl, and mixtures or combinations thereof, wherein the alkyl or alkoxy independently contains 1 to 6 carbon atoms.

[0223] In other embodiments, R 1 and R 2 The group is selected from the group consisting of 2-thienylmethyl, 2-(2-thienyl)ethyl, 3-methoxybenzyl, 4-methoxybenzyl, pyridin-2-ylmethyl, pyridin-4-ylmethyl, pyridin-4-ylmethyl, 4-dimethylaminobenzyl, 3-dimethylaminobenzyl, carbazole, 3,6-dimethoxycarbazole, and mixtures or combinations thereof.

[0224] In a specific embodiment, R a and R b The groups may independently be -O(R c O) n -、-R d O(R c O) n -group, -O(R c O) n R e -group, -R d O(R c O) n R e -group or R aa Group, where R c , R d , R e and R aa may independently be a hydrocarbyl linking group, and each n is independently an integer having a value from 1 to 6. In other embodiments, R a and R b The groups may independently be -O((CH2) m O) n -, wherein m is an integer having a value from 1 to 3, and n is an integer having a value from 1 to 6.

[0225] In other embodiments, R a and R b The groups may independently be -O((CH2) m1 )((CH2) m2 O) n (CH2) m3 - group, wherein m1, m2 and m3 are integers having values ​​from 1 to 3, and n is an integer having a value from 1 to 8. In other embodiments, R a and R b The groups may independently be -((CH2) m1 )((CH2) m2 O) n (CH2) m3 - group or -(CH2)m1 -, wherein m1, m2 and m3 are integers having values ​​from 1 to 3, and n is an integer having a value from 1 to 6. Illustrative examples include, but are not limited to: -O(CH2O) n -group, -O(CH2CH2O) n -group, -O(CH2CH2CH2O) n -group, -CH2O(CH2O) n -group, -O(CH2O) n CH2- group, -CH2O(CH2O) n CH2- group, -CH2O(CH2CH2O) n -group, -O(CH2CH2O) n CH2- group, -CH2O(CH2CH2O) n CH2-group, -CH2CH2O(CH2CH2O) n -group, -O(CH2CH2O) n CH2CH2- group, -CH2CH2O(CH2CH2O) n A CH2CH2- group, or a higher analog, or -(CH2) n - group, wherein n is an integer having a value from 1 to 6. It should be appreciated that R a and R b The choice will depend on Q 1 and Q 2 The agonist is selected such that the agonist does not contain specific moieties such as a -CNO- moiety, a -OO- moiety, or other linkages that are unstable or decompose into undesirable by-products.

[0226] In certain embodiments, the Z group may be -R f N(R 4 )R g -group, -R f N + (R 4 R 5 A - )R g -group, -R f C(R 6 )(N(R 4 R 5 ))R g -group, -R f C(R 6 )(N(R 4 R 5 R 7 A - ))R g -group, -Rf C(R 6 )(R h N(R 4 R 5 ))R g -group or -R f C(R 6 )(R h N(R 4 R 5 R 7 A - ))R g - group, wherein (a) R 4 , R 5 , R 6 and R 7 groups are independently a hydrocarbon group or a heterohydrocarbon group, (b) R f and R g The groups are independently C1-C3 alkenyl linking groups, and (c) A - Groups are independently counterions.

[0227] In other embodiments, the Z group includes -G 1 -JG 2 - group, wherein (a) the J group comprises an arylene group or a heteroarylene group; (b) G 1 and G 2 The groups are independently -R f -(R 8 )N-group, -R f -(R 8 )NR g -group, -R f -O-group, -R f -OR g -group, -C(=O)-group, -C(=O)-R g -group, -C(=O)N(R 8 )-group, -C(=O)N(R 8 )-R g -group, -C(=O)O-group, -C(=O)OR g -group, -R f -(R 8 )NC(=O)-group, -R f -(R 8 )NC(=O)-R g -group, -R f -(R 8 )NC(=O)N(R 8 )-group, -R f -(R 8)NC(=O)N(R 8 )-R g -group, -R f -(R 8 )NC(=O)O-group, -R f -(R 8 )NC(=O)OR g -group, -R f -OC(=O)- group, -R f -OC(=O)-R g -group, -R f -OC(=O)N(R 8 )-group, -R f -OC(=O)N(R 8 )-R g -group, -R f -OC(=O)O- group or -R f -OC(=O)OR g -group; (c) R f and R g The groups are independently C1-C3 alkenyl linking groups; (d) R 8 The A groups are independently hydrogen atoms or C1-C8 hydrocarbon groups; and (e) the A groups independently include counterions.

[0228] In particular embodiments, the Z group may include a hydrocarbyl or heterohydrocarbyl linking group, including any of the hydrocarbyl or heterohydrocarbyl linking groups disclosed herein.

[0229] In other embodiments, the Z group may include a hydrocarbyl or heterohydrocarbyl group, wherein the hydrocarbyl or heterohydrocarbyl group includes one or more moieties that are protonated at biological pH and / or carry a charge associated with an acceptable counterion. Illustrative examples of Z groups that include a hydrocarbyl or heterohydrocarbyl group (the hydrocarbyl or heterohydrocarbyl group includes at least one moiety that is protonated at biological pH and / or carries a charge associated with an acceptable counterion) include, but are not limited to, groups derived from pyrrole, pyrrole-2,3-dicarboxylic acid (dicarboxylic acid), pyridine, pyridine-2,3-dicarboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid, pyridine-3,4-dicarboxylic acid, pyridine-2,4-dicarboxylic acid, pyridine-2,5-dicarboxylic acid, pyridine-2,6-dicarboxylic acid, pyridine-3,4-dicarboxylic acid, pyridine-3,5-dicarboxylic acid, or other heterohydrocarbyl groups. In other embodiments, the Z group can be derived from a hydrocarbyl group including, but not limited to, 1-amino-benzene-2,4-dicarboxylic acid, 1-amino-benzene-2,5-dicarboxylic acid, 1-amino-benzene-2,6-dicarboxylic acid, 1-amino-benzene-3,4-dicarboxylic acid, 1-amino-benzene-3,5-dicarboxylic acid, 1,2,3-trihydroxybenzene, 1,2,4-trihydroxybenzene, 1,2,5-trihydroxybenzene, 1,3,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, 1 -amino-2,3-dihydroxybenzene, 1-amino-2,4-dihydroxybenzene, 1-amino-2,5-dihydroxybenzene, 1-amino-3,4-dihydroxybenzene, 1-amino-3,5-dihydroxybenzene, orthoformic acid, glycerol, 2-amino-1,3-dihydroxypropane, diethanolamine, N-methyldiethanolamine, dipropanolamine, N-methyldipropanolamine, diisopropanolamine, N-methyldiisopropanolamine, higher dialkanolamines, higher N-methyldialkanolamines or other hydrocarbon groups.

[0230] In certain embodiments, when present and not a hydrogen atom, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8The groups may independently be unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclyl group, a heterocyclylalkyl group, a heterocyclylaryl group, a hydroxyl group, an alkoxy group, an azido group, a haloalkoxy group, a hydroxyalkyl group, an aryloxy group, a hydroxyaryl group, an alkoxyaryl group, a halogen atom, a haloalkyl group, a haloaryl group, an amino group, an alkylamino group , dialkylamino group, arylamino group, diarylamino group, -NHC(=O)(alkyl) group, -NHC(=O)(aryl) group, -NHC(=O)(aralkyl) group, -NHC(=O)(haloalkyl) group, -NHSO2(alkyl) group, -NHSO2(aryl) group, -NHSO2(aralkyl) group, alkoxycarbonyl group, alkoxycarbonylalkyl group, -OC(=O)(alkylamino) group and -OC(=O)(dialkylamino) group.

[0231] Specific integrin activating pharmaceutical agents of formula (I)

[0232] In some embodiments, the integrin agonist of formula (I) comprises:

[0233] N,N,N',N'-Tetrakis(2-thienylmethyl)glutaramide;

[0234] N-(3-methoxybenzyl)-N,N',N'-tri(2-thienylmethyl)glutaramide;

[0235] N,N,N'-Tris(2-thienylmethyl)glutaramide;

[0236] N'-[2-(2-thienyl)ethyl]-N,N-bis(2-thienylmethyl)glutaramide;

[0237] N-[2-(2-thienyl)ethyl]-N,N',N'-tris(2-thienylmethyl)glutaramide;

[0238] N,N-bis(pyridin-4-ylmethyl)-N',N'-bis(2-thienylmethyl)glutaramide;

[0239] N,N-bis(pyridin-3-ylmethyl)-N',N'-bis(2-thienylmethyl)glutaramide;

[0240] N,N-bis(3-methoxybenzyl)-N',N'-bis(2-thienylmethyl)glutaramide;

[0241] N,N,N',N'-Tetrakis(4-methoxybenzyl)glutaramide;

[0242] N,N,N',N'-Tetrakis(2-thienylmethyl)adipamide;

[0243] N,N,N',N'-Tetrakis(4-methoxybenzyl)adipamide;

[0244] N,N,N',N'-Tetrakis(3-methoxybenzyl)adipamide;

[0245] N,N,N',N'-Tetrakis(2-thienylmethyl)pimelamide;

[0246] 2,2'-(1,3-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide];

[0247] N,N,N',N'-Tetrakis(4-methoxybenzyl)pimelamide;

[0248] N,N,N',N'-Tetrakis(2-thienylmethyl)octanediamide;

[0249] (3E)-N,N,N',N'-Tetrakis(2-thienylmethyl)hex-3-enediamide;

[0250] 2,2'-oxybis[N,N-bis(2-thienylmethyl)acetamide];

[0251] 3-Oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10-trioxa-2-azadodec-12-ylbis(2-thienylmethyl)carbamate (7HP349);

[0252] 3-Oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7-dioxa-2-azanonan-9-ylbis(2-thienylmethyl)carbamate (7HP577);

[0253] N,N,N',N'-Tetrakis(4-methoxybenzyl)succinamideethane-1,2-diylbis[bis(2-thienylmethyl)carbamate]; N,N,N',N'-Tetrakis(4-methoxybenzyl)octanediamide;

[0254] N,N,N',N'-Tetrakis(2-thienylmethyl)pyridine-3,5-dicarboxamide;

[0255] N,N,N',N'-Tetrakis(2-thienylmethyl)pyridine-2,6-dicarboxamide;

[0256] N,N,N',N'-Tetrakis(2-thienylmethyl)pyridine-2,4-dicarboxamide;

[0257] 2,2'-(1,4-phenylene)bis[N,N-bis(2-thienylmethyl)acetamide];

[0258] 8-{2-[bis(2-thienylmethyl)amino]-2-oxoethoxy}-N,N-bis(2-thienylmethyl)quinoline-2-carboxamide;

[0259] N,N'-bis(4-methoxybenzyl)-N,N'-bis(2-thienylmethyl)adipamide; and

[0260] Tert-butyl {(2S)-1,6-bis[bis(2-thienylmethyl)amino]-1,6-dioxohexan-2-yl}carbamate.

[0261] Specific integrin activating pharmaceutical agents of formula (II)

[0262] R a ZR b = (OCH2) n (CH3)(CH2O)

[0263] In certain embodiments, the integrin agonist of formula (II) comprises one or more agonists wherein R a ZR b Groups include -(OCH2) n N(CH3)(CH2O) n -, wherein n is an integer from 1 to 6. In other embodiments, the agonist of formula (II) comprises one or more of the following integrin activating compounds:

[0264] (a) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,6-diaza-6-methyl-hept-7-yl-bis(2-thienylmethyl)carbamate or 3,9-dioxo-1,11-bis(2-thienyl)-2,10-bis(2-thienylmethyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane,

[0265] (b) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undec-11-yl-bis(2-thienylmethyl)carbamate or 3,13-dioxo-1,15-bis(2-thienyl)-2,14-bis(2-thienylmethyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane,

[0266] (c) 3-Oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(2-thienylmethyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(2-thienylmethyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane,

[0267] (d) 3-Oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4-oxa-2,6-diaza-6-methyl-hept-7-yl-bis(3-methoxybenzyl)carbamate or 3,9-dioxo-1,11-bis(3-methoxyphenyl)-2,10-bis(3-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane,

[0268] (e) 3-Oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undec-11-yl-bis(3-methoxybenzyl)carbamate or 3,13-dioxo-1,15-bis(3-methoxyphenyl)-2,14-bis(3-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane,

[0269] (f) 3-Oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(3-methoxybenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(3-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecane,

[0270] (g) 3-Oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,6-diaza-6-methyl-hept-7-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,9-dioxo-1,11-bis(3-methoxyphenyl)-2,10-bis(3-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane,

[0271] (h) 3-Oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undec-11-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,13-dioxo-1,15-bis(3-methoxyphenyl)-2,14-bis(3-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane,

[0272] (i) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecan-15-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(3-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecan-15-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0273] (j) 3-Oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4-oxa-2,6-diaza-6-methyl-hept-7-yl-bis(4-methoxybenzyl)carbamate or 3,9-dioxo-1,11-bis(4-methoxyphenyl)-2,10-bis(4-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane,

[0274] (k) 3-Oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undec-11-yl-bis(4-methoxybenzyl)carbamate or 3,13-dioxo-1,15-bis(4-methoxyphenyl)-2,14-bis(4-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane,

[0275] (l) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(4-methoxybenzyl)carbamate or 3,17-dioxo-1,19-bis(4-methoxyphenyl)-2,18-bis(4-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecan-15-yl-bis(4-methoxybenzyl)carbamate,

[0276] (m) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,6-diaza-6-methyl-hept-7-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,9-dioxo-1,11-bis(4-methoxyphenyl)-2,10-bis(4-methoxybenzyl)-4,8-dioxa-2,6,10-triaza-6-methyl-undecane,

[0277] (n) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,10-trioxa-2,8-diaza-8-methyl-undec-11-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,13-dioxo-1,15-bis(4-methoxyphenyl)-2,14-bis(4-methoxybenzyl)-4,6,10,12-tetraoxa-2,8,14-triaza-8-methyl-pentadecane,

[0278] (o) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,6,8,12,14-pentaoxa-2,10-diaza-10-methyl-pentadecan-15-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate or 3,17-dioxo-1,19-bis(2-thienyl)-2,18-bis(4-methoxybenzyl)-4,6,8,12,14,16-hexaoxa-2,10,18-triaza-10-methyl-nonadecan-15-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0279] (p) N-methylbis[(9-carbazolylcarbonyloxy)methyl]amine,

[0280] (q) N-methylbis{[(9-carbazolylcarbonyloxy)methoxy]methyl}amine,

[0281] (r) N-methylbis({[(9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)amine,

[0282] (s) N-methylbis[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methyl]amine,

[0283] (t) N-methylbis{[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methyl}amine,

[0284] (u) N-methylbis({[(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)amine,

[0285] (v) a higher order analog, or

[0286] (w) mixtures and combinations thereof.

[0287] In other embodiments, the integrin agonist of formula (II) comprises one or more of the following integrin activating compounds:

[0288] (a) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(2-thienylmethyl)carbamate or 3,11-dioxo-1,13-bis(2-thienyl)-2,11-bis(2-thienylmethyl)-4,10-dioxa-2,6,12-triaza-7-methyl-tridecane,

[0289] (b) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(2-thienylmethyl)carbamate,

[0290] (c) 3-oxo-1-(2-thienyl)-2-(2-thienylmethyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-heneicosan-21-yl-bis(2-thienylmethyl)carbamate,

[0291] (d) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(3-methoxybenzyl)carbamate,

[0292] (e) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(3-methoxybenzyl)carbamate,

[0293] (f) 3-oxo-1-(3-methoxyphenyl)-2-(3-methoxybenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-heneicosan-21-yl-bis(3-methoxybenzyl)carbamate,

[0294] (g) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,7-diaza-7-methyl-non-9-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0295] (h) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecan-15-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0296] (i) 3-oxo-1-(3-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-heneicosan-21-yl-(3-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0297] (j) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4-oxa-2,7-diaza-7-methyl-nonan-9-yl-bis(4-methoxybenzyl)carbamate,

[0298] (k) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecan-15-yl-bis(4-methoxybenzyl)carbamate,

[0299] (l) 3-oxo-1-(4-methoxyphenyl)-2-(4-methoxybenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-heneicosan-21-yl-bis(4-methoxybenzyl)carbamate,

[0300] (m) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4-oxa-2,7-diaza-7-methyl-non-9-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0301] (n) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,13-trioxa-2,10-diaza-10-methyl-pentadecan-15-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0302] (o) 3-oxo-1-(4-methoxyphenyl)-2-(4-dimethylaminobenzyl)-4,7,10,16,19-pentaoxa-2,13-diaza-13-methyl-heneicosan-21-yl-(4-methoxybenzyl)(4-dimethylaminobenzyl)carbamate,

[0303] (p) 2-{[2-(9H-carbazol-9-ylcarbonyloxy)ethyl]-N-methylamino}ethyl 9H-carbazole-9-carboxylate,

[0304] (q) 2-[2-({2-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]ethyl}-N-methylamino)ethoxy]ethyl 9H-carbazole-9-carboxylate,

[0305] (r) 2-(2-{2-[(2-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}ethyl)-N-methylamino]ethoxy}ethoxy)ethyl 9-carbazolylcarboxylate,

[0306] (s) 2-{[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethyl]-N-methylamino}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0307] (t) 2-[2-({2-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]ethyl}-N-methylamino)ethoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0308] (u) 2-(2-{2-[(2-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}ethyl)-N-methylamino]ethoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0309] (v) a higher order analog, or

[0310] (w) mixtures and combinations thereof.

[0311] R a and R b = (OCH2) n or (CH3)(CH2O) n and Z = 2,6-dihydroxypyridine

[0312] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and the Z group is derived from 2,6-dihydroxypyridine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0313] (a) 2-[bis(thienylmethyl)aminocarbonyloxy],6-[bis(thienylmethyl)aminocarbonyloxy]pyridine,

[0314] (b) 2-[bis(3-methoxybenzyl)aminocarbonyloxy],6-[bis(3-methoxybenzyl)aminocarbonyloxy]pyridine,

[0315] (c) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine,

[0316] (d) 2-[bis(4-methoxybenzyl)aminocarbonyloxy],6-[bis(4-methoxybenzyl)aminocarbonyloxy]pyridine,

[0317] (e) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine,

[0318] (f) 6-(9H-carbazol-9-ylcarbonyloxy)-2-pyridyl 9H-carbazole-9-carboxylate,

[0319] (g) 6-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)-2-pyridyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or (h) mixtures and combinations thereof.

[0320] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0321] (a) 2-[bis(thienylmethyl)aminocarbonyloxymethoxy],6-[bis(thienylmethyl)aminocarbonyloxymethoxy]pyridine,

[0322] (b) 2-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy],6-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0323] (c) 2-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy],6-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]pyridine,

[0324] (d) 2-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy],6-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0325] (e) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine,

[0326] (f) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0327] (g) 2-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy],6-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]pyridine,

[0328] (h) 2-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy],6-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0329] (i) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine,

[0330] (j) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0331] (k) 2-{6-[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]-2-pyridyloxy}methyl 9H-carbazole-9-carboxylate,

[0332] (1) 2-[2-(6-{2-[2-(9-carbazolylcarbonyloxy)methoxy]methoxy}-2-pyridyloxy)methoxy]methyl 9-carbazolylcarboxylate,

[0333] (m) 2-{6-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methoxy]-2-pyridyloxy}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0334] (n) 2-[2-(6-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-2-pyridyloxy)methoxy]methyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0335] (o) a higher order analog, or

[0336] (p) mixtures and combinations thereof.

[0337] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0338] (a) 2-[bis(thienylmethyl)aminocarbonyloxyethoxy],6-[bis(thienylmethyl)aminocarbonyloxyethoxy]pyridine,

[0339] (b) 2-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy],6-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0340] (c) 2-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],6-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]pyridine,

[0341] (d) 2-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 6-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0342] (e) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine,

[0343] (f) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0344] (g) 2-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],6-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]pyridine,

[0345] (h) 2-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy], 6-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0346] (i) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine,

[0347] (j) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0348] (k) 2-{6-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-2-pyridyloxy}ethyl 9H-carbazole-9-carboxylate,

[0349] (1) 2-[2-(6-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 9-carbazolylcarboxylate,

[0350] (m) 2-{6-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]-2-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0351] (n) 2-[2-(6-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0352] (o) a higher order analog, or

[0353] (p) mixtures and combinations thereof.

[0354] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 2,6-dimethylolpyridine

[0355] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 2,6-dimethylolpyridine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0356] (a) 2-({bis[(2-thienyl)methyl]aminocarbonyloxy}methyl)-6-({bis[(2-thienyl)methyl]aminocarbonyloxy}methyl)pyridine,

[0357] (b) 2-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)-6-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)pyridine,

[0358] (c) 2-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)-6-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)pyridine,

[0359] (d) 2-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)-6-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)pyridine,

[0360] (e) 2-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)-6-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)pyridine,

[0361] (f) {6-[(9H-carbazol-9-ylcarbonyloxy)methyl]-2-pyridyl}methyl 9H-carbazole-9-carboxylate,

[0362] (g) {6-[(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methyl]-2-pyridyl}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or

[0363] (h) mixtures and combinations thereof.

[0364] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0365] (a) 2-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]pyridine,

[0366] (b) 2-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxymethoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxymethoxy)methyl]pyridine,

[0367] (c) 2-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0368] (d) 2-{bis(3-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]pyridine,

[0369] (e) 2-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-6-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0370] (f) 2-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-6-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine,

[0371] (g) 2-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-6-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0372] (h) 2-{bis(4-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]-6-{bis(4-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]pyridine,

[0373] (i) 2-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-6-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0374] (j) 2-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-6-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine,

[0375] (k) 2-[(6-{[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]methyl}-2-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate,

[0376] (1) 2-(2-{[6-({2-[2-(9H-carbazolylcarbonyloxy)methoxy]methoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 9-carbazolylcarboxylate,

[0377] (m) 2-[(6-{[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methoxy]methyl}-2-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0378] (n) 2-(2-{[6-({2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy)methoxy]methoxy}methyl)-2-pyridyl]methoxy}methoxy)ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0379] (o) a higher order analog, or

[0380] (p) mixtures and combinations thereof.

[0381] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0382] (a) 2-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]pyridine,

[0383] (b) 2-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxyethoxy)methyl]-6-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0384] (c) 2-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0385] (d) 2-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-6-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0386] (e) 2-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]-6-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0387] (f) 2-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-6-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0388] (g) 2-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]-6-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0389] (h) 2-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-6-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0390] (i) 2-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]-6-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0391] (j) 2-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-6-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0392] (k) 2-[(6-{[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate,

[0393] (1) 2-(2-{[6-({2-[2-(9H-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 9-carbazolylcarboxylate,

[0394] (m) 2-[(6-{[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0395] (n) 2-(2-{[6-({2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-2-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0396] (o) a higher order analog, or

[0397] (p) mixtures and combinations thereof.

[0398] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 3,5-dihydroxypyridine

[0399] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3,5-dihydroxypyridine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0400] (a) 3-[bis(thienylmethyl)aminocarbonyloxy],5-[bis(thienylmethyl)aminocarbonyloxy]pyridine,

[0401] (b) 3-[bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]pyridine,

[0402] (c) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine,

[0403] (d) 3-[bis(4-methoxybenzyl)aminocarbonyloxy],5-[bis(4-methoxybenzyl)aminocarbonyloxy]pyridine,

[0404] (e) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine,

[0405] (f) 5-(9H-carbazol-9-ylcarbonyloxy)-3-pyridyl 9H-carbazole 9-carboxylate,

[0406] (g) 5-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)-3-pyridyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or

[0407] (h) mixtures and combinations thereof.

[0408] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0409] (a) 3-[bis(thienylmethyl)aminocarbonyloxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxy]pyridine,

[0410] (b) 3-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0411] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]pyridine,

[0412] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0413] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine,

[0414] (f) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0415] (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]pyridine,

[0416] (h) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0417] (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]pyridine,

[0418] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]pyridine,

[0419] (k) 2-{5-[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]-3-pyridyloxy}ethyl 9H-carbazole-9-carboxylate,

[0420] (1) 2-[2-(5-{2-[2-(9-carbazolylcarbonyloxy)methoxy]methoxy}-3-pyridyloxy)ethoxy]ethyl 9-carbazolylcarboxylate,

[0421] (m) 2-{5-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methoxy]-3-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0422] (n) 2-[2-(5-{2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy)methoxy]methoxy}-3-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0423] (o) a higher order analog, or

[0424] (p) mixtures and combinations thereof.

[0425] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0426] (a) 3-[bis(thienylmethyl)aminocarbonyloxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxy]pyridine,

[0427] (b) 3-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0428] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]pyridine,

[0429] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0430] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine,

[0431] (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine,

[0432] (g) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0433] (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]pyridine,

[0434] (i) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0435] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine,

[0436] (k) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine,

[0437] (1) 2-{5-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy}ethyl 9H-carbazole-9-carboxylate,

[0438] (m) 2-[2-(5-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 9-carbazolylcarboxylate,

[0439] (n) 2-{5-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0440] (o) 2-[2-(5-{2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy)ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0441] (p) a higher order analog, or

[0442] (q) mixtures and combinations thereof.

[0443] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 3,5-dimethylolpyridine

[0444] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3,5-dimethylolpyridine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0445] (a) 3-({bis[(2-thienyl)methyl]aminocarbonyloxy}methyl)-5-({bis[(2-thienyl)methyl]aminocarbonyloxy}methyl)pyridine,

[0446] (b) 3-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)-5-({bis(3-methoxybenzyl)aminocarbonyloxy}methyl)pyridine,

[0447] (c) 3-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)-5-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)pyridine,

[0448] (d) 3-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)-5-({bis(4-methoxybenzyl)aminocarbonyloxy}methyl)pyridine,

[0449] (e) 3-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)-5-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methyl)pyridine,

[0450] (f) {5-[(9H-carbazol-9-ylcarbonyloxy)methyl]-3-pyridyl}methyl 9H-carbazole-9-carboxylate,

[0451] (g) {5-[(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methyl]-3-pyridyl}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or

[0452] (h) mixtures and combinations thereof.

[0453] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0454] (a) 3-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy}methoxy)methyl]pyridine,

[0455] (b) 3-{bis[(2-thienyl)methyl]aminocarbonyloxy}(methoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy}(methoxy)methyl]pyridine,

[0456] (c) 3-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-5-{bis(3-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0457] (d) 3-{bis(3-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]-5-{bis(3-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]pyridine,

[0458] (e) 3-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-5-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0459] (f) 3-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-5-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine,

[0460] (g) 3-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0461] (h) 3-{bis(4-methoxybenzyl)aminocarbonyloxy}(methoxyethoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}(methoxymethoxy)methyl]pyridine,

[0462] (i) 3-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]-5-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxy)methyl]pyridine,

[0463] (j) 3-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]-5-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}methoxymethoxy)methyl]pyridine,

[0464] (k) 2-[(5-{[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]methyl}-3-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (l) 2-(2-{[5-({2-[2-(9-carbazol-9-ylcarbonyloxy)methoxy]methoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 9-carbazolecarboxylate,

[0465] (m) 2-[(5-{[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methoxy]methyl}-3-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0466] (n) 2-(2-{[5-({2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0467] (o) a higher order analog, or

[0468] (p) mixtures and combinations thereof.

[0469] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0470] (a) 3-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]pyridine,

[0471] (b) 3-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]pyridine,

[0472] (c) 3-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]-5-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0473] (d) 3-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-5-{bis(3-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0474] (e) 3-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]-5-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0475] (f) 3-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxymethoxy)methyl]-5-(3-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0476] (g) 3-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0477] (h) 3-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0478] (i) 3-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]-5-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxy)methyl]pyridine,

[0479] (j) 3-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]-5-(4-methoxybenzyl, 4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl]pyridine,

[0480] (k) 2-[(5-{[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate,

[0481] (1) 2-(2-{[5-({2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 9-carbazolylcarboxylate,

[0482] (m) 2-[(5-{[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0483] (n) 2-(2-{[5-({2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}methyl)-3-pyridyl]methoxy}ethoxy)ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0484] (o) a higher order analog, or

[0485] (p) mixtures and combinations thereof.

[0486] R a and R b = (OCH2) n or (CH3)(CH2O) n and Z = 3,5-dihydroxy-dimethylaniline

[0487] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3,5-dihydroxy-dimethylaniline. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0488] (a) 3-[bis(thienylmethyl)aminocarbonyloxy],5-[bis(thienylmethyl)aminocarbonyloxy]dimethylaminobenzene,

[0489] (b) 3-[bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzene,

[0490] (c) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzene,

[0491] (d) 3-[bis(4-methoxybenzyl)aminocarbonyloxy],5-[bis(4-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzene,

[0492] (e) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzene,

[0493] (f) 3-(9H-carbazol-9-ylcarbonyloxy)-5-(dimethylamino)phenyl 9H-carbazole-9-carboxylate,

[0494] (g) 3-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)-5-(dimethylamino)phenyl-3,6-dimethoxy-9H-carbazole-9-carboxylate, or

[0495] (h) mixtures and combinations thereof.

[0496] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0497] (a) 3-[bis(thienylmethyl)aminocarbonyloxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxy]dimethylaminobenzene,

[0498] (b) 3-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene,

[0499] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene,

[0500] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene,

[0501] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene,

[0502] (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene,

[0503] (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene,

[0504] (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene,

[0505] (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzene,

[0506] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzene,

[0507] (k) 2-{3-[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]-5-(dimethylamino)phenoxy}methyl 9H-carbazole-9-carboxylate,

[0508] (1) 2-[2-(3-{2-[2-(9-carbazolylcarbonyloxy)methoxy]methoxy}-5-(dimethylamino)phenoxy)methoxy]ethyl 9-carbazolylcarboxylate,

[0509] (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)methoxy]-5-(dimethylamino)phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0510] (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-5-(dimethylamino)phenoxy)methoxy]methyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0511] (o) a higher order analog, or

[0512] (p) mixtures and combinations thereof.

[0513] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0514] (a) 3-[bis(thienylmethyl)aminocarbonyloxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxy]dimethylaminobenzene,

[0515] (b) 3-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene,

[0516] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene,

[0517] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene,

[0518] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene,

[0519] (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene,

[0520] (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene,

[0521] (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene,

[0522] (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene,

[0523] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene,

[0524] (k) 2-{3-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-(dimethylamino)phenoxy}ethyl 9H-carbazole-9-carboxylate,

[0525] (1) 2-[2-(3-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-(dimethylamino)phenoxy)ethoxy]ethyl 9-carbazolylcarboxylate,

[0526] (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]-5-(dimethylamino)phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0527] (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-(dimethylamino)phenoxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0528] (o) a higher order analog, or

[0529] (p) mixtures and combinations thereof.

[0530] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 3,5-dihydroxy-dimethylbenzylamine

[0531] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3,5-dihydroxy-dimethyl-benzylamine. In other embodiments, the integrin activating compound includes one or more of the following integrin activating compounds:

[0532] (a) 3-[bis(thienylmethyl)aminocarbonyloxy],5-[bis(thienylmethyl)aminocarbonyloxy]dimethylaminobenzylamine,

[0533] (b) 3-[bis(3-methoxybenzyl)aminocarbonyloxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzylamine,

[0534] (c) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzylamine,

[0535] (d) 3-[bis(4-methoxybenzyl)aminocarbonyloxy],5-[bis(4-methoxybenzyl)aminocarbonyloxy]dimethylaminobenzylamine,

[0536] (e) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]dimethylaminobenzylamine,

[0537] (f) 3-(9H-carbazol-9-ylcarbonyloxy)-5-[(methylamino)methyl]phenyl 9H-carbazole-9-carboxylate,

[0538] (g) 3-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)-5-[(dimethylamino)methyl]phenyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, or

[0539] (h) mixtures and combinations thereof.

[0540] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0541] (a) 3-[bis(thienylmethyl)aminocarbonyloxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine,

[0542] (b) 3-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy],5-[bis(thienylmethyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine,

[0543] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine,

[0544] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine,

[0545] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine,

[0546] (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], dimethylaminobenzylamine,

[0547] (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine,

[0548] (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxymethoxy]dimethylaminobenzylamine,

[0549] (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy]dimethylaminobenzylamine,

[0550] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxymethoxy]dimethylaminobenzylamine,

[0551] (k) 2-{3-[2-(9H-carbazol-9-ylcarbonyloxy)methoxy]-5-[(dimethylamino)methyl]phenoxy}methyl 9H-carbazole-9-carboxylate,

[0552] (1) 2-[2-(3-{2-[2-(9-carbazolylcarbonyloxy)methoxy]methoxy}-5-[(dimethylamino)methyl]phenoxy)methoxy]methyl 9-carbazolylcarboxylate,

[0553] (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}methyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0554] (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)methoxy]methoxy}-5-[(dimethylamino)methyl]phenoxy)methoxy]methyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0555] (o) a higher order analog, or

[0556] (p) mixtures and combinations thereof.

[0557] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0558] (a) 3-[bis(thienylmethyl)aminocarbonyloxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine,

[0559] (b) 3-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy],5-[bis(thienylmethyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine,

[0560] (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine,

[0561] (d) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine,

[0562] (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine,

[0563] (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], dimethylaminobenzylamine,

[0564] (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine,

[0565] (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine,

[0566] (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylaminobenzylamine,

[0567] (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzylamine,

[0568] (k) 2-{3-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}ethyl 9H-carbazole-9-carboxylate,

[0569] (1) 2-[2-(3-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy)ethoxy]ethyl 9-carbazolylcarboxylate,

[0570] (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazole-9-ylcarbonyloxy)ethoxy]-5-[(dimethylamino)methyl]phenoxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate,

[0571] (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolylcarboxylate,

[0572] (o) a higher order analog, or

[0573] (p) mixtures and combinations thereof.

[0574] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 2,6-pyridinedicarboxylic acid chloride class

[0575] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 2,6-pyridine dicarboxylic acid chloride. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0576] (a) N,N,N,N-tetrakis(2-thienylmethyl)-2,6-pyridinedicarboxamide,

[0577] (b) N,N,N,N-tetrakis(3-methoxybenzyl)-2,6-pyridinedicarboxamide,

[0578] (c) N,N-bis(3-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-2,6-pyridinedicarboxamide,

[0579] (d) N,N,N,N-tetrakis(4-methoxybenzyl)-2,6-pyridinedicarboxamide,

[0580] (e) N,N-bis(4-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-2,6-pyridinedicarboxamide,

[0581] (f) or mixtures and combinations thereof.

[0582] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0583] (a) bis(2-{bis(2-thienylmethyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate,

[0584] (b) bis(2-{bis(2-thienylmethyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate,

[0585] (c) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate,

[0586] (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate,

[0587] (e) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate,

[0588] (f) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate,

[0589] (g) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate,

[0590] (h) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate,

[0591] (i) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}methyl) 2,6-pyridinedicarboxylate,

[0592] (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 2,6-pyridinedicarboxylate,

[0593] (k) a higher order analog, or

[0594] (l) Mixtures and combinations thereof.

[0595] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0596] (a) bis(2-{bis(2-thienylmethyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate,

[0597] (b) bis(2-{bis(2-thienylmethyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0598] (c) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate,

[0599] (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0600] (e) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate,

[0601] (f) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0602] (g) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate,

[0603] (h) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0604] (i) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}ethyl) 2,6-pyridinedicarboxylate,

[0605] (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0606] (k) a higher order analog, or

[0607] (l) mixtures and combinations thereof.

[0608] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 3.5-pyridinedicarboxylic acid chloride class

[0609] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3,5-pyridinedicarboxylic acid (diecarboxylic acid) chloride. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0610] (a) N,N,N,N-tetrakis(2-thienylmethyl)-3,5-pyridinedicarboxamide,

[0611] (b) N,N,N,N-tetrakis(4-methoxybenzyl)-3,5-pyridinedicarboxamide,

[0612] (c) N,N-bis(3-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-3,5-pyridinedicarboxamide,

[0613] (d) N,N,N,N-tetrakis(4-methoxybenzyl)-3,5-pyridinedicarboxamide,

[0614] (e) N,N-bis(4-methoxybenzyl)-N,N-bis(4-dimethylaminobenzyl)-3,5-pyridinedicarboxamide, or

[0615] (f) mixtures and combinations thereof.

[0616] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0617] (a) bis(2-{bis(2-thienylmethyl]aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate,

[0618] (b) bis(2-{bis(2-thienylmethyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate,

[0619] (c) bis(2-{bis(3-methoxybenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate,

[0620] (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate,

[0621] (e) bis(2-{(3-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate,

[0622] (f) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate,

[0623] (g) bis(2-{bis(4-methoxybenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate,

[0624] (h) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate,

[0625] (i) bis(2-{bis(4-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}methyl) 3,5-pyridinedicarboxylate,

[0626] (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxymethoxy}methyl) 3,5-pyridinedicarboxylate,

[0627] (k) a higher order analog, or

[0628] (l) mixtures and combinations thereof.

[0629] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0630] (a) bis(2-{bis(2-thienylmethyl]aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate,

[0631] (b) bis(2-{bis(2-thienylmethyl]aminocarbonyloxyethoxy}ethyl) 3,5-pyridinedicarboxylate,

[0632] (c) bis(2-{bis(3-methoxybenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate,

[0633] (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0634] (e) bis(2-{(3-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate,

[0635] (f) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0636] (g) bis(2-{bis(4-methoxybenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate,

[0637] (h) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxyethoxy}ethyl) 3,5-pyridinedicarboxylate,

[0638] (i) bis(2-{bis(4-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy}ethyl) 3,5-pyridinedicarboxylate,

[0639] (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy}ethyl) 2,6-pyridinedicarboxylate,

[0640] (k) a higher order analog, or

[0641] (l) mixtures and combinations thereof.

[0642] R a and R b = (OCH2) n or CH3)(CH2O) n and Z = 3-dimethylamino-1,5-pentanediol

[0643] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a and R b Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is derived from 3-dimethylamino-1,5-pentanediol. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0644] (a) 1-[bis(2-thienylmethyl)aminocarbonyloxy]-5-[bis(2-thienylmethyl)aminocarbonyloxy]-3-(dimethylamino)pentane,

[0645] (b) 1-[bis(3-methoxybenzyl)aminocarbonyloxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane,

[0646] (c) 1-[(3-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-5-[bis(3-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane,

[0647] (d) 1-[bis(4-methoxybenzyl)aminocarbonyloxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane,

[0648] (e) 1-[(4-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-5-[bis(4-methoxybenzyl),(4-dimethylaminobenzyl)aminocarbonyloxy]-3-(dimethylamino)pentane, or

[0649] (f) mixtures and combinations thereof.

[0650] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0651] (a) 1-[bis(2-thienylmethyl)aminocarbonyloxymethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane,

[0652] (b) 1-[bis(2-thienylmethyl)aminocarbonyloxymethoxymethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane,

[0653] (c) 1-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane,

[0654] (d) 1-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane,

[0655] (e) 1-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-3-(dimethylamino)pentane,

[0656] (f) 1-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-3-(dimethylamino)pentane,

[0657] (g) 1-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxy]-3-(dimethylamino)pentane,

[0658] (h) 1-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxymethoxymethoxy]-3-(dimethylamino)pentane,

[0659] (i) 1-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxy}-3-(dimethylamino)pentane,

[0660] (j) 1-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxymethoxymethoxy}-3-(dimethylamino)pentane,

[0661] (k) a higher order analog, or

[0662] (l) mixtures and combinations thereof.

[0663] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0664] (a) 1-[bis(2-thienylmethyl)aminocarbonyloxyethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxyethoxy]-3-(dimethylamino)pentane,

[0665] (b) 1-[bis(2-thienylmethyl)aminocarbonyloxyethoxyethoxy]-5-[bis(2-thienylmethyl)aminocarbonyloxyethoxyethoxy]-3-(dimethylamino)pentane,

[0666] (c) 1-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]-3-(dimethylamino)pentane,

[0667] (d) 1-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]-5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]-3-(dimethylamino)pentane,

[0668] (e) 1-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-3-(dimethylamino)pentane,

[0669] (f) 1-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-5-{[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-3-(dimethylamino)pentane,

[0670] (g) 1-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy]-3-(dimethylamino)pentane,

[0671] (h) 1-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]-5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]-3-(dimethylamino)pentane,

[0672] (i) 1-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxy}-3-(dimethylamino)pentane,

[0673] (j) 1-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-5-{[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino]carbonyloxyethoxyethoxy}-3-(dimethylamino)pentane,

[0674] (k) a higher order analog, or

[0675] (l) mixtures and combinations thereof.

[0676] R a = (OCH2) n or CH3)(CH2O) n and Z = 3-dimethylamine species

[0677] In certain embodiments, the integrin agonist of formula (II) comprises one or more integrin agonists, wherein R a Groups include (OCH2) n or (OCH2CH2) n , wherein n is an integer from 1 to 6, and Z is dimethylamine. In other embodiments, the integrin agonist of formula (II) includes one or more of the following integrin activating compounds:

[0678] (a) 5-oxo-7-(2-thienyl)-6-(2-thienylmethyl)-2,4-dioxa-6-aza-heptyl-N,N-dimethylamine,

[0679] (b) 5-oxo-7-(3-methoxyphenyl)-6-(3-methoxybenzyl)-2,4-dioxa-6-aza-heptyl-N,N-dimethylamine,

[0680] (c) 5-oxo-7-(3-methoxyphenyl)-6-(4-dimethylaminobenzyl)-2,4-dioxa-6-aza-heptyl-N,N-dimethylamine,

[0681] (d) 5-oxo-7-(4-methoxyphenyl)-6-(4-methoxybenzyl)-2,4-dioxa-6-aza-heptyl-N,N-dimethylamine,

[0682] (e) 5-oxo-7-(4-methoxyphenyl)-6-(4-dimethylaminobenzyl)-2,4-dioxa-6-aza-heptyl-N,N-dimethylamine,

[0683] (f) 7-oxo-9-(2-thienyl)-8-(2-thienylmethyl)-2,4,6-trioxa-8-aza-nonyl-N,N-dimethylamine,

[0684] (g) 7-oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-2,4,6-trioxa-8-aza-undecyl-N,N-dimethylamine,

[0685] (h) 7-oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine,

[0686] (i) 7-oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine,

[0687] (j) 7-oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-2,4,6-trioxa-8-aza-dodecyl-N,N-dimethylamine,

[0688] (k) 9-oxo-11-(2-thienyl)-10-(2-thienylmethyl)-2,4,6,8-tetraoxa-10-aza-undecyl-N,N-dimethylamine,

[0689] (l) 9-oxo-11-(3-methoxyphenyl)-10-(3-methoxybenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine,

[0690] (m) 9-oxo-11-(3-methoxyphenyl)-10-(4-dimethylaminobenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine,

[0691] (n) 9-oxo-11-(4-methoxyphenyl)-10-(4-methoxybenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine,

[0692] (o) 9-oxo-11-(3-methoxyphenyl)-10-(4-dimethylaminobenzyl)-2,4,6,8-tetraoxa-10-aza-pentadecyl-N,N-dimethylamine,

[0693] (p) a higher order analog, or

[0694] (q) mixtures and combinations thereof.

[0695] In other embodiments, the integrin activating compound comprises one or more of the following integrin activating compounds:

[0696] (a) 7-oxo-9-(2-thienyl)-8-(2-thienylmethyl)-3,6-dioxa-8-aza-nonyl-N,N-dimethylamine,

[0697] (b) 7-oxo-9-(3-methoxyphenyl)-8-(3-methoxybenzyl)-3,6-dioxa-8-aza-nonyl-N,N-dimethylamine,

[0698] (c) 7-oxo-9-(3-methoxyphenyl)-8-(4-dimethylaminobenzyl)-3,6-dioxa-8-aza-nonyl-N,N-dimethylamine,

[0699] (d) 7-oxo-9-(4-methoxyphenyl)-8-(4-methoxybenzyl)-3,6-dioxa-8-aza-nonyl-N,N-dimethylamine,

[0700] (e) 7-oxo-9-(4-methoxyphenyl)-8-(4-dimethylaminobenzyl)-3,6-dioxa-8-aza-nonyl-N,N-dimethylamine,

[0701] (f) 10-oxo-12-(2-thienyl)-11-(2-thienylmethyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine,

[0702] (g) 10-oxo-12-(3-methoxyphenyl)-11-(3-methoxybenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine,

[0703] (h) 10-oxo-12-(3-methoxyphenyl)-11-(4-dimethylaminobenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine,

[0704] (i) 10-oxo-12-(3-methoxyphenyl)-11-(3-methoxybenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine,

[0705] (j) 10-oxo-12-(3-methoxyphenyl)-11-(4-dimethylaminobenzyl)-3,6,9-trioxa-11-aza-dodecyl-N,N-dimethylamine,

[0706] (k) 13-oxo-15-(2-thienyl)-14-(2-thienylmethyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine,

[0707] (l) 13-oxo-15-(3-methoxyphenyl)-14-(3-methoxybenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine,

[0708] (m) 13-oxo-15-(3-methoxyphenyl)-14-(4-dimethylaminobenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine,

[0709] (n) 13-oxo-15-(4-methoxyphenyl)-14-(4-methoxybenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine,

[0710] (o) 13-oxo-15-(3-methoxyphenyl)-14-(4-dimethylaminobenzyl)-3,6,9,12-tetraoxa-14-aza-pentadecyl-N,N-dimethylamine,

[0711] (p) a higher order analog, or

[0712] (q) mixtures and combinations thereof.

[0713] Appropriate reagents and materials

[0714] Surfactants

[0715] Zwitterionic surfactants

[0716] Suitable zwitterionic surfactants for use in the present disclosure include, but are not limited to, phospholipids, betaines, sultaines, sulfobetaines, amidobetaines, imidazoline betaines, or any combination thereof.

[0717] Suitable zwitterionic compounds include, but are not limited to: (1) having the general structure R 6 R 7 R 8 N + -R 9 -CO Any compound wherein R 6 , R 7 and R 8 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups or mixtures thereof, and R 9 is an alkenyl group, an oxyalkylene group or a mixture thereof; (2) having the general structure R 10 (R 7 R 8 N + -R 9 -CO ) n Any compound wherein R 7 and R 8 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups or mixtures thereof, R 9 is an alkenyl group, an oxyalkylene group or a mixture thereof, and R 10 is a polyvalent substituent having a valence n of 2 to about 6, such as a CH2 moiety (when n is 2), a CH moiety (when n is 3), a C atom (when n is 4); (3) having a general structure R 12 - C(O) - N(R11 ) - R 13 -N + (R 7 R 8 )- R 9 -CO A compound wherein R 7 , R 8 , R 11 and R 12 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups or mixtures thereof, and R 9 and R 13 are the same or different alkenyl groups, oxyalkylene groups or mixtures thereof; (4) having the general structure R 14 - [R 15 - C(O) - N(R 11 ) - R 13 -N + (R 7 R 8 ) -R 9 -CO ] m Any compound wherein R 7 , R 8 and R 11 are the same or different carbon-containing groups, amide carbon-containing groups, ether carbon-containing groups or mixtures thereof, R 9 , R 13 and R 15 are the same or different alkenyl groups, oxyalkylene groups or mixtures thereof, and R 14is a multivalent substituent having a valence m of 2 to about 6; other similar ammonium acid zwitterionic agents; or mixtures or combinations thereof. Preferred zwitterionic compounds are betaines such as cocamidopropyl betaine, 5-(1-piperidinylmethyl)-1H-tetrazolium or similar zwitterionic compounds. Other zwitterionic compounds used in the present invention include, but are not limited to, phospholipids capable of presenting a zwitterionic state, such as phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingomyelin and other ceramides, and various other zwitterionic phospholipids. Preferred sulfo-betaines and related zwitterionic compounds include, but are not limited to, N-decyl-N,N-dimethyl-3-ammonium-1-propanesulfonate; dimethylbenzyl-(3-sulfopropyl)ammonium; dimethylethyl-(3-sulfopropyl)ammonium; dimethyl-(2-hydroxyethyl)-(3-sulfopropyl)ammonium; 4-n-hexylbenzoylamido-propyl-dimethylammonium sulfobetaine; -methyl-N-(3-sulfopropyl)morpholinium; 4-n-octylbenzoylamido-propyl-dimethylammonium sulfobetaine; 1-(3-sulfopropyl)pyridium; N-tetradecyl-N,N-dimethyl-3-ammonium-1-propanesulfonate, or analogs or mixtures or combinations thereof.

[0718] Illustrative examples of phospholipids include, but are not limited to, phosphatidylcholine, 1-lysophosphatidylcholine, alkylglycerol monooxygenase, cardiolipin, dinogunellin, 1,2-dioleoyl-sn-glycerophosphoethanolamine, dipalmitoylphosphatidylcholine, polyterpenyl β-d-glucosyl phosphate, edelfosine, egg lecithin, soybean lecithin, endothelial lipase, glycerophospholipids, hydroxylated lecithin, phosphatidylcholine, lysophosphatidic acid, lysophosphatidylethanolamine, lysophosphatidylinositol, monolysocardiolipin, myo-inositol trispyrophosphate, perifosine, phosphatidylethanol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, (3,4,5)-phosphatidylinositol triphosphate, phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 3,5-bisphosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol phosphate, phosphatidylinositol-4-phosphate 5-kinase, phosphatidylinositol-inositol mannoside, phosphatidylserine, phosphatidylcholine, phytosome, PIP2 (disambiguation), POPC, SignaFresh, sphingomyelin, sphingosylphosphatide or any mixture thereof.

[0719] Illustrative examples of sulfobetaine include, but are not limited to, sulfobetaine 8 (SB-8), sulfobetaine 10 (SB-10), sulfobetaine 12 (SB-12), sulfobetaine 14 (SB-14), sulfobetaine 16 (SB-16), and / or sulfobetaine 18 (SB-18), available from Taiwan Hopax Chemicals Mfg. Co., Ltd.

[0720] Nonionic surfactants

[0721] Suitable nonionic surfactants are classified according to their hydrophilic-lipophilic balance (HLB) number, where low values ​​(≤10) correspond to greater lipophilicity and higher values ​​(≥10) correspond to higher hydrophilicity. Low HLB (<10) emulsifiers include, but are not limited to (a) phosphatidylcholine and phosphatidylcholine / solvent mixtures, such as phosphatidylcholine, phosphatidylcholine in propylene glycol, phosphatidylcholine in medium chain triglycerides, and phosphatidylcholine in safflower oil; (b) unsaturated polyglycolized glycerides, such as oleoyl macrogolglyceride and linoleoyl macrogolglyceride; (c) sorbitan esters, such as sorbitan monooleate, sorbitan monostearate, sorbitan monolaurate, and sorbitan monopalmitate; or (d) mixtures or combinations thereof. High HLB (> 10) emulsifiers include, but are not limited to: (a) polyoxyethylene sorbitan esters, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; (b) polyoxyethylene (polyoxyl) castor oil derivatives, such as polyoxyethylene 35 castor oil and polyoxyethylene 40 hydrogenated castor oil; (c) polyoxyethylene polyoxypropylene block copolymers, such as poloxamer 188 and poloxamer 407; (d) saturated polyglycol glycerides, such as lauroyl polyglycol glycerides and stearoyl polyglycol glycerides; (e) PEG-8 caprylic / capric glycerides, such as capryloyl caprylic polyglycol glycerides; (f) vitamin E derivatives, such as tocopherol PEG succinate; or (g) mixtures or combinations thereof. Other suitable nonionic surfactants include, but are not limited to, polyol esters, cyclic polyol esters, polyethylene glycol (PEG) esters, or mixtures and combinations thereof. Illustrative examples include, but are not limited to, sorbitan mono- and / or poly-fatty acid esters, sorbitol mono- and / or poly-fatty acid esters, mono-fatty acid glycerides, polyethylene glycol (PEG) ester surfactants, including hydrophilic and / or hydrophobic gelucires, such as hydrophilic GELUCIRE ®44 / 14, Lauroyl Macrogol Glycerides 1500, Hydrophobic GELUCIRE ® 43 / 01、GELUCIRE ® 39 / 01, GELUCIRE ® 33 / 01 or other gelucire; polyethylene glycol modified castor oil, such as polyoxyl 35 hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil; polysorbates, such as polysorbate 20, 40, 60, 80, etc., and TWEEN ® Surfactants; and mixtures or combinations thereof.

[0722] Sorbitan esters and sorbitan esters

[0723] Suitable sorbitan esters and / or sorbitol esters for use in the present disclosure include, but are not limited to: sorbitan monoesters such as sorbitan octanoate, sorbitan undecylenate, sorbitan laurate, sorbitan palmitate, sorbitan isostearate, sorbitan oleate, sorbitan stearate, and the like; sorbitan sesquiesters such as sorbitan sesquioctanoate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, and the like; esters, etc.; sorbitan diesters, such as sorbitan diisostearate, sorbitan dioleate, sorbitan distearate, etc.; (2002) sorbitan triesters, such as sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate, etc.; mixed chain sorbitan esters, such as sorbitan cocoate, sorbitan oliveate, sorbitan palmitate, sorbitan theobroma grandiflorumsedate, etc.; or mixtures and combinations thereof. Other sorbitan esters or sorbitol esters include, but are not limited to, PEG sorbitan and sorbitan fatty acid esters, including PEG-20 sorbitan cocoate, PEG-40 sorbitan diisostearate, PEG-2 sorbitan isostearate, PEG-5 sorbitan isostearate, PEG-20 sorbitan isostearate, PEG-40 sorbitan lanolinate, PEG-75 sorbitan lanolinate, PEG-10 sorbitan laurate, PEG-40 sorbitan laurate, PEG-44 sorbitan laurate, PEG-75 sorbitan laurate, PEG-80 sorbitan laurate, PEG-3 sorbitan oleate, PEG-6 sorbitan oleate, PEG-80 sorbitan palmitate , PEG-40 sorbitan isostearate, PEG-40 sorbitan full oleate, PEG-3 sorbitan stearate, PEG-6 sorbitan stearate, PEG-40 sorbitan stearate, PEG-60 sorbitan stearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan tetraoleate, PEG-60 sorbitan stearate PEG-60 sorbitan tetrastearate, PEG-160 sorbitan triisostearate; PEG-20 sorbitan triisostearate, sorbitan polyoxyethylene ether (Sorbeth)-40 hexaoleate, sorbitan polyoxyethylene ether-50 hexaoleate, sorbitan polyoxyethylene ether-30 tetraoleate laurate, sorbitan polyoxyethylene ether-60 tetrastearate, and any mixture thereof.These PEG sorbitans or sorbitols range from tan, waxy solids and amber pastes to clear yellow liquids. Other exemplary nonionic surfactants include, but are not limited to, polyoxyethylene surfactants such as POE sorbitan monolaurate (Tween 20, HLB 17), POE sorbitan monopalmitate (Tween 40, HLB 15.6), POE sorbitan monostearate (Tween 60, HLB 15.0), POE sorbitan monooleate (Tween 80, HLB 15.0), POE sorbitan tristearate (Tween 65, HLB 10.5), POE sorbitan trioleate (Tween 85, HLB 11.0), POE triolein (Tagat TO, HLB 11.5), POE-40-hydrogenated castor oil (solid) Cremophore RH 40, HLB 14.0 to 16.0), POE-35-castor oil (Cremophore RH 40, HLB 14.0 to 16.0). EL (liquid), HLB 12.0-14.0), POE (10) oleyl ether (Brij 96, HLB 12.4), POE (23) lauryl ether (Brij 35, HLB 16.9), POE-vitamin E (α-tocopherol TPGS, HLB 13.0), and mixtures or combinations thereof.

[0724] Poloxamer

[0725] Suitable poloxamers include, but are not limited to, nonionic triblock copolymers consisting of a polyoxypropylene (poly(oxypropylene)) central hydrophobic chain flanked by two polyoxyethylene (poly(oxyethylene)) hydrophilic chains. Poloxamers are also known by the trade names Synperonics, Pluronics, and Kolliphor. Because the length of the polymer block can be customized, there are many different poloxamers with slightly different properties. For the general term poloxamer, these copolymers are usually named with the letter P (standing for poloxamer) followed by three digits: the first two digits multiplied by 100 give the approximate molecular weight of the polyoxypropylene core, and the last digit multiplied by 10 gives the percentage of polyoxyethylene content (e.g., P407 = a poloxamer with a polyoxypropylene molecular weight of 4000 g / mol and a polyoxyethylene content of 70%). For the trade names Pluronic and Synperonic, the codes for these copolymers begin with a letter to define their physical form at room temperature (L = liquid, P = paste, F = flake (solid)), followed by two or three digits. The first digit (two digits of a three-digit number) in the numerical designation multiplied by 300 represents the approximate molecular weight of the hydrophobic component; and the last digit multiplied by 10 represents the percentage of polyoxyethylene content (e.g., L61 represents a polyoxypropylene molecular weight of 1800 g / mol and a polyoxyethylene content of 10%). In a given example, Poloxamer 181 (P181) = Pluronic L61 and Synperonic PE / L 61.

[0726] Nonionic neutral polymer

[0727] Suitable nonionic neutral polymers include, but are not limited to, pH responsive nonionic polymers and temperature sensitive nonionic polymers. Illustrative examples of such pH responsive nonionic polymers include, but are not limited to, pH responsive dendrimers such as polyamidoamine (PAMAM) dendrimers, poly(propyleneimine) dendrimers, poly(l-lysine) esters, poly(hydroxyproline), poly(propyl acrylic acid), poly(methacrylic acid), Carbopol®, Eudragit® S-100, Eudragit® L-100, chitosan, poly(methacrylic acid) (PMMA), PMAA-PEG copolymers, N,N-dimethylaminoethyl methacrylate (DMAEMA), and any mixture thereof. Illustrative examples of temperature-sensitive polymers include, but are not limited to, poloxamers (Pluronics®), prolastin, poly(n-substituted acrylamides), poly(organophosphazenes), cyclotriphosphazenes with poly(ethylene glycol) and amino acid esters, block copolymers of poly(ethylene glycol) / poly(lactic-co-glycolic acid), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), PMAA, poly(vinyl alcohol) (PVA), various silk elastin-like polymers, poly(amino silicones) (poly(silamine)), poly(vinyl methyl ether) (PVME), poly (vinyl methyl oxazolidinone) (PVMO), poly(vinyl pyrrolidone) (PVP), poly(n-vinyl caprolactam), poly(N-vinyl isobutylamide), poly(vinyl methyl ether), poly(N-vinyl caprolactam) (PVCL), poly(siloxyethylene glycol), poly(dimethylaminoethyl methacrylate), poly(DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) triblock copolymer (PLGA-PEG-PLGA), cellulose derivatives, alginate, gellan gum, xyloglucan and any mixture thereof.

[0728] Anionic surfactants

[0729] Suitable anionic surfactants include, but are not limited to, anionic sulfate surfactants, alkyl ether sulfonates, alkyl aryl sulfonates, or mixtures or combinations thereof. Preferred alcohol ether sulfate ester sodium or ammonium salt surfactants include those having the general formula R 1 O-(CH2CH2O) n SO3NH4, where R 1is a carbon-containing group including alkyl, aryl, alkaryl, aralkyl or mixtures thereof. Particularly preferred alcohol ether sulfate sodium or ammonium salt surfactants include short chain alcohol ether sulfate sodium or ammonium salt surfactants having 2 to about 10 carbon atoms, particularly having about 4 to 10 carbon atoms, and long chain alcohol ether sulfate sodium or ammonium salt surfactants having about 10 to about 24 carbon atoms, more particularly having about 12 to about 18 carbon atoms, particularly having about 12 to about 14 carbon atoms. The alcohol ether sulfate sodium or ammonium salt surfactant is prepared by reacting 1 to 10 moles of ethylene oxide per mole of alkanol, preferably by reacting 3 moles of ethylene oxide per mole of alkanol.

[0730] Preferred alkylaryl sulfonates include, but are not limited to, alkylbenzene sulfonic acid and its salts, dialkylbenzene disulfonic acid and its salts, dialkylbenzene sulfonic acid and its salts, alkyltoluene / alkylxylene sulfonic acid and its salts, alkylnaphthalene sulfonic acid / condensed alkylnaphthalene sulfonic acid and its salts, alkylphenol sulfonic acid / condensed alkylphenol sulfonic acid and its salts, or mixtures or combinations thereof.

[0731] Preferred alkyl ether sulfonates include, but are not limited to, those having the general formula R 2 [-(OR 3 O)m-(R 4 O)n-(R 5 )] y Alkyl ether sulfonate, wherein: R 2 = alkyl, alkenyl, amine, alkylamine, dialkylamine, trialkylamine, aromatic, polyaromatic, cycloalkane, cycloalkene, R 3 , R 4 = C2H4 or C3H6 or C4H8, when y=1, R 4 = Straight or branched C7H 14 SO3X to C 30 H 60 SO3X, when y>1, R 5 = Straight or branched C7H 14 SO3X to C 30 H 60 SO3X or H, but at least one R 4 Must be a straight or branched chain C7H 14 SO3X to C 30 H 60 SO3X, M is greater than or equal to 1, n is greater than or equal to 0, n+m=1 to 30+, y is greater than or equal to 1, X=alkali metal or alkaline earth metal or ammonium or amine.

[0732] Cationic surfactants

[0733] Suitable cationic surfactants include, but are not limited to, Gemini di- or diquaternary ammonium surfactants, such as diquaternary ammonium halides of dihaloethane, propane, butane or higher halogenated alkyls (e.g., dichloroethane or dibromoethane) or dihalogenated ethers (e.g., dichloroethyl ether (DCEE)). Preferred diquaternary ammonium halides are prepared from substituted dimethyl tertiary amines, wherein the substituent comprises from about 4 to about 30 carbon atoms, preferably from about 6 to about 24 carbon atoms, and particularly from about 8 to about 24 carbon atoms, and wherein one or more carbon atoms may be substituted with an oxygen atom in the form of an ether and / or hydroxyl moiety, and / or substituted with an amide moiety by a nitrogen atom. Particularly preferred diquaternary ammonium halide hydrocarbons are prepared from naturally occurring acids, such as fatty acids, synthetic acids, modified naturally occurring acids, or mixtures or combinations thereof. Preferred naturally occurring acids are those found in naturally occurring oils, such as coconut oil, palm oil, palm kernel oil, soybean oil, safflower oil, sunflower oil, peanut oil, canola oil, or from animals, such as tallow and derivatives thereof. Preferred diquaternary ammonium halides are prepared from disubstituted methyl tertiary amines, wherein the substituents contain from about 4 to about 30 carbon atoms, preferably from about 6 to about 24 carbon atoms, and especially from about 8 to about 24 carbon atoms, and wherein one or more carbon atoms may be substituted with oxygen atoms in the form of ether and / or hydroxyl moieties, and / or with nitrogen atoms in the form of amide moieties, such as amidopropyl tertiary amines derived from the reaction of dimethylaminopropylamine (DMAPA) or similar blocked primary-tertiary diamines with the above oils or their corresponding fatty acids or hydroxy acids. Other preferred cationic surfactants are dimer acids or anhydrides, including alkyl substituted maleic anhydride, alkyl substituted diethylmalonic acid, or alkyl substituted higher diacids such as azelaic acid (C9), trimer acids such as NTA (nitriloacetic acid), and aconitic acid and trimetellic anhydride are useful, although higher trimers are produced. The tertiary amine can be obtained by reacting a diamine with a fatty acid or oil, reacting with an amine, and then converting another primary amine into a tertiary amine by adding tetrahydrofuran, ethylene oxide, propylene oxide, butylene oxide, epichlorohydrin, etc., and further wherein the terminal hydrogen of the primary amine can be alkylated using a formaldehyde / formic acid mixture.

[0734] Neutral lipids

[0735] Fatty acid esters

[0736] Suitable neutral lipids for use in the present disclosure include, but are not limited to, fatty acid esters, such as alkyl fatty acid esters and / or polyoxyalkylene fatty acid esters.

[0737] Illustrative examples of fatty acid esters include esters of any of the fatty acids listed above, including but not limited to monohydric alcohol esters, wherein the monohydric alcohol or polyhydric alcohol contains from 1 carbon atom to 20 carbon atoms, wherein one or more carbon atoms may be substituted with O, NR (R is a divalent carbyl or hydrocarbyl group having 1 to 5 carbon atoms), or S. Exemplary monohydric alcohols for forming free fatty acid esters include methanol, ethanol, propanol, butanol, pentanol, or mixtures thereof.

[0738] Illustrative examples of fatty acid esters include: (a) short chain fatty acid esters (SCFE), including all esters of fatty acids having less than six carbons; (b) medium chain fatty acid esters (MCFE), including all esters of fatty acids having 6 to 12 carbons; (c) long chain fatty acid esters (LCFE), including all esters of fatty acids having 13 to 21 carbons; and (d) very long chain fatty acid esters (VLCFE), including all esters of fatty acids having more than 22 carbons.

[0739] Fatty acid glycerides

[0740] Suitable mono-, di- and / or triglycerides include those derived from animals or plants - animal oils and vegetable oils. Exemplary animal oils include, but are not limited to, adipose tissue oil, beef tallow, blubber, bone oil, bottlenose oil, butter, milk fat, chicken fat, cod-liver oil, fish oil, ghee, goose fat, halibut-liver oil, hog lard, lanolin, lard, lard oil, lipid, lipoma, margarine, neat's-foot oil, oleo, oleo oil, oleomargarine, dolphin oil, salmon oil, sardine oil, seal oil, shark oil, shortening, sperm oil, suet, tallow, tallow oil, tuna oil, whale oil, wool fat or wool grease. Exemplary animal oils include, but are not limited to, coconut oil, corn oil, canola oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, almond oil, beech nut oil, Brazil nut oil, cashew oil, hazelnut oil, macadamia oil, mongongo nut oil, walnut oil, pine nut oil, pistachio oil, walnut oil, pumpkin seed oil, grapefruit seed oil, lemon oil, orange oil, bitter melon oil, bottle gourd oil, buffalo gourd oil, butternut squash seed oil, pumpkin seed oil, watermelon seed oil, and any mixture thereof.

[0741] Illustrative examples of monoglycerides include: (a) short-chain monoglycerides (SCM), including all glycerides with fatty acids having less than six carbons; (b) medium-chain monoglycerides (MCM), including all glycerides with fatty acids having from 6 to 12 carbons; (c) long-chain fatty acid monoglycerides (LCM), including all glycerides with fatty acids having from 13 to 21 carbons; and (d) very long-chain fatty acid monoglycerides (VLCM), including all glycerides with fatty acids having more than 22 carbons.

[0742] Illustrative examples of diglycerides include: (a) short-chain diglycerides (SCD), including all glycerides with fatty acids having less than six carbons; (b) medium-chain diglycerides (MCD), including all glycerides with fatty acids having from 6 to 12 carbons; (c) long-chain fatty acid diglycerides (LCD), including all glycerides with fatty acids having from 13 to 21 carbons; and (d) very long-chain fatty acid diglycerides (VLCD), including all glycerides with fatty acids having more than 22 carbons.

[0743] Illustrative examples of triglycerides include: (a) short-chain triglycerides (SCT), including all glycerides with fatty acids having less than six carbons; (b) medium-chain triglycerides (MCT), including all glycerides with fatty acids having from 6 to 12 carbons; (c) long-chain triglycerides (LCT), including all glycerides with fatty acids having from 13 to 21 carbons; and (d) very long-chain triglycerides (VLCT), including all glycerides with fatty acids having more than 22 carbons.

[0744] Biocompatible oil

[0745] Suitable biocompatible oils include but are not limited to any oil approved by the FDA or other government agencies for human, mammal or animal consumption. Exemplary biocompatible oils include but are not limited to oils of plant origin or oils of animal origin or derivatives thereof or synthetic oils. In a specific embodiment, natural oils are oils rich in phospholipids, such as the lecithin oil from soybean. The illustrative examples of oils of plant origin or oils of animal origin or derivatives thereof or synthetic oils include but are not limited to essential oils, vegetable oils and hydrogenated vegetable oils such as peanut oil, canola oil, avocado oil, safflower oil, olive oil, corn oil, soybean oil, sesame oil, vitamin A, vitamin D, vitamin E etc., animal oils, fish oils, krill oil etc., or its mixture.

[0746] In a specific embodiment, biocompatible oil is a neutral lipid. Suitable neutral lipid includes but is not limited to any neutral lipid, such as triglyceride. For the partial list of representative neutral lipids (such as triglyceride), specifically with reference to U.S. Patent number 4,950,656 and 5,043,329. Saturated triglyceride and unsaturated triglyceride can all be used in the composition of the present invention, and include triglyceride such as tripalmitin (saturated), triolein and trilinolein (unsaturated). However, these specific triglycerides are only the representative examples of available triglyceride.

[0747] Animal fats include, but are not limited to, lard, duck fat, butter, or mixtures or combinations thereof.

[0748] Vegetable fats include, but are not limited to, coconut oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, hemp oil, canola oil, or mixtures and combinations thereof.

[0749] gelatin

[0750] Suitable gelatin includes chemical materials with ATC (Anatomical Therapeutic Chemical Classification) registration number B05AA06 and CAS (Chemical Abstracts Service) registration number 0009000-70-8. Suitable gelatin has a chemical description of a purified protein obtained by partial acid hydrolysis (type A), partial alkaline hydrolysis (type B) or enzymatic hydrolysis of collagen from animals; it can also be a mixture of different types.

[0751] Gelatin is marketed under the following common names: Gelatin (official synonym: Japanese Accepted Name), Gélatine (official synonym: Dénomination Commune Française), Gelatin alba (unofficial synonym), Gelatin animalis (unofficial synonym), UNII-2G86QN327L (unofficial synonym), Gelatin (Pharmacopoeia name: BP 2018, JP XVII, The National Formulary 33, Ph. Eur. 9.3, Ph. Int. 7), Gelatin (Pharmacopoeia name: Ph. Eur. 9.3, Ph. Int. 7), Gelatine (Pharmacopoeia name: Ph. Eur. 9.3), Gélatine (Pharmacopoeia name: Ph. Eur. 9), Purified Gelatin (Pharmacopoeia name: JP XVII), Absorbable Gelatin (absorbable gelatin) (Pharmacopoeia name: USP 41), Gelatine Polysuccinat zur parenteralen Anwendung (unofficial synonym), Gelofusin (unofficial synonym), Modified fluid gelatin (modified fluid gelatin) (unofficial synonym) and Modified gelatine (unofficial synonym).

[0752] Gelatin is sold under the following trade names: Colagenan, produced by Herbarium Laboratório Botânico, Brazil; Gelatina Pharma Arte, produced by Pharma Arte, Paraguay; Gelfilm, produced by Pfizer, New Zealand; Gelfoam, produced by Pfizer, New Zealand; Gelofusine, produced by B. Braun, France; Gelofusine, produced by B. Braun [+ sodium chloride], Hungary, B. Braun Medical, Latvia, and JV Healthcare Limited, Malta; Geloplasma, produced by Fresenius Kabi, Estonia, Fresenius Kabi, Romania, Fresenius Kabi Austria, and Fresenius-Kabi, Argentina; Geloplasma [+ magnesium chloride, + potassium chloride, + sodium chloride, + sodium lactate], produced by Fresenius Kabi, Latvia; Glycerin AD [+ glycerol], produced by Pharco, Egypt; Glycerin Inf [+ glycerol], produced by Pharco, Egypt; Glycerin Pharco [+ glycerin], produced by Pharco in Kuwait; Glycerol Adult [+ glycerin], produced by Sedico in Egypt; Glycerol Infant [+ glycerin], produced by Sedico in Egypt; Intragel [+ sodium chloride] [for veterinary use], produced by Zoetis in the United States; Stomahesive [+ pectin, + carboxymethyl cellulose], produced by Bristol-Myers Squibb in Uruguay; Tego, produced by Armstrong Laboratorios deMexico in Mexico; Valcatil [+ cysteine, + methionine], produced by Panalab in Argentina and Panalab in Paraguay; Gelfilm, produced by Pfizer Japan in Japan; Gelfoam, produced by Pfizer Singapore and Pfizer Japan in Japan; Spongel, produced by Astellas in Japan; Eufusin, produced by Medacta Italia in Italy; Galafundin [+ calcium chloride, + sodium chloride], produced by Braun in Kuwait; Gelafundin, produced by Buminusantara in Indonesia BestariPerkasa / B Braun, produced by Pisa, Mexico; Gelafundin 4%, produced by B. Braun, Germany; GelafundinISO, produced by B. Braun, Germany.Braun; Gelafundina, produced by B. Braun Medical in Spain; Gelafusal, produced by Biomed New Zealand and Serumwerk Bernburg in Germany; Gelaspan, produced by B. Braun Medical in Spain, B. BraunB. Braun Melsungen in Romania and Braun in Norway; Gelaspan 4%, produced by B. BraunMedical in Estonia; Gelofusine, produced by B. Braun in Italy, B. Braun Medical in Denmark, B. BraunMedical in Ecuador, B. BraunMedical in the Netherlands, B. Braun Melsungen in Serbia, B. BraunB.Braun Melsungen in Romania and Biomed in New Zealand; Gelofusine [+ sodium chloride], produced by B. Braun in Bulgaria, B. Braun in the Czech Republic, B. Braun Austria in Austria, B. Braun Medical in China and Braun in Sweden; Geloplasma, produced by Fresenius in Spain Kabi; Geloplasma [+magnesium chloride, +potassium chloride, +sodium chloride, +sodium lactate], produced by Fresenius Kabi, Czech Republic, Fresenius Kabi, Slovenia, France; Infuplas, produced by Fresenius Kabi, Italy; Isoplex 4%, produced by Beacon Pharmaceuticals, UK; Volplex 4%, produced by Beacon, Malta, Beacon Pharmaceuticals, UK. .

[0753] Excipients or adjuvants

[0754] The formulations or compositions of the present disclosure may also include other chemicals, such as antioxidants (e.g., vitamins A, C, D, E, etc.), trace metals and / or polyvalent cations (aluminum, gold, copper, zinc, calcium, etc.), surfactants and / or solvents (e.g., propylene glycol / PPG, dimethyl sulfoxide / DMSO, medium chain triglycerides / MCT, etc.), non-toxic dyes and flavor enhancers may be added to the formulation during preparation to improve stability, fluidity / diffusivity, permeability, effectiveness, and consumer acceptance. These additives, excipients, and / or adjuvants may also serve as active agents.

[0755] Suitable organic solvents for use in the present disclosure are not limited to ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, or any combination thereof.

[0756] Experimental study of the present invention

[0757] Capsule filling preparations

[0758] Example 1

[0759] Preferred capsule filling formulations

[0760] The preferred capsule solution contains suitable for soft gelatin or two-piece capsule packaging (for 7HP349), 50 mg dosage form as shown in Table 5. The capsule fill formulation contains 5% w / w 7HP349 + 14% w / w ethanol + 81% w / w Phosal 53 MCT, an oil containing soy phosphatidylcholine (PC), the same excipients present in the 7HP349 capsule drug product. All materials used in formulation development and intended for placebo are GMP qualified pharmacopoeial inactive ingredients.

[0761] Table 5

[0762] 7HP349 dosage unit composition, drug function and quality standards

[0763]

[0764] The components in Phosal are in accordance with USP / NF and Ph. Eur. The ethanol content in the bulk fill formulation is 14.7%. A minimum of 10% ethanol is sufficient to maintain API solution stability. The excess ethanol added in the bulk fill formulation is to accommodate losses during capsule drying.

[0765] Phosal 53 MCT, an oil containing soy lecithin, has been shown to improve the oral bioavailability of small hydrophobic molecules. The ingredients and the pharmacopoeial status of the ingredients are summarized in Table 6.

[0766] Table 6

[0767] Phosal 53 MCT Composition and Pharmacopoeia Status of Ingredients

[0768]

[0769] Calculated based on the maximum range reported by the manufacturer for a 50 mg capsule

[0770] Formulation Development

[0771] Example 2

[0772] Physical stability of 7HP349 filled formulations

[0773] The physical stability of different 7HP349 filled formulations containing Phosal 53 MCT was tested at EurofinsAdvinus Limited at 2 to 8°C (long term), 25±2°C @ 60±5% RH (ambient) and 40±2°C @ 75±5% RH (accelerated) storage conditions for three months. The test conditions for physical stability are shown in Table 7. The composition of the different 7HP349 formulations tested is shown in Table 8.

[0774] Table 7

[0775] 7HP349 Test Conditions for Evaluation of Physical Stability of Filled Formulations

[0776]

[0777] Table 8

[0778] Testing of physical stability of different 7HP349 formulations

[0779]

[0780] The ethanol content in Phosal 53 MCT is 5.2%. The total ethanol content is the sum of the ethanol content in Phosal 53 MCT plus the added ethanol, making the resulting content ~15%.

[0781] Physical Stability Summary

[0782] All formulation samples were tested for precipitation, color change and phase separation during storage. In summary, all formulation samples stored under ambient conditions (25 ± 2°C, at 60 ± 5% RH) were found to be stable over 3 months without any physical appearance changes. Some formulation samples stored under refrigeration (2 to 8°C) and accelerated conditions (40 ± 2°C @ 75 ± 5% RH) showed phase separation with small globules and precipitation, which became clear solutions after vortex mixing and ultrasound.

[0783] Table 9

[0784] Summary of the 3-month physical stability of 7HP349 formulation

[0785]

[0786]

[0787] Example 3

[0788] Dosage Form Characterization

[0789] A summary of the initial evaluation values ​​and impurity levels for the different fill formulations and different fill-shell (two-piece capsule) combinations tested is shown in Table 10. The initial evaluation values ​​and impurity levels for two development batches of 7HP349 capsules (50 mg) are shown in Tables 11 and 12. In all formulations, 7HP349 remained stable and no new impurities were identified.

[0790] Table 10

[0791] Initial purity and related substances of different 7HP349 filler formulations and evaluated filler-shell combinations

[0792]

[0793] Phosal 53 MCT contains ~5% ethanol. Ethanol concentrations mentioned here are for further additions. Absolute % values ​​are for chromatographic purity determinations for fill formulations U28, U38 and U39. % label claims are for shell fill and capsules.

[0794] Example 4

[0795] The following examples illustrate compositions that can be administered to a patient parenterally, e.g., intravenously, intra-arterially, intramuscularly, or by injection, wherein the composition has anti-solid tumor activity, improves antigen presentation before, during, and / or after antigen administration, enhances antigen presenting cell (APC) activity, enhances immune response to a vaccine before, during, and / or after vaccine administration, enhances T cell activity, naive or antigen-activated T cells, enhances therapeutic antibody activity before, during, and / or after therapeutic antibody administration, enhances checkpoint inhibitor activity (therapeutic antibody checkpoint inhibitor administration), and / or enhances hematopoietic stem cell bone marrow reconstitution before, during, and / or after hematopoietic stem cell administration.

[0796] The composition contains the following ingredients:

[0797]

[0798] Phosal 53 MCT contains the following ingredient range:

[0799]

[0800] In a specific embodiment, the composition comprises the following ingredient ranges:

[0801]

[0802] In a specific embodiment, the ZIS comprises about 90 wt% phosphatidylcholine and about 10 wt% lysophosphatidylcholine, the organic solvent comprises alcohol, and the NL comprises about 94.12 wt% to about 99.56 wt% triglycerides, about 2.94 wt% to about 0.22 wt% ascorbic acid fatty acid esters, and about 2.94 wt% to about 0.22 wt% alpha-tocopherol. In other embodiments, the organic solvent comprises ethanol.

[0803] In a particular embodiment, the carrier comprises from about 30.76 wt % to about 28.71 wt % of one or more ZIS, from about 28.91 wt % to about 20.35 wt % of one or more NL, from about 9.56 wt % to about 16.18 wt % of one or more organic solvents, from about 23.05 wt % to about 21.71 wt % of one or more gelatins, and from about 7.72 wt % to about 13.05 wt % of a blend of sorbitol and glycerin.

[0804] When added to an aqueous injectable pharmaceutical carrier, the composition forms a stable emulsion.

[0805] Pharmacokinetic Example

[0806] Example 5

[0807] Several target 7HP349 solutions suitable for liquid-filled capsules were tested. Non-lipid-based solutions (e.g., "solutions") with high surfactant levels provided limited bioavailability. Medium chain triglycerides and high surfactant provided greater absorption (Formulation Q), while the addition of phospholipids to MCTs in U28 further improved bioavailability.

[0808] Table 11

[0809] Preparation U28 compared to other preparations

[0810]

[0811] Formulation Q: 7HP349 - 1.0 g, Capmul MCM - 2.125 g, polysorbate 80 - 1.875 g.

[0812] Formulation U28: 7HP349 - 5% w / w, Ethanol - 10% w / w, Phosal 53 MCT - 85% w / w.

[0813] Solution preparation: 5% DMSO + 10% Cremophor EL + 35% PEG400 + 0.1 M citric acid buffer pH 2.7

[0814] The preferred U28-based lipid-based formulation provides adequate exposure in humans. The optimal PK exposure involving integrins and improved adjuvant activity is a systemic plasma exposure with an AUC0-t of about 50 ng / mL / hr to about 100 ng / mL / hr.

[0815] Table 12

[0816] Human SAD PK Data

[0817]

[0818] Data are presented as mean ± SD (n = 6 per cohort), except for T max Except for the median (range).

[0819] Implementation of the Disclosure

[0820] Embodiment 1. A carrier composition, comprising:

[0821] one or more surfactants (SRF), and

[0822] One or more neutral lipids (NL).

[0823] Embodiment 2. A pharmaceutical composition, comprising:

[0824] A carrier composition, the carrier composition comprising:

[0825] One or more SRFs, and

[0826] One or more NL, and

[0827] One or more poorly water soluble pharmaceutical agents.

[0828] Embodiment 3. A pharmaceutical composition, comprising:

[0829] A soft gel capsule filled with a filling composition comprising:

[0830] A carrier composition, the carrier composition comprising:

[0831] One or more SRFs, and

[0832] One or more NL, and

[0833] One or more poorly water soluble pharmaceutical agents.

[0834] Embodiment 4. Embodiment 1, 2 or 3, further comprising:

[0835] One or more organic solvents.

[0836] Embodiment 5. Embodiment 1, 2, 3 or 4, wherein the one or more SRFs comprise:

[0837] one or more zwitterionic surfactants (ZIS), or

[0838] One or more nonionic surfactants (NIS), or

[0839] Any mixture or combination thereof.

[0840] Embodiment 6. Embodiment 5, wherein the one or more SRFs further comprise:

[0841] One or more ionic surfactants (IS).

[0842] Embodiment 7. Embodiment 1, 2, 3 or 4, wherein the one or more SRFs comprise:

[0843] One or more ZIS.

[0844] Embodiment 8. Embodiment 1, 2, 3 or 4, wherein the one or more SRFs comprise:

[0845] One or more NIS.

[0846] Embodiment 9. Embodiment 1, 2, 3 or 4, wherein the one or more SRFs comprise:

[0847] One or more ZIS, and

[0848] One or more NIS.

[0849] Embodiment 10. Embodiment 6, wherein the one or more SRFs comprise:

[0850] One or more ZIS,

[0851] One or more NIS, and

[0852] One or more IS.

[0853] Embodiment 11. Any of the preceding embodiments, wherein:

[0854] The one or more SRFs are present in an amount from about 5 wt % to about 95 wt % or any subrange thereof, and

[0855] The one or more NLs are present in an amount from about 95 wt % to about 5 wt % or any subrange thereof.

[0856] Embodiment 120. Any of the preceding embodiments, wherein:

[0857] about 99 wt % to about 75 wt % of a SRF / NL mixture comprising one or more SRFs and one or more NLs, or any subrange thereof, and

[0858] From about 1 wt % to about 25 wt % of one or more organic solvents, or any subrange thereof.

[0859] Embodiment 13. Any of the preceding embodiments, wherein the one or more SRFs comprise:

[0860] about 99 wt % to about 90 wt % of an SRF mixture comprising one or more ZIS, one or more NIS, or any mixture thereof, or any subrange thereof, and

[0861] From about 1 wt % to about 10 wt % of one or more IS, or any subrange thereof.

[0862] Embodiment 14. Any of the preceding embodiments, wherein:

[0863] The carrier composition is present in an amount from about 75% to about 97% by weight or any subrange thereof, and

[0864] The one or more poorly water soluble pharmaceutical agents are present in an amount from about 25 wt % to about 1 wt % or any subrange thereof.

[0865] Embodiment 15. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0866] about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and

[0867] From about 100 wt % to about 80 wt % of an NL mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any subrange thereof.

[0868] Embodiment 16. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0869] about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and

[0870] About 100 wt % to about 80 wt % of a MC mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any subrange thereof.

[0871] Embodiment 17. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0872] about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and

[0873] About 100 wt % to about 80 wt % of an LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any subrange thereof.

[0874] Embodiment 18. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0875] about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and

[0876] About 100 wt % to about 80 wt % of a VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any subrange thereof.

[0877] Embodiment 19. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0878] MC mixture, the MC mixture comprising one or more MCM, one or more MCD, one or more MCT, one or more MCFE, or any mixture thereof, or any sub-range thereof.

[0879] Embodiment 20. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0880] LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs or any mixture thereof, or any sub-range thereof.

[0881] Embodiment 21. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0882] A VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

[0883] Embodiment 22. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0884] one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof, and

[0885] One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof.

[0886] Embodiment 23. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0887] one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof, and

[0888] One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof.

[0889] Embodiment 24. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0890] One or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof,

[0891] one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof, and

[0892] One or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

[0893] Embodiment 25. Any of the preceding embodiments, wherein the one or more NLs comprise:

[0894] one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof, and

[0895] One or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

[0896] Embodiment 26. Any of the preceding embodiments, wherein the one or more poorly water-soluble pharmaceutical agents comprises:

[0897] One or more poorly water-soluble small molecule integrin agonist adjuvant drug agents.

[0898] Embodiment 27. Embodiment 26, wherein the one or more poorly water-soluble pharmaceutical agents have a Log P value in n-octanol relative to water greater than 5 (Log P > 5).

[0899] Embodiment 28. A drug carrier composition, comprising:

[0900] A vector, the vector comprising:

[0901] about 30.76 wt % to 28.71 wt % of one or more ZIS,

[0902] about 28.91 wt. % to 20.35 wt. % of one or more NLs,

[0903] about 9.56 wt % to 16.18 wt % of one or more organic solvents,

[0904] about 23.05% to 21.71% by weight of one or more gelatins, and

[0905] A blend of about 7.72% to 13.05% by weight of sorbitol and glycerin.

[0906] Embodiment 29. A pharmaceutical composition comprising:

[0907] about 1.50 wt % to about 4.20 wt % of one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents,

[0908] A vector, the vector comprising:

[0909] about 30.30 wt. % to about 27.50 wt. % of one or more ZIS,

[0910] about 28.48 wt. % to about 19.50 wt. % of one or more NLs,

[0911] from about 9.42% to about 15.50% by weight of one or more organic solvents,

[0912] from about 22.70% to about 20.80% by weight of one or more gelatins,

[0913] about 7.60% to about 12.50% by weight of a blend of sorbitol and glycerin, and

[0914] Contains essentially no water.

[0915] Medicinal aqueous injection system,

[0916] wherein the composition comprises a stable injectable emulsion.

[0917] Embodiment 30. An injectable pharmaceutical composition comprising:

[0918] A drug system, comprising:

[0919] about 1.50 wt % to about 4.20 wt % of one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents,

[0920] A vector, the vector comprising:

[0921] about 30.30 wt. % to 27.50 wt. % of one or more ZIS,

[0922] about 28.48 wt % to 19.50 wt % of one or more NLs,

[0923] about 9.42% to 15.50% by weight of one or more organic solvents,

[0924] about 22.70% to 20.80% by weight of one or more gelatins,

[0925] about 7.60% to 12.50% by weight of a blend of sorbitol and glycerin, and

[0926] Contains substantially no water, and

[0927] Medicinal aqueous injection system,

[0928] wherein the composition comprises a stable injectable emulsion.

[0929] Embodiment 31. Embodiment 28, 29 or 30, wherein the weight ratio of the drug system to the pharmaceutical aqueous injection system is about 1:2 to 1:10.

[0930] Embodiment 32. Embodiment 28, 29, 30 or 31, wherein the lecithin comprises:

[0931] One or more ZIS, and

[0932] One or more NLs.

[0933] Embodiment 33. Any of the preceding embodiments, wherein:

[0934] The one or more SRFs comprise:

[0935] one or more zwitterionic surfactants (ZIS),

[0936] One or more nonionic surfactants (NIS), or

[0937] any combination thereof;

[0938] The one or more NLs comprise:

[0939] one or more short chain monoglycerides (SCM),

[0940] one or more medium chain monoglycerides (MCM),

[0941] one or more long chain monoglycerides (LCM),

[0942] one or more long chain monoglycerides (VLCM),

[0943] one or more short chain diglycerides (SCD),

[0944] one or more medium chain diglycerides (MCD),

[0945] one or more long chain diglycerides (LCD),

[0946] one or more long chain monoglycerides (VLCD),

[0947] one or more short-chain triglycerides (SCT),

[0948] one or more medium chain triglycerides (MCT),

[0949] one or more long chain triglycerides (LCT),

[0950] one or more long chain monoglycerides (VLCT),

[0951] one or more short chain fatty acid esters (SCFE),

[0952] one or more medium chain fatty acid esters (MCFE),

[0953] one or more long chain fatty acid esters (LCFE),

[0954] One or more very long chain fatty acid esters (VLCFE), or

[0955] Any mixture thereof, or

[0956] The one or more organic solvents comprise:

[0957] one or more alcohols,

[0958] one or more non-alcoholic organic solvents, or

[0959] Any mixture thereof.

[0960] Embodiment 34. Any of the preceding embodiments, wherein the one or more poorly water-soluble pharmaceutical agents comprises:

[0961] One or more poorly water-soluble small molecule integrin agonist adjuvant drug agents.

[0962] Embodiment 35. Embodiment 34, wherein the one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents comprise:

[0963] one or more compounds of formula (I),

[0964] one or more compounds of formula (II), or

[0965] Any mixture of two or more compounds of formula (I) and formula (II).

[0966] Embodiment 36. A method of administering to a human or animal a pharmaceutical composition corresponding to any of the pharmaceutical compositions according to any of the preceding embodiments.

[0967] Conclusion - General Incorporation by Reference

[0968] All references cited herein are incorporated by reference. Although the present invention has been disclosed with reference to its preferred embodiments, those skilled in the art will appreciate from reading this specification that changes and modifications may be made without departing from the scope and spirit of the invention as described above and as claimed.

Claims

1. A carrier composition, comprising: one or more surfactants (SRF), and One or more neutral lipids (NL).

2. A pharmaceutical composition, comprising: A carrier composition, the carrier composition comprising: One or more SRFs, and One or more NL, and One or more poorly water soluble pharmaceutical agents.

3. A pharmaceutical composition, comprising: A soft gel capsule filled with a filling composition comprising: A carrier composition, the carrier composition comprising: One or more SRFs, and One or more NL, and One or more poorly water soluble pharmaceutical agents.

4. The composition according to claim 1, 2 or 3, further comprising: One or more organic solvents.

5. The composition of claim 1, 2, 3 or 4, wherein the one or more SRFs comprise: one or more zwitterionic surfactants (ZIS), or One or more nonionic surfactants (NIS), or Any mixture or combination thereof.

6. The composition of claim 5, wherein the one or more SRFs further comprises: One or more ionic surfactants (IS).

7. The composition of claim 1, 2, 3 or 4, wherein the one or more SRFs comprise: One or more ZIS.

8. The composition of claim 1, 2, 3 or 4, wherein the one or more SRFs comprise: One or more NIS.

9. The composition of claim 1, 2, 3 or 4, wherein the one or more SRFs comprise: One or more ZIS, and One or more NIS.

10. The composition of claim 6, wherein the one or more SRFs comprise: One or more ZIS, One or more NIS, and One or more IS.

11. A composition according to any preceding claim, wherein: The one or more SRFs are present in an amount from about 5 wt % to about 95 wt % or any subrange thereof, and The one or more NLs are present in an amount from about 95 wt % to about 5 wt % or any subrange thereof.

12. A composition according to any preceding claim, wherein: about 99 wt % to about 75 wt % of a SRF / NL mixture comprising one or more SRFs and one or more NLs, or any subrange thereof, and From about 1 wt % to about 25 wt % of the one or more organic solvents, or any subrange thereof.

13. A composition according to any preceding claim, wherein the one or more SRFs comprise: about 99 wt % to about 90 wt % of an SRF mixture comprising one or more ZIS, one or more NIS, or any mixture thereof, or any subrange thereof, and From about 1 wt % to about 10 wt % of one or more IS, or any subrange thereof.

14. A composition according to any preceding claim, wherein: The carrier composition is present in an amount from about 75% to about 97% by weight or any subrange thereof, and The one or more poorly water soluble pharmaceutical agents are present in an amount from about 25 wt % to about 1 wt % or any subrange thereof.

15. A composition according to any preceding claim, wherein the one or more NLs comprise: about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and From about 100 wt % to about 80 wt % of an NL mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any subrange thereof.

16. A composition according to any preceding claim, wherein the one or more NLs comprise: about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and About 100 wt % to about 80 wt % of a MC mixture comprising one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any subrange thereof.

17. A composition according to any preceding claim, wherein the one or more NLs comprise: about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and About 100 wt % to about 80 wt % of an LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any subrange thereof.

18. A composition according to any preceding claim, wherein the one or more NLs comprise: about 0 wt % to about 20 wt % of a SC mixture comprising one or more SCMs, one or more SCDs, one or more SCTs, one or more SCFEs, or any mixture thereof, or any subrange thereof, and About 100 wt % to about 80 wt % of a VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any subrange thereof.

19. A composition according to any preceding claim, wherein the one or more NLs comprise: MC mixture, the MC mixture comprising one or more MCM, one or more MCD, one or more MCT, one or more MCFE, or any mixture thereof, or any sub-range thereof.

20. A composition according to any preceding claim, wherein the one or more NLs comprise: LC mixture comprising one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs or any mixture thereof, or any sub-range thereof.

21. A composition according to any preceding claim, wherein the one or more NLs comprise: A VLC mixture comprising one or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

22. A composition according to any preceding claim, wherein the one or more NLs comprise: one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof, and One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof.

23. A composition according to any preceding claim, wherein the one or more NLs comprise: one or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof, and One or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof.

24. A composition according to any preceding claim, wherein the one or more NLs comprise: One or more MCMs, one or more MCDs, one or more MCTs, one or more MCFEs, or any mixture thereof, or any sub-range thereof, one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof, and One or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

25. A composition according to any preceding claim, wherein the one or more NLs comprise: one or more LCMs, one or more LCDs, one or more LCTs, one or more LCFEs, or any mixture thereof, or any sub-range thereof, and One or more VLCMs, one or more VLCDs, one or more VLCTs, one or more VLCFEs, or any mixture thereof, or any sub-range thereof.

26. A composition according to any preceding claim, wherein the one or more poorly water-soluble pharmaceutical agents comprises: One or more poorly water-soluble small molecule integrin agonist adjuvant drug agents.

27. The composition of claim 26, wherein the one or more poorly water-soluble pharmaceutical agents have a Log P value in n-octanol relative to water greater than 5 (Log P > 5).

28. A drug carrier composition, comprising: A vector, the vector comprising: about 30.76 wt % to 28.71 wt % of one or more ZIS, about 28.91 wt. % to 20.35 wt. % of one or more NLs, about 9.56 wt % to 16.18 wt % of one or more organic solvents, about 23.05% to 21.71% by weight of one or more gelatins, and A blend of about 7.72% to 13.05% by weight of sorbitol and glycerin.

29. A pharmaceutical composition comprising: about 1.50 wt % to about 4.20 wt % of one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents, A vector, the vector comprising: about 30.30 wt. % to about 27.50 wt. % of one or more ZIS, about 28.48 wt. % to about 19.50 wt. % of one or more NLs, from about 9.42% to about 15.50% by weight of one or more organic solvents, from about 22.70% to about 20.80% by weight of one or more gelatins, about 7.60% to about 12.50% by weight of a blend of sorbitol and glycerin, and Contains essentially no water. Medicinal aqueous injection system, wherein the composition comprises a stable injectable emulsion.

30. An injectable pharmaceutical composition, comprising: A drug system, comprising: about 1.50 wt % to about 4.20 wt % of one or more poorly water-soluble small molecule integrin agonist adjuvant pharmaceutical agents, A vector, the vector comprising: about 30.30 wt. % to about 27.50 wt. % of one or more ZIS, about 28.48 wt. % to about 19.50 wt. % of one or more NLs, from about 9.42% to about 15.50% by weight of one or more organic solvents, from about 22.70% to about 20.80% by weight of one or more gelatins, about 7.60% to about 12.50% by weight of a blend of sorbitol and glycerin, and Contains substantially no water, and Medicinal aqueous injection system, wherein the composition comprises a stable injectable emulsion.

31. The composition of claim 28, 29 or 30, wherein the weight ratio of the drug system to the pharmaceutical aqueous injection system is about 1:2 to 1:

10.

32. The composition of claim 28, 29, 30 or 31, wherein the lecithin comprises: One or more ZIS, and One or more NLs.

33. A composition according to any preceding claim, wherein: The one or more SRFs comprise: one or more zwitterionic surfactants (ZIS), One or more nonionic surfactants (NIS), or any combination thereof; The one or more NLs comprise: one or more short chain monoglycerides (SCM), one or more medium chain monoglycerides (MCM), one or more long chain monoglycerides (LCM), one or more long chain monoglycerides (VLCM), one or more short chain diglycerides (SCD), one or more medium chain diglycerides (MCD), one or more long chain diglycerides (LCD), one or more long chain monoglycerides (VLCD), one or more short-chain triglycerides (SCT), one or more medium chain triglycerides (MCT), one or more long chain triglycerides (LCT), one or more long chain monoglycerides (VLCT), one or more short chain fatty acid esters (SCFE), one or more medium chain fatty acid esters (MCFE), one or more long chain fatty acid esters (LCFE), One or more very long chain fatty acid esters (VLCFE), or Any mixture thereof, or The one or more organic solvents comprise: one or more alcohols, one or more non-alcoholic organic solvents, or Any mixture thereof.

34. A composition according to any preceding claim, wherein the one or more poorly water-soluble pharmaceutical agents comprises: One or more poorly water-soluble small molecule integrin agonist adjuvant drug agents.

35. The composition of claim 34, wherein the one or more poorly water-soluble small molecule integrin agonist adjuvant drug agents comprises: one or more compounds of formula (I), one or more compounds of formula (II), or Any mixture of two or more compounds of formula (I) and formula (II).

36. A method of administering to a human or animal a pharmaceutical composition corresponding to any of the pharmaceutical compositions according to any preceding claim.

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