Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/025—Boronic and borinic acid compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

• kits comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating wounds, and in particular, the enhanced tissue regeneration following treatment of a wound.
• methods of treating conditions associated with Wnt transcription products or Wnt signaling pathway activity in a mammal comprising administering a therapeutically effective amount of a compound or composition to a mammal.
• the Wnt pathway has been shown to play a key role in dermal fibrosis and scarring.
• the Wnt pathway is an evolutionary conserved pathway that regulates crucial aspects of cell fate determination, cell polarity, cell migration, neural patterning, and organogenesis during embryonic development. This pathway is instrumental in ensuring proper tissue development in embryos and tissue maintenance in adults. Wnt signaling is involved at the beginning stages of skin development, where following gastrulation, embryonic cells of the ectoderm and the mesoderm differentiate to form the epidermis and dermis, respectively.
• P-Catenin is the key effector molecule resulting from the signaling of the canonical Wnt pathway, and its protein levels are regulated through a “destruction complex.”
• the transcriptional activator P-catenin is actively degraded in the cell by the actions of a protein complex, designated the “destruction complex.”
• Axin-1 and -2 with adenomatous polypsis coli form a scaffold that facilitates P-catenin phosphorylation by casein-kinase 19a and glycogen synthase kinase 3p.
• Tankryase I and II are poly(ADP -ribose) polymerases (PARPs) that function to parsylate and destabilize Axin-1 and -2 proteins, thus destabilizing the P-catenin destruction complex. Once the destruction complex is destabilized, this allows P-catenin to be dephosphorylated, and subsequently stabilized and allowed to accumulate in the cytoplasm and enter the cell nucleus, where it interacts with members of the Tcf/Lef family.
• PARPs poly(ADP -ribose) polymerases
• Tcf proteins converts the Tcf proteins into potent transcriptional activators by recruiting co-activator proteins, thus ensuring efficient activation of Wnt target genes.
• the Wnt pathway once activated by the Wnt family of natural ligands, upregulates TNK1 and 2 to help destabilize the destruction complex. Studies have shown that TNK1 and 2 are critical regulators of canonical Wnt signaling.
• XAV939 is a small molecule that selectively inhibits Wnt/p-catenin-mediated transcription through TK 1 and TK2 inhibition with an IC50 of 11 nM/4nM in cell-free assays, regulates axin levels, and does not affect CRE, F-KB, or TGF-p.
• XAV939 significantly increased rate of wound closure with reduced fibrosis (scarring) (Bastakoty, D. et al. FASEB J., 2015, 29(12): 4881-4892).
• XAV939 was dissolved in dimethyl sulfoxide (DMSO) and used only as a “research tool” compound due to its very low aqueous solubility ( ⁇ 1 pg/mL).
• DMSO dimethyl sulfoxide
• a compound of Formula (I) or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and/or tautomer thereof wherein
• R 1 is hydrogen, deuterium, Ci-Csalkyl, -OH, -O-Ci-Csalkyl, -CH2OH, or -B(OH)2;
• R la is hydrogen, deuterium, or Ci-Csalkyl
• (k) -CH CH-R 5 where R 5 is phenyl or 5- or 6- membered heteroaryl, where the phenyl and the 5- or 6-membered heteroaryl are substituted with R 3 and additionally optionally substituted with 1, 2, or 3 R 3a groups;
• R 3 is independently selected from -B(0H)2, cyano, halo, halo-Ci-Cealkyl, -(Co- Cealkylene)-O-R 4 , or 5- to 10-membered heterocyclic wherein the 5- to 10-membered heterocyclic is optionally substituted with cyano; or when R 2 is (a), then R 3 and one R 3a , when on adjacent carbons, together with the carbons to which they are attached form
• R 4 is hydroxy-Ci-Cealkyl, Ci-Cealkoxy-Ci-Cealkyl, or Ci-Cealkoxycarbonyl-NH-Ci- Cealkyl; and provided that the compound is not -(4-(trifluoromethyl)phenyl)-3, 5, 7, 8-tetrahy dro-4H-thiopyrano[4,3-d]pyrimidin-4- one or a single stereoisomer or mixture of stereoisomers thereof; a single tautomer or mixture of tautomers thereof; and/or a pharmaceutically acceptable salt thereof; -(4-(4-methoxyphenyl)piperazin- 1 -y 1 )- 3 , 5 , 7, 8-tetrahy dro-4H-thiopyrano[4, 3 - d]pyrimidin-4-one or a single stereoisomer or mixture of stereoisomers thereof; a single tautomer or mixture of tautomers
• a compound of Formula (I) (or any embodiments thereof) or a single stereoisomer or mixture of stereoisomers thereof; a single tautomer or mixture of tautomers thereof; and/or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound of Formula (I) (or any embodiments thereof), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and/or tautomer thereof; and a pharmaceutically acceptable carrier.
• a method for inhibiting Wnt transcription products or Wnt signaling pathway activity in a subject comprising contacting an effective amount of a compound of Formula (I) (or any embodiments thereof), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and/or tautomer thereof.
• the compound of Formula (I) (or any embodiments thereof) is provided as a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof.
• a method of treating a disease, disorder, or condition associated with Wnt transcription products or Wnt signaling pathway activity in a mammal in need thereof comprising administering a compound of Formula (I) (or any embodiments thereof) or administering a pharmaceutical composition comprising a compound of Formula (I), or any prodrug, pharmaceutically acceptable salt, metabolite, polymorph, solvate, hydrate, stereoisomer, and/or tautomer thereof.
• R 1 is hydrogen, deuterium, Ci-Csalkyl, -OH, -O-Ci-Csalkyl, -CH2OH, or -B(OH)2;
• R la is hydrogen, deuterium, or Ci-Csalkyl
• a method of preparing a compound of Formula (I), comprising: a) contacting a compound of Formula ( b) contacting a compound of Formula (wherein R 20 is Me or CD3; or c) contacting a compound of Formula wherein LG 1 is fluoro, chloro, bromo, iodo, tritiate, mesylate, a triazole, a pyrazole, boronic acid, boronic ester, or aryl trifluoroborate; and optionally isolating the compound of Formula (I).
• the contacting is under basic conditions (in presence of a base).
• FIG. 1 shows inhibition of the Wnt transcription signaling pathway activity by a compound of Formula (I) (Compound 1) compared to a compound of Formula (I) and GO-HA (GO-HA + Compound 1) (Biological Example 3).
• FIG. 3 shows inhibition of the Wnt transcription signaling pathway activity by a compound of Formula (I) (Compound 8) compared to a compound of Formula (I) and GO-HA (GO-HA + Compound 8) (Biological Example 3).
• FIG. 7 shows the location of an embed cut across the center point of a healed wound for purposes of processing tissue after cartilage regeneration tests (rabbit ear study, see Biological Example 5).
• FIG. 7 (bottom) shows a slide with the cross section of sectioned tissue at the center of the wound. Resultant tissue sections placed on the slide are shown in images in FIGS. 9-11
• FIG. 18 depicts results of the 3 rd degree burn wound healing study (Biological Example 6) comparing a compound of Formula (I) and GO-HA (Compound 7 + GO-HA) to a saline control. Wound area (cm 2 ) was measured at 2-6 day intervals. Results from day 16 to day 22 are shown.
• FIG. 20 shows results of the closed excisional wound study (Biological Example 6): compounds of Formula (I) (Compound 1, Compound 8, and Compound 10), from day 1 to day 21. The sutures were removed at day 13.
• the cancer may include but is not limited to melanoma, breast cancer, and/or prostate cancer.
• compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in treating wounds, in particular, the enhanced tissue regeneration following treatment of a wound.
• methods of treating conditions associated with Wnt transcription products or Wnt signaling pathway activity in a mammal comprising administering a therapeutically effective amount of a compound or composition to a mammal.
• the mammal is a human.
• references to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se.
• description referring to “about X” includes description of “X”.
• the terms “about” and “approximately,” when used in connection with temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.
• phrases “a” or “an,” as used in herein means one or more, unless context clearly dictates otherwise.
• “pharmaceutically acceptable carrier” includes one or more ingredients as provided herein.
• linear alkyl refers to a chain of carbon and hydrogen atoms (e.g., ethane, propane, butane, pentane, hexane, etc.).
• branched alkyl refers to a chain of carbon and hydrogen atoms, without double or triple bonds that contains a fork, branch, and/or split in the chain. “Branching” refers to the divergence of a carbon chain, whereas “substitution” refers to the presence of non-carbon/non-hydrogen atoms in a moiety.
• alkylene refers to a divalent alkyl group, as defined herein for either the GO-HA linker or as defined for a compound of formula (I), as applicable.
• cycloalkyl refers to a completely saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. A cycloalkyl group may be unsubstituted, substituted, branched, and/or unbranched.
• the cycloalkyl group includes three to six carbon atoms, i.e., C3 to Ce cycloalkyl. In some or any embodiments, the cycloalkyl has 3, 4, 5, or 6 (C3-6) 3, 4, or 5 (C3-5); 3 or 4 (C3-4); 3 (C3); 4 (C4); or 5 (C5) carbon atoms. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In one or more embodiments, the cycloalkyl group is cyclobutyl.
• C3-Cio-cycloalkyl refers to a monovalent, saturated, monocyclic hydrocarbon or bicyclic (fused, bridged, or spirocyclic) ring.
• the terms “fused cycloalkyl” and “spirocycloalkyl” are embodiments of the cycloalkyl group.
• the cycloalkyl group includes three to six carbon atoms, i.e., C3 to Ce cycloalkyl.
• alkoxyalkyl refers to an alkyl group, as defined herein, substituted with one or two -OR' groups where each R' is alkyl, as defined herein, and is independently selected.
• alkoxyalkyl is Ci-Cealkoxy-Ci-Cealkyl.
• alkoxycarbonyl-NH-alkyl refers to an alkyl group substituted with -NH-C(O)O(alkyl), wherein alkyl is as defined herein.
• alkoxycarbonyl-NH-alkyl is Ci-Cealkoxycarbonyl-NH-Ci-Cealkyl.
• alkenyl as used herein for the GO-HA linker, means a straight or branched chain hydrocarbon having at least 2 carbon atoms, which contains at least one carboncarbon double bond.
• alkynyl as used herein for the GO-HA linker, means a straight or branched chain hydrocarbon having at least 2 carbon atoms, which contains at least one carboncarbon triple bond.
• amine or “amino” as used herein for the GO-HA linker are represented by a formula -NA1A2, where Ai and A2 are, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group where each of these groups are as described herein for the GO-HA linker.
• amine (or amino) refers to any of NH2, NH(alkyl), NH(aryl), N(alkyl)2, N(alkyl)(aryl), and N(aryl) 2 .
• aryl refers to a monovalent Ce- C15 carbocyclic ring system which comprises at least one aromatic ring wherein the aryl ring system is mono, di, or tricyclic.
• the aryl may be attached to the main structure through any of its rings, i.e. any aromatic or nonaromatic ring.
• the aryl group may be a bridged (where chemically feasible) or non-bridged, spirocyclic (where chemically feasible) or not spirocyclic, and/or fused or not fused multicyclic group.
• aryl is Ce-Cio aryl.
• aryl is Ce aryl, i.e. phenyl. In some or any embodiments, aryl is phenyl, naphthyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro- 57/-benzo[7]annulenyl, or tetrahydronaphthyl. When aryl is substituted, it can be substituted on any ring, i.e. on any aromatic or nonaromatic ring comprised by aryl.
• haloalkyl refers to an alkyl group substituted with 1, 2, 3, 4, or 5 halo groups.
• the haloalkyl is a halo-Ci-ealkyl.
• the haloalkyl is -CF 3 , -CH 2 F, -CHF 2 , or -CH 2 CF 3 .
• halogen and “halo,” as used herein, and unless otherwise specified, are synonymous and refer to chloro, bromo, fluoro, or iodo.
• heteroaryl refers to a monocyclic aromatic ring system or multicyclic aromatic ring system wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms is a heteroatom independently selected from O, S(0)o- 2 , NH, and N, and the remaining ring atoms are carbon atoms, and where the ring may be optionally substituted as described herein.
• the heteroaryl group is bonded to the rest of the molecule through any atom in the ring system, valency rules permitting.
• each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
• the heteroaryl has from 5 to 20, from 5 to 15, from 5 to 6 ring atoms, or from 5 to 10 ring atoms. When heteroaryl is substituted, it can be substituted on any ring.
• heteroaryl is a 5- to 10-membered heteroaryl.
• heteroaryl is a 5 or 6-membered heteroaryl.
• heteroaryl is a 6-membered heteroaryl.
• heteroaryl indicates the point of attachment of the heteroaryl to the rest of the molecule.
• monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
• tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl.
• heteroaryl is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout the specification, including in some embodiments with group(s) independently selected from Ci-ealkyl, hydroxy, halo, halo-Ci-ealkyl, Ci-ealkoxy, cyano, or phenyl.
• heterocyclic refers to a monovalent monocyclic non-aromatic ring system or a monovalent multicyclic ring system that contains at least one non-aromatic ring; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the monocyclic non-aromatic ring atoms is a heteroatom independently selected from O, S(0)o-2, and N, and the remaining ring atoms are carbon atoms; and wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of any of the ring atoms in the multicyclic ring system is a heteroatom(s) independently selected from O, S(0)o-2, and N, and the remaining ring atoms are carbon.
• heterocyclic does not include fully aromatic ring(s), i.e. does not include imidazole, pyrimidine, pyridine, and the like.
• the heterocyclic ring comprises one or two heteroatom(s) which are independently selected from nitrogen and oxygen.
• the heterocyclic ring comprises one or two heteroatom(s) which are oxygen.
• the heterocyclic ring comprises one or two heteroatom(s) which are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described herein).
• heterocyclic is multicyclic and comprises one heteroatom in a non-aromatic ring, or comprises one heteroatom in an aromatic ring, or comprises two heteroatoms in an aromatic ring, or comprises two heteroatoms where one is in an aromatic ring and the other is in a non-aromatic ring.
• the heterocyclic group has from 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms.
• the heterocyclic is a 4- to 10-membered heterocyclic.
• the heterocyclic is a 5- to 10-membered heterocyclic.
• heterocyclic is “heterocycloalkyl” which is 1) a saturated monovalent monocyclic group which contains at least one ring heteroatom, as described herein, or 2) a saturated monovalent bi- or tri-cyclic group in which at least one ring contains at least one heteroatom as described herein.
• heterocyclic is 3- to 6-membered heterocycloalkyl. In some or any embodiments, heterocyclic is 3- to 8-membered heterocycloalkyl. In some or any embodiments, heterocyclic is 3 - to 9- membered heterocycloalkyl. When heterocyclic and heterocycloalkyl are substituted, they can be substituted on any ring, i.e. on any aromatic or nonaromatic ring comprised by heterocyclic and heterocycloalkyl.
• such heterocyclic includes, but are not limited to, azepinyl, benzodi oxanyl, benzodi oxolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl,
• oxo-oxadiazolyl including but not limited to 5-oxo-l,2,4- oxadiazol-3-yl
• oxazolidinonyl oxazolidinyl
• oxiranyl piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidonyl
• isotopic enrichment refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance.
• deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.
• the isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
• Embodiments A and B provided is a compound of Formula (I), wherein
• R 3 is attached to the para-position of the phenyl ring
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is selected from the group consisting of one or more embodiments, R 3 is not halo or haloalkyl. In one or more embodiments, R 3 is B(O)2 or -(Co-Cealkylene)-O-R 4 . [00105] In one or more embodiments, including Embodiments A and B, provided is a
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is phenyl optionally substituted with 1, 2, or 3 R 3a groups and additionally substituted with -phenyl-R 3 where the phenyl in -phenyl-R 3 is optionally substituted with 1, 2, or 3 R 3a groups.
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is phenyl optionally substituted with 1, 2, or 3 R 3a groups and additionally substituted at its para-position with -phenyl-R 3 where the phenyl in -phenyl- R 3 is optionally substituted with 1, 2, or 3 R 3a groups and where the R 3 is in the para-position of the phenyl in -phenyl-R 3 .
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is selected from the group consisting of
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is selected from the group consisting of
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is 5- to 6- membered heteroaryl substituted with R 3 and additionally optionally substituted with 1, 2, or 3 R 3a groups; optionally wherein the R 3 is at the para-position of the 6-membered heteroaryl.
• Embodiments A and B provided is a compound of Formula (I), wherein when R 2 is (d), R 3 is B(O)2 or -(Co-Cealkylene)-O-R 4 .
• R 3 is B(O)2 or -(Co-Cealkylene)-O-R 4 .
• a compound of Formula (I) wherein when R 2 is (d), R 3 is B(O)2 or -(Ci-Cealkylene)-O-R 4 .
• Embodiments A and B provided is a compound of Formula (I), wherein
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is Cs-Cecycloalkyl substituted with R 3 and additionally optionally substituted with 1 or 2 R 3a groups.
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is , optionally wherein R 3 is 5- to
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is Cs-Cecycloalkyl substituted with 5- or 6-membered heteroaryl where the 5- or 6-membered heteroaryl is substituted with R 3 and additionally optionally substituted with 1, 2, or 3 R 3a groups, and where the cycloalkyl is optionally substituted with 1 or 2 R 3a groups.
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is Cs-Cecycloalkyl substituted with phenyl where the phenyl is substituted with R 3 and additionally optionally substituted with 1, 2, or 3 R 3a groups, and where the cycloalkyl is optionally substituted with 1 or 2 R 3a groups.
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is 3- to 8-membered heterocycloalkyl substituted with phenyl or 5- or 6- membered heteroaryl, where the phenyl and the 5- to 6- membered heteroaryl are substituted with R 3 and additionally optionally substituted with 1, 2, or 3 R 3a groups.
• Embodiments A and B provided is a compound of Formula (I), wherein R 2 is selected from the group consisting of
• R 2 is selected from the group consisting of
• a compound of Formula (I) wherein R 3 is cyano, -B(OH)2, or -(Co-Cealkylene)-O-R 4 .
• R 4 is hydroxy-Ci-Cealkyl (in some embodiments, hydroxy ethyl).
• R 4 is Ci-Cealkoxycarbonyl-NH-Ci-Cealkyl (in some embodiments, Ci-C6alkoxycarbonyl-NH-C2alkyl).
• R 4 is hydroxy-Ci-Cealkyl (in some embodiments, hydroxy ethyl).
• R 4 is hydroxy-Ci-Cealkyl (in some embodiments, hydroxyethyl).
• methods to obtain optically active materials include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated. This technique can be used if crystals of the separate stereoisomers exist, /. ⁇ ., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain a stereoisomerically pure or enriched synthetic precursor of the desired
• the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
• the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.
• compositions of a compound that comprises a substantially pure designated stereoisomer of the compound are substantially free of other stereoisomer.
• a composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight, of the designated stereoisomer, the remainder comprising other chemical species or stereoisomers.
• isotopically enriched compounds are also provided herein.
• Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
• KIE Kinetic Isotope Effect
• DKIE Deuterium Kinetic Isotope Effect
• the magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen.
• the DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen.
• High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.
• substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.
• substitution of isotopes for other elements including, but not limited to, 13 C or 14 C for carbon, 33 S, 34 S, or 36 S for sulfur, 15 N for nitrogen, and 17 O or 18 O for oxygen, may lead to a similar kinetic isotope effect.
• the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride.
• this method may not be applicable to all drug classes.
• deuterium incorporation can lead to metabolic switching.
• the concept of metabolic switching asserts that xenogens, when sequestered by Phase I enzymes, may bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity.
• the compounds described herein may be used as radiopharmaceuticals such as, for example, imaging agents.
• radiopharmaceuticals are positron emission tomography (PET) imaging agents.
• PET positron emission tomography
• substitution of radionuclides (e.g., positron emitting isotopes) for atoms in the compounds allows for the syntheses of radiopharmaceuticals that can function as imaging agents.
• radionuclides which can be substituted in the compounds described herein include, and are not limited to, 18 F, U C, 13 N, 15 O, 76 Br, and 124 I.
• the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms.
• the compound is administered as an isotopic composition.
• the animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system.
• enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion.
• CYPs cytochrome P450 enzymes
• esterases enzymes
• proteases e.g., reductases, dehydrogenases, and monoamine oxidases
• Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond.
• the resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and longterm toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.
• Formula (I) comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a compound of Formula (I), comprising: a) contacting a
• compositions comprising a compound of Formula (I), as described herein in some and any embodiments, and a pharmaceutically acceptable carrier.
• the composition is a topical composition.
• compositions containing at least one compound as described herein including a compound of Formula (I) if appropriate in a salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of wounds and/or conditions modulated by Wnt transcription products or Wnt signaling pathway activity.
• a compatible and pharmaceutically acceptable carriers such as diluents or adjuvants
• compositions as described herein including in the GO-HA pharmaceutical composition
• other pharmaceutical or therapeutic compounds may be included in addition to the compound of Formula (I).
• the compositions (including in the GO-HA pharmaceutical composition) with the compound of Formula (I) present can also serve as a base dispersion medium in which other pharmaceutical or therapeutic agents, especially those which are hydrophobic, may be dispersed, e.g., for topical administration to a wound.
• agents may include antifibrotic compounds such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc., anti-cancer agents, anti-inflammatory agents, analgesics, antibiotics, Wnt inhibitors, Hedgehog pathway inhibitors, TGF-P inhibitors, LOX inhibitors, etc.
• antifibrotic compounds such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc.
• anti-cancer agents anti-inflammatory agents
• analgesics antibiotics
• Wnt inhibitors Hedgehog pathway inhibitors
• TGF-P inhibitors TGF-P inhibitors
• LOX inhibitors etc.
• the compositions can include a second medication or therapeutic agent to the wound, comprising one or more of: corticosteroid, a cytotoxic drug, an antibiotic, an antiseptic, nicotine, an anti-platelet drug, an NSAID, colchicine, an anticoagulant, a vasoconstricting drug or an immunosuppressive, a growth factor, an antibody, a protease, a protease inhibitor, an antibacterial peptide, an adhesive peptide, a hemostatic agent, living cells, honey, or nitric oxide.
• a second medication or therapeutic agent to the wound comprising one or more of: corticosteroid, a cytotoxic drug, an antibiotic, an antiseptic, nicotine, an anti-platelet drug, an NSAID, colchicine, an anticoagulant, a vasoconstricting drug or an immunosuppressive, a growth factor, an antibody, a protease, a protease inhibitor, an antibacterial peptide, an adhesive peptide, a
• therapeutic agents can be delivered as separate dosage forms from the compositions described herein, or may be included as additional components of the compositions described herein, hence delivered together with the compound of Formula (I)(or any embodiments thereof, including in some embodiments, Compound 1, Compound 7, or Compound 8).
• the second agent can be formulated or packaged with the compound provided herein.
• the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration.
• the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
• the active agents provided herein may be administered by any conventional route, in particular parenterally, rectally, orally, by inhalation (e.g. in the form of aerosols), or topically.
• composition(s) of the present disclosure described herein can be administered by applying the composition(s) topically on the wound. If the composition is included in a medical device described herein which includes a substrate such as a patch or a pad, the medical device can be secured to the wound such that the composition contacts the wound.
• compositions for oral administration may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, in some or any embodiments, wetting, sweetening or flavoring products.
• the compositions for parenteral administration can be emulsions or sterile solutions.
• Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in some or any embodiments, ethyl oleate.
• compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in some or any embodiments, using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
• compositions provided herein is a pharmaceutical composition or a single unit dosage form.
• Pharmaceutical compositions and single unit dosage forms provided herein comprise a therapeutically effective amount of one or more therapeutic agents (e.g., a compound provided herein, or other therapeutic agent), and a typically one or more pharmaceutically acceptable carriers (e.g. excipients).
• therapeutic agents e.g., a compound provided herein, or other therapeutic agent
• typically one or more pharmaceutically acceptable carriers e.g. excipients.
• pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
• the term “carrier” includes a diluent, disintegrant, lubricant, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
• Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
• Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
• Suitable excipients are well-known to those skilled in the art of pharmacy, and in some or any embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
• composition or dosage form Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a mammal and the specific active ingredients in the dosage form.
• the composition or single unit dosage form if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• Lactose free compositions can comprise excipients that are well known in the art and are listed, in some or any embodiments, in the U.S. Pharmacopeia (USP 36-NF 31 S2).
• lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
• Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
• anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
• water e.g., 5%
• water is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379 80.
• water and heat accelerate the decomposition of some compounds.
• the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
• Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
• An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
• suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
• compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
• compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
• compositions and dosage forms that comprise one or more chemical permeation enhancer.
• chemical permeation enhancers include but are not limited to ethanol, amides (such as Ozone, Laurocapram), alkyl and benzoate esters, fatty acid esters (such as isopropyl myristate, propylene glycol monocaprylate and propyleneglycomonolaurate), Transcutol (Registered name), fatty acids (oleic acid), glycols, pyrrolidone (N-methyl-2-pyrrolidone and 2-pyrrolidone, dimethylsulfoxide (DMSO), terpenes (such as essential oils comprising terpenes), phospholipids, and/or cyclodeextrines.
• amides such as Ozone, Laurocapram
• alkyl and benzoate esters such as isopropyl myristate, propylene glycol monocaprylate and propyleneglycomonolaurate
• compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
• Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
• Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in some or any embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the mammal.
• the formulation should suit the mode of administration.
• the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a mammal, in some or any embodiments, a human.
• dosage forms include, but are not limited to: sprays, tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a mammal, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a mammal; and sterile solids e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a mammal.
• suspensions e.g.,
• composition, shape, and type of dosage forms provided herein will typically vary depending on their use.
• a dosage form used in the initial treatment of the disease, disorder, or condition may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same disease, disorder, or condition.
• a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder.
• compositions are supplied either separately or mixed together in unit dosage form, in some or any embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
• a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
• the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
• Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
• Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
• the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein.
• anhydrous ingredients as described in detail herein.
• the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
• Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
• Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
• excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
• excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
• tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
• a tablet can be prepared by compression or molding.
• Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient.
• Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• one or more of the following can be used in the pharmaceutical composition: benzyl alcohol, butyl paraben, butylated hydroxy toluene, calcium carbonate, candelilla wax, colloidal silicone dioxide, calcium stearate, calcium disodium EDTA, copolyvidone or copovidone, calcium hydrogen phosphate dihydrate, crosspovidone, calcium phosphate (di and tri basic), emollients (glyceryl monostearate), iron oxide ivyyellow yellow, and iron.
• fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
• the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
• suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
• a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
• Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
• Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, crosspovidone, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
• Additional lubricants include, in some or any embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
• AEROSIL 200 a syloid silica gel
• a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, TX
• CAB O SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
• lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
• a pharmaceutical composition for example, for treating a wound
• a matrix component comprising a conjugate of graphene oxide (GO) and hyaluronic acid (HA) where GO and HA are covalently linked via a linker; a compound of Formula (I) (or any embodiments thereof, including in some embodiments, Compound 1, Compound 7, or Compound 8); and water.
• the covalently-linked GO and HA is also referred to herein as GO-HA conjugate or simply GO-HA.
• the GO-HA conjugate can be made according to procedures known to a person of ordinary skill in the art, including those disclosed in US-2019-0105398-A1.
• Graphene oxide refers to an oxidized form of graphene, which is a single layer form of graphite.
• GO can be obtained by treating graphite with strong oxidizers.
• GO contains carbon, oxygen, and hydrogen in various amounts, depending on how it is made. It can be of length of several hundreds of nanometers up to several micrometers, its planar direction, and about 0.7-1.2 nm in thickness.
• GO can include various oxygen containing moieties, such as oxygen epoxide groups, carboxylic acid (-COOH), phenol, etc., when prepared using sulfuric acid (e.g. Hummers method).
• An example GO structure is shown below.
• Hyaluronic acid is an anionic, highly hydrophilic, non-sulfated glycosaminoglycan, occurring naturally throughout the human body. It can be several thousands of carbohydrate units long, and can bind to water giving it a gel of stiff viscous quality.
• An example structure of HA is provided below:
• the GO-HA linker can comprise a C2-C25 alkylene group, where the carbons and hydrogens in the alkylene group can be substituted by oxygen or other atoms or groups such as hydroxy, carboxy, amino, alkyl, alkoxy, alkenyl, alkynyl, nitro, etc.
• the GO-HA linker can comprise one or more -CH2CH2O- units.
• the GO-HA linker comprises -R x -R s -Ry-, wherein R x and R y are each independently selected from the group consisting of -CO-, -COO-, - H-, - H- H-, - H- H- CO-, -CS-, -S-, -O-, and wherein R s (which is also referred to as the spacer group in this application) can be an unsubstituted or substituted, saturated or unsaturated linear alkylene group having 2-20 backbone carbons.
• both R x and R y are *- H- H-CO- (* denoting the ends of the linker distal to Rs).
• the weight ratio of the compound of Formula (I) (such as Compound 1, Compound 7, or Compound 8) to GO-HA can be from about 1 : 100 to 100: 1, e.g., from about 1 :2 to about 2: 1.
• the weight ratio of GO:HA in the GO-HA conjugate, can be from about 1 : 1 to about 1 :20, or from about 1 :6 to about 1 : 10.
• the GO-HA pharmaceutical composition further comprises pharmaceutical carriers (e.g. excipients), compounds, or materials which enable the compositions to be presented in topically administrable semi-solid aqueous gel forms.
• pharmaceutical carriers e.g. excipients
• carboxymethylcellulose can be used as a gel -forming agent.
• other cellulose derivatives such as microcrystalline cellulose as well as polysaccharides such as alginate, agarose, tragacanth, guar gum, and xanthum gum; are also suitable as gel-forming agents.
• the gel may, if required, be made thicker and/or stiffer by addition of a relatively resilient gelforming material such as a cross-linked fibrous protein, e.g.
• the GO-HA pharmaceutical composition can be in a form of a cream, which can include those excipients suitable for a cream formulation, such as paraffin oil, vaseline, wax, organic esters such as cetyl palmitate, etc.
• the GO-HA pharmaceutical composition of the disclosure further comprises a thickener for desired viscosity of the composition for skin delivery.
• the thickener can include hydroxypropyl cellulose (HPC).
• HPC can make the GO-HA pharmaceutical composition into a smooth film for easy application. It also reduces evaporation and allows the wound to stay moist longer, a factor that has been shown to improve healing and result in decreased scarring.
• UPC available according to molecular weights or viscosity of certain concentrations of UPC water solution.
• the compound of Formula (I) (such as Compound 1, Compound 7, or Compound 8) can constitute from about 0.001 wt% to about 5 wt% of the total composition (including water). In one or more embodiments of the GO-HA pharmaceutical composition, the compound of Formula (I) (such as Compound 1, Compound 7, or Compound 8) can constitute from about 0.01 wt% to about 2 wt%, from about 0.02 wt% to about 1 wt%, or from about 0.05 wt% to about 0.5 wt% of the total composition.
• GO-HA constitutes from about 0.001 wt % to about 5 wt % of the total composition. In one or more embodiments, GO-HA can constitute from about 0.01 wt% to about 2 wt%, from about 0.02 wt% to about 1 wt%, or from about 0.05 wt% to about 0.5 wt% of the total composition.
• the GO-HA pharmaceutical composition overall can appear as a slightly dark or black viscous liquid.
• the compound of Formula (I) (such as Compound 1, Compound 7, or Compound 8) is evenly dispersed in the viscous suspension, which is stable at room temperature for months.
• the composition further comprises a surfactant that enhances mixability or solubility of hydrophobic substances in water.
• the surfactant can be a non-ionic hydrophilic material such as polyethylene glycol (PEG).
• the PEG can have a number-averaged molecular weight of from about 100 to about 10,000 Daltons, or about 200 to about 4000 Daltons, e.g., from about 200 to about 1000, from about 200 to about 800, from about 200 to about 500, from about 200 to about 400, from about 300 to about 400, from about 350 to about 450, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000 Daltons, etc.
• the PEG can be present in the composition in an amount of from about 0.1 to about 20 wt % of that of the total composition.
• the PEG can be from about 0.2 wt% to about 10 wt%, or from about 0.5 wt% to about 10 wt%, or from about 1 wt% to about 10 wt% of the total composition.
• Other non-ionic hydrophilic material such as copolymers of PEG and PPG (polypropylene glycol), e.g., poloxamers, can also be used.
• Poloxamer-188 which has an average molecular weight of about 8400 Daltons can be used.
• the GO-HA pharmaceutical compositions as described herein other pharmaceutical or therapeutic compounds may be included in addition to a compound of Formula (I) (such as Compound 1, Compound 7, or Compound 8).
• the GO-HA pharmaceutical compositions with compound(s) of Formula (I) (such as Compound 1, Compound 7, or Compound 8) present can also serve as a base dispersion medium in which other pharmaceutical or therapeutic agents, especially those which are hydrophobic, may be dispersed, e.g., for topical administration to a wound.
• agents may include antifibrotic compounds such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc., anticancer agents, anti-inflammatory agents, analgesics, antibiotics, Wnt inhibitors, Hedgehog pathway inhibitors, TGF-B inhibitors, LOX inhibitors, etc. Delayed Release Dosage Forms
• Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art.
• U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699
• Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in some or any embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
• Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
• unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release.
• Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
• the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
• a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989)).
• polymeric materials can be used.
• parenteral dosage forms can be administered to mammals by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses the mammal’s natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a mammal.
• parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
• Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
• suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
• Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
• Suitable carriers e.g., excipients and diluents
• other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
• excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable.
• Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
• the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
• the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
• Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
• stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent.
• Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
• the doctor will determine the posology which the doctor considers most appropriate according to the treatment needed (e.g. preventative or curative) and according to the age, weight, stage of the disease, disorder, or condition and other factors specific to the mammal to be treated.
• topical doses are described as mg per cm 2 of treatment site (e.g.
• a wound and are from about 0.001 to about 50 mg/cm 2 , or from about 0.005 to about 50 mg/cm 2 , or from about 0.01 to about 50 mg/cm 2 , or from about 0.01 to about 40 mg/cm 2 , or from about 0.01 to about 30 mg/cm 2 , or from about 0.01 to about 20 mg/cm 2 , or from about 0.01 to about 10 mg/cm 2 , or from about 0.05 to about 10 mg/cm 2 , or from about 0.05 to about 1 mg/cm 2 .
• topical and non-topical doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to about 50 mg per day for an adult. In some or any embodiments, doses are from about 5 to about 400 mg per day or about 25 to about 200 mg per day per adult. In some or any embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated.
• doses for subcutaneous administration are from about 1 to about 50 mg per day, or from about 1 to about 25 mg per day, or from about 1 to about 10 mg per day, or from about 1 to about 20 mg per day, or from about 5 to about 25 mg per day, or from about 5 mg to about 20 mg per day, or from about 10 to about 20 mg per day.
• doses for oral administration are from about 0.01 mg to about 100 mg per day, from about 0.01 to about 100 mg per day, or from about 0.01 mg to about 50 mg per day, from about 0.01 to about 25 mg per day, from about 0.01 to about 15 mg per day, from about 0.01 to about 10 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.05 to about 1 mg per day, from about 0.1 to about 100 mg per day, from about 0.1 to about 50 mg per day, from about 0.1 to about 25 mg per day, from about 0.1 to about 15 mg per day, from about 0.1 to about 10 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 mg to about 1 mg per day, or from about 10 mg to about 200 mg per day.
• the daily dose can be administered once a day. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided and administered twice a day. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided and administered three times a day.
• the mg/day amounts are for an adult.
• methods of treating a disease, disorder, or condition associated with Wnt signaling pathway activity in a mammal by administering to a mammal in need thereof, a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
• the amount of the compound or composition which will be therapeutically or prophylactically effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
• the frequency and dosage will also vary according to factors specific for each mammal depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the mammal.
• Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
• exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of mammal or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
• the dosage administered to a mammal is 0.01 mg/kg to 3 mg/kg of the mammal’s body weight, or 0.10 mg/kg to 3 mg/kg of the mammal’s body weight, based on weight of the active compound.
• the dosage administered to a mammal is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the mammal’s body weight. In some embodiments, the dosage is administered subcutaneously to a mammal and is between about 0.01 mg/kg to 1 mg/kg (inclusive), or between about 0.03 mg/kg to 0.5 mg/kg (inclusive) of the mammal’s body weight, based on weight of the active compound.
• the dosage is administered orally to a mammal and is between about 0.10 mg/kg to 5 mg/kg (inclusive) of the mammal’s body weight, or between about 0.10 mg/kg to 2 mg/kg (inclusive) of the mammal’s body weight, based on weight of the active compound.
• the recommended daily topical dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.01 mg to about 100 mg per day, given as a single once-a-day dose or as divided doses (e.g. in two or three doses) throughout a day.
• the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day.
• the daily dose is administered twice daily in equally divided doses.
• the daily dose is administered thrice daily in equally divided doses.
• the daily dose is administered four times daily in equally divided doses.
• a daily dose range should be from about 0.01 mg to about 400 mg per day, from about 0.1 mg to about 250 mg per day, from about 10 mg to about 200 mg per day, in other embodiments, or from about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the response of the mammal.
• compositions provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a mammal is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. In some or any embodiments, the dosage administered to the mammal may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular mammal is experiencing.
• the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a mammal is about 0.01 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, or about 15 mg/kg or more of a mammal’s body weight.
• the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a mammal is a unit dose selected from about 0.01 mg/kg to about 100 mg/kg, selected from about 0.1 mg to about 200 mg, selected from about 0.1 mg to about 100 mg, selected from about 0.1 mg to about 50 mg, selected from about 0.1 mg to about 25 mg, selected from about 0.1 mg to about 20 mg, selected from about 0.1 mg to about 15 mg, selected from about 0.1 mg to about 10 mg, selected from about 0.1 mg to about 7.5 mg, selected from about 0.1 mg to about 5 mg, 0.1 to about 2.5 mg, selected from about 0.25 mg to about 20 mg, selected from about 0.25 to about 15 mg, selected from about 0.25 to 12 mg, selected from about 0.25 to about 10 mg, selected from about 0.25 mg to about 7.5 mg, selected from about 0.25 mg to about 5 mg, selected from about 0.5 mg to about 2.5 mg, 1 mg to about 20 mg, selected from about 1
• a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the mammal.
• the steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the mammal such as height, weight and age.
• administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
• administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
• unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein.
• the unit dosage comprises 1 to 1000 mg, 1 to 100 mg or 10 to 50 mg active ingredient.
• the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient.
• Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
• dosages of the second agents to be used in a combination therapy are provided herein. In some or any embodiments, dosages lower than those which have been or are currently being used to treat the disease, disorder, or condition are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill in the art.
• the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart.
• the therapies are administered no more than 24 hours apart or
• the compound provided herein and the second agent are administered at about 2 to 3 days apart, 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
• administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
• administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
• the compound provided herein and the second agent are cyclically administered to a patient.
• Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and/or third agent e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
• a first agent e.g., a first prophylactic or therapeutic agent
• third agent e.g., a second and/or third prophylactic or therapeutic agent
• the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
• One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
• Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
• the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
• courses of treatment are administered concurrently to a patient, z.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent.
• one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
• the second agent can act additively or synergistically with the compound provided herein.
• the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition.
• a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions.
• a compound provided herein is administered prior to or subsequent to administration of a second agent.
• administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral.
• the second active agent when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
• suitable packaging includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a mammal.
• materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
• provided herein is a method of inhibiting Wnt transcription products or Wnt signaling pathway activity comprising contacting Wnt with a compound of Formula (I) or a compound selected from Compounds 1-44.
• the present disclosure provides for a method of improving the healing of a wound, the method comprising contacting the wound with an effective amount of the compositions of the present disclosure.
• the wound subject to an injury is contemplated to include, but not be limited to, those that arise from a surgical wounding caused by a physical impact that disrupts the structure and function of the skin (such as a laceration, abrasion, cut, scratch or puncture by a knife, scalpel, bullet, or other sharp or blunt objects).
• the present disclosure contemplates use on wounds arising by way of excessive (low or high) temperature such as a bum, ionizing radiation, chemotherapy, or unplanned acute injuries arising from accident or misadventure.
• the present disclosure contemplates use on chronic wounds arising as a consequence of an underlying condition, such as diabetic ulcerations.
• composition(s) of the present disclosure described herein can be administered by applying the composition(s) topically on the wound. If the composition is included in a medical device described herein which includes a substrate such as a patch or a pad, the medical device can be secured to the wound such that the composition contacts the wound.
• a method for preparing a composition of the present disclosure includes obtaining GO-HA (e.g., by the methods herein), adding or dissolving the GO-HA conjugate in water to obtain a GO-HA water solution, and adding the compound of Formula (I) (or any embodiments thereof, including in some embodiments, Compound 1, Compound 7, or Compound 8) to the GO-HA water solution to form a mixture (GO-HA + compound of Formula (I), or any embodiments thereof, including in some embodiments, GOHA + Compound 1, GO-HA + Compound 7, or GO-HA + Compound 8).
• this is accomplished by adding or dissolving the compound of Formula (I) (or any embodiments thereof, including in some embodiments, Compound 1, Compound 7, or Compound 8) first in a non-ionic hydrophilic polymer, e.g., PEG-400 (or PEG 400, having an average molar mass of about 400), and then the compound of Formula (I) (or any embodiments thereof, including in some embodiments, Compound 1, Compound 7, or Compound 8) solution is added into the GO-HA conjugate water solution generating GO-HA + compound of Formula (I) (or any embodiments thereof, including in some embodiments, GO-HA + Compound 1, GO-HA + Compound 7, or GO-HA/Compound 8).
• a non-ionic hydrophilic polymer e.g., PEG-400 (or PEG 400, having an average molar mass of about 400)
• the wound to be ameliorated, treated, repaired, or healed is selected from one or more of the group consisting of an acute wound, chronic wound, tear wound, abrasion wound, laceration wound, puncture wound, avulsion wound, skin cut, surgical wound, thermal wound, burn wound, ulcer, chemical wound, bite wound, stab wound, gunshot wound, other penetrating high velocity projectile wound, sting, electrical wound, chop wound, crush wound, poison wound, radiation wound, scalped wound, penetrating wound, incision wound, blunt force trauma wound, skin tear, internal wound, open wound, closed wound, excoriation, infected wound, weeping wound, non-healing wound, wound associated with dressing changes, amputation, necrotizing fasciitis wound, osteomyelitis wound, and posttrauma wound.
• the present disclosure contemplates use with chronic wounds arising as a consequence of an underlying condition, such as diabetic ulcerations.
• the wound to be ameliorated, treated, repaired, or healed is an acute or chronic wound and the compound is administered subcutaneously. In some or any embodiments, the wound to be ameliorated, treated, repaired, or healed is an acute or chronic wound and the compound is administered orally.
• the wound to be ameliorated, treated, repaired, or healed is a bum.
• the bum is a thermal burn.
• the burn is a chemical bum.
• the bum is an electric bum.
• the burn is a thermal bum.
• the wound is a radiation bum.
• the wound is a first degree burn.
• the wound is a second degree burn.
• the wound is a third degree burn.
• the compounds described herein are used for delaying the onset of a wound, or reducing the severity or duration of a wound. In some or any embodiments, the compounds described herein are used for the reduction of the severity or duration of a wound associated with Wnt transcription products or Wnt signaling pathway activity. In some embodiments, the compounds described herein are used for delaying or preventing onset of a wound.
• the compounds described herein are used for prevention of a wound or of a condition associated with Wnt transcription products or Wnt signaling pathway activity.
• the compounds described herein are used for treatment of a wound or of a condition associated with Wnt transcription products or Wnt signaling pathway activity.
• Compounds can be assayed for efficacy in treating a disease, disorder, or condition associated with Wnt signaling pathway activity according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein.
• the compounds and compositions provided herein are useful in methods of treatment of a wound and/or a condition associated with Wnt transcription products and/or Wnt signaling pathway activity, that comprise further administration of a second agent effective for the treatment of a wound and/or a Wnt transcription related disorder and/or a condition associated with Wnt transcription products and/or Wnt signaling pathway activity.
• the second agent used in the method of treatment can be any agent known to those of skill in the art to be effective for the treatment of a wound and/or a Wnt transcription related disorder and/or a condition associated with Wnt transcription products and/or Wnt signaling pathway activity, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States.
• Second medications are previously described herein and can be used in the methods of treatment.
• the second agent is a PARP inhibitor, silver, or a notich inhibitor.
• the second agent is one or more of: corticosteroid, a cytotoxic drug, an antibiotic, an antiseptic, nicotine, an anti-platelet drug, an NSAID, colchicine, an anti-coagulant, a vasoconstricting drug or an immunosuppressive, a growth factor, an antibody, a protease, a protease inhibitor, an antibacterial peptide, an adhesive peptide, a hemostatic agent, living cells, honey, nitric oxide, an antifibrotic compounds (such as pirfenidone, halofuginone, nintedanib, tocilizumab, rilonacept, etc.), an anti-cancer agent, an anti-inflammatory agent, an analgesic, a Wnt inhibitor, a Hedgehog pathway inhibitor, a TGF-P inhibitor, and/or a LOX inhibitor, etc.
• corticosteroid a cytotoxic drug
• an antibiotic an antiseptic
• nicotine an anti-platelet drug
• a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agents.
• the term “in combination” includes the use of more than one therapy (e.g. , one or more prophylactic and/or therapeutic agents).
• the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a mammal with a disorder.
• a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
• a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a mammal with a disorder.
• a second therapy e.g., a prophylactic or therapeutic agent
• the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies.
• a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a mammal with a disorder.
• a therapy e.g., a prophylactic or therapeutic agent
• a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder.
• a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
• the active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of a wound and/or a Wnt transcription related disorder and/or a condition associated with Wnt transcription products and/or Wnt signaling pathway activity.
• another therapeutic agent in particular an agent effective in the treatment of a wound and/or a Wnt transcription related disorder and/or a condition associated with Wnt transcription products and/or Wnt signaling pathway activity.
• effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
• the dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the wound or Wnt-transcription-related disorder to be alleviated. It is to be further understood that for any particular mammal, specific dosage regimens and schedules should be adjusted over time according
• reaction mixture was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100 x 30mm x lOum; mobile phase: [water (NH4HCO3) - can]; B%: 25%-55%, 8 mins) to provide 2-(3,5-difluoro-4-(2-(2 -methoxy ethoxy )propan-2-yl)phenyl)-3, 5,7, 8-tetrahydro- 4H-thiopyrano[4,3-d]pyrimidin-4-one (Compound 16).
• LC-MS 397.1 (M+l).

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