WO2019213335A1 - Promédicaments à biodisponibilité orale d'edaravone présentant des propriétés pharmacocinétiques modifiées et leurs procédés d'utilisation - Google Patents

Promédicaments à biodisponibilité orale d'edaravone présentant des propriétés pharmacocinétiques modifiées et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2019213335A1
WO2019213335A1 PCT/US2019/030300 US2019030300W WO2019213335A1 WO 2019213335 A1 WO2019213335 A1 WO 2019213335A1 US 2019030300 W US2019030300 W US 2019030300W WO 2019213335 A1 WO2019213335 A1 WO 2019213335A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
edaravone
bivalent
compound
salts
Prior art date
Application number
PCT/US2019/030300
Other languages
English (en)
Inventor
Andrew D. LEVIN
Original Assignee
Carnot2, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Carnot2, Llc filed Critical Carnot2, Llc
Publication of WO2019213335A1 publication Critical patent/WO2019213335A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the invention generally relates to orally bioavailable prodrugs of Edaravone (including analogs, derivatives, and salts thereof) with altered pharmacokinetic properties and methods of use thereof.
  • Edaravone is a chemical compound that contains three antioxidant groups, which makes this compound a powerful free radical scavenger. As such, Edaravone has been approved for treatment of numerous diseases and is being explored for treatment of numerous diseases. For example, Edaravone is approved for treatment of cardiovascular diseases due to the compounds potent antioxidant effects and radical scavenging effects. Edaravone is a medicine currently approved for treating acute ischemic stroke in clinical practice, which exerts neuroprotective effects by scavenging the oxygen free radicals generated during the ischemia reperfusion. Edaravone has been found in previous studies to reduce cerebral ischemia-reperfusion injury area, and suppress the gene expression of the Fas/FasL signaling pathway and thereby inhibit neuronal apoptosis.
  • Edaravone has been found in a recent research to inhibit the mitochondrion dependent apoptosis pathway in the N2a/ Swe.A9 cells. In the ischemia-reperfused elderly rats, Edaravone could reduce the glutathione peroxidase activity, suppress the JNK-c-Jun pathway and decrease the neuronal apoptosis. Edaravone also has therapeutic effects on other nervous system degenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. Edaravone has also been used for preventing and scavenging intracerebral Ab deposition, in particular for preventing and treating cerebral amyloid angiopathy (CAA).
  • CAA cerebral amyloid angiopathy
  • Edaravone is not orally bioavailable and is administered only via an intravenous formulation for any of its uses.
  • Various approaches have been attempted to enhance aqueous dissolution, including the use of cyclodextrin solutions and nanosizing. Those approaches are not sufficiently effective in permitting oral delivery for the treatment of medical conditions in which Edaravone is used. For instance, many cyclodextrins are associated with poor solubility, while nanoparticle methods are associated with highly variable absorption of the drug and are dependent on dosing with or without a fatty meal.
  • the invention provides orally bioavailable prodrugs of Edaravone (including analogs, derivatives, and salts thereof) having altered pharmacokinetic properties .
  • the invention recognizes that modifying the carbonyl group of Edaravone with certain chemical moieties dramatically improves the oral bioavailability and/or alters pharmacokinetic properties of such Edaravone (including analogs, derivatives, and salts thereof).
  • the compounds of the invention are prodrugs, that cleave in vivo to re-form the active parent Edaravone (including analogs, derivatives, and salts thereof). In that manner, the invention provides orally
  • Edaravone including analogs, derivatives, and salts thereof
  • PK pharmacokinetic
  • the invention provides compounds of formula I: A-L-B, wherein: A is Edaravone, analogs, derivatives, and salts thereof; L is a linker; and B is a moiety that enhances oral bioavailability and/or alters pharmacokinetic properties of the Edaravone, analogs, derivatives, and salts thereof.
  • the compounds of the invention are prodrugs and A is joined to L by a cleavable bond and L is joined to B by a cleavable bond.
  • Exemplary cleavable bonds are bonds that cleave in a subject (e.g., mammal (such as a human)) in vivo. Cleavage may be enzymatic cleavage or by any other mechanism that exists, such as chemical degradation.
  • Edaravone has the following structure:
  • linker L is a moiety that binds the carbonyl group of Edaravone (including analogs, derivatives, and salts thereof) to thereby convert the carbonyl bond to an ester bond. Numerous linkers are discussed herein. A preferred linker L is succinate.
  • B is an optionally substituted polyol.
  • the optionally substituted polyol is an optionally substituted glycerol.
  • L is succinate and the optionally substituted glycerol is conjugated to the succinate at a 2-position of the optionally substituted glycerol.
  • L-B is represented by formula II:
  • R 8 and R 9 are each independently selected from H, a C 1 -C 28 alkyl, and a C 1 -C 28 fatty acid.
  • A is Edaravone and R 8 and R 9 are each independently a C 1 -C 28 fatty acid, more preferably R and R are each independently a C 1 -C 3 fatty acid.
  • the compounds of the invention are formulated for oral administration.
  • oxidative stress related disorders in a subject (e.g., mammal (such as a human) by providing to the subject any of the compounds described herein.
  • exemplary oxidative stress related disorders include stroke, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and cerebral amyloid angiopathy (CAA).
  • FIG. 1 is a graph of results of NMR analysis of CV- 10029, a compound of the invention.
  • FIG. 2 is a graph of results of LC-MS analysis of CV-10029, a compound of the invention.
  • FIG. 3 is a graph of results of ESI-LC-MS analysis of CV- 10029, a compound of the invention.
  • FIG. 4 is a graph of results of HPLC analysis of CV- 10029, a compound of the invention.
  • FIG. 5 is a graph of results of NMR analysis of CV- 10042, a compound of the invention.
  • FIG. 6 is a graph of results of LC-MS analysis of CV-10042, a compound of the invention.
  • FIG. 7 is a graph of results of ESI-LC-MS analysis of CV- 10042, a compound of the invention.
  • FIG. 8 is a graph of results of HPLC analysis of CV- 10042, a compound of the invention.
  • FIG. 9 is a graph of results of NMR analysis of CV- 10043, a compound of the invention.
  • FIG. 10 is a graph of results of LC-MS analysis of CV- 10043, a compound of the invention.
  • FIG. 11 is a graph of results of ESI-LC-MS analysis of CV- 10043, a compound of the invention.
  • FIG. 12 is a graph of results of HPLC analysis of CV-10043, a compound of the invention.
  • FIG. 13 is a graph of results of NMR analysis of CV-10044, a compound of the invention.
  • FIG. 14 is a graph of results of LC-MS analysis of CV- 10044, a compound of the invention.
  • FIG. 15 is a graph of results of ESI-LC-MS analysis of CV- 10044, a compound of the invention.
  • FIG. 16 is a graph of results of HPLC analysis of CV-10044, a compound of the invention.
  • FIG. 17 is a graph of results of NMR analysis of CV-10045, a compound of the invention.
  • FIG. 18 is a graph of results of LC-MS analysis of CV-10045, a compound of the invention.
  • FIG. 19 is a graph of results of ESTLC-MS analysis of CV-10045, a compound of the invention.
  • FIG. 20 is a graph of results of HPLC analysis of CV-10045, a compound of the invention.
  • the invention generally relates to orally bioavailable Edaravone (including analogs, derivatives, and salts thereof) with altered pharmacokinetic properties and methods of use thereof.
  • the present invention provides compounds with good potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and/or metabolism.
  • PK pharmacokinetic
  • One important feature of the compounds as described herein is modification (by reversible bond) of the carbonyl of Edaravone with certain chemical moieties to thereby dramatically improve the oral bioavailability and/or alters pharmacokinetic properties of such compounds.
  • modification by reversible bond
  • the compounds of the invention are prodrugs, that cleave in vivo to form the active Edaravone parent compound (including analogs, derivatives, and salts thereof).
  • the invention provides compounds of formula I: A-L-B.
  • A is Edaravone (including analogs, derivatives, and salts thereof)
  • L is a linker
  • B is a moiety that enhances oral bioavailability and/or alters pharmacokinetic properties of Edaravone
  • the compounds of the invention are prodrugs and A is joined L by a cleavable bond, for example, a bond that is cleaved in a subject (e.g., mammal (such as a human)) in vivo.
  • L is bound to B by a cleavable bond, for example, a bond that is cleaved in a subject (e.g., mammal (such as a human)) in vivo.
  • Cleavage may be enzymatic cleavage or by any other mechanism that exists in vivo.
  • one or more hydrogen atoms on any of A, L, or B are replaced with one or more deuterium atom(s) and/or one or more tritium atom(s).
  • Edaravone including analogs, derivatives, and salts thereof
  • Edaravone has the chemical name of 3 -methyl- l-pheneyl-2-pyrazolin-5-one, molecular formula of C 10 H 10 N 2 0, molecular weight of 174.19, and the below chemical structure:
  • physiologically acceptable salts thereof can also be used as an active ingredient of the compounds of the present invention.
  • any hydrate or any solvate thereof may also be used.
  • tautomers as shown in the chemical structural formula in the upper part of Section 5 of JP Patent Publication (Examined Application) No. 5-31523, the content of which is incorporated by reference herein in its entirety. Needless to say, all of these tautomers are within the scope of the invention.
  • acid-added salts or base-added salts can be used.
  • mineral acid salts such as hydrochloride, sulfate, hydrobromate, or phosphate
  • organic acid salts such as methane sulfonate, paratoluene sulfonate, acetate, oxalate, citrate, malate, or fumarate
  • metal salts such as a sodium salt, potassium salt, or magnesium salt
  • ammonium salt or organic amine salts, such as ethanol amine or 2-amino-2-methyl-l -propanol
  • the types of salts are not particularly limited, as long as they are physiologically acceptable.
  • analogues of Edaravone comprise those in which methyl at the position 3 of the pyrazoline ring may be replaced with a lower (C 1-6 ) alkyl such as ethyl, propyl, etc., or replaced with a lower alkoxy such as methoxy, ethoxy, etc., or methyl at position 3 may be replaced with H while the position 4 is substituted with a lower alkyl or alkoxy.
  • derivatives of Edaravone comprise esters, i.e.
  • ketone in position 5 of the pyrazoline ring is transformed into enol, and reacts with a carboxylic acid to generate esters such as methyl esters, ethyl esters, etc.
  • esters such as methyl esters, ethyl esters, etc.
  • the ester (precursor) is converted again into ketone after hydrolysis in vivo.
  • phenyl is also optionally substituted with one or more substituents that are selected from a lower alkyl, a lower alkoxy, nitro, halogen, etc.
  • Alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”, also referred to herein as“lower alkyl”). In some
  • an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3 ).
  • the alkyl group is substituted C 1-10 alkyl.
  • Alkoxy refers to the group -OR where R is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl.
  • Particular alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Niro refers to the radical -NO 2 .
  • Halogen refers to any of the elements fluorine, chlorine, bromine, iodine, and astatine, occupying group VIIA (17) of the periodic table.
  • the invention takes advantage of the discovery that modifying the carbonyl group of Edaravone (including analogs, derivatives, and salts thereof) with certain chemical moieties dramatically improves the oral bioavailability and/or alters pharmacokinetic properties of Edaravone (including analogs, derivatives, and salts thereof).
  • L forms a cleavable bond with A (e.g., in vivo enzymatically cleavable bond) and does not cleave in vivo from B.
  • A e.g., in vivo enzymatically cleavable bond
  • two cleavable bonds are used.
  • the linkage between A and L is by a cleavable bond and the linkage between L and B is a cleavable bond.
  • B typically is the moiety that enhances oral bioavailability and/or alters pharmacokinetic properties and the bond between L and b cleaves first, leaving A-L. Then, the bond between A and L cleaves, leaving the parent molecule A, e.g., Edaravone (including analogs, derivatives, and salts thereof).
  • the bond between A and L and L and B can be cleaved by the same mechanism.
  • Exemplary mechanisms include enzymatic cleavage or chemical degradation, such as self-immolative linkers.
  • the bond between A and L and L and B can be cleaved by different mechanisms.
  • one or both of the bonds between A and L and L and B are enzymatically cleavable.
  • the same enzyme cleaves the bonds between A and L and L and B.
  • different enzymes cleave the bonds between A and L and L and B.
  • an exemplary linker is succinate and an exemplary moiety that enhances oral bioavailability and/or alters pharmacokinetic properties of Edaravone (including analogs, derivatives, and salts thereof) that is coupled to the linker (L) is a polyol (e.g., C 2 -C 20 polyol) that is optionally substituted (e.g., with one or more fatty acids).
  • the succinate forms a cleavable bond with A and a cleavable bond with the polyol (optionally substituted).
  • the bond between succinate and Edaravone is at the carbonyl of Edaravone (including analogs, derivatives, and salts thereof).
  • Edaravone including analogs, derivatives, and salts thereof
  • succinate and the polyol optionally substituted, e.g., with fatty acids
  • the bond between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the polyol (optionally substituted) is cleaved by different mechanisms.
  • Edaravone including analogs, derivatives, and salts thereof
  • succinate and the polyol are enzymatically cleavable.
  • the same enzyme cleaves the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the polyol (optionally substituted).
  • different enzymes cleave the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the polyol (optionally substituted).
  • different enzymes cleave the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the polyol (optionally substituted) and the cleavage occurs at different time point in vivo.
  • the bond between succinate and the polyol (optionally substituted) is cleaved first, leaving Edaravone (including analogs, derivatives, and salts thereof) bound to succinate. Then, the bond between Edaravone (including analogs, derivatives, and salts thereof) and succinate is cleaved enzymatically at a second time point.
  • the optionally substituted polyol is an optionally substituted glycerol.
  • L is succinate and the optionally substituted glycerol is conjugated to the succinate at a 2-position of the optionally substituted glycerol.
  • the invention encompasses conjugation at the l-position or 3-position of glycerol.
  • L-B is represented by formula II:
  • R 8 and R 9 are each independent selected from H, a C 1 -C 28 alkyl, and a C 1 -C 28 fatty acid.
  • the present disclosure provides the insight that, in some embodiments, the position of Edaravone (including analogs, derivatives, and salts thereof) on the glycerol moiety (via any linker, succinate in this embodiment) may have an effect on its pharmacological properties.
  • a glycerol moiety with Edaravone (including analogs, derivatives, and salts thereof) conjugated to the 2 position via the succinate may exhibit improved pharmacological properties over a glycerol moiety with Edaravone (including analogs, derivatives, and salts thereof) conjugated via the succinate to the 1 or 3 position.
  • the present disclosure proposes that, in some embodiments, the 1 and 3 positions of the glycerol backbone may be more susceptible to cellular lipases than the 2 position.
  • the present disclosure also provides the insight that, in some embodiments, a compound provided herein may isomerize, for example, undergoing positional isomerization.
  • a glycerol moiety comprises a free alcohol (e.g., a free alcohol at a position corresponding to *-OR or *-OR below)
  • a moiety conjugated to glycerol at the 2-position may migrate to a free alcohol (e.g., migrate from the 2-position to a position corresponding to *-OR or *-OR ).
  • a free alcohol e.g., migrate from the 2-position to a position corresponding to *-OR or *-OR
  • isomerization occurs prior to administration. In some embodiments, isomerization occurs after administration. In addition, the present disclosure provides the insight that, in some embodiments, a glycerol moiety that does not comprise a free alcohol will not isomerize. For example, in some embodiments, compound R and R are fatty acids, which prevents positional isomerization.
  • the succinate forms a cleavable bond with A and a cleavable bond with the optionally substituted glycerol.
  • the bond between succinate and Edaravone (including analogs, derivatives, and salts thereof) is at the carbonyl of Edaravone (including analogs, derivatives, and salts thereof).
  • the bond between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol is cleaved by the same mechanism.
  • the bond between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol is cleaved by different mechanisms.
  • one or both of the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol are enzymatically cleavable.
  • the same enzyme cleaves the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol.
  • different enzymes cleave the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol.
  • different enzymes or mechanism cleave the bonds between succinate and Edaravone (including analogs, derivatives, and salts thereof) and succinate and the optionally substituted glycerol and the cleavage occurs at different time point in vivo.
  • the bond between succinate and the optionally substituted glycerol is cleaved first, leaving Edaravone (including analogs, derivatives, and salts thereof) bound to succinate. Then, the bond between Edaravone (including analogs, derivatives, and salts thereof) and succinate is cleaved enzymatically at a second time point.
  • R 8 and R 9 are each independently a C 1 -C 28 alkyl or a C 1 -C 28 fatty acid, preferably a C 1 - C 28 fatty acid, such as a C 1 -C 3 fatty acid.
  • A may be Edaravone (including analogs, derivatives, and salts thereof), and preferably is Edaravone.
  • different enzymes or mechanisms cleave the bonds between succinate and the Edaravone (including analogs, derivatives, and salts thereof) and succinate and the substituted glycerol and the cleavage occurs at different time point in vivo.
  • the bond between succinate and the substituted glycerol is cleaved first, leaving the Edaravone (including analogs, derivatives, and salts thereof) bound to succinate. Then, the bond between Edaravone (including analogs, derivatives, and salts thereof) and succinate is cleaved enzymatically at a second time point, reestablishing the parent Edaravone (including analogs, derivatives, and salts thereof).
  • the lymphatic system consists of a specialized network of vessels, nodes and lymphoid tissues that are distributed throughout the body in close proximity to the vascular system.
  • the lymphatic system plays a number of key roles in immune response, fluid balance, nutrient absorption, lipid homeostasis, and tumor metastasis. Due to the unique anatomical and physiological characteristics of the lymphatic system, targeted drug delivery to and through the lymphatic system has been suggested as a means to improve both pharmacokinetic and pharmacodynamic profiles.
  • Lymphatic drug transport has the potential to enhance oral bioavailability through avoidance of first pass metabolism, to alter systemic drug disposition, and to enhance efficacy against lymph or lymphocyte mediated pathologies such as lymphoma, leukemia, lymphatic tumor metastasis, autoimmune disease, lymph resident infections and transplant rejection.
  • intestinal lymph lipoproteins that are assembled in intestinal absorptive cells (enterocytes) in response to lipid absorption. Association with these lipoproteins subsequently promotes drug transport into the lymph since their size precludes ready diffusion across the vascular endothelium lining the blood capillaries that drain the small intestine. Instead, these large colloidal structures enter the lymphatic capillaries since the lymphatic endothelium is considerably more permeable than that of the vascular endothelium.
  • drugs with high lymphatic transport have been highly lipophilic in order to promote physical association with lipoproteins (usually, but not exclusively, log D>5 and solubility in long chain triglyceride of >50 mg/g). Therefore, highly lipophilic analogues of drugs have been envisaged as one way to promote lymphatic drug transport.
  • dietary lipids such as triglycerides use a unique metabolic pathway to gain access to the lymph (and ultimately the systemic circulation) that is entirely distinct from that of other nutrients such as proteins and carbohydrates.
  • dietary triglycerides are hydrolyzed by luminal lipases to release one monoglyceride and two fatty acids for each molecule of triglyceride.
  • the monoglyceride and two fatty acids are subsequently absorbed into enterocytes, where they are re-esterified to triglycerides.
  • Resynthesized triglycerides are assembled into intestinal lipoproteins (primarily chylomicrons) and the chylomicrons so formed are exocytosed from enterocytes and
  • lipids in the form of chylomicrons drain through a series of capillaries, nodes and ducts, finally emptying into the systemic circulation at the junction of the left subclavian vein and internal jugular vein.
  • triglycerides in chylomicrons are preferentially and efficiently taken up by tissues with high expression of lipoprotein lipases such as adipose tissue, the liver and potentially certain types of tumor tissues.
  • lipid mimetic compounds such as the preferred embodiments, are expected to behave similarly to natural triglycerides and to be transported to and through the lymphatic system before reaching the systemic circulation.
  • the pharmacokinetic and pharmacodynamic profiles of the parent pharmaceutical agent here, Edaravone (including analogs, derivatives, and salts thereof)
  • Edaravone including analogs, derivatives, and salts thereof
  • Lipid mimetic compounds may also promote drug-targeting to sites within the lymph, lymph nodes and lymphoid tissues, and to sites of high lipid utilization and lipoprotein lipase expression such as adipose tissue and some tumors.
  • lipidated prodrugs that readily convert to parent drug after transport via the systemic circulation reduce free drug concentrations in the gastrointestinal (GI) tract, which may provide benefits in reducing gastrointestinal irritation, in taste masking, in promoting drug solubilization in intestinal bile salt micelles (due to similarities to endogenous monoglycerides) and in enhancing passive membrane permeability (by increasing lipophilicity).
  • GI gastrointestinal
  • Lipidated prodrugs also promote solubility in lipid vehicles comprising either lipids alone or mixtures of lipids with surfactants and/or co-solvents, and in doing so allow larger doses to be administered with the drug in solution than might be possible for parent drug.
  • L-B is represented by formula III:
  • A is Edaravone (including analogs, derivatives, and salts thereof), which is cleavably bound to L-B in this embodiment and defined as:
  • R 1 and R 2 independently represent H, or a residue of a C 2 -C 28 fatty acid;
  • - X- is selected from -0-, -NH- and -S-;
  • -Y- represents an optionally substituted -C 3 -C 20 alkyl-, -C 3 -C 20 alkenyl- or -C 3 -C 20 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl or alkynyl group may be replaced with NH, S, O, a C 5 -C 8 aromatic or aliphatic cyclic group or a C 5 -C 8 aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl or alkynyl group does not exceed a length equivalent to a linear C 2 oalkyl group;
  • -L- is -X'- or - X'C(O)-;
  • X' is O, S,
  • L is a linking group comprising an ester group, a carbamate group, a carbonyl group, a thioester group, a disulfide group, an ether group, an anhydride group, or an amide group;
  • B is a lipid moiety comprising an acyl, alky, alkylaryl, fluoroacyl, fluoroalkyl or fluoroalkylaryl group having from about 4 to about 40 carbon atoms.
  • the acyl or alkyl group may consist of one, two or three chains or an alkylaryl group.
  • B may be a diacylated moiety in which two acyl chains are linked to glycerol. More preferably, B may be dipalmitoylglyceryl,
  • L-C is preferably dipalmitoylglyceryl succinate, dimyristoylglyceryl succinate,
  • distearoylglyceryl succinate dioleoylglyceryl succinate or cholesterol succinate.
  • B may be a lipid moiety comprising a fluoroacyl, fluoroalkyl or fluoroalkylaryl group.
  • the acyl, alkyl or alkylaryl group may comprise one or more fluorine atoms, preferably from about 3 to about 23 fluorine atoms, more preferably from about 5 to about 18 fluorine atoms.
  • the terminal carbon atoms are preferably fluorinated.
  • the acyl, alkyl or alkylaryl group may be a perfluorinated group.
  • Perfluorinated means that all the hydrogen atoms, except those whose replacement would affect the nature of the characteristic groups present, are replaced by fluorine atoms.
  • bipyridine moieties may be perfluoroalkylated as described in Garelli and Vierling, Biochim. Biophys. Acta (1992) 1127:41-48, the disclosure of which is hereby incorporated by reference herein in its entirety.
  • Other fluorinated amphiphilic molecules which serve in this capacity are fluorosurfactants and the compounds disclosed in U.S. Pat. No. 5,562,893 and U.S. application Ser. No. 08/465,868, filed Jun. 6, 1995, the disclosures of which are hereby incorporated herein by reference in their entirety.
  • Edaravone (including analogs, derivatives, and salts thereof) is covalently bonded to a lipid moiety (B) via a linking group (L) of formula IV:
  • A is Edaravone (including analogs, derivatives, and salts thereof), which is cleavably bound to L-B in this embodiment and defined as:
  • L alone can impart improved oral bioavailability.
  • the invention provides compounds of A-L without B.
  • L acts as the chemical moiety that modifies the carbonyl (by a cleavable bond) in Edaravone (including analogs, derivatives, and salts thereof).
  • L is a moiety comprising an ester group, a carbamate group, a carbonyl group, a thioester group, a disulfide group, an ether group, an anhydride group, or an amide group.
  • the chemical moiety that modifies the carbonyl of Edaravone is a sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are organic compounds, typically derived from sugars.
  • Sugar alcohols have the general formula HOCH 2 (CHOH) n CH 2 OH.
  • Exemplary sugar alcohols that can modify (by cleavable bond) the carbonyl of Edaravone include glycerol (3-carbon), erythritol (4- carbon), threitol (4-carbon), arabitol (5-carbon), xylitol (5-carbon), ribitol (5-carbon), mannitol (6-carbon), sorbitol (6-carbon), salactitol (6-carbon), fucitol (6-carbon), iditol (6-carbon), inositol (6-carbon; a cyclic sugar alcohol), volemitol (7-carbon), isomalt (l2-carbon), maltitol (12- carbon), lactitol (l2-carbon), maltotriitol (l8-carbon), maltotetraitol (24-carbon), or polyglycitol.
  • the L moiety that modifies (by cleavable bond) the carbonyl of Edaravone is succinate or succinic acid.
  • Succinic acid has the structure: Succinate has the structure:
  • compositions of Prodrugs of Edaravone including Analogs, Derivatives, And
  • compositions containing one or more of the compounds described above may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patents 4,256,108, 4,166,452 and 4,265,874, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Pat. 6,214,841 and U.S. Pub. 2003/0232877, incorporated by reference herein in their entirety.
  • Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • An alternative oral formulation where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating.
  • Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in l,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral)
  • parenteral (by injection) administration parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the compounds provided herein When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically ("chronic administration").
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body.
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • Any disease or disorder known to be treated with Edaravone is within the scope of the invention and compounds of the invention can be used to treat any disease or disorder treated with Edaravone (including analogs, derivatives, and salts thereof).
  • the compounds of the invention treat disorders associated with oxidative stress.
  • Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by reactive oxygen species (ROS) generated, e.g. 0 2 _ (superoxide radical), OH (hydroxyl radical) and H 2 0 2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.
  • ROS reactive oxygen species
  • oxidative stress is thought to be involved in the development of ADHD, cancer, Parkinson's disease, Lafora disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, fragile X syndrome, sickle-cell disease, lichen planus, vitiligo, autism, [15] infection, chronic fatigue syndrome, and depression and seems to be characteristic of individuals with Asperger syndrome.
  • oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.
  • antioxidant defenses such as glutathione.
  • the effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state.
  • more severe oxidative stress can cause cell death, and even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis.
  • oxidative stress is a particularly destructive aspect of oxidative stress.
  • Such species include free radicals and peroxides.
  • Some of the less reactive of these species can be converted by oxido-reduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage.
  • Most long-term effects are caused by damage to DNA.
  • DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer.
  • Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions.
  • Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed H 2 0 2 reactions.
  • the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T).
  • G[8,5- Me]T 5-methyl group of an adjacent 3'-thymine
  • Most of these oxygen- derived species are produced by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Repair of oxidative damages to DNA is frequent and ongoing, largely keeping up with newly induced damages.
  • rat urine about 74,000 oxidative DNA adducts per cell per day are excreted. However, there is a steady state level of oxidative damages, as well, in the DNA of a cell.
  • Polyunsaturated fatty acids are primary targets for free radical and singlet oxygen oxidations.
  • the free radical oxidation of linoleic acid produces racemic mixtures of l3-hydroxy-9Z,HE- octadecadienoic acid, l3-hydroxy-9E,HE-octadecadienoic acid, 9-hydroxy- 10E,12-E- octadecadienoic acid (9-EE-HODE), and l l-hydroxy-9Z,l2-Z-octadecadienoic acid as well as 4- Hydroxynonenal while singlet oxygen attacks linoleic acid to produce 13 -hydroxy- 9Z, 11 E- octadecadienoic acid, 9-hydroxy- lOE,l2-Z-octadecadienoic acid, lO-hydroxy-8E,l2Z- octadecadienoic acid
  • hydroperoxy- and hydroxy- eicosatetraenoates and 4-hydroxyalkenals. While many of these products are used as markers of oxidative stress, the products derived from linoleic acid appear far more predominant than arachidonic acid products and therefore easier to identify and quantify in, for example, atheromatous plaques. Certain linoleic acid products have also been proposed to be markers for specific types of oxidative stress.
  • racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of linoleic acid whereas the presence of racemic lO-hydroxy-8E,l2Z-octadecadienoic acid and l2-hydroxy-9Z- l3-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid.
  • the linoleic and arachidonic acid products can contribute to tissue and/or DNA damage but also act as signals to stimulate pathways which function to combat oxidative stress.
  • Oxidative stress is suspected to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, Depression, and Multiple sclerosis.
  • MND or ALS Lou Gehrig's disease
  • Parkinson's disease Alzheimer's disease
  • Huntington's disease Huntington's disease
  • Depression Depression
  • Multiple sclerosis Indirect evidence via monitoring biomarkers such as reactive oxygen species, and reactive nitrogen species production, antioxidant defense indicates oxidative damage may be involved in the pathogenesis of these diseases, [48] [49] while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.
  • Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the vascular endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen reperfusion injury following hypoxia. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome. Oxidative stress also contributes to tissue injury following irradiation and hyperoxia, as well as in diabetes.
  • Oxidative stress is likely to be involved in age-related development of cancer.
  • the reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore mutagenic, and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis.
  • Infection by Helicobacter pylori which increases the production of reactive oxygen and nitrogen species in human stomach is also thought to be important in the
  • compounds of the invention can be used to treat any of the above conditions that are associated with or result from oxidative stress, because the compounds of the invention act as free radical scavengers, thereby reducing or eliminating oxidative stress in an animal (e.g., mammal (such as a human)).
  • an animal e.g., mammal (such as a human)
  • the compounds of the invention can be used for treatment of motor neuron diseases.
  • treatment of motor neuron diseases used in the present specification means not only treatment given for curing the disease, but widely means all types of treatment including treatment for delaying the progress of the disease, and treatment for alleviating and easing the symptoms of the disease.
  • motor neuron diseases used in the present invention has the broadest meaning, and it encompasses motor neuron disorders (motor neuropathy).
  • Motor neuron disease is a generic name of a disease group by which the voluntary motor nerve system is selectively impinged.
  • Motor neuron diseases are neurologic ally regressive and have strong tendencies to be exacerbated, although the degree of disease progression differs depending on specific disease types.
  • Specific examples of motor neuron diseases can include, but are not limited thereto, amyotrophic lateral sclerosis (ALS), spinal muscle atrophy (SMA), progressive bulbar palsy, primary lateral sclerosis (PLS), or arthrogryposis multiplex congenita (AMC).
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscle atrophy
  • PLS primary lateral sclerosis
  • AMC arthrogryposis multiplex congenita
  • Amyotrophic lateral sclerosis begins in middle age and later, and is a cryptogenic disease mainly characterized by muscular atrophy and fasciculation.
  • Pathologic findings include degenerated spinal anterior hom cells, degenerated medullary motor nucleus, and degenerated pyramidal tract.
  • the initial symptoms mainly include hand weakness, dyskinesia in the digits of the hand, and fasciculation in the upper limbs, and ALS can be classified into the upper limb type, bulbar type, lower limb type and mixed type according to the onset site. With any type of the disease, muscle groups of the whole body are impinged with the progress of the symptoms.
  • SMA Spinal muscle atrophy
  • Acute Werdnig-Hoffmann disease type I
  • Type II is characterized by severe generalized muscular weakness and hypotonia at birth and within 3 months after birth. Death usually occurs within the first two years of life due to dyspnea.
  • the remaining 2 groups are Intermediate type (type II) and Juvenile type (type III, Kugelberg-Welander disease).
  • Progressive bulbar palsy is caused by progressive atrophy of the motor nucleus of the medulla oblongata, and is closely associated with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Progressive bulbar palsy often begins in males in middle age and later, and sometimes occurs in familial forms. The disease is complicated by degeneration of upper and lower motor neurons as it progresses, and finally develops the clinical symptoms of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • SMA spinal muscular atrophy
  • PLS Primary lateral sclerosis
  • AMC Arthrogryposis multiplex congenita
  • congenital joint contracture (1 in 3000 births), and has symptoms derived from intrauterine fetal akinesia.
  • AMC is caused by any of oligoamnios, or various disorders relating to the central nerve system, skeletal muscle or spinal cord. Nerve degeneration and neuronophagy occurs in the anterior horn.
  • neurogenic AMC may be involved in acute spinal muscular atrophy, that is, SMA Werdnig-Hoffmann disorder type I.
  • Edaravone including analogs, derivatives, and salts thereof
  • the prodrugs of Edaravone including analogs, derivatives, and salts thereof
  • a particularly beneficial combination is a combination therapy that comprises N-acylethanolamide compounds, analogs, derivatives, or salts thereof or a prodrug of the N-acylethanolamide compounds, analogs, derivatives, or salts thereof; and Edaravone, analogs, derivatives, or salts thereof or a prodrug of Edaravone, analogs, derivatives, or salts thereof.
  • Another preferred combination also includes Edaravone (including analogs, derivatives, and salts thereof) or the prodrugs of Edaravone (including analogs, derivatives, and salts thereof); N-acylethanolamide compounds, analogs, derivatives, or salts thereof or a prodrug of the N-acylethanolamide compounds, analogs, derivatives, or salts thereof; and N-acylethanolamine acid amidase
  • NAAA N-(NAAA) inhibitors, analogs, derivatives, or salts thereof.
  • the combination therapy is formulated as a single unit dosage.
  • the combination therapy is formulated as a divided dosages.
  • the combination therapy includes N-acylethanolamide compounds, analogs, derivatives, or salts thereof and Edaravone, analogs, derivatives, or salts thereof.
  • the combination therapy includes a prodrug of the N- acylethanolamide compounds, analogs, derivatives, or salts thereof; the prodrugs of Edaravone, analogs, derivatives, or salts thereof as described herein; and optionally N-acylethanolamine acid amidase (NAAA) inhibitors, analogs, derivatives, or salts thereof.
  • the combination therapy is formulated as a single unit dosage for oral administration.
  • the combination therapy is formulated as a divided dosages, each for oral administration.
  • NAAA inhibitors, analogs, derivatives, or salts thereof are described for example in U.S. 2016/0068483, PCT/US 17/032981, U.S. 9,321,743, U.S. 9,353,075, and U.S. 9,828,338, the content of each of which is incorporated by reference herein in its entirety.
  • the prodrug of the N-acylethanolamide compounds, analogs, derivatives, or salts thereof is represented by formula 116:
  • the prodrug of the N-acylethanolamide compounds, analogs, derivatives, or salts thereof is represented by formula 116:
  • R 8 and R 9 are each independently selected from H, a C 1 -C 28 alkyl, and a C 1 -C 28 fatty acid.
  • R and R are each independently a C 1 -C 28 fatty acid.
  • a disease, disorder, or condition treated by the combination therapy is or comprises a neurologic, disease, disorder, or condition.
  • a disease, disorder or condition treated by the combination therapy is or comprises Huntington’s disease.
  • a disease, disorder or condition treated by the combination therapy is or comprises Parkinson’s disease.
  • a disease, disorder or condition treated by the combination therapy is or comprises Alzheimer’s disease.
  • a disease, disorder, or condition treated by the combination therapy is or comprises Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig’s disease).
  • a disease, disorder, or condition treated by the combination therapy is or comprises multiple sclerosis.
  • a disease, disorder, or condition treated by the combination therapy is or comprises neuropathic pain. In some embodiments, a disease, disorder, or condition treated by the combination therapy is or comprises cerebral ischemia. In some embodiments, a disease, disorder, or condition treated by the combination therapy is or comprises epilepsy.
  • a disease, disorder, or condition treated by the combination therapy is or comprises appetite loss. In some embodiments, a disease, disorder, or condition treated by the combination therapy is or comprises dental pain. In some embodiments, a disease, disorder, or condition treated by the combination therapy is or comprises osteoarthritis. In some embodiments, a disease, disorder, or condition treated by the combination therapy is or comprises reduced gastrointestinal motility.
  • a disease, disorder, or condition treated by the combination therapy is or comprises cancer.
  • a disease, disorder, or condition treated by the combination therapy is or comprises an ophthalmic condition. In some embodiments, a disease, disorder, or condition is or comprises glaucoma.
  • a disease, disorder, or condition treated by the combination therapy is or comprises atopic dermatitis.
  • a disease, disorder, or condition treated by the combination therapy is or comprises respiratory infection.
  • a disease, disorder, or condition treated by the combination therapy is or comprises post-traumatic stress disorder.
  • a disease, disorder, or condition treated by the combination therapy is or comprises obesity.
  • a disease, disorder, or condition treated by the combination therapy is or comprises insomnia.
  • a disease, disorder, or condition treated by the combination therapy is or comprises sleepiness.
  • N-acylethanolamide compounds, analogs, derivatives, or salts thereof and prodrugs of N- acylethanolamide compounds, analogs, derivatives, or salts thereof are described for example in PCT/US 17/56353, the content of which is incorporated by reference herein in its entirety.
  • a prodrug of an N-acylethanolamide compound for use in accordance with the present disclosure is one wherein an N-acylethanolamide is conjugated to a moiety selected from the group consisting of phosphate, butyric acid, glycerol, succinate, caprylic acid, gluconoic acid, eicosapentaeonoic acid, linoleic acid, succinate, and sucrose moieties, and combinations thereof.
  • an N-acylethanolamide is conjugated to one or more such moieties through use of a linker moiety.
  • an N- acylethanolamide is conjugated to two or more such moieties.
  • an N- acylethanolamide is conjugated to one, two, or three such moieties.
  • a provided compound has a chemical structure represented by formula I-a:
  • X 1 is an N-acylethanolamide
  • X 2 is a moiety conjugated to the N-acylethanolamide.
  • X 1 is selected from the group consisting of N- palmitoylethanolamide, N-oleoylethanolamide, and N-arachidonoylethanolamide; in some particular embodiments, X 1 is N-palmitoylethanolamide.
  • X 2 comprises a moiety selected from the group consisting of phosphate, butyric acid, glycerol, succinate, caprylic acid, gluconoic acid, eicosapentaeonoic acid, linoleic acid, succinate, and sucrose moieties.
  • a provided compound has a chemical structure represented by formula I:
  • each R 1 , R 2 , or R 3 is independently hydrogen or -T-R 4 , wherein at least one of R 1 , R 2 , or R 3 is -T-R 4 ;
  • R 4 is an optionally substituted group selected from the group consisting of C 1-40 aliphatic, -C(O)R, and X 1 ;
  • R is selected from the group consisting of hydrogen and optionally substituted C 1- 20 aliphatic;
  • X 1 is as defined above.
  • a provided compound has a chemical structure represented by formula I-b:
  • X 1 is as defined above;
  • X 3 is an optionally substituted group selected from the group consisting of -(CH 2 ) m - P(O)(0R) 2 , C 1-4O aliphatic, -T-X 4 ; further wherein
  • n is an integer select from the group consisting of 0-10;
  • X 4 is a saccharide moiety, in some particular embodiments, X 4 is a disaccharide, for example, sucrose.
  • the present disclosure provides compounds such as, for example:
  • a provided prodrug may be characterized by one or more desirable physical properties, which may, for example, be assessed relative to an appropriate reference N- acylethanolamide (e.g., to the parent N-acylethanolamide of the provided prodrug); in some embodiments, such desirable physical properties may be or include, for example, enhanced aqueous solubility (which may facilitate, for example, formulation into a pharmaceutical composition, particularly for oral or parenteral administration), enhanced absorption from the digestive tract, enhanced stability under relevant storage conditions, etc.
  • desirable physical properties may be or include, for example, enhanced aqueous solubility (which may facilitate, for example, formulation into a pharmaceutical composition, particularly for oral or parenteral administration), enhanced absorption from the digestive tract, enhanced stability under relevant storage conditions, etc.
  • Aliphatic means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon, bicyclic hydrocarbon, or polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-100 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-20 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1, 2, 3, or 4 aliphatic carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof.
  • alkyl is given its ordinary meaning in the art and may include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl has 1-100 carbon atoms.
  • a straight chain or branched chain alkyl has about 1-20 carbon atoms in its backbone (e.g., C 1 -C 20 for straight chain, C 2 -C 20 for branched chain), and alternatively, about 1- 10.
  • a cycloalkyl ring has from about 3-10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • an alkyl group may be a lower alkyl group, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g., C 1 -C 4 for straight chain lower alkyls).
  • Alkenyl As used herein, the term“alkenyl” refers to an alkyl group, as defined herein, having one or more double bonds.
  • Alkynyl As used herein, the term“alkynyl” refers to an alkyl group, as defined herein, having one or more triple bonds.
  • Protecting Group The phrase“protecting group,” as used herein, refers to temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • Si protecting group is a protecting group comprising a Si atom, such as Si-trialkyl (e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl), Si-triaryl, Si-alkyl-diphenyl (e.g., t- butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl).
  • Si-trialkyl e.g., trimethylsilyl, tributylsilyl, t-butyldimethylsilyl
  • Si-triaryl Si-alkyl-diphenyl (e.g., t- butyldiphenylsilyl), or Si-aryl-dialkyl (e.g., Si-phenyldialkyl).
  • Si-trialkyl e.g., trimethylsilyl, tributylsilyl, t-buty
  • Protected hydroxyl groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Examples of suitably protected hydroxyl groups further include, but are not limited to, esters, carbonates, sulfonates, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers.
  • suitable esters include formates, acetates, proprionates, pentanoates, crotonates, and benzoates.
  • esters include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetate), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate.
  • Examples of suitable carbonates include 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonate.
  • Examples of suitable silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisoprop ylsilyl ether, and other trialkylsilyl ethers.
  • alkyl ethers examples include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, and allyl ether, or derivatives thereof.
  • Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-
  • arylalkyl ethers examples include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- and 4-picolyl ethers.
  • Protected amines are well known in the art and include those described in detail in Greene (1999).
  • Suitable mono-protected amines further include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like.
  • suitable mono-protected amino moieties include t-butyloxycarbonylamino (-NHBOC), ethyloxycarbonylamino, methyloxycarbonylamino, trichloroethyloxycarbonylamino, allyloxycarbonylamino (-NHAlloc), benzyloxocarbonylamino (-NHCBZ), allylamino, benzylamino (-NHBn), fluorenylmethylcarbonyl (-NHFmoc), formamido, acetamido, chloroacetamido, dichloroacetamido, trichloroacetamido, phenylacetamido, trifluoroacetamido, benzamido, t- butyldiphen
  • Suitable di-protected amines include amines that are substituted with two substituents independently selected from those described above as mono-protected amines, and further include cyclic imides, such as phthalimide, maleimide, succinimide, and the like. Suitable di-protected amines also include pyrroles and the like, 2,2,5,5-tetramethyl- [l,2,5]azadisilolidine and the like, and azide.
  • Protected aldehydes are well known in the art and include those described in detail in Greene (1999). Suitable protected aldehydes further include, but are not limited to, acyclic acetals, cyclic acetals, hydrazones, imines, and the like. Examples of such groups include dimethyl acetal, diethyl acetal, diisopropyl acetal, dibenzyl acetal, bis(2-nitrobenzyl) acetal, 1,3- dioxanes, l,3-dioxolanes, semicarbazones, and derivatives thereof.
  • Suitable protected carboxylic acids are well known in the art and include those described in detail in Greene (1999). Suitable protected carboxylic acids further include, but are not limited to, optionally substituted C 1-6 aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters, amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is optionally substituted. Additional suitable protected carboxylic acids include oxazolines and ortho esters.
  • Protected thiols are well known in the art and include those described in detail in Greene (1999). Suitable protected thiols further include, but are not limited to, disulfides, thioethers, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates, and the like. Examples of such groups include, but are not limited to, alkyl thioethers, benzyl and substituted benzyl thioethers, triphenylmethyl thioethers, and trichloroethoxycarbonyl thioester, to name but a few. Substitution: As described herein, compounds of the disclosure may contain optionally substituted and/or substituted moieties.
  • the term“substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • the term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • SC(S)SR° -(CH 2 ) 0-4 SC(O)R°; -(CH 2 ) 0-4 C(O)NR° 2 ; -C(S)NR° 2 ; -C(S)SR°; -
  • SC(S)SR° -(CH 2 ) 0-4 0C(O)NR° 2 ; -C(O)N(0R°)R°; -C(O)C(O)R°; -C(O)CH 2 C(O)R°; - C(NOR°)R°; -(CH 2 ) 0-4 SSR°; -(CH 2 ) 0-4 S(O) 2 R°; -(CFF 2 ) 0-4 S(O) 2 OR°; -(CH 2 ) 0-4 0S(O) 2 R°; - S(O) 2 NR° 2 ; -(CH 2 ) 0-4 S(O)R°; -N(R°)S(O) 2 NR° 2 ; -N(R°)S(O) 2 R°; -N(OR°)R°; -C(NH)NR° 2 ; - P(O) 2 R°; -P(O)R° 2
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0- 2 R ⁇ , -(haloR ⁇ ), -(CH 2 ) 0-2 OH, -(CH 2)0-2 0RV -(CH 2)0-2 CH(0R ⁇ ) 2 ; -0(haloR ⁇ ), -CN, -N 3 , - (CH 2 ) 0-2 C(O)R ⁇ , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ⁇ , -(CH 2 ) 0-2 SR ⁇ , -(CH 2 ) 0-2 SH, -(CH 2 ) O- 2 NH 2 , -(CH 2 ) 0-2 NHR ⁇ , -(CH 2 ) 0-2 NRV -N0 2 ,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR 2 ) 2-3 0-, wherein each independent occurrence of R is selected from hydrogen, C
  • Suitable substituents on the aliphatic group of R * include halogen, -R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -0(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NRV or -N0 2 , wherein each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently Ci ⁇ aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • suitable substituents on a substitutable nitrogen include -R ⁇ , - NR ⁇ 2 , -C(O)R ⁇ , -C(O)OR ⁇ , -C(O)C(O)R ⁇ , -C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , - C(S)NR ⁇ 2 , -C(NH)NR ⁇ 2, or -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, - R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -0(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 , or -NO2, wherein each R ⁇ is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently C ⁇ aliphatic, -CH2Ph, -0(CH 2 ) 0-1 Ph, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • administration typically refers to the administration of a composition to a subject or system.
  • routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human.
  • administration may be ocular, oral, parenteral, topical, etc..
  • administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc.
  • bronchial e.g., by bronchial instillation
  • buccal which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc
  • enteral intra-arterial, intradermal, intragastric,
  • administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • agent in general, the term“agent”, as used herein, may be used to refer to a compound or entity of any chemical class including, for example, a polypeptide, nucleic acid, saccharide, lipid, small molecule, metal, or combination or complex thereof.
  • the term may be utilized to refer to an entity that is or comprises a cell or organism, or a fraction, extract, or component thereof.
  • the term may be used to refer to a natural product in that it is found in and/or is obtained from nature.
  • the term may be used to refer to one or more entities that is man-made in that it is designed, engineered, and/or produced through action of the hand of man and/or is not found in nature.
  • an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form.
  • potential agents may be provided as collections or libraries, for example that may be screened to identify or characterize active agents within them.
  • the term“agent” may refer to a compound or entity that is or comprises a polymer; in some cases, the term may refer to a compound or entity that comprises one or more polymeric moieties.
  • the term“agent” may refer to a compound or entity that is not a polymer and/or is substantially free of any polymer and/or of one or more particular polymeric moieties. In some embodiments, the term may refer to a compound or entity that lacks or is substantially free of any polymeric moiety
  • Agonist Those skilled in the art will appreciate that the term“agonist” may be used to refer to an agent condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e., the agonized agent).
  • an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or any other entity that shows the relevant activating activity.
  • an agonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, so that level or activity of the target is altered).
  • animal refers to any member of the animal kingdom.
  • animal refers to humans, of either sex and at any stage of development.
  • animal refers to non-human animals, at any stage of development.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig).
  • animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms.
  • an animal may be a transgenic animal, genetically engineered animal, and/or a clone.
  • the term“approximately” or“about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value.
  • the term“approximately” or“about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • Two events or entities are“associated” with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc
  • two or more entities are physically“associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
  • two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
  • Carrier refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered.
  • carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • carriers are or include one or more solid components.
  • Comparable refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • composition may be used to refer to a discrete physical entity that comprises one or more specified components.
  • a composition may be of any form - e.g., gas, gel, liquid, solid, etc.
  • composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method.
  • any composition or method described as “comprising” (or which "comprises") one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of” (or which "consists essentially of") the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method.
  • composition or method described herein as “comprising” or “consisting essentially of” one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of” (or “consists of”) the named elements or steps to the exclusion of any other unnamed element or step.
  • known or disclosed equivalents of any named essential element or step may be substituted for that element or step.
  • Dosage form or unit dosage form may be used to refer to a physically discrete unit of an active agent (e.g ., a therapeutic or diagnostic agent) for administration to a subject.
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population ( i.e ., with a therapeutic dosing regimen).
  • the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.
  • Dosing regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population ( i.e ., is a therapeutic dosing regimen).
  • Encapsulated The term“encapsulated” is used herein to refer to substances that are completely surrounded by another material.
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, 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.
  • Gel ⁇ refers to viscoelastic materials whose rheological properties distinguish them from solutions, solids, etc.
  • a composition is considered to be a gel if its storage modulus (G') is larger than its modulus (G").
  • a composition is considered to be a gel if there are chemical or physical cross- linked networks in solution, which is distinguished from entangled molecules in viscous solution.
  • Improved “ increased” or“ reduced” : As used herein, these terms, or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable reference agent.
  • an assessed value achieved in a subject or system of interest may be“improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc).
  • comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and/or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and/or prevalence of difference that is required or sufficient to achieve such statistical significance.
  • Intraperitoneal administration and “administered intraperitoneally” as used herein have their art-understood meaning referring to administration of a compound or composition into the peritoneum of a subject.
  • a“moiety” is a defined chemical group or entity with a particular structure and/or or activity, as described herein.
  • oral administration and“administered orally” as used herein have their art- understood meaning referring to administration by mouth of a compound or composition.
  • Parent N-acylethanolamide compound for purposes of the present disclosure, is a compound relative to which the present disclosure provides derivatives (e.g., to provide a compound of described herein).
  • a parent N- acylethanolamide compound has a structure as set forth below:
  • R x is C 1-4 o aliphatic.
  • R x is C 1 -40 aliphatic. In some embodiments, R x is C 1-35 aliphatic. In some embodiments, R x is C 1-30 aliphatic. In some embodiments, R x is C 1-25 aliphatic. In some embodiments, R x is C 1-20 aliphatic. In some embodiments, R x is C 1-5 aliphatic. In some embodiments, R x is C 1-10 aliphatic. In some embodiments, R x is C 1-5 aliphatic. In some embodiments, R x is C 5-30 aliphatic. In some embodiments, R x is C 10-25 aliphatic. In some embodiments, R x is C 10-20 aliphatic.
  • R x is C 5-15 aliphatic. In some embodiments, R x is C 15 _ 25 aliphatic.
  • a parent N-acylethanolamide compound is derived from a fatty acid selected from the group consisting of myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and cerotic acid.
  • a parent N- acylethanolamide compound is selected from the group consisting of N-palmitoylethanolamide, N-oleoylethanolamide, and N-arachidonoylethanolamide. In some embodiments, a parent N- acylethanolamide compound is N-palmitoylethanolamide. In some embodiments, a parent N- acylethanolamide compound is N-oleoylethanolamide. In some embodiments, a parent N- acylethanolamide compound is N-arachidonoylethanolamide.
  • parenteral administration and“administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.
  • a patient refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient displays one or more symptoms of a disorder or condition. In some embodiments, a patient has been diagnosed with one or more disorders or conditions. In some embodiments, the disorder or condition is or includes cancer, or presence of one or more tumors. In some embodiments, the patient is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient is suffering from or susceptible to one or
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • compositions that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • Predetermined By predetermined is meant deliberately selected, for example as opposed to randomly occurring or achieved.
  • Prevent or prevention refers to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • prodrug refers to a compound that is a drug precursor which, following administration, released the drug in vivo via a chemical or physiological process (e.g., a prodrug released the drug upon reaching physiological pH or through enzyme action is converted to the desired drug form).
  • Reference As used herein describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control.
  • subject refers to any organism to which a provided compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants.
  • a subject may be suffering from, and/or susceptible to a disease, disorder, and/or condition.
  • an individual who is “susceptible to” a disease, disorder, and/or condition is one who has a higher risk of developing the disease, disorder, and/or condition than does a member of the general public.
  • an individual who is susceptible to a disease, disorder and/or condition may not have been diagnosed with the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition.
  • an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.
  • Systemic The phrases “systemic administration,” “administered systemically,”
  • peripheral administration and “administered peripherally” as used herein have their art- understood meaning referring to administration of a compound or composition such that it enters the recipient’s system.
  • Tautomeric forms The phrase“tautomeric forms,” as used herein, is used to describe different isomeric forms of organic compounds that are capable of facile interconversion. Tautomers may be characterized by the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In some embodiments, tautomers may result from prototropic tautomerism (i.e ., the relocation of a proton). In some embodiments, tautomers may result from valence tautomerism (i.e., the rapid reorganization of bonding electrons). All such tautomeric forms are intended to be included within the scope of the present disclosure.
  • tautomeric forms of a compound exist in mobile equilibrium with each other, so that attempts to prepare the separate substances results in the formation of a mixture.
  • tautomeric forms of a compound are separable and isolatable compounds.
  • chemical compositions may be provided that are or include pure preparations of a single tautomeric form of a compound.
  • chemical compositions may be provided as mixtures of two or more tautomeric forms of a compound. In certain embodiments, such mixtures contain equal amounts of different tautomeric forms; in certain embodiments, such mixtures contain different amounts of at least two different tautomeric forms of a compound.
  • chemical compositions may contain all tautomeric forms of a compound. In some embodiments of the disclosure, chemical compositions may contain less than all tautomeric forms of a compound. In some embodiments of the disclosure, chemical compositions may contain one or more tautomeric forms of a compound in amounts that vary over time as a result of interconversion. In some embodiments of the disclosure, the tautomerism is keto-enol tautomerism.
  • keto-enol tautomer can be “trapped” (i.e., chemically modified such that it remains in the“enol” form) using any suitable reagent known in the chemical arts in to provide an enol derivative that may subsequently be isolated using one or more suitable techniques known in the art.
  • suitable reagent known in the chemical arts in to provide an enol derivative that may subsequently be isolated using one or more suitable techniques known in the art.
  • the present disclosure encompasses all tautomeric forms of relevant compounds, whether in pure form or in admixture with one another.
  • therapeutic agent refers to an agent that, when administered to a subject, has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect.
  • a therapeutic agent is any substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • therapeutically effective amount means an amount of a substance (e.g a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • Therapeutic regimen refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Unit dose refers to an amount administered as a single dose and/or in a physically discrete unit of a pharmaceutical composition.
  • a unit dose contains a predetermined quantity of an active agent.
  • a unit dose contains an entire single dose of the agent.
  • more than one unit dose is administered to achieve a total single dose.
  • administration of multiple unit doses is required, or expected to be required, in order to achieve an intended effect.
  • a unit dose may be, for example, a volume of liquid (e.g ., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may be present in a formulation that includes any of a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra.
  • acceptable carriers e.g., pharmaceutically acceptable carriers
  • diluents e.g., diluents, stabilizers, buffers, preservatives, etc.
  • a total appropriate daily dosage of a particular therapeutic agent may comprise a portion, or a plurality, of unit doses, and may be decided, for example, by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • the present invention provides derivatives of N-acylethanolamides with desirable pharmacological properties, for example, which may be or include one or more improved properties relative to appropriate N-acylethanolamide reference compounds (e.g., the parent compound of a particular derivative).
  • the present disclosure provides derivatives of parent N-acylethanolamide compounds that are characterized by one or more suboptimal pharmacological properties.
  • provided N-acylethanolamide derivative compounds may be characterized by one or more of the properties of increased oral bioavailability, increased cell permeability, increased water solubility, reduced first-pass effect, increased stability, active transport by intestinal transporters, or avoidance of efflux transporters, when compared to N- acylethanolamide reference compounds (e.g., the parent N-acylethanolamide compound of a particular derivative).
  • provided N-acylethanolamide derivative compounds may be characterized by increased oral bioavailability when compared to N- acylethanolamide reference compounds (e.g., the parent N-acylethanolamide compound of a particular derivative).
  • the present invention provides N-acylethanolamide derivative compounds that are administered orally.
  • the present invention provides N-acylethanolamide derivative compounds that may be administered orally at high dosages.
  • N-acylethanolamide derivative compounds may lead to its ability to function in the treatment of diseases, disorders, or conditions.
  • a compound for use in accordance with the present disclosure is one wherein an N-acylethanolamide is conjugated to a moiety selected from the group consisting of phosphate, butyric acid, glycerol, succinate, caprylic acid, gluconoic acid, eicosapentaeonoic acid, linoleic acid, succinate, and sucrose moieties, and combinations thereof.
  • an N-acylethanolamide is conjugated to one or more such moieties through use of a linker moiety.
  • an N-acylethanolamide is conjugated to two or more such moieties.
  • an N-acylethanolamide is conjugated to one, two, or three such moieties.
  • a provided compound has a chemical structure represented by formula I-a:
  • X 1 is an N-acylethanolamide
  • X 2 is a moiety conjugated to the N-acylethanolamide
  • X 1 is selected from the group consisting of N- palmitoylethanolamide, N-oleoylethanolamide, and N-arachidonoylethanolamide; in some particular embodiments, X 1 is N-palmitoylethanolamide.
  • X 2 comprises a moiety selected from the group consisting of phosphate, butyric acid, glycerol, succinate, caprylic acid, gluconoic acid, eicosapentaeonoic acid, linoleic acid, succinate, and sucrose moieties.
  • a provided compound has a chemical structure represented by formula I:
  • each R 1 , R 2 , or R 3 is independently hydrogen or -T-R 4 , wherein at least one of R 1 , R 2 , or R 3 is -T-R 4 ;
  • R 4 is an optionally substituted group selected from the group consisting of C 1-4 o aliphatic, -C(O)R, and X 1 ;
  • R is selected from the group consisting of hydrogen and optionally substituted C 1- 20 aliphatic;
  • X 1 is as defined above.
  • a provided compound has a chemical structure represented by formula I-b:
  • X 1 is as defined above;
  • X 3 is an optionally substituted group selected from the group consisting of -(CH 2 ) m -
  • n is an integer select from the group consisting of 0-10;
  • X 4 is a saccharide moiety, in some particular embodiments, X 4 is a disaccharide, for example, sucrose.
  • At least one of R 1 , R 2 , or R 3 is -T-R 4. In some embodiments, at least two of R 1 , R 2 , or R 3 is -T-R 4 .
  • one of R 1 , R 2 , or R 3 is -T-R 4. In some embodiments, two of R 1 , R 2 , or R 3 are each independently -T-R 4. In some embodiments, R 1 , R 2 , and R 3 are each independently -T-R 4 .
  • R 1 is hydrogen. In some embodiments, R 1 is -T-R 4 . In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is -T-R 4. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -T-R 4 .
  • R 1 and R 2 are hydrogen, and R 3 is -T-R 4. In some embodiments, R 2 and R 3 are hydrogen, and R 1 is -T-R4. In some embodiments, R 1 and R3 are hydrogen, and R 2 is -T-R 4. In some embodiments, R 1 is hydrogen, and R 2 and R 3 are each independently -T-R 4 . In some embodiments, R 2 is hydrogen, and R 1 and R 3 are each independently -T-R 4 . In some embodiments, R is hydrogen, and R and R are each independently -T-R . In some embodiments, each of R , R , and R are independently -T-R .
  • -T- represents a bivalent moiety.
  • -T- is a bivalent moiety derived from a dicarboxylic acid.
  • -T- is a bivalent moiety derived from an optionally substituted dicarboxylic acid selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, glutaconic acid, traumatic acid, muconic acid, glutinic acid, citraconic acid, mesaconic acid, malic acid, aspartic acid, glutamic acid, tartronic acid, tartaric acid, diaminopimelic acid, saccharic acid, mesoxalic acid, oxaloacetic acid, acetonedicarboxylic acid, arabinaric acid, phthalic acid, isophthalic acid, terephthalic acid, diphenic acid, and 2,6-napthal
  • -T- is a bivalent moiety derived from optionally substituted oxalic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted malonic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted succinic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted glutaric acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted adipic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted pimelic acid.
  • -T- is a bivalent moiety derived from optionally substituted suberic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted azelaic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted sebacic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted maleic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted fumaric acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted glutaconic acid.
  • -T- is a bivalent moiety derived from optionally substituted traumatic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted muconic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted glutinic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted citraconic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted mesaconic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted malic acid.
  • -T- is a bivalent moiety derived from optionally substituted aspartic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted glutamic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted tartronic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted tartaric acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted diaminopimelic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted saccharic acid.
  • -T- is a bivalent moiety derived from optionally substituted mesoxalic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted oxaloacetic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted acetonedicarboxylic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted arabinaric acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted phthalic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted isophthalic acid.
  • -T- is a bivalent moiety derived from optionally substituted terephthalic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted diphenic acid. In some embodiments, -T- is a bivalent moiety derived from optionally substituted 2,6-naphthalenedicarboxylic acid.
  • -T-R 4 is:
  • R 4 is as defined above;
  • Y is a bivalent C 1-20 straight or branched hydrocarbon chain.
  • Y is a bivalent C 1-20 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-15 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-12 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-10 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-8 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-5 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-4 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 1-2 straight or branched hydrocarbon chain.
  • Y is a bivalent C 1-20 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-15 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-12 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-10 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-8 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-6 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-5 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-4 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-3 straight hydrocarbon chain. In some embodiments Y is a bivalent C 1-2 straight hydrocarbon chain.
  • Y is a bivalent Ci hydrocarbon chain. In some embodiments Y is a bivalent C 2 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 3 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 4 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 5 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent C 6 straight or branched hydrocarbon chain. In some embodiments Y is a bivalent Cio straight or branched hydrocarbon chain.
  • Y is propylene. In some embodiments, Y is ethylene. In some embodiments, Y is methylene.
  • At least one of R 1 , R 2 , or R 3 is . In some embodiments, at least two of R 1 , R 2 , or R 3 are each independently
  • R 1 is In some embodi _ments, r R> 2 is In some embodiments, two of R 1 , R 2 , or
  • R 3 are each independently In some embodiments, R 1 , R 2 , and R 3 are each independently
  • R 4 is an optionally substituted group selected from the group consisting of C 1-40 aliphatic, -C(O)R, and Xj. In some embodiments, R 4 is optionally substituted C 1-40 aliphatic. In some embodiments, R 4 is optionally substituted C1-35 aliphatic. In some embodiments, R 4 is optionally substituted C 1-30 aliphatic. In some embodiments, R 4 is optionally substituted C 1-25 aliphatic. In some embodiments, R 4 is optionally substituted C 1-20 aliphatic. In some embodiments, R 4 is optionally substituted C 1-10 aliphatic. In some embodiments, R 4 is optionally substituted C 1-6 aliphatic. In some embodiments, R 4 is optionally substituted -C(O)R. In some embodiments, R 4 is X 1 .
  • X 1 is selected from N-palmitoylethanolamide, N- oleoylethanolamide, or N-arachidonoylethanolamide. In some embodiments, X 1 is N- palmitoylethanolamide. In some embodiments, X 1 is N-oleoylethanolamide. In some embodiments, X 1 is N-arachidonoylethanolamide.
  • R is selected from the group consisting of hydrogen and optionally substituted C 1-20 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1-20 aliphatic. In some embodiments, R is optionally substituted CM O aliphatic. In some embodiments, R is optionally substituted C 1-6 aliphatic. In some embodiments, R is optionally substituted C 1-3 aliphatic.
  • X 3 is an optionally substituted group selected from the group consisting of -(CH 2 ) m -P(O)(0R) 2 , C 1-40 aliphatic, and -T-X 4 . In some embodiments, X 3 is optionally substituted -(CH 2 ) m -P(O)(0R) 2 . In some embodiments, X 3 is optionally substituted C 1 - 4 o aliphatic. In some embodiments, X 3 is optionally substituted C 1-30 aliphatic. In some embodiments, X 3 is optionally substituted C 1-20 aliphatic. In some embodiments, X 3 is optionally substituted C 1-10 aliphatic. In some embodiments, X 3 is optionally substituted C 1-6 aliphatic. In some embodiments, X 3 is an optionally substituted -T-X 4 .
  • m is an integer select from the group consisting of 0-10. In some embodiments, m is an integer select from the group consisting of 0-5. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.
  • X 4 is a saccharide moiety. In some embodiments, X 4 is a disaccharide. In some embodiments, X 4 is sucrose.
  • a compound of formula I does not comprise a stereocenter within the glycerol backbone (e.g., when R and R are the same). In some embodiments, a compound of formula I comprises a stereocenter within the glycerol backbone (e.g., wherein R and R are different). In some embodiments, a compound of formula I is provided and/or utilized as a racemic mixture. In some embodiments, a compound of formula I is provided and/or utilized as a mixture of stereoforms that may or may not be a racemic mixture. In some embodiments, a compound of formula I is provided and/or utilized as a single enantiomer. In some embodiments, the present disclosure provides compounds of formula I' or I":
  • R 1 , R 2 , and R 3 are as defined above.
  • the present disclosure also provides the insight that, in some embodiments, the position of the N-acylethanolamide, e.g., PEA, on the glycerol moiety may have an effect on its pharmacological properties.
  • a glycerol moiety with an N-acylethanolamide moiety conjugated to the 2 position e.g., the position corresponding to *-OR of formulae I, I', or I
  • may exhibit improved pharmacological properties over a glycerol moiety with an N- acylethanolamide moiety conjugated to the 1 or 3 position e.g., the position corresponding to *- OR or *-OR of formulae I, I', or I"
  • the present disclosure proposes that, in some embodiments, the 1 and 3 positions of the glycerol backbone may be more susceptible to cellular lipases than the 2 position.
  • a compound provided herein may isomerize, for example, undergoing positional isomerization.
  • the present disclosure proposes that, in some embodiments, when a glycerol moiety comprises a free alcohol (e.g., a free alcohol at a position corresponding to *-OR or *-OR of formulae I, I', or I"), a moiety conjugated to glycerol (e.g., a moiety comprising an N-acylethanolamide at a position corresponding to *-OR of formulae I, I', or I"), may migrate to a free alcohol (e.g., migrate from a position corresponding to *-OR of formulae I, I', or I" to a position corresponding to *-OR 1 or *-OR 3 of formulae I, I', or I").
  • compounds 1-8 and 1-9 may interconvert among positional isomers.
  • isomerization occurs prior to administration. In some embodiments, isomerization occurs after administration.
  • a glycerol moiety that does not comprise a free alcohol will not isomerize.
  • compound 1-16 does not undergo positional isomerization.
  • the present disclosure provides compounds of formula II:
  • the present disclosure provides compounds of formula III:
  • the present disclosure provides compounds of formulae III' or
  • the present disclosure provides compounds of formula IV :
  • R 4a and R 4b are independently hydrogen, -
  • each R’ is independently selected from the group consisting of hydrogen and an optionally substituted C 1-20 aliphatic;
  • each Y is independently as defined above and described herein.
  • the present disclosure provides compounds of formulae IV or
  • R 4a and R 4b are as defined above and herein.
  • the present disclosure provides compounds of formula V:
  • R 4a and R 4c are independently hydrogen, -C(O)R', or -C(O)-Y-C(O)OR';
  • each R’ is independently selected from the group consisting of hydrogen and an optionally substituted C 1-20 aliphatic;
  • each Y is independently as defined above and described herein.
  • the present disclosure provides compounds of formulae V or V":
  • R 4a and R 4c are as defined above and herein.
  • R 4a is hydrogen. In some embodiments, R 4a is -C(O)R’. In some embodiments, R 4a is -C(O)-Y-C(O)OR'. In some embodiments, R 4b is hydrogen. In some embodiments, R 4b is -C(O)R’. In some embodiments, R 4b is -C(O)-Y-C(O)OR'. In some embodiments, R 4c is hydrogen. In some embodiments, R 4c is -C(O)R’. In some embodiments, R 4C is -C(O)-Y-C(O)OR'.
  • R’ is hydrogen. In some embodiments, R’ is optionally substituted Ci -2o aliphatic. In some embodiments, R’ is selected from the group consisting of:
  • R’ is selected from the group consisting of:
  • R’ is In some embodiments, R’ is
  • R 4a is -C(O)R ⁇ In some embodiments, R 4a is -C(O)R’, wherein R’ is optionally substituted C 1-20 aliphatic. In some embodiments, R 4a is selected from the group consisting of:
  • R 4a is selected from the group consisting of:
  • R 4a is In some embodiments, R 4a is
  • R 4a is In some embodiments.
  • R 4a is -C(O)-Y-C(O)OR". In some embodiments, R 4a is -C(O)-Y- C(O)OR", wherein R’ is optionally substituted C 1-20 aliphatic.
  • R 4a is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of hydrogen,
  • R 4a is -C(O)-Y-C(O)OR', wherein R’ is hydrogen. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-15 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-12 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-10 straight or branched hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-8 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent Ci straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-4 straight or branched hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight or branched hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-12 straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-10 straight hydrocarbon chain.
  • R 4a is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-8 straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent Ci straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-4 straight hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-3 straight hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent Ci hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 2 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 3 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 4 straight or branched hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C5 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 6 straight or branched hydrocarbon chain. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is a bivalent C10 straight or branched hydrocarbon chain.
  • R 4a is -C(O)-Y-C(O)OR', wherein, Y is propylene. In some embodiments, R 4a is -C(O)-Y-C(O)OR', wherein Y is ethylene. In some embodiments, R 4a is - C(O)-Y-C(O)OR', wherein Y is methylene.
  • R 4b is -C(O)R’. In some embodiments, R 4b is -C(O)R’, wherein R’ is optionally substituted C 1-20 aliphatic. In some embodiments, R 4b is selected from the group consisting of:
  • R 4b is selected from the group consisting of:
  • R 4b is In some embodiments, R 4b is In some
  • R 4b is In some embodiments.
  • R 4b is -C(O)-Y-C(O)OR'. In some embodiments, R 4b is -C(O)-Y- C(O)OR', wherein R’ is optionally substituted C 1-20 aliphatic.
  • R 4b is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of hydrogen,
  • R 4b is -C(O)-Y-C(O)OR', wherein R’ is hydrogen. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-15 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-12 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent CH O straight or branched hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 8 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 5 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C M straight or branched hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 3 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight or branched hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 15 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-12 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-10 straight hydrocarbon chain.
  • R 4b is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-8 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 5 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-4 straight hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 3 straight hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent Ci hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 2 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C3 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 4 straight or branched hydrocarbon chain.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C5 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 6 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein Y is a bivalent C10 straight or branched hydrocarbon chain. In some embodiments, R 4b is -C(O)-Y-C(O)OR', wherein, Y is propylene.
  • R 4b is -C(O)-Y-C(O)OR', wherein Y is ethylene. In some embodiments, R 4b is - C(O)-Y-C(O)OR', wherein Y is methylene.
  • R 4c is -C(O)R’. In some embodiments, R 4c is -C(O)R’, wherein R’ is optionally substituted C 1-20 aliphatic. In some embodiments, R 4c is selected from the group consisting of:
  • R 4c is selected from the group consisting of:
  • R is In some embodiments, R is In some embodiments, R is In some embodiments,
  • R 4c is -C(O)-Y-C(O)OR'. In some embodiments, R 4c is -C(O)-Y- C(O)OR', wherein R’ is optionally substituted C 1-20 aliphatic.
  • R 4c is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of hydrogen,
  • R’ is hydrogen.
  • R 4c is -C(O)-Y-C(O)OR', wherein R’ is selected from the group consisting of
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-15 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-12 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-10 straight or branched hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-8 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- 5 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-4 straight or branched hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-3 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight or branched hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-20 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1- is straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-12 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent CH O straight hydrocarbon chain.
  • R 4c is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 1-8 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-6 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-5 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)O-R', wherein Y is a bivalent C 1-4 straight hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-3 straight hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 1-2 straight hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent Ci hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 2 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 3 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y- C(O)OR', wherein Y is a bivalent C 4 straight or branched hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C5 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 6 straight or branched hydrocarbon chain. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is a bivalent C 10 straight or branched hydrocarbon chain.
  • R 4c is -C(O)-Y-C(O)OR', wherein, Y is propylene. In some embodiments, R 4c is -C(O)-Y-C(O)OR', wherein Y is ethylene. In some embodiments, R 4c is - C(O)-Y-C(O)OR', wherein Y is methylene.
  • each of R 4a , R 4b , and R 4c is hydrogen. In some embodiments, each of R 4a , R 4b , and R 4c is independently selected from the group consisting of:
  • each of R 4a , R 4b , and R 4c is independently selected from the group consisting of:
  • each of R 4a , R 4b , and R 4c is independently selected from the group consisting of:
  • R 4a and R 4b or R 4a and R 4c are the same. In some embodiments,
  • R 4a and R 4b are the same. In some embodiments, R 4a and R 4b are In some embodiments, O
  • R 4a and R 4b are In some embodiments, R 4a and R 4b are
  • R 4a and R 4b are In some embodiments and R 4b are In some
  • R 4a and R 4b are identical to embodiments.
  • R 4a and R 4b are identical to R 4a and R 4b.
  • R 4a and R 4c are the same. In some embodiments. R 4a and R 4c are h
  • R 4a and R 4c are In some embodiments, R 4a and R 4c are In some embodiments, R 4a and R 4c are
  • R 4C are In some embodiments
  • R 4a and R 4c are identical
  • the present disclosure provides N-acylethanolamide derivatives selected from those in Table 1.
  • the present disclosure provides compounds selected from those in Table l-a.
  • one or more hydrogen atoms are replaced with a deuterium atom(s).
  • one or more of R 1 , R 2 , or R 3 is or contains deuterium.
  • the compound CV- 10029 having the following structure:
  • CV- 10029 was made and analyzed.
  • the batch of CV- 10029 was determined to have a purity of 98.4% by LC-MS and 100% by HPLC.
  • FIG. 1 is a graph of results of NMR analysis of CV- 10029.
  • FIG. 2 is a graph of results of LC-MS analysis of CV-10029.
  • FIG. 3 is a graph of results of ESI-LC-MS analysis of CV- 10029. The compound was found to have an observed peak of 488.8 Da, in agreement with the predicted molecular weight of 489 Da.
  • FIG. 4 is a graph of results of HPLC analysis of CV- 10029.
  • the compound CV- 10042 having the following structure:
  • the batch of CV- 10042 was determined to have a purity of 100% by HPLC.
  • FIG. 5 is a graph of results of NMR analysis of CV- 10042.
  • FIG. 6 is a graph of results of LC-MS analysis of CV-10042.
  • FIG. 7 is a graph of results of ESI-LC-MS analysis of CV- 10042. The compound was found to have an observed peak of 244.8 Da, in agreement with the predicted molecular weight of 245 Da.
  • FIG. 8 is a graph of results of HPLC analysis of CV- 10042.
  • the compound CV- 10043 having the following structure:
  • the batch of CV- 10043 was determined to have a purity of 100% by HPLC.
  • FIG. 9 is a graph of results of NMR analysis of CV-10043.
  • FIG. 10 is a graph of results of LC-MS analysis of CV-10043.
  • FIG. 11 is a graph of results of ESI-LC-MS analysis of CV-10043. The compound was found to have an observed peak of 272.8 Da, in agreement with the predicted molecular weight of 273 Da.
  • FIG. 12 is a graph of results of HPLC analysis of CV-10043.
  • the compound CV- 10044 having the following structure:
  • the batch of CV- 10044 was determined to have a purity of 99.66% by HPLC.
  • FIG. 13 is a graph of results of NMR analysis of CV- 10044.
  • FIG. 14 is a graph of results of LC-MS analysis of CV- 10044.
  • FIG. 15 is a graph of results of ESI-LC-MS analysis of CV-10044. The compound was found to have an observed peak of 300.8 Da, in agreement with the predicted molecular weight of 301 Da.
  • FIG. 16 is a graph of results of HPLC analysis of CV-10044.
  • the compound CV- 10045 having the following structure:
  • the batch of CV- 10045 was determined to have a purity of 100% by HPLC.
  • FIG. 17 is a graph of results of NMR analysis of CV-10045.
  • FIG. 18 is a graph of results of LC-MS analysis of CV-10045.
  • FIG. 19 is a graph of results of ESI-LC-MS analysis of CV- 10045. The compound was found to have an observed peak of 600.8 Da, in agreement with the predicted molecular weight of 601 Da.
  • FIG. 20 is a graph of results of HPLC analysis of CV-10045. Example 8
  • Test groups are indicated in Table 2.
  • D PO Pharmacokinetic blood samples (0.2 mL/sample; K 2 EDTA) were collected at .0083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de manière générale des promédicaments à biodisponibilité orale d'edaravone (comprenant des analogues, des dérivés et des sels de ceux-ci) ayant des propriétés pharmacocinétiques modifiées et des procédés d'utilisation de ceux-ci.
PCT/US2019/030300 2018-05-04 2019-05-02 Promédicaments à biodisponibilité orale d'edaravone présentant des propriétés pharmacocinétiques modifiées et leurs procédés d'utilisation WO2019213335A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862667045P 2018-05-04 2018-05-04
US62/667,045 2018-05-04
US201862711482P 2018-07-28 2018-07-28
US62/711,482 2018-07-28

Publications (1)

Publication Number Publication Date
WO2019213335A1 true WO2019213335A1 (fr) 2019-11-07

Family

ID=68386786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/030300 WO2019213335A1 (fr) 2018-05-04 2019-05-02 Promédicaments à biodisponibilité orale d'edaravone présentant des propriétés pharmacocinétiques modifiées et leurs procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2019213335A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021229466A1 (fr) * 2020-05-12 2021-11-18 Tov «Medychnyi Tsentr «M.T.K.» Composition pharmaceutique contenant de l'édaravone comme principe actif
WO2022195288A1 (fr) * 2021-03-19 2022-09-22 Eliem Therapeutics (Uk) Limited Procédé de préparation d'un dérivé de n-acyléthanolamide
CN115607545A (zh) * 2021-10-22 2023-01-17 苏州澳宗生物科技有限公司 依达拉奉在自闭症谱系障碍治疗中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7090903B2 (en) * 2002-10-07 2006-08-15 Konica Corporation Ink-jet recording sheet
US8349901B2 (en) * 2004-08-26 2013-01-08 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US20170312253A1 (en) * 2014-11-05 2017-11-02 The Third Affiliated Hospital, Third Military Medical University, Pla Methods of preventing and treating cerebral amyloid angiopathy (caa) with an edaravone medicament
WO2018071679A1 (fr) * 2016-10-13 2018-04-19 Carnot, Llc Dérivés de n-acyléthanolamide et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7090903B2 (en) * 2002-10-07 2006-08-15 Konica Corporation Ink-jet recording sheet
US8349901B2 (en) * 2004-08-26 2013-01-08 Piramal Enterprises Limited and Apparao Satyam Prodrugs containing novel bio-cleavable linkers
US20170312253A1 (en) * 2014-11-05 2017-11-02 The Third Affiliated Hospital, Third Military Medical University, Pla Methods of preventing and treating cerebral amyloid angiopathy (caa) with an edaravone medicament
WO2018071679A1 (fr) * 2016-10-13 2018-04-19 Carnot, Llc Dérivés de n-acyléthanolamide et leurs utilisations

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021229466A1 (fr) * 2020-05-12 2021-11-18 Tov «Medychnyi Tsentr «M.T.K.» Composition pharmaceutique contenant de l'édaravone comme principe actif
WO2022195288A1 (fr) * 2021-03-19 2022-09-22 Eliem Therapeutics (Uk) Limited Procédé de préparation d'un dérivé de n-acyléthanolamide
CN115607545A (zh) * 2021-10-22 2023-01-17 苏州澳宗生物科技有限公司 依达拉奉在自闭症谱系障碍治疗中的应用
WO2023066330A1 (fr) * 2021-10-22 2023-04-27 苏州澳宗生物科技有限公司 Utilisation d'édaravone dans le traitement d'un trouble du spectre de l'autisme
CN115607545B (zh) * 2021-10-22 2023-11-10 苏州澳宗生物科技有限公司 依达拉奉在自闭症谱系障碍治疗中的应用

Similar Documents

Publication Publication Date Title
JP5022911B2 (ja) ゲムシタビンのアミドプロドラック、組成物、及びそれらの使用
AU2017341769B2 (en) N-Acylethanolamide derivatives and uses thereof
AU2018281327A1 (en) Multibiotic agents and methods of using the same
EP3458454B1 (fr) Dérivés de 2-hydroxy-n-(benzo[d]thiazol-2-yl)benzamide en tant que découplants mitochondriaux pour le traitement de maladies métaboliques et du cancer
US20200352894A1 (en) Combination therapy
WO2019213335A1 (fr) Promédicaments à biodisponibilité orale d'edaravone présentant des propriétés pharmacocinétiques modifiées et leurs procédés d'utilisation
WO2019213333A1 (fr) Polythérapies avec édaravone et promédicaments d'édaravone qui sont biodisponibles par voie orale et ont des propriétés pharmacocinétiques modifiées
FR2665701A1 (fr) Agents de blocage neuromusculaire.
EP0223674A1 (fr) Acyl-7 benzoxazinones et leurs dérivés, procédé pour les obtenir et compositions pharmaceutiques les contenant
EP2917204B1 (fr) Derives de 1h-indole-3-carboxamide et leurs utilisation comme antagonistes du p2y12
Morana et al. Synthesis and characterisation of a new class of stable S-adenosyl-l-methionine salts
FR2801055A1 (fr) Derives de beta-d-5-thioxylose, procede de preparation et utilisation en therapeutique
JP2020083811A (ja) １，５−アンヒドロフルクトース誘導体を含むａｍｐｋ活性化剤
EP0347305B1 (fr) [(Aryl-4-pipérazinyl-1)-2 éthoxy]-3 p-cymène, les dérivés ortho, méta, para monosubstitués ou disubstitués sur le noyau phényle dudit produit, le procédé de préparation desdits dérivés, et les médicaments contenant lesdits composés comme principe actif
WO2023011599A1 (fr) Promédicament de persulfure d'hydrogène et son utilisation pharmaceutique
CH641775A5 (fr) N-(1-methyl 2-pyrrolidinyl methyl) 2,3-dimethoxy 5-methylsulfamoyl benzamide et ses derives, son procede de preparation et composition le renferment.
FR2860234A1 (fr) Nouveaux derives 666 du thioxylose
KR101881115B1 (ko) 신규 2-치환된 테트라하이드로피란 또는 2-치환된 테트라하이드로퓨란 유도체 화합물, 이의 제조방법 및 이의 용도
FR3124946A1 (fr) Nouveaux composés dérivés des schweinfurthines G, E, F
TW202130619A (zh) 硝羥喹啉前藥及其用途
US7763650B2 (en) Pharmaceutical compound and method
EP0365416A1 (fr) Nouveaux dérivés de l'amino chromanol, leur procédé de préparation et les compositions pharmaceutiques les renfermant
FR2467847A1 (fr) Nouveaux derives de l'(hydroxybenzyl)-2 benzimidazole et les compositions pharmaceutiques en contenant
WO2004043983A1 (fr) Derive du 4-methyl-2-oxo-2h-1-benzopyran-7yl 5-thio-beta-d-xylopyranoside, son procede de preparation et composition pharmaceutique le contenant
EP2891655A1 (fr) Anilides-alkylthioéthers comme inhibiteurs de l'ACAT pour le traitement de maladies dermatologiques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19796495

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 03.03.2021)

122 Ep: pct application non-entry in european phase

Ref document number: 19796495

Country of ref document: EP

Kind code of ref document: A1