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WO2018025259A1 - Inhibiteurs d'enzymes - Google Patents

Inhibiteurs d'enzymes Download PDF

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Publication number
WO2018025259A1
WO2018025259A1 PCT/IL2017/050839 IL2017050839W WO2018025259A1 WO 2018025259 A1 WO2018025259 A1 WO 2018025259A1 IL 2017050839 W IL2017050839 W IL 2017050839W WO 2018025259 A1 WO2018025259 A1 WO 2018025259A1
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Prior art keywords
compound
alkoxy
cancer
group
formula
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PCT/IL2017/050839
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English (en)
Inventor
Ashraf Brik
Shimrit OHAYON
Pushparathinam GOPINATH
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Technion Research and Development Foundation Ltd
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Technion Research and Development Foundation Ltd
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Publication of WO2018025259A1 publication Critical patent/WO2018025259A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/02—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of hydrogen atoms by amino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
    • C07C46/04—Preparation of quinones by oxidation giving rise to quinoid structures of unsubstituted ring carbon atoms in six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention in some embodiments thereof, relates to small molecules (e.g., naphthoquinone derivatives) and using same for e.g., selective targeting of proteins that are overexpressed in cells (e.g., cancer cells).
  • small molecules e.g., naphthoquinone derivatives
  • cells e.g., cancer cells
  • ROS homeostasis is important for the survival and progression of both normal and cancerous cells. Certain amounts of ROS are required for proper functioning, including normal metabolism and signaling, but excessive amounts lead to oxidative stress—the imbalance between the production of ROS and the elimination thereof by molecules or enzymes with antioxidant activity. Extreme oxidative stress will lead to complete cell death, as in the case of treatment of tumors by photodynamic therapy (PDT), but the effect of mild conditions is much less predictable. The outcome depends very much on the primary target that will be modified by reacting with the ROS including lipids, DNA, proteins, particular enzymes, and more.
  • DLBs ubiquitination-counteracting deubiquitinases
  • the present invention in some embodiments thereof, relates to compounds comprising naphthoquinone derivatives and uses thereof for selective targeting of proteins that are overexpressed in cells (e.g., cancer cells).
  • the disclosed compounds may induce the formation of reactive oxygen species (ROS), thereby assisting the therapeutic activity.
  • ROS reactive oxygen species
  • R 1 is C1-C4 alkyl
  • substituents R 2 to R 6 in each instance, comprise or are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, hydroxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, amino, nitro, halo, trihalomethyl, cyano, amide, carboxy, sulfonyl, sulfoxy, sulfinyl, sulfonamide, and (c) wherein at least one substituent selected from R 3 to R 6 is alkoxy.
  • R 2 is hydrogen.
  • R 1 is methyl.
  • one or more substituents are selected from R 4 to R 5 is alkoxy.
  • each R 3 and R 6 is hydrogen.
  • either R 4 or R 5 is alkoxy. In some embodiments, the alkoxy is methoxy.
  • the compound is in the form of Formula IA:
  • the compound is in the form of Formula IB
  • the cancer is selected from the group consisting of: carcinoma, lymphoma, glioblastoma, and leukemia.
  • the carcinoma is selected from the group consisting of: breast cancer, and prostate cancer.
  • a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable agent selected from one or more of a stabilizer, a preservative, a chelating agent, a viscosity modifying agent, a buffering agent, and pH adjusting agent.
  • the pharmaceutical composition is formulated for parenteral, mucosal, nasal or oral administration.
  • the disease or disorder is associated with overexpression of cysteine protease.
  • the cysteine protease is selected from ubiquitination- counteracting deubiquitinases (DUBs).
  • DRBs ubiquitination- counteracting deubiquitinases
  • a method comprising: identifying a subject having overexpression of cysteine protease- associated disease and administering to the subject an effective amount of the disclosed compound in any embodiment thereof.
  • the process comprises
  • R 1 is C1-C4 alkyl
  • substituents from R 3 to R 6 in each instance, comprise or are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, hydroxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, amino, nitro, halo, trihalomethyl, cyano, amide, carboxy, sulfonyl, sulfoxy, sulfinyl, or sulfonamide, and (iii) wherein at least one substituent selected from R 3 to R 6 is alkoxy.
  • R 1 is methyl
  • R 6 is hydrogen
  • R 3 is hydrogen
  • either R 4 or R 5 is alkoxy. In some embodiments, the alkoxy is methoxy.
  • the organic solvent is Dimethyl sulfoxide (DMSO).
  • the hyper-valent iodine reagent is selected from phenyliodine diacetate (PIDA), [bis(trifluoroacetoxy)iodo]benzene (PIFA), Dess-Martin periodinane (DMP), and 2-iodoxybenzoic acid (IBX).
  • the hyper-valent iodine reagent and the compound of the Formula III are in molar ratio of from 3.5 to 4.5, respectively.
  • step (b) further comprises the presence of an oxidizing agent.
  • the oxidizing agent is sodium iodate.
  • step (b) further comprises presence of metal chloride.
  • step (a) the reaction of step (a) is conducted at a temperature range of about 10°C to about 50°C.
  • steps (a) and (b) are conducted in one pot.
  • Figure 1 presents the disclosed compound, referred to as: compounds 1-24 hereinthroughout .
  • Figures 2A-B present a scheme showing the synthesis of 1,2-naphthoquinones with different substituents on C4 (compound 1 to 7; Figure 2A), and the ⁇ NMR and 13 C-NMR spectra of compounds 1-3, and 5-7 ( Figure 2B) (NMR: nuclear magnetic resonance).
  • Figures 3A-B present synthesis scheme of naphthoquinone derivatives (compounds 8- 14) starting from tetralone derivatives ( Figure 3A) and the ⁇ -NMR and 13 C-NMR spectra of compounds 8-13 ( Figure 3B).
  • Figure 4 presents comparison of USP2 inhibition capability by compounds with either ortho- or /?ara-quinone moieties, at either 1 or 5 ⁇ concentrations.
  • Figure 5A-B present a graph showing a plot of the inactivation rate constants (£ 0 bs) vs. the concentration of compound 12 (nM), for obtaining the maximal rate of enzyme inactivation (kinact) (Figure 5A; each value represents the mean +SE of two independent experiments); and Mass spectrometry spectra of USP2 treated with A) upper panel: DMSO and B) lower panel: compound 12 for 15 min ( Figure 5B).
  • DMSO dimethyl sulfoxide.
  • Figure 6 presents schematic representation of redox cycling by o/ /zo-quinones and their mode of inhibition of DUBs via oxidation of the catalytic cys mainly to sulfinic acid.
  • Figure 7 presents bar graphs demonstrating apoptosis level in DU145 cells treated by compounds 7, 9, 12 and 18 for 2 hours using annexin V-FITC apoptosis detection kit (BD Biosciences) according to the manufacturer's protocol and monitored via flow-cytometry.
  • FITC fluorescein isothiocyanate.
  • Figure 8 presents a scheme showing a possible mechanism of hydrogen peroxide generation.
  • the present invention in some embodiments thereof, relates to small molecules capable of selectively targeting of proteins that are overexpressed in cells (e.g., cancer cells).
  • the disclosed small molecules induce the formation of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • the disclosed molecules are for use for treating a disease or disorder as described herein.
  • each of R ⁇ -R 6 represents a substituent as described below in some embodiments.
  • OR 1 is an electron-withdrawing group.
  • Non-limiting exemplary electron- withdrawing groups are selected from: carboxy, acyl halide, amide, sulfonate, and nitro.
  • R 1 is alkyl. In some embodiments, R 1 is C1-C4 alkyl.
  • substituents R 2 to R 6 in each instance, is hydrogen. In some embodiments, substituents R 2 to R 6 , in each instance is alkyl. In some embodiments, substituents R 2 to R 6 , in each instance, is cycloalkyl. In some embodiments, substituents R 2 to R 6 , in each instance is aryl. In some embodiments, substituents R 2 to R 6 , in each instance, is heteroalicyclic. In some embodiments, substituents R 2 to R 6 , in each instance, is heteroaryl. In some embodiments, substituents R 2 to R 6 , in each instance, is alkoxy.
  • substituents R 2 to R 6 in each instance, comprise hydroxyl. In some embodiments, substituents R 2 to R 6 , in each instance, comprise thiohydroxy. In some embodiments, substituents R 2 to R 6 , in each instance, comprise thioalkoxy. In some embodiments, substituents R 2 to R 6 , in each instance comprise aryloxy. In some embodiments, substituents R 2 to R 6 , in each instance comprise thioaryloxy. In some embodiments, substituents R 2 to R 6 , in each instance, comprise an amino group. In some embodiments, substituents R 2 to R 6 , in each instance, is nitro.
  • substituents R 2 to R 6 in each instance, comprise halo. In some embodiments, substituents R 2 to R 6 , in each instance, comprise trihalomethyl. In some embodiments, substituents R 2 to R 6 , in each instance, comprise cyano. In some embodiments, substituents R 2 to R 6 , in each instance, comprise amide. In some embodiments, substituents R 2 to R 6 , in each instance, comprise carboxy. In some embodiments, substituents R 2 to R 6 , in each instance, comprise sulfonyl. In some embodiments, substituents R 2 to R 6 , in each instance, comprise sulfoxy.
  • substituents R 2 to R 6 in each instance, comprise sulfinyl. In some embodiments, substituents R 2 to R 6 , in each instance, comprise sulfonamide. In some embodiments, substituents R 2 to R 6 , in each instance, comprise or is a fused ring.
  • substituted R 2 to R 6 in each instance it may refer to one substituent from R 2 to R 6 , two substituents from R 2 to R 6 , three substituents from R 2 to
  • R 6 four substituents from R 2 to R 6 , or five substituents from R 2 to R 6 .
  • R 2 is hydrogen
  • R 1 is methyl
  • R 2 is hydrogen
  • At least one substituent selected from R 4 to R 5 is alkoxy. In some embodiments, both R 4 to R 5 are alkoxy. In some embodiments, either R 4 or R 5 is alkoxy. In some embodiments, the alkoxy is methoxy.
  • the disclosed compound is in the form of Formula IA (also referred to as: "compound 13”):
  • the disclosed compound is in the form of Formula IB (also referred to as "compound 12"):
  • the disclosed compound is in the form of Formula IC:
  • alkyl describes an aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 21 to 100 carbon atoms, and more preferably 21-50 carbon atoms.
  • a numerical range; e.g., "21-100" is stated herein, it implies that the group, in this case the alkyl group, may contain 21 carbon atom, 22 carbon atoms, 23 carbon atoms, etc., up to and including 100 carbon atoms.
  • a "long alkyl” is an alkyl having at least 20 carbon atoms in its main chain (the longest path of continuous covalently attached atoms). A short alkyl therefore has 20 or less main-chain carbons.
  • the alkyl can be substituted or unsubstituted, as defined herein.
  • alkyl also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.
  • alkenyl describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond.
  • the alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.
  • alkynyl is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.
  • cycloalkyl describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system.
  • the cycloalkyl group may be substituted or unsubstituted, as indicated herein.
  • aryl describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi- electron system.
  • the aryl group may be substituted or unsubstituted, as indicated herein.
  • alkoxy describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
  • aryloxy describes an -O-aryl, as defined herein.
  • Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, alkoxy, nitro, amine, hydroxyl, thiol, thioalkoxy, thiohydroxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.
  • halide describes fluorine, chlorine, bromine or iodine.
  • haloalkyl describes an alkyl group as defined herein, further substituted by one or more halide(s).
  • haloalkoxy describes an alkoxy group as defined herein, further substituted by one or more halide(s).
  • hydroxyl or "hydroxy” describes a -OH group.
  • thiohydroxy or "thiol” describes a -SH group.
  • thioalkoxy describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein.
  • thioaryloxy describes both an -S-aryl and a -S-heteroaryl group, as defined herein.
  • amine describes a - R'R" group, with R' and R" as described herein.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • heteroalicyclic or “heterocyclyl” describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • Representative examples are piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.
  • a "nitro” group refers to a -NO2 group.
  • a "cyano" or "nitrile” group refers to a -C ⁇ N group.
  • azide refers to a -N3 group.
  • phosphinyl describes a -PR'R" group, with R' and R" as defined hereinabove.
  • alkaryl describes an alkyl, as defined herein, which substituted by an aryl, as described herein.
  • An exemplary alkaryl is benzyl.
  • heteroaryl describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • the heteroaryl group may be substituted or unsubstituted by one or more substituents, as described hereinabove. Representative examples are thiadiazole, pyridine, pyrrole, oxazole, indole, purine and the like.
  • haloalkyl describes an alkyl group as defined above, further substituted by one or more halide(s).
  • composition comprising one or more compounds described herein and a pharmaceutically acceptable carrier.
  • the composition is being packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment of a medical condition associated with any disease, medical condition, or disorder as described hereinthroughout.
  • a method of treating a medical condition associated with a disease, medical condition, or disorder as described hereinthroughout in a subject in need thereof comprising administering to the subject a therapeutically effective amount of one or more compounds as described herein.
  • subject (which is to be read to include “individual”, “animal”, “patient” or “mammal” where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated.
  • Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on.
  • the subject is a human.
  • phrases "pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • pharmaceutically acceptable salts is further meant to encompass salts of the active compounds (e.g., compounds as described herein) which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et ah, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compound as described herein to be converted into either base or acid addition salts.
  • the neutral forms of the compounds as described herein may be regenerated by contacting the salt with a base or acid and isolating the parent compounds in a conventional manner.
  • the parent form of the compounds may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the disclosed compound(s) for the purposes of the present invention.
  • prodrug refers to an agent, which is converted into the active compound (the active parent drug) in vivo.
  • Prodrugs are typically useful for facilitating the administration of the parent drug.
  • the prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions.
  • Prodrugs are also often used to achieve a sustained release of the active compound in vivo.
  • the compounds described herein may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention.
  • enantiomer describes a stereoisomer of a compound that is superposable with respect to its counterpart only by a complete inversion/reflection (mirror image) of each other.
  • Enantiomers have "handedness” since they refer to each other like the right and left hand.
  • Enantiomers have identical chemical and physical properties except when present in an environment which by itself has handedness, such as all living systems.
  • the compounds described herein may exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • solvate refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by a solute (the conjugate described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute.
  • Suitable solvents include, for example, ethanol, acetic acid and the like.
  • hydrate refers to a solvate, as defined hereinabove, where the solvent is water.
  • a "pharmaceutical composition” refers to a preparation of one or more of the compounds described herein (as active ingredient), or physiologically acceptable salts or prodrugs thereof, with other chemical components including, but not limited to, physiologically suitable carriers, stabilizers, preservatives, chelating agents, viscosity modifying agents, excipients, lubricants, buffering agents, antibacterial agents, bulking agents (e.g., mannitol), antioxidants (e.g. , ascorbic acid or sodium bisulfite), anti-inflammatory agents, anti-viral agents, chemotherapeutic agents, anti-histamines and the like.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.
  • active ingredient refers to a compound e.g., a compound disclosed herein, which is accountable for a biological effect.
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a drug.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the dosage, as described and specified herein, may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. l).
  • the pharmaceutical composition may be formulated for administration in either one or more of routes depending on whether local or systemic treatment or administration is of choice, and on the area to be treated. As further described hereinthroughout, administration may be done orally, by inhalation, or parenterally, for example by intravenous drip or intraperitoneal, subcutaneous, intramuscular or intravenous injection, or topically (including ophtalmically, vaginally, rectally, intranasally).
  • Formulations for topical administration may include but are not limited to lotions, ointments, gels, creams, suppositories, drops, liquids, sprays and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, sachets, pills, caplets, capsules or tablets. Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.
  • Formulations for parenteral administration may include, but are not limited to, sterile solutions which may also contain buffers, diluents and other suitable additives. Slow release compositions are envisaged for treatment.
  • compositions or a compound to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • the pharmaceutical composition may further comprise additional pharmaceutically active or inactive agents such as, but not limited to, an antibacterial agent, an antioxidant, a buffering agent, a bulking agent, a surfactant, an anti-inflammatory agent, an anti- viral agent, a chemotherapeutic agent and an anti-histamine.
  • additional pharmaceutically active or inactive agents such as, but not limited to, an antibacterial agent, an antioxidant, a buffering agent, a bulking agent, a surfactant, an anti-inflammatory agent, an anti- viral agent, a chemotherapeutic agent and an anti-histamine.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
  • Such notice for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • the present invention provides a method comprising: identifying a subject having overexpression of protease (e.g., cysteine protease)-associated disease and administering to the subject an effective amount of a compound represented by the structure of formula I or any embodiment thereof.
  • protease e.g., cysteine protease
  • Cysteine protease or “cysteine peptidase” refers to the family of peptidases which have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a histidine residue. Cysteine proteases may have characteristic molecular topologies, which can be seen not only in their three-dimensional structures, but also in the two-dimensional structures.
  • Cysteine proteases are divided into clans (proteins which are evolutionary related), and further sub-divided into families, on the basis of the architecture of their catalytic dyad or triad.
  • the cysteine proteases family includes, but not limited to, papain, cathepsins, caspases, legumain, calpains, calpain and adenain.
  • cyste protease refers to deubiquitinating enzymes.
  • Deubiquitinating enzymes also known as “deubiquitinating peptidases”, “deubiquitinating isopeptidases”, “deubiquitinases”, “ubiquitin proteases”, “ubiquitin hydrolases”, “ubiquitin isopeptidases”, are a large group of proteases that cleave ubiquitin from proteins and other molecules.
  • Families of DUBs may be selected from, without being limited thereto, the ubiquitin- specific protease (USP/UBP) superfamily, the ovarian tumor (OTU) superfamily (OTUB 1, OTUB2); the Machado-Josephin domain (MJD) superfamily; and (ATXN3, ATXN3L) the ubiquitin C-terminal hydrolase (UCH) superfamily (e.g., BAP1, UCHL1, UCHL3, UCHL5).
  • USP/UBP ubiquitin-specific protease
  • OTU ovarian tumor
  • MJD Machado-Josephin domain
  • UCH ubiquitin C-terminal hydrolase
  • Non-limiting examples of the ubiquitin-specific protease (USP/UBP) superfamily are USP1, USP2, USP3, USP4, USP5, USP6, USP7, USP8, USP9X, USP9Y, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17, USP17L2, USP17L3, USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP20, USP21, USP22, USP23, USP24, USP25, USP26, USP27X, USP28, USP29, USP30, USP31, USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP40, USP41, USP42, USP43, USP44, USP45, and USP46.
  • the ubiquitin-specific protease is USP2.
  • USP2 is associated with aggressive prostate cancer and triple negative breast cancer. USP2 is further associated with various known substrates in cell and affects the pathways that these substrates are involved in. The best-characterized substrate of USP2 is fatty acid synthase (FAS), responsible for protection of prostate cancer cells from apoptosis.
  • FAS fatty acid synthase
  • Certain embodiments of the present invention provide methods for treating disease or disorder is associated with overexpression of cysteine protease. Certain embodiments of the present invention provide methods for treating disease or disorder is associated with protease.
  • Certain embodiments of the present invention provide methods for the treatment, prevention, or amelioration of diseases, disorders, and conditions associated with overexpression of cysteine protease in an individual in need thereof.
  • the method comprises the step of contacting the cell with a composition comprising one or more compounds disclosed herein.
  • cysteine protease associated diseases, disorders, and conditions may include, without being limited thereto, inflammatory diseases, neurodegenerative diseases, cancer, and viral diseases.
  • the neurodegenerative disease may be ALS or FTD.
  • the neurodegenerative disease may be familial or sporadic.
  • cancer and “tumor” are used interchangeably herein to describe a class of diseases in which a group of cells display uncontrolled growth (division beyond the normal limits).
  • cancer encompasses malignant tumor as well as disease conditions evolving from primary or secondary tumors.
  • malignant tumor describes a tumor which is not self-limited in its growth, is capable of invading into adjacent tissues, and may be capable of spreading to distant tissues (metastasizing).
  • primary tumor describes a tumor that is at the original site where it first arose.
  • secondary tumor describes a tumor that has spread from its original (primary) site of growth to another site, close to or distant from the primary site.
  • the cancer is be selected from: carcinoma, sarcoma, leukemia, lymphoma, and germinoma.
  • Non-limiting examples of cancers which can be treated according to some embodiments of the invention can be solid or non- solid cancer and/or cancer metastasis, including, without being limited thereto, adrenocortical carcinoma, hereditary; bladder cancer; breast cancer; breast cancer, ductal; breast cancer, invasive intraductal; breast cancer, sporadic; breast cancer, susceptibility to; breast cancer, type 4; breast cancer, type 4; breast cancer- 1; breast cancer-3; breast-ovarian cancer; Burkitt's lymphoma; cervical carcinoma; colorectal adenoma; colorectal cancer; colorectal cancer, hereditary nonpolyposis, type 1; colorectal cancer, hereditary nonpolyposis, type 2; colorectal cancer, hereditary nonpolyposis, type 3; colorectal cancer,
  • the cancer is colonorectal cancer.
  • colonal cancer refers to malignant tumors of the epithelium of the colon or rectal, including but not limited to squamous cell (epidermoid) carcinomas, cloacogenic (basaloid transitional cell) tumors, and adenocarcinomas.
  • cancers treatable with the compounds described herein are non-solid cancers e.g., leukemia (e.g., T cell leukemia).
  • cancer metastases or any grammatical derivative thereof, describes cancer cells which have "broken away”, “leaked”, or “spilled” from a primary tumor, entered the lymphatic and/or blood vessels, circulated through the lymphatic system and/or bloodstream, settled down and proliferated within normal tissues elsewhere in the body thereby creating a secondary tumor.
  • the disease is associated with overly active nuclear factor kappa B (NF- ⁇ ). Therefore, in another embodiment, there is provided herein a method of inhibiting a nuclear factor kappa B (NF- ⁇ ) pathway in a cell, comprising the step of contacting the cell with a composition comprising one or more compounds disclosed herein.
  • NF- ⁇ nuclear factor kappa B
  • the synthesis route comprises:
  • R 1 is C1-C4 alkyl.
  • substituents R 3 to R 6 in each instance, comprise or are selected from: hydrogen, alkyl, cycloalkyl, aryl, heteroalicyclic, heteroaryl, alkoxy, hydroxy, thiohydroxy, thioalkoxy, aryloxy, thioaryloxy, amino, nitro, halo, trihalomethyl, cyano, amide, carboxy, sulfonyl, sulfoxy, sulfinyl, or sulfonamide, and wherein at least one substituent selected from R 3 to R 6 is alkoxy.
  • R 1 is methyl
  • R 6 is hydrogen
  • R 3 is hydrogen
  • either R 4 or R 5 is alkoxy. In some embodiments, the alkoxy is methoxy.
  • the reaction of step (a) is conducted at a temperature range of about 10°C to about 90°C. In exemplary embodiments, the reaction is performed at elevated temperature.
  • the reaction of step (a) is conducted for at least 30 min, 1 h , 2 h, 3 h, 4 h , 5 h, 6 h, 7 h , 8 h, 9 h, 10 h , 11 h, 12 h, 13 h , 14 h, or 15 h, including any value and range therebetween.
  • the reaction of step (a) is conducted while stirring.
  • the reaction of step (a) is conducted for 12 h to 14 h.
  • the organic solvent is dimethyl sulfoxide (DMSO).
  • hypo-valent iodine compound refers to three-, five-, seven-, or eight- coordinate iodine compounds.
  • the hyper-valent iodine reagent is selected from, without being limited thereto, phenyliodine diacetate (PIDA), [bis(trifluoroacetoxy)iodo]benzene (PIFA), Dess-Martin periodinane (DMP), and 2-iodoxybenzoic acid (IBX).
  • PIDA phenyliodine diacetate
  • PIFA [bis(trifluoroacetoxy)iodo]benzene
  • DMP Dess-Martin periodinane
  • IBX 2-iodoxybenzoic acid
  • the hyper-valent iodine reagent and the compound of the Formula III are in molar ratio of from 1: 3.5 to 1:4.5, respectively. In some embodiments, the molar ratio is about 1:4.
  • step (b) is performed in the presence of an oxidizing agent.
  • the oxidizing agent is iodate salt.
  • Non-limiting exemplary iodate salt is selected from: calcium iodate, sodium iodate, potassium iodate, magnesium iodate, zinc iodate, cupric iodate, and manganese iodate.
  • the oxidizing agent is sodium iodate.
  • the contacting of step (b) is performed in the presence of metal ion.
  • the metal ion is obtained from metal chloride source.
  • metal ion are cerium (Ce 3+ ), lanthanum (La 3+ ), copper (Cu 2+ ), and nickel (Ni 2+ ).
  • steps (a) and (b) are conducted in one pot. In some embodiments, steps (a) and (b) are conducted simultaneously. In some embodiments, steps (a) and (b) are conducted sequentially.
  • steps (a) and (b) are followed by step (c) of purification of the product, by any method known in the art (e.g., by using a column).
  • FIG. 3A presents a scheme showing non-limiting exemplary synthesis of C5-C7-substituted 1,2-naphthoquinones according to the disclosed synthesis route.
  • Ts may refer to a tosyl group.
  • reaction affords the corresponding 5-, 6- and 7- substituted 1,2 naphthoquinones (compound 8-11, respectively; Figure 3A).
  • reaction of compounds 9-11 with CeCh ⁇ fhO and sodium iodate in MeOH affords obtaining compounds 12-14 ( Figure 3A).
  • the synthesis comprises contacting methyl 3- mercaptopropionate (MMP), 3- mercaptopropionic acid (MPA), or 2-(Boc-amino) ethanethiol with 1,2 naphthoquinone, or a derivative thereof, so as to obtain the corresponding compounds 2-4 as described herein, or a derivative thereof.
  • MMP methyl 3- mercaptopropionate
  • MPA 3- mercaptopropionic acid
  • 2-(Boc-amino) ethanethiol 2-(Boc-amino) ethanethiol
  • methyl 3 -mercaptopropionate (MMP), 3- mercaptopropionic acid (MPA), or 2-(Boc-amino) ethanethiol are reacted with 1,2 naphthoquinone at room temperature (e.g., 15-30 °C), and may be further allowed to stir for e.g., 30 min., 1 h, 2, h or 3h (including any value therebetween) at elevated temperature.
  • “elevated temperature” refers to e.g., 35 °C, 40 °C, 50 °C, 60 °C, 70 °C, or 80°C, including any value therebetween.
  • 4-methoxy 1,2-naphthoquinone (compound 7), or a derivative thereof is obtained by the treatment of 1,2 naphthoquinone, or a derivative thereof, with methanol in the presence of cerium ions (e.g., in a salt CeCb).
  • 4- methoxy 1,2-naphthoquinone (compound 7), or a derivative thereof is obtained by the treatment of 1,2 naphthoquinone with methanol in the presence of cerium ions (e.g., in a salt CeCl 3 ) and further in the presence of sodium iodate.
  • compositions comprising, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.
  • Consisting of means “including and limited to”.
  • Consisting essentially of means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • Compound 25 was prepared according to the literature procedure (J. S. Sun, A. H. Geiser and B. Frydman, Tetrahedron Lett., 1998, 39, 8221-8224).
  • Figure 2B present H-NMR and C-NMR spectra of compounds 1-3, and 5-7.
  • Figure 3B presents HNMR spectra of compounds 8-13.
  • Compounds 2-7 contain different substitution on C4 position of the ortho- naphthoquinone 1: S-alkyl groups in compounds 2-4, amine in compound 5, SO3 " in compound 6, and methoxy in compound 7.
  • Compounds 2-4 did not exhibit measurable activity against USP2 at 1 ⁇ , which might be attributed to oxidation of the sulfide-moiety therein by the ROS.
  • Compound 6 with its electron-withdrawing sulfonyl group did not show any inhibition at 1 ⁇ , while compounds 5 and 7 with their electron-donating groups (-NH 2 and -OCH3, respectively) exhibited substantially increased activity relative to the parent compound 1.
  • Figure 5B presents the mass spectrometry of USP2 treated with DMSO with compound 12 for 15 min.
  • Cell culture In exemplary procedures, DU145 cells were grown in EMEM medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin and 100 mg/ml streptomycin in 37 °C humidified incubator with a 5% C0 2 , 95% air atmosphere.
  • Apoptosis studies Induction of apoptosis in DU-145 cell line by treatment with compounds 7, 9, 12 and 18 were determined after 2 h incubation in a dose dependent manner, using annexin V-FITC apoptosis detection kit (BD Biosciences) according to the manufacturer's protocol and monitored via flow-cytometry (fluorescence-activated cell sorting, FACS). Briefly, 2 x 10 5 cells/well were seeded in 6-well plates and treated with inhibitor for 2 hr in a dose dependent manner. The cells were then harvested and washed with PBS.
  • the cells were re-suspended with 85 ⁇ ⁇ binding buffer and stained with 10 ⁇ ⁇ annexin V-FITC reagent and 5 ⁇ ⁇ propidium iodide (PI) for 15 min in the dark.
  • the increase in fluorescence, which indicates the apoptosis level in the treated cells, were monitored using flow cytometry and compared to untreated cells containing DMSO as a control.
  • the cytotoxicity assay was performed using alamar blue assay.
  • U87 glioblastoma
  • A549 NSCLC
  • MCF-7 breast adenocarcinoma
  • Jurkat acute T cell leukemia
  • ROS generation affects the enzymatic activity of USP2, but in more realistic systems there may be more targets for those ROS and their identity might change as a function of the closeness of the particular ROS -generating molecule (naphthoquinones in the present case) to them.
  • the acidity of this trapped proton should be taken in account when analyzing the reaction with oxygen, by two means: a) it may induce an electron-coupled proton transfer to produce H0 2 ' rather than ionized O2 " ; and b) it may facilitate the subsequent reduction to hydrogen peroxide (Figure 8).

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Abstract

L'invention concerne des composés de naphtoquinone induisant la formation d'espèces réactives de l'oxygène (ROS). L'invention concerne également un procédé de préparation des composés de naphtoquinone. L'invention concerne également des utilisations des composés pour le traitement d'une maladie ou d'un trouble.
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CN113087833A (zh) * 2021-03-31 2021-07-09 湖北大学 一种聚合物负载人工催化三联体的催化剂及其制备方法与应用
CN115403451A (zh) * 2022-09-20 2022-11-29 阜阳欣奕华制药科技有限公司 4-甲氧基-2-萘酚的制备方法及其应用

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JPH09241104A (ja) * 1996-03-07 1997-09-16 Kagome Co Ltd ナフトキノン誘導体を有効成分とする抗菌剤
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113087833A (zh) * 2021-03-31 2021-07-09 湖北大学 一种聚合物负载人工催化三联体的催化剂及其制备方法与应用
CN113087833B (zh) * 2021-03-31 2022-04-01 湖北大学 一种聚合物负载人工催化三联体的催化剂及其制备方法与应用
CN115403451A (zh) * 2022-09-20 2022-11-29 阜阳欣奕华制药科技有限公司 4-甲氧基-2-萘酚的制备方法及其应用
CN115403451B (zh) * 2022-09-20 2024-01-19 阜阳欣奕华制药科技有限公司 4-甲氧基-2-萘酚的制备方法及其应用

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