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WO2018036501A1 - Composés apparentés à l'entacapone pour traiter une lésion - Google Patents

Composés apparentés à l'entacapone pour traiter une lésion Download PDF

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WO2018036501A1
WO2018036501A1 PCT/CN2017/098578 CN2017098578W WO2018036501A1 WO 2018036501 A1 WO2018036501 A1 WO 2018036501A1 CN 2017098578 W CN2017098578 W CN 2017098578W WO 2018036501 A1 WO2018036501 A1 WO 2018036501A1
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Prior art keywords
alkylene
alkyl
entacapone
aryl
independently
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Niu Huang
Shiming PENG
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National Institute of Biological Sciences Beijin
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National Institute of Biological Sciences Beijin
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Priority to CN201780052230.4A priority Critical patent/CN110225751A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • Wound healing is a physiological process by which skin or other body tissue, like blood vessel, repairs itself after trauma. After damage, a series of biochemical events, including tissue growth and vessel remodeling, occurs to repair the damage.
  • the invention relates to interventions to promote this capacity and heal or regenerate injured tissue.
  • Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used for treating Parkinson disease, typically administered in conjunction with dopamine derivatives levodopa (L-DOPA) or carbidopa, see Comtan Full Prescribing Information-Novartis.
  • WO2015095257 discloses treating diabetes or diabetic retinopathy with dopamine, and in embodiments the dopamine is administered in combination with a COMT inhibitor, such as entacapone, tolcapone, or nitecapone.
  • the invention provides entacapone-related compounds, compositions and methods to treat to treat tissue injury, particularly trauma, or to promote wound healing or tissue regeneration.
  • the invention provides a use or method of use of entacapone, an entacapone derivative or a stereoisomer, hydride, or pharmaceutically-acceptable salt thereof, in a person in need thereof, to treat or inhibit macular degeneration or age-related macular degeneration, preferably wherein the person does not have Parkinson’s disease, obesity, diabetes or diabetic retinopathy.
  • the invention may be practiced with a wide variety of entacapone derivatives, and activity is readily confirmed empirically; exemplary suitable derivatives are disclosed in US 5,112,861, WO2007144169, EP1978014A1 and WO/2017/206573. In particular embodiments the derivatives FTO inhibitors.
  • the entacapone derivative comprises a structure of formula I of WO/2017/206573, a stereoisomer thereof, a hydride thereof, or a pharmaceutically-acceptable salt thereof:
  • R1 and R2 are independently H or Me
  • R3 is H, OH or NHR, wherein R is H or an optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;
  • R4 is optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl.
  • the entacapone derivative comprises a structure of formula I of US5112861, a stereoisomer thereof, a hydride thereof, or a pharmaceutically-acceptable salt thereof:
  • R1 and R2 independently represent hydrogen, alkylcarbamoyl of 2 to 5 carbon atoms or alkylcarbonyl of 2 to 5 carbon atoms, X represents nitro or cyano and R3 represents
  • R4 represents cyano or alkylcarbonyl of 2 to 5 carbon atoms and R5represents cyano; alkylcarbonyl of 2 to 5 carbon atoms; or carbamoyl which is unsubstituted or substituted with alkyl of 1 to 8 carbon atoms, or hydroxyalkyl of 1 to 8 carbon atoms.
  • the entacapone derivative comprises a structure of formula I of WO2007144169, a stereoisomer thereof, a hydride thereof, or a pharmaceutically-acceptable salt thereof:
  • Y is sulfur or oxygen
  • R 1 is a group of the following formula II
  • R 1 can be in addition H,
  • R 2 is H or a group of formula II which may be the same as or different from R 1 , each R 3 is independently (Ci-C 20 ) -alkyl, (CR 4 R 5 ) X -R 6 , (C r C 20 ) -alkylene- (Ci-C 20 ) -alkoxy, (C 2 -C 20 ) -alkenyl, (C 2 -C 20 ) -alkynyl, (C 0 -C 20 ) -alkylene- (C 3 -Ci 8 ) -cycloalkyl, (C 0 -C 20 ) -alkylene- (3-l 8-membered) -heterocycloalky 1, (C i -C 2 o) -alkylene- (C 3 -C 18 ) -cycloalkenyl , (Co-C 20 ) -alkylene- (3-18-membered) -heterocycloalkeny
  • R 4 and R 5 of the same group (CR 4 R 5 ) or R 4 and R 5 of different groups (CR 4 R 5 ) may form together a carbocyclic or heterocyclic ring having from 3 to 6 atoms, additionally, one or more non adjacent groups (CR 4 R 5 ) may be replaced by O, CO, OCO, COO, CON (R 19 ) , N (R 20 ) CO, or NR 21 ,
  • R 6 is independently H, (C r C 20 ) -alkyl, (C 2 -C 20 ) -alkenyl, (C 2 -C 20 ) -alkynyl, OH, O- (C r C 8 ) -alkyl, O- (C 0 -C 8 ) -alkylene- (C 6 -Ci 4 ) -aryl, CO-O- (C, -C 8 ) -alkyl, CO-N (R 12 ) (R 13 ) , N (R 14 ) CO- (Ci-C 8 ) -alkyl, N (R 15 XR 16 ) , SO 3 R 18 , (C 0 -C 20 ) -alkylene- (5-18-membered) -heteroaryl, or (C 0 -C 20 ) - alkylene- (C 6 -Ci 8 ) -aryl,
  • R 7 , R 14 , R 17 , R 18 , R 19 , R 20 , R 21 are independently of one another H, or (Ci-C 2 o) -alkyl
  • R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 16 are independently of one another H, or (Ci-C 20 ) -alkyl
  • R 22 and R 23 are independently selected from the group consisting of H and (Cj-Ci 5 ) -alkyl
  • x is 1 to 14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkoxy, aryl, heteroaryl, alkenylene and alkylene groups may be unsubstituted or further substituted.
  • the use further comprises the step of detecting a resultant reduction in injury or promotion of wound healing or tissue regeneration.
  • the invention provides a pharmaceutical composition or formulation comprising a composition comprising entacapone, an entacapone derivative or a stereoisomer, hydride, or pharmaceutically-acceptable salt thereof, copackaged or coformulated with a second, different medicament for treating injury or to promote wound healing or tissue regeneration.
  • the composition or formulation does not include another anti-Parkinsons medicament, neuroactive agent, anti-obesity, anti-diabetes, and/or another active pharmaceutical ingredient (API) , such as wherein anti-Parkinson’s medicaments include L-DOPA, deprenyl, tyrosine hydroxylase, apomorphine, anticholinergic drugs such as benzhexol and orphenadrine, and mGluR4 potentiators such as N-phenyl-7-(hydroxylimino) cyclopropa [b]chromen-1a-carboxamide (PHCCC) ;
  • the composition or formulation wherein the second medicament is a perfusion drug like methylxanthines (e.g. pentoxifylline) , a prostacyclin analog (e.g. Iloprost) , an antimicrobial (e.g. antibiotic) , a nitric oxide donor (e.g. glyceryl trinitrate) , a calcium antagonist (e.g. diltiazem, nifedipine) , an antioxidant (e.g. zinc) , a collagenase inhibitor (e.g. phenytoin) , a retinoid, an analgesic, an anti-inflammatory (e.g. NSAID) , an anti-platelet (e.g. aspirin) , corticosteroid (e.g. prednisone) , warfarin, a vasoconstrictor (e.g. nicotine) .
  • methylxanthines e.g. pentoxifylline
  • the invention encompasses all combination of the particular embodiments recited herein, as if each had been separately, laboriously recited.
  • the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
  • genuses are recited as shorthand for a recitation of all members of the genus; for example, the recitation of (C1-C3) alkyl is shorthand for a recitation of all C1-C3 alkyls: methyl, ethyl and propyl, including isomers thereof.
  • a hydrocarbyl group is a substituted or unsubstituted, straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group which comprises 1-15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.
  • heteroatom as used herein generally means any atom other than carbon or hydrogen.
  • Preferred heteroatoms include oxygen (O) , phosphorus (P) , sulfur (S) , nitrogen (N) , and halogens
  • preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyanyl, thocyanyl, carbonyl, halo, hydroperoxyl, imine, aldimine, isocyanide, iscyante, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, and sulfhydryl.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C1-C8 means one to eight carbons) .
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono-or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1-and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 -CH 2 -CH 2 -CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkoxy " alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, P, Si and S, wherein the nitrogen, sulfur, and phosphorous atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom (s) O, N, P and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si (CH 3 ) 3 .
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl” , respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C3-C8 means three to eight carbons) and may also have one or two double bonds.
  • a heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include 1- (1, 2, 5, 6-tetrahydropyrid-yl) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • halo and “halogen, " by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl, " are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1) , where m'is the total number of carbon atoms in the alkyl group.
  • halo (C1-C4) alkyl is mean to include trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group) .
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m'is the total number of carbon atoms in the alkyl group.
  • perhalo (C1-C4) alkyl is meant to include trifluoromethyl, pentachloroethyl, 1, 1, 1-trifluoro-2-bromo-2-chloroethyl and the like.
  • acyl refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1, 2, 3, 4-tetrahydronaphthalene.
  • heteroaryl refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like) .
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naph
  • R', R"and R' each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl- (C1-C4) alkyl groups.
  • R'a nd R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) .
  • the aryl group When the aryl group is 1, 2, 3, 4-tetrahydronaphthalene, it may be substituted with a substituted or unsubstituted (C3-C7) spirocycloalkyl group.
  • the (C3-C7) spirocycloalkyl group may be substituted in the same manner as defined herein for"cycloalkyl" .
  • an aryl or heteroaryl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the invention.
  • an aryl or heteroaryl group will be unsubstituted or monosubstituted.
  • an aryl or heteroaryl group will be unsubstituted.
  • Preferred substituents for aryl and heteroaryl groups are selected from: halogen, -OR', -OC (O) R', -NR'R", -SR', -R', -CN, -NO 2 , -CO 2 R', -CONR'R", -C (O) R', -OC (O) NR'R", - NR"C (O) R', -S (O) R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, -N 3 , -CH (Ph) 2 , perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl, where R'a nd R"are as defined above.
  • substituents are selected from: halogen, -OR', -OC (O) R', -NR'R", -R', -CN, -NO 2 , -CO 2 R', -CONR'R", -NR"C (O) R', -SO 2 R', -SO 2 NR'R", -NR"SO 2 R, perfluoro (C1-C4) alkoxy and perfluoro (C1-C4) alkyl.
  • the substituent -CO 2 H includes bioisosteric replacements therefor; see, e.g., The Practice of Medicinal Chemistry; Wermuth, C. G., Ed. ; Academic Press: New York, 1996; p. 203.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C (O) - (CH 2 ) q-U-, wherein T and U are independently -NH-, -O-, -CH 2 -or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2) r-B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S (O) -, -S (O) 2 -, -S (O) 2 NR'-or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CH 2 ) s-X- (CH 2 ) t--, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2 -, or -S (O) 2 NR'-.
  • the substituent R'in -NR'-and -S (O) 2 NR'- is selected from hydrogen or unsubstituted (C1-C6) alkyl.
  • substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of the invention, i.e. substituents of any given compound may be combinatorially used with other compounds.
  • applicable substituents are independently substituted or unsubstituted heteroatom, substituted or unsubstituted, optionally heteroatom C1-C6 alkyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkenyl, substituted or unsubstituted, optionally heteroatom C2-C6 alkynyl, or substituted or unsubstituted, optionally heteroatom C6-C14 aryl, wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.
  • applicable substituents are independently aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, amine, azo, halogens, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halo, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, iscyante, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl or trifluromethyl ether (OCF3) .
  • OCF3 trifluoromethyl or trifluromethyl ether
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein, and suitable for pharmaceutical use.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • 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, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, 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 phospho
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the 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 invention.
  • the invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be more bioavailable by oral administration than the parent drug.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
  • the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) , iodine-125 ( 125 I) or carbon-14 ( 14 C) . All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
  • compositions for 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, lozenges 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 carriers and processing aids helpful for forming the desired dosing form.
  • compositions may be administered separately, jointly, or combined in a single dosage unit.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 5, 25 or 100 to about 5, 25, 100, 500, 1000 or 2000 mg, according to the particular application.
  • unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient.
  • microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10, 100, 1000, 10000, 20000 ug/kg to about 10, 100, 1000, 10000, 20000 or 80000 ug/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
  • a dosage regimen of the compounds can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
  • the subject entacapone derivative comprises a structure of formula I of WO/2017/206573, a stereoisomer thereof, a hydride thereof, or a pharmaceutically-acceptable salt thereof, :
  • R1 and R2 are independently H or Me
  • R3 is OH or NHR, wherein R is H or an optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl;
  • R4 is optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl
  • R1 and R2 are independently H or Me
  • R3 is H, OH or NHR, wherein R is H or C1-C4 alkyl
  • R4 is CONHR5
  • R5 is optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl
  • R1 and R2 are independently H or Me
  • R3 is H, OH or NHR, wherein R is H or C1-C4 alkyl
  • R4 is COR5
  • R1 and R2 are independently H or Me
  • R3 is H, OH or NHR, wherein R is H or C1-C4 alkyl
  • heterocyclic C3-C18 hydrocarbyl comprises:
  • a 3 membered ring that is an optionally substituted : aziridine, oxirane, oxaziridine;
  • a 4 membered ring that is an optionally substituted : azetidine, oxetane, oxazetidine;
  • a 5 membered ring that is an optionally substituted : pyrrole, 1, 2-diazole (pyrazole) , 1, 3 diazole (imidazole) , thiazole, isothiazole, oxazole, isoxazole, furan, dioxole, thiophene;
  • a 6 membered ring that is an optionally substituted: pyridine, diazine, triazine, oxazine, thiazine, dioxine, oxathiine, dithiine;
  • a 9 membered ring that is an optionally substituted: indole, benzothiazole, benzooxazole, benzofuran, benzodioxole, benzothiophene, benzodithiole; or
  • quinoline a 10 membered ring that is an optionally substituted: quinoline, quinoxaline, quinazoline, chromene, benzodioxine, thiochromene, benzodithiine.
  • the optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl in each instance is an optionally substituted C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, or C5-C14 aryl hydrocarbon, comprising 1-5 heteroatoms that are N, S, O or P, including 1-5 nitrogen atoms, or a heteroatom substituted with the hydrocarbon.
  • R1 and R2 is H
  • R3 is OH
  • R is H or C1-C4 alkyl, esp. Me.
  • subsection (a) encompasses combinations wherein: R1 and R2 are H; R3 is NH 2 ; and R4 is a 6 membered ring that is pyridine, and subsection (d) encompasses combinations wherein R1 and R2 are Me; R3 is OH; and R4 is 1, 3 diazole.
  • the inhibitor is of the following Tables.
  • EP1978014 discloses processes for preparing entacapone; synthesis of representative derivatives are fully disclosed in WO/2017/206573, and not repeated here.
  • Hyperpigmentation of large or chronic wounds was associated with tissue repair and scar formation.
  • the surface pigment in the wound healing area model group (5088) was significantly increased as compared with untreated group (758) (p ⁇ 0.001) .
  • the surface pigments in the wound healing areas of zebrafish treated with entacapone at concentrations of 0.5 ⁇ M, 1.5 ⁇ M and 5 ⁇ M were 3451, 3487 and 3708; and the wound healing promoting percentages were 38% (p ⁇ 0.001) , 37% (p ⁇ 0.001) and 32% (p ⁇ 0.001) , respectively.
  • tissue regeneration efficacy was calculated using the following formula:
  • Zebrafish have become a powerful vertebrate model for assessing the effect of promoting regeneration based on their regenerative ability.
  • the tail fin length was 201 pixels in the tail fin amputated zebrafish model group, and 236, 229 and 223 pixels in the tail fin amputated zebrafish treated with entacapone at concentrations of 15 ⁇ M, 50 ⁇ M and 100 ⁇ M.
  • Promoting effect (%) of entacapone on the tissue regeneration of amputated zebrafish tail fin were 18% (p ⁇ 0.001) , 14% (p ⁇ 0.01) and 11% (p ⁇ 0.05) , respectively (Table 2, Figure 3-4) . Results with representative entacapone derivatives were consistent, and indicate that entacapone and active derivatives promote tissue regeneration.

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Abstract

L'invention concerne l'utilisation d'entacapone, d'un dérivé entacapone ou d'un stéréoisomère, d'un hydrure ou d'un sel pharmaceutiquement acceptable de celui-ci, chez une personne qui en a besoin, dans le traitement d'une lésion ou pour favoriser la cicatrisation ou la régénération tissulaire. Et la composition ou la formulation pharmaceutique comprenant entacapone, un dérivé entacapone ou un stéréoisomère, un hydrure, ou un sel pharmaceutiquement acceptable de celui-ci, et un second médicament différent pour traiter une lésion ou favoriser la cicatrisation des plaies ou la régénération tissulaire.
PCT/CN2017/098578 2016-08-24 2017-08-23 Composés apparentés à l'entacapone pour traiter une lésion Ceased WO2018036501A1 (fr)

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CN112313229A (zh) * 2018-04-17 2021-02-02 马萨里克大学 作为核酸酶的抑制剂的经取代的氨基噻唑
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CN113069450B (zh) * 2021-02-20 2023-03-07 南方医科大学 Fto抑制剂在制备抗氧化产品中的应用
CN115089573A (zh) * 2022-07-06 2022-09-23 复旦大学 恩他卡朋在制备治疗急性肾损伤药物和铁死亡抑制剂中的应用
CN119546566A (zh) * 2022-07-29 2025-02-28 瑞璞鑫(苏州)生物科技有限公司 Fto抑制剂
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US10532976B2 (en) * 2015-06-23 2020-01-14 National Institute Of Biological Sciences, Beijing FTO inhibitors
CN112313229A (zh) * 2018-04-17 2021-02-02 马萨里克大学 作为核酸酶的抑制剂的经取代的氨基噻唑
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JP2023527698A (ja) * 2020-05-20 2023-06-30 エフ． ホフマン－ラ ロシュ アーゲー 新規マロニトリル誘導体

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