Entacapone-related compounds for the treatment of injuries

Abstract

The present invention provides the use of entacapone, an entacapone derivative, or a stereoisomer, hydrate, or pharmaceutically acceptable salt thereof, in a human in need thereof for treating an injury or promoting wound healing or tissue regeneration.

Description

Background Technology

[0001] Wound healing is a physiological process by which skin or other body tissues (such as blood vessels) repair themselves after injury. Following injury, a series of biochemical events occur, including tissue growth and vascular remodeling, to repair the damage. This invention relates to interventions that promote this ability and enable damaged tissue to heal or regenerate.

[0002] We previously disclosed in US 2014 / 0148383 A1 a structure-based virtual screening method for identifying entacapone ((2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide), a known FDA-approved drug as an FTO inhibitor, using a combination of bioactivity measurements, including enzyme activity, cell activity, and a high-fat diet-induced obesity (DIO) animal model. We also previously disclosed entacapone derivatives with related activities in PCT / CN 2015 / 082052.

[0003] Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used to treat Parkinson's disease, typically administered in combination with a dopamine derivative, levodopa (L-DOPA) or carbidopa; see full prescribing information for Comtan - Novartis. WO 2015095257 discloses the use of dopamine to treat diabetes or diabetic retinopathy, and in embodiments, dopamine is administered in combination with a COMT inhibitor such as entacapone, tocapone, or niticapone.

[0004] Here we disclose the use of entacapone and related formulations for the treatment of tissue damage and for promoting wound healing and tissue regeneration. Invention Overview

[0006] This invention provides entacapone-related compounds, compositions, and methods for treating tissue damage, particularly trauma, or promoting wound healing or tissue regeneration.

[0007] In one aspect, the present invention provides the use or method of use of entacapone, entacapone derivatives, or stereoisomers, hydrides, or pharmaceutically acceptable salts thereof in treating injuries or promoting wound healing or tissue regeneration in persons in need thereof, preferably wherein the person does not have Parkinson's disease, obesity, diabetes, or diabetic retinopathy.

[0008] This invention can be practiced with a wide variety of entacapone derivatives, and the activity can be readily verified empirically; exemplary suitable derivatives are disclosed in US5,112,861, WO 2007144169, EP 1978014 A1 and WO / 2016 / 206573. In a specific embodiment, the derivative is an FTO inhibitor.

[0009] In a specific implementation, the entacapone derivative comprises the structure of formula I of WO / 2016 / 206573, its stereoisomer, its hydride, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] R1 and R2 are independently H or Me;

[0013] R3 is H, OH, or NHR, where R is H or an optionally substituted, optionally heteroatom-containing, optionally cyclic C1-C18 hydrocarbon group; and

[0014] R4 is an optional substituted, optional heteroatom-containing, optional cyclic C1-C18 hydrocarbon group.

[0015] In a specific implementation, the entacapone derivative comprises the structure of formula I of US5112861, its stereoisomer, its hydride, or a pharmaceutically acceptable salt thereof:

[0016]

[0017] Where R1 and R2 independently represent hydrogen, an alkyl carbamoyl group with 2 to 5 carbon atoms, or an alkyl carbonyl group with 2 to 5 carbon atoms, X represents nitro or cyano, and R3 represents

[0018]

[0019] R4 represents a cyano or an alkyl carbonyl group with 2 to 5 carbon atoms, and R5 represents a cyano; an alkyl carbonyl group with 2 to 5 carbon atoms; or an unsubstituted carbamoyl group or a carbamoyl group substituted with an alkyl group with 1 to 8 carbon atoms or a hydroxyalkyl group with 1 to 8 carbon atoms.

[0020] In a specific implementation, the entacapone derivative comprises the structure of formula I of WO2007144169, its stereoisomer, its hydride, or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in

[0023] Y represents sulfur or oxygen.

[0024] R 1 It is a group of formula II below

[0025]

[0026] Or when Y is S, R 1 It could also be H.

[0027] R 2 It is an H or a group of formula II, which can react with R. 1 Same or different,

[0028] Each R 3 Independently is (C1-C) 20 )-alkyl, (CR 4 R 5 ) X -R 6 (C1-C) 20 )-alkylene-(C1-C 20 )-alkoxy, (C2-C 20 )-Alkenyl, (C2-C 20 )-Alkyne group, (C0-C 20 )-alkylene-(C3-C 18 )-cycloalkyl, (C0-C 20 )-alkylene-(3-18 quinary)-heterocyclic alkyl, (C1-C 20 )-alkylene-(C3-C 18 )-cycloalkenyl, (C0-C 20 )-alkylene-(3-18 quinone)-heterocyclic alkenyl, (C0-C 20 )-alkylene-(C6-C 18 )-Aryl, (C0-C 20 )-alkylene-(5-18 quinone)-heteroaryl, (C2-C 20 )-Ideinyl-(C3-C 18 )-cycloalkyl, (C2-C 20 )-Ideenyl-(3-18 quinone)-heterocyclic alkyl, (C2-C 20 )-Ideinyl-(C3-C 18 )-cycloalkenyl, (C2-C 20 )-Ideinyl-(3-18 quinone)-heterocyclic alkenyl, (C2-C 20 )-Ideinyl-(C6-C 18 )-aryl, or (C2-C 20 )-Ideenyl-(5-18)-heteroaryl, wherein R 3 The total number of carbon atoms is at most 30.

[0029] Each R 4 and R5 Choose independently the following groups: H, (C1-C 20 )-alkyl, (C1-C 20 )-alkylene-hydroxyl, (C0-C 20 )-alkylene-(C1-C 20 )-alkoxy, OH, (C0-C 20 )-alkylene-N(R 7 )CO-(C1-C 20 )-alkyl, (C0-C 20 )-alkylene-CON(R 8 (R) 9 (C0-C) 20 )-alkylene-COO-(C1-C 20 )-alkyl, (C0-C 20 )-alkylene-N(R 10 (R) 11 SO3R 17 (C0-C) 20 )-alkylene-(C6-C 18 )-aryl, and (CO-C 20 )-alkylene-(5-18 quinone)-heteroaryl,

[0030] or

[0031] Same group (CR) 4 R 5 ) of R 4 and R 5 or different groups (CR) 4 R 5 ) of R 4 and R 5 They can form carbon rings or heterocycles with 3 to 6 atoms together.

[0032] In addition, one or more non-adjacent groups (CR) 4 R 5 ) can be O, CO, OCO, COO, CON(R) 19 ), N(R 20 CO or NR 21 Replacement

[0033] R 6 Independently, it is H, (C1-C) 20 )-alkyl, (C2-C 20 )-Alkenyl, (C2-C 20 )-alkynyl, OH, O-(C1-C8)-alkyl, O-(C0-C8)-alkylene-(C6-C 14)-aryl, CO-O-(C1-C8)-alkyl, CO-N(R 12 (R) 13 ), N(R 14 CO-(C1-C8)-alkyl, N(R) 15 XR 16 SO3R 18 (C0-C) 20 )-alkylene-(5-18 quinone)-heteroaryl, or (C0-C 20 )-alkylene-(C6-C 18 )-Aryl,

[0034] R 7 R 14 R 17 R 18 R 19 R 20 R 21 They are independently H or (C1-C2o)-alkyl groups.

[0035] R 8 R 9 R 10 R 11 R 12 R 13 R 15 R 16 H or (C1-C) are independent of each other. 20 )-alkyl,

[0036] R 22 and R 23 Independently select the group consisting of the following items: H and (C1-C) 15 )-alkyl, and

[0037] x is from 1 to 14.

[0038] These alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkoxy, aryl, heteroaryl, alkenyl, and alkylene groups can be unsubstituted or further substituted.

[0039] In the implementation plan, the use further includes steps for detecting damage reduction, wound healing, or tissue regeneration promotion results.

[0040] In other respects, the present invention provides a pharmaceutical composition or formulation comprising: a composition containing entacapone, an entacapone derivative, or a stereoisomer, hydride, or pharmaceutically acceptable salt thereof, co-packaged or co-formulated with a second different drug for treating injury or promoting wound healing or tissue regeneration.

[0041] In the implementation plan:

[0042] - The composition or formulation does not contain another anti-Parkinson's drug, neuroactive agent, anti-obesity agent, anti-diabetic agent and / or another active pharmaceutical ingredient (API), such as anti-Parkinson's drugs including L-DOPA, propyne, tyrosine hydroxylase, apomorphine, anticholinergic drugs (such as benzhexol and orphenadrine), and mGluR4 synergists such as N-phenyl-7-(hydroxyimino)cyclopropion[b]chromene-1a-carboxamide (PHCCC);

[0043] - The composition or formulation wherein the entacapone, entacapone derivative or a pharmaceutically acceptable salt thereof is in unit dosage form; and / or

[0044] - The composition or formulation wherein the second drug is an infusion drug, such as methylxanthine (e.g., pentoxifylline), prostacyclin analogue (e.g., iloprost), antimicrobial agent (e.g., antibiotic), nitric oxide donor (e.g., trinitroglycerin), calcium channel blocker (e.g., diltiazem, nifedipine), antioxidant (e.g., zinc), collagenase inhibitor (e.g., phenytoin), retinoid, analgesic, anti-inflammatory agent (e.g., NSAID), antiplatelet agent (e.g., aspirin), corticosteroid (e.g., prednisone), warfarin, vasoconstrictor (e.g., nicotine).

[0045] This invention includes all combinations of the specific embodiments listed herein, as if each were listed individually and laboriously. Brief description of the attached diagram

[0047] Figure 1 The surface pigmentation of the wound healing group was significantly different from that in the model group (***p<0.001).

[0048] Figure 2 The wound healing promoting effect of entacapone (%) was significantly different from that in the model group (***p<0.001).

[0049] Figure 3 Caudal fin length, compared to the model, *p<0.05, **p<0.01, ***p<0.001

[0050] Figure 4 The tissue regeneration promoting effect (%) of entacapone compared with the model,

[0051] *p<0.05, **p<0.01, ***p<0.001 Invention Details

[0053] The following description of specific implementation schemes and embodiments is provided in an illustrative rather than limiting manner. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially similar results.

[0054] Unless otherwise prohibited or stated, in these descriptions and throughout the specification, the terms “an” and “a” mean one / one or more / multiple, the term “or” means and / or, and a polynucleotide sequence is understood to include the opposite strand as well as the alternative backbone described herein. Furthermore, genera are enumerated as shorthand for a list of all members of that genus; for example, the enumeration of (C1-C3)alkyl is a shorthand for a list of all C1-C3 alkyl groups: methyl, ethyl, and propyl (including their isomers).

[0055] The hydrocarbon group is a substituted or unsubstituted straight-chain, branched or cyclic alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, aryl-alkenyl, arylynyl, alkylaryl, alkenylaryl or alkynylaryl, which contains 1 to 15 carbon atoms and optionally includes one or more heteroatoms in its carbon skeleton.

[0056] As used herein, the term "heteroatom" generally refers to any atom other than carbon or hydrogen. Preferred heteroatoms include oxygen (O), phosphorus (P), sulfur (S), nitrogen (N), and halogens, and preferred heteroatom functional groups are haloformyl, hydroxyl, aldehyde, amine, azo, carboxyl, cyano, thiocyanyl, carbonyl, halogen, hydroperoxy, imine, aldehyde imine, isocyanate, isocyanate, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphonyl, sulfide, sulfonyl, sulfonyl, and mercapto.

[0057] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means a straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, that is fully saturated and has a specified number of carbon atoms (i.e., C1-C8 means 1 to 8 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0058] The term "alkenyl" itself, or as part of another substituent, refers to a straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, which can be monounsaturated or polyunsaturated, having a specified number of carbon atoms (i.e., C2-C8 means 2 to 8 carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and their higher homologues and isomers.

[0059] The term "alkynyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group or a combination thereof, which can be monounsaturated or polyunsaturated, having a specified number of carbon atoms (i.e., C2-C8 means 2 to 8 carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl, and their higher homologues and isomers.

[0060] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkyl group, such as -CH2-CH2-CH2-CH2-. Typically, an alkyl (or alkylene) will have from 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in this invention. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having 8 or fewer carbon atoms.

[0061] The terms “alkoxy,” “alkylamino,” and “alkathioyl” (or thioalkoxy) are used in their conventional sense and refer to those alkyl groups attached to the rest of the molecule by an oxygen, amino, or sulfur atom, respectively.

[0062] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight-chain or branched, or cyclic, hydrocarbon group, or a combination thereof, consisting of the stated number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, P, Si, and S, wherein nitrogen, sulfur, and phosphorus atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. The one or more heteroatoms O, N, P, and S may be located at any internal position of the heteroalkyl group. The heteroatom Si may be located at any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. At most two heteroatoms can be consecutive, such as in -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0063] Similarly, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, the heteroatom can also occupy any one or both chain ends (e.g., alkeneoxy, alkenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, the orientation of the linking group is not implied for either the alkylene or heteroalkylene linkage.

[0064] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" on their own or in combination with other terms refer to the cyclic form of "alkyl" and "heteroalkyl," respectively. Thus, a cycloalkyl group has a specified number of carbon atoms (i.e., C3-C8 means 3 to 8 carbons) and may also have one or two double bonds. A heteroalkyl group consists of a specified number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, Si, and S, wherein nitrogen and sulfur atoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Additionally, for heteroalkyl groups, heteroatoms may occupy positions where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocyclic alkyl groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc.

[0065] Unless otherwise stated, the terms “halogenated” and “halogen”, either on their own or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “halogenated alkyl” are intended to include alkyl groups substituted with a number of halogen atoms ranging from 1 to (2m'+1), where m' is the total number of carbon atoms in the alkyl group, and these halogen atoms may be the same or different. For example, the term “halogenated (C1-C4)alkyl” is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. Therefore, the term “halogenated alkyl” includes monohalogenated alkyl (alkyl groups substituted with one halogen atom) and polyhalogenated alkyl (alkyl groups substituted with a number of halogen atoms ranging from 2 to (2m'+1), where m' is the total number of carbon atoms in the alkyl group). Unless otherwise stated, the term “per-halogenated alkyl” refers to an alkyl group substituted with (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "perhalogenated (C1-C4)alkyl" is intended to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, etc.

[0066] The term "acyl" refers to those groups derived from organic acids by removing the hydroxyl group of the acid. Therefore, acyl is intended to include, for example, acetyl, propionyl, butyryl, decyl, neopentyl, benzoyl, etc.

[0067] Unless otherwise stated, the term "aryl" means a polyunsaturated, typically aromatic, hydrocarbon substituent, which can be a monocyclic or fused together or covalently linked polycyclic (up to three rings). Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, and 1,2,3,4-tetrahydronaphthalene.

[0068] The term "heteroaryl" refers to an aryl group (or ring) containing 0 to 4 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of heteroaryl groups include 1-pyrrole, 2-pyrrole, 3-pyrrole, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxolinyl, 5-quinoxolinyl, 3-quinolinyl, and 6-quinolinyl.

[0069] For the sake of brevity, when used in combination with other terms (e.g., aryloxy, arylthoxy, aralkyl), the term "aryl" includes both the aryl ring and the heteroaryl ring as defined above. Therefore, the term "aralkyl" is intended to include those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), and those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridoxymethyl, 3-(1-naphthoxy)propyl, etc.).

[0070] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") is intended to include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

[0071] Substituents used for alkyl and heteroalkyl groups (and those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from the following: -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR "C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2, in quantities ranging from 0 to 3, with those groups having 0, 1, or 2 substituents being particularly preferred. R', R" and R'" each independently refer to hydrogen, unsubstituted (C1-C8) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted alkyl, alkoxy, or thioalkoxy, or aryl-(C1-C4) alkyl. When R' and R" are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 5, 6, or 7-membered ring. For example, -NR'R" is intended to include 1-pyrrolidinyl and 4-morpholinyl. Typically, the alkyl or heteroalkyl group will have from 0 to 3 substituents, with those having two or fewer substituents being preferred in this invention. More preferably, the alkyl or heteroalkyl group will be unsubstituted or monosubstituted. Most preferably, the alkyl or heteroalkyl group will be unsubstituted. From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups such as trihaloalkyl groups (e.g., -CF3 and -CH2CF3).

[0072] Preferred substituents for alkyl and heteroalkyl groups are selected from: -OR', =O, -NR'R", -SR', halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, wherein R' and R" are as defined above. Further preferred substituents are selected from: -OR', =O, -NR'R", halogen, -OC(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R'", -SO2R', -SO2NR'R", -NR"SO2R, -CN, and -NO2.

[0073] Similarly, the substituents used for aryl and heteroaryl groups are varied and selected from: halogens, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in quantities ranging from 0 to aromatics. The total number of open valences on the ring system; and wherein R', R" and R'" are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl. When the aryl group is 1,2,3,4-tetrahydronaphthalene, it can be substituted with a substituted or unsubstituted (C3-C7)spirocycloalkyl group. The (C3-C7)spirocycloalkyl group can be substituted in the same manner as defined herein with respect to "cycloalkyl". Typically, the aryl or heteroaryl group will have from 0 to 3 substituents, wherein those groups having two or fewer substituents are preferred in this invention. In one embodiment of the invention, the aryl or heteroaryl group will be unsubstituted or monosubstituted. In another embodiment, the aryl or heteroaryl group will be unsubstituted.

[0074] Preferred substituents for aryl and heteroaryl groups are selected from: halogens, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -N3, -CH(Ph)2, perfluorinated (C1- C4)alkoxy and perfluoro(C1-C4)alkyl, wherein R' and R" are as defined above. Further preferred substituents are selected from: halogen, -OR', -OC(O)R', -NR'R", -R', -CN, -NO2, -CO2R', -CONR'R", -NR"C(O)R', -SO2R', -SO2NR'R", -NR"SO2R, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl.

[0075] As used herein, the substituent -CO2H includes its bioisosteric alternatives; see, for example, The Practice of Medicinal Chemistry; Wermuth, CG, Ed.; Academic Press: New York, 1996; p. 203.

[0076] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -TC(O)-(CH2)qU-, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -A-(CH2)rB-, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -(CH2)sX-(CH2)t--, where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted (C1-C6) alkyl groups.

[0077] Preferred substituents are disclosed herein and exemplified in the tables, structures, examples and claims, and can be applied to all different compounds of the invention; that is, substituents of any given compound can be used in combination with other compounds.

[0078] In a specific embodiment, the applicable substituents are independently substituted or unsubstituted heteroatoms, substituted or unsubstituted C1-C6 alkyl groups optionally containing heteroatoms, substituted or unsubstituted C2-C6 alkenyl groups optionally containing heteroatoms, substituted or unsubstituted C2-C6 alkynyl groups optionally containing heteroatoms, or substituted or unsubstituted C6-C14 aryl groups optionally containing heteroatoms, wherein each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0079] In more specific embodiments, applicable substituents are independently aldehydes, aldehyde imines, alkanoyloxys, alkoxys, alkoxycarbonyls, alkoxys, alkyls, amines, azo compounds, halogens, carbamoyls, carbonyls, formamidos, carboxyls, cyanos, esters, halogens, haloformyls, hydroperoxys, hydroxyl groups, imines, isocyanates, isocyanates, N-tert-butoxycarbonyls, nitrates, nitrites, nitros, nitroso, phosphates, phosphonyls, sulfides, sulfonyls, sulfonyl groups, mercaptos, thiocyanates, trifluoromethyls, or trifluoromethyl ethers (OCF3).

[0080] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases (depending on the specific substituents found on the compounds described herein) and suitable for pharmaceutical use. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts such as arginine salts, and organic acid salts such as glucuronic acid or galacturonic acid. Certain compounds of this invention contain both basic and acidic functional groups, which allow these compounds to be converted into basic or acid addition salts.

[0081] The neutral forms of these compounds can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but in other respects, for the purposes of this invention, these salts are equivalent to the parent form of the compound.

[0082] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, prodrugs can be slowly converted into the compounds of the present invention. Prodrugs are generally useful because, in some cases, they can be more readily administered than the parent drug. They can be more bioavailable than the parent drug, for example, when administered orally. Prodrugs also have improved solubility in pharmacological compositions compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those dependent on the hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs (but not limited to) can be the compounds of the present invention given as esters (“prodrugs”) but subsequently metabolized and hydrolyzed into carboxylic acids (the active entities). Other examples include peptide derivatives of the compounds of the present invention.

[0083] Some compounds of the present invention may exist in both solvated and solvated forms (including hydrated forms). Generally, these solvated forms are equivalent to the unsolvated forms and are intended to be included within the scope of the present invention. Some compounds of the present invention may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses contemplated by the present invention and are intended to fall within the scope of the present invention.

[0084] Some of the subject compounds have asymmetric carbon atoms (optical centers) or double bonds; racemic, diastereomers, geometric isomers and particularly specified or described chirality are preferred and, in many cases, critical for optimal activity; however, all such isomers are intended to be included within the scope of this invention.

[0085] The compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more sites among the atoms constituting such compounds. For example, these compounds may use radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variants of the compounds of this invention, whether or not radioactive, are intended to be included within the scope of this invention.

[0086] The term "therapeutic effective dose" refers to the amount of a subject compound that will elicit, to a certain extent, a biological or medical response in the tissue, system, animal, or human being being sought by a researcher, veterinarian, physician, or other clinician. This biological or medical response is such that, when administered, it is sufficient to prevent the development of one or more symptoms of the treated condition or disorder, or to alleviate them to a certain extent. Therapeutic effective doses will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0087] The present invention also provides pharmaceutical compositions comprising a subject compound and pharmaceutically acceptable excipients, particularly such compositions comprising a unit dose of the subject compound, especially such compositions co-packaged with an instruction manual describing the use of the composition for the treatment of an applicable disease or condition (hereinafter).

[0088] Compositions intended for administration may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, these compositions are presented in unit dosage forms to facilitate precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable for use as a single dose in human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect when combined with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled liquid compositions, ampoules or syringes of predicted quantities, or, in the case of solid compositions, pills, tablets, capsules, lozenges, etc. In such compositions, the compound is typically 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 consisting of various media or carriers and processing aids that facilitate the formation of the desired dosage form.

[0089] Suitable excipients or carriers and methods for preparing administerable compositions are known or obvious to those skilled in the art and are described in more detail in publications such as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991). Furthermore, these compounds can be advantageously used in combination with other therapeutic agents, particularly other antinecrotizing agents, as described herein or otherwise known in the art. Therefore, these compositions can be administered alone, in combination, or in a single dose unit.

[0090] The dosage administered depends on the compound formulation, route of administration, etc., and is typically determined empirically in routine trials, and will inevitably vary depending on the target, host, and route of administration. Generally, depending on the specific application, the amount of active compound in a unit dose of the formulation can vary or be adjusted from about 1, 5, 25, or 100 to about 5, 25, 100, 500, 1000, or 2000 mg. In specific embodiments, the unit dosage form is packaged in a suitable package (such as a blister pack) for continuous use containing at least 6, 9, or 12 tablets. The actual dose used can vary depending on the patient's request and the severity of the condition being treated. Determining the appropriate dose for a specific situation is within the scope of the art. Typically, treatment is started with smaller doses, which are less than the optimal dose of the compound. The dose is then increased in small increments until the optimal effect is achieved in these situations. For convenience, if desired, the total daily dose can be divided and administered in divided doses throughout the day.

[0091] For prophylactic and / or therapeutic treatment, these compounds can be administered by a variety of methods, including but not limited to parenteral, topical, oral, or local administration, such as via aerosol or transdermal. Furthermore, treatment regimens (e.g., dosage and timing of administration) can be varied based on the knowledge of a skilled clinician, the observed effects of the administered therapeutic agent on the patient, and the observed disease response to the administered therapeutic agent.

[0092] In the course of a treatment regimen for treating a patient, the therapeutic agent of the present invention can be administered at a therapeutically effective dose and amount. For more potent compounds, although the optimal dose is compound-specific and is generally determined empirically for each compound, micrograms (ug) 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.

[0093] Typically, routine trials in clinical trials determine the specific range for optimal therapeutic effect. The administration of each therapeutic agent, each dosing regimen, and to a particular patient will also be adjusted to an effective and safe range based on the patient's condition and responsiveness to the initial administration. However, the final dosing regimen will be adjusted based on the attending clinician's judgment, taking into account factors such as the patient's age, condition, and size, as well as the compound's potency and the severity of the disease being treated. For example, the compound's dosing regimen may be administered orally in 2 to 4 separate doses, ranging from 10 mg to 2000 mg / day, preferably 10 to 1000 mg / day, and more preferably 50 to 600 mg / day. Intermittent treatment (e.g., one week out of three weeks or three weeks out of four weeks) may also be used.

[0094] In the specific implementation scheme, the subject entacapone derivative comprises the structure of formula I of WO / 2016 / 206573, its stereoisomer, its hydride, or a pharmaceutically acceptable salt thereof:

[0095]

[0096] in:

[0097] (a)

[0098] R1 and R2 are independently H or Me;

[0099] R3 is OH or NHR, where R is H or an optionally substituted, optionally heteroatom-containing, optionally cyclic C1-C18 hydrocarbon group; and

[0100] R4 is an optional substituted, optional heteroatom-containing, optional cyclic C1-C18 hydrocarbon group;

[0101] (b)

[0102] R1 and R2 are independently H or Me;

[0103] R3 is H, OH or NHR, where R is H or a C1-C4 alkyl group;

[0104] R4 is CONHR5; and

[0105] R5 is an optional substituted, optional heteroatom-containing, optional cyclic C1-C18 hydrocarbon group;

[0106] (c)

[0107] R1 and R2 are independently H or Me;

[0108] R3 is H, OH or NHR, where R is H or a C1-C4 alkyl group;

[0109] R4 is COR5; and

[0110] R5 is an optionally substituted heterocyclic C3-C18 hydrocarbon group containing an n-membered ring, where n = 3-18, comprising 1 to n-1 heteroatoms independently selected from N, O, S, and P; or

[0111] (d)

[0112] R1 and R2 are independently H or Me;

[0113] R3 is H, OH, or NHR, where R is H or a C1-C4 alkyl group; and

[0114] R4 is an optionally substituted heterocyclic C3-C18 hydrocarbon group containing an n-membered ring, where n = 3-18, comprising 1 to n-1 heteroatoms independently selected from N, O, S, and P; in particular, compounds excluded from the inhibitors are: CAS IDS: 1364322-41-7, 1150310-12-5, 1150310-15-8, and 143542-72-7.

[0115] In embodiments of the inhibitor or composition, the heterocyclic C3-C18 hydrocarbon group comprises:

[0116] Optional substituted 3-membered rings: aziridine propane, ethylene oxide, aziridine propane;

[0117] Optionally substituted 4-membered rings: azirheptan, oxaheptan, oxazirheptan;

[0118] Optional substituted 5-membered rings: pyrrole, 1,2-diazole (pyrazole), 1,3-diazole (imidazolium), thiazole, isothiazole, oxazole, isoxazole, furan, dioxacyclopentene, thiophene;

[0119] Optionally substituted 6-membered rings: pyridine, diazine, triazine, oxazine, thiazine, dioxin, oxathiine, and dithiine;

[0120] Optional substituted 9-membered rings: indole, benzothiazole, benzoxazole, benzofuran, benzodioxane, benzothiophene, benzodithiacyclopentadiene; or

[0121] Optional substituted 10-membered rings: quinoline, quinoxaline, quinazoline, chromene, benzodioxin, thiochromene, benzodithiine.

[0122] In embodiments of the inhibitor or composition, the optionally substituted, optionally heteroatom-bearing, optionally cyclic C1-C18 hydrocarbon group is, in each case, an optionally substituted C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, or C5-C14 aryl hydrocarbon containing 1-5 heteroatoms (N, S, O, or P, including 1-5 nitrogen atoms), or a heteroatom substituted by the hydrocarbon.

[0123] In embodiments of the inhibitor or composition:

[0124] One or both of R1 and R2 are H;

[0125] R3 is OH; and / or

[0126] R is H or C1-C4 alkyl, especially Me.

[0127] This invention includes all combinations of the specific embodiments listed herein, as if each were listed individually and laboriously. For example, subsection (a) includes combinations in which: R1 and R2 are H; R3 is NH2; and R4 is a 6-membered ring (pyridine), and subsection (d) includes combinations in which R1 and R2 are Me; R3 is OH; and R4 is 1,3-diazole.

[0128] In the implementation plan, the inhibitor is listed in the table below.

[0129] Table 1. Subsection (a) Inhibitors

[0130]

[0131]

[0132] Table 2. Subsection (a) Inhibitors.

[0133]

[0134]

[0135] Table 3. Section (b) Inhibitors.

[0136]

[0137]

[0138]

[0139] Table 4. Section (c) Inhibitors.

[0140]

[0141]

[0142]

[0143] Table 5. Section (d) inhibitors.

[0144]

[0145]

[0146]

[0147] Compound preparation.

[0148] EP 1978014 discloses a method for preparing entacapone; the synthesis of representative derivatives is fully disclosed in WO / 2016 / 206573 and will not be repeated here.

[0149] Therapeutic activity

[0150] In these embodiments, we used the zebrafish model (Richardson, et al., Adult zebrafish as a model system for cutaneous wound-healing research. J Invest Dermatol 2013, 133(6), 1655-65) to measure the efficacy of entacapone and several representative entacapone derivatives in wound healing, and used the zebrafish model (Gemberling, et al., The zebrafish as a model for complex tissue regeneration. Trends Genet 2013, 29(11), 611-20) to measure their efficacy in tissue regeneration.

[0151] Wound healing promoting effect

[0152] We measured the therapeutic effects of entacapone and several representative entacapone derivatives on a zebrafish wound-healing model. A zebrafish wound-healing model was established by injecting 5% glacial acetic acid into the trunk of zebrafish. Three concentrations of entacapone or its derivatives were selected to evaluate their wound-healing effects over 2 days (0.5 μM, 1.5 μM, and 5 μM). Zebrafish treated with fish water served as an untreated control. The effects of the compounds on wound healing were calculated based on pigment analysis using the following formula:

[0153]

[0154] Hyperpigmentation in large or chronic wounds is associated with tissue repair and scar formation. Compared to the untreated group (758), the surface pigmentation in the wound healing area model group (5088) was significantly increased (p<0.001). The surface pigmentation in the wound healing area of ​​zebrafish treated with entacapone at concentrations of 0.5 μM, 1.5 μM, and 5 μM were 3451, 3487, and 3708, respectively; and the percentages of wound healing promotion were 38% (p<0.001), 37% (p<0.001), and 32% (p<0.001), respectively (Table 1 and...). Figure 1-2 When treated with 0.5 μM (80%), neovascularization in the wound healing region showed significant differences among zebrafish wound healing models (p < 0.001) (Table 1 and). Figure 1-2 The results for representative entacapone derivatives were consistent, and it was shown that entacapone and its active derivatives promote wound healing.

[0155] Table 1. Percentage of surface pigmentation and wound healing promotion effect of entacapone (n=10)

[0156]

[0157] Tissue regeneration promoting efficacy

[0158] We measured the therapeutic effects of entacapone and several representative entacapone derivatives on tissue regeneration in a zebrafish model. Zebrafish with their caudal fins removed (tissue regeneration model zebrafish) were treated with entacapone or its derivatives at consecutive concentrations of 15 μM, 50 μM, and 100 μM for 3 days. Zebrafish treated with fish water served as an untreated control. Tissue regeneration efficacy was calculated using the following formula:

[0159]

[0160] Zebrafish have become a powerful vertebrate model for evaluating their regenerative capacity and effectiveness in promoting regeneration. The caudal fin length in the caudal fin-removed zebrafish model group was 201 pixels, while the caudal fin lengths in zebrafish treated with entacapone at concentrations of 15 μM, 50 μM, and 100 μM were 236, 229, and 223 pixels, respectively. The promoting effects (%) of entacapone on tissue regeneration of the caudal fin in zebrafish were 18% (p<0.001), 14% (p<0.01), and 11% (p<0.05), respectively (Table 2). Figure 3-4 The results for representative entacapone derivatives were consistent, and it was shown that entacapone and its active derivatives promote tissue regeneration.

[0161] Table 2. Percentage of Caudal Fin Length and Tissue Regeneration Promotion Effect (n=10)

[0162]

[0163] Compared with the model, *p<0.05, **p<0.01, ***p<0.001

[0164] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or changes made based on them will be known to those skilled in the art and should be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications (including references thereto) cited herein are hereby incorporated in their entirety for all purposes.

Claims

1. Use of entacapone or a pharmaceutically acceptable salt thereof in the preparation of a medicine for promoting wound healing or tissue regeneration in persons in need of it.

2. The use of claim 1, wherein, The person does not have Parkinson's disease, obesity, diabetes, or diabetic retinopathy.

3. Use of an entacapone derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for promoting wound healing or tissue regeneration in persons in need thereof, wherein the entacapone derivative is selected from the following compounds: 。 4. The use of claim 3, wherein, The person does not have Parkinson's disease, obesity, diabetes, or diabetic retinopathy.

5. The use according to any one of claims 1-4, wherein, This medication contains a second, different drug that promotes wound healing or tissue regeneration.

6. The use according to any one of claims 1-4, wherein, This medication does not contain another anti-Parkinson's drug, neuroactive agent, anti-obesity agent, and / or anti-diabetic agent.

7. The use according to any one of claims 1-4, wherein, This drug is a unit dosage form.

8. The use of claim 5, wherein, The second different drug is a prostacyclin analogue, antimicrobial agent, nitric oxide donor, antioxidant, collagenase inhibitor, retinoid, analgesic, anti-inflammatory agent, or corticosteroid.

Images