EP4069370A1 - Phenolic dihydrobenzofurane derivatives, medical and cosmetic preparations containing these derivatives, and use thereof - Google Patents

Phenolic dihydrobenzofurane derivatives, medical and cosmetic preparations containing these derivatives, and use thereof

Info

Publication number
EP4069370A1
EP4069370A1 EP20714469.2A EP20714469A EP4069370A1 EP 4069370 A1 EP4069370 A1 EP 4069370A1 EP 20714469 A EP20714469 A EP 20714469A EP 4069370 A1 EP4069370 A1 EP 4069370A1
Authority
EP
European Patent Office
Prior art keywords
derivatives
dihydrobenzofurane
general formula
carboxylate
hydroxyphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20714469.2A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jiri Pospisil
Jiri Gruz
Miroslav Strnad
Lucie JANOVSKA
Milan Kolar
Lucie RAROVA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Palacky University Olomouc
Original Assignee
Palacky University Olomouc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Palacky University Olomouc filed Critical Palacky University Olomouc
Publication of EP4069370A1 publication Critical patent/EP4069370A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A61Q11/02—Preparations for deodorising, bleaching or disinfecting dentures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K15/00—Anti-oxidant compositions; Compositions inhibiting chemical change
    • C09K15/04—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds
    • C09K15/06—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing oxygen
    • C09K15/08—Anti-oxidant compositions; Compositions inhibiting chemical change containing organic compounds containing oxygen containing a phenol or quinone moiety
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Phenolic dihydrobenzofurane derivatives medical and cosmetic preparations containing these derivatives, and use thereof
  • the invention relates to a new generation of phenolic compounds based on dihydrobenzofurane derivatives, to their use in cosmetic and therapeutic applications, and to preparations containing these derivatives.
  • Dental plaque is a dense, tenacious deposit of oral bacteria. Calcification (mineralization) of dental plaque results in dental calculus. Calculus formation depends on the presence of plaque. Plaque forms and grows on the surface of teeth, preferentially in the cervical, interdental and fissure areas and also on dental restorations, crowns, bridges and dentures. Plaque is the obligate cause of dental caries; plaque and calculus are the causes of inflammatory destruction of the tooth-supporting gingival and periodontal structures (periodontitis).
  • Such germicides include phenolic compounds, halogenated bis-phenols (e.g. hexachlorophene), organic mercurials, hydroxyquinolines, iodine esters of hydroxybenzoic acids, chloramine T, and surface- active compounds (detergents). These germicides are excellent laboratory disinfectants but relatively poor in vivo plaque inhibitors, compared to cationic organic antibacterial agents, e.g.
  • alkylamines e.g. fluoride of N,N,N'-tris-(2-hydroxyethyl)-N'-octadecyl-l,3-diaminopropane
  • cationic amidines e.g. water soluble salts of chlorhexidines, such as Hibitane, Alexidine and Vantocil.
  • the dihydrobenzofurane derivatives of the invention are active substances suitable for use in prevention and treatment of a number of diseases associated with oxidative stress in skin, such as psoriasis. Oxidative stress and its processes also play a key role in development of fibrosis in fibrotic disorders such as scleroderma, GVHD, hypertrophic scars, NSF, and other skin pathologies.
  • This invention further provides the novel phenolic derivatives for treating periodontal disease and preventing tooth decay, for removing, killing, or inhibiting the growth of pathogens causing periodontal disease and tooth decay.
  • the dihydrobenzofurane derivatives of the present invention are suitable for use in the treatment of tooth and skin diseases induced by periodontal bacteria and increased oxidative stress.
  • the object of this invention are phenolic dihydrobenzofurane derivatives of the general formula I, wherein
  • R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and allyl;
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, and allyl;
  • R 3 is selected from the group consisting of H, C1-C8 alkyl and C2-C7 alkenyl;
  • R 4 , R 5 are independently selected from the group consisting of H, hydroxy, and C1-C8 alkoxy; R 6 is selected from the group consisting of H, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, and C2- C7 alkenyl.
  • the compounds of formula I may be optically active.
  • Formula I includes these compounds in the form of racemates, in the form of optically active isomers, as well as in the form of any mixtures of the optically active isomers.
  • alkyl denotes a branched or linear alkyl chain containing 1 to 8 carbon atoms, preferably selected from the group comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl
  • alkenyl denotes a branched or linear alkenyl chain containing 2 to 7 carbon atoms, preferably selected from the group comprising vinyl, allyl, 1-propenyl, 1-methylethenyl, but-1 to 3-enyl, pent-1 to 4-enyl, isopentenyl, hex-1 to 5-enyl, hept-1 to 6-enyl
  • alkoxy denotes -O-R a , wherein R a is alkyl as defined here
  • the derivatives of the formula I are selected from the group consisting of dihydrobenzofurane derivatives of the general formula I wherein R 1 is methyl, ethyl, n-propyl, or isopropyl, R 2 is methyl, ethyl, n-propyl, or isopropyl, R 3 is hydrogen, methyl or ethyl, R 4 is hydrogen, methoxy or ethoxy, R 5 is hydrogen, methoxy or ethoxy, and R 6 is hydrogen, methoxy or ethoxy.
  • the dihydrobenzofurane derivatives of the general formula I are: methyl (2R,3R)-2-(4-hydroxyphenyl)-5-((E)-3-methoxy-3-oxoprop-l-en-l-yl)-2,3-dihydrobenzofuran-3- carboxylate; methyl (25,35)-2-(4-hydroxyphenyl)-5-((E)-3-methoxy-3-oxoprop-l-en-l-yl)-2,3- dihydrobenzofuran-3-carboxylate; ethyl (2R,3R)-2-(4-hydroxyphenyl)-5-((E)-3-methoxy-3-oxoprop- l-en-l-yl)-2,3-dihydrobenzofuran-3-carboxylate; ethyl (2S,3S)-2-(4-hydroxyphenyl)-5-((E)-3- methoxy-3-oxoprop
  • dihydrobenzofurane derivatives the general formula I are selected from the group containing : methyl (2R, 3R) -2 -(4-hydroxyphenyl) -5 -((E) -3 -methoxy-3 -oxoprop- 1 -en- 1 -yl) -2 , 3 - dihydrobenzofuran-3-carboxylate; ethyl (2R,3R)-5-((E)-3-ethoxy-3-oxoprop-l-en-l-yl)-2-(4- hydroxyphenyl)-2,3-dihydrobenzofuran-3-carboxylate; propyl (2R,3R)-2-(4-hydroxyphenyl)-5-((E)-3- oxo-3-propoxyprop-l-en-l-yl)-2,3-dihydrobenzofuran-3-carboxylate; isopropyl (2R,3R)-2-(4- hydroxyphenyl
  • the dihydrobenzofurane derivatives of the general formula I have a wide range of biological activities, including antioxidant, anti-inflammatory, antibacterial, antisenescent and antiaging activities which are especially useful in pharmaceutical and cosmetic applications.
  • the compounds of this invention possess antioxidant and antibacterial activities with improved selectivities and efficiencies and lower or no toxicities, compared to active compounds used heretofore.
  • the present invention includes the dihydrobenzofurane derivatives of the general formula I for use for inhibition of microorganisms present in the oral cavity and for inhibition of plaque formation on teeth and dental restorations, thus simultaneously improving the oral hygiene and suppressing the inflammation of gums (gingivitis).
  • the present invention includes the dihydrobenzofurane derivatives of the general formula I for use for (complete) inhibition of growth of plaque without irritating the oral mucosae and without staining the teeth.
  • the present invention includes the dihydrobenzofurane derivatives of the general formula I for inhibiting the growth or for killing bacteria within the oral cavity of an animal, including human, wherein a therapeutically effective amount of the dihydrobenzofurane derivatives of the general formula I is administered within the oral cavity for a time sufficient to effectively eradicate said bacteria.
  • this invention also provides dihydrobenzofurane derivatives of the general formula I for preventing or treating a disease caused by bacterial infection by administering an effective amount of the modulator (inhibitor) of bacterial growth of general formula I.
  • This invention further provides dihydrobenzofurane derivatives of the general formula I for inhibiting the growth or for killing bacteria
  • said bacteria are selected from the group comprising Porphyromonas gingivalis, Strep, mutans, Strep, pyogenes, Bacteroides species, Actinobacillus action mycetemcomitons, Prevotella intermedia, Fusobacterium nucleatum, Campylobacter rectus, Eikenella corrodens, Peptostreptoloccus micros, Selenomonas sp., Eubacterium sp., Streptococcus species, Spirochetes treponema denticola, and Treponema pallidum.
  • This invention further provides a toothpaste containing at least one dihydrobenzofurane derivative of the general formula I for treating periodontal disease and preventing tooth decay, wherein the toothpaste is applied to a human's or animal's teeth and gums for a time sufficient to remove, kill, or inhibit the growth of pathogens causing said periodontal disease and tooth decay.
  • This invention finally provides novel antibacterial toothpaste and mouthwash formulations comprising therapeutically effective amounts of one or more novel dihydrobenzofurane derivatives of general formula I and at least one auxiliary substance.
  • the toothpaste or mouthwash are suitable in particular for inhibiting the growth of or for eradicating pathogens in the oral cavity of humans and animals.
  • the present invention includes the dihydrobenzofurane derivatives of the general formula I for use for antiseptic treatment of oral cavity, for inhibition of inflammation of oral mucosae and/of for deodorizing the oral cavity.
  • This invention further provides pharmaceutical (including toothpaste and mouthwash) compositions comprising one or more compounds of the general formula I and at least one pharmaceutically acceptable carrier.
  • Suitable routes for systemic administration are oral, inhalation, topical, injectable (intra vasal, intramuscular, subcutaneous), buccal, sublingual, and nasal.
  • Solutions, creams and ointments are suitable formulations for the treatment of scalp and skin diseases.
  • Mouthwashes, toothpastes, chewing gums and solutions are suitable formulations for the oral cavity.
  • the therapeutic and/or cosmetic compositions generally comprise about 1% to about 95% of the active ingredient.
  • Single -dose forms of administration preferably comprise about 20% to about 90% of the active ingredient and administration forms which are not single-dose preferably comprise about 5% to about 20% of the active ingredient.
  • Unit dose forms are, for example, coated tablets, tablets, ampoules, vials or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilising processes.
  • solutions of the active ingredient, and in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions are used, it being possible for these to be prepared before use, for example in the case of lyophilised compositions which comprise the active substance by itself or together with a carrier, for example mannitol.
  • the compositions can be sterilized and/or comprise excipients, for example, preservatives, stabilisers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/or buffers, and they are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes.
  • the solutions or suspensions mentioned can comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatine.
  • Suspensions in oil comprise, as the oily component, vegetable, synthetic or semi-synthetic oils customary for injection purposes.
  • Oils which may be mentioned are, in particular, liquid fatty acid esters which contain, as the acid component, a long-chain fatty acid having 8-22, in particular 12-22, carbon atoms (e., lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, acid, arachidonic acid, behenic acid, and the like) or corresponding unsaturated acids (e.g., oleic acid, elaidic acid, euric acid, brasidic acid or linoleic acid).
  • antioxidants such as vitamin E, b-carotene, or 3,5-di- tert-butyl-4-hydroxytoluene, and the like.
  • the alcohol component of these fatty acid esters generally contains no more than about 6 carbon atoms and can be mono- or polyhydric.
  • Mono-, di-, or trihydric alcohols such as methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof, can be used; glycols and glycerols are generally preferred.
  • Fatty acid esters can therefore include, for example, ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefosee, Paris), "Labrafil M 1944 CS” (unsaturated polyglycolated glycerides prepared by an alcoholysis of apricot kernel oil and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris), “Labrasol” (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris), and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C8 to C12 from Hiils AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame
  • compositions intended for human use should, of course, be carried out in the customary and approved manner under sterile conditions, and maintained under appropriate conditions up to and including the time of use.
  • compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, if appropriate granulating the resulting mixture, and, if desired, processing the mixture or granules to tablets or coated tablet cores, if appropriate by addition of additional excipients.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium diphosphate, or calcium hydrogen phosphate, and furthermore binders, such as starches, for example maize, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, desintegrators, such as the above mentioned starches, and furthermore carboxymethyl-starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium diphosphate, or calcium hydrogen phosphate
  • binders such as starches, for example
  • Additional excipients are, in particular, flow regulators and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • flow regulators and lubricants for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Coated tablet cores can be provided with suitable coatings which, if appropriate, are resistant to gastric juice, the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings which are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be admixed to the tablets or coated tablet coatings, for example for identification or characterisation of different doses of active ingredient.
  • suitable coatings which, if appropriate, are resistant to gastric juice
  • the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coating
  • compositions which can be used orally, can also be in the form hard capsules of gelatine and soft, closed capsules of gelatine and a plasticiser, such as glycerol or sorbitol.
  • the hard capsules can contain the active ingredient in the form of granules, mixed for example with fillers, such as maize starch, binders and/or lubricants, such as talc or magnesium stearate, and stabilisers if appropriate.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as greasy oils, paraffin oil or liquid polyethylene glycol's or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilisers and detergents such as, for example, the polyethylene sorbitan fatty acid ester type.
  • suitable liquid excipients such as greasy oils, paraffin oil or liquid polyethylene glycol's or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilisers and detergents such as, for example, the polyethylene sorbitan fatty acid ester type.
  • oral forms of administration include, for example, syrups prepared in the customary manner, which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration which results in a suitable individual dose, for example, when 5 or 10 ml are measured out.
  • Other forms include pulverulent or liquid concentrates for preparing shakes, beverages, and the like. Such concentrates can also be packed in unit dose quantities.
  • compositions which are suitable for parental administration are aqueous solutions of an active ingredient in water-soluble form, for example of water-soluble salt, or aqueous injection suspensions, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate, stabilizers.
  • the active ingredient can also be present here in the form of a lyophilisate, if appropriate together with excipients, and be dissolved before parenteral administration by addition of suitable solvents.
  • Solutions such as are used, for example, for parental administration can also be used as infusion solutions.
  • Preferred preservatives are, for example antioxidants, such as ascorbic acid, or microbicides, such as sorbic or benzoic acid.
  • Ointments are oil-in-water emulsions, which comprise not more than 70%, but preferably 20 - 50% of water or aqueous phase.
  • the fatty phase consists, in particular, hydrocarbons, for example vaseline, paraffin oil or hard paraffin's, which preferably comprise suitable hydroxy compounds, such as fatty alcohol's or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax, to improve the water-binding capacity.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example, glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • humectants such as polyalcohols, for example, glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • Fatty ointments are anhydrous and comprise, as the base, in particular, hydrocarbons, for example paraffin, vaseline or paraffin oil, and furthermore naturally occurring or semi-synthetic fats, for example, hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or distearate, and for example, the fatty alcohols. They also can contain emulsifiers and/or additives mentioned in connection with the ointments which increase uptake of water.
  • hydrocarbons for example paraffin, vaseline or paraffin oil
  • furthermore naturally occurring or semi-synthetic fats for example, hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono
  • Creams are oil-in-water emulsions, which comprise more than 50% of water.
  • Oily bases used are, in particular, fatty alcohols, for example, lauryl, cetyl or stearyl alcohols, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil.
  • Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty esters (Tweens), and furthermore polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example, sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are usually used in the presence of fatty alcohols, for example cetyl stearyl alcohol or stearyl alcohol.
  • corresponding non-ionic emulsifiers for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene
  • Additives to the aqueous phase are, inter alia, agents which prevent the creams from drying out, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example, titanium oxide or zinc oxide, and furthermore talc and/or aluminium silicates, which have the task of binding the moisture or secretions present.
  • metal oxides for example, titanium oxide or zinc oxide
  • talc and/or aluminium silicates which have the task of binding the moisture or secretions present.
  • the formulations comprise at least one base component and an active ingredient comprising phenolic compound, preferably, a highly purified (i.e. 98% and greater purity, more preferably about 98.5% to 99% purity).
  • a preferred concentration range of lthe phenolic compound in the toothpaste formulations is from about 10% to about 40%.
  • the one or more base components employed in the tooth paste formulation include those typically found in conventional toothpastes, and thus the amounts and types of such base components are known by those of ordinary skill in the art.
  • Exemplary base components include, but are not limited to, (a) sorbitol, a polyol which functions as a humectant/sweetener; (b) water, which functions as a diluent; (c) silica (e.g.
  • ZEODENT vended by Huber Corp.
  • glycerin which also serves as a humectant
  • surfactants such as sodium lauryl sulfate or Polysorbate 20, for example
  • binders and viscosity agents such as CEKOL cellulose gum, xantham gum
  • preservatives such as sodium benzoate and methyl parabens, for example.
  • Flavoring and coloring agents may be employed, as well.
  • the toothpaste formulation further comprises a pharmaceutically acceptable calcium compound, preferably pure calcium and/or a pharmaceutically acceptable magnesium compound, such as magnesium phosphate, for promoting stronger teeth.
  • a pharmaceutically acceptable calcium compound preferably pure calcium and/or a pharmaceutically acceptable magnesium compound, such as magnesium phosphate, for promoting stronger teeth.
  • Preferable tooth paste formulations comprise from about 18% to about 22% percent limonene.
  • Preferable percentage amounts of calcium range from about 1.25% to about 1.50%.
  • Preferable percentage amounts of magnesium phosphate range from about 1.25% to about 1.50%.
  • Mouthwash formulations for the inventive mouthwash effective in treating bacterial infections in the mouth include an active ingredient comprising phenolic compound of the general formula I, preferably a highly purified form (i.e 98.0% or greater purity, more preferably 98.5% to 99.0%) and one or more base components commonly employed in mouthwash formulations.
  • an active ingredient comprising phenolic compound of the general formula I, preferably a highly purified form (i.e 98.0% or greater purity, more preferably 98.5% to 99.0%) and one or more base components commonly employed in mouthwash formulations.
  • Exemplary base components include (a) sorbitol; (b) polyethylene glycol (e.g. PEG 6) as a carrier and surfactant; (c) polysorbate (surfactant); (d) water (diluent); and (e) flavoring agents (e.g. sucralose).
  • a preferred formulation comprises (a) from about 15% to about 25% of sorbitol, (b) from about 10% to about 20% of polyethylene glycol, (c) from about 2.5% to about 7.5% Polysorbate 20, (d) from about 2.5% to about 15% d-limonene, (e) from about 45% to about 65% water, (f) from about 0.2% to about 0.5% sucralose, and about 1.0% to 2.0% Belwood Wintergreen.
  • Administration of the inventive mouthwash is similar to conventional mouthwashes (i.e. about 30 ml placed within the mouth and swished about therein for about 30 seconds prior to expectoration); however, the administrated dose and time within the mouth may be varied as desired.
  • Foams i.e., liquid oil-in-water emulsions packaged in aerosol form
  • Propellant gases include halogenated hydrocarbons, such as polyhalogenated alkanes such as dichlorofluoromethane and dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous hydrocarbons, air, N2O, or carbon dioxide.
  • halogenated hydrocarbons such as polyhalogenated alkanes such as dichlorofluoromethane and dichlorotetrafluoroethane
  • non-halogenated gaseous hydrocarbons air, N2O, or carbon dioxide.
  • the oily phases used are, inter alia, those mentioned above for ointments and creams, and the additives mentioned there are likewise used.
  • Tinctures and solutions usually comprise an aqueous-ethanolic base to which, humectants for reducing evaporation, such as polyalcohols (e.g., glycerol, glycols, polyethylene glycol) and re-oiling substances, such as fatty acid esters with lower polyethylene glycols (e.g., lipophilic substances soluble in the aqueous mixture) to substitute the fatty substances removed from the skin with the ethanol, and, if necessary or desired, other excipients and additives, are admixed.
  • humectants for reducing evaporation such as polyalcohols (e.g., glycerol, glycols, polyethylene glycol) and re-oiling substances, such as fatty acid esters with lower polyethylene glycols (e.g., lipophilic substances soluble in the aqueous mixture) to substitute the fatty substances removed from the skin with the ethanol, and, if necessary or desired, other ex
  • Veterinary carriers are materials for administering the composition and may be solid, liquid, or gaseous materials, which are inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.
  • the invention also relates to a process or method for treatment of the disease states mentioned above.
  • the compounds can be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount, which is effective against the diseases mentioned.
  • a warm-blooded animal for example, a human requiring such treatment
  • the compounds are used, in particular, in the form of pharmaceutical composition.
  • a daily dose of about 0.1 to about 5 g, preferably 0.5 g to about 2 g, of a compound of the present invention is administered here for a body weight of about 70 kg.
  • the starting materials may be obtained from commercial sources (Sigma, Aldrich, Fluka, etc.) or can be prepared as described below.
  • Thin-layer chromatography was carried out on Silica 60 F254 plates (Merck) using CHCF/MeOH as a developing system and the spots were detected by UV light (254 and 365 nm) and/or 6% vanilline in absolute EtOH containing 1 % of H2SO4.
  • the column chromatography purification was carried out by silica Davisil 40-63 micron (Grace Davision). Elemental analysis was determined using Flash EA 1112 analyzer (Thermo Scientific).
  • the chromatographic purity and mass of prepared compounds was determined using an Alliance 2695 separation module (Waters) linked simultaneously to a DAD detector PDA 996 (Waters) and a Q-Tof micro (Waters) benchtop quadrupole orthogonal acceleration time-of-flight tandem mass spectrometer. Samples were dissolved in DMSO and diluted to a concentration of 10 pg/ml in initial mobile phase.
  • the eluent was introduced into the DAD (scanning range 210-400 nm, with 1.2 nm resolution) and an ESI source (source temperature 110 °C, capillary voltage +3.0 kV, cone voltage +20 V, desolvation temperature 250 °C). Nitrogen was used both as desolvation gas (5001/h) as well as cone gas (501/h). The data was obtained in positive (ESI+) ionization mode in the 50-1000 m/z range.
  • Methyl coumarate (20g, 112 mmol, 0.5 equiv) was dissolved in CH2CI2/CHCI3 mixture (56 + 504 mL; 1/9 (V/V); 0.21 to ester) and the resulting mixture was stirred at RT for 5 min.
  • K3[Fe(CN)6] (87g, 270 mmol, 1.2 equiv) in saturated aqueous solution of NaHCCL (560 mL, 0.2M to ester). Resulted homogenous brown solution was placed to dropping funnel and the whole mixture was added at RT to methyl coumarate solution within a period of lh.
  • Example 2 Methyl (2R,3R)-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-5-((E)-3-methoxy-3-oxoprop- 1 -en-1 -yl)-2,3-dihydrobenzofuran-3-carboxylate (compound 9 in Table 1) Prepared according to Example 1.
  • Example 4 In vitro cytotoxic activity of novel compounds on normal and cancer animal cells Low cytotoxicity of the compounds to normal cells is important factor affecting their possible cosmetic use.
  • One of the parameters used, as the basis for cytotoxicity assays, is the metabolic activity of viable cells.
  • a microtiter assay which uses the Calcein AM, is now widely used to quantitate cell proliferation and cytotoxicity. For instance, this assay is used in drug screening programs and in chemosensitivity testing. Because only metabolically active cells cleave Calcein AM, these assays detect viable cells exclusively. The quantity of reduced Calcein AM corresponds to the number of vital cells in the culture.
  • BJ human foreskin fibroblasts
  • G361 human malignant melanoma
  • K562 human bone marrow chronic myelogenous leukemia
  • the cell suspensions that were prepared and diluted according to the particular cell type and the expected target cell density (2.500-30.000 cells per well based on cell growth characteristics) were added by pipette (80 m ⁇ ) into 96/well microtiter plates. Inoculates were allowed a pre -incubation period of 24 hours at 37 °C and 5% CO2 for stabilisation. Four-fold dilutions of the intended test concentration were added at time zero in 20 m ⁇ aliquots to the microtiter plate wells. Usually, the compound tested was evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 166.7 mM, but it can be the matter of change dependent on the agent. All compound concentrations were examined in duplicates.
  • Fow cytotoxicity (high IC50) is a prerequisite for the use of these substances in cosmetic and medical applications.
  • Zero cytotoxic activity has been found for the new derivatives in comparison with the classical phenolic substances known from the previous inventions (coumaric acid).
  • Table 2 Cytotoxicity of novel compounds for different cell lines/ICso (pmol/L)
  • lymphocytes One of the most important parameters of specific cellular immunity is proliferative response of lymphocytes to antigens or polyclonal mitogens.
  • the majority of normal mammalian peripheral lymphocytes comprise resting cells.
  • Antigens or nonspecific polyclonal mitogens have the capacity to activate lymphoid cells and this is accompanied by dramatic changes of intracellular metabolism (mitochondrial activity, protein synthesis, nucleic acids synthesis, formation of blastic cells and cellular proliferation).
  • Compounds with ability to selectively inhibit lymphocyte proliferation are potent immunosuppressants. Variety of in vitro assays was developed to measure proliferative response of lymphocytes. The most commonly used is 3 H -thymidine incorporation method.
  • Human heparinized peripheral blood was obtained from healthy volunteers by cubital vein punction. The blood was diluted in PBS (1:3) and mononuclear cells were separated by centrifugation in Ficoll- Hypaque density gradient (Pharmacia, 1.077 g/ml) at 2200 rpm for 30 minutes. Following centrifugation, lymphocytes were washed in PBS and resuspended in cell culture medium (RMPI 1640, 2mM glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 10% fetal calf serum and sodium bicarbonate).
  • RMPI 1640 2mM glutamine
  • penicillin 100 ⁇ g/ml
  • streptomycin 10% fetal calf serum and sodium bicarbonate
  • the cells were diluted at target density of 1.100.000 cells/ml were added by pipette (180 ⁇ l) into 96/well microtiter plates. Four-fold dilutions of the intended test concentration were added at time zero in 20 m ⁇ aliquots to the microtiter plate wells. Usually, test compound was evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 266.7 mM. All drug concentrations were examined in duplicates. All wells with exception of unstimulated controls were activated with 50 m ⁇ of concanavalin A (25 ⁇ g/ml). Incubations of cells with test compounds lasted for 72 hours at 37 °C, in 5% CO 2 atmosphere and 100% humidity. At the end of incubation period, the cells were assayed by using the [ 3 H]TdR:
  • ED immunosuppressant
  • Example 7 Activation of transcription factor Nrf2
  • the ability of compounds to activate Nrf2-dependent expression was determined by EpRE-LUX reporter cell line. In brief, compounds at 100, 10, 1 and 0.1 mM concentrations were incubated for 24 h with cells. After cells lysis (10 mM Tris, 2 mM DTT), a buffer containing 0.2 mM luciferin was added to start luminescent reaction. The increase in luminescence was measured with microplate reader Infinite M200 (TEC AN). Compounds with Nrf2 value higher than 1 are more effective than dime thylfumar ate (DMF), a strong Nrf2 activator approved for the treatment of psoriasis and multiple sclerosis.
  • DMF dime thylfumar ate
  • Example 8 Antimicrobial activity Antimicrobial activities of the synthesized compounds were assessed using the standard dilution micromethod. Disposable microtitration plates were used for the tests. The compounds (10 mM) were diluted 50 times with Breath heart infusion broth (3.675 pL) for diluting the concentration of DMSO below 5%, which does not affect the growth of bacteria and then 2-128 times with an additional Breath heart infusion broth (50 pL) inoculated with the tested bacteria/yeast/mould at a concentration of 105-106 CFU mL -1 . Tested concentrations of compounds were 1.56 pM-200 pM. The concentrations of substances tested were 10 to 2000 pM. The minimum inhibitory concentration (MIC) of bacteria, yeast and fungi was read after 48 hours incubation at 30 °C.
  • MIC minimum inhibitory concentration
  • Staphylococcus aureus CCM 3953 >1000 >1000 250 Staphylococcus epidermidis CCM 7221 >1000 >1000 250 Enterococcus faecalis CCM 4224 >1000 >1000 500 Listeria monocytogenes CCM 4699 >1000 >1000 500 Bacillus cereus CCM 2010 250 31 250 Pseudomonas aeruginosa CCM 3955 >1000 >1000 >1000 Escherichia coli CCM 3954 >1000 >1000 500 Clostridium perfringens CCM 5744 >1000 >1000 250 Fusobacterium simiae CCM 3660 >1000 >1000 500 Candida albicans ATCC 90028 1000 >1000 500 Aspergilus niger CCM 8189 >1000 >1000 500 Example 9 Ames test
  • the test substances was (1, 2, 3, 4) assayed for the mutagenicity by the Bacterial Reverse Mutation Test.
  • the performed test was based on EU method B.13/14 Mutagenicity - Reverse mutation test using bacteria, which is analogous to the OECD Test Guideline No. 471.
  • Four indicator Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and one indicator Escherichia coli WP2 uvrA strain were used.
  • the test substance was dissolved in dimethylsulfoxide (DMSO) and assayed in doses of 10-1000 pg per plate, which were applied to plates in volume of 0.1 mL.
  • DMSO dimethylsulfoxide
  • the test substance 1 was assayed for in vitro skin irritation in the human epidermal model EpiDermTM.
  • the test was performed according to the OECD Test Guideline No. 439: In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method (2015) and Protocol for: In Vitro EpiDermTM Skin Irritation Test For use with MatTek Corporation's Reconstructed Human Epidermal Model EPI-200- SIT (see par. 1.4). In initial experiments either direct MTT reduction or colour interference were not found. In main experiment after pre -incubation of tissues, 25 mg of the test item was placed directly on previously moistened tissues and spread on the entire tissue surface. The length of exposure was 60 minutes. Three tissues were used for the test item and for positive and negative controls.
  • test substance 1 After removal of the test item, tissues were post-incubated for approximately 42 hours. Three hours incubation with MTT and two hours extraction period with shaking followed then. Optical density (OD570) of isopropyl alcohol extracts was measured on a spectrophotometer. Relative cell viability was calculated for each tissue as % of the mean viability of the negative control tissues. Under the above -described experimental design average viability of treated tissues was 96.0%, i.e. viability was > 50% The effect of the test item was negative in EpiDermTM model (tissues were not damaged). According to the classification criteria given in chapter 4.5. of this report, the test substance 1, is considered to have no category in regard to skin irritation.
  • a mouthwash formulation was manufactured by combining the following components:
  • a preferred toothpaste formulation comprises from about 10% to about 40% d-limonene (98.0% or higher purity, more preferably 98.5%-99.0%); from about 15% to about 35% of sorbitol; from about 15% to about 30% of a silica agent (e.g. ZEODENT 113 and ZEODENT 165), from about 10% to about 20% water; from about 5% to about 15% glycerin, from about 2% to about 7% of surfactant (e.g. Polysorbate 20), from about 1% to about 2% flavoring agent (including sodium saccharin), from about 0.5% to about 1.5% of titanium dioxide, from about 0.5% to about 1.5% of binder (e.g. CEKOL 2000 gum), from about 0.05% to about 0.15% of a preservative (e.g. sodium benzoate), from about 0.25% to about 1.75% of pure calcium, and from about 0.10% to about 1.75% of magnesium phosphate.
  • a silica agent e.g. ZEODENT
  • a toothpaste formulation was manufactured by combining the following components:
  • the foregoing components were combined as follows: the sodium saccharin and sodium benzoate were dissolved in the water and set aside. The Cekol and glycerin were combined, and, while mixing these two components together, the polyol was added. The solution of sodium saccharin and sodium benzoate were then added to the Cekol/glycerin, and polyol mixture. Next, Zeodent 165 was added to the mixture and blended in well, followed by the Zeodent 113, which in turn was blended in well until the mixture was free of lumps. Titanium dioxide, Polysorbate 20, and d-limonene were combined with the mixture and blended until the mixture was smooth. Finally, the calcium and magnesium phosphate was added, followed by the flavoring agent (i.e. Flavor 484).
  • the flavoring agent i.e. Flavor 484
  • the growth regulatory formulations usually contain from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of active ingredient mixture comprising a new phenolic derivative of this invention, from 1 to 99.9% by weight of a solid or liquid formulation adjuvant, and from 0 to 25% by weight, especially from 0.1 to 25% by weight, of a surfactant. Whereas commercial products are usually formulated as concentrates, the end user will normally employ dilute formulations.
  • compositions may also comprise further ingredients, such as stabilizers, e.g., vegetable oils or epoxidised vegetable oils (epoxidised coconut, rapeseed oil or soybean oil), antifoams, e.g., silicone oil, preservatives, viscosity regulators, binders, tackifiers, and also fertilisers or other active ingredients.
  • stabilizers e.g., vegetable oils or epoxidised vegetable oils (epoxidised coconut, rapeseed oil or soybean oil)
  • antifoams e.g., silicone oil, preservatives, viscosity regulators, binders, tackifiers, and also fertilisers or other active ingredients.
  • Composition Active ingredient: 1250 g; Talc:180 g; Wheat starch:120 g; Magnesium stearate:80 g; Lactose 20 g.
  • Preparation process The powdered substances mentioned are pressed through a sieve of mesh width 0.6 mm. Portions of 0.33 g of the mixture are transferred to gelatine capsules with the aid of a capsule-filling machine.
  • composition 250 g Active ingredient + 2 litres Lauroglycol
  • Preparation process The powdered active ingredient is suspended in Lauroglykol ® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet-pulveriser to a particle size of about 1 to 3 mm. Portions of in each case 0.419 g of the mixture are then transferred to soft gelatine capsules by means of a capsule-filling machine.
  • Lauroglykol ® propylene glycol laurate, Gattefosse S.A., Saint Priest, France
  • composition 250 g Active ingredient +1 litre PEG 400 +1 litre Tween 80
  • Preparation process The powdered active ingredient is suspended in PEG 400 (polyethylene glycol of Mr between 380 and about 420, Sigma, Fluka, Aldrich, USA) and Tween ® 80 (polyoxyethylene sorbitan monolaurate, Atlas Chem. Inc., Inc., USA, supplied by Sigma, Fluka, Aldrich, USA) and ground in a wet-pulveriser to a particle size of about 1 to 3 mm. Portions of in each case 0.43 g of the mixture are then transferred to soft gelatine capsules by means of a capsule-filling machine.
  • PEG 400 polyethylene glycol of Mr between 380 and about 420, Sigma, Fluka, Aldrich, USA
  • Tween ® 80 polyoxyethylene sorbitan monolaurate, Atlas Chem. Inc., Inc., USA, supplied by Sigma, Fluka, Aldrich, USA
  • the gel consistence may be additionally modified by addition of silica colloidalis anhydrica. It is again expected that the transdermal Transcutol P/Lauroglycol FCC system will increase the efficiency of compound 1. Silica colloidalis anhydrica will probably slow down the penetration of the active substance.
  • Example 15 Preparation procedure of a skin ointment The formulation components are given in grams per 200 g:
  • Phase A 2 grams of phenolic derivative 1 was dissolved in 20 g of Transcutol P while stirring continuously at room temperature in a separate glass or stainless-steel container. The dissolution process may be accelerated by heating the solution to a maximal temperature of 40°C.
  • Phase B 0.4 grams of Nipanox BHT and 0.4 g of Nipabutyl were dissolved while stirring continuously in 133.2 g of Lauroglycol FCC at a temperature of approximately 70°C in another separate glass or stainless-steel container. The clear oily solution is heated to a temperature of approximately 80°C and 44 g of Compritol 888 ATO are melted in it while stirring continuously.
  • composition for topical application to the skin contains the following ingredients by weight%:
  • Active ingredient Compound 1 0.1 %
  • Oil phase Cetyl alcohol 5.0 % Glyceryl monostearate 15.0 %
  • Aqueous phase Methylcellulose 100 cps 1.0 %
  • Methyl paraben and propyl paraben were dissolved in hot water and subsequently methylcellulose was dispersed in the hot water.
  • the mixture was chilled at 6°C until the methylcellulose dissolved.
  • the mixture was then heated to 72°C and added to the oil phase which was heated to 70°C while stirring continuously.
  • the phenolic derivative 1 was added at a temperature of 35°C and the resulting mixture was stirred continuously until dispersed.
  • This composition is applied to the skin on at least a daily basis until the desired skin-ameliorating effect is reached (gains aging).

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EP20714469.2A 2019-12-04 2020-03-13 Phenolic dihydrobenzofurane derivatives, medical and cosmetic preparations containing these derivatives, and use thereof Pending EP4069370A1 (en)

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