Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
  • A61K6/69—Medicaments
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
  • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • 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
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• Phenylpropanoid derivatives Technical Field
• the invention relates to novel phenylpropanoid derivatives, use thereof in medicine, cosmetics and biotechnology, and compositions containing these derivatives.
• Phenylpropanoids are the largest group of secondary metabolites produced by plants, in particular in response to biotic or abiotic stresses, wounding, UV irradiation, exposure to ozone, pollutants, and other environmental conditions. It is thought that the molecular basis for the protective action of phenylpropanoids in plants are their antioxidant and free radical scavenging properties. The phenylpropanoids are also major biologically active components of human diet and traditional medicines.
• Dental plaque is an adherent bacterial film, and is the main pathological agent for periodontal diseases.
• the formation of dental plaque can occur both supragingivally and subgingivally.
• the development of plaque is a three-step process. Following the formation of a pellicle, pioneer micro-organisms adhere to the pellicle, proliferate and form colonies. The final stage involves the aggregation of filamentous organisms and spirochetes into a cohesive biofilm.
• plaque bacteria Many products of the plaque bacteria reach the subepithelial tissue, causing inflammatory responses such as increased vascularity and leukocyte diapedesis. Both supragingival and subgingival plaque may form a hard, mineralized mass called calculus. The surface of calculus harbours bacteria, which may exacerbate the inflammatory response.
• An effective oral antiseptic must be active against a wide range of Gram-positive and Gram-negative bacterial species, including streptococci and fusobacteria. Ideally, an effective agent would also penetrate the plaque biofilm. Data show that essential oil and chlorhexidine mouthwashes have the broadest antimicrobial effects (Elkerbout et al., Int. J. Dent. Hyg.17, 3–15, 2019).
• Bacteria present in the oral biofilm are implicated in the pathogenesis of oral diseases, such as dental caries, periodontal diseases such as gingivitis and periodontitis, and even halitosiss.
• oral diseases such as dental caries, periodontal diseases such as gingivitis and periodontitis, and even halitosiss.
• effective biofilm control is important for preventing these conditions.
• Manual or power tooth brushing is recommended as the primary means of reducing plaque and gingivitis; however, effective mechanical plaque control is time consuming and requires motivation and dexterity-related skills (Farah et al., Australian Prescriber vol. 32 162–164 (2009). This is why chemical plaque control utilizing antimicrobial agents is important to complement the results of mechanical oral hygiene measures (Chye et al., Implant Dentistry vol.2874–85, 2019).
• mouthwashes In dentistry, oral rinses containing antimicrobials function by chemomechanical action, and are used for both preventative and therapeutic purposes. Mouthwashes act as an ideal medium for all inaccessible areas in the mouth and are necessary in order to allow proper wound healing in situations where oral hygiene is difficult or compromised (Van Der Weijden et al., Dent. Clin. NA 59, 799–829, 2015). Generally speaking, there are two types of mouthwash products: cosmetic and therapeutic. Cosmetic mouthwashes lack active ingredients that provide a true chemical or biological application, they may temporarily control bad breath by leaving a pleasant taste, but they do not kill the bacteria associated with it (Joshipuraet al., Nitric Oxide 71, 14–20, 2017).
• therapeutic mouthwashes contain active ingredients, such as cetylpyridinium chloride (CPC), chlorhexidine (CHX), fluoride, and peroxide.
• CPC cetylpyridinium chloride
• CHX chlorhexidine
• fluoride fluoride
• peroxide peroxide
• cosmetic mouthwashes cannot act as an antimicrobial and lack the bacteriostatic and bacteriocidal benefits that are provided by therapeutic mouthwashes.
• a therapeutic mouthwash is prescribed by a clinician, it is often short-term, and always evidence based for addressing specific conditions.
• the therapeutic mouthwashes are clinically effective in reducing dental biofilm accumulation, as well as an adjunct in the treatment of halitosis and periodontal disease, such as gingivitis and periodontitis (Elkerbout et al., Int. J. Dent.
• the present invention provides novel phenylpropanoid compounds showing strong antioxidative properties and/or exhibiting the ability to regulate expression of an importat stress transcription factor NRF2.
• the phenylpropanoid compounds of the invention are suitable for use in prevention and treatment of a number of diseases associated with oxidative stress in skin, for example, 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 phenylpropanoid 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 phenylpropanoid compounds of the present invention are thus 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 derivatives of phenylpropanoids of the general formula I, wherein each of R 1 , R 2 , R 3 is indenpendently selected from the group consisting of H, hydroxy, and C1-C8 alkoxy; R 4 is selected from –O-R 5 and –N(R 6 )(R 7 ); R 5 is selected from the group consisting of H, C1-C8 alkyl, C2-C7 alkenyl, and -CH[(CH 2 ) 0- 2 (COO(C1-C4 alkyl))][(CH 2 ) 0-2 (COO(C1-C4 alkyl))]; R 6 and R 7 is selected from the group consisting of H, C1-C8 alkyl, and C2-C7 alkenyl, or R 6 and R 7 together form -(CH 2 ) 3-6 -; and pharmaceutically acceptable salts thereof.
• each of R 1 , R 2 , R 3 is indenpendently selected from the group consisting of H, hydroxy, methoxy and ethoxy.
• R 1 is hydrogen, hydroxy, methoxy or ethoxy
• R 2 is hydroxy, or methoxy
• R 3 is hydrogen, hydroxy, methoxy or ethoxy.
• R 5 is selected from methoxy, ethoxy, allyl, and -CH[(CH 2 )(COO(C1-C4 alkyl))][(COO(C1-C4 alkyl))].
• R 6 and R 7 together form -(CH 2 ) 5 -.
• Some compounds of formula I may be optically active. When R 4 contains a center of chirality, 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 the indicated number 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 herein, preferably alkoxy is selected from the group comprising me
• the phenylpropanoid derivatives of the general formula I are: methyl (2E,4E)-5-(4-hydroxyphenyl)penta-2,4-dienoate, methyl (2E,4E)-5-(4-methoxyphenyl)penta-2,4- dienoate, methyl (2E,4E)-5-(3,4-dihydroxyphenyl)penta-2,4-dienoate, methyl (2E,4E)-5-(4-hydroxy- 3-methoxyphenyl)penta-2,4-dienoate, methyl (2E,4E)-5-(3,4-dihydroxy-5-methoxyphenyl)penta-2,4- dienoate, methyl (2E,4E)-5-(4-hydroxy-3,5-dimethoxyphenyl)penta-2,4-dienoate, methyl (2E,4E)-5- (3,4,5-trimethoxyphenyl)penta
• the most preferred phenylpropanoid derivatives of the general formula I are selected from: methyl (2E,4E)-5-(4-hydroxyphenyl)penta-2,4-dienoate, methyl (2E,4E)-5-(4-methoxyphenyl)penta- 2,4-dienoate, methyl (2E,4E)-5-(4-hydroxy-3,5-dimethoxyphenyl)penta-2,4-dienoate, methyl (2E,4E)- 5-(3,4,5-trimethoxyphenyl)penta-2,4-dienoate, methyl (2E,4E,6E)-7-(4-hydroxy-3,5- dimethoxyphenyl)hepta-2,4,6-trienoate, ethyl (2E,4E,6E)-7-(4-hydroxy-3-methoxyphenyl)hepta-2,4,6- trienoate, dimethyl (S)-2-(((2E))
• the phenylpropanoid derivatives of the general formula I have a wide range of biological activities, including antioxidant, antibacterial, anti-inflammatory activities which are especially useful in pharmaceutical and cosmetic applications.
• the present invention provides phenylpropanoid derivatives of the general formula I for use as medicaments. More specifically, the present invention provides phenylpropanoid derivatives of the general formula I for use in the treatment of psoriasis, scleroderma, GVHD, hypertrophic scars, NSF, periodontal disease and in the prevention of tooth decay.
• the present invention includes the phenylpropanoid derivatives of the general formula I for use for inhibition of oral microorganisms and of plaque formation on teeth and dental restorations, thus simultaneously improving oral hygiene and suppressing inflammation of gums (gingivitis).
• the present invention includes the phenylpropanoid derivatives of the general formula I for use in inhibition of growth of plaque.
• the present invention includes the phenylpropanoid derivatives of the general formula I for inhibiting the growth or for killing bacteria within the oral cavity of an animal, including a human, wherein a therapeutically effective amount of at least one phenylpropanoid derivative of the general formula I is administered within the oral cavity for a time sufficient to effectively eradicate said bacteria.
• this invention also provides phenylpropanoid derivatives of the general formula I for preventing or treating a disease caused by bacterial infection by administering an effective amount of a compound of general formula I.
• This invention further provides phenylpropanoid derivatives of the general formula I for inhibiting the growth or for killing bacteria wherein said bacteria are selected from the group of Streptococcus mitis, Streptococcus mutans, Streptococcus sanguinis, Lactobacillus acidophilus, Actinomyces odontolyticus, Peptostrepococcus anaerobius, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Listeria monocytogenes, Bacillus cereus, Escherichia coli, Clostridium perfringens, Fusobacterium simiae, Candida albicans, Aspergilus niger.
• This invention further provides a toothpaste or mouthwash containing phenylpropanoid derivatives of the general formula I and phenylpropanoid for treating periodontal disease and preventing tooth decay, wherein an effective amount of the toothpaste formulation 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 or mouthwash formulations comprising therapeutically effective amounts of one or more novel phenylpropanoid 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 phenylpropanoid 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 phenylpropanoid derivative of the general formula I and a pharmaceutically acceptable carrier system.
• Suitable routes for administration include oral, topical, dermal, buccal and sublingual.
• Suitable formulations for scalp and skin disease therapy include solutions, creams and ointments.
• Suitable formulations for oral cavity disease treatment include mouthwashes, toothpastes, chewing gums and solutions.
• 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.
• 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).
• a long-chain fatty acid having 8-22, in particular 12-22 carbon atoms
• 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
• unsaturated acids e.g
• antioxidants such as vitamin E, ⁇ -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 Gattefoseé, 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 Gattefoseé, Paris), “Labrasol” (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of glycerides and polyethylene glycol esters; from Gattefoseé, Paris), and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil,
• 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.
• pharmaceutical 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.
• 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.
• 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. 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.
• 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
• 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.
• 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.
• the formulations comprise at least one base component and an active ingredient comprising phenolic compound, preferably, highly purified (i.e.
• 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.
• 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, N 2 O, or carbon dioxide.
• halogenated hydrocarbons such as polyhalogenated alkanes such as dichlorofluoromethane and dichlorotetrafluoroethane
• non-halogenated gaseous hydrocarbons air, N 2 O, 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. With 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 following examples serve to illustrate the invention without limiting the scope thereof. Unless otherwise stated, all percentages and the like amounts are based on weight.
• the starting materials may be obtained from commercial sources (Sigma, Aldrich, Fluka, etc.) or can be prepared by known procedures.
• Thin-layer chromatography was carried out on Silica 60 F 254 plates (Merck) using n-hexane/EtOAc 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 H 2 SO 4 .
• 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 ⁇ g/ml in initial mobile phase.
• the samples (10 ⁇ l) were injected on a RP-column Symmetry C18 (150 mm x 2.1 mm x 3.5 ⁇ m, Waters) and separated at a flow rate of 0.2 ml/min with following binary gradient: 0 min, 10% B; 0-24 min, a linear gradient to 90% B, followed by 10 min isocratic elution of 90% B.
• the column was re-equilibrated to initial conditions. 15 mM formic acid adjusted to pH 4.0 by ammonium hydroxide was used as solvent (A) and methanol as the organic modifier (solvent B).
• 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 (500 l/h) as well as cone gas (50 l/h). The data was obtained in positive (ESI+) ionization mode in the 50-1000 m/z range.
• the reactions were carried out in 30 mL glass vials sealed with an Silicone/PTFE Vial caps top, which can be exposed to a maximum of 250 °C and 20 bar internal pressure. The temperature was measured with an IR sensor on the outer surface of the process vial. After the irradiation period, the reaction vessel was cooled to ambient temperature by gas jet cooling. General method for aldehyde synthesis This protocol was applied if a commercially unavailable aldehyde was used to prepare targeted structures of formula I.
• Example 1 Methyl (2E,4E)-5-(4-hydroxyphenyl)penta-2,4-dienoate (compound 5 in Table 1)
• Method A A suspension of (E)-3-(4-hydroxyphenyl)acrylaldehyde (0.741 g, 5.00 mmol, 1.0 equiv) and stabilized Wittig ylide (1.84 g, 5.5 mmol, 1.1 equiv) in toluene (5.0 mL, 1.0 M to aldehyde) was placed in a microwave vial (35 mL) equipped with a magnetic stirring bar. The vial was sealed an Silicone/PTFE Vial cap and placed in a CEM Discover reactor.
• Method B A solution of (E)-3-(4-hydroxyphenyl)acrylaldehyde (5.0 g, 33.7 mmol, 1.0 equiv) and malonic acid (5.27 g, 50.6 mmol, 1.5 equiv) in pyridine (10 mL, 3.5M to aldehyde) was stirred at RT for 5 min. Piperidine (0.58 mL, 5.1 mmol, 0.15 equiv) was added and the resulting mixture was stirred at 85°C in Schlenck tube for 8.5h. The resulting mixture was cooled to RT and the Schlenck tube was carefully opened and its contain was poured into ice/water bath (100g/150 mL placed in 500mL beaker).
• Example 8 methyl (2E,4E,6E)-7-(4-methoxyphenyl)hepta-2,4,6-trienoate (compound 20 in Table 1) Prepared according to Example 1.
• BJ human foreskin fibroblasts
• G361 human malignant melanoma
• MCF7 human breast cancer
• CEM human T cell 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 ⁇ l) into 96/well microtiter plates. Inoculates were allowed a pre-incubation period of 24 hours at 37 °C and 5% CO 2 for stabilisation. Four-fold dilutions of the intended test concentration were added at time zero in 20 ⁇ l 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 66.7 ⁇ M, but it can be the matter of change dependent on the agent. All compound concentrations were examined in duplicates.
• Example 13 Antiinflammatory activity
• 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.
• 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). The cells were diluted at target density of 1.100.000 cells/ml were added by pipette (180 ⁇ l) into 96/well microtiter plates.
• test compound was evaluated at six 4-fold dilutions. In routine testing, the highest well concentration was 266.7 ⁇ M. All drug concentrations were examined in duplicates. All wells with exception of unstimulated controls were activated with 50 ⁇ l 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.
• the cells were assayed by using the [ 3 H]TdR:
• Cell cultures were incubated with 0.5 ⁇ Ci (20 ⁇ l of stock solution 500 ⁇ Ci/ml) per well for 6 hours at 37 °C and 5% CO 2 .
• the automated cell harvester was used to lyse cells in water and adsorb the DNA onto glass-fiber filters in the format of microtiter plate.
• the DNA incorporated [ 3 H]TdR was retained on the filter while unincorporated material passes through.
• the filters were dried at room temperature overnight, sealed into a sample bag with 10-12 ml of scintillant.
• the amount of [ 3 H]TdR present in each filter was determined by scintillation counting in a Betaplate liquid scintillation counter.
• the ED 50 value the drug concentration inhibiting proliferation of 50% of lymphocytes, was calculated from the obtained dose response curves.
• To evaluate antiinlammatory activity of novel phenolic derivatives their ability to inhibit polyclonal mitogen induced proliferation of normal human lymphocytes was analyzed (Tab. 3).
• Disposable microtitration plates were used for the tests.
• the compounds (10mM) were diluted 50times with Breath heart infusion broth (3.675 ⁇ L) for diluting the concentration of DMSO below 5%, which does not affect the growth of bacteria and then 2–128times with an additional Breath heart infusion broth (50 ⁇ L) inoculated with the tested bacteria/yeast/mould at a concentration of 105–106CFUmL ⁇ 1 .
• Tested concentrations of compounds were 1.56 ⁇ M–200 ⁇ M.
• the minimum inhibitory concentration (MIC) of aerobic bacteria was read after 24h of incubation at 37°C as the minimum inhibitory concentration (MIC) of the tested substance that inhibited the growth of the bacterial strain.
• Example 17 Antimicrobial activity of novel compounds against different dental pathogens expressed as MIC ( ⁇ M)
• Example 17 Ames test The test substances was (1, 2, 12, 21) 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.
• test substance was dissolved in dimethylsulfoxide (DMSO) and assayed in doses of 10-1000 ⁇ g per plate, which were applied to plates in volume of 0.1 mL.
• DMSO dimethylsulfoxide
• Experiments were performed without as well as with metabolic activation with a supernatant of rat liver and a mixture of cofactors.
• the working procedure described is in accordance with the documents Method B.13/14, Mutagenicity: Reverse Mutation Test Using Bacteria, Council Regulation (EC) No.440/2008. Published in O.J. L 142, 2008 and OECD Test Guideline 471, Bacterial Reverse Mutation Test. Adopted July 21, 1997.
• Example 18 Mouthwash formulation A mouthwash formulation was manufactured by combining the following components (amounts in wt.%): Polyol 20.0% PEG 6/Ultra PEG 300 15.0% Polysorbate 20 5.0% Compound of formula I 5.0% Water 52.7% Sucralose 0.30% Belwood Wintergreen 2.0%
• Toothpaste formulations A preferred toothpaste formulation comprises 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; and may further comprise from about 10% to about 40% d-limonene (98.0% or higher purity, more preferably 98.5%-99.0%). Amounts are in wt.%.
• An example toothpaste formulation was manufactured by combining the following components: 25.00% polyol (sorbitol) 20.00% Zeodent 113 (silica abasive) 2.00% phenolic derivative (compound 1, at least 99.5% purity) 13.39% water 10.00% Glycerin Natural 5.00% Polysorbate 20 2.70% Zeodent 165 (silica abrasive) 1.00% Flavor 484 (Walmart brand) 1.00% titanium dioxide 1.00% CMC 9M31XF/Cekol 2000 (binder gum) 0.45% pure calcium 0.25% saccharin 0.11% magnesium phosphate 0.10% sodium benzoate The foregoing components were combined as follows: the sodium saccharin and sodium benzoate were dissolved in the water and set aside.
• Example 20 Gel formulation An ointment formulation was tested during a pilot clinical study with 4 volunteers with psoriatic skin disorders.
• Example 22 Preparation procedure of a skin ointment
• the formulation components are given in grams per 200 g: Recommended procedure Phase A: 2 grams of phenylpropanoid 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.
• the clear oily solution is cooled down to approximately 60°C and during continuous stirring and cooling down is mixed with phase A.
• the resulting whitish ointment-like substance is divided into approximately 15 gram portions and filled into prearranged plastic containers.
• Example 23 Formulation of a composition for topical application to the skin
• a 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 % Sorbitan monooleate 0.3 %
• Aqueous phase Methylcellulose 100 cps 1.0 % Methyl paraben 0.25 % Propyl paraben 0.15 %
• Purified water q.s. to 100 % 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 phenylpropanid 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.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Emergency Medicine (AREA)
• Birds (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Dermatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=81254761

Family Applications (1)

Country Status (2)

Citations (1)

Family Cites Families (4)

• 2022
  • 2022-01-04 CZ CZ2022-5A patent/CZ309814B6/cs not_active IP Right Cessation
  • 2022-03-10 WO PCT/CZ2022/050027 patent/WO2023131362A1/en active Application Filing

Patent Citations (1)

Non-Patent Citations (15)

Also Published As

Similar Documents

Legal Events