WO2023055020A1 - Composition pharmaceutique pour la prévention ou le traitement de maladies vasculaires, comprenant un composé à base de piperlongumine comme principe actif - Google Patents

Composition pharmaceutique pour la prévention ou le traitement de maladies vasculaires, comprenant un composé à base de piperlongumine comme principe actif Download PDF

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WO2023055020A1
WO2023055020A1 PCT/KR2022/014420 KR2022014420W WO2023055020A1 WO 2023055020 A1 WO2023055020 A1 WO 2023055020A1 KR 2022014420 W KR2022014420 W KR 2022014420W WO 2023055020 A1 WO2023055020 A1 WO 2023055020A1
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주성수
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to the use of piperongumine-based compounds for the treatment of vascular diseases.
  • Vascular diseases refer to diseases caused by narrowing of blood vessels, and include diseases caused by blood clots such as blood clots or accumulation of fat that obstruct blood flow, resulting in poor supply of gas and nutrients to tissues. .
  • Other causes of narrowing of the blood vessels include inflammation and necrosis of the arteries and vasospasm that suddenly becomes denser.
  • a representative example of such vascular diseases is arteriosclerosis.
  • Atherosclerosis is a condition in which arteries become narrow enough to severely reduce blood supply to vital organs such as the heart, brain, and intestines. When this phenomenon occurs in the blood vessels of the brain, a stroke occurs, and when it occurs in the heart, myocardial infarction or angina pectoris occurs. In addition, when an artery is completely blocked, necrosis may occur in each part of the body that is supplied with blood by the artery.
  • Arteriosclerosis may be caused by a complex action of various risk factors such as hypertension, diabetes, hypercholesterolemia, smoking, and obesity, which is an inflammatory disease that commonly occurs in blood vessels.
  • Arteriosclerosis can be prevented by treatment with drugs such as statins along with antiplatelet agents, and angioplasty and stunt implantation to widen blood vessels are used as active treatments.
  • MCP-1 monocyte chemoattractant protein-1
  • statin treatment Bacillus subtilis
  • heme oxygenase-1 (HO-1) protein has also been identified by various studies.
  • HO-1 heme oxygenase-1
  • plaque formation and lipid peroxidation are suppressed, and HO-1 expression as well as inhibition of monocyte adhesion or invasion of leukocytes to the vessel wall It has been reported that the formation of arteriosclerosis is suppressed in rats induced by .
  • An object of the present invention is to provide a use of piperongumine-based compounds for the treatment of vascular diseases.
  • the present invention provides a pharmaceutical composition for preventing or treating vascular disease comprising a compound represented by Formula 1 below, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient:
  • R 2 to R 4 are the same as or different from each other, and are each independently hydrogen, heavy hydrogen, halogen, nitro group, hydroxyl group, amino group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group, C 2 ⁇ C 40 alkynyl group, C 3 ⁇ C 40 cycloalkyl group, heterocycloalkyl group having 3 to 40 nuclear atoms, C 1 ⁇ C 20 alkoxy group, C 1 ⁇ C 20 ketone group, C 1 ⁇ C 20 ester group, a C 6 ⁇ C 20 aryl group, a heteroaryl group having 5 to 20 nuclear atoms, and a C 6 ⁇ C 20 aryloxy group; aryl or of 5 to 20 nuclear atoms A heteroaryl ring may be formed, except when R 2 to R 4 are the same;
  • R 1 is a substituent selected from the following structural formula,
  • X is a halogen element selected from the group consisting of F, Cl, Br and I,
  • Y is a C 1 ⁇ C 10 alkyl group
  • the alkyl group, ketone group, ester group, aryl group, and heteroaryl group of R 2 to R 4 are each independently deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group , C 2 ⁇ C 40 alkynyl group, C 6 ⁇ C 40 aryl group, 5 to 40 nuclear atoms heteroaryl group, C 6 ⁇ C 40 aryloxy group, C 1 ⁇ C 40 alkyloxy group, A C 6 ⁇ C 40 arylamine group, a C 3 ⁇ C 40 cycloalkyl group, a heterocycloalkyl group having 3 to 40 nuclear atoms, a C 1 ⁇ C 40 alkylsilyl group, a C 1 ⁇ C 40 alkyl boron group, At least one substituent selected from the group consisting of C 6 ⁇ C 40 arylboron group, C 6 ⁇ C 40 arylphosphine group,
  • the present invention provides a health functional food for preventing or improving vascular disease, comprising the above-mentioned piperongumine-based compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the present invention provides a method for preventing, ameliorating or treating vascular disease, comprising the step of administering the compound represented by Formula 1 above, or a pharmaceutically acceptable salt or solvate thereof to a subject.
  • the present invention provides the use of the compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of a drug for preventing, improving or treating vascular diseases.
  • the piperongumine-based compound according to the present invention promotes the expression of the HO-1 protein and suppresses the expression of the MCP-1 protein, so it can be usefully used for the treatment of vascular diseases such as atherosclerosis.
  • 1 is a graph showing the results confirming that the piperongumine-based compound according to the present invention promotes the expression of the HO-1 gene.
  • Figure 2 is a graph of the results confirming that the piperongumine-based compound according to the present invention inhibits the expression of the MCP-1 gene.
  • the present invention provides a pharmaceutical composition for preventing or treating vascular disease comprising a compound represented by Formula 1 below, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient:
  • R 2 to R 4 are the same as or different from each other, and are each independently hydrogen, heavy hydrogen, halogen, nitro group, hydroxyl group, amino group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group, C 2 ⁇ C 40 alkynyl group, C 3 ⁇ C 40 cycloalkyl group, heterocycloalkyl group having 3 to 40 nuclear atoms, C 1 ⁇ C 20 alkoxy group, C 1 ⁇ C 20 ketone group, C 1 ⁇ C 20 ester group, a C 6 ⁇ C 20 aryl group, a heteroaryl group having 5 to 20 nuclear atoms, and a C 6 ⁇ C 20 aryloxy group; aryl or of 5 to 20 nuclear atoms A heteroaryl ring may be formed, except when R 2 to R 4 are the same;
  • R 1 is a substituent selected from the following structural formula,
  • the corrugated part means the part where the bond with Formula 1 is made
  • X is a halogen element selected from the group consisting of F, Cl, Br and I,
  • Y is a C 1 ⁇ C 10 alkyl group
  • the alkyl group, ketone group, ester group, aryl group, and heteroaryl group of R 2 to R 4 are each independently deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group , C 2 ⁇ C 40 alkynyl group, C 6 ⁇ C 40 aryl group, 5 to 40 nuclear atoms heteroaryl group, C 6 ⁇ C 40 aryloxy group, C 1 ⁇ C 40 alkyloxy group, A C 6 ⁇ C 40 arylamine group, a C 3 ⁇ C 40 cycloalkyl group, a heterocycloalkyl group having 3 to 40 nuclear atoms, a C 1 ⁇ C 40 alkylsilyl group, a C 1 ⁇ C 40 alkyl boron group, At least one substituent selected from the group consisting of C 6 ⁇ C 40 arylboron group, C 6 ⁇ C 40 arylphosphine group,
  • piperongumine is a chalcone compound in which two rings are linked to an ⁇ , ⁇ -unsaturated carbonyl chain, and one of the two rings is a benzene ring with three methoxy groups (-OMe) linked to it. , the other has a 2-piperidone structure.
  • the 3, 4-position of the benzene ring of piperongumine is changed to a nitro group or other substituents, and the other ring synthesizes 2-pyrrolidone and/or various types of nitrogen compounds. It has a structure that connects it to an ⁇ , ⁇ -unsaturated carbonyl chain.
  • R 1 in Formula 1 may have a substituent selected from the following structural formula:
  • R 2 to R 4 are the same as or different from each other, and are each independently selected from the group consisting of hydrogen, a nitro group, a hydroxyl group, a C 1 -C 6 alkyl-containing ester group, and a C 1 -C 6 alkoxy group.
  • two adjacent substituents may combine with each other to form a C 6 -C 10 aryl group or a heterocycle having 5 to 10 nuclear atoms including at least one nitrogen and oxygen atom.
  • the alkyl group, ketone group, ester group, aryl group, and heteroaryl group of R 2 to R 4 are each independently deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group, C 2 ⁇ C 40 alkynyl group, C 6 ⁇ C 40 aryl group, 5 to 40 nuclear atoms heteroaryl group, C 6 ⁇ C 40 aryloxy group, C 1 ⁇ C 40 Alkyloxy group, C 6 ⁇ C 40 arylamine group, C 3 ⁇ C 40 cycloalkyl group, 3 to 40 nuclear atoms heterocycloalkyl group, C 1 ⁇ C 40 alkylsilyl group, C 1 ⁇ C 40 1 selected from the group consisting of an alkylboron group, a C 6 ⁇ C 40 arylboron group, a C 6 ⁇ C 40 arylphosphine group, a C 6 ⁇ C
  • the compound represented by Formula 1 may be represented by any one of Formulas 2 to 5:
  • R 1 is as defined above.
  • R 5 to R 7 are the same as or different from each other, and each independently represents hydrogen, a hydroxy group, a C 1 ⁇ C 6 alkyl group, a C 1 ⁇ C 6 alkoxy group, a C 1 ⁇ C 6 ketone group, and a C 1 ⁇ C 6 group. It is selected from the group consisting of C 6 ester groups.
  • Ring A may be a monocyclic or polycyclic hydrocarbon ring group having 20 or less carbon atoms, and specifically, may be selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring. At least one carbon constituting such ring A is composed of deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 6 ⁇ C 40 aryl group, and heteroaryl group having 5 to 40 nuclear atoms. It may be substituted with one or more substituents selected from the group.
  • the compound represented by Formula 1 may be selected from the group of compounds represented by the following formula:
  • alkyl refers to a monovalent substituent derived from a straight or branched chain saturated hydrocarbon having 1 to 40 carbon atoms. Examples thereof may include methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amyl, hexyl, and the like.
  • alkenyl refers to a monovalent substituent derived from a straight-chain or branched chain unsaturated hydrocarbon having 2 to 40 carbon atoms and having at least one carbon-carbon double bond. Examples thereof may include vinyl, allyl, isopropenyl, 2-butenyl, and the like.
  • alkynyl refers to a monovalent substituent derived from a straight-chain or branched unsaturated hydrocarbon having 2 to 40 carbon atoms and having at least one carbon-carbon triple bond. Examples thereof may include ethynyl, 2-propynyl, and the like.
  • aryl refers to a monovalent substituent derived from an aromatic hydrocarbon having 6 to 40 carbon atoms in a single ring or a combination of two or more rings.
  • a form in which two or more rings are simply attached to each other (pendant) or condensed may be included.
  • Examples of such aryls may include phenyl, naphthyl, phenanthryl, anthryl, and the like.
  • heteroaryl refers to a monovalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 5 to 40 nuclear atoms. At this time, at least one carbon, preferably 1 to 3 carbons in the ring is substituted with a heteroatom such as N, O, S or Se.
  • a form in which two or more rings are simply attached to each other or condensed may be included, and furthermore, a form condensed with an aryl group may be included.
  • heteroaryls include 6-membered monocyclic rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; Polycyclics such as phenoxathienyl, indolizinyl, indolyl, purinyl, quinolyl, benzothiazole, and carbazolyl ring; and 2-furanyl, N-imidazolyl, 2-isoxazolyl, 2-pyridinyl, 2-pyrimidinyl and the like.
  • alkyloxy is a monovalent substituent represented by R'O-, wherein R' means alkyl having 1 to 40 carbon atoms, and is linear, branched or cyclic. (cyclic) structure. Examples of alkyloxy may include methoxy, ethoxy, n-propoxy, 1-propoxy, t-butoxy, n-butoxy, pentoxy, and the like.
  • cycloalkyl refers to a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms.
  • examples of such cycloalkyls may include cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantine, and the like.
  • heterocycloalkyl means a monovalent substituent derived from a non-aromatic hydrocarbon having 3 to 40 nuclear atoms, and one or more carbons, preferably 1 to 3 carbons in the ring are N , is substituted with a heteroatom such as O, S or Se.
  • heterocycloalkyls may include morpholine, piperazine, and the like.
  • condensed ring refers to a condensed aliphatic ring, a condensed aromatic ring, a condensed heteroaliphatic ring, a condensed heteroaromatic ring, or a combination thereof.
  • the compound represented by Formula 1 may include a salt thereof, specifically a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt means a salt suitable for use in contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc. within the scope of pure medical judgment.
  • pharmaceutically acceptable salts are well known in the art and are described in detail, for example, in S.M. Berge et al., J. Pharmaceutical Sciences, 66, 1, 1977.
  • the salt may be prepared in situ during the final separation and purification of the compound of the present invention or separately reacted with an inorganic base or organic base.
  • base addition salts include ammonium salts, alkali salts and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium, etc., salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic Amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine , pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine, N-methyl-D-glucamine, 2-amino- 2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as arginine and lys
  • the compound represented by Formula 1 may include hydrates, solvates or derivatives thereof.
  • the solvent is not particularly limited, and may include all common solvents known in the art.
  • vascular disease refers to a disease caused by narrowing of a blood vessel due to a blood clot such as a thrombus or accumulation of fat.
  • the vascular disease may include all types of vascular diseases known in the art.
  • the vascular disease may include not only diseases caused by narrowing of blood vessels, but also diseases caused by bursting of blood vessels.
  • the vascular disease may include arteriosclerosis, atherosclerosis, atherosclerosis, cerebral infarction, angina pectoris, peripheral vascular occlusive disease, diabetic retinopathy or hypertensive retinopathy.
  • the pharmaceutical composition according to the present invention may include 10 to 95% by weight of the compound represented by Formula 1, which is an active ingredient, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may further include at least one active ingredient exhibiting the same or similar function in addition to the above active ingredient.
  • the pharmaceutical composition of the present invention may include carriers, diluents, excipients, or mixtures thereof commonly used in biological preparations.
  • Any pharmaceutically acceptable carrier may be used as long as it is suitable for delivering the composition in vivo.
  • the carrier is described in Merck Index, 13th ed., Merck & Co. Inc., saline, sterile water, Ringer's solution, dextrose solution, maltodextrin solution, glycerol, ethanol or mixtures thereof.
  • conventional additives such as antioxidants, buffers, bacteriostatic agents and the like may be added as needed.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be added.
  • the composition of the present invention may be formulated as an oral preparation or a parenteral preparation.
  • Oral preparations may include solid preparations and liquid preparations.
  • the solid preparation may be a tablet, pill, powder, granule, capsule or troche, and such a solid preparation may be prepared by adding at least one excipient to the composition.
  • the excipient may be starch, calcium carbonate, sucrose, lactose, gelatin or mixtures thereof.
  • the solid preparation may include a lubricant, examples of which include magnesium stearate and talc.
  • the liquid formulation may be a suspension, internal solution, emulsion or syrup. In this case, the liquid formulation may include excipients such as wetting agents, sweeteners, fragrances, and preservatives.
  • the parenteral formulation may include injections, suppositories, powders for respiratory inhalation, aerosols for sprays, powders and creams, and the like.
  • the injection may include a sterilized aqueous solution, a non-aqueous solvent, a suspending agent, an emulsion, and the like.
  • vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, or injectable esters such as ethyl oleate may be used as non-aqueous solvents or suspending solvents.
  • the present invention provides a health functional food for preventing or improving vascular disease, comprising the above-mentioned piperongumine-based compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
  • the piperongumine-based compound included in the health functional food of the present invention may have the characteristics as described above.
  • the piperongumine-based compound may be a compound represented by Formula 1 below:
  • R 2 to R 4 are the same as or different from each other, and are each independently hydrogen, heavy hydrogen, halogen, nitro group, hydroxyl group, amino group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group, C 2 ⁇ C 40 alkynyl group, C 3 ⁇ C 40 cycloalkyl group, heterocycloalkyl group having 3 to 40 nuclear atoms, C 1 ⁇ C 20 alkoxy group, C 1 ⁇ C 20 ketone group, C 1 ⁇ C 20 ester group, a C 6 ⁇ C 20 aryl group, a heteroaryl group having 5 to 20 nuclear atoms, and a C 6 ⁇ C 20 aryloxy group; aryl or of 5 to 20 nuclear atoms A heteroaryl ring may be formed, except when R 2 to R 4 are the same;
  • R 1 is a substituent selected from the following structural formula,
  • the corrugated part means the part where the bond with Formula 1 is made
  • X is a halogen element selected from the group consisting of F, Cl, Br and I,
  • Y is a C 1 ⁇ C 10 alkyl group
  • the alkyl group, ketone group, ester group, aryl group, and heteroaryl group of R 2 to R 4 are each independently deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 2 ⁇ C 40 alkenyl group , C 2 ⁇ C 40 alkynyl group, C 6 ⁇ C 40 aryl group, 5 to 40 nuclear atoms heteroaryl group, C 6 ⁇ C 40 aryloxy group, C 1 ⁇ C 40 alkyloxy group, A C 6 ⁇ C 40 arylamine group, a C 3 ⁇ C 40 cycloalkyl group, a heterocycloalkyl group having 3 to 40 nuclear atoms, a C 1 ⁇ C 40 alkylsilyl group, a C 1 ⁇ C 40 alkyl boron group, At least one substituent selected from the group consisting of C 6 ⁇ C 40 arylboron group, C 6 ⁇ C 40 arylphosphine group,
  • R 1 in Formula 1 may have a substituent selected from the following structural formula:
  • the compound represented by Formula 1 may be represented by any one of Formulas 2 to 5:
  • R 1 is as defined above.
  • R 5 to R 7 are the same as or different from each other, and each independently represents hydrogen, a hydroxy group, a C 1 ⁇ C 6 alkyl group, a C 1 ⁇ C 6 alkoxy group, a C 1 ⁇ C 6 ketone group, and a C 1 ⁇ C 6 group. It is selected from the group consisting of C 6 ester groups.
  • Ring A may be a monocyclic or polycyclic hydrocarbon ring group having 20 or less carbon atoms, and specifically, may be selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring. At least one carbon constituting such ring A is composed of deuterium, halogen, cyano group, nitro group, C 1 ⁇ C 40 alkyl group, C 6 ⁇ C 40 aryl group, and heteroaryl group having 5 to 40 nuclear atoms. It may be substituted with one or more substituents selected from the group.
  • the compound represented by Formula 1 may be selected from the group of compounds represented by the following formula:
  • the vascular disease may have characteristics as described above.
  • the compound represented by Formula 1 of the present invention may be added to food as it is or used together with other foods or food ingredients.
  • the content of the active ingredient added may be determined according to the purpose, and may generally be 0.01 to 90 parts by weight of the total food weight.
  • the form and type of health functional food is not particularly limited.
  • the health functional food may be in the form of tablets, capsules, powders, granules, liquids and pills.
  • the health functional food may include various flavors, sweeteners, or natural carbohydrates as additional ingredients.
  • the sweetener may be a natural or synthetic sweetener, and examples of the natural sweetener include thaumatin and stevia extract.
  • examples of synthetic sweeteners include saccharin and aspartame.
  • the natural carbohydrates may be monosaccharides, disaccharides, polysaccharides, oligosaccharides and sugar alcohols.
  • the health functional food of the present invention in addition to the above-mentioned additional ingredients, nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectanes and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, and preservatives , glycerin, alcohol, and the like may be further included. These components may be used independently or in combination.
  • the ratio of the additives may be selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
  • the present invention provides a method for preventing, ameliorating or treating vascular disease, comprising the step of administering the compound represented by Formula 1 above, or a pharmaceutically acceptable salt or solvate thereof to a subject.
  • the compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof for use in the method for preventing, improving or treating vascular diseases according to the present invention may have the characteristics as described above.
  • the vascular disease may also have the above-described characteristics.
  • the subject may be a mammal, specifically a human.
  • the administration may be administered orally or parenterally depending on the desired method.
  • Parenteral administration may include intraocular, subretinal, intraperitoneal, intrarectal, subcutaneous, intravenous, intramuscular or intrathoracic injection modes.
  • the administration may be administered in a pharmaceutically effective amount. This may vary depending on the type and severity of the disease, the activity of the drug, the patient's sensitivity to the drug, the administration time, the route of administration, the treatment period, and the drugs used simultaneously. However, for desirable effects, the amount of the active ingredient included in the pharmaceutical composition according to the present invention may be 0.0001 to 1,000 mg/kg, specifically 0.001 to 500 mg/kg. The administration may be once or several times a day.
  • administration can be performed alone or in combination with other therapeutic agents.
  • administration can be sequential or simultaneous.
  • the present invention provides the use of the compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of a drug for preventing, improving or treating vascular diseases.
  • the compound represented by Formula 1, or a pharmaceutically acceptable salt or solvate thereof for use in the preparation of a drug for preventing, improving or treating vascular diseases according to the present invention may have the above-described characteristics.
  • the vascular disease may also have the above-described characteristics.
  • Phenylselenylchloride (0.14 g, 0.75 mmol) was dissolved in tetrahydrofuran (3.75 ml), and the mixture was slowly added at -78°C and stirred for 4.5 hours. At the end of the reaction, water was added to decompose the remaining LDA, and the mixture was further stirred at 0° C. for 15 minutes and extracted twice with dichloromethane.
  • methylpiperazine (2d) (0.15 ml, 1.28 mmol) was slowly added to the reaction mixture and stirred at room temperature for 2 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to the mixture to terminate the reaction, and water was added to dilute the mixture.
  • Piperidin-2-one (compound 3e) (2.00 g, 20.18 mmol) was added to a 100 ml round bottom flask under an argon atmosphere, and chloroform (20.00 ml) was added, the temperature was lowered to 0 ° C, and phosphorus pentachloride (12.80 g, 61.33 mmol) was slowly added over 10 minutes, followed by stirring at reflux at 60°C. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was poured into ice water.
  • reaction was confirmed by TLC, and when the reaction was completed, the reaction temperature was returned to 0° C. and the reaction was terminated using 1.50 ml of 1 N hydrochloric acid solution. After further stirring at the same temperature for 10 minutes, extraction was performed three times with dichloromethane, and the organic layer was washed once with a saturated sodium chloride solution.
  • Acetic anhydride (8.0 ml, 84.6 mmol) was slowly added to a round-bottom flask containing potassium carbonate (3.32 g, 24.0 mmol) under an argon atmosphere at 0 ° C, and the temperature was gradually raised to room temperature and stirred for 5 minutes, followed by 3 -Nitrobenzalaldehyde (compound 14a) (3.02 g, 20.0 mmol) was added slowly. The reaction mixture was stirred at reflux at 165 °C for 15 hours. After the reaction was completed, the temperature was lowered to room temperature, ice water was added, and the solid was filtered using an apparatus, washed several times with water, and dried.
  • Acetic anhydride (4.0 ml, 42.2 mmol) was slowly added to a round-bottom flask containing potassium carbonate (1.04 g, 7.54 mmol) under an argon atmosphere at 0 ° C. The temperature was gradually raised to room temperature and stirred for 5 minutes, followed by 2,3- Dihydrobenzo[b][1,4]dioxin-6-carbaldehyde (Compound 18a) (0.99 g, 6.03 mmol) was added slowly. The reaction mixture was stirred at reflux at 165 °C for 15 hours. After the reaction was completed, the temperature was lowered to room temperature (solid production within 1 hour), ice water was added, the solid was filtered using a device, washed several times with water, and then dried.
  • Compound 18a 2,3- Dihydrobenzo[b][1,4]dioxin-6-carbaldehyde
  • Raw264.7 cell line a mouse monocytic cell line
  • DMEM Dulbecco's Modified Eagle Medium
  • fetal bovine serum 10% fetal bovine serum.
  • the cultured cells were suspended using 0.25% trypsin-EDTA, and the cell number was measured using a hemocytometer. This was dispensed in a 6-well plate to be 1.5 ⁇ 10 6 per well, and cultured for 2 hours.
  • the compounds 1 to 19 prepared above were treated with LPS at a concentration of 1 ⁇ g/ml and cultured for 20 hours.
  • Trizol reagent Invitrogen
  • cDNA synthesis using 1 ⁇ g of RNA was performed using the Improm-II reverse transcription system (Promega) and oligo dT primers. Thereafter, qPCR analysis was performed in a conventional manner using the cDNA obtained above and the primers in Table 1 below, using Rotor-Gene 6000 (Qiagen, USA). At this time, an untreated control group was used as a control group. As a result, the result of normalizing the measured HO-1 gene expression level to the expression level of the ⁇ -actin gene is shown in FIG. 1 .
  • the piperongumine-based compound according to the present invention significantly increased the expression of the HO-1 gene.
  • compounds 2, 5, 6, 7, 8, 15, 16, 17, 18 or 19 increased the expression of the HO-1 gene more than 5 times, showing more remarkable effects than other compounds.
  • MCP-1 monocyte chemoattractant protein-1
  • Asc ascorbic acid
  • the piperongumine-based compound according to the present invention significantly inhibited the expression of the MCP-1 gene.
  • compounds 1, 3, 9, 10, 11, 12, 13, 14, 15 or 18 inhibited the expression of the MCP-1 gene to a level similar to that of the positive control, Asc.
  • the piperongumine compound according to the present invention promotes the expression of the HO-1 gene or suppresses the expression of the MCP-1 gene, so it can be usefully used for the treatment of vascular diseases such as atherosclerosis confirmed.

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Abstract

La présente invention concerne l'utilisation d'un composé à base de piperlongumine pour le traitement de maladies vasculaires. Plus précisément, le composé à base de piperlongumine selon la présente invention favorise l'expression de la protéine HO-1 et, simultanément, inhibe l'expression de la protéine MCP-1, et peut ainsi être efficacement utilisé dans le traitement de maladies vasculaires telles que l'artériosclérose.
PCT/KR2022/014420 2021-09-29 2022-09-27 Composition pharmaceutique pour la prévention ou le traitement de maladies vasculaires, comprenant un composé à base de piperlongumine comme principe actif WO2023055020A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02225458A (ja) * 1989-02-28 1990-09-07 Nisshin Flour Milling Co Ltd ピロリジノン誘導体
JPH07179338A (ja) * 1993-12-22 1995-07-18 Tsumura & Co 脳機能改善剤
KR101468752B1 (ko) * 2006-06-19 2014-12-03 피에르 파브르 메디카먼트 신나모일-피페라진 유도체 및 ｐａｒ-1 길항제로서의 용도

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02225458A (ja) * 1989-02-28 1990-09-07 Nisshin Flour Milling Co Ltd ピロリジノン誘導体
JPH07179338A (ja) * 1993-12-22 1995-07-18 Tsumura & Co 脳機能改善剤
KR101468752B1 (ko) * 2006-06-19 2014-12-03 피에르 파브르 메디카먼트 신나모일-피페라진 유도체 및 ｐａｒ-1 길항제로서의 용도

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NAGASAKA TATSUO, MOMOSE KENICHI, HAMAGUCHI FUMIKO, YAMADA KENJI, YAMADA HIROAKI, SUZUKI YOSHIKUNI: "Synthesis of 1-trans-Cinnamoyl- and 1-[trans-3-(Pyridyl)acryloyl]-2-pyrrolidinone Derivatives and Their Effect on Hemicholinium-Induced Impairment of Water Maze Learning in Mice", YAKUGAKU ZASSHI : JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, PHARMACEUTICAL SOCIETY OF JAPAN, vol. 112, no. 2, 1 January 1992 (1992-01-01), pages 100 - 107, XP055902562, ISSN: 0031-6903, DOI: 10.1248/yakushi1947.112.2_100 *
SHI JINGSONG, JIANG SONG, QIU DANDAN, LE WEIBO, WANG XIAO, LU YINHUI, LIU ZHIHONG: "Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli", BIOMED RESEARCH INTERNATIONAL, HINDAWI PUBLISHING CORPORATION, vol. 2016, 1 January 2016 (2016-01-01), pages 1 - 13, XP093054311, ISSN: 2314-6133, DOI: 10.1155/2016/1634730 *

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