WO2015183970A1 - Compositions thérapeutiques contenant un flavonoïde et leurs utilisations - Google Patents

Compositions thérapeutiques contenant un flavonoïde et leurs utilisations Download PDF

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Publication number
WO2015183970A1
WO2015183970A1 PCT/US2015/032696 US2015032696W WO2015183970A1 WO 2015183970 A1 WO2015183970 A1 WO 2015183970A1 US 2015032696 W US2015032696 W US 2015032696W WO 2015183970 A1 WO2015183970 A1 WO 2015183970A1
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Prior art keywords
phe
arg
lys
aromatic
peptide
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PCT/US2015/032696
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English (en)
Inventor
D. Travis Wilson
Mark BAMBERGER
Peter OATES
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Stealth Peptides International, Inc.
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Publication of WO2015183970A1 publication Critical patent/WO2015183970A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present disclosure provides a method for treating or preventing mitochondrial permeability transition in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising flavonoids, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg- 2',6'-Dmt-Lys-Phe-NH 2 .
  • the present disclosure provides a method for treating atherosclerotic renal vascular disease (ARVD) in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising flavonoids, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • R 1 and R 2 are each independently selected from
  • the "administration" of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or
  • flavonoids any of a class of polyphenolic molecules based on a flavan nucleus, comprising 15 carbon atoms, arranged in three rings as C6-C3-C6. Flavonoids are generally classified into subclasses by the state of oxidation and the substitution pattern at the C2-C3 unit.
  • halo and halogen refer to the Group Vila elements (Group 17 elements in the 1990 IUPAC Periodic Table, IUPAC Nomenclature of Inorganic Chemistry, Recommendations 1990) and include CI, Br, F and I substituents. In some embodiments, halogen substituents are CI and F.
  • haloalkenyl embraces any C1-C5 alkenyl substituent having at least one halogen substituent; the halogen can be attached via any available valence on the C1-C5 alkenyl group.
  • One further subset of C1-C5 haloalkenyl is the subset with exactly one halogen substituent.
  • Another further subset of C1-C5 haloalkenyl is the subset with exactly one chloro substituent.
  • Another further subset of C1-C5 haloalkenyl is the subset with exactly one fluoro substituent.
  • a non-naturally-occurring composition can be derived from a naturally-occurring composition, e.g., as non-limiting examples, via purification, isolation, concentration, chemical modification (e.g., addition or removal of a chemical group), and/or, in the case of mixtures, addition or removal of ingredients or compounds.
  • a non-naturally-occurring composition can comprise or be derived from a non-naturally- occurring combination of naturally-occurring compositions.
  • a non-naturally-occurring composition can comprise a mixture of purified, isolated, modified and/or concentrated naturally-occurring compositions, and/or can comprise a mixture of naturally-occurring compositions in forms, concentrations, ratios and/or levels of purity not found in nature.
  • the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
  • the terms “subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
  • C1-C5 haloalkyl is the subset of C1-C5 perfluoroalkyl; that is, C1-C5 alkyl with all available valences replaced by fluorines, such as— CF 3 and— CF2-CF 3 .
  • Treating covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • the flavonoids of the compositions of the present technology are selected from the group consisting of chrysin, daidzein, diosmin, hesperetin, hesperidin, luteolin, quercetin, bromoquercetin, rutin, biochanin A, and/or metabolites or derivatives thereof.
  • Flavonoids There are a number of chemical variations of the flavonoids, such as, the state of oxidation of the bond between the C2-C3 position and the degree of hydroxylation, methoxylation or glycosylation (or other substituent moieties) in the A, B, and C rings and the presence or absence of a carbonyl at position 4. Flavonoids have generally been classified into 12 different subclasses by the state of oxidation and the substitution pattern at the C2-C3 unit.
  • Hesperetin is exemplified herein as one of a class of compounds known as flavonoids, which are polyphenolic molecules based on a flavan nucleus, comprising 15 carbon atoms, arranged in three rings as C6-C3-C6. Flavonoids are generally classified into subclasses by the state of oxidation and the substitution pattern at the C2-C3 unit.
  • An alternative flavonoid suitable for use as flavonoids of the compositions of the present technology is diosmin, or a derivative thereof.
  • Diosmin is a flavonoid extract, 7-[[6- 0-6-Deoxy-a-L-mannopyranosyl)- -D-glucopyranosyl]oxy]-5- hydroxy-2-(3 -hydroxy -4- methoxyphenyl)-4H-l-benzopyran-4-one. See The Merck Index (1996), Twelfth Edition, Merck & Co., Whitehouse Station, N.J., p. 558, and references cited therein.
  • tocopherol is meant any of a family of molecules (including both tocopherols and tocotrienols and derivatives thereof) which are characterized by a 6-chromanol ring structure and a side chain at the 2 position. Tocopherols possess a 4',8', 12'-trimethyltridecyl phytol side chain, and the tocotrienols differ by the presence of double bonds at the 3', 7' and 1 ⁇ positions of the side chain.
  • the composition comprises gamma-tocopherol in the range of about 10 to about 100 mg/kg body weight of mammalian subject, hesperetin in the range of about 10 to about 100 mg/kg body weight of mammalian subject and quercetin in a range of about 10 to about 100 mg/kg body weight of mammalian subject.
  • the aromatic-cationic peptides of the present technology include a minimum of three amino acids, covalently joined by peptide bonds.
  • the peptide comprises one or more non-naturally occurring amino acids, for example, one or more D-amino acids.
  • the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
  • the peptide has a minimum of four amino acids. The peptide may have a maximum of about 6, a maximum of about 9, or a maximum of about 12 amino acids.
  • the methods disclosed herein provide therapies for the treatment of medical disease or conditions and/or side effects associated with existing therapeutics against medical diseases or conditions comprising administering an effective amount of flavonoid alone or in combination with one or more aromatic-cationic peptides or pharmaceutically acceptable salts thereof, such as acetate, tartrate or trifluoroacetate.
  • flavonoids are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
  • flavonoids in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in reducing CD36 expression in renal tubular cells after unilateral ureteral obstruction (UUO) in a subject in need thereof.
  • UUO unilateral ureteral obstruction
  • the peptide conjugates of the present technology are useful in reducing lipid peroxidation in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • flavonoids in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe- NH 2
  • peptide conjugates of the present technology are useful in protecting against mitochondrial permeability transition (MPT) induced by Ca 2+ overload and 3-nitropropionic acid (3NP).
  • MPT mitochondrial permeability transition
  • 3-nitropropionic acid 3NP.
  • flavonoids or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in inhibiting mitochondrial swelling and cytochrome c release.
  • flavonoids or derivatives, analogues, or
  • the removed organ may be placed in a standard buffered solution, such as those commonly used in the art.
  • a removed heart may be placed in a cardioplegic solution containing the compositions described herein.
  • concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.1 nM to about 10 ⁇ .
  • peptide conjugates of the present technology are useful in ameliorating, diminishing or preventing the side effects of drugs such as adriamycin.
  • flavonoids are useful in inhibiting mitochondrial production of hydrogen peroxide, e.g., as measured by luminol chemiluminescence under basal conditions and/or upon stimulation by antimycin.
  • flavonoids are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
  • flavonoids in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the peptide conjugates of the present technology are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
  • Examples of cells, tissues or organs affected by oxidative damage include, but are not limited to, endothelial cells, epithelial cells, nervous system cells, skin, heart, lung, kidney, eye and liver.
  • lipid peroxidation and an inflammatory process are associated with oxidative damage for a disease or condition.
  • Lipid peroxidation refers to oxidative modification of lipids.
  • the lipids can be present in the membrane of a cell. This modification of membrane lipids typically results in change and/or damage to the membrane function of a cell.
  • lipid peroxidation can also occur in lipids or lipoproteins exogenous to a cell. For example, low-density lipoproteins are susceptible to lipid peroxidation.
  • An example of a condition associated with lipid peroxidation is atherosclerosis. Reducing oxidative damage associated with atherosclerosis is important because atherosclerosis is implicated in, for example, heart attacks and coronary artery disease.
  • the bacteria can be any bacteria, and include gram-negative and gram-positive bacteria.
  • Gram-negative bacteria contain lipopolysaccharide in the bacteria wall. Examples of gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Proteus species, Pseudomonas aeruginosa, Serratia, and Bacteroides. Examples of gram-positive bacteria include pneumococci and streptococci.
  • the neurodegenerative condition can be an acute condition, such as a stroke or a traumatic brain or spinal cord injury.
  • the neurodegenerative disease or condition is a chronic neurodegenerative condition.
  • the free radicals can, for example, cause damage to a protein.
  • An example of such a protein is amyloid precursor protein.
  • Non-limiting examples of chronic neurodegenerative diseases associated with damage by free radicals include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS).
  • the present technology provides methods of treating an individual afflicted with an insulin resistance-associated disease or disorder.
  • Nephrotoxins can cause direct toxicity on tubular epithelial cells.
  • Nephrotoxins include, but are not limited to, therapeutic drugs, e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides (e.g., paraquat), and environmental contaminants (e.g., trichloroethylene and dichloroacetylene).
  • therapeutic drugs e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides (e.g., paraquat), and environmental contaminants (e.g., trichloroethylene and dichloroacetylene).
  • PAN puromycin aminonucleoside
  • aminoglycosides such as gentamicin
  • flavonoids in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D- Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the tissue injury can be associated with, for example, aortic aneurysm repair, multiple trauma, peripheral vascular disease, renal vascular disease, myocardial infarction, stroke, seps
  • pulmonary capillary and alveolar epithelia When the integrity of pulmonary capillary and alveolar epithelia is compromised, plasma and blood leak into the interstitial and intra-alveolar spaces, resulting in pulmonary edema. A decrease in pulmonary function can occur in severely burned patients, as a result of bronchoconstriction caused by humoral factors, such as histamine, serotonin, and thromboxane A2.
  • kidney function is well known in the art and include, but are not limited to, using blood tests for serum creatinine, or glomerular filtration rate. Methods for assessing deterioration of kidney structure are also well known. Such methods include kidney imaging (e.g., MRI, ultrasound), or histological evaluation of kidney biopsy.
  • kidney imaging e.g., MRI, ultrasound
  • histological evaluation of kidney biopsy e.g., histological evaluation of kidney biopsy.
  • Flavonoids (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology may be administered to a subject at risk of receiving burns.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',
  • a subject may exhibit at least about 5%, at least about 10%, at least about 20%, or at least about 50% reduction in some triglycerides compared to the subject prior to receiving the flavonoids (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ), or peptide conjugates of the present technology.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe- Lys-NH 2 , or D-Arg-2',6'-Dmt-L
  • flavonoids in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D- Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2
  • the ophthalmic condition is selected from the group consisting of: dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, and oxygen-induced retinopathy.
  • flavonoids or derivatives, analogues, or pharmaceutically acceptable salts thereof or peptide conjugates of the present technology are useful in reducing the elevated expression of caspase-3 in high glucose-treated HRECs.
  • flavonoids (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-Phe-NH 2
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'- Dmt-Lys-P
  • the present methods provide for the prevention and/or treatment of an ophthalmic condition in a subject by administering an effective amount of flavonoids (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2 ), or peptide conjugates of the present technology to a subject in need thereof.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt- Lys-Phe-NH 2
  • flavonoids or derivatives, analogues, or pharmaceutically acceptable salts thereof or peptide conjugates of the present technology are useful in treating or preventing retinitis pigmentosa in a subject.
  • flavonoids or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',
  • prophylactic compositions of the present technology can occur prior to the manifestation of symptoms characteristic of the aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression.
  • flavonoids or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • peptide conjugates of the present technology act to enhance or improve mitochondrial function or reduce oxidative damage, and can be used for treating the subject.

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'invention concerne des procédés et des compositions de traitement et/ou de prévention de maladies ou d'états pathologiques consistant à administrer des flavonoïdes, et/ou des dérivés ou des analogues de ceux-ci d'origine naturelle ou artificielle, ou des sels de ceux-ci pharmaceutiquement acceptables, seuls ou en combinaison avec un ou plusieurs agents actifs (p. ex. un peptide aromatique-cationique). La présente technologie concerne des compositions à base de peptides aromatiques-cationiques liés à un flavonoïde, ainsi que des utilisations de ces compositions. Dans certains modes de réalisation, le peptide aromatique-cationique comprend un composé 2',6'-diméthyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH2 ou D-Arg-2',6'-Dmt-Lys-Phe-NH2.
PCT/US2015/032696 2014-05-28 2015-05-27 Compositions thérapeutiques contenant un flavonoïde et leurs utilisations WO2015183970A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115896201A (zh) * 2023-01-09 2023-04-04 成都欧康医药股份有限公司 一种4-甲氧基-3,5`,7`-三羟基黄烷酮的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011112156A1 (fr) * 2010-03-11 2011-09-15 Agency For Science, Technology And Research Véhicules pour l'administration d'agents anticancéreux capables de charges améliorées
US20130303436A1 (en) * 2012-12-06 2013-11-14 Stealth Peptides Internatioanl, Inc. Peptide therapeutics and methods for using same
WO2014022551A1 (fr) * 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methodes de traitement de l'atherosclerose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011112156A1 (fr) * 2010-03-11 2011-09-15 Agency For Science, Technology And Research Véhicules pour l'administration d'agents anticancéreux capables de charges améliorées
WO2014022551A1 (fr) * 2012-08-02 2014-02-06 Stealth Peptides International, Inc. Methodes de traitement de l'atherosclerose
US20130303436A1 (en) * 2012-12-06 2013-11-14 Stealth Peptides Internatioanl, Inc. Peptide therapeutics and methods for using same

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115896201A (zh) * 2023-01-09 2023-04-04 成都欧康医药股份有限公司 一种4-甲氧基-3,5`,7`-三羟基黄烷酮的制备方法
CN115896201B (zh) * 2023-01-09 2023-05-26 成都欧康医药股份有限公司 一种4-甲氧基-3,5`,7`-三羟基黄烷酮的制备方法

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