WO2007087738A1 - Tripeptides biologiquement actifs, leurs complexes avec le cuivre et leur sels - Google Patents

Tripeptides biologiquement actifs, leurs complexes avec le cuivre et leur sels Download PDF

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Publication number
WO2007087738A1
WO2007087738A1 PCT/CH2007/000050 CH2007000050W WO2007087738A1 WO 2007087738 A1 WO2007087738 A1 WO 2007087738A1 CH 2007000050 W CH2007000050 W CH 2007000050W WO 2007087738 A1 WO2007087738 A1 WO 2007087738A1
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Prior art keywords
skin
tripeptides
salts
formula
complexes
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PCT/CH2007/000050
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German (de)
English (en)
Inventor
Hugo Ziegler
Peter Wikstroem
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Pentapharm Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • 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
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides 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
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/58—Metal complex; Coordination compounds
    • 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 invention relates to biologically active tripeptides, their 1: 1 copper complexes and salts thereof.
  • GHK-Cu is a potent, selective activator for the skin in wound healing processes, removing scars or damaged tissue and forming and properly storing new tissue.
  • GHK-Cu is involved in the construction of new skin tissue by enhancing angiogenesis and generally stimulates the synthesis of extracellular matrix (ECM) molecules, such as the production of collagen I and III, the accumulation of glycosaminoglycans and proteoglycans, e.g. Decorin (but not biglycan) as well as elastin.
  • ECM extracellular matrix
  • GHK-Cu also stimulated the chemotaxis of leukocytes.
  • GHK-Cu basically stimulates the synthesis of ECM molecules, in serum of free primary culture it was shown that GHK-Cu reduces the excretion of TGF-ß-1 from normal fibroblasts and especially in keloid-forming (scar-forming) fibroblasts.
  • the improved healing of wounds or new formation of fresh Skin tissue by GHK-Cu is also based, inter alia, on a selective stimulation of MMP-9 and MMP-2 in an early or late phase of the wound healing process. This accelerates the breakdown of damaged protein and removes scars, and appropriately increases the synthesis of new collagen. Overall, there is improved wound healing with less scarring. Further effects are described in Cosmetics & Toiletries 118 (7), 24-28 (2003).
  • GHK-Cu topical cosmetic application
  • the positive effects of GHK-Cu in topical cosmetic application are i.a. an increase in skin thickness in the epidermis and dermis, improved skin hydration, significant smoothing of the skin through the stimulation of collagen synthesis, increased elasticity of the skin, marked improvement in skin contrast, increased production of collagen I, glycosaminoglycans and decorin Damaged skin (Nils Krüger et al., Cosmetic Medicine 2003 (1), 31-33; Alain Simeon et al., J. Invest Dermatol., 115, 962-968 (2000)).
  • GHK-Cu The topical application of GHK-Cu, however, is associated with two serious disadvantages.
  • the enzymatic stability of GHK-Cu to peptidases in the skin is very low. Within one minute, 95% GHK is degraded to glycine and HK. In addition, only between 0.1 and 0.3% of the applied amount can penetrate into the dermis. As a result, high concentrations (4%) of GHK-Cu have to be used for a still unsatisfactory effect (Loren Pickart, Published Studies on Copper-Peptide Induced Tissue Regeneration).
  • the object of the present invention was to find GHK-Cu analogous active ingredients whose stability is higher and / or their skin penetration rate significantly improved. It has now been found that, surprisingly, with selected artificial peptides, as they are defined herein below, stable 1: 1 copper complexes can be obtained and that the biological activity of these peptides not only remains intact but can even be improved in some cases. Description of the invention
  • the present invention relates to biologically active tripeptides of the general formula (I):
  • R 1 is hydrogen or C 1 -C 18 -alkylcarbonyl
  • R 2 is 4-imidazolyl or -CH 2 NH 2 ,
  • R 3 is hydrogen, C 1 -C 6 -alkyl or optionally substituted
  • Arylalkyl (C 1 -C 4 ), A is -CH 2 -, -CH 2 CH 2 -, C (CH 3 J 2 , -NH- or -CH (R 4 ) -, where the group [-CH (R 4 ) -] is D-configured; R 4 is C 1 -C 4 -alkyl or benzyl and X is oxygen (-O-) or -NH-;
  • A is -CH 2 -, -CH 2 -CH 2 - or -CH (R 4 ) -, wherein R 4 is CH 3 , and X is
  • A is -CH 2 -, X is -NH- and R 3 is hydrogen.
  • A is -CH 2 - or -CH (R 4 ) -, wherein R 4 is -CH 2 -CH 3 or -CH (CH 3 J 2 , R 2 is 4-imidazolinyl and X is oxygen.
  • the present invention also relates to compositions, in particular cosmetic preparations, which comprise at least one compound of the formula (I), their copper complexes and / or their salts, and to processes for the preparation of these preparations.
  • the present invention also relates to compositions, in particular cosmetic preparations, which contain at least one compound of the formula (I), their copper complexes and / or salts thereof and at least one further dermatologically cosmetic active ingredient.
  • tripeptides of the general formula (I) and 1: 1 complexes of these tripeptides with Cu +2 [Cu (II)], as racemates or in their enantiomerically pure form, as well as their salts the compounds of the formula (I ), their 1: 1 copper (II) complexes, salts of these copper (II) complexes with acids, and salts, ie salts of the tripeptides of the formula (I) per se and salts of 1: 1 complexes of the tripeptides of the formula (I ., to understand) with Cu +2 [Cu (II)], in particular those salts with acids, which salts are formed by the basic amino groups of the compounds of formula (I) with acids, preferably the 1: 1 copper (II) Complexes and salts of these copper (II) complexes with acids.
  • alkyl as a group per se and as a structural element for alkyl-containing groups are meant both linear and branched saturated hydrocarbon radicals. Examples are methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-hexadecanyl, n- Heptadecanyl, n-octadecanyl and n-nonadecanyl as unbranched radicals and as branched radicals: isopropyl, tert-butyl, isobutyl, sec-butyl and isoamyl.
  • Aryl represents aromatic hydrocarbon radicals, such as phenyl and naphthyl; preferred
  • substituents of the optionally substituted aryl groups are, for example, halogen, C 1 -C 5 -Al] CyI, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, -CN, amino (-NH 2 ), Ci C 6 alkylamino, di (C 1 -C 6 ) alkylamino, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl or di (C 1 -C 6 ) -alkylaminocarbonyl.
  • Halogen means fluorine, chlorine, bromine and iodine; preferred are fluorine and chlorine.
  • R 1 is preferably hydrogen or CH 3 C (O) -.
  • R 3 is preferably hydrogen or benzyl.
  • R 4 is preferably methyl.
  • the basic amino groups of the compounds of formula (I) and / or their copper complexes can turn with acids or multidentate / form homogeneous or mixed salts, for example with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid; or with suitable carboxylic acids, for example aliphatic mono- or dicarboxylic acids, such as formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, glycolic acid, succinic acid, fumaric acid, malonic acid, maleic acid, oxalic acid, phthalic acid, citric acid, lactic acid or tartaric acid; or with aromatic carboxylic acids, such as benzoic acid or salicylic acid; or with aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid; or with heteroaromatic carboxylic acids, such as nicotinic acid; or with aliphatic or aromatic sulfonic acids
  • the general formula (I) includes all possible isomeric forms as well as their mixtures, for example racemic mixtures and mixtures of rotamers.
  • the copper-free compounds of general formula I can be prepared according to known methods (1994 general rules of M. Bodanszky "The Practice of Peptide Synthesis” Springer Verlag, 2 nd Edition). Accordingly, the P-amino acid is derivatized at the carboxy-terminal end, deprotected the ⁇ -amino protecting group (eg a Boc group) and the peptide gradually built up with the customary in peptide synthesis reagents until the desired sequence is fully established. Subsequently, the side-chain protective groups (eg Z or Boc functions) are cleaved off and the tripeptide derivatives are purified by chromatography and / or by recrystallization.
  • ⁇ -amino protecting group eg a Boc group
  • the copper-free, purified peptide derivatives are dissolved in water or alcohol / water and reacted with the equimolar amount of a copper salt, e.g. Copper (II) chloride and copper (II) acetate or copper (II) hydroxide are added and the pH of the solution is adjusted, typically with sodium hydroxide (NaOH).
  • a copper salt e.g. Copper (II) chloride and copper (II) acetate or copper (II) hydroxide are added and the pH of the solution is adjusted, typically with sodium hydroxide (NaOH).
  • the compounds according to the invention can be used in concentrations which vary between 0.5 and 20,000 ppm (w / w), preferably between 1 and 5,000 ppm (w / w), in the final cosmetic product.
  • the compounds according to the invention may be in the form of a solution, a dispersion, an emulsion or encapsulated in carriers such as the macro-, micro- or nanocapsules, in liposomes or chylomicrons, or included in macro, micro or nanoparticles or in microsponges or absorbed on powdered organic polymers, talc, bentonite and other mineral carriers.
  • the compounds of this invention may be used in any galenic form: aqueous / oily and oily / aqueous emulsions, milk, lotions, ointments, gelling and viscous, stress active and emulsifying polymers, pomades, shampoos, soaps, gels, powders, sticks and sticks, sprays , Body oils, face masks, plasters.
  • the compounds according to the invention can be used with any other cosmetic ingredient commonly used: extraction lipids and / or synthetic lipids, gelling and viscous, active and emulsifying polymers, water or fat soluble active principles, plant extracts, tissue extracts, marine extracts, sunscreens, antioxidants, moisturizers and barrier agents. Skin revitalizing agents.
  • compositions according to the invention may contain a safe and effective amount of one or more anti-wrinkle active ingredients or anti-atrophic ingredients.
  • Exemplary anti-wrinkle / anti-atrophic agents suitable for use in the compositions of the invention include sulfur-containing D and L amino acids and their derivatives and salts, especially the N-acetyl derivatives, a preferred example of which is N-acetyl-L- cysteine is; Thiols, such as ethanethiol; Hydroxy acids (eg .alpha.-hydroxy acids such as lactic acid and glycolic acid or .beta.-hydroxy acids such as salicylic acid and salicylic acid derivatives such as the octanoyl derivatives), phytic acid, lipoic acid; Lysophosphatidic acid, skin peeling agents (eg, phenol and the like), vitamin B 3 compounds, and retinoids, which improve the skin smoothing benefits of the present invention.
  • Vitamin B3 compounds such as a preferred example of which is N-acetyl-L- cysteine is
  • Thiols such as ethanethiol
  • Hydroxy acids e
  • compositions of this invention may contain a safe and effective amount of a vitamin B3 compound.
  • Vitamin B3 compounds are particularly useful for the regulation of skin condition, as described in copending U.S. Patent Application Serial No. 08 / 834,010, filed April 11, 1997 (corresponding to International Publication WO 97/39733 A1, published on May 30, 1997) October 30, 1997).
  • Exemplary derivatives of said vitamin B 3 compounds include nicotinic acid esters including non-vasodilating esters of nicotinic acid (eg, tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide, and niacinamide N-oxide.
  • compositions of the invention may also contain a retinoid.
  • retinoid as used herein includes all natural and / or synthetic analogs of vitamin A or retinol-like compounds that have biological activity of vitamin A in the skin, as well as the geometric isomers and stereoisomers of these compounds.
  • the retinoid is preferably retinol, retinol esters (eg, C 2 to C 22 alkyl esters of retinol including retinyl palmitate, retinyl acetate, retinyl propionate), retinal and / or retinoic acid (including all-trans retinoic acid and / or 13-cis retinoic acid ), in particular retinoids other than retinoic acid.
  • retinol retinol esters
  • retinyl esters eg, C 2 to C 22 alkyl esters of retinol including retinyl palmitate, retinyl acetate, retinyl propionate
  • retinal and / or retinoic acid including all-trans retinoic acid and / or 13-cis retinoic acid
  • retinoids other than retinoic acid.
  • Suitable retinoids are tocopheryl retinoate [tocopherol esters of retinoic acid (trans or ice)], adapters ⁇ 6- [3- (1-adamantyl) -4-methoxyphenyl] -2-naphthoic acid ⁇ and tazarotene (ethyl-6- [2- (4 , 4-dimethylthiochroman-6-yl) ethynyl] nicotinate).
  • Preferred retinoids are retinol, retinyl palmitate, retinyl acetate, retinyl propionate, retinal and combinations thereof.
  • compositions of this invention may contain a safe and effective amount of the retinoid such that the resulting composition is safe and effective for regulating the condition of horny tissue, preferably for regulating visible and / or tactile discontinuities of the skin, particularly for regulating signs of aging of the skin. more preferably for the regulation of visible and / or tactile Skin surface texture discontinuities associated with skin aging.
  • compositions of this invention may contain a safe and effective amount of a hydroxy acid.
  • Preferred hydroxy acids for use in the compositions of this invention include salicylic acid and salicylic acid derivatives.
  • Additional peptides include, but are not limited to, di-, tri-, tetra-, penta- and hexapeptides. Derivatives thereof may be added to the compositions of this invention in safe and effective amounts.
  • peptides refers to both the naturally occurring peptides and the synthesized peptides, and also includes peptidomimetics and metal complexes of "peptides". The naturally occurring and commercially available compositions containing peptides are also useful herein.
  • Suitable dipeptides for use herein include carnosine ( ⁇ -Ala-His).
  • Suitable tripeptides for use herein include Gly-His-Lys, Arg-Lys-Arg, His-Gly-Gly.
  • Preferred tripeptides and derivatives thereof include palmitoyl-Lys-Val-Lys, which as SYN ® -COLL commercially available from Pentapharm, Switzerland is available, palmitoyl-Gly-His-Lys, which can be purchased as Biopeptide CL TM (100 ppm palmitoyl-Gly He-Lys, commercially available from Sederma, France), peptide CK (Arg-Lys-Arg), peptide CK + (ac-Arg-Lys-Arg-NH 2 ), and ⁇ -Ala-Pro-Dab-NH-benzyl, which is sold under the name SYN ® -AKE of Pentapharm, Switzerland, one.
  • Tetrapeptides suitable for use herein include Peptide E, Arg-Ser-Arg-Lys.
  • pentapeptides are Matrixyl (palmitoyl-Lys-Thr-Thr-Lys-Ser), available from Sederma, France, and those described in WO 03/037933 (Pentapharm, Switzerland).
  • a hexapeptide suitable for use is Argireline (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2) manufactured by Lipotec, Spain.
  • the compounds can be by the methods described below to known methods (general rules of M. Bodanszky "The Practice of Peptide Synthesis” Springer Verlag, 2 nd Edition 1994) are manufactured. Accordingly, the P-amino acid is derivatized at the carboxy-terminal end, the ⁇ -amino-protecting group (eg a Boc group) is deprotected and the peptide is built up stepwise with the reagents customary in peptide synthesis until the desired sequence is completely established. Subsequently, the side chain protection groups (eg Z or Boc functions) are split off.
  • the side chain protection groups eg Z or Boc functions
  • phase A While stirring, add phase A to phase B and homogenize.
  • the laminin V production per cell of in vitro cultured HaCaT keratinocytes was detected by an ELISA (Enzyme-Linked Immunosorbent Assay).
  • ELISA Enzyme-Linked Immunosorbent Assay
  • the human HaCaT keratinocytes were a gift of Prof. Fusenig from the German Cancer Research Center in Heidelberg and were in
  • AK P3H9-2, Santa Cruz Biotechnology, Inc.
  • AK 31430; Socochim S.A.
  • AK 1/500 with AK-Verd.Lsg.
  • the keratinocytes are incubated at a density of approximately 5000 cells / well seeded in 96well-plates for 3 days until confluency in the culture medium (37 C C 10% CO 2 ).
  • the medium is triplicate to test medium with three different concentrations replaced. The following controls are tested on each plate:
  • the plates are incubated for a further 72 hours. Thereafter, the deposited laminin V is detected and quantified according to the following protocol:
  • the laminin V production per cell is calculated according to the following formula: (value OD LamInn v / value RFU Ze ii z ahi) x 100
  • Type I collagen of in vitro cultured skin fibroblasts was detected by an enzyme-linked immunosorbent assay (ELISA). In the presence of the active ingredients, the increase in collagen production of the cells was quantified by this method.
  • ELISA enzyme-linked immunosorbent assay
  • the human dermal fibroblasts were isolated from foreskin and grown in the culture medium.
  • AK MAB1340, Chemicon
  • AK 31430, Socochim S.A.
  • the fibroblasts are for 3 days at a density of approximately 5000 cells / well in 96-well plates to confluence in the culture medium were incubated (37 0 C / 5% CO 2.
  • the medium is replaced with assay medium with three different concentrations in triplicate to the test substance The following controls are tested on each plate:
  • the plates are incubated for a further 72 hours. Thereafter, the deposited collagen I is detected and quantified according to the following protocol:

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Abstract

L'invention concerne des tripeptides biologiquement actifs de formule générale (I), dans laquelle R1 est un atome d'hydrogène ou un groupe alkylcarbonyle en C1-C16, R2 est un groupe 4-imidazolyle ou -CH2NH2, R3 est un atome d'hydrogène, un groupe alkyle en C1-C16 ou un groupe arylalkyle en (C1-C4) le cas échéant substitué, un groupe -CH2-, -CH2CH2-, C(CH3)2, -NH-; ou -CH(R4)-, le groupe [-CH(R4)-] ayant la configuration D, R4 est un groupe alkyle en C1 à C4 ou un groupe benzyle, et X est un radical oxygène (-O-) ou -NH-; des complexes 1:1 de ces tripeptides avec le Cu+2 [Cu(II)], sous la forme de racémates ou sous leur forme énantiomère pure ; des sels des tripeptides de formule (I) et des sels des complexes 1:1 de ces tripeptides avec le Cu+2 [Cu(II)], à condition que, lorsque R1 est un atome d'hydrogène et R2 un groupe 4-imidazolyle, A n’est pas -CH2-, -CH2-CH2-; ou -CH(R4)-, où R4 est CH3, et X en même temps un atome d’oxygène ; et A n'est pas non plus -CH2-, X -NH-; et R3 un atome d'hydrogène en même temps. L’invention concerne aussi des compositions contenant ces composés et possédant une efficacité dermato-cosmétologique.
PCT/CH2007/000050 2006-02-03 2007-02-01 Tripeptides biologiquement actifs, leurs complexes avec le cuivre et leur sels WO2007087738A1 (fr)

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WO2010106044A1 (fr) * 2009-03-16 2010-09-23 Dsm Ip Assets B.V. Utilisation de tripeptides
WO2011003696A1 (fr) * 2009-07-10 2011-01-13 Unilever Plc Compositions de traitement capillaire
JP2016520069A (ja) * 2013-05-10 2016-07-11 サザン・リサーチ・インスティテュート ＴＧＦ‐β活性阻害を介した疾患の治療のための化合物、組成物及び方法
CN107098950A (zh) * 2017-06-13 2017-08-29 湖北泓肽生物科技有限公司 一种ghk或ahk三肽的合成方法
CN110790816A (zh) * 2018-08-02 2020-02-14 浙江湃肽生物有限公司 一种多肽活性化合物及新型铜胜肽和制备方法
CN112263505A (zh) * 2020-10-29 2021-01-26 广州栋方生物科技股份有限公司 一种铜肽组合物及其制备方法和应用
WO2021247531A1 (fr) * 2020-06-01 2021-12-09 Balchem Corporation Chélates métalliques de diaminoacide ou chélates métalliques de triaminoacide
CN114636739A (zh) * 2022-03-07 2022-06-17 西北工业大学 一种基于三胜肽修饰的固态多纳米孔的铜离子超痕量检测的方法
CN115124593A (zh) * 2021-03-25 2022-09-30 深圳市图微安创科技开发有限公司 一种高纯度GHK-Cu的合成方法
CN115286688A (zh) * 2022-05-07 2022-11-04 浙江湃肽生物股份有限公司 一种新型铜胜肽及其制备方法和用途

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JP2016520069A (ja) * 2013-05-10 2016-07-11 サザン・リサーチ・インスティテュート ＴＧＦ‐β活性阻害を介した疾患の治療のための化合物、組成物及び方法
EP2994156A4 (fr) * 2013-05-10 2017-01-11 Southern Research Institute Composés, compositions et procédés permettant le traitement des maladies par inhibition de l'activité de tgf-
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CN107098950A (zh) * 2017-06-13 2017-08-29 湖北泓肽生物科技有限公司 一种ghk或ahk三肽的合成方法
CN110790816A (zh) * 2018-08-02 2020-02-14 浙江湃肽生物有限公司 一种多肽活性化合物及新型铜胜肽和制备方法
WO2021247531A1 (fr) * 2020-06-01 2021-12-09 Balchem Corporation Chélates métalliques de diaminoacide ou chélates métalliques de triaminoacide
CN112263505A (zh) * 2020-10-29 2021-01-26 广州栋方生物科技股份有限公司 一种铜肽组合物及其制备方法和应用
CN115124593A (zh) * 2021-03-25 2022-09-30 深圳市图微安创科技开发有限公司 一种高纯度GHK-Cu的合成方法
CN114636739A (zh) * 2022-03-07 2022-06-17 西北工业大学 一种基于三胜肽修饰的固态多纳米孔的铜离子超痕量检测的方法
CN114636739B (zh) * 2022-03-07 2024-04-16 西北工业大学 一种基于三胜肽修饰的固态多纳米孔的铜离子超痕量检测的方法
CN115286688A (zh) * 2022-05-07 2022-11-04 浙江湃肽生物股份有限公司 一种新型铜胜肽及其制备方法和用途

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