KR101224809B1 - Retinoic acid derivative, process for preparing the same, and cosmetic composition comprising the same - Google Patents
Retinoic acid derivative, process for preparing the same, and cosmetic composition comprising the same Download PDFInfo
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- KR101224809B1 KR101224809B1 KR1020120042495A KR20120042495A KR101224809B1 KR 101224809 B1 KR101224809 B1 KR 101224809B1 KR 1020120042495 A KR1020120042495 A KR 1020120042495A KR 20120042495 A KR20120042495 A KR 20120042495A KR 101224809 B1 KR101224809 B1 KR 101224809B1
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- SHGAZHPCJJPHSC-YCNIQYBTSA-N retinoic acid group Chemical class C\C(=C/C(=O)O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title claims abstract description 58
- 239000002537 cosmetic Substances 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 229930002330 retinoic acid Natural products 0.000 claims abstract description 21
- 229960001727 tretinoin Drugs 0.000 claims abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229920005989 resin Polymers 0.000 claims abstract description 12
- 239000011347 resin Substances 0.000 claims abstract description 12
- 229920005990 polystyrene resin Polymers 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims abstract description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 3
- LUULAWGQWYTHTP-UHFFFAOYSA-N 1-methylpyrrolidin-2-one;piperidine Chemical compound C1CCNCC1.CN1CCCC1=O LUULAWGQWYTHTP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000037303 wrinkles Effects 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- 230000009759 skin aging Effects 0.000 claims description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
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- 239000000516 sunscreening agent Substances 0.000 claims description 2
- 230000003796 beauty Effects 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 102000008186 Collagen Human genes 0.000 abstract description 14
- 108010035532 Collagen Proteins 0.000 abstract description 14
- 229920001436 collagen Polymers 0.000 abstract description 14
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- 150000001408 amides Chemical class 0.000 abstract description 5
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- 239000004475 Arginine Substances 0.000 description 20
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 20
- 150000001413 amino acids Chemical class 0.000 description 16
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
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- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 235000019155 vitamin A Nutrition 0.000 description 3
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- 229940045997 vitamin a Drugs 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 102000012422 Collagen Type I Human genes 0.000 description 2
- 108010022452 Collagen Type I Proteins 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 206010040880 Skin irritation Diseases 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
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- 230000001153 anti-wrinkle effect Effects 0.000 description 2
- 239000012888 bovine serum Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
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- 231100001083 no cytotoxicity Toxicity 0.000 description 2
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- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
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- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical group C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
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- 239000003906 humectant Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/18—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by nitrogen atoms
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Cosmetics (AREA)
Abstract
Description
본 발명은 레티노산과 알기닌 또는 펩타이드가 결합된 레티노산 유도체 및 이의 제조 방법에 관한 것이다. 보다 상세하게는, 본 발명은 레티노산과 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드와 결합된 레티노산 유도체 및 이의 제조 방법에 대한 것이다.The present invention relates to a retinoic acid derivative in which retinoic acid and arginine or a peptide are bound, and a method for preparing the same. More specifically, the present invention relates to a retinoic acid derivative coupled to a peptide consisting of two to five amino acids comprising retinoic acid and arginine or at least one arginine and a method for preparing the same.
화장품 분야에서 주름의 개선과 예방을 위한 다양한 기능성 원료가 개발되고 있다. 이러한 주름 개선 및 예방용 화장품 중, 비타민을 주성분으로 하는 화장품이 현재까지 가장 대표적이나, 안정성 측면에서 다른 재료에 비해 열세이기 때문에 이를 개선하려는 연구가 진행되고 있다.Various functional raw materials are being developed for improving and preventing wrinkles in the cosmetic field. Among the cosmetics for wrinkle improvement and prevention, cosmetics based on vitamins are the most representative until now, but research is being conducted to improve them because they are inferior to other materials in terms of stability.
가장 널리 알려진 주름 개선 원료 가운데 하나는 비타민 A류이다. 비타민 A는 통칭 레티노이드(retinoid)라 하며, 레티놀(retinol; 비타민 A), 레티노산(retinoic acid; 비타민 A산), 레티날(retinal) 등이 포함된다.One of the most widely known ingredients for wrinkle improvement is vitamin A. Vitamin A is commonly referred to as a retinoid, and includes retinol (vitamin A), retinoic acid (vitamin A acid), retinal, and the like.
레티노산은 피부자극성이 있어 화장품에 사용되지 못하나, 피부 노화 방지에 유효하다는 것이 알려져, 그 유도체인 레티놀이나 팔미틸산 레티놀(retinol palmitate) 등이 개발된 바 있다.Retinoic acid is not used in cosmetics because of skin irritation, but is known to be effective in preventing skin aging, and derivatives thereof, such as retinol and retinol palmitate, have been developed.
레티놀은 주름 개선 효과가 가장 우수한 성분 중의 하나로서, 콜라겐의 합성을 촉진하여 주름을 근본적으로 개선하는 효과가 있으나, 빛, 열 또는 산소에 의해 쉽게 파괴된다. 따라서, 레티노산에 펩타이드를 결합시켜, 레티노산의 콜라겐 합성 증진 능력을 유지 혹은 향상시키면서도, 세포 독성 및 피부 자극성이 없고, 안정성이 있는 물질을 합성하고자 하는 연구가 진행되고 있다.Retinol is one of the best anti-wrinkle effects, and promotes collagen synthesis to fundamentally improve wrinkles, but is easily destroyed by light, heat or oxygen. Therefore, studies have been conducted to combine a peptide to retinoic acid to synthesize a substance having no cytotoxicity and skin irritation and stability while maintaining or improving collagen synthesis enhancing ability of retinoic acid.
펩타이드는 아미노산의 중합분자로서, 일반적으로 2 내지 99개의 아미노산 중합체를 일컫으며, 분자량은 100,000 이하이다. 아미노산은 단백질의 기본 구성 단위로서, 아민기와 카르복시기 외에 다양한 잔기를 가지고 있는 생물학적 활성을 지닌 분자이다.Peptides are polymerized molecules of amino acids, generally 2 to 99 amino acid polymers, with a molecular weight of 100,000 or less. Amino acids are basic structural units of proteins and are biologically active molecules having various residues in addition to amine groups and carboxyl groups.
아미노산의 잔기는 크게 소수성 잔기와 친수성 잔기로 나눌 수 있는데, 탄화수소 사슬이나 고리를 갖는 아미노산은 소수성을 띠게 되며, 하이드록시기나 charge를 갖는 아미노산은 친수성을 띠게 된다.The amino acid residues can be broadly divided into hydrophobic residues and hydrophilic residues. Amino acids having hydrocarbon chains or rings are hydrophobic, and amino acids having hydroxyl groups or charges are hydrophilic.
펩타이드 결합은 카르복시기(-COOH)와 아민기(-NH2)와의 축합반응에 의해여 생성되는 아마이드(-CONH-)결합이다. 펩타이드를 구성하는 아미노산의수가 2,3,4 등의 펩타이드는 그 수에 따라서 각각 디펩타이드(dipeptide), 트리펩타이드(tripeptide), 테트라펩타이드(tetrapeptide) 등이라고 한다. 약 10개 이하의 아미노산 중합체를 올리고 펩타이드(oligopeptide)라고 하며, 그 이상의 다수 아미노산이 아마이드 결합으로 연결되는 것을 폴리펩타이드라고 한다.Peptide bonds are amide (-CONH-) bonds produced by the condensation reaction between a carboxyl group (-COOH) and an amine group (-NH 2 ). Peptides having 2, 3, 4 or the like amino acids constituting the peptide are called dipeptides, tripeptides, and tetrapeptides, respectively, depending on the number. Up to about 10 amino acid polymers are called oligopeptides, and many more amino acids are linked by amide bonds.
알기닌(arginine)은 친수성 아미노산이고, 세포 내에서 물질대사를 통해 프롤린으로 변환되어, 결과적으로 콜라겐 합성 증진을 돕는 것으로 알려져 있다.Arginine is a hydrophilic amino acid and is known to be converted to proline through metabolism in cells, resulting in enhanced collagen synthesis.
본 발명자들은 생체 친화적이며 세포 독성이 없고, 콜라겐 합성 증진 활성이 뛰어나게 향상된 레티노산 유도체를 합성하여 그 활성을 구체적으로 확인함으로써, 본 발명을 완성하기에 이르렀다.The present inventors have completed the present invention by synthesizing a retinoic acid derivative which is biocompatible, has no cytotoxicity, and has excellent collagen synthesis enhancing activity and specifically confirms the activity thereof.
본 발명의 기본적인 목적은 하기 화학식 (I)의 레티노산 유도체를 제공하는 것이다. 하기 화학식 (I)에서 R은 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드이고, R의 C-말단은 -CONH2 또는 -COOH이다.The basic object of the present invention is to provide a retinoic acid derivative of the formula (I). In formula (I), R is a peptide consisting of 2 to 5 amino acids comprising arginine or at least one arginine, and the C-terminus of R is -CONH 2 or -COOH.
본 발명의 다른 목적은 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드와 레티노산을 반응시키는 단계를 포함하는, 상기 화학식 (I)의 레티노산 유도체 제조 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a retinoic acid derivative of the above formula (I), comprising reacting a retinic acid with a peptide consisting of arginine or at least one arginine and from two to five amino acids. .
본 발명의 또 다른 목적은 상기 화학식 (I)의 레티노산 유도체 및 생리학적으로 허용되는 화장품 기제를 포함하는 주름 개선 및 피부 노화 방지용 화장품 조성물을 제공하는 것이다.Still another object of the present invention is to provide a cosmetic composition for improving wrinkles and preventing skin aging, comprising the retinoic acid derivative of formula (I) and a physiologically acceptable cosmetic base.
전술한 본 발명의 기본적인 목적은 하기 화학식 (I)의 레티노산 유도체를 제공함으로써 달성될 수 있다. 하기 화학식 (I)에서 R은 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드이고, R의 C-말단은 -CONH2 또는 -COOH이다.The basic object of the present invention described above can be achieved by providing a retinoic acid derivative of formula (I). In formula (I), R is a peptide consisting of 2 to 5 amino acids comprising arginine or at least one arginine, and the C-terminus of R is -CONH 2 or -COOH.
본 발명의 화학식 (I)의 레티노산 유도체는, 레티노산과 대비하여, 생체 독성이 더 낮고, 콜라겐 합성 활성을 더 향상시킨다.The retinoic acid derivatives of formula (I) of the present invention have lower biotoxicity and further improve collagen synthesis activity, as compared to retinoic acid.
본 발명의 레티노산 유도체에서, 상기 R은 -Gly-Arg-Glu-Pro-NH2 또는 -Phe-Arg-Tyr-NH2일 수 있다.In the retinoic acid derivative of the present invention, R may be -Gly-Arg-Glu-Pro-NH 2 or -Phe-Arg-Tyr-NH 2 .
전술한 본 발명의 다른 목적은 (i) 고체 수지상에 알기닌을 도입하거나, 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드를 합성하는 단계; (ii) 상기 (i)단계의 알기닌 또는 펩타이드에 레티노산을 결합시키는 단계; 및 (iii) 상기 고체상 수지로부터 하기 화학식 (I)의 화합물을 분리하는 단계를 포함하는, 하기 화학식 (I)의 레티노산 유도체 제조 방법을 제공함으로써 달성될 수 있다. 하기 화학식 (I)에서 R은 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드이고, R의 C-말단은 -CONH2 또는 -COOH이다.Another object of the present invention described above is (i) introducing an arginine on a solid resin or synthesizing a peptide consisting of 2 to 5 amino acids including at least one arginine; (ii) binding retinoic acid to the arginine or peptide of step (i); And (iii) separating the compound of formula (I) from the solid-phase resin, by providing a method for preparing a retinoic acid derivative of formula (I). In formula (I), R is a peptide consisting of 2 to 5 amino acids comprising arginine or at least one arginine, and the C-terminus of R is -CONH 2 or -COOH.
본 발명의 레티노산 유도체 제조 방법에 사용되는 고체 수지는 아미노메틸 폴리스티렌 수지(aminomethyl polystyrene resin) 또는 2-CTC 폴리스티렌 수지(2-chlorotrityl chloride polystyrene resin)일 수 있다. 또한, 상기 고체 수지는 링커가 도입된 수지일 수 있으며, 상기 링커는 링크 아마이드(Rink amide)일 수 있다.The solid resin used in the retinoic acid derivative manufacturing method of the present invention may be an aminomethyl polystyrene resin or 2-CTC polystyrene resin. In addition, the solid resin may be a resin in which a linker is introduced, and the linker may be a link amide.
본 발명의 레티노산 유도체 제조 방법의 (i)단계는 종래의 고체상 합성법에 따른 것이다. 즉, 링커(linker)가 도입된 고체상 수지 또는 링커가 도입되지 아니한 고체상 수지에 2 당량의 Fmoc-아미노산을 커플링제인 BOP(benzotriazole-1-yloxy-tris(dimethylamino)-phosphoniumhexafluoro-phosphate), HOBt(1-Hydroxybenzotriazole), DIEA(diisopropylethylamine) 및 N-메틸피롤리돈(NMP, N-methylpyrrolidone)의 존재하에서 반응시킴으로써 펩타이드를 합성한다. 물론, 상기 고체 수지에 알기닌만을 도입하는 방법도 당업계에 공지된 방법에 따라 수행될 수 있다.Step (i) of the retinoic acid derivative manufacturing method of the present invention is according to the conventional solid-phase synthesis method. That is, BOP (benzotriazole-1-yloxy-tris (dimethylamino) -phosphoniumhexafluorofluorophosphate), HOBt ( 1-Hydroxybenzotriazole), DIEA (diisopropylethylamine ) , and N - synthesizing the peptide by reaction in the presence of methyl-pyrrolidone (NMP, N -methylpyrrolidone). Of course, a method of introducing only arginine to the solid resin may also be performed according to methods known in the art.
본 발명의 레티노산 유도체 제조 방법의 (ii)단계에서, 레티노산은 Fmoc-아미노산과 동일한 방법으로 도입된다.In step (ii) of the retinoic acid derivative preparation method of the present invention, retinoic acid is introduced by the same method as Fmoc-amino acid.
상기 펩타이드의 C-말단은 상기 수지의 종류 및 링커의 종류에 따라 달라진다. 링크 아마이드가 도입된 아미노메틸 수지를 사용할 경우, 상기 펩타이드 C-말단은 아마이드(-CONH2)가 된다. 또한, 2-CTC 폴리스티렌 수지를 사용하는 경우에는, 상기 펩타이드의 C-말단이 카르복시기(-COOH)가 된다.The C-terminus of the peptide depends on the type of resin and the type of linker. When using an aminomethyl resin having a link amide introduced therein, the peptide C-terminus becomes an amide (-CONH 2 ). In the case of using 2-CTC polystyrene resin, the C-terminus of the peptide is a carboxy group (-COOH).
본 발명의 레티노산 유도체 제조 방법의 (iii)단계에서 트리플루오르아세트산 및 디클로로메탄을 사용하여 상기 화학식 (I)의 화합물을 상기 고체 수지로부터 분리할 수 있다.In step (iii) of the retinoic acid derivative manufacturing method of the present invention, the compound of formula (I) may be separated from the solid resin using trifluoroacetic acid and dichloromethane.
전술한 본 발명의 또 다른 목적은 하기 화학식 (I)의 레티노산 유도체 및 생리학적으로 허용되는 화장품 기제를 포함하는 주름 개선 및 피부 노화 방지용 화장품 조성물을 제공함으로써 달성될 수 있다. 하기 화학식 (I)에서 R은 알기닌 또는 적어도 하나의 알기닌을 포함하는 2개 내지 5개의 아미노산으로 이루어진 펩타이드이고, R의 C-말단은 -CONH2 또는 -COOH이다.Another object of the present invention described above can be achieved by providing a cosmetic composition for anti-wrinkle and skin aging comprising a retinoic acid derivative of formula (I) and a physiologically acceptable cosmetic base. In formula (I), R is a peptide consisting of 2 to 5 amino acids comprising arginine or at least one arginine, and the C-terminus of R is -CONH 2 or -COOH.
전술한 바와 같이, 본 발명의 화학식 (I)의 레티노산 유도체는, 레티노산과 대비하여, 생체 독성이 더 낮고, 콜라겐 합성 활성을 더 향상시킨다. 따라서 본 발명의 레티노산 유도체는 피부 주름 개선 및 피부 노화 방지용 화장품에 사용하기에 적합하다.As mentioned above, the retinoic acid derivative of the formula (I) of the present invention has lower biotoxicity and further improves collagen synthesis activity, as compared to retinoic acid. Therefore, the retinoic acid derivative of the present invention is suitable for use in cosmetics for improving skin wrinkles and preventing skin aging.
본 발명의 화장품 조성물에 포함되는 화장품 기제에는, 당업계에 알려진 바와 같이, 유분, 물, 계면활성제, 보습제, 저급 알콜, 증점제, 킬레이트제, 색소, 방부제, 향료 등이 있다.Cosmetic bases included in the cosmetic composition of the present invention include oils, water, surfactants, humectants, lower alcohols, thickeners, chelating agents, colorants, preservatives, fragrances, and the like, as known in the art.
본 발명의 화장품 조성물은 화장수, 유액, 크림, 팩 또는 미용액의 제형으로 제조될 수 있다.Cosmetic compositions of the present invention may be prepared in the form of a lotion, emulsion, cream, pack or cosmetic liquid.
또한, 자외선이 주름 생성의 주요한 원인임을 고려하여, 상기 화장품 조성물은 당업계에서 화장품에 사용될 수 있는 것으로 알려져 있는 자외선 차단제 또는 광산란제 등을 추가로 포함할 수 있다.In addition, considering that ultraviolet rays are a major cause of wrinkles, the cosmetic composition may further include a sunscreen or a light scattering agent and the like that are known to be used in cosmetics in the art.
본 발명의 레티노산 유도체는, 종래에 콜라겐 합성 증진 활성을 통해 탁월한 주름개선 및 피부 노화 방지 화장품 원료로 사용되어 온 레티노산과 대비하여, 세포 독성이 더 낮고, 콜라겐 합성 활성이 더 향상된 화합물이다.The retinoic acid derivative of the present invention is a compound having lower cytotoxicity and improved collagen synthesis activity as compared to retinoic acid, which has conventionally been used as an excellent wrinkle improvement and anti-aging cosmetic raw material through collagen synthesis enhancement activity.
본 발명의 레티노산 유도체를 포함하는 화장품 조성물의 피부의 주름 개선 및 피부 노화 방지 효과는 종래의 레티노산 함유 화장품보다 더 우수하다.The wrinkle improvement and anti-aging effects of the skin of the cosmetic composition comprising the retinoic acid derivative of the present invention are superior to the conventional retinoic acid-containing cosmetics.
도 1은, 본 발명의 실시예 4에서 레티노산 유도체를 세포에 처리한 경우, 상기 레티노산 유도체가 세포 독성을 나타내지 아니한다는 점을 보여 준다.
도 2는, 본 발명의 레티노산의펩타이드 유도체가 레티노산, 레티놀 및 비타민 C보다 콜라겐 합성 증진 능력이 탁월하다는 실시예 5의 결과를 보여 준다.1 shows that when the retinoic acid derivative in Example 4 was treated to cells, the retinoic acid derivative did not exhibit cytotoxicity.
Figure 2 shows the results of Example 5 that the peptide derivative of retinoic acid of the present invention is superior in collagen synthesis enhancing ability than retinoic acid, retinol and vitamin C.
이하, 다음의 실시예 또는 도면을 들어 본 발명을 보다 구체적으로 설명하고자 한다. 그러나 다음의 실시예 또는 도면에 대한 설명은 본 발명의 구체적인 실시 태양을 특정하여 설명하고자 하는 것일 뿐이며, 본 발명의 권리 범위를 이들에 기재된 내용으로 한정하거나 제한해석하고자 의도하는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples or drawings. It is to be understood, however, that the following description of the embodiments or drawings is intended to illustrate specific embodiments of the invention and is not intended to be exhaustive or to limit the scope of the invention to the precise forms disclosed.
실시예 1. 폴리스티렌 수지를 이용한 고체상 펩타이드 합성Example 1. Solid phase peptide synthesis using polystyrene resin
고체상 합성법을 이용하여, 링커가 도입된 폴리스티렌 수지 상에서 2 당량의 Fmoc-아미노산을 커플링 시약 BOP(benzotriazole-1-yloxy-tris(dimethylamino)-phosphoniumhexafluoro-phosphate), HOBt(1-Hydroxybenzotriazole), DIEA(Diisopropylethylamine) 및 N-메틸피롤리돈(NMP, N-methylpyrrolidone)의 존재하에서 2시간 동안 반응시켜 펩타이드를 합성하였다. 이후, 20% 피페리딘/NMP(piperidine/NMP)를 각각 3분, 7분씩 2회 처리하여 Fmoc을 제거하였다.
Using a solid phase synthesis method, two equivalents of Fmoc-amino acids were transferred onto a linker-introduced polystyrene resin using the coupling reagent BOP (benzotriazole-1-yloxy-tris (dimethylamino) -phosphoniumhexafluoro-phosphate), HOBt (1-Hydroxybenzotriazole), and DIEA ( Diisopropylethylamine) and N - by reacting for 2 hours in the presence of methyl-pyrrolidone (NMP, N -methylpyrrolidone) was synthesized peptide. Thereafter, 20% piperidine / NMP (piperidine / NMP) was treated twice for 3 minutes and 7 minutes, respectively, to remove Fmoc.
실시예Example 2. 알기닌을 포함하는 2. Containing Arginine 펩타이드가Peptide 도입된 새로운 레티노산 유도체의 제조 Preparation of New Retinoic Acid Derivatives
실시예 1의 펩타이드가 합성되어 있는 폴리스티렌 수지상에서, 레티노산을 Fmoc-아미노산과 같은 방식으로 도입하되 반응시간은 3시간으로 하여 신규한 레티노산 유도체를 제조하였다. 그 후, 25% 트리플루오르아세트산(trifluoroacetic acid; TFA)/디클로로메탄(dichloromethane; DCM)으로 처리하여 목표하는 물질을 상기 수지에서 분리하였다. 이후, 에테르를 사용하여 침전시켜서 연노랑색의 레티노산 유도체를 파우더 형태로 얻었다.
On the polystyrene resin in which the peptide of Example 1 was synthesized, a retinoic acid derivative was prepared by introducing retinoic acid in the same manner as Fmoc-amino acid but with a reaction time of 3 hours. The target material was then separated from the resin by treatment with 25% trifluoroacetic acid (TFA) / dichloromethane (DCM). Thereafter, precipitated using ether to give a pale yellow retinoic acid derivative in powder form.
실시예Example 3. 레티노산 유도체의 확인 3. Identification of Retinoic Acid Derivatives
실시예 2에서 얻은 결과물을 RP-HPLC를 사용하여 순도를 확인한 후에, ESI-MS를 사용하여 레티노산 유도체임을 확인하였다. 합성된 화합물의 화학식은 하기한 바와 같다. LC-MS로 분석한 결과 이 물질은 레티노산의 트랜스(trans)와 시스(cis) 이성질체를 포함하는 순수한 레티노산 유도체임을 확인하였다(표 1).
After confirming the purity of the result obtained in Example 2 using RP-HPLC, it was confirmed that the retinoic acid derivative using ESI-MS. The chemical formula of the synthesized compound is as follows. Analysis by LC-MS confirmed that this material was a pure retinoic acid derivative containing the trans and cis isomers of retinoic acid (Table 1).
aHPLC에 의해 결정
a determined by HPLC
실시예Example 4. 레티노산 유도체의 세포 독성 테스트 4. Cytotoxicity Testing of Retinoic Acid Derivatives
사람 섬유아세포(ATCC 2076)를 소혈청 10%를 함유한 IMDM(Iscove's modified Dulbeco's medium; BRL, USA)을 사용하여 60 mm 접시(dish)에 1 × 106의 밀도로 분주한 후 24시간 동안 37℃에서 배양하였다. 그 후, 배지를 소혈청이 함유되지 아니한 IMDM으로 교체하고, 시료를 첨가하여 24시간 동안 37℃에서 배양하였다. 사람 섬유아세포에 각각 5 μM 농도로 처리한 레티노산 유도체 모두 세포 독성을 보이지 아니하였다(도 1).
Human fibroblasts (ATCC 2076) were dispensed in a 60 mm dish at a density of 1 × 10 6 using an IMDMve's modified Dulbeco's medium (BRL, USA) containing 10% bovine serum, followed by 37 for 24 hours. Incubated at ℃. The medium was then replaced with IMDM free of bovine serum and incubated at 37 ° C. for 24 hours with the addition of samples. All of the retinoic acid derivatives treated at 5 μM concentration in human fibroblasts did not show cytotoxicity (FIG. 1).
실시예Example 5. 레티노산 유도체의 콜라겐 합성 증진 활성 테스트 5. Collagen Synthesis Enhancement Activity Test of Retinoic Acid Derivatives
배양한 세포의 배지를 제거하고 1 mL의 트리졸(Invitrogen)을 첨가하여 인비트로젠사의 RNA 분리법에 따라 RNA를 분리하였다. 자외선 검출기를 이용하여 260 nm에서 정량한 후, 역전사 중합 반응(reverse transcription-polymerase chain reaction)을 실시하였다. 역전사 중합 반응은 올인원 역전사 중합 반응 키트(All-in-one RT-PCR kit, Rexgen)를 사용하고, 매뉴얼에 따라 진행하였다. 각 밴드(band)를 정량한 결과 레티노산의 펩타이드가 1형 콜라겐(collagen type-1_의 유전자 발현을 증가시키는 것을 확인하였다. 레티노산-글리신-발린-알라닌-프롤린(RA-GVAP)과 레티노산-글리신-발린-알라닌-프롤린-글리신(RA-GVAPG)은 엘라스틴 펩타이드 유도체로서 1형 콜라겐의 유전자 발현을 각 1.2배, 1.4배 증가시켰다. 특히, 알기닌을 포함하는 펩타이드를 결합시킨, 레티노산-페닐알라닌-알기닌-티로신(RA-FRY), 레티노산-글리신-알기닌-글루탐산-프롤린(RA-GREP)은 1형 콜라겐 유전자 발현을 2~3배 가량 크게 증진시켰다(도 2). 이에 반해, 양성 대조군(positive control)으로서 사용된 비타민 C는 상기 펩타이드보다 114배 높은 농도로 처리하여도, 1형 콜라겐 유전자 발현을 1.3배 정도만 증진시키는 것으로 나타났다. 따라서 본 발명의 레티노산의 펩타이드들이 뛰어난 효능을 가지는 것을 확인하였다.The culture medium of the cultured cells was removed and 1 mL of Trizol (Invitrogen) was added to separate RNA according to the RNA separation method of Invitrogen. After quantification at 260 nm using an ultraviolet detector, a reverse transcription-polymerase chain reaction was performed. The reverse transcription polymerization was performed using an all-in-one reverse transcription polymerization kit (All-in-one RT-PCR kit, Rexgen), according to the manual. Quantification of each band confirmed that the peptide of retinoic acid increased gene expression of collagen type 1 (collagen type-1_. Retinoic acid-glycine-valine-alanine-proline (RA-GVAP) and retinoic acid. Acid-glycine-valine-alanine-proline-glycine (RA-GVAPG) increased the gene expression of collagen type 1.2 and 1.4-fold as elastin peptide derivatives, in particular, retinoic acid bound peptides containing arginine. -Phenylalanine-arginine-tyrosine (RA-FRY) and retinoic acid-glycine-arginine-glutamic acid-proline (RA-GREP) significantly enhanced type 1 collagen gene expression by 2-3 times (Fig. 2). Vitamin C, used as a positive control, was found to enhance only 1.3-fold type 1 collagen gene expression, even at 114-fold higher concentrations than the peptides. It confirmed that it has the ability.
Claims (10)
상기 화학식 (I)에서 R은 -Gly-Arg-Glu-Pro-NH2이다.Retinoic acid derivatives of formula (I)
R in formula (I) is -Gly-Arg-Glu-Pro-NH 2 .
(ii) 상기 (i)단계의 -Gly-Arg-Glu-Pro에 레티노산을 결합시키는 단계; 및
(iii) 25% 트리플루오르아세트산 및 디클로로메탄으로 처리하여 상기 고체상 수지로부터 하기 화학식 (I)의 화합물을 분리하는 단계를 포함하는, 하기 화학식 (I)의 레티노산 유도체 제조 방법:
상기 화학식 (I)에서 R은 -Gly-Arg-Glu-Pro-NH2이다.(i) 2 equivalents of Fmoc-amino acid on solid aminomethyl polystyrene resin or 2-chlorotrityl chloride polystyrene resin with linkamide introduced in the presence of coupling reagents BOP, HOBt, DIEA and N-methylpyrrolidone. Reacting for a period of time to synthesize -Gly-Arg-Glu-Pro, and then removing Fmoc by treating 20% piperidine / NMP twice for 3 minutes and 7 minutes, respectively;
(ii) binding retinoic acid to -Gly-Arg-Glu-Pro of step (i); And
(iii) separating the compound of formula (I) from the solid resin by treating with 25% trifluoroacetic acid and dichloromethane:
R in formula (I) is -Gly-Arg-Glu-Pro-NH 2 .
상기 화학식 (I)에서 R은 -Gly-Arg-Glu-Pro-NH2이다.A cosmetic composition for improving wrinkles and preventing skin aging comprising a retinoic acid derivative of formula (I) and a physiologically acceptable cosmetic base:
R in formula (I) is -Gly-Arg-Glu-Pro-NH 2 .
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| WO2018208124A3 (en) * | 2017-05-11 | 2019-03-28 | (주)케어젠 | Conjugate of isotretinoin and peptide |
| KR102420818B1 (en) * | 2021-11-29 | 2022-07-14 | (주)아크에이르 | Photoisomerization conversion reaction of 9-cis Retinoic acid in all-trans and its application method. |
| US12005123B2 (en) | 2017-05-11 | 2024-06-11 | Caregen Co., Ltd. | Conjugate of isotretinoin and peptide |
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| KR20070038509A (en) * | 2004-07-09 | 2007-04-10 | 디에스엠 아이피 어셋츠 비.브이. | Amino, amino acid or peptide conjugates of retinoic acid |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018208124A3 (en) * | 2017-05-11 | 2019-03-28 | (주)케어젠 | Conjugate of isotretinoin and peptide |
| CN110612125A (en) * | 2017-05-11 | 2019-12-24 | 凯尔格恩有限公司 | Conjugates of isotretinoin and peptides |
| US11351266B2 (en) | 2017-05-11 | 2022-06-07 | Caregen Co., Ltd. | Conjugate of isotretinoin and peptide |
| CN110612125B (en) * | 2017-05-11 | 2023-06-02 | 凯尔格恩有限公司 | Conjugates of isotretinoin and peptides |
| US12005123B2 (en) | 2017-05-11 | 2024-06-11 | Caregen Co., Ltd. | Conjugate of isotretinoin and peptide |
| KR102420818B1 (en) * | 2021-11-29 | 2022-07-14 | (주)아크에이르 | Photoisomerization conversion reaction of 9-cis Retinoic acid in all-trans and its application method. |
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