KR100439467B1 - Use of 3-position cyclosporin derivatives for hair growth - Google Patents

Use of 3-position cyclosporin derivatives for hair growth Download PDF

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KR100439467B1
KR100439467B1 KR10-2002-0070419A KR20020070419A KR100439467B1 KR 100439467 B1 KR100439467 B1 KR 100439467B1 KR 20020070419 A KR20020070419 A KR 20020070419A KR 100439467 B1 KR100439467 B1 KR 100439467B1
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methyl
cyclosporin
hair
hair growth
methylamino
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KR20020089300A (en
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김상년
안호정
이창우
이민호
김정훈
김종일
김승진
조호성
이헌식
김형진
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주식회사 엘지생활건강
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/12—Preparations containing hair conditioners
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides

Abstract

본 발명은 발모력이 우수한 사이클로스포린(Cyclosporin) 유도체를 주성분으로 하는 모발 성장 촉진제에 관한 것이다. 구체적으로는 사이클로스포린의 3위치가 치환된 유도체를 유효성분으로 함유하는 모발 성장 촉진제에 관한 것이다.The present invention relates to a hair growth promoter mainly comprising a cyclosporin derivative having excellent hair growth ability. Specifically, the present invention relates to a hair growth promoter containing a derivative substituted with the 3-position of cyclosporin as an active ingredient.

Description

모발 성장 효과를 갖는 사이클로스포린 3 위치 유도체를 유효성분으로 하는 모발 성장 촉진제 {Use of 3-position cyclosporin derivatives for hair growth}Use of 3-position cyclosporin derivatives for hair growth using a cyclosporine 3-position derivative having a hair growth effect as an active ingredient

본 발명은 사이클로스포린(cyclosporin) 유도체를 유효성분으로 하는 모발 성장 촉진제에 관한 것이다.The present invention relates to a hair growth accelerator comprising a cyclosporin derivative as an active ingredient.

구체적으로는, 사이클로스포린의 3위치가 치환된 유도체를 유효성분으로 함유하는 모발 성장 촉진제에 관한 것이다.Specifically, it relates to a hair growth accelerator containing a derivative substituted with the 3-position of cyclosporin as an active ingredient.

인체의 모발은 약 10 만 내지 15 만개 정도이며, 각각의 모발은 서로 다른주기를 가지며 성장기(anagen), 퇴행기(catagen), 휴지기(telogen)를 거쳐 성장, 탈락한다. 이러한 주기는 3 6 년에 걸쳐 반복되는데 그 결과 일일 평균 50 내지 100 개의 모발이 정상적으로 탈락하게 된다. 일반적으로 탈모증이라 함은 이러한 주기 중에서 성장기의 모발 비율이 짧아지고 퇴행기 또는 휴지기의 모발이 많아져 비정상적으로 모발이 탈락하는 숫자가 많아지는 것을 일컫는다.The human hair is about 100,000 to 150,000 pieces, each hair has a different cycle and grow and drop out through the anagen, catagen, telogen. This cycle is repeated over three to six years, with the result that on average 50-100 hairs fall out normally. Generally, the term alopecia refers to the increase in the number of hairs that fall abnormally due to shortening of the hair growth rate in the growth phase and more hair in the degenerative or resting phase.

탈모의 원인으로는 혈액순환 불량설, 남성호르몬 작용 과잉설, 피지 분비 과잉설, 과산화물, 세균 등에 의한 두피 기능 저하설, 유전적 요인, 노화, 스트레스 등이 논의되어 왔었다. 그러나 현재까지 탈모에 관한 명확한 원인은 밝혀져 있지 않으며, 최근 들어 식생활의 변화, 사회환경 등에 의한 스트레스의 증가 등으로 탈모로 고민하는 인구가 늘어나고 있는 추세이고 그 연령 또한 낮아지고 있으며, 여성의 탈모 인구도 늘어나고 있는 실정이다.The causes of alopecia have been discussed, such as poor blood circulation, excessive male hormone action, excessive sebum secretion, peroxide, bacteria, hypodermic function, genetic factors, aging, stress. However, to date, no clear cause of hair loss is known, and in recent years, a growing number of people are suffering from hair loss due to changes in diet and stress caused by social conditions. It is increasing.

이러한 탈모증의 치료나 예방에 있어서 현재까지 가장 널리 사용되는 제제는 미녹시딜 함유 제제로서, 현재까지 미국 FDA의 승인을 받은 두 가지 발모제 성분 중의 하나이다. 미녹시딜은 혈압강하의 목적으로 개발된 고혈압 치료제이었지만 사용상의 부작용으로 발모 현상이 나타나면서 현재에는 발모제로 더 유명한 약물이 되었다. 미녹시딜의 발모 작용 기전에 대해서는 정확히 밝혀져 있지는 않지만, 혈관 확장 효과를 통한 혈류량 증가로 모근에 영양을 공급하여 모발 성장을 촉진하는 것으로 생각되고 있다.The most widely used formulations for the treatment or prevention of such alopecia to date are minoxidil-containing formulations, and are currently one of two hair repellent components approved by the US FDA. Minoxidil was a drug for hypertension that was developed for the purpose of lowering blood pressure, but with the side effect of use, hair growth phenomenon has now become a more famous drug for hair growth. Although the mechanism of minoxidil's hair growth is not known exactly, it is thought to promote hair growth by nourishing hair roots by increasing blood flow through vasodilating effect.

이러한 혈류량 증가 모델은 미녹시딜이 모근을 구성하는 주요세포인 모유두(dermal papilla)에서 혈관 확장에 관련된 성장 인자인 혈관내피성장인자(VEGF; vascular endothelial growth factor)의 발현을 증가시킨다는 최근의 보고(Br. J. of Dermatol., 1998; 138; 407 411)에 의해서 간접적으로 증명된다. 또한 미녹시딜의 발모효과 기전에 있어 혈관 확장 효과 이외에도 체외 배양 중인 모근의 모유두 세포 활성화(Skin Pharmacol., 1996; 9; 3 8) 및 모낭 조직 배양에서 모낭의 성장을 촉진한다는 연구 보고(J. Invest. Dermatol., 1989; 92; 315 320) 등은 미녹시딜이 모근에 직접적인 성장 인자로 작용함을 시사하고 있다.This blood flow increase model is a recent report that minoxidil increases the expression of vascular endothelial growth factor (VEGF), a growth factor involved in vasodilation, in the dermal papilla, the major cell that makes up the hair root (Br. J. of Dermatol., 1998; 138; 407 411). In addition to the vasodilation effect in the hair growth effect of minoxidil, research reports that it promotes hair papillary cell activation of hair roots in vitro culture (Skin Pharmacol., 1996; 9; 3 8) and hair follicle growth in hair follicle tissue culture (J. Invest. Dermatol., 1989; 92; 315 320) and the like suggest that minoxidil acts as a direct growth factor on the hair root.

이밖에 최근에 발매가 시작된 머크(Merck)사의 프로페시아(Propecia) 주성분인 피나스테라이드(finasteride)는 남성호르몬 테스토스테론이 더 강력한 형태의 남성호르몬인 디히드로테스토스테론으로 전환되는 것을 억제한다. 1997년 12월 남성형 탈모증의 치료제로 1 ㎎ 타블렛이 FDA로부터 사용 승인을 받아 현재 시판 중으로, 임상결과 유의할 만한 효과를 나타내는 것으로 판명되었으나 일부 남성 기능 억제 부작용도 보고되고 있다(J. Am. Acad. Dermatol., 1998; 39; 578 589). 그러나 이 약물 또한 미녹시딜과 같이 임상효과가 그다지 탁월하지 못하고 부작용에 대한 우려 때문에 좀 더 우수한 발모제 탐색연구가 활발히 진행되고 있다.In addition, Merck's recently launched propecia, finasteride, inhibits the conversion of androgen testosterone to the more potent form of dihydrotestosterone. In December 1997, a 1 mg tablet was approved by the FDA for the treatment of androgenetic alopecia and is currently on the market. It has been shown to have a significant clinical effect, but some male side effects are reported (J. Am. Acad. Dermatol). , 1998; 39; 578 589). However, this drug, like minoxidil, is not very effective in clinical research, and researches for more excellent hair repellents are being actively conducted due to concerns about side effects.

한편, 사이클로스포린 류는 대표적인 면역 억제제인 동시에 바이러스, 진균, 원생동물을 억제하는 효과 및 부작용으로 신장독성, 간독성, 고혈압, 치주조직 비대, 발모효과 등 다양한 생리효과를 갖고 있다(Advances in Pharmacol., 1996; 35; 114 246 및 Drug Safety, 1994; 10; 310 317). 그 중 대표적인 사이클로스포린 A는 여러 개의 N-메틸아미노산(N-methyl amino acid)과 8번 위치에 D-알라닌(D-alanine)을 갖는 11 개 아미노산으로 구성된 환형의 펩타이드로 다음의 구조식 1로나타낸다.Cyclosporins, on the other hand, have various physiological effects such as renal toxicity, hepatotoxicity, hypertension, periodontal tissue enlargement, and hair growth effect as a representative immunosuppressive agent, and inhibiting viruses, fungi and protozoa (Advances in Pharmacol., 1996 35; 114 246 and Drug Safety, 1994; 10; 310 317). Representative cyclosporin A is a cyclic peptide consisting of 11 N-methyl amino acid (N-methyl amino acid) and 11 amino acids having D-alanine (D-alanine) at position 8 is represented by the following structural formula 1.

[구조식 1][Formula 1]

이 식에서,In this expression,

MeBmt는 N-메틸-(4R)-4-[(E)-2-뷰텐일]-4-메틸-L-트레오닌(N-methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine)이며,MeBmt is N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine (N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine)

Abu는 L- 아미노부티릭산(L- aminobutyric acid)이며,Abu is L-aminobutyric acid,

Sar은 살코신(Sarcosine)이며,Sar is Sarcosine,

MeLeu는 N-메틸-L-루신(N-methyl-L-leucine)이며,MeLeu is N-methyl-L-leucine,

Val은 L-발린(L-valine)이며, Ala는 L-알라닌(L-alanine)이며,Val is L-valine, Ala is L-alanine,

DAla는 D-알라닌(D-alanine)이며,DAla is D-alanine,

MeVal은 N-메틸-L-발린(N-methyl-L-Valine)이다.MeVal is N-methyl-L-Valine.

상기 사이클로스포린 A의 아미노산의 형태는 다른 언급이 없으면 L-배치(L-configuration)이며, 아미노산 잔기 번호는 [구조식 1]에서 보듯이 MeBmt를 1번으로 하고 시계방향 순서대로 마지막 MeVal (N-메틸-L-발린(N-methyl-L-Valine)를 11번 으로 지정 하였다. 사이클로스포린 A부터 사이클로스포린 Z의 다양한 유도체 명명법은 일반적으로 사용되는 방법을 따랐다 (Helv. Chim. Acta, 1987;70;13-36). 예를 들어 사이클로스포린 A의 2번 잔기인 Abu (L-α아미노부티릭산,L-αaminobutyric acid)만 각각 알라닌(L-alanine), 트레오닌(L-threonine), 발린(L-valine), 또는 노르발린(L-norvaline)으로 치환된 사이클로스포린 분자를 각각 사이클로스포린 B, C, D 및 G로 표시하였다. 또한 사이클로스포린 유도체 잔기가 사이클로스포린 A분자와 틀린 경우 유도체의 명명은 치환된 잔기만 표시하였다. 예를 들어 사이클로스포린 A의 3번 잔기인 살코신이 [N-메틸-D-아미노부티릭산3] ([N-methyl-D-Abu3]) 및 [N-메틸-D-노르발린3]([N-methyl-D-Nva3])으로 치환된 경우 각각 [N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3] cyclosporin A와 [N-메틸-D-노르발린3] 사이클로스포린 A([N-methyl-D-Nva3] cyclosporin A)으로 명명 하였다. 또 일반적으로 사용되는 아미노산 약어법 예를 들어 MeLeu은 N-메틸-L-루신을, MeIle는 N-메틸-L-이소루신을, MeVal는 N-메틸-L-발린을, MeAla는 N-메틸-L-알라닌을, MeNva는 N-메틸-L-노르발린을, Leu는 L-루신을, Ile는 L-이소루신을, Sar는 살코신을, Ser은 L-세린을, Val은 L-발린을, Ala는 L-알라닌을, DAla는 D-알라닌을, Abu를 Ｌ－아미노부티릭산(Abu, L-aminobutyric acid), Thr는 L-트레오닌 또는 Nva는 L-노르발린( L-norvaline)이며, 의미 하는 것으로 사용 하였다. 또한 사이클로스포린 분자의 7번 아미노산 카르보닐 산소에 황(sulfur)이 치환된 유도체는 문헌에 따라서 각각 사이클로스포린 7-티오아미드(Cyclosporin 7-Thioamide, [7Ψ8CS-NH]사이클로스포린) (Helv. Chim. Acta 1991, 74; 1953-1990, J. Org. Chem. 1993,58;673-677, J Org. Chem. 1994, 59;7249-7258)으로 명명 하였다.The amino acid form of cyclosporin A is L-configuration unless otherwise indicated, and the amino acid residue number is MeBmt 1 as shown in [Formula 1], and the last MeVal (N-methyl- L-valine (N-methyl-L-Valine) was designated as No. 11. The various derivative nomenclatures of cyclosporin A to cyclosporin Z followed commonly used methods (Helv. Chim. Acta, 1987; 70; 13-36). For example, only Abu (L-αaminobutyric acid), residue 2 of cyclosporin A, may be alanine, L-threonine, L-valine, or Cyclosporine molecules substituted with L-norvaline are denoted with cyclosporine B, C, D and G, respectively. In addition, when the cyclosporine derivative residues are different from the cyclosporine A molecules, the naming of the derivatives indicated only the substituted residues. Listen four Three residues of the Claus salko Lin A god [N- methyl -D- amino butyric acid 3] ([N-methyl- D-Abu 3]) and [N- methyl -D- norvaline 3] ([N- methyl-D-Nva 3]) in each case substituted [N- methyl -D- amino butyric acid 3] cyclosporin a ([N-methyl-D -Abu 3] cyclosporin a and [N- methyl -D- norvaline 3 ] Cyclosporin A ([N-methyl-D-Nva 3 ] cyclosporin A) Another commonly used amino acid abbreviation, for example MeLeu is N-methyl-L-leucine and MeIle is N-methyl- L-Isoleucine, MeVal is N-methyl-L-valine, MeAla is N-methyl-L-alanine, MeNva is N-methyl-L-norvaline, Leu is L-leucine, Ile is L Isoleucine, Sar is salcosine, Ser is L-serine, Val is L-valine, Ala is L-alanine, DAla is D-alanine, Abu is L-aminobutyric acid (Abu, L- aminobutyric acid), Thr is L-threonine or Nva is L-norvaline (L-norvaline), which was used as meaning. In addition, derivatives in which sulfur is substituted for the amino acid carbonyl oxygen of the cyclosporin molecule 7 are cyclosporin 7-Thioamide, [ 7 Ψ 8 CS-NH] cyclosporine, respectively (Helv. Chim. Acta 1991, 74; 1953-1990, J. Org. Chem. 1993, 58; 673-677, J Org. Chem. 1994, 59; 7249-7258).

사이클로스포린의 여러가지 부작용 중에서 모 과대 성장(발모) 부작용을 이용한 발모제로 개발 가능성이 그동안 여러 연구에 의해 수행되어 왔다. 그 중에는 동물 발모실험(Arch, Dermatol. Res., 1996; 288; 408 410), 인간 원형 탈모증(J. Am. Acad. Dermatol., 1990; 22; 242 250), 인간 남성형 탈모증(J. Am. Acad. Dermatol., 1990; 22; 251 253 및 Skin Pharmacol., 1994; 7; 101 104) 및 화학요법에 의한 탈모 동물 모델에서도 탈모억제 효과(Clin. Lab. Invest., 1995; 190; 192 196 및 Am. J. Pathol., 1997; 150; 1433 1441) 등 매우 광범위하게 연구되었고 마우스 등판 실험 결과로 비교한다면 미녹시딜 보다 약 100배 정도 우수한 효과를 보여주고 있다. 이런 결과를 토대로 사이클로스포린을 남성형 탈모증에 발모제로 활용하고자 하는 노력의 결과로 여러 특허가 출원되었다.Among the various side effects of cyclosporin, the possibility of developing as a hair regrowth agent using hair growth growth (hair growth) side effects has been conducted by various studies. Among them are animal hair growth experiments (Arch, Dermatol. Res., 1996; 288; 408 410), human alopecia areata (J. Am. Acad. Dermatol., 1990; 22; 242 250), human androgenetic alopecia (J. Am. Acad.Dermatol., 1990; 22; 251 253 and Skin Pharmacol., 1994; 7; 101 104) and hair loss inhibitory effects in alopecia animal models by chemotherapy (Clin. Lab. Invest., 1995; 190; 192 196 and Am. J. Pathol., 1997; Based on these results, several patents have been filed as a result of efforts to use cyclosporin as a hair regrowth agent for androgenetic alopecia.

예를 들어 일본공개 특허공보 소60-243008호, 소62-19512호, 및 소62-19513호와 8 번 위치가 변형된 사이클로스포린 유도체(유럽특허 공개공보 제0414632B1호), 이소 사이클로스포린(세계 특허 공개공보 제93/17039호) 등에서는 이들 사이클로스포린 및 유도체를 이용한 발모제를 제공하고 있고, 미국특허 제5,807,820호 및 영국특허 2,218,334A호에서는 사이클로스포린의 경피 흡수가 우수한 제제를 통하여 발모제로 활용을 모색하고 있다.For example, Japanese Patent Application Laid-Open Nos. 60-243008, 62-19512, and 62-19513 and cyclosporine derivatives modified at position 8 (European Patent Publication No. 0414632B1), Iso cyclosporine (World Patent Publication Publication No. 93/17039) and the like provide a hair regrowth agent using these cyclosporins and derivatives, and US Patent No. 5,807,820 and UK Patent No. 2,218,334A seek to use them as a hair regrowth agent through the preparation of cyclosporin with excellent transdermal absorption.

본 발명은 상기와 같은 종래기술의 문제점을 해결하기 위한 것으로, 발모력이 우수한 사이클로스포린(Cyclosporin) 유도체를 주성분으로 하는 모발 성장 촉진제에 관한 것이다. 이를 위하여 본 발명은 사이클로스포린 분자의 3 번 살코신(sarcosine)을 화학 합성을 통한 유도체화 및 발모 평가실험을 통해 탁월한 모발 성장효과를 갖는 모발 성장 촉진제를 제공하고자 한다.The present invention is to solve the problems of the prior art as described above, and relates to a hair growth accelerator having a cyclosporin derivative (excellent hair growth) as a main component. To this end, the present invention is to provide a hair growth promoter having excellent hair growth effect through derivatization and hair growth evaluation experiment through the chemical synthesis of sarcosine 3 of the cyclosporine molecule.

도1은 [N-메틸-D-아미노부티릭산3] 사이클로스포린 A1 shows [N-methyl-D-aminobutyric acid 3 ] cyclosporin A

([N-methyl-D-Abu3]cyclosporin A의1H-NMR 스펙트럼을 나타낸 것이다.([N-methyl-D- Abu 3] shows the 1 H-NMR spectrum of the cyclosporin A.

도 2는 [N-메틸-D-아미노부티릭산3] 사이클로스포린 AFigure 2 shows [N-methyl-D-aminobutyric acid 3 ] cyclosporin A

([N-methyl-D-Abu3]cyclosporin A의13C-NMR 스팩트럼을 나타낸 것이다.(The 13 C-NMR spectrum of [N-methyl-D-Abu 3 ] cyclosporin A is shown.

도 3은 [N-메틸-D-노르발린3] 사이클로스포린 AFigure 3 shows [N-methyl-D-norvaline 3 ] cyclosporin A

([N-methyl-D-Nva3]cyclosporin A의1H-NMR 스펙트럼을 나타낸 것이다.([N-methyl-D- Nva 3] shows the 1 H-NMR spectrum of the cyclosporin A.

도 4는 [N-메틸-D-노르발린3] 사이클로스포린 A4 shows [N-methyl-D-norvaline 3 ] cyclosporin A

([N-methyl-D-Nva3]cyclosporin A의13C-NMR 스팩트럼을 나타낸 것이다.(The 13 C-NMR spectrum of [N-methyl-D-Nva 3 ] cyclosporin A is shown.

도 5는 [D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 AFigure 5 shows [D-2- (methylamino) hexa-4-inoyl 3 ] cyclosporin A

([D-2-(methylamino) hexa-4-ynoyl3] cyclosporin A)의1H-NMR 스펙트럼 을 나타낸 것이다. 1 H-NMR spectrum of ([D-2- (methylamino) hexa-4-ynoyl 3 ] cyclosporin A) is shown.

도 6은 [D-2-(메틸아미노)헥사-4-이노일3] 사이클로스포린 AFigure 6 shows [D-2- (methylamino) hexa-4-inoyl 3 ] cyclosporin A

([D-2-(methylamino) hexa-4-ynoyl3] cyclosporin A)의13C-NMR 스팩트럼 을 나타낸 것이다.The 13 C-NMR spectrum of ([D-2- (methylamino) hexa-4-ynoyl 3 ] cyclosporin A) is shown.

도 7은 [D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린 AFigure 7 shows [D-2- (methylamino) pent-4-inoyl 3 ] cyclosporin A

([D-2-(Methylamino) pent-4-ynoyl3] cyclosporin A)의1H-NMR 스펙트럼을 나타낸 것이다. 1 H-NMR spectrum of ([D-2- (Methylamino) pent-4-ynoyl 3 ] cyclosporin A) is shown.

도 8은 [D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린 A8 shows [D-2- (methylamino) pent-4-inoyl 3 ] cyclosporin A

([D-2-(Methylamino) pent-4-ynoyl3] cyclosporin A)의13C-NMR 스팩트럼을 나타낸 것이다.The 13 C-NMR spectrum of ([D-2- (Methylamino) pent-4-ynoyl 3 ] cyclosporin A) is shown.

도 9는 [D-2-메틸티오살코신3] 사이클로스포린 A9 shows [D-2-methylthiosalcosine 3 ] cyclosporin A

([D-2-methylthio-Sar3]cyclosporin A)의1H-NMR 스펙트럼을 나타낸 것이 다. 1 H-NMR spectrum of ([D-2-methylthio-Sar 3 ] cyclosporin A) is shown.

도 10은 [D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3]10 shows [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ]

cyclosporin A)13C-NMR 스팩트럼을 나타낸 것이다.cyclosporin A) 13 C-NMR spectrum is shown.

도 11은 [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 AFIG. 11 shows [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A

(N-methyl-O-Propenyl-D-Ser3) cyclosporin A)의1H-NMR 스펙트럼을 나 타낸 것이다.(N-methyl-O-Propenyl-D-Ser 3 ) shows the 1 H-NMR spectrum of cyclosporin A).

도 12는 [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A12 shows [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A

(N-methyl-O-Propenyl-D-Ser3) cyclosporin A)의13C-NMR 스팩트럼을 나 타낸 것이다.The 13 C-NMR spectrum of (N-methyl-O-Propenyl-D-Ser 3 ) cyclosporin A) is shown.

도 13은 [N-메틸-D-세린3] 사이클로스포린 AFIG. 13 shows [N-methyl-D-serine 3 ] cyclosporin A

([N-methyl-D-Ser3]cyclosporin A)의1H-NMR 스펙트럼을 나타낸 것이다. 1 H-NMR spectrum of ([N-methyl-D-Ser 3 ] cyclosporin A) is shown.

도 14는 [N-메틸-D-세린3] 사이클로스포린 AFIG. 14 shows [N-methyl-D-serine 3 ] cyclosporin A

([N-methyl-D-Ser3]cyclosporin A)의13C-NMR 스팩트럼을 나타낸 것이다. 13 C-NMR spectrum of ([N-methyl-D-Ser 3 ] cyclosporin A) is shown.

본 발명은 신규 발모 성분을 개발하기 위하여 여러 유도체 합성 및 발모실험을 한 결과 화학식 1로 나타내는 신규발모 성장 촉진제 사이클로스포린 3번 유도체(3-Position Cyclosporin analog)를 유효성분으로 하는 모발 성장 촉진제를 제공하는 것을 목적으로 한다.The present invention is to provide a hair growth promoter using a novel growth growth promoter cyclosporin derivative 3 (3-Position Cyclosporin analog) represented by the formula (1) as a result of the synthesis and hair growth experiments of various derivatives to develop a new hair growth component The purpose.

상기 식에서,Where

A는 N-메틸-(4R)-4-[(E)-2-뷰텐일]-4-메틸-L-트레오닌(MeBmt, N-methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine), (2S,3R,4R,6E)-3-설프히드릴-4-메틸-2-(메틸아미노)-6-옥테노익산(2S,3R,4R,6E)-3-sulfhydryl-4-methyl-2-(methylamino)-6-octenoic acid 또는 (2S,4R,6E)-3-옥소-4-메틸-2-(메틸아미노)-6-옥테노익산 (2S,4R,6E)-3-oxo-4-methyl-2-(methylamino)-6-octenoic acid이며,A is N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine (MeBmt, N-methyl- (4R) -4-[(E) -2- butenyl] -4-methyl-L-threonine), (2S, 3R, 4R, 6E) -3-sulfhydryl-4-methyl-2- (methylamino) -6-octenoic acid (2S, 3R, 4R , 6E) -3-sulfhydryl-4-methyl-2- (methylamino) -6-octenoic acid or (2S, 4R, 6E) -3-oxo-4-methyl-2- (methylamino) -6-octeno Iksan (2S, 4R, 6E) -3-oxo-4-methyl-2- (methylamino) -6-octenoic acid,

B는 Ｌ－아미노부티릭산(Abu, L-aminobutyric acid), L-알라닌 (Ala, L-alanine), L-트레오닌 (Thr , L-threonine), L-발린(Val, L-valine), 또는 L-노르발린( Nva, L-norvaline)이며,B is L-aminobutyric acid (Abu), L-alanine (Ala, L-alanine), L-threonine (Thr, L-threonine), L-valine (Val, L-valine), or L-norvaline (Nva, L-norvaline),

C는 하기 일반식(1)으로 나타나는 D-아미노산 으로C is D-amino acid represented by the following general formula (1)

CH3NH-CH(R)-COOH (1)CH 3 NH-CH (R) -COOH (1)

여기서 R은Where R is

하이드로겐(hydrogen), C1-C6 직쇄(straight) 또는 분기(branch)상의 알킬(alkyl), 알케닐(alkenyl), 알키닐(alkynyl)탄소로 구성되고 이들 탄소에 하나 또는 하나 이상의 아미노(amino), 히드록시(hydroxy), 할로(halo), 할로알킬(haloalkyl), 에스터(ester), 알콕시(alkoxy), 시아노(cyano), 나이트로(nitro), 알킬아미노(alkylamino), 디알킬아미노(dialkylamino)등이 포함된다.Hydrogen, C1-C6 straight or branched alkyl, alkenyl, alkynylcarbons and one or more aminos in these carbons , Hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, dialkylamino ( dialkylamino) and the like.

R은 또 하기식(2) -X-R'의 구조를 포함한다.R also includes the structure of formula (2) -X-R '.

-X-R'(2)-X-R '(2)

X=산소(O) 또는 황(S)이며X = oxygen (O) or sulfur (S)

R' 하이드로겐(hydrogen), C1-C6 직쇄(straight) 또는 분기(branch)상의 알킬(alkyl), 알케닐(alkenyl), 알키닐(alkynyl)탄소로 구성되고 이들 탄소에 하나 또는 하나 이상의 아미노(amino), 히드록시(hydroxy), 할로(halo), 할로알킬(haloalkyl), 에스터(ester), 알콕시(alkoxy), 시아노(cyano), 나이트로(nitro), 알킬아미노(alkylamino), 디알킬아미노(dialkylamino)등이 포함된다.R 'hydrogen, C1-C6 straight or branched alkyl, alkenyl, alkynylcarbons and one or more aminos in these carbons ( amino, hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, dialkyl Dialkylamino and the like.

D는 N-메틸-L-루신( N-methyl L-leucine), 감마히드록시 N-메틸 L-루신(γ-hydroxy N- methyl L-leucine) 또는 L-발린( L-valine)이며,D is N-methyl L-leucine, gammahydroxy N-methyl L-leucine or L-valine

E는 L-발린(L-valine) 또는 L-노르발린(L-norvaline)이며,E is L-valine or L-norvaline,

F는 N-메틸-L-루신(N-methyl-L-leucine) 감마히드록시 N-메틸 L-루신(γ-hydroxy N- methyl L-leucine) 또는 L-루신(L-Leucine)이며,F is N-methyl-L-leucine gammahydroxy N-methyl L-leucine or L-Leucine,

G는 L-알라닌(L-alanine)또는 L-알라닌 티오아미드L-alanine thioamide, [7Ψ8CS-NH], NH-CHCH3-CS-이며,G is L-alanine or L-alanine thioamide, L-alanine thioamide, [ 7 Ψ 8 CS-NH], NH-CHCH 3 -CS-,

H는 하기 일반식(3)으로 나타나는 D-아미노산으로H is a D-amino acid represented by the following general formula (3)

-NH-CH(CH2R)-COOH (3)-NH-CH (CH 2 R) -COOH (3)

여기서 R은 하이드로겐(hydrogen)이고 또한 하기식(4) -X-R'을 포함한다.Wherein R is hydrogen and also includes formula (4) -X-R '.

-X-R'(4)-X-R '(4)

X=산소(O) 또는 황(S)이며X = oxygen (O) or sulfur (S)

R'는 하이드로겐(hydrogen), C1-C6 직쇄(straight) 또는 분기(branch)상의 알킬(alkyl), 알케닐(alkenyl), 알키닐(alkynyl)탄소로 구성되고 이들 탄소에 하나 또는 하나 이상의 아미노(amino), 히드록시(hydroxy), 할로(halo), 할로알킬(haloalkyl), 에스터(ester), 알콕시(alkoxy), 시아노(cyano), 나이트로(nitro), 알킬아미노(alkylamino), 디알킬아미노(dialkylamino)등이 포함된다.R 'is composed of hydrogen, C1-C6 straight or branched alkyl, alkenyl, alkynylcarbons and one or more amino groups on these carbons (amino), hydroxy, halo, haloalkyl, ester, alkoxy, cyano, nitro, alkylamino, di Dialkylamino and the like.

I는 N-메틸 L-루신( N-methyl L-leucine), 감마히드록시 N-메틸- L-루신 (γ-hydroxy- N- methyl L-leucine) 또는 L-루신( L-leucine)이며,I is N-methyl L-leucine, gammahydroxy N-methyl-L-leucine or L-leucine,

J는 N-메틸 L-루신( N-methyl L-leucine), 감마히드록시 N-메틸 L-루신 (γ-hydroxy-N-methyl-L-leucine) 또는 L-루신( L-leucine)이며,J is N-methyl L-leucine, gammahydroxy N-methyl L-leucine (γ-hydroxy-N-methyl-L-leucine) or L-leucine,

K는 N-메틸-L-발린 (N-methyl-L-valine) 또는 L-발린(L-valine) 이다.K is N-methyl-L-valine or L-valine.

상기 화학식 1에 있어서 바람직 하기로는 하기 화학식 2 로 나타내는 발모효과가 우수한 사이클로스포린 3번 유도체(3-Position Cyclosporin derivatives) 를 유효성분으로 하는 모발 성장 촉진제를 제공하는 것을 목적으로 한다.In the above formula 1, it is preferable to provide a hair growth promoter having an active ingredient of cyclosporin 3 derivative (3-Position Cyclosporin derivatives) having an excellent hair growth effect represented by the following formula (2).

상기 식에서,Where

MeBmt는 N-메틸-(4R)-4-[(E)-2-뷰텐일]-4-메틸-L-트레오닌 N-methyl-(4R)-4-[(E)-2-butenyl]-4- methyl-L-threonine), 이며,MeBmt is N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine N-methyl- (4R) -4-[(E) -2-butenyl]- 4-methyl-L-threonine),

A'는 Ｌ－아미노부티릭산(Abu, L-aminobutyric acid), L-알라닌 (Ala, L-alanine), L-트레오닌 (Thr , L-threonine), L-발린(Val, L-valine), 또는 L-노르발린( Nva, L-norvaline),A 'is L-aminobutyric acid (Abu, L-aminobutyric acid), L-alanine (Ala, L-alanine), L-threonine (Thr, L-threonine), L-valine (Val, L-valine), Or L-norvaline (Nva, L-norvaline),

B'는 N-메틸-D-아미노부티릭산 (N-methyl-D-Aminobutyric acid), N-메틸-D-노르발린 (N-methyl-D-Norvaline), D-2-(메틸아미노)헥사-4-이노일{( D-2-(Methylamino) hexa-4-ynoyl)}, D-2-(메틸아미노)펜트-4-이노일{(D-2-(Methylamino)pent-4-ynoyl)}, D-2-메틸티오살코신(D-2-methylthio-Sarcosine),N-메틸-O-프로페닐-D-세린 (N-methyl-O-Propenyl-D-Serine) 또는 N-메틸-D-세린 (N-methyl-D-Serine) 이며,B 'is N-methyl-D-Aminobutyric acid, N-methyl-D-Norvaline, D-2- (methylamino) hexa -4-inoyl {(D-2- (Methylamino) hexa-4-ynoyl)}, D-2- (methylamino) pent-4-inoyl {(D-2- (Methylamino) pent-4-ynoyl )}, D-2-methylthio-Sarcosine, N-methyl-O-propenyl-D-serine or N-methyl -D-serine (N-methyl-D-Serine)

C'는 N-메틸-L-루신( N-methyl-L-leucine), 감마히드록시 N-메틸-L-루신(γ-hydroxy -N- methyl L-leucine) 또는 L-발린( L-valine)이며,C ′ is N-methyl-L-leucine, gammahydroxy N-methyl-L-leucine or L-valine ),

D'는 L-발린(L-valine) 또는 L-노르발린(L-norvaline)이며,D 'is L-valine or L-norvaline,

E'는 N-메틸-L-루신(N-methyl-L-leucine) 감마히드록시 N-메틸 L-루신(γ-hydroxy N- methyl L-leucine) 또는 L-루신(L-Leucine)이며,E 'is N-methyl-L-leucine gammahydroxy N-methyl L-leucine or L-Leucine,

F'는 L-알라닌(L-alanine)또는 L-알라닌 티오아미드L-alanine thioamide, [7Ψ8 CS-NH] , NH-CHCH3-CS-이며,F 'is L-alanine or L-alanine thioamide, L-alanine thioamide, [7Ψ8 CS-NH], NH-CHCH3-CS-,

G'는 D-알라닌(D-alanine) 또는 D-세린(D-serine),G 'is D-alanine or D-serine,

H'는 N-메틸 L-루신( N-methyl L-leucine), 감마히드록시 N-메틸- L-루신 (γ-hydroxy- N- methyl L-leucine) 또는 L-루신( L-leucine)이며,H 'is N-methyl L-leucine, gammahydroxy N-methyl-L-leucine or L-leucine ,

I'는 N-메틸-L-루신(N-methyl-L-leucine), 감마 히드록시 N-메틸-L-루신(γ-hydroxy-N-methyl-L-leucine) 또는 L-루신(L-leucine)이며,I 'is N-methyl-L-leucine, gamma hydroxy N-methyl-L-leucine or L-leucine leucine),

MeVal은 N-methyl-L-valine이다.MeVal is N-methyl-L-valine.

상기 화학식 1에 있어서 바람직 하기로는 하기 화학식 3으로 나타내는 발모효과가 우수한 사이클로스포린 3위치 유도체(3-Position Cyclosporin derivatives) 를 유효성분으로 하는 모발 성장 촉진제를 제공하는 것을 목적으로 한다.In the above Formula 1, it is preferable to provide a hair growth accelerator having 3-Position Cyclosporin derivatives having an excellent hair growth effect represented by the following Formula 3 as an active ingredient.

상기 식에서,Where

MeBmt는 N-메틸-(4R)-4-[(E)-2-뷰텐일]-4-메틸-L-트레오닌 N-methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine)이며,MeBmt is N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine N-methyl- (4R) -4-[(E) -2-butenyl]- 4-methyl-L-threonine)

A"는 L-알라닌 (Ala, L-alanine), L-트레오닌 (Thr , L-threonine), L-발린(Val, L-valine), 또는 L-노르발린( Nva, L-norvaline) 이며,A ″ is L-alanine (Ala, L-alanine), L-threonine (Thr, L-threonine), L-valine (Val, L-valine), or L-norvaline (Nva, L-norvaline),

B"는 N-메틸-D-아미노부티릭산 (N-methyl-D-Aminobutyric acid), N-메틸-D-노르발린 (N-methyl-D-Norvaline), D-2-(메틸아미노)헥사-4-이노일{( D-2-(Methylamino) hexa-4-ynoyl)}, D-2-(메틸아미노)펜트-4-이노일{(D-2-(Methylamino)pent-4-ynoyl)}, D-2-메틸티오살코신(D-2-methylthio-Sarcosine), N-메틸-O-프로페닐-D-세린 (N-methyl-O-Propenyl-D-Serine) 또는 N-메틸-D-세린 (N-methyl-D-Serine) 이며,B "is N-methyl-D-Aminobutyric acid, N-methyl-D-Norvaline, D-2- (methylamino) hexa -4-inoyl {(D-2- (Methylamino) hexa-4-ynoyl)}, D-2- (methylamino) pent-4-inoyl {(D-2- (Methylamino) pent-4-ynoyl )}, D-2-methylthio-sarcosine, N-methyl-O-propenyl-D-serine or N-methyl -D-serine (N-methyl-D-Serine)

MeLeu는 N-메틸-L-루신(N-methyl-L-leucine)이며,MeLeu is N-methyl-L-leucine,

Val은 L-발린(L-valine)이며,Val is L-valine,

Ala는 L-알라닌 (L-alanine)이며,Ala is L-alanine,

DAla는 D-알라닌(D-alanine) 이며,DAla is D-alanine,

MeVal은 N-메틸-L-발린( N-methyl-L-valine)이다.MeVal is N-methyl-L-valine.

또한, 사이클로스포린 3위치 유도체(3-Position Cyclosporin derivatives)을함유한 조성물의 제형이 액상, 스프레이, 겔, 페이스트, 유제, 크림, 콘디셔너, 또는 샴푸인 모발성장 촉진제를 제공한다.In addition, formulations of compositions containing 3-Position Cyclosporin derivatives provide hair growth promoters that are liquid, spray, gel, paste, emulsion, cream, conditioner, or shampoo.

이하에서 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 상기 종래기술의 문제점을 고려하여, 발모력이 우수한 사이클로스포린(Cyclosporin) 유도체를 주성분으로 하는 모발 성장 촉진제에 관한 것이다. 이를 위하여 본 발명은 사이클로스포린 분자의 3 번 살코신(sarcosine)을 화학 합성을 통한 유도체화 및 발모 평가실험을 통해 모발 성장 촉진제를 제공하는 것을 목적으로 한다.The present invention, in view of the problems of the prior art, relates to a hair growth promoter based on a cyclosporin derivative (excellent hair growth) as a main component. To this end, an object of the present invention is to provide a hair growth promoter through derivatization and hair growth evaluation experiments using chemical synthesis of sarcosine 3 of the cyclosporine molecule.

실시예 1. 사이클로스포린 A 3위치 유도체의 합성.Example 1 Synthesis of Cyclosporin A 3-position Derivatives.

* 사이클로스포린 A(Cyclosporin A) 의 알킬화를 위한 일반적인 방법* General method for alkylation of cyclosporin A

질소하에 테트라 히드로 푸란(THF)에 디이소프로필 아민((i-Pr)2NH)을 가하고 -78℃에서 핵산에 녹아있는 부틸리튬(BuLi)을 가하고 30분간 교반하였다. 이렇게 생성된 LDA용액에 테트라 히드로 푸란(THF)에 녹인 사이클로스포린 A (Cyclosporin A)을 가한 후 1시간 교반한 후 친전자체(electrophile)를 가하였다.Diisopropyl amine ((i-Pr) 2 NH) was added to tetrahydrofuran (THF) under nitrogen, and butyllithium (BuLi) dissolved in nucleic acid was added at −78 ° C. and stirred for 30 minutes. Cyclosporin A dissolved in tetrahydrofuran (THF) was added to the LDA solution thus prepared, followed by stirring for 1 hour, followed by the addition of an electrophile.

실시예 1-1.Example 1-1.

[N-메틸-D-아미노부티릭산3] 사이클로스포린A ([N-methyl-D-Abu3] cyclosporin A (화합물 1)의 합성Synthesis of [N-methyl-D-aminobutyric acid 3 ] cyclosporin A ([N-methyl-D-Abu 3 ] cyclosporin A (Compound 1)

일반적인 방법을 이용하여 10 당량의 LDA용액에 테트라 히드로 푸란(THF)(50mL)에 녹인 사이클로스포린 A(Cyclosporin A)(1.0g)을 -78℃에서 가하였다. 반응 혼합물을 -78℃에서 2시간 교반한 후 에틸아이오다이드(ethyliodide) (0.4ml)을 가하였다. 실온으로 만든 후 24시간 더 교반시키고 20mL의 물을 가한 후 농축하였다. 잔사에 에테르(Et2O)를 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 마그네슘(MgSO4)으로 건조 후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피(실리카 겔 100g, 디클로로메탄 : 메틸알코올 = 96 : 4) 에 정제한 후 HPLC 로 정제하여 표제 화합물(0.1g)을 얻었다.Using a conventional method, cyclosporin A (1.0 g) dissolved in tetrahydrofuran (THF) (50 mL) in 10 equivalents of LDA solution was added at -78 ° C. The reaction mixture was stirred at −78 ° C. for 2 hours, and then ethyliodide (0.4 ml) was added. After cooling to room temperature, the mixture was further stirred for 24 hours, and 20 mL of water was added, followed by concentration. Ether (Et 2 O) was added to the residue, washed sequentially with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate (MgSO 4 ), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, dichloromethane: methyl alcohol = 96: 4) and then purified by HPLC to obtain the title compound (0.1 g).

FAB MS(ZMS AX 505H)로부터 분자량을 확인 하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒) (도 1) 와13C-NMR(Bruker NMR 150 MHz)(도 2) 을 이용하였다.Molecular weights were determined from FAB MS (ZMS AX 505H), and nuclear magnetic resonance 1 H-NMR (Bruker NMR 600MHz) (FIG. 1) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 2) were used for structural confirmation. Was used.

실시예 1-2.Example 1-2.

[N-메틸-D-노르발린3] 사이클로스포린 A([N-methyl-D-Nva3] cyclosporin A (화합물2)의 합성[N- methyl -D- norvaline 3] Synthesis of Cyclosporine A ([N-methyl-D -Nva 3] cyclosporin A ( Compound 2)

일반적인 방법을 이용하여 10 당량의 LDA용액에 테트라 히드로 푸란(THF)(50mL)에 녹인 사이클로스포린 A(Cyclosporin A)(1.0g)을 -78℃에서 가하였다. 반응 혼합물을 -78℃에서 2시간 교반한 후 프로필아이오다이드(propyliodide)(0.41ml)을 가하였다. 실온으로 만든 후 24시간 더 교반 시키고 20mL의 물을 가한 후 농축하였다. 잔사에 에테르(Et2O)를 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 마그네슘(MgSO4)으로 건조후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피(실리카 겔 100g, 디클로로메탄 : 메틸알코올 = 96 : 4)에 정제한 후 HPLC로 정제하여 표제 화합물(0.12g)을 얻었다. FAB MS(ZMS AX 505H)로부터 분자량을 확인 하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒)(도 3)과13C-NMR(Bruker NMR 150 MHz)(도 4)을 이용하였다.Using a conventional method, cyclosporin A (1.0 g) dissolved in tetrahydrofuran (THF) (50 mL) in 10 equivalents of LDA solution was added at -78 ° C. The reaction mixture was stirred at −78 ° C. for 2 hours, and then propyliodide (0.41 ml) was added. After the mixture was stirred at room temperature for 24 hours, 20 mL of water was added thereto, followed by concentration. Ether (Et 2 O) was added to the residue, washed sequentially with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate (MgSO 4 ), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100g, dichloromethane: methyl alcohol = 96: 4) and then purified by HPLC to obtain the title compound (0.12 g). Molecular weight was determined from FAB MS (ZMS AX 505H), and nuclear magnetic resonance 1 H-NMR (Bruker NMR 600 MHz) (FIG. 3) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 4) were used for structural confirmation. Was used.

실시예 1-3.Example 1-3.

[D-2-(메틸아미노)헥사-4-이노일3] 사이클로스포린 A ([D-2-(Methylamino) hexa-4-ynoyl3] cyclosporinA) (화합물 3)의 합성[D-2- (methylamino) hexa-4-yl Ino 3] Synthesis of Cyclosporine A ([D-2- (Methylamino ) hexa-4-ynoyl 3] cyclosporinA) ( Compound 3)

일반적인 방법을 이용하여 10 당량의 LDA용액에 테트라 히드로 푸란(THF)(50 mL)에 녹인 사이클로스포린 A(Cyclosporin A)(1.0g)을 -78℃에서 가하였다. 반응 혼합물을 -78℃에서 2시간 교반한 후 1-브로모-2-부틴(1-bromo-2-butyne)(0.73ml) 을 가하였다. 실온으로 만든 후 24시간 더 교반시키고 20mL의 물을 가한 후 농축하였다. 잔사에 에테르(Et2O)를 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 마그네슘(MgSO4)으로 건조 후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피 (실리카 겔 100g, 디클로로메탄 : 메틸알코올 = 96 : 4)에 정제한 후 HPLC로 정제하여 표제 화합물(0.13g)을 얻었다. FAB MS(ZMS AX 505H)로부터 분자량을 확인하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒)(도 5)과13C-NMR(Bruker NMR 150 MHz)(도 6)을 이용하였다.Cyclosporin A (1.0 g) dissolved in tetrahydrofuran (THF) (50 mL) in 10 equivalent LDA solution was added at -78 ° C. The reaction mixture was stirred at −78 ° C. for 2 hours and then 1-bromo-2-butyne (0.73 ml) was added. After cooling to room temperature, the mixture was further stirred for 24 hours, and 20 mL of water was added, followed by concentration. Ether (Et 2 O) was added to the residue, washed sequentially with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate (MgSO 4 ), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, dichloromethane: methyl alcohol = 96: 4) and then purified by HPLC to obtain the title compound (0.13 g). Molecular weight was confirmed from FAB MS (ZMS AX 505H), and nuclear magnetic resonance 1 H-NMR (Bruker NMR 600 MHz) (FIG. 5) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 6) were used to confirm the structure. Was used.

실시예 1-4.Example 1-4.

[D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린A ([D-2-(Methylamino) pent-4-ynoyl3]cyclosporinA) (화합물 4) 의 합성[D-2- (methylamino) pent-4-one Ino 3] Synthesis of Cyclosporine A ([D-2- (Methylamino ) pent-4-ynoyl 3] cyclosporinA) ( Compound 4)

일반적인 방법을 이용하여 테트라 히드로 푸란(THF)(200mL), 디이소프로필 아민((i-Pr)2NH)(3.2mL), 부틸리튬(BuLi)(8mL), 테트라 히드로 푸란(THF)(50mL)에 녹아있는 사이클로스포린 A(Cyclosporin A)(3.76g), 프로파질 브로마이드(propargyl bromide)(3.57g)을 사용하였다. 실온으로 만든 후 24시간 더 교반시키고 40mL의 물을 가한 후 농축하였다. 잔사에 에테르(Et2O)를 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 마그네슘(MgSO4)으로 건조 후 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피(실리카 겔 100g, 디클로로메탄 : 메틸알코올 = 96 : 4) 에 정제한후 HPLC로 정제하여 표제 화합물 3(0.18g)과 표제 화합물 4(0.08g)를 얻었다. FAB MS(ZMS AX 505H)로 부터 분자량을 확인하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒)(도 7)와13C-NMR(Bruker NMR 150 MHz)(도 8)을 이용하였다.Tetrahydrofuran (THF) (200 mL), diisopropyl amine ((i-Pr) 2 NH) (3.2 mL), butyllithium (BuLi) (8 mL), tetrahydrofuran (THF) (50 mL) Cyclosporin A (3.76 g) and propargyl bromide (3.57 g) dissolved in) were used. After cooling to room temperature, the mixture was further stirred for 24 hours, and 40 mL of water was added, followed by concentration. Ether (Et 2 O) was added to the residue, washed sequentially with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate (MgSO 4 ), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, dichloromethane: methyl alcohol = 96: 4) and purified by HPLC to obtain the title compound 3 (0.18 g) and the title compound 4 (0.08 g). Molecular weight was confirmed from FAB MS (ZMS AX 505H) and nuclear magnetic resonance method 1 H-NMR (Bruker NMR 600MHz) (FIG. 7) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 8) for structure confirmation. Was used.

실시예 1-5.Example 1-5.

[D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3]cyclosporin A)(화합물 5) 의 합성.Synthesis of [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) (Compound 5).

일반적인 방법을 이용하여 테트라 히드로 푸란(THF)(100 mL), 디이소프로필 아민((i-Pr)2NH)(1.6 mL), 부틸리튬(BuLi)(4.0mL), 테트라 히드로 푸란(THF)(30 mL)에 녹아있는 사이클로스포린 A(Cyclosporin A)(1.0 g), 메틸디설파이드(Me2S2)(1.5 mL)을 사용하였다. 0℃에서 14시 간 교반한후 20 mL의 물을 가한후 농축하였다. 잔사에 에테르를 가한후 물, 포화 염화 나트륨수로 순차적으로세척, 무수 황산 나트륨(MgSO4)으로 건조 후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피 (실리카 겔 100 g, 디클로로메탄 : 메틸알코올 = 50:1 ~ 96:4) 에 정제한후 HPLC 로 정제하여 표제 화합물5(0.36 g) 와 6( 0.05 g)을 얻었다. FAB MS(ZMS AX 505H)로부터 분자량을 확인 하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒) (도 9) 와13C-NMR(Bruker NMR 150 MHz)(도 10) 을 이용하였다.Tetrahydrofuran (THF) (100 mL), diisopropyl amine ((i-Pr) 2NH) (1.6 mL), butyllithium (BuLi) (4.0 mL), tetrahydrofuran (THF) ( Cyclosporin A (1.0 g) and methyl disulfide (Me2S2) (1.5 mL) dissolved in 30 mL) were used. After stirring for 14 hours at 0 ℃ 20 mL of water was added and concentrated. Ether was added to the residue, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate (MgSO 4), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, dichloromethane: methyl alcohol = 50: 1-96: 4) and purified by HPLC to obtain the title compound 5 (0.36 g) and 6 (0.05 g). . Molecular weight was determined from FAB MS (ZMS AX 505H), and nuclear magnetic resonance method 1 H-NMR (Bruker NMR 600MHz) (FIG. 9) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 10) were used for structural confirmation. Was used.

실시예 1-6.Example 1-6.

[N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A)(화합물 6)의 합성[N- methyl-propenyl -O- -D- serine 3] Synthesis of cyclosporin A (N-methyl -O-Propenyl -D-Ser 3) cyclosporin A) ( compound 6)

일반적인 방법을 이용하여 [D-메틸세린3]-사이클로스포린 A(0.62 g, 0.5 mmol), 테트라부틸암모늄 클로라이드(tetrabutylammonium chloride)(0.11 g, 0.5 mmol) 그리고 아릴브로마이드(all bromide)(0.24 g, 2.0 mmol)을 디클로로메탄(50 mL)에 녹인후 30% 수산화나트륨(NaOH)(1.5 mL)과 함께 2시간 교반 시키고 50 mL의디클로로메탄을 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 나트륨(MgSO4)으로 건조 후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피 (실리카 겔 100 g, 디클로로메탄 : 메틸알코올 = 97:3) 에 정제한 후 HPLC 로 정제하여 표제 화합물(0.4 g)을 얻었다. FAB MS(ZMS AX 505H)로부터 분자량을 확인 하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒) (도 11) 와13C-NMR(Bruker NMR 150 MHz)(도 12) 을 이용하였다.[D-methylserine3] -cyclosporine A (0.62 g, 0.5 mmol), tetrabutylammonium chloride (0.11 g, 0.5 mmol) and aryl bromide (0.24 g, 2.0) using conventional methods mmol) was dissolved in dichloromethane (50 mL), stirred with 30% sodium hydroxide (NaOH) (1.5 mL) for 2 hours, 50 mL of dichloromethane was added, and washed sequentially with water and saturated sodium chloride solution. After drying over sodium (MgSO 4), it was concentrated. The residue was purified by silica gel column chromatography (100 g of silica gel, dichloromethane: methyl alcohol = 97: 3) and then purified by HPLC to obtain the title compound (0.4 g). Molecular weight was determined from FAB MS (ZMS AX 505H), and nuclear magnetic resonance 1 H-NMR (Bruker NMR 600MHz) (FIG. 11) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 12) were used for structural confirmation. Was used.

실시예 1-7.Example 1-7.

[N-메틸-D-세린3] 사이클로스포린 A([N-methyl-D-Ser3]cyclosporin A)(화합물 7)의 합성[N- methyl -D- serine 3] Synthesis of Cyclosporine A ([N-methyl-D -Ser 3] cyclosporin A) ( Compound 7)

일반적인 방법을 이용하여 10 당량의 LDA용액에 테트라 히드로 푸란(THF)(50mL)에 녹인 사이클로스포린 A(Cyclosporin A)(1.0g)을 -78℃에서 가하였다. 반응 혼합물을 -78℃에서 2시간 교반한 후 파라포름알데히드(paraformaldehyde)(2.0g)을 가하였다. 실온으로 만든 후 24시간 더 교반 시키고 20mL의 물을 가한 후 농축하였다. 잔사에 에테르(Et2O)를 가한 후 물, 포화 염화 나트륨수로 순차적으로 세척, 무수 황산 마그네슘(MgSO4)으로 건조 후, 농축했다. 잔사를 실리카 겔 칼럼 크로마토그래피(실리카 겔 100g, 디클로로메탄 : 메틸알코올 = 96 : 4)에 정제한 후 HPLC로 정제하여 표제 화합물(0.3g)을 얻었다. FAB MS(ZMS AX 505H)로부터 분자량을 확인 하였고 구조 확인을 위해 핵자기공명법1H-NMR(Bruker NMR 600㎒)(도 13)과13C-NMR(Bruker NMR 150 MHz)(도 14)을 이용하였다.Using a conventional method, cyclosporin A (1.0 g) dissolved in tetrahydrofuran (THF) (50 mL) in 10 equivalents of LDA solution was added at -78 ° C. The reaction mixture was stirred at −78 ° C. for 2 hours and then paraformaldehyde (2.0 g) was added. After the mixture was stirred at room temperature for 24 hours, 20 mL of water was added thereto, followed by concentration. Ether (Et 2 O) was added to the residue, washed sequentially with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate (MgSO 4 ), and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, dichloromethane: methyl alcohol = 96: 4), and then purified by HPLC to obtain the title compound (0.3 g). Molecular weight was determined from FAB MS (ZMS AX 505H), and nuclear magnetic resonance 1 H-NMR (Bruker NMR 600 MHz) (FIG. 13) and 13 C-NMR (Bruker NMR 150 MHz) (FIG. 14) were used for structural confirmation. Was used.

제제예 1 . 발모토닉Formulation Example 1. Balmotoic

제제예 1-1. [N-메틸-D-아미노부티릭산Formulation Example 1-1. [N-methyl-D-aminobutyric acid 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Abu([N-methyl-D-Abu 33 ] cyclosporin A 함유 발모토닉의 제조)Preparation of Balsonic containing Cyclosporin A)

표 1에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 1에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the ingredients in the three formulations shown in Table 1 was mixed and stirred to completely dissolve the balmotonic was prepared. Comparing the formulation 1 shown in Table 1 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2.[N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3] cyclosporin A2. [N-methyl-D-aminobutyric acid 3 ] cyclosporin A ([N-methyl-D-Abu 3 ] cyclosporin A 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-2. [N-메틸-D-노르발린Formulation Example 1-2. [N-methyl-D-norvaline 33 ] 사이클로스포린 A([N-methyl-D-NvaCyclosporin A ([N-methyl-D-Nva 33 ] cyclosporin A 함유 발모토닉의 제조)Preparation of Balsonic containing Cyclosporin A)

표 2에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 2에나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the ingredients in the three formulations shown in Table 2 were mixed and stirred to completely dissolve to prepare a balmonic. Comparing the formulation 1 shown in Table 2 with the 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2. [N-메틸-D-노르발린3] 사이클로스포린 A ([N-methyl-D-Nva3] cyclosporin A2. [N- methyl -D- norvaline 3] cyclosporin A ([N-methyl-D -Nva 3] cyclosporin A 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-3. [D-2-(메틸아미노)헥사-4-이노일Formulation Example 1-3. [D-2- (methylamino) hexa-4-inoyl 33 ] 사이클로스포린 ACyclosporin A

([D-2-(Methylamino) hexa-4-ynoyl([D-2- (Methylamino) hexa-4-ynoyl 33 ] cyclosporin A) 함유 발모토닉의 제조)] Preparation of Cyclosporin A) -containing Balmonic

표 3에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 3에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the ingredients in the three formulations shown in Table 3 was mixed and stirred to completely dissolve to prepare a balmotonic. Comparing the formulation 1 shown in Table 3 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2.[D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 A ([D-2-(Methylamino) hexa-4-ynoyl3] cyclosporin A)2. [D-2- (methylamino) hexa-4-yl Ino 3] cyclosporin A ([D-2- (Methylamino ) hexa-4-ynoyl 3] cyclosporin A) 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-4. [D-2-(메틸아미노)펜트-4-이노일Formulation Example 1-4. [D-2- (methylamino) pent-4-inoyl 33 ] 사이클로스포린 ACyclosporin A

([D-2-(Methylamino)pent-4-ynoyl([D-2- (Methylamino) pent-4-ynoyl 33 ] cyclosporin A) 함유 발모토닉의 제조)] Preparation of Cyclosporin A) -containing Balmonic

표 4에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 4에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the raw materials in three formulations shown in Table 4 was mixed and stirred to completely dissolve the balmotonic was prepared. Comparing the formulation 1 shown in Table 4 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2.[D-2-(메틸아미노)펜트-4-이노일3]사이클로스포린 A ([D-2-(Methylamino)pent-4-ynoyl3] cyclosporin A)2. [D-2- (methylamino) pent-4-one 3 Ino] Cyclosporine A ([D-2- (Methylamino ) pent-4-ynoyl 3] cyclosporin A) 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-5. [D-2-메틸티오살코신Formulation Example 1-5. [D-2-methylthiosalcosine 33 ] 사이클로스포린 ACyclosporin A

([D-2-methylthio-Sar([D-2-methylthio-Sar 33 ]cyclosporin A) 함유 발모토닉의 제조)] Production of cyclosporin A) containing balmonic

표 5에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 5에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the ingredients in the three formulations shown in Table 5 were mixed and stirred to completely dissolve to prepare a balmotonic. Comparing the formulation 1 shown in Table 5 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2. [D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3] cyclosporin A)2. [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-6. [N-메틸-O-프로페닐-D-세린Formulation Example 1-6. [N-Methyl-O-propenyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

(N-methyl -O-Propenyl-D-Ser(N-methyl -O-Propenyl-D-Ser 33 ) cyclosporin A) 함유 발모토닉의 제조)a) Preparation of cyclosporin A) containing balmonic)

표 6에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 6에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the ingredients in the three formulations shown in Table 6 were mixed and stirred to completely dissolve to prepare a balmonic. Comparing the formulation 1 shown in Table 6 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below, confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2. [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A)2. [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A (N-methyl-O-propenyl-D-Ser 3 ) cyclosporin A) 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 1-7. [N-메틸-D-세린Formulation Example 1-7. [N-methyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Ser([N-methyl-D-Ser 33 ] cyclosporincyclosporin A) 함유 발모토닉의 제조)A) Preparation of Containing Balmonic)

표 7에 나타난 3 가지 제형으로 각각의 원료를 혼합하고 교반 하여 완전히 녹여서 발모토닉을 제조 하였다. 하기 실험예 1의 동물 평가 시험을 통하여 표 7에 나오는 제형 1 을 0.1% 사이클로스포린 A 함유 발모토닉과 비교해 본 결과 유사한 정도의 발모 효과를 확인하였다.Each of the raw materials in three formulations shown in Table 7 were mixed and stirred to completely dissolve the balmotonic. Comparing the formulation 1 shown in Table 7 with 0.1% cyclosporin A-containing balmonic through the animal evaluation test of Experimental Example 1 below confirmed a similar degree of hair growth effect.

원료명Raw material name 제형 1Formulation 1 제형 2Formulation 2 제형 3Formulation 3 1. 에탄올1. Ethanol 40.040.0 40.040.0 40.040.0 2.[N-메틸-D-세린3] 사이클로스포린 A ([N-methyl-D-Ser3] cyclosporin A)2. [N-methyl-D-serine 3 ] cyclosporin A ([N-methyl-D-Ser 3 ] cyclosporin A) 0.10.1 1.01.0 8.08.0 3. 초산토코페롤3. Tocopherol Acetate 0.10.1 0.10.1 0.10.1 4. 살리실산4. Salicylic Acid 0.30.3 0.30.3 0.30.3 5. 엘-멘톨5. L-menthol 0.30.3 0.30.3 0.30.3 6. 트윈 206. Tween 20 0.50.5 0.50.5 0.50.5 7. 향료7. Spices 적량Quantity 적량Quantity 적량Quantity 8. 색소8. Pigment 적량Quantity 적량Quantity 적량Quantity 9. 물9. Water 100 중량%가 될 때까지 첨가Add until 100% by weight

제제예 2. 헤어크림Formulation Example 2 Hair Cream

제제예 2-1. [N-메틸-D-아미노부티릭산Formulation Example 2-1. [N-methyl-D-aminobutyric acid 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Abu([N-methyl-D-Abu 33 ] cyclosporin A 함유 헤어크림의 제조] Preparation of Hair Cream containing cyclosporin A

표 8에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 8, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 8에 나오는 [N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3]cyclosporin A 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.[N-methyl-D-aminobutyric acid 3 ] cyclosporin A (0.1% cyclosporin containing 0.1% cyclosporin A [N-methyl-D-Abu 3 ] cyclosporin A shown in Table 8 through the animal evaluation test of Experimental Example 1 Compared with A-containing hair cream, a similar degree of hair growth was confirmed.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7. [N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3]cyclosporin A7. [N-methyl-D-aminobutyric acid 3 ] cyclosporin A ([N-methyl-D-Abu 3 ] cyclosporin A 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-2. [N-메틸-D-노르발린Formulation Example 2-2. [N-methyl-D-norvaline 33 ] 사이클로스포린 A ([N-methyl-D-NvaCyclosporine A ([N-methyl-D-Nva 33 ]]

cyclosporin A 함유 헤어크림의 제조Preparation of cyclosporin A-containing hair cream

표 9에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 9, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 9에 나오는 [N-메틸-D-노르발린3] 사이클로스포린 A ([N-methyl-D-Nva3]cyclosporin A 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.To animals coming in through the evaluation test of Experimental Example 1. Table 9 [N- methyl -D- norvaline 3] cyclosporin A ([N-methyl-D -Nva 3] cyclosporin A 0.1% containing 0.1% cyclosporin A hair cream Comparing the hair cream with the results confirmed a similar degree of hair growth effect.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7. [N-메틸-D-노르발린3] 사이클로스포린 A ([N-methyl-D-Nva3] cyclosporin A7. [N- methyl -D- norvaline 3] cyclosporin A ([N-methyl-D -Nva 3] cyclosporin A 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-3. [D-2-(메틸아미노)헥사-4-이노일Formulation Example 2-3. [D-2- (methylamino) hexa-4-inoyl 33 ] 사이클로스포린 ACyclosporin A

([D-2-(methylamino) hexa-4-ynoyl([D-2- (methylamino) hexa-4-ynoyl 33 ] cyclosporin A) 함유 헤어크림의 제조] Preparation of cyclosporin A) Hair Cream

표 10에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 10, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 10에 나오는 [D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 A ([D-2-(methylamino) hexa-4-ynoyl3] cyclosporinA) 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.To animals through the evaluation tests in Experimental Example 1 shown in Table 10 [D-2- (methylamino) hexa-4-yl Ino 3] cyclosporin A ([D-2- (methylamino ) hexa-4-ynoyl 3] cyclosporinA ) The hair cream containing 0.1% was compared with the hair cream containing 0.1% cyclosporine A, and similar hair growth effects were confirmed.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7.[D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 A ([D-2-(methylamino) hexa-4-ynoyl3] cyclosporin A)7. [D-2- (methylamino) hexa-4-yl Ino 3] cyclosporin A ([D-2- (methylamino ) hexa-4-ynoyl 3] cyclosporin A) 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-4. [D-2-(메틸아미노)펜트-4-이노일Formulation Example 2-4. [D-2- (methylamino) pent-4-inoyl 33 ] 사이클로스포린 ACyclosporin A

([D-2-(Methylamino)pent-4-ynoyl([D-2- (Methylamino) pent-4-ynoyl 33 ] cyclosporin A) 함유 헤어크림의 제조] Preparation of cyclosporin A) Hair Cream

표 11에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 11, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 11에 나오는 [D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린A ([D-2-(Methylamino)pent -4-ynoyl3]cyclosporin A) 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.To animals through the evaluation tests in Experimental Example 1 shown in Table 11 [D-2- (methylamino) pent-4-one 3 Ino] Cyclosporine A ([D-2- (Methylamino ) pent -4-ynoyl 3] cyclosporin A) Comparison of 0.1% hair cream with 0.1% cyclosporine A-containing hair cream showed similar hair growth effects.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7.[D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린 A ([D-2-(Methylamino)pent-4-ynoyl3]cyclosporin A)7. [D-2- (methylamino) pent-4-one 3 Ino] Cyclosporine A ([D-2- (Methylamino ) pent-4-ynoyl 3] cyclosporin A) 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-5. [D-2-메틸티오살코신Formulation Example 2-5. [D-2-methylthiosalcosine 33 ] 사이클로스포린 ACyclosporin A

([D-2-methylthio-Sar([D-2-methylthio-Sar 33 ] cyclosporin A) 함유 헤어크림의 제조] Preparation of cyclosporin A) Hair Cream

표 12에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 12, the oily and watery ingredients were separately mixed and heated to 80 ° C. to completely dissolve the raw materials. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 12에 나오는[D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3] cyclosporin A) 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.0.1% cyclosporine containing 0.1% hair cream containing [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) shown in Table 12 through the animal evaluation test of Experimental Example 1 Compared with A-containing hair cream, a similar degree of hair growth was confirmed.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7. [D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3] cyclosporin A)7. [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-6. [N-메틸-O-프로페닐-D-세린Formulation Example 2-6. [N-Methyl-O-propenyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

(N-methyl -O-Propenyl-D-Ser(N-methyl -O-Propenyl-D-Ser 33 ) cyclosporin A) 함유 헤어크림의 제조) Preparation of cyclosporin A) Hair Cream

표 13에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 13, the oily and watery ingredients were separately mixed and heated to 80 ° C to completely dissolve each of the raw materials. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 13에 나오는 [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A) 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.[N-methyl-O-propenyl-D-serine 3 ] cyclosporin A (N-methyl-O-Propenyl-D-Ser 3 ) cyclosporin A) 0.1% shown in Table 13 through the animal evaluation test of Experimental Example 1 Comparing the hair cream with 0.1% cyclosporin A-containing hair cream confirmed a similar degree of hair growth effect.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7. [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A)7. [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A (N-methyl-O-propenyl-D-Ser 3 ) cyclosporin A) 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 2-7.Formulation Example 2-7.

[N-메틸-D-세린[N-methyl-D-serine 33 ] 사이클로스포린 A ([N-methyl-D-SerCyclosporine A ([N-methyl-D-Ser 33 ]cyclosporin A) 함유 헤어크림의 제조] Preparation of cyclosporin A) Hair Cream

표 14에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어크림을 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 14, the oily material and the watery material were separately mixed and heated to 80 ° C to completely dissolve each raw material. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After emulsification was completed, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare hair cream. The amount was added to 100% by weight of the sum of the oil and water raw materials.

하기 실험예 1의 동물 평가 시험을 통하여 표 14에 나오는 [N-메틸-D-세린3] 사이클로스포린 A([N-methyl-D-Ser3]cyclosporin A) 0.1% 함유 헤어크림을 0.1% 사이클로스포린 A 함유 헤어크림과 비교해본 결과 유사한 정도의 발모 효과를 확인하였다.To animals through the evaluation tests in Experimental Example 1 shown in Table 14 [N- methyl -D- serine 3] cyclosporin A ([N-methyl-D -Ser 3] cyclosporin A) 0.1% cyclosporin A hair cream containing 0.1% Comparing the hair cream with the results confirmed a similar degree of hair growth effect.

1. 파라핀Paraffin 5.05.0 5.05.0 5.05.0 2. 세토스테아릴알코올2. Cetostearyl Alcohol 5.55.5 5.55.5 5.55.5 3. 페트로라툼3. Petrolatum 5.55.5 5.55.5 5.55.5 4. 글리세린모노스테아레이트4. Glycerin Monostearate 3.03.0 3.03.0 3.03.0 5. 폴리옥시에틸렌옥틸도데실에테르5. Polyoxyethylene octyldodecyl ether 3.03.0 3.03.0 3.03.0 6. 프로필파라벤6. Propylparaben 0.30.3 0.30.3 0.30.3 7. [N-메틸-D-세린3] 사이클로스포린 A ([N-methyl-D-Ser3]cyclosporin A)7. [N-methyl-D-serine 3 ] cyclosporin A ([N-methyl-D-Ser 3 ] cyclosporin A) 0.10.1 1.01.0 8.08.0 8. 글리세린8. Glycerin 7.07.0 7.07.0 7.07.0 9. 디프로필렌글리콜9. Dipropylene Glycol 20.020.0 20.020.0 20.020.0 10. 폴리에틸렌글리콜10. Polyethylene Glycol 5.05.0 5.05.0 5.05.0 11. 물11.water 1-11 합이 100%가 될 때까지 첨가Add until 1-11 sum is 100% 12. 향료12. Spices 적량Quantity 적량Quantity 적량Quantity 13. 색소13. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 3. 샴푸Formulation Example 3 Shampoo

제제예 3-1 [N-메틸-D-아미노부티릭산Formulation Example 3-1 [N-methyl-D-aminobutyric acid 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Abu([N-methyl-D-Abu 33 ]cyclosporin A 함유 샴푸의 제조] Production of cyclosporin A-containing shampoo

표 15에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 15, the ingredients, except flavors, pigments, and water, were mixed with each other, mixed with heating, stirred to dissolve completely, cooled to room temperature, and finally added with water after adding flavors and pigments. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3] cyclosporin A6. [N-methyl-D-aminobutyric acid 3 ] cyclosporin A ([N-methyl-D-Abu 3 ] cyclosporin A 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-2Formulation Example 3-2

[N-메틸-D-노르발린[N-methyl-D-norvaline 33 ] 사이클로스포린 A ([N-methyl-D-NvaCyclosporine A ([N-methyl-D-Nva 33 ]cyclosporin A 함유 샴푸의 제조] Production of cyclosporin A-containing shampoo

표 16에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 16, the ingredients, except flavors, pigments, and water, were mixed with each other, mixed with heating, stirred, completely dissolved, cooled to room temperature, and finally added with water after adding flavors and pigments. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [N-메틸-D-노르발린3] 사이클로스포린 A ([N-methyl-D-Nva3]cyclosporin A6. [N- methyl -D- norvaline 3] cyclosporin A ([N-methyl-D -Nva 3] cyclosporin A 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-3Formulation Example 3-3

[D-2-(메틸아미노)헥사-4-이노일[D-2- (methylamino) hexa-4-inoyl 33 ]사이클로스포린 A ([D-2-(methylamino) hexa-4-ynoyl] Cyclosporine A ([D-2- (methylamino) hexa-4-ynoyl 33 ] cyclosporin A) 함유 샴푸의 제조] Preparation of Cyclosporin A) Shampoo

표 17에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 17, the raw materials, except for flavoring, coloring, and water, were mixed with each other, mixed with heating, stirred, and completely dissolved. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 A ([D-2-(methylamino) hexa-4-ynoyl3] cyclosporin A)6. [D-2- (methylamino) hexa-4-yl Ino 3] cyclosporin A ([D-2- (methylamino ) hexa-4-ynoyl 3] cyclosporin A) 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-4Formulation Example 3-4

[D-2-(메틸아미노)펜트-4-이노일[D-2- (methylamino) pent-4-inoyl 33 ] 사이클로스포린A ([D-2-(Methylamino) pent-4-ynoylCyclosporine A ([D-2- (Methylamino) pent-4-ynoyl 33 ] cyclosporin A) 함유 샴푸의 제조] Preparation of Cyclosporin A) Shampoo

표 18에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 18, the ingredients, except flavors, pigments, and water, were mixed with each other, mixed with heating, stirred to dissolve completely, cooled to room temperature, and finally added with water after adding flavors and pigments. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린A ([D-2-(Methylamino) pent-4-ynoyl3] cyclosporin A)6. [D-2- (methylamino) pent-4-one 3 Ino] Cyclosporine A ([D-2- (Methylamino ) pent-4-ynoyl 3] cyclosporin A) 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-5Formulation Example 3-5

[D-2-메틸티오살코신[D-2-methylthiosalcosine 33 ] 사이클로스포린 A ([D-2-methylthio-SarCyclosporine A ([D-2-methylthio-Sar 33 ] cyclosporin A)함유 샴푸의 제조,] preparation of cyclosporin A) shampoo,

표 19에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 19, the raw materials, except for flavoring, coloring, and water, were mixed with each other, mixed with heating, stirred, and completely dissolved. After cooling to room temperature, the water was finally added after adding flavoring and coloring. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3] cyclosporin A)6. [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-6.Formulation Example 3-6.

[N-메틸-O-프로페닐-D-세린[N-Methyl-O-propenyl-D-serine 33 ] 사이클로스포린 A (N-methyl -O-Propenyl-D-SerCyclosporine A (N-methyl -O-Propenyl-D-Ser 33 ) cyclosporin A)함유 샴푸의 제조) Preparation of cyclosporin A) Shampoo

표 20에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 20, the ingredients, except flavors, pigments, and water, were mixed with each other, mixed with heating, stirred, and completely dissolved. After cooling to room temperature, the water was finally added after adding flavors and pigments. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A)6. [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A (N-methyl-O-propenyl-D-Ser 3 ) cyclosporin A) 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 3-7. [N-메틸-D-세린Formulation Example 3-7. [N-methyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Ser([N-methyl-D-Ser 33 ] cyclosporin A) 함유 샴푸의 제조] Preparation of Cyclosporin A) Shampoo

표 21에 나타낸 3 가지 제형으로 각각의 원료 중 향료, 색소, 및 물을 제외한 원료들을 혼합한 후 가열 하면서 교반하여 완전히 용해시키고, 상온으로 냉각한 후 향료와 색소를 첨가 후 최종적으로 물을 첨가 하여 100 중량%로 맞추어 샴푸를 제조 하였다.In the three formulations shown in Table 21, the ingredients, except flavors, pigments, and water, were mixed with each other, mixed with heating, stirred, and dissolved completely. Shampoo was prepared according to 100% by weight.

원료명Raw material name 1. POE라우릴황산나트륨(30%)1.POE sodium lauryl sulfate (30%) 40.040.0 40.040.0 40.040.0 2. 야자유지방산디에탄올아미드2. Palm oil fatty acid diethanolamide 3.03.0 3.03.0 3.03.0 3. 프로필렌글리콜3. Propylene Glycol 2.02.0 2.02.0 2.02.0 4. 파라옥시안식향산메틸4. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 5. 에탄올5. Ethanol 2.02.0 2.02.0 2.02.0 6. [N-메틸-D-세린3] 사이클로스포린 A ([N-methyl-D-Ser3] cyclosporin A)6. [N-methyl-D-serine 3 ] cyclosporin A ([N-methyl-D-Ser 3 ] cyclosporin A) 1.01.0 3.03.0 10.010.0 7. 살리실산7. Salicylic Acid 0.30.3 0.30.3 0.30.3 8. 엘-멘톨8. L-menthol 0.30.3 0.30.3 0.30.3 9. 향료9. Spices 적량Quantity 적량Quantity 적량Quantity 10. 색소10. Pigment 적량Quantity 적량Quantity 적량Quantity 물water 100중량%가 될 때까지 첨가Add until 100% by weight

제제예 4. 헤어컨디셔너Formulation Example 4 Hair Conditioner

제제예 4-1. [N-메틸-D-아미노부티릭산Formulation Example 4-1. [N-methyl-D-aminobutyric acid 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Abu([N-methyl-D-Abu 33 ] cyclosporin A 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A-Containing Hair Conditioner

표 22 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 22, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1.세탄올1.Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4 [N-메틸-D-아미노부티릭산3] 사이클로스포린 A ([N-methyl-D-Abu3] cyclosporin A4 [N-methyl-D-aminobutyric acid 3 ] cyclosporin A ([N-methyl-D-Abu 3 ] cyclosporin A 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-2.Formulation Example 4-2.

N-메틸-D-노르발린N-methyl-D-norvaline 33 ] 사이클로스포린 A ([N-methyl-D-NvaCyclosporine A ([N-methyl-D-Nva 33 ]cyclosporin A 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A-Containing Hair Conditioner

표 23 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 23, the oily and watery materials were separately mixed and heated to 80 ° C to completely dissolve each raw material. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1.세탄올1.Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4 [N-메틸-D-노르발린3] 사이클로스포린 A ([N-methyl-D-Nva3]cyclosporin A4 [N- methyl -D- norvaline 3] cyclosporin A ([N-methyl-D -Nva 3] cyclosporin A 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-3.Formulation Example 4-3.

[D-2-(메틸아미노)헥사-4-이노일[D-2- (methylamino) hexa-4-inoyl 33 ]사이클로스포린 ACyclosporine A

([D-2-(methylamino) hexa-4-ynoyl([D-2- (methylamino) hexa-4-ynoyl 33 ] cyclosporin A) 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A) Hair Conditioner

표 24 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 24, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1.세탄올1.Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4. [D-2-(메틸아미노)헥사-4-이노일3]사이클로스포린 A ([D-2-(methylamino) hexa-4-ynoyl3] cyclosporin A)4. [D-2- (methylamino) hexa-4-yl Ino 3] cyclosporin A ([D-2- (methylamino ) hexa-4-ynoyl 3] cyclosporin A) 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-4.Formulation Example 4-4.

[D-2-(메틸아미노)펜트-4-이노일[D-2- (methylamino) pent-4-inoyl 33 ] 사이클로스포린 ACyclosporin A

([D-2-(Methylamino) pent-4-ynoyl([D-2- (Methylamino) pent-4-ynoyl 33 ] cyclosporin A 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A-Containing Hair Conditioner

표 25 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 25, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1.세탄올1.Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4 .[D-2-(메틸아미노)펜트-4-이노일3] 사이클로스포린 A ([D-2-(Methylamino) pent-4-ynoyl3] cyclosporin A4. [D-2- (methylamino) pent-4-one 3 Ino] Cyclosporine A ([D-2- (Methylamino ) pent-4-ynoyl 3] cyclosporin A 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-5.Formulation Example 4-5.

[D-2-메틸티오살코신[D-2-methylthiosalcosine 33 ] 사이클로스포린 ACyclosporin A

([D-2-methylthio-Sar([D-2-methylthio-Sar 33 ] cyclosporin A 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A-Containing Hair Conditioner

표 26 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 26, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1. 세탄올1. Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4. [D-2-메틸티오살코신3] 사이클로스포린 A ([D-2-methylthio-Sar3] cyclosporin A4. [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-6.Formulation Example 4-6.

[N-메틸-O-프로페닐-D-세린[N-Methyl-O-propenyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

(N-methyl -O-Propenyl-D-Ser(N-methyl -O-Propenyl-D-Ser 33 ) cyclosporin A) 함유 헤어컨디셔너의 제조) Preparation of cyclosporin A) Hair Conditioner

표 27 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 27, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1. 세탄올1. Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4. [N-메틸-O-프로페닐-D-세린3] 사이클로스포린 A (N-methyl -O-Propenyl-D-Ser3) cyclosporin A)4. [N-methyl-O-propenyl-D-serine 3 ] cyclosporin A (N-methyl-O-propenyl-D-Ser 3 ) cyclosporin A) 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

제제예 4-7.Formulation Example 4-7.

N-메틸-D-세린N-methyl-D-serine 33 ] 사이클로스포린 ACyclosporin A

([N-methyl-D-Ser([N-methyl-D-Ser 33 ] cyclosporin A) 함유 헤어컨디셔너의 제조] Preparation of cyclosporin A) Hair Conditioner

표 28 에 나타낸 3 가지 제형으로 각각의 원료 중 유상원료 및 수상원료를 각각 별도로 혼합하고 80℃까지 가열 하여 완전히 녹였다. 제조된 80℃의 유상원료와 수상원료를 혼합하고 유화시킨다. 유화완료 후 상온까지 냉각한 후 향료와 색소를 첨가 혼합 하여 헤어콘디셔너를 제조 하였다. 물량은 유상원료와 수상원료의 합을 100 중량%로 맞추어 첨가 하였다.In each of the three formulations shown in Table 28, each of the oily and watery ingredients was separately mixed and heated to 80 ° C to completely dissolve. The prepared oily raw material and the watery raw material of 80 ° C. are mixed and emulsified. After the completion of emulsification, the mixture was cooled to room temperature, and then mixed with fragrance and pigment to prepare a hair conditioner. The amount was added to 100% by weight of the sum of the oil and water raw materials.

원료명Raw material name 1.세탄올1.Cetanol 3.03.0 3.03.0 3.03.0 2. 자기유화형모노스테아린산글리세린2. Self-emulsifying glycerin monostearate 2.02.0 2.02.0 3.03.0 3. 스쿠알렌3. Squalene 10.010.0 10.010.0 10.010.0 4. [N-메틸-D-세린3] 사이클로스포린 A ([N-methyl-D-Ser3] cyclosporin A)4. [N-methyl-D-serine 3 ] cyclosporin A ([N-methyl-D-Ser 3 ] cyclosporin A) 1.01.0 5.05.0 10.010.0 5. 프로필렌글리콜5. Propylene Glycol 2.02.0 2.02.0 2.02.0 6. 염화스테아릴디메칠벤질암모늄(25%)6. Stearyl Dimethylbenzyl Ammonium Chloride (25%) 8.08.0 8.08.0 8.08.0 7. 파라옥시안식향산메틸7. Methyl Paraoxybenzoate 0.20.2 0.20.2 0.20.2 8. 살리실산8. Salicylic Acid 0.30.3 0.30.3 0.30.3 9. 엘-멘톨9. L-menthol 0.30.3 0.30.3 0.30.3 10. 물10. Water 100%중량이되도록 첨가Add 100% by weight 11.향료11.Fragrance 적량Quantity 적량Quantity 적량Quantity 12. 색소12. Pigment 적량Quantity 적량Quantity 적량Quantity

실험예 1Experimental Example 1

(본 발명의 사이클로스포린 유도체의 모발 성장 촉진 효과 시험)(Test of hair growth promoting effect of the cyclosporin derivative of the present invention)

모발 성장 촉진 효과 시험은 생후 42∼49 일된 마우스(C57BL/6, female)를 사용하였다. 먼저 등 부위의 털을 전기면도기를 이용하여 제거하고 각 마우스의 무게를 재서 몸무게가 고루 분산이 되도록 여러 마리씩 나누었다. 하루 동안 적응 기간을 두고 다음 날부터 제모 부위에 상기 실시예 1의 각각의 사이클로스포린류와 사이클로스포린 유도체의 HPLC 분취액을 도포하였으며, 이때 개체당 등부위에 1일 1회, 100 마이크로리터(0.1 % w/v)를 30 일간 도포하였다. 그 결과는 털이 자란 정도를 육안 판정하여 털을 제거한 면적에 대하여 신생모가 자란 면적의 비율을 구하여 비교하였다.The hair growth promoting test was used 42-49 days old mice (C57BL / 6, female). First, the hair on the back was removed using an electric razor, and each mouse was weighed and divided into several pieces so that the weight was evenly distributed. After an adaptation period for one day, HPLC aliquots of each of the cyclosporins and cyclosporine derivatives of Example 1 were applied to the hair removal site from the following day, at which time, 100 microliters (0.1% w / v) was applied for 30 days. As a result, the degree of hair growth was visually determined, and the ratio of the area where the newborn hair was grown to the area from which hair was removed was compared.

하기 표 1에서 보는 바와 같이 사이클로스포린 유도체의 경우 베히클(vehicle)만을 도포한 대조군에 비해 현저한 모발 성장촉진 효과가 있었으며, 사이클로스포린 A와 동등 수준을 나타내었다. 30 일 실험 과정중 등판 상태를 비교한 결과 대조군및 모든 처리군에서 특이한 피부자극 소견이 발견되지 않았다.As shown in Table 1, the cyclosporin derivative had a significant hair growth promoting effect compared to the control group applied only vehicle, and showed the same level as cyclosporin A. As a result of comparing the climbing status during the 30-day experiment, no specific skin irritation was found in the control group and all treatment groups.

물질matter 베히클Vehicle 사이클로스포린 ACyclosporin A 화합물1Compound 1 화합물2Compound 2 화합물3Compound 3 화합물4Compound 4 화합물5Compound 5 화합물6Compound6 화합물7Compound7 유효면적%Effective area% 3535 9191 9595 9191 9595 9696 9393 9494 9090

이러한 결과를 적용하여 액상, 스프레이, 겔, 페이스트, 유제, 크림, 콘디셔너, 샴푸 등의 다양한 제형이 가능하나 상업적으로 많이 이용되는 발모토닉, 헤어크림, 헤어콘디셔너, 헤어샴푸를 제조하였고, 상기 실험예 1의 동물 평가 시험을 통하여 본 발명의 처리군이 대조군보다 우수한 발모 효과가 있는 것을 확인하였다.By applying these results, various formulations such as liquids, sprays, gels, pastes, emulsions, creams, conditioners and shampoos are possible, but commercially used balmonics, hair creams, hair conditioners and hair shampoos were prepared. The animal evaluation test of 1 confirmed that the treatment group of the present invention has a superior hair growth effect than the control group.

본 발명의 사이클로스포린 A 3위치 유도체를 유효성분으로 하는 모발 성장 촉진제는 탁월한 모발 성장 효과를 유지하여 우수한 발모효과를 나타낸다.The hair growth promoter using the cyclosporin A 3-position derivative of the present invention as an active ingredient maintains excellent hair growth effect and shows excellent hair growth effect.

Claims (3)

화학식 1로 나타내는 사이클로스포린 3위치 유도체를 유효성분으로 하는 모발 성장 촉진제:Hair growth promoter using the cyclosporin 3-position derivative represented by the formula (1) as an active ingredient: [화학식 1][Formula 1] 상기 식에서,Where MeBmt는 N-메틸-(4R)-4-[(E)-2-뷰텐일]-4-메틸-L-트레오닌(N-methyl-(4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine)이며,MeBmt is N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine (N-methyl- (4R) -4-[(E) -2-butenyl] -4-methyl-L-threonine) Abu는 Ｌ－아미노부티릭산(Abu, L-aminobutyric acid)이며,Abu is L-aminobutyric acid (Abu), A는 하기 일반식 (1)로 나타나는 D-아미노산으로,A is a D-amino acid represented by the following general formula (1), CH3NH-CH(R)-COOH (1)CH 3 NH-CH (R) -COOH (1) 여기에서, R은 하기 일반식 (2)의 구조를 나타내고,Here, R represents the structure of the following general formula (2), -X-R' (2)-X-R '(2) 여기에서, X는 황(S)이며, R'은 메틸(CH3)이거나, 또는 아미노(amino), 히드록시(hydroxy), 할로(halo), 할로알킬(haloalkyl), 에스테르(ester), 알콕시(alkoxy), 시아노(cyano), 나이트로(nitro), 알킬아미노(alkylamino) 및 디알킬아미노(dialkylamino)로 구성되는 그룹으로부터 선택된 1 내지 3 개의 치환기에 의해 치환된 메틸(CH3)이고,Wherein X is sulfur (S) and R 'is methyl (CH 3 ) or amino, hydroxy, halo, haloalkyl, ester, alkoxy methyl (CH 3 ) substituted by 1 to 3 substituents selected from the group consisting of (alkoxy), cyano, nitro, alkylamino and dialkylamino, MeLeu는 N-메틸-L-루신(N-methyl-L-leucine)이며,MeLeu is N-methyl-L-leucine, Val은 L-발린(L-valine)이며,Val is L-valine, Ala는 L-알라닌(L-alanine)이며,Ala is L-alanine, DAla는 D-알라닌(D-alanine)이며,DAla is D-alanine, MeVal은 N-메틸-L-발린(N-methyl-L-valine)이다.MeVal is N-methyl-L-valine. 제 1 항에 있어서, [D-2-메틸티오살코신3] 사이클로스포린 A([D-2-methylthio-Sar3] cyclosporin A)를 유효성분으로 하는 모발 성장 촉진제.The hair growth promoter according to claim 1, wherein [D-2-methylthiosalcosine 3 ] cyclosporin A ([D-2-methylthio-Sar 3 ] cyclosporin A) is used as an active ingredient. 제 1 항 또는 제 2 항에 있어서, 상기 모발 성장 촉진제의 제형이 액상, 스프레이, 겔, 페이스트, 유제, 크림, 콘디셔너 또는 샴푸인 것을 특징으로 하는 모발 성장 촉진제.3. Hair growth promoter according to claim 1 or 2, wherein the formulation of the hair growth promoter is liquid, spray, gel, paste, emulsion, cream, conditioner or shampoo.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190037540A (en) 2017-09-29 2019-04-08 (주)아모레퍼시픽 Composition for prevention of hair loss or promotion of hair growth, containing Camellia Sinensis-stem cell extract and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0414632A2 (en) * 1989-07-24 1991-02-27 Sandoz Ltd. Cyclosporin derivatives
WO1993017039A1 (en) * 1992-02-24 1993-09-02 Sandoz Ltd. Iso-cyclosporin salts
JPH07316023A (en) * 1994-05-26 1995-12-05 Shiseido Co Ltd Hair tonic
US5807820A (en) * 1988-05-13 1998-09-15 Novartis Ag Cyclosporin compositions for topical application
KR20010049236A (en) * 1999-11-19 2001-06-15 성재갑 Use of a nonimmunosuppressive cyclosporin A derivative for hair growth
KR20010051687A (en) * 1999-11-19 2001-06-25 성재갑 Use of nonimmunosuppressive cyclosporin derivatives for hair growth

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5807820A (en) * 1988-05-13 1998-09-15 Novartis Ag Cyclosporin compositions for topical application
EP0414632A2 (en) * 1989-07-24 1991-02-27 Sandoz Ltd. Cyclosporin derivatives
WO1993017039A1 (en) * 1992-02-24 1993-09-02 Sandoz Ltd. Iso-cyclosporin salts
JPH07316023A (en) * 1994-05-26 1995-12-05 Shiseido Co Ltd Hair tonic
KR20010049236A (en) * 1999-11-19 2001-06-15 성재갑 Use of a nonimmunosuppressive cyclosporin A derivative for hair growth
KR20010051687A (en) * 1999-11-19 2001-06-25 성재갑 Use of nonimmunosuppressive cyclosporin derivatives for hair growth

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190037540A (en) 2017-09-29 2019-04-08 (주)아모레퍼시픽 Composition for prevention of hair loss or promotion of hair growth, containing Camellia Sinensis-stem cell extract and preparation method thereof

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