TW200930412A - Topical compositions comprising non-proteogenic amino acids and methods of treating skin - Google Patents
Topical compositions comprising non-proteogenic amino acids and methods of treating skin Download PDFInfo
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- TW200930412A TW200930412A TW097146473A TW97146473A TW200930412A TW 200930412 A TW200930412 A TW 200930412A TW 097146473 A TW097146473 A TW 097146473A TW 97146473 A TW97146473 A TW 97146473A TW 200930412 A TW200930412 A TW 200930412A
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Description
200930412 九、發明說明: 【發明所屬之技術領域】 概言之’本發明係關於用於外敷施用於皮膚上之包含非 產蛋白質之胺基酸的組合物及該等組合物為皮膚提供益處 之用途。 【先前技術】 彈性纖維係包含藉由富含微纖維蛋白之微纖維套.膜包圍 之彈性蛋白核心的基本細胞外基質大分子(Kiety等人,j
Ce// ,2002年 7月 15 日;115 (Pt 14):2817-28)。彈性纖 維為諸如皮膚及肺等組織提供彈性及回彈性。產生成熟及 功能彈性纖維之過程極為複雜’因為其涉及多種組份且需 要緊密調控之沈積及多步驟分級組裝。彈性蛋白單體(原 彈性蛋白)藉由一或多個離胺醯氧化酶家族成員在細胞外 間隙中交聯形成彈性蛋白聚合物,其為成熟蛋白之功能形 式。吾人認為含有微纖維蛋白之微纖維藉由在原彈性蛋白 内作為排列交聯結構域之支架而在組裝過程中起重要作 用。 類離胺醯氧化酶-1 (LOXL1)係離胺醯氧化酶家族成員, 其藉由離胺酸或經基離胺酸侧鏈之氧化脫胺作用催化膠原 與彈性蛋白交聯。所得ε-醛離胺酸殘基可自發地與鄰近肽 齡或與肽基離胺酸之ε-胺基縮合產生共價交聯鍵(Lucer〇等 人,Ce// Mo/· Li/e 5W.,2006 年 10 月;63 (19-20):2304- 16)。LOXL1係與彈性蛋白纖維有關之細胞外酶(N〇blesse 等人,J· /«ναί. Dermoio/·,2004 年 3月;122 (3):621- 136163.doc 200930412 3〇·)。LOXL1在皮膚等效物之表皮及真皮中及在人類皮膚 中表現。LOXL1對於彈性纖維形成及彈性纖維内穩態之保 持極為重要。LOXL1基因剔除小鼠所具有之結締組織表型 之特徵在於由彈性蛋白含量降低所導致之雌性動物中骨盆 鬆他及肺部空氣間隙增大(Liu等人,,2〇〇4年2 月;36(2):178-82)。超微結構分析顯示肺及皮膚中之彈性 纖維發育不良、支離破碎及不連續。另外,缺少L〇XL1之 小鼠之產後子宮中不會沈積正常彈性纖維且伴隨原彈性蛋 白積聚會發生皮膚鬆弛及血管異常。最近之研究顯示,與 兒童成纖維細胞相比成人皮膚成纖維細胞中之L〇xu mRNA的含量降低(Genizo等人,五印.Derwaio/.,2006年8 月;15 (8):574-81.)。 美國專利公開案第2005/0188427號(其揭示内容以引用方 式併入本文中)揭示治療患有與彈性纖維喪失有關之狀泥 (例如皮廣鬆弛或起皺紋)之個體的方法,該方法包含向個 體投與治療有效量之LOXL1增強子。吾人認為l〇xli增強 子為LOXL1多肽或其活性片段、或編碼l〇xli多肽或其活 性片段之核酸。吾人亦認為LOXL1增強子包括藉由揭示於 彼公開案中之篩選方法所識別之小分子或其他治療性化合 物。美國專利公開案第2005/01 88427號中未揭示肽形式之 外的胺基酸增強LOXL1表現之用途。 胺基酸已成為化妝品之日益重要的成份。例如,已將多 種天然胺基酸納入化妝品中作為膠原及彈性蛋白合成之結 構單元、用於保濕、增強皮膚屏障、降低皮脂腺活力及其 136163.doc 200930412 他功能特性。然而,非天然非產蛋白質之胺基酸之使用在 化妝πσ工業中受到較少關注。迄今,非天•然胺基酸之使用 主要受限於賦予功能肽水解穩n按照定義,非產蛋白 質之胺基酸不會在新蛋白質合成中納入蛋白質中,且因此 預測外敷使用非產蛋白質之胺基酸不會在皮膚巾達成新蛋 白質合成及皮膚回春益處。非天然非產蛋白f之胺基酸之 内在功能在很大程度上被忽<。迄今,i人並不暸解非天 然非產蛋白質之胺基酸增強L〇XL·!及調節與皮膚衰老有 關之其他途徑的能力。 因此,本發明之目的在於提供使用非天然非產蛋白質之 胺基酸來增強皮膚中之L〇XL_ i產生的新親化妝品組合物 及方法。本發明之又一目的在於提供使用非天然非產蛋白 質之胺基酸來改善皮膚外觀的化妝品組合物及方法,該等 方法包括治療、逆轉及/或預防衰老迹象(例如皮膚皺紋)。 提供上文論述僅為更好地瞭解此技術領域所遇到問題之 實質且不應以任何方式理解為認可為先前技術且不應將本 文引用任何參考文獻理解為認可該參考文獻構成本申請案 之”先前技術"。 【發明内容】 與上述目的及其他一致,吾人驚奇地發現某些非產蛋白 質之胺基酸係LOXL-1之強效刺激劑,且由於L〇XL_〗能夠 重塑及保持皮膚中之彈性蛋白纖維,故期望提供數種皮膚 益處。如本文更全面論述’除L〇XL-1刺激外,預期非產 蛋白質之胺基酸在與皮膚衰老有關之一或多種額外生物途 136163.doc 200930412 徑中起有利作用,儘管該等額外益處並不嚴格需要。 在本發明之一個態樣中,提供用於治療與彈性蛋白纖維 喪失有關之皮膚狀況之化妝品組合物,該等化妝品組合物 在化妝品上可接受之媒冑中包含有‘效量的可增強LOXL] 之非產蛋白質之胺基酸或其衍生物。在較佳實施例中,非 產蛋白質之胺基酸包含具有雜環基團(較佳為雜芳基)之側 鏈。較佳之胺基酸包含含氮雜環或雜芳環。本發明之當前 較佳之非產蛋白質之胺基酸係具有以下結構之L-4-噻唑基 丙胺酸:
φ 在另一態樣中,所提供之化妝品組合物在化妝品上可接 受之媒劑中包含可有效增強皮膚中之L〇xL_丨之量的噻唑 基丙胺酸或其衍生物。噻唑基丙胺酸通常為L_噻唑基丙胺 酸或其衍生物,較佳為L-4-噻唑基丙胺酸或其衍生物。 • 本發明亦提供治療與皮膚中之彈性蛋白纖維喪失有關之 皮膚狀況的方法’該方法包含將可增強L〇xl_ 1之非產蛋 白質之胺基酸或其衍生物以可有效增強L〇XL_【之量外敷 施用於有需要之皮膚上。該非產蛋白質之胺基酸可進一步 具有一或多種選自由下列組成之群之額外活性:抑制鈣神 136163.doc 200930412 經素、增強βΐ整合素之表現、增強纖維連接蛋白之表現、 刺激Β-内啡肽及增強CGRP之表現。 在本發明之另-態樣t,提供治療、改善及/或預防人 類皮膚之細紋或皺紋或下垂的方法,其包含將包含可增強 loxl-1之非產蛋白質之胺基酸的組合物外敷施用於有需 要之皮膚上。在特定實施例中,非產蛋白質之胺基酸係嗟 土丙胺酸或其衍生物’更通常為L_n塞唾基丙胺酸或其衍 纟物’ ^較佳為L_44°坐基丙胺酸或其衍生物。因此,本 發明該態樣之治療細紋或皺紋的較佳方法包含將包含L_4_ 噻唑基丙胺酸之組合物外敷施用於細紋或皺紋上。 藉由參考以下詳細闞述及附圖可更好地理解本發明之該 等及其他態樣。 【實施方式】 除非另有規;t ’否則本文所用之所有術語皆意欲具有其 普通含義。 〇 冑語"胺基酸"通常係指在同-分子中含有胺基及缓基之 有機分子。術語”α·胺基酸"係指其中胺基及羧基與同一碳 原'子結合之胺基酸。術語,,卜胺基酸"係指其中胺基及缓基 與相鄰碳原子結合之胺基酸。 ' ”天然胺基酸”係指藉由自然界中之生物體合成之任何胺 基酸’其包括但不限於標準胺基酸L_丙胺酸、胺酸、 L-白胺酸、L-異白胺酸、L_脯胺酸、[_色胺酸、l_苯丙胺 酸L·甲硫胺酸、甘胺酸、L_絲胺酸、l_絡胺酸、蘇胺 酸、L-半胱胺酸、L_胱胺酸、L_天冬醯胺、l_麵胺醯胺、 136163.doc -10· 200930412 L-天冬胺酸、L_麩胺酸、L_離胺酸、L_精胺酸、L_組胺 酸、及其他非標準胺基酸(例如L_鳥胺酸)、及衍生物(例如 L-4-經基脯胺酸)。 廣義而言,"非天然胺基酸"係指除"天然胺基酸"之外的 任何胺基酸,且包括但不限於具有未在天然胺基酸中發現 之側鏈的(X-胺基酸以及β·胺基酸。"非天然胺基酸"亦係指 雖然呈不同立體化學組態但結構與天然胺基酸相同之胺基 酸。 廣義而言,"非產蛋白質”之胺基酸係指不能藉由活生物 體納入肽或蛋白質中之任何絲酸且包括非天然胺基酸。 本發明提供用於外敷施用之組合物,其包含有效量之一 或多種非產蛋白質之胺基酸以治療、逆轉、改善及/或預 皮膚衰老迹象。料皮膚衰老迹象包括但*限於以下: (a) 治療、減少及/或預防細紋或皺紋; (b) 減小皮膚毛孔大小; (c) 改善皮膚厚度、豐滿度及/或緊實度; (d) 改善皮膚柔順度及/或柔軟度; (e) 改善皮膚色調、光亮度及/或透明度; (f) 改善則膠原及/或勝原產生; (g) 改善彈性蛋白之保持及重塑; (h) 改善皮膚紋理及/或促進恢復原有紋理; (i) 改善皮膚屏障修復及/或機能; (j ) 改善皮膚輪靡之外觀; (k)恢復皮膚光澤及/或亮度; 136163.doc -11 - 200930412 (i)補充皮膚中之必需營養素及/或成份; (m)改善因衰老及/或絕經而減退之皮膚外觀; (η)改善皮膚濕潤性;及/或 (〇)增強皮膚彈性及/或回彈性。 實際上’將本發明組合物施用於需要治療之皮膚上。 即,皮膚患有任何上述屬性之缺失或喪失或否則將受益於 任何上述皮膚屬性之改善。 在某些較佳實施例中,本發明之組合物及方法係針對預 防、治療及/或改善皮膚細紋及/或皺紋。在該情形中,將 該等組合物施用於需要治療之皮膚上,所謂需要治療之皮 膚意指具有皺紋及/或細紋之皮膚。較佳地,將該等組合 物直接施用於細紋及/或皺紋上。該等組合物及方法適於 治療任何皮膚表面上之細紋及/或皺紋,包括但不限於 臉、頸及/或手之皮膚。 通常而言,該等組合物及方法可用於治療與彈性纖維喪 失有關之任何皮膚狀況。吾人認為該等益處至少部分係由 化合物能夠刺激LOXL-1產生而引起。換言之,本發明之 非產蛋白質之胺基酸係LOXL-1增強子。 本發明之胺基酸呈"游離"或單體形式,所謂呈"游離"或 單體形式意指其不與其他胺基酸共價結合,但或者可官能 化成本文所述之前藥及諸如此類。 用於實施本發明之胺基酸可為能夠減少、治療或預防一 或多種衰老迹象之任何非產蛋白質之胺基酸。通常,本發 明之非產蛋白質之胺基酸能夠刺激L〇XL_l。在一個實施 136163.doc 12 200930412 例中,該非產蛋白質之胺基酸具有式〗之結構: 0 R,-、、、、
其中η係0(零)至4之整數,通常為〇至2,且較佳為〇或 1 ’以使在η係〇之情形中胺基酸係α_胺基酸且在η係1之情 形中胺基酸係β-胺基酸; e 尺係包含任何有機取代基之側鏈,條件為在式I之胺基酸 呈L(左旋)組態之情形中,當以系❹(即,α_胺基酸)時側鍵 不為存在於產蛋白質之天然存在的胺基酸中之側鏈; R通常為包含1_20個碳原子及視情況包括一或多個雜原 子(例如氧、硫及氮原子)之烴基團。較佳地,r係選自經 取代或未經取代之具支鏈、直鏈或環狀Ci_C2q烷基、烯 基、炔基、芳基、苄基、雜芳基、烷基芳基芳基烷 基、烷基-雜芳基、雜芳基_烷基、雜芳基-芳基、二環烷 0 基、芳基或雜芳基基團及其組合;其中上述基團可經包括 以下之任何部分取代:例如,羥基、胺基、氰基、函素、 側氧基、鲮基、曱醯胺基、硝基、偶氮基、烷氧基、烷 基、烷基亞胺基、烷基胺基、二烷基胺基、硫代烷氧基及 其組合。 在較佳實施例中,R包含雜環。雜環可為單環或二環且 可為芳族部分飽和或完全飽和之雜環。較佳之雜環包含氮 原子。代表性雜環包括但不限於氮雜環丁基、笨并„米唾 136163.doc -13- 200930412 基、苯并售°坐基、苯并°塞吩基、苯并嗯β坐基、吱鳴基、咪 嗤基、咪唑啉基、異喹啉基、異噁唑基、異噁唑啶基、異 嗟唑基、異噻唑啶基、吲哚基、噁唑基、噁唑啶基、吡咯 基、吡咯啉基、吡咯啶基、吡唑基、吡唑啉基、吡唑啶 基、吡啶基、六氫吼啶基、》比嗪基、六氫吼嗪基、Ν-甲基 六氫°比嗪基、Ν-甲基氮雜環丁基、嘧啶基、嗒嗪基、嗎啉 基、喹啉基、噻唑基、噻唑啶基、噻吩基、三唑基及諸如 此類。 虛線意欲表示R可為與氮原子形成環之二價基團,如在 (例如)脯胺酸及羥基脯胺酸類似物之情形中,儘管該等結 構較不佳。 在一個實施例中,胺基酸係包含式Ia之雜環基團的心胺 基酸或β-胺基酸:
其中η係0(α-胺基酸)或1(β-胺基酸); 2可表示鍵(即’ Ζ被省略)或Ζ可表示與α_碳結合之連接 體部分,α-碳又通過取代基Υ與雜環q結合;其中ζ通常包 含1個至10個碳原子,視情況包括一或多個雜原子取代 基,例如氧、硫及氮。通常,Ζ係選自由下列組成之群: 氧、硫、NRn、C^o烷基、烯基、炔基、芳基、羰基、羧 136163.doc -14- 200930412 基、胺甲醯基,其中rn係氫、c^o烷基、烯基、炔基、芳 基或諸如此類。 Z較佳係鍵或選自由下列組成之群之部分:經取代或未 經取代之具支鏈或直鏈匚!-6烷基、烯基、炔基、芳基、雜 芳基、或烷基-芳基,包括但不限於呈-(CH2)a-形式(其中 "a"係1至6之整數)之直鏈烧基部分,包括(例如)_ch2-(亞甲 *) ' -ch2ch2- > -ch2ch2ch2- ^ ic-ch2ch2ch2ch2-;- 般形式為-(CH2)aO或-〇(CH2)a-(其中"a"係1至6之整數)之 直鏈烷氧基部分,包括(例如)-CH20-或-〇CH2-、-CH2CH20- 或-OCH2CH2-、-CH2CH2CH2O-或-OCH2CH2CH2- ; -〇(CH2)aO- ’其中"a"係如上文所定義;或呈_(cH2)b〇(;CH2)e_、 -(CH2)bS(CH2)c-或- (CH2)bNRN(CH2)c-形式(其中"b"及"c"獨 立為〇(零)至ό之整數且rn係如上文所定義)之部分。較佳 地,Z表示介於丫與心碳之間之單鍵或2係基團_Ch2_或 -CH2CH2-、,CH2〇-、-CH2S-、-CH2NRn·或-(〇〇)_。在一 個實例性實施例中,z係(·CHdw且更佳為_CH2_ ; Y係環Q與連接體或鍵z之結合點且通常為碳或雜原子, 且更通常選自C、CH、N或NRn,其中Rn係如上文所定 義;且 Q係3-14員雜環基團,其包括¥且可為單環、二環或三 環(包括稠合環系統)’且在環系統中包含一或多個通常選 自氧、氮及硫之雜原+,且視情況經與環系統在任何適宜 結合點上(例如’在任何碳或氮原子上)結合之-或多㈣ 基團取代, 136163.doc 200930412 其中Rl在每次出現時均獨立選自氫;函素(F、a、Br、 I} ’ 〇H ’ 视 R,_SH ; _CN ;側氧基;-CHO ; -C〇2H ; _〇_ (〇〇)-H ; -0-(C=0)_Ci i〇烧基;_〇 (c=〇)士 ; _(c哪〇_ Cm。烧基;-(C=0).〇_Ar ; _(c=〇) nrNrN ; _〇 Ci ^ 基 ’n 〇 ΑΓ ’ 冬Cl·10烷基;-S-芳基;-Ar ; -Cm。烷基; -NR -cho ; ; .c,10^^.〇.Cl 10^
❹ 基N;全氟烧基;環氧基;叠氣基;硫氰酸S旨基;_scv 硝基或諸如此類;其中Ar表示視情況經取代之芳基, R係如上文所定義且在取代基包含兩個團之情形中, 其可共同形成環;條件為當n=0(在α_胺基酸情形中)時,式 la化合物不為l-組胺酸或L-色胺酸。 在二實知例中,在Y為雜原子之情形中,q除γ外亦包 含至少一個雜原子,該至少一個額外雜原子係選自N、 〇 S B Si、As、P及諸如此類,但更通常選自N、〇及 S ° 二員雜環之非限制性實例包括但不限於氮丙啶、環氧乙 烧硫雜環丙烧、一氮丙°定(diaziridine)及氧氮丙咬 (oxaziddine卜四員雜環之非限制性實例包括但不限於氮 雜裒丁院環軋丙燒、硫雜環丁燒(thietane)、二氮雜環丁 烷、氧氮雜環丁烷(oxazetidine)及丨,2氧硫雜環丁埝 (oxathietane) ° 五員雜環表示本發明取代基Q之當前較佳實施例。五員 雜環之非限制性實例包括但不限於吡咯啶、四氫呋喃、四 氫噻吩、噁唑啶、噻唑啶、、丨,3_氧硫味、丨,爻 136163.doc -16· 200930412 二硫咪、味°坐咬、π比唾咬、°比p各、咬鳴、喧吩、°惡°坐、異 °惡0坐、°塞吐、異°塞β坐、口米°坐、°比β坐、1,3,4 - °惡二峻、1,2,4 -°惡二 °坐、1,3,4-°塞二哇、1,2,4-°塞二°坐、1,3,4-三吐、1,2,3-三唑及諸如此類。Q可選自(例如)以下芳族完全飽和或包 含一個或兩個雙鍵之五員雜環:
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應理解’在包含環% 取代基〇及/或s之每一上述五員環 中,與環之結合點不兔 馬硫或氧原子,意指Y為C、CH或 N,而非Ο或S。該等五g 員環可視情況經如上文所定義之一 或多個R丨基團官能化, ❹ J尤其知:及_基、羥基、側氧基、 硫醇基、Cw烷基(例如 甲基、乙基、異丙基等)、胺基 及烧土胺I此外,任何氮原子皆可視情況氧化成N-氧 化物,且任何硫原子皆可視情況氧化成亞礙。 適宜選擇用於Q之六 負衰之非限制性實例包括但不限於 2H-吡喃、四氫吡喃、六氮 咬 1,4-二鳴烧、嗎咐、六氫 吡嗪、1,4-二噻烷、硫嗎啉、 比咬、〇比嗓、。备嗓、喊咬、 1,2,3-二嗪、l,2,4-三嗪、1 3 $ 一 ’j,5-二嗪、1,2,3,4-四嗪及五 嗪,此僅為幾個實例。Q可潠 V J選自(例如)以下芳族完全飽和 136163.doc •20- 200930412
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Ν Ν' 應理解,在包含環取代其n;a /斗、^ 八丞〇及/或s之母一上述六員環 中’與環之結合點不為护4 两碼或氧原子,意指Y為C、CH或 Ν’而非Ο或S。該等六員提·^、日达 貝環可視情況經如上文所定義之一 或多個R〗基團官能化,可尤装 J疋再k及_基、羥基、側氧基、 ❹ 硫醇基、C卜4烧基(例如,甲其 1 ^ ^ ^ 甲暴、乙基、異丙基等)、胺基 及-烧基胺基。此外,任何氮原子皆可視情況氧化成^氧 化物’且任何硫原子皆可视情況氧化成亞砜。 七員雜環包括但不限於114备t _ 卜吸% 1H-氮呼、氧呼、硫呼、M二氮 呼、1,3-二氧呼、1,3_二硫晔、1U,,, ^ 苽呼、1H-1,3,5-三氮呼、1,2-氧氮 呼、1,3-硫氮呼、1,3,6-疏-备τ ^ IL 一虱呼、四亂呼、1,2,4,7-硫三 氮平及諸如此類。人員雜環包括但不限於I雜環辛間四 稀、2H-氧料辛三稀、况硫雜環辛三浠(thi。也卜以· -氛雜%辛間四烯、2H-1,4_氧氮雜環辛間四烯、三 136163.doc -22- 200930412 氮雜環辛間四烯及諸如此類。 Q亦可表示稍合雜環系統,例如,°引η朵、苯并咬喃、苯 并嘆吩、吲嗓、異吲哚、二氫吲哚、苯并°惡吐、苯并異《惡 唑、苯并噻唑、苯并異噻唑、苯并咪唑、1Η-吲唑、喹 琳、異嗜琳、喧嗓鑌、啥°圭琳、碎琳、啥喔淋、酜嗓、 1,5-萘啶、喋啶、9Η-嘌呤、腺嘌呤、鳥嘌呤及萘啶,此僅 為幾個實例。適於取代基Q之稠合雜環系統之非限制性實 例包括但不限於: (i)以下八員稠合雜環:
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136163.doc -24- 200930412<x
Η
N N、
十 -N
N
N
及(iii)以下十員稠合雜環:
136163.doc -25- 200930412 Ν Ν' ,Ν,
Ν • Ν' .Ν、 〇
Ν .Ν, .Ν'
ΝΗ
所有該等皆僅為舉例說明在本發明範圍之内的各種雜 ❹ 環。 應理解,在包含環取代基Ο及/或S之每一上述雜環系統 , 中,與環之結合點不為硫或氧原子,意指γ為c、CH或 N,而非Ο或S。在稠合環系統中,結合點可在任一環之任 » 何適宜位置上。該等環可視情況經如上文所定義之一或多 個R!基團官能化,可尤其提及鹵基、羥基、側氧基、硫醇 基、Cw烷基(例如,甲基、乙基、異丙基等)、胺基及二 烷基胺基。此外,任何氮原子皆可視情況氧化成N-氧化 136163.doc -26- 200930412 物,且任何硫原子皆可視情況氧化成亞砜。 在較佳實施例中,Q係在環系統中包含至少一個非γ雜 原子之5或6員環,該雜原子係選自氧、硫或氮。在另一較 4實施例中,Q包含芳環。在多個實施例中,卩係選自以 下之八員環.吡喃基、吡啶基、吡嗪基、嘧啶基、嗒嗪 基、2//-吡喃基、六氫吡啶基、六氫吡嗪基、嗎啉基、6扒 1,2,5-噻一嗪基、2//67/1,5 2_二噻嗪基、噻嗪基;1,2_二 噻烷基、丨,3-二噻烷基及1,4-二噻烷基;丨,2_二噁烷基、 =3-二噁烷基及丨,4_二噁烷基;^5-三嗪基丨或在六員雜 環上視.If、况包括基團R】取代之上文所提供之任何六員雜 環。更佳地,基團Q包含如下文所論述之五員環。 在-個實施例中,本發明之非產蛋白質之胺基酸包含式 lb之5-員雜環基團(較佳為雜芳基):
其中環Q進一步藉由取代基γ、T、U、乂及霤定義; η係如上文所定義且較佳為G(零)或⑽分別定^胺基酸 或β_胺基酸; ζ係如上文所定義且較佳表示單鍵或基團(ch^翠元, 其中k係1至3之整數,較佳為&,且仍更佳地,^為1 ; 較佳地,Z係亞甲基-CH2-; ’ 136163.doc -27- 200930412 Y係C、CH或N ;且 τ、u、乂及琛獨立選自CH、CRi、N、nrN、〇及s,其 巾〜及0係如上文载義;且其中環内部之虛線圓環表示 該環視情況為芳族環且可包含零個、一個或兩個雙鍵丨且 在其中丁、U、V及/或霄表示N(氮原子)之情形中氮原子可 視情況氧化成N_氧化物,且在其中T、U、V及/或W表示S - (硫原子)之情形中硫原子可視情況氧化成亞颯;且其中R1 較佳為烷基(例如,▼基、乙基等)、胺基、烷基胺 基、一烷基胺基、硫醇基、羥基、側氧基或由素。 在一個實施例中,γ係C(碳原子)或N且τ、U、¥及w中 至J 一個為N(氮原子)。在較佳實施例中,選自T、u、v 及w之一對相鄰或非相鄰取代基表示〇^^或d,且另一對 獨立表不〇(氧原子)、N(氮原子)、NRN或S(硫原子);其中 Ri及RN係如上文所定義。 在—些實施例中,取代基γ、T、y、、及W共同包含選 φ 自以下之五員環:噻吩基(2-噻吩基或3-噻吩基);呋喃基 (2_呋喃基或3-呋喃基);2_或3_氧雜環戊基;2_或3_四氫苯 琉基’ 1,2_二硫味基;1,3-二硫味基;2//-吡咯基(2i/-吡咯-3基、27/-吡咯_4-基、或2H_吡咯_5_基);吡咯基吡咯 讨 * . 土、2_吡咯基或3_吡咯基);咪唑基(2-咪唑基、4-咪唑基、 或5_咪唑基);吡唑基(1-吼唑基、3-"比唑基、比唑基、或 5_°比唾基);異嗟唑基(3-異噻唑基、4-異噻唑基、或5-異噻 吐基);異°惡唾基(3-異噁唑基、4-異噁唑基、或5-異噁唑 基)’ 3-呋咕基:吡咯啶基(丨_吡咯啶基、2_吡咯啶基或3_吡 136163.doc -28- 200930412 咯啶基);吡咯啉基(1-吡咯啉-2-基、2-吡咯啉-2-基、2-吡 各琳_3_基、2-吼洛琳·4-基、2-«*比洛啦-5-基);咪唾咬基(ι_ 咪唑啶基、2-咪唑啶基或4-咪唑啶基);咪唑啉基(2-啼峻 琳-2-基、2-17米吐琳-4-基、或2-11米〇坐琳-5-基);η比唾咬基(2_ °比唑咬基、3-吡唑咬基、或4-吼唑啶基);°比唑琳基(3_ 〇比 唑啉-1-基、3-吡唑啉_2_基、3-吡唑啉·3-基、3-吡唑啉_4_ 基、3-吡唑啉-5-基);噻唑基(噻唑-2-基、噻唑-4-基、或 噻唑_5_基);噁唑基(噁唑-2-基、噁唑-4-基、噁唑_5_基); 1,2,3-二唆基(1,2,3-二 β坐-1 -基、1,2,3-三°坐-4 -基、或 1,2 3_ 二0坐-5-基),1,2,4 -三 >»坐基(1,2,4-三°坐-1-基、1,2,4·= 口坐 _3_ 基、或1,2,4-二唾-5-基);異嗟嗤基(異嗟《»坐-3-基、異喧嗤_ 4- 基、或異噻唑-5-基);1//·四唑(1//-四唑-1-基或17/_四唾_ 5- 基);及亞胺唑基(imidizolyl)或1,3-二唾基(1,3-二唑·ι_ 基、1,3-二唑-2-基、l,3-二唑-4-基、1,3-二唑-5-基);此僅 為幾個實例,其中括號中所列示之種類係該等基團之多種 可能連接之代表且就結合點而言並不意欲具有限制意義。 應瞭解,上述之每一者皆代表本發明之各個實施例。 在一些實施例中,本發明之胺基酸具有式Ic之結構: 9 τ
其中Ω係雜環,較佳為五M雜環,且較佳選自以下可選 芳環: 136163.doc -29· 200930412
其中ε〗、ε2及ε3獨立選自n、NH、NRn、S及〇 ;條件 當結合點係ει、ε2或時,彼位置表示n ;且較佳地 t +為結 合點之ει、h及h中之至少一個表示N;且其中不為結合點 之碳原子可視情況經如上文所定義之心基團取代,其中rN 及尺!係如上文所定義,Rl較佳為Cl·4烷基(甲基、乙基、丙 ❹ 基、異丙基等)、胺基、烷基胺基、二烷基胺基、硫醇 基、羥基、Cm烷氧基(甲氧基、乙氧基等)、烷硫基、羥 基烷基(例如,羥基甲基、羥基乙基等)、全氟甲基、或鹵 素(氟亂漠、硬)。虛線圓環意欲表示每一環皆視情況 為芳族環,但或者可包含零個、一個或兩個雙鍵。 在式Ic之較佳實施例中,Ω係選自:
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其中X係氧原子、NRn或硫原子;且 R2及R·3獨立經選擇且可為上文對於Ri所定義之任何基 團,且較佳表示氫、羥基、鹵素(F、C1、Br、U、 NR R硫醇基、或C1-4院基(較佳為曱基);其中rn係如 上文所定義且在每次出現時均較佳為氫;且其中胺基酸可 包含R或S對映異構體。在較佳實施例中,χ係硫且心及化 各為氫。 仍更佳地,胺基酸係α-胺基酸(η=〇);卩係上文所列示之 基團(1);其中X係硫且I及I各表示氫由此定義具有以 下結構之4-噻嗤基丙胺酸(噻唑_4_基丙胺酸):
136163.doc -31 - 200930412 在一個實施例中,4-噻唑基丙胺酸為4-D-噻唑基丙胺酸 或4_L_嗟嗤基丙胺酸(CAS編號為1 19433-80-6),其中4_L- °塞〇圭基丙胺酸較佳。4-L-噻唑基丙胺酸之結構顯示於下文 中。
NH2 Ο
HO
4-L-噻唑基丙胺酸 4-L-售唾基丙胺酸可自pepTech (Burlington, MA)及 Synthetech (Albany,OR)購得。4-L-噻唑基丙胺酸之合成 闡述於Dickman等人之美國專利第5,275,950號中,其揭示 内容以引用方式併入本文中。 預期適於實施本發明之胺基酸之其他非限制性實例包括 式Ila或lib之脯胺酸類似物(L或D):
136I63.doc •32· 200930412 其中R係如上文所定義且其中胺基酸之α_碳可為尺或s組 態。 本發明之非天然胺基酸亦涵蓋在α-碳上具有反轉對掌性 之天然存在之胺基酸的變體’包括D-丙胺酸、〇_綠胺酸、 D-白胺酸、D-異白胺酸、D-脯胺酸、D-色胺酸、D_笨丙胺 酸、D-甲硫胺酸、D-絲胺酸、D-酪胺酸、D_蘇胺酸、D_半 胱胺酸、D-天冬醯胺、D-麩胺醯胺、D-天冬胺酸、D_麵胺 酸、D-離胺酸、D_精胺酸、及〇_組胺酸;或在異白胺酸及 蘇胺酸之情形中’令人關注之非天然胺基酸係[R,R]、 [S,S]、[S,R]、及[R,S]非對映異構體❶非天然胺基酸亦可 基於闡述於(例如)D· Seebach 等人,Helv. Chim. Acta 1998 81,932 ; D. Seebach等人,Helv. Chim. Acta 1996, 79, 913(其揭示内容以引用方式併入本文中)中之天然胺基酸的 β類似物。 熟習此項技術者應瞭解,本發明之胺基酸可呈兩性離子 形式存在。此外’本發明涵蓋使用該等胺基酸之化妝品上 或醫藥上可接受(例如,無毒性及/或無刺激性)之鹽。該等 鹽可為無機或有機酸或鹼加成鹽。適宜酸式鹽包括但不限 於乙酸鹽、己二酸鹽、藻酸鹽、擰檬酸鹽、天冬胺酸鹽、 苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟 腦續酸鹽、二葡萄糖酸鹽、環戊丙酸鹽、十二烷基硫酸 鹽、乙烷硫酸鹽、葡庚糖酸鹽、甘油磷酸鹽、半硫酸鹽、 庚酸鹽、己酸鹽、富馬酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸 鹽、2-經基乙烧硫酸鹽、乳酸鹽、馬來酸鹽、曱績酸鹽、 136163.doc -33- 200930412 於驗酸鹽、2-萘績酸鹽、草酸鹽、雙經萘酸鹽、果膠酸 鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙 酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、曱苯磺酸鹽及十 一烷酸鹽。尤其可提及鹽酸鹽。鹼加成鹽包括彼等與諸如 鋅、鈣、鉍、鋇、鎂、鋁、銅、鈷、鎳、鎘、鈉、鉀及諸 如此類等金屬陽離子或與自氨、N,N-二苄基乙二胺、£>-葡 萄糖胺、四乙基銨或乙二胺等形成之陽離子所形成之鹽 類。包括胺基官能團在内之含氮基團及含氮側鏈(例如, 雜環)可使用以下低碳數炫基齒化物四級化,如:甲基、 乙基、丙基及丁基氯化物、漠化物及埃化物;硫酸二烧基 酯,例如硫酸二曱基酯、硫酸二乙基酯、硫酸二丁基酯及 硫酸二戊基酯;長鏈鹵化物’如:癸基、月桂基、肉豆謹 基及硬脂基氣化物、溴化物及蛾化物;芳烧基齒化物, 如.苄基及苯乙基漠化物,此僅為幾個實例。 本發明亦涵蓋該等胺基酸之前藥形式,以改善真皮穿透 等的用途。本文所用之前藥係指可在活體内轉化成本發明 胺基酸之化合物。前藥可衍生自胺基、羧基或二者。適於 修飾該等官能團之前藥衍生物已為熟習此項技術者所熟知 且闡述於(例如)藥物設計與發現教科書(Textb〇〇k of Drug
Design and Discovery),第三版(2〇〇2),第 14章,第 4ιι_ 458頁中’其以引用方式併入本文中。 本發明亦涵蓋,可將本發明之非產蛋白質之胺基酸官能 化成N-醯基衍生物(包括Cii6醯基衍生物)或酯衍生物(包括 但不限於烷基酯衍生物),不加限制,不管所得化合 136163.doc -34- 200930412 物是否可在活體内水解成游離胺基酸。在一個實施例中, 為非產蛋白質之胺基酸提供Cii6 N-醯基衍生物以增強其 親油性》 ' 鹽、前藥、N-醯基衍生物及酯在本文中統稱為游離胺基 酸之"衍生物,,。 本發明之化妝品組合物可以多種形式調配以用於外敷施 用且包含約0.0001重量%至約90重量%之一或多種上述非 產蛋白質之胺基酸’且較佳包含約00001重量❶/。至約20重 © 量%、更佳約0J01重量%至約1〇重量%、且最佳約〇 〇〇1重 量%至約1重量〇/〇。 可將組合物調配成油包水或水包油乳液、洗劑、乳霜、 漿液(serum)、噴霧劑、棒狀物或適於外敷施用之其他形 式。 該組合物可視情況包含彼等熟習此項技術者所瞭解之其 他化妝品用活性物質及賦形劑,包括但不限於填充劑、乳 0 化劑、抗氧化劑、表面活性劑、成膜劑、螯合劑、膠凝 劑、增稠劑、潤膚劑、潤濕劑、保濕劑、維他命、礦物 質、黏性及/或流變性改性劑、防曬劑、去角質劑、色素 • 脫失劑、類視色素、激素化合物、α-羥基酸、α-酮基酸、 抗分枝桿菌劑、抗真菌劑、抗微生物劑、抗病毒劑、鎮痛 劑、脂質化合物、抗過敏劑、Η1或Η2抗組胺劑、抗炎 劑、抗刺激劑、抗腫瘤劑、免疫系統加強劑、免疫系統抑 制劑、接癌·劑、麻醉劑、防腐劑(antiseptics)、驅蟲劍、冷 膚化合物、護膚劑、皮膚促滲劑、磨砂劑、潤滑劑、芳香 136163.doc -35- 200930412 劑、著色劑、色素脫失劑、 ^ 色素淡化劑、防腐劑 (preservative)、穩定劑、藥 、劑光穩疋劑、防曬劑及其混 〇物。除上述外,本發明化 〇 之化妝口口組合物亦可含有用於治 療皮膚病症之任何其他化合物。 本發明亦提供治療衰老皮膚 甘**丄 夂屑之方法’其藉由將包含本發 明組合物,組合物外敷施用於受侵襲區域上保持足以減 少、改善哀老之皮膚病學迹象之時間段來實施。通常將該
組合物每24小時⑴次制於皮膚上保持達成期望抗衰老 效果所需要之時間段。Α癌^古安 .. 町门仅/口療方案可包含每日一次施用保持 至少-週、至少兩週、至少四週、至少八週、或至少十二 週0 該方法包括治療與年齡性及内在皮膚衰老二者有關之皮 膚變化。預期該方法尤其可用於治療受uv侵害之皮膚。 本毛明組合物及方法通常並不意欲用於治療牛皮癬,且 因此,在一個實施例中,本發明係關於將本文所述之一或 多種胺基酸(例如4-L-噻唑基丙胺酸)外敷施用於未受牛皮 癖侵襲之皮膚上。然而,倘若皮膚亦患有皮膚衰老迹象 (例如皺紋、下垂等),則將該等胺基酸組合物外敷施用於 受牛皮癬侵襲之皮膚上以治療相同皮膚區域在本發明之範 圍内。 實例 11實例1 :藉由L-4-噻唑基丙胺酸刺激L〇XL1活性 已發現酶類離胺醯氧化酶("L〇XL1")為彈性蛋白聚合 物更新之重要調控劑’該彈性蛋白聚合物係使結締組織 136163.doc •36- 200930412 皮膚L有彈性特性之細胞外基質組份。吾人 春期後不再產生彈性蛋白,青春期後彈性蛋白纖維之伴持 係競爭抗彈性蛋白酶-彈性蛋白酶活性之結果。隨著年齡 增長’注意到競爭活性不平衡,導致含有彈性蛋白之組織 喪失彈性。就皮膚而言’此彈性喪失最常見地可導致觀察 到敵紋。 儘管吾人並不瞭解更新/降解(即,抗彈性蛋白酶/彈性蛋 白酶活性)之準確機制,但已確定L〇xu為"抗彈性蛋白酶” 因子,其藉由使原彈性蛋白單體聚合而介導彈性蛋白纖維 更新(參見,例如,Kaganet等人,2003,j, Ce" 历“心所·,88:660-672 ;及。等人,2〇〇4,Nat 36:178-182,每一文獻之全部内容均以引用方式併入本文 中)。因此,預期能夠增3LOXL1轉錄及/或轉譯或L〇XLi 活性之藥劑可增強"抗彈性蛋白酶"活性,促進彈性蛋白纖 維更新並達成含有彈性蛋白之組織之彈性改善。使用螢光 素酶報導基因系統對L-4-噻唑基丙胺酸誘導l〇xli表現之 Ο 能力進行分析。已發現,向包含LOXL1調控元件之培養物 中添加L-4-噻唑基丙胺酸可誘導較對照顯著之報導基因表 現0 1·1·1 材料及方法 戴禮#建、#袭及4腐:藉由熟習此項技術者所習知之 標準方法並按照製造商說明書將L〇XL 1基因之啓動子區域 分離並選殖至PGL3螢光素酶報導基因質粒(promega)中。 使用Lip〇feetAMINETM LTX試劑(invitrogen)按照製造商指 示將LOXLl/pGL3載體及不含有調控元件之對照載體PRL- 136163.doc -37· 200930412 NULL (Promega)共轉染至人類纖維肉瘤系HTI080中。 使經轉染細胞恢復24 h。隨後用含有多種濃度之L_4_喧 嗤基丙胺酸之新鮮培養基代替該培養基,並將經轉染細胞 再培養24 h。 隨後用PBS洗滌培養物並將其暴露於10〇 μ1細胞裂解緩 衝液/25 cm2培養區域中並在室溫下輕輕振蕩3〇 mil^隨後 立即將含有細胞裂解物之培養燒瓶置於_8〇〇C下。 報導基因活性之測定\ ❹按照製造商說明書(雙螢光素酶(Dual-Luciferase)®報導 基因分析系統,Promega)測定報導基因螢火蟲螢光素酶之 活性》簡言之,相對於編碼第二螢光素酶基因之來自海洋 腔腸動物之對照載體的活性來測定該 報導基因之活性。比較來自測試及對照培養物之基因的相 對活性以測定調控序列活性之百分比改變。 1-1.2 結果 _ 因為PGL3載體缺少調控螢光素酶基因所必需之啓動子 區域,故該基因之表現係藉由經選殖之.調控元件來控制, 在該情形中為LOXL1基因之調控元件。在一式三份測試 中,已發現添加1 pg/ml L_4_噻唑基丙胺酸可使報導基因 之表現增強57% (ρ<〇.()5)β因此顯示L — _㈣基丙胺酸係 LOXL1表現之正性調控劑,意指對彈性蛋白更新具有次級 效應。 1.2實例2 : L-4-噻唑基丙胺酸抑制炎症性途徑 皮膚衰老之常見症狀係出現濕療樣損傷,表現為區域發 136163.doc -38- 200930412 紅及皮膚乾燥呈鱗狀。儘管並不瞭解病因學,但已 區域與慢性炎症有關。過去,通當i & ^ 通帘用外用腎上腺皮質類固 酵來治療該等損傷n已發現長期使用類輯會伴隨 熟習此項技術者所熟知之許多副作用(例如,纟膚萎縮、 條紋、色素脫失及毛細管擴張)。在2_年,職批准了 兩種用於外敷、冶療„之新㈣物:刚職㈣他克莫 司(tacroHmus))及阳聰⑧(吼美㈣(pime⑽Hmus)),其 ❹
後顯示該兩種藥可有效治療多種炎症性皮膚病。 、 他克莫司及比美莫司係絲胺酸/蘇胺酸蛋白酶鈣神經素 (亦稱為蛋白磷酸酶2B㈣"之抑制劑。抑制鈣神經素 可阻斷NFAT(激活性T_細胞之細胞核因子)去磷酸化以預防 產生炎症性細胞因子(參見,例如,Bekersky等人,2〇〇1, J. Am. Acad. Dermatol. 441:S17_S27,其全部内容以引用 方式併入本文中)。當外敷使用時,鈣神經素抑制劑可正 性控制局部皮膚刺激。 利用離體磷酸酶分析來評價L_4_噻唑基丙胺酸調節鈣神 經素活性之能力。已發現L_4_噻唑基丙胺酸以劑量依賴性 模式調控鈣神經素活性。 1.2.1 材料及方法 雜#媒瘦輕分於:使用熟習此項技術者所熟知之 DiFMUP(6,8-二氟-7-羥基_4·甲基香豆素磷酸酯)磷酸酶分 析來監測鈣神經素活性之調節(參見,例如,Wegner等 人 ’ 2007 ’ Methods Mol_ Biol. 365:61-69,其全部内容以 引用方式併入本文中)。DiFMUP去磷酸化導致形成具有高 136163.doc -39- 200930412 螢光性且穩定之產物:Di4MU。 將多種濃度之L-4-^°坐基丙胺酸添加至由5〇1111^1'1^- HCL (pH 7.4)、0.0125°/。BSA、0.1 mM CaCl、400 U/ml約 調蛋白及1 mM NiCl組成之反應緩衝液中。將l-4-噻唑基 丙胺酸/反應緩衝液混合物在37°C下培育30 min。隨後添加 DiFMU受質至10 μΜ濃度,並將混合物返回到37°C,再培 ' 育1 5 min。在螢光分光光度計上測定螢光強度。 1.2.2 結果 ® 已發現在所測試之最低濃度下L-4-°塞唾基丙胺酸略微增 強鈣神經素活性,在〇.〇〇〇1%重量/體積濃度下使活性增強 。然而,增大L-4-噻唑基丙胺酸之濃度可達成鈣神經素 活性之劑量依賴性抑制’在〇〇〇1%及〇〇1%濃度下分別使 /舌性降低11%及63%。估計化合物之IC_5〇值為〇 〇64%。該 等結果顯示外敷施用包含L_4_噻唑基丙胺酸之組合物可改 善與炎症性皮膚狀況有關之症狀。 〇 13實例3 : L-4-噻唑基丙胺酸調節pi整合素之表現 βΐ整合素係跨膜整合素異二聚體複合物之一種組份,該 複合物介導細胞與細胞外基質蛋白及其他細胞之結合。整 合素能夠與多種細胞外基質組份(包括膠原、層黏連蛋白 . 及纖維連接蛋白)結合,並起保持皮膚結構完整性之作 用。已顯示βΐ整合素表現降低會降低皮膚彈性,例如皮膚 衰老及/或受日光侵害。 使用全細胞ELIS Α分析來評價L_4_噻唑基丙胺酸暴露對 P1整合素表現之影響。已發現L-4-噻唑基丙胺酸暴露會使 136163.doc 200930412 人類成纖維細胞中之βΐ整合素的表現增強。 1.3.1 材料及方法 細廣禮赛:將人類真皮成纖維細胞(Cascade Biologies) 在生長培養基(DMEM,5% FBS,1% L-麩胺酸,及1%抗 生素)中於60 mm培養皿中以3.5xl05個細胞/ml培養過夜。 - 將細胞用稀釋於生長培養基中之測試活性物質或媒劑對照 . 進行處理並在37°C下培育24小時。 全細胞ELISA :於L-4-噻唑基丙胺酸處理後使用來自 ® Chemicon International之B1整合素套組對B 1整合素在細胞 表面上之表現進行分析。吸出培養基並將板在37°C下與細 胞離解緩衝液(與套組一起提供)培育20-25分鐘,將細胞離 心並再懸浮於無補充物之DMEM中。將100 μΐ細胞懸浮液 添加至預塗覆有鼠科動物抗人類βΐ抗體(Chemicon International)(非特異性結合已經阻斷)之微量滴定板上, 並將板在37 °C下培育2 h。藉由細胞染色套組(Chemicon International)按照製造商說明書定量黏附細胞。簡言之, ❹ 在PBS中洗滌板並藉由在室溫下於套組染色溶液中培育5 min對黏附細胞進行染色。將經染色之細胞在PBS中進行 " 洗滌並容許空氣乾燥1 0 min。隨後向每一孔中添加提取緩 - 衝液並在分光光度計上於570 nm下對板進行讀數。 1.3.2 結果 按照下式計算βΐ整合素表現之百分比變化: (經處理樣品之平均吸光度)-(對照樣品之平均吸光度)1ΛΛ -X1UU ° (對照樣品之平均吸光度) 136163.doc -41 - 200930412 素之表現增強225%。該等、甸 基丙胺酸之組合物會使0丨整 整性及/或彈性增強。 在L-4-噻唑基丙胺酸濃度為〇.〇i% (w/v)時量測到⑴整合 該等結果顯示外敷施用包含L-4-噻唑 吏βΐ整合素之表現增強,使皮膚之完 Μ實例4: L_4_嗟嗤基丙胺酸調節纖維連接蛋白之表現 纖維連接蛋白係有助於形成調控結締組織(包括皮膚)之
狀真皮中纖維連接蛋白之表現降低。 利用競爭性抑制£以8八分析來評價L-4-噻唑基丙胺酸對 〇 來自正常人類成人成纖維細胞之纖維連接蛋白之表現的影 響。已發現,L-4-噻唑基丙胺酸以劑量依賴性模式使來自 成纖維細胞之纖維連接蛋白之表現增強。 丨4·1 材料及方法 加應踣# :將人類真皮成纖維細胞(Cascade Bi〇1〇gics) 在12_孔組織培養板中於生長培養基(DMEM、5〇/〇 FBS、1% 麩胺酸、及1%抗生素)中進行培養並在37°C下培育24小 時。將細胞用稀釋於生長培養基中之測試活性物質進行處 理並在37 C下培育72小時,此後收集條件培養基並分析是 136163.doc •42· 200930412 否存在纖維連接蛋白。隨後將成纖維細胞培養物再培育72 hr。
麓笋從命鈔凡LLSd :藉由競爭性ELISA套組(Chemicon International)來分析測試樣品中是否存在纖維連接蛋白。 簡言之,將條件培養基之測試及對照樣品與偶聯HRP之兔 單株抗人類纖維連接蛋白抗體在室溫下培育約10分鐘。隨 後將樣品/抗體混合物轉移至預塗覆有標準量之人類纖維 連接蛋白(非特異形結合已經阻斷)之微量滴定板上。將該 板在室溫下培育1小時,隨後實施PBS洗滌並藉由熟習此項 技術者所習知之常規方法檢測結合抗體(即,檢測結合之 HRP)。結合抗體的量與樣品中纖維連接蛋白的量成反比。 1.4.2 結果 按照下式計算由於L-4-噻唑基丙胺酸處理而引起之纖維 連接蛋白表現之百分比變化: (經處理樣品之平均吸光度)-(對照樣品之平均吸光度。 (對照樣品之平均吸光度) 」 。 L-4-噻唑基丙胺酸濃度增加使得纖維連接蛋白之表現及/ 或產生增加(表1): 表1 濃度 百分比變化 0.001% 36.11%(P<0.05) 0.0001% 31.03%(P<0.05) 0.00001% 54.34% (P<0.05) 該等結果顯示外敷施用包含L-4-噻唑基丙胺酸之組合物 136163.doc -43 - 200930412 會使纖維連接蛋白之表現增強,增強皮膚之完整性及/或 改善皮膚結構。 5實例S:L-4-嘍唑基丙胺酸使活體内之真皮基質分子增加 為確定L-4-噻唑基丙胺酸對活體内人類皮膚中之膠原含 量的影響’對約25名年齡為35-65歲的女性實施測試。該 人類臨床研九已經由機構審查委員會(Instituti〇nai Revjevv Board)批准並在研究開始之前先取得受試個體同意。根據 聯邦法規(the Code of Federal Regulations)第 21 篇第 50及 56 部分實施該研究。 在丙二醇:乙醇:水比率為70:20:10之媒劑中配製o.oi 〇/〇 之L-4-嘆》坐基丙胺酸溶液。本測試之實驗設計如下:將嗟 唾基丙胺酸溶液或無噻唑基丙胺酸之媒劑溶液施用於外前 臂上2x2之皮膚區域上(以2 mg/cm2之量施用),在半封閉貼 片下保持24小時’此後移除貼片並施用新鮮貼片。此重複 5天(周一-周五),隨後使個體周末休息。在接下來的兩週 裏以相同方式連續實施貼片施用,總共施用15次。在研究 !〇束時’由委員會遇證之皮膚科醫生(B〇ar(j certified Dermatologist)自施用貼片之區域採集3 mm皮膚樣品,在 福爾馬林(formalin)中固定,包埋於石蠟中並進行組織學 處理。將皮膚樣品切片’並用可使膠原纖維顯影之三色染 色劑(Trichrome stain)及使糖胺聚糖(GAG)顯影之艾爾遜藍 染色劑(Alcian blue stain)進行染色。在顯微鏡下目測評估 膠原及GAG染色之強度。比較來自經嘍唑基丙胺酸處理之 部位的樣品與經媒劑處理之部位的樣品顯示,在18/21 136163.doc • 44· 200930412 (86%)之個體中在經L4-噻唑基丙胺酸處理之部位中觀察到 膠原染色增強。13/21 (62%)之經L4-嗟哇基丙胺酸治療之 個體亦顯示相對於經媒劑治療之皮膚而言GAG染色增強。 皮膚中之膠原及GAG增加可隨後改善衰老迹象外觀(例如 細紋、皺紋、緊致及下垂)。 1.6實例6 : L-4-噻唑基丙胺酸誘導降約素基因相關肽 (CGRP) CGRP係當前已知的最強效血管擴張劑,且因此其幫助 傷口癒合及/或當外敷使用時增加至特定組織之流通之潛 在用途尤其令人關注。 利用市售CGRP酶聯免疫分析來評價L-4-n塞嗤基丙胺酸 對來自神經元細胞之CGRP之表現的影響。已發現L_4_噻 峻基丙胺酸可誘導CGRP在活體外細胞培養物中之表現增 強。 ^6·1 材料及方法 細應楛# :按照熟習此項技術者所習知之常規方法在補 充有神經生長因子之FK12培養基中培養PC-12細胞。PC12 細胞係自大鼠嗜鉻細胞瘤獲得且在暴露於神經生長因子時 終末分化。在細胞開始分化後’其表現CGRP。將培養物 在含有L-4-噻唑基丙胺酸之培養基中再培育24 h,此後收 集條件培養基並分析是否存在CGRP。 龙疫分於:藉由夾心ELISA免疫分析套組來分析 測試樣品中是否存在CGRP。簡言之,將條件培養基之測 試及對照樣品與偶聯乙醯膽鹼酯酶之抗CGRP抗體(”示蹤 136163.doc • 45· 200930412 劑抗體")混合,並將混合物添加至預塗覆有非特異性結合 已經阻斷之單株抗CGRP抗體(其所結合之CGRP之抗原決 定部位與示蹤劑抗體不同)之板上。在板中對樣品進行培 育並洗滌板並使用Ellman試劑按照熟習此項技術者所習知 之常規方法對結合乙醯膽鹼酯酶之活性進行測定。試劑之 吸光度與樣品中之CGRP的濃度成正比。 1-6.2 結果
按照下式計算由於L_4_噻唑基丙胺酸處理而引起之 CGRP表現之百分比變化: (對照樣A之平均吸光度) xlOO 〇 在L-4-噻唑基丙胺酸濃度為〇〇1%時,cGRp之表現增強 69.93% (ρ<〇·05)。該等結果顯示外敷施用包含[·4·噻唑基 丙胺酸之組合物會使CGRp之表現增強,使皮膚修復及: 體皮膚狀況得以改善。 包括專利中請案及公開案在内之本文所引用之所有來考 文獻的全部内容出於所有目的皆以引用方式併入本文中, 2併入程度就如同每一公開案或專利或專利申請案 ==指出其全部内容出於所有目的以引用方式併入 又被等熟習此項技術者應瞭解,可在不背離 ^日月精神及範圍下對本發明實施多種修改文 述之具體實㈣心實例 本文所 項隨附中料利範心及Μ申ml本發明“限於各 物之全部範圍。 °等申凊專利範圍所授權之等效 136163.doc -46 200930412 【圖式簡單說明】 圖1舉例說明本發明之各種非產蛋白質之胺基酸。顯示 於圖1中之該等胺基酸僅為舉例說明且並不意欲具有限制 意義。
❹ 136163.doc -47·
Claims (1)
- 200930412 十、申請專利範圍: 1. 一種用於治療與彈性蛋白纖維喪失有關之皮膚狀況的化 妝品組合物,其在化妝品上可接受之媒劑中包含有效量 的可增強LOXL-1之非產蛋白質之胺基酸或其衍生物。 2. 如請求項1之組合物,其中該非產蛋白質之胺基酸係包 含式la之雜環基團的α_胺基酸或β_胺基酸··11 la, 其中η係0或1 ; Ζ 係選自由下列組成之群:鍵、氧、硫、nrn、c j 烷基、烯基、炔基、芳基、羰基、羧基、胺甲醯 基’其中rN係氫、Ci —烷基烯基炔基、或芳 基; Y係選自C、CH、N或NRn,其中rN係如上文所定 義;且 Q係3-10員雜環或環系統,其包括γ,且在該環或環 系統中包含一或多個選自氧、氮及硫之雜原子, 且視情況經與該環系統結合之—或多個R ^基圈取 代’其中1^在每次出現時均獨立選自氫;齒素. -OH ; -NH2 ’ -NRnRn ; -SH ; -CN ;侧氧基;’ -CHO ; -C02H ; -〇-(C=〇).H ; -〇-(C=〇)-Cl.,0^ 136163.doc 200930412 基;_0-(C=0)-Ar,-(〇=0)-〇-(::]·]〇院基;_(c=〇)_ O-Ar ; -(C=0)-NR R ’ _〇_Ci.i。院基;-〇_Ar ; C】.]。烧基;-S-Ar ; -Ar ·’ -Cuo 烧基;^尺>1_ CHO ; -NRN-CC^OVCmo烷基;-C丨·1〇烷基 _〇_Ci_i〇 烷基;全氟烷基;環氧基;疊氮基;硫氰酸醋 基;-S〇2-RN ;及硝基;其中RN係如上文所定義且 在該取代基包含兩個RN基團之情形中,其可共同 形成環; 條件為該式la化合物不為L-組胺酸或l·色胺酸。 3_如請求項2之組合物,其中Q包含芳環。 4. 如請求項2或3之組合物’其中Q係五或六員環。 5. 如請求項2或3之組合物,其中Q係五員環。 6. 如請求項2或3之組合物,其中γ係c。 7·如請求項2或3之組合物,其中Q在該環中包含氮原子。 8_如請求項2或3之組合物,其中可選取代基&獨立選自由 鹵素、-OH、-NH2、-SH、及-CH3組成之群。 9. 如請求項2或3之組合物,其中z表示鍵。 10. 如請求項2或3之組合物,其中11係〇(零)。 11. 如請求項2或3之組合物,其中j。 12·如請求項N3中任一項之組合物,其中式^之該非產蛋白 質之胺基酸呈L組態。 13. 如δ青求項1-3中任^—項之έ目入私 y . 視心,、且合物,其中式la之該非產蛋白 質之胺基酸呈D組態。 14. 如請求項1之組合物,其中該非產蛋白質之胺基酸包含 136163.doc 200930412 式lb之5-員雜環基團:11 lb, • 其中η係0(零)或1 ; ❹ Ζ係單鍵或基團(CH2)k單元,其中让係丨至3之整數; γ 係C、CH或Ν ;且 丁、u、v及 W獨立選自 CH、CRl、N、NH、nrN、〇及 s其中m係'如上文所定義;且其中該環視情 況為芳族環或可包含零個、一個或兩個雙鍵; 條件為該式lb化合物不為L-組胺酸。 15. 如請求項14之組合物,其中ζ表示單鍵。 16. 如請求項14或15之組合物,其中γ係匚。 〇 17·如請求項14或15之組合物,其中T、U、V及w中之至少 一個但並非全部為N(氮原子)。 I8·如請求項17之組合物,其中不為N(氮原子)之Τ、υ、γ及 W中之至少一個表示〇、s、ΝΗ或NRn。 19. 如請求項14或15之組合物,其中η係〇(零)。 20. 如請求項14或1 5之組合物,其中η係1。 21. 如請求項14或15之組合物,其中式Ia之該非產蛋白質之 胺基酸呈L組態。 22. 如請求項14或15之組合物,其中式。之該非產蛋白質之 136163.doc 200930412 胺基酸呈D組態。 23 如請求項1之組合物,其中Q表示選自以下之五員雜環:其中ει、4及ε3獨立選自N、NH、NRn、s及〇 ;條件 為當結合點Y係ει、4或以時,則γ表示N ;且 其中不為結合點之碳原子可視情況經Ri基團取代; 其中^及心係如上文所定義;且 且其中虛線圓環表示每一環皆可包含零個、一個或兩 個雙鍵。 24. 如請求項23之組合物’其中1^若存在時,則獨立表示Cw 烷基、胺基、烷基胺基、二烷基胺基、硫醇基、羥基、 Cw烷氧基、烷硫基、羥基烷基、全氟甲基、或鹵素。 25. 如請求項23之組合物,其中ε!、εζ及ε3中之至少一個表示 氮原子。 136163.doc -4- 200930412 26. 如清求項23之組合物’其中該五員雜環係芳族雜環。 27. 如請求項}之組合物,其中Q表示選自由下列組成之群之 五員雜環:其中X係氧原子、NRN或硫原子;且 Q R2及R3獨立選自氫、羥基、F、C卜Br、I、、 硫醇基、或Cw烷基;其中RN係如上文所定義;且 其中該胺基酸可包含R或S對映異構體。 28.如請求項27之組合物,其中χ係硫。 • 29.如請求項27或28之組合物,其中R2及R3各為氫。 30.如請求項1之組合物,其中該非產蛋白質之胺基峻具有 以下結構: 、 136163.doc 2009304123 1·如清求項3〇之組合物,其中該非產蛋白質之胺基酸具 以下結構: 、32.如請求項1之組合物,其中該有效量為該總組合物之約 0·0001重量❶/❶至約90重量%。 33'如請求項1之組合物,其中該有效量為該總組合物之約 〇.〇〇〇1重量%至約2〇重量0/〇。 34·如請求項1之組合物,其中該有效量為該總組合物之約 0·001重量%至約10重量%。 35. 一種化妝品組合物,其在化妝品上可接受之媒劑中包含 可有效增強皮膚中之LOXL-1之噻唑基丙胺酸或其衍生 36.如請求項35之化妝品組合物,其中該噻唑基丙胺酸係l_ 嘆唾基丙胺酸或其衍生物。 136163.doc 200930412 嗟11 坐基丙胺酸或其衍生物。 3 7.如請求項36之化妝品組合物,其中該^噻唑基丙胺酸係 L-4-噻唑基丙胺酸或其衍生物。 38. 如請求項36之化妝品組合物’其中該^噻唑基丙胺酸係 L-4_噻唑基丙胺酸。 39. 如請求項35之化妝品組合物,其中該化妝品上可接受之 媒劑包含油包水乳液。 40·如請求項35之化妝品組合物,其中該化妝品上可接受之 媒劑包含水包油乳液。 4 1. 一種治療與皮膚中之彈性蛋白纖維喪失有關之皮膚狀況 的方法,其包含將可增強LOXL—丨之非產蛋白質之胺基酸 或其衍生物以有效增強LOXL-1的量外敷施用於有需要之 皮膚上。 42. 如請求項41之方法,其中該非產蛋白質之胺基酸可進一 步具有一或多種選自由下列組成之群之額外活性:抑制 鈣神經素、增強βΐ整合素之表現、增強纖維連接蛋白之 表現、刺激Β-内啡肽及增強CGRP之表現。 43. 如請求項42之方法,其中該非產蛋白質之胺基酸能夠抑 制約神經素。 44. 如請求項42之方法,其中該非產蛋白質之胺基酸能夠增 強βΐ整合素之表現。 45. 如請求項42之方法,其中該非產蛋白質之胺基酸能夠增 強纖維連接蛋白之表現。 46. 如凊求項42之方法,其中該非產蛋白質之胺基酸能夠刺 136163.doc 200930412 激B-内啡狀。 47.如请求項15之方法,其中該非產蛋白質之胺基酸能夠增 強CGRP之表現。 48· 一種提供皮膚益處之方法,其包含將如請求項1-40中任 一項之組合物施用於該皮膚上,其中該皮膚益處係選自 由下列組成之群: (a) 治療、減少及/或預防細紋或皺紋; (b) 減小皮膚毛孔大小; (c) 改善皮膚厚度、豐滿度及/或緊實度; (d) 改善皮膚柔順度及/或柔軟度; (e) 改善皮膚色調、光亮度及/或透明度; (f) 改善前膠原及/或膠原產生; (g) 改善彈性蛋白之保持及重塑; (h) 改善皮膚紋理及/或促進恢復原有紋理; (0改善皮膚屏障修復及/或機能; (j) 改善皮膚輪廓之外觀; (k) 恢復皮膚光澤及/或亮度; (l) 補充皮膚中之必需營養素及/或成份; (m) 改善因絕經而減退之皮膚外觀; (η)改善皮膚濕潤性;或 (〇)增強皮膚彈性及/或回彈性。 49. 一種治療、改善及/或預防人類皮膚之細紋或皺紋或下垂 的方法’其包含將如请求項1_4〇中任一項之組合物外敷 施用於有需要之皮膚上。 136163.doc 200930412 5 0. —種治療細紋或皺紋之方法,其包含將包含L-4-噻唑基 丙胺酸之組合物外敷施用於細紋或皺紋上。136163.doc 9-
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CN102731446B (zh) * | 2011-04-12 | 2016-04-06 | 新疆大学 | 3-(噻唑-2-基)-L-丙氨酸过渡金属配合物催化氧化四氢呋喃制备γ-丁内酯和丁二酸的方法 |
US8568797B2 (en) * | 2011-09-13 | 2013-10-29 | Avon Products, Inc | Method for enhancing the growth and fullness of hair |
US9044408B2 (en) * | 2011-10-31 | 2015-06-02 | Avon Products, Inc. | Cosmetic use of N-heteroarylbisamide analogs and related compounds |
US20160153015A1 (en) * | 2013-06-27 | 2016-06-02 | Asymchem Laboratories (Tianjin) Co., Ltd | Synthesis method for l-heterocyclic amino acid and pharmaceutical composition having thereof |
EP3455403B1 (en) | 2016-05-09 | 2024-11-13 | North Carolina State University | Fractal-like polymeric particles and their use in diverse applications |
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