TWI474837B - 化合物之用於製造皺紋改善劑之用途 - Google Patents
化合物之用於製造皺紋改善劑之用途 Download PDFInfo
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- TWI474837B TWI474837B TW098139070A TW98139070A TWI474837B TW I474837 B TWI474837 B TW I474837B TW 098139070 A TW098139070 A TW 098139070A TW 98139070 A TW98139070 A TW 98139070A TW I474837 B TWI474837 B TW I474837B
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- Prior art keywords
- cysteine
- group
- methyl
- oxidized
- general formula
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
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Description
本發明是關於皺紋改善劑,進一步關於含有該皺紋改善劑之皮膚外用劑,更詳細為化妝材料等。又更進一步是關於具有皺紋改善效果之新穎化合物。
因年齡增加、壓力、暴露於紫外線等因素引起之皺紋、斑點、黯沉、鬆弛等皮膚症狀的惡化,是從外表即非常容易得知的老化徵兆。因此,人們對於皮膚的老化現象皆非常地關心,為保持肌膚的美觀已開發出各種方法。
皺紋是皮膚老化的現象之一,由於皺紋形成的機制複雜,而且實驗的再現非常困難,即使現在對其機制仍未完全瞭解。皺紋形成的機制,可例示有經由紫外線等的細胞損傷以及因此而亢進之細胞的細胞凋零(apoptosis)、因基質金屬蛋白酶(MMP)等蛋白酶的表現亢進而使膠原蛋白(collagen)等纖維成分的水解、以及因細胞激素(cytokine)亢進之纖維束的崩壞等。尤其是MMP具有分解由膠原蛋白、蛋白多醣及彈性蛋白等所構成之細胞外基質,以及表現於細胞表面之蛋白質等多種機能,有諸多亞型存在。MMP1分解第I型及第III型膠原蛋白(皮膚真皮基質的主要成分)。MMP2及MMP9分解基底膜成分之第IV型膠原蛋白、基膜素(laminin)以及真皮基質成分之彈性蛋白等。MMP3及MMP10分解蛋白多醣、第IV型膠原蛋白及基膜素等。經由這些分解作用,引起細胞外基質的減少、變性,而成為皮膚內形成皺紋、鬆弛等的重要因素(參照專利文獻1)。此外,已知TNF-α、IL-1及IL-6等發炎性細胞激素,經由誘導MMP的產生而參與皺紋、鬆他的形成(參照專利文獻2)。如此,深入參與皺紋、鬆弛等之皮膚老化現象的這些因子,難謂是獨立因子,可說是彼此互相影響,亦可說如此狀況使皺紋形成的機制複雜化。
對於皮膚老化之一之因紫外線照射之光老化結果所產生的皺紋,維生素A酸顯示改善效果已廣為人知(參照非專利文獻1)。在美國維生素A酸已被批准作為皺紋、粉刺的治療醫藥品,已使用於非常多的患者作為皮膚的新陳代謝藥,但在日本存在對皮膚刺激之安全性方面的問題而未被批准。又,已進行經由配合膠原蛋白、玻尿酸之皺紋改善的試驗(參照專利文獻3、4)之外,已知有抗壞血酸(參照專利文獻5)、生育醇(維生素E)(參照專利文獻6)等作為皺紋改善劑。然而,前記之皺紋改善劑的皺紋改善效果並不充分,在表現皺紋改善效果之濃度有所謂表現出不期望的藥效,而有安全性或安定性問題之情形,由於這些理由而未發現能充分滿足的皺紋改善材料,因此強列希望新的皺紋改善劑出現。
胺基酸中存在有諸多胺基酸,包括天然及非天然型的胺基酸。這些胺基酸成為控制身體構造的維持或身體反應之機能性高分子之外,已知顯示各種生理活性。天然型的胺基酸或其衍生物,在不僅期待生理活性,也期待高安全性之食品、化妝品、醫藥品等領域中已被廣泛活用。特別在化妝品領域中,已知丙胺酸顯示美白作用(參照專利文獻7),α-胺基酸衍生物顯示角化不全抑制作用、毛孔縮小作用或皮膚粗糙防止.改善作用(參照專利文獻8),氧化半胱胺酸或高氧化半胱胺酸顯示皮膚的剝離促進或表皮亢進刺激作用(參照專利文獻9),N-醯基胺基酸顯示育毛促進作用、保濕作用(參照專利文獻10),麩胺酸等之必須胺基酸顯示細胞活化作用(參照專利文獻11)。此外,已知丙胺酸具有皺紋改善作用(參照專利文獻12)。
專利文獻1:特開2001-192317號公報
專利文獻2:特開2005-089304號公報
專利文獻3:特開昭33-500號公報
專利文獻4:特開2007-191396號公報
專利文獻5:特開2003-267856號公報
專利文獻6:特開昭62-19511號公報
專利文獻7:特開平11-049629號公報
專利文獻8:特開2006-327971號公報
專利文獻9:特開平9-110627號公報
專利文獻10:特開平11-080105號公報
專利文獻11:特開昭61-289016號公報
專利文獻12:特開平11-49628號公報
非專利文獻1:老化防止.美白.保濕化妝材料之開發技術,CMC出版,鈴木正人監修。
本發明有鑑於上述各種狀況,以提供適宜作為皮膚外用劑之成分且具有新穎母核之皺紋改善劑為課題。
本案發明者們尋求具有皺紋改善作用之新穎母核,反覆精心研究之結果,發現下記一般式(1)表示之化合物、其立體異構物、及彼等之藥理學上容許的鹽,對於因暴露於紫外線等所形成之皺紋具有優異的皺紋改善效果而完成發明。
換言之,本發明如下所示。
<1>一種含有下記一般式(1)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽之皺紋改善劑,
[式中,R1
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R2
表示-SH、-SO3
H、-S-S-X1
、-S-X2
、-SO-X3
、-SO2
-X4
、-SO2
-NY1
-X5
、或-SO2
-NY2
-Y3
,前記X1
~X5
獨立地為氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分,前記Y1
~Y3
獨立地表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R3
表示氫原子、或具有碳原子數1~8之直鏈或分枝之烷基鏈的醯基;R4
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<2><1>記載之皺紋改善劑,其中前記一般式(1)表示之化合物為下記一般式(2)表示之化合物,
[式中,R5
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R6
表示-S-X2
,前記X2
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R7
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R8
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<3><1>記載之皺紋改善劑,其中前記一般式(1)表示之化合物為下記一般式(3)表示之化合物,
[式中,R9
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R10
表示-S-X2
,前記X2
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R11
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<4><1>記載之皺紋改善劑,其中前記一般式(1)表示之化合物為下記一般式(4)表示之化合物,
[式中,R12
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R13
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R14
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數]。
<5><1>記載之皺紋改善劑,其中前記一般式(1)表示之化合物為下記一般式(5)表示之化合物,
[式中,R15
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R16
表示-SO3
H或-SO2
-X4
,前記X4
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R17
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R18
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<6><1>記載之皺紋改善劑,其中前記一般式(1)表示之化合物為下記一般式(6)表示之化合物,
[式中,R19
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R20
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<7>一種下記一般式(5)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽,
[式中,R15
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R16
表示-SO3
H或-SO2
-X4
,前記X4
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R17
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R18
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<8>一種下記一般式(6)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽,
[式中,R19
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R20
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數]。
<9>一種皮膚外用劑,含有0.001~20質量%之<1>~<6>中任一項記載之皺紋改善劑。
<10><9>記載之皮膚外用劑,其為化妝材料。
<11>一種方法,其係皺紋改善方法,特徵為對有皺紋改善必要之部位投與下記一般式(1)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽,
[式中,R1
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R2
表示-SH、-SO3
H、-S-S-X1
、-S-X2
、-SO-X3
、-SO2
-X4
、-SO2
-NY1
-X5
、或-SO2
-NY2
-Y3
,前記X1
~X5
獨立地為氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分,前記Y1
~Y3
獨立地表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R3
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R4
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。]
根據本發明可提供新的皺紋改善劑。此外,可提供含有新的皺紋改善劑之皮膚外用劑、化妝材料。又,可提供具有皺紋改善作用之新穎化合物。
本發明之皺紋改善劑的有效成分為下記一般式(1)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽。
一般式(1)中R1
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R2
表示-SH、-SO3
H、-S-S-X1
、-S-X2
、-SO-X3
、-SO2
-X4
、-SO2
-NY1
-X5
、或-SO2
-NY2
-Y3
,前記X1
~X5
獨立地為氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分,前記Y1
~Y3
獨立地表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R3
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R4
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。此處,上記芳香族部分,除苯基、吡啶基、萘基、聯苯基等之芳香族基之外,也包括甲苯甲醯基、二甲苯基、苄基、萘基甲基等之芳香族烴基者。
作為此等一般式(1)表示之化合物,適宜者可例示後述之一般式(2)表示之化合物及後述之一般式(5)表示之化合物。一般式(2)表示之化合物中,較佳為一般式(3)表示之化合物,更佳為一般式(4)表示之化合物。又,一般式(5)表示之化合物中,較佳為一般式(6)表示之化合物。一般式(1)表示之化合物中,R2
為巰基之化合物,巰基部分經由二硫結合形成二聚體,如此之二聚體也包括於本發明之一般式(1)。當然,含有包括於一般式(1)之化合物、但不包括於一般式(2)表示之化合物及一般式(5)表示之化合物任一者之化合物的皺紋改善劑,也為本發明之皺紋改善劑。
前記R1
及R2
中之Y1
~Y3
可例示舉出具體例為氫原子、甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基等。較佳為碳原子數1~4之直鏈或分枝之烷基,更佳為氫原子、甲基、乙基。
前記R2
中X1
~X6
的具體例可舉出甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、苯基、甲苯甲醯基、苄基、苯乙基、苯丙基、吡啶基、喹啉基、萘基、聯苯基、2-羥基乙基、2-羥基丙基、3-羥基丙基、2,3-二羥基丙基等。
R2
中較佳為-SO3
H、-S-X2
、-SO2
-X4
。
前記R3
可例示舉出具體例為氫原子、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、三甲基乙醯基、己醯基、辛醯基等。此等之中較佳為氫原子、乙醯基、丙醯基。
前記R4
可例示舉出具體例為苯基、甲苯甲醯基、乙基苯基、丙基苯基、丁基苯基、戊基苯基、己基苯基、甲氧基苯基、乙氧基苯基、丙氧基苯基、丁氧基苯基、戊氧基苯基、己氧基苯基、羥基苯基、胺基苯基、氟苯基、三氟甲基苯基、氯苯基、二氯苯基、硝基苯基、氰基苯基、(N-甲基胺基)苯基、(N-乙基胺基)苯基、(N-丙基胺基)苯基、(N-丁基胺基)苯基、N,N-(二甲基胺基)苯基、N,N-(二乙基胺基)苯基、N,N-(二丙基胺基)苯基、N,N-(二丁基胺基)苯基、乙醯基苯基、丙醯基苯基、丁醯基苯基、羧基苯基、甲氧基羰基苯基、乙氧基羰基苯基、丙氧基羰基苯基、萘基、甲基萘基、甲氧基萘基、羥基萘基、胺基萘基、氟萘基、三氟甲基萘基、乙醯基萘基、羧基萘基、甲氧基羰基萘基、乙氧基羰基萘基、聯苯基、吡啶基、喹啉基等。此等之中較佳為苯基、甲苯甲醯基、乙基苯基、丙基苯基、甲氧基苯基、乙氧基苯基、氟苯基、三氟苯基、萘基、聯苯基等。
一般式(1)表示之化合物可經由後述之方法製造。由於該化合物對於皺紋改善效果的能力及/或化合物的皮膚保持性等優異,其結果為該化合物對於因暴露於紫外線等所形成之皺紋具有優異的皺紋改善效果之優點。此外,皮膚刺激性及敏感性低等,故對皮膚的安全性極高。再者,由於不僅對非極性溶劑的溶解性高,也對極性溶劑的溶解性高,因此限制化合物本身之配合量的可能性為零,或其可能性極低。這些化合物具有原膠原蛋白(procollagen)產生促進作用,而表現皺紋改善效果。除此之外,也認為經由上記MMP類、或IL-1或IL-6的阻害作用,而表現皺紋改善效果。
一般式(1)表示之化合物中,以下記一般式(2)、(3)、(4)表示之化合物說明。
一般式(2)中,R5
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R6
表示-S-X2
,前記X2
表示氫原子或碳原子可經雜原子取代、碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R7
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R8
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。
一般式(3)中,R9
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R10
表示-S-X2
,前記X2
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R11
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。
一般式(4)中,R12
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R13
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R14
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數。
按照上記,一般式(2)為一般式(1)的較佳形態,一般式(3)為更佳形態,一般式(4)為又更佳形態。
可具體地例示一般式(4)表示之化合物,有(N-苄醯基)半胱胺酸、(N-甲苯甲醯基)半胱胺酸、(N-甲氧基苄醯基)半胱胺酸、(N-聯苯基羰基)半胱胺酸、(N-苄基羰基)半胱胺酸、(N-苄醯基-S-甲基)半胱胺酸、(S-甲基-N-甲苯甲醯基)半胱胺酸、[N-(乙基苄醯基)-S-甲基]半胱胺酸、[S-甲基-N-(丙基苄醯基)]半胱胺酸、[N-(丁基苄醯基)-S-甲基]半胱胺酸、[N-(甲氧基苄醯基)-S-甲基]半胱胺酸、[N-(乙氧基苄醯基)-S-甲基]半胱胺酸、[N-(丙氧基苄醯基)-S-甲基]半胱胺酸、[N-(丁氧基苄醯基)-S-甲基]半胱胺酸、[N-(羥基苄醯基)-S-甲基]半胱胺酸、[N-(胺基苄醯基)-S-甲基]半胱胺酸、[N-(N’-甲基胺基苄醯基)-S-甲基]半胱胺酸、[N-(N’-乙基胺基苄醯基)-S-甲基]半胱胺酸、[N-(N’,N’-二甲基胺基苄醯基)-S-甲基]半胱胺酸、[N-(N’,N’-二乙基胺基苄醯基)-S-甲基]半胱胺酸、[N-(氟苄醯基)-S-甲基]半胱胺酸、[N-(三氟甲基苄醯基)-S-甲基]半胱胺酸、[N-(氯苄醯基)-S-甲基]半胱胺酸、[N-(二氯苄醯基)-S-甲基]半胱胺酸、[N-(硝基苄醯基)-S-甲基]半胱胺酸、[(N-氰基苄醯基)-S-甲基]半胱胺酸、[N-(羧基苄醯基)-S-甲基]半胱胺酸、[N-(甲氧基羰基苄醯基)-S-甲基]半胱胺酸、[N-(乙氧基羰基苄醯基)-S-甲基]半胱胺酸、[N-(乙醯基苄醯基)-S-甲基]半胱胺酸、[S-甲基-N-(丙醯基苄醯基)]半胱胺酸、[N-(丁醯基苄醯基)-S-甲基]半胱胺酸、[N-(萘甲醯基)-S-甲基]半胱胺酸、[N-(甲基萘甲醯基)-S-甲基]半胱胺酸、[N-(甲氧基萘甲醯基)-S-甲基]半胱胺酸、[N-(羥基萘甲醯基)-S-甲基]半胱胺酸、[N-(胺基萘甲醯基)-S-甲基]半胱胺酸、[N-(乙醯基萘甲醯基)-S-甲基]半胱胺酸、[N-(氟萘甲醯基)-S-甲基]半胱胺酸、[N-(甲氧基羰基萘甲醯基)-S-甲基]半胱胺酸、[N-(聯苯基羰基)-S-甲基]半胱胺酸、[N-(甲氧基聯苯基羰基)-S-甲基]半胱胺酸、[N-(苄基羰基)-S-甲基]半胱胺酸、[N-(苯乙基羰基)-S-甲基]半胱胺酸、[N-(苯丙基羰基)-S-甲基]半胱胺酸、[N-(甲苯甲醯基)甲基羰基]半胱胺酸、[N-(甲苯甲醯基乙基羰基)-S-甲基]半胱胺酸、[N-(甲苯甲醯基丙基羰基]-S-甲基]半胱胺酸、[S-甲基-N-(吡啶基羰基)]半胱胺酸、[S-甲基-N-(喹啉基羰基)]半胱胺酸、[(N-苄醯基-S-甲基)半胱胺酸]甲酯、[(N-苄醯基-S-甲基)半胱胺酸]乙酯、[(N-苄醯基-S-甲基)半胱胺酸]丙酯、[(S-甲基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-甲基-N-甲苯甲醯基)半胱胺酸]乙酯、[(S-甲基-N-甲苯甲醯基)半胱胺酸]丙酯、[S-甲基-N-(甲氧基苄醯基)半胱胺酸]甲酯、[S-甲基-N-(甲氧基苄醯基)半胱胺酸]乙酯、[S-甲基-N-(甲氧基苄醯基)半胱胺酸]丙酯、[N-(聯苯基羰基)-S-甲基半胱胺酸]甲酯、[N-(聯苯基羰基)-S-甲基半胱胺酸]乙酯、[[N-(聯苯基羰基)-S-甲基]半胱胺酸]丙酯、[[N-(苄基羰基)-S-甲基]半胱胺酸]甲酯、[[N-(苄基羰基)-S-甲基]半胱胺酸]乙酯、[[N-(苄基羰基)-S-甲基]半胱胺酸]丙酯、(N-苄醯基-S-乙基)半胱胺酸、(N-苄醯基-S-丙基)半胱胺酸、(N-苄醯基-S-丁基)半胱胺酸、(N-苄醯基-S-苯基)半胱胺酸、(N-苄醯基-S-苄基)半胱胺酸、(N-苄醯基-S-苯乙基)半胱胺酸、(N-苄醯基-S-吡啶基)半胱胺酸、(N-苄醯基-S-喹啉基)半胱胺酸、(N-苄醯基-S-萘基)半胱胺酸、(N-苄基-S-聯苯基)半胱胺酸、(S-乙基-N-甲苯甲醯基)半胱胺酸、(S-丙基-N-甲苯甲醯基)半胱胺酸、(S-丁基-N-甲苯甲醯基)半胱胺酸、(S-苯基-N-甲苯甲醯基)半胱胺酸、(S-苄基-N-甲苯甲醯基)半胱胺酸、(S-苯乙基-N-甲苯甲醯基)半胱胺酸、(S-吡啶基-N-甲苯甲醯基)半胱胺酸、(S-喹啉基-N-甲苯甲醯基)半胱胺酸、(S-萘基-N-甲苯甲醯基)半胱胺酸、(N-甲苯甲醯基-S-聯苯基)半胱胺酸、(S-乙基-N-甲氧基苄醯基)半胱胺酸、(N-甲氧基苄醯基-S-丙基)半胱胺酸、(S-丁基-N-甲氧基苄醯基)半胱胺酸、(N-甲氧基苄醯基-S-苯基)半胱胺酸、(S-苄基-N-甲氧基苄醯基)半胱胺酸、(N-甲氧基苄醯基-S-苯乙基)半胱胺酸、(N-甲氧基苄醯基-S-吡啶基)半胱胺酸、(N-甲氧基苄醯基-S-喹啉基)半胱胺酸、(N-甲氧基苄醯基-S-萘基)半胱胺酸、(S-聯苯基-N-甲氧基苄基)半胱胺酸、(N-聯苯基羰基-S-乙基)半胱胺酸、(N-聯苯基羰基-S-丙基)半胱胺酸、(N-聯苯基羰基-S-丁基)半胱胺酸、(N-聯苯基羰基-S-苯基)半胱胺酸、(N-聯苯基羰基-S-苄基)半胱胺酸、(N-聯苯基羰基-S-苯乙基)半胱胺酸、(N-聯苯基羰基-S-吡啶基)半胱胺酸、(N-聯苯基羰基-S-喹啉基)半胱胺酸、(N-聯苯基羰基-S-萘基)半胱胺酸、(N-聯苯基羰基-S-聯苯基)半胱胺酸、(N-苄基羰基-S-乙基)半胱胺酸、(N-苄基羰基-S-丙基)半胱胺酸、(N-苄基羰基-S-丁基)半胱胺酸、(N-苄基羰基-S-苯基)半胱胺酸、(N-苄基羰基-S-苄基)半胱胺酸、(N-苄基羰基-S-苯乙基)半胱胺酸、(N-苄基羰基-S-吡啶基)半胱胺酸、(N-苄基羰基-S-喹啉基)半胱胺酸、(N-苄基羰基-S-萘基)半胱胺酸、(N-苄基羰基-S-聯苯基)半胱胺酸、[(S-乙基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-丙基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-丁基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-苯基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-苄基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-苯乙基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-吡啶基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-喹啉基-N-甲苯甲醯基)半胱胺酸]甲酯、[(S-萘基-N-甲苯甲醯基)半胱胺酸]甲酯、[(N-甲苯甲醯基-S-聯苯基)半胱胺酸]甲酯、[(S-乙基-N-甲氧基苄醯基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-丙基)半胱胺酸]甲酯、[(S-丁基-N-甲氧基苄醯基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-苯基)半胱胺酸]甲酯、[(S-苄基-N-甲氧基苄醯基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-苯乙基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-吡啶基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-喹啉基)半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-萘基)半胱胺酸]甲酯、[(S-聯苯基-N-甲氧基苄基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-乙基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-丙基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-丁基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-苯基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-苄基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-苯乙基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-吡啶基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-喹啉基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-萘基)半胱胺酸]甲酯、[(N-聯苯基羰基-S-聯苯基)半胱胺酸]甲酯、[(N-苄基羰基-S-乙基)半胱胺酸]甲酯、[(N-苄基羰基-S-丙基)半胱胺酸]甲酯、[(N-苄基羰基-S-丁基)半胱胺酸]甲酯、[(N-苄基羰基-S-苯基)半胱胺酸]甲酯、[(N-苄基羰基-S-苄基)半胱胺酸]甲酯、[(N-苄基羰基-S-苯乙基)半胱胺酸]甲酯、[(N-苄基羰基-S-吡啶基)半胱胺酸]甲酯、[(N-苄基羰基-S-喹啉基)半胱胺酸]甲酯、[(N-苄基羰基-S-萘基)半胱胺酸]甲酯、[(N-苄基羰基-S-聯苯基)半胱胺酸]甲酯、(N-苄醯基)高半胱胺酸、(N-甲苯甲醯基)高半胱胺酸、(N-甲氧基苄醯基)高半胱胺酸、(N-聯苯基羰基)高半胱胺酸、(N-苄基羰基)高半胱胺酸、(N-苄醯基)甲硫胺酸、[N-(甲苯甲醯基)]甲硫胺酸、[N-(乙基苄醯基)]甲硫胺酸、[N-(丙基苄醯基)]甲硫胺酸、[N-(丁基苄醯基)]甲硫胺酸、[N-(甲氧基苄醯基)]甲硫胺酸、[N-(乙氧基苄醯基)]甲硫胺酸、[N-(丙氧基苄醯基)]甲硫胺酸、[N-(丁氧基苄醯基)]甲硫胺酸、[N-(羥基苄醯基)]甲硫胺酸、[N-(胺基苄醯基)]甲硫胺酸、[N-(N’-甲基胺基苄醯基)]甲硫胺酸、[N-(N’-乙基胺基苄醯基)]甲硫胺酸、[N-(N’,N’-二甲基胺基苄醯基)]甲硫胺酸、[N-(N’,N’-二乙基胺基苄醯基)]甲硫胺酸、[N-(氟苄醯基)]甲硫胺酸、[N-(三氟甲基苄醯基)]甲硫胺酸、[N-(氯苄醯基)]甲硫胺酸、[N-(二氯苄醯基)]甲硫胺酸、[N-(硝基苄醯基)]甲硫胺酸、[(N-氰基苄醯基)]甲硫胺酸、[N-(羧基苄醯基)]甲硫胺酸、[N-(甲氧基羰基苄醯基)]甲硫胺酸、[N-(乙氧基羰基苄醯基)]甲硫胺酸、[N-(乙醯基苄醯基)]甲硫胺酸、[N-(丙醯基苄醯基)]甲硫胺酸、[N-(丁醯基苄醯基)]甲硫胺酸、[N-(萘甲醯基)]甲硫胺酸、[N-(甲基萘甲醯基)]甲硫胺酸、[N-(甲氧基萘甲醯基)]甲硫胺酸、[N-(羥基萘甲醯基)]甲硫胺酸、[N-(胺基萘甲醯基)]甲硫胺酸、[N-(乙醯基萘甲醯基)]甲硫胺酸、[N-(氟萘甲醯基)]甲硫胺酸、[N-(羧基萘甲醯基)]甲硫胺酸、[N-(甲氧基羰基萘氧基)]甲硫胺酸、[N-(聯苯基羰基)]甲硫胺酸、[N-(甲氧基聯苯基羰基)]甲硫胺酸、N-(苄基羰基)甲硫胺酸、N-(苯乙基羰基)甲硫胺酸、N-(苯丙基羰基)甲硫胺酸、[N-(甲苯甲醯基甲基)羰基]甲硫胺酸、[N-(甲苯甲醯基乙基)羰基]甲硫胺酸、[N-(甲苯甲醯基丙基)羰基]甲硫胺酸、N-(吡啶基羰基)甲硫胺酸、N-(喹啉基羰基)甲硫胺酸、[(N-苄醯基)甲硫胺酸]甲酯、[(N-苄醯基)甲硫胺酸]乙酯、[(N-苄醯基)甲硫胺酸]丙酯、[(N-甲苯甲醯基)甲硫胺酸]甲酯、[(N-甲苯甲醯基)甲硫胺酸]乙酯、[(N-甲苯甲醯基)甲硫胺酸]丙酯、[N-(甲氧基苄醯基)甲硫胺酸]甲酯、[N-(甲氧基苄醯基)甲硫胺酸]乙酯、[N-(甲氧基苄醯基)甲硫胺酸]丙酯、[N-(聯苯基羰基)甲硫胺酸]甲酯、[N-(聯苯基羰基)甲硫胺酸]乙酯、[N-(聯苯基羰基)甲硫胺酸]丙酯、[N-(苄基羰基)甲硫胺酸]甲酯、[N-(苄基羰基)甲硫胺酸]乙酯、[N-(苄基羰基)甲硫胺酸]丙酯、前述化合物的立體異構物、或彼等之藥理學上容許的鹽等。此等之中更佳為N-(苄醯基)半胱胺酸、N-(甲苯甲醯基)半胱胺酸、N-(甲氧基苄醯基)半胱胺酸、N-(聯苯基羰基)半胱胺酸、N-(苄基羰基)半胱胺酸、[N-(苄醯基)-S-甲基]半胱胺酸、[N-(甲苯甲醯基)-S-甲基)半胱胺酸、[N-(甲氧基苄醯基)-S-甲基]半胱胺酸、[N-(聯苯基羰基)-S-甲基]半胱胺酸、[N-(苄基羰基)-S-甲基]半胱胺酸、[N-(苄醯基)半胱胺酸]甲酯、[N-(甲苯甲醯基)半胱胺酸]甲酯、[N-(甲氧基苄醯基)半胱胺酸]甲酯、[N-(聯苯基羰基)半胱胺酸]甲酯、[N-(苄基羰基)半胱胺酸]甲酯、(N-苄醯基)甲硫胺酸、[N-(甲苯甲醯基)]甲硫胺酸、此等化合物的立體異構物、或彼等之藥理學上容許的鹽。
一般式(3)表示之化合物中,不包括於一般式(4)之化合物,可具體地例示有(N-苄醯基-S-乙基)高半胱胺酸、(N-苄醯基-S-丙基)高半胱胺酸、(N-苄醯基-S-丁基)高半胱胺酸、(N-苄醯基-S-苯基)高半胱胺酸、(N-苄醯基-S-苄基)高半胱胺酸、(N-苄醯基-S-苯乙基)高半胱胺酸、(N-苄醯基-S-吡啶基)高半胱胺酸、(N-苄醯基-S-喹啉基)高半胱胺酸、(N-苄醯基-S-萘基)高半胱胺酸、(N-苄基-S-聯苯基)高半胱胺酸、(S-乙基-N-甲苯甲醯基)高半胱胺酸、(S-丙基-N-甲苯甲醯基)高半胱胺酸、(S-丁基-N-甲苯甲醯基)高半胱胺酸、(S-苯基-N-甲苯甲醯基)高半胱胺酸、(S-苄基-N-甲苯甲醯基)高半胱胺酸、(S-苯乙基-N-甲苯甲醯基)高半胱胺酸、(S-吡啶基-N-甲苯甲醯基)高半胱胺酸、(S-喹啉基-N-甲苯甲醯基)高半胱胺酸、(S-萘基-N-甲苯甲醯基)高半胱胺酸、(N-甲苯甲醯基-S-聯苯基)高半胱胺酸、(S-乙基-N-甲氧基苄醯基)高半胱胺酸、(N-甲氧基苄醯基-S-丙基)高半胱胺酸、(S-丁基-N-甲氧基苄醯基)高半胱胺酸、(N-甲氧基苄醯基-S-苯基)高半胱胺酸、(S-苄基-N-甲氧基苄醯基)高半胱胺酸、(N-甲氧基苄醯基-S-苯乙基)高半胱胺酸、(N-甲氧基苄醯基-S-吡啶基)高半胱胺酸、(N-甲氧基苄醯基-S-喹啉基)高半胱胺酸、(N-甲氧基苄醯基-S-萘基)高半胱胺酸、(S-聯苯基-N-甲氧基苄基)高半胱胺酸、(N-聯苯基羰基-S-乙基)高半胱胺酸、(N-聯苯基羰基-S-丙基)高半胱胺酸、(N-聯苯基羰基-S-丁基)高半胱胺酸、(N-聯苯基羰基-S-苯基)高半胱胺酸、(N-聯苯基羰基-S-苄基)高半胱胺酸、(N-聯苯基羰基-S-苯乙基)高半胱胺酸、(N-聯苯基羰基-S-吡啶基)高半胱胺酸、(N-聯苯基羰基-S-喹啉基)高半胱胺酸、(N-聯苯基羰基-S-萘基)高半胱胺酸、(N-聯苯基羰基-S-聯苯基)高半胱胺酸、(N-苄基羰基-S-乙基)高半胱胺酸、(N-苄基羰基-S-丙基)高半胱胺酸、(N-苄基羰基-S-丁基)高半胱胺酸、(N-苄基羰基-S-苯基)高半胱胺酸、(N-苄基羰基-S-苄基)高半胱胺酸、(N-苄基羰基-S-苯乙基)高半胱胺酸、(N-苄基羰基-S-吡啶基)高半胱胺酸、(N-苄基羰基-S-喹啉基)高半胱胺酸、(N-苄基羰基-S-萘基)高半胱胺酸、(N-苄基羰基-S-聯苯基)高半胱胺酸、[(S-乙基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-丙基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-丁基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-苯基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-苄基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-苯乙基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-吡啶基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-喹啉基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(S-萘基-N-甲苯甲醯基)高半胱胺酸]甲酯、[(N-甲苯甲醯基-S-聯苯基)高半胱胺酸]甲酯、[(S-乙基-N-甲氧基苄醯基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-丙基)高半胱胺酸]甲酯、[(S-丁基-N-甲氧基苄醯基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-苯基)高半胱胺酸]甲酯、[(S-苄基-N-甲氧基苄醯基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-苯乙基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-吡啶基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-喹啉基)高半胱胺酸]甲酯、[(N-甲氧基苄醯基-S-萘基)高半胱胺酸]甲酯、[(S-聯苯基-N-甲氧基苄基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-乙基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-丙基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-丁基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-苯基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-苄基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-苯乙基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-吡啶基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-喹啉基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-萘基)高半胱胺酸]甲酯、[(N-聯苯基羰基-S-聯苯基)高半胱胺酸]甲酯、[(N-苄基羰基-S-乙基)高半胱胺酸]甲酯、[(N-苄基羰基-S-丙基)高半胱胺酸]甲酯、[(N-苄基羰基-S-丁基)高半胱胺酸]甲酯、[(N-苄基羰基-S-苯基)高半胱胺酸]甲酯、[(N-苄基羰基-S-苄基)高半胱胺酸]甲酯、[(N-苄基羰基-S-苯乙基)高半胱胺酸]甲酯、[(N-苄基羰基-S-吡啶基)高半胱胺酸]甲酯、[(N-苄基羰基-S-喹啉基)高半胱胺酸]甲酯、[(N-苄基羰基-S-萘基)高半胱胺酸]甲酯、[(N-苄基羰基-S-聯苯基)高半胱胺酸]甲酯、此等化合物的立體異構物、或彼等之藥理學上容許的鹽等。
一般式(2)表示之化合物中,不包括於一般式(3)及(4)之化合物,可具體地例示有(N-乙醯基-N-苄醯基-S-甲基)半胱胺酸、(N-苄醯基-N-丙醯基-S-甲基)半胱胺酸、(N-苄醯基-N-丁醯基-S-甲基)半胱胺酸、(N-乙醯基-N-甲苯甲醯基-S-甲基)半胱胺酸、(S-甲基-N-丙醯基-N-甲苯甲醯基)半胱胺酸、(N-丁醯基-S-甲基-N-甲苯甲醯基)半胱胺酸、(N-乙醯基-S-甲基-N-甲氧基苄醯基)半胱胺酸、(N-甲氧基苄醯基-S-甲基-N-丙醯基)半胱胺酸、(N-丁醯基-N-甲氧基苄醯基-S-甲基)半胱胺酸、(N-乙醯基-N-聯苯基羰基-S-甲基)半胱胺酸、(N-聯苯基羰基-S-甲基-N-丙醯基)半胱胺酸、(N-丁醯基-N-聯苯基羰基-S-甲基)半胱胺酸、(N-乙醯基-N-苄基羰基-S-甲基)半胱胺酸、(N-丙醯基-N-苄基羰基-S-甲基)半胱胺酸、(N-丁醯基-N-苄基羰基-S-甲基)半胱胺酸、(N-乙醯基-N-苄醯基)甲硫胺酸、(N-苄醯基-N-丙醯基)甲硫胺酸、(N-苄醯基-N-丁醯基)甲硫胺酸、(N-乙醯基-N-甲苯甲醯基)甲硫胺酸、(N-丙醯基-N-甲苯甲醯基)甲硫胺酸、(N-丁醯基-N-甲苯甲醯基)甲硫胺酸、(N-乙醯基-N-甲氧基苄醯基)甲硫胺酸、(N-甲氧基苄醯基-N-丙醯基)甲硫胺酸、(N-丁醯基-N-甲氧基苄醯基)甲硫胺酸、(N-乙醯基-N-聯苯基羰基)甲硫胺酸、(N-聯苯基羰基-N-丙醯基)甲硫胺酸、(N-丁醯基-N-聯苯基羰基)甲硫胺酸、(N-乙醯基-N-苄基羰基)甲硫胺酸、(N-丙醯基-N-苄基羰基)甲硫胺酸、(N-丁醯基-N-苄基羰基)甲硫胺酸、此等化合物的立體異構物、或彼等之藥理學上容許的鹽等。
一般式(1)表示之化合物內,以一般式(5)及(6)表示之化合物來說明。一般式(5)及(6)表示之化合物皆為新穎化合物。
一般式(5)中,R15
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R16
表示-SO3
H、或-SO2
-X4
,前記X4
表示氫原子或碳原子可經雜原子取代之碳原子數1~8之脂肪族烴基或碳原子數5~12之芳香族部分;R17
表示氫原子、或具有碳原子數1~8之直鏈或分枝烷基鏈之醯基;R18
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。
一般式(6)中,R19
表示氫原子、或碳原子數1~8之直鏈或分枝之烷基;R20
表示無取代或可具有取代基之碳原子數5~12之芳香族基或多環稠合芳香族基;m表示0~3的整數;n表示1或2的整數。
按照上記,一般式(5)為一般式(1)的較佳形態,一般式(6)為更佳形態。可具體地例示一般式(6)表示之化合物,有N-(苄醯基)氧化半胱胺酸、N-(甲苯甲醯基)氧化半胱胺酸、N-(乙基苄醯基)氧化半胱胺酸、N-(丙基苄醯基)氧化半胱胺酸、N-(丁基苄醯基)氧化半胱胺酸、N-(戊基苄醯基)氧化半胱胺酸、N-(己基苄醯基)氧化半胱胺酸、N-(庚基苄醯基)氧化半胱胺酸、N-(辛基苄醯基)氧化半胱胺酸、N-(甲氧基苄醯基)氧化半胱胺酸、
N-(乙氧基苄醯基)氧化半胱胺酸、N-(丙氧基苄醯基)氧化半胱胺酸、N-(丁氧基苄醯基)氧化半胱胺酸、N-(羥基苄醯基)氧化半胱胺酸、N-(胺基苄醯基)氧化半胱胺酸、N-(N’-甲基胺基苄醯基)氧化半胱胺酸、N-(N’-乙基胺基苄醯基)氧化半胱胺酸、N-(N’,N’-二甲基胺基苄醯基)氧化半胱胺酸、N-(N’,N’-二乙基胺基苄醯基)氧化半胱胺酸、N-(氟苄醯基)氧化半胱胺酸、N-(三氟甲基苄醯基)氧化半胱胺酸、N-(氯苄醯基)氧化半胱胺酸、N-(二氯苄醯基)氧化半胱胺酸、N-(硝基苄醯基)氧化半胱胺酸、(N-氰基苄醯基)氧化半胱胺酸、N-(羧基苄醯基)氧化半胱胺酸、N-(甲氧基羰基苄醯基)氧化半胱胺酸、N-(乙氧基羰基苄醯基)氧化半胱胺酸、N-(乙醯基苄醯基)氧化半胱胺酸、N-(丙醯基苄醯基)氧化半胱胺酸、N-(丁醯基苄醯基)氧化半胱胺酸、N-(萘甲醯基)氧化半胱胺酸、N-(甲基萘甲醯基)氧化半胱胺酸、N-(甲氧基萘甲醯基)氧化半胱胺酸、N-(羥基萘甲醯基)氧化半胱胺酸、N-(胺基萘甲醯基)氧化半胱胺酸、N-(乙醯基萘甲醯基)氧化半胱胺酸、N-(氟萘甲醯基)氧化半胱胺酸、N-(甲氧基羰基萘甲醯基)氧化半胱胺酸、(N-聯苯基羰基)氧化半胱胺酸、(N-甲氧基聯苯基羰基)氧化半胱胺酸、N-(苄基羰基)氧化半胱胺酸、N-(苯乙基羰基)氧化半胱胺酸、N-(苯丙基羰基)氧化半胱胺酸、N-(苯丁基羰基)氧化半胱胺酸、N-(甲苯甲醯基甲基羰基)氧化半胱胺酸、N-(甲苯甲醯基乙基羰基)氧化半胱胺酸、N-(甲苯甲醯基丙基羰基)氧化半胱胺酸、N-(甲苯甲醯基丁基羰基)氧化半胱胺酸、N-(吡啶羰基)氧化半胱胺酸、N-(喹啉羰基)氧化半胱胺酸、(N-苄醯基氧化半胱胺酸)甲酯、(N-苄醯基氧化半胱胺酸)乙酯、(N-苄醯基氧化半胱胺酸)丙酯、(N-苄醯基氧化半胱胺酸)丁酯、(N-甲苯甲醯基氧化半胱胺酸)甲酯、
(N-甲苯甲醯基氧化半胱胺酸)乙酯、(N-甲苯甲醯基氧化半胱胺酸)丙酯、(N-甲苯甲醯基氧化半胱胺酸)丁酯、[(N-甲苯甲醯基)氧化半胱胺酸]甲酯、[(N-甲苯甲醯基)氧化半胱胺酸]乙酯、[(N-甲苯甲醯基)氧化半胱胺酸]丙酯、[(N-甲氧基苄醯基)氧化半胱胺酸]甲酯、[(N-甲氧基苄醯基)氧化半胱胺酸]乙酯、[(N-甲氧基苄醯基)氧化半胱胺酸]丙酯、[(N-聯苯基羰基)氧化半胱胺酸]甲酯、[(N-聯苯基羰基)氧化半胱胺酸]乙酯、[(N-聯苯基羰基)氧化半胱胺酸]丙酯、[(N-苄基羰基)氧化半胱胺酸]甲酯、[(N-苄基羰基)氧化半胱胺酸]乙酯、[(N-苄基羰基)氧化半胱胺酸]丙酯、N-(苄醯基)高氧化半胱胺酸、N-(甲苯甲醯基)高氧化半胱胺酸、N-(乙基苄醯基)高氧化半胱胺酸、N-(丙基苄醯基)高氧化半胱胺酸、N-(丁基苄醯基)高氧化半胱胺酸、N-(戊基苄醯基)高氧化半胱胺酸、N-(己基苄醯基)高氧化半胱胺酸、N-(庚基苄醯基)高氧化半胱胺酸、N-(辛基苄醯基)高氧化半胱胺酸、N-(甲氧基苄醯基)高氧化半胱胺酸、N-(乙氧基苄醯基)高氧化半胱胺酸、N-(丙氧基苄醯基)高氧化半胱胺酸、N-(丁氧基苄醯基)高氧化半胱胺酸、N-(羥基苄醯基)高氧化半胱胺酸、N-(胺基苄醯基)高氧化半胱胺酸、N-(N’-甲基胺基苄醯基)高氧化半胱胺酸、N-(N’-乙基胺基苄醯基)高氧化半胱胺酸、N-(N’,N’-二甲基胺基苄醯基)高氧化半胱胺酸、N-(N’,N’-二乙基胺基苄醯基)高氧化半胱胺酸、N-(氟苄醯基)高氧化半胱胺酸、N-(三氟甲基苄醯基)高氧化半胱胺酸、N-(氯苄醯基)高氧化半胱胺酸、N-(二氯苄醯基)高氧化半胱胺酸、N-(硝基苄醯基)高氧化半胱胺酸、(N-氰基苄醯基)高氧化半胱胺酸、N-(羧基苄醯基)高氧化半胱胺酸、N-(甲氧基羰基苄醯基)高氧化半胱胺酸、N-(乙氧基羰基苄醯基)高氧化半胱胺酸、N-(乙醯基苄醯基)高
氧化半胱胺酸、N-(丙醯基苄醯基)高氧化半胱胺酸、N-(丁醯基苄醯基)高氧化半胱胺酸、N-(萘甲醯基)高氧化半胱胺酸、N-(甲基萘甲醯基)高氧化半胱胺酸、N-(甲氧基萘甲醯基)高氧化半胱胺酸、N-(羥基萘甲醯基)高氧化半胱胺酸、N-(胺基萘甲醯基)高氧化半胱胺酸、N-(乙醯基萘甲醯基)高氧化半胱胺酸、N-(氟萘甲醯基)高氧化半胱胺酸、N-(甲氧基羰基萘甲醯基)高氧化半胱胺酸、N-(聯苯基羰基)高氧化半胱胺酸、N-(甲氧基聯苯基羰基)高氧化半胱胺酸、N-(苄基羰基)高氧化半胱胺酸、N-(苯乙基羰基)高氧化半胱胺酸、N-(苯丙基羰基)高氧化半胱胺酸、N-(苯丁基羰基)高氧化半胱胺酸、N-(苯戊基羰基)高氧化半胱胺酸、N-(萘基甲基羰基)高氧化半胱胺酸、N-(萘基乙基羰基)高氧化半胱胺酸、N-(吡啶羰基)高氧化半胱胺酸、N-(喹啉羰基)高氧化半胱胺酸、[N-(苄醯基)高氧化半胱胺酸]甲酯、[N-(苄醯基)高氧化半胱胺酸]乙酯、[N-(苄醯基)高氧化半胱胺酸]丙酯、[N-(苄醯基)高氧化半胱胺酸]丁酯、[N-(甲苯甲醯基)高氧化半胱胺酸]甲酯、[N-(甲苯甲醯基)高氧化半胱胺酸]乙酯、[N-(甲苯甲醯基)高氧化半胱胺酸]丙酯、[N-(甲苯甲醯基)高氧化半胱胺酸]丁酯、[N-(甲氧基苄醯基)高氧化半胱胺酸]甲酯、[N-(甲氧基苄醯基)高氧化半胱胺酸]乙酯、[N-(甲氧基苄醯基)高氧化半胱胺酸]丙酯、[N-(甲氧基苄醯基)高氧化半胱胺酸]丁酯、[N-(聯苯基羰基)高氧化半胱胺酸]甲酯、[N-(聯苯基羰基)高氧化半胱胺酸]乙酯、[N-(聯苯基羰基)高氧化半胱胺酸]丙酯、[N-(聯苯基羰基)高氧化半胱胺酸]丁酯、[N-(苄基羰基)高氧化半胱胺酸]甲酯、[N-(苄基羰基)高氧化半胱胺酸]乙酯、[N-(苄基羰基)高氧化半胱胺酸]丙酯、[N-(苄基羰基)高氧化半胱胺酸]丁酯、前述化合物的立體異構物及/或彼等之藥理學上容許的鹽
等。此等之中更佳為N-(苄醯基)氧化半胱胺酸、N-(甲苯甲醯基)氧化半胱胺酸、N-(甲氧基苄醯基)氧化半胱胺酸、N-(聯苯基羰基)氧化半胱胺酸、N-(苄基羰基)氧化半胱胺酸、N-(苄醯基)高氧化半胱胺酸、N-(甲苯甲醯基)高氧化半胱胺酸、N-(甲氧基苄醯基)高氧化半胱胺酸、N-(聯苯基羰基)高氧化半胱胺酸、N-(苄基羰基)高氧化半胱胺酸、其立體異構物、及彼等之藥理學上容許的鹽等。
一般式(5)表示之化合物中,不包括於一般式(6)之化合物,可具體地例示有(N-乙醯基-N-苄醯基)氧化半胱胺酸、(N-苄醯基-N-丙醯基)氧化半胱胺酸、(N-苄醯基-N-丁醯基)氧化半胱胺酸、(N-苄醯基-N-異丁醯基)氧化半胱胺酸、(N-苄醯基-N-戊醯基)氧化半胱胺酸、(N-苄醯基-N-異戊醯基)氧化半胱胺酸、(N-苄醯基-N-三甲基乙醯基)氧化半胱胺酸、(N-苄醯基-N-己醯基)氧化半胱胺酸、(N-苄醯基-N-辛醯基)氧化半胱胺酸、(N-乙醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-丙醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-丁醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-異丁醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-甲苯甲醯基-N-戊醯基)氧化半胱胺酸、(N-異戊醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-三甲基乙醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-己醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-辛醯基-N-甲苯甲醯基)氧化半胱胺酸、(N-乙醯基-N-甲氧基苄醯基)氧化半胱胺酸、(N-甲氧基苄醯基-N-丙醯基)氧化半胱胺酸、(N-丁醯基-N-甲氧基苄醯基)氧化半胱胺酸、(N-異丁醯基-N-甲氧基苄醯基)氧化半胱胺酸、(N-甲氧基苄醯基-N-戊醯基)氧化半胱胺酸、(N-異戊醯基-N-甲氧基苄醯基)氧化半胱胺酸、(N-甲氧基苄醯基N-三甲基乙醯基)氧化半胱胺酸、(N-己醯基-N-甲氧基苄醯基)
氧化半胱胺酸、(N-甲氧基苄醯基N-辛醯基)氧化半胱胺酸、(N-乙醯基-N-聯苯基羰基)氧化半胱胺酸、(N-聯苯基羰基-N-丙醯基)氧化半胱胺酸、(N-聯苯基羰基-N-丁醯基)氧化半胱胺酸、(N-聯苯基羰基-N-異丁醯基)氧化半胱胺酸、(N-聯苯基羰基-N-戊醯基)氧化半胱胺酸、(N-聯苯基羰基-N-異戊醯基)氧化半胱胺酸、(N-聯苯基羰基-N-三甲基乙醯基)氧化半胱胺酸、(N-聯苯基羰基-N-己醯基)氧化半胱胺酸、(N-聯苯基羰基-N-辛醯基)氧化半胱胺酸、(N-乙醯基-N-苄基羰基)氧化半胱胺酸、(N-苄基羰基-N-丙醯基)氧化半胱胺酸、(N-苄基羰基-N-丁醯基)氧化半胱胺酸、(N-苄基羰基-N-異丁醯基)氧化半胱胺酸、(N-苄基羰基-N-戊醯基)氧化半胱胺酸、(N-苄基羰基-N-異戊醯基)氧化半胱胺酸、(N-苄基羰基-N-三甲基乙醯基)氧化半胱胺酸、(N-苄基羰基-N-己醯基)氧化半胱胺酸、(N-苄基羰基-N-辛醯基)氧化半胱胺酸、(N-乙醯基-N-苄醯基)高氧化半胱胺酸、(N-苄醯基-N-丙醯基)高氧化半胱胺酸、(N-苄醯基-N-丁醯基)高氧化半胱胺酸、(N-苄醯基-N-戊醯基)高氧化半胱胺酸、(N-苄醯基-N-三甲基乙醯基)高氧化半胱胺酸、(N-苄醯基-N-己醯基)高氧化半胱胺酸、(N-苄醯基-N-辛醯基)高氧化半胱胺酸、(N-乙醯基-N-甲苯甲醯基)高氧化半胱胺酸、(N-丙醯基-N-甲苯甲醯基)高氧化半胱胺酸、(N-丁醯基-N-甲苯甲醯基)高氧化半胱胺酸、(N-乙醯基-N-甲氧基苄醯基)高氧化半胱胺酸、(N-丙醯基-N-甲氧基苄醯基)高氧化半胱胺酸、(N-丁醯基-N-甲氧基苄醯基)高氧化半胱胺酸、(N-乙醯基-N-聯苯基羰基)高氧化半胱胺酸、(N-聯苯基羰基-N-丙醯基)高氧化半胱胺酸、(N-聯苯基羰基-N-甲苯甲醯基)高氧化半胱胺酸、(N-乙醯基-N-苄基羰基)高氧化半胱胺酸、(N-苄基羰基-N-丙醯基)高氧化半胱胺酸、(N-苄基羰
基-N-丁醯基)高氧化半胱胺酸、前述化合物的立體異構物、或彼等之藥理學上容許的鹽等。
前記一般式(1)~(6)表示之化合物對於因暴露於紫外線等所形成之皺紋具有優異的皺紋改善效果,經由原膠原蛋白產生促進作用而表現皺紋改善效果。除此之外,也認為經由MMP1、MMP9、MMP13等之基質金屬蛋白酶阻害作用或IL-1、IL-6等之細胞激素產生抑制作用,而表現皺紋改善效果。
一般式(1)~(6)表示之化合物,可使用市售之試藥為原料,依照後記之製造例所示之方法來製造。該化合物可以其原樣利用作為本發明之皺紋改善劑,亦可與藥理學上容許的酸或鹼一起處理變換為鹽之形式來使用。舉例而言,適宜的可例示有鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、碳酸鹽等之無機酸鹽,順丁烯二酸鹽、反丁烯二酸鹽、草酸鹽、檸檬酸鹽、乳酸鹽、酒石酸鹽、甲烷磺酸鹽、對甲苯磺酸鹽、苯磺酸鹽等之有機酸鹽,鈉鹽、鉀鹽等之鹼金屬,鈣鹽、鎂鹽等之鹼土類金屬,三乙基胺鹽、三乙醇胺鹽、銨鹽、單乙醇胺鹽、哌啶鹽等之有機胺鹽,離胺酸鹽、褐藻酸鹽等之鹼性胺基酸鹽等。
以下顯示本發明之皺紋改善劑的製造例。
N-(甲苯甲醯基)甲硫胺酸(化合物1)
將L-甲硫胺酸5(g)(33.5mmol)(和光純藥)、1,4-二烷20(mL)(和光純藥)及水10(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序滴下8(N)氫氧化鈉水溶液9.21(mL)、對甲苯甲醯氯4.21(mL)(Aldrich)。滴完後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除1,4-二烷。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。以乙酸乙酯溶解所析出之結晶,萃取後以飽和食鹽水洗淨,以無水硫酸鈉脫水。濃縮所得乙酸乙酯溶液並結晶化。以二異丙基醚洗淨所得之結晶後,過濾及乾燥,得到具有上記構造之化合物16.99(g)(26.1mmol)。物化性質如以下所示。
1
H-NMR(CDCl3
):δ2.13(3H,s)、2.18(1H,m)、2.35(1H,m)、2,40(3H,s)、2.66(2H,t)、4.91(1H,q)、7.13(1H,d)、7.24(2H,d)、7.71(2H,d)。
FAB-MS(正離子模式):M/z=268([M+H]+
)
將S-甲基-L-半胱胺酸5(g)(37.0mmol)(東京化成)、1,4-二烷20(mL)(和光純藥)及水10(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序滴下8(N)氫氧化鈉水溶液10.2(mL)、對甲苯甲醯氯4.9(mL)(Aldrich)。滴完後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除1,4-二烷。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。以乙酸乙酯溶解所析出之結晶,萃取後以飽和食鹽水洗淨,以無水硫酸鈉脫水。濃縮所得乙酸乙酯溶液並結晶化。以二異丙基醚洗淨所得之結晶後,過濾及乾燥得到粗製結晶。將所得粗製結晶懸浮於乙酸乙酯,升溫至60℃。確認完全溶解後,滴下二異丙基醚40(mL),析出結晶。將該懸浮液放冷至室溫後,過濾及乾燥得到具有上記構造之化合物22.87(g)(11.3mmol)。物化性質如以下所示。
1
H-NMR(CDCl3
):δ 2.16(3H,s)、2.40(3H,s)、3.15(2H,m)、4.98(1H,q)、7.09(1H,d)、7.25(2H,d)、7.72(2H,d)。
FAB-MS(正離子模式):M/z=254([M+H]+
)、276([M+Na]+
)
N-(甲苯甲醯基)氧化半胱胺酸(化合物3)
將L-氧化半胱胺酸1水合物5(g)(26.7mmol)(Aldrich)、1,4-二烷20(mL)(和光純藥)及水10(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序滴下8(N)氫氧化鈉水溶液10.7(mL)、對甲苯甲醯氯3.36(mL)(Aldrich)。滴完後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除1,4-二烷。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。冷凍乾燥所得水溶液,以甲醇萃取目的物。減壓蒸餾去除甲醇
後,結晶化並過濾。乾燥濾取的結晶,得到具有上記構造之化合物35.79(g)(20.2mmol)。物化性質如以下所示。
1
H-NMR(D2
O):δ 2.32(3H,s)、3.46(2H,m)、4.87(1H,m)、7.25(2H,d)、7.64(2H,d)。
FAB-MS(負離子模式):M/z=286([M-H]-
)、308([M+Na-H]-
)
N-(4-苯基苄醯基)-L-氧化半胱胺酸(化合物4)
將L-氧化半胱胺酸2(g)(11.8mmo])(東京化成)、四氫呋喃12(mL)(和光純藥)及水12(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序添加碳酸鉀2.94(g)(21.3mmol)(和光純藥)、4-苯基苄醯氯2.05(g)(東京化成)。冰浴下反應1.5小時後,再度添加4-苯基苄醯氯1.02(g)(東京化成)。添加後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除四氫呋喃。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。過濾所析出之結晶,以水洗淨。以丙酮懸浮清洗所得結晶後,過濾。在60℃乾燥所濾取之結晶,得到具有上記構造之化合物42.37(g)(678mmol)。物化性質如以下所示。
1
H-NMR(DMSO-d6):δ 2.96(2H,m)、4.54(1H,q)、7.42(1H,m)、7.51(2H,m)、7.74(2H,d)、7.80(2H,d)、7.90(2H,d)、8.94(1H,d)。
FAB-MS(負離子模式):M/z=348([M-H]-
)
N-(4-甲氧基苄醯基)-L-氧化半胱胺酸(化合物5)
將L-氧化半胱胺酸2(g)(11.8mmol)(東京化成)、四氫呋喃12(mL)(和光純藥)及水12(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序添加碳酸鉀2.94(g)(21.3mmol)(和光純藥)、4-甲氧基苄醯氯1.61(g)(東京化成)。冰浴下反應1小時後,再度添加4-甲氧基苄醯氯0.81(g)(東京化成)。添加後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除四氫呋喃。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。過濾所析出之結晶,以水洗淨。濃縮濾液,過濾再度析出的結晶。合併所得之結晶後,以丙酮懸浮清洗。過濾結晶後,在60℃乾燥所濾取之結晶,得到具有上記構造之化合物52.47(g)(8.14mmol)。物化性質如以下所示。
1
H-NMR(D2
O):δ 3.45(2H,m)、3.81(3H,s)、4.85(1H,m)、7.00(2H,d)、7.72(2H,d)。
FAB-MS(負離子模式):M/z=302([M-H]-
)
N-甲苯甲醯基-DL-高氧化半胱胺酸(化合物6)
將DL-高氧化半胱胺酸2(g)(10.9mmol)(Aldrich)、四氫呋喃12(mL)(和光純藥)及水12(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,添加碳酸鉀2.71(g)(19.6mmol)(和光純藥)。以液溫不上升的方式依順序添加對甲苯甲醯氯149(g)(Aldrich)。冰浴下反應1小時後,再度添加對甲苯甲醯氯0.76(g)(Aldrich)。添加後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除四氫呋喃。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。過濾溶液後,濃縮濾液,添加甲醇。過濾出所析出之結晶後,以水懸浮清洗。過濾結晶,在60℃乾燥所濾取之結晶,得到具有上記構造之化合物61.95(g)(6.47mmol)。物化性質如以下所示。
1
H-NMR(DMSO-d6):δ 2.12(2H,m)、2,35(3H,s)、2.57(2H,t)、4.37(1H,m)、7.26(2H,d)、7.79(2H,d)、9.02(1H,d)。
FAB-MS(負離子模式):M/z=300([M-H]-
)
N-(間甲苯甲醯基)-氧化半胱胺酸(化合物7)
將L-氧化半胱胺酸3(g)(17.7mmol)(東京化成)、四氫呋喃18(mL)(和光純藥)及水18(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,以液溫不上升的方式依順序添加碳酸鉀4.40(g)(31.6mmol)(和光純藥)、間甲苯甲醯氯
2.19(g)(東京化成)。冰浴下反應1小時後,再度添加間甲苯甲醯氯1.09(g)(東京化成)。添加後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除四氫呋喃。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。濃縮濾液,添加水(18ml)。過濾出所析出之結晶。以丙酮懸浮清洗所得結晶並濾取。在60℃乾燥所濾取之結晶,得到具有上記構造之化合物71.65(g)(5.74mmol)。物化性質如以下所示。
1
H-NMR(DMSO-d6):δ 2.36(3H,s)、2.94(2H,m)、4.41(1H,m)、7.36(2H,d)、7.58(2H,t)、8.84(1H,d)、12.5(1H,bs)。
FAB-MS(負離子模式):M/z=286([M-H]-
)
N-(鄰甲苯甲醯基)-L-氧化半胱胺酸(化合物8)
將L-氧化半胱胺酸3(g)(17.7mmol)(東京化成)、四氫呋喃18(mL)(和光純藥)、水18(mL)置入100(mL)茄子型燒瓶後,以冰浴冷卻。充分冷卻後,添加碳酸鉀4.40(g)(31.6mmol)(和光純藥)。以液溫不上升的方式依順序添加鄰甲苯甲醯氯3.28(g)(東京化成)。添加後,移除冰浴,在室溫攪拌。以薄層色層分析確認反應的進行後,減壓蒸餾去除四氫呋喃。以乙酸乙酯洗淨所得殘渣後,以鹽酸調整pH至2以下。濃縮濾液,添加水(20ml)。濾取析出的結晶,以丙酮懸浮清洗結晶。在60℃乾燥所濾取之結晶,得到具有上記構造之化合物80.78(g)(2.72mmol)。物化性質如以下所示。
1
H-NMR(D2
O):δ2.31(3H,s)、3.42(2H,m)、4.86(1H,m)、7.24(2H,m)、7.35(2H,m)。
FAB-MS(負離子模式):M/z=286([M-H]-
)
上記製造例是一般式(1)表示之化合物的製造方法之一例,經由適宜變更原料或反應條件可合成上記化合物1~8以外的化合物。本發明之皺紋改善劑,對於因暴露於紫外線等所形成之皺紋發揮優異的皺紋改善作用,因此有用於作為皮膚外用劑。對於皮膚外用劑欲達到如此作用,則相對於皮膚外用劑全量,以總量含有0.001質量%~20質量%之本案發明之皺紋改善劑,亦即一般式(1)~(6)表示之化合物為佳,更佳為0.01質量%~10質量%,又更佳為0.1質量%~5質量%。相對於皮膚外用劑全量之含有量少於0.001質量%時,則有皺紋改善作用之效果降低的情形,又,即使使用超過20質量%之量,效果已達極限,有徒然損失處方自由度的情形。
一般式(1)表示之化合物中,也存在對於因暴露於紫外線等所形成之皺紋具優異之皺紋改善作用以外的作用者。即使以此等作用的表現為目的而含有本發明之皺紋改善劑的皮膚外用劑,由於發揮皺紋改善效果之情形是利用本發明的效果,因此屬於本發明之技術的範圍。皺紋改善以外的作用,可舉出保濕作用、光線性角化症或非光線性角化症改善作用、皮膚的剝離、表皮更新的刺激及老化改善作用等。
本發明之皮膚外用劑,除本發明之皺紋改善劑以外,可含有通常之皮膚外用劑所使用的任意成分。此等任意成分,可舉出例如夏威夷豆油、鰐梨油、玉蜀黍油、橄欖油、油菜籽油、芝麻油、蓖麻油、葵花油、棉花子油、荷荷芭油、椰子油、棕櫚油、液狀綿羊油、氫化椰子油、氫化油、木蠟、氫化蓖麻油、蜂蠟、小燭樹蠟(Candelilla wax)、卡那巴蠟(Carnauba wax)、白蠟、綿羊油、還原綿羊油、硬質綿羊油、荷荷芭蠟等之油、蠟類;流動石蠟、角鯊烷、異十九烷(pristane)、地蠟(ozokerite)、石蠟、地蠟(ceresin)、凡士林、微晶蠟等之烴類;油酸、異硬脂酸、月桂酸、肉豆蔻酸、棕櫚酸、硬脂酸、二十二酸、十一碳烯酸等之高級脂肪酸類;鯨蠟基醇、硬酯醇、異硬酯醇、二十二基醇、辛基十二烷醇、十四基醇、十八十六醇等之高級醇等;異辛烷酸十六酯、肉豆蔻酸異丙酯、異硬脂酸己基癸酯、己二酸二異丙酯、癸二酸二-2-乙基己酯、乳酸十六酯、蘋果酸二異硬酯基酯、二-2-乙基己酸乙二醇、二癸酸新戊二醇、二-2-庚基十一酸甘油、三-2-乙基己酸甘油、三-2-乙基己酸三羥甲基丙烷、三異硬脂酸三羥甲基丙烷、四-2-乙基己酸異戊四醇等之合成酯油類;二甲基聚矽氧烷、甲基苯基聚矽氧烷、二苯基聚矽氧烷等之鏈狀聚矽氧烷;八甲基環四矽氧烷、十甲基環五矽氧烷、十二甲基環六矽氧烷等之環狀聚矽氧烷;胺基變性聚矽氧烷、聚醚變性聚矽氧烷、烷基變性聚矽氧烷、氟變性聚矽氧烷等之變性聚矽氧烷等的聚矽氧油等油劑類;脂肪酸皂(月桂酸鈉、棕櫚酸鈉等)、月桂基硫酸鉀、烷基硫酸三乙醇胺醚等之陰離子界面活性劑類;氯化硬酯基三甲基銨、氯化苯二甲烴銨、月桂基氧化胺等之陽離子界面活性劑類;咪唑啉系兩性界面活性劑(2-椰油醯基-2-咪唑鎓氫氧化物-1-羧基乙氧基2鈉鹽等)、甜菜鹼系界面活性劑(烷基甜菜鹼、醯胺甜菜鹼、磺酸基甜菜鹼等)、醯基甲基牛磺酸等之兩性界面活性劑類;山梨糖醇酐脂肪酸酯類(山梨糖醇酐單硬脂酸、倍半油酸山梨糖醇酐等)、甘油脂肪酸類(單硬脂酸甘油等)、丙二醇脂肪酸酯類(單硬脂酸丙二醇等)、氫化蓖麻油衍生物、甘油烷基醚、POE山梨糖醇酐脂肪酸酯類(POE山梨糖醇酐單油酸酯、單硬脂酸聚氧乙烯山梨糖醇酐等)、POE山梨醇脂肪酸酯類(POE-山梨醇單月桂酸酯等)、POE甘油脂肪酸酯類(POE-甘油單異硬脂酸酯等)、POE脂肪酸酯類(聚乙二醇單油酸酯、POE二硬脂酸酯等)、POE烷基醚類(POE2-辛基十二基醚等)、POE烷基苯基醚類(POE壬基苯基醚等)、Pluronic型類、POE‧POP烷基醚類(POE‧POP2-癸基四癸基醚等)、Tetronic類、POE蓖麻油‧氫化蓖麻油衍生物(POE蓖麻油、POE氫化蓖麻油等)、蔗糖脂肪酸酯、烷基葡萄糖苷等之非離子性界面活性劑類;聚乙二醇、甘油、1,3-丁二醇、赤藻糖醇、山梨糖醇、木糖醇、麥芽糖醇、丙二醇、二丙二醇、二甘油、異戊二醇、1,2-戊二醇、2,4-己二醇、1,2-己二醇、1,2-辛二醇等之多元醇類;吡咯啶酮羧酸鈉、乳酸、乳酸鈉等之保濕成分類;表面可經處理之雲母、滑石、高嶺土、合成雲母、碳酸鈣、碳酸鎂、無水矽酸(二氧化矽)、氧化鋁、硫酸鋇等之粉體類;表面可經處理之紅色氧化鐵(bengala)、黃色氧化鐵、黑色氧化鐵、氧化鈷、群青(ultramarine)、普魯士藍(Prussian blue)、氧化鈦、氧化鋅之無機顏料類;表面可經處理之雲母鈦、魚鱗箔、氧氯化鉍等之珍珠光澤化劑類;可經不溶化之紅色202號、紅色228號、紅色226號、黃色4號、藍色404號、黃色5號、紅色505號、紅色230號、紅色223號、橙色201號、紅色213號、黃色204號、黃色203號、藍色1號、綠色201號、紫色201號、紅色204號等之有機色素類;聚乙烯粉末、聚甲基丙烯酸甲酯、尼龍粉末、有機聚矽氧烷彈性體等之有機粉體類;對胺基苯甲酸系紫外線吸收劑;鄰胺苯甲酸酸系紫外線吸收劑;水楊酸系紫外線吸收劑;桂皮酸系紫外線吸收劑;二苯基酮系紫外線吸收劑;糖系紫外線吸收劑;2-(2’-羥基-5’-t-辛基苯基)苯并三唑、4-甲氧基-4’-t-丁基二苄醯基甲烷等之紫外線吸收劑類;乙醇、異丙醇等之低級醇類;維生素A或其衍生物、維生素B6鹽酸鹽、維生素B6三棕櫚酸酯、維生素B6二辛酸酯、維生素B2或其衍生物、維生素B12、維生素B15或其衍生物等之維生素B類;α-生育醇、β-生育醇、γ-生育醇、維生素E乙酸酯等之維生素E類、維生素D類、維生素H、泛酸、泛雙硫醇(pantethine)、吡咯并喹啉醌等之維生素類等;苯氧基乙醇等之抗菌劑等。
本發明之皺紋改善劑以及依照常法處理上記任意成分之化妝水、乳液、精華液、乳霜、面膜化妝材料、洗淨料等,可製造本發明之皮膚外用劑。本發明之皮膚外用劑,只要能以外用適用於皮膚者,則無特別限定可適用,可適用於含有醫藥外用品(quasi-drugs)之化妝材料、皮膚外用醫藥、皮膚外用雜貨等。特佳為含有醫藥外用品之化妝材料。由於本發明之皺紋改善劑的安全性高,因此可連續地使用。
關於本發明,以下舉出實施例加以更詳細地說明,當然本發明不被僅限定於此等實施例。
經由先前所述之方法合成化合物1。依照以下所示處方,調製含有本發明之皺紋改善劑的化妝材料1(化妝水)。
關於上記化妝材料1,在使用光老化模式之試驗中評價皺紋改善效果。
試驗開始時是以6週齡的無毛小鼠1組5隻,經由在對照組(乙醇溶劑投與組)及檢體投與組2組共10隻之無毛小鼠背部,以1日1回、每週3回的頻率連續10週照射UVB來誘發光老化。UVB照射量在最初第1週是50mJ/cm2
,第2週以後為100mJ/cm2
。
於檢體投與組,將上記化妝材料1投與至無毛小鼠背部。10週之UVB照射完成後,從第2天開始於無毛小鼠背部投與化妝材料1,1日1回100μL投與8週。於對照組則投與乙醇取代表1的化妝材料1(化妝水1),之後的處置則與檢體投與組同樣地進行。投與完成1日後採取模印(replica),使用在30度的斜光照明下投影之2cm平方的模印(replica)像,由測定者依照皺紋計分基準(表2)進行計分化作業,評價皺紋改善效果。計分化作業是由3名測定者個別地進行,經由目視計分1~6,以每0.5評價的結果算出平均值。
化合物1的皺紋改善效果示於第1圖。從該圖可知,本發明之化合物1具有優異的皺紋改善效果。
經由先前所述之方法合成化合物2及3。將化合物1變為化合物2及3以外,以與實施例1同樣的方法調製化妝材料2及化妝材料3。與化妝材料1之情形同樣地評價皺紋改善作用之結果,示於第2圖及第3圖。從這些圖可知,本發明之化合物2及化合物3具有優異的皺紋改善效果。
經由先前所述之方法合成本發明之化合物1~8,評價原膠原蛋白(procollagen)產生促進作用。
使用角質細胞增殖用培養基(Humedia-KG2,Kurabo Industries Ltd.),將4.5×104
細胞之來自人類正常角質細胞的培養細胞播種於24井平板,在37℃、5%二氧化碳濃度中培養4日。同時使用已添加10%FBS之DMEM培養基(SIGMA製),將2.5×104
細胞之來自人類正常皮膚纖維母細胞的培養細胞播種於24井平板,在37℃、5%二氧化碳濃度中培養。
然後,以最終濃度為10μM之方式將化合物1~8分別添加於已添加2% FBS之DMEM培養基(SIGMA製)來製作培養物。此外,比較對照組(Control)是取代化合物1~8,而以最終濃度為0.01×10-3
(v/v%)的方式添加二甲亞碸(Sigma‧Aldrich製)及50%乙醇(Sigma‧Aldrich製)來製作培養基。
以PBS(和光純藥工業股份有限公司製)洗淨培養之角質細胞後,置換為合有上述個別化合物之培養基以及含有二甲亞碸及50%乙醇的培養基,在37℃、5%二氧化碳濃度中培養24小時。24小時後,回收該培養上清液。
以PBS洗淨培養之纖維母細胞後,取代為回收之培養上清液,在37℃、5%二氧化碳濃度中培養48小時。48小時後,以PBS洗淨纖維母細胞後,取代為DMEM(SIGMA製),在37℃、5%二氧化碳濃度中培養2小時後,回收培養上清液。使用ELISA法測定該培養上清中的原膠原蛋白量。
以添加二甲亞碸及50%乙醇之培養基培養的纖維母細胞作為比較對照組(Control),相較於比較對照組,化合物1~8個別之原膠原蛋白產生量的比率示於第4~7圖。
從第4~7圖之結果,可明瞭本發明之化合物具有優異的原膠原蛋白產生促進效果。
本發明之皺紋改善劑可適用於化妝材料等之皮膚外用劑。由於安全性高及皺紋改善作用優異,非常有用於作為化妝材料原料。
第1圖為顯示本發明中化合物1之使用光老化模式的皺紋改善作用的圖。
第2圖為顯示本發明中化合物2之使用光老化模式的皺紋改善作用的圖。
第3圖為顯示本發明中化合物3之使用光老化模式的皺紋改善作用的圖。
第4圖為顯示本發明之化合物1及2之原膠原蛋白產生作用的圖。
第5圖為顯示本發明之化合物3及4之原膠原蛋白產生作用的圖。
第6圖為顯示本發明之化合物5及6之原膠原蛋白產生作用的圖。
第7圖為顯示本發明之化合物7及8之原膠原蛋白產生作用的圖。
Claims (7)
- 一種下記一般式(1)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽之用途,其係用於製造皺紋改善劑,
- 如申請專利範圍第1項之用途,其中該一般式(1)表示之化合物為下記一般式(3)表示之化合物,
- 如申請專利範圍第1項之用途,其中該一般式(1)表示之化合物為下記一般式(4)表示之化合物,
- 如申請專利範圍第1項之用途,其中該一般式(1)表示之化合物為下記一般式(6)表示之化合物,
- 一種下記一般式(6)表示之化合物、其立體異構物、或彼等之藥理學上容許的鹽,
- 一種皮膚外用劑,其含有0.001~20質量%之藉由如申請專利範圍第1至4項中任一項之用途所製造的皺紋改善劑。
- 如申請專利範圍第6項之皮膚外用劑,其為化妝材料。
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JP5911209B2 (ja) * | 2011-06-14 | 2016-04-27 | ポーラ化成工業株式会社 | 皮膚外用剤 |
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