TW201625268A - 包含阿茲海默症之治療劑的有關神經細胞之軸索功能不全之疾患之治療劑 - Google Patents
包含阿茲海默症之治療劑的有關神經細胞之軸索功能不全之疾患之治療劑 Download PDFInfo
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Abstract
本發明提供一種用於臨床上可實用化的阿茲海默症(AD)的根本療法的藥劑,並應用AD根本治療的作用機制而提供一種神經細胞的軸索的功能不全相關的AD以外的神經疾患的治療劑。該藥劑或治療劑係由薯蕷皂苷配基、薯蕷皂苷配基衍生物、及此等的藥學上可容許的鹽選出的1種以上的化合物在食用油懸浮的經口投藥劑。
Description
本發明是關於神經細胞的軸索(以下,亦單稱為「軸索」。)有關的功能不全的疾患,在臨床上可能實用化的預防劑或治療劑。更具體而言,是關於臨床上可能實用化的阿茲海默症(Alzheimer Disease)的預防劑或治療劑。
阿茲海默症(以下,也稱為AD。),定義為作為進行性的認知功能減低及與通常的老化不一致的功能障礙的狀態而定義,其診斷記載於美國精神醫學會發表的Diagnostic and Statistical Manual of Mental Disorders,第4版(DSM-IV)。
現在,AD的治療,限於乙醯膽鹼酯酶抑制劑所代表的症狀改善劑的對症療法,抑制、治療疾病的進行的根本療法劑還沒有開發出來。對AD的根本療法劑的
新創,需要對病態的發症原因機制的解明及控制發症原因的新方法的開發。AD的原因機制而言,有提倡膽鹼作用性假說,A β假說,及τ假說等,為了特定AD的原因機制,有龐大數目的研究在進行。
在學習及記憶上的乙醯膽鹼的角色受到議論中,在大腦基底部的膽鹼能性神經元(cholinergic neurons)的變性,以及與其有關連的大腦皮質及其他領域的膽鹼能性神經傳達的缺損,在AD患者所見的認知功能的減低上認為有很大關連的「阿茲海默症的膽鹼假說」受到議論(非專利文獻1)。根據該作用機制,抑制腦的突觸中乙醯膽鹼的分解的乙醯膽鹼酯酶抑制劑成為AD的治療藥而在市場中有販賣。例如可舉多奈派齊(Donepezil)、加蘭他敏(galantamine)、利凡斯的明(rivastigmine)等乙醯膽鹼酯酶抑制劑。
又,類澱粉質前驅物蛋白(以下,也稱為APP。)的代謝產物的A β蛋白,被認為與神經細胞的變性及脫落,再者與認知障礙的呈現有很大的關連(非專利文獻2、3)。在A β蛋白的形成上,有β-分泌酶及γ-分泌酶參與,由蛋白質分解部位的差異,而產生由胺基酸38個所成的A β(1-38),C末端有胺基酸增加2個的A β(1-40),及C末端有胺基酸增加4個的A β(1-42)等。該等的A β,凝集性高(非專利文獻4),成為老人斑的主要構成成分(非專利文獻4、5、6、7)。即,該等的凝集體是最後變化成為AD的病理學的特徴的不溶性的沈著物及高濃度的神經
突起溶菌斑(非專利文獻8)。再者,在家族性AD所見的APP及早老素(preselinin)基因的變異,已知會増加該等的A β蛋白(非專利文獻9、10、11)。因此,減低A β的產生的化合物,受期待作為AD的進行抑制劑或預防藥。據此,例如,將A β產生減低作為目的,嘗試A β抗體及分泌酶抑制劑等的藥物的新創。根據該假說有AD治療藥的若干候補品現正在臨床試驗中,有對AD患者有某種程度的有效性的報告(非專利文獻12,非專利文獻13)。
如以上所述,現在,對AD患者在臨床上被使用的藥劑,即使能預防或延緩AD的發症或進行,但還不能達到認知功能的改善。即,現在的AD的治療,限於以乙醯膽鹼酯酶抑制劑代表的症狀改善劑的對症療法,改善疾病本身的根本療法劑是還沒有開發出來。對AD的根本療法劑的新創,有需要開發控制神經功能不全的要因的方法。再者,有真摯需求適合於新機制的化合物的提供。
在非專利文獻15及非專利文獻16中,由將薯蕷皂苷配基(diosgenin)對小鼠在腹腔內投藥,在正常小鼠或在AD模型小鼠觀察到記憶力加強的報告。又,在非專利文獻15及非專利文獻16中,也有報告記憶力的加強,係由於軸索的進展。由該文獻,可期待薯蕷皂苷配基有效於AD的根本療法。但是,在該文獻中,為了確認薯蕷皂苷配基的效果而做的試驗是全部以腹腔內投藥實施,但腹腔內投藥,例如以人作為對象時,並不是在臨床上實用的投藥方法。
[非專利文獻1]Francis, P et al., J Neurol Neurosurg Psychiatry 66; pp137-147, 1999.
[非專利文獻2]Klein, WL et al., Proceeding of the National Academy of Science USA, Sep, 2;100(18), pp.10417-10422, 2003.
[非專利文獻3]Nitsch, RM et al., Neuron, May 22, 38, pp.547-554, 2003.
[非專利文獻4]Jarrett, JT et al., Biochemistry, 32(18), pp.4693-4697, 1993.
[非專利文獻5]Glenner, GG et al., Biochemical and Biophysical Research Communications, May 16, 120(3), pp.885-890, 1984.
[非專利文獻6]Masters, CL等,Proceeding of the National Academy of Science USA, Jun, 82(12), pp.4245-4249, 1985.
[非專利文獻7]Gong, Y et al., PNAS 100; pp.10417-10422, 2003.
[非專利文獻8]Hardy, J et al., Science 297; pp.353-356, 2002.
[非專利文獻9]Gouras, GK et al., American Journal of Pathology, Jan, 156(1), p.15-20, 2000.
[非專利文獻10]Scheuner,D et al., Nature Medicine, 1996, Aug, 2(8), pp.864-870.
[非專利文獻11]Forman, MS et al., Journal of Biological Chemistry, Dec, 19, 272(51), pp.32247-32253, 1997.
[非專利文獻12]Mount, C et al., Nature Medicine 12; pp-780-784, 2006.
[非專利文獻13]Siemers, ER et al., Clinical Neuropharmacology, 30; pp.317-325, 2007.
[非專利文獻14]Cho, S et al., Experimental Neurology, 203; pp.274-278, 2007.
[非專利文獻15]SCIENTIFIC REPORTS, Volume 2, Number 535, pp1-11.
[非專利文獻16]Tohda C, Lee YA, Goto Y, Nemere I. Sci Rep. 2013 Dec 2;3:3395. pp1-8.
有鑑於上述的狀況,本發明是以將新創在臨床上可能實用化的AD的根本療法使用的藥劑作為主要的課題。又,本發明也以應用在AD根本治療上的作用機制,提供軸索的功能不全相關的AD以外的神經疾患的治療劑作為重要課題。再者,該等以外的課題,由本說明書本文中可以明白。
為了解決上述課題,本發明者等,反覆精心檢討的結果,預想外地,將薯蕷皂苷配基溶解於水系溶媒(有機溶媒與水的混合液)的溶液經口投藥的方法,不能得到薯蕷皂苷配基的記憶加強效果,另一方面,將薯蕷皂苷配基懸浮於油脂的懸浮液經口投藥時,可得有效的記憶加強效果(特別是,比腹腔內投藥,以低用量就可得到有效的記憶加強效果),得到本發明特有的顯著而有用的新發現。再更推進檢討,不只是薯蕷皂苷配基,薯蕷皂苷配基衍生物化合物也同樣地,懸浮於油脂而經口投藥時,得到顯著的記憶加強效果的本申請案特有的有用的新發現,再進行重複試驗,而達到本發明的完成。
即,本發明是關於以下各項。
[1]經口投藥劑,係將由薯蕷皂苷配基、薯蕷皂苷配基衍生物[薯蕷皂苷配基的C3位的羥基經取代的化合物(例如,胺基酸衍生物、胺基磺酸衍生物、胺基甲酸酯衍生物、鹵化衍生物等)],及該等的藥學上可容許的鹽所選出的1種以上的化合物懸浮或溶解於油脂為特徴。
[2]如在[1]所述之劑,係至少含有薯蕷皂苷配基。
[3]如在[1]或[2]所述之劑,其中薯蕷皂苷配基衍生物是由下述式(I-1)代表的化合物及其藥學上可容許的鹽選出的至少1種
(式中,R1、R2、R3及R4,相同或不同,代表氫原子或取代基。但,R2、R3及R4是氫原子時,R1不是羥基。)。
[4]如在[3]所述之劑,其式(I-1)中,取代基是烴基、羥基、基-O-(CH2)n-CH3、基-O-(CH2)m-NH2、基-O-(CH2)m-COOH、基-O-(CH2)m-SO3H、基-O-CO-(CH2)n-CH3、基-O-CO-NH-(CH2)n-CH3、基-O-CO-NR-(CH2)n-CH3、基-O-CO-NH-CH(Rb)-COOH、基-O-(CH2)n-CO-NH-AD(式中,AD代表金剛烷基)、基-O-CO-NH-(CH2)m-SO3H、基-O-CO-NH-(CH2)m-COOH、基-O-CO-O-(CH2)n-CH3、基-O-CO-S-(CH2)n-CH3、基-O-SU(式中,SU代表糖鏈)、基-O-SO2-OH、基-O-PO2-OH、基-(OCH2CH2)m-CH3、基-(OCH2CH2CH2)m-CH3、羧基、基-COO(CH2)n-CH3、基-CO-NH-(CH2)n-CH3、基-SO3H、基-SO2-(CH2)n-CH3、基-SO2-Ph(式中,Ph是代表苯基。)、基-CO-NH-CH(Rb)-COOH、基-CO-NH-(CH2)n-SO3H、胺基、基-NH-(CH2)n-CH3、基-NH-(CH2)n-NH2、基-NH-CH(Rb)-COOH、基-NH-(CH2)m-SO3H、基-NH-(CH2)m-SO2H、基-NH-CO-O-(CH2)n-CH3、基-NH-CO-NH2、基-NH-CO-NH-AD(式中,AD代表金剛烷基)、基-NH-CO-NH-CH(Rb)-COOH、基-NH-CO-NH-(CH2)m-SO3H、
基-NH-CO-NH-(CH2)m-COOH、巰基、基-S-(CH2)n-CH3、基-S-(CH2)m-COOH、基-S-(CH2)m-CH(NH2)-COOH、基-S-CO-NH-AD(式中,AD代表金剛烷基)、基-S-S-(CH2)m-CH(NH2)-COOH、基-SO3H、基-PO3H、胺基酸基,或鹵原子(上述式中,m代表1以上的整數,n代表0以上的整數,Rb代表氫原子或烴基。)。
[5]如在[1]至[4]中任一項所述之劑,其中薯蕷皂苷配基衍生物是由(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯、(3 β,25R)-3-氟螺甾-5-烯、(3 β,25R)-3-(2-胺基乙基磺醯氧基)-螺甾-5-烯、(3 β,25R)-3-(2-胺基丙基磺醯氧基)-螺甾-5-烯、(3 β,25R)-3-[N-(2、6-二甲基金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯、(3 β,25R)-3-{[N-(2,6-二甲基金剛烷-1-基)胺甲醯基]胺基}-螺甾-5-烯、(3 β,25R)-3-[N-(2,6-二甲基金剛烷-1-基)胺甲醯基硫基]-螺甾-5-烯、(3 β,25R)-3-{[N-(金剛烷-1-基)胺甲醯基]胺基}-螺甾-5-烯、(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯基硫基1-螺甾-5-烯、(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯、及該等的藥學上可容許的鹽所成的群選出的1種以上。
[6]如在[1]至[5]中任一項所述之劑,係為其神經細胞的軸索的功能不全相關的疾患的預防劑或治療劑。
[7]如在[6]所述之劑,其中神經細胞的軸索功能不全為要因的疾患是阿茲海默症。
[8]如在[6]所述之劑,其中神經細胞的軸索功能不全為要因的疾患是脊髄損傷。
[9]如在[1]至[5]所述之劑,係為神經細胞的軸索的伸展劑。
[10]如在[1]至[5]所述之劑,係為變性的神經細胞的軸索的修復劑。
[11]如在[1]至[5]所述之劑,係為記憶増進劑(記憶加強劑)或記憶力減低(例如,伴隨老化的記憶力的減低)的抑制劑(或預防劑)。
[12]如在[1]至[11]中任一項所述之劑,係併用已知對軸索的功能不全相關的疾患的治療或預防有用的1種以上的化合物,或其藥學上容許的鹽。
[13]如在[1]至[12]所述之劑,其中劑形是由液劑、懸浮劑、膠囊劑、軟性膠囊劑、錠劑、顆粒劑、散劑、糖漿劑、凝膠劑、口腔內崩壊錠、及咀嚼錠所成的群選出的1種以上。
[14]健康功能食品,係含有如在[1]至[13]中任一項所述的劑。
[15]下述式(III)代表的(3 β,25R)-3-氟螺甾-烯
又,在本發明中,亦包含將前述經口投藥
劑,對包含人類的動物投藥之(1)神經細胞的軸索的功能不全相關的疾患的預防及/或治療方法,(2)神經細胞的軸索的伸展方法,(3)變性的神經細胞的軸索的修復方法,或(4)記憶的増進方法(或加強方法)或記憶力減低(例如,伴隨老化的記憶力的減低)的抑制方法(或預防方法)。
在本發明中,包含新穎的薯蕷皂苷配基衍生物(例如,前述式(III)代表的化合物)。
又,在本發明中,也包含由薯蕷皂苷配基衍生物(例如,後述的式(I-1)代表的化合物)及其在藥學上可容許的鹽選出的至少1種化合物之神經細胞的軸索的功能不全相關的疾患的預防劑或治療劑。前述疾患是阿茲海默症或脊髄損傷,尤其是,脊髄損傷。
再者,在本發明中,也包含神經細胞的軸索的伸展劑,變性神經細胞的軸索的修復劑,記憶増進劑(記憶加強劑)或記憶力減低(例如,伴隨老化的記憶力的減低)的抑制劑(或預防劑),該等係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物。
再者,在本發明中,也包含醫藥(或醫藥組成物),該醫藥係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物。
又,在本發明中,也包含健康功能食品,該健康功能食品係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物。
再者,在本發明中,也包含將含有由薯蕷皂苷配基衍
生物及其藥學上可容許的鹽選出的至少1種化合物(由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物的前述劑,含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物的醫藥,或含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物的健康功能食品),對包含人類的動物投藥之(1)神經細胞的軸索的功能不全相關的疾患的預防及/或治療方法,(2)神經細胞的軸索的伸展方法,(3)變性神經細胞的軸索的修復方法,或(4)記憶的増進方法(或加強方法)或記憶力減低(例如,伴隨老化的記憶力的減低)的抑制方法(或預防方法)。
又,本發明者等發現,薯蕷皂苷配基衍生物具有1,25D3-MARRS的刺激活性,然後,這種具有1,25D3-MARRS的刺激活性的物質,對神經疾患(阿茲海默症,脊髄損傷等前述例示的神經細胞的軸索的功能不全相關的疾患等)的預防及/或治療有效。
因此之故,在本發明中,也包含下述的發明。
[A]薯蕷皂苷配基衍生物,係為神經疾患的預防及/或治療用。
[B]前述[A]所述的薯蕷皂苷配基衍生物,其中前述神經疾患是阿茲海默症、認知症,巴金森病,脊髄損傷或腦挫傷。
[C]前述[A]或[B]所述的薯蕷皂苷配基衍生物,係用於製造神經疾患的預防及/或治療用的藥劑。
[D]前述[C]所述的使用,其中前述神經疾患是阿茲海默症、認知症、巴金森病、脊髄損傷或腦挫傷。
[E]前述[A]所述的薯蕷皂苷配基衍生物,在神經疾患的預防及/或治療上的使用。
[F]前述[E]所述的薯蕷皂苷配基衍生物,其中前述神經疾患是阿茲海默症、認知症、巴金森病、脊髄損傷或腦挫傷。
[G]神經疾患治療用的醫藥組成物,係含有前述[A]所述的薯蕷皂苷配基衍生物的治療有效量。
[H]前述[F]所述的醫藥組成物,其中前述神經疾患是阿茲海默症、認知症、巴金森病、脊髄損傷或腦挫傷。
[I]前述[G]或[H]所述的醫藥組成物,係再含有已知對疾患的治療或預防有用的1種以上的化合物,或其藥學上可容許的鹽的治療有效量。
[J]前述[I]所述的醫藥組成物,其中已知對疾患的治療或預防有用的1種以上的化合物,或其藥學上可容許的鹽,係已知對神經疾患的治療或預防有用的1種以上的化合物,或其藥學上可容許的鹽。
[K]一種醫藥組成物的調製方法,係將前述[H]至[J]中任一項所述的醫藥組成物,與至少1種的載劑混合為特徴。
[L]一種神經疾患的預防及/或治療方法,係將前述[A]所述的薯蕷皂苷配基衍生物,對包含人類的動物投藥為特徴。
[M]如前述[L]所述的方法,係將前述[A]所述的薯蕷皂苷配基衍生物,與已知對神經疾患的治療或預防有用的1種以上的化合物,或其藥學上可容許的其鹽併用為特徴。
[N]如前述[L]或[M]所述的方法,其中前述神經疾患是阿茲海默症、認知症、巴金森病、脊髄損傷或腦挫傷。
[O]在神經疾患的預防及/或治療上使用的套組,係含有前述[A]所述的薯蕷皂苷配基衍生物。
[P]如前述[O]所述的套組,係包含前述[A]所述的薯蕷皂苷配基衍生物,及容器。
[Q]一種將1,25D3-MARRS活化的方法,係將薯蕷皂苷配基衍生物投藥為特徴。
[R]一種預防或治療阿茲海默症的方法,係將薯蕷皂苷配基衍生物投藥為特徴。
[S]一種減少類澱粉質斑、τ沉澱、τ析出物、PHF-τ,或神經原纖維變化的方法,係將薯蕷皂苷配基衍生物對人等哺乳動物投藥為特徴。
[T]一種抑制A β(1-42)誘導的軸索的萎縮的方法,係將薯蕷皂苷配基衍生物對人等哺乳動物投藥為特徴。
[U]一種刺激1,25D3-MARRS之活化信號傳達路徑的方法,係為將薯蕷皂苷配基衍生物對人等哺乳動物投藥為特徴。
[V]含有薯蕷皂苷配基衍生物的健康食品,功能性食品,或特定保健用食品。
依據本發明,則可提供臨床上可能實用化之AD的根本療法用的劑。加之,依據本發明,則可提供AD以外的軸索的功能不全相關的疾患的預防劑或治療劑。再者,依據本發明,則也可提供軸索的伸展劑,變性軸索的修復劑。
第1圖是顯示物體認知記憶試驗(實施例1至4及比較例1)的結果。
第2圖是顯示物體認知記憶試驗(實施例5、6及比較例2)的結果。
第3圖是顯示物體認知記憶試驗(實施例7、8及比較例3)的結果。
第4圖是顯示使用脊髄損傷模型小鼠的後胺運動功能評估試驗(實施例10及比較例5)的結果。第4圖A是,後胺運動功能評估(Basso Mouse Scale,BMS)的評估結果,第4圖B是富山小鼠尺度(Toyama Mouse Scale,TMS)的評估結果。
第5圖A是顯示參考試驗1的自發運動量的測定結果,第5圖B是顯示參考試驗1的體重測定的結果。
第6圖是顯示參考試驗2的結果。第6圖A是顯示參考例1的結果,第6圖B是顯示參考例2的結果。
第7圖是顯示參考試驗3的結果。
第8圖是顯示物體認知記憶試驗(實施例11及比較例
6)的結果。
第9圖是顯示物體認知記憶試驗(比較例7及比較例8)的結果。
第10圖是顯示物體認知記憶試驗(實施例12及比較例9)的結果。
以下,詳細說明本發明。
本發明的1種態樣是關於含有由薯蕷皂苷配基、薯蕷皂苷配基衍生物及該等的藥學上可容許的鹽選出的1種以上的化合物的經口投藥劑。
又,在本說明書中,將「由薯蕷皂苷配基、薯蕷皂苷配基衍生物及該等的藥學上可容許的鹽選出的1種以上的化合物」也簡稱為「薯蕷皂苷配基等」。
薯蕷皂苷配基是,下述化學式(I)代表的類固醇皂苷素(steroid sapogenin),
已知在山藥(Dioscorea rhizome)、及胡盧巴屬(Trigonella spp.)、黃精屬(Polygonatum spp.)、菝葜屬(Smilax spp.)等草藥等若干種植物中含有。薯蕷皂苷配基已報告為抗癌(Yan,
L.L等,Exp Oncol,31,pp.27-32,2009.)、抗食物過敏(Huang,C.H.等,Planta Med,75,pp.1300-1305,2009.)、半乳糖投藥引起的氧化壓力誘發性的記憶障礙的抑制效果(Chiu,C.S.等,Am J Chin Med,39,pp.551-563,2011.)及抗糖尿病性神經障礙(Kang,T.H.等,Biol Pharm Bull,34,pp.1493-1498,2011.)等。再者,已知有皮膚的美白效果(日本專利特表2010-535758號說明書),消除皺紋等皮膚改善(日本專利特表2009-501209號說明書,日本專利特開2007-016013號說明書),發毛效果(日本專利特開2006-273754號說明書)等效果。
在本發明可使用的薯蕷皂苷配基,只要不損失本發明的效果的範圍內沒有特別的限定,可為市售的化合物,或,亦可為以公知方法,本身公知方法或遵照該等的方法而製造的化合物,亦可為由天然物的萃取物。
在本發明中,薯蕷皂苷配基衍生物意指,可以成為薯蕷皂苷配基的等值物的化合物。薯蕷皂苷配基衍生物,可使用市售的化合物,或,亦可使用以公知方法,本身公知方法或遵照該等的方法製造的化合物,亦可使用由天然物的萃取物。例如,薯蕷皂苷配基衍生物,可為在薯蕷皂苷配基導入取代基,改換取代基的化學修飾而可達成的等值物,亦可為由天然物萃取的薯蕷皂苷配基配糖體(薯蕷素(dioscin)等)。
薯蕷皂苷配基衍生物而言,沒有特別的限定,例如,作為具體例可列舉薯蕷皂苷配基的C3位的羥
基被取代的化合物、在C2位有取代基的化合物(或C2位的氫原子被取代的化合物)、在C4位有取代基的化合物(或C4位的氫原子被取代的化合物)、在C6位有取代基的化合物(或C6位的氫原子被取代的化合物)、或該等的鹽等,例如,可列舉C3位的羥基的酯衍生物(例如,胺基酸衍生物、胺基磺酸衍生物、胺基甲酸酯衍生物),或C3位的羥基的鹵化衍生物等。
薯蕷皂苷配基衍生物(及其鹽)而言,例如,可舉下述式(I-1)代表的化合物及其鹽(藥學上可容許的鹽)等。
R1中,取代基而言,可列舉烴基{例如,烷基[例如,甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、戊基等直鏈或支鏈烷基(例如,C1-12烷基,理想是C1-8烷基)]、環烷基(例如,環戊基、環己基、環庚基、環辛基等C4-10環烷基、理想是C5-8環烷基)、芳烷基(例如,苯甲基、苯乙基等C6-10芳基C1-4烷基)、多環式
脂肪族烴基(例如,十氫萘基、降崁基、金剛烷基、二甲基金剛烷基等)等飽和或不飽和脂肪族烴基;芳基(例如,苯基、甲苯基、二甲苯基等C6-10芳基)等芳香族烴基}、含有雜原子(氮原子、氧原子、硫原子、磷原子等)之基團{例如,含有氧原子的基團[例如,羥基、側氧基(=O)、基-ORa、基-O-CO-Ra、基-O-CO-N(Rb)2、基-O-CO-O-Ra、基-O-CO-S-Ra、基-ORc、基-O-SO2-OH、基-O-PO2-OH、基-(ORd)k-Re、羧基、基-CO-O-Ra、基-CO-N(Rb)2等]、含有氮原子的基團[例如,胺基、基-NRaRb、基-NRb-CO-O-Ra、基-NRb-CO-N(Rb)2、含有氮之環狀基團(例如,對應於吡啶、二氫吡咯、吡咯、吲哚等的基團)等]、含有硫原子的基團[例如,巰基、基-SRa、基-S-S-Ra、磺醯基(-SO3H)、基-SO2-Rb、基-S-CO-N(Rb)2等]、含有磷原子的基團[例如,磷酸基(H2PO4-)、基-PO3H等]、胺基酸基[或胺基酸的殘基,例如,構成薯蕷皂苷配基的3位(對應於上述式中R1的取代位置)的羥基、與胺基酸(甘胺酸、丙胺酸等)的羧基以酯鍵形成的基團]等}、鹵原子(例如,氟原子、氯原子、溴原子、碘原子等)等。
又,在上述式中,分別地Ra是代表烴基(例如,烷基等前述例示的烴基等),Rb是代表氫原子或烴基(例如,烷基等前述例示的烴基),Rc代表糖(或糖鏈或糖的殘基),Rd代表伸烷基(例如,伸乙基、伸丙基、三亞甲基等的C2-4伸烷基基),Re代表氫原子、羥基或烴基(例如,烷基(甲基等)等前述例示的烴基),k代表2以上的整數(例如,2至10),
Ra及Rb可以是相同或不相同的基團,Rb有多數時,可相同或不相同。
在Ra及Rb中,烴基(烷基等)可再有取代基。取代基而言,沒有特別的限定,可列舉前述例示的取代基,例如,含有氧原子的基團(例如,羥基、羧基、基-ORa、基-O-CO-Ra等),含有氮原子的基團(例如,胺基、基-NRaRb),含有硫原子的基團(例如,巰基,基-SRa、磺醯基、基-SO2-Rb等)。
烴基可具有該等的取代基單獨或2種以上組合。
烴基有取代基、時,取代基的數是1以上即可,例如,可為1至10(例如,1至8),理想是1至6(例如,1至4),更理想是1至3程度。
R1是取代基時,代表性的R1,例如,可列舉烴基[例如,烷基(例如,基-(CH2)n-CH3)、環烷基、芳烷基等]、含有雜原子的基團{例如,含有氧原子的基團[例如,羥基、基-O-(CH2)n-CH3、基-O-(CH2)m-NH2、基-O-(CH2)m-COOH、基-O-(CH2)m-SO3H、基-O-CO-(CH2)n-CH3、基-O-CO-NH-(CH2)n-CH3、基-O-CO-NR-(CH2)n-CH3、基-O-CO-NH-CH(Rb)-COOH、基-O-(CH2)n-CO-NH-AD(式中,AD代表金剛烷基(1-金剛烷基、2,6-二甲基金剛烷-1-基等))、基-O-CO-NH-(CH2)m-SO3H、基-O-CO-NH-(CH2)m-COOH、基-O-CO-O-(CH2)n-CH3、基-O-CO-S-(CH2)n-CH3、基-O-SU(式中,SU代表糖鏈)、基-O-SO2-OH、基-O-PO2-OH、基-(OCH2CH2)m-CH3、基-(OCH2CH2CH2)m-CH3、羧基、基-COO(CH2)nCH3、基-CO-NH-
(CH2)n-CH3、基-SO3H、基-SO2-(CH2)n-CH3、基-SO2-Ph(式中,Ph是代表苯基。)、基-CO-NH-CH(Rb)-COOH、基-CO-NH-(CH2)n-SO3H等]、含有氮原子的基團[例如,胺基、基-NH-(CH2)n-CH3、基-NH-(CH2)n-NH2、基-NH-CH(Rb)-COOH、基-NH-(CH2)m-SO3H、基-NH-(CH2)m-SO2H、基-NH-CO-O-(CH2)n-CH3、基-NH-CO-NH2、基-NH-CO-NH-AD(式中,AD代表金剛烷基(1-金剛烷基、2,6-二甲基金剛烷-1-基等))、基-NH-CO-NH-CH(Rb)-COOH、基-NH-CO-NH-(CH2)m-SO3H、基-NH-CO-NH-(CH2)m-COOH等]、含有硫原子的基團[例如,巰基、基-S-(CH2)n-CH3、基-S-(CH2)m-COOH、基-S-(CH2)m-CH(NH2)-COOH、基-S-CO-NH-AD(式中,AD代表金剛烷基(1-金剛烷基、2,6-二甲基金剛烷-1-基等))、基-S-S-(CH2)m-CH(NH2)-COOH、基-SO3H等]、含有磷原子的基團[例如,基-PO3H等]、胺基酸基(例如,基-O-CO-CH2-NH2等)等}、鹵原子(例如,氟原子、氯原子、溴原子、碘原子等)等。
又,在上述式中,m代表1以上的整數(例如,1至10,理想是1至4,更理想是1或2),n代表0以上的整數(例如,0至10,理想是0至7),Rb是與前述相同[即,氫原子或烴基(例如,烷基等)]。
在R2、R3及R4中,取代基而言,可舉與在R1的項中所例示的取代基同樣的取代基。
R2及/或R4是取代基時,代表性的取代基而言,可舉含有氧原子的基團、含有氮原子的基團、含有硫原子的基
團、胺基酸基、鹵原子等。
又,R3是取代基時,代表性的取代基而言,可舉鹵原子等。
在式(I-1)中,R1至R4的組合,沒有限定,包含所有的組合。在代表性的R1至R4的組合,例如,可舉以下的組合等。
(1)R1是羥基以外的取代基,R2至R4是氫原子的組合
(2)R1是羥基以外的取代基,R2是取代基,R3及R4是氫原子的組合
(3)R1是羥基以外的取代基,R3是取代基,R2及R4是氫原子的組合
(4)R1是羥基以外的取代基,R2及R3是取代基,R4是氫原子的組合
(5)R1是羥基以外的取代基,R2、R3及R4是取代基的組合
(6)R1是羥基以外的取代基,R2及R3是氫原子,R4是取代基的組合
(7)R1是羥基以外的取代基,R3是氫原子,R2及R4是取代基的組合
(8)R1是羥基以外的取代基,R2是氫原子,R3及R4是取代基的組合
(9)R1是羥基,R2是取代基,R3及R4是氫原子的組合
(10)R1是羥基,R3是取代基,R2及R4是氫原子的組合
(11)R1是羥基,R2及R3是取代基,R4是氫原子的組合
(12)R1是羥基,R2至R4是取代基的組合
(13)R1是羥基,R2及R3是氫原子,R4是取代基的組合
(14)R1是羥基,R2是氫原子,R3及R4是取代基的組合
(15)R1是羥基,R3是氫原子,R2及R4是取代基的組合
薯蕷皂苷配基衍生物而言,沒有特別的限定,具體而言例如,可舉下述式(II)代表的(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯{(3 β,25R)-3-(2-Aminoethanoyloxy)-spirost-5-ene},及其藥學上可容許的鹽
或下述化學式(III)代表的(3 β,25R)-3-氟螺甾-烯{(3 β,25R)-3-Fluorospirost-5-ene}
以及,(3 β,25R)-3-(2-胺基乙基磺醯氧基)-螺甾-5-烯{(3 β,25R)-3-(2-Aminoethylsulfonyl-oxy)-spirost-5-ene},(3 β,25R)-3-(2-胺基丙基磺醯氧基)-螺甾-5-烯,(3 β,25R)
-3-[N-(2,6-二甲基金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯,(3 β,25R)-3-{[N-(2,6-二甲基金剛烷-1-基)胺甲醯基]胺基}-螺甾-5-烯,(3 β,25R)-3-[N-(2,6-二甲基金剛烷-1-基)胺甲醯基硫]-螺甾-5-烯,(3 β,25R)-3-{[N-(金剛烷-1-基)胺甲醯基]胺基}-螺甾-5-烯,(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯基硫基]-螺甾-5-烯,及(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯[或(3 β,25R)-3-(1-金剛烷基-胺基羰氧基)-螺甾-5-烯{(3 β,25R)-3-(1-adamantyl-aminocarbonyloxy)-spirost-5-ene}]等。
又,薯蕷皂苷配基衍生物(或其鹽),可使用市售品,也可使用以公知的方法合成的化合物。例如,在R1要導入取代基時,經由薯蕷皂苷配基本來有的羥基(3位的羥基)可導入種種的取代基。又,要在R2或R3導入鹵原子時,可採用將R1以側氧基取代(氧化),而將所產生的酮隣接的碳鹵化,進行R2或R3為鹵素(再者,視必要,而將側氧基改回羥基(還原))的方法等。再者,將鹵原子作為R4而導入時,可經由對不飽和鍵的求電子性的鹵化等而導入。再者,使用含有雜原子(氧原子、氮原子、硫原子等)的求核劑,也可導入種種的取代基。
在本發明中,「藥學上可容許的鹽」(或「鹽」),包含與薯蕷皂苷配基等形成藥學上可容許的鹽的化合物,沒有特別的限定。具體而言,例如可列舉鹵化氫酸鹽(例如氟化氫酸鹽、鹽酸鹽、溴化氫酸鹽、碘化氫酸鹽等)、無機酸鹽(例如硫酸鹽、硝酸鹽、過氯酸鹽、磷酸鹽、
碳酸鹽、碳酸氫鹽等)、有機羧酸鹽(例如乙酸鹽、草酸鹽、順丁烯二酸鹽、酒石酸鹽、反丁烯二酸鹽、檸檬酸鹽等)、有機磺酸鹽(例如甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、樟腦磺酸鹽等)、胺基酸鹽(例如天門冬酸鹽、麩胺酸鹽等)、有機胺鹽(例如,與三甲基胺、三乙基胺、吡啶、甲吡啶、二環己胺、N,N’-二苯甲基乙二胺、精胺酸及離胺酸等有機鹼的鹽)、四級胺鹽、鹼金屬鹽(例如鈉鹽、鉀鹽等)、鹼土金屬鹽(例如鎂鹽、鈣鹽等)等。
本發明的經口投藥劑中由薯蕷皂苷配基,薯蕷皂苷配基衍生物及該等的藥學上可容許的鹽選出的1種以上的化合物(以下,也簡稱為薯蕷皂苷配基等),懸浮於油脂為理想。本發明者等在本發明的檢討中發現,將薯蕷皂苷配基等懸浮於油脂,則出乎意料之外,由經口投藥所投藥的薯蕷皂苷配基等可得顯著的高藥效。
又,在本發明中「油脂」,在經口投藥時不需要呈液體的狀態,亦可為液體、半固體,或固體等狀態。又,在本發明中的油脂,包含食用油,及在醫藥品中的溶劑、賦形劑、乳化劑等所使用的油脂,以及油狀的醫藥品。
又,在本發明中,亦可使用將薯蕷皂苷配基等溶解於油脂的溶液。
在本發明可使用的食用油而言,只要不損失本發明的效果的話,沒有特別的限定,例如,可舉大豆油、菜籽油(油菜籽油、芥花油),高油酸菜籽油、玉米油、
胡麻油、胡麻沙拉油、白胡麻油、紫蘇油、亞麻仁油、落花生油、紅花油(紅花籽油)、高油酸紅花油、向日葵油、高油酸向日葵油、綿實油、葡萄籽油、澳洲胡桃油、榛子油、花生油、杏仁油、胡桃油、核桃油、南瓜子油、核桃油、檸檬油、苦茶油、茶實油、荏胡麻油、琉璃苣油(borage oil)、橄欖油、米油、米糠油、小麥胚芽油、棕櫚油、軟棕櫚油、棕櫚油硬脂、棕櫚核油、椰子油、椰子脂等植物油;牛脂、豬脂(lard)、雞脂、乳脂、魚油(例如,鰯油、鯖油、鱈油、鯨油、肝油等)等動物油,脂肪酸類(二十二碳六烯酸(DHA)、二十碳五烯酸(EPA)等),脂溶性維他命類(維他命A、維他命E等)等,在醫藥品中使用的油脂而言,上述食用油之外,可舉中鏈脂肪酸三甘油酯,碘化芥子脂肪酸酯等。該等可單獨,或可2種以上組合使用。
在本發明中,將薯蕷皂苷配基等與油脂懸浮的方法是沒有特別的限定,可為將化合物(水溶性化合物或脂溶性化合物)懸浮於油脂時所用的公知方法,亦可藉由本身公知的方法或遵照該等的方法而懸浮。具體而言,例如,在薯蕷皂苷配基等添加油脂,可藉由以均質機等攪拌而懸浮。
在本發明的1種態樣中,將薯蕷皂苷配基等懸浮於油脂的懸浮液中之薯蕷皂苷配基等與油脂的含有比率,只要能得到本發明的效果的話,沒有特別的限定。對油脂的單位容量(mL)的薯蕷皂苷配基等的莫耳量表示時,例如,通常,可以是約1nmol/mL至約1000nmol/mL,由提
高薯蕷皂苷配基等的生物可利用性的觀點等,理想是約10nmol/mL至約100nmol/mL。又,將薯蕷皂苷配基等溶解於油脂的溶液中的薯蕷皂苷配基等及油脂的含有比率也可作為同樣的值。
本發明的前述經口投藥劑,薯蕷皂苷配基等是只要懸浮在油脂,則其劑形沒有特別的限定,例如,可列舉液劑、懸浮劑、膠囊劑、軟性膠囊劑、錠劑、顆粒劑、散劑、糖漿劑、凝膠劑、口腔內崩壊錠、咀嚼錠等,該等是可由慣用的方法製造。
本發明的前述經口投藥劑,薯蕷皂苷配基等及油脂之外,視希望,也可以含有安定化劑、乳化劑、懸浮化劑、界面活性劑、pH調製劑、緩衝劑、防腐劑、著色料,香料、矯味矯臭劑等。
安定化劑而言,沒有特別的限定,例如,可列舉抗氧化劑(例如,抗壞血酸、生育酚、山梨酸、視網醇等),鉗合劑(例如,乙二胺四乙酸、檸檬酸、酒石酸等,及該等的鹽)等。
乳化劑而言,沒有特別的限定,例如,可列舉氯化苯二甲烴銨(benzalkonium chloride)、甘油、丙二醇、鯨醇、卵磷脂、羊毛脂、月桂硫酸鈉等。
懸浮化劑而言,沒有特別的限定,例如,可舉阿拉伯樹膠、氯化苯二甲烴銨、高嶺土、羧甲基纖維素(calmerose)、月桂硫酸鈉、月桂胺基丙酸、單硬脂酸甘油、聚乙烯醇、聚乙烯吡咯酮、羧甲基纖維素鈉、甲基纖維素、
羥甲基纖維素、羥乙基纖維素、羥丙基纖維素等。
界面活性劑而言,沒有特別的限定,例如,可列舉聚山梨糖醇酯(例如,聚山梨糖醇酯20、聚山梨糖醇酯40、聚山梨糖醇酯60、聚山梨糖醇酯65、聚山梨糖醇酯80等)、聚氧乙烯‧聚氧丙烯共聚物、聚氧乙烯硬化蓖麻油、去水山梨醇單硬脂酸酯、月桂硫酸鈉等。
緩衝劑而言,沒有特別的限定,例如,可列舉磷酸鹽、碳酸鹽、乙酸鹽、檸檬酸鹽、乳酸鹽等。
pH調節劑而言,沒有特別的限定,例如,可列舉鹽酸、磷酸等無機酸,及乙酸、檸檬酸、乳酸等有機酸、氫氧化鈉、氫氧化鉀、碳酸鈉等無機鹼基及葡甲胺(meglumine)、緩血酸胺(torometamol)等有機鹼基。
防腐劑而言,沒有特別的限定,例如,可列舉對羥基苯甲酸酯類、氯丁醇、苯甲醇、苯乙醇、脫氫乙酸、山梨酸等。
著色料而言,沒有特別的限定,例如,可列舉食用色素、β-胡蘿蔔素、核黃素等。
香料而言,沒有特別的限定,例如,可列舉檸檬油、橙油、薄荷醇、薄荷油等。
矯味矯臭劑而言,沒有特別的限定,例如,可列舉檸檬酸、己二酸、抗壞血酸、果糖、D-山梨醇、葡萄糖、糖精鈉、單糖漿、白糖、蜂蜜、八仙花、甘草、檸檬酸、己二酸、抗壞血酸、橙油、橙皮酊、茴香油、薄荷、薄荷醇等。
本發明的前述經口投藥劑的有效成分的薯蕷皂苷配基等,理想是有軸索的伸展及/或變性軸索的修復作用。
在SCIENTIFIC REPORTS,Volume 2,Number 535,pp1-11中,報告薯蕷皂苷配基藉由刺激1,25D3-MARRS促進軸索的伸展,由軸索的伸展作用,顯示記憶力的加強作用的效果。本發明所用的薯蕷皂苷配基等的作用,亦可為依據同樣的作用機制者。
在本發明的1種態樣中,前述經口投藥劑是軸索的功能不全相關的疾患的預防劑或治療劑。軸索的功能不全相關的疾患而言,沒有特別的限定,例如,可舉脊髄損傷、腦挫傷、AD(阿茲海默症)、巴金森病、認知症等。又,在本發明中,前述認知症是,不包含阿茲海默症,而包含腦血管性型認知症,路易體型認知症,前頭側頭型認知症,匹克氏病等。該等的疾患中,尤其是,AD或脊髄損傷的預防劑或治療劑為理想。
本發明的前述經口投藥劑的有效成分的薯蕷皂苷配基等的含有量,沒有特別的限定,設定為用於治療、改善、緩和、或恢復伴隨疾患的症狀足夠的用量為理想。
本發明的前述經口投藥劑的投藥量,例如可視投藥的對象的症狀的程度、年齡、性別、體重、投藥形態、鹽的種類、疾患的具體的種類等,而適宜選擇,沒有特別的限定,以投藥對象的單位體重的薯蕷皂苷配基等
的有效成分的莫耳量表示時,例如,通常,可以是約0.001至約1000μmol/kg/日,理想是約0.01至約10μmol/kg/日,較理想是0.01至約1μmol/kg/日。
尤其是,在本發明,以比較少的投藥量也可得到充分的效果。例如,在前述非專利文獻15及16中,投藥量作為10μmol/kg/日,但在本發明是,比該投藥量較少的投藥量,即,未達10μmol/kg/日(例如,5μmol/kg/日以下),理想是3μmol/kg/日以下(例如,0.001至2μmol/kg/日),更理想是1μmol/kg/日以下(例如,0.003至0.5μmol/kg/日),特別也可設定為0.3μmol/kg/日以下(例如,0.005至0.2μmol/kg/日)。
可以將上述投藥量,設定1日1次,或分成數次投藥。
本發明的前述經口投藥劑的投藥對象,沒有特別的限定,包含人類的哺乳動物為理想。包含人類的哺乳動物而言,沒有特別的限定,例如,可舉人類、猴、狒狒、黑猩猩、小鼠、大鼠、天竺鼠、倉鼠、兔、貓、狗、綿羊、山羊、豬、牛及馬等。
在本發明的1種方式中,前述經口投藥劑,可以併用已知的對軸索的功能不全相關的疾患的治療或預防有用的1種以上化合物,或其藥學上容許的鹽。
在本發明的1種理想態様中,軸索的功能不全相關的疾患是AD時,本發明的經口投藥劑,在薯蕷皂苷配基等之外,也可以含有已知對AD及其症狀的治療或預防有用的1種以上化合物。或者,在本發明的另1種理
想態樣中,本發明的經口投藥劑,也可以併用含有已知對AD及其症狀的治療或預防有用的1種以上化合物的醫藥組成物。
在併用時,其方式是沒有特別的限定,合劑、配合劑等也可以。
已知對前述AD及其症狀的治療或預防有用的的化合物而言,可列舉起因於類澱粉質β-(A β)的疾患,例如為了用於AD、老年性痴呆、唐氏綜合症或類澱粉變性症等的治療,有以下的機制的化合物。
具體而言例如,可列舉具有以下機制的化合物:膽鹼脂酶抑制劑(例如,多奈呱齊(donepezil)、石杉鹼甲(huperzine A)、塔克林(tacrine)、利凡斯的明(rivastigmine)、加蘭他敏(galantamine));AMPA受體拮抗劑(例如,3-(2-氰苯基)-5-(2-吡啶基)-1-苯基-1,2-二氫吡啶基-2-酮等1,2-二氫吡啶基化合物);NMDA受體拮抗劑(例如,美金剛胺(memantine));乙醯膽鹼放出刺激劑(例如,普拉西坦(pramiracetam);阿尼西坦(aniracetam));鈣離子通道促效劑(例如,奈非西坦(nefiracetam));自由基清除劑(例如,Egb 761);血小板活性因子拮抗劑(例如,Egb 761);血小板凝集拮抗劑(例如,EGb 761、三氟醋鉚酸(triflusal));胰島素敏化劑(例如,羅格列酮(rosiglitazone));過氧化體増殖因子-活化受體促效劑(例如,羅格列酮);過氧化體増殖因子-活化受體γ-促效劑(例如,羅格列酮);單胺氧化酶B抑制劑(例如,雷沙吉蘭(rasagiline)、司來吉蘭(selegiline)、
普魯卡因(procaine));肉鹼(carnitine)乙醯轉移酶刺激劑(例如,乙醯-L-肉鹼(levacecarnine));NSAIDs(例如,三氟醋鉚酸(triflusal)、希樂葆(celecoxib)等環氧化酶-2抑制劑(cyclooxygenase-2 inhibitors));神經成長因子促效劑(例如,扎利羅登(xaliproden)、FPF 1070);β-類澱粉質抑制劑(例如,他伏比爾(tarenflurbil)、高牛磺酸(tramiprosate)、柳普林(leuprorelin-D);免疫調節劑(例如、他伏比爾(tarenflurbil)、免疫球蛋白(immune globulin)、二十碳五烯酸酯(icosapentethyl ester));NF-κ B抑制劑(例如,他伏比爾(tarenflurbil));促甲狀腺激素(thyrotropin)釋放激素(例如,他替瑞林(taltirelin));多巴胺D2受體拮抗劑(例如,理思必妥(risperidone));血清素2受體(serotonin)拮抗劑(例如,理思必妥(risperidone));蕈鹼類受器M1受體(Muscarinic receptor M1)促效劑(例如,西維美林(cevimeline));α 1腎上腺素能受體促效劑(alpha 1 adrenergic receptor agonist)(例如,莫達菲尼(modafinil));血清素3受體拮抗劑(例如,阿洛司瓊(alosetron));多巴胺D2受體促效劑(例如,阿立哌唑(aripiprazole));多巴胺D2受體拮抗劑(例如,阿立哌唑(aripiprazole));血清素1A受體促效劑(例如,阿立哌唑(aripiprazole));血清素2A受體拮抗劑(例如,阿立哌唑(aripiprazole));糖皮質激素(glucocorticoids)拮抗劑(例如,米非司酮(mifepristone));助孕酮(progesterone)拮抗劑(例如,米非司酮(mifepristone));HMG-CoA還原酶抑制劑(例如,阿托伐他汀(atorvastatin)、辛伐他汀(simvastatin));腺
核苷攝取抑制劑(adenosine uptake inhibitor)(例如,丙戊茶鹼(propentofylline));磷酸二酯酶抑制劑(例如,丙戊茶鹼(propentofylline));乙醯膽鹼受體促效劑(例如,甘磷酸膽鹼(choline alfoscerate));膜透過增強劑(例如,甘磷酸膽鹼(choline alfoscerate));大麻鹼(cannabinoid)1受體拮抗劑(例如,利莫那班(rimonabant));大麻鹼受體促效劑(例如,屈大麻酚(dronabinol));血管形成抑制劑(例如,紫杉醇(paclitaxel));免疫抑制劑(例如,紫杉醇(paclitaxel));微管蛋白拮抗劑(tubulin antagonist)(例如,紫杉醇(paclitaxel));凝血脂素(thromboxane)A合成酶抑制劑(例如,三氟醋鉚酸(triflusal));抗氧化劑(例如,艾地苯(idebenone));腎上腺素性受體(adrenergic receptors)拮抗劑(例如,麥角溴烟酯(nicergoline));雌性素(estrogen)拮抗劑(例如,結合型雌性素(conjugated estrogen)、曲洛斯坦(trilostane));3-β-羥基類固醇脫氫酶抑制劑(例如,曲洛斯坦(trilostane));信號傳達路徑抑制劑(例如,曲洛斯坦(trilostane));褪黑激素(melatonin)受體促效劑(例如,雷美替胺(ramelteon));免疫刺激劑(例如,免疫球蛋白(immune globulin)、二十碳五烯酸酯(icosapentethyl ester)、普魯卡因(procaine));HIV侵入抑制劑(例如,普魯卡因(procaine));鈉通道拮抗劑(例如,普魯卡因(procaine));微細管抑制劑(例如,CPH 82);甘胺酸NMDA促效劑(例如,環絲胺酸);腺核苷A1受體拮抗劑(例如,KW 3902);三磷酸腺苷酶刺激劑(例如,三乙醯尿苷(ATPase));粒線體(mitochondria)功能增強劑(例如,三乙
醯尿苷);成長激素釋放因子促效劑(例如,替莫瑞林(tesamorelin));丁基膽鹼酯酶抑制劑(例如,比司諾昔絲林bisnorcymserine);腎上腺素性受體(adrenergic receptors)拮抗劑(例如,麥角溴烟酯(nicergoline));NO合成酶II型抑制劑(例如,阿倫酸(arundic acid));鉗化劑(例如,PBT 2);類澱粉質原纖維生成抑制劑(例如,TTP488、PF 4494700);血清素4受體促效劑(例如,PRX 03140);血清素6受體拮抗劑(例如,SB 742457);苯二氮平(benzodiazepine)受體逆促效劑(例如雷地奎尼(radequinil));鈣通道拮抗劑(例如,沙芬醯胺(safinamide));尼古丁受體促效劑(例如,異丙克蘭(ispronicline));或BACE抑制劑(例如,CTS 21166)等。
更具體的化合物而言,例如,可列舉西洛他唑(Cilostazol)、多奈呱齊(donepezil)、石杉鹼甲(huperzine A)、塔克林(tacrine)、利凡斯的明(rivastigmine)、加蘭他敏(galantamine)、普拉西坦(pramiracetam)、阿尼西坦(aniracetam)、奈非西坦(nefiracetam)、EGb761、羅格列酮(rosiglitazone)、雷沙吉蘭、乙醯-L-肉鹼(levacecarnine)、希樂葆(celecoxib)、3-(2-氰苯基)-5-(2-吡啶基)-1-苯基-1,2-二氫吡啶基-2-酮、他侖帕奈(talampanel)、貝坎帕奈(becampanel)、美金剛胺(memantine)、扎利羅登(xaliproden)、他伏比爾(tarenflurbil)、高牛磺酸(tramiprosate)、柳普林(leuprorelin-D)、他替瑞林(taltirelin)、理思必妥(risperidone)、西維美林(cevimeline)、莫達非尼(modafinil)、阿洛司瓊(alosetron)、阿立哌唑
(aripiprazole)、米非司酮(mifepristone)、阿托伐他汀(atorvastatin)、丙戊茶鹼(propentofylline)、甘磷酸膽鹼(choline alfoscerate)、FPF 1070(CAS No.143637-01-8)、利莫那班(rimonabant)、屈大麻酚(dronabinol)、二十二碳六烯酸(docosahexaenoic acid)、紫杉醇(paclitaxel)、三氟醋鉚酸(triflusa)1、艾地苯(idebenone)、麥角溴烟酯(nicergoline)、結合型雌性激素(conjugated estrogens)、曲洛斯坦(trilostane)、辛伐他汀(simvastatin)、司來吉蘭(selegiline)、雷美替胺(ramelteon)、免疫球蛋白(immune globulin)、二十碳五烯酸酯(icosapentethyl ester)、普魯卡因(procaine)、CPH 82、環絲胺酸、KW3902(CAS No.136199-02-5)、三乙醯尿苷、雌性激素失智症治療劑(estrogen dementia therapeutics)(例如,MIGENIX公司,溫哥華,加拿大))、替莫瑞林(tesamorelin)、比司諾昔絲林(bisnorcymserine)、麥角溴烟酯(nicergoline)、阿倫酸(arundic acid)、PBT 2、TTP488、PF 4494700、PRX 03140、SB 742457、雷地奎尼(radequinil)、沙芬醯胺(safinamide)、異丙克蘭(ispronicline)、CTS 21166、巴匹珠單抗(Bapineuzumab)、NP 031112、(2S、3aS、7aS)-1{[(R,R)-2-苯基環丙基]羰基}-2-[(四氫噻唑-3-基)羰基]八氫-1H-吲哚、西酞普蘭(citalopram)、文拉法辛(venlafaxine)、柳普林(levprorelin)、普拉雄酮(prasterone)、胜肽T(peptide T)(CAS No.53-43-0)、貝西吡啶(besipiridine)、來昔帕泛(lexipafant)、司他可茶鹼(stacofylline)、SGS 742(CAS No.123690-78-8)、T 588(CAS No.
142935-03-3)、尼利司吡啶(nerispiridine)、地塞米諾(dexanabinol)、沙可美林(sabcomeline)、GTS 21(CAS No.156223-05-1)、CX516(CAS No.154235-83-3)、ABT 089(CAS No.161417-03-4)、安波孛司(anapsos)、特索芬辛(tesofensine)、SIB 1553A(即,4-[[2-(1-甲基-基-2-吡咯啶基)乙基]硫雜]苯酚)、拉多替吉(ladostigil)、雷地奎尼(radequinil)、GPI 1485、異丙克蘭(ispronicline)、阿倫酸(arundic acid)、MEM 1003(即,3-異丙基5-(2-甲氧基)4-(2-氯-3-氰苯基)-2,6-二甲基吡啶基-3,5-二羧酶)、V3381(即,2-(2,3-二氫-1H-茚-3-基胺基)乙醯胺鹽酸鹽)、法蘭帕托(farampator)、帕利羅登(paliroden)、普拉雄酮-帕拉丁(prasterone-paladin)、尿皮質素(urocortin)、DP b99(即、2,2’-(乙烯二氧基)雙(2,1-伸苯基)雙[N-[2-[2-(辛氧基)乙氧基]-2-側氧乙基]亞胺基]雙(乙酸))、卡波昔羅德(capserod)、DU 125530、巴匹珠單抗(bapineuzumab)、AL 108(即,L-天門冬醯胺醯基-L-丙胺醯基-L-脯胺醯基-L-纈胺醯基-L-絲胺醯基-L-異白胺醯基-L-脯胺醯基-L-麩醯胺酸)、DAS 431、DEBIO 9902、DAR 100、米托蒽醌(mitoquinone)、IPL 455903(即,5(S)-[3-(環戊氧基)-4-甲氧基苯基]-3(S)-(3-甲基苯甲基)哌啶-2-酮)、E2CDS、PYM 50028、PBT 2、多甲藻素螢光素(lecozotan)、SB 742457、CX 717、AVE 1625(即,1-(雙(4-氯苯基)甲基)-3-((3,5-二氟苯基)(甲基磺醯基)亞甲基)四氫吖唉(azetidine)、LY 450139(即,N2-[2(s)-羥-3-甲基丁醯基]-N1-[3-甲基-2-側氧
基-2,3,4,5-四氫-1H-3-苯并氮雜卓-1(S)-基]-L-丙胺酸醯胺)、EM 1421(即、4,4’-[(2R,3S)-2,3-二甲基丁烷-1,4-二基]雙(1,2-二甲氧基苯)、SRN 001、TTP 488、PRX 03140、二甲弗林(dimebolin)、甘胺酸-脯胺酸-麩胺酸酯、C105、AL 208、MEM 3454、AC 1202、L 830982、LY 451395(即,(R)-N-[2-[4’-(甲基磺醯胺甲基)聯苯-4-基]丙基]丙烷-2-磺醯胺)、MK 0249、LY 2062430、二乙基降亞精胺(diethyl norspermine)、奈波胺(neboglamine)、S 18986、SA 4503(CAS No.165377-44-6)、GRI 1、S 17092(即,(2S,3aS,7aS)-1{[(R,R)-2-苯基環丙基]羰基}-2-[(四氫噻唑-3-基)羰基]八氫-1H-吲哚)、SL 251188、EUK 189、R 1450、6,6-二甲基-3-(2-羥乙基)硫-1-(噻唑-2-基)-6,7-二氫-2-苯并噻吩-4(5H)-酮、CERE 110、右依法克生(dexefaroxan)、CAD 106、HF 0220、HF 0420、EHT 0202、VP 025、MEM 1414、BGC 201259(即,N,N-二甲基胺甲酸、4-[1(S)-(甲基胺基)-3-(4-硝苯氧基)丙基]苯酯)、EN 100、ABT 834、ABT 239(即,4-[2-[2-[(2R)-2-甲基吡咯啶基]乙基]-苯并呋喃-5-基]苯甲腈)、SGS 518、R 1500、C 9138、SSR 180711、阿法雌二醇(alfatradiol)、R 1577、T 817MA(即,1-[3-[2-(1-苯并噻吩-5-基)乙氧基]丙基]四氫吖唉-3-醇順丁烯二酸鹽)、CNP 1061(即,4-甲基-5-(2-硝氧基乙基)噻唑)、KTX 0101(即,β-羥酪酸鈉)、GSK 189254(即,6-[3-環丁基-2,3,4,5-四氫-1H-苯并[d]吖呯(azepine)-7-基氧基]-N-甲基尼古丁醯胺)、AZD 1080、ACC 001、PRX 07034、咪達唑侖
(midazolam)、R-苯基絲胺酸(phenserine)、AZD 103(CAS No.488-59-5)、SN 522、NGX 267(CAS No.503431-81-0)、N-PEP-12、RN 1219、FGLL、AVE 8112、EVT 101、NP 031112、MK 0752、MK 0952、LX 6171、PAZ 417、AV 965、PF 3084014、SYN 114、GSI 953、SAM 315、SAM 531、D-絲胺酸、來普立寧鉀(leteprinim potassium)、BR 16A(CAS No.149175-77-9)、RPR 107393(CAS No.190841-57-7)、NXD 2858、REN 1654、CDD 0102、NC 1900(CAS No.132925-74-7)、環孢素(ciclosporin)、NCX 2216(即,(E)-4-(硝氧基)丁基3-[4-[2-(2-氟聯苯-4-基)丙醯氧基]-3-甲氧基苯基]丙烯酸酯)、NXD 3109、NXD 1191、ZSET 845(即,3,3-二苯基咪唑[1,2-a]吡啶基-2-(3H)-酮)、ET 002、NT 13、RO 638695(即,[1,6-(1,6-二側氧基己基)]二吡咯啶-(2R)-羧酸)、比司諾昔絲林(bisnorcymserine)、BA 1016、XD 4241、EUK 207(即,(SP-5-13)-(乙酸基-κ O)[13,16,19,22-四氧雜-3,6-二氮雜三環[21.3.18.12]二十八碳-1(27),2,6,8,10,12(28),23,25-八烯-27,28-二醇酯(2-)-κ N3,κ N6,κ O27,κ O28]鎂鹽)、LG 617抑制劑、ZSET 1446、PAN 811、F 14413(即,2-[5-氟-2(S)-甲氧基-2,3-二氫-1,4-苯并二噁烷-2-基]-4,5-二氫-1H-咪唑)、FP 7832(即,N-[2-(5-甲氧基-1-亞硝基-1H-吲哚-3-基)乙基]乙醯胺)、ARA 014418(即,N-(4-甲氧基苯甲基)-N’-(5-硝基-1,3-噻唑-2-基)脲)、AZD 3102、KP 544(即,2-胺基-5-(4-氯苯基乙炔基)-4-(4-反-羥環己胺基)嘧啶)、DP 155、5-氯-N-[3-[2-(二甲基胺基)乙基]-1H-吲
哚-5-基]萘-2-磺醯胺、TAK 070、石杉鹼(huperzine)、N-[2-(3,5-二甲基金剛烷-1-基)乙基]乙醯胺鹽酸鹽、6-[4-[(二甲基胺基)甲基]-5-乙基-2-甲氧基苯基]吡啶基-2-胺、4,6-二苯基-3-(4-(嘧啶-2-基)哌-1-基)嗒、N-[(1S,2R)-3-(3,5-二氟苯基)-1-羥基-1-[(5S,6R)-5-甲基-6-(新戊氧基)嗎福林-3-基]丙烷-2-基]乙醯胺鹽酸鹽、N-[(1R,2S)-3-(3,5-二氟苯基)-1-羥基-1-[(2R,4R)-4-苯氧基吡咯啶-2-基]丙烷-2-基]-3-[(R)-2-(甲氧基甲基)吡咯啶-1-羰基]-5-甲基苯甲醯胺、R 1589、米達福太(midafotel)、苯基絲胺酸(phennoserine)、考拉西坦(coluracetam)、毒扁豆鹼(physostigmine)、西拉利生(cipralisant)、硝基氟吡洛芬(nitroflurbiprofen)、PPI 1019(即,(3 α,5 β,7 α,12 α)-三羥基膽烷-24-醯基-L-白胺醯基-L-纈胺醯基-L-苯基丙胺醯基-L-苯基丙胺醯基-L-丙胺酸)、氨苯碸(dapsone)、MDL 100453(CAS No.129938-34-7)、NS 377、米達茶鹼(midaxifylline)、丙泊酚磷酸鹽(propofol phosphate)、美曲磷酯(metrifonate)、西羅普利(ceronapril)、替尼西坦(tenilsetam)、蘇弗沙嗪(sufoxazine)、司格列肽(seglitide)、依比拉肽(ebiratide)、奈拉西坦(nebracetam)、米拉醋胺(milacemide)、碘多柔比星(iododoxorubicin)、SM 10888(CAS No.129297-21-8)、U 80816(CAS No.138554-11-7)、YM 954(CAS No.132041-85-1)、SUT 8701(CAS No.123577-73-1)、阿撲長春胺(apovincamine)、FR 121196(CAS No.133920-65-7)、LY 274614(CAS No.
136109-04-1)、CL 275838(CAS No.115931-65-2)、伊格美新(igmesine)、K 7259(CAS No.133667-88-6)、長春考酯(vinconate)、伊他司瓊(itasetron)、CL 287663(CAS No.125109-98-0)、WAY 100289(CAS No.136013-69-9)、SR 46559A(CAS No.137733-33-6)、GYKI 46903(CAS No.142999-59-5)、L 670548(CAS No.121564-89-4)、Y 29794(CAS No.129184-48-1)、AF 125(CAS No.7631-86-9)、KFM 19(CAS No.133058-72-7)、ST 796(即,(S)-3-[3-(三氟甲基)苯甲醯基)胺基]六氫吖呯(azepine)-2-酮)、RU 33965(CAS No.122321-05-5)、SDZ 210086(即,(-)-1’,2(S)-二甲基螺[1,3-二噁烷-4,4’-哌啶])、L 689660(CAS No.144860-79-7)、L 689560(CAS No.139051-78-8)、ST 618(即,1-(6,7-二甲氧基-1,2,3,4-te四氫-2-萘基)-4-羥基吡咯啶-2-酮)、U 74500A(CAS No.110101-65-0)、GEA 857(CAS No.120493-42-7)、BIBN 99(CAS No.145301-48-0)、DX 9366、ONO 1603(CAS No.114668-76-7)、MDL 102234(CAS No.137766-81-5)、P 9939(CAS No.157971-37-4)、PD 140532(CAS No.157971-39-6)、氮替瑞林(azetirelin)、MR 16728(CAS No.147614-21-9)、達貝洛汀(dabelotine)、MDL 102503(即,8-[1(R)-甲基-2-苯基乙基]-1,3-二丙基-7H-黃嘌呤)、PD 141606(即,(±)-(Z)-3-(3-苯基-2-丙炔基氧基亞胺基)-1-氮雜雙環[2.2.1]庚烷)、SNK 882(CAS No.152221-12-0)、L 696986(CAS No.141553-45-9)、他唑美林(tazomeline)、LY 235959(CAS No.137433-06-8)、2-(2-硫酮基吡咯啶-1-基)乙醯胺、
AK 30 NGF、ABT 418(CAS No.147402-53-7)、依他美林(itameline)、HUP 13、西波吡啶(sibopirdine)、KST 5452(CAS No.157998-88-4)、TJ 54、U 92798(即,7-[4-[雙(4-氟苯基)甲基]全氫-1,4-二吖呯(azepine)-1-基甲基]-4-異丙基-2-甲氧基-2,4,6-環庚三烯-1-酮)、U 92032(CAS No.142223-92-5)、3-(胺磺醯氧基)雌甾烷-1,3,5(10)-三烯-17-酮、P 11012(CAS No.164723-36-8)、A 82695(CAS No.147388-86-1)、FR 76659(CAS No.116904-25-7)、阿帕茶鹼(apaxifylline)、CX 417、7MEOTA(CAS No.5778-80-3)、BU 4514N(CAS No.151013-39-7)、妊烯醇酮(pregnenolone)、美昔得樂(mexidol)、ST 857(CAS No.154755-63-2)、RU 49041(CAS No.123828-80-8)、RU 35929(CAS No.111711-47-8)、P 878184、P 128(CAS No.157716-52-4)、泛溫他汀A(eurystatin A)、泛溫他汀B(eurystatin B)、LK 12、NBI 108、NBI 107、NBI 117、L 705106、假馬齒莧皂苷(bacoside A+B)、黃皮醯胺(Clausenamide)、SM 21(CAS No.155156-22-2)、阿萊肽(alaptide)、RS 17017(即,1-(4-胺基-5-氯-2-甲氧基苯基)-5-(1-哌啶基)-1-戊酮鹽酸鹽)、AF 150(S)(即,(S)-[1-甲基-哌啶-4-螺-(2’-甲基噻唑啉)])、RO 153505(CAS No.78771-13-8)、PV 113(即,1,2,3,4-四氫吡咯-[1,2-a]-吡)、阿利蘇加辛(arisugacin)、A 98284(即,2(R)-(3-甲基噁唑-5-基)醌啶)、AP5(CAS No.136941-85-0)、BD 1054、SDZ NDD 094(即,雙-(2-(2-甲基咪唑-1-基]甲基)-吡啶-三(氫-反丁烯二酸鹽)、AZ 36041(CAS No.173324-76-0)、喹洛斯的明
(quilostigmine)、A 84543(即,3-[1-甲基吡咯啶-2-(S)-基甲氧基]吡啶基反丁烯二酸鹽)、BTG 4247(即,(2-[2-氯乙氧基[4-(二甲基胺基)苯基]磷醯基]-乙醯肼)、CGP 50068(CAS No.158647-49-5)、希來波洛司特(cerebrocrast)、去鐵-降達諾沙敏(desferri-nordanoxamine)、異地衣多糖(isolichenan)、MHP 133(即,3-(N,N-二甲氧基胺甲醯氧基)-1-甲基-2-(4-苯基-半卡腺基甲基)吡啶鎓氯化物)、FR 152558(CAS No.151098-08-7)、GVS 111(CAS No.157115-85-0)、P 11149(CAS No.164724-79-2)、PDC 008004、KST 2818(CAS No.158623-26-8)、KST 5410(CAS No.158623-27-9)、RU 52583(CAS No.123829-33-4)、PD 151832(CAS No.149929-39-5)、UCL 1199(即,4-[2-[(5-硝吡啶基-2-基硫烷基)乙基]-1H-咪唑)、異香藍石杉鹼甲(isovanihuperzine A)、SIB 1765F(CAS No.179120-52-6)、JWS USC 751X(即,3-[[[2-[[(5-二甲基胺基乙基)-2-呋喃基]甲基]硫基]乙基]胺基]-4-硝嗒)、GR 175737(即,3-(4-氯苯甲基)-5-[2-(1H-咪唑-4-基)乙基]-1,2,4-噁噻唑)、KS 505A(CAS No.131774-53-3)、ZTTA 1(即,N-苯甲氧羰基-硫丙基-硫丙醛基-二甲基縮醛)、AGN 190837(CAS No.136527-40-7)、P 10358(188240-59-7)、WAY 131256(CAS No.174001-71-9)、DBO 83(即,3-(6-氯吡-3-基)-二氮雜雙環[3.2.1]辛烷二鹽酸鹽一水和物)、FUB 181(CAS No.152029-80-6)、RJR 2557、WSU 2088、LVV血啡肽-7(LVV-haemorphin-7)、M 40(即,加拉寧(galanin)[1-12]-Pro3-(Ala-Leu)2-Ala-NH2)、SIB 1757、SKF 74652(即,[5-氯-2-(4-
甲氧基苯基)-3-苯并呋喃基][4-[3-(二甲基胺基)-丙氧基]苯基]甲酮)、CGP 71982、SCH 57790(即,4-環己基-α-[4-[[4-甲氧基苯基]亞磺醯基]苯基]-1-哌乙腈)、腐胺-D-YiA β 11(Putrescine-D-YiAbeta11)、DU 14(即,p-O-(胺磺醯基)-N-四癸醯基酪胺)、CLZ 4、SL 340026、PPRT 424、西普洛昔芬(ciproxifan)、UR 1827(即,2-(1-苯甲哌啶-4-基)-1-[4-(5-甲基嘧啶-4-基胺基)苯基]-1-乙酮)、開普洛他敏(caproctamine)、TGS 20(即,L-焦麩胺酸-D-丙胺酸醯胺)、PG9(即,2-[(4-溴)苯基]丙酸α-莫著烷(tropanyl)酯)、TEI 3356(即,(16S)-15-去氧-16-羥基-16-甲基-9-(O)-甲基-DELTA6(9 α)-前列腺素I1)、LY 392098(即,噻吩、3-[(2-甲基乙基-2)磺醯基胺基丙基-2]苯基-4-基-)、PG 1000、DM 232、NEPP 11(即,12-異-15-去氧-18-(4-甲基)苯基-13,14-二氫-δ 7-前列腺素A1甲基酯)、VA 100(即,(2,3-二氫-2-[[(4-氟苯甲醯基)胺基]乙基]-1-甲基-5-苯基-1H-1,4-苯二氮平)、VA 101(即,(2,3-二氫-2-[[(2-乙炔羰基)胺基]乙基]-1-甲基-5-苯基-1H-1,4-苯二氮平)、NC 111585(即,(3S)-1,3-雙-[3-[(3-氮雜雙環[2.2.2]辛基)-1,2,5-噻二唑-4-基氧]-1-丙炔-1-基]苯、2L-(+)-酒石酸鹽)、IN 201、依莫普洛昔芬(imoproxifan)、肯諾可二醇(kanokodiol)、胡黃連苷I(picroside I)、胡黃連苷II、DM 235(即,1-(4-苯甲醯基哌-1-基)丙烷-1-酮)、單株抗體10D5、JLK2、JLK 6、JLK 7、DAPT(即,N-[N-(3,5-二氟酚乙醯)-L-丙胺基]-S-苯基甘胺酸三級丁酯)、石杉鹼X(huperine X)、
SGS 111(即,(S)-乙基2-[1-(2-苯基乙醯基)吡咯啶-2-羧醯胺]乙酸酯)、NP 7557、C 9136、C 7617、R 1485、羅菲可西保(rofecoxib)、維吖啶(velnacrine)、孟替瑞林(montirelin)、拉扎貝胺(lazabemide)、ORG 2766(CAS No.50913-82-1)、沙貝鲁唑(sabeluzole)、金剛芬酯(adafenoxate)、CAS No.9061-61-4、伊匹達克林(ipidacrine)、貝美司瓊(bemesetron)、咪唑克生(idazoxan)、利諾吡啶(linopirdine)、塞福太(selfotel)、舒立托唑(suritozole)、米拉美林(milameline)、占諾美林(xanomeline)、TJ 960、法索西坦(fasoracetam)、依斯的明(eptastigmine)、恩沙庫林(ensaculin)、扎那哌齊(zanapezil)、泊替瑞林(posatirelin)、扎考必利(zacopride)、RS 86(CAS No.3576-73-6)、ORG 5667(CAS No.37552-33-3)、RX 77368(CAS No.76820-40-1)、BMS 181168(CAS No.123259-91-6)、BY 1949(CAS No.90158-59-1)、AWD 5239(CAS No.109002-93-9)、YM 796(171252-79-2)、阿洛西坦(aloracetam)、CI 933(CAS No.91829-95-7)、ST 793(CAS No.99306-37-3)、西巴西坦(cebaracetam)、齊羅矽酮(zifrosilone)、他沙利定(talsaclidine)、阿伐美林(alvameline)、JTP 2942(148152-77-6)、OPC 14117(CAS No.103233-65-4)、依齊維林(elziverine)、AP 521(即,N-(1,3-苯并二噁唑-5-基甲基)-1,2,3,4-四氫[1]苯并噻吩基[2,3-c]吡啶-3(R)-羧醯胺鹽酸鹽)、S8510(CAS No.151466-23-8)、JTP 4819(CAS No.162203-65-8)、艾考哌齊(icopezil)、SC 110、FK 960(CAS No.133920-70-4)、DMP 543(CAS No.
160588-45-4)、更斯的明(ganstigmine)、CI 1017(即,(R)-(-)-(Z)-1-氮雜雙環[2.2.1]庚烷-3-酮、O-(3-(3’-甲氧基苯基)-2-丙醯基)-肟順丁烯二酸)、T82(即,2-[2-(1-苯甲哌啶-4-基)乙基]-2,3-二氫-9-甲氧基-1H-吡咯并[3,4-b]喹啉-1-酮1/2反丁烯二酸鹽)、NGD 971、天門冬胺醯基-丙胺醯基-麩胺醯基-苯基丙胺醯基-精胺醯基-組胺醯基-天門冬胺醯基-絲胺醯基-甘胺醯基酪胺醯基-麩胺醯基-纈胺醯基-組胺醯基-組胺醯基-麩醯胺醯基-離胺醯基-白胺醯基-纈胺醯基-苯基丙胺醯基-苯基丙胺醯基-丙胺醯基-麩胺醯基-天門冬胺醯基-纈胺醯基-甘胺醯基-絲胺醯基-天門冬醯胺醯基-離胺醯基-甘胺醯基-丙胺醯基-異白胺醯基-異白胺醯基-甘胺醯基白胺醯基-甲硫胺醯基-纈胺醯基-甘胺醯基-甘胺醯基-纈胺醯基-纈胺醯基-異白胺醯基-丙胺酸的疫苗、PBT 1(CAS No.130-26-7)、TCH 346、FK 962(即,N-(1-乙醯哌啶-4-基)-4-氟苯甲醯胺)、伏高利特(voxergolide)、KW 6055(CAS No.63233-46-5)、硫代匹鲁卡品、ZK 93426(CAS No.89592-45-0)、SDZ NVI 085(CAS No.104195-17-7)、CI 1002(CAS No.149028-28-4)、Z321(CAS No.130849-58-0)、米立司瓊(mirisetron)、CHF 2060(即,N-庚基胺甲酸2,4a,9-三甲基-2,3,4,4a,9,9a-六氫-1,2-噁并[6,5-b]吲哚-6-基酯-L-酒石酸鹽)、吉多卡爾(gedocarnil)、特貝喹尼(terbequinil)、HOE 065(CAS No.123060-44-6)、SL 650102、GR 253035、ALE 26015、SB 271046(即,5-氯-N-(4-甲氧基-3-哌-1-基-苯基)-3-甲基
-2-苯并噻吩磺醯胺)、iAbeta5、SCH 211803(即,3-氯苯基[4-[1-[1-(2-胺基-3-甲基苯甲醯基)-4-哌啶基]-4-哌啶基甲基]苯基]碸)、EVT 301、α-次亞麻油酸/亞麻油酸、加味歸脾湯(Kamikihi-To)、西高苷(siagoside)、FG 7142(CAS No.78538-74-6)、RU 47067(CAS No.111711-92-3)、RU 35963(CAS No.139886-03-6)、FG 7080(CAS No.100332-18-1)、E 2030(CAS No.142007-70-3)、轉化生長因子-β-1(transforming growth factor beter-1)、A 72055(即,2’,1-二甲基螺[哌啶-4,5’-噁唑啶]-3’-甲醛)、NS 626、地來西坦(dimiracetam)、GT3001、GT2501、GT2342、GT 2016(CAS No.152241-24-2)、ORG 20091(CAS No.141545-50-8)、BCE 001(CAS No.95678-81-2)、CGP 35348(CAS No.123690-79-9)、WAY 100635(CAS No.146714-97-8)、E 4804(CAS No.162559-34-4)、LIGA 20(CAS No.126586-85-4)、NG 121(即,2-[4,8-二甲基-3(E),7(E)-壬二烯基]-3,5-二羥基-2-甲基-3,4,7,9-四氫-2H-氟[3,4-h]-1-苯并吡喃-7-酮)、MF 247(即,N-[10-(二甲基胺基)癸基]胺甲酸(3aS,8aR)-1,3a,8-三甲基-1,2,3,3a,8,8a-六氫吡咯基[2,3-b]吲哚-5-基酯)、JTP 3399(即,N-苯甲-2(S)-[2(S)-(苯氧基乙醯)吡咯啶-1-基羰基]吡咯啶-1-羧醯胺)、KF 17329、硫丙咪胺(thioperamide)、F 3796(即,1-[2-(1-苯甲哌啶-4-基)乙基]-3-[3,4-(亞甲基-二氧基)苯甲醯基]硫脲)、GT 4001、GT 4002、FPL 14995(CAS No.123319-03-9)、RU 34332(CAS No.137157-58-5)、SR 96777A(CAS No.115767-94-7)、SIB T1980、NS 649(CAS No.
146828-02-6)、PD 142505(CAS No.149929-08-8)、GYKI 52466(CAS No.102771-26-6)、RO 246173(CAS No.159723-57-6)、SCH 50911(CAS No.160415-07-6)、Z 4105(CAS No.119737-52-9)、RS 67333(CAS No.168986-60-5)、NS 1546、ZM 241385(CAS No.139180-30-6)、RO 249975(即,[1S,3S(2’S),5R]-3-(1-苯甲基-5-側氧基吡咯啶-2-基甲基)-5-(1H-咪唑-5-基甲基)環己烷-1-乙醯胺)、AF 185(即,8-甲基-3-(2-丙炔基)-1,3,8-三氮雜螺[4,5]癸烷-2,4-二酮)、CEP 427、CX 423、CX 438、CX 480、CDP-乙醇胺、GT 4003、GT 4011、GT 5011、MS 430(CAS No.122113-44-4)、MBF 379(即,[3,3-雙(羥甲基)-8-羥基-3,4-二氫-2H-1,4-苯并噁-5-基][3’,5’-二羥基-4’-(2-側氧基-2-苯基乙氧基)苯基]甲酮)、NGD 187(CAS No.163565-48-8)、DUP 856、MR 3066、MF 8615(即,5-胺基-6-氯-4-羥基-3,4-二氫-1H-噻喃并-[3,4-b]喹啉)、喜巴辛(himbacine)、ABS 300、RJR 2403(CAS No.538-79-4)、MF 268(CAS No.174721-00-7)、RO 465934(即,N,N-二甲基胺甲酸3-(2-環己基)-2,3,3a,4,5,9b-六氫-1H-苯并[e]吲哚-6-基酯)、NS 393、RGH 2716(CAS No.134069-68-4)、WIN 678702(12、12-雙(3-呋喃基)-6,11-二氫-6,11-乙基苯并[b]喹嗪鎓氯化物)、RS 66252(即,1-丁基-2-[(2’-(2H-四唑-5-基)-聯苯-4-基)甲基]-1H-吲哚-3-羧酸)、AIT 034(CAS No.138117-48-3)、NG 012(CAS No.131774-53-3)、PD 142012(CAS No.5778-84-7)、GT 4054、GT 4077、GT 4035、P 26(CAS No.152191-74-7)、RGH 5279
(即,(-)-(13aR,13bS)-13a-乙基-2,3,5,6,13a,13b-六氫-1H-吲哚基[3,2,1-de]吡啶基[3,2,1-ij][1,5]萘啶-12-羧酸2-乙醯氧基乙基酯)、AIT 083、CeNeS、雌甾烷二醇(即,1,3,5(10)-雌甾烷三烯-3,17-β-二醇)、WAY 132983((3R,4R)-3-(3-六硫烷基吡-2-基氧基)-1-氮雜雙環[2.2.1]庚烷鹽酸鹽)、ABS 205、ABS 401、SX 3507(即,3-(3-丙基-1,2,4-噁二唑-5-基)喹啉-2(1H)-酮)、ARR 17779(即,(-)-螺[1-氮雜雙環[2.2.2]八烯-3,5-噁唑啶]-2-酮)、XE 991(即,10,10-雙(4-吡啶基甲基)蒽-10(9H)-酮)、苯乙基降昔絲林(phenethylnorcymserine)、RO 657199、RJR 1781(即,R(+)-2-(3-吡啶基)-1-氮雜雙環[2.2.2.]辛烷)、RJR 1782(即,S(-)-2-(3-吡啶基)-1-氮雜雙環[2.2.2.]辛烷)、吉拉肽(gilatide)、脫色林(tolserine)、TC 2559(即,(E)-N-甲基-4-[3-(5-乙氧基吡啶基)基]-3-丁烯-1-胺)、ER 127528(即,1-(3-氟苯甲基)-4-[(2-氟-5,6-二甲氧基-1-二氫茚酮-2-基)甲基]哌啶鹽酸鹽)、噻脫色林(thiatolserine)、塔加西普特(targacept)、阿克索尼克斯(axonyx)、昔絲林(cymserine)、噻昔絲林(thiacymserine)、單株抗體266、Apan-CH、DP 103、SPI 339(即,4-[3-(4-側氧基-4,5,6,7-四氫吲哚-1-基)丙醯基胺基]安息香酸乙酯)、S 37245(即,4-(1,4-苯并二噁烷-5-基)-1-[3(S)-羥基-5-硝基-二氫茚-2-基]-哌)、LLG 88、AZD 2858、緩血酸胺(trometamol)、AN 240、NG 002(即,5-羥基-5-(2-羥基-1-甲基乙基)-4-甲氧基呋喃-2(5H)-酮)、UCB 29427(即,2-環丙基-4-(環丙基胺基)-6-(N-嗎啉基)-1,3,5-三
)、TRH-SR、RO 401641(CAS No.122199-02-4)、MPV 1743AIII(CAS No.150586-64-4)、IDRA 21(CAS No.22503-72-6)、CEP 431、ACPD(CAS No.67684-64-4)、CT 3577(即,3,7-二甲基-1-[11-(3,4,5-三甲氧基苯甲胺基)-11-側氧十一碳基]黃嘌呤)、CT 2583、NXD 9062、去鐵-降達諾沙敏(Desferri-nordanoxamine)、DP b99、PBT 1、T 817MA、阿法雌二醇(Alfatradiol)(CAS No.57-91-0)、AL 108、SL 650102、RS 67333(CAS No.168986-60-5)、RS 17017、SGS 518、SYN 114、SB 271046、RO 657199、PRX 07034、舒立托唑(Suritozole)(CAS No.110623-33-19)、特貝喹尼(Terbequinil)(CAS No.113079-82-6)、FG 7142(CAS No.78538-74-6)、RU 34332(CAS No.137157-58-5)、SX 3507、RO 153505(CAS No.78771-13-8)、RU 33965(CAS No.122321-05-5)、S8510(CAS No.151466-23-8)、沙貝鲁唑(Sabeluzole)(CAS No.104383-17-7)、希來波洛卡司特(Cerebrocrast)(CAS No.118790-71-9)、NS 626、NS 649(CAS No.146828-02-6)、U 92032(CAS No.142223-92-5)、MEM 1003、U 92798、RGH 2716(CAS No.134069-68-4)、沙芬醯胺(Safinamine)(CAS No.133865-89-1)、AZD 0328、MEM 63908、ABT 418(CAS No.147402-53-7)、ARR 17779、RJR 2403(CAS No.538-79-4)、TC 2559、A 82695(CAS No.147388-86-1)、A 84543、A 98284、DBO 83、RJR 2557、SIB 1765F(CAS No.179120-52-6)、GTS 21(CAS No.156223-05-1)、MEM 3454、SIB 1553A、EVP 6124、SSR 180711、
ABT 089(CAS No.161417-03-4)、ABT 107、ABT 560、TC 5619、TAK 070、N-[(1S,2R)-3-(3,5-二氟苯基)-1-羥基-1-[(5S,6R)-5-甲基-6-(新戊氧基)嗎啉-3-基]丙烷-2-基]乙醯胺鹽酸鹽、6-氟-5-(2-氟-5-甲基苯基)-3,4-二氫吡啶、2-胺基-6-[2-(3’-甲氧基聯苯-3-基)乙基]-3,6-二甲基-5,6-羥嘧啶-4(3H)-酮、AZD 1080、ARA 014418、XD 4241、Z 321(CAS No.130849-58-0)、ONO 1603(CAS No.114668-76-7)、JTP 3399、泛溫他汀A(Eurystatin A)(CAS No.137563-63-4)、泛溫他汀B(Eurystatin B)(CAS No.137563-64-5)、P 128(CAS No.157716-52-4)、Y 29794(CAS No.129184-48-1)、ZTTA 1、JTP 4819(CAS No.162203-65-8)、單株抗體266、度洛西汀(duloxetine)、草酸依地普侖(escitalopram oxalate)、氟西汀(fluoxetine)、馬來酸氟伏沙明(fluvoxamine maleate)、帕羅西汀(paroxetine)、舍曲林(sertraline)、達泊西汀(dapoxetine)、去甲文拉法辛(desvenlafaxine)、西布曲明(sibutramine)、奈法唑酮(nefazodone)、米那普侖(milnacipran)、地昔帕明(desipramine)、度洛西汀(duloxetine)、或比西發定(bicifadine)等。
本發明的組成物,視所希望,可以含有有效成分的1種以上的單位劑形的包裝物(pack)或分配器(dispenser)裝置等的容器的套組(kit)的形狀提供。
本發明,也可個別的藥劑組成物組合成為套組的形態。該套件可以含有2種類或更多的個別的藥劑組成物。例如,包含本發明的化合物與已知對AD的治療
或預防有用的1種以上的化合物,及/或本發明的化合物及AD以外的治療上有顯現藥效的化合物。該套組,通常,例如包含分割式瓶(separable bottle)或分割式箔封包(foil paket)等,含有個別的組成物的容器,但個別的組成物也可收容於單一的非分割式容器。套組形係將個別的成分以不同的投藥形(例如,經口或非經口的)投藥為理想的情況時,將個別的成分以不同的投藥間隔投藥的情況時,或有需要經處方醫師將組合的個別的成分滴定的情況時,尤其有用。
包裝物是,例如,可包含金屬或塑膠箔,例如泡罩包裝物(blister pack)。泡罩包裝物是在包裝業界周知的,在製藥的單位投藥形(錠劑膠囊等)的包裝物廣泛被利用。泡罩包裝物一般而言,以透明的塑膠材料箔被覆的比較硬質材料的薄片所成的為理想。包裝物處理過程中,該塑膠箔中形成凹陷。該等的凹陷,與受包裝的個別的膠囊等的大小及形狀配合。其次將膠囊等放入於凹陷中,在有形成凹陷的方向相反的箔面,將比較硬的硬質材料的薄片對塑膠箔密封。其結果膠囊等是在該塑膠箔與該薄片之間的凹陷中密封。薄片的強度是在凹陷處以手在凹陷加壓而在薄片上形成開口,而可將膠囊等能由泡罩包裝物取出的強度為理想。可將錠劑或膠囊由前述開口取出。
包裝或分配器裝置,可以附上為了投藥的附帶文件,產品包裝物說明書(product package insert)。可適應於管理包裝或分配器等的容器,醫藥的製造,使用或
販賣的政府機關、當局的通告。
在本發明的1種態樣中,前述經口投藥劑,可為軸索的伸展劑及/或變性軸索的修復劑。理想地,經由上述的薯蕷皂苷配基等的作用機制,而發揮軸索的伸展劑及/或變性軸索的修復作用。在本態樣中,軸索的伸展劑及/或變性軸索的修復劑的投藥量、投藥對象,與上述同樣即可。
又,化合物的軸索的伸展,或變性軸索的修復作用,通常可以使用在該領域所使用的公知方法,本身公知的方法或遵照該等的方法而評估。具體而言,例如,可由以下的方法測定:將各小鼠麻酔,以經冷卻的生理食鹽水經心臓灌流。依照常法,將該小鼠的腦慎重地由頭蓋骨拿出,即刻浸漬於10至30%(w/v)蔗糖-PBS,在-80℃保存。將腦使用低溫恆溫器(CM3050S,Leica公司,海德堡,德國)頭頂領域(前囟(bregma)1.4-2mm)的部位內每隔100μm,切出20μm的連續冠狀切片。將切片使用4%(w/v)聚甲醛(paraformaldehyde)/(0.1mol/L)磷酸緩衝液固定,對A β(1-40/42)(1:300)的多株抗體(Chemicon,Temecula,California,USA),對pNF-H(1:500)的單株抗體(Covance,Emeryville,California,USA),在4℃染色20小時。作為二次抗體,使用Alexa Fluor 488標識山羊抗小鼠IgG抗體(1:300)及Alexa Fluor 568標識山羊抗兔抗體(1:300)(Molecular Probes公司,Eugene,Oregon,USA)。軸索及A β(1-40/42)的螢光影像是,使用螢光顯微鏡(BX61),攝影
每張324μm×430μm的影像。由小鼠為了定量而切出前額葉的3個連續的腦切片及海馬區的5個連續腦切片。細胞外類澱粉質斑是由大小(比50μm較大的寬度)決定,將其面積使用影像解析軟體ImageJ(http://rsbweb.nih.gov/ij)測定。軸索的伸展是將pNF-H陽性的纖維狀的軸索的長度,使用Neurocyte(倉敷紡績,大阪)或者,Metamorph(Molecular Device,Sunnyvale,CA,USA)測定。變性軸索的測定是限定於類澱粉質斑的內側的領域內,將pNF-H陽性的球狀軸索的面積,使用ImageJ定量而實施,評估變形軸索的修復。
更具體的軸索的伸展或修復的測定方法,例如,可參考Tohda C,Urano T,Umezaki M,Nemere I,Kuboyama T,Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice.Sci.Rep.,2,535;DOI:10.1038/srep00535(2012)等的說明。
本發明的另1種態樣是關於含有本發明的經口投藥劑的飲食品、飼料、食品添加劑、或飼料添加劑等。
下面說明本發明的前述飲食品。
本發明的前述飲食品,可添加一種以上的一般用於飲食品的食品添加劑,例如甜味料、著色料、保存料、増粘安定劑、抗氧化劑、發色料、漂白料、防黴劑、膠基劑、苦味料、酵素、光澤劑、酸味料、調味料、乳化劑、強化
劑、製造用劑、香料、香辛料萃取物等。又,在本發明的前述飲食品中,包含健康食品、功能性食品、特定保健用食品、乳兒用食品、幼兒用食品、妊產婦用食品、高齡者用食品、病患用食品等。
本發明的前述飲食品的形態,沒有特別的限定。具體而言,例如,可列舉所謂作為營養輔助食品(supplement)的錠劑、膠囊劑、顆粒劑、散劑或飲料劑等。該等以外,例如可列舉茶飲料、清涼飲料、碳酸飲料、營養飲料、果實飲料、乳酸飲料等飲料,蕎麵、烏龍麵、中華麵、即席麵等麵類,飴、糖果、口香糖、巧克力、零嘴糕餅、餅乾、果凍、果醬、奶油、烤餅乾、麵包等糕餅及麵包類,魚板、火腿、香腸等水產或畜產加工食品、加工乳、發酵乳等乳製品,沙拉油、炸油、瑪琪琳、沙拉醬、酥油、稠奶油、沙拉用調料等油脂及油脂加工食品,醬油、佐料等調味料,咖哩、燉‧燜的食品、丼、粥、雜炊等軟罐頭食品,冰淇淋、果子露、剉冰等冰菓等。
本發明的前述飲食品的攝取量,沒有特別的限定,視飲食品的形態、攝取飲食品的對象的年齡、性別、狀態等的條件而設定即可。
本發明的另1種態様是關於包含將本發明的經口投藥劑給對象投藥的製程之減少類澱粉質斑、τ沉澱、τ析出物、PHF-τ,或神經原纖維變化的方法。在本態樣中,投藥對象,投藥量等,與上述同樣即可。
又,本發明的再另1種態樣是關於包含將本
發明的經口投藥劑給對象投藥的製程之抑制由類澱粉質β(A β)(1-42)誘導的軸索的萎縮的方法。在本態樣中,投藥對象、投藥量等,與上述同樣即可。
再者,本發明的另1種態樣是關於包含將本發明的經口投藥劑給對象投藥的製程之刺激1,25D3-MARRS,使信號傳達路徑活化的方法。在本態樣中,投藥對象、投藥量等,與上述同樣即可。
又,本發明的再另1種態樣是關於包含將本發明的經口投藥劑給對象投藥的製程之增進、提高正常的記憶力的方法。又,「正常的記憶力」,包含「在沒有類澱粉質斑、τ沉澱、τ析出物、PHF-τ、或神經原纖維變化,或,沒有A β(1-42)誘導的軸索的萎縮等的疾患存在的狀態的對象的記憶力」。在本態樣中,投藥對象、投藥量等,與上述同樣即可。
(薯蕷皂苷配基衍生物及其用途)
本發明的另1種態樣中,包含新穎的薯蕷皂苷配基衍生物。這種薯蕷皂苷配基衍生物而言,可列舉在前述式(I-1)代表的化合物或其鹽(藥學上可容許的鹽)中,非公知的薯蕷皂苷配基衍生物(例如,前述式(III)代表的化合物等)等。
又,在本發明中,亦包含含有薯蕷皂苷配基衍生物(例如,前述式(I-1)代表的化合物或其鹽)之軸索的功能不全相關的疾患的預防劑或治療劑。
這種軸索的功能不全相關的疾患而言,與前述同樣的疾患,例如,可列舉脊髄損傷、腦挫傷、AD(阿茲海默症)、
巴金森病、認知症等。該等的疾患中,尤其是,AD或脊髄損傷為理想。
再者,在本發明中,也包含含有薯蕷皂苷配基衍生物之神經細胞的軸索的伸展劑或變性神經細胞的軸索的修復劑。
再者,在本發明中,也包含醫藥(或醫藥組成物),該醫藥係含有薯蕷皂苷配基衍生物。
又,在本發明中,也包含健康功能食品,該食品係含有薯蕷皂苷配基衍生物。
又,這種薯蕷皂苷配基衍生物的各種用途(預防劑、治療劑、軸索的伸展劑、修復材、健康功能食品等),只要含有薯蕷皂苷配基衍生物,則如前面所述在油脂懸浮或溶解的特定的經口投藥劑的適用沒有限定,可以適用種種的方式。
劑形而言,例如,可列舉錠劑、懸浮劑、散劑、細粒劑、顆粒劑、乾糖漿劑、被覆錠劑、口腔內崩壊錠、可咀嚼錠、膠囊劑、軟性膠囊劑、糖漿劑、經口液劑、喉錠劑、凝膠劑、吸入劑、栓劑、注射劑、軟膏劑、點眼劑、眼軟膏劑、點鼻劑、點耳劑、貼敷劑、洗劑、外用液劑、噴霧劑、外用氣膠劑、霜劑、凝膠劑、膠帶劑、口頰錠、舌下錠、陰道栓劑、陰道錠、直腸軟性膠囊劑等。製劑化時,通常使用的添加劑,例如,賦形劑、黏合劑、崩壊劑、被覆劑、滑澤劑、著色劑、矯味矯臭劑,及視需要而可使用安定化劑、乳化劑、吸收促進劑、界面活性劑、
pH調製劑、防腐劑、抗氧化劑等,配合一般做為醫藥品製劑的原料而使用的成分而可依照常法製劑化。
投藥形態而言,沒有特別的限定,可經口投藥,亦可非經口投藥。非經口投藥而言,例如,可列舉直腸投藥、經鼻投藥、經肺投藥、注射投藥(例如、静脈內投藥、脊椎腔內投藥、硬膜外腔內投藥、肌肉內投藥、皮下投藥、腹腔內投藥、動脈內投藥、關節內投藥、心臓內投藥、嚢內投藥、皮內投藥、病灶內投藥、眼內投藥、胸腔內投藥、蜘蛛膜下投藥、子宮內投藥、腦室內投藥)等。
其他,前述特定的經口投藥劑以外的方式(投藥量、投藥對象等),與前述相同。
其次,舉實驗例、實施例而更具體說明本發明,但本發明不受該等的實施例任何限定,在本領域內有通常的知識者可以在本發明的技術的思想內做很多的變形。
<統計處理>
在本實施例中,所得的結果實施以下的統計處理:
單因子變異數分析(one-way ANOVA),事後鄧奈特(Dunnett)檢定,及對應t-檢定是使用Graphpad Prism 5(Graphpad Software公司,La Jolla,california,USA)實施。將*P<0.05作為在統計學上顯著,將平均值與SE一起顯示。
<供試動物>
ddY小鼠是,由日本SLC(濱松,日本)取得。在本實施例中,正常小鼠,使用雄性並且是6週齡的ddY小鼠。所有的小鼠,自由攝取餌及水,在22±2℃,50±5%的濕度,由上午7時開始控制12小時的明暗週期的環境飼養。
基因轉殖的小鼠(5XFAD)被認為是AD的動物模式,由Jackson研究所(Bar Harbor,Main,USA)入手。5XFAD小鼠是,在神經元特異的小鼠Thy-1啟動子的轉錄控制下,有過份呈現瑞典(Swedish)(K670N及M671L),弗洛里達(Florida)(I716V)及倫敦(London)(V717I)有變異的人的APP695 cDNA,及人的PS1 cDNA(M146L及L286V的變異)(Oakley,H.etc.,J Neurosci,26,10129-10140,2006.)。該等是由B6/SJL F1種畜與半接合基因轉殖的小鼠交配而維持。
在本實施例中,AD模型小鼠,使用24至27週齡的雄性及雌性的5XFAD小鼠,或28至31週齡的雌性的5XFAD小鼠。所有的小鼠是,以能自由攝取餌及水的狀態下,控制在22±2℃,50±5%的濕度,由上午7時開始的12小時的明暗週期的環境飼養。
<自發運動量測定>
在本參考試驗1中,自發運動量測定是如以下的方式實施:對供試驗的各小鼠,將在開放場所箱(open field box)馴化10分鐘時的小鼠的移動路徑,使用數位照相機系統而
追蹤。將在10分鐘內所走動的距離使用EthoVision3.0(Noldus公司,Wageningen,荷蘭)分析移動活動。
<物體認知記憶試驗>
在本實施例中,物體認知記憶試驗是如以下所述實施:自發運動量測定的翌日,依照發明者等的文獻(Joyashiki,E.etc.,Int J Neurosci,121,pp.181-190,2011.,及Tohda,C.etc.,Int J Neurosci,121,pp.641-648,2011.)的記載,實施物體認知記憶試驗。試驗是在比較減低照明的房間(約100lux)實施。訓練階段及試驗階段間的適切的時間間隔是,由另外的小鼠組預先試驗而決定。物體認知記憶試驗就是利用動物對新東西會表現興趣的習性的試驗。實施試驗的開放場所箱的內側牆壁上,沒有任何標誌。在訓練階段在場所內放置2個相同的物體使其作10分鐘的探索行動。在試驗的階段,將物體的一個以新物體取代,但不改變放置的位置,使其作10分鐘的探索行動。將小鼠對取代的新物體表現興趣而増加探索行動的次數,作為物體記憶能力的指標。即,在試驗階段中,確認其有沒有記住在訓練階段所見的物體的試驗。在本實施例中,對總探索時間內對新物體的探索次數的比率(%)當作探索指向指數(Preference index)而算出。
<物體場所記憶試驗>
在本實施例中,物體場所記憶試驗是如以下所述實施:試驗是在比較減低照明的房間(約100lux)實施。訓練階段與試驗階段之間的適切的時間間隔,使用另一組小鼠
預先試驗而決定。物體場所記憶試驗就是利用動物會對新的東西表現興趣的習性的試驗。實施試驗的開放場所箱的內側的4方的牆壁中,相對面的2個牆壁貼上可作為標誌的有特徵的模樣的壁紙。在訓練階段時在場內放置小鼠未看過的2個相同的物體使其作10分鐘的探索行動。在試驗的階段時,將其中的物體之一的位置改變,使其作10分鐘的探索行動。小鼠會對雖是相同但放置的位置有改變的物體表現興趣而増加探索行動的次數,而將其作為空間記憶能力的指標。即,在試驗階段中,確認其有沒有記住在訓練階段所看到的物體的試驗。在本實施例中,對總探索時間內對改變場所的物體的探索次數的比率(%)作為探索指向指數(Preference index)而算出。又,本試驗是參考Tohda C.,Joyashiki E.Sominone enhances neurite outgrowth and spatial memory mediated by the neurotrophic factor receptor,RET.British Journal of Pharmacology(2009)157,1427-1440.的記述而實施。
在2.07mg的薯蕷皂苷配基(和光純藥社製)添加5mL的胡麻油(金田(Kaneda)公司製),以微均質機攪拌,懸浮均勻而得懸浮液。將此懸浮液0.5mL與胡麻油49.5mL混合均勻,得對胡麻油(mL)的薯蕷皂苷配基的重量是0.00414mg/mL的懸浮液(實施品1)。薯蕷皂苷配基的投藥量,對小鼠的單位體重將實施品1日1次,對AD模型小鼠(5XFAD,雄性及雌性,24至27週齡)經口投藥0.1μmol/kg/日。投
藥期間是20日。對該小鼠,實施物體認知記憶試驗。又,最終投藥的翌日實施訓練階段。又,訓練階段與試驗階段的間隔是設定為1小時。
除將薯蕷皂苷配基的投藥量,設定為小鼠的單位體重10μmol/kg/日以外,與實施例1同樣實施。
除將實施例1中的胡麻油,改為橄欖油(金田公司製)而使用實施品3以外,與實施例1同樣實施。
除將實施例1中的胡麻油,改為大豆油(金田公司製)而使用實施品4以外,與實施例1同樣實施。
除將實施品1改為只用胡麻油以外,與實施例1同樣實施。
代替AD模型小鼠而使用野生型小鼠(24至27週齡以外,與比較例1同樣實施。
結果示於第1圖。
實施例1至4的小鼠,記憶障礙改善達到與作為對照所使用的野生型小鼠為同等的水準。
在1.30mg的(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯的鹽酸鹽{(3 β,25R)-3-(2-Aminoethanoyloxy)-spirost-5-en鹽
酸鹽}(合成品,以下,本說明書中簡稱為Dios-G。)添加2.544mL的胡麻油(金田公司製),以微均質機攪拌,懸浮均勻而得懸浮液。取所得的懸浮液0.5mL,添加胡麻油49.5mL而混合均勻,得對胡麻油(mL)的Dios-G的重量是0.005081mg/mL的懸浮液(實施品5)。
Dios-G的投藥量,對AD模型小鼠(5XFAD,雌性,28至31週齡),將實施品5以1日1次對小鼠的單位體重經口投藥0.1μmol/kg/日。投藥期間是20日。對該小鼠,實施物體認知記憶試驗。又,最終投藥的翌日實施訓練階段。又,訓練階段與試驗階段的間隔是設定為1小時。
代替實施品5,而改用(3 β,25R)-3-氟螺甾-烯{(3 β,25R)-3-氟螺甾-5-烯}(合成品,以下,在本說明書中簡稱為Dios-F略稱。)而使用實施品6以外,與實施例5同樣實施。又,實施品6是,依照以下的方式調製:在1.13mg的Dios-F添加2.712mL的胡麻油而攪拌,而懸浮均勻,在所得的懸浮液0.5mL,再添加49.5mL的胡麻油而混合均勻,調製對胡麻油(mL)的Dios-F的重量為0.004166mg/mL的懸浮液(實施品6)。
除將實施品5改變為只有胡麻油以外,與實施例5同樣實施。
代替AD模型小鼠而使用野生型小鼠(31週齡)以外,
與比較例2同樣實施。
結果示於第2圖。
實施例5及6的小鼠,記憶障礙是改善達到與作為對照使用的野生型小鼠為同等的水準。
與實施例5同樣,得到在胡麻油懸浮Dios-G的懸浮液(實施品7)。Dios-G的投藥量,將實施品7對小鼠的單位體重0.1μmol/kg/日1日1次,對AD模型小鼠(5XFAD,雌性,28至31週齡)經口投藥。投藥期間,設定為25日。對該小鼠,實施物體認知記憶試驗。又,在最終投藥的翌日實施訓練階段。又,訓練階段及試驗階段的間隔是設定為24小時。
與實施例6同樣,除使用在胡麻油懸浮Dios-F而調製的懸浮液(實施品8)以外,與實施例7同樣實施。
除將實施品7改為只有胡麻油以外,與實施例7同樣實施。
代替AD模型小鼠而使用野生型小鼠(31週齡以外,與比較例3同樣實施。
結果示於第3圖。
將物體認知記憶試驗的間隔延長為24小時的本試驗中,實施例7及8的小鼠,有顯示記憶障礙的改善的傾向。
與實施例6同樣,得在胡麻油懸浮Dios-F的懸浮液(實施品9)。Dios-F的投藥量,將實施品91日1次以小鼠的單位體重0.1μmol/kg/日,對AD模型小鼠(5XFAD,雌性,28至31週齡)經口投藥。投藥期間,設定為22日。對該小鼠,實施物體場所記憶試驗。又,在最終投藥的翌日實施訓練階段。又,訓練階段及試驗階段的間隔設定為24小時。
除將實施品9改為只有胡麻油以外,與實施例9同樣實施。
代替AD模型小鼠而使用野生型小鼠(31週齡)以外,與比較例4同樣實施。
試驗的結果,實施例9的小鼠,觀察到記憶障礙的改善。
<<試驗例:由BMS、TMS做後肢運動功能的評估>>
為確認薯蕷皂苷配基衍生物對脊髄損傷小鼠的後肢功能的影響,實施使用脊髄損傷模型小鼠的試驗。
8週齡的雌性ddY小鼠(SLC)如下述的方式產生挫傷,作為脊髄損傷(SCI)模式:小鼠是在能自由攝取餌及水狀態,維持在一定的環境條件(22±2℃,50±5%濕度,及上午7時開始12小時的明暗週期)。挫傷是依照常法將小鼠的
腰椎露出,對第一腰椎(L1)使用定位固定裝置(成茂(Narishige)公司製)由高度2cm將6.5g的錘掉下一次而產生。之後,依照常法施加縫合等的外科的處置。給予挫傷1小時後,將小鼠逢機取出,分類於各試驗區而實施後述的實施例10及比較例5所述的投藥試驗。
將投藥試驗後的小鼠個別移動於開放場所(42cm×48cm×15cm),觀察5分鐘,評估後肢運動功能。作為評估在脊髄損傷的模式試驗的後肢的運動功能的基準是一般所用的後肢運動傳送功能評估(Basso Mouse Scale,BMS)(例如,Engesser-Cesar C,Anderson AJ,Basso DM et al.(2005).Voluntary wheel running improves recovery from a moderate spinal cord injury.J Neurotrauma 22:157-171),及為了要提高試驗的精度而使用本發明者等將BMS改變的0至30分的富山小鼠尺度(Toyama Mouse Scale,TMS),評估在開放場所的移動行動。
新的得分的富山小鼠尺度(TMS),為了要提高試驗的精度,本發明者等將BMS得分加以改變的得分,將此TMS使用於在SCI小鼠的後肢功能的評估。TMS的得分數表示於第1表。又,表中,括弧內的數字是得分數,每項目判定得分數,加算而評估。
與實施例6同樣,在胡麻油懸浮Dios-F而得懸浮液(實施品10)。Dios-F的投藥量,將實施品10對脊髄損傷小鼠以小鼠的單位體重0.1μmol/kg/日1日1次,經口投藥。初次的投藥是在挫傷1小時後實施,第2次的投藥是在其翌日(1日後)實施,投藥期間設定為14日。對該小鼠,實施後肢運動功能評估。
除將實施品10改為胡麻油以外,與實施例10同樣實施。
又,實施例10的供試小鼠的個體數是3,後肢是計6隻(n=6)及比較例5的供試小鼠的個體數是6,後肢是計12隻(n=12)進行評估。
結果示於第4圖。第4圖A是以BMS(後肢運動傳送功能評估)評估的結果,第4圖B是以TMS(富山小鼠尺度)評估結果。將Dios-F經口投藥的小鼠(實施例10,第4圖的黒圓圈表示的群),只投藥對照的胡麻油的小鼠(比較例5,第4圖的白圓圈表示的群)比較,後肢運動功能是有顯著的提高。
<<參考試驗1>>懸浮食用油的薯蕷皂苷配基衍生物的經口投藥的自發運動量及對體重變動的影響的確認。
與實施例5及6同樣,調製將Dios-G或Dios-F懸浮於胡麻油的懸浮液。薯蕷皂苷配基衍生物(Dios-G或Dios-F)
的投藥量,將懸浮液1日1次以小鼠的單位體重0.1μmol/kg/日,對AD模型小鼠(5XFAD,雌性,28至31週齡)經口投藥。在第20日的投藥的1小時後測定自發運動量。之後,再繼續投藥,總投藥期間設定為25日。投藥期間的25日中,每日測定體重。
又,作為比較,對AD模型小鼠(5XFAD,雌性,28至31週齡)或野生型小鼠(31週齡)只投藥胡藥麻油,在投藥第20日實施自發運動量,及,體重的測定。
將自發運動量的測定結果示於第5圖A,將體重測定的結果示於第5圖B。
有薯蕷皂苷配基衍生物投藥的AD模型小鼠,沒有將薯蕷皂苷配基衍生物投藥的AD模型小鼠及野生型小鼠之間,在自發運動量及體重的變化沒有觀察到有顯著的差異。
<<參考試驗2>>溶解於水系溶媒的薯蕷皂苷配基以經口投藥對記憶力沒有顯示加強效果。
將4.9mg的薯蕷皂苷配基溶解於1.182mL的乙醇,成為10mM的薯蕷皂苷配基乙醇溶液。與此溶液之外另外,將2.3g的葡萄糖溶解於46mL的水,調製5%葡萄糖水溶液。將10mM薯蕷皂苷配基乙醇溶液1mL添加於5%葡萄糖水溶液9mL而混合,得薯蕷皂苷配基的水系溶媒溶液(參考品1)。薯蕷皂苷配基的投藥量,將參考品1,1日1次,以小鼠的單位體重10μmol/kg/日,對正常小鼠(ddY,雄性,6週齡)經口投藥。投藥期間設定為5日。對該小鼠,
實施物體場所記憶試驗。又,在最終投藥的翌日實施訓練階段。又,訓練階段及試驗階段的間隔設定為48小時。
與參考例1同樣調製薯蕷皂苷配基的水系溶媒溶液(參考品2),將投藥方法改為腹腔內投藥以外,與參考例1同樣實施。
結果示於第6圖。在將溶解於水系溶媒的薯蕷皂苷配基經口投藥的參考例1的小鼠,沒有觀察到記憶力的加強效果(第6圖A)。另一方面,將水溶解於系溶媒的薯蕷皂苷配基在腹腔內投藥的參考例2的小鼠,則觀察到顯著的記憶力的加強效果。
<<參考試驗3>>以薯蕷皂苷配基的低用量的正常小鼠的記憶力加強作用的確認。
與參考例1同樣,得薯蕷皂苷配基的水系溶媒溶液(參考品3)。薯蕷皂苷配基的投藥量,將參考品3,1日1次,以小鼠的單位體重0.1μmol/kg/日,對正常小鼠(ddY,雄性,6週齡)在腹腔內投藥。投藥期間,設定為7日。對該小鼠,實施物體認知記憶試驗。又,在最終投藥的翌日實施訓練階段。又,將訓練階段及試驗階段的間隔設定為48小時。
除將薯蕷皂苷配基的投藥量,改為小鼠的單位體重1μmol/kg/日以外,與參考例3同樣實施。
除將薯蕷皂苷配基的投藥量,改為小鼠的單位體重10μmol/kg/日以外,與參考例3同樣實施。
除將參考品3改為只有胡麻油以外,與參考例3同樣實施。
結果示於第7圖。參考例3至5的小鼠是,每一隻都觀察到記憶力的加強。
上述的結果是薯蕷皂苷配基及特定的薯蕷皂苷配基衍生物的結果,但其他的薯蕷皂苷配基衍生物也確認可以得到同樣的結果。例如,Dios-F是薯蕷皂苷配基的3位的羥基經氟取代的化合物,而對薯蕷皂苷配基的2位(α或β)是經氟取代的化合物,及薯蕷皂苷配基的4位(α或β)是經氟取代的化合物,各分別實施1,25D3-MARRS的對接模擬(docking simulation)的結果,得到與薯蕷皂苷配基及Dios-F同樣的結合親和力(Binding affinity)的值(kcal/mol)。又,結合親和力(Binding affinity)的值(kcal/mol)是,越低表示越高的結合活性。
下面示其結果。在表中,「ds」代表「薯蕷皂苷配基」,「dsF-3 β」代表在薯蕷皂苷配基的3位羥基經氟取代的化合物,「dsF-2 β」代表在薯蕷皂苷配基的2位(β)經氟取代的化合物,「dsF-2 α」代表在薯蕷皂苷配基的2位(α)經氟取代的化合物,「dsF-4 β」代表薯蕷皂苷配基的4位(β)經氟取代的化合物,「dsF-4 α」代表薯蕷皂苷配基的4位(α)
經氟取代的化合物。
<合成例1>Dios-G((3 β,25R)-3-(2-胺乙醯基氧基)-螺甾-5-烯鹽酸鹽)的合成方法
將薯蕷皂苷配基(和光純藥社製)(1.00g,2.41mmol)及Fmoc-Gly-OH(2.15g,7.24mmol)溶解於CH2Cl2(24.0mL),在此溶液在冰冷下依序添加EDCI(1-(3-二甲基胺基丙基)-3-乙基碳二亞胺)(1.39g,7.24mmol)及DMAP(N,N-二甲基-4-胺基吡啶基)(29.4mg,0.241mmol)及i-Pr2Net(N,N-二異丙基乙基胺)(1.12g,8.68mmol)。之後,在室溫攪拌24小時後添加水而停止反應後,以乙酸乙酯(30mL)萃取。將收集的有機層以飽和食鹽水(10mL)清洗後,以硫酸鎂乾燥,在減壓下,餾去有機溶媒。將所得的殘質以急速矽膠層析法(溶出液:己烷/乙酸乙酯=70:30)精製,得薯蕷皂苷配基-Fmoc-甘胺酸酯(diosgenin Fmoc-glycinate)(1.19g,71%)。
將上述的薯蕷皂苷配基-Fmoc-甘胺酸酯(1.19g,1.71
mmol)溶解於CH3CN-CH2Cl2混合溶液(15mL,3:2 v/v),在室溫下,在此溶液添加哌啶(piperidine)(1.46g,17.1mmol),在室溫下攪拌1小時則成為懸浮液。在此懸浮液添加甲苯(10mL)而成為澄清溶液後,在減壓下,餾去有機溶媒。在所得的殘質添加(10mL)成為溶液後,減壓下,餾去有機溶媒。將此操作再重複1次後,將所得的殘質以急速矽膠層析法(溶出液:己烷/乙酸乙酯=80:20至0:100)精製,得(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯(3 β,25R)-3-(2-胺乙醯基氧)-螺甾-5-烯)(693mg,86%)。
將上述的(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯(590mg,1.25mmol)溶解於Et2O(50mL),在冰冷下,滴下鹽酸(HCl)的二乙醚(Et2O)溶液(1.0M,3.13mL,3.13mmol),在室溫下,攪拌30分鐘。濾取產生的沉澱,得到標題化合物(535mg,84%)的白色固體。將標題化合物的1H NMR與既有的報告(Wang,X.;Ye,Z.;Wang,L.Faming Zhuanli Shenging Gongkai Shuomingshu(2004),CN 151760 A 20040804.)的對照而確認。
Mp 194-197℃;IR(KBr)3400,2951,1746,1598cm-1;1H NMR(500MHz,CD3OD)δ 5.42(1H,d,J=5.6Hz),4.72-4.66(1H,m),4.41-4.37(1H,m),3.80(3H,s),3.46-3.43(2H,m),2.43-2.38(3H,m),2.06-1.88(5H,m),1.79-1.13(17H,m),1.08(3H,s),0.95(3H,d,J=7.2Hz),0.81(3H,s),0.78(3H,d,J=6.4Hz);13C NMR(125MHz,CD3OD)δ 167.9,140.6,123.9,110.5,82.1,77.6,67.8,63.7,57.7,51.5,42.9,41.4,
41.2,40.8,38.9,38.0,37.9,33.1,32.7,32.4,31.4,29.9,28.6,21.9,19.74,19.70,17.5,16.8,14.9;LRMS(FAB)m/z 508([M+H]+);HRMS(FAB)m/z計算值C29H47O4ClN([M+H]+)508.31936,實測值508.31852.
<合成例2>Dios-F((3 β,25R)-3-氟螺甾-5-烯)的合成方法
在將XtalFluor-E(登錄商標,Sigma Aldrich公司)(85.9mg,0.375mmol)懸浮於二氯甲烷(CH2Cl2)(0.63mL)的溶液中,在室溫下依序添加三乙基胺三氟化氫酸鹽(Et3N‧3HF)(0.16mL,1.00mmol)及薯蕷皂苷配基(和光純藥社製)(118mg,0.25mmol),將此溶液在室溫攪拌21小時。以TLC確認原料消失後,添加5% Na2CO3水溶液而停止反應,以乙酸乙酯(1mL)萃取3次。將收集的有機層以飽和食鹽水(1mL)清洗後,以硫酸鎂乾燥,濾別固體後,在減壓下,餾去有機溶媒。將所得的殘質以急速矽膠層析法(溶出液:己烷/乙酸乙酯,98:2)精製,得標題化合物(49.3mg,47%)的白色固體。再將此白色固體由乙酸乙酯再結晶,得19.1mg的無色透明的針狀結晶。
Mp 224-226℃;Rf=0.36(矽膠,己烷/乙酸乙酯,98:2);1H NMR(500MHz,CDCl3)δ 5.39(1H,d,J=4.2Hz),4.46-4.39(1H,m),4.38(1H,dm,2JH-F=50Hz),3.43(1H,dd,J=10.9,10.9Hz),3.38(1H,dd,J=10.9,3.1Hz),2.46-2.44(2H,m),2.03-1.96(3H,m),1.90-1.85(2H,m),1.79-1.43(14H,m),1.36-1.26(1H,m),1.21-1.07(2H,m),1.04(3H,s),0.97(3H,
d,J=6.8Hz),0.80-0.78(6H,m);13C NMR(125MHz,CDCl3)δ 139.3(d,3JC-F=11.9Hz),122.7,109.3,92.7(d,1JC-F=173Hz),80.8,66.8,62.1,56.4,49.91,49.84,41.6,40.2,39.7,39.3(d,2JC-F=19.3Hz),36.7,36.3(d,3JC-F=11.0Hz),32.0,31.8,314,30.3,28.8,28.7(d,2JC-F=17.3Hz),20.9,19.3,17.1,16.3,14.5;LRMS(EI)m/z 417[M+];HRMS(EI)m/z計算值C27H41FO2 416.3091[M+],實測值416.3137.
在12.92mg的野生山藥乾燥萃取物(ASK藥品公司製,含有薯蕷皂苷配基16.05%)添加5mL的大豆油(金田公司製),以微均質機攪拌,得懸浮均勻的懸浮液。將此懸浮液0.5mL與大豆油49.5mL混合均勻,得對大豆油(mL)的薯蕷皂苷配基的重量是0.004146mg/mL的懸浮液(實施品11)。薯蕷皂苷配基投藥量,將實施品11,1日1次,以小鼠的單位體重0.1μmol/kg/日,對AD模型小鼠(5XFAD,雄性及雌性,30至47週齡)經口投藥。投藥期間設定為14日。對此小鼠,實施物體認知記憶試驗。又,在最終投藥的翌日實施訓練階段。又,訓練階段及試驗階段的間隔設定為1小時。
除將實施品11改為只有大豆油以外,與實施例11同樣實施。
代替AD模型小鼠而使用野生型小鼠(34至36週齡)以
外,與比較例6同樣實施。
結果示於第8圖。又,在第8圖中,「preferential index」就是,如前述的探索指向指數,「Wild」就是野生型小鼠,「5XFAD」就是AD模型小鼠,「Yam」就是使用野生山藥乾燥萃取物(即,與實施例11對應),「Veh」就是沒有使用野生山藥萃取物乾燥萃取物(即,與比較例6及對照對應),圖的左側的3條棒圖是訓練階段,圖的右側的3條的棒圖是試驗階段的結果(在第9圖亦同)。
由第8圖的結果可明白,實施例11的小鼠,記憶障礙改善達到與作為對照使用的野生型小鼠為同等的水準。
在12.92mg的野生山藥乾燥萃取物(ASK藥品公司製,含有薯蕷皂苷配基16.05%)添加5mL的蒸餾水,以微均質機攪拌,得懸浮均勻的懸浮液。將此懸浮液0.5mL與蒸餾水49.5mL混合,得對蒸餾水(mL)的薯蕷皂苷配基的重量是0.004146mg/mL的懸浮液(實施品12)。薯蕷皂苷配基的投藥量,將實施品12,1日1次,以小鼠的單位體重0.1μmol/kg/日,對AD模型小鼠(5XFAD,雄性,30至47週齡)經口投藥。投藥期間設定為14日。對此小鼠實施物體認知記憶試驗。又,在最終投藥的翌日實施訓練階段。又,訓練階段及試驗階段的間隔是設定為1小時。
除將實施品12改為只用蒸餾水以外,與比較例7同樣實施。
代替AD模型小鼠而改用野生型小鼠(39至43週齡)以外,與比較例8同樣實施。
結果示於第9圖。
由第9圖的結果可明白,使用蒸餾水的比較例7沒有顯著的改善記憶障礙。
在2.07mg的薯蕷皂苷配基(和光純藥社製)添加5mL的胡麻油(金田公司製),以微均質機攪拌,得懸浮均勻的懸浮液。將此懸浮液0.5mL與胡麻油49.5mL混合均勻,得對胡麻油(mL)的薯蕷皂苷配基的重量是0.004146mg/mL的懸浮液(實施品13)。薯蕷皂苷配基的投藥量,實施品13,1日1次,以小鼠的單位體重0.1μmol/kg/日,對ddY小鼠(雄性及雌性,9週齡)經口投藥。投藥期間設定為4日。對此小鼠,實施物體認知記憶試驗。又,在最終投藥的1小時後實施訓練試驗。又,訓練階段及試驗階段的間隔設定為48小時。
除將實施品13改為只有胡麻油的以外,與實施例12同樣實施。
結果示於第10圖。將在胡麻油懸浮的薯蕷皂苷配基經口投藥的實施例12的小鼠,觀察到物體認知記憶有顯著加強。
依據本發明,則以往只以對症療法對症的阿茲海默症,可提供在根本療法可有效使用的可臨床化的預防劑或治療劑。再者,依據本發明,對軸索的功能不全相關之阿茲海默症以外的疾患,也可提供可以臨床化的預防劑或治療劑。
由於本案的圖為試驗結果圖,並非本案的代表圖。故本案無指定代表圖。
Claims (21)
- 一種經口投藥劑,係將由薯蕷皂苷配基、薯蕷皂苷配基衍生物、及此等的藥學上可容許的鹽選出的1種以上的化合物懸浮或溶解於油脂。
- 如申請專利範圍第1項所述之經口投藥劑,係至少含有薯蕷皂苷配基。
- 如申請專利範圍第1項或第2項所述之經口投藥劑,其中,薯蕷皂苷配基衍生物是由下述式(I-1)代表的化合物及其藥學上可容許的鹽選出之至少1種
- 如申請專利範圍第3項所述之經口投藥劑,其中,在式(I-1)中,取代基是烴基、羥基、基-O-(CH2)n-CH3、基-O-(CH2)m-NH2、基-O-(CH2)m-COOH、基-O-(CH2)m-SO3H、基-O-CO-(CH2)n-CH3、基-O-CO-NH-(CH2)n-CH3、基-O-CO-NR-(CH2)n-CH3、基-O-CO-NH-CH(Rb)-COOH、基-O-(CH2)n-CO-NH-AD(式中,AD代表金剛烷基)、基-O-CO-NH-(CH2)m-SO3H、基-O-CO-NH-(CH2)m-COOH、基 -O-CO-O-(CH2)n-CH3、基-O-CO-S-(CH2)n-CH3、基-O-SU(式中,SU代表糖鏈)、基-O-SO2-OH、基-O-PO2-OH、基-(OCH2CH2)m-CH3、基-(OCH2CH2CH2)m-CH3、羧基、基-COO(CH2)nCH3、基-CO-NH-(CH2)n-CH3、基-SO3H、基-SO2-(CH2)n-CH3、基-SO2-Ph(式中,Ph是代表苯基)、基-CO-NH-CH(Rb)-COOH、基-CO-NH-(CH2)n-SO3H、胺基、基-NH-(CH2)n-CH3、基-NH-(CH2)n-NH2、基-NH-CH(Rb)-COOH、基-NH-(CH2)m-SO3H、基-NH-(CH2)n-SO2H、基-NH-CO-O-(CH2)n-CH3、基-NH-CO-NH2、基-NH-CO-NH-AD(式中,AD代表金剛烷基)、基-NH-CO-NH-CH(Rb)-COOH、基-NH-CO-NH-(CH2)m-SO3H、基-NH-CO-NH-(CH2)m-COOH、巰基、基-S-(CH2)n-CH3、基-S-(CH2)m-COOH、基-S-(CH2)m-CH(NH2)-COOH、基-S-CO-NH-AD(式中,AD代表金剛烷基)、基-S-S-(CH2)m-CH(NH2)-COOH、基-SO3H、基-PO3H胺基酸基,或鹵原子,上述式中,m代表1以上的整數,n代表0以上的整數,Rb代表氫原子或烴基。
- 如申請專利範圍第1項至第4項中任一項所述之經口投藥劑,其中,薯蕷皂苷配基衍生物是由(3 β,25R)-3-(2-胺基乙醯氧基)-螺甾-5-烯、(3 β,25R)-3-氟螺甾-5-烯、(3 β,25R)-3-(2-胺基乙基磺醯氧基)-螺甾-5-烯、(3 β,25R)-3-(2-胺基丙基磺醯氧基)-螺甾-5-烯、(3 β,25R)-3-[N-(2,6-二甲基金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯、(3 β,25R)-3-{[N-(2,6-二甲基金剛烷-1-基) 胺甲醯基]胺基}-螺甾-5-烯、(3 β,25R)-3-[N-(2,6-二甲基金剛烷-1-基)胺甲醯基硫基]-螺甾-5-烯、(3 β,25R)-3-{[N-(金剛烷-1-基)胺甲醯基]胺基}-螺甾-5-烯、(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯基硫基]-螺甾-5-烯、(3 β,25R)-3-[N-(金剛烷-1-基)胺甲醯氧基]-螺甾-5-烯,及此等的藥學上可容許的鹽所成的群選出的1種以上的化合物。
- 如申請專利範圍第1項至第5項中任一項所述之經口投藥劑,其係神經細胞的軸索的功能不全相關的疾患的預防劑或治療劑。
- 如申請專利範圍第6項所述之經口投藥劑,其中,以神經細胞的軸索功能不全為要因的疾患是阿茲海默症。
- 如申請專利範圍第6項所述之經口投藥劑,其中,以神經細胞的軸索功能不全為要因的疾患是脊髄損傷。
- 如申請專利範圍第1項至第5項中任一項所述之經口投藥劑,其係神經細胞的軸索的伸展劑。
- 如申請專利範圍第1項至第5項中任一項所述之經口投藥劑,其係變性神經細胞的軸索的修復劑。
- 如申請專利範圍第1項至第10項中任一項所述之經口投藥劑,其係記憶増進劑或記憶力減低的抑制劑。
- 如申請專利範圍第1項至第11項中任一項所述之經口投藥劑,其係併用已知對軸索的功能不全相關的疾患的治療或預防有用的1種以上的化合物,或其藥學上 容許的鹽。
- 如申請專利範圍第1項至第12項中任一項所述之經口投藥劑,其劑形是由液劑、懸浮劑、膠囊劑、軟性膠囊劑、錠劑、顆粒劑、散劑、糖漿劑、凝膠劑、口腔內崩壊錠、及咀嚼錠所成的群選出的1種以上者。
- 一種健康功能食品,係含有如申請專利範圍第1項至第13項中任一項所述之經口投藥劑。
- 一種下述式(III)代表的(3 β,25R)-3-氟螺甾-烯
- 一種神經細胞的軸索的功能不全相關的疾患的預防劑或治療劑,係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種的化合物。
- 如申請專利範圍第16項所述之預防劑或治療劑,其中,疾患是脊髄損傷。
- 一種神經細胞的軸索的伸展劑,係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種化合物。
- 一種變性神經細胞的軸索的修復劑,係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種 化合物。
- 一種記憶増進劑或記憶力減低的抑制劑,係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種的化合物。
- 一種健康功能食品,係含有由薯蕷皂苷配基衍生物及其藥學上可容許的鹽選出的至少1種的化合物,或如申請專利範圍第16項至第20項中任一項所述之劑。
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