TWI414289B - 吲哚衍生物作為nurr-1活化劑之用途 - Google Patents
吲哚衍生物作為nurr-1活化劑之用途 Download PDFInfo
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- TWI414289B TWI414289B TW098123503A TW98123503A TWI414289B TW I414289 B TWI414289 B TW I414289B TW 098123503 A TW098123503 A TW 098123503A TW 98123503 A TW98123503 A TW 98123503A TW I414289 B TWI414289 B TW I414289B
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Description
本發明係關於一種在治療及/或預防涉及核受體NURR-1之疾病之某些吲哚衍生物之新穎醫療用途。更具體地說,本發明係關於一種此等化合物於製備治療及/或預防帕金森氏症之藥劑上之用途。
如上所述之神經退化性疾病,其特徵為神經系統之進行性機能障礙。他們經常與受到影響的中樞或周邊神經系統結構萎縮有關。其中特別包括如:老年癡呆症(Alzheimer's disease)、克雅氏病(Creutzfeldt-Jakob disease)、亨廷頓舞蹈病(Huntington's disease)、帕金森氏症、溶酶體缺陷症、進行性核上性麻痹、多發性硬化與肌萎縮側索硬化。在神經退化性疾病中,帕金森氏症係一種影響世界上約四百萬人之疾病。雖然其可能影響任何年齡之個人,但最常發生在老年人(65歲以上的族群中就有2%受此疾病影響)。其特徵為黑質之多巴胺能細胞退化。
多巴胺係一種神經傳遞素,其在控制自主運動、認知功能及與情感相關之行為發展上扮演核心角色。
當今治療帕金森氏症之醫療策略在於減輕其症狀,透過代謝前驅物(如:L-DOPA)補償多巴胺不足。
目前,由於此病變出現之頻率升高,因此必須發展新的治療劑,此藥劑在神經元細胞分化與生存中扮演有利的作用。
此發展已經導致判別能夠活化涉及帕金森氏症病理機制之核受體之化合物。
在大腦中高度表現之轉錄因子NURR-1,係屬於孤細胞核受體超級家族之一員,已經確認在發展與維持中腦多巴胺能神經元中具有重要作用(Zetterstrom,Solomin等人1997,科學1997年4月11日;276(5310):248-50)。
NURR-1核受體經由調節多巴胺能(DA)神經元之特異性基因而干預多巴胺能表型之維持。其亦藉由保護他們以防止毒性攻擊,而有利於DA神經元存活。NURR-1核受體因此作為多巴胺能神經元之特異性轉錄因子,其活性可由調控帕金森氏症中多巴胺能神經傳遞來調節。
此受體呈單體、同二聚體或與RXR(類視黃素X受體,係一種可與核受體家族之很多其他成員雜聚合之核受體)形成雜二聚體之形式與DNA結合。RXR干預多種生理過程,如:脂肪代謝、葡萄糖代謝、發展與分化。因此NURR-1會與RXR之α與γ異構體相互作用。RXRα的表現係普遍存在,然而RXRγ的表現則主要集中在大腦,更特定言之在紋狀體、丘腦下部與腦下垂體中。
所形成之NURR-1/RXRα與NURR-1/RXRγ複合物能夠因應RXR之配體調節轉錄作用。因此,RXR可正向調節活化NURR-1轉錄作用之潛力。
因此若能識別能夠誘發NURR-1/RXRα與NURR-1/RXRγ複合物之活性之化合物,則應該可以創造可以治療帕金森氏症的新途徑。
文獻WO 2003/015780已揭示具有治療帕金森氏症之活性之雜環化合物。
此外,在文獻WO 2004/072050、FR 2 903 105、FR 2 903 106與FR 2 903 107中揭示之化合物為NURR-1受體之活化劑,而可調節NGFI-B家族(其中NURR-1係其中成員)受體活性之雜環化合物之用途已揭示於文獻WO 2005/047268中。
最後,文獻WO 2005/056522揭示吲哚衍生物,其為PPAR核受體之活化劑,並發現其可作為治療某些心血管疾病之藥物之活性成份使用。
本文中已發現(且此發現構成本發明之基礎)某些衍生自吲哚之化合物屬於文獻WO 2005/056522所示之通式,係選擇性NURR-1/RXRα與NURR-1/RXRγ促效劑,能夠抑制帕金森氏症中所觀察到之神經元之退化。
因此,已驚訝地發現,本發明化合物及更進一步發現其PPAR活化劑效力,極有潛力活化NURR-1/RXRα與NURR-1/RXRγ雜二聚物。因此,此等化合物根據其獨特性質之優點,特別適合用於治療或預防涉及NURR-1受體之疾病,尤指神經退化性疾病,更特定言之帕金森氏症。
因此,本發明首先提供衍生自吲哚之化合物作為新穎產物,其係選自
已經觀察到(且係本發明化合物之本性)其同時出現:-異丙基取代基或第三丁基取代基在苯磺醯基之間位;及-鹵素或三氟甲基在吲哚之位置5,其使得本發明化合物對NURR-1受體具有顯著且完全令人意外之活性。
因此本發明化合物之化學結構雖然大體上包括在文獻WO 2005/056522中所述之通式範圍內,但其並非習此相關技藝之人士選擇用於研究計畫用於治療帕金森氏症之化合物之結果。
其次,本發明提供以前面所提到之化合物作為藥物活性物質之用途,並且亦提供含其之藥物組合物。
第三,本發明提供以至少一種式(I)化合物或其中一種醫藥上可接受之鹽作為活性成份,於製備計畫用於治療涉及NURR-1受體之疾病之藥物上的用途,尤指神經退化性疾病,如:更特定言之帕金森氏症。
本說明中,C1
至C4
烷基係直鏈或分支鏈之飽和烴鏈並具有1至4個碳原子,且更特定言之為甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基或1,1-二甲基乙基。
鹵素為氟原子或氯原子。
式(I)化合物係其中R2
代表氫原子之羧酸,其可呈游離酸或鹽之形式使用,該鹽藉由該酸結合無毒性有機鹼或無機鹼(其較佳為醫藥上可接受)獲得。可使用之無機鹼包括例如氫氧化鈉、氫氧化鉀、氫氧化鎂或氫氧化鈣。可使用之有機鹼包括例如,胺、胺基醇、鹼性胺基酸(例如離胺酸或精胺酸)或其他帶有如:內銨鹽或膽鹼之四級銨官能基之化合物。
根據本發明此化合物可利用第一種方法製備,其包括:
a)由式(II)化合物與式(III)苯磺醯氯反應
b)由式(IV)化合物進行環化反應,例如,與醋酸銅(II)(舉例見J.Org.Chem.,2004,69(4),1126-1136),在例如1,2-二氯乙烷之溶劑中,在接近溶劑回流溫度下反應約15小時,得到式(Ia)化合物
c)若有需要,水解式(Ia)化合物之酯官能團,例如與無機鹼(如;氫氧化鋰),根據熟悉此項技術者所知之步驟反應,在酸處理後,得到游離酸形式之式(I)化合物:
a)由式(II)化合物
b)由式(V)化合物與式(III)苯磺醯氯反應
c)若需要,水解式(Ia)化合物之酯官能團,例如(若為第三丁酯時)利用有機酸之作用,如:三氟醋酸,在如:二氯甲烷之溶劑中,根據熟悉此項技術者所知之步驟反應,得到呈其游離酸形式之式(I)化合物:
在第二個變化中,式(I)化合物可透過以下方法獲得,其包括:
a)使式(VI)化合物與式(III)苯磺醯氯反應
b)由式(VII)化合物與式(VIII)乙炔衍生物反應
c)由上式(IV)化合物在類似上述進行步驟(b)所說明之條件下環化,得到式(Ia)吲哚化合物
d)若需要,水解式(Ia)化合物之酯官能團,例如(若為第三丁酯時)利用有機酸(例如三氟醋酸),在如:二氯甲烷之溶劑中,根據熟悉此項技術者所知之製程反應,得到呈其游離酸形式之式(I)化合物:
請注意,在某些條件下,本方法之步驟b)與c)宜以單一操作法(所謂的一鍋法)進行。
式(II)中R1
代表鹵素或三氟甲基,R2
代表C1
至C4
烷基並且n代表3或4之化合物可透過式(VI)鄰碘苯胺與式(VIII)炔酸酯反應獲得
式(VIII)炔酸酯
式(Ib)酸與有機或無機鹼形成鹽形式之本發明化合物可採用常規方法,使用熟悉此項技術者所知之方法獲得,例如於溶劑中,例如水或水與酒精混合物,混合化學計量之式(Ib)酸與鹼,然後凍乾所得之溶液。
上述某些反應步驟中,可能宜改用微波加熱法,使用適合此種類型之反應器替代傳統加熱方法。熟悉此項技術者咸了解,此時之加熱時間將比傳統加熱法所需時間大幅縮短。
將可自下列根據結構式(I)化合物製法實例更了解本發明。
在此等不限制本發明範圍之實例中,標題為「製法」之實例闡述中間產物之合成法,標題為「實例」者闡述根據本發明式(I)化合物之合成法。
採用以下縮寫:
-mM:毫莫耳
-THF:四氫呋喃
-DMF:二甲基甲醯胺
-DCM:二氯甲烷。
熔點用柯夫勒板(Kofler plate)測量,且核磁共振光譜值之特徵為相對於TMS(四甲基矽烷),由與信號相關之質子數量及信號之形式(s為單峰,d為雙峰,t為參峰,q為肆峰,m為多峰)計算之化學位移。每種化合物都指示操作頻率與所使用之溶劑。
周溫為20℃±5℃。
製備含42.90克(150.39毫莫耳)6-[2-胺基-5-(三氟甲基)苯基]-5-己炔酸甲酯之500毫升吡啶溶液,並添加37.90克(173.29毫莫耳)3-(1-甲基乙基)苯磺醯氯。在周溫下攪拌混合物15小時,然後倒至冰與鹽酸之混合物上。用乙酸乙酯萃取所得之酸性混合物三次。合併之有機相用硫酸鎂乾燥,並在減壓條件下濃縮。殘留之油狀物經矽膠層析法純化,用環己烷/乙酸乙酯混合物(9/1;v/v)洗提。產生29.09克呈赭色油形式之所預期化合物(產率=41%)。
1H NMR(DMSOd6,250 MHz)δ=1.12(d,J=6.9,6H),1.76(q,J=7.0,2H),2.40(t,J=7.0,2H),2.44(t,J=7.0,2H),2.92(q,J=6.9,1H),3.62(s,3H),7.47-7.51(m,4H),7.62-7.66(m,3H),9.68(s,1H)。
製備含28.12克(60.15毫莫耳)根據製法1獲得之酯之250毫升1,2-二氯乙烷溶液,並添加12.49克(62.55毫莫耳)醋酸銅(二價銅)單水合物。混合物置於氮氣中,並於回流下攪拌約15小時。過濾反應混合物,並用DCM洗滌過濾器上之過濾殘留固體。在減壓條件下濃縮合併之濾液。獲得27.70克所預期之米色晶體化合物(產率=99%)。
熔點=115℃。
將27.50克(58.82毫莫耳)根據實例1獲得的酯與450毫升之THF混合,且添加含4.23克(176.47毫莫耳)氫氧化鋰之100毫升水。將混合物在周溫下攪拌約15小時,然後冷卻至0℃。然後,在均勻攪拌下逐漸添加180毫升N鹽酸。分離有機相,並在不加熱之減壓條件下蒸發排除一半溶劑。用二氯甲烷萃取蒸發後之的殘質。合併之有機相用硫酸鎂乾燥,過濾並在減壓條件下濃縮。產生26.22克白色粉末形式之所預期產物(產率=98%)。
熔點=160℃。
將含68毫克(0.15毫莫耳)根據實例2所製得酸之4毫升四氫呋喃溶液與含6毫克(0.15毫莫耳)氫氧化鈉之3毫升水溶液混合。在周溫下攪拌混合物6小時,然後在減壓條件下濃縮。得到65毫克白色粉狀晶體形式之所預期鹽(產率=91%)。
熔點=231℃。
取400毫克(0.88毫莫耳)根據實例2所獲得之酸溶於10毫升之四氫呋喃,並添加76毫克(0.88毫莫耳)哌嗪。在周溫條件下攪拌反應混合物過夜,然後在減壓條件下濃縮。得到400毫克白色晶體粉末形式之所預期鹽(產率=46%)。熔點=147℃。
取400毫克(0.88毫莫耳)根據實例2所得之酸溶於10毫升之四氫呋喃,並添加106.85毫克(0.88毫莫耳)參(羥甲基)胺基甲烷。加入3毫升水,得到其溶液。在周溫下攪拌反應混合物過夜並在減壓條件下濃縮。用甲醇溶解殘質三次,隨後在減壓條件下汽提溶劑。得到480毫克白色晶體粉末形式之所預期鹽(產率=95%)。
熔點=126℃。
依製法1之同樣製程,始於6-(2-胺基-5-氯苯基)-5-己炔酸之甲酯,得到所預期化合物之棕色油狀物(產率=96%)。1H NMR(DMSOd6,300 MHz)δ=1.13(d,J=6.9,6H)1.71(q,J=7.1,2H),2.33(t,J=7.1,2H),2.42(t,J=7.4,2H),2.91(q,J=6.9,1H),3.61(s,3H),7.26(d,J=7.3,1H),7.34-7.40(m,3H),7.49-7.57(m,2H),7.76-7.78(m,1H),9.68(s,1H)。
製備含0.3克(0.69毫莫耳)根據製法2所獲得酯之13毫升1,2-二氯乙烷溶液,並添加0.21克(1.05毫莫耳)之醋酸銅單水合物。在微波爐中於120℃下照射反應混合物15分鐘,然後冷卻並過濾。用DCM洗滌過濾器上之殘質後,濾液減壓濃縮。用矽膠層析法純化粗產物,用環己烷/乙酸混合物(9/1;v/v)洗提。得到23克米色固體形式之預期化合物(產率=77%)。
熔點=94-97℃。
1H NMR(DMSOd6,250 MHz)δ=1.11(d,J=6.9,6H),1.95(q,J=7.4,2H),2.42(t,J=7.4,2H),2.94(q,J=7.4,1H),3.02(t,J=7.4,2H),3.59(s,3H),6.61(s,1H),7.32(dd,J=2.2 and 8.9,1H),7.47(t,J=7.9,1H),7.56-7.63(m,4H),8.06(d,J=8.9,1H)。
類似實例2之方法進行,始於根據實例3獲得之化合物,得到深米色固體形式之預期產物(產率=93%)。
熔點=128℃
將8.00克(63.41毫莫耳)6-庚炔酸溶於137毫升無水二氯甲烷與0.70毫升無水二甲基甲醯胺之混合物中。滴加16.10克(126.83毫莫耳)草醯氯。在氮氣氛圍及周溫下攪拌反應混合物1小時,然後在氮氣氛圍下蒸發。殘留產物溶於137毫升四氫呋喃中。冷卻混合物至0℃並且分批與14.23克(126.83毫莫耳)第三丁醇鉀混合。於周溫下攪拌反應混合物一小時。然後加入200克冰與200毫升水。用200毫升乙醚萃取混合物3次,然後組合有機相,用硫酸鎂乾燥並且在減壓條件下濃縮。得到7.46克褐色油狀形式之預期化合物(產率=65%)。
1H NMR(DMSOd6,250 MHz)δ=1.40(s,9H),1.40-1.45(m,4H),2.13-2.22(m,4H),2.75(t,J=2.7,1H)。
製備含9.78克(34.07毫莫耳)根據製法3獲得之2-碘-4-(三氟甲基)苯胺與7.45克(40.89毫莫耳)6-庚炔酸之酯於136毫升三乙胺之溶液。添加1.20克(1.70毫莫耳)雙三苯基膦)二氯化鈀與0.3克(1.70毫莫耳)之碘化亞銅。攪拌反應混合物,並於氮氣氛圍下回流加熱3小時,然後在減壓條件下濃縮。殘質溶於乙酸乙酯中,並且用碳酸氫鈉溶液(約1M水溶液)洗滌,然後用1N鹽酸,最後用蒸餾水洗滌。有機相用硫酸鎂乾燥,過濾,並在減壓條件下濃縮。得到12.38克棕色油狀形式之預期化合物(產率=71%)。
1H NMR(DMSOd6,250 MHz)δ=1.40(s,9H),1.53-1.68(m,4H),2.24(t,J=8.4,2H),2.48(t,J=8.1,2H),5.93(s,2H),6.78(d,J=10.2,1H),7.28-7.33(m,2H)。
製備含7.63克(22.35毫莫耳)7-[2-胺基-5-(三氟甲基)苯基]-6-庚炔酸之第三丁酯之44.70毫升1,2-二氯乙烷溶液,並且添加6.69克(33.52毫莫耳)醋酸銅單水合物。攪拌並且回流混合物48小時。在尼龍濾器上過濾反應混合物,然後在減壓條件下濃縮濾液。粗產物經矽膠層析法純化,用環己烷/乙酸乙酯(9/1;v/v)混合物洗提。得到3.42克黃色粉狀形式之預期化合物(產率=45%)。
1H NMR(DMSOd6,250 MHz)δ=1.38(s,9H),1.51-1.57(m,2H),1.67-1.73(m,2H),2.23(t,J=8.4,2H),2.75(t,J=8.7,2H),6.31(s,1H),7.28(dd,J=2.1 and 10.2,1H),7.44(d,J=10.2,1H),7.79(s,1H)。
0℃下,在含200.00毫克(0.59毫莫耳)根據製法5所得酯之0.5毫升DMF溶液中添加46.87毫克(1.17毫莫耳)氫化鈉(60%在油中)。攪拌混合物5分鐘,且仍然在0℃下添加含192.20毫克(0.88毫莫耳)3-(1-甲基乙基)苯磺醯氯之0.5毫升DMF溶液。於周溫下攪拌混合物3小時,然後添加氯化銨溶液以中和微量的氫化鈉。用二氯甲烷萃取混合物。減壓條件下濃縮有機相,所得反應混合物未再純化即用於下一個步驟。
製備含200.00毫克(0.38毫莫耳)根據實施例5所得酯之1毫升DCM溶液,並且添加1毫升三氟醋酸。於周溫下攪拌反應混合物3小時然後溶於DCM,並減壓濃縮。粗產物經矽膠層析法純化,用環己烷/乙酸乙酯混合物(6/4;v/v)洗提。得到50.00毫克白色粉末形式之預期化合物(產率=26%)。
熔點=119℃。
製備含1.03克(3.59毫莫耳)2-碘-4-(三氟甲基)苯胺之5毫升吡啶溶液,並且添加1.00克(4.31毫莫耳)3-(1,1-二甲基乙基)苯磺醯氯。隨後於周溫下攪拌反應混合物4小時。用1 N鹽酸洗滌反應混合物,並且用乙酸乙酯萃取兩次。有機相用硫酸鎂乾燥,然後過濾,在減壓下濃縮。經矽膠層析法純化粗產物,同時用環己烷/乙酸乙酯混合物(梯度從100/0至90/10;v/v)洗提。得到730毫克白色晶體狀粉末之預期化合物(產率=42%)。
熔點=111℃。
在氮氣氛圍條件下製備含250毫克(0.52毫莫耳)根據製法6獲得之化合物、4.93毫克(0.03毫莫耳)碘化亞銅、9.08毫克(0.01毫莫耳)雙(三苯基膦)二氯化鈀與3毫升三乙胺之混合物。於周溫下攪拌反應混合物10分鐘。添加120.31毫克(0.95毫莫耳)5-己炔酸甲酯之3毫升二甲基甲醯胺溶液。在回流下加熱反應混合物3小時,然後用水沖洗並且用乙酸乙酯萃取。有機相用硫酸鎂乾燥並在減壓下濃縮。粗產物經矽膠層析法純化,同時用環己烷/乙酸乙酯混合物(95/5;v/v)洗提。得到115毫克米色晶體粉末形式之預期產物(產率=46%)。
熔點=84℃。
如實例2之同樣方法,始於根據實例7所得之化合物,得到白色粉末狀形式之預期產物(產率=27%)。
熔點=135-141℃。
在氮氣條件下製備含57.93克(119.87毫莫耳)根據製法6獲得之化合物與350毫升二甲基甲醯胺之混合物,並且攪拌直到產物完全溶解。接下來連續添加21.84克(155.83毫莫耳)4-戊炔酸之甲酯、1.14克(5.99毫莫耳)碘化亞銅與1.68克(2.40毫莫耳)雙(三苯基膦)二氯化鈀。在周溫下攪拌混合物15分鐘,然後滴加混合174毫升三乙胺。於80℃下加熱反應混合物14小時,冷卻,然後用1升水水解並用乙酸乙酯萃取。有機相用硫酸鎂乾燥,過濾,在減壓條件下濃縮。所得油狀產物於40℃下溶於異丙醚。所得溶液過濾,在減壓條件下濃縮。所得產物從140毫升異丙醇與60毫升水之混合物中再結晶。得到46.51克白色固體形式之預期產物(產率=78%)。
熔點=77℃。
如實例2之同樣方法進行,始於根據實例9獲得之化合物,得到白色固體形式之預期產物(產率=94%)。
熔點=135℃。
上述根據本發明化合物已示於下表中:
以本發明化合物進行生物測試,以評估其在治療或預防某些神經退化病理學上之潛力。
首先,使用活體外分析法,檢測根據本發明化合物作為NURR-1核受體與RXR核受體所形成雜二聚體之活化劑之能力。
使用轉活化分析法作為主要篩選試驗。取Cos-7細胞經表現人類受體NURR-1-Ga14受體之嵌合體之質體(係一種表現RXR人類受體(RXRα或RXR受體)之質體)與報導子質體5Ga14pGL3-TK-Luc共同轉染。利用一種化學製劑(Jet PEI)進行轉染。
轉染細胞分佈在384-孔板上,靜置24小時。
24小時以後,更換培養基。在培養基中添加試驗產物(最終濃度在10-4
與3.10-10
M之間)。在培養過夜之後,在加入「SteadyGlo」之後,依據製造商(試劑盒)說明,檢測螢光素酶之表現。
使用2×10-5
M(RXR促效劑)4-[[6-甲基-2-苯基-5-(2-丙烯基)-4-嘧啶基]胺基]苯甲酸(稱作XCT0135908)作為參照物。
相對於各雜二聚體之基礎活性,計算誘導程度。其結果以相對於參照物所得誘導程度(以參照物誘導程度設為100%)之誘導程度百分比表示。
根據本發明化合物所展示之誘導程度至高達104%(NURR1/RXRα)與88%(NURR1/RXRγ)並且EC50值降至26 nM(NURR1/RXRα)與20 nM(NURR1/RXRγ)。
根據本發明某些化合物具有低於100 nM之EC50值,尤其針對NURR-1/RXRα雜二聚體。
例如:根據本發明化合物中,得到以下對照結果,以相對於NURR-1/RXR活化劑化合物(XCT0135908)參照物之百分比表示:
亦採用由專利申請案WO 2007/026097之實例76製造之結構極類似根據本發明化合物作為對照試驗,且其結果顯示該化合物在最大效力之半值(EC50)下之濃度至少比本發明所述化合物高10倍。
使用許多種根據本發明化合物進行第一系列活體內測試,其目的為決定其在雄性小鼠C57B16之大腦與血漿中之藥物動力學型態,並且因此證實此化合物可通過血腦障壁。
所使用之方法如下:
採用來自法國Janvier,Le Genest-St-Isle的雄性小鼠C57B16(25至30克)用於此研究(每劑量12隻小鼠)。
給動物餵養標準齧齒動物飼料(Purina Mills,St.Louis,MO),置於籠中並且經過12h/12h光/暗循環,室溫保持溫度於22±2℃並且濕度為55±10%。
小鼠在投藥前不禁食。整個研究中可自由飲水。
經口投與10毫克/公斤之試驗化合物。
經口投與10毫升/公斤時,係經由胃管對動物投與10毫升/公斤於1%甲基纖維素400 cp中製成懸浮液之試驗化合物。
分別在經胃管投藥後15分鐘,30分鐘,1小時,3小時,6小時與8小時,動物在麻醉下安樂死。
每次分別收集每隻死亡動物的血液並且取出大腦。
收集1毫升血液至1.5毫升含有20微升已蒸發濃縮之抗凝血劑之試管(肝素鈉溶液為1000 UI/mL)中,於4500 g下離心3分鐘,獲得約400微升血漿。將200微升血漿分為2份,儲存於-20℃,直到利用蛋白質沉澱法萃取為止,之後經液相層析法串聯質譜法(LC-MS/MS)定量試驗化合物。
在取出大腦後,立即放入液態氮中,於-20℃儲藏以備分析。隨後將大腦於水性/有機溶劑混合物之存在下磨製,得到勻漿物。隨後將這些勻漿物離心,並且利用溶液-溶液萃取法,自所得上清液萃取試驗化合物,然後經過LC-MS/MS定量。
藥物動力學參數係依據Excel中非室性分析法(non-compartmental approach in Excel)決定。採用線性梯形法決定曲線下面積(AUC0-t
)。
例如:實例2、8與10化合物所得結果如下:
採用本發明化合物進行第二系列之活體內測試,其目的為證實該分子確實具有預期之保護神經之效果。
於使用1-甲基-4-苯基-1,2,3,6-四氫吡啶(MPTP)處理小鼠之模式中,測試實例2化合物,以確認其潛在活性。MPTP係一種神經毒素,其透過破壞大腦灰質中某些神經元,造成永久性之帕金森氏症症狀。所用方法如下。
取雄性小鼠C57BL6/J,在本研究開始時為10-12周齡,分為每組8隻。每天經口投與該化合物兩次,總共11天。在用MPTP毒素(20或25毫克/公斤)處理前三天開始投藥。經腹膜內注射MPTP,每天一次,注射5天。在MPTP處理後連續投與試驗化合物3天。一組小鼠僅接受媒劑(0.5%甲基纖維素溶液)。最後一次經胃管投藥後,將動物安樂死,然後取出紋狀體。從紋狀體中萃取多巴胺,以高效液相層析法(HPLC)與電化學檢測法測定多巴胺含量,以每克紋狀體之奈克含量表示(平均值±SEM)。
所獲得之結果附於圖式1至3。
結果顯示,投與MPTP使紋狀體中出現多巴胺含量減少的特徵,且實例2、8與10化合物可隨劑量變化減少MPTP的作用,其係一種造成帕金森式症候群之毒素。
因此,在10與30毫克/公斤觀察到顯著效應:經口投與之本發明化合物可在大腦內重新建立被MPTP抑制之多巴胺能活性。
這種可穿過血腦障壁並在神經元之間具有有利之交流效果之化合物有利於在治療帕金森氏症之藥物中用作有效組分。
此等活體外測試與活體內測試的結果顯示,本發明化合物能夠在某些動物與細胞模式中調整疾病機制,並藉由產生可對抗多巴胺能神經元細胞死亡之神經保護劑來遏止退化過程。因此,該結果證明這些化合物的有利之處在於作為計畫用於預防或治療神經退化性疾病,更特定言之帕金森氏症之藥物之活性組分上之用途。
同樣地,本發明提供一種醫藥組合物,其包括至少一種式(I)化合物,或其中一種醫藥上可接受之鹽作為活性組分。
另一態樣,本申請案目標為包括以這種醫藥組合物於預防或治療涉及NURR-1受體之疾病,尤其為神經退化性疾病,更特定言之帕金森氏症上之用途。
這些醫藥組合物可用常規方法,使用醫藥上可接受賦形劑製備,以得到可採用非經腸式投藥或者較佳為經口投藥之形式,例如藥片或膠囊。
若為注射形式時,宜使用可溶於水性介質之式(I)化合物之鹽形式。如上所示,鹽較佳係由式(Ib)化合物(酸)與藥理學可接受之無毒性鹼之間所形成。該調配物可為含在有可溶性賦形劑存在下的等張性水性介質中之化合物溶液,或者為化合物之凍乾產物,臨用前才添加稀釋溶劑。這些製劑可呈輸液形式或大丸藥的形式注射,依病人的需要決定。
從實際觀點來看,若以非經腸式投與化合物時,人類每日劑量較佳為2至250毫克之間。
用於經口投與的製劑較佳為膠囊或藥片形式,其中包含細粉狀或更佳為微粉化的本發明化合物,與熟悉此項技術者所知賦形劑混合一起,如,例如;乳糖、預糊化澱粉與硬脂酸鎂。
例如,由包含500克細粉狀實例2化合物、500克預糊化澱粉、1250克乳糖、15克十二烷基硫酸鈉與235克聚乙烯吡咯烷酮之混合物製成顆粒。隨後添加該顆粒混合物至20克硬脂酸鎂與80克微晶纖維素中,並在研磨與過篩後,將此混合物分裝成260毫克膠囊。產生各包含50毫克有效組分之膠囊。
從實際觀點來看,若經口投與化合物時,人類的每日劑量較佳為5至500毫克之間。
圖式1至3出示採用實例2、8與10之化合物進行活體內試驗,以證實該分子確實具有所預期神經保護效果時,以HPLC與電化學檢測法測得之多巴胺(DA)含量,以每克紋狀體中奈克含量表示。
無元件符號說明
Claims (8)
- 一種衍生自吲哚之化合物,尤其為適用於醫療之化合物,其特徵為其係選自i)式(I)化合物
- 如請求項1之化合物,其特徵為上式(I)中,R3 代表異丙基。
- 如請求項1之化合物,其特徵為上式(I)中,R3 代表第三丁基。
- 如請求項1至3中任一項之化合物,其特徵為上式(I)中,R2 代表氫原子。
- 一種醫藥組合物,其特徵為其包括至少一種如請求項1至4中任一項之化合物作為活性物質,及至少一種醫藥上可接受之賦形劑。
- 一種如請求項1至4中任一項之吲哚衍生物之用途,其用於製備計畫供治療或預防涉及NURR-1受體之疾病之藥物。
- 如請求項6之用途,其用於製備計畫供治療與預防神經組織退化性疾病之藥物。
- 如請求項7之用途,其特徵為該上述疾病為帕金森氏症。
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