TWI421080B - 新穎二氫苯并氧雜噻氮呯化合物,其製備方法及包含該等化合物之醫藥組合物 - Google Patents
新穎二氫苯并氧雜噻氮呯化合物,其製備方法及包含該等化合物之醫藥組合物 Download PDFInfo
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- TWI421080B TWI421080B TW100132314A TW100132314A TWI421080B TW I421080 B TWI421080 B TW I421080B TW 100132314 A TW100132314 A TW 100132314A TW 100132314 A TW100132314 A TW 100132314A TW I421080 B TWI421080 B TW I421080B
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- C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
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Description
本發明係關於新穎二氫苯并氧雜噻氮呯化合物,其製備方法,包含該等化合物之醫藥組合物,以及其作為AMPA受體之正向異位調節劑之用途。
現在已經認識到興奮性胺基酸(尤其麩胺酸)在神經元可塑性之生理學過程中及在涉及學習及記憶之機制中起關鍵作用。病理生理學研究已清楚地顯示麩胺酸神經傳遞不足與阿滋海默氏(Alzheimer's)病之發生密切相關(Neuro-science and Biobehavioral Reviews,1992,16
,13-24;Progress in Neurobiology,1992,39
,517-545)。
另外,近年來的一些研究已經證實興奮性胺基酸受體亞型的存在及其功能性相互作用(Molecular Neuropharmaco-logy,1992,2
,15-31)。
在該等受體之中,AMPA(α-胺基-3-羥基-5-甲基-4-異噁唑-丙酸)受體似乎最大程度地涉及生理神經元興奮性現象,及尤其涉及記憶過程所涉及的現象。例如,已經顯示學習與AMPA結合海馬體(對記憶及認知過程必要的大腦區域之一)中其受體的增加相關。同樣地,益智劑(nootropic agents)(諸如茴拉西坦(aniracetam))最近被描述為以正面方式調節神經元細胞之AMPA受體(J. Neurochemistry,1992,58
,1199-1204)。
在文獻中,具有苯甲醯胺結構之化合物已被描述為具有該相同作用機制並改善記憶性能(Synapse,1993,15
,326-329)。化合物BA 74尤其是該等新穎藥理製劑中最具活性者。
近來,專利申請案WO 99/42456描述苯并噻二嗪及苯并噻二氮呯化合物作為AMPA受體調節劑,及專利申請案WO 02/100865描述苯并氧雜氮呯化合物對AMPA流具有促進活性。
本發明有關之二氫苯并氧雜噻氮呯化合物係新穎的且組成AMPA受體之有效正向異位調節劑。
更具體言之,本發明係關於式(I)之化合物:
其中R1
表示氫原子、氰基、直鏈或分支鏈(C1
-C6
)烷氧基羰基、(C1
-C6
)烷基磺醯基胺基-(C1
-C6
)烷基(其中烷基部份各為直鏈或分支鏈)、N-羥基甲脒或雜環基,其對映體和非對映異構物,以及亦關於其與醫藥可接受的酸或鹼的加成鹽,應理解術語「雜環基」表示包含1-4個相同或不同及選自氮、氧及硫之雜原子的5員單環芳基,該雜環基可視需要經相同或不同及選自直鏈或分支鏈(C1
-C6
)烷基及直鏈或分支鏈(C1
-C6
)多鹵素烷基的一或多個取代基取代。
在醫藥可接受的酸中,可提到(並無任何限制)鹽酸、氫溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、富馬酸、酒石酸、馬來酸、檸檬酸、抗壞血酸、草酸、甲磺酸、苯磺酸及樟腦酸。
在醫藥可接受的鹼中,可提到(並無任何限制)氫氧化鈉、氫氧化鉀、三乙胺及第三丁胺。
R1
較佳地表示雜環基。
R1
更佳地表示包含至少1個氮原子的5員單環芳族雜環基,該基團可視需要經相同或不同及選自直鏈或分支鏈(C1
-C6
)烷基及直鏈或分支鏈(C1
-C6
)多鹵素烷基的一或多個取代基取代。
R1
有利地表示吡咯基、吡唑基、咪唑基、三唑基、四唑基、異噁唑基、噁唑基、異噻唑基、噻唑基、噻二唑基、二噻唑基及噁二唑基,各基團可視需要經相同或不同及選自直鏈或分支鏈(C1
-C6
)烷基及直鏈或分支鏈(C1
-C6
)多鹵素烷基的一或多個取代基取代。
尤其更佳的為下列化合物,其中R1
表示噁二唑基及噻唑基及,尤其1,2,4-噁二唑基及1,3-噻唑基,各較佳基團可視需要經相同或不同及選自直鏈或分支鏈(C1
-C6
)烷基及直鏈或分支鏈(C1
-C6
)多鹵素烷基的一或多個取代基取代。
作為雜環基的取代基,較佳係甲基或三氟甲基。
基團R1
較佳地處在攜帶其的苯氧基環的間或對位。基團R1
有利地處在間位。
根據本發明之較佳化合物為:
● 8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物;
● 8-[3-(3-甲基-1,2,4-噁二唑-5-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物。
本發明較佳化合物之與醫藥可接受酸或鹼的加成鹽形成本發明之不可分割的一部分。
本發明亦係關於一種從式(II)之化合物開始製備式(I)之化合物的方法:
其中Hal表示鹵素原子,比如氟、氯或溴及R'表示直鏈或分支鏈(C1
-C6
)烷基,其在鹼性介質中與2-氯乙胺反應產生式(III)之化合物:
其中Hal及R'係如上所定義,其接著與含硼化合物反應產生式(IV)之化合物:
其中Hal係如上所定義,其繼而環化產生式(V)之化合物:
其中Hal係如上所定義,其進行保護氮原子的反應以產生式(VI)之化合物:
其中Hal係如上所定義及R"表示胺官能基之保護基因,例如第三丁氧基羰基,其轉變成硼酸,產生式(VII)之化合物:
其中R"係如上所定義,其與式(VIII)之醇反應:
其中R1
係如式(I)所定義,產生式(IX)之化合物:
其中R1
及R"係如上所定義;其隨後進行脫胺官能基保護基因之反應以產生式(I)之化合物,式(I)化合物製備之變體包含水解式(VII)之化合物以產生式(X)之化合物:
其中R"係如上所定義,其與式(XI)之硼酸化合物反應:
其中R1
係如式(I)所定義,產生式(IX)之化合物,其隨後進行脫胺官能基保護基因之反應以產生式(I)之化合物,式(I)化合物製備之另一變體包含於式(IX)化合物製備後,利用習知化學反應以進而改變苯氧基環之取代基,接著式(I)之化合物根據習知分離技術進行純化,並視需要轉變成其與醫藥可接受酸或鹼的加成鹽,若適當,根據習知的分離技術,分離成其異構體(如存在)。
式(II)、(VIII)及(XI)之化合物係可購得或可由熟習該項技術者利用習知化學反應或文獻中描述的化學反應輕易獲得。
式(V)之化合物為新穎的,且為式(I)化合物的合成中間物,亦構成本發明的一部份。
根據本發明之式(I)化合物具有AMPA受體活化性質,使得其可用於治療或預防與年齡、焦慮或抑鬱症狀、漸進性神經退化疾病、阿滋海默氏病、帕金森氏(Parkinson's)症、皮克氏(Pick's)症、亨丁頓氏(Huntington's)舞蹈症、科爾薩科夫氏(Korsakoff's)症、精神分裂症、急性神經退化性疾病之後遺症、額葉及皮質下失智症、局部缺血後遺症及癲癇症之後遺症有關之記憶及認知疾病。
本發明亦關於醫藥組合物,其包括作為活性成分之至少一種式(I)化合物及一或多種適當的惰性無毒賦形劑。在根據本發明之醫藥組合物中,尤其可提到適於經口、非經腸(靜脈內或皮下)或經鼻投與之錠劑或糖衣錠、舌下錠劑、膠囊、口含錠(lozenges)、栓劑、乳膏、軟膏、皮膚凝膠(dermal gels)、可注射製劑及可飲用懸浮液。
有用劑量可根據疾病之性質及嚴重性、投與途徑及患者年齡及體重變化,且範圍由每日0.01至1000 mg,分一或多次投與。
下述實例說明本發明,但是不以任何方式限制。
使用之起始材料為已知的或根據已知操作程序製備的產品。
實例中描述的化合物結構係根據常用分光光度法(紅外、NMR、質譜法)測定。
下述製法產生合成本發明化合物中所用之起始化合物。
步驟A
:N',3-二羥基苯甲脒
將32 ml(0.228 mol)三乙胺加入含15.84 g(0.228 mol)鹽酸羥胺之75 ml DMSO懸浮液中。激烈攪拌該溶液30分鐘及繼而用少量THF稀釋。攪拌10分鐘後,濾掉鹽酸三乙胺及殘質用THF沖洗。濃縮濾液(蒸發掉THF)後,將10 g(83.9 mmol) 3-羥基苯甲腈加入所得溶液中。在周溫下攪拌該溶液16小時。冷水稀釋後,混合物利用乙酸乙酯提取3次及有機相經鹽水洗滌。經MgSO4
乾燥及蒸發後,獲得所期產物。
步驟B
:3-[N'-(乙醯氧基)甲脒基]苯基乙酸酯
將28 ml(0.201 mol)三乙胺加入含10.2 g(67 mmol)以上步驟A中獲得之產物之150 ml CH2
Cl2
懸浮液中。逐滴添加13.9 ml(0.147 mol)乙酸酐及在周溫下攪拌該溶液過夜。水洗3次後,再用鹽水洗滌,有機相經MgSO4
乾燥及蒸發。所得固體溶於異丙醚中,然後過濾及乾燥以產生標題化合物。
熔點:128℃
步驟C
:3-(5-甲基-1,2,4-噁二唑-3-基)苯基乙酸酯
將150 mg對甲苯磺酸加入含9.40 g(39.8 mmol)以上步驟B中獲得之產物之300 ml甲苯溶液中,並利用迪安-斯達克系統(Dean-Stark system),回流下加熱該反應混合物12小時。在利用旋轉蒸發器蒸發掉甲苯後,獲得標題產物。
熔點:94℃
步驟D
:3-(5-甲基-1,2,4-噁二唑-3-基)苯酚
使含8.55 g(39.18 mmol)以上步驟C中獲得之產物之120 ml 1 N HCl溶液在回流下加熱90分鐘,然後,於周溫下攪拌過夜。濾掉沉澱物,獲得標題產物。
熔點:118℃
步驟A
:2-(3-甲氧基苯基)-1,3-噁唑
使包含1.16 ml 1-溴-3-甲氧基苯(9.2 mmol)、2.12 ml 2-(三丁基錫基)-1,3-噁唑(5.9 mmol)及276 mg(0.2 mmol)四[三苯基膦]鈀之50 ml甲苯懸浮液於氬氣中回流下攪拌過夜。利用旋轉蒸發器蒸發掉甲苯,然後將殘質懸浮於乙酸乙酯中。過濾懸浮液後,蒸幹濾液及粗製品經矽膠色譜純化,以CH2
Cl2
及再以CH2
Cl2
/丙酮98/2洗脫,得到油狀標題產物。
步驟B
:3-(1,3-噁唑-2-基)苯酚
將以上步驟A中獲得之產物(250 mg、1.13 mmol)懸浮在10 ml 48% HBr水溶液中,及將該反應混合物在115℃下攪拌過夜。冷卻至周溫後,將該混合物傾入10 ml 10% NaHCO3
溶液中。調節pH至7及水相利用乙酸乙酯萃取。洗滌(飽和NaCl)有機相及乾燥(MgSO4
)以在過濾及蒸發後得到白色固體形式之標題產物。
步驟A
:N'-羥基-4-碘苯甲脒
將17.3 g(249 mmol)鹽酸羥胺並再將35 ml(251 mmol)三乙胺添加至80 ml DMSO中。形成膨體白色沉澱,及反應混合物用少量THF稀釋。攪拌1小時後,過濾沉澱物。收集濾液並再將其轉移至燒瓶中,向其中添加9.55 g(41.7 mmol)4-碘苯甲腈。在周溫下攪拌反應混合物過夜,然後在冰浴中冷卻並添加200 mL水。濾出沉澱物,產生所期產物。
步 驟B
:N'-(乙醯氧基)-4-碘苯甲脒
將6.72 ml(48.2 mmol)三乙胺加入含以上步驟A中獲得之產物(8.43 g,32.17 mmol)之200 ml CH2
Cl2
懸浮液中。逐滴添加3.34 ml(35.4 mmol)乙酸酐及在周溫下攪拌該溶液過夜。水洗3次後,再用鹽水洗滌,有機相經MgSO4
乾燥及蒸發。將所得固體溶於異丙醚中,然後過濾以產生標題產物。
熔點:139℃
步 驟C
:3-(4-碘苯基)-5-甲基-1,2,4-噁二唑
將150 mg對甲苯磺酸加入含以上步驟B中獲得之產物(9.7 g,31.9 mmol)之300 ml甲苯溶液中,並利用迪安-斯達克裝置,使該反應混合物在回流下加熱24小時。蒸幹混合物並且利用真空泵乾燥。
熔點:91℃
步驟D
:5-甲基-3-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯基]-1,2,4-噁二唑
將510 mg(5.2 mmol)乙酸鉀及577 mg(2.28 mmol)雙(頻哪醇根基)硼烷加入含以上步驟C中獲得之產物(500 mg,1.74 mmol)之5 ml DMF溶液中。利用氮氣將反應混合物脫氣30分鐘,然後添加20 mg(0.09 mmol)Pd(OAc)2
。在85℃下加熱該反應混合物3小時。冷卻至周溫後,接著加水,反應混合物利用乙酸乙酯萃取。合併有機相,洗滌(飽和NaCl)及乾燥(MgSO4
)。粗產物經矽膠色譜純化,利用庚烷/乙酸乙酯7/3之混合物洗脫,產生所期產物。
熔點:128℃
步驟E
:[4-(5-甲基-1,2,4-噁二唑-3-基)苯基]硼酸
在18.4 g(86.0 mmol)偏過碘酸鈉及70 ml 1M乙酸銨水溶液存在下,將含以上步驟D中獲得之產物(6.5 g,22.7 mmol)之230 ml丙酮懸浮液攪拌24小時。利用旋轉蒸發器蒸發掉丙酮,及加水後,反應混合物利用乙酸乙酯萃取。合併有機相,洗滌(NaCl)及乾燥(MgSO4
)以在蒸發後產生所期產物。
步驟A
:N'-乙醯基-3-碘苯并醯肼
將DIPEA(1.83 ml,10.48 mmol)及TBTU(2.59 g,8.06 mmol)陸續地加入含3-碘苯甲酸(2.0 g,8.06 mmol)之60 ml THF懸浮液中。在周溫下將該反應混合物攪拌過夜。添加1.19 g(16.12 mmol)乙醯基醯肼及使該反應混合物在回流下加熱30小時。蒸幹後,將殘質溶於含有少量CH2
Cl2
的水中;形成厚沉澱物,過濾出,得到所期產物。
熔點:178℃
步驟B
:2-(3-碘苯基)-5-甲基-1,3,4-噁二唑
使以上步驟A中獲得之產物(2.9 g,9.54 mmol)在120℃下於35 ml POCl3
中加熱3小時。蒸發POCl3
後,將殘質溶於甲苯中及再次蒸幹混合物。將蒸發後之殘質溶於乙酸乙酯中及有機相依次用10% NaHCO3
溶液、水及再用鹽水洗滌。有機相經MgSO4
乾燥,蒸發後產生米白色固體形式之所期產物。
熔點:115℃
步驟C
:2-甲基-5-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯基]-1,3,4-噁二唑
標題產物係按照製法3之步驟D中敘述之程式,以在上述步驟B中敘述之化合物替代3-(4-碘苯基)-5-甲基-1,2,4-噁二唑作為起始物質而獲得。
熔點:153℃
步驟D
:[3-(5-甲基-1,3,4-噁二唑-2-基)苯基]硼酸
標題產品係按照製法3之步驟E中敘述之程式,以在上述步驟C中敘述之化合物替代5-甲基-3-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯基]-1,2,4-噁二唑作為起始物質而獲得。
熔點:254℃
步驟A
:5-溴-2-甲氧基苯磺醯基氯
將35 ml(0.279 mol)4-溴苯甲醚逐滴加入冷卻至0-5℃的氯磺酸(140 mL,2 mol)中。在0℃下攪拌溶液30分鐘,然後在周溫下攪拌約16小時;將其緩慢地傾至冰上,然後再攪拌數分鐘。濾出形成的白色沉澱物,然後用大量水洗滌。
熔點:107℃
步驟B
:5-溴-N-(2-氯乙基)-2-甲氧基苯磺醯胺
將34 ml(0.241 mol)三乙胺加入含13.4 g(0.115 mol)2-氯乙胺鹽酸鹽之150 ml CH2
Cl2
懸浮液中,然後逐滴加入溶於200 ml CH2
Cl2
之30 g(0.105 mol)上述步驟A中獲得之產物。周溫下攪拌溶液2小時,然後用1 N HCl溶液、水和鹽水洗滌。有機相經MgSO4
乾燥及蒸發。將固體再懸浮於乙醚中並過濾產生標題產物。
熔點:150℃
步驟C
:5-溴-N-(2-氯乙基)-2-羥基苯磺醯胺
在周溫下,將200 mL(200 mmol) 1 M BBr3
之CH2
Cl2
溶液加入含29.9 g(91 mmol)上述步驟B中獲得之產物之450 ml CH2
Cl2
懸浮液中。攪拌30分鐘後,將溶液傾至冰/水混合物上,同時繼續攪拌。分離及利用CH2
Cl2
萃取一次後,以鹽水洗滌有機相,經MgSO4
乾燥及蒸發。油狀殘質在庚烷中研磨直到形成結晶。過濾收集標題產物。
熔點:109℃
步驟D
:[(5-溴-2-羥基苯基)磺醯基](2-氯乙基)-胺基甲酸第三丁基酯
將溶於200 ml CH2
Cl2
之11.32 g(81.2 mmol)三乙胺逐滴加入含25.55 g(81.2 mmol)以上步驟C中獲得之產物、17.72 g(81.2 mmol)二-第三丁基二碳酸酯及496 mg(4.06 mmol)二甲基胺基吡啶之500 mL CH2
Cl2
溶液中。在周溫下攪拌混合物過夜。洗滌(飽和NaCl)有機相、乾燥(MgSO4
)及利用旋轉蒸發器蒸發,產生標題產物。
步驟E
:8-溴-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
在溶於1.2 L乙醇之2.69 g(16 mmol)KI及33.6 g(240 mmol) K2
CO3
存在下,將37 g(81 mmol)以上步驟D中獲得之產物在回流下加熱約18小時。冷卻後,濾出鹽及用丙酮沖洗。蒸發後,將濾液溶於水中。混合物利用1 N HCl溶液酸化,然後利用CH2
Cl2
萃取3次。有機相用鹽水洗滌兩次,經MgSO4
乾燥及蒸發。再將所得殘質(~22 g)在庚烷中研磨,然後分離混合物,以除去庚烷上清液。再將殘質在庚烷/異丙醚混合物中研磨,獲得固體。過濾後,迅速地乾燥產物,然後在研缽中研磨。將所得固體溶於庚烷中,攪拌約1小時並過濾產生所期產物。
熔點:129℃
步驟F
:8-溴-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
將溶於125 ml CH2
Cl2
之23.1 g(106 mmol)二-第三丁基二碳酸酯逐滴加入含19.65 g(70.6 mmol)以上步驟E中獲得之產物及259 mg(2 mmol) DMAP之200 ml CH2
Cl2
溶液中。周溫下攪拌反應混合物,在3小時後,添加100 mg DMAP。攪拌溶液45分鐘。利用水及鹽水洗滌兩次後,有機相經MgSO4
乾燥及蒸發。蒸發後之殘質在庚烷中研磨。將所得固體溶於庚烷中並攪拌48小時,產生沉澱物,過濾產生標題產物。
熔點:119℃
步驟G
:[2-(第三丁氧基羰基)-1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基]硼酸
在N2
下,將90 ml(143 mmol) 1.6 M nBuLi溶液加入冷卻至-65℃之含以上步驟F中獲得之產物(21.6 g,57.3 mmol)及40 ml硼酸三異丙酯之210 ml THF溶液中。在-65℃下攪拌反應混合物1小時,及回至周溫。攪拌1小時後,使溶液在冰浴中冷卻及藉由添加320 ml 0.5 M HCl溶液進行水解。CH2
Cl2
萃取3次後,利用鹽水洗滌有機相,經MgSO4
乾燥及蒸發。將殘質溶於庚烷中,及蒸發後,在庚烷中研磨並過濾,產生標題產物。
熔點:197℃
步驟H
:8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
使包含2.5 g(7.28 mmol)以上步驟G中獲得之產物、1.17 g(6.62 mmol)製法1之化合物、1.61 ml(19.9 mmol)吡啶、1.8 g(9.9 mmol)乙酸銅及8 g 4篩子之125 ml CH2
Cl2
懸浮液在周溫下,於大氣中攪拌20小時。濾掉篩子及濾液用125 ml CH2
Cl2
/MeOH混合物沖洗。然後,將6 g SiO2
加至濾液中,再蒸幹。粗產物經矽膠色譜純化,利用CH2
Cl2
/丙酮97/3之混合物洗脫,產生蛋糖霜形式之所期產物。
步驟I
:8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
將1.92 g(4.05 mmol)以上步驟H中獲得之產物之15 ml 4 N HCl之二噁烷溶液在80℃下加熱2小時。蒸幹混合物並真空乾燥。粗產物經矽膠色譜純化,利用CH2
Cl2
/AcOEt之混合物洗脫。將固體溶於異丙醚中,並過濾產生標題產物。
熔點:177℃
步驟A
:8-[3-(1,3-噻唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係按照實例1之步驟H中所述之方法,利用(3-噻唑-2-基)苯酚(其製法描述於Bioorg. Med. Chem. 2003,11
(7),1235-48中)替代製法1之化合物而獲得。
步驟B
:8-[3-(1,3-噻唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:148℃
步驟A
:8-[3-(1,3-噻唑-5-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,利用(3-噻唑-5-基)苯酚(其製法敘述於Bioorg. Med. Chem. 2003,11
(7),1235-48中)替代製法1之化合物而獲得。
步驟B
:8-[3-(1,3-噻唑-5-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:60℃(蛋糖霜)
步驟A
:8-[3-(1,3-噁唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,利用製法2之化合物代替製法1之化合物而獲得。
步驟B
:8-[3-(1,3-噁唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:180℃
步驟A
:8-羥基-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
在5.27 g(34 mmol)四水高硼酸鈉存在下,使4.7 g(13.69 mmol)實例1之步驟G之產物於90 ml THF及90 ml水之混合物中之懸浮液在周溫下攪拌過夜。反應混合物藉由添加飽和NH4
Cl水溶液稀釋,然後利用CH2
Cl2
萃取。合併有機相,洗滌(飽和NaCl),乾燥(MgSO4
)及利用旋轉蒸發器蒸發。在幾滴異丙醚存在下,將蒸發後之殘質溶於庚烷中並研磨;形成沉澱物,濾出產生所期產物。
熔點:143℃
步驟B
:8-[4-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,利用製法3之化合物代替製法1之化合物而獲得。
步 驟C
:8-[4-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟B中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:171℃
步驟A
:8-[3-(5-甲基-1,3,4-噁二唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,藉由實例5之步驟A中獲得之產物與製法4之化合物而非製法1之化合物反應而獲得。
步驟B
:8-[3-(5-甲基-1,3,4-噁二唑-2-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:192℃
步驟A
:8-[3-(乙氧基羰基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,藉由實例5之步驟A中獲得之產物與[3-(乙氧基羰基)苯基]-硼酸反應而獲得。
步驟B
:3-[(1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基)氧基]苯甲酸乙酯
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:120℃
步驟A
:8-(3-氰基苯氧基)-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,藉由實例5之步驟A中獲得之產物與(3-氰基苯基)硼酸之反應而獲得。
步驟B
:3-[(1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基)氧基]-苯甲腈
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯而獲得。
熔點:131℃
步驟A:
8-(3-{[(甲基磺醯基)胺基]甲基}苯氧基)-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,藉由實例5之步驟A中獲得之產物與(3-{[(甲基磺醯基)-胺基]甲基}苯基)硼酸之反應而獲得。
步驟B
:N-{3-[(1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基)氧基]-苄基}甲烷磺醯胺
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:57-60℃
步驟A
:8-苯氧基-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物
標題產物係根據實例1之步驟H描述之方法,藉由實例5之步驟A中獲得之產物與苯基硼酸之反應而獲得。
步驟B
:8-苯氧基-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
標題產物係根據實例1之步驟I中敘述之方法,利用以上步驟A中獲得之化合物替代8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-2-羧酸第三丁基酯1,1-二氧化物而獲得。
熔點:110℃
標題產物係根據製法1之步驟A描述之方法,利用實例8之化合物代替3-羥基苯甲腈而獲得。
熔點:163-166℃
將958 μl(6.87 mmol)三乙胺及再將701 μl(5.04 mmol)三氟乙醋酐逐滴加入實例11之化合物(800 mg,2.29 mmol)之15 ml CH2
Cl2
懸浮液中。周溫下攪拌1小時後,反應混合物用水,再用飽和NaCl溶液洗滌並經MgSO4
乾燥。粗產物經矽膠色譜純化,利用CH2
Cl2
洗脫,產生蛋糖霜形式之所期產物。
步驟A
:3-[(1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基)氧基]苯甲酸
使1.0 g(2.23 mmol)實例7之步驟A中獲得之產物於20 ml 1 N NaOH溶液及1 ml THF中之懸浮液在100℃下攪拌3小時。冷卻至周溫後,反應混合物藉由緩慢地添加1 N HCl溶液進行酸化。濾出白色沉澱物及乾燥,產生所期產物。
步驟B
:3-[(1,1-二氧-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯-8-基)氧基]-N-[(1Z)-N-羥基乙醯亞胺醯基]苯甲醯胺
將516 mg(1.61 mmol)TBTU及隨後之364 μl(2.09 mmol)DIEA陸續地加入以上步驟A中獲得之產物(540 mg,1.61 mmol)之10 ml CH2
Cl2
懸浮液中。攪拌20分鐘後,添加120 mg(1.61 mmol)N-羥基乙脒及使該反應混合物在周溫下攪拌1.5小時。反應混合物用水,然後用飽和NaCl溶液洗滌,乾燥(MgSO4
)及蒸幹。將殘質溶於CH2
Cl2
中;形成白色沉澱,濾出得到所期產物。
步驟C
:8-[3-(3-甲基-1,2,4-噁二唑-5-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物
將35 mg對甲苯磺酸加入390 mg(0.99 mmol)以上步驟B中獲得之產物之50 ml甲苯溶液中,並利用迪安-斯達克系統,使該反應混合物在回流下加熱12小時。蒸發後,粗反應產物經矽膠純化,利用CH2
Cl2
/AcOEt 9/1之混合物洗脫,得到所期產物。
熔點:140℃
藥理學研究
實例A:在大鼠神經元之原始培養物中該等化合物對由AMPA引起之膜去極化之影響的研究。
該試驗包括藉由螢光,體外測量在大鼠胚胎神經元培養物中因AMPA與試驗化合物之接合作用引起的膜去極化,並與僅AMPA的作用相比較。將腦細胞置於培養物中並在細胞培養箱中保留18天。培養後,取出培養基並替換為負載螢光探針之培養基以測量膜電位(20 μl;來自Molecular Devices之膜電位套組)及在周溫下保留1小時。讀取每孔的基礎螢光數(來自Hamamatsu之FDSS儀器),然後,各孔注入AMPA(20 μl;濃度範圍:3至100 μM)並動力學上測量AMPA之作用。然後,將測試化合物引入各孔中(20 μl;濃度範圍與AMPA濃度範圍相交)並動力學上測量化合物之作用。在每次動力學測量結束時,各孔結果為最後15秒之平均讀數。繪製AMPA在不同化合物濃度下之效果曲缐。對於每一濃度之化合物,結果為在該濃度下之AMPA曲缐下的面積,並計算EC2X
(使得由AMPA引起之膜電位加倍之化合物的濃度)。
本發明之化合物極大地加強AMPA之興奮效果。舉例來說,實例1及實例13之化合物分別具有5與18 μM之EC2X
。
目標識別試驗(Behav. Brain Res.,1988,31,47-59)係基於動物的自發探索活動並具有人類情節記憶的特徵。此記憶試驗對老化(Eur. J. Pharm. 1997,325,173-180)及對膽鹼能功能障礙(Pharm. Biochem. Behav.,1996,53(2),277-283)敏感並基於2目標(一者熟悉,另一者新穎)探索之差別。已針對CD1小鼠進行調整之試驗程式包括3個階段,並在同一試驗盒內進行。在持續30分鐘之第一階段期間,使小鼠適應該環境(適應階段)。在第二天進行之第二階段期間,將兩個相同目標置於盒中且小鼠自由探索(熟悉階段)。探索持續時間達到20秒時,將小鼠從盒中移出。在第三階段(5分鐘,回憶階段)中,6小時後,再次呈現同樣目標中之一者(了解「熟悉」目標)以及另一目標(「新」目標)。分別記下兩目標之探索持續時間(用秒表示)。在熟悉階段前60分鐘,事先經口投與載體的對照動物在回憶階段期間以相同時間探索「熟悉」目標及「新」目標,其表明已遺忘先前呈現之目標。接受促進記憶認知之化合物的動物優先地探索新目標,表明已保留先前呈現之目標的記憶。
由本發明化合物得到的結果表明:在0.3、1及3 mg/kg PO之劑量下,新目標比熟悉目標消耗明顯更多之探索,相比「熟悉」目標,「新」目標之探索時間加倍甚至變為三倍,其表明本發明之化合物極大地提高了記憶。
製備分別含有10 mg 8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物之1000錠劑之配方
(實例1)................................................................ 10 g
羥丙基纖維素.........................................................2 g
小麥澱粉.............................................................. 10 g
乳糖................................................................... 100 g
硬脂酸鎂................................................................3 g
滑石.......................................................................3 g
Claims (21)
- 一種式(I)之化合物:
- 如請求項1之式(I)之化合物,其中R1 表示雜環基。
- 如請求項1之式(I)之化合物,其中R1 表示含有至少1個氮原子的5員單環芳族雜環基,該基團可視需要經一或多個相同或不同及選自直鏈或分支鏈(C1 -C6 )烷基及直鏈或分支鏈(C1 -C6 )多鹵素烷基的取代基取代。
- 如請求項1之式(I)之化合物,其中R1 表示吡咯基、吡唑基、咪唑基、三唑基、四唑基、異噁唑基、噁唑基、異噻唑基、噻唑基、噻二唑基、二噻唑基及噁二唑基,各基團可視需要經一或多個相同或不同及選自直鏈或分支 鏈(C1 -C6 )烷基及直鏈或分支鏈(C1 -C6 )多鹵素烷基的取代基取代。
- 如請求項1之式(I)之化合物,其中R1 表示噻唑基或噁二唑基,各基團可視需要經一或多個相同或不同及選自直鏈或分支鏈(C1 -C6 )烷基及直鏈或分支鏈(C1 -C6 )多鹵素烷基的取代基取代。
- 如請求項1之式(I)之化合物,其中R1 表示1,3-噻唑基或1,2,4-噁二唑基,各基團可視需要經一或多個相同或不同及選自直鏈或分支鏈(C1 -C6 )烷基及直鏈或分支鏈(C1 -C6 )多鹵素烷基的取代基取代。
- 如請求項1之式(I)之化合物,其中R1 表示經甲基或三氟甲基取代之1,3-噻唑基或1,2,4-噁二唑基。
- 如請求項1之式(I)之化合物,其中R1 係於攜帶其之苯氧基環的間位上。
- 如請求項1之式(I)之化合物,其為:8-[3-(5-甲基-1,2,4-噁二唑-3-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物;8-[3-(3-甲基-1,2,4-噁二唑-5-基)苯氧基]-3,4-二氫-2H-5,1,2-苯并氧雜噻氮呯1,1-二氧化物;其對映體及非對映異構體,及其與醫藥可接受酸或鹼的加成鹽。
- 一種製備如請求項1之式(I)之化合物的方法,其特徵在於式(II)之化合物用作起始物質:
- 如請求項10之方法,其中鹵素原子係選自氟、氯及溴。
- 如請求項10之方法,其中R"表示第三丁氧基羰基。
- 一種式(V)之化合物:
- 如請求項13之式(V)之化合物,其中鹵素原子係選自氟、氯及溴。
- 一種醫藥組合物,其包括作為活性成分之如請求項1至9中任一項的化合物與一或多種惰性無毒的醫藥可接受載劑組合。
- 如請求項15之醫藥組合物,其用作AMPA受體之調節劑。
- 如請求項15之醫藥組合物,其係用於治療或預防與年齡、焦慮或抑鬱症狀、漸進性神經退化疾病、阿滋海默氏(Alzheimer's)病、帕金森氏(Parkinson's)症、皮克氏(Pick's)症、亨丁頓氏(Huntington's)舞蹈症、科爾薩科夫氏(Korsakoff's)症、精神分裂症、急性神經退化性疾病之後遺症、額葉及皮質下失智症、局部缺血後遺症及癲癇症之後遺症有關之記憶及認知疾病。
- 一種如請求項1至9中任一項之式(I)之化合物之用途,其係用於製備用作AMPA受體之調節劑之藥劑。
- 一種如請求項1至9中任一項之式(I)之化合物之用途,其係用於製備用於治療或預防與年齡、焦慮或抑鬱症狀、漸進性神經退化疾病、阿滋海默氏病、帕金森氏症、皮克氏症、亨丁頓氏舞蹈症、科爾薩科夫氏症、精神分裂症、急性神經退化性疾病之後遺症、額葉及皮質下失智症、局部缺血後遺症及癲癇症之後遺症有關之記憶及認知疾病之藥劑。
- 如請求項1至9中任一項之式(I)之化合物,其用作AMPA受體之調節劑。
- 如請求項1至9中任一項之式(I)之化合物,其係用於治療 或預防與年齡、焦慮或抑鬱症狀、漸進性神經退化疾病、阿滋海默氏病、帕金森氏症、皮克氏症、亨丁頓氏舞蹈症、科爾薩科夫氏症、精神分裂症、急性神經退化性疾病之後遺症、額葉及皮質下失智症、局部缺血後遺症及癲癇症之後遺症有關之記憶及認知疾病。
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