TW202002974A - 神經細胞內鈣濃度上升抑制劑 - Google Patents
神經細胞內鈣濃度上升抑制劑 Download PDFInfo
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- TW202002974A TW202002974A TW108111163A TW108111163A TW202002974A TW 202002974 A TW202002974 A TW 202002974A TW 108111163 A TW108111163 A TW 108111163A TW 108111163 A TW108111163 A TW 108111163A TW 202002974 A TW202002974 A TW 202002974A
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Abstract
本發明以提供神經細胞內鈣濃度上升抑制劑為課題。
本發明提供一種神經細胞內鈣濃度上升抑制劑，其含有下述化學式所代表的環狀胺衍生物或其藥理學上可容許之鹽作為有效成分。
Description
本發明有關於神經細胞內鈣濃度上升抑制劑。
於神經細胞中，細胞內鈣作為細胞內訊息傳導的傳訊者，而對於所謂分化、增殖、成長、生存、細胞凋亡、基因轉錄、膜興奮、神經傳導物質釋出、突觸可塑性之細胞機能的調節有極為重要的作用(非專利文獻1及2)。
相對於平常時的細胞內係鈣濃度被保持在數十~百nmol/L左右，而若對細胞加以各樣的刺激，則該鈣濃度上升為數百nmol/L~數十μmol/L，藉由此細胞內鈣濃度上升，會引起多樣的生命回應。而若必要的生命回應結束，則細胞內鈣濃度會回到平常時。所以，為使細胞的機能正常地作用，透過各樣的受體或離子通道等來嚴密地控制於細胞內外流入或流出之細胞內鈣之濃度是不可欠缺的。
於神經細胞中，若細胞內鈣濃度上升，則會產生為神經細胞之最重要的機能的興奮性傳導。若因某些原因而無法進行神經細胞內的鈣濃度之嚴密的控制， 則導致異常之細胞內鈣濃度上升，而其結果會有許多神經疾病及神經病變產生。此異常之細胞內鈣濃度上升係以例如，超過正常範圍之細胞內鈣濃度、超過正常範圍之細胞內鈣濃度上升持續時間的長度、或超過正常範圍之每單位時間的細胞內鈣濃度上升次數表現。例如，癲癇被認為是因大腦神經細胞之異常興奮，具體而言是因每單位時間的細胞內鈣濃度上升次數異常地增加而被引起之疾病之一。為其治療藥的加巴潘汀(Gabapentin)，已知係與存在於興奮性神經的突觸前之電位相關性鈣通道結合而抑制細胞內鈣流入，抑制興奮性突觸傳導，以發揮抗癲癇作用(非專利文獻3)。所以，神經細胞內鈣濃度上升抑制劑有用於因伴隨神經細胞之細胞內鈣濃度上升的異常興奮而被引起的各種神經疾病及病變之預防或治療。
專利文獻1及2中揭示環狀胺衍生物具有鎮痛作用，但完全沒有揭示或暗示關於神經細胞內鈣濃度上升抑制的效果。
專利文獻1：國際公開第2013/147160號
專利文獻2：國際公開第2016/136944號
非專利文獻1：Berridge，Neuron，1998年，第21 卷，p.13-26
非專利文獻2：Pchitskaya等人，Cell Calcium，2018年，第70卷，p.87-94
非專利文獻3：Fink等人，British Journal of Pharmacology，2000年，第130卷，p.900-906
本發明以提供神經細胞內鈣濃度上升抑制劑為目的。
本發明人等為了解決上述課題而專心致力反覆進行了研究的結果，完成了發現環狀胺衍生物或其藥理學上可容許之鹽對於神經細胞內鈣濃度上升具有顯著之抑制效果。
亦即，本發明提供一種神經細胞內鈣濃度上升抑制劑，其含有下述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽作為有效成分。
[式中，A表示下述通式(IIa)、(IIb)或(IIc)所示之基，
R1表示羥基或氫原子，R2表示甲基、乙基、正丙基、異丙基、正丁基、二氟甲基或2,2,2-三氟乙基，R3表示氫原子、氟原子、溴原子或氯原子，R4各自獨立表示甲基或乙基，n表示1或2，R1表示羥基之情形，附帶＊之碳表示不對稱碳。]
於上述環狀胺衍生物中，較佳為A係通式(IIa)所示之基，此時，R2較佳為甲基、乙基、正丙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子，R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。可藉由限定為此等，而提高神經細胞內鈣濃度上升抑制作用。
於上述環狀胺衍生物中，較佳為A係通式(IIb)所示之基，此時，R2較佳為甲基、乙基、正丙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子，R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。可藉由限定為此等，而提高神經細胞內鈣濃度上升抑制作用。
於上述環狀胺衍生物中，較佳為A係通式(IIc)所示之基，n為1或2，此時，R2較佳為甲基、乙基、正丙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子，R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。可藉由限定為此等，而提高神經細胞內鈣濃度上升抑制作用。
於上述環狀胺衍生物中，較佳為R1係氫原子，此時，R2較佳為甲基、乙基、正丙基、異丙基、正 丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。可藉由限定為此等，而更提高神經細胞內鈣濃度上升抑制作用。
於上述環狀胺衍生物中，較佳為R1係羥基，此時，R2較佳為甲基、乙基、正丙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子，附帶＊之不對稱碳之立體化學較佳為S構形。可藉由限定為此等，而進一步提高神經細胞內鈣濃度上升抑制作用。
又，本發明提供一種用以治療或預防與神經細胞之異常興奮相關之疾病的醫藥組成物，其含有上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽、及藥理學上可容許之賦形劑等。
又，本發明提供一種上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽，其係用以使用於與神經細胞之異常興奮相關之疾病的治療或預防。
又，本發明提供一種上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽的用途，其係用以治療或預防與神經細胞之異常興奮相關之疾病。
又，本發明提供一種上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽的用途，其係用於治療或預防與神經細胞之異常興奮相關之疾病的醫藥之製造。
又，本發明提供一種方法，係治療或預防與神經細胞之異常興奮相關之疾病的方法，其包含將治療有效量的上述通式(I)所示之環狀胺衍生物或其藥理學上 可容許之鹽對於有治療之必要的患者進行投藥。
又，本發明提供一種方法，係抑制神經細胞內鈣濃度上升的方法，其包含使有效量的上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽接觸神經細胞。
又，本發明提供一種方法，係抑制神經細胞內鈣濃度上升的方法，其包含將有效量的上述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽，對需要此之對象進行投藥。
又，上述的與神經細胞之異常興奮相關之疾病並不只受限於此，但可舉出例如，阿茲海默氏症、帕金森氏症、亨汀頓氏舞蹈病、庫賈氏病、肌肉萎縮性脊髓側索硬化症(ALS)、脊髓小腦退化症、脊髓小腦失調症、唐氏症、多發性硬化症、思覺失調症、憂鬱症、躁症、焦慮性神經病、強迫症、恐慌症、躁鬱症、大腦皮質基底核退化症、進行性上眼神經核麻痺症(progressive supranuclear palsy)、路易氏體失智症、額顳葉退化症、為阿茲海默氏症之前病變的輕度知能障礙、額顳葉失智症、癲癇、酒精依賴、藥物依賴、焦慮症狀、不適精神狀態、輕鬱症、循環性情感疾患、神經過敏症、自閉症、昏厥、縱欲、性慾望不足等之中樞神經疾病；頭部外傷、脊髓損傷、腦水腫、感覺機能異常、糖尿病性神經病變、自主神經機能障礙、揮鞭式創傷(whiplash injury)等之中樞及末梢神經病變；老年性失智症、腦血管性失智症、健忘症等之記憶障礙、腦出血、腦中風等及其後遺症/併 發症；無症狀性腦血管病變、暫時性腦缺血發作、高血壓性腦病變、血腦障壁的障礙等之腦血管病變、腦血管病變的再發或者是後遺症；腦血管阻塞後的中樞機能低下症、腦循環/腎循環自動調節功能的障礙或者是異常；原發性常壓性水腦症、阻塞性水腦症、感染性或是代謝性的腦病變等之代謝異常症；視神經脊髓炎、邊緣系腦炎(limbic encephalitis)等之自體免疫疾病；神經上皮組織性腫瘤(神經膠瘤、神經細胞性腫瘤等)、神經鞘性腫瘤(神經鞘瘤、神經纖維瘤等)、腦脊髓膜性腫瘤(腦脊髓膜瘤、其他的間葉性腫瘤)、蝶鞍部腫瘤、轉移性腫瘤等之腫瘤性疾病、睡眠障礙或搔癢病。
本說明書包含為本案之優先權之基礎的日本國專利申請編號2018-066541號的揭載內容。
本發明之環狀胺衍生物或其藥理學上可容許之鹽可抑制神經細胞內鈣濃度上升。
本說明書中使用的以下用語，若無特別註明，則如下述的定義。
本發明之一實施形態的環狀胺衍生物係特徵為以下述的通式(I)表示。
[式中，A表示下述通式(IIa)、(IIb)或(IIc)所示之基，
R1表示羥基或氫原子，R2表示甲基、乙基、正丙基、異丙基、正丁基、二氟甲基或2,2,2-三氟乙基，R3表示氫原子、氟原子、溴原子或氯原子，R4各自獨立表示甲基或乙基，n表示1或2，R1表示羥基之情形，附帶＊之碳表示不對稱碳。]
於上述環狀胺衍生物中，較佳為A係通式(IIa)所示之基，此時，R2較佳為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。而R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為A係通式(IIa)所示之基，此時，R2較佳為正丙基，R3較佳為氫原子或氯原子。而R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為A係通式(IIb)所示之基，此時，R2較佳為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。而R1 為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為A係通式(IIb)所示之基，此時，R2較佳為正丙基，R3較佳為氫原子或氯原子。而R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為A係通式(IIc)所示之基，n為1或2，此時，R2較佳為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。而R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為A係通式(IIc)所示之基，n為1或2，此時，R2較佳為正丙基，R3較佳為氫原子或氯原子。而R1為羥基之情形，附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為R1係氫原子，此時，R2較佳為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。
於上述環狀胺衍生物中，較佳為R1係氫原子，此時，R2較佳為正丙基，R3較佳為氫原子或氯原子。
於上述環狀胺衍生物中，較佳為R1係羥基，此時，R2較佳為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3較佳為氫原子或氯原子。而附帶＊之不對稱碳之立體化學較佳為S構形。
於上述環狀胺衍生物中，較佳為R1係羥基， 此時，R2較佳為正丙基，R3較佳為氫原子或氯原子。而附帶＊之不對稱碳之立體化學較佳為S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIa)所示之基，R1為氫原子，R2為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R2係甲基、乙基或2,2,2-三氟乙基，較佳為R3係氫原子。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIa)所示之基，R1為氫原子，R2為正丙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R3係氫原子。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIa)所示之基，R1為羥基，R2為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R3係氫原子或氯原子。而於本實施形態中，較佳為R2係甲基、乙基或2,2,2-三氟乙基，較佳為R3係氫原子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIa)所示之基，R1為羥基，R2為正丙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R3係氫原子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構 形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIb)所示之基，R1為羥基，R2為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R2係甲基、乙基或2,2,2-三氟乙基，較佳為R3係氫原子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIb)所示之基，R1為羥基，R2為正丙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R3係氫原子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIc)所示之基，n為1或2，R1為羥基，R2為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R2係甲基、乙基或2,2,2-三氟乙基，較佳為R3係氫原子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIc)所示之基，n為1或2，R1為羥基，R2為正丙基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基。於本實施形態中，較佳為R3係氫原 子。而於本實施形態中，較佳為附帶＊之不對稱碳之立體化學係S構形。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIa)所示之基，R1為羥基或氫原子，R2為正丙基、異丙基或正丁基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基，R1為羥基之情形，附帶＊之碳表示不對稱碳。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIb)所示之基，R1為羥基或氫原子，R2為正丙基、異丙基或正丁基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基，R1為羥基之情形，附帶＊之碳表示不對稱碳。
本發明之別的實施形態的環狀胺衍生物係A為通式(IIc)所示之基，R1為羥基或氫原子，R2為正丙基、異丙基或正丁基，R3為氫原子、氟原子、溴原子或氯原子，R4各自獨立為甲基或乙基，n為1或2，R1為羥基之情形，附帶＊之碳表示不對稱碳。
於表1-1、表1-2及表1-3呈示上述通式(I)所示之環狀胺衍生物(以下稱為「環狀胺衍生物(I)」)的較佳具體例，但本發明並不受限於此等。
再者，當環狀胺衍生物(I)中有鏡像異構物、立體異構物等之異構物存在之情形，環狀胺衍生物(I)包含任意一方的異構物及該等之混合物。又，當環狀胺衍生物(I)中有鏡像異構物、立體異構物等之異構物存在之情形，環狀胺衍生物(I)亦可為包含任意一方的異構物或該等之混合物的混合物。又，當環狀胺衍生物(I)中有因構形所致的異構物存在之情形，環狀胺衍生物(I)包含任 意一方的異構物及該等之混合物。作為目的之異構物，可藉由公知方法或按照其之方法來獲得。例如，當環狀胺衍生物(I)中有鏡像異構物存在之情形，環狀胺衍生物(I)亦包含自環狀胺衍生物(I)被分割之一方的鏡像異構物。
作為目的之鏡像異構物，可藉由公知手段(例如，使用光學活性的合成中間產物、或對於最終產物的外消旋混合物使用公知方法或按照其之方法(例如，光學分割))來獲得。
又，環狀胺衍生物(I)中包含環狀胺衍生物(I)的前藥或其藥理學上可容許之鹽。環狀胺衍生物(I)的前藥，係指在活體內酵素性或化學性地被轉換為環狀胺衍生物(I)的化合物。環狀胺衍生物(I)的前藥之活性本體為環狀胺衍生物(I)，但環狀胺衍生物(I)的前藥自身亦可具有活性。
就環狀胺衍生物(I)的前藥而言，可舉出例如，環狀胺衍生物(I)之羥基經烷化、磷酸化或硼酸化的化合物。此等之化合物可依照公知方法而自環狀胺衍生物(I)來合成。
又，環狀胺衍生物(I)的前藥亦可為在記載於公知文獻(「醫藥品的開發」，廣川書店，1990年，第7卷、p.163~198及Progress in Medicine，第5卷，1985年，p.2157~2161)之生理條件下，會變化成環狀胺衍生物(I)者。
環狀胺衍生物(I)亦可被標記同位素，就所標 記之同位素而言，可舉出例如，2H、3H、13C、14C、15N、15O及/或18O。
就環狀胺衍生物(I)之藥理學上可容許之鹽而言，可舉出例如，鹽酸鹽、硫酸鹽、磷酸鹽或者是氫溴酸鹽等之無機酸鹽；或草酸鹽、丙二酸鹽、檸檬酸鹽、富馬酸鹽、乳酸鹽、蘋果酸鹽、琥珀酸鹽、酒石酸鹽、醋酸鹽、三氟醋酸鹽、馬來酸鹽、葡萄糖酸鹽、安息香酸鹽、水楊酸鹽、昔萘酸鹽(xinafoate)、亞甲基雙羥萘酸鹽(Pamoate)、抗壞血酸鹽、己二酸鹽、甲磺酸鹽、對甲苯磺酸鹽或者是桂皮酸鹽等之有機酸鹽。
環狀胺衍生物(I)或其藥理學上可容許之鹽中包含其水合物及溶劑合物。
當環狀胺衍生物(I)或其藥理學上可容許之鹽中有結晶多形體存在之情形，環狀胺衍生物(I)或其藥理學上可容許之鹽中包含全部的結晶多形體及該等之混合物。
環狀胺衍生物(I)或其藥理學上可容許之鹽可依照記載於例如，公知文獻(國際公開第2013/147160號)或公知文獻(國際公開第2016/136944號)的方法來合成。
於本說明書中，「細胞內鈣濃度上升」意指細胞內的鈣濃度上升到異常之神經細胞的興奮性傳導產生的程度，係以例如超過正常範圍之細胞內鈣濃度、超過正常範圍之細胞內鈣濃度上升持續時間的長度、或超過正常範圍之每單位時間的細胞內鈣濃度上升次數作為 指標表示。
於本說明書中，「細胞內鈣濃度上升抑制」意指抑制所產生之異常之神經細胞的興奮性傳導、或維持不產生異常之神經細胞的興奮性傳導的狀態，係以例如正常範圍內之細胞內鈣濃度、正常範圍內之細胞內鈣濃度上升持續時間的長度、或正常範圍內之每單位時間的細胞內鈣濃度上升次數作為指標表示。又，「細胞內鈣濃度上升抑制」亦意指，與不抑制細胞內鈣濃度上升之情形比較，而抑制10%以上、20%以上、30%以上、40%以上、50%以上、60%以上、70%以上、80%以上、90%以上或100%細胞內鈣濃度上升。
又，上述的與神經細胞之異常興奮相關之疾病並不只受限於此，但可舉出例如，阿茲海默氏症、帕金森氏症、亨汀頓氏舞蹈病、庫賈氏病、肌肉萎縮性脊髓側索硬化症(ALS)、脊髓小腦退化症、脊髓小腦失調症、唐氏症、多發性硬化症、思覺失調症、憂鬱症、躁症、焦慮性神經病、強迫症、恐慌症、躁鬱症、大腦皮質基底核退化症、進行性上眼神經核麻痺症、路易氏體失智症、額顳葉退化症、為阿茲海默氏症之前病變的輕度知能障礙、額顳葉失智症、癲癇、酒精依賴、藥物依賴、焦慮症狀、不適精神狀態、輕鬱症、循環性情感疾患、神經過敏症、自閉症、昏厥、縱欲、性慾望不足等之中樞神經疾病；頭部外傷、脊髓損傷、腦水腫、感覺機能異常、糖尿病性神經病變、自主神經機能障礙、揮鞭式創傷等之中樞及末梢神經病變；老年性失智症、腦 血管性失智症、健忘症等之記憶障礙、腦出血、腦中風等及其後遺症/併發症；無症狀性腦血管病變、暫時性腦缺血發作、高血壓性腦病變、血腦障壁的障礙等之腦血管病變、腦血管病變的再發或者是後遺症；腦血管阻塞後的中樞機能低下症、腦循環/腎循環自動調節功能的障礙或者是異常；原發性常壓性水腦症、阻塞性水腦症、感染性或是代謝性的腦病變等之代謝異常症；視神經脊髓炎、邊緣系腦炎等之自體免疫疾病；神經上皮組織性腫瘤(神經膠瘤、神經細胞性腫瘤等)、神經鞘性腫瘤(神經鞘瘤、神經纖維瘤等)、腦脊髓膜性腫瘤(腦脊髓膜瘤、其他的間葉性腫瘤)、蝶鞍部腫瘤、轉移性腫瘤等之腫瘤性疾病、睡眠障礙或搔癢病。
環狀胺衍生物(I)或其藥理學上可容許之鹽可作為用於哺乳動物(例如，小鼠、大鼠、倉鼠、兔、貓、犬、牛、羊、猴或人)，尤其是與人的神經細胞之異常興奮相關之疾病的治療或預防之醫藥來使用。
使用環狀胺衍生物(I)或其藥理學上可容許之鹽作為醫藥之情形，可將環狀胺衍生物(I)或其藥理學上可容許之鹽以其原樣或者是摻合作為醫藥可容許之載體，而進行經口或非經口投藥。
將含有環狀胺衍生物(I)或其藥理學上可容許之鹽作為有效成分的醫藥予以經口投藥之情形，就劑型而言，可舉出例如，錠劑(包含糖衣錠及膜衣錠)、丸劑、顆粒劑、散劑、膠囊劑(包含軟膠囊劑及微膠囊劑)、糖漿劑、乳劑或懸浮劑。又，將含有環狀胺衍生物(I)或 其藥理學上可容許之鹽作為有效成分之醫藥予以非經口投藥之情形，就劑型而言，可舉出例如，注射劑、注入劑、點滴劑、栓劑、擦劑或貼劑。此外，將環狀胺衍生物(I)或其藥理學上可容許之鹽與適當之基劑(例如，酪酸的聚合物、甘醇酸的聚合物、酪酸-甘醇酸的共聚物、酪酸的聚合物與甘醇酸的聚合物之混合物或聚甘油脂肪酸酯)組合而作成緩釋性製劑亦有效。
上述劑型之製劑的調製，可依照製劑領域中一般所使用之公知的製造方法來進行。此情形，可因應需要使其含有製劑領域中一般所使用之賦形劑、結合劑、潤滑劑、崩散劑、甘味劑、界面活性劑、助懸劑或乳化劑等而進行製造。
錠劑的調製，可使其含有例如賦形劑、結合劑、崩散劑或潤滑劑而進行。丸劑及顆粒劑的調製，可使其含有例如賦形劑、結合劑或崩散劑而進行。又，散劑及膠囊劑的調製，可使其含有例如賦形劑而進行。糖漿劑的調製，可使其含有例如甘味劑而進行。乳劑或懸浮劑的調製，可使其含有例如界面活性劑、助懸劑或乳化劑而進行。
就賦形劑而言，可舉出例如，乳糖、葡萄糖、澱粉、蔗糖、微晶纖維素、甘草粉、甘露醇、碳酸氫鈉、磷酸鈣或硫酸鈣。
就結合劑而言，可舉出例如，澱粉糊液、阿拉伯膠液、明膠液、黃蓍膠液、羧甲基纖維素液、褐藻酸鈉液或甘油。
就崩散劑而言，可舉出例如，澱粉或碳酸鈣。
就潤滑劑而言，可舉出例如，硬脂酸鎂、硬脂酸、硬脂酸鈣或純化滑石。
就甘味劑而言，可舉出例如，葡萄糖、果糖、轉化糖、山梨醇、木糖醇、甘油或單糖漿。
就界面活性劑而言，可舉出例如，硫酸月桂酯鈉、聚山梨醇酯80、山梨醇酐單脂肪酸酯或聚乙二醇40硬脂酸酯。
就助懸劑而言，可舉出例如，阿拉伯膠、褐藻酸鈉、羧甲基纖維素鈉、甲基纖維素或皂土。
就乳化劑而言，可舉出例如，阿拉伯膠、黃蓍膠、明膠或聚山梨醇酯80。
此外，於將含有環狀胺衍生物(I)或其藥理學上可容許之鹽作為有效成分之醫藥調製成上述的劑型之情形，可添加製劑領域中一般所使用之著色劑、保存劑、芳香劑、調味劑、安定劑或增稠劑等。
含有環狀胺衍生物(I)或其藥理學上可容許之鹽作為有效成分之醫藥之每1日的投藥量，會因患者的狀態或者是體重、化合物的種類或投藥途徑等而不同。例如，於對成人(體重約60kg)經口投藥之情形，較佳為將環狀胺衍生物(I)或其藥理學上可容許之鹽以1~1000mg之範圍作為有效成分量，分為1~3次投藥。於對成人(體重約60kg)非經口投藥之情形，若為注射劑，則較佳為將環狀胺衍生物(I)或其藥理學上可容許之鹽以每1kg體重0.01~100mg之範圍作為有效成分量，藉由 靜脈注射來投藥。
環狀胺衍生物(I)或其藥理學上可容許之鹽，為了治療或者是預防效果的補足或增強、或是投藥量的減少，與其他藥劑適量摻合或併用亦無妨。環狀胺衍生物(I)或其藥理學上可容許之鹽可與其他藥劑同時投藥，亦可以任意順序連續地進行投藥。就其他藥劑而言，並不只受限於此，但可舉出上述與神經細胞之異常興奮相關之疾病的治療藥。可舉出例如，多奈派齊(Donepezil)、美曼停(Memantine)、加蘭他敏(Galantamine)、重酒石酸卡巴拉汀(Rivastigmine)、恩他卡朋(Entacapone)、左旋多巴(Levodopa)、本捨拉再鹽酸鹽(Benserazide hydrochloride)、卡比多巴(Carbidopa)、唑尼沙胺(Zonisamide)、鹽酸金剛烷胺、甲磺酸溴隱亭(Bromocriptine mesilate)、甲磺酸培高利特(Pergolide mesilate)、卡麥角林(Cabergoline)、鹽酸普拉克索(Pramipexole hydrochloride)水合物、羅替戈汀(Rotigotine)、鹽酸他利克索(Talipexole hydrochloride)、鹽酸羅匹尼羅(Ropinirole hydrochloride)、鹽酸阿樸嗎啡(Apomorphine hydrochloride)水合物、鹽酸希利治林(Selegiline hydrochloride)、鹽酸三己苯尼迪(Trihexyphenidyl hydrochloride)、鹽酸比培力汀(Biperiden hydrochloride)、鹽酸普敏太定(Promethazine hydrochloride)、伊曲茶鹼(Istradefylline)、屈昔多巴(Droxidopa)、利魯唑(Riluzole)、普羅瑞林酒石酸鹽(Protirelin tartrate)水合物、他替瑞林(Taltirelin)水合 物、氯普麻(Chlorpromazine)、氟派醇(Haloperidol)、斯比樂(Sulpiride)、理思必妥(Risperidone)、哌羅匹隆(Perospirone)、奧氮平(Olanzapine)、喹硫平(Quetiapine)、帕羅西汀(Paroxetine)、氟伏沙明(Fluvoxamine)、舍曲林(Sertraline)、艾司西酞普蘭(Escitalopram)、米那普侖(Milnacipran)、度洛西汀(Duloxetine)、米氮平(Mirtazapine)、安莫散平(Amoxapine)、阿米曲替林(Amitriptyline)、伊米帕明(Imipramine)、可洛米普明(Clomipramine)、度硫平(Dosulepin)、曲米帕明(Trimipramine)、去甲替林(Nortriptyline)、洛非帕明(Lofepramine)、司普替林(Setiptiline)、馬普替林(Maprotiline)、米安色林(Mianserin)、碳酸鋰、卡巴馬平(Carbamazepine)、丙戊酸鈉(Sodium valproate)、拉莫三嗪(Lamotrigine)、托非索泮(Tofisopam)、氯西泮(Clotiazepam)、依替唑侖(Etizolam)、勞拉西泮(Lorazepam)、阿普唑侖(Alprazolam)、溴西泮(Bromazepam)、地西泮(Diazepam)、可那氮平(Clonazepam)、氯唑侖(Cloxazolam)、氟氮平酸酯(Ethyl loflazepate)、氟托西泮(Flutoprazepam)、檸檬酸坦度螺酮(Tandospirone citrate)、二硫龍(Disulfiram)、氰胺、阿坎酸(Acamprosate)、丙戊酸(valproic acid)、乙琥胺(Ethosuximide)、苯巴比妥、卡巴馬平(Carbamazepine)、苯妥英(Phenytoin)、氯化阿伯農(Ambenonium Chloride)、氯化騰喜憂(Edrophonium Chloride)、氯化乙 醯膽鹼(Acetylcholine chloride)、溴化新斯的明(Neostigmine bromide)、舒更葡糖鈉(sugammadex sodium)、硫酸甲酯新斯的明(Neostigmine methylsulfate)、比拉西坦(Piracetam)、溴化吡啶斯的明(Pyridostigmini bromidum)、氯化脲酯膽(Bethanechol chloride)、硫酸甲酯新斯的明、硫酸阿托平(Atropine sulfate)水合物、普瑞巴林(Pregabalin)、依帕司他(Epalrestat)、墨西律定(Mexiletine)、阿斯匹靈、鹽酸梯可匹定(Ticlopidine hydrochloride)、硫酸克洛平格(Clopidogrel sulfate)、西洛他唑(Cilostazol)、華法林鉀(Warfarin potassium)、甲磺酸達比加群酯(Dabigatran etexilate mesylate)、甲苯磺酸依度沙班(Edoxaban tosilate)水合物、利伐沙班(Rivaroxaban)、阿哌沙班(Apixaban)、異戊巴比妥(Amobarbital)、右旋佐匹克隆(Eszopiclone)、伊疊唑侖(Estazolam)、夸西泮(Quazepam)、蘇沃雷生(Suvorexant)、司可巴比妥鈉(Secobarbital sodium)、佐匹克隆(Zopiclone)、酒石酸唑吡坦(Zolpidem tartrate)、鹽酸右美托咪定(Dexmedetomidine hydrochloride)、三唑侖(Triazolam)、三氯福司鈉(Triclofos sodium)、硝西泮(Nitrazepam)、鹵噁唑侖(Haloxazolam)、苯巴比妥鈉、氟硝西泮(Flunitrazepam)、鹽酸氟路洛(Flurazepam hydrochloride)、伯替唑侖(Brotizolam)、溴異戊醯脲(Bromovalerylurea)、戊巴比妥鈣(Pentobarbital calcium)、水合三氯乙醛(chloral hydrate)、咪達唑侖 (midazolam)、雷美替胺(Ramelteon)、鹽酸利馬紮封(Rilmazafone hydrochloride)、氯甲西泮(Lormetazepam)或鹽酸納呋拉啡(Nalfurafine hydrochloride)。
以下，根據實施例具體地說明本發明，但本發明並不受限於此等。
就受測化合物而言，係使用表2中所示1-(4-(二甲胺基)哌啶-1-基)-3-(1-乙基-1H-咪唑-2-基)-3-羥基丙烷-1-酮(以下稱為「化合物1」)、(S)-1-(4-(二甲胺基)哌啶-1-基)-3-羥基-3-(1-甲基-1H-咪唑-2-基)丙烷-1-酮(以下稱為「化合物2」)、1-(4-(二甲胺基)哌啶-1-基)-3-羥基-3-(1-(2,2,2-三氟乙基)-1H-咪唑-2-基)丙烷-1-酮(以下稱為「化合物3」)及1-(4-(二甲胺基)哌啶-1-基)-3-(1-甲基-1H-咪唑-2-基)丙烷-1-酮硫酸鹽一水合物(以下稱為「化合物4」)，依照記載於公知文獻(國際公開第2013/147160號及國際公開第2016/136944號)的方法來合成。
此外，作為受測化合物而使用表3中所示1-((R)-3-(3-(二甲胺基)哌啶-1-基)-3-羥基-3-(1-甲基-1H-咪唑-2-基)丙烷-1-酮(以下稱為「化合物5」)、3-羥基-3-(1-甲基-1H-咪唑-2-基)-1-(4-(4-甲哌
-1-基)哌啶-1-基)丙烷-1-酮(以下稱為「化合物6」)、1-(4-(二甲胺基)哌啶-1-基)-3-(1-丙基-1H-咪唑-2-基)-3-羥基丙烷-1-酮(以下稱為「化合物7」)、1-((R)-3-(二甲胺基)吡咯啶-1-基)-3-羥基-3-(1-甲基-1H-咪唑-2-基)丙烷-1-酮(以下稱為「化合物8」)、3-(5-氯-1-甲基-1H-咪唑-2-基)-1-(4-(二甲胺基)哌啶-1-基)-3-羥基丙烷-1-酮(以下稱為「化合物9」)、1-(4-(二甲胺基)哌啶-1-基)-3-(1-異丙基-1H-咪唑-2-基)-3-羥基丙烷-1-酮(以下稱為「化合物10」)、1-(4-(二甲胺基)哌啶-1-基)-3-(1-(2-甲氧基乙 基)-1H-咪唑-2-基)-3-羥基丙烷-1-酮(以下稱為「比較例1之化合物」)及1-(4-(二甲胺基)哌啶-1-基)-3-(1-(3,3,3-三氟丙基)-1H-咪唑-2-基)-3-羥基丙烷-1-酮(以下稱為「比較例2之化合物」)。
表3中所示受測物質當中，化合物5、化合物6及化合物8係依照記載於公知文獻(國際公開第2013/147160號及國際公開第2016/136944號)的方法來合成。化合物7、化合物9及化合物10之化合物係以記載於以下之實施例的方法合成。關於比較例1之化合物及比較例2之化合物，係以記載於以下之參考例的方法合成。又，此等之原料及中間產物，係以記載於以下之參考例的方法合成。再者，關於參考例化合物的合成所使用之化合物中未有合成法之記載之物，係使用市售化合物。
於以下的記載中，NMR資料中所示溶媒名係表示測定中使用之溶媒。又，400MHz NMR光譜係使用JNM-AL400型核磁共振裝置(JEOL Ltd.製)測定。化學位移係以四甲基矽烷為基準，以δ(單位：ppm)表示，訊號分別以s(單峰)、d(雙重峰)、t(三重峰)、q(四重峰)、quint(五重峰)、sept(七重峰)、m(多重峰)、br(寬峰)、dd(雙重雙重峰)、dt(雙重三重峰)、ddd(雙重雙重雙重峰)、dq(雙重四重峰)、td(三重雙重峰)、tt(三重三重峰)表示。ESI-MS光譜係使用Agilent Technologies 1200 Series G6130A(Agilent Technology,Inc.製)測定。溶媒全部使用市售之物。快速管柱層析法(flash column chromatography)係使用YFLC W-prep2XY(Yamazen Corporation製)。
(參考例1)1-丙基-1H-咪唑-2-甲醛(Carbaldehyde)的合成：
於1H-咪唑-2-甲醛(1.00g，10.4mmol)的N,N-二甲基甲醯胺(10.0mL)溶液中加入1-碘丙烷(1.22mL，12.5mmol)與碳酸鉀(2.16g，15.6mmol)，在60℃攪拌3小時。於反應液中加入水，以乙酸乙酯進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(矽膠，己烷/乙酸乙酯)純化殘渣，獲得呈黃色油狀物的1-丙基-1H-咪唑-2-甲醛(0.786g，5.69mmol，55%)。
1H-NMR(400MHz,CDCl3)δ：0.93(3H,t,J=7.4Hz),1.77-1.85(2H,m),4.37(2H,t,J=7.2Hz),7.16(1H,s),7.28(1H,s),9.82(1H,s).
(參考例2)5-氯-1-甲基-1H-咪唑-2-甲醛的合成：
在0℃，於(5-氯-1-甲基-1H-咪唑-2-基)甲醇(0.300g，2.05mmol)的二氯甲烷(20.0mL)溶液中加入戴斯-馬丁(Dess-Martin)試藥(1.04g，2.46mmol)，在相同溫度攪拌3小時。於反應液中加入10%硫代硫酸鈉水溶液與飽和碳酸氫鈉水溶液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(矽膠，己烷/乙酸乙酯)純化殘渣，獲得呈白色固體的5-氯-1-甲基-1H-咪唑-2-甲醛(0.235g，1.62mmol，79%)。
1H-NMR(400MHz,CDCl3)δ：3.98(3H,s),7.24(1H,s),9.70(1H,s).
(參考例3)1-異丙基-1H-咪唑-2-甲醛的合成：
於1H-咪唑-2-甲醛(1.00g，10.4mmol)的N,N-二甲基甲醯胺(10mL)溶液中加入2-碘丙烷(1.26mL，12.5mmol)與碳酸鉀(2.16g，15.6mmol)，在60℃攪拌3小時。於反應液中加入水，以乙酸乙酯進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(矽膠，己烷/乙酸乙酯)純化殘渣，獲得呈黃色油狀物的1-異丙基-1H-咪唑-2-甲醛(0.703g，5.09mmol，49%)。
1H-NMR(400MHz,CDCl3)δ：1.47(6H,t,J=6.6Hz), 5.48(1H,q,J=6.6Hz),7.30(1H,s),7.33(1H,s),9.83(1H,s).
(參考例4)1-(2-甲氧基乙基)-1H-咪唑-2-甲醛的合成：
於1H-咪唑-2-甲醛(1.00g，10.4mmol)的N,N-二甲基甲醯胺(10.0mL)溶液中加入2-溴乙基甲基醚(1.20mL，12.5mmol)、碳酸鉀(2.16g，15.6mmol)與碘化鈉(0.468g，3.12mmol)，在60℃攪拌3小時。於反應液中加入水，以乙酸乙酯進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(矽膠，己烷/乙酸乙酯)純化殘渣，獲得呈白色固體的1-(2-甲氧基乙基)-1H-咪唑-2-甲醛(0.535g，3.47mmol，33%)。
1H-NMR(400MHz,CDCl3)δ：3.32(3H,s),3.67(2H,t,J=5.0Hz),4.59(2H,t,J=5.0Hz),7.23-7.30(2H,m),9.81(1H,s).
(參考例5)1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛的合成：
於1H-咪唑-2-甲醛(0.500g，5.20mmol)的N,N-二甲基甲醯胺(5.20mL)溶液中加入1,1,1-三氟-3-碘丙烷(0.710mL，6.24mmol)及碳酸鉀(1.08g，7.81mmol)，在60℃攪拌5小時。於反應液中加入水，以乙酸乙酯進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(矽膠，己烷/乙酸乙酯)純化殘渣，獲得呈無色油狀物的1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛(0.0863g，0.449mmol，8.6%)。
1H-NMR(400MHz,CDCl3)δ：2.60-2.72(2H,m),4.61(2H,t,J=6.8Hz),7.18(1H,s),7.32(1H,s),9.83(1H,s).
(參考例6)比較例1之化合物的合成：
在-78℃將二異丙胺鋰的四氫呋喃溶液(2.0M，0.969mL，1.94mmol)滴入1-(4-二甲胺基哌啶-1-基)乙酮(0.300g，1.76mmol)的四氫呋喃(6.00mL)溶液，在相同溫度攪拌1小時。在相同溫度，於反應液中加入1-(2-甲氧基乙基)-1H-咪唑-2-甲醛(0.292g，2.12mmol)的四氫呋喃溶液(2.80mL)，攪拌1小時後，在0℃進一步攪拌1小時。於反應液中依序加入飽和氯化銨水溶液、碳酸鉀水溶 液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(NH矽膠，氯仿/甲醇)純化殘渣，獲得呈無色油狀物的比較例1之化合物(0.193g，0.594mmol，34%)。
1H-NMR(400MHz,DMSO-d6)δ：1.04-1.40(2H,m),1.62-1.80(2H,m),2.10-2.35(7H,m),2.46-2.59(1H,m),2.80-2.90(1H,m),2.95-3.10(2H,m),3.24(3H,s),3.61(2H,t,J=5.5Hz),3.90-4.00(1H,m),4.10-4.38(3H,m),5.05-5.11(1H,m),5.38-5.42(1H,m),6.73(1H,s),7.07(1H,s).
(參考例7)比較例2之化合物的合成：
在-78℃將二異丙胺鋰的四氫呋喃溶液(2.0M，0.246mL，0.492mmol)滴入1-(4-二甲胺基哌啶-1-基)乙酮(0.0760g，0.448mmol)的四氫呋喃(1.80mL)溶液，在相同溫度攪拌1小時。在相同溫度，於反應液中加入1-(3,3,3-三氟丙基)-1H-咪唑-2-甲醛(0.0860g，0.448mmol)的四氫呋喃溶液(0.70mL)，攪拌1小時後，在0℃進一步攪拌1小時。於反應液中依序加入飽和氯化銨水溶液、碳酸鉀水溶液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減 壓濃縮。以快速管柱層析法(NH矽膠，氯仿/甲醇)純化殘渣，獲得呈無色油狀物的比較例2之化合物(0.0845g，0.233mmol，52%)。
1H-NMR(400MHz,DMSO-d6)δ：1.03-1.40(2H,m),1.63-1.79(2H,m),2.10-2.33(7H,m),2.47-2.59(1H,m),2.78-2.90(3H,m),2.95-3.13(2H,m),3.90-3.98(1H,m),4.21-4.36(3H,m),5.03-5.10(1H,m),5.49-5.54(1H,m),6.77(1H,s),7.17(1H,s).
ESI-MS：m/z=363(M+H)+.
(實施例1)化合物7的合成：
在-78℃將二異丙胺鋰的四氫呋喃溶液(2.0M，0.969mL，1.94mmol)滴入1-(4-二甲胺基哌啶-1-基)乙酮(0.300g，1.76mmol)的四氫呋喃(6.00mL)溶液，在相同溫度攪拌1小時。在相同溫度，於反應液中加入1-丙基-1H-咪唑-2-甲醛(0.292g，2.12mmol)的四氫呋喃溶液(2.8mL)，攪拌1小時後，在0℃進一步攪拌1小時。於反應液中依序加入飽和氯化銨水溶液、碳酸鉀水溶液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(NH矽膠，氯仿/甲醇)純化殘渣，獲得 呈無色油狀物的化合物7(0.296g，0.960mmol，55%)。
1H-NMR(400MHz,DMSO-d6)δ：0.85(3H,t,J=7.4Hz),1.00-1.40(2H,m),1.61-1.80(4H,m),2.10-2.33(7H,m),2.45-2.59(1H,m),2.73-2.88(1H,m),2.93-3.13(2H,m),3.86-4.00(3H,m),4.25-4.35(1H,m),4.98-5.05(1H,m),5.34-5.40(1H,m),6.72(1H,s),7.07(1H,s).
ESI-MS：m/z=309(M+H)+.
(實施例2)化合物9的合成：
在-78℃將二異丙胺鋰的四氫呋喃溶液(2.0M，0.745mL，1.49mmol)滴入1-(4-二甲胺基哌啶-1-基)乙酮(0.231g，1.36mmol)的四氫呋喃(5.10mL)溶液，在相同溫度攪拌1小時。在相同溫度，於反應液中加入5-氯-1-甲基-1H-咪唑-2-甲醛(0.235g，1.63mmol)的四氫呋喃溶液(1.70mL)，攪拌1小時後，在0℃進一步攪拌1小時。於反應液中依序加入飽和氯化銨水溶液、碳酸鉀水溶液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(NH矽膠，氯仿/甲醇)純化殘渣，獲得呈無色油狀物的化合物9(0.159g，0.505mmol，37%)。
1H-NMR(400MHz,DMSO-d6)δ：1.04-1.21(1H,m),1.28-1.40(1H,m),1.64-1.80(2H,m),2.15(6H,s), 2.24-2.35(1H,m),2.44-2.60(1H,m),2.78-2.88(1H,m),2.95-3.11(2H,m),3.59(3H,s),3.90-3.98(1H,m),4.27-4.35(1H,m),5.00-5.10(1H,m),5.50-5.58(1H,m),6.85(1H,s).
ESI-MS：m/z=315(M+H)+.
(實施例3)化合物10的合成：
在-78℃將二異丙胺鋰的四氫呋喃溶液(2.0M，0.969mL，1.94mmol)滴入1-(4-二甲胺基哌啶-1-基)乙酮(0.300g，1.76mmol)的四氫呋喃(6.00mL)溶液，在相同溫度攪拌1小時。在相同溫度，於反應液中加入1-異丙基-1H-咪唑-2-甲醛(0.292g，2.12mmol)的四氫呋喃溶液(2.8mL)，攪拌1小時後，在0℃進一步攪拌1小時。於反應液中依序加入飽和氯化銨水溶液、碳酸鉀水溶液，以氯仿進行萃取。將有機層以10%氯化鈉水溶液清洗後，以無水硫酸鈉乾燥，進行過濾，並將濾液減壓濃縮。以快速管柱層析法(NH矽膠，氯仿/甲醇)純化殘渣，獲得呈無色油狀物的化合物10(0.302g，0.979mmol，56%)。
1H-NMR(400MHz,DMSO-d6)δ：1.04-1.41(8H,m),1.62-1.80(2H,m),2.16(6H,s),2.25-2.34(1H,m),2.48-2.59(2H,m),2.76-2.88(1H,m),2.95-3.16(2H,m),3.90-4.00(1H,m),4.27-4.38(1H,m),5.05-5.12(1H,m), 5.36-5.42(1H,m),6.77(1H,s),7.20(1H,s).
ESI-MS：m/z=309(M+H)+.
(實施例4)環狀胺衍生物(I)或其藥理學上可容許之鹽對 於大鼠背根神經節(DRG)神經細胞的高鉀誘發細胞內鈣濃度上升之效果：
探討環狀胺衍生物(I)或其藥理學上可容許之鹽之對於DRG神經細胞的高鉀誘發細胞內鈣濃度上升之抑制效果。
(1)DRG的採集
將SD大鼠(4~6週齡，雄；CHARLES RIVER LABORATORIES JAPAN,INC.)於麻醉下切開腹部大動脈，藉由放血使其安樂死。切開後背部之後，取出背柱並進行冰冷卻。切取背柱背側，由背柱腹側將脊髓去除之後，以精密鑷子取出連同神經纖維束的DRG(L4~L6)。使取出之DRG浸漬於經冰冷卻之Leibovitz’s L-15培養基(Thermo Fisher Scientific)，於立體顯微鏡下去除神經纖維束，將DRG分離。
(2)DRG神經細胞的分散培養
將所分離之DRG以眼科剪刀剪出細微的切口之後，以膠原蛋白酶A(Roche Molecular Systems)在37℃保溫20分鐘。以200×g、5分鐘進行離心分離後，去除上清液，加入0.05%的胰蛋白酶-EDTA(Thermo Fisher Scientific)，在37℃保溫5分鐘。加入含1%青黴素-鏈黴素(Thermo Fisher Scientific)及10%胎牛血清(Thermo Fisher Scientific)的DMEM(Thermo Fisher Scientific)，以200×g、5分鐘進行離心分離後，去除上清液。去除上 清液後，加入了作為DRG神經培養培養基所調製之含1%青黴素-鏈黴素及2%B-27(Thermo Fisher Scientific)的Neurobasal-A培養基(Thermo Fisher Scientific)之後，以微量吸管進行吸排混合，使細胞分散。分散後，使其通過70μm細胞過濾器(Greiner)，以200×g、5分鐘進行離心。離心分離後，去除上清液，加入培養基而使細胞懸浮。將此細胞懸浮液接種於預先塗覆層連結蛋白(laminin)(Sigma-Aldrich)之塗覆有聚離胺酸35mm盤(Matsunami Glass Ind.,Ltd.)，在37℃、5%CO2下培養一夜後，用於細胞內鈣濃度變化測定。
(3)鈣螢光色素的荷載
使用Cal-520,AM(註冊商標)(AAT Bioquest)作為螢光鈣色素。由盤中所培養之細胞去除培養基，以灌流液(perfusate)清洗2次之後，添加調製成4μmol/L之Cal-520,AM溶液，在37℃、5%CO2下培養1~1.5小時。灌流液係使用調製成pH7.4之含NaCl(140mmol/L)、KCl(5mmol/L)、CaCl2‧2H2O(1.2mmol/L)、MgCl2‧6H2O(2mmol/L)、D(+)-Glucose(14mmol/L)及HEPES(10mmol/L)的水溶液。然後，藉由對盤以10分鐘、2mL/分鐘灌流灌流液來進行清洗。
(4)細胞內鈣濃度變化之測定
細胞內鈣濃度變化之測定，係藉由利用分析軟體，分析以共焦雷射掃描顯微鏡系統(Nikon Instech Co.,Ltd.) 攝影荷載鈣螢光色素之細胞的螢光強度變化之影像而進行。雷射波長為488nm，影像係以1分鐘中57~60張的間隔取得。
為了誘發因細胞膜之去極化所致細胞內鈣濃度上升來作為神經細胞之興奮誘發，而進行使用了高鉀溶液之處理(以下稱為「高鉀處理」)。對於細胞之高鉀處理、及使用了環狀胺衍生物(I)或其藥理學上可容許之鹽(化合物1~10、比較例1之化合物及比較例2之化合物)之處理(以下稱為「化合物處理」)，係藉由溶液的灌流取代來進行。灌流速度係以貫流泵控制使其成為2mL/分鐘。利用高鉀處理之細胞內鈣濃度上升誘發，係藉由以調製成pH7.4之含NaCl(125mmol/L或115mmol/L)、KCl(32.5mmol/L或30mmol/L)、CaCl2‧2H2O(1.2mmol/L)、MgCl2‧6H2O(2mmol/L)、D(+)-Glucose(14mmol/L)及HEPES(10mmol/L)的水溶液，對細胞處理1分鐘來進行。高鉀處理以5分鐘間隔進行8次。化合物處理係將化合物1~10、比較例1之化合物及比較例2之化合物，以成為100mmol/L之方式溶解於蒸餾水(大塚製藥工廠)後，將以成為30μmol/L之方式而以灌流液稀釋的溶液對細胞處理來進行。化合物處理，係自第3次高鉀處理開始的3分鐘前至第8次高鉀處理結束後連續地進行(以下稱此為「化合物處理組」)。作為對照，自第3次高鉀處理開始的3分鐘前至第8次高鉀處理結束後，連續地進行使用以灌流液稀釋了蒸餾水之溶液的處理(以下稱此為「溶媒處理組」)。但是，關於化合物5~10、比較例 1之化合物及比較例2之化合物，利用高鉀處理之細胞內鈣濃度上升誘發，係藉由以調製成pH7.4之含NaCl(115mmol/L)、KCl(30mmol/L)、CaCl2‧2H2O(1.2mmol/L)、MgCl2‧6H2O(2mmol/L)、D(+)-Glucose(14mmol/L)及HEPES(10mmol/L)的水溶液，對細胞處理1分鐘來進行。
(5)影像分析及細胞內鈣濃度上升抑制率的計算
所攝影之影像藉由ImageJ 1.51j8(National Institutes of Health)進行分析。經時地測定各細胞之輝度值而做出經時變化輝度值曲線，計算各高鉀處理時之經時變化輝度值曲線下面積(AUC)。各細胞的反應率係藉由以下之式1，以第7次及第8次高鉀處理時之AUC之和對第1次及第2次高鉀處理時之AUC之和的比例來計算。接著，以各細胞的反應率及溶媒處理組之全細胞的反應率之平均值為基礎，藉由以下之式2來計算各細胞的細胞內鈣濃度上升抑制率。將各組之全細胞的抑制率之平均值當成各組的抑制率，將溶媒處理組的細胞內鈣濃度上升抑制率當成0%。
各細胞的反應率=第7次及第8次高鉀處理時之AUC之和÷第1次及第2次高鉀處理時之AUC之和×100．．．式1
各細胞的細胞內鈣濃度上升抑制率(%)=(1-各細胞的反應率÷溶媒處理組之全細胞的反應率之平均值)×100．．．式2
於表4呈示化合物1~4對於DRG神經細胞之藉由高鉀處理所誘發的細胞內鈣濃度上升之抑制效果。表中之「抑制率」表示所計算之細胞內鈣濃度上升抑制率(為平均值，各組之細胞數為106~262個)。表中之「化合物1」、「化合物2」、「化合物3」及「化合物4」表示利用各化合物之化合物處理組。表中之「#」及「###」表示與溶媒處理組比較，為統計上顯著(#：p<0.05，###：p<0.001，Dunnet型多重比較檢定)之差。
在任一化合物處理組，與溶媒處理組比較，細胞內鈣濃度上升都被顯著地抑制。亦即，可知化合物1~4會抑制DRG神經細胞之高鉀誘發細胞內鈣濃度上升。又，利用通式(I)中R1為羥基之化合物1~3的化合物處理組之神經細胞內鈣濃度上升抑制率，比起利用R1為氫原子之化合物4的化合物處理組要強。
於表5呈示以與上述同樣之方法所測定的化合物5~10、比較例1之化合物及比較例2之化合物的抑制效果(為平均值，各組之細胞數為60~250個)。表中之「化合物5」、「化合物6」、「化合物7」、「化 合物8」、「化合物9」、「化合物10」、「比較例1之化合物」及「比較例2之化合物」表示利用各化合物之化合物處理組。表中之「###」表示與溶媒處理組比較，為統計上顯著(###：p<0.001、Dunnet型多重比較檢定)之差。
在化合物5~10處理組，細胞內鈣濃度上升被抑制。其中又在化合物5~8處理組，與溶媒處理組比較，細胞內鈣濃度上升被顯著地抑制。另一方面，在比較例1之化合物處理組及比較例2之化合物處理組，細胞內鈣濃度上升並未被抑制。
由上所述，顯示環狀胺衍生物(I)或其藥理學上可容許之鹽為神經細胞內鈣濃度上升抑制劑。
本發明之環狀胺衍生物(I)或其藥理學上可 容許之鹽由於會顯著地抑制神經細胞內鈣濃度上升，而可利用來作為對於與神經細胞之異常興奮相關之疾病的醫藥。
本說明書中引用之全部的刊物、專利及專利申請，係原封不動地藉由引用而併入本說明書。
Claims (10)
- 一種神經細胞內鈣濃度上升抑制劑，其含有下述通式(I)所示之環狀胺衍生物或其藥理學上可容許之鹽作為有效成分，
- 如請求項1之神經細胞內鈣濃度上升抑制劑，其中A為通式(IIa)所示之基。
- 如請求項1之神經細胞內鈣濃度上升抑制劑，其中A為通式(IIb)所示之基。
- 如請求項1之神經細胞內鈣濃度上升抑制劑，其中A為通式(IIc)所示之基。
- 如請求項1之神經細胞內鈣濃度上升抑制劑，其中R 1為氫原子。
- 如請求項1之神經細胞內鈣濃度上升抑制劑，其中R 1 為羥基。
- 如請求項1至6中任一項之神經細胞內鈣濃度上升抑制劑，其中R 2為甲基、乙基、異丙基、正丁基或2,2,2-三氟乙基。
- 如請求項1至6中任一項之神經細胞內鈣濃度上升抑制劑，其中R 2為正丙基。
- 如請求項1至6中任一項之神經細胞內鈣濃度上升抑制劑，其中R 3為氫原子或氯原子。
- 如請求項1至4及6中任一項之神經細胞內鈣濃度上升抑制劑，其中附帶＊之不對稱碳之立體化學為S構形。
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| EP3777858A1 (en) | 2021-02-17 |
| CN111902143B (zh) | 2024-01-02 |
| RU2020135329A (ru) | 2022-05-04 |
| KR20200136895A (ko) | 2020-12-08 |
| CA3095723A1 (en) | 2019-10-03 |
| JP7264158B2 (ja) | 2023-04-25 |
| BR112020019284A2 (pt) | 2021-01-05 |
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