TWI437987B - 具有膀胱排尿肌收縮及尿道括約肌鬆弛之作用的化合物 - Google Patents
具有膀胱排尿肌收縮及尿道括約肌鬆弛之作用的化合物 Download PDFInfo
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- TWI437987B TWI437987B TW099118684A TW99118684A TWI437987B TW I437987 B TWI437987 B TW I437987B TW 099118684 A TW099118684 A TW 099118684A TW 99118684 A TW99118684 A TW 99118684A TW I437987 B TWI437987 B TW I437987B
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Description
本發明乃有關具有膀胱排尿肌收縮及尿道括約肌鬆弛作用之通式(I)(式中,所有符號之說明如同下述)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物(下文將通式(I)所示之化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物簡稱為本發明化合物)以及含有該等作為有效成分之醫藥組成物。
最近,對於有關無法完全放空膀胱(incomplete bladder emptying),無法充分排尿收縮之病狀,提倡低活動性膀胱的新概念。
低活動性膀胱乃由於膀胱收縮障礙,即,膀胱排尿肌之收縮力降低(低活動性排尿肌)之病況,或尿道鬆弛障礙(下部尿道通導障礙),即,尿道括約肌之鬆弛不充分之病況和膀胱收縮障礙之間之合併而造成,隨其原因,可分類為神經性低活動性膀胱、肌原性低活動性膀胱、藥劑性低活動性膀胱、增齡性低活動性膀胱,以及其他原因所造成之低活動性膀胱(例如下部尿道閉塞、感染、精神壓力等所造成之低活動性膀胱)。
神經性低活動性膀胱之病因疾病,例如糖尿病、椎間盤赫尼亞、脊柱狹窄症、吉朗-拜雷症候群(Guillain-Barre syndrome)或帶狀疱疹所致末梢神經炎等之末梢神經障礙、核上型脊髓捐傷、脊髓腫瘤、頸椎症、背髓血管障礙、二分脊椎、脊髓髓膜瘤或脊髓牽扯症候群(Tethered cord syndrome)等之脊髓疾病,癡呆症、腦血管障礙、帕金森症、脊髓小腦變性症、橄欖體橋腦小腦萎縮症(Olivopontocerebellar atrophy;OPCA)、夏依-杜力格症候群(Shy-Drager syndrome)、腦腫瘤、多發性硬化症、腦外傷或腦炎等之腦疾病等,或由骨盤內臟器之外科手術(例如子宮癌或直腸癌)所造成之調節排尿機能之骨盤神經、下腹神經或陰部神經等之外科損傷所引起之低活動性膀胱。
肌原性低活動性膀胱乃多數為原因不詳之膀胱排尿肌之活動降低所造成。
藥劑性低活動性膀胱可舉例如抗膽鹼藥劑、抑制乙醯膽鹼釋放之藥劑等所造成之低活動性膀胱。
又,一般高齡者常見因膀胱活動降低所致排尿障礙,所以隨增齡而發生之低活動性膀胱成為高齡化社會之重要問題之一。
會引起低活動性膀胱之其他原因有例如攝護腺肥大症、膀胱頸部硬化症、子宮脫垂症等下部尿道閉塞、膀胱炎或尿道炎等感染,或精神壓力等(參考非專利文獻1、2及3)。
目前,治療低活動性膀胱使用增強膀胱排尿肌之收縮力用藥劑,或鬆弛尿道括約肌而減弱尿道阻力用藥劑等。該增強膀胱排尿肌之收縮力用藥劑,例如氨甲醯甲膽鹼(bethanechol)等之膽鹼促效藥、雙吡己胺(Distigmine)等乙醯膽鹼酯酶阻斷藥等。然而,例如氨甲醯甲膽鹼會使蓄尿期之膀胱排尿肌也收縮而損及蓄尿功能,同時尚有流淚、發汗、胃腸障礙、腹痛等副作用,對於妊婦、消化性潰瘍、器質性腸管閉塞、氣喘、甲狀腺機能亢進症等之病患有禁忌之問題。乙醯膽鹼酯酶阻斷劑例如用雙吡己胺、新吡己明(Neostigmine)等。乙醯膽鹼酯酶阻斷劑在排尿時增強自骨盤神經末端遊離之乙醯膽鹼之作用,使排尿時之膀胱排尿肌之收縮增強,因此,考慮排尿之生理機構時,雖為優異之藥劑,然而雙吡己胺除使膀胱排尿肌收縮,因其增大的尼古丁狀作用,也使尿道括約肌收縮,增加尿道阻力,因此,排尿效率不良,臨床使用上效果不足,且亦被指摘有高壓排尿之危險性存在(參考非專利文獻4)。
又,使尿道括約肌鬆弛,減弱尿道阻力之藥劑,例如使用他蘇洛辛(Tamsalosin)、哌唑嗪(Prazosin)、阿夫唑嗪(Alfuzosin)、萘駢地爾(Naphtopidil)、烏拉地爾(Urapidil)等之α1受體拮抗劑,據報告對於改善殘尿感、夜間頻尿等之自覺症狀有效,惟有起立性低血壓等之降壓作用之副作用,因此,其投與必須謹慎,並無對於低活動性膀胱有充分之藥效之報告。
換言之,現在使用於低活動性膀胱之治療藥劑,就其效果及安全性之觀點而言,臨床上尚無令人滿意之藥劑。
另一方面,改善馬尾神經組織之血流之化合物,已公開有下列通式(A)所示化合物:
(式中,AA
環示含有1至3個選自氮原子、氧原子及硫原子之雜原子,尚可具有取代基之5或6員環狀基,XA
及YA
分別獨立表示氮原子或碳原子,DA
示可具有取代基之烴基,EA
示結合鍵,氧原子或可經氧化之硫原子,GA
示結合鍵,可具有取代基之烴基或可具有取代基之雜環基,JA
示可經保護之酸性基,WA
示可具有取代基之烴基)。又,通式(A)所示化合物對於起因於馬尾神經壓迫之膀胱障礙有效乙事亦已經公開(參考專利文獻1)。
又,具有神經再生或保護作用之化合物,已公開有下列通式(B)所示化合物:
(式中,E1B
示氧原子或可經氧化之硫原子,RB
示氫原子或C1-8之脂肪族烴基,R1B
示氫原子或C1-4之脂肪族烴基,R2B
示可具有取代基之烴基)(參考專利文獻2)。
本發明化合物到目前為止,未揭示於任何文獻中。
又,本發明化合物能作用在膀胱排尿肌及尿道括約肌,而提升膀胱排尿肌之收縮力,另外,能鬆弛尿道括約肌,藉由上述兩個作用能改善膀胱收縮障礙或尿道鬆弛障礙,此外,更對於例如肌原性、藥劑性、增齡等所造成之低活動性膀胱顯示藥效等迄今皆未見任何記載。另外,本發明化合物對於泌尿器系、循環器系及消化器系之副作用之危險性少,更具備經口吸收性、代謝安定性及藥效持續性等優異藥物動態,也未見任何記載或暗示。
[專利文獻]
專利文獻1:國際公開第2005/053707號說明書。
專利文獻2:國際公開第2006/129788號說明書。
[非專利文獻]
非專利文獻1:Nursing Standard,2005 May 11-17;19(35):57-94;quiz 66-7
非專利文獻2:難治性‧慢性排尿障礙之實況,Urology View,2卷,5號,57-65頁2004年刊。
非專利文獻3:下部尿道機能有關術語基準;國際禁制學會標準化部會報告,日本排尿機能學會雜誌,第14卷第2號,104-118頁,平成15年12月20日發行。
非專利文獻4:神經性膀胱之診斷及治療,第2版,醫學書院,105至106頁,139頁,1990年刊行。
已往,治療低活動性膀胱所使用之膽鹼促效藥,乙醯膽鹼酯酶阻斷劑,α1受體拮抗藥,其作用機制,如非增強膀胱排尿肌之收縮力,就是鬆弛尿道括約肌,僅就其一方發揮作用,所以臨床上之效果不足。另外,因該藥劑也作用在自律神經系統,而被指摘在膀胱以外之臟器上也表現副作用。
有鑑於上述實情,希望有作用於有關排尿之平滑肌,特別是可作用在膀胱排尿肌及尿道括約肌,而使膀胱收縮,且使尿道鬆弛,排尿效果非常高之藥劑問市。
又,對於低活動性膀胱這種慢性疾病,通常,必須長期性投藥,所以考慮對於病患之安全性或方便性,更期待有副作用少,可經口投藥之治療藥劑出現。
本發明研究者經努力從事研究結果,發現本發明化合物能作用在膀胱排尿肌及尿道平滑肌兩種平滑肌,一方面增強膀胱排尿肌之收縮,另一方面鬆弛尿道括約肌等同時具有兩種驚人之作用,可提供能改善膀胱收縮障礙及尿道鬆弛障礙之任意症狀用效果極高之低活動性膀胱治療劑。同時,本發明研究者也發現本發明化合物,對於泌尿器系、循環器系及消化器系之副作用之危險性少,且具有優異之經口吸收性,代謝安定性及藥效持續性等藥物動態,終於完成了本發明。
換言之,本發明有關下述項目:
1. 下述通式(I)所示化合物,其鹽,其溶劑化物或其等之前藥或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物有關:
(式中,符號示α-組態,符號示β-組態,符號示α-組態,β-組態,或其等之任意之混合物)。
2. 如同上述1所記載之化合物,其中,通式(I)所示化合物係(1) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,(2) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,或(3) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4R)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸。
3. 如同上述1所記載之任意比例之混合物,其中,通式(I)所示化合物係2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,其非對映異構物係2-[(2-{(1S,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸。
4. 一種醫藥組成物,其含有下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物為有效成分:
(式中,所有符號之意義如上述1所記載)。
5. 如同上述4所記載之醫藥組成物,其係膀胱排尿肌收縮及尿道括約肌鬆弛劑。
6. 如同上述5所記載之醫藥組成物,其係膀胱收縮障礙及/或尿道鬆弛障礙之預防、治療及/或症狀改善劑。
7. 如同上述6所記載之醫藥組成物,其中,該膀胱收縮障礙及/或尿道鬆弛障礙係低活動性膀胱者。
8. 一種醫藥,係由下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,以及選自α1受體拮抗藥及乙醯膽鹼酯酶阻斷藥之一種以上組合而成者
(式中,所有符號之意義如同上述1所記載)。
9. 一種膀胱排尿肌之收縮及尿道括約肌之鬆弛方法,其特徵為投與哺乳動物有效量之下列通式(I)所示化合物,其鹽,其溶劑化物或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,
(式中,所有符號之意義如同上述1所記載)。
10. 一種預防、治療及/或改善膀胱收縮障礙及/或尿道鬆弛障礙之症狀之方法,其特徵為投與哺乳動物以有效量之下列通式(I)所示化合物,其鹽,其溶劑化物或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,
(上式中,所有符號之意義如同上述1所記載)。
11. 一種下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物之用途,係用於製造膀胱排尿肌收縮及尿道括約肌鬆弛劑者:
(上式中,所有符號之意義如同上述1所記載)。
12. 一種下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物之用途,係用於製造膀胱收縮障礙及/或尿道鬆弛障礙之預防、治療及/或症狀改善劑者:
(上式中,所有符號之意義如同上述1所記載)。
13. 一種用於使膀胱排尿肌收縮,且可鬆弛尿道括約肌之下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,
(上式中,所有符號之意義如同上述1所記載)。
14. 一種用於膀胱收縮障礙及/或尿道鬆弛障礙之預防、治療及/或症狀改善之下列通式(I)所示化合物,其鹽,其溶劑化物,或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,
(上式中,所有符號之意義如同上述1所記載)。
本發明化合物具有膀胱排尿肌之收縮及尿道括約肌之鬆弛作用,所以能改善膀胱收縮障礙及/或尿道鬆弛障礙,係做為低活動性膀胱預防及/或治療劑有效。又,做為低活動性膀胱之各種症狀之改善劑也有效。
又,本發明化合物之泌尿器系副作用之危害性少。例如有效用量範圍內,泌尿器系疾病患者危害性最大之膀胱容量減少等之蓄尿症狀也不出現。
再者,本發明化合物在有效用量範圍內固然安全,即使高用量投與也無血壓或心搏數之變動,對具有高血壓等循環器系病症之背景之病患,其循環器系之副作用之危害性很少。本發明化合物對於心臟功能之影響也很少。
另外,投與本發明化合物之際,在有效用量範圍內,對於消化器系之副作用,例如下痢症狀等消化器症狀也不發生。
又,本發明化合物之膜透過性良好,乃經口吸收性優異之化合物。
此外,本發明化合物對於肝代謝也安定,全身性廓清率也小,所以能持續性發揮其藥效。
由上述顯示本發明化合物係排尿效果極高,安全性優異,且藥物動態也優異之化合物。
本發明乃有關下列通式(I)所示化合物,或其鹽,或其溶劑化物或其等之前藥,或和其非對映異構物之任意比率之混合物,或其環糊精包接化合物,以及含有該等作為有效成分之醫藥組成物,
(上式中,所有符號之意義如同上述所記載)。
本發明中,倘無特別說明,如同該領域者所熟習,符號之示結合於紙面對側向(即,α-組態),符號示結合於紙面上方向(即,β-組態),符號之示α-組態、β-組態或其等之任意之混合物。
本發明化合物中較佳者例如有:
(1) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,
(2) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,或
(3) 2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4R)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,其中,更佳者為實施例17中所記載之2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(化合物(17))。
其鹽以水溶性者為較佳。適佳之鹽例如有鹼金屬鹽(鉀鹽、鈉鹽等),鹼土金屬鹽(鈣鹽、鎂鹽等),銨鹽,藥學上容許之有機胺(四甲銨、三乙胺、甲胺、二甲胺、環戊胺、苯甲胺、苯乙胺、單乙醇胺、二乙醇胺、參(羥甲基)胺基甲烷、離胺酸、精胺酸、N-甲基-D-還原葡糖胺(glucamine)等)鹽或酸加成鹽。
該酸加成鹽以水溶性者為較佳。適佳之酸加成鹽,例如鹽酸鹽、溴氫酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽等之無機酸鹽,或例如乙酸鹽、乳酸鹽、酒石酸鹽、苯甲酸鹽、枸櫞酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙磺酸鹽、葡糖醛酸鹽、葡萄糖酸鹽等之有機酸鹽。
通式(I)所示化合物或其鹽,可藉任意方法轉換成為其溶劑化物。
該溶劑化物以低毒性且水溶性者為較佳。適佳之溶劑化物,例如水、醇系溶劑(例如乙醇等)之溶劑化物。
又,通式(I)所示化合物,其鹽,其溶劑化物之前藥乃指在生物體內藉由酵素或胃酸等之反應而能轉換成為通式(I)所示化合物,其鹽,其溶劑化物之化合物。通式(I)所示化合物,其鹽,其溶劑化物之前藥,可舉例如通式(I)所示化合物之羥基經醯化、烷化、磷酸化、硼酸化之化合物(例如通式(I)所示化合物之羥基被乙醯化、棕櫚醯化、丙醯化、三甲基乙醯化、琥珀醯化、富馬醯化、丙胺醯化、二甲胺基甲基羰化之化合物等);通式(I)所示化合物之羧基被酯化、醯胺化之化合物(例如通式(I)所示化合物之羧基被甲酯化、乙酯化、丙酯化、異丙酯化、丁酯化、異丁酯化、第三丁酯化、苯酯化、羧甲酯化、二甲胺基甲酯化、三甲基乙醯氧基甲酯化、1-{(乙氧基羰基)氧基}乙酯化、酞酯化、(5-甲基-2-側氧基-1,3-二噁環戊烯(dioxolene)-4-基)甲酯化、1-{[(環己氧基)羰基]氧基}乙酯化、甲醯化之化合物等)等。
該等化合物可藉由周知方法製造。又,通式(I)所示化合物之前藥可任意為溶劑化物或非溶劑化物。又,通式(I)所示化合物之前藥亦可為日本廣川書店1990年出版之「醫藥品之開發」第7卷「分子設計」,163至198頁中所記載之生理條件下,能轉變成為通式(I)所示化合物者。
此外,通式(I)所示化合物尚可藉由同位素(例如2
H、3
H、11
C、13
C、14
C、13
N、15
N、15
O、17
O、18
O、35
S、18
F、36
Cl、123
I或125
I等)標識之。
通式(I)所示化合物,其鹽,其溶劑化物之前藥,例如可由通式(I-a)表示之。
(上式中,R1
示甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基等C1-4烷基,其他符號之意義如同上述所記載)。
通式(I)所示化合物,其鹽,其溶劑化物或其等之前藥,或和其非對映異構物之任意比率之混合物,可使用α-、β-或γ-環糊精或其等之混合物,按照日本特公昭50-3362號,特公昭52-31404號或特公昭61-52146號說明書中所記載方法將其轉變成環糊精包接化合物。藉由轉變成環糊精包接化合物可增加其安定性或水溶性,而方便於藥劑上之使用。通式(I)所示化合物,其鹽,其溶劑化物或其等之前藥係包接於環糊精,可藉由差示掃描熱量分析或粉末X光衍射試驗結果而確認之。
又,本發明包括通式(I)所示化合物之非對映異構物,以及通式(I)所示化合物之任意比率之非對映異構物之混合物。
非對映異構物可舉例如下式化合物(20)。
2-[(2-{(1S,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(化合物20)。
上述任意比率之混合物,例如以對於通式(I)所示化合物之非對映異構物之比率在1至20%之混合物為較佳,其中,更佳為通式(I)所示化合物:非對映異構物=9:1之混合物。
本發明化合物可藉由周知方法,例如國際公開第2005/053707號說明書,國際公開第2006/129788號說明書,Synlett 2002,No. 1,239至242頁,或Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2nd Edition(Richard C. Larock,John Wiley & Sons Inc,1999)中所記載方法,下列所示方法,或實施例所示方法等加以適度改進,組配而製造。
例如通式(I)所示化合物,可由下列通式(II)所示化合物,
(式中,AC
示乙醯基,R示羧基之保護基(例如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基等C1-4烷基等))。
與下列通式(III)所示化合物,
(式中,R101
示芳基(例如1-苯基-1H-四唑基、苯基等),R102
示保護基(例如三甲基矽烷基、第三丁基二甲基矽烷基等))
進行下列反應,再進行乙醯基之脫保護反應及氧化反應,再行保護基之脫保護反應而製造。
通式(II)所示化合物和通式(III)所示化合物之反應乃周知反應,例如在有機溶劑(例如無水四氫呋喃、二甲氧基乙烷、甲苯、二甲基甲醯胺等)中,鹼(例如六甲基二矽胺化鉀、二異丙基胺化鋰、丁基鋰等)之存在下,在約-100至-20℃之溫度下進行反應。
乙醯基等保護基之脫保護反應為周知者,可按照下述方法進行。
羧基之保護基,例如甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基等C1-4烷基,烯丙基、三氯乙基、苯甲基(Bn)、苯乙基等。
羥基之保護基,例如甲基、三苯甲基、甲氧基甲基(MOM)、1-乙氧基乙基(EE)、甲氧基乙氧基甲基(MEM)、2-四氫哌喃基(THP)、三甲基矽烷基(TMS)、三乙基矽烷基(TES)、第三丁基二甲基矽烷基(TBDMS或TBS)、第三丁基二苯基矽烷基(TBDPS)、乙醯基(Ac)、三甲基乙醯基、苯甲醯基、苯甲基(Bn)、對-甲氧基苯甲基、烯丙氧基羰基(Alloc)、2,2,2-三氯乙氧基羰基(Troc)等。
羧基或羥基之保護基,除上述例舉之外,只要容易且能選擇性地去除之基,就別無限制。例如T.W.Greene,Protective Groups in Organic Synthesis,Wiley,New York,1999年所記載者可供利用。
羧基或羥基之保護基之脫保護反應為十分周知者,其例舉如下:
(1)藉鹼性水解之脫保護反應,
(2)酸性條件下之脫保護反應,
(3)藉加氫分解之脫保護反應,
(4)矽烷基之脫保護反應,
(5)使用金屬之脫保護反應,
(6)使用金屬配位化合物之脫保護反應等。
上述方法具體說明如下:
(1)藉鹼性水解之脫保護反應,例如在有機溶劑(例如甲醇、四氫呋喃、二噁烷等)中,使用鹼金屬之氫氧化物(例如氫氧化鈉、氫氧化鉀、氫氧化鋰等),鹼土金屬之氫氧化物(例如氫氧化鋇、氫氧化鈣等),或碳酸鹽(例如碳酸鈉、碳酸鉀等)或其水溶液或其混合物,在約0至40℃之溫度下進行反應。
(2)酸性條件下之脫保護反應,例如在有機溶劑(例如二氯甲烷、氯仿、二噁烷、乙酸乙酯、苯甲醚等)中,有機酸(例如乙酸、三氟乙酸、甲磺酸、對-甲苯磺酸等),或無機酸(例如鹽酸、硫酸等)或其混合物(例如溴化氫/乙酸等)中,在約0至100℃溫度下進行反應。
(3)藉加氫分解之脫保護反應,例如在溶劑(例如醚系(四氫呋喃、二噁烷、二甲氧基乙烷、二乙醚等),醇系(例如甲醇、乙醇等),苯系(例如苯、甲苯等),酮系(例如丙酮、甲乙基酮等),腈系(例如乙腈等),醯胺系(例如二甲基甲醯胺系等),水,乙酸乙酯,乙酸或其等2種以上之混合溶劑等)中,觸媒(例如鈀-碳、鈀黑、氫氧化鈀、氧化鉑、雷氏(Raney)鎳等)之共存下,常壓或加壓下之氫氣氛圍中,或甲酸銨之存在下,在約0至200℃之溫度下進行反應。
(4)矽烷基之脫保護反應,例如在可跟水混合之有機溶劑(例如四氫呋喃、乙腈等)中,使用四丁基銨氟化物在約0至40℃之溫度下進行反應。
(5)使用金屬之脫保護反應,例如在酸性溶劑(例如乙酸、pH值約4.2至7.2之緩衝液中或該等溶液和四氫呋喃等有機溶劑之混合液)中,粉末狀鋅之存在下,必要時在超音波處理下,以約0至40℃之溫度進行反應。
(6)使用金屬配位化合物之脫保護反應,例如在有機溶劑(例如二氯甲烷、二甲基甲醯胺、四氫呋喃、乙酸乙酯、乙腈、二噁烷、乙醇等),水或其等之混合溶劑中,捕集(trap)劑(例如氫化三丁錫、三乙基矽烷、雙甲酮、味啉、二乙胺、吡咯啶等),有機酸(例如乙酸、甲酸、2-乙基己酸等)及/或有機酸鹽(例如2-乙基己酸鈉、2-乙基己酸鉀等)之存在下,膦系試劑(例如三苯膦等)之存在或不存在下,使用金屬配位化合物(例如肆-三苯膦鈀(0)、二氯化雙(三苯膦)鈀(II)、乙酸鈀(II)、氯化參(三苯膦)銠(I)等,在約0至40℃之溫度下進行反應。
上述之外,例如依據T. W. Greene,Protective Groups in Organic Syntheis,Wiley,New York,1999年中所記載方法等,也可進行脫保護反應。
從業者應容易瞭解選擇適當之上述脫保護反應,即可容易地製造目的之本發明之有效成分之化合物。
氧化反應乃周知反應,例如在有機溶劑(例如氯仿、二氯甲烷、四氫呋喃、四苯、乙腈、乙酸乙酯、水等)中,或其等之混合溶劑中,使用TEMPO試劑(2,2,6,6-四甲基六氫吡啶1-氧化物(1-oxyl))及再氧化劑(過氧化氫水溶液、次氯酸鈉、3-氯過苯甲酸、碘化苯二乙酸酯、過氧化單硫酸鉀(OXONE,商品名)等),在季銨鹽(例如四丁銨氯化物、四丁銨溴化物等)之存在下或不存在下,無機鹽(例如溴化鈉、溴化鉀等)之存在下或不存在下,無機鹼(例如碳酸氫鈉、乙酸鈉等)之存在下或不存在下,以約-20至60℃之溫度下進行反應。
本發明說明書之各反應中,所使用原料化合物為周知化合物,或可藉由周知方法簡單地製成。例如通式(II)所示化合物可依據國際公開第2006/129788號說明書所記載方法容易地製成。又,通式(III)所示化合物,例如可藉由下列實施例所記載方法,同樣容易地製成。
本發明說明書之各反應中,須加熱之反應係如同業者所周知可利用水浴、油浴、砂浴,或微波設備而進行。
本發明說明書之各反應中,可適度使用負載於高分子聚合物(例如聚苯乙烯、聚丙烯醯胺、聚丙烯、聚乙二醇等)之固相負載試劑。
本發明說明書之各反應中,反應產物可藉由一般精製方法,例如常壓下或減壓下之蒸餾、使用矽膠或矽酸鎂之高速液相層析法、薄層層析法、離子交換樹脂、除渣樹脂或管柱層析,或洗淨,再結晶等方法而精製之。精製可在每一反應中進行,或於若干反應終了後再進行。
本發明化合物之副作用非常低,做為醫藥使用而言,十分安全。
本發明化合物對有關低活動性膀胱之膀胱排尿肌及尿道括約肌兩種平滑肌產生作用,係具有提高膀胱排尿肌之收縮力,同時可鬆弛尿道括約肌之特性。一般而言,能作用在平滑肌之藥物,只要能促進收縮力者,對於任何平滑肌皆能發揮收縮作用,而能促進鬆弛力者,對於任何平滑肌皆能誘導鬆弛作用,罕見像本發明化合物對於某種平滑肌促進其收縮,同時對於另外之平滑肌則促進其鬆弛之藥物。
本發明化合物作用在平滑肌上,特別是作用於膀胱排尿肌及尿道括約肌,促進膀胱排尿肌之收縮及尿道括約肌之鬆弛,所以能改善膀胱收縮障礙及尿道鬆弛障礙,做為低活動性膀胱之預防及/或治療劑有效,又作為對低活動性膀胱中之各種症狀,例如尿勢下降、尿線分割、尿線斷絕、排尿遲緩、腹壓排尿、殘尿感覺、溢流性尿失禁、閉尿及/或終尿下滴等之改善劑皆能收效。
又,本發明化合物做為脊柱管狹窄症,頸椎症,末梢神經系疾病,免疫症(肌萎縮性側索硬化症(ALS)、多發性硬化症、夏依-格林症候群、慢性風濕性關節炎、全身性紅斑症等自身免疫疾病、臟器移植後之排斥反應等),過敏性疾病(例如支氣管氣喘、過敏性鼻炎、過敏性結膜炎、異位性皮膚炎、食物過敏症等)。神經細胞死亡,月經困難症,早產,流產,秃頭症,青光眼等網膜神經障礙,勃起不全,關節炎,肺部傷害,肺纖維症,肺氣腫,支氣管炎,慢性閉塞性呼吸器疾病,肝傷害,急性肝炎,肝硬變,休克,腎炎(急性腎炎、慢性腎炎),腎不全,胰炎,全身性炎症反應症候群,敗血症,血球貪食症候群,巨噬細胞活化症候群,史底耳氏病(Still’s disease),川崎病,熱傷,全身性肉芽腫,潰瘍性大腸炎,克隆氏病(Crohn’s disease),人工透析時之高細胞素血症,多臟器不全,骨疾症(骨折、再骨折、難治性骨折、骨癒合不全、假關節病變、骨軟化症、變形性骨炎、僵直性脊椎炎、癌骨轉移、變形性關節症及其等類似疾病之骨、軟骨損壞等)等之預防及/或治療也有效。
本發明化合物可為了:1)該化合物之預防及/或治療效果之補足及/或增強,2)該化合物之動態、吸收改善、降低投與量,及/或3)該化合物之副作用之減輕,而配合其他藥劑,作為併用劑而投與。
本發明化合物和其他藥劑之併用劑,可在一種製劑中調配兩種成分而以調配劑之形態投與,亦可製成分別之製劑而投與。以上述分別製劑形態投與時,包括同時投與及時間差投與。又,時間差投與時,可先投與本發明化合物,再投與其他藥劑,或先投與其他藥劑,再投與本發明化合物,各個投與方法可相同或不同。
補足及/或增強本發明化合物效果用之其他製劑可舉例如乙醯膽鹼酯酶阻斷藥(例如雙吡己胺、新吡己胺等),或α1受體拮抗藥(例如他蘇洛辛、哌唑嗪、阿夫唑嗪、萘駢地爾、烏拉地爾等)等。
本發明化合物和其他藥劑間之重量比率並無特別侷限。
其他藥劑可任意調配2種以上之同種或異種之藥劑而投與。
又,補足及/或增強本發明化合物之效果之其他藥劑,除去已發現之依據上述機制作用之藥劑外,也包括日後可能發現之藥劑。
依據上述目的使用本發明化合物,或本發明化合物和其他藥劑之併用劑時,一般,對於全身或局部,以經口或非經口形態投與之。
該投與量,視所使用藥物種類而異,同時,隨年齡、體重、症狀、治療效果、投與方法、處理時間等而有所不同。一般,成人一人計,一次以1ng至100mg範圍下,一日一次至數次經口投與,或成人一人計,一次以0.1ng至10mg範圍下,一日一次至數次以非經口投與,或一日1小時至24小時範圍內,以靜脈內持續投與之。
自然,如同上述之投與量係隨各條件而變動,可能少於上述投與量,也可能必需超過上述範圍而投與。
本發明化合物,或本發明化合物和其他藥劑間之併用劑,投與之際,可使用經口投與用內服用固形劑、內服用液劑,以及非經口投與用注射劑、外用劑、栓劑、吸入劑等。
經口投與用內服用固形劑包括錠劑、丸劑、膠囊劑、散劑、顆粒劑等。膠囊劑包括硬膠囊劑及軟膠囊劑。
該內服用固形劑中,一種或一種以上之活性化合物可單獨,或混合賦形劑(例如乳糖、甘露糖醇、葡萄糖、微晶狀纖維素、澱粉等),黏結劑(例如羥丙基纖維素、聚乙烯吡咯啶酮、矽酸鋁酸鎂等),崩解劑(纖維素乙醇酸鈣等),潤滑劑(硬脂酸鎂等),安定劑,溶解補助劑(例如麩胺酸、天冬胺酸等)等,按照一般方法製劑而使用。又,必要時可使用包衣劑(例如白糖、明膠、羥丙基纖維素、羥丙基甲基纖維素酞酸酯等)被覆之,或以2層以上加以被覆之。又,也包括明膠等容易吸收之物質之膠囊。
經口投與用之內服用液劑包括藥劑上容許之水劑、懸濁劑、乳劑、糖漿劑、酏劑等。該類液劑中,一種或一種以上之活性物質係以一般使用之稀釋劑(例如精製水、乙醇或其混合液等)加以溶解,懸濁或乳化而成。此外,該液劑中,尚可含有濕潤劑、懸濁化劑、乳化劑、甘味劑、風味劑、芳香劑、保存劑、緩衝劑等。
非經口投與用之外用劑之形態,例如軟膏劑、凝膠劑、乳霜劑、濕布劑、貼附劑、擦劑、噴霧劑、吸入劑及噴塗劑等。該等劑含有一種或一種以上之活性物質,藉由周知方法或一般常用配方而製成。
軟膏劑係依據周知或一般常用配方而製造。例如以一種或一種以上之活性物質與基劑碾磨或熔解而調製之。軟膏基劑係選自周知或一般常用者。例如將選自高級脂肪酸或高級脂肪酸酯(例如己二酸、肉豆蔻酸、棕櫚酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕櫚酸酯、硬脂酸酯、油酸酯等),蠟類(例如蜜蠟、鯨蠟、地蠟等),界面活化劑(例如聚氧化乙烯烷基醚磷酸酯等),高級醇類(例如鯨蠟醇、硬脂醇、鯨蠟硬脂醇(cetostearyl alcohol)等),矽油(例如二甲基聚矽氧烷等),烴類(例如親水性凡士林、白色凡士林、精製羊毛脂、液態石蠟等),二醇類(例如乙二醇、二乙二醇、丙二醇、聚乙二醇(macrogol)等),植物性油(例如蓖麻籽油、橄欖油、芝麻油、松節油等),動物性油(例如貂油、蛋黃油、角鯊烷、角鯊烯等),水,吸收促進劑,皮疹防止劑之一種或兩種以上混合使用。除上述之外,尚可含有保濕劑、保存劑、安定化劑、抗氧化劑、賦香劑等。
凝膠劑係依據周知或一般常用配方而製成。例如熔解一種或一種以上之活性物質於基劑中而調製之。凝膠基劑係選自周知或一般常用者。例如自低級醇類(例如乙醇、異丙醇等)、凝膠化劑(例如羧甲基纖維素、羥乙基纖維素、羥丙基纖維素、乙基纖維素等)、中和劑(例如三乙醇胺、二異丙醇胺等)、界面活化劑(例如單硬脂酸聚乙二醇等)、樹膠(gum)類、水、吸收促進劑、皮疹防止劑等中選擇一種或兩種以上而混合使用。除上述之外,尚可包含保存劑、抗氧化劑、賦香劑等。
乳霜劑係依據周知或一般常用配方而製成。例如熔解或乳化一種或兩種以上之活性物質於基劑中而調製之。乳霜基劑係選自周知或一般常用者。例如將選自高級脂肪酸酯,低級醇類,烴類,多元醇(例如丙二醇、1,3-丁二醇等)、高級醇類(例如2-己基癸醇、鯨蠟醇等),乳化劑(例如聚氧化乙烯烷基醚類、脂肪酸酯等),水,吸收促進劑,皮疹防止劑之一種或兩種以上混合而使用。除上述之外,尚可包含保存劑、抗氧化劑、賦香劑等。
濕布劑係依據周知或一般常用之配方而製成。例如熔解一種或兩種以上之活性物質於基劑中作為練合物展延塗布於載體上而製造。
濕布基劑係選自周知或一般常用者。例如將選自增黏劑(例如聚丙烯酸、聚乙烯吡咯啶酮、阿拉伯膠、澱粉、明膠、甲基纖維素等),潤濕劑(尿素、甘醇、丙二醇等),填充劑(高嶺土、氧化鋅、滑石、鈣、鎂等),水,溶解輔助劑,黏性賦與劑,皮疹防止劑等中一種或兩種以上混合而使用。此外,尚可包含保存劑、抗氧化劑、賦香劑等。
貼附劑係依據周知或一般常用配方而製成。例如熔解一種或兩種以上之活性物質於基劑中,展延塗布於載體上而製造。貼附劑用基劑係將選自周知或一般常用者。例如選自高分子基劑、油脂、高級脂肪酸、黏性賦與劑、皮疹防止劑之一種或兩種以上混合而使用。再者,可包含保存劑、抗氧化劑、賦香劑等。
擦劑係依據周知或一般常用配方而製成。例如將一種或兩種以上之活性物質溶解、懸濁或乳化於選自水,醇類(例如乙醇、聚乙二醇等),高級脂肪酸,甘醇,肥皂,乳化劑,懸濁化劑等之一種或兩種以上之混合物中而製造。再者,亦可包含保存劑、抗氧化劑、賦香劑等。
噴霧劑,吸入劑及噴塗劑除去一般常用之稀釋劑以外,尚可含有亞硫酸氫鈉等安定劑,以及含有賦與等張性之緩衝劑例如氯化鈉,枸櫞酸鈉或枸櫞酸等之等張劑。
非經口投與用之注射劑,例如溶液、懸濁液、乳濁液以及使用時溶解或懸濁於溶劑而使用之固形注射劑等。注射劑乃將一種或兩種以上之活性物質溶解、懸濁或乳化於溶劑中而使用,溶劑可使用例如注射用蒸餾水、生理食鹽水、植物性油、丙二醇、聚乙二醇、乙醇等醇類等以及該等之組合。再者,該注射劑中尚可含有安定劑、溶解輔助劑(例如麩胺酸、天冬胺酸、吐溫80(Polysorbate 80,註冊商標)等),懸濁化劑、乳化劑、止痛劑、緩衝劑、保存劑等。該等係於最終步驟中藉殺菌或無菌處理等而製造。另外,也可製成無菌固形劑,例如製成冷凍乾燥品,在使用前溶解於無菌化或無菌之注射用蒸餾水或其他溶劑而使用。
非經口投與用之吸入劑:例如氣溶劑、吸入用粉劑或吸入用液劑等,該吸入用液劑用亦可為使用時以水或其他適當媒體溶解或懸濁而使用之形態者。
上述吸入劑係依據周知方法製造。
例如吸入用液劑時,必要時可選擇防腐劑(例如氯苄烷銨、對羥基苯甲酸酯類等),著色劑,緩衝化劑(磷酸鈉、乙酸鈉等),等張劑(例如氯化鈉、濃甘油等),增黏劑(羧乙烯基聚合物等),吸收促進劑中適當者而調製。
吸入用粉劑時,必要時可選擇潤滑劑(例如硬脂酸及其鹽等),黏結劑(例如澱粉、糊精等),賦形劑(例如乳糖、纖維素等),著色劑,防腐劑(例如氯苄烷銨、對羥基苯甲酸酯類等),吸收促進劑中適當者而調製。
投與吸入用液劑時,一般使用噴霧器(例如霧化器(atomizer),噴霧器(nebulizer)等)。投與吸入用粉劑時,一般使用粉末藥劑用吸入投與器。
非經口投與用之其他組成物,例如含有一種或兩種以上之活性物質,藉由常法配方之直腸內投與用之栓劑及腔內投與用之子宮托等。
本發明藉由實施例詳述如下。唯本發明不侷限於實施例範圍。
本說明中,藉由層析法分離處及薄層析法中,括弧內之溶劑表示所使用之洗提溶劑或展開用溶劑、比率以容積比表示之。
倘無特別說明,NMR資料乃300MHz下之1
H-NMR資料,NMR處括弧內所示為測定用溶劑。
本說明書中所使用化合物之名稱乃使用按照一般IUPAC規定進行命名之電腦資料,ACD/批式命名(name batch)(註冊商標),或依據IUPAC命名法命名。例如下列通式命名為:
2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸。
於含有4,5,5-三氟戊-4-烯酸(CAS No. 110003-22-0(5.0g))之二氯甲烷(64mL)溶液中,在冷水浴中加入N,O-二甲基羥胺鹽酸鹽(3.5g),1-乙基-3-(3-二甲胺基丙基)碳化二亞胺鹽酸鹽(6.9g)及三乙胺(9.2mL),室溫下攪拌一夜。濃縮反應溶液,並以乙酸乙酯稀釋之。稀釋液用1N鹽酸,水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(6.4g)。
TLC:Rf 0.50(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ2.51-2.77(m,4H),3.19(s,3H),3.69(s,3H)。
在-78℃下,慢慢滴加乙酸乙酯(48mL)於六甲基二矽胺化鋰/四氫呋喃溶液(1M,48mL)中,並攪拌30分鐘。反應溶液中,在相同溫度下慢慢滴加含有化合物1(6.4g)之無水四氫呋喃(33mL)溶液,並攪拌30分鐘。加入2N鹽酸(30mL)於反應溶液中,使用乙酸乙酯萃取之。以水及飽和食鹽水洗淨有機層,用無水硫酸鈉乾燥,並濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=20:1→15:1)精製,而得具有下列物性值之標題化合物(4.94g)。
TLC:Rf 0.63(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ1.29(t,J=7.1 Hz,3H),2.50-2.71(m,2H),2.83(t,J=7.2 Hz,2H),3.47(s,2H),4.21(q,2H)。
冰冷下,慢慢滴加含有化合物2(4.71g)之第三丁基甲基醚(52mL)溶液於硼氫化鋰(1.4g)中,並在室溫下攪拌4小時。冰冷下,將反應溶液注入飽和氯化銨水溶液中,用乙酸乙酯萃取之。有機層以飽和食鹽水洗淨,用硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(3.87g)。
TLC:Rf 0.31(乙酸乙酯:己烷=2:1);NMR(CDCl3
):δ1.66-1.83(m,4H),2.17-2.66(m,2H),3.71-4.06(m,3H)。
溶解化合物3(3.87g)於甲苯(50mL)及2N氫氧化鈉水溶液(50mL)中,冰冷下加入四丁基溴化銨(700mg)及對甲苯磺醯氯(4.10g),並攪拌30分鐘。添加1-苯基-1H-四唑-5-硫醇(4.60g)至反應溶液中,在60℃下攪拌一夜。反應溶液注入水中,使用第三丁基甲基醚萃取之。有機層以飽和食鹽水洗淨,用硫酸鈉乾燥,並濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=4:1→7:3)精製,而得具有下列物性值之標題化合物(5.43g)。
TLC:Rf 0.37(乙酸乙酯:己烷=2:1);NMR(CDCl3
):δ1.64-1.83(m,2H),1.88-2.02(m,2H),2.31-2.61(m,2H),3.34-3.88(m,3H),7.46-7.69(m,5H)。
冰冷下,添加溴化鉀(830mg),2,2,6,6-四甲基六氫吡啶1-氧化物(199mg)及次氯酸鈉水溶液(10%,6.1mL)於含有化合物4(2.18g)之乙腈(32mL)溶液中,並攪拌2小時。在相同溫度下,添加飽和硫代硫酸鈉水溶液於反應溶液中,以乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,經濃縮而得具有下列物性值之標題化合物(2.17g)。
TLC:Rf 0.50(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ2.48-2.77(m,4H),3.14(t,J=6.4 Hz,2H),3.57(t,J=6.4 Hz,2H),7.54(s,5H)。
在-78℃下添加甲基鎂溴化物/二乙醚溶液(3.0M,4.2mL)於含有化合物5(2.17g)之無水四氫呋喃(22mL)溶液中,在相同溫度下攪拌30分鐘,然後在冰冷下攪拌30分鐘。冰冷下添加飽和碳酸氫鈉水溶液於反應溶液中,以乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,並濃縮之。所得殘渣用矽膠管柱層析法(已烷:乙酸乙酯=7:3)精製,而得具有下列物性值之標題化合物(1.88g)。
TLC:Rf 0.39(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ1.29(s,3H),1.69-1.92(m,2H),1.99-2.19(m,2H),2.30-2.59(m,2H),3.33-3.67(m,2H),7.42-7.70(m,5H)。
冰冷下,添加七鉬酸六銨四水合物(318mg)及過氧化氫水溶液(30%,1.8mL)於含有化合物6(1.84g)之甲醇(26mL)溶液中,並在室溫下攪拌一夜。冰冷下添加飽和硫代硫酸鈉水溶液於反應溶液中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(2.0g)。
TLC:Rf 0.41(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ1.30(s,3H),1.69-1.86(m,2H),2.06-2.24(m,2H),2.30-2.57(m,2H),3.80-4.00(m,2H),7.51-7.78(m,5H)。
冰冷下,添加咪唑(524mg)及三甲基矽烷基氯(0.79mL)於含有化合物7(2.0g)之二甲基甲醯胺(11mL)溶液中,並在室溫下攪拌5小時。反應溶液注入水中,用乙酸乙酯萃取之。有機層用飽和食鹽水洗淨,以無水硫酸鈉乾燥後濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=9:1)精製,而得具有下列物性值之標題化合物(2.16g)。
TLC:Rf 0.72(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ0.15(s,9H),1.35(s,3H),1.66-1.86(m,2H),1.96-2.19(m,2H),2.25-2.46(m,2H),3.74-3.88(m,2H),7.56-7.67(m,3H),7.68-7.74(m,2H)。
10℃下,添加三乙胺(3.7mL)及三氧化硫‧吡啶配位化合物(1.7g)於含有2-({2-[(1R,2S,5S)-2-(乙醯氧基)-5-(羥甲基)環戊基]乙基}硫基)-1,3-噻唑-4-羧酸乙酯(國際公開第2006/129788號說明書所記載之化合物7(500mg))之二甲亞碸(4.0mL)/乙酸乙酯(8.0mL)溶液中,並在室溫下攪拌30分鐘。添加1N鹽酸於反應溶液中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(497mg)。
TLC:Rf 0.27(己烷:乙酸乙酯=2:1);NMR(CDCl3
):δ1.32-1.49(m,3H) 1.78-2.15(m,9H) 2.35-2.51(m,1H) 2.69-2.84(m,1H) 3.10-3.31(m,2H) 4.32-4.48(m,2H) 5.29-5.37(m,1H) 8.02(s,1H) 9.67(d,J
=2.74 Hz,1H)。
在-78℃下,慢慢滴加六甲基二矽胺化鉀/甲苯溶液(0.5M,4.8mL)於含有化合物8(1.13g)之1,2-二甲氧基乙烷(8.0mL)溶液中。在相同溫度下攪拌30分鐘後,在相同溫度下慢慢滴加含有化合物9(461mg)之1,2-二甲氧基乙烷(5.0mL)溶液於反應溶液中。並在相同溫度下攪拌30分鐘後,升溫至0℃,添加飽和碳酸氫鈉水溶液,用乙酸乙酯萃取之。有機層以水,飽和食鹽水洗淨,用無水硫酸鈉乾燥,並濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=8:1)精製,而得具有下列物性值之標題化合物(703mg)。
TLC:Rf 0.71(乙酸乙酯:己烷=1:2);NMR(CDCl3
):δ0.10(s,9H),1.39(t,J=7.1 Hz,3H),1.49-2.48(m,17H),3.10-3.40(m,2H),4.40(q,J=7.1 Hz,2H),5.18-5.53(m,3H),8.02(s,1H)。
冰冷下,添加2N氫氧化鈉水溶液(2.4mL)於含有化合物10(703mg)之乙醇(6.0mL)溶液中,並在室溫下攪拌一夜。在相同溫度下,添加1N鹽酸於反應溶液中,並攪拌30分鐘。反應溶液中加入水,用乙酸乙酯萃取之。有機層用飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(538mg)。
TLC:Rf 0.21(乙酸乙酯:甲醇=5:1);NMR(CDCl3
):δ1.19(s,3H),1.32-1.50(m,2H),1.61-1.92(m,4H),1.94-2.56(m,8H),2.81-2.99(m,1H),3.49-3.67(m,1H),4.56(m,1H),5.27-5.62(m,2H),8.08(s,1H)。
冰冷下,添加乙酸酐(0.33mL)於含有化合物11(538mg)之吡啶(6.0mL)溶液中,並在室溫下攪拌一夜。反應溶液注入1N鹽酸中,用乙酸乙酯萃取之。有機層用飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(589mg)。
TLC:Rf 0.27(乙酸乙酯:甲醇=5:1);NMR(CDCl3
):δ1.16-1.21(m,3H),1.34-2.54(m,17H),3.10-3.53(m,2H),5.33-5.61(m,3H),8.11(s,1H)。
室溫下,添加4,4-二甲胺基吡啶(567mg)於含有化合物12(589mg)之甲苯(58mL)溶液中。反應溶液加熱至100℃後,添加2,4,6-三氯苯甲醯氯(0.37mL),攪拌15分鐘後,放置冷卻至室溫。反應溶液注入飽和碳酸氫鈉水溶液中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,並濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=15:1)精製,而得具有下列物性值之標題化合物(化合物13A:200mg,化合物13B:120mg)。
TLC:Rf 0.49(乙酸乙酯:己烷=1:4);NMR(CDCl3
):δ1.32-2.22(m,14H),2.27-2.50(m,3H),2.55-2.75(m,2H),2.78-3.00(m,2H),3.22-3.40(m,1H),5.26-5.35(m,1H),5.37-5.50(m,1H),5.55-5.71(m,1H),7.98(s,1H)。
TLC:Rf 0.46(乙酸乙酯:己烷=1:4);NMR(CDCl3
):δ1.32-2.61(m,19H),2.80-3.01(m,2H),3.18-3.32(m,1H),5.26-5.36(m,1H),5.44-5.69(m,2H),7.96(s,1H)。
溶解化合物13A(200mg)於甲醇(1.0mL)及四氫呋喃(2.0mL)中,加入2N氫氧化鈉水溶液(0.62mL),在室溫下攪拌一夜。反應溶液注入1N鹽酸中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(190mg)。
TLC:Rf 0.21(乙酸乙酯:甲醇=5:1);NMR(CDCl3
):δ1.19(s,3H),1.33-1.52(m,2H),1.59-2.14(m,7H),2.20(d,J
=6.6 Hz,2H),2.25-2.51(m,3H),2.81-3.01(m,1H),3.50-3.67(m,1H),4.51-4.59(m,1H),5.31-5.54(m,2H),8.07(s,1H)。
添加碳酸鉀(340mg)及碘化甲烷(0.09mL)於含有化合物14(190mg)之二甲基甲醯胺(2.1mL)溶液中,在室溫下攪拌一夜。反應溶液注入水中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥,濃縮而得具有下列物性值之標題化合物(196mg)。
TLC:Rf 0.36(乙酸乙酯:己烷=1:1);NMR(CDCl3
):δ1.18(s,3H),1.29-1.49(m,2H),1.53-1.88(m,4H),1.91-2.11(m,3H),2.19(d,J=6.2 Hz,2H),2.27-2.52(m,3H),2.82-2.97(m,1H),3.50-3.68(m,1H),3.92(s,3H),4.42-4.53(m,1H),5.30-5.51(m,2H),7.98(s,1H)。
冰冷下,添加二異丙基乙胺(0.43mL)及三氧化硫‧吡啶配位化合物(196mg)於含有化合物15(196mg)之二甲亞碸(1.4mL)/乙酸乙酯(2.8mL)溶液中,並攪拌15分鐘。加水於反應溶液中,用乙酸乙酯萃取之。有機層以1N鹽酸,水及飽和食鹽水洗淨,以無水硫酸鈉乾燥後濃縮之,所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=3:2)精製,而得具有下列物性值之標題化合物(152mg)。
TLC:Rf 0.45(乙酸乙酯:己烷=1:1);NMR(CDCl3
):δ1.16(s,3H),1.46-2.63(m,14H),3.37-3.49(m,2H),3.91(s,3H),5.45-5.57(m,1H),5.61-5.76(m,1H),8.01(s,1H)。
溶解化合物16(152mg)於1,2-二甲氧基乙烷(2.0mL)/水(1.0mL)中,冰冷下加入氫氧化鋰(16.0mg),在室溫下攪拌2小時。反應溶液注入5%硫酸氫鉀水溶液中,用乙酸乙酯萃取之。有機層用水及飽和食鹽水洗淨,以無水硫酸鈉乾燥後濃縮之。所得殘渣用矽膠管柱層析法(己烷:乙酸乙酯=1:1→甲醇:乙酸乙酯=1:10)精製,而得具有下列物性值之標題化合物(127mg,非晶狀黏性油)。
TLC:Rf 0.20(乙酸乙酯:甲醇=5:1);NMR(CDCl3
):δ1.21(s,3H),1.55-1.80(m,3H),1.88-2.60(m,11H),3.37(t,J=7.50 Hz,2H),5.54(dd,J=14.82,7.68 Hz,1H),5.62-5.76(m,1H),8.11(s,1H)。
替代化合物13A而改用化合物13B,按照實施例14→實施例15→實施例16→實施例17同樣方法處理,而得標題化合物(57.3mg,非晶狀黏性油)。
TLC:Rf 0.20(乙酸乙酯:甲醇=5:1);NMR(CDCl3
):δ1.21(s,3H),1.56-1.79(m,3H),1.91-2.59(m,11H),3.31-3.42(m,2H),5.54(dd,J=15.57,8.04 Hz,1H),5.61-5.77(m,1H),8.11(s,1H)。
替代化合物14而改用化合物11,按照實施例15→實施例16→實施例17相同方法處理,而得標題化合物(7.6mg,非晶狀黏性油)。
TLC:Rf 0.71(乙酸乙酯:甲醇:乙酸=8:1:1);NMR(CDCl3
):δ1.21(s,3H),1.56-1.80(m,3H),1.90-2.60(m,11H),3.18-3.62(m,2H),5.54(dd,J=15.3,7.8 Hz,1H),5.60-5.75(m,1H),8.10(s,1H)。
TLC:Rf 0.50(甲醇:氯仿=1:9);NMR(CDCl3
):δ8.13(s,1H),5.66(dt,J=15,6 Hz,1H),5.40(dd,J=15,9 Hz,1H),3.50-3.25(m,2H),3.15-3.05(m,1H),3.00-2.50(m,1H),2.50-2.25(m,4H),2.23(d,J=6 Hz,2H),2.20-2.00(m,3H),2.00-1.85(m,1H),1.85-1.60(m,3H),1.21(s,3H)。
TLC:Rf 0.38(乙酸乙酯:己烷=1:1);NMR(CDCl3
):δ1.19(s,3H),1.60-1.80(m,2H),1.95(m,1H),2.23(d,J=7.5 Hz,2H),2.20-2.48(m,4H),3.30(m,1H),3.44-3.58(m,2H),3.91(s,3H),5.48(dd,J=15.0,8.4 Hz,1H),5.84(dt,J=15.0,7.2 Hz,1H),6.17(dd,J=5.7,2.1 Hz,1H),7.49(dd,J=5.7,2.4 Hz,1H),8.01(s,1H)。
秤取化合物17之鈉鹽(8.12mg)及β-環糊精(56.88 mg),溶解於精製水(5mL)中。靜置該溶液30分鐘之後,凍結乾燥之。室溫下,減壓乾燥一夜,而得標題化合物(64.8 mg)。
源自2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸鈉之尖峰:7.81(s,1H),5.57-5.40(m,2H),3.26-3.19(m,2H),2.49(m,1H),2.35-1.98(m,9H),1.83(m,1H),1.64(m,1H),1.55-1.46(m,2H),1.01(s,3H)。
源自β-環糊精之尖峰:4.91(d,J=3.6Hz,1H),3.81-3.63(m,4H),3.51-3.41(m,2H)。
依據下列實驗可證實本發明化合物兼具有膀胱收縮作用及尿道鬆弛作用,且副作用少,實為經口吸收性等藥物動態良好之化合物。
又,為顯示本發明化合物較先前技術中所記載之化合物,具更有優異之安全性及經口吸收性等藥物動態,而與下列比較化合物進行比較實驗。
比較化合物A:2-[(2-{(1R,2R)-2-[(1E,4S)-4-羥基-4,7-二甲基-1,7-辛二烯-1-基]-5-側氧基環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(國際公開第2006/129788號說明書中記載之化合物18-6之4S體)
比較化合物B:2-[(2-{(1R,2R)-2-[(1E,4S)-4-羥基-4-甲基-1-壬烯-1-基]-5-側氧基環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(國際公開第2006/129788號說明書中記載之化合物17-1)
比較化合物C:2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-8,8,8-三氟-4-羥基-4-甲基-1-辛烯基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(國際公開第2006/129788號說明書中記載之化合物18-1之4S體)
比較化合物D:2-[(2-{(1R,2R)-2-[(1E,4S)-4-羥基-4-甲基-1,7-辛二烯-1-基]-5-側氧基環戊基}乙基)硫基]-1,3-噻唑-4-羧酸(國際公開第2006/129788號說明書中記載之化合物32之4S體)
比較化合物E:2-[(2-{(4S)-2-側氧基-4-[(1E,4S)-8,8,8-三氟-4-羥基-4-甲基-1-辛烯基]-1,3-噁唑啶-3-基}乙基)硫基]-1,3-噻唑-4-羧酸(國際公開第2005/053707號說明書中記載之化合物65-2)
使用戊巴比妥將大鼠麻醉,切開腹部,摘取膀胱及尿道。膀胱於縱方向切斷,製作得約10×3mm長條狀標本。又,尿道也製成約10×3mm之標本。所製成標本懸垂於經95%氧氣及5%二氧化碳之混合氣體通氣過之克列伯氏緩衝液(37℃,5mL)中。標本之張力係使用備有等長傳感器(isometric transducer)及放大器之馬格納斯(Magnus)裝置系統,經由資料收集系統記錄在電腦中。
以約0.5g之負荷懸垂標本,經過1小時後,添加氯化鉀(100mmol/L),觀察其最大收縮反應。用克列伯氏緩衝液洗淨後,以約0.5g之負荷懸垂標本,待安定後,添加氯化鉀溶液(7.5mmol/L)使引發收縮。待該引發反應安定後,累積性添加被檢驗化合物,測定其藥物處理前後之反應。
以約0.5g之負荷懸垂標本,經過1小時後,添加氯化鉀(100mmol/L),觀察其最大收縮反應。使用克列伯氏緩衝液洗淨後,以約0.5g之負荷懸垂標本,待其安定後使用脫羥腎上腺素(phenylephrine,亦稱為去甲羥麻黃鹼)(100mmol/L),使之引發收縮。待該引發反應安定後,累積性添加被檢驗化合物,測定藥物處理前後之反應。
上述實驗結果示於表1及表2。
由上述實驗結果確知化合物17可使膀胱排尿肌收縮,也使尿道括約肌鬆弛。因此,本發明化合物可作用在膀胱及尿道,能改善膀胱收縮障礙及尿道鬆弛障礙,有效於低活動性膀胱。
按照下述方法製作低活動性膀胱模式。藉由腹腔內投與戊巴比妥鈉(40mg/kg)而麻醉雌性Wistar大鼠(8至9週齡),背部除毛後,以腹臥狀固定之。用雙氯苯雙胍己烷(5%洗必泰溶液)消毒其背部後,沿著腰部正中間剖開而露出脊椎。切除第5腰椎棘突起後,從以微鑽刀所鑽洞孔,朝向第6腰椎方向插入矽膠管。為防止感染症,在手術終了時,滴加苯甲基青黴素鉀於受創傷部位(25000U/0.25mL/body),創傷部位之肌肉及皮膚使用縫合絲線縫合,塗布碘酊於縫合處。手術後,以手壓排尿一日3次進行排尿之維護,為防止感染,皮下投與青黴素G鉀(1.25萬單位/body)。於膀胱容積壓力檢法評估之5日以前,膀胱內留置膀胱內壓測定用導管。使用戊巴比妥鈉(40mg/kg腹腔內投與)麻醉,切開下腹部正中央,切開膀胱頂部。從頂部洞孔插入充滿生理食鹽液之膀胱內壓測定用導管,並以縫合絲線結紮而固定之。導管之另一端固定於背部皮下,再將腰背部及下腹部之切開部分以縫合絲線縫合。將苄星青黴素G(bicillin S500,明治製菓公司製品,10mg力價/0.1mL,蒸餾水/大鼠)注入臀部肌肉內。
製作模式兩星期後,用乙醚麻醉大鼠,收容於鮑爾曼籠中。膀胱導管之先端經由三通旋栓連接於壓力傳感器,使用應變壓力用放大記錄計來記錄膀胱內壓。三通旋栓之另一端連接在安裝於灌輸泵之膀胱內注入用注射筒,又一端連接在充滿生理食鹽水之延長管而供殘尿排出用途。經上述處理之大鼠靜置至從麻醉覺醒。
經口投與注射用水(媒劑組)及被檢驗化合物(5mg/kg),1小時後,以2mL/h之注入速度將生理食鹽水灌流至膀胱內,而測定排尿參數(膀胱容量及殘尿量),開始灌流經1小時後,在排尿後立即停止灌流,除去膀胱內之殘尿。分別計算其膀胱容積壓力檢驗時之排尿參數,殘尿量係比較投與媒劑組和被檢驗化合物組之值,而膀胱容量乃係比較正常組及投與被檢驗化合物組之值。
上述結果示於第1圖及第2圖。在低活動性膀胱模式中,顯著減少殘尿量之化合物17之用量(0.01mg/kg)對於膀胱容量並無影響。另一方面,比較化合物A在有效用量(0.01mg/kg)時,顯著減少膀胱容量。
膀胱容量較之正常水準減少,乃有關無法蓄尿之蓄尿症狀,可認為會誘發頻尿之泌尿器系之副作用。
由上述結果顯示本發明化合物可做為低活動性膀胱之治療劑有效,此外,有效用量時不會誘發泌尿器系之副作用。
使用雌性Wistar系大鼠,按照下述方法測定血壓及心搏數。測定當天在乙醚麻醉下進行血壓、心搏數測定用導管留置。切開頸背部,從頸背部導入充滿含有肝素生理食鹽水之營養導管(Atommedical公司提供),導管插入總頸動脈後,封閉開刀創傷口。在覺醒下於鮑爾曼籠內進行測定,確認各參數值安定後開始評估。使用含有等莫耳氫氧化鈉之注射用水所調製之被檢驗化合物,在確認血壓及心搏數安定後經口投與5mL/kg之容量。
連接從頸背部導出之導管於壓力傳感器(DX-200,日本光電公司製品),經由壓力測定用放大器(Gould instrument公司製品)測定血壓及心搏數。血壓及心搏數以記錄計(Linearcorder WR3320型,Graphtec公司製品)記錄之。計算投與前、30分鐘、60分鐘、120分鐘、180分鐘時之平均血壓及心搏數之各個體之各者對於投與前值之增減之比率,而評估被檢驗化合物投與前後之血壓及心搏數之變動情形。
第3圖及第4圖示投與本發明化合物(0.3mg/kg)及比較化合物(0.3mg/kg)時之結果。
化合物17在投與用量為0.3mg/kg之濃度時不影響血壓。此外,化合物17之投與用量提高至1mg/kg之濃度,也不影響血壓。相對地,比較化合物A在投與用量為0.3mg/kg之濃度已表現提高血壓之傾向,當1mg/kg之濃度時,血壓提高約10%。另外,比較化合物B,比較化合物C及比較化合物D在投與用量為0.3mg/kg之濃度時表現血壓下降之傾向。
又,化合物17在投與用量為0.3mg/kg之濃度時,對於心搏數無影響。相對地,比較化合物B,比較化合物C及比較化合物D在投與用量為0.3mg/kg之濃度時,使心搏數上升約20%。
由上述結果顯示比較化合物有影響血壓及心搏數之危險,而本發明化合物顯示對於血壓及心搏數幾乎無影響。因此,可知本發明化合物係無循環系副作用風險之化合物。
使用雄性原發性高血壓大鼠,按照下述方法測定血壓及心搏數。測定當日在乙醚麻醉下進行血壓、心搏數測定用及被檢驗物質投與用之導管留置。切開頸背部,從頸背部導入充滿含有肝素生理食鹽水之營養管(Atommedical公司提供),導管插入總頸動脈及內頸靜脈,然後封閉開刀創傷口。在覺醒下於鮑爾曼籠內進行測定,確定各參數安定化後開始評估。確認血壓及心搏數安定後,以5mL/kg/h之流速,進行30分鐘之被檢驗化合物之靜脈內持續投與。
由頸背部導出來之導管連接在壓力傳感器(DX-200型,日本光電公司製品),經由壓力測定用放大器(Gould instrument公司製品)測定血壓及心搏數。血壓及心搏數利用記錄計(Linearcorder WR3320型,Graphtec公司製品)記錄於記錄紙上。血壓及心搏數在投與前,及投與後分別在2.5分鐘、5分鐘、10分鐘、15分鐘、30分鐘、45分鐘及60分鐘從記錄紙上變換為數值,評估對於各評估參數之各個體之各者對於投與前值(0分鐘時之值)之增減比率。
上述測定結果示於第5圖及第6圖。
化合物17對於血壓不影響。另一方面,比較化合物B在100ng/kg/min之投與量時,降低約10%血壓,此外,在300ng/kg/min之投與量時降低約25%左右之血壓。
由上述結果可知本發明化合物,對於具有高血壓等循環器系疾病背景之病患,其循環器系副作用之風險甚低。
使用6週齡雄性大鼠,將被檢驗化合物以0.1mg/kg用量進行重複經口投與4日,並觀察其一般狀態。對照組投與媒體之注射用水。
投與化合物17組,看不到軟糞便等消化器症狀。相對地,比較化合物C投與組,從投與第1日就觀察到軟糞便。從上述結果可知本發明化合物乃不誘發消化器系副作用之安全化合物。
使用人工膜之藥物膜透過性在下列條件下藉由平行人工膜透過性分析(Parallel Artificial Membrane Permeability Assay,(PAMPA)而測定之。測定時使用PAMPA系統(pION公司製品)。膜透過性乃以3處pH所測定之膜透過係數之合計值(PAMPA(SUM)(cm/sec)而進行評估。
脂質膜:GIT-0(pION公司製品)
測定波長:190至498nm
培養時間:4小時
培養溫度:25℃
供體:含有5%二甲亞碸之緩衝液
pH:5.2、6.2、7.4等3處
化合物濃度:50μmol/L
化合物17之膜透過係數為59.3cm/sec,其膜透過性非常良好。比較化合物E之膜透過係數僅為0.6cm/sec,可知膜透過性很低。
由上述結果可知本發明化合物之膜透過性良好,推測係經口吸收性優異之化合物。
添加等莫耳氫氧化鈉及注射用蒸餾水於各被檢驗化合物而調製成1mg/mL水溶液,再用生理食鹽水稀釋而調製0.001mg/mL之投與用液,以0.001mg/mL/kg之用量藉由橈側皮靜脈快速投與食蟹猴。投與後在2分鐘、5分鐘、15分鐘及30分鐘、1小時、2小時、4小時、6小時、8小時及24小時後,使用添加肝素之注射器從橈側皮靜脈(非投與部位)採取血液。經離心後分離血漿,在進行前處理以前保存在-80℃下。血漿之前處理係與乙腈混合後,離心除去蛋白而進行,再以LC/MS/MS測定之。血漿中濃度之遷移用WinNonlin 4.0.1解析而求得全身廓清率。
化合物17之全身廓清率為3.6mL/min/kg,藥物從體內之消失緩慢,推測能持續性發揮藥效。另一方面,比較化合物D之全身廓清率為23.9mL/min/kg,較之化合物17其全身廓清率顯然大很多,可知從體內非常快速消失。
將被檢驗化合物(調製成乙腈或甲醇溶液,最終濃度為1%以下),含融解之人類凍結肝細胞(活細胞之最終濃度為1×106
細胞/mL)之KHEM5100培養基在37℃培養,從反應開始後即刻及經時性採取部分試料。
使用LC/MS/MS測定所採取試料中之被檢驗化合物濃度,依據下式計算得對於開始後即刻之殘存率。
殘存率=反應後試料中被檢驗化合物濃度/反應開始後即刻之試料中被檢驗化合物濃度×100(%)
然後,相對於反應時間將殘存率進行單向對數標繪,求得消失速度常數。試驗以n=2進行,用其平均值加以評估。
上述結果示於表3。
比較化合物B之殘存率在反應1小時後為80%以下,2小時後約為60%。相對之,化合物17在反應1小時後殘存率為100%,2小時後仍有80%以上之殘存率。
由上述結果顯示本發明化合物對肝中代謝而言,乃係非常安定之化合物。
使用戊巴比妥(導入:20至30mg/kg,靜脈內投與,維持:4至5mg/kg/hr,靜脈內持續投與)麻醉食蟹猴之後,插入氣管,在人工呼吸下(新鮮大氣+純氧氣,換氣量:10至15mL/kg,換氣次數:10至15次/分鐘)進行實驗。在右橫臥處剖開左胸部第4至5肋骨間。剝離冠狀動脈(左前降枝或迴旋枝起始部)及上行性大動脈起始部,並分別安裝血流測定用變換器。血流量以電磁氣血流量計或超音波血流量計測定之。血壓係藉由將導管插入右大腿動脈,而左心室內壓係將導管由左頸動脈插入左心室內,以壓力傳感器測定之。心電圖藉由設置針狀電極於右腋部及左胸部而測定之。投與用導管係插入左右之橈側皮靜脈及大腿靜脈內,經此投與被檢驗化合物,戊巴比妥(維持麻醉用)或灌輸液(含有1.2%碳酸氫鈉之Solita-T3號)。被檢驗化合物藉由持續注入裝置以30分鐘之持續注入而投與靜脈內。血壓、左心室內壓、冠狀動脈血流量、大動脈血流量及心電圖係同時帶入Power Lab系統(Lab chart 6型,AD Instruments公司製品)中,藉此測定/計算平均血壓、心搏數、冠狀動脈平均血流量、心搏出量、一次搏出量(心搏出量/心搏數)、左室內壓一次微分最大值、總末梢血管阻抗(平均血壓/心搏出量)、心臟工作量(平均血壓×心搏出量)以及做為心肌氧消耗之指標用雙重乘積(double product)(收縮期血壓×心搏數)。
上述所有評估項目皆在投與開始前,投與開始後10分鐘、20分鐘及30分鐘分別求得1分鐘之平均值,以投與前值為100%而計算得變化率。
第7圖及第8圖分別示上述心臟工作量及雙重乘積之測定結果。
化合物17在30ng/kg/min及100ng/kg/min之投與量時,對於心臟工作量及雙重乘積皆不發生影響。另外,對於冠狀動脈血流量等其他心臟功能之參數也沒有影響。相對地,比較化合物B對於心臟功能顯示抑制作用。
由上述結果可知本發明化合物乃對於心臟功能不影響之安全的化合物。
按照下述方法準備排尿障礙模式動物。將食蟹猴麻醉後,自恥骨上端至腹部之體毛加以剃除,以仰臥位固定之。消毒剃毛處,並固定其四肢。使用電刀將恥骨上端至臍部之皮膚切開,繼之,剖開腹膜。再用電刀損害其骨盤神經,摘出子宮。開完刀後用含有苄星青黴素之生理食鹽水滴加在創傷處。用絲線縫合創傷部分之腹膜及皮膚,並行消毒。從手術後當日起投與苄星青黴素7天。又,以疼痛管理為目的,每日投與美樂昔康(Meloxicam)一次,合計7天以資術後鎮痛。
令食蟹猴坐在猴椅上,用繩固定其四肢。經口投與注射用水後,藉由靜脈內持續投與生理食鹽水及被檢驗化合物(60ng/kg/h),令之自然排尿,設置尿重量測定傳感器,測定其最大尿流率。
對於排尿障礙模式動物之最大尿流率,化合物17較之媒劑組能改善61%。相對之,比較化合物B及比較化合物D較之媒劑組僅能分別改善27%及36%。
由上述結果顯示本發明化合物之排尿促進效果非常高。
從上述生物學上實施例(1)至(10)之結果,顯示本發明化合物具有膀胱收縮作用及尿道鬆弛作用,並具備強大排尿促進效果。此外,本發明化合物乃係先前技術所記載之任何化合物所無法達成之對於泌尿器系,循環器系及消化器系可回避其所有副作用風險,而具有優異安全性,且經口吸收性、代謝安定性等藥物動力學皆優異之化合物。
按照常法混合化合物17(5.0g)、羧甲基纖維素鈣(20g)、硬脂酸鎂(10g)及微晶狀纖維素(920g)之後,製錠而得每錠中含有0.5mg之活性成分之錠劑1萬粒。
按照常法混合化合物17(2.0g)、甘露糖醇(500g)及蒸餾水(10L)之後,再依照常法將溶液殺菌之後,以每瓶1mL裝分裝於管形瓶,而得每一管形瓶中含有0.2mg活性成分之管形瓶1萬瓶。
本發明化合物具有膀胱排尿肌之收縮作用及尿道括約肋之鬆弛作用,因此,對於膀胱收縮障礙及/或尿道鬆弛障礙有效,特別是做為低活動性膀胱之預防及/或治療劑有效。又,做為低活動性膀胱中之各種症狀之改善劑也有效。此外,本發明化合物之安全性高,經口吸收性等之藥物動力學上之性狀也很優異,所以做為醫藥非常有用。
第1圖示低活動性膀胱模式中,本發明化合物對於殘尿量(上段)及膀胱容量(下段)之作用情形。
第2圖示低活動性膀胱模式中,比較化合物對於殘尿量(上段)及膀胱容量(下段)之作用情形。
第3圖示正常大鼠中,本發明化合物及比較化合物對血壓之作用情形。
第4圖示正常大鼠中,本發明化合物及比較化合物對心搏數之作用情形。
第5圖示高血壓大鼠中,本發明化合物對血壓之作用情形。
第6圖示高血壓大鼠中,比較化合物對於血壓之作用情形。
第7圖示食蟹猴中,投與本發明化合物(上段)及比較化合物(下段)時之心臟工作量。
第8圖示食蟹猴中,投與本發明化合物(上段)及比較化合物(下段)時之雙重乘積。
由於本案的圖式僅係試驗數據,並非本案的代表圖。故本案無指定代表圖。
Claims (14)
- 一種化合物,其係下列通式(I)所示化合物、其鹽、其溶劑化物、或和其非對映異構物之任意比率之混合物、或其環糊精包接化合物:
- 如申請專利範圍第1項所述之化合物,其中,通式(I)所示化合物係下列化合物:(1)2-[(2-{(1R,5R)-2-側氧基-5-[(1E)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,(2)2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,或(3)2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4R)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸。
- 一種申請專利範圍第1項所述之化合物之任意比率之混合物,其中,通式(I)所示化合物係2-[(2-{(1R,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基 -1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸,其非對映異構物係2-[(2-{(1S,5R)-2-側氧基-5-[(1E,4S)-7,8,8-三氟-4-羥基-4-甲基-1,7-辛二烯-1-基]環戊基}乙基)硫基]-1,3-噻唑-4-羧酸。
- 一種醫藥組成物,其含有下列通式(I)所示化合物、其鹽、其溶劑化物、或和其非對映異構物之任意比率之混合物、或其環糊精包接化合物作為有效成分,
- 如申請專利範圍第4項所述之醫藥組成物,其中,該醫藥組成物係膀胱排尿肌收縮及尿道括約肌鬆弛劑。
- 如申請專利範圍第5項所述之醫藥組成物,其中,該醫藥組成物係膀胱收縮障礙及/或尿道鬆弛障礙之預防、治療及/或症狀改善劑。
- 如申請專利範圍第6項所述之醫藥組成物,其中,膀胱收縮障礙及/或尿道鬆弛障礙係低活動性膀胱者。
- 一種醫藥,其係由下列通式(I)所示化合物、其鹽、其溶劑化物、或和其非對映異構物之任意比率之混合物、或其環糊精包接化合物:
- 一種化合物,其係下列通式(I-a)所示化合物、或和其非對映異構物之任意比率之混合物、或其環糊精包接化合物:
- 一種醫藥組成物,其含有下列通式(I-a)所示化合物、或和其非對映異構物之任意比率之混合物、或其環糊精包接化合物作為有效成分:
- 如申請專利範圍第10項所述之醫藥組成物,其中,該醫藥組成物係膀胱排尿肌收縮及尿道括約肌鬆弛劑。
- 如申請專利範圍第10項所述之醫藥組成物,其中,該醫藥組成物係膀胱收縮障礙及/或尿道鬆弛障礙之預防、治療及/或症狀改善劑。
- 如申請專利範圍第12項所述之醫藥組成物,其中,膀胱收縮障礙及/或尿道鬆弛障礙係低活動性膀胱者。
- 一種醫藥,其係由下列通式(I-a)所示化合物、和其非對映異構物之任意比率之混合物、或其環糊精包接化合物:
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TW099118684A TWI437987B (zh) | 2009-06-10 | 2010-06-09 | 具有膀胱排尿肌收縮及尿道括約肌鬆弛之作用的化合物 |
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EP (1) | EP2441760B1 (zh) |
JP (1) | JP4807478B2 (zh) |
KR (1) | KR101633149B1 (zh) |
CN (1) | CN102803239B (zh) |
AU (1) | AU2010259585B2 (zh) |
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HK (1) | HK1169117A1 (zh) |
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TW (1) | TWI437987B (zh) |
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PT2441760E (pt) * | 2009-06-10 | 2014-01-07 | Ono Pharmaceutical Co | Composto com actividade de contracção muscular do detrusor e actividade de relaxação muscular do esfíncter uretral |
WO2014034902A1 (ja) | 2012-08-31 | 2014-03-06 | 小野薬品工業株式会社 | アミン塩とその結晶 |
EP3027199B1 (en) | 2013-08-01 | 2019-06-26 | Dignify Therapeutics, LLC | Compositions and methods for inducing urinary voiding and defecation |
CA2966594A1 (en) * | 2014-11-03 | 2016-05-12 | William Beaumont Hospital | Method for treating underactive bladder syndrome |
JP2022517315A (ja) * | 2018-12-31 | 2022-03-08 | アダマ・マクテシム・リミテッド | 1,1,2-トリフルオロ-4-(置換スルホニル)-ブテ-1-エンの合成 |
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---|---|---|---|---|
JPS503362B1 (zh) | 1970-06-10 | 1975-02-04 | ||
JPS5231404B1 (zh) | 1971-04-28 | 1977-08-15 | ||
JPS57156460A (en) | 1981-03-20 | 1982-09-27 | Ono Pharmaceut Co Ltd | Stabilized composition of prostaglandin and prostaglandin mimic compound, and its preparation |
JPS60197667A (ja) | 1984-03-19 | 1985-10-07 | Ono Pharmaceut Co Ltd | 6―ケト―プロスタグランジン類似化合物及びその製造方法 |
ES2196527T3 (es) | 1997-02-10 | 2003-12-16 | Ono Pharmaceutical Co | Derivados de 11,15-o-dialquilprostaglandina e, su procedimiento de produccion y medicamentos que incluyen estos como principio activo. |
JPH11130678A (ja) | 1997-08-27 | 1999-05-18 | Kaken Pharmaceut Co Ltd | 神経圧迫による神経障害改善剤 |
PT1417975E (pt) | 2001-07-23 | 2011-05-30 | Ono Pharmaceutical Co | Medicamentos que cont?m um agonista de ep4 como princ?pio activo destinados a doen?as associadas a perda de massa ?ssea |
JP2005053707A (ja) | 2001-07-30 | 2005-03-03 | Kankyo Device Kenkyusho:Kk | 可視光応答性材料の製造方法 |
IL163866A0 (en) | 2002-03-05 | 2005-12-18 | Ono Pharmaceutical Co | 8-Azaprostaglandin derivative compounds and drugs containing the compounds s active ingredient |
AU2002345285A1 (en) | 2002-07-11 | 2004-02-02 | Nokia Corporation | Method and device for automatically changing a digital content on a mobile device according to sensor data |
US7256211B1 (en) | 2003-01-21 | 2007-08-14 | Ono Pharmaceutical Co., Ltd. | 8-azaprostaglandin derivatives and medical use thereof |
EP1609480A1 (en) | 2003-04-03 | 2005-12-28 | Ono Pharmaceutical Co., Ltd. | Remedy for spinal canal stenosis |
WO2005053707A1 (ja) * | 2003-12-05 | 2005-06-16 | Ono Pharmaceutical Co., Ltd. | 馬尾神経組織血流増加剤 |
WO2005061492A1 (ja) | 2003-12-22 | 2005-07-07 | Ono Pharmaceutical Co., Ltd. | 含窒素複素環化合物およびそれらを有効成分とする薬剤 |
WO2006016689A1 (ja) | 2004-08-10 | 2006-02-16 | Ono Pharmaceutical Co., Ltd. | Ep4アゴニストを含有してなる下部尿路系疾患の予防および/または治療剤 |
JP4893999B2 (ja) | 2004-10-22 | 2012-03-07 | 小野薬品工業株式会社 | 吸入用医薬組成物 |
JP2006129788A (ja) | 2004-11-05 | 2006-05-25 | Nippon Starch Chemical Co Ltd | 揚げ物用ミックス |
NZ563863A (en) | 2005-06-03 | 2011-02-25 | Ono Pharmaceutical Co | Agent for regeneration and/or protection of nerves |
WO2009148163A1 (ja) * | 2008-06-06 | 2009-12-10 | 小野薬品工業株式会社 | 膀胱排尿筋収縮および尿道括約筋弛緩剤 |
PT2441760E (pt) * | 2009-06-10 | 2014-01-07 | Ono Pharmaceutical Co | Composto com actividade de contracção muscular do detrusor e actividade de relaxação muscular do esfíncter uretral |
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AU2010259585A1 (en) | 2012-01-19 |
PL2441760T3 (pl) | 2014-05-30 |
CN102803239A (zh) | 2012-11-28 |
HK1169117A1 (en) | 2013-01-18 |
US20120088805A1 (en) | 2012-04-12 |
WO2010143661A1 (ja) | 2010-12-16 |
RU2531350C2 (ru) | 2014-10-20 |
DK2441760T3 (en) | 2014-02-17 |
CA2764782A1 (en) | 2010-12-16 |
US8716490B2 (en) | 2014-05-06 |
CN102803239B (zh) | 2015-04-15 |
KR20120026088A (ko) | 2012-03-16 |
ZA201109103B (en) | 2012-08-29 |
EP2441760A4 (en) | 2012-12-05 |
MX2011013283A (es) | 2012-01-12 |
EP2441760A1 (en) | 2012-04-18 |
NZ596960A (en) | 2013-04-26 |
US8410281B2 (en) | 2013-04-02 |
EP2441760B1 (en) | 2013-11-20 |
BRPI1013152B1 (pt) | 2019-06-18 |
ES2444500T3 (es) | 2014-02-25 |
US20130184236A1 (en) | 2013-07-18 |
US9150528B2 (en) | 2015-10-06 |
JP4807478B2 (ja) | 2011-11-02 |
AU2010259585B2 (en) | 2015-11-19 |
US20140171387A1 (en) | 2014-06-19 |
IL216856A0 (en) | 2012-03-01 |
KR101633149B1 (ko) | 2016-06-23 |
TW201103539A (en) | 2011-02-01 |
JPWO2010143661A1 (ja) | 2012-11-29 |
BRPI1013152A2 (pt) | 2016-04-05 |
PT2441760E (pt) | 2014-01-07 |
CA2764782C (en) | 2017-07-25 |
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