TWI401249B - 苯并咪唑衍生物 - Google Patents
苯并咪唑衍生物 Download PDFInfo
- Publication number
- TWI401249B TWI401249B TW098113755A TW98113755A TWI401249B TW I401249 B TWI401249 B TW I401249B TW 098113755 A TW098113755 A TW 098113755A TW 98113755 A TW98113755 A TW 98113755A TW I401249 B TWI401249 B TW I401249B
- Authority
- TW
- Taiwan
- Prior art keywords
- phenyl
- bicyclo
- methyl
- propyl
- ethyl
- Prior art date
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- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 3
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
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- -1 Methoxy-1H-benzimidazol-2-yl Chemical group 0.000 claims description 25
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 25
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- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
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- QHODEHDUXLKSJI-XIWHWFKQSA-N [(1s,5s,9s)-9-[2-[3-(4,7-dimethoxy-1h-benzimidazol-2-yl)propyl-methylamino]ethyl]-7-phenyl-9-bicyclo[3.2.2]non-6-enyl] 2-methylpropanoate Chemical compound C([C@@]1([H])[C@](CCN(C)CCCC=2NC3=C(OC)C=CC(OC)=C3N=2)(OC(=O)C(C)C)C[C@@]2(CCC1)[H])=C2C1=CC=CC=C1 QHODEHDUXLKSJI-XIWHWFKQSA-N 0.000 claims 1
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Description
本發明係關於新穎苯并咪唑衍生物及其在慢性穩定性心絞痛、高血壓、局部缺血(腎及心臟)、包括心房纖維顫動之心律不整、心肥大或充血性心臟衰竭之治療或預防中作為有效鈣通道阻斷劑的用途;係關於含有此等衍生物之醫藥組合物;且係關於其製備方法。本發明之苯并咪唑衍生物亦可單獨或以醫藥組合物之形式用於治療人類及其他哺乳動物之腎病、糖尿病及其併發症、高醛固酮症、癲癇症、神經痛或癌症。
許多心血管病症已與由異常升高之鈣流入通過心臟及血管平滑肌細胞之質膜所導致的「鈣超載」相關。存在3個細胞外之鈣可通過其進入此等細胞的主要途徑:1)受體激活型鈣通道;2)配位體門控型鈣通道;及3)電壓操控型鈣通道(VOC)。
VOC已分為6個主要種類:L(持久型)、T(瞬時型)、N(神經元)、P(普爾金耶細胞(Purkinje cell))、Q(P後)及R(剩餘或抗性)。
L型鈣通道造成引發心臟及平滑肌細胞收縮之鈣向內移動,暗示此等通道之阻斷劑在心血管領域中之推定應用。鑒於此,L型鈣通道阻斷劑自60年代早期已用於臨床且現建議將其作為收縮性-舒張性高血壓及心絞痛之一線治療。
T型鈣通道可見於諸如冠狀動脈及周圍維管、竇房結及普爾金耶纖維、大腦、腎上腺之各種組織中及腎臟中。此廣泛分布暗示T型通道阻斷劑具有推定心血管保護作用,對睡眠障礙、情緒障礙、抑鬱症、偏頭痛、高醛固酮症、早產、尿失禁、大腦老化或諸如阿茲海默氏病之神經退化性病症具有作用。
第一L型及T型鈣通道阻斷劑米貝拉地爾(Mibefradil)()表現出優於主要標靶L通道之鈣通道阻斷劑的效應。米貝拉地爾用於治療高血壓及心絞痛,而並不顯示因L通道阻斷劑而常見之負面副作用,如:收縮力、反射性心動過速;血管收縮激素釋放;或周邊水腫。此外,米貝拉地爾展示潛在心臟保護效應(Villame,Cardiovascular Drugs and Therapy 15,41-28,2001;Ramires,J Mol Cell Cardiol1998
,30,475-83)、腎保護效應(Honda,Hypertension 19,2031-37,2001),且展示治療心臟衰竭之積極的效果(Clozel,Proceedings Association American Physicians1999
,111,429-37)。
儘管對此概況之化合物存在巨大需要,但由於CYP 3A4藥物相互作用不可接受,米貝拉地爾於1998年(其投入市場一年後)退出市場。此外,亦報導ECG異常(亦即QT延長)及與MDR-1介導之地高辛流出之相互作用(du Souich,Clin Pharmacol Ther 67,249-57,2000;Wandel,Drug Metab Dispos2000
,28,895-8)。
顯然,需要用作T/L型鈣通道阻斷劑但具有關於米貝拉地爾之改良安全概況的新穎化合物。
本發明之化合物為有效T/L通道阻斷劑,且因此適用於涉及T通道及L通道二者之疾病。
i)本發明之第一態樣由式(I)之苯并咪唑衍生物組成:
其中:R 2
表示未經取代或者經單取代、二取代或三取代之芳基,其中該等取代基係獨立地選自由(C1-4
)烷基、(C1-4
)烷氧基、鹵素及三氟甲基組成之群;R 2
表示氫或-CO-R 21
;R 21
表示(C1-5
)烷基、(C1-3
)氟烷基、或(C3-6
)環烷基;m
表示整數2或3;p
表示整數2或3;且R 3
表示氫或(C1-5
)烷基。
以下段落提供本發明之化合物的各個化學部分之定義,且意欲在本說明書及申請專利範圍中始終一致地應用,除非另外明確闡述之定義提供更廣或更窄之定義。
術語「(C1-5
)烷基」意謂具有1至5個碳原子之直鏈或支鏈烷基。較佳為具有1至4個碳原子之基團。術語「(Cx-y
)烷基」(x及y為整數)係指含有x至y個碳原子之直鏈或支鏈烷基。(C1-5
)烷基之實例為甲基、乙基、正丙基、異丙基、正丁基、第二-丁基、第三-丁基、異丁基、正戊基,及異戊基。較佳為甲基、乙基、正丙基及異丙基。最佳為甲基。至於取代基R 21
,最佳為異丙基。
術語「(C1-3
)氟烷基」意謂經1至7個氟原子取代之直鏈或支鏈(C1-3
)烷基。(C1-3
)氟烷基之實例為三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基,及五氟乙基。較佳為三氟甲基、2,2,2-三氟乙基,及五氟乙基。最佳為三氟甲基。至於取代基R 21
,最佳為2,2,2-三氟乙基。
術語「(C3-6
)環烷基」意謂具有3至6個碳原子之飽和環狀烷基。(C3-6
)環烷基之實例為環丙基、環丁基、環戊基,及環己基。至於取代基R 21
,最佳為環丙基。
術語「(C1-5
)烷氧基」意謂式(C1-5
)烷基-O-之基團,其中術語(C1-5
)烷基具有先前賦予之意義。術語「(Cx-y
)烷氧基」(x及y為整數)係指含有x至y個碳原子之直鏈或支鏈烷氧基。(C1-5
)烷氧基之實例為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二-丁氧基,及第三-丁氧基。較佳為甲氧基及乙氧基。
術語「鹵素」意謂氟、氯、溴,或碘,尤其氟或氯。
術語「芳基」意謂苯基或萘基。較佳為苯基。芳基可為未經取代,或者經單取代、二取代或三取代,其中取代基係獨立地選自由(C1-4
)烷基、(C1-4
)烷氧基、鹵素,及三氟甲基組成之群。在一子實施例中,芳基較佳為未經取代。「芳基」之實例為苯基、萘基、2-甲基苯基、3-甲基苯基、4-甲基苯基、3,4-二甲基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,6-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2,3-二甲氧基苯基、3,4-二甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3-氯苯基、2,3-二氯苯基、3,4-二氯苯基、2-三氟甲基苯基、3-三氟甲基苯基,及4-三氟甲基苯基。較佳為苯基。
在下文中描述本發明之其他實施例。
ii)本發明之另一實施例係關於實施例i)之式(I)之化合物,其中橋式環己烯部分之組態為使得環己烯部分之取代基R2
-O-與橋基-(CH2
)p
-呈順式關係(亦即,絕對組態如下式(IE1
)或式(IE2
)所描繪)。
iii)本發明之另一實施例係關於實施例i)之式(I)之化合物,其中絕對組態如式(IE1
)所描繪:
iv)本發明之另一實施例係關於實施例i)之式(I)之化合物,其中絕對組態如式(IE2
)所描繪:
v)本發明之另一實施例係關於實施例i)至實施例iv)中任一者之式(I)之化合物,其中R 1
表示未經取代之苯基。
vi)本發明之另一實施例係關於實施例i)至實施例v)中任一者之式(I)之化合物,其中p
表示整數2。
vii)本發明之另一實施例係關於實施例i)至實施例v)之式(I)之化合物,其中p
表示整數3。
viii)本發明之另一實施例係關於實施例i)至vii)中任一者之式(I)之化合物,其中R 2
表示-CO-R 21
。
ix)本發明之另一實施例係關於實施例i)至實施例viii)中任一者之式(I)之化合物,其中R 21
表示(C1-5
)烷基或(C3-6
)環烷基。
x)本發明之另一實施例係關於實施例i)至實施例ix)中任一者之式(I)之化合物,其中R 21
表示(C1-5
)烷基(尤其異丙基)。
xi)本發明之另一實施例係關於實施例i)至vii)中任一者之式(I)之化合物,其中R 2
表示氫。
xii)本發明之另一實施例係關於實施例i)至實施例xi)中任一者之式(I)之化合物,其中m
表示整數3。
xiii)本發明之另一實施例係關於實施例i)至xii)中任一者之式(I)之化合物,其中R 3
表示氫。
xiv)本發明之另一實施例係關於實施例i)至實施例xii)中任一者之式(I)之化合物,其中R 3
表示(C1-5
)烷基(尤其甲基)。
式(I)之化合物含有立體對稱中心或不對稱中心,諸如不對稱碳原子。因此,式(I)之化合物可以立體異構體之混合物或較佳地以純立體異構體形式存在。可以熟習此項技術者已知之方式分離立體異構體混合物。
較佳式(I)之化合物選自由以下各物組成之群:(1R,2R,4R)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇;(1S,2S,4S)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇;及(1R*,5R*,6R*)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-醇。
此外,實施例i)之更佳式(I)之化合物係選自由以下各物組成之群:異丁酸(1R,2R,4R)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯;異丁酸(1S,2S,4S)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯;及異丁酸(1R*,5R*,6R*)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯。
立體異構體之相對組態如下所示:例如,異丁酸(1R*,5R*,6R*)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯命名異丁酸(1R,5R,6R)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯;異丁酸(1S,5S,6S)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯;或此兩個對映異構體之混合物。
在化合物、鹽、醫藥組合物、疾病及其類似物使用複數形式的情況下,此複數形式亦意欲意謂單一化合物、鹽或類似物。
若適當且有利時,對式(I)、式(IE1
)及/或式(IE2
)之化合物的任何提及均應理解為亦指該等化合物之鹽(且尤其醫藥學上可接受之鹽)。
術語「醫藥學上可接受之鹽」係指無毒、無機或有機之酸及/或鹼加成鹽。可參考「Salt selection for basic drugs」,Int
.J
.Pharm
.(1986),33,201-217。
式(I)、式(IE1
)及/或式(IE2
)之化合物及其醫藥學上可接受之鹽可用作藥物,例如,以用於經腸或非經腸投藥之醫藥組合物的形式。
可以任何熟習此項技術者應熟悉之方式(參見,例如Remington,The Science and Practice of Pharmacy
,第21版(2005)
,第5部分,「Pharmaceutical Manufacturing」[Lippincott Williams & Wilkins出版]),藉由使所描述之式(I)之化合物或其醫藥學上可接受之鹽,視情況組合其他治療上有價值之物質連同適合、無毒、惰性、治療上相容之固體或液體載劑材料及(若需要)常見醫藥佐劑形成草本(galenical)投藥形式而製造醫藥組合物。
式(I)之化合物或其醫藥學上可接受之鹽適用於製備藥物,該藥物係用於:
● 治療或預防慢性穩定性心絞痛、高血壓、局部缺血(腎及心臟)、包括心房纖維顫動之心律不整、心肥大或充血性心臟衰竭。
式(I)之化合物或其醫藥學上可接受之鹽進一步亦適用於製備單獨或以任何組合針對以下疾病群之藥劑:
■ 用於治療人類及其他哺乳動物之腎病、糖尿病及其併發症、高醛固酮症、癲癇症、神經痛,或癌症;
■ 用作抗纖顫劑、抗哮喘劑、抗動脈粥樣硬化劑、肺旁通之心臟麻痹液添加劑、溶血栓療法之佐劑、抗凝集劑,或用於治療不穩定性心絞痛之藥劑;
■ 用於治療或預防高血壓,尤其門靜脈高血壓、繼發於用紅血球生成素治療之高血壓及低腎素性高血壓;
■ 用於低氧或缺血性疾病;或用作治療(例如)心臟、腎及大腦局部缺血及再灌注(例如,發生於心肺繞通手術後)、冠狀動脈及腦血管痙攣以及類似病症之抗缺血劑;用於治療周圍血管病(例如雷諾氏病(Raynaud's disease)、間歇性跛行、高安氏病(Takayashus disease))、鐮狀細胞病(包括疼痛危象之起始及/或發展);
■ 用於治療或預防與腎、腎小球及系膜細胞功能相關之病症,包括急性及慢性腎衰竭、糖尿病性腎病、高血壓致腎病、腎小球損傷、與年齡或透析相關之腎損傷、腎硬化、與成像及對比劑以及環孢素相關之腎毒性、腎缺血、原發性膀胱輸尿管逆流,或腎小球硬化症;
■ 用於治療心肌梗死;治療心肥大、原發性及繼發性肺循環高血壓;治療充血性心臟衰竭,包括抑制纖維化、抑制左心室擴張、重塑及功能異常,或者血管成形術或血管支架術後再狹窄;
■ 用於治療內毒血症或者內毒素休克或出血性休克;
■ 藉由改良生殖器(尤其為海綿體)之血流量來治療男性性功能障礙(例如,由於糖尿病、脊髓損傷、根除性前列腺切除術、心因性病原學及其他原因導致之勃起困難)及女性性功能障礙二者;
■ 用於預防及/或減輕癌症或與細胞增殖相關之末梢器官損傷;
■ 用於治療代謝障礙或慢性炎性疾病、胰島素依賴型及非胰島素依賴型糖尿病及其併發症(例如,神經病、視網膜病)、高醛固酮症、骨骼重塑、牛皮癬、關節炎、類風濕性關節炎、骨關節炎類肉瘤病,或濕疹性皮炎;
■ 用於治療肝臟毒性及猝死;早期及晚期肝臟疾病及損傷,包括伴隨併發症(例如肝臟毒性、纖維化、硬化);腫瘤之不利結果,諸如由血管外皮瘤導致之高血壓、泌尿道及/或膀胱痙攣病、肝腎症候群;涉及脈管炎之免疫性疾病,諸如狼瘡、全身性硬化症、混合型冷凝球蛋白血症;與腎功能障礙及肝中毒相關之纖維化;
■ 用於胃腸疾病,諸如潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、胃黏膜損傷、潰瘍炎性腸病及缺血性腸病;基於膽囊或膽管之疾病,諸如膽管炎;胰腺炎;細胞生長調節;良性前列腺肥大或移植;或用作抗腹瀉劑;
■ 用於治療涉及支氣管收縮之病症,或者慢性或急性炎症病症,諸如阻塞性肺病及成人呼吸窘迫症候群;
■ 用於緩解疼痛,包括神經痛、周圍疼痛及與癌症相關之疼痛,諸如與前列腺癌或骨癌相關之疼痛;
■ 用於治療中樞神經系統血管性病症,諸如中風、短暫性缺血性中風、偏頭痛及蛛網膜下出血;中樞神經系統行為障礙;治療癡呆,包括阿茲海默氏癡呆、老年癡呆症及血管性癡呆症;癲癇症或睡眠障礙;或
■ 因以上效用而用於降低總體發病率及/或死亡率。
本發明亦係關於一種預防或治療本文中提及之疾病或病症的方法,其包含投與個體醫藥活性量之式(I)之化合物。
此外,式(I)之化合物亦可有利地組合一或多種選自下列之藥劑使用:降脂劑,諸如斯他汀(statin);抗凝劑,諸如香豆素(coumarin);抗血栓劑,諸如克羅匹多(clopidogrel);β-阻斷劑;及其他心臟保護劑。
此外,所指出之式(I)之化合物(無論化合物自身、其鹽、含有該化合物或其鹽之組合物、該化合物或其鹽之用途等)之任何優先選擇可對(IE1
)及/或(IE2
)之化合物加以必要變更;且反之亦然。
本發明之另一態樣為一種用於製備本發明之式(I)之化合物的方法。亦可依本身已知之方式將所得化合物轉化成其醫藥學上可接受之鹽。
通常,可根據如文獻中所描述或如概述於以下流程1至流程3中之程序中所描述的眾所周知之標準方法進行所有化學轉化。若並未另外指明,則通用基團或整數R1
、R2
、R3
、p及m係如式(I)所定義。所使用之其他縮寫係於實驗部分中定義。在某些情況下,通用基團R1
、R2
、R3
可能與說明於以下流程中之組合不相容,且因此將需要使用保護基(PG)。保護基的使用在此項技術中廣為人知(參見,例如「Protective Groups in Organic Synthesis」,T.W. Greene,P.G.M. Wuts,Wiley-Interscience,1999)。出於此論述之目的,假定該等保護基必要時處於適當位置。
根據以下流程1中概述之程序製備式(I)之化合物。
式(I)中R2
表示H之化合物製法可在室溫下,使用諸如LiOH或NaOH之標準鹼性條件,於如乙醇、甲醇、THF或水之溶劑中,或在室溫下,使用諸如HCl水溶液或TFA之標準酸性條件,於如乙醇、甲醇、THF、DCM或水之溶劑中,將酯K皂化,產生酸衍生物1.1。接著,較佳在室溫下,使用諸如EDC、HOBt或PyBOP之標準偶合試劑,在諸如NEt3
或DIPEA之鹼的存在下且在諸如THF、DCM或DMF之溶劑中,使此酸與苯并咪唑衍生物BB偶合,產生醯胺衍生物1.2。接著,在0℃至室溫之間的溫度下,使用如LiAlH4
或Red-Al之標準還原劑,於諸如甲苯之適當溶劑中還原醯胺1.2,獲得所需式(I)之化合物,其中R2
表示H。
可在0℃與65℃之間的溫度下,使用標準試劑(諸如酸氯化物、酸酐、氯甲酸酯、異氰酸酯或胺甲醯氯),必要時在諸如MgBr2
之路易斯酸之存在下或在諸如NEt3
之鹼存在下,於諸如DCM或THF之惰性溶劑中,由式(I)之化合物醇(其中,R 2
表示H)醯化,獲得式(I)之化合物,其中R 2
表示-COR21
。
根據流程2製備關鍵中間體K。可根據已知程序製備二酮2.1及單保護之酮2.2(Can. J. Chem.1992
,70,974-980;Can. J. Chem.1968
,46,3713-17;J.Org.Chem.1978
,43,4648-4650)。
在-78℃與室溫之間的溫度下於如Et2
O或THF之適當溶劑中,以如格林納試劑(Grignard reagent)或鋰化試劑(使用標準反應條件,由相應溴化合物與(例如)丁基鋰製得;諸如溴化苯基鎂)之親核試劑,由酮2.2烷基化,產生醇2.3。
較佳在室溫下於諸如丙酮之適當溶劑中使用標準脫氫試劑及程序(諸如TsOH)使醇衍生物2.3之縮酮水解且隨後消除水,產生酮2.4。
或者,此去保護/消除反應可以兩個步驟進行。如以上所描述,在室溫下於諸如丙酮之溶劑中使用諸如TsOH之質子條件使醇衍生物2.3之縮酮水解以產生酮衍生物2.5。可在0℃與室溫之間的溫度下在如NEt3
之鹼存在下且在如DCM之適當溶劑中使用諸如Ms-Cl之標準條件,或在0℃與室溫之間的溫度下於如THF之適當溶劑中使用伯吉斯試劑(Burgess reagent)消除水,產生酮衍生物2.4。
在另一變形中,可在約0℃之溫度下藉由適當親核試劑(如格林納試劑)於標準溶劑(如Et2
O或THF)中選擇性地使二酮2.1直接單烷基化成酮衍生物2.5。接著,可施加與以上提及相同之條件消除水。
在-50℃與室溫之間的溫度下,藉由添加諸如格林納試劑或諸如第三-丁基乙酸鋰(在-50℃之溫度下於諸如甲苯-THF或己烷-THF之適當溶劑混合物中,使用溴乙酸第三-丁酯、正丁基鋰及DIPA原位製得)之烷基鋰之親核試劑將酮衍生物2.4轉化成所需關鍵中間體K。
在流程3中概述苯并咪唑衍生物BB(流程1)之合成。在室溫下、在諸如DIPEA、NEt3
、DMAP之鹼存在下於如THF、DCM之溶劑中使用標準偶合試劑及條件(諸如EDC/HOBt)將適當經取代之雙苯胺衍生物3.1(其係根據標準程序或根據以下實驗部分給出之方法由(例如)1,4-二甲氧-2,3-二硝基-苯合成(Eur.J.Org.Chem. 2006,2786-2794))偶合至上述經保護之市售N-烷基胺基-烷酸衍生物以獲得苯胺衍生物3.2,其中PG係指諸如Cbz或BOC之胺基保護基。較佳在微波條件下將純淨或處於諸如甲苯或乙酸之適當溶劑中的3.2加熱至約150℃以產生經保護之胺基烷基苯并咪唑衍生物3.3。視情況,若R3
為烷基,則可使用標準反應引入取代基,諸如在約0℃之溫度下、在如NaH或K2
CO3
之鹼存在下,於如丙酮、DMF或THF之溶劑中以適當之烷基鹵化物進行烷基化。使用標準去保護程序(針對PG=Cbz之氫化;針對PG=BOC之TFA或HCl)進行去保護,獲得所需胺基烷基苯并咪唑衍生物BB。
若所得式(I)之化合物呈對映異構體混合物之形式,則可使用熟習此項技術者已知之方法分離對映異構體:例如,藉由形成及分離非對映異構體鹽;或藉由HPLC經對掌性固定相,諸如Regis Whelk-O1(R,R)(10μm)管柱、Daicel ChiralCel OD-H(5-10μm)管柱,或者Daicel ChiralPak IA(10μm)管柱或AD-H(5μm)管柱。典型對掌性HPLC條件為溶離劑A(EtOH,在存在或不存在諸如NEt3
、二乙胺之胺的情況下)與溶離劑B(己烷)之等位溶劑混合物,流動速率為0.8mL/min至150mL/min。
以下實例說明本發明但完全不限制其範疇。
所有溫度均以℃陳述。以以下方法表徵化合物:1
H-NMR(400MHz)或13
C-NMR(100MHz)(Bruker;化學移動以相對於所使用溶劑之ppm給出;多重性:s=單重峰、d=雙重峰、t=三重峰、q=四重峰、p=五重峰、hex=六重峰、hept=七重峰、m=多重峰;br=寬峰;偶合常數以Hz給出);LC-MS(具有HP 1100二元泵及DAD之Finnigan Navigator;管柱:4.6×50mm,Zorbax SB-AQ,5μm,120;梯度:5-95%於水中之乙腈,1min,具有0.04%三氟乙酸;流量:4.5mL/min),tR
以分鐘給出;藉由TLC(來自Merck之TLC薄板,矽膠60 F254
);或藉由熔點。藉由製備HPLC(管柱:X-terra RP18,50×19mm,5μm;梯度:10-95%於水中之乙腈,其含有0.5%甲酸)或藉由在矽膠管柱層析來純化化合物。可藉由製備HPLC(較佳條件:Daicel,ChiralCel OD 20×250mm,10μm;4%於己烷中之乙醇;流量10-20mL/min)將外消旋體分離成其對映異構體。
縮寫
:(如用於本文中或用於以上描述中)
aq. 水溶液
Ac 乙醯基
anh. 無水
BOC 第三
-丁氧羰基
BSA 牛血清白蛋白
Bu 丁基
Cbz 苯甲基氧羰基
CC 矽膠管柱層析
伯吉斯試劑 氫氧化(甲氧基羰基胺磺醯基)三乙基銨
d 天
DCM 二氯甲烷
dil. 稀
DIPA 二異丙基胺
DIPEA 二異丙基-乙胺;許尼希氏鹼(base);乙基-二異丙基胺
DMAP 二甲胺基吡啶
DMF 二甲基甲醯胺
DMSO 二甲基亞碸
EDC N
-(3-二甲基胺基丙基)-N
'-乙基碳化二亞胺
eq. 當量
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
Et2
O 乙醚
h 小時
Hept 庚烷
Hex 己烷
HOBt 1-羥基苯并三唑
HPLC 高效液相層析
LC-MS 液相層析-質譜
Me 甲基
MeCN 乙腈
MeOH 甲醇
min 分鐘
Ms 甲磺醯基
NEt3
三乙胺
Pd/C 披鈀碳
prep. 製備
PyBOP 六氟磷酸苯并三唑-1-基-氧基-三-吡咯啶-鏻
sat. 飽和
tert.
- 第三(tert
-butyl=t-丁基=第三-丁基)
TFA 三氟乙酸
THF 四氫呋喃
TLC 薄層層析
Red-Al 氫化鈉雙(2-甲氧乙氧基)鋁
rt 室溫
tR
滯留時間
Ts 對-甲苯磺醯基
TsOH 對-甲苯磺酸
關鍵中間體K1A及K2A為雙環[2.2.2]辛-5-烯-2-基或雙環[3.2.2]壬-8-烯-6-基衍生物,係獲得為具有相對組態(R*,R*,R*)(亦即,環己烯部分之橋基-(CH2
)p
-相對於為羥基之基團-OR2
為順式)之主要外消旋體與各別具有相對組態(R*,S*,R*)或(R*,R*,S*)(亦即,環己烯部分之橋基-(CH2
)p
-(其中p各別表示2或3)相對於為羥基之基團-OR2
為反式)之次要外消旋體之間的混合物。可如所描述分離主要外消旋體與次要外消旋體以用於程序A1.5中之關鍵中間體K1A。若未另外闡述,則僅分離主要外消旋體且用於以下實例之製備中。
將25mL 2-(三甲基矽烷氧基)-1,3-環己二烯與13mL α-乙醯氧基丙烯腈混合並在150℃下於密閉容器中加熱22h。將所獲暗橘色黏性油溶解於200mL MeOH中。逐滴添加2.2g甲醇鈉於150mL MeOH中之溶液之後,在室溫下攪拌反應混合物3h,傾入冰/水中且以DCM萃取。在真空中濃縮有機相,且藉由CC以EtOAc-Hept(1:2)純化粗製殘餘物以產生7.9g外消旋-(1R*,4R*)-雙環[2.2.2]辛烷-2,5-二酮。
LC-MS:tR
=0.44min。
向溶解於120mL甲苯中之4.0g外消旋-(1R*,4R*)-雙環[2.2.2]辛烷-2,5-二酮(中間體K1A.1)添加1.7mL乙二醇及0.27g TsOH,且在劇烈攪拌下將溶液加熱至回流歷時3.5h。將反應混合物冷卻至室溫,以飽和NaHCO3
水溶液中止反應,以Et2
O萃取,且蒸發有機相。藉由CC以Hex-EtOAc(7:3)純化粗產物以產生2.41g呈黃色油狀之外消旋-(1R*,4R*)-螺[雙環[2.2.2]辛烷-2,2'-[1,3]二氧戊環]-5-酮。
LC-MS:tR
=0.64min;[M+H+CH3
CN]+
:224.35。
經10min向2.41g外消旋-(1R*,4R*)-螺[雙環[2.2.2]辛烷-2,2'-[1,3]二氧戊環]-5-酮(中間體K1A.2)於80mL Et2
O中之溶液逐滴添加14.5mL溴化苯基鎂溶液(1M於Et2
O中)。在室溫下攪拌反應混合物4h。接著,小心地以冰中止反應混合物,添加8mL 2N HCl且進行相分離。蒸發有機相,且藉由CC以Hept-EtOAC(7:3)純化粗產物以獲得0.37g呈無色油狀之7,10-(1,2-伸乙基)-8-苯基-1,4-二氧雜-螺[4.5]癸-8-醇。(有可能藉由CC分離非對映異構體,但僅在說明時進行)。
LC-MS:tR
=0.84min;[M-H2
O+H]+
:243.34。
向0.54g 7,10-(1,2-伸乙基)-8-苯基-1,4-二氧雜-螺[4.5]癸-8-醇(中間體K1A.3)於20mL丙酮中之溶液添加200mg TsOH,且接著在室溫下將混合物攪拌2天。以飽和NaHCO3
水溶液中止反應混合物,以EtOAC萃取且蒸發有機相。藉由CC以Hept-EtOAC(7:3)純化粗產物以獲得0.34g呈無色油狀之外消旋-(1R*,4R*)-5-苯基-雙環[2.2.2]辛-5-烯-2-酮。
LC-MS:tR
=0.93min;[M+H+CH3
CN]+
:240.11。
在-20℃下向0.51mL DIPA於0.5mL THF中之溶液逐滴添加2.2mL正丁基鋰(1.6M於己烷中)。10min之後,添加0.5mL甲苯且攪拌溶液30min。將混合物冷卻至-50℃,添加0.73mL乙酸第三-丁酯且在-50℃下繼續攪拌1h。接著,添加溶解於1mL THF中之0.32g外消旋-(1R*,4R*)-5-苯基-雙環[2.2.2]辛-5-烯-2-酮(中間體K1A.4),且在-50℃至-20℃下將溶液攪拌2.5h。將反應混合物傾於冰/HCl水溶液上,分離有機相,洗滌且蒸發。藉由CC以Hept-EtOAc(9:1)純化粗反應產物以產生0.30g呈白色固體狀之主要外消旋體,外消旋-(1R*,2R*,4R*)-2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三-丁酯及0.07g呈無色油狀之次要外消旋體,外消旋-(1R*,2S*,4R*)-2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三-丁酯。
LC-MS(主要外消旋體):tR
=1.06min;[M-(CH3
)3
-H2
O+H]+
:241.11。
LC-MS(次要外消旋體):tR
=1.05min;[M+H]+
:315.18。
使用製備對掌性HPLC(管柱:Daicel ChiralPak AD-H,20×250 mm,5μm;Hex/EtOH 95:5;流量:0.8mL/min)、對掌性分析HPLC(Daicel ChiralPak AD-H,4.6×250mm,5μm;Hex/EtOH 95:5;流量:0.8mL/min)將外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三-丁酯分離成各別對映異構體:
對映異構體A:tR
=6.70min。
對映異構體B:tR
=7.93min。
在0℃下,在15min期間向1.4g外消旋-(1R*,5R*)-雙環[3.2.2]壬烷-6,8-二酮(根據已知程序合成:Can.J.Chem. 1968,46,3713-3717)於45mL Et2
O中之懸浮液依次添加10.3mL溴化苯基鎂溶液(1M於THF中),且在室溫下攪拌混合物2h。接著,將反應混合物冷卻至0℃,以冰-水中止反應,以HCl水溶液酸化且以Et2
O萃取。以鹽水洗滌有機相,經MgSO4
乾燥且在真空中濃縮以獲得呈黃色油狀之粗製標題化合物。
LC-MS:tR
=0.79min;[M+H+CH3
CN]+
:272.33。
將以上粗產物8-羥基-8-苯基-雙環[3.2.2]壬烷-6-酮(中間體K2A.1)溶解於55mL丙酮中,添加1.7g TsOH且在室溫下攪拌混合物隔夜。再添加3.5g TsOH且繼續再攪拌5h。接著,以EtOAc稀釋反應混合物,以飽和NaHCO3
水溶液洗滌有機相且蒸發。藉由CC以Hept-EtOAC(4:1)純化粗物料以產生0.9g呈微黃色油狀之外消旋-(1R*,5R*)-8-苯基-雙環[3.2.2]壬-8-烯-6-酮。
LC-MS:tR
=0.99min;[M+H]+
:213.11。
使用程序A1.5由外消旋-(1R*,5R*)-8-苯基-雙環[3.2.2]壬-8-烯-6-酮(中間體K2A.2)製備。
LC-MS(主要外消旋體):tR
=1.11min;[M-(CH3
)3
-H2
O+H]+
:254.02。
藉由將6.0g 1,4-二甲氧基-2,3-二硝基-苯(Eur.J.Org.Chem.2006
,2786-2794)溶解於220mL EtOH中,以N2
排空3次且添加600mg 10重量% Pd/C來合成3,6-二甲氧基-苯-1,2-二胺。在H2
氣氛(氣球)下攪拌反應。2天之後再添加300mg 10重量% Pd/C,且再攪拌混合物24h。經矽藻土襯墊過濾且以EtOH及EtOAc洗滌,在真空中濃縮之後產生4.3g呈黑色固體狀之3,6-二甲氧基-苯-1,2二胺。
LC-MS:tR
=0.48min;[M+H]+
:169.09。
向3.1g 4-(苯甲基氧基羰基-甲基-胺基)-丁酸於80mL DCM中之溶液添加6.5mL DIPEA、1.8g HOBt、2.6g EDC及154mg DMAP。攪拌10min後,添加溶解於20mL DCM中之2.1g 3,6-二甲氧基-苯-1,2-二胺,且在室溫下攪拌混合物隔夜。以飽和NaHCO3
水溶液中止反應,進行相分離且以鹽水洗滌有機相,經MgSO4
乾燥且在真空中濃縮以產生呈黑色油狀之粗製標題化合物。
LC-MS:tR
=0.88min;[M+H]+
:402.06。
向以上粗製3-(2-胺基-3,6-二甲氧基-苯胺甲醯基)-丙基]-甲基-胺基甲酸苯甲酯於16mL甲苯中之混合物添加4mL DMF及1.9g TsOH,且在微波中將反應加熱至150℃,歷時2h。添加飽和NaHCO3
水溶液且進行相分離。以鹽水洗滌有機相,經MgSO4
乾燥,在真空中濃縮,與EtOAc一起經較短矽膠襯墊過濾且再次濃縮。藉由CC以EtOAc進行純化,產生2.7g呈棕色樹脂狀之3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基-甲基-胺基甲酸苯甲酯。
LC-MS:tR
=0.85min;[M+H]+
:384.62。
將2.6g[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基甲酸苯甲酯於60mL EtOH中之溶液以N2
排空3次,接著添加260mg 10重量% Pd/C。接著在室溫下於H2
氣氛(氣球)下攪拌反應混合物5h。經矽藻土襯墊過濾且以EtOH洗滌,在真空中濃縮之後產生1.7g呈棕色發泡體狀之[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺。
LC-MS:tR
=0.57min;[M+H]+
:250.13。
向4.0g外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三-丁酯於25mL EtOH中之溶液添加2.1g LiOH.H2
O、8mL H2
O及22mL MeOH。在室溫下將反應混合物攪拌3天且接著濃縮。使殘餘物在水與Et2
O之間分溶。分離水層且以1N HCl酸化,致使形成白色固體。過濾固體,以5mL稀HCl洗滌且於真空中乾燥以獲得3.2g呈白色固體狀之外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸。
LC-MS:tR
=0.86min;[M-H2
O+H]+
:241.28。
在室溫下向280mg外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸於7mL THF中之溶液添加0.58mL DIPEA、175mg HOBt及250mg EDC。攪拌10min之後,添加270mg[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)。丙基]-甲基-胺,且在室溫下攪拌反應混合物隔夜。以飽和NaHCO3
水溶液中止反應混合物,進行相分離且以水及鹽水洗滌有機相,經MgSO4
乾燥且在真空中濃縮。藉由CC使用EtOAc-MeOH(5:1至2:1)進行純化,產生475mg呈白色發泡體狀之外消旋-(1R*,2R*,4R*)-N-[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-2-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-N-甲基-乙醯胺。
LC-MS:tR
=0.91min;[M+H]+
:490.06。
在0℃下向310mg外消旋-(1R*,2R*,4R*)-N-[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-2-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-N-甲基-乙醯胺於8mL甲苯中之溶液逐滴添加0.77mL Red-Al溶液(65%於甲苯中)。在0℃下攪拌10min之後,移除冷卻浴且在室溫下繼續攪拌3h。接著,小心地將反應混合物傾於1M NaOH/冰之混合物上且攪拌10min。以甲苯萃取水相,以鹽水洗滌合併之有機相,經MgSO4
乾燥且在真空中濃縮。藉由CC使用EtOAc-MeOH(2:1)進行純化,產生230mg呈白色發泡體狀之外消旋-(1R*,2R*,4R*)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇。
LC-MS:tR
=0.79min;[M+H]+
:476.13。
在0℃下向199mg外消旋-(1R*,2R*,4R*)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇於4mL DCM中之溶液添加0.2mL NEt3
及0.1mL異丁醯基氯。攪拌反應混合物隔夜以使溫度緩慢達到室溫。以飽和NaHCO3
水溶液中止反應,進行相分離且以DCM再萃取水相。以鹽水洗滌合併之有機相,經MgSO4
乾燥,且在真空中濃縮。將殘餘物再溶解於3mL EtOAc中,添加矽膠及1.5mL MeOH且劇烈攪拌混合物7天。過濾混合物,以EtOAc-MeOH(2:1)澈底洗滌且蒸發。藉由CC使用EtOAc-MeOH(5:1至3:1+0.1% NEt3
)進行純化,產生186mg呈米色發泡體狀之外消旋-異丁酸(1R*,2R*,4R*)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯。
LC-MS:tR
=0.90min;[M+H]+
:546.23。
可使用以下程序將以上產物轉化成對應二鹽酸鹽。
在0℃下向186mg外消旋-異丁酸(1R*,2R*,4R*)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基。胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯於2mL EtOAc中之溶液添加存於EtOAc中之0.3mL 3M HCl。在不加熱的情況下將反應混合物蒸發至乾以獲得199mg外消旋-異丁酸(1R*,2R*,4R*)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯之二鹽酸鹽。
根據實例1中之程序P1.1,使用外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三丁酯之對映異構體B(參見K1A.6)來製備。
LC-MS:tR
=0.91min;[M-H2
O+H]+
:241.10。
根據實例1中之程序P1.2至程序P1.3使用以上(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸來製備。
LC-MS:tR
=0.78min;[M+H]+
:476.09。
根據實例1A中程序P1.4,使用以上2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇(實例2之化合物)製備。
LC-MS:tR
=0.89min;[M+H]+
:546.19。
根據實例1中程序P1.1,使用外消旋-(1R*,2R*,4R*)-(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸第三-丁酯之對映異構體A(參見K1A.6)製備。
LC-MS:tR
=0.91min;[M-H2
O+H]+
:241.16。
根據實例1中之程序P1.2至程序P1.3使用以上(2-羥基-5-苯基-雙環[2.2.2]辛-5-烯-2-基)-乙酸製備。
LC-MS:tR
=0.79min;[M+H]+
:476.09。
根據實例1A中之程序P1.4,使用以上2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-醇(實例3之化合物)製備。
LC-MS:tR
=0.89min;[M+H]+
:546.11。
根據實例1中之程序P1.1,使用外消旋-((1R*,5R*,6R*)-6-羥基-8-苯基-雙環[3.2.2]壬-8-烯-6-基)-乙酸第三-丁酯(參見R2A.3)製備。
LC-MS:tR
=0.96min;[M+Na+H]+
:296.10。
根據實例1中之程序P1.2至程序P1.3,使用外消旋-(1R*,5R*,6R*)-(6-羥基-8-苯基-雙環[3.2.2]壬-8-烯-6-基)-乙酸製備。
LC-MS:tR
=0.80min;[M+H]+
:490.06。
根據實例1A中之程序P1.4,使用外消旋-(1R*,5R*,6R*)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-醇製備。
LC-MS:tR
=0.91min;[M+H]+
:560.05。
根據以下實驗方法測定式(I)之化合物的L通道拮抗活性(IC50
值)。
除佐劑亞單位β-2a及α2δ-1之外,使表現人類Cav
1.2通道之人類胚胎腎(HEK293)細胞在培養基(含有10%熱失活之胎牛血清(FCS)、100U/ml盤尼西林(penicillin)、100μg/ml鏈黴素、100μg/ml G418、40μg/ml勻黴素(zeocin)及100μg/ml潮黴素(hygromycin)之DMEM)中生長。將細胞以20,000個細胞/孔接種至384孔黑色透明底無菌培養盤(塗佈聚-L-離胺酸,Becton Dickinson)中。在37℃下於5% CO2
中將接種之培養盤培養隔夜。於檢定緩衝液(含有0.1% BSA、20mM HEPES、0.375g/L NaHCO3
之HBSS,以NaOH調節至pH 7.4)中製備KCl溶液之80mM儲備溶液,供用於在20mM之最終濃度下進行檢定。成為於DMSO中之製備拮抗劑之10mM儲備溶液,接著在384孔培養盤中,首先以DMSO繼而以檢定緩衝液稀釋,獲得3×儲備溶液。在檢定當日,將25μl染色緩衝液(含有20mM HEPES、0.375g/L NaHCO3
及3μM螢光鈣指示劑fluo-4 AM(於DMSO中之1mM儲備溶液,含有10%普流尼克(pluronic)之HBSS)添加至經接種之培養盤的各孔。在37℃下於5% CO2
中將384孔細胞培養盤培養60min,隨後在室溫下使用檢定緩衝液以2×50微升/孔洗滌,留下50微升/孔之此緩衝劑用於平衡(30-60min)。在螢光成像培養盤讀取器(FLIPR,Molecular Devices)內,以每25微升/孔之體積將拮抗劑添加至培養盤中,培養3min且最終添加25微升/孔之KCl溶液供細胞去極化。以2秒之時間間隔量測各孔之螢光,歷時8分鐘,且將各螢光峰曲線下面積與改用20mM KCl及媒劑替代拮抗劑所誘發螢光的峰面積進行比較。測定各拮抗劑之IC50
值(抑制50% KCl所誘發螢光反應時所需的化合物濃度(以nM計))達至10μM。
此檢定中尚未測試實例1、實例2、實例3、實例4之化合物。實例化合物1A、2A、3A及4A之IC50
值處於156nM至439nM之範圍內,平均為305nM。
根據以下實驗方法測定式(I)之化合物的T通道拮抗活性(IC50
值),且數據示於表1中。
使分別表現人類Cav
3.1、Cav
3.2或Cav
3.3通道之人類胚胎腎(HEK293)細胞在培養基(含有10%熱失活胎牛血清(FCS)、100U/ml盤尼西林、100μg/ml鏈黴素及1mg/ml G418之DMEM)中生長。以20,000個細胞/孔將細胞接種至384孔黑色透明底無菌培養盤(經聚-L-離胺酸塗佈,Becton Dickinson)中。在37℃下於5% CO2
中將經接種之培養盤培養隔夜。Ca2+
溶液製備成為於100mM四乙基氯化銨(氯化TEA)、50mM HEPES、2.5mM CaCl2
、5mM KCl、1mM MgCl2
(以氫氧化TEA調節至pH 7.2)中的100mM儲備溶液,供用於在10mM之最終濃度下進行檢定。拮抗劑製備成為於DMSO中之10mM儲備溶液,接著在384孔培養盤中首先以DMSO、繼而以100mM氯化TEA、50mM HEPES、2.5mM CaCl2
、5mM KCl、1mM MgCl2
(以氫氧化TEA調節至pH 7.2)稀釋以獲得9×儲備溶液。在檢定當日,將25μl染色緩衝液(含有20mM HEPES、0.375g/l NaHCO3
及3μM螢光鈣指示劑fluo-4 AM(於DMSO中之1mM儲備溶液,含有10%普流尼克)之HBSS)添加至經接種之培養盤的各孔。在37℃下於5% CO2
中將384孔細胞培養盤培養60min,隨後在室溫下使用含有0.1% BSA、20mM HEPES、0.375g/l NaHCO3
之HBSS以2×50微升/孔洗滌,留下50微升/孔之此緩衝劑用於平衡(30-60min)。在螢光成像培養盤讀取器(FLIPR,Molecular Devices)內,以6.25微升/孔之體積將拮抗劑添加至培養盤,培養3min且最終添加6.25微升/孔Ca2+
溶液。以2秒之時間間隔量測各孔之螢光,歷時8分鐘,且將各螢光峰之曲線下面積與由10mM Ca2+
與媒劑替代拮抗劑誘發之螢光的峰面積進行比較。測定各拮抗劑之IC50
值(抑制50% Ca2+
所誘發之螢光反應所需的化合物濃度(以nM計))達至10μM。
測試化合物之降血壓潛力及其對心肌收縮性之作用。根據文獻(Doring HJ.,The isolated perfused heart according to Langendorff technique--function--application,Physiol. Bohemoslov.1990
,39(6)
,481-504;Kligfield P,Horner H,Brachfeld N.,A model of graded ischemia in the isolated perfused rat heart,J. Appl. Physiol.1976
年6月,40(6)
,1004-8)測定對經分離之小鼠心臟的EC50
值。
已使用以上針對蘭根道爾夫氏實驗所描述之程序量測實例1A之化合物,EC50
為5nM。
Claims (8)
- 一種醫藥組合物,其含有式(I)之化合物或其醫藥學上可接受之鹽作為活性成分,
- 如請求項1之醫藥組合物,其中該橋式環己烯部分之組態使得環己烯部分之取代基R2 -O-與橋基-(CH2 )p -呈順式關係。
- 如請求項1或2之醫藥組合物,其中: R 1 表示未經取代之苯基。
- 如請求項1或2之醫藥組合物,其中:R 21 表示(C1-5 )烷基。
- 如請求項1或2之醫藥組合物,其中:m 表示整數3。
- 如請求項1之醫藥組合物,其中該化合物係選自以下化合物:異丁酸(1R,2R,4R)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯;異丁酸(1S,2S,4S)-2-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-5-苯基-雙環[2.2.2]辛-5-烯-2-基酯;異丁酸(1R,5R,6R)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯;及異丁酸(1S,5S,6S)-6-(2-{[3-(4,7-二甲氧基-1H-苯并咪唑-2-基)-丙基]-甲基-胺基}-乙基)-8-苯基-雙環[3.2.2]壬-8-烯-6-基酯;或該化合物之醫藥學上可接受之鹽。
- 一種如請求項1至6中任一項所定義之式(I)之化合物或其醫藥學上可接受之鹽的用途,其係用於製造供治療或預防慢性穩定性心絞痛、高血壓、腎或心臟局部缺血、包括心房纖維顫動之心律不整、心肥大或充血性心力衰竭 的藥物。
- 如請求項1或2之醫藥組合物,其係用於治療或預防慢性穩定性心絞痛、高血壓、腎或心臟局部缺血、包括心房纖維顫動之心律不整、心肥大或充血性心力衰竭。
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US4808605A (en) * | 1986-11-14 | 1989-02-28 | Hoffmann-La Roche Inc. | Tetrahydronaphthalene derivatives as calcium antagonists |
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