TWI582079B - σ配體類於與第2型糖尿病有關之疼痛上之用途 - Google Patents
σ配體類於與第2型糖尿病有關之疼痛上之用途 Download PDFInfo
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- TWI582079B TWI582079B TW101117809A TW101117809A TWI582079B TW I582079 B TWI582079 B TW I582079B TW 101117809 A TW101117809 A TW 101117809A TW 101117809 A TW101117809 A TW 101117809A TW I582079 B TWI582079 B TW I582079B
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- compound
- pain
- diabetes
- pyrazol
- yloxy
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Description
本發明涉及與σ受體結合的化合物於製備供預防及/或治療疼痛和與第2型糖尿病有關之疼痛相關症狀的藥物之用途。
糖尿病係由遺傳、環境、免疫及生活方式因素的相互作用所引起的代謝紊亂。世界衛生組織(WTO)預計截至2030年全世界將有3.66億人罹患糖尿病[Wild S.et al.,Diabetes Care 2004,27,1047-1053]。
根據美國糖尿病協會(ADA;http://www.diabetes.org/home.jsp),已確定糖尿病的四種主要類型,其包括:
- 第1型糖尿病:身體無法產生胰島素。
- 第2型糖尿病:因胰島素抗性所致,並結合相對的胰島素缺乏。
- 妊娠性糖尿病:懷孕期間發生。
- 葡萄糖耐量受損(即糖尿病前期):人血糖濃度高於正常值但未高於足以診斷為第2型糖尿病。
糖尿病性神經病變包含影響周圍神經的很多狀況。糖尿病性神經病變係最常見的慢性糖尿病併發症。事實上,目前糖尿病性神經病變係工業化國家最常見的神經病變且可能係世界上最為常見的神經病變。約30%糖尿病患者出現感覺性神經病變,特別是疼痛。此外,糖尿病性神經病
變的患病率隨年齡增長上升,20至29歲年齡患者的患病率為5%,而70至79歲年齡患者的患病率達約44%,患病率亦隨疾病的持續期間而上升,特別是患病達20年以上者。血糖控制不佳的患者之患病率亦較高。糖尿病性神經病變之最突出的表現係疼痛和營養性潰瘍(例如糖尿病性足潰瘍),該兩者皆與大量發病率和殘疾相關[Said G.Advanced Studies in Medicine 2001,1(11),457-459]。
周圍神經病變能導致感覺喪失而引發神經性潰瘍,其係截肢的主要原因[Poncelet A.N.,Geriatrics.2003,58(6),16-8,24-5,30;Vileikyte L.Diabetes Metab.Res.Rev.2004,20 Suppl 1,S13-18]。
糖尿病性周圍神經病變(DPN,亦稱為遠端對稱性神經病變或感覺運動神經病變或糖尿病性多發性神經病)係第1和2型糖尿病最常見的併發症之一。基於群體的研究,22%糖尿病患者出現中等或嚴重等級的周圍神經病變[Abbott C.A.et al.,Diabet.Med.2002,19:377-384]。1/6糖尿病患者出現長期存在的與周圍神經病變有關的周圍神經性疼痛[Daousi C.et al.,Diabet.Med.2004,21,976-982]。
大多數評估DPN的治療選擇的臨床前期研究已在鏈脲菌素所誘導的糖尿病齧齒動物進行,該糖尿病與第1型糖尿病類似。然而,已有證據顯示,第1和2型糖尿病之糖尿病性神經病變的病原學和病理學可能不同[Sima A.A.,Front.Biosci.2008,13,4809-4816]。
亦使用第2型糖尿病動物模型進行研究,但不如使用第1型糖尿病動物模型頻繁[Sima A.A.et al.,Diabetología2000,43,786-793;Li F.et al.,Neurobiol.Dis.2006,22,669-676;Oltman C.L.et al.,Am.J.Physiol.Endocrinol.Metabol.2005,289,E113-E122]。
文獻Shaw et al.,Proc.Soc.Exp.Biol.Med.1983,173(1),68-75和Friedman et al.,Am.J.Physiol.1991,261(6 Pt 1),E782-E788]首次描述朱克(Zucker)糖尿病性脂肪(ZDF)大鼠。雄性肥胖ZDF(fa/fa或ZDF7Drt-fa;Charles River)係引發無功能瘦素受體(fa/fa)的錯義突變的純合子。8至10周大的ZDF大鼠開始發胖並罹患初始高胰島素血症(胰島素抗性)且隨後罹患糖尿病[Cheng D.et al.,Diabetes Obes.Metab.2005,7,307-317]。多篇文獻已描述神經異常,其包括傳導速度減慢和感言測試變化[Li F.et al.,Neurobiol.Dis.2006,22,669-676;Oltman C.L.et al.,Diabetes Obes.Metab.2008,10,64-74]。
第2型糖尿病的病理過程中可能經常出現進一步的併發症,諸如周圍血管疾病、糖尿病性神經病變、糖尿病性足部問題、糖尿病性視網膜病變及腎病。至少某些該等併發症可能導致輕微、中度或嚴重的疼痛症狀,其為許多糖尿病患者的大問題。
約一半罹患第2型糖尿病的患者已證實患有周圍多發性神經病變(DPN)。該慢性疾病非良性,且第2型糖尿病患者會罹患多種導致發病和死亡的微血管和大血管之併發
症。
感覺性神經病變的結果包括對熱、觸覺及振動刺激的知覺變化,其包括自痛覺過敏和異常性疼痛至痛覺減退的疼痛相關症狀[Vinik A.et al.,Nature Clinical Practice Endocrinology & Metabolism,2006,2,2-13]。
總結,DPN表示對周圍神經的彌漫性對稱性和長期依賴性損害,其對生活品質(QOL)、發病率及由公共健康角度出發的成本皆有重大影響[Boulton A.J.et al.,Diabetes Care 2005,28,956-962;Gordois A.et al.,Diabetes Care 2003,26,1790-1795]。DPN影響16%糖尿病患者,DPN經常係未經報告者(12.5%),且更經常係未經治療或未經適當治療的(39%)[Daousi C.et al.,Diabet.Med.2004,21,976-982]。DPN一直是患者、看護者及醫師的管理難題。因此,需要尋找治療與第2型糖尿病有關之疼痛的新穎方法。
本發明解決上述需要,因為本發明涉及與σ受體結合的化合物於製備供治療及/或預防與第2型糖尿病有關的疼痛及與第2型糖尿病有關之疼痛相關狀(優選地與第2型糖尿病有關之神經性疼痛)的藥物之新用途。
因此,本發明的一方面涉及σ配體,其係用於治療及/或預防與第2型糖尿病有關的疼痛和相關症狀。優選地
,該與第2型糖尿病有關之疼痛係源自糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性肌萎縮、胃輕癱、糖尿病性腹瀉、沙爾科(Charcot)氏關節病變、膀胱神經病變、糖尿病性腎病及/或糖尿病性足部問題。
在優選的實施方案中,該σ配體具有通式(I):
其中R1選自氫、經取代或未經取代的烷基、經取代或未經取代的環烷基、經取代或未經取代的烯基、經取代或未經取代的芳基、經取代或未經取代的芳烷基、經取代或未經取代的非芳香族雜環基、經取代或未經取代的芳香族雜環基、經取代或未經取代的雜環烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9或鹵素;R2選自氫、經取代或未經取代的烷基、經取代或未經取代的環烷基、經取代或未經取代的烯基、經取代或未經取代的芳基、經取代或未經取代的芳烷基、經取代或未經取代的芳香族或非芳香族雜環基、經取代或未經取代的雜環烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8
、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9或鹵素;R3和R4獨立選自氫、經取代或未經取代的烷基、經取代或未經取代的環烷基、經取代或未經取代的烯基、經取代或未經取代的芳基、經取代或未經取代的芳烷基、經取代或未經取代的芳香族或非芳香族雜環基、經取代或未經取代的雜環烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9或鹵素,或R3和R4一起形成任意地經取代的稠合環系統;R5和R6獨立選自氫、經取代或未經取代的烷基、經取代或未經取代的環烷基、經取代或未經取代的烯基、經取代或未經取代的芳基、經取代或未經取代的芳烷基、經取代或未經取代的芳香族或非芳香族雜環基、經取代或未經取代的雜環烷基、-COR8、-C(O)OR8、-C(O)NR8R9、-CH=NR8、-CN、-OR8、-OC(O)R8、-S(O)t-R8、-NR8R9、-NR8C(O)R9、-NO2、-N=CR8R9或鹵素,或R5和R6與彼等連接的氮原子一起形成經取代或未經取代的芳香族或非芳香族雜環基;n選自1、2、3、4、5、6、7或8;t係1、2或3;R8和R9各別獨立選自氫、經取代或未經取代的烷基、經取代或未經取代的環烷基、經取代或未經取代的烯基、經取代或未經取代的芳基、經取代或未經取代的芳香族
或非芳香族雜環基、經取代或未經取代的烷氧基、經取代或未經取代的芳氧基或鹵素;或其藥學上可接受的鹽、異構體、前藥或溶劑化物。
本發明的另一方面涉及σ配體(優選地通式(I)之σ配體)或其藥學上可接受的鹽、異構體、前藥或溶劑化物於製備供預防及/或治療與第2型糖尿病有關之疼痛和相關症狀的藥物之用途。
本發明的另一方面係一種治療及/或預防與第2型糖尿病有關之疼痛和相關症狀之方法,其包含對需要該治療或預防的患者施予治療有效量的σ配體(優選地通式(I)之σ配體)或其藥學上可接受的鹽、異構體、前藥或溶劑化物。
本發明的另一方面涉及藥物或醫藥組成物,其包含至少一種σ配體和至少一種藥學上可接受的賦形劑以用於治療及/或預防與第2型糖尿病有關之疼痛和相關症狀。
本發明的另一方面涉及至少一種σ配體和至少一種其他活性物質之組合以用於治療及/或預防與第2型糖尿病有關之病徵和症狀,其包括疼痛。
該等方面和彼等之優選實施方案係另於申請專利範圍中界定。
本發明文本中,下述術語茲詳細說明如下。
“烷基”係指含有1至12個碳原子的不含有不飽和鍵
的直鏈或支鏈烴鏈基,其係經單鍵與分子的其他部分連接,例如甲基、乙基、正丙基、異丙基、正丁基、三級丁基、正戊基等。烷基可任意地經一或多個取代基取代,該等取代基係諸如芳基、鹵素、羥基、烷氧基、羧基、氰基、羰基、醯基、烷氧羰基、胺基、硝基、巰基、烷硫基等。優選的烷基含有1至6個碳原子。若經芳基取代,則相當於“芳烷基”,諸如苯甲基或苯乙基。若經雜環基取代,則相當於“雜環烷基”。
“烯基”係指含有2至12個碳原子並包含至少一個不飽和鍵的直鏈或支鏈烴鏈基,其係經單鍵與分子的其他部分連接。烯基可任意地經一或多個取代基取代,該等取代基係諸如芳基、鹵素、羥基、烷氧基、羧基、氰基、羰基、醯基、烷氧羰基、胺基、硝基、巰基、烷硫基等。優選的烯基含有2至6個碳原子。
“環烷基”係指安定的3至10員單環基或雙環基,其係呈飽和或部分飽和且僅含有碳原子和氫原子,諸如環己基或金剛烷基。除非說明書另有特殊描述,“環烷基”包括任意地經一或多個取代基(諸如烷基、鹵素、羥基、胺基、氰基、硝基、烷氧基、羧基、烷氧羰基等)取代的環烷基。
“芳基”係指一或多個芳香環基,其包括含有單獨及/或稠合芳基的多環基。典型的芳基含有1至3個單環或稠合環和6至約18個碳環原子,諸如苯基、萘基、茚基、菲基或蒽基。芳基可任意地經一或多個取代基取代,該等取
代基係諸如羥基、巰基、鹵素、烷基、苯基、烷氧基、鹵烷基、硝基、氰基、二烷基胺基、胺基烷基、醯基、烷氧羰基等。
“雜環基”係指安定的3至15員環且係由碳原子及1至5個雜原子組成(該雜原子選自氮、氧或硫),優選地含有一或多個雜原子的4至8員環,更優選地含有一或多個雜原子的5或6員環。雜環基可屬芳香族或非芳香族。對本發明的目的,雜環可為單環、雙環或三環系統,其可包括稠合環系統;且雜環基的氮、碳或硫原子可任意地經氧化;氮原子可任意地經季銨化;且雜環基可呈部分或全部飽和或屬芳香族。該雜環的實例包括但不限於吖庚因、苯並咪唑、苯並噻唑、呋喃、異噻唑、咪唑、吲哚、哌啶、哌嗪、嘌呤、喹啉、噻二唑、四氫呋喃、香豆素、嗎啉、吡咯、吡唑、噁唑、異噁唑、三唑、咪唑等。
“烷氧基”係指式-ORa基,其中Ra係前述具有一或多個(例如1、2、3或4個)氧鍵和1至約12個碳原子(優選地1至約6個碳原子)的烷基,例如甲氧基、乙氧基、丙氧基等。
“芳氧基”係指式-O-芳基,其中芳基係如前述。該芳氧基的某些實例係-O-苯基、-O-對甲苯基、-O-間甲苯基、-O-鄰甲苯基或-O-萘基。
“胺基”係指式-NH2、-NHRa或-NRaRb基,其可任意地經季胺化,例如甲胺基、乙胺基、二甲胺基、二乙胺基、丙胺基等。
“鹵素/鹵”係指溴、氯、碘及氟。
本發明化合物的取代基係指在一或多個可供使用的位置(例如1、2、3或4個)上經一或多個合適的基團取代的指定部分,該合適的基團係諸如氟、氯、溴及碘的鹵素;氰基;羥基;硝基;疊氮基;醯基,諸如烷醯基,例如C1-6烷醯基及類似基;羧醯胺基;烷基,其包括含有1至約12個碳原子或1至約6個碳原子且更優選地1至3個碳原子者;烯基和炔基,其包括含有一或多個(例如1、2、3或4個)不飽和鍵和2至約12個碳原子或2至約6個碳原子的基;烷氧基,其含有一或多個(例如1、2、3或4個)氧鍵和1至約12個碳原子或1至約6個碳原子的基;芳氧基,諸如苯氧基;烷硫基,其包括含有一或多個(例如1、2、3或4個)硫醚鍵和1至約12個碳原子或1至約6個碳原子的基;烷基亞磺醯基,其包括含有一或多個(例如1、2、3或4個)亞磺醯基鍵和1至約12個碳原子或1至約6個碳原子的基;烷基磺醯基,其包括含有一或多個(例如1、2、3或4個)磺醯基鍵和1至約12個碳原子或1至約6個碳原子的基;胺基烷基,其包括含有一或多個(例如1、2、3或4個)N原子和1至約12個碳原子或1至約6個碳原子的基;含有6或多個碳原子的碳環芳基,尤其是苯基、萘基、芳烷基,諸如苯甲基。除非另有說明,任意地經取代之基可在該基的每個可供取代之位置上經取代,且每個取代基係相互獨立的。
本發明的化合物優選地係呈中性、鹼性或酸性形式、
鹽(優選地生理上可接受的鹽)、溶劑化物或多晶型物及/或外消旋化合物、純立體異構體(特別是對映異構體或非對映異構體形式)或立體異構體(特別是對映異構體或非對映異構體)的混合形式及/或經任意比例混合。
根據本發明,術語“鹽”必須理解為本發明之活性化合物的任何形式,其中該鹽假定係以離子形式存在或帶電荷,且係與抗衡離子(陽離子或陰離子)結合或以溶液形式存在。據此,該鹽亦必須理解為活性化合物與其他分子和離子組成的複合物,特別是經離子相互作用複合的複合物。特別地該鹽包括生理上可接受的鹽;該鹽必須被理解為相當於“藥理上可接受的鹽”或“藥學上可接受的鹽”。
本發明上下文中的術語“生理上可接受的鹽”或“藥學上可接受的鹽”特別地理解為與生理上可耐受的酸所形成的鹽(諸如上述)(亦即具有生理上可耐受性者,特別是施於人及/或哺乳動物體的無機酸或有機酸的特定活性化合物的鹽),或與至少一種生理上可耐受的(特別是若施於人及/或哺乳動物體時)優選地無機陽離子所形成的鹽。由特定酸形成的生理上可耐受的鹽之實例係鹽酸鹽、氫溴酸鹽、硫酸鹽、氫溴化物、一氫溴化物、一氫鹽化物或鹽化物、甲碘化物、甲磺酸鹽、甲酸鹽、醋酸鹽、草酸鹽、琥珀酸鹽、蘋果酸鹽、酒石酸鹽、扁桃酸鹽、富馬酸鹽、乳酸鹽、檸檬酸鹽、麩胺酸鹽、馬尿酸鹽、苦味酸鹽及/或天冬胺酸鹽。特殊鹼所形成的生理上可耐受的鹽之實例係鹼金屬鹽和鹼土金屬鹽及與NH4形成的鹽。
根據本發明的術語“溶劑化物”應該理解為本發明之活性化合物的任何形式,其中該化合物係經非共價鍵與另一分子(最可能是極性溶劑)結合,特別地包括水合物和醇化物,例如甲醇化物。
σ配體之前藥的任何化合物,尤其是式(I)的化合物的前藥,亦落入本發明的範圍。術語“前藥”具有廣義上的含義,其包括能在活體內轉化成本發明之化合物的衍生物。前藥的實例包括但不限於式I化合物的衍生物,其包括可生物水解之部分,例如生物水解性醯胺、生物水解性酯、生物水解性胺甲酸酯、生物水解性碳酸鹽、生物水解性醯脲及生物水解性磷酸鹽類似物。優選地,含有羧基言能團的化合物的前藥係羧酸的低級烷酯。羧酸酯可由分子中的任何羧酸部分經酯化而輕易得到。典型地,可使用習知方法製備前藥,諸如由Burger“Medicinal Chemistry and Drug Discovery 6th ed.”(Donald J.Abraham ed.,2001,Wiley),“Design and Applications of Prodrugs”(H.Bundgaard ed.,1985,Harwood Academic Publishers)及Krogsgaard-Larsen et al.,“Textbook of Drug design and Discovery”Taylor & Francis(2002年4月)所描述的方法製備。
上述式(I)所示的本發明的化合物可包括取決於所存在的手性中心的對映異構體或取決於所存在的多重鍵(例如Z或E)的異構體。單一異構體、對映異構體或非對映異構體及彼等之混合物皆落入本發明的範圍。
此外,本文所涉及的任何化合物皆可以互變異構體之
形式存在。特別地,互變異構體係指化合物的2或多個結構異構體的一者,該等異構體平衡地存在,且可自異構體的一種形式轉換成另一種形式。常見的互變異構體對係胺-亞胺、醯胺-亞胺酸、酮-烯醇、內醯胺-內醯亞胺等。
除非另有說明,本發明的化合物亦包括同位素標記的形式,亦即區別僅在於富含一或多個同位素原子的化合物。例如,具有目前結構,但至少一個氫原子被氘或氚取代,或至少一個碳原子被富含13C或14C的碳原子取代,或至少一個氮原子被富含15N的氮原子取代的化合物,該等化合物亦落入本發明的範圍。
σ配體,尤其是式(I)化合物或其鹽或溶劑化物,優選地係以藥學上可接受或基本上純的形式存在。藥學上可接受的形式尤其係指具有藥學上可接受的純度,不包括常見的藥學添加劑,諸如稀釋液和載體,且不包括正常劑量以上具毒性的物質。藥物的純度優選地係50%以上,更優選地70%以上,最優選地90%以上。優選的實施方案中,式(I)化合物或其鹽、溶劑化物或前藥的純度係95%以上。
如前所述,術語“藥學上可接受的鹽、溶劑化物或前藥”係指任何鹽、溶劑化物或當施予接受者時能提供(直接或間接地)本發明所述化合物的任意其他化合物。然而,將能理解的是,非藥學上可接受的鹽、溶劑化物和前藥亦落入本發明的範圍,因為彼等可用於製備藥學上可接受的鹽、溶劑化物和前藥。可由本領域習知的方法製備該藥學上可接受的鹽、溶劑化物和前藥。
本文所使用的術語“治療”和“治療方法”大抵包括根除、去除、逆轉、緩和、減輕或控制與第2型糖尿病有關的疼痛和疼痛相關症狀。
本文所使用的術語“預防”和“預防性治療”係指在與第2型糖尿病有關的疼痛和疼痛相關症狀發生前,特定物質能避免、降低或阻礙其發病或進展的能力。
疼痛經由國際疼痛研究協會(IASP)定義為“與實際或潛在組織損傷相關或依據該損傷而描述的不舒服感覺和情緒體驗”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210]。雖然疼痛總是主觀的,但是可將其原因或症狀分類。
本發明所使用的術語“疼痛”係指與第2型糖尿病有關之疼痛。
如本發明所界定者,與第2型糖尿病有關之疼痛優選地包括與第2型糖尿病有關的任意形式和類型的疼痛/疼痛症狀。優選地,該與第2型糖尿病有關之疼痛係源自糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性肌萎縮、胃輕癱、糖尿病性腹瀉、沙爾科氏關節病變、膀胱神經病變、糖尿病性腎病及/或任意地糖尿病足部問題。
如本發明所界定者,術語“源自”具有與術語“起因於”及/或“相關於”相同的含義,因此其係指導致疼痛的糖尿病之病理過程的結果。
本發明之優選實施方案中,該糖尿病性神經病變優選地包含自主神經病變、感覺運動神經病變、遠端對稱性感
覺運動神經病變、局竈性和多竈性神經病變及/或感覺運動多發性神經病變。
根據IASP,“異常性疼痛”定義為“由通常不會引發疼痛的刺激所引發的疼痛”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210]。雖然異常性疼痛通常被認為是神經性疼痛的症狀,但是未必總是如此,因此雖然在某些領域中異常性疼痛的範圍比神經性疼痛廣泛,但是亦可能發生與神經性疼痛無關的異常性疼痛。
IASP列出“異常性疼痛”、“痛覺過敏”及“疼痛性觸覺過敏”的區別[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),212]:
本發明之優選實施方案中,該與第2型糖尿病有關之疼痛係異常性疼痛。根據一個以上之特殊實施方案,該異常性疼痛係機械性異常性疼痛。根據另一個以上之特殊實施方案,該異常性疼痛係熱異常性疼痛。
本發明的另一優選實施方案中,該與第2型糖尿病有關之疼痛係痛覺過敏。根據一個以上之特殊實施方案,該痛覺過敏係機械性痛覺過敏。根據另一個以上之特殊實施方案,該痛覺過敏係熱痛覺過敏。
本發明的另一優選實施方案中,該與第2型糖尿病有
關之疼痛係疼痛性觸覺過敏。
根據IASP,“神經病變”定義為“神經系統的原發性損害或機能障礙”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),211]。神經性疼痛可能是中樞或周圍原發性的。
本發明的優選實施方案中,該與第2型糖尿病有關之疼痛係源自神經病變。根據一個以上之特殊實施方案,該與第2型糖尿病有關之疼痛係源自周圍神經病變。根據另一個以上之特殊實施方案,該與第2型糖尿病有關之疼痛係源自中樞神經病變。
根據IASP,“神經炎”定義為“神經發炎/炎症”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),212]。
本發明的優選實施方案中,該與第2型糖尿病有關之疼痛係源自神經炎。
根據IASP,“神經痛”定義為“分佈在神經的疼痛”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),212]。
本發明的優選實施方案中,該與第2型糖尿病有關之疼痛係界定為神經痛。
根據IASP,“灼痛”定義為“通常與血管舒縮和分泌汗的運動神經障礙及隨後的營養變化的持續性燒灼痛、異常性疼痛及疼痛性觸覺過敏的症狀”[IASP,Classification of chronic pain,2nd Edition,IASP Press(2002),210]。
在本發明的優選方面,本發明所述與第2型糖尿病有關之疼痛係界定為灼痛。
本文所使用的術語“σ配體”或“σ受體配體”係指與σ受體結合的任意化合物。
本文所界定的與σ受體結合的化合物可為拮抗劑、反相激動劑、激動劑、部分拮抗劑及/或部分激動劑。
根據本發明,σ配體優選地係以(中性)拮抗劑、反相激動劑或部分拮抗劑形式存在的σ受體拮抗劑。
本發明之高度優選實施方案中,該化合物與σ-1受體結合。
本發明之可能實施方案中,本文所界定的與σ受體結合的化合物係以混合的激動劑/拮抗劑作用於σ受體。
本發明的另一實施方案中,本文所界定的與σ受體結合的化合物係以拮抗劑作用於σ受體。
本發明的另一實施方案中,本文所界定的與σ受體結合的化合物係以拮抗劑作用於σ-1受體。
本發明的另一實施方案中,本文所界定的與σ受體結合的化合物係以反相激動劑作用於σ受體。
本發明的另一實施方案中,本文所界定的與σ受體結合的化合物係以部分拮抗劑作用於σ受體。
本發明的另一可能實施方案中,本文所界定的與σ受體結合的化合物係以激動劑作用於σ受體。
“激動劑”界定為結合受體並產生內在效果的化合物,因此當與受體接觸時能增加受體的基礎活性。
“部分激動劑”界定為對受體具有親和性的化合物,但不同於完全激動劑,雖然該化合物佔據高比例的受體,但是僅引發對受體而言為程度小之特有藥理反應。
“拮抗劑”界定為與激動劑或反相激動劑競爭結合受體的化合物,因此能阻斷激動劑或反相激動劑對受體的作用。然而,拮抗劑(亦稱為“中性”拮抗劑)對組成型受體的活性並無影響。拮抗劑藉由結合受體的活性位點或變構位點而顯現調節作用,或者在獨特的結合位點互相作用,該等獨特的結合位點通常並不參與受體活性的生物學調控。拮抗劑活性是否可逆係取決於拮抗劑-受體複合物的壽命,而此亦相應地取決於拮抗劑受體結合的性質。
“部分拮抗劑”界定為結合受體且產生拮抗反應的化合物;然而,部分拮抗劑並不會產生完全的拮抗反應。部分拮抗劑是一種弱的拮抗劑,因此只能部分阻斷激動劑或反相激動劑對受體的作用。
“反相激動劑”界定為藉由佔據與激動劑相同的受體但產生與之相反作用的化合物,因此降低受體的基礎活性(亦即受體媒介的信號傳遞)。該等化合物通常亦稱為負性拮抗劑。反相激動劑是受體的配體,相對於無其他任何配體的基礎狀態,能使受體接受非活性狀態。因此,雖然拮抗劑能抑制激動劑的活性,但反相激動劑係能在無激動劑的情況下改變受體的構象之配體。
本發明使用的術語“σ受體”是屬習知並引用下述界定:“該結合位點代表著不同於類鴉片、NMDA、多巴胺及其他
已知之神經遞質或激素受體家族的典型蛋白”[G.Ronsisvalle et al.,Pure Appl.Chem.2001,73,1499-1509]。基於受體結合研究、解剖學分佈及生物化學特徵的藥理學資料,區分至少兩種σ受體的亞型[R.Quiron et al.,Trends Pharmacol.Sci.1992,13,85-86;M.L.Leitner,Eur.J.Pharmacol.1994,259,65-69;S.B.Hellewell和W.D.Bowen,Brain Res.,1990,527,244-253;G.Ronsisvalle et al.,Pure Appl.Chem.2001,73,1499-1509]。σ1受體的蛋白質序列在本領域係屬習知[例如Prasad,P.D.et al.,J.Neurochem.1998,70,443-451]。對於不同的鎮痛劑(例如鎮痛新),σ1受體顯示極高之親和性。
本發明所使用的“與σ受體結合的化合物”或“σ配體”界定為對σ受體的IC50值5000 nM,優選地1000 nM,更優選地500 nM的化合物。優選地,IC50值250 nM。更優選地,IC50值100nM。最優選地,IC50值50nM。半數最大抑制濃度(IC50)是化合物抑制生物學或生化功能的效力量度。IC50係指取代50%放射性配體的特異性結合所需要的競爭性配體濃度。此外,本發明所使用的術語“與σ受體結合的化合物”界定為使用10 nM特異於σ受體的放射性配體(例如優選地[3H]-(+)鎮痛新)即能取代至少50%放射性配體,其中σ受體可為任何σ受體亞型。優選地,該化合物結合σ-1受體亞型。
與σ受體結合的化合物,通常亦被稱為σ配體,在本領域係屬習知。其中多者皆包括在上述界定的“與σ受體
結合的化合物”中。雖然σ配體的許多應用係屬習知(諸如作為抗精神病藥物、抗焦慮藥、抗抑鬱藥、中風治療藥、抗癲癇藥及用於治療許多其他適應症,其包括偏頭痛和一般疼痛),但在此等化合物的技術領域中並未提及能用於治療與第2型糖尿病有關之疼痛。
本領域技術人員習知能產生特定作用之化合物的前藥的習知方法(例如Krogsgaard-Larsen et al.,Textbook of Drug design and Discovery,Taylor & Francis(2002年4月))。
優選的實施方案中,本發明的σ配體具有如上述通式(I)。
優選的實施方案中,該式(I)化合物中R1選自H、-COR8或經取代或未經取代的烷基。優選地,R1選自H、甲基或乙醯基。更優選的實施方案中R1係H。
另一優選實施方案中,式(I)化合物中R2表示H或烷基,更優選地甲基。
本發明之另一優選實施方案中,式(I)化合物中R3和R4位於苯基的間位和對位,優選地彼等獨立選自鹵素或經取代或未經取代的烷基。
本發明之特別優選實施方案中,式(I)化合物中R3和R4與苯基一起形成任意地經取代的稠合環系統(例如可與苯基結合的經取代或未經取代的芳基或經取代或未經取代的芳香族或非芳香族雜環基),更優選地萘基環系統。
式(I)化合物中,本發明之優選實施方案中n選自2、
3或4,更優選地n係2。
最後,另一實施方案中,式(I)化合物中優選地R5和R6各自獨立係C1-6烷基,或與彼等連接的氮原子一起形成經取代或未經取代的雜環基,特別地選自嗎啉基、哌啶基或吡咯啶基。更優選地,R5和R6一起形成嗎啉-4-基。
另一優選實施方案中,組合上述優選的不同取代基。本發明亦針對式(I)的上述優選取代基的組合。
本發明之優選變體中,式(I)的σ配體選自:
[1]4-{2-(1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基)乙基}嗎啉
[2]2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[3]1-(3,4-二氯苯基)-5-甲基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[4]1-(3,4-二氯苯基)-5-甲基-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[5]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌啶
[6]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[7]3-{1-[2-(1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基)乙基]哌啶-4-基}-3H-咪唑並[4,5-b]吡啶
[8]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-4-甲基哌嗪
[9]4-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌嗪羧酸乙酯
[10]1-(4-(2-(1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基)乙基)哌嗪-1-基)乙酮
[11]4-{2-[1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}嗎啉
[12]1-(4-甲氧基苯基)-5-甲基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[13]1-(4-甲氧基苯基)-5-甲基-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[14]1-[2-(1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基)乙基]哌啶
[15]1-{2-[1-(4-甲氧基苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[16]4-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}嗎啉
[17]1-(3,4-二氯苯基)-5-苯基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[18]1-(3,4-二氯苯基)-5-苯基-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[19]1-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}哌啶
[20]1-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}-1H-咪唑
[21]2-{2-[1-(3,4-二氯苯基)-5-苯基-1H-吡唑-3-基氧基]乙基}-1,2,3,4-四氫異喹啉
[22]4-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}嗎啉
[23]1-(3,4-二氯苯基)-5-甲基-3-[4-(吡咯啶-1-基)丁氧基]-1H-吡唑
[24]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}哌啶
[25]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-4-甲基哌嗪
[26]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-1H-咪唑
[27]4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]-N,N-二乙基丁-1-胺
[28]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-4-苯基哌啶
[29]1-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-6,7-二氫-1H-吲哚-4(5H)-酮
[30]2-{4-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]丁基}-1,2,3,4-四氫異喹啉
[31]4-{2-[1-(3,4-二氯苯基)-5-異丙基-1H-吡唑-3-基氧基]乙基}嗎啉
[32]2-[1-(3,4-二氯苯基)-5-異丙基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[33]1-(3,4-二氯苯基)-5-異丙基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[34]1-(3,4-二氯苯基)-5-異丙基-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[35]1-{2-[1-(3,4-二氯苯基)-5-異丙基-1H-吡唑-3-基氧基]乙基}哌啶
[36]2-{2-[1-(3,4-二氯苯基)-5-異丙基-1H-吡唑-3-基氧基]乙基}-1,2,3,4-四氫異喹啉
[37]4-{2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]乙基}嗎啉
[38]2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[39]1-(3,4-二氯苯基)-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[40]1-{2-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]乙基}哌啶
[41]1-(3,4-二氯苯基)-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[42]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}哌嗪
[43]1-{2-[1-(3,4-二氯苯基)-5-甲基-1H-吡唑-3-基氧基]乙基}吡咯啶-3-胺
[44]4-{2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]乙基}嗎啉
[45]2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]-N,N-二乙基乙胺
[46]1-(3,4-二氯苯基)-4,5-二甲基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
[47]1-(3,4-二氯苯基)-4,5-二甲基-3-[3-(吡咯啶-1-基)丙氧基]-1H-吡唑
[48]1-{2-[1-(3,4-二氯苯基)-4,5-二甲基-1H-吡唑-3-基氧基]乙基}哌啶
[49]4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}嗎啉
[50](2S,6R)-4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}-2,6-二甲基嗎啉
[51]1-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}哌啶
[52]1-(3,4-二氯苯基)-3-[4-(吡咯啶-1-基)丁氧基]-1H-吡唑
[53]4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N,N-二乙基丁-1-胺
[54]N-苄基-4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N-甲基丁-1-胺
[55]4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]-N-(2-甲氧乙基)-N-甲基丁-1-胺
[56]4-{4-[1-(3,4-二氯苯基)-1H-吡唑-3-基氧基]丁基}硫代嗎啉
[57]1-[1-(3,4-二氯苯基)-5-甲基-3-(2-嗎啉乙氧基)-1H-吡唑-4-基]乙酮
[58]1-{1-(3,4-二氯苯基)-5-甲基-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑-4-基}乙酮
[59]1-{1-(3,4-二氯苯基)-5-甲基-3-[2-(哌啶-1-基)乙氧基]-1H-吡唑-4-基}乙酮
[60]1-{1-(3,4-二氯苯基)-3-[2-(二乙基胺基)乙氧基]-5-甲基-1H-吡唑-4-基}乙酮
[61]4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}嗎啉
[62]N,N-二乙基-2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙胺
[63]1-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}哌啶
[64]5-甲基-1-(萘-2-基)-3-[2-(吡咯啶-1-基)乙氧基]-1H-吡唑
或其藥學上可接受的鹽、異構體、前藥或溶劑化物。
本發明之優選實施方案中,式(I)的σ配體係4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}嗎啉。該特定化合物係本發明的實施例指定的化合物n° 61。
更優選的實施方案中,式(I)的σ配體係4-{2-[5-甲基-1-(萘-2基)-1H-吡唑-3-基氧基]乙基}嗎啉鹽酸鹽。該特定化合物係本發明的實施例指定的化合物n° 1。
可藉由先前申請案WO 2006/021462公開的方法製備
式(I)化合物及其鹽或溶劑化物。
如上所述,本發明的一方面涉及如前界定的σ配體於製備供治療及/或預防與第2型糖尿病有關之疼痛的藥物之用途。
本發明的另一方面涉及不同藥物形式的藥物或組成物,其包含至少一種與σ受體結合的化合物(優選地式(I)化合物)、任意地至少一種其他活性物質及至少一種藥學上可接受的賦形劑,該藥物或組成物係用於治療及/或預防與第2型糖尿病有關之疼痛。
優選地,該藥物適於口服或腸胃外施予,更優選地適於口服、靜脈內、腹膜內、肌肉內、皮下、鞘內、經直腸、經皮、經黏膜或鼻施予。
口服施予的藥物優選地選自片劑、糖錠、膠囊、粉末、滴劑、凝膠劑、汁液、糖漿、溶液或懸濁液。
本發明的口服施予藥物亦可呈多顆粒的形式,優選地微粒、微片、丸劑或小顆粒,任意地經壓縮成片劑、填充入膠囊或在合適液體中懸浮。合適的液體係本領域技術人員所習知。
個別藥物亦可根據其施予途徑而含有一或多種本領域技術人員所習知的賦形劑。根據本發明,該藥物可依據本領域技術人員所習知的標準方法製備。
術語“賦形劑”係指除活性成分以外的藥物化合物的成分(由歐洲藥品管理局EMA所獲得的定義)。賦形劑優選地包括“載體、佐劑及/或載劑”。載體係使物質併入其中以改
善遞送和藥效的形式。藥物載體在藥物遞送系統(諸如控制釋放技術)中用於體內延長藥物作用、降低藥物代謝並減少藥物毒性。載體亦用於設計增強藥物對藥理作用的靶位點的遞送效果(美國國家醫學圖書館,國立衛生研究烷)。佐劑係加入藥品製劑的物質,其係以可預見的方式對活性成分作用。載劑是輔料或物質,優選地不具有治療作用且作為施予的散裝藥物的媒質(Stedman's Medical Spellchecker,© 2006 Lippincott Williams & Wilkins)。該等藥學載體、佐劑或載劑可為無菌液體,諸如水和油,其包括石油、動物、植物或合成來源的水和油,諸如花生油、豆油、礦物油、芝麻油等,賦形劑、崩解劑、濕潤劑或稀釋劑。E.W.Martin,"Remington's Pharmaceutical Sciences"描述合適的藥物載體。該等賦形劑的選擇和使用劑量將取決於藥物組成物的施予形式。
人和動物的每日用量可隨各物種因素或其他因素(諸如年齡、性別、體重或疾病嚴重程度等)改變。人的每日用量可優選地為1至2000 mg,優選地1至1500 mg,更優選地1至1000 mg活性物質,每天一次或幾次攝取。
本發明亦提供至少一種如上界定的σ配體和至少一種其他活性物質之組合以用於治療及/或預防第2型糖尿病相關病徵和症狀,其包括疼痛。
術語“其他活性物質”係指除σ配體外的任何活性物質或活性藥物成分(API)。
本發明的另一方面係一種治療受與第2型糖尿病有關
之疼痛或可能受因第2型糖尿病引發之疼痛的患者(特別是人)之方法,該方法包含對需要該治療或預防的患者施予治療有效量的如上界定的σ配體。
下述實施例僅用於闡述本發明的特定實施方案而不被認為以任何形式限制本發明。
在生理鹽水(0.9%)中溶解實施例1化合物並使用NaOH將pH值校正至5。通過腹膜內(i.p.)途徑施予該化合物。本研究使用的藥物劑量是64 mg/kg於腹膜內急性施用和25 mg/kg於每天兩次(BID)持續14天腹膜內慢性治療。使用0.5 ml體積施予pH值調至5的化合物和鹽水(賦形劑)。
所有實驗方案都嚴格遵照歐盟關於管理和使用實驗動物的規定進行(86/609/EEC)。使用自Charles Rivers Genetic Models Inc.獲得的雄性ZDF(朱克糖尿病脂肪)大鼠(ZDF/Gmi,fa/fa)進行研究。將6周大的大鼠分成兩組並放入標準透明籠中安置,提供12小時明暗周期環境,並使動物隨意攝取Purina 5008(16.7千卡%脂肪)的食物和無菌飲水。定期監測非空腹血糖濃度和體重。
急性實施例1:在行為測試前30分鐘,動物接受一次實施例1化合物(64 mg/kg腹膜內注射,0.5 ml)(n=8)。
對照:在行為測試前30分鐘,動物接受一次賦形劑注射(0.5 ml)(將0.001%醋酸溶液稀釋在生理鹽水中)(n=8)。
慢性實施例1:動物接受一次實施例1化合物(25 mg/kg每天2次,持續14天)的注射(0.5 ml)(n=8)。在治療過程中每周進行一次行為測試,在最後一次施用後一周處死動物,並進行電生理學和心血管實驗。
慢性賦形劑:動物接受賦形劑注射(0.5 ml腹膜內,每天2次,持續14天)(n=8)。在治療過程中每周進行一次行為測試,並在最後一次體內測定後處死動物,並進行電生理學和心血管實驗。
足底測試:使用37370足底測試儀(Ugo Basile,Comerio VA,義大利)測試熱痛覺過敏(熱傷害感受)。記錄自施用於後爪中間蹠面的輻射熱聚焦光束的縮回潛伏期。在實驗
開始時,調整光強度以使對照平均基線潛伏期為約8秒,強制截止潛伏期為30秒。測量每隻爪的縮回潛伏期並使用平均值進行資料分析。與對照基線潛伏期相比,縮回潛伏期的增加證實治療的抗痛覺過敏效果。
Von Frey檢測:使用電子Von Frey儀(EVF3,Bioseb,BP89,Chaville Cedez,法國)評估機械性觸誘發痛。將大鼠單獨置於升高的鐵網底部,經透明的塑膠籠子罩住,並允許適應檢測環境至少15分鐘。藉由應用von Frey纖絲穿過鐵網底部至每隻後爪的蹠面進行檢測。
進行3次檢測,試驗間隔約3分鐘。將3次試驗的平均值進行資料分析。機械性觸誘發痛界定為觸發機械性刺激後爪縮回的壓力閾的顯著下降。截止上限為50 g。
自發性活動:使用單獨的光電活動室(Cibertec,西班牙)評估。施用藥物後50分鐘,將大鼠置入記錄室中(55×40 cm,光束間隔3 cm),記錄光電光束的干擾數量30分鐘以上。
為使疼痛或不適降到最低,頸椎脫臼法處死動物。在多毛的後爪皮膚上皮下,解剖並切除隱神經及神經支配區域。將皮膚真皮向上釘入器言浴槽中,並使用合成的組織間液(SIF)[(以mM為單位):108,NaCl;3.5。KCl;0.7。MgSO4;26,NaHCO3;1.7,NaH2PO4;1.5,CaCl2;9.6,葡糖酸鈉;5.5,葡萄糖;7.6,蔗糖]]將其冷卻(16 ml/分鐘)
,該合成的組織間質液經卡波金(95% O2至5% CO2)飽和,保持溫度為32±0.5℃和pH值為7.38的條件下。將隱神經通過小洞拉入記錄室,置於小鏡子上並用石蠟油層覆蓋。使用金線電極記錄神經元活動。用磨尖的鑷子重復剖開神經的小纖絲直到能夠記錄彼等之單一單元的活動。擴增、過濾觸發的動作電位,通過類比數位轉換器將其引入示波器和監聽器並發送到電腦上,在其上通過採集系統(Microstar DAP 3000a電路板和波峰/SPIDI套裝軟體(C.Forster,University of Erlangen-Nurnberg,德國))進行線上取樣。隨後使用SPIDI軟體離線分析波峰。
藉由使用鈍玻璃杆手動探測皮膚施加500 mN以上的壓力以尋找感受域(RF),從而首次確定單元。然後只詳細研究對這種刺激有反應的單元。為描述單元的特徵,藉由使用聚四氟乙烯塗層鋼微小神經照相術電極(軸徑1 mm,禿尖直徑5-10 μm阻抗1-5 MΩ)超強的方波脈衝(脈衝寬度0.5 ms;群頻0.2 Hz;可變強度)電子刺激RF評估傳導速度(CV);將惰性電極置於器言浴附近。使用置於感受域上的記錄電極和刺激電極之間的距離和傳導延緩以評估單元的CV。
一旦確定單一單元,使其進入1分鐘的控制期以記錄自發性活動,限定為放電率1波峰/分鐘,然後使用具有塑膠圓筒形探針(平頭電極;直徑:1 mm,Cibertec®)的刺激器進行機械性刺激,使用顯微操縱器將該刺激器垂直地置於單元的皮膚RF最敏感部位上。每次刺激開始時有3
秒的適應期,其中刺激器的探針接觸皮膚但不施加任何壓力。
在任何刺激抵消之後,將探針從組織上卸下,且為避免纖維損傷(脫敏作用),依據方案兩次連續刺激的時間間隔是5分鐘。刺激方案如下:首先,單元的機電閾,限定為觸發首次波峰的壓力,該首次波峰之後在下一個8 mN增量(修改自Suzuki et al.,Neurosci.Res.2002,43,171-178)內產生另一波峰,該機電閾藉由應用增壓刺激(自0至200 mN以8 mN/s的速度不斷增加刺激[Schlegel T.et al.,Neurosci.Lett.2004,361,163-167])測定。對進行增力刺激抵消前30秒期間內顯示自發放電的單元,計算該30秒內放電率平均值(基礎活性,脈衝/秒(imp/s)),並測定閾最低力,其中波峰的暫態頻率不斷超過基礎活性平均值+標準誤差。
其次,施加5秒的恆定閾上壓力8刺激(~閾+40 mN,階躍壓力刺激)。
最後,為探查單元的熱敏感度,完成機械性刺激方案後,藉由在冰冷和熱溫度下對感受域推注1 ml SIF溶液以檢驗對冷(~11℃)和毒性熱(~52℃)的反應,該感受域藉由自封閉金屬環(1 cm直徑)被分離,並使用注射器除去環內的槽液。使平緩置入環內並幾乎要接觸到皮膚的熱電偶測量環內達到的溫度。當在操作期間單元放電至少3個動作電位時,對真實的冷或熱放電評分,32℃下液體的對照操作未觸發放電。對冷和熱刺激的反應只作定性報告。冷
和熱操作的間隔是5分鐘。
此研究只集中在機械性敏感傳入神經單元上,其CV在有髓Aδ纖維範圍內。與對大鼠的其他研究一致,傳導2.5至24.0 m/秒的單元被認為是Aδ。沒有纖維顯示出CV>13.5 m/秒,這被認為是區分Aδ和Aβ纖維的界限。
為分析對階躍壓力刺激的機械性反應,並為避免壓力波動,由每次刺激的第一秒和最後一秒引出的波峰不包括在計算的總波峰內。
足底測試結果描述為自兩隻後爪所獲得的熱潛伏期平均值百分比。
Von Frey檢測結果描述為自兩隻後爪所獲得的機械閾平均值百分比。
自發性活動描述為30分鐘以上光電光束交叉平均數百分比。
資料描述為平均值+標準誤差平均值(SEM)。通過方差分析(ANOVA),接著在適當的情況下,通過進一步的紐曼-凱爾斯檢驗或Bonferroni檢驗進行多組間藥效顯著差異的統計分析。P<0.05認為是統計上顯著的。
可通過先前申請案WO 2006/021462所公開的方法製備化合物61。可根據下述方法獲得彼之鹽酸鹽:將化合物61(6.39 g)溶解於經鹽酸飽和的乙醇中,然後攪拌混合物數分鐘並蒸發至乾燥。殘餘物用異丙醇進行結晶。一次結晶後的母液通過濃縮進行二次結晶。兩次結晶一共獲得5.24 g(63%)相應的鹽酸鹽(熔點=197至199℃)。
1H-NMR(DMSO-d6)δ ppm:10.85(bs,1H),7.95(m,4H),7.7(dd,J=2.2,8.8 Hz,1H),7.55(m,2H),5.9(s,1H),4.55(m,2H),3.95(m,2H),3.75(m,2H),3.55-3.4(m,4H),3.2(m,2H),2.35(s,3H)。
HPLC純度:99.8%
圖1a至1c顯示7周大(在神經病變前)、13周大(患神經病變後)的ZDF大鼠的傷害感受和運動及通過一次腹膜內施用實施例1化合物(64 mg/kg)或賦形劑所誘發的效
果。使對照值標準化(對照組=100)以簡化比較。兩因素方差分析後使用邦弗朗尼多重比較檢驗經計算之統計性差異並標記如下:* vs.第7周的對應組;# vs.第13周的對應組;+vs.賦形劑(第13周)。
在分配接受實施例1化合物處理的大鼠組,ZDF大鼠在第7周顯示平均血糖濃度(mg/dL)為91.8±8.6,而在分配經賦形劑處理的大鼠組為84.4±7。6周後(第13周),兩組的葡萄糖濃度已顯著升高,分別為414.3±46.2%和412.9±18.9%。
截止至第13周,ZDF大鼠已患顯著的熱痛覺過敏(圖1a)和機械性觸誘發痛(圖1b),使用實施例1化合物(64 mg/kg)進行急性腹膜內治療以恢復至第7周發現的基線值(在患第2型糖尿病和由彼引發的第2型糖尿病神經病變和疼痛前)。
在試驗前30分鐘,實施例1化合物(64 mg/kg劑量)對ZDF大鼠腹膜內施用顯著地增加後爪縮回對熱刺激的潛伏期(亦即逆轉熱痛覺過敏):經實施例1化合物處理的動物為25.5±9.1%,而經賦形劑處理的動物為12.6±6.9%(圖1a)。
關於機械性觸誘發痛,與7周大的大鼠的記錄值相比,觸發縮回反應的壓力閾在13周大的ZDF大鼠降低(其在分配經賦形劑處理的組降低29.2±3.1%,而在分配經實施例1化合物處理治療的組降低26.1±4.5%)。藉由使用實施例1化合物的治療顯著增加閾值(亦即逆轉機械性觸誘發
痛),返回至第7周基礎值(圖1b)。
所有分析組的自發性活動都有顯著差異(圖1c)。
圖2a至2c顯示7周大(神經病變前)、13周大(患神經病變後)的ZDF大鼠的傷害感受和運動及藉由每天2次,持續14天(第13至15周)腹膜內施予實施例1化合物(25 mg/kg)或賦形劑誘發的效果。使對照值標準化(對照組=100)以簡化比較。兩因素方差分析後使用邦費羅尼多重比較檢驗經計算之統計性差異並標記如下:* vs.第7周的對應組;# vs.第13周的對應組;+vs.賦形劑(第13周)。
施予實施例1化合物(25 mg/kg腹膜內,每天2次)14天,該治療對傷害感受和運動的效果在首次注射後14天評估。神經病變已發展時,在第13周開始治療。
在實施例1化合物施予14天後,完全逆轉熱痛覺過敏(圖2a)和機械性觸誘發痛(圖2b),且記錄值與患神經病變前的值(7周大)相似。
自發性活動在預處理值和經實施例1化合物或賦形劑處理組的記錄值之間沒有差異(圖2c)。
圖3a至3c顯示實施例1化合物的慢性治療對傷害感受器的周圍電生理學反應的效果。從威斯塔大鼠(非糖尿病大鼠)和每天2次持續14天腹膜內施予實施例1化合物(25 mg/kg)或賦形劑的ZDF大鼠身上取得組織。兩因素方差分析後使用邦費羅尼多重比較檢驗經計算之統計性差異並標記如下:+實施例1化合物vs.賦形劑。
與對照威斯塔(非糖尿病)大鼠記錄的反應相比,ZDF大鼠的經賦形劑處理組中,如在所有刺激方案所觀察者,對機械性刺激的周圍電生理學反應出現顯著增加(圖3a至3c)。
與賦形劑處理的ZDF大鼠相比,每天2次持續14天以25 mg/kg劑量對ZDF大鼠腹膜內施予實施例1化合物降低對機械性刺激的反應閾,並增加由機械性刺激觸發的電生理學反應(波峰總數量)(圖3a至3c)。
從以上實驗資料可得下述結論:
a)ZDF大鼠產生機械性觸誘發痛和熱痛覺過敏,這些變化被認為是周圍神經病變的可靠跡象。
b)單獨施予實施例1化合物(64 mg/kg,腹膜內)逆轉機械性觸誘發痛和熱痛覺過敏的閾值變化。在實施例1化合物施用後之記錄值與在神經病變產生前獲得的值相似。
c)以25 mg/kg劑量每天2次持續14天慢性治療後,沒有產生對實施例1化合物發揮的抗異常性疼痛和抗痛覺過敏作用的耐受性。
d)藉由對自發活動的非特異性效果未能掩蓋實施例1
化合物對異常性疼痛和熱痛覺過敏發揮的抑制效果。
e)在行為測試中的機械性觸誘發痛與記錄在Aδ纖維上的對機械性刺激反應的電生理學的高反應性相關。因此,在行為測試中實施例1化合物對機械性觸誘發痛的抑制效果與在電生理學記錄中發現的對機械性刺激反應的高反應性降低相關。
圖1a:實施例1對熱痛覺過敏的急性治療效果。柱顯示熱潛伏期(足底測試)的變化的均值百分比±標準誤差均值(SEM)。
圖1b:實施例1對機械性觸誘發痛的急性治療效果。柱顯示對機械性刺激(Von Frey檢測)反應閾的變化的均值百分比±標準誤差均值。
圖1c:實施例1對自發性活動能力的急性治療效果。柱顯示對總交叉數(自發性活動)的變化的均值百分比±標準誤差均值。
圖2a:實施例1對熱痛覺過敏的慢性治療效果。柱顯示熱潛伏期(足底測試)的變化的均值百分比±標準誤差均值。
圖2b:實施例1對機械性觸誘發痛的慢性治療效果。柱顯示對機械性刺激(Von Frey檢測)反應閾的變化的均值百分比±標準誤差均值。
圖2c:實施例1對自發性活動的慢性治療效果。柱顯
示對總交叉數(自發性活動)的變化的均值百分比±標準誤差均值。
圖3a:實施例1對增加力量(機電閾值;斜升)的機械性刺激的慢性治療效果。
圖3b:實施例1對使用施予無害力(恆定的閾上壓力;階躍)的重復刺激(階躍)的機械性刺激的慢性治療效果。
圖3c:實施例1對使用施予有害力(恆定的超強壓力;有害性階躍)的重復刺激(階躍)的機械性刺激的慢性治療效果。
Claims (3)
- 一種σ配體於製備用於治療及/或預防與第2型糖尿病有關之疼痛的藥物之用途,其中該σ配體係4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}嗎啉或其藥學上可接受的鹽。
- 如申請專利範圍第1項之用途,其中與第2型糖尿病有關之疼痛係源自糖尿病性神經病變、糖尿病性視網膜病變、糖尿病性肌萎縮、胃輕癱、糖尿病性腹瀉、沙爾科(Charcot)氏關節病變、膀胱神經病變、糖尿病性腎病及/或糖尿病性足部問題。
- 如申請專利範圍第1項之用途,其中該σ配體係4-{2-[5-甲基-1-(萘-2-基)-1H-吡唑-3-基氧基]乙基}嗎啉鹽酸鹽。
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EP2818166A1 (en) | 2013-06-26 | 2014-12-31 | Laboratorios del Dr. Esteve S.A. | Use of sigma receptor ligands for the prevention and treatment of pain associated to interstitial cystitis/bladder pain syndrome (IC/BPS) |
SG11201601304XA (en) | 2013-09-12 | 2016-03-30 | Esteve Labor Dr | Nsaid and sigma receptor ligand combinations |
CA2933511A1 (en) | 2013-12-17 | 2015-06-25 | Laboratorios Del Dr. Esteve, S.A. | Serotonin-norepinephrine reuptake inhibitors (snris) and sigma receptor ligands combinations |
JP2017503765A (ja) | 2013-12-17 | 2017-02-02 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | ガバペンチノイドおよびシグマ受容体の組み合わせ |
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2011
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- 2012-05-18 JP JP2014510817A patent/JP6029190B2/ja not_active Expired - Fee Related
- 2012-05-18 CN CN201280023925.7A patent/CN103547264B/zh not_active Expired - Fee Related
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- 2012-05-18 KR KR1020137033787A patent/KR101937255B1/ko active IP Right Grant
- 2012-05-18 TW TW101117809A patent/TWI582079B/zh not_active IP Right Cessation
- 2012-05-18 UA UAA201314869A patent/UA113849C2/uk unknown
- 2012-05-18 AR ARP120101785A patent/AR086636A1/es not_active Application Discontinuation
- 2012-05-18 BR BR112013029609-7A patent/BR112013029609A2/pt not_active IP Right Cessation
- 2012-05-18 MX MX2013013479A patent/MX343437B/es active IP Right Grant
- 2012-05-18 CA CA2836353A patent/CA2836353A1/en not_active Abandoned
- 2012-05-18 EP EP12722716.3A patent/EP2709620A1/en not_active Withdrawn
- 2012-05-18 WO PCT/EP2012/059232 patent/WO2012156497A1/en active Application Filing
- 2012-05-18 SG SG2013083852A patent/SG194924A1/en unknown
- 2012-05-18 AU AU2012258219A patent/AU2012258219B2/en not_active Ceased
- 2012-05-18 RU RU2013156367A patent/RU2608943C2/ru not_active IP Right Cessation
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- 2013-11-27 ZA ZA2013/08926A patent/ZA201308926B/en unknown
- 2013-12-11 CO CO13290099A patent/CO6831985A2/es not_active Application Discontinuation
- 2013-12-18 MA MA36591A patent/MA35401B1/fr unknown
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US20100190781A1 (en) * | 2004-08-27 | 2010-07-29 | Christian Laggner | Sigma receptor inhibitors |
US20090325975A1 (en) * | 2005-07-15 | 2009-12-31 | Helmut H Buschmann | Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain |
US20110112095A1 (en) * | 2008-04-25 | 2011-05-12 | Laboratorios Del Dr. Esteve, S.A. | 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof |
WO2011018487A1 (en) * | 2009-08-14 | 2011-02-17 | Laboratorios Del Dr. Esteve, S.A. | Sigma ligands for the prevention or treatment of pain induced by chemotherapy |
Also Published As
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AU2012258219B2 (en) | 2017-01-19 |
CA2836353A1 (en) | 2012-11-22 |
KR101937255B1 (ko) | 2019-01-11 |
AR086636A1 (es) | 2014-01-15 |
NZ617590A (en) | 2015-05-29 |
IL229495B (en) | 2018-02-28 |
SG194924A1 (en) | 2013-12-30 |
RU2013156367A (ru) | 2015-06-27 |
CO6831985A2 (es) | 2014-01-10 |
CN103547264A (zh) | 2014-01-29 |
EP2709620A1 (en) | 2014-03-26 |
MA35401B1 (fr) | 2014-09-01 |
MX2013013479A (es) | 2014-08-21 |
JP2014518869A (ja) | 2014-08-07 |
MX343437B (es) | 2016-11-04 |
KR20140033442A (ko) | 2014-03-18 |
IL229495A0 (en) | 2014-01-30 |
US20140107111A1 (en) | 2014-04-17 |
RU2608943C2 (ru) | 2017-01-26 |
TW201300365A (zh) | 2013-01-01 |
MY169731A (en) | 2019-05-14 |
WO2012156497A1 (en) | 2012-11-22 |
TN2013000460A1 (en) | 2015-03-30 |
US9789117B2 (en) | 2017-10-17 |
JP6029190B2 (ja) | 2016-11-24 |
BR112013029609A2 (pt) | 2020-08-25 |
AU2012258219A1 (en) | 2013-11-28 |
UA113849C2 (xx) | 2017-03-27 |
CN103547264B (zh) | 2017-06-09 |
EP2524694A1 (en) | 2012-11-21 |
ZA201308926B (en) | 2015-02-25 |
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