TWI501767B - 治療認知損傷之套組、組成物、產品或藥劑之用途 - Google Patents
治療認知損傷之套組、組成物、產品或藥劑之用途 Download PDFInfo
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- TWI501767B TWI501767B TW098106666A TW98106666A TWI501767B TW I501767 B TWI501767 B TW I501767B TW 098106666 A TW098106666 A TW 098106666A TW 98106666 A TW98106666 A TW 98106666A TW I501767 B TWI501767 B TW I501767B
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- pyridine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
本發明係關於一種經由合併神經退變性疾病(neurodegenerative disease)之治療劑及特定結構之雜環化合物之治療認知損傷之方法。
近年來,於預防及治療疾病、延緩症狀發作、補償或增進活性、經由減少投與藥物的劑量而減少副作用、改善病患服從性及壓抑抗藥性產生之目的,多種具不同功能機制之藥物被合併投與之相伴治療(concomitant therapy)已用於許多疾病之藥物治療。
阿茲海默氏症(Alzheimer's disease(AD))為一種漸進的神經退變性疾病,以認知損傷為其主要症狀。於目前社會狀況中社會逐漸地老年化,認知損傷之治療成為極重要的議題。目前雖然有4種藥,多奈哌齊鹽酸鹽(donepezil hydrochloride)、卡巴拉汀酒石酸鹽(rivastigmine tartrate)、加蘭他敏氫溴酸鹽(galantamine hydrobromide)及美金剛鹽酸鹽(memantine hydrochloride),被認可作為AD之治療劑,但日本目前僅核准多奈哌齊之使用。
以使此等少數藥物作有效的使用的觀點,或為了便由治標治療轉為治本治療,已嘗試如上述之使用不同功能機制之藥物的相伴治療。例如,乙醯膽鹼酯酶(acetylcholinesterase)抑制劑、多奈哌齊及NMDA(N-甲基-D-天冬胺酸酯)抑制劑、美金剛之共同使用的效果,已被公認(JAMA 2004;291:317-324)。此外,儘管仍於發展階段,已有報告與FK960之共同使用(Pharmacology,Biochemistry and Behavior,73,511-519(2002))。
認知損傷不僅由AD引起,亦可由各種其他病況造成諸如腦血管疾病,路易體痴呆症(Lewy body dementia)及帕金森氏症(Parkinson's disease)。因此,尋找廣範圍具此種認知損傷相伴效果之藥劑為重要的。另一方面,含有基礎骨架結構中具咪唑并[1,2-a]吡啶-2(3H)-酮的雜環化合物之認知增強劑被揭示於WO 01/09131及WO 02/060907。
然而,此等雜環化合物被揭示於罹患AD及老年癡呆者作為治療記憶損傷及記憶獲得/儲存損傷之認知增強劑,未揭示與現存之神經退變性疾病治療劑相伴使用有關的活性。此外,由於其不具有乙醯膽鹼酯酶抑制功能,反而增加游離乙醯膽鹼及多巴胺的量,此等雜環化合物已被發現具有不同於現存藥劑之功能機制(Neurosci. Res. 2002,26(suppl):S131;J. Pharmacol. Exp. Ther. 317:1079-1087(2006))。
專利文獻1 WO 01/09131
專利文獻2 WO 02/060907
非專利文獻1 JAMA 2004;291:317-324
非專利文獻2 Pharmacology,Biochemistry and Behavior,73,511-519(2002)
非專利文獻3 Neurosci. Res. 2002,26(suppl):S131
非專利文獻4 J. Pharmacol. Exp. Ther. 317:1079-1087(2006)
本發明提供一種治療認知損傷用之套組或藥劑,包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽。
本發明亦提供一種治療認知損傷之醫藥組成物,包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽。
本發明亦提供一種組成物,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽。
本發明亦提供一種產品,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽,作為同時、分開或連續使用於認知損傷之治療之合併製劑。
本發明亦提供一種藥劑,其包括神經退變性疾病用治療劑,用於與下列通式(I)代表之雜環化合物或其水合物、溶劑化物或醫藥上可接受的鹽合併治療認知損傷:
本發明亦提供一種藥劑,其包括下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽,用於與神經退變性疾病用治療劑合併治療認知損傷。
本發明提供一種藉由神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物或其水合物、溶劑化物或醫藥上可接受的鹽治療認知損傷之方法:
於通式(I),自多種形式之具有通式(III)的結構單元選擇具有通式(II)之結構單元:
通式(II):
通式(III):
此外,於通式(I),R1
及R2
各自獨立選自氫原子、鹵素原子、羥基、胺基、乙醯基胺基、苄基胺基、三氟甲基、C1
-C6
烷基、C1
-C6
烷氧基、及-O-(CH2
)n
-R5
組成之群,其中R5
為乙烯基、C3
-C6
環烷基、或苯基,及n為0或1。
又,於通式(I),R3
及R4
各自獨立選自氫原子、C1
-C6
烷基、C3
-C8
環烷基、及-CH(R7
)-R6
組成之群;或者,R3
及R4
一起形成具有通式(IV)之螺環:
上列R6
選自乙烯基;乙炔基;可選擇經C1
-C6
烷基、C1
-C6
烷氧基、羥基、1或2個鹵素原子、二C1
-C6
烷基胺基、氰基、硝基、羧基、或苯基取代之苯基;苯乙基;吡啶基;噻吩基;及呋喃基組成之群。上列R7
為氫原子或C1
-C6
烷基。
於通式(IV),結構單元B選自多種形式之具有通式(V)的結構單元。結構單元B結合於通式(V)中經*標記的位置以形成螺環:
此處,R8
為1或多個選自氫原子、鹵素原子、羥基、C1
-C6
烷氧基、氰基、及三氟甲基組成之群之取代基。
雜環化合物較佳為至少一個選自下列組成之群之雜環化合物:螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、3,3-二苄基-8-異丙氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-環丙基甲氧基-咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-6-氯咪唑并[1,2-a]吡啶-2(3H)-酮、8-烯丙氧基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮、8-苄氧基-3,3-雙(1-苯基乙基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-5,7-二甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-環戊氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-6,8-二氯咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-氯-6-三氟甲基咪唑并[1,2-a]吡啶-2(3H)-酮、8-苄氧基-3,3-雙(3-甲基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-甲基-3,3-雙(4-吡啶基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-氟苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-二甲基胺基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(3-氯苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-甲氧基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-聯苯基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-氰基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-羥基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基-8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(3-苯基-1-丙基)咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[2,3]二氫萉]、3,3-雙(2,4-二氟苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-噻吩基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-乙醯基胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-呋喃基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丁基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二(2-丙炔基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-羥基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-苄基胺基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-硝基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-甲氧基羰基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、5,5-雙(4-氟苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-二苄基咪唑并[2,1-b]噻唑-6(5H)-酮、3,3-二苄基咪唑并[1,2-a]嘧啶-2(3H)-酮、5,5-雙(4-甲基苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-雙(4-氰基苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-二苄基-2-甲基咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-雙(2-噻吩基甲基)咪唑并[2,1-b]壓唑-6(5H)-酮、3,3-雙(2-噻吩基甲基)咪唑并[1,2-a]嘧啶-2(3H)-酮、5,5-二苄基-2,3-二氫咪唑并[2,1-b]噻唑-6(5H)-酮、2-羥基-3-(2-萘基甲基)咪唑并[1,2-a]吡啶、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[f]茚滿]、3-苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二(2-丁醯基)咪唑并[1,2-a]嘧啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氟茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-甲氧基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-碘茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氰基茚滿)]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[1,2-a]嘧啶-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-三氟甲基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[e]茚滿]、3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-環己烯基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基咪唑并[2,1-a]異喹啉-2(3H)-酮、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,4'-(1'-環戊烯)]、螺[8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、3,3-二丙基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二環己基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丁基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、螺[7,8,9,10-四氫咪唑并[2,1-a]異喹啉-2(3H)-酮-3,1'-環戊烷]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,1'-環戊烷]、螺[5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[f]茚滿]、螺[5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、3,3-雙(4-氯苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-環丙基甲氧基-3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-羥基茚滿)]、螺[8-羥基咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、螺[8-甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、螺[8-環丙基甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、8-胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮鹽酸鹽、8-苄基胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、及螺[8-乙醯基胺基咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
雜環化合物更佳為至少一個選自下列組成之群之雜環化合物:3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、3,3-二丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丁基咪唑并[1,2-a]吡啶-2(3H)-酮、5,5-二苄基咪唑并[2,1-b]噻唑-6(5H)-酮、3,3-二苄基咪唑并[1,2-a]嘧啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氟茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-甲氧基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氰基茚滿)]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[1,2-a]嘧啶-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,4'-(1'-環戊烯)]、3,3-雙(4-氯苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-環丙基甲氧基-3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-羥基茚滿)]、螺[8-羥基-咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、螺[8-甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、螺[8-乙醯基胺基咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]及螺[8-環丙基甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]。
更佳地,雜環化合物為螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
認知損傷可由腦血管疾病、路易體痴呆症、阿茲海默氏症、帕金森氏症、皮克氏症(Pick’s disease)、亨丁頓舞蹈症(Huntington’s disease)或唐氏症(Down’s disease)引起,或可為由於老化引起之記憶損傷。
神經退變性疾病用治療劑較佳為乙醯膽鹼酯酶抑制劑,諸如多奈哌齊鹽酸鹽、卡巴拉汀酒石酸鹽或加蘭他敏氫溴酸鹽,或非競爭性NMDA受體拮抗劑諸如美金剛鹽酸鹽。
神經退變性疾病用治療劑及雜環化合物、其水合物或醫藥上可接受的鹽可被同時、分開或連續投與。
本發明之具體實施例描述如下。
根據本發明之第一態樣,一種治療認知損傷用之套組或藥劑,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽。
根據本發明之第二態樣,一種治療認知損傷用之醫藥組成物,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽。
根據本發明之第三態樣,一種組成物,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽:根據本發明之第四態樣,一種產品,其包括神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽,作為同時、分開或連續使用於認知損傷之治療之合併製劑。
根據本發明之第五態樣,一種藥劑,其包括神經退變性疾病用治療劑,用於與下列通式(I)代表之雜環化合物或其水合物、溶劑化物或醫藥上可接受的鹽合併治療認知損傷:
根據本發明之第六態樣,一種藥劑,其包括下列通式(I)代表之雜環化合物:
或其水合物、溶劑化物或醫藥上可接受的鹽,用於與神經退變性疾病用治療劑合併治療認知損傷。
根據本發明之第七態樣,一種治療認知損傷之方法,其包括於需要的標的投與神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物之合劑:
或其水合物、溶劑化物或醫藥上可接受的鹽。
於通式(I),具有通式(II)的結構單元係選自具有通式(III)的結構單元:
通式(II):
通式(III):
此外,於通式(I),R1
及R2
各自獨立選自氫原子、鹵素原子、羥基、胺基、乙醯基胺基、苄基胺基、三氟甲基、C1
-C6
烷基、C1
-C6
烷氧基、及-O-(CH2
)n
-R5
組成之群,其中R5
為乙烯基、C3
-C6
環烷基、或苯基,及n為0或1。
此外,於通式(I),R3
及R4
各自獨立選自氫原子、C1
-C6
烷基、C3
-C8
環烷基、及-CH(R7
)-R6
組成之群;或者,R3
及R4
一起形成具有通式(IV)之螺環:
上列R6
選自乙烯基;乙炔基;可選擇經C1
-C6
烷基、C1
-C6
烷氧基、羥基、1或2個鹵素原子、二C1
-C6
烷基胺基、氰基、硝基、羧基、或苯基取代之苯基;苯乙基;吡啶基;噻吩基;及呋喃基組成之群。上列R7
為氫原子或C1
-C6
烷基。
於通式(IV),結構單元B選自多種形式之具有通式(V)的結構單元。結構單元B結合於通式(V)中經*標記的位置以形成螺環:
此處,R8
為1或多個選自氫原子、鹵素原子、羥基、C1
-C6
烷氧基、氰基、及三氟甲基組成之群之取代基。
當具有通式(I)之雜環化合物於結構中具有非對稱碳原子時,於非對稱碳原子處存有其異構物及其混合物(外消旋修飾)。於此種情形,下文描述之具體實施例使用的雜環化合物包括所有異構物。
此雜環化合物具有通式(I)。於通式(I),下列各詞具有以下特定實例之意義。
"C1
-C6
"一詞係指1至6個碳原子,除非另有定義。"C3
-C3
"一詞係指3至8個碳原子,除非另有定義。"C1
-C6
烷基"一詞包括直線或分支烷基,諸如甲基、乙基、n-丙基、異丙基、n-丁基、第三丁基、第二丁基、n-戊基、及n-己基。"C1
-C6
烷氧基"一詞包括直線或分支烷氧基,諸如甲氧基、乙氧基、n-丙氧基、異丙氧基、n-丁氧基、第三丁氧基、第二丁氧基、n-戊氧基、及n-己氧基。"C3
-C8
環烷基"一詞包括環丙基、環丁基、環戊基、環己基、環庚基、及環辛基。"鹵素原子"一詞包括氟、氯、溴及碘。
於本發明實施中有用的雜環化合物並未特別限制,只要其具有上述特定結構即可,例如,可使用下列化合物:螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、3,3-二苄基-8-異丙氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-環丙基甲氧基-咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-6-氯咪唑并[1,2-a]吡啶-2(3H)-酮、8-烯丙氧基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮、8-苄氧基-3,3-雙(1-苯基乙基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-5,7-二甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-環戊氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-6,8-二氯咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-氯-6-三氟甲基咪唑并[1,2-a]吡啶-2(3H)-酮、8-苄氧基-3,3-雙(3-甲基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-甲基-3,3-雙(4-吡啶基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-氟苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-二甲基胺基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(3-氯苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-甲氧基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-聯苯基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-氰基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-羥基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基-8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(3-苯基-1-丙基)咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[2,3]二氫萉]、3,3-雙(2,4-二氟苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-噻吩基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-乙醯基胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-呋喃基甲基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二甲基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丁基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二(2-丙炔基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-羥基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二苄基-8-苄基胺基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-硝基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(4-甲氧基羰基苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、5,5-雙(4-氟苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-二苄基咪唑并[2,1-b]噻唑-6(5H)-酮、3,3-二苄基咪唑并[1,2-a]嘧啶-2(3H)-酮、5,5-雙(4-甲基苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-雙(4-氰基苄基)咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-二苄基-2-甲基咪唑并[2,1-b]噻唑-6(5H)-酮、5,5-雙(2-噻吩基甲基)咪唑并[2,1-b]噻唑-6(5H)-酮、3,3-雙(2-噻吩基甲基)咪唑并[1,2-a]嘧啶-2(3H)-酮、5,5-二苄基-2,3-二氫咪唑并[2,1-b]噻唑-6(5H)-酮、2-羥基-3-(2-萘基甲基)咪唑并[1,2-a]吡啶、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[f]茚滿]、3-苄基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二(2-丁醯基)咪唑并[1,2-a]嘧啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氟茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-甲氧基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-碘茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氰基茚滿)]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[1,2-a]嘧啶-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-三氟甲基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[e]茚滿]、3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-雙(2-環己烯基)咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二烯丙基咪唑并[2,1-a]異喹啉-2(3H)-酮、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,4'-(1'-環戊烯)]、螺[8-苄氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、3,3-二丙基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二環己基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、3,3-二丁基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮、螺[7,8,9,10-四氫咪唑并[2,1-a]異喹啉-2(3H)-酮-3,1'-環戊烷]、螺[咪唑并[2,1-a]異喹啉-2(3H)-酮-3,1'-環戊烷]、螺[5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-苯并[f]茚滿]、螺[5,6,7,8-四氫咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、3,3-雙(4-氯苄基)咪唑并[1,2-a]吡啶-2(3H)-酮、8-環丙基甲氧基-3,3-二烯丙基咪唑并[1,2-a]吡啶-2(3H)-酮、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-羥基茚滿)]、螺[8-羥基咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、螺[8-甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、螺[8-環丙基甲氧基咪唑并[1,2-a]吡啶-2(3H)-酮-3,4'-(1'-環戊烯)]、8-胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮鹽酸鹽、8-苄基胺基-3,3-二苄基咪唑并[1,2-a]吡啶-2(3H)-酮、或螺[8-乙醯基胺基咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
式(I)之雜環化合物可為水合物、溶劑化物或為醫藥可接受的鹽之酸加成鹽。可能的溶劑化物包括有機溶劑化物,諸如二甲基亞碸溶劑化物、N,N-二甲基甲醯胺溶劑化物或醇溶劑化物(如乙醇、甲醇及n-丙醇溶劑化物)。可能的酸加成鹽包括無機酸鹽,如鹽酸鹽、硫酸鹽、氫溴酸鹽、硝酸鹽、及磷酸鹽,或有機酸鹽,諸如乙酸鹽、草酸鹽、丙酸鹽、乙醇酸鹽、乳酸鹽、丙酮酸鹽、丙二酸鹽、琥珀酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、蘋果酸鹽、酒石酸鹽、檸檬酸鹽、苯甲酸鹽、肉桂酸鹽、甲烷磺酸鹽、苯磺酸鹽、p-甲苯磺酸鹽、及水楊酸鹽。
本發明中使用之神經退變性疾病用治療劑並未特別限制,但較佳應為1或多種選自乙醯膽鹼酯酶抑制劑、多奈哌齊鹽酸鹽、卡巴拉汀酒石酸鹽及加蘭他敏氫溴酸鹽;及非競爭性NMDA受體拮抗劑、美金剛鹽酸鹽之藥物。
本發明之治療方法或使用本發明治療之方法係藉由合併(A)上述通式(I)表示之雜環化合物、其水合物、其溶劑化物或其醫藥上可接受的鹽;及(B)神經退變性疾病用治療劑之藥物療法。此外,藥物A及藥物B本身可為多種藥物之合劑,且亦可含有佐藥、稀釋劑及載劑。本發明之治療方法可為合併藥物A及藥物B於相同醫藥組成物中,或同時、分開、或連續投與藥物A及藥物B。此外,若分開投與,藥物A可於投與藥物B之前投與,或相反地,藥物B可於投與藥物A之前投與。遞送方法及每日投劑數目可相同或相異,藥物A及藥物B間之重量比並無特殊限制。
此外,於儲存、運送或販賣時,提供之套組或產品可為藥物A及藥物B同時儲存於其中者。亦可提供實用的套組或產品,其中藥物A及藥物B於使用時分開準備。此外,藥物A及藥物B各可提供說明或指示,其中描述其相伴投與。
認知損傷可由腦血管疾病、路易體痴呆症、阿茲海默氏症、帕金森氏症、皮克氏症、亨丁頓舞蹈症或唐氏症引起,或可由於老化而記憶損傷。
此外,依據本發明之具體實施例,上列通式(I)表示之雜環化合物、其水合物、溶劑化物或醫藥上可接受的鹽之劑量,及神經退變性疾病用治療劑,端視年齡、重量、症狀、治療效果及遞送方法而異,此劑量應為每公斤體重至少約0.0001mg,於口服遞送的情形。更佳地,上列通式(I)表示之雜環化合物含量或劑量應為至少約0.001mg/kg,同時使用的神經退變性疾病用治療劑之劑量應為至少約0.01mg/kg。此外,於其他具體實施例,此等藥物可以5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100mg的單位被遞送。
此外,於含上列通式(I)表示之雜環化合物、其水合物、溶劑化物或醫藥上可接受的鹽、及神經退變性疾病用治療劑之單一製劑之口服遞送的情形、其可以口服遞送用之可消化固體或可消化液體的型式。
口服投與用之調配物包括可消化固體、錠劑、包衣錠、粉劑、顆粒、膠囊、微膠囊及糖漿。
此等調配物或組成物可經由使用醫藥上可接受的賦形劑、結合劑、潤滑劑、崩解劑、懸浮液、乳化劑、防腐劑、安定劑、及分散劑而製備,諸如乳糖、蔗糖、澱粉、糊精、結晶纖維素、高嶺土、碳酸鈣、滑石、硬脂酸鎂、蒸餾水及生理食鹽水溶液。
本發明者們研究下列作用,例如,同時投與上列通式(I)表示之雜環化合物中的螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]與為乙醯膽鹼酯酶抑制劑的多奈哌齊鹽酸鹽於鼠的莨菪胺誘發的記憶損傷的作用。結果,其於單獨使用個別藥物時未觀察到活性的劑量下,觀察到清楚的相伴活性。
如此,可同時投與低劑量之上列通式(I)表示之雜環化合物及低劑量之治療神經退變性疾病用之治療劑。因此,無論是否此等藥物於低劑量僅顯示有限功效,或是否於低劑量共同投與時此等藥物顯示所有任何習知的功效,上述藥物能夠誘導治療活性或於低劑量能夠達到優異治療活性仍係可能的。當單獨投與兩藥劑時如此低的劑量一般為次治療劑量(sub-therapeutic dose)。如此低的劑量之例包括少於0.1mg/kg之多奈哌齊及少於0.001mg/kg之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]之劑量,更具體而言,少於0.01mg/kg之多奈哌齊及少於0.0001mg/kg之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。於人類投劑時,例示性之低劑量包括1mg、2mg、3mg或4mg多奈哌齊鹽酸鹽,及1mg、2mg、3mg、4mg或5mg之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。上列通式(I)表示之雜環化合物,例如,螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿],及治療神經退變性疾病用之治療劑,例如,多奈哌齊鹽酸鹽,可以單一整體的的醫藥組成物之一部分或個別醫藥組成物之一部分被投與。
此外,上列通式(I)表示之雜環化合物可與有效劑量之治療神經退變性疾病用之治療劑共同投與。此時,可投與低劑量或有效劑量之上列通式(I)表示之雜環化合物。此外,當上述藥劑共同投與而不是個別投與時,治療神經退變性疾病用之治療劑的治療效果,或上列通式(I)表示之雜環化合物的治療效果可明顯的受到改善。此有效劑量之蝕例包括0.1mg/kg劑量之多奈哌齊與0.01mg/kg劑量之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。此低劑量之實例包括少於0.001mg/kg劑量之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿],具體而言,少於0.0001mg/kg螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。關於人類劑量,例示性之有效劑量包括1mg或5mg多奈哌齊鹽酸鹽及0.1mg螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。例示性之低劑量包括1mg、2mg、3mg或4mg多奈哌齊鹽酸鹽及1mg、2mg、3mg、4mg或5mg螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。例如螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]之通式(I)所示之雜環化合物,及例如多奈哌齊鹽酸鹽之治療神經退變性疾病用之治療劑,可以作為單一醫藥組成物之部分或可以作為分離之醫藥組成物之部分投與。
此外,當提及"有效量"或"治療上有效量"時,其不僅指治療上於個體為有效的數量,而且包括低治療有效量,其為與本發明合併而非單獨投與之有效量。
此外,本發明人研究例如,一起同時投與上述通式(I)所指之雜環化合物中的螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]與作為乙醯膽鹼酯酶抑制劑之多奈哌齊鹽酸鹽,於海馬迴(hippocampus)中細胞外乙醯膽鹼數量上之效果。結果顯示,細胞外乙醯膽鹼於一劑量可見明顯的增加,此係於單獨投與多奈哌齊鹽酸鹽上沒有觀察到的活性。
儘管上列已敘述及說明本發明之較佳具體實施例,必須了解的是,其為本發明之例示且不應認為是對本發明之限制。
例如,一些較佳的口服有效劑量之範圍被界定於上述具體實施例中。然而,於其他投與型式可決定其他有效劑量之範圍。例如,投與之有效劑量的較佳範圍可被適當地決定。此外,除了僅以例行實驗之有效量外,投與間隔之較佳範圍可針對特定投與型式而決定。
於下文中,本發明將以實施例更詳細的解說。然而,本發明並非特別侷限於下述實施例。
(螺[咪唑并-[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿])及多奈哌齊於莨菪胺(scopolamine)誘導之認知損傷上之合併效果,以小鼠之被動迴避試驗(Passive avoidance task)。
試驗中使用八至九週齡之雄性ICR系小鼠(Charles River Laboratories Japan,Inc.),以3或4隻為一組圈養於籠中,籠中維持22℃,12小時之光照/黑暗循環,食物及飲水為隨意提供。所有動物之照料及治療係依據Guidelines for the Care and Use of Laboratory Animals(Central Research Laboratory,Zenyaku Kogyo Co.,Ltd.所建立)之指導。
將化合物1及多奈哌齊懸浮於1%羧甲基纖維素(CMC),莨菪胺(Sigma)溶於0.9% NaCl中。對於化合物1與多奈哌齊之共同投與研究,將兩種藥物之懸浮液混合在一起,並注射此混合懸浮液。所有藥物在使用前立即調配,並經口投與10ml/kg之劑量。
被動迴避裝置(Neuroscience Inc.)由一光照室及一較大暗室所組成,二室由一閘門隔開。在學習試驗前60分鐘,經口投與0.0001mg/kg或0.001mg/kg之化合物1及/或0.01及0.1mg/kg劑量之多奈哌齊。在學習試驗前20分鐘,將莨菪胺(1mg/kg)腹膜內注射。相應之對照組僅給予媒劑。在學習試驗期間,將每隻小鼠置於光照室。立即在進入暗室後,關閉閘門並透過地板電網傳遞使其無法避免的攀爬的電休克(100V,0.4mA,1.5秒),24小時後,每隻小鼠置於光照室用於滯留試驗(retention trial)。置於光照室與進入暗室間之間隔被量測為步入潛伏期(step through latency)(最多300秒)。
使用Mann-Whitney U-試驗,比較1% CMC-莨菪胺組與1% CMC-生理食鹽水組間的結果(各顯示於第1圖中第二及第一長條柱)。當有明顯差異時,認知損傷被認為是由莨菪胺引起。使用Steel氏試驗,將結果與1% CMC-莨菪胺組比較,P值<0.05被認為是試驗具有統計學上顯著意義之表示。其次,使用Steel氏試驗,將結果與1% CMC+莨菪胺組比較,且各組於第1圖中以*及**表示;1% CMC+多奈哌齊(0.01mg/kg)+莨菪胺及化合物1(0.0001或0.001mg/kg)+多奈哌齊(0.01mg/kg)+莨菪胺(第1圖中以++表示);與1% CMC+多奈哌齊(0.1mg/kg)+莨菪胺及化合物1(0.0001或0.001mg/kg)+多奈哌齊(0.1mg/kg)+莨菪胺(第1圖中以$表示)。
在滯留試驗中,以1% CMC及莨菪胺處理之組別的步入潛伏期顯著地短於以1% CMC及食鹽水處理者(P<0.01)。這些結果證實莨菪胺減弱被動迴避表現。當與以1% CMC及莨菪胺處理之組別比較時,經口投與0.0001mg/kg劑量之化合物1或0.01mg/kg劑量之多奈哌齊並無明顯延長步入潛伏期。另一方面,經口投與0.1mg/kg劑量之多奈哌齊或0.001mg/kg劑量之化合物1可延長步入潛伏期(P<0.05)。
當與以1% CMC及莨菪胺處理之組別比較時,共同投與化合物1(0.0001mg/kg)、多奈哌齊(0.01或0.1mg/kg)及莨菪胺顯著地延長步入潛伏期(P<0.05)。此外,當與以1% CMC及莨菪胺處理之組別比較時,共同投與化合物1(0.001mg/kg)、多奈哌齊(0.1mg/kg)及莨菪胺顯著地延長步入潛伏期(P<0.01)。此外,當與以多奈哌齊(0.01mg/kg)及莨菪胺處理之組別比較時,共同投與化合物1(0.0001或0.001mg/kg)、多奈哌齊(0.01mg/kg)及莨菪胺顯著地延長步入潛伏期(P<0.01)。同樣地,當與以多奈哌齊(0.01mg/kg)及莨菪胺處理之組別比較時,共同投與化合物1(0.001mg/kg)、多奈哌齊(0.1mg/kg)及莨菪胺亦顯著地延長步入潛伏期(P<0.01)。
本研究最重要的發現在於,共同投與化合物1及次有效劑量之多奈哌齊,以及有效劑量,在被動迴避試驗中,協同地改善由莨菪胺所引起之認知損傷。這些結果提出二種藥物不同的機制間協同性相互影響。
試驗中使用八至九週齡之雄性Wistar系大鼠(Japan Laboratory Animals Inc.)。將大鼠以2或3隻為一組圈養於籠中,籠中維持22℃,12小時之光照/黑暗循環,食物及飲水為隨意提供。所有動物之照料及治療係依據Guidelines for the Care and Use of Laboratory Animals(Central Research Laboratory,Zenyaku Kogyo Co.,Ltd.所建立)之指導。
將化合物1及多奈哌齊懸浮於1% CMC。對於化合物1與多奈哌齊之共同投與研究,將兩種藥物之懸浮液混合在一起,且此混合懸浮液在使用前立即調配,並經口投與1ml/kg之劑量。
將大鼠以戊巴比妥(pentobarbital;50mg/kg)麻醉,並固定於立體定位儀(David Kopf Instruments,Tujunga,CA,USA)。將頭蓋骨暴露出來,並根據Paxinos and Watson之圖解(1982),將無菌鋼質引導管(AG-8,Eicom,Kyoto)植入海馬迴(A-5.8;L 4.8;V 4.0mm)。手術後次日,將具有3-mm-長纖維素膜管(A-I-8-03,Eicom)之微透析術探針經由植入之引導管***海馬迴。
探針以流速1.0微升/分鐘之林格氏液(Ringer's solution;147mM NaCl,4.02mM KCl,及2.25mM CaCl2
)浸滿。每20分鐘收集透析液,並以電化學偵測法(ECD)之HPLC系統檢測ACh濃度。使用管柱(Eicompac AC-Gel 2.0 x 150mm,Eicom)將ACh由透析液分離。含乙醯膽鹼酯酶(AChE)及膽鹼氧化酶之酵素反應器,其催化由ACh及膽鹼形成過氧化氫,所產生之H2
O2
藉由ECD(ECD-300,Eicom),以白金電極(WE-PT,Eicom)於450mV檢測。
組別間差異的統計顯著性係根據Dunnett氏多重比較試驗,以單因子變異分析計算。
當與以1% CMC處理之組別比較時,經口投與0.001mg/kg劑量之化合物1或1mg/kg劑量之多奈哌齊並無顯著增加海馬迴中ACh之細胞外濃度。然而,當與以1% CMC處理之組別比較時,共同投與化合物1(0.001mg/kg)與多奈哌齊(1mg/kg)顯著地增加ACh之細胞外濃度。
本研究最重要的發現在於,共同投與化合物1及多奈哌齊,於各藥物之次有效劑量協同地增加海馬迴中ACh之細胞外濃度。
關於具體實施例中化合物之製備
一些具有通式(I)之雜環化合物及敘述於WO 01/09131實施例的製備方法以實施例之方式敘述於下文。更具體而言,其參照WO 01/09131及WO 2002/060907手冊合成。製備
具有下式之螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿](化合物1)的例示性製備說明如下。
化合物1:
將56.1g(1.04mol)數量之甲氧化鈉溶於15L甲醇中,隨後於室溫添加90.0g(0.0345mol)溴化2-胺基-1-(乙氧基羰基甲基)吡啶鎓及60.0g(0.0342mol)α,α'-二氯-o-二甲苯。反應混合物於室溫攪拌隔夜,然後將溶劑於減壓下移除。
添加二氯甲烷至殘餘物,並將不溶性物質濾除。在減壓下濃縮濾液,並將殘餘物通過矽凝膠管柱(乙酸乙酯:甲醇=15:1),產生粗產物。使用乙酸乙酯清洗粗產物,然後自甲醇中再結晶,產生36g(40%)白色結晶型式之標題化合物。所得之化合物的分析結果如下,該結果顯示,所得之化合物為標的化合物。
熔點:206℃(分解);NMR(CDCl3
)δ:3.16(2H,d,J=16Hz),3.89(2H,d,J=16Hz),6.49(1H,t,J=7Hz),7.1-7.2(2H,m),7.2-7.3(4H,m),7.61(1H,t,J=7Hz);MS m/z:236(M+
)。
式(I)之其他化合物可根據WO 01/09131及WO 02/060907之適當方法,由適當起始物質製備,該文獻於本文一併作為參考。
本發明以實施例說明如上,該實施例以實例之方式提供,熟悉技術者可理解,可進行不同的修正,且這些修正亦包含於本發明之範圍。
例如,以上之實施例已使用化合物1作為雜環化合物,多奈哌齊作為神經退變性疾病用治療劑,且小鼠作為其之哺乳動物受試者。然而,可使用其他雜環化合物、其他神經退變性疾病之治療劑,及/或其他包括人類之哺乳動物。上述化合物於包括人類之哺乳動物中亦可展現關於認知損傷之治療效果。
本說明書所引用之專利案、專利申請案及公開案的揭示內容於本說明書一併作為參考資料。
第1圖描繪一種說明化合物1(ZSET1446)及多奈哌齊對於鼠的被動迴避試驗中莨菪胺誘發的認知損傷的活性的圖解表現。各值代表平均S.E.M。長條柱中的數值指出動物數目。## P<0.01,與媒劑處理對照組比較(Mann-Whitney U-test)。* P<0.05,** P<0.01,與給與1% CMC的莨菪胺處理鼠比較(Steel's test)。++P<0.01,與以1% CMC+多奈哌齊(0.01mg/kg)及莨菪胺處理的組比較(Steel's test)。$ P<0.05,與以1% CMC+多奈哌齊(0.1mg/kg)及莨菪胺處理的組比較(Steel's test)。
Claims (15)
- 一種神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物或其醫藥上可接受的鹽用於製造治療認知損傷之套組之用途,
- 一種神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物或其醫藥上可接受的鹽用於製造治療認知損傷之組成物之用途,
- 一種神經退變性疾病用治療劑及下列通式(I)代表之雜環化合物或其醫藥上可接受的鹽用於製造治療認知損傷之產品之用途,該產品係作為同時、分開或連續使用於認知損傷之治療之合併製劑;
- 一種神經退變性疾病用治療劑用於製造治療認知損傷之藥劑之用途,該藥劑用於與下列通式(I)代表之雜環化合物或其醫藥上可接受的鹽合併以治療認知損傷:
- 一種下列通式(I)代表之雜環化合物或其醫藥上可接受的鹽用於製造治療認知損傷之藥劑之用途,該藥劑係用於合併神經退變性疾病用治療劑以治療認知損傷;
- 如申請專利範圍第1至5項中任一項之用途,其中該雜環化合物為選自下列所組成之群中至少一雜環化合物:螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氟茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(5'-甲氧基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-氰基茚滿)]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-[1,2,5]噻二唑并[4,5-c]茚滿]、螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-(4'-羥基茚滿)]、及螺[8-羥基-咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
- 如申請專利範圍第1至5項中任一項之用途,其中該雜環化合物為螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
- 如申請專利範圍第1至5項中任一項之用途,其中該認 知損傷由腦血管疾病、路易體痴呆症(Lewy body dementia)、阿茲海默氏症、帕金森氏症、皮克氏症(Pick’s disease)、亨丁頓舞蹈症(Huntington’s disease)或唐氏症(Down’s disease)所引起。
- 如申請專利範圍第1至5項中任一項之用途,其中該認知損傷為因老化之記憶損傷。
- 如申請專利範圍第1及3至5項中任一項之用途,其中該神經退變性疾病用治療劑及該雜環化合物或其醫藥上可接受的鹽被同時投與。
- 如申請專利範圍第1及3至5項中任一項之用途,其中該神經退變性疾病用治療劑及該雜環化合物或其醫藥上可接受的鹽為單一、單元的醫藥劑量型式。
- 如申請專利範圍第1及3至5項中任一項之用途,其中該神經退變性疾病用治療劑及該雜環化合物或其醫藥上可接受的鹽被分開投與。
- 如申請專利範圍第1及3至5項中任一項之用途,其中該神經退變性疾病用治療劑及該雜環化合物或其醫藥上可接受的鹽被連續投與。
- 如申請專利範圍第1及3至5項中任一項之用途,其中該神經退變性疾病用治療劑及該雜環化合物或其醫藥上可接受的鹽被投與的量為單獨投與時係次治療的量。
- 如申請專利範圍第1至5項中任一項之用途,其中該神經退變性疾病用治療劑為多奈哌齊鹽酸鹽,且該雜環化合物為螺[咪唑并[1,2-a]吡啶-2(3H)-酮-3,2'-茚滿]。
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FR2974729B1 (fr) * | 2011-05-02 | 2013-04-19 | Servier Lab | Nouvelle association entre le 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide et un inhibiteur de l'acetylcholinesterase et les compositions pharmaceutiques qui la contiennent |
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WO2019190823A1 (en) | 2018-03-28 | 2019-10-03 | Vtv Therapeutics Llc | Pharmaceutically acceptable salts of [3-(4- {2-butyl-1-[4-(4-chlorophenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine |
WO2020076668A1 (en) | 2018-10-10 | 2020-04-16 | Vtv Therapeutics Llc | Metabolites of [3-(4-{2-butyl-l-[4-(4-chloro-phenoxy)-phenyl]-lh-imidazol-4-yl } -phen ox y)-prop yl] -diethyl-amine |
KR20210072569A (ko) * | 2019-12-09 | 2021-06-17 | 주식회사 종근당 | 도네페질 및 메만틴을 포함하는 복합 제제 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1377351A (zh) * | 1999-07-30 | 2002-10-30 | 全药工业株式会社 | 氮杂吲哚嗪酮衍生物和以其为有效成分的脑功能改善剂 |
CN1531540A (zh) * | 2001-01-30 | 2004-09-22 | ������ҩ��ҵ��ʽ���� | 杂环化合物和以其为有效成分的脑机能改善剂 |
TW200825080A (en) * | 2006-10-13 | 2008-06-16 | Zenyaku Kogyo Kk | An Alzheimer's disease progression inhibitor containing heterocyclic compound having specific structure |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6746678B1 (en) * | 1991-02-22 | 2004-06-08 | Howard K. Shapiro | Method of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with medicaments |
JPH10259126A (ja) * | 1997-01-17 | 1998-09-29 | Takeda Chem Ind Ltd | アルツハイマー病治療・予防剤 |
US6262081B1 (en) * | 1998-07-10 | 2001-07-17 | Dupont Pharmaceuticals Company | Composition for and method of treating neurological disorders |
AU754719B2 (en) * | 1998-08-31 | 2002-11-21 | Merck & Co., Inc. | Method of treating neurodegenerative diseases |
US20070004641A1 (en) * | 2001-05-24 | 2007-01-04 | Neuren Pharmaceuticals Limited | Cognitive enhancement and cognitive therapy using glycyl-L-2-methylprolyl-L-glutamate |
ES2275007T3 (es) * | 2001-05-25 | 2007-06-01 | Schering Corporation | Uso de derivados de azetidinona sustitudos en el tratamiento de la enfermedad de alzeimer. |
CN100375619C (zh) * | 2002-06-14 | 2008-03-19 | 富山化学工业株式会社 | 改善脑功能的药物组合物及其用途 |
IL150509A (en) * | 2002-07-01 | 2007-07-04 | Joseph Kaspi | Pharmaceutical preparations containing donafazil hydrochloride |
WO2004037234A2 (en) * | 2002-10-24 | 2004-05-06 | Merz Pharma Gmbh & Co. Kgaa | Combination therapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors |
US20050031651A1 (en) * | 2002-12-24 | 2005-02-10 | Francine Gervais | Therapeutic formulations for the treatment of beta-amyloid related diseases |
US20050182044A1 (en) * | 2004-02-17 | 2005-08-18 | Bruinsma Gosse B. | Combinatorial therapy with an acetylcholinesterase inhibitor and (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3,-b]indol-5-yl phenylcarbamate |
US20060246003A1 (en) * | 2004-12-27 | 2006-11-02 | Eisai Co. Ltd. | Composition containing anti-dementia drug |
EP1881756B1 (en) * | 2005-02-11 | 2016-08-10 | Stephen Wills | Treating microvasculature diseases with acetyl cholinesterase inhibitors |
US20090131480A1 (en) * | 2005-04-04 | 2009-05-21 | Eisai Co., Ltd. | Dihydropyridine Compounds for Neurodegenerative Diseases and Dementia |
WO2007025177A2 (en) * | 2005-08-26 | 2007-03-01 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
AR061637A1 (es) * | 2006-06-26 | 2008-09-10 | Epix Delaware Inc | Composiciones y metodos de tratamiento de trastornos del snc |
US20090221554A1 (en) * | 2008-02-28 | 2009-09-03 | Zenyaku Kogyo Kabushiki Kaisha | Method of treating cognitive impairment |
-
2008
- 2008-02-28 US US12/039,192 patent/US20090221554A1/en active Pending
-
2009
- 2009-02-27 AU AU2009219546A patent/AU2009219546A1/en not_active Abandoned
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- 2011-12-15 US US13/326,535 patent/US20120083486A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1377351A (zh) * | 1999-07-30 | 2002-10-30 | 全药工业株式会社 | 氮杂吲哚嗪酮衍生物和以其为有效成分的脑功能改善剂 |
CN1531540A (zh) * | 2001-01-30 | 2004-09-22 | ������ҩ��ҵ��ʽ���� | 杂环化合物和以其为有效成分的脑机能改善剂 |
TW200825080A (en) * | 2006-10-13 | 2008-06-16 | Zenyaku Kogyo Kk | An Alzheimer's disease progression inhibitor containing heterocyclic compound having specific structure |
Non-Patent Citations (4)
Title |
---|
Kenichi Tokita et. al. Combination of a novel antidementia drug FK960 with donepezil synergistically improves memory deficits in rats. Pharmacology, Biochemistry and Behavior, 2002, Vol.73, p.511-519 * |
Yamaguchi Y. et. al. Antiamnesic effects of azaindolizinone derivative ZSET845 on impaired learning and decreased ChAT activity induced by amyloid- 25-35 in the rat. Brain Research, 2002, Vol. 945, p.259-265 * |
Yoshimasa Yamaguchi et. al. Ameliorative Effects of Azaindolizinone Derivative ZSET845 on Scopolamine-Induced Deficits in Passive Avoidance and Radial-Arm Maze Learning in the Rat. Jpn. J. Pharmacol, 2001, Vol.87, p.240-244 * |
Yoshimasa Yamaguchi et. al. Effects of a Novel Cognitive Enhancer, Spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on Learning Impairments Induced by Amyloid-β1–40 in the Rat. The Journal of Pharmacology and Experimental Therapeutics, 2006, Vol. 317, No.3, p.1079-1087 * |
Also Published As
Publication number | Publication date |
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TW200942236A (en) | 2009-10-16 |
KR20100121500A (ko) | 2010-11-17 |
US20120083486A1 (en) | 2012-04-05 |
AU2009219546A1 (en) | 2009-09-03 |
JP5666910B2 (ja) | 2015-02-12 |
MX2010009390A (es) | 2010-11-30 |
US20110059998A1 (en) | 2011-03-10 |
JP2011513200A (ja) | 2011-04-28 |
EP2257290A4 (en) | 2013-07-31 |
EA201071006A1 (ru) | 2011-02-28 |
CA2716757C (en) | 2014-06-17 |
CA2716757A1 (en) | 2009-09-03 |
US20090221554A1 (en) | 2009-09-03 |
WO2009107401A1 (en) | 2009-09-03 |
BRPI0908334A2 (pt) | 2018-01-30 |
ZA201006087B (en) | 2011-10-26 |
EA023751B1 (ru) | 2016-07-29 |
KR101325324B1 (ko) | 2013-11-08 |
CN101969948B (zh) | 2014-07-16 |
CN101969948A (zh) | 2011-02-09 |
IL207811A0 (en) | 2010-12-30 |
EP2257290A1 (en) | 2010-12-08 |
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