CN1122033C - 三唑并嘌呤衍生物、含有该衍生物的药物组合物 - Google Patents
三唑并嘌呤衍生物、含有该衍生物的药物组合物 Download PDFInfo
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- CN1122033C CN1122033C CN99806269A CN99806269A CN1122033C CN 1122033 C CN1122033 C CN 1122033C CN 99806269 A CN99806269 A CN 99806269A CN 99806269 A CN99806269 A CN 99806269A CN 1122033 C CN1122033 C CN 1122033C
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- Prior art keywords
- phenyl
- butyl
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- compound
- lower alkoxy
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供通式(1)表示的三唑并嘌呤衍生物,(式中,R1和R2分别表示如说明书所述的基团,A表示下列基团(式中R3表示如说明书所述的基团))。由于该化合物对腺苷A3受体具有亲和性,可以含在药物组合物中,作为腺苷A3受体亲和剂或哮喘治疗剂使用。
Description
技术领域
本发明涉及对腺苷A3受体显示亲和性的新型三唑并嘌呤衍生物、含有该衍生物的药物组合物、腺苷A3受体亲和剂和哮喘治疗剂。
背景技术
《杂环化学杂志》J.Heterocyclic Chem.,31,1171(1994)中主要公开了2-芳基-8-氟苄基-1,2,4-三唑并〔5,1-i〕嘌呤作为腺苷A2受体拮抗剂是有用的。
本发明的目的在于提供一种对腺苷A3受体具有亲和性的新型化合物。
发明公开
本发明的三唑并嘌呤衍生物如通式(1)所示。
(式中,R1表示烷基或可选被低级烷基取代的苯基,R2表示吡啶基、呋喃基、噻吩基、低级烷基、可选具有1~3个低级烷氧基作为取代基的苯基低级烷基、可选具有1~3个低级烷氧基作为取代基的苯乙烯基、可选具有羟基作为取代基的萘基或可选具有选自低级烷基、低级烷氧基、硝基、羟基、氨基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、低级烷氧基低级烷基、苯基低级烷氧基低级烷基和卤素原子的1~3个基团作为取代基的苯基,A表示下述基团:或
(式中,R3表示低级烷基或苯基低级烷基))。
上述本发明的三唑并嘌呤衍生物是文献中未记载的新型化合物。
本发明中,特别优选上述A为以下基团的三唑并嘌呤衍生物。这时,上述R2最好是吡啶基、呋喃基、苯乙烯基、可选具有羟基作为取代基的萘基、可选具有选自低级烷基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、羟基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基。
特别优选选自下述(I)、(II)和(III)中的化合物。
(I)R1是烷基或低级烷基取代的苯基,R2是苯基的化合物。
(II)R1是正丁基,R2是吡啶基、呋喃基、苯乙烯基、可选具有羟基作为取代基的萘基、可选具有选自低级烷基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷基氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、羟基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基的化合物。
(III)R1是苯基,R2是具有3个低级烷氧基的苯基的化合物。
更优选下述(i)或(ii)的化合物。
(i)R1是低级烷基,R2是苯基的化合物。
(ii)R1是正丁基,R2是可选具有羟基作为取代基的萘基、可选具有选自低级烷基、N,N-二低级烷氨基、N-苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基的化合物。
本发明化合物的优选例是选自5-正丁基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-氯苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-甲氧基苯基)-1H-1,2,4-三唑〔5,1-i〕嘌呤、5-正丁基-8-〔4-(N,N-二甲氨基)苯基〕-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-丙氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-乙氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、8-(4-联苯基)-5-正丁基-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤和5-正戊基-8-苯基-1H-1,2,4-三唑并〔5,1-i〕嘌呤的化合物,特别是5-正丁基-8-(4-甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤和8-(4-联苯基)-5-正丁基-1H-1,2,4-三唑并〔5,1-i〕嘌呤。
由于本发明的三唑并嘌呤衍生物具有优良的腺苷A3受体亲和性,作为与腺苷A3受体结合的化合物,期待它可以用作降血压剂、抗过敏剂、抗炎剂、缺血性疾病治疗剂、白血病治疗剂、止痒剂、去痰剂、镇咳剂、哮喘治疗剂、镇痛剂等。
因此,本发明还提供含有上述三唑并嘌呤衍生物和制剂学允许的载体的药物组合物。
具体来说,本发明提供了含有上述三唑并嘌呤衍生物作为有效成分的腺苷A3受体亲和剂以及含有上述三唑并嘌呤衍生物作为有效成分的哮喘治疗剂。
发明的最佳实施方式
本发明中,上述低级烷基例如甲基、乙基、丙基、丁基、异丁基、叔丁基、戊基、己基等碳原子数为1~6的直链或支链状低级烷基。
另外,作为烷基,除上述低级烷基外,还可以举出庚基、辛基等碳原子数为7~8的烷基。
低级烷氧基例如甲氧基、乙氧基、丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等碳原子数为1~6的直链或支链状低级烷氧基。
卤素原子例如氟、氯、溴或碘。
吡啶基例如2-吡啶基、3-吡啶基或4-吡啶基。
呋喃基例如2-呋喃基或3-呋喃基等。
噻吩基例如2-噻吩基或3-噻吩基。
可选具有羟基作为取代基的萘基例如1-萘基、2-萘基、1-羟基-2-萘基、3-羟基-2-萘基、4-羟基-2-萘基、5-羟基-2-萘基、6-羟基-2-萘基、7-羟基-2-萘基、8-羟基-2-萘基、2-羟基-1-萘基、3-羟基-1-萘基、4-羟基-1-萘基、5-羟基-1-萘基、6-羟基-1-萘基、7-羟基-1-萘基、8-羟基-1-萘基等。
作为可选具有选自低级烷基、低级烷氧基、硝基、羟基、氨基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、低级烷氧基低级烷基、苯基低级烷氧基低级烷基和卤素原子的基团作为取代基的苯基,除苯基之外,例如2-甲基苯基、3-甲基苯基、4-甲基苯基、4-乙基苯基、4-丙基苯基、4-异丙基苯基、4-丁基苯基、4-叔丁基苯基、4-戊基苯基、4-己基苯基、2,3-二甲基苯基、2,4-二甲基苯基、2,5-二甲基苯基、2,6-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、3,4-二乙基苯基、3,4-二丙基苯基、3,4-二丁基苯基、3,4-二戊基苯基、3,4-二己基苯基、3,4,5-三甲基苯基、2,3,4-三甲基苯基、2,3,5-三甲基苯基、2,3,6-三甲基苯基、2,4,6-三甲基苯基、2,4,5-三甲基苯基、3,4,5-三乙基苯基、3,4,5-三丙基苯基、3,4,5-三丁基苯基、3,4,5-三戊基苯基、3,4,5-三己基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、4-乙氧基苯基、4-丙氧基苯基、4-丁氧基苯基、4-戊氧基苯基、4-己氧基苯基、2,3-二甲氧基苯基、2,4-二甲氧基苯基、2,5-二甲氧基苯基、2,6-二甲氧基苯基、3,4-二甲氧基苯基、3,5-二甲氧基苯基、3,4-二乙氧基苯基、3,4-二丙氧基苯基、3,4-二丁氧基苯基、3,4-二戊氧基苯基、3,4-二己氧基苯基、3,4,5-三甲氧基苯基、2,3,4-三甲氧基苯基、2,3,5-三甲氧基苯基、2,3,6-三甲氧基苯基、2,4,6-三甲氧基苯基、2,4,5-三甲氧基苯基、3,4,5-三乙氧基苯基、3,4,5-三丙氧基苯基、3,4,5-三丁氧基苯基、3,4,5-三戊氧基苯基、3,4,5-三己氧基苯基、2-羟基苯基、3-羟基苯基、4-羟基苯基、2,3-二羟基苯基、2,4-二羟基苯基、2,5-二羟基苯基、2,6-二羟基苯基、3,4-二羟基苯基、3,5-二羟基苯基、3,4,5-三羟基苯基、2,3,4-三羟基苯基、2,3,5-三羟基苯基、2,3,6-三羟基苯基、2,4,6-三羟基苯基、2,4,5-三羟基苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2,3-二硝基苯基、2,4-二硝基苯基、2,5-二硝基苯基、2,6-二硝基苯基、3,4-二硝基苯基、3,5-二硝基苯基、3,4,5-三硝基苯基、2,3,4-三硝基苯基、2,3,5-三硝基苯基、2,3,6-三硝基苯基、2,4,6-三硝基苯基、2,4,5-三硝基苯基、2-氨基苯基、3-氨基苯基、4-氨基苯基、3,4-二氨基苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-碘苯基、3-碘苯基、4-碘苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,4-二氯苯基、2,3-二氯苯基、3,5-二氯苯基、3,4-二氯苯基、2,5-二氯苯基、2,6-二氯苯基、2,4-二氟苯基、2,4-二溴苯基、2,4-二碘苯基、3,4,5-三氯苯基、2,4,6-三氯苯基、4-甲氧基-3-甲基苯基、4-甲氧基-2-甲基苯基、3-甲氧基-2-甲基苯基、4-甲氧基-3,5-二甲基苯基、4-羟基-3-甲基苯基、4-羟基-2-甲基苯基、3-羟基-2-甲基苯基、2-羟基-4-甲基苯基、2-羟基-4-甲氧基苯基、4-羟基-3,5-二甲基苯基、3,5-二叔丁基-4-羟基苯基、4-羟基-3,5-二甲氧基苯基、3,5-二羟基-4-甲氧基苯基、4-氯-3-甲氧基苯基、3-氯-4-甲氧基苯基、4-氯-2-羟基苯基、4-氯-3-羟基苯基、4-氯-3-甲基苯基、3-氯-4-甲基苯基、4-氯-3,5-二甲氧基苯基、4-氯-3,5-二甲基苯基、4-(N-甲氨基)苯基、4-(N-乙氨基)苯基、4-(N-丙氨基)苯基、4-(N-丁氨基)苯基、4-(N-戊氨基)苯基、4-(N-己氨基)苯基、3-(N-甲氨基)苯基、2-(N-甲氨基)苯基、4-(N,N-二甲氨基)苯基、4-(N,N-二乙氨基)苯基、4-(N,N-二丙氨基)苯基、4-(N,N-二丁氨基)苯基、4-(N,N-二戊氨基)苯基、4-(N,N-二己氨基)苯基、3-(N,N-二甲氨基)苯基、2-(N,N-二甲氨基)苯基、4-(N-苯甲基氨基)苯基、4-〔N-(2-苯基乙基)氨基〕苯基、4-〔N-(3-苯基丙基)氨基〕苯基、4-〔N-(4-苯基丁基)氨基〕苯基、4-〔N-(5-苯基戊基)氨基〕苯基、4-〔N-(6-苯基己基)氨基〕苯基、3-(N-苯甲基氨基)苯基、2-(N-苯甲基氨基)苯基、4-(N,N-二苯甲基氨基)苯基、4-〔N,N-二(2-苯基乙基)氨基〕苯基、4-〔N,N-二(3-苯基丙基)氨基〕苯基、4-〔N,N-二(4-苯基丁基)氨基〕苯基、4-〔N,N-二(5-苯基戊基)氨基〕苯基、4-〔N,N-二(6-苯基己基)氨基〕苯基、3-(N,N-二苯甲基氨基)苯基、2-(N,N-二苯甲基氨基)苯基、4-联苯基、3-联苯基、2-联苯基、4-苯氧基苯基、3-苯氧基苯基、2-苯氧基苯基、4-苯甲氧基苯基、4-(2-苯基乙氧基)苯基、4-(3-苯基丙氧基)苯基、4-(4-苯基丁氧基)苯基、4-(5-苯基戊氧基)苯基、4-(6-苯基己氧基)苯基、3-苯甲氧基苯基、2-苯甲氧基苯基、4-三氟甲基苯基、4-五氟乙基苯基、4-七氟丙基苯基、4-九氟丁基苯基、4-十一氟戊基苯基、4-十三氟己基苯基、3-三氟甲基苯基、2-三氟甲基苯基、4-三氟甲氧基苯基、4-五氟乙氧基苯基、4-七氟丙氧基苯基、4-九氟丁氧基苯基、4-十一氟戊氧基苯基、4-十三氟己氧基苯基、3-三氟甲氧基苯基、2-三氟甲氧基苯基、4-二甲氧基磷酰基甲基苯基、4-二乙氧基磷酰基甲基苯基、4-二丙氧基磷酰基甲基苯基、4-二丁氧基磷酰基甲基苯基、4-二戊氧基磷酰基甲基苯基、4-二己氧基磷酰基甲基苯基、3-二乙氧基磷酰基甲基苯基、2-二乙氧基磷酰基甲基苯基、4-甲硫基苯基、4-乙硫基苯基、4-丙硫基苯基、4-丁硫基苯基、4-戊硫基苯基、4-己硫基苯基、3-甲硫基苯基、2-甲硫基苯基、4-甲氧基甲基苯基、3-甲氧基甲基苯基、2-甲氧基甲基苯基、4-乙氧基甲基苯基、4-丙氧基甲基苯基、4-丁氧基甲基苯基、4-戊氧基甲基苯基、4-己氧基甲基苯基、4-(2-甲氧基乙基)苯基、4-(3-甲氧基丙基)苯基、4-(4-甲氧基丁基苯基)、4-(5-甲氧基戊基)苯基、4-(6-甲氧基己基)苯基、4-苯甲氧基甲基苯基、3-苯甲氧基甲基苯基、2-苯甲氧基甲基苯基、4-(2-苯甲氧基乙基)苯基、4-(3-苯甲氧基丙基)苯基、4-(4-苯甲氧基丁基)苯基、4-(5-苯甲氧基戊基)苯基、4-(6-苯甲氧基己基)苯基、4-(2-苯基乙氧基甲基)苯基、4-(3-苯基丙氧基甲基)苯基、4-(4-苯基丁氧基甲基)苯基、4-(5-苯基戊氧基甲基)苯基、4-(6-苯基己氧基甲基)苯基等可选具有1~3个取代基的苯基。
作为可选被低级烷基取代的苯基,除苯基之外,例如2-甲基苯基、3-甲基苯基、4-甲基苯基、2,4-二甲基苯基、3,4-二甲基苯基、3,5-二甲基苯基、3,4,5-三甲基苯基、4-乙基苯基、4-丙基苯基、4-丁基苯基、4-戊基苯基、4-己基苯基等。
苯基低级烷基例如苯甲基、2-苯基乙基、1-苯基乙基、3-苯基丙基、4-苯基丁基、5-苯基戊基、6-苯基己基等。
作为可选具有1~3个低级烷氧基作为取代基的苯基低级烷基,除上述苯基低级烷基之外,例如2-甲氧基苯甲基、3-甲氧基苯甲基、4-甲氧基苯甲基、2,4-二甲氧基苯甲基、3,4-二甲氧基苯甲基、3,5-二甲氧基苯甲基、3,4,5-三甲氧基苯甲基、4-乙氧基苯甲基、4-丙氧基苯甲基、4-丁氧基苯甲基、4-戊氧基苯甲基、4-己氧基苯甲基、2-(4-甲氧基苯基)乙基、3-(4-甲氧基苯基)丙基、4-(4-甲氧基苯基)丁基、5-(4-甲氧基苯基)戊基、6-(4-甲氧基苯基)己基、2-(3,4,5-三甲氧基苯基)乙基、3-(3,4,5-三甲氧基苯基)丙基、4-(3,4,5-三甲氧基苯基)丁基、5-(3,4,5-三甲氧基苯基)戊基、6-(3,4,5-三甲氧基苯基)己基等。
作为可选具有1~3个低级烷基作为取代基的苯乙烯基,除苯乙烯基之外,例如2-甲氧基苯乙烯基、3-甲氧基苯乙烯基、4-甲氧基苯乙烯基、2,4-二甲氧基苯乙烯基、3,4-二甲氧基苯乙烯基、3,5-二甲氧基苯乙烯基、3,4,5-三甲氧基苯乙烯基、4-乙氧基苯乙烯基、4-丙氧基苯乙烯基、4-丁氧基苯乙烯基、4-戊氧基苯乙烯基、4-己氧基苯乙烯基等。
本发明化合物(1)的具体实例如表1~8所示。各表中,Me表示甲基,Et表示乙基,n-Pr表示正丙基,n-Bu表示正丁基,n-Pe表示正戊基,n-Hx表示正己基,n-Hp表示正庚基,n-Oc表示正辛基,Ph表示苯基,Bn表示苯甲基。表1 表2表3表4表5表6 表7表8
本发明化合物(1)可以经下述反应方程式-1制得。反应方程式-1(式中,R1、R2和A与上述相同,Z表示低级烷基。)
也就是说,首先使式(2)所示化合物与式(3)所示原酸酯衍生物反应,得到式(4)所示的亚氨酸酯衍生物。
该反应是在无溶剂或在惰性溶剂中,相对于化合物(2)添加等摩尔至过量的原酸酯衍生物(3),在50℃~回流温度下加热约10分钟~5小时进行的。上述惰性溶剂例如可以使用N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、二甲基亚砜(DMSO)、甲醇、二苯基醚、二甲苯、二甘醇二甲醚等。
生成的亚氨酸酯衍生物(4)不经过精制或按照常规方法精制后,与式(5)所示的酰肼衍生物反应得到本发明化合物(1)。
该反应是在惰性溶剂中,相对于亚氨酸酯衍生物(4)添加等摩尔至略微过量的酰肼衍生物(5),必要时加入催化量的1,8-二氮杂二环〔5,4,0〕-7-十一碳烯,在50℃~回流温度下加热约1~50小时进行的。惰性溶剂例如与上述相同的溶剂。而且,必要时在上述加热反应之后,也可以添加氢氧化钠水溶液、氢氧化钾水溶液等调节为碱性,在0℃~室温下再处理约10分钟~5小时。
也就是说,首先在盐酸、硫酸等无机酸水溶液中回流5分钟~1小时将化合物(1)转变成胺化合物(6)。
其次,将胺化合物(6)酰化。这种酰化可以通过在例如吡啶、二甲基吡啶、三乙胺、4-(N,N-二甲氨基)吡啶等胺类惰性溶剂中,使胺化合物(6)与酰氯(7)反应进行。在该反应中,酰氯(7)使用1~过剩当量,反应在0℃~室温下进行10分钟~3小时终了。另外,这种酰化反应中,由于有时混有多个酰基取代的化合物,必要时在甲醇、乙醇等惰性溶剂中,与催化量的无水碳酸钾、无水碳酸钠等碱一起回流10分~2小时,可以将混在物质转变成单酰基化合物(8)。
然后,通过环化反应将上述得到的单酰基化合物(8)转变成化合物(1a)。该环化反应是通过在惰性溶剂中在碱存在下使卤代三烷基甲硅烷作用于单酰基化合物(8)而进行的。
这里,惰性溶剂可以使用苯、甲苯、二甲苯、石油醚等芳香烃和脂肪烃类,二乙基醚、四氢呋喃等醚类,二氯甲烷、氯仿、四氯化碳、1,2-二氯乙烷等卤代烃类等。碱优选使用三乙胺、N,N-二乙基苯胺、N-甲基吗啉、吡啶、4-(N,N-二甲氨基)吡啶等叔胺。另外,卤代三烷基甲硅烷优选使用例如氯代三甲基甲硅烷、氯代三乙基甲硅烷、氯代乙基二甲基甲硅烷、氯代二甲基丙基甲硅烷、氯代丁基二甲基甲硅烷、氯代三丙基甲硅烷、三丁基氯代甲硅烷、氯代乙基甲基丙基甲硅烷等氯代三烷基甲硅烷。
上述氯代三烷基甲硅烷和碱的用量没有特别的限定,一般相对于单酰基化合物(8)为1~过剩当量,优选3~20当量。环化反应通常在0~100℃下进行0.5~30小时终了。
上述反应方程式所示各步骤中的目的化合物可以按照通常的分离手段容易地分离精制。这种分离手段例如吸附层析法、制备薄层层析法、重结晶、溶剂萃取等。
另外,本发明化合物(1)中,R2为可选具有1~3个低级烷氧基作为取代基的苯乙烯基时,化合物存在E型和Z型几何异构体。本发明也包括这两种异构体及其混合物。另外,这两种异构体可以通过采用上述分离手段分离。
本发明化合物(1)可以制成可药用的酸加成盐,这些盐也包括在本发明内。可以形成所述酸加成盐的酸例如盐酸、氢溴酸、硫酸等无机酸,草酸、富马酸、马来酸、酒石酸、柠檬酸、对甲苯磺酸等有机酸。酸加成盐的形成可以按照常规方法进行。
另外,本发明化合物可以按照常规方法制成钠盐、钾盐等碱金属盐;钙盐、镁盐等碱土金属盐以及铜盐等,这些盐也包括在本发明内。
本发明化合物(1)可以与适当的无毒性制剂载体一同使用,一般作为药物制剂的形态使用。上述制剂载体例如根据制剂的使用形态通常使用的填充剂、增量剂、粘合剂、湿润剂、崩解剂、表面活性剂、润滑剂等稀释剂或赋形剂等,可以根据所得制剂的给药单位形态适当选择使用。
使用本发明化合物(1)的药物制剂的给药单位形态可以根据治疗目的选择各种形态,其中具有代表性的例如片剂、丸剂、散剂、液体制剂、悬浊剂、乳剂、颗粒剂、胶囊剂、栓剂、注射剂(液体制剂、悬浊剂)、软膏剂等。
制成片剂的形态时,上述制剂载体可以使用例如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸、磷酸钾等赋形剂;水、乙醇、丙醇、单糖浆、葡萄糖液、淀粉液、明胶溶液、羧甲基纤维素、羟丙基纤维素、甲基纤维素、聚乙烯吡咯烷酮等粘合剂;羧甲基纤维素钠、羧甲基纤维素钙、低取代度羟丙基纤维素、干燥淀粉、海藻酸钠、琼脂粉末、褐藻淀粉(laminaran)粉末、碳酸氢钠、碳酸钙等崩解剂;聚氧乙烯脱水山梨醇脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯等表面活性剂;白糖、三硬脂酸甘油酯、可可脂、氢化油等崩解抑制剂;季铵盐、月桂基硫酸钠等吸收促进剂;甘油、淀粉等保湿剂;淀粉、乳糖、高岭土、膨润土、胶态硅酸等吸附剂;精制滑石粉、硬脂酸盐、硼酸粉末、聚乙二醇等润滑剂等。
这些片剂必要时可以制成具有常规包衣的片剂,例如糖衣片、明胶包衣片、肠溶衣片、薄膜衣片剂或二层片、多层片。
制成丸剂的形态时,制剂载体可以使用例如葡萄糖、乳糖、淀粉、可可脂、硬化植物油、高岭土、滑石粉等赋形剂;阿拉伯胶粉末、西黄蓍胶粉末、明胶、乙醇等粘合剂;褐藻淀粉、琼脂等崩解剂等。
制成栓剂的形态时,制剂载体可以使用例如聚乙二醇、可可脂、高级醇、高级醇的酯类、明胶、半合成甘油酯等。
胶囊剂可以按照常规方法调制,通常将本发明化合物(1)与上述列举的各种制剂载体混合,填充到硬明胶胶囊、软胶囊等中。
制成液体制剂、乳剂、悬浊剂等注射剂时,优选已灭菌并与血液等渗的制剂。配制注射剂时,可以使用水、乙醇、聚乙二醇、丙二醇、乙氧基化异硬脂醇、聚氧化异硬脂醇、聚氧乙烯脱水山梨醇脂肪酸酯类等作为稀释剂。另外,这时为了配制等渗溶液也可以含有足够量的食盐、葡萄糖、甘油等,另外也可以添加通常的溶解助剂、缓冲剂、止痛剂等。
而且,在上述药物制剂中必要时可以含有着色剂、防腐剂、香料、风味剂、甜味剂等或其它药品。
制成糊剂、霜剂、凝聚剂等软膏剂的形态时,可以使用白凡士林、石蜡、甘油、纤维素衍生物、聚乙二醇、硅氧烷、膨润土等作为稀释剂。
对上述药物制剂中所应含有的本发明化合物(1)的量没有特别的限定,可以在较宽范围内适当选择,通常在药物制剂中优选含有约1~85重量%。
上述药物制剂的给药方法没有特别的限定,可以根据剂型、患者的年龄、性别和其它条件、疾病的程度等适当决定。例如片剂、丸剂、液体制剂、悬浊剂、乳剂、颗粒剂、胶囊剂可口服给药,注射剂可单独或与葡萄糖、氨基酸等常规的补充液混合后静脉给药,必要时也可单独肌肉内、皮内、皮下或腹腔给药,栓剂可直肠内给药。
上述药物制剂的给药量可以根据其用法、患者的年龄、性别和其它条件、疾病的程度等适当决定,通常本发明化合物(1)每日的给药量为每1kg体重约0.5~20mg,优选1~10mg。另外,上述药物制剂可以1日分1~4次给药。工业实用性
本发明的三唑并嘌呤衍生物由于对腺苷A3受体具有亲和性,可以期待用作降血压剂、抗过敏剂、抗炎剂、缺血性疾病治疗剂、白血病治疗剂、止痒剂、去痰剂、镇咳剂、哮喘治疗剂、镇痛剂等。实施例
以下结合参考例、实施例、实验例和制剂例详细说明本发明化合物。参考例1〔N-(5-氰基咪唑-4-基)乙亚氨酸甲酯的制备〕
将4-氨基-5-氰基咪唑5g悬浊在DMF 10ml中,加入原乙酸甲酯10ml,在90℃下搅拌30分钟。在减压条件下浓缩反应液,用乙酸乙酯稀释残渣,过滤收集析出的目的化合物的晶体4.2g。另外,浓缩母液,用硅胶柱层析法(洗脱液:乙酸乙酯)精制残渣,再用乙酸乙酯-正己烷重结晶,得到目的化合物的晶体2.9g。熔点:147~149℃参考例2
与参考例1同样,制备N-(5-氰基咪唑-4-基)戊亚氨酸甲酯。熔点:114~116℃参考例3
与参考例1同样,制备N-(5-氰基咪唑-4-基)苯甲亚氨酸甲酯。熔点:157~159℃
而且,与参考例1同样可以制备下述化合物。·N-(5-氰基咪唑-4-基)丙亚氨酸甲酯·N-(5-氰基咪唑-4-基)丁亚氨酸甲酯·N-(5-氰基咪唑-4-基)己亚氨酸甲酯·N-(5-氰基咪唑-4-基)庚亚氨酸甲酯·N-(5-氰基咪唑-4-基)辛亚氨酸甲酯·N-(5-氰基咪唑-4-基)壬亚氨酸甲酯·N-(5-氰基咪唑-4-基)-3-甲基苯甲亚氨酸甲酯参考例4
使用5-氨基-1-苯甲基-4-氰基咪唑作为原料,与参考例1同样,制备下述各化合物。·N-(1-苯甲基-4-氰基咪唑-5-基)乙亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)丙亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)丁亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)戊亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)己亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)庚亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)辛亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)壬亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)苯甲亚氨酸甲酯·N-(1-苯甲基-4-氰基咪唑-5-基)-3-甲基苯甲亚氨酸甲酯参考例5
分别使用4-氨基-1-苯甲基-5-氰基咪唑、5-氨基-4-氰基-1-甲基咪唑、4-氨基-5-氰基-1-甲基咪唑、5-氨基-4-氰基-1-乙基咪唑和4-氨基-5-氰基-1-乙基咪唑作为原料,与参考例1同样制备下述各化合物。·N-(1-苯甲基-5-氰基咪唑-4-基)庚亚氨酸甲酯·N-(5-氰基-1-甲基咪唑-4-基)庚亚氨酸甲酯·N-(4-氰基-1-甲基咪唑-5-基)庚亚氨酸甲酯·N-(5-氰基-1-乙基咪唑-4-基)庚亚氨酸甲酯·N-(4-氰基-1-乙基咪唑-5-基)庚亚氨酸甲酯实施例1〔5-甲基-8-苯基-1H-1,2,4-三唑并〔5,1-i〕嘌呤的制备〕
将上述参考例1得到的N-(5-氰基咪唑-4-基)乙亚氨酸甲酯4.0g和N-苯甲酰肼3.65g溶解于DMF 40ml中,在80℃下搅拌1小时,然后在150℃下搅拌15小时。然后,将反应液放冷至室温,滴加10%氢氧化钠水溶液13ml,将pH调节为9~10,在室温下搅拌1小时。反应终了后,依次加入10%盐酸和水,调节为pH3,过滤收集析出的晶体,用热乙醇洗涤,得到目的化合物的晶体5.5g。所得目的化合物的结构和熔点如表8所示。实施例2~20
分别使用上述参考例1~3得到的各化合物和一定的酰肼衍生物,与实施例1同样,制备具有表9和表10所示结构和熔点的各种化合物。在表9、表10中,Me表示甲基,n-Bu表示正丁基,pH表示苯基。表9 表10
另外,所得各化合物的NMR测定结果如下所示。·实施例1的化合物1H-NMR(DMSO-d6)δ:3.03(3H,s),7.5-7.7(3H,m),8.3-8.4(2H,m),8.48(1H,s),13.6-14.1(1H,brs)·实施例2的化合物1H-NMR(DMSO-d6)δ:2.98(3H,s),3.76(3H,s),3.92(6H,s),7.56(2H,s),8.42(1H,s),13.6-14.1(1H,brs)·实施例3的化合物1H-NMR(DMSO-d6)δ:3.05(3H,s),7.69(1H,dd,J=4.9,7.9),8.50(1H,s),8.65(1H,d,J=7.9),8.81(1H,d,J=4.9),9.49(1H,s),13.5-14.1(1H,brs)·实施例4的化合物1H-NMR(DMSO-d6)δ:1.05(3H,t,J=7.4),1.5-1.6(2H,m),1.9-2.1(2H,m),3.43(2H,t,J=7.4),7.6-7.7(3H,m),8.3-8.4(2H,m),8.50(1H,s),13.6-14.2(1H,brs)·实施例5的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.8-2.0(2H,m),2.40(3H,s),3.35(2H,t,J=7.4),7.38(2H,d,J=7.9),8.16(2H,d,J=7.9),8.42(1H,s),13.5-14.0(1H,brs)·实施例6的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.8-2.0(2H,m),3.36(2H,t,J=7.7),7.0-7.1(2H,m),7.42(1H,t,J=8.2),8.17(1H,d,J=7.9),8.48(1H,s),11.21(1H,s),13.7-14.1(1H,brs)·实施例7的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.0(2H,m),3.34(2H,t,J=6.9),6.94(2H,d,J=8.9),8.11(2H,d,J=8.9),8.40(1H,s),9.7-10.2(1H,brs),13.3-14.2(1H,brs)·实施例8的化合物1H-NMR(DMSO-d6)δ:1.04(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.1(2H,m),3.37(2H,t,J=7.4),3.92(3H,s),7.17(2H,d,J=7.9),8.17(1H,s),8.27(2H,d,J=7.9)·实施例9的化合物1H-NMR(DMSO-d6)δ:0.96(3H,t,J=7.4),1.4-1.5(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.5),7.5-7.7(3H,m),8.0-8.2(1H,m),8.47(1H,s)·实施例10的化合物1H-NMR(DMSO-d6)δ:0.96(3H,t,J=6.9),1.4-1.5(2H,m),1.8-2.0(2H,m),3.30(2H,t,J=7.4),7.81(1H,t,J=7.9),7.89(1H,t,J=7.9),8.03(1H,d,J=7.9),8.21(1H,d,J=7.9),8.46(1H,s),13.7-14.1(1H,brs)·实施例11的化合物1H-NMR(DMSO-d6)δ:0.99(3H,t,J=6.9),1.4-1.6(2H,m),1.8-2.0(2H,m),3.33(2H,t,J=7.9),8.37(2H,d,J=8.9),8.43(1H,s),8.45(2H,d,J=8.9)·实施例12的化合物1H-NMR(DMSO-d6)δ:1.04(3H,t,J=7.4),1.5-1.6(2H,m),2.0-2.1(2H,m),3.48(2H,t,J=7.4),3.95(3H,s),4.00(6H,s),7.65(2H,s),8.19(1H,s)·实施例13的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.8-2.0(2H,m),3.38(2H,t,J=7.4),7.62(1H,dd,J=5.0,7.9),8.44(1H,s),8.59(1H,d,J=7.9),8.75(1H,d,J=5.0),9.42(1H,s)·实施例14的化合物1H-NMR(DMSO-d6)δ:0.99(3H,t,J=6.9),1.4-1.6(2H,m),1.9-2.0(2H,m),3.38(2H,t,J=7.4),8.18(2H,d,J=5.9),8.46(1H,s),8.81(2H,d,J=5.9)·实施例15的化合物1H-NMR(DMSO-d6)δ:0.97(3H,t,J=7.4),1.4-1.5(2H,m),1.8-2.0(2H,m),3.33(2H,t,J=7.4),6.75(1H,dd,J=2.0,3.5),7.29(1H,brd,J=3.5),7.97(1H,brs),8.43(1H,s),13.6-14.0(1H,brs)·实施例16的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=6.9),1.4-1.6(2H,m),1.8-2.0(2H,m),3.32(2H,t,J=7.4),7.27(1H,dd,J=3.5,4.9),7.80(1H,dd,J=1.0,4.9),7.92(1H,dd,J=1.0,3.5),8.43(1H,s),13.5-14.1(1H,brs)·实施例17的化合物1H-NMR(DMSO-d6)δ:0.96(3H,t,J=7.4),1.4-1.5(2H,m),1.8-2.0(2H,m),3.30(2H,t,J=7.8),7.3-7.5(4H,m),7.7-7.8(2H,m),7.87(1H,d,J=16.3),8.41(1H,s),13.5-14.0(1H,brs)·实施例18的化合物1H-NMR(DMSO-d6)δ:7.5-7.6(3H,m),7.6-7.7(3H,m),8.2-8.3(2H,m),8.4-8.5(2H,m),8.54(1H,s),13.7-14.2(1H,brs)·实施例19的化合物1H-NMR(DMSO-d6)δ:3.84(3H,s),3.97(6H,s),7.59(2H,s),7.7-7.8(3H,m),8.5-8.6(2H,m),8.58(1H,s)·实施例20的化合物1H-NMR(DMSO-d6)δ:7.6-7.7(4H,m),8.5-8.6(4H,m),8.7-8.8(1H,m),9.43(1H,s)实施例21~33和38~40
分别使用上述参考例1~4得到的各化合物和一定的酰肼衍生物,与实施例1同样,制备具有表11和表12所示结构和熔点的各种化合物。实施例34〔5-戊基-8-苯基-1H-1,2,4-三唑并〔5,1-i〕嘌呤的制备〕
将实施例1得到的化合物4.4g加入到浓盐酸20ml的水50ml溶液中,加热回流30分钟。将反应液冷却到室温,加入25%氨水,调节为pH8,过滤收集析出的晶体,用75%乙醇重结晶,得到3-(4-氨基吡唑-5-基)-5-苯基-1,2,4-三唑的晶体2.58g。
然后,将如上所述得到的晶体2g溶解于吡啶20ml中,在0℃下滴加己酰氯4.16g,在0℃下搅拌30分钟,然后在室温下搅拌30分钟。用乙酸乙酯稀释反应液,依次用柠檬酸水溶液、碳酸氢钠水溶液和饱和食盐水洗涤后,用无水硫酸镁干燥,减压干燥。用硅胶柱层析(洗脱液是氯仿,然后是氯仿∶甲醇=30∶1)精制残渣,得到油状物5g。将该油状物溶解于乙醇40ml中,加入无水碳酸钾10mg,加热回流30分钟。将反应液冷却到室温,过滤收集析出的晶体,用乙醇洗涤后,干燥得到3-〔4-(N-己酰氨基)吡唑-5-基〕-5-苯基-1,2,4-三唑的晶体1.9g。
接着,将如上所示得到的晶体0.4g悬浊在四氢呋喃8ml中,加入三乙胺1.77ml和氯代三甲基甲硅烷0.63ml,加热回流20小时。反应终了后,依次加入冰水和柠檬酸2g搅拌,用乙酸乙酯萃取。合并有机层,依次用水和饱和食盐水洗涤,用无水硫酸镁干燥,减压浓缩。用硅胶柱层析(洗脱液是氯仿,然后是氯仿∶甲醇=25∶1)精制残渣,再用甲醇-水重结晶,得到目的化合物的晶体0.15g。得到的目的化合物的结构和熔点如表12所示。实施例35~37
与实施例34同样,制备具有表12所示结构和熔点的各种化合物。
另外,所得各化合物的NMR测定结果如下所示。·实施例21的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=6.9),1.4-1.6(2H,m),1.8-2.0(2H,m),3.35(2H,t,J=7.4),7.64(2H,d,J=8.4),8.27(2H,d,J=8.4),8.43(1H,s),13.6-14.0(1H,s,brs)·实施例22的化合物1H-NMR(DMSO-d6)δ:1.46(3H,t,J=7.4),3.39(2H,q,J=7.4),7.5-7.7(3H,m),8.2-8.3(2H,m),8.43(1H,s),13.6-14.0(1H,brs)·实施例23的化合物1H-NMR(DMSO-d6)δ:1.07(3H,t,J=7.4),1.9-2.1(2H,m),3.33(2H,t,J=7.7),7.5-7.7(3H,m),8.2-8.3(2H,m),8.43(1H,s)·实施例24的化合物1H-NMR(DMSO-d6)δ:1.46(3H,t,J=7.4),3.40(2H,q,J=7.4),3.76(3H,s),3.92(6H,s),7.56(2H,s),8.43(1H,s),13.6-14.0(1H,brs)·实施例25的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.8-2.0(2H,m),3.34(2H,t,J=7.7),7.6-7.7(2H,m),8.2-8.3(2H,m),8.43(1H,s)·实施例26的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.9),3.88(3H,s),7.12(1H,d,J=8.4),7.49(1H,dd,J=7.7,8.4),7.79(1H,s),7.86(1H,d,J=7.7),8.43(1H,s),13.6-14.0(1H,brs)·实施例27的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H.m),1.8-2.0(2H,m),3.34(2H,t,J=7.4),3.86(3H,s),7.11(2H,d,J=8.9),8.20(2H,d,J=8.9),8.41(1H,s)·实施例28的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H.m),1.8-2.0(2H,m),2.43(3H,s),3.34(2H,t,J=7.7),7.35(1H,d,J=7.7),7.45(1H,t,J=7.7),8.07(1H,d,J=7.7),8.08(1H,s),8.42(1H,s),13.5-14.0(1H,brs)·实施例29的化合物1H-NMR(DMSO-d6)δ:0.95(3H,t,J=7.2),1.3-1.5(2H,m),1.8-2.0(2H,m),2.54(3H,s),3.25(2H,t,J=7.9),8.38(1H,s)·实施例30的化合物1H-NMR(DMSO-d6)δ:0.95(3H,t,J=7.2),1.3-1.5(2H,m),1.8-2.0(2H,m),3.28(2H,t,J=7.9),4.25(2H,s),7.2-7.5(5H,m),8.38(1H,s)·实施例31的化合物1H-NMR(DMSO-d6)δ:0.96(3H,t,J=7.4),1.3-1.6(2H,m),1.8-2.0(2H,m),3.29(3H,t,J=7.4),3.71(3H,s),3.87(6H,s),7.13(2H,s),7.46(1H,d,J=16.3),7.81(1H,d,J=16.3),8.41(1H,s),13.5-14.0(1H,brs)·实施例32的化合物1H-NMR(DMSO-d6)δ:0.94(3H,t,J=7.2),1.4-1.5(2H,m),1.8-2.0(2H,m),3.0-3.4(6H,m),3.61(3H,s),3.73(6H,s),6.61(2H,s),8.39(1H,s)·实施例33的化合物1H-NMR(CDCl3)δ:1.02(3H,t,J=7.2),1.5-1.6(2H,m),2.0-2.1(2H,m),3.44(2H,t,J=7.4),5.78(2H,s),7.3-7.4(3H,m),7.5-7.6(5H,m),8.04(1H,s),8.3-8.4(2H,m)·实施例34的化合物1H-NMR(DMSO-d6)δ:0.91(3H,t,J=6.9),1.3-1.5(4H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.4),7.5-7.6(3H,m),8.2-8.3(2H,m),8.43(1H,s)·实施例35的化合物1H-NMR(DMSO-d6)δ:2.49(3H,s),7.4-7.6(5H,m),8.2-8.4(4H,m),8.54(1H,s)·实施例36的化合物1H-NMR(DMSO-d6)δ:0.88(3H,t,J=7.2),1.2-1.6(6H.m),1.9-2.0(2H,m),3.36(2H,t,J=7.7),7.4-7.7(3H,m),8.2-8.3(2H,m),8.43(1H,s),13.6-14.1(1H,brs)·实施例37的化合物1H-NMR(DMSO-d6)δ:0.86(3H,t,J=6.9),1.2-1.5(8H,m),1.8-2.0(2H,m),3.34(2H,t,J=7.9),7.5-7.6(3H,m),8.2-8.3(2H,m),8.43(1H,s)·实施例38的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.7),7.41(2H,t,J=8.9),8.31(2H,dd,J=6.4,8.9),8.43(1H,s)·实施例39的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.0(2H,m),3.35(2H,t,J=7.4),7.78(2H,d,J=8.4),8.21(2H,d,J=8.4),8.43(1H,s)·实施例40的化合物1H-NMR(DMSO-d6)δ:1.04(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.1(2H,m),3.39(2H,t,J=7.2),5.70(2H,s),6.76(2H,d,J=8.7),8.02(2H,d,J=8.7),8.44(1H,s)实施例41~73
分别使用上述参考例1~5得到的各化合物和一定的酰肼衍生物,与实施例1同样,制备具有表13~表15所示结构和熔点的各种化合物。
另外,所得各化合物的NMR测定结果如下所示。·实施例41的化合物1H-NMR(CDCl3)δ:1.03(3H,t,J=7.2),1.5-1.6(2H,m),1.9-2.1(2H,m),3.45(2H,t,J=7.4),5.49(2H,s),7.3-7.4(5H,m),7.5-7.6(3H,m),7.97(1H,s),8.4-8.5(2H,m).·实施例42的化合物1H-NMR(DMSO-d6)δ:1.04(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.1(2H,m),3.07(6H,s),3.40(2H,t,J=7.4),6.91(2H,d,J=8.7),8.15(2H,d,J=8.7),8.45(1H,s).·实施例43的化合物1H-NMR(CDCl3)δ:1.02(3H,t,J=7.2),1.5-1.6(2H,m),2.0-2.1(2H,m),3.44(2H,t,J=7.4),4.30(3H,s),7.5-7.6(3H,m),7.99(1H,s),8.3-8.4(2H,m).·实施例44的化合物1H-NMR(CDCl3)δ:1.04(3H,t,J=7.4),1.5-1.6(2H,m),2.0-2.1(2H,m),3.45(2H,t,J=7.4),3.97(3H,s),7.5-7.6(3H,m),7.97(1H,s),8.4-8.5(2H,m).·实施例45的化合物1H-NMR(DMSO-d6)δ:0.9-1.1(6H,m),1.4-1.6(2H,m),1.7-1.8(2H,m),1.9-2.0(2H,m),3.34(2H,t,J=7.7),4.02(2H,t,J=6.4),7.11(2H,d,J=8.4),8.19(2H,d,J=8.4),8.41(1H,s).·实施例46的化合物1H-NMR(CDCl3)δ:1.02(3H,t,J=7.4),1.5-1.6(2H,m),1.74(3H,t,J=7.4),2.0-2.1(2H,m),3.44(2H,t,J=7.7),4.63(2H,q,J=7.4),7.5-7.6(3H,m),8.04(1H,s),8.3-8.4(2H,m).·实施例47的化合物1H-NMR(CDCl3)δ:1.04(3H,t,J=7.4),1.5-1.6(2H,m),1.61(3H,t,J=7.4),1.9-2.1(2H,m),3.44(2H,t,J=7.4),4.39(2H,q,J=7.4),7.4-7.6(3H,m),8.00(1H,s),8.4-8.5(2H,m).·实施例48的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.38(3H,t,J=6.9),1.4-1.6(2H,m),1.9-2.0(2H,m),3.34(2H,t,J=7.4),4.12(2H,q,J=6.9),7.09(2H,d,J=8.7),8.19(2H,d,J=8.7),8.41(1H,s).·实施例49的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=6.9),1.4-1.6(2H,m),1.8-2.0(2H,m),3.34(2H,t,J=7.4),5.20(2H,s),7.20(2H,d,J=8.9),7.3-7.5(5H,m),8.21(2H,d,J=8.9),8.41(1H,s).·实施例50的化合物1H-NMR(DMSO-d6)δ:0.99(3H,t,J=7.2),1.4-1.6(2H,m),1.8-2.0(2H,m),3.38(2H,t,J=7.7),7.3-7.6(3H,m),7.78(2H,d,J=8.2),7.89(2H,d,J=7.7),8.36(2H,d,J=7.7),8.43(1H,s).·实施例51的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=6.9),3.86(3H,s),3.90(3H,s),7.15(1H,d,J=8.2),7.78(1H,s),7.86(1H,d,J=8.2),8.41(1H,s).·实施例52的化合物1H-NMR(DMSO-d6)δ:0.96(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.1(2H,m),3.35(2H,t,J=7.4),7.65(1H,dd,J=2.0,8.4),7.86(1H,d,J=2.0),8.15(1H,d,J=8.4),8.45(1H,s).·实施例53的化合物1H-NMR(DMSO-d6)δ:0.95(3H,t,J=7.4),1.5-1.6(2H,m),1.8-2.0(2H,m),3.28(2H,t,J=7.4),3.72(3H,s),3.73(3H,s),4.18(2H,s),6.89(2H,s),7.01(1H,s),8.37(1H,s).·实施例54的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.15(6H,t,J=6.9),1.4-1.6(2H,m),1.9-2.0(2H,m),3.33(2H,t,J=7.4),3.42(4H,q,J=6.9),6.80(2H,d,J=8.9),8.06(2H,d,J=8.9),8.38(1H,s).·实施例55的化合物1H-NMR(DMSO-d6)δ:0.97(3H,t,J=6.9),1.20(3H,t,J=6.9),1.4-1.5(2H,m),1.8-2.0(2H,m),3.0-3.2(2H,m),3.32(2H,t,J=7.9),6.13(1H,brs),6.69(2H,d,J=7.4),8.00(2H,d,J=7.4),8.38(1H,s),13.5-13.9(1H,brs).·实施例56的化合物1H-NMR(DMSO-d6)δ:0.9-1.0(6H,m),1.4-1.6(4H,m),1.7-1.8(2H,m),1.8-2.0(2H,m),3.35(2H,t,J=7.4),4.07(2H,t,J=6.4),7.11(2H,d,J=8.9),8.20(2H,d,J=8.9),8.40(1H,s),13.5-14.0(1H,brs).·实施例57的化合物1H-NMR(DMSO-d6)δ:0.91(3H,t,J=6.9),0.98(3H,t,J=7.4),1.3-1.6(6H,m),1.7-1.8(2H,m),1.8-2.0(2H,m),3.34(2H,t,J=7.4),4.05(2H,t,J=6.4),7.10(2H,d,J=8.9),8.19(2H,d,J=8.9),8.41(1H,s),13.5-14.0(1H,brs).·实施例58的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.4),7.58(2H,d,J=8.6),8.39(2H,d,J=8.6),8.44(1H,s),13.6-14.0(1H,brs).·实施例59的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.8-2.0(2H,m),3.33(2H,t,J=7.7),7.92(2H,d,J=7.9),8.43(1H,s),8.44(2H,d,J=7.9).·实施例60的化合物1H-NMR(DMSO-d6)δ:0.95(3H,t,J=7.2),1.3-1.5(2H,m),1.8-2.0(2H,m),3.30(2H,t,J=7.7),4.80(4H,s),6.85(2H,d,J=8.4),7.2-7.4(10H,m),8.00(2H,d,J=8.4),8.37(1H,s).·实施例61的化合物1H-NMR(DMSO-d6)δ:0.97(3H,t,J=7.2),1.3-1.5(2H,m),1.8-2.0(2H,m),3.31(2H,t,J=7.4),4.37(2H,d,J=5.9),6.74(2H,d,J=8.7),6.82(1H,t,J=5.9),7.2-7.4(5H,m),7.98(2H,d,J=8.7),8.38(1H,s),13.5-14.0(1H,brs).·实施例62的化合物1H-NMR(DMSO-d6)δ:0.97(3H,t,J=7.2),1.4-1.6(2H,m),1.8-2.0(2H,m),3.35(2H,t,J=7.4),7.0-7.3(5H,m),7.46(2H,t,J=7.4),8.27(2H,d,J=7.7),8.42(1H,s).·实施例63的化合物1H-NMR(DMSO-d6)δ:0.97(3H,t,J=7.4),1.4-1.6(2H,m),1.8-2.0(2H,m),2.76(3H,d,J=5.0),3.32(2H,t,J=7.4),6.22(1H,d,J=5.0),6.68(2H,d,J=8.4),8.02(2H,d,J=8.4),8.38(1H,s),13.5-14.0(1H,brs).·实施例64的化合物1H-NMR(DMSO-d6)δ:1.00(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.40(2H,t,J=7.7),7.5-7.7(2H,m),8.0-8.1(1H,m),8.10(1H,d,J=8.4),8.1-8.2(1H,m),8.37(1H,d,J=8.4),8.44(1H,s),8.88(1H,s).·实施例65的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.1-1.2(6H,m),1.4-1.6(2H,m),1.9-2.0(2H,m),3.2-3.4(4H,m),3.9-4.1(4H,m),7.48(2H,d,J=7.9),8.22(2H,d,J=7.9),8.43(1H,s),13.6-14.0(1H,brs).·实施例66的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),2.56(3H,s),3.35(2H,t,J=7.4),7.44(2H,d,J=8.7),8.19(2H,d,J=8.7),8.41(1H,s).·实施例67的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.24(3H,t,J=7.4),1.4-1.6(2H,m),1.9-2.0(2H,m),2.70(2H,q,J=7.4),3.35(2H,t,J=7.9),7.41(2H,d,J=7.9),8.19(2H,d,J=7.9),8.42(1H,s).·实施例68的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.4),1.26(6H,d,J=6.9),1.4-1.6(2H,m),1.9-2.0(2H,m),2.99(1H,quint.,J=6.9),3.36(2H,t,J=7.4),7.44(2H,d,J=7.9),8.20(2H,d,J=7.9),8.42(1H,s).·实施例69的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.35(9H,s),1.4-1.5(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=7.7),7.60(2H,d,J=8.2),8.21(2H,d,J=8.2),8.42(1H,s).·实施例70的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=6.9),1.4-1.6(2H,m),1.9-2.0(2H,m),3.35(2H,t,J=6.9),3.36(3H,s),4.51(2H,s),7.50(2H,d,J=8.4),8.25(2H,d,J=8.4),8.42(1H,s).·实施例71的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.38(2H,t,J=7.7),4.60(2H,s),4.64(2H,s),7.2-7.4(5H,m),7.56(2H,d,J=8.2),8.28(2H,d,J=8.2),8.42(1H,s),13.6-14.0(1H,brs).·实施例72的化合物1H-NMR(DMSO-d6)δ:0.98(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.36(2H,t,J=8.2),7.11(1H,dd,J=2.0,8.4),7.16(1H,d,J=2.0),8.16(1H,d,J=8.4),8.49(1H,s),11.49(1H,brs).·实施例73的化合物1H-NMR(DMSO-d6)δ:1.00(3H,t,J=7.2),1.4-1.6(2H,m),1.9-2.0(2H,m),3.42(2H,t,J=7.7),7.3-7.6(3H,m),7.79(1H,d,J=7.9),8.03(1H,d,J=8.7),8.50(1H,s),8.83(1H,s),11.14(1H.brs).13.7-14.1(1H,brs).实验例〔三唑并嘌呤衍生物(1)的腺苷A3受体亲和能试验〕
按照《分子药理学》Molecular Pharmacology,45,978(1994)记载的方法,进行腺苷A3受体亲和能试验。
也就是说,在pH7.7的Tris-盐酸缓冲液中,按照常规方法分离用编码腺苷A3受体的质粒转化的人肾脏内皮细胞HEK-293的细胞膜,用125I标记的N6-(4-氨基苯甲基)-9-〔5-(甲基羰基)-β-D-呋喃核糖基〕腺嘌呤(AB-MECA)对其进行处理,制备该化合物结合的细胞膜。
其次,把该细胞膜与供试化合物共温育,测定游离出的〔125I〕AB-MECA的量。而且,根据供试化合物在各种浓度下的测定值,以50%〔125I〕AB-MECA游离时的供试化合物浓度作为IC50。
另外,按照《药理学进展》Archives of Pharmacology,336,204(1987)以及《药理学与实验治疗学杂志》The Journal ofPharmacology and Experimental Therapeutics,251(3),888(1989)记载的方法测定供试化合物的腺苷A1受体亲和能以及腺苷A2受体亲和能,以IC50进行评价。
测定结果如下表所示。
表16
实施例No. | 受体亲和能(IC50)(nM) | ||
腺苷A1 | 腺苷A2 | 腺苷A3 | |
1234567912131517181920212223252627283435 | 101N.D.2.6×10322178————1×103228421.3×1036.49321———————————————— | 551N.D.3×1037118424758182.5×10389920872323546312.6×10336111556671.6×103188205111 | 2.196951以下1以下1以下1.81以下1以下1.21以下1.11以下1.57.41以下1以下1以下1.11以下1以下1以下1以下1以下 |
表17
实施例No. | 受体亲和能(IC30)(nM) | ||
腺苷A1 | 腺苷A2 | 腺苷A3 | |
363742454849505154585960616263646566676869 | —————————————————————————————————————————— | 7.8×1033.7×1031×104以上1×104以上3.8×1031×104以上1×104以上1×104以上1×104以上1×104以上1×104以上1×104以上1.8×1031×104以上2.4×1037161×104以上1×104以上1.8×1031×104以上1×104以上 | 2.29.01以下1以下1以下1.75.01.67.85.81以下151以下6.61.01以下3.73.35.45.11.2 |
由表可知本发明化合物对腺苷A3受体具有亲和性,其选择性也较高。制剂例1(片剂的制备)
按照以下配方,制备每片含有300mg实施例1制得的化合物(5-甲基-8-苯基-1H-1,2,4-三唑并〔5,1-i〕嘌呤)作为有效成分的片剂(2000片)。
实施例1制得的化合物 600g
乳糖(日本药典品) 67g
玉米淀粉(日本药典品) 33g
羧甲基纤维素钙(日本药典品) 25g
甲基纤维素(日本药典品) 12g
硬脂酸镁(日本药典品) 3g
也就是说,按照上述配方,将实施例1得到的化合物、乳糖、玉米淀粉和羧甲基纤维素钙充分混合,用甲基纤维素水溶液将混合物造粒,过24目筛,将其与硬脂酸镁混合,压片,得到所需片剂。制剂例2(胶囊剂的制备)
按照以下配方,制备每1粒胶囊含有200mg实施例12制得的化合物(5-正丁基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤)作为有效成分的硬明胶胶囊(2000粒胶囊)。
实施例12制得的化合物 400g
结晶纤维素(日本药典品) 60g
玉米淀粉(日本药典品) 34g
滑石粉(日本药典品) 4g
硬脂酸镁(日本药典品) 2g
也就是说,按照上述配方,将各成分粉碎成很细的粉末,混合制成均一的混合物后,填充在具有所需大小的口服给药用明胶胶囊中,得到所需胶囊剂。
Claims (10)
3、如权利要求2所述的三唑并嘌呤衍生物,上述R2是吡啶基、呋喃基、苯乙烯基、可选具有羟基作为取代基的萘基、可选具有选自低级烷基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、羟基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基。
4、如权利要求3所述的三唑并嘌呤衍生物,是选自下述(I)、(II)和(III)中的化合物,
(I)R1是烷基或低级烷基取代的苯基,R2是苯基的化合物
(II)R1是正丁基,R2是吡啶基、呋喃基、苯乙烯基、可选具有羟基作为取代基的萘基、可选具有选自低级烷基、N-低级烷氨基、N,N-二低级烷氨基、N-苯基低级烷氨基、N,N-二苯基低级烷基氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基、羟基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基的化合物
(III)R1是苯基,R2是具有3个低级烷氧基的苯基的化合物。
5、如权利要求4所述的三唑并嘌呤衍生物,是选自下述(i)或(ii)的化合物,
(i)R1是低级烷基,R2是苯基的化合物
(ii)R1是正丁基,R2是可选具有羟基作为取代基的萘基、具有选自低级烷基、N,N-二低级烷氨基、N-苯基低级烷氨基、苯基、苯氧基、苯基低级烷氧基、卤代低级烷基、卤代低级烷氧基、二低级烷基磷酰基甲基、低级烷硫基和卤素原子中的1个基团作为取代基的苯基、被羟基和卤素原子取代的苯基或具有1~3个低级烷氧基作为取代基的苯基的化合物。
6、如权利要求5所述的三唑并嘌呤衍生物,选自5-正丁基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-氯苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-甲氧基苯基)-1H-1,2,4-三唑〔5,1-i〕嘌呤、5-正丁基-8-〔4-(N,N-二甲氨基)苯基〕-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-丙氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-乙氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、8-(4-联苯基)-5-正丁基-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(4-三氟甲基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤和5-正戊基-8-苯基-1H-1,2,4-三唑并〔5,1-i〕嘌呤。
7、如权利要求6所述的三唑并嘌呤衍生物,选自5-正丁基-8-(4-甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤、5-正丁基-8-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑并〔5,1-i〕嘌呤和8-(4-联苯基)-5-正丁基-1H-1,2,4-三唑并〔5,1-i〕嘌呤。
8、含有权利要求1至7中任意一项所述的三唑并嘌呤衍生物和制剂学允许的载体的药物组合物。
9、如权利要求8所述的药物组合物,其用作腺苷A3受体亲和剂。
10、如权利要求8所述的药物组合物,其用作哮喘治疗剂。
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EP (1) | EP1069126B1 (zh) |
JP (1) | JP4077155B2 (zh) |
KR (1) | KR100513062B1 (zh) |
CN (1) | CN1122033C (zh) |
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DE (1) | DE69908335T2 (zh) |
ES (1) | ES2195545T3 (zh) |
NO (1) | NO317709B1 (zh) |
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CA2385865A1 (en) | 1999-09-28 | 2001-04-05 | Takashi Okamura | Triazolopurine derivatives, pharmaceutical compositions containing the derivatives, and adenosine a3 receptor affinitive agents |
CN1491227A (zh) * | 2001-02-05 | 2004-04-21 | 株式会社大V制药工厂 | 三唑并喹唑啉和吡唑并三唑并嘧啶衍生物、医药组合物、腺苷 a 3受体亲和剂、降眼压剂、预防和治疗青光眼的制剂及降低眼压的方法 |
AR037243A1 (es) | 2001-10-15 | 2004-11-03 | Schering Corp | Antagonistas del receptor de adenosina a2a,a5-amino-imidazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pirimidina, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento |
WO2011010306A1 (en) | 2009-07-21 | 2011-01-27 | Ramot At Tel-Aviv University Ltd. | A3 adenosine receptor ligands for modulation of pigmentation |
IL275817B2 (en) * | 2018-01-04 | 2024-04-01 | Impetis Biosciences Ltd | Tricyclic compounds, preparations and their medical applications |
US11718622B2 (en) | 2020-03-16 | 2023-08-08 | Exelixis Inc. | Heterocyclic adenosine receptor antagonists |
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AU612331B2 (en) * | 1986-09-30 | 1991-07-11 | Ciba-Geigy Ag | 2-substituted-e-fused-(1,2,4)triazolo(1,5-c)pyrimidines pharmaceutical compositions |
IT1277392B1 (it) * | 1995-07-28 | 1997-11-10 | Schering Plough S P A | Analoghi eterociclici di 1,2,4-triazolo(1,5-c]pirimidine ad attivita' antagonista per il recettore a2a dell'adenosina |
WO1998015555A1 (fr) * | 1996-10-07 | 1998-04-16 | Kyowa Hakko Kogyo Co., Ltd. | Derives de purine fondue |
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- 1999-03-26 AT AT99909349T patent/ATE241629T1/de not_active IP Right Cessation
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Publication number | Publication date |
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NO317709B1 (no) | 2004-12-06 |
WO1999051606A1 (fr) | 1999-10-14 |
EP1069126B1 (en) | 2003-05-28 |
TW553945B (en) | 2003-09-21 |
CA2326716A1 (en) | 1999-10-14 |
JP4077155B2 (ja) | 2008-04-16 |
KR100513062B1 (ko) | 2005-09-05 |
CA2326716C (en) | 2006-12-12 |
DE69908335D1 (de) | 2003-07-03 |
NO20004953D0 (no) | 2000-10-02 |
CN1301266A (zh) | 2001-06-27 |
ES2195545T3 (es) | 2003-12-01 |
EP1069126A4 (en) | 2002-03-27 |
NO20004953L (no) | 2000-11-28 |
KR20010042240A (ko) | 2001-05-25 |
ATE241629T1 (de) | 2003-06-15 |
AU2856899A (en) | 1999-10-25 |
EP1069126A1 (en) | 2001-01-17 |
DE69908335T2 (de) | 2004-04-29 |
US6288070B1 (en) | 2001-09-11 |
AU760399B2 (en) | 2003-05-15 |
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