N-端修饰的葡萄糖依赖性促胰岛素多肽（GIP）类似物

摘要

本发明提供了一系列新的葡萄糖依赖性促胰岛素多肽化合物的类似物，包含所述化合物的药物组合物，及所述化合物作为GIP受体激动剂或拮抗剂用于治疗GIP受体介导的疾病例如非胰岛素依赖性糖尿病和肥胖中的用途。

主权项

通式(I)的化合物或其可药用盐，(R²R³)‑A¹‑A²‑A³‑A⁴‑A⁵‑A⁶‑A⁷‑A⁸‑A⁹‑A¹⁰‑A¹¹‑A¹²‑A¹³‑A¹⁴‑A¹⁵‑A¹⁶‑A¹⁷‑A¹⁸‑A¹⁹‑A²⁰‑A²¹‑A²²‑A²³‑A²⁴‑A²⁵‑A²⁶‑A²⁷‑A²⁸‑A²⁹‑A³⁰‑A³¹‑A³²‑A³³‑A³⁴‑A³⁵‑A³⁶‑A³⁷‑A³⁸‑A³⁹‑A⁴⁰‑A⁴¹‑A⁴²‑A⁴³‑R¹,           (I)其中：A¹是Cpa,His,4Hppa,2‑Pal,3‑Pal,4‑Pal,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,Taz,3Thi,7HO‑Tic,Tyr(Ac),Tyr(Me),β‑Tyr,3Br‑Tyr,3,5Br‑Tyr,3Cl‑Tyr,2F‑Tyr,3F‑Tyr,hTyr,3I‑Tyr,3,5I‑Tyr,αMe‑Tyr,2,6Me‑Tyr,3MeO‑Tyr,3NH₂‑Tyr,3NO₂‑Tyr,3OH‑Tyr,或3(HO‑CH₂)Tyr；A²是Ala,Abu,D‑Abu,Acc,Aib,β‑Ala,D‑Ala,Gaba,Gly,Ser,D‑Ser,Thr,D‑Thr,Val,或D‑Val；A³是Glu,Aib,Asp,N‑Me‑Asp,Dhp,Dmt,N‑Me‑Glu,3Hyp,4Hyp,4Ktp,Pro,hPro,Thz,或Tic；A⁴是Gly,Acc,Aib,或β‑Ala；A⁵是Thr,Acc,Aib,或Ser；A⁶是Phe,Acc,Aib,Aic,Cha,1Nal,2Nal,2‑Pal,3‑Pal,4‑Pal,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,或Trp；A⁷是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val；A⁸是Ser,Aib,或Thr；A⁹是Asp,Aib,或Glu；A¹⁰是Tyr,Acc,Cha,1Nal,2Nal,2‑Pal,3‑Pal,4‑Pal,Phe,或(X⁴,X⁵,X⁶,X⁷,X⁸)Phe；A¹¹是Ser,Acc,Aib,Nle,或Thr；A¹²是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val；A¹³是Ala,Acc,Aib,β‑Ala,D‑Ala,Gly,或Ser；A¹⁴是Met,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,Phe,Tle,或Val；A¹⁵是Asp,Aib,或Glu；A¹⁶是Lys,Amp,Apc,Arg,hArg,Orn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃)；A¹⁷是Ile,Abu,Acc,Aib,Ala,Cha,Leu,Nle,Phe,Tle,或Val；A¹⁸是His,Amp,Arg,2‑Pal,3‑Pal,4‑Pal,Phe,或Tyr；A¹⁹是Gln,Aib,或Asn；A²⁰是Gln,Aib,或Asn；A²¹是Asp,Aib,或Glu；A²²是Phe,Acc,Aib,Aic,Cha,1Nal,2Nal,2‑Pal,3‑Pal,4‑Pal,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,或Trp；A²³是Val,Abu,Acc,Aib,Ala,Cha,Ile,Leu,Nle,或Tle；A²⁴是Asn,Aib,或Gln；A²⁵是Trp,Acc,Aib,1Nal,2Nal,2‑Pal,3‑Pal,4‑Pal,Phe,或(X⁴,X⁵,X⁶,X⁷,X⁸)Phe；A²⁶是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,或Tle；A²⁷是Leu,Acc,Aib,Cha,Ile,Nle,Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,或Tle；A²⁸是Ala,Acc,或Aib；A²⁹是Gln,Aib,Asn,或缺失；A³⁰是Lys,Amp,Apc,Arg,hArg,Orn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³¹是Gly,Aib,Acc,β‑Ala,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³²是Lys,Amp,Apc,Arg,hArg,Orn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³³是Lys,Amp,Apc,Arg,hArg,Orn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁴是Asn,Aib,Gln,Ser,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁵是Asp,Aib,Glu,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁶是Trp,Acc,Aib,1Nal,2Nal,2‑Pal,3‑Pal,4‑Pal,Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁷是Lys,Amp,Apc,Arg,hArg,Orn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁸是His,Amp,2‑Pal,3‑Pal,4‑Pal,Phe,Tyr,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A³⁹是Asn,Aib,Gln,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A⁴⁰是Ile,Acc,Aib,Ser,Thr,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A⁴¹是Thr,Acc,Aib,Asn,Gln,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A⁴²是Gln,Acc,Aib,Asn,HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；A⁴³是Acc,Ado,Aib,Ala,Asn,Asp,His,Gln,Phe,Thr,Trp,Orn(N‑C(O)‑(CH₂)₁₀‑CH₃),HN‑CH((CH₂)_n‑N(R⁴R⁵))‑C(O),Cys(琥珀酰亚胺‑N‑烷基),hCys(琥珀酰亚胺‑N‑烷基),Pen(琥珀酰亚胺‑N‑烷基),Cys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_x‑C(O)‑NH‑(CH₂)_y‑CH₃),Cys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),hCys(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),Pen(琥珀酰亚胺‑N‑(CH₂)_s‑NH‑C(O)‑(CH₂)_t‑CH₃),或缺失；R¹是OH,NH₂,(C₁‑C₃₀)烷氧基,或NH‑X²‑CH₂‑Z⁰,其中X²是(C₀‑C₃₀)烃基，Z⁰是H,OH,CO₂H,或CONH₂；R²,R³,R⁴和R⁵各独立选自H,(C₁‑C₃₀)烷基,(C₁‑C₃₀)杂烷基,(C₁‑C₃₀)酰基,(C₂‑C₃₀)烯基,(C₂‑C₃₀)炔基,芳基(C₁‑C₃₀)烷基,芳基(C₁‑C₃₀)酰基,取代的(C₁‑C₃₀)烷基,取代的(C₁‑C₃₀)杂烷基,取代的(C₁‑C₃₀)酰基,取代的(C₂‑C₃₀)烯基,取代的(C₂‑C₃₀)炔基,取代的芳基(C₁‑C₃₀)烷基,和取代的芳基(C₁‑C₃₀)酰基；假设R²是(C₁‑C₃₀)酰基,芳基(C₁‑C₃₀)酰基,取代的(C₁‑C₃₀)酰基,或取代的芳基(C₁‑C₃₀)酰基,则R³是H,(C₁‑C₃₀)烷基,(C₁‑C₃₀)杂烷基,(C₂‑C₃₀)烯基,(C₂‑C₃₀)炔基,芳基(C₁‑C₃₀)烷基,取代的(C₁‑C₃₀)烷基,取代的(C₁‑C₃₀)杂烷基,取代的(C₂‑C₃₀)烯基,取代的(C₂‑C₃₀)炔基,或取代的芳基(C₁‑C₃₀)烷基；进一步假设R⁴是(C₁‑C₃₀)酰基,芳基(C₁‑C₃₀)酰基,取代的(C₁‑C₃₀)酰基,或取代的芳基(C₁‑C₃₀)酰基,则R⁵是H,(C₁‑C₃₀)烷基,(C₁‑C₃₀)杂烷基,(C₂‑C₃₀)烯基,(C₂‑C₃₀)炔基,芳基(C₁‑C₃₀)烷基,取代的(C₁‑C₃₀)烷基,取代的(C₁‑C₃₀)杂烷基,取代的(C₂‑C₃₀)烯基,取代的(C₂‑C₃₀)炔基,或取代的芳基(C₁‑C₃₀)烷基；n是各自独立的1至5包括端点的整数。s,t,x和y分别是各自独立的1至30包括端点的整数。X⁴,X⁵,X⁶,X⁷和X⁸分别是各自独立的H,F,CF₃,Cl,Br,I,(C_1‑10)烷基,取代的(C_1‑10)烷基,芳基,取代的芳基,OH,NH₂,‑CH₂NH₂,NO₂,或CN；假设A₁是4Hppa，则R₂和R₃是缺失；进一步假设化合物的1、2和3位的超过1个氨基酸是取代或修饰的；并进一步假设如果1位的氨基酸是修饰的，则其不具有下述修饰：(a)N‑端烷基化；(b)N‑端乙酰化；(c)N‑端酰化；(d)添加N‑端异丙基；或(e)添加N端焦谷氨酸。