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    • 28. 发明授权
    • Conformationally constrained LH-RH analogues, their uses and
pharmaceutical compositions containing them
    • 构象约束的LH-RH类似物,其用途和含有它们的药物组合物
    • US6153587A
    • 2000-11-28
    • US317125
    • 1999-05-24
    • Remi DelansorneJacques Paris
    • Remi DelansorneJacques Paris
    • A61K45/00A61K38/00A61K38/09A61P15/10A61P35/00C07K7/23
    • C07K7/23A61K38/00Y10S930/13
    • LH-RH analogues with excellent affinity for LH-RH receptors, of the formula A.sub.1 -A.sub.2 -W-A.sub.3 -A.sub.4 -SPL-A.sub.5 -A.sub.6 -Pro-Z(I) in which:-A.sub.1 is pGlu, AcSar or an aromatic D-amino acid;-A.sub.2 is a direct bond, His, DPhe, DpFPhe or DpClPhe;*W is an aromatic L- or D-amino acid;-A.sub.3 is Ala, Thr, Ser, DSer, Ser(OBzl) or MeSer;-A.sub.4 is Tyr, Phe, cPzACAla, L- or D-PicLys, L- or D-NicLys or L- or D-IprLys;*SPL is the spirolactam of formula: ##STR1## -A.sub.5 is an amino acid with a (C.sub.1 -C.sub.8)alkyl or (C.sub.3-C.sub.6)cycloalkyl side chain;-A.sub.6 is L- or D-(Arg, HArg, Lys, HLys, Orn, Cit, HCit or Aph), where L- or D-(Arg and HArg) can be substituted by one or two (C.sub.1 -C.sub.4)alkyl groups and L- or D-(Lys, HLys, Orn and Aph) can be substituted by an isopropyl, nicotinoyl or picolinoyl group; and*Z is GlyNH.sub.2, DAlaNH.sub.2, AzaGlyNH.sub.2 or --NHR.sub.1 where R.sub.1 is a (C.sub.1 -C.sub.4)alkyl optionally substituted by a hydroxy or one or several fluorine atoms, a (C.sub.3 -C.sub.6)cycloalkyl or a heterocyclic radical selected from the group consisting of morpholinyl, pyrrolidinyl and piperidyl;or its pharmaceutically acceptable salts.
    • 式A1-A2-W-A3-A4-SPL-A5-A6-Pro-Z(I)的LH-RH受体具有优异亲和力的LH-RH类似物,其中:-A1是pGlu,AcSar或芳香族 D-氨基酸; -A2是直接键,His,DPhe,DpFPhe或DpClPhe; * W是芳族L-或D-氨基酸; -A3是Ala,Thr,Ser,DSer,Ser(OBzl)或MeSer; -A4是Tyr,Phe,cPzACAla,L或D-PicLys,L或D-NicLys或L或D-IprLys; * SPL是下式的螺内酰胺:-A5是具有(C1-C8)烷基或(C3-C6)环烷基侧链的氨基酸; -A6是L-或D-(Arg,HArg,Lys,HLys,Orn,Cit,HCit或Aph),其中L-或D-(Arg和HArg)可被一个或两个(C 1 -C 4)烷基取代 基团和L-或D-(Lys,HLys,Orn和Aph)可以被异丙基,烟酰基或吡啶酰基取代; 和* Z是GlyNH 2,DAla NH 2,Aza GlyNH 2或-NHR 1,其中R 1是任选被羟基或一个或多个氟原子取代的(C 1 -C 4)烷基,(C 3 -C 6)环烷基或选自以下的杂环基: 吗啉基,吡咯烷基和哌啶基; 或其药学上可接受的盐。