| 摘要 |
The present invention deals with LHRH analogs which contain cytotoxic moieties, have influence on the release of gonadotropins from the pituitary in mammals (possess high agonistic or antagonistic activity) and have antineoplastic effect. The compounds of this invention are represented by Formula I: X-R1-R2-R3-Ser-R5-R6(Q)-Leu-Arg-Pro-R10-NH2, wherein R1 is pGlu or D-Nal(2), R2 is His or D-Phe(4Cl), R3 is Trp, D-Trp or D-Pal(3), R5 is Tyr or Arg, R6 is D-Lys or D-Orn, R10 is Gly or D-Ala, X is hydrogen or a lower alkanoyl group of 2-5 carbon atoms, Q is a cytotoxic moiety having the formula -Q4 or -A(Q3) or -B(Q1)2 or -B(AQ2)2, wherein A is -NH-(CH2)n-CO- or -OC-(CH2)n-CO- where n is 2-6, B is -NH-CH2-(CH2)m-CH(NH)-(CH2)n-CO- where m is 0 or 1, n is 0 or 1, the -CO moiety of A- and of B- being bonded to an amino group on R6, and in the group B(AQ2)2, the -CO moiety of A- and of B- being bonded to the episilon or delta amino group of R6 when R6 is Lys or Orn respectively, and in the group B(AQ2)2, the -CO moiety of A being bonded to an amino group on B, Q1 is D or L-Mel, cyclopropanealkanoyl, aziridine-2-carbonyl, epoxyalkyl or 1,4-naphthoquinone-5-oxy-carbonyl-ethyl, Q2 is Q1, 2-anthraquinonyl-methylenoxy or doxorubicinyl, Q3 is Q2, mitomicinyl, esperamycinyl or methotrexoyl, Q4 is Q1 or methotrexoyl and pharmaceutically acceptable salts thereof and methods of use pertaining these compounds.
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