Patent ID: 6242563
Filing Date: 2001-06-05
Classification: A61K,C07K

Abstract:
A peptide of formula (I),(R.sup.1 R.sup.2)A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -A.sup.10 -A.sup.11-A.sup.12 -A.sup.13 -A.sup.14 -A.sup.15 -A.sup.16 -A.sup.17 -A.sup.18 -A.sup.19 -A.sup.20 -A.sup.21 -A.sup.22-A.sup.23 -A.sup.24 -A.sup.25 -A.sup.26 -A.sup.27 -A.sup.28 -A.sup.29 -A.sup.30 -A.sup.31 -A.sup.32 -A.sup.33 -A.sup.34-A.sup.35 -A.sup.36 -A.sup.37 -A.sup.38 -R.sup.3 (I)or a pharmaceutically acceptable salt thereof, wherein,A.sup.1 is His or Pal;A.sup.2 is Ser, Thr or hSer;A.sup.3 is Asp or Glu;A.sup.4 is Gly, .beta.-Ala, Gaba, Ava, Aib, Acc or HN--(CH.sub.2).sub.m --C(O);A.sup.5 is Ile, Leu, Cha, Nle, Val, Tle, Abu, Aib, Acc or Nva;A.sup.6 is Phe, p-X-Phe, .beta.-Nal, Cha, Tyr, Trp, Acc or Aib;A.sup.7 is Thr, Ser or Val;A.sup.8 is Asp or Glu;A.sup.9 is Ser, Thr or hSer;A.sup.10 is Tyr, p-X-Phe, Phe, Amp, .beta.-Nal, Trp or Acc;A.sup.11 is Ser, Thr or hSer; A.sup.12, A.sup.14 and A.sup.15 are each independently selected from the group consisting of Arg, Lys, Orn, hArg and HN--CH((CH.sub.2).sub.n --NH--R.sup.4)--C--(O);A.sup.13 is Tyr, p-X-Phe, Phe, Amp, .beta.-Nal, Trp or Acc;A.sup.16 is Gln, Glu, Asp or Asn;A.sup.17 is Met, Leu, Nle, Abu, Tle, Val, Ile, Cha, Ala, Aib, Acc or Nva;A.sup.18 is Ala, Aib or Acc;A.sup.19 is Val, Leu, Ile, Ala, Abu, Tle, Cha, Aib, Acc, Nle or Nva;A.sup.20, A.sup.21, A.sup.29, A.sup.30, A.sup.32, A.sup.34, A.sup.36 and A.sup.38 are each independently selected from the group consisting of Lys, Arg, Orn, hArg and HN--CH((CH.sub.2).sub.n --NH--R.sup.4)--C(O) or is deleted;A.sup.22 is Tyr, p-X-Phe, Phe, Amp, .beta.-Nal, Trp, Acc or is deleted;A.sup.23 is Leu, Ile, Nle, Tle, Met, Val, Ala, Aib, Acc, Cha, Phe, p-X-Phe, Abu, Nva or is deleted;A.sup.24 is Ala, Aib, Val, Abu, Acc, Ile, Leu, Nle, Tle, Nva or is deleted;A.sup.25 is Ala, Glu, Aib, Val, Abu, Acc, Ile, Leu, Nle, Nva, Tle or is deleted;A.sup.26 is Val, Leu, Ile, Ala, Abu, Tle, Cha, Aib, Acc, Nva, Nle or is deleted;A.sup.27 is Leu, Ile, Nle, Tle, Met, Val, Ala, Aib, Acc, Nva, Cha, Phe, p-X-Phe, Abu or is deleted;A.sup.28 is Gly, Aib, Acc, .beta.-Ala, Gaba, Ava, HN--(CH.sub.2).sub.m --C(O) or is deleted;A.sup.31 is Tyr, p-X-Phe, Phe, Amp, .beta.-Nal, Trp, Acc or is deleted;A.sup.33 is Gln, Asn, Glu, Asp or is deleted;A.sup.35 is Val, Leu, Ile, Ala, Abu, Tle, Cha, Aib, Nva, Acc, Nle or is deleted;A.sup.37 is Asn, Gln, Asp, Glu, Ala, Aib, Acc or is deleted;R.sup.1 and R.sup.2 are each independently selected from the group consisting of H, (C.sub.1 -C.sub.30)alkyl, (C.sub.2 -C.sub.30)alkenyl, phenyl-(C.sub.1 -C.sub.30)alkyl, naphthyl-(C.sub.1 -C.sub.30)alkyl, hydroxy-(C.sub.1 -C.sub.30)alkyl, hydroxy(C.sub.2 -C.sub.30)alkenyl, hydroxy-phenyl-(C.sub.1 -C.sub.30)alkyl or hydroxy-naphthyl-(C.sub.1 -C.sub.30)alkyl; or one of R.sup.1 or R.sup.2 is COX.sup.2 where X.sup.2 is (C.sub.1 -C.sub.30)alkyl, (C.sub.2 -C.sub.30)alkenyl, phenyl-(C.sub.1 -C.sub.30)alkyl, naphthyl-(C.sub.1 -C.sub.30)alkyl, hydroxy-(C.sub.1 -C.sub.30)alkyl, hydroxy-(C.sub.2 -C.sub.30)alkenyl, hydroxy-phenyl-(C.sub.1 -C.sub.30)alkyl or hydroxy-naphthyl-(C.sub.1 -C.sub.30)alkyl;R.sup.3 is OH, NH.sub.2, (C.sub.1 -C.sub.30)alkoxy or NH--Y--CH.sub.2 --Z, where Y is a (C.sub.1 -C.sub.30) hydrocarbon moiety and Z is CO.sub.2 H or CONH.sub.2 ;where X for each occurrence is independently selected from the group consisting of OH, OCH.sub.3, F, Cl, Br and CH.sub.3 ;m for each occurrence is independently an integer from 5-10;n for each occurrence is independently an integer from 1-5; andR.sup.4 for each occurrence is independently (C.sub.1 -C.sub.30)alkyl, (C.sub.1 -C.sub.30)acyl or --C((NH)(NH.sub.2));provided that the peptide of formula (I) is not:(R.sup.1 R.sup.2)PACAP(1-27 to 1-38)-X where X is OH or NH.sub.2, R.sup.1 is H and R.sup.2 is H or (C.sub.1 -C.sub.18)acyl;(R.sup.1 R.sup.2)(Nle.sup.17)PACAP(1-27 to 1-38)-NH.sub.2, where R.sup.1 is H and R.sup.2 is (C.sub.10 -C.sub.18)acyl;PACAP(1-23 to 1-26)-X, where X is OH or NH.sub.2 ; or(Y)-PACAP(1-27 to 1-38)-X where X is OH or NH.sub.2 and Y is one or more amino acid substitutions selected from the group consisting of Glu.sup.3, Glu.sup.8, Thr.sup.11 and Nle.sup.17.