Patent ID: 6307017
Filing Date: 2001-10-23
Classification: A61K,C07K

Abstract:
A therapeutic peptide comprising between seven and ten amino acid residues, inclusive, said peptide being an analog of one of tLe following naturally occurring peptides terminating at the carboxy-terminus with a Met residue: (a) litoein; (b) the ten amino acid carboxy-terminal region of mammalian gastrin releasing peptide; and (c) the ten amino acid carboxy-terminal region of amphibian bombesin; said therapeutic peptide being of the formula: ##STR14##whereinA.sup.0 =Gly, Nle, .alpha.-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, or .beta.-Nal, or is deleted;A.sup.1 =the D or L-isomer of any of pGlu, Nle, or .alpha.-aminobutyric acid, or the D-isomer of any of Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), F.sub.5 -Phe, Trp, Cys, or B-Nal, or is deleted;A.sup.2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Ci, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, .beta.-Nal, His, 1-methyl-His, or 3-methyl-His;A.sup.4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, or .beta.-Nal;A.sup.5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, .alpha.-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Ci, Br, OH, H or CH.sub.3), Trp, Thr, or .beta.-Nal;A.sup.6 =Sar, Gly, or the D-isomer of any of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO.sub.2, OH, H or CH.sub.3), Trp, Cys, or .beta.-Nal;A.sup.7 =1-methyl-His, 3-methyl-His, or His; provided that, if A.sup.0 is present, A.sup.1 cannot be pGlu; further provided that, if A.sup.0 or A.sup.1 is present, A.sup.2 cannot be pGlu; further provided that, when A.sup.0 is deleted and A.sup.1 is pGlu, R.sub.1 must be H and R.sub.2 must be the portion of Glu that forms the imine ring in pGlu; and further provided that, W can be any one of the following: ##STR15##wherein R.sub.3 is CHR.sub.20 --(CH.sub.2).sub.n1 (where R.sub.20 is either of H or OH; and. n.sub.1 is either of 1 or 0), or is deleted, and Z.sub.1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, Gln, p-X-Phe (where X=H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), F.sub.5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or .beta.-nal; and V is either OR.sub.4, or ##STR16##where R.sub.4 is any of C.sub.1-20 alkyl, C.sub.3-20 alkenyl, C.sub.3-20 alkinyl, phenyl, naphthyl, or C.sub.7-10 phenylalkyl, and each R.sub.5, and R.sub.6, independently, is any of H, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl, lower acyl, or, ##STR17##where R.sub.22 is any of H, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl, or lower acyl; provided that, when one of R.sub.5 or R.sub.6 is --NHR.sub.22, the other is H; ##STR18##wherein Z.sub.1 is the identifying group of any one of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, .beta.-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO.sub.2, OH or CH.sub.3), F.sub.5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z.sub.2, Z.sub.3, and Z.sub.4, independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or ##STR19##wherein each Z.sub.20 and Z.sub.30, independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z.sub.20 or Z.sub.30 is other than H, A.sup.7 is His, A.sup.6 is Gly, A.sup.5 is Val, A.sup.4 is Ala, A.sup.2 is His, and either of R.sub.1 or R.sub.2 is other than H, A.sup.1 must be other than deleted; further provided that, for the formulas (I) through (III) any asymmetric carbon atom can be R, S or a racemic mixture; and further provided that each R.sub.1 and R.sub.2, independently, is H, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl, COE.sub.1 (where E.sub.1 is C.sub.1-20 alkyl, C.sub.3-20 alkenyl, C.sub.3-20 alkinyl, phenyl, naphthyl, or C.sub.7-10 phenylalkyl), or lower acyl, and R.sub.1 and R.sub.2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R.sub.1 or R.sub.2 is COE.sub.1, the other must be H, or a pharmaceutically acceptable salt thereof.