Patent ID: 6083915
Filing Date: 2000-07-04
Classification: A61K,A61P,Y02A,Y10S

Abstract:
The method for treating hepatoma in a mammalian subject, which method includes administering to said subject a composition comprising a therapeutically effective amount of a bombesin analog of the formula: ##STR17## wherein A.sup.0 is Gly, a D- or L-isomer selected from the group consisting of pGlu, Nle, .alpha.-aminobutyric acid, Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X is H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, .beta.-Nal, and Cys, or is deleted;A.sup.1 is a D- or L-isomer selected from the group consisting of pGlu, Nle, .alpha.-aminobutyric acid, Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X is He F, Cl, Br, NO.sub.2, OH, or CH.sub.3) Asp, Glu, F.sub.5 -Phe, Trp, .beta.-Nal, Cys, and Lys, or deleted;A.sup.2 is Gly, a D- or L-isomer selected from the group consisting of pGlu, Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X is Hs Fe Cl, Br, NO.sub.2, OH, or CH.sub.3) Trp, .beta.-Nal, Asp, Glu, His, 1-methyl-His, 3-methyl-His, Cys, and Lys, or deleted;A.sup.3 is a D- or L-isomer selected from the group consisting of p-X-Phe (where X is H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), .beta.-Nal, and Trp;A.sup.4 is Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, .alpha.-aminobutyric acid, p-X-phe (where X is H. F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, or .beta.-Nal;A.sup.5 is Gln, Asn, Gly, Ala, Leu, Ile, Nle, .alpha.-aminobutyric acid, Val, p-X-Phe (where X is He F, Cl, Br, NO.sub.2, OH, or CH.sup.3), Trp, Thr, or .beta.-Nal;A.sup.6 is Sar, Gly, a D-isomer selected from the group consisting of Ala, N-methyl-Ala, Val, Gln, Asn, Leu, Ile, p-X-Phe (where X is H, Fe Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, Cys, and .beta.-Nal, or deleted;A.sup.7 is 1-methyl-His, 3-methyl-His, His, Lys, Asp, or Glu;A.sup.8 is Leu, Ile, Val, Nle, .alpha.-aminobutyric acid, Trp, Thr, .beta.-Nal, Lys, Asp, Glu, or Cys;A.sup.9 is L-isomer of any of Met, Met-oxide, Leu, Ile, Nle, .alpha.-aminobutyric acid, p-X-Phe (where X is H, F, Cl, Br, NO.sub.2, OH, or CH.sub.3), Trp, .beta.-Nal, CHxAla, Cys, or deleted;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 alkynyl, phenyl, naphthyl, or C.sub.7-10 phenylalkyl), or C.sub.1 -C.sub.12 acyl, and R.sub.1 and R.sub.2 are bonded to the nitrogen adjacent to the .varies.-carbon of the N-terminal amino acid residue of the analog; provided that when one of R.sub.1 or R.sub.2 is COE.sub.1, the other must be H; and R.sub.3 is OH, NH.sub.2, C.sub.1-12 alkoxy, C.sub.7-10 phenylalkoxy, or C.sub.3-20 naphthylalkoxy and is bonded to the .varies.-carbonyl carbon of the C-terminal amino acid residue of the analog;provided that, if A.sup.0 is present, A.sup.1 cannot be pGlu; and, 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, one of R.sup.1 and R.sup.2 must be H; further provided that, where A.sup.0 is deleted and A.sup.1 is not pGlu, .varies.-amino group of A.sup.1 can be coupled with .varies.-carboxyl group of A.sup.9 through an amide bridge, or where A.sup.0 and A.sup.1 are deleted and A.sup.2 is not PGlu, .varies.-amino group of A.sup.2 can be coupled with .varies.-carboxyl group of A.sup.9 through an amide bridge, or where A.sup.0, Al.sup.1, and A.sup.2 are deleted, .varies.-amino group of A.sup.3 can be coupled with .varies.-carboxyl group of A.sup.9 through an amide bridge; further provided that both terminal residues cannot be Asp or Glu and Lys, respectively, and that side chain carboxyl group of Asp or Glu can be coupled with .epsilon.-amino group of Lys through an amide bridge; further provided that either one of A.sup.1 or A.sup.2 can be Cys and coupled with one of A.sup.8 or A.sup.9 through a disulfide bridge, where one of A.sup.8 or A.sup.9 is cys; and further provided that where A.sup.0 and A.sup.1 are deleted and A.sup.6 is D-Ala, A.sup.8 --A.sup.9 --R.sub.3 cannot be Leu-Met-NH.sub.2 or a pharmaceutically acceptable salt thereof.