US2005026827A1PendingUtilityA1
Octapeptide bombesin analogs
Est. expirySep 24, 2007(expired)· nominal 20-yr term from priority
C07K 14/57572C07K 7/02C07K 7/086C07K 7/18A61K 38/00C07K 14/685
65
PatentIndex Score
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Claims
Abstract
A linear (i.e., non-cyclic) analog of biologically active amphibian bombesin, mammalian gastrin-releasing peptide (GRP), or mammalian growth hormone releasing factor (GRF), having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell. Cleavage of a peptide bond in the active site of naturally occurring bombesin, GRP, or GRF is unnecessary for in vivo biological activity. The analog has one of the following modifications: (a) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, (b) a replacement of two amino acid residues within the active site with a synthetic amino acid, a β-amino acid, or a γ-amino acid residue, or (c) a non-peptide bond. instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue.
Claims
exact text as granted — not AI-modified1 - 8 . (canceled)
9 . A method of inhibiting tumor growth which comprises administering to a patient in need thereof an effective amount of a therapeutic peptide of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
10 . The method of claim 9 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
11 . The method of claim 10 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
12 . The method of claim 10 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
13 . The method of claim 10 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
14 . The method of claim 9 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
15 . The therapeutic peptide of claim 14 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
16 . The therapeutic peptide of claim 10 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
17 . The method of claim 9 wherein said tumor is located in the gastrointestinal tract, pancreas, colon, prostrate or breast.
18 . The method of claim 9 wherein said tumor is a small-cell lung carcinoma.
19 . The method of claim 9 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
20 . The method of claim 9 wherein said effective amount is 250 mg/patient/day.
21 . A method of inhibiting pancreatic adenocarcinomas which comprises administering to a patient in need thereof an effective amount of a therapeutic compound of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
22 . The method of claim 21 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
23 . The method of claim 22 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
24 . The method of claim 22 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
25 . The method of claim 22 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
26 . The method of claim 21 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
27 . The therapeutic peptide of claim 26 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
28 . The therapeutic peptide of claim 22 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
29 . The method of claim 21 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
30 . The method of claim 21 wherein said effective amount is 250 mg/patient/day.
31 . A method of inhibiting gastric acid secretion which comprises administering to a patient in need thereof an effective amount of a therapeutic compound of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
32 . The method of claim 31 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
33 . The method of claim 32 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
34 . The method of claim 32 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
35 . The method of claim 32 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
36 . The method of claim 31 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
37 . The therapeutic peptide of claim 36 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
38 . The therapeutic peptide of claim 32 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
39 . The method of claim 31 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
40 . A method of treating motility disorders of the GI tract which comprises administering to a patient in need thereof an effective amount of a therapeutic compound of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu;
further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
41 . The method of claim 40 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
42 . The method of claim 41 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
43 . The method of claim 41 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
44 . The method of claim 41 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
45 . The method of claim 40 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
46 . The therapeutic peptide of claim 45 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
47 . The therapeutic peptide of claim 41 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
48 . The method of claim 40 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
49 . A method of suppressing amylase release which comprises administering to a patient in need thereof an effective amount of a therapeutic peptide of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
50 . The method of claim 49 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
51 . The method of claim 50 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
52 . The method of claim 50 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
53 . The method of claim 50 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
54 . The method of claim 49 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
55 . The therapeutic peptide of claim 54 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
56 . The therapeutic peptide of claim 50 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
57 . The method of claim 49 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
58 . A method of treating cancer cachexia which comprises administering to a patient in need thereof an effective amount of a therapeutic compound of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
59 . The method of claim 58 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
60 . The method of claim 59 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
61 . The method of claim 59 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
62 . The method of claim 59 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
63 . The method of claim 58 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-1 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
64 . The therapeutic peptide of claim 63 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
65 . The therapeutic peptide of claim 59 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
66 . The method of claim 58 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.
67 . A method of inhibiting growth hormone release which comprises administering to a patient in need thereof an effective amount of a therapeutic peptide of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
68 . The method of claim 67 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
69 . The method of claim 68 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
70 . The method of claim 68 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
71 . The method of claim 68 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
72 . The method of claim 67 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
73 . The therapeutic peptide of claim 72 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
74 . The therapeutic peptide of claim 68 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
75 . The method of claim 67 wherein said growth hormone is a factor in the progression of muscular dystrophy in a patient.
76 . The method of claim 67 wherein said growth hormone is a factor in the onset of diabetes in a patient.
77 . The method of claim 67 wherein said growth hormone is a factor in the development of diabetes-related retinopathy in a patient.
78 . The method of claim 67 wherein said effective amoun is 0.5 μg/kg/day to 5 mg/kg/day.
79 . The method of claim 67 wherein said effective amount is 0.01 μg/kg/day to 1000 μg/kg/day.
80 . The method of claim 67 wherein said effective amount is 0.1 μg/kg/day to 100 μg/kg/day.
81 . A method of treating artherosclerosis which comprises administering to a patient in need thereof an effective amount of a therapeutic peptide of the formula:
wherein
A 0 =Gly, Nle, α-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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal, or is deleted;
A 1 =the D or L-isomer of any of pGlu, Nle, or α-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 2 , OH, H or CH 3 ), F 5 -Phe, Trp, Cys, or β-Nal, or is deleted;
A 2 =pGlu, Gly, Ala, Val, Gln, Asn, Leu, Ile, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, β-Nal, His, 1-methyl-His, or 3-methyl-His;
A 4 =Ala, Val, Gln, Asn, Gly, Leu, Ile, Nle, α-aminobutyric acid, Met, p-X-Phe (where X=F, Cl, Br, NO 2 , OH, H or CH 3 ), Trp, Cys, or βNal;
A 5 =Gln, Asn, Gly, Ala, Leu, Ile, Nle, α-aminobutyric acid, Met, Val, p-X-Phe (where X=F, Cl, Br, OH, H or CH 3 ), Trp, Thr, or β-Nal;
A 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 2 , OH, H or CH 3 ), Trp, Cys, or β-Nal;
A 7 =1-methyl-His, 3-methyl-His or His;
provided that, if A 0 is present, A 1 cannot be pGlu; further provided that, if A 0 or A 1 is present, A 2 cannot be pGlu; further provided that, when A 0 is deleted and A 1 is pGlu, R 1 must be H and R 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:
wherein R 3 is CHR 20 —(CH 2 ) n1 (where R 20 is either of H or OH; and n1 is either of 1 or 0), or is deleted, and Z 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 2 , OH, or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, HyPro, cyclohexyl-Ala, or β-Nal; and V is either OR 4 , or
where R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and each R 5 , and R 6 , independently, is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, lower acyl, or
where R 22 is any of H, C 1-12 alkyl, C 7-10 phenylalkyl, or lower acyl; provided that, when one of R 5 or R 6 is —NR 22 , the other is H;
wherein Z 1 is the identifying group of any of the amino acids Gly, Ala, Val, Leu, Ile, Ser, Asp, Asn, Glu, β-Nal, Gln, p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ), F 5 -Phe, Trp, Cys, Met, Pro, or HyPro; and each Z 2 , Z 3 , and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; or
wherein each Z 20 and Z 30 , independently, is H, lower alkyl, lower phenylalkyl, lower naphthylalkyl; further provided that, when either of Z 20 or Z 30 is other than H, A 7 is His, A 6 is Gly, A 5 is Val, A 4 is Ala, A 2 is His, and either of R 1 or R 2 is other than H, A 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 1 and R 2 , independently, is H, C 1-12 alkyl, C 7-10 phenylalkyl, COE 1 (where E 1 is C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl), or lower acyl, and R 1 and R 2 are bonded to the N-terminal amino acid of said peptide, and further provided that when one of R 1 or R 2 is COE 1 , the other must be H, or a pharmaceutically acceptable salt thereof.
82 . The method of claim 81 wherein said therapeutic peptide is of the formula:
A 0 =Gly, D-Phe, or is deleted; A 1 =p-Glu, D-Phe, D-Ala, D-β-Nal, D-Cpa, or D-Asn; A 2 =Gln, His, 1-methyl-His, or 3-methyl-His; A 4 =Ala; A 5 =Val; A 6 =Sar, Gly, D-Phe, or D-Ala; A 7 =His; and, where W is (I) and R 3 is CH 2 or CH 2 —CH 2 , Z 1 is the identifying group of Leu or Phe, where W is (I) and R 3 is CHOH—CH 2 , Z 1 is the identifying group of Leu, cyclohexyl-Ala, or Phe and each R 5 and R 6 is H; and where W is (I), V is NHR 6 , and R 6 is NH 2 ; where W is (II), Z 1 is the identifying group of any one of the amino acids Leu or p-X-Phe (where X=H, F, Cl, Br, NO 2 , OH or CH 3 ); and each Z 2 , Z 3 and Z 4 , independently, is H, lower alkyl, lower phenylalkyl, or lower naphthylalkyl; and where W is (III), each Z 20 and Z 30 , is H; and each R 1 and R 2 , independently, is H, lower alkyl, or lower acyl.
83 . The method of claim 82 wherein said therapeutic peptide is of the formula:
D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ethylamide.
84 . The method of claim 82 wherein said therapeutic peptide is of the formula:
p-Glu-Gln-Trp-Ala-Val-Gly-His-statine-amide.
85 . The method of claim 82 wherein said therapeutic peptide is of the formula:
D-Cpa-Gln-Trp-Ala-Val-Gly-His-β-Leu-NH 2 .
86 . The method of claim 81 wherein said therapeutic peptide is of the formula: W is (I), V is OR 4 , and R 4 is any of C 1-20 alkyl, C 3-20 alkenyl, C 3-20 alkinyl, phenyl, naphthyl, or C 7-10 phenylalkyl, and A 6 is N-methyl-D-Ala or A 1 is D-F 5 -Phe.
87 . The therapeutic peptide of claim 86 of the formula:
D-Phe-Gln-Trp-Ala-Val-N-methyl-D-Ala-His-Leu-methylester.
88 . The therapeutic peptide of claim 82 of the formula:
D-Cpa-Gln-Trp-Ala-Val-D-Ala-His-β-Leu-NH 2 .
89 . The method of claim 81 wherein said effective amount is 0.5 μg/kg/day to 5 mg/kg/day.Join the waitlist — get patent alerts
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