RU2006126637A - IMPROVED DERIVATIVES OF PEPTIDE RELEASING GASTRITIS - Google Patents

Claims (16)

1. The compound selected from the group including DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QWAVaHLM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-f-QWAVGHLM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-f-WAVGHLL-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-f-QWAVGHL-NH-pentyl; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-y-QWAV-Bala-HF-Nle-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-f-QWAV-Bala-HF-Nle-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QWAVGHFL-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QWAVGNMeH-LM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-LWAVGSF-M-NH ₂ ; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-HWAVGHLM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-LWAGHFM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QWAVGHFM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QRLGNQWAVGHLM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QRYGNQWAVGHLM-NH _2; DO3A-monoamide-Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-QKYGNQWAVGHLM-NH _2; Pglu-Q-Lys (DO3A-monoamide) -Gly- (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid-LGNQWAVGHLM-NH _2; DO3A-monoamide-Gly-3-amino-3-deoxycholic acid-QRLGNQWAVGHLM-NH _2; DO3A-monoamide-Gly-3-amino-3-deoxycholic acid-QRYGNQWAVGHLM-NH _2; DO3A-monoamide-Gly-3-amino-3-deoxycholic acid-QKYGNQWAVGHLM-NH ₂ ; Pglu-Q-Lys (DO3A-monoamide-G-3-amino-3-deoxycholic acid) -LGNQWAVGHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFL-NH _2; DO3A-monoamide-4-aminomethylbenzoic acid-L-1-naphthylalanine-QWAVGHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QWAVGNMeHisLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QWAVaHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHLL-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHL-NH-pentyl; DO3A-monoamide-G-4-aminobenzoic acid-yQWAV-Bala-HFNle-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-fQWAV-Bala-HFNle-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-LWAVGSFM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-HWAVGHLM-NH _2; , DO3A-monoamide-G-4-aminobenzoic acid-LWATGHFM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QRLGNQWAVGHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QRYGNQWAVGHLM-NH ₂ ; DO3A-monoamide-G-4-aminobenzoic acid-QKYGNQWAVGHLM-NH ₂ ; Pglu-Q-Lys (DO3A-monoamide-G-4-aminobenzoic acid) -LGNQWAVGHLM-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-QWAVaHLM-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-fQWAVGHLM-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-fQWAVGHLL-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-fQWAVGHL-NH-pentyl; DO3A-monoamide-G-3-amino-3-deoxycholic acid-yQWAV-Bala-HFNle-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-fQWAV-Bala-HFNle-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-QWAVGHFL-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-QWAVGNMeHLM-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-LWAVGSFM-NH _2; DO3A-monoamide-G-3-amino-3-deoxycholic acid-HWAVGHLM-NH ₂ ; DO3A-monoamide-G-3-amino-3-deoxycholic acid-LWATGHFM-NH ₂ ; and DO3A-monoamide-G-3-amino-3-deoxycholic acid-QWAVGHFM-NH ₂ . 2. The compound of General formula M-N-O-P-G where M represents DO3A, optionally in combination with a radioisotope; N represents 0, alpha or non-alpha amino acid, substituted bile acid or another linker group; O represents an alpha or non-alpha amino acid or substituted bile acid; P represents 0, alpha or non-alpha amino acid, substituted bile acid or other linker group; and G is a peptide targeting a GRP receptor; where at least one of N, O or P is 8-amino-3,6-dioxaoctanoic acid, (3β, 5β, 12α) -3-amino-12-hydroxycholan-24-oic acid or 4-aminobenzoic acid; and where the peptide targeting the GRP receptor is selected from the group consisting of QWAVGHLM-NH ₂ , QWAVGNMeHLM-NH ₂ , QWAVGHFL-NH ₂ , LWATGSFM-NH ₂ , QWAVaHLM-NH ₂ , Nme-QWAVGHLM-NH ₂ , Q-Ψ [CSNH] WAVGHLM-NH ₂ , Q-H - [CH WAVGHLM-NH ₂ , Q-Ψ [CH = CH] WAVGHLM-NH ₂ , α-MeQWAVGHLM-NH ₂ , QNme-WAVGHLM-NH ₂ , QW-Ψ [CSNH] -AVGHLM-NH ₂ , QW-Ψ [CH2NH] -AVGHLM-NH ₂ , QW-Ψ [CH = CH] -AVGHLM-NH ₂ , Q-α-Me-WAVGHLM-NH ₂ , QW-Nme-AVGHLM-NH ₂ , QWA = Ψ [CSNH] -VGHLM-NH ₂ , QWA-Ψ [CH2NH] -VGHLM-NH ₂ , QW-Aib-VGHLM-NH ₂ , QWAV-Sar-HLM-NH ₂ , QWAVG-Ψ [CSNH] -HLM-NH ₂ , QWAVG-Ψ [CH = CH] -HLM-NH ₂ , QWAV-Dala-HLM-NH ₂ , QWAVG-Nme-His-LM-NH ₂ , QWAVG-H-Ψ [CSNH] -LM-NH ₂ , QWAVG-H-Ψ [CH2NH] -LM-NH ₂ , QWAVGH-Ψ [CH = CH] -LM-NH ₂ , QWAVG-α-Me-HLM-NH ₂ , QWAVGH-Nme-LM-NH ₂ , QWAVGH-α-MeLM-NH ₂ and QWAVGHF -L-NH ₂ . 3. A method for targeting a gastrin-releasing peptide receptor (GRP-R) and a neuromedin-B receptor (NMB-R), comprising administering a compound of the general formula M-N-O-P-G where M is an optical label or metal complexon, optionally in complex with a radioisotope; N represents 0, alpha or non-alpha amino acid or other linker group; O represents an alpha or non-alpha amino acid; P represents 0, an alpha or non-alpha amino acid or other linker group; and G is a peptide targeting a GRP receptor; and where at least one of N, O or P is a non-alpha amino acid. 4. The method according to claim 3, where at least one of N, O or P is a non-alpha amino acid with a cyclic group. 5. The method according to claim 4, where N is Gly, O is 4-aminobenzoic acid and P is 0. 6. A method for targeting GRP-R and NMB-R, comprising administering a compound of general formula M-N-O-P-G where M is an optical label or metal complexon, optionally in complex with a radioisotope; N represents 0, an alpha amino acid, a substituted bile acid or other linker group; O represents an alpha amino acid or substituted bile acid; P represents 0, an alpha amino acid, a substituted bile acid or other linker group; G is a peptide targeting a GRP receptor; and where at least one of N, O or P is a substituted bile acid. 7. The method according to claim 6, where N is Gly, O is (3β, 5β, 7α, 12α) -3-amino-7,12-dihydroxycholan-24-oic acid, and P is 0. 8. The method according to any one of claims 3 to 7, where the peptide targeting the GRP receptor is selected from the group consisting of Nme-QWAVGHLM- NH ₂ , Q-Ψ [CSNH] WAVGHLM-NH ₂ , Q-Ψ [CH ₂ NH] -WAVGHLM-NH ₂ , Q-Ψ [CH = CH] WAVGHLM-NH ₂ , α-MeQWAVGHLM-NH ₂ , QNme-WAVGHLM-NH ₂ , QW-Ψ [CSNH] -AVGHLM-NH ₂ , QW-Ψ [CH ₂ NH] -AVGHLM-NH ₂ , QW-Ψ [CH = CH] -AVGHLM-NH ₂ , Q-α-Me-WAVGHLM-NH ₂ , QW-Nme-AVGHLM-NH ₂ , QWA = Ψ [CSNH] -VGHLM-NH ₂ , QWA-Ψ [CH ₂ NH] -VGHLM-NH ₂ , QW-Aib-VGHLM-NH ₂ , QWAV-Sar-HLM-NH ₂ , QWAVG-Ψ [CSNH] -HLM-NH ₂ , QWAVG-Ψ [CH = CH] -HLM-NH ₂ , QWAV-Dala-HLM-NH ₂ , QWAVG-Nme-His-LM-NH ₂ , QWAVG-H-Ψ [CSNH] -LM-NH ₂ , QWAVG-H-Ψ [CH ₂ NH] -LM-NH ₂ , QWAVGH-Ψ [CH = CH] -LM-NH ₂ , QWAVG-α-Me-HLM-NH ₂ , QWAVGH-Nme-LM-NH ₂ , and QWAVGH-α-MeLM-NH ₂ . 9. A method for improving the in vivo activity of a compound of general formula M-N-O-P-G where M is an optical label or metal complexon, optionally in complex with a radioisotope; N represents 0, alpha or non-alpha amino acid, substituted bile acid or another linker group; O represents an alpha or non-alpha amino acid or substituted bile acid; P represents 0, alpha or non-alpha amino acid, substituted bile acid or other linker group; G is a peptide targeting a GRP receptor; and where at least one of N, O or P is 8-amino-3,6-dioxaoctanoic acid, (3β, 5β, 12α) -3-amino-12-hydroxycholan-24-oic acid or 4-aminobenzoic an acid comprising the step of modifying a peptide targeting a GRP receptor so as to reduce the proteolytic cleavage of said peptide. 10. A method of reducing proteolytic cleavage of a compound of general formula M-N-O-P-G where M is an optical label or metal complexon, optionally in complex with a radioisotope; N represents 0, alpha or non-alpha amino acid, substituted bile acid or another linker group; O represents an alpha or non-alpha amino acid or substituted bile acid; P represents 0, alpha or non-alpha amino acid, substituted bile acid or other linker group; G is a peptide targeting a GRP receptor; and where at least one of N, O or P is 8-amino-3,6-dioxaoctanoic acid, (3β, 5β, 12α) -3-amino-12-hydroxycholan-24-oic acid or 4-aminobenzoic acid comprising the step of modifying the peptide bond in the peptide targeting the GRP-R receptor so as to reduce the proteolytic cleavage of said peptide. 11. The method according to any one of claims 9 or 10, wherein the modified peptide targeting GRP-R is an agonist. 12. The method according to any one of claims 9 or 10, wherein M is DO3A, optionally in combination with a radioisotope. 13. The method according to any one of claims 9 or 10, wherein the component targeting GRP-R is selected from the group consisting of Nme-QWAVGHLM-NH ₂ , Q-Ψ [CSNH] WAVGHLM-NH ₂ , Q-Ψ [CH ₂ NH] -WAVGHLM-NH ₂ , Q-Ψ [CH = CH] WAVGHLM-NH ₂ , α-MeQWAVGHLM-NH ₂ , QNme-WAVGHLM-NH ₂ , QW-Ψ [CSNH] -AVGHLM-NH ₂ , QW-Ψ [CH ₂ NH] -AVGHLM-NH ₂ , QW-Ψ [CH = CH] -AVGHLM-NH ₂ , Q-α-Me-WAVGHLM-NH ₂ , QW-Nme-AVGHLM-NH ₂ , QWA = Ψ [CSNH] -VGHLM-NH ₂ , QWA-Ψ [CH ₂ NH] -VGHLM-NH ₂ , QW-Aib-VGHLM-NH ₂ , QWAV-Sar-HLM-NH ₂ , QWAVG-Ψ [CSNH] -HLM-NH ₂ , QWAVG-Ψ [CH = CH] -HLM-NH ₂ , QWAV-Dala-HLM-NH ₂ , QWAVG-Nme-His-LM-NH ₂ , QWAVG-H-Ψ [CSNH] -LM-NH ₂ , QWAVG-H-Ψ [CH ₂ NH] -LM-NH ₂ , QWAVGH-Ψ [CH = CH] -LM-NH ₂ , QWAVG-α-Me-HLM-NH ₂ , QWAVGH-Nme-LM-NH ₂ , and QWAVGH-α-MeLM-NH ₂ . 14. A method of imparting specificity to a GRP-R and / or NMB-R compound comprising an optical label or metal complexon, optionally in complex with a radioisotope, and a peptide targeting GRP-R, comprising including a linker of the general formula in such a compound N-o-p where N is 0, an alpha or non-alpha amino acid, a substituted bile acid, or other linker group; O represents an alpha or non-alpha amino acid or substituted bile acid; P represents 0, alpha or non-alpha amino acid, substituted bile acid or other linker group; and where at least one of N, O or P is a non-alpha amino acid substituted with bile acid or a non-alpha amino acid with a cyclic group. 15. A method for improving the in vivo activity of a compound comprising an optical label or metal complexon, optionally in combination with a radioisotope, and a peptide targeting GRP-R, comprising including a linker of the general formula in such compounds N-o-p where N is 0, an alpha or non-alpha amino acid, a substituted bile acid, or other linker group; O represents an alpha or non-alpha amino acid or substituted bile acid; P represents 0, alpha or non-alpha amino acid, substituted bile acid or other linker group; and where at least one of N, O or P is a non-alpha amino acid substituted with bile acid or a non-alpha amino acid with a cyclic group. 16. The method according to any one of paragraphs. 14 or 15, where at least one of N, O or P is 8-amino-3,6-dioxo-octanoic acid, (3β, 5β, 12α) -3-amino-12-hydroxycholan-24-oic acid or 4-aminobenzoic acid.