CA2549318A1 - Composes peptidiques de liberation de gastrine ameliores - Google Patents

Info

Publication number

CA2549318A1

CA2549318A1 CA002549318A CA2549318A CA2549318A1 CA 2549318 A1 CA2549318 A1 CA 2549318A1 CA 002549318 A CA002549318 A CA 002549318A CA 2549318 A CA2549318 A CA 2549318A CA 2549318 A1 CA2549318 A1 CA 2549318A1

Authority

CA

Canada

Prior art keywords

acid

alpha

amino

monoamide

do3a

Prior art date

2003-12-24

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• PUBCCFNQJQKCNC-XKNFJVFFSA-N gastrin-releasingpeptide Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(C)C)[C@@H](C)O)C(C)C)C1=CNC=N1 PUBCCFNQJQKCNC-XKNFJVFFSA-N 0.000 title claims description 29
• 150000001875 compounds Chemical class 0.000 claims abstract description 174
• 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 116
• 238000000034 method Methods 0.000 claims abstract description 115
• 229910052751 metal Inorganic materials 0.000 claims abstract description 89
• 239000002184 metal Substances 0.000 claims abstract description 89
• 230000008685 targeting Effects 0.000 claims abstract description 86
• 108090001053 Gastrin releasing peptide Proteins 0.000 claims abstract description 83
• 239000002738 chelating agent Substances 0.000 claims abstract description 74
• 230000003287 optical effect Effects 0.000 claims abstract description 44
• 125000005647 linker group Chemical group 0.000 claims description 128
• 102000004862 Gastrin releasing peptide Human genes 0.000 claims description 82
• 102000005962 receptors Human genes 0.000 claims description 74
• 108020003175 receptors Proteins 0.000 claims description 74
• 235000008206 alpha-amino acids Nutrition 0.000 claims description 71
• 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 68
• 239000003613 bile acid Substances 0.000 claims description 27
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 24
• 238000001727 in vivo Methods 0.000 claims description 24
• 125000004122 cyclic group Chemical group 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
• ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 13
• 239000000556 agonist Substances 0.000 claims description 13
• 230000000694 effects Effects 0.000 claims description 13
• 229960004050 aminobenzoic acid Drugs 0.000 claims description 10
• RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 claims description 6
• 230000006337 proteolytic cleavage Effects 0.000 claims description 6
• HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical group OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 claims description 5
• 108010073466 Bombesin Receptors Proteins 0.000 claims 25
• 102000047481 Gastrin-releasing peptide receptors Human genes 0.000 claims 19
• FDJOMAIZVIIHGU-XLJSZMODSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]acetyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-n-[(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-4-methylpentanamide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C(C)C)C1=CN=CN1 FDJOMAIZVIIHGU-XLJSZMODSA-N 0.000 claims 8
• 102000052872 Neuromedin B receptors Human genes 0.000 claims 6
• 241000179948 Sarcophaga beta Species 0.000 claims 1
• 238000003384 imaging method Methods 0.000 abstract description 24
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• 229920005989 resin Polymers 0.000 description 329
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 300
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 236
• 239000002253 acid Substances 0.000 description 215
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 170
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 156
• 108010062050 bombesin (7-14) Proteins 0.000 description 134
• 239000000203 mixture Substances 0.000 description 121
• 239000007983 Tris buffer Substances 0.000 description 118
• 230000015572 biosynthetic process Effects 0.000 description 112
• 238000003786 synthesis reaction Methods 0.000 description 112
• 239000007787 solid Substances 0.000 description 105
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 80
• 238000004128 high performance liquid chromatography Methods 0.000 description 79
• 239000000126 substance Substances 0.000 description 74
• -1 TETMA Chemical compound 0.000 description 69
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 63
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 62
• 239000003153 chemical reaction reagent Substances 0.000 description 60
• BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 60
• 239000000047 product Substances 0.000 description 59
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
• JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 52
• 238000006243 chemical reaction Methods 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
• DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical group C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 48
• 210000004027 cell Anatomy 0.000 description 45
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 44
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
• 230000002829 reductive effect Effects 0.000 description 42
• 239000000725 suspension Substances 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
• 238000010647 peptide synthesis reaction Methods 0.000 description 41
• 239000002244 precipitate Substances 0.000 description 41
• 230000027455 binding Effects 0.000 description 40
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
• 229940024606 amino acid Drugs 0.000 description 39
• 235000001014 amino acid Nutrition 0.000 description 39
• 238000002953 preparative HPLC Methods 0.000 description 38
• 239000003446 ligand Substances 0.000 description 36
• 108010051479 Bombesin Proteins 0.000 description 35
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• 206010028980 Neoplasm Diseases 0.000 description 34
• 238000005859 coupling reaction Methods 0.000 description 34
• 150000001413 amino acids Chemical class 0.000 description 33
• 230000008878 coupling Effects 0.000 description 33
• 238000010168 coupling process Methods 0.000 description 33
• 102000004196 processed proteins & peptides Human genes 0.000 description 33
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 32
• 239000007790 solid phase Substances 0.000 description 32
• 210000001519 tissue Anatomy 0.000 description 31
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
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• 239000011734 sodium Substances 0.000 description 26
• 238000002360 preparation method Methods 0.000 description 25
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 20
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• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 18
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