WO2006051341A1 - Isotopically marked quinoline derivatives as adenosin a3 receptor ligands - Google Patents
Isotopically marked quinoline derivatives as adenosin a3 receptor ligands Download PDFInfo
- Publication number
- WO2006051341A1 WO2006051341A1 PCT/HU2005/000120 HU2005000120W WO2006051341A1 WO 2006051341 A1 WO2006051341 A1 WO 2006051341A1 HU 2005000120 W HU2005000120 W HU 2005000120W WO 2006051341 A1 WO2006051341 A1 WO 2006051341A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- branched
- straight
- general formula
- alkyl group
- Prior art date
Links
- 239000003446 ligand Substances 0.000 title abstract description 5
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title description 44
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 15
- -1 methylenedioxy group Chemical group 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 239000005864 Sulphur Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 238000004007 reversed phase HPLC Methods 0.000 claims 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 125000005270 trialkylamine group Chemical group 0.000 claims 1
- 238000000825 ultraviolet detection Methods 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 7
- 229910052740 iodine Inorganic materials 0.000 abstract description 7
- 239000011630 iodine Substances 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000005557 antagonist Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- 239000002287 radioligand Substances 0.000 description 22
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 21
- 229960005305 adenosine Drugs 0.000 description 21
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 16
- 102000009346 Adenosine receptors Human genes 0.000 description 14
- 108050000203 Adenosine receptors Proteins 0.000 description 14
- 230000027455 binding Effects 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
- 229910001629 magnesium chloride Inorganic materials 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 5
- 102000055025 Adenosine deaminases Human genes 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 239000003365 glass fiber Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- RIRGCFBBHQEQQH-SSFGXONLSA-N (-)-n6-(2-phenylisopropyl)adenosine Chemical compound C([C@@H](C)NC=1C=2N=CN(C=2N=CN=1)[C@H]1[C@@H]([C@H](O)[C@@H](CO)O1)O)C1=CC=CC=C1 RIRGCFBBHQEQQH-SSFGXONLSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical class N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- 102000030621 adenylate cyclase Human genes 0.000 description 3
- 108060000200 adenylate cyclase Proteins 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 230000014155 detection of activity Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229960001479 tosylchloramide sodium Drugs 0.000 description 3
- LOGOEBMHHXYBID-WBKNRDRNSA-N (2s,3s,4r,5r)-5-[6-[(4-amino-3-iodanylphenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=C([125I])C(N)=CC=3)=C2N=C1 LOGOEBMHHXYBID-WBKNRDRNSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 102100036664 Adenosine deaminase Human genes 0.000 description 2
- 238000009010 Bradford assay Methods 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000013391 scatchard analysis Methods 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XSMYYYQVWPZWIZ-IDTAVKCVSA-N (2r,3r,4s,5r)-2-[2-chloro-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC(Cl)=NC(NC3CCCC3)=C2N=C1 XSMYYYQVWPZWIZ-IDTAVKCVSA-N 0.000 description 1
- IPSYPUKKXMNCNQ-PFHKOEEOSA-N (2s,3s,4r,5r)-5-[2-chloro-6-[(3-iodophenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC(Cl)=NC(NCC=3C=C(I)C=CC=3)=C2N=C1 IPSYPUKKXMNCNQ-PFHKOEEOSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical group C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- FFBDFADSZUINTG-LEZITTIZSA-N 8-cyclopentyl-1,3-bis(1,3-ditritiopropyl)-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(C([3H])CC[3H])C(=O)N(C([3H])CC[3H])C=2N=C1C1CCCC1 FFBDFADSZUINTG-LEZITTIZSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- PAOANWZGLPPROA-RQXXJAGISA-N CGS-21680 Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC(NCCC=3C=CC(CCC(O)=O)=CC=3)=NC(N)=C2N=C1 PAOANWZGLPPROA-RQXXJAGISA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- QQGCPTDXKGIBQZ-UHFFFAOYSA-N N-[3-cyano-4-(thiophen-2-ylmethylamino)-6-tributylstannylquinolin-2-yl]benzamide Chemical compound CCCC[Sn](CCCC)(CCCC)c1ccc2nc(NC(=O)c3ccccc3)c(C#N)c(NCc3cccs3)c2c1 QQGCPTDXKGIBQZ-UHFFFAOYSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000002580 adenosine A3 receptor antagonist Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000001091 dromotropic effect Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- KYYLEMJRBIDGSG-UHFFFAOYSA-N n-[3-cyano-6-iodo-4-(thiophen-2-ylmethylamino)quinolin-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=NC2=CC=C(I)C=C2C(NCC=2SC=CC=2)=C1C#N KYYLEMJRBIDGSG-UHFFFAOYSA-N 0.000 description 1
- IXBDEGGYYXHTMR-UHFFFAOYSA-N n-[4-(benzylamino)-3-cyano-6-iodoquinolin-2-yl]-4-methoxybenzamide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=NC2=CC=C(I)C=C2C(NCC=2C=CC=CC=2)=C1C#N IXBDEGGYYXHTMR-UHFFFAOYSA-N 0.000 description 1
- WBZZJHBXJUIJMU-UHFFFAOYSA-N n-[4-(benzylamino)-3-cyano-6-tributylstannylquinolin-2-yl]-4-methoxybenzamide Chemical compound N#CC1=C(NCC=2C=CC=CC=2)C2=CC([Sn](CCCC)(CCCC)CCCC)=CC=C2N=C1NC(=O)C1=CC=C(OC)C=C1 WBZZJHBXJUIJMU-UHFFFAOYSA-N 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
Definitions
- the present invention relates to adenozin A 3 receptor ligands labeled with iodine isotops of mass number 125, within those favourably to antagonists and their isomers, to the experimental materials containing them, to a process for the preparation of the compounds of the general formula (I)
- Adenosine is a well-known component of several endogenous molecules (ATP, NAD + , nucleic acids). Besides, it plays an important regulatory role in many physiological processes. The effect of adenosine on heart function was discovered already in 1929. (Drury and Szentgy ⁇ rgyi, J Physiol 68:213, 1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new adenosine receptor subtypes give possibilities for therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998).
- the receptors for adenosine have been classified into three main classes: Ai, A 2 and A 3 .
- the Ai subtype is partly responsible for inhibiting the adenylate cyclase by coupling to Gj membrane protein, partly influences other second messenger systems.
- the A 2 receptor subtype can be subdivided into two further subtypes - A 2a and A 2b -, which receptors stimulate the adenylate cyclase activity.
- the sequence of adenosine A 3 receptors have been recently identified from rat testis cDNA library. Later it was proved that it corresponds to a novel, functional adenosine receptor.
- the activation of the A 3 receptors is connected also with several second- messenger systems: inhibiting of adenylate cyclase, stimulating phospholipase C and D.
- the adenosine receptors are found in several organs and regulate their functions. Both Ai and A 2a receptors play important roles in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by Ai receptors. In the heart, also the Ai receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine.
- the adenosine A 2a receptors which located relatively in a higher amount in the striatum, display a functional interaction with dopamine receptors in regulating the synaptic transmission.
- the A 2a adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.
- the A 2b adenosine receptors are widely distributed in different tissues. They have been identified almost in every cell type, but its expression is the highest in the intestine and the bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.
- a 3 adenosine receptors are rather low comparing to other subtypes and highly species dependent.
- a 3 adenosine receptors are expressed primarily in the central nervous system, testis, immun system and appear to be involved in the modulation of mediator release from mast cells in immediate hypersensitivity reaction.
- Our present invention relates to the compounds of the general formula (I) labeled with iodo isotops of mass number 125, and to their salts, solvates and isomers, which have great selectivity for the A 3 sub-type of the adenosine receptor.
- the [ H]-MRE 3008-F20 adenosine A 3 receptor antagonist radioligand is known from the literature. (P. G. Baraldi, Bioorganic and Medicinal Chemistry Letters, 10, 209-211, 2000). Also known is the [ 3 H]PSB-I l A 3 receptor antagonist radioligand (CH. M ⁇ ller, Bioorganic and Medicinal Chemistry Letters, 12, 501-503, 2002).
- R 1 stands for hydrogen atom or a straight or branched C 1-4 alkyl group, or a C 3-6 cycloalkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted with one or more straight or branched C 1 - 4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom, or for a 5- or 6-membered heteroaromatic ring -containing one, two or three nitrogen atoms-, or for a 5-membered heteroaromatic ring - containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom- optionally substituted with one or more straight or branched C 1 . 4 alkyl group, straight or branched C 1-4 alkoxy group, or halogen atom;
- R 2 stands for hydrogen atom or for a straight or branched Cj -4 alkyl group, or for a phenyl-, benzyl-, thienyl- or furyl-group -optionally substituted with a methylenedioxy group, or one or more straight or branched Ci -4 alkyl group, or straight or branched C 1-4 alkoxy-, hydroxyl-, trifluoromethyl- or cyano-group, or halogen atom-, or for a 5- or 6- membered heteroaromatic ring -containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulphur atom -optionally substituted with one or more straight or branched Ci -4 alkyl group, straight or branched Ci -4 alkoxy group, or halogen atom.
- Ci -4 alkyl group we mean methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, secondary-butyl-, tert.-butyl-, preferably ethyl- or methyl group.
- Ci -4 alkoxy group we mean methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec.-butoxy-, tert.-butoxy-, preferably ethoxy- or methoxy group.
- C 3 .. 6 cycloalkyl group we mean cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl group.
- the heteroaromatic ring containing one or two or three nitrogen atoms may mean pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1 ,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine and 1,3,4-triazine ring.
- the ring is optionally substituted with a Ci -4 alkyl, or alkoxy group or by a halogen atom.
- the heteroaromatic ring containing one nitrogen atom and one oxygen or one sulphur atom means oxazole, isoxazole, thiazole, isothiazole ring.
- the ring is optionally substituted with a Ci -4 alkyl, or alkoxy group or by a halogen atom.
- R 1 stands for phenyl-, thienyl- or furyl group
- R 2 stands for 4-methoxyphenyl-, 3-methylphenyl-, 3-methoxyphenyl-,
- the compounds of the general formula (I) are prepared by reacting the appropriate compounds of the general formula (II) with unsupported [ I]NaI, in the presence of an oxidant.
- the reaction is carried out in aqueous methanolic medium (pH 3), at room temperature.
- peroxides for example hydrogen peroxide, N- halogeno-succinamides e.g. JV-chloro-succinamide, or chlorosulphonamides, preferably chloramine-T
- oxidizing agents for example hydrogen peroxide, N- halogeno-succinamides e.g. JV-chloro-succinamide, or chlorosulphonamides, preferably chloramine-T
- the product is purified by reversed-phase high-performance liquid chromatographic (RP-HPLC) method using silica gel based Ci 8 modified packing as stationary phase and methanol-water binary mixture containing 0.1% (v/v) trifluoroacetic acid as eluent system, with flow rate of 0.9 ml/min. Detection is carried out by UV at 272 nm; detection of radioactivity is carried out by flow liquid scintillation method.
- RP-HPLC reversed-phase high-performance liquid chromatographic
- R 1 and R 2 have the meanings as defined above and X stands for iodo- or bromo atom- by reacting it in the presence of palladium catalyst, organic or inorganic base and organic solvent, with a hexaalkyl-distannane compound.
- the product of general formula (II) is isolated.
- the exchange of the halogen atom for trialkyl-stannyl group is carried out in an organic solvent, for example in dioxane or dimethylformamide, or favourably in N- methyl-2-pyrrolidone.
- the reaction can be performed in a wide temperature range, preferably between 2O 0 C - 100 0 C.
- organic base trialkylamines preferably triethylamine can be applied.
- inorganic base alkali hydroxides carbonates and acetates, preferably potassium acetate can be used.
- palladium acetate palladium chloride or tetrakis(triphenylphosphine)palladium(0) catalysts can be used (Z.P. Zhuang. M.P. Kung, C. Hou, D.M. Skovronsky, T.L. Gur, K. Plossl, J.Q. Trojanowski, V.M.Y. Lee, H.F. Kung, J. Med. Chem.
- R 1 stands for phenyl group
- R 2 stands for 4- methoxyphenyl group.
- the united toluene phase is dried over sodium sulfate, filtered and evaporated under reduced pressure.
- the residue is chromatographed on a silicagel coloumn using chloroform - ethyl acetate (10 : 0.5) mixture as eluent. After evaporation of the pure fractions 250 mg of the title compound is obtained.
- R stands for thienyl group
- R stands for 4- methoxyphenyl group.
- N-(6-tributylstannyl-4- [2-thienylmethylamino] -3 -cyanoquinolin-2- yl)benzamide are added 25 ⁇ l (1.1 nmol) of 1% (v/v) methanolic solution of trifluoroacetic acid and 70 MBq [ 125 I]NaI solution (21 ⁇ l).
- To the reaction mixture 5 ⁇ l (2 nmol) of 0.1 mg/ml aqueous solution of chloramine-T is added and the mixture is stirred at room temperature for 15 minutes. After the incubation period the reaction is stopped by the addition of 7 ⁇ l (3.5 nmol) of 0.1 mg/ml sodium pyrosulfite solution and the product is immediately purified by RP-HPLC method, while applying UV and radioactivity detection.
- the united toluene phase is dried over sodium sulfate, filtered and evaporated under reduced pressure.
- the residue is chromatographed on a silicagel coloumn using chloroform - ethyl acetate (10 : 0.5) mixture as eluent. By evaporating the pure fractions 235 mg of the title compound is obtained.
- Preparing membrane suspension collect ovarium cells of cloned Chinese hamster expressing human Ai receptors (further: CHOhAi), wash them three times with PBS, centrifuge (1000 x g 10 min.) and homogenize (B.Braun Potter S) at 1500/min rotation speed. Buffer: 50 mM Tris HCl, pH 7,4. Centrifuge this homogenized mixture (43.000 g, 10 min), suspense the pellet in the above buffer with adjustment of the protein concentration to 5 mg/mL (Bradford method) and complete with 2 U/mL ADA.
- Binding protocol incubate CHO-hAi membrane preparation (50 ⁇ g protein content), in the presence of the test compound and 10 nM [ 3 H]CCPA (2-chloro-N 6 -cyclopenthyl-adenosine) (80.000 dpm) in incubation buffer (50 mM Tris HCl, pH 7.4, 2 U/mL adenosine deaminase).
- the non-specific binding is defined in the presence of 10 ⁇ M R-PIA (N 6 -[L-2- phenylisopropyl] adenosine) in a total volume of 100 ⁇ L for 3 hr at room temperature.
- Binding protocol incubate 20.8 ⁇ g of membranes (human A 2 b adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), in the presence of the test compound and 32.4 nM [ 3 H]DPCPX (8-cyclopenthyl-l,3-dipropylxanthine) (800.000 dpm) in incubation buffer (50 niM Tris-HCl, 10 niM MgCl 2 , 1 mM EDTA, 0.1 mM benzamidine, 2 U/mL adenosine deaminase, pH 6.5).
- Preparing membrane suspension collect ovarium cells of cloned Chinese hamster expressing human A 3 receptors (further: CHO-IiA 3 ), wash them three times with PBS, centrifuge (1000 x g 10 min.) and homogenize (B.Braun Potter S) at 1500/min rotation speed. Buffer: 50 mM Tris, 1OmM MgCl 2 , 1 mM EDTA, pH 8.0. Centrifuge this homogenized mixture (43.000 g, 10 min), suspense the pellet in the above buffer with adjustment of the protein concentration to 0.1 mg/mL (Bradford method) and complete with 2 U/mL ADA.
- the dissociation constant (K D ) of the new radioligand of Example 2/a on CHO-IiA 3 membrane preparation is determined.
- K D dissociation constant
- Figure 1 Scatchard saturation curve of the new radioligand of Example 2/a in the presence of CHO-hA. 3 membrane preparation
- Example 2/b i.e. of the un-labeled analogue of the new radioligand of
- Example 2/a were calculated on the basis of the IC 50 values.
- the reference compounds exhibited similar affinity values in the presence of the known and of the new radoligands, proving the suitability of the radioligand of Example
Abstract
The invention relates to adenozin A3 receptor ligands labeled with iodine isotops of mass number 125, within those favourably to antagonists and their isomers, to the experimental materials containing them, to a process for the preparation of the compounds of the general formula (I) and their isomers, to the new intermediates of the general formula (II) and to the preparation thereof.
Description
ISOTOPICALLY MARKED QUINOLINE DERIVATIVES AS ADENOSIN A3 RECEPTOR LIGANDS
The present invention relates to adenozin A3 receptor ligands labeled with iodine isotops of mass number 125, within those favourably to antagonists and their isomers, to the experimental materials containing them, to a process for the preparation of the compounds of the general formula (I)
R
H
N
D1
Adenosine is a well-known component of several endogenous molecules (ATP, NAD+, nucleic acids). Besides, it plays an important regulatory role in many physiological processes. The effect of adenosine on heart function was discovered already in 1929. (Drury and Szentgyόrgyi, J Physiol 68:213, 1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new
adenosine receptor subtypes give possibilities for therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998). To date, the receptors for adenosine have been classified into three main classes: Ai, A2 and A3. The Ai subtype is partly responsible for inhibiting the adenylate cyclase by coupling to Gj membrane protein, partly influences other second messenger systems. The A2 receptor subtype can be subdivided into two further subtypes - A2a and A2b -, which receptors stimulate the adenylate cyclase activity. The sequence of adenosine A3 receptors have been recently identified from rat testis cDNA library. Later it was proved that it corresponds to a novel, functional adenosine receptor. The activation of the A3 receptors is connected also with several second- messenger systems: inhibiting of adenylate cyclase, stimulating phospholipase C and D.
The adenosine receptors are found in several organs and regulate their functions. Both Ai and A2a receptors play important roles in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by Ai receptors. In the heart, also the Ai receptors mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The adenosine A2a receptors, which located relatively in a higher amount in the striatum, display a functional interaction with dopamine receptors in regulating the synaptic transmission. The A2a adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.
On the basis of mRNA identification, the A2b adenosine receptors are widely distributed in different tissues. They have been identified almost in every cell type, but its expression is the highest in the intestine and the
bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.
Contrary to A1 and A2a receptors, where the tissue distribution was detected on the protein level, the presence of A2b and A3 receptors was detected on the basis of their mRNA level. Expression levels for A3 adenosine receptors are rather low comparing to other subtypes and highly species dependent. A3 adenosine receptors are expressed primarily in the central nervous system, testis, immun system and appear to be involved in the modulation of mediator release from mast cells in immediate hypersensitivity reaction.
For therapeutic use it is essential to ensure that the molecule does not bind, or bind only in the case of very high concentration to the Ai, A2a and A2b sub-types of the adenosine receptor. Our present invention relates to the compounds of the general formula (I) labeled with iodo isotops of mass number 125, and to their salts, solvates and isomers, which have great selectivity for the A3 sub-type of the adenosine receptor.
The [ H]-MRE 3008-F20 adenosine A3 receptor antagonist radioligand is known from the literature. (P. G. Baraldi, Bioorganic and Medicinal Chemistry Letters, 10, 209-211, 2000). Also known is the [3H]PSB-I l A3 receptor antagonist radioligand (CH. Mϋller, Bioorganic and Medicinal Chemistry Letters, 12, 501-503, 2002).
Our aim was to prepare A3 radioligands of antagonistic effect labelled with iodine isotop of mass number 125, since these have higher specific activity compared to those labelled with tritium. The goal was to prepare radioligands having strong affinity to the adenosin A3 receptor, but at the. same time showing high selectivity within the subtypes, i.e., binding in much higher concentration to the Ai, A2a and A2b receptors. A further aim was to
have radioligands suitable for the characterisation of the A3 receptor in the different tissues and for the study of the mechanism of action of A3 antagonists.
The subject of our invention is compounds of the general formula (I)
R1 stands for hydrogen atom or a straight or branched C1-4 alkyl group, or a C3-6 cycloalkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted with one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, or halogen atom, or for a 5- or 6-membered heteroaromatic ring -containing one, two or three nitrogen atoms-, or for a 5-membered heteroaromatic ring - containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom- optionally substituted with one or more straight or branched C1.4 alkyl group, straight or branched C1-4 alkoxy group, or halogen atom;
R2 stands for hydrogen atom or for a straight or branched Cj-4 alkyl group, or for a phenyl-, benzyl-, thienyl- or furyl-group -optionally substituted with a methylenedioxy group, or one or more straight or branched Ci-4 alkyl group, or straight or branched C1-4 alkoxy-, hydroxyl-, trifluoromethyl- or cyano-group, or halogen atom-, or for a 5- or 6- membered heteroaromatic ring -containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom
and one sulphur atom -optionally substituted with one or more straight or branched Ci-4 alkyl group, straight or branched Ci-4 alkoxy group, or halogen atom.
Detailed meanings of the above substituents are as follows:
By straight or branched Ci-4 alkyl group we mean methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, secondary-butyl-, tert.-butyl-, preferably ethyl- or methyl group.
By straight or branched Ci-4 alkoxy group we mean methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec.-butoxy-, tert.-butoxy-, preferably ethoxy- or methoxy group.
By C3..6 cycloalkyl group we mean cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexyl group.
The heteroaromatic ring containing one or two or three nitrogen atoms may mean pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1 ,2,4-triazole, pyridine, pyrimidine, pyridazine, pyrazine and 1,3,4-triazine ring. The ring is optionally substituted with a Ci-4 alkyl, or alkoxy group or by a halogen atom. The heteroaromatic ring containing one nitrogen atom and one oxygen or one sulphur atom means oxazole, isoxazole, thiazole, isothiazole ring. The ring is optionally substituted with a Ci-4 alkyl, or alkoxy group or by a halogen atom.
A favourable group of compounds of the general formula (I) is formed by the compounds -wherein
R1 stands for phenyl-, thienyl- or furyl group R2 stands for 4-methoxyphenyl-, 3-methylphenyl-, 3-methoxyphenyl-,
2-thienyl-, 3-thienyl-, 2-furyl- or 3-furyl group.
Especially favourable are the following compounds complying with the above criteria:
4-Methoxy-iY-(6-[ I]iodo-4-benzylamino-3-cyanoqumolin-2- yl)benzamide
4-Methoxy-iV-(6-[ I]iodo-4-[2-thienylmethylamino]-3-cyanoqumolin- 2-yl)benzamide.
Further subject of the invention is the preparation of the compounds of the general formula (I)
R 1
H
N
In the process according to our invention the compounds of the general formula (I) are prepared by reacting the appropriate compounds of the general formula (II) with unsupported [ I]NaI, in the presence of an oxidant. The reaction is carried out in aqueous methanolic medium (pH 3), at room temperature.
As oxidizing agents, peroxides for example hydrogen peroxide, N- halogeno-succinamides e.g. JV-chloro-succinamide, or chlorosulphonamides, preferably chloramine-T can be used. The product is purified by reversed-phase high-performance liquid chromatographic (RP-HPLC) method using silica gel based Ci8 modified packing as stationary phase and methanol-water binary mixture containing 0.1% (v/v) trifluoroacetic acid as eluent system, with flow rate of 0.9 ml/min. Detection is carried out by UV at 272 nm; detection of radioactivity is carried out by flow liquid scintillation method.
According to our invention the compound of general formula (II)
-wherein R1 and R2 have the meanings as defined above and X stands for iodo- or bromo atom- by reacting it in the presence of palladium catalyst, organic or inorganic base and organic solvent, with a hexaalkyl-distannane compound. The product of general formula (II) is isolated. The exchange of the halogen atom for trialkyl-stannyl group is carried out in an organic solvent, for example in dioxane or dimethylformamide, or favourably in N- methyl-2-pyrrolidone. The reaction can be performed in a wide temperature range, preferably between 2O0C - 1000C. As organic base trialkylamines, preferably triethylamine can be applied. For inorganic base alkali hydroxides, carbonates and acetates, preferably potassium acetate can be used. In the reaction palladium acetate, palladium chloride or tetrakis(triphenylphosphine)palladium(0) catalysts can be used (Z.P. Zhuang. M.P. Kung, C. Hou, D.M. Skovronsky, T.L. Gur, K. Plossl, J.Q. Trojanowski, V.M.Y. Lee, H.F. Kung, J. Med. Chem. 44, 1905, (2001)), but we have found that with tetrakis(tri(o-tolyl)phosphine)palladium(0) catalyst faster reaction and better yield is achived. The compounds of the general formula (III)
can be synthesized by the method described in patent application WO 02/096879.
The process according to our invention is shown in Reaction Scheme 1.
ine-T
Further details of the invention are demonstrated in the Examples, without limiting the claims to the Examples.
Examples Example 1.
4-Methoxy-JV-(6-[125I]iodo-4-benzylamino-3-cyanoquinolin-2- yl)benzamide
In the general formula (I) R1 stands for phenyl group, R2 stands for 4- methoxyphenyl group. a.) To 8 μl of 0.1 mg/ml methanolic solution of 4-methoxy-iV-(6- tributylstannyl-4-benzylamino-3-cyanoquinolin-2-yl)benzamide are added 25 μl (1.1 nmol) of 1% (v/v) methanolic solution of trifluoroacetic acid and 70 MBq [125I]NaI solution (21 μl). To the reaction mixture 5 μl (2 nmol) of 0.1 mg/ml aqueous solution of chloramine-T is added and the mixture is stirred at room temperature for 15 minutes. After the incubation period the reaction is stopped by the addition of 7μl (3.5 nmol) of 0.1 mg/ml sodium pyrosulfite solution and the product is immediately purified by using RP-HPLC method, applying UV and radioactivity detection. By this manner 31 MBq of the title compound is obtained (molar activity 81.4 GBq/mmol), radiochemical purity >95%. The purified product is stored in methanol-water (0.1% TFA) 3: 1 mixture (activity concentration: 29 MBq/ml). b.) 4-Methoxy-N-(6-tributylstannyl-4-benzylamino-3-cyanoquinolin-2- yl)benzamide.
0.33 g of 4-methoxy-N-(6-iodo-4-benzylamino-3-cyanoquinolin-2- yl)benzamide is dissolved in 5 ml of N-methyl-2-pyrrolidone and to the solution 240 mg of potassium acetate, 50 mg of tetrakis(tri(o- tolyl)phosphine)palladium(O) and 0.6 ml of hexabutyl distannane are added. The reaction mixture is stirred at room temperature under argon atmosphere for 16 hours, then it is poured onto 20 ml of water and extracted with 2 x 20 ml of toluene. The united toluene phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on a
silicagel coloumn using chloroform - ethyl acetate (10 : 0.5) mixture as eluent. After evaporation of the pure fractions 250 mg of the title compound is obtained.
1H-NMR (CDCl3) δ 0.9 (m, 9H), 1.1 (M5 6H)5 1.3 (m, 6H), 1.55 (m5 6H)5 3.8 (s, 3H)5 5.08 (d, 2H), 7.06 (d, 2H)5 7.2-7.4 (m, 5H)5 7.55 (d, 2H)5 7.9-8.1 (m, 3H), 8.66 (m, IH), 10.7 (s, IH).
Example 2.
4-Methoxy-7V-(6-[125I]iodo-4-[2-thienylmethylamino]-3-cyanoquinolin- 2-yl)benzamide
In the general formula (I) R stands for thienyl group, R stands for 4- methoxyphenyl group. a.) To 8 μl (1.1 nmol) of 0.1 mg/ml methanolic solution of 4-methoxy-
N-(6-tributylstannyl-4- [2-thienylmethylamino] -3 -cyanoquinolin-2- yl)benzamide are added 25 μl (1.1 nmol) of 1% (v/v) methanolic solution of trifluoroacetic acid and 70 MBq [125I]NaI solution (21 μl). To the reaction mixture 5 μl (2 nmol) of 0.1 mg/ml aqueous solution of chloramine-T is added and the mixture is stirred at room temperature for 15 minutes. After the incubation period the reaction is stopped by the addition of 7μl (3.5 nmol) of 0.1 mg/ml sodium pyrosulfite solution and the product is immediately purified by RP-HPLC method, while applying UV and radioactivity detection.
By this manner 28 MBq of the title compound is obtained (molar activity 81.4
GBq/mmol), radiochemical purity >95%. The purified product is stored in methanol-water (0.1% TFA) 3:1 solvent mixture (activity concentration: 28 MBq/ml). b .) 4-Methoxy-iV-(6-tributylstannyl-4- [2-thienylmethylamino] -3 - cyanoquinolin-2-yl)benzamide.
0.3 g 4-Methoxy-N-(6-iodo-4-[2-thienylmethylamino]-3- cyanoquinolin-2-yl)benzamide is dissolved in 5 ml of JV-methyl-2-pyrrolidone
and to the solution 240 mg of potassium acetate, 50 mg of tetrakis(tri(o- tolyl)phosphine)palladium(O) and 0.6 ml of hexabutyl distannane are added. The reaction mixture is stirred at room temperature under argon atmosphere for 16 hours, then it is poured onto 20 ml of water and extracted with 2 x 20 ml of toluene. The united toluene phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on a silicagel coloumn using chloroform - ethyl acetate (10 : 0.5) mixture as eluent. By evaporating the pure fractions 235 mg of the title compound is obtained. 1H-NMR (CDCl3) δ 0.9 (m, 9H), 1.1 (M, 6H), 1.3 (m, 6H), 1.55 (m, 6H), 3.85 (s, 3H), 5.1 (d, 2H), 6.9-7.17 (m, 4H), 7.43-7.54 (m, 2H), 8.03 (m, 3H), 8.72- 8.82 (m, 2H), 10.86 (s, IH).
Example 3.
A./ Biological methods
Human Adenozin A1 receptor binding
Preparing membrane suspension: collect ovarium cells of cloned Chinese hamster expressing human Ai receptors (further: CHOhAi), wash them three times with PBS, centrifuge (1000 x g 10 min.) and homogenize (B.Braun Potter S) at 1500/min rotation speed. Buffer: 50 mM Tris HCl, pH 7,4. Centrifuge this homogenized mixture (43.000 g, 10 min), suspense the pellet in the above buffer with adjustment of the protein concentration to 5 mg/mL (Bradford method) and complete with 2 U/mL ADA.
Binding protocol: incubate CHO-hAi membrane preparation (50 μg protein content), in the presence of the test compound and 10 nM [3H]CCPA (2-chloro-N6-cyclopenthyl-adenosine) (80.000 dpm) in incubation buffer (50 mM Tris HCl, pH 7.4, 2 U/mL adenosine deaminase). The non-specific
binding is defined in the presence of 10 μM R-PIA (N6-[L-2- phenylisopropyl] adenosine) in a total volume of 100 μL for 3 hr at room temperature. Filter over Whatman GF/B glass fibre filters (presoaked in 0.5% polyethylimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM Tris HCl (pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in 96-well plate in the presence of HiSafe-3 cocktail in beta-counter (1450 Microbeta, Wallac). Inhibition [%] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non-specific activity))* 100
Human adenosine A2a receptor binding
Incubate 7 μg of membranes (human A2a adenosine receptors transfected into HEK-293 cells, source: Receptor Biology, Inc.), in the presence of the test compound and 20 nM [3H]CGS-21680 (2-[/?-(2- carbonylethyl)phenylethylamino]-5Λ-N-ethylcarboxamido-adenosine) (200.000 dpm) in incubation buffer (50 mM Tris HCl, 10 mM MgCl2, 1 mM EDTA, 2 U/mL adenosine deaminase, pH 7.4). The non-specific binding is defined in the presence of 100 μg ΝECA (5 -iV-ethylcarboxamido-adenosme) in a total volume of 100 μl for 90 min at room temperature. Filter in vacuum over Whatman GF/B glass fibre filters (presoaked for 3 hours in 0.5% polyethylimine), wash 4x with 1 mL ice-cold buffer (50 mM Tris HCl, 10 mM MgCl2, 1 mM EDTA, 0.9 % NaCl, pH 7.4) on 96-well Brandel Cell Harvester. Detection of activity: in beta-counter (1450 Microbeta, Wallac) in the presence of 200 μL HiSafe-3 cocktail. Inhibition [%] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non- specific activity))* 100.
Human adenosine A2b receptor binding
Binding protocol: incubate 20.8 μg of membranes (human A2b adenosine receptors transfected into HEK-293 cells, source: Receptor
Biology, Inc.), in the presence of the test compound and 32.4 nM [3H]DPCPX (8-cyclopenthyl-l,3-dipropylxanthine) (800.000 dpm) in incubation buffer (50 niM Tris-HCl, 10 niM MgCl2, 1 mM EDTA, 0.1 mM benzamidine, 2 U/mL adenosine deaminase, pH 6.5). The non-specific binding is defined in the presence of 100 μM NECA (5'-N-ethylcarboxamido-adenosine) in a total volume of 100 μL for 30 min at room temperature. Filter under 25 Hgmm vacuum over Whatman GF/C glass fibre filters (presoaked in 0.5% polyethylimine for 3 hours), wash 4x with 1 mL ice-cold 50 mM Tris HCl (pH 6.5) on 96-well Brandel Cell Harvester. Detection of activity: in beta- counter (1450 Microbeta, Wallac) in the presence of 200 μL of HiSafe-3 cocktail. Inhibition [%] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non-specific activity))* 100
Human adenosine A3 receptor binding
Preparing membrane suspension: collect ovarium cells of cloned Chinese hamster expressing human A3 receptors (further: CHO-IiA3), wash them three times with PBS, centrifuge (1000 x g 10 min.) and homogenize (B.Braun Potter S) at 1500/min rotation speed. Buffer: 50 mM Tris, 1OmM MgCl2, 1 mM EDTA, pH 8.0. Centrifuge this homogenized mixture (43.000 g, 10 min), suspense the pellet in the above buffer with adjustment of the protein concentration to 0.1 mg/mL (Bradford method) and complete with 2 U/mL ADA.
Receptor binding in the presence of [125I]AB-MECA :
Incubate the CHO-IiA3 membrane preparation (protein content 2 μg) in the presence of the test compound and 0.5 nM [ I]AB-MECA (4-amino-3- iodo-benzyl-5Λ-7V-methylcarboxamide-adenosine) (100.000 cpm) in incubation buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA, 2 U/mL
adenosine deaminase, pH 8.0). The non-specific radioligand binding is defined in the presence of 100 μM R-PIA (N6-[L-2- phenylisopropyl]adenosine) in a total volume of 50 μL for 60 min at room temperature. Filter under 25 Hgmm vacuum over Whatman GF/C glass fibre filters (presoaked in 0.5% polyethylimine for 3 hours), wash 4x with 1 mL ice-cold buffer (50 mM Tris, 10 mM MgCl2, 1 mM EDTA, pH 8) on 96-well Brandel Cell Harvester. Detection of radioactivity: in gamma-counter (1470 Wizard, Wallac). Inhibition [%] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non-specific activity))* 100.
Receptor binding in the presence of the radioactive iodine-containing compound of Example 2/a:
Incubate the CHO-IiA3 membrane preparation (protein content 4 μg) in the presence of the test compound and 0.5 nM of the compound containing radioactive iodine (100.000 cpm), described in Example 2/a, in incubation buffer (50 mM Tris, pH 8.0, 10 mM MgCl2, 1 mM EDTA, 0.08% CHAPS, 0.5% BSA, 2 U/mL adenosine deaminase). The non-specific radioligand binding is defined in the presence of 100 μM R-PIA (N6-[L-2- phenylisopropyl]adenosine) in a total volume of 50 μL for 60 min at room temperature. Keep the isotop preparation and the reaction mixture in polyethylene tube to decrease adsorption. Filter under 25 Hgmm vacuum over Whatman GF/C glass fibre filters (presoaked in 0.5% polyethylimine for 3 hours), wash 4x with 1 mL ice-cold buffer (50 mM Tris (pH 8), 10 mM MgCl2, 1 mM EDTA, 0.08% CHAPS, 0.25% BSA) on 96-well Brandel Cell Harvester. Detection of radioactivity: in gamma-counter (1470 Wizard, Wallac). Inhibition [%] = 100-((activity in the presence of test compound - non-specific activity)/(total activity - non-specific activity))* 100.
B./ Biological results
I Affinity of the ιm-labeled iodine-containing compound given in Example 2/b as starting material (i.e. the un-labeled analogue of the new radioligand given in Example 2/a) to the adenosine receptor sub-types in the presence of known radioligands
The affinity of the starting compound of Example 2/b to the adenosine A3 receptor (Ki = 1.5 nM) exhibits at least thousand-fold selectivity compared to the other adenosine receptor sub-types (Table 1).
Table 1 Characterisation of the starting compound of Example 2/b as regards its affinity to the adenosine receptors
II/A Investigation of the new radioactive iodine-containing compound of Example 2/a on the human adenosine A3 receptor by Scatchard analysis used for the characterisation of radioligands
On the basis of radioisotop saturation curves, by Scatchard analysis (G.
Scatchard, Ann. N. Y. Acad. Sci. 51 :660, 1949) the dissociation constant (KD) of the new radioligand of Example 2/a on CHO-IiA3 membrane preparation is determined. In the investigated concentration range (0.156 nM - 10 nM) the radioligand binds to only one binding place in the presence of a membrane
preparate containing 4 μg of protein. The value of KD was found to be 4 nM, the maximal binding capacity 985 femtomol/1 mg protein (see Figure 1 ).
Figure 1 : Scatchard saturation curve of the new radioligand of Example 2/a in the presence of CHO-hA.3 membrane preparation
II/B Comparison of a known adenosine A3 radioligand with the new radioligand of Example 2/a on the basis of the affinity values of reference compounds, in the presence of 4 μg CHOhA3 preparate
Knowing the KD values, by the Cheng-Prusoff equation (Y. J. Cheng and W. H. Prusoff, Biochem. Pharmacol. 22:3099, 1973) the K; constants of the investigated reference compounds and that of the starting compound of
Example 2/b (i.e. of the un-labeled analogue of the new radioligand of
Example 2/a) were calculated on the basis of the IC50 values. The reference compounds exhibited similar affinity values in the presence of the known and of the new radoligands, proving the suitability of the radioligand of Example
2/a. The un-labeled analogue of the new radioligand exhibited a Kj value nearly equal to the KD value of the isotop-labeled form (4.0 nM and 1.3 nM), also proving the specific binding of the new radioligand (see Table 2).
Table 2. Comparison of a known adenosine A3 radioligand and the new radioligand of Example 2/a with the help of affinity values of reference compounds, in the presence of 4 μg CHO-IiA3 preparation.
The radioligand given
[125I]AB-MECA in Example 2/a
Ki
R-PIA 65 nM 15O nM
Cl-IB-MECA 3.3 nM 5.9 nM
The starting compound of 1.5 nM 1.3 nM Example 2/b
Claims
1. Compounds of the general formula (I)
R1 stands for hydrogen atom or a straight or branched Ci-4 alkyl group, or a C3-6 cycloalkyl group, or a phenyl group, thienyl group, or furyl group, optionally substituted with one or more straight or branched Cμ4 alkyl group, straight or branched Ci_4 alkoxy group, or halogen atom, or for a 5- or 6 membered heteroaromatic ring -containing one, two or three nitrogen atoms-, or 5-membered heteroaromatic ring -containing one nitrogen atom and one oxygen atom or one nitrogen atom and one sulphur atom- optionally substituted with one or more straight or branched Ci_4 alkyl group, straight or branched Cμ4 alkoxy group, or halogen atom; R2 stands for hydrogen atom or for a straight or branched Ci-4 alkyl group, or for a phenyl-, benzyl-, thienyl- or furyl-group -optionally substituted with a methylenedioxy group, or one or more straight or branched Ci-4 alkyl group, or straight or branched Ci-4 alkoxy-, hydroxyl-, trifluoromethyl- or cyano-group or halogen atom-, or for a 5- or 6-membered heteroaromatic ring -containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulphur atom- optionally substituted with one or more straight or branched Ci-4 alkyl group, straight or branched Ci_4 alkoxy group, or halogen atom. 2. Compounds of the general formula (I)
R1 stands for phenyl- or thienyl- or furyl-group R2 stands for 4-methoxyphenyl-, 3-methylphenyl-, 3-methoxyphenyl-,
2-thienyl-, 3-thienyl-, 2-furyl- or 3-furyl group.
3. The following compounds according to Claim 1-2: 4-Methoxy-iV-(6-[125I]iodo-4-benzylamino-3-cyanoquinolin-2-yl)benzamide 4-Methoxy-iV-(6-[125I]iodo-4-[2-thienylmethylamino]-3-cyanoquinolin-2- yl)benzamide.
4. Process for the preparation of the compounds of the general formula (D
,1
- where R and R have the meanings as defined in Claim 1. and R stands for straight or branched C1-4 alkyl group- is reacted with [125I]NaI, in the presence of an oxidant.
5. Process as defined in Claim 4, characterized in that as oxidant a peroxide, like hydrogen peroxide, or an TV-halogeno-succinamide, like TV- chloro-succinamide, or a chlorosulfonamide, preferably chloramin-T is used.
6. Process as defined in Claim 4., characterized in that un-supported [125I]NaI is used.
7. Process as defined in Claim 4., characterized in that the reaction is carried out in aqueous-methanolic medium (pH 3), at room temperature.
8. Process as defined in Claim 4., characterized in that the product is isolated from the reaction mixture by RP-HPLC method.
9. Process as defined in Claim 8., characterized in that during the isolation by RP-HPLC method, silica gel based Cis modified packing is used as stationary phase and the separation is performed using methanol-water binary eluent system containing 0.1% (v/v) trifluoroacetic acid, with flow-rate of 0.9 ml/min3 under UV detection and on-line radioactivity detection.
10. Compounds of the general formula (II)
11. Compounds of the general formula (II)
12. Process for the preparation of the compounds of the general formula (II) 
- where in the formula R1 and R2 have the meanings as defined in Claim 1. and R3 stands for straight or branched CM alkyl group- characterized in that a compound of the general formula (III)
D1
- where in the formula R and R have the meanings as defined in Claim 1. - is reacted with hexaalkyl distannane, in an organic solvent, in the presence of a base and palladium catalyst.
13. Process according to Claim 12., characterized in that as organic solvent dioxane, dimethyl formamide, preferably iV-methyl-2-pyrrolidone is used.
14. Process according to Claim 12., characterized in that as base, an organic base, like trialkylamine, preferably triethylamine, or an inorganic base, like alkali hydroxide, -carbonate or -acetate, preferably potassium acetate is used.
15. Process according to Claim 12., characterized in that as catalyst, palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium(0), preferably tetrakis(tri(o- tolyl)phosphine)palladium(O) catalyst is used.
16. Process according to Claim 12., characterized in that as hexaalkyl distannane, hexabutyl distannane is used.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2005303544A AU2005303544B2 (en) | 2004-11-15 | 2005-11-09 | Isotopically marked quinoline derivatives as adenosin A3 receptor ligands |
| EP05806497A EP1814857B1 (en) | 2004-11-15 | 2005-11-09 | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands |
| CN2005800388317A CN101056859B (en) | 2004-11-15 | 2005-11-09 | Quinoline derivatives as isotope labeling for adenosine a3 receptor ligand |
| BRPI0517816-9A BRPI0517816A (en) | 2004-11-15 | 2005-11-09 | isotopically labeled quinoline derivatives as adenosine α3 receptor ligands |
| JP2007540727A JP2008519816A (en) | 2004-11-15 | 2005-11-09 | Isotopically labeled quinoline derivatives as adenosine A3 receptor ligands |
| AT05806497T ATE479660T1 (en) | 2004-11-15 | 2005-11-09 | ISOTOPICALLY LABELED QUINOLINE DERIVATIVES AS LIGANDS OF THE ADENOSINE A3 RECEPTOR |
| CA002588073A CA2588073A1 (en) | 2004-11-15 | 2005-11-09 | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands |
| MX2007005768A MX2007005768A (en) | 2004-11-15 | 2005-11-09 | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands. |
| DE602005023334T DE602005023334D1 (en) | 2004-11-15 | 2005-11-09 | ISOTOPENMARKED CHINOLINE DERIVATIVES AS LIGANDS OF THE ADENOSINE A3 RECEPTOR |
| IL182971A IL182971A0 (en) | 2004-11-15 | 2007-05-03 | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands |
| US11/748,098 US7964731B2 (en) | 2004-11-15 | 2007-05-14 | Isotopically marked quinoline derivatives as adenosin A3 receptor ligands |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0402371A HUP0402371A2 (en) | 2004-11-15 | 2004-11-15 | Novel 125-i-labeled amino-quinoline derivatives |
| HUP0402371 | 2004-11-15 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US11/748,098 Continuation US7964731B2 (en) | 2004-11-15 | 2007-05-14 | Isotopically marked quinoline derivatives as adenosin A3 receptor ligands |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006051341A1 true WO2006051341A1 (en) | 2006-05-18 |
Family
ID=89985606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2005/000120 WO2006051341A1 (en) | 2004-11-15 | 2005-11-09 | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US7964731B2 (en) |
| EP (1) | EP1814857B1 (en) |
| JP (1) | JP2008519816A (en) |
| KR (1) | KR20070084202A (en) |
| CN (1) | CN101056859B (en) |
| AT (1) | ATE479660T1 (en) |
| AU (1) | AU2005303544B2 (en) |
| BR (1) | BRPI0517816A (en) |
| CA (1) | CA2588073A1 (en) |
| DE (1) | DE602005023334D1 (en) |
| HU (1) | HUP0402371A2 (en) |
| IL (1) | IL182971A0 (en) |
| MX (1) | MX2007005768A (en) |
| RU (1) | RU2379290C2 (en) |
| WO (1) | WO2006051341A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002096879A1 (en) * | 2001-05-31 | 2002-12-05 | Sanofi-Synthelabo | Aminoquinoline and aminopyridine derivatives and their use as adenosine a3 ligands |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6921825B2 (en) * | 1998-09-16 | 2005-07-26 | King Pharmaceuticuals Research & Development, Inc. | Adenosine A3 receptor modulators |
-
2004
- 2004-11-15 HU HU0402371A patent/HUP0402371A2/en unknown
-
2005
- 2005-11-09 RU RU2007122396/04A patent/RU2379290C2/en not_active IP Right Cessation
- 2005-11-09 JP JP2007540727A patent/JP2008519816A/en not_active Withdrawn
- 2005-11-09 MX MX2007005768A patent/MX2007005768A/en active IP Right Grant
- 2005-11-09 KR KR1020077010909A patent/KR20070084202A/en not_active Application Discontinuation
- 2005-11-09 BR BRPI0517816-9A patent/BRPI0517816A/en not_active IP Right Cessation
- 2005-11-09 AT AT05806497T patent/ATE479660T1/en not_active IP Right Cessation
- 2005-11-09 AU AU2005303544A patent/AU2005303544B2/en not_active Ceased
- 2005-11-09 WO PCT/HU2005/000120 patent/WO2006051341A1/en active Application Filing
- 2005-11-09 EP EP05806497A patent/EP1814857B1/en not_active Not-in-force
- 2005-11-09 CN CN2005800388317A patent/CN101056859B/en not_active Expired - Fee Related
- 2005-11-09 DE DE602005023334T patent/DE602005023334D1/en active Active
- 2005-11-09 CA CA002588073A patent/CA2588073A1/en not_active Abandoned
-
2007
- 2007-05-03 IL IL182971A patent/IL182971A0/en unknown
- 2007-05-14 US US11/748,098 patent/US7964731B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002096879A1 (en) * | 2001-05-31 | 2002-12-05 | Sanofi-Synthelabo | Aminoquinoline and aminopyridine derivatives and their use as adenosine a3 ligands |
Non-Patent Citations (3)
| Title |
|---|
| BARALDI P G P G ET AL: "Synthesis and preliminary biological evaluation of [<3>H]-MRE 3008-F20: the first high affinity radioligand antagonist for the human A3 adenosine receptors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 10, no. 3, February 2000 (2000-02-01), pages 209 - 211, XP004188818, ISSN: 0960-894X * |
| DRURY; SZENTGY6RGYI, J PHYSIOL, vol. 68, no. 213, 1929 |
| MÜLLER ET AL.: "[3H]8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]-purin-5-one ([3H]PSB-11), a Novel High-Affinity Antagonist Radioligand for Human A3 Adenosine Receptors", BIOORG. MED. CHEM. LETT., vol. 12, 2002, pages 501 - 503, XP002367060 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070084202A (en) | 2007-08-24 |
| MX2007005768A (en) | 2007-07-16 |
| IL182971A0 (en) | 2007-08-19 |
| EP1814857A1 (en) | 2007-08-08 |
| BRPI0517816A (en) | 2008-10-21 |
| US20080027225A1 (en) | 2008-01-31 |
| DE602005023334D1 (en) | 2010-10-14 |
| RU2007122396A (en) | 2008-12-20 |
| JP2008519816A (en) | 2008-06-12 |
| HUP0402371A2 (en) | 2006-09-28 |
| US7964731B2 (en) | 2011-06-21 |
| CN101056859A (en) | 2007-10-17 |
| CN101056859B (en) | 2010-05-05 |
| AU2005303544B2 (en) | 2011-06-02 |
| CA2588073A1 (en) | 2006-05-18 |
| HU0402371D0 (en) | 2005-03-29 |
| RU2379290C2 (en) | 2010-01-20 |
| EP1814857B1 (en) | 2010-09-01 |
| AU2005303544A1 (en) | 2006-05-18 |
| ATE479660T1 (en) | 2010-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10035789B2 (en) | Compounds useful for treating disorders related to RET | |
| US10183928B2 (en) | Inhibitors of RET | |
| AU2012250517B2 (en) | Compounds for inhibiting cell proliferation in EGFR-driven cancers | |
| TWI788424B (en) | Receptor inhibitor | |
| EP3596083A1 (en) | Heteroaryl compounds useful as mk2 inhibitors | |
| WO2019062637A1 (en) | Quinoline derivative and application thereof as tyrosine kinase inhibitor | |
| JP6139792B2 (en) | Pyrido [2,3-d] pyrimidin-4-one compounds as tankyrase inhibitors | |
| JP2021523875A (en) | Pyrazine-2 (1H) -one compound as an FGFR inhibitor | |
| JP2021532103A (en) | Substituted triazoloquinoxaline derivative | |
| CA2448561C (en) | Aminoquinoline derivatives and their use as adenosine a3 ligands | |
| KR20200037806A (en) | LXR modulators containing amines or (thio) amines | |
| CA3085498C (en) | Crystal form and salt form of tgf-.beta.ri inhibitor and preparation method therefor | |
| AU2002353240B2 (en) | Triazolo-quinolin derivatives useful as adenosine receptor ligands | |
| Xia et al. | Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists | |
| EP1814857B1 (en) | Isotopically marked quinoline derivatives as adenosin a3 receptor ligands | |
| AU2002353241B2 (en) | Imidazoquinoline derivatives | |
| JP6900406B2 (en) | Dihydropyrazoloazepine compounds as Akt inhibitors | |
| CN115667253A (en) | Compounds useful for inhibition of RET kinase | |
| WO2015174417A1 (en) | Pyrazine derivative | |
| WO2000050416A1 (en) | 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both | |
| CN113527304A (en) | Preparation method of quinoline TGF-beta 1 inhibitor | |
| CN115960032A (en) | Aryloxy propanol amine beta-adrenaline receptor ligand with beta-arrestin biased agonistic activity and application thereof | |
| CN106795164A (en) | Method of the one kind for preparing alkyl amino imidazo [1,2 b] pyridyl derivatives of 3 phenyl/heteroaryl, 6 phenoxy group 8 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 1393/KOLNP/2007 Country of ref document: IN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2005806497 Country of ref document: EP |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 182971 Country of ref document: IL |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2588073 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2007/005768 Country of ref document: MX Ref document number: 2007540727 Country of ref document: JP Ref document number: 200580038831.7 Country of ref document: CN Ref document number: 11748098 Country of ref document: US Ref document number: 2005303544 Country of ref document: AU Ref document number: 1020077010909 Country of ref document: KR |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| ENP | Entry into the national phase |
Ref document number: 2005303544 Country of ref document: AU Date of ref document: 20051109 Kind code of ref document: A |
|
| WWP | Wipo information: published in national office |
Ref document number: 2005303544 Country of ref document: AU |
|
| ENP | Entry into the national phase |
Ref document number: 2007122396 Country of ref document: RU Kind code of ref document: A |
|
| WWP | Wipo information: published in national office |
Ref document number: 2005806497 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 11748098 Country of ref document: US |
|
| ENP | Entry into the national phase |
Ref document number: PI0517816 Country of ref document: BR |