TW200946129A - Divalent hydrazide compound conjugates for inhibiting cystic fibrosis transmembrane conductance regulator - Google Patents

Info

Publication number

TW200946129A

TW200946129A TW098111395A TW98111395A TW200946129A TW 200946129 A TW200946129 A TW 200946129A TW 098111395 A TW098111395 A TW 098111395A TW 98111395 A TW98111395 A TW 98111395A TW 200946129 A TW200946129 A TW 200946129A

Authority

TW

Taiwan

Prior art keywords

mono

group

phenyl

hydroxy

alkoxy

Prior art date

2008-04-04

Links

• Espacenet
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• 108010079245 Cystic Fibrosis Transmembrane Conductance Regulator Proteins 0.000 title claims abstract description 145
• 102000012605 Cystic Fibrosis Transmembrane Conductance Regulator Human genes 0.000 title claims abstract description 143
• 150000001875 compounds Chemical class 0.000 title claims description 312
• 230000002401 inhibitory effect Effects 0.000 title claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
• 206010012735 Diarrhoea Diseases 0.000 claims abstract description 38
• 201000010099 disease Diseases 0.000 claims abstract description 35
• 201000009881 secretory diarrhea Diseases 0.000 claims abstract description 25
• 230000037427 ion transport Effects 0.000 claims abstract description 17
• 125000005843 halogen group Chemical group 0.000 claims description 253
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 240
• 125000003545 alkoxy group Chemical group 0.000 claims description 219
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 211
• -1 functional Chemical group 0.000 claims description 156
• 125000001624 naphthyl group Chemical group 0.000 claims description 143
• 125000000217 alkyl group Chemical group 0.000 claims description 121
• 229910052739 hydrogen Inorganic materials 0.000 claims description 113
• 239000001257 hydrogen Substances 0.000 claims description 112
• 125000006850 spacer group Chemical group 0.000 claims description 84
• 239000002585 base Substances 0.000 claims description 65
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 60
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 60
• 229910052794 bromium Inorganic materials 0.000 claims description 60
• 238000000034 method Methods 0.000 claims description 59
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
• 229920000642 polymer Polymers 0.000 claims description 56
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 52
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 48
• 150000002431 hydrogen Chemical class 0.000 claims description 47
• 239000007983 Tris buffer Substances 0.000 claims description 41
• 125000005647 linker group Chemical group 0.000 claims description 41
• 239000007789 gas Substances 0.000 claims description 40
• 125000003118 aryl group Chemical group 0.000 claims description 38
• 239000000203 mixture Substances 0.000 claims description 36
• 125000000524 functional group Chemical group 0.000 claims description 34
• 125000001072 heteroaryl group Chemical group 0.000 claims description 33
• 150000003839 salts Chemical class 0.000 claims description 28
• 239000002253 acid Substances 0.000 claims description 27
• 239000000460 chlorine Substances 0.000 claims description 27
• WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 26
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 25
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 24
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• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 22
• 229910052801 chlorine Inorganic materials 0.000 claims description 20
• 239000000651 prodrug Substances 0.000 claims description 20
• 229940002612 prodrug Drugs 0.000 claims description 20
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
• 102000009016 Cholera Toxin Human genes 0.000 claims description 17
• 108010049048 Cholera Toxin Proteins 0.000 claims description 17
• 125000004104 aryloxy group Chemical group 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
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• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 11
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
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• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 159000000000 sodium salts Chemical class 0.000 claims description 10
• 125000006612 decyloxy group Chemical group 0.000 claims description 9
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• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
• SGBQUMZTGSQNAO-UHFFFAOYSA-N 2-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(O)=CC=C21 SGBQUMZTGSQNAO-UHFFFAOYSA-N 0.000 claims description 8
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• 150000002367 halogens Chemical class 0.000 claims description 8
• YSCNMFDFYJUPEF-OWOJBTEDSA-N 4,4'-diisothiocyano-trans-stilbene-2,2'-disulfonic acid Chemical compound OS(=O)(=O)C1=CC(N=C=S)=CC=C1\C=C\C1=CC=C(N=C=S)C=C1S(O)(=O)=O YSCNMFDFYJUPEF-OWOJBTEDSA-N 0.000 claims description 7
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
• 241000607142 Salmonella Species 0.000 claims description 7
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• 239000000147 enterotoxin Substances 0.000 claims description 7
• 231100000655 enterotoxin Toxicity 0.000 claims description 7
• 239000000463 material Substances 0.000 claims description 7
• 239000011734 sodium Substances 0.000 claims description 7
• 229910052708 sodium Inorganic materials 0.000 claims description 7
• NZWRKZGKRMQQEC-UHFFFAOYSA-N 3-hydroxynaphthalene-1,2-disulfonic acid Chemical compound C1=CC=C2C(S(O)(=O)=O)=C(S(O)(=O)=O)C(O)=CC2=C1 NZWRKZGKRMQQEC-UHFFFAOYSA-N 0.000 claims description 6
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• 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
• FEPBITJSIHRMRT-UHFFFAOYSA-N 4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1 FEPBITJSIHRMRT-UHFFFAOYSA-N 0.000 claims description 5
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
• 241000702670 Rotavirus Species 0.000 claims description 5
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
• RXXCIBALSKQCAE-UHFFFAOYSA-N 3-methylbutoxymethylbenzene Chemical compound CC(C)CCOCC1=CC=CC=C1 RXXCIBALSKQCAE-UHFFFAOYSA-N 0.000 claims description 4
• 241000228212 Aspergillus Species 0.000 claims description 4
• 241000223935 Cryptosporidium Species 0.000 claims description 4
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• 108010079723 Shiga Toxin Proteins 0.000 claims description 4
• 241000607768 Shigella Species 0.000 claims description 4
• 241000607626 Vibrio cholerae Species 0.000 claims description 4
• 238000002512 chemotherapy Methods 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
• 150000003254 radicals Chemical class 0.000 claims description 4
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• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
• 230000005856 abnormality Effects 0.000 claims description 3
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• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
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