NZ548399A - 1-N-phenyl-amino-1H-imidazole derivatives and pharmaceutical compositions containing them - Google Patents

Info

Publication number

NZ548399A

NZ548399A NZ548399A NZ54839904A NZ548399A NZ 548399 A NZ548399 A NZ 548399A NZ 548399 A NZ548399 A NZ 548399A NZ 54839904 A NZ54839904 A NZ 54839904A NZ 548399 A NZ548399 A NZ 548399A

Authority

NZ

New Zealand

Prior art keywords

imidazol

amino

cyanophenyl

methyl

benzonitrile

Prior art date

2003-12-15

Links

• Espacenet
• Global Dossier
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• 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
• ACOLGRUIHSRLDA-UHFFFAOYSA-N 1-phenylimidazol-2-amine Chemical class N=C1NC=CN1C1=CC=CC=C1 ACOLGRUIHSRLDA-UHFFFAOYSA-N 0.000 title description 2
• 239000001257 hydrogen Substances 0.000 claims abstract description 56
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 45
• 102100038021 Steryl-sulfatase Human genes 0.000 claims abstract description 37
• 239000002253 acid Substances 0.000 claims abstract description 35
• 150000003839 salts Chemical class 0.000 claims abstract description 34
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
• 102000014654 Aromatase Human genes 0.000 claims abstract description 30
• 108010078554 Aromatase Proteins 0.000 claims abstract description 30
• 108010087999 Steryl-Sulfatase Proteins 0.000 claims abstract description 26
• 102000003846 Carbonic anhydrases Human genes 0.000 claims abstract description 22
• 108090000209 Carbonic anhydrases Proteins 0.000 claims abstract description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
• 230000001419 dependent effect Effects 0.000 claims abstract description 20
• 150000002460 imidazoles Chemical class 0.000 claims abstract description 20
• 201000010099 disease Diseases 0.000 claims abstract description 16
• 229940088597 hormone Drugs 0.000 claims abstract description 14
• 239000005556 hormone Substances 0.000 claims abstract description 14
• 210000004291 uterus Anatomy 0.000 claims abstract description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
• 230000006870 function Effects 0.000 claims abstract description 7
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 6
• 230000003211 malignant effect Effects 0.000 claims abstract description 6
• 230000001850 reproductive effect Effects 0.000 claims abstract description 6
• 239000003098 androgen Substances 0.000 claims abstract description 5
• 210000000481 breast Anatomy 0.000 claims abstract description 5
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims abstract description 4
• 210000002307 prostate Anatomy 0.000 claims abstract description 4
• 210000001550 testis Anatomy 0.000 claims abstract description 4
• 206010039966 Senile dementia Diseases 0.000 claims abstract description 3
• 230000003920 cognitive function Effects 0.000 claims abstract description 3
• 210000001672 ovary Anatomy 0.000 claims abstract description 3
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 136
• 150000001875 compounds Chemical class 0.000 claims description 113
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 96
• -1 phenyl ester Chemical class 0.000 claims description 79
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 49
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
• 230000000694 effects Effects 0.000 claims description 42
• 229910052736 halogen Inorganic materials 0.000 claims description 40
• 150000002367 halogens Chemical class 0.000 claims description 40
• LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 39
• 230000005764 inhibitory process Effects 0.000 claims description 37
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 35
• 125000003545 alkoxy group Chemical group 0.000 claims description 31
• 150000002431 hydrogen Chemical group 0.000 claims description 24
• VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 19
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 229960005309 estradiol Drugs 0.000 claims description 18
• 229930182833 estradiol Natural products 0.000 claims description 17
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 16
• 241001465754 Metazoa Species 0.000 claims description 16
• 230000002265 prevention Effects 0.000 claims description 15
• JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 claims description 14
• JKKFKPJIXZFSSB-UHFFFAOYSA-N 1,3,5(10)-estratrien-17-one 3-sulfate Natural products OS(=O)(=O)OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 JKKFKPJIXZFSSB-UHFFFAOYSA-N 0.000 claims description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
• 238000004519 manufacturing process Methods 0.000 claims description 12
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 10
• 125000002252 acyl group Chemical group 0.000 claims description 10
• 239000003814 drug Substances 0.000 claims description 9
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
• 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 claims description 7
• 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 claims description 7
• RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 7
• 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims description 7
• 239000000556 agonist Substances 0.000 claims description 7
• 229960005471 androstenedione Drugs 0.000 claims description 7
• 239000005557 antagonist Substances 0.000 claims description 7
• XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 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
• 239000000583 progesterone congener Substances 0.000 claims description 7
• 230000002280 anti-androgenic effect Effects 0.000 claims description 5
• 239000000051 antiandrogen Substances 0.000 claims description 5
• 238000002474 experimental method Methods 0.000 claims description 5
• 238000007920 subcutaneous administration Methods 0.000 claims description 5
• NXXYYJXTSXCOTN-UHFFFAOYSA-N 4-[(3-bromo-4-hydroxyphenyl)methyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=C(Br)C(O)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 NXXYYJXTSXCOTN-UHFFFAOYSA-N 0.000 claims description 4
• WDSXYXFECHGQAX-UHFFFAOYSA-N 4-[(4-hydroxy-n-imidazol-1-ylanilino)methyl]benzonitrile Chemical compound C1=CC(O)=CC=C1N(N1C=NC=C1)CC1=CC=C(C#N)C=C1 WDSXYXFECHGQAX-UHFFFAOYSA-N 0.000 claims description 4
• 229940046836 anti-estrogen Drugs 0.000 claims description 4
• 230000001833 anti-estrogenic effect Effects 0.000 claims description 4
• 239000000328 estrogen antagonist Substances 0.000 claims description 4
• 230000001568 sexual effect Effects 0.000 claims description 4
• FURVSEVWPXHUEK-UHFFFAOYSA-N 1,2$l^{6},3-benzoxathiazine 2,2-dioxide Chemical compound C1=CC=C2C=NS(=O)(=O)OC2=C1 FURVSEVWPXHUEK-UHFFFAOYSA-N 0.000 claims description 3
• ODVIREIJIDSAMP-UHFFFAOYSA-N 4-(n-imidazol-1-yl-4-nitroanilino)benzonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1N(N1C=NC=C1)C1=CC=C(C#N)C=C1 ODVIREIJIDSAMP-UHFFFAOYSA-N 0.000 claims description 3
• HCBJIEXSVJQKIF-UHFFFAOYSA-N 4-[(4-hydroxy-3-nitrophenyl)methyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=C([N+]([O-])=O)C(O)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 HCBJIEXSVJQKIF-UHFFFAOYSA-N 0.000 claims description 3
• FCVGKDKXSCNMBV-UHFFFAOYSA-N 4-[2-(4-hydroxyphenoxy)ethyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=CC(O)=CC=C1OCCN(N1C=NC=C1)C1=CC=C(C#N)C=C1 FCVGKDKXSCNMBV-UHFFFAOYSA-N 0.000 claims description 3
• 229940126588 endocrine therapeutic agent Drugs 0.000 claims description 3
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
• 239000002243 precursor Substances 0.000 claims description 3
• 239000000126 substance Substances 0.000 claims description 3
• DRLUWQXJGGKULE-UHFFFAOYSA-N 3h-1,2$l^{6},3-benzoxathiazole 2,2-dioxide Chemical compound C1=CC=C2OS(=O)(=O)NC2=C1 DRLUWQXJGGKULE-UHFFFAOYSA-N 0.000 claims description 2
• APUUHKZXMCBVJG-UHFFFAOYSA-N 4-[(4-cyano-n-imidazol-1-ylanilino)methyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 APUUHKZXMCBVJG-UHFFFAOYSA-N 0.000 claims description 2
• MQUJQZCDSNRUMV-UHFFFAOYSA-N 4-[(4-hydroxy-3-methoxyphenyl)methyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=C(O)C(OC)=CC(CN(C=2C=CC(=CC=2)C#N)N2C=NC=C2)=C1 MQUJQZCDSNRUMV-UHFFFAOYSA-N 0.000 claims description 2
• ZDGDIGHTTPLPTL-UHFFFAOYSA-N 4-[(n-imidazol-1-yl-4-methoxyanilino)methyl]benzonitrile Chemical compound C1=CC(OC)=CC=C1N(N1C=NC=C1)CC1=CC=C(C#N)C=C1 ZDGDIGHTTPLPTL-UHFFFAOYSA-N 0.000 claims description 2
• WZHHXUADKLLFIS-UHFFFAOYSA-N 5-[(4-cyano-n-imidazol-1-ylanilino)methyl]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 WZHHXUADKLLFIS-UHFFFAOYSA-N 0.000 claims description 2
• 229940122014 Lyase inhibitor Drugs 0.000 claims description 2
• 230000000708 anti-progestin effect Effects 0.000 claims description 2
• 239000003418 antiprogestin Substances 0.000 claims description 2
• 239000003433 contraceptive agent Substances 0.000 claims description 2
• 230000002254 contraceptive effect Effects 0.000 claims description 2
• 239000002697 lyase inhibitor Substances 0.000 claims description 2
• GBFFDIQZXFOUQW-UHFFFAOYSA-N n-(4-cyanophenyl)-3-(4-hydroxyphenyl)-n-imidazol-1-ylpropanamide Chemical compound C1=CC(O)=CC=C1CCC(=O)N(N1C=NC=C1)C1=CC=C(C#N)C=C1 GBFFDIQZXFOUQW-UHFFFAOYSA-N 0.000 claims description 2
• JWRXRQWCOHXRKK-UHFFFAOYSA-N n-(4-cyanophenyl)-4-hydroxy-n-imidazol-1-ylbenzenesulfonamide Chemical compound C1=CC(O)=CC=C1S(=O)(=O)N(N1C=NC=C1)C1=CC=C(C#N)C=C1 JWRXRQWCOHXRKK-UHFFFAOYSA-N 0.000 claims description 2
• 230000001225 therapeutic effect Effects 0.000 claims description 2
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims 2
• NMFCLLGNWUECTK-UHFFFAOYSA-N [3-[2-(4-cyano-n-imidazol-1-ylanilino)-2-oxoethyl]-1-benzothiophen-6-yl] sulfamate Chemical compound C=1SC2=CC(OS(=O)(=O)N)=CC=C2C=1CC(=O)N(N1C=NC=C1)C1=CC=C(C#N)C=C1 NMFCLLGNWUECTK-UHFFFAOYSA-N 0.000 claims 2
• CQEQDWFJJMJVHM-UHFFFAOYSA-N 4-[(3-formyl-4-hydroxyphenyl)methyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=C(C=O)C(O)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 CQEQDWFJJMJVHM-UHFFFAOYSA-N 0.000 claims 1
• KPFRHIVUAMJZCG-UHFFFAOYSA-N 4-[(4-hydroxyphenyl)methyl-imidazol-1-ylamino]benzonitrile Chemical compound C1=CC(O)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 KPFRHIVUAMJZCG-UHFFFAOYSA-N 0.000 claims 1
• PQQJWNPTOGIKKE-UHFFFAOYSA-N 4-[(6-hydroxy-1,1-dioxo-1-benzothiophen-3-yl)-imidazol-1-ylamino]benzonitrile Chemical compound C=1S(=O)(=O)C2=CC(O)=CC=C2C=1N(N1C=NC=C1)C1=CC=C(C#N)C=C1 PQQJWNPTOGIKKE-UHFFFAOYSA-N 0.000 claims 1
• SKWMEIROEMMWRB-UHFFFAOYSA-N 4-[imidazol-1-yl-[(2,3,5,6-tetrafluoro-4-hydroxyphenyl)methyl]amino]benzonitrile Chemical compound FC1=C(F)C(O)=C(F)C(F)=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 SKWMEIROEMMWRB-UHFFFAOYSA-N 0.000 claims 1
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• LBSQJFOEXMWEQS-UHFFFAOYSA-N [2-bromo-4-[(4-cyano-n-imidazol-1-ylanilino)methyl]phenyl] sulfamate Chemical compound C1=C(Br)C(OS(=O)(=O)N)=CC=C1CN(N1C=NC=C1)C1=CC=C(C#N)C=C1 LBSQJFOEXMWEQS-UHFFFAOYSA-N 0.000 claims 1
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• 125000001424 substituent group Chemical group 0.000 abstract 1
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