ZA200401312B - Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. - Google Patents
Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. Download PDFInfo
- Publication number
- ZA200401312B ZA200401312B ZA200401312A ZA200401312A ZA200401312B ZA 200401312 B ZA200401312 B ZA 200401312B ZA 200401312 A ZA200401312 A ZA 200401312A ZA 200401312 A ZA200401312 A ZA 200401312A ZA 200401312 B ZA200401312 B ZA 200401312B
- Authority
- ZA
- South Africa
- Prior art keywords
- thien
- chloro
- methyl
- amino
- ethyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 9
- 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 title 1
- 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 title 1
- -1 di-substituted, amide Chemical class 0.000 claims description 507
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 239000001257 hydrogen Substances 0.000 claims description 92
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 75
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 72
- 150000002431 hydrogen Chemical group 0.000 claims description 67
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 60
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000004104 aryloxy group Chemical group 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 125000002757 morpholinyl group Chemical group 0.000 claims description 18
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 102000004190 Enzymes Human genes 0.000 claims description 15
- 108090000790 Enzymes Proteins 0.000 claims description 15
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 13
- 206010012601 diabetes mellitus Diseases 0.000 claims description 13
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 208000008589 Obesity Diseases 0.000 claims description 10
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 10
- 235000020824 obesity Nutrition 0.000 claims description 10
- 102000004277 11-beta-hydroxysteroid dehydrogenases Human genes 0.000 claims description 9
- 108090000874 11-beta-hydroxysteroid dehydrogenases Proteins 0.000 claims description 9
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 claims description 8
- 208000001132 Osteoporosis Diseases 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 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 6
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
- 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 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000001769 aryl amino group Chemical group 0.000 claims description 6
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 6
- 125000005110 aryl thio group Chemical group 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 230000002519 immonomodulatory effect Effects 0.000 claims description 6
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical compound O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 208000013016 Hypoglycemia Diseases 0.000 claims description 5
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 5
- 201000001421 hyperglycemia Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 206010012289 Dementia Diseases 0.000 claims description 4
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 4
- 241000236488 Lepra Species 0.000 claims description 4
- 206010024229 Leprosy Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 4
- 201000008980 hyperinsulinism Diseases 0.000 claims description 4
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims 48
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 35
- 229940124530 sulfonamide Drugs 0.000 claims 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 8
- 238000000034 method Methods 0.000 claims 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 6
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims 5
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims 5
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims 5
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims 4
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims 4
- KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 208000031226 Hyperlipidaemia Diseases 0.000 claims 3
- 241000700605 Viruses Species 0.000 claims 3
- 208000027866 inflammatory disease Diseases 0.000 claims 3
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 2
- 101710088194 Dehydrogenase Proteins 0.000 claims 2
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 claims 2
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 claims 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims 2
- VAJCYQHLYBTSHG-UHFFFAOYSA-N ethyl n,n-diethylcarbamate Chemical compound CCOC(=O)N(CC)CC VAJCYQHLYBTSHG-UHFFFAOYSA-N 0.000 claims 2
- 125000002541 furyl group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims 2
- BDRXGHKAXUUANM-UHFFFAOYSA-N 2,4,6-trichloro-n-(4-phenylthiophen-3-yl)benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC(Cl)=C1S(=O)(=O)NC1=CSC=C1C1=CC=CC=C1 BDRXGHKAXUUANM-UHFFFAOYSA-N 0.000 claims 1
- HVWWHVMGSZBHML-UHFFFAOYSA-N 2,4,6-trichloro-n-[2-(2-morpholin-4-ylethyl)thiophen-3-yl]benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC(Cl)=C1S(=O)(=O)NC1=C(CCN2CCOCC2)SC=C1 HVWWHVMGSZBHML-UHFFFAOYSA-N 0.000 claims 1
- NIYLZHXEUXVCOS-UHFFFAOYSA-N 2,4-dichloro-6-methyl-n-[4-(2-morpholin-4-ylethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC1=CC(Cl)=CC(Cl)=C1S(=O)(=O)NC1=CSC=C1CCN1CCOCC1 NIYLZHXEUXVCOS-UHFFFAOYSA-N 0.000 claims 1
- NNZHXJMTOOWXMR-UHFFFAOYSA-N 2,4-dichloro-n-[2-(2,5-dimethylfuran-3-yl)thiophen-3-yl]-6-methylbenzenesulfonamide Chemical compound O1C(C)=CC(C2=C(C=CS2)NS(=O)(=O)C=2C(=CC(Cl)=CC=2C)Cl)=C1C NNZHXJMTOOWXMR-UHFFFAOYSA-N 0.000 claims 1
- FCXPQVCOVOXYMF-UHFFFAOYSA-N 2,4-dichloro-n-[2-(2-chloro-5-nitrophenyl)thiophen-3-yl]-6-methylbenzenesulfonamide Chemical compound CC1=CC(Cl)=CC(Cl)=C1S(=O)(=O)NC1=C(C=2C(=CC=C(C=2)[N+]([O-])=O)Cl)SC=C1 FCXPQVCOVOXYMF-UHFFFAOYSA-N 0.000 claims 1
- MNXCUWPTMVJKHW-UHFFFAOYSA-N 2,4-dichloro-n-[4-(2-morpholin-4-yl-2-oxoethyl)thiophen-3-yl]benzenesulfonamide Chemical compound ClC1=CC(Cl)=CC=C1S(=O)(=O)NC1=CSC=C1CC(=O)N1CCOCC1 MNXCUWPTMVJKHW-UHFFFAOYSA-N 0.000 claims 1
- HIFGQHGWMTZMOH-UHFFFAOYSA-N 2-(trifluoromethoxy)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1OC(F)(F)F HIFGQHGWMTZMOH-UHFFFAOYSA-N 0.000 claims 1
- LVYRGDYKPDZTTL-UHFFFAOYSA-N 2-[3-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-2-yl]acetic acid Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=C(CC(O)=O)SC=C1 LVYRGDYKPDZTTL-UHFFFAOYSA-N 0.000 claims 1
- DLLUFZTZNOOQAV-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]acetic acid Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CC(O)=O DLLUFZTZNOOQAV-UHFFFAOYSA-N 0.000 claims 1
- DXPXZOCZKCNJTJ-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl 2-methylpropanoate Chemical compound CC(C)C(=O)OCCC1=CSC=C1NS(=O)(=O)C1=CC=CC(Cl)=C1C DXPXZOCZKCNJTJ-UHFFFAOYSA-N 0.000 claims 1
- VLRHWMANGHXRMB-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl acetate Chemical compound CC(=O)OCCC1=CSC=C1NS(=O)(=O)C1=CC=CC(Cl)=C1C VLRHWMANGHXRMB-UHFFFAOYSA-N 0.000 claims 1
- IMBZOHGZTSEBBH-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl benzoate Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CCOC(=O)C1=CC=CC=C1 IMBZOHGZTSEBBH-UHFFFAOYSA-N 0.000 claims 1
- STEWPSGWUMFETD-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl furan-2-carboxylate Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CCOC(=O)C1=CC=CO1 STEWPSGWUMFETD-UHFFFAOYSA-N 0.000 claims 1
- WRMMTFVNFRTVOD-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl morpholine-4-carboxylate Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CCOC(=O)N1CCOCC1 WRMMTFVNFRTVOD-UHFFFAOYSA-N 0.000 claims 1
- QFPVKQQQGWMRAE-UHFFFAOYSA-N 2-[4-[(3-chloro-2-methylphenyl)sulfonylamino]thiophen-3-yl]ethyl n-ethylcarbamate Chemical compound CCNC(=O)OCCC1=CSC=C1NS(=O)(=O)C1=CC=CC(Cl)=C1C QFPVKQQQGWMRAE-UHFFFAOYSA-N 0.000 claims 1
- UAYLFPXPMKOTKN-UHFFFAOYSA-N 2-methylsulfanyl-4-thiophen-2-ylpyrimidine Chemical compound CSC1=NC=CC(C=2SC=CC=2)=N1 UAYLFPXPMKOTKN-UHFFFAOYSA-N 0.000 claims 1
- QKCZKVSAMDZDTC-UHFFFAOYSA-N 3-bromo-5-chloro-n-[4-(2-chlorophenyl)thiophen-3-yl]thiophene-2-sulfonamide Chemical compound S1C(Cl)=CC(Br)=C1S(=O)(=O)NC1=CSC=C1C1=CC=CC=C1Cl QKCZKVSAMDZDTC-UHFFFAOYSA-N 0.000 claims 1
- CVUDLDGZTWBYBU-UHFFFAOYSA-N 3-chloro-2-methyl-n-(2-phenylthiophen-3-yl)benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=C(C=2C=CC=CC=2)SC=C1 CVUDLDGZTWBYBU-UHFFFAOYSA-N 0.000 claims 1
- CULJJNUUCVJZAR-UHFFFAOYSA-N 3-chloro-2-methyl-n-(4-phenylthiophen-3-yl)benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1C1=CC=CC=C1 CULJJNUUCVJZAR-UHFFFAOYSA-N 0.000 claims 1
- QCRMRUILRLRVMK-UHFFFAOYSA-N 3-chloro-2-methyl-n-[2-(2-morpholin-4-yl-2-oxoethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=C(CC(=O)N2CCOCC2)SC=C1 QCRMRUILRLRVMK-UHFFFAOYSA-N 0.000 claims 1
- AUVIRLFYCHHBMO-UHFFFAOYSA-N 3-chloro-2-methyl-n-[2-(2-morpholin-4-ylethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=C(CCN2CCOCC2)SC=C1 AUVIRLFYCHHBMO-UHFFFAOYSA-N 0.000 claims 1
- BWFCKWPHFLMIPO-UHFFFAOYSA-N 3-chloro-2-methyl-n-[2-(2-oxopentyl)thiophen-3-yl]benzenesulfonamide Chemical compound S1C=CC(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)C)=C1CC(=O)CCC BWFCKWPHFLMIPO-UHFFFAOYSA-N 0.000 claims 1
- WDJIOUFYICGGPX-UHFFFAOYSA-N 3-chloro-2-methyl-n-[2-[2-(3-oxomorpholin-4-yl)ethyl]thiophen-3-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=C(CCN2C(COCC2)=O)SC=C1 WDJIOUFYICGGPX-UHFFFAOYSA-N 0.000 claims 1
- XUOGJWSCHAZLIC-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-(2-morpholin-4-yl-2-oxoethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CC(=O)N1CCOCC1 XUOGJWSCHAZLIC-UHFFFAOYSA-N 0.000 claims 1
- DUUFVMXLPZHVLH-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-(2-morpholin-4-ylethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=CSC=C1CCN1CCOCC1 DUUFVMXLPZHVLH-UHFFFAOYSA-N 0.000 claims 1
- RKHWOOYVVLOWJT-UHFFFAOYSA-N 3-chloro-2-methyl-n-[4-(2-propan-2-yloxyethyl)thiophen-3-yl]benzenesulfonamide Chemical compound CC(C)OCCC1=CSC=C1NS(=O)(=O)C1=CC=CC(Cl)=C1C RKHWOOYVVLOWJT-UHFFFAOYSA-N 0.000 claims 1
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Description
INHIBITORS OF 11-BETA-HYDROXY STEROID DEHYDROGENASE
TYPE 1 . RELATED APPLICATIONS
This application claims priority to Swedish application number 0103913-0, filed on
November 22, 2001, Swedish application number 0104051-8, filed on November 30, 2001,
Swedish application number 0103915-5, filed on November 22, 2001, U.S. provisional application number 60/348,468, filed on January 14, 2002, U.S. provisional application number 60/348,340, filed on January 14, 2002, the contents of which are incorporated herein by reference.
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-B-hydroxysteroid dehydrogenase type 1 enzyme (11pHSD1).
1. Glucorticoids, diabetes and hepatic glucose production 1t has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C.D. and F.D.W. Leukins (1936) J. Exp. Med. 63: 465-490; Houssay, B.A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.
The role of 11RHSDT zs ar imnertant regulstor of local glucoccrticoid effect and thug of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J.
Endocrinol. 165: p. 685-692). The hepatic insulin sensitivity was improved in healthy human volunteers treated with the non-specific 11BHSD1 inhibitor carbenoxolone (Walker, B.R. et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism ‘ has been established by different experiments with mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-d-phoshate (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 11BHSD1 gene knocked-out. Data from this model also confirm that inhibition of 11HSD1 will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929).
Arzneim.-Forsch./Drug Res; 44 (II), No. 7, 821-826, 1994, discloses the hypoglycemic compounds 4-(3-methyl-5-oxo-2-pyrazolin-1-yl)benzoic acid and 1- (mesitylen-2-sulfonyl)-1H-1,2,4-triazole. The structures of these compounds differ considerably from the structure of the compounds of the present invention, in that the latter are thiophenes having an (hetero)arylsulfonamido substituent.
FR 2,384,498 discloses compounds having a high hypoglycemic effect. Therefore, treatment of hyperglycemia with these compounds may lead to hypoglycemia. ’ 2. Possible reduction of obesity and obesity related cardiovascular risk factors
Obesity is an important factor in syndrome X as well as in the majority (> 80%) of type 2 diabetic, and omenial fat appears to be of central importance. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X (e.g. raised blood pressure, decreased levels of
HDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes 49: 883-888, 2000). © Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced centrai obesity (Bujaiska, i.J., S.
Kumar, and P.M. Stewart (1997) Lancet 349: 1210-1213).
Inhibition of 11BHSD1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1) — an independent cardiovascular risk factor (Halleux, C.M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid “activity” and cardiovascular risk factore suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B.R. et al. (1998) Hypertension 31; 891-895; Fraser, R. et al. (1999) Hypertension 33: 1364-1368).
Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11BHSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S.C. et al. (1998) Science, 280: 1378-1383). 3. Possible beneficial effect on the pancreas
Inhibition of 11BHSDI in isolated murine pancreatic B-cells improves the glucose- stimulated insulin secretion (Davani, B. et al. (2000) J. Biol. Chem. 2000 Nov 10; 275(45): 34841-4). Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B.C.J. Sutter (1979) Horm. Metab. Res. 11: 555-560). Thus, inhibition of 11BHSDI is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat. 4. Possible beneficial effects on cognition and dementia
Stress and glucocorticoids influence cognitive function (de Quervain, D.J.-F., B.
Roozendaal, and J.L. McGaugh (1998) Nature 394: 787-790). The enzyme 11pHSD1 controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, V., C.R.W. Edwards, and J.R. Seckl, J. (1996) Neuroscience 16: 65-70; Seckl, I.R.,
Front. (2000) Neuroendocrinol. 18: 49-99), Unpublished results indicate significant memory improvement in rats treated with a non-specific 11B3HSDI1 inhibitor (J. Seckl, personal communication). Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 11 3HSDT ir ths brain may result in reduced anxisty (Tronche, F. et al. (1999) Nature Genetics 23: 99-103). Thus, taken together, the hypothesis is that inhibition of 11pHSD1 in the human brain would prevent reactivation of cortisone into cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).
WO 98/27081 and WG 99/02502 disclose SHT receptor antagonists for the treatment of CNS disorders. None of these compounds fall within formula (I) according to the present invention. Furthermore, nothing is said about the activity on 118HSD1. 5. Possible use of immuno-modulation using 113HSD] inhibitors
The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo- pituitary-adrenal) axis (Rook, G.A.W. (1999) Bailliér's Clin. Endocrinol. Metab. 13: 576- 581). The balance between the cell-mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11BHSD1 has been suggested as a means of shifting the response towards a cell-based reaction.
In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is normaly biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11HSD]1, local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology
Today 12: 57-60; Rook et al., supra).
An analogous use of 113HSDI1 inhibition, in this case temporal, would be to booster the immune response in association with immunization to ensure that a cell based response would be obtained, when desired.
6. Reduction of intraocular pressure : Recent data suggest that the levels of the glucocorticoid target receptors and the 11BHSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest. ) 5 Ophthalmol. 41: 1629-1638). Further, inhibition of 11BHSD1 was recently presented as a novel approach to lower the intraocular pressure (Walker E. A. et al, poster P3-698 at the
Endocrine society meeting June 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non- specific inhibitor of 11BHSD1, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 11BHSD1 is confined to basal cells of the comeal epithelium and the non-pigmented epithelialium of the comea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11BHSD2 is highly expressed in the non-pigmented ciliary epithelium and comeal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11BHSDI is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both. 7. Reduced osteoporosis
Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression of osteoblast proliferation and collagen synthesis (Kim, C.H., S.L. Cheng, and G.S. Kim (1999) J. Endocrinol. 162: 371- 379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 11HSD1 in the glucocorticoid effect (Bellows, C.G., A. Ciaccia, and J.N.M. Heersche, (1998) Bone 23: 119-125). Other data suggest a role of 11BHSDI in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M.S. et al. (2000) Bone 27: } 375-381). Taken together, these different data suggest that inhibition of 11BHSD1 may have a0 beneficial effects against osteoporosis Ty mere than one mechanism working i= parallel
8. Reduction of hypertension
Bile acids inhibit 11B-hydroxysteroid dehydrogenase type 2. This resulis in a shift in the overall body balance in favour of cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ. 2001. J Clin Invest. Nov;108(9):1299-305. "Reduced activity of 11beta-hydroxysteroid dehydrogenase in patients with cholestasis".). Reducing the activity of 11bHSD1 in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction.
WO 99/65884 discloses carbon substituted aminothiazole inhibitors of cyclin dependent kinases. These compounds may e.g. be used against cancer, inflammation and arthritis. US 5,856,347 discloses an antibacterial preparation or bactericide comprising 2- aminothiazole derivative and/or salt thereof. Further, US 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4- cJpyridines. Fr. Addn. (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 94123 19690704 CAN 72:100685 AN 1970:100685 CAPLUS and 4,5,6,7-Tetrahydrothiazolo[5,4- c]pyridines. Neth. Appl. (1967), 39 pp. CODEN: NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS. However, none of the above disclosures discloses the compounds according to the present invention, or their use for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depressicn, and hypertension.
WO 98/16520 discloses compounds inhibiting matrix metelloproteinases (MMPs) and
TNF-a converting enzyme (TACE). EP 0 749 964 Al and US 5,962,490 disclose compounds having an endothelin receptor antagonist activity. WO 00/02851 discloses compounds associated with a disturbed cGMP balance. None of these compounds fall within formula (I) © according to the present invention. Furthermore, nothing is said about the activityon ~~ 7 11BHSD1.
US 5,783,657 discloses thiophene derivatives as inhibitors of PGEZ and LTB4.
Nothing is said about the activity on 11BHSDI.
EP 0558 258, EP 0 569 193, and EP 1 069 114 disclose isoxazole derivatives as endothelin agonists and antagonists. Nothing is said about the activity on 11HSDI1. ; Consequently, there is a need of new compounds that are useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, ) 5 and hypertension.
The compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 11-B-hydroxysteroid dehydrogenase type 1 enzyme (11-B-HSD;), and may therefore be of use in the treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and hypertension.
One object of the present invention is a compound of formula (I)
Rr!
T. N B
N ~ 2 0) 0
By Ss Ba wherein:
T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C,.¢-alkyl, optionally halogenated C;_¢-alkoxy, C\g-alkylsulfonyl, carboxy, cyano, nitre, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings can firther be optionally substituted in one or more positions independently of each other by Cy.¢-acyl, C¢-alkylthio, cyano, nitro, ’ 25 hydrogen, halogen, optionally halogenated Ci.s-alkyl, optionally halogenated C; s-alkoxy,
amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2- thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl] amino } carbonyl);
R! is hydrogen or Cy¢-alkyl; .
B, and B, are Bs or Z, provided that B; and B; have different meanings, wherein: eo Zis selected from an aryl ring or heteroaryl ring, which can further be optionally ) substituted in one or more positions independently of each other by hydrogen, C;.¢-alkyl, halogenated C;.¢-alkyl, halogen, C,.¢-alkoxy, nitro, C,.¢-alkoxycarbonyl, Ci.6~ alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R?, wherein ¢ XisCH;or CO; e Y is CH,, CO or a single bond; e R’is selected from C.¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-ox0-4- 5 morpholinolinylmethyiene, C.¢-alkoxycarbonyl, 5-methyl-1,3,4-0xadiazoi-2-yi;
NR>R*, wherein R® and R* are each independently selected from hydrogen, Ci6-alkyl, optionally halogenated C;.¢-alkylsulfonyl, Cy¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C;.¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Cy.¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NRR* represent together heterocyclic systems which can be imidazoie, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, i,i- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl}, (18,45)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems can be optionally substituted by
Ci.s-alkyl, Cy.¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR’R?, wherein R> and R* are each independently selected from hydrogen, C;-6-
EE alkyl or form together with the N-atom to which they are attached morpholinyl; oT
R30, wherein R’is hydrogen, optionally halogenated Ci¢-alkyl, aryl, heteroaryi, Ci.¢- acyl, Ci¢-alkylsulfonyl, arylcarbonyl, hetercarylcarbonyl, 2-carbomethoxyphenyi; e 1B, is hydrogen, Ci¢-alkyl or dimethylaminomethyl;
RECTIFIED SHEET (RULE a1}
or a salt, hydrate or solvate thereof; with the proviso that when: ’ Z is X-Y-R?, wherein X is CO and Y is a single bond, then R? is not methyl, chloro, hydroxy, optionally halogenated Cy¢-alkoxy, aryloxy, heteroaryloxy, amino, and phenylamino;
Z is X-Y-R?, wherein X is CH, and Y is a single bond, then R? is not methoxy.
It is preferred that: ‘
T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl, thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R! is hydrogen or methyl;
B; and B; are Bs or Z, provided that B, and B, have different meanings, wherein: eZ is selected from 1-benzothien-3-yi, 3-(2,5-dimethyifuryl), pyridinyl; thieny! optionally substituted with one or more of chloro, methylsulfonyl; ’ phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R?, wherein ap eo XisCH;orCO; e Y is CH,, CO or a single bond;
RECTIFIED SHEET (RULE 91)
e R’is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyioxymethyl,
NR’R?, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidy?; or
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyi, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1Thepi-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl;
OCONR’R*, wherein R® and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl,
R’0, wherein Ris acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; » Bs is hydrogen, methyl or dimethylaminomethyl; with the previse that when: 71s X-Y-R?, wherein X is CO and Y is a single bond, hen R is noi chloro, hydroxy, benzyloxy, ethoxy, 2-fluoroethoxy, isopropyloxy, methoxy, 2-carbomethoxyphenoxy, phenoxy, 3-pyridinyloxy, 2,2,2-trifluoroethoxy, amino, and phenylamino; 7 is X-Y-R?, wherein X is CH, and Y is PY single bond, then R? is not methoxy. "777 When R! is hydrogen or methyl, Bs is hydrogen, methyl or dimethylaminomethyl, and ~~ 7 is X-Y-R?, wherein X is CO and Y is a single bond, then it is preferred that:
Claims (4)
1. A compound of formula (I) R “ A Ba B4 Ss Bs wherein: T is an aryl ring or heteroaryl ring, optionally independently substituted by [Rlp, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci.¢-alkyl, optionally halogenated Ci¢-alkoxy, Ci¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by C.¢-acyl, Ci.¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C;¢-alkyl, optionally halogenated C;¢-alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2- thienylmethylamino or ({{4-(2-cthoxy-2-cxoethyl)-1,3-thiazol-2-yi] amino } carbonyl); R'is hydrogen or Cy_g-alkyl; Bi and B; are Bj; or Z, provided that B; and B; have different meanings, wherein: e Zis selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, Ci.¢-alkyl, halogenated Cy.¢-alkyl, halogen, Cy.¢-alkoxy, nitro, Ci.¢s-alkoxycarbonyl, Ci¢- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally : substituted in one or more positions independently of each other by hydrogen and : halogen; or is X-Y-R?, wherein eo Xis CH, or CO; : e Yis CH; CO ore single bond; RECTIFIED SHEET (RULE 91)
oR’ is selected from Cy¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, Ci.¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl; NR’R*, wherein R® and R* are each independently selected from hydrogen, Cy-alkyl, optionally halogenated C¢-alkylsulfonyl, Cis-alkoxy, 2-hydroxyethyl, 1- methylimidazolylsulfonyl, C;¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C,.s-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (15,4S)-2-0xa-5- azabicyclo[2.2.1]hept-5-y], which heterocyclic systems are optionally substituted by Ci. s-alkyl, Ci¢-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR’R?, wherein R? and R* are each independently selected from hydrogen, Ci.s- alkyl or form together with the N-atom to which they are attached morpholinyl; R°0, wherein R® is hydrogen, optionally halogenated C,¢-alkyl, aryl, heteroaryl, C;.- acyl, C,¢-2lkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; s Bj is hydrogen, C,.¢-alkyl or dimethylaminomethyl; or a salt, hydrate or solvate thereof; with the proviso that when: Z is X-Y-R?, wherein X is CO and Y is a single bond, then R? is not methyl, ethyl, butylamino, 1,1-dimethylpropylamino, 5,6,7,8-tetrahydronaphthalenylamino, chloro, hydroxy, optionally halogenated Ci.¢-alkoxy, aryloxy, heteroaryloxy, amino, and phenylamino, benzylamino, naphthylamino, alkylphenylamino, dialkylphenylamino, thienylmethylamino, phenylethylamino, indanylamino; and when Z is X-Y-R?, wherein X is CH, and Y is a single bond, then R? is not methoxy.
2. The compound according to claim 1, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chlore-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; Amended Sheet — 14-04-2005 :
thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl;
phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chlorc, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R' is hydrogen or methyl;
B, and B; are Bj or Z, provided that B; and B; have different meanings, wherein:
» Z is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl, thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R?, wherein
» Xis CH; or CO;
e Y is CH,, CO or a single bond;
e R?is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo0-4- morpholinolinylmethylene, ethoxycarbonyl, S-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R?, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, methyl, 4-(1-methylimidazolyl) sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or
Amended Sheet — 14-04-2005
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (15,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; pipericinyl; pyrrolidinyl; pyrrolidonyl, thiomorphelinyl; 1,1- dioxido-thiomorpholinyl; OCONR’R?, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; RO, wherein R° is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridiny!, 2,2,2-trifluoroethyl; s B; is hydrogen, methyl or dimethylaminomethyl; with the proviso that when: 7 is X-Y-R%, wherein X is CO and Y is a single bond, then R? 1s not chloro, hydroxy, benzyloxy, ethoxy, 2-fluoroethoxy, isopropyloxy, methoxy, 2-carbomethoxyphenoxy, phenoxy, 3-pyridinyloxy, 2,2,2-trifluoroethoxy, amino, phenylamino, benzylamino, phenylethylamino; Z 1s X-Y-R%, wherein X is CH, and Y is a single bond, then R? is not methoxy.
3. The compound according to claim 1, wherein T is 3-chloro-2-methylphenyl.
4. The compound of any one of claims 1 to 3 selected from the group consisting of: » ethyl (4-{[(3-chloro-2-methylphenyl)suifonyl]amino}thien-3-yl)acetate s (4-{[(3-chloro-2-methylphenyl)sulfonyl] amino }thien-3-yl)acetic acid » 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-yl)-N-methylacetamide + 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-y1)-N-cthylacetamide e 2,5-dichloro-N-(3-chloro-2,3'-bithien-4'-yl)benzenesulfonamide s isopropyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]lamino}thien-3-yl)acetate » 3-chloro-N-[4-(2-hydroxyethyl)thien-3-y1]-2-methylbenzenesulfonamide » 3-chloro-N-[4-(2-ethoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide s 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-y1)-N,N-diethylacetamide » methyl (4-1 (3-chicre-Zemethyishenylsifonyl arin inien-3-y acetals » 3-chloro-N-[4-(2-isopropoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide Amended Sheet — 14-04-2005 o 3-chloro-N-[4-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyllamino} thien-3-yl)ethyl methanesulfonate o 2-(4-{[(3-chloro-2-methylphenyl)sulfonyljamino}thien-3-yl)acetamide e 3-chloro-N-{4-[2-(2-flucroethoxy)ethyl]thien-3-y1}-2-methylbenzenesulfonamide e 3-chloro-2-methyl-N-{4-[2-(2,2,2-trifluoroethoxy)ethyl]thien-3- yl}benzenesulfonamide o 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl acetate * 3-chloro-2-methyl-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide o N-[4-(2-bromoethyl)thien-3-y1]-3-chloro-2-methylbenzenesulfonamide * 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl morpholine-4- carboxylate s 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-yl) ethyl diethylcarbamate e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl amino} thien-3-yl)ethyl propionate o 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl 2- methylpropanoate » 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl 2-furoate e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl benzoate » 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-y1)-N-methoxy-N- methylacetamide s 3-chloro-N-{4-[2-(dicthylaminc)ethy!l]thien-3-y1}-2-methylbenzenesulfonamide e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl ethylcarbamate e N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-yl)ethyl]-N- ethylacetamide s 3-chloro-2-methyl-N-[4-(2-oxopentyl)thien-3-yl|benzenesulfonamide eo N-{4-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl |thien-3-yl}-4- propylbenzenesulfonamide e 2.4 6-trichloro-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide e 2 A4-dichloro-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide e 3-chloro-2-methyl-N-{4-[2-(3-oxomorpholin-4-yl)ethy!]thien-3- yi}benzenesulfonamics
* 2,4-dichloro-6-methyl-N-[4-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide * N-[4-(2-morpholin-4-ylethyl)thien-3-yl] -4-propylbenzenesulfonamide
: . 2,4-dichloro-6-methyl-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3- yllbenzenesulfonamide
5 . 2,4,6-trichloro-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-ylJbenzenesul fonamide ® N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1 "-biphenyl-4-sulfonamide * N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl] -4-propylbenzenesulfonamide * N-[4-(2-oxo-2-thiomorpholin-4-ylethyl)thien-3-yl]-1,1 "-biphenyl-4-sulfonamide * N-[4-(2-ox0-2-thiomorpholin-4-ylethyl)thien-3-y1] -4-propylbenzenesulfonamide
10 . 2,4-dichloro-6-methyl-N-[4-(2-0x0-2-thiomorpholin-4-ylethyl)thien-3- yl]benzenesulfonamide * N-[4-(2-0x0-2-piperidin-1-ylethyl)thien-3-y1]-1,1-biphenyl-4-sulfonamide * N-[4-(2-0x0-2-piperidin-1-ylethyl)thien-3-y1]-4-propylbenzenesul fonamide * 2,4-dichloro-6-methyl-N-[4-(2-ox0-2-piperidin-1-ylethyl)thien-3- yl]benzenesulfonamide * 24,6-trichloro-N-[4-(2-oxo-2-piperidin-1-ylethyl)thien-3 -ylJbenzenesulfonamide * N-(4-phenylthien-3-yl)-4-propylbenzenesulfonamide ethyl (4-{[(3-chloro-2-methylphenyl)sulfonyl]amino } thien-3 -yl)(oxo)acetate * 3-chloro-2-methyl-N-(4-phenylthien-3-yl)benzenesulfonamide * 3-chloro-N-[4-(4-fluorc-3-methylphenyl)thien-3-yi}-2-methylbenzenesulfonamide * 2,4,6-trichloro-N-(4-phenylthien-3-yl)benzenesulfonamide ® N-(4-phenylthien-3-yl)-1,1"-biphenyl-4-sulfonamide s 2,/4-dichloro-6-methyl-N-(4-phenylthien-3-y1)benzenesulfonamide * 2-{4-[(1,1"-biphenyl-4-ylsulfonyl)amino]thien-3-y1}-N- ethyl-N-methylacetamide * N-ethyl-N-methyl-2-(4-{[(4-propylphenylsulfonyl]amino} thien 3-yDacctamide * 2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino} thien-3-y1) -N-ethyl-N- ) methylacetamide ¢ N-ethyl-N-methyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino} thien-3 -yl)acetamide ‘ ¢ 2,4,6-trichloro-N-[4-(2-ox0-2-thiomorpholin-4-ylethyl)thien-3- yiibenzanssulfonemids e 2-{4-[(1,1-biphenyl-4-ylsulfonyl)amino]thien-3-yl} -N-isopropyl-N-methylacetamide eo 2-{4-[(1,1'-biphenyl-4-ylsulfonyl)amino]thien-3-yl}-N,N-diethylacetamide e N,N-diethyl-2-(4- {[(4-propylphenyl)sulfonyl]amino} thien-3-yi)acetamide } o 2-(4-{[(2,4-dichloro-6-methylphenyl)sulfonyllamino} thien-3-y1)-N,N- diethylacetamide e N.N-diethyl-2-(4- {{(2,4,6-trichiorophenyl)sulfonyl]Jamino} thien-3-yl)acetamide e 2-{4-[(1,1"-biphenyl-4-ylsulfonyi)amino]thien-3-yl}-N,N-diisopropylacetamide e N,N-diisopropyl-2-(4-{[(4-propylphenyl)sulfonyljamino}thien-3-yi)acetamide e 2-(4-{[(2,4-dichloro-6-methylphenyDsulfonyl]amino} thien-3-y1}-N,N- diisopropylacetamide ¢ N,N-diisopropyl-2-(4-{[(2,4,6-trichlorophenyl)sulfonyl]amino} thien-3-yl)acetamide ¢ N-[4-(4-{[(4-propylphenyl)sulfonyl]amino}thien-3-yl)phenyl]acetamide e 4-propyl-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide e N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide e N-[4-(2-chlorophenyl)thien-3-yl1]-4-propylbenzenesulfonamide ¢ 3-chioro-N-[4-(2-chloro-5-nitrophenyljthien-3-yl}-2-methylbenzenesulfonamide e 3-chloro-N-(5-chloro-2,3'-bithien-4'-yl)-2-methylbenzenesulfonamide ¢ 3-chloro-N-[4-(2-chlorophenyl)thien-3-yl]-2-methylbenzenesulfonamide eo N-[4-(4-{[(2,4,6-trichlorophenyl)sulfonyljamino}thien-3-yl)phenyl]acetamide e 2.4 6-trichloro-N-(4-pyridin-3-ylthien-3-yl)benzenesulfonamide e 2,4,6-trichloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-ylJbenzenesulfonamide e 2,4,6-trichloro-N-{5-chloro-2,3'-bithien-4'-yl)benzenesulfonamide e 2.4 6-trichloro-N-[4-(2-chiorophenyli)thien-3-yilbenzenesulfonamide » N-(4-{4-[(1,1'-biphenyl-4-ylsulfonyl)amino]thien-3-yi} phenyl)acetamide e N-(4-pyridin-3-ylthien-3-y1)-1,1'-biphenyl-4-sulfonamide e N-[4-(2-chloro-5-nitrophenyl)thien-3-y1}-1,1"-biphenyl-4-sulfonamide ~~ e N-[4-(2-chlorophenyl)thien-3-y1]-1,1"biphenyl-4-sulfonamide ST CT e N-[4-(4-{[(2,4-dichloro-6-meihylphenyi) sulfonyl] amino }thien-3-yljphenyl]acetamide e 24-dichloro-6-methyl-N-(4-pyridin-3-yithien-3-yl)benzenesulfonarnide e 2 4-dichloro-N-[4-(2-chloro-5-nitrophenyl)thien-3-yl]-6-methylbenzenesulfonamide
* 2,4-dichloro-N-(5-chloro-2,3 “-bithien-4'-yl)-6-methylbenzenesulfonamide * 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-y1)-N,N-dipropylacetamide
: . 3-chloro-2-methyl-N-[4-(2-o0x0-2-piperazin-1-ylethyl)thien-3-ylbenzenesul fonamide * 2,4-dichloro-N-[4-(2,5-dimethyl-3 ~furyl)thien-3-yl]-6-methylbenzenesulfonamide * N-(3-chloro-2,3"-bithien-4'-yl)-4-propylbenzenesulfonamide ¢ 3-chloro-N-(3 -chloro-2,3'-bithien-4'-y1)-2-methylbenzenesulfonamide * 2,4,6-trichloro-N-(3-chloro-2,3"-bithien-4'-yl)benzenesulfonamide * 2,4-dichloro-N-(3-chloro-2,3"bithien-4'-y1)-6-methylbenzenesulfonamide * 2,4-dichloro-N-[4-(2-chlorophenyl)thien-3-y1]-6-methylbenzenesul fonamide
10 . 4-bromo-2-methyl-N-[4-(2-morpholin-4-y1-2-oxoethyl)thien-3 - yl]benzenesulfonamide ® N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-2,4- bis(trifluoromethyl)benzenesulfonamide * 2-methyl-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-4- (trifluoromethoxy)benzenesulfonamide * N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-4-phenoxybenzenesul fonamide ® 4-chloro-2,6-dimethyl-N-[4-(2-morpholin-4-yl-2-oxo ethyl)thien-3- yl]benzenesulfonamide * 2,4-dichloro-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]benzenesulfonamide o fert-butyl 4-[(4-{[(3-chlorc-2-methylphenyl)sulfonyl] amino} thien-3- yhacetyl]piperazine-1-carboxylate e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino }thien-3 -y1)-N,N-dimethylacetamide e 3-chloro-2-methyl-N-{4-[2-(pyridin-3-yloxy) ethyl]thien-3-yl} benzenesulfonamide ~*® 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]aminoc } thien-3 -y1)-N-isopropyl-N- methylacetamide e 2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino }thien-3-y1)-N-ethyl-N- methylacetamide 3-chloro-2-methyl-N-[4~(2-0x0-2-thiomorpholin-4-ylethyl)thien-3- yl]benzenesulfonamide e 3-chloro-2-methyl-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide e 2-(4-{[(3-chloro-2-methylphenyi)sulfonyl]amino}thien-3-y1)-N,N- diisopropylacetamide ¢ 3-chloro-2-methyl-N-[4-(2-ox0-2-pyrrolidin-1-ylethyl)thien-3-yiJbenzenesulfonamide e 3-chloro-2-methyl-N-[4-(2-ox0-2-piperidin-1-ylethyl)thien-3-ylJbenzenesulfonamide ¢ 3-chioro-2-methyl-N-[4-(morpholin-4-ylmethyi)thien-3-yl]benzenesulfonamide ¢ 3-chloro-N-{4-[2-(1H-imidazol-1-yl)ethyl]thien-3-yl}-2-methylbenzenesulfonamide e 2.4 5-trichloro-N-(3-chlore-2,3'-bithien-4"-vI}benzenesulfonamide e 2,3,4-trichloro-N-(3-chloro-2,3"-bithien-4'-yl)benzenesulfonamide eo 2,3 4-trichloro-N-[4-(2-chlorophenyl)thien-3-yl]benzenesulfonamide e N-[4-(4- {[(4-bromo-2,5-difluorophenyl)sulfonylJamino} thien-3-yl)phenyl]acetamide ® 4-bromo-N-(3-chloro-2,3"-bithien-4'-y1)-2,5-difluorobenzenesulfonamide e 4,5-dichloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide e N-[4-(4-{[(2,4,5-trichlorophenyl)sulfonyl Jamino } thien-3-yl)phenyl]acetamide © 4-bromo-5-chloro-N-(3-chioro-2,3"-bithien-4'-yljthiophene-2-suifonamide e 3-bromo-5-chloro-N-[4-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide e N-[4-(4-{[(2,6-dichlorophenyl)sulfonyl]amino} thien-3-yl)phenyljacetamide e 2,6-dichloro-N-(3-chioro-2,3'-bithien-4'-yl)benzenesulfonamide e N-[2-(4- {[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-3-yl)ethyl]acetamide ¢ 3-chloro-2-methyl-N-(4-{2-[(methylsulfonyl)amino]ethyl} thien-3- yhbenzenesulfonamide e 3-chloro-2-methyl-N-{4-[2-(3-0x0-1,4-0xazepan-4-yl)ethyl]thien-3- yl}benzenesulfonamide ¢ 3-chloro-2-methyl-N-{4-[2-(2-oxopyrrolidin-1-yl)ethyl]thien-3- yl}benzenesulfonamide oe 2 3 4-txichloro-N- {4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- = TT yl}benzenesulfonamide ¢ N-[4-(2-chloro-6-flucrophenybthien-3-yl}-4-propylbenzenesulfonamide
* 4-bromo-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3-y1}-2,5- difluorobenzenesulfonamide ’ ¢ 4,5-dichloro-N-[4~(2-chloro-6-flucrophenyl)thien-3-yl]thicphene-2-sulfonamide * 4-bromo-5-chloro-N-{4-[2,6-dichloro-4-(triflucromethyl)phenyl]thien-3- yl}thiophene-2-sulfonamide * 24-dichloro-N-[4-(2-chloro-6-flucrophenyl)thien-3-yl]-6-methylbenzenesul fonamide * 4-bromo-N-[4-(2-chloro-6-fluorophenyl)thien-3-yl]-2-methylbenzenesulfonamide * 3-chloro-2-methyl-N-(4-{2-[methyl(methylsulfonyl)amino] ethyl} thien-3- yhbenzenesulfonamide * N-[2-(4-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-3-yl)ethyl]-N- methylcyclopropanecarboxamide * 3-chloro-2-methyl-N-{4-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]thien-3- yl}benzenesulfonamide * 3-chloro-2-methyl-N-{4-(2-{[(trifluoromethyl)sulfonyl amino } ethyl)thien-3- yl]benzenesulfonamide * N-[4-(4-{[(4-bromo-5-chlorothien-2-y1)sulfonyl]amino} thien-3-y1)phenyl]acetamide * 2 ,4-dichloro-N-{4-[2-(3-oxomorpholin-4-yl)ethyl|thien-3-yl} benzenesul fonamide e 2A4-dichloro-6-methyl-N- {4-[2-(3-0xomorpholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide * 24,6-trichloro-N-{4-[2-(3-oxomorpholin-4-ylethyl]thien-3-y1} benzenesulfonamide * 4-(2-furyl)-N-[4~(Z-morpholin-4-yi-2-oxoethyl)thien-3-yl]benzenesulfonamide * 5-fluoro-2*-methoxy-N-[4~(2-morpholin-4-yl-2-oxosthyl)thien-3-y1]-1,1-biphenyl-4- sulfonamide * 4-(5-methylthien-2-yl)-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide e 3'-acetyl-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1"-biphenyl-4-sulfonamide * N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4'-(trifluoromethoxy)-1,1-biphenyl-4- sulfonamide e 3'4-dichloro-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1'-biphenyl-4- sulfonamids
J 4-(1,3-benzodioxol-5-yl)-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide ® 4-(5-chlorethien-2-yl)-N-[4-(2-morpholin-4-yl-2-oxoethyi)thien-3- ) yl]benzenesulfonamide J N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-4-pyridin-4-ylbenzenesulfonamide eo N-[4-({ [4-(Z-morpholin-4-yl-2-oxoethyl)thien-3-yl] amino} sulfonyl)-1,1'-biphenyl-3- yl]acetamide ° N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-3-ylbenzenesulfonamide ° N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide ® 4'-(methylthio)-N-{4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1'-biphenyi-4- sulfonamide e N- [4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-3 L5'-bis(trifluoromethyl)-1,1'- biphenyl-4-sulfonamide o 4'-chloro-N-[4-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]- 1,1'-biphenyl-4-sulfonamide © N-[{4-(2-morpholin-4-yi-2-oxoethyi)thien-3 ~yl]-3"-nitro-1,1"-biphenyl-4-sulfonamide e 3-chloro-2-methyl-N-[4-(2-{ methyl[(trifluoromethyl)sulfonyl]aminc} ethyl)thien-3- yl]benzenesulfonamide oe N-[2-(4-{[(3 -chloro-2-methylphenyl)sulfonyl]amino} thien-3 -yl)ethyl}-1-methyl-1H- imidazole-4-sulfonamide e 3-chloro-N- {4-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]thien-3 -yl}-2- methylbenzenesulfonamide ¢ 4,5-dichloro-N-{4-[2-(3 -oxomorpholin-4-yl)ethyl]thien-3-yl1} thiophene-2- sulfonamide ® N-{4-[2-(3-oxomorpholin-4-y1) ethyllthien-3-y1}-4-phenoxybenzenesulfonamide e 3-fiuoro-N- {4-[2-(3-oxomorpholin-4-yljethyl]thien-3-yl} benzenesuifonamide = N-{4 [2-(3-oxomorpholin-4-yl)ethyl]jthien-3 -yl}-5-pyridin-2-yithiophene-2- ~~ sulfonamide = ____ _ a EERE oe * N-{2-chloro-4-[({4- [2-(3-oxomorpholin-4-yl)ethyl]thien-3- yl}amino)sulfonyljphenyl} acetamide e ethyl (3-{[(3-chlorc-2 methylphenylsulfonyl] amino} thien-2-yi)acetate s (3- {[(3-chloro-2-methylphenyl)sulfonyljaminc} thien-2-yl)acetic acid ¢ 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl] amino} thien-2-yl)-N-methylacetamide * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl] amino} thien-2-yl)-N-ethylacetamide * 2,5-dichloro-N-(3'-chloro-2,2"-bithien-3-yl)benzenesulfonamide ¢ isopropyl (3-{ [(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)acetate * 3-chloro-N-[2-(2-hydroxyethyl)thien-3-yl]-2-methylbenzenesulfonamide * 3-chloro-N-[2-(2-cthoxyethyl)thien-3-y1]-2-methylbenzenesulfonamide * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N,N-diethylacetamide e methyl (3-{[(3-chloro-2-methylphenyl)sulfonyl]amino }thien-2-yl)acetate * 3-chloro-N-[2-(2-isopropoxyethyl)thien-3-v1] -2-methylbenzenesulfonamide * 3-chloro-N-[2-(2-methoxyethyl)thien-3-yl]-2-methylbenzenesulfonamide * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl methanesulfonate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)acetamide ~ ® 3-chloro-N-{2-[2-(2-fluoroethoxy)ethyl]thien-3-y1}-2-methylbenzenesulfonamide * 3-chloro-2-methyl-N-{2-[2-(2,2,2-trifluoroethoxy)ethyllthien-3- yl}benzenesulfonamide * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl acetate * 3-chloro-2-methyl-N-[2-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide * N-[2-(2-bromoethyl)thien-3-y1]-3-chloro-2-methylbenzenesulfonamide e 2-(3-{[(3-chlorc-2-methylphenyl)sulfonyljamino} thien-2-yl)ethyl morpholine-4- carboxylate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyljamino} thien-2-yl)ethyl diethylcarbamate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl propionate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyljamino} thien-2-yl)ethyl 2- methylpropanoate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl 2-furocate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl benzoate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1) -N-methoxy-N- , methylacetamide * 3-chioro-N-{Z- 2-{cietnyiamino)sinyi]thien-3-yi}-Z-methyibenzenesulfonamide
* 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl ethylcarbamate * N-[2-3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)ethyl]-N- ethylacetamide ‘ : ¢ 3-chloro-2-methyl-N-[2-(2-oxopentyl)thien-3-yl]benzenesulfonamide * N-{2-[2-(1,1-dioxidothiomorpholin-4-yl)-2-oxoethyl jthien-3-y1} -4- propylbenzenesulfonamide e 2,4,6-trichloro-N-[2-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide ¢ 24-dichloro-N-[2-(2-morpholin-4-ylethyl)thien-3-yi]benzenesulfonamide ¢ 3-chloro-2-methyl-N-{2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3- yl}benzenesulfonamide e 24-dichloro-6-methyl-N-[2-(2-morpholin-4-ylethyl)thien-3-yl]benzenesulfonamide e N-[2-(2-morpholin-4-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide ¢ 24-dichloro-6-methyl-N-{2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide e 24,6-trichloro-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl Jbenzenesulfonamide e N-[2-(2-morpholin-4-yl-2-oxcethyl)thien-3-y11-1,1"-biphenyl-4-sulfonamide ® N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl}-4-propylbenzenesulfonamide e N-[2-(2-0x0-2-thiomorpholin-4-ylethyl)thien-3-yl]-1,1'-biphenyl-4-sulfonamide ¢ N-[2-(2-0x0-2-thiomorpholin-4-ylethyl)thien-3-yl]-4-propylbenzenesulfonamide ¢ 2,4-dichloro-6-methyl-N-[2-(2-0x0-2-thiomorpholin-4-ylethyl)thien-3- yl]benzenesulfonamide ° N-[2-(2-0x0-2-piperidin-1-ylethyl)thien-3-yi]-1,1-biphenyl-4-sulfonamide e N-[2-(2-oxo0-2-piperidin-1-ylethyl)thien-3-y1]-4-propylbenzenesulfonamide e 2,4-dichloro-6-methyl-N-[2-(2-oxo0-2-piperidin-1-yiethyi)thien-3- yijoenzenesuifonamide e 24,6-trichloro-N-[2-(2-0x0-2-piperidin-1-ylethyl)thien-3-yl]benzenesulfonamide - — = - -e N=«(2-phenylthien-3<yl)-4-propylbenzenesutfonamide ~~ Co o cthyl 3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-yl)(oxo)acetate o 3-chloro-2-methyl-N-(2-phenylthien-3-yl)benzenesulfonamide ¢ 3-chloro-N-[2-(4-fluoro-3-methylphenyi)thien-3-yl]-2-methylbenzenesuifonamide e 2.4.6-trichloro-N-(2-phenylthien-3-yl)benzenesulfonamide e N-(2-phenylthien-3-yl)-1,1"biphenyl-4-sulfonamide ' s 2 4-dichlorc-6-methyl-N-(2-phenylthien-3-yl)benzenesulfonamide * 2-{3-[(1,1'-biphenyl-4-ylsulfonyl)amino]thien-2-yl} -N-ethyl-N-methylacetamide * N-ethyl-N-methyl-2-(3-{[(4-propylphenyl)sulfonyl]amino} thien-2-yl)acetamide e 2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino} thien-2-yl)-N-ethyl-N- methylacetamide ¢ N-ethyl-N-methyl-2-(3- {[(2,4,6-trichlorophenyl)sulfonyl]amino} thien-2-yl)acetamide s 2,4,6-trichloro-N-[2-(2-ox0-2-thiomorpholin-4-ylethyl)thien-3- yl]benzenesulfonamide s 2-{3-[(1,1-biphenyl-4-ylsulfonyl)amino]thien-2-yl}-N-isopropyl-N-methylacetamide o 2-{3-[(1,1"-biphenyl-4-ylsulfonyl)amino]thien-2-yl}-N,N-diethylacetamide s N,N-diethyl-2-(3- {[(4-propylphenyl)sulfonyllamino} thien-2-yl)acetamide s 2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl] amino} thien-2-y1)-N,N- diethylacetamide e N,N-diethyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino} thien-2-yl)acetamide » 2-{3-[(1,1'-biphenyl-4-ylsulfonyl)amino]thien-2-y1}-N,N-diisopropylacetamide e N,N-diisopropyl-2-(3-{[(4-propylphenyl)sulfonyl]amino} thien-2-y1)acetamide o 2-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}thien-2-y1)-N,N- diisopropylacetamide s N,N-diisopropyl-2-(3-{[(2,4,6-trichlorophenyl)sulfonyl]amino}thien-2-yl)acetamide * N-[4-(3-{[(4-propylphenyl)sulfonyl]amino} thien-2-yl)phenyl acetamide e 4-propyl-N-(2-pyridin-3-ylthien-3-yl)benzenesulfonamide e N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-4-propylbenzenesulfonamide e N-[2-(2-chlorophenyl)thien-3-yl]-4-propylbenzenesulfonamide e 3-chloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-2-methylbenzenesulfonamide * 3-chloro-N-(5'-chioro-2,2'-bithien-3-y1)-2-methylbenzenesulfonamide * 3-chloro-N-[2-(2-chlorophenylthien-3-y1]-2-methylbenzenesulfonamide s N-[4-(3-{[(2,4,6-trichlorophenyl)sulfonyl amino} thien-2-yl)phenyl]acetamide s 2,4,6-trichicro-N-{Z-pyridin-3-yithien-3-yi)benzenesulionamide
° 2,4,6-trichloro-N-[2-(2~chloro-5-nitrophenyl)thien-3-yl]benzenesul fonamide * 2,4,6-trichloro-N-(5'-chloro-2,2"-bithien-3-yl)benzenesulfonamide e 2,4,6-trichloro-N-[2-(2-chiorophenyl)thien-3-yi]benzenesuifonamide * N-(4-{3-[(1,1-biphenyl-4-ylsulfonyl)amino]thien-2-yl} phenyl)acetamide * N-(2-pynidin-3-ylthien-3-yl)-1,1'-biphenyl-4-sulfonamide * N-[2-(2-chloro-5-nitrophenyl)thien-3-y1}-1,1'-biphenyl-4-sulfonamide ¢ N-[2-(2-chlorophenyl)thien-3-yl]-1,1'-biphenyl-4-suifonamide ¢ N-[4-(3-{[(2,4-dichloro-6-methylphenyl)sulfonyl] amino} thien-2-yl)phenyl]jacetamide e 2.A4-dichloro--6-methyl-N-(?-pyridin-3-ylthien-3-yDbenzenesulfonamide 2,4-dichloro-N-[2-(2-chloro-5-nitrophenyl)thien-3-yl]-6-methylbenzenesulfonamide e 2,4-dichloro-N-(5-chloro-2,2'-bithien-3-yl)-6-methylbenzenesulfonamide e 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N,N-dipropylacetamide * 3-chloro-2-methyl-N-[2-(2-0x0-2-piperazin-1-ylethyl)thien-3-yl]benzenesulfonamide * 2,4-dichloro-N-[2-(2,5-dimethyl-3-furyl)thien-3-yl]-6-methylbenzenesulfonamide ¢ N-(3'-chloro-2,2"-bithien-3-yl)-4-propylbenzenesulfonamide © 3-chloro-N-(3'-chloro-2,2'-vithien-3-yi)-2-methylbenzenesuifonamide o 2,4 6-trichloro-N-(3'-chloro-2,2"-bithien-3-yl)benzenesulfonamide ¢ 2,4-dichloro-N-(3'-chloro-2,2'"-bithien-3-yl)-6-methylbenzenesulfonamide ¢ 2,4-dichloro-N-[2-(2-chlorophenyl)thien-3-y1]-6-methylbenzenesulfonamide e 4-bromo-2-methyl-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl}benzenesulfonamide e N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-2,4- bis(trifluoromethyl)benzenesulfonamide e 2-methyl-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4- (trifluoromethoxy)benzenesulfonamide J N-[2-(2-morpholin-4-yl-2-oxoethyljthien-3-y1]-4-phenoxybenzenesulfonamide ~~ 7s 4-chloro-2,6-dimethyl-N-[2-(2-morpholin-4-y]-2-oxoethyl)thien-3- ST yl]benzenesulfonamide J 2,4-dichloro-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yi]benzenesulfonamide :
o tert-butyl 4-[(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino }thien-2- yDacetyl]piperazine-1-carboxylate * 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N,N-dimethylacetamide ¢ 3-chloro-2-methyl-N-{2-[2-(pyridin-3-yloxy)ethyl]thien-3-yl} benzenesulfonamide s 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N-isopropyl-N- methylacetamide o 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N-ethyl-N- methylacetamide e 3-chloro-2-methyl-N-[2-(2-0x0-2-thiomorpholin-4-ylethyl)thien-3- yl]benzenesulfonamide s 3-chloro-2-methyl-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide e 2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino} thien-2-y1)-N,N- diisopropylacetamide e 3-chloro-2-methyl-N-[2-(2-0x0-2-pyrrolidin-1-ylethyl)thien-3-yl ]benzenesulfonamide e 3-chloro-2-methyl-N-[2-(2-ox0-2-piperidin-1-ylethyl)thien-3-yl]becnzenesulfonamide e 3-chloro-2-methyl-N-[2-(morpholin-4-ylmethyl)thien-3-yl|benzenesulfonamide ¢ 3-chloro-N-{2-[2-(1H-imidazol-1-yl)ethyl]thien-3-y1}-2-methylbenzenesulfonamide e 2.4 5-trichloro-N-(3'-chloro-2,2"-bithien-3-yi)benzenesulfonamide o 2.3 A-trichloro-N-(3'-chloro-2,2'-bithien-3-v1)benzenesulfonamide o 2.3 4-trichloro-N-[2-(2-chlorophenyl)thien-3-yl]benzenesulfonamide o N-[4-(3-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}thien-2-yl)phenyl]acetamide e 4-bromo-N-(3'-chloro-2,2"-bithien-3-yl)-2,5-difluorobenzenesulfonamide e 4,5-dichloro-N-[2-(2-chlorophenyl)thien-3-yl]thiophene-2-sulfonamide e N-[4-(3-{[(2,4,5-trichlorophenyl)sulfonyl amino} thien-2-yl)phenyllacetamide e 4-bromo-5-chloro-N-(3'-chloro-2,2'-bithien-3-yl)thiophene-2-sulfonamide e 3-bromo-5-chloro-N-[2-(2-chlorophenyl)thien-3-y1]thiophene-2-sulfonamide s N-[4-(3-{[(2,6-dichlorophenyl)sulfonyl]amino} thien-2-yl)phenyl]acetamide : e 2,6-dichloro-N-(3'-chloro-2,2'-bithien-3-yl)benzenesulfonamide s N-[2-(3-{ 3-ciioro-Z-melnyipnenyl sulfonyl] amine} thien-2-yi)ethyi acetamide e 3-chloro-2-methyl-N-(2- {2-[(methylsulfonyl)amino]ethyl} thien-3- yl)benzenesulfonamide s 3-chloro-2-methyl-N-{2-[2-(3-0x0-1,4-0xazepan-4-yl)ethyi]thien-3- : yl}benzenesulfonamide e 3-chloro-2-methyl-N- {2-[2-(2-oxopyrrolidin-1-yl)ethyl]|thien-3- yl}benzenesulfonamide e 2,3,4-trichloro-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl}thien-3- yl}benzenesulfonamide e N-[2-(2-chloro-6-fluorophenyi)thien-3-yl]-4-propylbenzenesuifonamide e 4-bromo-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyljthien-3-y1}-2,5- difluorobenzenesulfonamide e 4 5-dichloro-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]thiophene-2-sulfonamide e 4-bromo-5-chloro-N-{2-[2,6-dichloro-4-(trifluoromethyl)phenyl]thien-3- yl}thiophene-2-sulfonamide e 2 4-dichioro-N-[2-(2-chioro-6-fiuorophenyi)thien-3-yl]-6-methyibenzenesulfonamide e 4-bromo-N-[2-(2-chloro-6-fluorophenyl)thien-3-yl]-2-methylbenzenesulfonamide e 3-chloro-2-methyl-N-(2- {2-[methyl(methylsulfonyl)amino]ethyl} thien-3- yl)benzenesulfonamide e N-[2-(3-{[(3-chloro-2-methylphenyl)suifonyl]amino} thien-2-yl)ethyl]-N- methylcyclopropanecarboxamide ¢ 3-chloro-2-methyl-N-{2-[2-(4-methyl-2-oxopiperazin-1-yl)ethyl]thien-3- yi}benzenesulfonamide e 3-chloro-2-methyl-N-[2-(2-{[{trifluoromethyl)suifonyl]amino} ethyl)thien-3- yl]benzenesulfonamide s N-[4-(3-{[(4-bromo-5-chlorothien-2-yl)sulfonyl]amino} thien-2-yDphenyl]acetamide e 2,4-dichioro-N-{2-[2-(3-oxomorpholin-4-yi)ethyijthien-3-yi} benzenesulfonamide oo. ...e_ 2A4-dichloro-6-methyi-N-{2-[2-(3-oxomorpholin-4-yi)ethyl}thien-3- = Cl yl}benzenesulfonamide ¢ 2,4,6-trichloro-N-{2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3-yl} benzenesulfonamide : ¢ 4-(2-furyl)-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl[benzenesulfonamide o 5'-fluoro-2'-methoxy-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1"-biphenyl-4- sulfonamide ¢ 4-(5-methylthien-2-y1)-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yllbenzenesulfonamide * 3acetyl-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-1,1'-biphenyl-4-sulfonamide e N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4'-(trifluoromethoxy)-1,1-biphenyl-4- sulfonamide s 3'4'-dichloro-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-y1]-1,1'-biphenyl-4- sulfonamide s 4-(1,3-benzodioxol-5-y1)-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide es 4-(5-chlorothien-2-yl)-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3- yl]benzenesulfonamide * N-[2-(2-morpholin-4-yi-2-oxoethyl)thien-3-yi]-4-pyridin-4-ylbenzenesulfonamide s N-[4-({[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]amino} sulfonyl)-1,1'-biphenyl-3- yl]acetamide * N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl}-4-thien-3-ylbenzenesulfonamide ® N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-4-thien-2-ylbenzenesulfonamide o 4'-(methylthio)-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl1]-1,1'-biphenyl-4- sulfonamide e N-{2-(2-morpholin-4-yi-2-oxoethyl)thien-3-yl]-3',5-bis(trifluoromethyi)-1,1'- biphenyl-4-sulfonamide » 4'-chloro-N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-1,1'-biphenyl-4-sulfonamide » N-[2-(2-morpholin-4-yl-2-oxoethyl)thien-3-yl]-3"nitro-1,1"-biphenyl-4-sulfonamide e 3-chloro-2-methyl-N-[2-(2-{methyl[(trifluoromethyl)sulfonyljamino}ethyl)thien-3- yl]benzenesulfonamide s N-[2-(3-{[(3-chloro-2-methylphenyl)sulfonyl]amino}thien-2-yl)ethyl]-1-methyl-1H- imidazole-4-sulfonamide e 3-chloro-N-{2-[2-(2-hydroxy-3-oxomorpholin-4-yl)ethyl]thien-3-yl}-2- ac methyibenzenssulforamide
® 4 5-dichloro-N-{2-[2-(3-oxomorpholin-4-yl}ethyl]thien-3-yl} thiophene-2- sulfonamide ® N-{2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3-yl}-4-phenoxybenzenesulfonamide » 3-fluoro-N-{2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3-yl} benzenesulfonamide » N-{2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3-yl}-5-pyridin-2-ylthiophene-2- sulfonamide s N-{2-chloro-4-[({2-[2-(3-oxomorpholin-4-yl)ethyl]thien-3- yl} amino)sulfonyl]phenyl} acetamide » methyl (3-{[(5-fluoro-2-methylphenyl)sulfonyl]amino} thien-2-yl)acetate » methyl (3-{[(3-cyanophenyl)sulfonyl]amino} thien-2-yl)acetate » methyl (3-{[(4-butoxyphenyl)sulfonyllamino}thien-2-yl)acetate » methyl (3-{[(2-methylsulfanylpyrimidin-4-ylthiophene)sulfonyl]amino} thien-2- yl)acetate » methyl (3-{[(1-methylimidazol-4-yl)sulfonyl]amino}thien-2-yl)acetate » methyl (3-{[(4-methylphenyl)sulfonyl]amino}thien-2-yl)acetate.
5. The compound of any one of claims 1-3 having formula (II): R' T N z Ng pd F XX / \ Bj S Bs wherein T, R!. By and Z are as defined in either claim 1 or claim 2.
6. The compound of any one of claims 1-4 having formula (III): R' T B ~N pd 3 oF Xo / \ Zz S Bs wherein 7, R', 33 anc Z are as dened in ster claim 1 orelaim 2. Amended Sheet — 14-04-2005
7. A compound according to anyone of claims 1-6, for medical use.
8. A compound of formula (I) rR! T N B Ng ~~ 2 Oo 0 B4 S Bs which compound inhibits the human 11-B-hydroxysteroid dehydrogenase type 1 enzyme, wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]y, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C,-alkyl, optionally halogenated C,¢-alkoxy, Ci.¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in Amended Sheet — 14-04-2005
: one or more positions independently of each other by C;¢-acyl, Cy.¢-alkylthio, cyano, nitro,
hydrogen, halogen, optionally halogenated C;.¢-alkyl, optionally halogenated C;.s-alkoxy,
amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2- ’
thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl amino} carbonyl); R'is hydrogen or Ci.¢-alkyl; Bi and B; are Bj or Z, provided that B; and B, have different meanings, wherein:
» Zis selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, Ci.-alkyl, halogenated C,.s-alkyl, halogen, C;¢-alkoxy, nitro, C;.¢-alkoxycarbonyl, C;.-
allkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R?, wherein
» Xis CH; or CO;
+ Yis CH, CO or a single bond;
15» Ris selected from Cy ¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-0x0-4- morpholinolinylmethyl . Cy¢-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-y1;
NR’R*, wherein R? and R” are each independently selected from hydrogen, Ci-6-alkyl, optionally halogenated C.¢-alkylsulfonyl, Ci.¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl,
1-methylimidazolylsulfony!, Cy.¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Cjs-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine,
pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydre-2(1H)isoquinoclinyl), or (18,48)-2-0xa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Ci.¢- alkyl, Ci6-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR®R*, wherein R® and R* are each independently selected from hydrogen, Cy.q- alkyl or form together with the N-atom to which they are attached morpholinyl; ] RECTIFIED SHEET (RULE 91)
R’0, wherein R’ is hydrogen, optionally halogenated Ci.¢-alkyl, aryl, heteroaryl, Cie-acyl, C1-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; » Bj; is hydrogen, C.¢-alkyl or dimethylaminomethyl; or a salt, hydrate or solvate therecf; with the proviso that when: Z is X-Y-R? wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy for use in a method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation.
9. A compound according to claim 8, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
10. A compound according to to either claim 8 or claim 9, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxel-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, S-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yljamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsultanylphenyl, 5-methyl-2-thienyl, A-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pynidyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R'is hydrogen or methyl; B, and B; are Bj or Z, provided that By and 3; nave different meanings, waereil Amended Sheet — 14-04-2005
» Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R?, wherein e Xis CH; or CO; » Y is CH,, CO or a single bond; » R?is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-0xo-4- morpholinclinylmethylene, ethoxycarbenyl, S-methyl-1 ,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR’R®, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyi, n-propyl, tetrahycro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (18,4S)-2-0xa-5-aza- bicyelo[2.2.1Thept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidenyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl; OCONR’R*, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R°0, wherein R’is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; s Bj is hydrogen, methyl or dimethylaminomethyl; with the proviso that when: Z is X-Y-R?, wherein X is CO, Y is a single bond, and R’ is not methoxy, chloro or hydroxy.
11. The compound accotding to clei LC, wherein Tis 3-cilore-2-meinylnienyl. Amended Sheet — 14-04-2005
12. A compound according to any one of claims 8-11, wherein the compound is selected from the compounds as defined in claim 4.
13. A compound of formula (I):
R
™. A Bo B4 Ss Bs wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci.¢-alkyl, optionally halo genated Cy ¢-alkoxy, Cie-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsuifonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by Cis-acyl, C 1s-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C.-alkyl, optionally halogenated Ci.6- alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1 ,3-thiazol-2-yl]amino} carbonyl); R! is hydrogen or C,¢-alky}; B, and B; are Bj or Z, provided that B; and B; have different meanings, wherein: « 7 is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C,¢-alkyl, halogenated C,s-alkyl, halogen, Ci¢-alkoxy, nitro, Cy.¢-alkoxycarbonyl, Ci.¢- alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R%, wherein es Xis CH, or CO; : s Y is CH,, CO or a single bond; » RZ%ig selected from Cyg-alkyl, azido, arylthio, heteroarylthic, halegen, hydroxymethyl, 2- hydroxyethylaminemethyi, methyisuifonyioxymetiyi, 3-0X0-4- morpholinolinylmethylene, C, s-alkoxycarbonyl, 5-methyl-1,3 ,4-oxadiazol-2-yl; Amended Sheet — 14-04-2005
NR’R*, wherein R® and R* are each independently selected from hydrogen, Ci.c-alkyl, optionally halogenated C,.¢-alkylsulfonyl, Ci.¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, Cy¢-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C;.¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-0xa-3- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by Cie- alkyl, C).¢-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONR’R®, wherein R® and R* are each independently selected from hydrogen, Ci.6- alkyl or form together with the N-atom to which they are attacked morpholinyl; R’0, wherein R’ is hydrogen, optionally halogenated Ci.¢-alkyl, aryl, heteroaryl, Ci.- acyl, Ci¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl, s Bj; is hydrogen, Ci.¢-alkyl or dimethylaminomethyl; or a salt, hydrate or solvate thereof; with the proviso that when: Z is X-Y-R?, wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy for use in a method for inhibiting a human 1 1-B-hydroxysteroid dehydrogenase type 1 enzyme, wherein the method comprises administering to a subject in need thereof an effective amount of the compound.
14. A compound according to claim 13, wherein T is selected from 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; I-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(triflucromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylamincphenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodicxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(t fiucremetnyl) phenyl, 37ome, SUISKy, CETSSXY, S28TS, 4-czrsonyoneny., 3-calcre-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]aminc} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- Amended Sheet — 14-04-2005
72a furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- Amended Sheet — 14-04-2005 nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, : trifluoromethyl; or Rlis hydrogen or methyl; B; and B; are Bj or Z, provided that B; and B; have different meanings, wherein: e Zis selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or 1s X-Y-R?, wherein eo XisCH;or CO; eo Yis CH,, CO or a single bond,
. R? is selected from n-propyl, azide, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NRR?, wherein R® and R? are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or NRR* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,68)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-y1, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-0xazepinyl, 2- oxooxazolinyl, pipcrazinyl; piperidinyl; pyrrolidinyl; pymrolidonyl, thicmorphelinyl; 1,1- dioxido-thiomorpholinyl; OCONR’R*, wherein R® and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; RECTIFIED SHEET (RULE 91)
R’0, wherein R® is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; » Bj is hydrogen, methyl or dimethylaminomethyl; with the proviso that when: Z is X-Y-R?, wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy.
15. The compound according to claim 14, wherein T is 3-chloro-2-methylphenyl.
16. A compound according to any one of claims 13 to 15, wherein the compound is selected from the compounds as defined in claim 4.
17. A compound according to any one of claims 13-16, wherein the subject is a human.
18. A compound of formula (I) R' T B No ~ 2 A 7 No / \ By Ss Bs wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]p, wherein 1 is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Ci.¢c-alkyl, optionally halogenated C.¢-alkoxy, Ci .¢-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each cther by Ci.s-acyl, Ci.¢-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Cy.s-alkyl, optionally halogenated C,.¢-alkoxy, amide which is onticnally mene or disubstituted, (benzoylamine)methy!, carboxy, 2- thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl] amino } carbonyl); Amended Sheet — 14-04-2005
WO §3/044009 PCT/SE02/02138
R'is hydrogen or C,.¢-alkyl, Bi and B; are B; or Z, provided that B, and B; have different meanings, wherein:
= Zs selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, C;.¢-alkyl, halogenated C;¢-alkyl, halogen, C;¢-alkoxy, nitro, Ci¢-alkoxycarbonyl, Ci. alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R?, wherein s Xis CH; or CO;
* Yis CH, CO or a single bond;
« Ris selected from C.s-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C, s-alkoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl,
NR’R®, wherein R? and R* are each independently selected from hydrogen, Ci.¢-alkyl, optionally halogenated C;.¢-alkylsulfonyl, C,¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, C,.s-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or C,¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or
NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1- dioxidothiomorpholine, 2-(3,4-dihydro-2(1H)isoquinolinyl), or (1S,4S)-2-0xa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems arc optionally substituted by Cj 4- alkyl, C,.¢-acyl, hydroxy, oxo, t-butoxycarbonyl;
OCONR’R®, wherein R* and R” are each independently selected from hydrogen, Ci .¢- alkyl or form together with the N-atom to which they are attached morpholinyl;
R’0, wherein R’ is hydrogen, optionally halogenated Ci.¢-alkyl, aryl, heteroaryl, C,4- acyl, Ci¢-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl,
e Bj; is hydrogen, Ci.¢-alkyl or dimethylaminomethyl;
or a salt, hydrate or solvate thereof. with the proviso that when: 7 is X-V-R? wherein ¥X is CO, V is 2 single bond, and R? is not methoxy, chloro or hydroxy for use in a method for treating a 11-B-hydroxysteroid dehydrogenase type 1
Amended Sheet — 14-04-2005 enzyme-mediated disorder, wherein the method comprises administering to a subject in need thereof an effective amount of the compound.
19. A compound according to claim 18, wherein the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and immuno-modulation, wherein the treatment of hyperglycemia does not cause hypoglycemia.
20. A compound according to either claim 18 or claim 19, wherein the immuno- modulation is selected from tuberculosis, lepra, and psoriasis.
21. A compound according to any one of claims 18-20, wherein T is selected from 5-chloro-1,3-dimethyl-1 H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazolyl; 5-(dimethylamino)-1-naphthyl; 1-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamine)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(triflucromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chlore-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-Z-yl]amino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl, 4-methyl-1-piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyt, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; B, and B; are Bj or Z, provided that B, and B; have different meanings, wherein: e 7 is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl, phenyl optionally substituted with one or more of SnCXysersony., Tie, TuCs, mety, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R?, wherein Amended Sheet — 14-04-2005 o X is CH, or CC; * Y is CH;, CO or a single bond; s R?is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-0x0-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-o0xadiazol-2-yl, hydroxymethyl, 2-hydrexyethylaminomethyl, methylsulfonyloxymethyl; NR3R* wherein R® and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2- furanylmethyl, triflucromethylsulfonyl, N-carbethoxypiperidyl; or NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyi, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (15,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl; OCONR’R*, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R>0, wherein R’ is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; s Bj is hydrogen, methyl or dimethylaminomethyl; with the proviso that when: Z is X-Y-R? wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy.
22. The compound according to claim 21, wherein T is 3-chioro-2-methylphenyl.
23. A compound according to any one of claims 18-22, wherein the compound is selected from the compounds as defined in claim 4. Amended Sheet — 14-04-2005
24. A compound according to any one of claims 18-23, wherein the subject is a human.
25. The use of a compound of formula (I) R'
™N. AN B, B4 Ss B3 which compound inhibits the human 11-f-hydroxysteroid dehydrogenase type 1 enzyme, wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R],, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C-alkyl, optionally halogenated C,.¢-alkoxy, C,.s-alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally monc- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by C,¢-acyl, Ci.s-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Ci¢-alkyl, optionally halogenated C,.¢-alkoxy, amide which is optionally mone or disubstituted, (benzoylamino)methyl, carbexy, 2- thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino} carbonyl); R'is hydrogen or Cj.¢-alkyl; B; and B; are Bj or Z, provided that B and B; have different meanings, wherein: s Z is selected from an aryl ring or heteroaryl ring, which is further optionally substituted in one or more positions independently of each other by hydrogen, Ci.-alkyl, halogenated C,¢-alkyl, halogen, C,¢-alkoxy, nitro, C,s-alkoxycarbonyl, C,.¢- alkylsulfonyl, acetylamine or aryloxy, wherein the aryloxy is further optionally substituted in one or more positions independently of each other by hydrogen and halogen; or is X-Y-R%, wherein » XisCH,cr CC e Y is CH,, CO or a single bond; Amended Sheet — 14-04-2005
» R?is selected from C,.¢-alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2- hydrox yethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- morpholinolinylmethylene, C.¢-alkoxycarbonyl, S-methyl-1,3,4-oxadiazol-2-yl; NR’R*, wherein R® and R* are each independently selected from hydrogen, C;.¢-alkyl, optionally halogenated Cj.¢-alkylsulfonyl, C,¢-alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1- methylimidazolylsulfonyl, C,4-acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N- carbethoxypiperidyl, or Cy.¢-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR’R* represent together heterocyclic systems which are imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1-dioxidothiomorpholine, 2- (3,4-dihydro-2(1H)isoquinolinyl), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by C,.¢-alkyl, Ci¢-acyl, hydroxy, oxo, t- butoxycarbonyl; OCONR’R®, wherein R? and R* are each independently selected from hydrogen, C;_¢-alkyl or form together with the N-atom to which they are attached morpholinyl; R’0, wherein R’ is hydrogen, optionally halogenated C,4-alkyl, aryl, heteroaryl, C, 4-acyl,
Ci.s-alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; e Bj is hydrogen, C,s-alkyl or dimethylaminomethyl; or a salt, hydrate or solvate thereof; with the proviso that when: Z is X-Y-R?, wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immunec-modulation.
26. The use according to claim 25, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.
27. The use according to either claim 25 or claim 26, wherein T is selected from S-chloro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1- benzoxadiazoly.; 5-(dimethylamino)-i-napatnyi; 1-metnylimidazol-4-yl; 1-naphthyl; 2- naphthyl; 8-quinolinyl; Amended Sheet — 14-04-2005 thienyl substituted with one or more of (benzoylamine)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1-methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamine, 3-acetylaminophenyl, 3-
acetylphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, benzylamine, 3,5- bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4-carboxyphenyl, 3-chloro-2- cyanophenoxy, 4-chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, ({[4-(2- ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]amino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2- furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1-piperazinyl,
4-methyl-1-piperdinyl, 4-methylsulfanylphenyl, S-methyl-2-thienyl, 4-morpholinyl, nitro, 3- nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamino, 1-pyrrolidinyl, 2- thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or
R! is hydrogen or methyl;
Bi and B, are Bj or Z, provided that B; and B, have different meanings, wherein:
o Zis selected from 1-benzothien-3-vl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl; or is X-Y-R%, wherein s Xis CH, or CO;
» Y is CH,, CO or a single bond;
» R”is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl;
NR’R*, wherein R? and R* are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2- hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(1- methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1S)-phenylethyl, n-propyl, tetrahydro-2-
furanylmethyl, triflucromethylsulfonyl, N-cerbsthoxypiperidyl; or
RECTIFIED SHEET (RULE 91)
NR’R* represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-1- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxcmorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1S,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-ox0-1,4-0xazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1- dioxido-thiomorpholinyl; OCONR’R?, wherein R? and R* are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; RO, wherein R° is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n- propionyl, 3-pynidinyl, 2,2,2-trifluoroethyi; » Bj is hydrogen, methyl or dimethylaminomethyl; with the proviso that when: Z is X-Y-R?, wherein X is CO, Y is a single bond, and R? is not methoxy, chloro or hydroxy.
28. The compound according to claim 27, wherein T is 3-chloro-2-methylphenyl.
29. The use according to any one of claims 25-28, wherein the compound is selected from the compounds as defined in claim 4.
30. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any of the claims 1-4, and a pharmaceutically acceptable carrier.
31. The use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for use in a method for inhibiting a human 11-B- hydroxysteroid dehydrogenase type 1 enzyme in a subject in need thereof,
32. The use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for use in a method for treating a human 11-B-hydroxysteroid dehydrogenase tyse | enzyme-medizted diserder in 2 subject in need therect Amended Sheet — 14-04-2005
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0103913 | 2001-11-22 |
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| Publication Number | Publication Date |
|---|---|
| ZA200401312B true ZA200401312B (en) | 2005-03-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200401312A ZA200401312B (en) | 2001-11-22 | 2004-02-18 | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. |
| ZA200401311A ZA200401311B (en) | 2001-11-22 | 2004-02-18 | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| ZA200401311A ZA200401311B (en) | 2001-11-22 | 2004-02-18 | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. |
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| ZA (2) | ZA200401312B (en) |
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2004
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| ZA200401311B (en) | 2005-03-10 |
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