MXPA05012052A - Use of sulphonamide derivatives for the manufacture of a medicament for the prophylaxis and/or treatment of disorders of food ingestion - Google Patents
Use of sulphonamide derivatives for the manufacture of a medicament for the prophylaxis and/or treatment of disorders of food ingestionInfo
- Publication number
- MXPA05012052A MXPA05012052A MXPA/A/2005/012052A MXPA05012052A MXPA05012052A MX PA05012052 A MXPA05012052 A MX PA05012052A MX PA05012052 A MXPA05012052 A MX PA05012052A MX PA05012052 A MXPA05012052 A MX PA05012052A
- Authority
- MX
- Mexico
- Prior art keywords
- sulfonamide
- indol
- optionally
- substituted
- mono
- Prior art date
Links
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 37
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 230000000069 prophylaxis Effects 0.000 title claims abstract description 16
- 230000037406 food intake Effects 0.000 title claims abstract description 14
- 201000010099 disease Diseases 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 235000013305 food Nutrition 0.000 title claims abstract description 5
- 230000000875 corresponding Effects 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000011780 sodium chloride Substances 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 13
- -1 alkyl radical Chemical class 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 47
- 125000005842 heteroatoms Chemical group 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 150000002431 hydrogen Chemical group 0.000 claims description 20
- 125000002950 monocyclic group Chemical group 0.000 claims description 20
- 125000002619 bicyclic group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 9
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 7
- 235000020824 obesity Nutrition 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- CYRQMGSDPZJXOB-UHFFFAOYSA-N N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]-N-ethylnaphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)N(CC)C3=CC=C4NC=C(C4=C3)CCN(CC)CC)=CC=C21 CYRQMGSDPZJXOB-UHFFFAOYSA-N 0.000 claims description 4
- VDZROAIEYLMUAT-UHFFFAOYSA-N N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CC)CC)=CC=C21 VDZROAIEYLMUAT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000003367 polycyclic group Chemical class 0.000 claims description 4
- KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 claims description 3
- JVYUJTOTNLYRGJ-UHFFFAOYSA-N 5-chloro-N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]-3-methyl-1-benzothiophene-2-sulfonamide Chemical compound S1C2=CC=C(Cl)C=C2C(C)=C1S(=O)(=O)NC1=CC=C2NC=C(CCN(CC)CC)C2=C1 JVYUJTOTNLYRGJ-UHFFFAOYSA-N 0.000 claims description 3
- ZHONXOSWPFCSGQ-UHFFFAOYSA-N 5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3-methyl-1-benzothiophene-2-sulfonamide Chemical compound S1C2=CC=C(Cl)C=C2C(C)=C1S(=O)(=O)NC1=CC=C2NC=C(CCN(C)C)C2=C1 ZHONXOSWPFCSGQ-UHFFFAOYSA-N 0.000 claims description 3
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 206010061428 Decreased appetite Diseases 0.000 claims description 3
- 101710006116 IL31RA Proteins 0.000 claims description 3
- MLLKJGGUSYHRQW-UHFFFAOYSA-N N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulfonamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=CC2=CC=CN=C12 MLLKJGGUSYHRQW-UHFFFAOYSA-N 0.000 claims description 3
- 230000037396 body weight Effects 0.000 claims description 3
- 230000003893 regulation of appetite Effects 0.000 claims description 3
- JYFZTHMGIJASIF-NTEUORMPSA-N (E)-N-[3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-5-yl]-2-phenylethenesulfonamide Chemical compound C1CN(C)CCN1CC(C1=C2)=CNC1=CC=C2NS(=O)(=O)\C=C\C1=CC=CC=C1 JYFZTHMGIJASIF-NTEUORMPSA-N 0.000 claims description 2
- YRFRIJABNSLKIC-FYWRMAATSA-N (E)-N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]-2-phenylethenesulfonamide Chemical compound C1=C2C(CCN(CC)CC)=CNC2=CC=C1NS(=O)(=O)\C=C\C1=CC=CC=C1 YRFRIJABNSLKIC-FYWRMAATSA-N 0.000 claims description 2
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- XQIZCPRJWQBHCO-UHFFFAOYSA-N 5-chloro-3-methyl-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-1-benzothiophene-2-sulfonamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=C(C)C2=CC(Cl)=CC=C2S1 XQIZCPRJWQBHCO-UHFFFAOYSA-N 0.000 claims description 2
- HYKSBOYHYALPPR-UHFFFAOYSA-N 5-chloro-3-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-5-yl]-1-benzothiophene-2-sulfonamide Chemical compound C1CN(C)CCN1CC(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=C(C)C2=CC(Cl)=CC=C2S1 HYKSBOYHYALPPR-UHFFFAOYSA-N 0.000 claims description 2
- IXFIZZJAUYTVFQ-UHFFFAOYSA-N 5-chloro-N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]thiophene-2-sulfonamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=C(Cl)S1 IXFIZZJAUYTVFQ-UHFFFAOYSA-N 0.000 claims description 2
- HEXLAVRQPAXCGQ-UHFFFAOYSA-N 5-chloro-N-[3-[(dimethylamino)methyl]-1H-indol-5-yl]-3-methyl-1-benzothiophene-2-sulfonamide Chemical compound S1C2=CC=C(Cl)C=C2C(C)=C1S(=O)(=O)NC1=CC=C2NC=C(CN(C)C)C2=C1 HEXLAVRQPAXCGQ-UHFFFAOYSA-N 0.000 claims description 2
- VBNSQPAQKREKCT-UHFFFAOYSA-N 5-chloro-N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CC)CC)=CC=CC2=C1Cl VBNSQPAQKREKCT-UHFFFAOYSA-N 0.000 claims description 2
- NGSSZCPZKZXHLL-UHFFFAOYSA-N 5-chloro-N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]thiophene-2-sulfonamide Chemical compound C1=C2C(CCN(CC)CC)=CNC2=CC=C1NS(=O)(=O)C1=CC=C(Cl)S1 NGSSZCPZKZXHLL-UHFFFAOYSA-N 0.000 claims description 2
- GRAZEJPPQICHTB-UHFFFAOYSA-N 5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(C)C)=CC=CC2=C1Cl GRAZEJPPQICHTB-UHFFFAOYSA-N 0.000 claims description 2
- OOIQBABUMXSCPC-UHFFFAOYSA-N 5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound ClC1=CC=CC2=CC(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(C)C)=CC=C21 OOIQBABUMXSCPC-UHFFFAOYSA-N 0.000 claims description 2
- WSSVKAAIGVWZQY-UHFFFAOYSA-N 5-chloro-N-[3-[2-(dipropylamino)ethyl]-1H-indol-5-yl]-3-methyl-1-benzothiophene-2-sulfonamide Chemical compound S1C2=CC=C(Cl)C=C2C(C)=C1S(=O)(=O)NC1=CC=C2NC=C(CCN(CCC)CCC)C2=C1 WSSVKAAIGVWZQY-UHFFFAOYSA-N 0.000 claims description 2
- RZAXUKVIIWUIOM-UHFFFAOYSA-N 6-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]imidazo[2,1-b][1,3]thiazole-5-sulfonamide Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1NS(=O)(=O)C1=C(Cl)N=C2N1C=CS2 RZAXUKVIIWUIOM-UHFFFAOYSA-N 0.000 claims description 2
- YOIWOMIOVRDSRT-UHFFFAOYSA-N N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulfonamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=C(C=2C=CC=CC=2)C=C1 YOIWOMIOVRDSRT-UHFFFAOYSA-N 0.000 claims description 2
- WUSDVPWNSLONFH-UHFFFAOYSA-N N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=CC2=CC=CC=C12 WUSDVPWNSLONFH-UHFFFAOYSA-N 0.000 claims description 2
- GQVMAJQCWHEMNR-UHFFFAOYSA-N N-[3-(2-morpholin-4-ylethyl)-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C=1C=C2C=CC=CC2=CC=1S(=O)(=O)NC(C=C12)=CC=C1NC=C2CCN1CCOCC1 GQVMAJQCWHEMNR-UHFFFAOYSA-N 0.000 claims description 2
- RCDGUOLXQRCAEF-UHFFFAOYSA-N N-[3-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C1CN(C)CCN1CCC(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 RCDGUOLXQRCAEF-UHFFFAOYSA-N 0.000 claims description 2
- ZMWFJTOJCAGXKR-UHFFFAOYSA-N N-[3-[2-(dibutylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CCCC)CCCC)=CC=CC2=C1 ZMWFJTOJCAGXKR-UHFFFAOYSA-N 0.000 claims description 2
- UIRIEFKMLBIEPD-UHFFFAOYSA-N N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]-4-phenylbenzenesulfonamide Chemical compound C1=C2C(CCN(CC)CC)=CNC2=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C1=CC=CC=C1 UIRIEFKMLBIEPD-UHFFFAOYSA-N 0.000 claims description 2
- SHPWEOLFTNUCFL-UHFFFAOYSA-N N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide;hydrochloride Chemical compound Cl.C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CC)CC)=CC=CC2=C1 SHPWEOLFTNUCFL-UHFFFAOYSA-N 0.000 claims description 2
- JKOSQHWDQUDFSI-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-2,1,3-benzothiadiazole-4-sulfonamide Chemical compound C1=CC2=NSN=C2C(S(=O)(=O)NC2=CC=C3NC=C(C3=C2)CCN(C)C)=C1 JKOSQHWDQUDFSI-UHFFFAOYSA-N 0.000 claims description 2
- GJMVQIFNKWHCSE-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-4-phenoxybenzenesulfonamide Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1NS(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 GJMVQIFNKWHCSE-UHFFFAOYSA-N 0.000 claims description 2
- SNTNUEYGURUYLJ-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-4-phenylbenzenesulfonamide Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1NS(=O)(=O)C(C=C1)=CC=C1C1=CC=CC=C1 SNTNUEYGURUYLJ-UHFFFAOYSA-N 0.000 claims description 2
- VIFGXFJFKMSNKU-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(C)C)=CC=CC2=C1 VIFGXFJFKMSNKU-UHFFFAOYSA-N 0.000 claims description 2
- MPZZPMPAWOTSIY-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(C)C)=CC=C21 MPZZPMPAWOTSIY-UHFFFAOYSA-N 0.000 claims description 2
- XPRKZGSAGJCUOL-UHFFFAOYSA-N N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]quinoline-8-sulfonamide Chemical compound C1=CN=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(C)C)=CC=CC2=C1 XPRKZGSAGJCUOL-UHFFFAOYSA-N 0.000 claims description 2
- LBWBRGTZCKDBNN-UHFFFAOYSA-N N-[3-[2-(dipropylamino)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CCC)CCC)=CC=CC2=C1 LBWBRGTZCKDBNN-UHFFFAOYSA-N 0.000 claims description 2
- XHDVQKJVBJXDDG-UHFFFAOYSA-N N-[3-[2-(dipropylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCN(CCC)CCC)=CC=C21 XHDVQKJVBJXDDG-UHFFFAOYSA-N 0.000 claims description 2
- YPQQPLDCWAKIGB-UHFFFAOYSA-N N-[3-[3-(diethylamino)propyl]-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C1=CC=CC2=CC(S(=O)(=O)NC3=CC=C4NC=C(C4=C3)CCCN(CC)CC)=CC=C21 YPQQPLDCWAKIGB-UHFFFAOYSA-N 0.000 claims description 2
- DYGGJLONAFOLBL-UHFFFAOYSA-N N1(CCOCC1)CCC1=CNC2=CC=C(C=C12)C1=C(C=CC(=C1)C1=CC=CC=C1)S(=O)(=O)N Chemical compound N1(CCOCC1)CCC1=CNC2=CC=C(C=C12)C1=C(C=CC(=C1)C1=CC=CC=C1)S(=O)(=O)N DYGGJLONAFOLBL-UHFFFAOYSA-N 0.000 claims description 2
- YDJYZCPLSIJYFH-UHFFFAOYSA-N N1(CCOCC1)CCC1=CNC2=CC=C(C=C12)C1=C(C=CC=2SC(=C(C=21)C)S(=O)(=O)N)Cl Chemical compound N1(CCOCC1)CCC1=CNC2=CC=C(C=C12)C1=C(C=CC=2SC(=C(C=21)C)S(=O)(=O)N)Cl YDJYZCPLSIJYFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- ZFIFHAKCBWOSRN-UHFFFAOYSA-N naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)N)=CC=CC2=C1 ZFIFHAKCBWOSRN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 7
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- CTHJPTSKLMLUCQ-UHFFFAOYSA-N 2,4-difluoro-N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]benzenesulfonamide Chemical compound COC1=NC=C(B2OC(C)(C)C(C)(C)O2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F CTHJPTSKLMLUCQ-UHFFFAOYSA-N 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- UPXLYFQKWYVDPZ-UHFFFAOYSA-N 5-chloro-N-[3-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C1CN(C)CCN1CCC(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=CC2=C(Cl)C=CC=C12 UPXLYFQKWYVDPZ-UHFFFAOYSA-N 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- BKEVGLNYKZLFEH-UHFFFAOYSA-N 6-chloro-N-[3-[2-(diethylamino)ethyl]-1H-indol-5-yl]imidazo[2,1-b][1,3]thiazole-5-sulfonamide Chemical compound C1=C2C(CCN(CC)CC)=CNC2=CC=C1NS(=O)(=O)C1=C(Cl)N=C2N1C=CS2 BKEVGLNYKZLFEH-UHFFFAOYSA-N 0.000 claims 1
- TVGKDKBOGMPNLH-UHFFFAOYSA-N N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulfonamide;hydrochloride Chemical compound Cl.C1CN(C)CCC1C(C1=C2)=CNC1=CC=C2NS(=O)(=O)C1=CC=CC2=CC=CC=C12 TVGKDKBOGMPNLH-UHFFFAOYSA-N 0.000 claims 1
- ICLYOGTUYWWVTN-UHFFFAOYSA-N N-[3-(2-pyrrolidin-1-ylethyl)-1H-indol-5-yl]naphthalene-1-sulfonamide Chemical compound C=1C=CC2=CC=CC=C2C=1S(=O)(=O)NC(C=C12)=CC=C1NC=C2CCN1CCCC1 ICLYOGTUYWWVTN-UHFFFAOYSA-N 0.000 claims 1
- WWJUEGBQBBZAGT-UHFFFAOYSA-N N-[3-(2-pyrrolidin-1-ylethyl)-1H-indol-5-yl]naphthalene-2-sulfonamide Chemical compound C=1C=C2C=CC=CC2=CC=1S(=O)(=O)NC(C=C12)=CC=C1NC=C2CCN1CCCC1 WWJUEGBQBBZAGT-UHFFFAOYSA-N 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 18
- 239000002904 solvent Substances 0.000 description 14
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- 238000002360 preparation method Methods 0.000 description 11
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
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Abstract
The present invention relates to the use of sulphonamide derivatives of general formula (1), optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding physiologically acceptable salts or corresponding solvates, for the manufacture of a medicament for the prophylaxis and/or treatment of disorders of food ingestion.
Description
USE OF SULFONAMIDE DERIVATIVES FOR THE MANUFACTURE OF A
MEDICATION FOR PROPHYLAXIS AND / OR TREATMENT OF TRANSTORNES OF FOOD INTAKE
FIELD OF THE INVENTION
The present invention relates to the use of sulfonamide derivatives of the general formula (I),
(I)
optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemates or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or the corresponding salts or corresponding physiologically acceptable solvates, for the manufacture of a medicament for the prophylaxis and / or treatment of disorders of food intake.
BACKGROUND OF THE INVENTION
The super-family of serotonin (5-HT) receptors includes 7 classes (5-HT_ to 5-HT7) that span 14 subclasses of human [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419]. The 5-HT6 receptor is the most recently identified serotonin receptor by molecular cloning in both rats [F.J. Monsma, et al., Mol. Pharmacol. , 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun. , 1993, 193, 268] as in humans [R. Kohen, et al., J. Neurochem. , 1996, 66, 47]. Compounds with affinity for the 5-HT 6 receptor are useful for the treatment of various disorders of the central nervous system and the gastrointestinal tract, such as irritable bowel syndrome. Compounds with affinity for the 5-HT6 receptor are also useful in the treatment of anxiety, depression and cognitive memory disorders
[M. Yoshioka, et al., Ann. NY Acad. Sci. , 1998, 861, 244;
A. Bourson, et al., Br. J. Pharmacol. 1998, 125, 1562; D.C. Rogers, et al., Br. J. Pharmacol. Suppl. , 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther. , 1995, 274, 173; A.J. Sleight, et al., Behav. Brain Res. , 1996, 73, 245; T.A. Branchek, et al., Nnu. Rev. Pharmacol. Toxicol , 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol. , 2000, 130, 1606). It has been shown that anti-
Typical and atypical psychotics to treat schizophrenia have a high affinity for 5-HT6 receptors [B.L. Roth, et al., «7. Pharmacol. Exp. Ther. , 1994, 268, 1403; EC. Glatt, et al., Mol. Med., 1995, 1, 398; F.J. Mosma, et al., Mol. Pharmacol. , 1993, 43, 320; T. Shinkai, et al., Am. J. Med. Genet. , 1999, 88, 120]. Compounds with affinity for the 5-HT6 receptor are useful for treating childhood hyperkinesia (ADHD, attention deficit / hyperactivity disorder) [W.D. Hirst, et al., Br. J. Pharmacol. , 2000, 130, 1597; C. Gérard, et al., Brain Research, 1997, 746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379]. Likewise, it has been demonstrated that the 5-HT6 receptor also plays a role in food intake [Neuropharmacology, 41, 2001, 210-219].
BRIEF DESCRIPTION OF THE INVENTION
Disorders of food intake, particularly obesity, are a serious, rapidly growing threat to the health of humans of all age groups, because it increases the risk of developing other serious diseases, which they even put into life danger such as diabetes or coronary heart disease.
Therefore, the objective of the present invention is to provide medicaments comprising compounds with affinity for the 5-HT6 receptor and which are suitable for the prophylaxis and / or treatment of disorders related to food intake.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that the sulfonamide derivatives of the general formula (I) given below show affinity for the 5-HT 6 receptor. Therefore, these compounds are also suitable for the manufacture of a medicament for the prophylaxis and / or treatment of disorders caused by the ingestion of food (food intake), in particular for the regulation of appetite, for maintenance, increase or reduction of body weight, for the prophylaxis and / or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes (diabetes mellitus not dependent on insulin), preferably type II diabetes, which is caused by obesity. Therefore, one aspect of the present invention is the use of at least one sulfonamide derivative of the general formula (I),
(I)
wherein R1 represents hydrogen, an optionally linear or branched alkyl radical, at least mono-substituted, a phenyl radical, optionally at least mono-substituted or optionally at least mono-substituted benzyl radical, R2 represents a portion - NR4R5 or a saturated or unsaturated cycloaliphatic radical, optionally at least mono-substituted, optionally containing at least one heteroatom as a member of the ring, which may be fused with a monocyclic or bicyclic cycloaliphatic ring system optionally containing minus one heteroatom as ring member, saturated or unsaturated, optionally at least mono-substituted, R3 represents hydrogen or a linear or branched alkyl radical, optionally at least mono-substituted, R4 and R5, identical or different, represent hydrogen or an optionally at least mono-substituted linear or branched alkyl radical, or
R4 and R5 together with the nitrogen atom forming the bridge structure form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and / or may be condensed with a monocyclic or bicyclic cycloaliphatic ring system optionally containing at least one heteroatom as ring member, saturated or unsaturated, optionally at least mono-substituted, A represents a monocyclic or polycyclic aromatic ring system optionally at least mono-substituted, which may be linked by an optionally at least mono-substituted alkylene, alkenylene or alkynylene group and / or may contain at least one heteroatom as a ring member in one or more of its rings, represents 0, 1, 2, 3 or 4; optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a physiologically acceptable corresponding solvate, for the manufacture of a medicament for the prophylaxis and / or treatment of a
food intake disorder If one or more of the residues R1, R3, R4 and R 'represents an alkyl radical, which is substituted with one or more substituents, unless otherwise defined, each of the substituents it can preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl. If R 1 represents a phenyl radical or a benzyl radical, which is substituted with one or more substituents, unless otherwise defined, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C1-C4 alkyl, branched or unbranched Ci-C4 alkoxy, branched or unbranched C1-C4 perfluoroalkyl and branched or unbranched C4- or C4 perfluoroalkoxy. If R2 represents a cycloaliphatic radical optionally containing at least one heteroatom as ring member, saturated or unsaturated, which is substituted with one or more substituents and / or if it comprises a monocyclic or bicyclic cycloaliphatic ring system optionally containing at least one heteroatom as ring member, saturated or unsaturated, which is substituted with one or more substituents, unless otherwise defined, each
one of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C4-C4 alkyl, branched or unbranched C_-C alkoxy, perfluoroalkyl of C_- C4 branched or unbranched, branched or unbranched C _. C 4 perfluoroalkoxy and benzyl, preferably from the group consisting of branched or unbranched C __. ~ C 4 alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and / or the monocyclic or bicyclic cycloaliphatic ring system, independently of one another, can preferably be selected from the group consisting of nitrogen, sulfur and oxygen, most preferably the hetero atom is nitrogen. If R4 and R5 together with the nitrogen atom forming the bridge structure form a heterocyclic ring optionally containing at least one additional heteom as ring member, saturated or unsaturated, which is substituted with one or more substituents and / or which is condensed with a monocyclic or bicyclic cycloaliphatic ring system optionally containing at least one heteom as ring member, saturated or unsaturated, which is substituted with one or more substituents, unless otherwise defined , each of the substituents can be selected
preferably, from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched Ci-C4 alkyl, branched or unbranched C_-C alkoxy, branched or unbranched C? -C perfluoroalkyl, perfluoroalkoxy of branched or unbranched C_-C4 and benzyl, preferably from the group consisting of branched or unbranched C1-C4 alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms and / or one or both of the monocyclic or bicyclic rings contain one or more heteroatoms, these heteroatoms, independent of each other, can preferably be selected from the group consisting of nitrogen, sulfur and oxygen, most preferably the hetero atom is nitrogen. If A represents a monocyclic or polycyclic aromatic ring system, which is substituted with one or more substituents, and which may be linked by an alkylene, alkenylene, or alkynylene group optionally at least mono-substituted and / or may contain at least one heteroatom as a ring member unless otherwise defined, each substituent may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C?-C 4 alkyl , branched or unbranched C? -C4 alkoxy, perfluoroalkyl of C_-C4
branched or unbranched, branched or unbranched C_-C4 perfluoroalkoxy, an optionally at least mono-substituted phenyl radical, an optionally at least mono-substituted phenoxy radical, and a 5- or 6-membered heteroaryl, more preferably from the group consisting of halogen, branched or unbranched C_-C4 alkyl, an optionally at least mono-substituted phenyl radical, an optionally at least mono-substituted phenoxy radical and 5- or 6-membered heteroaryl radical, more preferred from the group consisting of fluorine, chlorine, branched or unbranched C?-C 4 alkyl, a phenyl radical, optionally at least mono-substituted, an optionally at least mono-substituted phenoxy radical and a heteroaryl of 5 or 6 members which is selected from the group consisting of furyl, thienyl and pyridyl. If one or more of the rings of the monocyclic or polycyclic aromatic ring system contains one or more heteroatoms, these heteroatoms - like the heteroatoms of the aforementioned 5- or 6-membered heteroaryl radical - can be preferably selected from the group that It consists of oxygen, sulfur and nitrogen. If the aforementioned phenyl radical is itself substituted with one or more substituents, each of the substituents can preferably be selected from the group consisting of fluorine,
chlorine, bromine, linear or branched C1-C4 alkyl, linear or branched C1-C4 alkoxy, straight or branched C1.-C4 alkylthio, a trifluoromethyl portion, a cyano portion and an -NR8R9 portion, in which R8 and R9, identical or different, represent hydrogen or straight or branched C? -C4 alkyl. If the aforementioned alkylene, alkenylene or alkynylene group is substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C? -C4 alkyl. , branched or unbranched C1-C4 alkoxy, branched or unbranched C1-C4 perfluoroalkyl, branched or unbranched C?-C4 perfluoroalkoxy or a phenyl radical, optionally at least mono-substituted. If said phenyl radical is itself substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of fluorine, chlorine, bromine, straight or branched C_-C4 alkyl, alkoxy Linear or branched C1-C4, linear or branched C1-C4 alkylthio, a trifluoromethyl portion, a cyano portion and a portion NR8R9, in which R8 and R9, identical or different, represent hydrogen or straight or branched C1-C4 alkyl .
Preference is given to using sulfonamide derivatives of the general formula (I), in which R.sub.1 represents hydrogen, an optionally linear or branched C 1-4 alkyl radical at least mono-substituted, a phenyl radical, optionally at least mono-substituted or a benzyl radical, optionally at least mono-substituted, more preferred hydrogen, a linear or branched C1-4 alkyl radical or a benzyl radical, more preferably hydrogen, and R2 to R5, A and n are as defined above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a Physiologically acceptable corresponding solvate. Preference is also given to the use of sulfonamide derivatives of the general formula (I), wherein R 2 represents an -NR 4 R 5 moiety or a 5- or 6-membered cycloaliphatic radical optionally containing at least one hetero atom as a ring member, optionally at least mono-substituted, saturated or unsaturated, which may be fused with a monocyclic or bicyclic cycloaliphatic ring system optionally containing at least one heteroatom as a member of the
ring, saturated or unsaturated, optionally at least mono-substituted, in which the ring (s) is / are of 5 or 6 members, preferably a -NR4R5 portion or a portion that is selected from the group consisting of
in which, if present, the dotted line represents an optional chemical bond and R6 represents hydrogen, a linear or branched C? ~C 4 alkyl radical or a benzyl radical, preferably hydrogen or an alkyl radical of C_-C2, and R1, R3 to R5, A and n are as defined above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers or diastereomers, at any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate. Also preferred is the use of sulfonamide derivatives of the general formula (I), in which R3
represents hydrogen or a linear or branched, optionally at least mono-substituted, C_-C4 alkyl radical, preferably hydrogen or a straight or branched C _ C 4 alkyl radical, more preferably hydrogen or an alkyl radical of C 1. -C2, and R1, R2, R4, R5, A and n are as defined above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate. Likewise, preference is also given to the use of sulfonamide derivatives of the general formula (I), in which R 4 and R 5, identical or different, represent hydrogen or a straight or branched C 1 -C alkyl radical, optionally at least mono -substituted, or R4 and R5 together with the nitrogen atom forming the bridge structure form a 5-6 membered heterocyclic ring, saturated or unsaturated, optionally at least mono-substituted, which may contain at least one additional heteroatom as a member of the ring and / or may be fused with a monocyclic or bicyclic aliphatic ring system optionally containing at least one heteroatom as ring member, optionally
at least mono-substituted, saturated or unsaturated, in which the ring (s) is / are of 5, 6 or 7 members, and R1,
R * R? A and n are as defined above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate. Particular preference is given to the use of sulfonamide derivatives of the general formula (I), in which R 4 and R 5, which are identical or different, represent hydrogen or a linear or branched C?-C 4 alkyl radical, preferably an alkyl radical of Ci-C4 linear or branched, or R4 and R5 together with the nitrogen atom forming the bridge structure form a portion that is selected from the group consisting of
in which R7 represents hydrogen, an alkyl radical
of straight or branched C1-C4 or a benzyl radical, preferably hydrogen or an alkyl radical of C? -C2, and R to R3, A and n are as defined above, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate. Also preferred is the use of sulfonamide derivatives of the general formula (1), in which A represents an optionally at least mono-substituted monocyclic or bicyclic aromatic ring system, in which the ring (s) is / are of 5 or 6 members, which may be linked by an optionally at least mono-substituted C al-C4 alkylene group, an optionally at least mono-substituted C2-C4 alkenylene or an alkynylene group of C C4 optionally at least ono-substituted and / or may contain at least one heteroatom as a ring member, preferably an optionally at least mono-substituted monocyclic or bicyclic aromatic ring system, in which the ring (s) is / are of 5 or 6 members and in which one or both rings contains (n) at least one heteroatom, or a portion that
is selected from the group consisting of
wherein X, Y, Z are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, straight or branched C1-C4 alkyl, linear or branched C?-C4 alkoxy, alkylthio of linear or branched C1-C4, a trifluoromethyl portion, a cyano portion and a portion NR8R9, in which R8 and R9, identical or different, represent hydrogen or straight or branched C? -C4 alkyl, represents a simple chemical bond between the two rings, a group CH2, O, S or a portion NR10, in which R10 is hydrogen or straight or branched C1-C alkyl and m is O, 1, 2, 3 04. and R1 to R5 and n are as previously defined, optionally in the form of one of the stereoisomers, preferably enantiomers or diastereomers, the racemate or in the form of a mixture of
at least two of the stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate. More preferred is the use of one or more sulfonamide derivatives which are selected from the group consisting of: [1] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -5-chloro- 3-methylbenzo [b] thiophene-2-sulfonamide, [2] N- [3- (2-diethylaminoethyl) - lH-indol-5-yl] -naphthalene-1-sulfonamide, [3] N-Hydrochloride [3- (2-diethylaminoethyl) -1H-indol-5-yl] naphthalene-1-sulfonamide, [4] N- [3- (2-diethylaminoethyl) -1 H -indol-5-yl] -3,5 -dichlorobenzenesulfonamide, [5] N- [3- (2-diethylaminoethyl) -1 H -indol-5-yl] -4-phenylbenzenesulfonamide, [6] N- [3- (2-diethylaminoethyl) -lH-indole-5 -yl] -5-chlorothiophen-2-sulfonamide, [7] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide , [8] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -naphthalene-1-sulfonamide, [9] N- [3- (2-dimethylamino-ethyl) -lH-indole- 5-yl] -6-chloroimidazo [2, 1-b] thiazole-5-sulfonamide,
[10] N- [3- (l-methyl-piperidin-4-yl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [11] N-Hydrochloride [3- (l-methyl-piperidin-4-yl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [12] N- [3- (l-methylpiperidine -4-yl) -lH-indol-5-yl] -naphthalene-1-sulfonamide, [13] N- [3- (l-methylpiperidin-4-yl) -lH-indol-5-yl] naphthalene hydrochloride -1-sulfonamide, [14] N- [3- (l-methylpiperidin-4-yl) -lH-indol-5-yl] -5-chlorothiophen-2-sulfonamide, [15] N- [3- (l -methylpiperidin-4-yl) -lH-indol-5-yl] -4-phenylbenzenesulfonamide, [16] N- [3- (l-methylpiperidin-4-yl) -lH-indol-5-yl] -quinolin- 8-sulfonamide, [17] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -naphthalene-2-sulfonamide, [18] N- [3- (l-methyl-l, 2,3,6 -tetrahydropyridin-4-yl) -1H-indol-5-yl] -naphthalene-1-sulfonamide, [19] N- [3- (4-methyl-piperazin-1-yl) methyl-1H-indol-5-yl] - 5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [20] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -5- (2-pyridyl) thiophen-2 sulfonamide, [21] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -2, 1, 3-benzothiadiazole-4-sulfonamide, [22] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -
quinolin-8-sulfonamide, [23] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -5-chloronaphthalene-2-sulfonamide, [24] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -4-phenoxybenzenesulfonamide, [25] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -4-phenylbenzenesulfonamide, [26] N- [3- ( 2-diethylaminoethyl) -1H-indol-5-yl] -N-ethyl-naphthalene-2-sulfonamide, [27] N-. { 3- [2- (morpholin-4-yl) ethyl] -1H-indol-5-yl) -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [28] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-ind? L-5-yl} -naphthalene-1-sulfonamide, [29] N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] -naphthalene-2-sulfonamide, [30] N- [3-dimethylaminomethyl-1H-indole- 5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [31] N- [3- (2-dipropylaminoethyl) -1H-indol-5-yl] -naphthalene-1-sulfonamide, [32] N- [3- (2-dipropylaminoethyl) -1H-indol-5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [33] N- [3- (2- dibutylaminoethyl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [34] N- [3- (2-dibutylaminoethyl) -lH-indol-5-yl] -naphthalene-l-sulfonamide,
[35] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -5-chloronaphthalene-1-sulfonamide, [36) N- [3- (2-diethylaminoethyl) -1H-indole-5 -yl] -trans-β-styrenesulfonamide, [37] N- [3- (4-methyl-piperazin-1-yl) methyl-1H-indol-5-yl] -trans-β-styrenesulfonamide, [38] N- [ 3- (Octahydroindolizin-7-yl) -lH-indol-5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [39] N- [3- (2-diethylaminoethyl) -1H -indol-5-yl] -6-chloroimidazo [2, lb] thiazole-5-sulfonamide, [40] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} Naphthalene-2-sulfonamide, [41] N- [3- (4-methylpiperazin-1-yl) methyl-1H-indol-5-yl] -a-toluenesulfonamide, [42] N- [3- (3-diethylaminopropyl ) -lH-indol-5-yl] -naphthalene-2-sulfonamide, [43] N- [3- (3-diethylaminopropyl) -lH-indol-5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [44] N-. { 3- [2- (pyidin-1-yl) ethyl] -lH-indol-5-yl} -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [45] N-. { 3- [2- (pyidin-1-yl) ethyl] -1H-indol-5-yl} naphthalene-1-sulfonamide, [46] N-. { 3- [2- (pyidin-1-yl) ethyl] -1H-indol-5-yl} Naphthalene-2-sulfonamide, [47] N- [3- (2-dipropylaminoethyl) -lH-indol-5-yl] -
Naphthalene-2-sulfonamide, [48] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -5-chloronaphthalene-1-sulfonamide, [49] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -naphthalene-2-sulfonamide, [50] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} -quinolin-8-sulfonamide, [51] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} -4-phenylbenzenesulfonamide, [52] N- [3- (4-methyl-piperazin-1-yl) ethyl-lH-indol-5-yl] -naphthalene-2-sulfonamide and [53] N- [3- (4-methylpiperazine -l-yl) ethyl-lHrindol-5-yl] -5-chloronaphthalen-1-sulfonamide. The sulfonamide derivatives of the general formula (I), in which R1, R2, R3, n and A have the meanings defined above, can preferably be prepared according to the following methods:
Method A At least one compound of the general formula (II) is reacted,
(II) in which A has the meaning that was defined
above and L is an appropriate leaving group, preferably a halogen atom, particularly preferably chlorine; at least one substituted 5-aminoindole of the general formula (III)
wherein R x, R 2, R 3 and n have the meanings as defined above, or a derivative thereof protected in an appropriate manner, and, if present, the protecting groups are removed, in order to obtain the corresponding sulfonamide derivative of the general formula (I), which can be purified and / or isolated by conventional methods known to those skilled in the art. The reaction between the compounds of the general formulas (II) and (III) is usually carried out in the presence of an organic reaction medium, such as a dialkyl ether, in particular diethyl ether, or a cyclic ether, in particular tetrahydrofuran or dioxane, a halogenated organic hydrocarbon, in particular methylene chloride or chloroform, an alcohol, in particular methanol or ethanol, an aprotic dipolar solvent, in particular
acetonitrile, pyridine or dimethylformamide, or any other appropriate reaction medium. Of course, mixtures of at least two of the aforementioned classes of compounds or of at least two compounds of one class can also be used. Preferably, the reaction is carried out in the presence of an appropriate base, for example an inorganic base such as hydroxides and / or alkali metal carbonates, or an organic base, in particular triethylamine or pyridine. The most appropriate reaction temperatures range from 0 ° C to room temperature, ie about 25 ° C, and the reaction time of preference is from 5 minutes to 24 hours. The resulting sulfonamide derivative of the general formula (I) can be purified and / or isolated according to conventional methods known to those skilled in the art. Preferably, the sulfonamide derivatives of the general formula (I) can be isolated by evaporating the reaction medium, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration; or it can be extracted using a solvent immiscible with water, such as chloroform, and purified by
chromatography or recrystallization from an appropriate solvent. The compounds of the general formula (II) can be obtained commercially or can be prepared according to standard methods known to those skilled in the art, for example by methods analogous to those described in the literature [E.E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of the general formula (III) can also be prepared according to standard methods known to those skilled in the art, for example by methods analogous to those described in the literature [J.E. Macor, R. Post and K. Ryan, Synt Comm. , 1993, 23, 1, 65-72; J. Guillaume, C. Dumont, J. Laurent and N. Nédélec, Eur. J. Med. Chem., 1987, 22, 33-43; M.L. Saccarello, R. Stradi, Synthesis, 1979, 727]. The descriptions of the respective literature are incorporated for reference and form part of the description.
Method B The sulfonamide derivatives of the general formula (I), wherein R x, R 2, n and A are as defined above and R 3 represents a linear or branched C 1 -C 4 alkyl radical, optionally at least mono-substituted , can also be prepared by
alkylation of a corresponding sulfonamide derivative of the general formula (I), in which Ri, R2, n and A are as defined above and R3 represents a hydrogen atom, with an alkyl halide or a dialkyl sulfate. The alkylation reaction is preferably carried out preferably in the presence of an appropriate base, such as hydroxides and / or alkali metal carbonates, metal hydrides, alkoxides such as sodium methoxide or potassium tert-butoxide, organic compounds. metals such as butyl lithium or tert-butyl lithium, in the presence of an organic reaction medium, such as dialkyl ether, in particular diethyl ether, or a cyclic ether, in particular tetrahydrofuran or dioxane, a hydrocarbon, in particular toluene, an alcohol, in particular methanol or ethanol, an aprotic dipolar solvent, in particular acetonitrile, pyridine or dimethylformamide, or any other appropriate reaction medium. Of course, mixtures of at least two of the aforementioned classes of compounds and / or of at least two compounds of one class can also be used. The most appropriate reaction temperatures range from 0 ° C to the boiling point of the reaction medium, and the reaction times preferably vary
from 1 to 24 hours. The resulting sulfonamide derivative of the general formula (I) can preferably be isolated by filtration, concentration of the filtrate under reduced pressure, addition of water and optionally adjustment of the pH so that it is obtained as a solid that can be isolated by filtration, or it may be extracted with a water-immiscible solvent such as chloroform and purified by chromatography or recrystallization from an appropriate solvent.
Method C By condensation of a compound of the general formula (I), in which R x, R 3, and A are as defined above, n is 0 and R 2 represents a hydrogen atom, with a 4-piperidone substituted in appropriate form the corresponding compound of the general formula (I) is obtained, in which Rif R3 and A are as defined above, n is 0 and R2 represents a substituted 1,2,3,6-tetrahydropyridin-4-yl radical in the form appropriate The reaction can occur both in an acidic reaction medium and in a basic medium, preferably in an appropriate solvent, preferably at temperatures ranging from 25 to 150 ° C.
The appropriate basic conditions can be provided by the use of inorganic bases such as sodium or potassium hydroxide, or organic bases such as pyrrolidine or triethylamine in solvents such as methanol or ethanol. Preferably, sodium ethoxide solutions are used in refluxing methanol. The reaction times vary from 1 to 48 hours. Suitable acidic conditions can be provided by the use of hydrochloric acid in ethanol or trifluoroacetic acid in acetic acid at temperatures that preferably range from 50 to 100 ° C and the reaction times vary from 1 to 48 hours. The resulting sulfonamide derivative of the general formula (I) can be isolated by dilution in water, optionally by adjusting the pH, to obtain a solid that can be isolated by filtration; or it may be extracted with a water-immiscible solvent such as chloroform and purified by chromatography or by recrystallization from an appropriate solvent. The compounds of the general formula (I) in which Ri, R3 and A are as defined above, n is
0 and R2 represents a hydrogen atom, can be prepared according to method A from the corresponding 5-aminoindole.
Method D The compound of the general formula (I) in which R_ # R3 and A are as defined above can be prepared, n is 0 and R2 represents a 4-piperidinyl radical substituted in an appropriate manner by reducing a compound of the general formula (I) in which Rx, R3 and A are as defined above, n is 0 and R2 represents a substituted 1, 2, 3, 6-tetrahydropyridin-4-yl radical in an appropriate form that is prepared according to the method C. The hydrogenation is preferably carried out with the aid of a metal catalyst such as palladium, platinum or rhodium in an appropriate support such as carbon, aluminum oxide or barium sulfate, preferably palladium on carbon, with a hydrogen pressure. initial between 1 and 10 atmospheres, preferably between 2 and 5 atmospheres, in a solvent such as methanol or ethanol. The reaction time varies from 1 hour to 3 days. The resulting sulfonamide can be isolated by filtering the catalyst and concentrating the filtrate under reduced pressure. The recovered product can be used as such or it can be purified by chromatography or by recrystallization from an appropriate solvent.
Method E The pharmacologically acceptable salts of the compounds with the general formula (I) can be prepared using conventional methods known to those skilled in the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric acids. , nitric or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic acid, methanesulfonic acid, etc., in a suitable solvent such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone and is obtained with the common techniques of precipitation or crystallization of the corresponding salts. Preferred physiologically acceptable salts of the sulfonamide derivatives of the general formula (I) are the addition salts of mineral acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and organic acids, such as citric acid, maleic acid, tartaric acid or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid, camphor sulfonic acid, etc. Physiologically acceptable solvates, in particular hydrates, of the sulfonamide derivatives of the general formula (I) or of the physiologically acceptable salts
acceptable ones can be prepared using conventional methods known to those skilled in the art. During one of the synthesis sequences described above, or in the preparation of the appropriate reactants used it may be necessary and / or desirable to protect the sensitive or reactive groups in some of the molecules employed. This can be done by means of conventional protecting groups such as those described in the literature [Protective groups in Organic Chemistry, ed J. F.. McOmie, Plenum Press, 1973; T.. Greene & P.G.M. uts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991]. The protecting groups can be removed at an appropriate later stage using methods known to those skilled in the art. The descriptions of the respective literature are incorporated in the present invention for reference and form part of the description. If the sulfonamide derivatives of the general formula (I) are obtained in the form of a mixture of stereoisomers, in particular enantiomers or diastereomers, said mixtures can be separated using standard procedures known to those skilled in the art, for example chromatographic or crystallization methods. with chiral reagents. The medicine
obtained in accordance with the present invention is suitable, in particular, for administration to mammals, including humans. The drug of preference can be administered to humans of all age groups, ie children, adolescents as well as adults. A further aspect of the present invention is the use of at least one sulfonamide derivative of the general formula (I) given above, optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate, for the manufacture of a medicament for the regulation of appetite, for the reduction, increase or maintenance of body weight, for the prophylaxis and / or treatment of obesity, bulimia, anorexia, cachexia or type II diabetes, preferably type II diabetes caused by obesity. Particular preference is given to the use of at least one sulfonamide derivative of the general formula (I) given above, optionally in the form of one of its stereoisomers, preferably enantiomers or
diastereomers, their racemate or in the form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, at any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate, for the manufacture of a medicament for prophylaxis and / or treatment of obesity. The preparation of the corresponding pharmaceutical compositions as well as the formulated medicaments can be carried out by conventional methods known to those skilled in the art, for example from the tables of contents of "Pharmaceutics: the Science of Dosage Forms", second edition, Aulton, ME (Ed.) Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", second edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modem Pharmaceutics", fourth edition, Banker G.S. and Rhodes C.T. (Eds.) Marcel Dekker, Inc. New York 2002 and "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. and Anig J. (Eds.), Lea & Febiger, Philadelphia (1986). The descriptions of the respective literature are incorporated for reference and are part of the description. The pharmaceutical compositions as well as the formulated medicaments that are prepared in accordance with
The present invention may comprise, in addition to at least one sulfonamide derivative of the general formula (I), optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, their racemate or in the form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate, conventional auxiliaries additional ones known to those skilled in the art, such as excipients, fillers, solvents, diluents, coloring agents, coating agents, matrix agents and / or binders. As is also known to those skilled in the art, the choice of auxiliary substances and the amounts thereof to be used depend on the intended route of administration, for example orally, rectally, intravenously, intraperitoneally, intramuscularly, intranasal, buccal or topical. Medicaments suitable for oral administration are for example, tablets, sugar-coated pills, capsules or multiple particulate materials, such as granules or tablets, which are optionally compacted as tablets, used to fill capsules or are suspended in a liquid
appropriate, solutions or suspensions. Medicaments suitable for parenteral, topical or inhalation administration can preferably be selected from the group consisting of solutions, suspensions, dry preparations that can be easily reconstituted and also sprays. Suitable medicaments, for example drugs for oral or percutaneous use, can release the sulfonamide compounds of the general formula (I) in a delayed form, in which the preparation of these delayed-release drugs is generally known to those skilled in the art. The technique. The appropriate delayed release forms as well as the materials and methods for their preparation are known to those skilled in the art, for example from the tables of contents of "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, - J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Relay Technology", ise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery", Vol. I, Basic Concepts, Bruck, S.D. (Ed.), CRC Press Inc., Boca Raton (1983) and Takada, K. and Yoshikawa, H., "Oral Drug Delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J.,
"Oral drug delivery, small intestine and colon",
Encyclopedia of Controlled Drug Delivery, Mathiowitz, E.
(Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2,
698-728. The respective descriptions are incorporated for reference and are part of the description. The medicament of the present invention may also have at least one enteric coating that dissolves as a function of pH. Due to this coating, the medicament can pass through the stomach without dissolving and the compounds of the general formula (I) are only released in the intestinal tract. The enteric coating is preferably dissolved at a pH between 5 and 7.5. Suitable materials and methods for the preparation of enteric coatings are also known to those skilled in the art. Typically, the pharmaceutical compositions and medicaments comprise from 1 to 60% by weight of one or more sulfonamide derivatives of the general formula (I) and from 40 to 99% by weight of one or more excipients. The amount of active ingredient that is administered to the patient varies depending on the weight of the patient, the route of administration, the indication and the degree of severity of the disorder. They are usually administered to the patient in need of treatment from 1 to 5000 mg, preferably 1 to 2500 mg, in a more
preferred 1 to 500 mg of at least one sulfonamide derivative of the general formula (I) per day. The total daily dose can be administered to the patient in one or more portions.
Pharmacological methods Binding to serotonin receptor 5HT6 The cell membranes of HEK-293 cells expressing recombinant human 5HT6 receptor are supplied by Receptor Biology. In said membranes, the concentration of the receptor is 2.18 pmol / mg protein and the protein concentration is 9.17 mg / ml. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytriptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403] with the following slight changes. The respective part of the description of the literature is incorporated in the present invention for reference and forms part of the description. The commercial membrane is diluted (1:40 dilution) with the regulatory solution for binding: 50 mM Tris-HCl, 10 mM MgCl 2, 0.5 mM EDTA (pH 7.4). The radioligand used is [3H] -LSD at a concentration of
2. 7 nM with a final volume of 200 μl. Incubation is started by adding 100 μl of membrane suspension, («22.9 μg of membrane protein), and it is prolonged for 60 minutes at a temperature of 37 ° C. Incubation is terminated by rapid filtration in a Brandel cell harvester through GF 3362 glass fiber filters manufactured by Schleicher & amp;; Schuell previously treated with a 0.5% polyethyleneimine solution. The filters are washed three times with three milliliters of 50 mM Tris-HCl buffer, pH 7.4. The filters are transferred to flasks and 5 ml of the Ecoscint H liquid scintillation mixture are added to each flask. The flasks are allowed to equilibrate for several hours before they are counted with a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 100 μM of serotonin. The tests are carried out in triplicate. Inhibition constants (K_, nM) are calculated by linear regression analysis using the EBDA / LIGAND program described in Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220, which is incorporated in the present invention for reference and forms a part of the description.
Measurement of food intake (behavioral model) Male W rats (200-270 g) obtained from Harán, S.A. Animals are acclimated to the animal building for at least 5 days before they undergo any treatment. During this period the animals are housed (in groups of five) in translucent cages and provided with food and water ad libitum. At least 24 hours before the start of the treatment, the animals adapt to individual housing conditions. The acute effect of the sulfonamide derivatives of the general formula (I) used according to the invention on food intake in fasting rats is then determined as follows: The rats are fasted for 23 hours in their cages individual After this period, the rats are dosed orally or intraperitoneally with a composition comprising a sulfonamide derivative of the general formula (I) or a corresponding composition (vehicle) without said sulfonamide derivative. Immediately after this, the rats are left with a pre-weighed amount of feed and the cumulative feed intake is measured after 1, 2, 4 and 6 hours. Said method for measuring food intake is also described in Kask literature publications
et al., European Journal of Pharmacology 414 (2001), 215-224 and Turnbull et al., Diabetes, Vol. 51, August 2002. The respective parts of the descriptions are incorporated in the present invention for reference and form a part of the description. The present invention is illustrated below with the help of examples. These illustrations are given by way of example only and do not limit the general scope of the present invention.
EXAMPLES
METHOD A EXAMPLE 7 Preparation of N- [3- (2-di-ethylaminoethyl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] iofen-2-sulfonamide
To a solution of 3.05 g (15 mol) of 5-amino-3- (2-dimethylaminoethyl) -lH-indole in 100 ml of pyridine is added dropwise at room temperature a solution of 4.21 g (15 mmol) of 5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonyl in 20 ml of pyridine. The reaction mixture is stirred at room temperature for 20 hours. This is then evaporated to dryness, slightly alkalized with dilute ammonia and dissolved
in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, which is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether to obtain 5.5 g (82%) of N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -5- chloro-3-methyl-benzo [b] thiophen-2-sulfonamide as a solid with mp = 226-227 ° C.
METHOD B
EXAMPLE 26 Preparation of N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] -N-ethyl-naphthalene-2-sulfonamide
A mixture of 285 mg (0.7 mmoles) of N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] naphthalene-2-sulfonamide is stirred.
(example 17) and 80 mg (0.7 mmol) of potassium t-butoxide in 3 ml of DMSO for 30 minutes at room temperature. Then, 105 mg (0.7 mmol) of ethyl iodide are added and the mixture is left stirring for 3 hours. Water is added and extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude material is purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride / methanol / ammonia, to produce N- [3- (2-diethylaminoethyl) -
lH-indol-5-yl] -N-ethyl-naphthalene-2-sulfonamide as a solid with m.p. = 49-50 ° C.
METHOD C
EXAMPLE 18 Preparation of N- [3- (l-methyl-l, 2,3-, 6-tetrahydropyridin-4-yl) -lH-indol-5-yl] aftalen-1-sulfonamide
To a solution of 712 mg (13.2 mmol) of sodium methoxide in 100 ml of methanol is added 850 mg
(2.64 mmol) of N- [lH-indol-5-yl] naphthalene-1-sulfonamide followed by 596 mg (5.28 mmol) of l-methyl-4-piperidone and the resulting solution is refluxed for 48 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by chromatography on silica gel, using methylene chloride / methanol / ammonia as eluent to obtain 573 mg (52%) of N- [3 - (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -lH-indol-5-yl] naphthalene-1-sulfonamide as a solid with mp = 244-245 ° C.
METHOD D EXAMPLE 12 Preparation of N- [3- (l-methyl-piperidin-4-yl) -lH-indol-5-yl] aftalen-1-sulfonamide
To a solution of 417 mg (1 mmol) of N- [3- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) -lH-indol-5-yl] -naphthalene-1-sulfonamide 50 mg of 5% palladium on charcoal are added in 50 ml of methanol. The mixture is hydrogenated at room temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to provide a crude product which is suspended in ethyl ether, to obtain 272 mg (65%) of N- [3- (l-methyl-piperidin-4- il) -lH-indol-5-yl] naphthalene-1-sulfonamide as a solid with mp = 254-256 ° C.
METHOD AND EXAMPLE 3 Preparation of N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] af alen-1-sulfonamide hydrochloride
Dissolve 1.05 g (2.5 mmol) of N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] naphthalene-1-sulfonamide
(example 2) in 10 ml of ethanol and 0.6 ml of a 4.2 N solution of hydrochloric acid in ethanol are added. Allow to crystallize at room temperature. The N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -naphthalene-1-sulfonamide hydrochloride is obtained as a solid with m.p.
255-257 ° C. The melting point and spectroscopic data to identify some of the compounds used in accordance with the present invention are shown in the following table:
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
fifteen
EXAMPLE 54 Tablet comprising a sulfonamide compound of the general formula (I) used in accordance with the invention
Formula per tablet
Compound according to example 1 5 mg
Lactose 60 mg
Crystalline cellulose 25 mg
Povidone K90 5 mg
3 mg pre-gelatinized starch
Colloidal silicon dioxide 1 mg
Magnesium stearate 1 mg
Total weight per 100 mg tablet
Pharmacological data The binding of the sulfonamide derivatives of the general formula (I) used according to the invention is determined as described above. The binding results of some sulfonamide derivatives are given in the following Table 1:
TABLE 1
Compound of% inhibition Ki (nM) conforming to the 10"6 M example 1 98.1 ± 4.0 0.28
3 96.6 ± 5.2 3.5
4 96.2 ± 0.6 9.3
101.2 ± 0.1 1.0
6 97.6 ± 1.8 8.7
7 103.0 ± 7.9 0.13
8 94.5 ± 7.0 0.76
9 96.8 ± 3.7 2.2
11 101.3 0.98
13 98.3 4.7 14 95.7 ± 3.4 24.3
97.4 ± 0.8 6.8
16 94.4 + 8.6 21.2
17 102.0 5.3
Claims (16)
1. - The use of at least one sulfonamide derivative of the general formula (I), (I) wherein R1 represents hydrogen, an optionally linear or branched alkyl radical, at least mono-substituted, a phenyl radical, optionally at least mono-substituted or optionally at least mono-substituted benzyl radical, R2 represents a portion - NRR5 or a saturated or unsaturated cycloaliphatic radical, optionally at least mono-substituted, optionally containing minus one heteroatom as ring member, which may be fused to a monocyclic or bicyclic cycloaliphatic ring system optionally containing at least one heteroatom as ring member, saturated or unsaturated, optionally at least mono-substituted, R3 represents hydrogen or a linear or branched alkyl radical, optionally at least mono-substituted, R4 and R5, identical or different, represent hydrogen or an optionally linear or branched alkyl radical, at least mono-substituted, or R4 and R5 together with the The nitrogen atom forming the bridge structure forms a saturated or unsaturated heterocyclic ring, optionally at least mono-substituted, which may contain at least one additional heteroatom as a ring member and / or may be fused to a of monocyclic or bicyclic cycloaliphatic ring optionally containing at least one heteroatom as ring member, saturated or unsaturated, optionally at least mono-substituted, A represents an optionally at least mono-substituted monocyclic or polycyclic aromatic ring system, which may be attached via an optionally at least mono-substituted alkylene group, an alkenylene group optionally at least mono- substituted or an alkynylene group optionally at least mono-substituted and / or may contain at least one heteroatom as a ring member in one or more of its rings, n represents 0, 1, 2, 3 or 4; optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt or a corresponding physiologically acceptable solvate, for the manufacture of a medicament for the prophylaxis and / or treatment of a disorder of food ingestion.
2. The use according to claim 1, characterized in that Rx represents hydrogen, a straight or branched C4 alkyl radical, optionally at least mono-substituted, an optionally at least mono-substituted phenyl radical or a benzyl radical optionally at least mono-substituted, preferably hydrogen, a linear or branched C? _ alkyl radical or a benzyl radical, more preferably hydrogen.
3. The use according to claim 1 or 2, characterized in that R2 represents a portion -NR4R5 or a 5 or 6 membered cycloaliphatic radical optionally containing at least one heteroatom as a ring member, optionally at least mono-substituted, saturated or unsaturated, which may be fused with a monocyclic or bicyclic cycloaliphatic ring system which optionally contains at least one heteroatom as ring member, saturated or unsaturated, optionally at least monosubstituted, in which the ring (s) is / are of 5 or 6 members, preferably a -NR4R5 portion or a portion that is selected from the group consisting of in which, if present, the dotted line represents an optional chemical bond and R6 represents hydrogen, a straight or branched C4- C4 alkyl radical or a benzyl radical, preferably hydrogen or an alkyl radical of C_-C2.
4. The use according to any of claims 1 to 3, characterized in that R3 represents hydrogen or a linear C_-C_ alkyl radical or branched, optionally at least mono-substituted, preferably hydrogen or a linear or branched C?-C 4 alkyl radical, more preferably hydrogen or a C radical-C2 alkyl radical.
5. The use according to any of claims 1 to 4, characterized in that R4 and R5, identical or different, represent hydrogen or optionally at least mono-substituted linear or branched alkyl radical of Ca-C4, or R4 and R5 together with the nitrogen atom forming the bridge structure form a 5 or 6 membered heterocyclic ring, saturated or unsaturated, optionally at least mono-substituted, which may contain at least one additional heteroatom as a member of the ring and / or may be fused with a monocyclic or bicyclic aliphatic ring system optionally containing at least one heteroatom as ring member, optionally at least mono-substituted, saturated or unsaturated, in which ring (s) (s) is / are of 5, 6 or 7 members.
6. - Use in accordance with the claim 5, characterized in that R 4 and R 5, which are identical or different, represent hydrogen or a straight or branched C?-C 4 alkyl radical, preferably a linear or branched C_-C 4 alkyl radical, or R 4 and R 5 together with the nitrogen atom which way the bridge structure form a portion that is selected from the group consisting of wherein R7 represents hydrogen, a straight or branched C_-C4 alkyl radical or a benzyl radical, preferably hydrogen or an alkyl radical of C_-C2.
7. The use according to any of claims 1 to 6, characterized in that A represents an optionally at least mono-substituted monocyclic or bicyclic aromatic ring system, in which the ring (s) is / are of 5 or 6 members, which may be linked by an optionally at least mono-substituted alkylene group of C_-C4, an optionally at least mono-substituted C2-C4 alkenylene or a C2-C4 alkynylene group optionally at least mono-substituted and / or may contain at least one heteroatom as a ring member, preferably an optionally at least mono-substituted monocyclic or bicyclic aromatic ring system, in which the ring (s) is / are of 5 or 6 members and in which one or both rings contains (n) at least one heteroatom, or a portion that is selected from the group consisting of wherein X, Y, Z are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C_-C_ alkyl, linear or branched C? -C4 alkoxy, alkylthio of linear or branched _-C4, a trifluoromethyl portion, a cyano portion and a portion NR8R9, in which R8 and R9, identical or different, represent hydrogen or straight or branched C1-C4 alkyl, represents a simple chemical bond between the two rings, a group CH2, O, S or a portion NR10, in which R10 is hydrogen or straight or branched C __-C4 alkyl and m is O, 1, 2, 3 04.
8. - Use in accordance with a or more of claims 1-7 of at least one sulfonamide derivative of the general formula (I), (I) wherein n represents 0, 1, 2, 3 or 4; R1 represents hydrogen, or a portion that is selected from the group consisting of in which, if present, the dotted line represents an optional chemical bond and R6 represents hydrogen, a methyl group or an ethyl group, R3 represents hydrogen, a methyl group or an ethyl group, R4 and R5, identical or different, represent a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group, an sec-butyl group, or a tert-butyl group, or R4 and R5 together with the nitrogen atom forming the bridge structure form a portion that is selected from the group consisting of wherein R7 represents hydrogen, a methyl group or an ethyl group, A represents a portion that is selected from the group consisting of in which RA and RB are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, pyridyl, thienyl and furyl, XY, Z is each independently selected from of the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, and -CF3, represents a simple chemical bond between the two rings, a CH2, O, S group or a portion NR10, in which R10 is hydrogen, methyl or ethyl, m is 0, 1, 2, 3 or 4.
9. The use according to any of claims 1-8, characterized in that the compound is selected from the group consisting of: [1] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [2] N- [3- (2- diethylaminoethyl.} - lH-indol-5-yl] -naphthalene-1-sulfonamide, [3] N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] naphthalene-1-sulfonamide hydrochloride, [4] N- [3- (2-diethylaminoethyl) -1 H -indol-5-yl] -3,5-dichlorobencensu lfonamide, [5] N- [3- (2-diethylaminoethyl) -1 H -indol-5-yl] -4-phenylbenzenesulfonamide, [6] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -5-chlorothiophen-2-sulfonamide, [7] N- [3- (2-dimethylaminoethyl) -1H-indole-5 -yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [8] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -naphthalene-l-sulfonamide, [ 9] N- [3- (2-dimethylamino-ethyl) -lH-indol-5-yl] -6-chloroimidazo [2, 1-b] thiazole-5-sulfonamide, [10] N- [3- (l -methylpiperidin-4-yl) -lH-indol-5-yl] -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [11] N- [3- (l-methylpiperidin-4-hydrochloride il) -lH-indol-5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [12] N- [3- (l-methylpiperidin-4-yl) -1H-indole- 5-yl] -naphthalene-1-sulfonamide, [13] N- [3- (l-methylpiperidin-4-yl) -1H-indol-5-yl] naphthalene-1-sulfonamide hydrochloride, [14] N- [3- (l-methyl-piperidin-4-yl) -lH-indol-5-yl] -5-chlorothiophen-2-sulfonamide, [15] N- [3- (l-methyl-piperidin-4-yl) -lH- indol-5-yl] -4-phenylbenzenesulfonamide, [16] N- [3- (l-methylpiperidin-4-yl) -1H-indol-5-yl] -quinolin-8-sulfonamide, [17] N- [ 3- (2-diethylamine oethyl) -lH-indol-5-yl] -naphthalene-2-sulfonamide, [18] N- [3- (l-methyl-l, 2,3,6-tetrahydro-iridin-4-) il) -lH-indol-5-yl] naphthalene-1-sulfonamide, [19] N- [3- (4-methyl-piperazin-1-yl) methyl-lH-indol-5-yl] -5-chloro-3 -methylbenzo [b] thiophene-2-sulfonamide, [20] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -5- (2-pyridyl) thiophene-2-sulfonamide, [21] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -2,1,3-benzothiadiazole-4-sulfonamide, [22] N- [3- (2-dimethylaminoethyl) -lH-indole- 5-yl] -quinolin-8-sulfonamide, [23] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -5-chloronaphthalene-2-sulfonamide, [24] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -4-phenoxybenzenesulfonamide, [25] N- [3- (2-dimethylaminoethyl) -lH-indol-5-yl] -4-phenylbenzenesulfonamide, [26] N - [3- (2-diethylaminoethyl) -1H-indol-5-yl] -N-ethyl-naphthalene-2-sulfonamide, [27] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl) -5-chloro-3-methyl-benzo [b] thiophen-2-sulfonamide, [28] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} -naphthalene-1-sulfonamide, [29] N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -naphthalene-2-sulfonamide, [30] N- [3-dimethylaminomethyl-lH-indole- 5-yl] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [31] N- [3 - (2-dipropylaminoethyl) -1H-indol-5-yl] -naphthalene-1-sulfonamide, [32] N- [3- (2-dipropylaminoethyl) -lH-indol-5-yl ] -5-chloro-3-methylbenzo [b] thiophen-2-sulfonamide, [33] N- [3- (2-dibutylaminoethyl) -lH-indol-5-yl] -5-chloro-3-methylbenzo [b] ] thiophen-2-sulfonamide, [34] N- [3- (2-dibutylaminoethyl) -1H-indol-5-yl] -naphthalene-1-sulfonamide, [35] N- [3- (2-diethylaminoethyl) - 1H-indol-5-yl] -5-chloronaphthalene-1-sulfonamide, [36) N- [3- (2-diethylaminoethyl) -lH-indol-5-yl] -trans-β-styrenesulfonamide, [37] N - [3- (4-methyl-piperazin-1-yl) methyl-1H-indol-5-yl] -trans-β-styrenesulfonamide, [38] N- [3 ~ (octahydroindolizin-7-yl) -lH-indole -5-yl] -5-chloro-3-methylbenzo [b] thiofen-2-sulfonamide, [39] N- [3- (2-diethylaminoethyl) -1H-indol-5-yl] -6-chloroimidazo [ 2, 1-b] thiazole-5-sulfonamide, [40] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} naphthalene-2-sulfonamide, [41] N- [3- (4-methyl-piperazin-1-yl) methyl-lH-indol-5-yl] -a-toluenesulfonamide, [42] N- [3- (3- diethylaminopropyl) -1H-indol-5-yl] -naphthalene-2-sulfonamide, [43] N- [3 - (3-diethylaminopropyl) -lH-indol-5-yl] -5- chloro-3-methylbenzo [b] thiofen-2-sulfonamide, [44] N-. { 3- [2- (pyrrolidin-1-yl) ethyl] -lH-indol-5-yl} -5-chloro-3-methylbenzo [b] thiof en-2-sulfonamide, [45] N-. { 3- [2- (pyrrolidin-1-yl) ethyl] -lH-indol-5-yl} naphthalene-l-sulfonamide, [46] N-. { 3- [2- (pyrrolidin-1-yl) ethyl] -lH-indol-5-yl} Naphthalene-2-sulfonamide, [47] N- [3- (2-dipropylaminoethyl) -lH-indol-5-yl] -naphthalene-2-sulfonamide, [48] N- [3- (2-dimethylaminoethyl) -1H -indol-5-yl] -5-chloronaphthalene-1-sulfonamide, [49] N- [3- (2-dimethylaminoethyl) -1H-indol-5-yl] -naphthalene-2-sulfonamide, [50] N- . { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} -quinolin-8-sulfonamide, [51] N-. { 3- [2- (morpholin-4-yl) ethyl] -lH-indol-5-yl} -4-phenylbenzenesulfonamide, [52] N- [3- (4-methyl-piperazin-1-yl) ethyl-lH-indol-5-yl] -naphthalene-2-sulfonamide and [53] N- [3- (4-methylpiperazine -l-yl) ethyl-lH-indol-5-yl] -5-chloronaphthalene-1-sulfonamide.
10. The use according to any of claims 1-9 for the regulation of appetite.
11. - The use according to any of claims 1-9 for the reduction, increase or maintenance of body weight.
12. The use according to any of claims 1-9 for the prophylaxis and / or treatment of obesity.
13. The use according to any of claims 1-9 for the prophylaxis and / or treatment of bulimia.
14. - The use according to any of claims 1-9 for the prophylaxis and / or treatment of anorexia.
15. Use according to any of claims 1-9 for the prophylaxis and / or treatment of cachexia.
16. The use according to any of claims 1-9 for the prophylaxis and / or treatment of type II diabetes.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ESP200301077 | 2003-05-09 | ||
ESP200301782 | 2003-07-28 |
Publications (1)
Publication Number | Publication Date |
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MXPA05012052A true MXPA05012052A (en) | 2006-10-17 |
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