HRP20050993A2 - N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors - Google Patents
N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors Download PDFInfo
- Publication number
- HRP20050993A2 HRP20050993A2 HR20050993A HRP20050993A HRP20050993A2 HR P20050993 A2 HRP20050993 A2 HR P20050993A2 HR 20050993 A HR20050993 A HR 20050993A HR P20050993 A HRP20050993 A HR P20050993A HR P20050993 A2 HRP20050993 A2 HR P20050993A2
- Authority
- HR
- Croatia
- Prior art keywords
- pyrrolidin
- ylbenzamide
- dichloro
- isobutyl
- benzamide
- Prior art date
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229940076279 serotonin Drugs 0.000 title claims abstract description 21
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 230000000966 norepinephrine reuptake Effects 0.000 title abstract 2
- 230000000697 serotonin reuptake Effects 0.000 title abstract 2
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical class NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 54
- 125000003118 aryl group Chemical group 0.000 claims abstract description 33
- 125000001424 substituent group Chemical group 0.000 claims abstract description 29
- 150000002367 halogens Chemical class 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 26
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 19
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 5
- 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 41
- 238000011282 treatment Methods 0.000 claims description 37
- -1 anthracyl Chemical group 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 208000002193 Pain Diseases 0.000 claims description 17
- 230000033228 biological regulation Effects 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229960002748 norepinephrine Drugs 0.000 claims description 16
- 230000036407 pain Effects 0.000 claims description 16
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 15
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000010511 deprotection reaction Methods 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 101710164184 Synaptic vesicular amine transporter Proteins 0.000 claims description 7
- 102100034333 Synaptic vesicular amine transporter Human genes 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- FRDRXDWYERPNFJ-UHFFFAOYSA-N 2,4-dichloro-n-cyclopentyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C1CNCC1)C1CCCC1 FRDRXDWYERPNFJ-UHFFFAOYSA-N 0.000 claims description 4
- UZTWDJWLZPYOIJ-UHFFFAOYSA-N 3,4-dichloro-n-cyclopentyl-n-pyrrolidin-3-ylbenzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(=O)N(C1CNCC1)C1CCCC1 UZTWDJWLZPYOIJ-UHFFFAOYSA-N 0.000 claims description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 3
- 150000001266 acyl halides Chemical class 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 206010036596 premature ejaculation Diseases 0.000 claims description 3
- COAHLKJSSMFMQK-UHFFFAOYSA-N 2,3,4-trichloro-n-(2,2-dimethylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Cl)=C(Cl)C=1C(=O)N(CC(C)(C)C)C1CCNC1 COAHLKJSSMFMQK-UHFFFAOYSA-N 0.000 claims description 2
- QOGJBAPAXASGJV-UHFFFAOYSA-N 2,3,4-trichloro-n-(2-cyclopropylethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=C(Cl)C(Cl)=CC=C1C(=O)N(C1CNCC1)CCC1CC1 QOGJBAPAXASGJV-UHFFFAOYSA-N 0.000 claims description 2
- NLORJZAYXBWZAC-UHFFFAOYSA-N 2,3,4-trichloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Cl)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 NLORJZAYXBWZAC-UHFFFAOYSA-N 0.000 claims description 2
- YIIQEDQCKWWPBV-UHFFFAOYSA-N 2,3,4-trichloro-n-(cyclobutylmethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=C(Cl)C(Cl)=CC=C1C(=O)N(C1CNCC1)CC1CCC1 YIIQEDQCKWWPBV-UHFFFAOYSA-N 0.000 claims description 2
- MWFRJZJLBUCCRT-UHFFFAOYSA-N 2,3,5-trichloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(Cl)=CC(Cl)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 MWFRJZJLBUCCRT-UHFFFAOYSA-N 0.000 claims description 2
- OLYURNJVYZUZGG-UHFFFAOYSA-N 2,3-dichloro-4-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(F)C(Cl)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 OLYURNJVYZUZGG-UHFFFAOYSA-N 0.000 claims description 2
- RACGQDOAZWZUIY-UHFFFAOYSA-N 2,3-dichloro-5-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(F)=CC(Cl)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 RACGQDOAZWZUIY-UHFFFAOYSA-N 0.000 claims description 2
- DJLPMBDKYCOKFB-UHFFFAOYSA-N 2,3-dichloro-6-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound FC=1C=CC(Cl)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 DJLPMBDKYCOKFB-UHFFFAOYSA-N 0.000 claims description 2
- GZAWVIWERRSMCS-UHFFFAOYSA-N 2,3-dichloro-n-(2-cyclopropylethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(CCC2CC2)C2CNCC2)=C1Cl GZAWVIWERRSMCS-UHFFFAOYSA-N 0.000 claims description 2
- PIKCALBGLDBAKK-NSHDSACASA-N 2,3-dichloro-n-(2-methylpropyl)-n-[(3s)-pyrrolidin-3-yl]benzamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCNC1 PIKCALBGLDBAKK-NSHDSACASA-N 0.000 claims description 2
- LNGWEWRIDKMMEI-UHFFFAOYSA-N 2,3-dichloro-n-(3,3-dimethylbutan-2-yl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(C(C)C(C)(C)C)C1CCNC1 LNGWEWRIDKMMEI-UHFFFAOYSA-N 0.000 claims description 2
- DNAHFBSJJUVGJA-UHFFFAOYSA-N 2,3-dichloro-n-(3-methylbutan-2-yl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(C(C)C(C)C)C1CCNC1 DNAHFBSJJUVGJA-UHFFFAOYSA-N 0.000 claims description 2
- DUSNURPCQWWGEK-UHFFFAOYSA-N 2,3-dichloro-n-(3-methylbutyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(CCC(C)C)C1CCNC1 DUSNURPCQWWGEK-UHFFFAOYSA-N 0.000 claims description 2
- SMUOKMOUIPKGOA-UHFFFAOYSA-N 2,3-dichloro-n-(4-fluorophenyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C1=CC(F)=CC=C1N(C(=O)C=1C(=C(Cl)C=CC=1)Cl)C1CNCC1 SMUOKMOUIPKGOA-UHFFFAOYSA-N 0.000 claims description 2
- KTXOPCLGYNRVBZ-UHFFFAOYSA-N 2,3-dichloro-n-(cyclobutylmethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(CC2CCC2)C2CNCC2)=C1Cl KTXOPCLGYNRVBZ-UHFFFAOYSA-N 0.000 claims description 2
- JQUVOUGCSOVTFG-UHFFFAOYSA-N 2,3-dichloro-n-cyclobutyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(C2CCC2)C2CNCC2)=C1Cl JQUVOUGCSOVTFG-UHFFFAOYSA-N 0.000 claims description 2
- QQSBFGNEUOJMLY-UHFFFAOYSA-N 2,3-dichloro-n-cyclohexyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(C2CNCC2)C2CCCCC2)=C1Cl QQSBFGNEUOJMLY-UHFFFAOYSA-N 0.000 claims description 2
- MPGDFMOXIHFZSL-UHFFFAOYSA-N 2,3-dichloro-n-cyclopentyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(C2CCCC2)C2CNCC2)=C1Cl MPGDFMOXIHFZSL-UHFFFAOYSA-N 0.000 claims description 2
- PMZYRKGBQBCWOA-UHFFFAOYSA-N 2,3-dichloro-n-pentan-3-yl-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(C(CC)CC)C1CCNC1 PMZYRKGBQBCWOA-UHFFFAOYSA-N 0.000 claims description 2
- IAPNVLHDPZOUSQ-UHFFFAOYSA-N 2,3-dichloro-n-phenyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC=CC(C(=O)N(C2CNCC2)C=2C=CC=CC=2)=C1Cl IAPNVLHDPZOUSQ-UHFFFAOYSA-N 0.000 claims description 2
- NSCOJYQRNCDGIJ-UHFFFAOYSA-N 2,3-dimethyl-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(C)=C(C)C=1C(=O)N(CC(C)C)C1CCNC1 NSCOJYQRNCDGIJ-UHFFFAOYSA-N 0.000 claims description 2
- WAHGOJZNXRVCGA-UHFFFAOYSA-N 2,4,5-trichloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(Cl)=C(Cl)C=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 WAHGOJZNXRVCGA-UHFFFAOYSA-N 0.000 claims description 2
- SZCRHSRRYURQEQ-UHFFFAOYSA-N 2,4-dichloro-3-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(F)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 SZCRHSRRYURQEQ-UHFFFAOYSA-N 0.000 claims description 2
- UTKPKDHMSDNLGR-UHFFFAOYSA-N 2,4-dichloro-3-methyl-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(C)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 UTKPKDHMSDNLGR-UHFFFAOYSA-N 0.000 claims description 2
- ULVTVXTUDDHYBY-JTQLQIEISA-N 2,4-dichloro-5-fluoro-n-(2-methylpropyl)-n-[(3s)-pyrrolidin-3-yl]benzamide Chemical compound C=1C(F)=C(Cl)C=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCNC1 ULVTVXTUDDHYBY-JTQLQIEISA-N 0.000 claims description 2
- ULVTVXTUDDHYBY-UHFFFAOYSA-N 2,4-dichloro-5-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(F)=C(Cl)C=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 ULVTVXTUDDHYBY-UHFFFAOYSA-N 0.000 claims description 2
- ZSXFONSBYOQYMR-UHFFFAOYSA-N 2,4-dichloro-n-(2-cyclopropylethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C1CNCC1)CCC1CC1 ZSXFONSBYOQYMR-UHFFFAOYSA-N 0.000 claims description 2
- GOECCNKDOKBGOI-UHFFFAOYSA-N 2,4-dichloro-n-(2-ethylbutyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(CC(CC)CC)C1CCNC1 GOECCNKDOKBGOI-UHFFFAOYSA-N 0.000 claims description 2
- IDJLHSSQHKZAPT-LBPRGKRZSA-N 2,4-dichloro-n-(2-methylpropyl)-n-[(3s)-pyrrolidin-3-yl]benzamide Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCNC1 IDJLHSSQHKZAPT-LBPRGKRZSA-N 0.000 claims description 2
- WKMUOUQFXHDAKU-UHFFFAOYSA-N 2,4-dichloro-n-(3-methylbutan-2-yl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(C(C)C(C)C)C1CCNC1 WKMUOUQFXHDAKU-UHFFFAOYSA-N 0.000 claims description 2
- WUFFPKSZFKXXNQ-UHFFFAOYSA-N 2,4-dichloro-n-(3-methylbutyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(CCC(C)C)C1CCNC1 WUFFPKSZFKXXNQ-UHFFFAOYSA-N 0.000 claims description 2
- BFBBKHGCALZIFO-UHFFFAOYSA-N 2,4-dichloro-n-(4-fluorophenyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C1=CC(F)=CC=C1N(C(=O)C=1C(=CC(Cl)=CC=1)Cl)C1CNCC1 BFBBKHGCALZIFO-UHFFFAOYSA-N 0.000 claims description 2
- SUKDVYDHNNJVMJ-UHFFFAOYSA-N 2,4-dichloro-n-(cyclobutylmethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C1CNCC1)CC1CCC1 SUKDVYDHNNJVMJ-UHFFFAOYSA-N 0.000 claims description 2
- JZVBBSVOKXYHHS-UHFFFAOYSA-N 2,4-dichloro-n-(cyclopentylmethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C1CNCC1)CC1CCCC1 JZVBBSVOKXYHHS-UHFFFAOYSA-N 0.000 claims description 2
- JDMXCZREYXHEGU-UHFFFAOYSA-N 2,4-dichloro-n-cyclobutyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C1CNCC1)C1CCC1 JDMXCZREYXHEGU-UHFFFAOYSA-N 0.000 claims description 2
- QVOKIIJLRYXRCI-UHFFFAOYSA-N 2,4-dichloro-n-pentan-3-yl-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C=C(Cl)C=1C(=O)N(C(CC)CC)C1CCNC1 QVOKIIJLRYXRCI-UHFFFAOYSA-N 0.000 claims description 2
- NZSZPRJIMGILDA-UHFFFAOYSA-N 2,4-dichloro-n-phenyl-n-pyrrolidin-3-ylbenzamide Chemical compound ClC1=CC(Cl)=CC=C1C(=O)N(C=1C=CC=CC=1)C1CNCC1 NZSZPRJIMGILDA-UHFFFAOYSA-N 0.000 claims description 2
- WPVYCUXMQFNZQN-UHFFFAOYSA-N 2,5-dichloro-4-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(Cl)=C(F)C=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 WPVYCUXMQFNZQN-UHFFFAOYSA-N 0.000 claims description 2
- UAOCSOBBQYATOV-UHFFFAOYSA-N 2,5-dichloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C(Cl)=CC=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 UAOCSOBBQYATOV-UHFFFAOYSA-N 0.000 claims description 2
- QIGLEQXOOPLZLP-UHFFFAOYSA-N 2-bromo-4-chloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C=C(Br)C=1C(=O)N(CC(C)C)C1CCNC1 QIGLEQXOOPLZLP-UHFFFAOYSA-N 0.000 claims description 2
- NYMDLTGWMCRNLB-UHFFFAOYSA-N 2-chloro-3,6-difluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound FC=1C=CC(F)=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 NYMDLTGWMCRNLB-UHFFFAOYSA-N 0.000 claims description 2
- LEYVZUUANVQBPG-ZDUSSCGKSA-N 2-chloro-3-methyl-n-(2-methylpropyl)-n-[(3s)-pyrrolidin-3-yl]benzamide Chemical compound C=1C=CC(C)=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCNC1 LEYVZUUANVQBPG-ZDUSSCGKSA-N 0.000 claims description 2
- GZJJRCVIVJXCPO-UHFFFAOYSA-N 2-chloro-4-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(F)C=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 GZJJRCVIVJXCPO-UHFFFAOYSA-N 0.000 claims description 2
- WPYCZZUEOTZVCT-UHFFFAOYSA-N 2-chloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC=C(Cl)C=1C(=O)N(CC(C)C)C1CCNC1 WPYCZZUEOTZVCT-UHFFFAOYSA-N 0.000 claims description 2
- NIDHUODJXUXWAP-UHFFFAOYSA-N 3,4-dichloro-2-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Cl)=C(F)C=1C(=O)N(CC(C)C)C1CCNC1 NIDHUODJXUXWAP-UHFFFAOYSA-N 0.000 claims description 2
- CAHIVVRVAKMCHC-UHFFFAOYSA-N 3,4-dichloro-2-methyl-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Cl)=C(C)C=1C(=O)N(CC(C)C)C1CCNC1 CAHIVVRVAKMCHC-UHFFFAOYSA-N 0.000 claims description 2
- JVIKPFIJPCEZJS-UHFFFAOYSA-N 3,4-dichloro-n-(2,2-dimethylpropyl)-2-methyl-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=C(Cl)C(Cl)=CC=C1C(=O)N(CC(C)(C)C)C1CNCC1 JVIKPFIJPCEZJS-UHFFFAOYSA-N 0.000 claims description 2
- ZMEHJZMEBDWMRH-LBPRGKRZSA-N 3,4-dichloro-n-(2-methylpropyl)-n-[(3s)-pyrrolidin-3-yl]benzamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(=O)N(CC(C)C)[C@H]1CCNC1 ZMEHJZMEBDWMRH-LBPRGKRZSA-N 0.000 claims description 2
- PRRVSBBOWWFBGE-UHFFFAOYSA-N 3,4-dichloro-n-(3-methylbutyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(=O)N(CCC(C)C)C1CCNC1 PRRVSBBOWWFBGE-UHFFFAOYSA-N 0.000 claims description 2
- GWKBGZUJWBVDLK-UHFFFAOYSA-N 3,4-dichloro-n-(cyclobutylmethyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(=O)N(C1CNCC1)CC1CCC1 GWKBGZUJWBVDLK-UHFFFAOYSA-N 0.000 claims description 2
- JWCNXOYNOJAWRE-UHFFFAOYSA-N 3,4-dichloro-n-phenyl-n-pyrrolidin-3-ylbenzamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(=O)N(C=1C=CC=CC=1)C1CNCC1 JWCNXOYNOJAWRE-UHFFFAOYSA-N 0.000 claims description 2
- XWHCGSLRLXTVIH-UHFFFAOYSA-N 3-bromo-4-chloro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(Cl)C(Br)=CC=1C(=O)N(CC(C)C)C1CCNC1 XWHCGSLRLXTVIH-UHFFFAOYSA-N 0.000 claims description 2
- UWLXWGKTAMTBSF-UHFFFAOYSA-N 3-chloro-2-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(F)C=1C(=O)N(CC(C)C)C1CCNC1 UWLXWGKTAMTBSF-UHFFFAOYSA-N 0.000 claims description 2
- VJADHLVJCCCGKY-UHFFFAOYSA-N 3-chloro-2-methyl-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=CC(Cl)=C(C)C=1C(=O)N(CC(C)C)C1CCNC1 VJADHLVJCCCGKY-UHFFFAOYSA-N 0.000 claims description 2
- MIHORKBDQUKGGZ-UHFFFAOYSA-N 3-chloro-4-fluoro-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(F)C(Cl)=CC=1C(=O)N(CC(C)C)C1CCNC1 MIHORKBDQUKGGZ-UHFFFAOYSA-N 0.000 claims description 2
- DVQQBOVJNBWKGC-UHFFFAOYSA-N 3-chloro-4-methyl-n-(2-methylpropyl)-n-pyrrolidin-3-ylbenzamide Chemical compound C=1C=C(C)C(Cl)=CC=1C(=O)N(CC(C)C)C1CCNC1 DVQQBOVJNBWKGC-UHFFFAOYSA-N 0.000 claims description 2
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- 229960001693 terazosin Drugs 0.000 description 1
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- AVTRFXLSIJUASF-AWEZNQCLSA-N tert-butyl (3s)-3-[(2,3-dichlorobenzoyl)-(2-methylpropyl)amino]pyrrolidine-1-carboxylate Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCN(C(=O)OC(C)(C)C)C1 AVTRFXLSIJUASF-AWEZNQCLSA-N 0.000 description 1
- STYSMBNJIVAFNF-ZDUSSCGKSA-N tert-butyl (3s)-3-[(2,4-dichloro-5-fluorobenzoyl)-(2-methylpropyl)amino]pyrrolidine-1-carboxylate Chemical compound C=1C(F)=C(Cl)C=C(Cl)C=1C(=O)N(CC(C)C)[C@H]1CCN(C(=O)OC(C)(C)C)C1 STYSMBNJIVAFNF-ZDUSSCGKSA-N 0.000 description 1
- CMIBWIAICVBURI-ZETCQYMHSA-N tert-butyl (3s)-3-aminopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)C1 CMIBWIAICVBURI-ZETCQYMHSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FJAOXMCSYYGOHT-SSDOTTSWSA-N tert-butyl n-[(3r)-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)C(F)(F)F)C1 FJAOXMCSYYGOHT-SSDOTTSWSA-N 0.000 description 1
- DQQJBEAXSOOCPG-SSDOTTSWSA-N tert-butyl n-[(3r)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCNC1 DQQJBEAXSOOCPG-SSDOTTSWSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
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- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
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- 229960002004 valdecoxib Drugs 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
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- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
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- 150000003751 zinc Chemical class 0.000 description 1
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Abstract
Spoj Formule (I) i njegovi farmaceutski i/ili veterinarski prihvatljivi derivati, gdje R1 je H, C1-6alkil, -C(X)Y, C3-8cikloalkil, aril, het, aril-C1-4alkil ili het-C1-4alkil, gdje su cikloalkilne, arilne ili het skupine izborno supstituirane s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila; R2 je aril ili heteroaril, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila; R3 je C1-6alkil, C3-8cikloalkil, C3-8cikloalkil-C1-6alkil, aril, het, aril-C1-4alkil ili het-C1-4alkil, gdje su cikloalkilne, arilne ili het skupine izborno supstituirane snajmanje 1 supstituentom, kojeg se neovisno bira između C1-6alkila, C1-6alkoksi, OH, halogena, CF3,OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila; X je S ili O; Y je H, C1-6alkil, aril, het, aril-C1-4alkil ili het-C1- 4alkil; a n je 1 ili 2, uz uvjet da kada n je 1, tada m je 0 ili 1, a kada n je 2, tada m je 0, gdje ako m je 0, * predstavlja kiralni centar. Spojevi prema ovom izumu pokazuju aktivnost kao inhibitori povratnog unosa i serotonina i noradrenalina, te su stoga korisni u nizu različitih terapijskih područja, primjerice inkontinencije mokraće.
Description
Ovaj izum odnosi se na nove amidne spojeve koji inhibiraju povratni unos monoamina, na postupke njihovog dobivanja, na farmaceutske pripravke koji ih sadrže, te na njihovu upotrebu u medicini.
Spojevi prema ovom izumu pokazuju aktivnost kao inhibitori povratnog unosa i serotonina i noradrenalina, te su stoga korisni u nizu različitih terapijskih područja. Kao primjer, spojevi prema ovom izumu korisni su u liječenju poremećaja kod kojih je implicirana regulacija funkcije monoaminskih transportera; specifičnije poremećaja kod kojih je implicirana inhibicija povratnog unosa serotonina ili noradrenalina; a osobito poremećaja kod kojih je implicirana inhibicija i serotonina i noradrenalina, poput inkontinencije mokraće.
Prema prvom aspektu, ovaj izum osigurava spoj formule (I),
[image]
i njegove farmaceutski i/ili veterinarski prihvatljive derivate, gdje
R1 je H, C1-6alkil, -C(X)Y, C3-8cikloalkil, aril, het, aril-C1-4alkil ili het-C1-4alkil, gdje su cikloalkilne, arilne ili het skupine izborno supstituirane s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8 alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila;
R2 je aril ili heteroaril izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila;
R3 je C1-6alkil, C3-8cikloalkil, C3-8cikloalkil-C1-6alkil, aril, het, aril-C1-4alkil ili het-C1-4alkil, gdje su cikloalkilne, arilne ili het skupine izborno supstituirane s najmanje 1 supstituentom, kojeg se neovisno bira između C1-6alkila, C1-6alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila;
X je S ili O;
Y je H, C1-6alkil, C1-6alkoksi, aril, het, aril-C1-4alkil ili het-C1-4alkil;
n je 1 ili 2, uz uvjet da kada n je 1, tada m je 0 ili 1, a kada n je 2, tada m je 0, gdje ako m je 0, * predstavlja kiralni centar;
aril je fenil, naftil, antracil ili fenantril;
heteroaril je aromatski 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom, izborno kondenziran s arilnom skupinom; i
het je aromatski ili nearomatski 4-, 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom, izborno kondenziran s 5 ili 6- članom karbocikličkom skupinom, ili drugi 4-, 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom.
U izvedbi prema ovom izumu R1 je H, a R2, R3 i m su definirani kao gore.
U sljedećoj izvedbi prema ovom izumu m je 0, a R1, R2 i R3 su definirani kao gore. Kada m je 0, * predstavlja R- ili S-enantiomernu konfiguraciju. Prema tome, u sljedećoj izvedbi m je 0, R1, R2 i R3 su definirani kao gore, a * predstavlja S-enantiomer.
U još daljnjoj izvedbi R1, R3 i m su definirani kao gore, a R2 je fenil, naftil ili kinolinil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila. U još daljnjoj izvedbi supstituente se može birati između halogena, OH, C1-4alkila, C1-4alkoksi i CF3. Izborno, fenilna, naftilna ili kinolinilna skupina može biti supstituirana s 1, 2 ili 3 supstituenta, od kojih se svakog neovisno bira između halogena, OH i C1-4alkila. U sljedećoj izvedbi R2 je fenil i supstituiran je s 2 supstituenta, koje se bira između klora, fluora, OH i C1-4alkila. U još daljnjoj izvedbi R2 je diklorfenil.
U još daljnjoj izvedbi R1, R2 i m su definirani kao gore, a R3 je C1-6alkil, C3-8cikloalkil ili C3-8cikloalkil-C1-6alkil. U sljedećoj izvedbi R3 je C1-6alkil, C3-6cikloalkil ili C3-6cikloalkil-C1-4alkil.
U još daljnjoj izvedbi prema ovom izumu osiguran je spoj Formule II
[image]
i njegove farmaceutski i/ili veterinarski prihvatljive derivate, gdje
R4 je fenil, naftil, ili kinolinil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4 alkoksi-C1-6alkila i C-4alkil-S-C1-4alkila;
R5 je C1-6alkil, C3-8cikloalkil, C3-8cikloalkil-C1-6alkil, aril ili aril-C1-4alkil, gdje su cikloalkilne i arilne skupine izborno supstituirane s najmanje 1 supstituentom, od kojih se svakog neovisno bira između C1-6alkila, C1-6 alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila; i
m je 0 ili 1, gdje ako m je 0, * predstavlja R- ili S-enantiomer.
U sljedećoj izvedbi R5 i m su definirani kao gore, a R4 je fenil, 1-naftil ili 2-naftil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila. Supstituente se izborno može birati između C1-6alkila, C1-6alkoksi, OH, halogena i CF3. Fenilne ili naftilne skupine mogu biti supstituirane s 1, 2 ili 3 supstituenta. U jednoj izvedbi fenilne ili naftilne skupine su supstituirane s 2 supstituenta. U sljedećoj izvedbi fenilne ili naftilne skupine su supstituirane s 2 supstituenta, koje se neovisno bira između klora, fluora, C1-4alkila i OH. U još daljnjoj izvedbi fenilne ili naftilne skupine su supstituirane s 2 klorne skupine.
U još daljnjoj izvedbi R4 i m su definirani kao gore, a R5 je C1-6alkil, C3-6cikloalkil ili C3-6cikloalkil-C1-4alkil.
U još daljnjoj izvedbi R4 i R5 su definirani kao gore, a m je 0. U ovoj izvedbi * predstavlja R- ili S-enantiomer.
U sljedećoj izvedbi m je 0, a * predstavlja S-enantiomer.
U još daljnjoj izvedbi osiguran je spoj Formule III
[image]
i njegovi farmaceutski i/ili veterinarski prihvatljivi derivati,
gdje je R6 fenil, naftil ili kinolinil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između halogena, OH, C1-6alkila, C1-6alkoksi i CF3;
R7 je C1-6alkil, C3-6cikloalkil, C3-6cikloalkil-C1-4alkil, aril ili aril-CH2-, gdje su cikloalkil i arilne skupine izborno supstituirane s najmanje 1 skupinom, od kojih se svaku neovisno bira između halogena, OH, C1-4 alkila, C1-4alkoksi i CF3; i
* predstavlja R- ili S-enantiomer.
U sljedećoj izvedbi R7 i * su definirani kao gore, a R6 je fenil, 1-naftil ili 2-naftil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između halogena, OH, C1-6alkila, C1-6alkoksi i CF3. Supstituente se izborno može birati između klora, fluora, C1-4alkila, OMe i OH. Fenilne i naftilne skupine mogu biti supstituirane s 1, 2 ili 3 supstituenta. U sljedećoj izvedbi fenilne i naftilne skupine su supstituirane s 1, 2 ili 3 halogene skupine, koje se neovisno bira između fluora i klora.
U sljedećoj izvedbi R6 i * su definirani kao gore i R7 je C1-6alkil, C3-6cikloalkil ili C3-6cikloalkil-C1-4alkil. U još daljnjoj izvedbi R7 je C1-6alkil, izborno a C3-6alkil. Kada R7 je C3-6alkil, može biti a razgranati C3-6alkil.
U još daljnjoj izvedbi R6 i R7 su definirani kao gore, a * predstavlja S-enantiomer.
U još daljnjoj izvedbi osiguran je spoj Formule IV:
[image]
i njegovi farmaceutski i/ili veterinarski prihvatljivi derivati, gdje
R8 je fenil, izborno supstituiran s 1-3 halogena supstituenta;
R9 je C1-6alkil; i
* predstavlja R- ili S-enantiomer.
Izborno, R8 je diklorfenil, R9 je C3-4 razgranati alkil, a * predstavlja S-enantiomer. R9 može biti izobutilna skupina.
U sljedećoj izvedbi ovaj izum osigurava spoj kojeg se bira između:
2,3-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
2,4-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
2-klor-3-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-fluor-2-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-metoksi-2-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-klor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
4-klor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3,4-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
N-(2-naftilmetil)-N-[(3S)-pirolidin-3-il]benzamida;
N-(2-naftilmetil)-N-[(3R)-pirolidin-3-il]benzamida;
N-izobutil-N-[(3S)-pirolidin-3-il]-2-naftamida;
N-butil-N-[(3S)-pirolidin-3-il]-1-naftamida;
4-klor-N-(3,4-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamida;
4-klor-N-(2,3-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamida;
i njihovih farmaceutski i/ili veterinarski prihvatljivih derivata.
Daljnji, neograničujući primjeri spojeva koji ulaze u opseg zaštite ovog izuma uključuju:
N-pirolidin-3-il-N-(5,6,7,8-tetrahidronaftalen-1-ilmetil)benzamid;
N-(2,4-diklorbenzil)-N-pirolidin-3-ilbenzamid;
N-(3-klor-4-metilbenzil)-2-fluor-N-pirolidin-3-ilbenzamid;
butil(pirolidin-3-il)amid naftalen-2-karboksilne kiseline;
izobutil(pirolidin-3-il)amid naftalen-2-karboksilne kiseline;
(2,2-dimetilpropil)(pirolidin-3-il)amid naftalen-2-karboksilne kiseline;
3-klor-N-izobutil-4-metil-N-pirolidin-3-ilbenzamid;
N-izobutil-2,3-dimetil-N-pirolidin-3-ilbenzamid;
3-klor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamid;
2-klor-4-fluor-N-izobutil-N-pirolidin-3-ilbenzamid;
2-klor-N-izobutil-N-pirolidin-3-ilbenzamid;
3-klor-2-fluor-N-izobutil-N-pirolidin-3-ilbenzamid;
3-klor-4-fluor-N-izobutil-N-pirolidin-3-ilbenzamid;
N-butil-2,4-diklor-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-ciklopentilmetil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(2-etilbutil)-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamid;
2,3,4-triklor-N-izobutil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(2-ciklopropiletil)-N-pirolidin-3-ilbenzamid;
izobutil(pirolidin-3-il)amid naftalen-1-karboksilne kiseline;
2,4-diklor-5-fluor-N-izobutil-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(2,2-dimetilpropil)-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamid;
3,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(1,2-dimetilpropil)-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(1,2-dimetilpropil)-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-cikloheksil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamid;
3,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamid;
sec-butil(pirolidin-3-il)amid naftalen-1-karboksilne kiseline;
N-sec-butil-2,3-diklor-N-pirolidin-3-ilbenzamid;
N-sec-butil-2,4-diklor-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(1-etilpropil)-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(1-etilpropil)-N-pirolidin-3-ilbenzamid;
(1-etilpropil)pirolidin-3-ilamid naftalen-1-karboksilne kiseline;
2,3-diklor-N-ciklobutil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-ciklobutil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-pirolidin-3-il-N-(1,2,2-trimetilpropil)benzamid;
N-tert-butil-2,3-diklor-N-pirolidin-3-ilbenzamid;
ciklopentil(pirolidin-3-il)amid naftalen-1-karboksilne kiseline;
2,3-diklor-N-fenil-N-pirolidin-3-ilbenzamid;
3,4-diklor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamid;
3-klor-N-izobutil-2-metil-N-pirolidin-3-ilbenzamid;
N-butil-2,3-diklor-N-pirolidin-3-ilbenzamid;
N-butil-3,4-diklor-N-pirolidin-3-ilbenzamid;
ciklobutilmetil(pirolidin-3-il)amid naftalen-2-karboksilne kiseline;
ciklobutilmetil(pirolidin-3-il)amid naftalen-1-karboksilne kiseline;
3,4-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamid;
4-klor-N-izobutil-2-metoksi-N-pirolidin-3-ilbenzamid;
4-klor-N-izobutil-3-metil-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-izobutil-3-metil-N-pirolidin-3-ilbenzamid;
(3-metilbutil)pirolidin-3-ilamid naftalen-1-karboksilne kiseline;
(2,2-dimetilpropil)pirolidin-3-ilamid naftalen-1-karboksilne kiseline;
3,4-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(4-fluorfenil)-N-pirolidin-3-ilbenzamid;
2,4-diklor-N-(4-fluorfenil)-N-pirolidin-3-ilbenzamid;
(4-fluorfenil)pirolidin-3-ilamid naftalen-1-karboksilne kiseline;
N-butil-2,3,4-triklor-N-pirolidin-3-ilbenzamid;
2,3,4-triklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamid;
N-pirolidin-3-il-N-(3-trifluormetilbenzil)benzamid;
2,4-diklor-N-fenil-N-pirolidin-3-ilbenzamid;
3,4-diklor-N-fenil-N-pirolidin-3-ilbenzamid;
2,3,4-triklor-N-(2,2-dimetilpropil)-N-pirolidin-3-ilbenzamid;
fenil(pirolidin-3-il)amid naftalen-1-karboksilne kiseline;
2,3,4-triklor-N-(2-ciklopropiletil)-N-pirolidin-3-ilbenzamid;
2,3-diklor-N-(2-ciklopropiletil)-N-pirolidin-3-ilbenzamid;
2-brom-4-klor-N-izobutil-N-pirolidin-3-ilbenzamid;
4-klor-2-etoksi-N-izobutil-N-pirolidin-3-ilbenzamid;
3-brom-4-klor-N-izobutil-N-pirolidin-3-ilbenzamid;
3,4-diklor-N-izobutil-2-metil-N-pirolidin-3-ilbenzamid;
2,4-diklor-3-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,3-diklor-4-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,3-diklor-5-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,4,5-triklor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,5-diklor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,5-diklor-4-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,3,5-triklor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,3-diklor-6-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
3,4-diklor-6-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
3,4-diklor-2-fluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2-klor-3,6-difluor-N-izobutil-N-[pirolidin-3-il]benzamid;
2,4-diklor-5-fluor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamid;
i njihove farmaceutski i/ili veterinarski prihvatljive derivate.
Pod farmaceutski i/ili veterinarski prihvatljivim derivatom misli se na bilo koji farmaceutski ili veterinarski prihvatljivu sol, solvat, ester ili amid, ili sol ili solvat takvog estera ili amida, spojeva formule (I), (II), (III) ili (IV), ili bilo koji drugi spoj, koji prilikom primjene na primaocu može osigurati (izravno ili posredno) spoj formule (I), (II), (III) ili (IV), ili njrgov aktivni metabolit ili ostatak.
Prilikom farmaceutske ili veterinarske upotrebe gore navedene soli će biti farmaceutski ili veterinarski prihvatljive soli, no može se upotrijebiti i druge soli, primjerice u dobivanju spojeva formule (I), (II), (III) ili (IV) i njihovih farmaceutski ili veterinarski prihvatljive soli.
Gore navedene farmaceutski ili veterinarski prihvatljive soli uključuju njihove kisele adicijske i bazične soli.
Pogodne kisele adicijeske soli dobiva se iz kiselina koje tvore netoksične soli. Primjeri uključuju acetatne, aspartatne, benzoatne, besilatne, bikarbonatne/karbonatne, bisulfatne/sulfatne, kamsilatne, citratne, edisilatne, hemiedisilatne, esilatne, fumaratne, gluceptatne, glukonatne, glukuronatne, hibenzatne, hidrokloridne/kloridne, hidrobromidne/bromidne, hidrojodidne/jodidne, izetionatne, laktatne, malatne, maleatne, malonatne, mesilatne, metilsulfatne, 2-napsilatne, nikotinatne, nitratne, orotatne, pamoatne, fosfatne/hidrogenfosfatne/dihidrogenfosfatne, glukaratne, stearatne, sukcinatne, tartaratne, te tosilatne soli.
Pogodne bazične soli dobiva se iz baza koje tvore netoksične soli. Primjeri uključuju aluminijeve, argininske, benzatinske, kalcijeve, kolinske, dietilaminske, diolaminske, glicinske, lizinske, magnezij, megluminske, olaminske, kalijeve, natrijeve, trometaminske i cinkove soli.
Pregled pogodnih soli vidjeti u Stahl i Wermuth: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", (Wiley-VCH, Weinheim, Germany, (2002.)).
Farmaceutski prihvatljivu sol spoja formule (I), (II), (III) ili (IV) lako se dobije miješanjem zajedno otopina spoja i željene kiseline ili baze, po potrebi. Sol se može istaložiti iz otopine i prikupiti filtracijom ili se može prikupiti prilikom otparavanja otapala. Stupanj ionizacije soli može varirati od posve ionizirane do gotovo neionizirane.
Farmaceutski prihvatljivi solvati prema ovom izumu uključuju hidrate i solvate spojeva formule (I), (II), (III) ili (IV).
U opseg zaštite ovog izuma također ulaze i kompleksi, poput klatrata, inkluzijski kompleksi lijek-domaćin, gdje, za razliku od gore navedenih solvata, lijek i domaćin dolaze u stehiometrijskim ili nestehiometrijskim količinama. U ovaj izum također ulaze i kompleksi farmaceutskog lijeka koji sadrže dvije ili više organskih i/ili anorganskih komponenti koje mogu biti u stehiometrijskim ili nestehiometrijskim količinama. Dobiveni kompleksi mogu biti ionizirani, djelomično ionizirani ili neionizirani. Pregled takvih kompleksa vidjeti u Haleblian: J. Pharm. Sci., 64 (8), 1269-1288, (kolovoz, 1975.).
Spojeve formule (I), (II), (III) ili (IV) može se modificirati kako bi se dobilo njihove farmaceutski ili veterinarski prihvatljive derivate na bilo kojoj od funkcionalnih skupina u spojevima. Primjeri takvih derivata opisani su u: Drugs of Today, sv. 19, br. 9, str. 499-538, (1983.); Topics in Chemistry, pogl. 31, str. 306-316; te u H. Bundgaard: "Design of Prodrugs", Elsevier, (1985.), pogl. 1 (otkrića iz ovih dokumenata uključena su u ovu specifikaciju kao reference) te uključuju: estere, karbonatne estere, hemiestere, fosfatne estere, nitro estere, sulfatne estere, sulfokside, amide, sulfonamide, karbamate, azo-spojeve, fosfamide, glikozide, etere, acetale i ketale.
Stručnjaci u ovom području tehnike će također shvatiti da se izvjesne ostatke, poznate u struci kao "predostaci", kao što je primjerice opisano u H. Bundgaard: "Design of Prodrugs" (ibid.), može staviti na odgovarajuće funkcionalne skupine kada su takve funkcionalne skupine prisutne u spojevima prema ovom izumu.
Spojevi formule (I), (II), (III) ili (IV) mogu sadržavati jedan ili više kiralnih centara, zbog asimetričnog atoma ugljika definiranog određenim značenjima R1 do R9 (npr. s-butil), ili vrijednošću cijelog broja m. Takvi spojevi postoje u nizu stereoizomernih oblika (npr. u obliku para optičkih izomera ili enantiomera). Treba imati na umu da ovaj izum obuhvaća sve izomere spojeva prema ovom izumu, uključujući sve geometrijske, tautomerne i optičke oblike, te njihove smjese (npr. tautomerne ili racemične smjese).
Spojevi prema ovom izumu mogu postojati u jednom ili više tautomernih oblika. Svi tautomeri i njihove smjese ulaze u opseg zaštite ovog izuma. Kao primjer, traženje zaštite za 2-hidroksipiridinil također bi pokrilo i njegov tautomerni oblik, α-piridonil.
Treba imati na umu da ovaj izum uključuje radioaktivno obilježene spojeve formule (I), (II), (III) ili (IV).
Spojevi formule (I), (II), (III) ili (IV) i njihovi farmaceutski i veterinarski prihvatljivi derivati također mogu postojati u više kristalnih oblika, što je karakteristika poznata kao polimorfija. Svi takav polimorfni oblici ("polimorfi") ulaze u opseg zaštite ovog izuma. Polimorfija je općenito moguća kao odgovor na promjene u temperaturi ili tlaku ili oboje, a do toga također može doći zbog varijacija u kristalizaciji. Polimorfi se mogu razlikovati različitim fizičkim karakteristikama; u pravilu polimorfe se razlikuje prema uzorcima rendgenske difrakcije, topivosti, te talištu spoja.
Ukoliko se ne ukaže drugačije, svaka alkilna skupina može biti nerazgranata ili razgranata i ima 1-8 atoma ugljika, primjerice 1-6 atoma ugljika ili 1-4 atoma ugljika, primjerice metilna, etilna, n-propilna, i-propilna, n-butilna, i-butilna, s-butilna ili t-butilna skupina. Kada alkilna skupina ima više od jednog atoma ugljika, može biti nezasićena. Prema tome, termin C1-6 alkil uključuje C2-6 alkenil i C2-6 alkinil. Slično tome, termin C1-8 alkil uključuje C2-8 alkenil i C2-8 alkinil, a termin C1-4 alkil uključuje C2-4 alkenil i C2-4 alkinil.
Termin halogen se upotrebljava sa značenjem fluor, klor, brom ili jod.
Ukoliko se ne ukaže drugačije, termin het uključuje sve aromatske, zasićene ili nezasićene 4-, 5- ili 6- člane heterocikle s do 4 heteroatoma, koje se bira između N, O i S. Primjeri takavih heterocikličkih skupina uključuju furil, tienil, pirolil, pirolinil, pirolidinil, imidazolil, dioksolanil, oksazolil, tiazolil, imidazolil, imidazolinil, imidazolidinil, pirazolil, pirazolinil, pirazolidinil, izoksazolil, izotiazolil, oksadiazolil, triazolil, tiadiazolil, piranil, piridil, piperidinil, dioksanil, morfolino, ditianil, tiomorfolino, piridazinil, pirimidinil, pirazinil, piperazinil, sulfolanil, tetrazolil, triazinil, azepinil, oksazapinil, tiazepinil, diazepinil i tiazolinil. Uz to, termin heterocikl uključuje i kondenzirane heterociklilne skupine, primjerice benzimidazolil, benzoksazolil, imidazopiridinil, benzoksazinil, benzotiazinil, oksazolopiridinil, benzofuranil, kinolinil, kinazolinil, kinoksalinil, dihidrokinazdinil, benzotiazolil, ftalimido, benzodiazepinil, indolil i izoindolil. Termine het, heterociklil i heterocikl treba gledati na sličan način.
Kako bi se izbjeglo sumnju, ukoliko se ne ukaže drugačije, termin supstituiran znači supstituiran s jednom ili više definiranih skupina. U slučaju kada se skupine može birati između više alternativnih skupina, odabrane skupine mogu biti iste ili različite. Nadalje, termin neovisno znači da kada se bira više supstituenata između niza mogućih supstituenata, ti supstituenti mogu biti isti ili različit.
Nadalje, spojeve formule (I), (II), (III) i (IV) i njihove farmaceutski i veterinarski prihvatljive derivate, radioaktivno obilježene analoge prethodno navedenih, izomere prethodno navedenih, te polimorfe prethodno navedenih, navodi se kao "spojeve prema ovom izumu".
U jednoj izvedbi prema ovom izumu spojevi prema ovom izumu su farmaceutski i veterinarski prihvatljivi derivati spojeva formule (I), (II), (III) ili (IV), poput farmaceutski ili veterinarski prihvatljivih soli ili solvata spojeva formule (I), (II), (III) ili (IV), (npr. farmaceutski ili veterinarski prihvatljive soli spojeva formule (I), (II), (III) ili (IV)).
U još daljnjoj izvedbi prema ovom izumu osiguran je spoj prema ovom izumu koji je inhibitor povratnog unosa monoamina za serotonin i/ili noradrenalin, s vrijednostima IC50 za SRI ili NRI od 200 nM ili manje. U sljedećoj izvedbi spoj ima vrijednosti IC50 SRI i/ili NRI od 100 nM ili manje. U još daljnjoj izvedbi spoj ima vrijednosti IC50 za SRI ili NRI od 50 nM ili manje. U još daljnjoj izvedbi spoj ima vrijednosti IC50 za SRI i NRI od 50 nM ili manje. U još daljnjoj izvedbi spoj ima vrijednosti IC50 za SRI i NRI od 25 nM ili manje.
Prema Shemi 1, spojeve Formule (V) može se dobiti iz spojeva Formule (VI) reakcijom s aldehidom R3'CHO, te reakcijom s kiselinom ili kiselinskim kloridom R2COX (gdje X je OH ili halogen), uz uklanjanje zaštite.
Shema 1
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U gornjoj shemi R2 i m su definirani kao gore, PG je zaštitna skupina, a ostatak -CH2R3' zadovoljava definiciju R3.
(a) – Reduktivna aminacija
Reakcija primarnog amina (VI) s aldehidom kako bi se dobilo sekundarni amin (VII) je reakcija reduktivne aminacije, u kojoj dehidrataciju amina i aldehida slijedi redukcija dobivenog imina metalnim hidridnim reagensom ili hidrogenacijom, u pogodnom otapalu, na sobnoj temperaturi.
U ovoj reakciji se ekvimolarne količine amina i aldehida u pravilu obrađuje bilo natrijevim triacetoksiborohidridom (STAB), NaCN(BH)3, ili s NaBH4, u pogodnom otapalu (npr. DCM, THF), na sobnoj temperaturi u trajanju od 1-24 sata. Alternativno se dodaje reducens (npr. NaBH4, LiAlH4, STAB) u suvišku u pogodnom otapalu (npr. THF, MeOH, EtOH) nakon što se amin i aldehid miješa 1-18 sati, izborno u prisutnosti desikansa (npr. molekularno sito) ili uz uklanjanje vode Dean-Starkovim uređajem, uz pogodno otapalo (npr. toluen, ksilen). Sljedeća alternativa uključuje katalitičku hidrogenaciju u prisutnosti paladijskog ili niklenog katalizatora (npr. Pd/C, Raney® Ni) u atmosferi H2, izborno na povišenoj temperaturi i pod povišenim tlakom, u pogodnom otapalu (npr. EtOH).
Specifičniji primjer reduktivne aminacije uključuje obradu aldehida aminom u prisutnosti bilo 10 % Pd/C, izborno u prisutnosti trietilamina, u etanolu, pod približno 415 kPa (približno 60 psi) vodika, na sobnoj temperaturi, u trajanju od 18 sati, ili natrijevog borohidrida u suvišku u metanolu, na sobnoj temperaturi, u trajanju od 6 sati.
(b) – Dobivanje amida
Dobivanje peptidne spojnice između kiseline ili kiselinskog halogenida i amina (VII) može se provesti s bilo:
acil-halogenidom i aminom (VII), uz kiselinski akceptor u suvišku, u pogodnom otapalu, ili
kiselinom, izborno uz konvencionalno kondenzacijsko sredstvo, i aminom (VII), izborno u prisutnosti katalizatora, uz kiselinski akceptor u suvišku, u pogodnom otapalu.
Primjeri takve reakcije su sljedeći:
Kiselinski klorid (izborno dobiven na licu mjesta) reagira s aminom u suvišku (VII), izborno uz tercijarni amin poput Et3N, Hünigove baze ili NMM u suvišku, u DCM-u ili dioksanu, izborno na povišenoj temperaturi, u trajanju od 1-24 sata;
Kiselina, WSCDI/DCCI/TBTU i HOBT/HOAT reagiraju s aminom u suvišku (VII), uz NMM, Et3N ili Hünigovu bazu u suvišku, u THF-u, DCM-u ili EtOAc, na sobnoj temperaturi, u trajanju od 4-48 sati; ili
Kiselina i PYBOP®/PyBrOP®/Mukaiyamain reagens reagiraju s aminom (VII) u suvišku, uz NMM, Et3N, Hünigovu baza u suvišku, u THF-u, DCM-u ili EtOAc, na sobnoj temperaturi, u trajanju od 4-24 sata.
Kada je kiselinski halogenid kiselinski klorid (tj. X = Cl), može ga se standardnom metodologijom dobiti na licu mjesta, te reagira s aminom (VII), uz trietilamin, u diklormetanu, na 70 °C, u trajanju od 90 minuta.
(c) – Uklanjanje zaštite
Kada PG je pogodna zaštitna skupina za amin, po mogućnosti BOC, trifluoracetat ili benzil, uklanjanje PG iz (VIII), kako bi se dobilo nezaštićeni amin (V), provodi se postupkom selektivnim za zaštitnu skupinu, kao što je detaljno opisano u T.W. Greene i P.G.M. Wuts: "Protective Groups in Organic Synthesis", 3. izd., John Wiley & Sons, Inc., (1999.), uključenom u ovu specifikaciju kao referenca.
Primjeri takvih reakcija uklanjanja zaštite su sljedeći:
Kada PG je BOC, uklanjanje zaštite uključuje obradu (VIII) jakom kiselinom u suvišku (npr. s HCl, TFA), na sobnoj temperaturi, u pogodnom otapalu (npr. DCM, EtOAc, dioksan).
Kada PG je trifluoractetat, uklanjanje zaštite uključuje obradu (VIII) bazom (npr. s K2CO3, Na2CO3, NH3, Ba(OH)2) u alkoholnom otapalu (npr. MeOH, EtOH), izborno uz voda, te izborno na povišenoj temperaturi.
Kada PG je Bz, uklanjanje zaštite uključuje bilo prijenosnu hidrogenaciju uz prijelazni metal ili sol prijelaznog metala kao hidrogenacijski katalizator (npr. Pd/C, Pd(OH)2), u prisutnosti donora vodika (npr. NH4+HCO2–), u polarnom otapalu (npr. tetrahidrofuran, etanol, metanol), izborno na povišenoj temperaturi i/ili pod povišenim tlakom, ili katalitičku hidrogenaciju, u prisutnosti paladijskog ili niklenog katalizatora (npr. Pd/C, Raney® Ni), u atmosferi H2, izborno na povišenoj temperaturi i pod povišenim tlakom, u pogodnom otapalu.
Specifičnije:
Kada PG je BOC, uklanjanje zaštite uključuje obradu bilo 4 M klorovodičnom kiselinom u suvišku, u dioksanu, u trajanju od 18 sati, na sobnoj temperaturi. Ili s TFA u DCM-u, u trajanju od 4,5 sati, na sobnoj temperaturi.
Kada PG je trifluoractetat, uklanjanje zaštite uključuje obradu s K2CO3, u smjesi metanol/voda (5:1 do 10:1), na sobnoj temperaturi, u trajanju od 18 sati.
Kada PG je Bz, uklanjanje zaštite uključuje obradu s NH4+HCO2– i 10 % Pd/C, u etanolu, na blagom refluksu, između 6 i 20 sati.
Prema Shemi 2, spojevi Formule (IX) može se dobiti iz spojeva Formule (VI) reakcijom s R3-L, gdje L je izlazna skupina, u pogodnim uvjetima. Dobiveni spoj Formule (IX) može se zatim prevesti u spoj Formule (II) dobivanjem amida i uklanjanjem zaštite na način analogan onom opisanom gore, prema Shemi 1.
Shema 2
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U gornjoj shemi R2, R3 i m su definirani kao gore, PG je pogodna zaštitna skupina, a L je izlazna skupina, čije značenje ovisi, između ostalog, o prirodi reakcije i upotrebljenim specifičnim reakcijskim uvjetima. Pogodne izlazne skupine bit će odmah očigledne stručnjaku i opisane su u mnogim standardnim radovima iz organske kemije, primjerice: Jerry March: "Advanced Organic Chemistry", 3. izd., str. 587, Wiley, (1985.), uključenom u ovu specifikaciju kao referenca; one uključuju halogen (npr. Br) i sulfonatne estere (npr. metansulfonat ili trifluormetansulfonat).
Pogodno R3 je arilna skupina, L je Br, a reakciju (d) provodi se u pogodnom otapalu na povišenim temperaturama, u prisutnosti paladijsklog katalizatora. Takve reakcije arilne aminacije posredstvom paladija dobro su poznate stručnjacima u ovom području tehnike.
Specifičniji primjer postupka prema Shemi 2 uključuje obradu aril-bromida aminom Formule (VI), u prisutnosti tris(dibenzilidenaceton)dipaladija, 2,2'-bis(difenilfosfino)-1,1'-binaftila i natrijevog tert-butoksida, u toluenu, na 100°C, u trajanju od 18 sati.
Prema Shemi 3, spojeve Formule (IX) može se dobiti iz ketona Formule (XII) reakcijom s primarnim aminom R3-NH2, u pogodnim uvjetima. Dobiveni spoj Formule (IX) može se zatim prevesti u spoj Formule (II) dobivanjem amida, uz uklanjanje zaštite na način analogan onom opisanom gore, prema Shemi 1.
Shema 3
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U gornjoj shemi R2, R3 i m su definirani kao gore, a PG je pogodna zaštitna skupina.
Reakcija (e) primarnog amina R3-NH2 s ketonom (XII) može pogodno biti reakcija reduktivne aminacije, u kojoj dehidrataciju amina i ketona slijedi redukcija dobivenog imina, primjerice metalnim hidridnim reagensom ili hidrogenacijom, u pogodnim uvjetima.
Pogodno se reakciju amina i ketona provodi u prisutnosti titanijevog(IV) tetraizopropoksida, u THF-u, na sobnoj temperaturi, u trajanju od 18 sati, uz redukciju natrijevim borohidridom u suvišku, u metanolu, na sobnoj temperaturi, u trajanju od 5 sati.
Stručnjak može odabrati najprikladniji put sinteze do željenog spoja Formule (I), (II), (III) ili (IV). Gornje sheme može se, naravno, po potrebi modificirati u skladu s općim znanjem stručnjaka u ovom području tehnike.
Kao primjer, stručnjak će svakako shvatiti da se vodik vezan na piperidinski ili pirolidinski dušik (ovisno o vrijednost m) u amidu s kojeg je skinuta zaštita (II) ili (V) može, po želji, zamijeniti alternativnim skupinama kako bi se dobilo spoj Formule (I) gdje n je 1, a m je 0 ili 1, uz upotrebu konvencionalnih sintetskih metodologija.
Uz to, spojeve Formule (I) gdje n je 2, a m je 0 može se dobiti postupcima analognim onima opisanim gore, iz odgovarajućih polaznih materijala.
Stručnjaci u ovom području tehnike će shvatiti da jednu ili više osjetljivih funkcionalnih skupina možda moglo trebati zaštititi ili s njih ukloniti zaštitu tijekom sinteze spoja Formule (I), (II), (III) ili (IV). To se može postići konvencionalnim tehnikama, kao što je primjerice opisano u T.W. Greene i P.G.M Wuts: "Protective Groups in Organic Synthesis", 3. izd, John Wiley & Sons, Inc., (1999.), uključenom u ovu specifikaciju kao referenca, gdje se također opisuju postupci uklanjanja takvih skupina.
Stručnjacima u ovom području tehnike će biti očigledno da izvjesni zaštićeni derivati spojeva prema ovom izumu, koje se može dobiti prije koraka konačnog uklanjanja zaštite, ne moraju posjedovati farmakološku aktivnost kao takvu, no može ih se, u izvjesnim okolnostima, primijeniti oralno ili parenteralno, te naknadno metabolizirati u organzmu, čime se dobije spojeve prema ovom izumu koji su farmakološki aktivni. Takve derivate može se stoga opisati kao predlijekove. Nadalje, izvjesni spojevi prema ovom izumu mogu djelovati kao predlijekovi drugih spojeva prema ovom izumu.
Prema tome, prema sljedećem aspektu ovog izuma, osiguran je postupak dobivanja spojeva Formule (I), (II), (III) ili (IV), koji se sastoji u reakciji spoja formule (X):
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gdje su R3, n i m definirani kao gore, a Y je R1 ili zaštitna skupina, s kiselinom ili acil-halogenidom: R2COX, gdje X je OH ili halogen, te uz uklanjanje zaštite ako je nužno.
Kada R3 uključuje metilenski ostatak, izravno vezan na atom dušika, spoj Formule (X) može se dobiti reakcijom spoja Formule (XXI) s aldehidom R3CHO (gdje -CH2R3' zadovoljava definiciju R3).
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Alternativno se spoj Formule (X) može dobiti reakcijom spoja Formule (XXI) sa spojem R3-L, gdje L je izlazna skupina, koju se izborno bira između halogenida, metansulfonata i trifluormetansulfonata.
Nadalje, spoj Formule (X) može se dobiti reakcijom spoja Formule (XXII) sa spojem R3-NH2.
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Izvjesni međuprodukti opisani gore su novi spojevi, te treba shvatiti da su svi novi međuprodukti u ovoj specifikaciji daljnji aspekti ovog izuma.
Racemične spojeve može se razdvojiti bilo preparativnim HPLC-om, na stupcu s kiralnom nepokretnom fazom, ili tako razdvojiti da se postupcima poznatim stručnjacima u ovom području tehnike dobije pojedinačne enantiomere. Uz to, kiralne međuprodukte može se razdvojiti i upotrijebiti u dobivanju kiralnih spojeva prema ovom izumu.
Prema sljedećem aspektu ovog izuma osiguran je jedan ili više metabolita spojeva prema ovom izumu prilikom dobivanja in vivo.
Moguća prednost spojeva prema ovom izumu je to što su potentniji, dulje djeluju, imaju širi raspon aktivnosti, stabilniji su, imaju manje nuspojava ili su selektivniji, ili imaju druga korisnija svojstva od spojeva iz prethodnog stanja tehnike.
Spojevi prema ovom izumu korisni su jer imaju farmakološku aktivnost kod sisavaca, uključujući ljude. Prema tome, korisni su u liječenju ili sprječavanju poremećaja kod kojih je implicirana regulacija funkcije monoaminskih transportera, specifičnije poremećaja kod kojih je implicirana inhibicija povratnog unosa serotonina ili noradrenalina, a osobito onih kod kojih je implicirana inhibicija povratnog unosa serotonina i noradrenalina.
Prema tome, spojevi prema ovom izumu su korisni u liječenju inkontinencije mokraće, poput prave stresne inkontinencije (GSI), urinarne stresne inkontinencije (USI) ili inkontinencije mokraće kod starijih; hiperaktivnog mokraćnog mjehura (OAB), uključujući idiopatsku nestabilnost detruzora, hiperaktivnost detruzora zbog neuroloških bolesti (npr. Parkinsonova bolest, multipla skleroza, ozljeda kralježnične moždine i inzult) i hiperaktivnost detruzora zbog opstrukcije istjecanja iz mokraćnog mjehura (npr. benigna hiperplazija prostate (BPH), suženje ili stenoza uretre); noćnog mokrenja; inkontinencije mokraće zbog kombinacije gore navedenih stanja (npr. prava stresna inkontinencija povezana s hiperaktivnim mokraćnim mjehurom); te urinarnih simptoma, poput učestalosti i hitnosti.
U pogledu njihove gore navedene farmakološke aktivnosti spojevi prema ovom izumu su također korisni u liječenju depresije, poput velike depresije, povratne depresije, depresivne epizode, supsindromne simptomatske depresije, depresije kod bolesnika s rakom, depresije kod parkinsoničara, depresije nakon infarkta miokarda, pedijatrijske depresija, depresije zbog zlostavljanja u djetinjstvu, depresije kod neplodnih žena, poslijeporođajne depresije, predmenstrualne disforije i sindroma starog nezadovoljnika.
U pogledu njihove gore navedene farmakološke aktivnosti spojevi prema ovom izumu su također korisni u liječenju kognitivnih poremećaja, poput demencije, osobito degenerativne demencije (uključujući senilnu demenciju, Alzheimerovu bolest, Pickovu bolest, Huntingdonovu koreju, Parkinsonovu bolest i Creutzfeldt-Jakobovu bolest) i vaskularne demencije (uključujući multiinfarktnu demenciju), kao i demencije povezane s lezijama, traumama, infekcijama i srodnim stanjima (uključujući HIV infekciju) u intrakranijalnom prostoru, metabolizmom, toksinima, anoksijom i nedostatkom vitamina; blagog kognitivnog poremećaja povezanog sa starenjem, osobito poremećaja pamćenja povezanog sa starenjem (AAMI), amnestičkog poremećaja i opadanja kognitivnih funkcija povezanog sa starenjem (ARCD); psihotičnih poremećaja, poput shizofrenije i manije; anksioznih poremećaja, poput općeg anksioznog poremećaja, fobija (npr. agorafobija, socijalna fobija i jednostavje fobije), paničnog poremećaja, opsesivno-kompulzivnog poremećaja, posttraumatskog stresnog poremećaja, miješane anksioznosti i depresije; poremećaja ličnosti, poput izbjegavajućeg poremećaja ličnosti i poremećaja nedostatka pažnje s hiperaktivnošću (ADHD); spolne disfunkcije, poput prijevremene ejakulacije, erektilne disfunkcije kod muškaraca (MED) i spolne disfunkcije kod žena (FSD) (npr. poremećaj spolne pobude kod žena (FSAD)); predmenstrualnog sindroma; sezonskog afektivnog poremećaja (SAD); poremećaja jedenja, poput anoreksije nervoze i bulimije nervoze; pretilosti; suzbijanja teka; ovisnosti o kemijskim sredstvima zbog navikavanja na lijekove ili zloupotrebe tvari, poput ovisnosti o nikotinu, alkoholu, kokainu, heroinu, fenobarbitonu i benzodiazepinima; sindroma ustezanja, poput onih koji mogu nastati zbog gore navedenih ovisnosti o kemijskim sredstvima; boli na području glave, poput migrene, klaster glavobolje, kronične paroksizmalne hemikranije, glavobolje povezane s vaskularnim poremećajima, glavobolje povezane s ovisnostima o kemijskim sredstvima ili sindromima ustezanja zbog ovisnosti o kemijskim sredstvima, te tenzijske glavobolje; boli; Parkinsonovih bolesti, poput demencije kod Parkinsonove bolesti, neurolepticima uzrokovanog parkinsonizma i tardivnih diskinezija); endokrinih poremećaja, poput hiperprolaktinemije; vazospazma, primjerice cerebralne vaskulature; cerebelarne ataksije; Touretteovog sindroma; trihotilomanije; kleptomanije; emocionalne nestabilonosti; patološkog plača; poremećaja spavanja (katapleksije); te šoka.
U pogledu njihove gore navedene farmakološke aktivnosti spojevi prema ovom izumu su također korisni u liječenju niza drugih stanja ili poremećaja, uključujući hipotenziju; poremećaja gastrointestinalnog sustava (uključujući promjene u pokretljivosti i lučenju) poput sindroma iritabilnih crijeva (IBS), ileusa (npr. postoperativni ileus i ileus tijekom sepse), gastropareze (npr. dijabetična gastropareza), peptičkog vrijeda, bolesti gastroezofagealnog refluksa (GORD, ili njegov sinonim GERD), nadutosti i drugih funkcionalnih poremećaja crijeva, poput dispepsije (npr. neulcerozna dispepsija (NUD)) i boli u prsima nesrčanog podrijetla (NCCP); te fibromialgijskog sindroma.
U pogledu njihove gore navedene farmakološke aktivnosti, spojevi prema ovom izumu također mogu biti korisni u liječenju boli. Kao primjer, bol zbog nategnuća ili iščašenja, postoperativna bol (bol nakon bilo kojeg tipa kirurškog zahvata), posttraumatska bol, opekline, infarkt miokarda, akutni pankreatitis, te bubrežni kolici. Također i sindromi akutne boli povezani s rakom, koje obično uzrokuju terapijska međudjelovanja, poput toksičnog djelovanja kemoterapije, imunoterapije, hormonske terapije i radioterapije. Daljnji primjeri uključuju bol koju uzrokuje tumor (npr. bol u kostima, glavobolja i facijalna bol, visceralna bol) ili povezana s terapijom raka (npr. postkemoterapijski sindromi, sindromi kronične postoperativne boli, postradijacijski sindromi), bol u leđima, čiji uzrok može biti hernija ili ruptura intervertebralnih diskova ili abnormalnosti slabinskih facetnih zglobova, sakroilijačnih zglobova, paraspinalnih mišića ili stražnjeg longitudinalnog ligamenta.
Uz to, spojevi prema ovom izumu mogu biti korisni u liječenju neuropatske boli. Nju se definira kao bol koju započinje ili uzrokuje primarna lezija ili disfunkcija živčanog sustava (definicija prema IASP-u). Oštećenje živaca može biti posljedica traume i bolesti, te stoga termin "neuropatska bol" obuhvaća mnoge poremećaje različitih etiologija. To uključuje, no ne ograničuje se na dijabetičnu neuropatiju, posterpetičnu neuralgiju, bol u leđima, neuropatiju kod raka, kemoterapijom uzrokovanu neuropatiju, HIV neuropatiju, bol u fantomskom udu, sindrom karpalnog tunela, kronični alkoholizam, hipotireoidizam, trigeminalnu neuralgiju, uremiju, traumom uzrokovanu neuropatiju, ili nedostatke vitamine.
Drugi oblici boli uključuju, no ne ograničuje se na:
Upalnu bol, poput artritične boli, uključujući reumatoidni artritis (RA) i ostoeartritis (OA), te upalnu bolest crijeva (IBD);
Mišićno-koštane poremećaje, uključujući, no ne ograničujući se na mialgiju, fibromialgiju, spondilitis, seronegativne (nereumatoidne) artropatije, nezglobni reumatizam, distrofinopatiju, glikogenolizu, polimiozitis, piomiozitis;
Centralnu bol ili "talamičnu bol", kao što je definira bol koju uzrokuje lezija ili disfunkcija živčanog sustava, uključujući, no ne ograničujući se na centralnu bol nakon inzulta, multiplu sklerozu, ozljedu kralježnične moždine, Parkinsonovu bolest i epilepsiju;
Srčanu i vaskularnu bol uključujući, no ne ograničujući se na anginu, infarkt miokarda, mitralnu stenozu, perikarditis, Rainaudov fenomen, sklerodomu, ishemiju skeletnog mišića;
Visceralnu bol i gastrointestinalne poremećaje, uključujući bol povezanu s dismenorejom, bol u zdjelici, cistitis i pankreatitis;
Bol na području glave uključujući, no ne ograničujući se na migrenu, migrenu s aurom, migrenu bez aure, klaster glavobolju, tenzijsku glavobolju; i
Orofacijalnu bol, uključujući, no ne ograničujući se na zubobolju, tempormandibularnu miofascijalnu bol.
Poremećaji od osobitog interesa uključuju inkontinenciju mokraće, poput miješane inkontinencije, GSI i USI; bol; depresiju; anksiozne poremećaje, poput opsesivno-kompulzivnog poremećaja i posttraumatskog stresnog poremećaja; poremećaje ličnosti, poput ADHD; spolnu disfunkciju; te ovisnosti o kemijskim sredstvima i sindrome ustezanja zbog ovisnosti o kemijskim sredstvima.
Prema tome, prema daljnjim aspektima, ovaj izum osigurava:
- spoj prema ovom izumu namijenjen upotrebi u humanoj ili veterinarskoj medicini;
- spoj prema ovom izumu namijenjen upotrebi u liječenju poremećaja kod kojeg je implicirana regulacija funkcije monoaminskih transportera, poput inkontinencije mokraće;
- upotrebu spoja prema ovom izumu u proizvodnji lijeka za liječenje poremećaja kod kojeg je implicirana regulacija funkcije monoaminskih transportera;
- spoj prema ovom izumu namijenjen upotrebi u liječenju poremećaja kod kojeg je implicirana regulacija serotonina ili noradrenalina;
- upotreba spoja prema ovom izumu u proizvodnji lijeka za liječenje poremećaja kod kojeg je implicirana regulacija serotonina ili noradrenalina;
- spoj prema ovom izumu namijenjen upotrebi u liječenju poremećaja kod kojeg je implicirana regulacija serotonina i noradrenalina;
- upotreba spoja prema ovom izumu u proizvodnji lijeka za liječenje poremećaja kod kojeg je implicirana regulacija serotonina i noradrenalina;
- spoj prema ovom izumu namijenjen upotrebi u liječenju inkontinencije mokraće, poput GSI ili USI;
- upotreba spoja prema ovom izumu u proizvodnji lijeka za liječenje inkontinencije mokraće, poput GSI ili USI;
- postupak liječenja poremećaja kod kojeg je implicirana regulacija funkcije monoaminskih transportera, koji se sastoji u primjeni terapijski djelotvorne količine spoja prema ovom izumu na pacijentu kojem je potrebno takvo liječenje;
- postupak liječenja poremećaja kod kojeg je implicirana regulacija serotonina ili noradrenalina, koji se sastoji u primjeni terapijski djelotvorne količine spoja prema ovom izumu na pacijentu kojem je potrebno takvo liječenje;
- postupak liječenja poremećaja kod kojeg je implicirana regulacija serotonina i noradrenalina, koji se sastoji u primjeni terapijski djelotvorne količine spoja prema ovom izumu na pacijentu kojem je potrebno takvo liječenje; i
- postupak liječenja inkontinencije mokraće, poput GSI ili USI, koji se sastoji u primjeni terapijski djelotvorne količine spoja prema ovom izumu na pacijentu kojem je potrebno takvo liječenje.
Treba imati na umu da sve reference na liječenje u ovoj specifikaciji uključuju kurativno, palijativno i propilaktičko liječenje, ukoliko se izričito ne kaže drugačije.
Spojeve prema ovom izumu može se primijeniti same ili kao dio kombinacijske terapije. Ako se primjenjuje kombinacija terapijskih sredstava, aktivne sastojke se može primijeniti bilo uzastopce ili istodobno, u odvojenim ili kombiniranim farmaceutskim formulacijama.
Primjeri pogodnih sredstava za adjunktivnu terapiju uključuju:
- estrogenski agonist ili selektivni modulator estrogenskog receptora (npr. HRT terapije ili lasofoksifen);
- agonist α-adrenergičkih receptora, poput fenilpropanolamina ili R-450;
- antagonist α-adrenergičkih receptora (npr. fentolamin, doksazosin, tamsulosin, terazosin i prazosin), uključujući selektivn antagonist α1L-adrenergičkog receptora (npr. Primjer 19 u dokumentu WO98/30560);
- β-adrenergički agonist (npr. klenbuterol);
- antagonist muskarinskih receptora (npr. tolterodin ili oksibutinin), uključujući antagonist muskarinskog receptora M3 (npr. darifenacin);
- inhibitor COX, poput inhibitora COX-2 (npr. celekoksib, rofekoksib, valdekoksib parekoksib ili etorikoksib);
- antagonist tahikininskih receptora, poput neurokininskog antagonista (npr. antagonist NK1, NK2 ili NK3);
- agonist β3-receptora;
- ligand 5-HT1 (npr. buspiron);
- agonist 5-HT1, poput triptana (npr. sumatriptana ili naratriptana);
- agonist dopaminskih receptora (npr. apomorfin, gdje se učenja o njegovoj upotrebi kao farmaceutskog sredstva može naći u dokumentu US-A-5945117), uključujući agonist dopaminskog receptora D2 (npr. premipriksal, Pharmacia Upjohn spoj br. PNU95666; ili ropinirol);
- agonist melanokortinskog receptora (npr. melanotan II);
- antagonist PGE receptora;
- agonist PGE1 (npr. alprostadil);
- daljnji inhibitor monoaminskog transporta, poput inhibitora povratnog unosa noradrenalina (npr. reboksetin), inhibitora povratnog unosa serotonina (npr. sertralin, fluoksetin ili paroksetin) ili inhibitora povratnog unosa dopamina; antagonista 5-HT3 receptora (npr. ondansetron, granisetron, tropisetron, azasetron, dolasetron ili alosetron);
- inhibitor fosfodiesteraze (PDE), poput inhibitora PDE2, (npr. erythro-9-(2-hidroksil-3-nonil)adenin ili Primjer 100 u dokumentu EP 0771799, uključenom u ovu specifikaciju kao referenca), osobito inhibitora PDE5 (npr. sildenafil; 1-{[3-(3,4-dihidro-5-metil-4-okso-7-propilimidazo[5,1-f]-as-trazin-2-il)-4-etoksifenil]sulfonil}-4-etilpiperazin, tj. vardenafil, također poznati kao Bayer BA 38-9456; ili Icos Lillyjev IC351, strukturu vidjeti niže).
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Ovaj izum stoga osigurava, u daljnjem aspektu, kombinaciju spoja prema ovom izumu s daljnjim terapijskim sredstvom.
Prilikom upotrebe na ljudima spojeve prema ovom izumu može se primijeniti same, no u humanoj terapiji općenito ih se primjenjuje u smjesi s pogodnom farmaceutskom pomoćnom tvari, razrjeđivačem ili podlogom, koje se bira s obzirom na namjeravani način primjene i standardnu farmaceutsku praksu.
Kao primjer, spojeve prema ovom izumu može se primijeniti oralno, bukalno ili sublingvalno, u obliku tableta, kapsula (uključujući meke želatinske kapsule), ovula, ljekovitih napitaka, otopina ili suspenzija, koje mogu sadržavati arome ili boje, za trenutno, odgođeno, modificirano, produljeno, dvojno, kontrolirano otpuštanje ili aplikacije za pulsni unos. Spojeve prema ovom izumu također se može primijeniti intrakavernoznom injekcijom. Spojeve prema ovom izumu također se može primijeniti pomoću brzodispergirajućih ili brzootapajućih oblika doziranja.
Takve tablete mogu sadržavati pomoćne tvari, poput mikrokristalne celuloze, laktoze, natrijevog citrata, kalcijevog karbonata, dvobaznog kalcijevog fosfata, glicina, te škroba (po mogućnosti kukuruznog, krumpirovog ili tapiokinog škroba), sredstva za raspadanje, poput natrij-karboksimetilškroba, umrežene natrij-karboksimetilceluloze i izvjesnih složenih silikata, te granulacijska veziva, poput polivinilpirolidona, hidroksipropilmetilceluloze (HPMC), hidroksipropilceluloze (HPC), saharoze, želatine i arapske gume. Uz to, može se uključiti i maziva, poput magnezijevog stearata, stearinske kiseline, gliceril-behenata i talka.
Čvrste pripravke sličnog tipa također se može upotrijebiti kao punila u želatinskim kapsulama. Poželjne pomoćne tvari s tim u vezi uključuju laktozu, škrob, celulozu, mliječni šećer ili visokomolekulske polietilen-glikole. Kod vodenih suspenzija i/ili ljekovitih napitaka spojevi prema ovom izumu, i njihove farmaceutski prihvatljive soli, može se pomiješati s različitim sladilima ili aromama, bojama ili bojilima, s emulgatorima i/ili suspendirajućim sredstvima, te s razrjeđivačima poput vode, etanola, propilen-glikola i glicerola, i njihovim kombinacijama.
Oblici doziranja s modificiranim i pulsnim otpuštanjem mogu sadržavati pomoćne tvari poput onih detaljno opisanih za oblike doziranja s trenutnim otpuštanjem, zajedno s dodatnim pomoćnim tvari koje djeluju kao modifikatori brzine otpuštanja, koji su obloženi na i/ili su uključeni u tijelo sredstva. Modifikatori brzine otpuštanja uključuju, no ne ograničuju se isključivo na hidroksipropilmetilcelulozu, metilcelulozu, natrij-karboksimetilcelulozu, etilcelulozu, celulozni acetat, polietilen-oksid, ksantansku gumu, karbomer, amoniometakrilatni kopolimer, hidrogenirano ricinusovo ulje, karnauba-vosak, parafinski vosak, celulozni acetat-ftalat, hidroksipropilmetilcelulozni ftalat, kopolimer metakrilne kiseline i njihove smjese. Oblici doziranja s modificiranim i pulsnim otpuštanjem mogu sadržavati jedan ili kombinaciju pomoćnih tvari za modificiranje brzine otpuštanja. Pomoćne tvari za modificiranje brzine otpuštanja mogu biti prisutni i unutar oblika doziranja, tj. u matriksu, i/ili na obliku doziranja, tj. na površini ili oblozi.
Brzodispergirajuće ili -otapajuće formulacije doziranja (FDDF) mogu sadržavati sljedeće sastojke: aspartam, acesulfam-kalij, limunsku kiselinr, umreženu natrij-karboksimetilcelulozu, umreženi povidon, diaskorbinsku kiselinu, etil-akrilat, etilcelulozu, želatinu, hidroksipropilmetilcelulozu, magnezijev stearat, manitol, metil-metakrilat, aromu metvica, polietilen-glikol, koloidni silicijev dioksid, silicijev dioksid, natrij-karboksimetilškrob, natrijev stearil-fumarat, sorbitol, te ksilitol. Termini dispergirajući ili otapajući, kao što ih se upotrebljava u ovoj specifikaciji za opisivanje FDDF, ovise o topivosti upotrijebljene ljekovite tvari tj. kada je ljekovita tvar netopiva, može se načiniti je brzodispergirajući oblik doziranja, a kada je ljekovita tvar topiva, može se načiniti brzootapajući oblik doziranja.
Spojeve prema ovom izumu također se može primijeniti parenteralno, primjerice, intravenski, intraarterijski, intraperitonealno, intratekalno, intraventrikularno, intrauretralno, intrasternalno, intrakranijalno, intramuskularno ili supkutano, ili ih se može primijeniti infuzijskim tehnikama. Prilikom takve parenteralne primjene najbolje ih se upotrebljava u obliku sterilne vodene otopine, koja može sadržavati i druge tvari, primjerice dovoljno soli ili glukoze da se otopinu učini otopina izotoničnom s krvlju. Vodene otopine trebalo bi, ako je nužno, pogodno puferirati (po mogućnosti do pH 3-9). Pripravu pogodnih parenteralnih formulacija u sterilnim uvjetima je lako se postiže standardnim farmaceutskim tehnikama, dobro poznatim stručnjacima u ovom području tehnike.
Prilikom oralne i parenteralne primjene na ljudskim pacijentima dnevna razina doze spojeva prema ovom izumu, ili njihovih soli ili solvata, općenito se kreće od 10-500 mg (u jednoj ili podijeljenim dozama).
Prema tome, tablete ili kapsule spojeva prema ovom izumu, ili njihove soli ili solvati, mogu, primjerice, sadržavati 5-250 mg aktivnog spoja za primjenu jednom ili dvije ili više istodobno, po potrebi. U svakom slučaju, liječnik određuje stvarnu dozu, najpogodniju za svakog pojedinog pacijenta, što ovisi o dobi, težini i odgovoru pojedinog pacijenta. Gore navedene doze primjeri su prosječnog slučaja. Mogući su, naravno, pojedinačni slučajevi gdje treba uzeti u obzir više ili niže raspone doza, što također ulazi u opseg zaštite ovog izuma. Stručnjak će također imati na umu da se, u liječenju izvjesnih stanja (uključujući PE), spojeve prema ovom izumu može uzeti kao jednu dozu "po potrebi", (tj. po potrebi ili želji).
Primjer tabletne formulacije
Tabletna formulacija općenito u pravilu može sadržavati između približno 0,01 mg i 500 mg spoja prema ovome izumu (ili njegove soli), dok težine tabletnog punjenja mogu kretati u rasponu od 50-1000 mg. Prikazan je primjer formulacije tablete od 10 mg:
[image] * Ovu količinu u pravilu se podešava u skladu s aktivnošću lijeka, a bazira se na težini slobodne baze.
Spojeve prema ovom izumu također se može primijeniti intranazalno ili inhalacijom i pogodno ih se unaša u obliku inhalatora sa suhim prahom ili prezentacijom aerosolnog spreja iz spremnika, pumpe, spreja ili nebulizatora pod tlakom uz upotrebu pogodnog pogonskog plina, npr. diklordifluormetana, triklorfluormetana, diklortetrafluoretana, fluoriranog ugljikovodika poput 1,1,1,2-tetrafluoretana (HFA 134A [robni žig]) ili 1,1,1,2,3,3,3-heptafluorpropana (HFA 227EA [robni žig]), ugljičnog dioksida ili drugog pogodnog plina. U slučaju aerosola pod tlakom, jedinicu doziranja može se odrediti ventilom, kojim se unaša odmjerena količina. Spremnik, pumpa, sprej ili nebulizator pod tlakom mogu sadržavati otopinu ili suspenziju aktivnog spoja, npr. koristeći smjesu etanola i pogonskog plina kao otapalo, uz mogući dodatak maziva, npr. sorbitan-trioleat. Kapsule i ulošci (načinjeni, primjerice, od želatine) namijenjene upotrebi u inhalatoru ili insuflatoru može se tako formulirati da sadrže praškastu smjesu spoja prema ovom izumu i pogodne praškaste podloge, poput laktoze ili škroba.
Aerosolne ili formulacije sa suhim prahom po mogućnosti se tako podesi da svaka odmjerena doza ili "dašak" sadrži 1-50 mg spoja prema ovom izumu za unos u pacijenta. Ukupna dnevna doza s aerosolom bit će u rasponu od 1-50 mg, što se može primijeniti u jednoj dozi ili, uobičajenije, u podijeljenim dozama tijekom dana.
Spojeve prema ovom izumu također se može formulirati za unos raspršivačem. Formulacije za raspršivače mogu sadržavati sljedeće sastojke: solubilizatori, emulgatori ili suspendirajuća sredstva: vodu, etanol, glicerol, propilen-glikol, niskomolekulski polietilen-glikole, natrijev klorid, fluorirane ugljikovodike, polietilen-glikolne etere, sorbitan-trioleat, te oleinsku kiselinu.
Alternativno se spojeve prema ovom izumu može primijeniti u obliku supozitorija ili pesara, ili ih se može primijeniti topikalno u obliku gela, hidrogela, losiona, otopine, kreme, masti ili posipa. Spojeve prema ovom izumu također se može primijeniti i dermalno ili transdermalno, primjerice uz upotrebu flastera. Također ih se može primijeniti okularno, pulmonalno ili rektalno.
Prilikom očne upotrebe, spojeve se može formulirati kao mikronizirane suspenzije u izotoničnoj, sterilnoj fiziološkoj otopini, podešenog pH, ili, po mogućnosti, kao otopine u izotoničnoj, sterilnoj fiziološkoj otopini, podešenog pH, izborno u kombinaciji s konzervansom, poput benzilalkonijevog klorida. Alternativno ih se može formulirati u mast, poput vazelina.
Prilikom topikalne primjene na kožu, spojeve prema ovom izumu može se formulirati kao pogodnu mast, koja sadrži aktivni spoj suspendiran ili otopljen u, primjerice, smjesi s jedinim ili više od sljedećeg: mineralnim uljem, tekućim vazelinom, bijelim vazelinom, propilen-glikolom, polioksietilen-polioksipropilenskim spojem, emulgatorima voskom i vodom. Alternativno ih se može formulirati kao pogodni losion ili kremu, suspendirane ili otopljene u, primjerice, smjesi s jednim ili više od sljedećeg: mineralnim uljem, sorbitan-monostearatom, polietilen-glikolom, tekućim parafinom, polisorbatom 60, cetilnim esterima, voskom, cetearil-alkoholom, 2-oktildodekanolom, benzil-alkoholom i vodom.
Spojeve prema ovom izumu također se može upotrijebiti u kombinaciji s ciklodekstrinom. Za ciklodekstrine se zna da tvore inkluzijske i neinkluzijske komplekse s molekulama lijeka. Tvorba kompleksa lijek-ciklodekstrin može modificirati topivost, brzinu otapanja, biodostupnost i/ili stabilnost molekule lijeka. Kompleksi lijek-ciklodekstrin općenito su korisni za većinu oblika doziranja i načine primjene. Kao alternativa izravnom kompleksiranju s lijekom ciklodekstrin se može upotrijebiti kao pomoćni aditiv, npr. kao podloga, razrjeđivač ili solubilizator. Najčešće se upotrebljava α-, β- i �-ciklodekstrine, a pogodni primjeri opisani su u dokumentima WO-A-91/11172, WO-A-94/02518 i WO-A-98/55148.
Prilikom oralne ili parenteralne primjene na ljudskim pacijentima dnevne razine doze spojeva formule (I), i njihovih farmaceutski prihvatljivih soli, su 0,01-30 mg/kg (u jednoj ili podijeljenim dozama), po mogućnosti u rasponu od 0,01-5 mg/kg. Tako će tablete sadržavati 1 mg do 0,4 g spoja za primjenu jednom ili dva ili više istodobno, po potrebi. U svakom slučaju, liječnik će odrediti stvarnu dozu, najpogodniju za bilo kojeg pojedinog pacijenta, što ovisi o dobi, težini i odgovoru pojedinog pacijenta. Gore navedene doze su, naravno samo primjeri prosječnog slučaja, no mogući su slučajevi gdje su nužne više ili niže doze, što također ulazi u opseg zaštite ovog izuma.
Poželjna je oralna primjena.
Prilikom upotrebe u veterini, spoj prema ovom izumu se primjenjuje kao pogodna prihvatljiva formulacija, u skladu s normalnom veterinarskom praksom, gdje veterinar određuje režim doziranja i način primjene najprikladniji za pojedinu životinju.
Tako, prema daljnjem aspektu, ovaj izum osigurava farmaceutsku formulacija koja sadrži spoj prema ovom izumu i farmaceutski prihvatljiv adjuvans, razrjeđivač ili podlogu.
Gore navedene kombinacije također se može pogodno prezentirati za upotrebu u obliku farmaceutske formulacije, te stoga farmaceutske formulacije koje sadrže kombinaciju kao što je definirano gore, zajedno s farmaceutski prihvatljivim adjuvansom, razrjeđivačem ili podlogom, čine sljedeći aspekt ovog izuma. Pojedinačne komponente takvih kombinacija može se primijeniti bilo uzastopno ili istodobno, u odvojenim ili kombiniranim farmaceutskim formulacijama.
Kada se spoj prema ovom izumu upotrebljava u kombinaciji s drugim terapijskim sredstvom, doza svakog spoja može biti različita od one kada se spoj upotrebljava sam. Stručnjaci u ovom području tehnike će lako shvatiti koje su to odgovarajuće doze.
Ovaj izum ilustriraju sljedeći neograničujući primjeri, u kojima su moguće sljedeće kratice i definicije:
APCI Kemijska ionizacija pod atmosferskim tlakom
Arbacel® filtarsko sredstvo
br širok
BOC tert-butoksikarbonil
CDI karbonildiimidazol
δ kemijski pomak
d dublet
Δ grijanje
DCCI dicikloheksilkarbodiimid
DCM diklormetan
DMF N,N-dimetilformamid
DMSO dimetil-sulfoksid
ES+ elektrosprej-ionizacija, pozitivno skeniranje
ES– elektrosprej-ionizacija, negativno skeniranje
h sati
HOAT 1-hidroksi-7-azabenzotriazol
HOBT 1-hidroksibenzotriazol
HPLC visokotlačna tekućinska kromatografija
m/z signal spektra masa
min minuta
MS spektar masa
NMM N-metilmorfolin
NMR nuklearna magnetska rezonanca
q kvartet
s singlet
t triplet
TBTU 2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluronijev tetrafluoroborat
Tf trifluormetansulfonil
TFA trifluoroctena kiselina
THF tetrahidrofuran
TLC tankoslojna kromatografija
TS+ termosprej-ionizacija, pozitivno skeniranje
WSCDI 1-(3-dimetilaminopropil)-3-etilkarbodiimid-hidroklorid
Priprave i Primjeri koji slijede ilustriraju ovaj izum, no ne ograničuju ga ni na koji način. Sve temperature su u °C. Flash-kromatografija na stupcu provedena je na Merck silikagelu 60 (9385). Ekstrakcijska kromatografija u čvrstoj fazi (SPE) provedena je na Varian Mega Bond Elut (Si) ulošcima (Anachem), u vakuumu od 2 kPa (15 mmHg). Tankoslojna kromatografija (TLC) provedena je na Merck silikagel 60 pločama (5729). Tališta su određena uređajem Gallenkamp MPD350 i nekorigirana su. NMR je proveden na spektrometrima Varian-Unity Inova 400 MHz NMR ili Varian Mercury 400 MHz NMR. Spektrometrija masa provedena je spektrometrima masa koristeći jednokvadrupolni elektrosprej Finnigan Navigator ili Finnigan aQa APCI.
Priprava 1
tert-butil-(3R)-1-(trifluoracetil)pirolidin-3-ilkarbamat
[image]
(3R)-3-(tert-butoksikarbonilamino)pirolidin (3,0 g, 16,1 mmol - dostupan na tržištu od strane firme Fluorchem) i piridin (3,87 ml, 48,3 mmol) otopi se u diklormetanu (55 ml), a reakcijsku smjesu miješa 1 sat u atmosferi dušika na 0°C. Otopinu anhidrida trifluoroctene kiseline (2,74 ml, 32,2 mmol) u diklormetanu (5 ml) ukapava se 10 minuta u reakcijsku smjesu. Reakcijsku smjesu ostavi se da se zagrije do sobne temperature, te miješa 2 sata. Reakcijsku smjesu razrijedi se diklormetanom (100 ml), te ispere zasićenom otopinom natrijevog hidrogenkarbonata, vodom, te slanom vodom. Organski sloj se odvoji, osuši preko magnezijevog sulfata, te koncentrira u vakuumu. Sirovi produkt azeotropira se toluenom (2 × 30 ml) kako bi se dobilo naslovni produkt.
1H-NMR (DMSO-d6, 400 MHz): 1,40 (s, 9H), 1,82 (dd, 1H), 2,08 (dd, 1H), 3,33 (m, 1H), 3,46 (m, 1H), 3,59-3,77 (br m, 2H), 4,06 (m, 1H), 7,22 (m, 1H).
MS: ES+ m/z 281 [MH]+.
Priprava 2
(3R)-1-(trifluoracetil)pirolidin-3-amin-hidroklorid
[image]
Amin iz Priprave 1 (4,59 g, 16,1 mmol) zaštićen s Boc otopi se u diklormetanu (100 ml), a reakcijsku smjesu miješa 1 sat na 0°C. Zatim se kroz otopinu 10 minuta propuhuje plinoviti klorovodik, a reakcijsku smjesu ostavi da se zagrije do sobne temperature. Zatim se kroz otopinu 15 odnosno 10 minuta propuhuje plinoviti klorovodik, te plinoviti dušik, a reakcijsku smjesu koncentrira u vakuumu kako bi se dobilo naslovni produkt.
1H-NMR (CDCl3, 400 MHz): 1,27 (m, 2H), 1,65 (m, 1H), 1,81 (m, 1H), 2,10 (m, 2H), 3,32 (m, 2H), 3,61 (m, 1H).
MS: ES+ m/z 183 [MH]+.
Priprava 3
tert-butil-(3S)-3-(izobutilamino)pirolidin-1-karboksilat
[image]
tert-butilni ester (3S)-3-aminopirolidin-1-karboksilne kiseline (3 g, 16,1 mmol) doda se u otopinu izobutiraldehida (1,61 ml, 17,7 mmol) i 10 % Pd/C (360 mg) u etanolu (60 ml), a reakcijsku smjesu ostavi 18 sati pod tlakom od približno 415 kPa (približno 60 psi) plinovitog vodika. Reakcijsku smjesu filtira se kroz Arbocel®, uz pomno ispiranje etil-acetatom. Filtrat se koncentrira u vakuumu, a sirovi produkt pročisti kromatografijom na stupcu silikagela, uz eluiranje 1:1 sustavom etil-acetat/pentan kako bi se dobilo naslovni produkt, 2,8 g, (73 %).
1H-NMR (CDCl3, 400 MHz): 0,92 (d, 6H), 1,44 (s, 9H), 1,63 (m, 2H), 2,00 (m, 1H), 2,39 (m, 2H), 3,02 (m, 1H), 3,25 (m, 2H), 3,48 (m, 2H), 3,60 (m, 1H).
MS: APCI+ 243 [MH]+.
Priprava 4
(3S)-N-butil-1-(trifluoracetil)pirolidin-3-amin
[image]
Trietilamin (1,9 ml, 13,72 mmol) i butanal (1,3 ml, 14,41 mmol) doda se u otopinu (S)-1-(trifluoracetil)pirolidin-3-ilamina (3,0 g, 13,72 mmol) (J. Med. Chem., 39 (14), str. 2771, br. 6, (1996.)) u etanolu (60 ml). Reakcijsku smjesu obradi se s 10 % Pd/C (300 mg), te stavi pod tlak od približno 415 kPa (približno 60 psi) vodika, na sobnoj temperaturi, u trajanju od 18 sati. Reakcijsku smjesu filtira se kroz Arbocel®, uz ispiranje etil-acetatom. Filtrat se ispere zasićenom otopinom natrijevog hidrogenkarbonata, osuši preko magnezijevog sulfata, te koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje sustavom etil-acetat/pentan/trietilamin, 25:75:0 do 100:0:0 do 99:0:1, kako bi se dobilo naslovni produkt.
1H-NMR (CDCl3, 400 MHz): 1,01 (t, 3H), 1,38 (m, 2H), 1,47 (m, 2H), 1,86-2,09 (m, 2H), 2,62 (m, 2H), 3,38-3,87 (br m, 6H).
MS: APCI+ m/z 239 [MH]+.
Priprava 5
(3S)-N-izobutil-1-(trifluoracetil)pirolidin-3-amin
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 4, iz izobutiraldehida.
1H-NMR (CDCl3, 400 MHz): 0,91 (t, 6H), 1,26 (d, 2H), 1,47 (m, 2H), 1,72 (m, 1H), 2,42 (m, 2H), 3,39 (m, 2H), 3,77 (m, 1H), 4,09 (m, 1H).
MS: APCI+ m/z 239 [MH]+.
Priprava 6
(3S)-1-benzil-N-(2-naftilmetil)pirolidin-3-amin
[image]
Otopinu 2-naftaldehida (2,0 g, 12,8 mmol) i (3S)-1-benzil-3-aminopirolidina (2,37 g, 13,4 mmol) u metanolu (30 ml) miješa se 6 sati u atmosferi dušika, na sobnoj temperaturi. Doda se natrijev borohidrid (969 mg, 25,6 mmol), a reakcijsku smjesu ostavi 18 sati na sobnoj temperaturi. Reakcijsku smjesu razrijedi se vodom, te ekstrahira u etil-acetat (× 3), a organske faze pomiješa, osuši preko magnezijevog sulfata, te koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje sustavom diklormetan/metanol, 100:0 do 97:3, kako bi se dobilo naslovni produkt, 4,01 g.
1H-NMR (CDCl3, 400 MHz): 1,62 (m, 1H), 2,19 (m, 1H), 2,48 (m, 2H), 2,80 (m, 2H), 3,42 (m, 1H), 3,63 (s, 2H), 3,92 (m, 2H), 7,26 (m, 5H), 7,44 (m, 3H), 7,78 (m, 4H).
MS: APCI+ m/z 317 [MH]+.
Priprava 7
(3R)-1-benzil-N-(2-naftilmetil)pirolidin-3-amin
[image]
Naslovni spoj dobije se postupkom sličnim onom opisanom u Pripravi 6, iz (3R)-1-benzil-3-aminopirolidina.
1H-NMR (CDCl3, 400 MHz): 1,65 (m, 1H), 2,18 (m, 1H), 2,51 (m, 2H), 2,78 (m, 2H), 3,41 (m, 1H), 3,63 (m, 2H), 3,94 (s, 2H), 7,22 (m, 1H), 7,28 (m, 4H), 7,43 (m, 3H), 7,79 (m, 4H).
MS: APCI+ m/z 317 [MH]+.
Priprava 8
(3R)-N-(3,4-diklorbenzil)-1-(trifluoracetil)pirolidin-3-amin
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 6, iz amina iz Priprave 2 i 3,4-diklorbenzaldehida.
1H-NMR (DMSO-d6, 400 MHz): 1,88 (m, 2H), 2,63 (m, 1H), 3,36-3,78 (m, 7H), 7,32 (m, 1H), 7,59 (m, 2H).
MS: APCI+ m/z 341 [MH]+.
Priprava 9
(3R)-N-(2,3-diklorbenzil)-1-(trifluoracetil)pirolidin-3-amin
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 6, iz amina iz Priprave 2 i 2,3-diklorbenzaldehida.
1H-NMR (DMSO-d6, 400 MHz): 1,92 (m, 2H), 3,29-3,74 (m, 7H), 3,83 (m, 1H), 7,27 (m, 1H), 7,51 (m, 2H).
MS: APCI+ m/z 341 [MH]+.
Priprave 10-12
[image]
Odgovarajuću karboksilnu kiselinu, RCO2H (1 mmol), otopi se u diklormetanu (5 ml), ohladi u ledenoj kupelji, a ohlađenu otopinu obradi oksalil-kloridom (0,248 ml, 2,5 mmol) i 1 kapi N,N-dimetilformamida. Led se ukloni, a reakcijsku smjesu ostavi da se zagrije do sobne temperature, te miješa 2 sata na sobnoj temperaturi. Reakcijsku smjesu koncentrira se u vakuumu, a produkt doda u otopinu trietilamina (0,229 ml, 1,64 mmol) i amina iz Priprave 3 (200 mg, 0,83 mmol) u dioksanu (10 ml). Reakcijsku smjesu grije se 45 minuta do 70°C, te ostavi da se ohladi do sobne temperature. Reakcijsku smjesu koncentrira se u vakuumu, a produkt preuzme u diklormetan, te ispere 10 % otopinom limunske kiseline i 2 M otopinom natrijevog hidroksida. Organski sloj se odvoji, te koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje sustavom diklormetan/metanol, 100:0 do 98:2, kako bi se dobilo naslovne produkte.
[image]
Priprava 13
tert-butil-(3S)-3-[(2,3-diklorbenzoil)(izobutil)amino]pirolidin-1-karboksilat
[image]
Amin iz Priprave 3 (200 mg, 0,826 mmol) doda se u otopinu trietilamina (0,229 ml, 1,652 mmol) u dioksanu (5 ml), a reakcijsku smjesu obradi 2,3-diklorbenzoil-kloridom (207 mg, 0,99 mmol). Reakcijsku smjesu grije se do 70°C, te miješa 90 minuta. Reakcijsku smjesu koncentrira se u vakuumu, a produkt preuzme u diklormetan, te ispere 2 M natrijevim hidroksidom i 10 % otopinom limunske kiseline. Organske faze se odvoji, te koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje diklormetanom kako bi se dobilo naslovni produkt, 278 mg, (81 %).
MS: APCI+ m/z 315 [MH]+.
Priprave 14-17
[image]
Sljedeće spojeve s općom formulom gore dobije se postupkom sličnim onom opisanom u Pripravi 13, iz amina iz Priprave 3 i odgovarajućeg kiselinskog klorida.
[image]
Priprava 18
N-[(3S)-1-benzilpirolidin-3-il]-N-(2-naftilmetil)benzamid
[image]
Benzoil-klorid (0,12 ml, 1,043 mmol) doda se u otopinu amina iz Priprave 6 (300 mg, 0,948 mmol) i trietilamina (0,26 µl, 1,896 mmol) u diklormetanu (5 ml), a reakcijsku smjesu ostavi 18 sati u atmosferi dušika, na sobnoj temperaturi. Reakcijsku smjesu ispere se vodom, te slanom vodom, osuši preko magnezijevog sulfata, te koncentrira u vakuumu kako bi se dobilo naslovni produkt, 380 mg.
1H-NMR (CDCl3, 400 MHz): 1,83-2,62 (br m, 4H), 2,84 (m, 2H), 3,62 (m, 2H) 4,56 (m, 1H), 5,05 (m, 2H), 7,24 (m, 4H), 7,31-7,60 (m, 9H), 7,78 (m, 4H).
MS: ES+ m/z 421 [MH]+.
Priprava 19
N-[(3R)-1-benzilpirolidin-3-il]-N-(2-naftilmetil)benzamid
[image]
Naslovni spoj dobije se postupkom sličnim onom opisanom u Pripravi 18, iz amina iz Priprave 7.
1H-NMR (CDCl3, 400 MHz): 1,94-2,58 (br m, 6H), 2,86 (m, 2H), 3,62 (m, 1H), 5,08 (m, 2H), 7,23 (m, 4H), 7,34-7,60 (m, 9H), 7,79 (m, 4H).
MS: APCI+ m/z 421 [MH]+.
Priprava 20
N-butil-N-[(3S)-1-(trifluoracetil)pirolidin-3-il]-1-naftamid
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 18, iz amina iz Priprave 4 i 1-naftoil-klorida.
1H-NMR (CDCl3, 400 MHz): 0,61 (m, 2H), 0,98 (m, 3H), 1,32-1,60 (br m, 4H), 3,06 (m, 2H), 3,27-3,76 (m, 4H), 5,28 (m, 1H), 7,39 (m, 1H), 7,45 (m, 3H), 7,72 (m, 1H), 7,89 (m, 2H).
MS: APCI+ m/z 393 [MH]+.
Priprava 21
N-izobutil-N-[(3S)-1-(trifluoracetil)pirolidin-3-il]-2-naftamid
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 18, iz 1-naftoil-klorida i amina iz Priprave 3.
1H-NMR (CDCl3, 400 MHz): 0,84 (m, 8H), 2,00 (m, 1H), 3,25 (m, 2H), 3,93 (m, 2H),4,38 (br m, 1H), 5,31 (m, 2H), 7,24 (m, 2H), 7,38-7,62 (m, 5H).
MS: APCI+ m/z 393 [MH]+.
Priprava 22
4-klor-N-(3,4-diklorbenzil)-N-[(3R)-1-(trifluoracetil)pirolidin-3-il]benzamid
[image]
Amin iz Priprave 8 (180 mg, 0,58 mmol) otopi se u diklormetanu (3 ml), a reakcijsku smjesu obradi trietilaminom (0,16 ml, 1,16 mmol). Reakcijsku smjesu ohladi se do 0°C, te se ukapa 4-klorbenzoil-klorid (0,08 ml, 0,63 mmol). Reakcijsku smjesu miješa se 18 sati u atmosferi dušika. Reakcijsku smjesu razrijedi se s još diklormetana, te ispere vodom. Organski sloj osuši se preko magnezijevog sulfata, te koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje sustavom diklormetan/metanol, 100:0 do 95:5, kako bi se dobilo naslovni produkt.
1H-NMR (DMSO-d6, 400 MHz): 2,02 (m, 2H), 3,37-3,72 (m, 4H), 4,61 (m, 2H), 5,68 (m, 1H), 7,22-7,59 (m, 7H).
MS: APCI+ m/z 479 [MH]+.
Priprava 23
4-klor-N-(2,3-diklorbenzil)-N-[(3R)-1-(trifluoracetil)pirolidin-3-il]benzamid
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u Pripravi 22, iz amina iz Priprave 9.
1H-NMR (DMSO-d6, 400 MHz): 2,04 (m, 2H), 3,37-3,76 (m, 4H), 4,46-4,76 (m, 3H), 7,22-7,58 (br m, 7H).
MS: APCI+ m/z 479 [MH]+.
Primjer 1
2,3-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamid-citrat
[image]
Produkt iz Priprave 13 (10,55 g, 25,4 mmol) zaštićen s Boc otopi se u diklormetanu (20 ml) u atmosferi dušika, a reakcijsku smjesu obradi trifluoroctenom kiselinom (20 ml, 260,5 mmol). Reakcijsku smjesu se zatim miješa 4,5 sati na sobnoj temperaturi. Reakcijsku smjesu koncentrira se u vakuumu, a ostatak preuzme u diklormetan (200 ml), te ispere 1 M otopinom natrijevog hidroksida (100 ml). Organsku fazu se odvoji, osuši preko magnezijevog sulfata, te koncentrira u vakuumu. Ostatak se azeotropira etil-acetatom (10 ×), te osuši u vakuumu kako bi se dobilo slobodnu bazu naslovnog produkta u obliku bezbojnog ulja, 7,281 g (91 %). Dio ovog produkta (3,327 g, 10,56 mmol) obradi se otopinom limunske kiseline (2,028 g, 10,56 mmol) u metanolu, koncentrira u vakuumu, te osuši u visokom vakuumu kako bi se dobilo naslovni produkt u obliku ružičaste krutine, 4,71 g.
1H-NMR (MeOD, 400 MHz): 0,80 (t, 6H), 1,89 (m, 2H), 2,11 (br m, 2H), 2,53 (m, 2H), 2,68-2,91 (m, 4H), 3,59 (m, 1H), 3,82 (m, 2H), 4,37 (m, 1H), 7,40 (m, 2H), 7,61 (m, 1H).
MS: APCI+ m/z 315 [MH]+.
Primjer 2
2,4-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamid-hidroklorid
[image]
Produkt iz Priprave 14 (157 mg, 0,561 mmol) zaštićen s BOC doda se u otopinu 4 M klorovodične kiseline u dioksanu (1 ml) u diklormetanu (5 ml), a reakcijsku smjesu miješa 18 sati na sobnoj temperaturi. Reakcijsku smjesu koncentrira se u vakuumu, a produkt azeotropira diklormetanom i eterom, te triturira eterom kako bi se dobilo naslovni produkt, 103,3 mg, (87 %).
1H-NMR (MeOD, 400 MHz): 0,80 (m, 6H), 1,89 (m, 1H), 2,51 (m, 2H), 2,90 (m, 1H), 3,20 (m, 2H), 3,52 (m, 1H), 3,78 (m, 2H), 4,30 (m, 1H), 7,40 (m, 1H), 7,46 (d, 1H), 7,58 (s,1H).
MS: APCI+ m/z 315 [MH]+.
Primjeri 3-8
[image]
Sljedeće spojeve s općom formulom gore dobije se postupkom sličnim onom opisanom u primjeru 2 kako bi se dobilo hidrokloridne soli prikazanih spojeva.
[image]
Primjer 9
N-(2-naftilmetil)-N-[(3S)-pirolidin-3-il]benzamid-hidroklorid
[image]
Otopinu benzilom zaštićenog produkta iz Priprave 18 (370 mg, 88 mmol), amonijevog formijata (555 mg, 8,798 mmol) i 10 % Pd/C (40 mg) u etanolu (5 ml) refluksira se 6 sati u atmosferi dušika. Reakcijsku smjesu filtira se kroz Arbocel®, uz ispiranje etanolom, a filtrat koncentrira u vakuumu. Sirovi produkt pročisti se kromatografijom na stupcu silikagela, uz eluiranje sustavom diklormetan/metanol/0,88 amonijak, 100:0:0 do 90:10:1. Produkt se otopi u minimalnoj količini otopine eterske otopine klorovodične kiseline u diklormetanu, te koncentrira u vakuumu. Produkt se triturira eterom (× 3), te osuši u vakuumu kako bi se dobilo naslovni produkt, 120 mg, (36 %).
1H-NMR (DMSO-d6, 400 MHz): 2,06 (m, 2H), 2,98 (br s, 1H), 3,79 (m, 3H), 4,43 (m, 1H), 4,71 (m, 2H), 7,25-7,59 (m, 9H), 7,78 (m, 1H), 7,93 (m, 3H).
MS: APCI+ m/z 331 [MH]+.
Primjer 10
N-(2-naftilmetil)-N-[(3R)-pirolidin-3-il]benzamid-hidroklorid
[image]
Naslovni spoj dobije se postupkom sličnim onom opisanom u primjeru 9, iz benzilom zaštićenog produkta iz Priprave 19 kao polaznog materijala. Prikupi se 160 mg, (47 %) naslovnog produkta.
1H-NMR (DMSO-d6, 400 MHz): 2,11 (m, 2H), 3,00 (m, 1H), 3,35 (br m, 3H), 4,44 (m, 1H), 4,78 (m, 2H), 7,28-7,56 (br m, 9H), 7,81 (m, 1H), 7,96 (m, 3H).
MS: ES+ m/z 331 [MH]+.
Primjer 11
N-izobutil-N-[(3S)-pirolidin-3-il]-2-naftamid-hidroklorid
[image]
Kalijev karbonat (92 mg, 0,66 mmol) doda se u otopinu trifluoracetatom zaštićenog produkta iz Priprave 21 (130 mg, 0,33 mmol) u vodi (0,5 ml) i metanolu (5 ml), a reakcijsku smjesu miješa 18 sati na sobnoj temperaturi. Reakcijsku smjesu koncentrira se u vakuumu, a sirovi produkt otopi u 1:1 smjesi 10 % otopina kalijevog karbonata/etil-acetat (25 ml). Organsku fazu osuši se preko magnezijevog sulfata, te koncentrira u vakuumu. Sirovi produkt otopi se u etil-acetatu, obradi 1 M klorovodičnom kiselinom u eteru, te miješa 1 sat na sobnoj temperaturi. Reakcijsku smjesu koncentrira se u vakuumu kako bi se dobilo naslovni produkt.
1H-NMR (MeOD, 400 MHz): 0,79 (d, 6H), 1,93 (m, 1H), 2,56 (m, 2H), 3,25 (m, 3H), 3,55 (t, 1H), 3,80 (m, 2H), 4,36 (m, 1H), 7,48 (d, 1H), 7,59 (m, 2H), 7,96 (m, 4H).
MS: ES+ m/z 298 [MH]+.
Primjer 12
N-butil-N-[(3S)-pirolidin-3-il]-1-naftamid-hidroklorid
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Ovaj spoj dobije se postupkom sličnim onom opisanom u primjeru 11, iz trifluoracetatom zaštićenog produkta iz Priprave 20 kao polaznog materijala.
1H-NMR (MeOD, 400 MHz): 0,62 (m, 3H), 1,04 (m, 2H), 1,72 (m, 2H), 2,65 (m, 2H), 3,07 (m, 2H), 3,21 (m, 1H), 3,59 (m, 1H), 3,87 (m, 2H), 4,42 (m, 1H), 7,30 (s, m, 1H), 7,57 (m, 3H), 7,78 (m, 1H), 8,00 (m, 2H).
MS: ES+ m/z 297 [MH]+.
Primjer 13
4-klor-N-(3,4-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamid-hidroklorid
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u primjeru 11, iz trifluoracetatom zaštićenog produkta iz Priprave 22 kao polaznog materijala. Prikupi se 75 mg, (47 %) naslovnog produkta.
1H-NMR (DMSO-d6, 400 MHz): 1,58 (m, 1H), 1,83 (m, 1H), 2,60 (m, 1H), 2,81 (m, 2H), 3,42 (m, 2H), 4,61 (m, 2H), 7,25 (m, 1H), 7,39-7,59 (m, 7H).
Primjer 14
4-klor-N-(2,3-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamid-hidroklorid
[image]
Ovaj spoj dobije se postupkom sličnim onom opisanom u primjeru 11, iz trifluoracetatom zaštićenog produkta iz Priprave 23 kao polaznog materijala. Prikupi se 90 mg, (52 %) naslovnog produkta.
1H-NMR (DMSO-d6, 400 MHz): 1,62 (m, 1H), 1,88 (m, 1H), 2,61 (m, 2H), 2,85 (m, 2H), 4,28 (m, 1H), 4,59 (t, 2H), 7,24 (m, 1H), 7,36 (m, 1H), 7,42-7,58 (m, 6H).
MS: ES+ m/z 385 [MH]+.
Primjer 15
2,4-diklor-5-fluor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamid-hidroklorid
[image]
tert-butil-(3S)-3-[(2,4-diklor-5-fluorbenzoil)(izobutil)amino]pirolidin-1-karboksilat dobije se postupkom sličnim onom opisanom u Pripravi 13, iz amina iz Priprave 3 i 2,4-diklor-5-fluorobenzoil-klorida, kako bi se dobilo željeni produkt, 340 mg.
MS: ES+ m/z 455 [MNa]+.
2,4-diklor-5-fluor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamid-hidroklorid dobije se iz prethodnog spoja postupkom sličnim onom opisanom u primjeru 2, kako bi se dobilo naslovni produkt u obliku prljavobijele krutine, 100 mg.
MS: APCI+ m/z 333 [MH]+.
Opaženo: C, 47,22; H, 5,87; N, 7,08 %;
izračunato za C15H19C12FN2O·HCl·0,7H2O: C, 47,17; H, 5,64; N, 7,33 %.
Primjer 16
NRI IC50 i SRI IC50 za spojeve iz Primjera 1-14 određeni su na sljedeći način. Rezultati su iznijeti niže, u Tablici 1.
Biološka aktivnost
Spojevi su ispitani na biološku aktivnost preko svoje sposobnosti da inhibiraju unos serotonina i/ili noradrenalina ljudskim transporterima serotonina i/ili noradrenalina, kao što slijedi.
Kultura stanica
Ljudske embrionalne stanice bubrega (HEK-293), stabilno transficirane s bilo ljudskim transporterom serotonina (hSERT), transporterom noradrenalina (hNET) ili transporterom dopamina (hDAT) uzgajane su uz standardne tehnike kulture stanica (stanice su rasle na 37°C, uz 5 % CO2, bilo u Dulbeccovom Modificiranom Eagleovom mediju (DMEM) za kulturu, uz dodatak 10 % dijaliziranog fetalnog telećeg seruma (FCS), 2 mM l-glutamina i 250 µg/ml geneticina (hSERT i hNET stanice), ili u DMEM mediju za kulturu, uz dodatak 5 % FCS, 5 % seruma novorođenog teleta, 2 mM l-glutamina i 2,5 mg/ml puromicina (hDAT stanice)). Prije ispitivanja stanice su prikupljene disocijacijom, pomoću otopine za disocijaciju stanica (Sigma), i centrifugiranjem, te resuspendirane u standardnom puferu za ispitivanje (vidjeti niže), uz gustoću vijabilnih stanica od 750.000 stanica po ml.
Određivanje potentnosti inhibitora
Svi ispitivani spojevi otopljeni su u 100 % DMSO-u u koncentraciji od 4 mM, te razrijeđeni u 1 % DMSO-u u vodi kako bi se dobilo odgovarajuće koncentracije za ispitivanje. Ispitivanja provedene su na pločama s 96 jažica s filtarskim dnom. Stanice koje eksprimiraju odgovarajući ljudski transporterski protein (75.000 stanica po jažici za ispitivanje) predinkubirane su 5 minuta na 25°C u standardnom puferu za ispitivanje koji sadrži bilo ispitivani spoj, standardni inhibitor (pozitivna kontrola) ili vehikulumski spoj (DMSO u vodi; konačna koncentracija DMSO-a bila je 0,1 % u svakoj jažici za ispitivanje). Reakcije su započete dodavanjem bilo 3H-serotoninskih, 3H-noradrenalinskih ili 3H-dopaminskih supstrata. Sve reakcije provedene su na 25 °C, u tresućem inkubatoru. Trajanja inkubacije bila su 5 minuta za ispitivanja na hSERT i hDAT, te 15 minuta za ispitivanje na hNET. Reakcije su prekinute dodavanjem ledeno hladnog pufera za ispiranje (vidjeti niže), te filtracijom smjese za ispitivanje pomoću višestrukog vakuumskog nosača, te brzim ispiranjem ledeno hladnim puferom za ispiranje. Zatim je određena količina 3H-supstrata ugrađenog u stanice: filtrirane, te isprane ploče za ispitivanje sušene su 1 sat na 45°C, dodana je scintilacijska tekućina, a radioaktivnost je izmjerena scintilacijskim brojačem. Potentnost ispitivanih spojeva određena je kao vrijednosti IC50 (koncentracija ispitivanog spoja potrebna da 50 % inhibira specifični unos radioaktivno obilježenog supstrata u stanice u odnosu na maksimalni (samo vehikulumski spoj) i minimalni (potpuna inhibicija standardnim inhibitorom) odgovor).
Sastav standardnog pufera za ispitivanje:
Tris(hidroksimetil)aminometan-hidroklorid (26 mM)
NaCl (124 mM)
KCl (4,5 mM)
KH2PO4 (1,2 mM)
MgCl2·6H2O (1,3 mM)
Askorbinska kiselina (1,136 mM)
Glukoza (5,55 mM)
pH 7,40
CaCl2 (2,8 mM)
Pargilin (100 µM)
Napomena: pH pufera podešen je s 1 M NaOH na 7,40 prije dodavanja CaCl2 i pargilina.
Sastav pufera za ispiranje:
Tris(hidroksimetil)metilamin (26 mM)
NaCl (124 mM)
KCl (4,5 mM)
KH2PO4 (1,2 mM)
MgCl2·6H2O (1,3 mM)
Askorbinska kiselina (1,136 mM)
pH 7,40 na 4 °C s 6 M HCl.
Sažeti prikaz parametara ispitivanja
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Tablica 1
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Pogodnosti radi, spojevi prema ovom izumu izdvojeni su nakon dorade u obliku slobodnih baza, no konvencionalnim načinima farmaceutski prihvatljive kisele adicijske može se dobiti i soli spojeva prema ovom izumu. Solvate (npr. hidrati) spojeva prema ovom izumu može se dobiti postupkom dorade u jednom od gore navedenih koraka postupka.
Kada se spojeve dobiva na način opisan u prethodnom Primjeru, stručnjak će shvatiti da postoji mogućnost da bude nužno ili poželjno upotrijebiti drugačije uvjete dorade ili pročišćavanja.
Claims (23)
1. Spoj Formule (I)
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i njegovi farmaceutski i/ili veterinarski prihvatljivi derivati,
naznačen time što
R1 je H;
R2 je aril ili heteroaril, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8akila, C1-8alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-6alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila;
R3 je C1-6alkil, C3-8cikloalkil, C3-8cikloalkil-C1-6alkil, aril, het, aril-C1-4alkil ili het-C1-4alkil, gdje cikloalkilne, arilne ili het skupine su izborno supstituirane s najmanje 1 supstituentom, kojeg se neovisno bira između C1-6 alkila, C1-6alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila;
X je S ili O:
Y je H, C1-6alkil, aril, het, aril-C1-4alkil ili het-C1-4alkil;
n je 1 ili 2, uz uvjet da kada n je 1, tada m je 0 ili 1, a kada n je 2, tada m je 0, gdje ako m je 0, * predstavlja kiralni centar;
aril je fenil, naftil, antracil ili fenantril;
heteroaril je aromatski 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom, izborno kondenziran s arilnom skupinom;
het je aromatski ili nearomatski 4-, 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom, izborno kondenziran s 5- ili 6- članom karbocikličkom skupinom, ili drugi 4-, 5- ili 6- člani heterocikl, koji sadrži najmanje 1 N, O ili S heteroatom;
uz uvjet da:
spoj nije N-etil-N-piperidin-4-ilbenzamid ili N-etil-N-piperidin-4-ilbenzamid; i
kada R2 je
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ili
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,
tada R3 nije
[image]
,
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,
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,
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ili
[image]
.
2. Spoj prema patentnom zahtjevu 1, naznačen time što m je 0, a * predstavlja R- ili S-enantiomer.
3. Spoj prema patentnom zahtjevu 2, naznačen time što * predstavlja S-enantiomer.
4. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što R2 je fenil, naftil ili kinolinil, od kojih je svaki izborno supstituiran s najmanje 1 supstituentom, kojeg se neovisno bira između C1-8alkila, C1-8 alkoksi, OH, halogena, CF3, OCF3, SCF3, hidroksi-C1-6alkila, C1-4alkoksi-C1-6alkila i C1-4alkil-S-C1-4alkila.
5. Spoj prema patentnom zahtjevu 4, naznačen time što R2 je fenil ili naftil, od kojih je svaki izborno supstituiran s 1, 2 ili 3 supstituenta, koje se neovisno bira između halogena, OH, C1-4alkila i CF3.
6. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time što R3 je C1-6alkil, C3-8cikloalkil, C3-8cikloalkil-C1-4alkil ili aril-C1-4alkil.
7. Spoj prema patentnom zahtjevu 6, naznačen time što R3 je C1-6alkil, C3-6cikloalkil, C3-6cikloalkil-C1-2alkil, fenil-CH2- ili naftil-CH2-.
8. Spoj prema patentnom zahtjevu 1, naznačen time što
R1 je H;
R2 je fenil ili naftil, od kojih je svaki izborno supstituiran s 1, 2 ili 3 supstituenta, koje se neovisno bira između halogena, OH, C1-4alkila i CF3;
R3 je C1-6alkil, C3-6cikloalkil, C3-6cikloalkil-C1-3alkil, fenil-CH2- ili naftil-CH2-; i
m je 0.
9. Spoj prema patentnom zahtjevu 1, naznačen time što ga se bira između:
2,3-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
2,4-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
2-klor-3-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-fluor-2-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-metoksi-2-metil-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3-klor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
4-klor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3,4-diklor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
N-(2-naftilmetil)-N-[(3S)-pirolidin-3-il]benzamida;
N-(2-naftilmetil)-N-[(3R)-pirolidin-3-il]benzamida;
N-izobutil-N-[(3S)-pirolidin-3-il]-2-naftamida;
N-butil-N-[(3S)-pirolidin-3-il]-1-naftamida;
4-klor-N-(3,4-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamida;
N-pirolidin-3-il-N-(5,6,7,8-tetrahidronaftalen-1-ilmetil)benzamida;
N-(2-diklorbenzil)-N-pirolidin-3-ilbenzamida;
N-(3-klor-4-metilbenzil)-2-fluor-N-pirolidin-3-ilbenzamida;
butil(pirolidin-3-il)amida naftalen-2-karboksilne kiseline;
izobutil(pirolidin-3-il)amida naftalen-2-karboksilne kiseline;
(2,2-dimetilpropil)pirolidin-3-ilamida naftalen-2-karboksilne kiseline;
3-klor-N-izobutil-4-metil-N-pirolidin-3-ilbenzamida;
N-izobutil-2,3-dimetil-N-pirolidin-3-ilbenzamida;
3-klor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamida;
2-klor-4-fluor-N-izobutil-N-pirolidin-3-ilbenzamida;
2-klor-N-izobutil-N-pirolidin-3-ilbenzamida;
3-klor-2-fluor-N-izobutil-N-pirolidin-3-ilbenzamida;
3-klor-4-fluor-N-izobutil-N-pirolidin-3-ilbenzamida;
N-butil-2,4-diklor-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-ciklopentilmetil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(2-etilbutil)-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamida;
2,3,4-triklor-N-izobutil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(2-ciklopropiletil)-N-pirolidin-3-ilbenzamida;
izobutil(pirolidin-3-il)amida naftalen-1-karboksilne kiseline;
2,4-diklor-5-fluor-N-izobutil-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(2-dimetilpropil)-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamida;
3,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(1,2-dimetilpropil)-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(1,2-dimetilpropil)-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-cikloheksil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamida;
3,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamida;
sec-butilpirolidin-3-ilamida naftalen-1-karboksilne kiseline;
N-sec-butil-2,3-diklor-N-pirolidin-3-ilbenzamida;
N-sec-butil-2,4-diklor-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(1-etilpropil)-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(1-etilpropil)-N-pirolidin-3-ilbenzamida;
(1-etilpropil)pirolidin-3-ilamida naftalen-1-karboksilne kiseline;
2,3-diklor-N-ciklobutil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-ciklobutil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-ciklopentil-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-pirolidin-3-il-N-(1,2,2-trimetilpropil)benzamida;
N-tert-butil-2,3-diklor-N-pirolidin-3-ilbenzamida;
naftalen-1-karboksilna kiselina ciklopentil(pirolidin-3-il)amida;
2,3-diklor-N-fenil-N-pirolidin-3-ilbenzamida;
3,4-diklor-N-(2,2-dimetilpropil)-2-metil-N-pirolidin-3-ilbenzamida;
3-klor-N-izobutil-2-metil-N-pirolidin-3-ilbenzamida;
N-butil-2,3-diklor-N-pirolidin-3-ilbenzamida;
N-butil-3,4-diklor-N-pirolidin-3-ilbenzamida;
ciklobutilmetil(pirolidin-3-il)amida naftalen-2-karboksilne kiseline;
ciklobutilmetil(pirolidin-3-il)amida naftalen-1-karboksilne kiseline;
3,4-diklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamida;
4-klor-N-izobutil-2-metoksi-N-pirolidin-3-ilbenzamida;
4-klor-N-izobutil-3-metil-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-izobutil-3-metil-N-pirolidin-3-ilbenzamida;
(3-metilbutil)pirolidin-3-ilamida naftalen-1-karboksilne kiseline;
(2,2-dilmetilpropil)pirolidin-3-ilamida naftalen-1-karboksilne kiseline;
3,4-diklor-N-(3-metilbutil)-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(4-fluorfenil)-N-pirolidin-3-ilbenzamida;
2,4-diklor-N-(4-fluorfenil)-N-pirolidin-3-ilbenzamida;
(4-fluorfenil)pirolidin-3-ilamida naftalen-1-karboksilne kiseline;
N-butil-2,3,4-triklor-N-pirolidin-3-ilbenzamida;
2,3,4-triklor-N-ciklobutilmetil-N-pirolidin-3-ilbenzamida;
N-pirolidin-3-il-N-(3-trifluormetilbenzil)benzamida;
2,4-diklor-N-fenil-N-pirolidin-3-ilbenzamida;
3,4-diklor-N-fenil-N-pirolidin-3-ilbenzamida;
2,3,4-triklor-N-(2,2-dimetilpropil)-N-pirolidin-3-ilbenzamida;
fenil(pirolidin-3-il)amida naftalen-1-karboksilne kiseline;
2,3,4-triklor-N-(2-ciklopropiletil)-N-pirolidin-3-ilbenzamida;
2,3-diklor-N-(2-ciklopropiletil)-N-pirolidin-3-il-benzamida;
2-brom-4-klor-N-izobutil-N-pirolidin-3-ilbenzamida;
4-klor-2-etoksi-N-izobutil-N-pirolidin-3-ilbenzamida;
3-brom-4-klor-N-izobutil-N-pirolidin-3-ilbenzamida;
2,4-diklor-5-fluor-N-izobutil-N-[(3S)-pirolidin-3-il]benzamida;
3,4-diklor-N-izobutil-2-metil-N-pirolidin-3-ilbenzamida;
2,4-diklor-3-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,3-diklor-4-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,3-diklor-5-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,4,5-triklor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,5-diklor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,5-diklor-4-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,3,5-triklor-N-izobutil-N-[pirolidin-3-il]benzamida;
2,3-diklor-6-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
3,4-diklor-6-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
3,4-diklor-2-fluor-N-izobutil-N-[pirolidin-3-il]benzamida;
2-klor-3,6-difluor-N-izobutil-N-[pirolidin-3-il]benzamida; i
4-klor-N-(2,3-diklorbenzil)-N-[(3R)-pirolidin-3-il]benzamida,
ili njihovih farmaceutski i/ili veterinarski prihvatljivih derivata.
10. Spoj prema patentnom zahtjevu 9, naznačen time što je to 2,3-diklor-N-izobutil-N-[(3S)-pirolidin-3-il] benzamid, ili njegovi farmaceutski i/ili veterinarski prihvatljivi derivati.
11. Farmaceutski pripravak, naznačen time što sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 10 i farmaceutski prihvatljiv adjuvans, razrjeđivač ili podlogu.
12. Spoj prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time što je namijenjen upotrebi kao lijek.
13. Upotreba spoja prema bilo kojem od patentnih zahtjeva 1 do 10, naznačena time što je navedeni spoj namijenjen proizvodnji lijeka za liječenje poremećaja kod kojeg je implicirana regulacija funkcije monoaminskih transportera kod sisavaca.
14. Upotreba spoja prema bilo kojem od patentnih zahtjeva 1 do 10, naznačena time što je navedeni spoj namijenjen proizvodnji lijeka za liječenje poremećaja kod kojeg je implicirana regulacija serotonina ili noradrenalina kod sisavaca.
15. Upotreba prema patentnom zahtjevu 14, naznačena time što je tu implicirana regulacija serotonina i noradrenalina.
16. Upotreba spoja prema bilo kojem od patentnih zahtjeva 1 do 10, naznačena time što je navedeni spoj namijenjen proizvodnji lijeka za liječenje poremećaja mokraćnog sustava, depresije, boli, prijevremene ejakulacije, ADHD ili fibromialgije kod sisavaca.
17. Upotreba spoja prema patentnom zahtjevu 16, naznačena time što je navedeni spoj namijenjen liječenju inkontinencije mokraće, poput GSI ili USI, kod sisavaca.
18. Postupak liječenja poremećaja kod kojeg je implicirana regulacija funkcije monoaminskih transportera, naznačen time što se sastoji u primjeni terapijski djelotvorne količine spoja prema bilo kojem od patentnih zahtjeva 1 do 10 na pacijentu kojem je potrebno takvo liječenje.
19. Postupak liječenja poremećaja kod kojeg je implicirana regulacija serotonina ili noradrenalina, naznačen time što se sastoji u primjeni terapijski djelotvorne količine spoja prema bilo kojem od patentnih zahtjeva 1 do 10 na pacijentu kojem je potrebno takvo liječenje.
20. Postupak prema patentnom zahtjevu 19, naznačen time što je tu implicirana regulacija serotonina i noradrenalina.
21. Postupak liječenja poremećaja mokraćnog sustava, depresije, boli, prijevremene ejakulacije, ADHD ili fibromialgije, naznačen time što se sastoji u primjeni terapijski djelotvorne količine spoja prema bilo kojem od patentnih zahtjeva 1 do 10 na pacijentu kojem je potrebno takvo liječenje.
22. Postupak prema patentnom zahtjevu 21, naznačen time što poremećaj mokraćnog sustava je inkontinencija mokraće, poput GSI ili USI.
23. Postupak dobivanja spoja prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time što se sastoji u reakciji spoja formule (X):
[image]
gdje su R3, n i m definirani kao gore, a Y je R1 ili zaštitna skupina, s kiselinom ili acil-halogenidom, R2COX, gdje X je OH ili halogen, i uklanjanju zaštite ako je to nužno ili poželjno.
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GBGB0314048.0A GB0314048D0 (en) | 2003-06-17 | 2003-06-17 | Novel compounds |
US49312603P | 2003-08-06 | 2003-08-06 | |
PCT/IB2004/001943 WO2004110995A1 (en) | 2003-06-17 | 2004-06-07 | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
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HRP20050993A2 true HRP20050993A2 (en) | 2006-03-31 |
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HR20050993A HRP20050993A2 (en) | 2003-06-17 | 2005-12-14 | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors |
HR20080339T HRP20080339T3 (hr) | 2003-06-17 | 2008-07-09 | Derivati n-pirolidin-3-il amida kao inhibitori ponovnog unosa serotonina i noradrenalina |
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HR20080339T HRP20080339T3 (hr) | 2003-06-17 | 2008-07-09 | Derivati n-pirolidin-3-il amida kao inhibitori ponovnog unosa serotonina i noradrenalina |
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US (2) | US7378436B2 (hr) |
EP (1) | EP1638933B1 (hr) |
JP (1) | JP4137159B2 (hr) |
KR (1) | KR100803796B1 (hr) |
AP (1) | AP2005003467A0 (hr) |
AR (1) | AR044715A1 (hr) |
AT (1) | ATE398107T1 (hr) |
AU (1) | AU2004247487B2 (hr) |
BR (1) | BRPI0411594A (hr) |
CA (1) | CA2530159C (hr) |
CY (1) | CY1110434T1 (hr) |
DE (1) | DE602004014372D1 (hr) |
DK (1) | DK1638933T3 (hr) |
EA (1) | EA009881B1 (hr) |
EC (1) | ECSP056232A (hr) |
ES (1) | ES2305776T3 (hr) |
HR (2) | HRP20050993A2 (hr) |
IL (1) | IL172063A0 (hr) |
IS (1) | IS8136A (hr) |
MA (1) | MA27885A1 (hr) |
MX (1) | MXPA05013960A (hr) |
NL (1) | NL1026438C2 (hr) |
NZ (1) | NZ544046A (hr) |
PA (1) | PA8605301A1 (hr) |
PE (1) | PE20050631A1 (hr) |
PL (1) | PL1638933T3 (hr) |
PT (1) | PT1638933E (hr) |
SI (1) | SI1638933T1 (hr) |
TW (1) | TW200505852A (hr) |
UY (1) | UY28360A1 (hr) |
WO (1) | WO2004110995A1 (hr) |
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CN101094846A (zh) | 2004-10-18 | 2007-12-26 | 伊莱利利公司 | 用作mglur3受体拮抗剂的1-(杂)芳基-3-氨基-吡咯烷衍生物 |
US7122683B2 (en) | 2004-11-23 | 2006-10-17 | Pfizer Inc. | Amides useful as monoamine re-uptake inhibitors |
GB0425766D0 (en) * | 2004-11-23 | 2004-12-22 | Pfizer Ltd | Novel compounds |
JP2008523136A (ja) * | 2004-12-14 | 2008-07-03 | ファイザー・リミテッド | セロトニンおよびノルアドレナリン再取り込み阻害剤としてのn−ピロリジン−3−イル−アミド誘導体 |
EP1828121A2 (en) * | 2004-12-14 | 2007-09-05 | Pfizer Limited | N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenalin re-uptake inhibitors |
TWI439452B (zh) | 2005-05-13 | 2014-06-01 | Otsuka Pharma Co Ltd | 吡咯烷化合物(二) |
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JP5219465B2 (ja) * | 2006-11-10 | 2013-06-26 | 大塚製薬株式会社 | 医薬 |
JPWO2008093737A1 (ja) * | 2007-01-31 | 2010-05-20 | 大日本住友製薬株式会社 | アミド誘導体 |
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CA2708866A1 (en) * | 2007-12-19 | 2009-06-25 | Hiroyuki Nakahira | Bicyclic heterocyclic derivative |
ES2434250T3 (es) | 2008-07-24 | 2013-12-16 | Theravance, Inc. | Compuestos de 3-(fenoxifenilmetil)pirrolidina |
JP5598798B2 (ja) | 2008-11-14 | 2014-10-01 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | 4−[2−(2−フルオロフェノキシメチル)フェニル]ピペリジン化合物を調製するためのプロセス |
EP2419405A1 (en) * | 2009-04-15 | 2012-02-22 | Theravance, Inc. | 3-(phenoxypyrrolidin-3-yl-methyl)heteroaryl, 3-(phenylpyrrolidin-3-ylmethoxy)heteroaryl, and 3-(heteroarylpyrrolidin-3-ylmethoxy)heteroaryl compounds |
US8658639B2 (en) | 2009-06-24 | 2014-02-25 | Dainippon Sumitomo Pharma Co., Ltd | N-substituted-cyclic amino derivative |
US7994209B2 (en) * | 2009-07-13 | 2011-08-09 | Theravance, Inc. | 3-phenoxymethylpyrrolidine compounds |
JP5714580B2 (ja) | 2009-07-21 | 2015-05-07 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | 3−フェノキシメチルピロリジン化合物 |
WO2011085291A1 (en) * | 2010-01-11 | 2011-07-14 | Theravance, Inc. | 1 - (2 - phenoxymethylphenyl) piperazine compounds as serotonin and norepinephrine reuptake inhibitors |
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- 2004-06-07 DE DE602004014372T patent/DE602004014372D1/de not_active Expired - Lifetime
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- 2004-06-07 KR KR1020057024147A patent/KR100803796B1/ko not_active IP Right Cessation
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- 2004-06-07 WO PCT/IB2004/001943 patent/WO2004110995A1/en active IP Right Grant
- 2004-06-07 AT AT04736241T patent/ATE398107T1/de not_active IP Right Cessation
- 2004-06-07 ES ES04736241T patent/ES2305776T3/es not_active Expired - Lifetime
- 2004-06-07 DK DK04736241T patent/DK1638933T3/da active
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- 2004-06-07 MX MXPA05013960A patent/MXPA05013960A/es active IP Right Grant
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- 2004-06-14 PE PE2004000590A patent/PE20050631A1/es not_active Application Discontinuation
- 2004-06-16 TW TW093117317A patent/TW200505852A/zh unknown
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- 2005-12-16 MA MA28674A patent/MA27885A1/fr unknown
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