HRP20050179A2 - Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof - Google Patents
Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof Download PDFInfo
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- HRP20050179A2 HRP20050179A2 HR20050179A HRP20050179A HRP20050179A2 HR P20050179 A2 HRP20050179 A2 HR P20050179A2 HR 20050179 A HR20050179 A HR 20050179A HR P20050179 A HRP20050179 A HR P20050179A HR P20050179 A2 HRP20050179 A2 HR P20050179A2
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- Prior art keywords
- phenyl
- alkyl
- ethyl
- ylmethyl
- group
- Prior art date
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- -1 carboxamide compounds Chemical class 0.000 title claims abstract description 288
- 238000000034 method Methods 0.000 title claims abstract description 88
- 150000001875 compounds Chemical class 0.000 title claims description 104
- 239000003814 drug Substances 0.000 title abstract description 16
- 230000000694 effects Effects 0.000 title abstract description 10
- 238000004519 manufacturing process Methods 0.000 title description 13
- 238000011282 treatment Methods 0.000 claims abstract description 59
- 208000008589 Obesity Diseases 0.000 claims abstract description 39
- 235000020824 obesity Nutrition 0.000 claims abstract description 39
- 229910052796 boron Inorganic materials 0.000 claims abstract description 31
- 229910052721 tungsten Inorganic materials 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 17
- 206010061428 decreased appetite Diseases 0.000 claims abstract description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 10
- 206010006550 Bulimia nervosa Diseases 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 8
- 208000032841 Bulimia Diseases 0.000 claims abstract description 7
- 108010047068 Melanin-concentrating hormone receptor Proteins 0.000 claims abstract description 7
- 208000022531 anorexia Diseases 0.000 claims abstract description 6
- 229940044551 receptor antagonist Drugs 0.000 claims abstract description 6
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 6
- 208000030814 Eating disease Diseases 0.000 claims abstract description 5
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 5
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 5
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 5
- 206010020710 Hyperphagia Diseases 0.000 claims abstract description 4
- 102000006953 melanin-concentrating hormone receptor activity proteins Human genes 0.000 claims abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 116
- 239000002904 solvent Substances 0.000 claims description 100
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 88
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 70
- 239000013543 active substance Substances 0.000 claims description 52
- 125000004122 cyclic group Chemical group 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 50
- VBYIYDQHYIBKLT-UHFFFAOYSA-N 2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethanamine Chemical compound C1=CC(CCN)=CC=C1CN1CCCC1 VBYIYDQHYIBKLT-UHFFFAOYSA-N 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 44
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 30
- 229920006395 saturated elastomer Polymers 0.000 claims description 29
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- FIMRRWLTRBEAOM-UHFFFAOYSA-N 4-(4-chlorophenyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(Cl)C=C1 FIMRRWLTRBEAOM-UHFFFAOYSA-N 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 239000005557 antagonist Substances 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 230000037396 body weight Effects 0.000 claims description 16
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 230000002265 prevention Effects 0.000 claims description 16
- 239000012317 TBTU Substances 0.000 claims description 15
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 10
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 10
- 206010003246 arthritis Diseases 0.000 claims description 10
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 7
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 7
- 208000019901 Anxiety disease Diseases 0.000 claims description 7
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims description 6
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 6
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 6
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 6
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 208000002249 Diabetes Complications Diseases 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 5
- UHBKRBDMZUQJBZ-UHFFFAOYSA-N 3-[2-[4-(3-azaspiro[5.5]undecan-3-ylmethyl)phenyl]ethyl]-7-(4-chlorophenyl)-1,2,3-benzotriazin-4-one Chemical compound C1=CC(Cl)=CC=C1C1=CC=C2C(=O)N(CCC=3C=CC(CN4CCC5(CCCCC5)CC4)=CC=3)N=NC2=C1 UHBKRBDMZUQJBZ-UHFFFAOYSA-N 0.000 claims description 5
- SXWGICMJWIPPTI-UHFFFAOYSA-N 4-(4-bromophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C1=CC(Br)=CC=C1C1=CC=C(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)C=C1 SXWGICMJWIPPTI-UHFFFAOYSA-N 0.000 claims description 5
- WLOGMDLGOQTBOB-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[2-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(CCNC(=O)C=2C=CC(=CC=2)C=2C=CC(Cl)=CC=2)C(F)=CC=1CN1CCCC1 WLOGMDLGOQTBOB-UHFFFAOYSA-N 0.000 claims description 5
- XNXMRTHXJJWSOI-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(CN2CCCC2)C(OC)=CC=1CCNC(=O)C(C=C1)=CC=C1C1=CC=C(Cl)C=C1 XNXMRTHXJJWSOI-UHFFFAOYSA-N 0.000 claims description 5
- YLAZAKIYXJWIJT-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)cyclohexyl]ethyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C(=O)NCCC2CCC(CN3CCCC3)CC2)C=C1 YLAZAKIYXJWIJT-UHFFFAOYSA-N 0.000 claims description 5
- XTLAJCBQIWYEEK-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]-3,6-dihydro-2h-pyridine-1-carboxamide Chemical compound C1=CC(Cl)=CC=C1C1=CCN(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 XTLAJCBQIWYEEK-UHFFFAOYSA-N 0.000 claims description 5
- HAKKERAGHOXDDR-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)C=C1 HAKKERAGHOXDDR-UHFFFAOYSA-N 0.000 claims description 5
- KVAJHLSBDDVJOR-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperidine-1-carboxamide Chemical compound C1=CC(Cl)=CC=C1C1CCN(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 KVAJHLSBDDVJOR-UHFFFAOYSA-N 0.000 claims description 5
- PNQYZKFFFUKYBK-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]propyl]benzamide Chemical compound C=1C=C(CN2CCCC2)C=CC=1C(C)CNC(=O)C(C=C1)=CC=C1C1=CC=C(Cl)C=C1 PNQYZKFFFUKYBK-UHFFFAOYSA-N 0.000 claims description 5
- OVOCPCKORZMCDI-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-methyl-2-[4-(pyrrolidin-1-ylmethyl)phenyl]propyl]benzamide Chemical compound C=1C=C(CN2CCCC2)C=CC=1C(C)(C)CNC(=O)C(C=C1)=CC=C1C1=CC=C(Cl)C=C1 OVOCPCKORZMCDI-UHFFFAOYSA-N 0.000 claims description 5
- NLVRNLUYDGRJTF-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[[4-(pyrrolidin-1-ylmethyl)phenyl]methoxy]benzamide Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C(=O)NOCC=2C=CC(CN3CCCC3)=CC=2)C=C1 NLVRNLUYDGRJTF-UHFFFAOYSA-N 0.000 claims description 5
- BBUQOQOCPWXCAH-UHFFFAOYSA-N 4-cyclohexyl-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperidine-1-carboxamide Chemical compound C1CC(C2CCCCC2)CCN1C(=O)NCCC(C=C1)=CC=C1CN1CCCC1 BBUQOQOCPWXCAH-UHFFFAOYSA-N 0.000 claims description 5
- PXTGRFIHXMQYFA-UHFFFAOYSA-N 4-piperidin-1-yl-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(N2CCCCC2)C=CC=1C(=O)NCCC(C=C1)=CC=C1CN1CCCC1 PXTGRFIHXMQYFA-UHFFFAOYSA-N 0.000 claims description 5
- WOFBOMJPFBPUGR-UHFFFAOYSA-N 5-(4-chlorophenyl)-2-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]-3h-isoindol-1-one Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C(=O)N(CCC=2C=CC(CN3CCCC3)=CC=2)C2)C2=C1 WOFBOMJPFBPUGR-UHFFFAOYSA-N 0.000 claims description 5
- GSNQAMUYAPMCRN-UHFFFAOYSA-N 6-(4-chlorophenyl)-2-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]isoquinolin-1-one Chemical compound C1=CC(Cl)=CC=C1C1=CC=C2C(=O)N(CCC=3C=CC(CN4CCCC4)=CC=3)C=CC2=C1 GSNQAMUYAPMCRN-UHFFFAOYSA-N 0.000 claims description 5
- NEMZEOGGJZBCCY-UHFFFAOYSA-N 7-(4-chlorophenyl)-3-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]quinazolin-4-one Chemical compound C1=CC(Cl)=CC=C1C1=CC=C2C(=O)N(CCC=3C=CC(CN4CCCC4)=CC=3)C=NC2=C1 NEMZEOGGJZBCCY-UHFFFAOYSA-N 0.000 claims description 5
- JKPOEURLDWJJDS-UHFFFAOYSA-N 7-(4-chlorophenyl)-3-[2-[4-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]phenyl]ethyl]quinazolin-4-one Chemical compound C1CC(O)(C=2C=CC=CC=2)CCN1CC(C=C1)=CC=C1CCN(C(C1=CC=2)=O)C=NC1=CC=2C1=CC=C(Cl)C=C1 JKPOEURLDWJJDS-UHFFFAOYSA-N 0.000 claims description 5
- 206010012655 Diabetic complications Diseases 0.000 claims description 5
- 206010046543 Urinary incontinence Diseases 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 5
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 claims description 5
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical class C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000006595 (C1-C3) alkylsulfinyl group Chemical group 0.000 claims description 4
- 125000006602 (C1-C3) alkylsulfonylamino group Chemical group 0.000 claims description 4
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 4
- 125000005838 1,3-cyclopentylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:2])C([H])([H])C1([H])[*:1] 0.000 claims description 4
- VRWWCRNCXHQFSX-UHFFFAOYSA-N 2-(4-methylphenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperidine-1-carboxamide Chemical compound C1=CC(C)=CC=C1C1N(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CCCC1 VRWWCRNCXHQFSX-UHFFFAOYSA-N 0.000 claims description 4
- BRYDLOYWASHVMM-UHFFFAOYSA-N 2-methyl-3-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]-7-[4-(trifluoromethyl)phenyl]quinazolin-4-one Chemical compound CC1=NC2=CC(C=3C=CC(=CC=3)C(F)(F)F)=CC=C2C(=O)N1CCC(C=C1)=CC=C1CN1CCCC1 BRYDLOYWASHVMM-UHFFFAOYSA-N 0.000 claims description 4
- NYDXOPYTOGGQKB-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(piperidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C1=CC(Cl)=CC=C1C1=CC=C(C(=O)NCCC=2C=CC(CN3CCCCC3)=CC=2)C=C1 NYDXOPYTOGGQKB-UHFFFAOYSA-N 0.000 claims description 4
- QDJMMGIVDMMNRQ-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]cyclohexane-1-carboxamide Chemical compound C1=CC(Cl)=CC=C1C1CCC(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 QDJMMGIVDMMNRQ-UHFFFAOYSA-N 0.000 claims description 4
- JMLYYTPQHKHZIM-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperazine-1-carboxamide Chemical compound C1=CC(Cl)=CC=C1N1CCN(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 JMLYYTPQHKHZIM-UHFFFAOYSA-N 0.000 claims description 4
- VETIKOKPOQQSDW-UHFFFAOYSA-N 4-(4-chlorophenyl)-n-[2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]ethyl]benzamide Chemical compound C1CN(C)CCN1C(N=C1)=CC=C1CCNC(=O)C1=CC=C(C=2C=CC(Cl)=CC=2)C=C1 VETIKOKPOQQSDW-UHFFFAOYSA-N 0.000 claims description 4
- XCUHTSQIVYYDJW-UHFFFAOYSA-N 4-(4-ethylphenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C1=CC(CC)=CC=C1C1=CC=C(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)C=C1 XCUHTSQIVYYDJW-UHFFFAOYSA-N 0.000 claims description 4
- ZOYANYCYKPVGLQ-UHFFFAOYSA-N 4-(4-fluorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C1=CC(F)=CC=C1C1=CC=C(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)C=C1 ZOYANYCYKPVGLQ-UHFFFAOYSA-N 0.000 claims description 4
- YMMPMGCLFJXVMV-UHFFFAOYSA-N 4-(4-fluorophenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperidine-1-carboxamide Chemical compound C1=CC(F)=CC=C1C1CCN(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 YMMPMGCLFJXVMV-UHFFFAOYSA-N 0.000 claims description 4
- GXAFKYXIWVWSQZ-UHFFFAOYSA-N 4-(4-methoxyphenyl)-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]piperazine-1-carboxamide Chemical compound C1=CC(OC)=CC=C1N1CCN(C(=O)NCCC=2C=CC(CN3CCCC3)=CC=2)CC1 GXAFKYXIWVWSQZ-UHFFFAOYSA-N 0.000 claims description 4
- XAVVMVUGDWOKQN-UHFFFAOYSA-N 4-[(4-oxocyclohexylidene)methyl]-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(C=C2CCC(=O)CC2)C=CC=1C(=O)NCCC(C=C1)=CC=C1CN1CCCC1 XAVVMVUGDWOKQN-UHFFFAOYSA-N 0.000 claims description 4
- SWLOGIYVRRDNGZ-UHFFFAOYSA-N 4-benzyl-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(CC=2C=CC=CC=2)C=CC=1C(=O)NCCC(C=C1)=CC=C1CN1CCCC1 SWLOGIYVRRDNGZ-UHFFFAOYSA-N 0.000 claims description 4
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- NSSNDZJIWHUMLB-UHFFFAOYSA-N 4-cyclohexyl-n-[2-[4-(pyrrolidin-1-ylmethyl)phenyl]ethyl]benzamide Chemical compound C=1C=C(C2CCCCC2)C=CC=1C(=O)NCCC(C=C1)=CC=C1CN1CCCC1 NSSNDZJIWHUMLB-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- 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
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Abstract
Izum se odnosi na karboksamidne spojeve opće formuleu kojoj skupine i radikali A, B, W, X, Y, Z, R1, R2, R3 i k imaju značenja navedena u zahtjevu 1.Izum se također odnosi na postupke za pripravu gore spomenutih karboksamidnih spojeva i na lijekovekoji sadrže najmanje jedan karboksamid prema izumu. Zbog njihovog antagonističkog djelovanja prema MCH receptoru, lijekovi prema izumu prikladni su za lijecenje poremecaja metabolizma i/ili prehrane,posebno debljine, bulimije, anoreksije, hiperfagije i dijabetesa.The invention relates to carboxamide compounds of the general formula in which the groups and radicals A, B, W, X, Y, Z, R1, R2, R3 and k have the meanings given in claim 1. The invention also relates to processes for the preparation of the above-mentioned carboxamide compounds and on medicaments containing at least one carboxamide according to the invention. Due to their MCH receptor antagonist activity, the drugs according to the invention are suitable for the treatment of metabolic and / or eating disorders, in particular obesity, bulimia, anorexia, hyperphagia and diabetes.
Description
Predmet predloženog izuma su novi karboksamidni spojevi, postupci za njihovu pripravu i njihove fiziološki podnošljive soli kao i njihova upotreba kao MCH-antagonista i njihova upotreba za proizvodnju lijeka koji je prikladan za profilaksu i/ili liječenje pojava i/ili bolesti uzrokovanih s MCH ili su s MCH u drugačijoj uzročnoj vezi. Daljnji predmet izuma odnosi se na upotrebu spoja prema izumu za utjecanje na ponašanje sisavaca pri uzimanju hrane i za smanjenje tjelesne težine i/ili za sprečavanje porasta tjelesne težine sisavca. Nadalje, predmet ovog izuma su sastavi i lijekovi koji u svakom slučaju sadrže spoj prema izumu, kao i postupci za njihovu proizvodnju. The subject of the proposed invention are new carboxamide compounds, processes for their preparation and their physiologically tolerable salts as well as their use as MCH-antagonists and their use for the production of a drug that is suitable for the prophylaxis and/or treatment of phenomena and/or diseases caused by MCH or are with MCH in a different causal relationship. A further object of the invention relates to the use of the compound according to the invention for influencing the behavior of mammals when taking food and for reducing the body weight and/or for preventing the increase in the body weight of the mammal. Furthermore, the subject of this invention are compositions and medicines which in any case contain the compound according to the invention, as well as processes for their production.
Pozadina izuma Background of the invention
Uzimanje hrane i njezina pretvorba u tijelu ima važnu ulogu u životu svih živih bića. Zbog toga odstupanja kod uzimanja hrane i pretvorbe hrane dovodi u pravilu do poremećaja i također do bolesti. Promjene u načinu života i prehrambenih navika ljudi, posebno u industrijskim zemljama posljednjih desetljeća, pogodovalo je debljini. Kod pogođenih ljudi debljina dovodi neposredno do ograničenja mobilnosti i do smanjenje kvalitete života. Uz to debljina često ima za posljedicu i druge bolesti, kao na primjer dijabetes, dislipidemiju, visoki krvni tlak, arterio-sklerozu i koronarne srčane bolesti. Osim toga, sama visoka tjelesna težina dovodi do povećanog opterećenja nosećeg i aparata za kretanje, što može dovesti do kroničnih tegoba i bolesti, kao što je artritis ili osteoartritis. Zbog toga je debljina ozbiljan zdravstveni problem društva. Taking food and its transformation in the body plays an important role in the life of all living beings. Because of this, deviations in food intake and food conversion usually lead to disorders and also to diseases. Changes in people's lifestyles and eating habits, especially in industrialized countries in recent decades, have favored obesity. In affected people, obesity leads directly to a limitation of mobility and a reduction in the quality of life. In addition, obesity often results in other diseases, such as diabetes, dyslipidemia, high blood pressure, arteriosclerosis and coronary heart disease. In addition, high body weight itself leads to an increased load on the bearing and movement apparatus, which can lead to chronic ailments and diseases, such as arthritis or osteoarthritis. This is why obesity is a serious health problem for society.
Pojam debljine znači suvišak adipoznog tkiva. S tim u svezi, debljinom se načelno smatra povećana količina masti koja dovodi do opasnosti za zdravlje. U posljednjim analizama nije moguće povući točnu granicu između normalnih pojedinaca i pojedinaca sklonih debljini, međutim stalno raste opasnost za zdravlje koja je vjerojatno povezana s povećanjem debljine. Zbog pojednostavljenja u svezi s predloženim izumom, kao pojedinci skloni debljanju smatraju se ponajprije osobe s indeksom tjelesne težine (BMI = body mass index) iznad vrijednosti 25, posebno iznad 30, a koji indeks je definiran kao tjelesna težina izmjerena u kilogramima i podijeljena s visinom (u metrima) na kvadrat. The term obesity means an excess of adipose tissue. In this regard, obesity is generally considered to be an increased amount of fat that leads to health hazards. In the latest analyses, it is not possible to draw an exact line between normal individuals and individuals prone to obesity, however, there is an ever-increasing health hazard that is probably associated with an increase in obesity. For the sake of simplification in relation to the proposed invention, individuals with a body mass index (BMI = body mass index) above 25, especially above 30, and which index is defined as body weight measured in kilograms and divided by height, are considered to be individuals prone to gaining weight. (in meters) per square.
Neovisno o tjelesnoj aktivnosti i promjeni prehrane, za sada ne postoji uvjerljiva mogućnost za učinkovito smanjenje tjelesne težine. Međutim, kako debljina predstavlja glavni faktor rizika za razvoj ozbiljnih i čak za život opasnih bolesti, postaje sve važnije pripraviti aktivnu tvar za profilaksu i/ili liječenje debljine. U novije vrijeme predložena je terapeutska upotreba MCH antagonista (između ostalog u WO 01/21577, WO 01/82925). Regardless of physical activity and dietary changes, there is currently no convincing possibility for effective weight loss. However, since obesity represents the main risk factor for the development of serious and even life-threatening diseases, it becomes increasingly important to prepare an active substance for the prophylaxis and/or treatment of obesity. More recently, the therapeutic use of MCH antagonists has been proposed (among others in WO 01/21577, WO 01/82925).
Hormon koji koncentrira melanin (melanin-concentrating hormone, MCH) je ciklički neuropeptid koji se sastoji iz 19 amino kiselina. On se u sisavcima sintetizira pretežno u hipotalamusu i odatle putuje u ostale dijelove mozga preko projekcija hipotalamičnih neurona. Njegovo biološko djelovanje je u ljudima posredovano preko dva različita receptora povezana s glikoproteinom (GPCR) iz porodice rodopsinu srodnog GPCR, naime MCH receptora 1 i 2 (MCH-1R i MCH-2R). Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. In mammals, it is synthesized mainly in the hypothalamus and from there it travels to other parts of the brain via the projections of hypothalamic neurons. Its biological action in humans is mediated through two different glycoprotein-linked receptors (GPCRs) from the rhodopsin-related GPCR family, namely MCH receptors 1 and 2 (MCH-1R and MCH-2R).
Istraživanja funkcije MCH u životinjskim modelima dala su dobre indikacije za ulogu peptida u regulaciji ravnoteže energije, tj. promjene metaboličke aktivnosti i uzimanja hrane [1, 2]. Na primjer, nakon intraventrikulne aplikacije MCH štakorima, uzimanje hrane se je povećalo u usporedbi s kontrolnim životinjama. Osim toga genetski promijenjeni štakori, koji proizvode više MHC nego kontrolne životinje, reagirali su nakon davanja hrane bogate masnoćom sa značajnim većim porastom težine nego životinje kojima nije eksperimentalno promijenjena količina MCH. Također se je moglo utvrditi da postoji pozitivna korelacija između faza povećane želje za hranom i količine MCH mRNA u hipotalamusu štakora. Međutim, pokusi s MCH knock out miševima su posebno važni što se tiče funkcije MCH. Gubitak neuropeptida dovodi do mršavih životinja smanjene tjelesne mase, koji uzimaju značajno manje hrane nego kontrolne životinje. Research into the function of MCH in animal models gave good indications for the role of the peptide in the regulation of energy balance, i.e. changes in metabolic activity and food intake [1, 2]. For example, after intraventricular administration of MCH to rats, food intake increased compared to control animals. In addition, genetically altered rats, which produce more MHC than control animals, responded after being fed a high-fat diet with a significantly greater weight gain than animals whose amount of MCH was not experimentally altered. It could also be determined that there is a positive correlation between the stages of increased desire for food and the amount of MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock out mice are particularly important regarding the function of MCH. Loss of the neuropeptide results in lean animals with reduced body mass, which take in significantly less food than control animals.
Anorektične učinke MCH-a kod glodavaca posreduju MCH-1R povezani preko Gons-a [3-6]. Za razliku od primata, lasica i pasa, kod glodavaca se do sada nije mogao dokazati nijedan drugi receptor. Nakon gubitka MCH-1R, knock out miševi imaju manje masne mase, povećani utrošak energije i kad se hrane s hranom obogaćenom s mastima, oni ne dobivaju na težini u usporedbi s kontrolnim životinjama. Daljnja indikacija za važnost sistema MCH-MCH-1R u regulaciji bilance energije dolazi iz pokusa s receptor-antagonistima (SNAP-7941) [3]. U dugotrajnim pokusima životinje koje su primale antagoniste značajno su izgubile na težini. The anorectic effects of MCH in rodents are mediated by Gons-linked MCH-1Rs [3-6]. Unlike primates, weasels and dogs, no other receptor has been demonstrated in rodents so far. After loss of MCH-1R, knock out mice have less fat mass, increased energy expenditure, and when fed a high-fat diet, they do not gain weight compared to control animals. Further indication for the importance of the MCH-MCH-1R system in the regulation of energy balance comes from experiments with receptor antagonists (SNAP-7941) [3]. In long-term experiments, animals receiving antagonists significantly lost weight.
Osim njegovog anorektičnog učinka, u pokusima ponašanja štakora [3] s MCH-1R antagonistima SNAP-7941 postižu se i dodatni anksiolitički i antidepresivni učinci. Tako, dakle, postoje jasni dokazi da je sistem MCH-MCH-1R uključen ne samo u regulaciju bilance energije, već on također djeluje i na afektivnost. In addition to its anorectic effect, additional anxiolytic and antidepressant effects are achieved in rat behavioral experiments [3] with the MCH-1R antagonist SNAP-7941. Thus, there is clear evidence that the MCH-MCH-1R system is involved not only in the regulation of energy balance, but also affects affectivity.
Literatura: Literature:
1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 1996. 380(6571): str. 243-7. 1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature, 1996. 380(6571): p. 243-7.
2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396(6712): str. 670-4. 2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.
3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med, 2002. 8(8): str. 825-30. 3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med, 2002. 8(8): p. 825-30.
4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results u hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143(7): str. 2469-77. 4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143(7): p. 2469-77.
5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): str. 3240-5. 5. Marsh, D.J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): p. 3240-5.
6. Takekawa, S., et al., T-226296 : A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): str. 129-35. 6. Takekawa, S., et al., T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p. 129-35.
U patentnoj literaturi predloženi su određeni aminski spojevi kao MCH antagonisten. Tako se u WO 01/21577 (Takeda) opisuju spojevi formule Certain amine compounds have been proposed in the patent literature as MCH antagonists. Thus, compounds of the formula are described in WO 01/21577 (Takeda).
[image] [image]
u kojoj Ar1 predstavlja cikličku skupinu, X je spacer, Y je veza ili spacer, Ar je aromatski prsten, koji se može kondenzirati s nearomatskim prstenom, R1 i R2 su međusobno neovisno H ili ugljikovodična skupina, pri čemu R1 i R2 zajedno sa susjednim N atomom mogu tvoriti hetero prten koji sadrži N, a R2 s Ar također može tvoriti spirociklički prsten, R zajedno sa susjednim N atomom i Y može tvoriti hetero prsten koji sadrži N, kao MCH antagoniste za liječenje, između ostalog, debljine. in which Ar1 represents a cyclic group, X is a spacer, Y is a bond or spacer, Ar is an aromatic ring, which can be condensed with a non-aromatic ring, R1 and R2 are independently H or a hydrocarbon group, where R1 and R2 together with an adjacent N atom can form a hetero ring containing N, and R2 with Ar can also form a spirocyclic ring, R together with an adjacent N atom and Y can form a hetero ring containing N, as MCH antagonists for the treatment of, among other things, obesity.
Osim toga, u WO 01/82925 (Takeda) su također opisani spojevi formule In addition, compounds of the formula are also described in WO 01/82925 (Takeda).
[image] [image]
u kojoj Ar' predstavlja cikličku skupinu, X i Y su skupine spacera, Ar je prema potrebi supstituirani kondenzirani policiklički aromatski prsten, R1 i R2 su međusobno neovisno H ili ugljikovodična skupina, pri čemu R1 i R2 zajedno sa susjednim N atomom mogu tvoriti heterociklički prstena koji sadrži N, a R2 zajedno sa susjednim N atomom i Y može tvoriti hetero prsten koji sadrži N, kao MCH antagoniste za liječenje, između ostalog, debljine. in which Ar' represents a cyclic group, X and Y are spacer groups, Ar is an optionally substituted condensed polycyclic aromatic ring, R1 and R2 are independently H or a hydrocarbon group, whereby R1 and R2 together with the adjacent N atom can form heterocyclic rings containing N, and R2 together with the adjacent N atom and Y can form a hetero ring containing N, as MCH antagonists for the treatment of, among other things, obesity.
Daljnji aminski spojevi s MCH-antagonističkim djelovanjem predloženi su u WO 02/057233 (Schering Corp.). Ti spojevi spadaju pod opću formulu Further amine compounds with MCH-antagonistic activity are proposed in WO 02/057233 (Schering Corp.). These compounds fall under the general formula
[image] [image]
u kojoj Ar1, Ar2, Ar3 predstavljaju između ostalog aril ili heteroaril, X O, S ili N-CN, Y je jednostruka veza ili C1-4-alkilen, a R1 i R2 imaju navedena značenja. in which Ar1, Ar2, Ar3 represent, among others, aryl or heteroaryl, X O, S or N-CN, Y is a single bond or C1-4-alkylene, and R1 and R2 have the indicated meanings.
MCH-antagonistički učinak je također opisan u WO 02/051809 (Schering Corp.) u svezi s piperidinskim derivatima formule The MCH-antagonistic effect is also described in WO 02/051809 (Schering Corp.) in connection with piperidine derivatives of the formula
[image] [image]
u kojoj W predstavlja pobliže definiranu aminokarbonilnu ili karbonilamino skupinu, X je -CHR8, -CO-, -C(=NOR9)- ili -CR8=, Y je CH, C(OH), C(C1-4-alkoksi) ili u slučaju dvostruke veze na C, R2 je supstituirana arilna ili hetero-arilna skupina, R10 je H, C1-6-alkil ili aril, a preostali radikali imaju navedena značenja. in which W represents a more closely defined aminocarbonyl or carbonylamino group, X is -CHR8, -CO-, -C(=NOR9)- or -CR8=, Y is CH, C(OH), C(C1-4-Alkoxy) or in the case of a double bond at C, R 2 is a substituted aryl or hetero-aryl group, R 10 is H, C 1-6 -alkyl or aryl, and the remaining radicals have the indicated meanings.
Karboksamidi kao antagonisti humanih 11CBy receptora predloženi su u WO 02/10146 (Smithkline Beecham). Ovi spojevi su primjeri etera opće strukturne formule Carboxamides as antagonists of human 11CBy receptors are proposed in WO 02/10146 (Smithkline Beecham). These compounds are examples of ethers of the general structural formula
[image] [image]
u kojoj A predstavlja H, alkil, alkoksi, alkenil, acil, halogen, OH, CN ili CF3, R3 je H, metil ili etil, R4 je prema potrebi supstituirani aromatski karbociklički ili heterociklički prsten, Z je O, S, NH, CH2 ili jednostruka veza, R5 je prema potrebi supstituirani aromatski, zasićen ili nezasićen karbociklički ili heterociklički prsten, i Q je skupina -X-Y-NR1(R2), dok prema različitim konfiguracijama X može biti O, S ili N, Y je alkilenska ili cikloalkilenska skupina, koja također može biti supstituirana, a R1 i R2 mogu biti alkil ili fenil-alkil, pri čemu R1 i R2, R1 i Y ili R1 i X mogu također biti međusobno povezani uz tvorbu prstenastog sistema, kao što je opisano. in which A represents H, alkyl, alkoxy, alkenyl, acyl, halogen, OH, CN or CF3, R3 is H, methyl or ethyl, R4 is optionally substituted aromatic carbocyclic or heterocyclic ring, Z is O, S, NH, CH2 or a single bond, R5 is optionally substituted aromatic, saturated or unsaturated carbocyclic or heterocyclic ring, and Q is the group -X-Y-NR1(R2), while according to different configurations X can be O, S or N, Y is an alkylene or cycloalkylene group , which may also be substituted, and R 1 and R 2 may be alkyl or phenyl-alkyl, wherein R 1 and R 2 , R 1 and Y or R 1 and X may also be linked together to form a ring system, as described.
Daljnji spojevi s MCH-antagonističkim svojstvima predloženi su u objavljenim patentnim prijavama WO 03/035055, WO 03/033480, WO02/06245, WO 02/04433, WO 01/87834, WO 01/21169 i JP 2001/226269. Further compounds with MCH-antagonistic properties are proposed in published patent applications WO 03/035055, WO 03/033480, WO02/06245, WO 02/04433, WO 01/87834, WO 01/21169 and JP 2001/226269.
Kinazolinonski spojevi opće formule Quinazolinone compounds of the general formula
[image] [image]
opisani su u WO 01/23365 (Merck), u kojoj Z predstavlja vezu ili fenilen, i u WO 01/23364 (Merck), gdje Z predstavlja cikloheksilen. Osim toga Y predstavlja vezu ili C2-4-alkenil i R4 je aril, cikloalkil, fenilalkil ili heterociklički sistem. Ovi spojevi su opisani kao GPIbIX inhibitori, posebno kao inhibitori tog receptora s ligandima von Willebrandovog faktora (vWF). are described in WO 01/23365 (Merck), where Z represents a bond or phenylene, and in WO 01/23364 (Merck), where Z represents cyclohexylene. In addition, Y represents a bond or C2-4-alkenyl and R4 is aryl, cycloalkyl, phenylalkyl or a heterocyclic system. These compounds are described as GPIbIX inhibitors, particularly as inhibitors of this receptor with von Willebrand factor (vWF) ligands.
Osim toga, u literaturi su za druge indikacije predloženi i aromatski spojevi koji mogu sadržavati amidni most i aminsku skupinu. Tako su u WO 99/01127 (Smithkline Beecham Corp.) opisani spojevi opće formule Ar-A-E, u kojoj Ar predstavlja prema potrebi supstituiranu aromatsku mono- ili bicikličku skupinu, A je amidni ili aminski most i E je između ostalog fenilna skupina, koja u para položaju može biti supstituirana preko spacer skupine B sa supstituiranom aminoalkilenskom skupinom. Ti spojevi se predlažu kao CCR5 receptor ligandi za liječenje, između ostalog, astme, površinskih oboljenja i reumatoidnog artritisa. In addition, aromatic compounds that may contain an amide bridge and an amine group have been proposed in the literature for other indications. Thus, in WO 99/01127 (Smithkline Beecham Corp.) compounds of the general formula Ar-A-E are described, in which Ar represents an optionally substituted aromatic mono- or bicyclic group, A is an amide or amine bridge and E is, among other things, a phenyl group, which in the para position it can be substituted via the spacer group B with a substituted aminoalkylene group. These compounds are proposed as CCR5 receptor ligands for the treatment of, among others, asthma, superficial diseases and rheumatoid arthritis.
U WO 01/72712 (Cor Therapeutics Inc.) opisani su izokinolinski spojevi slijedeće formule WO 01/72712 (Cor Therapeutics Inc.) describes isoquinoline compounds of the following formula
[image] [image]
u kojoj A predstavlja prema potrebi supstituiranu amino ili amidino skupinu, Z je veza ili alkilna, cikloalkilna, alkenilna, alkinilna ili arilna spacer skupina, m i n su 0 do 3, D je veza ili navedeni most, X je NR12 ili CHR12, p je 0 do 3, E je također i veza osim navedene eterske, aminske, amidne i karboksilne skupine, J je veza, cikloalkilenska, fenilenska, naftilenska ili heteroarilna skupina, G je pobliže specificirana amidna, imino ili amidino skupina, a prestali radikali imaju navedena značenja. Ovi spojevi se predlažu kao inhibitori izoliranog faktora Xa kao i koagulacije krvi i time kao antitrombotičke i trombolitičke aktivne tvari. in which A represents an optionally substituted amino or amidino group, Z is a bond or an alkyl, cycloalkyl, alkenyl, alkynyl or aryl spacer group, m and n are 0 to 3, D is a bond or the specified bridge, X is NR12 or CHR12, p is 0 to 3, E is also a bond other than the mentioned ether, amine, amide and carboxyl group, J is a bond, cycloalkylene, phenylene, naphthylene or heteroaryl group, G is a more specifically specified amide, imino or amidino group, and the terminated radicals have the indicated meanings. These compounds are proposed as inhibitors of isolated factor Xa as well as of blood coagulation and thus as antithrombotic and thrombolytic active substances.
U DE 197 18 181 A1 (Boehringer Ingelheim) se predlažu disupstituirani biciklički heterocikli formule DE 197 18 181 A1 (Boehringer Ingelheim) proposes disubstituted bicyclic heterocycles of the formula
Ra-A-Het-Ar-E Ra-A-Het-Ar-E
u kojoj Ra predstavlja pobliže specificiranu amino skupinu ili prema potrebi također R4-SO2-NR5 ili skupinu R4-SO2, pri čemu R4 i R5 imaju navedena značenja, A je fenilen-C1-3-alkilenska skupina, n-C2-6-alkilenska skupina ili C5-7-cikloalkilen-C1-3-alkilenska skupina, koja može biti supstituirana kako je navedeno, Het je prema potrebi supstituirana benzimidazolna, indolna, tetrahidro-kinolinonska ili kinazolinonska skupina, Ar je prema potrebi supstituirani fenilen, naftilen, tienilen, tiazolilen, piridinilen, pirimidinilen, pirazinilen ili piridazinilen, i E je cijano ili skupina RbNH-C(=NH), u kojoj Rb predstavlja H, OH, C1-3-alkil ili ostatak koji se može odcijepiti in vivo. Ovi spojevi se predlažu kao inhibitori trombina i aktivne tvari koje produljuju vrijeme trombina. in which Ra represents a more precisely specified amino group or, if necessary, also R4-SO2-NR5 or a group R4-SO2, wherein R4 and R5 have the given meanings, A is a phenylene-C1-3-alkylene group, n-C2-6-alkylene group or a C5-7-cycloalkylene-C1-3-alkylene group, which may be substituted as indicated, Het is an optionally substituted benzimidazole, indole, tetrahydro-quinolinone or quinazolinone group, Ar is an optionally substituted phenylene, naphthylene, thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene, and E is cyano or the group RbNH-C(=NH), wherein Rb represents H, OH, C1-3-alkyl or a residue that can be cleaved in vivo. These compounds are proposed as thrombin inhibitors and thrombin time prolonging agents.
Cilj izuma Object of the invention
Predloženi izum se temelji na zadatku da se priprave novi karboksamidni spojevi, posebno takovi koji imaju djelovanje MCH antagonista. Jedan zadatak ovog izuma je također pripraviti nove karboksamidne spojeve koji omogućuju djelovanje na ponašanje sisavaca pri uzimanju hrane, i postizanje, posebno kod sisavaca, smanjenja tjelesne težine i/ili sprečavanje porasta tjelesne težine. Zadatak predloženog izuma je nadalje priprava novih lijekova koji su prikladni za profilaksu i/ili liječenje pojava i/ili bolesti uzrokovanih s MCH ili koje su drugačije uzročno povezane s MCH. Ovaj izum se posebno temelji na zadatku da se na raspolaganje dadu lijekovi za liječenje metaboličkih poremećaja, kao što je debljina i/ili dijabetes, kao i bolesti i/ili poremećaja koji su povezani s debljinom i s dijabetesom. Daljnji zadatak predloženog izuma odnosi se na dokazivanje korisne upotrebe spojeva prema izumu. Također, jedan zadatak ovog izuma je osigurati postupak za proizvodnju karboksamidnih spojeva. Daljnji zadaci predloženog izuma su stručnjaku vidljivi neposredno iz gornjih i slijedećih izvedbi. The proposed invention is based on the task of preparing new carboxamide compounds, especially those that have the effect of MCH antagonists. One task of the present invention is also to prepare new carboxamide compounds that enable an effect on the feeding behavior of mammals, and achieve, especially in mammals, a reduction in body weight and/or prevention of an increase in body weight. The task of the proposed invention is furthermore the preparation of new drugs which are suitable for prophylaxis and/or treatment of phenomena and/or diseases caused by MCH or which are otherwise causally related to MCH. This invention is particularly based on the task of providing drugs for the treatment of metabolic disorders, such as obesity and/or diabetes, as well as diseases and/or disorders associated with obesity and diabetes. A further task of the proposed invention relates to proving the beneficial use of the compounds according to the invention. Also, one object of this invention is to provide a process for the production of carboxamide compounds. Further tasks of the proposed invention are immediately apparent to the expert from the above and following embodiments.
Glavni predmet izuma The main subject of the invention
Prvi predmet predloženog izuma su karboksamidni spojevi opće formule I The first object of the proposed invention are carboxamide compounds of the general formula I
[image] [image]
u kojoj where
R1 i R2 međusobno neovisno predstavljaju H, C1-8-alkilnu ili C3-7-cikloalkilnu skupinu koja je prema potrebi supstituirana sa skupinom R11 ili fenilnu skupinu prema potrebi mono- ili polisupstituiranu sa skupinom R12 i/ili monosupstituiranu s nitro, ili R1 and R2 independently of each other represent H, C1-8-alkyl or C3-7-cycloalkyl group which is optionally substituted with the group R11 or a phenyl group optionally mono- or polysubstituted with the group R12 and/or monosubstituted with nitro, or
R1 i R2 tvore C2-8-alkilenski most u kojem R1 and R2 form a C2-8-alkylene bridge in which
- jedna ili dvije -CH2- skupine mogu se zamijeniti međusobno neovisno sa -CH=N- ili -CH=CH- i/ili - one or two -CH2- groups can be replaced independently of each other by -CH=N- or -CH=CH- and/or
- jedna ili dvije -CH2- skupine mogu se zamijeniti međusobno neovisno sa -O-, -S-, -CO-, -C(=CH2)- ili -NR13-tako da heteroatomi nisu međusobno izravno povezani, - one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -CO-, -C(=CH2)- or -NR13- so that the heteroatoms are not directly connected to each other,
dok se u gore definiranom alkilenskom mostu jedan ili više H atoma može zamijeniti s R14, i/ili while in the alkylene bridge defined above, one or more H atoms can be replaced by R14, and/or
gore definiran alkilenski most može biti supstituiran s jednom ili dvije jednake ili različite karbo- ili heterocikličke skupine Cy na takav način da veza između alkilenskog mosta i skupina Cy nastaje The alkylene bridge defined above can be substituted with one or two identical or different carbo- or heterocyclic Cy groups in such a way that the bond between the alkylene bridge and the Cy groups is formed
- preko jednostruke ili dvostruke veze, - via single or double connection,
- preko zajedničkog C atoma koji tvori spirociklički prstenasti sistem, - through a common C atom that forms a spirocyclic ring system,
- preko dva zajednička, susjedna C i/ili N atoma koji tvore kondenzirani biciklički prstenasti sistem ili - over two common, adjacent C and/or N atoms that form a condensed bicyclic ring system or
- preko tri ili više C i/ili N atoma koji tvore premošteni prstenasti sistem, - over three or more C and/or N atoms that form a bridged ring system,
R3predstavlja H, C1-6-alkil, C3-7-cikloalkil, C3-7-cikloalkil-C1-4-alkil-, C3-7-cikloalkenil, C3-7-cikloalkenil-C1-4-alkil-, fenil, fenil-C1-4-alkil-, C1-3-alkoksi-C2-6-alkil-, amino-C2-6-alkil-, C1-3-alkil-amino-C2-6-alkil- ili di-(C1-3-alkil)-amino-C2-6-alkil-, R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl-, C3-7-cycloalkenyl, C3-7-cycloalkenyl-C1-4-alkyl-, phenyl, phenyl -C1-4-alkyl-, C1-3-Alkoxy-C2-6-alkyl-, amino-C2-6-alkyl-, C1-3-alkyl-amino-C2-6-alkyl- or di-(C1- 3-alkyl)-amino-C2-6-alkyl-,
X predstavlja jednostruku vezu ili C1-8-alkilenski most u kojem X represents a single bond or a C1-8-alkylene bridge in which
- jedna ili dvije -CH2- skupine se mogu zamijeniti međusobno neovisno sa -CH=CH- ili -C≡C- i/ili - one or two -CH2- groups can be replaced independently of each other by -CH=CH- or -C≡C- and/or
- jedna ili dvije -CH2- skupine se mogu zamijeniti međusobno neovisno s -O-, -S-, -(SO)-, -(SO2)-, -CO- ili - one or two -CH2- groups can be replaced independently of each other by -O-, -S-, -(SO)-, -(SO2)-, -CO- or
- -NR4- na takav način da u svakom slučaju dva O, S ili N atoma ili jedan O atom i S atom nisu izravno međusobno povezani, - -NR4- in such a way that in each case two O, S or N atoms or one O atom and an S atom are not directly connected to each other,
dok jedan ili dva C atoma međusobno neovisno mogu biti supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi skupinom i/ili u svakom slučaju s jednom ili dvije jednake ili različite C1-6-alkilne skupine, i/ili while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or in each case with one or two identical or different C 1-6 -alkyl groups, and/or
alkilenski most može biti povezan na R1 tako da uključuje N atom povezan na R1 i X, tvoreći heterocikličku skupinu, an alkylene bridge may be attached to R1 so as to include the N atom attached to R1 and X, forming a heterocyclic group,
Z predstavlja C1-4-alkilenski most, u kojem dva susjedna C atoma s dodatnim C1-4-alkilenskim mostom mogu biti međusobno povezani, dok se u skupini Z skupina -CH2- može zamijeniti s -O- ili -NR5-, Z represents a C1-4-alkylene bridge, in which two adjacent C atoms with an additional C1-4-alkylene bridge can be interconnected, while in the Z group the -CH2- group can be replaced by -O- or -NR5-,
i jedan ili dva C atoma alkilenskog mosta mogu biti supstituirani međusobno neovisno s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom, C1-3-alkoksi skupinom, amino-C1-3-alkilom, C1-3-alkil-amino-C1-3-alkilom ili di-(C1-3-alkil)-amino-C1-3-alkilom i/ili s jednom ili dvije jednake ili različite C1-6-alkilne skupine, i/ili and one or two C atoms of the alkylene bridge can be substituted independently of each other with a hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl, C1-3-alkoxy group, amino -C1-3-alkyl, C1-3-alkyl-amino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl and/or with one or two identical or different C1- 6-alkyl groups, and/or
R3 može biti povezan na Z tako da uključuje N atom povezan na R3 tvoreći heterocikličku skupinu, R3 may be linked to Z by including an N atom linked to R3 forming a heterocyclic group,
A i Y međusobno neovisno imaju jedno od značenja datih za Cy, A and Y independently of each other have one of the meanings given for Cy,
dok R1 može biti povezan na Y tako da uključuje skupinu X i N atom povezan na R1 i X, tvoreći heterocikličku skupinu kondenziranu na Y, i/ili while R1 may be linked to Y so as to include a group X and an N atom linked to R1 and X, forming a heterocyclic group fused to Y, and/or
R3 može biti povezan na Y tako da uključuje skupinu Z i N atom povezan na R3 i Z, tvoreći zasićenu ili djelomično nezasićenu heterocikličku skupinu kondenziranu na Y, ili R 3 may be attached to Y so as to include a group Z and an N atom attached to R 3 and Z, forming a saturated or partially unsaturated heterocyclic group fused to Y, or
A i R3 mogu biti međusobno povezani na takav način da skupina formule I A and R 3 can be interconnected in such a way that the group of formula I
[image] [image]
predstavlja skupinu djelomične formule II represents a group of partial formula II
[image] [image]
i and
Q predstavlja skupinu odabranu između djelomičnih formula IIIa do IIIg Q represents a group selected from partial formulas IIIa to IIIg
[image] [image]
L1, L2 i L3 međusobno neovisno imaju jedno od značenja datih za R20, L1, L2 and L3 independently of each other have one of the meanings given for R20,
B predstavlja C1-6-alkil, C1-6-alkenil, C1-6-alkinil, C3-7-cikloalkil-C1-3-alkil-, C3-7-cikloalkenil-C1-3-alkil-, C3-7-cikloalkil-C1-3-alkenil- ili C3-7-cikloalkil-C1-3-alkinil-, pri čemu jedan ili više C atoma može biti mono- ili polisupstituirano s halogenim i/ili monosupstituirano s hidroksi ili cijano i/ili cikličke skupine mogu biti mono- ili polisupstituirane s R20, ili B represents C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-3-alkyl-, C3-7- cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, or
B ima jedno od značenja datih za Cy, dok veza sa skupinom W ili prema potrebi izravno sa skupinom A ide preko C atoma karbocikličke jedinice ili prema potrebi kondenziranog fenilnog ili piridinskog prstena ili preko N ili C atoma heterocikličke jedinice, B has one of the meanings given for Cy, while the bond with the group W or, if necessary, directly with the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit,
dok, ako k = 0, skupina B i skupina A mogu biti međusobno povezane preko zajedničkog C atoma tvoreći spirociklički prstenasti sistem ili while, if k = 0, group B and group A can be interconnected via a common C atom forming a spirocyclic ring system or
preko dva zajednička, susjedna atoma koji tvore kondenzirani, biciklički prstenasti sistem, via two shared, neighboring atoms that form a condensed, bicyclic ring system,
W predstavlja jednostruku vezu, -O-, C1-4-alkilen, C2-4-alkenilen, C2-4-alkinilen, C1-4-alkilenoksi-, oksi-C1-4-alkilen-, C1-3-alkilen-oksi-C1-3-alkilen-, imino, N-(C1-3-alkil)-imino-, imino-C1-3-alkilen-, N-(C1-3-alkil)-imino-C1-4-alkilen-, C1-4-alkilen-imino- ili C1-4-alkilen-N-(C1-3-alkil)-imino- skupinu, W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy -C1-3-alkylene-, imino, N-(C1-3-alkyl)-imino-, imino-C1-3-alkylene-, N-(C1-3-alkyl)-imino-C1-4-alkylene- , C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino- group,
dok jedan ili dva C atoma međusobno neovisno mogu biti supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi skupinom i/ili s jednom ili dvije jednake ili različite C1-6-alkilne skupine, i/ili while one or two C atoms can be independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy group and/ or with one or two identical or different C1-6-alkyl groups, and/or
W s definicijom alkilena, oksialkilena i alkilenoksi-alkilena može također biti povezan na B preko dvostruke veze, W defined as alkylene, oxyalkylene and alkyleneoxy-alkylene may also be linked to B via a double bond,
k predstavlja 0 ili 1, k represents 0 or 1,
Cy predstavlja karbo- ili heterocikličku skupinu odabranu između slijedećih značenja: Cy represents a carbo- or heterocyclic group selected from the following meanings:
- zasićena 3- do 7-člana karbociklička skupina, - saturated 3- to 7-membered carbocyclic group,
- nezasićena 5- do 7-člana karbociklička skupina, - unsaturated 5- to 7-membered carbocyclic group,
- fenilna skupina, - phenyl group,
- zasićena 4- do 7-člana ili nezasićena 5- do 7-člana heterociklička skupina s N, O ili S atomom kao hetero-atomom, - saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with N, O or S atom as hetero-atom,
- zasićena ili nezasićena 5- do 7-člana heterociklička skupina s dva ili više N atoma ili s jednim ili dva N atoma i O ili S atomom kao heteroatomima, - saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms,
- aromatska heterociklička 5- ili 6-člana skupina s jednim ili više jednakih ili različitih heteroatoma odabranih između N, O i/ili S, - aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S,
dok gore spomenute 4, 5, 6 ili 7-člane skupine mogu biti povezane preko dva zajednička, susjedna C atoma, kondenzirana s fenilnim ili piridinskim prstenom, i while the above-mentioned 4, 5, 6 or 7-membered groups can be linked via two common, adjacent C atoms, fused to a phenyl or pyridine ring, and
u gore spomenutim 5-, 6- ili 7-članim skupinama jedna ili dvije nesusjedne -CH2- skupine mogu se zamijeniti sa -CO-, -C(=CH2)-, -(SO)- ili -(SO2)- skupinom, i in the above-mentioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2- groups can be replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and
gore spomenute zasićene 6- ili 7-člane skupine mogu također biti prisutne kao premošteni prstenasti sistemi s imino, N-(C1-4-4-alkil)-imino, metilenskim, C1-4-alkil-metilenskim ili di-(C1-4-alkil)-metilenskim mostom, i the aforementioned saturated 6- or 7-membered groups may also be present as bridged ring systems with imino, N-(C1-4-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1- 4-alkyl)-methylene bridge, i
gore spomenute cikličke skupine mogu biti mono- ili polisupstituirane na jednom ili više C atoma s R20, i u slučaju fenilne skupine također dodatno mogu biti mono-supstituirane s nitro, i/ili mogu biti supstituirane s R21 na jednom ili više N atoma, the above-mentioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, and in the case of phenyl groups they can also additionally be mono-substituted with nitro, and/or they can be substituted with R21 on one or more N atoms,
R4 i R5 međusobno neovisno imaju jedno od značenja datih za R16, R4 and R5 independently of each other have one of the meanings given for R16,
R6, R7, R8 i R9 međusobno neovisno predstavljaju H, C1-6-alkil, ω-C1-3-alkoksi-C1-3-alkil ili ω-hidroksi-C1-3-alkilnu skupinu, i R6, R7, R8 također međusobno neovisno predstavljaju halogen, R 6 , R 7 , R 8 and R 9 independently represent H, C 1-6 -alkyl, ω-C 1-3 -alkoxy-C 1-3 -alkyl or ω-hydroxy-C 1-3 -alkyl, and R 6 , R 7 , R 8 also independently of each other represent halogen,
R11 predstavlja R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-ili Cy-, R11 represents R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-or Cy-,
R12 ima jedno od značenja datih za R20, R12 has one of the meanings given for R20,
R13 ima jedno od značenja datih za R17, R13 has one of the meanings given for R17,
R14predstavlja halogen, C1-6-alkil, R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-, R15-O-C1-3-alkil-, R15-O-CO-C1-3-alkil-, R16R17N-C1-3-alkil-, R18R19N-CO-C1-3-alkil- ili Cy-C1-3-alkil-, R14 represents halogen, C1-6-alkyl, R15-O-, R15-O-CO-, R16R17N-, R18R19N-CO-, R15-O-C1-3-alkyl-, R15-O-CO-C1-3- alkyl-, R16R17N-C1-3-alkyl-, R18R19N-CO-C1-3-alkyl- or Cy-C1-3-alkyl-,
R15predstavlja H, C1-4-alkil, C3-7-cikloalkil, C3-7-cikloalkil-C1-3-alkil-, fenil, fenil-C1-3-alkil- ili piridinil, R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl, phenyl-C1-3-alkyl- or pyridinyl,
R16 predstavlja H, C1-6-alkil, C3-7-cikloalkil, C3-7-cikloalkil-C1-3-alkil-, C4-6-cikloalkenil, C4-7-cikloalkenil-C1-3-alkil, ω-hidroksi-C2-3-alkil-, ω-(C1-3-alkoksi)-C2-3-alkil-, amino-C1-6-alkil-, C1-3-alkil-amino-C1-6-alkil- ili di-(C1-3-alkil)-amino-C1-6-alkil-, R16 represents H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, C4-6-cycloalkenyl, C4-7-cycloalkenyl-C1-3-alkyl, ω-hydroxy -C2-3-alkyl-, ω-(C1-3-alkoxy)-C2-3-alkyl-, amino-C1-6-alkyl-, C1-3-alkyl-amino-C1-6-alkyl- or di -(C1-3-alkyl)-amino-C1-6-alkyl-,
R17 ima jedno od značenja datih za R16 ili predstavlja fenil, fenil-C1-3-alkil-, piridinil, dioksolan-2-il, C1-3-alkilkarbonil, hidroksikarbonil-C1-3-alkil-, C1-4-alkoksi-karbonil, C1-3-alkilkarbonilamino-C2-3-alkil-, C1-3-alkil-sulfonil- ili C1-3-alkilsulfonilamino-C2-3-alkil-, R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, pyridinyl, dioxolan-2-yl, C1-3-alkylcarbonyl, hydroxycarbonyl-C1-3-alkyl-, C1-4-alkoxy- carbonyl, C1-3-alkylcarbonylamino-C2-3-alkyl-, C1-3-alkyl-sulfonyl- or C1-3-alkylsulfonylamino-C2-3-alkyl-,
R18 i R19 međusobno neovisno predstavljaju H ili C1-6-alkil, R18 and R19 independently represent H or C1-6-alkyl,
R20 predstavlja halogen, hidroksi, cijano, C1-4-alkil, C3-7-cikloalkil, hidroksi-C1-3-alkil, R22-C1-3-alkil- ili ima jedno od značenja datih za R22, R20 represents halogen, hydroxy, cyano, C1-4-alkyl, C3-7-cycloalkyl, hydroxy-C1-3-alkyl, R22-C1-3-alkyl- or has one of the meanings given for R22,
R21 predstavlja C1-3-alkil, ω-hidroksi-C2-3-alkil-, fenil, fenil-C1-3-alkil-, C1-3-alkil-karbonil, karboksi, C1-4-alkoksi-karbonil, C1-3-alkilsulfonil, fenilkarbonil ili fenil-C1-3-alkil-karbonil, R21 represents C1-3-alkyl, ω-hydroxy-C2-3-alkyl-, phenyl, phenyl-C1-3-alkyl-, C1-3-alkyl-carbonyl, carboxy, C1-4-alkoxy-carbonyl, C1- 3-alkylsulfonyl, phenylcarbonyl or phenyl-C1-3-alkyl-carbonyl,
R22 predstavlja piridinil, fenil, fenil-C1-3-alkoksi-, C1-3-alkoksi, C1-3-alkiltio, karboksi, H-CO-, C1-3-alkil-karbonil, C1-4-alkoksikarbonil, aminokarbonil, C1-3-alkil-aminokarbonil, di-(C1-3-alkil)-aminokarbonil, C1-3-alkil-sulfonil-, C1-3-alkil-sulfinil-, C1-3-alkil-sulfonilamino-, amino, C1-3-alkilamino-, di-(C1-3-alkil)-amino-, fenil-C1-3-alkilamino- ili N-(C1-3-alkil)-fenil-C1-3-alkilamino-, acetilamino-, propionilamino-, fenilkarbonil, fenil-karbonilamino-, fenilkarbonilmetilamino-, hidroksi-alkil-aminokarbonil, (4-morfolinil)karbonil, (1-pirolidinil)-karbonil, (1-piperidinil)karbonil, (heksahidro-1-azepinil)-karbonil, (4-metil-1-piperazinil)karbonil, metilendioksi-, aminokarbonilamino- ili alkilaminokarbonilamino-, R22 represents pyridinyl, phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, H-CO-, C1-3-Alkyl-carbonyl, C1-4-Alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C1-3-alkyl-sulfonyl-, C1-3-alkyl-sulfinyl-, C1-3-alkyl-sulfonylamino-, amino, C1 -3-alkylamino-, di-(C1-3-alkyl)-amino-, phenyl-C1-3-alkylamino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetylamino-, propionylamino-, phenylcarbonyl, phenyl-carbonylamino-, phenylcarbonylmethylamino-, hydroxy-alkyl-aminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)-carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)-carbonyl , (4-methyl-1-piperazinyl)carbonyl, methylenedioxy-, aminocarbonylamino- or alkylaminocarbonylamino-,
dok u skupinama i ostacima A, B, W, X, Y, Z, R1 do R9 i R11 do R22 u svakom slučaju jedan ili više C atoma može biti mono- ili polisupstituirano s F i/ili u svakom slučaju jedan ili dva C atoma mogu biti međusobno neovisno mono-supstituirani sa Cl ili Br, i/ili u svakom slučaju jedan ili više fenilnih prstenova mogu imati međusobno neovisno i dodatno jedan, dva ili tri supstituenta odabrana iz skupine koju čine F, Cl, Br, I, C1-4-alkil, C1-4-alkoksi, difluor-metil, trifluormetil, hidroksi, amino, C1-3-alkil-amino-, di-(C1-3-alkil)-amino-, acetilamino-, amino-karbonil, CN, difluormetoksi, trifluormetoksi, amino-C1-3-alkil-, C1-3-alkilamino-C1-3-alkil- i di-(C1-3-alkil)-amino-C1-3-alkil-i/ili mogu biti monosupstituirani s nitro, i while in groups and residues A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently mono-substituted with Cl or Br, and/or in any case one or more phenyl rings can have mutually independently and additionally one, two or three substituents selected from the group consisting of F, Cl, Br, I, C1 -4-alkyl, C1-4-Alkoxy, difluoro-methyl, trifluoromethyl, hydroxy, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl)-amino-, acetylamino-, amino-carbonyl, CN, difluoromethoxy, trifluoromethoxy, amino-C1-3-alkyl-, C1-3-alkylamino-C1-3-alkyl- and di-(C1-3-alkyl)-amino-C1-3-alkyl- and/or can be monosubstituted with nitro, i
H atom bilo koje prisutne karboksi skupine ili H atom povezan na N atom može se zamijeniti u svakom slučaju sa skupinom koju se može odcijepiti in vivo, The H atom of any carboxy group present or the H atom attached to the N atom can be replaced in each case by a group that can be cleaved in vivo,
njihovi tautomeri, diastereomeri, enantiomeri, njihove smjese i njihove soli. their tautomers, diastereomers, enantiomers, their mixtures and their salts.
Daljnji predmet izuma su također dotični spojevi u obliku pojedinačnih optičkih izomera, smjesa pojedinačnih enantiomera ili racemata, u obliku tautomera kao i u obliku slobodnih baza ili odgovarajućih kiselinskih adicijskih soli s farmakološki nedvojbenim kiselinama. Predmetom izuma su također obuhvaćeni i spojevi, uključiv njihove soli, u kojima je jedan ili više vodikovih atoma zamijenjeno s deuterijem. A further subject of the invention are also the respective compounds in the form of individual optical isomers, mixtures of individual enantiomers or racemates, in the form of tautomers as well as in the form of free bases or corresponding acid addition salts with pharmacologically unmistakable acids. The subject of the invention also includes compounds, including their salts, in which one or more hydrogen atoms have been replaced with deuterium.
Daljnji predmet predloženog izuma je postupak za proizvodnju karboksmidnih spojeva formul I A further object of the proposed invention is a process for the production of carboxamide compounds of formula I
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u kojoj A, B, W, X, Y, Z, R1, R2, R3 i k imaju jedno od ovdje ranije navedenih značenja, pri čemu in which A, B, W, X, Y, Z, R1, R2, R3 and k have one of the meanings hereinbefore set forth, wherein
ako A predstavlja skupinu R3 koja nije povezana sa skupinom A: if A represents a group R3 which is not related to the group A:
a) u slučaju da A predstavlja heterocikličku skupinu s dušikom koja je povezana s karboksamidnom skupinom preko dušikovog atoma, koja može također imati dodatno uz dušikov atom i jedan ili više heteroatoma odabranih između N, O i S, najmanje jedan aminski spoj formule I-1 a) in the event that A represents a heterocyclic group with nitrogen which is connected to a carboxamide group through a nitrogen atom, which may also have, in addition to the nitrogen atom and one or more heteroatoms selected from N, O and S, at least one amine compound of the formula I-1
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u kojoj R1, R2, R3, X, Y i Z imaju gore ranije data značenja, wherein R1, R2, R3, X, Y and Z have the meanings given above,
reagira sa CDT (1,1'-karbonildi-(1,2,4-triazol)) i najmanje jedan sekundarni aminski spoj formule I-2 reacts with CDT (1,1'-carbonyldi-(1,2,4-triazole)) and at least one secondary amine compound of formula I-2
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u kojoj A, B, W i k imaju gore ranije data značenja, a i skupina A ima sekundarnu aminsku funkcionalnu skupinu, in which A, B, W and k have the meanings given above, and the group A has a secondary amine functional group,
u otapalu ili u mješavini otapala u prisutnosti najmanje jedne baze, i in a solvent or in a mixture of solvents in the presence of at least one base, and
b) u ostalim slučajevima, namanje jedna karboksilna kiselina formule I-3 b) in other cases, at least one carboxylic acid of formula I-3
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u kojoj A, B, W i k imaju ovdje ranije data značenja, wherein A, B, W and k have the meanings hereinbefore given,
reagira s TBTU (2-(1H-benzotriazol-1-il)-1,1,3,3-tetra-metiluronijev tetrafluorborat) i najmanje jedan aminski spoj formule I-1 reacts with TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate) and at least one amine compound of formula I-1
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u kojoj R1, R2, R3, X, Y i Z imaju ovdje ranije data značenja, wherein R1, R2, R3, X, Y and Z have the meanings hereinbefore given,
u otapalu ili u mješavini otapala u prisutnosti najmanje jedne baze, i in a solvent or in a mixture of solvents in the presence of at least one base, and
ako B predstavlja skupinu R3 povezanu na skupinu A: if B represents the group R3 attached to the group A:
a) u slučaju skupine Q koja ima značenje -CR6R7- (IIIa), dok R6 i R7 su definirani kao ovdje ranije, amin formule Ia.1 a) in the case of the group Q having the meaning -CR6R7- (IIIa), while R6 and R7 are defined as here before, the amine of formula Ia.1
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u kojoj R1, R2, X, Y i Z imaju navedena značenja, in which R1, R2, X, Y and Z have the given meanings,
reagira s esterskim derivatom o-brom-metil-benzojeve kiseline formule Ia.2 reacts with the ester derivative of o-bromo-methyl-benzoic acid of formula Ia.2
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u kojoj R6, R7, W, B i k imaju navedena značenja, wherein R 6 , R 7 , W , B and k have the given meanings,
b) u slučaju skupine Q koja ima značenje -CR6=CR7- (IIIb), u kojoj su R6 i R7 definirani kao ovdje ranije, b) in the case of the group Q having the meaning -CR6=CR7- (IIIb), in which R6 and R7 are defined as here before,
izokinolinonski derivat formule Ib.2 isoquinolinone derivative of formula Ib.2
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u kojoj R6, R7, W, B i k imaju navedena značenja, wherein R 6 , R 7 , W , B and k have the given meanings,
reagira s elektrofilnim spojem formule Ib.3 reacts with an electrophilic compound of formula Ib.3
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u kojoj Y i Z imaju navedena značenja, a OMs predstavlja prikladnu izlaznu skupinu, ponajprije mesilat, čime se dobije izokinolinski derivat formule Ib.4 in which Y and Z have the given meanings, and OMs represents a suitable leaving group, primarily mesylate, which results in an isoquinoline derivative of formula Ib.4
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u kojoj R6, R7, W, B, Y, Z i k imaju navedena značenja, i izokinolinski derivat formule Ib.4 se dalje derivatizira poznatim postupcima, čime se dobije spoj formule I, in which R6, R7, W, B, Y, Z and k have the indicated meanings, and the isoquinoline derivative of formula Ib.4 is further derivatized by known methods, which results in the compound of formula I,
c) u slučaju skupine Q koja ima značenje -N=CR8- (IIIc), u kojoj je R8 definiran kao ovdje ranije, ftalazinonski derivat formule Ic.4 c) in the case of the group Q having the meaning -N=CR8- (IIIc), in which R8 is defined as here before, the phthalazinon derivative of the formula Ic.4
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u kojoj R8, W, B i k imaju navedena značenja, wherein R 8 , W, B and k have the given meanings,
reagira s elektrofilnim spojem formule Ic.5 reacts with the electrophilic compound of formula Ic.5
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u kojoj Y i Z imaju navedena značenja, a OMs predstavlja izlaznu skupina, ponajprije mesilat, čime se dobije ftalazinonski derivat formule Ic.6 in which Y and Z have the indicated meanings, and OMs represents a leaving group, primarily mesylate, which results in the phthalazinon derivative of formula Ic.6
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u kojoj R8, W, B, Y, Z i k imaju navedena značenja, i tako dobiven ftalazinonski derivat formule Ic.6 se dalje derivatizira poznatim postupcima, čime se dobije formule I u kojoj Q predstavlja -N=CR8- (IIIc), in which R8, W, B, Y, Z and k have the indicated meanings, and thus obtained phthalazinone derivative of the formula Ic.6 is further derivatized by known procedures, thereby obtaining the formula I in which Q represents -N=CR8- (IIIc),
d) u slučaju skupine Q koja ima značenje -N=N- (IIId), o-amino-benzamidni derivat formule Id.1 d) in the case of group Q, which has the meaning -N=N- (IIId), o-amino-benzamide derivative of formula Id.1
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u kojoj R1, R2, W, B, X, Y, Z i k imaju navedena značenja, wherein R1, R2, W, B, X, Y, Z and k have the meanings indicated,
reagira u prisutnosti prikladnog nitritnog spoja i kiseline, čime se dobije spoj formule I u kojoj Q predstavlja -N=N-, reacts in the presence of a suitable nitrite compound and an acid, resulting in a compound of formula I in which Q represents -N=N-,
e) u slučaju skupine Q koja ima značenje -CO-NR9- (IIIe), u kojoj je R9 definiran kao ovdje ranije, o-amino-benzamidni derivat formule Ie.1 e) in the case of the group Q having the meaning -CO-NR9- (IIIe), in which R9 is defined as hereinbefore, an o-amino-benzamide derivative of the formula Ie.1
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u kojoj R1, R2, R9, W, B, X, Y, Z i k imaju navedena značenja, reagira u prisutnosti CDI (karbonildiimidazol) čime se dobije spoj formule I u kojoj Q predstavlja -CO-NR9-, in which R1, R2, R9, W, B, X, Y, Z and k have the given meanings, reacts in the presence of CDI (carbonyldiimidazole) to obtain a compound of formula I in which Q represents -CO-NR9-,
f) u slučaju skupine Q koja ima značenje -CR8=N- (IIIf), u kojoj je R3 definiran kao ovdje ranije, o-amino-benzamidni derivat formule If.1 f) in the case of the group Q having the meaning -CR8=N- (IIIf), in which R3 is defined as hereinbefore, an o-amino-benzamide derivative of the formula If.1
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u kojoj R1, R2, W, B, X, Y, Z i k imaju navedena značenja, reagira s karboksilnom kiselinom R8COOH u kojoj R9 ima navedeno značenje i/ili s odgovarajućim aktiviranim derivatom iste karboksilne kiseline, čime se dobije kinazolinonski derivat formule I u kojoj Q predstavlja -CR8=N-, in which R1, R2, W, B, X, Y, Z and k have the given meanings, reacts with the carboxylic acid R8COOH in which R9 has the given meaning and/or with the corresponding activated derivative of the same carboxylic acid, thereby obtaining a quinazolinone derivative of formula I in where Q represents -CR8=N-,
g) slučaju skupine Q koja ima značenje -CO- (IIIg) izobenzofurandionski derivat formule Ig.2 g) in the case of group Q, which has the meaning -CO- (IIIg) isobenzofurandione derivative of formula Ig.2
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u kojoj W, B i k imaju navedena značenja, reagira s aminom formule Ig.1 in which W, B and k have the indicated meanings, reacts with the amine of formula Ig.1
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u kojoj R1, R2, X, Y i Z imaju navedena značenja, čime se dobije spoj formule I u kojoj Q predstavlja -CO-. in which R 1 , R 2 , X, Y and Z have the indicated meanings, thereby obtaining a compound of formula I in which Q represents -CO-.
Izum također obuhvaća i fiziološki podnošljive soli prethodnih i u nastavku opisanih karboksamidnih spojeva prema izumu. The invention also includes physiologically tolerable salts of the previous and below described carboxamide compounds according to the invention.
Predmet ovog izuma su također i sastavi koji sadrže najmanje jedan karboksamidni spoj i/ili sol prema izumu pored prema potrebi jedne ili više fiziološki podnošljivih pomoćnih tvari. The subject of this invention are also compositions containing at least one carboxamide compound and/or salt according to the invention in addition to one or more physiologically tolerable excipients, if necessary.
Nadalje, predmet predloženog izuma su lijekovi koji sadrže najmanje jedan karboksamidni spoj prema izumu i/ili sol prema izumu, prema potrebi zajedno s jednim ili više inertnih nosača i/ili sredstava za razrjeđivanje. Furthermore, the subject of the proposed invention are medicines containing at least one carboxamide compound according to the invention and/or a salt according to the invention, if necessary together with one or more inert carriers and/or diluents.
Predmet ovog izuma je također i upotreba najmanje jednog karboksamidnog spoja prema izumu za utjecanje na ponašanje sisavaca pri uzimanju hrane. The subject of this invention is also the use of at least one carboxamide compound according to the invention for influencing the feeding behavior of mammals.
Izum se također odnosi na upotrebu najmanje jednog karboksamidnog spoja i/ili soli prema izumu za smanjenje tjelesne težine i/ili za prevenciju porasta tjelesne težine sisavca. The invention also relates to the use of at least one carboxamide compound and/or salt according to the invention for reducing body weight and/or for preventing body weight gain in a mammal.
Također, predmet predloženog izuma je i upotreba najmanje jednog karboksamidnog spoja i/ili soli prema izumu za proizvodnju lijeka koji djeluje kao antagonist MCH receptora. Also, the subject of the proposed invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug that acts as an MCH receptor antagonist.
Predmet ovog izuma je nadalje upotreba najmanje jednog karboksamidnog spoja prema izumu i/ili soli za proizvodnju lijeka koji je prikladan za prevenciju i/ili liječenje simptoma i/ili bolesti koje uzrokuje MCH ili su su drugačije uzročno povezane s MCH. The subject of this invention is furthermore the use of at least one carboxamide compound according to the invention and/or salt for the production of a medicament suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally related to MCH.
Daljnji predmet ovog izuma je upotreba najmanje jednog karboksamidnog spoja i/ili soli prema izumu za proizvodnju lijeka, koji je prikladan za prevenciju i/ili liječenje metaboličkih poremećaja i/ili poremećaja prehrane, posebno debljine, bulimije, neurotične bulimije, kaheksije, anoreksije, neurotične anoreksije i hiperfagije. A further subject of this invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug, which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, especially obesity, bulimia, neurotic bulimia, cachexia, anorexia, neurotic anorexia and hyperphagia.
Također je predmet ovog izum i upotreba najmanje jednog karboksamidnog spoja i/ili soli prema izumu za proizvodnju lijeka, koji je prikladan za prevenciju i/ili liječenje bolesti i/ili poremećaja povezanih s debljinom, posebno dijabetesa, naročito tipa II dijabetesa, komplikacija povezanih s dijabetesom koje uključuju dijabetsku retinopatiju, dijabetsku neuropatiju, dijabetsku nefropatiju, inzulinsku otpornost, patološku toleranciju glukoze, encefaloragiju, kardijalnu insuficijenciju, kardiovaskularne bolesti, posebno arteriosklerozu i visok krvni tlak, artritis i gonitis. The subject of this invention is also the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug, which is suitable for the prevention and/or treatment of obesity-related diseases and/or disorders, especially diabetes, especially type II diabetes, complications related to diabetes, which include diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, heart failure, cardiovascular diseases, especially arteriosclerosis and high blood pressure, arthritis and gonitis.
Nadalje, predloženi izum se odnosi na upotrebu najmanje jednog karboksamidnog spoja i/ili soli prema izumu za proizvodnju lijeka koji je prikladan za prevenciju i/ili liječenja hiperlipidemije, celulitisa, akumulacije masti, maligne mastocitoze, sistemske mastocitoze, emocionalnih poremećaja, afektivnih poremećaja, depresije, anksioznosti, poremećaja spavanja, reproduktivnih poremećaja, spolnih poremećaja, poremećaja pamćenja, epilepsije, oblika demencije i hormonalnih poremećaja. Furthermore, the proposed invention relates to the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug suitable for the prevention and/or treatment of hyperlipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression , anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.
Nadalje, predmet ovog izuma je upotreba najmanje jednog karboksamidnog spoja i/ili soli prema izumu za proizvodnju lijeka koji je prikladan za prevenciju i/ili liječenje poremećaja mokrenja, kao što je na primjer urinarna inkontinencija, hiperaktivan mokraćni mjehur, urgencija, nikturija i enureze. Furthermore, the subject of this invention is the use of at least one carboxamide compound and/or salt according to the invention for the production of a drug suitable for the prevention and/or treatment of urinary disorders, such as for example urinary incontinence, overactive bladder, urgency, nocturia and enuresis.
Nadalje, predmet ovog izuma odnosi se na postupak za proizvodnju lijeka prema izumu koji je karakteriziran time da se najmanje jedan karboksamidni spoj prema izumu i/ili odgovarajuća sol nekemijskim putem ugradi u jedan ili više inertnih nosača i/ili sredstava za razrjeđivanje. Furthermore, the subject of this invention relates to a process for the production of a drug according to the invention, which is characterized by the fact that at least one carboxamide compound according to the invention and/or a corresponding salt is non-chemically incorporated into one or more inert carriers and/or diluents.
Daljnji predmet ovog izuma je lijek koji sadrži prvu aktivnu tvar odabranu između karboksamidnih spojeva i/ili odgovarajućih soli, kao i drugu aktivnu tvar odabranu između aktivnih tvari za liječenje dijabetesa, aktivnih tvari za liječenje dijabetičkih komplikacija, aktivnih tvari za liječenje debljine, ponajprije različitih od MCH antagonista, aktivnih tvari za liječenje visokog krvnog tlaka, aktivnih tvari za liječenje hiperlipidemije, uključiv arteriosklerozu, aktivnih tvari za liječenje artritisa, aktivnih tvari za liječenje anksioznosti i aktivnih tvari za liječenje depresije, prema potrebi zajedno s jednim ili više inertnih nosača i/ili sredstava za razrjeđivanje. A further subject of this invention is a medicine containing a first active substance selected from carboxamide compounds and/or corresponding salts, as well as a second active substance selected from active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably different from MCH antagonists, active agents for the treatment of high blood pressure, active agents for the treatment of hyperlipidemia, including arteriosclerosis, active agents for the treatment of arthritis, active agents for the treatment of anxiety and active agents for the treatment of depression, as appropriate together with one or more inert carriers and/or diluents.
Opis izuma u pojedinostima Description of the invention in detail
Ako nije navedeno drugačije, skupine, ostaci, supstituenti i indeksi, posebno A, B, W, X, Y, Z, R1 do R9, R11 do R22, L1, L2, L3 i k imaju jedno od prethodnih i/ili u nastavku navedenih značenja. Unless otherwise stated, groups, residues, substituents and indices, in particular A, B, W, X, Y, Z, R1 to R9, R11 to R22, L1, L2, L3 and k have one of the preceding and/or below meanings.
Izvedbeni oblik ovog izuma kojem se daje prednost obuhvaća spojeve formule I, u kojoj A preferred embodiment of the present invention comprises compounds of formula I, wherein
R3 predstavlja H, C1-6-alkil, C3-7-cikloalkil, C1-7-cikloalkil-C1-4-alkil-, C1-3-alkoksi-C2-6-alkil-, amino-C2-6-alkil-, C1-3-alkil-amino-C2-6-alkil- ili di-(C1-3-alkil)-amino-C2-6-alkil-, R3 represents H, C1-6-alkyl, C3-7-cycloalkyl, C1-7-cycloalkyl-C1-4-alkyl-, C1-3-alkoxy-C2-6-alkyl-, amino-C2-6-alkyl- , C1-3-alkyl-amino-C2-6-alkyl- or di-(C1-3-alkyl)-amino-C2-6-alkyl-,
B ima jedno od značenja datih za Cy, dok veza prema skupini W ili prema potrebi izravno na skupinu A ide preko C atoma karbocikličke jedinice ili prema potrebi kondenziranog fenilnog ili piridinskog prstena ili preko N ili C atoma heterocikličke jedinice, B has one of the meanings given for Cy, while the connection to the group W or, if necessary, directly to the group A goes through the C atom of the carbocyclic unit or, if necessary, the condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic unit,
dok, ako k = 0, skupina B i skupina A mogu biti međusobno povezane preko jednog zajedničkog C atoma tvoreći spirociklički prstenasti sistem ili while, if k = 0, group B and group A can be interconnected through one common C atom forming a spirocyclic ring system or
preko dva zajednička, susjedna atoma tvoreći kondenzirani, biciklički prstenasti sistem, over two common, neighboring atoms forming a condensed, bicyclic ring system,
Cy predstavlja karbo- ili heterocikličku skupinu odabranu između slijedećih značenja: Cy represents a carbo- or heterocyclic group selected from the following meanings:
- zasićena 3- do 7-člana karbociklička skupina, - saturated 3- to 7-membered carbocyclic group,
- nezasićena 5- do 7-člana karbociklička skupina, - unsaturated 5- to 7-membered carbocyclic group,
- fenilna skupina, - phenyl group,
- zasićena 4- do 7-člana ili nezasićena 5- do 7-člana heterociklička skupina s N, O ili S atomom kao hetero-atomom, - saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with N, O or S atom as hetero-atom,
- zasićena ili nezasićena 5- do 7-člana heterociklička skupina s dva ili više N atoma ili s jednim ili dva N atoma i O ili S atomom kao heteroatomima, - saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms,
- aromatska heterociklička 5- ili 6-člana skupina s jednim ili više jednakih ili različitih heteroatoma odabranih između N, O i/ili S, - aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S,
dok gore spomenute 4, 5, 6 ili 7-člane skupine mogu biti povezane preko dva zajednička, susjedna C atoma, kondenzirana s fenilnim ili piridinskim prstenom, i while the above-mentioned 4, 5, 6 or 7-membered groups can be linked via two common, adjacent C atoms, fused to a phenyl or pyridine ring, and
u gore spomenutim 5-, 6- ili 7-članim skupinama jedna ili dvije nesusjedne -CH2- skupine mogu se zamijeniti sa -CO-, -C(=CH2)-, -(SO)- ili -(SO2)- skupinom, i in the above-mentioned 5-, 6- or 7-membered groups, one or two non-adjacent -CH2- groups can be replaced by a -CO-, -C(=CH2)-, -(SO)- or -(SO2)- group, and
gore spomenute zasićene 6- ili 7-člane skupine mogu također biti prisutne kao premošteni prstenasti sistemi s imino, N-(C1-4-4-alkil)-imino, metilenskim, C1-4-alkil-metilenskim ili di-(C1-4-alkil)-metilenskim mostom, i the aforementioned saturated 6- or 7-membered groups may also be present as bridged ring systems with imino, N-(C1-4-4-alkyl)-imino, methylene, C1-4-alkyl-methylene or di-(C1- 4-alkyl)-methylene bridge, i
gore spomenute cikličke skupine mogu biti mono- ili polisupstituirane na jednom ili više C atoma s R20, i u slučaju fenilne skupine također dodatno monosupstituirane s nitro, i/ili supstituirane s R21 na jednom ili više N atoma, the aforementioned cyclic groups can be mono- or polysubstituted on one or more C atoms with R20, and in the case of the phenyl group also additionally monosubstituted with nitro, and/or substituted with R21 on one or more N atoms,
R15predstavlja H, C1-4-alkil, C3-7-cikloalkil, C3-7-cikloalkil-C1-3-alkil-, fenil ili fenil-C1-3-alkil-, R15 represents H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, phenyl or phenyl-C1-3-alkyl-,
R17 ima jedno od značenja datih za R16 ili predstavlja fenil, fenil-C1-3-alkil-, dioksolan-2-il, C1-3-alkil-karbonil, hidroksikarbonil-C1-3-alkil-, C1-3-alkilkarbonil-amino-C2-3-alkil-, C1-3-alkilsulfonil- ili C1-3-alkil-sulfonilamino-C2-3-alkil-, R17 has one of the meanings given for R16 or represents phenyl, phenyl-C1-3-alkyl-, dioxolan-2-yl, C1-3-alkyl-carbonyl, hydroxycarbonyl-C1-3-alkyl-, C1-3-alkylcarbonyl- amino-C2-3-alkyl-, C1-3-alkylsulfonyl- or C1-3-alkyl-sulfonylamino-C2-3-alkyl-,
R22 predstavlja fenil, fenil-C1-3-alkoksi-, C1-3-alkoksi, C1-3-alkiltio, karboksi, C1-3-alkilkarbonil, C1-3-alkoksikarbonil, aminokarbonil, C1-3-alkilaminokarbonil, di-(C1-3-alkil)-aminokarbonil, C1-3-alkilsulfonil, C1-3-alkilsulfinil, C1-3-alkil-sulfonilamino-, amino, C1-3-alkil-amino-, di-(C1-3-alkil)-amino-, fenil-C1-3-alkil-amino- ili N-(C1-3-alkil)-fenil-C1-3-alkilamino-, acetil-amino-, propionilamino-, fenilkarbonil, fenilkarbonil-amino-, fenilkarbonilmetilamino-, hidroksialkilamino-karbonil, (4-morfolinil)karbonil, (1-pirolidinil)karbonil, (1-piperidinil)karbonil, (heksahidro-1-azepinil)karbonil, (4-metil-1-piperazinil)karbonil, metilendioksi, aminokarbonil-amino- ili alkilaminokarbonilamino-, R 22 represents phenyl, phenyl-C1-3-Alkoxy-, C1-3-Alkoxy, C1-3-Alkylthio, carboxy, C1-3-Alkylcarbonyl, C1-3-Alkoxycarbonyl, aminocarbonyl, C1-3-Alkylaminocarbonyl, di-( C1-3-alkyl)-aminocarbonyl, C1-3-alkylsulfonyl, C1-3-alkylsulfinyl, C1-3-alkyl-sulfonylamino-, amino, C1-3-alkyl-amino-, di-(C1-3-alkyl) -amino-, phenyl-C1-3-alkyl-amino- or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-, acetyl-amino-, propionylamino-, phenylcarbonyl, phenylcarbonyl-amino-, phenylcarbonylmethylamino -, hydroxyalkylamino-carbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonyl -amino- or alkylaminocarbonylamino-,
dok u skupinama A, B, W, X, Y, Z, R1 do R9 i R11 do R22 u svakom slučaju jedan ili više C atoma može biti mono- ili polisupstituirano s F i/ili u svakom slučaju jedan ili dva C atoma mogu biti međusobno neovisno monosupstituirani sa Cl ili Br, while in groups A, B, W, X, Y, Z, R1 to R9 and R11 to R22 in each case one or more C atoms can be mono- or polysubstituted with F and/or in each case one or two C atoms can be mutually independently monosubstituted with Cl or Br,
H atom bilo koje prisutne karboksi skupine ili H atom povezan na N atom u svakom slučaju sa skupinom koju se može odcijepiti u vivo može se zamijeniti, The H atom of any carboxy group present or the H atom attached to the N atom in any case with a group that can be cleaved in vivo may be replaced,
njihovi tautomeri, diastereomeri, enantiomeri, njihove smjese i njihove soli. their tautomers, diastereomers, enantiomers, their mixtures and their salts.
Prema prvoj skupini izvedbenih oblika kojima se daje prednost skupine A i ostatak R3 nisu izravno međusobno povezani. Zbog toga skupina A ima jedno od značenja datih za Cy. According to the first group of preferred embodiments, group A and the residue R3 are not directly connected to each other. Therefore, group A has one of the meanings given for Cy.
Prema drugoj skupini izvedbenih oblika kojima se daje prednost skupine A i ostatak R3 su međusobno povezani na takav način da skupina formule I According to another group of preferred embodiments, group A and the residue R3 are interconnected in such a way that the group of formula I
[image] [image]
predstavlja skupinu djelomične formule II represents a group of partial formula II
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i and
Q predstavlja skupinu odabranu između djelomičnih formula IIIa do IIIg Q represents a group selected from partial formulas IIIa to IIIg
[image] . [image] .
Značenja skupine Q su ponajprije odabrana između djelomičnih formula IIIb, IIId, IIIe, IIIf i IIIg, posebno IIId, IIIe, IIIf i IIIg. The values of group Q are preferably selected from partial formulas IIIb, IIId, IIIe, IIIf and IIIg, especially IIId, IIIe, IIIf and IIIg.
Povoljna značenja supstituenata R6, R7, R8 i R9 su međusobno neovisno H i C1-4-alkil-, posebno H, metil ili etil. Favorable meanings of the substituents R6, R7, R8 and R9 are independently of each other H and C1-4-alkyl-, especially H, methyl or ethyl.
Supstituenti L1, L2, L3 imaju ponajprije međusobno neovisno sljedeća značenja: H, F, CI, Br, CH3, CHF2, CF3, C2H5, C3H7, CH(CH3)2, OCH3, OCHF2, OCF3, OC2H5, OC3H7 i OCH(CH3)2. Substituents L1, L2, L3 primarily independently have the following meanings: H, F, CI, Br, CH3, CHF2, CF3, C2H5, C3H7, CH(CH3)2, OCH3, OCHF2, OCF3, OC2H5, OC3H7 and OCH(CH3 )2.
Ponajprije, samo jedan od supstituenata L1, L2, L3 ima značenje različito od H, posebno jedno od značenja koja su ranije navedena kao povoljna. Posebno povoljno sva tri supstituenta L1, L2, L3 znače H. Preferably, only one of the substituents L1, L2, L3 has a meaning other than H, especially one of the meanings previously mentioned as favorable. Particularly advantageously, all three substituents L1, L2, L3 mean H.
Ponajprije skupine R1, R2 predstavljaju međusobno neovisno H, C1-6-alkil, C3-7-cikloalkil, C3-7-cikloalkil-C1-3-alkil-, ω-hidroksi-C2-3-alkil, ω-(C1-3-alkoksi)-C2-3-alkil-, C1-4-alkoksi-karbonil-C1-3-alkil, amino-C2-4-alkil-, C1-3-alkil-amino-C2-4-alkil- ili di-(C1-3-alkil)-amino-C2-4-alkil-, fenil ili fenil-C1-3-alkil-, dok u gore spomenutim skupinama i ostacima jedan ili više C atoma može biti mono- ili polisupstituirano s F i/ili s jedan ili dva C atoma mogu biti međusobno neovisno monosupstituirani sa Cl ili Br, i fenilna skupina može biti mono- ili polisupstituirana s gore definiranom skupinom R12 i/ili monosupstituirana s nitro. First of all, groups R1, R2 represent mutually independent H, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkyl-, ω-hydroxy-C2-3-alkyl, ω-(C1- 3-Alkoxy)-C2-3-alkyl-, C1-4-Alkoxy-carbonyl-C1-3-alkyl, amino-C2-4-alkyl-, C1-3-alkyl-amino-C2-4-alkyl- or di-(C1-3-alkyl)-amino-C2-4-alkyl-, phenyl or phenyl-C1-3-alkyl-, while in the above-mentioned groups and residues one or more C atoms can be mono- or polysubstituted with F and/or with one or two C atoms can be mutually independently monosubstituted with Cl or Br, and the phenyl group can be mono- or polysubstituted with the above-defined group R12 and/or monosubstituted with nitro.
Najpovoljnije je da ostaci R1 i R2 međusobno neovisno predstavljaju H, C1-4-alkil, C3-7-cikloalkil, C3-7-ciklo-alkil-C1-3-alkil-, ω-hidroksi-C2-3-alkil, ω-(C1-3-alkoksi)-C2-3-alkil-, C1-4-alkoksi-karbonil-C1-3-alkil, pri čemu ostaci R1 i R2 mogu također značiti H. It is most favorable that the residues R1 and R2 independently represent H, C1-4-alkyl, C3-7-cycloalkyl, C3-7-cyclo-alkyl-C1-3-alkyl-, ω-hydroxy-C2-3-alkyl, ω -(C1-3-Alkoxy)-C2-3-Alkyl-, C1-4-Alkoxy-carbonyl-C1-3-Alkyl, wherein the residues R1 and R2 can also mean H.
Ponajprije, također, R1 i R2 tvore također alkilenski most na takav način da je skupina R1R2N odabrana iz niza koji čine azetidin, pirolidin, piperidin, azepan, 2,5-dihidro-1H-pirol, 1,2,3,6-tetrahidro-piridin, 2,3,4,7-tetrahidro-1H-azepinil, 2,3,6,7-tetrahidro-1H-azepin, piperazin, gdje slobodna imino funkcionalna skupina može biti supstituirana s R13, morfolinom i tiomorfolinom, pri čemu, prema općoj definiciji za R1 i R2, jedan ili više H atoma može biti zamijenjeno s R14, i/ili ranije spomenute skupine mogu biti supstituirane s jednom ili dvije jednake ili različite karbo- ili heterocikličke skupine Cy na način opisan u općoj definiciji za R1 i R2. Also preferably, R1 and R2 also form an alkylene bridge in such a way that the group R1R2N is selected from the group consisting of azetidine, pyrrolidine, piperidine, azepane, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro -pyridine, 2,3,4,7-tetrahydro-1H-azepinyl, 2,3,6,7-tetrahydro-1H-azepine, piperazine, where the free imino functional group can be substituted with R13, morpholine and thiomorpholine, whereby , according to the general definition for R1 and R2, one or more H atoms can be replaced by R14, and/or the previously mentioned groups can be substituted with one or two identical or different carbo- or heterocyclic groups Cy in the manner described in the general definition for R1 and R2.
Posebno povoljno, skupina Especially good, group
[image] [image]
ima značenje definirano prema jednoj od slijedećih djelomičnih formula has the meaning defined according to one of the following partial formulas
[image] [image]
[image] [image]
[image] [image]
u kojima se jedan ili više H atoma heterocikla nastalog sa skupinom R1R2N- može zamijeniti s R14 i prsten povezan s heterociklom nastao sa skupinom R1R2N može biti mono- ili polisupstituiran na jednom ili više C atoma s R20, i u slučaju fenilnog prstena, on može također biti dodatno monosupstituiran s nitro. in which one or more H atoms of the heterocycle formed with the group R1R2N- can be replaced by R14 and the ring connected to the heterocycle formed with the group R1R2N can be mono- or polysubstituted on one or more C atoms with R20, and in the case of a phenyl ring, it can also be additionally monosubstituted with nitro.
Najpovoljnije su gore opisane skupine R1R2N u kojim R1 i R2 s N atomom skupine R1R2N tvore pirolidin, piperidin ili 2,5-dihidro-1H-pirolni prsten, koji može biti supstituiran kako je navedeno. The most favorable are the groups R1R2N described above in which R1 and R2 with the N atom of the group R1R2N form a pyrrolidine, piperidine or 2,5-dihydro-1H-pyrrole ring, which can be substituted as indicated.
Povoljna značenja za skupinu R14 jesu C1-4-alkil-, C1-4-cikloalkil-, hidroksi-, C1-4-alkoksi, C1-4-alkoksi-C1-3-alkil-, hidroksi-C1-3-alkil, C1-4-alkil-karbonil-, C1-4-alkoksi-karbonil-, C1-4-alkoksi-karbonil-C1-3-alkil-, C1-4-alkoksi-karbonilamino-, C1-4-alkoksi-karbonilamino-C1-3-alkil-, amino, (C1-4-alkil)-amino-, di-(C1-4-alkil)-amino-, fenil, fenil-oksi-, piridinil, piridinil-oksi. Favorable meanings for the group R14 are C1-4-alkyl-, C1-4-cycloalkyl-, hydroxy-, C1-4-alkoxy, C1-4-alkoxy-C1-3-alkyl-, hydroxy-C1-3-alkyl, C1-4-Alkyl-carbonyl-, C1-4-Alkoxy-carbonyl-, C1-4-Alkoxy-carbonyl-C1-3-Alkyl-, C1-4-Alkoxy-carbonylamino-, C1-4-Alkoxy-carbonylamino- C1-3-alkyl-, amino, (C1-4-alkyl)-amino-, di-(C1-4-alkyl)-amino-, phenyl, phenyl-oxy-, pyridinyl, pyridinyl-oxy.
Piperidinska skupina kojoj se daje prednost supstituirana je sa skupinom Cy i ima strukturu A preferred piperidine group is substituted with a Cy group and has the structure
[image] [image]
u kojoj Cy znači ponajprije fenil, koji može biti supstituiran kako je navedeno. wherein Cy is preferably phenyl, which may be substituted as indicated.
Ponajprije, alkilenski most X nema nijedne ili ima najviše jednu -NR4 skupinu. Položaj NR4 skupine unutar alkilenskog mosta X je odabran ponajprije tako da ona zajedno s amino skupinom NR1R2 ili drugom susjednom amino skupinom ne tvori aminsku funkcionalnu skupinu ili da su dva N atoma međusobno susjedni. Zbog toga alkilenski most, u slučaju da je jedna -CH2 skupina zamijenjena s -NR4-, ima ponajprije značenje C2-7-alkilen-NR4-C0-5-alkilen, pri čemu most X osim N atoma ima najviše 7 C atoma mosta i pri čemu C atomi mogu biti supstituirani na navedeni način. Preferably, the alkylene bridge X has no or at most one -NR4 group. The position of the NR4 group within the alkylene bridge X is chosen primarily so that it together with the amino group NR1R2 or another adjacent amino group does not form an amine functional group or that two N atoms are adjacent to each other. That is why the alkylene bridge, in the case that one -CH2 group is replaced by -NR4-, primarily has the meaning C2-7-alkylene-NR4-C0-5-alkylene, whereby the bridge X has, in addition to N atoms, a maximum of 7 C atoms of the bridge and whereby the C atoms can be substituted in the specified manner.
X znači ponajprije jedostruku vezu ili nerazgranati most odabran iz niza koji čine C1-6-alkilen, C2-6-alkenilen, C2-6-alkinilen, C1-6-alkilenoksi, karbonil, karbonil-C1-6-alkilen ili C1-6-alkilen-amino-, pri čemu amino skupina može biti supstituirana s R4, i pri čemu jedan ili dva C atoma mogu biti supstituirani kako je navedeno prema općoj definiciji za X, i/ili alkilenski most može biti povezan s R1 na navedeni način. X means preferably a single bond or an unbranched bridge selected from the group consisting of C1-6-alkylene, C2-6-alkenylene, C2-6-alkynylene, C1-6-alkylenoxy, carbonyl, carbonyl-C1-6-alkylene or C1-6 -alkylene-amino-, wherein the amino group may be substituted by R 4 , and wherein one or two C atoms may be substituted as specified according to the general definition for X, and/or an alkylene bridge may be linked to R 1 in the manner specified.
Posebno povoljno, X znači jednostruku vezu, karbonil ili alkilenski most odabran iz niza koji čine metilen, 1,2-etilen, 1,3-propilen i 1,4-butilen, gdje jedan ili dva C atom mogu biti međusobno neovisno supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi ostatkom i/ili u svakom slučaju s jednim ili dva jednaka ili različita C1-4-alkilna ostatka, i pri čemu u svakom slučaju jedan ili više C atoma mogu biti jednostruko ili višestruko supstituirani s F i/ili u svakom slučaju jedan ili dva C atoma mogu biti međusobno neovisno jednostruko supstitirani s Cl ili Br. Particularly advantageously, X means a single bond, a carbonyl or an alkylene bridge selected from the group consisting of methylene, 1,2-ethylene, 1,3-propylene and 1,4-butylene, where one or two C atoms can be mutually independently substituted with hydroxy . 4-alkyl radicals, and in each case one or more C atoms can be mono- or multi-substituted with F and/or in each case one or two C atoms can be independently mono-substituted with Cl or Br.
Ako su u skupini X jedan ili dva C atoma supstituirani s hidroksi i/ili C1-3-alkoksi ostatkom, tada supstituirani C atom ponajprije nije neposredno susjedan do amino skupine, posebno -NR1R2 ili -NR4-. If in the group X one or two C atoms are substituted with a hydroxy and/or C1-3-alkoxy residue, then the substituted C atom is preferably not immediately adjacent to the amino group, especially -NR1R2 or -NR4-.
Posve posebno je povoljno kad most X znači jednostruku vezu, -CH2- ili -CH(CH3)-. It is especially advantageous when the bridge X means a single bond, -CH2- or -CH(CH3)-.
U slučaju da je u mostu Z jedna -CH2- skupina zamijenjena s -NR5-, položaj NR5 skupine unutar skupine Z je odabran ponajprije tako da ona zajedno s amino skupinom -NR3- ili s drugom susjednom amino skupinom ne tvori aminalnu funkcionalnu skupinu ili da su dva N atoma međusobno susjedni. In the event that one -CH2- group is replaced by -NR5- in the Z bridge, the position of the NR5 group within the Z group is chosen primarily so that it together with the amino group -NR3- or another adjacent amino group does not form an aminal functional group or are two N atoms adjacent to each other.
Povoljno značenje mosta Z je metilen, 1,2-etilen, 1,3-propilen, 1,4-butilen, metilenoksi, 1,2-etilenoksi, 1,3-propilenoksi i 1,4-butilenoksi, gdje jedan ili dva C atoma mogu biti međusobno neovisno supstiuirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi ostatkom i/ili u svakom slučaju s jednim ili dva jednaka ili različita C1-4-alkilna ostatka, i pri čemu u svakom slučaju jedan ili više C atoma mogu biti jednostruko ili višestruko supstituirani s F i/ili u svakom slučaju jedan ili dva C atoma mogu biti međusobno neovisno jednostruko supstituirani s Cl ili Br i pri čemu R3 može biti povezan sa Z uz uključenje s R3 povezanog N atoma uz tvorbu heterocikličke skupine. A preferred meaning of the bridge Z is methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, methyleneoxy, 1,2-ethyleneoxy, 1,3-propyleneoxy and 1,4-butylenoxy, where one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω-(C1-3-alkoxy)-C1-3-alkyl and/or C1-3-alkoxy radical and/or in any case with one or two identical or different C1-4-alkyl residues, and in each case one or more C atoms can be single or multiple substituted with F and/or in each case one or two C atoms can be mutually independently single substituted with Cl or Br and wherein R3 can be connected to Z with the inclusion of the N atom connected to R3 with the formation of a heterocyclic group.
Ako je u skupini Z jedan ili su dva C atoma supstituirana s hidroksi i/ili sa C1-3-alkoksi ostatkom, tada supstituirani C atom ponajprije nije neposredno susjedan do amino skupine, posebno do -NR3- ili -NR5-. If in group Z one or two C atoms are substituted with a hydroxy and/or with a C1-3-alkoxy residue, then the substituted C atom is preferably not immediately adjacent to the amino group, especially to -NR3- or -NR5-.
Posebno povoljno Z je odabran iz niza koji čine -CH2-, -CH2-CH2-, -CH2-CH(CH2)-, -CH2-C(CH3)2-, -CH(CH3)-CH2-, -C(CH3)2-CH2- i -CH2-O-, posebno -CH2-CH2- ili -CH(CH3)-CH2-. Z is particularly advantageously selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-CH(CH2)-, -CH2-C(CH3)2-, -CH(CH3)-CH2-, -C( CH3)2-CH2- and -CH2-O-, especially -CH2-CH2- or -CH(CH3)-CH2-.
U skladu s posebno povoljnom definicijom Z je povezan s R3 tako da skupina djelomične formule According to a particularly advantageous definition, Z is linked to R 3 so that the group of the partial formula
[image] [image]
ima značenje odabrano iz niza koji čine 1,3-pirolidinilen, 1,3-piperidinilen, 1,2,5,6-tetrahidropiridin-1,3-ilen i 3-hidroksi-1,3-piperidinilen. has a meaning selected from the group consisting of 1,3-pyrrolidinylene, 1,3-piperidinylene, 1,2,5,6-tetrahydropyridin-1,3-ylene and 3-hydroxy-1,3-piperidinylene.
Ostatak R3 je odabran ponajprije iz niza koji čine metil, etil, n-propil, izo-propil, 2-hidroksietil, 3-hidroksi-n-propil ili 2-hidroksi-1-metil-etil, pri čemu u navedenim skupinama jedan, dva ili tri H atoma mogu biti zamijenjeni s F, ili je R3 odabran iz niza koji čine H, amino-C2-3-alkil, C1-3-alkil-amino-C2-3-alkil ili di-(C1-3-alkil)-amino-C2-3-alkil. The residue R3 is selected primarily from the group consisting of methyl, ethyl, n-propyl, iso-propyl, 2-hydroxyethyl, 3-hydroxy-n-propyl or 2-hydroxy-1-methyl-ethyl, wherein in the mentioned groups one, two or three H atoms may be replaced by F, or R3 is selected from H, amino-C2-3-alkyl, C1-3-alkyl-amino-C2-3-alkyl or di-(C1-3- alkyl)-amino-C2-3-alkyl.
Posebno povoljna značenja radikala R3 jesu H, metil ili etil, posebno H ili metil. Particularly favorable meanings of the radical R3 are H, methyl or ethyl, especially H or methyl.
Posebno povoljna značenja radikala R4 i/ili R5 su H, C1-4-alkil, C3-6-cikloalkil i C3-6-cikloalkil-C1-3-alkil, posebno H i C1-4-alkil. Particularly favorable meanings of the radicals R4 and/or R5 are H, C1-4-alkyl, C3-6-cycloalkyl and C3-6-cycloalkyl-C1-3-alkyl, especially H and C1-4-alkyl.
Povoljna značenja skupina R11 su C1-6-cikloalkil, hidroksi, C1-4-4-alkoksi, amino, C1-4-alkil-amino- i di-(C1-4-alkil)-amino-. Favorable meanings of the groups R 11 are C 1-6 -cycloalkyl, hydroxy, C 1-4-4 -alkoxy, amino, C 1-4 -alkyl-amino- and di-(C 1-4 -alkyl)-amino-.
Povoljno značenje skupine R20 je halogen, hidroksi, cijano, C1-4-alkil, C3-7-cikloalkil i hidroksi-C1-3-alkil. Posebno povoljno R20 znači F, Cl, Br, I, OH, cijano, metil, difluormetil, trifluormetil, etil, n-propil, izo-propil, metoksi, difluormetoksi, trifluormetoksi, etoksi, n-propoksi ili izo-propoksi. A favorable meaning of the group R20 is halogen, hydroxy, cyano, C1-4-alkyl, C3-7-cycloalkyl and hydroxy-C1-3-alkyl. R 20 is particularly preferably F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso-propyl, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy or iso-propoxy.
Skupina Y je odabrana ponajprije iz niza dvovalentnih cikličkih skupina koji čine 1,2-ciklopropilen, 1,3-ciklo-butilen, 1,3-ciklopentilen, 1,3-ciklopentenilen, 1,3- i 1,4-cikloheksilen, 1,3-fenilen, 1,4-fenilen, 1,3- i 1,4-cikloheksenilen, 1,4-cikloheptilen, 1,4-cikloheptenilen, 1,3-pirolidinilen, 1,3-pirolinilen, 1,3-pirolilen, 1,4-piperidinilen, 1,4-tetrahidropiridinilen, 1,4-dihidro-piridinilen, 2,4- i 2,5-piridinilen ili 1,4-piperazinilen, pri čemu ranije navedene 5-, 6- ili 7-člane skupine mogu biti povezane preko dva zajedničkna susjedna C atoma kondenzirana s fenilnim ili piridinskim prstenom, pri čemu ranije navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili više C atoma s R2, a u slučaju fenilne skupine također dodatno jednostruko s nitro, i/ili na jednom ili više N atoma s R21, i pri čemu R1 može biti povezan s Y i/ili R3 s Y na način opisan u općoj definiciji. Group Y is selected primarily from a number of divalent cyclic groups consisting of 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1 ... pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydro-pyridinylene, 2,4- and 2,5-pyridinylene or 1,4-piperazinylene, wherein the previously mentioned 5-, 6- or 7 -membered groups can be connected via two common adjacent C atoms condensed with a phenyl or pyridine ring, whereby the previously mentioned cyclic groups can be single or multiple substituted on one or more C atoms with R2, and in the case of a phenyl group also additionally single with nitro, and/or on one or more N atoms with R 21 , and wherein R 1 may be linked to Y and/or R 3 to Y in the manner described in the general definition.
Posve posebno povoljno značenje ima skupina Y koja je odabrana iz niza cikličkih struktura koji čine: The group Y, which is selected from a number of cyclic structures that make up:
[image] [image]
pri čemu cikličke skupine mogu biti jednostruko ili dvostruko, ponajprije jednostruko supstituirane s R20, ponajprije s halogenim, CF3, C1-4-alkilom i/ili C1-4-alkoksi. wherein the cyclic groups can be singly or doubly, preferably singly substituted with R20, preferably with halogen, CF3, C1-4-alkyl and/or C1-4-alkoxy.
Nadalje, skupina Y također može biti povezana s ostatkom R1 na takav način da skupina djelomične formule Furthermore, the group Y can also be linked to the residue R1 in such a way that the group of the partial formula
[image] [image]
ima značenje odabrano iz niza slijedećih djelomičnih formula has a meaning selected from the following partial formulas
[image] i [image] . [image] and [image] .
Povoljno značenje skupine A odabrano je iz niza dvovalentnih cikličkih skupina koji čine 1,2-ciklopropilen, 1,3-ciklobutilen, 1,3-ciklopentilen, 1,3-ciklopentenilen, 1,3- i 1,4-cikloheksilen, 1,3- i 1,4-fenilen, 1,3- i 1,4-cikloheksenilen, 1,4-cikloheptilen, 1,4-cikloheptenilen, 1,3-pirolidinilen, 1,3-pirolinilen, 1,3-pirolilen, 1,4-piperidinilen, 1,4-tetrahidropiridinilen, 1,4-dihidro-piridinilen, 2,4- i 2,5-piridinilen, 1,4-piperazinilen, 7-aza-biciklo[2.2.1]heptan-2,7-diil i 8-aza-biciklo[3.2.1]-oktan-3,8-diil, pri čemu gore navedene 5-, 6- ili 7-člane skupine mogu biti povezane preko dva zajednička susjedna C atoma kondenzirana s fenilnim ili piridinskim prstenom, i pri čemu gore navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili više C atoma s R20, a u slučaju fenilne skupine također dodatno jednostruko s nitro, i/ili na jednom ili više N atoma s R21. A preferred meaning of group A is selected from a series of divalent cyclic groups comprising 1,2-cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene, 1,3-cyclopentenylene, 1,3- and 1,4-cyclohexylene, 1, 3- and 1,4-phenylene, 1,3- and 1,4-cyclohexenylene, 1,4-cycloheptylene, 1,4-cycloheptenylene, 1,3-pyrrolidinylene, 1,3-pyrrolinilene, 1,3-pyrrolylene, 1,4-piperidinylene, 1,4-tetrahydropyridinylene, 1,4-dihydro-pyridinylene, 2,4- and 2,5-pyridinylene, 1,4-piperazinylene, 7-aza-bicyclo[2.2.1]heptane-2 . or a pyridine ring, and wherein the above-mentioned cyclic groups can be single or multiple substituted on one or more C atoms with R20, and in the case of a phenyl group also additionally single with nitro, and/or on one or more N atoms with R21.
Posve posebno povoljno značenje skupine A je odabrano iz niza cikličkih struktura koji čine: The particularly favorable meaning of group A is selected from a series of cyclic structures that make up:
[image] [image]
pri čemu cikličke skupine mogu biti jednostruko ili dvostruko, ponajprije jednostruko supstituirane s R20, ponajprije s halogenim, CF3, C1-4-alkilom i/ili C1-4-alkoksi. wherein the cyclic groups can be singly or doubly, preferably singly substituted with R20, preferably with halogen, CF3, C1-4-alkyl and/or C1-4-alkoxy.
U dvovalentnim cikličkim skupinama, koje su navedene za Y i/ili A, su u svakom slučaju također uključeni i oblici zrcalnih slika, tj. oblici u kojima se izmjenjuje veza sa susjednim skupinama, u slučaju Y sa X i Z, kao i u slučaju A sa CO i W. Tako na primjer 1,4-cikloheksenilen znači kako In the divalent cyclic groups, which are listed for Y and/or A, mirror image forms are also included in each case, i.e. forms in which the bond with neighboring groups is exchanged, in the case of Y with X and Z, as well as in the case of A with CO and W. So for example 1,4-cyclohexenylene means how
[image] tako također i [image] . [image] so also [image] .
Gore navedene dvovalentne cikličke skupine Y i A uključuju sve moguće izomere. U nastavku će se pobliže objasniti gore navedena značenja kojima se daje prednost. The divalent cyclic groups Y and A mentioned above include all possible isomers. The above preferred meanings will be explained in more detail below.
Definicija tetrahidropiridinilena obuhvaća značenje 1,2,3,4-tetrahidropiridin-1,4- i -3,6-ilen, 1,2,3,6-tetrahidropiridin-1,4-, -2,5- i -3,6-ilen, 2,3,4,5-tetrahidropiridin-2,5- i -3,6-ilen. Značenje kojem se daje prednost je 1,2,3,6-tetrahidropiridin-1,4-ilen. The definition of tetrahydropyridinylene includes the meaning of 1,2,3,4-tetrahydropyridin-1,4- and -3,6-ylene, 1,2,3,6-tetrahydropyridin-1,4-, -2,5- and -3, 6-ylene, 2,3,4,5-tetrahydropyridin-2,5- and -3,6-ylene. A preferred meaning is 1,2,3,6-tetrahydropyridin-1,4-ylene.
Definicija dihidropiridinilena obuhvaća značenje 1,4- i 1,2-dihidro-piridin-1,4-ilen kao i 1,2-, 1,4-, 1,6-, 2,3-, 2,5-, 3,4-, 4,5- i 5,6-dihidropiridin-2,5-ilen. Pri tome značenje kojem se daje prednost je 1,2-dihidropiridin-1,4-ilen. The definition of dihydropyridinylene includes the meaning of 1,4- and 1,2-dihydro-pyridin-1,4-ylene as well as 1,2-, 1,4-, 1,6-, 2,3-, 2,5-, 3 ,4-, 4,5- and 5,6-dihydropyridin-2,5-ylene. Here, the preferred meaning is 1,2-dihydropyridin-1,4-ylene.
Skupine A i/ili B kojima se daje prednost nisu supstituirane ili su jednostruko ili dvostruko supstituirane s R20, posebno povoljno one nisu supstituirane ili su jednostruko supstituirane s R20. Preferred groups A and/or B are unsubstituted or mono- or di-substituted with R 20 , particularly preferably they are unsubstituted or mono-substituted with R 20 .
Skupina B kojoj se daje prednost prema prvom izbedbenom obliku odabrana je iz niza koji čine C1-6-alkil, C1-6-alkenil, C1-6-alkinil, C3-7-cikloalkil-C1-3-alkil-, C3-7-cikloalkenil-C1-3-alkil-, C3-7-cikloalkil-C1-3-alkenil- ili C3-7-cikloalkil-C1-3-alkinil-, u kojoj jedan ili više C atoma može biti jednostruko ili višestruko supstituirano s halogenim i/ili jednostruko s hidroksi ili cijano i/ili cikličke skupine mogu biti jednostruko ili višestruko supstituirane s R20, i Group B which is preferred according to the first preferred form is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7 -cycloalkenyl-C1-3-alkyl-, C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, in which one or more C atoms can be singly or multiply substituted with halogen and/or singly with hydroxy or cyano and/or cyclic groups may be singly or multiply substituted with R20, and
W znači jednostruku vezu, -O-, C1-4-alkilen-, C2-4-alkenilen, C2-4-alkinilen, C1-4-alkilenoksi-, oksi-C1-4-alkilen-, C1-3-alkilen-oksi-C1-3-alkilen-, imino-, N-(C1-3-alkil)-imino-, imino-C1-4-alkilen-, N-(C1-3-alkil)-imino-C1-4-alkilen-, C1-4-alkilen-imino- ili C1-4-alkilen-N-(C1-3-alkil)-imino skupinu, pri čemu jedan ili dva C atoma mogu biti međusobno neovisno supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi ostatkom i/ili s jednim ili dva jednaka ili različita C1-4-alkilna ostatka, i W means a single bond, -O-, C1-4-alkylene-, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene- oxy-C1-3-alkylene-, imino-, N-(C1-3-alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino-C1-4- alkylene-, C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino group, whereby one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy- by C1-3-alkyl, ω-(C1-3-alkyloxy)-C1-3-alkyl and/or a C1-3-alkyl radical and/or with one or two identical or different C1-4-alkyl radicals, and
k je 0 ili 1, posebno 1, i k is 0 or 1, especially 1, and
R20 ima jedno od gore navedenih značenja. R20 has one of the above meanings.
U gore navedenim značenjima kojima se daje prednost za B, k ima ponajprije vrijednost 1 i W ima ponajprije značenje jednostruke veze, imino- ili N-(C1-3-alkil)-imino-, posebno jednostruke veze. In the above preferred meanings for B, k preferably has the value 1 and W preferably has the meaning of a single bond, imino- or N-(C1-3-alkyl)-imino-, especially a single bond.
Pri tome, posebno povoljno skupina B predstavlja C3-6-alkinil, posebno C3-6-alk-1-inil, i/ili skupina W predstavlja jednostruku vezu, pri čemu k = 1. In this case, particularly advantageously, the group B represents C3-6-alkynyl, especially C3-6-alk-1-ynyl, and/or the group W represents a single bond, where k = 1.
Značenje za skupinu B kojem se daje prednost je prema drugom obliku izvede odabrano iz niza koji čine cikličke skupine ciklopropil, ciklobutil, ciklopentil, ciklo-pentenil, cikloheksil, cikloheksanonil, cikloheksenil, fenil, cikloheptil, cikloheptenil, aziridinil, azetidinil, pirolidinil, pirolinil, pirolil, piperidinil, tetrahidro-piridinil, dihidropiridinil, piridinil, azepanil, piperazinil, 1H-pirazolil, imidazolil, triazolil, tetrazolil, morfolinil, tiomorfolinil, indolil, izoindolil, kinolinil, benzoimidazolil, izokinolinil, furanil i tienil, pri čemu pri čemu veza prema skupini W ili prema potrebi neposredno prema skupini A ide preko C atoma karbocikličkog dijela ili prema potrebi dokondenziranog fenilnog ili piridinskog prstena ili preko N ili C atoma heterocikličkog dijela, ili je B, zajedno sa skupinom W povezanom preko dvostruke veze, odabran iz skupine koju čine ciklo-pentiliden-metil, cikloheksiliden-metil i cikloheksanon-4-iliden-metil, i pri čemu gore spomenute cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili više C atoma s R20, a u slučaju fenilne skupine također i dodatno jednostruko s nitro, i/ili na jednom ili više N atoma s R21. The preferred meaning for group B is according to another form derived from the series consisting of the cyclic groups cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexanonyl, cyclohexenyl, phenyl, cycloheptyl, cycloheptenyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidinyl, tetrahydro-pyridinyl, dihydropyridinyl, pyridinyl, azepanyl, piperazinyl, 1H-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, morpholinyl, thiomorpholinyl, indolyl, isoindolyl, quinolinyl, benzoimidazolyl, isoquinolinyl, furanyl and thienyl, wherein the bond to to the W group or, if necessary, directly to the A group via the C atom of the carbocyclic part or, if necessary, the co-condensed phenyl or pyridine ring or through the N or C atom of the heterocyclic part, or B, together with the W group connected via a double bond, is selected from the group consisting of cyclo-pentylidene-methyl, cyclohexylidene-methyl and cyclohexanone-4-ylidene-methyl, and wherein the aforementioned cyclic s blackberry can be singly or multiply substituted on one or more C atoms with R20, and in the case of a phenyl group also additionally singly substituted with nitro, and/or on one or more N atoms with R21.
Značenje skupine B kojem se daje posve posebnu prednost je fenil, koji je jednostruko, dvostruko ili trostruko, ponajprije jednostruko ili dvostruko supstituiran s R20. A particularly preferred meaning of group B is phenyl, which is singly, doubly or triply, preferably singly or doubly substituted with R 20 .
S gore datim definicijama za B uključeni su svi mogući izomeri dotičnih skupina. Tako su obuhvaćeni posebno slijedeći izomeri: ciklopenten-1-, 3- i 4-il, ciklo-heksanon-4-il, cikloheksen-1-, 3- i 4-il, ciklohepten-1-, 3-, 4- i 5-il, aziridin-1-il, azetidin-1-il, pirolidin-1-il, pirolin-1-il, pirol-1-il, piperidin-1- i 4-il, piridin-2-, -3- i -4-il, azepan-1-il, piperazin-1-il, 4-metil-piperazin-1-il, morfolin-4-il, tiomorfolin-4-il, kinolin-2-, 3-, 4-, 5-, 6-, 7- i 8-il, izokinolin-1-, 3-, 4-, 5-, 6-, 7- i 8-il, 1H-benzoimidazol-1-, 2-, 4-, 5-, 6- i 7-il. With the above definitions for B, all possible isomers of the respective groups are included. Thus, the following isomers are included in particular: cyclopenten-1-, 3- and 4-yl, cyclo-hexanon-4-yl, cyclohexen-1-, 3- and 4-yl, cyclohepten-1-, 3-, 4- and 5-yl, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrole-1-yl, piperidin-1- and 4-yl, pyridin-2-, -3 - and -4-yl, azepan-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, quinolin-2-, 3-, 4 -, 5-, 6-, 7- and 8-yl, isoquinolin-1-, 3-, 4-, 5-, 6-, 7- and 8-yl, 1H-benzoimidazol-1-, 2-, 4 -, 5-, 6- and 7-il.
Definicija pirazola obuhvaća izomere 1H-, 3H- i 4H-pirazol. Ponajprije, pirazolil znači 1H-pirazol-1-il. The definition of pyrazole includes the 1H-, 3H- and 4H-pyrazole isomers. Preferably, pyrazolyl means 1H-pyrazol-1-yl.
Definicija imidazola obuhvaća izomere 1H-, 2H- i 4H-imidazol. Imidazolil je ponajprije 1H-imidazol-1-il. The definition of imidazole includes the 1H-, 2H- and 4H-imidazole isomers. Imidazolyl is preferably 1H-imidazol-1-yl.
Definicija tetrahidropiridina obuhvaća izomere 1,2,3,4-, 1,2,3,6- i 2,3,4,5-tetrahidropiridina. Ponajprije tetrahidropiridinil znači 1,2,3,4- i 1,2,3,6-tetrahidro-piridin-1-il. The definition of tetrahydropyridine includes the 1,2,3,4-, 1,2,3,6- and 2,3,4,5-tetrahydropyridine isomers. In particular, tetrahydropyridinyl means 1,2,3,4- and 1,2,3,6-tetrahydro-pyridin-1-yl.
Definicija dihidropiridina obuhvaća izomere 1,2-, 1,4-, 2,3-, 2,5- i 4,5-dihidropiridin. Dihidropiridinil znači ponajprije 1,2- i 1,4-dihidropiridin-1-il. The definition of dihydropyridine includes the isomers 1,2-, 1,4-, 2,3-, 2,5- and 4,5-dihydropyridine. Dihydropyridinyl means primarily 1,2- and 1,4-dihydropyridin-1-yl.
Definicija triazola obuhvaća izomere 1H-, 3H- i 4H-[1,2,4]-triazola kao i 1H-, 2H- i 4H-[1,2,3]-triazola. Definicija triazolila obuhvaća stoga 1H-[1,2,4]-triazol-1-, 3- i 5-il, 3H-[1,2,4]-triazol-3- i 5-il, 4H-[1,2,4]-triazol-3-, 4- i 5-il, 1H-[1,2,3]-triazol-1-, 4- i 5-il, 2H-[1,2,3]-triazol-2-, 4- i 5-il kao i 4H-[1,2,3]-triazol-4- i 5-il. The definition of triazole includes isomers of 1H-, 3H- and 4H-[1,2,4]-triazole as well as 1H-, 2H- and 4H-[1,2,3]-triazole. The definition of triazolyl thus includes 1H-[1,2,4]-triazol-1-, 3- and 5-yl, 3H-[1,2,4]-triazol-3- and 5-yl, 4H-[1, 2,4]-triazol-3-, 4- and 5-yl, 1H-[1,2,3]-triazol-1-, 4- and 5-yl, 2H-[1,2,3]-triazole -2-, 4- and 5-yl as well as 4H-[1,2,3]-triazol-4- and 5-yl.
Pojam tetrazola obuhvaća izomere 1H-, 2H- i 5H-tetrazol. Defenicija tetrazolila obuhvaća stoga 1H-tetrazol-1- i 5-il, 2H-tetrazol-2- i 5-il kao i 5H-tetrazol-5-il. The term tetrazole includes the 1H-, 2H- and 5H-tetrazole isomers. The definition of tetrazolyl thus includes 1H-tetrazol-1- and 5-yl, 2H-tetrazol-2- and 5-yl as well as 5H-tetrazol-5-yl.
Definicija indola obuhvaća izomere 1H- i 3H-indol. Pojam indolila znači ponajprije 1H-indol-1-il. The definition of indole includes the 1H- and 3H-indole isomers. The term indolyl means primarily 1H-indol-1-yl.
Definicija izoindola obuhvaća izomere 1H- i 2H-izoindol. Pojam izoindolila znači ponajprije 2H-izoindol-2-il. The definition of isoindole includes the isomers 1H- and 2H-isoindole. The term isoindolyl means primarily 2H-isoindol-2-yl.
Općenito, veza prema jednom od gore spomenutih heterocikličkih skupina, posebno prema pirazolilu, imidazolilu, tetrahidropiridinilu, dihidropiridinilu, triazolilu, tetrazolilu, indolilu ili izoindolilnoj skupini može ići preko C atoma ili prema potrebi preko N atoma iminske funkcionalne skupine. In general, the bond to one of the above-mentioned heterocyclic groups, especially to pyrazolyl, imidazolyl, tetrahydropyridinyl, dihydropyridinyl, triazolyl, tetrazolyl, indolyl or isoindolyl group can go through the C atom or, if necessary, through the N atom of the imine functional group.
Skupina B ponajprije nije supstituirana, ili je jednostruko, dvostruko ili trostruko supstituirana s R20. Posebno povoljno, B je jednostruko ili dvostruko supstituiran s R20. U slučaju da B predstavlja supstituirani česteročlani prsten, supstituent se nalazi ponajprije u para položaju prema vezi sa skupinom Group B is preferably unsubstituted, or is mono-, di- or tri-substituted with R 20 . Particularly advantageously, B is mono- or doubly substituted with R 20 . In the case that B represents a substituted four-membered ring, the substituent is primarily in the para position relative to the bond with the group
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Indeks k može imati vrijednost 0 ili 1. U slučaju kojem se daje prednost k = 1, most W ima navedeno značenje, ponajprije značenje jednostruke veze, -CH2- ili -CH=. Značenje djelomične formule -A-W-B kojem se daje prednost odabrano je između dolje navedenih struktura, pri čemu V predstavlja C ili N atom, ponajprije C atom, i navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili na više C atoma s R20, a u slučaju fenilne ili fenilenske skupine također i dodatno jednostruko s nitro: The index k may have a value of 0 or 1. In the preferred case of k = 1, the bridge W has the indicated meaning, preferably the meaning of a single bond, -CH2- or -CH=. A preferred meaning of the partial formula -A-W-B is selected from the structures listed below, wherein V represents a C or N atom, preferably a C atom, and the said cyclic groups may be mono- or multi-substituted on one or more C atoms with R20, and in in the case of a phenyl or phenylene group also additionally single with nitro:
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Posve posebnu prednost daje se spojevima formule I, u kojoj k = 1, i W je jednostruka veza. Particular preference is given to compounds of formula I, in which k = 1, and W is a single bond.
Indeks k može također imati vrijednost 0. Prema prvoj pod-inačici, skupina A je povezana sa skupinom B preko zajedničkog C atoma uz tvorbu spirocikličkog prstena, dok skupina A predstavlja zasićenu 5- do 7-članu, a skupina B zasićenu 4- do 7-članu karbo- ili heterocikličku skupinu, i pri čemu heterocikličke skupine imaju u svakom slučaju N, O ili S atom, i pri čemu preko dva susjedna C atoma na 5- do 7-članu skupinu B može biti kondenziran fenilni ili piridinski prsten, i pri čemu gore navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili na više C atoma s R20, a u slučaju dokondenziranog fenilnog prstena također i dodatno jednostruko s nitro, i/ili na jednom ili više N atoma s R21. The index k can also have a value of 0. According to the first sub-version, group A is connected to group B through a common C atom with the formation of a spirocyclic ring, while group A represents saturated 5- to 7-membered, and group B saturated 4- to 7-membered -membered carbo- or heterocyclic group, and wherein the heterocyclic groups have in each case an N, O or S atom, and wherein a phenyl or pyridine ring can be condensed via two adjacent C atoms on the 5- to 7-membered group B, and whereby the above-mentioned cyclic groups can be singly or multiply substituted on one or more C atoms with R20, and in the case of a condensed phenyl ring also additionally singly substituted with nitro, and/or on one or more N atoms with R21.
Značenje djelomične formule -A-W-B kojem se daje prednost prema ovoj drugoj pod-inačici odabrano je između struktura navedenih u slijedećoj tablici, pri čemu navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili na više C atoma s R20, a u slučaju dokondenziranog fenilnog prstena također i dodatno jednostruko s nitro: The meaning of the partial formula -A-W-B which is preferred according to this second sub-version is selected from the structures listed in the following table, wherein the mentioned cyclic groups can be mono- or multi-substituted on one or more C atoms with R20, and in the case of a fused phenyl ring also additionally single with nitro:
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Prema drugoj pod-inačici u slučaju da k = 0, skupina B je povezana sa skupinom A preko dva zajednička, susjedna atoma uz tvorbu kondenziranog, bicikličkog zasićenog, nezasićenog ili aromatskog, 8- do 12-članog prstenastog sistema, koji može sadržavati jedan ili više jednakih ili različitih heteroatoma odabranih između N, O i/ili S, i pri čemu biciklički prstenasti sistem može biti jednostruko ili višestruko supstituiran na jednom ili više C atoma s R20, a u slučaju dokondenziranog fenilnog pstena također i dodatno jednostruko s nitro, i/ili na jednom ili više N atoma s R21. According to another sub-version in the case that k = 0, group B is connected to group A via two common, adjacent atoms with the formation of a condensed, bicyclic saturated, unsaturated or aromatic, 8- to 12-membered ring system, which may contain one or several identical or different heteroatoms selected from N, O and/or S, and whereby the bicyclic ring system can be singly or multiply substituted on one or more C atoms with R20, and in the case of co-condensed phenyl psten also additionally singly substituted with nitro, and/ or on one or more N atoms with R21.
Značenje djelomične formule -A-W-B kojem se daje prednost prema toj prvoj pod-inačici odabrano je između struktura navedenih u slijedećih tablici, pri čemu navedene cikličke skupine mogu biti jednostruko ili višestruko supstituirane na jednom ili na više C atoma s R20, a u slučaju fenilnog prstena također i dodatno jednostruko s nitro. The meaning of the partial formula -A-W-B which is preferred according to this first sub-version is selected from the structures listed in the following table, whereby the mentioned cyclic groups can be single or multi-substituted on one or more C atoms with R20, and in the case of a phenyl ring also and additionally single with nitro.
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Spojevi prema izumu kojima se daje prednost su oni u kojima jedna ili više skupina, ostataka, supstituenata i/ili indeksa imaju jedno od gore navedenih značenja kojima se daje prednost. Preferred compounds according to the invention are those in which one or more groups, residues, substituents and/or indices have one of the above preferred meanings.
Značenje supstituenta R20 kojem se daje prednost odabrano je iz skupine koju čine fluor, klor, brom, CF3, C1-4-alkil, C1-4-alkoksi. A preferred meaning of the substituent R20 is selected from the group consisting of fluorine, chlorine, bromine, CF3, C1-4-alkyl, C1-4-alkoxy.
Posebnu prednost daje se onim spojevima prema izumu u kojima Special preference is given to those compounds according to the invention in which
Y i A su međusobno neovisno odabrani iz niza koji čine dvovalentne cikličke skupine 1,4-fenilen, 1,4-ciklo-heksilen, 1,4-cikloheksenilen, 1,4-piperidinilen, 1,2,3,6-tetrahidro-piridin-1,4-ilen, 2,5-piridinilen i 1,4-piperazinilen, dok A može također biti povezan na R3 prema zahtjevu 3, i gore spomenute cikličke skupine mogu biti mono- ili polisupstituirane s R20 na jednom ili više C atoma, u slučaju fenilne skupine ona može također dodatno biti monosupstituirana s nitro, i/ili može biti supstituirana s R21 na jednom ili više N atoma, Y and A are mutually independently selected from the series consisting of bivalent cyclic groups 1,4-phenylene, 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-piperidinylene, 1,2,3,6-tetrahydro- pyridin-1,4-ylene, 2,5-pyridinylene and 1,4-piperazinylene, while A may also be attached to R 3 according to claim 3, and the aforementioned cyclic groups may be mono- or polysubstituted by R 20 at one or more C atoms, in the case of a phenyl group it may additionally be monosubstituted with nitro, and/or may be substituted with R21 on one or more N atoms,
B predstavlja fenil ili cikloheksil, dok gore spomenute skupine mogu biti mono- ili polisupstituirane s R20 i/ili fenilni prsten može dodatno biti monosupstituiran s nitro, dok R20 ima značenje dato u zahtjevu 1, i B represents phenyl or cyclohexyl, while the aforementioned groups can be mono- or polysubstituted by R20 and/or the phenyl ring can additionally be monosubstituted by nitro, while R20 has the meaning given in claim 1, and
k ima vrijednost 1, k has the value 1,
W je jednostruka veza, -CH2- ili-CH=, i W is a single bond, -CH2- or -CH=, i
Z predstavlja -CH2-CH2-, -CH2-CH(CH3)-, -CH2C(CH3)2-, -CH(CH3)-CH2-, -C(CH3)2-CH2- ili -CH2-O- ili Z represents -CH2-CH2-, -CH2-CH(CH3)-, -CH2C(CH3)2-, -CH(CH3)-CH2-, -C(CH3)2-CH2- or -CH2-O- or
je povezan na R3 na takav način da skupina djelomične formule is connected to R3 in such a way that the group of the partial formula
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iz formule I ima značenje odabrano između 1,3-pirolidinilena i 1,3-piperidinilena. of formula I has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene.
Posebnu prednost daje se spojevima prema izumu slijedeće skupine formula I.1 do I.14: Particular preference is given to compounds according to the invention of the following groups of formulas I.1 to I.14:
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u kojima in which
U i V međusobno neovisno predstavljaju C ili N, U and V independently represent C or N,
R23 i R24 međusobno neovisno predstavljaju H, F, metil, trifluormetil, etil, izo-propil ili n-propil, R23 and R24 independently represent H, F, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl,
dok u formulama 1.1 do 1.6 radikal R24 može biti povezan s R3 na takav način da skupina of djelomične formule while in formulas 1.1 to 1.6 the radical R24 can be connected to R3 in such a way that the group of the partial formula
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ima značenje odabrano između 1,3-pirolidinilena i 1,3-piperidinilena, i has a meaning selected from 1,3-pyrrolidinylene and 1,3-piperidinylene, and
R25, R26 R27 imaju međusobno neovisno značenja data za R20 prema zahtjevu 1 ili 2 ili u slučaju fenilne skupine također jednostavno predstavljaju nitro, dok skupine R25, R26 i R27 koje se pojavljuju više puta mogu imati jednaka ili različita značenja, i R 25 , R 26 R 27 independently of each other have the meanings given to R 20 according to claim 1 or 2 or in the case of a phenyl group also simply represent nitro, while the groups R 25 , R 26 and R 27 appearing more than once can have the same or different meanings, and
j je 0, 1, 2, 3 ili 4 i j is 0, 1, 2, 3 or 4 and
m, n međusobno neovisno predstavlja 0, 1 ili 2. m, n represent 0, 1 or 2 independently of each other.
Posve posebnu prednost daje se spojevima prema izumu gornjih formula I.1, I.2, I.8, I.10 i I.12. Posebno, naročitu prednost može se pripisati spojevima slijedećih formula A very special preference is given to compounds according to the invention of the above formulas I.1, I.2, I.8, I.10 and I.12. In particular, a particular advantage can be attributed to the compounds of the following formulas
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pri čemu ostaci i supstituenti imaju gore i u nastavku definirana značenja. whereby residues and substituents have the meanings defined above and below.
Nadalje, prednost se daje spojevima prema izumu slijedeće djelomične formule: Furthermore, preference is given to compounds according to the invention of the following partial formula:
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u kojoj where
B je odabran iz niza koji čine C1-6-alkil, C1-6-alkenil, C1-6-alkinil, C3-7-cikloalkil-C1-3-alkil-, C3-7-cikloalkenil-C1-4-alkil-, C3-7-cikloalkil-C1-3-alkenil- ili C3-7-cikloalkil-C1-3-alkinil-, pri čemu jedan ili više C atoma može biti mono- ili polisupstituirano s halogenim i/ili monosupstituirano s hidroksi ili cijano i/ili cikličke skupine mogu biti mono- ili polisupstituirane s R20, i B is selected from the group consisting of C1-6-alkyl, C1-6-alkenyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl-, C3-7-cycloalkenyl-C1-4-alkyl- , C3-7-cycloalkyl-C1-3-alkenyl- or C3-7-cycloalkyl-C1-3-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups may be mono- or polysubstituted by R20, i
W predstavlja jednostruku vezu, -O-, C1-4-alkilen, C2-4-alkenilen, C2-4-alkinilen, C1-4-alkilenoksi-, oksi-C1-4-alkilen-, C1-3-alkilen-oksi-C1-3-alkilen-, imino, N-(C1-3-alkil)-imino-, imino-C1-4-alkilen-, N-(C1-3-alkil)-imino-C1-4-alkilen-, C1-4-alkilen-imino- ili C1-4-alkilen-N-(C1-3-alkil)-imino skupina, dok jedan ili dva C atoma mogu biti međusobno neovisno supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi skupinom i/ili s jednom ili dvije jednake ili različite C1-4-alkilne skupine, i W represents a single bond, -O-, C1-4-alkylene, C2-4-alkenylene, C2-4-alkynylene, C1-4-alkyleneoxy-, oxy-C1-4-alkylene-, C1-3-alkylene-oxy -C1-3-alkylene-, imino, N-(C1-3-alkyl)-imino-, imino-C1-4-alkylene-, N-(C1-3-alkyl)-imino-C1-4-alkylene- , C1-4-alkylene-imino- or C1-4-alkylene-N-(C1-3-alkyl)-imino group, while one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3 -alkyl, ω-(C1-3-Alkoxy)-C1-3-Alkyl and/or C1-3-Alkoxy group and/or with one or two identical or different C1-4-Alkyl groups, and
k predstavlja 0 ili 1. k represents 0 or 1.
Nadalje, prema ovoj izvedbi, prednost se daje takovim spojevima u kojima je skupina B je odabrana iz niza koji čine C1-6-alkil, C1-6-alkinil, C3-7-cikloalkil-C1-3-alkil- ili C3-7-cikloalkenil-C1-4-alkinil-, pri čemu jedan ili više C atoma može biti mono- ili polisupstituirano s halogenim i/ili monosupstituirano s hidroksi ili cijano i/ili cikličke skupine mogu biti mono- ili polisupstituirane s R20, i/ili Furthermore, according to this embodiment, preference is given to such compounds in which group B is selected from the group consisting of C1-6-alkyl, C1-6-alkynyl, C3-7-cycloalkyl-C1-3-alkyl- or C3-7 -cycloalkenyl-C1-4-alkynyl-, wherein one or more C atoms can be mono- or polysubstituted with halogen and/or monosubstituted with hydroxy or cyano and/or cyclic groups can be mono- or polysubstituted with R20, and/or
W predstavlja jednostruku vezu, -O-, imino, N-(C1-3-alkil)-imino-, dok jedan ili dva C atoma mogu biti međusobno neovisno supstituirani s hidroksi, ω-hidroksi-C1-3-alkilom, ω-(C1-3-alkoksi)-C1-3-alkilom i/ili C1-3-alkoksi skupinom i/ili s jednom ili dvije jednake ili različite C1-4-alkilne skupine, i W represents a single bond, -O-, imino, N-(C1-3-alkyl)-imino-, while one or two C atoms can be mutually independently substituted with hydroxy, ω-hydroxy-C1-3-alkyl, ω- (C1-3-Alkoxy)-C1-3-Alkyl and/or C1-3-Alkoxy group and/or with one or two identical or different C1-4-Alkyl groups, and
k predstavlja ili 1. k represents either 1.
Posve posebnu prednost daje se značenjima skupine Special priority is given to group meanings
-W-B prema ovom obliku izvedbe koja je odabrana iz niza koji čine C1-8-alkil, -C≡C-C1-6-alkil, -CH=CH-C1-6-alkil, -O-C1-6-alkil, -NH(C1-6-alkil) i -N(C1-6-alkil)(C1-3-alkil), posebno iz skupine koju čine C3-8-alkil, -C≡C-C3-6-alkil, -CH=CH-C3-6-alkil, -O-C3-6-alkil, -NH(C3-6-alkil) i -N(C3-6-alkil)(C1-3-alkil). -W-B according to this embodiment which is selected from the group consisting of C1-8-alkyl, -C≡C-C1-6-alkyl, -CH=CH-C1-6-alkyl, -O-C1-6-alkyl, -NH(C1-6-alkyl) and -N(C1-6-alkyl)(C1-3-alkyl), especially from the group consisting of C3-8-alkyl, -C≡C-C3-6-alkyl, - CH=CH-C3-6-alkyl, -O-C3-6-alkyl, -NH(C3-6-alkyl) and -N(C3-6-alkyl)(C1-3-alkyl).
Među spojevima prema izumu koji su prethodno opisani posebnu prednost se daje onima, posebno djelomičnih formula I.1 do I.15, u kojima ostaci R1, R2, R3, L1, L2, L3 i/ili skupina X imaju u svakom slučaju značenja kojima se daje prednost. Among the compounds according to the invention previously described, particular preference is given to those, especially partial formulas I.1 to I.15, in which the residues R1, R2, R3, L1, L2, L3 and/or the group X have in each case the meanings which is preferred.
Posebno, naročitu prednost daje se onim spojevima prema izumu u kojima je X odabran između -CH2-, -CH(CH3)- ili -C(CH3)2-. In particular, particular preference is given to those compounds according to the invention in which X is selected from -CH2-, -CH(CH3)- or -C(CH3)2-.
Također, posebnu prednost daje se onim spojevima djelomičnih formula I.1 do I.15 u kojima Also, special preference is given to those compounds of partial formulas I.1 to I.15 in which
a) skupina U je N atom, a skupina V je C atom, ili a) group U is an N atom, and group V is a C atom, or
b) skupina U je C atom, a skupina V je N atom, ili b) group U is a C atom, and group V is an N atom, or
c) obje skupine U i V predstavljaju u svakom slučaju C atom. c) both groups U and V represent a C atom in each case.
U spojevima prema izumu kojima se daje posebnu prednost, supstituenti R25, R26, R27 imaju međusobno neovisno značenje odabrano iz niza koji čine F, Cl, Br, I, OH, cijano, metil, difluormetil, trifluormetil, etil, n-propil, izo-propil, metoksi, difluormetoksi, trifluor-metoksi, etoksi, n-propoksi ili izo-propoksi, a u slučaju supstitucije fenilne skupine također i jednostruko nitro, pri čemu ostaci R25, R26, R27, koji se pojavljuju više puta, mogu imati jednaka ili različita značenja, j je 0, 1 ili 2, m i n su međusobno neovisno 0 ili 1. In the compounds according to the invention which are given particular preference, the substituents R25, R26, R27 have a mutually independent meaning selected from the series consisting of F, Cl, Br, I, OH, cyano, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso -propyl, methoxy, difluoromethoxy, trifluoro-methoxy, ethoxy, n-propoxy or iso-propoxy, and in the case of substitution of the phenyl group also single nitro, whereby the residues R25, R26, R27, which appear more than once, can have the same or different meanings, j is 0, 1 or 2, m and n are independently 0 or 1.
Značenja ostataka R6, R7, R8 i/ili R9, kojima se u spojevima prema izumu daje prednost, jesu međusobno neovisno H, metil, trifluormetil, etil, izo-propil ili n-propil, a u slučaju R6, R7, također i F. The meanings of the residues R6, R7, R8 and/or R9, which are preferred in the compounds according to the invention, are independently of each other H, methyl, trifluoromethyl, ethyl, iso-propyl or n-propyl, and in the case of R6, R7, also F.
Posebnu prednost imaju pojedinačni spojevi koji su odabrani iz skupine koju čine Particular advantage is given to individual compounds that are selected from the group they comprise
(1) 7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (1) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(2) 3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-p-tolil-3H-kinazolin-4-on (2) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one
(3) 3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-(4-tri-fluormetil-fenil)-3H-kinazolin-4-on (3) 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-tri-fluoromethyl-phenyl)-3H-quinazolin-4-one
(4) 7-(4-metoksi-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (4) 7-(4-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(5) 7-(3,4-diklor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (5) 7-(3,4-dichloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(6) 7-(4-fluor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (6) 7-(4-fluoro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(7) 7-(4-etil-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (7) 7-(4-ethyl-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(8) 2-metil-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-(4-trifluormetil-fenil)-3H-kinazolin-4-on (8) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoromethyl-phenyl)-3H-quinazolin-4-one
(9) 2-metil-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-p-tolil-3H-kinazolin-4-on (9) 2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one
(10) 7-(4-klor-fenil)-2-metil-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (10) 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(11) 7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-1 H-kinazolin-2,4-dion (11) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1 H-quinazoline-2,4-dione
(12) 7-(4-klor-fenil)-3-{2-[4-((S)-2-metoksimetil-pirolidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on (12) 7-(4-chloro-phenyl)-3-{2-[4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
(13) 7-(4-klor-fenil)-3-[2-(4-dimetilaminometil-fenil)-etil]-3H-kinazolin-4-on (13) 7-(4-chloro-phenyl)-3-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(14) 7-(4-klor-fenil)-3-[2-(4-piperidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (14) 7-(4-chloro-phenyl)-3-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(15) 7-(4-klor-fenil)-3-[2-(4-morfolin-4-ilmetil-fenil)-etil]-3H-kinazolin-4-on (15) 7-(4-chloro-phenyl)-3-[2-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(16) 7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-benzo[d][1,2,3]triazin-4-on (16) 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-benzo[d][1,2,3]triazin-4- he
(17) 5-(4-fluor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-izoindol-1,3-dion (17) 5-(4-fluoro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-isoindol-1,3-dione
(18) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (18) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(19) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-dietil-aminometil-fenil)-etil]-amid (19) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-amide
(20) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-piperidin-1-ilmetil-fenil)-etil]-amid (20) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide
(21) 4'-metoksi-bifenil-4-karboksilna kiselina [2-(4-di-etilaminometil-fenil)-etil]-amid (21) 4'-methoxy-biphenyl-4-carboxylic acid [2-(4-di-ethylaminomethyl-phenyl)-ethyl]-amide
(22) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-dietil-aminometil-fenil)-etil]-metil-amid (22) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-diethyl-aminomethyl-phenyl)-ethyl]-methyl-amide
(23) 4-(4-klor-fenil)-cikloheksanekarboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (23) 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(24) 4-metilfenil-piperidine-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (24) 4-methylphenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(25) 4-(4-klor-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]amid (25) 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]amide
(26) 4-(4-klor-fenil)-piperidin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (26) 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(27) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-propil]-amid (27) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide
(28) 4'-klor-bifenil-4-karboksilna kiselina (4-pirolidin-1-ilmetil-benziloksi)-amid (28) 4'-chloro-biphenyl-4-carboxylic acid (4-pyrrolidin-1-ylmethyl-benzyloxy)-amide
(29) 4-cikloheksil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (29) 4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(30) 4'-klor-bifenil-4-karboksilna kiselina [2-(3-metoksi-4-pirolidin-1-ilmetil-fenil)-etil]-amid (30) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(31) 7-(4-klor-fenil)-3-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-3H-kinazolin-4-on (31) 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one
(32) 4'-klor-bifenil-4-karboksilna kiselina {2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amid (32) 4'-chloro-biphenyl-4-carboxylic acid {2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide
(33) 7-(3-metoksi-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on (33) 7-(3-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
(34) 4-(4-okso-cikloheksil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (34) 4-(4-oxo-cyclohexyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(35) 4-cikloheksil-1-ciloheksilkarboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (35) 4-cyclohexyl-1-cylohexylcarboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(36) 4-benzil-piperidin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (36) 4-benzyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(37) 4-cikloheksil-piperidin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (37) 4-cyclohexyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(38) 4-(4-klor-fenil)-piperazin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (38) 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(39) 4-(4-fluor-fenil)-piperidin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (39) 4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(40) 4-(4-metoksi-fenil)-piperazin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (40) 4-(4-Methoxy-phenyl)-piperazine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(41) 4-fenil-piperidin-1-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (41) 4-phenyl-piperidine-1-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(42) (4'-klor-bifenil-4-il)-[3-(4-pirolidin-1-ilmetil-fenil)-piperidin-1-il]-metanon (42) (4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-1-yl]-methanone
(43) 4'-klor-bifenil-4-karboksilna kiselina [2-metil-2-(4-pirolidin-1-ilmetil-fenil)-propil]-amid (43) 4'-chloro-biphenyl-4-carboxylic acid [2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide
(44) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-cikloheksil)-etil]-amid (44) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide
(45) 4-benzil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (45) 4-benzyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(46) 4-(4-okso-cikloheksilidenmetil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (46) 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(47) 4'-klor-bifenil-4-karboksilna kiselina [2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etil]-amid (47) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(48) 5-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2,3-dihidro-izoindol-1-on (48) 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one
(49) 4-piperidin-1-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (49) 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(50) 7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-benzo[d][1,2,3]-triazin-4-on (50) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][ 1,2,3]-triazin-4-one
(51) 7-(4-klor-fenil)-3-{2-[4-(3-aza-spiro[5.5]undec-3-il-metil)-fenil]-etil}-3H-kinazolin-4-on (51) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-quinazolin-4 -he
(52) 7-(4-klor-fenil)-3-{2-[4-(3-aza-spiro[5.5]undec-3-il-metil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on (52) 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5.5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-benzo[d ][1,2,3]triazin-4-one
(53) 7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on (53) 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
(54) 7-(4-klor-fenil)-3-(2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etil)-3H-kinazolin-4-on (54) 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4 -he
(55) 6-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2H-izokinolin-1-on (55) 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one
(56) 4'-klor-bifenil-4-karboksilna kiselina [2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid (56) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(57) 4'-klor-bifenil-4-karboksilna kiselina [2-(3-metil-4-pirolidin-1-ilmetil-fenil)-etil]-amid (57) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(58) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1-etil-piperidin-2-il)-fenil]-etil}-amid (58) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide
(59) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(4-acetil-piperazin-1-ilmetil)-fenil]-etil}-amid (59) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide
(60) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2-aza-biciklo[2.2.1]hept-5-en-2-ilmetil)-fenil]-etil}-amid (60) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-aza-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-phenyl]-ethyl}-amide
(61) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1,3-di-hidro-izoindol-2-ilmetil)-fenil]-etil}-amid (61) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1,3-dihydro-isoindol-2-ylmethyl)-phenyl]-ethyl}-amide
(62) 4'-klor-bifenil-4-karboksilna kiselina (2-{4-[(di-izopropilamino)-metil]-fenil}-etil)-amid (62) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(di-isopropylamino)-methyl]-phenyl}-ethyl)-amide
(63) 4'-klor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid (63) 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
(64) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2-di-metilaminometil-pirolidin-1-ilmetil)-fenil]-etil}-amid (64) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-di-methylaminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
(65) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(3-di-metilamino-pirolidin-1-ilmetil)-fenil]-etil}-amid (65) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-di-methylamino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
(66) 4'-klor-bifenil-4-karboksilna kiselina [2-(2-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid (66) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(67) 4-pent-1-inil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (67) 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(68) 4'-klor-bifenil-4-karboksilna kiselina [2-(6-pirolidin-1-ilmetil-piridin-3-il)-etil]-amid (68) 4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide
(69) 4'-klor-bifenil-4-karboksilna kiselina [2-(1-pirolidin-1-il-indan-5-il)-etil]-amid (69) 4'-chloro-biphenyl-4-carboxylic acid [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide
(70) 4'-klor-bifenil-4-karboksilna kiselina [2-(2-nitro-4-pirolidin-1-ilmetil-fenil)-etil]-amid (70) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(71) 2',4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (71) 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(72) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(3-amino-pirolidin-1-ilmetil)-fenil]-etil}-amid (72) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
(73) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2-amino-metil-pirolidin-1-ilmetil)-fenil]-etil}-amid (73) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-amino-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
(74) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2-metil-2,6-diaza-spiro[3.4]okt-6-ilmetil)-fenil]-etil}-amid (74) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-2,6-diaza-spiro[3.4]oct-6-ylmethyl)-phenyl]-ethyl}-amide
(75) 4'-klor-bifenil-4-karboksilna kiselina [2-(5-pirolidin-1-ilmetil-piridin-2-il)-etil]-amid (75) 4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide
(76) 4'-klor-bifenil-4-karboksilna kiselina [2-(3-etil-4-pirolidin-1-ilmetil-fenil)-etil]-amid (76) 4'-chloro-biphenyl-4-carboxylic acid [2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(77) 4'-brom-bifenil-4-karboksilna kiselina {2-[4-(2,5-di-hidro-pirol-1-ilmetil)-fenil]-etil}-amid (77) 4'-bromo-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
(78) 4-(5-klor-tiofen-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (78) 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
(79) 4'-klor-bifenil-4-karboksilna kiselina [2-(2-metil-4-pirolidin-1-ilmetil-fenil)-etil]-amid (79) 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(80) 4'-brom-3-fluor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid (80) 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
(81) 4'-klor-2-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (81) 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(82) 4'-etil-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (82) 4'-ethyl-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(83) terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-ilmetil]-karbaminat (83) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-2-ylmethyl]-carbamate
(84) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2-metil-piperidin-1-ilmetil)-fenil]-etil}-amid (84) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2-methyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
(85) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-{2-metil-pirolidin-1-ilmetil)-fenil]-etil}-amid (85) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-{2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
(86) 4'-klor-bifenil-4-karboksilna kiselina (2-{4-[(ciklo-propil metil-amino)-metil]-fenil}-etil)-amid (86) 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(cyclo-propyl methyl-amino)-methyl]-phenyl}-ethyl)-amide
(87) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(3,4-di-hidro-1H-izokinolin-2-ilmetil)-fenil]-etil}-amid (87) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethyl}-amide
(88) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-{[(2-hidroksi-etil)-metil-amino]-metil}-fenil)-etil]-amid (88) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-phenyl)-ethyl]-amide
(89) terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-3-il]-karbaminat (89) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-3-yl]-carbamate
(90) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2,6-di-metil-piperidin-1-ilmetil)-fenil]-etil}-amid (90) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
(91) 4'-klor-bifenil-4-karboksilna kiselina [2-(4-azetidin-1-ilmetil-fenil)-etil]-amid (91) 4'-chloro-biphenyl-4-carboxylic acid [2-(4-azetidin-1-ylmethyl-phenyl)-ethyl]-amide
(92) 3,4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (92) 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(93) 4'-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-il metil-fenil)-etil]-amid (93) 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-yl methyl-phenyl)-ethyl]-amide
(94) 4'-klor-3-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (94) 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(95) 2'-fluor-4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (95) 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(96) 5-(4-klor-fenil)-piridin-2-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (96) 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(97) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(2,5-di-hidro-pirol-1-ilmetil)-fenil]-etil}-amid (97) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
(98) 4'-brom-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid (98) 4'-bromo-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
(99) 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-amid (99) 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-amide
Posve posebnu prednost imaju gore navedeni pojedinačni spojevi broj (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (25), (26), (27), (28), (29), (30), (47) kao i (50) do (99). The above-mentioned individual compounds number (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), ( 11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23) , (24), (25), (25), (26), (27), (28), (29), (30), (47) as well as (50) to (99).
U nastavku se će potpunije definirati neki izrazi koji se rabe gore i u nastavku za opis spojeva prema izumu. In the following, some terms used above and below to describe compounds according to the invention will be more fully defined.
Pojam halogen označava atom odabran između F, Cl, Br i I. The term halogen means an atom selected from F, Cl, Br and I.
Pojam C1-n-alkil, gdje n ima vrijednost od 3 do 8, označava zasićenu, razgranatu ili nerazgranatu ugljiko-vodičnu skupinu s 1 do n C atoma. Primjeri takovih skupina uključuje metil, etil, n-propil, izo-propil, butil, izo-butil, sek-butil, terc-butil, n-pentil, izo-pentil, neo-pentil, terc-pentil, n-heksil, izo-heksil, itd. The term C1-n-alkyl, where n has a value from 3 to 8, means a saturated, branched or unbranched carbon-hydrogen group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
Pojam C1-n-alkilen, gdje n može imati vrijednost od 1 do 8, označava zasićen, razgranat ili nerazgranat ugljikovodični most s 1 do n C atoma. Primjeri takovih skupina uključuju metilen (-CH2-), etilen (-CH2-CH2-), 1-metil-etilen (-CH(CH3)-CH2-), 1,1-dimetil-etilen (-C(CH3)2-CH2-), n-prop-1,3-ilen (-CH2-CH2-CH2-), 1-metilprop-1,3-ilen (-CH(CH3)-CH2-CH2-), 2-metilprop-1,3-ilen (-CH2-CH(CH3)-CH2-), itd., kao također i odgovarajuće zrcalno simetrične oblike. The term C1-n-alkylene, where n can have a value from 1 to 8, means a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylene (-CH2-CH2-), 1-methyl-ethylene (-CH(CH3)-CH2-), 1,1-dimethyl-ethylene (-C(CH3)2 -CH2-), n-prop-1,3-ylene (-CH2-CH2-CH2-), 1-methylprop-1,3-ylene (-CH(CH3)-CH2-CH2-), 2-methylprop- 1,3-ylene (-CH2-CH(CH3)-CH2-), etc., as well as corresponding mirror-symmetric forms.
Pojam C2-n-alkenil, gdje n ima vrijednost od 3 do 6, označava razgranatu ili nerazgranatu ugljikovodičnu skupinu s 2 do n C atoma i najmanje jednom C=C dvostrukom vezom. Primjeri takovih skupina uključuje vinil, 1-propenil, 2-propenil, izo-propenil, 1,3-butadienil, 1-butenil, 2-butenil, 3-butenil, 2-metil-1-propenil, 1-pentenil, 2-pentenil, 3-pentenil, 4-pentenil, 3-metil-2-butenil, 1-heksenil, 2-heksenil, 3-heksenil, 2,4-heksadienil, 5-heksenil itd. The term C2-n-alkenyl, where n has a value of 3 to 6, means a branched or unbranched hydrocarbon group with 2 to n C atoms and at least one C=C double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, etc.
Pojam C1-n-alkoksi označava -O-C1-n-alkilnu skupinu, pri čemu je C1-n-alkil definiran kao gore. Primjeri takovih skupina uključuju metoksi, etoksi, n-propoksi, izo-propoksi, n-butoksi, izo-butoksi, sek-butoksi, terc-butoksi, n-pentoksi, izo-pentoksi, neo-pentoksi, terc-pentoksi, n-heksoksi, izo-heksoksi itd. The term C 1-n -Alkoxy means an -O-C 1-n -alkyl group, wherein C 1-n -alkyl is defined as above. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n- hexoxy, iso-hexoxy etc.
Pojam C1-n-alkiltio označava -S-C1-n-alkilnu skupina, pri čemu je C1-n-alkil definiran kao gore. Primjeri takovih skupina uključuju metiltio, etiltio, n-propiltio, izo-propiltio, n-butiltio, izo-butiltio, sek-butiltio, terc-butiltio, n-pentiltio, izo-pentiltio, neo-pentiltio, terc-pentiltio, n-heksiltio, izo-heksiltio, itd. The term C1-n-alkylthio means a -S-C1-n-alkyl group, wherein C1-n-alkyl is defined as above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n- hexylthio, iso-hexylthio, etc.
Pojam C1-n-alkilkarbonil označava -C(=O)-C1-n-alkilnu skupinu, pri čemu je C1-n-alkil definiran kao gore. Primjeri takovih skupina uključuju metilkarbonil, etil-karbonil, n-propilkarbonil, izo-propilkarbonil, n-butil-karbonil, izo-butilkarbonil, sek-butilkarbonil, terc-butil-karbonil, n-pentilkarbonil, izo-pentilkarbonil, neo-pentil-karbonil, terc-pentilkarbonil, n-heksilkarbonil, izo-heksilkarbonil, itd. The term C1-n-alkylcarbonyl means a -C(=O)-C1-n-alkyl group, wherein C1-n-alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentyl- carbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
Pojam C3-n-cikloalkil označava zasićenu mono-, bi-, tri- ili spirokarbocikličku skupinu s 3 do n C atoma. Primjeri takovih skupina uključuju ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, ciklooktil, ciklo-nonil, ciklododecil, biciklo[3.2.1.]oktil, spiro[4.5]decil, norpinil, norbonil, norkaril, adamantil, itd. The term C3-n-cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
Pojam C3-n-cikloalkilkarbonil označava -C(=O)-C3-n-cikloalkilnu skupinu, pri čemu je C3-n-cikloalkil definiran kao gore. The term C3-n-cycloalkylcarbonyl means a -C(=O)-C3-n-cycloalkyl group, wherein C3-n-cycloalkyl is defined as above.
Pojam aril označava karbociklički, aromatski prstenasti sistem, kao što je na primjer fenil, bifenil, naftil, antracenil, fenantrenil, fluorenil, indenil, pentalenil, azulenil, bifenilenil, itd. The term aryl means a carbocyclic, aromatic ring system, such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc.
Pojam heteroaril, kako se rabi u ovoj prijavi, označava heterociklički, aromatski prstenasti sistem koji dodatno, uz najmanje jedan C atom, obuhvaća jedan ili više heteroatoma odabranih između N, O i/ili S. Primjeri takovih skupina jesu furanil, tiofenil (tienil), pirolil, oksazolil, tiazolil, imidazolil, izoksazolil, izotiazolil, 1,2,3-triazolil, 1,3,5-triazolil, piranil, piridil, piridazinil, pirimidinil, pirazinil, 1,2,3-triazinil, 1,2,4-triazinil, 1,3,5-triazinil, 1,2,3-oksadiazolil, 1,2,4-oksadiazolil, 1,2,5-oksadiazolil, 1,3,4-oksadiazolil, 1,2,3-tiadiazolil, 1,2,4-tiadiazolil, 1,2,5-tiadiazolil, 1,3,4-tiadiazolil, tetrazolil, tiadiazinil, indolil, izoindolil, benzofuranil, benzotiofenil (tianaftenil), indazolil, benzimidazolil, benztiazolil, benzizotiazolil, benzoksazolil, benz-izoksazolil, purinil, kinazolinil, kinozilinil, kinolinil, izokinolinil, kinoksalinil, naftiridinil, pteridinil, karbazolil, azepinil, diazepinil, akridinil, itd. Pojam heteroarila također obuhvaća i djelomično hidrogenirani heterociklički, aromatski prstenasti sistem, djelomično one koji su gore navedeni. Primjeri takovih djelomično hidrogeniranih prstenastih sistema jesu 2,3-dihidrobenzo-furanil, pirolinil, pirazolinil, indolinil, oksazolidinil, oksazolinil, oksazepinil, itd. The term heteroaryl, as used in this application, denotes a heterocyclic, aromatic ring system which, in addition to at least one C atom, includes one or more heteroatoms selected from N, O and/or S. Examples of such groups are furanyl, thiophenyl (thienyl) , pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2 ,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3 -thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benz-isoxazolyl, purinyl, quinazolinyl, quinozylinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl also includes the moiety ohmically hydrogenated heterocyclic, aromatic ring system, partially those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc.
Pojmovi kao aril-C1-n-alkil, heteroaril-C1-n-alkil, itd. odnose se na C1-n-alkil, definiran kao gore, koji je supstituiran s arilnom ili heteroarilnom skupinom. Mnogi od gore datih pojmova mogu se upotrijebiti više puta u definiciji formule ili skupine i u svakom slučaju mogu imati međusobno neovisno jedno od gore datih značenja. The terms aryl-C1-n-alkyl, heteroaryl-C1-n-alkyl, etc. refer to C1-n-alkyl, as defined above, which is substituted with an aryl or heteroaryl group. Many of the terms given above may be used more than once in the definition of a formula or group and in each case may have one of the meanings given above independently of each other.
Pojam "nezasićena karbociklička skupina" ili "nezasićena heterociklička skupina", kako se rabi djelomično u definiciji skupine Cy, uz potpuno nezasićene skupine, obuhvaća dodatno i odgovarajuće samo djelomično nezasićene skupine, posebno mono- i dinezasićene skupine. The term "unsaturated carbocyclic group" or "unsaturated heterocyclic group", as used partially in the definition of the group Cy, in addition to fully unsaturated groups, also includes corresponding only partially unsaturated groups, especially mono- and diunsaturated groups.
Pojam "prema potrebi supstituiran", koji se rabi u ovoj prijavi, znači da tako konstruirana skupina nije supstituirana ili je mono- ili polisupstituirana s navedenim supstituentima. Ako je dotična skupina poli-supstituirana, supstituenti mogu biti jednaki ili različiti. The term "optionally substituted", which is used in this application, means that the group thus constructed is not substituted or is mono- or polysubstituted with the specified substituents. If the group in question is poly-substituted, the substituents may be the same or different.
Gore opisani ostaci i supstituenti mogu biti mono- ili polisupstituirani s fluorom kako je opisano. Fluorirane alkilne skupine kojima se daje prednost jesu fluormetil, difluormetil i trifluormetil. Fluorirane alkoksi skupine kojima se daje prednost jesu fluormetoksi, difluormetoksi i trifluormetoksi. Fluorirane alkilsulfinilne i alkil-sulfonilne skupine kojima se daje prednost jesu trifluor-metilsulfinil i trifluormetilsulfonil. The residues and substituents described above may be mono- or polysubstituted with fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulfinyl and alkylsulfonyl groups are trifluoromethylsulfinyl and trifluoromethylsulfonyl.
Spojevi opće formule I prema izumu mogu imati kiselinske skupine, pretežno karboksilne skupine, i/ili bazične skupine kao što su npr. amino funkcionalne skupine. Spojevi opće formule I mogu stoga postojati kao unutarnje soli, kao soli s farmaceutski korisnim anorganskim kiselinama, kao što je solna kiselina, sumporna kiselina, fosforna kiselina, sulfonska kiselina ili s organskim kiselinama (kao na primjer maleinska kiselina, fumarna kiselina, limunska kiselina, vinska kiselina ili octena kiselina) ili kao soli s farmaceutski korisnim bazama kao što su hidroksidi ili karbonati alkalijskih ili zemno alkalijskih metala, cinkovi ili amonijevi hidroksidi ili organski amini kao što je npr. dietilamin, trietilamin, trietanolamin, između ostalih. The compounds of the general formula I according to the invention may have acid groups, predominantly carboxyl groups, and/or basic groups such as, for example, amino functional groups. The compounds of the general formula I can therefore exist as internal salts, as salts with pharmaceutically useful inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, sulphonic acid, or with organic acids (such as, for example, maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useful bases such as hydroxides or carbonates of alkali or alkaline earth metals, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine, among others.
Spojevi prema izumu mogu se dobiti primjenom postupaka sinteze koji su načelno poznati. Spojevi kojima se daje prednost dobiveni su postupkom priprave koji je gore opisan i u nastavku je potpunije objašnjen. The compounds according to the invention can be obtained using synthesis methods that are known in principle. Preferred compounds are obtained by the preparation process described above and explained more fully below.
U postupku priprave prema izumu za dobivanje prve skupine izvedbi kojima se daje prednsot, tj. onih spojeva u kojima skupina A i skupina R3 nisu međusobno izravno povezane, načelno se razlikuju dva slučaja. In the preparation process according to the invention for obtaining the first group of embodiments that are given preference, i.e. those compounds in which group A and group R3 are not directly connected to each other, two cases are fundamentally distinguished.
Prvi slučaj obuhvaća one spojeve formule I u kojoj skupina A označava heterocikličku skupinu s dušikom koja je povezana preko dušikovog atoma s karboksamidnom skupinom, koja osim dušikovog atoma može sadržavati dodatno još jedan ili više heteroatoma odabranih između N, O i S. Reakcija amina formule 1-1 sa sekundarnim aminom formule I-2 prikazana je u slijedećoj općoj shemi reakcije: The first case includes those compounds of the formula I in which the group A denotes a heterocyclic group with nitrogen that is connected via a nitrogen atom to a carboxamide group, which, in addition to the nitrogen atom, may additionally contain one or more heteroatoms selected from N, O and S. Reaction of amines of formula 1 -1 with secondary amine of formula I-2 is shown in the following general reaction scheme:
Shema reakcije 1: Reaction scheme 1:
[image] [image]
Ponajprije, aminski spoj formule 1-1 najprije reagira sa CDT (1,1'-karbonildi-(1,2,4-triazol)) u otapalu ili u mješavini otapala i zatim reakcijska smjesa reagira dalje s aminskim spojem formule I-2, dok se u reakcijsku smjesu prije i/ili nakon reakcije aminskog spoja sa CDT doda minimalnu količinu baze. Aminski spoj formule 1-1 reagira sa CDT povoljno u temperaturnom području od -20°C do 20oC i zatim ta reakcijska smjesa reagira s aminskim spojem formule I-2 u temperaturnom području od 40oC do 100oC u molarnom omjeru aminskog spoja formule I-1 : aminskom spoju formule I-2 : CDT : bazi od 1±0,25 : 1±0,25 : 1±0,25 : 3±1,5. Ponajprije, kao baza se upotrebljava baza koja sadrži dušik, posebno terc. amin, kao što je kao na primjer trietilamin. Preferably, the amine compound of formula 1-1 is first reacted with CDT (1,1'-carbonyl-(1,2,4-triazole)) in a solvent or solvent mixture and then the reaction mixture is further reacted with the amine compound of formula I-2, while a minimal amount of base is added to the reaction mixture before and/or after the reaction of the amine compound with CDT. The amine compound of formula 1-1 reacts with CDT favorably in the temperature range from -20°C to 20°C and then this reaction mixture reacts with the amine compound of formula I-2 in the temperature range from 40°C to 100°C in the molar ratio of the amine compound of formula I-1: to the amine compound of formula I-2 : CDT : base of 1±0.25 : 1±0.25 : 1±0.25 : 3±1.5. First of all, a nitrogen-containing base, especially tert, is used as a base. amine, such as for example triethylamine.
Aminski spoj formule I-2 može biti zasićen N-hetero-ciklički spoj, kao što je kao na primjer piperazinski derivat prema slijedećoj shemi reakcije 2. The amine compound of formula I-2 can be a saturated N-heterocyclic compound, such as, for example, a piperazine derivative according to the following reaction scheme 2.
Shema reakcije 2 Reaction scheme 2
[image] [image]
Drugi slučaj postupka priprave obuhvaća ostale spojeva formule I koji nisu obuhvaćeni sa slučajem 1, pri čemu skupina A nije izravno povezana na R3. Reakcija karboksilne kiseline spoja formule I-3 s TBTU (2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluranij-tetrafluorborat) i aminskog spoja formule I-1 u otapalu ili smjesi otapala u prisutnosti najmanje jedne baze prikazana je u shemi reakcije 3. The second case of the preparation procedure includes other compounds of formula I that are not covered by case 1, whereby group A is not directly connected to R3. The reaction of the carboxylic acid compound of formula I-3 with TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluranium-tetrafluoroborate) and the amine compound of formula I-1 in a solvent or solvent mixture in the presence of at least of one base is shown in reaction scheme 3.
Shema reakcije 3: Reaction scheme 3:
[image] [image]
Ponajprije, karboksilna kiselina, spoj formule I-3 reagira s TBTU u otapalu ili mješavini otapala i zatim reakcijska smjesa dalje reagira s aminskim spoj formule I-1, dok se u reakcijsku smjesu prije i/ili nakon reakcije spoja karboksilne kiseline s TBTU doda minimalnu količinu baze. Umjesto karboksilne kiseline također se mogu upotrijebiti odgovarajući aktivirani derivati karboksilne kiseline, kao što su na primjer esteri, orto-esteri, kloridi karboksilne kiseline ili anhidridi. Upotrebljava se ponajprije bazu koja sadrži dušik, posebno terc-amine, kao što je na primjer trietilamin. Spoj karboksilna kiselina formule I-3 reagira povoljno s TBTU i zatim se tu reakcijsku smjesu upotrebljava s aminskim spojem formule I-1 u temperaturnom području od 0°C do 60°C u molarnom omjeru spoja karboksilne kiseline formule I-3 : aminski spoj formule 1-1 : TBTU : baza od 1±0,25 : 1±0,25 : 1+0,25 : 1 do 4. First of all, the carboxylic acid, the compound of formula I-3 is reacted with TBTU in a solvent or solvent mixture and then the reaction mixture is further reacted with the amine compound of formula I-1, while the minimum amount is added to the reaction mixture before and/or after the reaction of the carboxylic acid compound with TBTU amount of base. Suitable activated carboxylic acid derivatives, such as for example esters, ortho-esters, carboxylic acid chlorides or anhydrides, can also be used instead of the carboxylic acid. A nitrogen-containing base, especially a tert-amine, such as triethylamine, is primarily used. The carboxylic acid compound of the formula I-3 reacts favorably with TBTU and then this reaction mixture is used with the amine compound of the formula I-1 in the temperature range from 0°C to 60°C in the molar ratio of the carboxylic acid compound of the formula I-3: amine compound of the formula 1-1 : TBTU : base from 1±0.25 : 1±0.25 : 1+0.25 : 1 to 4.
Polazni spoj formule I-3 može se dobiti postupcima koji su stručnjaku poznati. Tako se biarilni spojevi mogu dobiti Suzuki-jevim povezivanjem, na primjer počevši od derivata p-bromarilkarboksilne kiseline i derivata aril-borne kiseline u prisutnosti Pd[0] katalizatora. The starting compound of formula I-3 can be obtained by methods known to the expert. Thus, biaryl compounds can be obtained by Suzuki coupling, for example starting from p-bromoarylcarboxylic acid derivatives and arylboronic acid derivatives in the presence of Pd[0] catalyst.
U postupku priprave prema izumu za drugu skupinu izvedbi kojima se daje prednost, tj. onih spojeva u kojima je skupina A povezana sa skupinom R3, razlikuje se sedam slučajeva, ovisno o značenjima IIIa do IIIg za skupinu Q. In the preparation process according to the invention for the second group of preferred embodiments, i.e. those compounds in which group A is connected to group R3, seven cases are distinguished, depending on the meanings of IIIa to IIIg for group Q.
Prema prvom slučaju, u kojem Q označava -CR6R7- (IIIa), aminski spoj formule Ia.1 reagira s derivatom o-brom-metil-benzojeve kiseline formule Ia.2, kako prikazuje slijedeća shema reakcije 4, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the first case, in which Q stands for -CR6R7- (IIIa), the amine compound of formula Ia.1 reacts with the o-bromo-methyl-benzoic acid derivative of formula Ia.2, as shown in the following reaction scheme 4, in which they are omitted for clarity substituents L1, L2, L3 on the phenyl ring.
Shema reakcije 4: Reaction Scheme 4:
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Ponajprije, derivat estera o-brom-metil-benzojeve kiseline formule Ia.2 reagira s aminskim spojem formule Ia.1 u otapalu ili u mješavini otapala, pri čemu se doda najmanje jednu bazu. Umjesto esterskog derivata o-brom-metil-benzojeve kiseline formule Ia.2 također se mogu upotrijebiti i drugi odgovarajući esterski derivati o-benzil-benzojeve kiseline (jod ili mesilat umjesto broma). Kao bazu se može povoljno upotrijebiti kalijev karbonat ili cezijev karbonat, ali su također uobičajene i baze terc. amini kao što je trietilamin. Upotrebljava se ponajprije esterski derivat o-brom-metil-benzojeve kiseline formule Ia.2 u acetonitrilu s aminom formule Ia.1 i s kalijevim karbonatom kao bazom u temperaturnom području od 40-80°C u molarnom omjeru od esterskog derivata o-brom-metil-benzojeve kiseline formule Ia.2 : amin formule Ia.1 : kalijec karbonat od 1+0,25 : 1+0,25 : 3+0,50. Preferably, the o-bromo-methyl-benzoic acid ester derivative of formula Ia.2 is reacted with an amine compound of formula Ia.1 in a solvent or solvent mixture, whereby at least one base is added. Instead of the o-bromo-methyl-benzoic acid ester derivative of formula Ia.2, other suitable o-benzyl-benzoic acid ester derivatives (iodine or mesylate instead of bromine) can also be used. Potassium carbonate or cesium carbonate can be advantageously used as a base, but tert bases are also common. amines such as triethylamine. The o-bromo-methyl-benzoic acid ester derivative of the formula Ia.2 in acetonitrile with the amine of the formula Ia.1 and with potassium carbonate as a base in the temperature range of 40-80°C is used primarily in a molar ratio of the o-bromo-methyl ester derivative -benzoic acids of formula Ia.2: amine of formula Ia.1: potassium carbonate of 1+0.25: 1+0.25: 3+0.50.
Prema drugom slučaju u kojem Q označava -CR8=R7- (IIIb), izokinolinonski derivat formule Ib.3 reagira s elektrofilnim spojem formule Ib.4, čime nastaje izokinolinski derivat formule Ib.5, koji se dalje derivatizira poznatim postupcima, čime se dobije spoj formule I. Derivat izokinolinona formule Ib.3 se može dobiti iz derivata cinaminske kiseline formule Ib.1 reakcijom s (EtO)2P(O)N3. Sintezu bazične tvari opisali su M. Becker et al. u Bioorganic & Medicinal Chemistry Letters 9 (1999), 2753-2758. Reakcija je prikazana u slijedećoj shemi reakcije 5, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the second case in which Q denotes -CR8=R7- (IIIb), the isoquinolinone derivative of the formula Ib.3 reacts with the electrophilic compound of the formula Ib.4, resulting in the isoquinoline derivative of the formula Ib.5, which is further derivatized by known procedures, resulting in compound of formula I. The isoquinolinone derivative of formula Ib.3 can be obtained from the cinnamic acid derivative of formula Ib.1 by reaction with (EtO)2P(O)N3. The synthesis of the basic substance was described by M. Becker et al. in Bioorganic & Medicinal Chemistry Letters 9 (1999), 2753-2758. The reaction is shown in the following reaction scheme 5, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 5: Reaction Scheme 5:
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Spoj formule Ib.2 se korisno dobije sekvencnom reakcijom opisanom ovdje kasnije. Derivat akrilne kiseline Ib.1 najprije reagira djelovanjem sredstva za kloriranje kao što je tionil klorid, fosforni pentaklorid ili oksalil klorid, bez otapala ili prema potrebi u inertnom otapalu kao što je diklorometan, čime se dobije kiselinski klorid pri temperaturi između 0°C i 80°C. On se dodatkom natrijevog azida u otapalu ili mješavini otapala prevede u derivat azida akrilne kiseline. Kao otapalo se može upotrijebiti na primjer dioksan, tetrahidrofuran ili voda. Ponajprije, derivat izocijanata Ib.2 se sintetizira izravno djelovanjem difenil ester azida fosforne kiseline na derivat akrilne kiseline Ib.1 u prisutnosti baze u otapalu pri temperaturi između 0oC i 150oC. Prikladna otapala uključuju na primjer toluen ili dioksan. Tercijarni amini kao što je na primjer trietilamin mogu se upotrijebiti kao baze. Vrijeme gornje reakcije je između jednog i dvanaest sati. Povoljno, reakcija derivata akrilne kiseline Ib.1 s difenil ester azidom fosforne kiseline i trietilaminom u molarnom omjeru od 1±0,25 : 1±0,25 : 1±0,25 odvija se u toluenu kao otapalu. Derivat izocijanata Ib.2 se grije u otapalu prema potrebi u prisutnosti baze kao što je na primjer tributilamin, čime nastaje derivat izokinolona formule Ib.3. Ponajprije, reakcija se odvija u difenil eteru u području tališta. Izvor topline koji se može upotrijebiti jesu uljne, metalne kupelji ili mikrovalna grijalica. A compound of formula Ib.2 is advantageously prepared by the sequential reaction described hereinbelow. The acrylic acid derivative Ib.1 is first reacted with a chlorinating agent such as thionyl chloride, phosphorus pentachloride or oxalyl chloride, without a solvent or, if necessary, in an inert solvent such as dichloromethane, which gives the acid chloride at a temperature between 0°C and 80 °C. By adding sodium azide in a solvent or solvent mixture, it is converted into an acrylic acid azide derivative. For example, dioxane, tetrahydrofuran or water can be used as a solvent. First of all, the isocyanate derivative Ib.2 is synthesized directly by the action of phosphoric acid diphenyl ester azide on the acrylic acid derivative Ib.1 in the presence of a base in a solvent at a temperature between 0oC and 150oC. Suitable solvents include for example toluene or dioxane. Tertiary amines such as for example triethylamine can be used as bases. The time of the above reaction is between one and twelve hours. Advantageously, the reaction of acrylic acid derivative Ib.1 with phosphoric acid diphenyl ester azide and triethylamine in a molar ratio of 1±0.25 : 1±0.25 : 1±0.25 takes place in toluene as a solvent. The isocyanate derivative Ib.2 is heated in a solvent as needed in the presence of a base such as, for example, tributylamine, whereby the isoquinolone derivative of the formula Ib.3 is formed. First of all, the reaction takes place in diphenyl ether in the melting point range. Heat sources that can be used are oil, metal baths or a microwave heater.
Reakcija derivata izokinolona formule Ib.3 s mesilatnim derivativom formule Ib.4 kojom se dobije izokinolonski derivat formule Ib.5 provodi se u otapalu u prisutnosti baze pri temperaturi između 0°C i 150°C. Povoljno, reakcija izokinolonskog derivata Ib.3 s mesilatnim derivatom formule Ib.4 i natrijevim hidridom u molarnom omjeru od 1±0,25 : 1±0,25 : 1±0,25 odvija se u DMF-u kao otapalu. Izokinolonski derivat formule Ib.5 najprije reagira u otapalu u prisutnosti kiseline, čime se acetal prevede u odgovarajući aldehid. On se prevede u spoj formule Ib u prisutnosti sredstva za pretvorbu hibrida, amina i kiseline u otapalu. Primjeri sredstava za pretvorbu hibrida uključuju na primjer natrijev triacetoksibor-hidrid, natrijev borhidrid i natrijev cijanoborhidrid. Povoljno, reakcija aldehida, oslobođenog iz izokinolonskog derivata Ib.5, s aminom i natrijevim cijanoborhidridom u molarnom omjeru od 1±0,25 : 1±0,25 : 0,8±0,25 odvija se u metanolu i octenoj kiselini pri temperaturi oko 20°C. The reaction of the isoquinolone derivative of the formula Ib.3 with the mesylate derivative of the formula Ib.4, which gives the isoquinolone derivative of the formula Ib.5, is carried out in a solvent in the presence of a base at a temperature between 0°C and 150°C. Advantageously, the reaction of the isoquinolone derivative Ib.3 with the mesylate derivative of the formula Ib.4 and sodium hydride in a molar ratio of 1±0.25 : 1±0.25 : 1±0.25 takes place in DMF as a solvent. The isoquinolone derivative of formula Ib.5 first reacts in a solvent in the presence of an acid, which converts the acetal into the corresponding aldehyde. It is converted to a compound of formula Ib in the presence of a hybridizing agent, an amine, and an acid in the solvent. Examples of hybrid conversion agents include, for example, sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. Advantageously, the reaction of the aldehyde, released from the isoquinolone derivative Ib.5, with the amine and sodium cyanoborohydride in a molar ratio of 1±0.25 : 1±0.25 : 0.8±0.25 takes place in methanol and acetic acid at a temperature around 20°C.
Sinteza izokinolina formule Ib, uključiv i polaznih spojeva i slijedeća derivatizacija za dobivanje amina, bit će prikazane sa slijedećom shemom sinteze specifičnog spoja, dok se sintezu edukta 1 može vidjeti u slijedećem dijagramu 6 za pripravu ftalazinona (dijagram 8). The synthesis of isoquinolines of formula Ib, including starting compounds and subsequent derivatization to obtain amines, will be shown with the following scheme of the synthesis of a specific compound, while the synthesis of educt 1 can be seen in the following diagram 6 for the preparation of phthalazinone (diagram 8).
Shema reakcije 6: Reaction Scheme 6:
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Prema trećem slučaju u kojem Q označava -N=CR8- (IIIc), ftalazinonski derivat formule Ic.4 reagira s elektrofilnim spojem formule Ic.5, čime se dobije ftalazinonski derivat formule Ic.6, koji se dalje derivatizira postupcima koji su poznati za dobivanje spoja formule Ic. Ftalazinonski derivat formule Ic.4, za R8 = vodik, može se dobiti počevši od feniloksazolnog derivata formule Ic.1 aciliranjem čime se dobije o-oksazolil-benzaldehidni derivat formule Ic.2 i zatim ciklizacijom kojom se dobije 3-hidroksi-3H-izobenzofuran-1-onski derivat formule Ic.3. Sintezu bazične tvari opisali su M. Napoletano et al., Bioorganic & Medicinal Chemistry Letters 12 (2002), 5-8. According to the third case in which Q denotes -N=CR8- (IIIc), the phthalazinon derivative of the formula Ic.4 reacts with the electrophilic compound of the formula Ic.5, thereby obtaining the phthalazinon derivative of the formula Ic.6, which is further derivatized by methods known to obtaining a compound of formula Ic. The phthalazinon derivative of formula Ic.4, for R8 = hydrogen, can be obtained starting from the phenyloxazole derivative of formula Ic.1 by acylation, which gives the o-oxazolyl-benzaldehyde derivative of formula Ic.2, and then by cyclization, which gives 3-hydroxy-3H-isobenzofuran -1-one derivative of formula Ic.3. The synthesis of the basic substance is described by M. Napoletano et al., Bioorganic & Medicinal Chemistry Letters 12 (2002), 5-8.
Reakcija za dobivanje spojeva opće formule Ic prikazana je u slijedećoj shemi reakcije 7, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. The reaction for obtaining compounds of the general formula Ic is shown in the following reaction scheme 7, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 7: Reaction Scheme 7:
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Gornje sekvence reakcija su u nastavku opisane s više pojedinosti. Derivat oksazolina Ic.1 se metalizira upotrebom prikladnog organometalnog reagenta i zatim reagira s formaldehidnim ekvivalentom kao što je na primjer dimetilformamid ili ortoformat pri temperaturi između -70°C i 20°C, ponajprije pri temperaturi između -20°C i 0°C, čime se dobije spoj formule Ic.2. Prikladna otapala uključuju na primjer dioksan, tetrahidrofuran ili dietil eter. Djelovanjem vodene sumporne kiseline u otapalu kao što je na primjer etanol pri temperaturi blizu vrelišta otapala ili u mješavini otapala tijekom perioda od jednog do 24 sata može se dobiti spoj opće formule Ic.3. Ftalazinonski derivat formule Ic.4 može se dobiti reakcijom spoja formule Ic.3 s hidrazinom u octenoj kiselina i prema potrebi u otapalu pri temperaturi u području između 20 i 120 stupnjeva Celzija. Sinteza za dobivanje ftalazinonskog derivata formule Ic se provodi analogno reakcijama koje su opisane za sintezu spoja opće formule Ib. The above reaction sequences are described in more detail below. The oxazoline derivative Ic.1 is metalized using a suitable organometallic reagent and then reacted with a formaldehyde equivalent such as for example dimethylformamide or orthoformate at a temperature between -70°C and 20°C, preferably at a temperature between -20°C and 0°C, thus obtaining the compound of formula Ic.2. Suitable solvents include for example dioxane, tetrahydrofuran or diethyl ether. By the action of aqueous sulfuric acid in a solvent such as, for example, ethanol at a temperature close to the boiling point of the solvent or in a mixture of solvents for a period of one to 24 hours, a compound of the general formula Ic.3 can be obtained. The phthalazinon derivative of formula Ic.4 can be obtained by reacting the compound of formula Ic.3 with hydrazine in acetic acid and, if necessary, in a solvent at a temperature in the range between 20 and 120 degrees Celsius. The synthesis to obtain the phthalazinone derivative of formula Ic is carried out analogously to the reactions described for the synthesis of compounds of general formula Ib.
Sinteza ftalazinonskih derivata formule Ic, posebno polaznih spojeva i zatim derivatizacija će se sada prikazati pomoću sheme za sintezu 8 za specifičan spoj u kojoj kratice imaju slijedeća značenja: LAH označava litij aluminijev hidrid, BuLi je n-butil-litij, DMF je dimetil-formamid, MeOH je metanol i Ms-Cl je klorid metansulfonske kiseline. The synthesis of phthalazinone derivatives of formula Ic, especially the starting compounds and then the derivatization will now be shown using the synthesis scheme 8 for a specific compound in which the abbreviations have the following meanings: LAH stands for lithium aluminum hydride, BuLi is n-butyllithium, DMF is dimethylformamide , MeOH is methanol and Ms-Cl is methanesulfonic acid chloride.
Shema reakcije 8 Reaction scheme 8
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Prema četvrtom slučaju, u kojem Q označava -N=N- (IIId), o-amino-benzamidni derivat formule Id.1 reagira u prisutnosti prikladnog nitritnog spoja i kiseline preko diazonijevog intermedijata, čime se dobije benzotri-azinonski derivat formule Id. Reakcija je prikazana u slijedećoj shemi reakcija 9, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the fourth case, in which Q stands for -N=N- (IIId), the o-amino-benzamide derivative of formula Id.1 reacts in the presence of a suitable nitrite compound and an acid via a diazonium intermediate, thereby obtaining a benzotri-azinone derivative of formula Id. The reaction is shown in the following reaction scheme 9, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 9: Reaction Scheme 9:
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Ponajprije, spoj opće formule Id.1 reagira u otapalu, kao što je na primjer metanol, u prisutnosti anorganske kiseline, na primjer solne kiseline, i soli koja sadrži nitritne ione pri temperaturi između -10°C i 30°C. Povoljno se reakcija amino spoja Id.1 s natrijevim nitritom u molarnom omjeru od 1±0,25 : 1,5±0,25 odvija u metanolu kao otapalu i u prisutnosti solne kiseline. Preferably, the compound of general formula Id.1 is reacted in a solvent, such as for example methanol, in the presence of an inorganic acid, for example hydrochloric acid, and a salt containing nitrite ions at a temperature between -10°C and 30°C. The reaction of the amino compound Id.1 with sodium nitrite in a molar ratio of 1±0.25 : 1.5±0.25 takes place advantageously in methanol as a solvent and in the presence of hydrochloric acid.
Prema petom slučaju, u kojem Q označava -CO-NR9- (IIIe), o-amino-benzamidni derivat formule Ie.1 reagira u prisutnosti CDI, čime se dobije kinazolindionski derivat formule Ie. CDI se doda k benzamidnom derivatu formule Ie.1 u molarnom omjeru većem od 1 ili jednakom 1 i reakcija se provodi barem djelomično u temperaturnom području od 35°C do 100°C, ponajprije u području temperature vrelišta reakcijske smjese. Reakcija je prikazana u slijedećoj shemi reakcije 10, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the fifth case, in which Q stands for -CO-NR9- (IIIe), the o-amino-benzamide derivative of formula Ie.1 is reacted in the presence of CDI to give the quinazolinedione derivative of formula Ie. CDI is added to the benzamide derivative of formula Ie.1 in a molar ratio greater than or equal to 1 and the reaction is carried out at least partially in the temperature range from 35°C to 100°C, preferably in the range of the boiling temperature of the reaction mixture. The reaction is shown in the following reaction scheme 10, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 10: Reaction scheme 10:
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Prema šestom slučaju, u kojem Q označava -CR8=N- (IIIf), o-amino-benzamidni derivat formule If.1 reagira s karboksilnom kiselinom R8COOH i/ili s odgovarajućim aktiviranim derivatom karboksilne kiseline, čime se dobije kinazolinonski derivat formule If. Prikladni aktivirani derivati karboksilne kiseline jesu na primjer esteri, orto-esteri, kloridi karboksilne kiseline i anhidridi. Prema potrebi, aktiviranu karboksilnu kiselinu doda se karboks-amidnom spoju formule If.1 u molarnom omjeru većem od 1 ili jednakom 1 i reakcije se odvija barem djelomično u temperaturnom području od 35°C do 100°C, ponajprije u području temperature vrelišta reakcijske smjese. Reakcija je prikazana u slijedećoj shemi reakcije 11, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the sixth case, in which Q denotes -CR8=N- (IIIf), the o-amino-benzamide derivative of formula If.1 reacts with the carboxylic acid R8COOH and/or with the appropriate activated carboxylic acid derivative, thereby obtaining the quinazolinone derivative of formula If. Suitable activated carboxylic acid derivatives are for example esters, ortho-esters, carboxylic acid chlorides and anhydrides. If necessary, the activated carboxylic acid is added to the carboxamide compound of the formula If.1 in a molar ratio greater than 1 or equal to 1, and the reaction takes place at least partially in the temperature range from 35°C to 100°C, preferably in the temperature range of the boiling point of the reaction mixture . The reaction is shown in the following reaction scheme 11, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 11: Reaction scheme 11:
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Sinteza kinazolinonskog derivata formule If, posebno polaznih spojeva, bit će prikazana pomoću sheme sinteze 12 specifičnog spoja, u kojoj se upotrebljavaju slijedeće kratice: CDI je karbonildiimidazol, TBTU je 2-(1H-benzo-triazol-1-il)-1,1,3,3-tetrametiluronijev tetrafluorborat i NEt3 je trietilamin. Najprije je prikazana sheme sinteze za dva polazna spoja 1 i 2. The synthesis of the quinazolinone derivative of the formula If, especially the starting compounds, will be shown using the synthesis scheme of the specific compound 12, in which the following abbreviations are used: CDI is carbonyldiimidazole, TBTU is 2-(1H-benzo-triazol-1-yl)-1,1 ,3,3-tetramethyluronium tetrafluoroborate and NEt3 is triethylamine. First, the synthesis schemes for the two starting compounds 1 and 2 are presented.
Shema reakcije 12 Reaction scheme 12
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Polazni spojevi 1 i 2 se međusobno povezuju preko amidne veze upotrebom TBTU. Nitro skupina u orto položaju prema amidnoj vezi dobije se redukcijom, čime se dobije amin u prisutnosti PtO2. Ciklizacija za dobivanje kinazolinona provodi se upotrebom karboksilne kiseline, u ovom slučaju mravlje kiseline. The starting compounds 1 and 2 are connected to each other via an amide bond using TBTU. The nitro group in the ortho position to the amide bond is obtained by reduction, which gives the amine in the presence of PtO2. Cyclization to obtain quinazolinone is carried out using a carboxylic acid, in this case formic acid.
Prema sedmom slučaju u kojem Q označava -CO- (IIIg), izobenzofurandionski derivat formule Ig.2 reagira s aminskim spojem formule Ig.1 čime se dobije izoindoldionski derivat formule Ig. Reakcija je prikazana u slijedećoj shemi reakcija 13, u kojoj su zbog jasnoće izostavljeni supstituenti L1, L2, L3 na fenilnom prstenu. According to the seventh case in which Q denotes -CO- (IIIg), the isobenzofurandione derivative of the formula Ig.2 reacts with the amine compound of the formula Ig.1 to obtain the isoindoledione derivative of the formula Ig. The reaction is shown in the following reaction scheme 13, in which the substituents L1, L2, L3 on the phenyl ring are omitted for clarity.
Shema reakcije 13: Reaction Scheme 13:
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Izobenzofurandionski derivat Ig.2 reagira u otapalu, kao što je na primjer octena kiselina, s aminom opće formule Ig.1 u molarnom omjeru od 1±0,25 : 1,5±0,25. Temperatura tijekom reakcije je ponajprije temperatura vrelišta otapala. The isobenzofurandion derivative Ig.2 reacts in a solvent, such as acetic acid for example, with the amine of the general formula Ig.1 in a molar ratio of 1±0.25 : 1.5±0.25. The temperature during the reaction is primarily the temperature of the boiling point of the solvent.
Međutim, izoindoldionaki derivat formule Ig može se također dobiti i prema slijedećoj shemi sinteze 14. Svaki stručnjak može sintezu pojedinačnog spoja, kako je prikazano, lako primijeniti i na druge spojeve formule Ig, i prema potrebi modificirati. Prije svega, izoindoldionsku funkcionalnu skupinu dobije se iz izobenzofurandionskog derivata, vezanjem amina, i zatim se dalje arilnu skupinu dodaje Suzukijevim povezivanjem u prisutnosti Pd[0]. However, the isoindoledione derivative of the formula Ig can also be obtained according to the following synthesis scheme 14. Any expert can easily apply the synthesis of the individual compound, as shown, to other compounds of the formula Ig, and modify it as necessary. First of all, the isoindoledione functional group is obtained from the isobenzofurandione derivative by amine binding, and then the aryl group is further added by Suzuki coupling in the presence of Pd[0].
Shema reakcije 14 Reaction scheme 14
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Gore opisane moguće postupke za sintezu spojeva prema izumu stručnjak može se lako modificirati i/ili nadopuniti za pojedinačne spojeve koje se želi sintetizirati, barem što se tiče širine njihovog prikaza, primjenom poznatih postupaka kako su opisani na primjer u Houben-Weyl, Methoden der organischen Chemie. The above-described possible procedures for the synthesis of the compounds according to the invention can be easily modified and/or supplemented by a person skilled in the art for the individual compounds to be synthesized, at least as far as the breadth of their representation is concerned, using known procedures as described for example in Houben-Weyl, Methoden der organischen Chemistry.
U gore opisanim reakcijama, bilo koju prisutnu reaktivnu skupinu kao što je hidroksi, karboksi, amino ili imino skupina, može se zaštititi tijekom reakcije postupcima koji su poznati iz literature s uobičajenim zaštitnim skupinama koje se ponovno odcjepljuju nakon reakcije; posebno, mogu se upotrijebiti zaštitne skupine koje se uobičajeno koriste u kemiji peptida. Informaciju o tome može se naći, na primjer, u WO 98/11128. In the reactions described above, any reactive group present, such as a hydroxy, carboxy, amino or imino group, can be protected during the reaction by methods known from the literature with the usual protecting groups being cleaved off again after the reaction; in particular, protecting groups commonly used in peptide chemistry can be used. Information on this can be found, for example, in WO 98/11128.
Stereoizomerni spojevi formule (I) mogu se rastaviti načelno uobičajenim postupcima. Diastereomeri se mogu rastaviti na osnovi njihovih različitih fizičko-kemijskih svojstava, npr. frakcijskom kristalizacijom iz prikladnih otapala, visokotlačnom tekućinkom kromatografijom ili kromatografijom na stupcu, upotrebom kiralne ili ponajprije ne-kiralne stacionarne faze. Stereoisomeric compounds of formula (I) can be separated in principle by usual procedures. Diastereomers can be resolved on the basis of their different physicochemical properties, eg by fractional crystallization from suitable solvents, high pressure liquid chromatography or column chromatography, using a chiral or preferably non-chiral stationary phase.
Kao što je već spomenuto, spojevi formule (I) mogu se prevesti u njihove soli, posebno za farmaceutsku upotrebu u njihove fiziološki i farmakološki prihvatljive soli. Te soli mogu biti s jedne strani u obliku fiziološki i farmakološki prihvatljivih kiselinskih adicijskih soli spojeva formule (I) s anorganskim ili organskim kiselinama. S druge strane, u slučaju kiselinski povezanog vodika, spoj formule (I) može se također prevesti reakcijom s anorganskom bazom u fiziološki i farmakološki prihvatljive soli s kationima alkalijskih ili zemno alkalijskih metala kao ionima suprotnog naboja. Kiselinske adicijske soli mogu se proizvesti, na primjer, upotrebom solne kiseline, bromo-vodične kiseline, sumporne kiseline, fosforne kiseline, metansulfonske kiselina, octene kiseline, fumarne kiseline, sukcinske kiseline, mliječne kiseline, limunske kiseline, vinske kiselina ili maleinske kiseline. Osim toga, mogu se upotrijebiti i mješavine gore spomenutih kiselina. Za pripravu soli alkalijskih i zemno alkalijskih metala i spojeva formule (I) s kiselinski povezanim vodikom, upotrebljavaju se ponajprije hidroksidi i hidridi alkalijskih i zemno alkalijskih metala, pri čemu se prednost daje hidroksidima i hidridima alkalijskih metala, posebno natrijevim i kalijevim, a najveću prednost se daje natrijevom i kalijevom hidroksidu. As already mentioned, the compounds of formula (I) can be translated into their salts, especially for pharmaceutical use into their physiologically and pharmacologically acceptable salts. These salts can be, on the one hand, in the form of physiologically and pharmacologically acceptable acid addition salts of compounds of formula (I) with inorganic or organic acids. On the other hand, in the case of acid-bonded hydrogen, the compound of formula (I) can also be converted by reaction with an inorganic base into physiologically and pharmacologically acceptable salts with cations of alkali or alkaline earth metals as ions of opposite charge. Acid addition salts can be produced, for example, using hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, mixtures of the above-mentioned acids can also be used. For the preparation of salts of alkali and alkaline earth metals and compounds of formula (I) with acid-bonded hydrogen, hydroxides and hydrides of alkali and alkaline earth metals are primarily used, with preference being given to hydroxides and hydrides of alkali metals, especially sodium and potassium, and the greatest preference is given to sodium and potassium hydroxide.
Spojevi prema predloženom izumu, uključiv i njihove fiziološki prihvatljive soli, su učinkoviti kao antagonisti MCH receptora, posebno MCH-1 receptora, i oni pokazuju dobar afinitet u proučavanjima vezanja MCH receptora. Sistemi farmakoloških ispitivanja za MCH-antagonistička svojstva su opisani u slijedećem eksperimentalnom dijelu. The compounds according to the proposed invention, including their physiologically acceptable salts, are effective as antagonists of the MCH receptor, especially the MCH-1 receptor, and they show good affinity in MCH receptor binding studies. Pharmacological test systems for MCH-antagonistic properties are described in the following experimental section.
Kao antagonisti MCH receptora spojevi prema izumu su korisno prikladni kao farmaceutski aktivne tvari za prevenciju i/ili liječenje simptoma i/ili bolesti uzrokovanih s MCH ili bolesti koje su na neki način uzročno povezane s MCH. Općenito spojevi prema izumu imaju nisku toksičnost, oni se dobro apsorbiraju oralnim putem i imaju intracerebralnu tranzitivnost, posebno dostupnost mozgu. As MCH receptor antagonists, the compounds according to the invention are advantageously suitable as pharmaceutically active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or diseases that are somehow causally related to MCH. In general, the compounds according to the invention have low toxicity, they are well absorbed orally and they have intracerebral transitivity, especially availability to the brain.
Zbog toga su MCH antagonisti koji sadrže najmanje jedan spoj prema izumu posebno prikladni za sisavce, kao što su na primjer štakori, miševi, zamorci, zečevi, psi, mačke, ovce, konji, svinje, goveda, majmuni, a također i ljudi, za liječenje i/ili prevenciju simptoma i/ili bolesti koje su uzrokovane s MCH ili su drugačije uzročno povezane s MCH. Therefore, MCH antagonists containing at least one compound according to the invention are particularly suitable for mammals, such as for example rats, mice, guinea pigs, rabbits, dogs, cats, sheep, horses, pigs, cattle, monkeys, and also humans, for treatment and/or prevention of symptoms and/or diseases that are caused by MCH or otherwise causally related to MCH.
Bolesti uzrokovane s MCH ili koje su drugačije uzročno povezane s MCH su posebno metabolički poremećaji, kao što je na primjer debljina i poremećaji prehrane, kao što je na primjer bulimija, uključiv i neurotičnu bulimiju. Indikacije debljine uključuju posebno egzogenu debljinu, hiperinzulinemijsku debljinu, hiperplazmičnu debljinu, hiperfizealnu adipoznost, hipoplazmičnu debljinu, hipotiroidnu debljinu, hipotalamičnu debljinu, simptomatičnu debljinu, infantilnu debljinu, debljinu gornjeg dijela tijela, alimentarnu debljinu, hipogonadalnu debljinu, centralnu debljinu. Ta područja indikacija također uključuju kaheksiju, anoreksiju i hiperfagiju. Spojevi prema izumu mogu biti posebno prikladni za smanjenje gladi, obuzdavanje apetita, kontrolu ponašanja kod jela i/ili za izazivanje osjećaja sitosti. Diseases caused by MCH or otherwise causally related to MCH are in particular metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. Indications of obesity include especially exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity. These indication areas also include cachexia, anorexia and hyperphagia. The compounds of the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behavior and/or inducing satiety.
Dodatno, bolesti uzrokovane s MCH ili koje se drugačije uzročno povezane s MCH također uključuju hiper-lipidemiju, celulitis, akumulaciju masti, malignantnu mastocitozu, sistemsku mastocitozu, emocionalne poremećaje, afektivne poremećaje, depresiju, anksiozna stanja, reproduktivne poremećaje, poremećaje memorije, oblike demencije i hormonalne poremećaje. Additionally, diseases caused by MCH or otherwise causally related to MCH also include hyper-lipidemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety states, reproductive disorders, memory disorders, forms of dementia and hormonal disorders.
Spojevi prema izumu također su prikladni kao aktivne tvari za prevenciju i/ili liječenje drugih bolesti i/ili poremećaja, posebno onih koji prate debljinu, kao što je na primjer dijabetes, dijabetes melitus, posebno tip II dijabetesa, hiperglicemija, posebno kronična hiper-glicemija, komplikacije dijabetesa koje uključuju dijabetičku retinopatiju, dijabetičku neuropatiju, dijabetičku nefropatiju, itd., inzulinsku otpornost, patološku toleranciju glukoze, kardiovaskularne bolesti, posebno arteriosklerozu i visok krvni tlak, te gonitis. The compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other diseases and/or disorders, especially those accompanying obesity, such as for example diabetes, diabetes mellitus, especially type II diabetes, hyperglycemia, especially chronic hyperglycemia , complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, abnormal glucose tolerance, cardiovascular diseases, especially arteriosclerosis and high blood pressure, and gonitis.
MCH antagonisti i formulacije prema izumu mogu se povoljno upotrijebiti u kombinaciji s dijetnom terapijom, kao što je na primjer dijetno liječenje dijabetesa, i vježbanje. The MCH antagonists and formulations according to the invention can advantageously be used in combination with dietary therapy, such as for example dietary treatment of diabetes, and exercise.
Drugo područje indikacija za koje su spojevi prema izumu povoljno prikladni je prevencija i/ili liječenje mikturicijskih poremećaja, kao što je na primjer urinarna inkontinencija, hiperaktivan mjehur, nukturija, enureza, dok hiperaktivan mjehur i urinarna inkontinencija mogu ili ne mogu biti povezane s benignom hiperplazijom prostate. Another field of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, overactive bladder, nocturia, enuresis, while overactive bladder and urinary incontinence may or may not be associated with benign hyperplasia prostate.
Doziranje potrebno za postizanje takovog učinka je uobičajeno, intravenskim ili supkutanim putem 0,001 do 30 mg/kg tjelesne težine, ponajprije 0,01 do 5 mg/kg tjelesne, a oralnim ili nazalnim putem ili inhalacijom 0,01 do 50 mg/kg tjelesne težine, ponajprije 0,1 do 30 mg/kg tjelesne težine, u svakom slučaju 1 do 3 × dnevno. The dosage required to achieve such an effect is usual, intravenously or subcutaneously 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and orally or nasally or by inhalation 0.01 to 50 mg/kg of body weight , preferably 0.1 to 30 mg/kg of body weight, in any case 1 to 3 times a day.
Za tu svrhu, spojevi formule I proizvedeni prema izumu mogu se formulirati, prema potrebi zajedno s drugim aktivnim tvarima kako je opisano u nastavku, zajedno s jednim ili više fiziološki prihvatljivih pomoćnih sredstava, s inertnim uobičajenim nosačima i/ili sredstvima za razrjeđivanje, kao što su npr. s kukuruzni škrob, laktoza, glukoza, mikrokristalinična celuloza, magnezijev stearat, polivinilpirolidon, limunska kiselina, vinska kiselina, voda, voda/etanol, voda/glicerol, voda/sorbitol, voda/polietilen glikol, propilen glikol, cetilstearil alkohol, karboksimetilceluloza ili masne tvari kao što je tvrda mast ili njihove prikladne mješavine za proizvodnju uobičajenih galenskih pripravaka kao što je su ravne ili prevučene tablete, kapsule, puderi, granule, otopine, emulzije, sirupi, aerosoli za inhalaciju, masti ili čepići. For this purpose, the compounds of formula I produced according to the invention may be formulated, optionally together with other active substances as described below, together with one or more physiologically acceptable excipients, with inert conventional carriers and/or diluents, such as are, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof for the production of conventional galenic preparations such as flat or coated tablets, capsules, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments or suppositories.
Osim farmaceutskih sastava izum također uključuje i sastave koji sadrže najmanje jedan karboksamidni spoj prema izumu i/ili sol prema izumu, prema potrebi zajedno s jednim ili više fiziološki prihvatljivih pomoćnih sredstava. Takovi sastavi mogu također biti na primjer živežne namirnice koje mogu biti krute ili tekuće, i u koje je ugrađen spoj prema izumu. In addition to pharmaceutical compositions, the invention also includes compositions containing at least one carboxamide compound according to the invention and/or a salt according to the invention, if necessary together with one or more physiologically acceptable auxiliary agents. Such compositions can also be, for example, foodstuffs which can be solid or liquid, and in which the compound according to the invention is incorporated.
U gore spomenutim kombinacijama kao dodatne aktivne tvari mogu se upotrijebiti posebno one koje, na primjer, pojačavaju terapeutski učinak MCH antagonista prema izumu u smislu jedne od gore spomenutih indikacija i/ili koje omogućuju smanjenje doziranja MCH antagonista prema izumu. Bira se ponajprije jednu ili više dodatnih aktivnih tvari iz niza koji čine In the above-mentioned combinations, as additional active substances can be used especially those which, for example, enhance the therapeutic effect of the MCH antagonist according to the invention in terms of one of the above-mentioned indications and/or which enable a reduction in the dosage of the MCH antagonist according to the invention. First of all, one or more additional active substances are chosen from the series that make up
- aktivne tvari za liječenje dijabetesa, - active substances for the treatment of diabetes,
- aktivne tvari za liječenje dijabetičkih komplikacija, - active substances for the treatment of diabetic complications,
- aktivne tvari za liječenje debljine, ponajprije različite od MCH antagonista, - active substances for the treatment of obesity, preferably different from MCH antagonists,
- aktivne tvari za liječenje visokog krvnog tlaka, - active substances for the treatment of high blood pressure,
- aktivne tvari za liječenje hiperlipidemije, uključiv i arterioskleroze, - active substances for the treatment of hyperlipidemia, including arteriosclerosis,
- aktivne tvari za liječenje artritisa, - active substances for the treatment of arthritis,
- aktivne tvari za liječenje anksioznih stanja, - active substances for the treatment of anxiety states,
- aktivne tvari za liječenje depresije. - active substances for the treatment of depression.
Gore spomenute kategorije aktivnih tvari će se sada objasniti s više pojedinosti pomoću primjera. The categories of active substances mentioned above will now be explained in more detail by means of examples.
Primjeri aktivnih tvari za liječenje dijabetesa jesu insulinski senzibilizatori, sredstva za ubrzavanje izlučivanja inzulina, bigvanidi, inzulini, inhibitori α-glukozidaze, agonisti β3 adreno-receptora. Examples of active substances for the treatment of diabetes are insulin sensitizers, agents for accelerating insulin secretion, biguanides, insulins, α-glucosidase inhibitors, β3 adreno-receptor agonists.
Inzulinski senzibilizatori uključuju pioglitazon i njegove soli (ponajprije hidrokloride), troglitazon, rosiglitazon i njegove soli (ponajprije maleat), JTT-501, Gl-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702, GW-1929. Insulin sensitizers include pioglitazone and its salts (primarily hydrochlorides), troglitazone, rosiglitazone and its salts (primarily maleate), JTT-501, Gl-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP -297, R-119702, GW-1929.
Sredstva za ubrzavanje izlučivanja inzulina uključuju sulfoniluree, kao što je na primjer tolbutamid, klor-propamid, trazamid, acetoheksamid, glidlopiramid i njegove amonijeve soli, glibenclamid, gliklazid, glimepirid. Daljnji primjeri sredsatva za ubrzavanje izlučivanja inzulina jesu repaglinid, nateglinid, mitiglinid (KAD-1229) i JTT-608. Agents for accelerating insulin secretion include sulfonylureas, such as for example tolbutamide, chlorpropamide, trazamide, acetohexamide, glidlopyramid and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of agents for accelerating insulin secretion are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.
Bigvanidi uključuju metformin, buformin i fenformin. Biguanides include metformin, buformin and phenformin.
Inzulini uključuju one koji se dobivaju od životinja, posebno goveda ili svinja, polusintetičke humane inzuline koji se sintetiziraju enzimski iz insulina dobivenog od životinja, humani inzulin dobiven genetskim inženjeringom, npr. iz Escherichi coli ili kvaščevih gljivica. Osim toga, pojam inzulina također uključuje i inzulin-cink (koji sadrži 0,45 do 0,9 mas. postotaka cinka) i protamin-inzulin-cink koji se može dobiti iz cinkovog klorida, protamin sulfata i inzulina. Inzulin se može također dobiti iz inzulinskih fragmenata ili derivata (na primjer INS-1, itd.). Insulins include those obtained from animals, especially bovine or porcine, semi-synthetic human insulins synthesized enzymatically from animal-derived insulin, human insulin obtained by genetic engineering, eg from Escherichia coli or yeasts. In addition, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 wt. percent zinc) and protamine-insulin-zinc which can be obtained from zinc chloride, protamine sulfate, and insulin. Insulin can also be obtained from insulin fragments or derivatives (eg INS-1, etc.).
Inzulin može također uključiti i različite vrste, npr. što se tiče vremena pojave učinka i trajanja učinka ("ultra imediate action type", "imediate action type", "two phase type", "intermediate type", "prolonged action type", itd.) koji se biraju ovisno o patološkom stanju pacijenta. Insulin can also include different types, e.g. in terms of time of onset of effect and duration of effect ("ultra immediate action type", "immediate action type", "two phase type", "intermediate type", "prolonged action type", etc.) which are chosen depending on the pathological condition of the patient.
Inhibitori α-glukozidaze uključuju akarbozu, voglibozu, miglitol, emiglitat. α-glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.
Agonisti β3 adreno receptora uključuju AJ-9677, BMS-196085, SB-226552, AZ40140. β3 adrenoreceptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.
Aktivne tvari za liječenje dijabetesa, različite od onih koje su gore spomenute, uključuju ergoset, pramlintid, leptin, BAY-27-9955 kao također i inhibitore glikogen fosforilaze, inhibitore sorbitol dehidrogenaze, inhibitore protein tirozin fosfataze 1B, inhibitore dipeptidil proteaze, glipazid, gliburid. Active substances for the treatment of diabetes other than those mentioned above include ergocet, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide .
Aktivne tvari za liječenje dijabetičkih komplikacija uključuju, na primjer, inhibitore aldoza reduktaze, inhibitore glikacije i inhibitore protein kinaze C. Active substances for the treatment of diabetic complications include, for example, aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors.
Inhibitori aldoza reduktaze jesu na primjer tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-SOi, AS-3201. Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-SOi, AS-3201.
Jedan primjer inhibitora glikacije je pimagedin. One example of a glycation inhibitor is pimagedin.
Inhibitori protein kinaze C jesu na primjer NGF, LY-333531. Protein kinase C inhibitors are for example NGF, LY-333531.
Aktivne tvari različite od onih koje su gore spomenute za liječenje dijabetičkih komplikacije uključuju alprostadil, tiaprid hidroklorid, kilostazol, meksiletin hidroklorid, etil eikozapentat, memantin, pimagedin (ALT-711). Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, tiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).
Aktivne tvari za liječenje debljine, ponajprije različite od MCH antagonista, uključuju inhibitore lipaze i anorektike. Active substances for the treatment of obesity, preferably other than MCH antagonists, include lipase inhibitors and anorectics.
Primjer inhibitora lipaze kojem se daje prednost je orlistat. An example of a preferred lipase inhibitor is orlistat.
Primjeri anorektika kojima se daje prednost jesu fentermin, mazindol, deksfenfluramin, fluoksetin, sibutramin, baiamin, (S)-sibutramin, SR-141716, NGD-95-1. Examples of preferred anorectics are phentermine, mazindole, dexfenfluramine, fluoxetine, sibutramine, baiamin, (S)-sibutramine, SR-141716, NGD-95-1.
Aktivne tvari različite od onih koje su gore spomenute za liječenje debljine uključuje lipstatin. Active substances other than those mentioned above for the treatment of obesity include lipstatin.
Osim toga za svrhu ove prijave aktivne tvari iz skupine aktivnih tvari protiv debljine također uključuju i anorektike, od kojih se moraju obuhvatiti β3 agonisti, tiromimetičke aktivne tvari i NPY antagonisti. Svrha aktivnih tvari protiv debljanja ili anorektika kojima se ovdje daje prednost pokazana je u slijedećem dodatnom popisu u obliku primjera: fenilpropanolamin, efedrin, pseudoefedrin, fentermin, holecistokinin-A (koji se ovdje kasnije navodi kao CCK-A) agonist, inhibitor ponovnog vezanja monoamina (kao što je na primjer sibutramin), simpatomimetičke aktivne tvari, serotonergne aktivne tvari (kao na primjer deksfenfluramin ili fenfluramin), dopamin antagonisti (kao na primjer bromokriptin), agonist ili mimetik receptora hormona koji stimulira melanocite, analog hormona koji stimulira melanocite, kanabinoid receptor antagonist, MCH antagonist, OB protein (koji se ovdje u nastavku naziva leptin), leptin analog, leptin receptor agonist, gatanin antagonist, inhibitor ili reducer GI lipaze (kao što je na primjer orlistat). Drugi anorektici uključuje bombesin agoniste, dehidroepiandrosteron ili njegove analoge, glukokortikoid receptor agoniste i antagoniste, oreksin receptor antagoniste, antagoniste proteina koji veže urokortin, agoniste receptora glukagonu sličnog peptida 1, kao što su na primjer eksendin i cilijarni neurotrofni faktori, kao što su na primjer aksokini. In addition, for the purpose of this application, active substances from the group of active substances against obesity also include anorectics, which must include β3 agonists, thyromimetic active substances and NPY antagonists. The purpose of the anti-obesity or anorectic active agents preferred herein is exemplified in the following additional list: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, cholecystokinin-A (hereinafter referred to as CCK-A) agonist, monoamine reuptake inhibitor (such as sibutramine), sympathomimetic agents, serotonergic agents (such as dexfenfluramine or fenfluramine), dopamine antagonists (such as bromocriptine), melanocyte-stimulating hormone receptor agonist or mimetic, melanocyte-stimulating hormone analog, cannabinoid receptor antagonist, MCH antagonist, OB protein (hereinafter referred to as leptin), leptin analog, leptin receptor agonist, gatanin antagonist, GI lipase inhibitor or reducer (such as orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogs, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin-binding protein antagonists, glucagon-like peptide 1 receptor agonists, such as exendin, and ciliary neurotrophic factors, such as axokines.
Aktivne tvari za liječenje visokog krvnog tlaka uključuju inhibitore enzima koji pretvara angiotenzin, antagoniste kalcija, sredstva za otvaranje kalijevog kanala i angiotenzin II antagoniste. Active agents for the treatment of high blood pressure include angiotensin-converting enzyme inhibitors, calcium antagonists, potassium channel openers, and angiotensin II antagonists.
Inhibitori enzima koji pretvara angiotenzin uključuju kaptopril, enalapril, alacepril, delapril (hidroklorid), lizinopril, imidapril, benazepril, kilazapril, temokapril, trandolapril, manidipin (hidroklorid). Angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temokapril, trandolapril, manidipine (hydrochloride).
Primjeri kalcijevih antagonista su nifedipin, amlodipin, efonidipin, nikardipin. Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.
Sredstva za otvaranje kalijevog kanala uključuju levkromakalim, L-27152, AL0671, NIP-121. Potassium channel openers include leucromakalim, L-27152, AL0671, NIP-121.
Angiotenzin II antagonisti uključuju telmisartan, losartan, kandesartan, cileksetil, valsartan, irbeartan, CS-866, E4177. Angiotensin II antagonists include telmisartan, losartan, candesartan, cilexetil, valsartan, irbeartan, CS-866, E4177.
Aktivne tvari za liječenje hiperlipidemije, uključiv arterioskleroze, uključuju inhibitore HMG-CoA reduktaze, fibratne spojeve. Active substances for the treatment of hyperlipidemia, including arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds.
Inhibitori HMG-CoA reduktaze uključuju pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 i njihove soli. HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, ZD-4522 and salts thereof.
Fibratni spojevi uključuju bezafibrat, klinofibrat, klofibrat i simfibrat. Fibrate compounds include bezafibrate, clinofibrate, clofibrate, and simfibrate.
Aktivne tvari za liječenje artritisa uključuju ibuprofen. Active substances for the treatment of arthritis include ibuprofen.
Aktivne tvari za liječenje anksioznih stanja uključuju klordiazepoksid, diazepam, oksozolam, medazepam, kloksazolam, bromazepam, lorazepam, alprazolam, fludiazepam. Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.
Aktivne tvari za liječenje depresije uključuju fluoksetin, fluvoksamin, imipramin, paroksetin, sertralin. Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.
Doziranje ovih aktivnih tvari je uobičajeno 1/5 od najniže normalno propisane doze pa sve do 1/1 od normalne propisane doze. The dosage of these active substances is usually 1/5 of the lowest normally prescribed dose up to 1/1 of the normal prescribed dose.
U drugoj izvedbi izum se također odnosi na upotrebu najmanje jednog karboksamidnog spoja prema izumu i/ili soli prema izumu za utjecanje na ponašanje sisavca pri prehrani. Ta se upotreba posebno temelji na činjenici da spojevi prema izumu mogu biti prikladni za smanjenje gladi, ograničenje apetita, kontrolu ponašanja pri jelu i/ili za izazivanje osjećaja sitosti. Na ponašanje pri jelu utječe se povoljno tako da se smanji unošenje hrane. Zbog toga se spojevi prema izumu uzimaju ponajprije za smanjenje tjelesne težine. Druga upotreba prema izumu je prevencija porasta tjelesne težine, na primjer kod ljudi koji su ranije poduzeli korake za smanjenje težine i zainteresirani su za održavanje njihove manje tjelesne težine. Prema ovoj izvedbi prednost se daje ne-terapeutskoj upotrebi. Takova ne-terapeutska upotreba može biti kozmetička upotreba, na primjer za promjenu vanjskog izgleda, ili primjena za poboljšanje općeg zdravlja. Spojevi prema izumu upotrebljavaju se ponajprije ne-terapeutski za sisavce, posebno ljude koji ne pate od bilo kojeg dijagnosticiranog poremećaja prehrane, kojima nije dijagnosticirana debljina, bulimija, dijabetes i/ili kojima nisu dijagnosticirani mikturicijski poremećaji, posebno urinarna inkontinencija. Ponajprije, spojevi prema izumu su prikladni za ne-terapeutsku upotrebu kod ljudi čiji BMI (e, body mass index = indeks tjelesne mase), definiran kao njihova tjelesna težina u kilogramima podijeljena s njihovom visinom (u metrima) na kvadrat, je ispod razine 30, posebno ispod 25. In another embodiment, the invention also relates to the use of at least one carboxamide compound according to the invention and/or a salt according to the invention for influencing the feeding behavior of a mammal. This use is based in particular on the fact that the compounds of the invention may be suitable for reducing hunger, curbing appetite, controlling eating behavior and/or inducing satiety. Eating behavior is favorably influenced by reducing food intake. For this reason, the compounds according to the invention are taken primarily for weight reduction. Another use according to the invention is the prevention of weight gain, for example in people who have previously taken steps to reduce weight and are interested in maintaining their lower body weight. According to this embodiment, non-therapeutic use is preferred. Such non-therapeutic use may be a cosmetic use, for example to change the external appearance, or an application to improve general health. The compounds of the invention are preferably used non-therapeutically for mammals, especially humans who do not suffer from any diagnosed eating disorder, who are not diagnosed with obesity, bulimia, diabetes and/or who are not diagnosed with micturition disorders, especially urinary incontinence. In particular, the compounds of the invention are suitable for non-therapeutic use in humans whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in meters) squared, is below 30 , especially under 25.
Primjeri koji slijede namijenjeni su za prikaz izuma. The following examples are intended to illustrate the invention.
Prethodne napomene: Previous notes:
U pravilu, tališta, 1H-NMR i/ili maseni spektri dobiveni su za proizvedene spojeve. Ako nije navedeno drugačije, vrijednosti Rf su utvrđene upotrebom 60 TLC pločica silika gela gotovih za upotrebu F254 (E. Merck, Darmstadt, proizvod br. 1.05714) bez zasićenja komore. Vrijednosti Rf su dobivene upotrebom DC gotovih pločica F254 iz aluminijevog oksida 60 TLC (E. Merck, Darmstadt, proizvod br. 1.05713) bez zasićenja komore. As a rule, melting points, 1H-NMR and/or mass spectra were obtained for the produced compounds. Unless stated otherwise, Rf values were determined using 60 ready-to-use silica gel TLC plates F254 (E. Merck, Darmstadt, product no. 1.05714) without saturating the chamber. Rf values were obtained using DC ready-made F254 alumina 60 TLC plates (E. Merck, Darmstadt, product no. 1.05713) without saturating the chamber.
Navedeni HPLC podaci izmjereni su pod dolje navedenim parametrima: The above HPLC data were measured under the following parameters:
Stupac Zorbax (Agilent Technologies), SB (Stable Bond) - C18; 3,5 μm; 4,6 x 75 mm; temperatura stupca: 30°C; protok: 0,8 ml/min; volumen ubrizgavanja: 5 μl; detekcija pri 254 nm. Column Zorbax (Agilent Technologies), SB (Stable Bond) - C18; 3.5 μm; 4.6 x 75 mm; column temperature: 30°C; flow rate: 0.8 ml/min; injection volume: 5 μl; detection at 254 nm.
Postupak A: voda:acetonitril:mravlja kiselina 9:1:0,01 prema 1:9:0,01 kroz 9 minuta. Procedure A: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 for 9 minutes.
Postupak B: voda:acetonitril:mravlja kiselina 9:1:0,01 prema 1:9:0,01 kroz 4 minute, zatim 6 min 1:9:0,01 Procedure B: water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 for 4 minutes, then 6 minutes 1:9:0.01
Ako nije data specifična informacija o konfiguraciji, ostaje otvoreno pitanje da li se radi o čistim enantiomerima ili je došlo do djelomične ili čak potpune racemizacije. If no specific configuration information is given, it remains an open question whether these are pure enantiomers or whether partial or even complete racemization has occurred.
Gore i u nastavku upotrebljavaju se slijedeće kratice: The following abbreviations are used above and below:
BOC-anhidrid terc-butiloksikarbonil-anhidrid BOC-anhydride tert-butyloxycarbonyl-anhydride
GDI karbonildiimidazol GDI carbonyldiimidazole
CDT 1,1 '-karbonildi-(1,2,4-triazol) CDT 1,1 '-carbonyldi-(1,2,4-triazole)
DMF dimetilfomnamid DMF dimethylformamide
etil acetat/EtOAc etil acetat ethyl acetate/EtOAc ethyl acetate
eter dietil eter ether diethyl ether
HOBt 1-hidroksibenzotriazol-hidrat HOBt 1-hydroxybenzotriazole hydrate
Hünigova baza N,N-diizopropil-etilamin Hünig's base N,N-diisopropyl-ethylamine
conc. koncentriran conc. concentrated
Me metil Me methyl
MeOH metanol MeOH methanol
RT sobna temperatura (pribl. 20°C) RT room temperature (approx. 20°C)
TBTU 2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluronijev tetrafluorborat TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
THF tetrahidrofuran THF tetrahydrofuran
eq. ekivalent eq. equivalent
calc. izračunato calc. calculated
fnd. pronađeno fnd. found
Opći radni postupak I (TBTU povezivanje): General working procedure I (TBTU connection):
Trietilamin (1,5 ekv.) i TBTU (1,0 ekv.) se dodaju uzastopce u otopinu karboksilne kiseline (1,0 ekv.) u THF-u ili DMF-u. Ovisno o karboksilnoj kiselini smjesu se miješa 10 minuta do 12 sati između sobne temperature i 40°C prije dodatka amina (1,0 ekv.). Reakcijsku smjesu se miješa 30 minuta do 2 sata između sobne temperature i 40°C, i zatim se doda poluzasićenu otopinu NaHCO3. Nakon ekstrakcije vodene faze s prikladnim otapalom (npr. etil acetat) organsku fazu se osuši preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje; daljnje čišćenje se vrši kromatografijom na stupcu ili pomoću HPLC. Reakciju se može također provesti i u Chemspeed automatskom uređaju za sintezu. Triethylamine (1.5 eq.) and TBTU (1.0 eq.) were added sequentially to a solution of the carboxylic acid (1.0 eq.) in THF or DMF. Depending on the carboxylic acid, the mixture is stirred for 10 minutes to 12 hours between room temperature and 40°C before the addition of the amine (1.0 eq.). The reaction mixture is stirred for 30 minutes to 2 hours between room temperature and 40°C, and then half-saturated NaHCO3 solution is added. After extraction of the aqueous phase with a suitable solvent (eg ethyl acetate), the organic phase is dried over magnesium sulfate. The solvent was removed on a rotary evaporator; further purification is performed by column chromatography or HPLC. The reaction can also be carried out in a Chemspeed automatic synthesis device.
Opći radni postupak II (CDT povezivanje): General working procedure II (CDT connection):
CDT (1 ekv.) se doda u otopinu primarnog amina (1,0 ekv.) u DMF-u (1 mol/ml) pri 0°C i smjesu se miješa pri 0°C još 30 minuta. Reakcijsku smjesu se zagrije na 25°C i doda se trietilamin (3 ekv.). Zatim se doda sekundarni amin (1,0 ekv.) u DMF-u (0,25 mol/ml) i reakcijsku otopinu se grije 30 minuta do 3 dana pri 60 do 80°C. DMF se odstrani u vakuumu i ostatak se preuzme s diklormetanom i 5%-tnom otopinom Na2CO3 ili s vodom i terc-butilmetil eterom. Organsku fazu se ekstrahira s vodom i otapalo se odstrani na rotacijskom uređaju za isparavanje, prema potrebi nakon sušenja preko magnezijevog sulfata; daljnje čišćenje se vrši kromatografijom na stupcu ili kristalizacijom. Reakcija se može također provesti u Chemspeed automatskom uređaju za sintezu. CDT (1 eq.) was added to a solution of the primary amine (1.0 eq.) in DMF (1 mol/ml) at 0 °C and the mixture was stirred at 0 °C for another 30 min. The reaction mixture was heated to 25°C and triethylamine (3 eq.) was added. Secondary amine (1.0 eq.) in DMF (0.25 mol/ml) is then added and the reaction solution is heated for 30 min to 3 days at 60 to 80°C. DMF is removed in vacuo and the residue is taken up with dichloromethane and 5% Na2CO3 solution or with water and tert-butylmethyl ether. The organic phase is extracted with water and the solvent is removed on a rotary evaporator, if necessary after drying over magnesium sulfate; further purification is done by column chromatography or crystallization. The reaction can also be carried out in a Chemspeed automated synthesizer.
Primjer 1.1: Example 1.1:
7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.1.a. 4-brom-2-nitro-benzojeva kiselina 1.1.a. 4-bromo-2-nitro-benzoic acid
U reakcijsku smjesu od 82 g (0,379 mol) 4-brom-2-nitro-toluena u 700 ml piridina i 500 ml vode doda se u obrocima 174,5 g (1,104 mola) kalijevog permanganata tijekom osam sati. Reakcijsku smjesu se miješa 12 sati pri 60oC. Zatim se uzastopce doda daljnjih 20 g (0,092 mola) 4-brom-2-nitro-toluena, 50 ml piridina i 30 g (0,189 mola) kalijevog permanganata. Reakcijsku smjesu se miješa 12 sati pri 60°C, pomiješa se s 200 ml etanola i refluktira se 30 minuta. Zatim se reakcijsku smjesu vruću filtrira i filtrat se ispari na rotacijskom uređaju za isparavanje. Ostatak se zaluži s 10%-tnom otopinom natrijevog hidroksida i ekstrahira se s dietil eterom. Vodenu fazu se odvoji i zakiseli se s razrijeđenom solnom kiselinom. Nastali kristali se odfiltriraju, isperu s vodom, azeotropski se osuše s tetrahidrofuranom i pomiješaju s diizopropil eterom. To the reaction mixture of 82 g (0.379 mol) of 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water, 174.5 g (1.104 mol) of potassium permanganate were added in portions over eight hours. The reaction mixture was stirred for 12 hours at 60°C. A further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are then successively added. The reaction mixture was stirred for 12 hours at 60°C, mixed with 200 ml of ethanol and refluxed for 30 minutes. The reaction mixture is then filtered hot and the filtrate is evaporated on a rotary evaporator. The residue is basified with 10% sodium hydroxide solution and extracted with diethyl ether. The aqueous phase is separated and acidified with dilute hydrochloric acid. The resulting crystals are filtered off, washed with water, azeotropically dried with tetrahydrofuran and mixed with diisopropyl ether.
Iskorištenje: 37 g (32,8% od teorijskog). Yield: 37 g (32.8% of theoretical).
C7H4BrNO4 (M = 246,018) C7H4BrNO4 (M = 246.018)
Izračunato: molekulska masa (M+Na)+: 268/270 Calculated: molecular weight (M+Na)+: 268/270
Nađeno: molekulska masa (M+Na)+: 268/270 Found: molecular weight (M+Na)+: 268/270
Rf vrijednost: 0,46 (silika gel, diklormetan/metanol/octena kiselina 8:2:0,1) Rf value: 0.46 (silica gel, dichloromethane/methanol/acetic acid 8:2:0.1)
1.1.b. 4'-klor-3-nitro-bifenil-4-karboksilna kiselina 1.1.b. 4'-chloro-3-nitro-biphenyl-4-carboxylic acid
0,288 g (0,25 mmola) tetrakis-(trifenilfosfin)-paladija, 1,25 g (7,99 mmolova) 4-klor-fenil-borne kiseline u 30 ml metanola i 2,31 g (21,7 mmola) natrijevog karbonata u 14 ml vode doda se uzastopce u otopinu od 1,92 g (7,81 mmolova) 4-brom-2-nitro-benzojeve kiseline u 30 ml dioksana. Reakcijsku smjesu se grije jedan sat pri 110°C u mikrovalnoj grijalici pri 300 Watta. Zatim se reakcijsku smjesu ispari na rotacijskom uređaju za isparavanje, ostatak se preuzme u vodu i namjesti na pH 3 s 1 M solnom kiselinom. Vodenu otopinu se ekstrahira s etil acetatom. Organsku fazu se osuši preko natrijevog sulfata, otapalo se izdestilira na rotacijskom uređaju za isparavanje i ostatak se pomiješa s diizopropil eterom. 0.288 g (0.25 mmol) of tetrakis-(triphenylphosphine)-palladium, 1.25 g (7.99 mmol) of 4-chloro-phenyl-boronic acid in 30 ml of methanol and 2.31 g (21.7 mmol) of sodium of carbonate in 14 ml of water is added successively to a solution of 1.92 g (7.81 mmol) of 4-bromo-2-nitro-benzoic acid in 30 ml of dioxane. The reaction mixture is heated for one hour at 110°C in a microwave heater at 300 Watts. The reaction mixture is then evaporated on a rotary evaporator, the residue is taken up in water and adjusted to pH 3 with 1 M hydrochloric acid. The aqueous solution was extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off on a rotary evaporator and the residue is mixed with diisopropyl ether.
Iskorištenje: 2,04 g (93,9% od teorijskog). Yield: 2.04 g (93.9% of theoretical).
C13H8ClNO4 (M = 277,666) C13H8ClNO4 (M = 277.666)
Izračunato: molekulska masa (M-H)-: 276 Calculated: molecular weight (M-H)-: 276
Nađeno: molekulska masa (M-H)-: 276 Found: molecular weight (M-H)-: 276
Rf vrijednost: 0,5 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.5 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.1.c. Etil 4-cijanometil-benzoat 1.1.c. Ethyl 4-cyanomethyl-benzoate
U otopinu od 147,5 g (2,263 mola) kalijevog cijanida u 250 ml vruće vode doda se kap po kap otopinu od 500 g (2,057 mola) etil 4-brom-metil-benzoata u 1000 ml etanola. Reakcijsku smjesu se refluktira jedan sat i miješa se još 12 sati pri sobnoj temperaturi. Doda se daljnjih 73,7 g (0,5 mola) kalijevog cijanida i smjesu se refluktira dva sata. Krute tvari u reakcijskoj smjesi se odfiltriraju i filtrat se filtrira kroz smjesu silika gela i aktivnog ugljena. Dobiveni filtrat se ispari i ostatak se prelije na 1000 ml vode. Vodenu otopinu se ekstrahira s terc-butilmetil eterom i organsku fazu se ekstrahira tri puta s vodom. Zatim se organsku fazu osuši preko magnezijevog sulfata i otapalo se izdestilira na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu silika gela (petrol eter/etil acetat 8:2). To a solution of 147.5 g (2.263 moles) of potassium cyanide in 250 ml of hot water, a solution of 500 g (2.057 moles) of ethyl 4-bromo-methyl-benzoate in 1000 ml of ethanol is added drop by drop. The reaction mixture is refluxed for one hour and stirred for another 12 hours at room temperature. A further 73.7 g (0.5 mol) of potassium cyanide was added and the mixture was refluxed for two hours. The solids in the reaction mixture are filtered off and the filtrate is filtered through a mixture of silica gel and activated carbon. The resulting filtrate is evaporated and the residue is poured into 1000 ml of water. The aqueous solution was extracted with tert-butylmethyl ether and the organic phase was extracted three times with water. Then the organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).
Iskorištenje: 164,46 g (42,2% od teorijskog). Yield: 164.46 g (42.2% of theoretical).
C11H11NO2 (M = 189,216) C11H11NO2 (M = 189.216)
Izračunato: molekulska masa (M+H)+: 190 Calculated: molecular weight (M+H)+: 190
Nađeno: molekulska masa (M+H)+: 190 Found: molecular weight (M+H)+: 190
Rf vrijednost: 0,3 (silika gel, petrol eter/etil acetat 8:2) Rf value: 0.3 (silica gel, petroleum ether/ethyl acetate 8:2)
1.1.d. 4-cijanometil-benzojeva kiselina 1.1.d. 4-cyanomethyl-benzoic acid
Otopinu od 10 g (53 mmola) etil 4-cijanometil-benzoata i 2,02 ml 1 M otopine natrijevog hidroksida u 100 ml etanola refluktira se jedan sat. Reakcijsku otopinu se ispari i ostatak se pomiješa s ledenom vodom. U reakcijsku otopinu doda se kap po kap koncentriranu solnu kiselinu do prestanka stvaranja taloga. Talog se odfiltrira, ispere se dva puta s vodom i osuši. A solution of 10 g (53 mmol) of ethyl 4-cyanomethyl-benzoate and 2.02 ml of a 1 M sodium hydroxide solution in 100 ml of ethanol is refluxed for one hour. The reaction solution was evaporated and the residue was mixed with ice water. Concentrated hydrochloric acid is added drop by drop to the reaction solution until the formation of a precipitate stops. The precipitate is filtered off, washed twice with water and dried.
Iskorištenje: 4,7 g (55% od teorijskog). Yield: 4.7 g (55% of theoretical).
C9H7NO2 (M = 161,162) C9H7NO2 (M = 161.162)
Izračunato: molekulska masa (M-H)-: 160 Calculated: molecular weight (M-H)-: 160
Nađeno: molekulska masa (M-H)-: 160 Found: molecular weight (M-H)-: 160
1.1.e. (4-hidroksimetil-fenil)-acetonitril 1.1.e. (4-hydroxymethyl-phenyl)-acetonitrile
5,17 g (32 mmola) CDI doda se u otopinu od 4,7 g (29 mmolova) 4-cijanometil-benzojeve kiseline u 250 ml tetra-hidrofurana i miješa se do prestanka razvijanja plina. Tu reakcijsku smjesu se doda kap po kap u otopinu od 3,29 g (87 mmolova) natrijevog borhidrida u 200 ml vode u na takav način da temperatura ne poraste iznad 30°C. To se miješa dva sata i reakcijsku smjesu se namjesti na pH 3-4 s otopinom kalijevog hidrogen sulfata. Zatim ju se ekstrahira s etil acetatom, organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. 5.17 g (32 mmol) of CDI was added to a solution of 4.7 g (29 mmol) of 4-cyanomethyl-benzoic acid in 250 ml of tetrahydrofuran and stirred until gas evolution ceased. This reaction mixture is added drop by drop to a solution of 3.29 g (87 mmol) of sodium borohydride in 200 ml of water in such a way that the temperature does not rise above 30°C. This is stirred for two hours and the reaction mixture is adjusted to pH 3-4 with potassium hydrogen sulfate solution. It is then extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.
Iskorištenje: 2,6 g (60,9% od teorijskog). Yield: 2.6 g (60.9% of theoretical).
C9H9NO (M = 147,178) C9H9NO (M = 147.178)
Izračunato: molekulska masa (M-H)-: 146 Calculated: molecular weight (M-H)-: 146
Nađeno: molekulska masa (M-H)-: 146 Found: molecular weight (M-H)-: 146
1.1.f. (4-brom-metil-fenil)-acetonitril 1.1. f. (4-bromo-methyl-phenyl)-acetonitrile
0,86 ml (9 mmolova) fosfornog tribromida doda se kap po kap pri 0°C u otopinu od 2,6 g (17,66 mmolova) (4-hidroksimetil-fenil)-acetonitrila u 25 ml terc-butilmetil etera. Po završetku reakcije, reakcijsku smjesu se pomiješa s vodom pri sobnoj temperaturi, organsku fazu se odvoji i ekstrahira uzastopce s otopinom natrijevog hidrogen karbonata i vodom. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se izdestilira na rotacijskom uređaju za isparavanje. 0.86 ml (9 mmol) of phosphorus tribromide was added dropwise at 0°C to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 ml of tert-butylmethyl ether. At the end of the reaction, the reaction mixture is mixed with water at room temperature, the organic phase is separated and extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate and the solvent is distilled off on a rotary evaporator.
Iskorištenje: 2,9 g (78,1% od teorijskog). Yield: 2.9 g (78.1% of theoretical).
C9H8BrN (M = 210,075) C9H8BrN (M = 210.075)
Izračunato: molekulska masa (M+H)+: 209/211 Calculated: molecular weight (M+H)+: 209/211
Nađeno: molekulska masa (M+H)+: 209/211 Found: molecular weight (M+H)+: 209/211
1.1.g. (4-pirolidin-1-ilmetil-fenil)-acetonitril 1.1.g. (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile
0,446 ml (5,44 mmolova) pirolidina i 1,366 g (9,882 mmolova) kalijevog karbonata doda se u 20 ml dimetilform-amida. Uz miješanje se doda 1,038 g (4,941 mmola) (4-brom-metil-fenil)-acetonitrila i smjesu se miješa 12 sati pri sobnoj temperaturi. Reakcijsku smjesu se ispari na rotacijskom uređaju za isparavanje i ostatak se ekstrahira s etil acetatom i vodom. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. 0.446 ml (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate were added to 20 ml of dimethylformamide. With stirring, 1.038 g (4.941 mmol) of (4-bromo-methyl-phenyl)-acetonitrile was added and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated on a rotary evaporator and the residue was extracted with ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator.
Iskorištenje: 0,732 g (74% od teorijskog). Yield: 0.732 g (74% of theoretical).
C13H16N2 (M = 200,286) C13H16N2 (M = 200.286)
Izračunato: molekulska masa (M+H)+: 201 Calculated: molecular weight (M+H)+: 201
Nađeno: molekulska masa (M+H)+: 201 Found: molecular weight (M+H)+: 201
Rf vrijednost: 0,5 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.1.h 2-(4-pirolidin-1-ilmetil-fenil)-etilamin 1.1.h 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine
Reakcijsku smjesu od 0,73 g (3,66 mmola) (4-pirolidin-1-ilmetil-fenil)-acetonitrila i 0,1 g Raney nikla u 25 ml metanolne otopine amonijaka se hidrogenira 9 h pri 50oC i 3 bara tlaka vodika. The reaction mixture of 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile and 0.1 g of Raney nickel in 25 ml of methanolic ammonia solution is hydrogenated for 9 h at 50oC and 3 bar hydrogen pressure .
Iskorištenje: 0,72 g (96,4% od teorijskog). Yield: 0.72 g (96.4% of theoretical).
C13H20N2 (M = 204,31) C13H20N2 (M = 204.31)
Izračunato: molekulska masa (M+H)+: 205 Calculated: molecular weight (M+H)+: 205
Nađeno: molekulska masa (M+H)+: 205 Found: molecular weight (M+H)+: 205
Rf vrijednost: 0,23 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.23 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.1.i. 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil )-etil]-amid 1.1.i. 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Otopinu od 0,4 (1,44 mmola) 4'-klor-3-nitro-bifenil-4-karboksilne kiseline, 0,29 g (1,44 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina, 0,46 g (1,44 mmola) TBTU, 0,19 g (1,44 mmola) HOBT i 0,42 ml (3 mmola) trietilamina u 30 ml tetrahidrofurana miješa se 14 sati pri sobnoj temperaturi. Reakcijsku smjesu se ispari na rotacijskom uređaju za isparavanje, ekstrahira s vodom i etil acetatom i osuši preko magnezijevog sulfata. Čišćenje se vrši kromato-grafijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/metanol/amonijak = 90:10:1). A solution of 0.4 (1.44 mmol) 4'-chloro-3-nitro-biphenyl-4-carboxylic acid, 0.29 g (1.44 mmol) 2-(4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine, 0.46 g (1.44 mmol) TBTU, 0.19 g (1.44 mmol) HOBT and 0.42 ml (3 mmol) triethylamine in 30 ml tetrahydrofuran were stirred for 14 hours at room temperature. The reaction mixture is evaporated on a rotary evaporator, extracted with water and ethyl acetate and dried over magnesium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 90:10:1).
Iskorištenje: 0,47 g (70,3% od teorijskog). Yield: 0.47 g (70.3% of theoretical).
C26H26ClN3O3 (M = 463,96) C26H26ClN3O3 (M = 463.96)
Izračunato: molekulska masa (M+H)+: 464/466 Calculated: molecular weight (M+H)+: 464/466
Nađeno: molekulska masa (M+H)+: 464/466 Found: molecular weight (M+H)+: 464/466
Rf vrijednost: 0,36 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.1.j. 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il metil-fenil)-etil]-amid 1.1.j. 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl methyl-phenyl)-ethyl]-amide
Reakcijsku smjesu od 0,47 g (1,01 mmola) 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida i 0,1 g Raney nikla u 50 ml metanolne otopine amonijaka hidrogenira se 24 sata pri 20°C i 3 bara tlaka vodika. Sirov proizvod dalje reagira bez čišćenja. The reaction mixture of 0.47 g (1.01 mmol) of 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide and 0.1 g of Raney nickel in 50 ml of methanolic ammonia solution is hydrogenated for 24 hours at 20°C and 3 bar of hydrogen pressure. The crude product reacts further without purification.
Iskorištenje: 0,46 g, sirovo. Yield: 0.46 g, raw.
C26H28ClN3O (M = 433,98) C26H28ClN3O (M = 433.98)
Izračunato: molekulska masa (M+H)+: 434/436 Calculated: molecular weight (M+H)+: 434/436
Nađeno: molekulska masa (M+H)+: 434/436 Found: molecular weight (M+H)+: 434/436
Rf vrijednost: 0,34 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.34 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.1.k. 7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 1.1.k. 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
0,46 g (1,06 mmola) 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amida i 5 ml mravlje kiseline se miješa 3 h pri sobnoj temperaturi i 2 h pri 100oC. Reakcijsku smjesu se pomiješa s vodom, zaluži se s 6N otopinom natrijevog hidroksida i talog se odsisa. Talog se preuzme u diklor-metan i osuši preko magnezijevog sulfata. Otapalo se izdestilira na rotacijskom uređaju za isparavanje i ostatak se triturira s diizopropil eterom. 0.46 g (1.06 mmol) of 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 5 ml of formic acid is mixed for 3 hours at room temperature and 2 hours at 100oC. The reaction mixture is mixed with water, made alkaline with 6N sodium hydroxide solution and the precipitate is filtered off with suction. The precipitate is taken up in dichloromethane and dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator and the residue is triturated with diisopropyl ether.
Iskorištenje: 0,3 g (64,6% od teorijskog). Yield: 0.3 g (64.6% of theoretical).
Talište: 178-179°C Melting point: 178-179°C
C27H26ClN3O (M = 443,98) C27H26ClN3O (M = 443.98)
Izračunato: molekulska masa (M+H)+: 444 Calculated: molecular weight (M+H)+: 444
Nađeno: molekulska masa (M+H)+: 444 Found: molecular weight (M+H)+: 444
Rf vrijednost: 0,35 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.2 Example 1.2
3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-p-tolil-3H-kinazolin-4-on 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one
[image] [image]
1.2.a. 4'-metil-3-nitro-bifenil-4-karboksilna kiselina 1.2.a. 4'-methyl-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 4-metil-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-methyl-phenyl-boronic acid.
Iskorištenje: 1,48 g (70,8% od teorijskog). Yield: 1.48 g (70.8% of theoretical).
C14H11NO4 (M = 257,24) C14H11NO4 (M = 257.24)
Izračunato: molekulska masa (M-H)-: 256 Calculated: molecular weight (M-H)-: 256
Nađeno: molekulska masa (M-H)-: 256 Found: Molecular Weight (M-H)-: 256
Rf vrijednost: 0,54 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.54 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.2.b. 4'-metil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.2.b. 4'-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-metil-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-methyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.
Iskorištenje: 0,51 g (78,3% od teorijskog). Yield: 0.51 g (78.3% of theoretical).
C27H29N3O3 (M = 443,55) C27H29N3O3 (M = 443.55)
Izračunato: molekulska masa (M+H)+: 444 Calculated: molecular weight (M+H)+: 444
Nađeno: molekulska masa (M+H)+: 444 Found: molecular weight (M+H)+: 444
Rf vrijednost: 0,35 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.2.c. 4'-metil-3-amino-bifenil-4-karboksilna kiselina-[2- (4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.2.c. 4'-methyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.j iz 4'-metil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.1.j from 4'-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,2 g (69,2% od teorijskog). Yield: 0.2 g (69.2% of theoretical).
C28H31N3O (M = 413,56) C28H31N3O (M = 413.56)
Izračunato: molekulska masa (M+H)+: 414 Calculated: molecular weight (M+H)+: 414
Nađeno: molekulska masa (M+H)+: 414 Found: molecular weight (M+H)+: 414
Rf vrijednost: 0,36 (silika gel, diklormetan/metanol/ aminonijak 9:1:0,1) Rf value: 0.36 (silica gel, dichloromethane/methanol/aminoniacin 9:1:0.1)
Primjer 1.3: Example 1.3:
3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-7-(4-trifluor-metil-fenil)-3H-kinazolin-4-on 3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-7-(4-trifluoro-methyl-phenyl)-3H-quinazolin-4-one
[image] [image]
1.3.a. 4'-trifluormetil-3-nitro-bifenil-4-karboksilna kiselina 1.3.a. 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 4-trifluormetil-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-trifluoromethyl-phenyl-boronic acid.
Iskorištenje: 1,24 g (49% od teorijskog). Yield: 1.24 g (49% of theoretical).
C14H8F3NO4 (M = 311,21) C14H8F3NO4 (M = 311.21)
Izračunato: molekulska masa (M-H)-: 310 Calculated: molecular weight (M-H)-: 310
Nađeno: molekulska masa (M-H)-: 310 Found: molecular weight (M-H)-: 310
R1 vrijednost: 0,3 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) R1 value: 0.3 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.3.b. 4'-trifluormetil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.3.b. 4'-trifluoromethyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-trifluor-metil-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-trifluoro-methyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.
Iskorištenje: 0,36 g (49,3% od teorijskog). Yield: 0.36 g (49.3% of theoretical).
C27H26F3N3O3 (M = 497,52) C27H26F3N3O3 (M = 497.52)
Izračunato: molekulska masa (M+H)+: 498 Calculated: molecular weight (M+H)+: 498
Nađeno: molekulska masa (M+H)+: 498 Found: molecular weight (M+H)+: 498
R1 vrijednost: 0,3 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) R1 value: 0.3 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.3.c. 4'-trifluormetil-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.3.c. 4'-trifluoromethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Reakcijsku smjesu od 0,1 g (0,2 mmola) 4'-trifluor-metil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amida i 0,08 g oksida platine u 50 ml etil acetata hidrogenira se 2,5 h pri 20oC. Katalizator se odfiltrira. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/ metanol/amonijak = 90:10:1). The reaction mixture of 0.1 g (0.2 mmol) of 4'-trifluoro-methyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 0.08 g of platinum oxide in 50 ml of ethyl acetate is hydrogenated for 2.5 h at 20oC. The catalyst is filtered off. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 90:10:1).
Iskorištenje: 0,06 g (63,8% od teorijskog). Yield: 0.06 g (63.8% of theoretical).
C27H28N3N3O (M = 467,53) C27H28N3N3O (M = 467.53)
Izračunato: molekulska masa (M+H)+: 468 Calculated: molecular weight (M+H)+: 468
Nađeno: molekulska masa (M+H)+: 468 Found: molecular weight (M+H)+: 468
Rf vrijednost: 0,46 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.46 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.4: Example 1.4:
7-(4-metoksi-fenil)-3-[2-(4-pirolidin-1-il-metil-fenil)-etil]-3H-kinazolin-4-on 7-(4-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.4.a. 4'-metoksi-3-nitro-bifenil-4-karboksilna kiselina 1.4.a. 4'-Methoxy-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 4-metoksi-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-methoxy-phenyl-boronic acid.
Iskorištenje: 0,38 g (48,9% od teorijskog) Yield: 0.38 g (48.9% of theoretical)
C14H11NO5 (M = 273,24) C14H11NO5 (M = 273.24)
Izračunato: molekulska masa (M-H)-: 272 Calculated: molecular weight (M-H)-: 272
Nađeno: molekulska masa (M-H)-: 272 Found: molecular weight (M-H)-: 272
Rf vrijednost: 0,39 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.4.b. 4'-metoksi-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 1.4.b. 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.j iz 4'-metoksi-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina. It is produced analogously to example 1.1.j from 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.
Iskorištenje: 0,23 g (57% od teorijskog). Yield: 0.23 g (57% of theoretical).
C27H29N3O4 (M = 459,55) C27H29N3O4 (M = 459.55)
Izračunato: molekulska masa (M+H)+: 460 Calculated: molecular weight (M+H)+: 460
Nađeno: molekulska masa (M+H)+: 460 Found: molecular weight (M+H)+: 460
Rf vrijednost: 0,48 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.48 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.4.c. 4'-metoksi-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.4.c. 4'-methoxy-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-metoksi-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 4'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,09 g (42% od teorijskog). Yield: 0.09 g (42% of theoretical).
C27H31N3O2 (M = 429,56) C27H31N3O2 (M = 429.56)
Izračunato: molekulska masa (M+H)+: 430 Calculated: molecular weight (M+H)+: 430
Nađeno: molekulska masa (M+H)+: 430 Found: molecular weight (M+H)+: 430
Rf vrijednost: 0,44 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.44 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.5: Example 1.5:
7-(3,4-diklor-fenil)-3-[2-(4-pirolidin-1-il-metil-fenil)-etil]-3H-kinazolin-4-on 7-(3,4-dichloro-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.5.a. 3',4'-diklor-3-nitro-bifenil-4-karboksilna kiselina 1.5.a. 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 3,4-diklor-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 3,4-dichloro-phenyl-boronic acid.
Iskorištenje: 0,72 g (28,4% od teorijskog). Yield: 0.72 g (28.4% of theoretical).
C13H7Cl2NO4 (M = 312,11) C13H7Cl2NO4 (M = 312.11)
Izračunato: molekulska masa (M-H)-: 310/312/314 Calculated: molecular weight (M-H)-: 310/312/314
Nađeno: molekulska masa (M-H)-: 310/312/314 Found: molecular weight (M-H)-: 310/312/314
Rf vrijednost: 0,39 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.5.b. 3',4'-diklor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.5.b. 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.1 iz 3',4'-diklor-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina. It is produced analogously to example 1.1.1 from 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine.
Iskorištenje: 0,47 g (64,2% od teorijskog). Yield: 0.47 g (64.2% of theoretical).
C26H25Cl2N3O3 (M = 498,41) C26H25Cl2N3O3 (M = 498.41)
Izračunato: molekulska masa (M+H)+: 498/500/502 Calculated: molecular weight (M+H)+: 498/500/502
Nađeno: molekulska masa (M+H)+: 498/500/502 Found: molecular weight (M+H)+: 498/500/502
Rf vrijednost: 0,24 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.24 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.5.c. 3',4'-diklor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.5.c. 3',4'-dichloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 3',4'-diklor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 3',4'-dichloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,11 g (25% od teorijskog). Yield: 0.11 g (25% of theoretical).
C26H25Cl2N3O (M = 468,43) C26H25Cl2N3O (M = 468.43)
Izračunato: molekulska masa (M+H)+: 468/470/472 Calculated: molecular weight (M+H)+: 468/470/472
Nađeno: molekulska masa (M+H)+: 468/470/472 Found: molecular weight (M+H)+: 468/470/472
Rf vrijednost: 0,46 (silika gel, dicnlorometan/metanol/ amonijak 9:1:0,1) Rf value: 0.46 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.6: Example 1.6:
7-(3-metoksi-fenil)-3-[2-(4-pirolidin-1-il-metil-fenil)-etil]-3H-kinazolin-4-on 7-(3-methoxy-phenyl)-3-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.6.a. 3'-metoksi-3-nitro-bifenil-4-karboksilna kiselina 1.6.a. 3'-Methoxy-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 3-metoksi-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 3-methoxy-phenyl-boronic acid.
Iskorištenje: 0,39 g (73,6% od teorijskog). Yield: 0.39 g (73.6% of theoretical).
C14H11NO5 (M = 273,24) C14H11NO5 (M = 273.24)
Izračunato: molekulska masa (M+H)+: 274 Calculated: molecular weight (M+H)+: 274
Nađeno: molekulska masa (M+H)+: 274 Found: molecular weight (M+H)+: 274
Rf vrijednost: 0,35 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.35 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.6.b. 3'-metoksi-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.6.b. 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.1 iz 3'-metoksi-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-il-metil-fenil)-etilamina. It is produced analogously to example 1.1.1 from 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.
Iskorištenje: 0,39 g (57% od teorijskog). Yield: 0.39 g (57% of theoretical).
C27H29N3O4 (M = 459,55) C27H29N3O4 (M = 459.55)
Izračunato: molekulska masa (M+H)+: 460 Calculated: molecular weight (M+H)+: 460
Nađeno: molekulska masa (M+H)+: 460 Found: molecular weight (M+H)+: 460
Rf vrijednost: 0,23 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.23 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.6.c. 3'-metoksi-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.6.c. 3'-methoxy-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.j iz 3'-metoksi-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.1.j from 3'-methoxy-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,11 g (30,6% od teorijskog). Yield: 0.11 g (30.6% of theoretical).
C27H31N3O2 (M = 429,56) C27H31N3O2 (M = 429.56)
Izračunato: molekulska masa (M+H)+: 430 Calculated: molecular weight (M+H)+: 430
Nađeno: molekulska masa (M+H)+: 430 Found: molecular weight (M+H)+: 430
Rf vrijednost: 0,36 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.7: Example 1.7:
7-(4-fluor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-(4-fluoro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.7.a. 4'-fluor-3-nitro-bifenil-4-karboksilna kiselina 1.7.a. 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 4-fluor-fenil-borne kiseline. It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-fluoro-phenyl-boronic acid.
Iskorištenje: 1,3 g (61,2% od teorijskog). Yield: 1.3 g (61.2% of theoretical).
C13H8FNO4 (M = 261,21) C13H8FNO4 (M = 261.21)
Izračunato: molekulska masa (M-H)-: 260 Calculated: molecular weight (M-H)-: 260
Nađeno: molekulska masa (M-H)-: 260 Found: molecular weight (M-H)-: 260
Rf vrijednost: 0,34 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.34 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.7.b. 4'-fluor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 1.7.b. 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-fluor-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-il-metil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.
Iskorištenje: 0,38 g (57,8% od teorijskog). Yield: 0.38 g (57.8% of theoretical).
C26H26FN3O3 (M = 447,51) C26H26FN3O3 (M = 447.51)
Izračunato: molekulska masa (M+H)+: 448 Calculated: molecular weight (M+H)+: 448
Nađeno: molekulska masa (M+H)+: 448 Found: molecular weight (M+H)+: 448
Rf vrijednost: 0,24 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.24 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.7.c. 4'-fluor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 1.7.c. 4'-fluoro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-fluor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 4'-fluoro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,06 g (32% od teorijskog). Yield: 0.06 g (32% of theoretical).
C26H28FN3O (M = 417,53) C26H28FN3O (M = 417.53)
Izračunato: molekulska masa (M+H)+: 418 Calculated: molecular weight (M+H)+: 418
Nađeno: molekulska masa (M+H)+: 418 Found: molecular weight (M+H)+: 418
Rf vrijednost: 0,63 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.63 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.8: Example 1.8:
7-(4-etil-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-(4-ethyl-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.8.a. 4'-vinil-3-nitro-bifenil-4-karboksilna kiselina 1.8.a. 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 1.1.b iz 4-brom-2-nitro-benzojeve kiseline i 4-vinil-fenil-borne kiseline. Iskorištenje: 0,58 g (53% od teorijskog). It is produced analogously to example 1.1.b from 4-bromo-2-nitro-benzoic acid and 4-vinyl-phenyl-boronic acid. Yield: 0.58 g (53% of theoretical).
C15H11NO4 (M = 269,25) C15H11NO4 (M = 269.25)
Izračunato: molekulska masa (M-H)-: 268 Calculated: molecular weight (M-H)-: 268
Nađeno: molekulska masa (M-H)-: 268 Found: molecular weight (M-H)-: 268
Rf vrijednost: 0,39 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.39 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.8.b. 4'-vinil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 1.8.b. 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-vinil-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-pirolidin-1-il-metil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid and 2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethylamine.
Iskorištenje: 0,38 g (56,8% od teorijskog). Yield: 0.38 g (56.8% of theoretical).
C28H29N3O3 (M = 455,56) C28H29N3O3 (M = 455.56)
Izračunato: molekulska masa (M+H)+: 456 Calculated: molecular weight (M+H)+: 456
Nađeno: molekulska masa (M+H)+: 456 Found: molecular weight (M+H)+: 456
Rf vrijednost: 0,21 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.21 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.8.c. 4'-etil-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 1.8.c. 4'-ethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-vinil-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amid. It is produced analogously to example 1.3.c from 4'-vinyl-3-nitro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,15 g (63,9% od teorijskog). Yield: 0.15 g (63.9% of theoretical).
C28H33N3O (M = 427,59) C28H33N3O (M = 427.59)
Izračunato: molekulska masa (M+H)+: 428 Calculated: molecular weight (M+H)+: 428
Nađeno: molekulska masa (M+H)+: 428 Found: molecular weight (M+H)+: 428
Rf vrijednost: 0,47 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.47 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Slijedeći spojevi su proizvedeni analogno primjeru 1.1.k: The following compounds were produced analogously to example 1.1.k:
[image] [image]
Rf vrijednost: A = (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.9 Example 1.9
[image] [image]
1.9.a 7-(4-trifluormetil-fenil)-2-metil-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 1.9.a 7-(4-trifluoromethyl-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
Otopinu od 0,07 g (0,15 mmola) 4'-trifluormetil-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amid (vidi primjer 1.3.c) u 4 ml octene kiseline i 0,028 ml (0,3 mmola) octenog anhidrida refluktira se 12 sati. Reakcijsku otopinu se razrijedi s vodom, namjesti na pH 8 s razrijeđenom otopinom natrijevog hidroksida i ekstrahira se s diklormetanom. Organsku fazu se osuši preko magnezijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/ metanol/amonijak 90:10:1). A solution of 0.07 g (0.15 mmol) of 4'-trifluoromethyl-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amide ( see example 1.3.c) in 4 ml of acetic acid and 0.028 ml (0.3 mmol) of acetic anhydride is refluxed for 12 hours. The reaction solution is diluted with water, adjusted to pH 8 with dilute sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over magnesium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia 90:10:1).
Iskorištenje: 0,008 g (11% od teorijskog) C29H28F3N3O (M = 491,56) Yield: 0.008 g (11% of theory) C29H28F3N3O (M = 491.56)
Izračunato: molekulska masa (M+H)+: 492 Calculated: molecular weight (M+H)+: 492
Nađeno: molekulska masa (M+H)+: 492 Found: molecular weight (M+H)+: 492
Rf vrijednost: 0,36 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.36 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Slijedeći spojevi su proizvedeni analogno primjeru 1.9.a: The following compounds were produced analogously to example 1.9.a:
[image] [image]
[image] [image]
Rf vrijednost: A = (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.10: Example 1.10:
2-metil-3-[2-(4-piralidin-1-ilmetil-fenil)-etil]-7-p-tolil-3H-kinazolin-4-on 2-methyl-3-[2-(4-pyralidin-1-ylmethyl-phenyl)-ethyl]-7-p-tolyl-3H-quinazolin-4-one
Primjer 1.11: Example 1.11:
7-(4-klor-fenil)-2-metil-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-(4-chloro-phenyl)-2-methyl-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
Primjer 1.12 Example 1.12
[image] [image]
1.12.a 7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-1H-kinazolin-2,4-dion 1.12.a 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1H-quinazolin-2,4-dione
Reakcijsku smjesu od 0,3 g (0,69 mmola) of 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amida (vidi primjer 1.1.j) i 0,1 g (0,65 mmola) CDI u 50 ml tetrahidrofurana se refluktira 24 sata. Zatim se doda daljnjih 0,1 g CDI i reakcijsku smjesu se refluktira daljnjih 24 sata. Reakcijsku smjesu se ispari na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/metanol/amonijak 60:1:0,1). The reaction mixture of 0.3 g (0.69 mmol) of 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]- amide (see example 1.1.j) and 0.1 g (0.65 mmol) of CDI in 50 ml of tetrahydrofuran is refluxed for 24 hours. A further 0.1 g of CDI was then added and the reaction mixture was refluxed for a further 24 hours. The reaction mixture is evaporated on a rotary evaporator. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia 60:1:0.1).
Iskorištenje: 0,2 g (62,9% od teorijskog). Yield: 0.2 g (62.9% of theoretical).
Talište: 274-276oC Melting point: 274-276oC
C27H26ClN3O2 (M = 459,98) C27H26ClN3O2 (M = 459.98)
Izračunato: molekulska masa (M+H)+: 460/462 Calculated: molecular weight (M+H)+: 460/462
Nađeno: molekulska masa (M+H)+: 460/462 Found: molecular weight (M+H)+: 460/462
Rf vrijednost: 0,1 (silika gel, diklormetan/metanol/amonijak 50:1:0,1) Rf value: 0.1 (silica gel, dichloromethane/methanol/ammonia 50:1:0.1)
Primjer 1.13: Example 1.13:
7-(4-klor-fenil)-3-{2-E4-((S)-2-metoksimetil-pirolidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-E4-((S)-2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.13.a [4-(2-(S)-metoksimetil-pirolidin-1-ilmetil)-fenil]-acetonitril 1.13.a [4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 2-(S)-metoksimetil-pirolidina i (4-brom-metil-fenil)-aceto-nitrila. It is produced analogously to example 1.1.g from 2-(S)-methoxymethyl-pyrrolidine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 0,9 g (51,6% od teorijskog). Yield: 0.9 g (51.6% of theoretical).
C15H20N2O (M = 244,33) C15H20N2O (M = 244.33)
Izračunato: molekulska masa (M+H)+: 245 Calculated: molecular weight (M+H)+: 245
Nađeno: molekulska masa (M+H)+: 245 Found: molecular weight (M+H)+: 245
Rf vrijednost: 0,3 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.3 (silica gel, cyclohexane/ethyl acetate 1:1)
1.13.b 2-[4-(2-(S)-metoksimetil-pirolidin-1-ilmetil)-fenil]-etilamin 1.13.b 2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethylamine
Proizveden je analogno primjeru 1.1.h iz [4-(2-(S)-metoksimetil-pirolidin-1-ilmetil)-fenil]-acetonitrila. Iskorištenje: 0,5 g (54,7% od teorijskog). It was produced analogously to example 1.1.h from [4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-acetonitrile. Yield: 0.5 g (54.7% of theoretical).
C15H24N2O (M = 248,37) C15H24N2O (M = 248.37)
Izračunato: molekulska masa (M+H)+: 249 Calculated: molecular weight (M+H)+: 249
Nađeno: molekulska masa (M+H)+: 249 Found: molecular weight (M+H)+: 249
Rf vrijednost: 0,3 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.3 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.13.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(2-(S)-metoksimetil-pirolidin-1-ilmetnil)-fenil]-etil}-amid 1.13.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethnyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[4-(2-(S)-metoksi-metil-pirolidin-1-ilmetil)-fenil]-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(2-(S)-methoxy-methyl-pyrrolidin-1-ylmethyl)-phenyl]- ethylamine.
Iskorištenje: 0,5 g (54,7% od teorijskog). Yield: 0.5 g (54.7% of theoretical).
C28H30ClN3O4 (M = 508,02) C28H30ClN3O4 (M = 508.02)
Izračunato: molekulska masa (M+H)+: 508/510 Calculated: molecular weight (M+H)+: 508/510
Nađeno: molekulska masa (M+H)+: 508/510 Found: molecular weight (M+H)+: 508/510
Rf vrijednost: 0,6 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.6 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.13.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(2-(S)-metoksimetil-pirolidin-1-ilmetil)-fenil]-etil}-amid 1.13.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxymethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(2-(S)-metoksi-metil-pirolidin-1-ilmetil)-fenil]-etil}-amida. It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(2-(S)-methoxy-methyl-pyrrolidin-1-ylmethyl)-phenyl] -ethyl}-amide.
Iskorištenje: 0,24 g (51% od teorijskog). Yield: 0.24 g (51% of theoretical).
C28H32VlN3O2 (M = 478,03) C28H32VlN3O2 (M = 478.03)
Izračunato: molekulska masa (M+H)+: 478/480. Calculated: molecular weight (M+H)+: 478/480.
Nađeno: molekulska masa (M+H)+: 478/480 Found: molecular weight (M+H)+: 478/480
R1 vrijednost: 0,2 (silika gel, diklormetan/metanol/amonijak 10:1:0,1) R1 value: 0.2 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)
Primjer 1.14: Example 1.14:
7-(4-klor-fenil)-3-[2-(4-dimetilaminometil-fenil)-etil]-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.14.a (4-dimetilaminometil-fenil)-acetonitril 1.14.a (4-dimethylaminomethyl-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.g iz dimetilamina i (4-brom-metil-fenil)-acetonitrila. It is produced analogously to example 1.1.g from dimethylamine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 1,0 g (30% od teorijskog). Yield: 1.0 g (30% of theoretical).
C11H14N2 (M = 174,24) C11H14N2 (M = 174.24)
Izračunato: molekulska masa (M+H)+: 175 Calculated: molecular weight (M+H)+: 175
Nađeno: molekulska masa (M+H)+: 175 Found: molecular weight (M+H)+: 175
Rf vrijednost: 0,2 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.2 (silica gel, cyclohexane/ethyl acetate 1:1)
1.14.b 2-(4-dimetilaminometil-fenil)-etilamin 1.14.b 2-(4-dimethylaminomethyl-phenyl)-ethylamine
Proizveden je analogno primjeru 1.1.h iz (4-dimetil-aminometil-fenil)-acetonitrila. It was produced analogously to example 1.1.h from (4-dimethyl-aminomethyl-phenyl)-acetonitrile.
Iskorištenje: 1,0 g, sirov. Yield: 1.0 g, raw.
C11H18N2 (M = 178,28) C11H18N2 (M = 178.28)
Izračunato: molekulska masa (M+H)+: 179 Calculated: molecular weight (M+H)+: 179
Nađeno: molekulska masa (M+H)+: 179 Found: molecular weight (M+H)+: 179
Rf vrijednost: 0,2 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.14.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-dimetilaminometil-fenil)-etil]-amid 1.14.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-dimetilamino-metil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-dimethylamino-methyl-phenyl)-ethylamine.
Iskorištenje: 0,5 g (63,4% od teorijskog). Yield: 0.5 g (63.4% of theoretical).
C24H24ClN3O3 (M = 437,93) C24H24ClN3O3 (M = 437.93)
Izračunato: molekulska masa (M+H)+: 438/440 Calculated: molecular weight (M+H)+: 438/440
Nađeno: molekulska masa (M+H)+: 438/440 Found: molecular weight (M+H)+: 438/440
Rf vrijednost: 0,35 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.35 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.14.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-dimetilaminometil-fenil)-etil]-amid 1.14.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-dimethylaminomethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-dimetilamino-metil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-dimethylamino-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,2 g (43% od teorijskog). Yield: 0.2 g (43% of theoretical).
C24H26ClN3O (M = 407,94) C24H26ClN3O (M = 407.94)
Izračunato: molekulska masa (M+H)+: 408/410 Calculated: molecular weight (M+H)+: 408/410
Nađeno: molekulska masa (M+H)+: 408/410 Found: molecular weight (M+H)+: 408/410
Rf vrijednost: 0,2 (silika gel, diklormetan/metanol/amonijak 20:1:0,1) Rf value: 0.2 (silica gel, dichloromethane/methanol/ammonia 20:1:0.1)
Primjer 1.15: Example 1.15:
7-(4-klor-fenil)-3-[2-(4-piperidin-1-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.15.a {4-piperidin-1-ilmetil-fenil)-acetonitril 1.15.a {4-piperidin-1-ylmethyl-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.g iz piperidina i (4-brom-metil-fenil)-acetonitrila. It was produced analogously to example 1.1.g from piperidine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 1,6 g (39% od teorijskog). Yield: 1.6 g (39% of theoretical).
C14H18N2 (M = 214,31) C14H18N2 (M = 214.31)
Izračunato: molekulska masa (M+H)+: 215 Calculated: molecular weight (M+H)+: 215
Nađeno: molekulska masa (M+H)+: 215 Found: molecular weight (M+H)+: 215
Rf vrijednost: 0,4 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.4 (silica gel, cyclohexane/ethyl acetate 1:1)
1.15.b 2-(4-piperidin-1-ilmetil-fenil)-etilamin 1.15.b 2-(4-piperidin-1-ylmethyl-phenyl)-ethylamine
Proizveden je analogno primjeru 1.1.h iz (4-piperidin-1-ilmetil-fenil)-acetonitrila. It was produced analogously to example 1.1.h from (4-piperidin-1-ylmethyl-phenyl)-acetonitrile.
Iskorištenje: 1,4 g (85,9% od teorijskog). Yield: 1.4 g (85.9% of theoretical).
C14H22N2 (M = 218,34) C14H22N2 (M = 218.34)
Izračunato: molekulska masa (M+H)+: 219 Calculated: molecular weight (M+H)+: 219
Nađeno: molekulska masa (M+H)+: 219 Found: molecular weight (M+H)+: 219
Rf vrijednost: 0,2 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.2 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.15.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-piperidin-1-ilmetil-fenil)-etil]-amid 1.15.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-piperidin-1-il-metil-fenil)-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-piperidin-1-yl-methyl-phenyl)-ethylamine.
Iskorištenje: 0,07 g (40,7% od teorijskog). Yield: 0.07 g (40.7% of theoretical).
C27H28ClN3O3 (M = 477,99) C27H28ClN3O3 (M = 477.99)
Izračunato: molekulska masa (M+H)+: 478/480 Calculated: molecular weight (M+H)+: 478/480
Nađeno: molekulska masa (M+H)+: 478/480 Found: molecular weight (M+H)+: 478/480
Rf vrijednost: 0,5 (silika gel, diklormetan/etanol/amonijak 20:1:0,1) Rf value: 0.5 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
1.15.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-piperidin-1-ilmetil-fenil)-etil]-amid 1.15.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-piperidin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,05 g (76,4% od teorijskog). Yield: 0.05 g (76.4% of theoretical).
C27H30ClN3O (M = 448,01) C27H30ClN3O (M = 448.01)
Primjer 1.16: Example 1.16:
7-{4-klor-fenil)-3-[2-(4-morfolin-4-ilmetil-fenil)-etil]-3H-kinazolin-4-on 7-{4-chloro-phenyl)-3-[2-(4-morpholin-4-ylmethyl-phenyl)-ethyl]-3H-quinazolin-4-one
[image] [image]
1.16.a (4-morfolin-4-ilmetil-fenil)-acetonitril 1.16.a (4-morpholin-4-ylmethyl-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.g iz morfolina i (4-brom-metil-fenil)-acetonitrila. It is produced analogously to example 1.1.g from morpholine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 1,63 g (98,9% od teorijskog). Yield: 1.63 g (98.9% of theoretical).
C13H16N2O (M = 216,28) C13H16N2O (M = 216.28)
Izračunato: molekulska masa (M+H)+: 217 Calculated: molecular weight (M+H)+: 217
Nađeno: molekulska masa (M+H)+: 217 Found: molecular weight (M+H)+: 217
Rf vrijednost: 0,33 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate 1:1)
1.16.b 2-(4-morfolin-1-ilmetil-fenil)-etilamin 1.16.b 2-(4-morpholin-1-ylmethyl-phenyl)-ethylamine
Proizveden je analogno primjeru 1.1.h iz (4-morfolin-1-ilmetil-fenil)-acetonitrila. It was produced analogously to example 1.1.h from (4-morpholin-1-ylmethyl-phenyl)-acetonitrile.
Iskorištenje: 1,65 g (99,4% od teorijskog). Yield: 1.65 g (99.4% of theoretical).
C13H20N2O (M = 220,31) C13H20N2O (M = 220.31)
Izračunato: molekulska masa (M+H)+: 221 Calculated: molecular weight (M+H)+: 221
Nađeno: molekulska masa (M+H)+: 221 Found: molecular weight (M+H)+: 221
Rf vrijednost: 0,54 (silika gel, diklormetan/etanol/ amonijak 9:1:0,1) Rf value: 0.54 (silica gel, dichloromethane/ethanol/ammonia 9:1:0.1)
1.16.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-morfolin-1 -ilmetil-fenil)-etil]-amid 1.16.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.1.1 iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-(4-morfolin-1-il-metil-fenil)-etilamina. It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-morpholin-1-yl-methyl-phenyl)-ethylamine.
Iskorištenje: 0,53 g (76,6% od teorijskog). Yield: 0.53 g (76.6% of theoretical).
C26H26ClN3O4 (M = 479,97) C26H26ClN3O4 (M = 479.97)
Izračunato: molekulska masa (M+H)+: 480/482 Calculated: molecular weight (M+H)+: 480/482
Nađeno: molekulska masa (M+H)+: 480/482 Found: molecular weight (M+H)+: 480/482
Rf vrijednost: 0,5 (silika gel, diklormetan/etanol/amonijak 90:1:0,1) Rf value: 0.5 (silica gel, dichloromethane/ethanol/ammonia 90:1:0.1)
1.16.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-morfolin-1-ilmetil-fenil)-etil]-amid 1.16.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-[2-(4-morfolin-1-il-metil-fenil)-etil]-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-[2-(4-morpholin-1-yl-methyl-phenyl)-ethyl]-amide.
Iskorištenje: 0,45 g (90,6% od teorijskog). Yield: 0.45 g (90.6% of theoretical).
C26H28ClN3O2 (M = 449,98) C26H28ClN3O2 (M = 449.98)
Izračunato: molekulska masa (M+H)+: 450/452 Calculated: molecular weight (M+H)+: 450/452
Nađeno: molekulska masa (M+H)+: 450/452 Found: molecular weight (M+H)+: 450/452
Rf vrijednost: 0,67 (silika gel, diklormetan/etanol/amonijak 90:1:0,1) Rf value: 0.67 (silica gel, dichloromethane/ethanol/ammonia 90:1:0.1)
Slijedeći spojevi su proizvedeni analogno primjeru 1.1.k: The following compounds were produced analogously to example 1.1.k:
[image] [image]
[image] [image]
[image] [image]
Rf vrijednost: Rf value:
A = (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
C = (silika gel, diklormetan/metanol/amonijak 10:1:0,1) C = (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)
D = (silika gel, diklormetan/etanol/amonijak 20:1:0,1) D = (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1)
Primjer 1.17 Example 1.17
7-(4-klor-fenil)-3-{2-[6-(4-metriil-piperazin-1-il)-piridin-3-il]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[6-(4-metriyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.17.a (6-klor-piridin-3-il)-acetonitril 1.17.a (6-chloro-pyridin-3-yl)-acetonitrile
Otopinu od 7,5 g (41,66 mmola) 2-klor-5-klormetil-piridina, otopljenog u 100 ml etanola, doda se kap po kap u otopinu od 6,91 g (41,66 mmola) kalijevog jodida i 2,24 g (49,01 mmolova) natrijevog cijanida u 400 ml mješavine etanola i vode (9:1). Zatim se reakcijsku smjesu grije pet sati pri 85°C. Otapalo se uglavnom izdestilira u vakuumu i ostatak se ekstrahira s vodom i etil acetatom. Organsku fazu se ispere s vodom tri puta i osuši preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/etanol). A solution of 7.5 g (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine, dissolved in 100 ml of ethanol, was added dropwise to a solution of 6.91 g (41.66 mmol) of potassium iodide and 2 .24 g (49.01 mmol) of sodium cyanide in 400 ml of a mixture of ethanol and water (9:1). Then the reaction mixture is heated for five hours at 85°C. The solvent is mostly distilled off in vacuo and the residue is extracted with water and ethyl acetate. The organic phase is washed with water three times and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: dichloromethane/ethanol).
Iskorištenje: 2,9 g (45,6% od teorijskog). Yield: 2.9 g (45.6% of theoretical).
C7H5ClN2 (M = 152,58) C7H5ClN2 (M = 152.58)
Izračunato: molekulska masa (M+H)+: 151/153 Calculated: molecular weight (M+H)+: 151/153
Nađeno: molekulska masa (M+H)+: 151/153 Found: molecular weight (M+H)+: 151/153
1.17.b [6-(4-metil-piperazin-1-il)-piridin-3-il]-acetonitril 1.17.b [6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-acetonitrile
Otopinu od 2,9 g (19 mmolova) (6-klor-piridin-3-il)-acetonitrila, 5,27 ml (38 mmolova) trietilamina i 2,1 ml (19 mmolova) N-metilpiperazina u 50 ml n-butanola grije se 2 sata pri 180°C u mikrovalnoj grijalici. Otapalo se izdestilira u vakuumu, ostatak se suspendira u vodi i zatim se ekstrahira s etil acetatom. Sjedinjenje organske faze se ekstrahiraju tri puta s vodom i osuše se preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu Alox (sredstvo za ispiranje: petrol eter/etil acetat 1:1). A solution of 2.9 g (19 mmol) of (6-chloro-pyridin-3-yl)-acetonitrile, 5.27 ml (38 mmol) of triethylamine and 2.1 ml (19 mmol) of N-methylpiperazine in 50 ml of n- butanol is heated for 2 hours at 180°C in a microwave heater. The solvent is distilled off in vacuo, the residue is suspended in water and then extracted with ethyl acetate. The organic phase compounds are extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on an Alox column (eluent: petroleum ether/ethyl acetate 1:1).
Iskorištenje: 1 g (24,6% od teorijskog). Yield: 1 g (24.6% of theoretical).
Talište: 58-59°C Melting point: 58-59°C
C12H16N4 (M = 216,28) C12H16N4 (M = 216.28)
Izračunato: molekulska masa (M+H)+: 217 Calculated: molecular weight (M+H)+: 217
Nađeno: molekulska masa (M+H)+: 217 Found: molecular weight (M+H)+: 217
Rf vrijednost: 0,35 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1). Rf value: 0.35 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1).
1.17.c 2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil-amin 1.17.c 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl-amine
Proizveden je analogno primjeru 1.1.i iz [6-(4-metil-piperazin-1 -il)-piridin-3-il]-acetonitrila. It is produced analogously to example 1.1.i from [6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-acetonitrile.
Iskorištenje: 0,94 g (96% od teorijskog). Yield: 0.94 g (96% of theoretical).
C12H20N4 (M = 220,32) C12H20N4 (M = 220.32)
Izračunato: molekulska masa (M+H)+: 221 Calculated: molecular weight (M+H)+: 221
Nađeno: molekulska masa (M+H)+: 221 Found: molecular weight (M+H)+: 221
1.17.d 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amid 1.17.d 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.j iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etilamina. It is produced analogously to example 1.1.j from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethylamine.
Iskorištenje: 0,48 g (36,7% od teorijskog). Yield: 0.48 g (36.7% of theoretical).
Talište: 158-159°C Melting point: 158-159°C
C25H26ClN5O3 (M = 479,97) C25H26ClN5O3 (M = 479.97)
Izračunato: molekulska masa (M+H)+: 480/482 Calculated: molecular weight (M+H)+: 480/482
Nađeno: molekulska masa (M+H)+: 480/482 Found: molecular weight (M+H)+: 480/482
1.17.e 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amid 1.17.e 4'-chloro-3-amino-biphenyl-4-carboxylic acid-[2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amida. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl }-amide.
Iskorištenje: 0,12 g (64% od teorijskog). Yield: 0.12 g (64% of theoretical).
Talište: 198-199°C Melting point: 198-199°C
C25H28ClN5O (M = 449,98) C25H28ClN5O (M = 449.98)
Izračunato: molekulska masa (M+H)+: 450/452 Calculated: molecular weight (M+H)+: 450/452
Nađeno: molekulska masa (M+H)+: 450/452 Found: molecular weight (M+H)+: 450/452
1.17.f 7-(4-klor-fenil)-3-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-3H-kinazolin-4-on 1.17.f 7-(4-chloro-phenyl)-3-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-3H-quinazolin-4-one
Proizveden je analogno primjeru 1,1,1 iz 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amida i mravlje kiseline. It is produced analogously to example 1,1,1 from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl] -ethyl}-amide and formic acid.
Iskorištenje: 0,06 g (53,5% od teorijskog). Yield: 0.06 g (53.5% of theoretical).
Talište: 263-264°C Melting point: 263-264°C
C26H26ClN5O (M = 459,98) C26H26ClN5O (M = 459.98)
Izračunato: molekulska masa (M+H)+: 460/462 Calculated: molecular weight (M+H)+: 460/462
Nađeno: molekulska masa (M+H)+: 4460/462 Found: molecular weight (M+H)+: 4460/462
Primjer 1.18 Example 1.18
7-(4-klor-fenil)-3-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-3H-benzo[d][1,2,3]triazin-4-on 7-(4-chloro-phenyl)-3-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3H-benzo[d][1,2,3]triazin-4-one
[image] [image]
1.18.a 7-(4-klor-fenil)-3-{2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on 1.18.a 7-(4-chloro-phenyl)-3-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-3H-benzo[d][1,2, 3]triazin-4-one
Otopinu od 0,09 g (0,93 mmola) natrijevog nitrita u 2 ml vode doda se polako kap po kap u otopinu od 0,27 g (0,62 mmola) 4'-klor-3-amino-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amida (vidi primjer 1.1.j) u 10 ml metanola i 1N solnoj kiselini pri temperaturi između 0oC i 5°C. Zatim se reakcijsku smjesu miješa tri sata pri sobnoj temperaturi, zatim se razrijedi s 30 ml vode i zaluži s otopinom amonijaka. Vodenu otopinu se ekstrahira s etil acetatom. Sjedinjene organske faze se isperu s vodom tri puta, osuše se preko natrijevog sulfata i filtriraju kroz aktivirani ugljen. Otapalo se odstrani i ostatak se ispere s diizopropil eterom. A solution of 0.09 g (0.93 mmol) of sodium nitrite in 2 ml of water is slowly added drop by drop to a solution of 0.27 g (0.62 mmol) of 4'-chloro-3-amino-biphenyl-4- carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide (see example 1.1.j) in 10 ml of methanol and 1N hydrochloric acid at a temperature between 0°C and 5°C. The reaction mixture is then stirred for three hours at room temperature, then diluted with 30 ml of water and made alkaline with an ammonia solution. The aqueous solution was extracted with ethyl acetate. The combined organic phases are washed with water three times, dried over sodium sulfate and filtered through activated carbon. The solvent was removed and the residue was washed with diisopropyl ether.
Iskorištenje: 0,09 g (32,5% od teorijskog). Yield: 0.09 g (32.5% of theoretical).
Talište: 151-152°C Melting point: 151-152°C
C26H25ClN4O (M = 444,96) C26H25ClN4O (M = 444.96)
Izračunato: molekulska masa (M+H)+: 445/447 Calculated: molecular weight (M+H)+: 445/447
Nađeno: molekulska masa (M+H)+: 445/447 Found: molecular weight (M+H)+: 445/447
Rf vrijednost: 0,35 (silika gel, diklormetan/etanol = 10:1). Rf value: 0.35 (silica gel, dichloromethane/ethanol = 10:1).
Primjer 1.19 Example 1.19
7-(4-klor-fenil)-3-(4-pirolidin-1-ilmetil-benzil)-3H-benzo[d][1,2,3]triazin-4-on 7-(4-chloro-phenyl)-3-(4-pyrrolidin-1-ylmethyl-benzyl)-3H-benzo[d][1,2,3]triazin-4-one
[image] [image]
1.19.a 4-(1-pirolidin-1-il-etil)-benzonitril 1.19.a 4-(1-pyrrolidin-1-yl-ethyl)-benzonitrile
Proizveden je analogno primjeru 1.1.g iz piperidina i 4-brom-metil-benzonitrila. It is produced analogously to example 1.1.g from piperidine and 4-bromo-methyl-benzonitrile.
Iskorištenje: 2,4 g (85,9% od teorijskog). Yield: 2.4 g (85.9% of theoretical).
C12H14N2 (M = 186,25) C12H14N2 (M = 186.25)
Izračunato: molekulska masa (M+H)+: 187 Calculated: molecular weight (M+H)+: 187
Nađeno: molekulska masa (M+H)+: 187 Found: molecular weight (M+H)+: 187
Rf vrijednost: 0,63 (silika gel, diklormetan/metanol/amonijak = 8:2:1). Rf value: 0.63 (silica gel, dichloromethane/methanol/ammonia = 8:2:1).
1.19.b 4-(1-pirolidin-1-il-eti1)-benzilamin 1.19.b 4-(1-pyrrolidin-1-yl-ethyl)-benzylamine
Proizveden je analogno primjeru 1.1.h iz 4-(1-pirolidin-1 -il-etil)-benzonitrila. It is produced analogously to example 1.1.h from 4-(1-pyrrolidin-1-yl-ethyl)-benzonitrile.
Iskorištenje: 2,42 g (98,7% od teorijskog) Yield: 2.42 g (98.7% of theoretical)
C12H18N2 (M = 190,29) C12H18N2 (M = 190.29)
Izračunato: molekulska masa (M+H)+: 191 Calculated: molecular weight (M+H)+: 191
Nađeno: molekulska masa (M+H)+: 191 Found: molecular weight (M+H)+: 191
Rf vrijednost: 0,26 (silika gel, diklormetan/metanol/ amonijak = 90:10:1). Rf value: 0.26 (silica gel, dichloromethane/methanol/ammonia = 90:10:1).
1.19.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-4-(1-pirolidin-1-il-etil)-benzilamid 1.19.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide
Proizveden je analogno primjeru 1.1.1 iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina i 2-(4-4-(1-pirolidin-1-il-etil)-benzilamina. It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-(4-4-(1-pyrrolidin-1-yl-ethyl)-benzylamine.
Iskorištenje: 0,28 g (28,8% od teorijskog). Yield: 0.28 g (28.8% of theoretical).
C25H24ClN3O3 (M = 449,94) C25H24ClN3O3 (M = 449.94)
Izračunato: molekulska masa (M+H)+: 450/452 Calculated: molecular weight (M+H)+: 450/452
Nađeno: molekulska masa (M+H)+: 450/452 Found: molecular weight (M+H)+: 450/452
1.19.d 3-amino-4'-klor-bifenil-4-karboksilna kiselina-4-(1-pirolidin-1 -il-etil)-benzilamid 1.19.d 3-amino-4'-chloro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-4-(1-pirolidin-1-il-etil)-benzilamida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide.
Iskorištenje: 0,19 g (72,7% od teorijskog). Yield: 0.19 g (72.7% of theoretical).
C25H26ClN3O (M = 419,95) C25H26ClN3O (M = 419.95)
Izračunato: molekulska masa (M+H)+: 420/422 Calculated: molecular weight (M+H)+: 420/422
Nađeno: molekulska masa (M+H)+: 420/422 Found: molecular weight (M+H)+: 420/422
1.19.e 7-(4-klor-fenil)-3-[4-(1-pirolidin-1-il-etil)-benzil]-3H-benzo[d][1,2,3]triazin-4-on 1.19.e 7-(4-chloro-phenyl)-3-[4-(1-pyrrolidin-1-yl-ethyl)-benzyl]-3H-benzo[d][1,2,3]triazin-4- he
Proizveden je analogno primjeru 1.18.a iz 3-amino-4'-klor-bifenil-4-karboksilna kiselina-4-(1-pirolidin-1-il-etil)-benzilamida. It is produced analogously to example 1.18.a from 3-amino-4'-chloro-biphenyl-4-carboxylic acid-4-(1-pyrrolidin-1-yl-ethyl)-benzylamide.
Iskorištenje: 0,045 g (31,4% od teorijskog). Yield: 0.045 g (31.4% of theoretical).
Talište: 147-148°C Melting point: 147-148°C
C25H23ClN4O (M = 430,94) C25H23ClN4O (M = 430.94)
Izračunato: molekulska masa (M+H)+: 431/433 Calculated: molecular weight (M+H)+: 431/433
Nađeno: molekulska masa (M+H)+: 431/433 Found: molecular weight (M+H)+: 431/433
Rf vrijednost: 0,3 (silika gel, diklormetan/etanol = 10:1). Rf value: 0.3 (silica gel, dichloromethane/ethanol = 10:1).
Primjer 1.20 Example 1.20
5-(4-fluor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-izoindol-1,3-dion 5-(4-fluoro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-isoindol-1,3-dione
[image] [image]
1.20.a 5-brom-2-{2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-izoindol-1,3-dion 1.20.a 5-bromo-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione
Otopinu od 0,8 g (3,52 mmola) 5-brom-izobenzofuran-1,3-diona i 0,72 g (3,52 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (vidi primjer 1.1.h) u 10 ml octene kiseline grije se 4 sata pri 110°C. Zatim se reakcijsku smjesu prelije u vodu, zaluži s 2N otopinom natrijevog hidroksida i talog se odfiltrira. Talog se ispere nekoliko puta s vodom i osuši. A solution of 0.8 g (3.52 mmol) of 5-bromo-isobenzofuran-1,3-dione and 0.72 g (3.52 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine ( see example 1.1.h) in 10 ml of acetic acid is heated for 4 hours at 110°C. The reaction mixture is then poured into water, made alkaline with a 2N sodium hydroxide solution and the precipitate is filtered off. The precipitate is washed several times with water and dried.
Iskorištenje: 0,5 g (34,3% od teorijskog). Yield: 0.5 g (34.3% of theoretical).
C21H21BrN2O2 (M = 413,31) C21H21BrN2O2 (M = 413.31)
Izračunato: molekulska masa (M+H)+: 413/415 Calculated: molecular weight (M+H)+: 413/415
Nađeno: molekulska masa (M+H)+: 413/415 Found: molecular weight (M+H)+: 413/415
1.20.b. 5-(4-fluor-fenil)-2-{2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-izoindol-1,3-dion 1.20.b. 5-(4-fluoro-phenyl)-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione
Proizveden je analogno primjeru 1.1.b iz 5-brom-2-{2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-izoindol-1,3-diona i 4-fluor-fenilborne kiseline. It was produced analogously to example 1.1.b from 5-bromo-2-{2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione and 4-fluoro- phenylboronic acid.
Iskorištenje: 0,01 g (4,8% od teorijskog). Yield: 0.01 g (4.8% of theoretical).
C27H25FN2O2 (M = 428,51) C27H25FN2O2 (M = 428.51)
Izračunato: molekulska masa (M+H)+: 429 Calculated: molecular weight (M+H)+: 429
Nađeno: molekulska masa (M+H)+: 429 Found: molecular weight (M+H)+: 429
Primjer 1.21: Example 1.21:
7-(4-klor-fenil)-3-{2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.21.a [4-(4-fenil-piperidin-1-ilmetil)-fenil]-acetonitril 1.21.a [4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 4-fenil-piperidina i (4-brom-metil-fenil)-acetonitrila. It is produced analogously to example 1.1.g from 4-phenyl-piperidine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 3,8 g (98% od teorijskog). Yield: 3.8 g (98% of theoretical).
C20H22N2 (M = 290,41) C20H22N2 (M = 290.41)
Izračunato: molekulska masa (M+H)+: 291 Calculated: molecular weight (M+H)+: 291
Nađeno: molekulska masa (M+H)+: 291 Found: molecular weight (M+H)+: 291
Rf vrijednost: 0,5 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.5 (silica gel, cyclohexane/ethyl acetate 1:1)
1.21.b 2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etilamin 1.21.b 2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine
Proizveden je analogno primjeru 1.1.h iz [4-(4-fenil-piperidin-1-ilmetil )-fenil]-acetonitrila. It was produced analogously to example 1.1.h from [4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile.
Iskorištenje: 3,6 g, sirov. Yield: 3.6 g, raw.
C20H26N2 (M = 294,44) C20H26N2 (M = 294.44)
Izračunato: molekulska masa (M+H)+: 295 Calculated: molecular weight (M+H)+: 295
Nađeno: molekulska masa (M+H)+: 295 Found: molecular weight (M+H)+: 295
Rf vrijednost: 0,49 (silika gel, diklormetan/etanol 20:1) Rf value: 0.49 (silica gel, dichloromethane/ethanol 20:1)
1.21.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperidin-1-ilmetil )-fenil]-etil}-amid 1.21.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine.
Iskorištenje: 1,33 g (70,7% od teorijskog). Yield: 1.33 g (70.7% of theoretical).
C33H32ClN3O3 (M = 554,09) C33H32ClN3O3 (M = 554.09)
Izračunato: molekulska masa (M+H)+: 554/556 Calculated: molecular weight (M+H)+: 554/556
Nađeno: molekulska masa (M+H)+: 554/556 Found: molecular weight (M+H)+: 554/556
Rf vrijednost: 0,58 (silika gel, diklormetan/etanol/ amonijak 10:1:0,1) Rf value: 0.58 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)
1.21.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperidin-1 -ilm etil )-fenil]-etil}-amid 1.21.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.
Iskorištenje: 0,82 g (65,2% od teorijskog). Yield: 0.82 g (65.2% of theoretical).
C33H32ClN3O (M = 524,11) C33H32ClN3O (M = 524.11)
Izračunato: molekulska masa (M+H)+: 524/526/528 Calculated: molecular weight (M+H)+: 524/526/528
Nađeno: molekulska masa (M+H)+: 524/526/528 Found: molecular weight (M+H)+: 524/526/528
Rf vrijednost: 0,65 (silika gel, diklormetan/metanol 10:1) Rf value: 0.65 (silica gel, dichloromethane/methanol 10:1)
Primjer 1.22: Example 1.22:
7-(4-klor-fenil)-3-{2-[4-(4-fenil-piperazin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.22.a [4-(4-fenil-piperazin-1-ilmetil)-fenil]-acetonitril 1.22.a [4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 4-fenil-piperazina i (4-brom-metil-fenil)-acetonitrila. It is produced analogously to example 1.1.g from 4-phenyl-piperazine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 3,7 g (97% od teorijskog). Yield: 3.7 g (97% of theoretical).
C19H21N3 (M =291,39) C19H21N3 (M = 291.39)
Izračunato: molekulska masa (M+H)+: 292 Calculated: molecular weight (M+H)+: 292
Nađeno: molekulska masa (M+H)+: 292 Found: molecular weight (M+H)+: 292
Rf vrijednost: 0,6 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.6 (silica gel, cyclohexane/ethyl acetate 1:1)
1.22.b 2-[4-(4-fenil-piperazin-1-ilmetil)-fenil]-etilamin 1.22.b 2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethylamine
Proizveden je analogno primjeru 1.1.h iz [4-(4-fenil-piperazin-1-ilmetil)-fenil]-acetonitrila. It was produced analogously to example 1.1.h from [4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-acetonitrile.
Iskorištenje: 1,1 g (28,6% od teorijskog). Yield: 1.1 g (28.6% of theoretical).
C19H25N2 (M = 295,43) C19H25N2 (M = 295.43)
Izračunato: molekulska masa (M+H)+: 296 Calculated: molecular weight (M+H)+: 296
Nađeno: molekulska masa (M+H)+: 296 Found: molecular weight (M+H)+: 296
1.22.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperazin-1-ilmetil )-fenil]-etil}-amid 1.22.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[4-(4-fenil-piperazin-1-ilmetil)-fenil]-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethylamine.
Iskorištenje: 0,32 g (18,2% od teorijskog). Yield: 0.32 g (18.2% of theoretical).
C32H31ClN4O3 (M = 555,08) C32H31ClN4O3 (M = 555.08)
Izračunato: molekulska masa (M+H)+: 555/557 Calculated: molecular weight (M+H)+: 555/557
Nađeno: molekulska masa (M+H)+: 555/557 Found: molecular weight (M+H)+: 555/557
1.22.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperazin-1-ilmetil)-fenil]-etil}-amid 1.22.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperazin-1-ilmetil)-fenil]-etil}-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide.
Iskorištenje: 0,11 g (38,8% od teorijskog). Yield: 0.11 g (38.8% of theoretical).
C32H33ClN4O (M = 525,09) C32H33ClN4O (M = 525.09)
Izračunato: molekulska masa (M+H)+: 525/527 Calculated: molecular weight (M+H)+: 525/527
Nađeno: molekulska masa (M+H)+: 525/527 Found: molecular weight (M+H)+: 525/527
Primjer 1.23: Example 1.23:
7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.23.a [4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-acetonitril 1.23.a [4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 4-hidroksi-4-fenilpiperidina i (4-brom-metil-fenil)-acetonitrila. It is produced analogously to example 1.1.g from 4-hydroxy-4-phenylpiperidine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 3,8 g (98% od teorijskog). Yield: 3.8 g (98% of theoretical).
C20H22N2O (M = 306,41) C20H22N2O (M = 306.41)
Izračunato: molekulska masa (M+H)+: 307 Calculated: molecular weight (M+H)+: 307
Nađeno: molekulska masa (M+H)+: 307 Found: molecular weight (M+H)+: 307
Rf vrijednost: 0,1 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.1 (silica gel, cyclohexane/ethyl acetate 1:1)
1.23.b 2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etilamin 1.23.b 2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine
Proizveden je analogno primjeru 1.1.h iz [4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-acetonitrila. It was produced analogously to example 1.1.h from [4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-acetonitrile.
Iskorištenje: 3,36 g (92,1% od teorijskog). Yield: 3.36 g (92.1% of theoretical).
C20H26N2O (M = 310,44) C20H26N2O (M = 310.44)
Izračunato: molekulska masa (M+H)+: 311 Calculated: molecular weight (M+H)+: 311
Nađeno: molekulska masa (M+H)+: 311 Found: molecular weight (M+H)+: 311
Rf vrijednost: 0,1 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1) Rf value: 0.1 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1)
1.23.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amid 1.23.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethylamine.
Iskorištenje: 1,2 g (65,3% od teorijskog). Yield: 1.2 g (65.3% of theoretical).
C33H32ClN3O4 (M = 570,09) C33H32ClN3O4 (M = 570.09)
Izračunato: molekulska masa (M+H)+: 570/572 Calculated: molecular weight (M+H)+: 570/572
Nađeno: molekulska masa (M+H)+: 570/572 Found: molecular weight (M+H)+: 570/572
Rf vrijednost; 0,35 (silika gel, diklormetan/metanol/ amonijak 10:1:0,1) Rf value; 0.35 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)
1.23.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amid 1.23.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amida. It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl }-amide.
Iskorištenje: 1,04 g (91,5% od teorijskog). Yield: 1.04 g (91.5% of theoretical).
C33H34ClN3O2 (M = 540,11) C33H34ClN3O2 (M = 540.11)
Talište: 175-180°C Melting point: 175-180°C
Izračunato: molekulska masa (M+H)+: 540/542/544 Calculated: molecular weight (M+H)+: 540/542/544
Nađeno: molekulska masa (M+H)+: 540/542/544 Found: molecular weight (M+H)+: 540/542/544
Rf vrijednost: 0,34 (silika gel, diklormetan/metanol/ amonijak 10:1:0,1) Rf value: 0.34 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1)
1.23.e. 7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 1.23.e. 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
Proizveden je analogno primjeru 1.1.k. iz 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil )-fenil]-etil}-amida. It is produced analogously to example 1.1.k. from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.
Iskorištenje: 0,025 g (8,2% od teorijskog). Yield: 0.025 g (8.2% of theoretical).
Talište: 204-205°C Melting point: 204-205°C
C34H32ClN3O2 (M = 550,10) C34H32ClN3O2 (M = 550.10)
Izračunato: molekulska masa (M+H)+: 550/552 Calculated: molecular weight (M+H)+: 550/552
Nađeno: molekulska masa (M-HH)+: 550/552 Found: molecular weight (M-HH)+: 550/552
Rf vrijednost: 0,46 (silika gel, diklormetan/etanol/ amonijak 10:1:0,1) Rf value: 0.46 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)
Primjer 1.24: Example 1.24:
7-(4-klor-fenil)-3-{2-[4-(4-fenil-3,6-dihidro-2H-piperidin-1-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4- he
[image] [image]
1.24.a. 7-(4-klor-fenil)-3-{2-[4-(4-fenil-3,6-dihidro-2H-piperidin-1 -ilmetil)-fenil]-etil}-3H-kinazolin-4-on 1.24.a. 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-3,6-dihydro-2H-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4- he
Proizveden je analogno primjeru 1.1.k. iz 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amida kao sporedan proizvod u primjeru 123.e. It is produced analogously to example 1.1.k. from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide as a side product in example 123.e.
Iskorištenje: 0,08 g (27.1% od teorijskog). Yield: 0.08 g (27.1% of theoretical).
Talište: 166-167°C Melting point: 166-167°C
C34H30ClN3O (M = 532,09) C34H30ClN3O (M = 532.09)
Izračunato: molekulska masa (M+H)+: 532/534 Calculated: molecular weight (M+H)+: 532/534
Nađeno: molekulska masa (M+H)+: 532/534 Found: molecular weight (M+H)+: 532/534
Rf vrijednost: 0,57 (silika gel, diklormetan/etanol/ amonijak 10:1) Rf value: 0.57 (silica gel, dichloromethane/ethanol/ammonia 10:1)
Primjer 1.25: Example 1.25:
7-(4-klor-fenil)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-etil}-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-3H-quinazolin-4-one
[image] [image]
1.25.a [4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-acetonitril 1.25.a [4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 3-aza-spiro-[5,5]undekana i (4-brom-metil-fenil)-acetonitrila. It was produced analogously to example 1.1.g from 3-aza-spiro-[5,5]undecane and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 3,38 g (98% od teorijskog). Yield: 3.38 g (98% of theoretical).
C19H26N2 (M = 282,43) C19H26N2 (M = 282.43)
Izračunato: molekulska masa (M+H)+: 283 Calculated: molecular weight (M+H)+: 283
Nađeno: molekulska masa (M+H)+: 283 Found: molecular weight (M+H)+: 283
Rf vrijednost: 0,56 (silika gel, cikloheksan/etil acetat 1:1) Rf value: 0.56 (silica gel, cyclohexane/ethyl acetate 1:1)
1.25.b 2-[4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-etil-amin 1.25.b 2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl-amine
Proizveden je analogno primjeru 1.1.h iz [4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-acetonitrila. It was produced analogously to example 1.1.h from [4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-acetonitrile.
Iskorištenje: 3,33 g (96,6% od teorijskog). Yield: 3.33 g (96.6% of theoretical).
C19H30N2 (M = 286,46) C19H30N2 (M = 286.46)
Izračunato: molekulska masa (M+H)+: 287 Calculated: molecular weight (M+H)+: 287
Nađeno: molekulska masa (M+H)+: 287 Found: molecular weight (M+H)+: 287
Rf vrijednost: 0,18 (silika gel, diklormetan/etanol 20:1) Rf value: 0.18 (silica gel, dichloromethane/ethanol 20:1)
1.25.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-etil)-amid 1.25.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl)-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-[4-(3-aza-spiro-[5,5]undec-3-ilmetil)-fenil]-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl] -ethylamine.
Iskorištenje: 1 g (52,5% od teorijskog). Yield: 1 g (52.5% of theoretical).
C32H36ClN3O3 (M = 546,11) C32H36ClN3O3 (M = 546.11)
Izračunato: molekulska masa (M+H)+: 546/548 Calculated: molecular weight (M+H)+: 546/548
Nađeno: molekulska masa (M+H)+: 546/548 Found: molecular weight (M+H)+: 546/548
Rf vrijednost: 0,3 (silika gel, diklormetan/etanol 20:1) Rf value: 0.3 (silica gel, dichloromethane/ethanol 20:1)
1.25.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-etil}-amid 1.25.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-{2-[4-(3-aza-spiro-[5,5]undec-3-ilmetil)-fenil]-etil}-amida. It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl ]-ethyl}-amide.
Iskorištenje: 0,8 g (84,7% od teorijskog). Yield: 0.8 g (84.7% of theoretical).
C32H38ClN3O (M = 516,13) C32H38ClN3O (M = 516.13)
Izračunato: molekulska masa (M+H)+: 516/518 Calculated: molecular weight (M+H)+: 516/518
Nađeno: molekulska masa (M+H)+: 516/518 Found: molecular weight (M+H)+: 516/518
Rf vrijednost: 0,38 (silika gel, diklormetan/metanol 10:1) Rf value: 0.38 (silica gel, dichloromethane/methanol 10:1)
Primjer 1.26: Example 1.26:
7-(4-klor-fenil)-3-(2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etil)-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4-one
[image] [image]
1.26.a {4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-acetonitril 1.26.a {4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 2-(piperidin-4-iloksi)-piridina i (4-brom-metil-fenil)-acetonitrila. It was produced analogously to example 1.1.g from 2-(piperidin-4-yloxy)-pyridine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 0,91 g (49,8% od teorijskog). Yield: 0.91 g (49.8% of theoretical).
C19H21N3O (M = 307,39) C19H21N3O (M = 307.39)
Izračunato: molekulska masa (M+H)+: 308 Calculated: molecular weight (M+H)+: 308
Nađeno: molekulska masa (M+H)+: 308 Found: molecular weight (M+H)+: 308
Rf vrijednost: 0,49 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.49 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.26.b 2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etilamin 1.26.b 2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethylamine
Proizveden je analogno primjeru 1.1.h iz {4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-aceto-nitrila. It was produced analogously to example 1.1.h from {4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-acetonitrile.
Iskorištenje: 0,92 g (99,8% od teorijskog). Yield: 0.92 g (99.8% of theoretical).
C19H25N30 (M = 311,43) C19H25N30 (M = 311.43)
Izračunato: molekulska masa (M+H)+: 312 Calculated: molecular weight (M+H)+: 312
Nađeno: molekulska masa (M+H)+: 312 Found: molecular weight (M+H)+: 312
Rf vrijednost: 0,16 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.16 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.26.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etil)-amid 1.26.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide
Proizveden je analogno primjeru 1.1.1 iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etilamina. It is produced analogously to example 1.1.1 from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}- ethylamine.
Iskorištenje: 0,8 g (97,2% od teorijskog). Yield: 0.8 g (97.2% of theoretical).
C32H31ClN4O4 (M = 571,08) C32H31ClN4O4 (M = 571.08)
Izračunato: molekulska masa (M+H)+: 571/573 Calculated: molecular weight (M+H)+: 571/573
Nađeno: molekulska masa (M+H)+: 571/573 Found: molecular weight (M+H)+: 571/573
Rf vrijednost: 0,52 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.52 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.26.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetil]-fenil}-etil)-amid 1.26.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-iloksi)-piperidin-1-ilmetill-fenil}-etil)-amida. It was produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-yloxy)-piperidin-1-ylmethyl-phenyl}- ethyl)-amide.
Iskorištenje: 0,38 g (50% od teorijskog). Yield: 0.38 g (50% of theoretical).
C32H33ClN4O2 (M = 541,09) C32H33ClN4O2 (M = 541.09)
Izračunato: molekulska masa (M+H)+: 541/543 Calculated: molecular weight (M+H)+: 541/543
Nađeno: molekulska masa (M+H)+: 541/543 Found: molecular weight (M+H)+: 541/543
Rf vrijednost: 0,5 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Primjer 1.27: Example 1.27:
7-(4-klor-fenil)-3-(2-{4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-etil)-3H-kinazolin-4-on 7-(4-chloro-phenyl)-3-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-3H-quinazolin-4-one
[image] [image]
1.27.a {4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-acetonitril 1.27.a {4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-acetonitrile
Proizveden je analogno primjeru 1.1.g iz 2-(piperidin-4-ilamino)-piridina i (4-brom-metil-fenil)-acetonitrila. It was produced analogously to example 1.1.g from 2-(piperidin-4-ylamino)-pyridine and (4-bromo-methyl-phenyl)-acetonitrile.
Iskorištenje: 1,57 g (86,1% od teorijskog). Yield: 1.57 g (86.1% of theoretical).
C19H22N4 (M = 306,41) C19H22N4 (M = 306.41)
Izračunato: molekulska masa (M+H)+: 307 Calculated: molecular weight (M+H)+: 307
Nađeno: molekulska masa (M+H)+: 307 Found: molecular weight (M+H)+: 307
Rf vrijednost: 0,43 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.43 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.27.b 2-{4-[4-(piridtn-2-ilamino)-piperidin-1-ilmetil]-fenil}-etilamin 1.27.b 2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethylamine
Proizveden je analogno primjeru 1.1.h iz {4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-aceto-nitrila. It was produced analogously to example 1.1.h from {4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-acetonitrile.
Iskorištenje: 1,62 g (99,8% od teorijskog). Yield: 1.62 g (99.8% of theoretical).
C19H26N4 (M =310,44) C19H26N4 (M = 310.44)
Izračunato: molekulska masa (M+H)+: 311 Calculated: molecular weight (M+H)+: 311
Nađeno: molekulska masa (M+H)+: 311 Found: molecular weight (M+H)+: 311
Rf vrijednost: 0,1 (silika gel, diklormetan/metanol/ amonijak 9:1:0,1) Rf value: 0.1 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.27.c 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-etil)-amid 1.27.c 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide
Proizveden je analogno primjeru 1.1.i iz 4'-klor-3-nitro-bifenil-4-karboksilne kiseline i 2-{4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-etilamina. It is produced analogously to example 1.1.i from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid and 2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}- ethylamine.
Iskorištenje: 0,36 g (43,8% od teorijskog). Yield: 0.36 g (43.8% of theoretical).
C32H32ClN5O33 (M = 570,09) C32H32ClN5O33 (M = 570.09)
Izračunato: molekulska masa (M+H)++: 570/572 Calculated: molecular weight (M+H)++: 570/572
Nađeno: molekulska masa (M+H)+: 570/572 Found: molecular weight (M+H)+: 570/572
Rf vrijednost: 0,28 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.28 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
1.27.d 4'-klor-3-amino-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-etil)-amid 1.27.d 4'-chloro-3-amino-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl}-ethyl)-amide
Proizveden je analogno primjeru 1.3.c iz 4'-klor-3-nitro-bifenil-4-karboksilna kiselina-(2-{4-[4-(piridin-2-ilamino)-piperidin-1-ilmetil]-fenil}-etil)-amida. It is produced analogously to example 1.3.c from 4'-chloro-3-nitro-biphenyl-4-carboxylic acid-(2-{4-[4-(pyridin-2-ylamino)-piperidin-1-ylmethyl]-phenyl} -ethyl)-amide.
Iskorištenje: 0,29g (85,7% od teorijskog). Yield: 0.29g (85.7% of theoretical).
C32H34ClN5O (M = 540,11) C32H34ClN5O (M = 540.11)
Izračunato: molekulska masa (M+H)+: 540/542 Calculated: molecular weight (M+H)+: 540/542
Nađeno: molekulska masa (M+H)+: 540/542 Found: molecular weight (M+H)+: 540/542
Rf vrijednost: 0,27 (silika gel, diklormetan/metanol/amonijak 9:1:0,1) Rf value: 0.27 (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
Slijedeći spojevi su proizvedeni je analogno primjeru 1.1.k: The following compounds were produced analogously to example 1.1.k:
[image] [image]
[image] [image]
Rf vrijednost: Rf value:
A = (silika gel, diklormetan/metanol/amonijak 9:1:0,1) A = (silica gel, dichloromethane/methanol/ammonia 9:1:0.1)
E = (silika gel, diklormetan/etanol 10:1) E = (silica gel, dichloromethane/ethanol 10:1)
F = (silika gel, diklormetan/etanol/amonijak 10:1:0,1) F = (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1)
Primjer 1.28 Example 1.28
7-(4-klor-fenil)-3-{2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][1,2,3]triazine -4-he
[image] [image]
1.28.a 7-(4-klor-fenil)-3-{2-[4-(4-fenil-piperidin-1-il-metil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on 1.28.a 7-(4-chloro-phenyl)-3-{2-[4-(4-phenyl-piperidin-1-yl-methyl)-phenyl]-ethyl}-3H-benzo[d][1, 2,3]triazin-4-one
Proizveden je analogno primjeru 1.18.a iz 4'-klor-3-amino-bipnenil-4-karboksilna kiselina-{2-[4-(4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amida. It is produced analogously to example 1.18.a from 4'-chloro-3-amino-bipenenyl-4-carboxylic acid-{2-[4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide.
Iskorištenje: 0,13 g (50,9% od teorijskog). Yield: 0.13 g (50.9% of theoretical).
Talište: 183-184°C Melting point: 183-184°C
C33H31ClN4O (M = 535,09) C33H31ClN4O (M = 535.09)
Izračunato: molekulska masa (M+H)+: 535/537 Calculated: molecular weight (M+H)+: 535/537
Nađeno: molekulska masa (M+H)+: 535/537 Found: molecular weight (M+H)+: 535/537
Rf vrijednost: 0,66 (silika gel, diklormetan/etanol 10:1) Rf value: 0.66 (silica gel, dichloromethane/ethanol 10:1)
Primjer 1.29 Example 1.29
7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-benzo[c/][1,2,3]triazin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[c/][1, 2,3]triazin-4-one
[image] [image]
1.29.a 7-(4-klor-fenil)-3-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-3H-benzo[d][1,2,3]-triazin-4-on 1.29.a 7-(4-chloro-phenyl)-3-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-3H-benzo[d][ 1,2,3]-triazin-4-one
Proizveden je analogno primjeru 1.18.a iz 4'-klor-3-amino-bifenil-4-karboksilna kiselina-{2-[4-(4-hidroksi-4-fenil-piperidin-1-ilmetil)-fenil]-etil}-amida. It was produced analogously to example 1.18.a from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(4-hydroxy-4-phenyl-piperidin-1-ylmethyl)-phenyl]-ethyl }-amide.
Iskorištenje: 0,21 g (68,7% od teorijskog). Yield: 0.21 g (68.7% of theoretical).
Talište: 265-266°C Melting point: 265-266°C
C33H31ClN4O2 (M = 551,09) C33H31ClN4O2 (M = 551.09)
Izračunato: molekulska masa (M+H)+: 551/553 Calculated: molecular weight (M+H)+: 551/553
Nađeno: molekulska masa (M+H)+: 551/553 Found: molecular weight (M+H)+: 551/553
Rf vrijednost: 0,53 (silika gel, diklormetan/etanol 10:1) Rf value: 0.53 (silica gel, dichloromethane/ethanol 10:1)
Primjer 1.30 Example 1.30
7-(4-klor-fenil)-3-{2-[4-(3-aza-spiro[5,5]undec-3-il-metil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-yl-methyl)-phenyl]-ethyl}-3H-benzo[d] [1,2,3]triazin-4-one
[image] [image]
1.30.a 7-(4-klor-fenil)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ilmetil)-fenil]-etil}-3H-benzo[d][1,2,3]triazin-4-on 1.30.a 7-(4-chloro-phenyl)-3-{2-[4-(3-aza-spiro[5,5]undec-3-ylmethyl)-phenyl]-ethyl}-3H-benzo[d ][1,2,3]triazin-4-one
Proizveden je analogno primjeru 1.18.a iz 4'-klor-3-amino-bifenil-4-karboksitickiselina-{2-[4-(3-aza-spiro-[5,5]undec-3-ilmetil)-fenil]-etil}-amida. It was produced analogously to example 1.18.a from 4'-chloro-3-amino-biphenyl-4-carboxylic acid-{2-[4-(3-aza-spiro-[5,5]undec-3-ylmethyl)-phenyl] -ethyl}-amide.
Iskorištenje: 0,14 g (54,9% od teorijskog). Yield: 0.14 g (54.9% of theoretical).
Talište: 165-166°C Melting point: 165-166°C
C32H35ClN4O (M = 527,11) C32H35ClN4O (M = 527.11)
Izračunato: molekulska masa (M+H)+: 527 Calculated: molecular weight (M+H)+: 527
Nađeno: molekulska masa (M+H)+: 527 Found: molecular weight (M+H)+: 527
Rf vrijednost: 0,56 (silika gel, diklormetan/etanol 10:1) Rf value: 0.56 (silica gel, dichloromethane/ethanol 10:1)
Primjer 1.31: Example 1.31:
6-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2H-izokinolin-1-on 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one
[image] [image]
1.31.a. 2-[2-(4-brom-fenil)-etoksi]-tetrahidro-piran 1.31.a. 2-[2-(4-bromo-phenyl)-ethoxy]-tetrahydro-pyran
0,025 g p-toluensulfonske kiseline i 2,575 ml (28,22 mmolova) dihidropirana se doda uzastopce u otopinu od 4,83 g (24,02 mmola) 2-(4-brom-fenil)-etanola u 12 ml diklor-metana pri 0°C. Zatim se reakcijsku smjesu miješa tri sata pri sobnoj temperaturi. Reakcijsku smjesu se ekstrahira s otopinom natrijevog hidrogen karbonata i organsku fazu se osuši preko natrijevog sulfata. Čišćenje se vrši kromato-grafijom na stupcu Alox (sredstvo za ispiranje: ciklo-heksan/etil acetat = 8:2). 0.025 g of p-toluenesulfonic acid and 2.575 ml (28.22 mmol) of dihydropyran were added successively to a solution of 4.83 g (24.02 mmol) of 2-(4-bromo-phenyl)-ethanol in 12 ml of dichloromethane at 0°C. The reaction mixture is then stirred for three hours at room temperature. The reaction mixture is extracted with sodium hydrogen carbonate solution and the organic phase is dried over sodium sulfate. Purification is performed by chromatography on an Alox column (eluent: cyclohexane/ethyl acetate = 8:2).
Iskorištenje: 37 g (32,8% od teorijskog). Yield: 37 g (32.8% of theoretical).
C13H17BrO2 (M = 285,18) C13H17BrO2 (M = 285.18)
Izračunato: molekulska masa (M)+: 284/286 Calculated: molecular weight (M)+: 284/286
Nađeno: molekulska masa (M)+: 284/286 Found: molecular weight (M)+: 284/286
1.31.b 4-[2-(tetrahidro-piran-2-iloksi)-etil]-benzaldehid 1.31.b 4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde
11,5 ml (18,41 mmolova) 1,6 M otopine n-butil-litija doda se kap po kap u otopinu od 5 g (17,53 mmolova) 2-[2-(4-brom-fenil)-etoksi]-tetrahidro-pirana u 80 ml tetra-hidrofurana pri -70°C i miješa se jedan sat pri toj temperaturi. Zatim se doda kap po kap 2,8 ml (36,46 mmolova) dimetilformamida i reakcijsku smjesu se miješa još dva sata pri -70°C. Reakcijsku smjesu se pomiješa s otopinom amonijevog klorida i ekstrahira se s etil acetatom. Sjedinjene organske faze se ekstrahiraju tri puta sa zasićenom otopinom natrijevog klorida i osuše se preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: cikloheksan/ etil acetat = 6:4). 11.5 ml (18.41 mmol) of a 1.6 M solution of n-butyllithium was added dropwise to a solution of 5 g (17.53 mmol) of 2-[2-(4-bromo-phenyl)-ethoxy ]-tetrahydropyran in 80 ml of tetrahydrofuran at -70°C and stirred for one hour at that temperature. Then 2.8 ml (36.46 mmol) of dimethylformamide was added drop by drop and the reaction mixture was stirred for another two hours at -70°C. The reaction mixture was mixed with ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are extracted three times with saturated sodium chloride solution and dried over sodium sulfate. Cleaning is done by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate = 6:4).
Iskorištenje: 2,8 g (68,2% od teorijskog). Yield: 2.8 g (68.2% of theoretical).
C14H18O3 (M = 234,29) C14H18O3 (M = 234.29)
Izračunato: molekulska masa (M+H)+: 235 Calculated: molecular weight (M+H)+: 235
Nađeno: molekulska masa (M+H)+: 235 Found: molecular weight (M+H)+: 235
Rf vrijednost: 0,57 (silika gel, petrol eter/etil acetat 3:1) Rf value: 0.57 (silica gel, petroleum ether/ethyl acetate 3:1)
1.31.c 4-(2-hidroksi-etil)-benzaldehid 1.31.c 4-(2-hydroxy-ethyl)-benzaldehyde
Otopinu od 2,8 g (11,95 mmolova) 4-[2-{tetrahidro-piran-2-iloksi)-etil]-benzaldehida u mješavini od 48 ml 1M solne kiseline i 60 ml acetona miješa se pet sati pri 5oC. Reakcijsku smjesu se pomiješa sa 140 ml zasićene otopine natrijevog hidrogen karbonata i ekstrahira se s etil acetatom. Sjedinjene organske faze se ekstrahiraju tri puta s vodom i osuše preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gel (sredstvo za ispiranje: cikloheksan/etil acetat = 1:1). A solution of 2.8 g (11.95 mmol) of 4-[2-{tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde in a mixture of 48 ml of 1M hydrochloric acid and 60 ml of acetone was stirred for five hours at 5°C. The reaction mixture was mixed with 140 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate = 1:1).
Iskorištenje: 1,3 g (72,4% od teorijskog). Yield: 1.3 g (72.4% of theoretical).
C9H10O2 (M = 150,17) C9H10O2 (M = 150.17)
Izračunato: molekulska masa (M+H)+: 151 Calculated: molecular weight (M+H)+: 151
Nađeno: molekulska masa (M+H)+: 151 Found: molecular weight (M+H)+: 151
Rf vrijednost: 0,52 (silika gel, petrol eter/etil acetat 1:1) Rf value: 0.52 (silica gel, petroleum ether/ethyl acetate 1:1)
1.31.d 2-(4-[1,3]dioksan-2-il-fenil)-etanol 1.31.d 2-(4-[1,3]dioxan-2-yl-phenyl)-ethanol
Suspenziju od 9,4 g (62,59 mmola) 4-(2-hidroksi-etil)-benzaldehida, 15,83 ml (219,07 mmolova) 1,3-propandiola, 0,3 g p-toluensulfonske kiseline i 150 ml toluena se refluktira tri sata. Reakcijsku smjesu se ekstrahira tri puta sa zasićenom otopinom natrijevog hidrogen karbonata i organsku fazu se osuši preko natrijevog sulfata. A suspension of 9.4 g (62.59 mmol) of 4-(2-hydroxy-ethyl)-benzaldehyde, 15.83 ml (219.07 mmol) of 1,3-propanediol, 0.3 g of p-toluenesulfonic acid and 150 ml of toluene is refluxed for three hours. The reaction mixture is extracted three times with saturated sodium hydrogen carbonate solution and the organic phase is dried over sodium sulfate.
Iskorištenje: 8 g (61,4% od teorijskog). Yield: 8 g (61.4% of theoretical).
C12H16O3 (M = 208,26) C12H16O3 (M = 208.26)
Izračunato: molekulska masa (M+H)+: 209 Calculated: molecular weight (M+H)+: 209
Nađeno: molekulska masa (M+H)+: 209 Found: molecular weight (M+H)+: 209
1.31.e Metansulfonska kiselina-2-(4-[1,3]dioksan-2-il-fenil)-etil ester 1.31.e Methanesulfonic acid-2-(4-[1,3]dioxan-2-yl-phenyl)-ethyl ester
8 g (38,41 mmolova) 2-(4-[1,3]dioksan-2-il-fenil)-etanola i 10,65 ml (42,25 mmola) trietilamina se otopi u 300 ml diklormetana i pri 0°C pomiješa se s 3,27 ml klorida metansulfonske kiseline otopljenog u 50 ml diklormetana. Reakcijsku smjesu se miješa jedan sat pri sobnoj temperaturi, ekstrahira se tri puta s vodom i organsku fazu se osuši preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: petrol eter/etil acetat = 1:1). 8 g (38.41 mmol) of 2-(4-[1,3]dioxan-2-yl-phenyl)-ethanol and 10.65 ml (42.25 mmol) of triethylamine are dissolved in 300 ml of dichloromethane and at 0° C is mixed with 3.27 ml of methanesulfonic acid chloride dissolved in 50 ml of dichloromethane. The reaction mixture is stirred for one hour at room temperature, extracted three times with water and the organic phase is dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate = 1:1).
Iskorištenje: 7,7 g (70% od teorijskog). Yield: 7.7 g (70% of theoretical).
C13H18O5S (M = 286,34) C13H18O5S (M = 286.34)
Izračunato: molekulska masa (M+H)+: 287 Calculated: molecular weight (M+H)+: 287
Nađeno: molekulska masa (M+H)+: 287 Found: molecular weight (M+H)+: 287
Rf vrijednost: 0,49 (silika gel, petrol eter/etil acetat 1:1) Rf value: 0.49 (silica gel, petroleum ether/ethyl acetate 1:1)
1.31.f (E)-3-{3-brom-fenil)-akriloilazid 1.31.f (E)-3-{3-bromo-phenyl)-acryloylazide
U otopinu od 25 g (111,1 mmolova) (E)-3-(3-brom-fenil)-akrilne kiseline i 15,26 ml (110,10 mmolova) trietilamina u 800 ml acetona doda se kap po kap pri 0°C 11,5 ml (121,11 mmola) etil klorformata. Nakon jednog sata doda se također kap po kap pri 0°C 11,45 g (176,16 mmolova) natrijevog azida, otopljenog u 88 ml destilirane vode. Reakcijsku smjesu se pusti zagrijati na sobnu temperaturu i zatim se prelije na 1,3 l ledene vode. Nastali talog se odfiltrira, ispere s vodom i osuši pri 30°C u optočnoj sušilici. A solution of 25 g (111.1 mmol) of (E)-3-(3-bromo-phenyl)-acrylic acid and 15.26 ml (110.10 mmol) of triethylamine in 800 ml of acetone was added dropwise at 0 °C 11.5 ml (121.11 mmol) of ethyl chloroformate. After one hour, 11.45 g (176.16 mmol) of sodium azide, dissolved in 88 ml of distilled water, was also added drop by drop at 0°C. The reaction mixture is allowed to warm to room temperature and then poured into 1.3 l of ice water. The resulting precipitate is filtered off, washed with water and dried at 30°C in a circulating dryer.
Iskorištenje: 21,1 g (76,1% od teorijskog). Yield: 21.1 g (76.1% of theoretical).
C9H6BrN3O (M = 252,07) C9H6BrN3O (M = 252.07)
Izračunato: molekulska masa (M+H)+: 256/258 Calculated: molecular weight (M+H)+: 256/258
Nađeno: molekulska masa (M+H)+: 256/258 Found: molecular weight (M+H)+: 256/258
Rf vrijednost: 0,85 (silika gel, petrol eter/etil acetat 1:1) Rf value: 0.85 (silica gel, petroleum ether/ethyl acetate 1:1)
1.31.g 6-brom-2H-izokinolin-1-on 1.31.g 6-bromo-2H-isoquinolin-1-one
150 g bifenil etera i 7,08 ml (29,75 mmolova) tributilamina zagrije se na 100°C. Pri toj temperaturi se doda 5 g (19,83 mmolova) (E)-3-(3-brom-fenii)-akriloilazida i zatim se grije dva sata pri 195-205°C. Zatim se reakcijsku smjesu se pusti ohladiti i prelije u ohlađen n-heksan. Talog se odfiltrira i ispere s mješavinom ohlađenog n-heksana i dietil etera. Zatim se krutu tvar osuši u optočnoj sušilici pri 50°C. Krutu tvar se pomiješa s mješavinom diizopropil etera i etil acetata i sušenje se ponovi. 150 g of biphenyl ether and 7.08 ml (29.75 mmol) of tributylamine are heated to 100°C. At this temperature, 5 g (19.83 mmol) of (E)-3-(3-bromo-phenyl)-acryloylazide are added and then heated for two hours at 195-205°C. The reaction mixture is then allowed to cool and poured into cooled n-hexane. The precipitate is filtered off and washed with a mixture of cooled n-hexane and diethyl ether. Then the solid substance is dried in a circulating dryer at 50°C. The solid was mixed with a mixture of diisopropyl ether and ethyl acetate and drying was repeated.
Iskorištenje: 0,6 g (13,5% od teorijskog). Yield: 0.6 g (13.5% of theoretical).
C9H6BrN3O (M = 224,05) C9H6BrN3O (M = 224.05)
Izračunato: molekulska masa (M+H)+: 224/226 Calculated: molecular weight (M+H)+: 224/226
Nađeno: molekulska masa (M+H)+: 224/226 Found: molecular weight (M+H)+: 224/226
1.31.h 6-(4-klor-fenil)-2H-izokinolin-1-on 1.31.h 6-(4-chloro-phenyl)-2H-isoquinolin-1-one
Reakcijsku smjesu od 0,57 g (2,54 mmola) 6-brom-2H-izokinolin-1-ona, 0,398 g (2,54 mmola) 4-klorfenilborne kiseline, 2,6 ml 2M otopine natrijevog karbonata u 20 ml dioksana i 5 ml metanola grije se pri 110oC dva sata u mikrovalnoj grijalici. Zatim se reakcijsku smjesu prelije u vodu, talog se odfiltrira i osuši u optočnoj sušilici pri 40°C. A reaction mixture of 0.57 g (2.54 mmol) of 6-bromo-2H-isoquinolin-1-one, 0.398 g (2.54 mmol) of 4-chlorophenylboronic acid, 2.6 ml of a 2M solution of sodium carbonate in 20 ml of dioxane and 5 ml of methanol are heated at 110oC for two hours in a microwave heater. Then the reaction mixture is poured into water, the precipitate is filtered off and dried in a circulating dryer at 40°C.
Iskorištenje: 0,42 g (64,6% od teorijskog). Yield: 0.42 g (64.6% of theoretical).
C15H10ClNO (M = 255,70) C15H10ClNO (M = 255.70)
Izračunato: molekulska masa (M+H)+: 256/258 Calculated: molecular weight (M+H)+: 256/258
Nađeno: molekulska masa (M+H)+: 256/258 Found: molecular weight (M+H)+: 256/258
Rf vrijednost: 0,6 (silika gel, diklormetan/etanol 10:1) Rf value: 0.6 (silica gel, dichloromethane/ethanol 10:1)
1.31.i 2-[2-(4-formil-fenil)-etil]-6-(4-klor-fenil)-2H-izokinolin-1-on 1.31.i 2-[2-(4-formyl-phenyl)-ethyl]-6-(4-chloro-phenyl)-2H-isoquinolin-1-one
Otopinu od 0,41 g (1,6 mmola) 6-(4-klor-fenil)-2H-izokinolin-1-ona u 10 ml dimetilformamida se pomiješa s 0,18 g (1,6 mmola) kalijevog terc-butoksida i miješa se 30 minuta pri 50°C. Zatim se doda 0,46 g (1,6 mmola) metan-sulfonska kiselina-2-(4-[1,3]dioksan-2-il-fenil)-etil estera. Reakcijsku smjesu se grije u mikrovalnoj grijalici pet sati pri 180°C i zatim se prelije na 10% otopinu limunske kiseline. To se ekstrahira s etil acetatom. Organsku fazu se ekstrahira tri puta s vodom i osuši preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: petrol eter/ etil acetat = 3:1 do 1:1). A solution of 0.41 g (1.6 mmol) of 6-(4-chloro-phenyl)-2H-isoquinolin-1-one in 10 ml of dimethylformamide was mixed with 0.18 g (1.6 mmol) of potassium tert-butoxide and stirred for 30 minutes at 50°C. Then 0.46 g (1.6 mmol) of methanesulfonic acid-2-(4-[1,3]dioxan-2-yl-phenyl)-ethyl ester was added. The reaction mixture is heated in a microwave oven for five hours at 180°C and then poured onto a 10% solution of citric acid. This is extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate = 3:1 to 1:1).
Iskorištenje: 0,15 g (24,1% od teorijskog). Yield: 0.15 g (24.1% of theoretical).
C24H18ClNO2 (M = 387,87) C24H18ClNO2 (M = 387.87)
Izračunato: molekulska masa (M+H)+: 388/390 Calculated: molecular weight (M+H)+: 388/390
Nađeno: molekulska masa (M+H)+: 388/390 Found: molecular weight (M+H)+: 388/390
Rf vrijednost: 0,7 (silika gel, petrol eter/etil acetat 1:1) Rf value: 0.7 (silica gel, petroleum ether/ethyl acetate 1:1)
1.31.j 6-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2H-izokinolin-1-on 1.31.j 6-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2H-isoquinolin-1-one
0,14 g (0,36 mmola) 2-[2-(4-formil-fenil)-etil]-6-(4-klor-fenil)-2H-izokinolin-1-ona i 0,03 ml (0,36 mmola) pirolidina otopi se u 40 ml diklormetana. pH se namjesti na tri s ledenom octenom kiselinom. Zatim se doda 0,076 g (0,36 mmola) natrijevog triacetoksiborhidrida i smjesu se miješa 48 sati pri sobnoj temperaturi. Zatim se reakcijsku smjesu ekstrahira s 2M otopinom natrijevog karbonata i osuši se preko natrijevog sulfata. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/etanol 10:1 to 1:1). 0.14 g (0.36 mmol) of 2-[2-(4-formyl-phenyl)-ethyl]-6-(4-chloro-phenyl)-2H-isoquinolin-1-one and 0.03 ml (0 .36 mmol) of pyrrolidine is dissolved in 40 ml of dichloromethane. The pH was adjusted to three with glacial acetic acid. Then 0.076 g (0.36 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred for 48 hours at room temperature. The reaction mixture is then extracted with 2M sodium carbonate solution and dried over sodium sulfate. Purification is performed by chromatography on a silica gel column (eluent: dichloromethane/ethanol 10:1 to 1:1).
Iskorištenje: 0,04 g (25% od teorijskog). Yield: 0.04 g (25% of theoretical).
Talište: 136-137oC Melting point: 136-137oC
C28H27ClN2O (M = 442,99) C28H27ClN2O (M = 442.99)
Izračunato: molekulska masa (M+H)+: 443 Calculated: molecular weight (M+H)+: 443
Nađeno: molekulska masa (M+H)+: 443 Found: molecular weight (M+H)+: 443
Rf vrijednost: 0,5 (silika gel, diklormetan/metanol 10:1) Rf value: 0.5 (silica gel, dichloromethane/methanol 10:1)
Slijedeći spojevi su proizvedeni analogno primjerima 1.1 do 1.31: The following compounds were produced analogously to examples 1.1 to 1.31:
[image] [image]
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Primjer 2.1: Example 2.1:
4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.1.a 4'-klor-bifenil-4-karboksilna kiselina 2.1.a 4'-chloro-biphenyl-4-carboxylic acid
5,83 g (29,0 mmolova) 4-brom-benzojeve kiseline se otopi u 50 ml dioksana i 29 ml 2M otopini natrijevog karbonata. Uzastopce se doda 4,5 g (29,0 mmolova) 4-klor-fenilborne kiselina i 1,68 g (1,45 mmola) tetrakis-(trifenilfosfin)-paladija i reakcijsku smjesu se refluktira 6 h. Vruću reakcijsku otopinu se odsisa kroz filter od staklenih vlakana. Filtrat se ekstrahira s etil acetatom. Vodenu fazu se zakiseli s limunskom kiselinom i miješa se jedan sat pri 0°C. Nastali talog se odfiltrira, ispere s vodom i osuši u vakuumu. 5.83 g (29.0 mmol) of 4-bromobenzoic acid are dissolved in 50 ml of dioxane and 29 ml of 2M sodium carbonate solution. 4.5 g (29.0 mmol) of 4-chloro-phenylboronic acid and 1.68 g (1.45 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The hot reaction solution is sucked off through a glass fiber filter. The filtrate is extracted with ethyl acetate. The aqueous phase is acidified with citric acid and stirred for one hour at 0°C. The resulting precipitate is filtered off, washed with water and dried in a vacuum.
Iskorištenje: 5,1 g (75,6% od teorijskog). Yield: 5.1 g (75.6% of theoretical).
C13H9ClO2 (M = 232,668) C13H9ClO2 (M = 232.668)
Izračunato: molekulska masa (M-H)-: 231/233 Calculated: molecular weight (M-H)-: 231/233
Nađeno: molekulska masa (M-H)-: 231/233 Found: molecular weight (M-H)-: 231/233
2.1.b. 4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.1.b. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
471 mg (1,47 mmola) TBTU i 0,26 ml (1,47 mmola) Hünigove baze doda se u suspenziju od 251 mg (1,08 mmola) 4'-klor-bifenil-4-karboksilne kiseline u 5 ml THF-a pri sobnoj temperaturi. Reakcijsku smjesu se miješa 10 min i zatim se doda 200 mg (0,98 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (vidi primjer 1.1.h). Smjesu se miješa preko noći. Reakcijsku otopinu se pomiješa sa zasićenom otopinom NaHCO3, vodenu fazu se ekstrahira s etil acetatom i organsku fazu se osuši preko magnezijevog sulfata. Otapalo se izdestilira na rotacijskom uređaju za isparavanje i ostatak se pomiješa s terc-butilmetil eterom uz grijanje. Nastalu krutu tvar se odfiltrira, ispere s malo terc-butilmetil etera i osuši na zraku. 471 mg (1.47 mmol) of TBTU and 0.26 ml (1.47 mmol) of Hünig's base are added to a suspension of 251 mg (1.08 mmol) of 4'-chloro-biphenyl-4-carboxylic acid in 5 ml of THF - and at room temperature. The reaction mixture was stirred for 10 min and then 200 mg (0.98 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine was added (see example 1.1.h). The mixture is stirred overnight. The reaction solution is mixed with saturated NaHCO3 solution, the aqueous phase is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator and the residue is mixed with tert-butylmethyl ether under heating. The resulting solid is filtered off, washed with a little tert-butylmethyl ether and air-dried.
Iskorištenje: 210 mg (51,2% od teorijskog). Yield: 210 mg (51.2% of theoretical).
C26H27ClN2O (M = 418,971) C26H27ClN2O (M = 418.971)
Izračunato: molekulska masa (M-HH)+: 419/421 Calculated: molecular weight (M-HH)+: 419/421
Nađeno: molekulska masa (M+H)+: 419/421 Found: molecular weight (M+H)+: 419/421
Rf vrijednost: 0,57 (silika gel, diklormetan/metanol/octena kiselina 9:1:0,1). Rf value: 0.57 (silica gel, dichloromethane/methanol/acetic acid 9:1:0.1).
Primjer 2.2: Example 2.2:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-dietilamino-metil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethylamino-methyl-phenyl)-ethyl]-amide
[image] [image]
2.2.a (4-dietilaminometil-fenil)-acetonitril 2.2.a (4-diethylaminomethyl-phenyl)-acetonitrile
0,88 ml (8,38 mmolova) dietilamina se otopi u 30 ml acetona i uzastopce se doda 2,1 g (15,2 mmolova) kalijevog karbonata i 1,6 g (7,62 mmolova) (4-brom-metil-fenil)-acetonitrila (vidi 1.1.f). Reakcijsku smjesu se miješa 2 h pri sobnoj temperaturi, filtrira se kroz staklenu fritu i ispere s etil acetatom. Filtrat se ispari na rotacijskom uređaju za isparavanje, ekstrahira se s vodom i etil acetatom. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. Daljnje čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/ metanol 9:1). 0.88 ml (8.38 mmol) of diethylamine was dissolved in 30 ml of acetone and 2.1 g (15.2 mmol) of potassium carbonate and 1.6 g (7.62 mmol) of (4-bromo-methyl -phenyl)-acetonitrile (see 1.1.f). The reaction mixture was stirred for 2 h at room temperature, filtered through a glass frit and washed with ethyl acetate. The filtrate is evaporated on a rotary evaporator, extracted with water and ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: dichloromethane/methanol 9:1).
Iskorištenje: 900 mg (58,4% od teorijskog). Yield: 900 mg (58.4% of the theoretical).
C13H22N2 (M = 202,30) C13H22N2 (M = 202.30)
Izračunato: molekulska masa (M+H)+: 203 Calculated: molecular weight (M+H)+: 203
Nađeno: molekulska masa (M+H)+: 203 Found: molecular weight (M+H)+: 203
Rf vrijednost: 0,65 (silika gel, diklormetan/metanol 9:1). Rf value: 0.65 (silica gel, dichloromethane/methanol 9:1).
2.2.b. 2-(4-dietilaminometil-fenil)-etilamin 2.2.b. 2-(4-diethylaminomethyl-phenyl)-ethylamine
Otopinu od 900 mg (4,45 mmola) (4-dietilaminometil-fenil)-acetonitrila u 20 ml metanolne otopine amonijaka pomiješa se sa 100 mg Raney nikla i mućka se pri 50°C i pod 5 bara u autoklavu. Katalizator se odsisa i otapalo se odstrani na rotacijskom uređaju za isparavanje. A solution of 900 mg (4.45 mmol) of (4-diethylaminomethyl-phenyl)-acetonitrile in 20 ml of methanolic ammonia solution was mixed with 100 mg of Raney nickel and shaken at 50°C and under 5 bar in an autoclave. The catalyst is suctioned off and the solvent is removed on a rotary evaporator.
Iskorištenje: 900 mg (98,0% od teorijskog). Yield: 900 mg (98.0% of theoretical).
C13H22N2 (M = 206,334) C13H22N2 (M = 206.334)
Izračunato: molekulska masa (M+H)+: 207 Calculated: molecular weight (M+H)+: 207
Nađeno: molekulska masa (M+H)+: 207 Found: molecular weight (M+H)+: 207
Rf vrijednost: 0,12 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.12 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
2.2.c. 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-di-etilaminometil-fenil)-etil]-amid 2.2.c. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-di-ethylaminomethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 2.1.b iz 4'-klor-bifenil-4-karboksilne kiseline (248 mg, 1,07 mmola) i 2-(4-dietilaminometil-fenil)-etilamina (200 mg, 0,97 mmola). It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (248 mg, 1.07 mmol) and 2-(4-diethylaminomethyl-phenyl)-ethylamine (200 mg, 0.97 mmol).
Iskorištenje: 280 mg (68,6% od teorijskog). Yield: 280 mg (68.6% of theoretical).
C26H29ClN2O (M = 420,987) C26H29ClN2O (M = 420.987)
Izračunato: molekulska masa (M+H)+: 421/423 Calculated: molecular weight (M+H)+: 421/423
Nađeno: molekulska masa (M+H)+: 421/423 Found: molecular weight (M+H)+: 421/423
Rf vrijednost: 0,49 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.49 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.3: Example 2.3:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-piperidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.3.a. 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-piperidin-1-ilmetil-prienil)-etil]-amid 2.3.a. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-piperidin-1-ylmethyl-prienyl)-ethyl]-amide
Proizveden je analogno primjeru 2.1.b iz 4'-klor-bifenil-4-karboksilne kiseline (234 mg, 1,01 mmola) i 2-(4-piperidin-1-ilmetil-fenil)-etilamina (vidi 1.15.b, 200 mg, 0,92 mmola). It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (234 mg, 1.01 mmol) and 2-(4-piperidin-1-ylmethyl-phenyl)-ethylamine (see 1.15.b, 200 mg, 0.92 mmol).
Iskorištenje: 260 mg (65,6% od teorijskog). Yield: 260 mg (65.6% of theoretical).
C27H29ClN2O (M = 432,998) C27H29ClN2O (M = 432.998)
Izračunato: molekulska masa (M+H)+: 433/435 Calculated: molecular weight (M+H)+: 433/435
Nađeno: molekulska masa (M+H)+: 433/435 Found: molecular weight (M+H)+: 433/435
Rf vrijednost: 0,57 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.57 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.4: Example 2.4:
4'-metoksi-bifenil-4-karboksilna kiselina-[2-(4-dietil-aminometil-fenil)-etil]-amid 4'-methoxy-biphenyl-4-carboxylic acid-[2-(4-diethyl-aminomethyl-phenyl)-ethyl]-amide
[image] [image]
2.4.a 1-(4'-metoksi-bifenil-4-il)-etanon 2.4.a 1-(4'-methoxy-biphenyl-4-yl)-ethanone
4-metoksibifenil se doda u otopinu od 11,3 g (85,0 mmolova) aluminijevog klorida u 100 ml ugljikovog disulfida. Smjesu se zagrije na 40oC i zatim se vrlo polako doda 6,07 ml (81,4 mmola) acetil klorida. Reakcijsku smjesu se refluktira jedan sat. Kad se ohladi, reakcijsku otopinu se doda k 100 g leda i 25 ml konc. solne kiselina. Nakon ekstrakcije s diklormetanom organsku fazu se osuši preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i ostatak se prekristalizira iz izopropanola. 4-Methoxybiphenyl is added to a solution of 11.3 g (85.0 mmol) of aluminum chloride in 100 ml of carbon disulfide. The mixture is heated to 40°C and then 6.07 ml (81.4 mmol) of acetyl chloride is added very slowly. The reaction mixture is refluxed for one hour. When cooled, the reaction solution is added to 100 g of ice and 25 ml of conc. hydrochloric acid. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is recrystallized from isopropanol.
Iskorištenje: 8,8 g (48,0% od teorijskog). Yield: 8.8 g (48.0% of theoretical).
C15H14O2 (M= 226,278) C15H14O2 (M= 226.278)
Izračunato: molekulska masa (M+H)+: 227 Calculated: molecular weight (M+H)+: 227
Nađeno: molekulska masa (M+H)+: 227 Found: molecular weight (M+H)+: 227
2.4.b 4'-metoksi-bifenil-4-karboksilna kiselina 2.4.b 4'-methoxy-biphenyl-4-carboxylic acid
6,0 ml (117 mmolova) broma se doda polako kap po kap u otopinu od 15,6 g (390,9 mmolova) NaOH u 70 ml vode pri 0oC. Zatim se polako doda 8,8 g (39,1 mmolova) 1-(4'-metoksi-bifenil-4-il)-etanona u 50 ml dioksana. Nakon tri sata nastalu krutu tvar se odfiltrira, preuzme se u diklor-metan i ponovno se profiltrira. Filtrat se oslobodi od otapala na rotacijskom uređaju za isparavanje. 6.0 ml (117 mmol) of bromine is slowly added dropwise to a solution of 15.6 g (390.9 mmol) of NaOH in 70 ml of water at 0°C. Then 8.8 g (39.1 mmol) of 1-(4'-methoxy-biphenyl-4-yl)-ethanone in 50 ml of dioxane were added slowly. After three hours, the resulting solid is filtered off, taken up in dichloromethane and filtered again. The filtrate is freed from the solvent on a rotary evaporator.
Iskorištenje: 9,0 g (100,0% od teorijskog). Yield: 9.0 g (100.0% of theoretical).
C15H14O2 (M = 228,250) C15H14O2 (M = 228.250)
Izračunato: molekulska masa (M-H)-; 227 Calculated: molecular weight (M-H)-; 227
Nađeno: molekulska masa (M-H)-: 227 Found: molecular weight (M-H)-: 227
2.4.c Klorid 4'-metoksi-bifenil-4-karboksilne kiseline 2.4.c Chloride of 4'-methoxy-biphenyl-4-carboxylic acid
Otopinu od 3,0 g (0,013 mola) 4'-metoksi-bifenil-4-karboksilne kiselina u 47,4 ml (0,65 mola) tionil klorida miješa pri 50oC tri sata. Nakon odstranjivanja tionil klorida na rotacijskom uređaju za isparavanje proizvod se dobije kao žućkasta kruta tvar, koju se odloži u hladnjak. A solution of 3.0 g (0.013 mol) of 4'-methoxy-biphenyl-4-carboxylic acid in 47.4 ml (0.65 mol) of thionyl chloride was stirred at 50°C for three hours. After removal of thionyl chloride on a rotary evaporator, the product is obtained as a yellowish solid, which is stored in the refrigerator.
Iskorištenje: 3,2 g (99,8% od teorijskog) Yield: 3.2 g (99.8% of theoretical)
C15H14O2 (M = 246,696) C15H14O2 (M = 246.696)
Izračunato: molekulska masa (M+H)+: 246/248 Calculated: molecular weight (M+H)+: 246/248
Nađeno: molekulska masa (M+H)+: 246/248 Found: molecular weight (M+H)+: 246/248
2.4.d 4'-metoksi-bifenil-4-karboksilna kiselina-[2-(4-dietilaminometil-fenil)-etil]-amid 2.4.d 4'-methoxy-biphenyl-4-carboxylic acid-[2-(4-diethylaminomethyl-phenyl)-ethyl]-amide
287 mg (1,16 mmola) kiselinskog klorida doda se pri 0°C u otopinu od 200 mg (0,97 mmola) 2-(4-dietilaminometil-fenil)-etilamina i 0,25 ml (1,45 mmola) Hünigove baze u 5 ml diklormetana. Reakcijsku smjesu se miješa preko noći i zatim se pomiješa s poluzasićenom otopinom NaHCO3. Vodenu fazu se ispere s diklormetanom i sjedinjene organske faze se osuše preko magnezijevog sulfata. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje se triturira s terc-butilmetil eterom i nastalu krutu tvar se odsisa. 287 mg (1.16 mmol) of acid chloride is added at 0°C to a solution of 200 mg (0.97 mmol) of 2-(4-diethylaminomethyl-phenyl)-ethylamine and 0.25 ml (1.45 mmol) of Hünig's base in 5 ml dichloromethane. The reaction mixture was stirred overnight and then mixed with half-saturated NaHCO 3 solution. The aqueous phase is washed with dichloromethane and the combined organic phases are dried over magnesium sulfate. The residue after removal of the solvent on a rotary evaporator is triturated with tert-butylmethyl ether and the resulting solid is filtered off with suction.
Iskorištenje: 90 mg (22,3% od teorijskog). Yield: 90 mg (22.3% of theoretical).
C27H32N2O2 (M = 416,568) C27H32N2O2 (M = 416.568)
Izračunato: molekulska masa (M+H)+: 417 Calculated: molecular weight (M+H)+: 417
Nađeno: molekulska masa (M+H)+: 417 Found: molecular weight (M+H)+: 417
Rf vrijednost: 0,46 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.5. Example 2.5.
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-dietilamino-etil-fenil)-etil]-metil-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethylamino-ethyl-phenyl)-ethyl]-methyl-amide
[image] [image]
2.5.a Terc-butil [2-(4-dietilaminometil-fenil)-etil]-karbaminat 2.5.a Tert-butyl [2-(4-diethylaminomethyl-phenyl)-ethyl]-carbamate
815 mg (3,73 mmola) BOC-anhidrida se doda u otopinu od 700 mg (3,93 mmola) 2-(4-dietilaminometil-fenil)-etilamina u 5,0 ml diklormetana i 0,52 ml (3,73 mmola) trietilamina i miješa se preko noći pri sobnoj temperaturi. Smjesu se pomiješa sa zasićenom otopinom NaHCO3. Vodenu fazu se ispere s diklormetanom, a organsku fazu se osuši preko magnezijevog sulfata. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje očisti se kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/metanol/NH3 = 9:1:0,1). 815 mg (3.73 mmol) of BOC anhydride was added to a solution of 700 mg (3.93 mmol) of 2-(4-diethylaminomethyl-phenyl)-ethylamine in 5.0 ml of dichloromethane and 0.52 ml (3.73 mmol) of triethylamine and stirred overnight at room temperature. The mixture is mixed with saturated NaHCO3 solution. The aqueous phase is washed with dichloromethane, and the organic phase is dried over magnesium sulfate. The residue after removing the solvent on a rotary evaporator is purified by chromatography on a silica gel column (eluent: dichloromethane/methanol/NH3 = 9:1:0.1).
Iskorištenje: 600 mg (57,7% od teorijskog). Yield: 600 mg (57.7% of theoretical).
C18H30N2O2 (M =306,452) C18H30N2O2 (M = 306.452)
Izračunato: molekulska masa (M+H)+: 307 Calculated: molecular weight (M+H)+: 307
Nađeno: molekulska masa (M+H)+: 307 Found: molecular weight (M+H)+: 307
2.5.b [2-(4-dietilaminometil-fenil)-etil]-metil-amin 2.5.b [2-(4-diethylaminomethyl-phenyl)-ethyl]-methyl-amine
600 mg (1,96 mmola) terc-butil [2-(4-dietilaminometil-fenil)-etil]-karbaminata u THF-u se doda polako kap po kap u suspenziju od 250 mg (6,59 mmolova) litij aluminijevog hidrida u 10 ml tetrahidrofurana. Reakcijsku smjesu se miješa preko noći i grije se pri 50°C još jedan sat. Obrada se vrši uzastopnim dodatkom 0,25 ml vode, 0,25 ml 15%-tne otopine NaOH i 0,75 ml vode. Nakon filtracije, organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. 600 mg (1.96 mmol) of tert-butyl [2-(4-diethylaminomethyl-phenyl)-ethyl]-carbamate in THF was added slowly dropwise to a suspension of 250 mg (6.59 mmol) of lithium aluminum hydride in 10 ml of tetrahydrofuran. The reaction mixture is stirred overnight and heated at 50°C for another hour. The treatment is carried out by successively adding 0.25 ml of water, 0.25 ml of 15% NaOH solution and 0.75 ml of water. After filtration, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator.
Iskorištenje: 350 mg (81,1% od teorijskog). Yield: 350 mg (81.1% of theoretical).
C14H24N2 (M =220,361) C14H24N2 (M = 220.361)
Izračunato: molekulska masa (M+H)+: 221 Calculated: molecular weight (M+H)+: 221
Nađeno: molekulska masa (M+H)+: 221 Found: molecular weight (M+H)+: 221
2.5.c 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-dietil-aminometil-fenil)-etil]-metil-amid 2.5.c 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-diethyl-aminomethyl-phenyl)-ethyl]-methyl-amide
Proizveden je analogno primjeru 2.1.b iz 4'-klor-bifenil-4-karboksilne kiseline (222 mg, 0,95 mmola) i [2-(4-dietilaminometil-fenil)-etil]-metil-amina (175 mg, 0,79 mmola). It was produced analogously to example 2.1.b from 4'-chloro-biphenyl-4-carboxylic acid (222 mg, 0.95 mmol) and [2-(4-diethylaminomethyl-phenyl)-ethyl]-methyl-amine (175 mg, 0.79 mmol).
Iskorištenje: 60 mg (17.4% od teorijskog). Yield: 60 mg (17.4% of theoretical).
C27H31ClN2O (M = 435,014) C27H31ClN2O (M = 435.014)
Izračunato: molekulska masa (M+H)+: 435/437 Calculated: molecular weight (M+H)+: 435/437
Nađeno: molekulska masa (M+H)+: 435/437 Found: molecular weight (M+H)+: 435/437
Rf vrijednost: 0,39 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.39 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.6: Example 2.6:
[image] [image]
2.6.a. 4-(4-klor-fenil)-cikloheksankarboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.6.a. 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 4-(4-klor-fenil)-cikloheksankarboksilne kiseline (239 mg, 1,0 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,0 mmola). It was prepared according to general procedure I from 4-(4-chloro-phenyl)-cyclohexanecarboxylic acid (239 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1 .0 mmol).
Iskorištenje: 65 mg (15,3% od teorijskog). Yield: 65 mg (15.3% of theoretical).
C26H33ClN2O (M = 425,019) C26H33ClN2O (M = 425.019)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Rf vrijednost: 0,3 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.3 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.7: Example 2.7:
4-piperidin-1-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.7.a etil 4-piperidin-1-il-benzoat 2.7.a ethyl 4-piperidin-1-yl-benzoate
0,41 ml piperidina se doda u suspenziju od 0,5 ml (4,13 mmola) etil 4-fluor-benzoata i 571 mg (4,13 mmola) kalijevog karbonata u 20 ml DMSO. Reakcijsku smjesu se miješa preko noći pri 70°C, doda se daljnju 1 ml (2,44 mmola) piperidina i miješanje se nastavi još 6 h pri 70°C. Nakon filtracije doda se vodu, smjesu se ekstrahira s etil acetatom, organsku fazu se odvoji i otapalo odstrani na rotacijskom uređaju za isparavanje. Proizvod dalje reagira bez čišćenja. 0.41 ml of piperidine was added to a suspension of 0.5 ml (4.13 mmol) of ethyl 4-fluorobenzoate and 571 mg (4.13 mmol) of potassium carbonate in 20 ml of DMSO. The reaction mixture was stirred overnight at 70°C, a further 1 ml (2.44 mmol) of piperidine was added and stirring was continued for another 6 h at 70°C. After filtration, water is added, the mixture is extracted with ethyl acetate, the organic phase is separated and the solvent is removed on a rotary evaporator. The product reacts further without cleaning.
Iskorištenje: 706 mg (73,2% od teorijskog). Yield: 706 mg (73.2% of theoretical).
C14H19NO2 (M = 233,313) C14H19NO2 (M = 233.313)
Izračunato: molekulska masa (M+H)+: 234 Calculated: molecular weight (M+H)+: 234
Nađeno: molekulska masa (M+H)+: 234 Found: molecular weight (M+H)+: 234
Vrijeme retencije HPLC: 6,2 min (postupak A) HPLC retention time: 6.2 min (method A)
2.7.b 4-piperidin-1-il-benzojeva kiselina 2.7.b 4-piperidin-1-yl-benzoic acid
0,78 ml (0,74 mmola) 2N NaOH doda se u otopinu od 350 mg (1,50 mmola) etil 4-piperidin-1-il-benzoata u 10 ml etanola. Reakcijsku otopinu se miješa 2 h pri 60°C i zatim se pH namjesti na 6-7 s 1N HCl. Nastali talog se osuši preko noći nakon filtracije pod visokim vakuumom. 0.78 ml (0.74 mmol) of 2N NaOH was added to a solution of 350 mg (1.50 mmol) of ethyl 4-piperidin-1-yl-benzoate in 10 ml of ethanol. The reaction solution was stirred for 2 h at 60°C and then the pH was adjusted to 6-7 with 1N HCl. The resulting precipitate is dried overnight after filtration under high vacuum.
Iskorištenje: 158 mg (51,3% od teorijskog). Yield: 158 mg (51.3% of theoretical).
C12H15NO2 (M = 205,259) C12H15NO2 (M = 205.259)
Izračunato: molekulska masa (M+H)+: 206 Calculated: molecular weight (M+H)+: 206
Nađeno: molekulska masa (M+H)+: 206 Found: molecular weight (M+H)+: 206
Vrijeme retencije HPLC: 6,2 min (metoda A) HPLC retention time: 6.2 min (method A)
2.7.c 4-piperidin-1-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.7.c 4-piperidin-1-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (157 mg, 0,77 mmola) i 4-piperidin-1-il-benzojeve kiseline (158 mg, 0,77 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (157 mg, 0.77 mmol) and 4-piperidin-1-yl-benzoic acid (158 mg, 0.77 mmol).
Iskorištenje: 102 mg (33,8% od teorijskog). Yield: 102 mg (33.8% of theoretical).
C25H33N3O (M =391,561) C25H33N3O (M =391.561)
Izračunato: molekulska masa (M+H)+: 392 Calculated: molecular weight (M+H)+: 392
Nađeno: molekulska masa (M+H)+: 392 Found: molecular weight (M+H)+: 392
Vrijeme retencije HPLC: 4,4 min (metoda A) HPLC retention time: 4.4 min (method A)
Primjer 2.8: Example 2.8:
[image] [image]
2.8.a 4-benzil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.8.a 4-benzyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema gore opisanom općem radnom postupku I iz difenilmetan-4-karboksilne kiseline (104 mg, 0,49 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (100 mg, 0,49 mmola). It was produced according to the general procedure I described above from diphenylmethane-4-carboxylic acid (104 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol). .
Iskorištenje: 66 mg (33,9% od teorijskog). Yield: 66 mg (33.9% of theoretical).
C27H30N2O (M = 398,553) C27H30N2O (M = 398.553)
Izračunato: molekulska masa (M+H)+: 399 Calculated: molecular weight (M+H)+: 399
Nađeno: molekulska masa (M+H)+: 399 Found: molecular weight (M+H)+: 399
Rf vrijednost: 0,46 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.9: Example 2.9:
4-(4-okso-cikloheksilidenmetil)-N-[2-(4-pirolidin-1-il-metil-fenil)-etil]-benzamid 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide
[image] [image]
2.9.a Etil 4-(1,4-dioksa-spiro[4,5]dec-8-ilidenmetil)-benzoat 2.9.a Ethyl 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoate
350 ml (0,56 mol, 1,6 M u heksanu) otopine n-BuLi doda se kap po kap pri -20°C u otopinu od 90,0 ml (0,63 mola) diizopropilamina u 100 ml THF-a i reakcijsku otopinu se miješa 30 min pri –20oC. Polako, kap po kap, doda se 112 g (0,37 mol) etil 4-(dietoksi-fosforilmetil)-benzoata u 100 ml THF-a. Reakcijsku otopinu se miješa 1 h pri –20oC i zatim 58 g (0,37 mol) 1,4-dioksa-spiro[4,5]dekan-8-ona u 200 ml THF-a. Reakcijsku otopinu se miješa 30 min pri -12°C i zatim se zagrije na sobnu temperaturu tijekom 2 h. Doda se vodu i vodenu fazu se ekstrahira s eterom, etil acetatom i diklormetanom. Organsku fazu se filtrira kroz silika gel. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje se očisti kromatografijom (silika gel, petrol eter/etil acetat 9:1). 350 ml (0.56 mol, 1.6 M in hexane) of n-BuLi solution was added dropwise at -20°C to a solution of 90.0 ml (0.63 mol) of diisopropylamine in 100 ml of THF and the reaction solution is stirred for 30 min at -20oC. 112 g (0.37 mol) of ethyl 4-(diethoxy-phosphorylmethyl)-benzoate in 100 ml of THF are added slowly, dropwise. The reaction solution was stirred for 1 h at –20oC and then 58 g (0.37 mol) of 1,4-dioxa-spiro[4,5]decan-8-one in 200 ml of THF. The reaction solution was stirred for 30 min at -12°C and then warmed to room temperature for 2 h. Water is added and the aqueous phase is extracted with ether, ethyl acetate and dichloromethane. The organic phase is filtered through silica gel. The residue after removal of the solvent on a rotary evaporator is purified by chromatography (silica gel, petroleum ether/ethyl acetate 9:1).
Iskorištenje: 80 g (72,0% od teorijskog). Yield: 80 g (72.0% of theoretical).
2.9.b 4-(1,4-dioksa-spiro[4,5]dec-8-ilidenmetil)-benzojeva kiselina 2.9.b 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoic acid
20 g NaOH u 130 ml vode doda se u otopinu od 35 g (0,12 mola) etil 4-(1,4-dioksa-spiro[4,5]dec-8-iliden-metil)-benzoata u 150 ml etanola i smjesu se refluktira 2 h. Reakcijsku otopinu se doda k 400 g leda i 60 ml konc. solne kiseline, vodenu fazu se ekstrahira s etil acetatom i otapalo se odstrani na rotacijskom uređaju za isparavanje. 20 g of NaOH in 130 ml of water is added to a solution of 35 g (0.12 mol) of ethyl 4-(1,4-dioxa-spiro[4,5]dec-8-ylidene-methyl)-benzoate in 150 ml of ethanol. and the mixture is refluxed for 2 h. The reaction solution is added to 400 g of ice and 60 ml of conc. hydrochloric acid, the aqueous phase is extracted with ethyl acetate and the solvent is removed on a rotary evaporator.
Iskorištenje: 32 g (91,4% od teorijskog). Yield: 32 g (91.4% of theoretical).
Talište: 164-165°C. Melting point: 164-165°C.
2.9.c 4-(4-okso-cikloheksilidenmetil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.9.c 4-(4-oxo-cyclohexylidenemethyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 4-(1,4-dioksa-spiro[4,5]dec-8-ilidenmetil)-benzojeve kiseline (134 mg, 0,49 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (100 mg, 0,49 mmola). It was produced according to general procedure I from 4-(1,4-dioxa-spiro[4,5]dec-8-ylidenemethyl)-benzoic acid (134 mg, 0.49 mmol) and 2-(4-pyrrolidine-1 -ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol).
Iskorištenje: 57 mg (28,0% od teorijskog). Yield: 57 mg (28.0% of theoretical).
C27H32N2O2 (M = 416,568) C27H32N2O2 (M = 416.568)
Izračunato: molekulska masa (M+H)+: 417 Calculated: molecular weight (M+H)+: 417
Nađeno: molekulska masa (M+H)+: 417 Found: molecular weight (M+H)+: 417
Rf vrijednost: 0,36 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.10: Example 2.10:
[image] [image]
2.10.a 4-(4-okso-cikloheksil)-N-[2-(4-pirolidin-1-il-metil-fenil)-etil]-benzamid 2.10.a 4-(4-oxo-cyclohexyl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 4-(4-okso-cikloheksil)-benzojeve kiseline (128 mg, 0,49 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (100 mg, 0,49 mmola). It was produced according to general procedure I from 4-(4-oxo-cyclohexyl)-benzoic acid (128 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0 .49 mmol).
Iskorištenje: 26 mg (13,1% od teorijskog). Yield: 26 mg (13.1% of theoretical).
C26H32N2O2 (M = 404,557) C26H32N2O2 (M = 404.557)
Izračunato: molekulska masa (M+H)+: 405 Calculated: molecular weight (M+H)+: 405
Nađeno: molekulska masa (M+H)+: 405 Found: molecular weight (M+H)+: 405
Rf vrijednost: 0,31 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.31 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.11: Example 2.11:
4-cikloheksil-1-cikloheksilkarboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etnil]-amid 4-cyclohexyl-1-cyclohexylcarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethnyl]-amide
[image] [image]
2.11.a 4-cikloheksil-1-cikloheksilkarboksilna kiselina 2.11.a 4-cyclohexyl-1-cyclohexylcarboxylic acid
0,44 ml konc. solne kiseline i 100 mg oksida platine doda se u otopinu od 500 mg (2,10 mmola) 4-(4-klorfenil)-cikloheksankarboksilne kiseline u 10 ml metanola. Reakcijsku smjesu se miješa 3 sata pri 50°C i pod 5 bara tlaka vdika. Nakon odvajanja katalizatora, otapalo se odstrani na rotacijskom uređaju za isparavanje. 0.44 ml conc. of hydrochloric acid and 100 mg of platinum oxide are added to a solution of 500 mg (2.10 mmol) of 4-(4-chlorophenyl)-cyclohexanecarboxylic acid in 10 ml of methanol. The reaction mixture is stirred for 3 hours at 50°C and under 5 bar vacuum pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator.
Iskorištenje: 440 mg (99,9% od teorijskog). Yield: 440 mg (99.9% of theoretical).
C13H22O2 (M = 210,319) C13H22O2 (M = 210.319)
Izračunato: molekulska masa (M-H)-: 209 Calculated: molecular weight (M-H)-: 209
Nađeno: molekulska masa (M-H)-: 209 Found: molecular weight (M-H)-: 209
2.11.b 4-cikloheksil-1-cikloheksilkarboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.11.b 4-cyclohexyl-1-cyclohexylcarboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz biciklo-heksil-4-karboksilne kiseline (103 mg, 0,49 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (100 mg, 0,49 mmola). It was produced according to general procedure I from bicyclohexyl-4-carboxylic acid (103 mg, 0.49 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (100 mg, 0.49 mmol) .
Iskorištenje: 2,0 mg (1,0% od teorijskog). Yield: 2.0 mg (1.0% of theoretical).
C26H40N2O2 (M = 396,622) C26H40N2O2 (M = 396.622)
Izračunato: molekulska masa (M+H)+: 397 Calculated: molecular weight (M+H)+: 397
Nađeno: molekulska masa (M+H)+: 397 Found: molecular weight (M+H)+: 397
Rf vrijednost: 0,46 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.12: Example 2.12:
[image] [image]
2.12.a 4-metilfenil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.12.a 4-methylphenyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema gore opisanom općem radnom postupku II iz 4-metilfenil-piperidina (175 mg, 1,0 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,0 mmola). It was prepared according to general procedure II described above from 4-methylphenyl-piperidine (175 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.0 mmol).
Iskorištenje: 90,0 mg (22,2% od teorijskog). Yield: 90.0 mg (22.2% of theoretical).
C26H35N3O (M = 405,558) C26H35N3O (M = 405.558)
Izračunato: molekulska masa (M+H)+: 406 Calculated: molecular weight (M+H)+: 406
Nađeno: molekulska masa (M+H)+: 406 Found: molecular weight (M+H)+: 406
Rf vrijednost: 0,30 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.13: Example 2.13:
4-(4-klor-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina-[2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.13.a 4-(4-klor-fenil)-1,2,3,6-tetrahidro-piridin 2.13.a 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine
4-klor-metilstiren se doda kap po kap pri 60°C u 100 ml (1,2 mola) otopine formalina (37% u vodi) i 32,1 g (0,6 mola) amonijevog klorida. Reakcijsku smjesu se miješa 3 h pri 60°C i zatim se ohladi na sobnu temperaturu. Doda se 100 ml metanola i smjesu se miješa preko noći. Ostatak nakon isparavanja otapala na rotacijskom uređaju za isparavanje se pomiješa sa 150 ml konc. solne kiseline i miješa se 4 h pri 100°C. Kad se ohladi na sobnu temperaturu doda se na led i zaluži se s ljuskicama NaOH. Nakon ponovne ekstrakcije s eterom, organsku fazu se osuši preko natrijevog sulfata. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje se očisti kromato-grafijom na stupcu silika gela (sredstvo za ispiranje: etil acetat:metanol:NH3 9:1:0,1). 4-Chloromethylstyrene is added dropwise at 60°C to 100 ml (1.2 mol) of formalin solution (37% in water) and 32.1 g (0.6 mol) of ammonium chloride. The reaction mixture was stirred for 3 h at 60°C and then cooled to room temperature. 100 ml of methanol is added and the mixture is stirred overnight. The residue after evaporation of the solvent on a rotary evaporator is mixed with 150 ml conc. of hydrochloric acid and stirred for 4 h at 100°C. When it cools down to room temperature, it is added to ice and made alkaline with flakes of NaOH. After re-extraction with ether, the organic phase is dried over sodium sulfate. The residue after removing the solvent on a rotary evaporator is purified by chromatography on a silica gel column (eluent: ethyl acetate:methanol:NH3 9:1:0.1).
Iskorištenje: 17.0 g (29,3% od teorijskog). Yield: 17.0 g (29.3% of theoretical).
C11H12ClN (M = 193,678) C11H12ClN (M = 193.678)
Izračunato: molekulska masa (M+H)+: 194 Calculated: molecular weight (M+H)+: 194
Nađeno: molekulska masa (M+H)+: 194 Found: molecular weight (M+H)+: 194
Rf vrijednost: 0,26 (silika gel, etil acetat/metanol/NH3 6:4:0,4). Rf value: 0.26 (silica gel, ethyl acetate/methanol/NH3 6:4:0.4).
2.13.b 4-(4-klor-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.13.b 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-klor-fenil)-1,2,3,6-tetrahidro-piridina (193 mg, 1,0 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,0 mmola). It was prepared according to general procedure II from 4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine (193 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl- phenyl)-ethylamine (204 mg, 1.0 mmol).
Iskorištenje: 40,0 mg (9,4% od teorijskog). Yield: 40.0 mg (9.4% of theoretical).
C25H30ClN3O (M = 423,990) C25H30ClN3O (M = 423.990)
Izračunato: molekulska masa (M+H)+: 424/426 Calculated: molecular weight (M+H)+: 424/426
Nađeno: molekulska masa (M+H)+: 424/426 Found: molecular weight (M+H)+: 424/426
Rf vrijednost: 0,30 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.14: Example 2.14:
[image] [image]
2.14.a 3,4,5,6-tetrahidro-2H-[4,4']bipiridinil-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.14.a 3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 1,2,3,4,5,6-heksahidro-[4,41bipiridinila (81 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 1,2,3,4,5,6-hexahydro-[4,41bipyridinyl (81 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)- ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 43,8 mg (22,3% od teorijskog). Yield: 43.8 mg (22.3% of theoretical).
C24H32N4O (M = 392,549) C24H32N4O (M = 392.549)
Izračunato: molekulska masa (M+H)+: 393 Calculated: molecular weight (M+H)+: 393
Nađeno: molekulska masa (M+H)+: 393 Found: molecular weight (M+H)+: 393
Rf vrijednost: 0,14 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.14 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.15: Example 2.15:
[image] [image]
2.15.a 4-benzil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.15.a 4-benzyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-benzil-piperidina (87.7 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-benzyl-piperidine (87.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 33,5 mg (16,5% od teorijskog). Yield: 33.5 mg (16.5% of theoretical).
C26H35N3O (M = 405,6) C26H35N3O (M = 405.6)
Izračunato: molekulska masa (M+H)+: 406 Calculated: molecular weight (M+H)+: 406
Nađeno: molekulska masa (M+H)+: 406 Found: molecular weight (M+H)+: 406
Rf vrijednost: 0,36 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.16: Example 2.16:
[image] [image]
2.16.a 4-(1H-indol-3-il)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.16.a 4-(1H-indol-3-yl)-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 3-piperidin-4-il-1H-indola (100 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 3-piperidin-4-yl-1H-indole (100 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 56,5 mg (26,2% od teorijskog). Yield: 56.5 mg (26.2% of theoretical).
C27H34N4O (M = 430,6) C27H34N4O (M = 430.6)
Izračunato: molekulska masa (M+H)+: 431 Calculated: molecular weight (M+H)+: 431
Nađeno: molekulska masa (M+H)+: 431 Found: molecular weight (M+H)+: 431
Rf vrijednost: 0,36 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.36 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.17: Example 2.17:
[image] [image]
2.17.a Terc-butil 1'-[2-(4-pirolidin-1-ilmetil-fenil)-etilkarbamoil]-[4,4']bipiperidinil-1-karboksilat 2.17.a Tert-butyl 1'-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylcarbamoyl]-[4,4']bipiperidinyl-1-carboxylate
Proizveden je prema općem radnom postupku II iz terc-butil[4,4']bipiperidinil-1-karboksilata (134 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from tert-butyl[4,4']bipiperidinyl-1-carboxylate (134 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg , 0.50 mmol).
Iskorištenje: 51,0 mg (20,5% od teorijskog). Yield: 51.0 mg (20.5% of theoretical).
C29H46N4O3 (M = 498,7) C29H46N4O3 (M = 498.7)
Izračunato: molekulska masa (M+H)+: 499 Calculated: molecular weight (M+H)+: 499
Nađeno: molekulska masa (M+H)+: 499 Found: molecular weight (M+H)+: 499
Rf vrijednost: 0,40 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.18: Example 2.18:
4-cikloheksil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4-cyclohexyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.18.a 4-cikloheksil-piperidin 2.18.a 4-cyclohexyl-piperidine
U otopinu od 1,0 g (6,4 mmolova) 4-fenilpiridina u 20 ml metanola doda se 1,35 ml konc. solne kiseline i 200 mg oksida platine. Reakcijsku smjesu se miješa 2,5 sata pri 50°C i 3 bara tlaka vodika. Nakon odvajanja katalizatora otapalo se odstrani na rotacijskom uređaju za isparavanje, pri čemu se proizvod istaloži kao hidroklorid. In a solution of 1.0 g (6.4 mmol) of 4-phenylpyridine in 20 ml of methanol, 1.35 ml of conc. hydrochloric acid and 200 mg of platinum oxide. The reaction mixture is stirred for 2.5 hours at 50°C and 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator, whereby the product is precipitated as the hydrochloride.
Iskorištenje: 1,2 (91,4% od teorijskog). Yield: 1.2 (91.4% of theoretical).
C11H21N·HCl (M = 203,758) C11H21N·HCl (M = 203.758)
Izračunato: molekulska masa (M+H)+: 168 Calculated: molecular weight (M+H)+: 168
Nađeno: molekulska masa (M+H)+: 168 Found: molecular weight (M+H)+: 168
2.18.b 4-cikloheksil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.18.b 4-cyclohexyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-cikloheksil-piperidina (83,7 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-cyclohexyl-piperidine (83.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 38,0 mg (19,1% od teorijskog). Yield: 38.0 mg (19.1% of theoretical).
C25H39N3O (M = 397,6) C25H39N3O (M = 397.6)
Izračunato: molekulska masa (M+H)+: 398 Calculated: molecular weight (M+H)+: 398
Nađeno: molekulska masa (M+H)+: 398 Found: molecular weight (M+H)+: 398
Rf vrijednost: 0,54 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.54 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.19: Example 2.19:
4-(4-klor-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.19.a 4-(4-klor-fenil)-piperidin 2.19.a 4-(4-chloro-phenyl)-piperidine
U otopinu od 5,0 g (21,7 mmola) 4-(4-klor-fenil)-1,2,3,6-tetrahidro-piridina (vidi 2.13.a) u 20 ml metanola doda se 500 mg Pd/C. Reakcijsku smjesu se miješa 7 h pri sobnoj temperaturi i 10 psi vodika. Nakon odvajanja katalizatora, otapalo se odstrani na rotacijskom uređaju za isparavanje. Daljnje čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/ metanol/amonijak = 5:4,9:0,1). 500 mg of Pd/ C. The reaction mixture was stirred for 7 h at room temperature and 10 psi of hydrogen. After separation of the catalyst, the solvent is removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: dichloromethane/methanol/ammonia = 5:4.9:0.1).
Iskorištenje: 3,2 (75,3% od teorijskog). Utilization: 3.2 (75.3% of theoretical).
C11H14ClN (M = 195,694) C11H14ClN (M = 195.694)
Izračunato: molekulska masa (M+H)+: 196/198 Calculated: molecular weight (M+H)+: 196/198
Nađeno: molekulska masa (M+H)+: 196/198. Found: molecular weight (M+H)+: 196/198.
Rf vrijednost: 0,37 (silika gel, diklormetan/metanol/NH3 5:4,9:0,1). Rf value: 0.37 (silica gel, dichloromethane/methanol/NH3 5:4.9:0.1).
2.19.b 4-(4-klor-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.19.b 4-(4-chloro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-klor-fenil)-piperidina (97,9 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-chloro-phenyl)-piperidine (97.9 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 9,0 mg (4,2% od teorijskog). Yield: 9.0 mg (4.2% of theoretical).
C25H32ClN3O (M = 426,0) C25H32ClN3O (M = 426.0)
Izračunato: molekulska masa (M+H)+: 426/428 Calculated: molecular weight (M+H)+: 426/428
Nađeno: molekulska masa (M+H)+: 426/428 Found: molecular weight (M+H)+: 426/428
Rf vrijednost: 0,49 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.49 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.20: Example 2.20:
[image] [image]
2.20.a 4-hidroksi-4-(4-trifluormetil-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.20.a 4-hydroxy-4-(4-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-hidroksi-4-(4-trifluormetil-fenil)-piperidina (123 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-hydroxy-4-(4-trifluoromethyl-phenyl)-piperidine (123 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 35,0 mg (14,7% od teorijskog). Yield: 35.0 mg (14.7% of theoretical).
C26H32F3N3O2 (M= 475,6) C26H32F3N3O2 (M= 475.6)
Izračunato: molekulska masa (M+H)+: 476 Calculated: molecular weight (M+H)+: 476
Nađeno: molekulska masa (M+H)+: 476 Found: molecular weight (M+H)+: 476
Rf vrijednost: 0,45 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.45 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.21: Example 2.21:
[image] [image]
2.21.a 3-fenil-8-aza-biciklo[3,2,1]oktan-8-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.21.a 3-phenyl-8-aza-bicyclo[3,2,1]octane-8-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 3-fenil-8-aza-biciklo[3,2,1]oktana (93,7 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 3-phenyl-8-aza-bicyclo[3,2,1]octane (93.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl) -ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 26,0 mg (12,5% od teorijskog). Yield: 26.0 mg (12.5% of theoretical).
C27H35N3O (M = 417,6) C27H35N3O (M = 417.6)
Izračunato: molekulska masa (M+H)+: 418 Calculated: molecular weight (M+H)+: 418
Nađeno: molekulska masa (M+H)+: 418 Found: molecular weight (M+H)+: 418
Rf vrijednost: 0,51 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.51 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.22: Example 2.22:
[image] [image]
2.22.a 4-(4-klor-fenil)-piperazin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.22.a 4-(4-chloro-phenyl)-piperazine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-klor-fenil)-piperazina (117 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-chloro-phenyl)-piperazine (117 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 13,0 mg (6,1% od teorijskog). Yield: 13.0 mg (6.1% of theoretical).
C24H31ClN4O (M = 427,0) C24H31ClN4O (M = 427.0)
Izračunato: molekulska masa (M+H)+: 427/429 Calculated: molecular weight (M+H)+: 427/429
Nađeno: molekulska masa (M+H)+: 427/429 Found: molecular weight (M+H)+: 427/429
Rf vrijednost: 0,42 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.42 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.23: Example 2.23:
[image] [image]
2.23.a 4-cijano-4-fenil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.23.a 4-cyano-4-phenyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-cijano-4-fenil-piperidina (111 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-cyano-4-phenyl-piperidine (111 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol ).
Iskorištenje: 27,0 mg (13,0% od teorijskog). Yield: 27.0 mg (13.0% of theoretical).
C26H32N4O (M = 416,6) C26H32N4O (M = 416.6)
Izračunato: molekulska masa (M+H)+: 417 Calculated: molecular weight (M+H)+: 417
Nađeno: molekulska masa (M+H)+: 417 Found: molecular weight (M+H)+: 417
Rf vrijednost: 0,46 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.46 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.24: Example 2.24:
[image] [image]
2.24.a 3-aza-spiro[5,5]undekan-3-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.24.a 3-aza-spiro[5,5]undecane-3-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 3-aza-spiro[5,5]undekana (76,7 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenilj-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 3-aza-spiro[5,5]undecane (76.7 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenylj-ethylamine (102 mg, 0 .50 mmol).
Iskorištenje: 24,0 mg (12,5% od teorijskog). Yield: 24.0 mg (12.5% of theoretical).
C24H37N3O (M = 383,6) C24H37N3O (M = 383.6)
Izračunato: molekulska masa (M+H)+: 384 Calculated: molecular weight (M+H)+: 384
Nađeno: molekulska masa (M+H)+: 384 Found: molecular weight (M+H)+: 384
Rf vrijednost: 0,49 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.49 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.25: Example 2.25:
[image] [image]
2.25.a 4-(4-fluor-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.25.a 4-(4-fluoro-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-fluor-fenil)-piperidina (108 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-fluoro-phenyl)-piperidine (108 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 32,0 mg (15,6% od teorijskog). Yield: 32.0 mg (15.6% of theoretical).
C25H32FN3O (M = 409,6) C25H32FN3O (M = 409.6)
Izračunato: molekulska masa (M+H)+: 410 Calculated: molecular weight (M+H)+: 410
Nađeno: molekulska masa (M+H)+: 410 Found: molecular weight (M+H)+: 410
Rf vrijednost: 0,50 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.50 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.26: Example 2.26:
[image] [image]
2.26.a 1,2-dihidro-1-(metilsulfonil)-spiro[3H-indol-3,4'-piperidin]-1-karboksilna kiselina-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amid 2.26.a 1,2-dihydro-1-(methylsulfonyl)-spiro[3H-indole-3,4'-piperidine]-1-carboxylic acid-[2-(4-pyrrolidin-1-yl-methyl-phenyl) -ethyl]-amide
Proizveden je prema općem radnom postupku II iz 1,2-dihidro-1-(metilsulfonil)-spiro[3H-indol-3,4'-piperidina] (133,2 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 1,2-dihydro-1-(methylsulfonyl)-spiro[3H-indole-3,4'-piperidine] (133.2 mg, 0.50 mmol) and 2-(4- pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 28,0 mg (11,3% od teorijskog). Yield: 28.0 mg (11.3% of theoretical).
C27H36N4O3S (M = 496,7) C27H36N4O3S (M = 496.7)
Izračunato: molekulska masa (M+H)+: 497 Calculated: molecular weight (M+H)+: 497
Nađeno: molekulska masa (M+H)+: 497 Found: molecular weight (M+H)+: 497
Rf vrijednost: 0,42 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.42 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.27: Example 2.27:
[image] [image]
2.27.a 4-(4-klor-fenil)-4-hidroksi-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.27.a 4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-klor-fenil)-4-hidroksi-piperidina (106 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-chloro-phenyl)-4-hydroxy-piperidine (106 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 32,0 mg (14,5% od teorijskog). Yield: 32.0 mg (14.5% of theoretical).
C25H32ClN3O2 (M = 442,0) C25H32ClN3O2 (M = 442.0)
Izračunato: molekulska masa (M+H)+: 442/444 Calculated: molecular weight (M+H)+: 442/444
Nađeno: molekulska masa (M+H)+: 442/444 Found: molecular weight (M+H)+: 442/444
Rf vrijednost: 0,44 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.44 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.28: Example 2.28:
[image] [image]
2.28.a 4-(4-metoksi-fenil)-piperazine-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.28.a 4-(4-methoxy-phenyl)-piperazine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-metoksi-fenil)-piperazina (133 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-methoxy-phenyl)-piperazine (133 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 35,0 mg (16,6% od teorijskog). Yield: 35.0 mg (16.6% of theoretical).
C25H34N4O2 (M = 422,6) C25H34N4O2 (M = 422.6)
Izračunato: molekulska masa (M+H)+: 423 Calculated: molecular weight (M+H)+: 423
Nađeno: molekulska masa (M+H)+: 423 Found: molecular weight (M+H)+: 423
Rf vrijednost: 0,47 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.47 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.29: Example 2.29:
[image] [image]
2.29. 4-(2-metoksi-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.29. 4-(2-Methoxy-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(2-metoksi-fenil)-piperidina (114 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamin (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(2-methoxy-phenyl)-piperidine (114 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 20,0 mg (9,5% od teorijskog). Yield: 20.0 mg (9.5% of theoretical).
C26H35N3O2 (M =421,6) C26H35N3O2 (M = 421.6)
Izračunato: molekulska masa (M+H)+: 422 Calculated: molecular weight (M+H)+: 422
Nađeno: molekulska masa (M+H)+: 422 Found: molecular weight (M+H)+: 422
Rf vrijednost: 0,55 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.55 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.30: Example 2.30:
[image] [image]
2.30.a 1,3-dihidro-izoindol-2-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.30.a 1,3-dihydro-isoindole-2-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 1,3-dihidro-izoindola (77.8 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 1,3-dihydro-isoindole (77.8 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 13,0 mg (7,4% od teorijskog). Yield: 13.0 mg (7.4% of theoretical).
C22H27N3O (M = 349,48) C22H27N3O (M = 349.48)
Izračunato: molekulska masa (M+H)+: 350 Calculated: molecular weight (M+H)+: 350
Nađeno: molekulska masa (M+H)+: 350 Found: molecular weight (M+H)+: 350
Rf vrijednost: 0,30 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.30 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.31: Example 2.31:
[image] [image]
2.31.a 1,2,4,5-tetrahidro-benzo[d]azepin-3-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.31.a 1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 1,2,4,5-tetrahidro-benzo[d]azepina (73,6 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 1,2,4,5-tetrahydro-benzo[d]azepine (73.6 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 12,0 mg (6,4% od teorijskog). Yield: 12.0 mg (6.4% of theoretical).
C24H31N3O (M = 377,534) C24H31N3O (M = 377.534)
Izračunato: molekulska masa (M+H)+: 378 Calculated: molecular weight (M+H)+: 378
Nađeno: molekulska masa (M+H)+: 378 Found: molecular weight (M+H)+: 378
Rf vrijednost: 0,33 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.33 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.32: Example 2.32:
[image] [image]
2.32.a 4-fenil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.32.a 4-phenyl-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-fenil-piperidina (80,6 mg, 0,50 mmola) i 2-{4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-phenyl-piperidine (80.6 mg, 0.50 mmol) and 2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 24,0 mg (12,3% od teorijskog). Yield: 24.0 mg (12.3% of theoretical).
C25H33N3O (M =391,561) C25H33N3O (M =391.561)
Izračunato: molekulska masa (M+H)+: 392 Calculated: molecular weight (M+H)+: 392
Nađeno: molekulska masa (M+H)+: 392 Found: molecular weight (M+H)+: 392
Rf vrijednost: 0,35 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.35 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.33: Example 2.33:
4-(4-diimetilaminometil-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4-(4-Dimethylaminomethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.33.a Terc-butil 4-(4-dimetilaminometil-fenil)-4-hidroksi-piperidin-1-karboksilat 2.33.a Tert-butyl 4-(4-dimethylaminomethyl-phenyl)-4-hydroxy-piperidine-1-carboxylate
236 ml (0,38 mola, 1,6 M u heksanu) n-BuLi se doda kap po kap tijekom 35 min pri -65°C u otopinu od 81 g (0,38 mola) 4-bromdimetilbenzilamina u 450 ml THF-a. 75 g (0,38 mol) terc-butil 4-okso-piperidin-1-karboksilata u 150 ml THF-a se doda kap po kap tijekom 60 min tako da temperatura ne poraste iznad –60oC. Reakcijsku otopinu se miješa 2h pri –65oC i još daljnjih 17 h pri sobnoj temperaturi. Reakcijsku smjesu se pomiješa s 300 ml etera, ohladi se na 5°C i nastali talog se odsisa. Talog se pomiješa s 200 ml vode i 700 ml etera i miješa se 10 min. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. Dobiveni proizvod se osuši u vakuumu. 236 ml (0.38 mol, 1.6 M in hexane) of n-BuLi was added dropwise over 35 min at -65°C to a solution of 81 g (0.38 mol) of 4-bromodimethylbenzylamine in 450 ml of THF- And. 75 g (0.38 mol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 150 ml of THF is added dropwise over 60 min so that the temperature does not rise above –60oC. The reaction solution is stirred for 2 hours at -65oC and for a further 17 hours at room temperature. The reaction mixture was mixed with 300 ml of ether, cooled to 5°C and the resulting precipitate was filtered off with suction. The precipitate is mixed with 200 ml of water and 700 ml of ether and stirred for 10 min. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. The obtained product is dried in a vacuum.
Iskorištenje: 45 g (35,7% od teorijskog). Yield: 45 g (35.7% of theoretical).
2.33.b Dimetil-[4-(1,2,3,6-tetrahidro-piridin-4-il)-benzil]-amin 2.33.b Dimethyl-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-amine
70 ml trifluoroctene kiseline se doda kap po kap u otopinu od 45 g (0,14 mola) terc-butil 4-(4-dimetil-amino-metil-fenil)-4-hidroksi-piperidin-1-karboksilata u 140 ml diklormetana pri -10°C. Otopinu se miješa 1,5 h pri sobnoj temperaturi, ohladi se na –10oC i doda se 30 ml konc. sumporne kiseline. Nakon pola sata doda se daljnjih 10 ml sumporne kiseline. Nakon 1 h otapalo se odstrani na rotacijskom uređaju za isparavanje i doda se k 300 g leda. pH se namjesti na 14 sa 6 N otopinom NaOH. Vodenu fazu se zasiti s kalijevim karbonatom i ekstrahira dva puta s eterom. Sjedinjene organske faze se koncentriraju do suhog na rotacijskom uređaju za isparavanje. 70 ml of trifluoroacetic acid is added dropwise to a solution of 45 g (0.14 mol) tert-butyl 4-(4-dimethyl-amino-methyl-phenyl)-4-hydroxy-piperidine-1-carboxylate in 140 ml of dichloromethane at -10°C. The solution is stirred for 1.5 h at room temperature, cooled to -10oC and 30 ml conc. sulfuric acid. After half an hour, a further 10 ml of sulfuric acid is added. After 1 h, the solvent is removed on a rotary evaporator and added to 300 g of ice. The pH was adjusted to 14 with 6 N NaOH solution. The aqueous phase is saturated with potassium carbonate and extracted twice with ether. The combined organic phases are concentrated to dryness on a rotary evaporator.
Iskorištenje: 25,2 g (86,9%). Yield: 25.2 g (86.9%).
2.33.c Dimetil-(4-piperidin-4-il-benzil)-amin 2.33.c Dimethyl-(4-piperidin-4-yl-benzyl)-amine
6 g Pd/BaSO4 se doda u otopinu od 16 g (74 mmola) dimetil-[4-(1,2,3,6-tetrahidro-piridin-4-il)-benzil]-amina u 200 ml metanola. Otopinu se miješa 1 h pri sobnoj temperaturi u atmosferi vodika, katalizator se odfiltrira i otapalo odstrani na rotacijskom uređaju za isparavanje. Ostatak se otopi u metanolu, doda se metanolnu solnu kiselinu i zatim eter sve dok smjesa postane mutna. Nakon držanja pri -20°C dobiveni hidroklorid se odsisa. 6 g of Pd/BaSO4 was added to a solution of 16 g (74 mmol) of dimethyl-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-amine in 200 ml of methanol. The solution is stirred for 1 h at room temperature in a hydrogen atmosphere, the catalyst is filtered off and the solvent is removed on a rotary evaporator. The residue is dissolved in methanol, methanolic hydrochloric acid is added and then ether until the mixture becomes cloudy. After keeping at -20°C, the resulting hydrochloride is suctioned off.
Iskorištenje: 16 g (84,9%). Yield: 16 g (84.9%).
2.33.d 4-(4-dimetilaminometil-fenil)-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.33.d 4-(4-dimethylaminomethyl-phenyl)-piperidine-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-(4-dimetilaminometil-fenil)-piperidina (127 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-(4-dimethylaminomethyl-phenyl)-piperidine (127 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0, 50 mmol).
Iskorištenje: 37,0 mg (16,5% od teorijskog). Yield: 37.0 mg (16.5% of theoretical).
C28H40N4O (M = 448,657) C28H40N4O (M = 448.657)
Izračunato: molekulska masa (M+H)+: 449 Calculated: molecular weight (M+H)+: 449
Nađeno: molekulska masa (M+H)+: 449 Found: molecular weight (M+H)+: 449
Rf vrijednost: 0,37 (silika gel, diklormetan/metanol/NH3 9:1:0,1). Rf value: 0.37 (silica gel, dichloromethane/methanol/NH3 9:1:0.1).
Primjer 2.34: Example 2.34:
4'-klor-bifenil-4-il)-[3-(4-pirolidin-1-il-metil-fenil)-piperidin-1-il]-metanon 4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-yl-methyl-phenyl)-piperidin-1-yl]-methanone
[image] [image]
2.34.a 1-(4-brom-benzil)-pirolidin 2.34.a 1-(4-bromo-benzyl)-pyrrolidine
20,0 g (0,080 mola) 4-brombenzilbromida u THF-u se polako doda, kap po kap, u otopinu od 13,1 ml (0,16 mmola) pirolidina i 200 ml tetrahidrofurana, tako da temperatura ne poraste iznad 20oC. Reakcijsku otopinu se miješa preko noći i zatim se pomiješa s ledom i zakiseli se s koncentriranom solnom kiselinom. Nakon ekstrakcije s eterom vodenu fazu se zaluži s otopinom natrijevog hidroksida i zasiti se s kalijevim karbonatom. Nakon ekstrakcije s eterom, organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. 20.0 g (0.080 mol) of 4-bromobenzyl bromide in THF is slowly added, dropwise, to a solution of 13.1 ml (0.16 mmol) of pyrrolidine and 200 ml of tetrahydrofuran, so that the temperature does not rise above 20oC. The reaction solution was stirred overnight and then mixed with ice and acidified with concentrated hydrochloric acid. After extraction with ether, the aqueous phase is made alkaline with sodium hydroxide solution and saturated with potassium carbonate. After extraction with ether, the organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator.
Iskorištenje: 18,1 g (94,2% od teorijskog). Yield: 18.1 g (94.2% of theoretical).
C11H14BrN (M = 240,145) C11H14BrN (M = 240.145)
Izračunato: molekulska masa (M+H)+: 240/242 Calculated: molecular weight (M+H)+: 240/242
Nađeno: molekulska masa (M+H)+: 240/242 Found: molecular weight (M+H)+: 240/242
Rf vrijednost: 0,19 (silika gel, petrol eter/etil acetat 8:2). Rf value: 0.19 (silica gel, petroleum ether/ethyl acetate 8:2).
2.34.b 3-(4-pirolidin-1-ilmetil-fenil)-piridin 2.34.b 3-(4-pyrrolidin-1-ylmethyl-phenyl)-pyridine
1,11 g (4,64 mmola) 1-(4-brom-benzil)-pirolidina se otopi u 10 ml dioksana i 5 ml 2M otopine natrijevog karbonata. Uzastopce se doda 570 mg (4,64 mmola) piridin-3-borne kiseline i 270 mg (0,23 mmola) tetrakis-(trifenil-fosfin)-paladija i reakcijsku smjesu se refluktira 6 h. Reakcijsku otopinu se odsisa kroz filter od staklenih vlakana. Filtrat se ekstrahira nekoliko puta s etil acetatom. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. Daljnje čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: etil acetat/ metanol/NH3 = 8:2:0,1). 1.11 g (4.64 mmol) of 1-(4-bromo-benzyl)-pyrrolidine was dissolved in 10 ml of dioxane and 5 ml of 2M sodium carbonate solution. 570 mg (4.64 mmol) of pyridine-3-boronic acid and 270 mg (0.23 mmol) of tetrakis-(triphenyl-phosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The reaction solution is sucked off through a glass fiber filter. The filtrate is extracted several times with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (eluent: ethyl acetate/methanol/NH3 = 8:2:0.1).
Iskorištenje: 500 mg (45,2% od teorijskog). Yield: 500 mg (45.2% of the theoretical).
C16H18N2 (M = 238,335) C16H18N2 (M = 238.335)
Izračunato: molekulska masa (M+H)+: 239 Calculated: molecular weight (M+H)+: 239
Nađeno: molekulska masa (M+H)+: 239 Found: molecular weight (M+H)+: 239
2.34.c 3-(4-pirolidin-1 -ilmetil-fenil)-piperidin 2.34.c 3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine
4 ml 1M solne kiseline i 200 mg oksida platine doda se u otopinu od 500 mg (2,10 mmola) 3-(4-pirolidin-1-ilmetil-fenil)-piridina u 10 ml etanola. Reakcijsku smjesu se miješa 4,5 sata pri sobnoj temperature i pod 3 bara tlaka vodika. Nakon odvajanja katalizatora, otapalo se odstrani na rotacijskom uređaju za isparavanje, pri čemu se proizvod istaloži kao hidroklorid. 4 ml of 1M hydrochloric acid and 200 mg of platinum oxide were added to a solution of 500 mg (2.10 mmol) of 3-(4-pyrrolidin-1-ylmethyl-phenyl)-pyridine in 10 ml of ethanol. The reaction mixture is stirred for 4.5 hours at room temperature and under 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator, the product being precipitated as the hydrochloride.
Iskorištenje: 600 mg (100% od teorijskog). Yield: 600 mg (100% of theoretical).
C16H24N2·HCl (M = 280,844) C16H24N2·HCl (M = 280.844)
Izračunato: molekulska masa (M+H)+: 245 Calculated: molecular weight (M+H)+: 245
Nađeno: molekulska masa (M+H)+: 245 Found: molecular weight (M+H)+: 245
2.34.d (4'-klor-bifenil-4-il)-[3-(4-pirolidin-1-ilmetil-fenil)-piperidin-1-il]-metanon 2.34.d (4'-chloro-biphenyl-4-yl)-[3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-1-yl]-methanone
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (183 mg, 0,78 mmola) i 3-(4-pirolidin-1-ilmetil-fenil)-piperidina (200 mg, 0,71 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (183 mg, 0.78 mmol) and 3-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine (200 mg, 0, 71 mmol).
Iskorištenje: 20,0 mg (6,1% od teorijskog). Yield: 20.0 mg (6.1% of theoretical).
C29H31ClN2O (M = 459,036) C29H31ClN2O (M = 459.036)
Izračunato: molekulska masa (M+H)+: 459/461 Calculated: molecular weight (M+H)+: 459/461
Nađeno: molekulska masa (M+H)+: 459/461 Found: molecular weight (M+H)+: 459/461
Rf vrijednost: 0,58 (silika gel, etil acetat/metanol/NH3 Rf value: 0.58 (silica gel, ethyl acetate/methanol/NH3
9:1:0,1). 9:1:0,1).
Primjer 2.35: Example 2.35:
4'-klor-bifenil-4-karboksilna kiselina-[2-metil-2-(4-pirolidin-1-ilmetil-fenil)-propil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide
[image] [image]
2.35.a 2-metil-2-(4-pirolidin-1-ilmetil-fenil)-propionitril 2.35.a 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile
3,4 g (30 mmola) kalijevog terc-butoksida doda se u otopinu od 2,0 g (10,0 mmolova) (4-pirolidin-1-ilmetil-fenil)-acetonitrila (vidi 1,1,g) u 50 ml tetrahidrofuranu pri sobnoj temperaturi. Reakcijsku otopinu se kratko promiješa, zatim se pomiješa s 1,9 ml (30 mmolova) metil jodida, miješa se daljnjih 2 h pri sobnoj temperaturi i zatim se ispari do suhog na rotacijskom uređaju za isparavanje. Ostatak se podijeli između vode i etil acetata, organsku fazu se ispere s vodom i osuši preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i sirov proizvod dalje reagira bez čišćenja. 3.4 g (30 mmol) of potassium tert-butoxide was added to a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) in 50 ml of tetrahydrofuran at room temperature. The reaction solution was stirred briefly, then mixed with 1.9 ml (30 mmol) of methyl iodide, stirred for a further 2 h at room temperature and then evaporated to dryness on a rotary evaporator. The residue is divided between water and ethyl acetate, the organic phase is washed with water and dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the crude product is further reacted without purification.
Iskorištenje: 1,4 g (61,3% od teorijskog). Yield: 1.4 g (61.3% of theoretical).
C15H20N22 (M = 228,340) C15H20N22 (M = 228.340)
Izračunato: molekulska masa (M+H)+: 229 Calculated: molecular weight (M+H)+: 229
Nađeno: molekulska masa (M+H)+: 229 Found: molecular weight (M+H)+: 229
Rf vrijednost: 0,40 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.35.b 2-metil-2-(4-pirolidin-1-ilmetil-fenil)-propilamin 2.35.b 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine
150 mg Raney nikela se doda u otopinu od 1,4 g (6,13 mmolova) 2-metil-2-(4-pirolidin-1-ilmetil-fenil)-propio-nitrila u 20 ml metanolne otopine amonijaka. Reakcijsku smjesu se miješa preko noći pri 50°C pod tlakom od 5 bara atmosfere vodika. Kad se katalizator odfiltrira, otapalo se odstrani na rotacijskom uređaju za isparavanje. 150 mg of Raney nickel was added to a solution of 1.4 g (6.13 mmol) of 2-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile in 20 ml of methanolic ammonia solution. The reaction mixture is stirred overnight at 50°C under a pressure of 5 bar hydrogen atmosphere. When the catalyst is filtered off, the solvent is removed on a rotary evaporator.
Iskorištenje: 1,4 g (98,3% od teorijskog). Yield: 1.4 g (98.3% of theoretical).
C15H24N2 (M = 232,372) C15H24N2 (M = 232.372)
Izračunato: molekulska masa (M+H)+: 233 Calculated: molecular weight (M+H)+: 233
Nađeno: molekulska masa (M+H)+: 233 Found: molecular weight (M+H)+: 233
Rf vrijednost: 0,30 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.35.c 4'-klor-bifenil-4-karboksilna kiselina-[2-metil-2-(4-pirolidin-1-il metil-fenil )-propil]-amid 2.35.c 4'-chloro-biphenyl-4-carboxylic acid-[2-methyl-2-(4-pyrrolidin-1-yl methyl-phenyl)-propyl]-amide
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (233 mg, 1,0 mmola) i 2-metil-2-(4-pirolrdin-1-ilmetil-fenil)-propilamina (232 mg, 1,0 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (233 mg, 1.0 mmol) and 2-methyl-2-(4-pyrrolrdin-1-ylmethyl-phenyl)-propylamine (232 mg, 1.0 mmol).
Iskorištenje: 400 mg (89,5% od teorijskog). Yield: 400 mg (89.5% of theoretical).
C28H31ClN2O (M = 447,025) C28H31ClN2O (M = 447.025)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Rf vrijednost: 0,35 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.35 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.36: Example 2.36:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-propil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide
[image] [image]
2.36.a 2-(4-pirolidin-1-ilmetil-fenil)-propionitril 2.36.a 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile
1,12 g (10 mmolova) kalijevog terc-butoksida se doda u otopinu od 2,0 g (10,0 mmolova) (4-pirolidin-1-ilmetil-fenil)-acetonitrila (vidi 1.1.g) u 50 ml tetrahidrofurana pri sobnoj temperaturi. Reakcijsku otopinu se miješa 30 min i zatim se pomiješa s 0,63 ml (10 mmolova) metil jodida. Reakcijsku smjesu se miješa 1 h pri 50oC i zatim se koncentrira do suhog na rotacijskom uređaju za isparavanje. Ostatak se podijeli između vode i etil acetata, organsku fazu se ispere dva puta s vodom i osuši preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i sirov proizvod koji sadrži pribl. 20% dimetiliranog spoja dalje reagira bez čišćenje. 1.12 g (10 mmol) of potassium tert-butoxide is added to a solution of 2.0 g (10.0 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) in 50 ml of tetrahydrofuran at room temperature. The reaction solution was stirred for 30 min and then mixed with 0.63 ml (10 mmol) of methyl iodide. The reaction mixture was stirred for 1 h at 50°C and then concentrated to dryness on a rotary evaporator. The residue is divided between water and ethyl acetate, the organic phase is washed twice with water and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the crude product containing approx. 20% of the dimethylated compound reacts further without purification.
Iskorištenje: 0,5 g (23,3% od teorijskog). Yield: 0.5 g (23.3% of theoretical).
C14H18N2 (M = 214,313) C14H18N2 (M = 214.313)
Izračunato: molekulska masa (M+H)+: 215 Calculated: molecular weight (M+H)+: 215
Nađeno: molekulska masa (M+H)+: 215 Found: molecular weight (M+H)+: 215
Rf vrijednost: 0,40 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.40 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.36.b 2-(4-pirolidin-1-ilmetil-fenil)-propilamin 2.36.b 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine
100 mg Raney nikla se doda u otopinu od 400 mg (1,87 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-propionitrila u 20 ml metanolne otopine amonijaka. Reakcijsku smjesu se miješa preko noći pri 50°C i 5 bara atmosfere vodika. Kad se katalizator odfiltrira, otapalo se odstrani na rotacijskom uređaju za isparavanje. Amin, koji sadrži pribl. 20% dimetiliranog spoja, dalje reagira bez ikakvog daljnjeg čišćenja. 100 mg of Raney nickel was added to a solution of 400 mg (1.87 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propionitrile in 20 ml of methanolic ammonia solution. The reaction mixture is stirred overnight at 50°C and 5 bar hydrogen atmosphere. When the catalyst is filtered off, the solvent is removed on a rotary evaporator. Amine, containing approx. 20% of the dimethylated compound, reacts further without any further purification.
Iskorištenje: 0,4 g (98,6% od teorijskog). Yield: 0.4 g (98.6% of theoretical).
C15H22N2 (M = 218,345) C15H22N2 (M = 218.345)
Izračunato: molekulska masa (M+H)+: 219 Calculated: molecular weight (M+H)+: 219
Nađeno: molekulska masa (M+H)+: 219 Found: molecular weight (M+H)+: 219
Rf vrijednost: 0,30 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.30 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.36.c 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-propil]-amid 2.36.c 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-propyl]-amide
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (233 mg, 1,0 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-propilamina (218 mg, 1,0 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (233 mg, 1.0 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-propylamine (218 mg, 1, 0 mmol).
Iskorištenje: 10 mg (2,3% od teorijskog). Yield: 10 mg (2.3% of theoretical).
C28H31ClN2O (M = 447,025) C28H31ClN2O (M = 447.025)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Rf vrijednost: 0,35 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.35 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.37: Example 2.37:
4'-klor-bifenil-4-karboksilna kiselina-(4-pirolidin-1-ilmetil-benziloksi)-amid 4'-chloro-biphenyl-4-carboxylic acid-(4-pyrrolidin-1-ylmethyl-benzyloxy)-amide
[image] [image]
2.37.a 2-(4-pirolidin-1-ilmetil-benziloksi)-izoindol-1,3-dion 2.37.a 2-(4-pyrrolidin-1-ylmethyl-benzyloxy)-isoindol-1,3-dione
Smjesu od 8,2 g (50 mmolova) N-hidroksi-ftalimida i 8,7 ml (50 mmola) Hünigove baze u 125 ml acetonitrila doda se pri sobnoj temperaturi u otopinu od 13,2 g (50 mmolova) α,α'-dibrom-p-ksilena u 125 ml acetonitrila. Reakcijsku otopinu se miješa 10 min, zatim se doda 4,1 ml (50 mmolova) pirolidina i miješanje se nastavi još jedan sat. Kad se matičnicu profiltrira, ispari se do suhog na rotacijskom uređaju za isparavanje. Ostatak se očisti kromatografijom na silika gelu (sredstvo za ispiranje: etil acetat/metanol/ amonijak). Ova tvar dalje reagira neposredno nakon čišćenja. A mixture of 8.2 g (50 mmol) of N-hydroxyphthalimide and 8.7 ml (50 mmol) of Hünig's base in 125 ml of acetonitrile was added at room temperature to a solution of 13.2 g (50 mmol) of α,α' -dibromo-p-xylene in 125 ml of acetonitrile. The reaction solution was stirred for 10 min, then 4.1 ml (50 mmol) of pyrrolidine was added and the stirring was continued for another hour. When the royal jelly is filtered, it is evaporated to dryness on a rotary evaporator. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia). This substance reacts further immediately after cleaning.
Iskorištenje: 1,0 g (5,9% od teorijskog). Yield: 1.0 g (5.9% of theoretical).
Rf vrijednost: 0,60 (Alox, etil acetat/petrol eter 1:1). Rf value: 0.60 (Alox, ethyl acetate/petroleum ether 1:1).
2.37.b O-(4-pirolidin-1-ilmetil-benzil)-hidroksilamin 2.37.b O-(4-pyrrolidin-1-ylmethyl-benzyl)-hydroxylamine
50 ml 40%-tne otopine metilamina u vodi doda se u otopinu od 1,0 g (2,97 mmola) 2-(4-pirolidin-1-ilmetil-benziloksi)-izoindol-1,3-diona u 50 ml toluena i smjesu se miješa 2,5 dana pri sobnoj temperaturi. Nakon odvajanja organske faze, vodenu fazu se ekstrahira dva puta s terc-butilmetil eterom. Sjedinjene organske faze se isperu s vodom i osuše preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i dobiveni proizvod dalje reagira bez čišćenja. 50 ml of a 40% solution of methylamine in water is added to a solution of 1.0 g (2.97 mmol) of 2-(4-pyrrolidin-1-ylmethyl-benzyloxy)-isoindol-1,3-dione in 50 ml of toluene. and the mixture was stirred for 2.5 days at room temperature. After separation of the organic phase, the aqueous phase is extracted twice with tert-butylmethyl ether. The combined organic phases are washed with water and dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the resulting product reacts further without purification.
Iskorištenje: 260 mg (42,4% od teorijskog). Yield: 260 mg (42.4% of theoretical).
C12H18N2O (M= 206,290) C12H18N2O (M= 206.290)
Izračunato: molekulska masa (M+H)+: 207 Calculated: molecular weight (M+H)+: 207
Nađeno: molekulska masa (M+H)+: 207 Found: molecular weight (M+H)+: 207
2.37.c 4'-klor-bifenil-4-karboksilna kiselina-(4-pirolidin-1-ilmetil-benziloksi)-amid 2.37.c 4'-chloro-biphenyl-4-carboxylic acid-(4-pyrrolidin-1-ylmethyl-benzyloxy)-amide
Proizveden je prema općem radnom postupku I iz 4'-klora-bifenil-4-karboksilne kiseline (116 mg, 0,5 mmola) i O-(4-pirolidin-1-ilmetil-benzil)-hidroksilamina (103 mg, 0,5 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and O-(4-pyrrolidin-1-ylmethyl-benzyl)-hydroxylamine (103 mg, 0, 5 mmol).
Iskorištenje: 10,0 mg (4,8% od teorijskog). Yield: 10.0 mg (4.8% of theoretical).
C29H25ClN2O2 (M = 420,943) C29H25ClN2O2 (M = 420.943)
Izračunato: molekulska masa (M+H)+: 421/423 Calculated: molecular weight (M+H)+: 421/423
Nađeno: molekulska masa (M+H)+: 421/423 Found: molecular weight (M+H)+: 421/423
Rf vrijednost: 0,38 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.38: Example 2.38:
4'-klor-bifenil-4-karboksilna kiselina-[1,1-dimetil-2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.38.a Etil (4-pirolidin-1-ilmetil-fenil)-acetat 2.38.a Ethyl (4-pyrrolidin-1-ylmethyl-phenyl)-acetate
3,0 g (15 mmolova) (4-pirolidin-1-ilmetil-fenil)-acetonitrila (vidi 1.1.g) se otopi u etanolnoj solnoj kiselini (zasićenoj) i refluktira se 4 sata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i ostatak se preuzme s razrijeđenom otopinom NaHCO3 i terc-butilmetil eterom. Organsku fazu se osuši s natrijevim sulfatom, odsisa se kroz aktivirani ugljen i zatim se otapalo odstrani na rotacijskom uređaju za isparavanje. 3.0 g (15 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (see 1.1.g) is dissolved in ethanolic hydrochloric acid (saturated) and refluxed for 4 hours. The solvent was removed on a rotary evaporator and the residue was taken up with dilute NaHCO3 solution and tert-butylmethyl ether. The organic phase is dried with sodium sulfate, filtered off with suction through activated carbon, and then the solvent is removed on a rotary evaporator.
Iskorištenje: 3,4 g (91,6% od teorijskog). Yield: 3.4 g (91.6% of theoretical).
C15H21NO2 (M = 247,340) C15H21NO2 (M = 247,340)
Izračunato: molekulska masa (M+H)+: 248 Calculated: molecular weight (M+H)+: 248
Nađeno: molekulska masa (M+H)+: 248 Found: molecular weight (M+H)+: 248
Rf vrijednost: 0,25 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.25 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.38.b 2-metil-1-(4-pirolidin-1-ilmetil-fenil)-propan-2-ol 2.38.b 2-methyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-2-ol
3,4 g (13,8 mmolova) etil (4-pirolidin-1-ilmetil-fenil)-acetata u 20 ml tetrahidrofurana doda se kap po kap u 13,3 ml (40 mmolova) 3,0 M otopine metilmagnezijevog klorida u tetrahidrofuranu pri sobnoj temperaturi. Temperatura poraste na 40°C. Reakcijsku smjesu se miješa jedan sat i zatim se prelije na 100 ml otopine amonijevog klorida. Vodenu fazu se ekstrahira nekoliko puta s diklor-metanom. Sjedinjene organske faze se isperu sa zasićenom otopinom NaCl i osuše se preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i ostatak se očisti kromatografijom na stupcu Alox (aktivnosti 2-3) (sredstvo za ispiranje: cikloheksan:etil acetat 4:1). 3.4 g (13.8 mmol) of ethyl (4-pyrrolidin-1-ylmethyl-phenyl)-acetate in 20 ml of tetrahydrofuran was added dropwise to 13.3 ml (40 mmol) of a 3.0 M solution of methylmagnesium chloride in tetrahydrofuran at room temperature. The temperature rises to 40°C. The reaction mixture was stirred for one hour and then poured onto 100 ml of ammonium chloride solution. The aqueous phase is extracted several times with dichloromethane. The combined organic phases are washed with saturated NaCl solution and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was purified by chromatography on an Alox column (activities 2-3) (eluent: cyclohexane:ethyl acetate 4:1).
Iskorištenje: 800 mg (24,9% od teorijskog). Yield: 800 mg (24.9% of theoretical).
C15H23NO (M = 233,357) C15H23NO (M = 233.357)
Izračunato: molekulska masa (M+H)+: 234 Calculated: molecular weight (M+H)+: 234
Nađeno: molekulska masa (M+H)+: 234 Found: molecular weight (M+H)+: 234
Rf vrijednost: 0,50 (Alox, petrol eter/etil acetat 6:4). Rf value: 0.50 (Alox, petroleum ether/ethyl acetate 6:4).
2.38.c N-[1,1-dimetil-2-(4-pirolidin-1-ilmetil-fenil)-etil]-formamid 2.38.c N-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-formamide
Mješavinu od 2 ml sumporne kiseline i 1 ml ledene octene kiseline doda se kap po kap u otopinu od 250 mg (5,0 mmolova) natrijevog cijanida u 2 ml ledene octene kiseline tako da temperatura reakcijske smjese ne poraste iznad 20°C. Zatim se doda kap po kap 800 mg (3,43 mmola) 2-metil-1-(4-pirolidin-1-ilmetil-fenil)-propan-2-ola u 2 ml ledene octene kiseline. Temperaturu se drži ispod 20oC. Reakcijsku otopinu se miješa jedan sat pri sobnoj temperaturi i zatim se prelije na led i neutralizira s otopinom natrijevog karbonata. Vodenu fazu se ekstrahira s eterom i organsku fazu se osuši preko magnezijevog sulfata. Otapalo se odstrani na rotacijskom uređaju za isparavanje i proizvod dalje reagira bez čišćenje. A mixture of 2 ml of sulfuric acid and 1 ml of glacial acetic acid is added drop by drop to a solution of 250 mg (5.0 mmol) of sodium cyanide in 2 ml of glacial acetic acid so that the temperature of the reaction mixture does not rise above 20°C. Then 800 mg (3.43 mmol) of 2-methyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-2-ol in 2 ml of glacial acetic acid was added dropwise. The temperature is kept below 20oC. The reaction solution is stirred for one hour at room temperature and then poured onto ice and neutralized with sodium carbonate solution. The aqueous phase is extracted with ether and the organic phase is dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the product reacts further without purification.
Iskorištenje: 520 mg (58.2% od teorijskog). Yield: 520 mg (58.2% of theoretical).
C16H24N2O (M = 260,382) C16H24N2O (M = 260.382)
Izračunato: molekulska masa (M+H)+: 261 Calculated: molecular weight (M+H)+: 261
Nađeno: molekulska masa (M+H)+: 261 Found: molecular weight (M+H)+: 261
2.38.d 1,1-dimetil-2-(4-pirolidin-1-ilmetil-fenil)-etilamin 2.38.d 1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine
25 ml konc. solne kiseline doda se u otopinu od 520 mg (2 mmola) N-[1,1-dimetil-2-(4-pirolidin-1-ilmetil-fenil)-etil]-formamida u 10 ml etanola i smjesu se refluktira preko noći. Reakcijsku otopinu se ohladi i zatim se zaluži s 25% vodenom otopinom natrijevog hidroksida i vodenu fazu se ekstrahira nekoliko puta s terc-butilmetil eterom. Sjedinjene organske faze se isperu s vodom, osuše se preko magnezijevog sulfata i filtriraju kroz aktivirani ugljen. Otapalo se odstrani na rotacijskom uređaju za isparavanje. 25 ml conc. of hydrochloric acid is added to a solution of 520 mg (2 mmol) of N-[1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-formamide in 10 ml of ethanol and the mixture is refluxed overnight . The reaction solution was cooled and then basified with 25% aqueous sodium hydroxide solution and the aqueous phase was extracted several times with tert-butylmethyl ether. The combined organic phases are washed with water, dried over magnesium sulfate and filtered through activated carbon. The solvent was removed on a rotary evaporator.
Iskorištenje: 380 mg (81,8% od teorijskog). Yield: 380 mg (81.8% of theoretical).
C15H24N2 (M = 232,372) C15H24N2 (M = 232.372)
Izračunato: molekulska masa (M+H)+: 233 Calculated: molecular weight (M+H)+: 233
Nađeno: molekulska masa (M+H)+: 233 Found: molecular weight (M+H)+: 233
Rf vrijednost: 0,10 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.10 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
2.38.e 4'-klor-bifenil-4-karboksilna kiselina-[1,1-di-metil-2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.38.e 4'-chloro-biphenyl-4-carboxylic acid-[1,1-di-methyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (116 mg, 0,5 mmola) i 1,1-dimetil-2-(4-pirolidin-1-ilmetil-fenil)-etilamina (116 mg, 0,5 mmola). It was produced according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.5 mmol) and 1,1-dimethyl-2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (116 mg, 0.5 mmol).
Iskorištenje: 73,0 mg (32,7% od teorijskog. Yield: 73.0 mg (32.7% of the theoretical.
C28H31ClN2O2 (M = 447,025) C28H31ClN2O2 (M = 447.025)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Rf vrijednost: 0,48 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.48 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.39: Example 2.39:
4'-klor-bifenil-4-karboksilna kiselina-4-(2-piirolidin-1-il-etil)-benzilamid 4'-chloro-biphenyl-4-carboxylic acid-4-(2-pyrrolidin-1-yl-ethyl)-benzylamide
[image] [image]
2.39.a 4-(2-pirolidin-1-il-etil)-benzonitril 2.39.a 4-(2-pyrrolidin-1-yl-ethyl)-benzonitrile
91 mg (0,56 mmola) kalijevog jodida, 453 mg (3,28 mmola) kalijevog karbonata i 0,33 ml (2,74 mmola) 1,4-dibrom-butana doda se uzastopce u otopinu od 500 mg (2,74 mmola) 4-(2-amino-etil)-benzonitrila u 50 ml acetonitrila. Reakcijsku smjesu se miješa 6 h pri 78°C. Zatim se doda drugih 0,08 ml (0,66 mmola) 1,4-dibrombutana i reakcijsku smjesu se miješa preko noći pri 78°C. Nakon filtracije, filtrat se ispari do suhog. Daljnje čišćenje se vrši kromatografijom na stupcu silika gela (diklormetan/metanol 8:2). 91 mg (0.56 mmol) of potassium iodide, 453 mg (3.28 mmol) of potassium carbonate and 0.33 ml (2.74 mmol) of 1,4-dibromobutane were added successively to a solution of 500 mg (2, 74 mmol) of 4-(2-amino-ethyl)-benzonitrile in 50 ml of acetonitrile. The reaction mixture was stirred for 6 h at 78°C. Another 0.08 ml (0.66 mmol) of 1,4-dibromobutane was then added and the reaction mixture was stirred overnight at 78°C. After filtration, the filtrate is evaporated to dryness. Further purification is performed by chromatography on a silica gel column (dichloromethane/methanol 8:2).
Iskorištenje: 183,0 mg (33,4% od teorijskog). Yield: 183.0 mg (33.4% of theoretical).
C13H16N2 (M = 200,286) C13H16N2 (M = 200.286)
Izračunato: molekulska masa (M+H)+: 201 Calculated: molecular weight (M+H)+: 201
Nađeno: molekulska masa (M+H)+: 201 Found: molecular weight (M+H)+: 201
2.39.b 4-(2-pirolidin-1-il-etil)-benzilamin 2.39.b 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine
75 mg Raney nikla se doda u otopinu od 183 mg (0,91 mmola) 4-(2-pirolidin-1-il-etil)-benzonitrila u 20 ml etanolne otopine amonijaka. Reakcijsku otopinu se miješa preko noći pri 50°C i 3 bara tlaka vodika. Doda se drugih 75 mg Raney nikla i smjesu se miješa još daljnjih 6 h pri 50°C i 3 bara tlaka vodika. Katalizator se odfiltrira i otapalo se odstrani na rotacijskom isparivaču. Sirov proizvod se može upotrijebiti bez daljnjeg čišćenja. 75 mg of Raney nickel was added to a solution of 183 mg (0.91 mmol) of 4-(2-pyrrolidin-1-yl-ethyl)-benzonitrile in 20 ml of ethanolic ammonia solution. The reaction solution is stirred overnight at 50°C and 3 bar hydrogen pressure. Another 75 mg of Raney nickel was added and the mixture was stirred for a further 6 h at 50°C and 3 bar hydrogen pressure. The catalyst is filtered off and the solvent is removed on a rotary evaporator. The raw product can be used without further purification.
Iskorištenje: 114,0 mg (61,0% od teorijskog). Yield: 114.0 mg (61.0% of theory).
C13H20N2 (M =204,318) C13H20N2 (M = 204.318)
Izračunato: molekulska masa (M+H)+: 205 Calculated: molecular weight (M+H)+: 205
Nađeno: molekulska masa (M+H)+: 205 Found: molecular weight (M+H)+: 205
2.39.c 4'-klor-bifenil-4-karboksilna kiselina-4-(2-pirolidin-1 -il-etil)-benzilamid 2.39.c 4'-chloro-biphenyl-4-carboxylic acid-4-(2-pyrrolidin-1-yl-ethyl)-benzylamide
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (130 mg, 0,56 mmola) i 4-(2-pirolidin-1-il-etil)-benzilamina (114 mg, 0,56 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (130 mg, 0.56 mmol) and 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine (114 mg, 0, 56 mmol).
Iskorištenje: 75,0 mg (32,1% od teorijskog). Yield: 75.0 mg (32.1% of theoretical).
C26H27ClN2O (M = 418,971) C26H27ClN2O (M = 418.971)
Izračunato: molekulska masa (M+H)+: 419/421 Calculated: molecular weight (M+H)+: 419/421
Nađeno: molekulska masa (M+H)+: 419/421 Found: molecular weight (M+H)+: 419/421
Rf vrijednost: 0,38 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.40: Example 2.40:
[image] [image]
2.40.a [1,4']bipiperidinil-1'-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.40.a [1,4']bipiperidinyl-1'-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-piperidinopiperidina (84,1 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola). It was prepared according to general procedure II from 4-piperidinopiperidine (84.1 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol).
Iskorištenje: 3,0 mg (1,5% od teorijskog). Yield: 3.0 mg (1.5% of theoretical).
C24H38N4O (M = 398,597) C24H38N4O (M = 398.597)
Izračunato: molekulska masa (0,5 M+H)+: 200 Calculated: molecular weight (0.5 M+H)+: 200
Nađeno: molekulska masa (0,5 M+H)+: 200 Found: Molecular Weight (0.5 M+H)+: 200
Vrijeme retencije HPLC: 1,59 min (metoda A) HPLC retention time: 1.59 min (method A)
Primjer 2.41: Example 2.41:
[image] [image]
2.41.a 4-cikloheksil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.41.a 4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 4-ciklo-heksilbenzojeve kiseline (102 mg, 0,50 mmola) i 4-(2-pirolidin-1-il-etil)-benzilamina (102 mg, 0,50 mmola). Iskorištenje: 2,0 mg (1,0% od teorijskog). It was prepared according to general procedure I from 4-cyclohexylbenzoic acid (102 mg, 0.50 mmol) and 4-(2-pyrrolidin-1-yl-ethyl)-benzylamine (102 mg, 0.50 mmol). Yield: 2.0 mg (1.0% of theoretical).
C26H34N2O (M= 390,574) C26H34N2O (M= 390.574)
Izračunato: molekulska masa (M+H)+: 391 Calculated: molecular weight (M+H)+: 391
Nađeno: molekulska masa (M+H)+: 391 Found: molecular weight (M+H)+: 391
Rf vrijednost: 0,38 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.38 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.42: Example 2.42:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-cikloheksil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide
[image] [image]
2.42.a 2-(4-pirolidin-1 -ilmetil-cikloheksil)-etilamin 2.42.a 2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethylamine
1,52 ml konc. solne kiseline i 300 mg oksida platine doda se u otopinu od 500 mg (2,45 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (vidi primjer 1.1.h) u 10 ml metanola. Reakcijsku smjesu se miješa 50 h pri 50°C i pod 5 bara tlaka vodika. Nakon ovajanja katalizatora, otapalo se odstrani na rotacijskom uređaju za isparavanje. Daljnje čišćenje se vrši kromatografijom na stupcu silika gela (diklormetan/metanol/amonijak 8:2:0,2). 1.52 ml conc. hydrochloric acid and 300 mg of platinum oxide are added to a solution of 500 mg (2.45 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (see example 1.1.h) in 10 ml of methanol. The reaction mixture was stirred for 50 h at 50°C and under 5 bar hydrogen pressure. After coating the catalyst, the solvent is removed on a rotary evaporator. Further purification is performed by chromatography on a silica gel column (dichloromethane/methanol/ammonia 8:2:0.2).
Iskorištenje: 130 mg (25,3% od teorijskog). Yield: 130 mg (25.3% of theoretical).
C13H26N2 (M = 210,366) C13H26N2 (M = 210.366)
Izračunato: molekulska masa (M+H)+: 211 Calculated: molecular weight (M+H)+: 211
Nađeno: molekulska masa (M+H)+: 211 Found: molecular weight (M+H)+: 211
Rf vrijednost: 0,14 (silika gel, diklormetan/metanol/NH3 8:2:0,2). Rf value: 0.14 (silica gel, dichloromethane/methanol/NH3 8:2:0.2).
2.42.b 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-cikloheksil)-etil]-amid 2.42.b 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 4'-klor-bifenil-4-karboksilne kiseline (116 mg, 0,50 mmola) i 2-(4-pirolidin-1-ilmetil-cikloheksil)-etilamina (105 mg, 0,50 mmola). It was prepared according to general procedure I from 4'-chloro-biphenyl-4-carboxylic acid (116 mg, 0.50 mmol) and 2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethylamine (105 mg, 0, 50 mmol).
Iskorištenje: 53,0 mg (24,9% od teorijskog). Yield: 53.0 mg (24.9% of theoretical).
C26H33ClN2O (M = 425,019) C26H33ClN2O (M = 425.019)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Rf vrijednost: 0,16 (silika gel, etil acetat/metanol/NH3 9:1:0,1). Rf value: 0.16 (silica gel, ethyl acetate/methanol/NH3 9:1:0.1).
Primjer 2.43: Example 2.43:
4'-klor-bifenil-4-karboksilna kiselina-[2-(3-metoksi-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.43.a 4-cijanometil-2-metoksi-benzojeva kiselina 2.43.a 4-cyanomethyl-2-methoxy-benzoic acid
Proizvedena je analogno primjeru 1.1.d iz metil 4-cijanometil-2-metoksi-benzoata. It is produced analogously to example 1.1.d from methyl 4-cyanomethyl-2-methoxy-benzoate.
Iskorištenje: 6,5 g (69,8% od teorijskog). Yield: 6.5 g (69.8% of theoretical).
C10H9NO3 (M = 191,18) C10H9NO3 (M = 191.18)
Izračunato: molekulska masa (M+H)+: 192 Calculated: molecular weight (M+H)+: 192
Nađeno: molekulska masa (M+H)+: 192 Found: molecular weight (M+H)+: 192
Rf vrijednost: 0,64 (silika gel, diklormetan/etanol 10:1). Rf value: 0.64 (silica gel, dichloromethane/ethanol 10:1).
2.43.b (4-hidroksimetil-3-metoksi-fenil)-acetonitril 2.43.b (4-hydroxymethyl-3-methoxy-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.e iz 4-cijano-metil-2-metoksi-benzojeve kiseline. It is produced analogously to example 1.1.e from 4-cyano-methyl-2-methoxy-benzoic acid.
Iskorištenje: 4,81 g (81% od teorijskog). Yield: 4.81 g (81% of theoretical).
C10H11NO2 (M = 177,20) C10H11NO2 (M = 177.20)
Izračunato: molekulska masa (M)+: 177 Calculated: Molecular Weight (M)+: 177
Nađeno: molekulska masa (M)+: 177 Found: Molecular Weight (M)+: 177
2.43.c (4-brom-metil-3-metoksi-fenil)-acetonitril 2.43.c (4-bromo-methyl-3-methoxy-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.f iz (4-hidroksi-metil-3-metoksi-fenilj-acetonitrila. It was produced analogously to example 1.1.f from (4-hydroxy-methyl-3-methoxy-phenyl-acetonitrile.
Iskorištenje: 4,2 g (64,6% od teorijskog). Yield: 4.2 g (64.6% of theoretical).
C10H10BrNO (M = 240,10) C10H10BrNO (M = 240.10)
Izračunato: molekulska masa (M)+: 239/241 Calculated: molecular weight (M)+: 239/241
Nađeno: molekulska masa (M)+: 239/241 Found: molecular weight (M)+: 239/241
Rf vrijednost: 0,84 (silika gel, diklormetan/etanol 50:1). Rf value: 0.84 (silica gel, dichloromethane/ethanol 50:1).
2.43.d (3-metoksi-4-pirolidin-1-ilmetil-fenil)-acetonitril 2.43.d (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile
Proizveden je analogno primjeru 1.1.g iz (4-brom-metil-3-metoksi-fenil)-acetonitrila i piperidina. It was produced analogously to example 1.1.g from (4-bromo-methyl-3-methoxy-phenyl)-acetonitrile and piperidine.
Iskorištenje: 0,95 g (24,2% od teorijskog). Yield: 0.95 g (24.2% of theoretical).
C14H18N2O (M = 230,31) C14H18N2O (M = 230.31)
Izračunato: molekulska masa (M+H)+: 231 Calculated: molecular weight (M+H)+: 231
Nađeno: molekulska masa (M+H)+: 231 Found: molecular weight (M+H)+: 231
2.43.e (3-metoksi-4-pirolidin-1-ilmetil-fenil)-etilamin 2.43.e (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine
Proizveden je analogno primjeru 1.1.h iz (3-metoksi-4-pirolidin-1-ilmetil-fenil)-acetonitrila. Sirov proizvod dalje reagira neposredno bez čišćenja. It was produced analogously to example 1.1.h from (3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile. The crude product further reacts directly without cleaning.
2.43.f 4'-klor-bifenil-4-karboksilna kiselina-[2-(3-metoksi-4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.43.f 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 2-(3-metoksi-4-pirolidin-1-ilmetil-fenil)-etilamina i 4'-klor-bifenil-4-karboksilne kiseline. It is produced according to general procedure I from 2-(3-methoxy-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 4'-chloro-biphenyl-4-carboxylic acid.
Iskorištenje: 0,5 g (86,2% od teorijskog). Yield: 0.5 g (86.2% of theoretical).
Talište: 162-163oC Melting point: 162-163oC
C27H29ClN2O2 (M = 448,99) C27H29ClN2O2 (M = 448.99)
Izračunato: molekulska masa (M+H)+: 449/451 Calculated: molecular weight (M+H)+: 449/451
Nađeno: molekulska masa (M+H)+: 449/451 Found: molecular weight (M+H)+: 449/451
Rf vrijednost: 0,85 (silika gel, diklormetan/etanol/amonijak 5:1:0,1). Rf value: 0.85 (silica gel, dichloromethane/ethanol/ammonia 5:1:0.1).
Primjer 2.44: Example 2.44:
4'-klor-bifenil-4-karboksilna kiselina-[2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.44.a (E)-3-(4-cijano-2-fluor-fenil)-akrilna kiselina 2.44.a (E)-3-(4-cyano-2-fluoro-phenyl)-acrylic acid
2,75 g (10 mmolova) paladijevog acetata i 7,0 g (25 mmolova) tri-o-tolilfosfana doda se u otopinu od 20,0 g (100 mmolova) 4-brom-3-fluor-benzonitrila u 200 ml DMF-a. Zatim se doda 50 ml trietilamina i 30 ml (30 mmolova) etil akrilata. Reakcijsku smjesu se miješa 3 h pri 100°C. Kad se ohladi, razrijedi se sa 400 ml diklormetana i ispere dva puta s vodom. Otapalo se odstrani na rotacijskom uređaju za isparavanje i ostatak se preuzme u 250 ml metanola uz grijanje. Netopivi sastojci se odsisaju filtracijom kroz dijatomejsku zemlju i filtrat se ispari na polovicu na rotacijskom uređaju za isparavanje. Nakon ponovne filtracije pomiješa se sa 150 ml THF-a, 100 ml MeOH i 43 ml 2N NaOH i miješa se 2 h pri sobnoj temperaturi. Otapalo se odstrani na rotacijskom uređaju za isparavanje i ostatak se pomiješa sa 100 ml vode. Nakon ekstrakcije s eterom, vodenu fazu se zakiseli s konc. solnom kiselinom. Kristaliničan talog se otopi u 300 ml toplog etil acetata, a vodenu fazu se odvoji. Etil acetat se izdestilira i dobiveni kristali se suspendiraju u eteru i odsisaju. 2.75 g (10 mmol) of palladium acetate and 7.0 g (25 mmol) of tri-o-tolylphosphane were added to a solution of 20.0 g (100 mmol) of 4-bromo-3-fluoro-benzonitrile in 200 ml of DMF. -And. Then 50 ml of triethylamine and 30 ml (30 mmol) of ethyl acrylate are added. The reaction mixture was stirred for 3 h at 100°C. When it cools down, it is diluted with 400 ml of dichloromethane and washed twice with water. The solvent was removed on a rotary evaporator and the residue was taken up in 250 ml of methanol with heating. The insolubles are suctioned off by filtration through diatomaceous earth and the filtrate is evaporated to half on a rotary evaporator. After repeated filtration, it is mixed with 150 ml of THF, 100 ml of MeOH and 43 ml of 2N NaOH and stirred for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was mixed with 100 ml of water. After extraction with ether, the aqueous phase was acidified with conc. hydrochloric acid. The crystalline precipitate is dissolved in 300 ml of warm ethyl acetate, and the aqueous phase is separated. Ethyl acetate is distilled off and the resulting crystals are suspended in ether and filtered off with suction.
Iskorištenje: 11,5 g (60,2% od teorijskog). Yield: 11.5 g (60.2% of theoretical).
Talište: 214-218°C. Melting point: 214-218°C.
2.44.b 3-(4-cijano-2-fluor-fenil)-propionska kiselina 2.44.b 3-(4-cyano-2-fluoro-phenyl)-propionic acid
Otopinu od 11,5 g (60 mmolova) (E)-3-(4-cijano-2-fluor-fenil)-akrilne kiseline u 200 ml vode pomiješa se sa 4,0 g 5% Pd/C i 24,4 g kalijevog karbonata. Smjesu se mućka 6 h pri sobnoj temperaturi i pod normalnim tlakom vodika u autoklavu. Kad se katalizator odsisa, matičnicu se zakiseli s konc. solnom kiselinom. Istaloženi kristali se otope u 250 ml toplog etil acetata i osuše, i etil acetat se izdestilira. Dobiveni kristali se pomiješaju s eter/ heksanom i odsisaju. A solution of 11.5 g (60 mmol) of (E)-3-(4-cyano-2-fluoro-phenyl)-acrylic acid in 200 ml of water was mixed with 4.0 g of 5% Pd/C and 24.4 g of potassium carbonate. The mixture is shaken for 6 h at room temperature and under normal hydrogen pressure in an autoclave. When the catalyst is sucked off, the mother liquor is acidified with conc. hydrochloric acid. The precipitated crystals are dissolved in 250 ml of warm ethyl acetate and dried, and the ethyl acetate is distilled off. The resulting crystals are mixed with ether/hexane and suctioned off.
Iskorištenje: 900 mg (98,0% od teorijskog). Yield: 900 mg (98.0% of theoretical).
Talište: 102-106°C. Melting point: 102-106°C.
2.44.c Terc-butil [2-(4-cijano-2-fluor-fenil)-etil]-karbaminat 2.44.c Tert-butyl [2-(4-cyano-2-fluoro-phenyl)-ethyl]-carbamate
1,25 ml trietilamina i 0,61 ml (2,8 mmola) difenil-fosforilazida se doda u otopinu od 500 mg (2,6 mmola) od 3-(4-cijano-2-fluor-fenil)-propionske kiseline u 5 ml terc-butanola. Reakcijsku smjesu se refluktira preko noći i zatim se otapalo odstrani na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu silika gela (diklormetan/metanol 9:1). 1.25 ml of triethylamine and 0.61 ml (2.8 mmol) of diphenyl-phosphoryl azide were added to a solution of 500 mg (2.6 mmol) of 3-(4-cyano-2-fluoro-phenyl)-propionic acid in 5 ml tert-butanol. The reaction mixture was refluxed overnight and then the solvent was removed on a rotary evaporator. Purification is performed by chromatography on a silica gel column (dichloromethane/methanol 9:1).
Iskorištenje: 138 mg (20,2% od teorijskog). Yield: 138 mg (20.2% of theoretical).
C14H17FN2O2 (M = 264,302) C14H17FN2O2 (M = 264.302)
Izračunato: molekulska masa (M+H)+: 265 Calculated: molecular weight (M+H)+: 265
Nađeno: molekulska masa (M+H)+: 265 Found: molecular weight (M+H)+: 265
2.44.d Terc-butil [2-(4-aminometil-2-fluor-fenil)-etil]-karbaminat 2.44.d Tert-butyl [2-(4-aminomethyl-2-fluoro-phenyl)-ethyl]-carbamate
Otopinu od 138 mg (0,52 mmola) terc-butil [2-(4-cijano-2-fluor-fenil)-etil]-karbaminata u 15 ml etanolne otopine amonijaka pomiješa se sa 75 mg Raney nikla i smjesu se mućka preko noći pri 50°C i pod 3 bar tlaka vodika u autoklavu. Zatim se katalizator odsisa, a otapalo se odstrani na rotacijskom uređaju za isparavanje. A solution of 138 mg (0.52 mmol) of tert-butyl [2-(4-cyano-2-fluoro-phenyl)-ethyl]-carbamate in 15 ml of ethanolic ammonia solution was mixed with 75 mg of Raney nickel and the mixture was shaken over overnight at 50°C and under 3 bar hydrogen pressure in an autoclave. Then the catalyst is sucked off, and the solvent is removed on a rotary evaporator.
Iskorištenje: 137 mg (97,8% od teorijskog). Yield: 137 mg (97.8% of theoretical).
C14H21FN2O2 (M = 268,334) C14H21FN2O2 (M = 268.334)
Izračunato: molekulska masa (M+H)+: 269 Calculated: molecular weight (M+H)+: 269
Nađeno: molekulska masa (M+H)+: 269 Found: molecular weight (M+H)+: 269
2.44.e Terc-butil [2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etil]-karbaminat 2.44.e Tert-butyl [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-carbamate
U otopinu od 300 mg (1,12 mmola) terc-butil [2-(4-aminometil-2-fluor-fenil)-etil]-karbaminata u 15 ml aceto-nitrila doda se uzastopce 42 mg (0,25 mmola) kalijevog jodida, 180 mg (1,30 mmola) kalijevog karbonata i 0,13 ml (1,11 mmola) 1,4-dibrombutana. Reakcijsku smjesu se miješa 6 h pri 78°C. Zatim se doda drugih 0,08 ml (0,66 mmola) 1,4-dibromobutana i reakcijsku smjesu se miješa preko noći pri 78°C. Otapalo se odstrani na rotacijskom uređaju za isparavanje i proizvod daljnji reagira bez čišćenja. To a solution of 300 mg (1.12 mmol) of tert-butyl [2-(4-aminomethyl-2-fluoro-phenyl)-ethyl]-carbamate in 15 ml of acetonitrile, 42 mg (0.25 mmol) are added successively of potassium iodide, 180 mg (1.30 mmol) of potassium carbonate and 0.13 ml (1.11 mmol) of 1,4-dibromobutane. The reaction mixture was stirred for 6 h at 78°C. Another 0.08 ml (0.66 mmol) of 1,4-dibromobutane was then added and the reaction mixture was stirred overnight at 78°C. The solvent is removed on a rotary evaporator and the product reacts further without cleaning.
Iskorištenje: 320 mg (88,8% od teorijskog). Yield: 320 mg (88.8% of theoretical).
C18H27FN2O2 (M = 322,426) C18H27FN2O2 (M = 322.426)
Izračunato: molekulska masa (M+H)+: 323 Calculated: molecular weight (M+H)+: 323
Nađeno: molekulska masa (M+H)+: 323 Found: molecular weight (M+H)+: 323
2.44.f 2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etilamin 2.44.f 2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine
U otopinu od 232 mg (0,72 mmola) terc-butil [2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etil]-karbaminata u 5 ml diklormetana doda se 1,5 ml trifluoroctene kiseline. Reakcijsku smjesu se miješa 2 h pri sobnoj temperaturi. Otapalo se odstrani na rotacijskom uređaju za isparavanje i sirov proizvod dalje reagira bez čišćenje. 1.5 ml of trifluoroacetic acid was added to a solution of 232 mg (0.72 mmol) of tert-butyl [2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-carbamate in 5 ml of dichloromethane. The reaction mixture was stirred for 2 h at room temperature. The solvent is removed on a rotary evaporator and the crude product is further reacted without purification.
Iskorištenje: 160 mg (100% od teorijskog). Yield: 160 mg (100% of theoretical).
C13H19FN2 (M = 222,308) C13H19FN2 (M = 222.308)
Izračunato: molekulska masa (M+H)+: 223 Calculated: molecular weight (M+H)+: 223
Nađeno: molekulska masa (M+H)+: 223 Found: molecular weight (M+H)+: 223
2.44.g 4'-klor-bifenil-4-karboksilna kiselina-[2-(2-fluor-4-pirolidin-1-i I metil-fenil)-etil]-amid 2.44.g 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 2-(2-fluor-4-pirolidin-1-ilmetil-fenil)-etilamina (160 mg, 0,72 mmola) i 4'-klor-bifenil-4-karboksilne kiseline (168 mg, 0,72 mmola). It was prepared according to general procedure I from 2-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (160 mg, 0.72 mmol) and 4'-chloro-biphenyl-4-carboxylic acid (168 mg, 0.72 mmol).
Iskorištenje: 49 mg (15,6% od teorijskog). Yield: 49 mg (15.6% of theoretical).
C26H26ClFN2O (M = 436,961) C26H26ClFN2O (M = 436.961)
Izračunato: molekulska masa (M+H)+: 437/439 Calculated: molecular weight (M+H)+: 437/439
Nađeno: molekulska masa (M+H)+: 437/439 Found: molecular weight (M+H)+: 437/439
Vrijeme retencije HPLC: 6,6 min (metoda A) HPLC retention time: 6.6 min (method A)
Primjer 2.45: Example 2.45:
4-piridin-4-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-pyridin-4-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.45.a Metil 4-piridin-4-il-benzoat 2.45.a Methyl 4-pyridin-4-yl-benzoate
3,0 g (15 mmola) 4-brom-piridina se otopi u 50 ml dioksana i 15 ml 2M otopine natrijevog karbonata. Uzastopce se doda 2,7 g (15 mmolova) 4-metoksikarbonilfenil-borne kiseline i 1,73 g (2 mmola) tetrakis-(trifenilfosfin)-paladija i reakcijsku smjesu se refluktira 6 h. Vruću reakcijsku otopinu se odsisa kroz filter od staklenih vlakana. Otapalo se odstrani na rotacijskom uređaju za isparavanje i čišćenje vrši kromatografijom na stupcu silika gela (diklormetan/metanol 9:1). 3.0 g (15 mmol) of 4-bromopyridine is dissolved in 50 ml of dioxane and 15 ml of 2M sodium carbonate solution. 2.7 g (15 mmol) of 4-methoxycarbonylphenylboronic acid and 1.73 g (2 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The hot reaction solution is sucked off through a glass fiber filter. The solvent is removed on a rotary evaporator and cleaning is performed by chromatography on a silica gel column (dichloromethane/methanol 9:1).
Iskorištenje: 845 mg (26,4% od teorijskog). Yield: 845 mg (26.4% of theoretical).
C13H11NO2 (M = 213,238) C13H11NO2 (M = 213.238)
Izračunato: molekulska masa (M+H)+: 214 Calculated: molecular weight (M+H)+: 214
Nađeno: molekulska masa (M+H)+: 214 Found: molecular weight (M+H)+: 214
Vrijeme retencije HPLC: 4,1 min (metoda A) HPLC retention time: 4.1 min (method A)
2.45.b 4-piridin-4-il-benzojeva kiselina 2.45.b 4-pyridin-4-yl-benzoic acid
0,37 ml (0,74 mmola) 2N NaOH doda se u otopinu od 150 mg (0,70 mmola) metil 4-piridin-4-il-benzoata u 10 ml etanola. Reakcijsku otopinu se miješa 2 h pri 60oC i zatim se pH namjesti na 6-7 s 1N HCl. Nakon filtracije nastali talog se osuši preko noći pod visokim vakuumom. 0.37 ml (0.74 mmol) of 2N NaOH was added to a solution of 150 mg (0.70 mmol) of methyl 4-pyridin-4-yl-benzoate in 10 ml of ethanol. The reaction solution is stirred for 2 h at 60oC and then the pH is adjusted to 6-7 with 1N HCl. After filtration, the resulting precipitate is dried overnight under high vacuum.
Iskorištenje: 84 mg (60,0% od teorijskog). Yield: 84 mg (60.0% of theoretical).
C12H9NO2 (M = 199,211) C12H9NO2 (M = 199.211)
Izračunato: molekulska masa (M+H)+: 200 Calculated: molecular weight (M+H)+: 200
Nađeno: molekulska masa (M+H)+: 200 Found: molecular weight (M+H)+: 200
Vrijeme retencije HPLC: 2,5 min (metoda A) HPLC retention time: 2.5 min (method A)
2.45.c 4-piridin-4-il-W-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.45.c 4-pyridin-4-yl-W-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (86 mg, 0,42 mmola) i 4-piridin-4-il-benzojeve kiseline (84 mg, 0,42 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (86 mg, 0.42 mmol) and 4-pyridin-4-yl-benzoic acid (84 mg, 0.42 mmol).
Iskorištenje: 65 mg (40,0% od teorijskog). Yield: 65 mg (40.0% of theoretical).
C25H27N3O (M = 385,513) C25H27N3O (M = 385.513)
Izračunato: molekulska masa (M+H)+: 386 Calculated: molecular weight (M+H)+: 386
Nađeno: molekulska masa (M+H)+: 386 Found: molecular weight (M+H)+: 386
Vrijeme retencije HPLC: 4,7 min (Stable Bond C18; 3,5 μm; vode:acetonitril:mravlja kiselina 91:9:0,01). HPLC retention time: 4.7 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 91:9:0.01).
Primjer 2.46: Example 2.46:
5-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2,3-dihidro-izoindol-1-on 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one
[image] [image]
2.46.a Etil 4-brom-2-metil- benzoat 2.46.a Ethyl 4-bromo-2-methyl-benzoate
Otopinu od 5,0 g (23,3 mmola) 4-brom-2-metil-benzojeve kiseline u 50 ml etanolne solne kiseline miješa se 8 h pri 45°C. Reakcijsku otopinu se ohladi na sobnu temperaturu preko noći i zatim se otapalo odstrani na rotacijskom uređaju za isparavanje. Ostatak se preuzme u eter, profiltrira se i otapalo se odstrani na rotacijskom uređaju za isparavanje. Ostatak dalje reagira bez čišćenja. A solution of 5.0 g (23.3 mmol) of 4-bromo-2-methyl-benzoic acid in 50 ml of ethanolic hydrochloric acid was stirred for 8 h at 45°C. The reaction solution was cooled to room temperature overnight and then the solvent was removed on a rotary evaporator. The residue is taken up in ether, filtered and the solvent removed on a rotary evaporator. The residue reacts further without cleaning.
Rf vrijednost: 0,88 (silika gel, diklormetan/etanol 95:5). Rf value: 0.88 (silica gel, dichloromethane/ethanol 95:5).
2.46.b etil 4'-klor-3-metil-bifenil-4-karboksilat 2.46.b ethyl 4'-chloro-3-methyl-biphenyl-4-carboxylate
1,66 g (6,83 mmolova) etil 4-brom-2-metil- benzoata se otopi u 70 ml dioksana i 7 ml 2M otopine natrijevog karbonata. Uzastopce se doda 1,07 g (6,83 mmolova) 4-klor-fenil-borne kiseline i 0,40 g (0,34 mmola) tetrakis-(trifenilfosfin)-paladija. Reakcijsku smjesu se refluktira 6 h i miješa se daljnjih 60 h pri sobnoj temperaturi. Vruću reakcijsku otopinu se odsisa kroz filter od staklenih vlakana. Otapalo se odstrani na rotacijskom uređaju za isparavanje. Ostatak se pomiješa s vodom i vodenu fazu ekstrahira s etil acetatom. Organsku fazu se osuši preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu silika gela (petrol eter/etil acetat 8:2). 1.66 g (6.83 mmol) of ethyl 4-bromo-2-methylbenzoate was dissolved in 70 ml of dioxane and 7 ml of 2M sodium carbonate solution. 1.07 g (6.83 mmol) of 4-chloro-phenylboronic acid and 0.40 g (0.34 mmol) of tetrakis-(triphenylphosphine)-palladium are added successively. The reaction mixture was refluxed for 6 h and stirred for a further 60 h at room temperature. The hot reaction solution is sucked off through a glass fiber filter. The solvent was removed on a rotary evaporator. The residue was mixed with water and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was removed on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).
Iskorištenje: 1,3 g (69.3% od teorijskog). Yield: 1.3 g (69.3% of theoretical).
C16H15ClO2 (M = 274,750) C16H15ClO2 (M = 274.750)
Izračunato: molekulska masa (M+H)+: 275/277 Calculated: molecular weight (M+H)+: 275/277
Nađeno: molekulska masa (M+H)+: 275/277 Found: molecular weight (M+H)+: 275/277
Rf vrijednost: 0,67 (silika gel, petrol eter/etil acetat 8:2). Rf value: 0.67 (silica gel, petroleum ether/ethyl acetate 8:2).
2.46.c Etil 3-brom-metil-4'-klor-bifenil-4-karboksilat 2.46.c Ethyl 3-bromo-methyl-4'-chloro-biphenyl-4-carboxylate
78 mg (0,47 mmola) 2,2'-azobis(izobutironitril)-a se doda u otopinu od 1,3 g (4,73 mmola) etil 4'-klor-3-metil-bifenil-4-karboksilata i 0,84 g (4,73 mmola) N-bromsukcin-imida u 10 ml ugljikovog tetraklorida. Reakcijsku smjesu se refluktira preko noći. Nakon filtracije, otapalo se ispari na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu silika gel (petrol eter/etil acetat 8:2). 78 mg (0.47 mmol) of 2,2'-azobis(isobutyronitrile) was added to a solution of 1.3 g (4.73 mmol) of ethyl 4'-chloro-3-methyl-biphenyl-4-carboxylate and 0.84 g (4.73 mmol) of N-bromosuccinimide in 10 ml of carbon tetrachloride. The reaction mixture is refluxed overnight. After filtration, the solvent is evaporated on a rotary evaporator. Purification is performed by chromatography on a silica gel column (petroleum ether/ethyl acetate 8:2).
Iskorištenje: 1,6 g (62,1% od teorijskog). Yield: 1.6 g (62.1% of theoretical).
C16H14BrClO2 (M = 353,646) C16H14BrClO2 (M = 353.646)
Izračunato: molekulska masa (M+H)+: 353/355/357 Calculated: molecular weight (M+H)+: 353/355/357
Nađeno: molekulska masa (M+H)+: 353/355/357 Found: molecular weight (M+H)+: 353/355/357
Rf vrijednost: 0,57 (silika gel, petrol eter/etil acetat 8:2). Rf value: 0.57 (silica gel, petroleum ether/ethyl acetate 8:2).
2.46.d 5-(4-klor-fenil)-2-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-2,3-dihidro-izoindol-1-on 2.46.d 5-(4-chloro-phenyl)-2-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one
375 mg (1,47 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina se polako doda kap po kap pri sobnoj temperaturi u suspenziju od 800 mg (1,47 mmola) etil 3-brom-metil-4'-klor-bifenil-4-karboksilata i 508 mg (3,68 mmola) kalijevog karbonata u 7,5 ml acetonitrila. Reakcijsku smjesu se refluktira 5 sati. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje preuzme se u vodu i etil acetat. Vodenu fazu se ekstrahira s etil acetatom i sjedinjene organske faze se osuše preko magnezijevog sulfata. Ostatak nakon odstranjivanja otapala na rotacijskom uređaju za isparavanje se otopi u DMF-u i očisti HPLC kromatografijom (Stable Bond C18; 3,5 μm; vodae:acetonitril:mravlja kiselina 9:1:0,01 prema 1:9:0,01 za 9 min). 375 mg (1.47 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine was slowly added dropwise at room temperature to a suspension of 800 mg (1.47 mmol) of ethyl 3-bromo-methyl- 4'-chloro-biphenyl-4-carboxylate and 508 mg (3.68 mmol) of potassium carbonate in 7.5 ml of acetonitrile. The reaction mixture was refluxed for 5 hours. The residue after removal of the solvent on a rotary evaporator is taken up in water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. The residue after removing the solvent on a rotary evaporator is dissolved in DMF and purified by HPLC chromatography (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 1:9:0.01 in 9 min).
Iskorištenje: 82 mg (12,9% od teorijskog). Yield: 82 mg (12.9% of theoretical).
C27H27ClN2O2 (M = 430,982) C27H27ClN2O2 (M = 430.982)
Izračunato: molekulska masa (M+H)+: 431/433 Calculated: molecular weight (M+H)+: 431/433
Nađeno: molekulska masa (M+H)+: 431/433 Found: molecular weight (M+H)+: 431/433
Vrijeme retencije HPLC: 6,13 min (metoda A) HPLC retention time: 6.13 min (method A)
Primjer 2.47: Example 2.47:
4-piperidin-1-ilmetil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 4-piperidin-1-ylmethyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.47.a 4-piperidin-1-ilmetil-piridin 2.47.a 4-piperidin-1-ylmethyl-pyridine
242 ml piperidina (2,44 mol) doda se kap po kap u otopinu od 100 g (0,61 mola) 4-klormetil-piridina u 600 ml suhog metanola i reakcijsku smjesu se miješa jedan sat pri 50°C. Otapalo se odstrani na rotacijskom uređaju za isparavanje. Ostatak se zaluži sa 40%-tnom otopinom natrijevog hidroksida i vodenu fazu se ekstrahira s eterom. Organsku fazu se osuši preko natrijevog sulfata i nakon filtracije kroz aktivirani ugljen, otapalo se odstrani na rotacijskom uređaju za isparavanje. Sirov proizvod dalje reagira bez čišćenja. 242 ml of piperidine (2.44 mol) were added dropwise to a solution of 100 g (0.61 mol) of 4-chloromethyl-pyridine in 600 ml of dry methanol and the reaction mixture was stirred for one hour at 50°C. The solvent was removed on a rotary evaporator. The residue is made alkaline with a 40% sodium hydroxide solution and the aqueous phase is extracted with ether. The organic phase is dried over sodium sulfate and after filtration through activated carbon, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.
Iskorištenje: 106 g (98% od teorijskog). Yield: 106 g (98% of theoretical).
2.47.b 4-piperidin-1-ilmetil-piperidin 2.47.b 4-piperidin-1-ylmethyl-piperidine
Otopinu od 106 g (0,6 mola) 4-piperidin-1-ilmetil-piridina u 1,0 l ledene octene kiseline se pomiješa sa 7 g oksida platine i mućka se u autoklavu pri sobnoj temperaturi i 3 bara tlaka vodika. Kad se katalizator odsisa, otapalo se odstrani na rotacijskom uređaju za isparavanje. Sirov proizvod dalje reagira bez čišćenja. A solution of 106 g (0.6 mol) of 4-piperidin-1-ylmethyl-pyridine in 1.0 l of glacial acetic acid was mixed with 7 g of platinum oxide and shaken in an autoclave at room temperature and 3 bar hydrogen pressure. When the catalyst is sucked off, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.
Iskorištenje: 48 g (43,9% od teorijskog). Yield: 48 g (43.9% of theoretical).
2.47.c 4-piperidin-1-ilmetil-piperidin-1-karboksilna kiselina-[2-(4-pirolidin-1-ilmetii-fenil)-etil]-amid 2.47.c 4-piperidin-1-ylmethyl-piperidin-1-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 4-piperidin-1-ilmetil-piperidina (182 mg, 1,00 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,00 mmol). It was prepared according to general procedure II from 4-piperidin-1-ylmethyl-piperidine (182 mg, 1.00 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.00 mmol ).
Iskorištenje: 160,0 mg (38,8% od teorijskog). Yield: 160.0 mg (38.8% of theoretical).
C25H40N4O (M = 412,624) C25H40N4O (M = 412.624)
Izračunato: molekulska masa (M+H)+: 413 Calculated: molecular weight (M+H)+: 413
Nađeno: molekulska masa (M+H)+: 413 Found: molecular weight (M+H)+: 413
Vrijeme retencije HPLC: 1,75 min (Stable Bond C18; 3,5 μm; vode:acetonitril:mravlja kiselina 9:1:0,01 prema 4:6:0,01 za 8 min). HPLC retention time: 1.75 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 4:6:0.01 in 8 min).
Primjer 2.48: Example 2.48:
[image] [image]
2.48.a 4-(1H-benzoimidazol-2-il)-piperidin-1-karboksilna kiselina-[2-{4-pirolidin-1 -ilm etil-feni l)-etil]-amid 2.48.a 4-(1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid-[2-{4-pyrrolidin-1-yl]ethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku II iz 2-piperidin-4-il-1H-benzoimidazola (164 mg, 1,00 mmola) i 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,00 mmola). It was prepared according to general procedure II from 2-piperidin-4-yl-1H-benzoimidazole (164 mg, 1.00 mmol) and 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1, 00 mmol).
Iskorištenje: 80,0 mg (18,5% od teorijskog). Yield: 80.0 mg (18.5% of theoretical).
C26H33N5O (M = 431,586) C26H33N5O (M = 431.586)
Izračunato: molekulska masa (M+H)+: 432 Calculated: molecular weight (M+H)+: 432
Nađeno: molekulska masa (M+H)+: 432 Found: molecular weight (M+H)+: 432
Vrijeme retencije HPLC: 2,80 min (Stable Bond C18; 3,5 μm; voda:acetonitril:mravlja kiselina 9:1:0,01 prema 4:6:0,01 za 8 min). HPLC retention time: 2.80 min (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01 to 4:6:0.01 in 8 min).
Primjer 2.49: Example 2.49:
4-(1-metil-piperidin-4-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(1-methyl-piperidin-4-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.49.a metil 4-piperidin-4-il-benzoat 2.49.a methyl 4-piperidin-4-yl-benzoate
4,0 ml 1M solne kiseline i 200 mg oksida platine doda se u otopinu od 695 mg (3,26 mmola) metil 4-piridin-4-il-benzoata (vidi primjer 2.45.a) u 10 ml etanola. Reakcijsku smjesu se miješa 2 h pri sobnoj temperaturi i 3 bara tlaka vodika. Kad se u reakcijsku smjesu doda drugih 300 mg oksida platine i 6,0 ml 1M solne kiseline, smjesu se miješa još daljnjih 16 h pri sobnoj temperaturi i 3 bara tlaka vodika. Nakon odvajanja katalizatora, otapalo se odstrani na rotacijskom uređaju za isparavanje. Sirov proizvod dalje reagira bez čišćenje. 4.0 ml of 1M hydrochloric acid and 200 mg of platinum oxide are added to a solution of 695 mg (3.26 mmol) of methyl 4-pyridin-4-yl-benzoate (see example 2.45.a) in 10 ml of ethanol. The reaction mixture is stirred for 2 h at room temperature and 3 bar hydrogen pressure. When another 300 mg of platinum oxide and 6.0 ml of 1M hydrochloric acid were added to the reaction mixture, the mixture was stirred for another 16 h at room temperature and 3 bar hydrogen pressure. After separation of the catalyst, the solvent is removed on a rotary evaporator. The crude product reacts further without purification.
Iskorištenje: 589 mg (82,4% od teorijskog). Yield: 589 mg (82.4% of theoretical).
C13H17NO2 (M = 219,286) C13H17NO2 (M = 219.286)
Izračunato: molekulska masa (M+H)+: 220 Calculated: molecular weight (M+H)+: 220
Nađeno: molekulska masa (M+H)+: 220 Found: molecular weight (M+H)+: 220
Vrijeme retencije HPLC: 3,5 min (metoda A) HPLC retention time: 3.5 min (method A)
2.49.b metil 4-(1-metil-piperidin-4-il)-benzoat 2.49.b methyl 4-(1-methyl-piperidin-4-yl)-benzoate
48 mg (2,00 mmola) natrijevog hidrida doda se u obrocima u otopinu od 429 mg (1,96 mmola) metil 4-piperidin-4-il-benzoata u 10 ml DMF-a pod atmosferom dušika pri 0°C. Reakcijsku smjesu se miješa 1 h pri sobnoj temperaturi. Kap po kap doda se 0,13 ml (2,10 mmola) metil jodida i otopinu se miješa dva sata pri sobnoj temperaturi. Reakcijsku otopinu se pomiješa s vodom, vodenu fazu se ekstrahira s etil acetatom, sjedinjene organske faze se osuše preko magnezijevog sulfata i otapalo se odstrani na rotacijskom uređaju za isparavanje. Čišćenje se vrši kromatografijom na stupcu (silika gel; diklormetan/metanol 8:2). 48 mg (2.00 mmol) of sodium hydride was added portionwise to a solution of 429 mg (1.96 mmol) of methyl 4-piperidin-4-yl-benzoate in 10 ml of DMF under a nitrogen atmosphere at 0°C. The reaction mixture was stirred for 1 h at room temperature. 0.13 ml (2.10 mmol) of methyl iodide was added drop by drop and the solution was stirred for two hours at room temperature. The reaction solution is mixed with water, the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried over magnesium sulfate and the solvent is removed on a rotary evaporator. Purification is performed by column chromatography (silica gel; dichloromethane/methanol 8:2).
Iskorištenje: 70 mg (15,3% od teorijskog). Yield: 70 mg (15.3% of theoretical).
C14H19NO2 (M = 233,313) C14H19NO2 (M = 233.313)
Izračunato: molekulska masa (M+H)+: 234 Calculated: molecular weight (M+H)+: 234
Nađeno: molekulska masa (M+H)+: 234 Found: molecular weight (M+H)+: 234
Vrijeme retencije HPLC: 2,7 min (metoda A) HPLC retention time: 2.7 min (method A)
2.49.c 4-(1-metil-piperidin-4-il)-benzojeva kiselina 2.49.c 4-(1-methyl-piperidin-4-yl)-benzoic acid
0,37 ml (0,74 mmola) 2N NaOH doda se u otopinu od 70 mg (0,30 mmola) metil 4-(1-metil-piperidin-4-il)-benzoata u 10 ml etanola. Reakcijsku otopinu se miješa 2 h pri 60oC i zatim se namjesti na pH 6-7 upotrebom 1N HCl. Talog koji nastane nakon filtracije se osuši preko noći pod visokim vakuumom. 0.37 ml (0.74 mmol) of 2N NaOH was added to a solution of 70 mg (0.30 mmol) of methyl 4-(1-methyl-piperidin-4-yl)-benzoate in 10 ml of ethanol. The reaction solution was stirred for 2 h at 60oC and then adjusted to pH 6-7 using 1N HCl. The precipitate formed after filtration is dried overnight under high vacuum.
Iskorištenje: 50 mg (76,0% od teorijskog). Yield: 50 mg (76.0% of theoretical).
C13H17NO2 (M = 219,286) C13H17NO2 (M = 219.286)
Izračunato: molekulska masa (M+H)+: 220 Calculated: molecular weight (M+H)+: 220
Nađeno: molekulska masa (M+H)+: 220 Found: molecular weight (M+H)+: 220
Vrijeme retencije HPLC: 1,5 min (metoda A) HPLC retention time: 1.5 min (method A)
2.49.d 4-(1-metil-piperidin-4-il)-W-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.49.d 4-(1-methyl-piperidin-4-yl)-W-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (47 mg, 0,23 mmola) i 4-(1-metil-piperidin-4-il)-benzojeve kiseline (50 mg, 0,23 mmola). It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (47 mg, 0.23 mmol) and 4-(1-methyl-piperidin-4-yl)-benzoic acid ( 50 mg, 0.23 mmol).
Iskorištenje: 22 mg (23,8% od teorijskog). Yield: 22 mg (23.8% of theoretical).
C26H35N3O (M = 405,588) C26H35N3O (M = 405.588)
Izračunato: molekulska masa (M+H)+: 406 Calculated: molecular weight (M+H)+: 406
Nađeno: molekulska masa (M+H)+: 406 Found: molecular weight (M+H)+: 406
Vrijeme retencije HPLC: 2,4 min (metoda A) HPLC retention time: 2.4 min (method A)
Primjer 2.50: Example 2.50:
[image] [image]
1.21.a 4'-klor-bifenil-4-karboksilna kiselina-{2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etil}-amid 1.21.a 4'-chloro-biphenyl-4-carboxylic acid-{2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethyl}-amide
Proizveden je analogno primjeru 1.1.i iz 2-[6-(4-metil-piperazin-1-il)-piridin-3-il]-etilamina i 4'-klor-bi-fenil-4-karboksilne kiseline. It is produced analogously to example 1.1.i from 2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ethylamine and 4'-chloro-bi-phenyl-4-carboxylic acid.
Iskorištenje: 0,94 g (96% od teorijskog). Yield: 0.94 g (96% of theoretical).
Talište: 211-213oC Melting point: 211-213oC
C25H27ClN4O (M = 434,97) C25H27ClN4O (M = 434.97)
Izračunato: molekulska masa (M+H)+: 435/437 Calculated: molecular weight (M+H)+: 435/437
Nađeno: molekulska masa (M+H)+: 435/437 Found: molecular weight (M+H)+: 435/437
Primjer 2.51: Example 2.51:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(4-metil-piperazin-1-karbonil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide
[image] [image]
2.51.a [4-(4-metil-piperazin-1-karbonil)-fenil]-acetonitril 2.51.a [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile
Otopinu od 2 g (12,41 mmolova) 4-cijanometil-benzojeve kiseline, 1,25 g (12,5 mmolova) N-metilpiperazina, 4,01 g (12,5 mmolova) TBTU i 3,48 ml (25 mmolova) trietilamina u 40 ml DMF-a miješa se 12 sati pri sobnoj temperaturi. Zatim se reakcijsku smjesu ispari do određene mjere i pomiješa se s vodom. Tu smjesu se ekstrahira s etil acetatom i otapalo se izdestilira na rotacijskom uređaju za isparavanje. Vodenu fazu se također ispari i organsku fazu se pomiješa s ostatkom. Čišćenje se vrši kromatografijom na stupcu silika gela (sredstvo za ispiranje: diklormetan/etanol/amonijak 30:1:0,1). A solution of 2 g (12.41 mmol) 4-cyanomethyl-benzoic acid, 1.25 g (12.5 mmol) N-methylpiperazine, 4.01 g (12.5 mmol) TBTU and 3.48 ml (25 mmol ) of triethylamine in 40 ml of DMF was stirred for 12 hours at room temperature. The reaction mixture is then evaporated to a certain extent and mixed with water. This mixture is extracted with ethyl acetate and the solvent is distilled off on a rotary evaporator. The aqueous phase is also evaporated and the organic phase is mixed with the residue. Cleaning is done by chromatography on a silica gel column (eluent: dichloromethane/ethanol/ammonia 30:1:0.1).
Iskorištenje: 2,6 g (86% od teorijskog). Yield: 2.6 g (86% of theoretical).
C14H14N3O (M = 243,31) C14H14N3O (M = 243.31)
Izračunato: molekulska masa (M+H)+: 244 Calculated: molecular weight (M+H)+: 244
Nađeno: molekulska masa (M+H)+: 244 Found: molecular weight (M+H)+: 244
Rf vrijednost: 0,35 (silika gel, diklormetan/etanol/amonijak 20:1:0,1). Rf value: 0.35 (silica gel, dichloromethane/ethanol/ammonia 20:1:0.1).
2.51.b [4-(2-amino-etil)-fenil]-(4-metil-piperazin-1-il)-metanon 2.51.b [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone
Proizveden je analogno primjeru 1.1.i iz [4-(4-metil-piperazin-1-karbonil)-fenil]-acetonitrila. It is produced analogously to example 1.1.i from [4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetonitrile.
Iskorištenje: 2,9 g (90% od teorijskog). Yield: 2.9 g (90% of theoretical).
C14H21N3O x HCl (M = 283,80) C14H21N3O x HCl (M = 283.80)
Rf vrijednost: 0,25 (silika gel, diklormetan/etanol/amonijak 10:1:0,1). Rf value: 0.25 (silica gel, dichloromethane/ethanol/ammonia 10:1:0.1).
2.51.c 4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(4-metil-piperazin-1-karbonil)-fenil]-etil}-amid 2.51.c 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ethyl}-amide
Proizveden je prema općem radnom postupku I iz [4-(2-amino-etil)-fenil]-(4-metil-piperazin-1-il)-metanona i 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from [4-(2-amino-ethyl)-phenyl]-(4-methyl-piperazin-1-yl)-methanone and 4'-chloro-biphenyl-4-carboxylic acid.
Iskorištenje: 0,18 g (48,4% od teorijskog). Yield: 0.18 g (48.4% of theoretical).
Talište: 217-218°C Melting point: 217-218°C
C27H28ClN3O2 (M = 461,99) C27H28ClN3O2 (M = 461.99)
Izračunato: molekulska masa (M+H)+: 462/464 Calculated: molecular weight (M+H)+: 462/464
Nađeno: molekulska masa (M+H)+: 462/464 Found: molecular weight (M+H)+: 462/464
Rf vrijednost: 0,25 (silika gel, diklormetan/metanol/amonijak 10:1:0,1). Rf value: 0.25 (silica gel, dichloromethane/methanol/ammonia 10:1:0.1).
Primjer 2.52: Example 2.52:
4'-brom-bifenil-4-karboksilna kiselina-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-bromo-biphenyl-4-carboxylic acid-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.52.a metil 4'-brom-bifenil-4-karboksilat 2.52.a methyl 4'-bromo-biphenyl-4-carboxylate
0,54 g (2,5 mmola) metil 4-brom-benzoata se otopi u 10 ml dioksana i 2,5 ml 2M otopini natrijevog karbonata. Uzastopce se doda 0,6 g (3 mmola) 4-bromfenil-borne kiseline i 0,12 g (0,1 mmola) tetrakis-(trifenilfosfin)-paladija i reakcijsku smjesu se refluktira 5 sati. Reakcijsku smjesu se pomiješa s vodom i EtOAc, profiltrira se i faze se odvoje. Vodenu fazu se ekstrahira s EtOAc i sjedinjene organske faze se osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, ostatak se triturira s acetonitrilom, odsisa i osuši na zraku. 0.54 g (2.5 mmol) of methyl 4-bromobenzoate is dissolved in 10 ml of dioxane and 2.5 ml of 2M sodium carbonate solution. 0.6 g (3 mmol) of 4-bromophenylboronic acid and 0.12 g (0.1 mmol) of tetrakis-(triphenylphosphine)-palladium are added successively and the reaction mixture is refluxed for 5 hours. The reaction mixture was mixed with water and EtOAc, filtered and the phases separated. The aqueous phase was extracted with EtOAc and the combined organic phases were dried over MgSO4. After removal of drying agent and solvent, the residue is triturated with acetonitrile, suction and dried in air.
Iskorištenje: 100 mg (13,7% od teorijskog). Yield: 100 mg (13.7% of the theoretical).
C14H11BrO2 (M = 291,15) C14H11BrO2 (M = 291.15)
Izračunato: molekulska masa (M+H)+: 291/293 Calculated: molecular weight (M+H)+: 291/293
Nađeno: molekulska masa (M+H)+: 291/293 Found: molecular weight (M+H)+: 291/293
Rf vrijednost: 0,68 (silika gel, petrol eter/EtOAc 8:2). Rf value: 0.68 (silica gel, petroleum ether/EtOAc 8:2).
2.52.b 4'-brom-bifenil-4-karboksilna kiselina 2.52.b 4'-bromo-biphenyl-4-carboxylic acid
Otopinu od 100 mg (0,34 mmola) metil 4'-brom-bifenil-4-karboksilata u 3 ml THF-a se pomiješa s 3 ml 1M otopine NaOH u vodi i refluktira se 3 h. Reakcijsku smjesu se ispari u vakuumu, vodeni ostatak se zakiseli s 1 M HCl, istaloženi proizvod se odfiltrira i osuši na zraku. A solution of 100 mg (0.34 mmol) of methyl 4'-bromo-biphenyl-4-carboxylate in 3 ml of THF was mixed with 3 ml of a 1M NaOH solution in water and refluxed for 3 h. The reaction mixture is evaporated in vacuo, the aqueous residue is acidified with 1 M HCl, the precipitated product is filtered off and dried in air.
Iskorištenje: 60 mg (63,1% od teorijskog). Yield: 60 mg (63.1% of theoretical).
C13H9BrO2 (M = 277,19) C13H9BrO2 (M = 277.19)
Izračunato: molekulska masa (M-H)-: 275/277 Calculated: molecular weight (M-H)-: 275/277
Nađeno: molekulska masa (M-H)-: 275/277 Found: molecular weight (M-H)-: 275/277
Vrijeme retencije HPLC: 8,48 min (metoda A) HPLC retention time: 8.48 min (method A)
2.52.c 4'-brom-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.52.c 4'-bromo-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 45 mg (0,22 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 60 mg (0,22 mmola) 4'-brom-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 45 mg (0.22 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 60 mg (0.22 mmol) of 4'-bromo-biphenyl-4-carboxylic acid.
Iskorištenje: 28 mg (27,5% od teorijskog). Yield: 28 mg (27.5% of theoretical).
C26H27BrN2O (M = 463,42) C26H27BrN2O (M = 463.42)
Izračunato: molekulska masa (M+H)+: 463/465 Calculated: molecular weight (M+H)+: 463/465
Nađeno: molekulska masa (M+H)+: 463/465 Found: molecular weight (M+H)+: 463/465
Vrijeme retencije HPLC: 6,46 min (metoda A) HPLC retention time: 6.46 min (method A)
Primjer 2.53: Example 2.53:
4'-etil-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-ethyl-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 113 mg (0,5 mmola) 4'-etil-bifenil-4-karboksilne kiseline (Lancaster). It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 113 mg (0.5 mmol) of 4'-ethyl-biphenyl-4-carboxylic acid (Lancaster).
Iskorištenje: 65 mg (31,5% od teorijskog). Yield: 65 mg (31.5% of theoretical).
C28H32N2O (M =412,58) C28H32N2O (M = 412.58)
Izračunato: molekulska masa (M+H)+: 463 Calculated: molecular weight (M+H)+: 463
Nađeno: molekulska masa (M+H)+: 463 Found: molecular weight (M+H)+: 463
Vrijeme retencije HPLC: 6,64 min (metoda A) HPLC retention time: 6.64 min (method A)
Primjer 2.54: Example 2.54:
Bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid Biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 99 mg (0,5 mmola) bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 99 mg (0.5 mmol) of biphenyl-4-carboxylic acid.
Iskorištenje: 46 mg (23,9% od teorijskog). Yield: 46 mg (23.9% of theoretical).
C26H28N2O (M = 384,53) C26H28N2O (M = 384.53)
Izračunato: molekulska masa (M+H)+: 385 Calculated: molecular weight (M+H)+: 385
Nađeno: molekulska masa (M+H)+: 385 Found: molecular weight (M+H)+: 385
Vrijeme retencije HPLC: 5,70 min (metoda A) HPLC retention time: 5.70 min (method A)
Primjer 2.55: Example 2.55:
4'-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.55a. 4'-fluor-bifenil-4-karboksilna kiselina 2.55a. 4'-fluoro-biphenyl-4-carboxylic acid
14,27 g (71 mmol) 4-brom-benzojeve kiseline se otopi u 120 ml dioksana i 70 ml 2M otopine Na2CO3. Uzastopce se doda 10 g (71 mmol) 4-fluorfenil-borne kiseline i 4,1 g (4 mmola) tetrakis-(trifenilfosfin)-paladija i reakcijsku smjesu se refluktira 6 h. Katalizator se odsisa i ispere s vrućom vodom. Reakcijsku smjesu se pomiješa s EtOAc, faze kao odvoje i vodenu fazu se zakiseli s limunskom kiselinom. Nastali talog se odsisa, ispere s vodom i osuši pri 45oC u vakuumu. 14.27 g (71 mmol) of 4-bromobenzoic acid are dissolved in 120 ml of dioxane and 70 ml of 2M Na2CO3 solution. 10 g (71 mmol) of 4-fluorophenylboronic acid and 4.1 g (4 mmol) of tetrakis-(triphenylphosphine)-palladium were added successively and the reaction mixture was refluxed for 6 h. The catalyst is sucked off and washed with hot water. The reaction mixture was mixed with EtOAc, the phases were separated and the aqueous phase was acidified with citric acid. The resulting precipitate is suctioned off, washed with water and dried at 45oC in a vacuum.
Iskorištenje: 4,9 g (31,9% od teorijskog). Yield: 4.9 g (31.9% of theoretical).
C13H9FO2 (M = 216,21) C13H9FO2 (M = 216.21)
Izračunato: molekulska masa (M-H)-: 215 Calculated: molecular weight (M-H)-: 215
Nađeno: molekulska masa (M-H)-: 215 Found: molecular weight (M-H)-: 215
2.55.b. 4'-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.55.b. 4'-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 108 mg (0,5 mmola) 4'-fluor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 108 mg (0.5 mmol) of 4'-fluoro-biphenyl-4-carboxylic acid.
Iskorištenje: 12 mg (6,0% od teorijskog). Yield: 12 mg (6.0% of theoretical).
C26H27FN2O (M = 402,52) C26H27FN2O (M = 402.52)
Izračunato: molekulska masa (M+H)+: 403 Calculated: molecular weight (M+H)+: 403
Nađeno: molekulska masa (M+H)+: 403 Found: molecular weight (M+H)+: 403
Vrijeme retencije HPLC: 5,83 min (metoda A) HPLC retention time: 5.83 min (method A)
Primjer 2.56: Example 2.56:
4'-hidroksi-3'-nitro-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-hydroxy-3'-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 130 mg (0,5 mmola) 4'-fluor-3'-nitro-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 130 mg (0.5 mmol) of 4'-fluoro-3'-nitro- biphenyl-4-carboxylic acids.
Iskorištenje: 9 mg (4,0% od teorijskog). Yield: 9 mg (4.0% of theoretical).
C26H27N3O4 (M = 445,52) C26H27N3O4 (M = 445.52)
Izračunato: molekulska masa (M+H)+: 446 Calculated: molecular weight (M+H)+: 446
Nađeno: molekulska masa (M+H)+: 446 Found: molecular weight (M+H)+: 446
Vrijeme retencije HPLC: 5,83 min (metoda A) HPLC retention time: 5.83 min (method A)
Primjer 2.57: Example 2.57:
3'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 3'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.57.s. 3'-klor-bifenil-4-karboksilna kiselina 2.57.s. 3'-chloro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55.a iz 9,64 g (47,96 mmolova) 4-brom-benzojeve kiseline i 7,5 g (47,96 mmolova) 3-klorfenil-borne kiseline. It was produced analogously to example 2.55.a from 9.64 g (47.96 mmol) of 4-bromobenzoic acid and 7.5 g (47.96 mmol) of 3-chlorophenylboronic acid.
Iskorištenje: 6,2 g (55,6% od teorijskog). Yield: 6.2 g (55.6% of theoretical).
C13H9ClO2 (M = 232,67) C13H9ClO2 (M = 232.67)
Izračunato: molekulska masa (M-H)-: 231/233 Calculated: molecular weight (M-H)-: 231/233
Nađeno: molekulska masa (M-H)-: 231/233 Found: molecular weight (M-H)-: 231/233
2.57.b. 3'-klor-bifenil-4-karboksilna kiselina [2-(4- pirolidin-1-ilmetil-fenil)-etil]-amid 2.57.b. 3'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 116 mg (0,5 mmola) 3'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 116 mg (0.5 mmol) of 3'-chloro-biphenyl-4-carboxylic acid.
Iskorištenje: 63 mg (30,1% od teorijskog). Yield: 63 mg (30.1% of theoretical).
C26H27ClN2O (M = 418,97) C26H27ClN2O (M = 418.97)
Izračunato: molekulska masa (M+H)+: 419/421 Calculated: molecular weight (M+H)+: 419/421
Nađeno: molekulska masa (M+H)+: 419/421 Found: molecular weight (M+H)+: 419/421
Vrijeme retencije HPLC: 6,20 min (metoda A) HPLC retention time: 6.20 min (method A)
Primjer 2.58: Example 2.58:
3',4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 3',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.58.a. 3',4'-diklor-bifenil-4-karboksilna kiselina 2.58.a. 3',4'-dichloro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55.a iz 5,27 g (26,20 mmolova) 4-brom-benzojeve kiseline i 5,0 g (26,20 mmolova) 3',4'-diklor-fenilborne kiseline. It was produced analogously to example 2.55.a from 5.27 g (26.20 mmol) of 4-bromo-benzoic acid and 5.0 g (26.20 mmol) of 3',4'-dichloro-phenylboronic acid.
Iskorištenje: 4,05 g (57,9% od teorijskog). Yield: 4.05 g (57.9% of theoretical).
C13H18Cl2O2 (M = 267,11) C13H18Cl2O2 (M = 267.11)
Izračunato: molekulska masa (M-H)-: 265/267/269 Calculated: molecular weight (M-H)-: 265/267/269
Nađeno: molekulska masa (M-H)-: 265/267/269 Found: molecular weight (M-H)-: 265/267/269
2.58.b. 3',4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil )-etil]-amid 2.58.b. 3',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 134 mg (0,5 mmola) 3',4'-diklor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 3',4'-dichloro-biphenyl- 4-carboxylic acids.
Iskorištenje: 45 mg (19,8% od teorijskog). Yield: 45 mg (19.8% of theoretical).
C26H26Cl2N2O (M = 453,42) C26H26Cl2N2O (M = 453.42)
Izračunato: molekulska masa (M+H)+: 453/455/457 Calculated: molecular weight (M+H)+: 453/455/457
Nađeno: molekulska masa (M+H)+: 453/455/457 Found: molecular weight (M+H)+: 453/455/457
Vrijeme retencije HPLC: 6,45 min (metoda A) HPLC retention time: 6.45 min (method A)
Primjer 2.59: Example 2.59:
2',4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.59.a. 2',4'-diklor-bifenil-4-karboksilna kiselina 2.59.a. 2',4'-dichloro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55.a iz 5,23 g (26,0 mmolova) 4-brom-benzojeve kiseline i 10,0 g (52,0 mmola) 2,4-diklorafenil-borne kiseline, refluktiranjem reakcijske smjese 48 h. It was produced analogously to example 2.55.a from 5.23 g (26.0 mmol) of 4-bromobenzoic acid and 10.0 g (52.0 mmol) of 2,4-dichlorophenylboronic acid, by refluxing the reaction mixture for 48 h.
Iskorištenje: 1,5 g (21,6% od teorijskog). Yield: 1.5 g (21.6% of theoretical).
C13H8Cl2O2 (M = 267,11) C13H8Cl2O2 (M = 267.11)
Izračunato: molekulska masa (M-H)-: 265/267/269 Calculated: molecular weight (M-H)-: 265/267/269
Nađeno: molekulska masa (M-H)-: 265/267/269 Found: molecular weight (M-H)-: 265/267/269
2.59.b 2',4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 2.59.b 2',4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 134 mg (0,5 mmola) 2',4'-diklor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 2',4'-dichloro-biphenyl- 4-carboxylic acids.
Iskorištenje: 72 mg (31,8% od teorijskog). Yield: 72 mg (31.8% of theoretical).
C26H26Cl2N2O (M = 453,42) C26H26Cl2N2O (M = 453.42)
Izračunato: molekulska masa (M+H)+: 453/455/457 Calculated: molecular weight (M+H)+: 453/455/457
Nađeno: molekulska masa (M+H)+: 453/455/457 Found: molecular weight (M+H)+: 453/455/457
Vrijeme retencije HPLC: 6,84 min (metoda A) HPLC retention time: 6.84 min (method A)
Primjer 2.60: Example 2.60:
2'-fluor-4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.60.a 2'-fluor-4'-klor-bifenil-4-karboksilna kiselina 2.60.a 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55.a iz 0,52 g (2,5 mmola) 1-brom-4-klor-2-fluorbenzena i 0,5 g (3,0 mmola) 4-karboksifenil-borne kiseline. It was produced analogously to example 2.55.a from 0.52 g (2.5 mmol) of 1-bromo-4-chloro-2-fluorobenzene and 0.5 g (3.0 mmol) of 4-carboxyphenyl-boronic acid.
Iskorištenje: 0,5 g (79,8% od teorijskog). Yield: 0.5 g (79.8% of theoretical).
C13H8ClFO2 (M = 250,66) C13H8ClFO2 (M = 250.66)
Izračunato: molekulska masa (M-H)-: 249/251 Calculated: molecular weight (M-H)-: 249/251
Nađeno: molekulska masa (M-H)-: 249/251 Found: molecular weight (M-H)-: 249/251
Vrijeme retencije HPLC: 8,39 min (metoda A) HPLC retention time: 8.39 min (method A)
2.60.b. 2'-fluor-4'-klor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.60.b. 2'-fluoro-4'-chloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 125 mg (0,5 mmola) 2'-fluor-4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 125 mg (0.5 mmol) of 2'-fluoro-4'-chloro- biphenyl-4-carboxylic acids.
Iskorištenje: 36 mg (16,5% od teorijskog). Yield: 36 mg (16.5% of theoretical).
C26H26ClFN2O (M = 436,96) C26H26ClFN2O (M = 436.96)
Izračunato: molekulska masa (M+H)+: 437/439 Calculated: molecular weight (M+H)+: 437/439
Nađeno: molekulska masa (M+H)+: 437/439 Found: molecular weight (M+H)+: 437/439
Vrijeme retencije HPLC: 6,32 min (metoda A) HPLC retention time: 6.32 min (method A)
Primjer 2.61: Example 2.61:
3,4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.61.a. 3,4'-diklor-bifenil-4-karboksilna kiselina 2.61.a. 3,4'-dichloro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55a iz 0,59 g (2,5 mmola) 4-brom-2-klor-benzojeve kiseline i 0,47 g (3,0 mmola) 4-klorfenil-borne kiseline. It was produced analogously to example 2.55a from 0.59 g (2.5 mmol) of 4-bromo-2-chloro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.
Iskorištenje: 0,55 g (82,4% od teorijskog). Yield: 0.55 g (82.4% of theoretical).
C13H8Cl2O2 (M = 267,11) C13H8Cl2O2 (M = 267.11)
Izračunato: molekulska masa (M-H)-: 265/267/269 Calculated: molecular weight (M-H)-: 265/267/269
Nađeno: molekulska masa (M-H)-: 265/267/269 Found: molecular weight (M-H)-: 265/267/269
Vrijeme retencije HPLC: 8,83 min (metoda A) HPLC retention time: 8.83 min (method A)
2.61.b. 3,4'-diklor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 2.61.b. 3,4'-dichloro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 134 mg (0,5 mmola) 3,4'-diklor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 134 mg (0.5 mmol) of 3,4'-dichloro-biphenyl-4 -carboxylic acids.
Iskorištenje: 24 mg (10,6% od teorijskog) Yield: 24 mg (10.6% of theoretical)
C26H26Cl2N2O (M = 453,42) C26H26Cl2N2O (M = 453.42)
Izračunato: molekulska masa (M+H)+: 453/455/457 Calculated: molecular weight (M+H)+: 453/455/457
Nađeno: molekulska masa (M+H)+: 453/455/457 Found: molecular weight (M+H)+: 453/455/457
Vrijeme retencije HPLC: 6,41 min (metoda A) HPLC retention time: 6.41 min (method A)
Primjer 2.62: Example 2.62:
4'-klor-3-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.62a. 4'-klor-3-fluor-bifenil-4-cart)oksilna kiselina 2.62a. 4'-chloro-3-fluoro-biphenyl-4-cart)oxylic acid
Proizvedena je analogno primjeru 2.55.a iz 0,55 g (2,5 mmola) 4-brom-2-fluor-benzojeve kiseline i 0,47 g (3,0 mmola) 4-klorfenil-borne kiseline. It was produced analogously to example 2.55.a from 0.55 g (2.5 mmol) of 4-bromo-2-fluoro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.
Iskorištenje: 0,60 g (95,7% od teorijskog). Yield: 0.60 g (95.7% of theoretical).
C13H8ClFO2 (M = 250,66) C13H8ClFO2 (M = 250.66)
Izračunato: molekulska masa (M-H)-: 249/251 Calculated: molecular weight (M-H)-: 249/251
Nađeno: molekulska masa (M-H)-: 249/251 Found: molecular weight (M-H)-: 249/251
Vrijeme retencije HPLC: 8,22 min (metoda A) HPLC retention time: 8.22 min (method A)
2.62.b. 4'-klor-3-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.62.b. 4'-chloro-3-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etnilamina i 125 mg (0,5 mmola) of 4'-klor-3-fluor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethnylamine and 125 mg (0.5 mmol) of 4'-chloro-3-fluoro- biphenyl-4-carboxylic acids.
Iskorištenje: 37 mg (16,9% od teorijskog). Yield: 37 mg (16.9% of theoretical).
C26H26ClFN2O (M = 436,96) C26H26ClFN2O (M = 436.96)
Izračunato: molekulska masa (M+H)+: 437/439 Calculated: molecular weight (M+H)+: 437/439
Nađeno: molekulska masa (M+H)+: 437/439 Found: molecular weight (M+H)+: 437/439
Vrijeme retencije HPLC: 6,45 min (metoda A) HPLC retention time: 6.45 min (method A)
Primjer 2.63: Example 2.63:
4'-klor-2-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1 -ilmetil-fenil)-etil]-amid 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.63.a 4'-klor-2-fluor-bifenil-4-karboksilna kiselina 2.63.a 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid
Proizvedena je analogno primjeru 2.55.a iz 0,66 g (3,0 mmola) 4-brom-3-fluor-benzojeve kiseline i 0,47 g (3,0 mmola) 4-klorfenil-borne kiseline. It was produced analogously to example 2.55.a from 0.66 g (3.0 mmol) of 4-bromo-3-fluoro-benzoic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.
Iskorištenje: 0,60 g (79,8% od teorijskog). Yield: 0.60 g (79.8% of theoretical).
C13H8ClFO2 (M = 250,66) C13H8ClFO2 (M = 250.66)
Izračunato: molekulska masa (M-H)-: 249/251 Calculated: molecular weight (M-H)-: 249/251
Nađeno: molekulska masa (M-H)-: 249/251 Found: molecular weight (M-H)-: 249/251
Vrijeme retencije HPLC: 8,50 min (metoda A) HPLC retention time: 8.50 min (method A)
2.63.b. 4'-klor-2-fluor-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.63.b. 4'-chloro-2-fluoro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 163 mg (0,8 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 201 mg (0,8 mmola) 4'-klor-2-fluor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 163 mg (0.8 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 201 mg (0.8 mmol) of 4'-chloro-2-fluoro-biphenyl -4-carboxylic acids.
Iskorištenje: 74 mg (21,2% od teorijskog). Yield: 74 mg (21.2% of theoretical).
C26H26ClFN2O (M = 436,96) C26H26ClFN2O (M = 436.96)
Izračunato: molekulska masa (M+H)+: 437/439 Calculated: molecular weight (M+H)+: 437/439
Nađeno: molekulska masa (M+H)+: 437/439 Found: molecular weight (M+H)+: 437/439
Vrijeme retencije HPLC: 6,61 min (metoda A) HPLC retention time: 6.61 min (method A)
Primjer 2.64: Example 2.64:
3-nitro-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 3-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.64.a. 3-nitro-bifenil-4-karboksilna kiselina 2.64.a. 3-nitro-biphenyl-4-carboxylic acid
150 mg (0,13 mmola) tetrakis-(trifenilfosfin)-paladija doda se u otopinu od 1,0 g (4,07 mmola) 4-brom-2-nitro-benzojeve kiseline u 20 ml toluena i miješa se 10 min pri sobnoj temperaturi. Zatim se doda otopinu od 0,5 g (4,10 mmola) fenilborne kiseline u 10 ml MeOH i otopinu od 1,0 g Na2CO3 u 10 ml vode. Reakcijsku smjesu se refluktira 5 h i miješa pri sobnoj temperaturi preko vikenda. Otapala se odstrane u vakuumu, ostatak se pomiješa s vodom, zakiseli se s konc. HCl, ekstrahira s EtOAc, organsku fazu se osuši preko Na2SO4 i zatim se otapalo odstrani. 150 mg (0.13 mmol) of tetrakis-(triphenylphosphine)-palladium is added to a solution of 1.0 g (4.07 mmol) of 4-bromo-2-nitro-benzoic acid in 20 ml of toluene and stirred for 10 min at room temperature. Then a solution of 0.5 g (4.10 mmol) of phenylboronic acid in 10 ml of MeOH and a solution of 1.0 g of Na2CO3 in 10 ml of water are added. The reaction mixture was refluxed for 5 h and stirred at room temperature over the weekend. Solvents are removed under vacuum, the residue is mixed with water, acidified with conc. HCl, extracted with EtOAc, the organic phase was dried over Na2SO4 and then the solvent was removed.
Iskorištenje: 0,87 g (87,5% od teorijskog). Yield: 0.87 g (87.5% of theoretical).
Rf vrijednost: 0,40 (silika gel, diklormetan/etanol 3:1). Rf value: 0.40 (silica gel, dichloromethane/ethanol 3:1).
2.64.b. 3-nitro-bifenil-4-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.64.b. 3-nitro-biphenyl-4-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 122 mg (0,5 mmola) 3-nitro-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 122 mg (0.5 mmol) of 3-nitro-biphenyl-4-carboxylic acid .
Iskorištenje: 100 mg (46,6% od teorijskog). Yield: 100 mg (46.6% of the theoretical).
C26H27N3O3 (M = 429,52) C26H27N3O3 (M = 429.52)
Izračunato: molekulska masa (M+H)+: 430 Calculated: molecular weight (M+H)+: 430
Nađeno: molekulska masa (M+H)+: 430 Found: molecular weight (M+H)+: 430
Vrijeme retencije HPLC: 5,83 min (metoda A) HPLC retention time: 5.83 min (method A)
Primjer 2.65: Example 2.65:
5-(4-klor-fenil)-piridin-2-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.65.a. 5-(4-klor-fenil)-piridin-2-karboksilna kiselina 2.65.a. 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid
Proizvedena je analogno primjeru 2.55a iz 0,51 g (2,5 mmmol) 5-brom-piridin-2-karboksilne kiseline i 0,47 g (3,0 mmola) 4-klorfenil-borne kiseline. It was produced analogously to example 2.55a from 0.51 g (2.5 mmol) of 5-bromo-pyridine-2-carboxylic acid and 0.47 g (3.0 mmol) of 4-chlorophenyl-boronic acid.
Iskorištenje: 0,23 g (39,4% od teorijskog). Yield: 0.23 g (39.4% of theoretical).
C12H8ClNO2 (M = 233,66) C12H8ClNO2 (M = 233.66)
Izračunato: molekulska masa (M-H)-: 232/234 Calculated: molecular weight (M-H)-: 232/234
Nađeno: molekulska masa (M-H)-: 232/234 Found: molecular weight (M-H)-: 232/234
Vrijeme retencije HPLC: 5,89 min (metoda A) HPLC retention time: 5.89 min (method A)
2.65.b. 5-(4-klor-fenil)-piridin-2-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.65.b. 5-(4-chloro-phenyl)-pyridine-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 116 mg (0,5 mmola) 5-(4-klor-fenil)-piridin-2-karboksilne kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 116 mg (0.5 mmol) of 5-(4-chloro-phenyl)- pyridine-2-carboxylic acids.
Iskorištenje: 7 mg (3,3% od teorijskog). Yield: 7 mg (3.3% of theoretical).
C25H26ClN3O (M = 419,96) C25H26ClN3O (M = 419.96)
Izračunato: molekulska masa (M+H)+: 420/422 Calculated: molecular weight (M+H)+: 420/422
Nađeno: molekulska masa (M+H)+: 420/422 Found: molecular weight (M+H)+: 420/422
Vrijeme retencije HPLC: 6,40 min (metoda A) HPLC retention time: 6.40 min (method A)
Primjer 2.66: Example 2.66:
N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-tiofen-3-il-benzamid N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-3-yl-benzamide
[image] [image]
2.66.a. Etil 4-tiofen-3-il-benzoat 2.66.a. Ethyl 4-thiophen-3-yl-benzoate
Proizveden je analogno primjeru 2.46.b iz 414 mg (1,5 mmola) etil 4-jod-benzoata i 230 mg (1,8 mmola) tiofen-3-borne kiseline. It was produced analogously to example 2.46.b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophene-3-boronic acid.
Iskorištenje: 348 mg (100% od teorijskog). Yield: 348 mg (100% of theoretical).
C13H12O2S (M = 232,30) C13H12O2S (M = 232.30)
Izračunato: molekulska masa (M+H)+: 233 Calculated: molecular weight (M+H)+: 233
Nađeno: molekulska masa (M+H)+: 233 Found: molecular weight (M+H)+: 233
Vrijeme retencije HPLC: 6,20 min (metoda B) HPLC retention time: 6.20 min (method B)
2.66.b. 4-tiofen-3-il-benzojeva kiselina 2.66.b. 4-thiophen-3-yl-benzoic acid
Proizvedena je analogno primjeru 2.7.b iz 280 mg (1,5 mmola) etil 4-tiofen-3-il-benzoata . It was produced analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-3-yl-benzoate.
Iskorištenje: 146 mg (59,3% od teorijskog). Yield: 146 mg (59.3% of theoretical).
C11H8O2S (M = 204,25) C11H8O2S (M = 204.25)
Izračunato: molekulska masa (M-H)-: 203 Calculated: molecular weight (M-H)-: 203
Nađeno: molekulska masa (M-H)-: 203 Found: molecular weight (M-H)-: 203
Vrijeme retencije HPLC: 7,60 min (metoda A) HPLC retention time: 7.60 min (method A)
2.66.c. N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-tiofen-3-il-benzamid 2.66.c. N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-3-yl-benzamide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 102 mg (0,5 mmola) 4-tiofen-3-il-benzojeve kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 mg (0.5 mmol) of 4-thiophen-3-yl-benzoic acid. .
Iskorištenje: 103 mg (53,0% od teorijskog). Yield: 103 mg (53.0% of theoretical).
C24H26N2OS (M = 390,55) C24H26N2OS (M = 390.55)
Izračunato: molekulska masa (M+H)+: 391 Calculated: molecular weight (M+H)+: 391
Nađeno: molekulska masa (M+H)+: 391 Found: molecular weight (M+H)+: 391
Vrijeme retencije HPLC: 6,10 min (metoda A) HPLC retention time: 6.10 min (method A)
Primjer 2.67: Example 2.67:
N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-tiofen-2-il-benzamid N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-2-yl-benzamide
[image] [image]
2.67a. Etil 4-tiofen-2-il-benzoat 2.67a. Ethyl 4-thiophen-2-yl-benzoate
Proizveden je analogno primjeru 2.46.b iz 414 mg (1,5 mmola) etil 4-jod-benzoata i 230 mg (1,8 mmola) tiofen-2-borne kiseline. It was produced analogously to example 2.46.b from 414 mg (1.5 mmol) of ethyl 4-iodo-benzoate and 230 mg (1.8 mmol) of thiophene-2-boronic acid.
Iskorištenje: 348 mg (100% od teorijskog). Yield: 348 mg (100% of theoretical).
C13H12O2S (M = 232,30) C13H12O2S (M = 232.30)
Izračunato: molekulska masa (M+H)+: 233 Calculated: molecular weight (M+H)+: 233
Nađeno: molekulska masa (M+H)+: 233 Found: molecular weight (M+H)+: 233
Vrijeme retencije HPLC: 6,29 min (metoda B) HPLC retention time: 6.29 min (method B)
2.67.b. 4-tiofen-2-il-benzojeva kiselina 2.67.b. 4-thiophen-2-yl-benzoic acid
Proizvedena je analogno primjeru 2.7.b iz 280 mg (1,5 mmola) etil 4-tiofen-2-il-benzoata. It was produced analogously to example 2.7.b from 280 mg (1.5 mmol) of ethyl 4-thiophen-2-yl-benzoate.
Iskorištenje: 126 mg (51,2% od teorijskog). Yield: 126 mg (51.2% of theoretical).
C11H8O2S (M = 204,25) C11H8O2S (M = 204.25)
Izračunato: molekulska masa (M-H)-: 203 Calculated: molecular weight (M-H)-: 203
Nađeno: molekulska masa (M-H)-: 203 Found: molecular weight (M-H)-: 203
Vrijeme retencije HPLC: 7,60 min (metoda A) HPLC retention time: 7.60 min (method A)
2.67.c. N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-tiofen-2-il-benzamid 2.67.c. N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-thiophen-2-yl-benzamide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 102 mg (0,5 mmola) 4-tiofen-2-il-benzojeve kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 mg (0.5 mmol) of 4-thiophen-2-yl-benzoic acid. .
Iskorištenje: 112 mg (57,5% od teorijskog). Yield: 112 mg (57.5% of theoretical).
C24H26N2OS (M = 390,55) C24H26N2OS (M = 390.55)
Izračunato: molekulska masa (M+H)+: 391 Calculated: molecular weight (M+H)+: 391
Nađeno: molekulska masa (M+H)+: 391 Found: molecular weight (M+H)+: 391
Vrijeme retencije HPLC: 6,05 min (metoda A) HPLC retention time: 6.05 min (method A)
Primjer 2.68: Example 2.68:
4-(5-klor-tiofen-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.68a. 4-(5-klor-tiofen-2-il)-benzojeva kiselina 2.68a. 4-(5-chloro-thiophen-2-yl)-benzoic acid
Proizvedena je analogno primjeru 2.55.a iz 300 mg (1,52 mmola) 2-brom-5-klortiofena i 277 mg (1,67 mmola) 4-karboksifenil-borne kiseline upotrebom ootpine KHSO4 za zakiseljavanje pri obradi reakcijske smjese. It was produced analogously to example 2.55.a from 300 mg (1.52 mmol) of 2-bromo-5-chlorothiophene and 277 mg (1.67 mmol) of 4-carboxyphenyl-boronic acid using KHSO4 solution for acidification during processing of the reaction mixture.
Iskorištenje: 76 mg (21,0% od teorijskog). Yield: 76 mg (21.0% of theoretical).
C11H7ClO2S (M = 238,69) C11H7ClO2S (M = 238.69)
Izračunato: molekulska masa (M-H)-: 237/239 Calculated: molecular weight (M-H)-: 237/239
Nađeno: molekulska masa (M-H)-: 237/239 Found: molecular weight (M-H)-: 237/239
Vrijeme retencije HPLC: 8,75 min (metoda A) HPLC retention time: 8.75 min (method A)
2.68.b. 4-(5-klor-tiofen-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.68.b. 4-(5-chloro-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 61 mg (0,3 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 71 mg (0,3 mmola) 4-(5-klor-tiofen-2-il)-benzojeve kiseline. It was produced according to general procedure I from 61 mg (0.3 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 71 mg (0.3 mmol) of 4-(5-chloro-thiophene-2 -yl)-benzoic acid.
Iskorištenje: 29 mg (22,9% od teorijskog). Yield: 29 mg (22.9% of theoretical).
C24H25ClN2OS (M = 425,0) C24H25ClN2OS (M = 425.0)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Vrijeme retencije HPLC: 6,65 min (metoda A) HPLC retention time: 6.65 min (method A)
Primjer 2.69: Example 2.69:
4-furan-2-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-furan-2-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.69.a. 4-furan-2-il-benzojeva kiselina 2.69.a. 4-furan-2-yl-benzoic acid
Proizvedena je analogno primjeru 2.68a iz 302 mg (1,5 mmola) 4-brom-benzojeve kiseline i 201 mg (1,8 mmola) furan-2-borne kiseline. It was produced analogously to example 2.68a from 302 mg (1.5 mmol) of 4-bromo-benzoic acid and 201 mg (1.8 mmol) of furan-2-boronic acid.
Iskorištenje: 166 mg (58,8% od teorijskog). Yield: 166 mg (58.8% of theoretical).
C11H8O3 (M = 188,19) C11H8O3 (M = 188.19)
Izračunato: molekulska masa (M-H)-: 187 Calculated: molecular weight (M-H)-: 187
Nađeno: molekulska masa (M-H)-: 187 Found: molecular weight (M-H)-: 187
Vrijeme retencije HPLC: 6,82 min (metoda A) HPLC retention time: 6.82 min (method A)
2.69b. 4-furan-2-il-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.69b. 4-furan-2-yl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 94 mg (0,5 mmola) 4-furan-2-il-benzojeve kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 94 mg (0.5 mmol) of 4-furan-2-yl-benzoic acid .
Iskorištenje: 91 mg (48,4% od teorijskog). Yield: 91 mg (48.4% of theoretical).
C24H26N2O2 (M = 374,49) C24H26N2O2 (M = 374.49)
Izračunato: molekulska masa (M+H)+: 375 Calculated: molecular weight (M+H)+: 375
Nađeno: molekulska masa (M+H)+: 375 Found: molecular weight (M+H)+: 375
Vrijeme retencije HPLC: 6,48 min (metoda A) HPLC retention time: 6.48 min (method A)
Primjer 2.70: Example 2.70:
4-(5-metil-piridin-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(5-methyl-pyridin-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.70a. 4-(5-metil-piridin-2-il)-benzojeva kiselina 2.70a. 4-(5-methyl-pyridin-2-yl)-benzoic acid
Proizvedena je analogno primjeru 2.55.a iz 430 mg (2,50 mmola) 2-brom-5-metilpiridina i 498 mg (3,00 mmola) 4-karboksifenil-borne kiseline. It was produced analogously to example 2.55.a from 430 mg (2.50 mmol) of 2-bromo-5-methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenyl-boronic acid.
Iskorištenje: 300 mg (56,3% od teorijskog). Yield: 300 mg (56.3% of the theoretical).
C13H11NO2 (M = 213,24) C13H11NO2 (M = 213.24)
Izračunato: molekulska masa (M+H)+: 214 Calculated: molecular weight (M+H)+: 214
Nađeno: molekulska masa (M+H)+: 214 Found: molecular weight (M+H)+: 214
Vrijeme retencije HPLC: 4,55 min (metoda A) HPLC retention time: 4.55 min (method A)
2.70.b. 4-(5-metil-piridin-2-il)-N-[2-(4-pirolidin-1-il-metil-fenil)-etill-benzamid 2.70.b. 4-(5-methyl-pyridin-2-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl-benzamide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 107 mg (0,5 mmola) 4-(5-metil-piridin-2-il)-benzojeve kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 107 mg (0.5 mmol) of 4-(5-methyl-pyridin-2 -yl)-benzoic acid.
Iskorištenje: 53 mg (26,5% od teorijskog). Yield: 53 mg (26.5% of theoretical).
C26H29N3O (M = 399,54) C26H29N3O (M = 399.54)
Izračunato: molekulska masa (M+H)+: 400 Calculated: molecular weight (M+H)+: 400
Nađeno: molekulska masa (M+H)+: 400 Found: molecular weight (M+H)+: 400
Vrijeme retencije HPLC: 3,98 min (metoda A) HPLC retention time: 3.98 min (method A)
Primjer 2.71: Example 2.71:
4-(6-metil-piridin-3-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(6-methyl-pyridin-3-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.71.a. 4-(6-metil-piridin-3-il)-benzojeva kiselina 2.71.a. 4-(6-Methyl-pyridin-3-yl)-benzoic acid
Proizvedena je analogno primjeru 2.55.a iz 430 mg (2,50 mmola) 5-brom-2-metilpiridina i 498 mg (3,00 mmola) 4-karboksifenil-borne kiseline. It was produced analogously to example 2.55.a from 430 mg (2.50 mmol) of 5-bromo-2-methylpyridine and 498 mg (3.00 mmol) of 4-carboxyphenylboronic acid.
Iskorištenje: 300 mg (56,3% od teorijskog). Yield: 300 mg (56.3% of the theoretical).
C13H11NO2 (M = 213,24) C13H11NO2 (M = 213.24)
Izračunato: molekulska masa (M+H)+: 214 Calculated: molecular weight (M+H)+: 214
Nađeno: molekulska masa (M+H)+: 214 Found: molecular weight (M+H)+: 214
Vrijeme retencije HPLC: 2,66 min (metoda A) HPLC retention time: 2.66 min (method A)
2.71.b. 4-(6-metil-piridin-3-il)-N-[2-(4-pirolidin-1-il-metil-fenil)-etil]-benzamid 2.71.b. 4-(6-methyl-pyridin-3-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 102 mg (0,5 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 107 mg (0,5 mmola) 4-(6-metil-piridin-3-il)-benzojeve kiseline. It was produced according to general procedure I from 102 mg (0.5 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 107 mg (0.5 mmol) of 4-(6-methyl-pyridin-3 -yl)-benzoic acid.
Iskorištenje: 48 mg (24,0% od teorijskog). Yield: 48 mg (24.0% of theoretical).
C26H29N3O (M = 399,54) C26H29N3O (M = 399.54)
Izračunato: molekulska masa (M+H)+: 400 Calculated: molecular weight (M+H)+: 400
Nađeno: molekulska masa (M+H)+: 400 Found: molecular weight (M+H)+: 400
Vrijeme retencije HPLC: 3,06 min (metoda A) HPLC retention time: 3.06 min (method A)
Primjer 2.72: Example 2.72:
4-(4-klor-fenil)-tiofen-2-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4-(4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.72.a. Metil 4-(4-klor-fenil)-tiofen-2-karboksilat 2.72.a. Methyl 4-(4-chloro-phenyl)-thiophene-2-carboxylate
420 mg (1,25 mmola) metil 4-brom-tiofen-2-karboksilata se otopi u 10 ml dioksana i 5 ml 2M otopine Na2CO3. Uzastopce se doda 196 mg (0,06 mmola) 4-klor-fenil-borne kiseline i 72 mg (0,06 mmola) tetrakis-(trifenilfosfin)-paladija, reakcijsku smjesu se refluktira 6 h i miješa se još daljnjih 60 h pri sobnoj temperaturi. Kad se ponovno zagrije, vruću reakcijsku otopinu se odsisa kroz filter od staklenih vlakana, ispere se s dioksanom, pomiješa s poluzasićenom otopinom NaHCO3 i ekstrahira se s EtOAc. Sjedinjene organske faze se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti kromatografijom na stupcu silika gela (petrol eter/ etil acetat 9:1). 420 mg (1.25 mmol) of methyl 4-bromo-thiophene-2-carboxylate are dissolved in 10 ml of dioxane and 5 ml of 2M Na2CO3 solution. 196 mg (0.06 mmol) of 4-chloro-phenyl-boronic acid and 72 mg (0.06 mmol) of tetrakis-(triphenylphosphine)-palladium are successively added, the reaction mixture is refluxed for 6 h and stirred for a further 60 h at room temperature. temperature. When rewarmed, the hot reaction solution was filtered off with suction through a glass fiber filter, washed with dioxane, mixed with semi-saturated NaHCO 3 solution, and extracted with EtOAc. The combined organic phases are dried over MgSO4. The residue after removing the drying agent and solvent is purified by chromatography on a silica gel column (petroleum ether/ethyl acetate 9:1).
Iskorištenje: 150 mg (47,3% od teorijskog). Yield: 150 mg (47.3% of theoretical).
C12H9ClO2S (M = 252,72) C12H9ClO2S (M = 252.72)
Izračunato: molekulska masa (M+H)+: 253/255 Calculated: molecular weight (M+H)+: 253/255
Nađeno: molekulska masa (M+H)+: 253/255 Found: molecular weight (M+H)+: 253/255
Vrijeme retencije HPLC: 6,21 min (metoda B) HPLC retention time: 6.21 min (method B)
2.72.b. 4-(4-klor-fenil)-tiofen-2-karboksilna kiselina 2.72.b. 4-(4-Chloro-phenyl)-thiophene-2-carboxylic acid
2 ml 1M otopine NaOH doda se u otopinu od 150 mg metil 4-(4-klor-fenil)-tiofen-2-karboksilata u 10 ml EtOH i reakcijsku otopinu se miješa pri sobnoj temperaturi preko vikenda. Otapalo se ispari u vakuumu, ostatak se pomiješa s 2 ml 1N solne kiseline i ohladi se na 0°C . Istaložen proizvod se odsisa, ispere s vodom i osuši pri 50°C. 2 ml of 1M NaOH solution was added to a solution of 150 mg of methyl 4-(4-chloro-phenyl)-thiophene-2-carboxylate in 10 ml of EtOH and the reaction solution was stirred at room temperature over the weekend. The solvent is evaporated in a vacuum, the residue is mixed with 2 ml of 1N hydrochloric acid and cooled to 0°C. The precipitated product is sucked off, washed with water and dried at 50°C.
Iskorištenje: 140 mg (98,7% od teorijskog). Yield: 140 mg (98.7% of theoretical).
C11H7ClO2S (M = 238,69) C11H7ClO2S (M = 238.69)
Izračunato: molekulska masa (M+H)+: 239/241 Calculated: molecular weight (M+H)+: 239/241
Nađeno: molekulska masa (M+H)+: 239/241 Found: molecular weight (M+H)+: 239/241
Vrijeme retencije HPLC: 8,31 min (metoda A) HPLC retention time: 8.31 min (method A)
2.72.c. 4-(4-klor-fenil)-tiofen-2-karboksilna kiselina [2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.72.c. 4-(4-chloro-phenyl)-thiophene-2-carboxylic acid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 144 mg (0,70 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 140 mg (0,59 mmola) 4-(4-klor-fenil)-tiofen-2-karboksilne kiseline. It was produced according to general procedure I from 144 mg (0.70 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 140 mg (0.59 mmol) of 4-(4-chloro-phenyl)- thiophene-2-carboxylic acids.
Iskorištenje: 78 mg (31,3% od teorijskog). Yield: 78 mg (31.3% of theoretical).
C26H29N3O (M = 425,00) C26H29N3O (M = 425.00)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Vrijeme retencije HPLC: 3,90 min (metoda A) HPLC retention time: 3.90 min (method A)
Primjer 2.73: Example 2.73:
4-(5-acetil-tiofen-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(5-acetyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.73a. 4-jod-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.73a. 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2,04 g (10,0 mmolova) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 2,48 g (10,0 mmolova) 4-jod-benzojeve kiseline. It was produced according to general procedure I from 2.04 g (10.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 2.48 g (10.0 mmol) of 4-iodo-benzoic acid .
Iskorištenje: 1,91 g (44,0% od teorijskog). Yield: 1.91 g (44.0% of theoretical).
C20H23IN2O (M = 434,32) C20H23IN2O (M = 434.32)
Izračunato: molekulska masa (M+H)+: 435 Calculated: molecular weight (M+H)+: 435
Nađeno: molekulska masa (M+H)+: 435 Found: molecular weight (M+H)+: 435
Vrijeme retencije HPLC: 5,40 min (metoda A) HPLC retention time: 5.40 min (method A)
2.73b. 4-(5-acetil-tiofen-2-il)-N-[2-(4-pirolidin-1-il-metil-fenil)-etil]-benzamid 2.73b. 4-(5-acetyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-benzamide
Proizveden je analogno primjeru 2.46b iz 250 mg (0,58 mmola) 4-jod-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benz-amida i 118 mg (0,69 mmola) 5-acetil-2-tiofen-borne kiseline, refluktiranjem reakcijske smjese 15 h. It was produced analogously to example 2.46b from 250 mg (0.58 mmol) of 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide and 118 mg (0.69 mmol ) of 5-acetyl-2-thiophene-boronic acid, by refluxing the reaction mixture for 15 h.
Iskorištenje: 50 mg (20,2% od teorijskog). Yield: 50 mg (20.2% of theoretical).
C26H28N2O2S (M = 432,59) C26H28N2O2S (M = 432.59)
Izračunato: molekulska masa (M+H)+: 433 Calculated: molecular weight (M+H)+: 433
Nađeno: molekulska masa (M+H)+: 433 Found: molecular weight (M+H)+: 433
Vrijeme retencije HPLC: 3,91 min (metoda B) HPLC retention time: 3.91 min (method B)
Primjer 2.74: Example 2.74:
4-(5-formil-tiofen-2-il)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(5-formyl-thiophen-2-yl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
Proizveden je analogno primjeru 2.46.b iz 250 mg (0,58 mmola) 4-jod-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benz-amida i 107 mg (0,69 mmola) 5-formil-2-tiofen-borne kiseline, refluktiranjem reakcijske smjesu 15 h. It was produced analogously to example 2.46.b from 250 mg (0.58 mmol) of 4-iodo-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide and 107 mg (0.69 mmol) of 5-formyl-2-thiophene-boronic acid, by refluxing the reaction mixture for 15 h.
Iskorištenje: 22 mg (9,1% od teorijskog). Yield: 22 mg (9.1% of theoretical).
C25H26N2O2S (M = 418,56) C25H26N2O2S (M = 418.56)
Izračunato: molekulska masa (M+H)+: 419 Calculated: molecular weight (M+H)+: 419
Nađeno: molekulska masa (M+H)+: 419 Found: molecular weight (M+H)+: 419
Vrijeme retencije HPLC: 3,82 min (metoda B) HPLC retention time: 3.82 min (method B)
Primjer 2.75: Example 2.75:
4'-klor-bifenil-4-karboksilna kiselina [2-(4-aminometil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(4-aminomethyl-phenyl)-ethyl]-amide
[image] [image]
2.75.a. Etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoat 2.75.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate
20 ml tionil klorida i 1 ml DMF-a se doda kap po kap u 9,31 g (40 mmolova) 4'-klor-bifenil-4-karboksilne kiseline. Reakcijsku smjesu se grije 2 h pri 60°C. Zatim se suvišak tionil klorida odstrani u vakuumu pri 50°C i ostatak se preuzme u 200 ml CH2Cl2. Tu otopinu se doda kap po kap k 9,19 g (40 mmolova) etil 4-(2-amino-etil)-benzoata, upotrijebljenog u obliku hidroklorida, u 100 ml 10%-tne vodene otopine Na2CO3 i reakcijsku smjesu se miješa daljnji sat pri sobnoj temperaturi. Nakon dodatka vode i CH2Cl2, organsku fazu se odvoji, vodenu fazu se ekstrahira sa CH2Cl2, sjedinjene organsku faze se isperu s poluzasićenom otopinom NaHCO3 i vodom i osuše se preko MgSO4. Nakon odstranjivanja sredstva za sušenje otopinu se filtrira kroz aktivirani ugljen, ispari se u vakuumu i ostatak se prekristalizira iz terc-butilmetil etera. 20 ml of thionyl chloride and 1 ml of DMF were added dropwise to 9.31 g (40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. The reaction mixture is heated for 2 h at 60°C. Then excess thionyl chloride is removed in vacuo at 50°C and the residue is taken up in 200 ml of CH2Cl2. 9.19 g (40 mmol) of ethyl 4-(2-amino-ethyl)-benzoate, used in the form of hydrochloride, in 100 ml of a 10% aqueous Na2CO3 solution were added dropwise to that solution and the reaction mixture was further stirred hour at room temperature. After adding water and CH2Cl2, the organic phase is separated, the aqueous phase is extracted with CH2Cl2, the combined organic phases are washed with half-saturated NaHCO3 solution and water and dried over MgSO4. After removing the drying agent, the solution is filtered through activated carbon, evaporated in vacuo and the residue recrystallized from tert-butylmethyl ether.
Iskorištenje: 11,93 g (73,1% od teorijskog) Yield: 11.93 g (73.1% of theoretical)
C24H22ClNO3 (M = 407,90) C24H22ClNO3 (M = 407.90)
Izračunato: molekulska masa (M+H)+: 408 Calculated: molecular weight (M+H)+: 408
Nađeno: molekulska masa (M+H)+: 408 Found: molecular weight (M+H)+: 408
Vrijeme retencije HPLC: 9,8 min (metoda A) HPLC retention time: 9.8 min (method A)
2.75.b. 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeva kiselina 2.75.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid
50 ml 2M otopine NaOH doda se u otopinu od 11,93 g (29,25 mmolova) etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoata u 150 ml EtOH i miješa se 2 h pri sobnoj temperaturi. Reakcijsku otopinu se namjesti na pH 6-7 s 1N otopinom HCl, istaloženi proizvod se odfiltrira i osuši u vakuumskoj peći. 50 ml of 2M NaOH solution is added to a solution of 11.93 g (29.25 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate in 150 ml EtOH and stirred for 2 h at room temperature. The reaction solution is adjusted to pH 6-7 with 1N HCl solution, the precipitated product is filtered off and dried in a vacuum oven.
Iskorištenje: 10,74 g (96,7% od teorijskog). Yield: 10.74 g (96.7% of theoretical).
C22H22ClNO3 (M = 379,85) C22H22ClNO3 (M = 379.85)
Izračunato: molekulska masa (M+H)+: 380/382 Calculated: molecular weight (M+H)+: 380/382
Nađeno: molekulska masa (M+H)+: 380/382 Found: molecular weight (M+H)+: 380/382
Vrijeme retencije HPLC: 8,0 min (metoda A) HPLC retention time: 8.0 min (method A)
2.75c. 4'-klor-bifenil-4-karboksilna kiselina [2-(4-hidroksimetil-fenil)-etil]-amid 2.75c. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-hydroxymethyl-phenyl)-ethyl]-amide
4,82 g (29,69 mmola) CDI-a se doda u otopinu od 10,74 g (28,28 mmolova) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeve kiseline u 150 ml suhog THF-a i reakcijsku smjesu se grije 2 h pri 50°C. Tu otopinu se doda u suspenziju od 2,14 g (56,56 mmolova) NaBH4 u 5 ml vode i snažno se miješa daljnji sat pri sobnoj temperaturi. Pomoću 1N otopine HCl namjesti se pH otopine na 6, i to se zatim pomiješa s EtOAc i profiltrira. Filtrat se ispere s poluzasićenom otopinom NaHCO3 i vodom i osuši se preko MgSO4. Kako ostatak još uvijek sadrži neizreagiranu 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojevu kiselinu nakon odstranjivanja sredstva za sušenje i otapala, gornji postupak redukcije se ponovi. Dobiveni proizvod se osuši pri 40°C. 4.82 g (29.69 mmol) of CDI was added to a solution of 10.74 g (28.28 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]- of ethyl}-benzoic acid in 150 ml of dry THF and the reaction mixture is heated for 2 h at 50°C. This solution was added to a suspension of 2.14 g (56.56 mmol) of NaBH 4 in 5 ml of water and stirred vigorously for a further hour at room temperature. The pH of the solution was adjusted to 6 using 1N HCl solution, and this was then mixed with EtOAc and filtered. The filtrate was washed with half-saturated NaHCO3 solution and water and dried over MgSO4. As the residue still contains unreacted 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid after removal of drying agent and solvent, the above reduction procedure is repeated. The obtained product is dried at 40°C.
Iskorištenje: 9,3 g (89,9% od teorijskog) Yield: 9.3 g (89.9% of theoretical)
C22H20ClNO2 (M = 365,86) C22H20ClNO2 (M = 365.86)
Izračunato: molekulska masa (M+H)+: 366/368 Calculated: molecular weight (M+H)+: 366/368
Nađeno: molekulska masa (M+H)+: 366/368 Found: molecular weight (M+H)+: 366/368
Vrijeme retencije HPLC: 8,11 min (metoda A) HPLC retention time: 8.11 min (method A)
2.75.d. 4'-klor-bifenil-4-karboksilna kiselina [2-(4-brom-metil-fenil)-etil]-amid 2.75 d. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-bromo-methyl-phenyl)-ethyl]-amide
1,22 ml PBr3 se doda kap po kap u otopinu od 7,9 g (21,59 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-hidroksimetil-fenil)-etil]-amida u 300 ml CH2Cl2. Reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. Nastali talog se odsisa i filtrat se ispari. Ostatak se triturira s malo acetonitrila i CH2Cl2, odsisa se, pomiješa s prvim dobivenim talogom i osuši na zraku. 1.22 ml of PBr3 was added dropwise to a solution of 7.9 g (21.59 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-phenyl)-ethyl]-amide in 300 ml of CH2Cl2. The reaction mixture was stirred overnight at room temperature. The resulting precipitate is suctioned off and the filtrate is evaporated. The residue is triturated with a little acetonitrile and CH2Cl2, filtered off with suction, mixed with the first precipitate obtained and dried in air.
Iskorištenje: 8,6 g (92,9% od teorijskog). Yield: 8.6 g (92.9% of theoretical).
C22H19BrClNO (M = 428,76) C22H19BrClNO (M = 428.76)
Izračunato: molekulska masa (M+H)+: 428/430/432 Calculated: molecular weight (M+H)+: 428/430/432
Nađeno: molekulska masa (M+H)+: 428/430/432 Found: molecular weight (M+H)+: 428/430/432
Rf vrijednost: 0,40 (silika gel, CH2Cl2). Rf value: 0.40 (silica gel, CH2Cl2).
2.75.e. 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-aminometil-fenil)-etil]-amid 2.75.e. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-aminomethyl-phenyl)-ethyl]-amide
3 ml 0,5 M otopine NH3 u dioksanu doda se u otopinu od 150 mg (0,35 mmola) 4'-klor-bifenil-4-karboksilna kiselina- [2-(4-brom-metil-fenil)-etil]-amida u 10 ml acetonitrila i miješa se 3 dana pri sobnoj temperaturi. Reakcijsku smjesu se ispari i ostatak se očisti kromatografijom na stupcu (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). 3 ml of a 0.5 M solution of NH3 in dioxane is added to a solution of 150 mg (0.35 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl] -amide in 10 ml of acetonitrile and stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is purified by column chromatography (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
Iskorištenje: 8 mg (6,3% od teorijskog). Yield: 8 mg (6.3% of theoretical).
C22H21ClN2O (M = 364,88) C22H21ClN2O (M = 364.88)
Izračunato: molekulska masa (M+H)+: 365/367 Calculated: molecular weight (M+H)+: 365/367
Nađeno: molekulska masa (M+H)+: 365/367 Found: molecular weight (M+H)+: 365/367
Vrijeme retencije HPLC: 5,97 min (metoda A) HPLC retention time: 5.97 min (method A)
Primjer 2.76: Example 2.76:
4'-klor-bifenil-4-karboksilna kiselina (2-{4-[(diizopropil-amino)-metil]-fenil}-etil)-amid 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(diisopropyl-amino)-methyl]-phenyl}-ethyl)-amide
[image] [image]
47 μl (0,33 mmola) diizopropilamina se doda u suspenziju od 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 55 mg (0,4 mmola) K2CO3 u 20 ml acetonitrila i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. To se razrijedi sa CH2Cl2, profiltrira se da se odstrane neotopljene anorganske soli i filtrat se ispari. Ostatak se triturira s acetonitrilom, odsisa i osuši na zraku. 47 μl (0.33 mmol) of diisopropylamine was added to a suspension of 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]- amide and 55 mg (0.4 mmol) of K2CO3 in 20 ml of acetonitrile and the reaction mixture was stirred overnight at room temperature. This is diluted with CH 2 Cl 2 , filtered to remove undissolved inorganic salts and the filtrate is evaporated. The residue is triturated with acetonitrile, suction and dried in air.
Iskorištenje: 75 mg (55,7% od teorijskog). Yield: 75 mg (55.7% of theoretical).
C28H33ClN2O (M = 449,04) C28H33ClN2O (M = 449.04)
Izračunato: molekulska masa (M+H)+: 449/451 Calculated: molecular weight (M+H)+: 449/451
Nađeno: molekulska masa (M+H)+: 449/451 Found: molecular weight (M+H)+: 449/451
Rf vrijednost: 0,35 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.77: Example 2.77:
4'-klor-bifenil-4-karboksilna kiselina {2-[4-(3-okso-piperazin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-oxo-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.76 iz 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 33 mg (0,33 mmola) piperazin-2-ona. It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 33 mg (0.33 mmol) of piperazin-2-one.
Iskorištenje: 23 mg (17,1% od teorijskog). Yield: 23 mg (17.1% of theoretical).
C26H26ClN3O2 (M = 447,97) C26H26ClN3O2 (M = 447.97)
Izračunato: molekulska masa (M+H)+: 448/450 Calculated: molecular weight (M+H)+: 448/450
Nađeno: molekulska masa (M+H)+: 448/450 Found: molecular weight (M+H)+: 448/450
Rf vrijednost: 0,10 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.10 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.78: Example 2.78:
Etil [(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-metil-aminoj-acetat Ethyl [(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-methyl-aminoj-acetate
[image] [image]
Proizveden je analogno primjeru 2,76 iz 257 mg (0,6 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida, 193 mg K2CO3 i 101 mg (0,66 mmola) etil metilamino-acetata (upotrijebljenog u obliku hidroklorida). It was produced analogously to example 2.76 from 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 193 mg of K2CO3 and 101 mg (0.66 mmol) of ethyl methylaminoacetate (used in the form of hydrochloride).
Iskorištenje: 152 mg (54,5% od teorijskog). Yield: 152 mg (54.5% of theoretical).
C27H29ClN2O3 (M = 465,0) C27H29ClN2O3 (M = 465.0)
Izračunato: molekulska masa (M+H)+: 465/467 Calculated: molecular weight (M+H)+: 465/467
Nađeno: molekulska masa (M+H)+: 465/467 Found: molecular weight (M+H)+: 465/467
Rf vrijednost: 0,40 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.40 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.79: Example 2.79:
[(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-metil-amino]-octena kiselina [(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-methyl-amino]-acetic acid
[image] [image]
0,3 ml 1M otopine NaOH doda se u otopinu od 80 mg (0,17 mmola) etil [(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-metil-amino]-acetata u 3 ml EtOH i refluktira se 1 h. Otapalo se ispari u vakuumu i ostatak se pomiješa s vodom i 0,3 ml 1 M HCl. Talog se odsisa i osuši pri 40°C. 0.3 ml of 1M NaOH solution was added to a solution of 80 mg (0.17 mmol) ethyl [(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl) -methyl-amino]-acetate in 3 ml of EtOH and refluxed for 1 h. The solvent was evaporated in vacuo and the residue was mixed with water and 0.3 ml of 1 M HCl. The precipitate is sucked off and dried at 40°C.
Iskorištenje: 76 mg (100% od teorijskog). Yield: 76 mg (100% of theoretical).
C25H25ClN2O3 (M = 436,94) C25H25ClN2O3 (M = 436.94)
Izračunato: molekulska masa (M+H)+: 437/439 Calculated: molecular weight (M+H)+: 437/439
Nađeno: molekulska masa (M+H)+: 437/439 Found: molecular weight (M+H)+: 437/439
Vrijeme retencije HPLC: 6,35 min (metoda A) HPLC retention time: 6.35 min (method A)
Primjer 2.80: Example 2.80:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(4-acetil-piperazin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(4-acetyl-piperazin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.76 iz 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 42 mg (0,33 mmola) 1-piperazin-1-il-etanona. It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 42 mg (0.33 mmol) of 1-piperazin-1-yl-ethanone.
Iskorištenje: 60 mg (42,0% od teorijskog). Yield: 60 mg (42.0% of theoretical).
C28H30ClN3O2 (M = 476,02) C28H30ClN3O2 (M = 476.02)
Izračunato: molekulska masa (M+H)+: 476/478 Calculated: molecular weight (M+H)+: 476/478
Nađeno: molekulska masa (M+H)+: 476/478 Found: molecular weight (M+H)+: 476/478
Rf vrijednost: 0,15 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.15 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.81: Example 2.81:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-aza-biciklo[2,2,1]hept-5-en-2-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aza-bicyclo[2,2,1]hept-5-en-2-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.76 iz 129 mg (0,3 mmola) of 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 31 mg (0,33 mmola) 2-aza-biciklo[2,2,1]hept-5-ena. It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 31 mg (0, 33 mmol) of 2-aza-bicyclo[2,2,1]hept-5-ene.
Iskorištenje: 100 mg (75,2% od teorijskog). Yield: 100 mg (75.2% of theoretical).
C28H27ClN2O (M = 442,99) C28H27ClN2O (M = 442.99)
Izračunato: molekulska masa (M+H)+: 443/445 Calculated: molecular weight (M+H)+: 443/445
Nađeno: molekulska masa (M+H)+: 443/445 Found: molecular weight (M+H)+: 443/445
Rf vrijednost: 0,08 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.82: Example 2.82:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(1,3-dihidro-izoindol-2-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(1,3-dihydro-isoindol-2-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.76 iz 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etnil]-amida, 97 mg K2CO3 i 51 mg (0,33 mmola) 2,3-dihidro-1H-izoindola (upotrijebljen u obliku hidro-klorida). It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethnyl]-amide, 97 mg of K2CO3 and 51 mg (0.33 mmol) of 2,3-dihydro-1H-isoindole (used as hydrochloride).
Iskorištenje: 80 mg (57,1% od teorijskog). Yield: 80 mg (57.1% of theoretical).
C30H27ClN2O (M = 467,02) C30H27ClN2O (M = 467.02)
Izračunato: molekulska masa (M+H)+: 467/469 Calculated: molecular weight (M+H)+: 467/469
Nađeno: molekulska masa (M+H)+: 467/469 Found: molecular weight (M+H)+: 467/469
Rf vrijednost: 0,40 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.40 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.83: Example 2.83:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(7-metil-2,7-diaza-spiro[4,4]non-2-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(7-methyl-2,7-diaza-spiro[4,4]non-2-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.76 iz 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 46 mg (0,33 mmola) 2-metil-2,7-diaza-spiro[4,4]nonana. It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 46 mg (0.33 mmol) of 2-methyl-2,7-diaza-spiro[4,4]nonane.
Iskorištenje: 42 mg (28,7% od teorijskog). Yield: 42 mg (28.7% of theoretical).
C30H34ClN3O (M = 488,08) C30H34ClN3O (M = 488.08)
Izračunato: molekulska masa (M+H)+: 488/490 Calculated: molecular weight (M+H)+: 488/490
Nađeno: molekulska masa (M+H)+: 488/490 Found: molecular weight (M+H)+: 488/490
Rf vrijednost: 0,05 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.05 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.84: Example 2.84:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(3-dietil-amino-azetidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-diethyl-amino-azetidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2,76 iz 129 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida, 138 mg K2CO3 i 66 mg (0,33 mmola) azetidin-3-il-dietil-amina (upotrijebljen u obliku bis-hidroklorida); proizvod se očisti kromatografijom na stupcu. It was produced analogously to example 2.76 from 129 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 138 mg of K2CO3 and 66 mg (0.33 mmol) of azetidin-3-yl-diethylamine (used in the form of bis-hydrochloride); the product is purified by column chromatography.
Iskorištenje: 15 mg (10,5% od teorijskog). Yield: 15 mg (10.5% of theoretical).
C29H34ClN3O (M = 476,07) C29H34ClN3O (M = 476.07)
Izračunato: molekulska masa (M+H)+: 476/478 Calculated: molecular weight (M+H)+: 476/478
Nađeno: molekulska masa (M+H)+: 476/478 Found: molecular weight (M+H)+: 476/478
Rf vrijednost: 0,10 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,1). Rf value: 0.10 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.1).
Primjer 2.85: Example 2.85:
Etil (S)-1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-karboksilat Ethyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate
[image] [image]
Proizveden je analogno primjeru 2.76 iz 257 mg (0,6 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida, 193 mg K2CO3 i 119 mg (0,66 mmola) etil (S)-pirolidin-2-karboksilata (upotrijebljen u obliku hidroklorida); proizvod se očisti kromatografijom na stupcu. It was produced analogously to example 2.76 from 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 193 mg of K2CO3 and 119 mg (0.66 mmol) ethyl (S)-pyrrolidine-2-carboxylate (used as hydrochloride); the product is purified by column chromatography.
Iskorištenje: 160 mg (54,3% od teorijskog). Yield: 160 mg (54.3% of theoretical).
C29H31ClN2O3 (M = 491,04) C29H31ClN2O3 (M = 491.04)
Izračunato: molekulska masa (M+H)+: 491/493 Calculated: molecular weight (M+H)+: 491/493
Nađeno: molekulska masa (M+H)+: 491/493 Found: molecular weight (M+H)+: 491/493
Rf vrijednost: 0,60 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.60 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.86: Example 2.86:
(S)-1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-karboksilna kiselina (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylic acid
[image] [image]
Proizvedena je analogno primjeru 2,79 iz 130 mg (0,27 mmola) etil (S)-1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-karboksilat. It was produced analogously to example 2.79 from 130 mg (0.27 mmol) ethyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl )-pyrrolidine-2-carboxylate.
Iskorištenje: 120 mg (97,8% od teorijskog). Yield: 120 mg (97.8% of theoretical).
C27H27ClN2O3 (M = 462,98) C27H27ClN2O3 (M = 462.98)
Izračunato: molekulska masa (M+H)+: 463/465 Calculated: molecular weight (M+H)+: 463/465
Nađeno: molekulska masa (M+H)+: 463/465 Found: molecular weight (M+H)+: 463/465
Vrijeme retencije HPLC: 6,20 min (metoda A) HPLC retention time: 6.20 min (method A)
Primjer 2.87: Example 2.87:
Terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-3-il]-karbaminat Tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-3-yl]-carbamate
[image] [image]
Proizveden je analogno primjeru 2.76 iz 429 mg (1,0 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 205 mg (1,10 mmola) terc-butil pirol idin-3-il-karbaminata. It was produced analogously to example 2.76 from 429 mg (1.0 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 205 mg (1.10 mmol) of tert-butyl pyrrole idin-3-yl-carbamate.
Iskorištenje: 500 mg (93,6% od teorijskog). Yield: 500 mg (93.6% of the theoretical).
C31H36ClN3O3 (M = 534,10) C31H36ClN3O3 (M = 534.10)
Izračunato: molekulska masa (M+H)+: 534/536 Calculated: molecular weight (M+H)+: 534/536
Nađeno: molekulska masa (M+H)+: 534/536 Found: molecular weight (M+H)+: 534/536
Rf vrijednost: 0,33 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.33 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.88: Example 2.88:
4'-klor-bifenil-4-karboksilna kiselina{2-[4-(3-amino-pirolidin-1-ilmetil)-fenil]-etil)-amid 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl)-amide
[image] [image]
1 ml trifluoroctene kiselina se doda u otopinu od 500 mg (0,94 mmola) terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-3-il]-karbaminata u 15 ml CH2Cl2 i reakcijsku smjesu se miješa preko noći. To se zatim ispari, a ostatak se preuzme u malo CH2Cl2 i pomiješa se s poluzasićenom otopinom NaHCO3. Istaložen proizvod se odsisa, triturira se s acetonitrilom i osuši pri 40°C. 1 ml of trifluoroacetic acid is added to a solution of 500 mg (0.94 mmol) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl )-pyrrolidin-3-yl]-carbamate in 15 ml of CH2Cl2 and the reaction mixture was stirred overnight. This is then evaporated and the residue taken up in a little CH2Cl2 and mixed with half-saturated NaHCO3 solution. The precipitated product is filtered off with suction, triturated with acetonitrile and dried at 40°C.
Iskorištenje: 240 mg (59,1% od teorijskog). Yield: 240 mg (59.1% of theoretical).
C26H28ClN3O (M = 433,99) C26H28ClN3O (M = 433.99)
Izračunato: molekulska masa (M+H)+: 434/436 Calculated: molecular weight (M+H)+: 434/436
Nađeno: molekulska masa (M+H)+: 434/436 Found: molecular weight (M+H)+: 434/436
Rf vrijednost: 0,22 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.22 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
Primjer 2.89: Example 2.89:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(3-dimetil-amino-pirolidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-dimethyl-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
0,12 ml 37%-tne vodene otopine formaldehida, 28 mg (0,45 mmola) NaBH3CN i jednu kap ledene octene kiseline doda se u otopinu od 60 mg (0,14 mmola) 4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(3-amino-pirolidin-1-ilmetil)-fenil]-etil}-amida u 5 ml acetonitrila. Reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi i zatim se pomiješa s razrijeđenom otopinom NaOH i EtOAc. Faze se odvoje, organsku fazu se osuši preko MgSO4 i zatim se oslobodi od sredstva za sušenje i otapala. Ostatak se očisti kromatografijom na stupcu. 0.12 ml of a 37% aqueous solution of formaldehyde, 28 mg (0.45 mmol) of NaBH3CN and one drop of glacial acetic acid were added to a solution of 60 mg (0.14 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3-amino-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide in 5 ml of acetonitrile. The reaction mixture was stirred overnight at room temperature and then treated with a dilute solution of NaOH and EtOAc. The phases are separated, the organic phase is dried over MgSO4 and then freed from the drying agent and solvent. The residue is purified by column chromatography.
Iskorištenje: 10 mg (15,7% od teorijskog). Yield: 10 mg (15.7% of theoretical).
C28H32ClN3O (M = 462,04) C28H32ClN3O (M = 462.04)
Izračunato: molekulska masa (M+H)+: 462/464 Calculated: molecular weight (M+H)+: 462/464
Nađeno: molekulska masa (M+H)+: 462/464 Found: molecular weight (M+H)+: 462/464
Vrijeme retencije HPLC: 5,16 min (metoda A) HPLC retention time: 5.16 min (method A)
Primjer 2.90: Example 2.90:
Terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-ilmetil]-karbaminat Tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidin-2-ylmethyl]-carbamate
[image] [image]
Proizveden je analogno primjeru 2,76 iz 230 mg (0,54 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida i 116 mg (1,10 mmola) terc-butil pirolidin-2-ilmetil-karbaminata. It was produced analogously to example 2.76 from 230 mg (0.54 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide and 116 mg (1 .10 mmol) of tert-butyl pyrrolidin-2-ylmethyl-carbamate.
Iskorištenje: 230 mg (78,3% od teorijskog). Yield: 230 mg (78.3% of theoretical).
C32H38ClN3O3 (M =548,13) C32H38ClN3O3 (M = 548.13)
Izračunato: molekulska masa (M+H)+: 548/550 Calculated: molecular weight (M+H)+: 548/550
Nađeno: molekulska masa (M+H)+: 548/550 Found: molecular weight (M+H)+: 548/550
Rf vrijednost: 0,35 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5).
Primjer 2.91: Example 2.91:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-aminometil-pirolidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.88 iz 230 mg (0,42 mmola) terc-butil [1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-ilmetil]-karbaminata. It was produced analogously to example 2.88 from 230 mg (0.42 mmol) tert-butyl [1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine -2-ylmethyl]-carbamate.
Iskorištenje: 188 mg (100% od teorijskog). Yield: 188 mg (100% of theoretical).
C27H30ClN3O (M = 448,01) C27H30ClN3O (M = 448.01)
Izračunato: molekulska masa (M+H)+: 448/450 Calculated: molecular weight (M+H)+: 448/450
Nađeno: molekulska masa (M+H)+: 448/450 Found: molecular weight (M+H)+: 448/450
Rf vrijednost: 0,35 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
Primjer 2.92: Example 2.92:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-dimetil-aminometil-pirolidin-1-ilmetil )-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-dimethyl-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.89 iz 40 mg (0,09 mmola) 4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-aminometil-pirolidin-1-ilmetil)-fenil]-etil}-amida, 0,08 ml 37%-tne vodene otopine formaldehida i 19 mg (0,30 mmola) NaBH3CN. It was produced analogously to example 2.89 from 40 mg (0.09 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-aminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}- amide, 0.08 ml of 37% aqueous formaldehyde solution and 19 mg (0.30 mmol) of NaBH3CN.
Iskorištenje: 10 mg (23,6% od teorijskog). Yield: 10 mg (23.6% of theoretical).
C29H34ClN3O (M = 476,07) C29H34ClN3O (M = 476.07)
Izračunato: molekulska masa (M+H)+: 476/478 Calculated: molecular weight (M+H)+: 476/478
Nađeno: molekulska masa (M+H)+: 476/478 Found: molecular weight (M+H)+: 476/478
Rf vrijednost: 0,12 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.12 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
Primjer 2.93: Example 2.93:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-metil-2,6-diaza-spiro[3,4]okt-6-ilmetil )-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-2,6-diaza-spiro[3,4]oct-6-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2,76 iz 250 mg (0,58 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida, 97 mg K2CO3 i 81 mg (0,64 mmola) 2-metil-2,6-diaza-spiro[3,4]oktana; proizvod se očisti pomoću HPLC. It was produced analogously to example 2.76 from 250 mg (0.58 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 97 mg of K2CO3 and 81 mg (0.64 mmol) of 2-methyl-2,6-diaza-spiro[3,4]octane; the product is purified by HPLC.
Iskorištenje: 20 mg (7,2% od teorijskog). Yield: 20 mg (7.2% of theoretical).
C29H32ClN3O (M = 474,05) C29H32ClN3O (M = 474.05)
Izračunato: molekulska masa (M+H)+: 474/476 Calculated: molecular weight (M+H)+: 474/476
Nađeno: molekulska masa (M+H)+: 474/476 Found: molecular weight (M+H)+: 474/476
Rf vrijednost: 0,20 (silika gel, CH2Cl3/MeOH/NH3 9:1:0,1). Rf value: 0.20 (silica gel, CH2Cl3/MeOH/NH3 9:1:0.1).
Primjer 2.94: Example 2.94:
3-[(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-etil-amino]-propionska kiselina 3-[(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-ethyl-amino]-propionic acid
[image] [image]
Suspenziju od 257 mg (0,6 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-brom-metil-fenil)-etil]-amida, 166 mg (1,2 mmola) K2CO3 i 138 mg 3-etilamino-propionske kiseline (0,9 mmol, upotrijebljena u obliku hidroklorida) u 20 ml acetonitrila miješa se 3 dana pri sobnoj temperaturi. Doda se 5 ml DMF-a i smjesu se grije 3 h pri 50°C. Reakcijsku smjesu se profiltrira, filtrat se ispari i ostatak se očisti pomoću HPLC. A suspension of 257 mg (0.6 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-bromo-methyl-phenyl)-ethyl]-amide, 166 mg (1.2 mmol) of K2CO3 and 138 mg of 3-ethylamino-propionic acid (0.9 mmol, used in the form of hydrochloride) in 20 ml of acetonitrile was stirred for 3 days at room temperature. 5 ml of DMF was added and the mixture was heated for 3 h at 50°C. The reaction mixture is filtered, the filtrate is evaporated and the residue is purified by HPLC.
Iskorištenje: 50 mg (17,9% od teorijskog). Yield: 50 mg (17.9% of theoretical).
C27H29ClN2O3 (M = 465,0) C27H29ClN2O3 (M = 465.0)
Izračunato: molekulska masa (M+H)+: 465/467 Calculated: molecular weight (M+H)+: 465/467
Nađeno: molekulska masa (M+H)+: 465/467 Found: molecular weight (M+H)+: 465/467
Vrijeme retencije HPLC: 5,85 min (metoda A) HPLC retention time: 5.85 min (method A)
Primjer 2.95: Example 2.95:
Metil (S)-1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-karboksilat Methyl (S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate
[image] [image]
2.95.a. Etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoat 2.95.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate
Proizveden je prema općem radnom postupku I iz 10,0 g (42,98 mmola) 4'-klor-bifenil-4-karboksilne kiseline i 9,87 g (42,98 mmola) etil 4-(2-amino-etil)-benzoata. It was produced according to general procedure I from 10.0 g (42.98 mmol) of 4'-chloro-biphenyl-4-carboxylic acid and 9.87 g (42.98 mmol) of ethyl 4-(2-amino-ethyl) -benzoate.
Iskorištenje: 10,64 g (60,7% od teorijskog). Yield: 10.64 g (60.7% of theoretical).
C24H22ClNO3 (M = 407,90) C24H22ClNO3 (M = 407.90)
Izračunato: molekulska masa (M+H)+: 408/410 Calculated: molecular weight (M+H)+: 408/410
Nađeno: molekulska masa (Mt-H)+: 408/410 Found: molecular weight (Mt-H)+: 408/410
Rf vrijednost: 0,87 (silika gel, CH2Cl2/MeOH 95:5). Rf value: 0.87 (silica gel, CH2Cl2/MeOH 95:5).
2.95.b. 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeva kiselina 2.95.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid
14 ml 2 M otopine NaOH doda se u otopinu od 10,64 g (26,08 mmolova) etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoata u 100 ml EtOH i reakcijsku smjesu se grije preko noći pri 60°C. Zatim se doda daljnjih 30 ml otopine NaOH i smjesu se drži pri toj temperaturi daljnjih 3 h. Reakcijsku smjesu se namjesti na pH 6-7 s 1M otopinom HCl, istaloženi proizvod se odfiltrira i osuši u vakuumu. 14 ml of 2 M NaOH solution was added to a solution of 10.64 g (26.08 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate in 100 ml of EtOH and the reaction mixture is heated overnight at 60°C. Then a further 30 ml of NaOH solution is added and the mixture is kept at this temperature for a further 3 h. The reaction mixture is adjusted to pH 6-7 with 1M HCl solution, the precipitated product is filtered off and dried in a vacuum.
Iskorištenje: 7,65 g (77,2% od teorijskog). Yield: 7.65 g (77.2% of theoretical).
C22H18ClNO3 (M = 379,85) C22H18ClNO3 (M = 379.85)
Izračunato: molekulska masa (M+H)+: 380/382 Calculated: molecular weight (M+H)+: 380/382
Nađeno: molekulska masa (M+H)+: 380/382 Found: molecular weight (M+H)+: 380/382
Vrijeme retencije HPLC: 8,1 min (metoda A) HPLC retention time: 8.1 min (method A)
2.95.c. 4'-klor-bifenil-4-karboksilna kiselina [2-(4-hidroksimetil-fenil)-etil]-amid 2.95.c. 4'-chloro-biphenyl-4-carboxylic acid [2-(4-hydroxymethyl-phenyl)-ethyl]-amide
3,24 g (20 mmola) CDI doda se u otopinu od 7,2 g (18,97 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeve kiseline u 150 ml suhog THF-a i reakcijsku smjesu se grije 2 h pri 50°C. Tu otopinu se doda u suspenziju od 1,44 g (38 mmolova) NaBH4 u 5 ml vode i miješa se još jedan sat. Reakcijsku smjesu se namjesti na pH 6-7 s 1M otopinom HCl i iscrpno se ekstrahira s EtOAc. Organsku fazu se ispere s otopinom NaHCO3 i s vodom i osuši se preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti kromatografijom (silika gel, CH2Cl2/MeOH 9:1). Kako u proizvodu još uvijek ima edukta, gore opisani postupak se ponovi s 50% od upotrijebljenih reagenata. 3.24 g (20 mmol) of CDI was added to a solution of 7.2 g (18.97 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoin acid in 150 ml of dry THF and the reaction mixture is heated for 2 h at 50°C. This solution was added to a suspension of 1.44 g (38 mmol) of NaBH 4 in 5 ml of water and stirred for another hour. The reaction mixture was adjusted to pH 6-7 with 1M HCl solution and extracted exhaustively with EtOAc. The organic phase is washed with NaHCO3 solution and with water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography (silica gel, CH2Cl2/MeOH 9:1). Since there is still an educt in the product, the procedure described above is repeated with 50% of the reagents used.
Iskorištenje: 2,85 g (41,0% od teorijskog). Yield: 2.85 g (41.0% of theoretical).
C22H20ClNO2 (M = 365,86) C22H20ClNO2 (M = 365.86)
Izračunato: molekulska masa (M+H)+: 366/368 Calculated: molecular weight (M+H)+: 366/368
Nađeno: molekulska masa (M+H)+: 366/368 Found: molecular weight (M+H)+: 366/368
Vrijeme retencije HPLC: 8,0 min (metoda A) HPLC retention time: 8.0 min (method A)
2.95.d. 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonat 2.95 d. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate
1,25 ml (9 mmolova) trietilamina doda se u otopinu od 1,0 g (2,73 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-hidroksimetil-fenil)-etil]-amida u 100 ml sugoh THF-a i smjesu se ohladi na -20°C. Zatim se doda kap po kap 0,64 ml (8,2 mmolova) klorida metannsulfonske kiseline i smjesu se miješa daljnjih 2 h pri toj temperaturi. Doda se 5%-tnu otopinu NaHCO3 i smjesu se iscrpno ekstrahira s EtOAc. Organsku fazu se osuši preko Na2SO4, sredstvo za sušenje i otapalo se odstrane i ostatak se osuši pri 30°C u vakuumu. 1.25 ml (9 mmol) of triethylamine was added to a solution of 1.0 g (2.73 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-phenyl)-ethyl]- of the amide in 100 ml of dry THF and the mixture was cooled to -20°C. Then, 0.64 ml (8.2 mmol) of methanesulfonic acid chloride was added drop by drop and the mixture was stirred for a further 2 h at this temperature. A 5% NaHCO3 solution was added and the mixture was exhaustively extracted with EtOAc. The organic phase is dried over Na2SO4, the drying agent and the solvent are removed and the residue is dried at 30°C in a vacuum.
Iskorištenje: 1,21 g (99,7% od teorijskog). Yield: 1.21 g (99.7% of theoretical).
C23H22ClNO4S (M = 443,95) C23H22ClNO4S (M = 443.95)
Izračunato: molekulska masa (M+H)+: 444/446 Calculated: molecular weight (M+H)+: 444/446
Nađeno: molekulska masa (M+H)+: 444/446 Found: molecular weight (M+H)+: 444/446
Vrijeme retencije HPLC: 8,8 min (metoda A) HPLC retention time: 8.8 min (method A)
2.95.e. Metil {S)-1-(4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil)-pirolidin-2-karboksilat 2.95.e. Methyl {S)-1-(4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl)-pyrrolidine-2-carboxylate
Pod atmosferom dušika otopinu od 50 mg (0,3 mmola) metil (2S)-pirolidin-2-karboksilata (upotrijebljena u obliku hidroklorida) i 0,7 ml (0,5 mmola) trietilamina u 4 ml DMF-a miješa se 20 min pri sobnoj temperaturi. Zatim se doda 111 mg (0,25 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i smjesu se grije 2 h pri 60°C. Reakcijsku smjesu se ispari u vakuumu i ostatak očisti pomoću HPLC. Under a nitrogen atmosphere, a solution of 50 mg (0.3 mmol) of methyl (2S)-pyrrolidine-2-carboxylate (used in the form of hydrochloride) and 0.7 ml (0.5 mmol) of triethylamine in 4 ml of DMF was mixed for 20 min at room temperature. Then 111 mg (0.25 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate was added and the mixture was heated for 2 h at 60°C. The reaction mixture was evaporated in vacuo and the residue was purified by HPLC.
Iskorištenje: 4 mg (3,4% od teorijskog). Yield: 4 mg (3.4% of theoretical).
C28H29ClN2O3 (M = 477,01) C28H29ClN2O3 (M = 477.01)
Izračunato: molekulska masa (M+H)+: 477/479 Calculated: molecular weight (M+H)+: 477/479
Nađeno: molekulska masa (M+H)+: 477/479 Found: molecular weight (M+H)+: 477/479
Vrijeme retencije HPLC: 6,51 min (metoda A) HPLC retention time: 6.51 min (method A)
Primjer 2.96: Example 2.96:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-metil-piperidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizvedena je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[{4-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 35 μl (0,3 mmola) 2-metil-piperidina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[{4-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 35 μl (0.3 mmol ) 2-methyl-piperidine without the use of triethylamine.
Iskorištenje: 7 mg (6,3% od teorijskog). Yield: 7 mg (6.3% of theoretical).
C28H31ClN2O (M = 447,03) C28H31ClN2O (M = 447.03)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Vrijeme retencije HPLC: 6,4 min (metoda A) HPLC retention time: 6.4 min (method A)
Primjer 2.97: Example 2.97:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2-metil-pirolidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 32 μl (0,3 mmola) 2-metil- pirolidina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 32 μl (0.3 mmol) of 2-methylpyrrolidine without the use of triethylamine.
Iskorištenje: 2 mg (1,8% od teorijskog). Yield: 2 mg (1.8% of theoretical).
C27H29ClN2O (M= 433,0) C27H29ClN2O (M= 433.0)
Izračunato: molekulska masa (M+H)+: 433/435 Calculated: molecular weight (M+H)+: 433/435
Nađeno: molekulska masa (M+H)+: 433/435 Found: molecular weight (M+H)+: 433/435
Vrijeme retencije HPLC: 6,3 min (metoda A) HPLC retention time: 6.3 min (method A)
Primjer 2.98: Example 2.98:
4'-klor-bifenil-4-karboksilna kiselina (2-{4-[(ciklopropil-metil-amino)-metil]-fenil}-etil)-amid 4'-chloro-biphenyl-4-carboxylic acid (2-{4-[(cyclopropyl-methyl-amino)-methyl]-phenyl}-ethyl)-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 26 μl (0,3 mmola) ciklopropilmetil-amina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 26 μl (0.3 mmol) of cyclopropylmethylamine without the use of triethylamine.
Iskorištenje: 4 mg (3,8% od teorijskog). Yield: 4 mg (3.8% of theoretical).
C26H27ClN2O (M = 418,97) C26H27ClN2O (M = 418.97)
Izračunato: molekulska masa (M+H)+: 418/420 Calculated: molecular weight (M+H)+: 418/420
Nađeno: molekulska masa (M+H)+: 418/420 Found: molecular weight (M+H)+: 418/420
Vrijeme retencije HPLC: 6,4 min (metoda A) HPLC retention time: 6.4 min (method A)
Primjer 2.99: Example 2.99:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(3,4-dihidro-1H-izokinolin-2-il metil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(3,4-dihydro-1H-isoquinolin-2-yl methyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 40 mg (0,3 mmola) 1,2,3,4-tetra-hidroizokinolina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 40 mg (0.3 mmol) of 1,2,3,4-tetrahydroisoquinoline without the use of triethylamine.
Iskorištenje: 21 mg (17,5% od teorijskog). Yield: 21 mg (17.5% of theoretical).
C26H27ClN2O (M = 481,04) C26H27ClN2O (M = 481.04)
Izračunato: molekulska masa (M+H)+: 481/483 Calculated: molecular weight (M+H)+: 481/483
Nađeno: molekulska masa (M+H)+: 481/483 Found: molecular weight (M+H)+: 481/483
Vrijeme retencije HPLC: 6,8 min (metoda A) HPLC retention time: 6.8 min (method A)
Primjer 2.100: Example 2.100:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-{[(2-hidroksi-etil}-metil-amino]-metil}-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-{[(2-hydroxy-ethyl}-methyl-amino]-methyl}-phenyl)-ethyl]-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 24 μl (0,3 mmola) 2-metilamino-etanola bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 24 μl (0.3 mmol) of 2-methylamino-ethanol without the use of triethylamine.
Iskorištenje: 13 mg (12,3% od teorijskog). Yield: 13 mg (12.3% of theoretical).
C25H27ClN2O2 (M = 422,96) C25H27ClN2O2 (M = 422.96)
Izračunato: molekulska masa (M+H)+: 423/425 Calculated: molecular weight (M+H)+: 423/425
Nađeno: molekulska masa (M+H)+: 423/425 Found: molecular weight (M+H)+: 423/425
Vrijeme retencije HPLC: 5,8 min (metoda A) HPLC retention time: 5.8 min (method A)
Primjer 2.101: Example 2.101:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2,6-dimetil-piperidin-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 41 μl (0,3 mmola) 2,6-dimetil-piperidina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 41 μl (0.3 mmol) of 2,6-dimethyl-piperidine without the use of triethylamine.
Iskorištenje: 8 mg (6,9% od teorijskog). Yield: 8 mg (6.9% of theoretical).
C29H33ClN2O (M = 461,05) C29H33ClN2O (M = 461.05)
Izračunato: molekulska masa (M+H)+: 461/463 Calculated: molecular weight (M+H)+: 461/463
Nađeno: molekulska masa (M+H)+: 461/463 Found: molecular weight (M+H)+: 461/463
Vrijeme retencije HPLC: 6,6 min (metoda A) HPLC retention time: 6.6 min (method A)
Primjer 2.102: Example 2.102:
4'-klor-bifenil-4-karboksilna kiselina-[2-(4-azetidin-1-il-metil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-azetidin-1-yl-methyl-phenyl)-ethyl]-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 111 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 20 μl (0,3 mmola) azetidina bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 111 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 20 μl (0.3 mmol) of azetidine without the use of triethylamine.
Iskorištenje: 3 mg (3,0% od teorijskog). Yield: 3 mg (3.0% of theoretical).
C25H25ClN2O (M = 404,94) C25H25ClN2O (M = 404.94)
Izračunato: molekulska masa (M+H)+: 405/407 Calculated: molecular weight (M+H)+: 405/407
Nađeno: molekulska masa (M+H)+: 405/407 Found: molecular weight (M+H)+: 405/407
Vrijeme retencije HPLC: 5,9 min (metoda A) HPLC retention time: 5.9 min (method A)
Primjer 2.103: Example 2.103:
4'-klor-bifenil-4-karboksilna kiselina-{2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
Proizveden je analogno primjeru 2.95.e iz 50 mg (0,11 mmola) of 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzil metansulfonata i 11 μl (0,14 mmola) 2,5-dihidro-1H-pirola bez upotrebe trietilamina. It was produced analogously to example 2.95.e from 50 mg (0.11 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzyl methanesulfonate and 11 μl (0, 14 mmol) of 2,5-dihydro-1H-pyrrole without the use of triethylamine.
Iskorištenje: 18 mg (38,2% od teorijskog). Yield: 18 mg (38.2% of theoretical).
C26H25ClN2O (M = 416,95) C26H25ClN2O (M = 416.95)
Izračunato: molekulska masa (M+H)+: 417/419 Calculated: molecular weight (M+H)+: 417/419
Nađeno: molekulska masa (M+H)+: 417/419 Found: molecular weight (M+H)+: 417/419
Vrijeme retencije HPLC: 6,2 min (metoda A) HPLC retention time: 6.2 min (method A)
Primjer 2.104: Example 2.104:
4'-brom-bifenil-4-karboksilna kiselina-{2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid 4'-bromo-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
[image] [image]
2.104.a. Etil 4'-brom-bifenil-4-karboksilat 2.104.a. Ethyl 4'-bromo-biphenyl-4-carboxylate
Proizveden je analogno primjeru 2.46.b iz 1,22 ml (7,47 mmolova) etil 4-brom-benzoata i 1,8 g (8,96 mmolova) 4-bromfenil-borne kiseline refluktiranjem 72 h. Proizvod kristalizira iz acetonitrila. It was produced analogously to example 2.46.b from 1.22 ml (7.47 mmol) of ethyl 4-bromobenzoate and 1.8 g (8.96 mmol) of 4-bromophenylboronic acid by refluxing for 72 h. The product crystallizes from acetonitrile.
Iskorištenje: 293 mg (12,8% od teorijskog). Yield: 293 mg (12.8% of theoretical).
C15H13BrO2 (M = 305,17) C15H13BrO2 (M = 305.17)
Izračunato: molekulska masa (M+H)+: 304/306 Calculated: molecular weight (M+H)+: 304/306
Nađeno: molekulska masa (M+H)+: 304/306 Found: molecular weight (M+H)+: 304/306
Rf vrijednost: 0,9 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.9 (silica gel, petroleum ether/EtOAc 6:4).
2.104.b. 4'-brom-bifenil-4-karboksilna kiselina 2.104.b. 4'-bromo-biphenyl-4-carboxylic acid
1,24 ml 2M otopine NaOH doda se u otopinu od 270 mg (0,89 mmola) etil 4'-brom-bifenil-4-karboksilata u 10 ml EtOH i reakcijsku smjesu se miješa 2 h pri sobnoj temperaturi. pH se namjesti na 6-7 s 1 M HCl, istaloženi proizvod se odfiltrira i osuši. 1.24 ml of 2M NaOH solution was added to a solution of 270 mg (0.89 mmol) of ethyl 4'-bromo-biphenyl-4-carboxylate in 10 ml of EtOH and the reaction mixture was stirred for 2 h at room temperature. The pH is adjusted to 6-7 with 1 M HCl, the precipitated product is filtered off and dried.
Iskorištenje: 205 mg (83,6% od teorijskog). Yield: 205 mg (83.6% of theoretical).
C13H9BrO2 (M = 277,12) C13H9BrO2 (M = 277.12)
Izračunato: molekulska masa (M-H)-: 275/277 Calculated: molecular weight (M-H)-: 275/277
Nađeno: molekulska masa (M-H)-: 275/277 Found: molecular weight (M-H)-: 275/277
Vrijeme retencije HPLC: 8,5 min (metoda A) HPLC retention time: 8.5 min (method A)
2.104.c. [4-(2-amino-etil)-fenil]-metanol 2.104.c. [4-(2-amino-ethyl)-phenyl]-methanol
580 mg Raney nikla se doda u 5,8 g (39,41 mmolova) (4-hidroksimetil-fenil)-acetonitrila (vidi primjer 1.1e.) u 116 ml metanolne otopine NH3 i reakcijsku smjesu se hidrogenira pod 50 psi H2. Po završetku reakcije, katalizator se odfiltrira, otapalo se odstrani i ostatak se očisti pomoću kromatografije (silika gel, EtOAc/MeOH/NH3 7:3:0,3) 580 mg of Raney nickel was added to 5.8 g (39.41 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile (see Example 1.1e.) in 116 ml of methanolic NH 3 solution and the reaction mixture was hydrogenated under 50 psi H 2 . At the end of the reaction, the catalyst is filtered off, the solvent is removed and the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 7:3:0.3)
Iskorištenje: 3,9 g (65,4% od teorijskog). Yield: 3.9 g (65.4% of theoretical).
C9H13NO (M = 151,21) C9H13NO (M = 151.21)
Izračunato: molekulska masa (M+H)+: 152 Calculated: molecular weight (M+H)+: 152
Nađeno: molekulska masa (M+H)+: 152 Found: molecular weight (M+H)+: 152
Rf vrijednost: 0,18 (silika gel, EtOAc/MeOH/NH3 8:2:0,2). Rf value: 0.18 (silica gel, EtOAc/MeOH/NH3 8:2:0.2).
2.104.d Terc-butil [2-(4-hidroksimetil-fenil)-etil]-karbaminat 2.104.d Tert-butyl [2-(4-hydroxymethyl-phenyl)-ethyl]-carbamate
17,36 ml 1M BOC anhidrida u CH2Cl2 doda se pri sobnoj temperaturi u otopinu od 2,5 g (16,53 mmolova) [4-(2-amino-etil)-fenil]-metanola u 50 ml CH2Cl2 i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. Doda se 100 ml otopine KHSO4, organsku fazu se odvoji, ispere s razrijeđenom otopinom NaHCO3 i vodom i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala dobije se željeni proizvod. 17.36 ml of 1M BOC anhydride in CH2Cl2 was added at room temperature to a solution of 2.5 g (16.53 mmol) [4-(2-amino-ethyl)-phenyl]-methanol in 50 ml of CH2Cl2 and the reaction mixture was stir overnight at room temperature. 100 ml of KHSO4 solution is added, the organic phase is separated, washed with diluted NaHCO3 solution and water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.
Iskorištenje: 4,06 g (97,7% od teorijskog). Yield: 4.06 g (97.7% of theoretical).
C14H21NO3 (M = 251,33) C14H21NO3 (M = 251.33)
Izračunato: molekulska masa (M+H)+: 252 Calculated: molecular weight (M+H)+: 252
Nađeno: molekulska masa (M+H)+: 252 Found: molecular weight (M+H)+: 252
Vrijeme retencije HPLC: 6,4 min (metoda A) HPLC retention time: 6.4 min (method A)
2.104.e. Terc-butil [2-(4-klormetil-fenil)-etil]-karbaminat 2.104.e. Tert-butyl [2-(4-chloromethyl-phenyl)-ethyl]-carbamate
1 ml piridina se doda u otopinu od 2,6 g (10,35 mmolova) terc-butil [2-(4-hidroksimetil-fenil)-etil]-karbaminata u 50 ml CH2Cl2, ohladi se na 0°C i doda se 1,03 ml (12,41 mmolova) tionil klorida. Smjesu se drži 1 h pri 0°C i zatim se pusti zagrijati na sobnu temperaturu. Reakcijsku smjesu se ispere s vodom, s razrijeđenom otopinom KHSO4 i ponovno s vodom, osuši se s MgSO4 i filtrira se kroz aktivirani ugljen. Nakon odstranjivanja otapala dobije se proizvod kao ulje, koje reagira dalje bez čišćenja. 1 ml of pyridine is added to a solution of 2.6 g (10.35 mmol) of tert-butyl [2-(4-hydroxymethyl-phenyl)-ethyl]-carbamate in 50 ml of CH2Cl2, cooled to 0°C and added 1.03 ml (12.41 mmol) of thionyl chloride. The mixture is kept for 1 h at 0°C and then allowed to warm to room temperature. The reaction mixture is washed with water, with a dilute solution of KHSO4 and again with water, dried with MgSO4 and filtered through activated carbon. After removing the solvent, the product is obtained as an oil, which reacts further without cleaning.
Iskorištenje: 1,8 g (64,5% od teorijskog). Yield: 1.8 g (64.5% of theoretical).
C14H20ClNO2 (M = 269,77) C14H20ClNO2 (M = 269.77)
Izračunato: molekulska masa (M-H)-: 268/270 Calculated: molecular weight (M-H)-: 268/270
Nađeno: molekulska masa (M-H)-: 268/270 Found: molecular weight (M-H)-: 268/270
Rf vrijednost: 0,62 (silika gel, petrol eter/EtOAc 7:3). Rf value: 0.62 (silica gel, petroleum ether/EtOAc 7:3).
2.104.f. Terc-butil {2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-karbaminat 2.104.f. Tert-butyl {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate
2,37 g (17,13 mmolova) K2CO3 i 0,8 ml (10,38 mmolova) 2,5-dihidro-1H-pirola doda se u otopinu od 1,4 g (5,19 mmolova) terc-butil [2-(4-klormetil-fenil)-etil]-karb-aminata u 50 ml acetonitrila i smjesu se miješa preko noći pri sobnoj temperaturi. Reakcijsku smjesu se razrijedi sa CH2Cl2, ispere se vodom i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapalo dobije se željeni proizvod. 2.37 g (17.13 mmol) of K2CO3 and 0.8 ml (10.38 mmol) of 2,5-dihydro-1H-pyrrole were added to a solution of 1.4 g (5.19 mmol) of tert-butyl [ of 2-(4-chloromethyl-phenyl)-ethyl]-carb-aminate in 50 ml of acetonitrile and the mixture was stirred overnight at room temperature. The reaction mixture is diluted with CH2Cl2, washed with water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.
Iskorištenje: 1,46 g (93,0% od teorijskog). Yield: 1.46 g (93.0% of theory).
C18H26N2O2 (M = 302,42) C18H26N2O2 (M = 302.42)
Izračunato: molekulska masa (M+H)+: 303 Calculated: molecular weight (M+H)+: 303
Nađeno: molekulska masa (M+H)+: 303 Found: molecular weight (M+H)+: 303
Rf vrijednost: 0,15 (silika gel, petrol eter/EtOAc 7:3). Rf value: 0.15 (silica gel, petroleum ether/EtOAc 7:3).
2.104.g 2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etilamin 2.104.g 2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine
5 ml trifluoroctena kiselina doda se u otopinu 1,21 g (4 mmola) terc-butil {2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-karbaminata u 50 ml CH2Cl2 i miješa se 2 h pri sobnoj temperaturi. Reakcijsku smjesu se ispari u vakuumu, ostatak se pomiješa s vodom i CH2Cl2 i zaluži s otopinom K2CO3. Organsku fazu se odvoji, ispere s vodom i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, dobije se željeni proizvod. 5 ml of trifluoroacetic acid is added to a solution of 1.21 g (4 mmol) of tert-butyl {2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and stirred for 2 h at room temperature. The reaction mixture is evaporated in vacuo, the residue is mixed with water and CH2Cl2 and basified with K2CO3 solution. The organic phase is separated, washed with water and dried over MgSO4. After removing the drying agent and solvent, the desired product is obtained.
Iskorištenje: 0,35 g (43,3% od teorijskog). Yield: 0.35 g (43.3% of theoretical).
C13H18N2 (M = 202,30) C13H18N2 (M = 202.30)
Izračunato: molekulska masa (M+H)+: 203 Calculated: molecular weight (M+H)+: 203
Nađeno: molekulska masa (M+H)+: 203 Found: molecular weight (M+H)+: 203
Rf vrijednost: 0,05 (silika gel, EtOAc/MeOH/NH3 9:1:0,1). Rf value: 0.05 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).
2.104.h 4'-brom-bifenil-4-karboksilna kiselina-{2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid 2.104.h 4'-bromo-biphenyl-4-carboxylic acid-{2-[4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide
Proizveden je prema općem radnom postupku I iz 139 mg (0,50 mmola) 4'-brom-bifenil-4-karboksilne kiselina i 101 mg (0,50 mmola) 2-[4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etilamina. It was produced according to general procedure I from 139 mg (0.50 mmol) of 4'-bromo-biphenyl-4-carboxylic acid and 101 mg (0.50 mmol) of 2-[4-(2,5-dihydro-pyrrole- 1-ylmethyl)-phenyl]-ethylamine.
Iskorištenje: 21 mg (9,1% od teorijskog). Yield: 21 mg (9.1% of theoretical).
C26H25BrN2O (M = 461,41) C26H25BrN2O (M = 461.41)
Izračunato: molekulska masa (M+H)+: 461/463 Calculated: molecular weight (M+H)+: 461/463
Nađeno: molekulska masa (M+H)+: 461/463 Found: molecular weight (M+H)+: 461/463
Vrijeme retencije HPLC: 6,46 min (metoda A) HPLC retention time: 6.46 min (method A)
Primjer 2.105: Example 2.105:
4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1-etil-piperidin-2-il)-fenil]-etil}-amid 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide
[image] [image]
2.105.a. (4-piridin-2-il-fenil)-acetonitril 2.105.a. (4-pyridin-2-yl-phenyl)-acetonitrile
Proizveden je analogno primjeru 2.46.b iz 0,52 ml (5,40 mmolova) 2-brom-piridina i 1,0 g (5,96 mmolova) 4-cijanometilfenil-borne kiseline. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se triturira s diizopropil eterom i osuši na zraku. It was produced analogously to example 2.46.b from 0.52 ml (5.40 mmol) of 2-bromopyridine and 1.0 g (5.96 mmol) of 4-cyanomethylphenylboronic acid. The residue after removal of drying agent and solvent is triturated with diisopropyl ether and dried in air.
Iskorištenje: 0,76 g (72,5% od teorijskog). Yield: 0.76 g (72.5% of theoretical).
C13H10N2 (M = 194,24) C13H10N2 (M = 194.24)
Izračunato: molekulska masa (M+H)+: 195 Calculated: molecular weight (M+H)+: 195
Nađeno: molekulska masa (M+H)+: 195 Found: molecular weight (M+H)+: 195
Vrijeme retencije HPLC: 3,56 min (metoda B) HPLC retention time: 3.56 min (method B)
2.105.b. 2-(4-cijanometil-fenil)-1-etil-piridinijev jodid 2.105.b. 2-(4-Cyanomethyl-phenyl)-1-ethyl-pyridinium iodide
0,38 ml (4,7 mmola) etil jodida doda se u otopinu od 760 mg (3,91 mmola) (4-piridin-2-il-fenil)-acetonitrila u 5 ml DMF-a i miješa se preko noći pri sobnoj temperaturi. Za dpvršenje reakcije, otopinu se stavi na 20 min u mikrovalnu grijalicu pri 120°C. Otapalo se ispari u vakuumu, ostatak se pomiješa s vodom i ekstrahira s EtOAc. Vodenu fazu se ispari, ostatak se triturira s THF i suspenziju se ohladi na 0°C . Proizvod se odsisa i osuši pri 50°C. 0.38 ml (4.7 mmol) of ethyl iodide was added to a solution of 760 mg (3.91 mmol) of (4-pyridin-2-yl-phenyl)-acetonitrile in 5 ml of DMF and stirred overnight at room temperature. To complete the reaction, the solution is placed in a microwave oven at 120°C for 20 minutes. The solvent was evaporated in vacuo, the residue was mixed with water and extracted with EtOAc. The aqueous phase is evaporated, the residue is triturated with THF and the suspension is cooled to 0°C. The product is sucked off and dried at 50°C.
Iskorištenje: 800 mg (58,4% od teorijskog). Yield: 800 mg (58.4% of theoretical).
C15H15JN2 (M = 350,21) C15H15JN2 (M = 350.21)
Izračunato: molekulska masa (M)+: 223 Calculated: Molecular Weight (M)+: 223
Nađeno: molekulska masa (M)+: 223 Found: Molecular Weight (M)+: 223
Vrijeme retencije HPLC: 1,76 min (metoda A) HPLC retention time: 1.76 min (method A)
2.105.c. 2-[4-(1-eti1-piperidin-2-il)-fenil]-etilamin 2.105.c. 2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethylamine
100 mg Raney nikla se doda u otopinu od 800 mg (2,28 mmola) 2-(4-cijanometil-fenil)-1-etil-piridinijevog jodida u 10 ml metanolnnog NH3 i reakcijsku smjesu se hidrogenira 24 h pod 20 psi i pri sobnoj temperaturi u autoklavu. Katalizator se odsisa, reakcijsku otopinu se pomiješa sa 100 mg PtO2 i ponovno se hidrogenira 30 h pri sobnoj temperaturi i pod 20 psi. Nakon odstranjivanja katalizatora dobije se proizvod (kao hidrojodid), koji dalje reagira bez daljenjg čišćenja. 100 mg of Raney nickel is added to a solution of 800 mg (2.28 mmol) of 2-(4-cyanomethyl-phenyl)-1-ethyl-pyridinium iodide in 10 ml of methanolic NH3 and the reaction mixture is hydrogenated for 24 h under 20 psi and at room temperature in an autoclave. The catalyst is sucked off, the reaction solution is mixed with 100 mg of PtO2 and hydrogenated again for 30 h at room temperature and under 20 psi. After removing the catalyst, a product (as hydroiodide) is obtained, which reacts further without further purification.
Iskorištenje: 700 mg (85,1% od teorijskog). Yield: 700 mg (85.1% of theoretical).
C15H24IN2 (M = 360,28) C15H24IN2 (M = 360.28)
Izračunato: molekulska masa (M)+: 233 Calculated: Molecular Weight (M)+: 233
Nađeno: molekulska masa (M)+: 233 Found: Molecular Weight (M)+: 233
Vrijeme retencije HPLC: 0,93 min (izokratno voda: acetonitril:mravlja kiselina 95:5:0,01 za 8 min). HPLC retention time: 0.93 min (isocratic water:acetonitrile:formic acid 95:5:0.01 for 8 min).
2.105.d. 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1-etil-piperidin-2-il)-fenil]-etil}-amid 2.105.d. 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethyl}-amide
Proizveden je prema općem radnom postupku I iz 480 mg (1.33 mmola) 2-[4-(1-etil-piperidin-2-il)-fenil]-etilamina (upotrijebljen u obliku hidrojodida) i 310 mg (1,33 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 480 mg (1.33 mmol) of 2-[4-(1-ethyl-piperidin-2-yl)-phenyl]-ethylamine (used in the form of hydroiodide) and 310 mg (1.33 mmol) 4'-chloro-biphenyl-4-carboxylic acids.
Iskorištenje: 20 mg (3,4% od teorijskog). Yield: 20 mg (3.4% of theoretical).
C28H31ClN2O (M = 447,03) C28H31ClN2O (M = 447.03)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Vrijeme retencije HPLC: 6,68 min (metoda A) HPLC retention time: 6.68 min (method A)
Primjer 2.106: Example 2.106:
4'-klor-bifenil-4-karboksilna kiselina [2-(1-pirolidin-1-il-indan-5-il)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide
[image] [image]
2.106.a. Etil (E)-3-(1-okso-indan-5-il)-akrilat 2.106.a. Ethyl (E)-3-(1-oxo-indan-5-yl)-acrylate
5,96 ml (55 mmolova) etil akrilata, 275 mg (1,21 mmola) Pd(OAc)2 i 704 mg (2,31 mmola) tri-o-tolilfosfina doda se u otopinu od 4,64 g (21,99 mmola) 5-brom-indan-1-ona u 110 ml trietilamina pod N2 i reakcijsku smjesu se grije 4 h pri 100oC. Otapalo se izdestilira, ostatak se pomiješa sa 150 ml EtOAc i 100 ml ledene vode, zakiseli se s konc. HCl, organsku fazu se ispere sa 100 ml vode i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije (silika gel, heksan/EtOAc 9:1 prema 8:2). 5.96 ml (55 mmol) of ethyl acrylate, 275 mg (1.21 mmol) of Pd(OAc)2 and 704 mg (2.31 mmol) of tri-o-tolylphosphine were added to a solution of 4.64 g (21, 99 mmol) of 5-bromo-indan-1-one in 110 ml of triethylamine under N2 and the reaction mixture is heated for 4 h at 100oC. The solvent is distilled off, the residue is mixed with 150 ml of EtOAc and 100 ml of ice water, acidified with conc. HCl, the organic phase is washed with 100 ml of water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography (silica gel, hexane/EtOAc 9:1 to 8:2).
Iskorištenje: 4,0 g (79,0% od teorijskog). Yield: 4.0 g (79.0% of theoretical).
Talište: 100-102oC Melting point: 100-102oC
2.106.b. (E)-3-(1-okso-indan-5-il)-akrilna kiselina 2.106.b. (E)-3-(1-oxo-indan-5-yl)-acrylic acid
10 ml 2 N NaOH doda se u otopinu od 4,0 g (17,0 mmolova) etil (E)-3-(1-okso-indan-5-il)-akrilata u 50 ml MeOH i reakcijsku smjesu se refluktira 30 min. Zatim se to pomiješa s 11 ml 2 N otopine HCl, MeOH se izdestilira, kristali se odsisaju i osuše. 10 ml of 2 N NaOH was added to a solution of 4.0 g (17.0 mmol) of ethyl (E)-3-(1-oxo-indan-5-yl)-acrylate in 50 ml of MeOH and the reaction mixture was refluxed for 30 min. This is then mixed with 11 ml of 2 N HCl solution, the MeOH is distilled off, the crystals are filtered off with suction and dried.
Iskorištenje: 3,0 g (87,3% od teorijskog). Yield: 3.0 g (87.3% of theoretical).
Talište: 240-244oC Melting point: 240-244oC
2.106.c. 3-(1-okso-indan-5-il)-propionska kiselina 2.106.c. 3-(1-oxo-indan-5-yl)-propionic acid
150 mg 10%-tnog Pd/C se doda u otopinu od 1,6 g (7,91 mmolova) (E)-3-(1-okso-indan-5-il)-akrilne kiseline u 50 ml MeOH i reakcijsku smjesu se mućka u Parr-ovom autoklavu pri sobnoj temperaturi i 3 bara tlaka H2 sve dok se dosegne teorijski utrošak vodika. Doda se 10 ml 1 N NaOH i otapalo se odstrani. Ostatak se zakiseli s razrijeđenom HCl, icrpno se ekstrahira s EtOAc i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se triturira s terc-butilmetil eterom, talog se odsisa i osuši. 150 mg of 10% Pd/C was added to a solution of 1.6 g (7.91 mmol) of (E)-3-(1-oxo-indan-5-yl)-acrylic acid in 50 ml of MeOH and the reaction the mixture is shaken in a Parr autoclave at room temperature and 3 bar H2 pressure until the theoretical hydrogen consumption is reached. 10 ml of 1 N NaOH was added and the solvent was removed. The residue was acidified with dilute HCl, exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. The residue after removal of drying agent and solvent is triturated with tert-butylmethyl ether, the precipitate is filtered off with suction and dried.
Iskorištenje: 500 mg (31,0% od teorijskog). Yield: 500 mg (31.0% of theoretical).
C12H12O3 (M =204,23) C12H12O3 (M = 204.23)
Izračunato: molekulska masa (M-H)-: 203 Calculated: molecular weight (M-H)-: 203
Nađeno: molekulska masa (M-H)-: 203 Found: molecular weight (M-H)-: 203
Rf vrijednost: 0,45 (silika gel, CH2Cl2/MeOH 9:1). Rf value: 0.45 (silica gel, CH2Cl2/MeOH 9:1).
2.106.d. Terc-butil [2-(1-okso-indan-5-il)-etil]-karbaminat 2.106.d. Tert-butyl [2-(1-oxo-indan-5-yl)-ethyl]-carbamate
1,6 g (7,83 mmolova) 3-(1-okso-indan-5-il)-propionske kiseline doda se u 25 ml terc-butanola i 2,5 ml trietilamina pod atmosferom argona. U tu otopinu se doda 2,22 ml (10,0 mmola) difenil azido-fosfata i grije se 3 h pri 80°C. Reakcijsku smjesu se ispari u vakuumu i ostatak se očisti pomoću kromatografije na silika gelu. 1.6 g (7.83 mmol) of 3-(1-oxo-indan-5-yl)-propionic acid was added to 25 ml of tert-butanol and 2.5 ml of triethylamine under an argon atmosphere. 2.22 ml (10.0 mmol) of diphenyl azido-phosphate was added to this solution and heated for 3 h at 80°C. The reaction mixture was evaporated in vacuo and the residue was purified by chromatography on silica gel.
Iskorištenje: 750 mg (34,8% od teorijskog). Yield: 750 mg (34.8% of theoretical).
C16H21NO3 (M = 275,35) C16H21NO3 (M = 275.35)
Izračunato: molekulska masa (M)+: 275 Calculated: Molecular Weight (M)+: 275
Nađeno: molekulska masa (M)+: 275 Found: Molecular Weight (M)+: 275
Rf vrijednost: 0,65 (silika gel, CH2Cl2/MeOH 95:5). Rf value: 0.65 (silica gel, CH2Cl2/MeOH 95:5).
2.106.e Terc-butil [2-(1-hidroksi-indan-5-il)-etil]-karbaminat 2.106.e Tert-butyl [2-(1-hydroxy-indan-5-yl)-ethyl]-carbamate
700 mg (18,5 mmolova) NaBH4 doda se u obrocima u otopinu od 700 mg (2,54 mmola) terc-butil [2-(1-okso-indan-5-il)-etil]-karbaminata u 70 ml MeOH i miješa se preko noći pri sobnoj temperaturi. Reakcijsku otopinu se oprezno pomiješa s 10%-tnom otopinom KHSO4, razrijedi se s vodom i iscrpno ekstrahira s terc—butilmetil eterom. Organsku fazu se ispere s vodom i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu. 700 mg (18.5 mmol) NaBH4 is added portionwise to a solution of 700 mg (2.54 mmol) tert-butyl [2-(1-oxo-indan-5-yl)-ethyl]-carbamate in 70 ml MeOH and stirred overnight at room temperature. The reaction solution is carefully mixed with 10% KHSO4 solution, diluted with water and exhaustively extracted with tert-butylmethyl ether. The organic phase is washed with water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel.
Iskorištenje: 350 mg (49,7% od teorijskog). Yield: 350 mg (49.7% of theoretical).
C16H23N03 (M = 277,37) C16H23N03 (M = 277.37)
Izračunato: molekulska masa (M)+: 277 Calculated: Molecular Weight (M)+: 277
Nađeno: molekulska masa (M)+: 277 Found: Molecular Weight (M)+: 277
Rf vrijednost: 0,30 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.30 (silica gel, petroleum ether/EtOAc 6:4).
2.106.f Terc-butil [2-(1-pirolidin-1-il-indan-5-il)-etil]-karbaminat 2.106.f Tert-butyl [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-carbamate
109 ml (1,5 mmola) tionil klorida (otopljen u malo CH2Cl2) doda se polako, kap po kap, u otopinu od 350 mg (1,26 mmola) terc-butil [2-(1-hidroksi-indan-5-il)-etil]-karbaminata u 7,5 ml CH2Cl2 ohlađene na 0°C. Miješanje se nastavi daljnjih 30 min pri 10oC. Reakcijsku otopinu se pomiješa s ledeno hladnom otopinom NaHCO3, organsku fazu se odvoji, ispere s hladnom vodom i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje, filtrat se ohladi na 0°C, kap po kap doda se 417 μl (5,0 mmolova) pirolidina i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. Reakcijsku smjesu se ispari i ostatak se očisti pomoću kromatografije on silika gelu. 109 ml (1.5 mmol) of thionyl chloride (dissolved in a little CH2Cl2) was added slowly, dropwise, to a solution of 350 mg (1.26 mmol) of tert-butyl [2-(1-hydroxy-indan-5- yl)-ethyl]-carbamate in 7.5 ml of CH2Cl2 cooled to 0°C. Mixing was continued for another 30 min at 10oC. The reaction solution is mixed with an ice-cold NaHCO3 solution, the organic phase is separated, washed with cold water and dried over MgSO4. After removing the drying agent, the filtrate is cooled to 0°C, 417 μl (5.0 mmol) of pyrrolidine is added dropwise and the reaction mixture is stirred overnight at room temperature. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel.
Iskorištenje: 120 mg (28,8% od teorijskog). Yield: 120 mg (28.8% of theoretical).
C20H30N2O2 (M = 330,47) C20H30N2O2 (M = 330.47)
Izračunato: molekulska masa (M+H)+: 331 Calculated: molecular weight (M+H)+: 331
Nađeno: molekulska masa (M+H)+: 331 Found: molecular weight (M+H)+: 331
Vrijeme retencije HPLC: 5,6 min (metoda A) HPLC retention time: 5.6 min (method A)
2.106.g. 2-(1-pirolidin-1-il-indan-5-il)-etilamin 2.106.g. 2-(1-pyrrolidin-1-yl-indan-5-yl)-ethylamine
100 μl trifluoroctene kiseline doda uz lagano hlađenje u otopinu od 100 mg (0,3 mmola) terc-butil [2-(1-pirolidin-1-il-indan-5-il)-etil]-karbaminata u 10 ml CH2Cl2 i miješa se 1 h pri sobnoj temperaturi. Za dovršetak reakcije doda se daljnjih 500 μl trifluoroctene kiseline uz hlađenje i smjesu se miješa još 2 h pri sobnoj temperaturi. Reakcijsku smjesu se ispari u vakuumu i proizvod (kao bis-trifluor-acetat) dalje reagira bez čišćenja. 100 μl of trifluoroacetic acid is added with slight cooling to a solution of 100 mg (0.3 mmol) of tert-butyl [2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-carbamate in 10 ml of CH2Cl2 and it is stirred for 1 h at room temperature. To complete the reaction, a further 500 μl of trifluoroacetic acid was added with cooling and the mixture was stirred for another 2 h at room temperature. The reaction mixture is evaporated in vacuo and the product (as bis-trifluoroacetate) is further reacted without purification.
Iskorištenje: 100 mg (72,7% od teorijskog). Yield: 100 mg (72.7% of theoretical).
C19H24F6N2O4 (M = 458,51) C19H24F6N2O4 (M = 458.51)
Izračunato: molekulska masa (M+H)+: 231 Calculated: molecular weight (M+H)+: 231
Nađeno: molekulska masa (M+H)+: 231 Found: molecular weight (M+H)+: 231
Rf vrijednost: 0,3 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.3 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
2.106.h. 4'-klor-bifenil-4-karboksilna kiselina-[2-(1-pirolidin-1 -il-indan-5-il)-etil]-amid 2.106 h. 4'-chloro-biphenyl-4-carboxylic acid-[2-(1-pyrrolidin-1-yl-indan-5-yl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 100 mg (0,29 mmola) 2-(1-pirolidin-1-il-indan-5-il)-etilamina (upotrijebljen u obliku bis-trifluoracetata) i 70 mg (0,3 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 100 mg (0.29 mmol) of 2-(1-pyrrolidin-1-yl-indan-5-yl)-ethylamine (used in the form of bis-trifluoroacetate) and 70 mg (0.3 mmol) of 4'-chloro-biphenyl-4-carboxylic acid.
Iskorištenje: 40 mg (30,0% od teorijskog). Yield: 40 mg (30.0% of theoretical).
C28H29ClN2O (M = 445,01) C28H29ClN2O (M = 445.01)
Izračunato: molekulska masa (M+H)+: 445/447 Calculated: molecular weight (M+H)+: 445/447
Nađeno: molekulska masa (M+H)+: 445/447 Found: molecular weight (M+H)+: 445/447
Vrijeme retencije HPLC: 6,65 min (metoda A) HPLC retention time: 6.65 min (method A)
Primjer 2.107: Example 2.107:
4'-klor-bifenil-4-karboksilna kiselina [2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.107.a. Metil 2-brom-4-cijanometil-benzoat 2.107.a. Methyl 2-bromo-4-cyanomethyl-benzoate
Otopinu od 98,55 g (0,32 mola) metil 2-brom-4-brom-metnil-benzoata u 60 ml EtOH doda se u otopinu od 24,51 g (0,5 mola) NaCN u 40 ml vode i reakcijsku smjesu se refluktira 5 h. Doda se 1 l terc-butilmetil etera i 500 ml vode, organsku fazu se odvoji, ispere nekoliko puta s vodom i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu (petrol eter /EtOAc 8:2). A solution of 98.55 g (0.32 mol) of methyl 2-bromo-4-bromo-methnyl-benzoate in 60 ml of EtOH is added to a solution of 24.51 g (0.5 mol) of NaCN in 40 ml of water and the reaction the mixture is refluxed for 5 h. 1 l of tert-butylmethyl ether and 500 ml of water are added, the organic phase is separated, washed several times with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (petroleum ether/EtOAc 8:2).
Iskorištenje: 15,0 g (16,6% od teorijskog). Yield: 15.0 g (16.6% of theoretical).
C10H8BrNO2 (M = 254,09) C10H8BrNO2 (M = 254.09)
Izračunato: molekulska masa (M-H)-: 252/254 Calculated: molecular weight (M-H)-: 252/254
Nađeno: molekulska masa (M-H)-: 252/254 Found: molecular weight (M-H)-: 252/254
2.107.b. 2-brom-4-cijanometil-benzojeva kiselina 2.107.b. 2-bromo-4-cyanomethyl-benzoic acid
35 ml 1M otopine NaOH doda se u otopinu od 7,9 g (31,0 mmola) metil 2-brom-4-cijanometil-benzoata u 100 ml EtOH, reakcijsku smjesu se refluktira 1 h i zatim se miješa preko noći pri sobnoj temperaturi. Doda se ledenu vodu i smjesu se zakiseli s razrijeđenom otopinom KHSO4. Talog se odsisa, ispere s vode i osuši pri 50°C. 35 ml of 1M NaOH solution was added to a solution of 7.9 g (31.0 mmol) of methyl 2-bromo-4-cyanomethyl-benzoate in 100 ml of EtOH, the reaction mixture was refluxed for 1 h and then stirred overnight at room temperature. Ice water is added and the mixture is acidified with dilute KHSO4 solution. The precipitate is suctioned off, washed with water and dried at 50°C.
Iskorištenje: 6,2 g (83,3% od teorijskog). Yield: 6.2 g (83.3% of theoretical).
C9H6BrNO2 (M = 240,06) C9H6BrNO2 (M = 240.06)
Izračunato: molekulska masa (M-H)-: 238/240 Calculated: molecular weight (M-H)-: 238/240
Nađeno: molekulska masa (M-H)-: 238/240 Found: molecular weight (M-H)-: 238/240
Vrijeme retencije HPLC: 3,99 min (metoda B) HPLC retention time: 3.99 min (method B)
2.107.c. (3-brom-4-hidroksimetil-fenil)-acetonitril 2.107.c. (3-Bromo-4-hydroxymethyl-phenyl)-acetonitrile
1,78 g (11 mmola) CDI doda se u otopinu od 2,4 g (10 mmola) 2-brom-4-cijanometil-benzojeve kiseline u 50 ml THF-a i vodenu kupelj se grije do prestanka razvoja plina. Zatim se to doda u otopinu od 0,76 g (20 mmolova) NaBH4 u 50 ml vode, ali temperatura ne smije porasti iznad 30°C. Miješanje se nastavi još daljnjih 2 h pri sobnoj temperaturi, reakcijsku smjesu se oprezno zakiseli s razrijeđenom otopinom KHSO4, ekstrahira se iscrpno s terc-butilmetil eterom, organsku fazu se ispere s vodom i osuši se preko MgSO4. To se filtrira kroz aktivirani ugljen i otapalo se odstrani u vakuumu. 1.78 g (11 mmol) of CDI was added to a solution of 2.4 g (10 mmol) of 2-bromo-4-cyanomethyl-benzoic acid in 50 ml of THF and the water bath was heated until gas evolution ceased. This is then added to a solution of 0.76 g (20 mmol) of NaBH4 in 50 ml of water, but the temperature must not rise above 30°C. Stirring is continued for a further 2 h at room temperature, the reaction mixture is carefully acidified with a dilute solution of KHSO4, extracted exhaustively with tert-butylmethyl ether, the organic phase is washed with water and dried over MgSO4. This is filtered through activated carbon and the solvent is removed in vacuo.
Iskorištenje: 2,2 g (97,3% od teorijskog). Yield: 2.2 g (97.3% of theoretical).
C9H8BrNO (M = 226,07) C9H8BrNO (M = 226.07)
Izračunato: molekulska masa (M-H)-: 224/226 Calculated: molecular weight (M-H)-: 224/226
Nađeno: molekulska masa (M-H)-: 224/226 Found: molecular weight (M-H)-: 224/226
Rf vrijednost: 0,6 (silika gel, CH2Cl2/MeOH 9:1). Rf value: 0.6 (silica gel, CH2Cl2/MeOH 9:1).
2.107.d. (3-brom-4-pirolidin-1-ilmetil-fenil)-acetonitril 2.107.d. (3-Bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile
1,25 ml (9 mmolova) trietilamina se doda u otopinu od 1,9 g (8,4 mmolova) (3-brom-4-hidroksimetil-fenil)-aceto-nitrila u 50 ml CH2Cl2, ohladi se na 0°C i doda kap po kap otopinu od 0,66 ml (8,5 mmolova) klorida metansulfonske kiseline u 10 ml CH2Cl2. Smjesu se miješa 1 h pri 0oC i zatim se doda kap po kap otopinu od 1,4 ml (17 mmolova) pirolidina u 10 ml CH2Cl2 uz održavanje hlađenja s ledom. Reakcijsku smjesu se grije preko noći pri sobnoj temperaturi, pomiješa s vodom, organsku fazu se odvoji, ispere se dva puta s vodom, filtrira se kroz aktivirani ugljen i ispari u vakuumu. Ostatak se ko-ispari dva puta s toluenom i dobiveni proizvod dalje reagira bez čišćenja. 1.25 ml (9 mmol) of triethylamine was added to a solution of 1.9 g (8.4 mmol) of (3-bromo-4-hydroxymethyl-phenyl)-acetonitrile in 50 ml of CH2Cl2, cooled to 0°C. and added dropwise a solution of 0.66 ml (8.5 mmol) of methanesulfonic acid chloride in 10 ml of CH2Cl2. The mixture was stirred for 1 h at 0°C and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH2Cl2 was added dropwise while cooling with ice. The reaction mixture is heated overnight at room temperature, mixed with water, the organic phase is separated, washed twice with water, filtered through activated carbon and evaporated in a vacuum. The residue is co-evaporated twice with toluene and the resulting product is further reacted without purification.
Iskorištenje: 2,25 g (95,9% od teorijskog). Yield: 2.25 g (95.9% of theoretical).
C13H15BrN2 (M = 279,18) C13H15BrN2 (M = 279.18)
Izračunato: molekulska masa (M+H)+: 279/281 Calculated: molecular weight (M+H)+: 279/281
Nađeno: molekulska masa (M+H)+: 279/281 Found: molecular weight (M+H)+: 279/281
Rf vrijednost: 0,5 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.5 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
2.107.e. 2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etilamin 2.107.e. 2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine
20 mg Raney nikla se doda u otopinu od 225 mg (0,81 mmola) (3-brom-4-pirolidin-1-ilmetil-fenil)-acetonitrila u 5 ml metanolnog NH3 i 5 ml EtOAc i mućka se u Parr-ovom autoklavu 1 h pri sobnoj temperaturi i pod 5 psi H2, katalizator se od filtrira, otapalo se ispari u vakuumu i proizvod dalje reagira bez čišćenje. 20 mg of Raney nickel was added to a solution of 225 mg (0.81 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile in 5 ml of methanolic NH3 and 5 ml of EtOAc and shaken in a Parr autoclave for 1 h at room temperature and under 5 psi H2, the catalyst is filtered off, the solvent is evaporated in vacuo and the product is further reacted without purification.
Iskorištenje: 225 mg (98,1% od teorijskog). Yield: 225 mg (98.1% of theoretical).
C13H19BrN2 (M = 283,21) C13H19BrN2 (M = 283.21)
Izračunato: molekulska masa (M+H)+: 283/285 Calculated: molecular weight (M+H)+: 283/285
Nađeno: molekulska masa (M+H)+: 283/285 Found: molecular weight (M+H)+: 283/285
Rf vrijednost: 0,08 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
2.107.f. 4'-klor-bifenil-4-karboksilna kiselina-[2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid hidroklorid 2.107.f. 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide hydrochloride
Proizveden je prema općem radnom postupku I iz 220 mg (0,78 mmola) 2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil-amina i 186 mg (0,8 mmola) 4'-klor-bifenil-4-karboksilne kiseline. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se preuzme u izopropanol/terc-butilmetil eter, pomiješa se s eterskom HCl i ispari u vakuumu. Ostatak se ponovno preuzme u 20 ml izopropanola, triturira se, odsisa, ispere s malo izopropanola i osuši pri 50°C. It was produced according to general procedure I from 220 mg (0.78 mmol) of 2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl-amine and 186 mg (0.8 mmol) of 4'-chloro -biphenyl-4-carboxylic acids. The residue after removal of drying agent and solvent is taken up in isopropanol/tert-butylmethyl ether, mixed with ethereal HCl and evaporated in vacuo. The residue is taken up again in 20 ml of isopropanol, triturated, suctioned off, washed with a little isopropanol and dried at 50°C.
Iskorištenje: 165 mg (39,6% od teorijskog) Yield: 165 mg (39.6% of theoretical)
C26H27BrCl2N2O (M = 534,33) C26H27BrCl2N2O (M = 534.33)
Izračunato: molekulska masa (M+H)+: 497/499/501 Calculated: molecular weight (M+H)+: 497/499/501
Nađeno: molekulska masa (M+H)+: 497/499/501 Found: molecular weight (M+H)+: 497/499/501
Rf vrijednost: 0,35 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). Rf value: 0.35 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1).
Primjer 2.108: Example 2.108:
4'-klor-bifenil-4-karboksilna kiselina-[2-(3-metil-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
17,3 mg (0,28 mmola) metilborne kiseline, 2,5 ml 2M ootpine Na2CO3 i 32 mg (0,03 mmola) tetrakis-(trifenil-fosfin)-paladija doda se u suspenziju od 150 mg (0,28 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid hidroklorida u 5 ml dioksana i reakcijsku smjesu se refluktira 5 h. Vruću suspenziju se odsisa kroz filter od staklenih vlakana, filtrat se pomiješa s poluzasićenom otopinom NaHCO3, iscrpno se ekstrahira s EtOAc i osuši se preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala ostatak se očisti pomoću kromatografije na silika gelu (CH2Cl2/MeOH 8:2). 17.3 mg (0.28 mmol) of methylboric acid, 2.5 ml of 2M Na2CO3 solution and 32 mg (0.03 mmol) of tetrakis-(triphenyl-phosphine)-palladium are added to a suspension of 150 mg (0.28 mmol ) 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide hydrochloride in 5 ml of dioxane and the reaction mixture was refluxed for 5 h. The hot suspension was filtered off with suction through a glass fiber filter, the filtrate was mixed with half saturated NaHCO 3 solution, extracted exhaustively with EtOAc and dried over MgSO 4 . The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH 8:2).
Iskorištenje: 20 mg (16,4% od teorijskog). Yield: 20 mg (16.4% of theoretical).
C27H29ClN2O (M = 433,0) C27H29ClN2O (M = 433.0)
Izračunato: molekulska masa (M+H)+: 433/435 Calculated: molecular weight (M+H)+: 433/435
Nađeno: molekulska masa (M+H)+: 433/435 Found: molecular weight (M+H)+: 433/435
Vrijeme retencije HPLC: 6,47 min (metoda A) HPLC retention time: 6.47 min (method A)
Primjer 2.109: Example 2.109:
4'-klor-bifenil-4-karboksilna kiselina-[2-(2-brom-4-pirolidin-1-ilmetil-fenil )-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.109.a. Etil 4-(2-amino-etil)-3-nitro-benzoat 2.109.a. Ethyl 4-(2-amino-ethyl)-3-nitro-benzoate
5,78 g (57 mmolova) KNO3 se doda u obrocima u otopinu od 12,0 g (52 mmola) etil 4-(2-amino-etil)-benzoata u 80 ml konc. H2SO4 ohlađene na -5°C i miješa se 1 h pri toj temperaturi. Reakcijsku otopinu se doda polako, kap po kap, u ledenu vodu (temperatura ne smije porasti iznad 0°C) i miješa se 1 h. Talog se odsisa, ispere s vodom i osuši pri 50°C. 5.78 g (57 mmol) of KNO3 was added in portions to a solution of 12.0 g (52 mmol) of ethyl 4-(2-amino-ethyl)-benzoate in 80 ml of conc. H2SO4 cooled to -5°C and stirred for 1 h at that temperature. Add the reaction solution slowly, drop by drop, to ice water (the temperature must not rise above 0°C) and mix for 1 h. The precipitate is suctioned off, washed with water and dried at 50°C.
Iskorištenje: 8,2 g (66,2% od teorijskog). Yield: 8.2 g (66.2% of theoretical).
C11H14N2O4 (M = 238,25) C11H14N2O4 (M = 238.25)
Izračunato: molekulska masa (M+H)+: 239 Calculated: molecular weight (M+H)+: 239
Nađeno: molekulska masa (M+H)+: 239 Found: molecular weight (M+H)+: 239
Vrijeme retencije HPLC: 3,64 min (metoda A) HPLC retention time: 3.64 min (method A)
2.109.b. Etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-nitro-benzoat 2.109.b. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate
Proizveden je prema općem radnom postupku I iz 8,2 g (34 mmola) etil 4-(2-amino-etil)-3-nitro-benzoata i 7,91 g (34 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 8.2 g (34 mmol) of ethyl 4-(2-amino-ethyl)-3-nitro-benzoate and 7.91 g (34 mmol) of 4'-chloro-biphenyl-4- carboxylic acids.
Iskorištenje: 7,7 g (50,0% od teorijskog). Yield: 7.7 g (50.0% of theoretical).
C24H22ClN2O5 (M = 452,90) C24H22ClN2O5 (M = 452.90)
Izračunato: molekulska masa (M+H)+: 452/454 Calculated: molecular weight (M+H)+: 452/454
Nađeno: molekulska masa (M+H)+: 452/454 Found: molecular weight (M+H)+: 452/454
Vrijeme retencije HPLC: 6,14 min (metoda B) HPLC retention time: 6.14 min (method B)
2.109.c. Etil 3-amino-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoat 2.109.c. Ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate
0,5 g Raney Nikla se doda u otopinu od 7,7 g (17 mmolova) etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-nitro-benzoata u 200 ml EtOAc i reakcijsku smjesu se mućka preko noći u autoklavu pri sobnoj temperaturi i pod 10 psi H2. Za dovršetak reakcije doda se 50 ml THF-a i smjesu se mućka daljnjih 2 h. Katalizator se odsisa, ispere temeljito s THF-om, otapalo se ispari u vakuumu, ostatak se triturira s EtOAc, odsisa se ponovno i osuši na zraku. 0.5 g of Raney Nickel is added to a solution of 7.7 g (17 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate in 200 ml EtOAc and the reaction mixture is shaken overnight in an autoclave at room temperature and under 10 psi H2. To complete the reaction, 50 ml of THF was added and the mixture was shaken for a further 2 h. The catalyst is filtered off with suction, washed thoroughly with THF, the solvent is evaporated in vacuo, the residue is triturated with EtOAc, filtered again with suction and dried in air.
Iskorištenje: 5,0 g (69,5% od teorijskog). Yield: 5.0 g (69.5% of theoretical).
C24H23ClN2O3 (M = 422,92) C24H23ClN2O3 (M = 422.92)
Izračunato: molekulska masa (M+H)+: 423/425 Calculated: molecular weight (M+H)+: 423/425
Nađeno: molekulska masa (M+H)+: 423/425 Found: molecular weight (M+H)+: 423/425
Vrijeme retencije HPLC: 5,71 min (metoda B) HPLC retention time: 5.71 min (method B)
2.109.d. Etil 3-brom-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoat 2.109.d. Ethyl 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoate
20 ml 48%-tne HBr doda se u otopinu od 5,0 g (7,69 mmolova) etil 3-amino-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoata u 20 ml vode i ohladi se na 0°C. Zatim se doda kap po kap otopinu od 0,9 g (13 mmolova) od NaNO2 u 5,2 ml vode tako da temperatura ne poraste iznad 5oC i smjesu se miješa još daljnjih 10 min pri 0oC. Zatim se odmah pri toj temperaturi doda kap po kap otopinu od 1,87 g (13 mmolova) CuBr u 6,65 ml 48%-tne HBr. Reakcijsku smjesu se zatim grije 1 h pri 60°C. Doda se vodu i smjesu se ekstrahira iscrpno s EtOAc. Organsku fazu se ispere s vodom i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu (petrol eter/EtOAc 6:4). 20 ml of 48% HBr is added to a solution of 5.0 g (7.69 mmol) ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl }-benzoate in 20 ml of water and cool to 0°C. Then a solution of 0.9 g (13 mmol) of NaNO2 in 5.2 ml of water is added drop by drop so that the temperature does not rise above 5oC and the mixture is stirred for another 10 min at 0oC. Then, immediately at that temperature, a solution of 1.87 g (13 mmol) CuBr in 6.65 ml of 48% HBr is added drop by drop. The reaction mixture is then heated for 1 h at 60°C. Water was added and the mixture was extracted exhaustively with EtOAc. The organic phase is washed with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (petroleum ether/EtOAc 6:4).
Iskorištenje: 1,3 g (34,7% od teorijskog). Yield: 1.3 g (34.7% of theoretical).
C24H21BrClNO3 (M = 486,80) C24H21BrClNO3 (M = 486.80)
Izračunato: molekulska masa (M+H)+: 486/488/490 Calculated: molecular weight (M+H)+: 486/488/490
nađeno: molekulska masa (M+H)+: 486/488/490 found: molecular weight (M+H)+: 486/488/490
Rf vrijednost: 0,55 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.55 (silica gel, petroleum ether/EtOAc 6:4).
2.109.e. 3-brom-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeva kiselina 2.109.e. 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-benzoic acid
6 ml 1N otopine NaOH doda se u suspenziju od 1,3 g (2,67 mmola) etil 3-brom-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoata u 20 ml EtOH i 5 ml THF i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. To se ispari u vakuumu, ostatak se pomiješa s vodom i neutralizira se s 1 N HCl, nakon čega se proizvod istaloži. Miješanje se nastavi još jedan sat uz hlađenje na ledu, smjesu se odsisa, ispere s vodom i proizvod se osuši pri 50°C. 6 ml of 1N NaOH solution was added to a suspension of 1.3 g (2.67 mmol) of ethyl 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}- benzoate in 20 ml of EtOH and 5 ml of THF and the reaction mixture was stirred overnight at room temperature. This is evaporated in vacuo, the residue is mixed with water and neutralized with 1 N HCl, after which the product is precipitated. Mixing is continued for another hour with cooling on ice, the mixture is sucked off, washed with water and the product is dried at 50°C.
Iskorištenje: 1,2 g (97,9% od teorijskog). Yield: 1.2 g (97.9% of theoretical).
C22H27BrClNO3 (M = 458,74) C22H27BrClNO3 (M = 458.74)
Izračunato: molekulska masa (M+H)+: 456/458/460 Calculated: molecular weight (M+H)+: 456/458/460
Nađeno: molekulska masa (M+H)+: 456/458/460 Found: molecular weight (M+H)+: 456/458/460
Vrijeme retencije HPLC: 5,51 min (metoda B) HPLC retention time: 5.51 min (method B)
2.109.f. 4'-klor-bifenil-4-karboksilna kiselina-[2-(2-brom-4-hidroksimetil-fenil)-etil]-amid 2.109.f. 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-hydroxymethyl-phenyl)-ethyl]-amide
0,64 g (3,92 mmola) CDI se doda u otopinu od 1,2 g (2,62 mmola) 3-brom-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzojeve kiseline u 10 ml DMF-a i smjesu se grije pri 50°C do prestanka razvijanja plina. Reakcijsku smjesu se doda k otopini od 0,3 g (7,85 mmolova) NaBH4 u 10 ml vode, miješa se 1 h pri sobnoj temperaturi, zakiseli se s razrijeđenom otopinom KHSO4 i iscrpno se ekstrahira s EtOAc. Organsku fazu se ispere s poluzasićenom otopinom NaHCO3 i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. 0.64 g (3.92 mmol) of CDI was added to a solution of 1.2 g (2.62 mmol) of 3-bromo-4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino ]-ethyl}-benzoic acid in 10 ml of DMF and the mixture is heated at 50°C until gas evolution stops. The reaction mixture was added to a solution of 0.3 g (7.85 mmol) of NaBH 4 in 10 ml of water, stirred for 1 h at room temperature, acidified with dilute KHSO 4 , and extracted exhaustively with EtOAc. The organic phase is washed with half-saturated NaHCO3 solution and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.
Iskorištenje: 0,87 g (74,8% od teorijskog). Yield: 0.87 g (74.8% of theoretical).
C22H19BrClNO2 (M = 444,76) C22H19BrClNO2 (M = 444.76)
Izračunato: molekulska masa (M+H)+: 444/446/448 Calculated: molecular weight (M+H)+: 444/446/448
Nađeno: molekulska masa (M+H)+: 444/446/448 Found: molecular weight (M+H)+: 444/446/448
Vrijeme retencije HPLC: 8,07 min (metoda A) HPLC retention time: 8.07 min (method A)
2.109.g. 4'-klor-bifenil-4-karboksilna kiselina [2-(2-brom-4-klormetil-fenil)-etil]-amid 2.109.g. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-amide
0,24 ml (2,93 mmola) piridina doda se u otopinu od 0,87 g (1,96 mmola) 4'-klor-bifenil-4-karboksilna kiselina- [2-(2-brom-4-hidroksimetil-fenil)-etil]-amida u 20 ml CH2Cl2 i ohladi se na 0°C. Doda se 0,21 ml (2,93 mmola) tionil klorida, smjesu se miješa 1 h pri toj temperaturi i zatim se pusti zagrijati na sobnu temperaturu. Zatim se doda vodu i smjesu se filtrira kroz Celite, vodenu fazu se ekstrahira s CH2Cl2 i sjedinjene organske faze se osuše preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. 0.24 ml (2.93 mmol) of pyridine is added to a solution of 0.87 g (1.96 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-hydroxymethyl- phenyl)-ethyl]-amide in 20 ml of CH2Cl2 and cooled to 0°C. 0.21 ml (2.93 mmol) of thionyl chloride was added, the mixture was stirred for 1 h at that temperature and then allowed to warm to room temperature. Then water is added and the mixture is filtered through Celite, the aqueous phase is extracted with CH2Cl2 and the combined organic phases are dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.
Iskorištenje: 0,66 g (72,8% od teorijskog). Yield: 0.66 g (72.8% of theoretical).
C22H18BrCl2NO (M = 463,21) C22H18BrCl2NO (M = 463.21)
Izračunato: molekulska masa (M+H)+: 462/464/466 Calculated: molecular weight (M+H)+: 462/464/466
Nađeno: molekulska masa (M+H)+: 462/464/466 Found: molecular weight (M+H)+: 462/464/466
Vrijeme retencije HPLC: 6,37 min (metoda B) HPLC retention time: 6.37 min (method B)
2.109.h 4'-klor-bifenil-4-karboksilna kiselina [2-(2-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.109.h 4'-chloro-biphenyl-4-carboxylic acid [2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
0,59 g (4,28 mmola) K2CO3 i 0,24 ml (2,85 mmola) pirolidina doda se u otopinu od 0,66 g (1,43 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(2-brom-4-klormetil-fenil)-etil]-amida u 20 ml acetonitrila i 6 ml DMF-a i miješa se 5 h pri sobnoj temperaturi. Doda se vodu, smjesu se ekstrahira iscrpno s EtOAc, organsku fazu se ispere nekoliko puta s vodom i osuši se preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu (CH2Cl2/MeOH 9:1). 0.59 g (4.28 mmol) of K2CO3 and 0.24 ml (2.85 mmol) of pyrrolidine were added to a solution of 0.66 g (1.43 mmol) of 4'-chloro-biphenyl-4-carboxylic acid- [2-(2-bromo-4-chloromethyl-phenyl)-ethyl]-amide in 20 ml of acetonitrile and 6 ml of DMF and stirred for 5 h at room temperature. Water is added, the mixture is extracted exhaustively with EtOAc, the organic phase is washed several times with water and dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH 9:1).
Iskorištenje: 0,2 g (28,2% od teorijskog). Yield: 0.2 g (28.2% of theoretical).
C26H26BrClN2O (M = 497,87) C26H26BrClN2O (M = 497.87)
Izračunato: molekulska masa (M+H)+: 497/499/501 Calculated: molecular weight (M+H)+: 497/499/501
Nađeno: molekulska masa (M+H)+: 497/499/501 Found: molecular weight (M+H)+: 497/499/501
Vrijeme retencije HPLC: 4,39 min (metoda B) HPLC retention time: 4.39 min (method B)
Primjer 2.110: Example 2.110:
4'-klor-bifenil-4-karboksilna kiselina-[2-(2-metil-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-methyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
Proizveden je analogno primjeru 2.108. iz 200 mg (0,40 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(2-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amida i 27,3 mg (0,44 mmola) metilborne kiseline refluktiranjem samo 2 h i čišćenjem proizvoda pomoću HPLC. It is produced analogously to example 2.108. from 200 mg (0.40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(2-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide and 27.3 mg ( 0.44 mmol) of methylboric acid by refluxing for only 2 h and purifying the product by HPLC.
Iskorištenje: 62 mg (35,6% od teorijskog). Yield: 62 mg (35.6% of theoretical).
C27H29ClN2O (M = 433,0) C27H29ClN2O (M = 433.0)
Izračunato: molekulska masa (M+H)+: 433/435 Calculated: molecular weight (M+H)+: 433/435
Nađeno: molekulska masa (M+H)+: 433/435 Found: molecular weight (M+H)+: 433/435
Vrijeme retencije HPLC: 6,15 min (metoda A) HPLC retention time: 6.15 min (method A)
Primjer 2.111: Example 2.111:
4'-klor-bifenil-4-karboksilna kiselina [2-(2-nitro-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.111.a. 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-nitro-benzojeva kiselina 2.111.a. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoic acid
2 ml 1N otopine NaOH doda se u otopinu od 200 mg (0,44 mmola) etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-nitro-benzoata (primjer 2.109.b) u 10 ml EtOH i reakcijsku smjesu se miješa 1 h pri sobnoj temperaturi. Smjesu se ispari u vakuumu, k ostatku se doda vodu i 2 ml 1N otopine HCl i suspenziju se miješa 30 min na ledenoj kupelji. Proizvod se odsisa, ispere s vodom i osuši pri 50°C. 2 ml of 1N NaOH solution was added to a solution of 200 mg (0.44 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoate ( example 2.109.b) in 10 ml of EtOH and the reaction mixture is stirred for 1 h at room temperature. The mixture is evaporated in a vacuum, water and 2 ml of 1N HCl solution are added to the residue and the suspension is stirred for 30 min in an ice bath. The product is sucked off, washed with water and dried at 50°C.
Iskorištenje: 180 mg (95,9% od teorijskog). Yield: 180 mg (95.9% of theoretical).
C22H17ClN2O5 (M = 424,84) C22H17ClN2O5 (M = 424.84)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Rf vrijednost: 0,07 (silika gel, EtOAc/MeOH/NH3 9:1:0,1). Rf value: 0.07 (silica gel, EtOAc/MeOH/NH3 9:1:0.1).
2.111.b. 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-hidroksimetil-2-nitro-fenil)-etil]-amid 2.111.b. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-2-nitro-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 2.109.f iz 180 mg (0,42 mmola) 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-nitro-benzojeve kiseline. It was produced analogously to example 2.109.f from 180 mg (0.42 mmol) of 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-nitro-benzoic acid.
Iskorištenje: 110 mg (63,1% od teorijskog). Yield: 110 mg (63.1% of theoretical).
C22H19ClN2O4 (M = 410,86) C22H19ClN2O4 (M = 410.86)
Izračunato: molekulska masa (M+H)+: 411/413 Calculated: molecular weight (M+H)+: 411/413
Nađeno: molekulska masa (M+H)+: 411/413 Found: molecular weight (M+H)+: 411/413
Vrijeme retencije HPLC: 8,27 min (metoda A) HPLC retention time: 8.27 min (method A)
2.111.c. 4'-klor-bifenil-4-karboksilna kiselina [2-(2-nitro-4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.111.c. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-nitro-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
23 μl klorida metansulfonske kiseline doda se polako, kap po kap, u otopinu od 110 mg (0,27 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-{4-hidroksimetil-2-nitro-fenil)-etil]-amida i 48 μl trietilamina u 5 ml CH2Cl2 ohlađenog na 5oC. Otopinu se grije 1 h pri 40°C, doda se 5 ml DMF-a i 115 μl (1,34 mmola) pirolidina i smjesu se grije pri 80°C još jedan sat, tijekom čega se CH2Cl2 ispari. Reakcijsku smjesu se ispari u vakuumu, ostatak se pomiješa s vodom, iscrpno se ekstrahira s EtOAc i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću HPLC. 23 μl of methanesulfonic acid chloride is added slowly, dropwise, to a solution of 110 mg (0.27 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-{4-hydroxymethyl-2-nitro-phenyl) -ethyl]-amide and 48 μl of triethylamine in 5 ml of CH2Cl2 cooled to 5oC. The solution is heated for 1 h at 40°C, 5 ml of DMF and 115 μl (1.34 mmol) of pyrrolidine are added and the mixture is heated at 80°C for another hour, during which the CH2Cl2 is evaporated. The reaction mixture is evaporated in vacuo, the residue is mixed with water, extracted exhaustively with EtOAc and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent is purified by HPLC.
Iskorištenje: 11 mg (8,8% od teorijskog). Yield: 11 mg (8.8% of theoretical).
C26H26ClN3O3 (M = 463,97) C26H26ClN3O3 (M = 463.97)
Izračunato: molekulska masa (M+H)+: 464/466 Calculated: molecular weight (M+H)+: 464/466
Nađeno: molekulska masa (M+H)+: 464/466 Found: molecular weight (M+H)+: 464/466
Vrijeme retencije HPLC: 6,44 min (metoda A) HPLC retention time: 6.44 min (method A)
Primjer 2.112: Example 2.112:
4'-klor-bifenil-4-karboksilna kiselina [2-(2-metansulfonil-amino-4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methanesulfonyl-amino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.112.a. Etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-metansulfonilamino-benzoat 2.112.a. Ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoate
44 μl (0,57 mmola) klorida metansulfonske kiseline se doda polako, kap po kap, u otopinu od 200 mg (0,47 mmola) etil 3-amino-4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-benzoata (primjer 2.109.c) u 5 ml piridina ohlađenu na 0°C i reakcijsku smjesu se miješa 1 h pri sobnoj temperaturi. To se pomiješa s ledenom vodom, ekstrahira se iscrpno s EtOAc, organsku fazu se ispere nekoliko puta s vodom i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. 44 μl (0.57 mmol) of methanesulfonic acid chloride was added slowly, dropwise, to a solution of 200 mg (0.47 mmol) of ethyl 3-amino-4-{2-[(4'-chloro-biphenyl-4 -carbonyl)-amino]-ethyl}-benzoate (example 2.109.c) in 5 ml of pyridine cooled to 0°C and the reaction mixture was stirred for 1 h at room temperature. This was mixed with ice water, extracted exhaustively with EtOAc, the organic phase was washed several times with water and dried over MgSO 4 . The residue after removal of desiccant and solvent continues to react without cleaning.
Iskorištenje: 230 mg (97,1% od teorijskog). Yield: 230 mg (97.1% of theoretical).
C25H25ClN2O5S (M = 501,01) C25H25ClN2O5S (M = 501.01)
Izračunato: molekulska masa (M+H)+: 501/503 Calculated: molecular weight (M+H)+: 501/503
Nađeno: molekulska masa (M+H)+: 501/503 Found: molecular weight (M+H)+: 501/503
Vrijeme retencije HPLC: 5,66 min (metoda B) HPLC retention time: 5.66 min (method B)
2.112.b. 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-metansulfonilamino-benzojeva kiselina 2.112.b. 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoic acid
Proizvedena je analogno primjeru 2.111.a iz 230 mg (0,46 mmola) etil 4-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-3-metansulfonilaminobenzoata. It was produced analogously to example 2.111.a from 230 mg (0.46 mmol) of ethyl 4-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylaminobenzoate.
Iskorištenje: 180 mg (82,9% od teorijskog). Yield: 180 mg (82.9% of theoretical).
C23H21ClN2O5S (M = 472,95) C23H21ClN2O5S (M = 472.95)
Izračunato: molekulska masa (M-H)-: 471/473 Calculated: molecular weight (M-H)-: 471/473
Nađeno: molekulska masa (M-H)-: 471/473 Found: molecular weight (M-H)-: 471/473
Vrijeme retencije HPLC: 7,67 min (metoda A) HPLC retention time: 7.67 min (method A)
2.112.c. 4'-klor-bifenil-4-karboksilna kiselina-[2-(4-hidroksimetil-2-metansulfonilamino-fenil)-etil]-amid 2.112.c. 4'-chloro-biphenyl-4-carboxylic acid-[2-(4-hydroxymethyl-2-methanesulfonylamino-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 2.109.f iz 180 mg (0,38 mmola) 4-{2-[{4'-klor-bifenil-4-karbonil)-amino]-etil}-3-metansulfonilamino-benzojeve kiseline. It was produced analogously to example 2.109.f from 180 mg (0.38 mmol) of 4-{2-[{4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-3-methanesulfonylamino-benzoic acid.
Iskorištenje: 150 mg (85,8% od teorijskog). Yield: 150 mg (85.8% of theoretical).
C23H23ClN2O4S (M = 458,97) C23H23ClN2O4S (M = 458.97)
Izračunato: molekulska masa (M+H)+: 459/461 Calculated: molecular weight (M+H)+: 459/461
Nađeno: molekulska masa (M+H)+: 459/461 Found: molecular weight (M+H)+: 459/461
Vrijeme retencije HPLC: 7,53 min (metoda A) HPLC retention time: 7.53 min (method A)
2.112.d. 4'-klor-bifenil-4-karboksilna kiselina [2-(2-metansulfonilamino-4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.112.d. 4'-chloro-biphenyl-4-carboxylic acid [2-(2-methanesulfonylamino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je analogno primjeru 2.111c iz 150 mg (0,33 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-{4-hidroksimetil-2-metansulfonilamino-fenil)-etil]-amida i 140 μl (1,64 mmola) pirolidina. Nakon čišćenje pomoću HPLC proizvod se dobije kao formatna sol. It was produced analogously to example 2.111c from 150 mg (0.33 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-{4-hydroxymethyl-2-methanesulfonylamino-phenyl)-ethyl]-amide and 140 μl ( 1.64 mmol) of pyrrolidine. After purification by HPLC, the product is obtained as a formate salt.
Iskorištenje: 18 mg (9,9% od teorijskog). Yield: 18 mg (9.9% of theoretical).
C27H30ClN3O3S*CH2O2 (M = 558,10) ;Izračunato: molekulska masa (M+H)+: 512/514 ;Nađeno: molekulska masa (M+H)+: 512/514 ;Vrijeme retencije HPLC: 6,13 min (metoda A) ;Primjer 2.113: ;4'-klor-bifenil-4-karboksilna kiselina-[2-(3-piridin-4-il-4-pirolidin-1-ilmetil-fenil)-etil]-amid ;[image] ;Proizveden je analogno primjeru 2.108 iz 200 mg (0,40 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(3-brom-4-pirolidin-1-ilmetil-fenil)-etil]-amida i 74 mg (0,60 mmola) piridin-4-borne kiseline, čišćenjem proizvoda pomoću HPLC. ;Iskorištenje: 13 mg (6,5% od teorijskog). ;C31H30ClN3O (M = 496,06) ;Izračunato: molekulska masa (M+H)+: 496/498 ;Nađeno: molekulska masa (M+H)+: 496/498 ;Vrijeme retencije HPLC: 6,37 min (metoda A) ;Primjer 2.114: ;Metil 5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-benzoat ;[image] ;2.114a. Metil 5-cijanometil-2-pirolidin-1-ilmetil-benzoat ;0,5 ml trietilamin (3,58 mmola), 40 mg (0,18 mmola) Pd(OAc)2 i 99 mg (0,18 mmola) 1,1'-difenilfosfino-ferocena doda se u otopinu od 500 mg (1,79 mmola) (3-brom-4-pirolidin-1-ilmetil-fenil)-acetonitrila (primjer 2.107.d) u 10 ml MeOH i 10 ml DMF-a. Reakcijsku smjesu se miješa 15 h pri 50°C u autoklavu pod 2 bara CO. Za dovršetak reakcije doda se daljnjih 0,5 ml trietilamina, 40 mg Pd(OAc)2 i 99 mg 1,1'-difenilfosfino-ferocena i smjesu se miješa daljnjih 10 h pri 50°C i pod 2 bara CO i preko noći pod 4 bara CO i pri 70oC. Otapala se ispare u vakuumu, ostatak se pomiješa s EtOAc i ekstrahira se dva puta s vodom. Vodenu fazu se zasiti s K2CO3, iscrpno se ekstrahira s EtOAc i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala proizvod se zaostane kao crno ulje koje dalje reagira bez čišćenja. ;Iskorištenje: 380 mg (82,1% od teorijskog). ;C15H18N2O2 (M = 258,32) ;Izračunato: molekulska masa (M+H)+: 259 ;Nađeno: molekulska masa (M+H)+: 259 ;Vrijeme retencije HPLC: 2,49 min (metoda B) ;2.114.b. Metil 5-(2-amino-etil)-2-pirolidin-1-ilmetil-benzoat ;100 mg Raney nikla se doda u otopinu od 380 mg (1,47 mmola) metil 5-cijanometil-2-pirolidin-1-ilmetil-benzoata u 20 ml metanolnog NH3 i reakcijsku smjesu se hidrogenira 27 sati pod 20 psi H2 pri sobnoj temperaturi. Katalizator se odsisa, otapalo se odstrani i ostatak dalje reagira bez čišćenja. ;Iskorištenje: 330 mg (85,5% od teorijskog). ;C15H22N2O2 (M = 262,36) ;Izračunato: molekulska masa (M+H)+: 263 ;Nađeno: molekulska masa (M+H)+: 263 ;Vrijeme retencije HPLC: 1,40 min (metoda A) ;2.114c. Metil 5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-benzoat ;Proizveden je prema općem radnom postupku I iz 330 mg (1,26 mmola) metil 5-(2-amino-etil)-2-pirolidin-1-ilmetil-benzoata i 293 mg (1,26 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 315 mg (52,5% od teorijskog). ;C28H29ClN2O3 (M = 477,01) ;Izračunato: molekulska masa (M+H)+: 477/479 ;Nađeno: molekulska masa (M+H)+: 477/479 ;Vrijeme retencije HPLC: 6,82 min (metoda A) ;Primjer 2.115: ;5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-benzojeva kiselina ;[image] ;Proizvedena je analogno primjeru 2.111.a iz 310 mg (0,65 mmola) metil 5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-benzoata. ;Iskorištenje: 85 mg (28,2% od teorijskog). ;C27H27ClN2O3 (M = 462,98) ;Izračunato: molekulska masa (M+H)+: 463/465 ;Nađeno: molekulska masa (M+H)+: 463/465 ;Vrijeme retencije HPLC: 6,30 min (metoda A) ;Primjer 2.116: ;Terc-butil (5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-fenil)-karbammat ;[image] ;0,27 ml (1,92 mmola) trietilamina i 0,41 ml (1,92 mmola) difenil azido-fosfata doda se u otopinu od 740 mg (1,6 mmola) 5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-benzojeve kiseline u 10 ml terc-butanola i reakcijsku smjesu se refluktira 5 h. To se ispari u vakuumu, ostatak se pomiješa sa CH2Cl2, ekstrahira se s 1N otopinom NaOH i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu. ;Iskorištenje: 85 mg (28,2% od teorijskog). ;C31H36ClN3O3 (M = 534,10) ;Izračunato: molekulska masa (M+H)+: 534/536 ;Nađeno: molekulska masa (M+H)+: 534/536 ;Vrijeme retencije HPLC: 4,82 min (metoda B) ;Primjer 2.117: ;4'-klor-bifenil-4-karboksilna kiselina-[2-(3-etil-4-pirolidin-1-ilmetil-fenil)-etil]-amid ;[image] ;2.117.a. (4-pirolidin-1-ilmetil-3-trimetilsilaniletinil-fenil)-acetonitril ;Suspenziju od 0,36 g (1,29 mmola) (3-brom-4-pirolidin-1-ilmetil-fenil)-acetonitrila (primjer 2.107.d), 0,36 ml (2,58 mmola) trimetilsililacetilena, 0,36 ml (2,58 mmola) trietilamina, 25 mg (0,13 mmola) CuI i 0,15 g (0,13 mmola) tetrakis-(trifenilfosfin)-paladija u 3 ml DMF-a miješa se u mikrovalnoj grijalici (CEM) 15 min pri 100°C i 200 Watta. Kad se ohladi, u reakcijsku smjesu se ddoa zasićenu otopinu NaCl, smjesu se iscrpno ekstrahira s EtOAc i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu (EtOAc). ;Iskorištenje: 50 mg (13,1% od teorijskog). ;C18H24N2Si (M = 296,49) ;Izračunato: molekulska masa (M+H)+: 297 ;Nađeno: molekulska masa (M+H)+: 297 ;Vrijeme retencije HPLC: 6,39 min (metoda A) ;2.117.b 2-(3-etil-4-pirolidin-1-ilmetil-fenil)-etilamin ;20 mg Raney nikla se doda u otopinu od 50 mg (0,17 mmola) (4-pirolidin-1-ilmetil-3-trimetilsilaniletinil-fenil)-acetonitrila u 5 ml metanolnog NH3 i reakcijsku smjesu se mućka 22 h pri sobnoj temperaturi i pod 3 bara H2. Katalizator se odsisa i otapalo se odstrani u vakuumu. Sirov proizvod dalje reagira bez čišćenje. ;Iskorištenje: 39 mg (100% od teorijskog). ;C15H24N2 (M = 232,37) ;Izračunato: molekulska masa (M+H)+: 233 ;Nađeno: molekulska masa (M+H)+: 233 ;2.117.c 4'-klor-bifenil-4-karboksilna kiselina [2-(3-etil-4-pirolidin-1-ilmetil-fenil)-etil]-amid ;Proizveden je prema općem radnom postupku I iz 40 mg (0,17 mmola) 2-(3-etil-4-pirolidin-1-ilmetil-fenil)-etil-amina i 48 mg (0,21 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 2 mg (2,6% od teorijskog). ;C28H31ClN2O (M = 447,03) ;Izračunato: molekulska masa (M+H)+: 447/449 ;Nađeno: molekulska masa (M+H)+: 447/449 ;Vrijeme retencije HPLC: 6,87 min (metoda A) ;Primjer 2.118: ;4'-klor-bifenil-4-karboksilna kiselina [2-(6-pirolidin-1-ilmetil-piridin-3-il)-etil]-amid ;[image] ;2.118a. Metil 6-dibrom-metil-nikotinat ;53,4 g (0,3 mola) NBS-a i 2 g dibenzoilperoksida se doda u otopinu od 38,96 g (0,25 mol) metil 6-metil-nikotinata u 1 l CCl4 i reakcijsku smjesu se refluktira preko noći. Zatim se doda drugih 26,7 g (0,15 mola) NBS-a i 1 g dibenzoilperoksida i smjesu se ponovno refluktira 24 h. Kad se reakcijska smjesa ohladi, talog se odsisa, otapalo se odstrani i ostatak se očisti pomoću kromatografije. ;Iskorištenje: 15,0 g (19,4% od teorijskog). ;C8H7Br2NO2 (M = 308,96) ;Izračunato: molekulska masa (M+H)+: 308/310/312 ;Nađeno: molekulska masa (M+H)+: 308/310/312 ;Rf vrijednost: 0,6 (silika gel, petrol eter/EtOAc 8:2). ;2.118.b. Metil 6-dimetoksimetil-nikotinat ;13,9 ml NaOMe u MeOH (30%, 75 mmola) u 100 ml MeOH zagrije se do ključanja. U kipuću otopinu doda kap po kap otopinu od 11,0 g (34,1 mmola) metil 6-dibrom-metil-nikotinata u 10 ml MeOH i refluktira se preko noći. Za dovršetak reakcije doda se daljnjih 1,5 ml (8,1 mmolova) otopine NaOMe i smjesu se refluktira ponovno 24 h. Reakcijsku smjesu se ispari u vakuumu, ostatak se pomiješa s razrijeđenom otopinom KHSO4, neutralizira s razrijeđenom otopinom NaHCO3, iscrpno se ekstrahira s EtOAc, organsku fazu se ispere s vodom i osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. ;Iskorištenje: 5,0 g (69,5% od teorijskog). ;C10H13NO4 (M = 211,22) ;Izračunato: molekulska masa (M+H)+: 212 ;Nađeno: molekulska masa (M+H)+: 212 ;Rf vrijednost: 0,44 (silika gel, petrol eter/EtOAc 6:4). ;2.118.c. 6-dimetoksimetil-nikotinska kiselina ;15 ml 1N otopine NaOH doda se u otopinu od 2,8 g (13,26 mmola) metil 6-dimetoksimetil-nikotinata u 50 ml MeOH i miješa se 24 h pri sobnoj temperaturi. Reakcijsku smjesu se neutralizira s 15 ml 1N HCl, ispari se u vakuumu, ostatak se triturira s MeOH/THF, talog se odsisa i filtrat se ispari. Dobiveni proizvod dalje reagira bez čišćenje. ;Iskorištenje: 2,6 g (99,4% od teorijskog). ;C9H11NO4 (M = 197,19) ;Izračunato: molekulska masa (M+H)+: 198 ;Nađeno: molekulska masa (M+H)+: 198 ;Vrijeme retencije HPLC: 3,65 min (metoda A) ;2.118.d. (6-dimetoksimetil-piridin-3-il)-metanol ;Proizveden je analogno primjeru 2.109.f iz 2,7 g (13,7 mmolova) 6-dimetoksimetil-nikotinske kiseline upotrebom THF-a kao otapala i terc-butilmetil etera za ekstrakciju. ;Iskorištenje: 2,1 g (83,7% od teorijskog). ;C9H13NO3 (M = 183,21) ;Izračunato: molekulska masa (M+H)+: 184 ;Nađeno: molekulska masa (M+H)+: 184 ;Vrijeme retencije HPLC: 2,85 min (metoda A) ;2.118.e. 5-klormetil-2-dimetoksimetil-piridin ;0,3 ml (4,14 mmola) tionil klorida, otopljenog u malo CH2Cl2, doda se polako, kap po kap, u otopinu od 500 mg (2,73 mmola) (6-dimetoksimetil-piridin-3-il)-metanola u 10 ml CH2Cl2 ohlađenu na 0°C i miješa se daljnjih 30 min pri toj temperaturi. Reakcijsku smjesu se razrijedi sa CH2Cl2, ispere se s hladnom otopinom NaHCO3 i osuši se preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. ;Iskorištenje: 500 mg (90,8% od teorijskog). ;C9H12ClNO2 (M = 201,65) ;Izračunato: molekulska masa (M+H)+: 202/204 ;Nađeno: molekulska masa (M+H)+: 202/204 ;Rf vrijednost: 0,3 (silika gel, petrol eter/EtOAc 6:4). ;2.118.f. (6-dimetoksimetil-piridin-3-il)-acetonitril ;20 ml DMSO doda se u 5,21 g (80 mmolova) KCN-a u 5,2 ml vode i pri 80°C doda se kap po kap otopinu od 500 mg (2,48 mmola) 5-klor-metil-2-dimetoksimetil-piridina u 10 ml DMSO i reakcijsku smjesu se drži daljnji sat pri 80oC. To se prelije na 200 ml vode, zasiti se s NaCl, ekstrahira se iscrpno s EtOAc, organsku fazu se osuši preko MgSO4 i filtrira kroz aktivirani ugljen. Filtrat se ispari i ostatak se očisti pomoću kromatografije ne silika gelu (CH2Cl2/MeOH 9:1). ;Iskorištenje: 330 mg (69,2% od teorijskog). ;C10H12N2O2 (M = 192,22) ;Izračunato: molekulska masa (M+H)+: 193 ;Nađeno: molekulska masa (M+H)+: 193 ;Rf vrijednost: 0,48 (silika gel, CH2Cl2/MeOH 9:1). ;2.118.g. 2-(6-dimetoksimetil-piridin-3-il)-etilamin ;50 mg Raney nikla se doda u otopinu od 330 mg (1,72 mmola) (6-dimetoksimetil-piridin-3-il)-acetonitrila u 10 ml metanolnog NH3 i reakcijsku smjesu se hidrogenira u Parr-ovom autoklavu 15 h pri 30°C i pod 3 bara H2. Katalizator se odfiltrira, otapalo se ispari u vakuumu i ostatak dalje reagira bez čišćenje. ;Iskorištenje: 340 mg (100% od teorijskog). ;C10H16N2O2 (M = 196,25) ;Izračunato: molekulska masa (M+H)+: 197 ;Nađeno: molekulska masa (M+H)+: 197 ;Vrijeme retencije HPLC: 1,3 min (metoda A) ;2.118.h. 4'-klor-bifenil-4-karboksilna kiselina [2-(6- ;dimetoksimetil-piridin-3-il)-etil]-amid ;Proizveden je prema općem radnom postupku I iz 340 mg (1,73 mmola) 2-(6-dimetoksimetil-piridin-3-il)-etilamina i 419 mg (1,80 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 210 mg (28,4% od teorijskog). ;C23H23ClN2O3 (M = 410,90) ;Izračunato: molekulska masa (M+H)+: 411/413 ;Nađeno: molekulska masa (M+H)+: 411/413 ;Rf vrijednost: 0,4 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). ;2.118.i. 4'-klor-bifenil-4-karboksilna kiselina [2-(6-formil-piridin-3-il)-etil]-amid ;5 ml 12%-tne HCl se doda u otopinu od 205 mg (0,5 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(6-di-metoksimetil-piridin-3-il)-etil]-amida u 10 ml MeOH i reakcijsku smjesu se miješa 4 h pri sobnoj temperaturi i grije se pri 80°C preko noći. Doda se drugih 2,5 ml 12% HCl, smjesu se grije daljnjih 8 h pri 80oC i preko noći pri 100°C. Reakcijsku smjesu se pomiješa s 50 ml vode, namjesti se na pH 8 s otopinom Na2CO3, iscrpno se ekstrahira sa CH2Cl2 i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. ;Iskorištenje: 180 mg (98,7% od teorijskog). ;C21H17ClN2O2 (M = 364,84) ;Izračunato: molekulska masa (M+H)+: 365/367 ;Nađeno: molekulska masa (M+H)+: 365/367 ;Vrijeme retencije HPLC: 5,25 min (metoda A) ;2.118.k. 4'-klor-bifenil-4-karboksilna kiselina [2-(6-pirolidin-1-ilmetil-piridin-3-il)-etil]-amid ;50 μl (0,6 mmola) pirolidina, 37,7 mg (0,6 mmola) NaBH3CN i 2 ml MeOH doda se u otopinu od 180 mg (0,49 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(6-formil-piridin-3-il)-etil]-amida u 5 ml acetonitrila. pH vrijednost se namjesti na 5-6 s ledenom octenom kiselinom i smjesu se miješa 5 h pri sobnoj temperaturi. Reakcijsku smjesu se zakiseli s 1M otopinom KHSO4, zaluži se s 2M otopinom Na2CO3, iscrpno se ekstrahira sa CH2Cl2 i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu (CH2Cl2/MeOH/NH3 9:1:0,1). ;Iskorištenje: 25 mg (12,1% od teorijskog). ;C25H26ClN3O (M = 419,96) ;Izračunato: molekulska masa (M+H)+: 420/422 ;Nađeno: molekulska masa (M+H)+: 420/422 ;Rf vrijednost: 0,2 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). ;Primjer 2.119: ;4'-klor-bifenil-4-karboksilna kiselina [2-(5-pirolidin-1-ilmetil-piridin-2-il)-etil]-amid ;[image] ;2.119.a. Metil 6-hidroksimetil-nikotinat ;Proizveden je analogno primjeru 2.109.f iz 5,0 g (27,6 mmola) 5-metil piridin-2,5-dikarboksilata, upotrebom THF-a kao otapala i terc-butilmetil etera za ekstrakciju. ;Iskorištenje: 2,0 g (43,3% od teorijskog). ;C8H9NO3 (M = 167,17) ;Izračunato: molekulska masa (M+H)+: 168 ;Nađeno: molekulska masa (M+H)+: 168 ;Rf vrijednost: 0,2 (silika gel, CH2Cl2/MeOH 95:5). ;2.119.b. Metil 6-klormetil-nikotinat ;U otopinu od 2,0 g (11,96 mmolova) metil 6-hidroksi-metil-nikotinata u 100 ml CH2Cl2 ohlađenu na OoC doda se 1,06 ml (13 mmolova) piridina i zatim polako, kap po kap, 1,08 ml (13 mmolova) tionil klorida. To se miješa dalje jedan sat pri 0oC i zatim se polako zagrije na sobnu temperaturu. Za dovršenje reakcije doda se dalje 1 ml (12 mmolova) tionil klorida i smjesu se miješa 1 h pri sobnoj temperaturi. U reakcijsku smjesu se doda vodu, organsku fazu se odvoji, ispere se s razrijeđenom otopinom NaHCO3 i vodom i osuši preko MgSO4. To se filtrira kroz aktivirani ugljen i otapalo se ispari u vakuumu. Dobiveni proizvod dalje reagira bez čišćenja. ;Iskorištenje: 1,7 g (65,1% od teorijskog). ;C8H8ClNO2 (M = 185,61) ;Izračunato: molekulska masa (M+H)+: 186/188 ;Nađeno: molekulska masa (M+H)+: 186/188 ;Vrijeme retencije HPLC: 6,7 min (metoda A) ;2.119.c. Metil 6-cijanometil-nikotinat ;Proizveden je analogno primjeru 2.118.f iz 1,5 g (8,08 mmolova) metil 6-klormetil-nikotinata i 5,2 g (80 mmolova) KCN-a, upotrebom cikloheksan/EtOAc 8:2 kao sredstva za ispiranje kod čišćenja pomoću kromatografije na silika gelu. ;Iskorištenje: 220 mg (15,5% od teorijskog). ;C9H9N2O2 (M = 176,18) ;Izračunato: molekulska masa (M+H)+: 177 ;Nađeno: molekulska masa (M+H)+: 177 ;Rf vrijednost: 0,6 (silika gel, petrol eter/EtOAc 1:1). ;2.119.d. Metil 6-(2-amino-etil)-nikotinat ;20 mg Raney nikla se doda u otopinu od 75 mg (0,43 mmola) metil 6-cijanometil-nikotinata u 5 ml metanolnog NH3 i reakcijsku smjesu se hidrogenira u Parr-ovom autoklavu 6 h pri 30oC pod 3 bara H2, katalizator se odfiltrira, otapalo se ispari u vakuumu i ostatak dalje reagira bez čišćenje. ;Iskorištenje: 70 mg (90,3% od teorijskog). ;C9H12N2O2 (M = 180,21) ;Izračunato: molekulska masa (M+H)+: 181 ;Nađeno: molekulska masa (M+H)+: 181 ;Vrijeme retencije HPLC: 2,5 min (metoda A) ;2.119.e. Metil 6-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-nikotinat ;Proizveden je prema općem radnom postupku I iz 70 mg (0,39 mmola) metil 6-(2-amino-etil)-nikotinata i 100 mg (0,43 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 150 mg (88,3% od teorijskog). ;C22H19ClN2O3 (M = 394,86) ;Izračunato: molekulska masa (M+H)+: 395/397 ;Nađeno: molekulska masa (M+H)+: 395/397 ;Vrijeme retencije HPLC: 8,6 min (metoda A) ;2.119.f. 6-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-nikotinska kiselina ;0,8 ml 1 M otopine NaOH doda se u otopinu od 150 mg (0,38 mmola) metil 6-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-nikotinata u 25 ml MeOH i reakcijsku smjesu se refluktira 1 h. To se neutralizira s 0,8 ml 1 N HCl, ispari se u vakuumu, ostatak se pomiješa s vodom i talog se odstrani odsisavanjem. To se otopi u THF-u, otopinu se osuši s MgSO4, profiltrira se i ispari u vakuumu. Ostatak dalje reagira bez čišćenje. ;Iskorištenje: 90 mg (62,2% od teorijskog). ;C21H17ClN2O3 (M = 380,83) ;Izračunato: molekulska masa (M+H)+: 381/383 ;Nađeno: molekulska masa (M+H)+: 381/383 ;Vrijeme retencije HPLC: 6,9 min (metoda A) ;2.119.g. 4'-klor-bifenil-4-karboksilna kiselina {2-(5-hidroksimetil-piridin-2-il)-etil]-amid ;Proizvedena je analogno primjeru 2.109.f iz 90 mg (0,24 mmola) 6-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-nikotinske kiseline, upotrebom THF-a kao otapala i terc-butilmetil etera za ekstrakciju. ;Iskorištenje: 50 mg (56,8% od teorijskog). ;C21H19ClN2O2 (M = 366,85) ;Izračunato: molekulska masa (M+H)+: 367/369 ;Nađeno: molekulska masa (M+H)+: 367/369 ;Rf vrijednost: 0,5 (silika gel, CH2Cl2/MeOH 9:1). ;2.119.h. 4'-klor-bifenil-4-karboksilna kiselina [2-(5-pirolidin-1-ilmetil-piridin-2-il)-etil]-amid ;22 μl tionil klorida doda se kap po kap u otopinu od 50 mg (0,14 mmola) 4'-klor-bifenil-4-karboksilna kiselina-[2-(5-hidroksimetil-piridin-2-il)-etil]-amida u 5 ml CH2Cl2 ohlađenu na 0°C i reakcijsku smjesu se polako pusti zagrijati na sobnu temperaturu. Nakon 1 h pri sobnoj temperaturi doda se kap po kap daljnjih 22 μl tionil klorida za dovršetak reakcije i miješanje se nastavi 1 h. Reakcijsku smjesu se razrijedi s 30 ml CH2Cl2, pomiješa se s ledenom vodom, zaluži se s otoinom NaHCO3, organsku fazu se odvoji, ispere s vodom i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje k toj se otopini doda 50 μl (0,6 mmola) pirolidina i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. To se ispari u vakuumu i ostatak se očisti pomoću HPLC kromatografije. ;Iskorištenje: 2,4 mg (4,1% od teorijskog). ;C25H26ClN3O (M = 419,96) ;Izračunato: molekulska masa (M+H)+: 420/422 ;Nađeno: molekulska masa (M+H)+: 420/422 ;Rf vrijednost: 0,3 (silika gel, CH2Cl2/MeOH 9:1). ;Vrijeme retencije HPLC: 6,0 min (metoda A) ;Primjer 2.120: ;4'-klor-bifenil-4-karboksilna kiselina{2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-amid ;[image] ;2.120.a. Terc-butil [2-(4-acetil-fenil)-etil]-karbaminat ;5,46 g (25 mmolova) BOC-anhidrida se doda u otopinu od 4,99 g (25 mmolova) 1-[4-{2-amino-etil)-fenil]-etanona (upotrijebljen u obliku hidroklorida) u 100 ml CH2Cl2 i pri sobnoj temperaturi se polako doda, kap po kap, 25 ml 1N otopine NaOH i po završetku dodavanja smjesu se miješa 2 h pri sobnoj temperaturi. Reakcijsku smjesu se filtrira kroz Celite, ispere dva puta s vodom i osuši preko MgSO4. To se filtrira kroz aktivirani ugljen, ispari u vakuumu i proizvod dalje reagira bez čišćenje. ;Iskorištenje: 6,4 g (97,2% od teorijskog). ;C12H21NO3 (M = 263,34) ;Izračunato: molekulska masa (M+H)+: 262 ;Nađeno: molekulska masa (M+H)+: 262 ;Rf vrijednost: 0,88 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). ;2.120.b. Terc-butil {2-[4-(1-hidroksi-etil)-fenil]-etil}-karbaminat ;4,72 g (125 mmola) NaBH4 se doda u obrocima pri sobnoj temperaturi u otopinu od 6,58 g (25 mmolova) terc-butil [2-(4-acetil-fenil)-etil]-karbaminata u 250 ml MeOH i reakcijsku smjesu se miješa preko vikenda. To se oprezno zakiseli s otopinom KHSO4, ekstrahira se iscrpno s tercbutilmetil eterom, organsku fazu se ispere sa zasićenom otopinom NaCl i osuši se preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, proizvod zaostane u obliku blago žućkastog ulja koje kristalizira kad se pusti stajati. ;Iskorištenje: 5,4 g (81,4% od teorijskog). ;C15H23NO3 (M = 265,36) ;Izračunato: molekulska masa (M+H)+: 266 ;Nađeno: molekulska masa (M+H)+: 266 ;Rf vrijednost: 0,4 (silika gel, petrol eter/EtOAc 6:4). ;2.120.c. Terc-butil {2-[4-(1-pirolidin-1-il-etil)-fenil]- etil}-karbaminat ;0,66 ml (8,5 mmolova) klorida metansulfonske kiseline, otopljenog u 10 ml CH2Cl2, doda se kap po kap u otopinu od 2,89 g (10,89 mmolova) terc-butil {2-[4-(1-hidroksi-etil)-fenil]-etil}-karbaminata u 50 ml CH2Ck2 i 1,25 ml trietil-amina ohlađenu na 0oC. Miješanje se nastavi 1 h pri toj temperaturi i zatim se polako doda kap po kap otopinu od 1,4 ml (17 mmolova) pirolidina u 10 ml CH2Cl2. Reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi, pomiješa s razrijeđenom otopinom KHSO4, organsku fazu se odvoji, ispere dva puta s razrijeđenom otopinom KHSO4, djedinjene vodene faze se zaluže s otopinom K2CO3 i iscrpno se ekstrahiraju s terc-butilmetil eterom. Sjedinjene organske faze se isperu nekoliko puta s malo vode i osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, proizvod dalje reagira bez čišćenja. ;Iskorištenje: 0,3 g (8,7% od teorijskog). ;C19H30N2O2 (M = 318,46) ;Izračunato: molekulska masa (M+H)+: 319 ;Nađeno: molekulska masa (M+H)+: 319 ;Rf vrijednost: 0,22 (silika gel, CH2Cl2/MeOH/NH3 9:1:0,1). ;2.120.d. 2-[4-(1-pirolidin-1-il-etil)-fenil]-etilamin ;0,72 ml trifluoroctene kiseline doda se u otopinu od 300 mg (0,94 mmola) terc-butil {2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-karbaminata u 20 ml CH2Cl2 i miješa se 1 h pri sobnoj temperaturi. za dovršetak reakcija doda se daljnjih 0,72 ml trifluoroctene kiseline i reakcijsku smjesu se drži 1 h pri sobnoj temperaturi. Otapalo se ispari u vakuumu, ostatak se preuzme u vodu, zaluži se s 2 N NaOH, iscrpno se ekstrahira s EtOAc i organsku fazu se osuši preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, proizvod dalje reagira bez čišćenja. ;Iskorištenje: 150 mg (72,9% od teorijskog). ;C14H22N2 (M = 218,35) ;Izračunato: molekulska masa (M+H)+: 219 ;Nađeno: molekulska masa (M+H)+: 219 ;Rf vrijednost: 0,15 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). ;2.120.e. 4'-klor-bifenil-4-karboksilna kiselina {2-[4-(1-pirolidin-1-il-etil)-fenil]-etil}-amid ;Proizveden je prema općem radnom postupku I iz 150 mg (0,69 mmola) 2-[4-(1-pirolidin-1-il-etil)-fenil]-etilamina i 176 mg (0,76 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 150 mg (88,3% od teorijskog). ;C27H29ClN2O (M = 433,0) ;Izračunato: molekulska masa (M+H)+: 433/435 ;Nađeno: molekulska masa (M+H)+: 433/435 ;Vrijeme retencije HPLC: 6,33 min (metoda A) ;Primjer 2.121: ;4'-klor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid ;[image] ;2.121.a. [4-(2-amino-etil)-2-brom-fenil]-metanol ;100 mg Raney nikla se doda u otopinu od 4 g (17,68 mmolova) (3-brom-4-hidroksimetil-fenil)-acetonitrila (vidi primjer 2.107.c) u 100 ml THF-a i 50 ml metanolnog NH3 i reakcijsku smjesu se mućka u Parr-ovom autoklavu 5 h pri sobnoj temperaturi i pod 5 psi H2. Katalizator se odfiltrira, otapalo se odstrani i proizvod dalje reagira bez čišćenja. ;Iskorištenje: 3,8 g (93,4% od teorijskog). ;C9H12BrNO (M = 230,11) ;Izračunato: molekulska masa (M+H)+: 230/232 ;Nađeno: molekulska masa (M+H)+: 230/232 ;Vrijeme retencije HPLC: 1,85 min (metoda A) ;2.121.b. Terc-butil [2-(3-brom-4-hidroksimetil-fenil)-etil]-karbaminat ;17 ml 1 M otopine BOC-anhidrida u CH2Cl2 doda se u otopinu od 3,8 g (16,51 mmolova) [4-(2-amino-etil)-2-brom-fenil]-metanola u 50 ml CH2Cl2 i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. To se razrijedi sa 100 ml razrijeđene otopine KHSO4, organsku fazu se odvoji, ispere s razrijeđenom otopinom NaHCO3 i vodom i osuši se preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala se očisti pomoću kromatografije na silika gelu. ;Iskorištenje: 2,3 g (42,2% od teorijskog) ;C14H20BrNO3 (M = 330,22) ;Rf vrijednost: 0,44 (silika gel, petrol eter/EtOAc 6:4). ;2.121.c. Terc-butil [2-(3-brom-4-klormetil-fenil)-etil]-karbaminat ;0,54 ml (6,5 mmolova) tionil klorida polako se doda, kap po kap, u otopinu od 1,98 g (6,0 mmolova) terc-butil [2-(3-brom-4-hidroksimetil-fenil)-etil]-karbaminata u 50 ml CH2Cl2 i 0,53 ml piridina ohlađenu na 0°C, miješa se daljnji sat pri 0°C i zatim se zagrije na sobnu temperaturu. U reakcijsku smjesu se doda vodu, organsku fazu se ispere s razrijeđenom otopinom KHSO4 i vodom i osuši se preko MgSO4. Nakon filtracije kroz aktivirani ugljen i odstranjivanja otapala, proizvod dalje reagira bez čišćenja. ;Iskorištenje: 2,0 g (95,6% od teorijskog). ;C14H19BrClNO2 (M = 348,67) ;Izračunato: molekulska masa (M+H)+: 348/350/352 ;Nađeno: molekulska masa (M+H)+: 348/350/352 ;Rf vrijednost: 0,6 (silika gel, petrol eter/EtOAc 6:4). ;2.121.d. Terc-butil{2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-karbamat ;0,84 ml (11 mmolova) 2,5-dihidro-1H-pirola doda se u suspenziju od 1,9 g (5,45 mmolova) terc-butil [2-(3-brom-4-klormetil-fenil)-etil]-karbaminata i 2,5 g (18,1 mmolova) K2CO3 u 50 ml acetonitrila i reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi. Suspenziju se profiltrira, filtrat se ispari u vakuumu i ostatak se očisti pomoću kromatografije na silika gelu. ;Iskorištenje: 0,5 g (24,1% od teorijskog). ;C18H25BrN2O2 (M = 381,32) ;Izračunato: molekulska masa (M+H)+: 381/383 ;Nađeno: molekulska masa (M+H)+: 381/383 ;Rf vrijednost: 0,58 (silika gel, CH2Cl2/MeOH 8:2). ;2.121.e. 2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etilamin ;5 ml trifluoroctene kiseline doda se u otopinu od 500 mg (1,31 mmola) terc-butil {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-karbaminata u 50 ml CH2Cl2 i reakcijsku smjesu se miješa za 2 h pri sobnoj temperaturi. To se ispari u vakuumu. Pomiješa se s vodom i CH2Cl2, namjesti na lužnati pH s otopinom K2CO3, organsku fazu se odvoji i ispere ponovno s vodom. To se ispari u vakuumu i proizvod se očisti pomoću kromatografije na silika gelu. ;Iskorištenje: 350 mg (95,0% od teorijskog). ;C13H17BrN2 (M =281,20) ;izračunato: molekulska masa (M+H)+: 281/283 ;Nađeno: molekulska masa (M+H)+: 281/283 ;Rf vrijednost: 0,08 (silika gel, CH2Cl2/MeOH/NH3 95:5:0,5). ;2.121.f 4'-klor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid ;Proizveden je prema općem radnom postupku I iz 141 mg (0,5 mmola) 2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etilamina i 116 mg (0,5 mmola) 4'-klor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 140 mg (56,5% od teorijskog). ;C26H24BrClN2O (M= 495,85) ;Izračunato: molekulska masa (M+H)+: 495/497/499 ;Nađeno: molekulska masa (M+H)+: 495/497/499 ;Vrijeme retencije HPLC: 6,6 min (metoda A) ;Primjer 2.122: ;4'-brom-3-fluor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid ;[image] ;2.122.a. 4'-brom-3-fluor-bifenil-4-karboksilna kiselina ;1,04 g (5 mmolova) 4-bromfenilborne kiseline, 115 mg (0,1 mmola) tetrakis-(trifenilfosfin)-paladijai 2 ml 2M otopine Na2CO3 doda se uzastopce u otopinu od 1,1 g (5 mmola) 4-brom-2-fluorbenzojeve kiseline u 5 ml DMF-a i 5 ml dioksana i reakcijsku smjesu se refluktira za 2 h. Za dovršetak reakcije doda se daljnjih 250 mg (1,25 mmola) 4-bromfenilborne kiseline i smjesu se refluktira daljnjih 2 h. Reakcijsku smjesu se filtrira vruću kroz filter od staklenih vlakana, ispere se s vodom, zakiseli se s razrijeđenom otopinom KHSO4, nastali talog se odsisa i ispere s vodom. Ostatak se triturira s acetonitrilom i malo MeOH, profiltrira se da se odstrane neotopljene tvari, filtrat se ispari, ostatak se triturira s MeOH i proizvod se odsisa. ;Iskorištenje: 140 mg (9,5% od teorijskog). ;C13H8BrFO2 (M = 295,11) ;Izračunato: molekulska masa (M+H)+: 293/295 ;Nađeno: molekulska masa (M+H)+: 293/295 ;Rf vrijednost: 0,5 (silika gel, CH2Cl2/MeOH 9:1). ;2.122.b 4'-brom-3-fluor-bifenil-4-karboksilna kiselina {2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etil}-amid ;Proizveden je prema općem radnom postupku I iz 141 mg (0,5 mmola) 2-[3-brom-4-(2,5-dihidro-pirol-1-ilmetil)-fenil]-etilaminai 140 mg (0,47 mmola) 4'-brom-3-fluor-bifenil-4-karboksilne kiseline. ;Iskorištenje: 10 mg (3,8% od teorijskog). ;C26H23Br2FN2O (M = 558,29) ;Izračunato: molekulska masa (M+H)+: 557/559/561 ;Nađeno: molekulska masa (M+H)+: 557/559/561 ;Vrijeme retencije HPLC: 7,0 min (metoda A) ;Primjer 2.123: ;4'-klor-bifenil-4-karboksilna kiselina E2-(3-amino-4-pirolidin-1-ilmetil-fenil)-etil]-amid ;[image] ;0,12 ml trifluoroctene kiseline doda se u otopinu od 40 mg (0,08 mmola) terc-butil (5-{2-[(4'-klor-bifenil-4-karbonil)-amino]-etil}-2-pirolidin-1-ilmetil-fenil)-karbaminata (vidi primjer 2.116) u 3 ml CH2Cl2 i reakcijsku smjesu se miješa pri sobnoj temperaturi preko vikenda. To se ispari vakuumu, pomiješa s poluzasićenom otopinom NaHCO3, ekstrahira s EtOAc i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala očisti se pomoću HPLC. ;Iskorištenje: 3 mg (7,3% od teorijskog). ;C26H28ClN3O*C2HF3O2 (M = 548,01) C27H30ClN3O3S*CH2O2 (M = 558.10) ;Calculated: molecular weight (M+H)+: 512/514 ;Found: molecular weight (M+H)+: 512/514 ;Retention time HPLC: 6.13 min ( method A) ;Example 2.113: ;4'-chloro-biphenyl-4-carboxylic acid-[2-(3-pyridin-4-yl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image ] ;It was produced analogously to example 2.108 from 200 mg (0.40 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]- amide and 74 mg (0.60 mmol) of pyridine-4-boronic acid, by purifying the product by HPLC. ;Utilization: 13 mg (6.5% of theoretical). ;C31H30ClN3O (M = 496.06) ;Calculated: molecular mass (M+H)+: 496/498 ;Found: molecular mass (M+H)+: 496/498 ;Retention time HPLC: 6.37 min (method A) ;Example 2.114: ;Methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate ;[image] ;2.114a. Methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl-benzoate; 0.5 ml triethylamine (3.58 mmol), 40 mg (0.18 mmol) Pd(OAc)2 and 99 mg (0.18 mmol) 1 ,1'-diphenylphosphino-ferrocene is added to a solution of 500 mg (1.79 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (Example 2.107.d) in 10 ml of MeOH and 10 ml of of DMF. The reaction mixture was stirred for 15 h at 50°C in an autoclave under 2 bar CO. To complete the reaction, a further 0.5 ml of triethylamine, 40 mg of Pd(OAc)2 and 99 mg of 1,1'-diphenylphosphino-ferrocene are added and the mixture is stirred for a further 10 h at 50°C and under 2 bar CO and overnight under 4 bar CO and at 70oC. The solvents were evaporated in vacuo, the residue was mixed with EtOAc and extracted twice with water. The aqueous phase was saturated with K2CO3, exhaustively extracted with EtOAc and dried over MgSO4. After removing the desiccant and solvent, the product remains as a black oil that reacts further without cleaning. ;Utilization: 380 mg (82.1% of theoretical). ;C15H18N2O2 (M = 258.32) ;Calculated: molecular weight (M+H)+: 259 ;Found: molecular weight (M+H)+: 259 ;Retention time HPLC: 2.49 min (method B) ;2.114 .b. Methyl 5-(2-amino-ethyl)-2-pyrrolidin-1-ylmethyl-benzoate; 100 mg Raney nickel is added to a solution of 380 mg (1.47 mmol) methyl 5-cyanomethyl-2-pyrrolidin-1-ylmethyl -benzoate in 20 ml of methanolic NH3 and the reaction mixture is hydrogenated for 27 hours under 20 psi H2 at room temperature. The catalyst is sucked off, the solvent is removed and the residue reacts further without cleaning. ;Utilization: 330 mg (85.5% of theoretical). ;C15H22N2O2 (M = 262.36) ;Calculated: molecular mass (M+H)+: 263 ;Found: molecular mass (M+H)+: 263 ;Retention time HPLC: 1.40 min (method A) ;2.114 c. Methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate; It was produced according to general procedure I from 330 mg (1.26 mmol) of methyl 5-(2-amino-ethyl)-2-pyrrolidin-1-ylmethyl-benzoate and 293 mg (1.26 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 315 mg (52.5% of theoretical). ;C28H29ClN2O3 (M = 477.01) ;Calculated: molecular mass (M+H)+: 477/479 ;Found: molecular mass (M+H)+: 477/479 ;Retention time HPLC: 6.82 min (method A) ;Example 2.115: ;5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoic acid ;[image] ;It is produced analogously to example 2.111.a from 310 mg (0.65 mmol) of methyl 5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoate. ;Utilization: 85 mg (28.2% of theoretical). ;C27H27ClN2O3 (M = 462.98) ;Calculated: molecular mass (M+H)+: 463/465 ;Found: molecular mass (M+H)+: 463/465 ;Retention time HPLC: 6.30 min (method A) ; Example 2.116: ; Tert-butyl (5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-phenyl)-carbamate ;[ image]; 0.27 ml (1.92 mmol) of triethylamine and 0.41 ml (1.92 mmol) of diphenyl azido-phosphate are added to a solution of 740 mg (1.6 mmol) of 5-{2-[(4 '-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidin-1-ylmethyl-benzoic acid in 10 ml of tert-butanol and the reaction mixture is refluxed for 5 h. This is evaporated in vacuo, the residue is mixed with CH2Cl2, extracted with 1N NaOH solution and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel. ;Utilization: 85 mg (28.2% of theoretical). ;C31H36ClN3O3 (M = 534.10) ;Calculated: molecular weight (M+H)+: 534/536 ;Found: molecular weight (M+H)+: 534/536 ;Retention time HPLC: 4.82 min (method B) ;Example 2.117: ;4'-chloro-biphenyl-4-carboxylic acid-[2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image] ;2.117.a . (4-pyrrolidin-1-ylmethyl-3-trimethylsilanylethynyl-phenyl)-acetonitrile; A suspension of 0.36 g (1.29 mmol) of (3-bromo-4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile (example 2.107 .d), 0.36 ml (2.58 mmol) trimethylsilylacetylene, 0.36 ml (2.58 mmol) triethylamine, 25 mg (0.13 mmol) CuI and 0.15 g (0.13 mmol) tetrakis- (triphenylphosphine)-palladium in 3 ml of DMF is stirred in a microwave heater (CEM) for 15 min at 100°C and 200 Watts. When cooled, saturated NaCl solution was added to the reaction mixture, the mixture was exhaustively extracted with EtOAc and the organic phase was dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (EtOAc). ;Utilization: 50 mg (13.1% of theoretical). ;C18H24N2Si (M = 296.49) ;Calculated: molecular weight (M+H)+: 297 ;Found: molecular weight (M+H)+: 297 ;Retention time HPLC: 6.39 min (method A) ;2.117 .b 2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine; 20 mg Raney nickel is added to a solution of 50 mg (0.17 mmol) (4-pyrrolidin-1-ylmethyl-3- of trimethylsilanylethynyl-phenyl)-acetonitrile in 5 ml of methanolic NH3 and the reaction mixture was shaken for 22 h at room temperature and under 3 bar H2. The catalyst is sucked off and the solvent is removed in vacuo. The crude product reacts further without purification. ;Utilization: 39 mg (100% of theoretical). ;C15H24N2 (M = 232.37) ;Calculated: molecular mass (M+H)+: 233 ;Found: molecular mass (M+H)+: 233 ;2.117.c 4'-chloro-biphenyl-4-carboxylic acid [2-(3-ethyl-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide; It was produced according to the general procedure I from 40 mg (0.17 mmol) of 2-(3-ethyl-4-pyrrolidine) -1-ylmethyl-phenyl)-ethyl-amine and 48 mg (0.21 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 2 mg (2.6% of theoretical). ;C28H31ClN2O (M = 447.03) ;Calculated: molecular mass (M+H)+: 447/449 ;Found: molecular mass (M+H)+: 447/449 ;Retention time HPLC: 6.87 min (method A) ;Example 2.118: ;4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide ;[image] ;2.118a. Methyl 6-dibromo-methyl-nicotinate; 53.4 g (0.3 mol) of NBS and 2 g of dibenzoyl peroxide are added to a solution of 38.96 g (0.25 mol) of methyl 6-methyl-nicotinate in 1 l CCl4 and the reaction mixture is refluxed overnight. Another 26.7 g (0.15 mol) of NBS and 1 g of dibenzoyl peroxide were then added and the mixture was refluxed again for 24 h. When the reaction mixture is cooled, the precipitate is filtered off with suction, the solvent is removed and the residue is purified by chromatography. Yield: 15.0 g (19.4% of theoretical). ;C8H7Br2NO2 (M = 308.96) ;Calculated: molecular weight (M+H)+: 308/310/312 ;Found: molecular weight (M+H)+: 308/310/312 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 8:2). ; 2.118.b. Methyl 6-dimethoxymethyl-nicotinate; 13.9 ml NaOMe in MeOH (30%, 75 mmol) in 100 ml MeOH was heated to boiling. A solution of 11.0 g (34.1 mmol) of methyl 6-dibromo-methyl-nicotinate in 10 ml of MeOH was added dropwise to the boiling solution and refluxed overnight. To complete the reaction, a further 1.5 ml (8.1 mmol) of NaOMe solution was added and the mixture was refluxed again for 24 h. The reaction mixture is evaporated in vacuo, the residue is mixed with dilute KHSO4 solution, neutralized with dilute NaHCO3 solution, exhaustively extracted with EtOAc, the organic phase is washed with water and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. Yield: 5.0 g (69.5% of theoretical). ;C10H13NO4 (M = 211.22) ;Calculated: molecular weight (M+H)+: 212 ;Found: molecular weight (M+H)+: 212 ;Rf value: 0.44 (silica gel, petroleum ether/EtOAc 6:4). ; 2.118.c. 6-dimethoxymethyl-nicotinic acid; 15 ml of 1N NaOH solution is added to a solution of 2.8 g (13.26 mmol) of methyl 6-dimethoxymethyl-nicotinate in 50 ml of MeOH and stirred for 24 h at room temperature. The reaction mixture is neutralized with 15 ml of 1N HCl, evaporated in vacuo, the residue is triturated with MeOH/THF, the precipitate is filtered off with suction and the filtrate is evaporated. The resulting product reacts further without cleaning. Yield: 2.6 g (99.4% of theoretical). ;C9H11NO4 (M = 197.19) ;Calculated: molecular weight (M+H)+: 198 ;Found: molecular weight (M+H)+: 198 ;Retention time HPLC: 3.65 min (method A) ;2.118 .d. (6-dimethoxymethyl-pyridin-3-yl)-methanol; It was produced analogously to example 2.109.f from 2.7 g (13.7 mmol) of 6-dimethoxymethyl-nicotinic acid using THF as a solvent and tert-butylmethyl ether for extraction. Yield: 2.1 g (83.7% of theoretical). ;C9H13NO3 (M = 183.21) ;Calculated: molecular weight (M+H)+: 184 ;Found: molecular weight (M+H)+: 184 ;Retention time HPLC: 2.85 min (method A) ;2.118 .e. 5-chloromethyl-2-dimethoxymethyl-pyridine; 0.3 ml (4.14 mmol) of thionyl chloride, dissolved in a little CH2Cl2, is added slowly, dropwise, to a solution of 500 mg (2.73 mmol) (6- of dimethoxymethyl-pyridin-3-yl)-methanol in 10 ml of CH2Cl2 cooled to 0°C and stirred for a further 30 min at that temperature. The reaction mixture is diluted with CH2Cl2, washed with cold NaHCO3 solution and dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. ;Utilization: 500 mg (90.8% of the theoretical). ;C9H12ClNO2 (M = 201.65) ;Calculated: molecular weight (M+H)+: 202/204 ;Found: molecular weight (M+H)+: 202/204 ;Rf value: 0.3 (silica gel, petroleum ether/EtOAc 6:4). ; 2.118. f. (6-dimethoxymethyl-pyridin-3-yl)-acetonitrile; 20 ml of DMSO is added to 5.21 g (80 mmol) of KCN in 5.2 ml of water and at 80°C a solution of 500 mg (2.48 mmol) of 5-chloro-methyl-2-dimethoxymethyl-pyridine in 10 ml of DMSO and the reaction mixture is kept for another hour at 80°C. This is poured into 200 ml of water, saturated with NaCl, extracted exhaustively with EtOAc, the organic phase is dried over MgSO4 and filtered through activated carbon. The filtrate was evaporated and the residue was purified by chromatography on silica gel (CH 2 Cl 2 /MeOH 9:1). ;Utilization: 330 mg (69.2% of theoretical). ;C10H12N2O2 (M = 192.22) ;Calculated: molecular weight (M+H)+: 193 ;Found: molecular weight (M+H)+: 193 ;Rf value: 0.48 (silica gel, CH2Cl2/MeOH 9 :1). 2.118. 2-(6-dimethoxymethyl-pyridin-3-yl)-ethylamine; 50 mg of Raney nickel is added to a solution of 330 mg (1.72 mmol) of (6-dimethoxymethyl-pyridin-3-yl)-acetonitrile in 10 ml of methanol NH3 and the reaction mixture is hydrogenated in a Parr autoclave for 15 h at 30°C and under 3 bar H2. The catalyst is filtered off, the solvent is evaporated under vacuum and the residue is further reacted without purification. ;Utilization: 340 mg (100% of theoretical). ;C10H16N2O2 (M = 196.25) ;Calculated: molecular weight (M+H)+: 197 ;Found: molecular weight (M+H)+: 197 ;Retention time HPLC: 1.3 min (method A) ;2.118 .h. 4'-Chloro-biphenyl-4-carboxylic acid [2-(6-;dimethoxymethyl-pyridin-3-yl)-ethyl]-amide; It was produced according to general procedure I from 340 mg (1.73 mmol) of 2- (6-dimethoxymethyl-pyridin-3-yl)-ethylamine and 419 mg (1.80 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 210 mg (28.4% of theoretical). ;C23H23ClN2O3 (M = 410.90) ;Calculated: molecular weight (M+H)+: 411/413 ;Found: molecular weight (M+H)+: 411/413 ;Rf value: 0.4 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1). ; 2.118.i. 4'-chloro-biphenyl-4-carboxylic acid [2-(6-formyl-pyridin-3-yl)-ethyl]-amide; 5 ml of 12% HCl is added to a solution of 205 mg (0.5 mmol ) 4'-chloro-biphenyl-4-carboxylic acid-[2-(6-di-methoxymethyl-pyridin-3-yl)-ethyl]-amide in 10 ml of MeOH and the reaction mixture is stirred for 4 h at room temperature and heated at 80°C overnight. Another 2.5 ml of 12% HCl is added, the mixture is heated for a further 8 hours at 80°C and overnight at 100°C. The reaction mixture is mixed with 50 ml of water, adjusted to pH 8 with Na2CO3 solution, extracted exhaustively with CH2Cl2 and the organic phase is dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning. ;Utilization: 180 mg (98.7% of theoretical). ;C21H17ClN2O2 (M = 364.84) ;Calculated: molecular weight (M+H)+: 365/367 ;Found: molecular weight (M+H)+: 365/367 ;Retention time HPLC: 5.25 min (method A) ; 2.118 k. 4'-chloro-biphenyl-4-carboxylic acid [2-(6-pyrrolidin-1-ylmethyl-pyridin-3-yl)-ethyl]-amide; 50 μl (0.6 mmol) pyrrolidine, 37.7 mg ( 0.6 mmol) of NaBH3CN and 2 ml of MeOH was added to a solution of 180 mg (0.49 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(6-formyl-pyridin-3-yl)- ethyl]-amide in 5 ml of acetonitrile. The pH value is adjusted to 5-6 with glacial acetic acid and the mixture is stirred for 5 h at room temperature. The reaction mixture is acidified with a 1M KHSO4 solution, basified with a 2M Na2CO3 solution, exhaustively extracted with CH2Cl2 and the organic phase is dried over MgSO4. The residue after removal of drying agent and solvent was purified by chromatography on silica gel (CH2Cl2/MeOH/NH3 9:1:0.1). ;Utilization: 25 mg (12.1% of theoretical). ;C25H26ClN3O (M = 419.96) ;Calculated: molecular weight (M+H)+: 420/422 ;Found: molecular weight (M+H)+: 420/422 ;Rf value: 0.2 (silica gel, CH2Cl2/MeOH/NH3 9:1:0.1). ;Example 2.119: ;4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide ;[image] ;2.119.a. Methyl 6-hydroxymethyl-nicotinate; It was produced analogously to example 2.109.f from 5.0 g (27.6 mmol) of 5-methyl pyridine-2,5-dicarboxylate, using THF as a solvent and tert-butyl methyl ether for extraction. Yield: 2.0 g (43.3% of theoretical). ;C8H9NO3 (M = 167.17) ;Calculated: molecular weight (M+H)+: 168 ;Found: molecular weight (M+H)+: 168 ;Rf value: 0.2 (silica gel, CH2Cl2/MeOH 95 :5). ; 2.119.b. Methyl 6-chloromethyl-nicotinate; In a solution of 2.0 g (11.96 mmol) of methyl 6-hydroxy-methyl-nicotinate in 100 ml of CH2Cl2 cooled to OoC, 1.06 ml (13 mmol) of pyridine is added and then slowly, drop by drop, 1.08 ml (13 mmoles) of thionyl chloride. This is further stirred for one hour at 0oC and then slowly warmed to room temperature. To complete the reaction, 1 ml (12 mmol) of thionyl chloride was added and the mixture was stirred for 1 h at room temperature. Water is added to the reaction mixture, the organic phase is separated, washed with diluted NaHCO3 solution and water and dried over MgSO4. This is filtered through activated carbon and the solvent is evaporated in vacuo. The resulting product reacts further without cleaning. Yield: 1.7 g (65.1% of theoretical). ;C8H8ClNO2 (M = 185.61) ;Calculated: molecular weight (M+H)+: 186/188 ;Found: molecular weight (M+H)+: 186/188 ;Retention time HPLC: 6.7 min (method A) ; 2.119.c. Methyl 6-cyanomethyl-nicotinate; It was produced analogously to example 2.118.f from 1.5 g (8.08 mmol) of methyl 6-chloromethyl-nicotinate and 5.2 g (80 mmol) of KCN, using cyclohexane/EtOAc 8: 2 as eluents for purification using silica gel chromatography. ;Utilization: 220 mg (15.5% of the theoretical). ;C9H9N2O2 (M = 176.18) ;Calculated: molecular weight (M+H)+: 177 ;Found: molecular weight (M+H)+: 177 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 1:1). 2.119.d. Methyl 6-(2-amino-ethyl)-nicotinate; 20 mg of Raney nickel is added to a solution of 75 mg (0.43 mmol) of methyl 6-cyanomethyl-nicotinate in 5 ml of methanolic NH3 and the reaction mixture is hydrogenated in Parr's autoclave for 6 h at 30oC under 3 bar H2, the catalyst is filtered off, the solvent is evaporated in a vacuum and the residue reacts further without cleaning. ;Utilization: 70 mg (90.3% of theoretical). ;C9H12N2O2 (M = 180.21) ;Calculated: molecular weight (M+H)+: 181 ;Found: molecular weight (M+H)+: 181 ;Retention time HPLC: 2.5 min (method A) ;2.119 .e. Methyl 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinate; It was produced according to the general procedure I from 70 mg (0.39 mmol) of methyl 6-(2- aminoethyl)-nicotinate and 100 mg (0.43 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 150 mg (88.3% of theoretical). ;C22H19ClN2O3 (M = 394.86) ;Calculated: molecular weight (M+H)+: 395/397 ;Found: molecular weight (M+H)+: 395/397 ;Retention time HPLC: 8.6 min (method A) ; 2.119.f. 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinic acid; 0.8 ml of 1 M NaOH solution is added to a solution of 150 mg (0.38 mmol) methyl of 6-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinate in 25 ml of MeOH and the reaction mixture was refluxed for 1 h. This is neutralized with 0.8 ml of 1 N HCl, evaporated in vacuo, the residue mixed with water and the precipitate removed with suction. This was dissolved in THF, the solution was dried over MgSO4, filtered and evaporated in vacuo. The rest reacts further without cleaning. ;Utilization: 90 mg (62.2% of theoretical). ;C21H17ClN2O3 (M = 380.83) ;Calculated: molecular weight (M+H)+: 381/383 ;Found: molecular weight (M+H)+: 381/383 ;Retention time HPLC: 6.9 min (method A) ; 2.119. 4'-chloro-biphenyl-4-carboxylic acid {2-(5-hydroxymethyl-pyridin-2-yl)-ethyl]-amide; It was produced analogously to example 2.109.f from 90 mg (0.24 mmol) 6-{ 2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-nicotinic acid, using THF as solvent and tert-butylmethyl ether for extraction. ;Utilization: 50 mg (56.8% of theoretical). ;C21H19ClN2O2 (M = 366.85) ;Calculated: molecular weight (M+H)+: 367/369 ;Found: molecular weight (M+H)+: 367/369 ;Rf value: 0.5 (silica gel, CH2Cl2/MeOH 9:1). 2.119 h. 4'-chloro-biphenyl-4-carboxylic acid [2-(5-pyrrolidin-1-ylmethyl-pyridin-2-yl)-ethyl]-amide; 22 μl of thionyl chloride is added dropwise to a solution of 50 mg ( 0.14 mmol) of 4'-chloro-biphenyl-4-carboxylic acid-[2-(5-hydroxymethyl-pyridin-2-yl)-ethyl]-amide in 5 ml of CH2Cl2 cooled to 0°C and the reaction mixture was slowly let it warm to room temperature. After 1 h at room temperature, a further 22 μl of thionyl chloride was added drop by drop to complete the reaction and stirring was continued for 1 h. The reaction mixture is diluted with 30 ml of CH2Cl2, mixed with ice water, made alkaline with NaHCO3 solution, the organic phase is separated, washed with water and dried over MgSO4. After removing the drying agent, 50 μl (0.6 mmol) of pyrrolidine was added to this solution and the reaction mixture was stirred overnight at room temperature. This was evaporated in vacuo and the residue was purified by HPLC chromatography. ;Utilization: 2.4 mg (4.1% of theoretical). ;C25H26ClN3O (M = 419.96) ;Calculated: molecular weight (M+H)+: 420/422 ;Found: molecular weight (M+H)+: 420/422 ;Rf value: 0.3 (silica gel, CH2Cl2/MeOH 9:1). ; HPLC retention time: 6.0 min (method A) ; Example 2.120: ; 4'-chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]- ethyl}-amide ; [image] ; 2.120.a. Tert-butyl [2-(4-acetyl-phenyl)-ethyl]-carbamate; 5.46 g (25 mmol) of BOC-anhydride is added to a solution of 4.99 g (25 mmol) of 1-[4-{2 -amino-ethyl)-phenyl]-ethanone (used in the form of hydrochloride) in 100 ml of CH2Cl2 and at room temperature slowly add, drop by drop, 25 ml of 1N NaOH solution and after the addition is complete, the mixture is stirred for 2 h at room temperature. The reaction mixture is filtered through Celite, washed twice with water and dried over MgSO4. This is filtered through activated carbon, evaporated under vacuum and the product is further reacted without purification. Yield: 6.4 g (97.2% of theoretical). ;C12H21NO3 (M = 263.34) ;Calculated: molecular weight (M+H)+: 262 ;Found: molecular weight (M+H)+: 262 ;Rf value: 0.88 (silica gel, CH2Cl2/MeOH/ NH3 9:1:0.1). ; 2.120.b. Tert-butyl {2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-carbamate; 4.72 g (125 mmol) of NaBH4 was added portionwise at room temperature to a solution of 6.58 g (25 mmol) of tert-butyl [2-(4-acetyl-phenyl)-ethyl]-carbamate in 250 ml of MeOH and the reaction mixture was stirred over the weekend. This is carefully acidified with KHSO4 solution, extracted exhaustively with tert-butylmethyl ether, the organic phase is washed with saturated NaCl solution and dried over MgSO4. After removing the drying agent and solvent, the product remains as a slightly yellowish oil which crystallizes on standing. Yield: 5.4 g (81.4% of theoretical). ;C15H23NO3 (M = 265.36) ;Calculated: molecular weight (M+H)+: 266 ;Found: molecular weight (M+H)+: 266 ;Rf value: 0.4 (silica gel, petroleum ether/EtOAc 6:4). ; 2.120.c. Tert-butyl {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-carbamate; 0.66 ml (8.5 mmol) of methanesulfonic acid chloride, dissolved in 10 ml of CH2Cl2, added was added dropwise to a solution of 2.89 g (10.89 mmol) of tert-butyl {2-[4-(1-hydroxy-ethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and 1.25 ml of triethylamine cooled to 0oC. Stirring was continued for 1 h at this temperature and then a solution of 1.4 ml (17 mmol) of pyrrolidine in 10 ml of CH2Cl2 was slowly added dropwise. The reaction mixture is stirred overnight at room temperature, mixed with dilute KHSO4 solution, the organic phase is separated, washed twice with dilute KHSO4 solution, the combined aqueous phases are made alkaline with K2CO3 solution and exhaustively extracted with tert-butylmethyl ether. The combined organic phases are washed several times with a little water and dried over MgSO4. After removing the desiccant and solvent, the product reacts further without cleaning. Yield: 0.3 g (8.7% of theoretical). ;C19H30N2O2 (M = 318.46) ;Calculated: molecular weight (M+H)+: 319 ;Found: molecular weight (M+H)+: 319 ;Rf value: 0.22 (silica gel, CH2Cl2/MeOH/ NH3 9:1:0.1). 2.120 d. 2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethylamine; 0.72 ml of trifluoroacetic acid is added to a solution of 300 mg (0.94 mmol) tert-butyl {2-[4- (1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-carbamate in 20 ml of CH2Cl2 and stirred for 1 h at room temperature. to complete the reaction, a further 0.72 ml of trifluoroacetic acid was added and the reaction mixture was kept for 1 h at room temperature. The solvent is evaporated in vacuo, the residue is taken up in water, basified with 2 N NaOH, extracted exhaustively with EtOAc and the organic phase is dried over MgSO4. After removing the desiccant and solvent, the product reacts further without cleaning. ;Utilization: 150 mg (72.9% of theoretical). ;C14H22N2 (M = 218.35) ;Calculated: molecular weight (M+H)+: 219 ;Found: molecular weight (M+H)+: 219 ;Rf value: 0.15 (silica gel, CH2Cl2/MeOH/ NH3 8:2:0.2). ; 2.120.e. 4'-Chloro-biphenyl-4-carboxylic acid {2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethyl}-amide; It was produced according to general procedure I from 150 mg (0, 69 mmol) of 2-[4-(1-pyrrolidin-1-yl-ethyl)-phenyl]-ethylamine and 176 mg (0.76 mmol) of 4'-chloro-biphenyl-4-carboxylic acid. ;Utilization: 150 mg (88.3% of theoretical). ;C27H29ClN2O (M = 433.0) ;Calculated: molecular weight (M+H)+: 433/435 ;Found: molecular weight (M+H)+: 433/435 ;Retention time HPLC: 6.33 min (method A) Example 2.121: 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide; [image] ; 2.121.a. [4-(2-amino-ethyl)-2-bromo-phenyl]-methanol; 100 mg of Raney nickel is added to a solution of 4 g (17.68 mmol) of (3-bromo-4-hydroxymethyl-phenyl)-acetonitrile (see example 2.107.c) in 100 ml of THF and 50 ml of methanolic NH3 and the reaction mixture is shaken in a Parr autoclave for 5 h at room temperature and under 5 psi of H2. The catalyst is filtered off, the solvent is removed and the product reacts further without cleaning. Yield: 3.8 g (93.4% of theoretical). ;C9H12BrNO (M = 230.11) ;Calculated: molecular weight (M+H)+: 230/232 ;Found: molecular weight (M+H)+: 230/232 ;Retention time HPLC: 1.85 min (method A) ; 2.121.b. Tert-butyl [2-(3-bromo-4-hydroxymethyl-phenyl)-ethyl]-carbamate; 17 ml of a 1 M solution of BOC-anhydride in CH2Cl2 is added to a solution of 3.8 g (16.51 mmol) [4 -(2-amino-ethyl)-2-bromo-phenyl]-methanol in 50 ml of CH2Cl2 and the reaction mixture was stirred overnight at room temperature. This is diluted with 100 ml of dilute KHSO4 solution, the organic phase is separated, washed with dilute NaHCO3 solution and water and dried over MgSO4. The residue after removal of drying agent and solvent is purified by chromatography on silica gel. ;Yield: 2.3 g (42.2% of theory) ;C14H20BrNO3 (M = 330.22) ;Rf value: 0.44 (silica gel, petroleum ether/EtOAc 6:4). ; 2.121.c. Tert-butyl [2-(3-bromo-4-chloromethyl-phenyl)-ethyl]-carbamate; 0.54 ml (6.5 mmol) of thionyl chloride was slowly added dropwise to a solution of 1.98 g (6.0 mmol) of tert-butyl [2-(3-bromo-4-hydroxymethyl-phenyl)-ethyl]-carbamate in 50 ml of CH2Cl2 and 0.53 ml of pyridine cooled to 0°C, stirred for a further hour at 0 °C and then warmed to room temperature. Water is added to the reaction mixture, the organic phase is washed with diluted KHSO4 solution and water and dried over MgSO4. After filtration through activated carbon and removal of the solvent, the product reacts further without cleaning. Yield: 2.0 g (95.6% of theoretical). ;C14H19BrClNO2 (M = 348.67) ;Calculated: molecular weight (M+H)+: 348/350/352 ;Found: molecular weight (M+H)+: 348/350/352 ;Rf value: 0.6 (silica gel, petroleum ether/EtOAc 6:4). 2.121.d. Tert-butyl {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate; 0.84 ml (11 mmol) 2,5-dihydro-1H -pyrrole is added to a suspension of 1.9 g (5.45 mmol) of tert-butyl [2-(3-bromo-4-chloromethyl-phenyl)-ethyl]-carbamate and 2.5 g (18.1 mmol) K2CO3 in 50 ml of acetonitrile and the reaction mixture was stirred overnight at room temperature. The suspension is filtered, the filtrate is evaporated in vacuo and the residue is purified by chromatography on silica gel. Yield: 0.5 g (24.1% of theoretical). ;C18H25BrN2O2 (M = 381.32) ;Calculated: molecular weight (M+H)+: 381/383 ;Found: molecular weight (M+H)+: 381/383 ;Rf value: 0.58 (silica gel, CH2Cl2/MeOH 8:2). ; 2.121.e. 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine; 5 ml of trifluoroacetic acid is added to a solution of 500 mg (1.31 mmol) of tert-butyl {2 -[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-carbamate in 50 ml of CH2Cl2 and the reaction mixture was stirred for 2 h at room temperature. This is evaporated in a vacuum. It is mixed with water and CH2Cl2, adjusted to alkaline pH with K2CO3 solution, the organic phase is separated and washed again with water. This is evaporated in vacuo and the product is purified by silica gel chromatography. ;Utilization: 350 mg (95.0% of theoretical). ;C13H17BrN2 (M =281.20) ;calculated: molecular weight (M+H)+: 281/283 ;Found: molecular weight (M+H)+: 281/283 ;Rf value: 0.08 (silica gel, CH2Cl2/MeOH/NH3 95:5:0.5). ;2.121.f 4'-chloro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide ;It is produced according to by general procedure I from 141 mg (0.5 mmol) of 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine and 116 mg (0.5 mmol) 4 '-chloro-biphenyl-4-carboxylic acids. ;Utilization: 140 mg (56.5% of theoretical). ;C26H24BrClN2O (M= 495.85) ;Calculated: molecular mass (M+H)+: 495/497/499 ;Found: molecular mass (M+H)+: 495/497/499 ;Retention time HPLC: 6, 6 min (method A) ; Example 2.122: ; 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)- phenyl]-ethyl}-amide ; [image] ; 2.122.a. 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid; 1.04 g (5 mmol) of 4-bromophenylboronic acid, 115 mg (0.1 mmol) of tetrakis-(triphenylphosphine)-palladium and 2 ml of 2M Na2CO3 solution added are successively added to a solution of 1.1 g (5 mmol) of 4-bromo-2-fluorobenzoic acid in 5 ml of DMF and 5 ml of dioxane and the reaction mixture is refluxed for 2 h. To complete the reaction, a further 250 mg (1.25 mmol) of 4-bromophenylboronic acid was added and the mixture was refluxed for a further 2 h. The reaction mixture is filtered hot through a glass fiber filter, washed with water, acidified with a dilute solution of KHSO4, the resulting precipitate is suctioned off and washed with water. The residue is triturated with acetonitrile and a little MeOH, filtered to remove undissolved material, the filtrate is evaporated, the residue is triturated with MeOH and the product is filtered off with suction. ;Utilization: 140 mg (9.5% of theoretical). ;C13H8BrFO2 (M = 295.11) ;Calculated: molecular weight (M+H)+: 293/295 ;Found: molecular weight (M+H)+: 293/295 ;Rf value: 0.5 (silica gel, CH2Cl2/MeOH 9:1). ;2.122.b 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid {2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethyl}-amide ;It was produced according to general procedure I from 141 mg (0.5 mmol) of 2-[3-bromo-4-(2,5-dihydro-pyrrol-1-ylmethyl)-phenyl]-ethylamine and 140 mg (0.47 mmol) of 4'-bromo-3-fluoro-biphenyl-4-carboxylic acid. ;Utilization: 10 mg (3.8% of theoretical). ;C26H23Br2FN2O (M = 558.29) ;Calculated: molecular weight (M+H)+: 557/559/561 ;Found: molecular weight (M+H)+: 557/559/561 ;HPLC retention time: 7, 0 min (method A) ;Example 2.123: ;4'-chloro-biphenyl-4-carboxylic acid E2-(3-amino-4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide ;[image] ;0 .12 ml of trifluoroacetic acid is added to a solution of 40 mg (0.08 mmol) tert-butyl (5-{2-[(4'-chloro-biphenyl-4-carbonyl)-amino]-ethyl}-2-pyrrolidine -1-ylmethyl-phenyl)-carbamate (see Example 2.116) in 3 ml of CH2Cl2 and the reaction mixture was stirred at room temperature over the weekend. This was evaporated in vacuo, mixed with half saturated NaHCO3 solution, extracted with EtOAc and the organic phase dried over MgSO4. The residue after removal of drying agent and solvent is purified by HPLC. ;Yield: 3 mg (7.3% of theory).;C26H28ClN3O*C2HF3O2 (M = 548.01)
Izračunato: molekulska masa (M+H)+: 434/436 Calculated: molecular weight (M+H)+: 434/436
Nađeno: molekulska masa (M+H)+: 434/436 Found: molecular weight (M+H)+: 434/436
Vrijeme retencije HPLC: 5,35 min (Stable Bond C18; 3,5 μM; voda:acetonitril:mravlja kiselina 6:4:0,015) HPLC retention time: 5.35 min (Stable Bond C18; 3.5 μM; water:acetonitrile:formic acid 6:4:0.015)
Primjer 2.124: Example 2.124:
4'-klor-bifenil-4-karboksilna kiselina-etil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.124.a. Etil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.124.a. Ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Otopinu od 89 μl (1,1 mmola) etil jodida u 1 ml THF-a doda se kap po kap u otopinu od 204 mg (1,0 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 0,17 ml trietilamina u 5 ml THF-a i reakcijsku smjesu se miješa 24 h pri sobnoj temperaturi. To se pomiješa sa zasićenom otopinom NaHCO3, ekstrahira se s EtOAc i organsku fazu se osuši preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. A solution of 89 μl (1.1 mmol) of ethyl iodide in 1 ml of THF was added dropwise to a solution of 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 0.17 ml of triethylamine in 5 ml of THF and the reaction mixture was stirred for 24 h at room temperature. This was mixed with saturated NaHCO3 solution, extracted with EtOAc and the organic phase dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.
Iskorištenje: 70 mg (30,1% od teorijskog). Yield: 70 mg (30.1% of theoretical).
2.124.b. 4'-klor-bifenil-4-karboksilna kiselina-etil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.124.b. 4'-chloro-biphenyl-4-carboxylic acid-ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 70 mg (0,3 mmola) etil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amina i 81 mg (0,35 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 70 mg (0.3 mmol) of ethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 81 mg (0.35 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.
Iskorištenje: 20 mg (14,9% od teorijskog). Yield: 20 mg (14.9% of theoretical).
C28H31ClN2O (M = 447,03) C28H31ClN2O (M = 447.03)
Izračunato: molekulska masa (M+H)+: 447/449 Calculated: molecular weight (M+H)+: 447/449
Nađeno: molekulska masa (M+H)+: 447/449 Found: molecular weight (M+H)+: 447/449
Vrijeme retencije HPLC: 6,92 min (metoda A) HPLC retention time: 6.92 min (method A)
Primjer 2.125: Example 2.125:
4'-klor-bifenil-4-karboksilna kiselina-izobutil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.125.a. Izobutil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.125.a. Isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Otopinu od 204 mg (1,0 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 91 μl (1,0 mmola) izobutir-aldehida u 20 ml THF-a se blago zakiseli s ledenom octenom kiselinom, pomiješa se s 253 mg (1,2 mmola) NaBH(OAc)3 i miješa se preko noći pri sobnoj temperaturi. Reakcijsku smjesu se pomiješa s poluzasićenom otopinom NaHCO3, iscrpno se ekstrahira s EtOAc; vodenu fazu se zasiti s K2CO3 i ekstrahira se s EtOAc. Sjedinjene organske faze se osuše preko MgSO4. Ostatak nakon odstranjivanja sredstva za sušenje i otapala dalje reagira bez čišćenja. A solution of 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 91 μl (1.0 mmol) of isobutyraldehyde in 20 ml of THF was slightly acidified with glacial acetic acid , mixed with 253 mg (1.2 mmol) of NaBH(OAc)3 and stirred overnight at room temperature. The reaction mixture was mixed with half-saturated NaHCO3 solution, extracted exhaustively with EtOAc; the aqueous phase is saturated with K2CO3 and extracted with EtOAc. The combined organic phases are dried over MgSO4. The residue after removal of desiccant and solvent continues to react without cleaning.
Iskorištenje: 250 mg (96,0% od teorijskog). Yield: 250 mg (96.0% of theoretical).
C17H28N2 (M = 260,43) C17H28N2 (M = 260.43)
Izračunato: molekulska masa (M+H)+: 261 Calculated: molecular weight (M+H)+: 261
Nađeno: molekulska masa (M+H)+: 261 Found: molecular weight (M+H)+: 261
Rf vrijednost: 0,4 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). Rf value: 0.4 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).
2.125.b. 4'-klor-bifenil-4-karboksilna kiselina-izobutil- 2.125.b. 4'-chloro-biphenyl-4-carboxylic acid-isobutyl-
[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid [2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 250 mg (0,96 mmola) izobutil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amina i 244 mg (1,05 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 250 mg (0.96 mmol) of isobutyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 244 mg (1.05 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.
Iskorištenje: 67 mg (14,7% od teorijskog). Yield: 67 mg (14.7% of theoretical).
C30H35ClN2O (M = 475,08) C30H35ClN2O (M = 475.08)
Izračunato: molekulska masa (M+H)+: 475/477 Calculated: molecular weight (M+H)+: 475/477
Nađeno: molekulska masa (M+H)+: 475/477 Found: molecular weight (M+H)+: 475/477
Vrijeme retencije HPLC: 7,67 min (metoda A) HPLC retention time: 7.67 min (method A)
Primjer 2.126: Example 2.126:
4'-klor-bifenil-4-karboksilna kiselina-cikloheks-3-enil-metil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-cyclohex-3-enyl-methyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.126.a. Cikloheks-3-enilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.126.a. Cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Proizveden je analogno primjeru 2.125.a. iz 204 mg (1,0 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 114 μl (1,0 mmola) 1,2,3,6-tetrahidrobenzaldehida. It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 114 μl (1.0 mmol) of 1,2,3,6-tetrahydrobenzaldehyde.
Iskorištenje: 100 mg (33,5% od teorijskog). Yield: 100 mg (33.5% of the theoretical).
C20H30N2 (M = 298,48) C20H30N2 (M = 298.48)
Rf vrijednost: 0,2 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). Rf value: 0.2 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).
2.126.b 4'-klor-bifenil-4-karboksilna kiselina-cikloheks-3-enilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.126.b 4'-chloro-biphenyl-4-carboxylic acid-cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 100 mg (0,34 mmola) cikloheks-3-enilmetil-[2-(4-pirolidin-1-il-metil-fenil)-etil]-amina i 86 mg (0,37 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 100 mg (0.34 mmol) of cyclohex-3-enylmethyl-[2-(4-pyrrolidin-1-yl-methyl-phenyl)-ethyl]-amine and 86 mg (0.37 mmol) of 4'-chloro-biphenyl-4-carboxylic acid.
Iskorištenje: 46 mg (26,8% od teorijskog). Yield: 46 mg (26.8% of theoretical).
C33H37ClN2O (M = 513,13) C33H37ClN2O (M = 513.13)
Izračunato: molekulska masa (M+H)+: 513/515 Calculated: molecular weight (M+H)+: 513/515
Nađeno: molekulska masa (M+H)+: 513/515 Found: molecular weight (M+H)+: 513/515
Vrijeme retencije HPLC: 8,20 min (metoda A) HPLC retention time: 8.20 min (method A)
Primjer 2.127: Example 2.127:
4'-klor-bifenil-4-karboksilna kiselina-benzil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.127a. Benzil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.127a. Benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Proizveden je analogno primjeru 2.125.a. iz 204 mg (1,0 mmola) 2-(4-pirolidin-1-iimetil-fenil)-etilamina i 102 μl (1,0 mmola) benzaldehida. It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 102 μl (1.0 mmol) of benzaldehyde.
Iskorištenje: 160 mg (54,3% od teorijskog). Yield: 160 mg (54.3% of theoretical).
C20H26N2 (M = 294,44) C20H26N2 (M = 294.44)
Rf vrijednost: 0,28 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). Rf value: 0.28 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).
2.127.b. 4'-klor-bifenil-4-karboksilna kiselina-benzil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.127.b. 4'-chloro-biphenyl-4-carboxylic acid-benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 160 mg (0,54 mmola) benzil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amina i 140 mg (0,60 mmol) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 160 mg (0.54 mmol) of benzyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 140 mg (0.60 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.
Iskorištenje: 16 mg (5,8% od teorijskog). Yield: 16 mg (5.8% of theoretical).
C33H33ClN2O (M = 509,10) C33H33ClN2O (M = 509.10)
Izračunato: molekulska masa (M+H)+: 509/511 Calculated: molecular weight (M+H)+: 509/511
Nađeno: molekulska masa (M+H)+: 509/511 Found: molecular weight (M+H)+: 509/511
Vrijeme retencije HPLC: 7,51 min (metoda A) HPLC retention time: 7.51 min (method A)
Primjer 2.128: Example 2.128:
4'-klor-bifenil-4-karboksilna kiselina-cikloheksilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.128.a Cikloheksilmetil-[2-{4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.128.a Cyclohexylmethyl-[2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Proizveden je analogno primjeru 2.125.a. iz 204 mg (1,0 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 121 μl (1,0 mmola) cikloheksankarbaldehida. It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 121 μl (1.0 mmol) of cyclohexanecarbaldehyde.
Iskorištenje: 100 mg (33,3% od teorijskog). Yield: 100 mg (33.3% of theoretical).
C20H32N2 (M = 300,49) C20H32N2 (M = 300.49)
Rf vrijednost: 0,18 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). Rf value: 0.18 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).
2.128.b. 4'-klor-bifenil-4-karboksilna kiselina-ciklo-heksilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.128.b. 4'-chloro-biphenyl-4-carboxylic acid-cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 100 mg (0,33 mmola) cikloheksilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amina i 86 mg (0,37 mmola) 4'-klor-bifenil-4-karboksilne kiseline. It was produced according to general procedure I from 100 mg (0.33 mmol) of cyclohexylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 86 mg (0.37 mmol) of 4'-chloro -biphenyl-4-carboxylic acids.
Iskorištenje: 70 mg (40,8% od teorijskog). Yield: 70 mg (40.8% of theoretical).
C33H33ClN2O (M = 515,15) C33H33ClN2O (M = 515.15)
Izračunato: molekulska masa (M+H)+: 515/517 Calculated: molecular weight (M+H)+: 515/517
Nađeno: molekulska masa (M+H)+: 515/517 Found: molecular weight (M+H)+: 515/517
Vrijeme retencije HPLC: 8,63 min (metoda A) HPLC retention time: 8.63 min (method A)
Primjer 2.129: Example 2.129:
4'-klor-bifenil-4-karboksilna kiselina-ciklopropilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amid 4'-chloro-biphenyl-4-carboxylic acid-cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
[image] [image]
2.129.a Ciklopropilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amin 2.129.a Cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine
Proizveden je analogno primjeru 2.125.a. iz 204 mg (1,0 mmola) 2-(4-pirolidin-1-ilmetil-fenil)-etilamina i 75 μl (1,0 mmola) ciklopropankarbaldehida. It is produced analogously to example 2.125.a. from 204 mg (1.0 mmol) of 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine and 75 μl (1.0 mmol) of cyclopropanecarbaldehyde.
Iskorištenje: 100 mg (38,7% od teorijskog). Yield: 100 mg (38.7% of theoretical).
C17H26N2 (M = 258,41) C17H26N2 (M = 258.41)
Rfvrijednost: 0,30 (silika gel, CH2Cl2/MeOH/NH3 8:2:0,2). Rf value: 0.30 (silica gel, CH2Cl2/MeOH/NH3 8:2:0.2).
2.129.b. 4'-klor-bifenil-4-karboksilna kiselina-ciklo-propilmetil-[2-{4-pirolidin-1-ilmetil-fenil)-etil]-amid 2.129.b. 4'-chloro-biphenyl-4-carboxylic acid-cyclo-propylmethyl-[2-{4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amide
Proizveden je prema općem radnom postupku I iz 100 mg (0,39 mmola) ciklopropilmetil-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-amina i 100 mg (0,43 mmola) 4'-klor-bifenil-4-karboksilna kiselina. It was produced according to general procedure I from 100 mg (0.39 mmol) of cyclopropylmethyl-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-amine and 100 mg (0.43 mmol) of 4'-chloro -biphenyl-4-carboxylic acid.
Iskorištenje: 23 mg (12,6% od teorijskog). Yield: 23 mg (12.6% of theoretical).
C30H33ClN2O (M = 473,06) C30H33ClN2O (M = 473.06)
Izračunato: molekulska masa (M+H)+: 473/475 Calculated: molecular weight (M+H)+: 473/475
Nađeno: molekulska masa (M+H)+: 473/475 Found: molecular weight (M+H)+: 473/475
Vrijeme retencije HPLC: 7,45 min (metoda A) HPLC retention time: 7.45 min (method A)
Primjer 2.130: Example 2.130:
4-pentil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-pentyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola) i 4-pentil-benzojeve kiseline (96 mg, 0,50 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-pentyl-benzoic acid (96 mg, 0.50 mmol).
Iskorištenje: 75 mg (39,6% od teorijskog). Yield: 75 mg (39.6% of theoretical).
C25H34N2O (M = 378,56) C25H34N2O (M = 378.56)
Izračunato: molekulska masa (M+H)+: 379 Calculated: molecular weight (M+H)+: 379
Nađeno: molekulska masa (M+H)+: 379 Found: molecular weight (M+H)+: 379
Vrijeme retencije HPLC: 6,5 min (metoda A) HPLC retention time: 6.5 min (method A)
Primjer 2.131: Example 2.131:
4-butil-W-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-butyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola) i 4-butil-benzojeve kiseline (89 mg, 0,50 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-butyl-benzoic acid (89 mg, 0.50 mmol).
Iskorištenje: 60 mg (32,9% od teorijskog). Yield: 60 mg (32.9% of theoretical).
C24H32N2O (M = 364,54) C24H32N2O (M = 364.54)
Izračunato: molekulska masa (M+H)+: 365 Calculated: molecular weight (M+H)+: 365
Nađeno: molekulska masa (M+H)+: 365 Found: molecular weight (M+H)+: 365
Vrijeme retencije HPLC: 6,0 min (metoda A) HPLC retention time: 6.0 min (method A)
Primjer 2.132: Example 2.132:
4-butilamino-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benz-amid 4-butylamino-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benz-amide
[image] [image]
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (204 mg, 1,0 mmola) i 4-butilamino-benzojeve kiseline (155 mg, 0,80 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (204 mg, 1.0 mmol) and 4-butylamino-benzoic acid (155 mg, 0.80 mmol).
Iskorištenje: 30 mg (9,9% od teorijskog). Yield: 30 mg (9.9% of theoretical).
C24H33N3O (M = 379,55) C24H33N3O (M = 379.55)
Izračunato: molekulska masa (M+H)+: 380 Calculated: molecular weight (M+H)+: 380
Nađeno: molekulska masa (M+H)+: 380 Found: molecular weight (M+H)+: 380
Vrijeme retencije HPLC: 6,0 min (metoda A) HPLC retention time: 6.0 min (method A)
Primjer 2.133: Example 2.133:
4-(1-metil-butil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-(1-methyl-butyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (82 mg, 0,40 mmola) i 4-(1-metil-butil)-benzojeve kiseline (75 mg, 0,39 mmola). It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (82 mg, 0.40 mmol) and 4-(1-methyl-butyl)-benzoic acid (75 mg, 0 .39 mmol).
Iskorištenje: 40 mg (27,1% od teorijskog). Yield: 40 mg (27.1% of theoretical).
C24H32N2O (M = 378,56) C24H32N2O (M = 378.56)
Izračunato: molekulska masa (M+H)+: 379 Calculated: molecular weight (M+H)+: 379
Nađeno: molekulska masa (M+H)+: 379 Found: molecular weight (M+H)+: 379
Vrijeme retencije HPLC: 4,3 min (metoda B) HPLC retention time: 4.3 min (method B)
Primjer 2.134: Example 2.134:
N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-(4,4,4-trifluor-butoksi)-benzamid N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-trifluorobutoxy)-benzamide
[image] [image]
2.134.a. Metil 4-(4,4,4-trifluor-butoksi)-benzoat 2.134.a. Methyl 4-(4,4,4-trifluorobutoxy)-benzoate
608 mg (4,4 mmola) K2CO3 doda se u otopinu od 304 mg (2,0 mmola) metil 4-hidroksibenzoata u 10 ml DMF-a i zatim 382 mg (2,0 mmola) 1-brom-4,4,4-trifluorbutana. Smjesu se miješa preko noći pri sobnoj temperaturi, ponovno se pomiješa s 1-brom-4,4,4-trfluorbutanom i miješa se daljnjih 24 h pri sobnoj temperaturi. Reakcijsku otopinu se razrijedi s vodom i iscrpno se ekstrahira dva puta s EtOAc. Sjedinjeni org. ekstrakti se osuše preko MgSO4 i ispare se u vakuumu. Sirov proizvod se upotrebljava bez daljnjeg čišćenja u slijedećem stupnju reakcije. 608 mg (4.4 mmol) of K2CO3 is added to a solution of 304 mg (2.0 mmol) of methyl 4-hydroxybenzoate in 10 ml of DMF and then 382 mg (2.0 mmol) of 1-bromo-4,4, 4-trifluorobutane. The mixture was stirred overnight at room temperature, mixed again with 1-bromo-4,4,4-trifluorobutane and stirred for a further 24 h at room temperature. The reaction solution was diluted with water and exhaustively extracted twice with EtOAc. United org. the extracts are dried over MgSO4 and evaporated in vacuo. The crude product is used without further purification in the next step of the reaction.
Iskorištenje: 500 mg (95,3% od teorijskog). Yield: 500 mg (95.3% of the theoretical).
C12H13F3O3 (M = 262,23) C12H13F3O3 (M = 262.23)
Izračunato: molekulska masa (M+H)+: 263 Calculated: molecular weight (M+H)+: 263
Nađeno: molekulska masa (M+H)+: 263 Found: molecular weight (M+H)+: 263
Rf vrijednost: 0,9 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.9 (silica gel, petroleum ether/EtOAc 6:4).
2.134.b. 4-(4,4,4-trifluor-butoksi)-benzojeva kiselina 2.134.b. 4-(4,4,4-trifluorobutoxy)-benzoic acid
10,0 ml (10,0 mmola) 1M otopine natrijevog hidroksida doda se u otopinu od 500 mg (1,9 mmola) metil 4-(4,4,4-trifluor-butoksi)-benzoata u 7 ml THF-a. Smjesu se miješa 8 h pod refluksom. THF se odstrani u vakuumu i ostatak se zakiseli sa solnom kiselinom. Nakon filtracije, nastali talog se osuši na zraku. 10.0 ml (10.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 500 mg (1.9 mmol) of methyl 4-(4,4,4-trifluoro-butoxy)-benzoate in 7 ml of THF. The mixture was stirred for 8 h under reflux. The THF was removed in vacuo and the residue acidified with hydrochloric acid. After filtration, the resulting precipitate is air-dried.
Iskorištenje: 350 mg (73,9% od teorijskog). Yield: 350 mg (73.9% of theoretical).
C11H11F3O3 (M = 248,20) C11H11F3O3 (M = 248.20)
Izračunato: molekulska masa (M-H)-: 247 Calculated: molecular weight (M-H)-: 247
Nađeno: molekulska masa (M-H)-: 247 Found: molecular weight (M-H)-: 247
Vrijeme retencije HPLC: 7,5 min (metoda A) HPLC retention time: 7.5 min (method A)
2.134.c N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-4-(4,4,4-trifluor-butoksi)-benzamid 2.134.c N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(4,4,4-trifluoro-butoxy)-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola) i 4-(4,4,4-trifluor-butoksi)-benzojeve kiseline (124 mg, 0,50 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 4-(4,4,4-trifluoro-butoxy)-benzoic acid ( 124 mg, 0.50 mmol).
Iskorištenje: 37 mg (17,0% od teorijskog). Yield: 37 mg (17.0% of theoretical).
C24H29F3N2O2 (M = 434,51) C24H29F3N2O2 (M = 434.51)
Izračunato: molekulska masa (M+H)+: 435 Calculated: molecular weight (M+H)+: 435
Nađeno: molekulska masa (M+H)+: 435 Found: molecular weight (M+H)+: 435
Vrijeme retencije HPLC: 5,8 min (metoda A) HPLC retention time: 5.8 min (method A)
Primjer 2.135: Example 2.135:
3-metil-4-pent-1-inil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 3-methyl-4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.135.a. Metil 3-metil-4-pent-1-inil-benzoat 2.135.a. Methyl 3-methyl-4-pent-1-ynyl-benzoate
0,39 ml (4,0 mmola) pentina, 0,56 ml (4,0 mmola) trietilamina, 70 mg (0,1 mmola) bis-(trifenilfosfin)-paladij(II) klorida i 19 mg (0,1 mmola) bakar(I) jodida doda se uzastopce u otopinu od 458 mg (2,0 mmola) metil 4-brom-3-metil-benzoata u 3,0 ml DMF-a. Reakcijsku otopinu se miješa u mikrovalnoj grijalici 10 min pri 200 Watta i 65°C. Doda se daljnjih 0,20 ml (2,0 mmola) pentina i reakcijsku otopinu se miješa za daljnjih 20 min u mikrovalnoj grijalici pri 200 Watta i 70oC. Smjesu se razrijedi s 30 ml EtOAc, filtrira se kroz Celite i filtrat se ispere tri puta s 50 ml vode. Sjedinjeni organski ekstrakti se osuše preko MgSO4, filtriraju kroz aktivirani ugljen i otapalo se odstrani u vakuumu. Čišćenje se vrši pomoću kromatografije na stupcu silikaa gel (cikloheksan i zatim cikloheksan/etil acetat 9:1). 0.39 ml (4.0 mmol) pentyne, 0.56 ml (4.0 mmol) triethylamine, 70 mg (0.1 mmol) bis-(triphenylphosphine)-palladium(II) chloride and 19 mg (0.1 mmol) of copper(I) iodide was added successively to a solution of 458 mg (2.0 mmol) of methyl 4-bromo-3-methyl-benzoate in 3.0 ml of DMF. The reaction solution is stirred in a microwave heater for 10 min at 200 Watts and 65°C. A further 0.20 ml (2.0 mmol) of pentyne was added and the reaction solution was stirred for a further 20 min in a microwave oven at 200 Watts and 70°C. The mixture was diluted with 30 ml of EtOAc, filtered through Celite and the filtrate was washed three times with 50 ml of water. The combined organic extracts were dried over MgSO4, filtered through activated carbon and the solvent was removed in vacuo. Purification is performed using chromatography on a silica gel column (cyclohexane and then cyclohexane/ethyl acetate 9:1).
Iskorištenje: 200 mg (46,2% od teorijskog). Yield: 200 mg (46.2% of the theoretical).
C14H16O2 (M = 216,28) C14H16O2 (M = 216.28)
Izračunato: molekulska masa (M+H)+: 217 Calculated: molecular weight (M+H)+: 217
Nađeno: molekulska masa (M+H)+: 217 Found: molecular weight (M+H)+: 217
Vrijeme retencije HPLC: 6,8 min (metoda B) HPLC retention time: 6.8 min (method B)
2.135.b. 3-metil-4-pent-1-inil-benzojeva kiselina 2.135.b. 3-methyl-4-pent-1-ynyl-benzoic acid
3,0 ml (3,0 mmola) 1M otopine natrijevog hidroksida doda se u otopinu od 200 mg (0,93 mmola) metil 3-metil-4-pent-1-inil-benzoata u 3 ml metanola Smjesu se refluktira 3 h. Reakcijsku otopinu se razrijedi s vodom i ekstrahira se jednom sa 40 ml EtOAc. Vodenu fazu se zakiseli s 1M otopinom KHSO4 otopinu i ekstrahira se dva puta sa 40 ml EtOAC. Sjedinjene organske faze se osuše preko MgSO4. Nakon odstranjivanja sredstva za sušenje i otapala, sirov proizvod se upotrebljava u slijedećem stupnju reakcije bez daljnjeg čišćenja. 3.0 ml (3.0 mmol) of 1 M sodium hydroxide solution is added to a solution of 200 mg (0.93 mmol) of methyl 3-methyl-4-pent-1-ynyl-benzoate in 3 ml of methanol. The mixture is refluxed for 3 h . The reaction solution was diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase is acidified with 1M KHSO4 solution and extracted twice with 40 ml of EtOAC. The combined organic phases are dried over MgSO4. After removing the drying agent and solvent, the crude product is used in the next step of the reaction without further purification.
Iskorištenje: 50 mg (26,7% od teorijskog). Yield: 50 mg (26.7% of theoretical).
C13H14O2 (M = 202,26) C13H14O2 (M = 202.26)
Izračunato: molekulska masa (M-H)-: 201 Calculated: molecular weight (M-H)-: 201
Nađeno: molekulska masa (M-H)-: 201 Found: molecular weight (M-H)-: 201
Vrijeme retencije HPLC: 5,6 min (metoda B) HPLC retention time: 5.6 min (method B)
2.135.c. 3-metil-4-pent-1-inil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.135.c. 3-methyl-4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (51 mg, 0,25 mmola) i 3-metil-4-pent-1-inil-benzojeve kiseline (50 mg, 0,25 mmola). It was produced according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (51 mg, 0.25 mmol) and 3-methyl-4-pent-1-ynyl-benzoic acid (50 mg , 0.25 mmol).
Iskorištenje: 22 mg (22,9% od teorijskog). Yield: 22 mg (22.9% of theoretical).
C26H32N2O (M = 388,558) C26H32N2O (M = 388.558)
Izračunato: molekulska masa (M+H)+: 389 Calculated: molecular weight (M+H)+: 389
Nađeno: molekulska masa (M+H)+: 389 Found: molecular weight (M+H)+: 389
Vrijeme retencije HPLC: 6,9 min (metoda A) HPLC retention time: 6.9 min (method A)
Primjer 2.136: Example 2.136:
4-pent-1-inil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.136.a. Etil 4-pent-1-inil-benzoat 2.136.a. Ethyl 4-pent-1-ynyl-benzoate
0,39 ml (4 mmola) 1-pentina, 0,56 ml trietilamina, 70 mg (0,1 mmola) bis-(trifenilfosfin)-paladij(II) klorida i 19 mg (0,1 mmola) CuI doda se uzastopce u otopinu od 552 mg (2,0 mmola) etil 4-jodbenzoata u 3 ml DMF-a. Reakcijsku otopinu se miješa 4 h pri 80°C. Smjesu se razrijedi s 30 ml EtOAc, filtrira se kroz Celite, filtrat se ispere tri puta s 50 ml vode u svakom slučaju i osuši se preko MgSO4. Nakon filtracije kroz aktivirani ugljen otapalo se odstrani u vakuumu. Čišćenje se vrši pomoću kromatografije na stupcu silika gela (cikloheksan i nakon toga cikloheksan/etil acetat 9:1). 0.39 ml (4 mmol) of 1-pentyne, 0.56 ml of triethylamine, 70 mg (0.1 mmol) of bis-(triphenylphosphine)-palladium(II) chloride and 19 mg (0.1 mmol) of CuI were added successively. in a solution of 552 mg (2.0 mmol) of ethyl 4-iodobenzoate in 3 ml of DMF. The reaction solution was stirred for 4 h at 80°C. The mixture is diluted with 30 ml of EtOAc, filtered through Celite, the filtrate is washed three times with 50 ml of water in each case and dried over MgSO4. After filtration through activated carbon, the solvent is removed under vacuum. Purification is performed using chromatography on a silica gel column (cyclohexane and then cyclohexane/ethyl acetate 9:1).
Iskorištenje: 150 mg (34,7% od teorijskog). Yield: 150 mg (34.7% of theoretical).
C14H16O2 (M = 216,282) C14H16O2 (M = 216.282)
Izračunato: molekulska masa (M+H)+: 217 Calculated: molecular weight (M+H)+: 217
Nađeno: molekulska masa (M+H)+: 217 Found: molecular weight (M+H)+: 217
Vrijeme retencije HPLC: 6,8 min (metoda B) HPLC retention time: 6.8 min (method B)
2.136.b. 4-pent-1-inil-benzojeva kiselina 2.136.b. 4-pent-1-ynyl-benzoic acid
5,0 ml (5,0 mmola) 1M otopine natrijevog hidroksida doda se u otopinu od 150 mg (0,69 mmola) etil 4-pent-1-inil-benzoata u 3 ml metanola. Smjesu se miješa 3 h pod refluksom. Reakcijsku otopinu se razrijedi s vodom i ekstrahira se jednom sa 40 ml EtOAc. Vodenu fazu se zakiseli s 1M otopinom KHSO4 i ekstrahira se dva puta sa 40 ml EtOAc. Sjedinjeni organski ekstrakti se osuši preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Sirov proizvod se upotrebljava za slijedeći stupanj reakcije bez daljnjeg čišćenja. 5.0 ml (5.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 150 mg (0.69 mmol) of ethyl 4-pent-1-ynyl-benzoate in 3 ml of methanol. The mixture was stirred for 3 h under reflux. The reaction solution was diluted with water and extracted once with 40 ml of EtOAc. The aqueous phase was acidified with 1M KHSO4 solution and extracted twice with 40 ml of EtOAc. The combined organic extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The crude product is used for the next step of the reaction without further purification.
Iskorištenje: 150 mg (115% od teorijskog). Yield: 150 mg (115% of the theoretical).
C12H12O2 (M = 188,23) C12H12O2 (M = 188.23)
Izračunato: molekulska masa (M-H)-: 187 Calculated: molecular weight (M-H)-: 187
Nađeno: molekulska masa (M-H)-: 187 Found: molecular weight (M-H)-: 187
Rf vrijednost: 0,2 (silika gel, petrol eter/EtOAc 8:2). Rf value: 0.2 (silica gel, petroleum ether/EtOAc 8:2).
2.136.c. 4-pent-1-inil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.136.c. 4-pent-1-ynyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (163 mg, 0,80 mmola) i 4-pent-1-inil-benzojeve kiseline (150 mg, 0,80 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (163 mg, 0.80 mmol) and 4-pent-1-ynyl-benzoic acid (150 mg, 0.80 mmol).
Iskorištenje: 122 mg (40,9% od teorijskog). Yield: 122 mg (40.9% of theoretical).
C25H30N2O (M = 374,53) C25H30N2O (M = 374.53)
Izračunato: molekulska masa (M+H)+: 375 Calculated: molecular weight (M+H)+: 375
Nađeno: molekulska masa (M+H)+: 375 Found: molecular weight (M+H)+: 375
Rf vrijednost: 0,35 (silika gel, EtOAc/metanol/NH3 Rf value: 0.35 (silica gel, EtOAc/methanol/NH3
9:1:0,1). 9:1:0,1).
Primjer 2.137: Example 2.137:
(4-pent-1-enil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid (4-pent-1-enyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
2.137a. metil 4-pent-1-enil-benzoat 2.137a. methyl 4-pent-1-enyl-benzoate
246 mg (2,2 mmola) kalijevog terc-butoksida se doda pri 0°C u otopinu od 1,08 g (2,2 mmola) (4-metoksikarbonil-benzil)-trifenil-fosfonijevog bromida u 20 ml THF-a pod atmosferom argona. Narančastu otopinu se miješa daljnjih 15 min pri 0oC i zatim se pomiješa s 0,18 ml (2,0 mmola) butiraldehida. Reakcijsku otopinu se refluktira 3 h i zatim se razrijedi s EtOAc. Organsku fazu se ispere dva puta s vodom, osuši se preko magnezijevog sulfata i otapalo se odstrani u vakuumu. Ostatak se triturira s diizopropil eterom, profiltrira se i filtrat se ispari. Daljnje čišćenje se vrši pomoću kromatografije na stupcu silika gela (petrol eter/EtOAc 6:4). Metil 4-pent-1-enil-benzoat se dobije kao 2:1 smjesa E/Z izomera. 246 mg (2.2 mmol) of potassium tert-butoxide was added at 0°C to a solution of 1.08 g (2.2 mmol) of (4-methoxycarbonyl-benzyl)-triphenyl-phosphonium bromide in 20 ml of THF under argon atmosphere. The orange solution was stirred for a further 15 min at 0°C and then mixed with 0.18 ml (2.0 mmol) of butyraldehyde. The reaction solution was refluxed for 3 h and then diluted with EtOAc. The organic phase is washed twice with water, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with diisopropyl ether, filtered and the filtrate is evaporated. Further purification is carried out by chromatography on a silica gel column (petroleum ether/EtOAc 6:4). Methyl 4-pent-1-enyl-benzoate is obtained as a 2:1 mixture of E/Z isomers.
Iskorištenje: 350 mg (56,5% od teorijskog). Yield: 350 mg (56.5% of theoretical).
C13H16O2 (M =204,27) C13H16O2 (M = 204.27)
Izračunato: molekulska masa (M+H)+: 204 Calculated: molecular weight (M+H)+: 204
Nađeno: molekulska masa (M+H)+: 204 Found: molecular weight (M+H)+: 204
Rf vrijednost: 0,90 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.90 (silica gel, petroleum ether/EtOAc 6:4).
2.137.b. 4-pent-1-enil-benzojeva kiselina 2.137.b. 4-pent-1-enyl-benzoic acid
5,0 ml (5,0 mmolova) 1M otopine natrijevog hidroksida doda se u otopinu od 350 mg (1,71 mmola) etil 4-pent-1-enil-benzoata u 4 ml metanola. Smjesu se refluktira 2 h. Otapalo se odstrani u vakuumu i ostatak se pomiješa sa 6M otopinom solne kiseline. Nastali talog se odsisa i osuši pri 35°C sušilici s optočnim zrakom. Daljnje čišćenje se vrši pomoću filtracije kroz stupac silika gela (petrol eter/EtOAc 6:4). 5.0 ml (5.0 mmol) of 1 M sodium hydroxide solution was added to a solution of 350 mg (1.71 mmol) of ethyl 4-pent-1-enyl-benzoate in 4 ml of methanol. The mixture is refluxed for 2 h. The solvent was removed in vacuo and the residue was mixed with 6M hydrochloric acid solution. The resulting precipitate is sucked off and dried at 35°C in a dryer with circulating air. Further purification is performed by filtration through a column of silica gel (petroleum ether/EtOAc 6:4).
Iskorištenje: 300 mg (92,1% od teorijskog). Yield: 300 mg (92.1% of theoretical).
C12H14O2 (M = 190,24) C12H14O2 (M = 190.24)
Izračunato: molekulska masa (M-H)-: 189 Calculated: molecular weight (M-H)-: 189
Nađeno: molekulska masa (M-H)-: 189 Found: molecular weight (M-H)-: 189
Rf vrijednost: 0,4 (silika gel, petrol eter/EtOAc 6:4). Rf value: 0.4 (silica gel, petroleum ether/EtOAc 6:4).
2.137.c. (4-pent-1-enil)-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 2.137.c. (4-pent-1-enyl)-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (306 mg, 1,50 mmola) i 4-pent-1-enil-benzojeve kiseline (300 mg, 1,56 mmola) kao 2:1 smjesa E/Z izomera. It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (306 mg, 1.50 mmol) and 4-pent-1-enyl-benzoic acid (300 mg, 1.56 mmol) as a 2:1 mixture of E/Z isomers.
Iskorištenje: 130 mg (23,0% od teorijskog). Yield: 130 mg (23.0% of theoretical).
C25H32N2O (M = 376,547) C25H32N2O (M = 376.547)
Izračunato: molekulska masa (M+H)+: 377 Calculated: molecular weight (M+H)+: 377
Nađeno: molekulska masa (M+H)+: 377 Found: molecular weight (M+H)+: 377
Vrijeme retencije HPLC: 6,9 min (metoda A) HPLC retention time: 6.9 min (method A)
Primjer 2.138: Example 2.138:
3-klor-4-cikloheksil-N-[2-(4-pirolidin-1-ilmetil-fenil)-etil]-benzamid 3-chloro-4-cyclohexyl-N-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-benzamide
[image] [image]
Proizveden je prema općem radnom postupku I iz 2-(4-pirolidin-1-ilmetil-fenil)-etilamina (102 mg, 0,50 mmola) i 3-klor-4-cikloheksil-benzojeve kiseline (119 mg, 0,50 mmola). It was prepared according to general procedure I from 2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethylamine (102 mg, 0.50 mmol) and 3-chloro-4-cyclohexyl-benzoic acid (119 mg, 0.50 mmol).
Iskorištenje: 46 mg (21,6% od teorijskog). Yield: 46 mg (21.6% of theoretical).
C26H33ClN2O (M = 425,019) C26H33ClN2O (M = 425.019)
Izračunato: molekulska masa (M+H)+: 425/427 Calculated: molecular weight (M+H)+: 425/427
Nađeno: molekulska masa (M+H)+: 425/427 Found: molecular weight (M+H)+: 425/427
Vrijeme retencije HPLC: 4,7 min (metoda B). HPLC retention time: 4.7 min (method B).
Sada će se opisati neki postupci za utvrđivanje antagonističkog djelovanja prema MCH-receptoru. K tome, korišteni su i drugi postupci ispitivanja koji su poznati stručnjacima, npr. inhibicija proizvodnje cAMP-a posredstvom inhibicije MCH-receptora, kako su opisali Hoogduijn M et al. u "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Comun. 296 (2002) 698-701 i biološki osjetljivim mjerenjem vezanja MCH na MCH receptor u prisutnosti antagonističkih tvari pomoću rezonancije plazmona, kako su opisali Karlsson OP i Lofas S. u "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Application in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Ostali postupci ispitivanja antagonističkog djelovanja prema MCH receptorima se nalaze u literaturi i patentnim dokumentima koji su ovdje ranije spomenuti, i opis postupaka ispitivanja je time uvršten u ovu prijavu. Some procedures for determining the antagonistic activity towards the MCH-receptor will now be described. In addition, other test methods known to those skilled in the art were used, eg inhibition of cAMP production by inhibition of the MCH-receptor, as described by Hoogduijn M et al. in "Melanin-concentrating hormone and its receptor are expressed and functional in human skin", Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biologically sensitive measurement of MCH binding to the MCH receptor in the presence of antagonists using plasmon resonance, as described by Karlsson OP and Lofas S. in "Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Application in Surface Plasmon Resonance Biosensors", Anal. Biochem. 300 (2002), 132-138. Other methods of testing antagonistic activity towards MCH receptors are found in the literature and patent documents previously mentioned herein, and the description of the testing methods is hereby incorporated into this application.
Pokus vezanja MCH-1 receptora MCH-1 receptor binding attempt
Postupak: Vezanje MCH na stanice transfektirane s hMCH-1R Vrsta: čovjek Procedure: Binding of MCH to cells transfected with hMCH-1R Species: human
Pokusne stanice: hMCH-1R stabilno transfektirane u stanice CHO/Galpha16 Experimental cells: hMCH-1R stably transfected into CHO/Galpha16 cells
Rezultati: vrijednosti IC50 Results: IC50 values
Membrane stanica CHO/Galpha16 stabilno transfektiranih s humanim hMCH-1R su ponovno suspendirane pomoću brizgaljke (igla 0,6 x 25 mm) i razrijeđene su u pokusnom puferu (50 mM HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7,00; 0,1% albumina goveđeg seruma (bez proteaze), 0,021% bacitracina, 1 μg/ml aprotinina, 1 μg/ml leupeptina i 1 μM fosforamidona) na koncentraciju od 5 do 15 μg/ml. 200 mikrolitara te membranske frakcije (koja sadrži 1 do 3 μg proteina) inkubirano je 60 minuta pri sobnoj temperaturi sa 100 pM hormona koji koncentrira 125I-tirozil melanin (125I-MCH može se dobiti komercijalno od tvrtke NEN) i rastućim koncentracijama ispitnog spoja u krajnjem volumenu od 250 mikrolitara. Nakon inkubacije reakcijska smjesa je profiltrirana upotrebom sredstva za skupljanje stanica kroz filtere od staklenih vlakana obrađenih s 0,5% PEI (GF/B, Unifilter Packard). Zatim je radioaktivnost vezana na membrane koja se je zadržala na filteru utvrđena nakon dodatka scintilacijske tvari (Packard Microscint 20) u mjerni uređaj (TopCount of Packard). Membranes of CHO/Galpha16 cells stably transfected with human hMCH-1R were resuspended using a syringe (0.6 x 25 mm needle) and diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 2 mM EGTA, pH 7.00; 0.1% bovine serum albumin (protease-free), 0.021% bacitracin, 1 μg/ml aprotinin, 1 μg/ml leupeptin and 1 μM phosphoramidon) at a concentration of 5 to 15 μg/ml. 200 microliters of this membrane fraction (containing 1 to 3 μg of protein) was incubated for 60 minutes at room temperature with 100 pM of 125I-tyrosyl melanin-concentrating hormone (125I-MCH can be obtained commercially from NEN) and increasing concentrations of the test compound in the final volume of 250 microliters. After incubation, the reaction mixture was filtered using a cell harvesting agent through glass fiber filters treated with 0.5% PEI (GF/B, Unifilter Packard). Then, the radioactivity bound to the membranes that remained on the filter was determined after the addition of scintillation substance (Packard Microscint 20) to the measuring device (TopCount of Packard).
Nespecifično vezanje definirano je kao vezana radioaktivnost u prisutnosti 1 mikromolarnog MCH tijekom perioda inkubacije. Nonspecific binding was defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.
Analiza krivulje koncentracije i vezanja izvršena je uz pretpostavku jednog mjesta vezanja receptora. The analysis of the concentration and binding curve was performed assuming a single receptor binding site.
Standard: Standard:
Neobilježeni MCH nadmeće se s obilježenim 125I-MCH za vezanje receptora s vrijednosti IC50 između 0,06 i 0,15 nM. Unlabeled MCH competes with labeled 125I-MCH for receptor binding with IC50 values between 0.06 and 0.15 nM.
KD vrijednost radioliganda je 0,156 nM. The KD value of the radioligand is 0.156 nM.
Pokus mobilizacije Ca2+ povezanog s MCH-1 receptorom An attempt to mobilize Ca2+ associated with the MCH-1 receptor
Postupak: Pokus mobilizacije kalcija s humanim MCH (FLIPR384) Procedure: Calcium mobilization experiment with human MCH (FLIPR384)
Vrsta: ljudska Species: human
Pokusne stanice: stanice CHO/Galpha 16 stabilno transfektirane s hMCH-R1 Experimental cells: CHO/Galpha 16 cells stably transfected with hMCH-R1
Rezultati: prvo mjerenje: % stimulacije usporedbe (MCH 10-6 M) Results: first measurement: % stimulation of comparison (MCH 10-6 M)
drugo mjerenje: pKB vrijednost second measurement: pKB value
Reagenti: Reagents:
HBSS (10x) (GIBCO) HBSS (10x) (GIBCO)
HEPES pufer (1M) (GIBCO) HEPES buffer (1M) (GIBCO)
Pluronic F-127 (Molecular Probes) Pluronic F-127 (Molecular Probes)
Fluo-4 (Molecular Probes) Fluo-4 (Molecular Probes)
Probenecid (Sigma) Probenecid (Sigma)
MCH (Bachem) MCH (Bachem)
albumin iz goveđeg seruma (bez proteaze) (Serva) bovine serum albumin (protease-free) (Serva)
DMSO (Serva) DMSO (Serva)
Ham's F12 (BioWhittaker) Ham's F12 (BioWhittaker)
FCS (BioWhittaker) FCS (BioWhittaker)
L-glutamin (GIBCO) L-glutamine (GIBCO)
higromicin B (GIBCO) hygromycin B (GIBCO)
PENStrep (BioWhittaker) PENStrep (BioWhittaker)
Zeocin (Invitrogen) Zeocin (Invitrogen)
Klonske stanice CHO/Galpha16 hMCH-R1 su uzgajane u Ham's F12 mediju za kulturu stanica (s L-glutaminom; BioWhittaker; kat. br. BE12-615F). On sadrži u 500 ml 10% FCS, 1% PENStrep, 5 ml L-glutamina (200 mM otopina za zalihu), 3 ml higromicina B (50 mg/ml u PBS-u) i 1,25 ml zeocina (100 μg/ml, zaliha otopine). Jedan dan prije pokusa stanice su stavljene u mikrotitarske pločice s 384 jamice (crne stijenke s prozirnim dnom, proizvođač Costar) gustoće 2500 stanica po jamici i uzgajane su u gornjem mediju preko noći pri 37°C, 5% CO2 i 95% relativne vlage. Na dan pokusa stanice su inkubirane s medijem za kulturu kojem je dodan 2 mM Fluo-4 i 4,6 mM Probenicid, 45 minuta pri 37oC. Nakon dodatka fluorescentne boje stanice su isprane četiri puta s otopinom Hanks-ovog pufera (1 x HBSS, 20 mM HEPES), koji je pomiješan s 0,07% probenicida. Ispitne tvari su razrijeđene u otopini Hanks-ovog pufera pomiješanog s 2,5% DMSO. Osnovna fluorescencija nestimuliranih stanica izmjerena je u prisutnosti tvari u mikrotitarskim pločicama s 384 jamice pet minuta nakon posljednjeg ispiranja u aparatu FLIPR384 (Molecular Devices; pobudna valna duljina: 488 nm; emisijska valna duljina: pojas traka 510 do 570 nm). Za stimulaciju stanica MCH je razrijeđen u Hanksovom puferu s 0,1% BSA, pipetiran je pločice od 384 jamica s kulturom 35 minuta nakon posljednjeg ispiranja i zatim je fluorescencija, stimulirana s MCH, izmjerena u aparatu FLIPR384. Clonal CHO/Galpha16 hMCH-R1 cells were grown in Ham's F12 cell culture medium (with L-glutamine; BioWhittaker; cat. no. BE12-615F). It contains in 500 ml 10% FCS, 1% PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin (100 μg/ ml, stock solution). One day before the experiment, cells were plated in 384-well microtiter plates (black walls with clear bottom, manufactured by Costar) at a density of 2500 cells per well and grown in the above medium overnight at 37°C, 5% CO2 and 95% relative humidity. On the day of the experiment, the cells were incubated with the culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid were added, for 45 minutes at 37oC. After the addition of the fluorescent dye, the cells were washed four times with Hanks buffer solution (1 x HBSS, 20 mM HEPES), which was mixed with 0.07% probenicid. Test substances were diluted in a solution of Hanks buffer mixed with 2.5% DMSO. Baseline fluorescence of unstimulated cells was measured in the presence of substance in 384-well microtiter plates five minutes after the last wash in a FLIPR384 apparatus (Molecular Devices; excitation wavelength: 488 nm; emission wavelength: band band 510 to 570 nm). To stimulate cells, MCH was diluted in Hanks' buffer with 0.1% BSA, 384-well culture plates were pipetted 35 minutes after the last wash, and MCH-stimulated fluorescence was then measured in a FLIPR384 apparatus.
Analiza podataka: Data analysis:
Prvo mjerenje: Celularna mobilizacija Ca2+ izmjerena je kao vršna vrijednost relativne fluorescencije minus osnovna fluorescencija i izražena je kao postotak od maksimalnog signala usporedbenog uzroka (MCH 10-6 M). To mjerenje služi za identifikaciju bilo kojeg mogućeg agonističkog učinka ispitne tvari. First measurement: Cellular Ca2+ mobilization was measured as peak relative fluorescence minus baseline fluorescence and expressed as a percentage of the maximum signal of the comparator (MCH 10-6 M). This measurement serves to identify any possible agonistic effect of the test substance.
Drugo mjerenje: Celularna mobilizacija Ca2+ izmjerena je kao vršna vrijednost relativne fluorescencije minus osnovna fluorescencija i izražena je kao postotak od maksimalnog signala usporedbenog uzroka (MCH 10-6 M, signal je standardiziran na 100%). Vrijednosti EC50 utvrđene su grafički iz krivulje djelovanja i MCH doziranja sa i bez ispitne tvari (definirane koncentracije) pomoću programa za krivulje GraphPad Prism 2.01. U grafičkom prikazu MCH antagonisti uzrokuju pomak krivulje MCH stimulacije na desno. Second measurement: Cellular Ca2+ mobilization was measured as peak relative fluorescence minus baseline fluorescence and was expressed as a percentage of the maximum signal of the comparator (MCH 10-6 M, signal standardized to 100%). EC50 values were determined graphically from the action curve and MCH dosing with and without the test substance (defined concentration) using the GraphPad Prism 2.01 curve program. In the graphic representation, MCH antagonists cause a shift of the MCH stimulation curve to the right.
Inhibicija je izražena kao pKB vrijednost: Inhibition is expressed as a pKB value:
pKB = log(EC50(ispitna tvar + MCH)/EC50(MCH) -1) –log c(ispitna tvar) pKB = log(EC50(test substance + MCH)/EC50(MCH) -1) –log c(test substance)
U gore opisanim pokusima spojevi prema izumu, uključiv njihove soli, pokazuju antagonističko djelovanje prema MCH-receptoru. Pomoću gore opisanog pokusa vezanja MCH-1 receptora dobiveno je antagonističko djelovanje u području doziranja od pribl. 10-10 do 10-5 M, posebno od 10-9 do 10-6 M. In the experiments described above, the compounds according to the invention, including their salts, show antagonistic action against the MCH-receptor. Using the MCH-1 receptor binding experiment described above, antagonistic action was obtained in the dosage range of approx. 10-10 to 10-5 M, especially from 10-9 to 10-6 M.
Slijedeće vrijednosti IC50 utvrđene su pomoću gore opisanog pokusa vezanja MCH-1 receptora: The following IC50 values were determined using the MCH-1 receptor binding assay described above:
[image] [image]
U nastavku će se opisati neki primjeri formulacija, pri čemu pojam "aktivna tvar" označava jedan ili više spojeva prema izumu, uključiv njihove soli. U slučaju kombinacije s jednom ili više opisanih aktivnih tvari, pojam "aktivna tvar" također uključuje i dodatne aktivne tvari. In the following, some examples of formulations will be described, whereby the term "active substance" means one or more compounds according to the invention, including their salts. In case of combination with one or more described active substances, the term "active substance" also includes additional active substances.
Primjer 3 Example 3
Kapsule s prahom za inhalaciju koje sadrže 1 mg aktivne tvari Capsules with powder for inhalation containing 1 mg of active substance
Sastav: Composition:
1 kapsula s prahom za inhalaciju sadrži: 1 capsule with powder for inhalation contains:
aktivna tvar 1,0 mg active substance 1.0 mg
laktoza 20,0 mg lactose 20.0 mg
tvrde želatinske kapsule 50,0 mg hard gelatin capsules 50.0 mg
71,0 mg 71.0 mg
Postupak priprave: Preparation process:
Aktivnu tvar se smelje na veličinu čestica koja je potrebna za inhalaciju. Smrvljenu aktivnu tvar se homogeno pomiješa s laktozom. Smjesu se pakira u tvrde želatinske kapsule. The active substance is ground to the particle size required for inhalation. The crushed active substance is homogeneously mixed with lactose. The mixture is packed in hard gelatin capsules.
Primjer 4 Example 4
Inhalacijska otopina za Respimat® koja sadrži 1 mg aktivne tvari Inhalation solution for Respimat® containing 1 mg of active substance
Sastav: Composition:
1 sprej sadrži: 1 spray contains:
aktivna tvar 1,0 mg active substance 1.0 mg
benzalkonijev klorid 0,002 mg benzalkonium chloride 0.002 mg
dizodijev edetat 0,0075 mg disodium edetate 0.0075 mg
pročišćena voda ad 15,0 μl purified water ad 15.0 μl
Postupak priprave: Preparation process:
Aktivna tvar i benzalkonijev kloride se otope u vodi i pakiraju se u umetke za Respimat®. The active substance and benzalkonium chloride are dissolved in water and packed in Respimat® inserts.
Primjer 5 Example 5
Inhalacijska otopina za atomizer koja sadrži 1 mg aktivne Inhalation solution for atomizer containing 1 mg of active
tvari substances
Sastav: Composition:
1 vijala sadrži: 1 vial contains:
aktivna tvar 0,1 g active substance 0.1 g
natrijev klorid 0,18 g sodium chloride 0.18 g
benzalkonijev klorid 0,002 g benzalkonium chloride 0.002 g
pročišćena voda ad 20,0 ml purified water ad 20.0 ml
Postupak priprave: Preparation process:
Aktivna tvar, natrijev klorid i benzalkonijev klorid se otope u vodi. The active substance, sodium chloride and benzalkonium chloride dissolve in water.
Primjer 6 Example 6
Aerosol s potisnim plinom i odmjeravanjem doze koji sadrži 1 mg aktivne tvari Aerosol with propellant gas and dose measurement containing 1 mg of active substance
Sastav: Composition:
1 sprej sadrži: 1 spray contains:
aktivna tvar 1,0 mg active substance 1.0 mg
lecitin 0,1% lecithin 0.1%
potisni plin do 50,0 μl propellant gas up to 50.0 μl
Postupak priprave: Preparation process:
Mikroniziranu aktivnu tvar se homogeno suspendira u mješavini lecitina i potisnog plina. Suspenziju se prenese u tlačni spremnik s odmjernim ventilom. The micronized active substance is homogeneously suspended in a mixture of lecithin and pressure gas. The suspension is transferred to a pressure tank with a metering valve.
Primjer 7 Example 7
Nazalni sprej koji sadrži 1 mg aktivne tvari Nasal spray containing 1 mg of active substance
Sastav: Composition:
aktivna tvar 1,0 mg active substance 1.0 mg
natrijev klorid 0,9 mg sodium chloride 0.9 mg
benzalkonijev klorid 0,025 mg benzalkonium chloride 0.025 mg
dinatijev edetat 0,05 mg dinate edetate 0.05 mg
pročišćena voda do 0,1 ml purified water up to 0.1 ml
Postupak priprave: Preparation process:
Aktivna tvar i pomoćna sredstva se otope u vodi i prenesu se u odgovarajući spremnik. The active substance and auxiliary agents are dissolved in water and transferred to a suitable container.
Primjer 8 Example 8
Injekcijska otopina koja sadrži 5 mg aktivne tvar u 5 ml Injection solution containing 5 mg of active substance in 5 ml
Sastav: Composition:
aktivna tvar 5 mg active substance 5 mg
glukoza 250 mg glucose 250 mg
albumin iz ljudskog seruma 10 mg albumin from human serum 10 mg
glikofurol 250 mg glycofurol 250 mg
voda za injekcije do 5 ml water for injections up to 5 ml
Priprava: Preparation:
Glikofurol i glukoza se otope u vodi za injekcije (Wfl); doda se albumin iz humanog seruma; aktivni sastojak se otopi uz grijanje; navedeni volumen se nadopuni s Wfl; prenese se u ampule pod plinom dušikom. Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; the specified volume is supplemented with Wfl; transfer to ampoules under nitrogen gas.
Primjer 9 Example 9
Injekcijska otopina koja sadrži 100 mg aktivne tvari u 20 ml Injection solution containing 100 mg of active substance in 20 ml
Sastav: Composition:
aktivn tvar 100 mg active substance 100 mg
monokalijev dihidrogen fosfat (KH2PO4) 12 mg monopotassium dihydrogen phosphate (KH2PO4) 12 mg
dinatrijev hidrogen fosfat (Na2HPO4·2H2O) 2 mg disodium hydrogen phosphate (Na2HPO4·2H2O) 2 mg
natrijev klorid 180 mg sodium chloride 180 mg
albumin iz humanog seruma 50 mg albumin from human serum 50 mg
Polysorbate 80 20 mg Polysorbate 80 20 mg
voda za injekcije do 20 ml water for injections up to 20 ml
Priprava: Preparation:
Polysorbate 80, natrijev klorid, monokalijev dihidrogen fosfat i dinatrijev hidrogen fosfat se otope u vodi za injekcije (Wfl); doda se albumin iz humanog seruma; aktivan sastojak se otopi uz grijanje; nadopuni se na navedeni volumen s Wfl; prenese se u ampule. Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; replenish to the specified volume with Wfl; transferred to ampoules.
Primjer 10 Example 10
Liofilizat koji sadrži 10 mg aktivne tvari Lyophilisate containing 10 mg of active substance
Sastav: Composition:
aktivna tvar 10 mg active substance 10 mg
manitol 300 mg mannitol 300 mg
albumin iz humanog seruma 20 mg albumin from human serum 20 mg
Priprava: Preparation:
Manitol se otopi u vodi za injekcije (Wfl); doda se albumin iz humanog seruma; aktivan sastojak se otopi uz grijanje; nadopuni se na navedeni volumen s Wfl; prenese se u vijale; osuši se smrzavanjem. Mannitol dissolves in water for injections (Wfl); human serum albumin is added; the active ingredient dissolves with heating; replenish to the specified volume with Wfl; transfer to vials; freeze dry.
Otapalo liofilizat: Solvent lyophilisate:
Polysorbate 80 = Tween 80 20 mg Polysorbate 80 = Tween 80 20 mg
manitol 200 mg mannitol 200 mg
voda za injekcije do 10 ml water for injections up to 10 ml
Priprava: Preparation:
Polysorbate 80 i manitol se otope u vodi za injekcije (Wfl); prenese se u ampule. Polysorbate 80 and mannitol are dissolved in water for injections (Wfl); transferred to ampoules.
Primjer 11 Example 11
Tablete koje sadrže 20 mg aktivne tvari Tablets containing 20 mg of active substance
Sastav: Composition:
aktivna tvar 20 mg active substance 20 mg
laktoza 120 mg lactose 120 mg
kukuruzni škrob 40 mg corn starch 40 mg
magnezijev stearat 2 mg magnesium stearate 2 mg
Povidone K25 18 mg Povidone K25 18 mg
Priprava: Preparation:
Homogeno se pomiješa aktivnu tvar, laktozu i kukuruzni škrob; granulira se s vodenom otopinom Povidona; pomiješa se s magnezijevim stearatom; preša se na preši za tablete; masa tablete je 200 mg. Homogeneously mix the active substance, lactose and corn starch; it is granulated with an aqueous solution of Povidone; mixed with magnesium stearate; it is pressed on a tablet press; the mass of the tablet is 200 mg.
Primjer 12 Example 12
Kapsule koje sadrže 20 ma aktivne tvari Capsules containing 20 mg of active substance
Sastav: Composition:
aktivna tvar 20 mg active substance 20 mg
kukuruzni škrob 80 mg corn starch 80 mg
visoko dispergirana silicijeva kiselina 5 mg highly dispersed silicic acid 5 mg
magnezijev stearat 2,5 mg magnesium stearate 2.5 mg
Priprava: Preparation:
Homogeno se pomiješa aktivnu tvar, kukuruzni škrob i silicijevu kiselinu; to pomiješa se s magnezijevim stearatom; smjesu se pakira u tvrde želatinske kapsule na stroju za punjenje kapsula. Homogeneously mix the active substance, corn starch and silicic acid; it is mixed with magnesium stearate; the mixture is packed into hard gelatin capsules on a capsule filling machine.
Primjer 13 Example 13
Čepići koji sadrže 50 mg aktivne tvari Suppositories containing 50 mg of active substance
Sastav: Composition:
aktivna tvar 50 mg active substance 50 mg
tvrda mast (Adeps solidus) q.s. do 1700 mg hard fat (Adeps solidus) q.s. up to 1700 mg
Priprava: Preparation:
Tvrdu mast se rastali pri pribl. 38°C; smrvljenu aktivnu tvar se homogeno dispergira u rastaljenoj tvrdoj masti; kad se ohladi na pril. 35°C lijeva se u pothlađene kalupe. The hard fat melted at approx. 38°C; the crushed active substance is homogeneously dispersed in melted hard fat; when it cools down to approx. 35°C is poured into cooled molds.
Primjer 14 Example 14
Injekcijska otopina koja sadrži 10 ma aktivne tvari u 1 ml Injection solution containing 10 mg of active substance in 1 ml
Sastav: Composition:
aktivna tvar 10 mg active substance 10 mg
manitol 50 mg mannitol 50 mg
albumin iz humanog seruma 10 mg albumin from human serum 10 mg
voda za injekcije do 1 ml water for injections up to 1 ml
Priprava: Preparation:
Manitol se otopi u vodi za injekcije (Wfl); doda se albumin iz humanog seruma; aktivnu tvar se otopi uz grijanje; nadopuni se na navedeni volumen s Wfl; prenese se u ampule pod plinom dušikom. Mannitol dissolves in water for injections (Wfl); human serum albumin is added; the active substance is dissolved with heating; replenish to the specified volume with Wfl; transfer to ampoules under nitrogen gas.
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PCT/EP2003/009099 WO2004024702A1 (en) | 2002-08-24 | 2003-08-16 | Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof |
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GB0124931D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
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ZA200500086B (en) | 2006-07-26 |
JP2006507246A (en) | 2006-03-02 |
AU2003258620A1 (en) | 2004-04-30 |
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PE20040974A1 (en) | 2005-01-12 |
NO20050068L (en) | 2005-03-04 |
DE10238865A1 (en) | 2004-03-11 |
EA012834B1 (en) | 2009-12-30 |
EA200500301A1 (en) | 2006-02-24 |
CA2496563A1 (en) | 2004-03-25 |
RS20050173A (en) | 2007-09-21 |
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TW200413332A (en) | 2004-08-01 |
ECSP055615A (en) | 2005-05-30 |
UA82853C2 (en) | 2008-05-26 |
EP1534689A1 (en) | 2005-06-01 |
CN1678591A (en) | 2005-10-05 |
AR043046A1 (en) | 2005-07-13 |
PL375344A1 (en) | 2005-11-28 |
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