EP1722792A1 - Antagonistes de cgrp selectionnes, procedes de fabrication et utilisation en tant que medicament - Google Patents
Antagonistes de cgrp selectionnes, procedes de fabrication et utilisation en tant que medicamentInfo
- Publication number
- EP1722792A1 EP1722792A1 EP05715592A EP05715592A EP1722792A1 EP 1722792 A1 EP1722792 A1 EP 1722792A1 EP 05715592 A EP05715592 A EP 05715592A EP 05715592 A EP05715592 A EP 05715592A EP 1722792 A1 EP1722792 A1 EP 1722792A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oxo
- piperidin
- ylmethyl
- tetrahydro
- benzodiazepin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 229940127597 CGRP antagonist Drugs 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 150000004677 hydrates Chemical class 0.000 claims abstract description 13
- 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 abstract description 9
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- 235000005985 organic acids Nutrition 0.000 claims abstract description 4
- -1 1H-indazol-5-ylmethyl Chemical group 0.000 claims description 196
- GOHSCIHNZMVWTO-UHFFFAOYSA-N 4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1N1C(=O)NC2=CC=CC=C2CC1 GOHSCIHNZMVWTO-UHFFFAOYSA-N 0.000 claims description 129
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 28
- 150000001408 amides Chemical class 0.000 claims description 28
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 24
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 150000003254 radicals Chemical class 0.000 claims description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- GRHLCKUKYPZZNW-UHFFFAOYSA-N 4-(3-oxo-5-phenyl-1h-1,2,4-triazol-2-yl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1N1C(=O)NC(C=2C=CC=CC=2)=N1 GRHLCKUKYPZZNW-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
- 150000003141 primary amines Chemical class 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- XXIOTYQIXIXURU-UHFFFAOYSA-N 1-[4-(dimethylamino)piperidin-1-yl]-2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CC(N(C)C)CCN1C(=O)C(CC=1C=C2C=NNC2=CC=1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3CC2)=O)CC1 XXIOTYQIXIXURU-UHFFFAOYSA-N 0.000 claims description 5
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 150000003335 secondary amines Chemical class 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- MYXRARGXENVRGP-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=NNC2=CC=1)C(=O)N(CC1)CCN1C1CCNCC1 MYXRARGXENVRGP-UHFFFAOYSA-N 0.000 claims description 4
- ZPFLALZYSGICAB-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=NNC2=CC=1)C(=O)N(CC1)CCC1C1CCNCC1 ZPFLALZYSGICAB-UHFFFAOYSA-N 0.000 claims description 4
- RFSSPVKNWPBMGC-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-1-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CN(C)CCN1C1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3C=NNC3=C(C)C=2)CC1 RFSSPVKNWPBMGC-UHFFFAOYSA-N 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 230000002757 inflammatory effect Effects 0.000 claims description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 230000024883 vasodilation Effects 0.000 claims description 4
- WSDBFOFLZFVDHZ-UHFFFAOYSA-N 1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-2-[[7-(trifluoromethyl)-1h-indazol-5-yl]methyl]butane-1,4-dione Chemical compound C1CN(C)CCC1N1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3C=NNC3=C(C=2)C(F)(F)F)CC1 WSDBFOFLZFVDHZ-UHFFFAOYSA-N 0.000 claims description 3
- QRLSZUJLPAFPMA-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)piperazin-1-yl]-2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1=CC(F)=CC=C1N1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3C=NNC3=CC=2)CC1 QRLSZUJLPAFPMA-UHFFFAOYSA-N 0.000 claims description 3
- HBMOEKOGIULTSS-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)piperidin-1-yl]-2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1C1=CC=C(F)C=C1 HBMOEKOGIULTSS-UHFFFAOYSA-N 0.000 claims description 3
- NWHIBYVNWIJHMQ-UHFFFAOYSA-N 1-[4-(dimethylamino)piperidin-1-yl]-2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CC(N(C)C)CCN1C(=O)C(CC=1C=C2C=NNC2=C(C)C=1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3CC2)=O)CC1 NWHIBYVNWIJHMQ-UHFFFAOYSA-N 0.000 claims description 3
- QVWBPCBGNLDSBR-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-4-[4-(3-oxo-5-phenyl-1h-1,2,4-triazol-2-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CN(C)CCC1N1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC(=N2)C=2C=CC=CC=2)=O)CC=2C=C3C=NNC3=CC=2)CC1 QVWBPCBGNLDSBR-UHFFFAOYSA-N 0.000 claims description 3
- YKMAWWQFZCYJOG-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-yl-1,4-diazepan-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=NNC2=CC=1)C(=O)N(CC1)CCCN1C1CCNCC1 YKMAWWQFZCYJOG-UHFFFAOYSA-N 0.000 claims description 3
- HHLNFGCMKQTFPE-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-pyridin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=NNC2=CC=1)C(=O)N(CC1)CCN1C1=CC=NC=C1 HHLNFGCMKQTFPE-UHFFFAOYSA-N 0.000 claims description 3
- ZJYIYOAMAOGNMK-UHFFFAOYSA-N 2-(1h-indol-5-ylmethyl)-1-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CN(C)CCC1N1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3C=CNC3=CC=2)CC1 ZJYIYOAMAOGNMK-UHFFFAOYSA-N 0.000 claims description 3
- HFLDDQPKRKQOGL-UHFFFAOYSA-N 2-(1h-indol-5-ylmethyl)-1-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CN(C)CCN1C1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3C=CNC3=CC=2)CC1 HFLDDQPKRKQOGL-UHFFFAOYSA-N 0.000 claims description 3
- HGYSRWFGBAQPOV-UHFFFAOYSA-N 2-(1h-indol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperazin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=CNC2=CC=1)C(=O)N(CC1)CCC1N1CCNCC1 HGYSRWFGBAQPOV-UHFFFAOYSA-N 0.000 claims description 3
- ITYWUFNHYXRDLZ-UHFFFAOYSA-N 2-(1h-indol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2C=CNC2=CC=1)C(=O)N(CC1)CCN1C1CCNCC1 ITYWUFNHYXRDLZ-UHFFFAOYSA-N 0.000 claims description 3
- LBZSSSUCYXLEBQ-UHFFFAOYSA-N 2-(2h-benzotriazol-5-ylmethyl)-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C1CC(N2C(NC3=CC=CC=C3CC2)=O)CCN1C(=O)CC(CC=1C=C2N=NNC2=CC=1)C(=O)N(CC1)CCC1C1CCNCC1 LBZSSSUCYXLEBQ-UHFFFAOYSA-N 0.000 claims description 3
- WUTXKMURVXRJDP-UHFFFAOYSA-N 2-[(1,7-dimethylindazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperazin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NN(C)C=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1N1CCNCC1 WUTXKMURVXRJDP-UHFFFAOYSA-N 0.000 claims description 3
- ALFGMMMQWSWUAD-UHFFFAOYSA-N 2-[(1,7-dimethylindazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NN(C)C=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 ALFGMMMQWSWUAD-UHFFFAOYSA-N 0.000 claims description 3
- CFZNTRPKVRIPOV-UHFFFAOYSA-N 2-[(1-methylindazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=C2N(C)N=CC2=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 CFZNTRPKVRIPOV-UHFFFAOYSA-N 0.000 claims description 3
- WWDIMHNQCZZVBR-UHFFFAOYSA-N 2-[(1-methylindazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=C2N(C)N=CC2=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1C1CCNCC1 WWDIMHNQCZZVBR-UHFFFAOYSA-N 0.000 claims description 3
- ABTADQJPOZKKRP-UHFFFAOYSA-N 2-[(7-bromo-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperazin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(Br)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1N1CCNCC1 ABTADQJPOZKKRP-UHFFFAOYSA-N 0.000 claims description 3
- IUEJVZYKJPZVOZ-UHFFFAOYSA-N 2-[(7-bromo-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(Br)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 IUEJVZYKJPZVOZ-UHFFFAOYSA-N 0.000 claims description 3
- UQIMMKCOGWQZKV-UHFFFAOYSA-N 2-[(7-ethyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperazin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(CC)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1N1CCNCC1 UQIMMKCOGWQZKV-UHFFFAOYSA-N 0.000 claims description 3
- ATWMCCCIVBMWPI-UHFFFAOYSA-N 2-[(7-ethyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(CC)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 ATWMCCCIVBMWPI-UHFFFAOYSA-N 0.000 claims description 3
- SOYSFKUGUAKDQZ-UHFFFAOYSA-N 2-[(7-ethyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(CC)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1C1CCNCC1 SOYSFKUGUAKDQZ-UHFFFAOYSA-N 0.000 claims description 3
- STPZZXREBBJADO-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-1-[4-(1-methylsulfonylpiperidin-4-yl)piperidin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1C1CCN(S(C)(=O)=O)CC1 STPZZXREBBJADO-UHFFFAOYSA-N 0.000 claims description 3
- ZNRGYKKAKIBSQD-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-yl-1,4-diazepan-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCCN1C1CCNCC1 ZNRGYKKAKIBSQD-UHFFFAOYSA-N 0.000 claims description 3
- AVQYBBNRZPTECQ-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 AVQYBBNRZPTECQ-UHFFFAOYSA-N 0.000 claims description 3
- NEJFXSKIWQAKFT-UHFFFAOYSA-N 2-[(7-methyl-2h-benzotriazol-5-yl)methyl]-1-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CN(C)CCN1C1CCN(C(=O)C(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3CC2)=O)CC=2C=C3N=NNC3=C(C)C=2)CC1 NEJFXSKIWQAKFT-UHFFFAOYSA-N 0.000 claims description 3
- DWRSHKHNLIAJHD-UHFFFAOYSA-N 2-[(7-methyl-2h-benzotriazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperazin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2N=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCC1N1CCNCC1 DWRSHKHNLIAJHD-UHFFFAOYSA-N 0.000 claims description 3
- CVASQQZUCJQTFC-UHFFFAOYSA-N 2-[(7-methyl-2h-benzotriazol-5-yl)methyl]-4-[4-(2-oxo-4,5-dihydro-1h-1,3-benzodiazepin-3-yl)piperidin-1-yl]-1-(4-piperidin-4-ylpiperazin-1-yl)butane-1,4-dione Chemical compound C=1C=2N=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2CC1)=O)C(=O)N(CC1)CCN1C1CCNCC1 CVASQQZUCJQTFC-UHFFFAOYSA-N 0.000 claims description 3
- IWKOBIPTTBNYKH-UHFFFAOYSA-N 2-amino-1-[4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl]-3-(7-methyl-1H-indazol-5-yl)propan-1-one Chemical compound C1CN(C)CCCN1C1CCN(C(=O)C(N)CC=2C=C3C=NNC3=C(C)C=2)CC1 IWKOBIPTTBNYKH-UHFFFAOYSA-N 0.000 claims description 3
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- 150000007530 organic bases Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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- FIADGNVRKBPQEU-UHFFFAOYSA-N pizotifen Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 FIADGNVRKBPQEU-UHFFFAOYSA-N 0.000 description 1
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- 238000002953 preparative HPLC Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940086766 sodium chloride 180 mg Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Definitions
- the present invention relates to selected CGRP antagonists of the general formula
- A, B, D, E, X, R 1 and R 2 are as defined in claim 1, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiological compatible salts with inorganic or organic acids, medicaments containing these compounds, their use and process for their preparation.
- A is a nitrogen atom or a CH group
- B is a nitrogen atom or a CH group
- D is a hydrogen atom or a methyl group
- E is a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl or trifluoromethyl group
- X is a methylene or NH group
- R 1 is a radical of the formula
- R is a radical of the formula
- a second embodiment of the present invention comprises those compounds of the general formula I in which the combination of A, B, D and E is a group of the formula
- R 1 is a radical of the formula
- R is a radical of the formula
- the compounds of the general formula (I) are prepared by methods known in principle. The following processes have proven particularly useful for the preparation of the compounds of the general formula (I) according to the invention:
- G is a nucleofugic group, preferably the phenoxy, 1H-imidazol-1-yl, 1H-1, 2,4-triazol-1-yl, trichloromethoxy or the 2,5-dioxopyrrolidin-1-yloxy Group means
- R 2 is defined as mentioned at the outset, with the proviso that these groups contain no further free primary or secondary aliphatic amino function.
- the basically two-stage reactions are usually carried out as a one-pot process, preferably in such a way that in the first stage one of the two components (III) or (V) with equimolar amounts of the carbonic acid derivative of the general formula (IV) in one suitable solvent to react at a lower temperature, then adds at least equimolar amounts of the other component (III) or (V) and the reaction is ended at a higher temperature.
- the reactions with bis (trichloromethyl) carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis (trichloromethyl) carbonate) of a tertiary base, for example triethylamine,, / -ethyldiisopropylamine, pyridine, 1, 5- Diaza-bicyclo- [4,3,0] -non-5-ene, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo- [5,4,0] -un-dec- 7-s.
- a tertiary base for example triethylamine,, / -ethyldiisopropylamine, pyridine, 1, 5- Diaza-bicyclo- [4,3,0] -non-5-ene, 1,4-diazabicyclo [2,2,2] octane or 1,8-diazabicyclo- [5,4,0] -
- Suitable solvents which should be anhydrous, are, for example, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, ⁇ / -methyl-2-pyrrolidone, 1, 3-dimethyl-2-imidazolidinone or acetonitrile when using bis- (t ⁇ chloromethyl) ) -carbonate as carbonyl component, anhydrous chlorinated hydrocarbons, for example dichloromethane, 1, 2-dichloroethane or trichlorethylene, are preferred.
- the reaction temperatures for the first reaction stage are between -30 ° C and + 25 ° C, preferably -5 ° C and + 10 ° C, for the second reaction stage between + 15 ° C and the boiling point of the solvent used, preferably between + 20 ° C and + 70 ° C
- the reaction temperatures for the first reaction stage are between -30 ° C and + 25 ° C, preferably -5 ° C and + 10 ° C
- for the second reaction stage between + 15 ° C and the boiling point of the solvent used, preferably between + 20 ° C and + 70 ° C
- HA Staab and W. Rohr "Syntheses with heterocyclic amides (azolides)", Newer Methods in Preparative Organic Chemistry, Volume V, pp. 53-93, Verlag Chemie, Weinheim / Bergstr. , 1967; P. Majer and RS Randad, J. Org. Chem. 59, p. 1937-1938 (1994); K. Takeda, Y.
- R 1 has the meanings mentioned above.
- the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2), for example carbodiimides, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) carbodiimide, 0- (1 / - / - benzothazol-1-yl) - / V, ⁇ / - / V, / V-tetramethyluronium hexafluorophosphate (HBTU ) or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
- carbodiimides such as, for example, dicyclohexylcarbod
- the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-di-hydro-1, 2,3-benzotriazine (HOObt).
- the couplings are normally made with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 ° C and + 30 ° C, preferably -20 ° C and + 25 ° C, performed.
- DIEA dimethylacetamide
- NMP ⁇ / methylpyrrolidone
- the mixed anhydride is obtained from the carboxylic acid of general formula (VI) to be coupled and the carbonic acid monoisobutyl ester.
- This mixed anhydride is prepared and coupled with amines in a one-pot process using the abovementioned solvents and at temperatures between -20 and + 25 ° C., preferably 0 ° C. and + 25 ° C.
- R 2 contains no primary or secondary amine
- Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom , an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl part, a phenylsulfonyloxy or naphthylsulfonyloxy group which is mono-, di- or trisubstituted, optionally by chlorine or bromine atoms, by methyl or nitro groups, it being possible for the substituents to be the same or different, a 1H- Imidazol-1-yl-, a 1 rV-pyrazol-1-yl- optionally substituted by one or two methyl groups in the carbon skeleton, a 1H-1, 2,4-triazol-1-yl-, 1H-1, 2,3 -Triazol-1 -
- R 1 is defined as mentioned at the beginning.
- the reaction is carried out under Schotten-Baumann or Einhorn conditions, ie the components are in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C , and optionally in the presence of solvents Brought reaction.
- Alkali and alkaline earth metal hydroxides for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for. B.
- alkali metal acetates for example sodium or potassium acetate
- tertiary amines for example pyridine, 2,4,6-tri-methylpyridine, quinoline, triethylamine, ⁇ / -ethyl-diisopropylamine, ⁇ / -ethyl-di - Cyclohexylamine, 1,4-di-azabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] -undec-7-ene, for example dichloromethane, tetrahydrofuran, 1,4-dioxane as solvents , Acetonitrile, dimethylformamide, dimethylacetamide, ⁇ / -methylpyrrolidone or mixtures thereof; if alkali or alkaline earth metal hydroxides, alkali carbonates or acetates are used as auxiliary bases, water
- A, B, D, E, R 1 and X are defined as mentioned at the beginning, with an amine R 2 with the proviso that no further free primary or secondary, aliphatic amino function is contained.
- Coupling is preferred using methods known from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol.
- carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) - carbodiimide, 0- (1H-benzotriazol-1-yl) - ⁇ /, ⁇ / - / V, / V-tetramethyluronium hexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 rV-benzotriazol-1- yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
- DCC dicyclohexylcarbodiimide
- DI diisopropylcarbodiimide
- ethyl (3-dimethylamino-propyl) - carbodiimide 0- (1H-benzotriazol-1-yl
- the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1, 2,3-benzotriazine (HOObt).
- the couplings are normally made with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethyl acetamide (DMA), ⁇ / methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and + 30 ° C, preferably -20 and + 25 ° C, carried out. If necessary, preference is given to additional auxiliary base / V-ethyldiisopropylamine (DIEA) (Hünig base).
- DIEA V-ethyldiisopropylamine
- This mixed anhydride is prepared and coupled with the amines R 2 in a one-pot process, using the abovementioned solvents and at temperatures between -20 ° C. and + 25 ° C., preferably between
- Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms in the alkyl part, one optionally by chlorine or bromine atoms, by methyl or nitro groups mono-, di- or tri-substituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents may be the same or different, a 1H-imidazol-1-yl, one optionally substituted by one or two methyl groups in the carbon skeleton 1H-pyrazol-1-yl-, a 1H-1, 2,4-triazol-1-yl-, 1 H-1, 2,3-triazol-1 -yl-, 1H-1, 2,3,4 -Tetrazol-1-yl-, a vinyl
- the reaction is carried out under Schotten-Baumann or Einhorn conditions, that is to say the components are in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C. and + 120 ° C., preferably -10 ° C. and + 30 ° C, and optionally reacted in the presence of solvents.
- Alkali and alkaline earth metal hydroxides for example sodium hydroxide, potassium hydroxide or barium hydroxide
- alkali metal carbonates for example sodium carbonate, potassium carbonate or cesium carbonate
- alkali metal acetates for example sodium or potassium acetate
- tertiary amines for example pyridine, 2,4,6-trimethylpyridine
- novel compounds of the general formula (I) according to the invention contain one or more centers of chirality. If, for example, there are two centers of chirality, the compounds can appear in the form of two diastereomeric pairs of antipodes.
- the invention includes the individual isomers as well as their mixtures.
- the respective diastereomers can be separated due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
- Racemates falling under the general formula (I) can be separated, for example, by HPLC on suitable chiral stationary phases (for example Chiral AGP, Chiralpak AD). Racemates containing a basic or acidic function can also be separated using the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (- ) -Diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - or (-) - camphorsulfonic acid, or an optically active base, for example with (R) - (+) - l-phenylethylamine, (S) - (-) - 1-Phenylethylamine or (S) -Brucin, arise.
- an optically active acid for example (+) - or (-) - tartaric acid, (+) - or (- ) -Diacetyltartaric
- the racemate of a compound of the general formula (I) is reacted with one of the optically active acids or bases given above in an equimolar amount in a solvent and the crystalline, diastereomeric, optically active salts obtained using their different solubilities Cut.
- This reaction can be carried out in any kind of solvent, as long as it is sufficient Difference in the solubility of the salts.
- Methanol, ethanol or mixtures thereof are preferably used, for example in a volume ratio of 50:50.
- Each of the optically active salts is then dissolved in water, carefully neutralized with a base, such as sodium carbonate or potassium carbonate, or with a suitable acid, for example with dilute hydrochloric acid or aqueous methanesulfonic acid, and the corresponding free compound in the (+) - or ( -) - Get shape.
- a base such as sodium carbonate or potassium carbonate
- a suitable acid for example with dilute hydrochloric acid or aqueous methanesulfonic acid
- the starting compounds of the general formula (III) are obtained, insofar as they are not known from the literature or are even commercially available, in accordance with the processes specified in WO 98/11128 and DE 199 52 146.
- the starting compounds of the general formula (IV) are commercially available.
- Compounds of the general formula (V) can be prepared from protected phenylalanines and amines of the general formula R 2 by methods familiar to the peptide chemist.
- the starting compounds of the general formula (VI) are obtained, for example, by reacting amines of the general formula R 2 with 2- (alkoxycarbonylmethyl) -3-aryl-propanoic acids and subsequent hydrolytic elimination of the alkyl group.
- Carboxylic acids of the general formula (VIII) can be prepared from generally accessible starting materials by the processes specified in WO 98/11128.
- the compounds of general formula (I) obtained if they contain suitable basic functions, in particular for pharmaceutical applications, be converted into their physiologically tolerable salts with inorganic or organic acids.
- suitable acids for this are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
- the new compounds of the formula (I) contain carboxylic acid function, they can, if desired, be converted into their addition salts with inorganic or organic bases, in particular for pharmaceutical use, into their physiologically tolerable addition salts.
- Suitable bases for this are, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the present invention relates to racemates if the compounds of the general formula (I) have only one chiral element.
- the application also includes the individual diastereomeric pairs of antipodes or their mixtures, which are present when more than one chiral element is present in the compounds of the general formula (I), and the individual optically active enantiomers from which the racemates mentioned are composed.
- Also included in the subject matter of this invention are the compounds according to the invention, including their salts, in which one or more hydrogen atoms have been replaced by deuterium.
- the new compounds of the general formula (I) and their physiologically tolerable salts have valuable pharmacological properties which are based on their selective CGRP-antagonistic properties.
- the invention further relates to medicaments containing these compounds, their use and their preparation.
- the new compounds mentioned above and their physiological Compatible salts have CGRP antagonistic properties and show good affinities in CGRP receptor binding studies.
- the compounds have CGRP-antagonistic properties in the pharmacological test systems described below.
- SK-N-MC cells are cultivated in "Dulbecco's modified Eagle Medium”. The medium of confluent cultures is removed. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by adding PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml "Balanced Salts Solution” [BSS (in mM): NaCI 120, KCI 5.4, NaHC0 3 16.2, MgS0 4 0.8, NaHPO 4 1.0, CaCI 2 1.8, D-Glucose 5.5, HEPES 30, pH 7.40] the cells are centrifuged twice at 100 xg and resuspended in BSS.
- BSS "Balanced Salts Solution”
- the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet is re-centrifuged and resuspended in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin (1st ml / 1,000,000 cells). The homogenate is frozen at -80 ° C. Under these conditions, the membrane preparations are stable for more than 6 weeks.
- the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenate are incubated for 180 minutes at room temperature with 50 pM 125 l-iodotyrosyl-calcitonin gene-related peptides (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. The incubation is done by rapid filtration ended with GF / B glass fiber filters treated with polyethyleneimine (0.1%) using a cell harvester. The radioactivity bound to protein is determined using a gamma counter. The bound radioactivity is defined as non-specific binding after the presence of 1 ⁇ M human CGRP-alpha during the incubation.
- assay buffer 50 mM Tris, 150 mM NaCl, 5 mM MgC
- concentration-binding curves are analyzed with the aid of a computer-aided non-linear curve fitting.
- SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l incubation buffer (Hanks ' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and at 37 ° C. for 15 minutes pre-incubated. After adding CGRP (10 ⁇ l) as an agonist in increasing concentrations (10 ⁇ 11 to 10 ⁇ 6 M) or additionally of substance in 3 to 4 different concentrations, incubation is continued for 15 minutes.
- incubation buffer Hanks ' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4
- Intracellular cAMP is then extracted by adding 20 ⁇ l of 1M HCl and centrifugation (2000 ⁇ g, 4 ° C. for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at -20 ° C.
- the cAMP contents of the samples are determined by means of a radioimmunoassay (from Amersham) and the pA 2 values of substances having an antagonistic effect are determined graphically.
- the compounds according to the invention show CGRP-antagonistic properties in a dose range between 10 "12 to 10 ⁇ 5 M.
- the Compounds according to the invention and their salts with physiologically tolerated acids thus for the acute and prophylactic treatment of headaches, in particular migraine headaches or cluster heads.
- the compounds according to the invention also have a positive influence on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM”), cardiovascular diseases, morphine tolerance, diarrheal diseases caused by clostritium toxin, skin diseases, in particular thermal and radiation-related skin damage including sunburn, inflammatory diseases, for example inflammatory joint diseases (Arthritis), neurogenic inflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases that are associated with excessive vasodilation and the resulting reduced tissue circulation, such as shock and sepsis.
- NIDDM non-insulin-dependent diabetes mellitus
- cardiovascular diseases morphine tolerance
- diarrheal diseases caused by clostritium toxin skin diseases, in particular thermal and radiation-related skin damage including sunburn
- inflammatory diseases for example inflammatory joint diseases (Arth
- the compounds according to the invention generally have an alleviating effect on painful conditions.
- the symptoms of menopausal hot flashes caused by vasodilation and increased blood flow in estrogen-deficient women and hormone-treated prostate carcinoma patients are influenced by the CGRP antagonists of the present application in a preventive and acute-therapeutic manner, whereby this therapeutic approach before hormone substitution is characterized by a lack of side effects.
- the dosage required to achieve a corresponding effect is expediently 0.0001 to 3 mg / kg body weight with intravenous or subcutaneous administration, preferably 0.01 to 1 mg / kg body weight, and 0.01 to 10 mg / kg body weight with oral, nasal or inhalation administration, preferably 0.1 up to 10 mg / kg body weight, 1 to 3 times a day.
- the compounds prepared according to the invention can either be used alone or optionally in combination with other active substances for the treatment of migraines intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations in particular being suitable for inhalation.
- the combinations can be administered either simultaneously or sequentially.
- Possible drug classes as combination partners are, for example, antiemetics, procinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, weak analgesic anticoagulants, non-analgesic anticoagulants, not Corticosteroids, calcium antagonists, 5-HT ⁇ s / i D agonists or other antimigraine agents, which together with one or more inert conventional carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid , Water, water / ethanol, water / glycerin, water / - sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carb
- the non-steroidal antiinflammatory drugs acclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketopunamid, lefloxamine, lefenamrofen, lefenamine Phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts as well as meloxicam and other selective COX2 inhibitors, such as rofecoxib and celecoxib, into consideration.
- the dose for these active substances is expediently 1/5 of the usually recommended lowest dose up to 1/1 of the normally recommended dose, for example 20 to 100 mg sumatriptan.
- the invention furthermore relates to the use of the compounds according to the invention as valuable auxiliaries for the production and purification (affinity chromatography) of antibodies and, after suitable radioactive labeling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with trithium or replacement of halogen atoms by tritium, in RIA and ELISA assays and as diagnostic and analytical tools in neurotransmitter research.
- Analytical column Zorbax column (Agilent Technologies), SB (Stable Bond) - C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm
- Phases were dried over magnesium sulfate, filtered over activated carbon and i. vac. concentrated.
- the crude product was triturated with diisopropyl ether and a little isopropanol, filtered off and the residue was washed with diisopropyl ether (3.60 g, 1st stereoisomer).
- the mother liquor was i. vac. concentrated and the residue was purified by column chromatography (silica gel, EtOAc / HOAc 10 / 0.1 v / v) and i. vac. dried (3.60 g, 2nd stereoisomer).
- R f 0.51 (silica gel, dichloromethane / MeOH / sat. Aqueous ammonia 50/45/5 v / v / v)
- Rf 0.05 (silica gel, dichloromethane / cyclohexane / MeOH / sat. Aqueous ammonia
- the intermediate was prepared analogously to intermediate 4 starting from methyl 2- (7-methyl-1H-indazol-5-ylmethyl) succinate and 3-piperidin-4-yl-1, 3,4,5-tetrahydro-1, 3-benzodiazepin-2-one obtained.
- the reaction mixture was diluted with 50 mL EtOAc and the org. Phase washed twice with 15% aqueous potassium carbonate solution. The org. Phase was dried over magnesium sulfate and i. vac. concentrated.
- the crude product was purified by means of column chromatography (silica gel, gradient dichloromethane / MeOH / sat. Aqueous ammonia 100/0/0 ⁇ 80/18/2). The residue was triturated with diisopropyl ether and i. vac. dried at 50 ° C. Yield: 520 mg (64% of theory)
- the crude product was purified by HPLC-MS (Agilent Zorbax Stable Bond SB C18, 5 ⁇ m, 75 x 4.6 mm, water / acetonitrile / formic acid 10/90 / 0.1 - 90/10 / 0.1 v / v / v).
- 1 capsule for powder inhalation contains: Active ingredient 1.0 mg Milk sugar 20.0 mg
- the active ingredient is ground to the grain size required for inhalants.
- the ground active ingredient is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.
- Composition: 1 hub contains:
- the active ingredient and benzalkonium chloride are dissolved in water and filled into Respimat® cartridges.
- composition 1 vial contains:
- Composition: 1 hub contains:
- the micronized active ingredient is homogeneously suspended in the mixture of lecithin and propellant.
- the suspension is filled into a pressure vessel with a metering valve.
- the active ingredient and excipients are dissolved in water and in a corresponding Container filled.
- Preparation Dissolve glycofurol and glucose in water for injections (Wfl); Add human serum albumin; Dissolve the active ingredient while heating; fill up to batch volume with Wfl; Fill into ampoules under nitrogen gas.
- Dissolve mannitol in water for injections Wfl
- Add human serum albumin Dissolve the active ingredient while heating; fill up to batch volume with Wfl; fill in vials; freeze-dry.
- Polysorbate 80 Tween 80 20 mg
- Dissolve mannitol in water for injections Wfl
- Add human serum albumin Dissolve the active ingredient while heating; fill up to batch volume with Wfl; Fill into ampoules under nitrogen gas.
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Abstract
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DE102004010254A DE102004010254A1 (de) | 2004-03-03 | 2004-03-03 | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
DE200410028751 DE102004028751A1 (de) | 2004-06-15 | 2004-06-15 | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
PCT/EP2005/002082 WO2005084672A1 (fr) | 2004-03-03 | 2005-02-26 | Antagonistes de cgrp selectionnes, procedes de fabrication et utilisation en tant que medicament |
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US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
CN100558728C (zh) * | 2002-06-05 | 2009-11-11 | 布里斯托尔-迈尔斯斯奎布公司 | 降钙素基因相关肽受体拮抗剂 |
US7842808B2 (en) | 2002-06-05 | 2010-11-30 | Bristol-Myers Squibb Company | Anti-migraine spirocycles |
DE10250082A1 (de) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
AR046787A1 (es) | 2003-12-05 | 2005-12-21 | Bristol Myers Squibb Co | Agentes antimigrana heterociclicos |
DE102004015723A1 (de) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
TW200533398A (en) | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
US7696195B2 (en) | 2004-04-22 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
US7384930B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7384931B2 (en) | 2004-11-03 | 2008-06-10 | Bristol-Myers Squibb Company | Constrained compounds as CGRP-receptor antagonists |
US7449586B2 (en) | 2004-12-03 | 2008-11-11 | Bristol-Myers Squibb Company | Processes for the preparation of CGRP-receptor antagonists and intermediates thereof |
US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
US8168592B2 (en) | 2005-10-21 | 2012-05-01 | Amgen Inc. | CGRP peptide antagonists and conjugates |
DE102005050892A1 (de) | 2005-10-21 | 2007-04-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
CN101309704B (zh) | 2005-11-14 | 2012-10-10 | 礼纳特神经***科学公司 | 针对降钙素基因相关肽的拮抗剂抗体及其使用方法 |
US7601844B2 (en) | 2006-01-27 | 2009-10-13 | Bristol-Myers Squibb Company | Piperidinyl derivatives as modulators of chemokine receptor activity |
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- 2005-02-26 WO PCT/EP2005/002082 patent/WO2005084672A1/fr not_active Application Discontinuation
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US20050227968A1 (en) | 2005-10-13 |
WO2005084672A1 (fr) | 2005-09-15 |
US7205294B2 (en) | 2007-04-17 |
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