HRP20010566A2 - (1-phenacy-3-phenyl-3-piperidylethyl)piperidine derivatives, method for the production thereof and pharmaceutical compositions containing the same - Google Patents

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Publication number

HRP20010566A2

HRP20010566A2 HR20010566A HRP20010566A HRP20010566A2 HR P20010566 A2 HRP20010566 A2 HR P20010566A2 HR 20010566 A HR20010566 A HR 20010566A HR P20010566 A HRP20010566 A HR P20010566A HR P20010566 A2 HRP20010566 A2 HR P20010566A2

Authority

HR

Croatia

Prior art keywords

formula

compound

image

salts

represented

Prior art date

1999-02-10

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• 238000000034 method Methods 0.000 title claims description 72
• 239000008194 pharmaceutical composition Substances 0.000 title description 7
• 150000003053 piperidines Chemical class 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 290
• 238000002360 preparation method Methods 0.000 claims description 65
• 150000003839 salts Chemical class 0.000 claims description 48
• -1 1-azetidinyl Chemical group 0.000 claims description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
• 239000002253 acid Substances 0.000 claims description 27
• 150000004677 hydrates Chemical class 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 239000012453 solvate Substances 0.000 claims description 26
• 208000002193 Pain Diseases 0.000 claims description 22
• 238000006243 chemical reaction Methods 0.000 claims description 22
• 150000007522 mineralic acids Chemical class 0.000 claims description 20
• 150000007524 organic acids Chemical class 0.000 claims description 20
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 19
• 239000004480 active ingredient Substances 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
• 235000005985 organic acids Nutrition 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 16
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
• 230000008569 process Effects 0.000 claims description 13
• 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 12
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
• 230000009471 action Effects 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 claims description 8
• 206010061218 Inflammation Diseases 0.000 claims description 8
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• 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 8
• 230000004054 inflammatory process Effects 0.000 claims description 8
• 125000004432 carbon atom Chemical group C* 0.000 claims description 7
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• 150000007975 iminium salts Chemical class 0.000 claims description 6
• 206010027599 migraine Diseases 0.000 claims description 6
• 230000007170 pathology Effects 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• 208000017520 skin disease Diseases 0.000 claims description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
• 208000019695 Migraine disease Diseases 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 230000002496 gastric effect Effects 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 4
• 229940127554 medical product Drugs 0.000 claims description 4
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
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• 210000000748 cardiovascular system Anatomy 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
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• 125000006239 protecting group Chemical group 0.000 claims description 3
• 230000000241 respiratory effect Effects 0.000 claims description 3
• 230000000707 stereoselective effect Effects 0.000 claims description 3
• 125000003944 tolyl group Chemical group 0.000 claims description 3
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
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• 125000001424 substituent group Chemical group 0.000 claims description 2
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• OAHFZIHKKGOREG-UHFFFAOYSA-N 2-[1-[2-[1-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-3-(3,4-dichlorophenyl)piperidin-3-yl]ethyl]piperidin-4-yl]-2-methylpropanamide Chemical compound C1CC(C(C)(C)C(N)=O)CCN1CCC1(C=2C=C(Cl)C(Cl)=CC=2)CN(C(=O)CC=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCC1 OAHFZIHKKGOREG-UHFFFAOYSA-N 0.000 claims 1
• FXQNHVVNCWWGFX-UHFFFAOYSA-N 2-[1-[2-[3-(3,4-dichlorophenyl)-1-[2-(3,5-dimethylphenyl)acetyl]piperidin-3-yl]ethyl]piperidin-4-yl]-2-methylpropanamide Chemical compound CC1=CC(C)=CC(CC(=O)N2CC(CCN3CCC(CC3)C(C)(C)C(N)=O)(CCC2)C=2C=C(Cl)C(Cl)=CC=2)=C1 FXQNHVVNCWWGFX-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 155
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
• 239000000203 mixture Substances 0.000 description 113
• 239000000243 solution Substances 0.000 description 103
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 87
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
• 239000000047 product Substances 0.000 description 75
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
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• 238000003756 stirring Methods 0.000 description 40
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
• 238000001704 evaporation Methods 0.000 description 33
• 230000008020 evaporation Effects 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
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