RU2560729C2 - Модуляторы никотиновых ацетилхолиновых рецепторов - Google Patents

Info

Publication number

RU2560729C2

RU2560729C2 RU2012129257/04A RU2012129257A RU2560729C2 RU 2560729 C2 RU2560729 C2 RU 2560729C2 RU 2012129257/04 A RU2012129257/04 A RU 2012129257/04A RU 2012129257 A RU2012129257 A RU 2012129257A RU 2560729 C2 RU2560729 C2 RU 2560729C2

Authority

RU

Russia

Prior art keywords

phenyl

alkyl

compound

substituted

compounds

Prior art date

2010-01-11

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• 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 title claims abstract description 38
• 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 title claims abstract description 38
• 150000001875 compounds Chemical class 0.000 claims abstract description 158
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 49
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
• 239000001257 hydrogen Substances 0.000 claims abstract description 27
• 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 23
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 22
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 16
• 229960002715 nicotine Drugs 0.000 claims abstract description 13
• SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims abstract description 13
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 10
• 125000005843 halogen group Chemical group 0.000 claims abstract description 6
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 12
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims abstract 2
• 239000001301 oxygen Substances 0.000 claims abstract 2
• 238000000034 method Methods 0.000 claims description 33
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 12
• 229910052727 yttrium Inorganic materials 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 102000005962 receptors Human genes 0.000 claims description 9
• 108020003175 receptors Proteins 0.000 claims description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
• 206010057852 Nicotine dependence Diseases 0.000 claims description 3
• 208000025569 Tobacco Use disease Diseases 0.000 claims description 3
• 150000002431 hydrogen Chemical class 0.000 claims 5
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 49
• 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 30
• 230000000694 effects Effects 0.000 abstract description 23
• 239000003814 drug Substances 0.000 abstract description 22
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 21
• 208000035475 disorder Diseases 0.000 abstract description 21
• 239000000126 substance Substances 0.000 abstract description 20
• 208000024891 symptom Diseases 0.000 abstract description 19
• 238000011282 treatment Methods 0.000 abstract description 17
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 abstract description 12
• 208000002193 Pain Diseases 0.000 abstract description 7
• 230000002265 prevention Effects 0.000 abstract description 5
• 201000005040 opiate dependence Diseases 0.000 abstract description 3
• 244000025254 Cannabis sativa Species 0.000 abstract description 2
• 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 abstract description 2
• 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 abstract description 2
• 108010009685 Cholinergic Receptors Proteins 0.000 abstract description 2
• ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 abstract 2
• 208000029197 Amphetamine-Related disease Diseases 0.000 abstract 1
• 208000018526 Narcotic-Related disease Diseases 0.000 abstract 1
• 102000034337 acetylcholine receptors Human genes 0.000 abstract 1
• 229960003920 cocaine Drugs 0.000 abstract 1
• 229940127240 opiate Drugs 0.000 abstract 1
• -1 etc.) Chemical compound 0.000 description 105
• 239000000203 mixture Substances 0.000 description 78
• 239000000243 solution Substances 0.000 description 42
• 125000003710 aryl alkyl group Chemical group 0.000 description 39
• 125000003118 aryl group Chemical group 0.000 description 35
• 125000000217 alkyl group Chemical group 0.000 description 33
• 125000001072 heteroaryl group Chemical group 0.000 description 31
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• 201000010099 disease Diseases 0.000 description 28
• 239000007787 solid Substances 0.000 description 24
• 239000012458 free base Substances 0.000 description 22
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
• 239000003795 chemical substances by application Substances 0.000 description 21
• 125000004446 heteroarylalkyl group Chemical group 0.000 description 21
• 238000002360 preparation method Methods 0.000 description 21
• 239000002552 dosage form Substances 0.000 description 20
• 239000000725 suspension Substances 0.000 description 19
• 0 C*CCCc1ccccc1 Chemical compound C*CCCc1ccccc1 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 18
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
• 229940079593 drug Drugs 0.000 description 17
• 239000000839 emulsion Substances 0.000 description 17
• 238000012360 testing method Methods 0.000 description 17
• 235000002639 sodium chloride Nutrition 0.000 description 16
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
• 241001465754 Metazoa Species 0.000 description 15
• 125000000547 substituted alkyl group Chemical group 0.000 description 15
• 238000013270 controlled release Methods 0.000 description 14
• 239000007788 liquid Substances 0.000 description 14
• 230000004044 response Effects 0.000 description 14
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
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• 239000002775 capsule Substances 0.000 description 13
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 11
• 229920000728 polyester Polymers 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 10
• 239000005977 Ethylene Substances 0.000 description 10
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 10
• 125000000304 alkynyl group Chemical group 0.000 description 10
• 230000037396 body weight Effects 0.000 description 10
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
• 150000001721 carbon Chemical group 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 150000003840 hydrochlorides Chemical class 0.000 description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
• 238000002347 injection Methods 0.000 description 9
• 239000007924 injection Substances 0.000 description 9
• 239000002502 liposome Substances 0.000 description 9
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 8
• 239000008187 granular material Substances 0.000 description 8
• 125000003107 substituted aryl group Chemical group 0.000 description 8
• 230000001225 therapeutic effect Effects 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 7
• 229930006000 Sucrose Natural products 0.000 description 7
• 235000019441 ethanol Nutrition 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• 239000005720 sucrose Substances 0.000 description 7
• 229960004793 sucrose Drugs 0.000 description 7
• 239000006188 syrup Substances 0.000 description 7
• 235000020357 syrup Nutrition 0.000 description 7
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
• OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 6
• 229960004373 acetylcholine Drugs 0.000 description 6
• 239000007864 aqueous solution Substances 0.000 description 6
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
• 239000003086 colorant Substances 0.000 description 6
• 239000003995 emulsifying agent Substances 0.000 description 6
• 239000000796 flavoring agent Substances 0.000 description 6
• 235000011187 glycerol Nutrition 0.000 description 6
• PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 6
• 239000008176 lyophilized powder Substances 0.000 description 6
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• 238000007911 parenteral administration Methods 0.000 description 6
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• 239000000047 product Substances 0.000 description 6
• 229940117958 vinyl acetate Drugs 0.000 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 description 5
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 5
• 241000700159 Rattus Species 0.000 description 5
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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• 239000006172 buffering agent Substances 0.000 description 5
• 239000008121 dextrose Substances 0.000 description 5
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
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• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
• NLPRAJRHRHZCQQ-UHFFFAOYSA-N 3-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane Chemical compound C1=NC(Cl)=CC=C1C1C(N2)CCC2C1 NLPRAJRHRHZCQQ-UHFFFAOYSA-N 0.000 description 4
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• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
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