TWI827037B - 作為nav1.8抑制劑之環烷基3-側氧基哌甲醯胺及環雜烷基3-側氧基哌甲醯胺 - Google Patents

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Publication number

TWI827037B

TWI827037B TW111116959A TW111116959A TWI827037B TW I827037 B TWI827037 B TW I827037B TW 111116959 A TW111116959 A TW 111116959A TW 111116959 A TW111116959 A TW 111116959A TW I827037 B TWI827037 B TW I827037B

Authority

TW

Taiwan

Prior art keywords

methyl

alkyl

cycloalkyl

chloro

formamide

Prior art date

2021-05-07

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• 239000003112 inhibitor Substances 0.000 title claims abstract description 24
• -1 Cycloalkyl 3-oxopiperazine carboxamides Chemical class 0.000 title claims description 152
• SDMXXELKHDUNQA-UHFFFAOYSA-N 3-oxopiperazine-1-carboxamide Chemical class NC(=O)N1CCNC(=O)C1 SDMXXELKHDUNQA-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 231
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 95
• 150000003839 salts Chemical class 0.000 claims abstract description 86
• 201000010099 disease Diseases 0.000 claims abstract description 55
• 230000000694 effects Effects 0.000 claims abstract description 51
• 208000003251 Pruritus Diseases 0.000 claims abstract description 46
• 238000011282 treatment Methods 0.000 claims abstract description 40
• 230000001684 chronic effect Effects 0.000 claims abstract description 20
• 206010011224 Cough Diseases 0.000 claims abstract description 16
• 230000002265 prevention Effects 0.000 claims abstract description 14
• 108091006146 Channels Proteins 0.000 claims abstract description 12
• 230000001154 acute effect Effects 0.000 claims abstract description 6
• 208000027520 Somatoform disease Diseases 0.000 claims abstract description 3
• 208000027753 pain disease Diseases 0.000 claims abstract description 3
• 125000000217 alkyl group Chemical group 0.000 claims description 777
• 125000001424 substituent group Chemical group 0.000 claims description 304
• 229910052739 hydrogen Inorganic materials 0.000 claims description 290
• 239000001257 hydrogen Substances 0.000 claims description 262
• 229910052736 halogen Inorganic materials 0.000 claims description 199
• 150000002367 halogens Chemical class 0.000 claims description 199
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 198
• ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 177
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 163
• 125000003342 alkenyl group Chemical group 0.000 claims description 125
• 208000002193 Pain Diseases 0.000 claims description 105
• 125000000304 alkynyl group Chemical group 0.000 claims description 90
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 89
• 230000036407 pain Effects 0.000 claims description 87
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 81
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 79
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 75
• 229910052805 deuterium Inorganic materials 0.000 claims description 75
• 150000002431 hydrogen Chemical class 0.000 claims description 74
• 125000003118 aryl group Chemical group 0.000 claims description 73
• 125000001072 heteroaryl group Chemical group 0.000 claims description 72
• 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 62
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 42
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 40
• 125000004432 carbon atom Chemical group C* 0.000 claims description 38
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 35
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 30
• 150000002148 esters Chemical class 0.000 claims description 30
• 229920006395 saturated elastomer Polymers 0.000 claims description 26
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
• RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 24
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 24
• PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 23
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 23
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 22
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 21
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 21
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 20
• 208000004296 neuralgia Diseases 0.000 claims description 20
• 208000021722 neuropathic pain Diseases 0.000 claims description 17
• 229940079593 drug Drugs 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 13
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 13
• 208000005298 acute pain Diseases 0.000 claims description 12
• DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 12
• MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 claims description 11
• GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 claims description 11
• JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical compound C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 claims description 11
• LPCWKMYWISGVSK-UHFFFAOYSA-N bicyclo[3.2.1]octane Chemical compound C1C2CCC1CCC2 LPCWKMYWISGVSK-UHFFFAOYSA-N 0.000 claims description 11
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
• FYGUBWKMMCWIKB-UHFFFAOYSA-N spiro[2.3]hexane Chemical compound C1CC11CCC1 FYGUBWKMMCWIKB-UHFFFAOYSA-N 0.000 claims description 11
• FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 claims description 11
• LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 claims description 11
• 125000005024 alkenyl aryl group Chemical group 0.000 claims description 10
• 125000005025 alkynylaryl group Chemical group 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• OGNAOIGAPPSUMG-UHFFFAOYSA-N spiro[2.2]pentane Chemical compound C1CC11CC1 OGNAOIGAPPSUMG-UHFFFAOYSA-N 0.000 claims description 10
• 238000006467 substitution reaction Methods 0.000 claims description 10
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
• 125000005217 alkenylheteroaryl group Chemical group 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 230000007803 itching Effects 0.000 claims description 9
• 239000001301 oxygen Substances 0.000 claims description 9
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 8
• 206010065390 Inflammatory pain Diseases 0.000 claims description 7
• 150000001345 alkine derivatives Chemical class 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 7
• 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 6
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 5
• 241000124008 Mammalia Species 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
• 125000002355 alkine group Chemical group 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
• 230000037429 base substitution Effects 0.000 claims description 3
• 238000002360 preparation method Methods 0.000 claims description 3
• 241000009298 Trigla lyra Species 0.000 claims 6
• 150000001336 alkenes Chemical class 0.000 claims 2
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 2
• 125000002009 alkene group Chemical group 0.000 claims 1
• 208000035475 disorder Diseases 0.000 abstract description 40
• 230000001404 mediated effect Effects 0.000 abstract description 22
• 230000001629 suppression Effects 0.000 abstract description 2
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 149
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
• 238000004808 supercritical fluid chromatography Methods 0.000 description 102
• 239000006184 cosolvent Substances 0.000 description 95
• 239000000203 mixture Substances 0.000 description 92
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
• 102000018674 Sodium Channels Human genes 0.000 description 50
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• 230000002829 reductive effect Effects 0.000 description 48
• 239000011734 sodium Substances 0.000 description 46
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 44
• 239000002585 base Substances 0.000 description 44
• 239000000460 chlorine Substances 0.000 description 40
• 239000000243 solution Substances 0.000 description 40
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
• 235000019439 ethyl acetate Nutrition 0.000 description 36
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
• 238000005160 1H NMR spectroscopy Methods 0.000 description 30
• 238000000034 method Methods 0.000 description 30
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 29
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• 239000012044 organic layer Substances 0.000 description 27
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• 238000010828 elution Methods 0.000 description 25
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 25
• 239000007832 Na2SO4 Substances 0.000 description 24
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
• 238000006243 chemical reaction Methods 0.000 description 24
• 229910052801 chlorine Inorganic materials 0.000 description 24
• 229910052731 fluorine Inorganic materials 0.000 description 24
• 229910052938 sodium sulfate Inorganic materials 0.000 description 24
• 235000011152 sodium sulphate Nutrition 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
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