TW201139406A - Voltage-gated sodium channel blockers - Google Patents

Info

Publication number

TW201139406A

TW201139406A TW100101047A TW100101047A TW201139406A TW 201139406 A TW201139406 A TW 201139406A TW 100101047 A TW100101047 A TW 100101047A TW 100101047 A TW100101047 A TW 100101047A TW 201139406 A TW201139406 A TW 201139406A

Authority

TW

Taiwan

Prior art keywords

phenyl

acid

ester

indolyl

oxy

Prior art date

2010-01-14

Links

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• 239000000664 voltage gated sodium channel blocking agent Substances 0.000 title claims abstract 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 237
• 238000000034 method Methods 0.000 claims abstract description 69
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
• 239000000543 intermediate Substances 0.000 claims abstract description 30
• 239000000539 dimer Substances 0.000 claims abstract description 20
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 230000000241 respiratory effect Effects 0.000 claims abstract description 19
• 208000023504 respiratory system disease Diseases 0.000 claims abstract description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 787
• -1 dimethylethyl Chemical group 0.000 claims description 688
• 125000001041 indolyl group Chemical group 0.000 claims description 328
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 308
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 282
• 239000011664 nicotinic acid Substances 0.000 claims description 273
• 229960003512 nicotinic acid Drugs 0.000 claims description 270
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 258
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 234
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 192
• 239000002253 acid Substances 0.000 claims description 183
• 125000000217 alkyl group Chemical group 0.000 claims description 163
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 149
• 150000002148 esters Chemical class 0.000 claims description 116
• PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 claims description 103
• 150000003839 salts Chemical class 0.000 claims description 94
• 125000001424 substituent group Chemical group 0.000 claims description 82
• 125000001072 heteroaryl group Chemical group 0.000 claims description 81
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 73
• 239000000203 mixture Substances 0.000 claims description 70
• 238000006243 chemical reaction Methods 0.000 claims description 64
• 239000007789 gas Substances 0.000 claims description 59
• 125000003118 aryl group Chemical group 0.000 claims description 58
• SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 57
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 49
• 239000003814 drug Substances 0.000 claims description 48
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 47
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 47
• 239000000052 vinegar Substances 0.000 claims description 47
• 235000021419 vinegar Nutrition 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 40
• 125000004076 pyridyl group Chemical group 0.000 claims description 39
• 206010011224 Cough Diseases 0.000 claims description 36
• 125000003545 alkoxy group Chemical group 0.000 claims description 35
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 35
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
• 150000001412 amines Chemical class 0.000 claims description 29
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 27
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 27
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
• 235000001968 nicotinic acid Nutrition 0.000 claims description 23
• 229910052760 oxygen Inorganic materials 0.000 claims description 23
• 239000001301 oxygen Substances 0.000 claims description 23
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 22
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 22
• GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 21
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 21
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
• 239000003795 chemical substances by application Substances 0.000 claims description 18
• 125000001544 thienyl group Chemical group 0.000 claims description 18
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 17
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 17
• 239000000460 chlorine Substances 0.000 claims description 17
• 125000004494 ethyl ester group Chemical group 0.000 claims description 17
• 125000002541 furyl group Chemical group 0.000 claims description 17
• 125000003386 piperidinyl group Chemical group 0.000 claims description 17
• 125000003277 amino group Chemical group 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 14
• PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 claims description 13
• 229910017711 NHRa Inorganic materials 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
• FBBHPHRBJLLIFM-UHFFFAOYSA-N pyridin-1-ium-1-carboxylate Chemical compound [O-]C(=O)[N+]1=CC=CC=C1 FBBHPHRBJLLIFM-UHFFFAOYSA-N 0.000 claims description 12
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 11
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
• 239000004305 biphenyl Substances 0.000 claims description 11
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 11
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
• 108010052164 Sodium Channels Proteins 0.000 claims description 10
• 102000018674 Sodium Channels Human genes 0.000 claims description 10
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
• OOGYVVYCCYJADG-UHFFFAOYSA-N acridine-1-carboxylic acid Chemical compound C1=CC=C2C=C3C(C(=O)O)=CC=CC3=NC2=C1 OOGYVVYCCYJADG-UHFFFAOYSA-N 0.000 claims description 10
• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
• 239000000126 substance Substances 0.000 claims description 10
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 125000003107 substituted aryl group Chemical group 0.000 claims description 9
• 229910052717 sulfur Inorganic materials 0.000 claims description 9
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• 125000006612 decyloxy group Chemical group 0.000 claims description 8
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 8
• HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 8
• 229940067157 phenylhydrazine Drugs 0.000 claims description 8
• 239000003195 sodium channel blocking agent Substances 0.000 claims description 8
• 150000003573 thiols Chemical class 0.000 claims description 8
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 7
• GTUYQJKGFYWMKR-UHFFFAOYSA-N CC(NN)S Chemical compound CC(NN)S GTUYQJKGFYWMKR-UHFFFAOYSA-N 0.000 claims description 7
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 7
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 7
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 7
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 239000011737 fluorine Substances 0.000 claims description 7
• 229910052731 fluorine Inorganic materials 0.000 claims description 7
• 125000000524 functional group Chemical group 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 210000004072 lung Anatomy 0.000 claims description 7
• 150000002923 oximes Chemical group 0.000 claims description 7
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
• 239000011734 sodium Substances 0.000 claims description 7
• 229940125794 sodium channel blocker Drugs 0.000 claims description 7
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 6
• IOKINIXDVQHKJP-UHFFFAOYSA-N 3-propan-2-ylpyridine-2-carboxylic acid Chemical compound CC(C)C1=CC=CN=C1C(O)=O IOKINIXDVQHKJP-UHFFFAOYSA-N 0.000 claims description 6
• 208000004852 Lung Injury Diseases 0.000 claims description 6
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
• 206010069363 Traumatic lung injury Diseases 0.000 claims description 6
• HEABMVBRFLKRDB-UHFFFAOYSA-N acridine-3-carboxylic acid Chemical compound C1=CC=CC2=NC3=CC(C(=O)O)=CC=C3C=C21 HEABMVBRFLKRDB-UHFFFAOYSA-N 0.000 claims description 6
• 208000006673 asthma Diseases 0.000 claims description 6
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