TW201000446A - New compounds useful in pain therapy - Google Patents

New compounds useful in pain therapy Download PDF

Info

Publication number: TW201000446A
Authority: TW; Taiwan
Prior art keywords: compound; group; trifluoromethoxy; doc; alkyl
Prior art date: 2008-05-30

Application number

TW098117487A

Other languages

English (en)

Chinese (zh)

Inventor

Yevgeni Besidski

Alf Claesson

Istvan Macsari

Gabor Csjernyik

Linda I Nilsson

Original Assignee

Astrazeneca Ab

Priority date (The priority date 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 date listed.)

2008-05-30

Filing date

2009-05-26

Publication date

2010-01-01

2009-05-26 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2010-01-01 Publication of TW201000446A publication Critical patent/TW201000446A/zh

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 194
208000002193 Pain Diseases 0.000 title claims abstract description 58
230000036407 pain Effects 0.000 title claims abstract description 48
238000002560 therapeutic procedure Methods 0.000 title claims abstract description 6
-1 C1-3alkl Chemical group 0.000 claims abstract description 78
239000001257 hydrogen Substances 0.000 claims abstract description 21
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
150000003839 salts Chemical class 0.000 claims abstract description 21
125000001153 fluoro group Chemical group F* 0.000 claims abstract description 14
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 12
125000005843 halogen group Chemical group 0.000 claims abstract description 12
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
125000003118 aryl group Chemical group 0.000 claims abstract description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
125000001424 substituent group Chemical group 0.000 claims abstract description 6
150000002431 hydrogen Chemical group 0.000 claims abstract 7
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 2
238000000034 method Methods 0.000 claims description 69
125000000217 alkyl group Chemical group 0.000 claims description 47
OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 28
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
238000011282 treatment Methods 0.000 claims description 26
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
125000003545 alkoxy group Chemical group 0.000 claims description 21
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
VKYTVITWNRXGGT-UHFFFAOYSA-N 2,3-dihydro-1h-isoindole-1-carboxamide Chemical compound C1=CC=C2C(C(=O)N)NCC2=C1 VKYTVITWNRXGGT-UHFFFAOYSA-N 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 10
239000007789 gas Substances 0.000 claims description 9
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 7
150000001412 amines Chemical class 0.000 claims description 7
125000000753 cycloalkyl group Chemical group 0.000 claims description 7
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
238000004519 manufacturing process Methods 0.000 claims description 6
239000000126 substance Substances 0.000 claims description 6
125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 5
125000006612 decyloxy group Chemical group 0.000 claims description 5
125000001041 indolyl group Chemical group 0.000 claims description 5
125000004438 haloalkoxy group Chemical group 0.000 claims description 4
125000001188 haloalkyl group Chemical group 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
239000008194 pharmaceutical composition Substances 0.000 claims description 4
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 3
125000002393 azetidinyl group Chemical group 0.000 claims description 3
125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
150000002148 esters Chemical class 0.000 claims description 3
125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 3
239000001301 oxygen Substances 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
150000003254 radicals Chemical group 0.000 claims description 3
QUERMGFVJPRMJL-UHFFFAOYSA-N tert-butyl azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1 QUERMGFVJPRMJL-UHFFFAOYSA-N 0.000 claims description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
DBGROTRFYBSUTR-UHFFFAOYSA-N [4-(trifluoromethoxy)phenyl]methanamine Chemical compound NCC1=CC=C(OC(F)(F)F)C=C1 DBGROTRFYBSUTR-UHFFFAOYSA-N 0.000 claims description 2
229930013930 alkaloid Natural products 0.000 claims description 2
150000003797 alkaloid derivatives Chemical class 0.000 claims description 2
229940037003 alum Drugs 0.000 claims description 2
125000001246 bromo group Chemical group Br* 0.000 claims description 2
125000001309 chloro group Chemical group Cl* 0.000 claims description 2
125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
MQUPWTBHHPUUMC-UHFFFAOYSA-N isoindole Chemical compound C1=CC=C[C]2C=NC=C21 MQUPWTBHHPUUMC-UHFFFAOYSA-N 0.000 claims description 2
229930182817 methionine Natural products 0.000 claims description 2
125000002757 morpholinyl group Chemical group 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
230000000144 pharmacologic effect Effects 0.000 claims description 2
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
239000000779 smoke Substances 0.000 claims description 2
125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
150000002923 oximes Chemical class 0.000 claims 2
125000006327 phenyl hydrazinyl group Chemical group [H]N(*)N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
YFKBXYGUSOXJGS-UHFFFAOYSA-N 1,3-Diphenyl-2-propanone Chemical compound C=1C=CC=CC=1CC(=O)CC1=CC=CC=C1 YFKBXYGUSOXJGS-UHFFFAOYSA-N 0.000 claims 1
GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 claims 1
RMCJQIKTPCGANQ-UHFFFAOYSA-N 2,3-dihydro-1H-isoindole-1-thiol Chemical compound C1(S)NCC2=C1C=CC=C2 RMCJQIKTPCGANQ-UHFFFAOYSA-N 0.000 claims 1
JPTNNRZYEUGJMX-UHFFFAOYSA-N 2h-quinoxaline-1-carboxamide Chemical compound C1=CC=C2N(C(=O)N)CC=NC2=C1 JPTNNRZYEUGJMX-UHFFFAOYSA-N 0.000 claims 1
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
GUNJVIDCYZYFGV-UHFFFAOYSA-K Antimony trifluoride Inorganic materials F[Sb](F)F GUNJVIDCYZYFGV-UHFFFAOYSA-K 0.000 claims 1
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
239000007983 Tris buffer Substances 0.000 claims 1
125000006307 alkoxy benzyl group Chemical group 0.000 claims 1
KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 claims 1
CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 claims 1
229960005286 carbaryl Drugs 0.000 claims 1
CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical group C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims 1
229910052736 halogen Inorganic materials 0.000 claims 1
150000002367 halogens Chemical class 0.000 claims 1
230000001939 inductive effect Effects 0.000 claims 1
150000002576 ketones Chemical class 0.000 claims 1
WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 claims 1
229960000485 methotrexate Drugs 0.000 claims 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims 1
229940067157 phenylhydrazine Drugs 0.000 claims 1
125000003386 piperidinyl group Chemical group 0.000 claims 1
IZUZIVIUDTZPFE-UHFFFAOYSA-N tert-butyl decanoate Chemical compound CCCCCCCCCC(=O)OC(C)(C)C IZUZIVIUDTZPFE-UHFFFAOYSA-N 0.000 claims 1
RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 claims 1
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract description 4
125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 5
125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 3
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 abstract 2
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 abstract 1
CCXDPQMZEYVPIN-UHFFFAOYSA-N 2-(cyclohexylmethyl)-3-oxo-n-[[2-(trifluoromethyl)phenyl]methyl]-1h-isoindole-1-carboxamide Chemical compound FC(F)(F)C1=CC=CC=C1CNC(=O)C1C2=CC=CC=C2C(=O)N1CC1CCCCC1 CCXDPQMZEYVPIN-UHFFFAOYSA-N 0.000 abstract 1
125000004043 oxo group Chemical group O=* 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 130
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 78
238000005481 NMR spectroscopy Methods 0.000 description 66
235000019439 ethyl acetate Nutrition 0.000 description 60
101150041968 CDC13 gene Proteins 0.000 description 42
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
239000007787 solid Substances 0.000 description 40
239000000203 mixture Substances 0.000 description 34
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
239000003643 water by type Substances 0.000 description 29
210000004027 cell Anatomy 0.000 description 27
239000000543 intermediate Substances 0.000 description 26
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
239000000243 solution Substances 0.000 description 21
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 13
108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 13
239000011541 reaction mixture Substances 0.000 description 13
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
239000012071 phase Substances 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 12
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 11
239000000523 sample Substances 0.000 description 11
238000000926 separation method Methods 0.000 description 11
238000006243 chemical reaction Methods 0.000 description 10
208000004296 neuralgia Diseases 0.000 description 10
239000000047 product Substances 0.000 description 10
208000004550 Postoperative Pain Diseases 0.000 description 9
239000000872 buffer Substances 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
239000002904 solvent Substances 0.000 description 9
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
208000008930 Low Back Pain Diseases 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
239000012267 brine Substances 0.000 description 8
MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 8
238000002360 preparation method Methods 0.000 description 8
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
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108091006146 Channels Proteins 0.000 description 7
102000018674 Sodium Channels Human genes 0.000 description 7
108010052164 Sodium Channels Proteins 0.000 description 7
235000019257 ammonium acetate Nutrition 0.000 description 7
229940043376 ammonium acetate Drugs 0.000 description 7
239000012043 crude product Substances 0.000 description 7
OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 7
239000012044 organic layer Substances 0.000 description 7
230000002829 reductive effect Effects 0.000 description 7
238000003786 synthesis reaction Methods 0.000 description 7
LWJQGKJCZOGGPJ-UHFFFAOYSA-N 2-methylsulfanylbenzoic acid Chemical class CSC1=CC=CC=C1C(O)=O LWJQGKJCZOGGPJ-UHFFFAOYSA-N 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
230000000202 analgesic effect Effects 0.000 description 6
238000003556 assay Methods 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
230000001684 chronic effect Effects 0.000 description 6
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238000004128 high performance liquid chromatography Methods 0.000 description 6
230000000302 ischemic effect Effects 0.000 description 6
238000000746 purification Methods 0.000 description 6
GQHWSLKNULCZGI-UHFFFAOYSA-N trifluoromethoxybenzene Chemical compound FC(F)(F)OC1=CC=CC=C1 GQHWSLKNULCZGI-UHFFFAOYSA-N 0.000 description 6
238000004293 19F NMR spectroscopy Methods 0.000 description 5
MQOFXVWAFFJFJH-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-amine Chemical compound NC1CCC(F)(F)CC1 MQOFXVWAFFJFJH-UHFFFAOYSA-N 0.000 description 5
206010058019 Cancer Pain Diseases 0.000 description 5
208000000094 Chronic Pain Diseases 0.000 description 5
206010028980 Neoplasm Diseases 0.000 description 5
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238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 5
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RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
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125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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125000000623 heterocyclic group Chemical group 0.000 description 4
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
238000002347 injection Methods 0.000 description 4
239000007924 injection Substances 0.000 description 4
150000002500 ions Chemical class 0.000 description 4
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
239000003589 local anesthetic agent Substances 0.000 description 4
229910052943 magnesium sulfate Inorganic materials 0.000 description 4
206010027599 migraine Diseases 0.000 description 4
BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
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238000012360 testing method Methods 0.000 description 4
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
230000008673 vomiting Effects 0.000 description 4
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SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
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CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
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SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
229960002715 nicotine Drugs 0.000 description 1
239000002840 nitric oxide donor Substances 0.000 description 1
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
125000004433 nitrogen atom Chemical group N* 0.000 description 1
210000000929 nociceptor Anatomy 0.000 description 1
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
239000002674 ointment Substances 0.000 description 1
238000011275 oncology therapy Methods 0.000 description 1
229940005483 opioid analgesics Drugs 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
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125000002971 oxazolyl group Chemical group 0.000 description 1
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238000012402 patch clamp technique Methods 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
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239000003016 pheromone Substances 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
102000054765 polymorphisms of proteins Human genes 0.000 description 1
229920001296 polysiloxane Polymers 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
108010083945 potassium channel protein TREK-1 Proteins 0.000 description 1
229910001414 potassium ion Inorganic materials 0.000 description 1
239000000843 powder Substances 0.000 description 1
AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
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238000002953 preparative HPLC Methods 0.000 description 1
238000004237 preparative chromatography Methods 0.000 description 1
230000008569 process Effects 0.000 description 1
WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
239000003586 protic polar solvent Substances 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000004076 pyridyl group Chemical group 0.000 description 1
238000011552 rat model Methods 0.000 description 1
230000008929 regeneration Effects 0.000 description 1
238000011069 regeneration method Methods 0.000 description 1
BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
239000013557 residual solvent Substances 0.000 description 1
230000000241 respiratory effect Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
230000002441 reversible effect Effects 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000002795 scorpion venom Substances 0.000 description 1
238000012216 screening Methods 0.000 description 1
DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
230000008313 sensitization Effects 0.000 description 1
230000001953 sensory effect Effects 0.000 description 1
210000001044 sensory neuron Anatomy 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
241000894007 species Species 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
210000000278 spinal cord Anatomy 0.000 description 1
230000008925 spontaneous activity Effects 0.000 description 1
239000007858 starting material Substances 0.000 description 1
230000003637 steroidlike Effects 0.000 description 1
150000003432 sterols Chemical class 0.000 description 1
235000003702 sterols Nutrition 0.000 description 1
229960002317 succinimide Drugs 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
238000004808 supercritical fluid chromatography Methods 0.000 description 1
239000000829 suppository Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
230000008961 swelling Effects 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
239000003104 tissue culture media Substances 0.000 description 1
229960004394 topiramate Drugs 0.000 description 1
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230000001988 toxicity Effects 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
230000001052 transient effect Effects 0.000 description 1
230000007704 transition Effects 0.000 description 1
230000008733 trauma Effects 0.000 description 1
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
230000003827 upregulation Effects 0.000 description 1
230000002485 urinary effect Effects 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
FVECELJHCSPHKY-JLSHOZRYSA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-JLSHOZRYSA-N 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1
238000005406 washing Methods 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Engineering & Computer Science (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Pain & Pain Management (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Indole Compounds (AREA)

TW098117487A 2008-05-30 2009-05-26 New compounds useful in pain therapy TW201000446A (en)

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US5731008P	2008-05-30	2008-05-30

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AR (1)	AR071954A1 (es)
CL (1)	CL2009001328A1 (es)
PE (1)	PE20100052A1 (es)
TW (1)	TW201000446A (es)
UY (1)	UY31854A (es)
WO (1)	WO2009145721A1 (es)

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US8278302B2 (en) *	2009-04-08	2012-10-02	Boehringer Ingelheim International Gmbh	Substituted piperidines as CCR3 antagonists
UA109290C2 (uk)	2010-10-07	2015-08-10		Спільні кристали і солі інгібіторів ccr3
WO2012053186A1 (en)	2010-10-18	2012-04-26	Raqualia Pharma Inc.	Arylamide derivatives as ttx-s blockers
AR090566A1 (es)	2012-04-02	2014-11-19	Boehringer Ingelheim Int	Proceso para la produccion de inhibidores de crr
US10213421B2 (en)	2012-04-04	2019-02-26	Alkahest, Inc.	Pharmaceutical formulations comprising CCR3 antagonists
US11046683B2 (en)	2016-12-15	2021-06-29	Ono Pharmaceutical Co., Ltd.	Activator of TREK (TWIK RElated K+ channels) channels
EP3851436B1 (en)	2018-09-10	2024-06-12	Kaken Pharmaceutical Co., Ltd.	Novel heteroaromatic amide derivative and medicine containing same

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US6995144B2 (en) *	2002-03-14	2006-02-07	Eisai Co., Ltd.	Nitrogen containing heterocyclic compounds and medicines containing the same
TW200613272A (en) *	2004-08-13	2006-05-01	Astrazeneca Ab	Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
GB0514017D0 (en) *	2005-07-07	2005-08-17	Ionix Pharmaceuticals Ltd	Chemical compounds
JP2009542803A (ja) *	2006-07-12	2009-12-03	アストラゼネカ・アクチエボラーグ	鎮痛剤としての３−オキソイソインドリン−１−カルボキサミド誘導体
TW200812962A (en) *	2006-07-12	2008-03-16	Astrazeneca Ab	New compounds I/418
GB0705882D0 (en) *	2007-03-27	2007-05-02	Glaxo Group Ltd	Novel compounds

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AR071954A1 (es)	2010-07-28
WO2009145721A1 (en)	2009-12-03
CL2009001328A1 (es)	2010-01-15
PE20100052A1 (es)	2010-02-20
UY31854A (es)	2010-01-05

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