JP6337124B2 - インダゾール及びその使用 - Google Patents
インダゾール及びその使用 Download PDFInfo
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- JP6337124B2 JP6337124B2 JP2016542142A JP2016542142A JP6337124B2 JP 6337124 B2 JP6337124 B2 JP 6337124B2 JP 2016542142 A JP2016542142 A JP 2016542142A JP 2016542142 A JP2016542142 A JP 2016542142A JP 6337124 B2 JP6337124 B2 JP 6337124B2
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- alkyl
- hydrogen
- pharmaceutically acceptable
- solvate
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- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 252
- 125000000217 alkyl group Chemical group 0.000 claims description 181
- 208000002193 Pain Diseases 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 78
- 239000001257 hydrogen Substances 0.000 claims description 77
- 239000012453 solvate Substances 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 66
- 230000036407 pain Effects 0.000 claims description 52
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 36
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 33
- 102000018674 Sodium Channels Human genes 0.000 claims description 29
- 108010052164 Sodium Channels Proteins 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 241000124008 Mammalia Species 0.000 claims description 26
- 208000035475 disorder Diseases 0.000 claims description 25
- 208000004296 neuralgia Diseases 0.000 claims description 25
- 208000021722 neuropathic pain Diseases 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
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- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
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- 125000001424 substituent group Chemical group 0.000 claims description 15
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- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 8
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- URRGQBSBELLHGF-INIZCTEOSA-N 2-[4-(1-methylindazol-4-yl)oxyphenyl]-6-[[(3S)-2-oxopyrrolidin-3-yl]amino]pyrimidine-4-carboxamide Chemical compound CN1N=CC2=C(C=CC=C12)OC1=CC=C(C=C1)C1=NC(=CC(=N1)C(=O)N)N[C@@H]1C(NCC1)=O URRGQBSBELLHGF-INIZCTEOSA-N 0.000 claims description 2
- HRZLCFGXAYYNML-QGZVFWFLSA-N 2-[4-(7-chloro-1-methylindazol-4-yl)oxyphenyl]-6-[(1s)-1,2-dihydroxyethyl]pyrimidine-4-carboxamide Chemical compound C1=CC(Cl)=C2N(C)N=CC2=C1OC(C=C1)=CC=C1C1=NC([C@H](O)CO)=CC(C(N)=O)=N1 HRZLCFGXAYYNML-QGZVFWFLSA-N 0.000 claims description 2
- NSDUARUSUDGMIH-UHFFFAOYSA-N 2-[4-(7-chloro-1-methylindazol-4-yl)oxyphenyl]pyrimidine-4-carboxamide Chemical compound ClC=1C=CC(=C2C=NN(C12)C)OC1=CC=C(C=C1)C1=NC=CC(=N1)C(=O)N NSDUARUSUDGMIH-UHFFFAOYSA-N 0.000 claims description 2
- VTIAGXARPPOPKJ-INIZCTEOSA-N 2-[4-(7-fluoro-1-methylindazol-4-yl)oxyphenyl]-6-[[(3S)-2-oxopyrrolidin-3-yl]amino]pyrimidine-4-carboxamide Chemical compound FC=1C=CC(=C2C=NN(C12)C)OC1=CC=C(C=C1)C1=NC(=CC(=N1)C(=O)N)N[C@@H]1C(NCC1)=O VTIAGXARPPOPKJ-INIZCTEOSA-N 0.000 claims description 2
- ZAVQNBXALRKXSF-LJQANCHMSA-N 4-[(1S)-1,2-dihydroxyethyl]-6-[4-(7-fluoro-1-methylindazol-4-yl)oxyphenyl]pyridine-2-carboxamide Chemical compound O[C@H](CO)C1=CC(=NC(=C1)C1=CC=C(C=C1)OC1=C2C=NN(C2=C(C=C1)F)C)C(=O)N ZAVQNBXALRKXSF-LJQANCHMSA-N 0.000 claims description 2
- RNYUPAUELLXBGU-UHFFFAOYSA-N 5-chloro-4-(7-chloro-1-methylindazol-4-yl)oxy-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide Chemical compound ClC=1C(=CC(=C(C1)S(=O)(=O)NC=1SC=NN1)F)OC1=C2C=NN(C2=C(C=C1)Cl)C RNYUPAUELLXBGU-UHFFFAOYSA-N 0.000 claims description 2
- GWTHXKOJXICFOE-LJQANCHMSA-N 6-[4-(7-chloro-1-methylindazol-4-yl)oxyphenyl]-4-[(1S)-1,2-dihydroxyethyl]pyridine-2-carboxamide Chemical compound ClC=1C=CC(=C2C=NN(C12)C)OC1=CC=C(C=C1)C1=CC(=CC(=N1)C(=O)N)[C@@H](CO)O GWTHXKOJXICFOE-LJQANCHMSA-N 0.000 claims description 2
- CGTMTIZYRLWLLB-UHFFFAOYSA-N 6-[4-(7-chloro-1-methylindazol-4-yl)oxyphenyl]pyridine-2-carboxamide Chemical compound ClC=1C=CC(=C2C=NN(C12)C)OC1=CC=C(C=C1)C1=CC=CC(=N1)C(=O)N CGTMTIZYRLWLLB-UHFFFAOYSA-N 0.000 claims description 2
- RAWUCHYNMJXRKB-NSHDSACASA-N 6-[[(2S)-1-amino-1-oxopropan-2-yl]amino]-2-[4-(7-fluoro-1-methylindazol-4-yl)oxyphenyl]pyrimidine-4-carboxamide Chemical compound NC([C@H](C)NC1=CC(=NC(=N1)C1=CC=C(C=C1)OC1=C2C=NN(C2=C(C=C1)F)C)C(=O)N)=O RAWUCHYNMJXRKB-NSHDSACASA-N 0.000 claims description 2
- 101000654386 Homo sapiens Sodium channel protein type 9 subunit alpha Proteins 0.000 claims description 2
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- JZZVMTJSEVRXQA-INIZCTEOSA-N 2-[4-(7-chloro-1-methylindazol-4-yl)oxyphenyl]-6-[[(3S)-2-oxopyrrolidin-3-yl]amino]pyrimidine-4-carboxamide Chemical compound ClC=1C=CC(=C2C=NN(C12)C)OC1=CC=C(C=C1)C1=NC(=CC(=N1)C(=O)N)N[C@@H]1C(NCC1)=O JZZVMTJSEVRXQA-INIZCTEOSA-N 0.000 claims 1
- ZAVQNBXALRKXSF-IBGZPJMESA-N 4-[(1R)-1,2-dihydroxyethyl]-6-[4-(7-fluoro-1-methylindazol-4-yl)oxyphenyl]pyridine-2-carboxamide Chemical compound O[C@@H](CO)C1=CC(=NC(=C1)C1=CC=C(C=C1)OC1=C2C=NN(C2=C(C=C1)F)C)C(=O)N ZAVQNBXALRKXSF-IBGZPJMESA-N 0.000 claims 1
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- -1 ureido, guanidino, carboxy Chemical group 0.000 description 76
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- 239000000203 mixture Substances 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
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- 125000006233 propoxy propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 238000007665 sagging Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940125794 sodium channel blocker Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000273 spinal nerve root Anatomy 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003463 sulfur Chemical group 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000030401 vitamin deficiency disease Diseases 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
- 150000003953 γ-lactams Chemical group 0.000 description 1
- 150000003954 δ-lactams Chemical group 0.000 description 1
- 150000003955 ε-lactams Chemical class 0.000 description 1
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
- C07D403/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- 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
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
式中、
Z1、Z2、及びZ3はそれぞれ独立にN及びCR11からなる群より選択され、
但し、Z1、Z2、及びZ3の少なくとも1はNであり、
Gはシアノ、ジヒドロキシアルキル及び−(CHR1a)m−C(=O)Eからなる群より選択され、
mは0、1、または2であり、
各R1aは独立に水素及びヒドロキシからなる群より選択され、
Eはヒドロキシ、アルコキシ、ヒドロキシアルキル、及び−NR1R2からなる群より選択され、
R1は水素、アルキル、アラルキル、(ヘテロシクロ)アルキル、(ヘテロアリール)アルキル、(アミノ)アルキル、(アルキルアミノ)アルキル、(ジアルキルアミノ)アルキル、(カルボキサミド)アルキル、(シアノ)アルキル、アルコキシアルキル、ヒドロキシアルキル、及びヘテロアルキルからなる群より選択され、
R2は水素及びアルキルからなる群より選択されるか、または
R1及びR2が、R1及びR2が結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R3は水素、アルキル、ヒドロキシアルキル、アミノアルキル、(アルキルアミノ)アルキル、及び(カルボキサミド)アルキルからなる群より選択され、
R4は水素、アルキル、ハロゲン、シアノ、ハロアルキル、ハロアルコキシ、アルコキシ、(アミノ)アルキル、(ヘテロシクロ)アルキル、(ヘテロシクロ)カルボニル、カルボキサミド、スルホンアミド、ヒドロキシアルキル、カルボキシ、及び任意選択で置換されたヘテロアリールからなる群より選択され、
R5は水素、ハロ、アルキル、ヒドロキシアルキル、アルケニル、シアノ、ヘテロシクロ、及び−X−R7からなる群より選択され、
R6は水素、ハロゲン、アルキル、ハロアルキル、及びシアノからなる群から選択され、
Xは−O−、−NR8a−、及び−(CH2)t−Y−からなる群より選択され、
Yは−O−及び−NR8b−からなる群より選択され、
tは1または2であり、
R7は水素、アルキル、ヒドロキシアルキル、
R8aは水素及びアルキルからなる群より選択され、
R8bは水素及びアルキルからなる群より選択されるか、または
R8b及びR7が、R8b及びR7が結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R9は水素、アルキル、及びヒドロキシアルキルからなる群より選択され、
R10a及びR10bは独立に水素及びアルキルからなる群より選択されるか、または
R10a及びR10bが、R10a及びR10bが結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R11は水素、アルキル、ハロゲン、シアノ、ハロアルキル、ハロアルコキシ、及びアルコキシからなる群より選択される、
上記化合物並びに上記それらの塩及び溶媒和物である。
式中、
Wは結合、−S(O)2N(Ra)−、−N(Ra)−、または−C(O)N(Ra)−であり、
Ar1は任意選択で置換された5員ヘテロアリールまたは
Raは水素またはアルキルであり、
nは0、1、2、3、または4であり、
Z1、Z2、及びZ3はそれぞれ独立にN及びCR11からなる群より選択され、
但し、Z1、Z2、及びZ3の少なくとも1はNであり、
Gはシアノ、ジヒドロキシアルキル及び−(CHR1a)m−C(=O)Eからなる群より選択され、
mは0、1、または2であり、
各R1aは独立に水素及びヒドロキシからなる群より選択され、
Eはヒドロキシ、アルコキシ、ヒドロキシアルキル、及び−NR1R2からなる群より選択され、
R1は水素、アルキル、アラルキル、(ヘテロシクロ)アルキル、(ヘテロアリール)アルキル、(アミノ)アルキル、(アルキルアミノ)アルキル、(ジアルキルアミノ)アルキル、(カルボキサミド)アルキル、(シアノ)アルキル、アルコキシアルキル、ヒドロキシアルキル、及びヘテロアルキルからなる群より選択され、
R2は水素及びアルキルからなる群より選択されるか、または
R1及びR2が、R1及びR2が結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R3は水素、アルキル、ヒドロキシアルキル、アミノアルキル、(アルキルアミノ)アルキル、及び(カルボキサミド)アルキルからなる群より選択され、
R4は水素、アルキル、ハロゲン、シアノ、ハロアルキル、ハロアルコキシ、アルコキシ、(アミノ)アルキル、(ヘテロシクロ)アルキル、(ヘテロシクロ)カルボニル、カルボキサミド、スルホンアミド、ヒドロキシアルキル、カルボキシ、及び任意選択で置換されたヘテロアリールからなる群より選択され、
R5は水素、ハロ、アルキル、ヒドロキシアルキル、アルケニル、シアノ、ヘテロシクロ、及び−X−R7からなる群より選択され、
R6は水素、ハロゲン、アルキル、ハロアルキル、及びシアノからなる群から選択され、
Xは−O−、−NR8a−、及び−(CH2)t−Y−からなる群より選択され、
Yは−O−及び−NR8b−からなる群より選択され、
tは1または2であり、
R7は水素、アルキル、ヒドロキシアルキル、
R8aは水素及びアルキルからなる群より選択され、
R8bは水素及びアルキルからなる群より選択されるか、または
R8b及びR7が、R8b及びR7が結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R9は水素、アルキル、及びヒドロキシアルキルからなる群より選択され、
R10a及びR10bは独立に水素及びアルキルからなる群より選択されるか、または
R10a及びR10bが、R10a及びR10bが結合している窒素原子と共に3〜8員の、任意選択で置換されたヘテロシクロを形成し、
R11は水素、アルキル、ハロゲン、シアノ、ハロアルキル、ハロアルコキシ、及びアルコキシからなる群より選択される、
上記化合物または上記それらの塩若しくは溶媒和物を提供する。
式IまたはIAの化合物は、本開示を考慮すると、従来の有機合成方法を用いて、または概括的スキーム1〜4に示す、例証となる方法によって調製することができる。
本開示の化合物を、ナトリウムチャネル遮断薬活性に関して、ナトリウム流動アッセイ及び/または電気生理学的アッセイによって評価した。本開示の一態様は、本開示の化合物のナトリウムチャネル遮断薬としての使用に基づく。この特性に基づいて、本開示の化合物は、ナトリウムイオンチャネルの遮断に対して応答性である疾病又は障害、例えば、卒中、頭部外傷に起因する神経損傷、てんかん、痙攣、熱性痙攣を伴う全身性てんかん、重症乳児ミオクロニーてんかん、全体的及び限局的虚血に続くニューロン欠損、偏頭痛、家族性原発性先端紅痛症、発作性激痛症、小脳萎縮、運動失調、ジストニア、振戦、精神遅滞、自閉症、神経変性障害(例えば、アルツハイマー病、筋萎縮性側索硬化症(ALS)、若しくはパーキンソン病)、躁うつ病、耳鳴り、ミオトニア、運動障害、心不整脈の治療、または局所麻酔の提供において有用であると考えられる。本開示の化合物はまた、例えば、急性疼痛;神経因性疼痛、術後疼痛、及び炎症性疼痛を始めとする、但しこれらに限定されない慢性疼痛;または術後疼痛などの疼痛の治療に有効であることも期待される。
FLIPR(登録商標)アッセイ
組換えNav1.7細胞株:ヒトNav1.7のα−サブユニット(Nav1.7、SCN9a、PN1、NE)をコードするcDNA(アクセッション番号NM_002977)を発現する組換え細胞株において、イン・ビトロアッセイを実施した。当該細胞株は、エール大学の研究者(Cumminsら、J.Neurosci. 18(23):9607〜9619(1998))によって提供された。Nav1.7発現クローンの優占選択のために、発現プラスミドは、ネオマイシン耐性遺伝子を共発現した。当該細胞株は、CMV主要後期プロモータの影響下で、ヒト胚性腎臓細胞株HEK293において構築し、限界希釈クローニング及びネオマイシン類似体G418を用いた抗生物質選別を用いて、安定なクローンを選別した。組換えβ−及びγ−サブユニットは、この細胞株に導入しなかった。他の種よりクローニングされた組換えNav1.7を発現する更なる細胞株もまた、単独で、または種々のβ−サブユニット、γ−サブユニット若しくはシャペロンと組み合わせて用いることができる。
3)最後に、180mMのKCl溶液(2倍濃縮液)を、2Mの原液をアッセイ緩衝液中で希釈することによって調製し、該溶液を100μL/ウェルにて上記細胞に添加する。細胞を37℃、暗所で30〜60分間インキュベートした後、それらの蛍光を測定する。
細胞 手動電気生理学:hNav1.7発現HEK−293細胞を、ポリ−D−リジンで予めコーティングした35mm培養皿上に、標準的なDMEM培地(メディアテック社、バージニア州ハーンドン)中でプレートし、5%CO2インキュベーター中、37℃でインキュベートする。培養した細胞はプレーティング後概略12〜48時間後に使用する。
Ki=[薬剤]*{FR/(1−FR)} 数式1
式中、[薬剤]は薬剤の濃度であり、
FR=I(薬剤後)/I(比較対照) 数式2
式中、Iはピーク電流の大きさである。多重の濃度を用いる場合には、Kiは、対応する薬剤の濃度に対してプロットしたFRに対するロジスティック方程式の当て嵌めにより決定される。
Kr=[薬剤]*{FR/(1−FR)} 数式3
式中、[薬剤]は薬剤の濃度であり、
FR=I(薬剤後)/I(比較対照) 数式2
式中、Iはピーク電流の大きさであり、休止遮断解離定数Krの推定に用いる。
h=I@Vh2/Imax 数式4
Kapp=[薬剤]*{FR/(1−FR)} 数式5
式中、[薬剤]は薬剤の濃度である。
Ki=(1−h)/((1/Kapp)−(h/Kr)) 数式6
本開示の化合物は、Hunskaarら、J.Neurosci.Methods 14:69〜76(1985)に記載されるように、それらの抗侵害受容活性について、ホルマリンモデルにおいて試験することができる。雄のスイス−ウェブスターNIHマウス(20〜30g、ハーラン社、カリフォルニア州サンディエゴ)を全ての実験に使用することができる。実験日には食餌を中止する。マウスを少なくとも1時間プレキシガラスのビンに入れておき、環境に順化させる。上記順化期間に続いて、マウスを体重測定し、これらに腹腔内投与若しくは経口投与による対象化合物または、比較対照としての、然るべき量のビヒクル(例えば、10% Tween−80または0.9% 生理食塩水、及び他の薬学的に許容されるビヒクル)を与える。腹腔内投与の15分後、及び経口投与の30分後に、マウスに右後足の背側面からホルマリン(20μLの5%ホルムアルデヒドの生理食塩水溶液)を注射する。マウスをプレキシガラスのビンに移し、注射をした足を舐めるまたは噛む動作に費やす時間を監視する。ホルマリン注射後1時間、舐める及び噛む動作の時間を5分間隔で記録する。全ての実験を、明周期の間に盲検法で行う。
試験動物:各実験は、実験開始時に200〜260gの間の体重のラットを使用する。上記ラットは群で飼育し、被験化合物の経口投与の前の、投与の前16時間の間餌を撤去する場合以外は、常に餌及び水を自由に摂れるようにする。比較対照群は、本開示の化合物を用いて処理したラットとの比較としての役割を果たす。上記比較対照群には、試験化合物に使用する担体を投与する。比較対照群に投与する担体の容量は、試験群に投与する担体及び試験化合物の容量と同一である。
マウスまたはラットにおいて、静脈内注射、経口投与、または腹腔内注射後に、最大電気ショック発作試験(MES)を始めとする多くの抗痙攣試験のいずれかを用いて、本開示の化合物を、イン・ビボ抗痙攣活性に関して試験することができる。体重15〜20gの間の雄のNSAマウス及び体重200〜225gの間の雄のスプラーグ−ドリーラットにおいて、Ugo Basile ECT装置(モデル7801)を用いて、電流(マウスに対して:50mA、60パルス/秒、パルス幅 0.8ミリ秒、継続時間 1秒、直流;ラットに対して:99mA、125パルス/秒、パルス幅 0.8ミリ秒、継続時間 2秒、直流)の印加により、最大電気ショック発作を誘発させる。マウスは、その背側面のたるんだ皮膚を把持することにより拘束し、生理食塩水を塗布した角膜電極を2つの角膜に対して軽く保持する。ラットは、実験台上で自由に行動させ、耳電極を用いる。電流を印加し、動物を、強直性後肢伸筋反応の発生に関して最大30秒間観察する。強直痙攣は、体の面から90度を超える後肢伸長として定義する。結果は素量的に扱うことができる。
本開示の化合物は、如何なる他の成分も存在しない、そのままの化学物質の形態で哺乳動物に対して投与することができる。本開示の化合物はまた、適宜の薬学的に許容される担体と組み合わされた当該化合物を含有する医薬組成物の一部として、哺乳動物に対して投与することもできる。かかる担体は、薬学的に許容される賦形剤及び助剤より選択することができる。
(実施例1)
7−クロロ−1−メチル−4−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェノキシ)−1H−インダゾール(化合物11)の合成
1−メチル−4−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェノキシ)−1H−インダゾール(化合物12):LC/MS:m/z=351[M+H]+(計算値:350)、及び
7−フルオロ−1−メチル−4−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェノキシ)−1H−インダゾール(化合物13):LC/MS:m/z=369[M+H]+(計算値:368)。
(S)−6−((1−アミノ−1−オキソプロパン−2−イル)アミノ)−2−クロロピリミジン−4−カルボキサミド(化合物18)の合成
(S)−2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド(化合物20)の合成
2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピリミジン−4−カルボキサミド(化合物21):1H NMR(400MHz,DMSO−d6):δ 9.11(d,J=5.1Hz,1H),8.65−8.72(m,2H),8.63(br s,1H),7.99(m,2H),7.89(d,J=4.8Hz,1H),7.44(d,J=8.1Hz,1H),7.21−7.29(m,2H),6.68(d,J=8.1Hz,1H),4.35(s,3H)。LC/MS:m/z=380[M+H]+(計算値:379)、
6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド(化合物22):1H NMR(400MHz,CD3OD):δ 8.30−8.37(m,1H),8.17−8.24(m,2H),8.02−8.09(m,2H),7.79(s,1H),7.31(d,J=8.1Hz,1H),7.16−7.22(m,2H),6.61(d,J=8.1Hz,1H),4.30(s,3H)。LC/MS:m/z=379[M+H]+(計算値:378)、
4−クロロ−6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリノニトリル(化合物23):LC/MS:m/z=395[M+H]+(計算値:394)、
(S)−6−((1−アミノ−1−オキソプロパン−2−イル)アミノ)−2−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピリミジン−4−カルボキサミド(化合物24):1H NMR(400MHz,CD3OD):δ: 8.26(m,2H),7.78(d,J=2.0Hz,1H),7.40(s,1H),7.16−7.25(m,3H),6.80(dd,J=8.4,2.9Hz,1H),4.84(q,J=7.0Hz,1H),4.25(s,3H),1.63(d,J=7.3Hz,3H)。LC/MS:m/z=450[M+H]+(計算値:449)、
(S)−2−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド(化合物25):1H NMR(400MHz,CD3OD):δ: 8.20(m,2H),7.76(d,J=2.2Hz,1H),7.33(s,1H),7.18−7.23(m,2H),7.13−7.17(m,1H),6.78(dd,J=8.4,2.9Hz,1H),5.13(t,J=9.6Hz,1H),4.23(s,3H),3.45−3.52(m,2H),2.60−2.71(m,1H),2.28−2.42(m,1H)。LC/MS:m/z=462[M+H]+(計算値:461)、及び
(S)−2−(4−((1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド(化合物26):1H NMR(400MHz,CD3OD):δ 8.25(m,2H),7.90(s,1H),7.47−7.57(m,2H),7.35(s, 1H),7.27(d,J=8.8Hz,2H),6.84−6.91(m,1H),5.16(t,J=9.6Hz,1H),4.14(s,3H),3.48−3.54(m,2H),2.62−2.73(m,1H),2.30−2.43(m,1H)。LC/MS:m/z=444[M+H]+(計算値:443)。
メチル2−クロロ−6−ビニルピリミジン−4−カルボキシレート(化合物29)の合成
6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−4−ビニルピコリノニトリル(化合物30):LC/MS:m/z=387[M+H]+(計算値:386)、及び
6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−4−ビニルピコリノニトリル(化合物31):LC/MS:m/z=371[M+H]+(計算値:370)。
2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−ビニルピリミジン−4−カルボキサミド(化合物33)の合成
(S)−2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−(1,2−ジヒドロキシエチル)ピリミジン−4−カルボキサミド(化合物34)の合成
(R)−4−(1,2−ジヒドロキシエチル)−6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリノニトリル(化合物36):LC/MS:m/z=405[M+H]+(計算値:404)、及び
(S)−6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−4−(1,2−ジヒドロキシエチル)ピコリノニトリル(化合物37):LC/MS:m/z=421[M+H]+(計算値:420)。
(S)−6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−4−(1,2−ジヒドロキシエチル)ピコリンアミド(化合物38)の合成
(S)−4−(1,2−ジヒドロキシエチル)−6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド(化合物39):1H NMR(400MHz,CD3OD):δ 8.20−8.26(m,2H),8.10(m,2H),7.82(d,J=2.0Hz,1H),7.16−7.21(m,2H),7.10(dd,J=11.6,8.3Hz,1H),6.64(dd,J=8.4,2.9Hz,1H),4.84−4.87(m,1H),4.25(s,3H),3.69−3.80(m,2H)。LC/MS:m/z=423[M+H]+(計算値:422)、及び
(R)−4−(1,2−ジヒドロキシエチル)−6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド(化合物40):1H NMR(400MHz,CD3OD):δ 8.20−8.26(m,2H),8.10(m,2H),7.82(d,J=2.0Hz,1H),7.16−7.21(m,2H),7.10(dd,J=11.6,8.3Hz,1H),6.64(dd,J=8.4,2.9Hz,1H),4.84−4.87(m,1H),4.25(s,3H),3.69−3.80(m,2H)。LC/MS:m/z=423[M+H]+(計算値:422)。
実施例1〜7において記載した合成手順及び上記概括的スキームに示した手順と同様の方法で、以下の化合物も調製した:
5−クロロ−4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)−2−フルオロ−N−(1,3,4−チアジアゾール−2−イル)ベンゼンスルホンアミド(化合物41):1H NMR(DMSO−d6):δ 14.60(br s,1H),8.83(s,1H),8.08(s,1H),7.99(d,J=7.1Hz,1H),7.42(d,J=8.1Hz,1H),7.23(d,J=10.6Hz,1H),6.70(d,J=8.1Hz,1H),4.34(s,3H)。LC/MS:m/z=474[M+H]+(計算値:473)。
4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)−N−(1,3,4−チアジアゾール−2−イル)ベンゼンスルホンアミド(化合物42):m/z=422.0[M+H]+(計算値:421.0)。
代表的な本開示の化合物を、詳細に上述した、ナトリウムチャネル遮断活性に関するFLIPR(登録商標)若しくはFLIPRTETRA(登録商標)アッセイ及び/またはEPアッセイにおいて試験した。
Claims (26)
- 式I
Z1、Z2、及びZ3はそれぞれ独立にN及びCR11からなる群より選択され、
但し、Z1、Z2、及びZ3の一つがNであり、
Gはシアノ、ジヒドロキシアルキル及び−(CHR1a)m−C(=O)Eからなる群より選択され、
mは0、1、若しくは2であり、
各R1aは水素であり、
Eはヒドロキシ、アルコキシ、及び−NR1R2からなる群より選択され、
R1は水素及びアルキルからなる群より選択され、
R2は水素及びアルキルからなる群より選択され、
R3は水素及びアルキルからなる群より選択され、
R4は水素、アルキル、ハロゲン、シアノ、及びハロアルキルからなる群より選択され、
R5は水素、ハロ、アルキル、ヒドロキシアルキル、及びアルケニルからなる群より選択され、
R6は水素であり、
R11は水素である。)
を有する化合物あるいは薬学的に許容されるその塩または溶媒和物。 - 式I’
Z1、Z2、及びZ3はそれぞれ独立にN及びCR11からなる群より選択され、
但し、Z1、Z2、及びZ3の少なくとも二つがNであり、
Gはシアノ、ジヒドロキシアルキル及び−(CHR1a)m−C(=O)Eからなる群より選択され、
mは0、1、若しくは2であり、
各R1aは水素であり、
Eはヒドロキシ、アルコキシ、及び−NR1R2からなる群より選択され、
R1は水素及びアルキルからなる群より選択され、
R2は水素及びアルキルからなる群より選択され、
R3は水素及びアルキルからなる群より選択され、
R4は水素、アルキル、ハロゲン、シアノ、及びハロアルキルからなる群より選択され、
R5aは水素、ハロ、アルキル、ヒドロキシアルキル、アルケニル、及び−X−R7からなる群より選択され、
R6は水素であり、
Xは−NR8a−であり、
R7は水素、アルキル、
R8aは水素であり、
R9は水素及びアルキルからなる群より選択され、
R10a及びR10bは独立に水素及びアルキルからなる群より選択され、
R11は水素である。)
を有する化合物あるいは薬学的に許容されるその塩または溶媒和物。 - Gがジヒドロキシアルキルである、請求項1または2に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- Gが−(CHR1a)m−C(=O)Eであり、
mが0である
請求項1または2に記載の化合物、あるいは薬学的に許容されるその塩または溶媒和物。 - 式II
を有する、請求項1に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。 - 式II’
を有する、請求項2に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。 - Z2がN及びCHからなる群より選択され、
R4が水素、ハロゲン、アルキル、及びハロアルキルからなる群より選択される、
請求項5または6に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。 - Z2がCHである、請求項1〜7のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- Eが−NR1R2であり、R1及びR2が水素である、請求項1、2及び4〜8のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- R5aが水素、ヒドロキシアルキル、及び−X−R7からなる群より選択される、請求項2または6に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- R5aが
- R5aが−X−R7である、請求項10に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- R7が
- R3が(C1〜C3)アルキルである、請求項1〜13のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- R4が水素、フルオロ、及びクロロからなる群より選択される、請求項1〜14のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
- 式IA
Wは−S(O)2N(Ra)−であり、
Ar1は任意選択で置換された5員ヘテロアリールであり、
Raは水素若しくはアルキルであり、
nは0、1、2、3、若しくは4であり、
R3は水素及びアルキルからなる群より選択され、
R4は水素、アルキル、ハロゲン、シアノ、及びハロアルキルからなる群より選択され、
R6は水素、ハロゲン、アルキル、ハロアルキル、及びシアノからなる群から選択され、
前記ヘテロアリール基は、チエニル、フリル、イミダゾリル、チアゾリル、イソチアゾリル、及びイソキサゾリルからなる群より選択され、かつ、
前記ヘテロアリール基は、無置換であるか、またはハロ、シアノ、ハロアルキル、アルキル、及び(シアノ)アルキルより独立に選択される、1〜4の置換基により置換されているかのいずれかである。)
を有する化合物あるいは薬学的に許容されるその塩または溶媒和物。 - Ar1が無置換の5員ヘテロアリールである、請求項16に記載の化合物あるいは薬学的に許容されるその塩または溶媒和物。
- RaがHである、請求項16または17に記載の化合物あるいは薬学的に許容されるその塩または溶媒和物。
- R6が水素またはハロゲンである、請求項16〜18のいずれか1項に記載の化合物あるいは薬学的に許容されるその塩または溶媒和物。
- nが0、1、または2である、請求項16〜19のいずれか1項に記載の化合物あるいは薬学的に許容されるその塩または溶媒和物。
- (S)−2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド、
2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピリミジン−4−カルボキサミド、
6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド、
(S)−6−((1−アミノ−1−オキソプロパン−2−イル)アミノ)−2−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピリミジン−4−カルボキサミド、
(S)−2−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド、
(S)−2−(4−((1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−((2−オキソピロリジン−3−イル)アミノ)ピリミジン−4−カルボキサミド、
(S)−2−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−6−(1,2−ジヒドロキシエチル)ピリミジン−4−カルボキサミド、
(S)−6−(4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)−4−(1,2−ジヒドロキシエチル)ピコリンアミド、
(S)−4−(1,2−ジヒドロキシエチル)−6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド、
(R)−4−(1,2−ジヒドロキシエチル)−6−(4−((7−フルオロ−1−メチル−1H−インダゾール−4−イル)オキシ)フェニル)ピコリンアミド
5−クロロ−4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)−2−フルオロ−N−(1,3,4−チアジアゾール−2−イル)ベンゼンスルホンアミド、及び
4−((7−クロロ−1−メチル−1H−インダゾール−4−イル)オキシ)−N−(1,3,4−チアジアゾール−2−イル)ベンゼンスルホンアミド
からなる群より選択される化合物、または薬学的に許容されるその塩若しくは溶媒和物。 - 請求項1〜21のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物、及び薬学的に許容される担体を含む医薬組成物。
- 哺乳動物における疾病若しくは障害を治療する、または哺乳動物における局所麻酔を提供するための薬剤の製造における、請求項1〜21のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物の使用であって、前記疾病若しくは障害が疼痛である、前記使用。
- 前記疼痛が、慢性疼痛、炎症性疼痛、神経因性疼痛、急性疼痛、及び術後疼痛からなる群より選択される、請求項23に記載の使用。
- イン・ビトロでの、細胞におけるナトリウムチャネルの調節方法であって、前記細胞に、少なくとも1種の、請求項1〜21のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物を接触させることを含み、Nav1.7ナトリウムチャネルが調節される、前記方法。
- 3H、11C、または14Cで放射標識された、請求項1〜21のいずれか1項に記載の化合物、または薬学的に許容されるその塩若しくは溶媒和物。
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