JP6143877B2 - 2−アリールセレナゾール化合物及びその薬剤組成物 - Google Patents
2−アリールセレナゾール化合物及びその薬剤組成物 Download PDFInfo
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- JP6143877B2 JP6143877B2 JP2015544335A JP2015544335A JP6143877B2 JP 6143877 B2 JP6143877 B2 JP 6143877B2 JP 2015544335 A JP2015544335 A JP 2015544335A JP 2015544335 A JP2015544335 A JP 2015544335A JP 6143877 B2 JP6143877 B2 JP 6143877B2
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- JP
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- Prior art keywords
- methyl
- selenazole
- formic acid
- cyano
- group
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 title claims description 72
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 114
- -1 R b is H Chemical group 0.000 claims description 44
- 201000005569 Gout Diseases 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- FICQFRCPSFCFBY-UHFFFAOYSA-N 2-[bis(methylsulfanyl)methylidene]propanedinitrile Chemical compound CSC(SC)=C(C#N)C#N FICQFRCPSFCFBY-UHFFFAOYSA-N 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 24
- 239000003814 drug Substances 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 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 201000001431 Hyperuricemia Diseases 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000004193 piperazinyl group Chemical class 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 239000003064 xanthine oxidase inhibitor Substances 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 7
- VWRYHVIUYDSFOD-UHFFFAOYSA-N 2-(3-cyano-4-naphthalen-1-ylphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C1=CC=C(C=2C3=CC=CC=C3C=CC=2)C(C#N)=C1 VWRYHVIUYDSFOD-UHFFFAOYSA-N 0.000 claims description 7
- ZEOSJTLLZKNHCC-UHFFFAOYSA-N 2-(3-cyano-4-propan-2-yloxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 ZEOSJTLLZKNHCC-UHFFFAOYSA-N 0.000 claims description 7
- JXWZPOXVTBYQLO-UHFFFAOYSA-N 2-(3-cyano-4-propan-2-ylsulfanylphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(SC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 JXWZPOXVTBYQLO-UHFFFAOYSA-N 0.000 claims description 7
- TVBIEBOKMSVPMT-UHFFFAOYSA-N 2-(6-cyano-1-pyridin-4-ylcyclohexa-2,4-dien-1-yl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound CC1=C([Se]C(=N1)C2(C=CC=CC2C#N)C3=CC=NC=C3)C(=O)O TVBIEBOKMSVPMT-UHFFFAOYSA-N 0.000 claims description 7
- VGMHPKSVFAHOHY-UHFFFAOYSA-N 2-[3-cyano-4-(3-methylbutoxy)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(OCCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 VGMHPKSVFAHOHY-UHFFFAOYSA-N 0.000 claims description 7
- HLFHKDUVCDXMNB-UHFFFAOYSA-N 2-[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1CN(C)CCN1C1=CC=C(C=2[se]C(=C(C)N=2)C(O)=O)C=C1C#N HLFHKDUVCDXMNB-UHFFFAOYSA-N 0.000 claims description 7
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- GYLQJSKRAQHYCO-UHFFFAOYSA-N 2-[3-cyano-4-(dimethylamino)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(N(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 GYLQJSKRAQHYCO-UHFFFAOYSA-N 0.000 claims description 6
- AWHNUHMUCGRKRA-UHFFFAOYSA-N benzylsulfonylmethylbenzene Chemical group C=1C=CC=CC=1CS(=O)(=O)CC1=CC=CC=C1 AWHNUHMUCGRKRA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- AIVRMJQFXVTQFW-UHFFFAOYSA-N 2-(3-cyano-4-ethoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(OCC)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 AIVRMJQFXVTQFW-UHFFFAOYSA-N 0.000 claims description 5
- LFAFXFBGJIKZDF-UHFFFAOYSA-N 2-(3-cyano-4-pyridin-2-ylsulfanylphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1C#N)=CC=C1SC1=CC=CC=N1 LFAFXFBGJIKZDF-UHFFFAOYSA-N 0.000 claims description 5
- ISFYDGWZVFOSLF-UHFFFAOYSA-N 2-(4-benzylsulfanyl-3-cyanophenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1C#N)=CC=C1SCC1=CC=CC=C1 ISFYDGWZVFOSLF-UHFFFAOYSA-N 0.000 claims description 5
- OIWASTVUDYNHDQ-UHFFFAOYSA-N 2-(6-cyano-1-pyridin-3-ylcyclohexa-2,4-dien-1-yl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C(#N)C1C=CC=CC1(C=1C=NC=CC=1)C=1[Se]C(=C(N=1)C)C(=O)O OIWASTVUDYNHDQ-UHFFFAOYSA-N 0.000 claims description 5
- WJFJPFIOFQKRCF-UHFFFAOYSA-N 2-[3-cyano-4-(2-methylpropylsulfanyl)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(SCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 WJFJPFIOFQKRCF-UHFFFAOYSA-N 0.000 claims description 5
- UGFYBXZHOBOTIB-UHFFFAOYSA-N 2-[3-cyano-4-(cyclohexylmethoxy)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1C#N)=CC=C1OCC1CCCCC1 UGFYBXZHOBOTIB-UHFFFAOYSA-N 0.000 claims description 5
- OZQRSDCVZYGMMZ-UHFFFAOYSA-N 2-[3-cyano-4-(cyclopropylmethoxy)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1C#N)=CC=C1OCC1CC1 OZQRSDCVZYGMMZ-UHFFFAOYSA-N 0.000 claims description 5
- MFFJRDFTNYKHRZ-UHFFFAOYSA-N 4-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C1=CC=CC(C(F)(F)F)=C1 MFFJRDFTNYKHRZ-UHFFFAOYSA-N 0.000 claims description 5
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- XWQZGBSSSNZOIO-UHFFFAOYSA-N 2-(3-cyano-4-cyclohexylsulfanylphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C(#N)C=1C=C(C=CC1SC1CCCCC1)C=1[Se]C(=C(N1)C)C(=O)O XWQZGBSSSNZOIO-UHFFFAOYSA-N 0.000 claims description 4
- GBYPWHXCDNXFQE-UHFFFAOYSA-N 2-(4-tert-butylsulfanyl-3-cyanophenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C1=CC=C(SC(C)(C)C)C(C#N)=C1 GBYPWHXCDNXFQE-UHFFFAOYSA-N 0.000 claims description 4
- BHAKKGAABUFYHN-UHFFFAOYSA-N 2-[3-bromo-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(Br)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 BHAKKGAABUFYHN-UHFFFAOYSA-N 0.000 claims description 4
- VOAFBCREWROANP-UHFFFAOYSA-N 2-[3-bromo-4-(phenylcarbamoyl)phenyl]-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1Br)=CC=C1C(=O)NC1=CC=CC=C1 VOAFBCREWROANP-UHFFFAOYSA-N 0.000 claims description 4
- UVMPOFNVOXGNFV-UHFFFAOYSA-N 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-(hydroxymethyl)-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(CO)=C(C(O)=O)[se]1 UVMPOFNVOXGNFV-UHFFFAOYSA-N 0.000 claims description 4
- XXYPCAUGDJXHHD-UHFFFAOYSA-N 4-methyl-2-[4-(2-methylpropoxy)-3-(trifluoromethyl)phenyl]-1,3-selenazole-5-carboxylic acid Chemical compound C1=C(C(F)(F)F)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)[se]1 XXYPCAUGDJXHHD-UHFFFAOYSA-N 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- VWPQHAKPTFXZFI-UHFFFAOYSA-N 2-(3-cyano-4-phenylmethoxyphenyl)-4-methyl-1,3-selenazole-5-carboxylic acid Chemical compound [se]1C(C(O)=O)=C(C)N=C1C(C=C1C#N)=CC=C1OCC1=CC=CC=C1 VWPQHAKPTFXZFI-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical class CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 3
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 238000012360 testing method Methods 0.000 description 86
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 35
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 29
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000008048 phenylpyrazoles Chemical class 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000001739 rebound effect Effects 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- AUMHDRMJJNZTPB-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(O)=C1CCS(=O)C1=CC=CC=C1 AUMHDRMJJNZTPB-UHFFFAOYSA-N 0.000 description 1
- IWOKCMBOJXYDEE-UHFFFAOYSA-N sulfinylmethane Chemical compound C=S=O IWOKCMBOJXYDEE-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229950004176 topiroxostat Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/02—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms not condensed with other rings
- C07D293/04—Five-membered rings
- C07D293/06—Selenazoles; Hydrogenated selenazoles
-
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Xは、C1-2アルキル基又はC1-2置換アルキル基から選ばれたものであり、
Yは、-COORa又は-CONHRaから選ばれたものであり、
R1は、ハロゲン、-CN、C1-2アルキル基、C1-2置換アルキル基、C1-3アルコキシ基又はC1-3置換アルコキシ基から選ばれたものであり、
R2は、H、D、ハロゲン、C1-2アルキル基、C1-2置換アルキル基、C1-3アルコキシ基又はC1-3置換アルコキシ基から選ばれたものであり、
R3は、-(CH2)n-O-Rb、-(CH2)n-S-Rb、-C(O)Rb、-NRcRd、-S(O)CHRcRd、-S(O)2CHRcRd、-(CH2)nC(O)NRcRd、アリール基、置換アリール基、複素環基、置換複素環基、ヘテロアリール又は置換ヘテロアリールから選ばれたものであり、
nは0-2であり、
Raは、H、C1-6アルキル基又はC1-6置換アルキル基から選ばれたものであり、
Rbは、H、C1-8アルキル基、C1-8置換アルキル基、アリール基、置換アリール基、複素環基、置換複素環基、ヘテロアリール又は置換ヘテロアリールから選ばれたものであり、
RcとRdはそれぞれ独立に、H、C1-8アルキル基又はC1-8置換アルキル基から選ばれたものであり、又はRcとRdを環化してシクロアルキル基、置換シクロアルキル基、複素環基又は置換複素環基を形成し、
X、Y、R1、R2、R3、Ra、Rb、Rc又はRdでの置換基は、D、-OH、-CN、-NH2、アシル基、アミド基、ハロゲン、C1-4アルキル基、C1-4ハロアルキル基、C1-4重水素化アルキル基、C1-2アルコキシ基又はC1-2アルコキシ基の中の1種又は数種から選ばれたものである。
更に、 Xは、-CH3、-CH2CH3、-CH2OH又は-CF3である。
更に、R3は、-ORb、-SRb、-C(O)Rb、-NRcRd、-S(O)2CHRcRd、-C(O)NRcRd、フェニル、置換フェニル、ピリジル基、置換ピリジル基、ナフチル基、置換ナフチル基、キノリル基、置換キノリル基、フェニルチオ基、置換フェニルチオ基、フェノキシ、置換フェノキシ、ピリジルチオ基、モルホリノ、ピペラジニル基、置換ピペラジニル基又はテトラヒドロチオフェンピリジル基から選ばれたものである。
2-(3-シアノ-4-エトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロポキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-メチル-ブトキシ)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(シクロヘキシルメトキシ基)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(フェニルメトキシ)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(シクロプロピルメトキシ基)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4'-ジメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-フッ素-4'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4',5'-トリメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-トリフルオロメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-クロロジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4'-二フルオロジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2',3',4',5',6'-五重水素化ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2',4'-ジメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(1-ナフチル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-ピリジル)-ベンゼン-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-ピリジル)-ベンゼン-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-[2-シアノ-4'-(1,2-重水素化エチル)-ジフェニル-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-6-重水素化ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソブチルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-クロロベンゼンチオ)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-トリフルオロメチルフェニルチオ基)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(2-ピリジルチオ)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-ベンジルチオ-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルスルホン-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-モルホリノ-4-イル-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-メチルピペラジン-1-イル)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-{3-シアノ-4-(6,7-ジヒドロ--テトラヒドロ-チオフェン[3,2-c]ピリジル)-フェニル}-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-ジメチルアミノ-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-塩素-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-トリフルオロメチル-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(イソプロピル硫化メチル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-ブロモ-4-(アニリンホルミル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸
2-(2-シアノ-2'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸
2-(3-シアノ-4-イソブトキシフェニル)-4-ヒドロキシメチル-セレナゾール-5-ギ酸、
2-(3-ブロモ-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルチオフェニル)-4-メチル-セレナゾール-5-ギ酸-(2-N-アセチル)エチル、
2-(3-シアノ-4-tert-ブチルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-シクロヘキシルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-トリフルオロメチルフェニル)-4-メチル-セレナゾール-5-ギ酸。
キサンチン酸化酵素の活性阻害試験:
一、原理
キサンチン酸化酵素(Xanthine Oxidase、XO)、西洋ワサビペルオキシダーゼ(Horseradish Peroxidase、HRP)及びその基質の二重酵素カップリング反応でキサンチン酸化酵素の活性阻害を測定する。まず、キサンチン酸化酵素でヒポキサンチンを酸化してキサンチンと過酸化水素が発生し、更にキサンチンを酸化して尿酸と過酸化水素が発生する。そして、西洋ワサビペルオキシダーゼの触媒作用で過酸化水素が10-acetyl-3,7-dihydroxyphenoxazine(Ampliflu Red)と反応して強い蛍光化合物であるレゾルフィン(Resorufin)が発生し、蛍光マイクロプレートリーダーでレゾルフィンの蛍光強度を測定する場合、キサンチン酸化酵素の活性と比例する。
所定量の試験化合物と対照化合物フェブキソスタット(Febuxostat、北京聯本医薬化学技術有限公司の製品)をDMSO(国薬集団化学試薬有限公司の製品)に溶解する。96ウェルポリプロピレンプレート(Greiner Bio One製品)にDMSOで試験化合物2.5倍シリーズを希釈して200倍濃度の溶液を取得する。更に超純水に希釈して3倍濃度のシリーズの希釈溶液を取得する。
9 μLの反応溶液Aを取って、9 μLの試験化合物の3倍濃度シリーズの希釈溶液を96ウェルテストボード(Greiner Bio One製品)に混合し、プレートシェーカーに置いて、30℃に100 rpmで30分間混合する。更に9 μLの反応溶液Bを添加する。30℃で30分間の酵素反応を行う。マイクロプレートリーダー(Perkin Elmer Vitor X4)により励起光530 nmと発射光590 nm部の蛍光強度を測定する。キサンチン酸化酵素がないもので対照する蛍光強度は0%であり、試験化合物で対照する蛍光強度は100%であり、試験化合物と対照化合物であるフェブキソスタットの50%の阻害濃度(IC50)を計算する。
Claims (13)
- 式(I)で示す2-アリールセレナゾール化合物又はその薬学的に許容可能な塩:
Xは、C1-2アルキル基又はC1-2置換アルキル基から選ばれたものであり、
Yは、-COORa又は-CONHRaから選ばれたものであり、
R1は、ハロゲン、-CN、C1-2アルキル基、C1-2置換アルキル基、C1-3アルコキシ基又はC1-3置換アルコキシ基から選ばれたものであり、
R2は、存在しないか、D、ハロゲン、C1-2アルキル基、C1-2置換アルキル基、C1-3アルコキシ基又はC1-3置換アルコキシ基から選ばれたものであり、
R3は、-(CH2)n-O-Rb、-(CH2)n-S-Rb、-C(O)Rb、-NRcRd、-S(O)CHRcRd、-S(O)2CHRcRd、-(CH2)nC(O)NRcRd、アリール基、置換アリール基、複素環基、又は置換複素環基から選ばれたものであり、
nは0-2であり、
Raは、H、C1-6アルキル基又はC1-6置換アルキル基から選ばれたものであり、
Rbは、H、メチル、エチル、プロピル、2-プロピル、n-ブチル、t-ブチル、ペンチル、C1-8置換アルキル基、アリール基、置換アリール基、複素環基、置換複素環基、ヘテロアリール又は置換ヘテロアリールから選ばれたものであり、
RcとRdはそれぞれ独立に、H、C1-8アルキル基又はC1-8置換アルキル基から選ばれたものであり、又はRcとRdを環化してシクロアルキル基、置換シクロアルキル基、複素環基又は置換複素環基を形成し、
X、Y、R1、R2、R3、Ra、Rb、Rc又はRdでの置換基は、D、-OH、-CN、-NH2、アシル基、アミド基、ハロゲン、C1-4アルキル基、C1-4ハロアルキル基、C1-4重水素化アルキル基、C1-2アルコキシ基又はC1-2アルキルアミノ基の中の1種又は数種から選ばれたものである化合物。 - Xは、-CH3、-CH2CH3、-CH2OH又は-CF3である請求項1又は2に記載の化合物。
- RaはH、C1-3アルキル基又はC1-3置換アルキル基である請求項3に記載の化合物。
- R1は、ハロゲン、-CN、-CH3、-CH2CH3、-CHF2、-CF3、-OCHF2又は-OCF3から選ばれたものである請求項4に記載の化合物。
- R2は、存在しないか又はDから選ばれたものである請求項5に記載の化合物。
- R3は、-ORb、-SRb、-C(O)Rb、-NRcRd、-S(O)CHRcRd、-S(O)2CHRcRd、-C(O)NRcRd、フェニル、置換フェニル、ピリジル基、置換ピリジル基、ナフチル基、置換ナフチル基、フェノキシ、置換フェノキシ、フェニルチオ基、置換フェニルチオ基、モルホリノ、置換モルホリノ、N-エチルモルホリン、置換N-エチルモルホリン、ピペラジニル基、置換ピペラジニル基、テトラヒドロチオフェンピリジル基、ベンジルスルホン基又は置換ベンジルスルホン基から選ばれたものであり、
Rbはメチル、エチル、プロピル、2-プロピル、n-ブチル、t-ブチル、ペンチル、C1-8置換アルキル基、フェニル又は置換フェニルであり、Rc又はRdはそれぞれ独立には、H、C1-8アルキル基又はC1-8置換アルキル基から選ばれたものであり、又はRcとRdを環化してシクロアルキル基、置換シクロアルキル基、複素環基又は置換複素環基を形成し、
前記置換基は、D、-OH、-NH2、-CN、アシル基、ハロゲン、C1-4アルキル基、C1-4ハロアルキル基、C1-4重水素化アルキル基又はC1-2アルコキシ基中の中の1種又は数種から選ばれたものである請求項4、5、6又は7に記載の化合物。 - R3は、-ORb、-SRb、-C(O)Rb、-NRcRd、-S(O)2CHRcRd、-C(O)NRcRd、フェニル、置換フェニル、ピリジル基、置換ピリジル基、ナフチル基、置換ナフチル基、フェニルチオ基、置換フェニルチオ基、フェノキシ、置換フェノキシ、モルホリノ、ピペラジニル基、置換ピペラジニル基又はテトラヒドロチオフェンピリジル基から選ばれたものであり、
Rbはメチル、エチル、プロピル、2-プロピル、n-ブチル、t-ブチル、ペンチル、C1-8置換アルキル基、フェニル又は置換フェニルであり、Rc又はRdはそれぞれ独立には、H、C1-8アルキル基又はC1-8置換アルキル基から選ばれたものであり、又はRcとRdを環化してシクロアルキル基、置換シクロアルキル基、複素環基又は置換複素環基を形成し、
前記置換基は、D、-OH、-CN、-NH 2 、-F、-Cl、-Br、-CH3、-CH2CH3、-CHDCH2D、-CF3、-OCH3又は-OCH2CH3の中の1種又は数種から選ばれたものである請求項8に記載の化合物。 - 以下の化合物又はその薬学的に許容可能な塩:
2-(3-シアノ-4-エトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロポキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-メチル-ブトキシ)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(シクロヘキシルメトキシ基)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(フェニルメトキシ)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(シクロプロピルメトキシ基)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4'-ジメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-フッ素-4'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4',5'-トリメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-トリフルオロメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-クロロジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3',4'-二フルオロジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2',3',4',5',6'-五重水素化ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2'-メトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2',4'-ジメトキシジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(1-ナフチル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-ピリジル)-ベンゼン-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-ピリジル)-ベンゼン-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-[2-シアノ-4'-(1,2-重水素化エチル)-ジフェニル-4-イル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-6-重水素化ジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソブチルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-クロロベンゼンチオ)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(3-トリフルオロメチルフェニルチオ基)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(2-ピリジルチオ)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-ベンジルチオ-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルスルホン-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-モルホリノ-4-イル-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(4-メチルピペラジン-1-イル)フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-{3-シアノ-4-(6,7-ジヒドロ--テトラヒドロ-チオフェン[3,2-c]ピリジル)-フェニル}-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-ジメチルアミノ-フェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-塩素-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-トリフルオロメチル-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-[3-シアノ-4-(イソプロピル硫化メチル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-[3-ブロモ-4-(アニリンホルミル)-フェニル]-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-4'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-3'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(2-シアノ-2'-トリフルオロメチルジフェニル-4-イル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソブトキシフェニル)-4-ヒドロキシメチル-セレナゾール-5-ギ酸、
2-(3-ブロモ-4-イソブトキシフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-イソプロピルチオフェニル)-4-メチル-セレナゾール-5-ギ酸-(2-N-アセチル)エチル、
2-(3-シアノ-4-tert-ブチルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-シアノ-4-シクロヘキシルチオフェニル)-4-メチル-セレナゾール-5-ギ酸、
2-(3-トリフルオロメチルフェニル)-4-メチル-セレナゾール-5-ギ酸から選ばれたものである請求項1に記載の化合物。 - 請求項1に記載の任意の化合物又はその薬学的に許容可能な塩を活性成分とする薬剤組成物。
- キサンチン酸化酵素の阻害剤薬物を調製するための、請求項1に記載の化合物又はその薬学的に許容可能な塩の使用。
- 前記キサンチン酸化酵素の阻害剤薬物が高尿酸症、痛風、糖尿病性腎症、炎症性疾患又は神経系疾患を予防又は治療する薬物である請求項12に記載の使用。
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