JP4769721B2 - 置換8−ヘテロアリールキサンチン - Google Patents
置換8−ヘテロアリールキサンチン Download PDFInfo
- Publication number
- JP4769721B2 JP4769721B2 JP2006524755A JP2006524755A JP4769721B2 JP 4769721 B2 JP4769721 B2 JP 4769721B2 JP 2006524755 A JP2006524755 A JP 2006524755A JP 2006524755 A JP2006524755 A JP 2006524755A JP 4769721 B2 JP4769721 B2 JP 4769721B2
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- JP
- Japan
- Prior art keywords
- alkyl
- aryl
- compound
- pyridyl
- xanthine
- 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.)
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- 150000001875 compounds Chemical class 0.000 claims description 194
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 193
- -1 pyrrolidyl Chemical group 0.000 claims description 184
- 229940075420 xanthine Drugs 0.000 claims description 100
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 98
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 86
- 239000001257 hydrogen Substances 0.000 claims description 84
- 229910052739 hydrogen Inorganic materials 0.000 claims description 84
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 48
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
- 150000002431 hydrogen Chemical group 0.000 claims description 37
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 32
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 30
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 28
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 25
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 230000000694 effects Effects 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000006413 ring segment Chemical group 0.000 claims description 13
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000005936 piperidyl group Chemical group 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 125000002785 azepinyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 8
- 229960005305 adenosine Drugs 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 8
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 208000024891 symptom Diseases 0.000 claims description 8
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 8
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 7
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000005592 polycycloalkyl group Polymers 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 206010012735 Diarrhoea Diseases 0.000 claims description 5
- 208000017442 Retinal disease Diseases 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 208000026935 allergic disease Diseases 0.000 claims description 4
- 230000008485 antagonism Effects 0.000 claims description 4
- 208000028867 ischemia Diseases 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
- 238000005481 NMR spectroscopy Methods 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 102000009346 Adenosine receptors Human genes 0.000 description 24
- 108050000203 Adenosine receptors Proteins 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 22
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 102000005962 receptors Human genes 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 0 Cc1nccc(*)c1 Chemical compound Cc1nccc(*)c1 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 8
- DFKVQPMXXSMIRH-UHFFFAOYSA-N 1,3-diethyl-8-(6-hydrazinylpyridin-3-yl)-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CC)C(=O)N(CC)C=2N=C1C1=CC=C(NN)N=C1 DFKVQPMXXSMIRH-UHFFFAOYSA-N 0.000 description 7
- LFXCYVITBNVTHL-UHFFFAOYSA-N 8-(6-chloropyridin-3-yl)-1,3-dipropyl-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1=CC=C(Cl)N=C1 LFXCYVITBNVTHL-UHFFFAOYSA-N 0.000 description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000007995 HEPES buffer Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229940125890 compound Ia Drugs 0.000 description 5
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- 238000007429 general method Methods 0.000 description 5
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- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 4
- 102000055025 Adenosine deaminases Human genes 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Natural products O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 125000005956 isoquinolyl group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 238000000159 protein binding assay Methods 0.000 description 4
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 125000005493 quinolyl group Chemical group 0.000 description 4
- 239000002287 radioligand Substances 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- 229960000278 theophylline Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- 125000001425 triazolyl group Chemical group 0.000 description 4
- FMEBIWNKYZUWFV-UHFFFAOYSA-N 6-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)N=C1 FMEBIWNKYZUWFV-UHFFFAOYSA-N 0.000 description 3
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- FFBDFADSZUINTG-UHFFFAOYSA-N DPCPX Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CCC)C=2N=C1C1CCCC1 FFBDFADSZUINTG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 3
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
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- RIRGCFBBHQEQQH-SSFGXONLSA-N (-)-n6-(2-phenylisopropyl)adenosine Chemical compound C([C@@H](C)NC=1C=2N=CN(C=2N=CN=1)[C@H]1[C@@H]([C@H](O)[C@@H](CO)O1)O)C1=CC=CC=C1 RIRGCFBBHQEQQH-SSFGXONLSA-N 0.000 description 2
- KYOSRONGDTVPDJ-NVQRDWNXSA-N (2r,3r,4s,5r)-2-(6-anilinopurin-9-yl)-5-(hydroxymethyl)-2-propan-2-yloxolane-3,4-diol Chemical compound C1=NC2=C(NC=3C=CC=CC=3)N=CN=C2N1[C@]1(C(C)C)O[C@H](CO)[C@@H](O)[C@H]1O KYOSRONGDTVPDJ-NVQRDWNXSA-N 0.000 description 2
- 125000004233 1,3-benzodiazepinyl group Chemical group N1C(=NC=CC2=C1C=CC=C2)* 0.000 description 2
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- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
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- 108010052968 leupeptin Proteins 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
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- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
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- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 230000005455 negative regulation of mast cell degranulation Effects 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-N sodium;2-[dodecanoyl(methyl)amino]acetic acid Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC(O)=O KSAVQLQVUXSOCR-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000003369 theophyllinelike Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960001479 tosylchloramide sodium Drugs 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P1/12—Antidiarrhoeals
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- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- 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
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Landscapes
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Transplantation (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本発明は、A2Bアデノシン受容体(AR)の選択的アンタゴニストである化合物および医薬組成物に関する。これらの化合物および組成物は医薬として有用である。
弱い非選択性アデノシンアンタゴニストであるアルキルキサンチンテオフィリン(下記化合物A)(Linden、J., et al., Cardiovascular Biology of Purines、eds. G. Burnstock, et al., 1998, pp 1-20参照)は、喘息の治療に治療上有用である。
Rは、水素、(C1−C5)アルキル、ハロ(C1−C8)アルキル、(C3−C5)アルケニル、または(C3−C5)アルキニルであり;
R1およびR2は独立に、水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C4−C10)複素環、(C4−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール,または(C5−C10)ヘテロアリール(C1−C8)アルキル−であり;
Xは、1つの窒素原子を有し、必要に応じて1、2または3個の非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)またはアミン−N(R9)−基が挿入された5〜10員のヘテロアリール環であり;
Zは、−OR3、−SR3、ハロ、−S(O)m−NR4R5、−NR4R5、または(C4−C10)複素環であり、この複素環は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C1−C8)アルキル、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
各Z1は独立に、(C1−C8)アルキル、(C2−C8)アルケニル、(C2−C8)アルキニル、−OR6、−SR6、ハロ、R6O(C1−C8)アルキル、R7R8N(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NR7R8、R7R8N(C1−C8)アルキル、−C(O)R6、−COOR6、および−C(O)NR7R8であり;
R3は、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−C(O)R6、または−C(O)NR7R8であり;
R4およびR5は、独立に水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C6−C18)ポリシクロアルキル、(C6−C18)ポリシクロアルキル(C1−C8)アルキル−、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、−NR7R8、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−(C2−C4−Y)q−(CH2)2−4−X1、−C(O)R6、−CO2R6、−C(O)NR7R8、または−S(O)2−NR7R8であるか、または、R4およびR5は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、さらに必要に応じてその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式−、二環式−または芳香環を形成し、その環は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
X1は、−OR6、−C(O)R6、−CO2R6,または−NR7R8であり;かつ、Yはオキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−であり;
このR1、R2、R3、R4およびR5基のアルキル、アルケニル、シクロアルキル、アルキニル、アリール、複素環またはヘテロアリール基は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1以上の置換基で置換されていてもよく;
R6は水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール、(C4−C10)ヘテロアリール(C1−C8)アルキル−であり;ここで、この複素環、ヘテロアリールまたはアリールは必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
R7、R8およびR9は独立に、水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール;−COORa、−C(O)Ra、または−C(O)NRbRcであり、この複素環、ヘテロアリールまたはアリールは必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;またはR7およびR8は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、必要に応じて、環は4〜8個の環原子を有し、さらに必要に応じてその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(Rb)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式−、二環式−または芳香環を形成し;
Raは、水素、または(C1−C6)アルキルであり;RbおよびRcは各々独立に水素、(C1−C6)アルキル、(C1−C6)アルコキシ、(C3−C8)シクロアルキル、(C1−C6)アルキルチオ、(C6−C10)アリール、(C6−C10)アリール(C1−C6)アルキル−、ヘテロアリール、またはヘテロアリール(C1−C6)アルキル−であるか;またはRbおよびRcはそれらが結合している窒素と一緒になって、ピロリジル、ピペリジル、ピペラジニル、アゼピニル、ジアゼピニル、モルホリニル、またはチオモルホリニル環を形成し;かつ
nは、0、1、2、3、4、5、6、7、または8であり;mは1、または2であり;qは1、2、3、または4である]。
「アリールアルキル」または「(C6−C10)アリール(C1−C8)アルキル−」は、式アリール(C1−C8)アルキル−を表し、ここで、アリールおよび(C1−C8)アルキルは本明細書で定義した通りである。
「a」および「an」は、特許請求の範囲を含む本明細書で用いる場合、特に断りのない限り、「少なくとも1つ」または「1以上」を意味する。
具体的なシクロアルキルアルキル基としては、シクロプロピルメチル、シクロブチルメチル、シクロプロピルエチル、シクロペンチルメチル、シクロヘキシルメチル、2−シクロペンチルエチル、および2−シクロヘキシルエチルである。
具体的なアリールアルキル基としては、ベンジルおよび2−フェニルエチルである。
具体的なハロアルキル基としては、ブロモエチル、クロロエチル、フルオロエチル、トリフルオロメチル、2,2,2−トリフルオロエチルまたは3−フルオロプロピルである。
もう1つのRの具体的な値としては、水素、メチル、エチル、−CH2−CH2−Cl、−CH2−CH2−Br、または−CH2−CH2−CH2−Fである。
R1の具体的な値としては、水素、(C1−C4)アルキル、(C3−C4)アルケニル、(C3−C4)アルキニル、フェニル、またはフェニル(C1−C4)アルキルである。
もう1つのR1の具体的な値としては、シクロプロピルまたはシクロプロピルメチルである。
もう1つのR1の具体的な値としては、エチル、n−プロピルまたはアリルである。
もう1つのR2の具体的な値としては、(C3−C6)シクロアルキルおよび(C3−C6)シクロアルキル(C1−C4)アルキル−である。
もう1つのR2の具体的な値としては、水素、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、n−ブチル、i−ブチル、フェニル、フェネチル、またはベンジルである。
もう1つのR2の具体的な値としては、エチル、n−プロピルまたはアリルである。
もう1つのZの具体的な値としては、−NR4R5である。
本発明は、下式Iの化合物、またはその医薬上許容される塩を提供する:
Rは水素、(C1−C5)アルキル、ハロ(C1−C8)アルキル、(C3−C5)アルケニル、または(C3−C5)アルキニルであり;
R1およびR2は独立に水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C4−C10)複素環、(C4−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール,または(C5−C10)ヘテロアリール(C1−C8)アルキル−であり;
Xは、1つの窒素原子を有し、必要に応じて1、2または3個の非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)またはアミン−N(R9)−基が挿入された5〜10員のヘテロアリール環であり;
Zは−OR3、−SR3、ハロ、−S(O)m−NR4R5、−NR4R5、または(C4−C10)複素環であり、この複素環は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C1−C8)アルキル、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
各Z1は独立に(C1−C8)アルキル、(C2−C8)アルケニル、(C2−C8)アルキニル、−OR6、−SR6、ハロ、R6O(C1−C8)アルキル、R7R8N(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NR7R8、R7R8N(C1−C8)アルキル、−C(O)R6、−COOR6、および−C(O)NR7R8であり;
R3は(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−C(O)R6、または−C(O)NR7R8であり;
R4およびR5は独立に水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C6−C18)ポリシクロアルキル、(C6−C18)ポリシクロアルキル(C1−C8)アルキル−、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、−NR7R8、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−(C2−C4−Y)q−(CH2)2−4−X1、−C(O)R6、−CO2R6、−C(O)NR7R8、または−S(O)2−NR7R8であるか、または、R4およびR5は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、さらに必要に応じてその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式−、二環式−または芳香環を形成し、その環は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
X1は−OR6、−C(O)R6、−CO2R6,または−NR7R8であり;かつ、Yはオキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−であり;
このR1、R2、R3、R4およびR5基のアルキル、アルケニル、シクロアルキル、アルキニル、アリール、複素環またはヘテロアリール基は必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1以上の置換基で置換されていてもよく;
R6は水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール、(C4−C10)ヘテロアリール(C1−C8)アルキル−であり;ここで、この複素環、ヘテロアリールまたはアリールは必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
R7、R8およびR9は独立に水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール;−COORa、−C(O)Ra、または−C(O)NRbRcであり、この複素環、ヘテロアリールまたはアリールは必要に応じて、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;またはR7およびR8は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、必要に応じて、環は4〜8個の環原子を有し、さらに必要に応じてその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(Rb)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式−、二環式−または芳香環を形成し;
Raは水素、または(C1−C6)アルキルであり;RbおよびRcは各々独立に水素、(C1−C6)アルキル、(C1−C6)アルコキシ、(C3−C8)シクロアルキル、(C1−C6)アルキルチオ、(C6−C10)アリール、(C6−C10)アリール(C1−C6)アルキル−、ヘテロアリール、またはヘテロアリール(C1−C6)アルキル−であるか;またはRbおよびRcはそれらが結合している窒素と一緒になって、ピロリジル、ピペリジル、ピペラジニル、アゼピニル、ジアゼピニル、モルホリニル、またはチオモルホリニル環を形成し;かつ
nは0、1、2、3、4、5、6、7、または8であり;mは1、または2であり;qは1、2、3、または4である]。
1,3−ジプロピル−8−(6−クロロ−3−ピリジル)キサンチン;
1−プロピル−3−プロパルギル−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(6−エチルアミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(6−(2−ヒドロキシエチル)アミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(4−アセチルピペラジニル)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(ベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(1−ピペリジニル)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−ピロリジニルピリド−3−イル)キサンチン;
1,3−ジプロピル−8−{6−[4−メチル(ペルヒドロ−1,4−ジアゼピン−1−イル)]−3−ピリジル}キサンチン;
1,3−ジプロピル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(4−メトキシベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(3−メチルピペリジノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(2−ヒドロキシプロピル)アミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(2,2−ジメトキシエチル)アミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(1−ヒドロキシ−2−プロピル)アミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−モルホリノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(6−ジメチルアミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[[6−(2−ヒドロキシエトキシ)エチルアミノ]−3−ピリジ]キサンチン;
1,3−ジプロピル−8−(6−ピペラジノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(2−ヒドロキシ−2−フェニルエチル)アミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(4−アミノメチルベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−フェニルアミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−シクロプロピルアミノ−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(6−ピリジルメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−(4−メチルピペラジノ)−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(3−ピリジルメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(2−メチルベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[2−(3,4−ジメトキシフェニル)エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[(N−プロピルカルバモイル)、メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(3−ペンチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(2,2−ジフェニルエチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[2−(1−エチルピロリジノメチルアミノ)]−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(3−メトキシベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[(N−フェニルカルバモイル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(フルフリルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[2−(4−メトキシフェニル)エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(2−メトキシベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(プロピルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(シクロペンチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−(シクロヘキシルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−7−エチル−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−7−(3−フルオロプロピル−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−7−メチル−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−7(2−ブロモエチル)−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(2−チオフェンメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[(N−(4−メトキシフェニルカルバモイル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[(N−(4−フルオロフェニルカルバモイル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−イソニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−メトキシカルボニルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−フェニルカルバモイル、N−(2−フェニルカルバモイルオキシエチル)アミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−{6−[4−(N−フェニルカルバモイル)]ピペラジノ−3−ピリジル}キサンチン;
1,3−ジプロピル−8−{6−[4−(N−イソニコチノイル)]ピペラジノ−3−ピリジル}キサンチン;
1−プロピル−3−(4−メトキシフェニル)エチル−8−(6−クロロ−3−ピリジル)キサンチン;
1−プロピル−3−(メトキシフェニルエチル)−8−(6−ピペラジノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−(4−ピリジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−{6−[4−(N−ニコチノイル)]ピペラジノ−3−ピリジル}キサンチン;
1,3−ジプロピル−8−[6−(ヘキサヒドロ−1,4−ジアゼピン−1−イル)−3−ピリジル]キサンチン;
1,3−ジエチル−8−(6−クロロ−3−ピリジル)キサンチン;
1,3−ジエチル−8−(6−ピペラジノ−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[(N−フェニルカルバモイル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−ニコチノイルエチルアミノ]−3−ピリジル)キサンチン;
1,3−ジエチル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−ニコチノイルシクロプロピルアミノ]−3−ピリジル)キサンチン;
1,3−ジシクロプロピルメチル−8−(6−メチルアミノピリジン−3−イル)キサンチン;
1−プロパルギル−3−メチル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
8−[6−(2,5−ジアザ−ビシクロ[2.2.2]オクト−2−イル)−ピリジン−3−イル}−1,3−ジプロピル−3,7−ジヒドロ−プリン−2,6−ジオン;
1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルエチルアミノ]−3−ピリジル)キサンチン;
1,3−ジアリル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1−シクロプロピルメチル−3−エチル−8−(6−メチルアミノピリジン−3−イル)キサンチン;
1,3−ジエチル−8−[6−(2−ピリジルメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(3−ピリジルメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(3−メトキシベンジルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[2−(3−ピリジル)−エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−[2−(3−ピリジル)−エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジプロピル−8−[6−[2−(2−ピリジル)−エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−[2−(2−ピリジル)−エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジエチル−8−(6−ピロリジニルピリド−3−イル)キサンチン;
1,3−ジエチル−8−[6−[2−(1−ピロリジニル)−エチルアミノ]−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(6−(2−メトキシエチル)アミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(6−(2−アセチルアミノエチル)アミノ−3−ピリジル)キサンチン;
1,3−ジエチル−8−(6−ブロモ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−{6−[4−(2−ピリジル)−ピペラジノ]−3−ピリジル}キサンチン;
1,3−ジエチル−8−{6−[4−(2−ピリジル)−ピペラジノ]−3−ピリジル}キサンチン;
1,3−ジエチル−8−[6−(トランス−2,5−ジメチルピペラジノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−{6−[4−(2−ピリミジニルl)−ピペラジノ]−3−ピリジル}キサンチン;
1,3−ジエチル−8−{6−[4−(2−ピリミジニルl)−ピペラジノ]−3−ピリジル}キサンチン;
1,3−ジエチル−8−(6−(2−メトキシエチル)アミノ−3−ピリジル)キサンチン;
1−プロパルギル、3−メチル−8−(6−ブロモ−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−ニコチノイル、N−(2−メトキシエチル)アミノ]−3−ピリジル)キサンチン;
1−プロパルギル、3−メチル−8−(6−(2−メトキシエチル)−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−イソニコチノイル、N−(2−メトキシエチル)アミノ]−3−ピリジル)キサンチン;
1−(5−(1,3−ジエチル−2,3,6,7−テトラヒドロ−2,6−ジオキソ−1H−プリン−8−イル)ピリジン−2−イル)−1−(2−メトキシエチル)−3−(ピリジン−4−イル)尿素;
1,3−ジメチル−8−(6−ブロモ−3−ピリジル)キサンチン;
1,3−ジメチル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1,3−ジメチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−ニコチノイル、N−(2−メトキシエチル)アミノ]−3−ピリジル)キサンチン;
1−プロパルギル、3−メチル−8−[6−[N−ニコチノイル、N−(2−メトキシエチル)アミノ]−3−ピリジル)キサンチン;
1−プロパルギル、3−メチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(2,6−ジクロロ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(2,6−ジメチルアミノ−3−ピリジル)キサンチン;
1,3−ジプロピル−8−(2,6−ジ(2−メトキシエチル)−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[2,6−ジ[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[2,6−ジ[N−ニコチノイル、N−メトキシエチル]−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−(2−ピラジンカルボニル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−(イソキサゾール−5−カルボニル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−(2−ピラジンカルボニル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−(イソキサゾール−5−カルボニル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−(5−メチルイソキサゾール−3−イル−3−カルボニル)メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−(2−クロロ−6−メトキシピリジニル−4−カルボニル)、N−メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジプロピル−8−[6−[N−(イソニコチノイル−N−オキシド)、N−メチルアミノ]−3−ピリジル)キサンチン;
1−プロピル−3−(4−メトキシフェニル)エチル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−[N−(イソニコチノイル−N−オキシド)、N−メチルアミノ]−3−ピリジル)キサンチン;
1,3−ジアリル−8−(6−クロロ−3−ピリジル)キサンチン;
1−プロピル−3−(4−メトキシフェニル)エチル−8−[6−(N−ニコチノイルメチルアミノ)−3−ピリジル]キサンチン;
1−プロピル−3−(4−メトキシフェニル)エチル−8−[6−(N−(6−クロロニコチノイル)メチルアミノ)−3−ピリジル]キサンチン;
1,3−ジアリル−8−[6−(N−ニコチノイルメチルアミノ)−3−ピリジル]キサンチン;
1,3−ジアリル−8−[6−(N−(6−クロロニコチノイル)メチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピルl−8−[6−(N−[6−(トリフルオロメチル)ニコチノイル]メチルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(2−ヒドロキシ−5−メチル)ベンズアルデヒドヒドラゾノ]−3−ピリジル]キサンチン;
1−シクロプロピル−3−プロピル−8−[6−(N−[6−(トリフルオロメチル)ニコチノイル]メチルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(ブロモピリジン−3−カルバルデヒドヒドラゾノ]−3−ピリジル]キサンチン;
1−シクロプロピル−3−エチル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1−プロピル−3−シクロプロピル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−(6−(2−メトキシエチル)アミノ−3−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(N−(6−クロロニコチノイル)メチルアミノ)−3−ピリジル]キサンチン;
1,3−ジプロピル−8−(2−クロロ−6−メトキシエチルアミノ−4−ピリジル)キサンチン;
1,3−ジプロピル−8−(2−クロロ−6−メチルアミノ−4−ピリジル)キサンチン;
1,3−ジプロピル−8−[2−[N−ニコチノイル、N−(2−メトキシエチル)アミノ]−6−クロロ−4−ピリジル)キサンチン;
1,3−ジプロピル−8−[2−[N−ニコチノイル、N−メチルアミノ]−6−クロロ−4−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−[6−[N−(6−クロロニコチノイル)メチルアミノ]−3−ピリジル)キサンチン;
1−エチル−3−シクロプロピル−8−(6−メチルアミノ−3−ピリジル)キサンチン;
1−エチル−3−シクロプロピル−8−(6−(2−メトキシエチル)アミノ−3−ピリジル)キサンチン;
1,3−ジエチル−8−[6−ヒドラジノ−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(シクロプロピルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−(シクロプロピルメチルアミノ)−3−ピリジル]キサンチン;
N’−[5−(1,3−ジエチル−2,6−ジオキソ−2,3,6,7−テトラヒドロ−1H−プリン−8−イル)−ピリジン−2−イル]−ヒドラジド;
N−[5−(1,3−ジエチル−2,6−ジオキソ−2,3,6,7−テトラヒドロ−1H−プリン−8−イル)−ピリジン−2−イル]−N’−(ピリジン−3−カルボニル)−ヒドラジド;
1,3−ジエチル−8−[6−(エチルアミノ)−3−ピリジル]キサンチン;
1,3−ジエチル−8−[6−[N−ニコチノイルシクロプロピルメチルアミノ]−3−ピリジル)キサンチン;および
1−シクロプロピルメチル−3−エチル−8−[6−[N−(6−クロロニコチノイル)メチルアミノ]−3−ピリジル)キサンチン
からなる群から選択される化合物、またはその医薬上許容される塩、もしくは必要に応じてその単一立体異性体形態、またはその混合物が提供される。
式IAの化合物は、P. J. Scammells, et al., J. Med. Chem. 37, 2704-2712 (1994)に記載の方法により製造することができる。ジアミノ−1,3−二置換ウラシルを5℃でピリジン中、6−クロロニコチノイルでアシル化して式(5a)の化合物を得る。得られたアミド(5a)を、水酸化ナトリウム水溶液を還流させることにより環化させて化合物IAを得る。塩化6-クロロニコチノイルを、反応スキーム1に示されているように触媒としてDMFを用いて塩化チオニル中で6−ヒドロキシニコチン酸を還流させることにより製造する。
[125I]ABA [125I]N6−(4−アミノベンジル)−アデノシン
125I−ABOPX 125I−3−(4−アミノ−3−ヨードベンジル)−8−オキシアセテート−1−プロピル−キサンチン
AR アデノシン受容体
CGS 21680 2−[4−[(2−カルボキシエチル)フェニル]エチル−アミノ]−5N−N−エチルカルバモイルアデノシン
CPX 8−シクロペンチル−1,3−ジプロピルキサンチン
DMEM ダルベッコ改変イーグル培地
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDTA エチレンジアミン四酢酸塩
HEK細胞 ヒト胚腎細胞
Ki 平衡阻害定数
NECA 5’−(N−エチルカルバモイル)アデノシン
R−PIA R−N6−フェニルイソプロピルアデノシン
TEA トリエチルアミン
TLC 薄層クロマトグラフィー
ZM 241385 4−(2−[7−アミノ−2−{フリル}{1,2,4}トリアゾロ{2,3−a}{1,3,5}トリアジン−5−イルアミノエチル)フェノール
本発明の化合物の、A2Bアデノシン受容体アンタゴニストとして働く能力は、当技術分野で周知の薬理学モデルを用いて、または下記の試験手順を用いて決定することができる。
Robeva, A. et al., Biochem. Pharmacol., 51, 545-555 (1996)に記載の技術を用い、ラットA2B受容体cDNAを発現プラスミドpDoubleTroubleにサブクローニングした。このプラスミドをコンピテントJM109細胞で増幅させ、Wizard Megaprepカラム(Promega Corporation, Madison, WI)を用いてプラスミドDNAを単離した。Felgner, P. L. et al., Proc. Natl. Acad. Sci. USA, 84, 7413-7417 (1987)に記載のようなリポフェクチンの手段により、A2Bアデノシン受容体をHEK−293細胞に導入した。
トランスフェクトされたHEK細胞を、37℃、5%CO2/95%O2で加湿した大気下で増殖させた。0.6mg/mL G418中での細胞増殖によりコロニーを選抜した。トランスフェクト細胞は、Hams F12栄養素混合物(1/1)、10%ウシ新生児血清、2mMグルタミンを添加し、50IU/mLペニシリン、50mg/mLストレプトマイシン、および0.2mg/mLゲネチシン(G418,Boehringer Mannheim)を含有するDMEMで維持した。細胞を10cm径の円形プレートで培養し、密集状態まで増殖した際(約72時間後)に継代培養した。
A2B受容体:HEK−A2B細胞の密集単層をPBS、その後、プロテアーゼ阻害剤(10μg/mLベンズアミジン、100μMフッ化フェニルメタンスルホニル、および2μg/mLのアプロチニン、ペプスタチンおよびロイペプチン)を含む氷冷バッファーA(10mM HEPES、10mM EDTA、pH7.4)で洗浄した。この細胞をポリトロン(Brinkmann)中で20分間ホモジナイズし、30,000xgで遠心分離し、ペレットをバッファーHE(プロテアーゼ阻害剤を含む10mM HEPES、1mM EDTA、pH7.4)で2回洗浄した。最終のペレットを、10%スクロースを添加したバッファーHEに再懸濁させ、アリコートを−80℃で冷凍した。結合アッセイのため、膜を解凍し、HEで5〜10倍希釈し、タンパク質週濃度約1mg/mLとした。タンパク質濃度を決定するため、膜とウシ血清アルブミン標品を0.2%NaOH/0.01%SDSに溶解し、フルオレスカミン蛍光を用いてタンパク質を測定した。Stowell, C. P. et al., Anal. Biochem., 85, 572-580 (1978)。
1つの密集T75フラスコからのHEK−A2B細胞をCa2+およびMg2+フリーのダルベッコのリン酸緩衝生理食塩水(PBS)ですすぎ、0.05%トリプシンおよび0.53mM EDTAを加えたCa2+およびMg2+フリーのHBSS中で、細胞が解離するまでインキュベートした。これらの細胞をPBS中、250xgで遠心分離することにより2回すすぎ、137mM NaCl、5mM KCl、0.9mM MgSO4、1.4mM CaCl2、3mM NaHCO3、0.6mM Na2HPO4、0.4mM KH3PO4、5.6mMグルコース、および10mM HEPES、pH7.4ならびにCa2+感受性蛍光色素インド−1−AM(5μM)からなるHBSS10mL中に37℃で60分間再懸濁させた。細胞を一度すすぎ、1U/mlアデノシンデアミナーゼを添加した色素フリーのHBSS25mLに再懸濁させ、室温に維持した。DMSOまたはビヒクル中の100倍液として調製したアデノシン受容体アンタゴニストを加え、細胞を37℃浴に2分間移した。次に、細胞(2ml中100万個)を、Aminco SLM 8000分光蛍光計(SML instruments, Urbana IL)内で37℃に維持した攪拌キュベットに移した。400および485nm(励起332nm)で得られたインド−1蛍光の比率をスリット幅4nmを用いて記録した。100秒の平衡期間の後にNECAを加えた。
サイクリックAMPの生成をDMEM/HEPESバッファー(50mMのHEPESを含有するDMEM、pH7.4、37℃)中で行った。細胞の各ウェルをDMEM/HEPESバッファーで2回洗浄した後、100μLのアデノシンデアミナーゼ(終濃度10IU/mL)およびロリプラムおよびシロスタミド(各終濃度10μM)の溶液10μLを加え、次いで試験化合物(適当な濃度)または50μLを加えた。15分後、培地を除去し、0.1M HCl 200μLを加えることで37℃でのインキュベーションを終わらせた。酸性抽出液をアッセイまで−20℃で保存した。サイクリックAMPの量は、cAMP結合タンパク質(PKA)を用いるプロトコール[van der Wenden et al., 1995]に従い、若干の改良を加えて測定した。アッセイバッファーは、150mM K2HPO4/10mM EDTA/0.2%BSA FV、pH7.5からなった。サンプル(20mL)を0℃で90分間インキュベートした。インキュベート物を、Brandel M−24セルハーベスターにてGF/Cガラスマイクロファイバーフィルター上で濾過した。フィルターをさらに、2mLの150mM K2HPO4/10mM EDTA(pH7.5、4℃)で4回すすいだ。2時間の抽出後、パンチしたフィルターをPackard Emulsifier Safeシンチレーション液中でカウントした。
プロトン核磁気共鳴法は、Varian−300MH分光計で行い、DMSO−d6またはCDCl3でスペクトルを採取した。特に記載がなければ、テトラメチルシランからのダウンフィールドppmまたはDMSO(2.5ppm)からの相対ppmとして表されている。エレクトロスプレーイオン化(ESI)質量分析をThermoFinnigan LCQ質量分析計を用いて行った。
塩化6−クロロニコチノイルの製造:
6−ヒドロキシニコチン酸(1.444g、10.4mmol)を塩化チオニル(8ml)に懸濁させた。DMF(0.50ml)を加えた。この混合物を2時間還流させた。反応物を冷却した後、塩化チオニルを窒素流により除去し、残渣を一晩真空乾燥させ、そのまま次の工程に用いた。
CH2Cl2(20ml)中、6−ヒドロキシニコチン酸(1.44g、10.4mmol)から製造した塩化6−クロロニコチノイルを、5℃に維持した乾燥ピリジン(8.2ml)中、5,6−ジアミノ−1,3−ジプロピルウラシル(1.81g、8mmol)の溶液に滴下した。この反応物を室温まで温め、さらに3時間攪拌した。水(50ml)を加えて反応物を急冷した。溶媒を蒸発させて暗色の油状物を得た。この油状物を2N NaOH(20ml)中で2時間還流させた。冷却後、濃HClでpHを注意深く7に調整した。固体が生じ、これを回収し、水(20ml)、エーテル(20ml)およびクロロホルム(20ml)で洗浄し、灰白色固体を得た(1.9g)。この生成物をさらに精製せずに次の工程に用いた。
化合物1(40mg、0.115mmol)および対応する置換アミン(0.5mlまたは0.5g)を耐圧試験管に入れた。(アミンの融点が80℃を超える場合には、エタノール4mlを溶媒として加えた。)この耐圧試験管をアルゴンでフラッシュし、密閉し、160℃で48〜60時間攪拌した。冷却後、エーテル(10ml)を加えた。得られた固体を回収し、シリカゲルカラムまたは分取TLC(溶媒A:CH2Cl2:MeOH=20:1〜10:1または溶媒B:CH2Cl2:MeOH:TEA=20:1:0.1〜4:1:0.1)で精製した。
アミノ置換ピリジル化合物(IC)(10mg)を耐圧試験管内の乾燥THF(5ml)中に懸濁させた。イソシアネート(0.25ml)を加えた。この混合物を90℃で48時間攪拌した。冷却後、溶媒を蒸発させた。残渣を分取TLC(CH2Cl2:MeOH=11:1)により精製した。
アミノ置換ピリジル化合物(15mg)および所望酸塩化物(4〜6当量)を乾燥DMF(2ml)中に再懸濁させた。この混合物にピリジン(0.1〜0.15ml)を加えた。この混合物を室温で24時間攪拌した。溶媒を除去し、残渣をシリカゲルカラムまたは分取TLC(CH2Cl2:MeOH=11:1または酢酸エチル:ヘキサン:MeOH=15:85:5)により精製した、
化合物1(500mg、1.44mmol)およびヒドラジン(4ml)を耐圧試験管に入れた。エタノール(30ml)を加えた。耐圧試験管をアルゴンでフラッシュし、密閉し、100〜160℃で10〜16時間攪した。冷却した後、得られた固体を回収し、メタノールおよびエーテルで洗浄し、化合物138(40mg)を得た。この生成物をさらに精製せずに次の工程で用いた。
化合物138(31.5mg、0.1mmol)を、耐圧試験管内の酢酸(5ml)に懸濁させた。アルデヒドまたはケトン(0.12mmol)を加えた。この耐圧試験管をアルゴンでフラッシュし、密閉し、100〜160℃で2〜10時間攪拌した。冷却後、得られた固体を回収し、シリカゲルカラムまたは分取TLC(CH2Cl2:MeOH=20:1〜10:1)により精製し、式ILの化合物を得た。
次の本発明の化合物は上記の手順を用いて製造した。
化合物1:1,3−ジプロピル−8−(6−クロロ−3−ピリジル)キサンチン
1H NMR (DMSO, d6):δ0.89(m, 6H), 1.59(m, 2H), 1.73(m, 2H), 3.88(t, 2H, J=7.2Hz), 4.00(t, 2H, J=7.2Hz), 7.68(d, 1H, J=8.4Hz), 8.50(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 9.07(d, 1H, J=2.4Hz).
MS: m/z 348 (M+H)+.
MS: m/z 316 (M+H)+.
1H NMR (DMSO, d6):δ0.89(m, 6H), 1.14(t, 3H, J=7.2Hz), 1.56(m, 2H), 1.72(m, 2H), 3.33(m, 2H), 3.84(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 6.52(d, 1H, J=8.7Hz), 7.09 (t, 1H), 8.00(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.72(d, 1H, J=2.4Hz).
MS: m/z 357 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.71(m, 2H), 3.36(m, 2H), 3.53(m, 2H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 4.73(t, 1H, J=5.4Hz), 6.57(d, 1H, J=8.7Hz), 7.11(t, 1H), 7.99(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.70(d, 1H, J=2.4Hz).
MS: m/z 373 (M+H)+.
1H NMR (DMSO, d6):δ0.84(m, 6H), 1.52(m, 2H), 1.68(m, 2H), 2.00(s, 3H), 3.52(m, 8H), 3.81(t, 2H, J=7.2Hz), 3.96(t, 2H, J=7.2Hz), 6.92(d, 1H, J=8.7Hz), 8.14(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.79(d, 1H, J=2.4Hz).
MS: m/z 440 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.54(m, 2H), 1.71(m, 2H), 3.84(t, 2H, J=7.2Hz), 3.98(t, 2H, J=7.2Hz), 4.54(d, 2H, J=6.5Hz), 6.61(d, 1H, J=8.7Hz), 7.22(m, 1H), 7.31(m, 4H), 7.66(t, 1H, J=6.0Hz), 8.02(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.71(d, 1H, J=2.4Hz).
MS: m/z 419 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.63(m, 10H), 3.61(t, 4H, J=5.7Hz), 3.85(t, 2H, J=7.2Hz), 4.00(t, 2H, J=7.2Hz), 6.91(d, 1H, J=9.0Hz), 8.12(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.79(d, 1H, J=2.4Hz).
MS: m/z 397 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.55(m, 2H), 1.73(m, 2H), 1.95(m, 4H), 3.43(m, 4H), 3.85(t, 2H, J=7.5Hz), 4.00(t, 2H, J=7.5Hz), 6.54(d, 1H, J=9.0Hz), 8.12(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.79(d, 1H, J=2.4Hz).
MS: m/z 383 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 1.88(m, 2H), 2.47(m, 5H), 2.60(m, 2H), 3.64(t, 2H. J=6.0Hz), 3.77(m, 2H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 6.73(d, 1H, J=9.0Hz), 8.12(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.78(d, 1H, J=2.4Hz).
MS: m/z 426 (M+2).
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.81(d, 3H, J=4.5Hz), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.52(d, 1H, J=8.7Hz), 7.08(q, 1H, J=4.5 Hz), 8.01(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.73(d, 1H, J=2.4Hz).
MS: m/z 343 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.59(m, 2H), 1.71(m, 2H), 3.71(s, 3H), 3.87(t, 2H, J=7.2Hz), 3.98(t, 2H, J=7.2Hz), 4.45(d, 2H, J=6.3Hz), 6.58(d, 1H, J=9.0Hz), 6.87(d, 2H, J=8.7Hz), 7.25(d, 2H, J=8.7Hz), 7.60(t, 1H), 8.01(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.71(d, 1H, J=2.4Hz).
MS: m/z 449 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 9H), 1.14(m, 1H), 1.40-1.80(m, 8H), 2.55(dt, 1H, J1=2.1Hz, J2=10.5Hz), 2.86(dt, 1H, J1=2.1Hz, J2=10.5Hz), 3.85(t, 2H, J=7.5Hz), 4.00(t, 2H, J=7.5Hz), 4.30(d, 2H, J=13.5Hz), 6.92(d, 1H, J=9.0Hz), 8.10(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.79(d, 1H, J=2.4Hz).
MS: m/z 411 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.08(d, 3H, J=6.0Hz), 1.56(m, 2H), 1.72(m, 2H), 3.26(m, 2H), 3.77(m, 1H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.76(d, 1H, J=4.5Hz), 6.60(d, 1H, J=9.0Hz), 7.10(t, 1H, J=6.0Hz), 7.99(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.69(d, 1H, J=2.4Hz).
MS: m/z 387 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 3.29(s, 6H), 3.45(t, 2H, J=5.7Hz), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.49(t, 1H, J=5.4Hz), 6.62(d, 1H, J=9.0Hz), 7.19(t, 1H, J=5.7Hz), 8.00(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.71(d, 1H, J=2.4Hz).
MS: m/z 417 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.12(d, 3H, J=6.6Hz), 1.56(m, 2H), 1.74(m, 2H), 3.27(m, 2H), 3.46(m, 1H), 3.85(t, 2H, J=7.2Hz), 3.98(t, 2H, J=7.2Hz), 4.74(t, 1H, J=5.4Hz), 6.56(d, 1H, J=9.0Hz), 6.90(d, 1H, J=7.5 Hz), 7.98(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.69(d, 1H, J=2.4Hz).
MS: m/z 387 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.57(m, 2H), 1.73(m, 2H), 3.55(m, 4H), 3.69(m, 4H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 6.94(d, 1H, J=9.0Hz), 8.17(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.83(d, 1H, J=2.4Hz).
MS: m/z 399 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.55(m, 2H), 1.75(m, 2H), 3.09(s, 6H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 6.73(d, 1H, J=9.0Hz), 8.13(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.80(d, 1H, J=2.4Hz).
MS: m/z 357 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.72(m, 2H), 3.49(m, 8H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.59(t, 1H, J=5.4Hz), 6.58(d, 1H, J=9.0Hz), 7.15(t, 1H), 8.00(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.71(d, 1H, J=2.4Hz), 13.42(s, 1H).
MS: m/z 417 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.78(m, 4H), 3.52(m, 4H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.88(d, 1H, J=9.0Hz), 8.13(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.80(d, 1H, J=2.4Hz).
MS: m/z 398 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 3.32(m, 1H), 3.55(m, 4H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 4.76(m, 1H), 5.55(d, 1H, J=4.5Hz), 6.63(d, 1H, J=8.7Hz), 7.20-7.40(m, 6H), 8.00(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.72(d, 1H, J=2.4Hz), 13.42(s, 1H).
MS: m/z 449 (M+H)+.
1H NMR (DMSO, d6):δ0.86(m, 6H), 1.55(m, 2H), 1.71(m, 2H), 3.72(s, 2H), 3.84(t, 2H, J=7.2Hz), 3.97(t, 2H, J=7.2Hz), 4.50(d, 1H, J=6.0 Hz), 6.57(d, 1H, J=9.0Hz), 7.27(s, 4H), 7.54(t, 1H, J=6.0Hz), 8.00(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.68(d, 1H, J=2.4Hz).
MS: m/z 448 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.55(m, 2H), 1.76(m, 2H), 3.86(t, 2H, J=7.5Hz), 4.01(t, 2H, J=7.5Hz), 6.93(m, 2H), 7.29(t, 2H, J=7.8Hz), 7.68(d, 2H, J=7.8Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.87(d, 1H, J=2.4Hz), 9.45(s, 1H).
MS: m/z 405 (M+H)+.
1H NMR (DMSO, d6):δ0.44(m, 2H), 0.72(m, 2H), 0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.58(m, 1H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.66(d, 1H, J=9.0Hz), 7.36(d, 1H, J=2.7Hz), 8.10(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.74(d, 1H, J=2.4Hz).
MS: m/z 369 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 3.84(t, 2H, J=7.2Hz), 3.98(t, 2H, J=7.2Hz), 4.62(d,2H, J=6.0Hz), 6.67(d, 1H, J=8.7Hz), 7.25(m, 2H), 7.73(m, 2H0, 8.04(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.51(d, 1H, J=4.8Hz), 8.69(d, 1H, J=2.4Hz).
MS: m/z 420 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.21(s, 3H), 2.38(t, 4H, J= 4.8Hz), 3.59(t, 4H, J=4.8Hz), 3.85(t, 2H, J=7.5Hz), 4.00(t, 2H, J=7.5Hz), 6.93(d, 1H, J=9.0Hz), 8.15(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.81(d, 1H, J=2.4Hz).
MS: m/z 412 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.71(m, 2H), 3.84(t, 2H, J=7.5Hz), 3.98(t, 2H, J=7.5Hz), 4.56(d, 2H, J=5.7 Hz), 6.63(d, 1H, J=8.7Hz), 7.33(dd, 1H, J1=4.5 Hz, J2= 7.8Hz), 7.71(m, 2H), 8.04(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.43(dd, 1H, J1=1.8Hz, J2=4.5Hz), 8.55(d, 1H, J=1.8Hz), 8.71(d, 1H, J=2.4Hz).
MS: m/z 420 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.31(s, 3H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 4.50(d, 2H, J=5.4 Hz), 6.62(d, 1H, J=8.7Hz), 7.10-7.25(m, 4H) 7.51(t, 1H, J=5.4Hz), 8.01(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.72(d, 1H, J=2.4Hz).
MS: m/z 433 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.77(t, 2H, J=7.5Hz), 3.49(m, 2H), 3.70(s, 3H), 3.73(s, 3H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.55(d, 1H, J=9.0Hz), 6.74(dd, 1H, J1=1.8Hz, J2=8.4Hz), 6.85 (m, 2H), 7.17(t, 1H, J=5.4Hz). 8.01(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.73(d, 1H, J=2.4Hz).
MS: m/z 493 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 9H), 1.54(m, 4H), 1.72(m, 2H), 3.17(m, 2H), 3.30(d, 3H, J=5.4Hz), 3.86(t, 2H, J=7.5Hz), 4.01(t, 2H, J=7.5Hz), 7.43(d, 1H, J=9.0Hz), 8.01(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.99(d, 1H, J=2.4Hz), 9.29(t, 1H, 5.4Hz).
MS: m/z 428 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 12H), 1.37-1.65(m, 6H), 1.72(m, 2H), 3.84(m, 3H), 3.98(t, 2H, J=7.2Hz), 6.54(d, 1H, J=8.7Hz), 6.90(d, 1H, J=8.4Hz), 7.96(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.67(d, 1H, J=2.4Hz).
MS: m/z 399 (M+H)+.
1H NMR (DMSO, d6):δ0.86(m, 6H), 1.54(m, 2H), 1.72(m, 2H), 3.82-4.00(m, 6H), 4.36(t, 1H, J=7.5Hz), 6.53(d, 1H, J=9.0Hz), 7.15-7.34(m, 11H), 7.97(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.75(d, 1H, J=2.4Hz).
MS: m/z 509 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.04(t, 2H, J=7.2Hz), 1.50-1.86(m, 8H), 2.12(m, 1H), 2.25(m, 1H), 2.58(m, 1H), 2.86(m, 1H), 3.09(m, 2H), 3.51(m, 1H), 3.84(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.60(d, 1H, J=9.0Hz), 6.98(br, 1H), 7.99(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.70(d, 1H, J=2.4Hz).
MS: m/z 440 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.54(m, 2H), 1.72(m, 2H), 3.71(s, 3H), 3.85(t, 2H, J=7.8Hz), 3.99(t, 2H, J=7.8Hz), 4.51(d, 2H, J=6.0Hz), 6.61(d, 1H, J=9.0Hz), 6.70-6.91(m, 3H), 7.22(t, 1H, J=7.5Hz), 7.64(t, 1H, J=6.0Hz), 8.02(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.71(d, 1H, J=2.4Hz).
MS: m/z 449 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.75(m, 2H), 3.44(s, 3H), 3.86(t, 2H, J=7.5Hz), 4.02(t, 2H, J=7.5Hz), 7.04(t, 1H, J=7.2Hz), 7.32(t, 2H, J=7.5Hz), 7.48(d, 1H, J=9.0Hz), 7.60(m, 3H), 8.47(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 9.12(d, 1H, J=2.4Hz).
MS: m/z 462 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.73(m, 2H), 3.87(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.52(d, 2H, J=5.7 Hz), 6.27(d, 1H, J=3.0 Hz), 6.38(m, 1H), 6.3(d, 1H, J=9.0 Hz), 7.56 (m, 2H), 8.03(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.73(d, 1H, J=2.4Hz).
MS: m/z 409 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.77(t, 2H, J=7.5 Hz), 3.47( q, 2H, t=7.5 Hz), 3.71(s, 3H), 3.85(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 6.55(d, 1H, J=9.0Hz), 6.85(d, 2H, J=8.4 Hz), 7.16(d, 2H, J=8.4 Hz), 8.00(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.73(d, 1H, J=2.4Hz).
MS: m/z 463 (M+H)+.
1H NMR (DMSO, d6):δ0.86(m, 6H), 1.56(m, 2H), 1.71(m, 2H), 3.82(s, 3H), 3.87(t, 2H, J=7.2Hz), 3.98(t, 2H, J=7.2Hz), 4.48(d, 2H, J=6.0Hz), 6.62(d, 1H, J=9.0Hz), 6.87 (t, 1H, J=7.2Hz), 6.98(d, 1H, J=7.5Hz), 7.20(m, 2H0, 7.46(t, 1H, J=6.0Hz), 8 (dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.70(d, 1H, J=2.4Hz).
MS: m/z 449 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 9H), 1.53(m, 4H), 1.72(m, 2H), 3.24 (q, 2H, J=6.3Hz), 3.85(t, 2H, J=7.5Hz), 3.98(t, 2H, J=7.5Hz), 6.53(d, 1H, J=8.7Hz), 7.13(t, 1H, J=5.7 Hz), 7.99(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.70(d, 1H, J=2.4Hz).
MS: m/z 371 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.40-1.75(m, 10H), 1.72(m, 2H), 3.84(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 4.17(m, 1H), 6.52(d, 1H, J=8.7Hz), 7.10(d, 1H, J=6.6 Hz), 7.99(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.70(d, 1H, J=2.4Hz).
MS: m/z 397 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.13-1.91(m, 14H), 1.72(m, 2H), 3.76(m, 1H), 3.84(t, 2H, J=7.5Hz), 3.98(t, 2H, J=7.5Hz), 6.52(d, 1H, J=9.0Hz), 7.00(d, 1H, J=7.8 Hz), 7.97(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.69(d, 1H, J=2.4Hz).
MS: m/z 411 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.33(t, 3h, J=7.2 Hz), 1.59(m, 2H), 1.73(m, 2H), 3.87(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 7.74(d, 1H, J=8.4Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 8.74(d, 1H, J=2.4Hz).
MS: m/z 376 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 2.09(m, 1H), 2.18(m, 1H), 3.89(t, 2H, J=7.5Hz), 3.98(t, 2H, J=7.5Hz), 4.29(t, 1H, J=5.4Hz), 4.43(m, 3H), 7.75(dd, 1H, J1=0.6Hz, J2=8.4Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 8.74(dd, 1H, J1=0.6Hz, J2=2.4Hz).
MS: m/z 408 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 3.86(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.01(s, 3H), 7.74(d, 1H, J=8.4Hz), 8.26(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 8.82(d, 1H, J=2.4Hz).
MS: m/z 362 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.59(m, 2H), 1.72(m, 2H), 3.85(m, 4H), 3.99(t, 2H, J=7.5Hz), 4.66(t, 2H, J=6.0Hz), 7.76(d, 1H, J=8.1Hz), 8.21(dd, 1H, J1=2.7 Hz, J2=8.1Hz), 8.76(d, 1H, J=2.7Hz).
MS: m/z 456 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.72(m, 2H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 4.70(d, 2H, J=6.0 Hz), 6.60(d, 1H, J=8.7 Hz), 6.94-7.03(m, 2H), 7.35(dd, 1H, J1=1.5Hz, J2=5.1 Hz), 7.70(t, 1H, J=6.0Hz), 8.04(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.75(d, 1H, J=2.4Hz).
MS: m/z 425 (M+H)+.
1H NMR (DMSO, d6):δ0.89(m, 6H), 1.56(m, 2H), 1.73(m, 2H), 3.43(s, 3H), 3.73(s, 3H), 3.87(t, 2H, J=7.2Hz), 4.02(t, 2H, J=7.2Hz), 6.89(dd, 2H, J=6.9Hz), 7.48 (m, 3H), 8.47(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 9.11(d, 1H, J=2.4Hz).
MS: m/z 492 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.57(m, 2H), 1.73(m, 2H), 3.49(s, 3H), 3.86(t, 2H, J=7.2Hz), 3.99(t, 2H, J=7.2Hz), 7.35(dd, 1H, J1=7.8Hz, J2=7.8 Hz), 7.41(d, 1H, J=8.4Hz), 7.71(dt , 1H, J1=1.5 Hz, J2=8.4Hz, ), 8.32(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 8.46(d, 1H, J=2.1), 8.54(dd, 1H, J1=2.1 Hz, J2=4.8Hz), 8.98(d, 1H, J=2.4 Hz).
MS: m/z 448 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.75(m, 2H), 3.44(s, 3H), 3.88(t, 2H, J=7.5Hz), 4.03(t, 2H, J=7.5Hz), 7.15(t, 2H, J=8.7Hz), 7.49(d, 1H, J=9.0Hz), 7.62(m, 2H), 8.47(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 9.12(d, 1H, J=2.4Hz).
MS: m/z 480 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.75(m, 2H), 3.47(s, 3H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 7.26(d, 2H, J=5.4Hz), 7.46(d, 1H, J=8.7Hz), 8.34(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 8.54(d, 2H, J=5.4Hz), 8.96(d, 1H, J=2.4Hz).
MS: m/z 448 (M+H)+.
MS: m/z 401 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.57(m, 2H), 1.75(m, 2H), 3.87(t, 2H, J=7.5Hz), 4.03(t, 2H, J=7.5Hz), 4.34(m, 4H), 6.92-7.57(m, 11H), 8.44(dd, 1H, J1=2.4 Hz, J2=8.7Hz), 9.12(d, 1H, J=2.4Hz), 9.58(s (br), 1H).
MS: m/z 611 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.73(m, 2H), 3.57(m, 4H), 3.67(m, 4H), 3.86(t, 2H, J=7.2Hz), 4.01(t, 2H, J=7.2Hz), 6.93(t, 1H, J=7.8 Hz), 6.99(d, 1H, J=9.0 Hz), 7.23(t, 2H, J=7.8Hz), 7.46(d, 2H, J=7.8Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.61(s, 1H), 8.85(d, 1H, J=2.4Hz).
MS: m/z 517 (M+H)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.73(m, 2H), 3.38(m, 2H), 3.64(m, 2H), 3.75(m, 4H), 3.86(t, 2H, J=7.2Hz), 4.00(t, 2H, J=7.2Hz), 6.96(d, 1H, J=9.0 Hz), 7.44(d, 2H, J=5.1 Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.69(d, 2H, J=5.1 Hz), 8.84(d, 1H, J=2.4Hz).
MS: m/z 503 (M+H)+.
1H NMR (DMSO, d6):δ0.84(t, 3H, J=7.2Hz), 1.53(m, 2H), 2.93(t, 2H, J=7.2Hz) 3.67(s, 3H), 3.83(t, 2H, J=7.2Hz), 4.20(t, 2H, J=7.2Hz), 6.81(d, 2H, J=8.1Hz), 7.12(d, 2H, J=8.1Hz), 7.68(d, 1H, J=8.4Hz), 8.44(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 8.98(d, 1H, J=2.4 Hz
MS: m/z 440 (M+H)+.
1H NMR (DMSO, d6):δ0.84(m, 3H), 1.52(m, 2H), 3.38(m, 2H), 2.77(m, 4H), 2.94(t, 2H, J=7.5Hz), 3.51(m, 4H), 3.69(s, 1H), 3.83(t, 2H, J=7.5Hz), 4.20(t, 2H, J=7.5Hz), 6.83(d, 2H, J=8.4 Hz), 6.89(d, 1H, J=9.0Hz), 7.14(d, 2H, J=8.4 Hz), 8.14(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.82(d, 1H, J=2.4Hz).
MS: m/z 490 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.74(m, 2H), 3.87(t, 2H, J=7.5Hz), 4.03(t, 2H, J=7.5Hz), 6.30(d, 2H, J=7.8Hz), 7.94(d, 1H, J=8.7Hz), 8.53(d, 1H, J=7.8Hz), 8.60(dd, 1H, J1=2.4 Hz, J2=8.7Hz ), 9.17(d, 1H, J=2.4 Hz).
MS: m/z 407 (M+2)+.
1H NMR (DMSO, d6):δ0.88(m, 6H), 1.56(m, 2H), 1.74(m, 2H), 3.46-3.83(m, 8H), 3.88(t, 2H, J=7.5Hz), 4.00(t, 2H, J=7.5Hz), 6.96(d, 1H, J=9.0Hz), 7.50(dd, 1H, J1=7.8 Hz, J2=7.8Hz ), 7.89(d, J=7.5Hz), 8.19(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.66(m, 2H), 8.84(d, 1H, J=2.4 Hz).
MS: m/z 503 (M+H)+.
1H NMR (DMSO, d6):δ0.87(m, 6H), 1.56(m, 2H), 1.74(m, 4H), 2.66(t, 2H, J=5.4Hz), 2.86(t, 2H, J=5.4Hz), 3.68(m, 4H), 3.85(t, 2H, J=7.5Hz), 3.99(t, 2H, J=7.5Hz), 6.72(d, 1H, J=9.0Hz), 8.10(dd, 1H, J1=2.4 Hz, J2=9.0Hz), 8.77(d, 1H, J=2.4 Hz).
MS: m/z 412 (M+H)+.
1H NMR (DMSO, d6):δ1.14(t, 3H, J=6.9Hz), 1.26(t, 3H, J=6.9Hz), 3.94(q, 2H, J=6.9Hz), 4.09(q, 2H, J=6.9Hz), 7.68(d, 1H, J=8.4Hz), 8.46(dd, 1H, J1=2.4 Hz, J2=8.4Hz), 9.07(d, 1H, J=2.4 Hz).
MS: m/z 320 (M+H)+.
MS: m/z 370 (M+H)+.
MS: m/z 434 (M+H)+.
MS: m/z 434 (M+H)+.
MS: m/z 315 (M+H)+.
MS: m/z 420 (M+H)+.
MS: m/z 446 (M+H)+.
MS: m/z 367 (M+H)+.
MS: m/z 311 (M+H)+.
MS: m/z 410 (M+H)+.
MS: m/z 472 (M+H)+.
MS: m/z 486 (M+H)+.
MS: m/z 339 (M+H)+.
MS: m/z 342 (M+H)+.
MS: m/z 392 (M+H)+.
MS: m/z 392 (M+H)+.
MS: m/z 421 (M+H)+.
MS: m/z 434 (M+H)+.
MS: m/z 406 (M+H)+.
MS: m/z 434 (M+H)+.
MS: m/z 406 (M+H)+.
MS: m/z 355 (M+H)+.
MS: m/z 398 (M+H)+.
MS: m/z 387 (M+H)+.
MS: m/z 414 (M+H)+.
MS: m/z 364 (M+H)+.
MS: m/z 475 (M+H)+.
MS: m/z 447 (M+H)+.
MS: m/z 398 (M+H)+.
MS: m/z 476 (M+H)+.
MS: m/z 448 (M+H)+.
MS: m/z 359 (M+H)+.
MS: m/z 360 (M+H)+.
MS: m/z 464 (M+H)+.
MS: m/z 355 (M+H)+.
MS: m/z 464 (M+H)+.
MS: m/z 479 (M+H)+.
MS: m/z 460 (M+H)+.
MS: m/z 287 (M+H)+.
MS: m/z 392 (M+H)+.
MS: m/z 492 (M+H)+.
MS: m/z 359 (M+H)+.
MS: m/z 416 (M+H)+.
MS: m/z 382 (M+H)+.
MS: m/z 372 (M+H)+.
MS: m/z 460 (M+H)+.
MS: m/z 582 (M+H)+.
MS: m/z 670 (M+H)+.
MS: m/z 421 (M+H)+.
MS: m/z 410 (M+H)+.
MS: m/z 449 (M+H)+.
MS: m/z 438 (M+H)+.
MS: m/z 452 (M+H)+.
MS: m/z 512 (M+H)+.
MS: m/z 464 (M+H)+.
MS: m/z 435 (M+H)+.
MS: m/z 436 (M+H)+.
MS: m/z 344 (M+H)+.
MS: m/z 540 (M+H)+.
MS: m/z 574 (M+H)+.
MS: m/z 444 (M+H)+.
MS: m/z 478 (M+H)+.
MS: m/z 516 (M+H)+.
MS: m/z 434 (M+H)+.
MS: m/z 446.
MS: m/z 483 (M+H)+.
MS: m/z 327 (M+H)+.
MS: m/z 341 (M+H)+.
MS: m/z 341 (M+H)+.
MS: m/z 385 (M+H)+.
MS: m/z 446(M+H)+.
MS: m/z 454 (M+H)+.
MS: m/z 421(M+H)+.
MS: m/z 377 (M+H)+.
MS: m/z 527 (M+H)+.
MS: m/z 482 (M+H)+.
MS: m/z 480 (M+H)+.
MS: m/z 327 (M+H)+.
MS: m/z 371 (M+H)+.
MS: m/z 316 (M+H)+.
MS: m/z 341 (M+H)+.
MS: m/z 355 (M+H)+.
MS: m/z 421 (M+H)+.
MS: m/z 526 (M+H)+.
MS: m/z 329 (M+H)+.
MS: m/z 460(M+H)+.
MS: m/z 480 (M+H)+.
Claims (43)
- 下記式Iの化合物、またはその医薬上許容される塩:
Rは、水素、(C1−C5)アルキル、ハロ(C1−C8)アルキル、(C3−C5)アルケニル、または(C3−C5)アルキニルであり;
R1は、(C3−C6)シクロアルキル、または(C3−C6)シクロアルキル(C1−C4)アルキル−であり、
R2は、水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C4−C10)複素環、(C4−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール,または(C5−C10)ヘテロアリール(C1−C8)アルキル−であり;
Zは、−SR3、−S(O)m−NR4R5、−NR4R5、または(C4−C10)複素環であり、この複素環は場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C1−C8)アルキル、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
各Z1は独立に、(C1−C8)アルキル、(C2−C8)アルケニル、(C2−C8)アルキニル、−OR6、−SR6、ハロ、R6O(C1−C8)アルキル、R7R8N(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NR7R8、R7R8N(C1−C8)アルキル、−C(O)R6、−COOR6、または−C(O)NR7R8であり;
R3は、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−C(O)R6、または−C(O)NR7R8であり;
R5は、−C(O)R6、−CO2R6、または−C(O)NHR7から選択され、
R4は、水素、(C1−C8)アルキル、(C3−C8)アルケニル、(C3−C8)アルキニル、(C1−C8)アルコキシ、(C3−C8)シクロアルキル、(C3−C8)シクロアルキル(C1−C8)アルキル−、(C6−C18)ポリシクロアルキル、(C6−C18)ポリシクロアルキル(C1−C8)アルキル−、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、−NR7R8、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C5−C10)ヘテロアリール、(C5−C10)ヘテロアリール(C1−C8)アルキル−、−((CH2)2−4−Y)q−(CH2)2−4−X1、−C(O)R6、−CO2R6、−C(O)NR7R8、または−S(O)2−NR7R8であるか、または、R4およびR5は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、さらに場合によってその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式環、または二環式環を形成し、その環は場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
X1は、−OR6、−C(O)R6、−CO2R6,または−NR7R8であり;かつ、Yはオキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(R9)−であり;
このR1、R2、R3、R4およびR5基のアルキル、アルケニル、シクロアルキル、アルキニル、アリール、複素環またはヘテロアリール基は、場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1以上の置換基で置換されていてもよく;
R6は、水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C3−C10)複素環(C1−C8)アルキル−、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール、(C4−C10)ヘテロアリール(C1−C8)アルキル−であり;ここで、この複素環、ヘテロアリールまたはアリールは場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;
R7、R8およびR9は独立に、水素、(C1−C8)アルキル、RaO(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、(C3−C10)複素環、(C6−C10)アリール、(C6−C10)アリール(C1−C8)アルキル−、(C4−C10)ヘテロアリール;−COORa、−C(O)Ra、または−C(O)NRbRcであり、この複素環、ヘテロアリールまたはアリールは場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよく;またはR7およびR8は、それらが結合している原子と一緒になって、3、4、5、6、7、または8個の環原子を有し、場合によって、環は4〜8個の環原子を有し、さらに場合によってその環に非過酸化物オキシ(−O−)、チオ(−S−)、スルフィニル(−SO−)、スルホニル(−S(O)2−)およびアミン−N(Rb)−から選択される1、2、3、または4個のヘテロ原子を含んでなる飽和または部分不飽和、単環式−、二環式−または芳香環を形成し;
Raは、水素、または(C1−C6)アルキルであり;RbおよびRcは各々独立に水素、(C1−C6)アルキル、(C1−C6)アルコキシ、(C3−C8)シクロアルキル、(C1−C6)アルキルチオ、(C6−C10)アリール、(C6−C10)アリール(C1−C6)アルキル−、ヘテロアリール、またはヘテロアリール(C1−C6)アルキル−であるか;またはRbおよびRcはそれらが結合している窒素と一緒になって、ピロリジル、ピペリジル、ピペラジニル、アゼピニル、ジアゼピニル、モルホリニル、またはチオモルホリニル環を形成し;かつ
nは0、1、2、3、4、5、6、7、または8であり;mは1、または2であり;qは1、2、3、または4である]。 - Rが、水素、メチル、エチル、アリル、プロパルギル、i-プロピル、n-プロピル、n-ブチル、i-ブチルまたはハロ(C1−C4)アルキルである、請求項1に記載の化合物。
- Rが、水素、メチル、エチル、−CH2−CH2−Cl、−CH2−CH2−Br、または−CH2−CH2−CH2−Fである、請求項1に記載の化合物。
- Rが水素である、請求項1に記載の化合物。
- R1が、シクロプロピルまたはシクロプロピルメチルである、請求項1に記載の化合物。
- R2が、水素、(C1−C4)アルキル、(C3−C4)アルケニル、(C3−C4)アルキニル、フェニル、フェニル(C1−C4)アルキル、または(メトキシフェニル)エチルである、請求項1に記載の化合物。
- R2が、(C3−C6)シクロアルキルまたは(C3−C6)シクロアルキル(C1−C4)アルキル−である、請求項1に記載の化合物。
- R2が、シクロプロピルまたはシクロプロピルメチルである、請求項1に記載の化合物。
- R2が、水素、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、n−ブチル、i−ブチル、フェニル、フェネチル、またはベンジルである、請求項1に記載の化合物。
- R2が、エチル、n−プロピルまたはアリルである、請求項1に記載の化合物。
- Zが、−NR4R5である、請求項1または10に記載の化合物。
- R4が、水素、(C1−C6)アルキル、(C3−C6)シクロアルキル、(C3−C6)シクロアルキル(C1−C4)アルキル−、(C3−C6)複素環、(C6−C10)アリール、(C6−C10)アリール(C1−C4)アルキル−、(C5−C6)ヘテロアリール、または(C5−C6)ヘテロアリール(C1−C4)アルキル−、−S(O2)NH2、−C(O)R6、−CO2R6、または−C(O)NR7R8である、請求項1に記載の化合物。
- R4が、水素、(C1−C4)アルキル、ヒドロキシ(C2−C4)アルキル、(C3−C6)シクロアルキル、(C6−C10)アリール、(C7−C10)アラルキル、(C5−C6)ヘテロアリール、−(CH2−CH2−O)q−(CH2−CH2)−ORa、−(CH2−CH2−O)q−(CH2−CH2)−COORa、−(CH2−CH2−O)q−(CH2−CH2)−NRaRb、−NR7R8、−C(O)R6、−CO2R6、または−C(O)NR7R8である、請求項1に記載の化合物。
- R4が、水素、メチル、エチル、プロピル、ペンチル、ヒドロキシエチル、ヒドロキシプロピル、エトキシエチル、ジエトキシエチル、メチルベンジル、アミノメチルベンジル、メトキシベンジル、メトキシフェネチル、フリルメチル、シクロプロピル、シクロプロピルメチル、シクロペンチル、シクロヘキシル、チオフェニル、−C(O)R6、−CO2R6、または−C(O)NHR7である、請求項1に記載の化合物。
- R4が、メチル、エチル、シクロプロピル、シクロプロピルメチル、−C(O)R6、−CO2R6、または−C(O)NHR7である、請求項1に記載の化合物。
- R4およびR5が、それらが結合している窒素と一緒になって、各々、場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよいピロリジル、ピペリジル、ピペラジニル、アゼピニル、ジアゼピニル、モルホリニル、またはチオモルホリニル環である、請求項1に記載の化合物。
- R6が、各々、場合によって、ハロ、シアノ、ニトロ、(C1−C8)アルキル、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcからなる群から独立に選択される1、2、または3個の置換基で置換されていてもよい(C1−C6)アルキル、(C3−C6)シクロアルキル、(C3−C6)シクロアルキル(C1−C4)アルキル−、(C3−C6)複素環、(C6−C10)アリール、(C6−C10)アリール(C1−C4)アルキル−、(C5−C6)ヘテロアリール、または(C5−C6)ヘテロアリール(C1−C4)−アルキル−である、請求項1に記載の化合物。
- R6が、各々、場合によって、ハロ、シアノ、ニトロ、(C1−C8)アルキル、ハロ(C1−C8)アルキル、−COORa、および−C(O)NRbRcから独立に選択される1、2、または3個の置換基で置換されていてもよい(C6−C10)アリール、(C5−C6)ヘテロアリールである、請求項1に記載の化合物。
- R6が、場合によって、F、Cl、Br、I、CF3、シアノ、ニトロ、−COORa、または−CONHRaで置換されていてもよい、ピリジルである、請求項1に記載の化合物。
- Rが、水素、メチル、またはエチルであり;
R1が、シクロプロピルまたはシクロプロピルメチルであり、
R2が、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、シクロプロピル、シクロプロピルメチル、またはn−ブチルであり;かつ、
Xが、6位においてZで置換された3−ピリジルであり、ここで、Zは(C4−C10)複素環または−NR4R5であり、R4はメチル、エチル、シクロプロピル、シクロプロピルメチルであり、R5は−C(O)R6であり、R6は、場合によって、ハロ、シアノ、ニトロ、ハロ(C1−C8)アルキル、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2または3個の置換基で置換されていてもよいヘテロアリールであり、Ra、RbおよびRcは独立に水素、メチル、エチル、プロピル、イソプロピル、またはシクロプロピルである、
請求項1に記載の化合物。 - Rが、水素、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、n−ブチル、i−ブチルまたはハロ(C1−C4)アルキルであり;かつ、R1およびR2が独立に水素、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、シクロプロピル、シクロプロピルメチル、n−ブチル、i−ブチル、フェニル、フェネチル、またはベンジルである、請求項1に記載の化合物。
- Rが水素、メチル、エチル、−CH2−CH2−Cl、−CH2−CH2−Br、または−CH2−CH2−CH2−Fであり;かつ、R1およびR2が独立に水素、メチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、シクロプロピル、シクロプロピルメチル、または(メトキシフェニル)エチルである、請求項1に記載の化合物。
- Zが、−NR4R5であり、R4が水素、(C1−C6)アルキル、(C3−C6)シクロアルキル、(C3−C6)複素環、(C6−C10)アリール、(C7−C12)アラルキル、(C5−C6)ヘテロアリール、または(C5−C6)ヘテロアリール(C1−C4)アルキル、−S(O2)NH2、−C(O)R6、−CO2R6、または−C(O)NR7R8である、請求項1に記載の化合物。
- Zが−NR4R5である、請求項1に記載の化合物。
- R4およびR5が、それらが結合している窒素と一緒になって、ピロリジル、ピペリジル、ピペラジニル、アゼピニル、ジアゼピニル、モルホリニル、またはチオモルホリニル環を形成し、この環が場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa,および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよい、請求項1に記載の化合物。
- R4が、水素、(C1−C4)アルキル、ヒドロキシ(C2−C4)アルキル、(C3−C6)シクロアルキル、(C6−C10)アリール、(C7−C10)アラルキル、(C5−C6)ヘテロアリール、−(CH2−CH2−O)q−(CH2−CH2)−ORa、−(CH2−CH2−O)q−(CH2−CH2)−COORa、−(CH2−CH2−O)q−(CH2−CH2)−NRaRb、−NR7R8、−C(O)R6、−CO2R6、または−C(O)NR7R8である、請求項1に記載の化合物。
- R4が、水素、メチル、エチル、プロピル、ペンチル、ヒドロキシエチル、ヒドロキシプロピル、エトキシエチル、ジエトキシエチル、メチルベンジル、アミノメチルベンジル、メトキシベンジル、メトキシフェネチル、フリルメチル、シクロペンチル、シクロヘキシル、チオフェニル、−C(O)R6、−CO2R6、または−C(O)NHR7である、請求項1に記載の化合物。
- R6が、メチル、メトキシ、またはピリジルであり、かつ、R7がフェニル、フルオロフェニル、またはメトキシフェニルである、請求項1に記載の化合物。
- Rが水素、メチル、またはエチルであり;
R1が、シクロプロピルまたはシクロプロピルメチルであり、
R1およびR2が独立にメチル、エチル、アリル、プロパルギル、i−プロピル、n−プロピル、シクロプロピル、シクロプロピルメチル、n−ブチル、i−ブチルであり;かつ、
Zが(C4−C10)複素環であり、この複素環は、場合によって、ハロ、シアノ、ニトロ、−ORa、−SRa、(C6−C10)アリール、−O(C6−C10)アリール、ヒドロキシ(C1−C8)アルキル、RbRcN(C1−C8)アルキル、ハロ(C1−C8)アルキル、−NRbRc、−C(O)Ra、−COORa、および−C(O)NRbRcから独立に選択される1、2、3、または4個の置換基で置換されていてもよい、請求項1に記載の化合物。 - R2がn−プロピルであり、Rが水素であり、かつ、nがゼロである、請求項1に記載の化合物。
- 1−シクロプロピル−3−プロピル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチンである請求項1に記載の化合物、またはその医薬上許容される塩。
- 1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;および
1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルエチルアミノ]−3−ピリジル)キサンチン;
からなる群から選択される請求項1に記載の化合物、またはその医薬上許容される塩。 - 1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1,3−ジシクロプロピルメチル−8−[6−[N−ニコチノイルエチルアミノ]−3−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−[6−[N−ニコチノイルメチルアミノ]−3−ピリジル)キサンチン;
1−シクロプロピル−3−プロピル−8−[6−[N−(6−クロロニコチノイル)メチルアミノ]−3−ピリジル)キサンチン;および
1−シクロプロピルメチル−3−エチル−8−[6−[N−(6−クロロニコチノイル)メチルアミノ]−3−ピリジル)キサンチン
からなる群から選択される請求項1に記載の化合物、またはその医薬上許容される塩。 - (a)治療上有効量の請求項1に記載の化合物と、
(b)医薬上許容される賦形剤
とを含んでなる、医薬組成物。 - (a)治療上有効量の請求項37に記載の化合物と、
(b)医薬上許容される賦形剤
とを含んでなる、医薬組成物。 - アデノシンA2B受容体の活性が関連し、その作用の拮抗が望まれる哺乳類において病状または病徴を予防または治療するための、請求項38または39に記載の医薬組成物。
- 喘息、アレルギー、アレルギー性疾患または自己免疫疾患を治療するための、請求項38または39に記載の医薬組成物。
- 下痢性疾患、インスリン抵抗性、糖尿病、癌、虚血/再潅流傷害、糖尿病性網膜症または高圧酸素誘発性網膜症を治療するための、請求項38または39に記載の医薬組成物。
- ヒトなどの哺乳類において疾病の治療に有用な薬剤の製造のための、請求項1に記載の化合物の使用。
Applications Claiming Priority (3)
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US49787503P | 2003-08-25 | 2003-08-25 | |
US60/497,875 | 2003-08-25 | ||
PCT/US2004/027133 WO2005021548A2 (en) | 2003-08-25 | 2004-08-20 | Substituted 8-heteroaryl xanthines |
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JP2007503443A JP2007503443A (ja) | 2007-02-22 |
JP2007503443A5 JP2007503443A5 (ja) | 2007-06-14 |
JP4769721B2 true JP4769721B2 (ja) | 2011-09-07 |
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JP2006524755A Active JP4769721B2 (ja) | 2003-08-25 | 2004-08-20 | 置換8−ヘテロアリールキサンチン |
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US (3) | US7342006B2 (ja) |
EP (2) | EP2295434B1 (ja) |
JP (1) | JP4769721B2 (ja) |
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