JP5465700B2 - P2x3およびp2x2/3アンタゴニストとしてのジアミノピリミジン - Google Patents
P2x3およびp2x2/3アンタゴニストとしてのジアミノピリミジン Download PDFInfo
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- JP5465700B2 JP5465700B2 JP2011172873A JP2011172873A JP5465700B2 JP 5465700 B2 JP5465700 B2 JP 5465700B2 JP 2011172873 A JP2011172873 A JP 2011172873A JP 2011172873 A JP2011172873 A JP 2011172873A JP 5465700 B2 JP5465700 B2 JP 5465700B2
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- Prior art keywords
- methoxy
- isopropyl
- hydrogen
- mmol
- alkyl
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- 239000005557 antagonist Substances 0.000 title description 6
- 102100040479 P2X purinoceptor 2 Human genes 0.000 title 1
- 101710189968 P2X purinoceptor 2 Proteins 0.000 title 1
- 102100040460 P2X purinoceptor 3 Human genes 0.000 title 1
- 101710189970 P2X purinoceptor 3 Proteins 0.000 title 1
- 229940058936 antimalarials diaminopyrimidines Drugs 0.000 title 1
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical class NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 title 1
- 239000001257 hydrogen Substances 0.000 claims description 202
- 229910052739 hydrogen Inorganic materials 0.000 claims description 202
- 125000000217 alkyl group Chemical group 0.000 claims description 171
- 150000001875 compounds Chemical class 0.000 claims description 85
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 84
- 125000001188 haloalkyl group Chemical group 0.000 claims description 79
- 125000001072 heteroaryl group Chemical group 0.000 claims description 79
- 125000003545 alkoxy group Chemical group 0.000 claims description 76
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 75
- 150000002431 hydrogen Chemical class 0.000 claims description 71
- 125000005843 halogen group Chemical group 0.000 claims description 69
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 68
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 60
- 125000000623 heterocyclic group Chemical group 0.000 claims description 59
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 47
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 45
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 41
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 41
- 125000003342 alkenyl group Chemical group 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 35
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 34
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 34
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 26
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 12
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 12
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 7
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 351
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 273
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 229
- -1 ethylene, propylene, 2-methylpropylene, butylene, pentylene Chemical group 0.000 description 220
- 239000000243 solution Substances 0.000 description 196
- 239000000203 mixture Substances 0.000 description 195
- 239000007787 solid Substances 0.000 description 149
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 142
- 235000019439 ethyl acetate Nutrition 0.000 description 129
- 239000011541 reaction mixture Substances 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 111
- 238000000034 method Methods 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
- 239000012267 brine Substances 0.000 description 88
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 88
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- 239000011734 sodium Substances 0.000 description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 72
- 238000003818 flash chromatography Methods 0.000 description 68
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 61
- 238000006243 chemical reaction Methods 0.000 description 59
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- 239000003921 oil Substances 0.000 description 53
- 235000019198 oils Nutrition 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 49
- 230000002829 reductive effect Effects 0.000 description 49
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 125000002346 iodo group Chemical group I* 0.000 description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 36
- 238000000746 purification Methods 0.000 description 35
- 201000010099 disease Diseases 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 30
- 238000010992 reflux Methods 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 27
- 125000001309 chloro group Chemical group Cl* 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 125000001246 bromo group Chemical group Br* 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 208000002193 Pain Diseases 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 125000001544 thienyl group Chemical group 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 16
- 239000000284 extract Substances 0.000 description 16
- 125000002541 furyl group Chemical group 0.000 description 16
- 125000002883 imidazolyl group Chemical group 0.000 description 16
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 16
- 125000000842 isoxazolyl group Chemical group 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 125000000168 pyrrolyl group Chemical group 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
- 239000000908 ammonium hydroxide Substances 0.000 description 15
- 229960004198 guanidine Drugs 0.000 description 15
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 206010020853 Hypertonic bladder Diseases 0.000 description 13
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- OMPGYSFGCUXAEG-UHFFFAOYSA-N 5-(5-amino-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine Chemical compound C1=C(N)C(OC)=CC(C(C)C)=C1OC1=CN=C(N)N=C1N OMPGYSFGCUXAEG-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 12
- 239000002552 dosage form Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 125000001715 oxadiazolyl group Chemical group 0.000 description 12
- 125000002971 oxazolyl group Chemical group 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000012746 preparative thin layer chromatography Methods 0.000 description 12
- 125000003226 pyrazolyl group Chemical group 0.000 description 12
- 125000000335 thiazolyl group Chemical group 0.000 description 12
- 125000001425 triazolyl group Chemical group 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 125000002947 alkylene group Chemical group 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical class NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 11
- 125000003831 tetrazolyl group Chemical group 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 210000005036 nerve Anatomy 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 10
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 9
- 102000002294 Purinergic P2X Receptors Human genes 0.000 description 9
- 108010000836 Purinergic P2X Receptors Proteins 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012346 acetyl chloride Substances 0.000 description 9
- 150000003840 hydrochlorides Chemical class 0.000 description 9
- 239000011593 sulfur Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- WZTGXCZSRLRAEO-UHFFFAOYSA-N 5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzonitrile Chemical compound C1=C(C#N)C(OC)=CC(C(C)C)=C1OC1=CN=C(N)N=C1N WZTGXCZSRLRAEO-UHFFFAOYSA-N 0.000 description 8
- 206010020751 Hypersensitivity Diseases 0.000 description 8
- 102000000033 Purinergic Receptors Human genes 0.000 description 8
- 108010080192 Purinergic Receptors Proteins 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 8
- 208000026935 allergic disease Diseases 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000010779 crude oil Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000009610 hypersensitivity Effects 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 7
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 7
- 208000026723 Urinary tract disease Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 238000004949 mass spectrometry Methods 0.000 description 7
- 208000020629 overactive bladder Diseases 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000012453 solvate Substances 0.000 description 7
- 208000014001 urinary system disease Diseases 0.000 description 7
- GVSGSHGXUXLQNS-UHFFFAOYSA-N 3-bromo-4,5-dihydroxybenzaldehyde Chemical compound OC1=CC(C=O)=CC(Br)=C1O GVSGSHGXUXLQNS-UHFFFAOYSA-N 0.000 description 6
- AATPYXMXFBBKFO-UHFFFAOYSA-N 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(N)N=C1N AATPYXMXFBBKFO-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
- STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
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- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 6
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 201000007094 prostatitis Diseases 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 210000001635 urinary tract Anatomy 0.000 description 6
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
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- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 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
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 239000013589 supplement Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
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- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
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- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
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- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical compound [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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Description
(式中、
Xは、−CH2−;−O−;−CHOH−;−S(O)n−:または−NRc−であり、ここで、nは0〜2であり、Rcは水素またはアルキルであり;
Yは、水素;または−NRdReであり、ここで、RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
Dは、場合により酸素であり;
R1は、アルキル;アルケニル;シクロアルキル;シクロアルケニル;ハロ;ハロアルキル;ヒドロキシアルキル;またはアルコキシであり;
R2、R3、R4、およびR5は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;アミノ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、ZはOまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になって、アルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;あるいは、R2およびR3は、一緒になって、アルキレンジオキシを形成していてもよく;あるいは、R2およびR3は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R6は、水素;アルキル;ハロ;ハロアルキル;アミノ;またはアルコキシであり;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
ただし、Xが−CH2−であり、R7、R8、Rd、およびReが水素である場合には、R1は、イソプロピル、イソプロペニル、シクロプロピル、またはヨードである)
で示される化合物またはその薬学的に許容されうる塩を提供する。
(式中、
Xは、−CH2−;−O−;−C(O)−;−CHOH−;−S(O)n−:または−NRc−であり、ここで、nは0〜2であり、Rcは水素またはアルキルであり;
Yは、水素;または−NRdReであり、ここで、RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
R1は、アルキル;アルケニル;シクロアルキル;シクロアルケニル;ハロ;ハロアルキル;またはアルコキシであり;
R2、R3、R4、およびR5は、各々独立して、水素;アルキル;アミノ;アミド;ハロアルキル;アルコキシ;アルキルスルホニル;アリールスルホニル;スルホンアミド;シアノ;アセチル;ヘテロアリール;カルボン酸;カルボン酸アミド;尿素;カルバメート;アセトアミド;または場合により置換されているフェノキシであるか;あるいは、R3およびR4は一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4はそれらが結合している原子と一緒になって、O、SおよびNから選択される1または2個のヘテロ原子を含む5または6員環を形成していてもよく;あるいは、R2およびR3は一緒になってアルキレンジオキシを形成していてもよく;あるいは、R2およびR3はそれらが結合している原子と一緒になって、O、SおよびNから選択される1または2個のヘテロ原子を含む5または6員環を形成していてもよく;
R6は、水素;アルキル;ハロアルキル;アミノ;またはアルコキシであり;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示される化合物またはその薬学的に許容されうる塩、溶媒和物、もしくはプロドラッグを投与することを含む。
塩酸、臭化水素酸、硫酸、硝酸、リン酸などの無機酸を用いて形成される酸付加塩;または、酢酸、ベンゼンスルホン酸、安息香酸、ショウノウスルホン酸、クエン酸、エタンスルホン酸、フマル酸、グルコヘプトン酸、グルコン酸、グルタミン酸、グリコール酸、ヒドロキシナフトエ酸、2−ヒドロキシエタンスルホン酸、乳酸、マレイン酸、リンゴ酸、マロン酸、マンデル酸、メタンスルホン酸、ムコン酸、2−ナフタレン−スルホン酸、プロピオン酸、サリチル酸、コハク酸、酒石酸、p−トルエンスルホン酸、トリメチル酢酸などの有機酸を用いて形成される酸付加塩;あるいは、
親化合物に存在する酸性プロトンが、金属イオン、例えばアルカリ金属イオン、アルカリ土類イオン、もしくはアルミニウムイオンにより置き換えられている場合に形成される塩;または、有機もしくは無機塩基と配位している場合に形成される塩が挙げられる。許容されうる有機塩基には、ジエタノールアミン、エタノールアミン、N−メチルグルカミン、トリエタノールアミン、トロメタミンなどが挙げられる。許容される無機塩基には、水酸化アルミニウム、水酸化カルシウム、水酸化カリウム、炭酸ナトリウム、および水酸化ナトリウムが挙げられる。
(i)疾病状態を予防すること、すなわち、疾病状態にさらされているかまたはその素因がある可能性があるが、まだ疾病状態の症状を経験または呈していない、被験体の疾病状態の臨床症状を発症させないこと、
(ii)疾病状態を抑止すること、すなわち、疾病状態またはその臨床症状の発症を停止させること、
(iii)疾病状態を寛解すること、すなわち、疾病状態またはその臨床症状の一時的または永久的減退を引き起こすこと
が含まれる。
(式中、
Xは、−CH2−;または−O−であり;
R1は、アルキル;アルケニル;シクロアルキル;またはシクロアルケニル;またはハロであり;
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になって、アルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示されていてもよい。
(式中、
R1は、イソプロピル;イソプロペニル;シクロプロピル;またはヨードであり;
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示されていてもよい。
(式中、
R1は、アルキル;アルケニル;シクロアルキル;またはシクロアルケニルであり;
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示されていてもよい。
(式中、
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示されていてもよい。
(式中、
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示されていてもよい。
(式中、
Xは、−CH2−;または−O−であり;
R1は、アルキル;アルケニル;シクロアルキル;またはシクロアルケニル;またはハロであり;
R2は、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;または−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであり;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
Qは、CR9であり、AおよびEの一方はO、S、またはNR10であり、他方はCR9またはNであるか;あるいは
Qは、Nであり、AおよびEの一方はNR10であり、他方はCR9であり;
各R9は、独立して、水素、アルキル、ハロ、またはアルコキシであり;
R10は、水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfである)
で示されていてもよい。
(式中、
Xは、−CH2−;または−O−であり;
R1は、アルキル;アルケニル;シクロアルキル;またはシクロアルケニル;またはハロであり;
R4は、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;または−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、ZはOまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであり;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
Qは、CR9であり、AおよびEの一方はO、S、またはNR10であり、他方はCR9またはNであるか;あるいは
Qは、Nであり、AおよびEの一方はNR10であり、他方はCR9であり;
各R9は、独立して、水素、アルキル、ハロ、またはアルコキシであり;
R10は、水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfである)
で示されていてもよい。
下記の調製例及び実施例は、当業者が本発明をより明確に理解し、実施できるように示されている。それらは、本発明の範囲を制限するものと見なされるべきではなく、単に本発明の代表的なものとして見なされるべきである。
工程1:ビス−ベンジルオキシカルボニル−N−(2−(R)−ヒドロキシ−1−メチル−エチル)−グアニジン
N−(3−エタンスルホニル−1−メチル−プロピル)−グアニジン;
4−グアニジノ−ピペリジン−1−カルボン酸エチルエステル;
N−(1−シクロプロピル−エチル)−グアニジン;
N−(テトラヒドロ−チオピラン−4−イル)−グアニジン;
N−[2−(4−アセチル−ピペラジン−1−イル)−1−メチル−エチル]−グアニジン;
N−(1−ヒドロキシメチル−プロピル)−グアニジン;
N−(1−メタンスルホニル−ピペリジン−4−イル)−グアニジン;及び
N−[3−ヒドロキシ−1−(2−ヒドロキシ−エチル)−プロピル]−グアニジン。
工程1.4−シクロプロピル−1,2−ジメトキシ−ベンゼン
工程1:5−(5−ヨード−2−イソプロピル−4−メトキシ−フェノキシ)−ピリミジン−2,4−ジアミン
工程1.5−[5−(4,5−ジヒドロ−1H−イミダゾール−2−イル)−2−イソプロピル−4−メトキシ−フェノキシ]−ピリミジン−2,4−ジアミン
工程1.5−(5−アミノ−2−イソプロピル−4−メトキシ−フェノキシ)−ピリミジン−2,4−ジアミン
(M+H)+=320。
工程1.5−(5−アミノ−2−イソプロピル−4−メトキシ−フェノキシ)−ピリミジン−2,4−ジアミン
(M+H)=340。
工程1.4−クロロ−N−[5−(2,4−ジアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−フェニル]−ブチルアミド
工程1.5−(2−イソプロピル−5−イソチオシアナート−4−メトキシ−フェノキシ)−ピリミジン−2,4−ジアミン
[MH]+=303。
工程1.5−(2,4−ジアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−ベンゼンスルホニルクロリド
上記工程3の2−イソプロピル−3−メトキシ−フェノールを使用し、続いて実施例2の工程5〜7の手順を使用して、5−(2−イソプロピル−3−メトキシ−フェノキシ)−ピリミジン−2,4−ジアミンを調製した。MS(M+H)=275。
工程1.5−[5−ヨード−2−イソプロピル−4−(2−トリメチルシラニルオキシ−エトキシ)−フェノキシ]−ピリミジン−2,4−ジアミン
工程1.5−(4−アミノ−2−エチルアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−ベンゾニトリル
M+H 381。
工程1.2−ブロモ−1−[4−イソプロピル−2−メトキシ−5−(トルエン−4−スルホニル)−フェニル]−エタノン
工程1.5−(2,4−ジアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−チオベンズアミド
この実施例の工程1で使用した5−(2,4−ジアミノ−ピリミジン−5−イルオキシ)−4−イソプロピル−2−メトキシ−ベンゾニトリルを、スキーム1に記載したように調製した。
無水エタノール5mL中2−(4−エチル−7−メチル−ベンゾ[b]チオフェン−5−イルオキシ)−3−フェニルアミノ−アクリロニトリル(360mg、1mmol)、グアニジンHCl(411mg、4mmol)及びナトリウムメトキシド(880ul、4mmol、メタノール中4.9M溶液)を無水エタノール5ml中で2時間加熱還流した。ピペットを介してEtOH 1ml中の予備混合したグアニジンHCl(411mg、4mmol)及びナトリウムメトキシド(880ul、4mmol、メタノール中4.9M溶液)を加え、反応混合物を2時間加熱還流した。反応混合物を冷却し、水で希釈し、EtOAcで2回抽出し、ブラインで洗浄し、硫酸マグネシウムで乾燥した。溶媒を真空下で除去し、5−(4−エチル−7−メチル−ベンゾ−[b]チオフェン−5−イルオキシ)−ピリミジン−2,4−ジアミン241mgを白色の固体として得た(74%)。質量分析 M+H=301、融点=181℃。この生成物175mgをMeOH及びHCl/ジエチルエーテルから再結晶化して、対応するHCl塩98mg、49%を得た。質量分析 M+H=301、融点>300℃。
塩化メチレン(15ml)中の5−メトキシ−1,3−ジメチル−6−トリフルオロメチル−1H−インドール(725mg、3mmol)を0℃に冷却し、シリンジを介してBBr3(塩化メチレン中の1N溶液14.9ml)をゆっくりと加えた。反応混合物を0℃で15分撹拌し、次に1時間撹拌しながら室温に温めた。反応混合物を1N NaOH 75mLでゆっくりとクエンチした。混合物を1N HClでpH約5に酸性化し、塩化メチレンで抽出し、合わせた有機層を水、ブラインで洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧下で除去し、残渣をクロマトグラフィー(20%EtOAc/ヘキサン)に付して、1,3−ジメチル−6−トリフルオロメチル−1H−インドール−5−オール235mg(75%)を得た。
実施例62の工程6〜9の手順を使用して、1,3−ジメチル−6−トリフルオロメチル−1H−インドール−5−オールを、5−(1,3−ジメチル−6−トリフルオロメチル−1H−インドール−5−イルオキシ)−ピリミジン−2,4−ジアミンに変換した(70mg)。対応するヒドロクロリド塩をMeOH/ジエチルエーテルから再結晶化した。質量分析 M+H=338、融点256℃。
質量分析 M+H=342 融点>300℃。
工程1.7−イソプロピル−4−メチル−ベンゾオキサゾール−6−オール
工程1.7−イソプロピル−2,4−ジメチル−ベンゾオキサゾール−6−オール
約0.025〜0.5%の活性化合物を含むいくつかの水性懸濁剤を、鼻腔用スプレー製剤として調製した。該製剤は、場合により、例えば、微結晶セルロース、カルボキシメチルセルロースナトリウム、デキストロースなどの不活性成分を含む。塩酸を加えてpHを調整してもよい。鼻腔用スプレー製剤は、典型的には1回の作動で約50〜100μlの製剤を送達する鼻腔用スプレー計量ポンプにより送達してもよい。典型的な投与スケジュールでは、4〜12時間毎に2〜4回噴霧する。
CHO−K1細胞を、クローン化ラットP2X3またはヒトP2X2/3受容体サブユニットでトランスフェクトさせ、フラスコ中で継代培養した。FLIPR実験の18〜24時間前に、細胞をそのフラスコから取り出し、遠心分離にかけ、2.5×105細胞/mlで栄養培地中に再懸濁した。細胞を、壁の黒い96ウェルプレートに50,000細胞/ウェルの密度で分注し、5%CO2中37℃で一晩インキュベートした。実験日に、細胞をFLIPR緩衝液(カルシウムおよびマグネシウムを含まないハンク平衡塩溶液、10mMのHEPES、2mMのCaCl2、2.5mMのプロベネシド;FB)中で洗浄した。各ウェルに、100μlのFBおよび100μlの蛍光ダイFluo−3AM[最終濃度2μM]を加えた。37℃での1時間のダイを負荷させたインキュベート後、細胞を4回FBで洗浄し、最後の75μl/ウェルのFBを各ウェルに残した。
Claims (3)
- 式(I)
(式中、
Xは、−CH2−または−CHOH−であり;
Yは、水素;または−NRdReであり、ここで、RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
Dは、場合により酸素であり;
R1は、イソプロピルであり;
R2、R3、R4、およびR5は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;アミノ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、ZはOまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になって、アルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;あるいは、R2およびR3は、一緒になって、アルキレンジオキシを形成していてもよく;あるいは、R2およびR3は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R6は、水素;アルキル;ハロ;ハロアルキル;アミノ;またはアルコキシであり;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示される化合物またはその薬学的に許容されうる塩。 - 前記化合物が、(a)式(II)
(式中、
Xは、−CH2−であり;
R1は、イソプロピルであり;
R3およびR4は、各々独立して、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであるか;あるいは、R3およびR4は、一緒になってアルキレンジオキシを形成していてもよく;あるいは、R3およびR4は、それらが結合している原子と一緒になって、O、S、およびNから選択される1または2個のヘテロ原子を場合により含む5または6員環を形成していてもよく;
R7およびR8の一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルであり;
RdおよびReの一方は水素であり、他方は、水素;アルキル;シクロアルキル;シクロアルキルアルキル;ハロアルキル;ハロアルコキシ;ヒドロキシアルキル;アルコキシアルキル;アセチル;アルキルスルホニル;アルキルスルホニルアルキル;アミノカルボニルオキシアルキル;ヒドロキシカルボニルアルキル;ヒドロキシアルキルオキシカルボニルアルキル;アリール;アラルキル;アリールスルホニル;ヘテロアリール;ヘテロアリールアルキル;ヘテロアリールスルホニル;ヘテロシクリル;またはヘテロシクリルアルキルである)
で示される化合物であるか、あるいは
(b)式(VII)
(式中、
Xは、−CH2−であり;
R1は、イソプロピルであり;
R2は、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;または−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、Zは、OまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであり;
R7、R8、Rd、およびReは、(a)に定義した通りであり;
Qは、CR9であり、AおよびEの一方はO、S、またはNR10であり、他方はCR9またはNであるか;あるいは
Qは、Nであり、AおよびEの一方はNR10であり、他方はCR9であり;
各R9は、独立して、水素、アルキル、ハロ、またはアルコキシであり;
R10は、水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfである)
で示される化合物であるか;あるいは
(c)式(VIII)
(式中、
Xは、−CH2−であり;
R1は、イソプロピルであり;
R4は、水素;アルキル;アルケニル;アミノ;ハロ;アミド;ハロアルキル;アルコキシ;ヒドロキシ;ハロアルコキシ;ニトロ;ヒドロキシアルキル;アルコキシアルキル;ヒドロキシアルコキシ;アルキニルアルコキシ;アルキルスルホニル;アリールスルホニル;シアノ;アリール;ヘテロアリール;ヘテロシクリル;ヘテロシクリルアルコキシ;アリールオキシ;ヘテロアリールオキシ;アラルキルオキシ;ヘテロアラルキルオキシ;場合により置換されているフェノキシ;または−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfであり、ここで、mおよびnは、各々独立して、0または1であり、ZはOまたはNRgであり、Rfは、水素、アルキル、ヒドロキシ、アルコキシ、アミノ、ヒドロキシアルキル、またはアルコキシアルキルであり、各Rgは、独立して、水素またはアルキルであり;
R7、R8、Rd、およびReは、(a)で定義した通りであり;
Qは、CR9であり、AおよびEの一方はO、S、またはNR10であり、他方はCR9またはNであるか;あるいは
Qは、Nであり、AおよびEの一方はNR10であり、他方はCR9であり;
各R9は、独立して、水素、アルキル、ハロ、またはアルコキシであり;
R10は、水素、アルキル、ヒドロキシアルキル、アルコキシアルキル、−(CH2)m−(Z)n−(CO)−Rf、または−(CH2)m−(Z)n−SO2−(NRg)n−Rfである)
で示される化合物である、請求項1の化合物。 - 薬学的に許容されうる賦形剤と請求項1に記載の化合物とを含む医薬組成物。
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