JP2010535190A - 置換ビシクロラクタム化合物 - Google Patents
置換ビシクロラクタム化合物 Download PDFInfo
- Publication number
- JP2010535190A JP2010535190A JP2010518764A JP2010518764A JP2010535190A JP 2010535190 A JP2010535190 A JP 2010535190A JP 2010518764 A JP2010518764 A JP 2010518764A JP 2010518764 A JP2010518764 A JP 2010518764A JP 2010535190 A JP2010535190 A JP 2010535190A
- Authority
- JP
- Japan
- Prior art keywords
- tautomer
- compound
- alkyl
- pharmaceutically acceptable
- methyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 234
- 150000003839 salts Chemical class 0.000 claims abstract description 81
- -1 cyano, hydroxyl Chemical group 0.000 claims description 101
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- 241000124008 Mammalia Species 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229920001774 Perfluoroether Polymers 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 208000008589 Obesity Diseases 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 235000020824 obesity Nutrition 0.000 claims description 14
- 239000003981 vehicle Substances 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 10
- 230000003278 mimic effect Effects 0.000 claims description 10
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000005724 cycloalkenylene group Chemical group 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- GYURLMXPLLUHTJ-RBSFLKMASA-N chembl2414687 Chemical compound C([C@H](OC1=NC=NC(N)=C1C1=O)C)N1C(C=C1)=CC=C1[C@H]1CC[C@H](CC(O)=O)CC1 GYURLMXPLLUHTJ-RBSFLKMASA-N 0.000 claims description 6
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 5
- SWUYRFGFZDOBPZ-UHFFFAOYSA-N 2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohexyl]acetonitrile Chemical compound O=C1C=2C(N)=NC=NC=2OCCN1C(C=C1)=CC=C1C1CCC(CC#N)CC1 SWUYRFGFZDOBPZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 5
- FJZSXKKPJQVONT-BZUAXINKSA-N C([C@H](OC1=NC=NC(N)=C1C1=O)C)N1C(C=C1)=CC=C1[C@H]1CC[C@H](CC#N)CC1 Chemical compound C([C@H](OC1=NC=NC(N)=C1C1=O)C)N1C(C=C1)=CC=C1[C@H]1CC[C@H](CC#N)CC1 FJZSXKKPJQVONT-BZUAXINKSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- GEVVQZHMFVFGLN-UHFFFAOYSA-N 2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohexyl]acetic acid Chemical compound O=C1C=2C(N)=NC=NC=2OCCN1C(C=C1)=CC=C1C1CCC(CC(O)=O)CC1 GEVVQZHMFVFGLN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 37
- 239000000126 substance Substances 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 116
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 23
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- 102000015868 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000000651 prodrug Substances 0.000 description 12
- 229940002612 prodrug Drugs 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 0 C*C(CC(CC1)CC=C1*1C(C)(C)C(C)(C)*1)=O Chemical compound C*C(CC(CC1)CC=C1*1C(C)(C)C(C)(C)*1)=O 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- RXNNHSKCCHGJQM-UHFFFAOYSA-N 4,6-dichloropyrimidine-5-carbonyl chloride Chemical compound ClC(=O)C1=C(Cl)N=CN=C1Cl RXNNHSKCCHGJQM-UHFFFAOYSA-N 0.000 description 5
- QNVNVTNWFNFJRS-UHFFFAOYSA-N 4-amino-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one Chemical compound O=C1C=2C(N)=NC=NC=2OCCN1C1=CC=C(I)C=C1 QNVNVTNWFNFJRS-UHFFFAOYSA-N 0.000 description 5
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 4
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- 208000032928 Dyslipidaemia Diseases 0.000 description 4
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- 208000017170 Lipid metabolism disease Diseases 0.000 description 4
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- 241001465754 Metazoa Species 0.000 description 4
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
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- SFWOKKQWKQQRLN-UHFFFAOYSA-N methyl 2-[4-[4-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6-yl)phenyl]cyclohex-3-en-1-yl]acetate Chemical compound C1C(CC(=O)OC)CCC(C=2C=CC(=CC=2)N2C(C3=C(N)N=CN=C3OCC2)=O)=C1 SFWOKKQWKQQRLN-UHFFFAOYSA-N 0.000 description 1
- QMVQQEFLNXBWEX-UHFFFAOYSA-N methyl 2-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl-(4,6-dichloropyrimidine-5-carbonyl)amino]-3-fluorophenyl]cyclohexyl]acetate Chemical compound C1CC(CC(=O)OC)CCC1C(C=C1F)=CC=C1N(CCO[Si](C)(C)C(C)(C)C)C(=O)C1=C(Cl)N=CN=C1Cl QMVQQEFLNXBWEX-UHFFFAOYSA-N 0.000 description 1
- WLMKVWUNPKQJNE-UHFFFAOYSA-N methyl 2-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-3-fluorophenyl]cyclohexyl]acetate Chemical compound C1CC(CC(=O)OC)CCC1C1=CC=C(NCCO[Si](C)(C)C(C)(C)C)C(F)=C1 WLMKVWUNPKQJNE-UHFFFAOYSA-N 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N p-toluenesulfonyl chloride Substances CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 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
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 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
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003234 polygenic effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- ORQXGJIOLBMWID-UHFFFAOYSA-N tert-butyl-[2-(4,6-dichloro-2H-pyrimidin-1-yl)ethoxy]-dimethylsilane Chemical compound [Si](C)(C)(C(C)(C)C)OCCN1CN=C(C=C1Cl)Cl ORQXGJIOLBMWID-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005863 α-amino(C1-C4)alkanoyl group Chemical group 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/00—Drugs for disorders of the metabolism
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- 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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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
【化1】
Description
R1は、H −(C1〜C4)アルキル、−(C1〜C4)ペルフルオロアルキル、−(C1〜C4)ペルフルオロアルコキシ、または−(C1〜C4)アルコキシであり、
R2およびR3は、別々に、独立して、H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであるか、
R2およびR3は、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルであり、
R4は、Hまたは−(C1〜C4)アルキルであり、
R5a、R5b、R5cおよびR5dは、各々独立して、H、F、Cl、Br、−(C1〜C4)アルキル、−OHまたは−O−(C1〜C4)アルキルであり、
Qは、−O−または結合であり、
Aは、−(C3〜C6)シクロアルキレン基、−(C3〜C6)シクロアルケニレン基またはフェニレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である。
一般に、本発明の式(1)の化合物は、特に本明細書に含有される説明を踏まえて、化学技術において知られているプロセスを包含する方法により調製することができる。本発明の式(1)の化合物を製造するための特定のプロセスは、下記の反応スキームにより例示される。他のプロセスは、実験の項に記載される。スキームおよび実施例に記載されている反応のための出発化合物の一部は、本明細書に例示されているように調製される。
以下で本明細書に記載される実施例は、例示目的のみのためである。本明細書において反映される組成物、方法、および様々なパラメーターは、本発明の様々な態様および実施形態を例示することのみが意図されており、決して特許請求の範囲に記載されている本発明の範囲を制限することは意図されていない。
DCMは、ジクロロメタンであり、
DMFは、ジメチルホルムアミドであり、
DPPFは、1,1’−ビス(ジフェニルホスフィノ)フェロセンであり、
EDCIは、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミドであり、
EtOAcは、酢酸エチルであり、
HClは、塩酸であり、
HOBtは、N−ヒドロキシベンゾトリアゾールであり、
MTHFは、2−メチルテトラヒドロフランであり、
RTは、分を単位とする保持時間であり、
TEAは、トリエチルアミンであり、
TFAは、トリフルオロ酢酸であり、
Tf2Oは、トリフルオロメタンスルホン酸(トリフリック酸)無水物であり、
THFは、テトラヒドロフランであり、
X−PHOSは、2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニルである。
メチル{トランス−4−[4−(4−クロロ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェニル]シクロヘキシル}アセテート
2.37 (m, 1H), 2.24 (m, 2H), 1.85 (m, 5H), 1.44 (m, 2H), 1.13 (m, 2H), 0.87 (s,
9H), 0.04 (s, 6H). m/z = 406.4 (M+1).
2H), 3.63 (s, 3H), 2.37 (m, 1H), 2.22 (m, 2H), 1.82 (m, 5H), 1.36 (m, 2H), 1.11
(m, 2H), 0.83 (s, 9H), 0.02 (s, 6H). m/z = 580.3 (M+1).
2H), 3.63 (s, 3H), 2.38 (m, 1H), 2.23 (m, 2H), 1.82 (m, 5H), 1.39 (m, 2H), 1.11
(m, 2H). m/z = 466.2 (M+1).
アセトニトリル中のメチル(トランス−4−{4−[[4,6−ジクロロピリミジン−5−イル)カルボニル](2−ヒドロキシ−エチル)アミノ]フェニル}シクロヘキシル)アセテート(4.78g、10.2mmol、ステップ3からの未精製材料)およびTEA(4.15g、41mmol)のスラリーを、6時間にわたって80℃にて撹拌した。反応物を冷却し、真空中で濃縮し、EtOAc中に希釈し、水(3×)、飽和水性食塩水で洗浄し、硫酸ナトリウムで乾燥し、真空中で濃縮すると、黄色の固体が得られた。この材料を、メタノール(10mL)中でスラリー化し、濾過し、固体をメタノール(2×3mL)で洗浄し、真空中で乾燥すると、黄色の固体として表題化合物4.03gが得られた。1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 7.22 (s, 4H), 4.75 (m, 2H), 4.03 (m, 2H), 3.63 (s,
3H), 2.50 (m, 1H), 2.23 (m, 2H), 1.87 (m, 5H), 1.44 (m, 2H), 1.19 (m,
2H). m/z = 430.3 (M+1).
メチル2−((1S,4s)−4−(4−((R)−4−クロロ−8−メチル−5−オキソ−7,8−ジヒドロピリミド−[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル)シクロヘキシル)アセテート
1.14 (m, 2 H) 1.25 - 1.30 (m, 3 H) 1.30 - 1.42 (m, 2 H) 1.78 (dd, J=28.30,
11.90 Hz, 5 H) 2.20 (d, J=7.03 Hz, 2 H) 2.28 - 2.39 (m, 1 H) 3.64 (s, 3 H) 3.83
- 3.97 (m, 2 H) 4.04 - 4.14 (m, 1 H) 7.00 (d, J=8.20 Hz, 2 H) 7.19 (d, J=8.59
Hz, 2 H) 8.53 (s, 1 H).
ジオキサン中4M HCl(25mL)を、メタノール(50mL)中のステップ2からのメチル[トランス−4−(4−{[(2R)−2−{[tert−ブチル(ジメチル)シリル]オキシ}プロピル][(4,6−ジクロロピリミジン−5−イル)カルボニル]アミノ}フェニル)シクロヘキシル]アセテート(3.95g、6.72mmol)の溶液に加えた。混合物を30分にわたって23℃にて撹拌した。反応混合物を濃縮し、溶媒を除去した。残渣をアセトニトリル(200mL)に溶かし、次いで、K2CO3(1.86g、13.5mmol)および5オングストロームモレキュラーシーブ(1.0g)をそれに加えた。反応混合物を30時間にわたって80℃にて撹拌した。EtOAc(250mL)および水(250mL)を反応混合物に加えた。有機層を分離し、MgSO4で乾燥し、濃縮した。粗材料を、ヘプタン中30〜50%EtOAcで溶出される120gシリカゲルカラムにより精製すると、表題化合物として無色の油1.85g(61%)が得られた。m/z=444.1(M+1). 1H NMR (400 MHz, クロロホルム-d) δ 1.09-1.23 (m, 2 H) 1.43 (d, J=6.64 Hz,
3 H) 1.44-1.57 (m, 2 H) 1.80-1.96 (m, 5 H) 2.26 (d, J=7.05 Hz, 2 H) 2.44-2.55
(m, 1 H) 3.68 (s, 3 H) 3.80-3.95 (m, 2 H) 5.00-5.12 (m, 1 H) 7.29 (s, 4 H) 8.76
(s, 1 H).
メチル(トランス−4−{4−[(7S)−4−クロロ−7−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)アセテート
(m, 1 H) 3.18 - 3.35 (m, 1 H) 3.51 (dd, J=9.75, 4.35 Hz, 1 H) m/z= 190.2 (M+1).
(d, J=6.22 Hz, 3 H) 1.44 (q, J=12.44 Hz, 2 H) 1.76 - 1.93 (m, 5 H) 2.23 (d,
J=7.05 Hz, 2 H) 2.34 (t, J=12.03 Hz, 1 H) 3.42 - 3.65 (m, 3 H) 3.67 (s, 3 H)
6.55 (d, J=8.29 Hz, 2 H) 6.99 (d, J=8.29 Hz, 2 H). m/z= 420.3 (M+1)
(d, J=6.64 Hz, 3 H) 1.28 - 1.45 (m, 2 H) 1.73 - 1.94 (m, 5 H) 2.23 (d, J=6.64
Hz, 2 H) 2.38 (t, J=11.61 Hz, 1 H) 3.51 - 3.66 (m, 2 H) 3.67 (s, 3 H) 4.84 -
5.03 (m, 1 H) 7.03 (d, J=8.71 Hz, 2 H) 7.34 (br. s., 2 H) 8.50 (s, 1 H).
m/z= 597.2 (M+4)
1.69 - 1.91 (m, 5 H) 2.23 (d, J=7.05 Hz, 2 H) 2.38 (t, J=12.23 Hz, 1 H) 3.60
(dd, J=11.61, 9.12 Hz, 1 H) 3.67 (s, 3 H) 3.78 (dd, J=11.82, 4.35 Hz, 1 H) 4.85
- 5.04 (m, 1 H) 7.07 (d, J=8.71 Hz, 2 H) 7.33 (br. s., 2 H) 8.52 (s, 1 H) m/z=
483.1 (M+4).
メチル[トランス−4−(4−{[(3S)−2−{オキシ}プロピル][(4,6−ジクロロピリミジン−5−イル)カルボニル]−アミノ}フェニル)シクロヘキシル]アセテート(0.8g、1.66mmol)、炭酸カリウム(0.46g、3.33mmol)およびモレキュラーシーブ200mgを、アセトニトリル41.6ml中に混ぜた。混合物を封管に加え、一夜にわたって80℃にて加熱した。反応混合物を濃縮し、次いで、EtOAcおよび水で希釈した。層を分離し、有機層を食塩水で洗浄し、次いで、乾燥し、濃縮した。ヘプタン中40%酢酸エチルのシリカ上で生成物のカラムを行い、0.22gを回収した。1H NMR (400 MHz, クロロホルム-d) δ 1.06 (d, J=7.05 Hz, 3 H) 1.10 - 1.25 (m, 2 H) 1.42 - 1.55 (m, 2 H)
1.73 - 1.98 (m, 5 H) 2.26 (d, J=6.64 Hz, 2 H) 2.41 - 2.59 (m, 1 H) 3.69 (s, 3
H) 4.27 - 4.42 (m, 1 H) 4.45 - 4.70 (m, 2 H) 7.17 (d, J=8.29 Hz, 2 H) 7.30 (d,
J=8.71 Hz, 2 H) 8.76 (s, 1 H) m/z= 444.0 (M+1).
メチル2−(4−(4−(4−クロロ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−3−フルオロフェニル)シクロヘキシル)アセテート
1H NMR
(400MHz, CDCl3): δ 7.24-7.41(m, 5H), 7.20(m,
1H), 7.16(m, 1H), 6.82(m, 1H), 5.10(m, 2H).
1H), 5.1(s, 2H), 3.66(s, 3H), 2.38(m, 2H), 2.3(d, 2H), 2.2(m, 1H), 2.1(m,1H),
1.9(m,2H), 1.4(m, 1H). m/z= 355.4(M+1).
2.2(d, 2H), 1.8(m,3H), 1.6(m,4H), 1.4(m,1H), 1,12(m,1H). m/z= 265.3
(M-1).
6.95(m,1H), 6.8(m, 1H), 3.8(m, 2H), 3.64(s, 3H), 3.2(m, 2H), 2.5, 2.3(m, 1H),
2.4, 2.2(d, 2H), 1.85(m, 2H), 1.64(m, 5H), 1.4(m,1H), 1.1(m, 1H), 0.88(s, 9H),
0.06(s, 6H). m/z=424.2(M+1).
ジオキサン中4M HCl(0.5mL)を、メタノール(1mL)中のメチル2−(4−(4−(N−(2−(tert−ブチルジメチルシリルオキシ)エチル)−4,6−ジクロロピリミジン−5−カルボキサミド)−3−フルオロフェニル)シクロヘキシル)アセテート(30mg、0.05mmol)の溶液に加えた。混合物を30分にわたって23℃にて撹拌した。反応混合物を濃縮し、溶媒を除去した。残渣をアセトニトリル(1mL)に溶かし、NEt3(0.05mL)をそれに加えた。反応混合物を18時間にわたって80℃にて撹拌した。EtOAc(15mL)および水(15mL)を反応混合物に加えた。有機層を分離し、MgSO4で乾燥し、濃縮した。粗材料を、ヘプタン中30〜50%EtOAcで溶出される4gシリカゲルカラムにより精製すると、無色の油としてメチル2−(4−(4−(4−クロロ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−3−フルオロフェニル)シクロヘキシル)アセテート(20mg)が得られた。m/z=448.4(M+1)。
メチル2−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)シクロヘキス−3−エニル)アセテート
4H), 5.65 (s, 1H)
2H), 3.65 (s, 3H), 3.95 (s, 4H)
4H), 3.71 (s, 3H)
1H), 3.65 (s, 3H), 5.74 (t, 1H)
1H), 2.20 (m, 2H), 2.56 (d, 2H), 3.67 (s, 3H), 6.50 (t, 1H).
メチル{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェニル]シクロヘキシル}アセテート
s, 1H), 4.63 (m, 2H), 3.98 (m, 2H), 3.64 (s, 3H), 2.44 (m, 1H), 2.21 (m, 2H),
1.81 (m, 5H), 1.42 (m, 2H), 1.10 (m, 2H). m/z = 411.3 (M+1). IC50
34.5nM (範囲30-40 nM).
{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}酢酸
2H), 2.42 (m, 1H), 2.08 (m, 2H), 1.75 (m, 5H), 1.42 (q, 2H), 1.05 (q, 2H)
. m/z = 397.3 (M+1). IC50 19.1nM (範囲5.2-63.6 nM).
(トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)酢酸
δ ppm 1.11 - 1.25 (m, 2 H) 1.36 (d, J=6.64 Hz, 3 H)
1.53 (q, J=12.88 Hz, 2 H) 1.75 - 1.96 (m, 5 H) 2.21 (d, J=7.03 Hz, 2 H) 2.46 -
2.58 (m, 1 H) 3.80 - 3.96 (m, 2 H) 4.92 - 5.03 (m, 1 H) 7.25 (d, 2 H) 7.31 (d,
2 H) 8.17 (s, 1 H). IC50 19.3nM (範囲7.0-30.4
nM).
メチル(トランス−4−{4−[(7S)−4−アミノ−7−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)アセテート
H) 1.74 - 2.04 (m, 5 H) 2.26 (d, J=6.64 Hz, 2 H) 2.43 - 2.64 (m, 1 H) 3.68 (s,
3 H) 3.95 - 4.16 (m, 1 H) 4.46 - 4.73 (m, 2 H) 7.10 (d, J=8.29 Hz, 2 H) 7.29
(d, J=8.29 Hz, 2 H) 8.22 (s, 1 H) m/z= 425.1 (M+1).
(トランス−4−{4−[(7S)−4−アミノ−7−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニルシクロヘキシル)酢酸
0.99 - 1.19 (m, 2 H) 1.08 (d, 3 H) 1.33 - 1.53 (m, 2 H) 1.57 - 1.88 (m, 5 H)
2.06 (d, J=6.65 Hz, 2 H) 2.30 - 2.61 (m, 1 H) 3.93 - 4.19 (m, 1 H) 4.38 - 4.69
(m, 2 H) 7.13 (d, J=8.31 Hz, 2 H) 7.26 (d, J=8.31 Hz, 2 H) 8.07 (s, 1 H) m/z=
411.2 (M+1). IC50 33.9nM.
2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−3−フルオロフェニル)シクロヘキシル)酢酸
2.64-2.5(m, 1H), 2.4, 2.2(d, 2H), 2.22(m, 1H), 1.90(m, 2H), 1.7(m, 4H), 1.54(m,
2H), 1.2(m, 2H). m/z=415.4(M+1). IC50 55.5nM (範囲29.1-89.6 nM).
(R1=H,R2=CH3,R3=CH3,R4=H,R9=CH2CH3)−エチル{トランス−4−[4−(4−アミノ−8,8−ジメチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}アセテートm/z = 453.3 (M+1) m/z = 453.3 (M+1); IC50 183nM
(R1=H,R2=CH3,R3=CH3,R4=H,R9=H)−{トランス−4−[4−(4−アミノ−8,8−ジメチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}酢酸1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.59 (br s, 1H) 7.20 (m, 4H), 3.79 (m, 2H), 2.42 (m,
1H), 2.08 (m, 2H), 1.78 (m, 4H), 1.67 (m, 1H), 1.43 (m, 2H), 1.24 (s, 6H), 1.05
(m, 2H). m/z = 425.3 (M+1). IC50 146nM (範囲125.0-170.0 nM)
(R1=CH3,R2=H、R3=H、R4=H、R9=CH3)−メチル{トランス−4−[4−(4−アミノ−2−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}アセテート。1H NMR (400 MHz, クロロホルム-d) ppm δ 1.04 - 1.32 (m, 2 H) 1.39 - 1.56 (m, 2 H) 1.77 - 1.98 (m, 5 H) 2.15
- 2.32 (m, 2 H) 2.38 (s, 0 H) 2.41 - 2.60 (m, 4 H) 3.68 (s, 3 H) 3.91 - 4.03
(m, 2 H) 4.56 - 4.73 (m, 2 H) 5.60 (br. s., 1 H) 7.12 - 7.22 (m, 2 H) 7.22 -
7.36 (m, 2 H) 8.23 (br. s., 1 H); m/z = 425.3 (M+1). IC50
239nM
(R1=CH3,R2=H,R3=H,R4=H,R9=H)−{トランス−4−[4−(4−アミノ−2−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−l)フェニル]シクロヘキシル}酢酸1H NMR (400 MHz, CDCl3) δ6.98 (m, 2H) 6.85 (m, 2H), 4.43 (m, 2H), 3.78 (m, 2H), 2.20 (m, 1H),
2.08 (s, 3H), 1.90 (m, 2H), 1.59 (m, 5H), 1.20 (m, 2H), 0.83 (m, 2H). m/z
= 411.4 (M+1). IC50 59.4nM (範囲49.9-78.2 nM)
(R1=H,R2=CH3,R3=H,R4=H,R9=H)−{4−[4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−シクロヘキシル}−酢酸1H NMR (400 MHz, メタノール-d4) δppm 1.11 - 1.27 (m, 2 H) 1.37 (d, J=4.98 Hz, 3 H) 1.46 - 1.62 (m, 2
H) 1.76 - 2.00 (m, 5 H) 2.21 (d, J=5.39 Hz, 2 H) 2.45 - 2.61 (m, 1 H) 3.80 -
3.98 (m, 2 H) 4.93 - 5.05 (m, 1 H) 7.20 - 7.28 (m, 2 H) 7.29 - 7.36 (m, 2 H)
8.17 (s, 1 H) m/z = 411.4, 409.5 (M+1). IC50 125nM (範囲52.8-492.0 nM)
(R1=H,
1.37 (d, J=6.64 Hz, 3 H) 1.53 (q, J=12.75 Hz, 2 H) 1.77 - 1.96 (m, 5 H) 2.21
(d, J=7.03 Hz, 2 H) 2.45 - 2.59 (m, 1 H) 3.85 - 3.92 (m, 2 H) 4.94 - 5.04 (m, 1
H) 7.22 - 7.28 (m, 2 H) 7.28 - 7.35 (m, 2 H) 8.17 (s, 1 H); m/z = 411.4, 409.5
(M+1). IC50 625nM
(R1=H,R2=CH2CH3,R3=H,R4=H,R9=H)−{4−[4−(4−アミノ−8−エチル−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−シクロヘキシル}−酢酸m/z = 425.2(M+1) IC50 1330nM (範囲1070-1660 nM)
(R1=H,R2=H,R3=H,
1.86 (m,5 H) 2.11 (d, J=7.06 Hz, 2 H) 2.36 - 2.45 (m, 1 H) 4.00 - 4.11 (m, 1 H)
4.44 - 4.54 (m, 1 H) 4.61 (d, J=11.22 Hz, 1 H) 7.14 (d, J=8.31 Hz, 2 H) 7.26
(d, J=8.31 Hz, 2 H) 8.07 (s, 1 H), m/z = 411.2 (M+1). IC50
24.7nM (範囲20.2-36.7 nM)
(R1=H,R2=H,R3=H,R4=CH3,R9=H)−4−[4−(4−アミノ−7−メチル−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−シクロヘキシル}−酢酸1H NMR (400 MHz, メタノール-d4) δ ppm 1.08 - 1.34 (m, 2 H) 1.26 (d, 3 H) 1.45 - 1.63 (m, 2 H) 1.76
-2.01 (m, 5 H) 2.22 (d, J=7.06 Hz, 2 H) 2.54 (t, J=7.69 Hz, 1 H) 4.16 - 4.37
(m, 1 H) 4.65 - 4.87 (m, 2 H) 7.17(d, J=8.31 Hz, 2 H) 7.33 (d, J=8.31 Hz, 2 H)
8.24 (s, 1 H) m/z = 411.2 (M+1). IC50 27.3nM (範囲13.6-77.9 nM)
下に示す、{シス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェニル]シクロヘキシル}酢酸
(R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)シクロヘキシル)酢酸
(400MHz, CD3OD): δ
8.18(s, 1H), 7.38(m, 1H), 7.10(m,2H), 4.96(m, 1H), 3.90(m, 2H), 2.9(m,1H),
2.8,2.3(m, 1H), 2.4, 2.2(d, 2H), 1.90(m, 2H), 1.7(m, 2H), 1.54(m, 2H),1.4(d,
3H), 1.2(m, 2H)
2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−クロロフェニル)シクロヘキシル)酢酸(400MHz, CD3OD): δ 8.18(s, 1H), 7.42(m, 2H),
7.14(m,1H), 4.66(m, 2H), 3.98(m, 2H), 3.0(m,1H), 2.3(m, 1H), 2.44, 2.2(d, 2H),
1.95-1.42(m, 6H), 1.2(m, 1H)
2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)シクロヘキシル)酢酸(400MHz, CD3OD): δ 8.18(s, 1H), 7.38(m, 1H),
7.1(m,2H), 4.68(m, 2H), 4.02(m, 2H), 2.9(m, 1H), 2.24(m, 1H), 2.4, 2.2(d, 2H),
1.90(m, 2H), 1.7(m, 2H), 1.54(m, 2H), 1.2(m, 2H)
2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−メチルフェニル)シクロヘキシル)酢酸(400MHz, CD3OD): δ 8.18(s, 1H), 7.32(m, 1H),
7.08(m,2H), 4.68(m, 2H), 3.98(m, 2H), 2.78(m, 1H), 2.38(s, 3H), 2.32(m, 1H),
2.4, 2.2(d, 2H), 1.90-1.5(m, 7H), 1.2(m, 7H)
(R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−メチルフェニル)シクロヘキシル)酢酸
(400MHz, CD3OD): δ
8.18(s, 1H), 7.36(m, 1H), 7.10(m,2H), 4.96(m, 1H), 3.92(m, 2H), 2.78(m,1H),
2.34(s, 3H), 2.3(m, 1H), 2.5, 2.2(d, 2H), 1.90(m, 1H), 1.7(m, 3H), 1.54(m,
3H),1.38(d, 3H), 1.2(m, 1H)
(R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−3−フルオロフェニル)シクロヘキシル)酢酸
(400MHz, CD3OD): δ
8.18(s, 1H), 7.28(m, 1H), 7.08(m, 2H), 4.96(m, 1H), 3.92(m, 2H), 2.6(m,1H),
2.4,2.2(d, 2H), 2.3(m, 1H), 1.90(m, 2H), 1.7(m, 4H),1.5(m, 1H), 1.4(d, 3H),
1.2(m, 1H)
2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]−オキサゼピン−6(5H)−イル)−3−メチルフェニル)シクロヘキシル)酢酸−1H NMR (400 MHz, メタノール-d4) δ ppm 1.12 - 1.25 (m, 1 H) 1.45 - 1.59 (m, 1 H) 1.62 - 1.76 (m, 3 H)
1.88 (t, J=15.61 Hz, 3 H) 2.22 (d, J=3.51 Hz, 3 H) 2.26 (d, J=3.90 Hz, 1 H)
2.43 (d, J=7.81 Hz, 2 H) 2.46 - 2.55 (m, 1 H) 3.78 - 4.05 (m, 2 H) 4.60 - 4.78
(m, 2 H) 7.07 - 7.26 (m, 3 H) 8.16 (s, 1 H); LCMSは411.4だった( t=2.0分).
(シス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]−2−フルオロフェニル}シクロヘキシル)酢酸(400MHz, CD3OD): δ 8.18(s, 1H), 7.38(m, 1H),
7.10(m,2H), 4.96(m, 1H), 3.90(m, 2H), 2.9(m,1H), , 2.4(d, 2H), 2.3(m, 1H),
1.90(m, 1H), 1.7-1.5(m, 6H), 1.4(d, 3H), 1.2(m, 1H)
(トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]−2−フルオロフェニル}シクロヘキシル)酢酸(400MHz, CD3OD): δ 8.18(s, 1H), 7.38(m, 1H),
7.10(m,2H), 4.96(m, 1H), 3.88(m, 2H), 2.8(m,1H), 2.2(d, 2H), 1.90(m, 5H),
1.58(q, 2H), 1.4(d, 3H), 1.2(m, 2H).
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(メチルスルホニル)アセトアミド
2H), 3.20 (s, 3H), 2.42 (m, 1H), 2.17 (m, 2H), 1.73 (m, 5H), 1.40 (m, 2H), 1.05
m, 2H). m/z = 474.4 (M+1). IC50 44.5nM (範囲34.2-75.0 nM).
(トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)アセトアミド
1.36 (d, J=6.24 Hz, 3 H) 1.45 - 1.60 (m, 2 H) 1.73 - 1.95 (m, 5 H) 2.12 (d,
J=7.03 Hz, 2 H) 2.52 (t, J=12.29 Hz, 1 H) 3.80 - 3.96 (m, 2 H) 4.92 - 5.03 (m,
1 H) 7.22 - 7.27 (m, 2 H) 7.27 - 7.34 (m, 2 H) 8.17 (s, 1 H). IC50
52.2nM (範囲11.4-68.1 nM).
(R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)シクロヘキシル)アセトアミド
DMSO): δ 8.18(s, 1H), 7.6(br s, 1H), 7.34(m, 3H),
7.20(m,2H), 6.72(br s, 1H), 4.9(m, 1H), 3.82(m, 2H), 2.87(m,1H), 2.2(m, 3H),
1.7-1.44(m, 8H), 1.2(d, 3H). IC50 11.3nM (範囲7.3-19.9 nM).
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−[(トリフルオロメチル)スルホニル]アセトアミド1H NMR (400 MHz, DMSO-d6): δ8.23 (s, 1H), 8.10 (br s, 2H) 7.22 (m, 4H), 4.62 (m, 2H), 3.99 (m,
2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.71 (m, 5H), 1.39 (m, 2H), 1.00 (m,
2H). m/z = 528.4 (M+1)
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}アセトアミド1H NMR (400 MHz, DMSO-d6): δ8.17 (s, 1H), 7.59 (br s, 2H) 7.24 (s, 4H), 4.58 (m, 2H), 3.96 (m,
2H), 2.44 (m, 1H), 1.97 (m, 2H), 1.78 (m, 4H), 1.68 (m, 1H), 1.42 (m, 2H), 1.03
(m, 2H). m/z = 396.2 (M+1)
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−1H−テトラゾール−5−イルアセトアミド
1H NMR
(400 MHz, DMSO-d6): δ8.17 (s, 1H), 7.63 (br
s, 2H) 7.22 (m, 4H), 4.57 (m, 2H), 3.90 (m, 2H), 2.40 (m, 1H), 2.33 (m, 2H),
1.78 (m, 5H), 1.40 (m, 2H), 1.10 (m, 2H). m/z = 464.4 (M+1)
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−エチルアセトアミド
1H NMR
(400 MHz, DMSO-d6) δppm 8.11 (s, 1 H) 7.74 (t, J=5.39
Hz, 1 H) 7.55 (br. s., 2 H) 7.18 - 7.27 (m, 4 H) 4.49 - 4.57 (m, 2 H) 3.86 -
3.95 (m, 2 H) 2.94 - 3.06 (m, 2 H) 2.36 - 2.48 (m, 1 H) 1.92 (d, J=6.64 Hz, 1
H) 1.73 (t, J=9.75 Hz, 6 H) 1.32 - 1.48 (m, 2 H) 0.88 - 1.09 (m, 5 H)
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−シクロヘキシルアセトアミド
質量スペクトルM/Z (M +1) 478; RT = 2.843
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−シクロペンチルアセトアミド
質量スペクトルM/Z (M +1) 464; RT = 2.6
2−{トランス−4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル)シクロヘキシル}−N−2−インダニル−アセトアミド
質量スペクトルM/Z (M +1) 512; RT = 2.586
2−{トランス−4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル)シクロヘキシル}−N−tert−ブチルアセトアミド
質量スペクトルM/Z (M +1) 452; RT = 2.633
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−[(1S)−1,2,2−トリメチルプロピル]アセトアミド質量スペクトルM/Z (M +1) 480; RT = 2.597
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(1,1−ジメチルプロピル)アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.763
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(2,2−ジメチルプロピル)アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.498
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−[(2S)−2−メチルブチル]アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.508
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(1−エチルプロピル)アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.463
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(1,2−ジメチルプロピル)アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.991
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−[(1S)−1−メチルブチル]アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.808
2−{4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−シクロヘキシル}−N−メチル−アセトアミド1H NMR (400 MHz, DMSO-d6) δppm
0.89 - 1.15 (m, 2 H) 1.30 - 1.50 (m, 2 H) 1.59 - 1.83 (m, 5 H) 1.85 - 1.98 (m,
2 H) 2.39 - 2.59 (m, 2 H) 3.02 - 3.38 (m, 3 H) 3.83 - 3.96 (m, 2 H) 4.46 - 4.59
(m, 2 H) 7.15 - 7.29 (m, 2 H) 7.47 - 7.59 (m, 2 H) 7.66 (br. s., 2 H) 8.11 (s,
1 H).
2−{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f]−[1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}−N−(2−メチルブチル)アセトアミド
質量スペクトルM/Z (M +1) 466; RT = 2.822
{トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}アセトニトリル
2H), 2.43 (m, 3H), 1.78 (m, 4H), 1.63 (m, 1H), 1.43 (m, 2H), 1.08 (m,
2H). m/z = 378.3 (M+1). IC50 64.3nM (範囲51.2-91.1 nM).
(トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)アセトニトリル
H) 1.69 - 1.84 (m, 1 H) 1.90 - 2.05 (m, 4 H) 2.31 (d, J=6.65 Hz, 2 H) 2.46 -
2.60 (m, 1 H) 3.76 - 3.96 (m, 2 H) 4.86 - 5.00 (m, 1 H) 5.58 (br. s., 1 H) 7.20
(d, 2 H) 7.27 (d, 2 H) 7.99 (br. s., 1 H) 8.29 (s, 1 H). IC50
38.4nM (範囲30.1-48.1 nM).
(R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)シクロヘキシル)アセトニトリル
CD3OD): δ 8.18(s, 1H), 7.38(m, 1H), 7.10(m,2H), 4.96(m,
1H), 3.90(m, 2H), 2.84(m,1H) , 2.6,2.4(d, 2H), 1.96-1.56(m, 4H), 1.4(d, 3H),
1.28(m, 1H), 0.88(m, 4H). IC50 12.9nM (範囲4.5-22.2 nM).
4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−シクロヘキサンカルボン酸
DMSO-d6) δ ppm 1.37 - 1.55 (m, 4 H) 1.81 (br. s., 2 H)
1.99 (br. s., 2 H) 2.25 (br. s., 2 H) 3.85 - 4.03 (m, 2 H) 4.45 - 4.61 (m, 2 H)
7.20 - 7.32 (m, 4 H) 7.58 (s, 2 H) 8.15 (s, 1 H). m/z = 381 (M-1).
IC50 7.8 nM (範囲5.8-10.5 nM)
4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプタン−6−イル)−フェニル]−シクロヘキサンカルボン酸メチルエステル
(m, 2 H) 2.03 - 2.14 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.46 - 2.58 (m, 1 H) 3.59 -
3.70 (m, 2 H) 3.91 - 4.03 (m, 2 H) 4.55 - 4.72 (m, 2 H) 5.64 (br. s., 1 H) 7.10
- 7.30 (m, 4 H) 8.14 (br. s., 1 H) 8.25 (s, 1 H). m/z = 397.4 (M+1).
IC50 47.3nM (範囲45.2-49.5 nM)
4−アミノ−6−{4−[4−(1H−テトラゾール−5−イルメチル)−シクロヘキシル]−フェニル}−7,8−ジヒドロ−6H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−5−オン
0.96 - 1.28 (m, 2 H) 1.25 - 1.45 (m, 2 H) 1.62 - 1.80 (m, 5 H) 2.31 - 2.50 (m,
1 H) 2.62 - 2.76 (m, 2 H) 3.85 - 3.95 (m, 2 H) 4.45 - 4.57 (m, 2 H) 7.13 - 7.29
(m, 4 H) 7.55 (br. s., 2 H) 8.10 (s, 1 H) m/z = 421.3 (M+1). IC50
76.2nM (範囲47.5-163 nM).
4−アミノ−6−(4−ヨードフェニル)−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−5(6H)−オン
0.92 (s, 9H), 0.04 (d, 6H). m/z = 378.2 (M+1).
(s, 1H), 7.62 (d, 2H), 7.17 (d, 2H), 4.07 (t, 2H), 3.91 (q, 2H). m/z =
438.0 (M+1).
2H). m/z = 402.0 (M+1).
2H), 3.96 (m, 2H).
m/z = 383.1 (M+1).
メチル(+)−{4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェニル]シクロヘキス−3−エン−1−イル}アセテート
(+)−{4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェニル]シクロヘキス−3−エン−1−イル}酢酸
Hz, 2 H), 7.31 (d, 2H), 6.13 (br. s., 1H), 4.58 (t, 2H), 3.97 (br. s., 2H),
2.42 (br. s., 2H), 2.32 (d, 2H), 2.23 (d, 2H), 1.92 - 2.03 (m, 1H), 1.83 - 1.93
(m, 1H), 1.31 - 1.45 (m, 1H). m/z = 395.3 (M+1). IC50
36.4nM (範囲33.8-39.3 nM).
メチル{4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6−(5H)−イル)フェノキシ]フェニル}アセテート
2H), 4.69 (m, 2H), 4.00 (m, 2H), 3.68 (s, 3H). m/z = 421.2 (M+1).
IC50 254nM.
±{(1R,3aS,4R,6aR)−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]オクタヒドロペンタレン−1−イル}酢酸
3H), ), 3.72 (s, 3H), 3.38 (d, 1H), 2.80 (m, 1H), 2.43 (m, 2H), 1.97 (m, 1H),
1.75-1.32 (m, 7H). m/z = 495.3 (M+1).
2H), 3.95 (m, 2H), 3.08 (d, 1H), 2.64 (m, 1H), 2.39 (m, 2H), 2.24 (m, 1H),
1.87-1.10 (m, 7H). m/z = 467.3 (M+1).
2H), 3.96 (m, 2H), 3.13 (s, 1H), 2.62-1.12 (m, 13H). m/z = 423.3
(M+1). IC50 <10nM (範囲<3-27.2
nM).
(1R,5R,6S)−6−[4−(4−アミノ−5−オキソ−7,8−ジヒドロ−5H−9−オキサ−1,3,6−トリアザ−ベンゾシクロヘプテン−6−イル)−フェニル]−トリシクロ[3.2.1.0*2,4*]オクタン−3−カルボン酸メチルエステル
(±)−(1R,5R,6S)−6−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]トリシクロ[3.2.1.0〜2,4〜]オクタン−3−カルボン酸
2H), 2.89 (s, 1H), 2.42 (m, 1H), 1.83 (m, 2H), 1.60 (m, 2H), 1.38 (ABパターン, 2H), 0.90 (s, 2H). m/z = 407.4 (M+1). IC50
34.7nM (範囲26.7-58.6 nM).
動物、特に、哺乳動物(例えば、ヒト)における式(1)の化合物、薬学的に許容できる化合物の塩(本明細書に記載されているような)の有用性は、以下で議論されるin vitroおよびin vivoアッセイを包含する当業者に知られている従来のアッセイにおけるそれらの活性により証明することができる。そのようなアッセイは、式(1)の化合物の活性を、他の知られている化合物の活性と比較することができる手段も提供する。
ヒト完全長ジアシルグリセロール:アシルCoAアシルトランスフェラーゼ1(DGAT−1)をSf9昆虫細胞で発現させ、次いで、細胞を溶解し、粗膜画分(105,000×gペレット)を調製した。DGAT−1遺伝子は、J.Biol.Chem.273:26765、1998およびUS6,100,077に記載されているヒトDGAT−1遺伝子である。
経口グルコース負荷試験(「OGTT」)は、少なくとも1930年代から(Pincusら、Am.J.Med.Sci、188:782(1934))ヒトで使用されており、患者における治療剤の有効性を評価するためではないが、ヒト糖尿病の診断で日常的に使用されている。
下記のスクリーニングを使用し、一晩絶食後のSprague−Dawleyラットにおける飼料摂取阻害への試験化合物の有効性を評価した。
Claims (27)
- 式
(式中、
(a)R1は、H −(C1〜C4)アルキル、−(C1〜C4)ペルフルオロアルキル、−(C1〜C4)ペルフルオロアルコキシ、または−(C1〜C4)アルコキシであり、
(b)R2およびR3は、別々に、独立して、H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであるか、
R2およびR3は、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルであり、
(c)R4は、Hまたは−(C1〜C4)アルキルであり、
(d)R5a、R5b、R5cおよびR5dは、各々独立して、H、F、Cl、Br、−(C1〜C4)アルキル、−OHまたは−O−(C1〜C4)アルキルであり、
(e)Qは、−O−または結合であり、
(f)Aは、−(C3〜C6)シクロアルキレン基、−(C3〜C6)シクロアルケニレン基またはフェニレンであり、
(g)Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
(h)R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
(i)R8は、−OR9またはNHR10であり、
(j)R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
(k)R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)。 - (a)R1、R2、R3およびR4が、各々独立して、Hまたは−CH3であり、
(b)R5bおよびR5cが、各々Hであり、
(c)R5dが、H、FまたはClであり、
(d)R5aが、H、F、Clまたはメチルであり、
(e)Zが、−CH2−または結合であり、
(f)R7が、C(O)R8またはシアノである
請求項1に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - Qが、結合であり、
Aが、−(C3〜C10)シクロアルキレン基または−(C3〜C10)シクロアルケニレン基である
請求項2に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - R5dが、Hである
請求項3に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - Aが、1,4−シクロヘキシレン、シクロヘキス−3−エン−1,4−ジ−イル、トリシクロ[3.2.1.0〜2,4〜]オクチレン−1,3−ジ−イルまたはオクタヒドロペンタレン−1,4−ジ−イルである
請求項4に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - 式
(式中、
R1は、Hまたは−CH3であり、
R2は、Hまたは−CH3であり、
R3は、Hまたは−CH3であり、
R4は、Hまたは−CH3であり、
R5aは、H、F、Clまたはメチルであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)。 - Zが、−CH2−である
請求項6に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - R7が、−C(O)NHR10である
請求項7に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - R7が、−CNである
請求項7に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - {トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}アセトニトリルである請求項9に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- R7が、−C(O)OHである
請求項7に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - 2−(4−(4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)シクロヘキシル)酢酸である請求項11に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- {トランス−4−[4−(4−アミノ−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)フェニル]シクロヘキシル}酢酸である請求項11に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- R2が、(R)−メチルである
請求項7に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - R7が、−CNである
請求項14に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - (トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)アセトニトリルである請求項14に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- R7が、−C(O)OHである
請求項14に記載の化合物、もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。 - (トランス−4−{4−[(8R)−4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル]フェニル}シクロヘキシル)酢酸である請求項17に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- (R)−2−(4−(4−(4−アミノ−8−メチル−5−オキソ−7,8−ジヒドロピリミド[5,4−f][1,4]オキサゼピン−6(5H)−イル)−2−フルオロフェニル)−シクロヘキシル)酢酸である請求項17に記載の化合物もしくはその互変異性体、または薬学的に許容できる前記化合物もしくは互変異性体の塩。
- (a)式
(式中、
R1は、H −(C1〜C4)アルキル、−(C1〜C4)ペルフルオロアルキル、−(C1〜C4)ペルフルオロアルコキシ、または−(C1〜C4)アルコキシであり、
R2およびR3は、別々に、独立して、H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであるか、
R2およびR3は、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルであり、
R4は、Hまたは−(C1〜C4)アルキルであり、
R5a、R5b、R5cおよびR5dは、各々独立して、H、F、Cl、Br、−(C1〜C4)アルキル、−OHまたは−O−(C1〜C4)アルキルであり、
Qは、−O−または結合であり、
Aは、−(C3〜C6)シクロアルキレン基、−(C3〜C6)シクロアルケニレン基またはフェニレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)、および
(b)薬学的に許容できる担体、ビヒクル、希釈剤または賦形剤
を含む医薬組成物。 - (a)式
(式中、
R1は、Hまたは−CH3であり、
R2は、Hまたは−CH3であり、
R3は、Hまたは−CH3であり、
R4は、Hまたは−CH3であり、
R5aは、H、F、Clまたはメチルであり、
Aは、1,4−シクロヘキシレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)、および
(b)薬学的に許容できる担体、ビヒクル、希釈剤または賦形剤
を含む請求項20に記載の医薬組成物。 - そのような治療を必要としている哺乳動物において2型糖尿病を治療するための方法であって、前記哺乳動物に、治療有効量の式
(式中、
R1は、H −(C1〜C4)アルキル、−(C1〜C4)ペルフルオロアルキル、−(C1〜C4)ペルフルオロアルコキシ、または−(C1〜C4)アルコキシであり、
R2およびR3は、別々に、独立して、H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであるか、
R2およびR3は、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルであり、
R4は、Hまたは−(C1〜C4)アルキルであり、
R5a、R5b、R5cおよびR5dは、各々独立して、H、F、Cl、Br、−(C1〜C4)アルキル、−OHまたは−O−(C1〜C4)アルキルであり、
Qは、−O−または結合であり、
Aは、−(C3〜C6)シクロアルキレン基、−(C3〜C6)シクロアルケニレン基またはフェニレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)を投与することを含む方法。 - そのような治療を必要としている哺乳動物において2型糖尿病を治療するための請求項22に記載の方法であって、前記哺乳動物に、治療有効量の式
(式中、
R1は、Hまたは−CH3であり、
R2は、Hまたは−CH3であり、
R3は、Hまたは−CH3であり、
R4は、Hまたは−CH3であり、
R5aは、H、F、Clまたはメチルであり、
Aは、1,4−シクロヘキシレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)を投与することを含む方法。 - 前記哺乳動物が、ヒトである請求項23に記載の方法。
- そのような治療を必要としている哺乳動物において肥満症を治療するための方法であって、前記哺乳動物に、治療有効量の式
(式中、
R1は、H −(C1〜C4)アルキル、−(C1〜C4)ペルフルオロアルキル、−(C1〜C4)ペルフルオロアルコキシ、または−(C1〜C4)アルコキシであり、
R2およびR3は、別々に、独立して、H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであるか、
R2およびR3は、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルであり、
R4は、Hまたは−(C1〜C4)アルキルであり、
R5a、R5b、R5cおよびR5dは、各々独立して、H、F、Cl、Br、−(C1〜C4)アルキル、−OHまたは−O−(C1〜C4)アルキルであり、
Qは、−O−または結合であり、
Aは、−(C3〜C6)シクロアルキレン基、−(C3〜C6)シクロアルケニレン基またはフェニレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)を投与することを含む方法。 - そのような治療を必要としている哺乳動物において肥満症を治療するための請求項25に記載の方法であって、前記哺乳動物に、治療有効量の式
(式中、
R1は、Hまたは−CH3であり、
R2は、Hまたは−CH3であり、
R3は、Hまたは−CH3であり、
R4は、Hまたは−CH3であり、
R5aは、H、F、Clまたはメチルであり、
Aは、1,4−シクロヘキシレンであり、
Zは、−C(R6a)(R6b)−または結合(R6aおよびR6bは、各々独立して、−Hまたは−(C1〜C4)アルキルであるか、R6aおよびR6bは、それらが接続している炭素と一緒になって、−(C3〜C6)シクロアルキルである)であり、
R7は、C(O)R8、シアノ、ヒドロキシル、−(C1〜C4)アルコキシ、−(C1〜C4)ペルフルオロアルコキシまたはカルボン酸模倣体であり、
R8は、−OR9またはNHR10であり、
R9は、−H、−(C1〜C4)アルキル、または−(C1〜C4)ペルフルオロアルキルであり、
R10は、−H、−(C1〜C4)アルキル、テトラゾリルまたはS(O)2CF3である)を投与することを含む方法。 - 前記哺乳動物が、ヒトである請求項26に記載の方法。
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KR (1) | KR20100032443A (ja) |
CN (1) | CN101772504A (ja) |
AP (1) | AP2010005163A0 (ja) |
AR (1) | AR067780A1 (ja) |
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CR (1) | CR11223A (ja) |
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DK (1) | DK2185567T3 (ja) |
DO (1) | DOP2010000046A (ja) |
EA (1) | EA201000050A1 (ja) |
EC (1) | ECSP109932A (ja) |
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MA (1) | MA31580B1 (ja) |
PA (1) | PA8791601A1 (ja) |
PE (1) | PE20090897A1 (ja) |
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PT (1) | PT2185567E (ja) |
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TW (1) | TWI356059B (ja) |
UA (1) | UA94833C2 (ja) |
WO (1) | WO2009016462A2 (ja) |
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JP2015535848A (ja) * | 2012-10-03 | 2015-12-17 | アドビナス セラピューティクス リミテッド | スピロ環化合物、その組成物及びその医薬応用 |
JP2016500109A (ja) * | 2012-11-23 | 2016-01-07 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーGlaxoSmithKline LLC | ジアシルグリセロールアシルトランスフェラーゼ阻害剤としての新規化合物 |
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