JPH11335373A - Arylmethylenepiperidinopyrimidine derivative - Google Patents
Arylmethylenepiperidinopyrimidine derivativeInfo
- Publication number
- JPH11335373A JPH11335373A JP10142621A JP14262198A JPH11335373A JP H11335373 A JPH11335373 A JP H11335373A JP 10142621 A JP10142621 A JP 10142621A JP 14262198 A JP14262198 A JP 14262198A JP H11335373 A JPH11335373 A JP H11335373A
- Authority
- JP
- Japan
- Prior art keywords
- group
- mes
- nap
- compound
- hep
- 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.)
- Withdrawn
Links
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- -1 2,4-dichloropyrimidine compound Chemical class 0.000 abstract description 46
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 abstract description 19
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 abstract description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 9
- 239000012442 inert solvent Substances 0.000 abstract description 9
- 208000019901 Anxiety disease Diseases 0.000 abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 5
- 230000036506 anxiety Effects 0.000 abstract description 5
- PYQBLUMMOYPILA-UHFFFAOYSA-N 4-(4-benzylidenepiperidin-1-yl)-n-(2-bromo-4-propan-2-ylphenyl)-n-ethyl-6-methylpyrimidin-2-amine;hydrochloride Chemical compound Cl.C=1C=C(C(C)C)C=C(Br)C=1N(CC)C(N=1)=NC(C)=CC=1N(CC1)CCC1=CC1=CC=CC=C1 PYQBLUMMOYPILA-UHFFFAOYSA-N 0.000 abstract description 2
- 102100021752 Corticoliberin Human genes 0.000 abstract 2
- 230000006806 disease prevention Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 57
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 206010008118 cerebral infarction Diseases 0.000 description 8
- 239000002274 desiccant Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 238000009739 binding Methods 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010048962 Brain oedema Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 208000030814 Eating disease Diseases 0.000 description 4
- 208000019454 Feeding and Eating disease Diseases 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 4
- 206010019196 Head injury Diseases 0.000 description 4
- 208000023105 Huntington disease Diseases 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 208000018737 Parkinson disease Diseases 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 208000006752 brain edema Diseases 0.000 description 4
- 208000026106 cerebrovascular disease Diseases 0.000 description 4
- 235000014632 disordered eating Nutrition 0.000 description 4
- 206010013663 drug dependence Diseases 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 208000011117 substance-related disease Diseases 0.000 description 4
- BTLKROSJMNFSQZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyrimidine Chemical compound CC1=CC(Cl)=NC(Cl)=N1 BTLKROSJMNFSQZ-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OVWOHBISQSURQC-UHFFFAOYSA-N C(C1=CC=CC=C1)=C1CCN(CC1)C1=NC(=NC(=C1)C)NC1=C(C=C(C=C1)C(C)C)Br Chemical compound C(C1=CC=CC=C1)=C1CCN(CC1)C1=NC(=NC(=C1)C)NC1=C(C=C(C=C1)C(C)C)Br OVWOHBISQSURQC-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- FIYRZOAUPPNGAO-UHFFFAOYSA-N 1-(diethoxyphosphorylmethyl)-4-fluorobenzene Chemical compound CCOP(=O)(OCC)CC1=CC=C(F)C=C1 FIYRZOAUPPNGAO-UHFFFAOYSA-N 0.000 description 1
- RRXCMCLPSLOZLY-UHFFFAOYSA-N 1-[2-(2-bromo-n-ethyl-4-propan-2-ylanilino)-6-methylpyrimidin-4-yl]piperidin-4-one Chemical compound C=1C=C(C(C)C)C=C(Br)C=1N(CC)C(N=1)=NC(C)=CC=1N1CCC(=O)CC1 RRXCMCLPSLOZLY-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- SNAVVLKSDXTQFW-UHFFFAOYSA-N 2-bromo-4-propan-2-ylaniline;hydrochloride Chemical compound Cl.CC(C)C1=CC=C(N)C(Br)=C1 SNAVVLKSDXTQFW-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- PVYCHTWXOPDNCE-UHFFFAOYSA-N 4-(1,3-dioxolan-2-yl)piperidine Chemical compound O1CCOC1C1CCNCC1 PVYCHTWXOPDNCE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GKHTYRZQRHFMIL-UHFFFAOYSA-N 4-benzylidenepiperidine;hydrochloride Chemical compound Cl.C1CNCCC1=CC1=CC=CC=C1 GKHTYRZQRHFMIL-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- CBYGSLVCENROCC-UHFFFAOYSA-N C(C1=CC=CC=C1)=C1CCN(CC1)C1=NC(=NC(=C1)C)Cl Chemical compound C(C1=CC=CC=C1)=C1CCN(CC1)C1=NC(=NC(=C1)C)Cl CBYGSLVCENROCC-UHFFFAOYSA-N 0.000 description 1
- 229940122010 Corticotropin releasing factor antagonist Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000958 aryl methylene group Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GLMHJKQHYAVPMZ-UHFFFAOYSA-N butyl piperidine-1-carboxylate Chemical compound CCCCOC(=O)N1CCCCC1 GLMHJKQHYAVPMZ-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000002769 corticotropin releasing factor antagonist Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004188 dichlorophenyl group Chemical group 0.000 description 1
- AIPRAPZUGUTQKX-UHFFFAOYSA-N diethoxyphosphorylmethylbenzene Chemical compound CCOP(=O)(OCC)CC1=CC=CC=C1 AIPRAPZUGUTQKX-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KEBXGLIHHLGNJH-UHFFFAOYSA-N n-methylsulfanylaniline Chemical compound CSNC1=CC=CC=C1 KEBXGLIHHLGNJH-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、うつ症、不安症、
アルツハイマー病、パーキンソン病、ハンチントン舞踏
病、摂食障害、高血圧、消化器疾患、薬物依存症、脳梗
塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患な
どCorticotropin Releasing Factor（ＣＲＦ）が関与し
ているとされる疾患の治療剤に関する。[0001] The present invention relates to depression, anxiety,
Corticotropin Releasing Factor (CRF) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases The present invention relates to a therapeutic agent for a disease in which is considered to be involved.
【０００２】[0002]
【従来の技術】ＣＲＦは４１個のアミノ酸から成るホル
モンであり（Science, 213, 1394-1397, 1981;J. Neuro
sci., 7, 88-100, 1987）、ストレスに対する生体反応
の中核的役割を果たしていることが示唆されている（Ce
ll. Mol. Neurobiol., 14, 579-588, 1994; Endocrino
l.,132, 723-728, 1994; Neuroendocrinol. 61, 445-45
2,1995)。ＣＲＦは視床下部−下垂体−副腎系を介して
末梢の免疫系、交感神経系に作用する経路と中枢神経系
において神経伝達物質として機能する２つの経路がある
（in CorticotropinReleasing Factor: Basic and Clin
ical Studies of aNeuropeptide, pp 29-52, 1990）。
下垂体除去ラット及び正常ラットにＣＲＦを脳室内投与
すると両ラットで不安様症状（Pharmacol. Rev., 43, 4
25-473, 1991; Brain Res. Rev., 15,71-100, 1990）が
惹起される。すなわち、ＣＲＦは視床下部−下垂体−副
腎系に対する関与と中枢神経系において神経伝達物質と
して機能する経路が考えられる。2. Description of the Related Art CRF is a hormone consisting of 41 amino acids (Science, 213, 1394-1397, 1981; J. Neuro
sci., 7, 88-100, 1987), suggesting that it plays a central role in biological responses to stress (Ce
ll. Mol. Neurobiol., 14, 579-588, 1994; Endocrino
l., 132, 723-728, 1994; Neuroendocrinol. 61, 445-45
2,1995). CRF has two pathways that act on the peripheral immune system and sympathetic nervous system via the hypothalamus-pituitary-adrenal system and two pathways that function as neurotransmitters in the central nervous system (in Corticotropin Releasing Factor: Basic and Clin).
ical Studies of aNeuropeptide, pp 29-52, 1990).
Intraventricular administration of CRF to hypophysectomized rats and normal rats caused anxiety-like symptoms in both rats (Pharmacol. Rev., 43, 4).
25-473, 1991; Brain Res. Rev., 15,71-100, 1990). That is, CRF may be involved in the hypothalamus-pituitary-adrenal system and a pathway that functions as a neurotransmitter in the central nervous system.
【０００３】ＣＲＦが関与した疾患は１９９１年 Owens
及び Nemeroff の総説（Pharmacol. Rev., 43, 425-47
4, 1991) にまとめられている。すなわち、うつ症、不
安症、アルツハイマー病、パーキンソン病、ハンチント
ン舞踏病、摂食障害、高血圧、消化器疾患、薬物依存
症、炎症、免疫関連疾患なでにＣＲＦが関与している。
最近はてんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷に
もＣＲＦが関与していることが報告されている（Brain
Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498,
1992; Dev. Brain Res. 91, 245-251, 1996; Brain Re
s. 744, 166-170,1997）ことより、ＣＲＦ受容体拮抗薬
はこれら疾患の治療剤として有用である。The disease associated with CRF was described in 1991 by Owens
And Nemeroff's review (Pharmacol. Rev., 43, 425-47).
4, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal diseases, drug dependence, inflammation, and immune-related diseases.
Recently, it has been reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema and head injury (Brain
Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498,
1992; Dev. Brain Res. 91, 245-251, 1996; Brain Re
s. 744, 166-170, 1997), CRF receptor antagonists are useful as therapeutic agents for these diseases.
【０００４】[0004]
【発明が解決しようとする課題】本発明の目的は、うつ
症、不安症、アルツハイマー病、パーキンソン病、ハン
チントン舞踏病、摂食障害、高血圧、消化器疾患、薬物
依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外
傷、炎症、免疫関連疾患など、ＣＲＦが関与していると
される疾患の治療剤又は予防剤に有効なＣＲＦ拮抗薬を
提供することにある。The object of the present invention is to provide depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal diseases, drug dependence, epilepsy, cerebral infarction, An object of the present invention is to provide a CRF antagonist which is effective as a therapeutic or preventive agent for diseases in which CRF is involved, such as cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases.
【０００５】[0005]
【課題を解決するための手段】本発明者らは誘導体につ
いて鋭意検討した結果、ＣＲＦ受容体に高い親和性を示
すアリールメチレンピペリジノピリミジン誘導体を見出
し、本発明を完成した。Means for Solving the Problems As a result of intensive studies on derivatives, the present inventors have found an arylmethylenepiperidinopyrimidine derivative exhibiting high affinity for the CRF receptor, and have completed the present invention.
【０００６】以下、本発明を説明する。Hereinafter, the present invention will be described.
【０００７】本発明は、式［Ｉ］The present invention provides a compound of the formula [I]
【０００８】[0008]
【化２】 Embedded image
【０００９】（式中、Ａｒはフェニル基、置換フェニル
基、ナフチル基を示し、Ｒ1は水素原子、低級アルキル
基、アミノ基又は置換アミノ基を示し、Ｒ2は低級アル
キル基、低級アルケニル基又は低級アルキニル基を示
し、Ｘ1、Ｘ2及びＸ3は同一又は異なって水素原子、ハ
ロゲン原子、低級アルキル基、低級アルコキシ基、低級
アルキルチオ基、低級アルキルアミノ基又は含窒素複素
環基を示す。）で表されるアリールメチレンペリジノピ
リミジン誘導体又はその医薬上許容される塩。(In the formula, Ar represents a phenyl group, a substituted phenyl group or a naphthyl group, R 1 represents a hydrogen atom, a lower alkyl group, an amino group or a substituted amino group, and R 2 represents a lower alkyl group or a lower alkenyl group. Or a lower alkynyl group, and X 1 , X 2 and X 3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group or a nitrogen-containing heterocyclic group ), Or a pharmaceutically acceptable salt thereof.
【００１０】本発明において、アリールメチレン（Ａｒ
−ＣＨ＝）の置換位置は３位又は４位である。置換フェ
ニル基とはハロゲン原子、炭素数１〜５のアルキル基、
炭素数１〜５のアルコキシ基及びトリフルオロメチル基
から任意に選択された１個、２個又は３個の置換基を有
するフェニル基を示し、例えば２−フルオロフェニル
基、３−フルオロフェニル基、４−フルオロフェニル
基、２−クロロフェニル基、３−クロロフェニル基、４
−クロロフェニル基、２−ブロモフェニル基、３−ブロ
モフェニル基、４−ブロモフェニル基、２−メチルフェ
ニル基、３−メチルフェニル基、４−メチルフェニル
基、２−メトキシフェニル基、３−メトキシフェニル
基、４−メトキシフェニル基、３,４−ジフルオロフェ
ニル基、３,５−ジフルオロフェニル基、２,４−ジフル
オロフェニル基、３,４−ジクロロフェニル基、３,５−
ジクロロフェニル基、３−トリフルオロメチル基などで
ある。低級アルキル基とは直鎖状、分岐鎖状又は環状の
炭素数１〜５のアルキル基を示し、例えばメチル基、エ
チル基、プロピル基、イソプロピル基、ブチル基、イソ
ブチル基、シクロプロピルメチル基、ペンチル基、イソ
ペンチル基、シクロペンチル基などである。低級アルキ
ルアミノ基とは直鎖状又は分岐鎖状の炭素数１〜５のア
ルキル基１個又は２個で置換されたアミノ基を示し、例
えばメチルアミノ基、ジメチルアミノ基、エチルアミノ
基、ジエチルアミノ基、プロピルアミノ基、ジプロピル
アミノ基、イソプロピルアミノ基などである。含窒素複
素環基とは少なくとも１個の窒素原子を含み、該窒素原
子の他に窒素原子、酸素原子又は硫黄原子を環構成原子
として含んでいてもよい、３ないし７員環の複素環基を
示し、例えばアジリジノ基、ピロリジノ基、ピペリジノ
基、ピペラジノ基、モルホリノ基、チオモルホリノ基な
どである。低級アルケニル基とは直鎖状又は分岐鎖状の
炭素数２〜５のアルケニル基を示し、例えば２−プロペ
ニル基、２−ブテン−１−イル基、３−メチル−２−ブ
テン−１−イル基などである。低級アルキニル基とは直
鎖状又は分岐鎖状の炭素数２〜５のアルキニル基を示
し、例えばプロパルギル基、２−ブチニル基などであ
る。ハロゲン原子とは、フッ素原子、塩素原子、臭素原
子又はヨウ素原子を示す。低級アルコキシ基とは直鎖状
又は分岐鎖状の炭素数１〜５のアルコキシ基を示し、例
えばメトキシ基、エトキシ基、プロポキシ基、イソプロ
ポキシ基、ブトキシ基、イソブトキシ基、ペンチルオキ
シ基、イソペンチルオキシ基などである。低級アルキル
チオ基とは直鎖状又は分岐鎖状の炭素数１〜５のアルキ
ルチオ基を示し、例えばメチルチオ基、エチルチオ基、
プロピルチオ基、イソプロピルチオ基、ブチルチオ基、
イソブチルチオ基、ペンチルチオ基、イソペンチルチオ
基などである。In the present invention, arylmethylene (Ar
The substitution position of -CH =) is the 3- or 4-position. A substituted phenyl group is a halogen atom, an alkyl group having 1 to 5 carbon atoms,
A phenyl group having 1, 2 or 3 substituents arbitrarily selected from an alkoxy group having 1 to 5 carbon atoms and a trifluoromethyl group, for example, a 2-fluorophenyl group, a 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4
-Chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl Group, 4-methoxyphenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-
Examples include a dichlorophenyl group and a 3-trifluoromethyl group. A lower alkyl group refers to a linear, branched or cyclic alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, A pentyl group, an isopentyl group and a cyclopentyl group. The lower alkylamino group refers to a linear or branched amino group substituted with one or two alkyl groups having 1 to 5 carbon atoms, such as a methylamino group, a dimethylamino group, an ethylamino group, and a diethylamino group. Group, propylamino group, dipropylamino group, isopropylamino group and the like. The nitrogen-containing heterocyclic group is a 3- to 7-membered heterocyclic group containing at least one nitrogen atom and optionally containing a nitrogen atom, an oxygen atom or a sulfur atom in addition to the nitrogen atom. And examples thereof include an aziridino group, a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, and a thiomorpholino group. The lower alkenyl group refers to a linear or branched alkenyl group having 2 to 5 carbon atoms, such as a 2-propenyl group, a 2-buten-1-yl group, or a 3-methyl-2-buten-1-yl And the like. The lower alkynyl group refers to a linear or branched alkynyl group having 2 to 5 carbon atoms, such as a propargyl group and a 2-butynyl group. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The lower alkoxy group means a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyl. And an oxy group. The lower alkylthio group refers to a linear or branched alkylthio group having 1 to 5 carbon atoms, such as a methylthio group, an ethylthio group,
Propylthio, isopropylthio, butylthio,
Examples include an isobutylthio group, a pentylthio group, and an isopentylthio group.
【００１１】また、本発明における医薬上許容される塩
とは、例えば硫酸、塩酸、燐酸などの鉱酸との塩、酢
酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン
酸、クエン酸、ベンゼンスルホン酸、メタンスルホン酸
などの有機酸との塩などである。The pharmaceutically acceptable salts in the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid and benzene. And salts with organic acids such as sulfonic acid and methanesulfonic acid.
【００１２】[0012]
【発明の実施の形態】式［Ｉ］の化合物は、以下の製造
法によって製造することができる［以下の反応式中、Ａ
ｒ、Ｒ1、Ｒ2、Ｘ1、Ｘ2及びＸ3は前記と同様であり、
Ｒ3は水素原子又はＲ2を示し、Ｒ4及びＲ5は同一又は異
なって炭素数１〜５のアルキル基を示すか、又は一緒に
なって隣接する酸素原子と共に１,２−エチレンジオキ
シ基若しくは１,３−プロピレンジオキシ基を示し（Ｒ4
Ｏ及びＲ5Ｏの結合位置は共に３位又は４位の同一炭素
原子である）、Ｒ6は炭素数１〜６のアルキル基を示
し、Ｘ4は塩素原子、臭素原子又はヨウ素原子を示
す。］ ＜製造法１＞BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [I] can be produced by the following production method.
r, R 1 , R 2 , X 1 , X 2 and X 3 are the same as above,
R 3 represents a hydrogen atom or R 2 , and R 4 and R 5 are the same or different and represent an alkyl group having 1 to 5 carbon atoms, or are taken together with an adjacent oxygen atom to form 1,2-ethylenedioxy A group or a 1,3-propylenedioxy group (R 4
Bonding position of O and R 5 O are the same carbon atoms of both the 3-position or 4-position), R 6 represents an alkyl group having 1 to 6 carbon atoms, X 4 represents a chlorine atom, a bromine atom or an iodine atom . <Manufacturing method 1>
【００１３】[0013]
【化３】 Embedded image
【００１４】工程Ａ：アリールメチレンピペリジン化合
物（１）を２,４−ジクロロピリミジン化合物（２）と
塩基の存在下、不活性溶媒中反応させ、式（３）の化合
物を得る。ここで塩基とは、例えばトリエチルアミン、
ジイソプロピルエチルアミン、ピリジン等のアミン類、
炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、
炭酸水素カリウム、水酸化ナトリウム、水素化ナトリウ
ム等の無機塩基、ナトリウムメトキシド、ナトリウムエ
トキシド、カリウム tert−ブトキシド等のアルコラー
ト類、ナトリウムアミド、リチウムジイソプロピルアミ
ド、カリウムビス（トリメチルシリル）アミド等の金属
アミド類等である。不活性溶媒とは、例えばメタノー
ル、エタノール、イソプロピルアルコール、エチレング
リコール等のアルコール類、ジエチルエーテル、テトラ
ヒドロフラン、ジオキサン、１,２−ジメトキシエタン
等のエーテル類、ベンゼン、トルエン等の炭化水素類、
Ｎ,Ｎ−ジメチルホルムアミド等のアミド類、アセトニ
トリル、水、又はこれらの混合溶媒等である。Step A: The arylmethylenepiperidine compound (1) is reacted with a 2,4-dichloropyrimidine compound (2) in the presence of a base in an inert solvent to obtain a compound of the formula (3). Here, the base is, for example, triethylamine,
Amines such as diisopropylethylamine and pyridine,
Sodium carbonate, potassium carbonate, sodium bicarbonate,
Inorganic bases such as potassium hydrogen carbonate, sodium hydroxide and sodium hydride; alcoholates such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal amides such as sodium amide, lithium diisopropylamide and potassium bis (trimethylsilyl) amide And so on. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and hydrocarbons such as benzene and toluene.
Examples include amides such as N, N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof.
【００１５】工程Ｂ：式（３）の化合物はアニリン化合
物（４）と塩基の存在下又は非存在下、不活性溶媒中反
応させ、本発明化合物（５）を得る。ここで塩基とは、
例えばトリエチルアミン、ジイソプロピルエチルアミ
ン、ピリジン等のアミン類、炭酸ナトリウム、炭酸カリ
ウム、炭酸水素ナトリウム、炭酸水素カリウム、水酸化
ナトリウム、水素化ナトリウム等の無機塩基、ナトリウ
ムメトキシド、ナトリウムエトキシド、カリウム tert
−ブトキシド等のアルコラート類、ナトリウムアミド、
リチウムジイソプロピルアミド、カリウムビス（トリメ
チルシリル）アミド等の金属アミド類等、ヨウ化メチル
マグネシウム、ブチルリチウム等のアルキル金属類であ
る。不活性溶媒とは、例えばメタノール、エタノール、
イソプロピルアルコール、エチレングリコール等のアル
コール類、ジエチルエーテル、テトラヒドロフラン、ジ
オキサン、１,２−ジメトキシエタン等のエーテル類、
ベンゼン、トルエン、キシレン等の炭化水素類、例えば
Ｎ,Ｎ−ジメチルホルムアミド等のアミド類、ジメチル
スルホキシド等である。Step B: The compound of the formula (3) is reacted with the aniline compound (4) in the presence or absence of a base in an inert solvent to obtain the compound (5) of the present invention. Here, the base is
For example, amines such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, and sodium hydride; sodium methoxide, sodium ethoxide, and potassium tert
Alcoholates such as butoxide, sodium amide,
Metal amides such as lithium diisopropylamide and potassium bis (trimethylsilyl) amide; and alkyl metals such as methylmagnesium iodide and butyllithium. Inert solvents include, for example, methanol, ethanol,
Isopropyl alcohol, alcohols such as ethylene glycol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Hydrocarbons such as benzene, toluene and xylene, for example, amides such as N, N-dimethylformamide, dimethyl sulfoxide and the like.
【００１６】＜製造法２＞<Production method 2>
【００１７】[0017]
【化４】 Embedded image
【００１８】工程Ｃ：化合物（５）のＲ3が水素原子で
ある化合物（６）はハライド（７）と塩基の存在下、不
活性溶媒中反応させることによって本発明化合物（８）
へ導かれる。Step C: Compound (6) wherein R 3 of compound (5) is a hydrogen atom is reacted with halide (7) in the presence of a base in an inert solvent to give compound (8) of the present invention.
Led to.
【００１９】ここで塩基とは、例えばトリエチルアミ
ン、ジイソプロピルエチルアミン、ピリジン等のアミン
類、例えば炭酸ナトリウム、炭酸カリウム、炭酸水素ナ
トリウム、炭酸水素カリウム、水酸化ナトリウム、水素
化ナトリウム等の無機塩基、例えばナトリウムメトキシ
ド、ナトリウムエトキシド、カリウム tert−ブトキシ
ド等のアルコラート類、例えばナトリウムアミド、リチ
ウムジイソプロピルアミド、カリウムビス（トリメチル
シリル）アミド等の金属アミド類等である。不活性溶媒
とは、例えばメタノール、エタノール、イソプロピルア
ルコール、エチレングリコール等のアルコール類、例え
ばジエチルエーテル、テトラヒドロフラン、ジオキサ
ン、１,２−ジメトキシエタン等のエーテル類、例えば
ベンゼン、トルエン、キシレン等の炭化水素類、例えば
Ｎ,Ｎ−ジメチルホルムアミド等のアミド類、アセトン
等のケトン類、ジメチルスルホキシド、アセトニトリ
ル、水、又はこれらの混合溶媒等である。Here, the term "base" refers to amines such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide and sodium hydride; Alcoholates such as methoxide, sodium ethoxide and potassium tert-butoxide, for example, metal amides such as sodium amide, lithium diisopropylamide and potassium bis (trimethylsilyl) amide. Examples of the inert solvent include alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; and hydrocarbons such as benzene, toluene, and xylene. Examples thereof include amides such as N, N-dimethylformamide, ketones such as acetone, dimethyl sulfoxide, acetonitrile, water, and a mixed solvent thereof.
【００２０】＜製造法３＞<Production Method 3>
【００２１】[0021]
【化５】 Embedded image
【００２２】式（９）で示される化合物を出発原料とし
ても本発明化合物を得ることができる。すなわち、式
（９）で示される化合物と２,４−ジクロロピリミジン
化合物（２）を原料とし、前記工程Ａ、Ｂ、及びＲ3が
水素原子であるときは続いて工程Ｃによってケタール化
合物（１０）を得ることができる。The compound of the present invention can be obtained also by using the compound represented by the formula (9) as a starting material. That is, when the compound represented by the formula (9) and the 2,4-dichloropyrimidine compound (2) are used as raw materials, and when the steps A, B and R 3 are hydrogen atoms, the ketal compound (10 ) Can be obtained.
【００２３】工程Ｄ：次いで、ケタール化合物（１０）
は不活性溶媒中、酸と処理することによってケトン化合
物（１１）を与える。ここで不活性溶媒とは、例えばメ
タノール、エタノール、イソプロピルアルコール、エチ
レングリコール等のアルコール類、例えばジエチルエー
テル、テトラヒドロフラン、ジオキサン、１,２−ジメ
トキシエタン等のエーテル類、例えばベンゼン、トルエ
ン、キシレン等の炭化水素類、アセトン、メチルエチル
ケトン等のケトン類、例えばＮ,Ｎ−ジメチルホルムア
ミド等のアミド類等である。酸とは、例えば塩酸、臭化
水素酸、硫酸等の無機酸、例えばｐ−トルエンスルホン
酸、メタンスルホン酸、トリフルオロ酢酸等の有機酸類
である。Step D: Next, the ketal compound (10)
Gives a ketone compound (11) by treatment with an acid in an inert solvent. Here, the inert solvent refers to, for example, alcohols such as methanol, ethanol, isopropyl alcohol, and ethylene glycol, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; for example, benzene, toluene, and xylene. Examples thereof include hydrocarbons, ketones such as acetone and methyl ethyl ketone, and amides such as N, N-dimethylformamide. The acid is an inorganic acid such as hydrochloric acid, hydrobromic acid and sulfuric acid, and an organic acid such as p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.
【００２４】工程Ｅ：ケトン化合物（１１）と、式（１
２）で示されるジアルキルアリールメチルホスホネート
又は式（１３）で示されるトリフェニルアリールメチル
ホスホニウム塩と塩基の存在下不活性溶媒中縮合するこ
とによっても本発明化合物（８）へ導かれる。Step E: The ketone compound (11) and a compound of the formula (1)
The compound (8) of the present invention can also be obtained by condensation with a dialkylarylmethylphosphonate represented by 2) or a triphenylarylmethylphosphonium salt represented by formula (13) in an inert solvent in the presence of a base.
【００２５】ここで塩基とは水素化ナトリウム、水素化
カリウム、ナトリウムメトキシド、カリウムｔ−ブトキ
シド、ｎ−ブチルリチウム、リチウムジイソプロピルア
ミド、リチウムビス（トリメチルシリル）アミド、ナト
リウムアミドなどであり、必要に応じ１５−クラウン−
５エーテル、１８−クラウン−６エーテルなどの触媒、
テトラメチルエチレンジアミン、ヘキサメチルホスホル
アミドなどを併用する。不活性溶媒とは、例えばジエチ
ルエーテル、テトラヒドロフラン、ジオキサンなどのエ
ーテル類、ベンゼン、トルエンなどの炭化水素類、エタ
ノールなどのアルコール類、Ｎ,Ｎ−ジメチルホルムア
ミド、Ｎ−メチルピロリドン、テトラメチル尿素、ジメ
チルスルホキシド、水、又はこれらの混合溶媒などであ
る。Here, the base is sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, and the like. 15-Crown-
Catalysts such as 5 ether, 18-crown-6 ether,
Tetramethylethylenediamine, hexamethylphosphoramide and the like are used in combination. The inert solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, alcohols such as ethanol, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl Examples thereof include sulfoxide, water, and a mixed solvent thereof.
【００２６】[0026]
【発明の効果】本発明により、ＣＲＦ受容体に高い親和
性を示す化合物が提供された。これらの化合物はＣＲＦ
が関与すると考えられる疾患、例えばうつ症、不安症、
アルツハイマー病、パーキンソン病、ハンチントン舞踏
病、摂食障害、高血圧、消化器疾患、薬物依存症、てん
かん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫
関連疾患等に有効である。According to the present invention, there is provided a compound having a high affinity for the CRF receptor. These compounds are CRF
Diseases that may be involved, such as depression, anxiety,
Effective for Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related diseases, etc. .
【００２７】[0027]
【実施例】以下に実施例及び試験例を示し本発明を具体
的に説明する。The present invention will be specifically described below with reference to examples and test examples.
【００２８】実施例１ ２−[Ｎ−(２−ブロモ−４−イソプロピルフェニル)−
Ｎ−エチルアミノ]−４−(４−ベンジリデンピペリジン
−１−イル)−６−メチルピリミジン塩酸塩の合成 （１）２,４−ジクロロ−６−メチルピリミジン３３３
ｍｇをエタノール６ｍｌに溶解し氷水にて冷却した。こ
の溶液に４−ベンジリデンピペリジン塩酸塩４２０ｍｇ
とジイソプロピルエチルアミン５３０ｍｇを加え、氷冷
下一夜撹拌した。反応溶液を飽和炭酸水素ナトリウム水
溶液に注ぎ、酢酸エチル抽出した。抽出液は飽和食塩水
にて洗浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤
を濾別後、濾液を減圧下濃縮し、残渣をシリカゲルカラ
ムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチ
ル＝１０：１−３：１）にて精製し、４−(４−ベンジ
リデンピペリジン−１−イル)−２−クロロ−６−メチ
ルピリミジン５１５ｍｇを得た。Example 1 2- [N- (2-bromo-4-isopropylphenyl)-
Synthesis of N-ethylamino] -4- (4-benzylidenepiperidin-1-yl) -6-methylpyrimidine hydrochloride (1) 2,4-dichloro-6-methylpyrimidine 333
mg was dissolved in 6 ml of ethanol and cooled with ice water. 420 mg of 4-benzylidenepiperidine hydrochloride was added to this solution.
And 530 mg of diisopropylethylamine were added, and the mixture was stirred overnight under ice cooling. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1-3: 1) to give 4- (4-benzylidenepiperidine- 515 mg of 1-yl) -2-chloro-6-methylpyrimidine were obtained.
【００２９】（２）４−(４−ベンジリデンピペリジン
−１−イル)−２−クロロ−６−メチルピリミジン３０
０ｍｇ、２−ブロモ−４−イソプロピルアニリン塩酸塩
２５１ｍｇ及びジイソプロピルエチルアミン１４２ｍｇ
をエチレングリコール２ｍｌ中で１時間加熱環流した。
反応溶液を飽和炭酸水素ナトリウム水溶液に注ぎ、酢酸
エチル抽出した。抽出液は水、飽和食塩水にて洗浄し、
無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別後、濾
液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグ
ラフィー（展開溶媒；ヘキサン：酢酸エチル＝７：１)
にて精製し、アモルファスとして２−[Ｎ−(２−ブロモ
−４−イソプロピルフェニル)アミノ]−４−(４−ベン
ジリデンピペリジン−１−イル)−６−メチルピリミジ
ンを３２５ｍｇを得た。(2) 4- (4-benzylidenepiperidin-1-yl) -2-chloro-6-methylpyrimidine 30
0 mg, 251 mg of 2-bromo-4-isopropylaniline hydrochloride and 142 mg of diisopropylethylamine
Was refluxed for 1 hour in 2 ml of ethylene glycol.
The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline,
It was dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 1).
To obtain 325 mg of 2- [N- (2-bromo-4-isopropylphenyl) amino] -4- (4-benzylidenepiperidin-1-yl) -6-methylpyrimidine as amorphous.
【００３０】（３）２−[Ｎ−(２−ブロモ−４−イソプ
ロピルフェニル)アミノ]−４−(４−ベンジリデンピペ
リジン−１−イル)−６−メチルピリミジン２６７ｍｇ
をＮ,Ｎ−ジメチルホルムアミド３ｍｌに溶解し、６０
％水素化ナトリウム／オイル２９ｍｇを加え、室温で１
時間撹拌した。この混合物にヨウ化エチル１２２ｍｇを
加え、一夜室温にて撹拌した。反応溶液を水に注ぎ、酢
酸エチル抽出した。抽出液は水、飽和食塩水にて洗浄
し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別
後、濾液を減圧下濃縮し、残渣をシリカゲルカラムクロ
マトグラフィー（展開溶媒；ヘキサン：アセトン＝１
０：１）にて精製した。得られたフリーアミン体はメタ
ノール中４規定塩化水素／酢酸エチル処理により塩酸塩
とし、エーテルより結晶化し、２−[Ｎ−(２−ブロモ−
４−イソプロピルフェニル)−Ｎ−エチルアミノ]−４−
(４−ベンジリデンピペリジン−１−イル)−６−メチル
ピリミジン塩酸塩２３７ｍｇを得た。本化合物の構造お
よびマススペクトルデータを表１に記した。(3) 267 mg of 2- [N- (2-bromo-4-isopropylphenyl) amino] -4- (4-benzylidenepiperidin-1-yl) -6-methylpyrimidine
Was dissolved in 3 ml of N, N-dimethylformamide, and 60
% Sodium hydride / oil 29 mg and added at room temperature.
Stirred for hours. 122 mg of ethyl iodide was added to the mixture, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: acetone = 1).
0: 1). The obtained free amine compound was converted into a hydrochloride by treatment with 4N hydrogen chloride / ethyl acetate in methanol, crystallized from ether, and subjected to 2- [N- (2-bromo-
4-isopropylphenyl) -N-ethylamino] -4-
237 mg of (4-benzylidenepiperidin-1-yl) -6-methylpyrimidine hydrochloride were obtained. Table 1 shows the structure and mass spectrum data of the compound.
【００３１】実施例２ ２−[Ｎ−(２−ブロモ−４−イソプロピルフェニル)−
Ｎ−エチルアミノ]−４−(４−（４−フルオロベンジリ
デン）ピペリジン−１−イル)−６−メチルピリミジン
の合成 （１）実施例１と同様にして２,４−ジクロロ−６−メ
チルピリミジンと４−(１,３−ジオキソラン−２−イ
ル)ピペリジンより得られた２−[Ｎ−(２−ブロモ−４
−イソプロピルフェニル)−Ｎ−エチルアミノ]−４−
[４−(１,３−ジオキソラン−２−イル)ピペリジン−１
−イル]−６−メチルピリミジン１４.２５ｇをテトラヒ
ドロフラン７５ｍｌに溶解し、４規定塩酸７５ｍｌを加
え、室温で６時間撹拌した。反応溶液を約８０ｍｌまで
減圧下濃縮し、これを飽和炭酸水素ナトリウム水溶液に
注ぎ、酢酸エチル抽出した。抽出液は飽和食塩水にて洗
浄し、無水硫酸ナトリウムにて乾燥した。乾燥剤を濾別
後、濾液を減圧下濃縮し、残渣をシリカゲルカラムクロ
マトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝
７：１〜６：１）にて精製し、油状の２−[Ｎ−(２−ブ
ロモ−４−イソプロピルフェニル)−Ｎ−エチルアミノ]
−６−メチル−４−(４−オキソピペリジン−１−イル)
ピリミジン１２.９３ｇを得た。Example 2 2- [N- (2-bromo-4-isopropylphenyl)-
Synthesis of N-ethylamino] -4- (4- (4-fluorobenzylidene) piperidin-1-yl) -6-methylpyrimidine (1) As in Example 1, 2,4-dichloro-6-methylpyrimidine And 2- [N- (2-bromo-4) obtained from 4- (1,3-dioxolan-2-yl) piperidine.
-Isopropylphenyl) -N-ethylamino] -4-
[4- (1,3-dioxolan-2-yl) piperidine-1
14.25 g of [-yl] -6-methylpyrimidine was dissolved in 75 ml of tetrahydrofuran, 75 ml of 4N hydrochloric acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to about 80 ml, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate =
7: 1 to 6: 1) to give oily 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino].
-6-methyl-4- (4-oxopiperidin-1-yl)
12.93 g of pyrimidine were obtained.
【００３２】（２）２−[Ｎ−(２−ブロモ−４−イソプ
ロピルフェニル)−Ｎ−エチルアミノ]−６−メチル−４
−(４−オキソピペリジン−１−イル)ピリミジン４３１
ｍｇ、ジエチル４−フルオロベンジルホスホネート２９
５ｍｇ及び１５−クラウン−５エーテル６ｍｇをテトラ
ヒドロフラン１０ｍｌに溶解し、この溶液に６０％水素
化ナトリウム（オイル中）４７ｍｇを加え、室温で１夜
攪拌した。反応溶液を飽和炭酸水素ナトリウム水溶液中
に注ぎ、酢酸エチル抽出した。抽出液は飽和炭酸水素ナ
トリウム水溶液中、飽和食塩水で順次洗浄し、無水硫酸
ナトリウムにて乾燥した。乾燥剤を濾別後、濾液を減圧
下濃縮し、残渣をシリカゲルカラムクロマトグラフィー
（展開溶媒；ヘキサン：アセトン＝１０：１）にて精製
し、２−[Ｎ−(２−ブロモ−４−イソプロピルフェニ
ル)−Ｎ−エチルアミノ]−４−(４−（４−フルオロベ
ンジリデン）ピペリジン−１−イル)−６−メチルピリ
ミジン４０８ｍｇを得た。(2) 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -6-methyl-4
-(4-oxopiperidin-1-yl) pyrimidine 431
mg, diethyl 4-fluorobenzylphosphonate 29
5 mg and 6 mg of 15-crown-5 ether were dissolved in 10 ml of tetrahydrofuran, 47 mg of 60% sodium hydride (in oil) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: acetone = 10: 1) to give 2- [N- (2-bromo-4-isopropyl). 408 mg of phenyl) -N-ethylamino] -4- (4- (4-fluorobenzylidene) piperidin-1-yl) -6-methylpyrimidine were obtained.
【００３３】本化合物及び同様にして得た化合物の構造
及びマススペクトルデータを表１に記した。Table 1 shows the structures and mass spectrum data of this compound and the compound obtained in the same manner.
【００３４】[0034]
【化６】 Embedded image
【００３５】 表１ Ｘ1,Ｘ2,Ｘ3-Ｐｈ Ｒ2 Ａｒ Ｍ++１ *２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｐｈ ５０５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ５２３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ５２３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ５３９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ５２３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ １-Ｎａｐ ５５５ ２,４-Ｂｒ2-Ｐｈ Ｅｔ Ｐｈ ５４１ ２,４-Ｂｒ2-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ５５９ ２,４-Ｂｒ2-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ５５９ ２,４-Ｂｒ2-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ５７５ ２,４-Ｂｒ2-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ５５９ ２,４-Ｂｒ2-Ｐｈ Ｅｔ １−Ｎａｐ ５９１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ５７５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５９３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５９３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ６０９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ５９３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ６２５ ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ６１１。Table 1 X 1 , X 2 , X 3 -Ph R 2 Ar M ++ 1 * 2-Br-4-i-Pr-Ph Et Ph 505 2-Br-4-i-Pr-Ph Et 2 -F-Ph 523 2-Br-4-i-Pr-Ph Et 3-F-Ph 523 2-Br-4-i-Pr-Ph Et 4-Cl-Ph 539 2-Br-4-i-Pr -Ph Et 4-F-Ph 523 2-Br-4-i-Pr-Ph Et 1-Nap 555 2,4-Br 2 -Ph Et Ph 541 2,4-Br 2 -Ph Et 2-F-Ph 559 2,4-Br 2 -Ph Et 3-F-Ph 559 2,4-Br 2 -Ph Et 4-Cl-Ph 575 2,4-Br 2 -Ph Et 4-F-Ph 559 2,4- Br 2 -Ph Et 1 -Nap 591 2-Br-4-i-Pr-Phn-Hep Ph 575 2-Br-4-i-Pr-Phn-Hep 2-F-Ph 593 2-Br-4 -i-Pr-Ph n-Hep 3-F-Ph 593 2-Br-4-i-Pr-Ph n-Hep 4-Cl-Ph 609 2-Br-4-i-Pr-Ph n-Hep 4-F-Ph 593 2-Br-4-i-Pr -Ph n-Hep 1-Nap 625 2,4-Br 2 -Ph n-Hep Ph 611.
【００３６】 ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ６２９ ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ６２９ ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ６４５ ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ６２９ ２,４-Ｂｒ2-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ６６１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ５３１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ５４９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ５４９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５６５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ５４９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５８１ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ５６７ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ５８５ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ５８５ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ６０１ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ５８５ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ６１７ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ５４５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ５６３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ５６３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５７９。2,4-Br 2 -Ph n-Hep 2-F-Ph 629 2,4-Br 2 -Ph n-Hep 3-F-Ph 629 2,4-Br 2 -Ph n-Hep 4- Cl-Ph 645 2,4-Br 2 -Ph n-Hep 4-F-Ph 629 2,4-Br 2 -Ph n-Hep 1-Nap 661 2-Br-4-i-Pr-Ph c-Pr -CH 2 Ph 531 2-Br-4-i-Pr-Ph c-Pr-CH 2 2-F-Ph 549 2-Br-4-4-i-Pr-Ph c-Pr-CH 2 3-F-Ph 549 2-Br-4-i-Pr-Ph c-Pr-CH 2 4-Cl-Ph 565 2-Br-4-4-Pr-Ph c-Pr-CH 2 4-F-Ph 549 2-Br -4-i-Pr-Ph c -Pr-CH 2 1-Nap 581 2,4-Br 2 -Ph c-Pr-CH 2 Ph 567 2,4-Br 2 -Ph c-Pr-CH 2 2- F-Ph 585 2,4-Br 2 -Ph c-Pr-CH 2 3-F-Ph 5 5 2,4-Br 2 -Ph c- Pr-CH 2 4-Cl-Ph 601 2,4-Br 2 -Ph c-Pr-CH 2 4-F-Ph 585 2,4-Br 2 -Ph c -Pr-CH 2 1-Nap 617 2-Br-4-i-Pr-Ph c-Bu-CH 2 Ph 545 2-Br-4-i-Pr-Ph c-Bu-CH 2 2-F-Ph 563 2-Br-4-i -Pr-Ph c-Bu-CH 2 3-F-Ph 563 2-Br-4-i-Pr-Ph c-Bu-CH 2 4-Cl-Ph 579.
【００３７】 ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ５６３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５９５ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ５８１ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ５９９ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ５９９ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ６１５ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ５９９ ２,４-Ｂｒ2-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ６３１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ５１５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ５３３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ５３３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５４９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ５３３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ５６５ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ５５１ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ５６９ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ５６９ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５８５ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ５６９ ２,４-Ｂｒ2-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ６０１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ５１７。[0037] 2-Br-4-i- Pr-Ph c-Bu-CH 2 4-F-Ph 563 2-Br-4-i-Pr-Ph c-Bu-CH 2 1-Nap 595 2,4 -Br 2 -Ph c-Bu-CH 2 Ph 581 2,4-Br 2 -Ph c-Bu-CH 2 2-F-Ph 599 2,4-Br 2 -Ph c-Bu-CH 2 3-F -Ph 599 2,4-Br 2 -Ph c-Bu-CH 2 4-Cl-Ph 615 2,4-Br 2 -Ph c-Bu-CH 2 4-F-Ph 599 2,4-Br 2- Ph c-Bu-CH 2 1-Nap 631 2-Br-4-i-Pr-Ph HC≡C-CH 2 Ph 515 2-Br-4-i-Pr-Ph HC≡C-CH 2 2-F -Ph 533 2-Br-4- i-Pr-Ph HC≡C-CH 2 3-F-Ph 533 2-Br-4-i-Pr-Ph HC≡C-CH 2 4-Cl-Ph 549 2 -Br-4-i-Pr- Ph HC≡C-CH 2 4-F-Ph 533 2-Br-4- -Pr-Ph HC≡C-CH 2 1 -Nap 565 2,4-Br 2 -Ph HC≡C-CH 2 Ph 551 2,4-Br 2 -Ph HC≡C-CH 2 2-F-Ph 569 2,4-Br 2 -Ph HC≡C-CH 2 3-F-Ph 569 2,4-Br 2 -Ph HC≡C-CH 2 4-Cl-Ph 585 2,4-Br 2 -Ph HC≡ C-CH 2 4-F- Ph 569 2,4-Br 2 -Ph HC≡C-CH 2 1-Nap 601 2-Br-4-i-Pr-Ph H 2 C = CH-CH 2 Ph 517.
【００３８】 ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ５３５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ５３５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５５１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ５３５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ５６７ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ５５３ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ５７１ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ５７１ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５８７ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ５７１ ２,４-Ｂｒ2-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ６０３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ５３５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ５５３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ５５３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ５６９ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ５５３ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５８５ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ５７１ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ５８９ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ５８９ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ６０５ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ５８９ ２,４-Ｂｒ2-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ６２１ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 Ｐｈ ５６７ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５８５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５８５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ６０１。2-Br-4-i-Pr-PhH 2 C = CH-CH 2 2-F-Ph 535 2-Br-4-i-Pr-Ph H 2 C = CH-CH 2 3-F -Ph 535 2-Br-4-i-Pr-Ph H 2 C = CH-CH 2 4-Cl-Ph 551 2-Br-4-i-Pr-Ph H 2 C = CH-CH 2 4-F -Ph 535 2-Br-4- i-Pr-Ph H 2 C = CH-CH 2 1-Nap 567 2,4-Br 2 -Ph H 2 C = CH-CH 2 Ph 553 2,4-Br 2 -Ph H 2 C = CH-CH 2 2-F-Ph 571 2,4-Br 2 -Ph H 2 C = CH-CH 2 3-F-Ph 571 2,4-Br 2 -Ph H 2 C = CH-CH 2 4-Cl-Ph 587 2,4-Br 2 -Ph H 2 C = CH-CH 2 4-F-Ph 571 2,4-Br 2 -Ph H 2 C = CH-CH 2 1- Nap 603 2-Br-4-i-Pr-Ph MeOCH 2 CH 2 Ph 535 2-Br-4-i-Pr-Ph MeOCH 2 CH 2 2-F-Ph 553 2-Br-4-i-Pr-Ph MeOCH 2 CH 2 3-F-Ph 553 2-Br-4-i-Pr-Ph MeOCH 2 CH 2 4-Cl- Ph 569 2-Br-4-i-Pr-Ph MeOCH 2 CH 2 4-F-Ph 553 2-Br-4-4-Pr-Ph MeOCH 2 CH 2 1-Nap 585 2,4-Br 2 -Ph MeOCH 2 CH 2 Ph 571 2,4-Br 2 -Ph MeOCH 2 CH 2 2-F-Ph 589 2,4-Br 2 -Ph MeOCH 2 CH 2 3-F-Ph 589 2,4-Br 2 -Ph MeOCH 2 CH 2 4-Cl-Ph 605 2,4-Br 2 -Ph MeOCH 2 CH 2 4-F-Ph 589 2,4-Br 2 -Ph MeOCH 2 CH 2 1-Nap 621 2-Br-4-- i-Pr-Ph PhCH 2 Ph 567 2-Br-4-i-Pr-Ph PhCH 2 2-F-Ph 585 2-Br- 4-i-Pr-Ph PhCH 2 3-F-Ph 585 2-Br-4-i-Pr-Ph PhCH 2 4-Cl-Ph 601.
【００３９】 ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５８５ ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ６１７ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 Ｐｈ ６０３ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ６２１ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ６２１ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ６３７ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ６２１ ２,４-Ｂｒ2-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ６５３ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｐｈ ４４１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ４５９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ４５９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ４７５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ４５９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｅｔ １-Ｎａｐ ４９１ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ Ｐｈ ４２７ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ４４５ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ４４５ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ４６１ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ４４５ ２,４,６-Ｍｅ3-Ｐｈ Ｅｔ １-Ｎａｐ ４７７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ５１１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５２９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５２９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ５４５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ５２９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ５６１ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ４９７ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５１５ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５１５ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ５３１ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ５１５ ２,４,６-Ｍｅ3-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ５４７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ４６７。2-Br-4-i-Pr-Ph PhCH 2 4-F-Ph 585 2-Br-4-i-Pr-Ph PhCH 2 1-Nap 617 2,4-Br 2 -Ph PhCH 2 Ph 603 2,4-Br 2 -Ph PhCH 2 2-F-Ph 621 2,4-Br 2 -Ph PhCH 2 3-F-Ph 621 2,4-Br 2 -Ph PhCH 2 4-Cl-Ph 637 2 , 4-Br 2 -Ph PhCH 2 4-F-Ph 621 2,4-Br 2 -Ph PhCH 2 1-Nap 653 2-Me-5-i-Pr-Ph Et Ph 441 2-Me-5-i -Pr-Ph Et 2-F-Ph 459 2-Me-5-i-Pr-Ph Et 3-F-Ph 459 2-Me-5-i-Pr-Ph Et 4-Cl-Ph 475 2-Me -5-i-Pr-Ph Et 4-F-Ph 459 2-Me-5-i-Pr-Ph Et 1-Nap 491 2,4,6-Me 3 -Ph Et Ph 427 2,4,6- M e 3 -Ph Et 2-F- Ph 445 2,4,6-Me 3 -Ph Et 3-F-Ph 445 2,4,6-Me 3 -Ph Et 4-Cl-Ph 461 2,4,6 -Me 3 -Ph Et 4-F-Ph 445 2,4,6-Me 3 -Ph Et 1-Nap 477 2-Me-5-i-Pr-Phn-Hep Ph 511 2-Me-5-i -Pr-Phn-Hep 2-F-Ph 529 2-Me-5-i-Pr-Phn-Hep 3-F-Ph 529 2-Me-5-i-Pr-Phn-Hep 4-Cl -Ph 545 2-Me-5-i-Pr-Phn-Hep 4-F-Ph 529 2-Me-5-i-Pr-Phn-Hep 1-Nap 561 2,4,6-Me 3- Ph n-Hep Ph 497 2,4,6-Me 3 -Ph n-Hep 2-F-Ph 515 2,4,6-Me 3 -Ph n-Hep 3-F-Ph 515 2,4,6- Me 3 -Phn-Hep 4-Cl-Ph 531 2,4,6-M e 3 -Ph n-Hep 4- F-Ph 515 2,4,6-Me 3 -Ph n-Hep 1-Nap 547 2-Me-5-i-Pr-Ph c-Pr-CH 2 Ph 467.
【００４０】 ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ４８５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ４８５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ−CＨ2 ４-Ｃｌ-Ｐｈ ５０１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ４８５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５１７ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ４５３ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ４７１ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ４７１ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４８７ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ４７１ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５０３ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ４８１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ４９９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ４９９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５１５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ４９９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５３１ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ４６７ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ４８５ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ４８５ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５０１ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ４８５ ２,４,６-Ｍｅ3-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５１７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ４５１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ４６９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ４６９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４８５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ４６９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ５０１ ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ４３７ ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ４５５。2-Me-5-i-Pr-Ph c-Pr-CH 2 2-F-Ph 485 2-Me-5-i-Pr-Ph c-Pr-CH 2 3-F-Ph 485 2 -Me-5-i-Pr-Ph c-Pr-CH 2 4-Cl-Ph 501 2-Me-5-i-Pr-Ph c-Pr-CH 2 4-F-Ph 485 2-Me-5 -i-Pr-Ph c-Pr-CH 2 1-Nap 517 2,4,6-Me 3 -Ph c-Pr-CH 2 Ph 453 2,4,6, -Me 3 -Ph c-Pr-CH 2 2-F-Ph 471 2,4,6-Me 3 -Ph c-Pr-CH 2 3-F-Ph 471 2,4,6-Me 3 -Ph c-Pr-CH 2 4-Cl-Ph 487 2,4,6-Me 3 -Ph c-Pr-CH 2 4-F-Ph 471 2,4,6,6-Me 3 -Ph c-Pr-CH 2 1-Nap 503 2-Me-5-i- Pr-Ph c-Bu-CH 2 Ph 481 2-Me-5-i-Pr-Ph c-Bu-CH 2 2-F-Ph 499 2 -Me-5-i-Pr-Ph c-Bu-CH 2 3-F-Ph 499 2-Me-5-i-Pr-Ph c-Bu-CH 2 4-Cl-Ph 515 2-Me-5 -i-Pr-Ph c-Bu -CH 2 4-F-Ph 499 2-Me-5-i-Pr-Ph c-Bu-CH 2 1-Nap 531 2,4,6-Me 3 -Ph c -Bu-CH 2 Ph 467 2,4,6-Me 3 -Ph c-Bu-CH 2 2-F-Ph 485 2,4,6-Me 3 -Ph c-Bu-CH 2 3-F-Ph 485 2,4,6-Me 3 -Ph c-Bu-CH 2 4-Cl-Ph 501 2,4,6-Me 3 -Ph c-Bu-CH 2 4-F-Ph 485 2,4,6 -Me 3 -Ph c-Bu-CH 2 1-Nap 517 2-Me-5-i-Pr-Ph HCＣＨC-CH 2 Ph 451 2-Me-5-i-Pr-Ph HC≡C-CH 2 2-F-Ph 469 2 -Me-5-i-Pr-Ph HC≡C-CH 2 3-F-Ph 469 2-Me-5-i- Pr-Ph HC @ C-CH 2 4-Cl-Ph 485 2-Me-5-i-Pr HC Ph @ C-CH 2 4-F-Ph 469 2-Me-5-i-Pr-Ph HC ≡C-CH 2 1-Nap 501 2,4,6-Me 3 -Ph HC≡C-CH 2 Ph 437 2,4,6-Me 3 -Ph HC≡C-CH 2 2 -F-Ph 455.
【００４１】 ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ４５５ ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４７１ ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ４５５ ２,４,６-Ｍｅ3-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ４８７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ４５３ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ４７１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ４７１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４８７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ４７１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ５０３ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ４３９ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ４５７ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ４５７ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４７３ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ４５７ ２,４,６-Ｍｅ3-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ４８９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ４７１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ４８９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ４８９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ５０５ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ４８９ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５２１ ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ４５７ ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ４７５ ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ４７５ ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ４９１。2,4,6-Me 3 -Ph HC≡C-CH 2 3-F-Ph 455 2,4,6, -Me 3 -Ph HC≡C-CH 2 4 -Cl-Ph 471 2,4 , 6-Me 3 -Ph HC≡C-CH 2 4-F-Ph 455 2,4,6-Me 3 -Ph HC≡C-CH 2 1-Nap 487 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 Ph 453 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 2-F-Ph 471 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 3-F-Ph 471 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 4-Cl-Ph 487 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 4-F-Ph 471 2-Me-5-i-Pr-Ph H 2 C = CH-CH 2 1-Nap 503 2,4,6-Me 3 -Ph H 2 C = CH-CH 2 Ph 439 2,4,6-Me 3 -Ph H 2 C = CH-CH 2 2-F-Ph 457 2,4,6-Me 3 -P h H 2 C = CH-CH 2 3-F-Ph 457 2,4,6-Me 3 -Ph H 2 C = CH-CH 2 4-Cl-Ph 473 2,4,6-Me 3 -Ph H 2 C = CH-CH 2 4-F-Ph 457 2,4,6-Me 3 -Ph H 2 C = CH-CH 2 1-Nap 489 2-Me-5-i-Pr-Ph MeOCH 2 CH 2 Ph 471 2-Me-5-i-Pr-Ph MeOCH 2 CH 2 2-F-Ph 489 2-Me-5-i-Pr-Ph MeOCH 2 CH 2 3-F-Ph 489 2-Me-5- i-Pr-Ph MeOCH 2 CH 2 4-Cl-Ph 505 2-Me-5-i-Pr-Ph MeOCH 2 CH 2 4-F-Ph 489 2-Me-5-i-Pr-Ph MeOCH 2 CH 2 1-Nap 521 2,4,6-Me 3 -Ph MeOCH 2 CH 2 Ph 457 2,4,6-Me 3 -Ph MeOCH 2 CH 2 2-F-Ph 475 2,4,6-Me 3 - Ph MeOCH 2 CH 2 3-F-Ph 475 2,4,6-Me 3 -Ph MeOCH 2 CH 2 4-Cl-Ph 491.
【００４２】 ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ４７５ ２,４,６-Ｍｅ3-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５０７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 Ｐｈ ５０３ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５２１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５２１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ５３７ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５２１ ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ５５３ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 Ｐｈ ４８９ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５０７ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５０７ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ５２３ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５０７ ２,４,６-Ｍｅ3-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ５３９ ２-ＭｅＳ-Ｐｈ Ｅｔ Ｐｈ ４３１ ２-ＭｅＳ-Ｐｈ Ｅｔ ２−Ｆ−Ｐｈ ４４９ ２-ＭｅＳ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ４４９ ２-ＭｅＳ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ４６５ ２-ＭｅＳ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ４４９ ２-ＭｅＳ-Ｐｈ Ｅｔ １-Ｎａｐ ４８１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｐｈ ４７３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ４９１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ４９１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ５０７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ４９１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ １-Ｎａｐ ５２３ ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ５０１ ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５１９ ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５１９ ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ５３５。2,4,6-Me 3 -Ph MeOCH 2 CH 2 4-F-Ph 475 2,4,6-Me 3 -Ph MeOCH 2 CH 2 1-Nap 507 2-Me-5-i-Pr -Ph PhCH 2 Ph 503 2-Me-5-i-Pr-Ph PhCH 2 2-F-Ph 521 2-Me-5-i-Pr-Ph PhCH 2 3-F-Ph 521 2-Me-5- i-Pr-Ph PhCH 2 4-Cl-Ph 537 2-Me-5-i-Pr-Ph PhCH 2 4-F-Ph 521 2-Me-5-i-Pr-Ph PhCH 2 1-Nap 553 2 , 4,6-Me 3 -Ph PhCH 2 Ph 489 2,4,6-Me 3 -Ph PhCH 2 2 -F-Ph 507 2,4,6-Me 3 -Ph PhCH 2 3-F-Ph 507 2 , 4,6-Me 3 -PhPhCH 2 4-Cl-Ph 523 2,4,6-Me 3 -Ph PhCH 2 4 -F-Ph 507 2,4,6-Me 3 -Ph PhCH 2 1- Nap 539 2-MeS-Ph Et Ph 431 2-MeS-Ph Et 2-F-Ph 449 2-MeS-Ph Et 3-F-Ph 449 2-MeS-Ph Et 4-Cl-Ph 465 2-MeS- Ph Et 4-F-Ph 449 2-MeS-Ph Et 1-Nap 481 2-MeS-4-i-Pr-Ph Et Ph 473 2-MeS-4-i-Pr-Ph Et 2-F-Ph 491 2-MeS-4-i-Pr-Ph Et 3-F-Ph 491 2-MeS-4-i-Pr-Ph Et 4-Cl-Ph 507 2-MeS-4-i-Pr-Ph Et 4- F-Ph 491 2-MeS-4-i-Pr-Ph Et 1-Nap 523 2-MeS-Ph n-Hep Ph 501 2-MeS-Ph n-Hep 2-F-Ph 519 2-MeS-Ph n -Hep 3-F-Ph 519 2-MeS-Phn-Hep 4-Cl-Ph 535.
【００４３】 ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ５１９ ２-ＭｅＳ-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ５５１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ５４３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５６１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５６１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ５７７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ５６１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ５９３ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ４５７ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ４７５ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ４７５ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４９１ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ４７５ ２-ＭｅＳ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５０７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ４９９ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ５１７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ５１７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５３３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ５１７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５４９ ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ４７１ ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ４８９ ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ４８９ ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５０５ ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ４８９。2-MeS-Phn-Hep 4-F-Ph 519 2-MeS-Phn-Hep 1-Nap 551 2-MeS-4-i-Pr-Phn-Hep Ph 543 2-MeS-4 -i-Pr-Phn-Hep 2-F-Ph 561 2-MeS-4-i-Pr-Phn-Hep 3-F-Ph 561 2-MeS-4-i-Pr-Phn-Hep 4 -Cl-Ph 577 2-MeS-4-i-Pr-Phn-Hep 4-F-Ph 561 2-MeS-4-i-Pr-Phn-Hep 1-Nap 593 2-MeS-Ph c- Pr-CH 2 Ph 457 2-MeS-Ph c-Pr-CH 2 2-F-Ph 475 2-MeS-Ph c-Pr-CH 2 3-F-Ph 475 2-MeS-Ph c-Pr-CH 2 4-Cl-Ph 491 2-MeS-Ph c-Pr-CH 2 4-F-Ph 475 2-MeS-Ph c-Pr-CH 2 1-Nap 507 2-MeS-4-i-Pr -Ph c-Pr-CH 2 Ph 499 2-MeS-4-i-Pr-Ph c-Pr-CH 2 2-F-Ph 517 2-MeS-4-i-Pr-Ph c-Pr-CH 2 3-F-Ph 517 2-MeS-4-i-Pr-Ph c-Pr-CH 2 4-Cl-Ph 533 2-MeS-4-i-Pr-Ph c-Pr-CH 2 4-F- Ph 517 2-MeS-4- i-Pr-Ph c-Pr-CH 2 1-Nap 549 2-MeS-Ph c-Bu-CH 2 Ph 471 2-MeS-Ph c-Bu-CH 2 2-F -Ph 489 2-MeS-Ph c -Bu-CH 2 3-F-Ph 489 2-MeS-Ph c-Bu-CH 2 4-Cl-Ph 505 2-MeS-Ph c-Bu-CH 2 4- F-Ph 489.
【００４４】 ２-ＭｅＳ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５２１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ５１３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ５３１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ５３１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５４７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ５３１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５６３ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ４４１ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ４５９ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ４５９ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４７５ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ４５９ ２-ＭｅＳ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ４９１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ４８３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ５０１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ５０１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５１７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ５０１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ５３３ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ４４３ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ４６１ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ４６１ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ４７７ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ４６１ ２-ＭｅＳ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ４９３。2-MeS-Ph c-Bu-CH 2 1-Nap 521 2-MeS-4-i-Pr-Ph c-Bu-CH 2 Ph 513 2-MeS-4-i-Pr-Ph c- Bu-CH 2 2-F-Ph 531 2-MeS-4-i-Pr-Ph c-Bu-CH 2 3-F-Ph 531 2-MeS-4-i-Pr-Ph c-Bu-CH 2 4-Cl-Ph 547 2-MeS-4-i-Pr-Phc-Bu-CH 2 4-F-Ph 531 2-MeS-4-i-Pr-Phc-Bu-CH 2 1-Nap 563 2-MeS-Ph HC≡C-CH 2 Ph 441 2-MeS-Ph HC≡C-CH 2 2-F-Ph 459 2-MeS-Ph HC≡C-CH 2 3-F-Ph 459 2-MeS -Ph HC≡C-CH 2 4-Cl-Ph 475 2-MeS-Ph HC≡C-CH 2 4-F-Ph 459 2-MeS-Ph HC≡C-CH 2 1-Nap 491 2-MeS- 4-i-Pr-P HC≡C-CH 2 Ph 483 2- MeS-4-i-Pr-Ph HC≡C-CH 2 2-F-Ph 501 2-MeS-4-i-Pr-Ph HC≡C-CH 2 3- F-Ph 501 2-MeS-4-i-Pr-Ph HC≡C-CH 2 4-Cl-Ph 517 2-MeS-4-i-Pr-Ph HC≡C-CH 2 4-F-Ph 501 2-MeS-4-i-Pr-Ph HC≡C-CH 2 1-Nap 533 2-MeS-Ph H 2 C = CH-CH 2 Ph 443 2-MeS-Ph H 2 C = CH-CH 2 2 -F-Ph 461 2-MeS-Ph H 2 C = CH-CH 2 3-F-Ph 461 2-MeS-Ph H 2 C = CH-CH 2 4-Cl-Ph 477 2-MeS-Ph H 2 C = CH-CH 2 4-F-Ph 461 2-MeS-Ph H 2 C = CH-CH 2 1-Nap 493.
【００４５】 ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ４８５ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ５０３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ５０３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５１９ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ５０３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ５３５ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ４６１ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ４７９ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ４７９ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ４９５ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ４７９ ２-ＭｅＳ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５１１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ５０３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ５２１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ５２１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ５３７ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ５２１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５５３ ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 Ｐｈ ４９３ ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５１１ ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５１１ ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ５２７ ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５１１。2-MeS-4-i-Pr-Ph H 2 C = CH-CH 2 Ph 485 2-MeS-4-i-Pr-Ph H 2 C = CH-CH 2 2-F-Ph 503 2 -MeS-4-i-Pr- Ph H 2 C = CH-CH 2 3-F-Ph 503 2-MeS-4-i-Pr-Ph H 2 C = CH-CH 2 4-Cl-Ph 519 2 -MeS-4-i-Pr- Ph H 2 C = CH-CH 2 4-F-Ph 503 2-MeS-4-i-Pr-Ph H 2 C = CH-CH 2 1-Nap 535 2-MeS -Ph MeOCH 2 CH 2 Ph 461 2-MeS-Ph MeOCH 2 CH 2 2-F-Ph 479 2-MeS-Ph MeOCH 2 CH 2 3-F-Ph 479 2-MeS-Ph MeOCH 2 CH 2 4-Cl -Ph 495 2-MeS-Ph MeOCH 2 CH 2 4-F-Ph 479 2-MeS-Ph MeOCH 2 CH 2 1-Nap 511 2-MeS-4-i-Pr-P MeOCH 2 CH 2 Ph 503 2- MeS-4-i-Pr-Ph MeOCH 2 CH 2 2-F-Ph 521 2-MeS-4-i-Pr-Ph MeOCH 2 CH 2 3-F-Ph 521 2- MeS-4-i-Pr-Ph MeOCH 2 CH 2 4-Cl-Ph 537 2-MeS-4-i-Pr-Ph MeOCH 2 CH 2 4-F-Ph 521 2-MeS-4-i-Pr- Ph MeOCH 2 CH 2 1-Nap 553 2-MeS-Ph PhCH 2 Ph 493 2-MeS-Ph PhCH 2 2-F-Ph 511 2-MeS-Ph PhCH 2 3-F-Ph 511 2-MeS-Ph PhCH 2 4-Cl-Ph 527 2 -MeS-Ph PhCH 2 4-F-Ph 511.
【００４６】 ２-ＭｅＳ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ５４３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 Ｐｈ ５３５ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５５３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５５３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ５６９ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５５３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ５８５ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ Ｐｈ ５４５ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ５６３ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ５６３ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ５７９ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ５６３ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｅｔ １-Ｎａｐ ５９５ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ Ｐｈ ５０６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ ２-Ｆ-Ｐｈ ５２４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ ３-Ｆ-Ｐｈ ５２４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ ４-Ｃｌ-Ｐｈ ５４０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ ４-Ｆ-Ｐｈ ５２４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｅｔ １-Ｎａｐ ５５６ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ６１５ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ６３３ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ６３３ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ６４９ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ ４-Ｆ-Ｐｈ ６３３ ２-Ｃｌ-４-Ｉ-Ｐｈ ｎ-Ｈｅｐ １-Ｎａｐ ６６５ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ Ｐｈ ５７６。2-MeS-PhPhCH 2 1-Nap 543 2-MeS-4-i-Pr-Ph PhCH 2 Ph 535 2-MeS-4-i-Pr-Ph PhCH 2 2-F-Ph 553 2- MeS-4-i-Pr-Ph PhCH 2 3-F-Ph 553 2-MeS-4-i-Pr-Ph PhCH 2 4-Cl-Ph 569 2-MeS-4-i-Pr-Ph PhCH 2 4 -F-Ph 553 2-MeS-4-i-Pr-PhPhCH 2 1-Nap 585 2-Cl-4-I-Ph Et Ph 545 2-Cl-4-I-Ph Et 2-F-Ph 563 2-Cl-4-I-Ph Et 3-F-Ph 563 2-Cl-4-I-Ph Et 4-Cl-Ph 579 2-Cl-4-I-Ph Et 4-F-Ph 563 2- Cl-4-I-Ph Et 1-Nap 595 2-Br-4-Me 2 N-Ph Et Ph 506 2-Br-4-Me 2 N-Ph Et 2-F-Ph 524 2 -Br-4-Me 2 N-Ph Et 3-F-Ph 524 2-Br-4-Me 2 N-Ph Et 4-Cl-Ph 540 2-Br-4-Me 2 N-Ph Et 4-F -Ph 524 2-Br-4-Me 2 N-Ph Et 1 -Nap 556 2-Cl-4-I-Ph n-Hep Ph 615 2-Cl-4-I-Ph n-Hep 2-F-Ph 633 2-Cl-4-I-Phn-Hep 3-F-Ph 633 2-Cl-4-I-Phn-Hep 4-Cl-Ph 649 2-Cl-4-I-Phn-Hep 4 -F-Ph 633 2-Cl-4-I-Ph n-Hep 1-Nap 665 2-Br-4-Me 2 N-Ph n-Hep Ph 576.
【００４７】 ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ ２-Ｆ-Ｐｈ ５９４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ ３-Ｆ-Ｐｈ ５９４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ ４-Ｃｌ-Ｐｈ ６１０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ ４−Ｆ−Ｐｈ ５９４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｎ-Ｈｅｐ １−Ｎａｐ ６２６ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ５７１ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ５８９ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ５８９ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ６０５ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ５８９ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ６２１ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 Ｐｈ ５３２ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ２-Ｆ-Ｐｈ ５５０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ３-Ｆ-Ｐｈ ５５０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５６６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 ４-Ｆ-Ｐｈ ５５０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｐｒ-ＣＨ2 １-Ｎａｐ ５８２ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ５８５ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ６０３ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ６０３ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ６１９ ２-Ｃｌ-４-Ｉ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ６０３ ２-Ｃｌ-４-Ｉ−Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ６３５ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 Ｐｈ ５４６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ２-Ｆ-Ｐｈ ５６４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ３-Ｆ-Ｐｈ ５６４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５８０。2-Br-4-Me 2 N-Ph n-Hep 2-F-Ph 594 2-Br-4-Me 2 N-Ph n-Hep 3-F-Ph 594 2-Br-4-Me 2 N-Phn-Hep 4-Cl-Ph 610 2-Br-4-Me 2 N-Phn-Hep 4-F-Ph 594 2-Br-4-Me 2 N-Phn-Hep 1-Nap 626 2-Cl-4-I-Ph c-Pr-CH 2 Ph 571 2-Cl-4-I-Ph c-Pr-CH 2 2-F-Ph 589 2-Cl-4-I-Ph c- Pr-CH 2 3-F-Ph 589 2-Cl-4-I-Ph c-Pr-CH 2 4-Cl-Ph 605 2-Cl-4-I-Ph c-Pr-CH 2 4-F- Ph 589 2-Cl-4- I-Ph c-Pr-CH 2 1-Nap 621 2-Br-4-Me 2 N-Ph c-Pr-CH 2 Ph 532 2-Br-4-Me 2 N- Ph c-Pr-CH 2 2-F-Ph 550 2-Br-4-Me 2 NP h c-Pr-CH 2 3-F-Ph 550 2-Br-4-Me 2 N-Ph c-Pr-CH 2 4-Cl-Ph 566 2-Br-4-Me 2 N-Ph c-Pr -CH 2 4-F-Ph 550 2-Br-4-Me 2 N-Ph c-Pr-CH 2 1-Nap 582 2-Cl-4-I-Ph c-Bu-CH 2 Ph 585 2-Cl -4-I-Ph c-Bu-CH 2 2-F-Ph 603 2-Cl-4-I-Ph c-Bu-CH 2 3-F-Ph 603 2-Cl-4-I-Ph c- Bu-CH 2 4-Cl-Ph 619 2-Cl-4-I-Ph c-Bu-CH 2 4-F-Ph 603 2-Cl-4-I-Ph c-Bu-CH 2 1-Nap 635 2-Br-4-Me 2 N-Ph c-Bu-CH 2 Ph 546 2-Br-4-Me 2 N-Ph c-Bu-CH 2 2-F-Ph 564 2-Br-4-Me 2 N-Ph c-Bu-CH 2 3-F-Ph 564 2-Br-4-Me 2 N-Ph c-Bu-CH 2 4-Cl-Ph 580.
【００４８】 ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 ４-Ｆ-Ｐｈ ５６４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ｃ-Ｂｕ-ＣＨ2 １-Ｎａｐ ５９６ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ５５５ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ５７３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ５７３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５８９ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ５７３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ６０５ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 Ｐｈ ５１６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ２-Ｆ-Ｐｈ ５３４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ３-Ｆ-Ｐｈ ５３４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５５０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 ４-Ｆ-Ｐｈ ５３４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＨＣ≡Ｃ-ＣＨ2 １-Ｎａｐ ５６６ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ５５７ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ５７５ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ５７５ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５９１ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ５７５ ２-Ｃｌ-４-Ｉ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ６０７ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 Ｐｈ ５１８ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ２-Ｆ-Ｐｈ ５３６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ３-Ｆ-Ｐｈ ５３６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｃｌ-Ｐｈ ５５２ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 ４-Ｆ-Ｐｈ ５３６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ Ｈ2Ｃ=ＣＨ-ＣＨ2 １-Ｎａｐ ５６８。2-Br-4-Me 2 N-Ph c-Bu-CH 2 4-F-Ph 564 2-Br-4-Me 2 N-Ph c-Bu-CH 2 1-Nap 596 2-Cl -4-I-Ph HC≡C-CH 2 Ph 555 2-Cl-4-I-Ph HC≡C-CH 2 2-F-Ph 573 2-Cl-4-I-Ph HC≡C-CH 2 3-F-Ph 573 2-Cl-4-I-Ph HC≡C-CH 2 4-Cl-Ph 589 2-Cl-4-I-Ph HC≡C-CH 2 4-F-Ph 573 2- Cl-4-I-Ph HC≡C-CH 2 1-Nap 605 2-Br-4-Me 2 N-Ph HC≡C-CH 2 Ph 516 2-Br-4-Me 2 N-Ph HC≡C -CH 2 2-F-Ph 534 2-Br-4-Me 2 N-Ph HC≡C-CH 2 3-F-Ph 534 2-Br-4-Me 2 N-Ph HC≡C-CH 2 4 -Cl-Ph 550 2-Br- 4-Me 2 N-Ph HC≡C-CH 2 4-F- h 534 2-Br-4- Me 2 N-Ph HC≡C-CH 2 1-Nap 566 2-Cl-4-I-Ph H 2 C = CH-CH 2 Ph 557 2-Cl-4-I- Ph H 2 C = CH-CH 2 2-F-Ph 575 2-Cl-4-I-Ph H 2 C = CH-CH 2 3-F-Ph 575 2-Cl-4-I-Ph H 2 C = CH-CH 2 4-Cl-Ph 591 2-Cl-4-I-Ph H 2 C = CH-CH 2 4-F-Ph 575 2-Cl-4-I-Ph H 2 C = CH-CH 2 1-Nap 607 2-Br -4-Me 2 N-Ph H 2 C = CH-CH 2 Ph 518 2-Br-4-Me 2 N-Ph H 2 C = CH-CH 2 2-F-Ph 536 2-Br-4-Me 2 N-Ph H 2 C = CH-CH 2 3-F-Ph 536 2-Br-4-Me 2 N-Ph H 2 C = CH-CH 2 4-Cl-Ph 552 2-Br-4-Me 2 N-Ph H 2 C = CH-CH 2 4-F-Ph 536 2-Br-4-Me 2 N-Ph H 2 C = CH -CH 2 1-Nap 568.
【００４９】 ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ５７５ ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ５９３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ５９３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ６０９ ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ５９３ ２-Ｃｌ-４-Ｉ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ６２５ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 Ｐｈ ５３６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ２-Ｆ-Ｐｈ ５５４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ３-Ｆ-Ｐｈ ５５４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｃｌ-Ｐｈ ５７０ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 ４-Ｆ-Ｐｈ ５５４ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＭｅＯＣＨ2ＣＨ2 １-Ｎａｐ ５８６ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 Ｐｈ ６０７ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ６２５ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ６２５ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ６４１ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ６２５ ２-Ｃｌ-４-Ｉ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ６５７ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 Ｐｈ ５６８ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 ２-Ｆ-Ｐｈ ５８６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 ３-Ｆ-Ｐｈ ５８６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 ４-Ｃｌ-Ｐｈ ６０２ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 ４-Ｆ-Ｐｈ ５８６ ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ ＰｈＣＨ2 １-Ｎａｐ ６１８。2-Cl-4-I-Ph MeOCH 2 CH 2 Ph 575 2-Cl-4-I-Ph MeOCH 2 CH 2 2-F-Ph 593 2-Cl-4-I-Ph MeOCH 2 CH 2 3-F-Ph 593 2- Cl-4-I-Ph MeOCH 2 CH 2 4-Cl-Ph 609 2-Cl-4-I-Ph MeOCH 2 CH 2 4-F-Ph 593 2-Cl-4- I-Ph MeOCH 2 CH 2 1-Nap 625 2-Br-4-Me 2 N-Ph MeOCH 2 CH 2 Ph 536 2-Br-4-Me 2 N-Ph MeOCH 2 CH 2 2-F-Ph 554 2 -Br-4-Me 2 N-Ph MeOCH 2 CH 2 3-F-Ph 554 2-Br-4-Me 2 N-Ph MeOCH 2 CH 2 4-Cl-Ph 570 2-Br-4-Me 2 N -Ph MeOCH 2 CH 2 4-F-Ph 554 2-Br-4-Me 2 N-Ph MeOCH 2 CH 2 1-Nap 586 2 -Cl-4-I-Ph PhCH 2 Ph 607 2-Cl-4-I-Ph PhCH 2 2-F-Ph 625 2-Cl-4-I-Ph PhCH 2 3-F-Ph 625 2-Cl- 4-I-Ph PhCH 2 4 -Cl-Ph 641 2-Cl-4-I-Ph PhCH 2 4-F-Ph 625 2-Cl-4-I-Ph PhCH 2 1-Nap 657 2-Br-4 -Me 2 N-Ph PhCH 2 Ph 568 2-Br-4-Me 2 N-Ph PhCH 2 2-F-Ph 586 2-Br-4-Me 2 N-Ph PhCH 2 3-F-Ph 586 2- Br-4-Me 2 N-Ph PhCH 2 4-Cl-Ph 602 2-Br-4-Me 2 N-Ph PhCH 2 4-F-Ph 586 2-Br-4-Me 2 N-Ph PhCH 2 1 -Nap 618.
【００５０】（注）（表１中の表記について）： ２-Ｂｒ-４-ｉ-Ｐｒ-Ｐｈ＝２−ブロモ−４−イソプロ
ピルフェニル基 ２,４-Ｂｒ2-Ｐｈ＝２,４−ジブロモフェニル基 ２-Ｍｅ-５-ｉ-Ｐｒ-Ｐｈ＝２−メチル−５−イソプロ
ピルフェニル基 ２,４,６-Ｍｅ3-Ｐｈ＝２,４,６−トリメチルフェニル
基 ２-ＭｅＳ-Ｐｈ＝２−メチルチオフェニル基 ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ＝２−メチルチオ−４−イ
ソプロピルフェニル基 ２-Ｃｌ-４-Ｉ-Ｐｈ＝２−クロロ−４−ヨウ化フェニル
基 ２-Ｂｒ-４-Ｍｅ2Ｎ-Ｐｈ＝２−ブロモ−４−ジメチル
アミノフェニル基 ｎ-Ｈｅｐ＝ｎ−ヘプチル基 ｃ-Ｐｒ-ＣＨ2＝シクロプロピルメチル基 ｃ-Ｂｕ-ＣＨ2＝シクロブチルメチル基 １-Ｎａｐ＝１−ナフチル基 Ｍ++１＝イオンスプレー ＭＳによる ＊：塩酸塩。(Note) (Notation in Table 1): 2-Br-4-i-Pr-Ph = 2-bromo-4-isopropylphenyl group 2,4-Br 2 -Ph = 2,4-dibromo phenyl 2-Me-5-i- Pr-Ph = 2- methyl-5-isopropylphenyl group 2,4,6-Me 3 -Ph = 2,4,6- trimethylphenyl group 2-MeS-Ph = 2 -Methylthiophenyl group 2-MeS-4-i-Pr-Ph = 2-methylthio-4-isopropylphenyl group 2-Cl-4-I-Ph = 2-chloro-4-iodinated phenyl group 2-Br-4 -Me 2 N-Ph = 2-bromo-4-dimethylaminophenyl group n-Hep = n-heptyl group c-Pr-CH 2 = cyclopropylmethyl group c-Bu-CH 2 = cyclobutylmethyl group 1-Nap = 1-naphthyl group M ++ 1 = by ion spray MS *: Hydrochloride.
【００５１】実施例３ ４−[（Ｅ）−３−ベンジリデンピペリジン−１−イル]
−２−[Ｎ−（２−メチルチオ−４−イソプロピルフェ
ニル）−Ｎ−エチルアミノ]−６−メチルピリミジン塩
酸塩 及び ４−[（Ｚ）−３−ベンジリデンピペリジ
ン−１−イル]−２−[Ｎ−（２−メチルチオ−４−イソ
プロピルフェニル）−Ｎ−エチルアミノ]−６−メチル
ピリミジン塩酸塩の合成 （１）水素化ナトリウム１.１０ｇと１５−クラウン−
５−エーテル１３８ｍｇをＴＨＦ３０ｍｌに溶解し、ジ
エチル ベンジルホスホネート６.３０ｇとＮ−ｔ−ブ
トキシカルボニル−３−ピペリドン５.００ｇをＴＨＦ
２０ｍｌに溶解した溶液を室温にて滴下した。 一昼夜
攪拌後水を注ぎ、酢酸エチルにて抽出後、有機層を１規
定の水酸化ナトリウム水溶液と飽和食塩水で順次洗浄
し、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、
濾液を減圧下濃縮し、残渣をシリカゲルカラムクロマト
グラフィー（展開溶媒；ヘキサン：酢酸エチル＝１０：
１）にて精製し、（Ｅ）−３−ベンジリデン−Ｎ−ｔ−
ブトキシカルボニルピペリジンと（Ｚ）−３−ベンジリ
デン−Ｎ−ｔ−ブトキシカルボニルピペリジンとの約
３：２の混合物３.０５ｇを得た。 （２）（１）で得た（Ｅ）−３−ベンジリデン−Ｎ−ｔ
−ブトキシカルボニルピペリジンと（Ｚ）−３−ベンジ
リデン−Ｎ−ｔ−ブトキシカルボニルピペリジンとの約
３：２の混合物３.０５ｇを４規定塩化水素／ジオキサ
ン溶液２８ｍｌに溶解し、室温にて１時間攪拌後、減圧
下溶媒を留去し、粗の（Ｅ）−３−ベンジリデンピペリ
ジン塩酸塩と（Ｚ）−３−ベンジリデンピペリジン塩酸
塩の混合物を得た。得られた粗の（Ｅ）−３−ベンジリ
デンピペリジン塩酸塩と（Ｚ）−３−ベンジリデンピペ
リジン塩酸塩の混合物をエタノール５ｍｌに溶解し、Ｎ
−エチルジイソプロピルアミン３.８１ｇを加えた後、
−１０℃に冷却し、２,４−ジクロロ−６−メチルピリ
ミジン１.９２ｇを加え、室温にて一晩攪拌した。反応
溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチ
ルにて抽出後、有機層を飽和食塩水で洗浄し、無水硫酸
ナトリウムにて乾燥した。 乾燥剤を濾別後、濾液を減
圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィ
ー（展開溶媒；ヘキサン：酢酸エチル＝４：１）にて精
製し、４−[（Ｅ）−３−ベンジリデンピペリジン−１
−イル]−２−クロロ−６−メチルピリミジン１.２５ｇ
と４−[（Ｚ）−３−ベンジリデンピペリジン−１−イ
ル]−２−クロロ−６−メチルピリミジン６８１ｍｇを
それぞれ黄色結晶として得た。 （３）（２）で得た４−[（Ｅ）−３−ベンジリデンピ
ペリジン−１−イル]−２−クロロ−６−メチルピリミ
ジン１.２５ｇとＮ−エチル−４−イソプロピル−２−
メチルチオアニリン０.８７２ｇをエチレングリコール
６ｍｌに溶解し、１時間加熱還流した。反応液に飽和炭
酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出
後、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウ
ムにて乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィー（展開
溶媒；ヘキサン：酢酸エチル＝１０：１）にて精製し、
油状の４−[（Ｅ）−３−ベンジリデンピペリジン−１
−イル]−２−[Ｎ−（２−メチルチオ−４−イソプロピ
ルフェニル）−Ｎ−エチルアミノ]−６−メチルピリミ
ジン１.３９ｇを得た。この油状の生成物は塩化メチレ
ン中４規定塩化水素／酢酸エチル処理により塩酸塩と
し、エーテルより結晶化して、４−[（Ｅ）−３−ベン
ジリデンピペリジン−１−イル]−２−[Ｎ−（２−メチ
ルチオ−４−イソプロピルフェニル）−Ｎ−エチルアミ
ノ]−６−メチルピリミジン塩酸塩１.３３ｇを得た。 （４）（３）と同様の操作により、（２）で得た４−
[（Ｚ）−３−ベンジリデンピペリジン−１−イル]−２
−クロロ−６−メチルピリミジン６８１ｍｇから４−
[（Ｚ）−３−ベンジリデンピペリジン−１−イル]−２
−[Ｎ−（２−メチルチオ−４−イソプロピルフェニ
ル）−Ｎ−エチルアミノ]−６−メチルピリミジン塩酸
塩６６５ｍｇを得た。本化合物及び同様にして得た化合
物の構造およびマススペクトルデータを表２に記した。Example 3 4-[(E) -3-benzylidenepiperidin-1-yl]
-2- [N- (2-methylthio-4-isopropylphenyl) -N-ethylamino] -6-methylpyrimidine hydrochloride and 4-[(Z) -3-benzylidenepiperidin-1-yl] -2- [ Synthesis of N- (2-methylthio-4-isopropylphenyl) -N-ethylamino] -6-methylpyrimidine hydrochloride (1) 1.10 g of sodium hydride and 15-crown-
138 mg of 5-ether was dissolved in 30 ml of THF, and 6.30 g of diethyl benzylphosphonate and 5.00 g of Nt-butoxycarbonyl-3-piperidone were added to THF.
A solution dissolved in 20 ml was added dropwise at room temperature. After stirring overnight, water was poured, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 1N aqueous solution of sodium hydroxide and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant,
The filtrate is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10:
Purified in 1), (E) -3-benzylidene-Nt-
3.05 g of an approximately 3: 2 mixture of butoxycarbonylpiperidine and (Z) -3-benzylidene-Nt-butoxycarbonylpiperidine were obtained. (2) (E) -3-benzylidene-Nt obtained in (1)
3.05 g of an approximately 3: 2 mixture of -butoxycarbonylpiperidine and (Z) -3-benzylidene-Nt-butoxycarbonylpiperidine is dissolved in 28 ml of a 4N hydrogen chloride / dioxane solution and stirred at room temperature for 1 hour. Thereafter, the solvent was distilled off under reduced pressure to obtain a crude mixture of (E) -3-benzylidenepiperidine hydrochloride and (Z) -3-benzylidenepiperidine hydrochloride. A mixture of the obtained crude (E) -3-benzylidenepiperidine hydrochloride and (Z) -3-benzylidenepiperidine hydrochloride was dissolved in 5 ml of ethanol, and N
-3.81 g of ethyldiisopropylamine are added,
After cooling to −10 ° C., 1.92 g of 2,4-dichloro-6-methylpyrimidine was added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1) to give 4-[(E) -3-benzylidenepiperidine- 1
-Yl] -2-chloro-6-methylpyrimidine 1.25 g
And 4-[(Z) -3-benzylidenepiperidin-1-yl] -2-chloro-6-methylpyrimidine (681 mg) were obtained as yellow crystals. (3) 1.25 g of 4-[(E) -3-benzylidenepiperidin-1-yl] -2-chloro-6-methylpyrimidine obtained in (2) and N-ethyl-4-isopropyl-2-
0.872 g of methylthioaniline was dissolved in 6 ml of ethylene glycol, and the mixture was heated under reflux for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1).
Oily 4-[(E) -3-benzylidenepiperidine-1
1.39 g of -yl] -2- [N- (2-methylthio-4-isopropylphenyl) -N-ethylamino] -6-methylpyrimidine were obtained. This oily product was converted to the hydrochloride salt by treatment with 4N hydrogen chloride / ethyl acetate in methylene chloride and crystallized from ether to give 4-[(E) -3-benzylidenepiperidin-1-yl] -2- [N- 1.33 g of (2-methylthio-4-isopropylphenyl) -N-ethylamino] -6-methylpyrimidine hydrochloride were obtained. (4) By the same operation as in (3), the 4-
[(Z) -3-benzylidenepiperidin-1-yl] -2
-Chloro-6-methylpyrimidine from 681 mg to 4-
[(Z) -3-benzylidenepiperidin-1-yl] -2
665 mg of-[N- (2-methylthio-4-isopropylphenyl) -N-ethylamino] -6-methylpyrimidine hydrochloride was obtained. Table 2 shows the structure and mass spectrum data of this compound and the compound obtained in the same manner.
【００５２】[0052]
【化７】 Embedded image
【００５３】 表２ Ｘ1,Ｘ2,Ｘ3-Ｐｈ Ｒ2 Ｅ/Ｚ Ａｒ Ｍ++１ *２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｅ Ｐｈ ４７３ *２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｚ Ｐｈ ４７３ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｅ ３-Ｆ-Ｐｈ ４９１ ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ Ｅｔ Ｚ ３-Ｆ-Ｐｈ ４９１。Table 2 X 1 , X 2 , X 3 -Ph R 2 E / Z Ar M ++ 1 * 2-MeS-4-i-Pr-Ph EtE Ph 473 * 2-MeS-4-i- Pr-PhEtZPh473 2-MeS-4-i-Pr-PhEtE3-F-Ph491 2-MeS-4-i-Pr-PhEtZ3-F-Ph491.
【００５４】（注）（表２中の表記について）： ２-ＭｅＳ-４-ｉ-Ｐｒ-Ｐｈ＝２−メチルチオ−４−イ
ソプロピルフェニル基 Ｅ/Ｚ＝ベンジリデンの立体 Ｍ++１＝イオンスプレー ＭＳによる ＊：塩酸塩。[0054] (Note) (Notation in Table 2): 2-MeS-4 -i-Pr-Ph = 2- methylthio-4-isopropylphenyl group E / Z = stereoscopic benzylidene M + + 1 = ion spray By MS *: hydrochloride.
【００５５】試験例［ＣＲＦ受容体結合実験] 受容体標品としてラット前頭皮質膜を用いた。125Ｉ標
識リガンドとして125Ｉ−ＣＲＦを用いた。125Ｉ標識リ
ガンドを用いた結合反応は、The Journal of Neuroscie
nce,７,８８(１９８７年)に記載された以下の方法で行
った。 受容体膜標品の調製：ラット前頭皮質を１０ｍＭＭｇＣ
ｌ2及び２ｍＭ ＥＤＴＡを含む５０ｍＭトリス塩酸緩衝
液（ｐＨ７.０）でホモジナイズし,４８,０００×ｇで
遠心分離し、沈渣をトリス塩酸緩衝液で１度洗浄した。
沈渣を１０ｍＭＭｇＣｌ2、２ｍＭ ＥＤＴＡ、０.１％
ウシ血清アルブミン及び１００カリクレインユニット／
ｍｌアプロチニンを含む５０ｍＭトリス塩酸緩衝液（ｐ
Ｈ７.０）に懸濁し、膜標品とした。Test Example [CRF Receptor Binding Experiment] Rat frontal cortical membrane was used as a receptor preparation. 125 I-CRF was used as the 125 I-labeled ligand. Binding reactions using 125 I-labeled ligands are described in The Journal of Neuroscie
nce, 7,88 (1987). Preparation of receptor membrane preparation: Rat frontal cortex was treated with 10 mM MgC
homogenized in l 2 and 50mM Tris-HCl buffer containing 2mM EDTA (pH7.0), and centrifuged at 48,000 × g, and washed once with sediment in Tris-HCl buffer.
The sediment was washed with 10 mM MgCl 2 , 2 mM EDTA, 0.1%
Bovine serum albumin and 100 kallikrein units /
50 mM Tris-HCl buffer (ml
H7.0) to give a membrane preparation.
【００５６】ＣＲＦ受容体結合実験：膜標品（０.３ｍ
ｇタンパク質／ｍｌ）、125Ｉ−ＣＲＦ（０.２ｎＭ）及
び被験薬を、２５℃で２時間反応させた。反応終了後、
０.３％ポリエチレンイミンで処理したガラスフィルタ
ー（ＧＦ／Ｃ）に吸引濾過し、ガラスフィルターを０.
０１％ＴｒｉｔｏｎＸ−１００を含むリン酸緩衝化生理
食塩水で３度洗浄した。洗浄後、濾紙の放射能をガンマ
ーカウンターにて測定した。CRF receptor binding experiment: membrane standard (0.3 m
g protein / ml), 125 I-CRF (0.2 nM) and the test drug were reacted at 25 ° C. for 2 hours. After the reaction,
The solution was suction-filtered through a glass filter (GF / C) treated with 0.3% polyethyleneimine.
Washed three times with phosphate buffered saline containing 01% Triton X-100. After washing, the radioactivity of the filter paper was measured with a gamma counter.
【００５７】１μＭ ＣＲＦ存在下で反応を行った時の
結合量を、125Ｉ−ＣＲＦの非特異結合とし、総結合と
非特異結合との差を特異結合とした。一定濃度（０.２
ｎＭ）の125Ｉ−ＣＲＦと濃度を変えた被験薬を上記の
条件で反応させることで抑制曲線を得、この抑制曲線か
ら125Ｉ−ＣＲＦ結合を５０％抑制する被験薬の濃度
（ＩＣ50）を求めた。The amount of binding when the reaction was performed in the presence of 1 μM CRF was defined as nonspecific binding of 125 I-CRF, and the difference between total binding and nonspecific binding was defined as specific binding. Constant concentration (0.2
An inhibitory curve was obtained by reacting a test drug having a different concentration with (nM) 125 I-CRF under the above conditions, and the concentration of the test drug that inhibited 125 I-CRF binding by 50% (IC 50 ) from the inhibition curve. I asked.
【００５８】その結果、ＩＣ50値が５００ｎＭ以下のア
リールメチレンピペリジノピリミジン誘導体が見出され
た。例えば、２−[Ｎ−(２−ブロモ−４−イソプロピル
フェニル)−Ｎ−エチルアミノ]−４−(４−ベンジリデ
ンピペリジン−１−イル)−６−メチルピリミジン塩酸
塩のＩＣ50値は２８２.６ｎＭであった。As a result, an arylmethylenepiperidinopyrimidine derivative having an IC 50 value of 500 nM or less was found. For example, the IC 50 value of 2- [N- (2-bromo-4-isopropylphenyl) -N-ethylamino] -4- (4-benzylidenepiperidin-1-yl) -6-methylpyrimidine hydrochloride is 282. 6 nM.
フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 31/505 ＡＡＭ Ａ６１Ｋ 31/505 ＡＡＭ ＡＢＡ ＡＢＡ ＡＢＥ ＡＢＥ ＡＢＮ ＡＢＮ ＡＢＵ ＡＢＵ ＡＣＪ ＡＣＪ ＡＤＲ ＡＤＲ ＡＥＤ ＡＥＤ (72)発明者 島崎 洋一 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 村山 真由美 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 冨沢 一雪 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内Continued on the front page (51) Int.Cl. 6 Identification symbol FI A61K 31/505 AAM A61K 31/505 AAM ABA ABA ABE ABE ABN ABN ABN ABU ABU ACJ ACJ ADR ADR ADR AED AED (72) Inventor Hirokazu Toshima, Tokyo 3-24-1, Takada Taisho Seiyaku Co., Ltd. (72) Inventor Mayumi Murayama 3-24-1, Takada, Toshima-ku, Tokyo In Taisho Seiyaku Co., Ltd. (72) Inventor Kazuki Tomizawa Takada, Toshima-ku, Tokyo 3-24-1, Taisho Pharmaceutical Co., Ltd.
Claims (1)
基を示し、Ｒ1は水素原子、低級アルキル基、アミノ基
又は置換アミノ基を示し、Ｒ2は低級アルキル基、低級
アルケニル基又は低級アルキニル基を示し、Ｘ1、Ｘ2及
びＸ3は同一又は異なって水素原子、ハロゲン原子、低
級アルキル基、低級アルコキシ基、低級アルキルチオ
基、低級アルキルアミノ基又は含窒素複素環基を示
す。）で表されるアリールメチレンピペリジノピリミジ
ン誘導体又はその医薬上許容される塩。(1) Formula (1) (In the formula, Ar represents a phenyl group, a substituted phenyl group, or a naphthyl group, R 1 represents a hydrogen atom, a lower alkyl group, an amino group or a substituted amino group, and R 2 represents a lower alkyl group, a lower alkenyl group, or a lower alkynyl. X 1 , X 2 and X 3 are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group or a nitrogen-containing heterocyclic group.) An arylmethylenepiperidinopyrimidine derivative represented or a pharmaceutically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10142621A JPH11335373A (en) | 1998-05-25 | 1998-05-25 | Arylmethylenepiperidinopyrimidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10142621A JPH11335373A (en) | 1998-05-25 | 1998-05-25 | Arylmethylenepiperidinopyrimidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11335373A true JPH11335373A (en) | 1999-12-07 |
Family
ID=15319605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10142621A Withdrawn JPH11335373A (en) | 1998-05-25 | 1998-05-25 | Arylmethylenepiperidinopyrimidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11335373A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002549A1 (en) * | 2000-07-05 | 2002-01-10 | Taisho Pharmaceutical Co., Ltd. | Tetrahydropyridino or piperidino heterocyclic derivatives |
| WO2008123395A1 (en) | 2007-03-28 | 2008-10-16 | Santen Pharmaceutical Co., Ltd. | Ocular hypotensive agent comprising compound capable of inhibiting histone deacetylase as active ingredient |
| JP2013530954A (en) * | 2010-06-04 | 2013-08-01 | エフ．ホフマン−ラ ロシュ アーゲー | Aminopyrimidine derivatives as LRRK2 modulators |
-
1998
- 1998-05-25 JP JP10142621A patent/JPH11335373A/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002002549A1 (en) * | 2000-07-05 | 2002-01-10 | Taisho Pharmaceutical Co., Ltd. | Tetrahydropyridino or piperidino heterocyclic derivatives |
| US6852732B2 (en) | 2000-07-05 | 2005-02-08 | Taisho Pharmaceutical Co., Ltd. | Tetrahydropyridino or piperidino heterocylic derivatives |
| US7160900B2 (en) | 2000-07-05 | 2007-01-09 | Taisho Pharmaceutical Co., Ltd. | Tetrahydropyridino or piperidino heterocyclic derivatives |
| WO2008123395A1 (en) | 2007-03-28 | 2008-10-16 | Santen Pharmaceutical Co., Ltd. | Ocular hypotensive agent comprising compound capable of inhibiting histone deacetylase as active ingredient |
| JP2013530954A (en) * | 2010-06-04 | 2013-08-01 | エフ．ホフマン−ラ ロシュ アーゲー | Aminopyrimidine derivatives as LRRK2 modulators |
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