CN1137878C - 芳氧基苯胺衍生物 - Google Patents
芳氧基苯胺衍生物 Download PDFInfo
- Publication number
- CN1137878C CN1137878C CNB988078430A CN98807843A CN1137878C CN 1137878 C CN1137878 C CN 1137878C CN B988078430 A CNB988078430 A CN B988078430A CN 98807843 A CN98807843 A CN 98807843A CN 1137878 C CN1137878 C CN 1137878C
- Authority
- CN
- China
- Prior art keywords
- meo
- carbon atom
- alkyl
- group
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 60
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 230000027455 binding Effects 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 210000003470 mitochondria Anatomy 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000019901 Anxiety disease Diseases 0.000 abstract description 5
- 230000036506 anxiety Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 144
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- -1 2- carboxymethyl phenyl Chemical group 0.000 description 65
- 239000000243 solution Substances 0.000 description 62
- 239000002904 solvent Substances 0.000 description 61
- 150000001875 compounds Chemical class 0.000 description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 42
- 125000001309 chloro group Chemical group Cl* 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 29
- 235000002639 sodium chloride Nutrition 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 27
- 239000007864 aqueous solution Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical group CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000376 reactant Substances 0.000 description 22
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000011780 sodium chloride Substances 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 239000000284 extract Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 230000000704 physical effect Effects 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 150000001298 alcohols Chemical class 0.000 description 13
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 12
- 239000003513 alkali Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 238000007670 refining Methods 0.000 description 9
- 239000000370 acceptor Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000003444 phase transfer catalyst Substances 0.000 description 7
- 229960003418 phenoxybenzamine Drugs 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 150000008282 halocarbons Chemical class 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910003844 NSO2 Inorganic materials 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 4
- VBQDSLGFSUGBBE-UHFFFAOYSA-N benzyl(triethyl)azanium Chemical compound CC[N+](CC)(CC)CC1=CC=CC=C1 VBQDSLGFSUGBBE-UHFFFAOYSA-N 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 230000006315 carbonylation Effects 0.000 description 4
- 238000005810 carbonylation reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 150000003983 crown ethers Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- 208000012661 Dyskinesia Diseases 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 208000000501 Lipidoses Diseases 0.000 description 3
- 206010024585 Lipidosis Diseases 0.000 description 3
- 206010061533 Myotonia Diseases 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 125000003047 N-acetyl group Chemical group 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 206010013663 drug dependence Diseases 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 208000019116 sleep disease Diseases 0.000 description 3
- 208000020685 sleep-wake disease Diseases 0.000 description 3
- 208000011117 substance-related disease Diseases 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006290 2-hydroxybenzyl group Chemical group [H]OC1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 2
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 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
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000003236 psychic effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 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
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004899 1-ethylpropylamino group Chemical group C(C)C(CC)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
- BNSRVFGXRITOQK-UHFFFAOYSA-N 2-(1,2-dichloroethyl)-4-methyl-1,3-dioxolane Chemical compound CC1COC(C(Cl)CCl)O1 BNSRVFGXRITOQK-UHFFFAOYSA-N 0.000 description 1
- IVEWTCACRDEAOB-UHFFFAOYSA-N 2-(2-methoxyphenyl)acetic acid Chemical class COC1=CC=CC=C1CC(O)=O IVEWTCACRDEAOB-UHFFFAOYSA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-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
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 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
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical class CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 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
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical class C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 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
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 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
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 150000001398 aluminium Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- KOCXMMTWVKMODE-UHFFFAOYSA-N bromobenzene;phosphane Chemical compound P.BrC1=CC=CC=C1 KOCXMMTWVKMODE-UHFFFAOYSA-N 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical class [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 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
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 108010061433 diazepam-binding inhibitor receptor Proteins 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical class C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 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
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-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
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical class COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- RQNMYNYHBQQZSP-UHFFFAOYSA-M methylmagnesium chloride Chemical class C[Mg]Cl RQNMYNYHBQQZSP-UHFFFAOYSA-M 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GYNAVKULVOETAD-UHFFFAOYSA-N n-phenoxyaniline Chemical compound C=1C=CC=CC=1NOC1=CC=CC=C1 GYNAVKULVOETAD-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy 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])C([H])([H])O* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- VSWLXYAZJZQIKA-UHFFFAOYSA-N tetrachloromethane;triphenylphosphane Chemical compound ClC(Cl)(Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VSWLXYAZJZQIKA-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
- C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/23—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/27—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Pyridine Compounds (AREA)
Abstract
一种由下式表示的芳氧基苯胺衍生物或其医药上允许的盐,[式中,Ar1和Ar2相同或不同,表示取代或未取代的苯基、取代或未取代的吡啶基或萘基;R1表示氢原子、取代或未取代的1~10个碳原子的烷基、1~10个碳原子的烷氧基、取代或未取代的苯基或者由式-NR2(R3)(式中,R2和R3相同或不同,表示氢原子或1~10个碳原子的烷基,或者表示与相邻氮原子一起构成4~10元环的环氨基)表示的基团;X1表示氢原子、1~5个碳原子的烷基、1~5个碳原子的烷氧基、苯氧基、卤原子、三氟甲基、氨基甲酰基或氨基磺酰基;Y1表示有支链或无支链的1~6个碳原子的亚烷基或单键]。本发明目的在于提供一种医药,以及对焦虑及与其有关的疾病、抑郁症、癫痫病、认知学习障碍、精神分裂症等中枢性疾病、肌强直引起的运动障碍、摄食障碍、循环障碍、药物依赖症、癌症、脂质代谢障碍、脑梗塞、艾滋病、阿尔茨海默氏病和亨廷顿舞蹈病等具有治疗和预防效果,对MDR具有高亲和性的药物。
Description
技术领域
本发明涉及医药,特别是涉及对MDR具有高亲和性的医药。
背景技术
现在,苯并二氮杂(BZ)受体,可以分为存在于GABAA受体/离子通道复合物上的中枢苯并二氮杂受体(CBR)和存在于中枢神经系统(神经胶质细胞)和肾上腺等中的线粒体DBI受体(MDR,DBI:安定(地西泮)结合抑制剂;《神经药理学》Neuropharmacol,30,1425-1433,1991)两种亚型(《临床神经药理学》Clin.Neuro-pharmacol.,16,401-417,1993)。
MDR的激动剂通过内源性神经甾体间接作用在GABAA受体/离子通道复合物上,由于发现其抗焦虑作用,所以对于用已有BZ类药物不能获得满意治疗效果的症状(强迫性障碍和恐慌障碍)来说是有用的,能够减轻据认为由BZ类药物所产生的过度镇静或精神依赖性等副作用。而且MDR的配体,间接通过GABAA受体,能够用作睡眠障碍、癫痫、肌强直引起的运动障碍、摄食障碍、循环障碍、认知学习障碍和药物依赖性的治疗药物(《神经生物学进展》Progress inNeurobiology,38,379-395,1992;同上,49,73-97,1996;《神经化学杂志》J.Neurochem.,58,1589-160;《神经药理学》Neuro-phamarcol.,30,1435-1440,1995)。此外,MDR的配体还能够用作癌症(《生物化学与生物物理学学报》Biochimica et BiophysicaActa,1241,453-470,1995)、脂质代谢障碍(《欧洲药理学杂志》Eur.J.Pharmacol.,294,601-607,1995)、精神分裂症(《神经药理学》Neurophamarcolgy,35,1075-1079,1996)、脑梗塞(《神经科学杂志》J.Neurosci.,15,5263-5274,1995)、艾滋病(《艾滋病第五届国际会议摘要》,458页,1989年)、阿尔茨海默氏病(《Alzhemer Dis.Assoc.Distd.》,2,331-336,1988)和亨廷顿舞蹈病(《脑研究》Brain Res.,248,396-401,1982)等疾病的治疗药物。
在WO9533715及JP61040249和JP57208295等专利中报告了苯氧基苯胺衍生物。但是在这些物质中,苯胺氮原子上的取代基是氢原子或烷基,没有报导以羧基为取代基的衍生物。而且,上述专利中记载的用途是,基于对花生四烯酸类作用的抗炎药、基于PGI2产量上升的抗动脉硬化药和热敏记录材料,没有记载对MDR的亲和性和基于对MDR亲和性的抗焦虑作用等。
本发明目的在于提供一种对使用已有BZ类药物不能获得满意治疗效果的症状有效的,而且据认为没有BZ类药物那种过度镇静作用或精神依赖性等副作用的,对于焦虑及与其有关的疾病、抑郁症、癫痫病等中枢神经系统疾病具有治疗和预防作用,对MDR具有高亲和性的药物。此外本发明目的还在于提供一种对睡眠障碍、肌强直引起的运动障碍、摄食障碍、循环障碍、认知学习障碍、药物依赖症、癌症、脂质代谢障碍、精神分裂症、脑梗塞、艾滋病、阿尔茨海默氏病和亨廷顿舞蹈病等的治疗药。
发明的公开
本发明人等就芳氧基苯胺衍生物进行了深入研究,结果发现对于MDR具有高亲和性的新颖的芳氧基苯胺衍生物,从而完成了本发明。
以下说明本发明。
本发明是由式(I)表示的芳氧基苯胺衍生物及其医药上允许的盐
[式中,Ar1和Ar2可以相同或不同,表示取代或未取代的苯基、取代或未取代的吡啶基或萘基;R1表示氢原子、取代或未取代的1~10个碳原子的烷基、1~10个碳原子的烷氧基、取代或未取代的苯基或者式-NR2(R3)(式中,R2和R3可以相同或不同,表示氢原子或1~10个碳原子的烷基,或者表示与相邻的氮原子一起构成4~10元环的环氨基)表示的基团;X1表示氢原子、1~5个碳原子的烷基、1~5个碳原子的烷氧基、苯氧基、卤原子、三氟甲基、氨基甲酰基或氨基磺酰基;Y1表示有支链或无支链的1~6个碳原子的亚烷基或单键]。
本发明中所说的取代的苯基,是从下列取代基中任意选出的1~3个取代基取代的苯基:1~10个碳原子的烷基、被(卤原子、羟基、1~10个碳原子的链烷酰氧基、羧基或烷氧羰基)取代的1~10个碳原子的烷基、2~10个碳原子的链烯基、1~10个碳原子的烷氧基、1~10个碳原子的烷硫基、由式-O-Z-R4(式中,Z表示有或无支链的1~10个碳原子的亚烷基,R4表示氨基、被一或二个1~7个碳原子的烷基取代的氨基、2~7个碳原子的环氨基、羟基、羧基或烷氧羰基)表示的基团、2~10个碳原子的链烷酰基或其缩酮体、甲酰基或其缩醛体、羧基、2~10个碳原子的烷氧羰基、氨基甲酰基、氮原子被一或二个1~10个碳原子的烷基取代的氨基甲酰基、氨基磺酰基、氮原子被一或二个1~10个碳原子的烷基取代的氨基磺酰基、卤原子和硝基。例如,2-甲基苯基、2-丙基苯基、2-异丙基苯基、2-环戊基苯基、2-(1-羟乙基)苯基、2-羧甲基苯基、2-甲氧羰基苯基、2-乙烯基苯基、2-甲氧基苯基、3-甲氧苯基、4-甲氧苯基、2-乙氧苯基、2-己氧苯基、2-异丙氧苯基、2-环戊氧苯基、2,5-二甲氧苯基、2,4,6-三甲氧苯基、4-甲硫基苯基、2-异丙硫基苯基、4-环己硫基苯基、2-(2-二甲基氨基乙氧基)苯基、2-(2-羟基乙氧基)苯基、2-羧基甲氧基苯基、2-甲氧羰基甲氧基苯基、2-乙酰苯基、2-(2-甲基-1,3-二氧杂戊环-2-基)苯基、2-甲酰基苯基、2-(1,3-二氧杂戊环-2-基)苯基、2-羧基苯基、2-(N-甲基氨基羰基)苯基、2-(N,N-二甲基氨基羰基)苯基、2-氨基羰基苯基、2-氨基磺酰基苯基、4-氨基磺酰基苯基、2-甲基氨基磺酰基苯基、2-二甲基氨基磺酰基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2,4-二氟苯基、2-硝基苯基、2-氨基苯基、2-吡咯烷基苯基、4-二甲基氨基苯基等。
所说的取代的吡啶基,表示被1~10个碳原子的直链或支链烷氧基取代的吡啶基,例如2-甲氧基-3-吡啶基、3-甲氧基-2-吡啶基、4-甲氧基-3-吡啶基等。所说的1~10个碳原子的烷基,表示直链、支链或环状烷基;例如甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、环丁基、环丙基甲基、戊基、异戊基、环戊基、环丁基甲基、1-乙基丙基、己基、异己基、环己基、环戊基甲基、1-乙基丁基、庚基、异庚基、环己基甲基、辛基、壬基、癸基等。所说的1~10个碳原子的取代烷基,表示被(羟基、链烷酰氧基、链烷酰基、烷氧基、卤原子、叠氮基、氨基、羧基)取代的烷基;例如羟甲基、乙酰氧甲基、甲氧甲基、氯代甲基、三氟甲基、叠氮基甲基、氨基甲基、二甲氨基甲基、吡咯烷基甲基等。所说的1~10个碳原子的烷氧基,表示直链、直链或环状烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、环丙基甲氧基、戊氧基、异戊氧基、己氧基、庚氧基、辛氧基、壬氧基、庚氧基等。R2和R2表示的1~10个碳原子的烷基,表示直链、支链或环状烷基;因此R2和R2表示1~10个碳原子的烷基时式-NR2(R3)表示的基团,例如有甲基氨基、乙基氨基、丙基氨基、异丙基氨基、丁基氨基、异丁基氨基、环丙基甲基氨基、戊基氨基、异戊基氨基、环戊基氨基、环丁基甲基氨基、1-乙基丙基氨基、己基氨基、异己基氨基、环己基氨基、环戊基甲基氨基、1-乙基丁基氨基、庚基氨基、异庚基氨基、环己基甲基氨基、辛基氨基、壬基氨基、癸基氨基、二甲基氨基、二乙基氨基、二丙基氨基、二丁基氨基、二戊基氨基、二己基氨基、N-甲基乙基氨基、N-甲基丙基氨基、N-甲基丁基氨基、N-甲基戊基氨基、N-甲基己基氨基、N-乙基丙基氨基、N-乙基丁基氨基和N-乙基戊基氨基等。而且所说的由式-NR2(R3)表示的4~10元环的环氨基,表示可还含有氮原子或氧原子的环氨基,例如有吡咯烷基、1-哌啶基、哌嗪基、N-甲基哌嗪基和吗啉基等。由X1表示的1~5个碳原子的烷基,表示直链、直链或环状的烷基,例如有甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、环丁基和环丙基甲基等;而且,所说的1~5个碳原子的烷氧基,表示直链、直链或环状的烷氧基,例如有甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基和环丙基甲氧基等。由Y1表示有支链或无支链的1~6个碳原子的亚烷基,表示例如亚甲基、亚乙基、亚丙基、甲基亚甲基和二甲基亚甲基等。所说的卤原子表示氟原子、氯原子、溴原子或碘原子等。
而且所说的本发明中的医药上允许的盐,例如有硫酸、盐酸、磷酸等无机酸的盐,醋酸、草酸、乳酸、酒石酸、富马酸、马来酸、甲磺酸和苯磺酸等有机酸的盐,与钠离子、钾离子和钙离子等金属离子形成的盐,以及与二乙醇胺等有机碱形成的盐等。
式(I)化合物可以用以下一般制法1~6制造(在以下反应式中,Ar1、Ar2、R1、X1和Y1与上述相同,Y2表示单键或被1~3个碳原子的烷基取代或未取代的1~5个碳原子的亚烷基,R5表示1~3个碳原子的烷基或氢原子,X2表示1~10个碳原子的酰氧基、氯原子、溴原子、羟基或1~5个碳原子的烷氧基,X3表示氯原子、溴原子或碘原子。)
[一般制法1]
在酸催化剂存在或不存在下,于惰性溶剂中通过使苯胺衍生物(1)与羰基衍生物(2)反应后还原,或者在酸催化剂存在或不存在下,于惰性溶剂中通过将苯胺衍生物(1)与羰基衍生物(2)的混合物还原,可以得到化合物(3)。在碱存在或不存在下,于惰性溶剂中通过使化合物(3)与N-羰基化试剂反应,可以得到化合物(4)。而且,使作为这些N-羰基化试剂的光气与化合物(3)反应,制成氯代羰基衍生物后,在碱存在或不存在下通过与醇类或胺类反应,可以得到本发明化合物(4)。
其中使用的催化剂,例如是氯化氢、溴化氢等卤化氢,盐酸、硫酸等无机酸,醋酸、对甲苯磺酸等有机酸,以及PPTS、哌啶盐酸盐等。
还原反应,可以使用例如硼氢化钠、硼氢化锂、氰基硼氢化钠等硼类还原剂,或者氢化铝锂等铝类还原剂,或者使用钯、二氧化铂或阮内镍等作为催化剂,进行加氢。所说的N-羰基化试剂,例如是酰卤、有机酸酐、烷氧羰基卤化物、卤代氨基甲酰、氰酸(在反应液中由氰酸钾与醋酸生成)和异氰酸盐等。所说的碱,例如有三乙胺、二异丙基乙基胺、吡啶等有机胺类,碳酸钾、氢氧化钠、氢化钠、金属钠等无机碱类。所说的惰性溶剂,例如有甲醇、乙醇等醇类,四氢呋喃等醚类,甲苯、苯等烃类,氯仿、二氯甲烷等卤代烃类溶剂,乙腈,水或其混合溶剂等。
在碱存在或不存在下,通过使苯胺衍生物(1)和化合物(5)表示的羧酸酐、酰卤、羧酸或羧酸酯于惰性溶剂中反应生成酰胺化合物(6),进而使之于惰性溶剂中进行还原剂反应,可以合成化合物(3)中R2为氢原子的化合物(7)。
[一般制法3]
在碱存在或不存在下,于惰性溶剂中使苯胺衍生物(1)和N-羰基化试剂反应生成化合物(8)后,在卤化物(9)和碱存在下,必要时使用相转移催化剂、铜粉、卤化亚铜等,使之于惰性溶剂中反应,可以得到本发明化合物(10)。而且,使用光气作为这些N-羰基化剂与化合物(1)反应,制成氯代羰基衍生物后,在碱存在下通过与醇类或胺类反应,也可以得到化合物(8)。
其中所说的N-羰基化剂,例如有酰卤、有机酸酐、烷氧羰基卤化物、氨基甲酰卤、氰酸(在反应液中由氰酸钾与醋酸生成)和异氰酸盐(酯)等。所说的碱,例如有三乙胺、二异丙基乙基胺和吡啶等有机胺类,碳酸钾、氢氧化钠、氢化钠和金属钠等无机碱类,叔丁醇钾、乙醇钠等醇盐类等。所说的相转移催化剂,例如有溴化苄基三乙基铵等季铵盐和18-冠醚-6等冠醚等。所说的惰性溶剂,例如有甲醇、乙醇等醇类,四氢呋喃等醚类,甲苯、苯等烃类,二氯甲烷、氯仿等卤代烃类溶剂,丙酮等酮类,乙腈、N,N-二甲基甲酰胺,硝基苯,水或其混合溶剂等。
[一般制法4]
当Ar1和/或Ar2中含有硝基的情况下,此硝基可以利用加氢或金属还原的方法转变成氨基。在碱存在下,必要时使用相转移催化剂,使此氨基与惰性溶剂中的卤化物反应,将其转变成被1~10个碳原子的直链、支链或环状烷基取代的氨基。
其中所说的加氢,表示使用钯、二氧化铂、阮内镍等催化剂时的加氢;所说的金属还原,表示通常使用锡、氯化亚锡等二价锡盐,铁、氯化亚铁等二价铁盐,锌等金属或金属盐时,在酸性、中性或碱性条件下的还原。所说的碱,例如有三乙胺、二异丙基乙基胺和吡啶等有机胺类,碳酸钾、氢氧化钠、氢化钠和金属钠等无机碱类,叔丁醇钾、乙醇钠等醇盐类等。所说的相转移催化剂,例如有溴化苄基三乙基铵等季铵盐和18-冠醚-6等冠醚等。所说的惰性溶剂,例如有甲醇、乙醇等醇类,四氢呋喃等醚类,甲苯、苯等烃类,二氯甲烷、氯仿等卤代烃类溶剂,乙腈、N,N-二甲基甲酰胺,水或其混合溶剂等。
[一般制法5]
当Ar1和/或Ar2中含有酰氧基的情况下,此酰氧基可以用酸性或碱性条件下水解的方法转变成羟基。这种羟基,在碱存在下,必要时使用相转移催化剂,通过与惰性溶剂中的卤化物反应,可以转变成1~10个碳原子的直链或支链烷氧基、被取代或未取代的氨基取代的1~10个碳原子的直链或支链烷氧基、或被羧基或烷氧羰基取代的1~10个碳原子的烷氧基。
其中所说的酸性或碱性条件下,表示在甲醇、乙醇等醇类,四氢呋喃、二氧六环等醚类,丙酮等酮类,乙腈、N,N-二甲基甲酰胺、水或其混合溶剂中,使用盐酸、硫酸等无机酸,或氢氧化钠、氢氧化钾等无机碱的条件。所说的碱,例如有三乙胺、二异丙基乙基胺和吡啶等有机胺类,碳酸钾、氢氧化钠、氢化钠和金属钠等无机碱类,叔丁醇钾、乙醇钠等醇盐类等。所说的相转移催化剂,例如有溴化苄基三乙基铵等季铵盐和18-冠醚-6等冠醚等。所说的惰性溶剂,例如有甲醇、乙醇等醇类,四氢呋喃等醚类,甲苯、苯等烃类,二氯甲烷、氯仿等卤代烃类溶剂,乙腈、N,N-二甲基甲酰胺,水或其混合溶剂等。
[一般制法6]
在Ar1和/或Ar2中含有烷氧羰基的情况下,此烷氧羰基可以采用通常的酯水解法转变成羧基。而且羧基通过酯化反应可以转变成1~10个碳原子的烷氧羰基,通过酰胺化反应能够转变成1~10个碳原子的烷基伯氨基羰基、烷基仲氨基羰基、伯或仲氨基羰基。
其中所说的水解条件,例如表示在甲醇、乙醇等醇类溶剂中,或在丙酮等酮类溶剂中的惰性溶剂中,使氢氧化钠、碳酸钠等碱,或盐酸、硫酸等无机酸反应。所说的酯化,表示使被氯原子、溴原子或碘原子取代的烷基化合物或二烷基硫酸,与例如氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、氢化钠等无机碱,或者与例如甲醇钠、叔丁氧基钠等醇盐类,例如三乙胺、二异丙基乙基胺等有机碱类一起反应,或者表示使醇与例如氯化氢、硫酸等酸一起反应。所说的酰胺化,表示用亚硫酰氯或三苯基膦-四氯化碳等将羧基变成酰卤后,与对应的胺衍生物反应,或者表示例如利用混合酸酐法或二环己基碳化二亚胺法等通常方法酰胺化。
[一般制法7]
在Ar1和/或Ar2中含有甲酰基或酰基的情况下,此甲酰基或酰基的羰基可以通过与Wittig试剂反应变成链烯基。进而将链烯基还原成烷基。
其中所说的Wittig试剂,表示具有1~9个碳原子的烷基的三苯基烷基卤化鏻或二乙基烷基膦酸酯等,例如在甲醇、乙醇等醇类,四氢呋喃等醚类,甲苯、苯等烃类,二氯甲烷、氯仿等卤代烃类或乙腈、N,N-二甲基甲酰胺等惰性溶剂中,使用氢化钠、叔丁醇钾、乙醇钠、正丁基锂等碱,必要时同时使用溴化苄基三乙基铵、18-冠醚-6等冠醚等相转移催化剂。所说的还原表示使用钯、二氧化铂或阮内镍等作为催化剂的加氢。
[一般制法8]
在Ar1和/或Ar2中含有甲酰基或酰基的情况下,此甲酰基或酰基的羰基可以通过与格氏试剂反应转变成仲醇或叔醇。进而通过用各种氧化剂将仲醇氧化,转变成酰基。
其中所说的格氏试剂,表示有1~9个碳原子的烷基或链烯基卤化镁,例如溴化甲基镁、溴化乙基镁等。所说的各种氧化剂,表示使用乙酰氯-二甲基亚砜的Swern氧化、铬类氧化剂或二氧化锰氧化剂等。
为了使用本发明的化合物作为医药,可以向本发明化合物中添加通常的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等,按照常规制剂技术制成片剂、丸剂、胶囊剂、颗粒剂、粉剂、乳剂、悬浮剂或注射剂等。
本发明化合物,对于成年患者可以将0.1~500毫克/日剂量,一日一次或分数次经口或不经口给药。此投药量可以根据疾病的种类、患者的年龄、体重和症状适当加减。
实施发明的最佳方式
以下,通过给出的实施例和试验例具体说明本发明。
实施例1
N-乙酰基-N-(2-异丙氧苄基)-2-苯氧基苯胺的合成
(1)将2-异丙氧基苯甲醛1.64克溶解在10毫升甲醇中,加入2-氨基二苯基醚1.85克,室温下搅拌30分钟后用冰水冷却。向此冷却的反应液中分数次少量添加共1.5克硼氢化钠,冰冷下搅拌30分钟,接着在室温下搅拌30分钟。向反应溶液中滴加醋酸水溶液(醋酸1.5毫升-水30毫升),室温下搅拌30分钟后用乙酸乙酯提取。提取液用饱和碳酸氢钠水溶液和饱和食盐水洗涤干净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶25)精制,得到了油状的N-(2-异丙氧苄基)-2-苯氧基苯胺2.65克。
(2)将N-(2-异丙氧苄基)-2-苯氧基苯胺2.65克和三乙胺1.5毫升溶解在30毫升四氢呋喃中,此溶液在搅拌下滴加0.8毫升乙酰氯,搅拌30分钟。将反应混合物注到水中后,提取到乙酸乙酯内,先后用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制,得到了油状的N-乙酰基-N-(2-异丙氧苄基)-2-苯氧基苯胺2.92克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例2
N-乙酰基-N-(2,4-二甲氧苄基)-2-苯氧基苯胺的合成
(1)将2-氨基二苯基醚3.70克和2,4-二甲氧基苯甲醛3.70克溶解在60毫升甲醇中,向其中加入氧化铂70毫克,在氢气流中和室温下搅拌过夜。向反应混合物中加入氯仿30毫升,析出物溶解后滤出催化剂。滤液在减压下浓缩,用甲醇使残余物重结晶,得到了N-(2,4-二甲氧苄基)-2-苯氧基苯胺5.06克。
(2)向N-(2,4-二甲氧苄基)-2-苯氧基苯胺1.00克在1.18克吡啶的溶液中,加入醋酐0.76克,室温下搅拌1天。将反应混合物注到水中后,提取到乙酸乙酯内,先后用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制,得到了油状的N-乙酰基-N-(2,4-二甲氧苄基)-2-苯氧基苯胺1.09克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例3
N-乙酰基-N-(2-氯代苄基)-2-苯氧基苯胺的合成
(1)冰冷却下,向2-苯氧基苯胺28.5克和25.8毫升三乙胺在250毫升二氯甲烷的溶液中,滴加乙酰氯11.5毫升。室温下搅拌1.5小时后,减压浓缩此反应混合物。将残余物注入水中后提取到乙酸乙酯中。先后用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制,得到了N-乙酰基-2-苯氧基苯胺33.7克。
(2)室温下,向400毫克氢化钠(60%油中的悬浮液)在30毫升二甲基甲酰胺的悬浮液中,加入N-乙酰基-2-苯氧基苯胺2.00克,进而在室温下搅拌30分钟。在搅拌下和室温下,向此溶液中滴加1.64克2-氯代苄基氯,搅拌30分钟后,向反应混合物中加入冰水,提取到乙醚中。提取液先后用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制,得到了油状的N-乙酰基-N-(2-氯代苄基)-2-苯氧基苯胺2.92克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例4
N-氨基羰基-N-(2-甲氧苄基)-2-苯氧基苯胺的合成
将按照与实施例1中(1)同样合成的N-(2-甲氧苄基)-2-苯氧基苯胺1.54克溶解在20毫升醋酸中,向此溶液中滴加氰酸钾水溶液(氰酸钾1.23克-水10毫升)后,室温下搅拌2.5小时。将反应混合物注入水中后,提取到乙酸乙酯中。先后用饱和碳酸氢钠水溶液和饱和食盐水洗涤干净后,用无水硫酸钠干燥。滤出干燥剂后,减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制,得到了N-氨基羰基-N-(2-甲氧苄基)-2-苯氧基苯胺1.69克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例5
N-(2-甲氧苄基)-N-(N-甲基氨基羰基)-2-苯氧基苯胺的合成
搅拌下向751毫克三光气在14毫升二氯甲烷中的溶液内,滴加2.03克N-(2-甲氧苄基)-2-苯氧基苯胺和1.03克二异丙基乙基胺在25毫升二氯甲烷中的溶液,室温下搅拌5分钟。搅拌下向此溶液中注入过量甲胺,室温下搅拌5分钟后减压浓缩。将反应混合物注入乙酸乙酯中。先后用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,析出的结晶用乙酸乙酯重结晶,得到了N-(2-甲氧苄基)-N-(N-甲基氨基羰基-2-苯氧基苯胺2.02克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例6
N-(2,5-二甲氧苄基)-N-(N-甲基氨基羰基)-2-苯氧基苯胺的合成
向3.43毫升醋酸和8.36毫升三乙胺在90毫升苯中的溶液内,加入12.9毫升二苯基膦酰基叠氮化物,加热回流2小时。向此反应液中加入与实施例2中(1)同样合成的N-(2,5-二甲氧苄基)-2-苯氧基苯胺2.01克,加热回流6小时。将反应混合物注入水中,分取有机相后,先后用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂。残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶2)精制,用二乙醚重结晶,得到了N-(2,5-二甲氧苄基)-N-(N-甲基氨基羰基-2-苯氧基苯胺1.20克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例7
N-(2-甲氧苄基)-N-甲氧羰基-2-苯氧基苯胺的合成
(1)搅拌下,将溶解有2.16克N-(2-甲氧苄基)-2-苯氧基苯胺和1.10克二异丙基乙基胺的25毫升二氯甲烷溶液缓缓滴加到14毫升775毫克三光气在二氯甲烷的溶液中,室温下搅拌15分钟。减压浓缩反应混合物,注入乙酸乙酯中,依次用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶15)精制,得到了油状的N-氯代羰基-N-(2-甲氧苄基)-2-苯氧基苯胺2.57克。
(2)在冰冷却和搅拌下,将溶解在5毫升四氢呋喃中的1.22克N-氯代羰基-N-(2-甲氧苄基)-2-苯氧基苯胺滴入226毫克甲醇钠在四氢呋喃中的5毫升溶液,室温下搅拌20分钟。将反应混合物减压浓缩后注入水中,提取到乙酸乙酯内,依次用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶6)精制后,用乙酸乙酯重结晶,得到了N-(2-甲氧苄基)-N-甲氧羰基-2-苯氧基苯胺1.18克。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例8
N-氨基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺的合成
(1)室温下,将与实施例1同样合成的1.51克N-氯代乙酰基-(2-甲氧苄基)-2-苯氧基苯胺和770毫克叠氮化钠的二甲基甲酰胺10毫升溶液搅拌过夜。将反应混合物注入水中后提取到乙酸乙酯中。提取液依次用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制后,得到了N-叠氮基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺1.55克。
(2)将647毫克N-叠氮基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺溶解在7毫升甲醇中,加入氧化铂20毫克,在氢气气氛和室温下搅拌一夜。用硅藻土过滤反应混合物,减压下浓缩后用乙酸乙酯-异丙醚重结晶,得到了0.24克N-氨基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。实施例9
N-羟基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺的合成
(1)80℃下在10毫升苯中将1.01克N-氯代乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺、1.30克乙酸钠和170毫克溴化四正丁基铵搅拌5小时。将反应混合物注入乙酸乙酯后,提取液依次用水和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制后,得到了油状N-乙酰氧基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺1.03克。
(2)将525毫克N-乙酰氧基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺溶解在6毫升甲醇中,加入537毫克碳酸钾,在50℃下搅拌7小时后,将反应混合物注入水中,提取到乙酸乙酯中。提取液依次用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制室温下放置后,得到了450毫克N-羟基乙酰基-N-(2-甲氧苄基)-2-苯氧基苯胺结晶。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例10
N-乙酰基-N-(2-吡咯烷基苄基)-2-苯氧基苯胺的合成
(1)将与实施例3同样合成的8.00克N-乙酰基-(2-硝基苄基)-2-苯氧基苯胺溶解在80毫升甲醇中,加入66毫克二氧化铂,在氢气气氛和室温下搅拌过夜。向反应混合物中加入40毫升氯仿将析出物溶解后,滤出催化剂。滤液经减压浓缩后,用甲醇对残余物重结晶,得到了6.88克N-乙酰基-N-(2-氨基苄基)-2-苯氧基苯胺。
(2)在10毫升N,N-二甲基甲酰胺中70℃下,将1.00克N-乙酰基-N-(2-氨基苄基)-2-苯氧基苯胺、680毫克1,4-二溴丁烷、1.03克碳酸钾和50毫克碘化钾搅拌3天。将反应混合物注入水中后,提取到乙酸乙酯中,提取液依次用水和饱和食盐水洗涤干净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制。将得到的生成物溶解在5毫升乙醚中,加入0.9毫升4当量氯化氢-乙酸乙酯溶液后,浓缩溶液,在乙酸乙酯-乙醚中重结晶,得到了0.49克N-乙酰基-N-(2-吡咯烷基苄基)-2-苯氧基苯胺一盐酸盐结晶。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例11
N-乙酰基-N-(2-羧基甲氧基苄基)-2-苯氧基苯胺的合成
(1)将1.74克2-乙酰氧基苯甲醛和1.85克2-苯氧基苯胺溶解在30毫升甲醇中,于室温下搅拌1小时后,加入3.00克硼氢化钠,于同温下搅拌30分钟。向反应溶液中滴加醋酸水溶液(3.0毫升醋酸-60毫升水),室温下搅拌10分钟后,用乙酸乙酯提取。提取液经饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,将残余物和4毫升三乙胺的50毫升二氯甲烷溶液冷却到0℃,搅拌下滴加2.00毫升乙酰氯,于室温下搅拌20分钟后,将反应混合物注入水中,并提取到乙酸乙酯中,依次用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗净,无水硫酸钠干燥。滤出干燥剂,减压浓缩溶剂,得到了N-乙酰基-N-(2-乙酰氧苄基)-2-苯氧基苯胺粗品。
将此粗品溶解在40毫升甲醇溶液中,加入14毫升5%氢氧化钾水溶液,室温下搅拌1小时。减压浓缩反应混合物,注入水中后,提取到乙酸乙酯中。提取液依次用5%盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗净,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用二异丙醚结晶,得到了1.86克N-乙酰基-N-(2-羟基苄基)-2-苯氧基苯胺。
(2)向666毫克N-乙酰基-N-(2-羟基苄基)-2-苯氧基苯胺的10毫升N,N-二甲基甲酰胺溶液中,加入80毫克60%氢化钠/油,室温下搅拌30分钟。向此物质中加入0.3毫升溴代醋酸甲酯,室温下搅拌30分钟。将反应液注入0.5N盐酸中,用乙酸乙酯萃取,提萃取液依次用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩滤液,得到了N-乙酰基-N-(2-甲氧羰基甲氧基苄基)-2-苯氧基苯胺粗品。
将此粗品溶解在10毫升甲醇溶液中,加入5毫升5%氢氧化钾水溶液,室温下搅拌1小时。向反应液中加入2N盐酸调成酸性,提取到乙酸乙酯中。提取液用饱和食盐水洗净,无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用二异丙醚结晶,得到了745毫克N-乙酰基-N-(2-羧基甲氧基苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例12
N-乙酰基-N-(2-丙基苄基)-2-苯氧基苯胺的合成
(1)将与实施例3同样合成的2.81克N-乙酰基-N-[2-(1,3-二氧戊环-2-基)苄基]-2-苯乙基苯胺溶解在40毫升丙酮中,加入0.10克对甲苯磺酸一水合物,室温下搅拌6小时。向反应液中加入饱和碳酸氢钠水溶液,减压下浓缩丙酮后,用乙酸乙酯提取残余物,经饱和碳酸氢钠水溶液和饱和食盐水洗净后,用无水硫酸钠干燥。滤出干燥剂,经减压浓缩后,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶3)精制,干燥后放置,经室温下放置得到了2.12克N-乙酰基-N-(2-甲酰基苄基)-2-苯氧基苯胺结晶。
(2)在氮气气流下,向4.34克乙基三苯基溴化鏻的20毫升四氢呋喃溶液中滴加反应液温度保持在-15~-10℃下的6.63毫升1.63M正丁基锂/己烷溶液。使反应液缓缓升至室温,并于室温下搅拌20分钟后,滴加1.01克N-乙酰基-N-(2-甲酰基苄基)-2-苯氧基苯胺的10毫升四氢呋喃溶液,再搅拌1小时。向反应液中加入饱和氯化铵水溶液,提取到乙酸乙酯中,经饱和食盐水洗净后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶液,得到了859毫克油状的N-乙酰基-N-[2-(丙烷-1-基)苄基]-2-苯氧基苯胺的3∶2的几何异构体的混合物。
(3)将757毫克N-乙酰基-N-[2-(丙烷-1-基)苄基]-2-苯氧基苯胺(约3∶2的几何异构体的混合物)溶解在7毫升乙醇中,加入氧化铂15毫克,在氢气气氛和室温下搅拌3小时。滤出反应液中的催化剂,减压下浓缩后用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制,得到了647毫克油状的N-乙酰基-N-(2-丙基苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例13
N-乙酰基-N-(2-乙酰苄基)-2-苯氧基苯胺的合成
(1)向冰冷却下的5.25毫升1M氯化甲基镁/四氢呋喃溶液经15毫升四氢呋喃稀释的稀释溶液中,滴加1.20克N-乙酰基-N-(2-甲酰苄基)-2-苯氧基苯胺的7毫升四氢呋喃溶液,进而在室温下搅拌1小时。反应液再经冰冷却后,向其中加入饱和氯化铵水溶液,提取到乙酸乙酯中,用饱和食盐水洗涤,和用无水硫酸钠干燥。滤出干燥剂后,经减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶1)精制后,得到了1.19克N-乙酰基-N-[2-(1-羟乙基)苄基]-2-苯氧基苯胺。
(2)在干冰-丙酮中将0.22毫升草酰氯的13.5毫升二氯甲烷溶液冷却到-70℃以下,向其中滴加0.24毫升二甲基亚砜的0.9毫升二氯甲烷溶液,再搅拌10分钟。向其中滴加0.48克N-乙酰基-N-[2-(1-羟乙基)苄基]-2-苯氧基苯胺的4.5毫升二氯甲烷溶液,使反应液温度缓缓升至-45℃,在同温度下再搅拌1小时。-40℃温度下,向此反应液中滴加1.34毫升三乙胺,于0℃下再搅拌20分钟。向此反应液中加入饱和氯化铵水溶液,提取到乙酸乙酯中,经饱和食盐水洗涤后,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶1)精制后,再经乙酸乙酯-己烷重结晶,得到了0.41克N-乙酰基-N-(2-乙酰苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例14
N-乙酰基-N-(2-二甲基氨基羰基苄基)-2-苯氧基苯胺的合成
(1)将与实施例2同样合成的2.26克N-乙酰基-N-(2-甲氧羰基苄基)-2-苯乙基苯胺加入到23毫升甲醇与3.6毫升2N氢氧化钾水溶液的混合液中,60℃下搅拌1小时。将反应混合物减压浓缩,向残余物中加入水,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶1)精制后,得到了油状的N-乙酰基-N-(2-羧基苄基)-2-苯氧基苯胺2.01克。
(2)将0.50克N-乙酰基-N-(2-羧基苄基)-2-苯氧基苯胺溶解在10毫升四氢呋喃和0.1毫升六亚甲基膦酰胺混合溶剂中,加入0.2毫升亚硫酰氯,室温下搅拌3小时。浓缩反应混合物,残余物溶解在10毫升四氢呋喃中,搅拌下滴加2毫升50%的二甲胺水溶液。将反应混合物注入水中,用乙酸乙酯萃取,依次用1N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥。滤出干燥剂后,减压浓缩溶剂,残余物用硅胶层析(展开溶剂∶乙酸乙酯-己烷=1∶3)法精制后,得到了0.49克N-乙酰基-N-(2-二甲氨基羰基苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例15
N-乙酰基-N-(2-乙氧羰基苄基)-2-苯氧基苯胺的合成
在10毫升N,N-二甲基甲酰胺中将0.5克N-乙酰基-N-(2-羧基苄基)-2-苯氧基苯胺、0.20克无水碳酸钾和0.22毫升硫酸二乙酯室温下搅拌3小时。将反应混合物注入水中后用乙酸乙酯提取,提取液依次用1N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶7)精制后,得到了0.50克油状N-乙酰基-N-(2-乙氧羰基苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例16
N-乙酰基-N-(2-甲氧羰基苄基)-2-苯氧基苯胺的合成
将2.27克N-乙酰基-2-苯氧基苯胺、1.3毫升2-碘代苯甲醚、1.38克碳酸钾、133毫克铜粉和200毫克溴化铜在20毫升硝基苯中加热回流8小时。反应液冷却到室温后,加入乙酸乙酯,滤出不溶物,依次用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶4)精制后,得到了660毫克油状的N-乙酰基-N-(2-甲氧基苄基)-2-苯氧基苯胺。
本化合物和同样得到的化合物的结构和物质性质数据示于表1和表2之中。
实施例17
N-乙酰基-N-[2-(2-甲氧苯基)乙基]-2-苯氧基苯胺的合成
(1)将4.98克2-甲氧苯基乙酸和0.5毫升N,N-二甲基甲酰胺溶解在30毫升甲苯中,加入4毫升亚硫酰氯,70℃下搅拌1小时后减压浓缩。残余物溶解在20毫升二氯甲烷中,搅拌下将其滴加到经冰冷却的5.55克2-苯氧基苯胺和4.6毫升三乙胺在30毫升二氯甲烷中的溶液内,再于室温下搅拌1小时。反应液减压下浓缩,加入冰水,用乙酸乙酯提取,依次用0.5N盐酸、饱和碳酸氢钠水溶液和饱和食盐水洗涤,用无水硫酸钠干燥。滤出干燥剂后减压浓缩溶剂。
将残余物溶解在40豪绅四氢呋喃中,将其滴加到1.70克氢化铝锂在40毫升四氢呋喃的悬浮液中,加热回流30分钟。反应混合物用冰水冷却,搅拌下滴加饱和硫酸钠水溶液。使反应液中的不溶物经过无水硫酸镁滤板过滤后,减压浓缩滤液,残余物用硅胶层析法(展开溶剂是乙酸乙酯-己烷=1∶10)精制后,得到了8.23克油状的N-[2-(2-甲氧苯基)乙基]-2-苯氧基苯胺。
(2)用3.19克N-[2-(2-甲氧苯基)乙基]-2-苯氧基苯胺,与实施例1的(2)同样进行反应,经过后处理,在己烷中结晶,得到了2.95克N-乙酰基-N-[2-(2-甲氧苯基)乙基]-2-苯氧基苯胺。
]本化合物和同样得到化合物的结构和物质性质数据示于表1和表2之中。表1Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)001 3 3-MeO-Ph-CH2 Ph Me H oil*6002 3 4-MeO-Ph-CH2 Ph Me H 99.5-100.0(Hex-Et2O)003 1 2-EtO-Ph-CH2 Ph Me H oil*6004 3 2-EtO-Ph-CH2 Ph Me 4-Cl 103.5-104.0(Hex)005 1 2-n-PrO-Ph-CH2 Ph Me H oil*6006 3 2-n-PrO-Ph-CH2 Ph Me 4-Cl 95.5-96.0(Hex)007 1 2-i-PrO-Ph-CH2 Ph Me H oil*6008 3 2-i-PrO-Ph-CH2 Ph Me 4-Cl 108.0-108.5(Hex)009 1 2-i-BuO-Ph-CH2 Ph Me H oil*6010 1 2-n-PenO-Ph-CH2 Ph Me H oil*6011 1 2-i-PenO-Ph-CH2 Ph Me H oil*6012 17 2-MeO-Ph-(CH2)2 Ph Me H 79.0-80.0(Hex*6)013 16 2-MeO-Ph Ph Me H oil*6014 2 2-MeO-Ph-CH(Me) Ph Me H 96.5-97.0(放置*6)015 3 2,3-(MeO)2-Ph-CH2 Ph Me H oil*6016 2 2,4-(MeO)2-Ph-CH2 Ph Me H oil*6017 3 2,5-(MeO)2-Ph-CH2 Ph Me H oil*6018 3 2,5-(MeO)2-Ph-CH2 Ph Me 4-Me oil*6019 3 2,5-(MeO)2-Ph-CH2 Ph Me 5-Me 108.0-109.0(放置*4)020 3 2,5-(MeO)2-Ph-CH2 Ph Me 4-F oil*6表1(续)Comp Exp Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)021 3 2,5-(MeO)2-Ph-CH2 Ph Me 5-F 92.5-93.5(IPE)022 3 2,5-(MeO)2-Ph-CH2 Ph Me 4-Cl 103.5-105.0(IPE)023 3 2,5-(MeO)2-Ph-CH2 Ph Me 5-Cl 114.0-114.5(IPE)024 2 2,6-(MeO)2-Ph-CH2 Ph Me H oil*6025 3 3,5-(MeO)2-Ph-CH2 Ph Me H oil*6026 2 2,4,6-(MeO)3-Ph-CH2 Ph Me H 122.0-123.0(AcOEt-Hex)027 11 2-HO-P′h-CH2 Ph Me H 123.0-124.5(IPE*6)028 11 2-MeCOO-Ph-CH2 Ph Me H oil*6029 3 2-Cl-Ph-CH2 Ph Me H oil*6030 3 3-Cl-Ph-CH2 Ph Me H oil*6031 3 4-Cl-Ph-CH2 Ph Me H 92.0-93.0(Hex-El2O)032 3 2-F-Ph-CH2 Ph Me H 90.0-90.5(IPE)033 3 2-Br-Ph-CH2 Ph Me H 84.0-84.5(IPE)034 3 2-MeS-Ph-CH2 Ph Me H oil*6035 11 2-HO2CCH2O-Ph-CH2 Ph Me H 156.5-157.0(IPE*6)036 11 2-HO2CC(Me)2O-Ph-CH2 Ph Me H 65.0-67.0(放置*4)037 1 2-(Me2N(CH2)2O)-Ph-CH2Ph Me H oil*6038 13 2-CH3(HO)CH-Ph-CH2 Ph Me H oil*6039 13 2-Et(HO)CH-Ph-CH2 Ph Me H oil*6040 2 2-MeO2C-Ph-CH2 Ph Me H 76.0-78.0(IPE)表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol*3)No.*1 No.*2 (℃)041 15 2-EtO2C-Ph-CH2 Ph Me H oil*6042 14 2-HO2C-Ph-CH2 Ph Me H oil*6043 14 2-MeNHCO-Ph-CH2 Ph Me H oil*6044 14 2-Me2NCO-Ph-CH2 Ph Me H oil*6045 3 2-(-O(CH2)2O-)CH-Ph-CH2Ph Me H oil*6046 12 2-OHC-Ph-CH2 Ph Me H 114.0-117.0(放置*4)047 13 2-CH3CO-Ph-CH2 Ph Me H 110.0-110.5(AcOEt-Her)048 13 2-EtCO-Ph-CH2 Ph Me H oil*6049 1 2-Me-Ph-CH2 Ph Me H 83.5-84.0(IPE)050 12 2-n-Pr-Ph-CH2 Ph Me H oil*6051 12 2-CH2=CH-Ph-CH2 Ph Me H oil*6052 1 2-NO2-Ph-CH2 Ph Me H 96.0-96.5(AcOEt-Hex)053 10 2-NH2-Ph-CH2 Ph Me H 155.5-156.0(MeOH)054 10 2-吡咯烷基-Ph-CH2 Ph Me H 110.0-112.5*7(AcOEt-Et2O)055 2 4-Me2N-Ph-CH2 Ph Me H oil*6056 3 Ph-CH2 Ph Me H 80.5-81.0(Et2O)057 3 2-Py-CH2 Ph Me H 86.5-87.5(Et2O)058 3 3-Py-CH2 Ph Me H 83.5-84.0(IPE)059 3 4-Py-CH2 Ph Me H 114.5-115.0(Et2O)060 1 3-MeO-2-Py-CH2 Ph Me H 95.0-96.0(放置*4)表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)061 1 2-MeO-3-Py-CH2 Ph Me H 78.5-79.0(IPE-Hex)062 1 4-MeO-3-Py-CH2 Ph Me H 90.5-91.0(放置*4)063 2 2-MeO-Ph-CH2 1-Naph Me H 66.0-68.0(AcOEt-Hex)064 3 2-MeO-Ph-CH2 Ph Et H oil*6065 3 2-MeO-Ph-CH2 Ph Et 4-Cl oil*6066 3 2-EtO-Ph-CH2 Ph Et 4-Cl 81.5-83.0(Hex)067 3 2-n-PrO-Ph-CH2 Ph Et 4-Cl 87.5-88.0(Hex)068 3 2-i-PrO-Ph-CH2 Ph Et 4-Cl oil*6069 3 2,5-(MeO)2-Ph-CH2 Ph Et 4-Cl oil*6070 2 2-MeO2C-Ph-CH2 Ph Et H oil*6071 1 2-MeO-Ph-CH2 Ph n-Pr H oil*6072 1 2-MeO-Ph-CH2 Ph i-Pr H 94.5-95.0(Et2O)073 1 2-MeO-Ph-CH2 Ph n-Bu H oil*6074 1 2-MeO-Ph-CH2 Ph i-Bu H oil*6075 1 2-MeO-Ph-CH2 Ph n-Pen H oil*6076 1 2-MeO-Ph-CH2 Ph c-Pr H 73.0-74.0(Et2O-Hex)077 1 2-MeO-Ph-CH2 Ph c-Bu H 85.0-86.0(Et2O-Hex)078 1 2-MeO-Ph-CH2 Ph c-Pen H 92.5-93.5(Et2O-Hex)079 1 2-MeO-Ph-CH2 Ph Ph H 125.5-127.0(AcOEt-Hex)080 1 2-MeO-Ph-CH2 Ph F2C H oil*6表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)081 1 2-MeO-Ph-CH2 Ph ClCH2 H 83.0-83.5(放置*4)082 9 2-MeO-Ph-CH2 Ph AcOCH2 H oil*6083 8 2-MeO-Ph-CH2 Ph N3CH2 H oil*6084 8 2-MeO-Ph-CH2 Ph NH2CH2 H 85.0-86.0(AcOEt-IPE)085 9 2-MeO-Ph-CH2 Ph HOCH2 H 70.0-71.0(放置*4)086 1 2-MeO-Ph-CH2 Ph HO2C(CH2)2H 136.5-138.5(AcOEt-Hex)087 3 2-MeO-Ph-CH2 Ph H H oil*6088 3 2-EtO-Ph-CH2 Ph H H oil*6089 4 2-MeO-Ph-CH2 Ph NH2 H 89.5-90.0(AcOEt)090 5 2-MeO-Ph-CH2 Ph NHMe H 133.0-134.0(AcOEt)091 5 2-EtO-Ph-CH2 Ph NHMe H 85.0-86.0(AcOEt-IPE)092 5 2-n-PrO-Ph-CH2 Ph NHMe H 82.0-83.0(AcOEt-IPE)093 5 2-i-PrO-Ph-CH2 Ph NHMe H 99.0-99.5(AcOEt-IPE)094 6 2-n-PenO-Ph-CH2 Ph NHMe H 82.5-83.5(Et2O)095 6 2,5-(MeO)2-Ph-CH2 Ph NHMe H 88.5-89.5(Et2O)096 5 2-MeO2C-Ph-CH2 Ph NHMe H 107.0-108.0(放置*4)097 5 2-MeO-Ph-CH2 Ph NMe2 H 94.5-95.0(放置*4)098 7 2-MeO-Ph-CH2 Ph OMe H oil*6099 7 2-MeO-Ph-CH2 Ph OEt H oil*6100 2 2-MeO-Ph-CH2 2-Me-Ph Me H oil*6表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)101 2 2-MeO-Ph-CH2 3-Me-Ph Me H oil*6102 2 2-MeO-Ph-CH2 4-Me-Ph Me H 79.0-80.0(AcOEt-Hex)103 2 2-MeO-Ph-CH2 2-MeO-Ph Me H oil*6104 2 2-MeO-Ph-CH2 3-MeO-Ph Me H oil*6105 2 2-MeO-Ph-CH2 4-MeO-Ph Me H oil*6106 2 2-MeO-Ph-CH2 4-MeS-Ph Me H 97.0-98.0(Et2O-Hex)107 2 2-MeO-Ph-CH2 2-F-Ph Me H 104.0-105.0(AcOEt-Hex)108 2 2-MeO-Ph-CH2 3-F-Ph Me H 54.0-55.0(AcOEt-Hex)109 2 2-MeO-Ph-CH2 4-F-Ph Me H oil*6110 2 2-MeO-Ph-CH2 4-Cl-Ph Me H 62.0-63.0(Et2O-Hex)111 2 2-MeO-Ph-CH2 4-Br-Ph Me H 116.0-117.0(AcOEt-Hex)112 2 2-MeO-Ph-CH2 2,4-F2-Ph Me H 81.0-82.0(Et2O-Hex)113 2 2-MeO-Ph-CH2 2-Py Me H 81.0-82.0(Et2O)114 2 2-MeO-Ph-CH2 3-Py Me H 64.0-65.0(AcOEt-Hex)115 2 2-MeO-Ph-CH2 4-Py Me H 93.0-94.0(Et2O)116 3 2-MeO-Ph-CH2 Ph Me 4-F 83.5-84.0(AcOEt-Hex)117 3 2-MeO-Ph-CH2 Ph Me 5-F 91.5-92.0(AcOEt-Hex)118 3 2-MeO-Ph-CH2 Ph Me 6-F oil*6119 3 2-MeO-Ph-CH2 Ph Me 3-Cl 105.5-106.5(AcOEt-Hex)120 3 2-MeO-Ph-CH2 Ph Me 4-Cl 113.0-114.5(AcOEt-Hex)表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)121 3 2-MeO-Ph-CH2 Ph Me 5-Cl 109.0-109.5(AcOEt-Hex)122 3 2-MeO-Ph-CH2 Ph Me 3-Me 84.5-85.5(AcOEt-Hex)123 3 2-MeO-Ph-CH2 Ph Me 4-Me 107.5-108.0(AcOEt-Hex)124 3 2-MeO-Ph-CH2 Ph Me 5-Me 81.5-82.0(AcOEt-Hex)125 3 2-MeO-Ph-CH2 Ph Me 5-CF3 113.0-113.5(AcOEt-Hex)126 3 2-MeO-Ph-CH2 Ph Me 5-MeO 125.5-126.0(AcOEt-Hex)127 3 2-MeO-Ph-CH2 Ph Me 4-PhO oil*6128 2 2-i-PrO-Ph-CH2 4-Me-Ph Me 4-Cl 95.0-96.0(Et2O-Hep)129 2 2-i-PrO-Ph-CH2 4-MeO-Ph Me 4-Cl 53.0-56.0(Et2O-Hep)130 2 2-i-PrO-Ph-CH2 4-F-Ph Me 4-Cl 82.0-83.0(Et2O-Hep)131 2 2,5-(MeO)2-Ph-CH2 4-Me-Ph Me 4-Cl 109.0-110.0(Et2O-Hep)132 2 2,5-(MeO)2-Ph-CH2 4-MeO-Ph Me 4-Cl 121.0-122.0(Et2O-Hep)133 2 2,5-(MeO)2-Ph-CH2 3-F-Ph Me 4-Cl 79.0-80.0(Et2O-Hep)134 2 2,5-(MeO)2-Ph-CH2 4-F-Ph Me 4-Cl 102.0-103.0(Et2O-Hep)135 2 2,5-(MeO)2-Ph-CH2 4-Me-Ph Me 5-Me 111.0-112.0(Et2O-Hex)136 2 2,5-(MeO)2-Ph-CH2 3-F-Ph Me 5-Me 98.0-99.0(Et2O-Hex)137 2 2-i-PrO-Ph-CH2 4-F-Ph Et 5-Me 96.0-97.0(Et2O-Hex)138 2 2,5-(MeO)2-Ph-CH2 4-MeO-Ph Et 5-Me 85.0-86.0(Et2O-Hex)139 2 2,5-(MeO)2-Ph-CH2 4-F-Ph Et 5-Me 79.0-80.0(Et2O-Hex)140 5 2-i-PrO-Ph-CH2 3-F-Ph NHMe 5-Me 95.0-96.0(Et2O-Hex)表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*6 (℃)141 5 2-i-PrO-Ph-CH2 4-F-Ph NHMe 5-Me 96.0-97.0(Et2O-Hex)142 5 2,5-(MeO)2-Ph-CH2 4-Me-Ph NHMe 4-Cl 130.0-131.0(Et2O)143 5 2,5-(MeO)2-Ph-CH2 4-MeO-Ph NHMe 4-Cl 153.0-154.0(Et2O)144 5 2,5-(MeO)2-Ph-CH2 3-F-Ph NHMe 4-Cl 133.0-134.0(Et2O)145 5 2,5-(MeO)2-Ph-CH2 4-F-Ph NHMe 4-Cl 127.0-128.0(Et2O)146 5 2,5-(MeO)2-Ph-CH2 4-MeO-Ph NHMe 5-Me 119.0-120.0(Et2O-Hex)147 5 2,5-(MeO)2-Ph-CH2 3-F-Ph NHMe 5-Me 113.0-114.0(Et2O-Hex)148 5 2,5-(MeO)2-Ph-CH2 4-F-Ph NHMe 5-Me 99.0-100.0(Et2O-Hex)149 2 2-MeO-Ph-CH2 3-Me2N-Ph Me H 50.0-51.0(Et2O-Hex)150 2 2-MeO-Ph-CH2 2-Me2NCH2-Ph Me H oil*6151 2 2-MeO-Ph-CH2 3-Me2NCH2-Ph Me H oil*6152 2 2-MeO-Ph-CH2 4-Me2NCH2-Ph Me H oil*6153 1 2-MeO-Ph-CH2 2-H2NCO-Ph Me H 199.0-200.0(放置*4)154 3 2-MeO-Ph-CH2 3-H2NCO-Ph Me H 125.0-127.0(放置*4)155 3 2-MeO-Ph-CH2 4-H2NCO-Ph Me H 204.0-206.5(放置*4)156 1 2-MeO-Ph-CH2 2-AcHNCO-Ph Me H 169.0-171.0(放置*4)157 3 2-MeO-Ph-CH2 4-H2NSO2-Ph Me H 78.0-79.0(放置*4)158 3 2,5-(MeO)2-Ph-CH2 4-H2NSO2-Ph Me H 150.0-152.0(放置*4)159 1 2,5-(MeO)2-Ph-CH2 2-H2NCO-Ph Me H 184.5-185.5(放置*4)160 3 2,5-(MeO)2-Ph-CH2 3-H2NCO-Ph Me H oil*6表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)161 3 2,5-(MeO)2-Ph-CH2 4-H2NCO-Ph Me H 178.0-180.0(放置*4)162 2 4-H2NSO2-Ph-CH2 Ph Me H 143.0-144.0(EtOH-Et2O)163 2 2-H2NSO2-Ph-CH2 Ph Me H 184.0-185.0(EtOH)164 2 4-H2NSO2-Ph-CH2 Ph Me 5-F 163.0-165.0(EtOH)165 2 2-H2NSO2-Ph-CH2 Ph Me 5-F 178.0-179.0(EtOH)166 2 2-HO-5-MeO-Ph-CH2 Ph Me 5-F 106.0-106.5(放置*4)167 2 2-i-PrO-Ph-CH2 3-F-Ph Me 4-Cl oil*6168 2 2-i-PrO-Ph-CH2 3-F-Ph Me 5-Me oll*6169 2 2-i-PrO-Ph-CH2 4-F-Ph Me 5-Me oil*6170 2 2-i-PrO-Ph-CH2 4-Me-Ph Me 5-Me oil*6171 2 2,5-(MeO)2-Ph-CH2 4-F-Ph Me 5-Me oil*6172 2 2,5-(MeO)2-Ph-CH2 4-MeO-Ph Me 5-Me 102.0-103.0(AcOEt-Hex)173 3 2-MeO-Ph-CH2 Ph Me 5-H2NCO 250.0-251.0(放置*4)174 3 2,5-(MeO)2-Ph-CH2 Ph Me 5-H2NCO 168.5-169.0(放置*4)175 3 2-MeO-Ph-CH2 Ph Me 5-H2NSO2 192.5-193.5(放置*4)176 3 2,5-(MeO)2-Ph-CH2 Ph Me 5-H2NSO2 170.0-171.0(放置*4)177 17 4-Cl-Ph-(CH2)2 Ph Me 5-H2NSO2 oil*6178 17 2-MeO-Ph-(CH2)2 Ph Me 5-H2NSO2 oil*6179 2 2-i-PrO-Ph-CH2 3-F-Ph Et 4-Cl oil*6180 2 2-i-PrO-Ph-CH2 4-F-Ph Et 4-Cl oil*6表1(续)Comp. Exp. Ar1-Y1 Ar2 R1 X1 m.p.(Recry.Sol.*3)No.*1 No.*2 (℃)181 2 2-i-PrO-Ph-CH2 4-Me-Ph Et 4-Cl 79.5-80.5(放置*4)182 2 2-i-PrO-Ph-CH2 4-MeO-Ph Et 4-Cl 86.0-87.0(Et2O-Hex)183 2 2,5-(MeO)2-Ph-CH2 3-F-Ph Et 4-Cl oil*6184 2 2,5-(MeO)2-Ph-CH2 4-F-Ph Et 4-Cl oil*6185 2 2,5-(MeO)2-Ph-CH2 4-Me-Ph Et 4-Cl 101.0-101.5(Et2O-Hex)186 2 2,5-(MeO)2-Ph-CH2 4-MeO-Ph Et 4-Cl oil*6187 2 2-i-PrO-Ph-CH2 3-F-Ph Et 5-Me oil*6188 2 2-i-PrO-Ph-CH2 4-Me-Ph Et 5-Me 70.0-71.0(Et2O-Hex)189 2 2-i-PrO-Ph-CH2 4-MeO-Ph Et 5-Me oil*6190 2 2,5-(MeO)2-Ph-CH2 3-F-Ph Et 5-Me 67.0-68.0(Et2O-Hex)191 2 2,5-(MeO)2-Ph-CH2 4-Me-Ph Et 5-Me 72.0-73.0(Et2O-Hex)192 5 2-i-PrO-Ph-CH2 4-F-Ph NHMe 4-Cl 98.0-99.0(Et2O-Hex)193 5 2-i-PrO-Ph-CH2 3-F-Ph NHMe 4-Cl oil*6194 5 2-i-PrO-Ph-CH2 4-Me-Ph NHMe 4-Cl oil*6195 5 2-i-PrO-Ph-CH2 4-MeO-Ph NHMe 4-Cl oil*6196 5 2-i-PrO-Ph-CH2 4-Me-Ph NHMe 5-Me 79.0-80.0(Et2O-Hex)197 5 2-i-PrO-Ph-CH2 4-MeO-Ph NHMe 5-Me oil*6198 5 2,5-(MeO)2-Ph-CH2 4-Me-Ph NHMe 5-Me 84.0-86.0(Et2O-Hex)备注:*1:化合物编号*2:化合物合成用实施例的编号*3:重结晶溶剂;Hex=己烷,Et2O=二乙醚,IPE=二异丙
醚,AcOEt=乙酸乙酯,Hep=庚烷*4:经硅胶层析法精制,干燥后,经室温放置结晶*5:用记载的溶剂结晶*6:表2中记载了油状物质的NMR和MS数据*7:一盐酸盐表中的符号表示如下:Me:甲基,Et:乙基,Pr:丙基,Bu:丁基,Pen:戊基,Ph:亚苯基,Py:吡啶基,Naph:萘基表2001*1:NMR(CDCl3)δ(ppm);1.92(3H,s),3.73(3H,s),4.51(1H,d,J=14.8Hz),5.07(1H,d,J=14.8Hz),6.70~7.37(13H,m)EIMS m/e;347(M+),121(M+-226,100%)003*1:NMR(CDCl3)δ(ppm);1.18(3H,t,J=7.5Hz),1.94(3H,s),3.66~3.93(2H,m),4.72(1H,d,J=J4.5Hz),5.17(H,d,J=14.5Hz),6.68~7.40(13H,m)FABMS m/e;362(M++1),135(M+-226,100%)005*1:NMR(CDCl3)δ(ppm);0.91(3H,t,J=7.3Hz),1.53~1.71(2H,m),1.93(3H,s),3.60~3.81(2H,m),4.73(1H,d,J=14.5Hz),5.18(1H,d,J=14.5Hz),6.69~7.37(13H,m)FABMS m/e;376(M++1),149(M+-226,100%)007*1:NMR(CDCl3)δ(ppm);1.09(3H,d,J=7.0Hz),1.17(3H,d,J=7.0Hz),1.93(3H,s),4.26~4.45(1H,m),4.69(1H,d,J=14.5Hz),5.17(1H,d,J=14.5Hz),6.71~7.40(13H,m)FABMS m/e;376(M++1),149(M+-226,100%)009*1:NMR(CDCl3)-δ(ppm);0.91(3H,d,J=6.8Hz),0.93(3H,d,J=6.8Hz),1.79~1.98(1H,m),1.96(3H,s),3.45~3.60(2H,m),4.72(1H,d,J=14.7Hz),5.19(1H,d,J=14.7Hz),6.69~7.36(13H,m)EIMS m/e;389(M+),163(M+-226,100%)010*1:NMR(CDCl3)δ(ppm);0.84~0.96(3H,m),1.23~1.38(4H,m),1.50~1.66(2H,m),1.95(3H,s),3.64~3.84(2H,m),4.70(H,d,J=14.6Hz),5.17(1H,d,J=14.6Hz),6.70~7.40(13H,m)EIMS m/e;403(M+),107(M+-296,100%)表2(续)011*1:NMR(CDCl3)δ(ppm);0.87(3H,d,J=6.6Hz),0.88(3H,d,J=6.6Hz),1.41~1.51(2H,m),1.58~1.78(1H,m),1.95(3H,s),3.67~3.88(2H,m),4.69(1H,d,J=14.7Hz),5.17(1H,d,J=14.7Hz),6.71~7.41(13H,m)EIMS m/e;403(M+),107(M+-296,100%)013*1:NMR(CDCl3)δ(ppm);1.97(3H×2/3,s),2.13(3H×1/3,s),3.98(3H,s),6.80~7.62(13H,m)EIMS m/e;333(M+),291(M+-42,100%)015*1:NMR(CDCl3)δ(ppm);1.96(3H,s),3.53(3H,s),3.81(3H,s),4.70(1H,d,J=14.5Hz),5.27(1H,d,J=14.5Hz),6.73~7.39(12H,m)FABMS m/e;378(M++1),151(M+-226,100%)016*1:NMR(CDCl3)δ(ppm);1.92(3H,s),3.52(3H,s),3.76(3H,s),4.65(1H,d,J=14.4Hz),5.09(1H,d,J=14.4Hz),6.28(1H,d,J=2.4Hz),6.35(1H,dd,J=8.4,2.4Hz),6.83~7.36(10H,m)EIMS m/e;377(M+),151(M+)-226,100%)017*1:NMR(CDCl3)-δ(ppm);1.96(3H,s),3.52(3H,s),3.52(3H,s),4.70(1H,d,J=15.0Hz),5.15(1H,d,J=15.0Hz),6.63~7.38(12H,m)FABMS m/e;378(M++1),151(M+-226,100%)018*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.23(3H,s),3.54(3H,s),3.66(3H,s),4.65(1H,d,J=14.5Hz),5.13(1H,d,J=14.5Hz),6.62~7.40(11H,m)SIMS m/e;392(M++1),151(M+-240,100%)表2(续)020*1:NMR(CDCl3)δ(ppm);1.96(3H,s),3.55(3H,s),3.66(3H,s),4.70(1H,d,J=15.0Hz),5.13(1H,d,J=15.0Ez),6.49(1H,dd,J=9.9,3.3Hz),6.55~7.44(10H,m)SIMS m/e;396(M++1),151(M+-244,100%)024*1:NMR(CDCl3)δ(ppm);1.90(3H,s),3.55(6H,s),4.91(1H,d,J=13.2Hz),5.27(1H,d,J=13.2Hz),6.34~6.43(2H,m),6.71~7.35(10H,m)EIMS m/e;377(M-),151(M+-226,100%)025*1:NMR(CDCl3)δ(ppm);1.96(3H,s),3.67(6H,s),4.52(1H,d,J=14.5Hz),5.08(1H,d,J=14.5Hz),6.26~6.39(3H,m),6.82~7.37(9H,m)EIMS m/e;377(M+),151(M+-226,100%)028*1:NMR(CDCl3)δ(ppm);1.89(3H,s),2.10(3H,s),4.38(1H,d,J=14.0Hz),5.38(1H,d,J=14.0Hz),6.86~7.20(13H,m)EIMS m/e;375(M+),185(M+-190,100%)029*1:NMR(CDCl3)δ(ppm);1.97(3H,s),4.81(1H,d,J=15.0Hz),5.29(1H,d,J=15.0Hz),6.84~7.53(13H,m)EIMS m/e;353(M++2),351(M+),316(M+-35,100%)030*1:NMR(CDCl3)δ(ppm);1.96(3H,s),4.63(1H,d,J=15.0Hz),5.04(1H,d,J=15.0Hz),6.83~7.39(13H,m)EIMS m/e;353(M-+2),351(M+),258(M+-93,100%)表2(续)034*1:NMR(CDCl3)δ(ppm);1.98(3H,s),2.31(3H,s),4.75(1H,d,J=14.8Hz),5.37(1H,d,J=14.8Hz),6.83~7.38(13H,m)EIMS m/e;363(M+),316(M+-47,100%)037*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.26(6H,s),2.44~2.58(2H,m),3.74~3.97(2H,m),4.72(1H,d,J=14.7Hz),5.17(1H,d,J=14.7Hz),6.71~7.38(13H,m)FABMS m/e;405(M++1,100%)038*1:NMR(CDCl3)δ(ppm);1.34(3H×1/2,d,J=6.2Hz),1.40(3H×1/2,d,J=6.2Hz),1.93(3H×1/2,s),1.97(3H×1/2,s),4.87(1H×1/2,d,J=13.0Hz),4.96(1H×1/2,d,J=13.0Hz),5.10(1H×1/2,d,J=13.0Hz),5.19(1H×1/2,d,J=13.0Hz),6.60~7.51(13H,m)EIMS m/e;361(M+),117(M+-244,100%)039*1:NMR(CDCl3)δ(ppm);0.88(3H×1/2,t,J=7.2Hz),0.91(3H×1/2,t,J=7.2Hz),1.40~1.85(2H,m),1.93(3H×1/2,s),1.96(3H×1/2,s),4.60~5.40(3H,m),6.64~7.42(13H,m)EIMS m/e;375(M+),228(M+-147,100%)041*1:NMR(CDCl3)δ(ppm);1.27(3H,i,J=7.3Hz),1.98(3H,s),4.18(2H,q,J=7.3Hz),5.20(1H,d,J=15.5Hz),5.55(1H,d,J=15.5Hz),6.80~7.44(11H,m),7.59~7.68(1H,m),7.74~7.83(1H,m)EIMS m/e;389(M+),346(M+-43,100%)042*1:NMR(CDCl3)δ(ppm);1.99(3H,s),4.93(1H,d,J=15.4Hz),5.29(1H,d,J=15.4Hz),6.92~7.47(11H,m),7.56~7.60(1H,m),7.82~7.87(1H,m)FABMS m/e;362(M++1,100%)表2(续)043*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.84(3H,d,J=4.5Hz),4.84(1H,d,J=15.0Hz),5.13(1H,d,J=15.0Hz),6.60~6.78(1H,m),6.82~7.53(13H,m)EIMS m/e;374(M+),300(M+-74,100%)044*1:NMR(CDCl3)δ(ppm);1.96(3H,s),2.62(3H,s),3.01(3H,s),4.57(1H,d,J=15.0Hz),5.26(1H,d,j=15.0Hz),6.79~7.48(13H,m)EIMS m/e;388(M+),300(M+-88,100%)045*1:NMR(CDCl3)δ(ppm);1.94(3H,s),3.90~4.14(4H,m),4.61(1H,d,J=14.7Hz),5.55(1H,d,J=14.7Hz),5.87(1H,s),6.91~6.99(5H,m),7.08~7.40(7H,m),7.50~7.62(1H,m)FABMS m/e;390(M++1),286(M+-103,100%)048*1:NMR(CDCl3)δ(ppm);1.02(3H,t,J=7.2Hz),1.97(3H,s),2.56~2.72(2H,m),1.07(1H,d,J=15.6Hz),5.35(1H,d,J=15.6Hz),6.85~7.75(13H,m)EIMS m/e;373(M+),330(M+-43,100%)050*1:NMR(CDCl3)δ(ppm);0.89(3H,1,J=7.3Hz),1.37~1.55(2H,m),1.96(3H,s),2.42~2.51(2H,m),4.68(1H,d,J=14.5Hz),5.20(1H,d,J=14.5Hz),6.81~7.37(13H,m)SIMS m/e;360(M++1,100%)051*1:NMR(CDCl3)δ(ppm);1.93(3H,s),4.67(1H,d,J=14.5Hz),5.22(1H,dd,J=10.8,1.5Hz),5.35(1H,d,J=14.5Hz),5.51(1H,dd,J=17.4,1.5Hz),6.80~7.44(14H,m)EIMS m/e;343(M+),117(M+-226,100%)表2(续)055*1:NMR(CDCl3)δ(ppm);1.92(3H,s),2.89(6H,s),4.44(1H,d,J=14.3Hz),5.09(1H,d,J=14,3Hz),6.53-6.60(2H,m),6.80~7.34(11H,m)EIMS m/e;360(M+),134(M+-226,100%)064*1:NMR(CDCl3)δ(ppm);1.08(3H,t,J=6.5Hz),2.16(2H,q,J=6.5Hz),3.56(3H,s),4.69(1H,d,J=14.5Hz),5.22(1H,d,J=14.5Hz),6.70~7.40(13H,m)EIMS m/e;361(M+),121(M+-240,100%)065*1:NMR(CDCl3)δ(ppm);1.10(3H,t,J=7.5Hz),2.16(2H,q,J=7.5Hz),3.59(3H,s),4.69(1H,d,J=14.4Hz),5.19(1H,d,J=14.4Hz),6.70~7.45(12H,m)EIMS m/e;397(M++2),395(M+),121(M+-274,100%)068*1:NMR(CDCl3)δ(ppm);1.05~1.38(9H,m),2.15(2H,q,J=7.4Hz),4.27~4.88(1H,m),4.69(1H,d,J=14.4Hz),5.18(1H,d,J=14.4Hz),6.66~7.42(12H,m)EIMS m/e;425(M++2),423(M+),149(M+-274,100%)069*1:NMR(CDCl3)δ(ppm);1.10(3H,t,J=7.5Hz),2.16(2H;q,J=7.5Hz),3.54(3H,s),3.68(3H,s),4.67(1H,d,J=14.5Hz),5.17(1H,d,J=14.5Hz),6.65~7.43(11H,m)EIMS m/e;427(M++2),425(M+),151(M+-274,100%)070*1:NMR(CDCl3)δ(ppm);1.09(3H,t,J=7.5Hz),2.20(2H,q,J=7.5Hz),3.69(3H,s),5.18(1H,d,J=15.5Hz),5.55(1H,d,J=15.5Hz),6.80~7.44(11H,m),7.59~7.68(1H,m),7.74~7.83(1H,m)EIMS m/e;389(M+),332(M+-57,100%)表2(续)071*1:NMR(CDCl3)δ(ppm);0.86(3H,t,J=7.4Hz),1.55~1.73(2H,m),2.12(2H,t,J=7.3Hz),3.57(3H,s),4.67(1H,d,J=14.6Hz),5.23(1H,d,J=14.6Hz),6.71~7.38(13H,m)EIMS m/e;375(M+),121(M+-254,100%)073*1NMR(CDCl3)δ(ppm);0.83(3H,t,J=7.3Hz),1.17~1.35(2H,m),1.52~1.69(2H,m),2.14(2H,t,J=7.5Hz),3.57(3H,s),4.66(1H,d,J=14.5Hz),5.23(1H,d,J=14.5Hz),6.71~7.38(13H,m)EIMS m/e;389(M+),121(M+-268,100%)074*1:NMR(CDCl3)δ(ppm);0.88(6H,d,J=6.6Hz),2.03(2H,d,J=6.6Hz),2.09~2.16(1H,m),3.58(3H,s),4.65(1H,d,J=14.5Hz),5.26(1H,d,J=14.5Hz),6.71~7.38(13H,m)EIMS m/e;389(M+),121(M+-268,100%)075*1:NMR(CDCl3)δ(ppm);0.81~0.87(3H,m),1.12~1.30(4H,m),1.51~1.69(2H,m),2.13(2H,t,1=7.5Hz),3.57(3H,s),4.66(1H,d,J=14.7Hz),5.23(1H,d,J=14.7Hz),6.71~7.37(13H,m)EIMS m/e,403(M+),121(M+-282,100%)080*1:NMR(CDCl3)δ(ppm);3.61(3H,s),4.66(1H,d,J=14.1Hz),5.40(1H,d,J=14.1Hz),6.72~7.44(13H,m)EIMS m/e;401(M+),121(M+-280,100%)082*1:NMR(CDCl3)δ(ppm);2.15(3H,s),3.58(3H,s),4.46(1H,d,J=14.8Hz),4.59(1H,d,J=14.8Hz),4.74(1H,d,J=14.5Hz),5.16(1H,d,J=14.5Hz),6.71~7.38(13H,m)EIMS m/e;405(M+),121(M+-284,100%)表2(续)083*1:NMR(CDCl3)δ(ppm);3.56(3H,s),3.64(1H,d.J=16.9Hz),3.76(1H,d,J=15.9Hz),4.78(1H,d,J=14.2Hz),5.18(1H,d,J=14.2Hz),6.71~7.40(13H,m)EIMS m/e;388(M+),121(M+-267,100%)087*1:NMR(CDCl3)δ(ppm);3.62(3H×3/4,s),3.78(3H×1/4,s),4.75(2H×1/4,s),4.99(2H×3/4,s),6.72~7.40(13H,m),8.35(1H×3/4,s),8.47(1H×1/4,s)CIMS m/e;334(M++1),121(M+-212,100%)088*1:NMR(CDCl3)δ(ppm);1.23(3H×3/4,t,J=6.9Hz),1.40(3H×1/4,t,J=6.9Hz),3.84(2H×3/4,q,J=6.9Hz),3.98(2H×1/4,q,J=6.9Hz),4.75(2H×1/4,s),5.00(2H×3/4,s),6.70~7.43(13H,m),8.34(1H×3/4,s),8.48(1H×1/4,s)CIMS m/e;348(M++1),135(M+-212,100%)098*1:NMR(CDCl2)δ(ppm);3.58(3H,s),3.63(3H,s),4.82(2H,br s),6.75~7.42(13H,m)EIMS m/e;363(M+),121(M+-242,100%)099*1:NMR(CDCl3)δ(ppm);1.06~1.25(3H,m),3.63(3H,s),3.98~4.15(2H,m),4.82(2H,br s),6.75~7.41(13H,m)EIMS m/e;377(M+),121(M+-256,100%)100*1:NMR(CDCl3)δ(ppm);2.00(3H,s),2.22(3H,s),3.58(3H,s),4.73(1H,d,J=14.6Hz),5.28(1H,d,J=14.6Hz),6.64(1H,dd,J=8.2,1.2Hz),6.65~7.34(10H,m),7.38(1H,dd,J=7.5,1.8Hz)EIMS m/e;361(M+),121(M+-240,100%)表2(续)101*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.33(3H,s),3.58(3H,s),4.71(1H,d,J=14.6Hz),5.16(1H,d,14.6Hz),6.70~7.30(11H,m),7.35(1H,dd,J=7.5,1.5Hz)EIMS m/e;361(M+),121(M+-240,100%)103*1:NMR(CDCl3)δ(ppm);2.02(3H,s),3.61(3H,s),3.75(3H,s),4.74(1H,d,J=14.7Hz),5.26(1H,d,14.7Hz),6.57(1H,dd,J=8.3,1.2Hz),6.76(1H,d,J=8.3Hz),6.78~7.26(9H,m),7.39(1H,dd,J=7.5,1.8Hz)EIMS m/e;377(M+),121(M+-256,100%)104*1:NMR(CDCl3)δ(ppm);1.94(3H,s),3.57(3H,s),3.79(3H,s),4.69(H,d,J=14.6Hz),5.17(1H,d,14.6Hz),6.43~6.55(2H,m),6.2~7.05(6H,m),7.10~7.29(3H,m),7.35(1H,dd,J=7.5,1.8Hz)EIMS m/e;377(M+),121(M+-256,100%)105NMR(CDCl3)δ(ppm);1.96(3H,s),3.58 (3H,s),3.81(3H,s),4.77(1H,d,J=14.6Hz),5.16(1H,d,14.6Hz),6.70~6.74(2H,m),6.79~7.25(9H,m),7.36(1H,dd,J=7.5,1.8Hz)EIMS m/e;377(M+),121(M+-256,100%)109*1:NMR(CDCl3)δ(ppm);1.94(3H,s),3.56(3H,s),4.75(1H,d,J=14.6Hz),5.12(1H,d,J=14.6Hz),6.67~7.25 (11H,m),7.34(1H,dd,J=7.5,1.8Hz)EIMS m/e;365(M+),121(M+-244,100%)118*1:NMR(CDCl3)δ(ppm);1.96(3H,s),3.52(3H,s),4.96(1H,d,J=14.5Hz),5.02(1H,d,J=14.5Hz),6.50~7.42(12H,m)FABMS m/e;366(M++1),121(M+-244,100%)表2(续)127*1:NMR(CDCl3)δ(ppm);1.97(3H,s),3.64(3H,s),4.70(1H,d,J=14.5Hz),5.16(1H,d,J=14.5Hz),6.47~6.60(2H,m),6.73~7.38(15H,m)FABMS m/e;440(M++1),121(M+-318,100%)150*1:NMR(CDCl3)δ(ppm);2.00(3H,s),2.25(6H,s),3.43(1H,d,J=115Hz),3.52(1H,d,J=11.5Hz),3.59(3H,s),4.68(1H,d,J=14.7Hz),5.30(1H,d,J=14.7Hz),6.64~7.56(12H,m)FABMS m/e;405(M++1,100%)151*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.24(6H,s),3.40(2H,s),3.59(3H,s),4.68(1H,d,J=14.6Hz),5.19(1H,d,J=14.6Hz),6.70~7.40(12H,m)FABMS m/e;405(M++1,100%)152*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.25(6H,s),3.40(2H,s),3.59(3H,s),4.68(1H,d,J=14.5Hz),5.19(1H,d,J=14.5Hz),6.68~7.40(12H,m)EIMS m/e;404(M+),317(M+-87,100%)160*1:NMR(CDCl3)δ(ppm);1.95(3H,s),3.53(3H,s),3.65(3H,s),4.77(1H,d,J=14.7Hz);5.04(1H,d,J=14.7Hz),6.60~7.63(11H,m)EIMS m/e;420(M+),151(M+-269,100%)167*1:NMR(CDCl3)δ(ppm);1.12(3H,d,J=6.2Hz),1.17(3H,d,J=6.2Hz),1.92(3H,s),4.37(1H,sept,J=6.2Hz),4.73(1H,d,J=14.3Hz),5.07(1H,d,J=14.3Hz),6.52(1H,ddd,J=9.7,2.4,2.4Hz),6.62~7.39(10H,m)FABMS m/e ;428(M++1),149(M+-278,100%)168*1:表2(续)NMR(CDCl3)δ(ppm);1.11(3H,d,J=6.0Hz),1.14(3H,d,J=6.0Hz),1.93(3H,s),2.25(3H,s),4.35(1H,sept,J=6.0Hz),4.68(1H,d,J=14.5Hz),5.03(1H,d,J=14,5Hz),6.42~6.53(1H,m),6.60~7.40(10H,m)FABMS m/e;408(M++1),149(M+-258,100%)169*1:NMR(CDCl3)δ(ppm);1.11(3H,d,J=6.0Hz),1.14(3H,d,J=6.0Hz),1.94(3H,s),2.22(3H,s),4.36(1H,sept,J=6.0Hz),4.73(1H,d,J=14.6Hz),5.04(1H,d,J=14.6Hz),6.65~7.20(10H,m),7.36(1H,dd,J=7.5,1.8Hz)FABMS m/e;408(M++1),149(M+-258,100%)170*1:NMR(CDCl2)δ(ppm);1.11(3H,d,J=6.0Hz),1.16(3H,d,J=6.0Hz),1.95(3H,s),2.20(3H,s),2.32(3H,s),4.37(1H,sept,J=6.0Hz),4.67(1H,d,J=14.7Hz),5.10(1E,d,J=14.7Hz),6.68~7.20(10H,m),7.38(1H,dd,J=7.5,1.5Hz)FABS m/e;404(M++1),149(M+-254,100%)171*1:NMR(CDCl3)δ(ppm);1.95(3H,s),2.24(3H,s),3.53(3H,s),3.67(3H,s),4.72(1H,d,J=14.7Hz),5.04(1H,d,J=14.7Hz),6.62~7.06(10H,m)FABMS m/e;410(M++1),151(M+-258,100%)177*1:NMR(CDCl3)δ(ppm);1.92(3H,s),2.74~3.12(2H,m),3.58~3.77(1H,m),4.05~4.21(1H,m),4.86~5.12(2H,m),6.93(1H,d,J=6.9Hz),6.97~7.53(10H,m),7.79(1H,dd,J=8.8,2.4Hz)FABMS m/e;445(M++1,100%)178*1:NMR(CDCl3)δ(ppm);1.93(3H,s),2.78~3.13(2H,m),3.60~3.92(1H,m),3.73(3H,s),4.04~4.23(1H,m),4.72~5.02(2H,m),6.77~7.50(11H,m),7.75(1H,dd,J=8.8,2.4Hz)FABMS m/e;441(M++1,100%)表2(续)179*1:NMR(CDCl3)δ(ppm);1.02~1.23(9H,m),2.12(2H,q,J=7.3Hz),4.37(1H,sept,J=6.0Hz),4.70(1H,d,J=14.3Hz),5.11(1H,d,J=14.3Hz),6.53(1H,ddd,J=9.7,2.3,2.3Hz),6.63~7.39(10H,m)FABMS m/e;442(M++1),154(M+-287,100%)180*1:NMR(CDCl3)δ(ppm);1.00~1.22(9H,m),2.14(2H,t,J=7.5Hz),4.38(1H,sept,J=6.0Hz),4.75(1H,d,J=14.3Hz),5.12(1H,d,J=14.3Hz),6.63~7.23(10H,m),7.36(1H,dd,J=7.5,1.5Hz)FABMS m/e;442(M++1),154(M+-287,100%)183*1:NMR(CDCl3)δ(ppm);1.10(3H,t,J=7.4Hz),2.13(2H,q,J=7.4Hz),3.53(3H,s),3.68(3H,s),4.68(1H,d,J=14.4Hz),5.11(1H,d,J=14.4Hz),6.51~7.06(9H,m),7.22~7.40(1H,m)FABMS m/e;444(M++1),154(M+-289,100%)184*1:NMR(CDCl3)δ(ppm);1.11(3H,t,J=7.5Hz),2.15(2H,q,J=7.5Hz),3.53(3H,s),3.68(3H,s),4.71(1H,d,J=14.5Hz),5.13(1H,d,J=14.5Hz),6.63~7.14(10H,m)FABMS m/e;444(M++1),151(M+-292,100%)186*1:NMR(CDCl3)δ(ppm);1.12(3H,t,J=7.5Hz),2.17(2H,q,J=7.5Hz),3.54(3H,s),3.69(3H,s),3.83(3H,s),4.72(1H,d,J=14.5Hz),5.16(1H,d,J=14.5Hz),6.65~7.00(10H,m)FABMS m/e;456(M++1),154(M+-301,100%)187*1:NMR(CDCl3)δ(ppm);1.00~1.24(9H,m),2.13(2H,q,J=7.5Hz),2.24(3H,s),4.35(1H,sept,J=5.9Hz),4.65(1H,d,J=14.5Hz),5.07(1H,d,J=14.7Hz),6.48(1H,dd,J=10.2,2.4,2.4Hz),6.58~6.90(6H,m),6.95~7.40(4H,m)FABMS m/e;422(M++1),149(M+-272,100%)表2(续)189*1:NMR(CDCl2)δ(ppm);1.02~1.25(9H,m),2.17(2H,q,J=7.5Hz),2.19(3H,s),3.80(3H,s),4.36(1H,sept,J=6.0Hz),4.71(1H,d,J=14.6Hz),5.12(1H,d,J=14.6Hz),6.64(1H,d,J=8.4Hz),6.62~6.99(8H,m),7.07~7.20(1H,m),7.41(1H,dd,J=7.6,1.7Hz)FABMS m/e;434(M++1),107(M+-326,100%)193*1:NMR(CDCl2)δ(ppm);1.18(6H,d,J=5.9Hz),2.75(3H,d,J=4.6Hz),4.44(1H,sept,J=5.9Hz),4.46(1H,br s),4.80(2H,s),6.55~7.40(11H,m)FABMS m/e;443(M++1),149(M+-293,100%)194*1:NMR(CDCl3)δ(ppm);1.18(6H,d,J=6.1Hz),2.35(3H,s),2.77(3H,d,J=4.8Hz),4.42(1H,sept,J=6.1Hz),4.43(1H,br s),4.86(2H,s),6.72~7.22(10H,m),7.42(1H,dd,J=7.5,1.8Hz)FABMS m/e;439(M++1),154(M+-284,100%)195*1:NMR(CDCl3)δ(ppm);1.18(6H,d,J=6.2Hz),2.79(3H,d,J=4.6Hz),3.82(3H,s),4.43(1H,sept,J=6.2Hz),4.44(1H,br s),4.87(2H,s),6.72(1H,d,J=2.2Hz),6.73~6.96(7H,m),7.00(1H,d,J=8.4Hz),7.12~7.23 (1H,m),7.42(1H,dd,J=7.5,1.8Hz)FABMS m/e;455(M++1),107(M+-347,100%)197*1:NMR(CDCl3)δ(ppm);1.16(6H,d,J=5.9Hz),2.22(3H,s),2.76(3H,d,J=4.6Hz),3.81(3H,s),4.41(1H,sept,J=5.9Hz),4.43(1H,br s),4.77~4.90(2H,m),6.63~7.22(10H,m),7.44~7.53(1.H,m)FABMS m/e;435(M++1),107(M+-327,100%)
*1:化合物番号(表1参照)试验例(MDR受体结合试验)
使用由鼠大脑皮质制备的线粒体成分作为受体标样。
使用[3H]PK11195作为[3H]标记配体。
使用[3H]标记配体的结合试验,是按照《药理学与治疗学杂志》Journal of Pharmacology and Therapeutics,262,971(1992年)上记载的以下方法进行的。
受体标样的制备:使用特氟隆均质器将鼠大脑皮质在含有湿重10倍体积的0.32M蔗糖的10mM HEPES缓冲液(pH7.4)中匀浆。使匀浆在900×g下离心分离10分钟,得到的上清液再于9000×g下离心分离10分钟。将沉淀渣悬浮在HEPES缓冲液中,使蛋白质浓度达到1毫克/毫升,然后于12000×g下离心分离10分钟。将得到的沉淀悬浮在HEPES缓冲液中,制成粗线粒体成分。
MDR结合试验:使线粒体标样(1.0毫克蛋白质/毫升)、[3H]PK11195(2nM)和被试药在4℃下反应90分钟。反应终止后,使用经0.3%聚乙烯亚胺处理过的玻璃过滤器(GF/B)抽滤,用液体闪烁计数仪测定了滤纸的放射能。
以10μM PK11195存在下使之反应时的结合作为[3H]PK11195的非特异结合,将总结合与非特异结合之差作为特异结合。使一定浓度的[3H]PK11195(2nM)和浓度变化的被试药在上述条件下反应,得到了抑制曲线,由此曲线求出使[3H]PK11195抑制50%时的被试药浓度(IC50),结果示于表3之中。表3
表3(续)
Comp.No. | MDRIC50(nM) | Comp.No. | MDRIC50(nM) |
001002003004005006007008009010011012013014015016017019021022023025027028 | 1.380.6580.1230.7910.1180.6770.09770.8700.1120.1490.1630.4539.772.210.2850.7220.08500.1960.3100.1790.4240.2603.203.20 | 029030031032033034040046047049050051052054055056060061062064066067071072 | 0.4861.961.236.733.510.1790.06430.3760.2654.230.2150.1964.641.261.832.920.9550.4981.050.09330.9251.081.263.51 |
Comp.No. | MDRIC50(nM) | Comp.No. | MDRIC50(nM) |
073075076077079080081082085087088089090091092093094095098099100101102103 | 1.521.830.9555.594.644.640.3438.903.850.5720.1633.514.641.830.7220.8700.9253.770.4980.8700.1120.2850.1230.722 | 104105108109110112116117118120121123124125126127 | 0.3430.1630.4130.2858.900.3760.3430.7920.4980.1962.010.8700.3432.218.113.51 |
产业上应用的可能性
本发明提供了一种对MDR具有高亲和性的药物。因此,这些药物可以用作与焦虑及与其有关的疾病、抑郁症、癫痫病、睡眠障碍、认知学习障碍、精神分裂症等中枢性疾病、肌强直引起的运动障碍、摄食障碍、循环障碍、药物依赖症、癌症、脂质代谢障碍、脑梗塞、艾滋病、阿尔茨海默氏病和亨廷顿舞蹈病等的治疗药和预防剂。
Claims (3)
1、一种由下式表示的芳氧基苯胺衍生物或其医药上允许的盐[式中,Ar1和Ar2相同或不同,表示取代或未取代的苯基、取代或未取代的吡啶基或萘基;R1表示氢原子、取代或未取代的1~10个碳原子的烷基、1~10个碳原子的烷氧基、取代或未取代的苯基或者由式-NR2(R3)(式中,R2和R3相同或不同,表示氢原子或1~10个碳原子的烷基,或者表示与相邻氮原子一起构成4~10元环的环氨基)表示的基团;X1表示氢原子、1~5个碳原子的烷基、1~5个碳原子的烷氧基、苯氧基、卤原子、三氟甲基、氨基甲酰基或氨基磺酰基;Y1表示有支链或无支链的1~6个碳原子的亚烷基或单键],
其中取代的苯基,是从下列取代基中任意选出的1~3个取代基取代的苯基:1~10个碳原子的烷基、被(卤原子、羟基、羧基或烷氧羰基)取代的1~10个碳原子的烷基、2~10个碳原子的链烯基、1~10个碳原子的烷氧基、1~10个碳原子的烷硫基、由式-O-Z-R4(式中,Z表示有或无支链的1~10个碳原子的亚烷基,R4表示氨基、被一或二个1~7个碳原子的烷基取代的氨基、2~7个碳原子的环氨基、羟基、羧基或烷氧羰基)表示的基团、2~10个碳原子的链烷酰基或其缩酮体、甲酰基或其缩醛体、羧基、2~10个碳原子的烷氧羰基、氨基甲酰基、氮原子被一或二个1~10个碳原子的烷基取代的氨基甲酰基、氨基磺酰基、氮原子被一或二个1~10个碳原子的烷基取代的氨基磺酰基、卤原子和硝基;取代的吡啶基,表示被1~3个1~10个碳原子的烷氧基取代的吡啶基。
2、一种药物组合物,其包括权利要求1所述的芳氧基苯胺衍生物或其医药上允许的盐和药用载体或赋形剂。
3、线粒体安定结合抑制剂受体的配体,其包括权利要求1所述的芳氧基苯胺衍生物或其医药上允许的盐为有效成分。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20912397 | 1997-08-04 | ||
JP209123/1997 | 1997-08-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1265642A CN1265642A (zh) | 2000-09-06 |
CN1137878C true CN1137878C (zh) | 2004-02-11 |
Family
ID=16567675
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB988078430A Expired - Fee Related CN1137878C (zh) | 1997-08-04 | 1998-08-03 | 芳氧基苯胺衍生物 |
Country Status (13)
Country | Link |
---|---|
US (2) | US6333358B1 (zh) |
EP (1) | EP1004573B1 (zh) |
KR (1) | KR100562808B1 (zh) |
CN (1) | CN1137878C (zh) |
AT (1) | ATE226932T1 (zh) |
AU (1) | AU729000B2 (zh) |
CA (1) | CA2299710C (zh) |
DE (1) | DE69809063T2 (zh) |
DK (1) | DK1004573T3 (zh) |
ES (1) | ES2186186T3 (zh) |
HK (1) | HK1030413A1 (zh) |
PT (1) | PT1004573E (zh) |
WO (1) | WO1999006353A1 (zh) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001234420A1 (en) * | 2000-02-03 | 2001-08-14 | Eli Lilly And Company | Potentiators of glutamate receptors |
JP4395549B2 (ja) * | 2000-11-16 | 2010-01-13 | ザ レジェンツ オブ ザ ユニヴァースティ オブ カリフォルニア | 薬物及び発酵生成物の発見のための海洋放線菌分類群 |
US7176232B2 (en) | 2002-06-24 | 2007-02-13 | The Regents Of The University Of California | Salinosporamides and methods for use thereof |
US6870069B2 (en) * | 2003-01-10 | 2005-03-22 | National Institute Of Radiological Sciences | Phenyloxyaniline derivatives |
NZ544858A (en) * | 2003-06-20 | 2009-07-31 | Univ California | Salinosporamides and methods for use thereof |
MXPA05013982A (es) * | 2003-06-20 | 2006-05-25 | Nereus Pharmaceuticals Inc | Metodos para utilizar compuestos {3.2.0} heterociclicos y sus analogos. |
AU2005283141B2 (en) * | 2004-04-30 | 2012-05-10 | Nereus Pharmaceuticals, Inc. | (3.2.0) heterocyclic compounds and methods of using the same |
WO2006060676A1 (en) * | 2004-12-03 | 2006-06-08 | Dana Farber Cancer Institute | Compositions and methods for treating neoplastic diseases |
EP1854781A1 (en) * | 2005-02-28 | 2007-11-14 | Taisho Pharmaceutical Co., Ltd | Radioactive halogen-labeled phenyloxyaniline derivatives |
US20080293969A1 (en) * | 2005-11-22 | 2008-11-27 | Ge Healthcare Limited | 18F-Labeled Daa Analogues and Method of Labeling These Analogues as Positron Emission Tomography (Pet) Tracers For Imaging Peripheral Benzodiazepine Receptors |
WO2008095195A2 (en) * | 2007-02-02 | 2008-08-07 | Nereus Pharmaceuticals, Inc. | Lyophilized formulations of salinosporamide a |
US8013181B2 (en) * | 2007-04-10 | 2011-09-06 | Dr. Reddy's Laboratories Limited | Preparation of rivastigmine and its salts |
WO2009057528A1 (ja) | 2007-10-31 | 2009-05-07 | Riken | 創薬のためのpetスクリーニング用分子プローブを製造するためのキット |
GB0722779D0 (en) * | 2007-11-20 | 2008-01-02 | Sterix Ltd | Compound |
US8394816B2 (en) * | 2007-12-07 | 2013-03-12 | Irene Ghobrial | Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom's Macroglobulinemia |
US8633245B2 (en) * | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
WO2009140287A1 (en) * | 2008-05-12 | 2009-11-19 | Nereus Pharmaceuticals, Inc. | Salinosporamide derivatives as proteasome inhibitors |
WO2010015340A1 (en) * | 2008-08-06 | 2010-02-11 | Bayer Schering Pharma Aktiengesellschaft | Daa-pyridine as peripheral benzodiazepine receptor ligand for diagnostic imaging and pharmaceutical treatment |
GB0904715D0 (en) * | 2009-03-19 | 2009-05-06 | Ge Healthcare Ltd | Aryloxyanilide derivataives |
EP2718464A1 (en) | 2011-06-06 | 2014-04-16 | Imperial Innovations Limited | Methods to predict binding affinity of tspo imaging agents to tspo |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57208295A (en) | 1981-06-19 | 1982-12-21 | Ricoh Co Ltd | Diazo base heat-sensitive recording material |
JPS6140249A (ja) | 1984-08-01 | 1986-02-26 | Morishita Seiyaku Kk | 3−(n−置換アミノ)−4−(2−メトキシフエノキシ)安息香酸誘導体 |
WO1995033715A1 (en) | 1994-06-02 | 1995-12-14 | Smithkline Beecham Corporation | Anti-inflammatory compounds |
IL117659A (en) * | 1995-04-13 | 2000-12-06 | Dainippon Pharmaceutical Co | Substituted 2-phenyl pyrimidino amino acetamide derivative process for preparing the same and a pharmaceutical composition containing same |
IT1293807B1 (it) * | 1997-08-01 | 1999-03-10 | Recordati Chem Pharm | Derivati 1- (n-fenilaminoalchil) piperazinici sostituiti alla posizione 2 dell'anello fenilico |
-
1998
- 1998-08-03 ES ES98935326T patent/ES2186186T3/es not_active Expired - Lifetime
- 1998-08-03 PT PT98935326T patent/PT1004573E/pt unknown
- 1998-08-03 DE DE69809063T patent/DE69809063T2/de not_active Expired - Lifetime
- 1998-08-03 AT AT98935326T patent/ATE226932T1/de active
- 1998-08-03 WO PCT/JP1998/003442 patent/WO1999006353A1/ja active IP Right Grant
- 1998-08-03 CA CA002299710A patent/CA2299710C/en not_active Expired - Fee Related
- 1998-08-03 DK DK98935326T patent/DK1004573T3/da active
- 1998-08-03 AU AU84625/98A patent/AU729000B2/en not_active Ceased
- 1998-08-03 CN CNB988078430A patent/CN1137878C/zh not_active Expired - Fee Related
- 1998-08-03 KR KR1020007001177A patent/KR100562808B1/ko not_active IP Right Cessation
- 1998-08-03 US US09/485,006 patent/US6333358B1/en not_active Expired - Fee Related
- 1998-08-03 EP EP98935326A patent/EP1004573B1/en not_active Expired - Lifetime
-
2001
- 2001-02-23 HK HK01101368A patent/HK1030413A1/xx not_active IP Right Cessation
- 2001-08-07 US US09/922,807 patent/US6476056B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US6333358B1 (en) | 2001-12-25 |
KR20010022586A (ko) | 2001-03-26 |
EP1004573B1 (en) | 2002-10-30 |
HK1030413A1 (en) | 2001-05-04 |
AU8462598A (en) | 1999-02-22 |
ES2186186T3 (es) | 2003-05-01 |
DK1004573T3 (da) | 2003-03-03 |
ATE226932T1 (de) | 2002-11-15 |
EP1004573A1 (en) | 2000-05-31 |
EP1004573A4 (en) | 2000-10-18 |
CA2299710A1 (en) | 1999-02-11 |
DE69809063D1 (de) | 2002-12-05 |
AU729000B2 (en) | 2001-01-25 |
DE69809063T2 (de) | 2003-06-12 |
CN1265642A (zh) | 2000-09-06 |
CA2299710C (en) | 2007-11-27 |
WO1999006353A1 (fr) | 1999-02-11 |
KR100562808B1 (ko) | 2006-03-21 |
US20020147191A1 (en) | 2002-10-10 |
PT1004573E (pt) | 2003-03-31 |
US6476056B2 (en) | 2002-11-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1137878C (zh) | 芳氧基苯胺衍生物 | |
CN100406007C (zh) | 哮喘和过敏性炎症调节剂 | |
CA2735593C (en) | Compositions including 6-aminohexanoic acid derivatives as hdac inhibitors | |
RU2463292C2 (ru) | Производные 4-замещенной феноксифенилуксусной кислоты | |
JP5138708B2 (ja) | オレキシンアンタゴニストとしてのアミノアミド | |
JP5148636B2 (ja) | オレキシンアンタゴニストとしてのマロンアミド | |
JP2006513201A (ja) | 1,5−ジアリール−ピロール−3−カルボキサミド誘導体およびそのカンナビノイド受容体モジュレーターとしての使用 | |
JP2009508864A (ja) | ヒスタミンh3受容体のモジュレーターとしてのシクロプロピルアミン | |
JP5778297B2 (ja) | 癌治療用のhdac阻害剤としての新規4−アミノ−n−ヒドロキシ−ベンズアミド | |
AU2005317950A1 (en) | Glycine transport inhibitors | |
KR20100092979A (ko) | 오렉신 길항제로서의 설폰아마이드 | |
JP2010527980A (ja) | 代謝障害を治療するための二環状アリールおよびヘテロアリール化合物 | |
JP2021532130A (ja) | ヒストン脱アセチル化酵素6阻害剤としての1,3,4−オキサジアゾール誘導体化合物およびそれを含む薬剤学的組成物 | |
JP5815033B2 (ja) | 癌治療用新規n−ヒドロキシ−ベンズアミド | |
US8202866B2 (en) | Ortho-aminoanilides for the treatment of cancer | |
CA2489396A1 (en) | Utilization of heteroarene carboxamide as dopamine-d3 ligands for the treatment of cns diseases | |
JP4302207B2 (ja) | アリールオキシアニリン誘導体 | |
CZ248195A3 (en) | Octahydro- or hexahydro-1h-isoindoles and pharmaceutical compositions based thereon | |
JP2010504311A (ja) | ピロリジン、インドリジンおよびキノリジンの誘導体、これらの調製およびこれらの治療上の使用 | |
EA009077B1 (ru) | Индазоламиды с аналгетической активностью | |
JP2009067784A (ja) | 環式基で置換された含窒素複素環誘導体を含有する鎮痛剤 | |
JP2768008B2 (ja) | アルコキシフェニルアルキルアミン誘導体 | |
JP2009179562A (ja) | グリシントランスポーター阻害剤 | |
JP4405455B2 (ja) | 3−アリール−3−メチル−キノリン−2,4−ジオン化合物、その製造方法及びそれを含む製薬組成物 | |
WO2002014277A1 (fr) | Composes de biphenylcarboxamidoisoindoline, procedes de preparation de ceux-ci et produits intermediaires destines a la synthese de ceux-ci |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040211 Termination date: 20120803 |