CN1283196A - N-苯基酰胺和n-吡啶基酰胺、其制备方法和含有它们的药物组合物 - Google Patents
N-苯基酰胺和n-吡啶基酰胺、其制备方法和含有它们的药物组合物 Download PDFInfo
- Publication number
- CN1283196A CN1283196A CN98812486A CN98812486A CN1283196A CN 1283196 A CN1283196 A CN 1283196A CN 98812486 A CN98812486 A CN 98812486A CN 98812486 A CN98812486 A CN 98812486A CN 1283196 A CN1283196 A CN 1283196A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- chr
- formula
- differently
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical class NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 49
- 239000002253 acid Substances 0.000 claims description 38
- -1 2,6-diisopropyl phenyl Chemical group 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 7
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 150000004982 aromatic amines Chemical class 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- ZLHLYESIHSHXGM-UHFFFAOYSA-N 4,6-dimethyl-1h-imidazo[1,2-a]purin-9-one Chemical compound N=1C(C)=CN(C2=O)C=1N(C)C1=C2NC=N1 ZLHLYESIHSHXGM-UHFFFAOYSA-N 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003981 vehicle Substances 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 230000003143 atherosclerotic effect Effects 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000002966 serum Anatomy 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 14
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 16
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 102000057234 Acyl transferases Human genes 0.000 abstract description 2
- 108700016155 Acyl transferases Proteins 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000012429 reaction media Substances 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 235000019198 oils Nutrition 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000005406 washing Methods 0.000 description 16
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000009835 boiling Methods 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 235000012000 cholesterol Nutrition 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 230000003098 cholesteric effect Effects 0.000 description 5
- 238000010908 decantation Methods 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000005826 halohydrocarbons Chemical class 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical group [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- 241000219161 Theobroma Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 150000001840 cholesterol esters Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- IYRWLNQMTOHCBR-UHFFFAOYSA-N 4-phenyl-2h-chromene-3-carbaldehyde Chemical compound C12=CC=CC=C2OCC(C=O)=C1C1=CC=CC=C1 IYRWLNQMTOHCBR-UHFFFAOYSA-N 0.000 description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000512259 Ascophyllum nodosum Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 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 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000005516 coenzyme A Substances 0.000 description 2
- 229940093530 coenzyme a Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 description 1
- 125000006558 (C6-C8) cycloalkyl group Chemical group 0.000 description 1
- DBGSRZSKGVSXRK-UHFFFAOYSA-N 1-[2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]acetyl]-3,6-dihydro-2H-pyridine-4-carboxylic acid Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CCC(=CC1)C(=O)O DBGSRZSKGVSXRK-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- LHNRHYOMDUJLLM-UHFFFAOYSA-N 1-hexylsulfanylhexane Chemical class CCCCCCSCCCCCC LHNRHYOMDUJLLM-UHFFFAOYSA-N 0.000 description 1
- QCYZNZPMKPZXSB-UHFFFAOYSA-N 2-(4-phenyl-2h-chromen-3-yl)acetonitrile Chemical compound C12=CC=CC=C2OCC(CC#N)=C1C1=CC=CC=C1 QCYZNZPMKPZXSB-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000014653 Carica parviflora Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010004103 Chylomicrons Proteins 0.000 description 1
- FITPCXSHEGAMCJ-JJKGCWMISA-N ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] Chemical compound ClC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.[Na] FITPCXSHEGAMCJ-JJKGCWMISA-N 0.000 description 1
- 241000243321 Cnidaria Species 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 206010012426 Dermal cyst Diseases 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
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000010305 Epidermal Cyst Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000000501 Lipidoses Diseases 0.000 description 1
- 206010024585 Lipidosis Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- LHUZAYREVYDAGJ-UHFFFAOYSA-N dichloromethane;ethyl acetate;methanol Chemical compound OC.ClCCl.CCOC(C)=O LHUZAYREVYDAGJ-UHFFFAOYSA-N 0.000 description 1
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 125000004031 fumaroyl group Chemical group C(\C=C\C(=O)*)(=O)* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229940093916 potassium phosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 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
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- WHAFDJWJDDPMDO-UHFFFAOYSA-N trimethyl(phenyl)phosphanium Chemical compound C[P+](C)(C)C1=CC=CC=C1 WHAFDJWJDDPMDO-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003643 water by type Substances 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
- C07D213/60—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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
- C07C57/50—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid containing condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
本申请涉及式(Ⅰ)的化合物,其中X、R1、R2和R3如权利要求1中所定义。这些化合物是胆甾烯基酰基转移酶(ACAT)抑制剂。
Description
本发明涉及新的N-苯基酰胺和N-吡啶基酰胺衍生物、制备这些化合物的方法和含有它们的药物组合物以及它们作为药物特别是作为治疗高脂血症和动脉粥样硬化的药物的用途。
已知脂质沉积特别是胆甾醇在血管中的沉积导致了动脉粥样硬化斑的形成,这是多种心血管疾病的病因,更精确地说,粉瘤是一种动脉粥样硬化,其特征在于脂质特别是胆甾醇酯在血管壁上过量沉积。最近发现,一种酶——酰基辅酶A:胆甾烯基酰基转移酶(ACAT)负责胆甾醇的酯化,已经发现在这种酶的活性增大与血管壁中胆甾醇酯的积累之间具有相关性。也已知饮食胆甾醇是以游离形式吸收的,然后被肠道ACAT酯化,以VLDL(极低密度脂质)和/或乳糜微粒形式释放到血流中。
虽然已经鉴定了好几种ACAT抑制剂(参见例如EP295637、EP415413或EP497201),但是还应当继续开发新的具有更好疗效的ACAT抑制剂。
进行了开发能预防肠道吸收饮食和胆汁胆甾醇以及抑制胆甾醇酯在血管壁上沉积的抑制ACAT的产品。
这种ACAT抑制剂的研究引导本发明人去开发一族新的N-苯基酰胺和N-吡啶基酰胺衍生物,并且发现这些产品表现了强大的抑制血管中ACAT的活性,这种抑制活性与对各种动物的强抗高脂血症作用有关。
本发明化合物的这些性能使得它们尤其在治疗高脂血症和动脉粥样硬化中具有特别有用的价值。
更精确地,本发明的化合物具有下列通式及其与一种药学上可接受的酸或碱的加成盐:
其中,X是O、S或CH2;
R1和R2可以相同或不同地为H、(C1-C6)烷基或(C6-C8)环烷基,或者可替换地,R1和R2及与它们相连的碳原子一起形成(C3-C8)环烷基;
R3是任选地被一个或多个相同或不同的Y基取代的(C6-C12)芳基;或者是任地被一个或多个相同或不同的Y基取代的并且包含1-3个选自O、S和N的环内杂原子(endocyclic heteroatom)的5-7员杂芳基;
Y是卤素、任选地被一个或多个卤素取代的(C1-C6)烷基、任选地被一个或多个卤素取代的(C1-C6)烷氧基、任选地被一个或多个卤素取代的(C1-C6)烷硫基、(C1-C7)酰基氨基、(C1-C3)酰氧基、羟基、硝基、氰基、氨基、(C1-C6)烷基氨基、二-(C1-C6)烷基氨基、吡咯烷酮子基(pyrrolidono)、哌啶子基、吗啉代、(C1-C4)烷基磺酰氨基、(C2-C5)烷氧羰基、羧基、(C2-C6)烷基羰基、氨基甲酰基、(C2-C5)烷基氨基甲酰基、二-(C2-C5)烷基氨基甲酰基或(C1-C6)烷基磺酰基;
R4和R5可以相同或不同地为Y基或可替换地为H;
Ar是下列基团A、B或C之一:
T1和T2可以相同或不同地为卤素、(C1-C6)烷氧基、(C1-C6)烷硫基或(C1-C6)烷基;
T是H或(C1-C6)烷基;
T3和T4可以相同或不同地为(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C6-C12)芳硫基、(C1-C6)烷氧羰基、(C1-C6)烷基羰基、(C6-C12)芳基羰基或-(CH2)p-OR,其中p为1、2、3或4,而R是(C2-C3)烷基;
R6和R7各自为H,或者
R6和R7一起为一个键;
Z为:
(ⅰ)二价基-CHR9-,其中R9是H或(C1-C6)烷基;或
(ⅱ)二价基-CHR10-CHR11-,其中R10和R11一起形成一条键,使得Z为-CH=CH-,或者R10和R11可以相同或不同地为如上所定义的R9;或
(ⅲ)二价基-CHR12-CHR13-CH2-,其中R12和R13一起形成一条键,使得Z为-CH=CH-CH2-,或者R12和R13可以相同或不同地为如上所定义的R9。
这些化合物与药学上可接受的酸或碱的加成盐也形成本发明的一个方面。这些盐的例子为与盐酸、对甲苯磺酸、反式丁烯二酸、柠檬酸、丁二酸、水杨酸、草酸、氢溴酸、磷酸、甲磺酸、酒石酸和苯乙醇酸形成的盐。
在某些情况下,本发明的化合物有一个或多个手性中心。应当明白,每种立体异构体都构成本发明的一个方面。
(C1-C6)烷基是含有1-6个碳原子的线性的或带支链的饱和烃基,因此(C1-C6)烷氧基是烷基-O-基,而(C1-C6)烷硫基是烷基-S-基,其中烷基如上所定义。
而且,应当明白,(C3-C8)环烷基是指包含3-8个碳原子的饱和单环或双环烃基,例如环丙基、环己基、环戊基和环庚基。
而且,术语(C6-C12)芳基是含有6-12个碳原子的单环或多环芳基,例如苯基、萘基或蒽基。因此,(C6-C12)芳硫基是(C6-C12)-芳基-S-基。
包含1-3个选自O、S和N的环内杂原子(endocyclic heteroatom)的5-7员杂环,可以是呋喃、噻吩、吡咯、噁唑、噻唑、咪唑、吡唑、异噁唑、异噻唑、吡啶、哒嗪、嘧啶和吡嗪。
卤原子是氯、溴、氟和碘。
术语酰基是烷基羰基,因此(C1-C7)酰基氨基是(C1-C7)烷基羰基氨基,而(C1-C3)酰氧基是(C1-C3)烷基羰基氧基。
在这些化合物中,优选6小组化合物。
第一小组由式Ⅰ中Y为卤素、(C1-C6)烷基、(C1-C6)烷氧基或三氟甲基的化合物组成。
第二小组包括式Ⅰ的化合物,其中:
R1和R2可以相同或不同地为H,或者R1和R2及与它们相连的碳原子一起形成(C3-C8)环烷基;
R3是任选地被一个或多个相同或不同的Y基取代的(C6-C12)芳基;
Y是卤素;
R4和R5各自为H;
Ar是下列基团A、B或C之一:
T1和T2可以相同或不同地为(C1-C6)烷基;
T是H或(C1-C6)烷基;
T3和T4可以相同或不同地为(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基;
R6和R7各自为H,或者
R6和R7一起为一条键;
Z为:
(ⅰ)二价基-CHR9-,其中R9是H或(C1-C6)烷基;或
(ⅱ)二价基-CHR10-CHR11-,其中R10和R11一起形成一条键,使得Z为-CH=CH-,或者R10和R11各自为H。
第三小组由式Ⅰ中Z为-CHR12-CHR13-CH2-(其中R12和R13如上所定义)的化合物组成。
在上述的第一、二和三小组的化合物中,更加特别优选其中R1和R2为H的化合物。
第四小组由式Ⅰ中X为O或S,而R1和R2及与它们相连的碳原子一起形成一个(C3-C8)环烷基的化合物组成。
第五小组优选化合物包括式Ⅰ中X为O或S,而Z为-CH=CH-或-CH=CH-CH2的化合物。
总之,优选的是使Ar为2,4-二甲硫基-6-甲基-3-吡啶基、2-甲氧基-4-己基硫基-3-吡啶基和2,6-二异丙基苯基。
第六小组由式Ⅰ中X为CH2的化合物组成。
在这些化合物中,更特别优选其中Ar为基团B或C的化合物。其中Ar的定义为2,4-二甲硫基-6-甲基-3-吡啶基和2-甲氧基-4-己基硫基-3-吡啶基又是特别有利的。
根据本发明的优选的实施方案,R3优选为被选择性取代的苯基、被任选取代的吡啶基或噻吩基,例如任选地在5-位取代的2-吡啶基或2-噻吩基。
本发明的化合物可以通过把式Ⅱ的一种酸
其中R1、R2、R3、R4、R5、R6、R7和Z如权利要求1所定义,与式Ⅲ的芳香胺偶合而制得:
Ar-NH2 (Ⅲ)
其中Ar如上所定义。
该方法以及下述的该方法的优选变种是本发明的主题。
式Ⅱ的酸与式Ⅲ的胺的偶合可以简单地通过使式Ⅲ的胺与式Ⅱ的酸的一种活性衍生物例如酰氯、酯或混合酸酐反应而完成。
更精确地,本领域技术人员已知他们可以设想把下列活性的酸衍生物胺化:P0-CO-SH、P0-CO-SR。P0-CO-Se-Me、P0-CO-B(OR)2、(P0-COO)4Si、P0-CO-C(hal)3或P0-CO-N3,其中
P0为:
hal是卤原子,而R是(C1-C6)烷基。
活化有机酸的方法是本领域中已知的。
而且,式Ⅱ的酸与胺Ⅲ的偶合可以通过使用液相肽合成中使用的任何技术而完成。这些技术例如为“肽合成方法”T.Wieland和H.Determann,Angew.Chem.Interm.Ed.Engl.,2,358,(1963)中所述的。
例如,式Ⅱ的酰基氯可以通过用SOCl2、草酰氯、PCl3或PCl5作用而得到。
也可以通过用三苯基膦在四氯化碳中与式Ⅱ的酸作用而制得酰氯。
为了制备酰基溴,可以使用相应的溴化剂例如草酰溴、PBr3或PBr5。
例如制备混合酸酐时,使双(2-氧代-3-噁唑烷基)次膦酸与式Ⅱ的酸作用。该反应优选象在绝大多数活化反应中一样在一种碱存在下进行。这种碱可以是吡啶、乙二胺或4-二甲基氨基吡啶。
因此,根据本发明的一种优选实施方式,式Ⅰ化合物是这样制备的:
使用下列步骤(ⅰ)和(ⅱ):
(ⅰ)在二甲基甲酰胺存在下,用草酰氯处理式Ⅱ的酸,然后
(ⅱ)用步骤(ⅰ)中得到的化合物与一种式Ⅲ的胺反应;
或者使用下列步骤(ⅰ)和(ⅱ):
(ⅰ)在一种碱存在下,用双(2-氧代-3-噁唑烷基)次膦酸处理式Ⅱ的酸,然后
(ⅱ)用步骤(ⅰ)中得到的化合物与一种式Ⅲ的胺反应。
例如,下列两种操作程序可以用于使酸Ⅱ与胺Ⅲ偶合。
方法A:
按照该方法,把式Ⅱ的酸活化成酰氯的形式,然后与胺Ⅲ偶合。
草酰氯与式Ⅱ的酸的反应在一种非极性的非质子传递溶剂(例如烃,如卤代烃)中进行。
保持在15-25℃的温度,优选在室温下,把草酰氯和催化量的二甲基甲酰胺加入式Ⅱ化合物的溶液中。然后把反应介质加热到30-70℃的温度,例如所用溶剂的回流温度。通过薄层色谱监测反应。然后蒸去溶剂,用非极性的非质子传递溶剂例如前面所用的卤代烃浸取残留物,然后添加芳香胺Ⅲ和碱例如吡啶或4-二甲基氨基吡啶。在15-85℃的温度下,优选在室温下持续反应必要长的时间。
方法B:
按照该方法,把式Ⅱ的酸活化成混合酸酐的形式,然后与胺Ⅲ偶合。
把一种弱碱例如三乙胺加入式Ⅱ的酸的非极性非质子传递溶剂例如卤代烃的溶液中,然后把反应介质加热到-10-10℃的温度,优选0-5℃的温度,然后加入双(2-氧代-3-噁唑烷基)次膦酰氯。当反应完成时,在维持在-10-10℃的温度(优选0-5℃的温度)下,向反应介质中一次性加入式Ⅲ的芳香胺。然后向反应介质中分小批加入碱的非极性非质子传递溶剂例如卤代烃的溶液。
然后分离并纯化得到的式Ⅰ化合物。
式Ⅲ的胺可以直接从商业得到,或者很容易地从商业产品得到。
在本文的其余部分,提供制备式Ⅱ化合物的方法。
式Ⅱ中Z为-CHR9-的化合物可以通过下列反应方案A得到。
第一步引入甲醛官能团。
使式Ⅷ中R1、R2、R3、R4、R5和X如上所定义的化合物与三氯氧化磷反应,该反应优选在极性的非质子传递溶剂例如二甲基甲酰胺(DMF)中进行。反应温度优选在-20℃-室温之间变化。优选地,反应在0-5℃之间进行,通过薄层色谱监测反应的进程。按照常规方式,通过把反应介质稀释在水-冰混合物中、中和,然后萃取和纯化,把得到的醛Ⅶ分离出来。
第二步是把醛官能团还原为羟甲基官能团,可以使用本领域中已知的任何方法进行反应,只要反应条件不会引起不需要的副反应。如果合适的话,把R1、R2、R3、R4和R5的活性官能团保护。
常用于达到这一目的反应试剂有氢化铝锂、硼氢化钠或氰基硼氢化钠。使用硼氢化钠时,反应优选在甲醇-水混合物中在-40-0℃的温度下,更优选在-25-15℃的温度下进行。又可按照已知的方法分离得到的混合物。
然后把分离出来的式Ⅵ的醇转变为相应的烷基氯化物。这种转变可以按照常规方式进行,只要反应条件不会引起副反应。如果合适的话,把R1、R2、R3、R4和R5的活性官能团保护。
已知的方法包括用亚硫酰氯在一种惰性溶剂例如甲苯或苯类芳烃中,在15-30的温度下,优选在室温下处理醇Ⅵ。
可用于氯化化合物Ⅵ的其它试剂是例如PCl3、PCl5或POCl3。
然后用碱金属氰化物(MCN)例如氰化钠在一种极性的非质子传递溶剂例如DMF中处理式Ⅴ的氯化物。根据氯化物Ⅴ的活性,反应温度保持在0-50℃。当MCN是氰化钠时,20-25℃的温度一般是合适的。按照常规方法把得到的式Ⅳ化合物分离并纯化。
式Ⅱ中R9为H的化合物可以很容易地通过用酸或碱处理腈Ⅳ而制得。为了达到这个目的,可以使用下列试剂体系:
-NaOH/H2O2或NaOH水溶液
-H2SO4
-HCOOH/HBr或Hcl
-AcOH/BF3
-AcOH/HCl
例如,可以用AcOH/HCl:40/60-60/40的混合物(1/1的混合物最合适)水解腈Ⅳ。在这种情况下,AcOH/HCl混合物优选起溶剂的作用,温度是不重要的,介于0-50℃,优选介于15-25℃。
为了得到式Ⅰ中R9为(C1-C6)烷基的化合物,在一种能去掉位于式Ⅱ化合物(R9=H)的羧基官能团的α-位的H的强碱存在下,用式R9-X中X为卤原子、基团(C1-C6)烷基磺酰氧基或任选地被(C1-C6)烷基取代的(C6-C10)芳基磺酰氧基,而R9为(C1-C6)烷基的卤代烷处理式Ⅱ中R9为H的相应化合物。这样的碱例如为二异丙基氨基锂(LDA)。
按照一种优选的实施方式,在-15-5℃的温度下,优选在0℃下,从正丁基锂和二异丙基胺原位制备LDA。用于生产LDA的溶剂是极性的非质子传递溶剂例如四氢呋喃。然后把卤化物R9-X和式Ⅱ的化合物加入反应介质中。反应温度例如为15-35℃,优选为20-25℃。
当式Ⅰ的化合物是其中Z为-CHR10-CHR11-的化合物时,可以按照方案B制备。
方案B
把溴原子引入式Ⅷ的化合物中是通过在没有湿气存在下,用N-溴代丁二酰亚胺(NBS)作用于溶于极性的非质子传递溶剂例如二甲基甲酰胺中而达到的。反应温度例如为室温,然而随着式Ⅷ化合物活性的不同,它可以在10-35℃之间变化。
第二步包括把得到的Ⅸ的溴代衍生物转变为式Ⅹ的化合物。为了达到这个目的,使式H2C=CH-COOR中R=(C1-C6)烷基的丙烯酸烷基酯与溴代衍生物Ⅸ在乙酸钯、膦和碱存在下反应。反应有益地在极性的非质子传递溶剂例如二甲基甲酰胺中进行。
碱可以是三乙胺、吡啶或4-二甲基氨基吡啶,优选三乙胺。
膦例如是式PAr’3的膦,其中Ar’优选为任选地被(C1-C6)烷基取代的C6-C12芳基。PAr’3例如为三苯基膦或三甲苯基膦。
为了使反应很好地进行,先使溶于DMF中的式Ⅸ的化合物,碱、膦和乙酸钯接触,然后向反应介质中加入式H2C=CH-COOR的丙烯酸酯。
按照常规方式把所得的式Ⅹ的酯分离出来,然后按照已知的方式皂化,得到式Ⅱ中R10和R11一起形成一条键的化合物。
以该化合物为原料,可以很容易地得到全部的式Ⅱ中Z为-CHR9-CHR10-的化合物。
使用Wittig反应,以式Ⅶ的醛为原料,可以得到式Ⅱ中Z为-CHR12-CHR13-CH2-的化合物(方案A)。例如可以使用由(ⅰ)式ROOC-CH2-CH2-P+A3,hal-的卤化鏻,其中R为H或(C1-C6)烷基,hal为H,而A选自任选地被(C1-C6)烷基取代的(C6-C12)芳基,和(ⅱ)一种诸如碱金属叔丁醇化物(tBuOK)、碱金属氢化物(NaH)或烷基锂(C4H9Li)的碱组成的试剂体系。反应有利地在一种极性的非质子传递溶剂例如二甲基甲酰胺或四氢呋喃中,在0-30℃的温度下进行。
本发明的另一个方面涉及含有至少一种式Ⅰ的化合物和一种或多种药学上可接受的载体的药物组合物。
可以使用的载体例如为填料、稀释剂、粘合剂、增湿剂、崩解剂、表面活性剂和润滑剂。药物组合物可以是任何所要的单位剂型,包括片剂、丸剂、粉末、液体、悬浮液、乳液、颗粒、胶囊、栓剂、注射液(溶液和悬浮液)等。
为了制备片剂,可以使用本领域已知的载体,例如赋形剂如乳糖、蔗糖、氯化钠、葡萄糖、脲、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸等;粘合剂如水、乙醇、丙醇、一种简单的糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、乳蚀、甲基纤维素、磷酸钾或聚乙烯基吡咯烷酮等;崩解剂如干燥的淀粉、藻酸钠、琼脂粉末、昆布粉末、碳酸氢钠、碳酸钙、聚氧基乙烯脱水三梨糖醇的脂肪酸酯、月桂基硫酸钠、硬脂酸单甘油酯、淀粉、乳糖等;崩解抑制剂如精制糖、硬脂酸甘油酯、可可油、氢化油等;吸收促进剂如季铵碱、月桂基硫酸钠等;增湿剂如甘油、淀粉等;吸附剂如淀粉、乳糖、高岭土、皂土、胶体硅酸等;润滑剂如纯化的滑石、硬脂酸盐、粉末状硼酸、聚乙二醇等。
而且,在制备片剂时,可以用常用的包衣材料给片剂包衣,把它转变为糖衣片剂、明胶膜包衣的片剂、含有肠衣的片剂、薄膜包衣的片剂或含有双层或多层的片剂。
为了制备丸剂,可以使用例如本领域常用的已知载体,例如赋形剂如葡萄糖、乳糖、淀粉、可可油、氢化的植物油、高岭土或滑石等;粘合剂如粉末状阿拉伯蚀、粉末状黄蓍树胶、明胶、乙醇等;和崩解剂如昆布粉末、琼脂等。
为了制备栓剂,可以使用本领域广泛使用的已知载体例如聚乙二醇、可可油、高级醇、高级醇酯、明胶、半合成的甘油酯等。
为了生产注射用制剂,把溶液和悬浮液灭菌,优选把它们制成与血液等渗的。为了生产注射用制剂,也可以使用本领域常用的载体,例如水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚氧基化的异硬脂醇、聚氧基乙烯脱水三梨糖醇的脂肪酸酯等。在这种情况下,为了制备等渗的溶液,可以向所要的药物制剂中加入适量的氯化钠。而且,如果合适的话,可以向所要的药物制剂中加入溶剂、缓冲液、常用的止痛剂以及着色剂、防腐剂、香料、调味剂、甜味剂和其它药物。
已经证明本发明的化合物是酰基-辅酶A的有效抑制剂。从而它们可用于治疗或预防高胆甾醇血症、动脉粥样硬化,甚至能预防可能发生的局部缺血事件例如心肌梗塞以及脑血管疾病。
本发明化合物的药理性能通过下列试验证明。
试验A:在体外测定大鼠肝ACAT的抑制:通过颈脱位法杀死体重为220-250g的雄性Wistar大鼠,取下肝脏,通过超离心匀浆制备微粒体组份,按照P.J.GLLIES等人在Exp.and Pathol.1986,44,329-339中描述的方法,把微粒体与14C-油基辅酶A一起培养,用甲醇-氯仿混合物把脂质从培养物中萃取出来,通过TLC把14C-油基胆甾醇分离出来,后者代表ACAT活性的测定值,结果用抑制浓度50(IC50)表示,它代表把ACAT的活性抑制50%时的化合物浓度值。
例如,化合物1、4和6的IC50值分别为94x1O-9mol/l、74x10-9mol/l和31x10-9mol/l。
试验B:测定大鼠肠道对胆甾醇的吸收:给体重为230-250g并且禁食了24小时的雄性Wistar大鼠口服试验物质,同时通过静脉内途径给药triton WR 1339,1小时以后,再次给它们口服3H-胆甾醇,3小时以后,从眶后窦取1ml血,用0.1ml血清测定血液的放射性,它代表对3H-胆甾醇吸收的测定值。结果用有效剂量50(ED50)mg/kg动物表示,它代表把肠道对胆甾醇的吸收抑制50%时的化合物的量。
例如,化合物1、4和6的ED50值分别为0.005mg/kg、0.038mg/kg和0.023mg/kg。
试验C:高胆甾醇血症模型:通过口服途径在进食了富含胆甾醇食物的动物中试验权利要求1的化合物。
例如,给雄性Wistar大鼠饲喂富含2.5%胆甾醇的食物8天,用1#化合物治疗2天,在剂量为0.78mg/kg时,总胆甾醇降低50%,注意到这种降低作用主要是针对VLDL(极低密度脂质)。
例如,在饲喂了富含0.5%胆甾醇的食物15天,并且同时用1#化合物治疗的兔中,在剂量为0.1mg/kg时,总胆甾醇降低70%,注意到这种降低作用主要是针对VLDL(极低密度脂质)。
为了说明,给出下列实施例作为优选的实施方式。
Ⅰ.式Ⅲ的芳香胺的制备
当Ar是2-(C1-C6)烷氧基-4-正己基硫基-3-吡啶基,随后的反应方案例如为:步骤1
(2-甲氧基-3-吡啶基)氨基甲酸叔丁基酯:
在氮气气氛和防止湿气进入的情况下,把3.72g(30mmol) 2-甲氧基-3-吡啶基胺在30ml四氢呋喃中的溶液加入100ml的反应器中,然后在室温下滴加60ml(60mmol)双(三甲基甲硅烷基)氨基钠的1M四氢呋喃溶液。
在室温下搅拌反应混合物20分钟后,向反应介质中滴加6.54g(30mmol)碳酸二叔丁基酯同时保持室温。
在室温搅拌3小时后,蒸去四氢呋喃,把残留物溶于乙酸乙酯中,用水洗涤,再用盐酸洗涤,再次用水洗涤(直到洗涤液的pH等于7)。有机相通过硫酸钠干燥,蒸去溶剂,得到一黑色油状物,在硅胶色谱上纯化(洗脱剂:乙酸乙酯-己烷:1-3)该油状物。蒸去溶剂后,得到6.1g瑚珀色的油状物,即产率为90.2%。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-2);Rf=0.4
I.R.:υ NH=3425,CO=1731
NMR:(CDCl3):1.5(s,9H);3.95(s,3H);6.8
(dd,1H,J=5Hz,J=7.8Hz);6.9(s,1H);7.7(dd,
1H,J=5Hz,J=1.6Hz);8.2(d,1H,J=7.8Hz).
步骤2
(4-正己基硫基-2-甲氧基-3-吡啶基)氨基甲酸叔丁基酯
在氮气气氛和防止湿气进入的情况下,把4.48g(20mmol)前一步中得到的化合物在100ml乙醚中的溶液和9.05ml(60mmol)四甲基乙二胺加入反应器中。
把溶液冷却到-70℃后,滴加37.5ml(60mmol)正丁基锂的己烷(1.6M)溶液。在-10℃搅拌反应介质2小时,然后在-70℃滴加14.1g(60mmol)二己基硫醚。
在室温下搅拌溶液12小时后,把反应介质加入水中,用乙醚萃取,有机相用盐酸(0.1M)洗涤,然后用水洗涤,直到洗涤液的pH等于7,最后通过硫酸钠干燥,在硅胶色谱上纯化(洗脱剂:乙酸乙酯-己烷:1-5)。蒸去溶剂后,得到5.6g油状物,使该油状物结晶,产率82.3%,熔点为72-74℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-3);Rf=0.3
I.R.:υ NH=3171,CO=1720
NMR:(CDCl3):0.85(t,3H);1.3(m,4H);1.45
(m,11H);1.7-1.8(m,2H);3.0(t,2H);4.25(s,3H);
6.7(d,1H,J=6.8Hz);7.85(d,1H,J=6.8Hz).
步骤3
4-正丁基硫基-2-甲氧基-3-氨基吡啶
在500ml的反应器中,在搅拌下把5.6g(16.45mmol)前一步中得到的化合物在140ml乙酸乙酯中的溶液和140ml 4M的盐酸溶液混合。
反应介质在室温下放置12小时,然后用碳酸氢钠中和(直到洗涤液的pH为7),然后水洗涤有机相,通过硫酸钠干燥,蒸馏。得到的油状物通过硅胶色谱纯化(洗脱剂:二氯甲烷)。蒸去溶剂后,得到3.63g油状物,产率为91.8%。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-3);Rf=0.6
NMR:(CDCl3):0.85(t,3H);1.2-1.3(m,4H);
1.3-1.4(m,2H);1.5-1.6(m,2H);2.85(t,2H);3.95
(s,3H);4.1(s,2H); 6.7(d,1H,J=6.7Hz);7.4(d,
1H,J=6.7Hz).
Ⅱ.其中Z为-CHR10-CHR11的式Ⅱ的羧酸的制备
1.3-[螺{环戊烷-1,2’-(4’-(4-氟苯基)-2’H-3’-苯并吡喃基)}]丙酸
步骤1
螺{环戊烷-1,2’-(3’-溴-4’-(4-氟苯基)-2’H-苯并吡喃基)}
把43.4g(0.3mol)N-溴代丁二酰亚胺在500ml二甲基甲酰胺中的溶液加入隔绝湿气的反应器中。在室温下向该溶液中滴加70.1g(0.25mmol)螺{环戊烷-1,2’-(4’-(4-氟苯基)-2’H-苯并吡喃基}在1升二甲基甲酰胺中的溶液,在室温下搅拌该溶液过夜,然后倒入3升冰冷的水中,用乙醚萃取反应介质,然后用水洗涤有机溶液(直到洗涤液的pH达到7),然后通过硫酸钠干燥。蒸去溶剂后,把得到的固体分散到100ml乙醇中,在-20℃下放置12小时,然后滗去液体,干燥,得到68.7g预期的产物,产率为76.5%。该产物熔点为107-109℃(乙醇)。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:2-100);Rf=0.7。
步骤2
3-螺{环戊烷-1,2’-(4’-(4-氟苯基)-2’H-3’-苯并吡喃基)]}-丙-2-烯酸乙酯
把14.1g(39.25mmol)前一步中得到的化合物在40ml二甲基甲酰胺中的溶液加入隔绝湿气的反应器中。向该溶液中滴加90ml三乙胺在90ml二甲基甲酰胺中的溶液,在室温下保温,然后依次向反应介质中加入下列试剂:
-0.72g(2.3mmol)三(2-甲苯基)膦、
-0.18g(0.79mmol)乙酸钯,然后在室温下滴加19.55ml丙烯酸乙酯(180.5mmol)。
然后加热回流(95℃)反应介质2小时,把反应介质倒入水/冰混合物中,用pH=1的浓盐酸溶液酸化。用二氯甲烷萃取得到的沉淀,有机相用水洗涤(直到洗涤液的pH达到7),通过硫酸钠干燥,蒸馏。
最后把得到的固体分散在100ml乙醇中,滗去液体,得到10.5g预期的化合物,产率为70.8%。该化合物的熔点为138-140℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:5-95);Rf=0.3。
I.R.:υ CO=1715cm-1.
步骤3
3-螺{环戊烷-1,2’-(4’-(4-氟苯基)-2’H-3’-苯并吡喃基)]}-丙-2-烯酸
把18.92g(50mmol)前一步中得到的化合物倒入700ml乙醇中,向该溶液中加入75ml(75mmol) 1N的氢氧化钠溶液。加热回流反应介质40分钟。蒸馏后,把得到的固体分散在乙醚中,滗去液体。把固体重新溶于水中,滤去不溶物。用盐酸酸化水相(酸化到pH=1),然后用乙酸乙酯萃取。有机相用水洗涤(直到洗涤液的pH达到7),蒸馏。
把得到的固体分散在戊烷中,滗去液体。
得到17.5g预期的化合物,产率为100%,该产物的熔点为172-174℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.46。
I.R.:υ CO=1682cm-1
NMR:(CDCl3):1.5-2.5(m,8H);5.5-5.8(d,1H);
6.5-7.5(m,9H); 10(s,1H).
百分比分析:C22H19FO3,0.25mol H2O
MW:354.87
C H N计算值% 74.39 5.49 5.35测定值% 74.65% 5.58 5.39
步骤4
3-[螺{环戊烷-1,2,-(4’-(4-氟苯基)-2’H-3’-苯并吡喃基)}]-丙酸
在氢气压力为100巴、温度为60℃的高压釜中,把由7g(20mmol)前一步中得到的酸、170ml四氢呋喃和5g Raney镍组成的溶液加热搅拌2小时30分钟。滤去催化剂,蒸去溶剂后,把固体残留物分散在己烷中,滗去液体。该化合物的熔点为177℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.60。
I.R.:ν CO=1706cm-1
2.式Ⅱ中Z为-CHR10-CHR11-的其它酸,及其相应的前体酯
按照上述对于3-[螺{环戊烷-1,2’-(4’-(4-氟苯基)-2’H-3’-苯并吡喃基)}]-丙酸的操作程序(Ⅱ.1),得到下列式Ⅱ的酸。
表1
制备序号 | X | R10 | R11 | R3 | R | R1 | R2 | 熔点(℃) |
Ⅰ.2.1 | O | H | H | 4-F-C6H4 | H | -(CH2)4- | 177 | |
Ⅰ.2.2 | S | H | H | C6H5 | H | H | H | 油(oil) |
Ⅰ.2.3 | O | 键 | 4-F-C6Hx | C2H5 | -(CH2)4- | 138-140 | ||
Ⅰ.2.4 | O | 键 | 4-F-C6H4 | H | -(CH2)4- | 172-174 | ||
Ⅰ.2.5 | S | 键 | C6H5 | C2H5 | H | H | 油 | |
Ⅰ.2.6 | S | 键 | C6H5 | H | H | H | 油 | |
Ⅰ.2.7 | O | 键 | C6H5 | C2H5 | H | H | 油 | |
Ⅰ.2.8 | 0 | 键 | C6H5 | H | H | H | 216-218 |
在上面的表1中,术语“键”是指R10+R11一起形成一条键,而4-F-C6H4是下式的基团:
表2汇集了形成上述表1的化合物的中间体溴化物。
Ⅲ.式Ⅱ中Z为-CHR9-的羧酸的制备
1.2-(4-苯基-2H-3-苯并[b]吡喃基)乙酸
步骤1
4-苯基-2H-3-苯并[b]吡喃基甲醛
在氮气气氛下,把3.13升(40.7mol)二甲基甲酰胺加入隔绝湿气的6升反应器中。在0-5℃下,向该溶液中滴加748ml(8.14mol)氯化氧磷。在5℃下搅拌反应介质20分钟,然后向溶液中加入175.28g(0.814mol)4-苯基-2H-苯并[b]吡喃溶于246ml二甲基甲酰胺。在室温下搅拌溶液48小时,然后把反应介质倒入冰水混合物中,用pH大于10的浓氢氧化钠溶液中和,在室温下搅拌1小时。然后用乙醚萃取反应介质3次。
用水洗涤有机溶液,通过硫酸钠干燥。蒸馏后,把得到的油状物分散在200m1庚烷中。在-20℃下静置溶液1小时,然后把形成的固体过滤出来并干燥,得到144.5g预期的产物,产率为75.1%。该化合物的熔点为78-80℃。
TLC:(MERCK“Kieselgel 60”硅胶;二氯甲烷-己烷:1-1):Rf=0.5。
NMR:(CDCl3):5.15(s,2H);6.9-7.5(m,9H);
9.45(s,1H)
I.R.:υ CO=1660cm-1.
步骤2
(4-苯基-2H-3-苯并[b]吡喃基)甲醇
在氮气气氛下,把302.6g(1.28mol)前一步中得到的化合物在7.7升甲醇和260ml水的混合物中的溶液加入20升反应器中,在室温下分小批向该溶液中加入53.3g(1.4088mol)硼氢化钠。加完后,搅拌反应介质30分钟。蒸去溶剂后,把残留物溶于乙醚中,用水洗涤有机溶液,直到洗涤液的pH达到7。蒸去溶剂后,得到的油状物在200ml戊烷中重结晶。在-20℃放置2小时后,把得到的固体倾滗出来,产率为88.3%。该化合物的熔点为67-68℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.5。
I.R.:υ CO=3356cm-1。
步骤3
3-(氯甲基)-4-苯基-2H-苯并[b]吡喃
在氮气气氛和隔绝湿气的条件下,把269.3g(1.13mol)前一步中得到的化合物在2.7升甲苯中的溶液加入6升的反应器中。
在室温下,向该溶液中滴加165ml(2.16mol)亚硫酰氯。反应介质逐渐变成暗红色。加完后,搅拌反应介质30分钟。蒸去溶剂后,把产率为溶于乙醚中。用水洗涤有机溶液,直到洗涤液的pH达到7,然后通过硫酸钠干燥。蒸去溶剂后,得到291.1g油状物,产率大约为100%。
步骤4
2-(4-苯基-2H-3-苯并[b]吡喃基)乙腈
在氮气气氛和隔绝湿气的条件下,把58.2g(1.186mol)氰化钠在1.36升二甲基亚砜中的悬浮液加入6升的反应器中。在室温下,向该溶液中滴加291.2g(1.13mol)在前一步中得到的化合物在1.2升二甲基亚砜中的溶液。加完后,搅拌反应介质48小时,把溶液倒入冰水混合物中,用二氯甲烷萃取形成的沉淀3次。有机溶液用水洗涤,然后通过硫酸钠干燥。蒸去溶剂后,得到262g油状物。把该油状物溶于二氯甲烷-庚烷:1-1的混合物中,通过硅胶色谱纯化。蒸去溶剂后,得到196.7g油状物,产率为70.5%。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-3);Rf=0.63。
I.R.:υ CN=2247cm-1
NMR:(CDCl3):3.1(s,2H);5.0(s,2H);6.65
(dd,1H);6.8(dd,1H);6.9(dd,1H);7.15-7.3(m,3H);
7.4-7.6(m,3H).
步骤5
2-(4-苯基-2H-3-苯并[b]吡喃基)乙酸
在2升的反应器中,把56.7g(0.229mol)在前一步中得到的化合物在300ml乙酸和300ml浓盐酸溶液的混合物中的溶液加热回流3小时。冷却后(在室温下静置12小时),形成沉淀。倾滗并用水冲洗后,把沉淀溶于二氯甲烷中。有机相用水洗涤(直到洗涤液的pH达到7),通过硫酸钠干燥,蒸馏。把得到的固体分散在戊烷中,然后倾滗,得到54g预期的化合物,产率为88%,该化合物的熔点为147-149℃。
I.R.:υ CO=1721cm-1
NMR:(CDCl3):3.1(s,2H);4.8(s,2H);6.6-7.3
(m,10H).
2.式Ⅱ中Z为-CHR9-的其它化合物。
通过使用上述制备2-(4-苯基-2H-3-苯并[b]吡喃基)乙酸的操作程序,制备了汇集在表3中的化合物。
这些化合物通过下列表4-7中的中间体得到。
更精确地,这些化合物是通过实施上述Ⅲ.1的步骤1中的方法,从合适的试剂制备的。
表5
中间体序号 | X | R3 | 熔点(℃) |
Ⅵ.1 | 0 | 4-F-C6H4- | 96-98 |
Ⅵ.2 | CH2 | C6H5- | 油 |
更精确地,这些化合物是通过实施上述Ⅲ.1的步骤2中的方法,从合适的试剂制备的。
更精确地,这些化合物是通过实施上述Ⅲ.1的步骤3中的方法,从合适的试剂制备的。
更精确地,这些化合物是通过实施上述Ⅲ.1的步骤4中的方法,从合适的试剂制备的。
实施例1
N-[2,4-二甲硫基-6-甲基-3-吡啶基]-2-(4-苯基-2H-3-苯并[b]吡喃基)乙酰胺
把45g(0.169mol) 2-(4-苯基-2H-3-苯并[b]吡喃基)乙酸和23.5ml(0.169mol)三乙胺在338ml二氯甲烷中的溶液加入隔绝湿气的2升反应器中。在0-5℃下分小批向溶液中加入43.02g(0.169mol)双(2-氧代-3-噁唑烷基)次膦酰氯,然后搅拌反应混合物1小时,然后一次性加入33.84g(0.169mol)2,4-二甲硫基-6-甲基-3-吡啶基胺。然后在0-5℃下用1小时的时间向溶液中滴入23.5ml(0.169mol)三乙胺在68ml二氯甲烷中的溶液。反应介质逐渐溶解,在室温下搅拌12小时。加入水和二氯甲烷后,过滤出沉淀并扔弃。通过静置让反应介质分层,然后用水洗涤有机相,再用盐酸溶液洗涤,最后用水洗涤,直到洗涤液的pH达到7。通过硫酸钠干燥后,蒸馏有机相。用30分钟时间把得到的固体分散在300ml乙醇中,然后倾滗,得到52g预期的产物(湿的)。然后使产物在4.5升乙醇中重结晶,在-20℃放置12小时。倾滗后,把得到的固体放在通风炉中干燥(在50-55℃下干燥2小时30分钟),然后在95℃下干燥20小时,得到30.5克期望的化合物,产率为40.2%,该化合物的熔点为201-203℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.51。
I.R.:υ NH=3198cm-1;CO=1661cm-1
NMR: (CDCl3): 2.3(sd,3H); 2.4(s, 3H);
2.8-3.1(sd,2H);4.8-5.0(sd,2H); 6.2-7.4(m,11H).
百分含量分析:C25H24N2O2S2 MW=448.5
C H N S计算值% 66.94 5.39 6.25 14.29测定值% 66.65 5.34 6.23 14.07
实施例2
N-[2,4-二甲硫基-6-甲基-3-吡啶基]-3-(4-苯基-2H-3-苯并[b]吡喃基)丙-2-烯酰胺
把1g(3.59mmol)3-(4-苯基-2H-3-苯并[b]吡喃基)丙-2-烯酸在30ml二氯甲烷中的溶液加入隔绝湿气的250ml的反应器中,向其中加入一滴二甲基甲酰胺。在室温下,向该溶液中滴入0.39ml(3.76mmol)草酰氯,然后加热回流反应介质1小时。蒸去溶剂后,用20ml二氯甲烷溶解反应介质,然后在0-5℃下把溶液倒入由0.75g(3.76mmol)2,4-二甲硫基-6-甲基-3-吡啶基胺、2.2ml吡啶和30ml二氯甲烷组成的混合物中。在室温下搅拌所得的反应介质12小时。加入水后,静置,分离出有机相,用2N盐酸溶液洗涤,然后用水洗涤,直到洗涤液的pH达到7。通过硫酸钠干燥后,蒸馏有机相。把所得的固体分散在10ml己烷中,倾滗,得到1.1g粗的预期产物。粗产物在140ml乙醇中重结晶(在-20℃重结晶12小时),然后倾滗并干燥,得到0.77g预期的化合物,产率为46.7%,该化合物的熔点为225-227℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.59。
I.R.:υ NH=3253,CO=1652
NMR:(CDCl3):2.35(s,3H);2.4(s,3H); 2.45
(s,3H); 4.7(s,lH); 5.0(s,1H); 5.9-5.95(d,1H);
6.25(s,1H);6.58(d,1H); 6.62-6.80(m,2H);
6.84-6.87(d,1H); 7.05-7.17(m,3H); 7.3-7.4(m,4H).
百分含量分析:C26H24N2O2S2 MW=460.62
C H N S计算值% 67.80 5.25 6.08 13.92测定值% 67.54 5.25 6.15 14.15
按照实施例1所述的方法,从合适的试剂制备下列实施例3-5的化合物。
下列实施例6-15中的化合物是按照实施例2的方法模式,从合适的试剂制备的。
这些化合物列于表8和9中。
在这两个表中,“键”是指R6和R7、R10和R11分别一起形成一条键。
实施例16
2-(4-苯基-2H-3-苯并[b]吡喃基)己酸
把3.1ml(22mmol)二异丙基胺在20ml四氢呋喃中的溶液加入隔绝湿气的250ml的反应器中,然后在0℃下向该溶液中滴加13.75ml(22mmol)正丁基锂的己烷(1.6M)溶液。在0℃搅拌反应介质15分钟后,在0℃下向该溶液中滴加2.66g(10mmol)2-(4-苯基-2H-3-苯并[b]吡喃基)乙酸,在0℃搅拌反应介质2小时,然后在该温度下向溶液中加入1.18ml(11mmol)1-溴丁烷。在室温下搅拌反应混合物72小时。加入水和盐酸(2M)后,用乙醚萃取反应混合物。用水洗涤有机相后,干燥,然后蒸馏。得到的油在硅胶色谱上纯化(洗脱剂:二氯甲烷)。蒸去溶剂后,把得到的结晶分散在戊烷中,然后倾滗,得到1.7g预期的化合物,产率为52.8%。该产物的熔点为117-119℃。
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1);Rf=0.5。
I.R:ν CO=1697cm-1。
实施例17
N-[2,4-二甲硫基-6-甲基-3-吡啶基]-4-(4-苯基-2H-3-苯并[b]吡喃基)丁-3-烯酰胺
步骤1
4-(4-苯基-2H-3-苯并[b]吡喃基)丁-2-烯-1-酸
把1.9g(0.008mol)4-苯基-2H-3-苯并[b]吡喃基甲醛和3.5g(0.0084mol)1-羧基丙基溴化鏻在20ml四氢呋喃中的悬浮液加入隔绝湿气的反应器中。在0℃下用1小时把1.9g(0.0176mol)叔丁醇钾在10ml四氢呋喃中的溶液加入该悬浮液中。在0-5℃搅拌反应介质30分钟,然后在室温下搅拌1小时。然后把反应介质倒入冰水混合物,然后用乙醚萃取。
用浓盐酸(pH=2)把水相酸化,用乙酸乙酯萃取水相。有机相通过硫酸钠干燥,蒸馏,得到2g固体,把该固体溶于二氯甲烷-乙酸乙酯:9-1的混合物中,通过硅胶色谱纯化。蒸去溶剂后,得到0.7g固体,产率为29.9%。
TLC:(MERCK“Kieselgel 60”硅胶;乙酸乙酯-二氯甲烷-甲醇:45-45-10);Rf=0.65。
I.R:γ CO2H=1718cm-1。
步骤2
在实施例1的条件下,从4-(4-苯基-2H-3-苯并[b]吡喃基)丁-2-烯-1-酸和2,4-二甲硫基-6-甲基-3-吡啶基胺制得N-[2,4-二甲硫基-6-甲基-3-吡啶基]-4-(4-苯基-2H-3-苯并[b]吡喃基)丁-3-烯酰胺。
熔点:204-206℃
TLC:(MERCK“Kieselgel 60”硅胶;AcOEt-己烷:1-1;Rf=0.6)。
I.R.:γNH=3203cm-1;γCO=1651cm-1
NMR: (CDCl3): 2.4(s,3H); 2.55(s,6H);
2.9-3.2(m,2H); 5.05-5.15(m,2H);5.9(m,1H); 6.3
(d,1H);6.6-7.5(m,11H).
Claims (20)
其中,X是O、S或CH2;
R1和R2可以相同或不同地为H、(C1-C6)烷基或(C3-C8)环烷基,或者R1和R2及与它们相连的碳原子一起形成(C3-C8)环烷基;
R3是任选地被一个或多个相同或不同的Y基取代的(C6-C12)芳基;或者是任选地被一个或多个相同或不同的Y基取代的并且包含1-3个选自O、S和N的环内杂原子的5-7员杂芳基;
Y是卤素、任选地被一个或多个卤素取代的(C1-C6)烷基、任选地被一个或多个卤素取代的(C1-C6)烷氧基、任选地被一个或多个卤素取代的(C1-C6)烷硫基、(C1-C7)酰基氨基、(C1-C3)酰氧基、羟基、硝基、氰基、氨基、(C1-C6)烷基氨基、二-(C1-C6)烷基氨基、吡咯烷酮子基、哌啶子基、吗啉代、(C1-C6)烷基磺酰氨基、(C2-C5)烷氧羰基、羧基、(C2-C6)烷基羰基、氨基甲酰基、(C2-C5)烷基氨基甲酰基、二-(C2-C5)烷基氨基甲酰基或(C1-C6)烷基磺酰基;
R4和R5可以相同或不同地为Y基或氢原子;
T1和T2可以相同或不同地为卤素、(C1-C6)烷氧基、(C1-C6)烷硫基或(C1-C6)烷基;
T是氢原子或(C1-C6)烷基;
T3和T4可以相同或不同地为(C1-C6)烷基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C6-C12)芳硫基、(C1-C6)烷氧羰基、(C1-C6)烷基羰基、(C6-C12)芳基羰基或-(CH2)p-OR,其中p为1、2、3或4,而R是(C2-C3)烷基;
R6和R7各自为氢原子,或者
R6和R7一起为一条键;
Z为:
(ⅰ)二价基-CHR9-,其中R9是氢原子或(C1-C6)烷基;或
(ⅱ)二价基-CHR10-CHR11-,其中R10和R11一起形成一条键,使得Z为-CH=CH-,或者R10和R11可以相同或不同地为如上的R9所定义;或
(ⅲ)二价基-CHR12-CHR13-CH2-,其中R12和R13一起形成一条键,使得Z为-CH=CH-CH2-,或者R12和R13可以相同或不同地为如上的R9所定义。
2.权利要求1的化合物,其特征在于:Y是卤素、(C1-C6)烷基、(C1-C6)烷氧基或三氟甲基。
3.上述权利要求中的任何一个的化合物,其特征在于:
R1和R2可以相同或不同为H,或者R1和R2及与它们相连的碳原子一起形成(C3-C8)环烷基;
R3是任选地被一个或多个相同或不同的Y基取代的(C6-C12)芳基;
Y是卤素;
R4和R5各自为氢原子;
Ar是下列基团A、B或C之一:
T1和T2可以相同或不同地为(C1-C6)烷基;
T是氢原子或(C1-C6)烷基;
T3和T4可以相同或不同地为(C1-C6)烷基、(C1-C6)烷氧基或(C1-C6)烷硫基;
R6和R7各自为氢原子,或者
R6和R7一起为一条键;
Z为:
(ⅰ)二价基-CHR9-,其中R9是氢原子或(C1-C6)烷基;或
(ⅱ)二价基-CHR10-CHR11-,其中R10和R11一起形成一条键,使得Z为-CH=CH-,或者R10和R11各自为氢原子。
4.上述权利要求中的任何一个的化合物,其特征在于:R1和R2为氢原子。
5.权利要求1的化合物,其特征在于:Z为-CHR12-CHR13-CH2-,R12和R13如权利要求1所定义。
6.权利要求1-5中任何一个的化合物,其特征在于:X为O或S,而R1和R2及与它们相连的碳原子一起形成一个(C3-C8)环烷基。
7.上述权利要求1-5中任何一个的化合物,其特征在于:X为O或S,而Z选自:
(ⅰ)-CH=CH-,和
(ⅱ)-CH=CH-CH2-。
8.权利要求1-7中任何一个的化合物,其特征在于:Ar选自2,4-二甲硫基-6-甲基-3-吡啶基、2-甲氧基-4-己基硫基-3-吡啶基和2,6-二异丙基苯基。
9.权利要求1-5中任何一个的化合物,其特征在于:X为CH2。
10.权利要求9的化合物,其特征在于:Ar是基团B或C之一,优选为2,4-二甲硫基-6-甲基-3-吡啶基或2-甲氧基-4-己基硫基-3-吡啶基。
11.制备权利要求1-10中任何一个的化合物的方法,其特征在于:使式Ⅱ的一种酸
其中R1、R2、R3、R4、R5、R6、R7和Z如权利要求1所定义,与式Ⅲ的芳香胺偶合:
Ar-NH2 (Ⅲ)
其中Ar如上所定义。
12.权利要求11的方法,其特征在于式Ⅱ化合物与胺Ⅲ的偶合包括:
(ⅰ)通过形成酰氯、酯或混合酐,把式Ⅱ的酸活化;和
(ⅱ)使式Ⅲ的胺与步骤(ⅰ)中得到的化合物反应。
13.权利要求11和12中任何一个的方法,其特征在于它包括下列步骤:
(ⅰ)在一种碱存在下,用双(2-氧代-3-噁唑烷基)次膦酸处理式Ⅱ的酸,和然后
(ⅱ)使式Ⅲ的胺与步骤(ⅰ)中得到的化合物反应。
14.权利要求11-13中任何一个的方法,其特征在于它包括下列步骤:
(ⅰ)在二甲基甲酰胺存在下,用草酰氯处理式Ⅱ的酸,然后
(ⅱ)使式Ⅲ的胺与步骤(ⅰ)中得到的化合物反应。
16.包含至少一种权利要求1-10中任何一个的化合物以及一种或多种药学上可接受的载体的药物组合物。
17.具有促血清脂质减少、抗动脉粥样硬化活性的权利要求16的药物,以试验单元使用,每个单元含有10mg-500mg活性组分和一种药学上可接受的赋形剂。
18.权利要求1的化合物在制备用于治疗高脂血症病人的药物中的用途。
19.权利要求1的化合物在制备用于治疗动脉粥样硬化的病人的药物中的用途。
其中X为O;
R1和R2可以相同或不同地为H、(C1-C6)烷基或(C3-C8)环烷基,或者R1和R2及与它们相连的碳原子一起形成(C3-C8)环烷基;
R3是任选地被一个或多个相同或不同的Y基取代的(C6-C12)芳基,或者是任选地被一个或多个相同或不同的Y基取代的并且包含1-3个选自O、S和N的环内杂原子的5-7员杂芳基;
Y是卤素、任选地被一个或多个卤素取代的(C1-C6)烷基、任选地被一个或多个卤素取代的(C1-C6)烷氧基、任选地被一个或多个卤素取代的(C1-C6)烷硫基、(C1-C7)酰基氨基、(C1-C3)酰氧基、羟基、硝基、氰基、氨基、(C1-C6)烷基氨基、二-(C1-C6)烷基氨基、吡咯烷酮子基、哌啶子基、吗啉代、(C1-C6)烷基磺酰氨基、(C2-C5)烷氧羰基、羧基、(C2-C6)烷基羰基、氨基甲酰基、(C2-C5)烷基氨基甲酰基、二-(C2-C5)烷基氨基甲酰基或(C1-C6)烷基磺酰基;
R4和R5可以相同或不同地为Y基或氢原子;
T是氢原子或(C1-C6)烷基;
T3和T4可以相同或不同地为(C1-C6)烷硫基;
R6和R7各自为氢原子,或者
R6和R7一起为一条键;
Z为:
(ⅰ)二价基-CHR9-,其中R9是氢原子或(C1-C6)烷基;或
(ⅱ)二价基-CHR10-CHR11-,其中R10和R11一起形成一条键,使得Z为-CH=CH-,或者R10和R11可以相同或不同地为如上的R9所定义;或
(ⅲ)二价基-CHR12-CHR13-CH2-,其中R12和R13一起形成一条键,使得Z为-CH=CH-CH2-,或者R12和R13可以相同或不同地为如上的R9所定义。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9716399A FR2772761B1 (fr) | 1997-12-23 | 1997-12-23 | Nouveaux derives de n-phenylamide et n-pyridylamide, leur procede de preparation et compositions pharmaceutiques les contenant |
FR97/16399 | 1997-12-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1283196A true CN1283196A (zh) | 2001-02-07 |
Family
ID=9515039
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN98812486A Pending CN1283196A (zh) | 1997-12-23 | 1998-12-11 | N-苯基酰胺和n-吡啶基酰胺、其制备方法和含有它们的药物组合物 |
Country Status (19)
Country | Link |
---|---|
US (2) | US6339097B1 (zh) |
EP (1) | EP1040109A1 (zh) |
JP (1) | JP2001527073A (zh) |
KR (1) | KR20010033414A (zh) |
CN (1) | CN1283196A (zh) |
AR (1) | AR017896A1 (zh) |
AU (1) | AU751291B2 (zh) |
BR (1) | BR9813712A (zh) |
CA (1) | CA2316382A1 (zh) |
FR (1) | FR2772761B1 (zh) |
HU (1) | HUP0004546A3 (zh) |
ID (1) | ID26506A (zh) |
MY (1) | MY132969A (zh) |
NO (1) | NO20003290L (zh) |
PL (1) | PL341241A1 (zh) |
RU (1) | RU2214409C2 (zh) |
SK (1) | SK9312000A3 (zh) |
WO (1) | WO1999033825A1 (zh) |
ZA (1) | ZA9811795B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0020498D0 (en) * | 2000-08-18 | 2000-10-11 | Sterix Ltd | Compound |
WO2002047723A1 (fr) * | 2000-12-11 | 2002-06-20 | Takeda Chemical Industries, Ltd. | Compositions medicamenteuses presentant une meilleure hydrosolubilite |
US7939545B2 (en) | 2006-05-16 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Inhibitors of human immunodeficiency virus replication |
ATE541841T1 (de) | 2007-11-15 | 2012-02-15 | Boehringer Ingelheim Int | Inhibitoren der replikation des human immunodeficiency virus |
EA201200631A1 (ru) | 2007-11-16 | 2012-11-30 | Джилид Сайенсиз, Инк. | Ингибиторы репликации вируса иммунодефицита человека |
US8217188B2 (en) * | 2008-08-27 | 2012-07-10 | Corning Incorporated | 2H-chromenes annelated at C5-C6 and methods of making and using thereof |
EP2511273B8 (en) | 2011-04-15 | 2019-06-26 | Hivih | Inhibitors of viral replication, their process of preparation and their therapeutical uses |
EP2821104A1 (en) | 2013-07-05 | 2015-01-07 | Laboratoire Biodim | Inhibitors of viral replication, their process of preparation and their therapeutical uses |
US9968604B2 (en) | 2015-04-16 | 2018-05-15 | Chiesi Farmaceutici S.P.A. | Chromene derivatives as phoshoinositide 3-kinases inhibitors |
EP3759086A1 (en) * | 2018-02-27 | 2021-01-06 | Artax Biopharma Inc. | Chromene derivatives as inhibitors of tcr-nck interaction |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL87019A (en) * | 1987-07-10 | 1993-07-08 | Hoffmann La Roche | Substituted alkene carboxamides and derivatives, their manufacture and pharmaceutical compositions containing them |
FR2642065B1 (fr) * | 1989-01-24 | 1991-05-24 | Lipha | Derives d'acides benzocycloalcenyl dihydroxy alcanoiques, procede de preparation et medicaments les contenant |
CA2026389A1 (en) * | 1989-09-29 | 1991-03-30 | Hideo Nakai | Chromene or thiochromene derivatives, process for preparing the same and intermediate therefor |
ATE124408T1 (de) * | 1990-10-16 | 1995-07-15 | Takeda Chemical Industries Ltd | Heterozyklische aminderivate, deren herstellung und deren verwendung. |
NO179904C (no) * | 1992-09-04 | 1997-01-08 | Takeda Chemical Industries Ltd | Kondenserte heterocykliske forbindelser og deres anvendelse |
US5491152A (en) * | 1994-03-23 | 1996-02-13 | The Du Pont Merck Pharmaceutical Company | Derivatives of cyclic ethers and sulfides for the treatment of atherosclerosis |
KR100866820B1 (ko) * | 2000-07-13 | 2008-11-04 | 다케다 야쿠힌 고교 가부시키가이샤 | 지질 풍부 플라크 퇴축제 |
-
1997
- 1997-12-23 FR FR9716399A patent/FR2772761B1/fr not_active Expired - Fee Related
-
1998
- 1998-12-11 BR BR9813712-3A patent/BR9813712A/pt not_active IP Right Cessation
- 1998-12-11 US US09/581,991 patent/US6339097B1/en not_active Expired - Fee Related
- 1998-12-11 EP EP98966302A patent/EP1040109A1/en not_active Withdrawn
- 1998-12-11 HU HU0004546A patent/HUP0004546A3/hu unknown
- 1998-12-11 CN CN98812486A patent/CN1283196A/zh active Pending
- 1998-12-11 AU AU22709/99A patent/AU751291B2/en not_active Ceased
- 1998-12-11 RU RU2000120167/04A patent/RU2214409C2/ru not_active IP Right Cessation
- 1998-12-11 CA CA002316382A patent/CA2316382A1/en not_active Abandoned
- 1998-12-11 PL PL98341241A patent/PL341241A1/xx unknown
- 1998-12-11 ID IDW20000852A patent/ID26506A/id unknown
- 1998-12-11 KR KR1020007006894A patent/KR20010033414A/ko not_active Application Discontinuation
- 1998-12-11 JP JP2000526507A patent/JP2001527073A/ja active Pending
- 1998-12-11 SK SK931-2000A patent/SK9312000A3/sk unknown
- 1998-12-11 WO PCT/EP1998/008101 patent/WO1999033825A1/en not_active Application Discontinuation
- 1998-12-18 AR ARP980106472A patent/AR017896A1/es not_active Application Discontinuation
- 1998-12-21 MY MYPI98005804A patent/MY132969A/en unknown
- 1998-12-22 ZA ZA9811795A patent/ZA9811795B/xx unknown
-
2000
- 2000-06-22 NO NO20003290A patent/NO20003290L/no not_active Application Discontinuation
-
2001
- 2001-11-01 US US09/985,002 patent/US6509362B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
ID26506A (id) | 2001-01-11 |
HUP0004546A2 (hu) | 2001-08-28 |
WO1999033825A8 (en) | 1999-08-26 |
NO20003290D0 (no) | 2000-06-22 |
MY132969A (en) | 2007-10-31 |
PL341241A1 (en) | 2001-03-26 |
AR017896A1 (es) | 2001-10-24 |
US6509362B2 (en) | 2003-01-21 |
CA2316382A1 (en) | 1999-07-08 |
SK9312000A3 (en) | 2001-04-09 |
JP2001527073A (ja) | 2001-12-25 |
RU2214409C2 (ru) | 2003-10-20 |
BR9813712A (pt) | 2000-12-12 |
AU751291B2 (en) | 2002-08-08 |
ZA9811795B (en) | 1999-06-22 |
NO20003290L (no) | 2000-08-22 |
KR20010033414A (ko) | 2001-04-25 |
US6339097B1 (en) | 2002-01-15 |
FR2772761B1 (fr) | 2000-05-26 |
AU2270999A (en) | 1999-07-19 |
HUP0004546A3 (en) | 2002-12-28 |
WO1999033825A1 (en) | 1999-07-08 |
EP1040109A1 (en) | 2000-10-04 |
FR2772761A1 (fr) | 1999-06-25 |
US20020068739A1 (en) | 2002-06-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1028174C (zh) | 制备具有类视黄酸生物活性的带有二取代的乙炔部分的化合物的方法 | |
CN1050605C (zh) | 环烷并吲哚和环烷并氮杂吲哚衍生物,其制备方法和含有它们的药物组合物 | |
CN1035552C (zh) | 噻唑的支链烷氨基衍生物、它们的制备方法以及含有它们的药物组合物 | |
CN1032203C (zh) | 制备取代2-吡啶酮和吡啶-2-硫酮的方法 | |
CN1106811A (zh) | 哌啶和哌嗪衍生物 | |
CN87107875A (zh) | 四氢化萘衍生物 | |
CN1215724A (zh) | 新颖化合物 | |
CN1168709C (zh) | 作为基质金属蛋白酶抑制剂的β-磺酰基异羟肟酸的α-羟基、-氨基和卤代衍生物 | |
CN1009831B (zh) | 杂环氧代-2,3-二氮杂萘基乙酸的制备方法 | |
CN1304401A (zh) | calcilytic化合物 | |
CN1283196A (zh) | N-苯基酰胺和n-吡啶基酰胺、其制备方法和含有它们的药物组合物 | |
CN1067052A (zh) | 取代的二氨基苯邻二酰亚胺及其类似物 | |
CN1494543A (zh) | 取代的苯并呋喃-2-酰胺衍生物 | |
CN1032135C (zh) | 具有粘液调节和抗局部缺血性质的2,3-二氢-5-氧-4,6,7-三甲基苯并呋喃的2-(rs)-衍生物的制备方法 | |
CN1074904A (zh) | 苯并呋喃基-和噻吩基甲硫基-链烷羧酸衍生物 | |
CN1051354A (zh) | 取代环烷并[b]二氢吲哚-和-吲哚磺酰胺 | |
CN1286823C (zh) | 用于制备紫杉烷的噁唑烷中间体 | |
CN1033800A (zh) | 茚满衍生物和其制备方法 | |
CN1092409A (zh) | 用于治疗白三烯有关的疾病的化合物 | |
CN1153766C (zh) | 新的硝酮化合物,其制备方法以及含有它们的药物组合物 | |
CN1309655A (zh) | 可用于治疗脂血异常、动脉粥样硬化和糖尿病的环状化合物、药物组合物和制备方法 | |
CN1461301A (zh) | 苯并[b]噻吩衍生物及其制备方法 | |
CN1038582C (zh) | 对缺血性疾病有效的苯衍生物 | |
CN1266131C (zh) | 制备杂环茚类似物的方法 | |
CN1015893B (zh) | 1,3-二烷类制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned | ||
C20 | Patent right or utility model deemed to be abandoned or is abandoned |