CN1293059C - 新的羧酸衍生物,其制备和应用 - Google Patents
新的羧酸衍生物,其制备和应用 Download PDFInfo
- Publication number
- CN1293059C CN1293059C CNB2004100027833A CN200410002783A CN1293059C CN 1293059 C CN1293059 C CN 1293059C CN B2004100027833 A CNB2004100027833 A CN B2004100027833A CN 200410002783 A CN200410002783 A CN 200410002783A CN 1293059 C CN1293059 C CN 1293059C
- Authority
- CN
- China
- Prior art keywords
- phenyl
- methyl
- ome
- och
- alkyl
- 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 - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 239000002253 acid Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- -1 methoxyl group Chemical group 0.000 claims description 157
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 110
- 239000000243 solution Substances 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- 238000013016 damping Methods 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims 1
- 239000000084 colloidal system Substances 0.000 claims 1
- 239000008187 granular material Substances 0.000 claims 1
- 210000001989 nasopharynx Anatomy 0.000 claims 1
- 239000006072 paste Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 17
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 228
- 239000002585 base Substances 0.000 description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000001301 oxygen Substances 0.000 description 36
- 229910052760 oxygen Inorganic materials 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 27
- 125000003545 alkoxy group Chemical group 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 18
- 125000004093 cyano group Chemical group *C#N 0.000 description 18
- 229910052736 halogen Inorganic materials 0.000 description 18
- 150000002367 halogens Chemical class 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 17
- 125000005843 halogen group Chemical group 0.000 description 17
- 102000002045 Endothelin Human genes 0.000 description 16
- 108050009340 Endothelin Proteins 0.000 description 16
- 239000005864 Sulphur Substances 0.000 description 16
- 239000003513 alkali Substances 0.000 description 16
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000001624 naphthyl group Chemical group 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- 102100033902 Endothelin-1 Human genes 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 210000004204 blood vessel Anatomy 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 102000010180 Endothelin receptor Human genes 0.000 description 5
- 108050001739 Endothelin receptor Proteins 0.000 description 5
- 101800004490 Endothelin-1 Proteins 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000002308 endothelin receptor antagonist Substances 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000012447 hatching Effects 0.000 description 4
- 150000002924 oxiranes Chemical class 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- 235000001258 Cinchona calisaya Nutrition 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 206010042434 Sudden death Diseases 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000005119 centrifugation Methods 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
- 239000012141 concentrate Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 229940017219 methyl propionate Drugs 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 229960000948 quinine Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- WYRSGXAIHNMKOL-UHFFFAOYSA-N $l^{1}-sulfanylethane Chemical compound CC[S] WYRSGXAIHNMKOL-UHFFFAOYSA-N 0.000 description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- 229940035437 1,3-propanediol Drugs 0.000 description 2
- OMAFFHIGWTVZOH-UHFFFAOYSA-O 1-methyl-2h-tetrazol-1-ium Chemical compound C[N+]1=CN=NN1 OMAFFHIGWTVZOH-UHFFFAOYSA-O 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- OGRHLWFQNOLTFY-UHFFFAOYSA-N 2-methyl-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound CC1=NC=C2CCCC2=N1 OGRHLWFQNOLTFY-UHFFFAOYSA-N 0.000 description 2
- NKTDTMONXHODTI-UHFFFAOYSA-N 2-pentyne Chemical compound CCC#CC NKTDTMONXHODTI-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010062575 Muscle contracture Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 210000001638 cerebellum Anatomy 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 208000006111 contracture Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000000199 molecular distillation Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- PGMYKACGEOXYJE-UHFFFAOYSA-N pentyl acetate Chemical compound CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 125000006033 1,1-dimethyl-2-propenyl group Chemical group 0.000 description 1
- 125000006060 1,1-dimethyl-3-butenyl group Chemical group 0.000 description 1
- 125000004747 1,1-dimethylethoxycarbonyl group Chemical group CC(C)(OC(=O)*)C 0.000 description 1
- 125000004866 1,1-dimethylethylcarbonyl group Chemical group CC(C)(C(=O)*)C 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000006035 1,2-dimethyl-2-propenyl group Chemical group 0.000 description 1
- 125000006063 1,2-dimethyl-3-butenyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 1
- 125000006066 1,3-dimethyl-3-butenyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YCBVTHJPQCNICU-UHFFFAOYSA-N 1-(propan-2-yldisulfanyl)propane Chemical compound CCCSSC(C)C YCBVTHJPQCNICU-UHFFFAOYSA-N 0.000 description 1
- ZVSGZORIEHXCDY-UHFFFAOYSA-N 1-(tert-butyldisulfanyl)-2-methylpropane Chemical compound CC(C)CSSC(C)(C)C ZVSGZORIEHXCDY-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- VZAWCLCJGSBATP-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundecane Chemical compound C1CCCCCCCCCC1N1NCCCCCCCCC1 VZAWCLCJGSBATP-UHFFFAOYSA-N 0.000 description 1
- 125000006080 1-ethyl-1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006082 1-ethyl-2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006037 1-ethyl-2-propenyl group Chemical group 0.000 description 1
- 125000006075 1-ethyl-3-butenyl group Chemical group 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
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006030 1-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006055 1-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000004743 1-methylethoxycarbonyl group Chemical group CC(C)OC(=O)* 0.000 description 1
- 125000004677 1-methylethylcarbonyl group Chemical group CC(C)C(=O)* 0.000 description 1
- 125000004678 1-methylpropylcarbonyl group Chemical group CC(CC)C(=O)* 0.000 description 1
- RTCUCQWIICFPOD-UHFFFAOYSA-N 1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(C(N)C)=CC=CC2=C1 RTCUCQWIICFPOD-UHFFFAOYSA-N 0.000 description 1
- KHSYYLCXQKCYQX-UHFFFAOYSA-N 1-naphthalen-2-ylethanamine Chemical compound C1=CC=CC2=CC(C(N)C)=CC=C21 KHSYYLCXQKCYQX-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000006067 2,2-dimethyl-3-butenyl group Chemical group 0.000 description 1
- 125000006070 2,3-dimethyl-3-butenyl group Chemical group 0.000 description 1
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 1
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000006078 2-ethyl-3-butenyl group Chemical group 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006056 2-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- 125000006188 2-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(C([H])=C([H])C([H])=C1[H])C([H])([H])* 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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 description 1
- 125000006054 3-methyl-3-pentenyl group Chemical group 0.000 description 1
- 125000006057 3-methyl-4-pentenyl group Chemical group 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ITDVJJVNAASTRS-UHFFFAOYSA-N 4,6-dimethoxy-2-methylsulfonylpyrimidine Chemical compound COC1=CC(OC)=NC(S(C)(=O)=O)=N1 ITDVJJVNAASTRS-UHFFFAOYSA-N 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000002528 4-isopropyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006058 4-methyl-4-pentenyl group Chemical group 0.000 description 1
- SLMFWJQZLPEDDU-UHFFFAOYSA-N 4-methylpent-2-yne Chemical compound CC#CC(C)C SLMFWJQZLPEDDU-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MUAMNDBPYAHPCU-UHFFFAOYSA-N CCC(C)[S] Chemical compound CCC(C)[S] MUAMNDBPYAHPCU-UHFFFAOYSA-N 0.000 description 1
- WAUHABGEEBVFTF-UHFFFAOYSA-N CCCC[S] Chemical compound CCCC[S] WAUHABGEEBVFTF-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 241000218691 Cupressaceae Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 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 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 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 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 208000022901 Reynold syndrome Diseases 0.000 description 1
- 208000016717 Reynolds syndrome Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 241001482311 Trionychidae Species 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- VYEUORPDGJZDRP-UHFFFAOYSA-N [Cl].CS(O)(=O)=O Chemical compound [Cl].CS(O)(=O)=O VYEUORPDGJZDRP-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- SNGGKXQANZWQHM-UHFFFAOYSA-N azanide manganese(3+) Chemical compound N[Mn+]N SNGGKXQANZWQHM-UHFFFAOYSA-N 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000006251 butylcarbonyl group Chemical group 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229960003609 cathine Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- 238000001085 differential centrifugation Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000006202 diisopropylaminoethyl group Chemical group [H]C([H])([H])C([H])(N(C([H])([H])C([H])([H])*)C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- BVURNMLGDQYNAF-UHFFFAOYSA-N dimethyl(1-phenylethyl)amine Chemical compound CN(C)C(C)C1=CC=CC=C1 BVURNMLGDQYNAF-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006261 foam material Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- MELUCTCJOARQQG-UHFFFAOYSA-N hex-2-yne Chemical compound CCCC#CC MELUCTCJOARQQG-UHFFFAOYSA-N 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
- 150000002430 hydrocarbons Chemical class 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 1
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 1
- DZNKOAWEHDKBEP-UHFFFAOYSA-N methyl 2-[6-[bis(2-methoxy-2-oxoethyl)amino]-5-[2-[2-[bis(2-methoxy-2-oxoethyl)amino]-5-methylphenoxy]ethoxy]-1-benzofuran-2-yl]-1,3-oxazole-5-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C1=CC=C(C)C=C1OCCOC(C(=C1)N(CC(=O)OC)CC(=O)OC)=CC2=C1OC(C=1OC(=CN=1)C(=O)OC)=C2 DZNKOAWEHDKBEP-UHFFFAOYSA-N 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- VWCJVPZDHAXHPV-UHFFFAOYSA-N methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropanoate Chemical class C1CCCCC1C(OC)(C(O)C(=O)OC)C1CCCCC1 VWCJVPZDHAXHPV-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 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
- MYWUZJCMWCOHBA-UHFFFAOYSA-N n-methyl-1-phenylpropan-2-amine Chemical compound CNC(C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical group O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical compound CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 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
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000006187 phenyl benzyl group Chemical group 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane of uncertain configuration Natural products CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 description 1
- 229950003779 propiram Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 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
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/20—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with no nitrogen atoms directly attached to a ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/30—Only oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
- C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
描述了式I羧酸衍生物(其中R-R6,X,Y和Z具有说明书中陈述的含义)及其制备。该新化合物适于防治疾病。
Description
本发明涉及新的羧酸衍生物,其制备和应用。
内皮素是一种由21种氨基酸构成的肽,它由血管的内皮合成并释放出来。内皮素存在三种异构体,ET-1,ET-2和ET-3。在下文中“内皮素”或“ET”表示一种或所有内皮素异构体。内皮素是一种有效的血管收缩剂并对血管张力有很强的作用。已公知内皮素结合在其受体上引起这种血管收缩(自然(Nature)
332,411-415,1988;FEBS通讯(Letters),
231 440-444,1988和生化及生物物理研究公报(Biochem.Biophys-Res.Commun.),
154,868-875,1988)。
增高的或反常的内皮素释放在周围血管,肾血管和大脑血管引起持续的血管收缩,这种收缩可导致疾病。如在文献中报告的,对高血压,急性心肌梗死,肺血管高压,雷诺氏综合症,动脉粥样硬化和呼吸道痉挛的病人来说已发现增高的内皮素血浆水平(Japan J.Hypertension,
12,79(1989),J.Vascular Med.Biology 2,207(1990),J.Am.Med.Association 264,2868(1990))。
因此特定抑制内皮素结合在受体上的物质也应当拮抗上述不同的内皮素生理效果并因此是有价值的药物。
现已找到,一定的羧酸衍生物是内皮素受体的好的抑制剂。
本发明的主题是式I羧酸衍生物
式中R为一甲酰基,四唑基,氰基,-COOH或一对COOH可水解的基并其余的取代基具有下述含义:
R2为氢,羟基,NH2,NH(C1-C4-烷基),N(C1-C4-烷基)2,卤素,C1-C4-烷基,C1-C4卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基或C1-C4烷基硫;
X为氮或CR14,其中R14为氢或C1-5-烷基或CR14与CR3形成一个5元或6元亚烷基环或亚烯基环,该环可通过一个或二个C1-C4-烷基取代并式中一个亚甲基总可由氧,硫,-NH或-N(C1-C4-烷基)替代;
R3为氢,羟基,NH2,NH(C1-C4-烷基),N(C1-C4-烷基)2,卤素,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,-NH-O-C1-4-烷基,C1-C4-烷基硫或如上所述CR3与CR14连接成一个5元或6元环;
R4和R5(二者可相同或不同)为:
苯基或萘基,二者可通过一个或多个下述基取代:卤素,硝基,氰基,羟基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,苯氧基,C1-C4-烷基硫,氨基,C1-C4-烷基氨基或C1-C4-二烷基氨基;或
苯基或萘基,二者邻位固定的经一直接键,亚甲基,亚乙基或亚乙烯基,一个氧原子或硫原子或一个SO2-,NH-或N-烷基互相结合或是C3-C7-环烷基;
R6为氢,C1-C8-烷基,C3-C6-链烯基,C3-C6-炔基或C3-C8-环烷基,其中这些基总可一次或多次通过下述基取代:卤素,硝基,氰基,C1-C4-烷氧基,C3-C6-链烯基氧,C3-C6-炔基氧,C1-C4-烷基硫,C1-C4-卤代烷氧基,C1-C4-烷基羰基,C1-C4-烷氧基羰基,C3-C8-烷基羰基烷基,C1-C4-烷基氨基,二-C1-C4-烷基氨基,苯基或一次或多次,例如一次至三次通过卤素,硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基或C1-C4-烷基硫取代的苯基或苯氧基;
苯基或萘基,二者总可通过一个或多个下述基取代:卤素,硝基,氰基,羟基,氨基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,苯氧基,C1-C4-烷基硫,C1-C4-烷基氨基,C1-C4-二烷基氨基,二氧亚甲基或二氧亚乙基;
一含有一个至三个氮原子和/或一个硫原子或氧原子的5元或6元的杂芳烃化合物,该芳烃可载有1个至4个卤原子和/或1至2个下述的基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C1-C4-烷基硫,苯基,苯氧基或苯基羰基,其中苯基方面可载有1至5个卤原子和/或1至3个下述基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫;
附加条件是:若Z不是单键时,则R6只可为氢;
Y为硫或氧或一单键;
Z硫或氧或一单键。
该化合物和其制备的中间产物,例如IV和VI,可具有1个或多个不对称取代的碳原子。这样的化合物可作为纯的对映体或非对映体或作为其混合物存在。对映体纯化合物的应用优选是作为有效物质。
另外本发明的主题是上面提到的用于制备药剂,特别是制备内皮素受体抑制剂的羧酸衍生物的应用。
本发明的另一个主题是制备纯对映体形式的式IV化合物。二次苯基-取代的烯烃的对映选择环氧化是已知的(有机化学杂志(J.Orgchem)1994,
59,4378-4380)。现出乎预料的发现,在此体系中既使酯基也可以高光学纯度环氧化。
制备本发明化合物(其中Z是硫或氧)从环氧化物IV出发,这种环氧化物以通常已知的方式,例如已在J.March,高等有机化学,第二版,1983,862页和750页描叙过,由酮II或烯烃III获得:
制备通式VI的羧酸衍生物,方法是使通式IV的环氧化物(例如R=ROOR10)与通式V的醇或硫醇(式中R6和Z具有在权利要求1中提到的含义)进行反应。
对此将通式IV化合物与式V化合物以摩尔比约从1∶1至1∶7,优选1至3摩尔当量加热到温度从50至200℃,优选80至150℃。
反应也可在一种稀释剂存在下进行。为此目的可使用所有对使用的反应物为惰性的溶剂。
这样的溶剂或稀释剂的例子是水,脂肪烃,脂环烃和芳烃,该烃必要时可氯化,例如己烷,环己烷,石油醚,粗汽油,苯,甲苯,二甲苯,二氯甲烷,氯仿,四氯化碳,二氯乙烷和三氯乙烯,醚,例如二异丙基醚,二丁基醚,甲基-特-丁基-醚-1.2-环氧丙烷,二恶烷和四氢呋喃,酮,例如丙酮,甲乙酮,甲异丙酮和甲异丁酮,烷基氰,例如乙腈和丙腈,醇,例如甲醇,乙醇,异丙醇,丁醇和乙二醇,酯,例如乙酸乙酯和乙酸戊酯,酰胺,例如二甲基甲酰胺,二甲基乙酰胺和N-甲基吡咯烷酮,烷基亚砜和砜,例如二甲基亚砜和环丁砜,碱,例如吡啶,环状的脲如1,3-二甲基咪唑烷-2-酮和1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮。
同时反应优选在0℃至溶剂或溶剂混合物的沸点之间的温度范围进行。
反应催化剂的存在是有益的。在这种情况作为催化剂可考虑强有机酸和无机酸以及路易斯酸。另外在此的例子是硫酸,盐酸,三氟乙酸,对-甲苯磺酸,三氟化硼-醚合物和钛(IV)-醇化物。
式VI化合物(其中R4和R5为环烷基)也可以下述方法制备,使式VI化合物经受核加氢,其中R4和R5为苯基,萘基或如上所描述的取代的苯基或萘基。
式VI化合物可得到纯对映体的形式,方法是从式IV纯对映体化合物出发并使其以所描叙的方式与式V化合物转化。
另外可得到式VI纯对映体化合物,方法是用式VI的消旋体的或非对映体的化合物与适宜的下述纯对映体的碱进行一种常规的消旋物分解,纯对映体的碱是,例如香木鳖碱,马钱子碱,奎宁,奎尼丁,脱甲氧基奎宁定,脱甲氧基奎宁碱,育享宾,吗啡,脱氢枞胺,麻黄碱(-),(+),脱氧麻黄碱(+),(-),苏-2-氨基-1-(对硝基苯基)-1,3-丙烷二醇(+),(-),苏-2-(N,N-二甲基氨基)-1-(对硝基苯基)-1,3-丙烷二醇(+),(-),苏-2-氨基-1-苯基-1,3-丙烷二醇(+),(-),α-甲基-苄基胺(+),(-),α-(1-萘基)乙基胺(+),(-),α-(2-萘基)乙基胺,氨基甲基蒎烷,N,N-二甲基-1-苯基乙基胺,N-甲基-1-苯基乙基胺,4-硝基苯基乙基胺,假麻黄碱,降麻黄碱,降假麻黄碱,氨基酸衍生物,肽衍生物。
本发明化合物(其中Y为氧并余下的取代基具有通式I已述过的含义)例如可这样制备,使通式VI羧酸衍生物(其中取代基具有已陈述的含义)与通式VII化合物进行反应,
式中R15为卤素或R16-SO2-,其中R16是C1-C4-烷基,C1-C4-卤代烷基或苯基。反应优选是在一种前面列举的惰性稀释剂中在添加适宜碱的情况下(也就是说一种引起中间产物VI脱质子的碱)在从室温直至溶剂沸点的温度范围内进行。
式VII化合物是已知的,部分地是可购得的或者按通常已知的方式可制备。
碱金属氢化物或碱土金属氢化物如氢化钠,氢化钾或氢化钙,碳酸盐如碱金属碳酸盐,例如碳酸钠或碳酸钾,碱金属氢氧化物或碱土金属氢氧化物如氢氧化钠或氢氧化钾,金属有机化合物如丁基锂或碱金属氨化物如二异丙基氨化锂可用作碱。
本发明化合物(其中Y为硫并其余的取代基具有通式I陈述的含义)例如可这样制备:使通式VIII羧酸衍生物(该羧酸衍生物以已知的方式由通式VI化合物可得到并其中取代基具有前面已陈述的含义)与通式IX化合物(其中R2,R3和X具有通式I已陈述的含义)进行反应。
反应优选在一上述的惰性稀释剂中在添加一种适宜碱的情况下,也就是说一种引起中间产物IX脱质子化的碱,在从室温直至溶剂沸点的温度范围内进行。
除了上面提到的碱还有有机碱如三乙胺,吡啶,咪唑或二氮双环十一烷可用作碱。
制备式VIa羧酸衍生物(在式VI中Z=直接键),方法是使式IV环氧化物与式XI铜酸盐反应:
铜酸盐可按在四面体通讯(Tetrahedron Letters)
23,3755(1982)所描述的制备。
式I化合物也可通过下述方法制备:从相应的羧酸,也就是说式I化合物(其中R为COOH)出发并首先以通常的方式使这种羧酸转化成一种活化的形式如酰卤,酐或咪唑烷并接着使这种化合物与一相应的羟基化合物HOR10进行转化。这种转化可在通常的溶剂中进行并常常采用添加一种碱,在这种情况下考虑上面提到的碱。这二种步骤例如也可通过下述方法简化:在脱水剂如碳化二亚胺存在下使羧酸对羟基化合物作用。
此外式I化合物也可通过下述方法制备:从相应的羧酸的盐发出,也就是说从式I化合物,其中R为COR1和R1为OM,同时M可以是一种碱金属阳离子或一种碱土金属阳离子的等同物。这种盐可与式R1-A的许多化合物进行反应,其中A为一通常的离核离去基,例如卤素如氯,溴,碘或必要时通过卤素,烷基或卤代烷基取代的芳基磺酰或烷基磺酰例如甲苯磺酰和甲基磺酰或一种其他的等同离去基。带有一可起反应的取代基A的式R1-A化合物是已知的或用普通的专业知识容易获得。这种转化可在通常的溶剂中进行并在添加碱的情况下进行是有益的,在这种情况考虑上面提到的碱。
在式I中基R是宽变化的,例如R为基
式中R1具有下述含义:
a)氢;
b)丁二酰亚胺氧基;
c)一个经氮原子连接的5-元杂芳香化物如吡咯基,吡唑基,咪唑基和三唑基,这种基可载有一至二个卤原子,特别是氟和氯和/或一至二个下面的基:
C1-C4-烷基如甲基,乙基,1-丙基,2-丙基,2-甲基-2-丙基,2-甲基-1-丙基,1-丁基,2-丁基;
C1-C4-卤代烷基,特别是C1-C2-卤代烷基例如氟甲基,二氟甲基,三氟甲基,氯二氟甲基,二氯氟甲基,三氯甲基,1-氟乙基,2-氟乙基,2,2-二氟乙基,2,2,2-三氟乙基,2-氯-2,2-二氟乙基,2,2-二氯-2-氟乙基,2,2,2-三氯乙基和五氟乙基;
C1-C4-卤代烷氧基,特别是C1-C2-卤代烷氧基如二氟甲氧基,三氟甲氧基,氯二氟甲氧基,1-氟乙氧基,2-氟乙氧基,2,2-二氟乙氧基,1,1,2,2-四氟乙氧基,2,2,2-三氟乙氧基,2-氯-1,1,2-三氟乙氧基和五氟乙氧基,特别是三氟甲氧基;
C1-C4-烷氧基如甲氧基,乙氧基,丙氧基,1-甲基乙氧基,丁氧基,1-甲基丙氧基,2-甲基丙氧基,1,1-二甲基乙氧基,特别是甲氧基,乙氧基,1-甲基乙氧基;
C1-C4-烷基硫如甲基硫,乙基硫,丙基硫,1-甲基乙基硫,丁基硫,1-甲基丙基硫,2-甲基-丙基硫,1,1-二甲基乙基硫,特别是甲基硫和乙基硫;
d)另外R1是基
式中m为0或1并R7和R8可以是相同或不同,具有下述含义:
氢
C1-C8-烷基,特别是如上面提到的C1-C4-烷基;
C3-C6-链烯基如2-丙烯基,2-丁烯基,3-丁烯基,1-甲基-2-丙烯基,2-甲基-2-丙烯基,2-戊烯基,3-戊烯基,4-戊烯基,1-甲基-2-丁烯基,2-甲基-2-丁烯基,3-甲基-2-丁烯基,1-甲基-3-丁烯基,2-甲基-3-丁烯基,3-甲基-3-丁烯基,1,1-二甲基-2-丙烯基,1,2-二甲基-2-丙烯基,1-乙基-2-丙烯基,2-己烯基,3-己烯基,4-己烯基,5-己烯基,1-甲基-2-戊烯基,2-甲基-2-戊烯基,3-甲基-2-戊烯基,4-甲基-2-戊烯基,3-甲基-3-戊烯基、4-甲基-3-戊烯基、1-甲基-4-戊烯基,2-甲基-4-戊烯基,3-甲基-4-戊烯基,4-甲基-4-戊烯基,1,1-二甲基-2-丁烯基,1,1-二甲基-3-丁烯基,1,2-二甲基-2-丁烯基,1,2-二甲基-3-丁烯基,1,3-二甲基-2-丁烯基,1,3-二甲基-3-丁烯基,2,2-二甲基-3-丁烯基,2,3-二甲基-2-丁烯基,2,3-二甲基-3-丁烯基,1-乙基-2-丁烯基,1-乙基-3-丁烯基,2-乙基-2-丁烯基,2-乙基-3-丁烯基,1,1,2-三甲基-2-丙烯基,1-乙基-1-甲基-2-丙烯基和1-乙基-2-甲基-2-丙烯基,特别是2-丙烯基,2-丁烯基,3-甲基-2-丁烯基和3-甲基-2-戊烯基;
C3-C6-炔基如2-丙炔基,2-丁炔基,3-丁炔基,1-甲基-2-丙炔基,2-戊炔基,3-戊炔基,4-戊炔基,1-甲基-3-丁炔基,2-甲基-3-丁炔基,1-甲基-2-丁炔基,1,1-二甲基-2-丙炔基,1-乙基-2-丙炔基,2-己炔基,3-己炔基,4-己炔基,5-己炔基,1-甲基-2-戊炔基,1-甲基-3-戊炔基,1-甲基-4-戊炔基,2-甲基-3-戊炔基,2-甲基-4-戊炔基,3-甲基-4-戊炔基,4-甲基-2-戊炔基,1,1-二甲基-2-丁炔基,1,1-二甲基-3-丁炔基,1,2-二甲基-3-丁炔基,2,2-二甲基-3-丁炔基,1-乙基-2-丁炔基,1-乙基-3-丁炔基,2-乙基-3-丁炔基和1-乙基-1-甲基-2-丙炔基,优选2-丙炔基,2-丁炔基,1-甲基-2-丙炔基和1-甲基-2-丁炔基,特别是2-丙炔基
C3-C8-环烷基,如环丙基,环丁基,环戊基,环己基,环庚基,环辛基,其中这些烷基,环烷基,链烯基,炔基各可载有1至5个卤原子,特别是氟或氯和/或1至2个下述的基:
C1-C4-烷基,C1-C4-烷氧基,C1-C4-烷基硫,C1-C4-卤代烷氧基如前面提到的,C3-C6-链烯基氧,C3-C6-链烯基硫,C3-C6-炔基氧、C3-C6-炔基硫,其中在这些基中存在的链烯基部分和炔基部分优选相应于上面提到的含义;
C1-C4-烷基羰基特别如甲基羰基,乙基羰基,丙基羰基,1-甲基乙基羰基,丁基羰基,1-甲基丙基羰基,2-甲基丙基羰基,1,1-二甲基乙基羰基;
C1-C4-烷氧基羰基如甲氧基羰基,乙氧基羰基,丙氧基羰基,1-甲基乙氧基羰基,丁氧基羰基,1-甲基丙氧基羰基,2-甲基丙氧基羰基,1,1-二甲基乙氧基羰基;
C3-C6-链烯基羰基,C3-C6-炔基羰基,C3-C6-链烯基氧羰基和C3-C6-炔基氧羰基,其中链烯基或炔基优选如前详举的定义;
苯基,必要时一次或多次,例如一至三次通过卤素,硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基或C1-C4-烷基硫取代的,例如2-氟苯基,3-氯苯基,4-溴苯基,2-甲基苯基,3-硝基苯基,4-氰基苯基,2-三氟甲基苯基,3-甲氧基苯基,4-三氟乙氧基苯基,2-甲基硫苯基,2,4-二氯苯基,2-甲氧基-3-甲基苯基,2,4-甲氧基苯基,2-硝基-5-氰基苯基,2,6-二氟苯基;
二-C1-C4-烷基氨基特别如二甲基氨基,二丙基氨基,N-丙基-N-甲基氨基,N-丙基-N-乙基氨基,二异丙基氨基,N-异丙基-N-甲基氨基,N-异丙基-N-乙基氨基,N-异丙基-N-丙基氨基;
另外R7和R8是苯基,该基可通过一个或多个例如1至3个下述基取代:卤素,硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基或C1-C4-烷基硫,特别如上列举的;
或R7和R8共同形成一个成一环封闭的,选择取代的,例如通过C1-C4-烷基取代的C4-C7-亚烷基链,该链可含有一个选自氧,硫或氮的杂原子,如-(CH2)4-,-(CH2)5-,-(CH2)6-,-(CH2)7-,-(CH2)2-O-(CH2)2-,-CH2-S-(CH2)3-,-(CH2)2-O-(CH2)3-,-NH-(CH2)3-,-CH2-NH-(CH2)2-,-CH2-CH=CH-CH2-,-CH=CH-(CH2)3-;
e)另外R1是基
式中k为0,1和2,p为1,2,3和4并R9为C1-C4-烷基,C1-C4-卤代烷基,C3-C6-链烯基,C3-C6-炔基或必要时取代的苯基,特别是如上提到的。
f)另外R1是一基OR10,式中R10为:
氢,碱金属阳离子如锂,钠,钾或碱土金属阳离子如钙,镁,钡或一种适合环境的有机铵离子如特-C1-C4-烷基铵或铵离子;
C3-C8-环烷基如前面提到的,该环烷基可载有1至3个C1-C4-烷基;
C1-C8-烷基特别如甲基,乙基,丙基,1-甲基-乙基,丁基,1-甲基丙基,2-甲基丙基,1,1-二甲基乙基,戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,1,2-二甲基丙基,1,1-二甲基丙基,2,2-二甲基丙基,1-乙基丙基,己基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,2-二甲基丁基,1,3-二甲基丁基,2,3-二甲基丁基,1,1-二甲基丁基,2,2-二甲基丁基,3,3-二甲基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基,1-乙基丁基,2-乙基丁基,1-乙基-2-甲基丙基,这样的基可载有1至5个卤原子,特别是氟或氯和/或一个下述基:
C1-C4-烷氧基,C1-C4-烷基硫,氰基,C1-C4-烷基羰基,C3-C8-环烷基,C1-C4-烷氧基羰基,苯基,苯氧基或苯基羰基,其中芳基方面各可载有1至5个卤原子和/或1至3个下述的基:硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫,特别如上面提到的;
一个C1-C8-烷基如前面提到的,这样的基可载有1至5个卤原子,特别是氟和/或氯并载有一个下述基:一个含有1至3个氮原子的5元杂芳香化物或一个含有一个氮原子和一个氧原子或硫原子的5元杂芳香化物,它可载有1至4个卤原子和/或1至2个下述的基;
硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,苯基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫。特别提到的是:1-吡唑基,3-甲基-1-吡唑基,4-甲基-1-吡唑基,3,5-二甲基-1-吡唑基,3-苯基-1-吡唑基,4-苯基-1-吡唑基,4-氯-1-吡唑基,4-溴-1-吡唑基,1-咪唑基,1-苯并咪唑基,1,2,4-三唑-1-基,3-甲基-1,2,4-三唑-1-基,5-甲基-1,2,4-三唑-1-基,1-苯并三唑基,3-异丙基异唑-5-基,3-甲基异唑-5-基,唑-2-基,噻唑-2-基,咪唑-2-基,3-乙基异唑-5-基,3-苯基-异唑-5-基,3-特-丁基异唑-5-基;
一个C2-C6-烷基,它在2-位载有一个下列基:C1-C4-烷氧基亚氨基,C3-C6-炔基氧亚氨基,C3-C6-卤代链烯基氧亚氨基或苄氧基亚氨基;
一个C3-C6-链烯基或一个C3-C6-炔基,其中这些基可载有1至5个卤原子;
另外R10是一苯基,它可载有1至5个卤原子和/或1至3个下述基:硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫,特别是如上面提到的;
一个含有1至3个氮原子的经一个氮原子连接的5-元杂芳香化物,它可载有1至2个卤原子和/或1至2个下述基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,苯基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫。特别提到的是:1-吡唑基,3-甲基-1-吡唑基,4-甲基-1-吡唑基,3,5-二甲基-1-吡唑基,3-苯基-1-吡唑基,4-苯基-1-吡唑基,4-氯-1-吡唑基,4-溴-1-吡唑基,1-咪唑基,1-苯并咪唑基,1,2,4-三唑-1-基,3-甲基-1,2,4-三唑-1-基,5-甲基-1,2,4-三唑-1-基,1-苯并三唑基,3,4-二氯-咪唑-1-基;
另外R10是一基
式中R11和R12(可以是相同或不同)为:
C1-C8-烷基,C3-C6-链烯基,C3-C6-炔基,C3-C8-环烷基,其中这些基可载有一个C1-C4-烷氧基,C1-C4-烷基硫和/或一个必要时取代的苯基,特别是如上面提到的;
苯基,它可以是通过一个或多个,例如1至3个下述基取代:卤素,硝基,氰基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基或C1-C4-烷基硫,其中这些基特别适应上面提到的;
或R11和R12共同形成一个C3-C12-亚烷基链,它可载有1至3个C1-C4-烷基并可含有氧,硫和氮中的一个杂原子,特别是如在R7和R8提到的。
g)另外R1是一基
式中R13为:
C1-C4-烷基,C3-C6-链烯基,C3-C6-炔基,C3-C8-环烷基,特别是如前面提到的,其中这些基可载有一个C1-C4-烷氧基,C1-C4-烷基硫和/或一个如上提到的苯基;
苯基,必要时是取代的,特别是如前面提到的。
h)R1是一基
式中R13具有上面提到的含义。
R另外可以是:四唑或腈。
鉴于生物活性通式I羧酸衍生物是(不仅作为纯的对映体或纯的非对映体而且作为其混合物)优选的,其中取代基具有下述含义:
R2为氢,羟基,N(C1-C4-烷基)2,在R1时详细提到的C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C1-C4-烷基硫基和卤原子,特别是氯,甲基,甲氧基,乙氧基,二氟甲氧基,三氟甲氧基;
X为氮或CR14,其中
R14为氢或烷基,或CR14与CR3一起形成一个4元至5元的亚烷基环或亚烯基环,其中每次可通过氧或硫替代一个亚甲基如-CH2-CH2-O-,-CH=CH-O-,-CH2-CH2-CH2-O-,-CH=CH-CH2O-,特别是氢,-CH2-CH2-O-,-CH(CH3)-CH(CH3)-O-,-C(CH3)=C(CH3)-O-,-CH=C(CH3)-O-或-C(CH3)=C(CH3)-S;
R3为在R1时提到的氢,羟基,N(C1-C4-烷基)2,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷基,C1-C4-烷基硫基和卤原子,特别是氯,甲基,甲氧基,乙氧基,二氟甲氧基,三氟甲氧基或与R14如上面提到的一样连接成一个5元或6元的环;
R4和R5为苯基或萘基,它可通过一个或多个例如1至3个下面的基取代:卤素,硝基,氰基,羟基,巯基,氨基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C1-C4-烷基硫,C1-C4-烷基氨基,二-C1-C4-烷基氨基,C1-C4-烷基羰基,C1-C4-烷氧基羰基;
苯基或萘基,它邻位固定的经一直接键,亚甲基,亚乙基或亚乙烯基,氧原子或硫原子或-SO2-,NH-或N-烷基互相连结,或C3-C7-环烷基;
R6为C1-C8-烷基,C3-C6-链烯基,C3-C6-炔基或C3-C8-环烷基特别是如上所提到的,其中这些基总可以一次或多次通过下述基取代:卤素,羟基,硝基,氰基,C1-C4-烷氧基,C3-C6-链烯基氧,C3-C6-炔基氧,C1-C4-烷基硫,C1-C4-卤代烷氧基,C1-C4-烷基羰基,羟基羰基,C1-C4-烷氧基羰基,C1-C4-烷基氨基,二-C1-C4-烷基氨基或必要时取代的苯基或苯氧基,特别是如前面提到;
苯基或萘基,它可通过一个或多个下面的基取代:卤素,硝基,氰基,羟基,氨基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,苯氧基,C1-C4-烷基硫,C1-C4-烷基氨基或C1-C4-二烷基氨基,特别是如在R7和R8时提到的;
一含有1至3个氮原子和/或一个硫原子或氧原子的5元或6元的杂芳香化物,它可载有1至4个卤原子和/或1至2个下述的基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,C1-C4-烷基硫,苯基,苯氧基或苯基羰基,其中苯基方面可载有1至5个卤原子和/或1至3个下述的基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基和/或C1-C4-烷基硫。特别是如在R4时提到的;
Y为硫,氧或一单键;
Z为硫,氧,-SO-,SO2-或一单键。
特别优选的式I化合物(不仅作为纯的对映体或纯的非对映体或作为其混合物)是其取代基具有下述含义:
R2为C1-C4-烷基,C1-C4-烷氧基,
X为氮或CR14,其中
R14为氢或烷基,或CR14与CR3一起形成一个4元至5元的亚烷基环或亚烯基环例如-CH2-CH2-CH2-,-CH=CH-CH2-,其中一个亚甲基总可通过氧或硫替代如-CH2-CH2-O-,-CH=CH-O-,-CH2-CH2-CH2-O-,-CH=CH-CH2O-,特别是氢,-CH2-CH2-O,-CH(CH3)-CH(CH3)-O-,-C(CH3)=C(CH3)-O-,-CH=C(CH3)-O-或-C(CH3)=C(CH3)-S;
R3为在R1时提到的C1-C4-烷基,C1-C4-烷氧基,C1-C4-烷基硫基或与R14如上提到的连接成一个5元或6元环;
R4和R5是苯基(相同或不同),它可通过1个或多个,例如1至3个下述的基取代:卤素,硝基,羟基,C1-C4-烷基,C1-C4-烷氧基,C1-C4-烷基硫或
R4和R5是苯基,它在邻位固定的经一直接键,亚甲基,亚乙基或亚乙烯基,氧原子或硫原子或-SO2-,NH-或N-烷基互相连结;或
R4和R5是C3-C7-环烷基;
R6为C1-C8-烷基,C3-C6-链烯基或C3-C8-环烷基,其中这些基各可一次或多次通过下述基取代:卤素,羟基,硝基,氰基,C1-C4-烷氧基,C3-C6-链烯基氧,C1-C4-烷基硫;
苯基或萘基,它可通过一个或多个下述基取代:卤素,硝基,氰基,羟基,氨基,C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-卤代烷氧基,苯氧基,C1-C4-烷基硫,C1-C4-烷基氨基或C1-C4-二烷基氨基;
一含有一个氮原子和/或一个硫原子或氧原子的5元或6元的杂芳香化物,它可载有1至4个卤原子和/或1至2个下述基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基,C1-C4-烷基硫,苯基,苯氧基或苯基羰基,其中苯基方面可载有1至5个卤原子和/或1至3个下述基:C1-C4-烷基,C1-C4-卤代烷基,C1-C4-烷氧基和/或C1-C4-烷基硫;
Y为硫,氧或一单键;
Z为硫,氧,-SO-,-SO2-或一单键。
本发明化合物提供一种新的在治疗学上的可能性用于治疗高血压,肺血管高压,心肌梗死,心绞痛,急性肾衰竭,肾功能不全,大脑血管痉挛,脑缺血,蛛网膜下腔出血,偏头痛,哮喘,动脉粥样硬化,内毒素性休克,内毒素性引起的器官衰竭,血管内凝血,血管成形术后的再狭窄,良性前列腺肥大,缺血的和由中毒引起的肾衰竭或高血压。
化合物好的效果可显示在下述试验中:
受体结合研究
为结合研究使用了克隆的人的表述ETA-受体的CHO细胞和与ETA-受体相比具有>60%ETB受体的豚鼠小脑膜。
膜制备
使表达ETA-受体的CHO-细胞在具有10%胎牛血清、1%谷氨酰胺、100E/ml盘尼西林和0.2链霉素(Gibco BRL,Gaithersburg,MD,USA)的F12-培养基中进行繁殖。48小时后用PBS洗涤细胞并用0.05%含胰蛋白酶的PBS孵化5分钟。此后用F12-培养基使中性化并通过离心分离在300×g时收集细胞。为溶解细胞短暂地用溶解缓冲液(5mM三-HCl,pH7.4,具有10%甘油)洗涤粒状物并接着在4℃在一浓度为107-细胞/ml溶解缓冲液中孵化30分钟。在20,000×g时使膜进行离心分离10分钟并使粒状物贮存于液氮中。
使豚鼠小脑在Potter-Elvejhem-匀化器中进行匀化并在1.000×g时通过微分离心分离10分钟并在20,000×g时通过重复的离心分离上清液10分钟取得豚鼠小脑。
结合试验
为ETA-和ETB-受体结合试验以一浓度为50μg蛋白质每试验液使膜悬浮在孵化缓冲液(50mM三-HCl,pH7.4,具有5mM MnCl2,40μg/ml杆菌肽和0.2%BSA)中并在25℃用25pm〔125J〕-ET1(ETA-受体试验)或25pm〔125J〕-RZ3(ETB-受体试验)在存在或不存在试验物质的情况下进行孵化。用10-7M ET1测定了非特定的结合。30分钟后经GF/B玻璃纤维过滤器(Whatman,England)通过过滤在施卡特隆-细胞收集器(Skatron,Lier,Norwegen)分离游离的和已结合的放射配位体并用冰冷的三-HCl-缓冲液(pH7.4,具有0.2%BSA)洗涤过滤器。在过滤器上收集的放射活性用一柏卡2200CA液体闪烁计数器进行计量。
为寻找内皮素-受体(亚型A)-拮抗剂在试管内试验体系中的功能
这种试验体系是一种功能性的,以细胞为基础的内皮素受体试验。当用内皮素1(ET1)刺激细胞时,一定的细胞显示细胞内的钙浓度上升。这种升高在完整的细胞中可测到(细胞载有钙-敏感的染料)。
由老鼠分离出的1-纤维细胞(其中证实了一种内生的A-亚型的内皮素受体),使如下述情况载以荧光染料富乐2-安(Fura 2-an):在胰蛋白酶化后使细胞悬浮在缓冲液A(120mM NaCl,5mM KCl,1.5mM MgCl2,1mM CaCl2,25mM HEPES,10mM葡萄糖,pH7.4)中直至密度为2×106/ml并在30分钟内在37℃在黑暗中用富乐2-阿姆(Fura 2-am)(2μm),普鲁兰尼克F-127(0.04%)和二甲基亚砜(0.2%)孵化。此后用缓冲液A洗涤细胞二次并重新悬浮至2×106/ml。
在30℃连续地记录在Ex/Em 380/510时2×105细胞/ml的荧光信号。试验物质和孵化3分钟后的ET1皆属此类细胞,对荧光最大的改变进行了测定。使事先不添加试验物质的细胞对ET1的反应用作对比物并使等于100%。
ET-结抗剂在体内的试验
雄性250-300g重的SD-鼠用阿姆巴比妥麻醉,进行人工呼吸,切断速走神经并去掉脊髓。颈动脉和颈静脉插入导管。
在监控中静脉内输入1μg/kg ET1导致明显的血压升高,这种升高的血压持续经过一较长的时间。
试验动物在输入ET1前5分钟轮流注射试验化合物(1mg/kg)。为测定ET-结抗剂的性能将试验动物的血压升高与对比动物的进行比较。
引起老鼠“突然死亡”的内皮素-1
试验原则在于通过用内皮素受体拮抗剂的预处理抑制由同内皮素引起的老鼠心脏突然死亡,这种突然死亡很可能是由心脏冠状血管变窄引起的。以体积为5ml/kg体重在静脉注射10hmol/kg内皮素后在几分钟内动物死亡。
每次对一小动物群测试内皮素-1的致死量。若静脉注射试验物质,则大多在此后5分钟进行对照群的致死的内皮素-1注射。在其他的给药方法预计时间延长了,必要时直至数小时。
记录存活率并测出保护24小时或更长时间50%的动物不遭受内皮素心脏死亡的有效剂量。
内皮素-受体拮抗剂的功能性血管试验
在兔的主动脉段上在施以2g预加应力和张弛时间1小时后在克雷伯氏-享塞勒特-溶液中在37℃和pH-值在7.3和7.4之间首先引发K+-挛缩。洗涤后制出一内皮素-剂量曲线直至最大值。
可能的内皮素-拮抗剂在内皮素-剂量曲线开始之前15分钟向相同容器的其他制剂用药。内皮素的效果以K+-挛缩的%计算,在有效的内皮素-拮抗剂情况发生内皮素-剂量曲线的血象右移。
本发明化合物可以通常的方式口服或肠胃外(皮下、静脉内、肌肉内,腹膜内)给药,给药也可用蒸汽或喷雾通过鼻-咽空间进行。
剂量与病人的年龄,身体状态和体重及用药方法有关。通常每日有效物剂量在0.5和50mg/kg体重之间(口服)和约在0.1和10mg/kg体重之间(肠胃外)。
新化合物可以常用的按处方配成的给药形式固体或液体使用:例如为片,包膜片,胶囊,粉,粒状物,糖衣药丸,栓剂,溶液,软膏,油膏或喷雾。这些药是以通常方法制备的。在这当中有效物质可与通常的按处方配成的辅剂如片粘结剂、填料、防腐剂、片分裂剂、流动调整剂、软化剂、润湿剂、分散剂、乳化剂、溶剂、延缓剂、抗氧化剂和/或驱动气体进行加工(Vgl.H.Sucker et al.:制药工艺(PharmazeutischeTechnologie),Thieme-Verlag,Stuttgart,1991)。这样得到的给药形式通常含有有效物质量为0.1至90重量-%。
合成实施例
实施例1
2-羟基-3-甲氧基-3,3-二苯基丙酸甲酯
使5g(19.6mmol)3,3-二苯基-2,3-环氧丙酸甲酯溶入50ml干甲醇并在0℃加入0.1ml三氟化硼醚合物。在0℃搅拌2小时并在室温继续搅拌12小时,蒸馏出溶剂,残渣溶入醋酸乙酯,用碳酸氢钠溶液和水洗涤并经硫酸镁干燥。蒸馏出溶剂后剩余5.5g(88%)一种淡黄色油。
实施例2
2-羟基-3-苯氧基-3,3-二苯基丙酸甲酯
使5g(19.6mmol)3,3-二苯基-2,3-环氧丙酸甲酯和5.6g(60mmol)酚一起在100℃加热6小时。在高真空蒸馏出过剩酚和用己烷/醋酸乙酯混合物在硅胶上色谱纯化残渣后得4.9g(77%)一种淡黄色油。
实施例3
2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基丙酸甲酯
使2.86g(10mmol)2-羟基-3-甲氧基-3,3-二苯基-丙酸甲酯溶入40ml二甲基甲酰胺中并加入0.3g(12mmol)氢化钠。搅拌1小时并接着添加2.2g(10mmol)4,6-二甲氧基-2-甲基磺酰嘧啶。在室温搅拌24小时后小心用10ml水水解,用醋酸调pH-值为5并在高真空蒸馏出溶剂,残渣溶入100ml醋酸乙酯中,用水洗涤,经硫酸镁干燥并蒸馏出溶剂。残渣掺入10ml醚并吸出产生的沉淀。干燥后剩下3.48g(82%)一种白色粉末。
熔点:81℃
实施例4
2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基-丙酸
2.12g(5mmol)2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基-丙酸甲酯溶入50ml二烷中,掺入10ml1N的KOH溶液并在100℃搅拌3小时。用300ml水稀释溶液并用醋酸乙酯提取去掉未转化的酯。接着用稀盐酸调水相pH为1-2并用醋酸乙酯提取。经硫酸镁干燥并蒸馏出溶剂后给残渣掺入醚/己烷混合物并吸出生成的沉淀。干燥后剩下1.85g(90%)一种白色粉末。
熔点:167℃
实施例5
2-(4,6-二甲氧基-嘧啶-2-基氧)3-甲氧基-3,3-二苯基-丙酸钠
1.68g(4mmol)2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基-丙酸溶入4ml 1N的NaOH和100ml水中,冷冻干燥溶液并定量地得到加入羧酸的钠盐。
实施例6
10g(34.9mmol)2-羟基-3-甲氧基-3,3-二苯基丙酸甲酯溶入各50ml甲醇和冰醋酸中,掺入在二烷中的1ml RuO(OH)2并在100巴和100℃在高压釜中加H2氢化30小时。滤出催化剂,浓缩溶液,掺入醚,用NaCl溶液洗涤,干燥有机相并浓缩。得10.1g 3,3-二环己基-2-羟基-3-甲氧基丙酸甲酯,为油状物。
实施例7
2-〔(4,6-二甲氧基-嘧啶-2-基)硫〕-3-甲氧基-3,3-二苯基丙酸甲酯
7.16g(25mmol)2-羟基-3-甲氧基-3,3-二苯基-丙酸甲酯溶入50ml二氯甲烷中,添加3g(30mmol)三乙胺并在搅拌情况下滴入3.2g(28mmol)甲磺酸氯。在室温搅拌2小时,用水洗涤,经硫酸镁干燥并在真空浓缩。使残渣溶入二甲基甲酰胺中并在0℃滴到一悬浮液中,该悬浮液组成为12.9g(75mmol)4,6-二甲氧基-嘧啶-2-硫醇和8.4g(100mmol)碳酸氢钠在100ml二甲基甲酰胺。在室温搅拌2小时并继续在60℃搅拌2小时后倒入1升冰水中并吸出生成的沉淀、干燥后剩下3.19g(29%)一种白色粉末。
实施例8
2-羟基-3,3-二苯基-丁酸甲酯
1.5g(5.9mmol)3,3-二苯基-2,3-环氧丙酸甲酯溶入10ml干醚中,滴加到一冷却至-78℃的铜酸盐溶液中,其由635mg(7mmol)铜-I-氰化物(溶入10ml干醚中)和8.14mg(13mmol)1.6当量的甲基锂溶液构成。在-78℃搅拌1小时并接着加热溶液至室温。然后用100ml醚和100ml水稀释,醚相用稀释的柠檬酸和用碳酸氢钠溶液洗涤并经硫酸镁干燥,粗产物在硅胶上用环己烷/醋酸乙酯混合物进行色谱纯化,得250mg(16%)一种浅黄色油。
实施例9
2-羟基-3-甲氧基-3,3-二苯基丙酸
91.11g(0.5mol)苯酚酮和45.92g(0.85mol)甲基化钠在室温悬浮入150ml甲基-特-丁基醚(MTB)中。在冷却至-10℃后添加92.24g(0.85mol)氯乙酸甲酯,使内部温度升至40℃,同时用-10℃的浴进一步冷却。接着无冷却下在原温度搅拌1小时。在添加250ml水和短时间搅拌后分离出水相。MTB相用250ml稀释的氯化钠溶液洗涤,在溶剂换成甲醇(250ml)后在室温添加一种由1g对甲苯磺酸在10ml甲醇中组成的溶液。在原温度搅拌1小时并接着回流加热。在蒸馏出甲醇情况下滴入400g 10%的氢氧化钠溶液并接着添加60ml水。蒸馏出甲醇直至底部温度达到97℃。冷却至55℃后掺加190ml MTB并用约77ml浓HCl酸化至pH为2。冷却至室温后分离出水相并有机相通过蒸馏浓缩为60ml MTB。通过加入500ml庚烷和慢慢冷却至室温结晶出产物。吸出粗晶固体,用庚烷洗涤并在真空干燥箱中在40℃干燥至恒重。产率108.9g(80%),HPLC>99.5%(面积)
实施例10
S-2-羟基-3-甲氧基-3,3-二苯基丙酸(用L-脯氨酸甲酯进行消旋物裂解)
向240g 57%的甲醇的L-脯氨酸甲酯-盐酸化物溶液(0.826mol)中在室温滴加148.8g 30%的甲醇的甲醇钠盐溶液(0.826mol),添加2.4升MTB和225g(0.826mol)2-羟基-3-甲氧基-3,3-二苯基丙酸。在蒸馏出2680ml MTB-甲醇-混合物并同时滴入2.4升MTB后慢慢冷却至室温,吸出结晶(R-2-羟基-3-甲氧基-3,3-二苯基丙酸XL-脯氨酸甲酯)并用15ml MTB洗涤固体物。滤液通过蒸馏出1.5升MTB被浓缩并掺入1.0升水。在室温用浓盐酸调pH为1.2,在搅拌和相分开后分出水相并用0.4升MTB再提取。合并的有机相用0.4升水提取。在抽出MTB后使残渣在回流情况下溶入650ml甲苯中并使产物通过变性处理和慢慢冷却进行结晶。在吸出,用甲苯洗涤和在真空干燥箱中干燥后得到78.7g S-2-羟基-3-甲氧基-3,3-二苯基丙酸(产率35%,以消旋物为基)。
手性HPLC:100%
HPLC:99.8%
实施例11
S-2-羟基-3-甲氧基-3,3-二苯基丙酸(用(S)-1-(4-硝基苯基)乙胺进行消旋物的裂解)
100g(0.368mol)2-羟基-3-甲氧基-3,3-二苯基丙酸在750ml丙酮和750ml MTB中在回流情况下向其掺入30.5g(0.184mol)(S)-1-(4-硝基苯基)乙胺,进行变性处理,在回流情况下煮沸1小时并在结晶情况下慢慢冷却到室温。吸出结晶(S-2-羟基-3-甲氧基-3,3-二苯基丙酸X(S)-1-(4-硝基苯基)乙胺)并用MTB洗涤。在残渣悬浮入500ml水和350ml MTB中以后在室温用浓盐酸调pH至1.2,在搅拌和相分开后分离出水相并用150ml MTB再提取。合并的有机相用100ml水提取。在蒸馏出370mlMTB后在回流情况下向其掺入390ml正-庚烷并在产物结晶情况下慢慢冷却至室温。在吸出,用正-庚烷冲洗和在真空干燥箱中干燥后得到35.0g S-2-羟基-3-甲氧基-3,3-二苯基丙酸(产率35%,以消旋物为基)。
手性HPLC:100%
HPLC:99.8%
实施例12
3-甲氧基-2-(4-甲氧基-6,7-二氢-5H-环戊二烯并嘧啶-2-基氧)-3,3-二苯基-丙酸苄基酯
24.48g(90mmol)3-甲氧基-3,3-二苯基-2-羟基丙酸溶入150ml二甲基甲酰胺中并掺入13.7g(99mmol)碳酸钾。悬浮液在室温搅拌30分钟。接着在超过5分钟的时间滴入10.7ml(90mmol)苄基溴并再搅拌1小时,与此同时温度升高至32℃。
向这种溶液先后加入24.84g(180mmol)K2CO3和20.52g(90mmol)2-甲烷磺酰-4-甲氧基-6,7-二氢-5H-环戊吡啶并在80℃搅拌3小时。
为加工稀释用约600ml H2O稀释瓶内物,小心地用浓HCl酸化并加入250ml醋酸乙酯。沉淀出31.4g纯净产物,过滤产物。
由母液分离醋酸乙酯相,再用醋酸乙酯提取水相并浓缩合并的有机相。油状残渣(19g)进行色谱纯化(环己烷/醋酸乙酯=9/1)并得另外的10.5g纯净产物。
总产率:41.9g(82.2mmol)
91%
熔点:143-147℃
MS:MH+=511
实施例13
3-甲氧基-2-(4-甲氧基-(6,7-二氢-5H-环戊二烯并嘧啶-2-基氧)-3,3-二苯基丙酸
40g(78.4mmol)3-甲氧基-2-(4-甲氧基-6,7-二氢-5H-环戊二烯并嘧啶-2-基氧)-3,3-二苯基-丙酸苄基酯溶入400ml醋酸乙酯/甲醇(4∶1)中,用约500mg活性炭上的钯载于(10%)掺加其中并使处于氢气氛中,直至不再吸收气体。滤出催化剂,蒸发浓缩溶液并使残渣由醚中结晶出来。
实施例14
2S-3,3-二苯基-环氧乙烷-2-羧酸乙酯
2.57g(10.2mmol)3,3-二苯基-丙烯酸乙酯和464mg 4-苯基吡啶-N-氧化物溶入24ml二氯甲烷并掺入432mg(6.5mol%)(5,5)-(+)-N,N’-双(3,5-二-特-丁基-水杨叉)-1,2-环己烷二氨基-锰(III)氯化物。在冰冷却情况下加入6.4ml12%的次氯酸钠溶液,在冰冷却时搅拌30分钟并在室温过夜。用水稀释反应溶液至200ml,用醚提取,干燥并蒸发浓缩。得2.85g无色油。在利用NPLC(环己烷∶醋酸乙酯=9∶1)纯化后得1.12g具有对映体比约为8∶1有利于S-构形的油。
1H-NMR〔CDCl3〕,
δ=1.0(tr,3H);3.9(m,3H);7.3(m,10H)
实施例15
2-甲基磺酰-6,7-二氢-5H-环戊二烯并嘧啶-4-醇
向29.6g(528mmol)KOH在396ml甲醇中先后加入46.9g(330mmol)环戊烷酮-2-羧酸甲酯和53.5g(192mmol)5-甲基异硫脲-硫酸盐并在室温搅拌过夜。用1N盐酸酸化反应混合物并用水稀释。吸出沉淀的结晶并干燥,得20g晶体。
实施例16
4-氯-2-甲基磺酰-6,7-二氢-5H-环戊二烯并嘧啶
向20g(110mmol)加入255ml三氯氧化磷并在80℃搅拌3小时。使三氯氧化磷蒸发,用冰分解残渣并吸出沉淀出的晶体。得18.5g带褐色的固体。
实施例17
4-甲氧基-2-甲基磺酰-6,7-二氢-5H-环戊二烯并嘧啶
18.05g(90mmol)4-氯-2-甲基磺酰-6,7-二氢-5H-环戊二烯并嘧啶溶入200ml甲醇中。在45℃滴入16.7g甲基钠(作为在甲醇中30%的溶液)并再搅拌2小时。蒸发浓缩反应溶液,收入醋酸乙酯中,用稀释的盐酸酸化并蒸发浓缩醋酸乙酯的提取物,剩下15.5g油。
1H-NMR〔DMSO〕,
δ=2.1(五重线,2H);2.5(S,3H);2.8(dtr,4H);3.9(S,3H)ppm
实施例18
2-甲基磺酰-4-甲氧基-6,7-二氢-5H-环戊二烯并嘧啶
15g(76.2mmol)4-甲氧基-2-甲基磺酰-6,7-二氢-5H-环戊二烯并嘧啶溶入160ml冰醋酸/二氯甲烷(1∶1)中并掺入1.3g钨酸钠盐。在35℃滴入17.5ml(170ml)30%的H2O2溶液。接着用500ml水和100ml二氯甲烷稀释,分离出有机相,干燥并蒸发浓缩,剩下14g油状物,由醚中结晶出。
1H-NMR〔CDCl3〕,
δ=2.2(五重线,2H);3.0(dtr.,4H);3.3(S,3H);4.1(S,3H)ppm
实施例19
1-苯磺酰-3-(4,6-二甲氧基嘧啶-2-基氧)-4-甲氧基-4,4-二苯基-丁烷-2-酮
0.37g(2.4mmol)苯基甲砜溶入10ml干四氢呋喃中;接着在-70℃滴入2当量丁基锂(2.94ml;1.6摩尔在己烷中的溶液)。在-70℃1小时后滴入1g(2.4mmol)2-(4,6-二甲氧基嘧啶-2-基氧)-3-甲氧基-3,3-二苯基丙酸甲酯(溶入5ml四氢呋喃中)。在-70℃,在-10℃各搅拌反应混合物1小时并接着加温至室温。
为加工滴入约10ml饱和的NH4Cl溶液,用乙酸乙酯彻底的提取,合并的有机相用饱和的N-Cl溶液(提出)并经Na2SO4干燥,干燥和浓缩后得到的残渣经硅胶色谱(正庚烷/乙酸乙酯15%-30%)纯化并接着在RP-硅胶上(乙腈/H2O+三氟乙酸)经MPLC纯化;作为产物得到0.3g白色无定形粉末。
实施例20
3,3-二苯基-环氧乙烷-2-腈
3.1g(54.9mmol)甲基钠盐悬浮于20ml干四氢呋喃中,并接着在-10℃滴入一由5g(27.4mmol)二苯酮和4.2g(54.9mmol)氯乙腈组成的混合物。
在-10℃再搅拌反应混合物约2小时,接着注入水中并用乙酸乙酯多次提取。合并的有机相经Na2SO4干燥,浓缩,并剩下的残渣通过在硅胶上(正庚烷/乙酸乙酯)进行色谱纯化。
产率:1.2g(20%)
1H-NMR〔CDCl3〕,
δ=3.9(S,1H);7.4-7.5(m,10H)ppm
实施例21
2-羟基-3-甲氧基-3,3-二苯基-丙腈
6.5g(29.4mmol)3,3-二苯基-环氧乙烷-2-腈溶入60ml甲醇中并在0℃掺入约2ml三氟化硼-醚合物溶液。使反应混合物在0℃再次搅拌1小时,然后在室温搅拌过夜。为加工用乙醚稀释,用饱和的NaCl-溶液洗涤,有机相经NaSO4干燥并浓缩。作为残渣剩下7.3g白色无定形粉末,它直接用于进一步的转化。
1H-NMR(CDCl3),
δ=2.95(宽S,OH),3.15(S,3H),5.3(S,1H),7.3-7.5(m,10)ppm
实施例22
2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基-丙腈
7.3g(28.8mmol)2-羟基-3-甲氧基-3,3-二苯基丙腈溶入90ml DMF中,并掺入4g(28.8mmol)K2CO3和6.3g(28.8mmol)2-甲磺酰-4,6-二甲氧基-嘧啶。在室温搅拌混合物约12小时,接着倒入水中并用乙酸乙酯提取。合并的有机相重新用水洗涤,干燥和浓缩。然后使这样获得的残渣在硅胶上通过色谱纯化(正庚烷/乙酸乙酯)。
产率:6.9g白色无定形粉末
FAB-MS:392(M+H+)
1H-NMR〔CDCl3〕,
δ=3.3(S,3H);4.95(S,6H),5.85(S,1H);6.3(S,1H);7.3-7.5(m,10H)ppm
实施例23
S-〔2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基)-丙基〕-1H-四唑
0.5g(1.3mmol)腈溶入10ml甲苯中,先后掺加85mg(1.3mmol)NaN3和460mg(1.4mmol)Bu3SnCl并接着在回流加热混合物约40小时。冷却后用乙酸乙酯稀释,用10%水的KF-溶液和用NaCl-溶液洗涤,经MgSO4干燥和浓缩后剩下1.0g黄色油,通过色谱在硅胶上使其纯化(正庚烷/乙酸乙酯)。
在馏分浓缩后得到60mg 1H-四唑和110mg 1-甲基-四唑(各为无定形白色)固体。
5-〔2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基)-丙基〕-1H-四唑
电射-MS:435(M+H+)
1H-NMR(CDCl3):
δ(ppm)3.28(S,3H),3.85(S,6H),5.75(S,1H),7.25-7.40(m,10H),7.50(S,1H)。
5-〔2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲氧基-3,3-二苯基)-丙基〕-1-甲基-四唑
电射-MS:471(M+H+)
1H-NMR(CDCl3);
δ(ppm)3.0(S,3H),3.35(S,3H),3.80(S,6H),5.75(S,1H),7.30-7.40(m,11H)
实施例24
2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲基亚硫酰基-3,3-二苯基-丙酸
1.2g(2.9mmol)2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲基磺酰-3,3-二苯基-丙酸在0℃放入15ml冰醋酸中并滴入294μl 30%的H2O2。在室温搅拌过夜,倒入水中,用CH2Cl2提取并用硫代硫酸钠溶液和食盐溶液洗涤。干燥后分离出1g白色泡沫物质。
实施例25
2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲基磺酰-3,3-二苯基-丙酸
0.6g(1.45mmol)2-(4,6-二甲氧基-嘧啶-2-基氧)-3-甲基磺酰-3,3-二苯基-丙酸在室温放入15ml冰醋酸中并滴入294μl 30%的H2O2。在室温搅拌过夜,在50℃继续加热3小时,倒入水中并用硫代硫酸钠溶液和食盐溶液洗涤。干燥后分离出400mg白色固体。
相类似可制备表1中所列举的化合物。
表I
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-1 | OMe | 苯基 | 甲基 | OMe | OMe | CH | O | O | 81 |
I-2 | OH | 苯基 | 甲基 | OMe | OMe | CH | O | O | 167 |
I-3 | OH | 苯基 | CH2-CH2-S-CH3 | OMe | OMe | CH | O | O | |
I-4 | OH | 苯基 | 乙基 | OMe | OMe | CH | O | O | 81(分解) |
I-5 | OH | 苯基 | 异丙基 | OMe | OMe | CH | O | O | 182 |
I-6 | OH | 苯基 | 甲基 | OMe | OMe | CH | O | S | 168 |
I-7 | OH | 苯基 | CH2-CH2-SO2-CH(CH3)2 | OMe | OMe | CH | O | O | |
I-8 | OH | 苯基 | CH2-CH2-SO2-CH(CH3)2 | OMe | OMe | CH | S | O | |
I-9 | OH | 苯基 | CH2-CH2-SO2-CH(CH3)2 | OMe | OMe | C-CH(CH3)2 | O | O | |
I-10 | OH | 苯基 | CH2-CH2-SO2-CH(CH3)2 | OMe | OMe | C-CH(CH3)3 | O | O | |
I-11 | OH | 苯基 | CH2-CH2-SO2-CH(CH3)2 | OMe | NH-OCH3 | CH | O | O | |
I-12 | OH | 苯基 | 正丙基 | OMe | OMe | CH | O | O | 174 |
I-13 | OMe | 苯基 | 正丙基 | OMe | OMe | CH | O | O | |
I-14 | OH | 苯基 | 正丙基 | OEt | OEt | CH | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-15 | OH | 苯基 | 正丁基 | OMe | OMe | CH | O | O | |
I-16 | OH | 苯基 | 异丁基 | OMe | OMe | CH | O | O | |
I-17 | OH | 苯基 | 异丁基 | OMe | O-CH2-CH2-C | O | O | ||
I-18 | OH | 苯基 | 特丁基 | OMe | OMe | CH | O | O | |
I-19 | OH | 苯基 | 环丙基 | OMe | OMe | CH | O | O | |
I-20 | OH | 苯基 | 环戊基 | OMe | OMe | CH | O | O | |
I-21 | OH | 苯基 | 环己基 | OMe | OMe | CH | O | O | |
I-22 | OH | 苯基 | (CH3)3C-CH2-CH2 | OEt | OEt | CH | O | O | |
I-23 | OH | 苯基 | (CH3)2CH-CH2-CH2-CH2 | OMe | OMe | CH | O | O | 173 |
I-24 | OH | 苯基 | HO-CH2-CH2 | OMe | OMe | CH | O | O | |
I-25 | OH | 苯基 | HO2C-(CH2)2- | OMe | OMe | CH | O | O | |
I-26 | OH | 苯基 | 环丙基亚甲基 | OMe | OMe | CH | O | O | 115 |
I-27 | OH | 苯基 | H | OMe | OMe | CH | O | O | |
I-28 | OH | 苯基 | 甲基 | OMe | OMe | CH | O | - | |
I-29 | OH | 苯基 | 苯基 | OMe | OMe | CH | O | O | 136 |
I-30 | OH | 苯基 | 苯基 | OMe | O-CH(CH3)-CH2-C | O | O | ||
I-31 | OMe | 苯基 | 苯基 | OMe | OMe | CH | O | O | |
I-32 | OH | 苯基 | 4-异丙基苯基 | OMe | OMe | CH | O | O | |
I-33 | OH | 苯基 | 4-Me-S-苯基 | OMe | OMe | CH | O | O | |
I-34 | OH | 苯基 | 4-Me-O-苯基 | OMe | OMe | CH | O | O | |
I-35 | OH | 苯基 | 3-Et-苯基 | OMe | OMe | CH | O | O | |
I-36 | OH | 苯基 | 2-Me-苯基 | OMe | OMe | CH | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-37 | OH | 苯基 | 2-Cl-苯基 | OMe | OMe | CH | O | O | |
I-38 | OH | 苯基 | 3-Br-苯基 | OMe | OMe | CH | O | O | |
I-39 | OH | 苯基 | 4-F-苯基 | OMe | OMe | CH | O | O | |
I-40 | OH | 苯基 | 4-F-苯基 | OMe | OMe | CH | S | O | |
I-41 | OH | 苯基 | 4-CH3-苯基 | OMe | OMe | CH | O | O | |
I-42 | OH | 苯基 | 3-NO2-苯基 | OMe | OMe | CH | O | O | |
I-43 | OH | 苯基 | 2-HO-苯基 | OMe | OMe | CH | O | O | |
I-44 | OH | 苯基 | 3,4-二甲氧基苯基 | OMe | OMe | CH | O | O | |
I-45 | OH | 苯基 | 3,4-二氧亚甲基苯基 | OMe | OMe | CH | O | O | |
I-46 | OH | 苯基 | 3,4,5-三甲氧基苯基 | OMe | OMe | CH | O | O | |
I-47 | OH | 苯基 | 苄基 | OMe | OMe | CH | O | O | |
I-48 | OH | 苯基 | 2-Cl-苄基 | OMe | OMe | CH | O | O | |
I-49 | OH | 苯基 | 3-Br-苄基 | OMe | OMe | CH | O | O | |
I-50 | OH | 苯基 | 4-F-苄基 | OMe | OMe | CH | O | O | |
I-51 | OH | 苯基 | 2-Me-苄基 | OMe | OMe | CH | O | O | |
I-52 | OH | 苯基 | 2-Me-苄基 | OMe | O-CH=CH-C | O | O | ||
I-53 | OH | 苯基 | 3-Et-苄基 | OMe | OMe | CH | O | O | |
I-54 | OH | 苯基 | 4-异丙基苄基 | OMe | OMe | CH | O | O | |
I-55 | OH | 苯基 | 4-NO2-丙基苄基 | OMe | OMe | CH | O | O | |
I-56 | OH | 苯基 | 2-Me-5-丙基苄基 | OMe | OMe | CH | O | O | |
I-57 | OH | 苯基 | 2-Me-5-丙基苄基 | OEt | OEt | CH | O | O | |
I-58 | OH | 苯基 | 4-Me-2-丙基苄基 | OMe | OMe | CH | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-59 | OH | 苯基 | 3,4-二氧亚甲基苄基 | OMe | OMe | CH | O | O | |
I-60 | OH | 4-F-苯基 | 甲基 | OMe | OMe | CH | O | O | 163-165(分解) |
I-61 | OMe | 4-F-苯基 | 甲基 | OEt | OEt | CH | O | O | |
I-62 | OH | 4-Cl-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-63 | OH | 4-Me-O-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-64 | OH | 4-Me-O-苯基 | 乙基 | OMe | OMe | CH | O | O | |
I-65 | OH | 4-Me-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-66 | OH | 4-Me-苯基 | 甲基 | OMe | O-CH2-CH2-C | O | O | ||
I-67 | OH | 3-CF3-苯基 | 正丙基 | OMe | OMe | CH | O | O | |
I-68 | OH | 3-CF3-苯基 | 正丙基 | OMe | O-CH(CH3)-CH2-C | O | O | ||
I-69 | OH | 4-NO2-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-70 | OH | 4-NO2-苯基 | 甲基 | OMe | O-CH=CH-C | O | O | ||
I-71 | OH | 3-Cl-苯基 | 乙基 | OMe | OMe | CH | O | O | |
I-72 | OH | 2-F-苯基 | 甲基 | OMe | OMe | CH | O | O | 193-194(分解) |
I-73 | OH | 2-F-苯基 | 甲基 | OMe | OMe | CH | S | O | |
I-74 | OH | 2-Me-O-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-75 | OH | 2-Me-O-苯基 | 甲基 | OMe | OMe | CH | O | S | |
I-76 | OH | 3,4-二甲氧基苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-77 | OH | 3,4-二氧亚甲基苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-78 | OH | p-CF3-苯基 | 甲基 | OMe | OMe | CH | O | O | |
I-79 | OH | 苯基 | 甲基 | OMe | OEt | CH | O | O | |
I-80 | OMe | 苯基 | 甲基 | OMe | OEt | CH | S | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-81 | OH | 苯基 | 乙基 | OMe | NH-OMe | CH | O | O | |
I-82 | OH | p-Me-O-苯基 | 正丙基 | OMe | OCF3 | CH | O | O | |
I-83 | OH | 苯基 | 甲基 | OMe | CF3 | CH | O | O | |
I-84 | OH | 苯基 | 甲基 | OMe | CF3 | N | O | O | |
I-85 | OH | 3,4-二甲氧基苯基 | 苄基 | Me | Me | O | O | ||
I-86 | OH | 3,4-二甲氧基苯基 | 甲基 | OMe | O-CH2-CH2-C | O | O | ||
I-87 | OH | 苯基 | 甲基 | OMe | O-CH2-CH2-C | O | O | 126(分解) | |
I-88 | OH | 苯基 | 甲基 | OMe | O-CH(CH3)-CH2-C | O | O | ||
I-89 | OH | 苯基 | 甲基 | OMe | N(CH3-CH=CH-C | O | O | 118 | |
I-90 | OH | 苯基 | 甲基 | OMe | S-C(CH3)=C(CH3)-C | O | O | ||
I-91 | OH | 苯基 | 甲基 | OMe | O-C(CH3)=CH-C | O | O | ||
I-92 | OH | 苯基 | 甲基 | Me | O-C(CH3)=CH-C | O | O | ||
I-93 | OH | 苯基 | 甲基 | Me | O-CH=CH-C | O | O | ||
I-94 | OH | 4-F-苯基 | 甲基 | Me | S-CH=CH-C | O | O | ||
I-95 | OH | 4-F-苯基 | H | OMe | OMe | CH | O | O | |
I-96 | OH | 苯基 | 甲基 | OMe | CH2-CH2-CH2-C | O | O | 149-151(分解) | |
I-97 | OH | 苯基 | 甲基 | Methyl | CH2-CH2-CH2-C | O | O | 157(分解) | |
I-98 | OH | 苯基 | 甲基 | Ethryl | CH2-CH2-CH2-CH2-C | O | O | ||
I-99 | OH | 苯基 | 甲基 | OMe | CH2-CH2-CH2-CH2-C | O | O | ||
I-100 | OH | 苯基 | 甲基 | Me | Me | CH | O | O | |
I-101 | OH | 苯基 | 甲基 | Et | Et | CH | O | O | |
I-102 | OH | 苯基 | 甲基 | Me | Me | C-CH3 | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-103 | OH | 苯基 | 甲基 | OMe | Me | CH | O | O | |
I-104 | OH | 环己基 | 甲基 | OMe | OMe | CH | O | O | |
I-105 | OH | 环己基 | 甲基 | OMe | CH2-CH2-CH2-C | O | O | ||
I-106 | OH | 苯基 | 甲基 | OCH3 | OCH3 | CH | S | S | |
I-107 | OH | 苯基 | 甲基 | OCH3 | OCH3 | CH | O | S | 134 |
I-108 | OCH3 | 苯基 | 甲基 | OCH3 | OCH3 | CH | S | S | |
I-109 | OH | 苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-110 | OCH3 | 2-氟苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-111 | OC2H5 | 3-氯苯基 | 甲基 | OCH3 | OCH3 | N | O | O | |
I-112 | ON(CH3)2 | 4-溴苯基 | 甲基 | CF3 | CF3 | CH | S | O | |
I-113 | O-CH2-C=CH | 苯基 | 乙基 | OCH3 | CF3 | CH | O | O | |
I-114 | OH | 苯基 | 丙基 | OCH3 | OCF3 | CH | O | S | |
I-115 | OCH3 | 苯基 | i-异丙基 | OCH3 | CH3 | CH | O | O | |
I-116 | OC2H5 | 苯基 | s-仲丁基 | OCH3 | Cl | CH | S | O | |
I-117 | ON(CH3)2 | 2-甲基苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-118 | ON(CH3)2 | 3-甲氧苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-119 | ON=C(CH3)2 | 4-硝基苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-120 | ON(CH3)2 | 苯基 | 1-苯基丙炔-3-基 | OCH3 | OCF3 | N | O | S | |
I-121 | ON=C(CH3)2 | 2-羟基苯基 | 甲基 | OCH3 | CH3 | N | O | O | |
I-122 | ONSO2C6H5 | 3-三氟甲基苯基 | 甲基 | OCH3 | Cl | N | O | O | |
I-123 | NHPhenyl | 4-二甲氨基苯基 | 甲基 | OCH3 | OCH3 | CH | S | O | |
I-124 | OC2H5 | 苯基 | 三氟乙基 | CH3 | CH3 | CH | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-125 | ON(CH3)2 | 苯基 | 苄基 | Cl | Cl | CH | O | O | |
I-126 | ON(CH3)2 | 苯基 | 2-甲氧乙基 | OCH3 | -O-CH2-CH2- | S | O | ||
I-127 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-128 | OH | 苯基 | 苯基 | OCH3 | -O-CH2-CH2- | O | O | ||
I-129 | OH | 苯基 | 苯基 | OCH3 | OCH3 | N | O | O | |
I-130 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | S | O | |
I-131 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | S | S | |
I-132 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | O | S | |
I-133 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-134 | OH | 苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-135 | OH | -(CH2)5- | 苯基 | Phenyl | OCH3 | CH | O | O | |
I-136 | OH | 苯基 | 2-噻唑基 | OCH3 | OCH3 | CH | O | O | |
I-137 | OCH3 | 2-氟苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-138 | OC2H5 | 3-氯苯基 | 苯基 | OCH3 | OCH3 | N | O | O | |
I-139 | ON(CH3)2 | 4-溴苯基 | 苯基 | CF3 | CF3 | CH | O | O | |
I-140 | O-CH2=CH | 苯基 | 2-氟苯基 | OCH3 | CF3 | CH | O | O | |
I-141 | OH | 苯基 | 3-氯苯基 | OCH3 | OCF3 | CH | O | S | |
I-142 | OCH3 | 苯基 | 4-溴苯基 | OCH3 | CH3 | CH | O | O | |
I-143 | OC2H5 | 苯基 | 4-噻唑基 | OCH3 | Cl | CH | S | O | |
I-144 | ON(CH3)2 | 2-甲基苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-145 | ON=C(CH3)2 | 3-甲氧苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-146 | OH | 苯基 | 甲基 | OCH3 | -CH2-CH2-CH2-C | O | O |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-147 | OH | 4-氟苯基 | 甲基 | OCH3 | OCH3 | CH | O | O | 168(分解) |
I-148 | OH | 4-氟苯基 | 甲基 | OCH3 | -CH2-CH2-CH2-C | O | O | ||
I-149 | NH-SO-C6H5 | 4-硝基苯基 | 苯基 | OCH3 | OCH3 | CH | O | O | |
I-150 | OCH3 | 苯基 | 3-咪唑基 | OCH3 | -O-CH2-CH2 | O | O | ||
I-151 | OC2H5 | 苯基 | 4-咪唑基 | OCH3 | CF3 | N | S | O | |
I-152 | ON(CH3)2 | 苯基 | 2-吡唑基 | OCH3 | OCF3 | N | O | S | |
I-153 | ON=C(CH3)2 | 2-羟基苯基 | 苯基 | OCH3 | CH3 | N | O | O | |
I-154 | NH-SO2-C6H5 | 3-三氟甲基苯基 | 苯基 | OCH3 | Cl | N | O | O | |
I-155 | NH苯基 | 4-二甲氨基苯基 | 苯基 | OCH3 | OCH3 | CH | S | O | |
I-156 | ONa | 苯基 | 苯基 | OCH3 | OCH3 | CH | S | S | |
I-157 | O-CH2-C≡C | 苯基 | 苯基 | OCH3 | OCH3 | N | S | S | |
I-158 | OH | 苯基 | 苯基 | CF3 | CF3 | CH | O | S | |
I-159 | OCH3 | 苯基 | 苯基 | OCF3 | OCF3 | CH | O | O | |
I-160 | OC2H5 | 苯基 | 2-二甲氨基苯基 | CH3 | CH3 | CH | O | O | |
I-161 | ON(CH3)2 | 苯基 | 3-羟基苯基 | Cl | Cl | CH | O | O | |
I-162 | ON=C(CH3)2 | 苯基 | 4-三氟甲基苯基 | OCH3 | -O-CH2-CH2- | S | O | ||
I-163 | NH-SO2-C6H5 | 苯基 | 2-唑基 | OCH3 | CF3 | N | S | S | |
I-164 | OH | 苯基 | 甲基 | CH3 | CH3 | CH | O | O | |
I-165 | OH | 环己基 | 甲基 | OCH3 | OCH3 | CH | O | O | |
I-166 | OH | 环己基 | 甲基 | OCH3 | CH2-CH2-CH-C | O | O | ||
I-167 | OH | 苯基 | 甲基 | N(CH3)2 | N(CH3)2 | CH | O | O | |
I-168 | OH | 苯基 | 甲基 | OCH3 | OCH3 | CH | O | SO2 |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-169 | OH | 苯基 | 甲基 | OCH3 | OCH3 | CH | O | SO2 | |
I-170 | OH | 3-F-苯基 | Me | OMe | OMe | CH | O | O | |
I-171 | OH | 3-F-笨基 | Me | OMe | CH2-CH2-CH2-C | O | O | ||
I-172 | OH | 4-F-苯基 | Me | OMe | CH2-CH2-CH2-C | O | O | 142-143191℃ | |
I-173 | OH | 3-MeO-苯基 | Me | OMe | CH2-CH2-CH2-C | O | O | 158-161(分解) | |
I-174 | OH | 3-MeO-苯基 | Me | OMe | OMe | CH | O | O | |
I-175 | OH | 3-MeO-苯基 | Et | OMe | CH2-CH2-CH2-C | O | O | ||
I-176 | OH | 苯基 | HO-CH2-CH2 | OMe | CH2-CH2-CH2-C | O | O | ||
I-177 | OH | 苯基 | Me | NMe2 | NMe2 | N | O | O | 181 |
I-178 | OH | 苯基 | Me | OMe | OMe | N | O | O | |
I-179 | OH | 3-F-苯基 | Me | OMe | Me | CH | O | O | |
I-180 | NH-SO2-苯基 | 苯基 | Me | OMe | OMe | CH | O | O | |
I-181 | NH-SO2-Me | 苯基 | Me | OMe | OMe | CH | O | O | |
I-182 | CH2-SO2-苯基 | 苯基 | Me | OMe | OMe | CH | O | O | |
I-183 | CH2-SO2-Me | 苯基 | Me | OMe | OMe | CH | O | O | |
I-184 | -CN | 苯基 | Me | OMe | OMe | CH | O | O | |
I-185 | 四唑 | 苯基 | Me | OMe | OMe | CH | O | O | |
I-186 | NH-SO2-苯基 | 苯基 | Me | OMe | OMe | CH | O | O | 167 |
I-187 | N-甲基四唑ol | 苯基 | Me | OMe | OMe | CH | O | O | |
I-188 | ONa | 苯基 | Me | OMe | -O-CH2-CH2-C- | O | O | 122-139(分解) | |
I-189 | OH | o-F-苯基 | Me | OMe | -O-CH2-CH2-C- | O | O | 140-144(分解) | |
I-190 | OH | m-Me-苯基 | Me | OMe | OMe | CH | O | O | 169-177 |
Nr. | R1 | R4,R5 | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
I-191 | OH | m-Me-苯基 | Me | OMe | -O-CH2-CH2-C- | O | O | 119-135(分解) | |
I-192 | OH | p-F-苯基 | Me | OMe | Me | CH | O | O | 137-140(分解) |
I-193 | OH | m-F-苯基 | Me | Me | -O-CH2-CH2-C- | O | O | 150-152 | |
I-194 | OH | p-F-苯基 | Me | Me | -O-OH2-CH2-C- | O | O | 169-170 |
表II
Nr. | R1 | A | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
II-1 | OH | 键 | 甲基 | OMe | OMe | CH | O | O | 96-98 |
II-2 | OH | CH2 | 甲基 | OMe | OMe | CH | O | O | |
II-3 | OH | CH2-CH2 | 甲基 | OMe | OMe | CH | O | O | |
II-4 | OH | CH=CH | 甲基 | OMe | OMe | CH | O | O | |
II-5 | OH | O | 甲基 | OMe | OMe | CH | O | O | |
II-6 | OH | S | 甲基 | OMe | OMe | CH | O | O | |
II-7 | OH | NH(CH3) | 甲基 | OMe | OMe | CH | O | O | |
II-8 | OH | 键 | 异丙基 | OMe | OMe | CH | O | O | 137-139 |
Nr. | R1 | A | R6 | R2 | R3 | X | Y | Z | 熔点[℃] |
II-9 | OH | 键 | 对异丙苯基 | OMe | OMe | CH | O | O | |
II-10 | OH | 键 | 苄基 | OMe | OMe | CH | O | O | |
II-11 | OH | CH=CH | 乙基 | OMe | OMe | CH | O | O | |
II-12 | OH | CH=CH | (CH3)2-CH2-CH2 | OMe | OMe | CH | O | O | |
II-13 | OH | CH=CH | 环丙基亚甲基 | OMe | OMe | CH | O | O | |
II-14 | OH | CH=CH | 甲基 | OMe | O-CH2-CH2-C | O | O | ||
II-15 | OH | CH2-CH2 | 乙基 | OMe | O-CH=CH-C | O | O | ||
II-16 | OH | CH2=CH2 | 甲基 | OMe | CH2-CH2-CH2-C | O | O | ||
II-17 | OH | 键 | 甲基 | OMe | CH2-CH2-CH2-C | O | O | 147 |
实施例35
根据上面描叙的结合试验对下述所列的化合物测定了受体结合数据。
结果载入表2中。
表2:受体结合数据(Ki-值)
化合物 | ETA[nM] | ETB[nM] |
I-2 | 6 | 34 |
I-29 | 86 | 180 |
I-5 | 12 | 160 |
I-4 | 7 | 2500 |
I-87 | 1 | 57 |
I-89 | 86 | 9300 |
I-103 | 0,4 | 29 |
I-107 | 3 | 485 |
I-12 | 19 | 1700 |
I-26 | 23 | 2000 |
I-23 | 209 | 1100 |
I-47 | 150 | 1500 |
I-60 | 33 | 970 |
I-96 | 0,6 | 56 |
II-3 | 107 | 7300 |
II-1 | 28 | 2300 |
Claims (7)
1.具有如下通式(I)的化合物和其盐:
其中:
X是CH;
Y是O;
Z是O;
R是CO2H;
R2是甲氧基;
R3是甲氧基;
R4是苯基;
R5是苯基;和
R6是甲基。
3.根据权利要求2的药剂,配制成经口服,肠胃外,皮下,静脉内,肌肉内,腹膜内,舌下,透皮和经鼻咽途径给药。
4.根据权利要求2的药剂,其中该药剂是固体形式。
5.据权利要求2的药剂,其中该药剂是液体形式。
6.根据权利要求2的药剂,其中该药剂配制成未包膜片,包膜片,胶囊,粉,颗粒剂,栓剂,溶液,胶体,软膏,膏剂,气雾剂或喷雾剂。
7.根据权利要求2的药剂,进一步包括下列物质中的一种或多种:片粘结剂,填料,防腐剂,片崩解剂,流动调节剂,软化剂,润湿剂,分散剂,乳化剂,溶剂,缓释剂,抗氧化剂或驱动气体。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4436851.8 | 1994-10-14 | ||
DE4436851 | 1994-10-14 | ||
DE19533023A DE19533023B4 (de) | 1994-10-14 | 1995-09-07 | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
DE19533023.4 | 1995-09-07 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB951956558A Division CN1142918C (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100999548A Division CN1923820B (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1513844A CN1513844A (zh) | 2004-07-21 |
CN1293059C true CN1293059C (zh) | 2007-01-03 |
Family
ID=6530833
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100999548A Expired - Lifetime CN1923820B (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
CNB951956558A Expired - Lifetime CN1142918C (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
CNB2004100027833A Expired - Lifetime CN1293059C (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006100999548A Expired - Lifetime CN1923820B (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
CNB951956558A Expired - Lifetime CN1142918C (zh) | 1994-10-14 | 1995-10-07 | 新的羧酸衍生物,其制备和应用 |
Country Status (32)
Country | Link |
---|---|
US (15) | USRE42462E1 (zh) |
EP (2) | EP1110952B9 (zh) |
JP (6) | JP3957748B2 (zh) |
KR (1) | KR100438339B1 (zh) |
CN (3) | CN1923820B (zh) |
AT (2) | ATE277911T1 (zh) |
BR (1) | BR9509338A (zh) |
CA (1) | CA2201785C (zh) |
CZ (1) | CZ294603B6 (zh) |
DE (4) | DE19533023B4 (zh) |
DK (1) | DK0785926T3 (zh) |
ES (2) | ES2162942T3 (zh) |
FI (1) | FI120492B (zh) |
FR (1) | FR08C0041I2 (zh) |
GR (1) | GR3036931T3 (zh) |
HK (2) | HK1066541A1 (zh) |
HR (2) | HRP950517B1 (zh) |
HU (1) | HU220621B1 (zh) |
IL (1) | IL115560A (zh) |
LU (1) | LU91487I2 (zh) |
MX (1) | MX9702658A (zh) |
NL (1) | NL300361I2 (zh) |
NO (2) | NO308846B1 (zh) |
NZ (1) | NZ294849A (zh) |
PL (1) | PL186850B1 (zh) |
PT (1) | PT785926E (zh) |
RU (1) | RU2180335C2 (zh) |
SI (1) | SI9520110A (zh) |
TW (1) | TW577880B (zh) |
UA (1) | UA45985C2 (zh) |
WO (1) | WO1996011914A1 (zh) |
ZA (1) | ZA958642B (zh) |
Families Citing this family (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19533023B4 (de) * | 1994-10-14 | 2007-05-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
DE19536891A1 (de) * | 1995-10-04 | 1997-04-10 | Basf Ag | Neue Aminosäurederivate, ihre Herstellung und Verwendung |
DE19614534A1 (de) * | 1996-04-12 | 1997-10-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
DE19614533A1 (de) * | 1996-04-12 | 1997-10-16 | Basf Ag | Neue alpha-Hydroxysäurederivate, ihre Herstellung und Verwendung |
DE19636046A1 (de) * | 1996-09-05 | 1998-03-12 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten |
WO1998027070A1 (de) | 1996-12-18 | 1998-06-25 | Basf Aktiengesellschaft | Heterozyklische carbonsäurederivate, ihre herstellung und verwendung als endothelinrezeptorantagonisten |
US6030975A (en) * | 1997-03-14 | 2000-02-29 | Basf Aktiengesellschaft | Carboxylic acid derivatives, their preparation and use in treating cancer |
SK1522000A3 (en) * | 1997-09-04 | 2000-08-14 | Basf Ag | Novel carboxylic acid derivatives, their production and their use as mixed eta/etb endothelin-receptor antagonists |
CZ299741B6 (cs) * | 1997-09-26 | 2008-11-05 | Abbott Gmbh & Co. Kg | Kombinace endotelinového antagonisty a RAS inhibitoru a její použití, farmaceutický prostredek s jejím obsahem a zpusob výroby tohoto prostredku |
DE19743142A1 (de) * | 1997-09-30 | 1999-04-01 | Knoll Ag | Pharmazeutische Kombinationspräparate |
DE19743143A1 (de) * | 1997-09-30 | 1999-04-01 | Knoll Ag | Pharmazeutische Kombinationspräparate |
DE19743681A1 (de) * | 1997-10-02 | 1999-04-08 | Knoll Ag | Methode zur Verhinderung der Transplantatabstoßung |
JP2001521927A (ja) * | 1997-10-31 | 2001-11-13 | ビーエーエスエフ アクチェンゲゼルシャフト | アミド側鎖を有する新規のカルボン酸誘導体、その製造およびエンドセリン受容体アンタゴニストとしての使用 |
DE19750529A1 (de) * | 1997-11-14 | 1999-05-20 | Basf Ag | Neue heterocyclisch substituierte alpha-Hydroxycarbonsäurederivate, ihre Herstellung und Verwendung als Endothelinrezeptorantagonisten |
DE19806438A1 (de) * | 1998-02-17 | 1999-08-19 | Basf Ag | Neue Carbonsäurederivate mit 5-substituiertem Pyrimidinring, ihre Herstellung und Verwendung |
DE19809635A1 (de) | 1998-03-06 | 1999-09-09 | Basf Ag | Verfahren zur Darstellung von Endothelinrezeptorantagonisten vom Sulfanyltyp |
DE19850301A1 (de) | 1998-10-30 | 2000-05-04 | Basf Ag | Verfahren zur Racematspaltung von 2-Hydroxypropionsäuren |
US7566452B1 (en) | 1999-05-04 | 2009-07-28 | New York University | Cancer treatment with endothelin receptor antagonists |
DE10002393A1 (de) | 2000-01-20 | 2001-07-26 | Basf Ag | Verfahren zur enantioselektiven Herstellung von 3,3-Diphenyl-2,3-epoxypropionsäureestern |
US8168616B1 (en) | 2000-11-17 | 2012-05-01 | Novartis Ag | Combination comprising a renin inhibitor and an angiotensin receptor inhibitor for hypertension |
DE10064797A1 (de) * | 2000-12-22 | 2002-06-27 | Knoll Ag | Orale und parenterale pharmazeutische Formulierung, umfassend eine niedermolekulare Thrombininhibitor-Pro-Pharmakon |
WO2002064573A1 (de) * | 2001-02-14 | 2002-08-22 | Abbott Gmbh & Co. Kg | Neue carbonsäurederivate mit alkylsubstituierten triazinen, ihre herstellung und verwendung als endothelin-rezeptorantagonisten |
ES2262567T3 (es) | 2001-03-20 | 2006-12-01 | Schwarz Pharma Ag | Nuevo uso de una clase peptidica de compuesto para tratamiento del dolor inflamatorio no neuropatico. |
PT1243263E (pt) | 2001-03-21 | 2003-03-31 | Sanol Arznei Schwarz Gmbh | Nova utilizacao de uma classe peptidica de composto para o tratamento de alodinia ou de outros tipos diferentes de dor cronica ou fantasma |
US6772708B2 (en) * | 2001-10-30 | 2004-08-10 | The Procter And Gamble Company | Wetness indicator having improved colorant retention |
DE10259382A1 (de) * | 2002-12-18 | 2004-07-01 | Abbott Gmbh & Co. Kg | 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung |
US20040204422A1 (en) | 2003-04-14 | 2004-10-14 | Abbott Gmbh & Co. Kg. | N-[(Piperazinyl)hetaryl]arylsulfonamide compounds |
GB0327839D0 (en) | 2003-12-01 | 2003-12-31 | Novartis Ag | Organic compounds |
NZ549535A (en) | 2004-03-17 | 2010-11-26 | Novartis Ag | Use of aliskiren for treating renal and other disorders |
KR20070007931A (ko) | 2004-04-16 | 2007-01-16 | 쉬바르츠파르마에이지 | 만성 두통의 예방 및 치료를 위한 펩티드 화합물의 용도 |
EP1604656A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS) |
JP2008510758A (ja) | 2004-08-27 | 2008-04-10 | シュヴァルツ・ファーマ・アーゲー | 骨肉腫の痛み、化学療法誘発性及びヌクレオシド誘発性の痛みを治療するためのペプチド化合物の新規使用 |
DE102005025161A1 (de) * | 2005-06-01 | 2006-12-07 | Phenion Gmbh & Co. Kg | Derivate des Pyrimidins und Triazins und deren Verwendung |
RU2448964C2 (ru) * | 2006-01-20 | 2012-04-27 | Шеринг Корпорейшн | КАРБОЦИКЛИЧЕСКИЕ И ГЕТЕРОЦИКЛИЧЕСКИЕ АРИЛСУЛЬФОНЫ, ИХ ПРИМЕНЕНИЕ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ, ОБЛАДАЮЩАЯ СВОЙСТВАМИ ИНГИБИТОРА γ-СЕКРЕТАЗЫ |
JP2009533420A (ja) * | 2006-04-13 | 2009-09-17 | アクテリオン ファーマシューティカルズ リミテッド | 早期特発性肺線維症の治療 |
MX2008016000A (es) | 2006-06-15 | 2009-03-05 | Sanol Arznei Schwarz Gmbh | Composicion farmaceutica con efecto anticonvulsivante sinergistico. |
WO2008073928A1 (en) | 2006-12-12 | 2008-06-19 | Gilead Colorado, Inc. | Composition for treating a pulmonary hypertension |
US20080262006A1 (en) * | 2007-02-02 | 2008-10-23 | Harbeson Scott L | Selective endothelin type-a antagonists |
AU2008282773B8 (en) * | 2007-07-31 | 2013-03-07 | Gilead Sciences, Inc. | Metabolites and derivatives of ambrisentan |
US20090069353A1 (en) * | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched ambrisentan |
DE102008037324A1 (de) | 2008-08-11 | 2010-02-18 | Ratiopharm Gmbh | Pharmazeutische Formulierung zur pulmonalen Blutdrucksenkung |
EP2350024A4 (en) * | 2008-11-05 | 2012-03-21 | Msn Lab Ltd | IMPROVED METHOD FOR THE PRODUCTION OF ENDOTHELIN RECEPTOR ANTAGONISTS |
DE202009009917U1 (de) | 2009-07-21 | 2010-02-11 | Ratiopharm Gmbh | Ambrisentan in spezifischer kristalliner Form |
WO2010091877A2 (en) | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
EP2712865B1 (en) | 2009-07-10 | 2016-03-16 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan |
US20110046163A1 (en) * | 2009-08-20 | 2011-02-24 | Moore Ii Bob M | Furanopyrimidine cannabinoid compounds and related methods of use |
EP2509942A2 (en) | 2009-12-07 | 2012-10-17 | Johns Hopkins University | Bis-acylated hydroxylamine derivatives |
MX2012006349A (es) * | 2009-12-07 | 2012-10-03 | Cardioxyl Pharmaceuticals Inc | Derivados de n-aciloxisulfonamida y n-hidroxi-n-acilsulfonamida. |
EP2547663A1 (en) * | 2010-03-15 | 2013-01-23 | Natco Pharma Limited | A process for the preparation of highly pure ambrisentan |
US20130184490A1 (en) * | 2010-08-04 | 2013-07-18 | Natco Pharma Limited | Process to prepare s-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid |
US20120269898A1 (en) | 2010-10-15 | 2012-10-25 | Luiz Belardinelli | Compositions and methods of treating pulmonary hypertension |
EP2476670A1 (en) | 2011-01-07 | 2012-07-18 | Zentiva, K.S. | Stable solid salts of ambrisentan |
CN102276536B (zh) * | 2011-06-10 | 2015-04-29 | 中国科学院化学研究所 | 一种光学纯的(+)-安倍生坦和光学纯的(+)-达芦生坦的制备方法 |
CN103012280B (zh) * | 2011-09-22 | 2015-04-29 | 江苏康缘药业股份有限公司 | 一种制备安立生坦的方法 |
KR101855506B1 (ko) | 2011-10-13 | 2018-05-08 | 주식회사 동진쎄미켐 | 방향족 고리 함유 고분자 및 이를 포함하는 레지스트 하층막 조성물 |
US20140256004A1 (en) | 2011-10-19 | 2014-09-11 | Cipla Limited | Process for the Preparation of an Endothelin Receptor Antagonist |
CA2875942A1 (en) | 2012-06-29 | 2014-01-03 | Kern Pharma, S.L. | Preparation process of carboxylic acid derivatives and intermediates thereof |
CN103524425A (zh) * | 2012-07-04 | 2014-01-22 | 天津药物研究院 | 一种安立生坦的晶型v及其制备方法和应用 |
CN103524424A (zh) * | 2012-07-04 | 2014-01-22 | 天津药物研究院 | 一种安立生坦的晶型vi及其制备方法和应用 |
CN104098462B (zh) * | 2013-04-12 | 2017-11-17 | 江苏豪森药业集团有限公司 | 2‑羟基‑3‑甲氧基‑3,3‑二苯基丙酸消旋物的拆分方法 |
CN104592129B (zh) * | 2013-10-30 | 2019-04-16 | 武汉启瑞药业有限公司 | 一种改进的制备安立生坦的方法 |
CN103709106A (zh) * | 2013-12-06 | 2014-04-09 | 石家庄博策生物科技有限公司 | 一种立体选择性制备安立生坦的方法 |
CN104744231A (zh) * | 2013-12-26 | 2015-07-01 | 天津药物研究院 | 一种拆分2-羟基丙酸消旋体的方法 |
CN105801404B (zh) * | 2014-12-31 | 2019-01-08 | 辽宁远大诺康生物制药有限公司 | 一种s-2-羟基-3-甲氧基-3,3-二苯基丙酸及其制备方法 |
CN106699626B (zh) * | 2015-11-13 | 2019-08-16 | 辽宁远大诺康生物制药有限公司 | 一种2-羟基-3-甲氧基-3,3-二苯基丙酸盐消旋体的制备方法 |
EP3235496A1 (en) | 2016-04-19 | 2017-10-25 | Noorik Biopharmaceuticals AG | Treatment of acute renal failure |
CN109705042B (zh) * | 2017-10-26 | 2021-12-21 | 正大天晴药业集团股份有限公司 | 一种安立生坦的制备方法 |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE403578C (de) | 1924-10-02 | Walter Beige | Verfahren zum Innen-Emaillieren von Roehren | |
JPS5729445B2 (zh) | 1974-06-25 | 1982-06-23 | ||
GB8912700D0 (en) | 1989-06-02 | 1989-07-19 | Shell Int Research | Herbicidal compounds |
JP2771604B2 (ja) * | 1988-06-20 | 1998-07-02 | クミアイ化学工業株式会社 | 除草剤及びその有効成分となる新規なアルカン酸誘導体 |
DE68914197T2 (de) * | 1988-06-20 | 1994-11-10 | Kumiai Chemical Industry Co | Alkansäurederivate und herbizide Mittel. |
JPH0331266A (ja) | 1989-06-27 | 1991-02-12 | Nissan Chem Ind Ltd | ピリミジン誘導体及び除草剤 |
US5270289A (en) | 1989-07-19 | 1993-12-14 | Schering Aktiengesellschaft | Herbicidal dimethoxy pyrimidinyloxy-fluorinated acids and salts |
IL94999A (en) | 1989-07-19 | 1994-10-07 | Schering Ag | History of Acid (A-pyrimidinyloxy) Theo (and A-triazinyloxy) Theo (carboxylic, and herbicides containing them) |
FR2650365B1 (fr) | 1989-07-28 | 1991-11-22 | Caillau Ets | Raccord rapide |
JPH03240777A (ja) | 1990-02-20 | 1991-10-28 | Ube Ind Ltd | 脂肪酸誘導体、その製造法及び除草剤 |
DE4029648A1 (de) | 1990-09-19 | 1992-03-26 | Hoechst Ag | 4-anilino-pyrimidine, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung als fungizide |
CA2053603A1 (en) | 1990-10-19 | 1992-04-20 | Katsumasa Harada | 3-alkoxyalkanoic acid derivative, process for preparing the same and herbicide using the same |
JPH05125058A (ja) * | 1990-10-19 | 1993-05-21 | Ube Ind Ltd | 3−アルコキシアルカン酸化合物、その中間体、その製造法及び除草剤 |
DE4035758A1 (de) | 1990-11-08 | 1992-05-14 | Schering Ag | Substituierte (alpha)-pyrimidinyloxy(thio)- und (alpha)-triazinyloxy(thio)-carbonsaeurederivate, verfahren zu ihrer herstellung und ihre verwendung als mittel mit herbizider, fungizider und pflanzenwachstumsregulierender wirkung |
JP2730021B2 (ja) | 1991-05-31 | 1998-03-25 | 宇部興産株式会社 | 3−ベンジルオキシアルカン酸誘導体、その製造法及び除草剤 |
JP2730022B2 (ja) * | 1991-06-07 | 1998-03-25 | 宇部興産株式会社 | 3−アルコキシブチリルイミダゾール誘導体、その製造法及び除草剤 |
EP0517215B1 (en) * | 1991-06-07 | 1998-09-02 | Ube Industries, Ltd. | Pyrimidine or triazine derivative, process for preparing the same and herbicide using the same |
DE4123469A1 (de) | 1991-07-16 | 1993-01-21 | Basf Ag | Herbizide mittel, die n-dichloracetyl-diazacycloalkane als antagonistische verbindungen enthalten |
CA2125570A1 (en) * | 1991-12-10 | 1993-06-24 | Frank Zurmuhlen | Pyrimidinyl- or triazinyl-oxy(or thio)aldehyde derivatives and their use as herbicides or plant-growth regulators |
DE4142570A1 (de) | 1991-12-21 | 1993-06-24 | Basf Ag | Glykolaldehyd- und milchsaeurederivate, deren herstellung und verwendung |
DE4201875A1 (de) | 1992-01-24 | 1993-07-29 | Basf Ag | Thiocarbonsaeurederivate, verfahren und zwischenprodukte zu ihrer herstellung |
US5376620A (en) | 1992-04-17 | 1994-12-27 | Ube Industries, Ltd. | Sulfonamide derivative, process for preparing the same and herbicide using the same |
AU4321693A (en) * | 1992-06-17 | 1994-01-04 | Ciba-Geigy Ag | Pyrimidinyl-and triazinyl compounds with herbicidal activity |
WO1994000987A2 (en) | 1992-07-08 | 1994-01-20 | Ciba-Geigy Ag | Selective herbicidal composition |
US5541148A (en) | 1992-07-08 | 1996-07-30 | Ciba-Geigy Corporation | Selective safened herbicidal composition comprising 2-ethoxycarbonyl-3-(4,6-dimethoxypyrimidine-2-yl) oxy-pyridine and an acylsulfamoylphenyl-urea safener |
JP2985992B2 (ja) | 1992-07-21 | 1999-12-06 | 宇部興産株式会社 | 3−アルコキシ−n−シクロアルキルスルホニルアルカン酸アミド誘導体、その製造法及び除草剤 |
DE4313413A1 (de) | 1993-04-23 | 1994-10-27 | Basf Ag | 3-(Het)aryloxy(thio)-Carbonsäurederivate, Verfahren und Zwischenprodukte zu ihrer Herstellung |
DE4313412A1 (de) * | 1993-04-23 | 1994-10-27 | Basf Ag | 3-(Het)aryl-Carbonsäurederivate, Verfahren und Zwischenprodukte zu ihrer Herstellung |
DE69423258T2 (de) * | 1993-06-03 | 2000-07-13 | Kanegafuchi Chemical Ind | Härtbare Zusammensetzung |
DE4335950A1 (de) * | 1993-10-21 | 1995-04-27 | Basf Ag | Derivate von 3-Hydroxycarbonsäuren, deren Herstellung und Verwendung |
DE4411225A1 (de) | 1994-03-31 | 1995-10-05 | Basf Ag | Verwendung von Carbonsäurederivaten als Arzneimittel |
WO1996000219A1 (en) | 1994-06-27 | 1996-01-04 | Ciba-Geigy Ag | Pyrimidinyl- and triazinyl-oxy and thio-3-haloalkyl-propionic acid derivatives as herbicides |
DE19533023B4 (de) | 1994-10-14 | 2007-05-16 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung |
WO1996012515A2 (en) | 1994-10-21 | 1996-05-02 | Glaxo Wellcome Inc. | Medicament carrier for dry powder inhalator and process for forming the same |
US6030975A (en) | 1997-03-14 | 2000-02-29 | Basf Aktiengesellschaft | Carboxylic acid derivatives, their preparation and use in treating cancer |
CZ299741B6 (cs) | 1997-09-26 | 2008-11-05 | Abbott Gmbh & Co. Kg | Kombinace endotelinového antagonisty a RAS inhibitoru a její použití, farmaceutický prostredek s jejím obsahem a zpusob výroby tohoto prostredku |
DE19743143A1 (de) | 1997-09-30 | 1999-04-01 | Knoll Ag | Pharmazeutische Kombinationspräparate |
DE19754082A1 (de) | 1997-12-05 | 1999-06-10 | Knoll Ag | Methode zur Bekämpfung der Fettleibigkeit |
DE19850301A1 (de) | 1998-10-30 | 2000-05-04 | Basf Ag | Verfahren zur Racematspaltung von 2-Hydroxypropionsäuren |
DE10002393A1 (de) | 2000-01-20 | 2001-07-26 | Basf Ag | Verfahren zur enantioselektiven Herstellung von 3,3-Diphenyl-2,3-epoxypropionsäureestern |
CN101491028A (zh) | 2006-07-12 | 2009-07-22 | 华为技术有限公司 | 用于控制拥塞的方法 |
AU2008282773B8 (en) | 2007-07-31 | 2013-03-07 | Gilead Sciences, Inc. | Metabolites and derivatives of ambrisentan |
-
1995
- 1995-09-07 DE DE19533023A patent/DE19533023B4/de not_active Expired - Fee Related
- 1995-10-07 PT PT95935916T patent/PT785926E/pt unknown
- 1995-10-07 SI SI9520110A patent/SI9520110A/sl unknown
- 1995-10-07 WO PCT/EP1995/003963 patent/WO1996011914A1/de active IP Right Grant
- 1995-10-07 EP EP01103889A patent/EP1110952B9/de not_active Expired - Lifetime
- 1995-10-07 KR KR1019970702413A patent/KR100438339B1/ko not_active IP Right Cessation
- 1995-10-07 CN CN2006100999548A patent/CN1923820B/zh not_active Expired - Lifetime
- 1995-10-07 EP EP95935916A patent/EP0785926B1/de not_active Expired - Lifetime
- 1995-10-07 DK DK95935916T patent/DK0785926T3/da active
- 1995-10-07 US US12/481,594 patent/USRE42462E1/en not_active Expired - Lifetime
- 1995-10-07 ES ES95935916T patent/ES2162942T3/es not_active Expired - Lifetime
- 1995-10-07 AT AT01103889T patent/ATE277911T1/de not_active IP Right Cessation
- 1995-10-07 ES ES01103889T patent/ES2226996T3/es not_active Expired - Lifetime
- 1995-10-07 CA CA002201785A patent/CA2201785C/en not_active Expired - Lifetime
- 1995-10-07 HU HU9701975A patent/HU220621B1/hu active Protection Beyond IP Right Term
- 1995-10-07 US US08/809,699 patent/US5932730A/en not_active Ceased
- 1995-10-07 BR BR9509338A patent/BR9509338A/pt not_active Application Discontinuation
- 1995-10-07 RU RU97107617/04A patent/RU2180335C2/ru active Protection Beyond IP Right Term
- 1995-10-07 UA UA97052223A patent/UA45985C2/uk unknown
- 1995-10-07 DE DE59510949T patent/DE59510949D1/de not_active Expired - Lifetime
- 1995-10-07 DE DE59509541T patent/DE59509541D1/de not_active Expired - Lifetime
- 1995-10-07 DE DE122008000049C patent/DE122008000049I1/de active Pending
- 1995-10-07 CN CNB951956558A patent/CN1142918C/zh not_active Expired - Lifetime
- 1995-10-07 CZ CZ19971132A patent/CZ294603B6/cs not_active IP Right Cessation
- 1995-10-07 AT AT95935916T patent/ATE204568T1/de active
- 1995-10-07 JP JP51291196A patent/JP3957748B2/ja not_active Expired - Lifetime
- 1995-10-07 MX MX9702658A patent/MX9702658A/es unknown
- 1995-10-07 CN CNB2004100027833A patent/CN1293059C/zh not_active Expired - Lifetime
- 1995-10-11 IL IL11556095A patent/IL115560A/xx not_active IP Right Cessation
- 1995-10-13 ZA ZA958642A patent/ZA958642B/xx unknown
- 1995-10-13 HR HR950517A patent/HRP950517B1/xx not_active IP Right Cessation
- 1995-10-17 TW TW084110900A patent/TW577880B/zh not_active IP Right Cessation
-
1997
- 1997-03-27 PL PL95319655A patent/PL186850B1/pl unknown
- 1997-03-27 NZ NZ294849A patent/NZ294849A/en not_active IP Right Cessation
- 1997-03-27 US US12/481,598 patent/USRE42477E1/en not_active Expired - Lifetime
- 1997-04-11 FI FI971529A patent/FI120492B/fi not_active IP Right Cessation
- 1997-04-11 NO NO971675A patent/NO308846B1/no not_active IP Right Cessation
-
1998
- 1998-11-02 US US09/184,152 patent/US5969134A/en not_active Expired - Lifetime
-
1999
- 1999-05-11 US US09/309,770 patent/US6197958B1/en not_active Expired - Lifetime
-
2000
- 2000-12-27 US US09/748,184 patent/US6600043B2/en not_active Expired - Lifetime
-
2001
- 2001-10-18 GR GR20010401798T patent/GR3036931T3/el unknown
-
2003
- 2003-06-24 US US10/602,275 patent/US7109205B2/en not_active Expired - Fee Related
-
2004
- 2004-04-22 HR HR20040364A patent/HRP20040364B1/xx not_active IP Right Cessation
- 2004-12-01 HK HK04109463A patent/HK1066541A1/xx not_active IP Right Cessation
-
2006
- 2006-03-16 US US11/377,879 patent/US7119097B2/en not_active Expired - Fee Related
- 2006-08-10 US US11/502,293 patent/US7601730B2/en not_active Expired - Fee Related
- 2006-08-10 US US11/502,257 patent/US20060276645A1/en not_active Abandoned
-
2007
- 2007-02-21 JP JP2007040760A patent/JP4787184B2/ja not_active Expired - Lifetime
- 2007-02-21 JP JP2007040758A patent/JP4512105B2/ja not_active Expired - Lifetime
- 2007-02-21 JP JP2007040759A patent/JP4512106B2/ja not_active Expired - Lifetime
- 2007-02-21 JP JP2007040761A patent/JP5160797B2/ja not_active Expired - Lifetime
- 2007-04-25 US US11/789,630 patent/US7582647B2/en not_active Expired - Fee Related
- 2007-09-04 HK HK07109567.7A patent/HK1104293A1/xx not_active IP Right Cessation
-
2008
- 2008-10-15 NL NL300361C patent/NL300361I2/nl unknown
- 2008-10-15 LU LU91487C patent/LU91487I2/fr unknown
- 2008-10-17 NO NO2008015C patent/NO2008015I2/no unknown
- 2008-10-21 FR FR08C0041C patent/FR08C0041I2/fr active Active
-
2009
- 2009-08-17 US US12/542,050 patent/US7863445B2/en not_active Expired - Fee Related
-
2010
- 2010-12-03 US US12/959,849 patent/US20110178294A1/en not_active Abandoned
-
2011
- 2011-10-06 US US13/267,178 patent/US8349843B2/en not_active Expired - Fee Related
-
2012
- 2012-02-01 JP JP2012019532A patent/JP5700378B2/ja not_active Expired - Lifetime
- 2012-11-27 US US13/686,182 patent/US20130317044A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1293059C (zh) | 新的羧酸衍生物,其制备和应用 | |
CN1189166C (zh) | Fc受体调节剂及其应用 | |
CN1036920C (zh) | 含杂环碳酸衍生物 | |
CN1261099C (zh) | 四氢喹啉衍生物 | |
CN1186332C (zh) | 新的甲状腺受体配位体及方法ⅱ | |
CN1016778B (zh) | 螺-取代的戊二酸单酰胺 | |
CN1656077A (zh) | 制备手性二醇砜和二羟基酸HMGCoA还原酶抑制剂的方法 | |
CN1812973A (zh) | 可用作蛋白激酶抑制剂的吲唑化合物 | |
CN1407972A (zh) | 4-嘧啶基-n-酰基-l-苯基丙氨酸类化合物 | |
CN1344160A (zh) | 用作生长激素促分泌剂的杂环芳族化合物 | |
CN1592623A (zh) | 具有mGluR5拮抗活性的乙炔衍生物 | |
CN1441782A (zh) | 作为nk1受体拮抗剂前药的4-苯基-吡啶衍生物的n-氧化物 | |
CN1202107A (zh) | 选择性β3肾上腺素兴奋剂 | |
CN1630633A (zh) | 用作缓激肽拮抗剂的在其甲基上具有取代基的n-联苯甲基氨基环烷烃羧酰胺衍生物 | |
CN1681789A (zh) | 1-吡啶-4-基-脲衍生物 | |
CN1234029A (zh) | 色烯-3-羚酸衍生物 | |
CN1040980C (zh) | 第二信使细胞信号传送抑制剂 | |
CN1449380A (zh) | 作为选择性5-羟色胺再摄取抑制剂的苯氧基苄胺衍生物 | |
CN1106389A (zh) | 氨基喹啉衍生物 | |
CN1599720A (zh) | 作为g-蛋白偶联受体(gpcr)的配体的四氢咔唑衍生物 | |
CN1139580C (zh) | 取代的苄胺及它们用于治疗抑郁症的用途 | |
CN1167710C (zh) | 吡咯烷羰基氨基环状二硫化物 | |
CN1121707A (zh) | 用作抗癌剂和抗原生动物剂的不饱和氨基化合物 | |
CN1251991A (zh) | 新的羧酸衍生物,它们的制备以及在癌症治疗方面的用途 | |
CN1575282A (zh) | 内酰胺化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1066541 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term |
Granted publication date: 20070103 |
|
EXPY | Termination of patent right or utility model |