JPH09508372A - 新規のロイコトリエン−b▲下4▼−誘導体、その製造方法およびその薬剤としての使用 - Google Patents
新規のロイコトリエン−b▲下4▼−誘導体、その製造方法およびその薬剤としての使用Info
- Publication number
- JPH09508372A JPH09508372A JP7519846A JP51984695A JPH09508372A JP H09508372 A JPH09508372 A JP H09508372A JP 7519846 A JP7519846 A JP 7519846A JP 51984695 A JP51984695 A JP 51984695A JP H09508372 A JPH09508372 A JP H09508372A
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- alkyl
- formula
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title claims description 8
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 title claims description 7
- 229940079593 drug Drugs 0.000 title claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 18
- 239000000460 chlorine Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 17
- 150000001336 alkenes Chemical class 0.000 claims abstract description 16
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011737 fluorine Substances 0.000 claims abstract description 8
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims abstract description 8
- 239000001301 oxygen Substances 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 7
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 239000011593 sulfur Substances 0.000 claims abstract description 7
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims abstract description 6
- 150000007524 organic acids Chemical group 0.000 claims abstract description 6
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000008030 elimination Effects 0.000 claims description 11
- 238000003379 elimination reaction Methods 0.000 claims description 11
- 238000007127 saponification reaction Methods 0.000 claims description 10
- 230000009467 reduction Effects 0.000 claims description 9
- 150000001735 carboxylic acids Chemical class 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000001212 derivatisation Methods 0.000 claims description 2
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 claims 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 claims 1
- 229940099552 hyaluronan Drugs 0.000 claims 1
- 229920002674 hyaluronan Polymers 0.000 claims 1
- -1 hydrogen salts Chemical class 0.000 abstract description 76
- 150000001875 compounds Chemical class 0.000 abstract description 46
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 7
- 229910052799 carbon Inorganic materials 0.000 abstract description 7
- 125000002947 alkylene group Chemical group 0.000 abstract description 6
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- 125000004429 atom Chemical group 0.000 abstract description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-M leukotriene B4(1-) Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC([O-])=O VNYSSYRCGWBHLG-AMOLWHMGSA-M 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 239000000243 solution Substances 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 239000002253 acid Substances 0.000 description 37
- 239000012230 colorless oil Substances 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 238000000034 method Methods 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 150000001299 aldehydes Chemical class 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- 150000002617 leukotrienes Chemical class 0.000 description 15
- 230000003647 oxidation Effects 0.000 description 15
- 238000007254 oxidation reaction Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000012027 Collins reagent Substances 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 150000002168 ethanoic acid esters Chemical class 0.000 description 6
- 125000001033 ether group Chemical group 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 5
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- YZGQDNOIGFBYKF-UHFFFAOYSA-N Ethoxyacetic acid Chemical compound CCOCC(O)=O YZGQDNOIGFBYKF-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 239000003810 Jones reagent Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- UOUJSJZBMCDAEU-UHFFFAOYSA-N chromium(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+3].[Cr+3] UOUJSJZBMCDAEU-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- WQEPLUUGTLDZJY-UHFFFAOYSA-N pentadecanoic acid Chemical compound CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 4
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000005973 Carvone Substances 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000003795 desorption Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 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
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003848 thrombocyte activating factor antagonist Substances 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004954 trialkylamino group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/54—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings and other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 一般式I: 〔式中、 R1は、CH2OH、CH3、CF3、COOR4、COOR5R6、かつ、 R2は、Hまたは炭素原子1〜15個を有する有機酸基を表し、 R3は、H、1個または多数個の置換を有していてもよいC1〜C14−アルキル 、C3〜C10−シクロアルキル、互いに独立して1個または多数個のハロゲン、 フェニル、C1〜C4−アルキル、C1〜C4−アルコキシ、フルオロメチル、クロ ロメチル、トリフルオロメチル、カルボニル、カルボキシルまたはヒドロキシル により置換されていてもよいC6〜C10−アリール基または少なくともヘテロ原 子1個を有する5〜6員芳香族複素環を表し、 R4は、水素、C1〜C10−アルキル、C3〜C10−シクロアルキル、1〜3個 のハロゲン、フェニル、 C1〜C4−アルキル、C1〜C4−アルコキシ、フルオロメチル、クロロメチル、 トリフルオロメチル、カルボキシルまたはヒドロキシルにより置換されていても よいC6〜C10−アリール基、CH2−CO−(C6〜C10)アリールまたは少な くともヘテロ原子1個を有する5〜6員環を表し、 Aは、トランス,トランス−CH=CH−CH=CH、CH2CH2−CH−C H−またはテトラメチレン基、 Bは、フッ素により置換されていてもよいC1〜C10−直鎖または分枝状鎖ア ルキレン基または基: を表し、 Dは、直接結合、酸素、硫黄、−C≡C−、−CH=CR7、またはBと一緒 に直接結合を表してもよく、 R5およびR6は、同じかまたは異なっており、かつHまたはヒドロキシル基に より置換されていてもよいC1〜C4−アルキルまたはR6がHかつR5がC1〜C1 5 −アルカノイルまたはR8SO2を表し、 R7は、H、C1〜C5−アルキル、塩素、臭素を表し、 R8は、R3と同じものを表し、 mは、1〜3を表し、 nは、2〜5であり、 XおよびYは直接結合を表し、その際、結果として生じるオレフィンEまたは Zは立体配置していてもよく、またはXはα−またはβ−位のフッ素原子を表し 、かつYはβ−位の水素原子を表す。〕のロイコトリエン−B4−誘導体ならび にR4が水素を表す場合には生理学的に許容性の塩基とのその塩およびそのシク ロデキストリン包接体。 2.請求項1記載の一般式Iのロイコトリエン−B4誘導体を含有することを 特長とする薬剤。 3.請求項1記載のロイコトリエン−B4誘導体を製造する方法において、式I I: 〔式中、A、B、D、R1、R2およびR3は上記のものを表し、かつR’1はR1 と同じものを表すかまたは基−CH2OR9(式中、R9は容易に脱離できるエー テル基を表す)を表す〕のアルコールを場合によればR2中の遊離ヒドロキシル 基を保護した後に、水脱離試薬または一般式III: F3SN(Alk)3 (III) 〔式中、Alkは、−CH3または−CH2CH3を表す〕のフッ素化試薬を用い て場合によれば塩基の存在下で変換させ、かつ場合により、引き続き任意の順序 で異性体を分離し、保護したヒドロキシル基を遊離させ、および/または遊離ヒ ドロキシル基をエステル化し、および/または1−ヒドロキシル基をカルボン酸 に酸化し、および/または二重結合を水素化し、および/またはエステル化カル ボキシル基を鹸化し、および/または還元し、および/またはカルボキシル基を エステル化し、および/または遊離カルボキシル基をアミドに誘導し、またはカ ルボキシル基を生理学的に許容性の塩基と一緒に塩に誘導してもよいことを特長 とするロイコトリエン−B4誘導体の製造方法。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP1994/000215 WO1995020563A1 (de) | 1994-01-27 | 1994-01-27 | Neue leukotrien-b4-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH09508372A true JPH09508372A (ja) | 1997-08-26 |
JP3565857B2 JP3565857B2 (ja) | 2004-09-15 |
Family
ID=8165822
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51984695A Expired - Fee Related JP3565857B2 (ja) | 1994-01-27 | 1994-01-27 | 新規のロイコトリエン−b▲下4▼−誘導体、その製造方法およびその薬剤としての使用 |
Country Status (10)
Country | Link |
---|---|
US (1) | US5783602A (ja) |
EP (1) | EP0741686B1 (ja) |
JP (1) | JP3565857B2 (ja) |
AU (1) | AU696792B2 (ja) |
DE (1) | DE59405814D1 (ja) |
DK (1) | DK0741686T3 (ja) |
ES (1) | ES2118379T3 (ja) |
FI (1) | FI962994A (ja) |
NO (1) | NO309678B1 (ja) |
WO (1) | WO1995020563A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19722846A1 (de) * | 1997-05-23 | 1998-12-24 | Schering Ag | Leukotrien-B¶4¶-Derivate, insbesondere 7-Methylcyclohexyl-LTB¶4¶-Antagonisten |
DE19722848A1 (de) * | 1997-05-23 | 1998-11-26 | Schering Ag | Leukotrien-B¶4¶-Derivate, insbesondere Oximo-LTB¶4¶-Antagonisten |
DE19722845A1 (de) * | 1997-05-23 | 1998-12-10 | Schering Ag | Leukotrien-B¶4¶-Derivate, insbesondere Interphenylen-7-Methylcyclohexyl-LTB¶4¶-Antagonisten |
US8729108B2 (en) * | 2008-06-17 | 2014-05-20 | Christopher J Dannaker | Waterborne topical compositions for the delivery of active ingredients such as azelaic acid |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3917597A1 (de) * | 1989-05-26 | 1990-11-29 | Schering Ag | Neue leukotrien-b(pfeil abwaerts)4(pfeil abwaerts)-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
DE4108351A1 (de) * | 1991-03-12 | 1992-09-17 | Schering Ag | Neue leukotrien-b(pfeil abwaerts)4(pfeil abwaerts)-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
DE4227790A1 (de) * | 1992-08-19 | 1994-02-24 | Schering Ag | Neue Leukotrien-B¶4¶-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
DE4242390A1 (de) * | 1992-12-09 | 1994-06-16 | Schering Ag | Neue Leukotiren-B¶4¶-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
-
1994
- 1994-01-27 US US08/682,699 patent/US5783602A/en not_active Expired - Fee Related
- 1994-01-27 DE DE59405814T patent/DE59405814D1/de not_active Expired - Fee Related
- 1994-01-27 ES ES94905713T patent/ES2118379T3/es not_active Expired - Lifetime
- 1994-01-27 DK DK94905713T patent/DK0741686T3/da active
- 1994-01-27 EP EP94905713A patent/EP0741686B1/de not_active Expired - Lifetime
- 1994-01-27 JP JP51984695A patent/JP3565857B2/ja not_active Expired - Fee Related
- 1994-01-27 WO PCT/EP1994/000215 patent/WO1995020563A1/de active IP Right Grant
- 1994-01-27 AU AU59714/94A patent/AU696792B2/en not_active Ceased
-
1996
- 1996-07-26 FI FI962994A patent/FI962994A/fi not_active Application Discontinuation
- 1996-07-26 NO NO963129A patent/NO309678B1/no not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO963129L (no) | 1996-09-27 |
FI962994A0 (fi) | 1996-07-26 |
JP3565857B2 (ja) | 2004-09-15 |
DE59405814D1 (de) | 1998-05-28 |
US5783602A (en) | 1998-07-21 |
AU5971494A (en) | 1995-08-15 |
NO309678B1 (no) | 2001-03-12 |
AU696792B2 (en) | 1998-09-17 |
DK0741686T3 (da) | 1999-02-22 |
ES2118379T3 (es) | 1998-09-16 |
EP0741686A1 (de) | 1996-11-13 |
FI962994A (fi) | 1996-07-26 |
EP0741686B1 (de) | 1998-04-22 |
NO963129D0 (no) | 1996-07-26 |
WO1995020563A1 (de) | 1995-08-03 |
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