CA2082818A1 - Leukotriene b4 derivatives, method for preparing them and their use as drugs - Google Patents
Leukotriene b4 derivatives, method for preparing them and their use as drugsInfo
- Publication number
- CA2082818A1 CA2082818A1 CA002082818A CA2082818A CA2082818A1 CA 2082818 A1 CA2082818 A1 CA 2082818A1 CA 002082818 A CA002082818 A CA 002082818A CA 2082818 A CA2082818 A CA 2082818A CA 2082818 A1 CA2082818 A1 CA 2082818A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- acid
- group
- chlorine
- bromine
- 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.)
- Abandoned
Links
- 150000002615 leukotriene B4 derivatives Chemical class 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 16
- 229940079593 drug Drugs 0.000 title description 3
- 239000003814 drug Substances 0.000 title description 3
- -1 organic acid radical Chemical class 0.000 claims abstract description 69
- 239000000460 chlorine Substances 0.000 claims abstract description 31
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 30
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 24
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 13
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims abstract description 12
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 10
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011737 fluorine Substances 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims abstract description 8
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 6
- 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 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 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims abstract 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 141
- 150000001875 compounds Chemical class 0.000 claims description 49
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 229910052740 iodine Chemical group 0.000 claims description 7
- 150000001735 carboxylic acids Chemical class 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 239000011630 iodine Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 74
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- 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 54
- 238000001704 evaporation Methods 0.000 description 50
- 230000008020 evaporation Effects 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- 239000012230 colorless oil Substances 0.000 description 40
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 229960001866 silicon dioxide Drugs 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 229910052786 argon Inorganic materials 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 19
- 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 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000012267 brine Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 14
- 230000003647 oxidation Effects 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- 239000012027 Collins reagent Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 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 12
- 150000002148 esters Chemical class 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 7
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 150000002617 leukotrienes Chemical class 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 229910052749 magnesium Inorganic materials 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- GWNVDXQDILPJIG-YKRBYRBKSA-N (5s,6r,7e,9e,11z,14z)-6-[(2s)-2-[[(4s)-4-amino-4-carboxybutanoyl]amino]-3-(carboxymethylamino)-3-oxopropyl]sulfanyl-5-hydroxyicosa-7,9,11,14-tetraenoic acid Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-YKRBYRBKSA-N 0.000 description 5
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000003810 Jones reagent Substances 0.000 description 5
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- NKRNGKIEDAVMHL-UHFFFAOYSA-L dihydroxy(dioxo)chromium;pyridine Chemical compound O[Cr](O)(=O)=O.C1=CC=NC=C1 NKRNGKIEDAVMHL-UHFFFAOYSA-L 0.000 description 5
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 150000004679 hydroxides Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 5
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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
- YVHAIVPPUIZFBA-UHFFFAOYSA-N Cyclopentylacetic acid Chemical compound OC(=O)CC1CCCC1 YVHAIVPPUIZFBA-UHFFFAOYSA-N 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 239000013078 crystal Substances 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
- 125000004185 ester group Chemical group 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 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
- 239000000463 material Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 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
- 238000006772 olefination reaction Methods 0.000 description 4
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 4
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- SZHOJFHSIKHZHA-UHFFFAOYSA-N tridecanoic acid Chemical compound CCCCCCCCCCCCC(O)=O SZHOJFHSIKHZHA-UHFFFAOYSA-N 0.000 description 4
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 4
- ASJCSAKCMTWGAH-RFZPGFLSSA-N (1r,2r)-cyclopentane-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCC[C@H]1C(O)=O ASJCSAKCMTWGAH-RFZPGFLSSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
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- NXKFMUFJMLNJOB-KNVOCYPGSA-N [(1r,2s)-2-(hydroxymethyl)cyclopentyl]methanol Chemical compound OC[C@H]1CCC[C@H]1CO NXKFMUFJMLNJOB-KNVOCYPGSA-N 0.000 description 1
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- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
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- 229960001123 epoprostenol Drugs 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
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- 235000003969 glutathione Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000037189 immune system physiology Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
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- 238000001764 infiltration Methods 0.000 description 1
- 239000005550 inflammation mediator Substances 0.000 description 1
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- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
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- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GLGNSAPAWZUDRT-UHFFFAOYSA-N morpholine-4-sulfonic acid Chemical compound OS(=O)(=O)N1CCOCC1 GLGNSAPAWZUDRT-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 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
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- HNDXKIMMSFCCFW-UHFFFAOYSA-N propane-2-sulphonic acid Chemical compound CC(C)S(O)(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- QXJQHYBHAIHNGG-UHFFFAOYSA-N trimethylolethane Chemical compound OCC(C)(CO)CO QXJQHYBHAIHNGG-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1
- 230000008728 vascular permeability Effects 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
- A61P11/00—Drugs for disorders of the respiratory system
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- 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
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- 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]
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/05—Alcohols containing rings other than six-membered aromatic rings
- C07C33/12—Alcohols containing rings other than six-membered aromatic rings containing five-membered rings
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- 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
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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Abstract
Abstract Leukotriene-B4 derivatives of formula I
(I) are described, in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, C1-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group
(I) are described, in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, C1-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group
Description
% ~ .J ~ ~ ~ J~, New Leuko~riene-B~ Derivatives, Proce~ for their Produatio~
and their ~se a~ Pharmaceutical ~gent~
LTB4 antagonists, which contain a six-membered ring as a ~asic structural element, are already known from German laid-open specification DE 39 17 597.
The invention relates to new leukotriene-B4 derivatives, the process for their production as well as their use as pharmaceutical agents.
Leukotriene B4 (LTB4) was discovered in 1979 by B.
Samuelsson et al. as a metabolite of arachidonic acid.- In the biosynthesis, leukotriene A4 is formed by the enzyme 5-lipoxy~genase first as a central intermediate product, which then is converted by a specific hydrolase to the LTB4.
COOH H OOH
~\ Lipoxygenase C~ =
Arachidonsaure 5-~'ETE
~~hydrase ~, ~,>~~ COOH
~=~ C5Hll Leukotrien A4 ( LTAA ) \ydrolase \~ H OH H OH
Giutathion- ~:~< COOH
S-transferase 1 , ~, CsHll HO H Leukotrien B4 ( LTB4 ) COOH
C5HIl H S
Cys-Gly ~-GIu Leukotrien C~ ( LTC4 ) - '.
,~ . - ` .
, ~ 3 KEY:
Arachidonsaure = arachidonic acid Leukotrien A4 (LTA4) = leukotriene A4 (LTA4) Glutathion S-transferase = glutathione - S-transferase Leukotrien B4 (LTB4) = leukotriene B4 (LTB4) Leukotrien C4 (LTC4) = leukotriene C4 (LTC4) ;
The nomsnclature of the leukotrienes can be gathered from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 645 (~980); 17, 785 (1979).
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological importance of leukotriene B4 is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. W.
Chakrin, D. M. Bailey, ~cademic Press 1~ b) Ju W. Gillard et al., Drugs of the Future 12, ~53 (1987). c) B. Samue~sson et al., Science 237, 1171 (1987). d) C. W. Parker, Drug Development Research lO, 277 (~987). It follows from the above that LTB4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
It is known from the LTB4 that it causes the adhesion of laukocytes on the blood vessel wall. LTB4 is chemotactically effective, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration.
Further, because of its chemotactic activity, it indirectly changes the vascular permeability, and a synergism with prostaglandin E2 is observed. LTB4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin diseases, which accompany inflammatory processes (increased vessel permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne.
.
c ~ ~
Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis.
Further, leukotrienes and LTB4 are involved especially in arthritis, chronic lung disease (e.g., asthma)~ rhinitis and inflammatory intestinal diseases.
Antagonists against LTB4 receptors or inhibitors of those enzymes which are involved in the synthesis of the LTB4 should b~
effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
Besides the therapeutic possibilities, which can be derived from counteracting of LTB4 action with LTB4 analogs, the usefulness and potential use of leukotriene-B4 agonists for the treatment of fungus diseases of the skin was also able to be shown (H. Katayama, Prostaglandins 34, 797 (1988)~.
The invention relates to leukotriene-B4 derivatives of formula I
- ~ , ~ Rl (I), A ~ B-D-R4 in which R1 means CH20H, CH3, CF3, COORs, CoNR6R7, or R1 together with R2 means a carbonyl group, .
t~
R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, Cl-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R means hydrogenl C1-C1o alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, Cl-C4 al~yl, C1-C4 alkoxy, fluoromethyl~ chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C~o) aryl or a 5-6-membered ring with at least l heteroatom, `
A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a Cl-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group -C-CH2-, (CHz) n D can mean a direct bond, oxygen, sulfur, -C-C-, -CH=CR8 or together with B can also mean a dirsct bond, R6 and R7 are the same or different and represent H or C~-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, c1-cS alkyl r chlorine, bromine, ,. , . - ' ', ~
' ' ' -~ J ~J ~
n is 3-5 as well as, if Rs means hydrogen, its salts with physiologically compatible bases and its cyclodextrin clathrates.
Groups o~2 and oR3 can be in ~- ox ~-position. Formula I
comprises both racemates and the possible pure diastereomers and enantiomers.
As alkyl groups R5, straight-chain or branched-chain alkyl groups with 1-10 C atoms are suitable, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl. Alkyl groups Rs can optionally be substituted once to several times by halogen atoms,.alkoxy groups, optionally substituted aryl or aroyl groups with 6-10 C
atoms (for substitution, see under Aryl R5), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl part, and the ~imple substitution is to be preferred. As substituents, there can be mentioned, for example, fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. As preferred alkyl groups R5, those with 1-4 C atoms are to be mentioned.
Cycloalkyl group R5 can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopentyl, cyclohexyl, methylcyclohexyl.
As aryl groups R5, both substituted and unsubstituted aryl groups with 6-10 C atoms are suitable, such as, for example, phenyl, 1-naphthyl and 2~naphthyl, which respectively can be substituted by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with respectively 1-4 C atoms, a chloromethyl, - :
fluoromethyl, ~rifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Preferred substituents in 3- and 4-position on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoromethyl, however, hydroxy in 4-position.
As heterocyclic groups R5, 5- and 6-membered aromatic heterocycles are suitable, which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-~etraæolyl, i.a.
As acid radical R6, physiologically compatible acid radicals are suitable~ Preferred acid~ are organic carboxylic acids and ~ulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsatuxated and/or polybasic and/or substituted in the usual way. As examples for the substituent~, C14 alkyl, hydroxy, C14 alkoxy~
oxo or amino groups or halogen atoms ~F, Cl, Br) can be mentioned. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimet~ylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trirhloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, Cl4 alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As especially preferred acyl radicals and alkanesulfonyl radicals, those with up to 10 carbon atoms are suitable. As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, ~-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-diethylaminosulfonic acid, N,N-bis-(~-chloroethyl)-aminosulfonic acid, N,N-diisobutylaminosul~onic acid, N,N-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, N-methylpiperazino, and morpholinosulfonic acid are suita~le.
As alkyl groups R4, straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-14, especially 1-10 C a*oms, are suitable, which optionally can be substituted by optionally substituted phenyl tfor substitution, see under Aryl R5). For example, there can be mentioned methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups. If alkyl groups " .
:~:, , ;' 2 ~
R4 are halogen-substituted, fluorine, chlorine and bromine are suitable as halogens.
As examples for halogen-substituted alkyl groups R4, al~yls with terminal trifluoromethyl groups are suitable.
Cycloalkyl group R4 can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl- -cyclohexyl.
As substituted or unsubstituted aryl groups R4, fo~ example, phenyl, l-naphthyl and 2-naphthyl, which respectively can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with respectively 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C1-C4 alkoxy or hydroxy group are suitable. The substitution in 3- and 4 position on the phenyl ring, for example, by fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy is preferred.
As heterocyclic aromatic groups R4, 5- and 6-membered heterocycles are suitable which contain at least 1 heteroatom, pre~erably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a.
As alkylene group B, straight-chain or branched-chain, saturated or unsaturat d alkylene radicals, pre~erably saturated with 1-10, especially with 1-5 C atoms are suitable, which optionally can be substituted by fluorine atoms. For example, ~' ' `
there can be mentioned: methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene, 1,2-difluoroethylene, l-fluoroethylene, l~methyltetramethylene, 1-methyltrimethylene, 1-methylene-ethylene, 1-methylenetetramethylene.
Alkylene group B can further represent the group -C-CH2-, in which n = 3-5, preferably 4-5. (CH2)n As acid radicals R2 and R3, physiologically compatible acid radicals are suitable. Preferred acids are organic ca~boxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocy¢lic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. As examples for the substituents, C~,4 alkyl, hydroxy, C14 alkoxy, oxo or amino groups or haloyen atoms (F, Cl, Br) can be mentioned.
For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, , ll - æ~
diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, Br), trifluoromethyl, hydroxy, C14 alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As especially preferred acid radicals R2 and R3, acyl radicals with up to 10 carbon atoms are suitable.
Alkyl radicals R6 and R7 are straight-chain or branched alkyl radicals, especially straight-chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, especially preferably methyl.
R8 as Cl5 alkyl means straight-chain or branched-chain alkyl radicals such as were already mentioned for R4 or R5. Preferred alkyl radicals R8 are methyl, ethyl, propyl and isopropyl.
Inorganic and organic bases are suitable for salt formation, as they are known to one skilled in the art for forming physiologically compatible salts. For example, there can be mentioned alXali hydroxides, such as sodium hydroxide and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
Pre~erred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
R1 is CH20H, COORs with Rs meaning a hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, `
, ~ 3 phenyl~ C14 alkyl, C~ 4 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy, A is a trans, trans-CH=CH-CH=CH- or tetramethylene group;
B is a straight-chain or branched-chain, saturated or unsaturated alkylene group with up to 10 C atoms, which optionally can be substituted by fluorine or the group -jC-CHz-~CH2) n with n = 3-5; --D is a direct bond, oxygen, sulfur, a -C_C- group or a -CH=CR8 group with R8 as hydrogen, C1s alkyl, chlorine or bromine;
B and D together are a direct bond;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-15 C atoms;
R1 and R2 together are a carbonyl group;
R4 is a hydrogen atom, C1l0 alkyl, cycloalkyl with 5-6 C
atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, C14 alkyl, C14 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy and if R5 means a hydrogsn atom, their salts with physiologically compatible bases and their cyclodextrin clathrates.
Especially preferred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
R1 is CH20H, COORs with R5 meaning a hydrogen a~om, an alkyl radical with 1-4 C atoms;
A is a trans, trans CH=CH-CH=CH- or tetramethylene group;
, ::
- ' : ~. ' ~, .
. ; . .
8 ~ ~
B is a straight-chain or branched chain alkylene group with up to 5 C atoms;
D is a direct bond or a -C-C- group or a -CH=CR~ group with R8 as hydrogen or C1 5 alkyl;
B and D together are a direct bond;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-6 C atoms;
R1 and R2 together are a carbonyl group;
R4 is a hydrogen atom or C110 alkyl and if R5 means a hydrogen atom, their salts with physiologically compat ble bases and their cyclodextrin clathrates.
The invention further relates to a process for the production of compounds of formula I accordiny to the invention, which is characterized in that an aldehyde of formula II
CHO
(II), A _~B-D-R4 in which A, B, D, R3 and R4 have the above-indicated meanings, optionally after protection of free hydroxy groups with a magnesium-organic compound of formula III, X-Mg-CH2-CH2-CH2-CH~-R9 (III), in which X represents chlorine, bromine or iodine and ~9 represents -CH3, CF3 or -OR10, in which R10 means an easily cleavable ether radical, is reacted and optionally then isomers are separated in any sequence, protected hydroxy groups are released and/or a free hydroxy group is esterified and/or the 1 - ' ' ~
~ .J ~ ~ ~ g ~ydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxyl group (R1 = COORs3 is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is converted to an amide (R1 = CoNHR6R7) or a carboxyl group with a physiologically compatible base is converted to a salt.
As ether radicals R9 in the compound of formula III, the radicals familiar to one skilled in the art are suitable. Easily cleavable ether radicals, such as, for example, dimethyl-tert-butylsilyl, trimethylsilyl, tribenzylsilyl, diphenyl-tert-butyl~ilyl, tetrahydropyranyl, tetrahydrofuranyl and ~-ethoxyethyl, to name only a few, are preferable.
The reaction of the compound of formula II with an organometallic compound of formula III takes place in a way known in the art in an inert solvent or solvent mixture, such as, for example, diethyl ether, tetrahydrofuran, dioxane, toluene, dimethoxyethane, preferably diethyl ether or tetrahydrofuran.
The reaction is performed at temperatures between -100C and 60C, preferably at -78C to 0C.
The production of the compound of formula III necessary for this reaction takes place by reaction of the corresponding hydroxy halide by etherification with dihydropyran and p-toluenesulfonic acid and subsequent reaction with magnesium.
The reduction to the compounds of formula I with R1 meaning a CH20H group is performed with a reducing agent suitable for the reduction of esters or carboxylic acids, such as, for example, lithium aluminum hydride, diisobutyl aluminum hydride, etc. As : ~
:, ' , , ~; r; ,~4 r~ 7 solvent, diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc., are suitable. The reduction is performed at temperatures of -30C up to boiling temperature of the solvent used, preferably 0C to 30C.
The esterification of the alcohols of formula I (R2 = H
and/or R3 = H) takes place in a way known in the art. For example, the esterification takes place în that an acid derivative, preferably an acid halide or acid anhydride, is reacted in the presence of a base, such as, for example, NaH, pyridine, triethylamine, tributylamine or 4-dimethylam~nopryidine with an alcohol of formula I. The reaction can be per~ormed without solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, DMSO at temperatures above or below room temperature, for example, between 80C to 100C, preferably at room temperature.
The oxidation of the l-hydroxy group is performed according to the methods known to one skilled in the art. As oxidizing agents, for example, there can be used: pyridinium dichromate (Tetrahedron Letters, 1979, 399~, ~ones reagent (J. Chem. Soc.
1953, 2555) or platinum/oxygen (Adv. in Carbohydrate Chem. 17, 169 (1962)) or Collins oxidation and subsequent Jones oxidation.
The oxidation with pyridinium dichromate is performed at temperatures of 0C to 100C~ preferably 20C to 40C in a solvent inert toward the oxidizing agent, for example, dimethylformamide.
The oxidation with Jones reagent is performed at temperatures of -40C to +40C, preferably 0C to 30C in acetone as solvent.
.
' Cs~$~j ~
The oxidation with platinum/oxygen is performed at temperatures of 0C to 60C, preferably 20C to 40C in a solvent inert toward the oxidizing agent, such as, e.g., ethyl acetate.
The saponification of the esters of formula I is performed according to the methods known to one s~illed in the art, such as, for example, with basic catalysts~ The compounds of formula I can be separated by the usual separating methods into the optical isomers.
~ he release of the functionally modified hydroxy groups takes place according to known methods. For example, the cleavage of hydroxy protecting groups, such as, for example, the tetrahydropyranyl radical, is performed in an aqueous solution of an organic acid, such as, e.q., oxalic acid, acetic acid, propionic acid, i.a., or in an aqueous solution of an inorganic acid, such as, e.g., hydrochloric acid. To improve the solubility, a water-miscible, inert organic solvent is suitably added. Suitable organic solvents are, e.g., alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used.
The cleavage is performed preferably at temperatures between 20C
and 80C. The cleavage of the silyl ether prot~cting groups takes place, for example, with tetrabutylammonium fluoride or with potassium fluoride in the presence of a crown ~ther. As solvent, for example, tetrahydro~uran, diethyl ether, dioxane, methylene chloride, etc., are suitable. The cleavage is performed preferably at temperatures between 0C and 80C.
. .
, ~t~i~js~f~
The saponification of the acyl groups takes place, for example, with alkali or alkaline-earth carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. As an alcohol, aliphatic alcohols are suitable, such as, e.g~, methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and hydroxides, potassium salts and sodium salts can be mentioned. The potassium salts are preferred.
As alkaline-ear*h carbonates and hydroxides, for example, calcium carbonate, calcium hydroxide and barium carbonate are suitable. The reaction takes place at -10C to +70C,-preferably at ~25C.
//
The introduction of ester group -C for R1, in which R5 ORs represents an alkyl group with 1-10 C atoms, takes place according to the methods known to one skilled in the art. The 1-carboxy compounds are reacted, for example, with diazohydrocarbons in a way known in the art. The esterification with diazohydrocarbons takes place, e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the l-carboxy compound in the same or in another inert solvent, such as, e.g., methylene chloride. After completion of the reaction in ~ to 30 minutes, the solvent is removed and the ester is purified in 'he usual way. Diazoalkanes are either known or can be produced according to known methods tOrg. Reactions Vol. 8, pages 389-394 (19S4~].
s~
The introduction of ester group -C for R1, in which Rs \oR5 represents a substituted or unsubstituted aryl group, takes place according to the methods known to one skilled in the art. For example, the l-carboxy compounds with the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example, pyridine, DMAP, triethylamine, in an inert solvent. As solvent, methylene ahloride, ethylene chloride, chloroform, ethyl acetate-, tetrahydrofuran, preferably chloro~orm, are suitable. The reaction is performed at temperatures between -30C and +50C, preferably at 10C.
If C=C double bonds contained in the primary product are to be reduced, the hydrogenation takes place according to methods known in the art.
The hydrogenation of the ~ 9 diene system is performed in a way known in the art at low temperatures, preferably at about -20C to +30C in a hydrogen atmosphere in the presence of a noble metal catalyst. As catalyst, for example, 10% palladium on carbon is suitable.
The leukotriene-B4 derivatives of formula I with Rs meaning a hydrogen atom can be converted to a salt with suitable amounts of the corresponding inorganic bases with neutralization. ~or example, during dissolving of the corresponding acids in water, which contains the stoichiometric amount of the base, the solid inorganic salt is obtained after evaporation of the water or ,, ` ' .
: , . .
~:
S~ 's3 '~ ;J '-' - ''' after addition of a water-miscible solvent, e.g., alcohol or acetone.
For the production of an amine salt, the LTB4 acid, e.g., is dissolved in a suitable solvent, for example, ethanol, acetone, diethyl ether, acetonitrile or benzene and at least the stoichiometric amount of the amine is added to this solution. In this way, the salt usually accumulates in solid form or is isolated after evaporation of the solvent in the usual way.
The introduction of amide group -C-NHR6 with R6 meaning alkanoyl takes place according to the methods known to one skilled in the art~ The carboxylic acids of formula I ~F~=H) are first converted to the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with chloroformic acid isobutyl ester. The reaction of ths mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R6=H) takes place in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at ~emperatures between -30C and ~60C, preferably at 0C to 30C.
Another possibility for the introduction of amide group Il -C-NHR6 consists in the reaction of a l-carboxylic acid of formula I (R~=H), in which ~ree hydroxy groups are optionally intermediately protected, with compounds of formula IV, 0 = C = N ~ R6 ~IV), in which R6 has the above-indicated meaning.
. .
' :; ~ - :
.
~',J .',j ,/J ' -' The reaction of the compound of formula I (F~=H) with an isocyanate of formula IV takes place optionally by adding a tertiary amine, such as, e.g., triethylamine or pyridine. The reaction can be performed without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80C to 100C, preferably at 0C to 30C.
For production of the other amides, for example, the desired acid anhydrides can be reacted with ammonia or the correspondiny amines.
If the initial product contains O~ groups in the leukotriene-B4 radical, these OH groups are also reacted. If finally end products are desired which contain free hydroxyl groups, a start is suitably made from initial products in which the latter are intermediately protected by preferably easily cleavable ether or acyl radicals.
The separation of enantiomers and/or diastereomers takes place according to the methods known to one skilled in the art, for example, high-pressure liquid chromatography on optically active vehicles.
The compounds of formula II being used as initial material can be produced, for example, by cis- or trans-bis-1,2-hydroxymethyl-cyclopentane (obtainàble by reduction from cis- or trans-cyclopentane-1,2-dicarboxylic acid, see, e.g., A. Padwa et al., J. Org. Chem. 54, 817 (1989); O. Caamaus et al., Eur. 3.
Med. Chem. 22, 311 (1987)) being converted in a way known in the art to the monosilylether of formula V
- ~.
, ~ , .
, % ~ J~
C~ o~-R'2- (V), OH
in which R11, R12 and R1s are the same or different and mean C1-C4 alkyl or phenyl.
By oxidation, e.g., with Collins reagent or by the Swern process, there is obtained the aldehyde of formula VI
., -Rl2 (VI~, ~,,~ \Rl3 CE~O
IVII~ or (EtO12PCH2C02Et IVII) o (EtO)2P-CH2CN-CII-COOEt (VIII~ ~ (VIII3, which is converted in a Wittig-Horner olefination with the phosphonate of formula VII and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, oxidation of the primary alcohol, repeated Wittig-Horner olefination with the phosphonate of formula VII and optionally subsequent hydrogenation to the ester of formula IX or in a Wittig-Horner reaction of the aldehyde of formula VI with a . -,. ~ .
2 ~ 3~
phosphate of formula VIII, in which A
Il OSi-RI2 \R13 (IX), A COOEt has the above-indicated meaning. As bases, for example, potassium-tert-butylate, diazabicyclononane or sodium hydride are suitable. Reduction of the ester group, for example with DIBAH
and subsequent oxidation of the obtained primary alcohol, e.g., with manganese dioxide or Collins reagent results in the aldehyde of formula X ~ Rll o~ 2_ ~P.'~ (X), The organometallic reaction of the aldehyde of formula X
with a Grignard reagent of formula XI, X-MG-B-D-R4 ~XI), in which B, D and R4 exhibit the above-indicated meanings and X
means chlorine, bromine or iodine, results, after protection of the hydroxy group and optionally diastereomer separation (for example, by acylation) in the compounds of formula XII
Rll ~R~3 (XII), A ~ ~-r~R4 o~3 -. 2~
C! ~
The production of the compound of formula XI necessary for the organometallic reaction takes pla~e by reaction of the corresponding terminal halide with magnesium. By reaction of silylether XII with tetrabutylan~lonium fluoride, the alcohol of formula XIII is obtained.
OH
A _~B-D-R4 (XIII), The oxidation of the primary alcohol group in XIII~ e.g., Collins reagent or pyridinium dichromate, results in t-he aldehyde of formula II.
The compounds of formula XII, in which B means a CHz group and D means a ~ClC- or CH=CR3 group, can be attained, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally subsequent Lindlar hydrogenation.
An alternative design of the lower chain starts from the aldehyde of formula XIV, which resulted from the Wittig-Horner reaction of aldehyde VI and su~sequent reduction and oxidation.
~Rll /~ OSi-Rl~
\RI3 (XIV), ~ CHO
Wittig Horner olefination of aldehyde XIII with a phosphonate of formula XV
O O
(C~3o~2pcH2-c-B-D-R4 (XV), .
" ': ~ ' ':.:
, :
24 2~s~
and reduction of the resulting ketone then resulted in the alcohol of formula XIII.
The incorporation of the chemically and metabolically labile cis-~6~7 double bond of the LTB4 in a cis- or trans-1,2-substituted cyclopentyl ring results in a stabilization, and especially by further derivatizing of the functional groups, LTB4 derivatives are obtained which can act as LTB4 antagonists.
The compounds of formula I act in an antiinflammatory and antiallergic manner. In addition, they have antimycotic properties. Consequently, the n~w leukotriene-B4 derivatives o~
~ormula I represent valuable pharmaceu~ical active ingredients.
The compounds of formula I are especially suitable for topical administration, since they exhibit a dissociation between desired topical effectiveness and undesirable systemic side effects.
The new leukotriene-B4 derivatives of formula I are suitable in combination with the auxiliary agents and vehicles usual in galenic pharmaceutics for topical treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, lupus erythematosus cutaneus, psoriasis, lichen ruber planus et verrucosis and similar skin diseases.
The production of the pha~maceutical agent specialties takes place in the usual way by the active ingredients being convexted with suitable additives to the desired form o~ administration, such as, for example: solutions, lotions, ointments, creams or plasters.
, ,.
, In the thus formulated pharmaceutical agents, the active ingredient concentration depends on the form of administration.
In lotions and ointments, an active ingredient concentration of 0.0001% to 1% is preferably used.
Further, the new compounds optionally in combination with the usual auxiliary agents and vehicles are also well-suited for the production of inhalants, which can be used to treat allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
Further, the new leukotriene-B4 derivatives are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dosage unit, and are also administered rectally to treat allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
The new leukotriene-B4 derivatives can also be used in combination, such as, e.g., with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonis~s, leukotriene-D4 antagonists, leukotriene-~4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.
The following embodiments are used to explain the process according to the invention in more detail. In the examples, diastereoisomers in 12-position not characterized in more detail , - ' . ~
' ~
. 26 ~7~$
were characterized as polar or nonpolar (e.g., diastereomer nonpolar (12)).
- , . ~, -,, ~ . . . : : , ;~7 ~ 5 B~amples ~xample 1 ~ (5RS~-5-Acetoxy-5-tcis-(2RS)-2-((lE,3E~-(5RS~-5-acetoxv-1 3~tridecadienyl)(1RS)-cyclopentyll-pentanoic acid diastereomer nonpolar (12) A solution o~ ll.1 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 10 ml of tetrahydrofuran is instilled in 2.44 g of magnesium at 25C under argon, a crystal ~ --of iodine is added, it is heated for 10 minutes to 70C, stirred for 30 minutes at 25C and diluted with 31 ml of tetra~ydrofuran.
A solution o~ 495 mg of cis-(lRS)-l-formyl-(2RS)-2[(1E,3~)-(5RS)-5-acetoxy-1,3 tridecadienyl]-cyclopentane (diastereomer nonpolar (12)) in 1.7 ml of tetrahydrofuran is instilled in 2.96 ml of the above magnesium-organic solution at -70C under argon and stirred for 1.5 hours at -70~C. It is mixed with 8 ml of saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether (8+2)/ 480 mg of the alcohol is obtained as colorless oil.
IR(CHCl3): 3600, Z930, 2860, 1725, 1373, 1450, 993, 836 cm .
For acetylation, 2.0 ml of acetic anhydride is added to a solution of 1.8 g of the above-described alcohol in 5 ml of pyridine and stirred for 23 hours at room temperature. Then it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With ' ' ' ':
- ~
2~
hexane/ether (8+2), 1.88 g of the acetate is obtained as colorless oil.
IR: 2930, 2862, 1730, 1610, 1375, 1255, 993, 840 cm~1.
For silylether cleavage, 1.35 g of the above-produced acetate in 80 ml of tetrahydrofuran is stirred with 2.26 g of tetrabutylammonium fluoride for 20 minutes at 0C and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with ether on silica gel. In this way7 960 mg of the l-alcohol is obtained as colorless oil.
IR: 3600 tbroad), 2930, 2860, 1736, 1610, 1373, 1250, 990 cm~1 ~
For oxidation of the l-hydroxy group, 5.4 g of Collins reagent is added to 940 mg of the above-produced alcohol in 54 ml of methylene chloride at 0C and stirred for 20 minutes at 0C.
Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexane/ether (l+1) and concentrated by evaporation in a vacuum. The thus obtained 1-aldehyde is immediately used without further purification.
1.67 ml of Jones reagent (J. Chem. Soc. 1953~ 25553 is instilled in a solution of 800 mg of the above-produced aldehyde in 29 ml of acetone with stirring at -25~C and stirred for 15 minutes at -25C under argon. Then, 5.8 ml of isopropanol is added, stirred for 5 minutes, diluted with 200 ml of ether, shaken twice with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is , - , 2g chromatographed on silica gel. With hexane/ether (1~1~, 570 ml of the title compound is obtained as colorless oil.
IR: 3S20 ~hroad), 2930, 2860, 1726, 1373, 1255, 990, 948 Cm-1.
The initial material for the above title compound is produced as follows:
la) 3-rcis-1-(tert-Butyl-dimethylsilvloxYmethyl)-cYclo~ent-2-y1]-(2Ea-propenoic acid ethvl ester 127 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 8.7 g of 2- --hydroxymethyl-cyclopentanecarboxylic acid lactone (O. Caamano et al., Euro. J. Med. Chem. 22, 311 (1987)) in 127 ml of toluene at 0C under argon and stirred for 50 minutes at 0C. Then, 25 ml of isopropanol and 63 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate/hexane (4+1), 7 g of cis-1,2-dihydroxymethyl-cyclopentane is obtained as colorless liquid.
IR: 3600, 3400, 2960, 1060 cm~1.
A solution of 13 g of the above-produced diol in 5 ml of tetrahydrofuran is instilled in a suspension of 4.36 g of sodium hydride (as a 55% suspension in mineral oil) in 200 ml of tetrahydrofuran at 22C and stirred for 45 minutes at 22C.
Then, 15 g of tert-butyldimethylsilyl chloride is-added, stirred for 45 minutes at 22C and then diluted with about 1.5 liters of ether. The ether extract is washed with 10% potassium carbonate . ~ :
C~ s~2&~J
solution, shaken three times with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether (95+5), 20.9 cis-l-(tert-butyl-dimethylsilyloxymethyl)-2-hydroxymethylcyclopentane is obtained as colorless liquid.
IR: 3420 (broad), 2960, 2863, 1260, 840 cm~1.
~ 4 g of Collins reagent ~chromic acid-pyridine complex) is added to a solution of 16.9 g of the above-described monosilylether in 835 ml of methylene chloride at 0C and stirred for 30 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (3+2), Celite is added, filtered and concentrated by evaporation in a vacuum. 16.2 g of the aldehyde is obtained which is used without further purification.
IR: 2958, 2930, 2860, 2740, 1713, 840 cm~1.
For Wittig olefination, 20.7 g of phosphonoacetic acid triethyl ester and 12.6 g of diazabicycloundecene (DBU) are added at 24C to a stirred suspension of 3.9 g of lithium chloride in 277 ml of acetonitrile and stirred for 15 minutes. Then, a solution of 16 g of the above-described aldehyde in 43 ml of acetonitrile is instilled, stirred for 2~ hours at 24C and then diluted with ether. It is shaken in succession with water, 10 sulfuric acid and water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with hexane/ether (95+5) on silica gel. In this way, 22.5 g o~ the title compound is obtained as colorless oil.
IR: 2960, 2860, 1710, 1650, 1260, 985, 840 cm~1.
~ . .
, "~J ~fJr S,~
lb) 5-rcis-1-ttert-butyl-dimethvlsilyloxYmethYl)-cyclo-~ent-2-yl]-(2E~4E~pentadienoic acid ethyl ester 120 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 22.~ g of the ~
unsaturated ester, produced according to example la, in 500 ml of toluene at -70C under argon and stirred for 30 minutes at -70C.
Then, 30 ml of isopropanol and then 60 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with methylene chloride and concentratsd by evaporation in a vacuum. 22.5 g of the allyl alcohol is obtained, which is used without further purification.
IR: 3600, 3400, 2958, 840 cm1.
A solution of 20.35 g of the above-produced alcohol in 654 ml of toluene is mixed with 80 g of manganese dioxide and stirred for 5 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ether ~92+8), 17.6 g of the aldehyde is eluted as colorless oil.
IR: 2960, 2860, 2745, 1730, 1633, 1470, 975, 840 cm~1.
For Wittig olefination, 20.5 g of phosphonoacetic acid triethyl ester and 12.4 g of diazabicycloundecene are added at 24C to a stirred suspension of 3.88 g of lithium chloride in 274 ml of acetonitriIe and stirred for 15 minutes. Then, a solution of 17.5 g of the above-described ,~-unsaturated aldehyde in 43 ml of acetonitrile is instilled, stirred for 4 hours at 24~C and then diluted with ether. It is shaken in succession with water, 10% citric acid solution and water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is .
:. ~ , chromatographed with hexane/ether (9+1) on silica gel. In this way, 15.7 g of the title compound is obtained as colorless oil.
IR: 2958, 2860, 1705, 1640, 1616, 1255, 1003, 970, 838 cm'1 .
lc) 5-rcis-1-(tert-Butyl dimethylsilyloxv-methyl-cyclo-pent-2-yll-pentadien-1-ol Bl ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 15 g of the ester, produced according to example lb, in 416 ml of toluene at -70C
under argon and stirred for 30 minutes at -70C. Then; 15 ml of isopropanol and then 40 ml of water are instilled, stirred for 3 hours at 23C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With hexanejether (8~2~, g~3 g of the alcohol is obtained as colorless oil.
IR: 3620, 3460, 838 cm~1.
A solution of 9.3 g of the above-produced alcohol in 273 ml of toluene is mixed with 27.3 g of manganese dioxide and stirred for 6 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ether (9~1), 6.9 g of the title compound is obtained as colorless oil.
IR: 2955, 285$, 2740, 1678, 1632, 986, 838 cm~1.
ld) (5RS~-5-Acetoxy~1-[cis-1-(tert-butvl-dimethylsilyloxymethyl~-cyclopentL-2-yll-(1E,3R)-tridecadiene A solution of 17~8 g of octyl bromide in 24 ml of ether is instilled in 2.24 g of magnesium in 12 ml of ether with heating and stirred for 30 minutes at 25C. A solution of 6.7 g of the ' aldehyde, produced according to example lc, in 100 ml of ether is instilled in 17.2 ml (31.7 mmol~ of this Grignard solution at -20C under argon and stirred for 45 minutes at -20C. It is mixed with saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried ....
on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel. With hexane/ethyl acetate mixtures, 3.35 of nonpolar diastereomeric alcohol and 3.6 g of the polar diastereomeric alcohol are obtained as colorless oils.
For acetylation, 3.1 ml of acetic anhydride is added to a solution of 3.35 g of the above-produced nonpolar diastereomeric alcohol in 8 ml of pyridine and stirred for 24 hours at room temperature.
Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel.
With hexane/ether (95+5), 3.5 g of the title compound ~nonpolar diastereomer) is o~tained as colorless oil.
IR: 2938, 2860, 1725, 1655, 1252, 990, 838 cm1.
Analogously, 3.7 g of the title compound (as polar diastereomer) is produced from 3.6 g of the above-produced polar diastereomeric alcohol with 3.3 ml of acetic anhydride and 8O6 ml of pyridine.
IR: 2915, 2860, 1725, 1655, 1252, 990, 838 cm~l.
:: . ........... : . . -.
..
le) cis-(lRS~-l-Formvl-(2RS~-2-r(lE 3E)-(5RS)-5-acetoxy-1 3-tridecadienyl~cyclopentane Diastereomer nonolar (12~
7.35 g of tetrabutylammonium fluoride is added to a solution of 3.5 g of the acetate ~nonpolar diastereomer), produced according to example ld, in 350 ml of t~trahydrofuran at 0C, stirred for 15 minutes at O~C and for 5.5 hours at 24C. Then, it is diluted with 1 liter of ether and washed three times with brine. It is dried on magnesium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ether (7+3), 2.45 g of the alGohol is eluted as colorless oil.
IR: 3620, 3450, 2930, 2860, 1725, 1260, 992 cm~1.
18.4 g of Collins reagent (chromic acid-pyridine complex) is added to a solution of 2.4 g of the above-produced alcohol in 75 ml of me$hylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, ~iltered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further purification.
IR: 2930, 2860, 2730, 1721, 12S0, 990 cm~1.
~xample 2 S+/-)-(SRS~-5-Hydroxy-5-rcis-(2l~S)-2-((lE,3~:~-L5RS)-5-hYdr 1 3-tridecadienyl)-(lR~-cvclopentyl~-pentanoic acid Diastereomer nonPolar f12) 7.7 ml of a 0.S n aqueous lithium hydroxide solution is added to a solution of 360 mg of the diacetate, produced , .. . , , . ., .. . . . . . ~ . .
. :
.
according to example 1, in 7.7 ml of methanol and stirred for 25 hours at 50C. Then, it is acidi~ied with a 10~ sulfuric acid to pH 5, diluted with ethyl acetate, shaken t~ree times with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with ether/ethanol (99+1) on silica gel. In this way, 197 mg of the title compound is obtained as colorless crystals (melting point 71C).
IR: 3400, 2928, 2850, 1725, 1360, 1230, 995, 930 cm~1. ~
~ampl~ 3 --~ )-(5RS)-5-Acetoxy-5-tcis-t2RS)-2-((lE 3E)-(5RS~-5-hydroxy-1 3~(tridecadienyl)-(lRS)-cvclopentvll-pentanoic acid Diastereomer nonPolar (12~
5.5 ml of a 0.5 n sodium hydroxide solution is added to a solution of 255 mg of the nonpolar diastereomeric diacetate, produced according to example 1, in 5.5 ml of methanol at 23C
and stirred for 1.5 hours at 23C under argon. Then, it is diluted with water and acidi~ied at ice bath temperature with 10%
sulfuric acid to pH 5. It is extracted with ethyl acetate, washed twice with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With ether/hexane (8+2), 202 mg o* the title compound is obtained as colorless oil.
IR: 3420, 2922, 2850, 1727, 1710, 1700, 1272, 990, 960 cm .
.
.. : :
~xzmpl~ 4 t+/-)-(5RS)-5-Hydroxy-5-~cis-(2RS)-2-5tlE 3E)-(5RS~-5-hvdroxy-1 3-tridecadienvl)-(lRS)-cyclo~entvll-pentan-l-ol Diastereomer nonpolar ~12~
180 mg of the nonpolar diastereomeric diacetate described in example 1 is stirred for 60 hours at 24C with 5.5 ml o~ a solution of potassium hydroxide in water and ethanol ~production:
5 g of potassium hydroxide is dissolved in 67.5 ml of water and 182.5 ml of ethanol). Then, it is acidified with 10~ citric acid ~olution to pH 6, extracted four times with 20 ml of methylene chloride each, the organic phase is shaken with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum.
Tha residue is chromatographed with ethyl a~etate on silica gel.
In this way, 103 mg of the title compound is obtained as colorless oil.
IR: 3610, 3370 (broad), 2930, 2860, 993 cm~1.
~xampl~ S
(+~ 5RSl-5-Ac~etoxy-5-tcis-f2RS~-2-((lE,3E)-(5RSl-5-acetoxy-1.3-tridecadienyl)-(lRS)-cyclopentyl~-pentanoic acid Diastereomer polar (12) A solution of 11.1 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 10 ml of tetrahydrofuran is instilled in 2.44 g of magnesium at 25C under argon, a crystal of iodine is added, heated for 10 minutes to 75C, stirred for 40 minutes at 25C and diluted with 31 ml of tetrahydrofuran.
:
37 ~ s~ ~
A solution of 1.6 g of cis-(lRS)-1-formyl-~2RS)-2~ ,3E)-(5RS)-5-acetoxy-1,3-~ridecadienyl]-(cyclopentane (diastereomer polar (~2)) in 5.5 ml of tetrahydrofuran is instilled in 9.6 ml of the above magnesium-organic solution at -70C under argon and stirred for 1 hour at -70C~
It is mixed with 30 ml of saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether ~8+2), 1.3 g of the alcohol is obtained as colorless oil.
IR: 3610, 2930, 2860, 1725, 1374, 1451, 993, 836 cm~1~
For acetylation, 2.1 g of acetic anhydride is added to a solution of 1.82 g of the above-described alcohol in 5.1 ml of pyridine and stirred for 22 hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/ether (9+1), 1.83 g of the acetate is obtained as colorless oil.
IR: 2930, 2860, 1728, 1608, 1375, 1255, ~93, 840 cm~1.
For silylether cleavage, 1.85 g of the above-produced acetate in 113 ml of tetrahydrofuran is stirred with 3~1 g of tetrabutylammonium fluoride for 20 minutes at 0C and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is - . . ~ , . -~, ~ . . ..
:: .
.
.f~ 3~ 3 chromatographed with ether/hexane (8~2) on silica gel. In this way, 1.3 g of the l-alcohol is obtained as colorless oil.
IR: 3620, 3500, 2930, 2860, 1725, 1608, 1375, 1250, 990 cm~l For oxidation of the l-hydroxy group, 7.2 g of Collins reagent is added to 1.25 g of the above-produced alcohol in 71 ml of methylene chloride and stirred for 20 minutes at 0C. ~hen, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexane/ether (1+1) and concentrated by evaporation in a vacuum~ The thus obtained 1-aldehyde is immediately used without further puri~ication.
2.3 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is instilled in a solution of 1.1 g of the above-produced aldehyde in 40 ml of acetone with stirring at -25C and stirred for 15 minutes at -25C under argon. Then, 8 ml of isopropanol is added, stirred for 5 minutes, diluted with 300 ml of ether, shaken twice with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel~ With ether/hexane (7+3), 681 mg of the title compound is obtained as colorless oil.
IR: 3520 (broad), 2930, 2859, 1725, 1373, 1250, 990, 948 cm-1 ~
The initial material for the above title compound is produced as follows:
"
-, , `~
:. ~ :
: .
39 ~f~
Sa) cis-(lRS)-l-FormY1-f2RS)-2-r(lE 3E)-(5RS)-5-acetox~-1.3-tridecadienyll-cyclopentane Diastareomer polar (12~
7.73 g of tetrabutylammonium fluoride is added to a solution of 3.68 g of (5RS)-S-acetoxy-l-tcis-l-(tert-butyl-dimethylsilyloxymethyl)-cyclopent-2-yl]-(lE,3E)-tridecadiene (polar diastereomer), produced according to example ld, in 360 ml of tetrahydrofuran at 0C, stirred for 30 minutes at 0C and for 5 hours at 24C. Then, it is diluted with 1 liter of ether and washed three times with brine. It is dried on magnesium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ether (7+3), Z.3 g of the alcohol is eluted as colorless oil~
IR: 3620, 3450, 2930, 2860, 1725, 1250, 991 cm~1.
14 g of Collins reagent ~chromic acid-pyridine complex) is added to a solution of 1.8 g of the above-produced al~ohol in 56 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture o~ hexane/ether (1~1), Celite is added, filtered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further purification.
IR: 2930, 2860, 1720, I250, 991 cm~l.
-, ;
, ~ .
4 0 ~ ~1 a ~
~xample 6 (+/-)-(5RS)-5-Hydroxy-5-[cis-~2~S)-2-((lE 3E~-(5RS)-5-hydroxy-1 3-tridecadienyl)-(1RS~-cyclo~entyll-~entanoic acid Diastereomer polar (12) Analogously to example 2, 174 mg of the title compound is obtained from 360 mg of the diacetate, produced according to example 5, as colorless oil.
IR: 3400, 2930, 2855, 1723, 1360, 1230, 995, 930 cm~l. ~
~xample 7 (+/-)-~5RS)-5-Acetoxy-5-[cis-(2RS)-2-((lE 3E)-(5RS)-5-hydroxy-1 3-tridecadienyl)-(lRS)-cyclopentyl]-pentanoic acid Diastereomer Polar (12) Analogously to example 3, 238 mg of the title compound is obtained from 305 mg of the diacetate, produced according to example 5, as colorless oil.
IR: 3520, 2930, 2860, 1723, 1250, 990, 962 cm ~xample 8 (+/-~-(5RSL-5-Hydroxy-5-tcis-(2RS)-2-t(~E 3E)-(5RS~-5-hydroxy-~3-tridecadieny~ Rs~-cyclopentyl]-pentan-l-ol Diastereomer olar (12) Analogously to example 4, 115 mg of the title compound is obtained from 1~0 mg of the diacetate (intermediate product with the hydroxy group in 1-position), produced according to example 5, as colorless oil.
IR: 3600, 3380 (broad), 2930, 2860, 992 cm~1.
- . : , -:.: ~ : ' : ~
f~ ~ ~, 73 ~xampl~ 9 (+/-)-(5RS)-5-Acetoxv-5-ttrans-(2RS)-2-((lE 3E)-(5RS~-5-acetoxy-1,3-tridecadienYl)-1 3-tridecadienvl)-(lRS)-cYclo~entYll-Dentanoic acid Diastereomer A
A solution of 22.3 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 20 ml of tetrahydrofuran is instilled in 4.~7 g of magnesium at 25C under argon, a crystal of iodine is added, heated for ~0 minutes to 70C, stirred for 30 minutes at 25C and diluted with 62.5 ml of tetrahydrofuran.
A solution of 8.1 g of trans-(l~S)-l-formyl-(2RS)~2-t(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclopentane in 27 ml of tetrahydrofuran is instilled in 48.3 ml of the above magnesium-organic solution at -70C under argon and stirred for 1.5 hours at -70C. It is mixed with ~00 ml of saturated ammonium chloride solution, extracted with ether~ the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with hexane/ethyl acetate (85+15).
8.2 g of the alcohol is obtained as colorless oil.
IR: 3450, 2930, 2860, 1725, 1374, 1255, 993, 840 cm~1.
For acetylation, 8.6 ml of acetic anhydride is added to a solution of 7.85 g of the above-produced alcohol in 50 ml of pyridine and stirred ~or 21 hours at room temperature. ~hen, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel with hexane/ethyl acetate (85+15). 7.6 g of the acetate is obtained as colorless oil.
' " :
42 ~ J~J~
IR: 2940, 2862, 1728, 1375, 1257, 992, 840 cm~1.
For silylether cleavage, 7.55 g of the above-produced acetate in 500 ml of $etrahydrofuran is stirred with 12.7 g of tetrabutylammonium fluoride for 1 hour at 0 and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexaneJethyl acetate mixtures, 1.7 g of the nonpolar diastereomeric alcohol (diastereomer A) and 2.3 g of the polar diastereomer alcohol (diastereomer B) are obtained by multiple chromatographies as colorless oil.
IR (nonpolar alcohol): 3630, 3500, 2938, 2iB62, 1727, 16~0, 1378, 1255, 992, 950 cm~1.
IR (polar alcohol): 3620, 3480, 2938, 2862, 1726, 1660, 1378, 1255, 992, 950 cm~1.
For oxidation of the l-hydroxy group, 10.7 g of Collins reagent is added to 1.55 g of the above-produced nonpolar alcohol (diastereomer A) in 122 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexanetether (1~1), Celite is add~d, filtered, washed with hexane/ether (1+1) and concentrated by evaporation in a vacuum. The thus obtained l-aldehyde is immediately used without further purification.
and their ~se a~ Pharmaceutical ~gent~
LTB4 antagonists, which contain a six-membered ring as a ~asic structural element, are already known from German laid-open specification DE 39 17 597.
The invention relates to new leukotriene-B4 derivatives, the process for their production as well as their use as pharmaceutical agents.
Leukotriene B4 (LTB4) was discovered in 1979 by B.
Samuelsson et al. as a metabolite of arachidonic acid.- In the biosynthesis, leukotriene A4 is formed by the enzyme 5-lipoxy~genase first as a central intermediate product, which then is converted by a specific hydrolase to the LTB4.
COOH H OOH
~\ Lipoxygenase C~ =
Arachidonsaure 5-~'ETE
~~hydrase ~, ~,>~~ COOH
~=~ C5Hll Leukotrien A4 ( LTAA ) \ydrolase \~ H OH H OH
Giutathion- ~:~< COOH
S-transferase 1 , ~, CsHll HO H Leukotrien B4 ( LTB4 ) COOH
C5HIl H S
Cys-Gly ~-GIu Leukotrien C~ ( LTC4 ) - '.
,~ . - ` .
, ~ 3 KEY:
Arachidonsaure = arachidonic acid Leukotrien A4 (LTA4) = leukotriene A4 (LTA4) Glutathion S-transferase = glutathione - S-transferase Leukotrien B4 (LTB4) = leukotriene B4 (LTB4) Leukotrien C4 (LTC4) = leukotriene C4 (LTC4) ;
The nomsnclature of the leukotrienes can be gathered from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 645 (~980); 17, 785 (1979).
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological importance of leukotriene B4 is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. W.
Chakrin, D. M. Bailey, ~cademic Press 1~ b) Ju W. Gillard et al., Drugs of the Future 12, ~53 (1987). c) B. Samue~sson et al., Science 237, 1171 (1987). d) C. W. Parker, Drug Development Research lO, 277 (~987). It follows from the above that LTB4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
It is known from the LTB4 that it causes the adhesion of laukocytes on the blood vessel wall. LTB4 is chemotactically effective, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration.
Further, because of its chemotactic activity, it indirectly changes the vascular permeability, and a synergism with prostaglandin E2 is observed. LTB4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin diseases, which accompany inflammatory processes (increased vessel permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne.
.
c ~ ~
Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis.
Further, leukotrienes and LTB4 are involved especially in arthritis, chronic lung disease (e.g., asthma)~ rhinitis and inflammatory intestinal diseases.
Antagonists against LTB4 receptors or inhibitors of those enzymes which are involved in the synthesis of the LTB4 should b~
effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
Besides the therapeutic possibilities, which can be derived from counteracting of LTB4 action with LTB4 analogs, the usefulness and potential use of leukotriene-B4 agonists for the treatment of fungus diseases of the skin was also able to be shown (H. Katayama, Prostaglandins 34, 797 (1988)~.
The invention relates to leukotriene-B4 derivatives of formula I
- ~ , ~ Rl (I), A ~ B-D-R4 in which R1 means CH20H, CH3, CF3, COORs, CoNR6R7, or R1 together with R2 means a carbonyl group, .
t~
R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, Cl-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R means hydrogenl C1-C1o alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, Cl-C4 al~yl, C1-C4 alkoxy, fluoromethyl~ chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C~o) aryl or a 5-6-membered ring with at least l heteroatom, `
A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a Cl-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group -C-CH2-, (CHz) n D can mean a direct bond, oxygen, sulfur, -C-C-, -CH=CR8 or together with B can also mean a dirsct bond, R6 and R7 are the same or different and represent H or C~-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, c1-cS alkyl r chlorine, bromine, ,. , . - ' ', ~
' ' ' -~ J ~J ~
n is 3-5 as well as, if Rs means hydrogen, its salts with physiologically compatible bases and its cyclodextrin clathrates.
Groups o~2 and oR3 can be in ~- ox ~-position. Formula I
comprises both racemates and the possible pure diastereomers and enantiomers.
As alkyl groups R5, straight-chain or branched-chain alkyl groups with 1-10 C atoms are suitable, such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl. Alkyl groups Rs can optionally be substituted once to several times by halogen atoms,.alkoxy groups, optionally substituted aryl or aroyl groups with 6-10 C
atoms (for substitution, see under Aryl R5), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl part, and the ~imple substitution is to be preferred. As substituents, there can be mentioned, for example, fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. As preferred alkyl groups R5, those with 1-4 C atoms are to be mentioned.
Cycloalkyl group R5 can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopentyl, cyclohexyl, methylcyclohexyl.
As aryl groups R5, both substituted and unsubstituted aryl groups with 6-10 C atoms are suitable, such as, for example, phenyl, 1-naphthyl and 2~naphthyl, which respectively can be substituted by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups with respectively 1-4 C atoms, a chloromethyl, - :
fluoromethyl, ~rifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Preferred substituents in 3- and 4-position on the phenyl ring are, for example, fluorine, chlorine, alkoxy or trifluoromethyl, however, hydroxy in 4-position.
As heterocyclic groups R5, 5- and 6-membered aromatic heterocycles are suitable, which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-~etraæolyl, i.a.
As acid radical R6, physiologically compatible acid radicals are suitable~ Preferred acid~ are organic carboxylic acids and ~ulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsatuxated and/or polybasic and/or substituted in the usual way. As examples for the substituent~, C14 alkyl, hydroxy, C14 alkoxy~
oxo or amino groups or halogen atoms ~F, Cl, Br) can be mentioned. For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimet~ylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trirhloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, Br) or trifluoromethyl, hydroxy, Cl4 alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As especially preferred acyl radicals and alkanesulfonyl radicals, those with up to 10 carbon atoms are suitable. As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, ~-chloroethanesulfonic acid, butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid, N,N-diethylaminosulfonic acid, N,N-bis-(~-chloroethyl)-aminosulfonic acid, N,N-diisobutylaminosul~onic acid, N,N-dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, N-methylpiperazino, and morpholinosulfonic acid are suita~le.
As alkyl groups R4, straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-14, especially 1-10 C a*oms, are suitable, which optionally can be substituted by optionally substituted phenyl tfor substitution, see under Aryl R5). For example, there can be mentioned methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups. If alkyl groups " .
:~:, , ;' 2 ~
R4 are halogen-substituted, fluorine, chlorine and bromine are suitable as halogens.
As examples for halogen-substituted alkyl groups R4, al~yls with terminal trifluoromethyl groups are suitable.
Cycloalkyl group R4 can contain 3-10, preferably 3-6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl- -cyclohexyl.
As substituted or unsubstituted aryl groups R4, fo~ example, phenyl, l-naphthyl and 2-naphthyl, which respectively can be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups with respectively 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C1-C4 alkoxy or hydroxy group are suitable. The substitution in 3- and 4 position on the phenyl ring, for example, by fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy is preferred.
As heterocyclic aromatic groups R4, 5- and 6-membered heterocycles are suitable which contain at least 1 heteroatom, pre~erably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a.
As alkylene group B, straight-chain or branched-chain, saturated or unsaturat d alkylene radicals, pre~erably saturated with 1-10, especially with 1-5 C atoms are suitable, which optionally can be substituted by fluorine atoms. For example, ~' ' `
there can be mentioned: methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene, 1,2-difluoroethylene, l-fluoroethylene, l~methyltetramethylene, 1-methyltrimethylene, 1-methylene-ethylene, 1-methylenetetramethylene.
Alkylene group B can further represent the group -C-CH2-, in which n = 3-5, preferably 4-5. (CH2)n As acid radicals R2 and R3, physiologically compatible acid radicals are suitable. Preferred acids are organic ca~boxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocy¢lic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. As examples for the substituents, C~,4 alkyl, hydroxy, C14 alkoxy, oxo or amino groups or haloyen atoms (F, Cl, Br) can be mentioned.
For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, , ll - æ~
diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, Br), trifluoromethyl, hydroxy, C14 alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid, cyclopentylpropionic acid. As especially preferred acid radicals R2 and R3, acyl radicals with up to 10 carbon atoms are suitable.
Alkyl radicals R6 and R7 are straight-chain or branched alkyl radicals, especially straight-chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, especially preferably methyl.
R8 as Cl5 alkyl means straight-chain or branched-chain alkyl radicals such as were already mentioned for R4 or R5. Preferred alkyl radicals R8 are methyl, ethyl, propyl and isopropyl.
Inorganic and organic bases are suitable for salt formation, as they are known to one skilled in the art for forming physiologically compatible salts. For example, there can be mentioned alXali hydroxides, such as sodium hydroxide and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
Pre~erred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
R1 is CH20H, COORs with Rs meaning a hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, `
, ~ 3 phenyl~ C14 alkyl, C~ 4 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy, A is a trans, trans-CH=CH-CH=CH- or tetramethylene group;
B is a straight-chain or branched-chain, saturated or unsaturated alkylene group with up to 10 C atoms, which optionally can be substituted by fluorine or the group -jC-CHz-~CH2) n with n = 3-5; --D is a direct bond, oxygen, sulfur, a -C_C- group or a -CH=CR8 group with R8 as hydrogen, C1s alkyl, chlorine or bromine;
B and D together are a direct bond;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-15 C atoms;
R1 and R2 together are a carbonyl group;
R4 is a hydrogen atom, C1l0 alkyl, cycloalkyl with 5-6 C
atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, C14 alkyl, C14 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy and if R5 means a hydrogsn atom, their salts with physiologically compatible bases and their cyclodextrin clathrates.
Especially preferred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
R1 is CH20H, COORs with R5 meaning a hydrogen a~om, an alkyl radical with 1-4 C atoms;
A is a trans, trans CH=CH-CH=CH- or tetramethylene group;
, ::
- ' : ~. ' ~, .
. ; . .
8 ~ ~
B is a straight-chain or branched chain alkylene group with up to 5 C atoms;
D is a direct bond or a -C-C- group or a -CH=CR~ group with R8 as hydrogen or C1 5 alkyl;
B and D together are a direct bond;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-6 C atoms;
R1 and R2 together are a carbonyl group;
R4 is a hydrogen atom or C110 alkyl and if R5 means a hydrogen atom, their salts with physiologically compat ble bases and their cyclodextrin clathrates.
The invention further relates to a process for the production of compounds of formula I accordiny to the invention, which is characterized in that an aldehyde of formula II
CHO
(II), A _~B-D-R4 in which A, B, D, R3 and R4 have the above-indicated meanings, optionally after protection of free hydroxy groups with a magnesium-organic compound of formula III, X-Mg-CH2-CH2-CH2-CH~-R9 (III), in which X represents chlorine, bromine or iodine and ~9 represents -CH3, CF3 or -OR10, in which R10 means an easily cleavable ether radical, is reacted and optionally then isomers are separated in any sequence, protected hydroxy groups are released and/or a free hydroxy group is esterified and/or the 1 - ' ' ~
~ .J ~ ~ ~ g ~ydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxyl group (R1 = COORs3 is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is converted to an amide (R1 = CoNHR6R7) or a carboxyl group with a physiologically compatible base is converted to a salt.
As ether radicals R9 in the compound of formula III, the radicals familiar to one skilled in the art are suitable. Easily cleavable ether radicals, such as, for example, dimethyl-tert-butylsilyl, trimethylsilyl, tribenzylsilyl, diphenyl-tert-butyl~ilyl, tetrahydropyranyl, tetrahydrofuranyl and ~-ethoxyethyl, to name only a few, are preferable.
The reaction of the compound of formula II with an organometallic compound of formula III takes place in a way known in the art in an inert solvent or solvent mixture, such as, for example, diethyl ether, tetrahydrofuran, dioxane, toluene, dimethoxyethane, preferably diethyl ether or tetrahydrofuran.
The reaction is performed at temperatures between -100C and 60C, preferably at -78C to 0C.
The production of the compound of formula III necessary for this reaction takes place by reaction of the corresponding hydroxy halide by etherification with dihydropyran and p-toluenesulfonic acid and subsequent reaction with magnesium.
The reduction to the compounds of formula I with R1 meaning a CH20H group is performed with a reducing agent suitable for the reduction of esters or carboxylic acids, such as, for example, lithium aluminum hydride, diisobutyl aluminum hydride, etc. As : ~
:, ' , , ~; r; ,~4 r~ 7 solvent, diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc., are suitable. The reduction is performed at temperatures of -30C up to boiling temperature of the solvent used, preferably 0C to 30C.
The esterification of the alcohols of formula I (R2 = H
and/or R3 = H) takes place in a way known in the art. For example, the esterification takes place în that an acid derivative, preferably an acid halide or acid anhydride, is reacted in the presence of a base, such as, for example, NaH, pyridine, triethylamine, tributylamine or 4-dimethylam~nopryidine with an alcohol of formula I. The reaction can be per~ormed without solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, DMSO at temperatures above or below room temperature, for example, between 80C to 100C, preferably at room temperature.
The oxidation of the l-hydroxy group is performed according to the methods known to one skilled in the art. As oxidizing agents, for example, there can be used: pyridinium dichromate (Tetrahedron Letters, 1979, 399~, ~ones reagent (J. Chem. Soc.
1953, 2555) or platinum/oxygen (Adv. in Carbohydrate Chem. 17, 169 (1962)) or Collins oxidation and subsequent Jones oxidation.
The oxidation with pyridinium dichromate is performed at temperatures of 0C to 100C~ preferably 20C to 40C in a solvent inert toward the oxidizing agent, for example, dimethylformamide.
The oxidation with Jones reagent is performed at temperatures of -40C to +40C, preferably 0C to 30C in acetone as solvent.
.
' Cs~$~j ~
The oxidation with platinum/oxygen is performed at temperatures of 0C to 60C, preferably 20C to 40C in a solvent inert toward the oxidizing agent, such as, e.g., ethyl acetate.
The saponification of the esters of formula I is performed according to the methods known to one s~illed in the art, such as, for example, with basic catalysts~ The compounds of formula I can be separated by the usual separating methods into the optical isomers.
~ he release of the functionally modified hydroxy groups takes place according to known methods. For example, the cleavage of hydroxy protecting groups, such as, for example, the tetrahydropyranyl radical, is performed in an aqueous solution of an organic acid, such as, e.q., oxalic acid, acetic acid, propionic acid, i.a., or in an aqueous solution of an inorganic acid, such as, e.g., hydrochloric acid. To improve the solubility, a water-miscible, inert organic solvent is suitably added. Suitable organic solvents are, e.g., alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used.
The cleavage is performed preferably at temperatures between 20C
and 80C. The cleavage of the silyl ether prot~cting groups takes place, for example, with tetrabutylammonium fluoride or with potassium fluoride in the presence of a crown ~ther. As solvent, for example, tetrahydro~uran, diethyl ether, dioxane, methylene chloride, etc., are suitable. The cleavage is performed preferably at temperatures between 0C and 80C.
. .
, ~t~i~js~f~
The saponification of the acyl groups takes place, for example, with alkali or alkaline-earth carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. As an alcohol, aliphatic alcohols are suitable, such as, e.g~, methanol, ethanol, butanol, etc., preferably methanol. As alkali carbonates and hydroxides, potassium salts and sodium salts can be mentioned. The potassium salts are preferred.
As alkaline-ear*h carbonates and hydroxides, for example, calcium carbonate, calcium hydroxide and barium carbonate are suitable. The reaction takes place at -10C to +70C,-preferably at ~25C.
//
The introduction of ester group -C for R1, in which R5 ORs represents an alkyl group with 1-10 C atoms, takes place according to the methods known to one skilled in the art. The 1-carboxy compounds are reacted, for example, with diazohydrocarbons in a way known in the art. The esterification with diazohydrocarbons takes place, e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the l-carboxy compound in the same or in another inert solvent, such as, e.g., methylene chloride. After completion of the reaction in ~ to 30 minutes, the solvent is removed and the ester is purified in 'he usual way. Diazoalkanes are either known or can be produced according to known methods tOrg. Reactions Vol. 8, pages 389-394 (19S4~].
s~
The introduction of ester group -C for R1, in which Rs \oR5 represents a substituted or unsubstituted aryl group, takes place according to the methods known to one skilled in the art. For example, the l-carboxy compounds with the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example, pyridine, DMAP, triethylamine, in an inert solvent. As solvent, methylene ahloride, ethylene chloride, chloroform, ethyl acetate-, tetrahydrofuran, preferably chloro~orm, are suitable. The reaction is performed at temperatures between -30C and +50C, preferably at 10C.
If C=C double bonds contained in the primary product are to be reduced, the hydrogenation takes place according to methods known in the art.
The hydrogenation of the ~ 9 diene system is performed in a way known in the art at low temperatures, preferably at about -20C to +30C in a hydrogen atmosphere in the presence of a noble metal catalyst. As catalyst, for example, 10% palladium on carbon is suitable.
The leukotriene-B4 derivatives of formula I with Rs meaning a hydrogen atom can be converted to a salt with suitable amounts of the corresponding inorganic bases with neutralization. ~or example, during dissolving of the corresponding acids in water, which contains the stoichiometric amount of the base, the solid inorganic salt is obtained after evaporation of the water or ,, ` ' .
: , . .
~:
S~ 's3 '~ ;J '-' - ''' after addition of a water-miscible solvent, e.g., alcohol or acetone.
For the production of an amine salt, the LTB4 acid, e.g., is dissolved in a suitable solvent, for example, ethanol, acetone, diethyl ether, acetonitrile or benzene and at least the stoichiometric amount of the amine is added to this solution. In this way, the salt usually accumulates in solid form or is isolated after evaporation of the solvent in the usual way.
The introduction of amide group -C-NHR6 with R6 meaning alkanoyl takes place according to the methods known to one skilled in the art~ The carboxylic acids of formula I ~F~=H) are first converted to the mixed anhydride in the presence of a tertiary amine, such as, for example, triethylamine, with chloroformic acid isobutyl ester. The reaction of ths mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R6=H) takes place in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at ~emperatures between -30C and ~60C, preferably at 0C to 30C.
Another possibility for the introduction of amide group Il -C-NHR6 consists in the reaction of a l-carboxylic acid of formula I (R~=H), in which ~ree hydroxy groups are optionally intermediately protected, with compounds of formula IV, 0 = C = N ~ R6 ~IV), in which R6 has the above-indicated meaning.
. .
' :; ~ - :
.
~',J .',j ,/J ' -' The reaction of the compound of formula I (F~=H) with an isocyanate of formula IV takes place optionally by adding a tertiary amine, such as, e.g., triethylamine or pyridine. The reaction can be performed without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80C to 100C, preferably at 0C to 30C.
For production of the other amides, for example, the desired acid anhydrides can be reacted with ammonia or the correspondiny amines.
If the initial product contains O~ groups in the leukotriene-B4 radical, these OH groups are also reacted. If finally end products are desired which contain free hydroxyl groups, a start is suitably made from initial products in which the latter are intermediately protected by preferably easily cleavable ether or acyl radicals.
The separation of enantiomers and/or diastereomers takes place according to the methods known to one skilled in the art, for example, high-pressure liquid chromatography on optically active vehicles.
The compounds of formula II being used as initial material can be produced, for example, by cis- or trans-bis-1,2-hydroxymethyl-cyclopentane (obtainàble by reduction from cis- or trans-cyclopentane-1,2-dicarboxylic acid, see, e.g., A. Padwa et al., J. Org. Chem. 54, 817 (1989); O. Caamaus et al., Eur. 3.
Med. Chem. 22, 311 (1987)) being converted in a way known in the art to the monosilylether of formula V
- ~.
, ~ , .
, % ~ J~
C~ o~-R'2- (V), OH
in which R11, R12 and R1s are the same or different and mean C1-C4 alkyl or phenyl.
By oxidation, e.g., with Collins reagent or by the Swern process, there is obtained the aldehyde of formula VI
., -Rl2 (VI~, ~,,~ \Rl3 CE~O
IVII~ or (EtO12PCH2C02Et IVII) o (EtO)2P-CH2CN-CII-COOEt (VIII~ ~ (VIII3, which is converted in a Wittig-Horner olefination with the phosphonate of formula VII and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, oxidation of the primary alcohol, repeated Wittig-Horner olefination with the phosphonate of formula VII and optionally subsequent hydrogenation to the ester of formula IX or in a Wittig-Horner reaction of the aldehyde of formula VI with a . -,. ~ .
2 ~ 3~
phosphate of formula VIII, in which A
Il OSi-RI2 \R13 (IX), A COOEt has the above-indicated meaning. As bases, for example, potassium-tert-butylate, diazabicyclononane or sodium hydride are suitable. Reduction of the ester group, for example with DIBAH
and subsequent oxidation of the obtained primary alcohol, e.g., with manganese dioxide or Collins reagent results in the aldehyde of formula X ~ Rll o~ 2_ ~P.'~ (X), The organometallic reaction of the aldehyde of formula X
with a Grignard reagent of formula XI, X-MG-B-D-R4 ~XI), in which B, D and R4 exhibit the above-indicated meanings and X
means chlorine, bromine or iodine, results, after protection of the hydroxy group and optionally diastereomer separation (for example, by acylation) in the compounds of formula XII
Rll ~R~3 (XII), A ~ ~-r~R4 o~3 -. 2~
C! ~
The production of the compound of formula XI necessary for the organometallic reaction takes pla~e by reaction of the corresponding terminal halide with magnesium. By reaction of silylether XII with tetrabutylan~lonium fluoride, the alcohol of formula XIII is obtained.
OH
A _~B-D-R4 (XIII), The oxidation of the primary alcohol group in XIII~ e.g., Collins reagent or pyridinium dichromate, results in t-he aldehyde of formula II.
The compounds of formula XII, in which B means a CHz group and D means a ~ClC- or CH=CR3 group, can be attained, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally subsequent Lindlar hydrogenation.
An alternative design of the lower chain starts from the aldehyde of formula XIV, which resulted from the Wittig-Horner reaction of aldehyde VI and su~sequent reduction and oxidation.
~Rll /~ OSi-Rl~
\RI3 (XIV), ~ CHO
Wittig Horner olefination of aldehyde XIII with a phosphonate of formula XV
O O
(C~3o~2pcH2-c-B-D-R4 (XV), .
" ': ~ ' ':.:
, :
24 2~s~
and reduction of the resulting ketone then resulted in the alcohol of formula XIII.
The incorporation of the chemically and metabolically labile cis-~6~7 double bond of the LTB4 in a cis- or trans-1,2-substituted cyclopentyl ring results in a stabilization, and especially by further derivatizing of the functional groups, LTB4 derivatives are obtained which can act as LTB4 antagonists.
The compounds of formula I act in an antiinflammatory and antiallergic manner. In addition, they have antimycotic properties. Consequently, the n~w leukotriene-B4 derivatives o~
~ormula I represent valuable pharmaceu~ical active ingredients.
The compounds of formula I are especially suitable for topical administration, since they exhibit a dissociation between desired topical effectiveness and undesirable systemic side effects.
The new leukotriene-B4 derivatives of formula I are suitable in combination with the auxiliary agents and vehicles usual in galenic pharmaceutics for topical treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, lupus erythematosus cutaneus, psoriasis, lichen ruber planus et verrucosis and similar skin diseases.
The production of the pha~maceutical agent specialties takes place in the usual way by the active ingredients being convexted with suitable additives to the desired form o~ administration, such as, for example: solutions, lotions, ointments, creams or plasters.
, ,.
, In the thus formulated pharmaceutical agents, the active ingredient concentration depends on the form of administration.
In lotions and ointments, an active ingredient concentration of 0.0001% to 1% is preferably used.
Further, the new compounds optionally in combination with the usual auxiliary agents and vehicles are also well-suited for the production of inhalants, which can be used to treat allergic diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
Further, the new leukotriene-B4 derivatives are also suitable in the form of capsules, tablets or coated tablets, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dosage unit, and are also administered rectally to treat allergic diseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
The new leukotriene-B4 derivatives can also be used in combination, such as, e.g., with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonis~s, leukotriene-D4 antagonists, leukotriene-~4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.
The following embodiments are used to explain the process according to the invention in more detail. In the examples, diastereoisomers in 12-position not characterized in more detail , - ' . ~
' ~
. 26 ~7~$
were characterized as polar or nonpolar (e.g., diastereomer nonpolar (12)).
- , . ~, -,, ~ . . . : : , ;~7 ~ 5 B~amples ~xample 1 ~ (5RS~-5-Acetoxy-5-tcis-(2RS)-2-((lE,3E~-(5RS~-5-acetoxv-1 3~tridecadienyl)(1RS)-cyclopentyll-pentanoic acid diastereomer nonpolar (12) A solution o~ ll.1 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 10 ml of tetrahydrofuran is instilled in 2.44 g of magnesium at 25C under argon, a crystal ~ --of iodine is added, it is heated for 10 minutes to 70C, stirred for 30 minutes at 25C and diluted with 31 ml of tetra~ydrofuran.
A solution o~ 495 mg of cis-(lRS)-l-formyl-(2RS)-2[(1E,3~)-(5RS)-5-acetoxy-1,3 tridecadienyl]-cyclopentane (diastereomer nonpolar (12)) in 1.7 ml of tetrahydrofuran is instilled in 2.96 ml of the above magnesium-organic solution at -70C under argon and stirred for 1.5 hours at -70~C. It is mixed with 8 ml of saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether (8+2)/ 480 mg of the alcohol is obtained as colorless oil.
IR(CHCl3): 3600, Z930, 2860, 1725, 1373, 1450, 993, 836 cm .
For acetylation, 2.0 ml of acetic anhydride is added to a solution of 1.8 g of the above-described alcohol in 5 ml of pyridine and stirred for 23 hours at room temperature. Then it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With ' ' ' ':
- ~
2~
hexane/ether (8+2), 1.88 g of the acetate is obtained as colorless oil.
IR: 2930, 2862, 1730, 1610, 1375, 1255, 993, 840 cm~1.
For silylether cleavage, 1.35 g of the above-produced acetate in 80 ml of tetrahydrofuran is stirred with 2.26 g of tetrabutylammonium fluoride for 20 minutes at 0C and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with ether on silica gel. In this way7 960 mg of the l-alcohol is obtained as colorless oil.
IR: 3600 tbroad), 2930, 2860, 1736, 1610, 1373, 1250, 990 cm~1 ~
For oxidation of the l-hydroxy group, 5.4 g of Collins reagent is added to 940 mg of the above-produced alcohol in 54 ml of methylene chloride at 0C and stirred for 20 minutes at 0C.
Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexane/ether (l+1) and concentrated by evaporation in a vacuum. The thus obtained 1-aldehyde is immediately used without further purification.
1.67 ml of Jones reagent (J. Chem. Soc. 1953~ 25553 is instilled in a solution of 800 mg of the above-produced aldehyde in 29 ml of acetone with stirring at -25~C and stirred for 15 minutes at -25C under argon. Then, 5.8 ml of isopropanol is added, stirred for 5 minutes, diluted with 200 ml of ether, shaken twice with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is , - , 2g chromatographed on silica gel. With hexane/ether (1~1~, 570 ml of the title compound is obtained as colorless oil.
IR: 3S20 ~hroad), 2930, 2860, 1726, 1373, 1255, 990, 948 Cm-1.
The initial material for the above title compound is produced as follows:
la) 3-rcis-1-(tert-Butyl-dimethylsilvloxYmethyl)-cYclo~ent-2-y1]-(2Ea-propenoic acid ethvl ester 127 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 8.7 g of 2- --hydroxymethyl-cyclopentanecarboxylic acid lactone (O. Caamano et al., Euro. J. Med. Chem. 22, 311 (1987)) in 127 ml of toluene at 0C under argon and stirred for 50 minutes at 0C. Then, 25 ml of isopropanol and 63 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate/hexane (4+1), 7 g of cis-1,2-dihydroxymethyl-cyclopentane is obtained as colorless liquid.
IR: 3600, 3400, 2960, 1060 cm~1.
A solution of 13 g of the above-produced diol in 5 ml of tetrahydrofuran is instilled in a suspension of 4.36 g of sodium hydride (as a 55% suspension in mineral oil) in 200 ml of tetrahydrofuran at 22C and stirred for 45 minutes at 22C.
Then, 15 g of tert-butyldimethylsilyl chloride is-added, stirred for 45 minutes at 22C and then diluted with about 1.5 liters of ether. The ether extract is washed with 10% potassium carbonate . ~ :
C~ s~2&~J
solution, shaken three times with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether (95+5), 20.9 cis-l-(tert-butyl-dimethylsilyloxymethyl)-2-hydroxymethylcyclopentane is obtained as colorless liquid.
IR: 3420 (broad), 2960, 2863, 1260, 840 cm~1.
~ 4 g of Collins reagent ~chromic acid-pyridine complex) is added to a solution of 16.9 g of the above-described monosilylether in 835 ml of methylene chloride at 0C and stirred for 30 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (3+2), Celite is added, filtered and concentrated by evaporation in a vacuum. 16.2 g of the aldehyde is obtained which is used without further purification.
IR: 2958, 2930, 2860, 2740, 1713, 840 cm~1.
For Wittig olefination, 20.7 g of phosphonoacetic acid triethyl ester and 12.6 g of diazabicycloundecene (DBU) are added at 24C to a stirred suspension of 3.9 g of lithium chloride in 277 ml of acetonitrile and stirred for 15 minutes. Then, a solution of 16 g of the above-described aldehyde in 43 ml of acetonitrile is instilled, stirred for 2~ hours at 24C and then diluted with ether. It is shaken in succession with water, 10 sulfuric acid and water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with hexane/ether (95+5) on silica gel. In this way, 22.5 g o~ the title compound is obtained as colorless oil.
IR: 2960, 2860, 1710, 1650, 1260, 985, 840 cm~1.
~ . .
, "~J ~fJr S,~
lb) 5-rcis-1-ttert-butyl-dimethvlsilyloxYmethYl)-cyclo-~ent-2-yl]-(2E~4E~pentadienoic acid ethyl ester 120 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 22.~ g of the ~
unsaturated ester, produced according to example la, in 500 ml of toluene at -70C under argon and stirred for 30 minutes at -70C.
Then, 30 ml of isopropanol and then 60 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with methylene chloride and concentratsd by evaporation in a vacuum. 22.5 g of the allyl alcohol is obtained, which is used without further purification.
IR: 3600, 3400, 2958, 840 cm1.
A solution of 20.35 g of the above-produced alcohol in 654 ml of toluene is mixed with 80 g of manganese dioxide and stirred for 5 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ether ~92+8), 17.6 g of the aldehyde is eluted as colorless oil.
IR: 2960, 2860, 2745, 1730, 1633, 1470, 975, 840 cm~1.
For Wittig olefination, 20.5 g of phosphonoacetic acid triethyl ester and 12.4 g of diazabicycloundecene are added at 24C to a stirred suspension of 3.88 g of lithium chloride in 274 ml of acetonitriIe and stirred for 15 minutes. Then, a solution of 17.5 g of the above-described ,~-unsaturated aldehyde in 43 ml of acetonitrile is instilled, stirred for 4 hours at 24~C and then diluted with ether. It is shaken in succession with water, 10% citric acid solution and water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is .
:. ~ , chromatographed with hexane/ether (9+1) on silica gel. In this way, 15.7 g of the title compound is obtained as colorless oil.
IR: 2958, 2860, 1705, 1640, 1616, 1255, 1003, 970, 838 cm'1 .
lc) 5-rcis-1-(tert-Butyl dimethylsilyloxv-methyl-cyclo-pent-2-yll-pentadien-1-ol Bl ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 15 g of the ester, produced according to example lb, in 416 ml of toluene at -70C
under argon and stirred for 30 minutes at -70C. Then; 15 ml of isopropanol and then 40 ml of water are instilled, stirred for 3 hours at 23C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With hexanejether (8~2~, g~3 g of the alcohol is obtained as colorless oil.
IR: 3620, 3460, 838 cm~1.
A solution of 9.3 g of the above-produced alcohol in 273 ml of toluene is mixed with 27.3 g of manganese dioxide and stirred for 6 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ether (9~1), 6.9 g of the title compound is obtained as colorless oil.
IR: 2955, 285$, 2740, 1678, 1632, 986, 838 cm~1.
ld) (5RS~-5-Acetoxy~1-[cis-1-(tert-butvl-dimethylsilyloxymethyl~-cyclopentL-2-yll-(1E,3R)-tridecadiene A solution of 17~8 g of octyl bromide in 24 ml of ether is instilled in 2.24 g of magnesium in 12 ml of ether with heating and stirred for 30 minutes at 25C. A solution of 6.7 g of the ' aldehyde, produced according to example lc, in 100 ml of ether is instilled in 17.2 ml (31.7 mmol~ of this Grignard solution at -20C under argon and stirred for 45 minutes at -20C. It is mixed with saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried ....
on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel. With hexane/ethyl acetate mixtures, 3.35 of nonpolar diastereomeric alcohol and 3.6 g of the polar diastereomeric alcohol are obtained as colorless oils.
For acetylation, 3.1 ml of acetic anhydride is added to a solution of 3.35 g of the above-produced nonpolar diastereomeric alcohol in 8 ml of pyridine and stirred for 24 hours at room temperature.
Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel.
With hexane/ether (95+5), 3.5 g of the title compound ~nonpolar diastereomer) is o~tained as colorless oil.
IR: 2938, 2860, 1725, 1655, 1252, 990, 838 cm1.
Analogously, 3.7 g of the title compound (as polar diastereomer) is produced from 3.6 g of the above-produced polar diastereomeric alcohol with 3.3 ml of acetic anhydride and 8O6 ml of pyridine.
IR: 2915, 2860, 1725, 1655, 1252, 990, 838 cm~l.
:: . ........... : . . -.
..
le) cis-(lRS~-l-Formvl-(2RS~-2-r(lE 3E)-(5RS)-5-acetoxy-1 3-tridecadienyl~cyclopentane Diastereomer nonolar (12~
7.35 g of tetrabutylammonium fluoride is added to a solution of 3.5 g of the acetate ~nonpolar diastereomer), produced according to example ld, in 350 ml of t~trahydrofuran at 0C, stirred for 15 minutes at O~C and for 5.5 hours at 24C. Then, it is diluted with 1 liter of ether and washed three times with brine. It is dried on magnesium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ether (7+3), 2.45 g of the alGohol is eluted as colorless oil.
IR: 3620, 3450, 2930, 2860, 1725, 1260, 992 cm~1.
18.4 g of Collins reagent (chromic acid-pyridine complex) is added to a solution of 2.4 g of the above-produced alcohol in 75 ml of me$hylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, ~iltered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further purification.
IR: 2930, 2860, 2730, 1721, 12S0, 990 cm~1.
~xample 2 S+/-)-(SRS~-5-Hydroxy-5-rcis-(2l~S)-2-((lE,3~:~-L5RS)-5-hYdr 1 3-tridecadienyl)-(lR~-cvclopentyl~-pentanoic acid Diastereomer nonPolar f12) 7.7 ml of a 0.S n aqueous lithium hydroxide solution is added to a solution of 360 mg of the diacetate, produced , .. . , , . ., .. . . . . . ~ . .
. :
.
according to example 1, in 7.7 ml of methanol and stirred for 25 hours at 50C. Then, it is acidi~ied with a 10~ sulfuric acid to pH 5, diluted with ethyl acetate, shaken t~ree times with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with ether/ethanol (99+1) on silica gel. In this way, 197 mg of the title compound is obtained as colorless crystals (melting point 71C).
IR: 3400, 2928, 2850, 1725, 1360, 1230, 995, 930 cm~1. ~
~ampl~ 3 --~ )-(5RS)-5-Acetoxy-5-tcis-t2RS)-2-((lE 3E)-(5RS~-5-hydroxy-1 3~(tridecadienyl)-(lRS)-cvclopentvll-pentanoic acid Diastereomer nonPolar (12~
5.5 ml of a 0.5 n sodium hydroxide solution is added to a solution of 255 mg of the nonpolar diastereomeric diacetate, produced according to example 1, in 5.5 ml of methanol at 23C
and stirred for 1.5 hours at 23C under argon. Then, it is diluted with water and acidi~ied at ice bath temperature with 10%
sulfuric acid to pH 5. It is extracted with ethyl acetate, washed twice with brine, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With ether/hexane (8+2), 202 mg o* the title compound is obtained as colorless oil.
IR: 3420, 2922, 2850, 1727, 1710, 1700, 1272, 990, 960 cm .
.
.. : :
~xzmpl~ 4 t+/-)-(5RS)-5-Hydroxy-5-~cis-(2RS)-2-5tlE 3E)-(5RS~-5-hvdroxy-1 3-tridecadienvl)-(lRS)-cyclo~entvll-pentan-l-ol Diastereomer nonpolar ~12~
180 mg of the nonpolar diastereomeric diacetate described in example 1 is stirred for 60 hours at 24C with 5.5 ml o~ a solution of potassium hydroxide in water and ethanol ~production:
5 g of potassium hydroxide is dissolved in 67.5 ml of water and 182.5 ml of ethanol). Then, it is acidified with 10~ citric acid ~olution to pH 6, extracted four times with 20 ml of methylene chloride each, the organic phase is shaken with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum.
Tha residue is chromatographed with ethyl a~etate on silica gel.
In this way, 103 mg of the title compound is obtained as colorless oil.
IR: 3610, 3370 (broad), 2930, 2860, 993 cm~1.
~xampl~ S
(+~ 5RSl-5-Ac~etoxy-5-tcis-f2RS~-2-((lE,3E)-(5RSl-5-acetoxy-1.3-tridecadienyl)-(lRS)-cyclopentyl~-pentanoic acid Diastereomer polar (12) A solution of 11.1 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 10 ml of tetrahydrofuran is instilled in 2.44 g of magnesium at 25C under argon, a crystal of iodine is added, heated for 10 minutes to 75C, stirred for 40 minutes at 25C and diluted with 31 ml of tetrahydrofuran.
:
37 ~ s~ ~
A solution of 1.6 g of cis-(lRS)-1-formyl-~2RS)-2~ ,3E)-(5RS)-5-acetoxy-1,3-~ridecadienyl]-(cyclopentane (diastereomer polar (~2)) in 5.5 ml of tetrahydrofuran is instilled in 9.6 ml of the above magnesium-organic solution at -70C under argon and stirred for 1 hour at -70C~
It is mixed with 30 ml of saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ether ~8+2), 1.3 g of the alcohol is obtained as colorless oil.
IR: 3610, 2930, 2860, 1725, 1374, 1451, 993, 836 cm~1~
For acetylation, 2.1 g of acetic anhydride is added to a solution of 1.82 g of the above-described alcohol in 5.1 ml of pyridine and stirred for 22 hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/ether (9+1), 1.83 g of the acetate is obtained as colorless oil.
IR: 2930, 2860, 1728, 1608, 1375, 1255, ~93, 840 cm~1.
For silylether cleavage, 1.85 g of the above-produced acetate in 113 ml of tetrahydrofuran is stirred with 3~1 g of tetrabutylammonium fluoride for 20 minutes at 0C and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is - . . ~ , . -~, ~ . . ..
:: .
.
.f~ 3~ 3 chromatographed with ether/hexane (8~2) on silica gel. In this way, 1.3 g of the l-alcohol is obtained as colorless oil.
IR: 3620, 3500, 2930, 2860, 1725, 1608, 1375, 1250, 990 cm~l For oxidation of the l-hydroxy group, 7.2 g of Collins reagent is added to 1.25 g of the above-produced alcohol in 71 ml of methylene chloride and stirred for 20 minutes at 0C. ~hen, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexane/ether (1+1) and concentrated by evaporation in a vacuum~ The thus obtained 1-aldehyde is immediately used without further puri~ication.
2.3 ml of Jones reagent (J. Chem. Soc. 1953, 2555) is instilled in a solution of 1.1 g of the above-produced aldehyde in 40 ml of acetone with stirring at -25C and stirred for 15 minutes at -25C under argon. Then, 8 ml of isopropanol is added, stirred for 5 minutes, diluted with 300 ml of ether, shaken twice with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel~ With ether/hexane (7+3), 681 mg of the title compound is obtained as colorless oil.
IR: 3520 (broad), 2930, 2859, 1725, 1373, 1250, 990, 948 cm-1 ~
The initial material for the above title compound is produced as follows:
"
-, , `~
:. ~ :
: .
39 ~f~
Sa) cis-(lRS)-l-FormY1-f2RS)-2-r(lE 3E)-(5RS)-5-acetox~-1.3-tridecadienyll-cyclopentane Diastareomer polar (12~
7.73 g of tetrabutylammonium fluoride is added to a solution of 3.68 g of (5RS)-S-acetoxy-l-tcis-l-(tert-butyl-dimethylsilyloxymethyl)-cyclopent-2-yl]-(lE,3E)-tridecadiene (polar diastereomer), produced according to example ld, in 360 ml of tetrahydrofuran at 0C, stirred for 30 minutes at 0C and for 5 hours at 24C. Then, it is diluted with 1 liter of ether and washed three times with brine. It is dried on magnesium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ether (7+3), Z.3 g of the alcohol is eluted as colorless oil~
IR: 3620, 3450, 2930, 2860, 1725, 1250, 991 cm~1.
14 g of Collins reagent ~chromic acid-pyridine complex) is added to a solution of 1.8 g of the above-produced al~ohol in 56 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture o~ hexane/ether (1~1), Celite is added, filtered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further purification.
IR: 2930, 2860, 1720, I250, 991 cm~l.
-, ;
, ~ .
4 0 ~ ~1 a ~
~xample 6 (+/-)-(5RS)-5-Hydroxy-5-[cis-~2~S)-2-((lE 3E~-(5RS)-5-hydroxy-1 3-tridecadienyl)-(1RS~-cyclo~entyll-~entanoic acid Diastereomer polar (12) Analogously to example 2, 174 mg of the title compound is obtained from 360 mg of the diacetate, produced according to example 5, as colorless oil.
IR: 3400, 2930, 2855, 1723, 1360, 1230, 995, 930 cm~l. ~
~xample 7 (+/-)-~5RS)-5-Acetoxy-5-[cis-(2RS)-2-((lE 3E)-(5RS)-5-hydroxy-1 3-tridecadienyl)-(lRS)-cyclopentyl]-pentanoic acid Diastereomer Polar (12) Analogously to example 3, 238 mg of the title compound is obtained from 305 mg of the diacetate, produced according to example 5, as colorless oil.
IR: 3520, 2930, 2860, 1723, 1250, 990, 962 cm ~xample 8 (+/-~-(5RSL-5-Hydroxy-5-tcis-(2RS)-2-t(~E 3E)-(5RS~-5-hydroxy-~3-tridecadieny~ Rs~-cyclopentyl]-pentan-l-ol Diastereomer olar (12) Analogously to example 4, 115 mg of the title compound is obtained from 1~0 mg of the diacetate (intermediate product with the hydroxy group in 1-position), produced according to example 5, as colorless oil.
IR: 3600, 3380 (broad), 2930, 2860, 992 cm~1.
- . : , -:.: ~ : ' : ~
f~ ~ ~, 73 ~xampl~ 9 (+/-)-(5RS)-5-Acetoxv-5-ttrans-(2RS)-2-((lE 3E)-(5RS~-5-acetoxy-1,3-tridecadienYl)-1 3-tridecadienvl)-(lRS)-cYclo~entYll-Dentanoic acid Diastereomer A
A solution of 22.3 g of 4-chloro-1-(tert-butyldimethylsilyloxy)-butane in 20 ml of tetrahydrofuran is instilled in 4.~7 g of magnesium at 25C under argon, a crystal of iodine is added, heated for ~0 minutes to 70C, stirred for 30 minutes at 25C and diluted with 62.5 ml of tetrahydrofuran.
A solution of 8.1 g of trans-(l~S)-l-formyl-(2RS)~2-t(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclopentane in 27 ml of tetrahydrofuran is instilled in 48.3 ml of the above magnesium-organic solution at -70C under argon and stirred for 1.5 hours at -70C. It is mixed with ~00 ml of saturated ammonium chloride solution, extracted with ether~ the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with hexane/ethyl acetate (85+15).
8.2 g of the alcohol is obtained as colorless oil.
IR: 3450, 2930, 2860, 1725, 1374, 1255, 993, 840 cm~1.
For acetylation, 8.6 ml of acetic anhydride is added to a solution of 7.85 g of the above-produced alcohol in 50 ml of pyridine and stirred ~or 21 hours at room temperature. ~hen, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel with hexane/ethyl acetate (85+15). 7.6 g of the acetate is obtained as colorless oil.
' " :
42 ~ J~J~
IR: 2940, 2862, 1728, 1375, 1257, 992, 840 cm~1.
For silylether cleavage, 7.55 g of the above-produced acetate in 500 ml of $etrahydrofuran is stirred with 12.7 g of tetrabutylammonium fluoride for 1 hour at 0 and for 4 hours at 24C under argon. Then, it is diluted with ether, washed three times with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexaneJethyl acetate mixtures, 1.7 g of the nonpolar diastereomeric alcohol (diastereomer A) and 2.3 g of the polar diastereomer alcohol (diastereomer B) are obtained by multiple chromatographies as colorless oil.
IR (nonpolar alcohol): 3630, 3500, 2938, 2iB62, 1727, 16~0, 1378, 1255, 992, 950 cm~1.
IR (polar alcohol): 3620, 3480, 2938, 2862, 1726, 1660, 1378, 1255, 992, 950 cm~1.
For oxidation of the l-hydroxy group, 10.7 g of Collins reagent is added to 1.55 g of the above-produced nonpolar alcohol (diastereomer A) in 122 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexanetether (1~1), Celite is add~d, filtered, washed with hexane/ether (1+1) and concentrated by evaporation in a vacuum. The thus obtained l-aldehyde is immediately used without further purification.
3.3 ml of Jones reagent (J. Chem. Soc. 1953, 25553 is instilled in a solution of 1.57 g of the above-produced aldehyde in 58 ml of acetone with stirring at -25C and stirred for 15 minutes at -25C under argon. Then, 11.5 ml of isopropanol is :, ; :
, , ~`
. 43 2~8~g added, stirred ~or 5 minutes, diluted with 400 ml of ether, shaken twice with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (6+4), 1.2 y of the title compound is obtained as colorless oil.
IR: 3520, 2930, 2860, 1725, 1658, 1360, 1250, 990, 946 cm-1 .
The initial material for the above title compound is produced as follows:
9a) 5-(trans-1-(tert-But~l-dimethylsilyloxymethyl)-cyclopent-2-yll-(2E,4E)-pentadienoic acid ethyl ester 3.4 ml of concentrated sulfuric acid is added to a solution of 25 g of trans-cyclopentane-1,2-dicarboxylic acid in 64 ml of methanol and refluxed for 14 hours. Then, the excess alcohol is -distilled off, the residue is poured on ice water, extracted four times with ether and the organic phase is washed with sodium bicarbonate solution and water. It is dried with sodium sulfate, concentrated by evaporation in a vacuum and the residue is distilled in a vacuum at 25 mtorr. At 56C, 27 g of trans-cyclopentane-1,2-dicarboxylic acid dimethyl ester is obtained as colorless liquid.
IR: 2955, 2873, 1725, 1435 cm1.
230 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 13 g of trans-cyclopentane-1,2-dicarboxylic acld dimethyl ester in 300 ml of toluene at 0C under argon and stirred for 2 hours at 0C. Then, .
.
., . - :
, ., .
.: :
t 20 ml of isopropanol is instilled, stirred for 5 minutes, 116 ml of water is instilled and stirred for 2 hours at 22C. It is filt~red, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate, 8 g of trans-1,2-dihydroxy-cyclopentane is obtained as colorless liquid.
IR: 3610, 3400, 2960, 1062 cm~1.
17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride ars added to a solution of 16 g of trans-1,2-dihydroxymethyl-cyclopentane in 146 ml of dimethylformamide at 0C and stirred for 22 hours at 24C. It is diluted with 1.6 1 of ether, shaken twice with 80 ml of 10% sulfuric acid each, washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (9+13 12 g of trans-1-(tert-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopentane is obtained as colorless liquid.
IR: 3400, 2960, 2860, 1260, 840 cm1.
70 g of Collins reagent (chromic acid-pyridine complex~ is added to a solution of 14.4 g of the above-described monosilylether in 750 ml of methylene chloride and stirred for 30 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (3+2), Celite is added, filtered and concentrated by evaporation in a Yacuum. 14 g of the aldehyde is obtained, which is used without further purification.
IR: 2958, 2860, 2720, 1719, 840 cm~1. -, , ~
J ~ ~J ~
For Wittig-Horner olefination, 16.1 g of phosphonocrotonic acid triethyl ester and 9.8 g of diazabicycloundecene (DBU) are added at 24C to a stirred suspension of 2.7 g of lithium chloride in 536 ml of acetonitrile and stirred for 10 minutes.
Then, a solution of 13 g of the above-described aldehyde in 107 ml of acetonitrile is instilled, stirred for 3.5 hours at 24C
and then diluted with ether. It is shaken in succession with water, 10% citric acid solution and water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with hexane/ethyl acetate on silica--gel. In this way, 11 g of the title compound is obtained as colorless oil.
IRo 2958, 2860, 1705, 1640, 1620, 1470, 1255, lO00, 838 cm 1 , 9b~ -5-[trans-l-(tert-Butyl-dimethylsilyloxYmethyl)-cyclopent-2-yll-(2E,4EL-~entadien-l-al 50 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 9.8 g of ester, produced according to example 9a, in 250 ml of toluene at -70C under argon and stirred for 30 minutes at -70C. Then, 10 ml of isopropanol and, after 5 minutes, 30 ml of water are instilled, stirred for 2.5 hours at 23C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ~6 s~ , 3 ~ ~
hexane/ether (7~3), 7.6 g of the alcohol is obtained as colorless oil.
IR: 3610, 34S0, 990, 940, ~40 cm~~.
For aldehyde production, a solution of 7.5 g of the above-produced alcohol in 250 ml of toluene is mixed with 22 g of manganese dioxide and stirred for 4 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ethyl acetate (8+2), 7.4 g of the title compound is obtained as colorless oil.
IR: 2960, 2860, 2740, 1682, 1638, 988, g40, 840 cm~1.
9c) (5-RS)-5-Acetoxy-l-Lt ans-l-ltert butyl-dimethylsilyloxymethvl)-cvclopent-2-yl]-1-(lE,3E)-tridecadiene A solution of 17.8 g of octyl bromide in 24 ml of ether is instilled in 2.24 g of magnesium in 12 ml of ether with heating and stirred for 30 minutes at 25~C. A solution of 7.4 g of aldehyde, produced according to example 9b, in 130 ml of ether is instilled in 16.4 ml ~=30.1 mmol) of this Grignard solution at -20C under argon and stirred for 45 minutes at -20C. It is mixed with saturated ammonium chloride solution, extracted thr~e times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel. With hexane/ethyl acetate (7+3), 8.6 g of alcohol (diastereomer mixture) is obtained as colorless oil.
For acetylation, 12.5 ml of acetic anhydride is added to a solution of 8.5 g of the above-produced alcohol in 85 ml of .
::
pyridine and stirred for 23 hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/ethyl acetate (97+3), 8.6 g of the title compound is obtained as colorless oil.
IR: 2938, 2860, 1725, lb57, 1255, 993, 945, 840 cm~1.
9d) trans-(lRS~ Formyl-(2RS)-Z-r~lE,3E)-(5RS)-5-acetoxy-1.3-tridecadienyl~-cyclopentane 19.9 g of tetrabutylammonium fluoride is added to-a solution of 9.1 g of the acetate, produced according to example 9c, in 900 ml of tetrahydrofuran at 0C, stirred ~or 15 minutes at 0C and for 4 hours at 24C. Then, it is diluted with 2 l of ether and washed three times with brine. It is dried with sodium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (7+3), 7.18 g of the alcohol is eluted as colorless oil.
IR: 3620, 34S0, 2938, 2862, 1730, 1255, 995 cm~1.
63 g of Collins reagent (chromic acid-pyridine ~omplex) is added to a solution of 8.1 g of the above-produc~d alcohol in 250 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture o~ hexane/ether ~1~1), Celite is added, filtered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further puri~ication.
IR: 2930, 2860, 2731, 1721, 1250, 990 cm~1.
, , ~`
. 43 2~8~g added, stirred ~or 5 minutes, diluted with 400 ml of ether, shaken twice with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (6+4), 1.2 y of the title compound is obtained as colorless oil.
IR: 3520, 2930, 2860, 1725, 1658, 1360, 1250, 990, 946 cm-1 .
The initial material for the above title compound is produced as follows:
9a) 5-(trans-1-(tert-But~l-dimethylsilyloxymethyl)-cyclopent-2-yll-(2E,4E)-pentadienoic acid ethyl ester 3.4 ml of concentrated sulfuric acid is added to a solution of 25 g of trans-cyclopentane-1,2-dicarboxylic acid in 64 ml of methanol and refluxed for 14 hours. Then, the excess alcohol is -distilled off, the residue is poured on ice water, extracted four times with ether and the organic phase is washed with sodium bicarbonate solution and water. It is dried with sodium sulfate, concentrated by evaporation in a vacuum and the residue is distilled in a vacuum at 25 mtorr. At 56C, 27 g of trans-cyclopentane-1,2-dicarboxylic acid dimethyl ester is obtained as colorless liquid.
IR: 2955, 2873, 1725, 1435 cm1.
230 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 13 g of trans-cyclopentane-1,2-dicarboxylic acld dimethyl ester in 300 ml of toluene at 0C under argon and stirred for 2 hours at 0C. Then, .
.
., . - :
, ., .
.: :
t 20 ml of isopropanol is instilled, stirred for 5 minutes, 116 ml of water is instilled and stirred for 2 hours at 22C. It is filt~red, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate, 8 g of trans-1,2-dihydroxy-cyclopentane is obtained as colorless liquid.
IR: 3610, 3400, 2960, 1062 cm~1.
17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride ars added to a solution of 16 g of trans-1,2-dihydroxymethyl-cyclopentane in 146 ml of dimethylformamide at 0C and stirred for 22 hours at 24C. It is diluted with 1.6 1 of ether, shaken twice with 80 ml of 10% sulfuric acid each, washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (9+13 12 g of trans-1-(tert-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopentane is obtained as colorless liquid.
IR: 3400, 2960, 2860, 1260, 840 cm1.
70 g of Collins reagent (chromic acid-pyridine complex~ is added to a solution of 14.4 g of the above-described monosilylether in 750 ml of methylene chloride and stirred for 30 minutes at 0C. Then, it is diluted with a mixture of hexane/ether (3+2), Celite is added, filtered and concentrated by evaporation in a Yacuum. 14 g of the aldehyde is obtained, which is used without further purification.
IR: 2958, 2860, 2720, 1719, 840 cm~1. -, , ~
J ~ ~J ~
For Wittig-Horner olefination, 16.1 g of phosphonocrotonic acid triethyl ester and 9.8 g of diazabicycloundecene (DBU) are added at 24C to a stirred suspension of 2.7 g of lithium chloride in 536 ml of acetonitrile and stirred for 10 minutes.
Then, a solution of 13 g of the above-described aldehyde in 107 ml of acetonitrile is instilled, stirred for 3.5 hours at 24C
and then diluted with ether. It is shaken in succession with water, 10% citric acid solution and water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with hexane/ethyl acetate on silica--gel. In this way, 11 g of the title compound is obtained as colorless oil.
IRo 2958, 2860, 1705, 1640, 1620, 1470, 1255, lO00, 838 cm 1 , 9b~ -5-[trans-l-(tert-Butyl-dimethylsilyloxYmethyl)-cyclopent-2-yll-(2E,4EL-~entadien-l-al 50 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 9.8 g of ester, produced according to example 9a, in 250 ml of toluene at -70C under argon and stirred for 30 minutes at -70C. Then, 10 ml of isopropanol and, after 5 minutes, 30 ml of water are instilled, stirred for 2.5 hours at 23C, filtered, washed with methylene chloride and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ~6 s~ , 3 ~ ~
hexane/ether (7~3), 7.6 g of the alcohol is obtained as colorless oil.
IR: 3610, 34S0, 990, 940, ~40 cm~~.
For aldehyde production, a solution of 7.5 g of the above-produced alcohol in 250 ml of toluene is mixed with 22 g of manganese dioxide and stirred for 4 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ethyl acetate (8+2), 7.4 g of the title compound is obtained as colorless oil.
IR: 2960, 2860, 2740, 1682, 1638, 988, g40, 840 cm~1.
9c) (5-RS)-5-Acetoxy-l-Lt ans-l-ltert butyl-dimethylsilyloxymethvl)-cvclopent-2-yl]-1-(lE,3E)-tridecadiene A solution of 17.8 g of octyl bromide in 24 ml of ether is instilled in 2.24 g of magnesium in 12 ml of ether with heating and stirred for 30 minutes at 25~C. A solution of 7.4 g of aldehyde, produced according to example 9b, in 130 ml of ether is instilled in 16.4 ml ~=30.1 mmol) of this Grignard solution at -20C under argon and stirred for 45 minutes at -20C. It is mixed with saturated ammonium chloride solution, extracted thr~e times with ether, the organic phase is shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel. With hexane/ethyl acetate (7+3), 8.6 g of alcohol (diastereomer mixture) is obtained as colorless oil.
For acetylation, 12.5 ml of acetic anhydride is added to a solution of 8.5 g of the above-produced alcohol in 85 ml of .
::
pyridine and stirred for 23 hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/ethyl acetate (97+3), 8.6 g of the title compound is obtained as colorless oil.
IR: 2938, 2860, 1725, lb57, 1255, 993, 945, 840 cm~1.
9d) trans-(lRS~ Formyl-(2RS)-Z-r~lE,3E)-(5RS)-5-acetoxy-1.3-tridecadienyl~-cyclopentane 19.9 g of tetrabutylammonium fluoride is added to-a solution of 9.1 g of the acetate, produced according to example 9c, in 900 ml of tetrahydrofuran at 0C, stirred ~or 15 minutes at 0C and for 4 hours at 24C. Then, it is diluted with 2 l of ether and washed three times with brine. It is dried with sodium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (7+3), 7.18 g of the alcohol is eluted as colorless oil.
IR: 3620, 34S0, 2938, 2862, 1730, 1255, 995 cm~1.
63 g of Collins reagent (chromic acid-pyridine ~omplex) is added to a solution of 8.1 g of the above-produc~d alcohol in 250 ml of methylene chloride at 0C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture o~ hexane/ether ~1~1), Celite is added, filtered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further puri~ication.
IR: 2930, 2860, 2731, 1721, 1250, 990 cm~1.
4~ ~3 ~xa~pl~ 1~
(+~-)-(5RS?-5-Hydroxy-5-~trans-(2-RS)-2-(lE 3E)-(5RS) 5-hydroxy-1,3-tridecadienyl~-(lRS)-cyclo~entyll-~entanoic acid Diastereomer A
Analogously to example 2, 168 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 9, as colorless oil.
IR (film): 3400, 2930, 2858, 1715, 1660, 1250, 989, 930 cm-1 .
Example 11 (+/-~5RS)-5-Acetoxy-5-ttrans-(2RS~-2-(lE 3E)-(5RS~-5-hydroxy-1,3-tridecadienyl)-~lRS)-cyclopentyl]-p2ntanoic acid Diastereomer A
Analogously to example 3, 204 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 9, as colorless oil.
IR (film): 3450, 2930, 2860, 1736, 1713, 1660, 1245, 99o cm ~
Example_12 (+~-L-l5RS)-5-Acetoxy-5-ttrans-(2RS) 2~(1E,3E)-(5RS~-5-acetoxy-1,3~tridecadienyl~ = f lRS)-cyclopentyl~-pentanoic acid Diastereomer B
15 g of Collins reagent is added to a solution of 2.2 g of the polar alcohol (diastereomer B), produced in example 9, in 173 ml of methylene chloride at 0C and stirred for 20 minutes at ,:
0C. Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexaneJether (1+1) and concentrated by evaporation in a vacuum. The thus obtained 1-aldehyde is immediately used without further purification. -4.7 ml of Jones reagent is instilled in a solution of 2.25 g of the above-produced aldehyde in 83 ml of acetone with stirring at -25C and stirred for 12 minutes at -25C under argon. Then, 16.5 ml of isopropanol is added, stirred for 5 minutes, diluted --with ether, shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (6+4), 1.6 g of the title compound is obtained as colorless oil.
IR: 3620, 2930, 2860, 1721, 1658, 1370, 1250, 989, 946 cm~1 .
Example 13 (+)-)- ~RS)-5-Hydroxy-5-[trans-(2RS)-2-(lE~3E)-(5S)-5-hydroxy-1/3-tridecadienyl~-(lRS)-cyclopentyl]-pentanoic acid Diastereomer B
Analogously to example 2, 178 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 12, as colorless oil.
IR: 3600, 3420, 2930, ~859, 1730, 1660, 1250, 990 cm~l.
- `
Example 14 (+~-3-(5RS)-5-Acetoxy-5-rtrans-(2RS~-2-(lE 3E3-(5S)-5-hvdroxy-1 3-tridecadienyl)-(lRS)-cyclopentyl~-pentanoic acid Diaste_eomer B
Analogously to example 3, 187 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 12, as colorless oil.
IR (film): 3450, 2925, 2850, 1730, 1708, 1660, 1245, 985 cm~1 ~
Example 15 (+/-~-(5RS~-5-Hydroxy-5-rcis-(2RS)-2-(lE 3E~-(5Sl-5-hydroxy-1,3-tridecadienvl)-(lRS)-cyclopentyll-pentanoic acid methyl ester Diastereomer nonPolar (12) An ethereal diazomethane solution is instilled in a solution of 85 mg of the acid, produced according to example 2, in 8 ml of methylene chloride at 0C until permanent yellow coloring and stirred for 15 minutes at 0C. Then, it is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (2+83, 69 mg of the title compound is o~tained as colorless oil.
IR (film): 3600, 2925, 2855, 1738, 1658, 990 cm~1.
: ~
' ':
Example 16 (+/-)-(5RS~-5-Hydroxy-5-[cis-(2RS)-2-(lE.3E)-(5S)-5-hydroxy-1,3-tridecadienyl)-flRS)-cyclopentyl]-pentanoic acid methyl ester Diastereomer polar (12) Analogously to example 15, 102 mg of the title compound is obtained from 120 mg of the acid, produced according to example 6, as oil.
IR (film): 3610, 2g25, 2855, 1737, 1660, 990 cm~1. -Example 17 --(+~ 5RS~-5 Acetoxy-5 rcis-(2RS)-2 (lE 3E)-(5S)-5-hydroxy-1,3-tridecadienyl)-~lRS)-cyclopentylJ-pentanoic acid methyl_ester Diastereomer polar ~12) Analogously to example 15, 71 mg of the title compound is obtained from 80 mg of the acid, produced according to example 7, as colorless oil.
IR (film~: 3400, 2924, 2858, 1739, 1658, 1240, 990 cm~1.
Example 18 (+~ (5Rs)-5-Hydroxy--5-[cis-(2-Rs)-2-(lE~3E)-(5s)-~-hydroxy-l~3 tridecagien~ RS)-cyclopentyl] pentanoic acid-tris-(hydroxvmethylL-aminomethane salt Diastereomer polar (12 A solution of 15 mg of tris-(hydroxymethyl)-aminomethane in 0.03 ml of water is added to a solution of 40 mg of the carboxylic acid, produced according to example 6, in 6 ml of acetonitrile at 70C. It is allowed to cool with stirring, is decanted after 16 hours from the solvent and the residue is dried 52 ~s~
in a vacuum. 1~ mg of the title compound is isolated as waxy mass.
Example 19 (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-(lE 3E)-(5S)-5-hydroxy-1 3-tridecadienyl ? - ( lRS)-cyclopentyll-pentanoic acid-1 5-lactone Diastereomer ~olar (12) 0.5 g of anhydrous magnesium sulfate is added to a solution of 27 mg of the carboxylic acid, produced according to example 6, in 5 ml of toluene at 24C over a period of 24 hours in portions and stirred for another 24 hours at 24C. Then, it is filtered and the evaporation residue is chromatographed on silica gel.
With toluene/ethyl acetate (7+3), 14 mg of the 1,5-lactone is eluted as colorless oil.
IR: 3600, 2930, 2860, 1728, 1250, 990 cm~1.
~ , , .
:-`
(+~-)-(5RS?-5-Hydroxy-5-~trans-(2-RS)-2-(lE 3E)-(5RS) 5-hydroxy-1,3-tridecadienyl~-(lRS)-cyclo~entyll-~entanoic acid Diastereomer A
Analogously to example 2, 168 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 9, as colorless oil.
IR (film): 3400, 2930, 2858, 1715, 1660, 1250, 989, 930 cm-1 .
Example 11 (+/-~5RS)-5-Acetoxy-5-ttrans-(2RS~-2-(lE 3E)-(5RS~-5-hydroxy-1,3-tridecadienyl)-~lRS)-cyclopentyl]-p2ntanoic acid Diastereomer A
Analogously to example 3, 204 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 9, as colorless oil.
IR (film): 3450, 2930, 2860, 1736, 1713, 1660, 1245, 99o cm ~
Example_12 (+~-L-l5RS)-5-Acetoxy-5-ttrans-(2RS) 2~(1E,3E)-(5RS~-5-acetoxy-1,3~tridecadienyl~ = f lRS)-cyclopentyl~-pentanoic acid Diastereomer B
15 g of Collins reagent is added to a solution of 2.2 g of the polar alcohol (diastereomer B), produced in example 9, in 173 ml of methylene chloride at 0C and stirred for 20 minutes at ,:
0C. Then, it is diluted with a mixture of hexane/ether (1+1), Celite is added, filtered, washed with hexaneJether (1+1) and concentrated by evaporation in a vacuum. The thus obtained 1-aldehyde is immediately used without further purification. -4.7 ml of Jones reagent is instilled in a solution of 2.25 g of the above-produced aldehyde in 83 ml of acetone with stirring at -25C and stirred for 12 minutes at -25C under argon. Then, 16.5 ml of isopropanol is added, stirred for 5 minutes, diluted --with ether, shaken with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (6+4), 1.6 g of the title compound is obtained as colorless oil.
IR: 3620, 2930, 2860, 1721, 1658, 1370, 1250, 989, 946 cm~1 .
Example 13 (+)-)- ~RS)-5-Hydroxy-5-[trans-(2RS)-2-(lE~3E)-(5S)-5-hydroxy-1/3-tridecadienyl~-(lRS)-cyclopentyl]-pentanoic acid Diastereomer B
Analogously to example 2, 178 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 12, as colorless oil.
IR: 3600, 3420, 2930, ~859, 1730, 1660, 1250, 990 cm~l.
- `
Example 14 (+~-3-(5RS)-5-Acetoxy-5-rtrans-(2RS~-2-(lE 3E3-(5S)-5-hvdroxy-1 3-tridecadienyl)-(lRS)-cyclopentyl~-pentanoic acid Diaste_eomer B
Analogously to example 3, 187 mg of the title compound is obtained from 250 mg of the diacetate, produced according to example 12, as colorless oil.
IR (film): 3450, 2925, 2850, 1730, 1708, 1660, 1245, 985 cm~1 ~
Example 15 (+/-~-(5RS~-5-Hydroxy-5-rcis-(2RS)-2-(lE 3E~-(5Sl-5-hydroxy-1,3-tridecadienvl)-(lRS)-cyclopentyll-pentanoic acid methyl ester Diastereomer nonPolar (12) An ethereal diazomethane solution is instilled in a solution of 85 mg of the acid, produced according to example 2, in 8 ml of methylene chloride at 0C until permanent yellow coloring and stirred for 15 minutes at 0C. Then, it is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (2+83, 69 mg of the title compound is o~tained as colorless oil.
IR (film): 3600, 2925, 2855, 1738, 1658, 990 cm~1.
: ~
' ':
Example 16 (+/-)-(5RS~-5-Hydroxy-5-[cis-(2RS)-2-(lE.3E)-(5S)-5-hydroxy-1,3-tridecadienyl)-flRS)-cyclopentyl]-pentanoic acid methyl ester Diastereomer polar (12) Analogously to example 15, 102 mg of the title compound is obtained from 120 mg of the acid, produced according to example 6, as oil.
IR (film): 3610, 2g25, 2855, 1737, 1660, 990 cm~1. -Example 17 --(+~ 5RS~-5 Acetoxy-5 rcis-(2RS)-2 (lE 3E)-(5S)-5-hydroxy-1,3-tridecadienyl)-~lRS)-cyclopentylJ-pentanoic acid methyl_ester Diastereomer polar ~12) Analogously to example 15, 71 mg of the title compound is obtained from 80 mg of the acid, produced according to example 7, as colorless oil.
IR (film~: 3400, 2924, 2858, 1739, 1658, 1240, 990 cm~1.
Example 18 (+~ (5Rs)-5-Hydroxy--5-[cis-(2-Rs)-2-(lE~3E)-(5s)-~-hydroxy-l~3 tridecagien~ RS)-cyclopentyl] pentanoic acid-tris-(hydroxvmethylL-aminomethane salt Diastereomer polar (12 A solution of 15 mg of tris-(hydroxymethyl)-aminomethane in 0.03 ml of water is added to a solution of 40 mg of the carboxylic acid, produced according to example 6, in 6 ml of acetonitrile at 70C. It is allowed to cool with stirring, is decanted after 16 hours from the solvent and the residue is dried 52 ~s~
in a vacuum. 1~ mg of the title compound is isolated as waxy mass.
Example 19 (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-(lE 3E)-(5S)-5-hydroxy-1 3-tridecadienyl ? - ( lRS)-cyclopentyll-pentanoic acid-1 5-lactone Diastereomer ~olar (12) 0.5 g of anhydrous magnesium sulfate is added to a solution of 27 mg of the carboxylic acid, produced according to example 6, in 5 ml of toluene at 24C over a period of 24 hours in portions and stirred for another 24 hours at 24C. Then, it is filtered and the evaporation residue is chromatographed on silica gel.
With toluene/ethyl acetate (7+3), 14 mg of the 1,5-lactone is eluted as colorless oil.
IR: 3600, 2930, 2860, 1728, 1250, 990 cm~1.
~ , , .
:-`
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Leukotriene-B4 derivatives of formula I
(I) in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent-H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, (C1-C10) alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A represents a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group , D can mean a direct bond, oxygen, sulfur, -C?C-, -CH=CR8 or together with B can also mean a direct bond, R6 and R7 are the same or different and represent H or C1-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1-C5 alkyl, chlorine, bromine, n is 3-5 as well as, if R5 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
(I) in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent-H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, (C1-C10) alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A represents a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group , D can mean a direct bond, oxygen, sulfur, -C?C-, -CH=CR8 or together with B can also mean a direct bond, R6 and R7 are the same or different and represent H or C1-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1-C5 alkyl, chlorine, bromine, n is 3-5 as well as, if R5 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
2. Process for the production of leukotriene-B4 derivatives of formula I
(I) in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, C1-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A represents a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group D can mean a direct bond, oxygen, sulfur, -C?C-, -CH=CR8 or together with B can also mean a direct bond, R6 and R7 are the same or different and represent H or C1-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1-C5 alkyl, chlorine, bromine, n is 3-5 as well as, if R5 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates,, characterized in that an aldehyde of formula II
(II), in which A, B, D, R3 and R4 have the above-indicated meaning, optionally after protection of free hydroxy groups is reacted with a magnesium-organic compound of formula III, X-Mg-CH2-CH2-CH2-CH2-R9 (III), in which X represents chlorine, bromine or iodine and R9 represents -CH3, CF3 or -OR10, in which R10 means an easily cleavable ether radical, and optionally then isomers are separated in any sequence, protected hydroxy groups are released and/or a free hydroxy group is esterified and/or the 1-hydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxyl group (R1 = COOR5) is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is converted to an amide (R1 = CONHR6R7) or a carboxyl group with a physiologically compatible base is converted to a salt.
(I) in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, C1-C10 alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A represents a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group D can mean a direct bond, oxygen, sulfur, -C?C-, -CH=CR8 or together with B can also mean a direct bond, R6 and R7 are the same or different and represent H or C1-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1-C5 alkyl, chlorine, bromine, n is 3-5 as well as, if R5 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates,, characterized in that an aldehyde of formula II
(II), in which A, B, D, R3 and R4 have the above-indicated meaning, optionally after protection of free hydroxy groups is reacted with a magnesium-organic compound of formula III, X-Mg-CH2-CH2-CH2-CH2-R9 (III), in which X represents chlorine, bromine or iodine and R9 represents -CH3, CF3 or -OR10, in which R10 means an easily cleavable ether radical, and optionally then isomers are separated in any sequence, protected hydroxy groups are released and/or a free hydroxy group is esterified and/or the 1-hydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxyl group (R1 = COOR5) is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is converted to an amide (R1 = CONHR6R7) or a carboxyl group with a physiologically compatible base is converted to a salt.
3. Pharmaceutical preparations which contain one or more compounds according to claim 1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4108351A DE4108351A1 (en) | 1991-03-12 | 1991-03-12 | NEW LEUKOTRIA-B (DOWN ARROW) 4 (DOWN ARROW) DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
DEP4108351.2 | 1991-03-12 |
Publications (1)
Publication Number | Publication Date |
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CA2082818A1 true CA2082818A1 (en) | 1992-09-13 |
Family
ID=6427320
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002082818A Abandoned CA2082818A1 (en) | 1991-03-12 | 1992-02-24 | Leukotriene b4 derivatives, method for preparing them and their use as drugs |
Country Status (14)
Country | Link |
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EP (1) | EP0529022B1 (en) |
JP (1) | JPH06500566A (en) |
AT (1) | ATE128460T1 (en) |
AU (1) | AU1267892A (en) |
CA (1) | CA2082818A1 (en) |
DE (2) | DE4108351A1 (en) |
DK (1) | DK0529022T3 (en) |
ES (1) | ES2079857T3 (en) |
GR (1) | GR3018361T3 (en) |
HU (1) | HUT63596A (en) |
IE (1) | IE920792A1 (en) |
NO (1) | NO924347L (en) |
PT (1) | PT100227B (en) |
WO (1) | WO1992016504A1 (en) |
Families Citing this family (5)
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ATE141593T1 (en) * | 1991-11-29 | 1996-09-15 | Schering Ag | LEUCOTRIEN-B 4? DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS |
US5783602A (en) * | 1994-01-27 | 1998-07-21 | Schering Aktiengesellschaft | Leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents |
DE19722848A1 (en) * | 1997-05-23 | 1998-11-26 | Schering Ag | Leukotriene B¶4¶ derivatives, especially Oximo LTB¶4¶ antagonists |
DE19722846A1 (en) * | 1997-05-23 | 1998-12-24 | Schering Ag | Leukotriene B¶4¶ derivatives, especially 7-methylcyclohexyl LTB¶4¶ antagonists |
US7327275B2 (en) | 2004-02-02 | 2008-02-05 | Gecko Alliance Group Inc. | Bathing system controller having abnormal operational condition identification capabilities |
Family Cites Families (2)
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EP0103445A3 (en) * | 1982-09-03 | 1984-10-17 | Teijin Limited | Process for production of prostaglandins E or F, and novel 7-(thiocarbo-acyloxy) prostaglandins E or F |
DE3917597A1 (en) * | 1989-05-26 | 1990-11-29 | Schering Ag | NEW LEUKOTRIA-B (DOWN ARROW) 4 (DOWN ARROW) DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS |
-
1991
- 1991-03-12 DE DE4108351A patent/DE4108351A1/en not_active Withdrawn
-
1992
- 1992-02-04 HU HU929203544A patent/HUT63596A/en unknown
- 1992-02-24 JP JP4504866A patent/JPH06500566A/en active Pending
- 1992-02-24 AT AT92905138T patent/ATE128460T1/en not_active IP Right Cessation
- 1992-02-24 EP EP92905138A patent/EP0529022B1/en not_active Expired - Lifetime
- 1992-02-24 AU AU12678/92A patent/AU1267892A/en not_active Abandoned
- 1992-02-24 CA CA002082818A patent/CA2082818A1/en not_active Abandoned
- 1992-02-24 ES ES92905138T patent/ES2079857T3/en not_active Expired - Lifetime
- 1992-02-24 WO PCT/DE1992/000151 patent/WO1992016504A1/en active IP Right Grant
- 1992-02-24 DE DE59203817T patent/DE59203817D1/en not_active Expired - Lifetime
- 1992-02-24 DK DK92905138.1T patent/DK0529022T3/en active
- 1992-03-11 PT PT100227A patent/PT100227B/en not_active IP Right Cessation
- 1992-03-12 IE IE079292A patent/IE920792A1/en not_active Application Discontinuation
- 1992-11-11 NO NO92924347A patent/NO924347L/en unknown
-
1995
- 1995-12-12 GR GR950403489T patent/GR3018361T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
ATE128460T1 (en) | 1995-10-15 |
IE920792A1 (en) | 1992-09-23 |
EP0529022B1 (en) | 1995-09-27 |
DE59203817D1 (en) | 1995-11-02 |
GR3018361T3 (en) | 1996-03-31 |
JPH06500566A (en) | 1994-01-20 |
AU1267892A (en) | 1992-10-21 |
NO924347D0 (en) | 1992-11-11 |
PT100227A (en) | 1993-07-30 |
HU9203544D0 (en) | 1993-01-28 |
DK0529022T3 (en) | 1996-02-05 |
DE4108351A1 (en) | 1992-09-17 |
WO1992016504A1 (en) | 1992-10-01 |
EP0529022A1 (en) | 1993-03-03 |
NO924347L (en) | 1992-11-11 |
ES2079857T3 (en) | 1996-01-16 |
HUT63596A (en) | 1993-09-28 |
PT100227B (en) | 1999-09-30 |
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