CA1251201A - 9-halogen prostaglandins - Google Patents
9-halogen prostaglandinsInfo
- Publication number
- CA1251201A CA1251201A CA000478989A CA478989A CA1251201A CA 1251201 A CA1251201 A CA 1251201A CA 000478989 A CA000478989 A CA 000478989A CA 478989 A CA478989 A CA 478989A CA 1251201 A CA1251201 A CA 1251201A
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkyl
- trans
- acid
- prosta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 229910052736 halogen Inorganic materials 0.000 title claims abstract description 16
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 75
- -1 hydroxymethylene group Chemical class 0.000 claims abstract description 45
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 40
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 239000001301 oxygen Substances 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 5
- 229960003903 oxygen Drugs 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract 9
- 229910052731 fluorine Inorganic materials 0.000 claims abstract 9
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract 9
- 239000000460 chlorine Substances 0.000 claims abstract 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract 3
- 125000004122 cyclic group Chemical group 0.000 claims abstract 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 3
- 229960001124 trientine Drugs 0.000 claims description 43
- 150000004702 methyl esters Chemical class 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- UKVVPDHLUHAJNZ-PMACEKPBSA-N prostane Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC UKVVPDHLUHAJNZ-PMACEKPBSA-N 0.000 claims description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 8
- 239000011737 fluorine Substances 0.000 claims 6
- 229940060038 chlorine Drugs 0.000 claims 5
- 235000017168 chlorine Nutrition 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 3
- 239000005864 Sulphur Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 2
- 125000001624 naphthyl group Chemical group 0.000 claims 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 150000003460 sulfonic acids Chemical class 0.000 claims 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 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 abstract description 14
- 239000000463 material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 3
- 230000002508 compound effect Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 235000013350 formula milk Nutrition 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229940093499 ethyl acetate Drugs 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- ICGWWCLWBPLPDF-UHFFFAOYSA-N furan-2-ol Chemical compound OC1=CC=CO1 ICGWWCLWBPLPDF-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 238000004587 chromatography analysis Methods 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 230000001120 cytoprotective effect Effects 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229960005349 sulfur Drugs 0.000 description 2
- 235000001508 sulfur Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- SJQBHNHASPQACB-UHFFFAOYSA-N 1,2-dimethoxyethene Chemical compound COC=COC SJQBHNHASPQACB-UHFFFAOYSA-N 0.000 description 1
- HAAITRDZHUANGT-UHFFFAOYSA-N 1-[2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 HAAITRDZHUANGT-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000905957 Channa melasoma Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000518994 Conta Species 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 101100326757 Drosophila melanogaster Capr gene Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 101150083807 HSD17B10 gene Proteins 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003509 anti-fertility effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000000572 bronchospasmolytic effect Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical group C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000029860 luteolysis Effects 0.000 description 1
- 230000003529 luteolytic effect Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 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
- 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
- 210000000496 pancreas Anatomy 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
Classifications
-
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
-
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
9-Halogen prostane derivatives of formula I
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH20H or -C-OR2 with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical , with R3 is an acid radical or the radical R2 A is a -CH2-CH2-, a trans-CH=CH- or a -C?C- group, W is a free functionally modified hydroxymethylene group or a free or func-tionally modified group, whereln the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group wtth 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxy-gen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkenyl group and, where R2 is a hydrogen atom, its salts with physiolog-ically tolerable bases useful as pharmaceuticals having compound effects over material prostaglandins.
9-Halogen prostane derivatives of formula I
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH20H or -C-OR2 with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical , with R3 is an acid radical or the radical R2 A is a -CH2-CH2-, a trans-CH=CH- or a -C?C- group, W is a free functionally modified hydroxymethylene group or a free or func-tionally modified group, whereln the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group wtth 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxy-gen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkenyl group and, where R2 is a hydrogen atom, its salts with physiolog-ically tolerable bases useful as pharmaceuticals having compound effects over material prostaglandins.
Description
~I.r~ 51.2~
The present Inventlon relates to 9-halogen prostaglan-dln derlvatlves, processes for thelr manufacture as well as thelr use as pharmaceutlcals.
From the extens/ve state of the art as regards prostaglandlns and thelr analogous substances It Is known that thls class of substance Is sultable for the treatment of mammals, man Included, because of thelr blologlcal and pharmacologlcal propert/es. However, the/r use as pharmaceutlcals often meets 10 wlth dlfflcultles. The effectlve duratlon of most natural prostaglandlns Is too short for therapeutlc purposes slnce they are rapldly metabollzed by varlous enzymatlc processes. All the structural changes have the alm of Increaslng the effect ~e dura-tlon as We// as the selectlvlty of the effect.
It was now found that 9-halogen prostaglandln derlva-tlves have outstandlng effectlve speclflclty, better effectlve-ness, longer effectlve duratlon than natural prostaglandlns and thelr derlvatlves and are especlally sultable for oral applIcatlon.
The Inventlon provldes to 9-halogen prostane derlva-tlves In accordance wlth formula I
}1~1 C
(I), A-h'-D-E-~
~ 5 l~
where Hal Is a chlorlne or fluorlne atom In the ~ or ~ -posltlon, R1 Is the radlcal CH20H or -C-OR2 wlth R2 /s a hydrogen atom, an alkyl, cycloal~yl, aryl or heterocycllc radlcal or R1 Is the ~t ~k '125 //
radlcal -C-NHR3, w/th ~ Is an acld radlcal or the radlcal R2 A
! s a -CH2-CH2-, a trans-~H=e~- or a -C--C- group, W Is a free functlonally modlfled hydroxymethylene group or a free or func-tlonally modlfled -C- group, whereln the OH group may be In the ~ or ~ -posltlon, D
~-~ d/~
and E together form a dlfferent bond or D Is a stralght-chaln, branched-chaln or cycllc alkylene group wlth 1 to 10 C-atoms, whlch may be substltuted by fluorlne atoms, E represents an oxy-gen or sulfur atom, a d/rect bond, a -C-C- bond or a -C~6=CR7-group, where P6 and R7 are dlfferent and are a hydrogen atom, a chlorlne atom or a C l -C4-a lky l group, ~4 a free or functlonally modlfled hydroxy group, and R5 Is a hydrogen atom, an alkyl, an alkenyl, a halogen-substltuted alkyl, a cycloalkyl, an aryl/~r a heterocyc//c group or when D and E forms a dlrect bond an ~k~
groUp and, where ~2 Is a hydrogen atom, Its salts wlth physlolog-lcally tolerable bases, R2 alkyl groups are stralght or branched alkyl groups w/th 1 to 10 C-atoms, e.g. methy/, ethyl, propyl, butyl, Isobutyl, terlary butyl, pentyl, neopentyl, hexyl, heptyl and decyl. The P2 alkyl groups may be slngle or multlply substl-tuted by halogen atoms, alkoxy groups, unsubstltuted and substl-tuted aryl and/or aroyl groups, dlalkylamlno and trlalkyl ammo-nlum, the slngle substltutlon belng preferred. Examples of sub-stltuents are flourlne, chlorlne or bromlne, phenyl, dlmethyl-amlno, dlethylamlno, methoxy, ethoxy. Preferred R2 alkyl groups are those w/th 1 to 4 C-atoms, e.g. methyl, ethyl, propyl, dlmethylamlnopropyl, Isobutyl and butyl.
Posslble P2 aryl groups are both unsubstltuted or sub-stltuted aryl groups such as phenyl, 1-naphthyl and ?-naphthyl, whlch can be respectlvely substltuted by 1 to 3 halogen atoms, one phenyl group, 1 to 3 alkyl groups wlth 1 to 4 C-atoms respec-tIvely, a chloromethyl, fluoromethyl, trlfluoromethyl, carboxyl,hydroxy or alkoxy group wlth 1 to 4 C-atoms. The substltuents In ~1 ~1 '~
~.2s~2o~
the 3rd and 4th-posltlon on the phenyl rlng are preferred, exam-ples belng f/uor/ne, ch/orlne, alkoxy or trlfluoromethyl or, In the 4th-posltlon, hydroxy.
The P2 cycloalkyl group may conta/n In the rlng 3 to 10, preferably 5 and 6 carbon atoms. The rlngs can be substl-tuted by alkyl groups wlth 1 to 4 carbon atoms. Examples are cyclopentyl, cyc I ohexyl, methyl cyc / ohexyl and adamantyl.
Posslble heterocycl/c groups for R2 are 5 and 6-member heterocyc//c groups that contaln at /east 1 heteroatom, prefer-ably n/trogen, oxygen or sulfur. Examp/es are 2-furyl, 2-thlenyl, 2-pyrldyl, 3-pyrldyl, 4-pyrldyl, oxazolyl, thlazolyl, pyrlmldlnyl, pyrldazlnyl, pyrazlnyl, 3-furyl, 3-thlenyl, and 2-tetrazolyl.
Physlolog/cally to/erab/e acId rad/cals can be used as the R3 acId radlcal. Sultable acIds are organ/c carboxy//c acIds and sulfonlc aclds wlth 1 to 15 carbon atoms that belong to the allphatlc, cycloallphat/c, aromat/c, aromatlc-allphatlc and hete-rocycllc serles. These aclds can be saturated, unsaturated and/or polybaslc and/or replaced In the customary fashlon. Exam-ples of the substltuents are alkyl, hydroxy, a/koxy, oxo or am/no groups or halogen atoms. The followlng carboxy/lc aclds are men~
tloned as examples: formlc ac/d, acet/c ac/d, prop/on/c ac/d, butyrlc acld, /sobutyr/c ac/d, valerlc ac/d, /sova/erlc ac/d, caprolc acld, enanthlc acld, capryllc ac/d, pe/argon/c ac/d, capr/c acld, undecyllc acld, laurlc ac/d, tr/decy//c ac/d, myrls-tlc acld, pentadecyllc ac/d, tr/methy/acetlc acld, dlethylacetlc acld, tert-butyl acetlc acld, cyclopropyl acet/c acld, cyclopentyl acetlc acId, cyclohexyl acetlc acId, cyclopropane carboxyllc acld, cyclohexane carboxyllc acld, phenyl acetlc acld, phenoxyacetlc acld, methoxyacetlc acld, ethoxyacetlc acld, mono-, dl- and trlchloroacet/c acld, am/noacet/c ac/d, dlethylamlno acetlc acld, plperldlnoacetlc acld, morpholInoacetlc acld, lactlc acld, succ/nlc ac/d, adlplc ac/d, benzolc ac/d, as we/l as sub-~'51~
stltuted benzolc aclds, nlcotlnlc acld, Isonlcotlnlc acld, furan-
The present Inventlon relates to 9-halogen prostaglan-dln derlvatlves, processes for thelr manufacture as well as thelr use as pharmaceutlcals.
From the extens/ve state of the art as regards prostaglandlns and thelr analogous substances It Is known that thls class of substance Is sultable for the treatment of mammals, man Included, because of thelr blologlcal and pharmacologlcal propert/es. However, the/r use as pharmaceutlcals often meets 10 wlth dlfflcultles. The effectlve duratlon of most natural prostaglandlns Is too short for therapeutlc purposes slnce they are rapldly metabollzed by varlous enzymatlc processes. All the structural changes have the alm of Increaslng the effect ~e dura-tlon as We// as the selectlvlty of the effect.
It was now found that 9-halogen prostaglandln derlva-tlves have outstandlng effectlve speclflclty, better effectlve-ness, longer effectlve duratlon than natural prostaglandlns and thelr derlvatlves and are especlally sultable for oral applIcatlon.
The Inventlon provldes to 9-halogen prostane derlva-tlves In accordance wlth formula I
}1~1 C
(I), A-h'-D-E-~
~ 5 l~
where Hal Is a chlorlne or fluorlne atom In the ~ or ~ -posltlon, R1 Is the radlcal CH20H or -C-OR2 wlth R2 /s a hydrogen atom, an alkyl, cycloal~yl, aryl or heterocycllc radlcal or R1 Is the ~t ~k '125 //
radlcal -C-NHR3, w/th ~ Is an acld radlcal or the radlcal R2 A
! s a -CH2-CH2-, a trans-~H=e~- or a -C--C- group, W Is a free functlonally modlfled hydroxymethylene group or a free or func-tlonally modlfled -C- group, whereln the OH group may be In the ~ or ~ -posltlon, D
~-~ d/~
and E together form a dlfferent bond or D Is a stralght-chaln, branched-chaln or cycllc alkylene group wlth 1 to 10 C-atoms, whlch may be substltuted by fluorlne atoms, E represents an oxy-gen or sulfur atom, a d/rect bond, a -C-C- bond or a -C~6=CR7-group, where P6 and R7 are dlfferent and are a hydrogen atom, a chlorlne atom or a C l -C4-a lky l group, ~4 a free or functlonally modlfled hydroxy group, and R5 Is a hydrogen atom, an alkyl, an alkenyl, a halogen-substltuted alkyl, a cycloalkyl, an aryl/~r a heterocyc//c group or when D and E forms a dlrect bond an ~k~
groUp and, where ~2 Is a hydrogen atom, Its salts wlth physlolog-lcally tolerable bases, R2 alkyl groups are stralght or branched alkyl groups w/th 1 to 10 C-atoms, e.g. methy/, ethyl, propyl, butyl, Isobutyl, terlary butyl, pentyl, neopentyl, hexyl, heptyl and decyl. The P2 alkyl groups may be slngle or multlply substl-tuted by halogen atoms, alkoxy groups, unsubstltuted and substl-tuted aryl and/or aroyl groups, dlalkylamlno and trlalkyl ammo-nlum, the slngle substltutlon belng preferred. Examples of sub-stltuents are flourlne, chlorlne or bromlne, phenyl, dlmethyl-amlno, dlethylamlno, methoxy, ethoxy. Preferred R2 alkyl groups are those w/th 1 to 4 C-atoms, e.g. methyl, ethyl, propyl, dlmethylamlnopropyl, Isobutyl and butyl.
Posslble P2 aryl groups are both unsubstltuted or sub-stltuted aryl groups such as phenyl, 1-naphthyl and ?-naphthyl, whlch can be respectlvely substltuted by 1 to 3 halogen atoms, one phenyl group, 1 to 3 alkyl groups wlth 1 to 4 C-atoms respec-tIvely, a chloromethyl, fluoromethyl, trlfluoromethyl, carboxyl,hydroxy or alkoxy group wlth 1 to 4 C-atoms. The substltuents In ~1 ~1 '~
~.2s~2o~
the 3rd and 4th-posltlon on the phenyl rlng are preferred, exam-ples belng f/uor/ne, ch/orlne, alkoxy or trlfluoromethyl or, In the 4th-posltlon, hydroxy.
The P2 cycloalkyl group may conta/n In the rlng 3 to 10, preferably 5 and 6 carbon atoms. The rlngs can be substl-tuted by alkyl groups wlth 1 to 4 carbon atoms. Examples are cyclopentyl, cyc I ohexyl, methyl cyc / ohexyl and adamantyl.
Posslble heterocycl/c groups for R2 are 5 and 6-member heterocyc//c groups that contaln at /east 1 heteroatom, prefer-ably n/trogen, oxygen or sulfur. Examp/es are 2-furyl, 2-thlenyl, 2-pyrldyl, 3-pyrldyl, 4-pyrldyl, oxazolyl, thlazolyl, pyrlmldlnyl, pyrldazlnyl, pyrazlnyl, 3-furyl, 3-thlenyl, and 2-tetrazolyl.
Physlolog/cally to/erab/e acId rad/cals can be used as the R3 acId radlcal. Sultable acIds are organ/c carboxy//c acIds and sulfonlc aclds wlth 1 to 15 carbon atoms that belong to the allphatlc, cycloallphat/c, aromat/c, aromatlc-allphatlc and hete-rocycllc serles. These aclds can be saturated, unsaturated and/or polybaslc and/or replaced In the customary fashlon. Exam-ples of the substltuents are alkyl, hydroxy, a/koxy, oxo or am/no groups or halogen atoms. The followlng carboxy/lc aclds are men~
tloned as examples: formlc ac/d, acet/c ac/d, prop/on/c ac/d, butyrlc acld, /sobutyr/c ac/d, valerlc ac/d, /sova/erlc ac/d, caprolc acld, enanthlc acld, capryllc ac/d, pe/argon/c ac/d, capr/c acld, undecyllc acld, laurlc ac/d, tr/decy//c ac/d, myrls-tlc acld, pentadecyllc ac/d, tr/methy/acetlc acld, dlethylacetlc acld, tert-butyl acetlc acld, cyclopropyl acet/c acld, cyclopentyl acetlc acId, cyclohexyl acetlc acId, cyclopropane carboxyllc acld, cyclohexane carboxyllc acld, phenyl acetlc acld, phenoxyacetlc acld, methoxyacetlc acld, ethoxyacetlc acld, mono-, dl- and trlchloroacet/c acld, am/noacet/c ac/d, dlethylamlno acetlc acld, plperldlnoacetlc acld, morpholInoacetlc acld, lactlc acld, succ/nlc ac/d, adlplc ac/d, benzolc ac/d, as we/l as sub-~'51~
stltuted benzolc aclds, nlcotlnlc acld, Isonlcotlnlc acld, furan-
2-carboxyllc acld, cyclopentylproplonlc acld, where the sub~
stltuents are halogen, trlfluoromethyl, hydroxy, alkoxy or car-boxy groups. Preferred acyl radlcals are those wlth up to 10 carbon atoms. Posslble sulfonlc aclds are, for example, alkane-sulfonlc acld wlth 1 to 10 C-atoms, e.g. methanesulfonlc acld, ethanesulfonlc acld, Isopropanesulfonlc acld and butanesulfonlc acld as well as ~ -chloroethane-sulfonlc acld, cyclopentanesul-fonlc acld, cyclohexanesulfonlc acld, benzenesulfonlc acld, p-toluenesulfonlc acld, p-chlorobenzenesulfonlc acld, N.N-dlmethy-lamlnosulfonlc acld, N.N.-dlethylamlnosulfonlc acld, N.N.-bls-(~
-chloroethyl)-amlnosulfonlc acld, pyrrolldlno, plperldlno, plper-azlno, N-methylplperazlno and morphollnosulfonlc acId. Acyl rad-lcals and/or alkanesulfonlc acld radlcals wlth 1 to 4 C-atoms are especlally preferred.
The hydroxy groups In W and R4 can be functlonally mod-lfled, for example by etherlfylng or esterlfy/ng, In whlch case the modlfled hydroxy group In W can be In the ~ or ~-posltlon, free hydroxy groups belng preferred.
Posslble ether and acyl radlcals are the radlcals famlllar to the expert. Easy-to-separate ether rad/cals, e.g.
the tetra-hydropyranyl, tetrahydrofuranyl, ~ -ethoxyethyl, trlmethylsllyl, dlmethyl-tert-butyl-sllyl and trlbenzyl-sllyl radlcals are preferred. Posslble acy/ radlcals are the same as glven for R3 under organlc carboxyllc aclds, namely e.g. acetyl, proplonyl, butyryl and benzoyl. Posslble alkyl and alkenyl groups In R5 are stralght and branched-chaln alkyl radlcals wlth 30 1 to 10 C-atoms and alkenyl radlcals wlth 2 to 10, In partlcular 1 to 6 respectlvely 2 to 6 C-atoms that can be substltuted by, as the case may be, substltuted phenyl, alkyl wlth 1 to 4 C-atoms or halogen. Examples are: methyl, ethyl, propyl, Isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, bu~enyl, Isobutenyl, propenyl, pentenyl, hexenyl as well as benzyl, and when D and E
together mean a dlrect bond, posslbly alkynyl wlth 2 to 6 C-atoms ~:~5~
substltuted In the lst-posltlon by fluorlne or C1-C4 alkyl. Pos-slble alkynyl radlcals are the followlng: ethynyl, propln-1-yl, propln-2-yl, 1-methyIpropln-2-yl, 1-fluoropropln-2-yl, 1-ethyl-propln-2-yl, 1-fluorobutln-2-yl, butln-2-yl, butln-3-yl, 1-methyl-butln-3-yl, 1-methylpentln-3-yl, 1-fluoropentln-3-yl, 1-methyl-pentln-2-yl, 1-fluoropentln-2-yl, 1-methylpentln-4-yl, 1-fluoropentln-4-yl, hexln-1-yl, 1-methylhexln-2-yl, 1-fluorohexln-2-yl, 1-methylhexln-3-yl, 1-mentylhexln-4-yl, hexln-3-yl, 1,1-dlmethylhexln-4-yl etc.
Bromlne, chlorlne and fluorlne are posslble halogen sUbst/tuents of the R5 alkyl and alkenyl groups, chlorlne and fluorlne belng preferred.
The R5 cycloalkyl group can contaln 3 to 10 carbon atoms In the rlng, preferably 3 to 6. The rlngs can be substl-tuted by alkyl groups wlth 1 to 4 carbon atoms. Examples are cyc lopropyl, cyc lobutyl, cyclopentyl, cyclohexyl, methy Icyclo-hexyl and adamantyl.
Posslble substltuted and/or unsubstltuted R5 aryl groups are, for example, the followlng phenyl, 1-naphthyl and 2-naphthyl, whlch can be respectlvely substltuted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups wlth 1 to 4 C-atoms respectlvely, a chloromethyl, fluoromethyl, trlfluoromethyl, car-boxyl, alkoxy or hydroxy group, Substltutlon In the 3rd and 4th-posltlon on the phenyl rlng, for example by fluorlne, chlorlne, alkoxy or trlfluoromethyl, or by hydroxy In the 4th-posltlon, /s preferred.
Posslble heterocyc/lc groups for R5 are 5 and 6-member heterocycllc groups that contaln at least 1 heteroatom, prefer-ably nltrogen, oxygen or sul fur. Examples are 2-furyl, 2-thlenyl, 2-pyrldyl, 3-pyrldyl, 4-pyrldyl, oxazolyl, thlazolyl, pyrlmldlnyl, pyrldazlnyl, pyrazlnyl, 3-furyl, and 3-thlenyl.
~ ~ - 5 _ - ~25~L~2(31 A posslble alkylene group for D are stralght-chaln or branched-chaln, cycllc, saturated and unsaturated alkylene radl-cals, preferably saturated ones wlth 1 to 10, In partlcular, 1 to 5 C-atoms that can posslbly be substltuted by fluorlne atoms.
Æxamples are: methylene, fluoromethylene, dlfluoromethy/ene, ethylene, 1,2-propylene, ethylethylene, trImethylene, tetramethy-lene, pentamethy/ene, 1.1-dlfluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-trl-.nethy/ene, 1-methyleneethy-lene, 1-methylene-tetraoethylene, 2-methyl-trImethy/ene, 2-1o methyl-tetramethylene, 1,1-trImethylene-ethylene, 1,2-methylene-ethylene.
If there Is a double bond It Is located In the alkylene radlcals In the 2nd, 3rd or 4th-posltlon.
Inorganlc and organ/c bases of the klnd fam/llar to the expert for the formatlon of physlologlcally tolerable salts are sultable for sa/t format/on. Examples are alkall hydroxldes such as sodlum and potasslum hydroxlde, earth alkall hydroxldes such as calc/um hydroxlde, ammonla, amlnes llk~e ethanolamlne, dlethanolamlne, trlethanolamlne, N-methylglucamlne, morphollne, trls(hydroxymethyl)methylamlne, etc.
The Inventlon also provldes a process for the manufac-ture of the 9-halogen prostane derlvatlves In accordance wlth formu/a I, whlch comprlses reactlng a compound of formu/a Tr o~l h ~--c ~ ~1 ( I I ), ~ w- D - E - l~ 5 where the 9-OH group can be In the ~ or ~ -posltlon and R1 represents the radlcal -C-OR2, wlth R2 meanlng alkyl, cycloalkyl, ?ryl or a heterocycllc radlcal or the radlcal-c~ wlth R3 meanlng an acld radlcal, an alkyl, cycloalkyl, àryl30r hetero-cycllc radlcal and A, D, E and R5 have the aforementloned mean-lngs, after protect/on of free OH groups In R4 and W, wlth carbon tetrachlorlde/trlphenylphosphlne, hexachloroethane/trIphenyl-phosphlne or dlethylamlnosulfur trlfluorlde or, after converslon of the 9-hydroxy group Into a 9-sulfonlc acld ester, wlth tetra-n-butyl-ammonlum fluorlde, and subsequently releaslng any sequence protected hydroxy groups and/or esterfylng, etherlfylng free hydroxy groups and/or hydrogenatlng doub/e bonds and/or saponlfylng an ester/f/ed carboxy/ group (R1 = -C-Q--OR2) and/or convert/ng a free carboxy/ group ~R2 = H) /nto an amlde ~R1 =
-CZO NHR3) and/or reduclng a free or esterlfled carboxy/ group (R 1 = -C~O-OR2), The convers/on of the compounds of formu/a rT Into the compounds of formula I wlth carbon tetrachlorlde and trl-phenylphosphlne or hexachloroethan0/trlphenjlphosphlne takesplace In an Inert solvent such as dlmethylformamlde, dlmethyl-acetamlde, acetonltrlle, methy/ene ch/orIde at temperatures between 0C and 80C, preferably 20C to 45C, In the presence of a base such as pyrldlne and trlethylamlne.
The convers/on of the compounds of formu/a II Into the compounds of formu/a I wlth Hal belng a fluorlne atom takes p/ace wlth dlethylamlnosulfur trlfluorlde In a solvent such as dlchloromethane at temperatures between -120C and 0C, prefer-ably at -70C, posslbly In the presence of a base such as pyrldlne.
If an alcohol of formula 1~ wlth a 9-hydroxy group In the ~ -posltlon Is used, compounds of formula I wlth a 9-halogen atom In the d -posltlon are obtalned, If an alcoho/ wlth hydroxy ,.
~L~5~2~3~
group In the ~ -posltlon Is used, compounds wlth a 9-halogen atom In the ~-posltlon are obtalned.
The reductlon to the compounds of formula I where R1 Is a -CH20H-group Is carrled out wlth a reduclng agent sultable for the reduct/on of esters or carboxyl/c aclds, examp/es belng llthlum alumlnum hydrlde, dllsobutyl alumlnum hydrlde, etc. Pos-slble solvents are dlethylether, terahydrofuran, dlmethoxyethane, toluene etc. The reductlon Is done at temperatures of -30C up to the bolllng temperature of the solvent used, preferably at 0C
to 30C.
The functlonally modlfled hydroxy groups are released by the known methods. For example, protectIve hydroxy groups such as the tetrahydropyranyl radlcal Is spllt off In an aqueous solutlon of an organ/c acld, e.g. oxallc acld, acet/c acld and proplonlc acld, or In an aqueous solutlon of an Inorganlc acld, e,g, hydrochlorlc acld.
To /mprove the solublllty It Is advlsable to add an Inert organlc solvent that can be mlxed wlth water. Sultable organ/c solvents are, for example, alcohols such as methanol and ethanol, and ethers such as dlmethoxyethane, dloxane and tetrahy-drofuran. Tetrahydrofuran Is preferably used. The separatlon takes place preferably at temperatures between 20C and 80C.
The acyl groups are saponlfled, for example, by alkall metal or alkalIne earth meta/ carbonates or hydroxldes In an alcohol or In the aqueous solutlon of an a l coho l . Posslble a/co-30 ho / s are alIphatlc alcohols such as methanol, ethanol, andbutanol, preferably methanol. Potasslum and sodlum slats are mentlGned as alkall carbonates and hydroxldes. The potasslum salts are preferred.
Calclum carbonate, calclum hydroxlde and barlum carbo-nate are e.g. sultable as earth alkall carbonates and hydroxldes.
.~.,,~ ,, ~l~5~
The reactlon takes place at -10C to f70C, preferably at +25C.
,~,0 `OR2 for R1, In whlch R2 represents an alkyl group wlth 1 to 10 C-atoms, /s /ntroduced by the methods famlllar to the expert. For example, the 1-carboxy compounds reacted wlth dlazo hydrocarbons In a conventlonal manner. The esterlflcatlon wlth dlazo hydrocarbons Is done, for examp/e, by mlxlng a solutlon of the dlazo hydrocarbon In an Inert solvent, preferably dlethylether, wlth the 1-carboxy compound In the same or another Inert solvent, e.g. methy/ene chlorlde. After comple-tlon of the reactlon In 1 to 30 mlnutes the solvent Is removed and the ster purlfled In the customary fashlon. Dlazoalkanes are elther known or can be manufactured by the known methods ~Org.
Reactlons, Vol. 8, pp 389-394 (1954)].
~0 The ester group -C~OR for R1, In whlch fl2 represents a substltuted or unsubstltuted aryl group, Is Introduced by the methods famlllar to the expert.
For example, the 1-carboxy compounds reacted wlth the correspondlng arylhydroxy compounds wlth dlcyclohexyl carbodl-lmlde In the presence of a sultable base, e.g. pyrldlne, DMAP and trlethylamlne, In an Inert solvent. Posslble solvents are methy-/ene ch/or/de, ethy/ene chlorIde, chloroform, acet/c ether and tetrahydrofuran, preferably chloroform. The react/on takes p/ace at temperatures of -30C to +50C. Preferably at 10C.
The prostaglandln derlvatlves In accordance wlth for-mula I wlth R2 In the meanlng of a hydrogen atom can be converted Into a salt wlth sultable amounts of the correspond/ng Inorganlc base together wlth neutrallzatlon. For examp/e, when the corre-spondlng PG aclds are dlssolved In water whtch contalns the stol-ch/ometr/c amount of base, the solld, Inorganlc salt Is obtalned after evaporatlon of the water or after the addltlon of a solvent that can be mlxed wlth water, e.g. alcohol or acetone.
_ 9 '~ .
\
For the manufacture of an amlne salt, whlch Is done In the customary fashlon, the PG acld Is, for example, dlssolved In a sultable solvent, e,g. ethanol, acetone, dlethylether, acetonl-trlle or benzene, and at least the stolchlometrlc vo/ume of the amlne /s added to thls solutlon. In thls connectlon the salt Is usually obtalned In solld form or Isolated after evaporatlon of the solvent In the customary fashlon.
,~0 The amlde group -C--NHR3 for Rl Is Introduced by the methods famlllar to the expert. The carboxyllc aclds of formula I (P2=H) are flrst converted Into the mlxed anhydrlde In the presence of a tert/ary amlne, e.g. trlethylamlne, wlth chloro-formlc acld Isobutyl ester. The reactlon of the mlxed anhydr-lde wlth the alkall metal salt of the correspondlng amlde or wlth ammonla (~3=H) or the reactlon of the correspondlng amlne takes place In an Inert solvent or m/xture of solvents, _ 10 -i r~ ! ' ~;~5~
e.g. tetrahydrofuran, dimethoxyethene, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures of between -30 C and +60 C, preferably at O C to 30 C.
Another way to introduce the amide group -C-NHR3 for R1 with R3 in the meaning of an acid radical is to make a 1-carboxylic acid of formula I (R2=H), in which the free hydroxy groups possibly have intermediate protection, react with compounds of formula III 5' O = C = N - R3 (III) where R3 has the meaning indicated above.
The reaction of the compound according to formula I (R2=H) with the isocyanate of formula III takes place after the possible addition of a tertiary amine, e.g. triethylamine or pyridine. The reaction can take place without solvents or in an inert solvent, preferably ace-tonitrile, tetrahydrofuran, acetone, dimethyl acetamide, methylene chloride, diethyl ether, toluene, at temperatures of between -80 C to 100 C, prefe-rably at O to 30 C.
If the primary product contains OH groups in the prostane radical, these OH groups are also made to react. If, in the end, final products are desired which contain free hydroxyl groups in the prostane radical, it is advisable to start with primary products in which intermediary protection is preferably provided by easy-to-separate ether or acyl radicals.
The compounds of formula II with a 9~ -hydroxy group that serve as primary products are either known or can be manufac-tured by the processes indicated in DE-OS 26 27 910.
The compunds of formula II with a 9B-hydroxy group are ob-tained from the 9~ -hydroxy compounds by way of an inversion reaction of the kind described in Synthesis, 292-294 (1980).
- `~
- 12 ~
In comparison to the PGE derivatives the new analogue prostaglandin substances are characterized by better stability.
The analogue prostaglandin substances of formula I are valuable pharmaceuticals because they have a much improved (higher specificity) and above all a much longer effect, with a similar range of effects, than the corresponding natural prostaglandins.
The new analogue prostaglandin substances have a strongly luteolytic eEfect, i.e. much lower doses are needed to initiate luteolysis than with the corresponding natural prostaglandins.
To start abortions, especially after oral or intravaginal application, much lower doses of the new analogue prosta-glandin substances are needed in comparison to the natural prostaglandins.
In the recordings of isotonic uterus contraction in the anesthesized rat and in the isolated rat uterus it can be seen that the substances in accordance with the invention are much more effective and longer-lasting than natural prostaglandins.
After a single enteral or parenteral application the new prostaglandin derivatives are able to induce menstruation or interrupt pregnancy. Furthermore, they are suitable for synchronizing the sexual cycle of female mammals such as rabbits, cattle, horses, pigs, etc. Furthermore, the prostaglandin derivatives in accordance with the invention are suitable for dila-tion of the cervix prior to diagnostic or therapeutic intervention.
~5~
The good tissue-specificit~ of the antifertility substances in accordance with the invention can be seen in the investi-gation of other unstriated muscle organs, e.g. the ileum of guinea pigs or isolated rabbit trachea where much less stimu-lation is to be observed than with the natural prostaglandins.
The substances in accordance with the invention also have a bronchospasmolytic effect. Moreover, they reduce the swelling of nasal mucous membrane.
The active insredients in accordance with the invention in~
hibit the secretion of gastric acid, display a cytoprotective and an ulcer-healing effect, and thereby counter the undesir-able consequences of non-steroidal antiphlogistic substances (prostaglandin synthesis inhibitors). They also have a cytoprotective effec-t on the liver, kidneys and pancreas.
Some of the compounds have the effect of reducing blood pressure, regulating cardiac rhythm disorders and inhibiting platelet aggregation, with the possible uses resulting therefrom. The new prostaglandins can also be used in combi-nation, e.g. with B-blockers, diuretics, phosphodiesterase inhibitors, calcium antagonists and antigestagens.
The dosage of the compounds is 1 to 1500 ~g/kg/day when administered to human patients.
For medical usage the active ingredients can be converted into a su:itable form for inhalation, oral, parenteral or local (e.g. vaginal) application. For inhalation it is advisable to produce aerosol solutions.
For oral application, for e~ample, tablets, dragees or capsules are suitable.
Sterile, injectable, aqueous or oily solutions are used for parenteral application.
5~2~L
Suppositories, for example, are sui-ta~le for vaginal appli-cation.
Thus the invention also relates to pharmaceuticals on the basis of the compounds of formula I and customary adjuvants and carrier su~stances, c~clodextrinclathrates included.
In conjunction with the adjuvants known and customary in galenicals the active ingredients in accordance with the invention are supposed to serve, for example, for the manu~
facture of preparations for initiation of an a~ortion, for control of the cycle, for initiation of birth, for treat-ment of hypertonia or for the treatment of gastrointestinal disorders, e.g. for healing gastric and duodenal ulcers.
The preparations can contain 0.01 to 100 mg of the active compound for this purpose as well as the other applications~
The following examples are supposed to explain the invention in more detail, without setting any limits.
Sl~
Example 1 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid methylester Drip a solution of 3.20 g of hexachloroethane and 3.80 ml of triethylamine in 60 ml of 1,2 dichlorethane into a solution of 1.80 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester and 3.37 g triphenylphosphine in 60 ml of 1,2 dichlorethane at 0 C. Stir for 1 hour at 20 C, then dilute with 200 ml of dichloromethane, agitate one after another with sodium hydrogen carbonate solution and brine, dry over MgS04 and concentrate in a vacuum. Chromatograph the residue on silica gel with toluene/ethyl acetate (95:5). 1.05 g of oily (9R,1lR,15R)-9-chloro-16,16-dimethyl-11,15-bis(tetrahydro-pyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester are obtained. To separate the protective groups stir the ester obtained with 15 ml of a mixture of acetic acid/water/
tetrahydrofuran (65/35/10) for 24 hours at 20 C. Then dilute with ice water, mix with diluted caustic soda until the neutral point is reached and extract several times with dichloromethane.
Shake the combined extracts with brine, dry over magnesium sulfate and evaporate in a vacuum. For puriEication chroma~
tograph on silica gel with hexane/10-40% ethyl acetate, thereby obtaining 580 mg of the title compound in the form of an oil.
IR: 3600, 3410, 2958, 1958, 1732, 1135, 1020, 976/cm.
The 9~ -alcohol used as the primary material is obtained as follows:
S~
~ 16 -la) (6RS,9S,11R,15R)-6,9-dihydroxy-16,16-dimethyl-11,15-bis (tetrahydropyran-2- lox )- rost-4-in-13-trans-en acid methylester Y Y P
Dissolve 7.29 g of diisopropylamine in 100 ml of ether with 12.90 g of hexamethylphosphoric acid triamide, cool to -20 C
and add dropwise under argon 48 ml of 1.5 M volatile solution of methy]lithium. Then cool to -70 C and add dropwise 3.53 g of dissolved 4-pentine acid into 70 ml of ether.
Stir another 2 hours at 20 C and add a solution of 2.80 g of (2RS,3aR,4R,5R,6aS)-4- ~(E)-t3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-1-octenyl~ -5-(tetrahydropyran-2-yloxy)-per-hydrocyclopenta ~bJ furan-2-ol dropwise into 60 ml of ether.
Stir for 48 hours at 20 C, dilute with water and acidify to pH 4 with citric acid. Extract several times with dichloro-methane, wash with brine, dry over magnesium sulfate and eva-porate in a vacuum. Treat the residue for 15 minutes with surplus volatile diazomethane and evaporate the solution until dry. The oily residue is chromatographed on silica gel with hexane/e-thyl acetate (1:1). 2.15 g of the title compound are obtained in the form of an oil.
IR: 3600, 2955, 2130, 1735, 1153, 1020, 980/cm.
lb) (6RS,9S,llR,15R)-6,9-diacetoxy-16,16-dimethyl-11~15-bis-(tetrahydropyran-2-yloxy)-prost-4-in-13-trans-en acid methylester Add 4ml of acetic acid anhydride to 2,l0 g of (6RS,9S,llR,15R)-6,9-dihydroxy-16,16-dimethyl-11,15-bis(te-trahydropyran-2-yloxy)-prost-4-in-13-trans-en acid methylester dissolved in 15 ml of pyridine and let stand for 16 hours at 20 C. Concentrate in a vacuum, dilute with ether, wash with water, dry over magnesium sulfate and evaporate in a vacuum. To clean, filter with hexane/ethylacetate (7:3) over silica gel, thereby obtaining 2.19 g of the title compound in the form of an oil.
IR: 29S8, 2125, 1738, 1252, 1023, 976/cm.
~S~
1c~
(9S,11R,15R)-9-acetoxy-16,16-dimethyl-11,15-bis-(tetra-hydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Drip and stir 23.2 ml of a 1.5 M solution of methyllithium in ether into 3.02 g of cuprous iodide suspended in 50 ml of water and cooled to -10 C. Then cool -to -75 C and add 50 ml of a volatile solution consisting of 2.10,g of (6RS,9S,11R, 15R)-6,9-diacetoxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-prost~4-in-13-trans-en acid methylester) dropwise within 15 minutes' time. Stir for 5 hours at -75 C, then dilute with ammonium chloride solution, stir for 1 hour at 20 C and extract with ether. Wash th~ extract with brine, dry over magnesium sulfate and evaporate in a vacuum. Chromatograph the residue on silica gel with hexane/20-70~ ethyl acetate thereby obtaining 1.10 g of the title compound in the form of an oil.
I~: 2951, 1977, 1738, 1248, 1021, 978/cm.
1d) (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahx~
dropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Add 300 mg of anhydrous potassium carbonate to 1.05 g of (9S,11R,15R)-9-acetoxy~16,16-dimethyl-11,15-bis-(tetrahydro-pyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 20 ml of methanol, and stir for 3 hours at room temperature. Concentrate in a vacuum at 30 C, dilute with water and extract several times with dichloromethane.
Shake the combined extracts with brine, dry over magnesium sulfate and evaporate in a vacuum. 920 mg of the title compound are obtained in the form of an oil.
IR: 3600, 2945, 1980, 1736, 1021, 976/cm.
5~2~L
Example 2 (9S,11R,15R)-9-chloro~ 15-dihydroxy-16~16-dimethyl-prosta 4 ! 5,13-trans-trien acid methylester By analogy with example 1, 145 mg of the title compound are obtained in the form of an oil from 500 mg of (9R,1lR,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylest~r.
IR: 3600, 3405, 2956, 1977, 1735, 1135, 1021, 976/cm.
The 9~-alcohol used as the primary material is manufactured as follows:
2a) (9R,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahvdro-~ran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Add 1.15 g of p-toluenesulfonic acid chloride at O C to 1.69 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 25 ml of pyridine. Remove the ice bath after 1 hour and let stand for 48 hours at 20 C. Then cool again to O C, mix with 0.1 ml of water and stir for 1 hour. To condition dilute with ice-cold ether, shake one after another with ice-cold 10% sulfuric acid, sodium hydrogen carbonate solution and brine, dry over magnesium sulfate and evaporate in a vacuum. One obtains 2.30 g of oily 9-tosylate, which is dissolved in 80 ml ofdimethylsulfoxide, mixed with 6 g of potassium nitrite and heated to 80 C for 3 hours.
Then dilute with water, extract with ether, wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. The residue is cleaned by chromatography on silica gel with hexane/ethyl acetate (20-50%), and 1.01 g of the title compound are ob-tained in the form of an oil.
IR: 3600, 3410, 1978, 1735, 1181, 1025, 972/cm.
5~
Example 3 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid Add 150 mg of potassium hydroxide dissolved in 1 ml of water to a solution consisting of 100 mg of (9R,11~,15R)-g~chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid methylester dissolved in 10 ml of methanol, and let stand for 5 hours at 20 C. After concentrating in a vacuum, dilute with water, acidify with citric acid to pH 4 and extract with ethyl acetate. Wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. 8S mg of the title compound are obtained in the form of an oil.
IR: 3600, 3420, 2955, 1976, 1712, 1178, 1022, 976/cm.
Example 4 (9P~,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta 4,5,13-trans-trien acid methylester By analogy with example 1, 410 mg of the title compound are obtained in the form of an oil from 1.25 g of (9S,11R,15S, 16RS)-9-hydroxy-16-methyl-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3405, 2958, 2885, 1976, 1732, 1021, 976/cm.
r The primary material for the production of the title compound is obtained in accordance with example 1a from (2RS,3aR,4R, 5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-oct-enyl~ -5-(tetrahydropyran-2-yloxy)-perhydrocyclopenta-~b~ furan-2-ol.
~5~2~
.
Example 5 (9R,11R,15S,16RS?- 9-chloro-11,15-dihydroxy-16-methyl-prosta 4,5,13-trans-trien acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4 r 5,13-trans-trien acid methylester.
IR: 3600, 3420, 2948, 1978, 1710, 1021, 978~cm.
Example 6 s (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-_etranor-prosta-4,5,13-trans-trien acid methylester By analogy with example 1, 310 mg of the title compound are obtained in the form of a colorless oil from 950 mg of ~9S,11R,15R)-9-hydroxy-16-phenoxy-11,15-bis(tetrahydropyran-2-yloxy)~17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3402, 2954, 2888, 1978, 1732, 1600, 1585, 1021, 978/cm.
The primary material for the manufacture o the title compound is obtained from (2RS, 3aR,4R,5R,6aS)-4-~(E)-(3R)-4-phenoxy-
stltuents are halogen, trlfluoromethyl, hydroxy, alkoxy or car-boxy groups. Preferred acyl radlcals are those wlth up to 10 carbon atoms. Posslble sulfonlc aclds are, for example, alkane-sulfonlc acld wlth 1 to 10 C-atoms, e.g. methanesulfonlc acld, ethanesulfonlc acld, Isopropanesulfonlc acld and butanesulfonlc acld as well as ~ -chloroethane-sulfonlc acld, cyclopentanesul-fonlc acld, cyclohexanesulfonlc acld, benzenesulfonlc acld, p-toluenesulfonlc acld, p-chlorobenzenesulfonlc acld, N.N-dlmethy-lamlnosulfonlc acld, N.N.-dlethylamlnosulfonlc acld, N.N.-bls-(~
-chloroethyl)-amlnosulfonlc acld, pyrrolldlno, plperldlno, plper-azlno, N-methylplperazlno and morphollnosulfonlc acId. Acyl rad-lcals and/or alkanesulfonlc acld radlcals wlth 1 to 4 C-atoms are especlally preferred.
The hydroxy groups In W and R4 can be functlonally mod-lfled, for example by etherlfylng or esterlfy/ng, In whlch case the modlfled hydroxy group In W can be In the ~ or ~-posltlon, free hydroxy groups belng preferred.
Posslble ether and acyl radlcals are the radlcals famlllar to the expert. Easy-to-separate ether rad/cals, e.g.
the tetra-hydropyranyl, tetrahydrofuranyl, ~ -ethoxyethyl, trlmethylsllyl, dlmethyl-tert-butyl-sllyl and trlbenzyl-sllyl radlcals are preferred. Posslble acy/ radlcals are the same as glven for R3 under organlc carboxyllc aclds, namely e.g. acetyl, proplonyl, butyryl and benzoyl. Posslble alkyl and alkenyl groups In R5 are stralght and branched-chaln alkyl radlcals wlth 30 1 to 10 C-atoms and alkenyl radlcals wlth 2 to 10, In partlcular 1 to 6 respectlvely 2 to 6 C-atoms that can be substltuted by, as the case may be, substltuted phenyl, alkyl wlth 1 to 4 C-atoms or halogen. Examples are: methyl, ethyl, propyl, Isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, bu~enyl, Isobutenyl, propenyl, pentenyl, hexenyl as well as benzyl, and when D and E
together mean a dlrect bond, posslbly alkynyl wlth 2 to 6 C-atoms ~:~5~
substltuted In the lst-posltlon by fluorlne or C1-C4 alkyl. Pos-slble alkynyl radlcals are the followlng: ethynyl, propln-1-yl, propln-2-yl, 1-methyIpropln-2-yl, 1-fluoropropln-2-yl, 1-ethyl-propln-2-yl, 1-fluorobutln-2-yl, butln-2-yl, butln-3-yl, 1-methyl-butln-3-yl, 1-methylpentln-3-yl, 1-fluoropentln-3-yl, 1-methyl-pentln-2-yl, 1-fluoropentln-2-yl, 1-methylpentln-4-yl, 1-fluoropentln-4-yl, hexln-1-yl, 1-methylhexln-2-yl, 1-fluorohexln-2-yl, 1-methylhexln-3-yl, 1-mentylhexln-4-yl, hexln-3-yl, 1,1-dlmethylhexln-4-yl etc.
Bromlne, chlorlne and fluorlne are posslble halogen sUbst/tuents of the R5 alkyl and alkenyl groups, chlorlne and fluorlne belng preferred.
The R5 cycloalkyl group can contaln 3 to 10 carbon atoms In the rlng, preferably 3 to 6. The rlngs can be substl-tuted by alkyl groups wlth 1 to 4 carbon atoms. Examples are cyc lopropyl, cyc lobutyl, cyclopentyl, cyclohexyl, methy Icyclo-hexyl and adamantyl.
Posslble substltuted and/or unsubstltuted R5 aryl groups are, for example, the followlng phenyl, 1-naphthyl and 2-naphthyl, whlch can be respectlvely substltuted by 1 to 3 halogen atoms, a phenyl group, 1 to 3 alkyl groups wlth 1 to 4 C-atoms respectlvely, a chloromethyl, fluoromethyl, trlfluoromethyl, car-boxyl, alkoxy or hydroxy group, Substltutlon In the 3rd and 4th-posltlon on the phenyl rlng, for example by fluorlne, chlorlne, alkoxy or trlfluoromethyl, or by hydroxy In the 4th-posltlon, /s preferred.
Posslble heterocyc/lc groups for R5 are 5 and 6-member heterocycllc groups that contaln at least 1 heteroatom, prefer-ably nltrogen, oxygen or sul fur. Examples are 2-furyl, 2-thlenyl, 2-pyrldyl, 3-pyrldyl, 4-pyrldyl, oxazolyl, thlazolyl, pyrlmldlnyl, pyrldazlnyl, pyrazlnyl, 3-furyl, and 3-thlenyl.
~ ~ - 5 _ - ~25~L~2(31 A posslble alkylene group for D are stralght-chaln or branched-chaln, cycllc, saturated and unsaturated alkylene radl-cals, preferably saturated ones wlth 1 to 10, In partlcular, 1 to 5 C-atoms that can posslbly be substltuted by fluorlne atoms.
Æxamples are: methylene, fluoromethylene, dlfluoromethy/ene, ethylene, 1,2-propylene, ethylethylene, trImethylene, tetramethy-lene, pentamethy/ene, 1.1-dlfluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl-trl-.nethy/ene, 1-methyleneethy-lene, 1-methylene-tetraoethylene, 2-methyl-trImethy/ene, 2-1o methyl-tetramethylene, 1,1-trImethylene-ethylene, 1,2-methylene-ethylene.
If there Is a double bond It Is located In the alkylene radlcals In the 2nd, 3rd or 4th-posltlon.
Inorganlc and organ/c bases of the klnd fam/llar to the expert for the formatlon of physlologlcally tolerable salts are sultable for sa/t format/on. Examples are alkall hydroxldes such as sodlum and potasslum hydroxlde, earth alkall hydroxldes such as calc/um hydroxlde, ammonla, amlnes llk~e ethanolamlne, dlethanolamlne, trlethanolamlne, N-methylglucamlne, morphollne, trls(hydroxymethyl)methylamlne, etc.
The Inventlon also provldes a process for the manufac-ture of the 9-halogen prostane derlvatlves In accordance wlth formu/a I, whlch comprlses reactlng a compound of formu/a Tr o~l h ~--c ~ ~1 ( I I ), ~ w- D - E - l~ 5 where the 9-OH group can be In the ~ or ~ -posltlon and R1 represents the radlcal -C-OR2, wlth R2 meanlng alkyl, cycloalkyl, ?ryl or a heterocycllc radlcal or the radlcal-c~ wlth R3 meanlng an acld radlcal, an alkyl, cycloalkyl, àryl30r hetero-cycllc radlcal and A, D, E and R5 have the aforementloned mean-lngs, after protect/on of free OH groups In R4 and W, wlth carbon tetrachlorlde/trlphenylphosphlne, hexachloroethane/trIphenyl-phosphlne or dlethylamlnosulfur trlfluorlde or, after converslon of the 9-hydroxy group Into a 9-sulfonlc acld ester, wlth tetra-n-butyl-ammonlum fluorlde, and subsequently releaslng any sequence protected hydroxy groups and/or esterfylng, etherlfylng free hydroxy groups and/or hydrogenatlng doub/e bonds and/or saponlfylng an ester/f/ed carboxy/ group (R1 = -C-Q--OR2) and/or convert/ng a free carboxy/ group ~R2 = H) /nto an amlde ~R1 =
-CZO NHR3) and/or reduclng a free or esterlfled carboxy/ group (R 1 = -C~O-OR2), The convers/on of the compounds of formu/a rT Into the compounds of formula I wlth carbon tetrachlorlde and trl-phenylphosphlne or hexachloroethan0/trlphenjlphosphlne takesplace In an Inert solvent such as dlmethylformamlde, dlmethyl-acetamlde, acetonltrlle, methy/ene ch/orIde at temperatures between 0C and 80C, preferably 20C to 45C, In the presence of a base such as pyrldlne and trlethylamlne.
The convers/on of the compounds of formu/a II Into the compounds of formu/a I wlth Hal belng a fluorlne atom takes p/ace wlth dlethylamlnosulfur trlfluorlde In a solvent such as dlchloromethane at temperatures between -120C and 0C, prefer-ably at -70C, posslbly In the presence of a base such as pyrldlne.
If an alcohol of formula 1~ wlth a 9-hydroxy group In the ~ -posltlon Is used, compounds of formula I wlth a 9-halogen atom In the d -posltlon are obtalned, If an alcoho/ wlth hydroxy ,.
~L~5~2~3~
group In the ~ -posltlon Is used, compounds wlth a 9-halogen atom In the ~-posltlon are obtalned.
The reductlon to the compounds of formula I where R1 Is a -CH20H-group Is carrled out wlth a reduclng agent sultable for the reduct/on of esters or carboxyl/c aclds, examp/es belng llthlum alumlnum hydrlde, dllsobutyl alumlnum hydrlde, etc. Pos-slble solvents are dlethylether, terahydrofuran, dlmethoxyethane, toluene etc. The reductlon Is done at temperatures of -30C up to the bolllng temperature of the solvent used, preferably at 0C
to 30C.
The functlonally modlfled hydroxy groups are released by the known methods. For example, protectIve hydroxy groups such as the tetrahydropyranyl radlcal Is spllt off In an aqueous solutlon of an organ/c acld, e.g. oxallc acld, acet/c acld and proplonlc acld, or In an aqueous solutlon of an Inorganlc acld, e,g, hydrochlorlc acld.
To /mprove the solublllty It Is advlsable to add an Inert organlc solvent that can be mlxed wlth water. Sultable organ/c solvents are, for example, alcohols such as methanol and ethanol, and ethers such as dlmethoxyethane, dloxane and tetrahy-drofuran. Tetrahydrofuran Is preferably used. The separatlon takes place preferably at temperatures between 20C and 80C.
The acyl groups are saponlfled, for example, by alkall metal or alkalIne earth meta/ carbonates or hydroxldes In an alcohol or In the aqueous solutlon of an a l coho l . Posslble a/co-30 ho / s are alIphatlc alcohols such as methanol, ethanol, andbutanol, preferably methanol. Potasslum and sodlum slats are mentlGned as alkall carbonates and hydroxldes. The potasslum salts are preferred.
Calclum carbonate, calclum hydroxlde and barlum carbo-nate are e.g. sultable as earth alkall carbonates and hydroxldes.
.~.,,~ ,, ~l~5~
The reactlon takes place at -10C to f70C, preferably at +25C.
,~,0 `OR2 for R1, In whlch R2 represents an alkyl group wlth 1 to 10 C-atoms, /s /ntroduced by the methods famlllar to the expert. For example, the 1-carboxy compounds reacted wlth dlazo hydrocarbons In a conventlonal manner. The esterlflcatlon wlth dlazo hydrocarbons Is done, for examp/e, by mlxlng a solutlon of the dlazo hydrocarbon In an Inert solvent, preferably dlethylether, wlth the 1-carboxy compound In the same or another Inert solvent, e.g. methy/ene chlorlde. After comple-tlon of the reactlon In 1 to 30 mlnutes the solvent Is removed and the ster purlfled In the customary fashlon. Dlazoalkanes are elther known or can be manufactured by the known methods ~Org.
Reactlons, Vol. 8, pp 389-394 (1954)].
~0 The ester group -C~OR for R1, In whlch fl2 represents a substltuted or unsubstltuted aryl group, Is Introduced by the methods famlllar to the expert.
For example, the 1-carboxy compounds reacted wlth the correspondlng arylhydroxy compounds wlth dlcyclohexyl carbodl-lmlde In the presence of a sultable base, e.g. pyrldlne, DMAP and trlethylamlne, In an Inert solvent. Posslble solvents are methy-/ene ch/or/de, ethy/ene chlorIde, chloroform, acet/c ether and tetrahydrofuran, preferably chloroform. The react/on takes p/ace at temperatures of -30C to +50C. Preferably at 10C.
The prostaglandln derlvatlves In accordance wlth for-mula I wlth R2 In the meanlng of a hydrogen atom can be converted Into a salt wlth sultable amounts of the correspond/ng Inorganlc base together wlth neutrallzatlon. For examp/e, when the corre-spondlng PG aclds are dlssolved In water whtch contalns the stol-ch/ometr/c amount of base, the solld, Inorganlc salt Is obtalned after evaporatlon of the water or after the addltlon of a solvent that can be mlxed wlth water, e.g. alcohol or acetone.
_ 9 '~ .
\
For the manufacture of an amlne salt, whlch Is done In the customary fashlon, the PG acld Is, for example, dlssolved In a sultable solvent, e,g. ethanol, acetone, dlethylether, acetonl-trlle or benzene, and at least the stolchlometrlc vo/ume of the amlne /s added to thls solutlon. In thls connectlon the salt Is usually obtalned In solld form or Isolated after evaporatlon of the solvent In the customary fashlon.
,~0 The amlde group -C--NHR3 for Rl Is Introduced by the methods famlllar to the expert. The carboxyllc aclds of formula I (P2=H) are flrst converted Into the mlxed anhydrlde In the presence of a tert/ary amlne, e.g. trlethylamlne, wlth chloro-formlc acld Isobutyl ester. The reactlon of the mlxed anhydr-lde wlth the alkall metal salt of the correspondlng amlde or wlth ammonla (~3=H) or the reactlon of the correspondlng amlne takes place In an Inert solvent or m/xture of solvents, _ 10 -i r~ ! ' ~;~5~
e.g. tetrahydrofuran, dimethoxyethene, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures of between -30 C and +60 C, preferably at O C to 30 C.
Another way to introduce the amide group -C-NHR3 for R1 with R3 in the meaning of an acid radical is to make a 1-carboxylic acid of formula I (R2=H), in which the free hydroxy groups possibly have intermediate protection, react with compounds of formula III 5' O = C = N - R3 (III) where R3 has the meaning indicated above.
The reaction of the compound according to formula I (R2=H) with the isocyanate of formula III takes place after the possible addition of a tertiary amine, e.g. triethylamine or pyridine. The reaction can take place without solvents or in an inert solvent, preferably ace-tonitrile, tetrahydrofuran, acetone, dimethyl acetamide, methylene chloride, diethyl ether, toluene, at temperatures of between -80 C to 100 C, prefe-rably at O to 30 C.
If the primary product contains OH groups in the prostane radical, these OH groups are also made to react. If, in the end, final products are desired which contain free hydroxyl groups in the prostane radical, it is advisable to start with primary products in which intermediary protection is preferably provided by easy-to-separate ether or acyl radicals.
The compounds of formula II with a 9~ -hydroxy group that serve as primary products are either known or can be manufac-tured by the processes indicated in DE-OS 26 27 910.
The compunds of formula II with a 9B-hydroxy group are ob-tained from the 9~ -hydroxy compounds by way of an inversion reaction of the kind described in Synthesis, 292-294 (1980).
- `~
- 12 ~
In comparison to the PGE derivatives the new analogue prostaglandin substances are characterized by better stability.
The analogue prostaglandin substances of formula I are valuable pharmaceuticals because they have a much improved (higher specificity) and above all a much longer effect, with a similar range of effects, than the corresponding natural prostaglandins.
The new analogue prostaglandin substances have a strongly luteolytic eEfect, i.e. much lower doses are needed to initiate luteolysis than with the corresponding natural prostaglandins.
To start abortions, especially after oral or intravaginal application, much lower doses of the new analogue prosta-glandin substances are needed in comparison to the natural prostaglandins.
In the recordings of isotonic uterus contraction in the anesthesized rat and in the isolated rat uterus it can be seen that the substances in accordance with the invention are much more effective and longer-lasting than natural prostaglandins.
After a single enteral or parenteral application the new prostaglandin derivatives are able to induce menstruation or interrupt pregnancy. Furthermore, they are suitable for synchronizing the sexual cycle of female mammals such as rabbits, cattle, horses, pigs, etc. Furthermore, the prostaglandin derivatives in accordance with the invention are suitable for dila-tion of the cervix prior to diagnostic or therapeutic intervention.
~5~
The good tissue-specificit~ of the antifertility substances in accordance with the invention can be seen in the investi-gation of other unstriated muscle organs, e.g. the ileum of guinea pigs or isolated rabbit trachea where much less stimu-lation is to be observed than with the natural prostaglandins.
The substances in accordance with the invention also have a bronchospasmolytic effect. Moreover, they reduce the swelling of nasal mucous membrane.
The active insredients in accordance with the invention in~
hibit the secretion of gastric acid, display a cytoprotective and an ulcer-healing effect, and thereby counter the undesir-able consequences of non-steroidal antiphlogistic substances (prostaglandin synthesis inhibitors). They also have a cytoprotective effec-t on the liver, kidneys and pancreas.
Some of the compounds have the effect of reducing blood pressure, regulating cardiac rhythm disorders and inhibiting platelet aggregation, with the possible uses resulting therefrom. The new prostaglandins can also be used in combi-nation, e.g. with B-blockers, diuretics, phosphodiesterase inhibitors, calcium antagonists and antigestagens.
The dosage of the compounds is 1 to 1500 ~g/kg/day when administered to human patients.
For medical usage the active ingredients can be converted into a su:itable form for inhalation, oral, parenteral or local (e.g. vaginal) application. For inhalation it is advisable to produce aerosol solutions.
For oral application, for e~ample, tablets, dragees or capsules are suitable.
Sterile, injectable, aqueous or oily solutions are used for parenteral application.
5~2~L
Suppositories, for example, are sui-ta~le for vaginal appli-cation.
Thus the invention also relates to pharmaceuticals on the basis of the compounds of formula I and customary adjuvants and carrier su~stances, c~clodextrinclathrates included.
In conjunction with the adjuvants known and customary in galenicals the active ingredients in accordance with the invention are supposed to serve, for example, for the manu~
facture of preparations for initiation of an a~ortion, for control of the cycle, for initiation of birth, for treat-ment of hypertonia or for the treatment of gastrointestinal disorders, e.g. for healing gastric and duodenal ulcers.
The preparations can contain 0.01 to 100 mg of the active compound for this purpose as well as the other applications~
The following examples are supposed to explain the invention in more detail, without setting any limits.
Sl~
Example 1 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid methylester Drip a solution of 3.20 g of hexachloroethane and 3.80 ml of triethylamine in 60 ml of 1,2 dichlorethane into a solution of 1.80 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester and 3.37 g triphenylphosphine in 60 ml of 1,2 dichlorethane at 0 C. Stir for 1 hour at 20 C, then dilute with 200 ml of dichloromethane, agitate one after another with sodium hydrogen carbonate solution and brine, dry over MgS04 and concentrate in a vacuum. Chromatograph the residue on silica gel with toluene/ethyl acetate (95:5). 1.05 g of oily (9R,1lR,15R)-9-chloro-16,16-dimethyl-11,15-bis(tetrahydro-pyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester are obtained. To separate the protective groups stir the ester obtained with 15 ml of a mixture of acetic acid/water/
tetrahydrofuran (65/35/10) for 24 hours at 20 C. Then dilute with ice water, mix with diluted caustic soda until the neutral point is reached and extract several times with dichloromethane.
Shake the combined extracts with brine, dry over magnesium sulfate and evaporate in a vacuum. For puriEication chroma~
tograph on silica gel with hexane/10-40% ethyl acetate, thereby obtaining 580 mg of the title compound in the form of an oil.
IR: 3600, 3410, 2958, 1958, 1732, 1135, 1020, 976/cm.
The 9~ -alcohol used as the primary material is obtained as follows:
S~
~ 16 -la) (6RS,9S,11R,15R)-6,9-dihydroxy-16,16-dimethyl-11,15-bis (tetrahydropyran-2- lox )- rost-4-in-13-trans-en acid methylester Y Y P
Dissolve 7.29 g of diisopropylamine in 100 ml of ether with 12.90 g of hexamethylphosphoric acid triamide, cool to -20 C
and add dropwise under argon 48 ml of 1.5 M volatile solution of methy]lithium. Then cool to -70 C and add dropwise 3.53 g of dissolved 4-pentine acid into 70 ml of ether.
Stir another 2 hours at 20 C and add a solution of 2.80 g of (2RS,3aR,4R,5R,6aS)-4- ~(E)-t3R)-4,4-dimethyl-3-(tetrahydro-pyran-2-yloxy)-1-octenyl~ -5-(tetrahydropyran-2-yloxy)-per-hydrocyclopenta ~bJ furan-2-ol dropwise into 60 ml of ether.
Stir for 48 hours at 20 C, dilute with water and acidify to pH 4 with citric acid. Extract several times with dichloro-methane, wash with brine, dry over magnesium sulfate and eva-porate in a vacuum. Treat the residue for 15 minutes with surplus volatile diazomethane and evaporate the solution until dry. The oily residue is chromatographed on silica gel with hexane/e-thyl acetate (1:1). 2.15 g of the title compound are obtained in the form of an oil.
IR: 3600, 2955, 2130, 1735, 1153, 1020, 980/cm.
lb) (6RS,9S,llR,15R)-6,9-diacetoxy-16,16-dimethyl-11~15-bis-(tetrahydropyran-2-yloxy)-prost-4-in-13-trans-en acid methylester Add 4ml of acetic acid anhydride to 2,l0 g of (6RS,9S,llR,15R)-6,9-dihydroxy-16,16-dimethyl-11,15-bis(te-trahydropyran-2-yloxy)-prost-4-in-13-trans-en acid methylester dissolved in 15 ml of pyridine and let stand for 16 hours at 20 C. Concentrate in a vacuum, dilute with ether, wash with water, dry over magnesium sulfate and evaporate in a vacuum. To clean, filter with hexane/ethylacetate (7:3) over silica gel, thereby obtaining 2.19 g of the title compound in the form of an oil.
IR: 29S8, 2125, 1738, 1252, 1023, 976/cm.
~S~
1c~
(9S,11R,15R)-9-acetoxy-16,16-dimethyl-11,15-bis-(tetra-hydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Drip and stir 23.2 ml of a 1.5 M solution of methyllithium in ether into 3.02 g of cuprous iodide suspended in 50 ml of water and cooled to -10 C. Then cool -to -75 C and add 50 ml of a volatile solution consisting of 2.10,g of (6RS,9S,11R, 15R)-6,9-diacetoxy-16,16-dimethyl-11,15-bis-(tetrahydropyran-2-yloxy)-prost~4-in-13-trans-en acid methylester) dropwise within 15 minutes' time. Stir for 5 hours at -75 C, then dilute with ammonium chloride solution, stir for 1 hour at 20 C and extract with ether. Wash th~ extract with brine, dry over magnesium sulfate and evaporate in a vacuum. Chromatograph the residue on silica gel with hexane/20-70~ ethyl acetate thereby obtaining 1.10 g of the title compound in the form of an oil.
I~: 2951, 1977, 1738, 1248, 1021, 978/cm.
1d) (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahx~
dropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Add 300 mg of anhydrous potassium carbonate to 1.05 g of (9S,11R,15R)-9-acetoxy~16,16-dimethyl-11,15-bis-(tetrahydro-pyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 20 ml of methanol, and stir for 3 hours at room temperature. Concentrate in a vacuum at 30 C, dilute with water and extract several times with dichloromethane.
Shake the combined extracts with brine, dry over magnesium sulfate and evaporate in a vacuum. 920 mg of the title compound are obtained in the form of an oil.
IR: 3600, 2945, 1980, 1736, 1021, 976/cm.
5~2~L
Example 2 (9S,11R,15R)-9-chloro~ 15-dihydroxy-16~16-dimethyl-prosta 4 ! 5,13-trans-trien acid methylester By analogy with example 1, 145 mg of the title compound are obtained in the form of an oil from 500 mg of (9R,1lR,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylest~r.
IR: 3600, 3405, 2956, 1977, 1735, 1135, 1021, 976/cm.
The 9~-alcohol used as the primary material is manufactured as follows:
2a) (9R,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahvdro-~ran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester Add 1.15 g of p-toluenesulfonic acid chloride at O C to 1.69 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 25 ml of pyridine. Remove the ice bath after 1 hour and let stand for 48 hours at 20 C. Then cool again to O C, mix with 0.1 ml of water and stir for 1 hour. To condition dilute with ice-cold ether, shake one after another with ice-cold 10% sulfuric acid, sodium hydrogen carbonate solution and brine, dry over magnesium sulfate and evaporate in a vacuum. One obtains 2.30 g of oily 9-tosylate, which is dissolved in 80 ml ofdimethylsulfoxide, mixed with 6 g of potassium nitrite and heated to 80 C for 3 hours.
Then dilute with water, extract with ether, wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. The residue is cleaned by chromatography on silica gel with hexane/ethyl acetate (20-50%), and 1.01 g of the title compound are ob-tained in the form of an oil.
IR: 3600, 3410, 1978, 1735, 1181, 1025, 972/cm.
5~
Example 3 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid Add 150 mg of potassium hydroxide dissolved in 1 ml of water to a solution consisting of 100 mg of (9R,11~,15R)-g~chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid methylester dissolved in 10 ml of methanol, and let stand for 5 hours at 20 C. After concentrating in a vacuum, dilute with water, acidify with citric acid to pH 4 and extract with ethyl acetate. Wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. 8S mg of the title compound are obtained in the form of an oil.
IR: 3600, 3420, 2955, 1976, 1712, 1178, 1022, 976/cm.
Example 4 (9P~,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta 4,5,13-trans-trien acid methylester By analogy with example 1, 410 mg of the title compound are obtained in the form of an oil from 1.25 g of (9S,11R,15S, 16RS)-9-hydroxy-16-methyl-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3405, 2958, 2885, 1976, 1732, 1021, 976/cm.
r The primary material for the production of the title compound is obtained in accordance with example 1a from (2RS,3aR,4R, 5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-oct-enyl~ -5-(tetrahydropyran-2-yloxy)-perhydrocyclopenta-~b~ furan-2-ol.
~5~2~
.
Example 5 (9R,11R,15S,16RS?- 9-chloro-11,15-dihydroxy-16-methyl-prosta 4,5,13-trans-trien acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4 r 5,13-trans-trien acid methylester.
IR: 3600, 3420, 2948, 1978, 1710, 1021, 978~cm.
Example 6 s (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-_etranor-prosta-4,5,13-trans-trien acid methylester By analogy with example 1, 310 mg of the title compound are obtained in the form of a colorless oil from 950 mg of ~9S,11R,15R)-9-hydroxy-16-phenoxy-11,15-bis(tetrahydropyran-2-yloxy)~17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3402, 2954, 2888, 1978, 1732, 1600, 1585, 1021, 978/cm.
The primary material for the manufacture o the title compound is obtained from (2RS, 3aR,4R,5R,6aS)-4-~(E)-(3R)-4-phenoxy-
3-(tetrahydropyran-2-yloxy)-1-buteny~7-5-(tetrahydropyran-2-yloxy)-perhydrocyclopenta~b~furan-2-ol in accordance with example 1a.
Example 7 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-~henoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13--trans-trien acid methylester.
IR: 3600, 3420, 2960, 2885, 1976, 1711, 1600, 1588, 1022, 977/cm.
Example 8 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-trimethylen-prosta-4,5,13-trans-trien acid methylester By analogy with example 1, 390 mg of the title compound are 5~
, - 21 - ~
obtained in the form of an oil from 1.20 g of (9S,11R, 15R)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16,16-trimethylen-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3405, 2948, 2882, 1975, 1735, 1021, 976/cm.
The primary material for the manufacture of the title compound is o~tained from (2RS,3aR,4R,5R,6aS)-4- ~(E)-(3R)-3-(tetrahydropyran-2-yloxS~)-4,4-trimethylen-1-octenyl~-5-(tetrahydropyran-2-yloxy)-perhydrocyclopenta ~b~ furan-2-ol.
Example 9 ~9R,llR,15R)-9-chloro-11,15-dihvdroxy-16,16-trimethylen-E_osta-4,5,13-trans-trien acid By analogy ~iith example 3, the title compound is obtained in the form of oil from (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-trimethylen-prosta-4,5,13-trans-trien acid methyl-ester.
IR: 3600, 3420, 2952, 2884, 1976, 1712, 1022, 976/cm.
Example 10 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-
Example 7 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-~henoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13--trans-trien acid methylester.
IR: 3600, 3420, 2960, 2885, 1976, 1711, 1600, 1588, 1022, 977/cm.
Example 8 (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-trimethylen-prosta-4,5,13-trans-trien acid methylester By analogy with example 1, 390 mg of the title compound are 5~
, - 21 - ~
obtained in the form of an oil from 1.20 g of (9S,11R, 15R)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16,16-trimethylen-prosta-4,5,13-trans-trien acid methylester.
IR: 3600, 3405, 2948, 2882, 1975, 1735, 1021, 976/cm.
The primary material for the manufacture of the title compound is o~tained from (2RS,3aR,4R,5R,6aS)-4- ~(E)-(3R)-3-(tetrahydropyran-2-yloxS~)-4,4-trimethylen-1-octenyl~-5-(tetrahydropyran-2-yloxy)-perhydrocyclopenta ~b~ furan-2-ol.
Example 9 ~9R,llR,15R)-9-chloro-11,15-dihvdroxy-16,16-trimethylen-E_osta-4,5,13-trans-trien acid By analogy ~iith example 3, the title compound is obtained in the form of oil from (9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-trimethylen-prosta-4,5,13-trans-trien acid methyl-ester.
IR: 3600, 3420, 2952, 2884, 1976, 1712, 1022, 976/cm.
Example 10 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-
4,5,13-trans-trien-18-in acid methylester By analogy with example 1, 320 mg of the title compound are obtained ir the form of an oil from 985 mg of (9S,11R,15S, 16RS)-9-hydroxy-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-prosta-4,5,13--trans-trien-18-in acid methylester.
IR: 3600, 3405, 2050, 1978, 1734, 1021, 974/cm.
The primary material for the manufacture of the title compound is obtained in accordance with example 1a from (2RS,3aR,4R, 5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-octen-6-inyl~-5-(tetrahydropyran-2-yloxy)-perhydr penta ~b~ furan~2-ol.
` ~S~L2~
Example 11 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid _ By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3415, 2955, 2884, 1978, 1710, 1022, 974/cm.
Example 12 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid methylester By analogy with example 1, 380 mg of the title compound are obtained in the form of an oil from 1.20 g of (9S,11R, 15S,16RS)-16,20-dimethyl-9-hydroxy-11,15-bis-(tetrahydro~
pyran-2-yloxy)-prosta-4,5,13-trans-trien-18-in acid methyl-ester.
IR: 3600, 3400, 2955, 1978, 1732, 1022, 976/cm.
The primaxy material for the manufacture of the title compound is obtained in accordance with 1a from (2RS,3aR,4R,5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-nonen-6-inyl~ -5-(tetrahydropyran-2-yloxy)-perhydrocyclo-penta ~b~ furan-2-ol.
Example 13 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,l3--trans-trien-18-in acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3409, 2952, 2880, 1978, 1711, 1023, 976/cm.
~s~
Example 14 (9R,11R,15R)-11,15-dihydroxy-16,16-dimethyl-9-fluor-prosta-4,5,13-trans-trien acid To 1.25 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy 11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 20 ml o dichloromethane and 0.5 ml of pyridine add 0.3 ml of diethylaminosulfur tri-fluoride (DAST) at -70 C and another 0.1 ml of DAST 15 minutes later. After another 15 minutes mix with 50 ml of 5%
sodium hydrogen carbonate solution, remove the ice bath, stir vigorously at 20 C for 10 minutes, then extract with dichloromethane, wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. Stir the residue for 24 hours with 20 ml of a mixture of acetic acid/water/tetra-hydrofuran (65/35/10), evaporate in a vacuum and ?urify the raw product by chromatography on silica gel with hexane/
diethyl ether (1:1). 410 mg of (9R,11R,15R)-11,15-dihydroxy-16,16-dimethyl-9-fluoro-prosta-4,5,13-trans-trien acid methylester are obtained in the form of an oil.
To saponify the ester, dissolve in 20 ml of methanol, mix with 500 mg of potassium hydroxide dissolved in 2 ml of water, and let stand for 4 hours at 20 C. Then concentrate in a vacuum, dilute with water, acidify with citric acid to pH 4 and extract with dichloromethane.Wash the extract with brine, dry over maynesium sulfate and evaporate in a vacuum. 370 mg of the title compound are obtained in the form of an oil.
IR: 3600, 3~20, 2948, 2878, 1976, 1710, 10~2, 978/cm.
Example 15 (9R,11R,15R)-11,15-dihydroxy-9-fluor-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid By analogy with example 14, 335 mg of the title compound are ob-tained in the form of an oil from 1.15 g of ~9S,1lR,15R)-9-hydroxy-16-phenoxy-11,15-bis-(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid methyl-ester.
IR: 3600, 3420, 2955, 2889, 1978, 1708, 1601, 1588, 1023, 976/cm.
Example 16 (9R,11R,15S,16RS)-11,15-dihydroxy-16,20-dimethyl-9-fluoro-prosta-4,5,13-trans-trien-18-in acid By analogy with example 14, 235 mg of the title compound are obtained in the form of an oil from 810 mg of (9S,11R,15S, 16RS)-16,20-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3418, 2949,2822, 1976, 1710, 1023, 978/cm.
Example 17 (9R,11R,15R)-11,15-dihydroxy-9-fluorG-16-phenoxy-17,18,19,20-_ tetranor-prosta-4,5,13-trans-trien acid phenacylester Dissolve 210 mg of (9R,11R,15R)-11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid in 10 ml of acetone, mix with 139 mg of ~-bromo-acetophenone and 1.5 ml of triethylamine, and stir overnight at 20 C. Dilute with ether, shake one after another with water and brine, dry over magnesium sulfate and evaporate in a vacuum. Purify the residue by chromatography on silica gel with dichloromethane/10% acetone, thereby obtaining 195 mg of the title compound in the form of an oil.
IR: 3600, 3010, 2948, 1978, 1708(wide), 1600, 1588, 1139, 1022, 974/cm.
IR: 3600, 3405, 2050, 1978, 1734, 1021, 974/cm.
The primary material for the manufacture of the title compound is obtained in accordance with example 1a from (2RS,3aR,4R, 5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-octen-6-inyl~-5-(tetrahydropyran-2-yloxy)-perhydr penta ~b~ furan~2-ol.
` ~S~L2~
Example 11 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid _ By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3415, 2955, 2884, 1978, 1710, 1022, 974/cm.
Example 12 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid methylester By analogy with example 1, 380 mg of the title compound are obtained in the form of an oil from 1.20 g of (9S,11R, 15S,16RS)-16,20-dimethyl-9-hydroxy-11,15-bis-(tetrahydro~
pyran-2-yloxy)-prosta-4,5,13-trans-trien-18-in acid methyl-ester.
IR: 3600, 3400, 2955, 1978, 1732, 1022, 976/cm.
The primaxy material for the manufacture of the title compound is obtained in accordance with 1a from (2RS,3aR,4R,5R,6aS)-4- ~(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-1-nonen-6-inyl~ -5-(tetrahydropyran-2-yloxy)-perhydrocyclo-penta ~b~ furan-2-ol.
Example 13 (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,l3--trans-trien-18-in acid By analogy with example 3, the title compound is obtained in the form of an oil from (9R,11R,15S,16RS)-9-chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3409, 2952, 2880, 1978, 1711, 1023, 976/cm.
~s~
Example 14 (9R,11R,15R)-11,15-dihydroxy-16,16-dimethyl-9-fluor-prosta-4,5,13-trans-trien acid To 1.25 g of (9S,11R,15R)-16,16-dimethyl-9-hydroxy 11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien acid methylester dissolved in 20 ml o dichloromethane and 0.5 ml of pyridine add 0.3 ml of diethylaminosulfur tri-fluoride (DAST) at -70 C and another 0.1 ml of DAST 15 minutes later. After another 15 minutes mix with 50 ml of 5%
sodium hydrogen carbonate solution, remove the ice bath, stir vigorously at 20 C for 10 minutes, then extract with dichloromethane, wash the extract with brine, dry over magnesium sulfate and evaporate in a vacuum. Stir the residue for 24 hours with 20 ml of a mixture of acetic acid/water/tetra-hydrofuran (65/35/10), evaporate in a vacuum and ?urify the raw product by chromatography on silica gel with hexane/
diethyl ether (1:1). 410 mg of (9R,11R,15R)-11,15-dihydroxy-16,16-dimethyl-9-fluoro-prosta-4,5,13-trans-trien acid methylester are obtained in the form of an oil.
To saponify the ester, dissolve in 20 ml of methanol, mix with 500 mg of potassium hydroxide dissolved in 2 ml of water, and let stand for 4 hours at 20 C. Then concentrate in a vacuum, dilute with water, acidify with citric acid to pH 4 and extract with dichloromethane.Wash the extract with brine, dry over maynesium sulfate and evaporate in a vacuum. 370 mg of the title compound are obtained in the form of an oil.
IR: 3600, 3~20, 2948, 2878, 1976, 1710, 10~2, 978/cm.
Example 15 (9R,11R,15R)-11,15-dihydroxy-9-fluor-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid By analogy with example 14, 335 mg of the title compound are ob-tained in the form of an oil from 1.15 g of ~9S,1lR,15R)-9-hydroxy-16-phenoxy-11,15-bis-(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid methyl-ester.
IR: 3600, 3420, 2955, 2889, 1978, 1708, 1601, 1588, 1023, 976/cm.
Example 16 (9R,11R,15S,16RS)-11,15-dihydroxy-16,20-dimethyl-9-fluoro-prosta-4,5,13-trans-trien-18-in acid By analogy with example 14, 235 mg of the title compound are obtained in the form of an oil from 810 mg of (9S,11R,15S, 16RS)-16,20-dimethyl-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-prosta-4,5,13-trans-trien-18-in acid methylester.
IR: 3600, 3418, 2949,2822, 1976, 1710, 1023, 978/cm.
Example 17 (9R,11R,15R)-11,15-dihydroxy-9-fluorG-16-phenoxy-17,18,19,20-_ tetranor-prosta-4,5,13-trans-trien acid phenacylester Dissolve 210 mg of (9R,11R,15R)-11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid in 10 ml of acetone, mix with 139 mg of ~-bromo-acetophenone and 1.5 ml of triethylamine, and stir overnight at 20 C. Dilute with ether, shake one after another with water and brine, dry over magnesium sulfate and evaporate in a vacuum. Purify the residue by chromatography on silica gel with dichloromethane/10% acetone, thereby obtaining 195 mg of the title compound in the form of an oil.
IR: 3600, 3010, 2948, 1978, 1708(wide), 1600, 1588, 1139, 1022, 974/cm.
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A 9-halogen prostane derivative of formula I
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH2OH or with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical , with R3 is an acid radical or the radical R2 A is a -CH2-CH2-, a trans-CH=CH- or a -C?C- group, W Is a free functionally modified hydroxymethylene group or a free or func-tionally modified group, wherein the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group with 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxy-gen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkynyl group and, where R2 is a hydrogen atom, its salts with physiolog-ically tolerable bases.
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH2OH or with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical , with R3 is an acid radical or the radical R2 A is a -CH2-CH2-, a trans-CH=CH- or a -C?C- group, W Is a free functionally modified hydroxymethylene group or a free or func-tionally modified group, wherein the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group with 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxy-gen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkynyl group and, where R2 is a hydrogen atom, its salts with physiolog-ically tolerable bases.
2. A prostane derivative according to claim 1 in which R2 is selected from hydrogen alkyl groups having 1 to 10 carbon atoms which may be unsubstituted or substituted by halogen, lower aIkoxy, phenyl, benzoyl, dl-lower aIkylamlno or trllower alkyl-amino groups, or is a phenyl or naphthyl group which may be sub-stituted by halogen, phenyl, C1-C4 alkyl, chloromethyl, fluo-romethyl, trifluoromethyl, carboxy, hydroxy or C1-C4 alkoxy groups, or is C3-C10 cycloalkyl which may be substituted with C1-C4 alkyl, or is a 5 or 6 membered heterocyclic groups containing oxygen, nitrogen or sulphur; R3 is an acid radical of organic carboxylic or sulfonic acids with 1 to 15 carbon atoms; R5 is an alkyl group with 1 to 10 carbon atoms, an alkenyl group with 2 to 10 carbon atoms which groups may be substituted by phenyl, alkyl with 1 to 4 carbon atoms or halogen or when D and E together rep-resent a direct bond alkynyl with 2 to 6 carbon atoms which may be substituted by fluorine or C1-C4 alkyl or is a cycloalkyl group having 3 to 10 carbon atoms or which ring may be substi-tuted by C1-C4 alkyl or is a phenyl or naphthyl group which may be substituted by halogen, phenyl, C1-C4 alkyl, chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C1-C4 alkoxy or hydroxy or is a 5 or 6 membered heterocylic group containing oxygen, sul-phur or nitrogen and W is a free hydroxymethylene group or .alpha.
group which groups may be esterified or etherified with an organic acyl group containing 1 to 10 carbon atoms or the tetra-hydropyranyl, tetrahydrofuranyl, .alpha. -ethoxyethyl, trimethylsilyl, dimethyl-tert-butyl-silyl or tribenzyl-silyl radicals.
group which groups may be esterified or etherified with an organic acyl group containing 1 to 10 carbon atoms or the tetra-hydropyranyl, tetrahydrofuranyl, .alpha. -ethoxyethyl, trimethylsilyl, dimethyl-tert-butyl-silyl or tribenzyl-silyl radicals.
3. A prostane derivative according to claim 2 in which R2 is hydrogen an alkyl group with 1 to 4 carbon atoms which may be singly substituted with fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy or is a phenyl, haphthyl or 2-naphthyl group which may be substituted in the 3 or 4-positions by fluorine, chlorine, C1-C4 alkoxy trifluoromethyl or hydroxy, or is a cycloalkyl group of 5 or 6 carbon atoms which may be substituted by C1-C4 alkyl or is a 5 to 6 membered hetero-cyclic group having a nitrogen, sulfur or oxygen atom in the ring, R3 is an acid radical of an alkane sulfonic acid having 1 to 4 carbon atoms or an acyl radical with 1 to 4 carbon atoms, R5 is an alkyl radical with 1 to 6 carbon atoms or an alkenyl radi-cal with 2 to 6 carbon atoms which radicals may be substituted by C1-C4 alkyl or halogen or when D and E are a direct bond alkynyl with 2 to 6 carbon atoms which may be substituted in the 1-posi-tion by C1-C4 alkyl or fluorine or is a cycloalkyl group having 3 to 6 ring carbon atoms which may be substituted by C1-C4 alkyl or is a phenyl, 1-naphthyl or 2-naphthyl group which may be sub-stituted in the 3-position of the phenyl ring of fluorine chlo-rine, C1-C4 alkoxy or trifluoromethyl or in the 4-position by hydroxy or is a 5 or 6 membered heterocylic group containing a nitrogen, oxygen or sulfur atom; D is a saturated alkylene group with 1 to 5 carbon atoms which may be substituted by fluorine or D and E form a direct bond.
4. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid methylester.
5. (9S,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13 trans-trien acid methylester.
6. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-prosta-4,5,13-trans-trien acid.
7. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien acid methylester.
8. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien acid.
9. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid methylester.
10. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid.
11. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-trimethylene-prosta-4,5,13-trans-trien acid methylester.
12. (9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-trimethylene-prosta-4,5,13-trans-trien acid.
13. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid methylester.
14. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16-methyl-prosta-4,5,13-trans-trien-18-in acid.
15. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid methylester.
16. (9R,11R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,20-dimethyl-prosta-4,5,13-trans-trien-18-in acid.
17. (9R,11R,15R)-11,15-Dihydroxy-16,16-dimethyl-9-fluoro-prosta-4,5,13-trans-trien acid.
18. (9R,11R,15R)-11,15-Dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid.
19. (9R,11R,15S,16RS)-11,15-dihydroxy-16,20-dimethyl-9-fluoro-prosta-4,5,13-trans-trien-18-in acid.
20. (9R,11R,15R)-11,15-dihydroxy-9-fluoro-16-phenoxy-17,18,19,20-tetranor-prosta-4,5,13-trans-trien acid phenacylester.
21. A process for the manufacture of a 9-halogen prostane-derivatives of formula I
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH2OH or with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical -CH2-CH2-, a trans-CH-CH- or a -C=C- group, W is a free functionally modified hydroxymethylene group or a free or functionally modified group, wherein the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group with 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxygen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkynyl group and, where R2 is a hydrogen atom, its salts with physiologically tolerable bases, in which a compound of formula II
(II), where the 9-OH group can be in the .alpha. or .beta.-position and R1 represents the radical , with R2 meaning alkyl, cycloalkyl, aryl or a heterocyclic radical or the radical with R3 meaning an acid radical, an alkyl, cycloalkyl, aryl or heterocyclic radical and A, D, E and R5 are as above, after protection of free OH groups in R4 and W, with carbon tetrachloride/triphenylphosphine, hexachloroethane/triphenylphosphine or diethylaminosulfur trifluoride or, after conversion of the 9-hydroxy group into a 9-sulfonic acid ester with tetra-n-butyl-ammonium fluoride, and subsequently releasing in any sequence protected hydroxy groups and/or esterfying, etherifying free hydroxy groups and/or hydrogenating double bonds and/or saponifying an esterfied carboxy group (R1 = ) and/or converting a free carboxy group (R2 = H) into an amide (R1 = ) and or reducing a free or esterified carboxyl group (R1 = ).
(I), wherein Hal is a chlorine or fluorine atom in the .alpha. or .beta. -position, R1 is the radical CH2OH or with R2 is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclic radical or R1 is the radical -CH2-CH2-, a trans-CH-CH- or a -C=C- group, W is a free functionally modified hydroxymethylene group or a free or functionally modified group, wherein the OH group may be in the .alpha. or .beta. -position, D
and E together form a direct bond or D is a straight-chain, branched-chain or cyclic alkylene group with 1 to 10 C-atoms, which may be substituted by fluorine atoms, E represents an oxygen or sulfur atom, a direct bond, a -C?C- bond or a -CR6=CR7-group, where R6 and R7 are different and are a hydrogen atom, a chlorine atom or a C1-C4-alkyl group, R4 a free or functionally modified hydroxy group, and R5 is a hydrogen atom, an alkyl, an alkenyl, a halogen-substituted alkyl, a cycloalkyl, an aryl or a heterocyclic group or when D and E forms a direct bond an alkynyl group and, where R2 is a hydrogen atom, its salts with physiologically tolerable bases, in which a compound of formula II
(II), where the 9-OH group can be in the .alpha. or .beta.-position and R1 represents the radical , with R2 meaning alkyl, cycloalkyl, aryl or a heterocyclic radical or the radical with R3 meaning an acid radical, an alkyl, cycloalkyl, aryl or heterocyclic radical and A, D, E and R5 are as above, after protection of free OH groups in R4 and W, with carbon tetrachloride/triphenylphosphine, hexachloroethane/triphenylphosphine or diethylaminosulfur trifluoride or, after conversion of the 9-hydroxy group into a 9-sulfonic acid ester with tetra-n-butyl-ammonium fluoride, and subsequently releasing in any sequence protected hydroxy groups and/or esterfying, etherifying free hydroxy groups and/or hydrogenating double bonds and/or saponifying an esterfied carboxy group (R1 = ) and/or converting a free carboxy group (R2 = H) into an amide (R1 = ) and or reducing a free or esterified carboxyl group (R1 = ).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843414509 DE3414509A1 (en) | 1984-04-13 | 1984-04-13 | NEW 9-HALOGEN PROSTAGLANDINE |
| DEP3414509.5 | 1984-04-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1251201A true CA1251201A (en) | 1989-03-14 |
Family
ID=6233830
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000478989A Expired CA1251201A (en) | 1984-04-13 | 1985-04-12 | 9-halogen prostaglandins |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0213129B1 (en) |
| JP (1) | JPS61501915A (en) |
| AT (1) | ATE82258T1 (en) |
| AU (1) | AU583267B2 (en) |
| CA (1) | CA1251201A (en) |
| DD (1) | DD234668A5 (en) |
| DE (2) | DE3414509A1 (en) |
| DK (1) | DK578785D0 (en) |
| ES (1) | ES542173A0 (en) |
| HU (1) | HU196746B (en) |
| IL (1) | IL74877A0 (en) |
| WO (1) | WO1985004656A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5807892A (en) * | 1994-09-30 | 1998-09-15 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1414383A (en) * | 1972-11-14 | 1975-11-19 | Syntex Corp | Prostatrienoic acid derivatives and process |
| ES449162A1 (en) * | 1975-06-23 | 1977-12-16 | Syntex Inc | 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives |
| US4178457A (en) * | 1978-07-10 | 1979-12-11 | Syntex (U.S.A.) Inc. | (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof |
| DE2950027A1 (en) * | 1979-12-10 | 1981-06-11 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | 9-CHLORINE PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT |
-
1984
- 1984-04-13 DE DE19843414509 patent/DE3414509A1/en active Granted
-
1985
- 1985-04-11 IL IL74877A patent/IL74877A0/en unknown
- 1985-04-12 WO PCT/DE1985/000120 patent/WO1985004656A1/en active IP Right Grant
- 1985-04-12 EP EP85901971A patent/EP0213129B1/en not_active Expired - Lifetime
- 1985-04-12 AT AT85901971T patent/ATE82258T1/en not_active IP Right Cessation
- 1985-04-12 ES ES542173A patent/ES542173A0/en active Granted
- 1985-04-12 CA CA000478989A patent/CA1251201A/en not_active Expired
- 1985-04-12 DD DD85275144A patent/DD234668A5/en unknown
- 1985-04-12 JP JP60501833A patent/JPS61501915A/en active Pending
- 1985-04-12 DE DE8585901971T patent/DE3586828D1/en not_active Expired - Lifetime
- 1985-04-12 HU HU852186A patent/HU196746B/en unknown
- 1985-04-12 AU AU42345/85A patent/AU583267B2/en not_active Expired - Fee Related
- 1985-12-13 DK DK578785A patent/DK578785D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DD234668A5 (en) | 1986-04-09 |
| EP0213129B1 (en) | 1992-11-11 |
| HUT38307A (en) | 1986-05-28 |
| DK578785A (en) | 1985-12-13 |
| ES8603172A1 (en) | 1985-12-16 |
| DK578785D0 (en) | 1985-12-13 |
| ATE82258T1 (en) | 1992-11-15 |
| WO1985004656A1 (en) | 1985-10-24 |
| IL74877A0 (en) | 1985-07-31 |
| DE3414509C2 (en) | 1992-07-02 |
| EP0213129A1 (en) | 1987-03-11 |
| DE3586828D1 (en) | 1992-12-17 |
| ES542173A0 (en) | 1985-12-16 |
| AU4234585A (en) | 1985-11-01 |
| JPS61501915A (en) | 1986-09-04 |
| DE3414509A1 (en) | 1985-10-24 |
| AU583267B2 (en) | 1989-04-27 |
| HU196746B (en) | 1989-01-30 |
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