DE3338327A1 - AMIDE DERIVATIVES OF 13,14-DIDEHYDRO-CYCLOALKYL-PROSTA-GLANDINES - Google Patents
AMIDE DERIVATIVES OF 13,14-DIDEHYDRO-CYCLOALKYL-PROSTA-GLANDINESInfo
- Publication number
- DE3338327A1 DE3338327A1 DE19833338327 DE3338327A DE3338327A1 DE 3338327 A1 DE3338327 A1 DE 3338327A1 DE 19833338327 DE19833338327 DE 19833338327 DE 3338327 A DE3338327 A DE 3338327A DE 3338327 A1 DE3338327 A1 DE 3338327A1
- Authority
- DE
- Germany
- Prior art keywords
- prost
- acid
- cyclohexyl
- oxo
- dihydroxy
- 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.)
- Withdrawn
Links
- 150000001408 amides Chemical class 0.000 title claims description 88
- 150000001875 compounds Chemical class 0.000 claims description 90
- 239000002253 acid Substances 0.000 claims description 79
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- -1 9-cyclohexylprost-5-en-13-yn acid amide Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 17
- 125000004423 acyloxy group Chemical group 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 150000003180 prostaglandins Chemical class 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000000460 chlorine Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 206010061459 Gastrointestinal ulcer Diseases 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000011630 iodine Chemical group 0.000 claims description 3
- 229910052740 iodine Chemical group 0.000 claims description 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- 206010055690 Foetal death Diseases 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000035558 fertility Effects 0.000 claims description 2
- 230000035876 healing Effects 0.000 claims description 2
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 claims description 2
- 230000009897 systematic effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 2
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 claims 1
- 241000921769 Arabella Species 0.000 claims 1
- 241000282412 Homo Species 0.000 claims 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims 1
- 241000907681 Morpho Species 0.000 claims 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- LXWHOYSOMNNXRS-UHFFFAOYSA-N pyrazolidine-1-carboxamide Chemical compound NC(=O)N1CCCN1 LXWHOYSOMNNXRS-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 3
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 125000002636 imidazolinyl group Chemical group 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 230000003529 luteolytic effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical class NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- 125000002755 pyrazolinyl group Chemical group 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000017105 transposition Effects 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 2
- 101800000989 Oxytocin Proteins 0.000 description 2
- 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 150000002148 esters Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 2
- 229960001723 oxytocin Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- UVYKKFKLOUEFAR-UHFFFAOYSA-N hydron;piperazine-1-carboxamide;chloride Chemical compound Cl.NC(=O)N1CCNCC1 UVYKKFKLOUEFAR-UHFFFAOYSA-N 0.000 description 1
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- 239000004006 olive oil Substances 0.000 description 1
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- UWBHMRBRLOJJAA-UHFFFAOYSA-N oxaluric acid Chemical compound NC(=O)NC(=O)C(O)=O UWBHMRBRLOJJAA-UHFFFAOYSA-N 0.000 description 1
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- 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)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
FARMITALIA CARLO ERBA S.p.Α., MAILAND / ITALIENFARMITALIA CARLO ERBA S.p.Α., MILAN / ITALY
Amidderivate von 13,^-Didehydro-cycloalkyl-prostaglandinenAmide derivatives of 13, ^ - didehydro-cycloalkyl-prostaglandins
Die vorliegende Erfindung betrifft Amide von 13,14-Didehydro-cycloalkyl-prostaglandinen, ein Verfahren zu deren Herstellung, diese enthaltende pharmazeutische und Veterinäre Zusammensetzungen sowie bestimmte Zwischenprodukte, die zu deren Herstellung anwendbar sind.The present invention relates to amides of 13,14-didehydro-cycloalkyl-prostaglandins, a process for their preparation, pharmaceutical and veterinary compositions containing them and certain Intermediate products that can be used for their manufacture.
Die Erfindung liefert optisch aktive oder racemische Prostaglandinderivate der Formel (I) 10The invention provides optically active or racemic prostaglandin derivatives of the formula (I) 10
1^ CHC-C-C-(CH2)n-R1 ^ CHC-CC- (CH 2 ) n -R
dadurch gekennzeichnet , dass R' undcharacterized in that R 'and
R" jeweils, unabhängig voneinander Wasserstoff, C1,-Alkyl,
Aryl oder einen Heterozyklus bedeuten oder
R' und R", zusammengenommen mit dem Stickstoffatom,
an das sie gebunden sind, einen heterozyklischen Ring bilden;R ″ each, independently of one another , denotes hydrogen, C 1 , -alkyl, aryl or a heterocycle or
R 'and R ", taken together with the nitrogen atom,
to which they are bound form a heterocyclic ring;
das Symbol eine Einfach- oder Doppelbindung darstellt, wobei:the symbol represents a single or double bond, where:
(a) im Falle, dass das Symbol eine Doppelbindung ist, R1 ein Wasserstoffatom ist und R2 und R^, zusammengenommen, eine Oxogruppe bilden;(a) in the event that the symbol is a double bond, R 1 is a hydrogen atom and R2 and R ^, taken together, form an oxo group;
(b) im Falle, dass das Symbol eine Einfachbindung ist, R- Hydroxy, R- Wasserstoff und R- Hydroxy oder Acyloxy sind oder R2 und R3, zusammengenommen, eine Oxogruppe bilden;(b) in the event that the symbol is a single bond, R- are hydroxy, R- are hydrogen and R- are hydroxy or acyloxy or R 2 and R 3 , taken together, form an oxo group;
einer der beiden Reste R. und R5 Hydroxy und der andere Wasserstoff sind;one of the two radicals R. and R 5 is hydroxy and the other is hydrogen;
R6 und R7 jeweils, unabghängig voneinander Wasserstoff, C1,-Alkyl oder Fluor bedeuten;R 6 and R 7 are each, independently of one another, hydrogen, C 1 , -alkyl or fluorine;
η 0, 1 , 2 oder 3 ist;η is 0, 1, 2 or 3;
Rg einen C,_~-Cycloalkylring darstellt, der unsubstituiert oder durch einen oder mehrere Substituenten substituiert ist, die ausRg represents a C, _ ~ -cycloalkyl ring which is unsubstituted or is substituted by one or more substituents selected from
(C)(b 1 )
(C)
(e1)(d ')
(e 1 )
Phenyl undC 1-4 -AIkOXy,
Phenyl and
ausgewählt sind;are selected;
sowie die pharmazeutisch oder Veterinär zulässigen Salze davon.
30as well as the pharmaceutically or veterinarily acceptable salts thereof.
30th
Die Verbindungen und Salze der vorliegenden Erfindung haben den Vorteil, dass sie im Falle oraler Verabreichung grössere Aktivität besitzen als verwandte Verbindungen, die bisher offenbart wurden, insbesondere jene, die spezifisch in der britischen Anmeldung Nr. 2 009 145A offenbart wurden. Diese grössere Aktivität wird durch deren bessere Magen-Darm-Absorption ermöglicht.The compounds and salts of the present invention have the advantage that they can be administered orally have greater activity than related compounds previously disclosed, in particular those specifically disclosed in British Application No. 2,009,145A. This greater activity is made possible by their better gastrointestinal absorption.
Die vorstehend für die Verbindungen, die durch diese Erfindung abgedeckt sind, dargelegte Formel schliesst alle möglichen Isomere, insbesondere Stereoisomere, als auch deren Mischungen, z.B. Mischungen von Epimeren, ein. Die Doppelbindung in 5 (6) ist eine cis-Doppelbindung. In den Formeln dieser Erfindung zeigen gestrichelte Linien (mnmm) an, dass die Substituenten in der ot-Konfiguration vorliegen, d.h. unterhalb der Ebene des Ringes oder einer Seitenkette.The formula set out above for the compounds which are covered by this invention includes all possible isomers, in particular stereoisomers, as well as mixtures thereof, for example mixtures of epimers. The double bond in 5 (6) is a cis double bond. In the formulas of this invention, dashed lines (mnmm) indicate that the substituents are in the ot configuration, that is, below the plane of the ring or a side chain.
Keile («*«* ) zeigen an, dass die Substituenten in der ß-Konfiguration vorliegen, d.h. oberhalb der Ebene des Ringes oder einer Seitenkette. Wellenlinien ( i> ) zeigen an, dass die Substituenten im Falle, dass das Kohlenstoffatom, an das sie gebunden sind, asymetrisch ist, entweder in der c6- oder ß-Konfiguration oder in der (<?O ,ß)-Konfiguration, das ist eine Mischung aus zwei Epimeren, vorliegen können. Zum Beispiel kann die Hydroxygruppe, die an das Kohlenstoffatom in Position 15 gebunden ist, in der Konfiguration fo6) , (ß) und (o6,ß) , d.h. eine Mischung aus den 15fod.)- und 15(ß)-Epimeren, vorliegen. Falls das KohlenstoffatomWedges («*« *) indicate that the substituents in the ß-configuration, i.e. above the level of the ring or a side chain. Wavy lines (i> ) indicate that the substituents, in the event that the carbon atom to which they are attached, are asymmetrical is, either in the c6 or ß configuration, or in the (<? O, ß) configuration, that's a mixture of two epimers, may be present. For example, the hydroxy group attached to the carbon atom bound in position 15 in the configuration fo6), (ß) and (o6, ß), i.e. a mixture of the 15fod.) - and 15 (β) epimers are present. If the carbon atom
in Position 16 zwei verschiedene Substituenten aufweist, können diese genauso 1 6 bO) , 16(ß) und 16(ok,ß), d.h. eine Mischung aus den zwei 16(cM- und 16(ß)-Epimeren, sein. Das Symbol S oder R eines jeweiligen chiralen Zentrums wird gemäss der Seguenzregel zugeordnet, die die Liganden nach fallender Atomzahl anordnet.has two different substituents in position 16, can these just as 1 6 bO), 16 (ß) and 16 (ok, ß), i.e. a mixture of the two 16 (cM and 16 (β) epimers, be. The symbol S or R of a respective chiral center is assigned according to the sequence rule, which arranges the ligands according to decreasing atomic number.
Die Alkyl-, Alkoxy- und Trihaloalkylgruppen können geradkettig oder verzweigt sein.The alkyl, alkoxy and trihaloalkyl groups can be straight-chain or branched.
Ein Halogenatom ist vorzugsweise Fluor, Chlor oder Brom. Wenn einer oder beide von R1 und R" C._,--Alkyl darstellen, sind sie vorzugsweise Methyl, Ethyl, Propyl oder Butyl.A halogen atom is preferably fluorine, chlorine or bromine. When either or both of R 1 and R "are C 1-4 alkyl, they are preferably methyl, ethyl, propyl, or butyl.
Wenn einer oder beide von R1 und R" Aryl darstellen, sind sie vorzugsweise Phenyl. Wenn einer oder beide von R1 und R" einen Heterozyklus darstellen, wird die heterozyklische Gruppe vorzugsweise aus Pyrrolyl, Pyrazolyl, Imidazolinyl, Imidazolidinyl, Pyrazolinyl, Piperidyl, Piperazinyl, Morpholinyl und Pyrazolidinyl ausgewählt.When either or both of R 1 and R "are aryl, they are preferably phenyl. When either or both of R 1 and R" are heterocyclic, the heterocyclic group is preferably selected from pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidyl, Piperazinyl, morpholinyl and pyrazolidinyl.
Wenn R1 und R", zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, einen heterozyklischen Ring bilden, wird der heterozyklische Ring vorzugsweise ausgewählt aus: Pyrrolyl, Pyrazolyl, Imidazolinyl,· Imidazolidinyl, Pyrazolinyl, Piperidino, Piperazinyl, Morpholino und Pyrazolidinyl. R1 und R" können als individuelle heterozyklische Gruppen auch PiperidinoWhen R 1 and R ″, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring, the heterocyclic ring is preferably selected from: pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl, piperidino, piperazinyl, morpholino and pyrazolidinyl. As individual heterocyclic groups, R 1 and R ″ can also be piperidino
oder Morpholino sein.or be morpholino.
Wenn R_ Acyloxy ist, ist dies vorzugsweise eine Benzoyloxygruppe oder eine C~_g-Alkanoyloxygruppe, z.B. Acetoxy oder Propionyloxy.When R_ is acyloxy, it is preferably a benzoyloxy group or a C ~ _ g alkanoyloxy, for example acetoxy or propionyloxy.
Wenn einer oder beide von R, und R- C. .-Alkyl darstellen, sind sie vorzugsweise Methyl oder Ethyl.When one or both of R 1 and R are C.. -Alkyl, they are preferably methyl or ethyl.
Wenn Rg eine C-^-Cycloalkylgruppe, die nach Wunsch substituiert ist, wie vorstehend unter Punkt (a1) bis (f) beschrieben, darstellt, ist R„ vorzugsweise eine Gruppe, die aus Cyclopentyl, Cyclohexyl und Cycloheptyl ausgewählt ist.When R g represents a C 1-4 cycloalkyl group substituted as desired as described in items (a 1 ) to (f) above, R "is preferably a group selected from cyclopentyl, cyclohexyl and cycloheptyl.
Bevorzugte Verbindungen der Erfindung sind Verbindungen der Formel (I), wobeiPreferred compounds of the invention are compounds of formula (I), wherein
Rf und R", unabhängig voneinander,Wasserstoff oder
C .-Alkyl sind; oder R1 und R", zusammengenommen mit
dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolyl-, Pyrazolyl-, Imidazolinyl-, Imidazolidinyl-,
Pyrazolinyl-, Piperidin-, Piperazinyl- oder Morpholinring bilden;
'R f and R ", independently of one another, are hydrogen or C. -Alkyl; or R 1 and R", taken together with the nitrogen atom to which they are attached, represent a pyrrolyl, pyrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl , Form piperidine, piperazinyl or morpholine ring;
'
das Symbol ------ eine Einfachbindung ist, R. Hydroxythe symbol ------ is a single bond, R. Hydroxy
ist, R„ Wasserstoff und R_ Hydroxy oder Acyloxy sind oder R2 und R3, zusammengenommen, eine Oxogruppe bilden;· R0 ein Radikal darstellt, das aus Cyclopentyl, οis, R "is hydrogen and R_ is hydroxy or acyloxy or R 2 and R 3 , taken together, form an oxo group; · R 0 represents a radical which is derived from cyclopentyl, ο
Cyclohexyl und Cycloheptyl ausgewählt ist, die jeweils unsubstituiert oder durch eines oder mehrere (a1)Cyclohexyl and cycloheptyl is selected, each unsubstituted or by one or more (a 1 )
Halogen, (b1) Trihalo-C^g-alkyl, (c1) C1-4-(d')
C1-4-AIkOXy, (e1) Phenyl, (f) Phenoxy substituiert
sind; R4, R5, Rg, R7 und η die vorher angegebenen
Bedeutungen haben;
5Halogen, (b 1 ) trihalo-C 1-4 alkyl, (c 1 ) C 1-4 (d ') C 1-4 alkOXy, (e 1 ) phenyl, (f) phenoxy are substituted; R 4 , R 5 , R g , R 7 and η have the meanings given above;
5
sowie die pharmazeutisch oder Veterinär zulässigen Salze davon.as well as the pharmaceutically or veterinarily acceptable salts thereof.
Besonders bevorzugte Verbindungen der Erfindung sind die Verbindungen der Formel (I), wobeiParticularly preferred compounds of the invention are the compounds of the formula (I), wherein
R1 und R", unabhängig voneinander, Wasserstoff oder Methyl sind; oder R1 und R", zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, einen Piperidin- oder Morpholinring bilden;R 1 and R "are independently hydrogen or methyl; or R 1 and R", taken together with the nitrogen atom to which they are attached, form a piperidine or morpholine ring;
das Symbol ^^2. eine Einfachbindung ist, R1 Hydroxy ist, R2 Wasserstoff und R_ Hydroxy sind oder R- und R_, zusammengenommen, eine Oxogruppe bilden; 20the symbol ^^ 2. is a single bond, R 1 is hydroxy, R 2 is hydrogen and R_ is hydroxy or R- and R_, taken together, form an oxo group; 20th
Rr und R-,, unabhängig voneinander, jeweils Wassero /R r and R- ,, independently of one another, each water /
stoff, Methyl oder Fluor darstellen;represent substance, methyl or fluorine;
R., R5 und η die vorher angegebenen Bedeutungen haben; R„ Cyclopentyl oder Cyclohexyl ist;R., R 5 and η have the meanings given above; R “is cyclopentyl or cyclohexyl;
sowie die pharmazeutisch oder Veterinär zulässigen Salze davon.as well as the pharmaceutically or veterinarily acceptable salts thereof.
Wie vorstehend festgestellt, deckt diese Erfindung auch pharmazeutisch oder Veterinär zulässige SalzeAs stated above, this invention also covers pharmaceutically or veterinarily acceptable salts
dieser Verbindungen ab.of these connections.
Beispiele von besonders bevorzugten Salzen der Verbindungen der Formel (I) schliessen Säure-Ädditions-Salze mit anorganischen Säuren, z.B. Salpeter-, Chlorwasserstoff-, Bromwasserstoff-, Jodwasserstoff-, Schwefel-, Perchlor- und Phosphorsäure, oder mit organischen Säuren, z.B. Essig-, Propion-, Glykol-, Milch-, Oxal-, Malon-, Äpfel-, Malein-, Wein-, Zitronen-, Benzoe-, Furaar-, Zimt-, Mandel-, Salicylsäure, sowie mit organischen Sulfonsäuren, z.B. Methansulf on-, p-Toluolsulfon- und Cyclohexylsulfonsäure, ein.Examples of particularly preferred salts of the compounds of the formula (I) include acid addition salts with inorganic acids, e.g. nitric, hydrogen chloride, hydrogen bromide, hydrogen iodide, Sulfuric, perchloric and phosphoric acid, or with organic acids, e.g. acetic, propionic, glycolic, Milk, oxal, malon, apple, malein, wine, lemon, Benzoic, furaar, cinnamon, almond, salicylic acid, as well as with organic sulfonic acids, e.g. methanesulf on-, p-toluenesulphonic and cyclohexylsulphonic acid, a.
OOOOOOOO
Beispiele von bevorzugten erfindungsgemässen Verbindungen sind:Examples of preferred compounds according to the invention are:
5ο-9<*ν 1 λΦ, 15(S)-Trihydroxy-20-nor-19-cyclohexylprost-5-en-13-in-säureamid, 5ο-9 <* ν 1 λΦ, 15 (S) -Trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yne acid amide,
5c-9^, 1 λ<ρ, 15 (S) -Trihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-in-säureamid, 5c-9 ^, 1 λ <ρ, 15 (S) -Trihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-yn acid amide,
5c-9 oO , 11oO, 1 5 (R) -Trihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-1 3-in-säureamid,5c-9 oO, 11oO, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide,
50-90^/11^15 (R,S)-Trihydroxy-1 6 (S)-f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säureamid, 50-90 ^ / 11 ^ 15 (R, S) -Trihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yne-acid amide,
5c-9ot, 1100,15 (S) -Trihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-13-in-säureamid, 205c-9ot, 11 0 0.15 (S) -trihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid amide, 20
5c-9ot/, 1 loU 15 (S) -Trihydroxy-1 9 ,20-dinor-1 8-cyclopentyl-prost-5-en-13-in-säureamid, 5c-9ot /, 1 loU 15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclopentyl-prost-5-en-13-yne-acid amide,
5c-9oL·, 11o6-, 15 (R) -Trihydroxy-1 6 (S) -fluor-1 9 ,20-dinor-1e-cyclohexyl-prost-S-en-i3-in-säureamid, 5c-9oL ·, 11o6-, 15 (R) -Trihydroxy-1 6 (S) -fluor-1 9, 20-dinor-1e-cyclohexyl-prost-S-en-i3-yne-acid amide,
5c-9c£, 110C, 1 5 (R,S) -Trihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-in-säureamid, 5c-9c £, 11 0 C, 1 5 (R, S) -Trihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yne acid amide,
5c-9ot, 1 lot, 15 (S) -Trihydroxy-18,1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-in-säureamid, 5c-9ot, 1 lot, 15 (S) -Trihydroxy-18,1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-yne-acid amide,
5c-9oLr 1 lot, 1 5 (S) -Trihydroxy-1 8 ,1 9 ,20-trinor-1 7-cyclopentyl-prost-5-en-i3-in-säureamid, 5c-9oLr 1 lot, 1 5 (S) -Trihydroxy-1 8, 1 9, 20-trinor-1 7-cyclopentyl-prost-5-en-i3-yne-acid amide,
5c-9d, 11οί', 1 5 (R) -Trihydroxy-1 6 (S) -fluor-1 8,19,20-trinor-IT-cyclohexyl-prost-S-en-i3-in-säureamid, 5c-9d, 11οί ', 1 5 (R) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-IT-cyclohexyl-prost-S-en-i3-yne-acid amide,
0 5c-9oL, 1 lot, 15 (R,S) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-0 5c-9oL, 1 lot, 15 (R, S) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-
trinor-17-cyclohexyl-prost-S-en-i3-in-säureamid,trinor-17-cyclohexyl-prost-S-en-i3-yne-acid amide,
5c-9oL, 11eL, 15 (R) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-S-en-i3-in-säureamid, 155c-9oL, 11eL, 15 (R) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-S-en-i3-yne-acid amide, 15th
5c-9oL, 11eL, 15 (R,S) -Trihydroxy-16 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säureamid, 5c-9oL, 11eL, 15 (R, S) -Trihydroxy-16 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yne-acid amide,
5c-9oL, 11cL, 15 (S) -Trihydroxy-17 ,18,19 ,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid, 5c-9oL, 11cL, 15 (S) -Trihydroxy-17, 18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide,
5c-9oC, 1 lot, 15 (S) -Trihydroxy-1 7,18,19 ,20-tetranor-1 6-cyclopentyl-prost-5-en-13-in-säureamid,5c-9oC, 1 lot, 15 (S) -trihydroxy-1 7,18,19, 20-tetranor-1 6-cyclopentyl-prost-5-en-13-yne acid amide,
5c-9oL, 1 lot, 1 5 (R) -Trihydroxy-1 6 (S) -f luor-1 7 ,18,1 9,20-tetranor-1S-cyclohexyl-prost-S-en-i3-in-säureamid, 5c-9oL, 1 lot, 1 5 (R) -Trihydroxy-1 6 (S) -f luor-1 7, 18,1 9,20-tetranor-1S-cyclohexyl-prost-S-en-i3-in- acid amide,
5c-9oL, 1 U, 15 (R,S) -Trihydroxy-1 6 (S) -f luor-1 7,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säureamid, 305c-9oL, 1 U, 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 7,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in- acid amide, 30th
5c-9oi., 110U 1 5 (R) -Trihydroxy-1 6 (S) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-insäureamid, 5c-9oi., 11 0 U 1 5 (R) -Trihydroxy-1 6 (S) -f luoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- insäureamid,
ν νν ν
7 15 (R,S)-Trihydroxy-16 (S)-fluor-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-in-säureamid, 7 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne-acid amide,
5c-9oC, 11dL, 15 (R) -Trihydroxy-1 6 (R) -f luor-1 6-methy1 18,1 9,20-trinor-iT-cyclohexyl-prost-S-en-i3-insäureamid, 5c-9oC, 11dL, 15 (R) -trihydroxy-1 6 (R) -f luoro-1 6-methy1 18.1 9.20-trinor-iT-cyclohexyl-prost-S-en-i3-insäureamid,
5c-9eC, 110L, 15 (S) -Trihydroxy-20-nor-1 9-cyclohexylprost-S-en-IS-in-säure-NjN-dimethylairiid, 5c-9eC, 110L, 15 (S) -Trihydroxy-20-nor-1 9-cyclohexylprost-S-en-IS-in-acid-NjN-dimethylairiid,
5c-9oL, 110L, 15 (S) -Trihydroxy-20-nor-i 9-cyclopentyl prost-5-en-13-in-säure-N,N-dimethylamid,5c-9oL, 110L, 15 (S) -trihydroxy-20-nor-i 9-cyclopentyl prost-5-en-13-yn-acid-N, N-dimethylamide,
5c-9oL,11oL,15 (R)-Trihydroxy-1 6 (S) -f luor-20-norig-cy
amid,5c-9oL, 11oL, 15 (R) -trihydroxy-16 (S) -f luor-20-norig-cy
amide,
5c-9oC, 1 lol, 15 (R,S) -Trihydroxy-16 (S) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethyl- amid,5c-9oC, 1 lol, 15 (R, S) -Trihydroxy-16 (S) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide,
5c-9oL, 110C, 15 (S) -Trihydroxy-1 9 ,20-dinor-1 8-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 255c-9oL, 110C, 15 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide, 25th
5c-9dL, 110L, 1 5 (S) -Trihydroxy-1 9 ,20-dinor-1 8-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9dL, 110L, 1 5 (S) -Trihydroxy-1 9, 20-dinor-1 8-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5c-9oC, 1 lot, 15 (R) -Trihydroxy-1 6(S) -f luor-1 9 ,2 0-dinor-1 8-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9oC, 1 lot, 15 (R) -trihydroxy-1 6 (S) -f luor-1 9, 2 0-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5c-9oL, 1 ld, 15 (R,S) -Trihydroxy-1 6 (R) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9oL, 11d, 15 (R, S) -Trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide ,
5c-9oC, 11oC, 15 (S) -Trihydroxy-18 ,1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-in-säure-N,N-dimethylamid, 5c-9oC, 11oC, 15 (S) -Trihydroxy-18, 1 9,20-trinor-i 7-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,
5c-9ci.f 11eL, 15 (S) -Trihydroxy-1 8 ,1 9 ,20-trinor-17-0 cyclopentyl-prost-5-en-i3-in-säure-N,N-dimethyl-5c-9ci. f 11eL, 15 (S) -Trihydroxy-1 8, 1 9, 20-trinor-17-0 cyclopentyl-prost-5-en-i3-yn-acid-N, N-dimethyl-
amid,amide,
5c-9oCf 1 U,, 15 (R) -Trihydroxy-1 6 (S) -fluor-1 8,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid, 5c-9oC f 1 U ,, 15 (R) -Trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide,
5c-9oL, 11oU 15 (R,S) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid,
205c-9oL, 11oU 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
20th
5c-9ol, 11oL, 15 (R) -Trihydroxy-1 6 (S) -f luor-18 ,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9ol, 11oL, 15 (R) -Trihydroxy-1 6 (S) -f luor-18, 19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N- dimethylamide,
5c-9oL,1U,15 (R,S)-Trihydroxy-1 6 (S)-f luor-1 8 ,1 9 ,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9oL, 1U, 15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 8, 1 9, 20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid- N, N-dimethylamide,
5c-9oC 11oL, 15 (S) -Trihydroxy-17 ,18,19 ,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethyl- amid,5c-9oC 11oL, 15 (S) -Trihydroxy-17, 18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethyl- amide,
ν/ ν» ν» W W L· I ν / ν »ν» WW L · I
5c-9o<-, 11cC, 15 (S) -Trihydroxy-17,18,19,20-tetranorlö-cyclopentyl-prost-S-en-IS-in-säure-N^N-dimethylamid, 5c-9o <-, 11cC, 15 (S) -Trihydroxy-17,18,19,20-tetranorlo-cyclopentyl-prost-S-en-IS-yn-acid-N ^ N-dimethylamide,
5c-9öl, 11ol, 15 (R)-Trihydroxy-1 6 (S)-fluor-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-IS-in-säure-NjN-dimethylamid, 5c-9oil, 11ol, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-IS-yn-acid-NjN-dimethylamide ,
5c-9oC, 11oC·, 15 (R,S) -Trihydroxy-1 6 (S) -f luor-17,18,19,20 tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9oC, 11oC ·, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20 tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5c-9oL 11ol, 1 5 (R) -Trihydroxy-16 (S) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-saure-N,N-dimethylamid, 5c-9oL 11ol, 1 5 (R) -Trihydroxy-16 (S) -f luoro-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid- N, N-dimethylamide,
5c-9o2-, 11σ0,15 (R,S) -Trihydroxy-1 6 (S) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid,
205c-9o2-, 11σ0.15 (R, S) -Trihydroxy-1 6 (S) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- in-acid-N, N-dimethylamide,
20th
5c-9<i, 1 lot, 15 (R) -Trihydroxy-1 6 (R) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5c-9 <i, 1 lot, 15 (R) -Trihydroxy-1 6 (R) -f luor-1 6-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- in-acid-N, N-dimethylamide,
5c-9-Oxo-11c6,15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-in-säureamid, 5c-9-Oxo-11c6,15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-yne acid amide,
5c-9-Oxo-11dL, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-in-säureamid,
305c-9-Oxo-11dL, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yne acid amide,
30th
5c-9-Oxo-11cL, 15 (R) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-1 3-in-säureamid,5c-9-Oxo-11cL, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-1 3-yn acid amide,
BADBATH
5c-9-Oxo-11cC, 15 (R,S) -dihydroxy-1 6 (S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säureamid, 5c-9-Oxo-11cC, 15 (R, S) -dihydroxy-1 6 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yne-acid amide,
5C-9-OXO-110C, 15 (S) -dihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-S-en-i3-in-säureamid, 5C-9-OXO-110C, 15 (S) -dihydroxy-1 9,20-dinor-1 8-cyclohexyl-prost-S-en-i3-yne-acid amide,
50-9-0x0-11^,15(S)-dihydroxy-19,20-dinor-i8-cyclopentyl-prost-5-en-13-in-säureamid, 50-9-0x0-11 ^, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yne-acid amide,
5C-9-OXO-1U,15(R)-dihydroxy-16(S)-fluor-1 9,20-dinor-1S-cyclohexyl-prost-S-en-i3-in-säureamid, 5C-9-OXO-1U, 15 (R) -dihydroxy-16 (S) -fluoro-1 9,20-dinor-1S-cyclohexyl-prost-S-en-i3-yne-acid amide,
5c-9-0XO-1 U,, 15 (R,S) -dihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-in-säureamid, 155c-9-0XO-1 U ,, 15 (R, S) -dihydroxy-1 6 (R) -f luor-20-nor-1g-cyclohexyl-prost-S-en-i3-yne acid amide, 15th
5c-9-Oxo-11ol, 15(S) -dihydroxy-18 ,1 9 ,20-trinor-17 cyclohexyl-prost-5-en-i3-in-säureamid,5c-9-oxo-11ol, 15 (S) -dihydroxy-18, 19, 20-trinor-17 cyclohexyl-prost-5-en-i3-yne-acid amide,
5c-9-Oxo-1 λά~, 15 (S) -dihydroxy-1 8,19 ,20-trinor-17-cyclopentyl-prost-5-en-i3-in-säureamid, 5c-9-Oxo-1 λά ~, 15 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclopentyl-prost-5-en-13-yne acid amide,
, 15 (R) -dihydroxy-1 β (S) -fluor-1 8,19,20-trinor-17-cyclohexyl-prost-S-en-i3-in-säureamid, , 15 (R) -dihydroxy-1 β (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-S-en-i3-yne acid amide,
5'c-9-0XO-11oL 1 5 (R,S) -dihydroxy-1 6 (S) -fluor-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid, 5'c-9-0XO-11oL 1 5 (R, S) -dihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid amide,
5c-9-Oxo-1 Ιοί/, 15 (R) -dihydroxy-16 (S) -f luor-18,19,20-trinor-17-cyclopentyl-prost-5-en-1 3-in-säureaitiid, 305c-9-oxo-1 Ιοί /, 15 (R) -dihydroxy-16 (S) -f luoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-1 3-yn acid aide, 30
5c-9-Oxo-11öL, 15 (R,S) -dihydroxy-1 6 (S) -f luor-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säureamid, 5c-9-Oxo-11oL, 15 (R, S) -dihydroxy-16 (S) -f luoro-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid amide ,
5C-9-OXO-11<£, 15(S) -dihydroxy-17 ,18,19 ,20-tetranor-1S-cyclohexyl-prost-S-en-i3-in-säureamid, 5C-9-OXO-11 <£, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1S-cyclohexyl-prost-S-en-i3-yne-acid amide,
5C-9-OXO-110C, 15 (S) -dihydroxy-17 ,18,19 ,20-tetranor-1S-cyclopentyl-prost-S-en-i3-in-säureamid, 5C-9-OXO-11 0 C, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1S-cyclopentyl-prost-S-en-i3-yne-acid amide,
5C-9-OXO-1 lot-, 15 (R) -dihydroxy-1 6 (S) -f luor-1 7,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid, 5C-9-OXO-1 lot-, 15 (R) -dihydroxy-16 (S) -fluoro-1 7,18,19,20-tetranor-16-cyclohexyl-prost-5-ene-13-yne acid amide,
0 5C-9-OXO-11ol, 15 (R, S) -dihydroxy-1 6 (S) -f luor-1 7 ,1 8 r1 9 ,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid, 0 5C-9-OXO-11ol, 15 (R, S) -dihydroxy-1 6 (S) -f luor-1 7, 1 8 r 1 9, 20-tetranor-16-cyclohexyl-prost-5-en- 13-yn acid amide,
5c-9-Oxo-11oC,15 (R)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-insäureamid, 5c-9-Oxo-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,
5C-9-OXO-11ol, 15 (R, S) -dihydroxy-16 (S)-fluor-16-methyl-18,19,20—trinor-17-cyclohexyl-prost-5-en-13-insäureamid,
205C-9-OXO-11ol, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,
20th
5C-9-OXO-11oC, 15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-insäureamid, 5C-9-OXO-11oC, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-ynamide,
5c-9-Oxo-11iL, 15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-in-säure-N,N-dimethylamid, 5c-9-Oxo-11iL, 15 (S) -dihydroxy-20-nor-1 9-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide,
5c-9-Oxo-1 IcL, 15 (S)-dihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-in-säure-N,N-dimethylamid, 305c-9-Oxo-1 IcL, 15 (S) -dihydroxy-20-nor-1 9-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide, 30
5c-9-Oxo-11C^, 15 (R) -dihydroxy-1 6 (S) -f luor-20-nor-i 9-cyclohexyl-prost-S-en-IS-in-säure-N^-dimethylamid, 5c-9-Oxo-11C ^, 15 (R) -dihydroxy-1 6 (S) -f luoro-20-nor-i 9-cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide ,
3A3A
5C-9-OXO-11eC, 15 (R,S) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5C-9-OXO-11eC, 15 (R, S) -dihydroxy-1 6 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide,
50-9-0x0-1106,15 (S) -dihydroxy-19,20-dinor-1 8-cyclohexyl-prost-5-en-i3-in-säure-N,N-dimethylamid, 50-9-0x0-1106.15 (S) -dihydroxy-19,20-dinor-1 8-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,
5C-9-OXO-11oU 15(S)-dihydroxy-19,20-dinor-i8-cyclopentyl-prost-S-en-i3-in-säure-N,N-dimethylamid, 5C-9-OXO-11oU 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethylamide,
5C-9-OXO-11ct, 15 (R) -dihydroxy-1 6 (S) -f luor-19 ,20-dinor-1S-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid,
155C-9-OXO-11ct, 15 (R) -dihydroxy-1 6 (S) -f luor-19, 20-dinor-1S-cyclohexyl-prost-S-en-i3-yn-acid-N, N- dimethylamide,
15th
50-9-OXO-HoC, 15 (R,S) -dihydroxy-16 (R)-fluor-20-nor-1 9-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 50-9-OXO-HoC, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-1 9-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5C-9-OXO-11oC, 1 5 (S) -dihydroxy-1 8,19 ,20-trinor-17-cyclohexyl-prost-5-en-i3-in-säure-N,N-dimethylamid, 5C-9-OXO-11oC, 1 5 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclohexyl-prost-5-en-i3-yn-acid-N, N-dimethylamide,
5C-9-OXO-11oL, 15 (S) -dihydroxy-1 8,19 ,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5C-9-OXO-11oL, 15 (S) -dihydroxy-1 8,19, 20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5C-9-OXO-110U15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid,
305C-9-OXO-110U15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
30th
5C-9-OXO-11Λ, 15(R,S)-dihydroxy-16(S)-fluor-18,1 9,20 trinor-17-cyclohexyl-prost-S-en-i 3-in-säure-N,N-dimethylamid, 5C-9-OXO-11Λ, 15 (R, S) -dihydroxy-16 (S) -fluoro-18.1 9.20 trinor-17-cyclohexyl-prost-S-en-i 3-yn-acid-N, N-dimethylamide,
5C-9-OXO-1ToC 15(R),dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-i3-in-säure-N,N-dimethylamid, 5C-9-OXO-1ToC 15 (R), dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-i3-yn-acid-N, N-dimethylamide ,
5C-9-OXO-1 1oC, 15 (R,S) -dihydroxy-16 (S) -fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-i3-in-säure-N,N-dimethylamid, 5C-9-OXO-11oC, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yn-acid-N , N-dimethylamide,
5C-9-OXO-1lot, 15 (S) -dihydroxy-17 ,18,1 9 ,20-tetranor-1e-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethyl- amid,5C-9-OXO-1lot, 15 (S) -dihydroxy-17, 18,19, 20-tetranor-1e-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide,
5C-9-OXO-11oC, 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5C-9-OXO-11oC, 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
5C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid,
205C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide,
20th
5C-9-OXO-11öl, 15 (R, S) -dihydroxy-1 6 (S) -fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid, 5C-9-OXO-11oil, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn acid -N, N-dimethylamide,
5c-9-Oxo-1 Ϊ(Κ, 15 (R) -dihydroxy-16 (S) -fluor-16-methyl-18,19 ^O-trinor-^-cyclohexyl-prost-S-en-IS-in-säure-N,N-dimethylamid, 5c-9-Oxo-1 Ϊ (Κ, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-IS-in acid-N, N-dimethylamide,
5C-9-OXO-11öC 15(R,S)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-i7-cyclohexyl-prost-5-en- 13-in-säure-N,N-dimethylamid,5C-9-OXO-11öC 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-i7-cyclohexyl-prost-5-en- 13-yn-acid-N, N-dimethylamide,
BAD ORIGINALBATH ORIGINAL
C, 15 (R,S) -dihydroxy-16 (R)-fluor-16-methyl-18,19,20—trinor-1T-cyclohexyl-prost-S-en-13-in-säure-N,N-dimethylamid, C, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N, N- dimethylamide,
Sc-S-Oxo-HoC-, 15 (S)-dihydroxy-20-nor-19-cyclohexyl prost»5~en-13-in-säure-morpholinamid,Sc-S-Oxo-HoC-, 15 (S) -dihydroxy-20-nor-19-cyclohexyl prost »5 ~ en-13-yn-acid-morpholinamide,
50-9-0x0-1 I0C, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-in~säure-morpholinamid, 1050-9-0x0-1 10C, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yn-acid morpholinamide, 10
5c-9-Oxo-11cC, 15 (R) -dihydroxy-16 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 5c-9-Oxo-11cC, 15 (R) -dihydroxy-16 (S) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
50-9-0x0-1101,15(R,S)-dihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 50-9-0x0-1101.15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-11oL, 15 (S) -dihydroxy-1 9 ,20-dinor-1 8-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 5C-9-OXO-11oL, 15 (S) -dihydroxy-1 9, 20-dinor-1 8-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-11öU 15(S)-dihydroxy-19,20-dinor-i8-cyclopentyl-prost-5-en-13-in-säure-morpholinamid, 5C-9-OXO-11öU 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-11<jl,15 (R) -dihydroxy-1 6 (S) -f luor-19 ,20-dinor-1S-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid, 5C-9-OXO-11 <jl, 15 (R) -dihydroxy-1 6 (S) -f luor-19, 20-dinor-1S-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamid,
5C-9-OXO-1 lot, 15 (R,S) -dihydroxy-16 (R) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 5C-9-OXO-1 lot, 15 (R, S) -dihydroxy-16 (R) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-11öW 15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-i3-in-säure-morpholinamid, 5C-9-OXO-11öW 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-i3-yn-acid-morpholinamide,
VV W V A. t VV WV A. t
5c-9-Oxo-11ö£,15 (S) -dihydroxy-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-morpholinainid, 5c-9-Oxo-11ö £, 15 (S) -dihydroxy-1 8,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinainid,
5c-9-Oxo-1 -id, 15 (R) -dihydroxy-16 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-morpho- linamid,5c-9-Oxo-1 -id, 15 (R) -dihydroxy-16 (S) -f fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-morpho - linamid,
5c-9-Oxo-11ot,15 (R,S)-dihydroxy-16 (S) -f luor-18,19 ,20 trinor-1V-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid, 5c-9-Oxo-11ot, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19, 20 trinor-1V-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamide,
5C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -f luor-18 ,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säuremorpholinamid,
155C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -f luor-18, 19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid morpholinamide,
15th
5c-9-Oxo-1 IcC, 15 (R,S) -dihydroxy-1 6 (S) -f luor-18 ,1 9,20-trinor-i7-cyclopentyl-prost-5-en-13-insäure-morpholinamid, 5c-9-Oxo-1 IcC, 15 (R, S) -dihydroxy-16 (S) -fluoro-18 , 1 9,20-trinor-17-cyclopentyl-prost-5-en-13-ynoic acid-morpholinamide,
5C-9-OXO-11cC> 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 5C-9-OXO-11cC> 15 (S) -dihydroxy-17,18,1 9,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-1 IcL1 15 (S) -dihydroxy-17 ,18,19 ,20-tetranor-16-cyclopentyl-prost-5-en-13-in-säure-morpholin- amid,5C-9-OXO-1 IcL 1 15 (S) -dihydroxy-17, 18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-morpholine amide,
5C-9-OXO-11σΟ* 15 (R) -dihydroxy-16 (S) -f luor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säuremorpholinamid, 5C-9-OXO-11σΟ * 15 (R) -dihydroxy-16 (S) -f luor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid morpholine amide,
SAD ORIGINALSAD ORIGINAL
5c-9-Oxo-11e6r15(R/S)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-1e-cyclohexyl-prost-5-en-13-in-säure-morpholinamid, 5c-9-Oxo-11e6r15 (R / S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1e-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide,
5C-9-OXO-1 \fL, 15 (R) -dihydroxy-1 6 (S) -fluor-1 6-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-in-säure-morpholinarnid, 5C-9-OXO-1 \ fL, 15 (R) -dihydroxy-1 6 (S) -fluoro-1 6-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13- in-acid-morpholinarnide,
5C-9-OXO-11ot,15 (R,S) -dihydroxy-16 (S) -fluor-1 6-0 methyl-18,19 f20-trinor-1V-cyclohexyl-prost-S-en-13-in-säure-morpholinamid, und5C-9-OXO-11ot, 15 (R, S) -dihydroxy-16 (S) -fluoro-1 6-0 methyl-18,19 f 20-trinor-1V-cyclohexyl-prost-S-en-13- in-acid-morpholinamid, and
5c-9-Oxo-11ßC, 15 (R,S) -dihydroxy-1 6 (R) -fluor-1 6-methyl-18,19,20-trinor-iT-cyclohexyl-prost-S-en-13-in-säure-morpholinamid. 5c-9-Oxo-11ßC, 15 (R, S) -dihydroxy-1 6 (R) -fluoro-1 6-methyl-18,19,20-trinor-iT-cyclohexyl-prost-S-en-13- in-acid-morpholinamide.
Wo in der vorstehenden Liste von Verbindungen und den Ansprüchen sowie nachfolgend in den Beispielen Bezug auf "Morpholinamid", "Piperidinamid", "Piperazinamid" und "Pyrazolidinamid" genommen wird, sollen diese Bezeichnungen Amidgruppen abdecken, in denen das Stickstoffatom der Amidgruppe ein Ring-Stickstoffatom in der heterozyklischen Gruppe ist. Entsprechend sind diese Gruppen jeweilsWhere in the above list of compounds and the claims as well as in the examples below Reference to "Morpholinamid", "Piperidinamid", "Piperazinamid" and "pyrazolidinamide" is taken, these terms are intended to cover amide groups in which the nitrogen atom of the amide group is a ring nitrogen atom is in the heterocyclic group. These groups are accordingly
-CON0, -CON ), -CON NH und -CON-CON0, -CON), -CON NH and -CON
Älternativnamen für diese Gruppen könnten jeweilsAlternative names for these groups could be
- 44 -- 44 -
N,N-Ethylenoxyethylenamid, N,N-Pentamethylenamid, Ν,Ν-Ethylenaminoethylenamid und Ν,Ν-n-Propylenaminoamid sein.N, N-ethyleneoxyethylene amide, N, N-pentamethylene amide, Ν, Ν-Ethylenaminoethylenamid and Ν, Ν-n-Propylenaminoamid be.
Die Verbindungen der allgemeinen Formel (I) können mittels eines Verfahrens hergestellt werden, das umfasst: The compounds of general formula (I) can be prepared by a process which comprises:
(a) ein reaktives Derivat einer optisch aktiven oder racemischen Verbindung von Formel (II)(a) a reactive derivative of an optically active or racemic compound of formula (II)
XOOHXOOH
R'R '
5| sC-C_C-(CH2)n-R8 ..RS R75 | sC -C_C- (CH 2 ) n -R 8 .. R S R 7
wobeiwhereby
im Falle, dass das Symbol eine Doppelbindungin the event that the icon a double bond
bedeutet^ R' ein Wasserstoffatom ist und R2 und R' , zusammengenommen, eine Oxogruppe bilden;means ^ R 'is a hydrogen atom and R 2 and R', taken together, form an oxo group;
während im Falle, dass das Symbol eine Einfachbindung bedeutet, R'.. Hydroxy oder eine durch ein Ethersauerstoffatom an den Ring gebundene Schutzgruppe ist, R2 Wasserstoff ist, R* Hydroxy, Äcyloxy oder eine durch ein Ethersauerstoffatom an den Ring gebundene Schutzgruppe ist, oder R_ und R' , zusammengenommen, eine Oxogruppe bilden;while in the case where the symbol denotes a single bond, R '.. is hydroxy or a protective group bonded to the ring through an ether oxygen atom, R 2 is hydrogen, R * is hydroxy, acyloxy or a protective group bonded to the ring through an ether oxygen atom, or R_ and R ', taken together, form an oxo group;
einer der beiden Reste R' und R' Hydroxy oder eine durch ein Ethersauerstoffatom gebundene Schutzgruppe und der andere Wasserstoff sind;one of the two radicals R 'and R' is hydroxy or one bonded through an ether oxygen atom Protecting group and the other are hydrogen;
sowie Rg, R7, η und Rg die in Anspruch 1 angegebenen Bedeutungen haben;and Rg, R 7 , η and R g have the meanings given in claim 1;
mit einer Verbindung der Formel (III)with a compound of the formula (III)
H-N (III)H-N (III)
^R"^ R "
zur Reaktion zu bringen, wobei R1 und R" die in Anspruch 1 angegebenen Bedeutungen haben, 30to bring to reaction, where R 1 and R "have the meanings given in claim 1, 30
um auf diese Weise eine optisch aktive oder racemische Verbindung der Formel (IV) zu ergebenso as to give an optically active or racemic compound of formula (IV)
ET/ET /
Rl R l
1C5C-C-C-(CH0) -R5 *> ^ Δ η ο 1 C 5 CCC- (CH 0 ) -R 5 *> ^ Δ η ο
R5 R7 R 5 R 7
wobei R1, R", R'3, R2, R1.,, R'4, R'5, Rg, R7, η und Rg die vorher angegebenen Bedeutungen haben,where R 1 , R ", R ' 3 , R 2 , R 1. ,, R' 4 , R ' 5 , R g , R 7 , η and Rg have the meanings given above,
sowie im Anschluss daran, falls nötig, die Hydroxy-Schutzgruppen zu entfernen; oderand then, if necessary, the hydroxy protective groups to remove; or
(b) eine optisch aktive oder racemische Verbindung der Formel (V)(b) an optically active or racemic compound of the formula (V)
* Ϋ * Ϋ
N.C—C-(CH2) B-R8 Ri R7NC-C- (CH 2 ) B -R 8 R i R 7
BAD ORlGlMAL.BAD ORlGlMAL.
wobeiwhereby
M -C=C- oder -CH=C- bedeutet und X Brom, Chlor oder Jod ist;M is -C = C- or -CH = C- and X is bromine, chlorine or iodine;
Z Hydroxy oder eine durch ein Ethersauerstoffatom an den Ring gebundene Schutzgruppe ist;Z is hydroxy or a protecting group attached to the ring through an ether oxygen atom;
einer der beiden Reste R". und- R1, Hydroxy oder eine durch ein Sauerstoffatom an den Ring gebundene Schutzgruppe und der andere Wasserstoff sind;one of the two radicals R ". and -R 1 is hydroxy or a protective group bonded to the ring through an oxygen atom and the other is hydrogen;
sowie Rg, Rj, η und Rß die in Anspruch 1 angegebe nen Bedeutungen haben,as well as Rg, Rj, η and R ß have the meanings given in claim 1,
mit einem Wittig-Reagenz, das eine - (CH,,) .-CON>^«ι Gruppe enthält, zur Reaktion zu bringen, wobei R1 und R" die in Anspruch 1 angegebenen Bedeutungen haben, um eine optisch aktive oder racemische Verbindung der Formel (VI) zu ergebenwith a Wittig reagent which contains a - (CH ,,).-CON> ^ «ι group to react, where R 1 and R" have the meanings given in claim 1 to an optically active or racemic compound of the formula (VI)
H OHH OH
.R'.R '
CON^ (VI)CON ^ (VI)
in der R! in the R !
R , Zt R R, Z t R
R,, RR ,, R
_, η und R0 die / ο_, η and R 0 the / ο
A' 5" 6 vorstehend angegebenen Bedeutungen haben und die, A ' 5 "6 have the meanings given above and
wenn die 11- und 15-Hydroxygruppen geschützt sind, verestert werden kann, falls gewünscht, um ein 9o^-Acyloxyderivat einer Verbindung der Formel (VI) zu ergeben und dann die Schutzgruppen in den 11- und/oder 15-Positionen, falls vorhanden, sowohl in einer Verbindung der Formel (VI) als auch in deren Acyloxyderivaten zu entfernen, um so eine Verbindung der Formel (I) zu ergeben, in der R_ Hydroxy oder Acyloxy, R2 Wasserstoff und R. Hydroxyif the 11- and 15-hydroxy groups are protected, esterification can be carried out, if desired, to give a 90 ^ acyloxy derivative of a compound of formula (VI) and then the protecting groups in the 11- and / or 15-positions, if present to remove both in a compound of the formula (VI) and in its acyloxy derivatives, so as to give a compound of the formula (I) in which R_ is hydroxy or acyloxy, R 2 is hydrogen and R. is hydroxy
sind, das Symbol eine Einfachbindung bedeutetare, the symbol means a single bond
und R1, R", R4, R5, R,, R7, η sowie Rg die in Anspruch 1 angegebenen Bedeutungen haben; oderand R 1 , R ", R 4 , R 5 , R ,, R 7 , η and R g have the meanings given in claim 1; or
(c) eine optisch aktive oder racemische Verbindung der Formel (VII) zu oxidieren(c) to oxidize an optically active or racemic compound of the formula (VII)
H OHH OH
(VII)(VII)
R" Rf, R " Rf,
>4 I6,> 4 I 6 ,
C5C-C-C-(CH2)n-Rg R5 R7 C 5 CCC- (CH 2 ) n -R g R 5 R 7
wobeiwhereby
Z' eine durch ein Ethersauerstoffatom an den Ring gebundene Schutzgruppe ist;Z 'one through an ether oxygen atom to the ring is attached protecting group;
einer der beiden Reste R". und R"5 eine durch ein Ethersauerstoffatom gebundene Schutzgruppeone of the two radicals R ". and R" 5 is a protective group bonded through an ether oxygen atom
BM3BM3
und der andere Wasserstoff sind;and the other are hydrogen;
sowie R1, R", R,, R„, η und Rß die in Anspruch 1 angegebenen Bedeutungen haben,and R 1 , R ", R ,, R", η and R ß have the meanings given in claim 1,
um eine optisch aktive oder racemische Verbindung von Formel (VIII) zu ergebento give an optically active or racemic compound of formula (VIII)
j ζ 2 η ο (VIII) j ζ 2 η ο (VIII)
R5 R7 R 5 R 7
in der R', R", Z', R" R1', R., R^, η und R0 diein which R ', R ", Z', R" R 1 ', R., R ^, η and R 0 die
4 O O / O4 O O / O
vorher angegebenen Bedeutungen haben, und die ihrerseits der Entfernung der Ether-Schutzgruppen unterzogen wird, um, abhängig von den Reaktionsbedingungen, entweder eine Verbindung der Formel (I) , in der eine Einfachbindung ist, Rhave previously given meanings, and in turn the removal of the ether protective groups is subjected to, depending on the reaction conditions, either a compound of the formula (I) in which there is a single bond, R
————— I————— I
Hydroxy ist, R_ und R,,, zusammengenommen, eine Oxogruppe bilden und R', R", R4, R5, Rg, R7, η und Rg die in Anspruch 1 angegebenen Bedeutungen haben, oder eine Verbindung der Formel (I), inHydroxy, R_ and R ,,, taken together, form an oxo group and R ', R ", R 4 , R 5 , Rg, R 7 , η and Rg have the meanings given in claim 1, or a compound of the formula (I ), in
der eine Doppelbindung ist, R, Wasserstoffwhich is a double bond, R, hydrogen
ist, R„ und Rn,, zusammengenommen, eine Oxogruppe bilden und R', R", R., R5, Rg, R7, η und Rg die in-Anspruch 1 angegebenen Bedeutungen haben, zu ergeben;is, R "and R n " taken together form an oxo group and R ', R ", R., R 5 , Rg, R 7 , η and R g have the meanings given in claim 1, to give;
V/ V V VV / V V V
und/oder eine Verbindung der Formel (I), falls gewünscht, in ein Salz zu überführenand / or to convert a compound of the formula (I), if desired, into a salt
oder eine von einem entsprechenden Salz freie Verbindung von Formel (I) zu erhaltenor to obtain a compound of formula (I) free of a corresponding salt
1010
und/oder eine Verbindung der Formel (I) oder ein entsprechendes Salz, falls gewünscht, in eine andere Verbindung der Formel (I) oder ein Salz davon zu überführenand / or a compound of the formula (I) or a corresponding salt, if desired, into a to convert another compound of the formula (I) or a salt thereof
und/oder eine Mischung von Isomeren, falls gewünscht, in die einzelnen Isomere umzulösen.and / or a mixture of isomers, if desired, to be converted into the individual isomers.
5 Eine durch ein Ethersauerstoffatom an den Ring oder die Seitenkette gebundene Schutzgruppe, d.h. eine Ethergruppe, sollte unter milden Reaktionsbedingungen, z.B. saure Hydrolyse, leicht in eine Hydroxygruppe überführbar sein. Beispiele sind Acetalether, Enolether und SiIylether. Die bevorzugten sind5 One through an ether oxygen atom to the ring or the protective group attached to the side chain, i.e. an ether group, should be used under mild reaction conditions, e.g. acid hydrolysis, easily convertible into a hydroxyl group. Examples are acetal ethers, enol ethers and SiIylether. The preferred ones are
(CH3)3Si0-(CH 3 ) 3 Si0-
O-AikO-Aik
0-0-
CH, I 3 CH, I 3
(CHj,C-Si-O-3 3 ι(CHj, C-Si-O-3 3 ι
CH
3CH
3
wobei G -0~ oder -CH2- ist und Alk eine niedrigere, z.B. Cj_4~Alky!gruppe,darstellt.wherein G ~ -0 or -CH 2 -, and Alk group, represents a lower, for example, Cj_ 4 ~ alky!.
Die Reaktionsbedingungen, die in der Reaktion zwischen einem reaktiven Derivat einer Verbindung von FormelThe reaction conditions used in the reaction between a reactive derivative of a compound of formula
(II) und einem Amin von Formel (III) anzuwenden sind, hängen in besonderem Masse von der Art der eingesetzten Reagentien ab.(II) and an amine of formula (III) are to be used, depend to a particular extent on the type of reagents used.
Ein reaktives Derivat einer Verbindung von Formel (II) kann ein reaktiver Ester, z.B. ein C, g-Alkylester; ein Acy !halogenid, z.B. Chlorid oder Bromid; ein Anhydrid; ein gemischtes Anhydrid; ein Azid; oder ein Salz, z.B. ein Alkali- oder Erdalkalisalz sein. Wenn das reaktive Derivat einer Verbindung der Formel (II) ein reaktiver Ester davon und die Verbindung von FormelA reactive derivative of a compound of formula (II) can be a reactive ester, e.g., a C 1-6 alkyl ester; an acyl halide such as chloride or bromide; a Anhydride; a mixed anhydride; an azide; or a Salt, e.g. an alkali or alkaline earth salt. When the reactive derivative of a compound of formula (II) a reactive ester thereof and the compound of formula
(III) Ammoniak sind, kann die Reaktion unter Anwendung gasförmigen Ammoniaks bei einer Temperatur von ca. 5 bis ca. 4O0C, vorzugsweise von 15 bis 25°C, durchgeführt werden; während die Reaktion, wenn eine Verbindung von Formel (III) ein Amin ist, vorzugsweise in einem inerten Lösungsmittel, z.B. Benzol, Toluol, bei Temperaturen von Raumtemperatur bis Rückfluss temperatur durchgeführt werden kann.(III) are ammonia, the reaction may be performed using gaseous ammonia at a temperature of about 5 to about 4O 0 C, preferably from 15 to 25 ° C, are carried out; while the reaction, when a compound of formula (III) is an amine, can preferably be carried out in an inert solvent, for example benzene, toluene, at temperatures from room temperature to reflux temperature.
Wenn ein reaktives Derivat einer Verbindung von Formel (II) ein Acy!halogenid, z.B. das Acylchlorid, ist, kann die Reaktion mit Ammoniak oder einem geeigneten Amin der Formel (III) in einem inerten Lösungsmittel, z.B. Benzol oder Toluol, oder in einem wässrigen Lösungsmittel, in diesem Fall in Gegenwart einer anorganischen Base, z.B. NaHCO3 oder Na3CO3, als Säureakzeptor,If a reactive derivative of a compound of formula (II) is an acyl halide, for example acyl chloride, the reaction with ammonia or a suitable amine of formula (III) can be carried out in an inert solvent, for example benzene or toluene, or in an aqueous Solvent, in this case in the presence of an inorganic base, e.g. NaHCO 3 or Na 3 CO 3 , as an acid acceptor,
C I .-C I .-
durchgeführt werden.be performed.
Wenn in dem Lactol von Formel (V) M -C=C- oder CH=CX-ist, worin X Brom oder Jod ist, kann die Wittig-Reaktion unter Einsatz von ca. 1 bis 4 Mol, vorzugsweise 2 Mol, Wittig-Reagenz pro Mol Lactol durchgeführt werden und von ca. 10 bis 20 Minuten bis einige Stunden dauern, abhängig von der Temperatur und der Konzentration der Reaktionsmischung und des eingesetztten Wittig-Reagenz. Wenn in dem Lactol von Formel (V) M -CH=CX-, worin X Chlor ist, darstellt, ist es notwenig, unter Einsatz von z.B. 1,5 bis 2,5 Mol Wittig-Reagenz pro Mol Lactol die Reaktionszeit auf bis zu 10 Stunden zu verlängern, oder es muss, falls kürzere Reaktionszeiten gewünscht werden, ein grosser Überschuss an Wittig-Reagenz angewandt werden: für Reaktionszeiten von ca. 30 Minuten mindestens 5 Mol Wittig-Reagenz pro Mol Lactol. Deshalb ist X im Falle, dass in dem Lactol von Formel (V) M -CH=CX- ist, vorzugsweise Brom oder Jod.When in the lactol of formula (V) M is -C = C- or CH = CX-, wherein X is bromine or iodine, the Wittig reaction can be carried out using about 1 to 4 moles, preferably 2 moles, Wittig reagent per mole of lactol can be carried out and from about 10 to 20 minutes to a few hours last, depending on the temperature and the concentration of the reaction mixture and the one used Wittig reagent. If in the lactol of formula (V) M is -CH = CX-, wherein X is chlorine, it is necessary using, for example, 1.5 to 2.5 moles of Wittig reagent per mole of lactol, the reaction time is up to 10 hours longer, or if shorter If reaction times are required, a large excess of Wittig reagent should be used: for reaction times 30 minutes at least 5 moles of Wittig reagent per mole of lactol. Therefore, X is in the case that in the lactol of formula (V) M is -CH = CX-, preferably bromine or iodine.
Wenn in dem Lactol von Formel (V) M -CH=CX-, worin X Brom, Chlor oder Jod ist, darstellt, können das an das Kohlenstoffatom in 13-Stellung gebundene Wasserstoffatom und das an das Kohlenstoffatom in 14-Stellung gebundene Halogenatom entweder in der transStellung, d.h. geometrische trans-Isomere, oder in der cis-Stellung, d.h. geometrische cis-Isomere, vorliegen. Vorzugsweise sind sie in der trans-Steilung.If in the lactol of formula (V) M represents -CH = CX-, wherein X is bromine, chlorine or iodine, this can be an the carbon atom in the 13-position bonded hydrogen atom and the halogen atom bonded to the carbon atom in the 14-position is either in the trans position, i.e., geometric trans isomers, or in the cis position, i.e. geometric cis isomers. Preferably they are in the trans position.
Die Wittig-Reaktion wird unter Anwendung von für diese Art von Reaktion üblichen Bedingungen vorgenommen,The Wittig reaction is carried out using the usual conditions for this type of reaction,
L-Jj^0-/ tLJ-i-1*--!?"-^--!? Λ t L-Jj ^ 0- / tLJ-i- 1 * - !? "- ^ - !? Λ t
d.h. in einem organischen Lösungsmittel, z.B. Diethylether, Hexan, Dimethylsulfoxid, Tetrahydrofuran, Dimethylformamid oder Hexamethylphosphoramid, in Gegenwart einer Base, vorzugsweise Natriumhydrid und Kaliumt-butoxid, bei Temperaturen von ca. O0C bis zur Rückflusstemperatur der Reaktionsmischung, vorzugsweise bei Raumtemperatur oder darunter. .ie in an organic solvent, for example diethyl ether, hexane, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, in the presence of a base, preferably sodium hydride and potassium t-butoxide, at temperatures from about 0 ° C. to the reflux temperature of the reaction mixture, preferably at room temperature or below . .
Die Bezeichnung "Wittig-Reagenz" schliesst Verbindungen der allgemeinen FormelThe term "Wittig reagent" includes compounds the general formula
(Q)3P-(CH2J4-CON(Q) 3 P- (CH 2 J 4 -CON
ein, wobei Q Aryl, d.h. Phenyl, oder C, g-Alkyl, d.h. Ethyl, darstellt; Hai Halogen, z.B. Brom oder Chlor, ist und R1 und R" die vorstehend angegebenen Bedeutungen haben.an, where Q is aryl, ie phenyl, or C1-6 alkyl, ie ethyl; Hal is halogen, for example bromine or chlorine, and R 1 and R ″ have the meanings given above.
Die Herstellung des Wittig-Reagenz wird im Detail von Trippett, Quart. Rev.: (1963) XVII, Nr. 4406, diskutiert. The preparation of the Wittig reagent is described in detail by Trippett, Quart. Rev .: (1963) XVII, No. 4406, discussed.
Wenn in dem Lactol von Formel (V) M -CH=CX-, worin X die vorstehend angegebene Bedeutung hat, darstellt, findet die Dehydrohalogenierung während der Reaktion mit dem Wittig-Reagenz genauso leicht statt, wenn das an das Kohlenstoffatom in der 13-Stellung gebundene Wasserstoffatom und das an das Kohlenstoffatom in der 14-Stellung gebundene Halogenatom in der trans-StellungWhen in the lactol of formula (V) M is -CH = CX-, wherein X is as defined above, the dehydrohalogenation takes place just as easily during the reaction with the Wittig reagent if that hydrogen atom bonded to the carbon atom in the 13-position and the hydrogen atom bonded to the carbon atom in the 14-position bound halogen atom in the trans position
yj \J <J C «-» C- I yj \ J <J C «-» C- I
vorliegen/ wie wenn sie in der cis-Stellung sind. Die auf Wunsch vorgenommene Acylierung der 9oL-Hydroxygruppe in einer Verbindung der Formel (VI) zur Herstellung des entsprechenden 9eC-Acyloxyderivats kann auf übliche Weise durchgeführt werden, z.B. durch Behandlung mit einem Anhydrid oder einem Halogenid, z.B. einem Chlorid einer Carboxylsäure ±n Gegenwart einer Base.present / as if they are in the cis position. The process conducted on the desired acylation of 9oL-hydroxy group in a compound of formula (VI) to produce the corresponding 9EC-Acyloxyderivats can be carried out in a customary manner, for example by treatment with an anhydride or a halide such as a chloride of a carboxylic acid ± n the presence of a Base.
Die Oxidation der 9^-Hydroxygruppe in einer Verbindung der Formel (VII) zur Herstellung des entsprechenden 9-Oxoderivats kann z.B. mittels des Jones-Reagenz, (G.I. Poos et al., Am. Soc. 75. r 422, 1953) oder des Moffat-Reagenz (Am. Soc. 8_7, 5661, 1965) durchgeführt werden.The oxidation of the 9 ^ hydroxy group in a compound of the formula (VII) for the preparation of the corresponding 9-oxo derivative can e.g. by means of the Jones reagent, (G.I. Poos et al., Am. Soc. 75. r 422, 1953) or des Moffat reagent (Am. Soc. 8_7, 5661, 1965) will.
Die Entfernung der bekannten, durch ein Ethersauerstoffatom an den Ring bzw. an die Seitenkette gebundenen Schutzgruppen kann, falls erforderlich, z.B.The removal of the known, through an ether oxygen atom protecting groups attached to the ring or to the side chain may, if necessary, e.g.
in einer Verbindung der Formel (IV) oder in einer Verbindung der Formel (VI) oder in deren 9i(.-Acyloxyderivaten, unter Bedingungen einer milden sauren Hydrolyse durchgeführt werden, z.B. mit einer Mono- oder PoIycarboxylsäure, z.B. Ameisen-, Essig-, Oxal-, Zitronen- und Weinsäure, sowie in einem Lösungsmittel, das z.B. Wasser, Aceton, Tetrahydrofuran, Dimethoxyethan und niedrigaliphatische Alkohole sowie eine Mischung davon sein kann, oder mit einer Sulfonsäure, z.B. p-Toluolsulfonsäure, in einem Lösungsmittel, wie einem niedrigaliphatischen Alkohol, z.B. in Methanol oder Ethanol, oder mit einem Polystyrolsulfonsäureharz.in a compound of the formula (IV) or in a compound of the formula (VI) or in their 9i (.- acyloxy derivatives, be carried out under conditions of mild acid hydrolysis, e.g. with a mono- or polycarboxylic acid, e.g. formic, acetic, oxalic, citric and tartaric acid, as well as in a solvent which e.g. Water, acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols and a mixture thereof or with a sulfonic acid, e.g., p-toluenesulfonic acid, in a solvent such as a lower aliphatic alcohol, e.g. in methanol or ethanol, or with a polystyrene sulfonic acid resin.
BAD OBlGJMALBATHROOM OBlGJMAL
Zum Beispiel wird eine Lösung von 0,1 bis 0,25N PoIycarboxylsäure in Wasser, z.B. Oxal- oder Zitronensäure, in Gegenwart eines geeigneten niedrigsiedenden Co-Lösungsmittels, das mit Wasser mischbar ist und am Ende der Reaktion leicht im Vakuum entfernt werden kann, angewandt. Wie früher erörtert, kann die Entfernung der Schutzgruppen in Verbindungen der Formel (VIII), abhängig von den Reaktionsbedingungen, entweder eine Verbindung von Formel (I), in der das Symbol ------ eine Einfachbindung ist, R1 Hydroxy ist und R2 und R3 zusammen eine Oxogruppe bilden, oderFor example, a solution of 0.1 to 0.25N polycarboxylic acid in water, for example oxalic or citric acid, is used in the presence of a suitable low-boiling co-solvent which is miscible with water and which can easily be removed in vacuo at the end of the reaction . As discussed earlier, depending on the reaction conditions, the removal of the protecting groups in compounds of formula (VIII) can either be a compound of formula (I) in which the symbol ------ is a single bond, R 1 is hydroxy and R2 and R 3 together form an oxo group, or
eine entsprechende Verbindung ergeben, in der result in a corresponding connection in which
eine Doppelbindung ist, R1 Wasserstoff ist und R2 und Rß zusammen eine Oxogruppe bilden. Die erste Verbindung kann als das einzige Reaktionsprodukt hergestellt werden, indem die Reaktion zwischen 15 uns 4O0C gehalten wird, während bei höheren Temperaturen, z.B. am Rückfluss über mehrere Stunden, nur die zweite erhalten wird.is a double bond, R 1 is hydrogen and R2 and Rß together form an oxo group. The first compound can be prepared as the only reaction product by us is held 4O 0 C, the reaction between 15 while only the second will be obtained at higher temperatures, for example at reflux for several hours.
Die Trennung einer Mischung von Isomeren in die einzelnen Isomere kann mittels konventioneller Verfahren vorgenommen werden. Beispielsweise kann die Trennung einer Mischung von Epimeren, z.B. 15(S)- und 15(R)-Epimere, mittels fraktionierter Kristallisation aus einem geeigneten Lösungsmittel oder mittels Chromatografie, entweder Säulenchromatografie oder Hochdruck-Flüssig-Chromatografie, durchgeführt werden.Separation of a mixture of isomers into the individual isomers can be carried out by conventional methods be made. For example, the separation of a mixture of epimers, e.g. 15 (S) - and 15 (R) -epimers, by means of fractional crystallization from a suitable solvent or by means of chromatography, either column chromatography or high pressure liquid chromatography, be performed.
Das reaktive Derivat der Säuren von Formel (II) sowie die Lactole von Formel (V) sind bekannte Verbindungen,The reactive derivative of the acids of formula (II) and the lactols of formula (V) are known compounds,
wie z.B. beschrieben in der GB-OS 2 009 145A der Anmelderin oder in der GB-PS 1 483 880 der Anmelderin, oder sie können durch bekannte Verfahren aus bekannten Verbindungen, z.B. aus den in den oben genannten britischen Patenten beschriebenen Verbindungen, erhalten werden.as described, for example, in the applicant's GB-OS 2 009 145A or in GB-PS 1 483 880 of the applicant, or they can be made by known methods from known Compounds such as those described in the UK patents cited above will.
Beispielsweise können Verbindungen mit Formel (V), worin M -C=C- ist, durch Dehydrohalogenierung der entsprechenden 14-Halogenderivate hergestellt werden. Die Dehydrohalogenierung kann in einem aprotischen Lösungsmittel, vorzugsweise aus Dimethylsulfoxid, Dimethylformamid und Hexamethylphosphoramid ausgewählt, durch Behandlung mit einer Base, vorzugsweise aus Kalium-t-butylat, einem Alkalimetallamid und dem CH^-SO-CH9 ~ -Anion ausgewählt, durchgeführt werden.For example, compounds of formula (V) in which M is -C = C- can be prepared by dehydrohalogenation of the corresponding 14-halogen derivatives. The dehydrohalogenation can be carried out in an aprotic solvent, preferably selected from dimethyl sulfoxide, dimethylformamide and hexamethylphosphoramide, by treatment with a base, preferably selected from potassium t-butoxide, an alkali metal amide and the CH ^ -SO-CH 9 ~ -anion.
Unter den vorstehend beschriebenen Reaktions-Zwischenprodukten ist die Verbindung von Formel (IV) neu und stellt ein weiteres Ziel der vorliegenden Erfindung dar.Among the reaction intermediates described above, the compound of formula (IV) is new and represents another object of the present invention.
Die Verbindungen von Formel (I) sind durch die allgemeine Formel der britischen Patentanmeldung Nr. 2 009 145A der Anmelderin abgedeckt, aber keine von ihnen ist darin spezifisch beschrieben.The compounds of formula (I) are represented by the general formula of British Patent Application No. 2 009 145A of the applicant, but none of them are specifically described therein.
Die Verbindungen von Formel (I) können bei Säugetieren unter all den Bedingungen angewandt werden, bei denen natürliche Prostaglandine indiziert sind. Sie werden auf üblichen Wegen verabreicht, z.B. oral,The compounds of formula (I) can be used in mammals under all the conditions at which natural prostaglandins are indicated. They are given in the usual ways, e.g. orally,
3AD GRfGiMAL3AD GRfGiMAL
parenteral, rektal oder mittels Aerosol, mit den Vorteilen einer überlegenen Resistenz gegen das Enzym 15-Prostaglandin-dihydrogenase, das natürliche Prostaglandine bekanntermassen rasch inaktiviert. Die neuen Verbindungen sind auch mit einer langer andauernden therapeutischen Aktivität als natürliche Prostaglandine ausgestattet, wenn sie auf üblichen Wegen und besonders oral verabreicht werden. Beispielsweise zeigen die Verbindungen von Formel (I), und insbesondere die 9 ck-Hydroxyderivate, Oxytocin-Wirkung, d.h. sie können anstelle von Oxytocin angewandt werden, um Wehen zu induzieren oder einen toten Fötus bei schwangeren Lebewesen zu abortieren, sowohl bei Mensch als auch bei Tier. Bei dieser Anwendung werden die Verbindungen entweder durch intravenöse Infusion mit einer Dosis von annähernd 0,01 μg/kg/min bis zum Ende der Wehen oder oral mit einer einzigen oder mehrfachen Dosis von ca. 0,1 mg bis ca. 5 mg/Dosis verabreicht. parenterally, rectally or by aerosol, with the advantages of superior resistance to the enzyme 15-prostaglandin dihydrogenase, the natural prostaglandin known to be rapidly inactivated. The new connections are also with a long lasting one therapeutic activity endowed as natural prostaglandins when in usual ways and especially administered orally. For example, show the compounds of formula (I), and in particular the 9 ck-hydroxy derivatives, oxytocin effect, i. they can be used in place of oxytocin to induce labor or to treat a dead fetus abort pregnant animals, both humans and animals. In this application, the Compounds either by intravenous infusion at a dose of approximately 0.01 μg / kg / min up to Administered at the end of labor or orally at a single or multiple dose of about 0.1 mg to about 5 mg / dose.
Des weiteren zeigen die Verbindungen von Formel (I), insbesondere die 9öC-Hydroxyderivate, auch luteolytische Aktivität und können deshalb bei der Fruchtbarkeitskontrolle angewandt werden, mit dem Vorteil einer beträchtlich reduzierten Kapazität zur Weichmuskelstimulierung. Deshalb sind die Nebeneffekte natürlicher Prostaglandine, wie Erbrechen und Diarrhöe, nicht gegeben. Die luteolytische Aktivität der neuen Verbindungen wurde beispielsweise bei Ratten ermittelt.Furthermore, the compounds of formula (I) show especially the 9oC-hydroxy derivatives, also luteolytic ones Activity and can therefore be used in fertility control with the advantage of a considerably reduced capacity for soft muscle stimulation. Therefore the side effects are more natural Prostaglandins such as vomiting and diarrhea not given. The luteolytic activity of the new compounds was found in rats, for example.
In diesem Test wurde, wie in Tabelle 1 gezeigt, ein Vergleich zwischen der Aktivität einer Verbindung derIn this test, as shown in Table 1, a comparison was made between the activity of a compound of
Erfindung (R = NH2) und derjenigen von zwei bisher angewandten Verbindungen entweder nach oraler (p.os.) oder subkutaner (s.c.) Verabreichung gezogen.Invention (R = NH 2 ) and that of two compounds previously used either after oral (p.os.) or subcutaneous (sc) administration.
/~-~^\==S~^S^ COR
OHOH
/ ~ - ~ ^ \ == S ~ ^ S ^ COR
OH
OCH3
OHNH 2
OCH 3
OH
3
42.5
3
4th
90
15040
90
150
EDc;n stellt die minimal wirksame Dosis dar, die bei 50 % der unter Behandlung stehenden Rattenpopulation luteolytische Aktivität induzieren kann. ED c; n represents the minimally effective dose which can induce luteolytic activity in 50% of the rat population under treatment.
Tabelle 1 zeigt, dass das Amidderivat das wirksamste bezüglich einer pharmakologxschen Stimulierung ist. Obwohl bei s.c.-Verabreichung die ED5Q-Werte sehrTable 1 shows that the amide derivative is the most effective in terms of pharmacological stimulation. Although with sc administration the ED 5Q values are very high
nahe beieinander liegen? ist es offensichtlich, dass insbesondere das Ämidderivat bei oraler Verabreichung das aktivste ist. Deshalb zeigt das Amid eine bessere Magen-Darm-Absorption, dies entspricht den unterschiedliehen hydrophilen Eigenschaften, die die an den C1-Kohlenstoff gebundenen chemischen Gruppen der Prostaglandinderivate besitzen.lie close together? it is evident that the amide derivative in particular is the most active when administered orally. The amide therefore shows better gastrointestinal absorption, which corresponds to the different hydrophilic properties which the chemical groups of the prostaglandin derivatives bound to the C 1 carbon have.
Eine andere nutzbringende pharmakologische Eigenschaft der Verbindungen von Formel (I), insbesondere der 9-Oxoderivate, ist deren antiulcerogene Aktivität. Tatsächlich sind sie anwendbar, um exzessive Magensekretion bei Säugetieren zu vermindern und zu kontrollieren. So reduzieren oder eliminieren sie die Bildung von Magen-Darm-Geschwüren und können gleichzeitig den Heilungsablauf eines jeden Geschwürs, das bereits im Magen-Darm-Trakt vorhanden ist, beschleunigen. Die Verbindungen von Formel (I) sind deshalb ebenfalls anwendbar, um die unerwünschten Magen-Darm-Nebeneffekte, die von systematischer Verabreichung von Anti-Entzündungs-Prostaglandin-Synthetase-Inhibitoren herrühren, zu verringern, und können deshalb zu diesem Zwecke in Assoziation mit ihnen angextfandt werden. Die Verbindungen von Formel (I) können gemäss dieser Zweckbestimmungen oral, parenteral, d.h. durch intravenöse Injektion oder Infusion, oder durch intramuskuläre Injektion, durch Inhalation oder rektal verabreicht werden. Bei oraler Verabreichung können die Verbindungen der Erfindung mit-einer Dosierung, die von ca= 1 mg bis ca. 10 mg, vorzugsweise 5 mg, einmal oder dreimal täglich reicht, angewandt werden. Bei intravenöser Infusion variiertAnother beneficial pharmacological property of the compounds of formula (I), particularly the 9-oxo derivatives, is their antiulcerogenic activity. Indeed are they applicable to reduce and control excessive gastric secretion in mammals. In this way they reduce or eliminate the formation of gastrointestinal ulcers and at the same time facilitate the healing process of any ulcer already present in the gastrointestinal tract. The connections of formula (I) can therefore also be used to reduce the undesirable gastrointestinal side effects, that of systematic administration of anti-inflammatory prostaglandin synthetase inhibitors originate from, and can therefore be found in association with them for this purpose. The connections of formula (I) can according to these purposes orally, parenterally, i.e. by intravenous injection or infusion, or by intramuscular injection, inhalation or rectally. With oral The compounds of the invention can be administered with a dosage ranging from approx. 1 mg to approx. 10 mg, preferably 5 mg once or three times a day is sufficient. Varies with intravenous infusion
die Dosierung von annähernd 0,01 μg bis 0,05 iig pro kg Körpergewicht pro Minute. Die gesamte tägliche Dosis, sowohl bei Injektion als auch bei Infusion, liegt in der Grössenordnung von 0,1 bis 20 mg. Bei den vorgenannten Behandlungsbedingungen hängt natürlich der exakte Behandlungsgrad von der Fallgeschichte des zu behandelnden Patienten ab. .the dosage of approximately 0.01 to 0.05 ug iig per kg body weight per minute. The total daily dose, both for injection and for infusion, is on the order of 0.1 to 20 mg. With the aforementioned treatment conditions, the exact degree of treatment naturally depends on the case history of the patient to be treated. .
Die Toxizität der Verbindungen von Formel (I) wurde als ziemlich vernachlässigbar herausgefunden, sie können daher sicher zur Therapie herangezogen werden. Die Ermittlung der Toxizität (als orientierende akute Toxizität, d.h. LD50 wurde z.B. wie folgt vorgenommen. Mäuse, die 9 Stunden unter Futterentzug standen, wurden oral bei einmaliger Verabreichung wachsender Dosen behandelt, sodann untergebracht und normal gefüttert; der LD-Q-Wert wurde am 7. Tage nach der Behandlung ermittelt. Zum Beisoiel wurde der LD5Q-Wert der Verbindung 5c-9o£, 1106,15 (R) -Trihydroxy-1 6 (S) fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in- säureamid mit >3.000 mg/kg Körpergewicht gefunden. Die Verbindungen von Formel (IV) sind mit denselben pharmakologischen Aktivitäten der Verbindungen von Formel (I) ausgestattet und werden Mensch oder Tier zu denselben therapeutischen Zwecken verabreicht, bei denselben Dosierungsgraden und über dieselben Wege der Verabreichung.The toxicity of the compounds of formula (I) has been found to be quite negligible, so they can be safely used in therapy. The determination of the toxicity (as indicative acute toxicity, ie LD 50 was carried out, for example, as follows. Mice which had been deprived of food for 9 hours were treated orally with a single administration of increasing doses, then housed and fed normally; the LD-Q value was determined on the 7th day after the treatment. For example, the LD 5Q value of the compound 5c-90 £, 1106.15 (R) -Trihydroxy-16 (S) fluoro-18,19,20-trinor-17- cyclohexyl-prost-5-en-13-one-acid amide found with> 3,000 mg / kg body weight The compounds of formula (IV) are endowed with the same pharmacological activities of the compounds of formula (I) and are therapeutic for humans or animals Administered for purposes, at the same dosage levels and by the same routes of administration.
Die pharmazeutischen Zusammensetzungen der Erfindung werden üblicherweise nach konventionellen Verfahren hergestellt und in einer pharmazeutisch geeigneten FormThe pharmaceutical compositions of the invention are usually made by conventional methods and in a pharmaceutically acceptable form
verabreicht. Beispielsweise können die festen oralen Formen, zusammen mit der aktiven Verbindung, Verdünnungsmittel t z.Bο Lactose, Dextrose, Saccharose, Zellulose, Mais- . · und Kartoffelstärke? Gleitmittel, ZoB. Silika, Talk, Stearinsäure, Magnesium- oder Kalziumstearat und/oder Polyethylenglykole; Bindemittel, ζ.Bο Stärken, Gummiarabikum, .Gelatine, Methylzellulose, Carboxymethylzellulose, Polyvinylpyrrolidon; disaggregierende Mittel, z.B. eine Stärke, Alginsäure, Alginate, Natrium-Stärkeglykolat; Schäumung smischungen; Farbstoffe; Süssungsmittel; Benetzungsmittel, z.B. Lecithin, Polysorbate, Laurylsulfate; sowie im allgemeinen nicht-toxische und pharmakologisch inaktive, in pharmazeutischen Formulierungen einge-administered. For example, the solid oral forms, together with the active compound, diluents t e.g. lactose, dextrose, sucrose, cellulose, corn. · And potato starch? Lubricant, ZoB. Silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; Binders, ζ.Bο starches, gum arabic, gelatine, methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; Foaming mixtures; Dyes; Sweeteners; Wetting agents, for example lecithin, polysorbates, lauryl sulfates; as well as generally non-toxic and pharmacologically inactive, included in pharmaceutical formulations
«
setzte Substanzen enthalten. Genannte pharmazeutische Präparationen können auf bekannte Weise gefertigt werden,
z.B. mittels Misch-, Granulier-, Tablettier-, Zuckerbeschichtungs- oder Filmbeschichtungsverfahren.
Die flüssigen Dispersionen zur oralen Verabreichung können beispielsweise ein Sirup, Emulsionen und Suspensionen
sein. Die Sirupformen können als Träger, z.B. Saccharose oder Saccharose mit Glycerin und/oder Mannitol
und/oder Sorbitol enthalten; insbesondere kann ein Diabetikern zu verabreichender Sirup als Trägersubstanzen
nur Produkte enthalten, die nicht zu Glukose metabolisieren
können oder nur in sehr kleiner Menge zu Glukose metabolisierbar sind, wie Sorbitol.«
put substances contained. The pharmaceutical preparations mentioned can be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating or film-coating processes. The liquid dispersions for oral administration can be, for example, a syrup, emulsions and suspensions. The syrup forms can contain, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol as a carrier; In particular, a syrup to be administered to diabetics can only contain products as carrier substances which cannot metabolize to glucose or which can only be metabolized to glucose in very small amounts, such as sorbitol.
Die Suspensionen und Emulsionen können als Träger beispielsweise einen natürlichen Gummi, Agar, Natriumalginat, Pectin, Methylzellulose, CarboxymethylzelluloseThe suspensions and emulsions can be used as a carrier, for example a natural gum, agar, sodium alginate, Pectin, methyl cellulose, carboxymethyl cellulose
oder Polyvinylalkohol enthalten. Die Suspensionen oder Lösungen für intramuskuläre Injektionen können zusammen mit der aktiven Verbindung einen pharmazeutisch zulässigen Träger, z.B. steriles Wasser, Olivenöl, Ethyloleat, Glykole, wie Propylenglykol, und, falls gewünscht, eine geeignete Menge an Lidocainhydrochlorid enthalten. Die Lösungen für intravenöse Injektionen oder Infusionen können als Träger beispielsweise steriles Wasser enthalten oder liegen vorzugsweise in Form von sterilen wässrigen isotonischen Kochsalzlösungen vor.or polyvinyl alcohol. The suspensions or solutions for intramuscular injections can be together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, Ethyl oleate, glycols such as propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride contain. The solutions for intravenous injections or infusions can be used as carriers for example contain sterile water or are preferably in the form of sterile aqueous isotonic Saline solutions.
Die Suppositorien können zusammen mit der aktiven Verbindung einen pharmazeutisch zulässigen Träger, z.B. Kakaobutter, Polyethylenglykol, ein Polyoxyethylen-sorbitol-karbonsäureester-Tensid oder Lecithin, enthalten.The suppositories can, together with the active compound, be a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitol carboxylic acid ester surfactant or lecithin.
Wie vorstehend festgestellt, kann ein weiterer Weg der Verabreichung die Inhalation sein. Für eine solche Anwendung können passende Zusammensetzungen eine Suspension oder Lösung des aktiven Bestandteils, vorzugsweise in Form eines Salzes, wie das Natriumsalz, in Wasser, zur Verabreichung mittels eines konventionellen Nebelgerätes umfassen. Alternativ dazu, können die Zusammensetzungen eine Suspension oder Lösung des aktiven Bestandteils in einem konventionellen verflüssigten Treibmittel, wie Dichlordifluormethan oder Dichlortetr-afluorethan, beinhalten, um aus einem Druckbehälter verabreicht zu werden, d.h. einem Aerosol-Dispenser.As noted above, another route of administration may be by inhalation. For such a Suitable compositions can use a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt, in water for administration by means of a conventional one Include fogger. Alternatively, the compositions can be a suspension or solution of the active Component in a conventional liquefied propellant such as dichlorodifluoromethane or dichlorotetr-afluoroethane, to be administered from a pressurized container, i.e. an aerosol dispenser.
Wenn das Medikament in dem Treibmittel nicht löslichIf the drug is not soluble in the propellant
ist, kann es notwendig sein, ein Co-Lösungsmittel, wie Ethanol, Dipropylenglykol, Isopropylmyristat und/oder ein oberflächenaktives Mittel der Zusammensetzung zuzufügen, um das Medikament in dem Treibmitte!medium zu verteilen. Solche Tenside können jegliche für diesen Zweck im allgemeinen angewandte Mittel sein, wie nicht-ionische Oberflächenagentien, ZoB. Lecithin. Andere geeignete pharmazeutische Formen können beispielsweise Pulver sein. Pulver können mittels einer geeigneten Einblasvorrichtung verabreicht werden, in diesem Fall können die Feinpartikel-Pulver des aktiven Bestandteils mit einem Verdünnungsmaterial, wie Lactose, vermischt werden.it may be necessary to use a co-solvent, such as ethanol, dipropylene glycol, isopropyl myristate and / or adding a surfactant to the composition to keep the medicament in the propellant medium to distribute. Such surfactants can be any generally used for this purpose Be means, such as non-ionic surface agents, ZoB. Lecithin. Other suitable pharmaceutical forms can for example be powder. Powder can means a suitable injection device, in which case the fine particle powder of the active ingredient are mixed with a diluent material such as lactose.
Die vorliegende Erfindung wird nun anhand der folgenden Beispiele erläutert, soll jedoch nicht darauf beschränkt sein.The present invention will now be explained with reference to the following examples, but is not intended to be restricted thereto be.
Die Abkürzungen THP, DIOX, DMSO, THF, DMF, DIBA, DIBA, E^o0 sowie EtOH beziehen sich auf Tetrahydropyranyl, Dioxanyl, Dimethylsulfoxid, Tetrahydrofuran, Dimethylformamid, Diisobutylaluminiumhydrid, Diethylether bzw. Ethy!alkohol. Alle Temperaturen sind in 0C ausgedrückt, die Messungen der optischen Drehung beziehen sich auf 200C und eine Konzentration von 1 Gew.% der Verbindung in dem spezifischen Lösungsmittel.The abbreviations THP, DIOX, DMSO, THF, DMF, DIBA, DIBA, E ^ o0 and EtOH refer to tetrahydropyranyl, dioxanyl, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diisobutylaluminum hydride, diethyl ether or ethyl alcohol. All temperatures are expressed in ° C., the measurements of the optical rotation relate to 20 ° C. and a concentration of 1% by weight of the compound in the specific solvent.
Eine Lösung von 5c-9cL, 11ol,15 (S) -Trihydroxy-18,19,20-trinor-1V-cyclohexyl-prost-S-en-i3-in-säuremethylester (0,5 g) in Methylalkohol (10 ml) wurde mit Kältesole gekühlt und trockenes NH3 in diese Lösung bis zur Sättigung geblubbert.A solution of 5c-9cL, 11ol, 15 (S) -trihydroxy-18,19,20-trinor-1V-cyclohexyl-prost-S-en-i3-yn-acid methyl ester (0.5 g) in methyl alcohol (10 ml ) was cooled with cold brine and dry NH 3 was bubbled into this solution until saturation.
Das Reaktionsgefäss wurde verschlossen und die Reaktionsmischung bei Raumtemperatur 24 Stunden lang gehalten; dann wurde das NH3 mittels N2 abgezogen und der Alkohol entfernt.The reaction vessel was closed and the reaction mixture was kept at room temperature for 24 hours; then the NH 3 was stripped off by means of N 2 and the alcohol removed.
Das Rohprodukt wurde mittels präparativer Chromatografie an Silikagel unter Einsatz von Hexan/Ethylacetat = 1:1 als Eluierungsmittel gereinigt. 0,42 g reines 5c-9oC, 1 ieM 5 (S)-Trihydroxy-18,1 9,20-trinor-17-cyclohexyvl-prost-5-en-13-in-säureamid wurden gewonnen.The crude product was purified by preparative chromatography on silica gel using hexane / ethyl acetate = 1: 1 as the eluent. 0.42 g of pure 5c-9oC, 1 ieM 5 (S) -trihydroxy-18,19,20-trinor-17-cyclohexy v 1-prost-5-en-13-yn acid amide were obtained.
/oC /_ = +34,8; /oi/^cc = +86,1 (C = 1 EtOH) / oC / _ = +34.8; / oi / ^ cc = +86.1 (C = 1 EtOH)
— — Jj — —- - yy - -
Durch analoges Vorgehen wurden die folgenden Verbin dungen erhalten:The following connections were obtained by an analogous procedure:
5c-9c6,11eC, 15 (S) -Trihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-in-säureamid /^.7D = +19,5;5c-9c6,11eC, 15 (S) -trihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn-acid amide /^.7 D = +19.5;
5c-9/,11*C, 15 (S)-Trihydroxy-20-nor-19-cyclopentylpros.t-5-en-13-in-säureamid /^i7n = +19,7; 305c-9 /, 11 * C, 15 (S) -Trihydroxy-20-nor-19-cyclopentylpros.t-5-en-13-yn-acid amide / ^ 17 n = +19.7; 30th
5c-9ct, 11<£, 15 (R) -Trihydroxy-16 (S) -f luor-20-nor-1 9-cyclohexyl-prost-S-en-IS-in-säureamid Zc6?D = +8,8;5c-9ct, 11 <£, 15 (R) -Trihydroxy-16 (S) -f luor-20-nor-1 9-cyclohexyl-prost-S-en-IS-yn-acid amide Zc6? D = +8.8;
5c-9a,11a,μ5(R,S)-Trihydroxy-16(S)-fluor - 20-nor-19-cyclohexyl-prost-5-en-i3-in-säureamid [a]_ = +7,2;5c-9a, 11a, µ5 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yne acid amide [a] _ = +7.2;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexyl-prost-S-en-IS-in-säureamid [a3D = + 13,9;5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexyl-prost-S-en-IS-yne-acid amide [a3 D = + 13.9;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säureamid [α]β = +24,7;5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid amide [α] β = +24.7;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor - 19,20-dinor-IS-cyclohexyl-prost-S-en-IS-in-säureamid [α]_ = +11,2;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-19,20-dinor-IS-cyclohexyl-prost-S-en-IS-yn-acid amide [α] _ = +11.2;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor - 20-nor-19-15 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro - 20-nor-19-15
cyclohexyl-prost-S-en-IS-in-säureamid [α]- = +38,7;cyclohexyl-prost-S-en-IS-yne-acid amide [α] - = +38.7;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-i7-cyclopentyl-prost-5-en-13-in-säureamid [a.]D = +31 ,0;5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid amide [a.] D = +31.0;
5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluor -18,19,20-0 trinor-17-cyclohexyl-prost-5-en-13-in-säureamid [a]D = +17,4? [Ct]365 = +66,9 (C = 1 EtOH);5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro -18,19,20-0 trinor-17-cyclohexyl-prost-5-en-13-yn-acid amide [a] D = + 17.4? [Ct] 365 = +66.9 (C = 1 EtOH);
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-S-en-i3-in-säureamid Ia]0'= +10,2;5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-S-en-13-yne-acid amide Ia] 0 '= +10.2;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclohexylprost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a, 15 (S) -Trihydroxy^O-nor-^-cyclopentylprost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -Trihydroxy ^ O-nor - ^ - cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;
5C-9CX, 11α, 15 (R) -Trihydroxy-16 (S) -fluor-20-nor·-!^ cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid;5C-9CX, 11α, 15 (R) -Trihydroxy-16 (S) -fluoro-20-nor · -! ^ cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-20-nor-1 iJ-cyclohexyl-prost-S-en-13-in-säure-N, N-dimethylamid;5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-1 iJ-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9a, 11a, 15 (S) -Trihydroxy-^^O-dinor-iS-cyclohexylpros t-5-en-13-in-säure-N,N-dimethylamid;5c-9a, 11a, 15 (S) -Trihydroxy - ^^ O-dinor-iS-cyclohexylpros t-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a/15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-i8-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 155c-9a, 11a / 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide; 15th
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9.a, 11a, 15 (R,S) -Trihydroxy-16 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-N,N- dimethylamid;5c-9.a, 11a, 15 (R, S) -Trihydroxy-16 (S) -f luoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid-N , N- dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säureamid [a]D = +18,1;5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid amide [a] D = +18 ,1;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-S-en-13-in-säureamid [a]D = +12,9;5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-S-en-13-yn-acid amide [a] D = +12.9;
5c-9a,11a,15(S)-Tr!hydroxy-17,18,19,20-tetranor-i6-cyclohexyl-prost-5-en-i3-in-säureamid [α]~ = +37,6;5c-9a, 11a, 15 (S) -Tr! Hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide [α] = +37.6;
5c-9α,11α,15(S)-Trihydroxy-17,18,19,20-tetranor-i6-cyclopentyl-prost-5-en-13-in-säureamid [a]D = +37,2;5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid amide [a] D = +37.2;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid [a]D = +6,5;5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid amide [a] D = +6.5;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-i3-in-säureamid [a]D = +11,2;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-i3-yne-acid amide [a] D = +11.2;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid [a]D = +7,7;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid amide [a] D = +7.7;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid
[a]D = +12,1;
305c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne acid amide [ a] D = +12.1;
30th
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid [a]D = 415,9;5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid amide [a] D = 415.9;
5c-9α,11α,15(S)-Trihydroxy-18,19,20-trinor-i7-cyclo hexyl-prost-5-en-13-in-säure-N,N-dimethylamid [cx]D = +29,6;5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide [cx] D = +29 , 6;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-i3-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-i3-in-säure-N,N- dimethylamid;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-i3-yn-acid-N, N- dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-17, iS^^O cyclohexyl-prost-S-en-IS-in-säure-NjN-dimethylamid; 155c-9a, 11a, 15 (S) -trihydroxy-17, iS ^^ O cyclohexyl-prost-S-en-IS-yn-acid-NjN-dimethylamide; 15th
5c-9a,11a,15(S)-Trihydroxy-17,18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19, 20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-0 tetranor-1ö-cyclohexyl-prost-S-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-0 tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid;
305c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
30th
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methy1-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methy1-18,19.2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-N,M-dimethylamid? 5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-N, M-dimethylamide?
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclohexylprost-5-en-13-in-säure-pyrazolidinamid; 105c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid pyrazolidinamide; 10
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclopentylprost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid? 5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-in-acid-pyrazolidinamide?
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-iS-cyclohexylprost-S-en-IS-in-säure-pyrazolidinamid? 5c-9a, 11a, 15 (S) -Trihydroxy-19,20-dinor-iS-cyclohexylprost-S-en-IS-in-acid-pyrazolidinamide?
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure-pyrazolidinamid; 255c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid pyrazolidinamide; 25th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinorle-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5c-9α,11α,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11α,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid;
105c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
10
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-säure-pyrazoli- dinamid;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-pyrazoli- dinamid;
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-rprost-S-en-IS-in-säure-pyrazolidinamid; 255c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-rprost-S-en-IS-yn-acid-pyrazolidinamide; 25th
5c-9α,11α,15(S)-Trihydroxy-17,18,19,2 0-tetranor-16-cyclopentyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,2 0-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-säure-pyrazo- lidinamid;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-acid-pyrazzo- lidinamide;
5c-9α,11α,15(R,S)-Tr!hydroxy-1 β (S)-fluor-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-in-säure-pyrazo-1idinamid? 5c-9α, 11α, 15 (R, S) -Tr! Hydroxy-1β (S) -fluoro-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-yn acid -pyrazo-1idinamide?
5c-9a,11α,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepyrazolidinamid; 5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- pyraz olidinamid;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- pyraz olidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-'pyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide ;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide ;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclopentylprost-5-en-13-in-säure-piperidinamid; 255c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide; 25th
5c-9a,11a,15(R)»Trihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) »trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;
5c-9a,i1a,15(R,S)=Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-piperidinamid; 5c-9a, i1a, 15 (R, S) = trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;
5c-9a, 11α, 15 (S) -Trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-in-säure-piperidinamid; 5c-9a, 11α, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-piperidinamide;
5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -f luor-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -f luoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure<-piperidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid <-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20—trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 155c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide; 15th
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperidinamid;
255c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18 , 19,20- trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
25th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
0 5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-piperidinamid; 0 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9α,11α,15(S)-Trihydroxy-17,18,19,20-tetranor-i6-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9α,11α,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-i3-in-säure-piperidinamid; 5c-9α, 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-piperidinamid;
105c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
10
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepiperidinamid ;5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide ;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20—trinor-17-cyclohexyl»prost-5-en-13-in-säure- piperidinamid ;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl »prost-5-en-13-yn-acid- piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepiperidinamid? 5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne-acid-piperidinamide?
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5~en-13-in-säure~morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5C-9CX/11α, 15 (S) -Trihydroxy^O-nor-^-cyclopentylprost-5-en-13-in-säure-morpholinamid; 5C-9CX / 11α, 15 (S) -Trihydroxy ^ O-nor - ^ - cyclopentylprost-5-en-13-yn-acid morpholinamide;
5c-9a,11α,15(R)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R/S)-Trihydroxy-16(S)-±luor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säure-morpholinamid; 5c-9a, 11a, 15 (R / S) -trihydroxy-16 (S) - ± luoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a/15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure-morpholinamid; 155c-9a, 11a / 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-morpholinamide; 15th
5c-9a,11a/15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid; 5c-9a, 11a / 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a/11a,15(S)-Trihydroxy-18,19/20—trinor-17-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5c-9a / 11a, 15 (S) -trihydroxy-18,19 / 20-trinor-17-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20—trinor-17-cyclopentyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19/20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 305c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19 / 20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide; 30th
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c«9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-säure-morpho-1inamid? 5c «9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-morpho-1inamid?
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-säure-morpho- 1inamidι5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-acid-morpho- 1inamidι
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16™cyclohexylT-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16 ™ cyclohexylT-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl~prost~5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;
5σ-9α,11α,15(R,S)-Trihydroxy-1 β (S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-i3-in-säure-morpho linamid;5σ-9α, 11α, 15 (R, S) -trihydroxy-1β (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpho linamid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluqr-16-methyl-18^19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säuremorpholinamidι 5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluqr-16-methyl-18 ^ 19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-säuremorpholinamidι
5c-9a,11α,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-5c-9a, 11α, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-
18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säuremorpholinamid
?
3018,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholinamide?
30th
5c-9a,11a/15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19/20-trinor-1V-cyclohexyl-prost-S-en-i3-in-säuremorpholinamid; und5c-9a, 11a / 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19 / 20-trinor-1V-cyclohexyl-prost-S-en-13-yne-acid morpholine amide; and
5C-9CX/11α, 15 (R) -Trihydroxy-16 (S) -f luor-18 /19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-piperazinamid. 5C-9CX / 11α, 15 (R) -Trihydroxy-16 (S) -f luoro-18 / 19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-piperazinamide.
Eine Lösung von Kalium-t-butoxid (2,325 g) in trockenem DMSO (15 ml) wurde unter trockenem Stickstoff gerührt; unter Wasserbadkühlung wurde der Lösung Triphenylphosphonium-pentansäure-N,N-dimethylamid-bromid (4,2 g) zugefügt. Die Temperatur der Reaktionsmischung wurde unterhalb 3O0C gehalten und die Zugabe in ca. Minuten beendet; dann wurde eine Lösung von 3d,5oC-Dihydroxy-2ß-/2-brom-3(S)-hydroxy-4(S)-fluor-5-cyclo- hexyl-pent-trans-i-enylj-iel-cyclopentanacetaldehyd- ^-lactol-bis-THP-ether (1,7 g) in trockenem DMSO (15 ml) der erhaltenen Mischung zugegeben.A solution of potassium t-butoxide (2.325 g) in dry DMSO (15 ml) was stirred under dry nitrogen; triphenylphosphonium pentanoic acid-N, N-dimethylamide bromide (4.2 g) was added to the solution while cooling with a water bath. The temperature of the reaction mixture was kept below 3O 0 C, and terminates the addition in about minutes; then a solution of 3d, 5oC- dihydroxy-2ß- / 2-bromo-3 (S) -hydroxy-4 (S) -fluoro-5-cyclohexyl-pent-trans-i-enylj-iel-cyclopentane acetaldehyde- ^ -lactol-bis-THP-ether (1.7 g) in dry DMSO (15 ml) was added to the mixture obtained.
Die Reaktion war in ca. 1 Stunde beendet, dann wurde die Mischung mit Wasser abgeschreckt und mit Diethylether extrahiert. Das Lösungsmittel wurde entfernt und das Rohprodukt mittels präparativer Chromatografie an Silikagel unter Einsatz von Ethylacetat/Hexan =1:1 als Eluierungsmittel gereinigt. 1,650 g 5c-9<^, 15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,M-dimethylamid-11,15-bis-THP-ethex wurden als Reinprodukt erhalten: /öt7D = +42,5 (C = 1 EtOH).The reaction was complete in about 1 hour, then the mixture was quenched with water and extracted with diethyl ether. The solvent was removed and the crude product was purified by preparative chromatography on silica gel using ethyl acetate / hexane = 1: 1 as the eluent. 1.650 g 5c-9 <^, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, M- dimethylamide-11,15-bis-THP-ethex were obtained as the pure product: / öt7 D = +42.5 (C = 1 EtOH).
Gemäss derselben Vorgehensweise und unter Anwendung der entsprechenden Triphenylphosphoniumderxvate sowie der passenden Bis-THP-etherlactole wurden die Amide, Ν,Ν-pimethylamide, Pyrazolidinamide, Piperidinamide und Morpholinamide^als 11,IS-Bis-THP-ether-Rohprodukte der folgenden Säuren erhalten, die für die nachfolgendenUsing the same procedure and using it the corresponding triphenylphosphonium derivatives and the appropriate bis-THP ether lactols were the amides, Ν, Ν-pimethylamide, pyrazolidinamides, piperidinamides and morpholinamides ^ as 11, IS-bis-THP-ether crude products of the following acids obtained for the following
Reaktionen anwendbar sind und gegebenenfalls durch Chromatografie gereinigt werden:Reactions are applicable and optionally purified by chromatography:
5c-9a,11a,15(S)-Trihydroxy-20-nor-i9-cyclopentylprost-5-en-13-in-säure; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn acid;
5c-9a/11a, 15 (S) -Trihydroxy-20-nor-.i 9-cyclohexyl-prost-5-en-13-in-säure; 5c-9a / 11a, 15 (S) -trihydroxy-20-nor-.i 9-cyclohexyl-prost-5-en-13-yn acid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn acid;
5c-9a, 11a, 15 (R,S)-Trihydroxy-16 (S)-fluor^O-nor-i 9-cyclohexyl-prost-5-en-i3-in-säure; 155c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro ^ O-nor-i 9-cyclohexyl-prost-5-en-13-yn acid; 15th
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-in-säure; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn acid;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn acid;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl:-prost-5-en-13-in-säure; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl: -prost-5-en-13-yn acid;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure; 305c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid; 30th
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid;
5c-9a,11α,15(R)-Trihydroxy-16(S)-£luor-18,19,20-trinor~1T-cyclohexyl-prost-S-en-i3-in-säure; 5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -luoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn acid;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor™1y-cyclohexyl-prost-S-en-IB-in-säure; 5c-9a, 1 1a, 15 (R, S) -trihydroxy-16 (S) -fluoro-1 8,19,20-trinor ™ 1y-cyclohexyl-prost-S-en-IB-yn acid;
5c-9a, 11α, 15 (R,S)-Trihydroxy-16 (S),-f luor-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-säure; 5c-9a, 11α, 15 (R, S) -trihydroxy-16 (S), -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-yn acid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-IV-cyclopentyl-prost-S-en-IS-in-säure; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclopentyl-prost-S-en-IS-yn acid;
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure; 155c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn acid; 15th
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5~en-13-in-säure; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn acid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-säure; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-yn acid;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-IG-cyclohexyl-prost-S-en-IS-in-säure; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-IG-cyclohexyl-prost-S-en-IS-yn acid;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20—trinor-17-cyclohexyl-prost-5-en-13-in-säure; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid;
5c-9a,11a,15(R,S)-Trihydroxy-1β (S)-fluor-16-methyl-18,1.9,20-trinor-17-cyclohexyl-prost-5-en-13-insäure; 5c-9a, 11a, 15 (R, S) -trihydroxy-1β (S) -fluoro-16-methyl-18,1.9,20-trinor-17-cyclohexyl-prost-5-en-13-yoic acid;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methy1-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-saure; und5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methy1-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne acid; and
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-18,19,20-trinor-n-cyclohexyl-prost-S-en-IS-in-säure. 5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-18,19,20-trinor-n-cyclohexyl-prost-S-en-IS-yn acid.
1,5 ml Jones-Reagenz wurden in eine Lösung von 5c-9oC, 1I0L, 15 (R) -Trihydroxy-1 6 (S) -f luor-18,1 9,20-trinor-1V-cyclohexyl-prost-S-en-i3-in-säureamid- 11,15-bis-THP-ether (1,07 g) in Aceton (15 ml), die auf -250C gekühlt war, getropft. Nach der Zugabe wurde ein Temperaturanstieg auf -80C zugelassen und die Reaktionsmischung 20 Minuten lang gerührt. Die Mischung wurde dann mit Benzol verdünnt, mit gesättigter wässriger (NH4)«SO.-Lösung bis zur Neutralität gewaschen, getrocknet und das Lösungsmittel bei 200C unter Vakuum verdampft. Der Rückstand (0,830 g) wurde in 30 ml Aceton gelöst und 8 Stunden lang bei 400C mit 1N Oxalsäurelösung (5,5 ml) behandelt.1.5 ml of Jones reagent was added to a solution of 5c-9oC, 1I 0 L, 15 (R) -trihydroxy-16 (S) -f luor-18,1 9,20-trinor-1V-cyclohexyl-prost -S-en-i3-in-amide 11,15-bis-THP-ether (1.07 g), which was cooled to -25 0 C in acetone (15 ml), dropwise. After the addition, a temperature rise to -8 0 C was admitted and the reaction mixture stirred for 20 minutes. The mixture was then diluted with benzene, washed with saturated aqueous (NH 4) "Sun solution to neutrality, dried and the solvent evaporated at 20 0 C under vacuum. The residue (0.830 g) was dissolved in 30 ml of acetone and treated with 1N oxalic acid solution (5.5 ml) at 40 ° C. for 8 hours.
Nach Beendigung der Reaktion wurde das Aceton unter Vakuum verdampft, um einen Rückstand zu ergeben, der durch Chromatografie an SiO2 unter Einsatz von Ethylacetat/Cyclohexan = 35:65 als Eluierungsmittel 0,325 g reines 5c-9-Oxo-11«£,15 (R)-dihydroxy-16 (S) -f luor-After the reaction was complete, the acetone was evaporated in vacuo to give a residue which could be obtained by chromatography on SiO 2 using ethyl acetate / cyclohexane = 35:65 as the eluent 0.325 g of pure 5c-9-oxo-11 «£, 15 ( R) -dihydroxy-16 (S) -f luor-
amid lieferte: /5.7Λ = -33,0; /*C7,<-* = -199,2 (C =amide provided: /5.7 Λ = -33.0; / * C7, <- * = -199.2 (C =
— — D — — JOD- - D - - IOD
EtOH).
25EtOH).
25th
Durch analoge Vorgehensweise wurden die folgenden Verbindungen erhalten:The following compounds were obtained by an analogous procedure:
5c-9-Oxo-110L4,15 (S) -dihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-in~säureamid /^-7n = -6,2?5c-9-Oxo-11 0 L 4 , 15 (S) -dihydroxy-20-nor-i 9-cyclohexylprost-5-en-13-yn acid amide / ^ - 7 n = -6.2?
"■ ■"" IJ"■ ■" "IJ
- 82 5c-9-0ΧΟ-11α,15(S)-dihydroxy-20-nor-19-cyclopentyl- - 82 5c-9-0ΧΟ-11α, 15 (S) -dihydroxy-20-nor-19-cyclopentyl-
prost-5-en-13-in-säureamid [ct]_ = -7,6;prost-5-en-13-yn acid amide [ct] _ = -7.6;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säureamid [a]D = -9,8;5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid amide [a] D = -9.8 ;
5C-9-OXO-11a-15(R,S)-dihydroxy-16(S)-fluor-20-nor-"ig-cyclohexyl-prost-S-en-IS-in-säureamid [a]D = -10,2;5C-9-OXO-11a-15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor- "ig-cyclohexyl-prost-S-en-IS-yn-acid amide [a] D = - 10.2;
5c-9-Oxo-11a,15(S)-dihydroxy-19,20-dinor-18-eyelohexyl-prost-5-en-13-in-säureamid tcx]_ = -6,9;5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-eyelohexyl-prost-5-en-13-yn-acid amide tcx] _ = -6.9;
5C-9-OXO-11a,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl
prost-5-en-13-in-säureamid [a]D = -7,7;
155C-9-OXO-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn acid amide [a] D = -7.7;
15th
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-19,20-dinorle-cyclohexylr-prost-S-en-IS-in-säureamid tec]- = -7,2;5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexylr-prost-S-en-IS-yn-acid amide tec] - = -7.2;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säureamid [ot]D = -16,8;5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid amide [ot] D = -16 ,8th;
5C-9-OXO-11a,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-in-säureamid [a]D = -11,6;5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid amide [a] D = -11.6;
5C-9-OXO-11a,15(S)-dihydroxy-18,19,20-trinor-17-5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-
cyclopentyl-prost-S-en-IS-in-säureamid [α]β = -9,1;cyclopentyl-prost-S-en-IS-yn-acid amide [α] β = -9.1;
5C-9-OXO-11a,15(R)-dihydroxy-16(R)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-IS-in-säureamid
ta]D = -13,5;5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yne-acid amide
ta] D = -13.5;
50-9-0x0-1 1α,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-i3-in-säureamid [a]D = -10,2;50-9-0x0-1 1α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-13-yne-acid amide [a ] D = -10.2;
5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluor-1.8,19,20-trinor-^-cyclopentyl-prost-S-en-i3-in-säureamid [a]D = -38,2;5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-1.8,19,20-trinor - ^ - cyclopentyl-prost-S-en-13-yne-acid amide [a] D = -38.2;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-0 trinor-17-cyclopentyl-prost~5-en-13-in-säureamid [aJD = -20,2;5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-0 trinor-17-cyclopentyl-prost-5-en-13-yne acid amide [aJ D = -20.2;
5C-9-OXO-11a,15(S)-dihydroxy-17,18,19,20-tetranor-15 5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-15
lö-cyclohexyl-prost-S-en-i3-in-säureamid [cx]D = -12,8;Lö-cyclohexyl-prost-S-en-13-yne-acid amide [cx] D = -12.8;
5C-9-OXO-11a,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-in-säureamid [α]_ = -13,1;5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn acid amide [α] _ = -13.1;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid [a]D = -42,4;5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne-acid amide [a] D = -42.4;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säureamid [a]D = -37,7;5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yne acid amide [ a] D = -37.7;
5c-9-Oxo-11a,15(R)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid [a]D. = -56,6;5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yne acid amide [ a] D. = -56.6;
5c-9-Oxo-11α,15(R,S)-dihydroxy-16(S)-fluor-16-methyl-18/19,20-trinor-1V-cyclohexyl-prost-S-en-i3-insäureamid [a]D = -37,8;5c-9-Oxo-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18 / 19,20-trinor-1V-cyclohexyl-prost-S-en-i3-ynamide [ a] D = -37.8;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- amid lo.]- = -35,1;5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid amide lo.] - = -35.1;
5C-9-OXO-11a,15(R)-dihydroxy-16(R)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-
dimethylamid;5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-
dimethylamide;
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-i9-cyclohexylprost-5-en-13-in-säure-N,N-dimethylamid;
155c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-N, N-dimethylamide;
15th
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-19-cyclopentyl prost-5-en-13-in-säure-N,N-dimethylamid;5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentyl prost-5-en-13-yn acid-N, N-dimethylamide;
5c-9-Oxo-11a,15(R)-dihydroxy-16(S)-fluor-20-nor-1g-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethyl- amid;5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-1g-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethyl- amide;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5C-9-OXO-11α,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9-Oxo-11α,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9-Oxo-11α, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
- 85 -- 85 -
5c-9-Oxo-11α,15(R)-dihydroxy-16(S)-fluor-19,20-dinor-1e-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid; 5c-9-Oxo-11α, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-1e-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(R)-fluor-20-nor- ^-cyclohexyl-prost-S-en-IS-in-säure-N^-dimethylamid; 5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor- ^ -cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide;
5C-9-OXO-11a,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-in-säure-N^-dimethylamid; 5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-S-en-IS-yn-acid-N1-dimethylamide;
5C-9-OXO-11a,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-S-en-IS-in-säure-N^-dimethylamid;
155C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-S-en-IS-yn-acid-N1-dimethylamide;
15th
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N- dimethylamide;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-IS-in-säure-N,!*!- dimethylamid?5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-acid-N,! * ! - dimethylamide?
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5C-9-OXO-11a,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopenty1-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopenty1-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9-Oxo-11a,15(R)-dihydroy-16(S)-fluor-17,i8,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; . ν5c-9-Oxo-11a, 15 (R) -dihydroy-16 (S) -fluor-17, 18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide; . ν
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(S)-fluor-17,i8,19,20-tetranor-lö-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid; 5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-17, 18,19,20-tetranor-Lö-cyclohexyl-prost-S-en-i3-yn-acid- N, N-dimethylamide;
5c-9-Oxo-11a,15(R)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- N, N-dimethylamide;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-16-methyl-ISi^^O-trinor-^-cyclohexyl-prost-S-en-IS-in-säure- N,N-dimethylamid;5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-ISi ^^ O-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid - N, N-dimethylamide;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid-N, N-dimethylamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(R)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid;
305C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
30th
5c-9-OXO-11a, 15 (S) -dihydroxy^O-nor-^-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9-OXO-11a, 15 (S) -dihydroxy ^ O-nor - ^ - cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
IIa, 15 (S)-dihydroxy-20-nor-19-eyelopentylprost-5-en-13-in-säure-pyrazolidinamid; IIa, 15 (S) -dihydroxy-20-nor-19-eyelopentylprost-5-en-13-yn-acid-pyrazolidinamide;
5c-9-Oxo-11a,15 (R) -dihydroxy-16 (S) cyclohexyl-prost-S-en-13-in-säure-pyrazolidinamid; 5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) cyclohexyl-prost-S-en-13-yn-acid-pyrazolidinamide;
5c-9-0XO-11a,15(R,S)-dihydroxy-16 (S)-fluor-20-nor-19-cyclohexyl-prost-S-en-13-in-säure-pyrazolidinamid; 5c-9-0XO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-yn-acid-pyrazolidinamide;
50-9-OxO-Ha,15(S)-dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 50-9-OxO-Ha, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-in-säure-pyrazolidinamid; 155c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide; 15th
5c-9-Oxo-11a,15(R)-dihydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9-oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
50-9-OxO-Ha, 15 (R,S)-dihydroxy-16 (R) -f luor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 50-9-OxO-Ha, 15 (R, S) -dihydroxy-16 (R) -f luoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5C-9-OXO-11α,15(S)-dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-*5-en-13-in-säure-pyrazolidinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost- * 5-en-13-yn-acid-pyrazolidinamide;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid; 5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-yn-acid-pyrazolidinamide;
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en~13-in-säure-pyrazolidinamid; 5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-säure-pyrazoli- dinamid;
5C-9-OXO-11a,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-i3-in-säure-pyrazolidinamid; 155C-9-OXO-11a, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide; 15th
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-in-säure-pyrazolidinamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säure-pyrazoli dinamid ;5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-pyrazoli dinamid;
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-13-in-säure-pyrazolidinamid; 5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-13-yn-acid- pyrazolidinamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepyrazolidinamid;
305C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;
30th
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepyrazolidinamid; 5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid pyrazolidinamide;
5C-9-OXO-11α,15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20—trinor-1T-cyclohexyl-prost-S-en-i3-in-säurepyrazolidinamid; 5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in- acid pyrazolidinamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(R)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5C-9-OXO-11a, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-i9-cyclohexyl-prost-5-en-13-in-sSure-piperidinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-s-acid-piperidinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-19-cyclopentylprost-5-en-13-in-säure-piperidinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-piperidinamid; 5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-piperidinamid; 205c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide; 20th
5c-9-Oxo-11a,15(S)-dihydroxy-19,20-dinor-i8-cyclohexylprost-5-en-13-in-säure-piperidinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säure-piperidinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-piperidinamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-19,20-dinorle-cyclohexyl-prost-S-en-iS-in-säure-piperidinamid; 5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-iS-yn-acid-piperidinamide;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-5-en-i3-in-säure-piperidinamid; 5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
Ha, 15 (S) -dihydroxy-18,19,20—trinor-17-cyclo hexyl-prost-5-en-13-in-säure-piperidinamid;Ha, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclo hexyl-prost-5-en-13-yn-acid-piperidinamide;
5C-9-OXO-11a,15(S)-dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-i3-in-säure-piperidinamid; 5C-9-OXO-11a, 15 (S) -dihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
IIa, 15 (R)-dihydroxy-16 (S)--fluor-18,19,20-trinor-IV-cyclohexyl-prost-S-en-i3-in-säure-piperidinamid; 10IIa, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclohexyl-prost-S-en-i3-yn-acid-piperidinamide; 10
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-18, 1 9,20-trinor-17-cyclohexy1-prost-5-en-13-in-säure-piperidinamid; 5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18, 1,9,20-trinor-17-cyclohexy1-prost-5-en-13-yn-acid-piperidinamide ;
50-9-Οχο-ΙΙα,15(R)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-piperidinamid; 50-9-Οχο-ΙΙα, 15 (R) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-piperi dinamid ;5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-piperi dinamid;
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 255C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide; 25th
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-in-säure-piperidinamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5-en-13-yn-acid-piperidinamide;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)-fluor-17, 18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-piperidin amid;5C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) -fluoro-17, 18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-piperidine amide;
5C-9-OXO-11α,15(R/S)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säure-piperidinamid; 5C-9-OXO-11α, 15 (R / S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-yne-acid- piperidinamide;
5c-9-Oxo-11a,15(R)-dihydroxy-16(S)-fluor-16-methy1-5c-9-Oxo-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methy1-
18,19,2 0-trinor-17-cyclohexyl-prost-S-en-13-in-säurepiperidinamid; 18,19,2 0-trinor-17-cyclohexyl-prost-S-en-13-yn-acid-piperidinamide;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- piperidinamid;5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid- piperidinamide;
5c-9-Oxo-11a,15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepiperidinamid; 5c-9-Oxo-11a, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid piperidinamide;
5C-9-OXO-11α,15(R)-dihydroxy-16(R)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-morpholinamid;
205C-9-OXO-11α, 15 (R) -dihydroxy-16 (R) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
20th
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-19-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5c-9-Oxo-11a,15(S)-dihydroxy-20-nor-19-cyclopentylprost-5-en-13-in-säure-morpholinamid; 5c-9-Oxo-11a, 15 (S) -dihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-morpholinamide;
5C-9-OXO-11a,15(R)-dihydroxy-16(S)-fluor-20-nor-19-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-5-en-i3-in-säure-morpholinamid; 5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c~9-Oxo~11α,15(S)-dihydroxy=19 ,2Q=dinor-18-cyclohexyl-prost-5-en~13-in~säure~sii©rpholinamid? 5c ~ 9-Oxo ~ 11α, 15 (S) -dihydroxy = 19, 2Q = dinor-18-cyclohexyl-prost-5-en ~ 13-yn ~ acid ~ sii © rpholinamide?
5c-9~Qxo=11a,,15 (S) -dihydroxy-19,20~dinor-18~cyclo~ pentyl~prost~5-en~13~in-s5c-9 ~ Qxo = 11a ,, 15 (S) -dihydroxy-19.20 ~ dinor-18 ~ cyclo ~ pentyl ~ prost ~ 5-en ~ 13 ~ in-s
5c-9-Oxo-1 Ία, 15 (R) -dihydroxy-Ί β (S).-f luor-19, 20-dinor-5c-9-Oxo-1 Ία, 15 (R) -dihydroxy-Ί β (S) .- fluoro-19, 20-dinor-
5~en=13=in~säure~morpholinamidj5 ~ en = 13 = in ~ acid ~ morpholinamidj
5c-9-Oxo=11af15(R,S)-dihydroxy-Ίβ (R)=fluor-20-nor» 19-cyclohexyl-prost-5=en-13-in-säure=morpholinamid?5c-9-Oxo = 11a f 15 (R, S) -dihydroxy-Ίβ (R) = fluoro-20-nor »19-cyclohexyl-prost-5 = en-13-yn-acid = morpholinamide?
5c-9»Oxo-11a, 15 (S) -dihydroxy=! 8,19,20-trinor~17·= cyclohessyl-prost-S-en-IS-iR-säure-morpholinamiäi 155c-9 »Oxo-11a, 15 (S) -dihydroxy =! 8,19,20-trinor ~ 17 * = cyclohessyl-prost-S-en-IS-iR-säure-morpholinamiäi 15th
5C-9-OXO-11a,15(S)-dihydroxy-13,19,20=trinor=17-cyclopentyl~prost-5=en~13-in=säure-morpholinamidf 5C-9-OXO-11a, 15 (S) -dihydroxy-13,19,20 = trinor = 17-cyclopentyl ~ prost-5 = en ~ 13-yne = acid-morpholine amidef
5c-9-Osso-11a, 1 5 (R) -dihydroxy-1 β (S) -f luor-18,19,20-trinor=17=cyclohexyl=prost=5=en=13-in-sMure-morpholin amid ϊ 5c-9-Osso-11a, 15 (R) -dihydroxy-1β (S) -f fluoro-18,19,20-trinor = 17 = cyclohexyl = prost = 5 = en = 13-yn-s-mure-morpholine amide ϊ
5C-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-18,19,20-trinor=17-cyclohexyl-prost=5-en=13-in-sMure-morpholinamid? 5C-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-18,19,20-trinor = 17-cyclohexyl-prost = 5-ene = 13-yn-s-morpholinamide?
5C-9-OXQ-11a,15(R)-dihydroxy=16(S)-fluor-1δ,19,20=
trinor=17=cyclopentyleprost=5-=en=13=in=säure-morpholinamid?
305C-9-OXQ-11a, 15 (R) -dihydroxy = 16 (S) -fluoro-1δ, 19.20 = trinor = 17 = cyclopentyl e prost = 5- = en = 13 = in = acid-morpholine amide?
30th
5c-9-OXO-11a,15 CR,S)-dihydroxy-1 β (S)-fluor-18,19,20= trinor=17=cyclopantyl-=prost=5=en=13=in=säure=morpholin= amid?5c-9-OXO-11a, 15 CR, S) -dihydroxy-1 β (S) -fluoro-18,19,20 = trinor = 17 = cyclopantyl- = prost = 5 = en = 13 = in = acid = morpholine = amide?
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;
5C-9-OXO-11α,15(S)-dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-i3-in-säure-morpholinamid; 5C-9-OXO-11α, 15 (S) -dihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-13-yn-acid-morpholinamide;
5C-9-OXO-11α,15(R)-dihydroxy-16(S)~fluor-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid;
105C-9-OXO-11α, 15 (R) -dihydroxy-16 (S) ~ fluoro-17,18,19,20-tetranor-ie-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamide;
10
5C-9-OXO-11α,15(R,S)-dihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5C-9-OXO-11α, 15 (R, S) -dihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid- morpholinamide;
5C-9-OXO-11a, 15(R)-dihydroxy-16(S)-fluor-16-methyl-5C-9-OXO-11a, 15 (R) -dihydroxy-16 (S) -fluoro-16-methyl-
18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säuremorpholinamid; 18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide;
5c-9-OXO-11a,15(R,S)-dihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- morpholinamid; und5c-9-OXO-11a, 15 (R, S) -dihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid- morpholinamide; and
5c-9-Oxo-11α,15(R,S)-dihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-sauremorpholinamid. 5c-9-Oxo-11α, 15 (R, S) -dihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in acid morpholinamide.
Kalium-t-butoxid (3,2 gl wurde in 20 ml trockenem DMSO unter trockenem Stickstoff gelöst und Triphenylphospho= nium-pentansäurearnid-bromiä C6,3 g) der Lösung unter Magnetrühren zugefügt=Potassium t-butoxide (3.2 gl was dissolved in 20 ml of dry DMSO Dissolved under dry nitrogen and triphenylphospho = nium-pentansäurearnid-bromiä C6.3 g) of the solution under Magnetic stirring added =
Di© Temperatur wurde mittels eines Wasserbades unterhalb 300C gehalten und eine Lösung von 3d,5^-D!hydroxy™ 2ß~^2~brom-=3 (S11R) -hydroxy-4 (S) -f luor=4=methyl=5-cyclopentyl-pent-trans-1-enyiy-itft-cyclopentanacetaldehydylactol-15-trimethylsilylether (1,9 g) in DMSO {3 ml) der vorher erhaltenen Mischung zugefügt» Wach Beendigung der Reaktion wurde die Mischung mit kaltem Wasser verdünnt und dann mit Diethylether extrahiert,, Das Lösungsmittel t-nxrde entfernt und das Rohprodukt, das ohne Schutsgruppe in 15-Stellung,, die während der Wittig-Reaktion abgespalten wurde^ anfiel, durch Chromatografie gereinigt, um 1,8 g 5c-=9^, 11^C, 15 (S,R) -Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-i7- cyclopent'yl-prost=5"-en='i3~in-säureamid zu ergebens • P-JO = +14,95? L\72S5 = +54,2 (C = 1 StOH)0 Di © temperature was maintained by a water bath below 30 0 C and a solution of 3d, 5 ^ -D! ™ 2ß hydroxy ~ ^ 2 ~ bromo-3 = (S 11 R) -hydroxy-4 (S) -f = luor 4 = methyl = 5-cyclopentyl-pent-trans-1-enyiy-itft-cyclopentanacetaldehydylactol-15-trimethylsilyl ether (1.9 g) in DMSO (3 ml) added to the previously obtained mixture Diluted water and then extracted with diethyl ether, the solvent was removed and the crude product, which was obtained without a protective group in the 15-position, which was split off during the Wittig reaction, was purified by chromatography to give 1.8 g of 5c- = 9 ^, 11 ^ C, 15 (S, R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-i7-cyclopent'yl-prost = 5 "-en = ' i3 ~ yn acid amide to give • PJ O = +14.95? L \ 7 2S5 = +54.2 (C = 1 StOH) 0
Durch analoge Vorgehensweise wurden die folgenden Verbindungen erhalten?The following compounds were obtained by an analogous procedure?
5c=9.oC, 110L, 15 (S) -Trihydroxy-20-nor-i 9-eyclohexyl prost-5-en~13=in-säureainid;5c = 9.oC, 1 1 0 L, 15 (S) -trihydroxy-20-nor-i 9-eyclohexyl prost-5-en-13 = yn-acid amide;
5c-9a, 1 "Ια, 15 (S) -Trihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-in-säureamid; 5c-9a, 1 "Ια, 15 (S) -trihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yn acid amide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-£luor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -luoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S).-fluor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) .- fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;
0 5c-9a, 11 a, 15 (S) -Trihydroxy-19,20^InOr-IS-CyClOhSXyI-prost-5-en-13-in-säureamid; 0 5c-9a, 11 a, 15 (S) -Trihydroxy-19.20 ^ InOr-IS-CyClOhSXyI-prost-5-en-13-yn-acid amide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-in-säureamid; 155c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn acid amide; 15th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-S-en-IS-yn-acid amide;
5c-9a , 11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn acid amide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid amide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säureamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn acid amide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,1 9,20-trinor-IT-cyclohexyl-prost-S-en-IS-in-säureamid; 305c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,1 9,20-trinor-IT-cyclohexyl-prost-S-en-IS-yn-acid amide; 30th
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-IV-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-IV-cyclohexyl-prost-S-en-IS-yn-acid amide;
5c-9a,11α,15(R)-Trihydroxy-16(S)-fluor-18,1 9,20-trinor-17»cyclopentyl=prost-5~en~13-in-säureamid? 5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-18,1 9,20-trinor-17 »cyclopentyl = prost-5 ~ en ~ 13-yn acid amide?
5c-9a,11a,15(R,S)-Trihyäroxy-1β (S)~fluor-18,19,20-trinor-17=cyclopentyl=prost-5=-en=13~in=säureamiä? 5c-9a, 11a, 15 (R, S) -Trihyäroxy-1β (S) ~ fluoro-18,19,20-trinor-17 = cyclopentyl = prost-5 = -en = 13 ~ in = acid amiä?
Sc-Ba11 11a, 15 (S) -Trihyäroxy-1 7,18,1-9,20-tetranor-16-cyclohexyl-prost-5-en=13=ia-=säur©amiä? Sc-Ba 11 11a, 15 (S) -Trihyäroxy-1 7,18,1-9,20-tetranor-16-cyclohexyl-prost-5-en = 13 = ia- = acid © amiä?
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost=-5-=en=13~in=säureamid? 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost = -5- = en = 13 ~ in = acid amide?
5c-9a,11a,15(R)-Trihydroxy-1β (S)-fluor-17,18,19,20-tetranor-16~cyclohexyl=prost-=5=en=-13-in-=säureamid? 155c-9a, 11a, 15 (R) -Trihydroxy-1β (S) -fluoro-17,18,19,20-tetranor-16 ~ cyclohexyl = prost- = 5 = en = -13-in = acid amide? 15th
5c-9af1 la,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-1S-cyclohexyl-prost-S-en-IS-in-säureamid; 5c-9a f 1 la, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prost-S-en-IS-yne acid amide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5=en-13-in-säure- amid;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5 = en-13-yn-acid- amide;
5c-9a,11a,15(R,S)-Trihydroxy-1β (S)-fluor-16-methyl-18,19,20-trinor=17-cyclohexyl-prost-5-en-13=in-säureamid? 5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-16-methyl-18,19,20-trinor = 17-cyclohexyl-prost-5-en-13 = yn-acid amide?
5c-9a, 11a, 15(R) -Trihydroxy-1 β (R) -f luor-16-rnethyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säureamid;
305c-9a, 11a, 15 (R) -trihydroxy-1β (R) -f luoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn acid amide;
30th
5c-9a,11a,15(S)-Trihydroxy-20-nor-i9=cyclohexylprost-5-en-13-in-säure-N,N-dimi 5c-9a, 11a, 15 (S) -Trihydroxy-20-nor-19 = cyclohexylprost-5-en-13-yn-acid-N, N-dimi
5c-9a, 11α, 15 (S) -Trihydroxy^O-nor-ig-cyclopentylprost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11α, 15 (S) -trihydroxy ^ O-nor-ig-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11α,15(R)-Trihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-S-en-i3-in-säure-N,N-dimethylamid; 5c-9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-S-en-IS-in-säure-N^-dimethylamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-yn-acid-N ^ -dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexylprost-S-en-IS-in-säure-N/N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-S-en-IS-yn-acid-N / N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-19,20~dinor-18-cyclopentylprost-5-en-13-in-säure-N,N-dimethylamid; 155c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentylprost-5-en-13-yn-acid-N, N-dimethylamide; 15th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinorle-cyclohexyl-prost-S-en-IS-in-säure-N/N-dimethylamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinorle-cyclohexyl-prost-S-en-IS-yn-acid-N / N-dimethylamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-19-cyclohexyl-prost-5-en-i3-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20—trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethylamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide;
5c-9a, 11a, 15 (R,S) -Trihydroxy-1 β (S) -f luor-18,19,20-trinor-17-eyclohexyl-prost~5-eii--13-in-säure-N,N-dimethy1 amid?5c-9a, 11a, 15 (R, S) -trihydroxy-1β (S) -f luoro-18,19,20-trinor-17-eyclohexyl-prost-5-eii-13-yn-acid-N , N-dimethy1 amide?
5e~9a, 11a, 15 (R) ~Trihydroxy~1 β (S) -f luor-1 8,19,20» trinor~17-eyelopentyl~prost-5-en=13-in-säure-N,Να imethy!amid?5e ~ 9a, 11a, 15 (R) ~ trihydroxy ~ 1 β (S) -f luor-1 8,19,20 » trinor ~ 17-eyelopentyl ~ prost-5-en = 13-yn-acid-N, Να imethy! amid?
5c-9a,11a,15(R,S)-Trihydroxy-1β (S)-fluor-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-säure-NjN- dimethylamid ?5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-säure-NjN- dimethylamide?
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en=13-in-säure-N,H-dimethylamid? 155c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en = 13-yn-acid-N, H-dimethylamide? 15th
5c~9a„11α,15(S)-Trihydroxy~17,18,19,20-tetranor-16-cyclopentyl-prost-5-en=13-in-säure-N,N-dimethylamid; 5c ~ 9a, 11α, 15 (S) -trihydroxy ~ 17,18,19,20-tetranor-16-cyclopentyl-prost-5-ene = 13-yn-acid-N, N-dimethylamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-0 tetranor-1 β-cyclohexyl-prost-5-en-13-in-säure-N,N-dimethy!amid ?5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-0 tetranor-1β-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethy! amide ?
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor= 16=cyclohe2cyl-prost=5 -en-13 -in-säure-N, N-dimethylamid? 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor = 16 = cyclohe2cyl-prost = 5-en-13-yn-acid-N, N-dimethylamide?
5c-9a„11α,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20=trinor-17-cyclohesyl-prost-5-en-13-in-säure-N,N^dimethylamid
?
305c-9a "11α, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20 = trinor-17-cyclohesyl-prost-5-en-13-yn-acid-N, N ^ dimethylamide?
30th
5c-9a,11a,15(R,S)-Trihydroxy=16(S)-fluor-16-methyl-18,19,20=trinor-17-cyclohessyl-prost-5-en-13-in-säure-N,H-dimethylamid ?5c-9a, 11a, 15 (R, S) -Trihydroxy = 16 (S) -fluoro-16-methyl-18,19,20 = trinor-17-cyclohessyl-prost-5-en-13-yn-acid- N, H-dimethylamide ?
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-Ν,Ν-dimethylamid; 5c-9a, 11a, 15 (R) -Trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-Ν, Ν-dimethylamide;
5c-9a,11a,15(S)-Trihydroxy^O-nor-^-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) -trihydroxy ^ O-nor - ^ - cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-i9-cyclopentyl-prost-5-en-13-in-säure-pyrazolidinamid; 105c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentyl-prost-5-en-13-yn-acid pyrazolidinamide; 10
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-in-säure-pyrazolidinamid;5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-18 cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 255c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18 cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide; 25th
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-i9-cyclohexyl-prost-5-en-i3-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9α, 11α, 15 (S) -Trihydroxy-18,19,20—trinor-17-cyclopentyl-prost~5-en=13=in-säore-pyrasolidinamid; 5c-9α, 11α, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-ene = 13 = in-acid-pyrasolidinamide;
5c-9af11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5~en--13-in-säure-pyrazalidin- amid?5c-9a f 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5 ~ en-13-yn-acid-pyrazalidin-amide?
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy»16(S)-fluor-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-säure-pyrazolidinamid?
155c-9a, 11a, 15 (R) -Trihydroxy »16 (S) -fluoro-18,19,20-trinor-IT-cyclopentyl-prost-S-en-IS-in-acid-pyrazolidinamide?
15th
5c-9ai,11ai15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-säure-pyrazolidinamidy 5c-9a i , 11a i 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-pyrazolidinamidy
5c-9a,11a, 15 (S) =Trihydro3sy-17,18,19 ,20-tetranor-16-cyclohexyl-prost~5-en-13-in-säure-pyrazolidinamid; 5c-9a, 11a, 15 (S) = trihydro3sy-17,18,19, 20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;
5c-9a, 1Ia4-IS(S) -Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-IS-in-säure-pyrazolidinamid; 255c-9a, 1Ia 4 -IS (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-pyrazolidinamide; 25th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-in-säure-pyrazolidinamid? 5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-IS-cyclohexyl-prost-S-en-IS-in-acid-pyrazolidinamide?
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-1S-cyclohexyl-prost-ö-en-i3-in-säure-pyrazolidinamid? 5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prost-ö-en-i3-yn-acid-pyrazolidinamide?
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säurepyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yne-acid pyrazolidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-in-säurepyrazolidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-1T-cyclohexyl-prost-S-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-in-säurepyrazolidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid pyrazolidinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-piperidinamid;
155c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
15th
5c-9a,11a,15(S)-Trihydroxy-20-nor-i9-cyclopentylprost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-£luor-20-nor-19-cyclohexyl-5-en-i3-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -luoro-20-nor-19-cyclohexyl-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-20-nor-i9-cyclohexyl-prost-S-en-IS-in-säure-piperidiftamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-S-en-IS-in-acid-piperidiftamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclohexylprost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-19,20-dinor-18-cyclopentyl· prost-5-en-13-in-säure-piperidinamid; 305c-9a, 11a, 15 (S) -trihydroxy-19,20-dinor-18-cyclopentyl prost-5-en-13-yn-acid-piperidinamide; 30th
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(R)-fluor-20-nor-i9-cyclohexyl-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor~17-eyclohexyl-prost-5=en-13-in=säure~piperidinamid? 5c-9a, 11a, 15 (S) -Trihydroxy-18,19,20-trinor ~ 17-eyclohexyl-prost-5 = en-13-yne = acid ~ piperidinamide?
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyi-prost-5-en-13-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyi-prost-5-en-13-yn-acid-piperidinamide;
5c=9a,11a,15(R)-Trihydroxy-1 δ (S)-fluor-18,1 9,20-trinor-17-cyclohesyl-prost-5-en=13-in-säure-piperidinamid? 5c = 9a, 11a, 15 (R) -trihydroxy-1 δ (S) -fluoro-18.1 9.20-trinor-17-cyclohesyl-prost-5-en = 13-yn-acid-piperidinamide?
5c-9a,11a,15(R,S)-Trihydroxy-1 β (S)-fluor-18,19,20-trinor-iy-cyelohexyl-prost-S-en-IS-in-säure-piperidin- amid y5c-9a, 11a, 15 (R, S) -Trihydroxy-1 β (S) -fluoro-18,19,20-trinor-iy-cyelohexyl-prost-S-en-IS-in-säure-piperidine- amid y
5c-9af11 a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prost-5-en=13-in-säure-piperidinamid? 5c-9a f 11 a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prost-5-en = 13-yn-acid-piperidinamide?
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-^-cyclopentyl-prost-S-en-IS-in-säure-piperidinamid?
255c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor - ^ - cyclopentyl-prost-S-en-IS-in-säure-piperidinamid?
25th
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-in-säure-piperidinamid; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-yn-acid-piperidinamide;
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5=en-13-in-säure-piperidinamidj 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-5 = en-13-yn-acid-piperidinamidj
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-säure-piperi- dinamid;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-iö-cyclohexyl-prost-S-en-IS-in-säure-piperi- dinamid;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säure-piperidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- piperidinamid;5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- piperidinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säurepiperidinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-16-methy1-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methy1-18,19,2
0-trinor-17-cyclohexyl-prost-5-en-13-in-säurepiperidinamid;
205c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methy1-18,19,2 0-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperidinamide;
20th
5c-9a,11a,15(S)-Trihydroxy^O-nor-ig-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy ^ O-nor-ig-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-20-nor-19-cyclopentylprost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-20-nor-19-cyclopentylprost-5-en-13-yn-acid morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prost-5-en-i3-in-säure-morpholinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11α,15(S)-Trihydroxy-19,20-dihor-18-cyclohexylprost-5-en-13-in-säure-morpholinamid; 5c-9a, 11α, 15 (S) -trihydroxy-19,20-dihor-18-cyclohexylprost-5-en-13-yn-acid-morpholinamide;
5c-9α,11α,15(S)-Trihydroxy-19,20~dinor-18-cyclopentylprost-5-en-13-in-säure-morpholinamid? 5c-9α, 11α, 15 (S) -Trihydroxy-19,20 ~ dinor-18-cyclopentylprost-5-en-13-yn-acid-morpholinamide?
5c~9a,11α, 15 (R)-Trihydroxy-16(S)-fluor-19,20-dinor-18-=cyclohe3syl-prost-5-en-13-in-säure-morpholinamid; 5c ~ 9a, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-19,20-dinor-18- = cyclohe3syl-prost-5-en-13-yn-acid-morpholinamide;
5c-9ai:11a, 15 (R,S) -Trihydroxy-16 (R) -fluor-20-nor-19-cyclohesyl-prost-S-en-IS-in-säure-morpholinamid; 5c-9ai: 11a, 15 (R, S) -trihydroxy-16 (R) -fluoro-20-nor-19-cyclohesyl-prost-S-en-IS-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclohexyl~prost~5=en-13-in-säure-morpholinamid; 155c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclohexyl-prost-5 = en-13-yn-acid-morpholinamide; 15th
5c-9a,11a,15(S)-Trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1V-cyclohexyl-prost-S-en-IS-in-säure-morpholin- 5c-9a, 11a, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1V-cyclohexyl-prost-S-en-IS-in-acid-morpholine-
5c-9a,11a,15(R,S)-Trihydroxy-1β (S)-fluor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-morpholinamidi 5c-9a, 11a, 15 (R, S) -Trihydroxy-1β (S) -fluoro-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-morpholinamidi
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1V-cyclopentyl-prost-S-en-i3-in-säure-morpho-1inamidj
305c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-1V-cyclopentyl-prost-S-en-i3-yn-acid-morpho-1inamidj
30th
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-in-säure-morpholinamid? 5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-1T-cyclopentyl-prost-S-en-i3-yn-acid-morpholinamide?
5C-9CX/11α, 15 (S) -Trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-in-säure-morpholinamid; 5C-9CX / 11α, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclohexyl-prost-S-en-IS-yn-acid-morpholinamide;
5c-9a,11a,15(S)-Trihydroxy-17,18,19,20-tetranor-i6-cyclopentyl-prost-S-en-IS-in-säure-morpholinamid; 5c-9a, 11a, 15 (S) -trihydroxy-17,18,19,20-tetranor-16-cyclopentyl-prost-S-en-IS-yn-acid-morpholinamide;
5c-Sa,11α,15(R)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-1ö-cyclohexyl-prost-S-en-i3-in-säure-morpholinamid;
105c-Sa, 11α, 15 (R) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-10-cyclohexyl-prost-S-en-13-yn-acid-morpholinamide;
10
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-in-säure-morpholinamid; 5c-9a, 11a, 15 (R, S) -trihydroxy-16 (S) -fluoro-17,18,19,20-tetranor-16-cyclohexyl-prost-5-en-13-yn-acid-morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säuremorpholinamid; 5c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide;
5c-9a,11a,15(R,S)-Trihydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure- morpholinamid;5c-9a, 11a, 15 (R, S) -Trihydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid- morpholinamide;
5c-9a,11a,15(R)-Trihydroxy-16(R)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säuremorpholinamid; und5c-9a, 11a, 15 (R) -trihydroxy-16 (R) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid morpholine amide; and
5c-9a,11a,15(R)-Trihydroxy-16(S)-fluor-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-in-säure-piperazinamid.
305c-9a, 11a, 15 (R) -trihydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-piperazinamide.
30th
Eine Lösung von 5c-9-Oxo-11^,15(S)-Dihydroxy-16(R) fluor-18,19,20-trinor-17-cycloheptyl-prost-5-en-13-in-säure-piperidinamid-11,15-bis-THP-ether (0,57 g) in Aceton (10 ml) wurde unter Behandlung mit 1N wässriger Oxalsäure (10 ml) 7 Stunden lang am Rückfluss gekocht <, Das überschüssige Aceton wurde unter Vakuum entfernt und die Lösung mit Diethylether extrahiert.A solution of 5c-9-Oxo-11 ^, 15 (S) -dihydroxy-16 (R) fluoro-18,19,20-trinor-17-cycloheptyl-prost-5-en-13-yn-acid-piperidinamide -11.15-bis-THP ether (0.57 g) in acetone (10 ml) became more aqueous upon treatment with 1N aqueous Oxalic acid (10 ml) refluxed for 7 hours <, The excess acetone was removed under vacuum and the solution extracted with diethyl ether.
Der organische Extrakt wurde eingeengt und an mit Säure gewaschenem Silikagel absorbiert. Eluierung mit Benzol/Diethylether lieferte 0,21 g 5c-9-Oxo-15(S) hydroxy-16(R)-fluor-18,19,20-trinor-i7-cycloheptylprosta-5,10-dien-13-in-säure-piperidinamid: /^.7n = +2,5 (C = 1 EtOH).The organic extract was concentrated and absorbed onto acid washed silica gel. Elution with benzene / diethyl ether gave 0.21 g of 5c-9-oxo-15 (S) hydroxy-16 (R) -fluoro-18,19,20-trinor-17-cycloheptylprosta-5,10-diene-13-yne Acid-piperidinamide: /^.7 n = +2.5 (C = 1 EtOH).
Unter Anwendung derselben Vorgehensweise, ausgehend von gemäss Beispiel 3 erhaltenen 9-Oxo-11,15-bis-THP-ether-Zwischenproduktderivaten, wurden die folgenden Verbindungen hergestellt:Using the same procedure, starting from 9-oxo-11,15-bis-THP-ether intermediate derivatives obtained according to Example 3, the following connections were made:
5c»9-Oxo-15 (S) -hydroxy^O-nor-^-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5c »9-Oxo-15 (S) -hydroxy ^ O-nor - ^ - cyclohexyl-prosta-5,10-diene-13-yne acid amide;
5c-9-Oxo-15 (S) -hydroxy-^O-nor-liJ-cyclopentyl-prosta-5,10-dien-13-in-säureamid; 5c-9-Oxo-15 (S) -hydroxy- ^ O-nor-liJ-cyclopentyl-prosta-5,10-diene-13-yne acid amide;
5C-9-OXO-15(R)-hydroxy-16(S)-fluor~20-nor-19-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide;
5C-9-OXO-15(R,S)-hydroxy-16(S)-fluor-20-nor-19-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R, S) -hydroxy-16 (S) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide;
5C-9-OXO-15(S)-hydroxy-19/20-dinor-18-cyclohexylprosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (S) -hydroxy-19/20-dinor-18-cyclohexylprosta-5,10-diene-13-yn acid amide;
5c-9-Oxo-15(S)-hydroxy-19,20-dinor-18-cyclopentylprosta-5,10-dien-13-in-säureamid; 5c-9-Oxo-15 (S) -hydroxy-19,20-dinor-18-cyclopentylprosta-5,10-diene-13-yn acid amide;
5C-9-OXO-15(R)-hydroxy-16(S)-fluor-19,20-dinor-18-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prosta-5,10-diene-13-yn acid amide;
5C-9-OXO-15(R/S)-hydroxy-16(R)-fluor-20-nor-i9-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 155C-9-OXO-15 (R / S) -hydroxy-16 (R) -fluoro-20-nor-19-cyclohexyl-prosta-5,10-diene-13-yne acid amide; 15th
5C-9-OXO-15(S)-hydroxy-18,19,20-trinor-17-cyclohexylprosta-5/10-dien-13-in-säureamid; 5C-9-OXO-15 (S) -hydroxy-18,19,20-trinor-17-cyclohexylprosta-5/10-diene-13-yn acid amide;
5C-9-OXO-15(S)-hydroxy-18/19,20-trinor-17-cyclopentylprosta-5/10-dien-13-in-säureamid; 5C-9-OXO-15 (S) -hydroxy-18 / 19,20-trinor-17-cyclopentylprosta-5/10-diene-13-yn acid amide;
5C-9-OXO-15(R)-hydroxy-16(S)-fluor-18/19/20-trinor-17-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-18/19/20-trinor-17-cyclohexyl-prosta-5,10-diene-13-yne acid amide;
5C-9-OXO-15(R/S)-hydroxy-16(S)-fluor-18/19,20-trinor-17-cyclohexyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R / S) -hydroxy-16 (S) -fluoro-18 / 19,20-trinor-17-cyclohexyl-prosta-5,10-diene-13-yne acid amide;
5c-9-Oxo-15(R)-hydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prosta-5,10-dien-13-in-säureamid; 305c-9-Oxo-15 (R) -hydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-diene-13-yn acid amide; 30th
5C-9-OXO-15(R/S)-hydroxy-16(S)-fluor-18,19,20-trinor-17-cyclopentyl-prosta-5,10-dien-13-in-säureamid; 5C-9-OXO-15 (R / S) -hydroxy-16 (S) -fluoro-18,19,20-trinor-17-cyclopentyl-prosta-5,10-diene-13-yne acid amide;
5C-9-OXO-15(S)-hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-dien-13-in-säureamid; 5C-9-OXO-15 (S) -hydroxy-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-diene-13-yne acid amide;
5C-9-OXO-15(S)-hydroxy-17/18,19,20-tetranor-16-cyclopentyl-prosta-5,10r-dien-13-in-säureamid; 5C-9-OXO-15 (S) -hydroxy-17 / 18,19,20-tetranor-16-cyclopentyl-prosta-5,10r-diene-13-yne acid amide;
5c-9~Oxo-15(R)-hydroxy-16(S)-fluor-17,18,19,20-tetranor-1S-cyclohexyl-prosta-5,1O-dien-13-in-säureamid; 5c-9 ~ Oxo-15 (R) -hydroxy-16 (S) -fluoro-17,18,19,20-tetranor-1S-cyclohexyl-prosta-5,1O-diene-13-yne acid amide;
5C-9-02CO-15 (R, S) -hydroxy-16 (S) -f luor-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-dien-13-in-säureamid ϊ 5C-9-02CO-15 (R, S) -hydroxy-16 (S) -f fluoro-17,18,19,20-tetranor-16-cyclohexyl-prosta-5,1O-diene-13-yne acid amide ϊ
5C-9-OXO-15(R)-hydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-dien-13-in-säure amid?5C-9-OXO-15 (R) -hydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-yn acid amide?
5C-9-OXO-15(R,S)-hydroxy-16(S)-fluor-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-dien-13-in-säureamid; sowie5C-9-OXO-15 (R, S) -hydroxy-16 (S) -fluoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-in acid amide; as
18,19,20-trinor-17-cyclohexyl-prosta-5,1O-dien-13-insäureamid.
2518,19,20-trinor-17-cyclohexyl-prosta-5,1O-diene-13-yoic acid amide.
25th
Zu einer Lösung von 5c-9<*·, 11dC, 15 (R)-Trihydroxy-16 (S) flüor-18,19,20—trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-piperazinamid (0,2 g) in 95 %-igem Ethylalkohol (5 ml) wurde eine stöchiometrische Menge 1N HCl gegeben. Das Lösungsmittel ,wurde zur Trockne verdampft, um auf diese Weise 5c-9ct-, 11<?C, 15 (R) -Trihydroxy-16(S)-fluor-18,19,20-trinor-i7-cyclohexylprost-S-en-IS-in-säure-piperazinamid-hydrochlorid als weisse Kristalle zu ergeben.To a solution of 5c-9 <* ·, 11dC, 15 (R) -Trihydroxy-16 (S) fluor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yne-acid- piperazinamide (0.2 g) in 95% ethyl alcohol (5 ml) became a stoichiometric amount Given 1N HCl. The solvent turned to dryness evaporated, in this way 5c-9ct-, 11 <? C, 15 (R) -Trihydroxy-16 (S) -fluoro-18,19,20-trinor-i7-cyclohexylprost-S-en-IS-in- acid piperazinamide hydrochloride as white crystals.
5c, 9oC, 11öC, 15 (R) -Trihydroxy-1 6 (S) -fluor-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-in-säure-N^- dimethylamid-11,15-bis-THP-ether (0,65 g) wurde in 10 ml trockenem CCl4 und 0,5 ml Pyridin gelöst und dann 0,1 ml Acetylchlorid in die Lösung getropft.5c, 9oC, 11oC, 15 (R) -Trihydroxy-1 6 (S) -fluoro-18,19,20-trinor-IT-cyclohexyl-prost-S-en-IS-in-acid-N ^ - dimethylamide- 11.15-bis-THP ether (0.65 g) was dissolved in 10 ml of dry CCl 4 and 0.5 ml of pyridine and then 0.1 ml of acetyl chloride was added dropwise to the solution.
Die Lösung wurde ca. 2 Stunden lang bei Raumtemperatur gerührt, mit 10 %-iger NaH3PO4-Lösung neutralisiert und mit Diethylether extrahiert.The solution was stirred for about 2 hours at room temperature, neutralized with 10% NaH 3 PO 4 solution and extracted with diethyl ether.
Das Lösungsmittel wurde entfernt und das Rohprodukt chromatografisch an Silikagel unter Einsatz von Ethylacetat/Cyclohexan = 80:20 als Eluierungsmittel gereinigt.The solvent was removed and the crude product chromatographed on silica gel using Purified ethyl acetate / cyclohexane = 80:20 as eluent.
Das reine 5c-9c*-, 110C, 15 (R) -Trihydroxy-1 6 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-insäure-N,N-dimethylamid-11,15-bis-THP-ether-9-acetat wurde gewonnen, in einer Mischung von Aceton (10 ml) und 1N Oxalsäure (10 ml) gelöst und 6 Stunden lang bei 400C gerührt. Die Reaktionslösung wurde mit 10 ml Wasser verdünnt, das Aceton abdestilliert und die Mischung mit Ethylether extrahiert.The pure 5c-9c * -, 11 0 C, 15 (R) -Trihydroxy-1 6 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-yn acid- N, N-dimethylamide-11,15-bis-THP-ether-9-acetate was obtained, dissolved in a mixture of acetone (10 ml) and 1N oxalic acid (10 ml) and stirred at 40 ° C. for 6 hours. The reaction solution was diluted with 10 ml of water, the acetone was distilled off and the mixture was extracted with ethyl ether.
Das Rohprodukt wurde an Silikagel unter Einsatz von Ethylacetat/Cyclohexan = 50:50 als Eluierungsmittel gereinigt, um auf diese Weise 0,320 mg reines 5c-9eC, 11oC, 15 (R) -Trihydroxy-1 6 (S) -fluor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-i3-in-säure-N,N- dimethylamid-9-acetat: /^JD = +76,2 (C = 1 EtOH) zu ergeben.The crude product was purified on silica gel using ethyl acetate / cyclohexane = 50:50 as the eluant to give 0.320 mg of pure 5c-9eC, 11oC, 15 (R) -trihydroxy-16 (S) -fluoro-18.19 To give 20-trinor-1T-cyclohexyl-prost-S-en-i3-yn-acid-N, N-dimethylamide-9-acetate: / ^ J D = +76.2 (C = 1 EtOH).
Durch analoge Vorgehensweise wurden die 9-Acetatderivate aller in Beispiel 1 aufgeführten Verbindungen erhalten.The 9-acetate derivatives were obtained by an analogous procedure all compounds listed in Example 1 obtained.
FORMULIERUNGSBEISPIELEFORMULATION EXAMPLES
Formulierung 1; Tablette (1 mg) Formulation 1 ; Tablet (1 mg)
Tabletten, die jeweils 80 mg wiegen und 1 mg der aktiven Substanz enthalten, werden wie folgt hergestellt;Tablets, each weighing 80 mg and containing 1 mg of the active substance, are prepared as follows;
Zusammensetzung (für 100.000 Tabletten)Composition (for 100,000 tablets)
5c-9$C, 11<^, 15 (R) -Trihydroxy-15 (S)-fluor-18/19,20-trinor-i7-cyclohexyl- 5c-9 $ C, 11 <^, 15 (R) -Trihydroxy-15 (S) -fluoro-18 / 19,20-trinor-i7-cyclohexyl-
prost-5-en-13-in-säureainid 100 gProst-5-en-13-yn acid amide 100 g
Lactose 5000 gLactose 5000 g
Maisstärke . 2720 gCornstarch. 2720 g
Talkpulver 150 gTalc powder 150 g
Magnesiumstearat 30 gMagnesium stearate 30 g
5c-9s<, 1 U, 15 (R) -Trihydroxy-16 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-IS-in-säureamid/ die Lactose und die Hälfte der Maisstärke werden vermischt; die Mischung wird dann durch ein Sieb von 0,5 mm Mesh geführt. Die Maisstärke (18 g) wird in warmem Wasser (180 ml) suspendiert. Die sich ergebende Paste wird herangezogen, um das Pulver zu granulieren. Das Granulat wird getrocknet, über einem Sieb von 1,4 mm Mesh fein zerkleinert, anschliessend wird die verbleibende Menge Stärke, Talk und Magnesiumstearat zugegeben, sorgfältig vermischt und die Mischung unter Anwendung von Prägestempeln von 5 mm Durchmesser zu Tabletten geformt.5c-9s <, 1 U, 15 (R) -Trihydroxy-16 (S) -f luor-18,19,20-trinor-1T-cyclohexyl-prost-S-en-IS-in-acid amide / the lactose and half the corn starch are mixed; the mixture is then passed through a 0.5 mm mesh screen. The corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, fine over a 1.4 mm mesh sieve crushed, then the remaining amount of starch, talc and magnesium stearate is added, carefully mixed and the mixture formed into tablets using dies of 5 mm diameter.
Formulierung 2; Kapsel (1 mg) Formulation 2; Capsule (1 mg)
Zusammensetzung^Composition ^
5c-9oC, 11oC, 15 (R) -Trihydroxy-16 (S) fluor-18,19,20-trinor-i7-cyclohexylprost-5-en-13-in-säureamid 1,0 mg5c-9oC, 11oC, 15 (R) -trihydroxy-16 (S) fluoro-18,19,20-trinor-17-cyclohexylprost-5-en-13-yn acid amide 1.0 mg
Laktose 89,8 mgLactose 89.8 mg
Maisstärke 9,0 mgCorn starch 9.0 mg
Magnesiumstearat ο ,2 mg Magnesium stearate ο , 2 mg
insgesamt 100,0 mgtotal 100.0 mg
Diese Formulierung wurde in Zwei-Stück-Hartgelatinekapseln eingekapselt.This formulation was encapsulated in two-piece hard gelatin capsules.
Claims (9)
R" jeweils, unabhängig voneinander Wasserstoff, C.,g-Alkyl, Aryl oder einen Heterozyklus bedeuten oder
R1 und R", zusammengenommen mit dem Stickstoffatom,
an das sie gebunden sind, einen heterozyklischen Ring bilden;characterized in that R 1 and
R ″ each, independently of one another, denotes hydrogen, C., g-alkyl, aryl or a heterocycle or
R 1 and R ", taken together with the nitrogen atom,
to which they are bound form a heterocyclic ring;
15as well as the pharmaceutically or veterinarily acceptable salts thereof.
15th
25R 'and R "are, independently of one another, hydrogen or a C -.- alkyl or R 1 and R", taken together with the nitrogen atom to which they are bonded, is a pyrole, pyrazole, imidazoline, imidazolidine, pyrazoline -, piperidine, piperazine or morpholine ring;
25th
30R 2 is hydrogen and R 3 is hydroxy or acyloxy or R- and R 7 , taken together, form an oxo group;
30th
5as well as the pharmaceutically or veterinarily acceptable salts thereof.
5
205c-9oC, 11oC, 15 (R, S) -trihydroxy-1 6 (S) -fluoro-1 8,19,20-trinor-17-cyclohexyl-prost-5-en-13-yn-acid-N , N-dimethylamide,
20th
205c-9oL, 11oU 15 (R, S) -Trihydroxy-1 6 (S) -f luoro-1 6-methyl-18,19 ^ O-trinor - ^ - cyclohexyl-prost-S-en-i 3-yn acid-N, N-dimethylamide,
20th
305c-9-Oxo-11oL, 15 (S) -dihydroxy-20-nor-i 9-cyclopentylprost-5-en-13-yne acid amide,
30th
205c-9-Oxo-11o6,15 (R, S) -dihydroxy-1 6 (S) -f luoro-16-methyl-18,19,20-trinor-17-cyclohexyl-prost-5-en-13- insäureamid /
20th
155c-9-Oxo-11oL, 15 (R) -dihydroxy-16 (S) -fluoro-19,20-dinor-18-cyclohexyl-prost-5-en-13-yn-acid-N, N-dimethylamide ,
15th
305C-9-OXO-11ct, 15 (R) -dihydroxy-16 (S) -f luoro-18,19,20-trinor - ^ - cyclohexyl-prost-S-en-i3-yn-acid-N, N -dimethylamide,
30th
205C-9-OXO-11oC, 15 (R) -dihydroxy-16 (S) -fluoro-1 7,18,19,20-tetranor-io-cyclohexyl-prost-5-en-13-yn acid -N, N-dimethylamide,
20th
155C-9-OXO-11c6,15 (R) -dihydroxy-1 6 (S) -f luor-18,19,20-trinor-17-cyclopentyl-prost-5-en-13-yn-acid morpholine amide,
15th
5contains as an active principle a compound of formula (I) according to any one of claims 1 to 4 and 6, or a pharmaceutically acceptable salt thereof.
5
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08231938A GB2130575B (en) | 1982-11-09 | 1982-11-09 | Amide derivatives of 13, 14-didehydro-cycloalkyl-prostaglandins |
Publications (1)
Publication Number | Publication Date |
---|---|
DE3338327A1 true DE3338327A1 (en) | 1984-05-10 |
Family
ID=10534131
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19833338327 Withdrawn DE3338327A1 (en) | 1982-11-09 | 1983-10-21 | AMIDE DERIVATIVES OF 13,14-DIDEHYDRO-CYCLOALKYL-PROSTA-GLANDINES |
Country Status (4)
Country | Link |
---|---|
JP (1) | JPS59101459A (en) |
BE (1) | BE898169A (en) |
DE (1) | DE3338327A1 (en) |
GB (1) | GB2130575B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1088966B (en) * | 1977-11-15 | 1985-06-10 | Erba Carlo Spa | 13,14-didehydro-prostaglandins |
CH656877A5 (en) * | 1981-11-27 | 1986-07-31 | Erba Farmitalia | OPTICALLY ACTIVE OR RACEMIC PROSTAGLAND DERIVATIVES. |
-
1982
- 1982-11-09 GB GB08231938A patent/GB2130575B/en not_active Expired
-
1983
- 1983-10-21 DE DE19833338327 patent/DE3338327A1/en not_active Withdrawn
- 1983-11-07 BE BE0/211834A patent/BE898169A/en not_active IP Right Cessation
- 1983-11-07 JP JP58207657A patent/JPS59101459A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
GB2130575B (en) | 1985-12-11 |
GB2130575A (en) | 1984-06-06 |
JPS59101459A (en) | 1984-06-12 |
BE898169A (en) | 1984-05-07 |
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