SE428207B - 9,11,15, -TRIHYDROXI-13-TIA-5-PROSTENIC ACID DERIVATIVES FOR USING LUTEOLYTIC AND PREPARATIONS CONTAINING THIS - Google Patents
9,11,15, -TRIHYDROXI-13-TIA-5-PROSTENIC ACID DERIVATIVES FOR USING LUTEOLYTIC AND PREPARATIONS CONTAINING THISInfo
- Publication number
- SE428207B SE428207B SE7809051A SE7809051A SE428207B SE 428207 B SE428207 B SE 428207B SE 7809051 A SE7809051 A SE 7809051A SE 7809051 A SE7809051 A SE 7809051A SE 428207 B SE428207 B SE 428207B
- Authority
- SE
- Sweden
- Prior art keywords
- acid
- formula
- thia
- compounds
- compound
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000003529 luteolytic effect Effects 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 57
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims 2
- 230000000996 additive effect Effects 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- -1 phenoxy, phenyl Chemical group 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000002329 infrared spectrum Methods 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 230000035935 pregnancy Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 241000699800 Cricetinae Species 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 210000004246 corpus luteum Anatomy 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 241000283690 Bos taurus Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 230000012173 estrus Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 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 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 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 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 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
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 230000029860 luteolysis Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- LIUSHSVUMMYGRB-UHFFFAOYSA-N 1-naphthalen-1-yl-n-phenoxymethanamine Chemical compound C=1C=CC2=CC=CC=C2C=1CNOC1=CC=CC=C1 LIUSHSVUMMYGRB-UHFFFAOYSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- 125000005976 1-phenylethyloxy group Chemical group 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- RUJHATQMIMUYKD-UHFFFAOYSA-N 2-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(CCN)=CC=CC2=C1 RUJHATQMIMUYKD-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical compound OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
Description
15 20 7809051-1 2 salter därav kan därför användas såsom medel för påverkan av fertiliteten. 2 salts thereof can therefore be used as agents for affecting fertility.
Föreliggande uppfinning avser föreningar med formeln I, i vilka H1, H2, m och n har ovan angiven betydelse.The present invention relates to compounds of formula I, in which H1, H2, m and n have the meaning given above.
Föreningarna med formeln I innehåller Ä asymmetriska kol- atomer vid femringen. I tioeter-sidokedjan kan ytterligare asym- metricentra uppträda. Föreningarna med formeln I kan därför upp- träda i ett flertal stereoísomera former; de föreligger i regel såsom racemiska blandningar.The compounds of formula I contain Ä asymmetric carbon atoms at the five ring. Additional asymmetric centers may appear in the thioether side chain. The compounds of formula I may therefore exist in a variety of stereoisomeric forms; they are usually present as racemic mixtures.
Föreliggande uppfinning avser förutom de enstaka racematen och racemiska blandningar även de optiskt aktiva isomererna med formeln I.In addition to the individual racemates and racemic mixtures, the present invention also relates to the optically active isomers of formula I.
Framställningen av en förening med formeln I samt av fysiolo- giskt ofarliga salter därav sker därigenom att man bringar en e förening med formeln II _ _ _ 1 CH2-cH_cH (cH2)3 coon II H vari A betecknar -CHOH- och Bl har den ovan angivna betydelsen, att reagera med en förening med formeln III 2 ' rH“CnH2n R Hs-caz-c(oH) III I 1 mH2m+1 vari R2, m och n har ovan angiven betydelse, eller att man bringar en förening med formeln IV H _ _ _ 1 Q -H2-ca-CH (cH2)3 coon Iv 2 . _ HO -ca?-co-(cnH¿n_1 R )a [EcH2)m b H _ vari a betecknar 1 eller 0 och b betecknar 0 eller 1 och R1, R2, m och n har ovan angiven betydelse, att reagera med en förening med formeln V M-(CnH2n-1-R2)c-{zCH2)m1d'H V vari M betecknar litíum, MgCl, MgBr eller MgJ, c betecknar 0 eller 1 och d betecknar 1 eller O och R2, m och n har den ovan angivna 10 15 20 25 30 H0 7809051-1 betydelsen, varvid a + b = 1, c + d = 1 och a + c = 1, eller att 3 man bringar en förening, som annars motsvarar formeln I, i vilken emellertid minst en hydroxigrupp och/eller COOR1-gruppen före- ligger 5 funktionellt omvandlad form, att reagera med ett solvo- lyserande medel, och/eller att man omvandlar en förening med formeln I (vanidock A = -CO-) genom reaktion med ett reducerande medel till en annan förening med formeln I (A = -CHOH-), och/eller att man omvandlar en förening med formeln I (El = H) genom reaktion med ett förestrande medel till en annan förening med formeln I (Bl = alkyl med l till 4 kolatomer), och/eller att man omvandlar en förening med formeln I genom reaktion med ett solvolyserande medel till en annan förening med formeln I, och/eller att man uppspjälkar en förening med formeln I i racematen därav och/eller enantiomerer- na därav, och/eller att man omvandlar en syra med formeln I (El = H) genom behandling med en bas till ett av de fysiolcgiskt ofarliga salterna därav eller ur ett av salterna därav fnigör en syra med formeln I genom behandling med en syra.The preparation of a compound of the formula I and of physiologically harmless salts thereof takes place by bringing an e compound of the formula II _ _ _ 1 CH2-cH_cH (cH2) 3 coon II H wherein A represents -CHOH- and B1 it has above, to react with a compound of formula III 2 'rH "CnH2n R Hs-caz-c (oH) III I 1 mH2m + 1 wherein R2, m and n have the meaning given above, or to bring a compound of formula IV H _ _ _ _ 1 Q -H2-ca-CH (cH2) 3 coon Iv 2. _ HO -ca? -Co- (cnH¿n_1 R) a [EcH2) mb H _ wherein a represents 1 or 0 and b represents 0 or 1 and R1, R2, m and n have the meaning given above, to react with a compound of the formula V M- (CnH2n-1-R2) c- {zCH2) m1d'H V wherein M represents lithium, MgCl, MgBr or MgJ, c represents 0 or 1 and d represents 1 or 0 and R2, m and n has the meaning given above, wherein a + b = 1, c + d = 1 and a + c = 1, or that 3 one brings a compound, which otherwise corresponds to the formula I, in which however, at least one hydroxy group and / or the COOR1 group is present in a functionally converted form, reacting with a solvolysing agent, and / or converting a compound of formula I (vanidock A = -CO-) by reaction with a reducing agent to another compound of formula I (A = -CHOH-), and / or converting a compound of formula I (E1 = H) by reaction with an esterifying agent to another compound of formula I (B1 = alkyl with 1 to 4 carbon atoms), and / or converting a compound of formula I by reaction with a solvating agent into another compound of formula I, and / or splitting a compound of formula I into the racemates thereof and / or the enantiomers thereof, and / or converts an acid of formula I (E1 = H) by treatment with a base into one of the physiologically harmless salts thereof or from one of its salts forms an acid of formula I by treatment with an acid.
Likaså avser föreliggande uppfinning farmaceutiska beredning- ar, som innehåller minst en förening med formeln I och/eller ett av de fysiologiskt ofarliga salterna därav, samt ett förfarande för framställning av farmaceutiska preparat, karakteriserat därav, att man bringar en förening med formeln I tillsammans med minst ett fast, vätskeformigt eller halvflytande hjälp- eller bärarämne och eventuellt tillsammans med ett ytterligare verksamt ämne i en lämp- lig doseringsform.The present invention also relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of the physiologically harmless salts thereof, and to a process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I is brought together with at least one solid, liquid or semi-liquid excipient or carrier, and optionally together with an additional active substance in a suitable dosage form.
I de föregående formlerna betecknar Rl speciellt väte, men även en alkylgrupp, företrädesvis en ogrenad med upp till 4 kol; afi0m@P, SåS0m metyl, etyl, propyl eller n-butyl, men även en grenad, såsom isopropyl eller tert.-butyl. 2 .In the foregoing formulas, R 1 especially represents hydrogen, but also an alkyl group, preferably an unbranched one having up to 4 carbons; a fi0 m @ P, SaSOm methyl, ethyl, propyl or n-butyl, but also a branched such as isopropyl or tert-butyl. 2.
R betecknar fenyl, fenoxi, en gång med F, Cl eller CF substituerad fenyl eller en med F, Cl eller CF3 substituerad - 2 u . fenoxi. Om R ar en substituerad fenyl- eller en substituerad fenoxigrupp, så är den företrädesvis substituerad, så att substi~ tuenten är att finna i o-ställning, speciellt emellertid i m- eller p-ställning. 3 '7 RL är därför företrädesvis m-fluorfenyl, p-fluorfenyl, m-klorfenyl, p-klorfenyl, m-trifluormetylfenyl, p-trifluormetyl- fenyl, f@n0Xi, m-fluørfenoxi, p-fluorfenoxi, m-klorfenoxi, p-klorfenoxi, p-bromfenoxi, fluormety1f@n0Xi_ m-trifluormetylfenoxi eller p-tri- kf! 10 15 20 25 50 35 HG 71809051-1 M Speciellt lämpliga är de föreningar med formeln I, i vilka minst en av symbolerna H1, R , m och n har en av ovan angivna betydelserna.R represents phenyl, phenoxy, phenyl once substituted by F, Cl or CF or one substituted by F, Cl or CF3 - 2 .mu.l. phenoxy. If R is a substituted phenyl or a substituted phenoxy group, it is preferably substituted so that the substituent is in the o-position, especially however in the m- or p-position. 3 '7 RL is therefore preferably m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, phnOXi, m-fluorophenoxy, p-fluorophenoxy, m-chlorophenoxy, p -chlorophenoxy, p-bromophenoxy, fluoromethylphenoxyl-m-trifluoromethylphenoxy or p-tri-kf! HG 71809051-1 M Particularly suitable are those compounds of the formula I in which at least one of the symbols H1, R, m and n has one of the meanings given above.
Några av dessa lämpliga grupper av föreningar kan känne- tecknas genom de efterstående delformlerna Ia till Ie, som annars motsvarar formeln I och i vilka de inte närmare betecknade sym- bolerna har den vid formeln I angivna betydelsen, vari dock , 1 1 Ia R = H, i Ib R1 = metyl eller etyl, i Ic n = O eller 1, i Id m = 1, i Ie R2 = m-fluorfenyl, p-fluorfenyl, m-klorfenyl, p-klorfenyl, m-fluorfenoxi, p-fluorfenoxí, m-klorfenoxi eller p-klorfenoxi.Some of these suitable groups of compounds may be characterized by the following sub-formulas Ia to Ie, which otherwise correspond to formula I and in which the symbols not further specified have the meaning given in formula I, wherein, however, 1 1 Ia R = H, i Ib R1 = methyl or ethyl, i Ic n = 0 or 1, i Id m = 1, i Ie R2 = m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenoxy, p- fluorophenoxy, m-chlorophenoxy or p-chlorophenoxy.
Föreningarna med formeln I är strukturellt besläktade med prostaglandinerna, som avledes från 7-(2-oktylcyklopentyl)-heptan- syra (prostansyra). Föreningarna med formeln I avledes från l3-tia- prostansyra.The compounds of formula I are structurally related to the prostaglandins derived from 7- (2-octylcyclopentyl) -heptanoic acid (prostanoic acid). The compounds of formula I are derived from β-thia-prostanoic acid.
M betecknar företrädesvis MgCl eller MgB- Vid de i det följande beskrivna reaktionerna för framställning av utgångsföreningarna, men även av föreningarna med formeln I, är det fråga om analogiförfaranden. Deras reaktionsbetingelser kan hämtas ur standardverken för preparativ organisk kemi, t.ex. HOUBEN- WEYL, Methoden der organischen Chemie, Georg Thieme Verlag, Stuttgart eller ORGANIC SYNTHESES, J. Wiley, New York - London - Sydney.M preferably represents MgCl or MgB- In the reactions described below for the preparation of the starting compounds, but also of the compounds of formula I, these are analogous processes. Their reaction conditions can be taken from the standard works for preparative organic chemistry, e.g. HOUBEN- WEYL, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart or ORGANIC SYNTHESES, J. Wiley, New York - London - Sydney.
Föreningarna med formeln II till V är kända eller kan framstäl- las ur kända föreningar i analogi till kända förfaranden. Så är exem- =pe1vis 7-(3-hydroxi-5-oxi-l-cyklopentenyl)-5-heptensyrametylestern beskriven i TETRAHEDRON LETTERS, 1973, häfte 25, sid 2313 - 2316. 7-(3-hydroxi-5-oxi-l-cyklopentenyl)-heptansyra är exempelvis be- skriven 1 REcsrRAvæHIM. g, sm 1421 - 1434 (1968). 7-(3,5-d1- hydroxi-l-cyklopentenyl)-heptansyra kan framställas därur genom reduktion av karbonylgruppen med ett lämpligt reduktionsmedel, före- trädesvis en komplex metallhydrid. Tiolerna med formeln III är till- gängliga ur de motsvarande 2-(CnH2n-Bl)-2-(Cfigflíflëoxiranerna genom reaktion med H23. Föreningar med formeln IV är exempelvis erhàllbara ur cyklopentenderivaten med formeln II genom anlagring av en etylen- ketal av en förening med formeln HS-CH2-CO-(CnH2n_l-R2)a-3CH2kJb-H och hydrolys. 10 15 20 25 30 35 H0 7809051-1 5 Föreningar, som annars motsvarar formeln I, i vilka emeller- tid minst en hydroxigrupp och/eller en COOR1-grupp föreligger i funktionellt omvandlad form, kan företrädesvis framställas enligt förfaranden, enligt vilka även föreningarna med formeln I är er- hållbara, varvid man visserligen utgår från förprodukter, i vilka de motsvarande hydroxigrupperna och/eller en COOR1-grupp före- ligger i funktionellt omvandlad form.The compounds of formula II to V are known or can be prepared from known compounds in analogy to known processes. Thus, for example, the 7- (3-hydroxy-5-oxy-1-cyclopentenyl) -5-heptenoic acid methyl ester is described in TETRAHEDRON LETTERS, 1973, booklet 25, pages 2313 - 2316. 7- (3-hydroxy-5-oxy -1-cyclopentenyl) -heptanoic acid is described, for example, in 1 REcsrRAvæHIM. g, cm 1421 - 1434 (1968). 7- (3,5-d1-hydroxy-1-cyclopentenyl) -heptanoic acid can be prepared therefrom by reduction of the carbonyl group with a suitable reducing agent, preferably a complex metal hydride. The thiols of formula III are available from the corresponding 2- (CnH2n-B1) -2- (Cfig2floxoxoxiranes by reaction with H23. Compounds of formula IV are obtained, for example, from the cyclopentene derivatives of formula II by the addition of an ethylene ketal of a compound of the formula HS-CH2-CO- (CnH2n_1-R2) a-3CH2kJb-H and hydrolysis Compounds otherwise corresponding to formula I, in which, however, at least one hydroxy group and / or a COOR1 group is present in functionally converted form, may preferably be prepared according to processes according to which the compounds of formula I are also obtainable, although starting from precursors in which the corresponding hydroxy groups and / or a COOR1 group are present is in functionally transformed form.
Grupperna, med vilka de angivna grupperna är funktionellt om- vandlade, skall vara lätt avspjälkbara, i regel emellertid bestån- diga gentemot föreningar med formeln V.The groups with which the indicated groups are functionally converted should be readily cleavable, but as a rule, however, resistant to compounds of formula V.
Vid funktionellt omvandlade OH-grupper är det företrädesvis fråga om t.ex. med en mättad eller omättad alífatisk, oykloalifatisk eller aromatisk, substituerad eller osubstituerad karbonsyra eller sulfonsyra, eller även med en organisk syra förestrade OH-grupper.In the case of functionally transformed OH groups, it is preferably a question of e.g. with a saturated or unsaturated aliphatic, cycloaliphatic or aromatic, substituted or unsubstituted carboxylic acid or sulfonic acid, or even with an organic acid esterified OH groups.
Lämpliga karbonsyraestrar avledes från fettsyror, som har l till 18, företrädesvis l till 6 kolatomer, såsom myrsyra, ättiksyra, smörsyra eller isosmörsyra, men t.ex. även pivalinsyra, tríklorättiksyra, bensoesyra, p-nitrobensoesyra, palmitinsyra, stearinsyra eller olje- syra. Lämpliga sulfonsyraestrar avledes från alkylsulfonsyror med 1 till 6 kolatomer, t.ex. metan- eller etansulfonsyra, eller aryl- sulfonsyror med 6 till 10 kolatomer, t.ex. bensen-, p-toluen-, l~ och 2-naftalensulfonsyra, även från substituerade sulfonsyror, såsom 2-hydroxietan- eller 4-brombensensulfonsyra. Lämpliga oorganiska syraestrar är sulfater och fosfater.Suitable carboxylic acid esters are derived from fatty acids having 1 to 18, preferably 1 to 6 carbon atoms, such as formic acid, acetic acid, butyric acid or isobutyric acid, but e.g. also pivalic acid, trichloroacetic acid, benzoic acid, p-nitrobenzoic acid, palmitic acid, stearic acid or oleic acid. Suitable sulfonic acid esters are derived from alkylsulfonic acids having 1 to 6 carbon atoms, e.g. methane or ethanesulfonic acid, or arylsulfonic acids having 6 to 10 carbon atoms, e.g. benzene, p-toluene, 1- and 2-naphthalenesulfonic acid, whether or not from substituted sulfonic acids, such as 2-hydroxyethane or 4-bromobenzenesulfonic acid. Suitable inorganic acid esters are sulphates and phosphates.
Funktionellt omvandlade OH-grupper kan även föreligga i för- etrad form, t.ex. såsom aralkoxí med företrädesvis 7 till 19 kol- atomer, såsom bensyloxi, p-metylbensyloxi, l- och 2-fenyletoxi, di- fenylmetoxi, trifenylmetoxi eller 1- eller 2-naftylmetoxi; alkoxi med företrädesvis upp till 6 kolatomer, speciellt metoxi, etoxi el- ler tert.-butoxi; tetrahydropyranyloxi; eller trialkylsilyloxi, fö- reträdesvis trimetylsilyloxi.Functionally transformed OH groups can also be present in etherified form, e.g. such as aralkoxy having preferably 7 to 19 carbon atoms, such as benzyloxy, p-methylbenzyloxy, 1- and 2-phenylethoxy, diphenylmethoxy, triphenylmethoxy or 1- or 2-naphthylmethoxy; alkoxy having preferably up to 6 carbon atoms, especially methoxy, ethoxy or tert-butoxy; tetrahydropyranyloxy; or trialkylsilyloxy, preferably trimethylsilyloxy.
Ketogrupper kan företrädesvis vara funktionellt omvandlade så- som hemiketaler, såsom -C(0H)(ORu)-, ketaler såsom -C(0Ru)2 eller cykliska, t.ex. etylenketaler, varvid grupperna Ru är lika eller olika och i regel betecknarlägre alkylgrupper med l till 6 kolato- mer. Då grupperna Ru emellertid endast utgör skyddsgrupper, som in- te längre uppenbarar sig i slutprodukten enligt föreliggande upp- finning, är deras natur i och för sig okritisk.Keto groups may preferably be functionally converted such as hemiketals, such as -C (OH) (ORu) -, ketals such as -C (ORu) 2 or cyclic, e.g. ethylene ketals, the groups Ru being the same or different and usually denoting lower alkyl groups having 1 to 6 carbon atoms. However, since the groups Ru only constitute protecting groups, which no longer appear in the final product according to the present invention, their nature is in itself uncritical.
Lämpliga funktionellt omvandlade COORI-grupper är sådana, som under milda reaktionsbetingelser, framför allt i basisk, neutral el- ler svagt sur miljö kan överföras till COORI-gruppen. Vid funktio- 7809051-1 6 nellt omvandlade COORI-grupper är det företrädesvis fråga om -CON3, -cN, -c(=NH)oR5, -C(=NR5)0R6, -cosa5, -cson5, -cssn5, -c(on5) ei- ler -COORY. R5 och R6 är lika eller olika och betecknar förutšm H en lågmolekylär organisk grupp, vars natur i och för sig är okri- tisk, då den inte uppenbarar sig i slutprodukten enligt föreliggan- de uppfinning, exempelvis alkyl med upp till 6 kolatomer. H7 kan i och för sig ha den för R5 och R6 angivna betydelserna, med undan- tag av de för Rl angivna. R7 betecknar speciellt en kiselorganisk grupp, företrädesvis en trialkylsilylgrupp, såsom trimetylsilyl el- 10 ler dimetyl-tert.-butylsilyl.Suitable functionally converted COORI groups are those which can be transferred to the COORI group under mild reaction conditions, especially in an alkaline, neutral or slightly acidic environment. In the case of functionally converted COORI groups, these are preferably -CON3, -cN, -c (= NH) oR5, -C (= NR5) OR6, -cosa5, -cson5, -cssn5, -c (on5) ei- ler -COORY. R5 and R6 are the same or different and represent, in addition to H, a low molecular weight organic group, the nature of which is in itself uncritical, since it does not appear in the final product of the present invention, for example alkyl having up to 6 carbon atoms. H7 may in itself have the meanings given for R5 and R6, with the exception of those given for R1. R 7 especially represents an organosilicon group, preferably a trialkylsilyl group, such as trimethylsilyl or dimethyl-tert-butylsilyl.
Reaktionen av en förening med formeln II med en tiol med for- meln III sker i regel i närvaro av en basisk katalysator och i fràn- varo eller närvaro av ett inert lösningsmedel vid temperaturer mellan cirka -20 och +50°C, företrädesvis mellan O och +30°C. Såsom lös- 15 ningsmedel lämpar sig företrädesvis alkoholer, såsom metanol eller etanol, vidare kolväten, såsom bensen eller toluen; även vatten eller vätskeformig ammoniak. Lämpliga basiska katalysatorer är t.ex. alka- limetall- eller jordalkalimetallhydroxider, såsom Na0H, KOH eller Ca(0H)2; alkalimetallalkoholater, såsom Na0CH3, NaOC2H5 eller K-tert.- 20 CÄH ; basiska salter, företrädesvis karbonater eller acetater, såsom KZCO eller NaOCOCH3; ammoniak; aminer, såsom trietylamin, tert.-bu- tylamin, cyklohexylamin, dicyklohexylamin, dimetylanilin, piperidin, pyrrolidin, pyridin, kinolin, diazabicyklo-[2,2,2]-oktan eller diaza- bicyklo-[3,4,0]-nonen; eller kvaternära ammoniumhydroxider, såsom 25 tetrametylammoniumhydroxid eller bensyltrimetylammoniumhydroxid.The reaction of a compound of formula II with a thiol of formula III usually takes place in the presence of a basic catalyst and in the absence or presence of an inert solvent at temperatures between about -20 and + 50 ° C, preferably between 0 ° C. and + 30 ° C. Suitable solvents are preferably alcohols, such as methanol or ethanol, further hydrocarbons, such as benzene or toluene; also water or liquid ammonia. Suitable basic catalysts are e.g. alkali metal or alkaline earth metal hydroxides such as NaOH, KOH or Ca (OH) 2; alkali metal alcoholates such as NaOCH 3, NaOC 2 H 5 or K-tert. basic salts, preferably carbonates or acetates, such as K 2 CO 3 or NaOCOCH 3; ammonia; amines such as triethylamine, tert-butylamine, cyclohexylamine, dicyclohexylamine, dimethylaniline, piperidine, pyrrolidine, pyridine, quinoline, diazabicyclo- [2,2,2] -octane or diazabicyclo- [3,4,0] - nuns; or quaternary ammonium hydroxides, such as tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide.
Reaktionen av en keton med formeln IV med en organometallför- ening med formeln V sker i de för sådana reaktioner vanliga lösnings- medlena, företrädesvis etrar, såsom dietyleter, 1,2-dimetoxietan, tetrahydrofuran (THF), kolväten, såsom bensen, toluen, xylen, eller 50 även i blandningar av dessa lösningsmedel, lämpligen vid.temperatu- rer mellan cirka -25 och +20°C.The reaction of a ketone of formula IV with an organometallic compound of formula V takes place in the solvents customary for such reactions, preferably ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF), hydrocarbons such as benzene, toluene, xylene, or even in mixtures of these solvents, suitably at temperatures between about -25 and + 20 ° C.
Reaktionen av föreningar, som annars motsvarar formeln I, i vilka emellertid minst en hydroxigrupp och/eller karbonylgruppen och/eller COORl-gruppen föreligger i funktionellt omvandlad form, 35 utföres med solvolyserande medel t.ex. vid temperaturer mellan -20 och ÅOOC. I regel arbetar man i närvaro av en sur, företrädesvis en basisk katalysator under användning av ett inert lösningsmedel.The reaction of compounds which otherwise correspond to formula I, in which, however, at least one hydroxy group and / or the carbonyl group and / or the COOR1 group is present in functionally converted form, is carried out with solvolizing agents, e.g. at temperatures between -20 and ÅOOC. As a rule, work is carried out in the presence of an acidic, preferably a basic catalyst, using an inert solvent.
Solvolyserande medel är företrädesvis hydrolyserande medel, såsom rent vatten eller vatten i blandning med organiska lösnings- U0 medel, mest i närvaro av en sur eller basisk katalysator. Såsom organiska lösningsmedel ifrâgakommer t.ex. alkoholer, såsom metanol, 'G1 10 15 20 25 50 35 H0 7 7809051 '-1 etanol, propanol, isopropanol, butanol, tert.-butylalkohol, amyl- alkohol, 2-metoxietanol eller 2-etoxietanol; etrar, såsom dietyleter, THF, dioxan eller etylenglykoldimetyleter, syror, såsom myrsyra, ättiksyra, propionsyra eller smörsyra; estrar, såsom etylacetat eller butylacetat; ketoner, såsom aceton; amider, såsom dimetylformamid (DMF) eller hexametylfosforsyratriamid (HMPT); nitriler såsom aceto- nitril; sulfoxider, såsom dimetylsulfoxid (DMSO); sulfoner, såsom tetrahydrotiofen-S,S-dioxid; samt blandningar av dessa lösningsmedel.Solvolizing agents are preferably hydrolyzing agents, such as pure water or water in admixture with organic solvents, most preferably in the presence of an acidic or basic catalyst. As organic solvents, e.g. alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, amyl alcohol, 2-methoxyethanol or 2-ethoxyethanol; ethers such as diethyl ether, THF, dioxane or ethylene glycol dimethyl ether, acids such as formic acid, acetic acid, propionic acid or butyric acid; esters such as ethyl acetate or butyl acetate; ketones such as acetone; amides such as dimethylformamide (DMF) or hexamethylphosphoric triamide (HMPT); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); sulfones such as tetrahydrotiophene-S, S-dioxide; and mixtures of these solvents.
Såsom sura katalysatorer lämpar sig vid en solvolys oorganiska syror, exempelvis saltsyra, svavelsyra, fosforsyra eller bromvätesyra; organiska syror, såsom kbrättiksyra, triklorättiksyra, eller trifluor- ättiksyra, metan-, etan-, bensen- eller p-toluensulfonsyra. Såsom basiska katalysatorer använder man vid en solvolys lämpligan alkali- metall- eller jordalkalimetallhydroxider, såsom natrium-, kalium- eller kalciumhydroxid, eller basiska salter, såsom natrium- eller kaliumkarbonat. Även organiska baser, t.ex. etyl-, dietyl-, trietyl-, isopropyl-, n-butyl- eller tri-n-butylamin, etanolamin, trietanol- amin, cyklohexylamin, dimetylanilin, pyrrolidin, piperidin, morfolin, pyridin, a-pikolin eller kinolin; eller kvarternära amm0HiUmhYdP°Xíd9P, såsom t.ex. tetrametylammoniumhydroxid eller bensyltrimetylammonium- hydroxid kan användas såsom basiska katalysatorer. Ett överskott av katalysatorn kan även användas i stället för ett lösningsmedel.As acid catalysts suitable for a solvolysis of inorganic acids, for example hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; organic acids such as hydrocyanic acid, trichloroacetic acid, or trifluoroacetic acid, methane, ethane, benzene or p-toluenesulfonic acid. As basic catalysts, suitable alkali metal or alkaline earth metal hydroxides, such as sodium, potassium or calcium hydroxide, or basic salts, such as sodium or potassium carbonate, are used in a solvolysis. Also organic bases, e.g. ethyl, diethyl, triethyl, isopropyl, n-butyl or tri-n-butylamine, ethanolamine, triethanolamine, cyclohexylamine, dimethylaniline, pyrrolidine, piperidine, morpholine, pyridine, α-picoline or quinoline; or quaternary amm0HiUmhYdP ° Xíd9P, such as e.g. tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide can be used as basic catalysts. An excess of the catalyst can also be used instead of a solvent.
Solvolystiderna ligger mellan cirka en timma och cirka 48 tim- mar; man arbetar vid temperaturer mellan cirka -5°C och cirka 80°C, företrädesvis vid rumstemperatur.Solvolytic times are between about one hour and about 48 hours; one operates at temperatures between about -5 ° C and about 80 ° C, preferably at room temperature.
En förening med formeln I (A = hydrider, speciellt komplexa metallhydrider, reduceras till motsvarande alkohol. Reduktionspotentialen hos hydriderna får inte vara så stor, att COORI-gruppen förändras. Lämpliga är t.ex. natriumborhydrid, eventuellt i närvaro av litiumbromid; vidare litiumborhydrid, speci- ellt även komplexa trialkylborhydrider, såsom litiumhexyllimonyl- boran eller borhydrider, såsom litium-perhydro-9b-borafenalylhydrid; kalciumborhydrid, magnesiumborhydrid, litium- och natriumalkoxi- aluminiumhydrider, t.ex. LiAl(O-tert.-C4H9)3H, natriumtrialkoxibor- hydrider, t.ex. natriumtrimetoxiborhydrid. Reduktionen utföres lämp- ligen i ett ínert lösningsmedel, exempelvis en alkohol, såsom meta- nol, etanol eller isopropylalkohol, en eter, såsom dietyleter, tetrahydrofuran eller dioxan, eller även i vatten, respektive i blandningar av dessa lösningsmedel vid temperaturer mellan -20°C och 40°C, företrädesvis vid rumstemperatur. Reaktionstiderna ligger mestadels mellan 15 minuter och 6 timmar.A compound of formula I (A = hydrides, especially complex metal hydrides, is reduced to the corresponding alcohol. The reduction potential of the hydrides must not be so great that the COORI group changes. Suitable are, for example, sodium borohydride, possibly in the presence of lithium bromide; , especially also complex trialkylborohydrides, such as lithium hexyllimonylborane or borohydrides, such as lithium perhydro-9b-boraphenalyl hydride; calcium borohydride, magnesium borohydride, lithium and sodium alkoxyaluminum hydrides, eg LiAl (O-tert.-C4H9) The reduction is conveniently carried out in an inert solvent, for example an alcohol, such as methanol, ethanol or isopropyl alcohol, an ether, such as diethyl ether, tetrahydrofuran or dioxane, or even in water, or in water, for example in sodium trialkoxyborohydrides. mixtures of these solvents at temperatures between -20 ° C and 40 ° C, preferably at room temperature.The reaction times are usually between 15 minutes and ch 6 hours.
-CO-) kan exempelvis med metall- 10 15 20 25 30 55 ÄO 7so9os1-1 En ester med formeln I (Bl = alkyl med l till 4 kolatomer) kan framställas ur en syra med formeln I (R = H) genom reaktion med ett förestrande medel. Förestrande medel är exempelvis alkoholer med upp till 4 kolatomer, företrädesvis i närvaro av en oorganisk eller organisk syra, såsom HCl, HBr, HJ, HZSO4, H3PO4, trifluoro- ättiksyra, en sulfonsyra, såsom bensensulfonsyra eller p-toluensul- fonsyra, eller en sur jonbytare; diazoalkaner med upp till 4 kol- atomer, företrädesvis diazometan; olefiner (t.ex. isobutylen), företrädesvis i närvaro av sura katalysatorer (t.ex. ZnCl2, BF3, H2SO¿, arylsulfonsyra, pyrofosforsyra, borsyra, oxalsyra); alkyl- halogenider med upp till 4 kolatomer, företrädesvis bromider, såsom etyl-, propyl-, isopropyl- eller butylbromid, men även de motsvaran- de -kloriderna eller -jodiderna; karbonsyra- eller sulfonsyraalkyl- estrar, varvid syragruppen kan vara godtycklig och alkylgruppen innehålla upp till 4 kolatomer, företrädesvis metyl-, etyl-, propyl-, isopropyl- eller butylacetat, -formiat, -metylsulfonat, -etylsulfo- :nat eller -p-toluensulfonat; och speciellt även dialkylsvavelsyra- estrar med upp till 4 kolatomer, såsom dimetylsulfat eller dietvl- sulfat.-CO-) can be prepared, for example, by metal- An ester of formula I (B1 = alkyl of 1 to 4 carbon atoms) can be prepared from an acid of formula I (R = H) by reaction with an esterifying agent. Eesterifying agents are, for example, alcohols having up to 4 carbon atoms, preferably in the presence of an inorganic or organic acid, such as HCl, HBr, HJ, H 2 SO 4, H 3 PO 4, trifluoroacetic acid, a sulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid, or a on ion exchange; diazoalkanes having up to 4 carbon atoms, preferably diazomethane; olefins (eg isobutylene), preferably in the presence of acid catalysts (eg ZnCl 2, BF 3, H 2 SO 3, arylsulfonic acid, pyrophosphoric acid, boric acid, oxalic acid); alkyl halides having up to 4 carbon atoms, preferably bromides, such as ethyl, propyl, isopropyl or butyl bromide, but also the corresponding chlorides or iodides; carboxylic acid or sulfonic acid alkyl esters, the acid group being arbitrary and the alkyl group containing up to 4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl or butyl acetate, formate, methylsulfonate, ethylsulfonate or -p- toluenesulfonate; and especially also dialkyl sulfuric acid esters having up to 4 carbon atoms, such as dimethyl sulphate or diethyl sulphate.
Förestringen sker lämpligen 1 ett inert företrädesvis vatten- fritt lösningsmedel, exempelvis en eter, såsom dietyleter eller THF, en alkohol, företrädesvis en av de angivna alkoholerna med upp till 4 kolatomer eller även i ett kolväte, såsom petroleumeter, hexan, r bensen eller toluen, eller i blandningar av dessa lösningsmedel vid temperaturer mellan -l0°C och 40°C, företrädesvis vid rumstemperatur.The esterification preferably takes place in an inert, preferably anhydrous solvent, for example an ether, such as diethyl ether or THF, an alcohol, preferably one of the indicated alcohols having up to 4 carbon atoms or also in a hydrocarbon, such as petroleum ether, hexane, benzene or toluene. , or in mixtures of these solvents at temperatures between -10 ° C and 40 ° C, preferably at room temperature.
Reaktionstiderna ligger i regel mellan 30 minuter och 20 timmar. estrar med formeln I (nl = alkyi med 'i 1-.111 4 xoiacomer) kan omvandlas genom solvolys till andra föreningar med formeln I (före- trädesvis med Rl = H). Lämplig är den basiska hydrolysen till syror- na med formeln I (respektive salterna därav). Man arbetar företrädes- vis i vattenhaltiga medier, exempelvis i blandningar av vatten med alkoholer, företrädesvis lágalkanoler, såsom metanol eller etanol, eller med etrar, såsom etylenglykol eller metyleter, etylenglykol- dimetyleter, TH eller dioxan vid temperaturer mellan OOC och 40°C, företrädesvis vid rumstemperatur. Reaktionstiden utgör ungefär en timma till 12 timmar.The reaction times are usually between 30 minutes and 20 hours. esters of formula I (nl = alkyl with 'in 1-.111 4 xoiacomer) can be converted by solvolysis to other compounds of formula I (preferably with R1 = H). The basic hydrolysis of the acids of the formula I (or the salts thereof) is suitable. It is preferred to work in aqueous media, for example in mixtures of water with alcohols, preferably lower alkanols, such as methanol or ethanol, or with ethers, such as ethylene glycol or methyl ether, ethylene glycol dimethyl ether, TH or dioxane at temperatures between 0 ° C and 40 ° C. preferably at room temperature. The reaction time is about one hour to 12 hours.
Man kan överföra de fria karbonsyrorna med formeln I (Bl = H) genom reaktion med en bas till ett av de fysiologiskt ofarliga me- tall- respektive ammoniumsalterna därav. Såsom salter ifrågakommer speciellt natrium-, kalium-, magnesium-, kalcium- och ammoniumsal- KF! 10 15 20 25 30 35 HO 9 7809051 '-1 terna, vidare substituerade ammoniumsalter, såsom dimetyl- och di- etylammonium-, monoetanol-, dietanol- och trietanolammonium-, cyklo- hexylammonium-, dicyklohexylammonium- och dibensyletylendiammonium- salter. Omvänt kan syrorna med formeln I firgöras ur metall- och ammoniumsalterna därav genom behandling med en syra, framför allt mineralsyror, såsom salt- eller svavelsyra.The free carboxylic acids of formula I (B1 = H) can be converted by reaction with a base into one of the physiologically harmless metal and ammonium salts thereof. As salts, sodium, potassium, magnesium, calcium and ammonium salts in particular are KF! Further substituted ammonium salts, such as dimethyl and diethylammonium, monoethanol, diethanol and triethanolammonium, cyclohexylammonium, dicyclohexylammonium and dibenzylethylenediammonium salts. Conversely, the acids of formula I can be removed from the metal and ammonium salts thereof by treatment with an acid, especially mineral acids, such as hydrochloric or sulfuric acid.
Föreningarna med formeln I erhålles mestadels såsom blandningar av olika stereoisomera former, dvs. i regel såsom blandningar av racemater. Racematen kan isoleras ur racematblandningarna och er- hållas rena, exempelvis genom omkristallisation av föreningarna själva och av väl kristalliserande derivat, genom destillation, speciellt emellertid med hjälp av kromatografiska metoder, varvid såväl adsorptionskromatografiska eller fördelningskromatografiska metoder såsom även blandformer ifrågakommer.The compounds of formula I are mostly obtained as mixtures of different stereoisomeric forms, i.e. usually as mixtures of racemates. The racemates can be isolated from the racemate mixtures and obtained pure, for example by recrystallization of the compounds themselves and by well crystallizing derivatives, by distillation, especially by means of chromatographic methods, both adsorption chromatographic or partition chromatographic methods as well as mixed forms.
Racematen kan separeras enligt kända metoder, såsom de som är angivna i litteraturen, till optiska antipoder därav. Metoden med kemisk separering föredrages. Så kan man bringa en optisk aktiv bas att reagera med karboxylgruppen av en förening med formeln I. T.ex. kan man bilda diastereomera salter med optiskt aktiva aminer, såsom kinin, cinkonidin, brucin, cinkonin, hydroxihydrindamin, morfin, l-fenyletylamin, 1-naftyletylamin, fenyloxinaftylmetylamin, kinidin, stryknin, basiska aminosyror, såsom lysin, arginin, aminosyraestrar.The racemates can be separated by known methods, such as those reported in the literature, into optical antipodes thereof. The method of chemical separation is preferred. Thus, an optically active base can be reacted with the carboxyl group of a compound of formula I. E.g. For example, diastereomeric salts can be formed with optically active amines such as quinine, cinconidine, brucine, cinconin, hydroxyhydrinamine, morphine, 1-phenylethylamine, 1-naphthylethylamine, phenyloxynaphthylmethylamine, quinidine, strychnine, basic amino acids such as lysine, arginine esters.
På liknande sätt låter sig ester-diastereomererna framställas genom förestring av karbonsyror med formeln I (RI = H) med optiskt aktiva alkoholer, såsom borneol, mentol, oktanol-2. De erhållna diastereo- mera salterna respektive estrarna separeras genom kristallisation och de optiskt aktiva föreningarna frigöras ur blandningen.Similarly, the ester diastereomers can be prepared by esterification of carboxylic acids of formula I (RI = H) with optically active alcohols, such as borneol, menthol, octanol-2. The resulting diastereomeric salts and esters are separated by crystallization and the optically active compounds are released from the mixture.
Men även de andra i föreningarna med formeln I närvarande funktionella grupperna kan anlitas för bildning av diastereomerer.However, the other functional groups present in the compounds of the formula I can also be used to form diastereomers.
Så kan man t.ex. förestra OH-grupper med optiskt aktiva syror, såsom (+)- och (-)-vinsyra eller kamfersyra eller bringa ketogrupperna att reagera med optiskt aktiva hydraziner, såsom metylhydrazin och ur dessa derivat utvinna de rena enantiomererna.Then you can e.g. esterify OH groups with optically active acids, such as (+) - and (-) - tartaric acid or camphoric acid or react the keto groups with optically active hydrazines, such as methylhydrazine, and recover from these derivatives the pure enantiomers.
Vidare är det naturligtvis möjligt att erhålla optiskt aktiva föreningar enligt de beskrivna metoderna, i det man använder ut- gångsämnen, som redan är optiskt aktiva.Furthermore, it is of course possible to obtain optically active compounds according to the methods described, using starting materials which are already optically active.
De nya föreningarna kan i blandning med fasta, vätskeformiga och/eller halvflytande bärare användas inom-human-eller* Vêtê~ rinärmedicinen. Såsom bärarsubstanser ifrågakommer sådana or- ganiska eller oorganiska ämnen, som är lämpliga för den paren- terala, enterala eller lokala användningen och som inte träder 10 15 20 25 30 35 H0 7809Û51~1 10 1 reaktion med de nya föreningarna, såsom vatten, vegetabi- liska oljor, bensylalkoholer, polyetylenglykoler, gelatiner, laktos, stärkelse, magnesiumstearat, talk, vaselin, kolesterol. För paten- teral användning tjänar speciellt lösningar, företrädesvis oljiga eller vattenhaltiga lösningar, samt suspensioner, emulsioner eller implantat. För den enterala användningen lämpar sig sig tabletter, drageer, siraper, safter eller suppositorier, för den lokala använd- ningen salver, krämer eller puder. De angivna beredningarna kan even- tuellt steriliseras eller försättas med hjälpämnen, såsom smörj- medel, konserveringsmedel, stabiliseringsmedel eller vätmedel, emul- germedel, salter för påverkan av det osmotiska trycket, buffertsub- stanser, färg-, smak- och/eller aromämnen.The new compounds can be used in admixture with solid, liquid and / or semi-liquid carriers in human or veterinary medicine. As carrier substances, there are those organic or inorganic substances which are suitable for parenteral, enteral or local use and which do not react with the new compounds, such as water, vegetables. - essential oils, benzyl alcohols, polyethylene glycols, gelatins, lactose, starch, magnesium stearate, talc, petrolatum, cholesterol. For patent use, solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants are particularly useful. For enteral use, tablets, dragees, syrups, juices or suppositories are suitable, for local use ointments, creams or powders. The indicated preparations may optionally be sterilized or supplemented with excipients, such as lubricants, preservatives, stabilizers or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, buffering substances, coloring, flavoring and / or flavoring agents.
Substanserna tillföres företrädesvis i en dosering från 0,01 till 200 mg per doseringsenhet; doseringen är beroende av den be- handlade patienten, av användningsformen och behandlingsändamàlet, den kan därför även under- respektive överskrida de ovan angivna värdena.The substances are preferably administered in a dosage of from 0.01 to 200 mg per dosage unit; the dosage depends on the patient being treated, on the form of use and the purpose of the treatment, it may therefore also fall or exceed the values given above.
IR-spektra (IR) karakteriserades genom angivande av huvudbanden (såsom film).IR spectra (IR) were characterized by indicating the main bands (such as film).
NM-spektra (NNE) mättes i CDCl3 mot tetrametylsilan och karak- teriserades genom angivande av signalerna i ppm; därvid betecknar m = multiplett, q = kvartett, t = triplett, d = dubblett och s = singulett. var och en av de i de följande exemplen angivna föreningarna med formeln I är speciellt lämpliga för framställningen av läke- medel.NM spectra (NNE) were measured in CDCl 3 against tetramethylsilane and characterized by indicating the signals in ppm; thereby denoting m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet. each of the compounds of formula I given in the following examples are particularly suitable for the preparation of medicaments.
Exempel 1. Man omrör en blandning av 1 g 11,15-dihydroxi-15-metyl- 16-p-fluorofenyl-9-oxo-13-tia-17,18,19,20-tetranor-5-prostensyra, 0,6 g NaBHu och 15 ml i 3 timmar vid rumstemperatur och upparbetar sedan reaktionsblandningen. Man erhåller 9,11,15-trihydroxi-15- metyl-16-p-fluorofenyl-15-tia-17,18,19,20-tetranor-5-prostensyra såsom Olja.Example 1. A mixture of 1 g of 11,15-dihydroxy-15-methyl-16-p-fluorophenyl-9-oxo-13-thia-17,18,19,20-tetranor-5-prostenoic acid is stirred. 6 g of NaBHu and 15 ml for 3 hours at room temperature and then work up the reaction mixture. 9,11,15-trihydroxy-15-methyl-16-p-fluorophenyl-15-thia-17,18,19,20-tetranor-5-prostenic acid such as Oil are obtained.
IR: 1210, 1510, 1705, 2700, 29H0, 3650 cm-1.IR: 1210, 1510, 1705, 2700, 29H0, 3650 cm-1.
Exempel 21 Analogt med exempel J. är ur_de motsvarande 9-oxo-för- (A = -COÉ) genom reaktion med NaBHu -- eningarna med formeln 1 erhållbart: *_ _ 9,ll,l5-trihydroxi-16-p-fluorofenoxè13-tia~17,l8,l9,20-tetranor-5- prostensyra, IR; 1210, 1505, 1710, 2100, 2900, 3700 cm'l NäR: 1,1-2,6 (m), 2,7-3,1 (m), 0,05 (m), u,2 (m), 5,30 (m), 5,u5 (m), 10 15 20 50 \.\1 M1 7009051-1 11 6,85 (S), 6;95 (d) 9,11,l5-trihydroxi-l6-m-klorofenoxi-l3-tia-17,l8,l9,20-tetranor-5- prostensyra Ia; 1710, 2400, 3650 cm' NMR: 1,1~2,6 (m), 2,6-3,1 (m), 4,05 (m), 4,2 (m), 5,3 (m), 5,4 (m), 6,6-7,4 (m). 9,ll-dihydroxí-15-metoxi-16-p-fluorofenoxí-13-tia-17,l8,l9,20-tetra- l nor-prostensyra IR; 1210, 1505, 1710, 2100, 2900, 3700 cm' ann: 1,1-2,6 (m), 2,95 (m), 3,50 (s), 3,75 (m), 4,0 (m), 4,10 (mä, 5,40 (m), 5,60 (m), 6,85 (d), 6,95 (d)- Exemgel 3. Analogt med exempel .1 är ur de motsvarande 9-oxo- -föreningarna genom reaktion med NaBH4 erhàllbart. 9,11,1S-tríhydroxí-15-metyl-16-m-klorofenoxi-13-tia-17,18,19,20- -tetranor-5-prostensyra IR; 1600, 1710, 2900, 3400 cm"; NMR: 1,4; 4,2; 4,95; 5,45; 6,7 - 7,3. 9,11,15-trihydroxi-15-metyl-17-fenyl-13-tia-18,19,20-trínor-5- -prostensyra, IR: 1600, 1700, 2950, 3400 cm'1; NMR: 1,35; 4,18; 5,42; 7,22. 9,11,15-tríhydroxi-15-metyl-17-m-klorfenyl-13-tia-18,19,20- trinor-5-prostensyra, IR; 1050, 1240, 1600, 1710, 2900, 3400 cm' NMR: 1,32; 4,0 - 4,3; 5,35; 7,0 - 7,2. 9,11,15-trihydroxi-15-metyl-17-m-trifluormetylfenyl-13-tia- 1 1 18,19,20-trínor-5-prostensyra, IR; 1720, 3450 cm"1; NMR: 1,35; 5,25; 5,48; 7,45.Example 21 In analogy to Example J., the corresponding 9-oxo-for- (A = -COÉ) by reaction with the NaBHu compounds of formula 1 is obtainable: 9,11,15-trihydroxy-16-p-fluorophenoxè13 -thia-17,18,19,20-tetranor-5-prostenic acid, IR; 1210, 1505, 1710, 2100, 2900, 3700 cm -1 When: 1.1-2.6 (m), 2.7-3.1 (m), 0.05 (m), u, 2 (m ), 5.30 (m), 5, u5 (m), 10 15 20 50 \. \ 1 M1 7009051-1 11 6.85 (S), 6.95 (d) 9.11, 15-trihydroxy- 16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-prostenic acid Ia; 1710, 2400, 3650 cm -1 NMR: 1.1 ~ 2.6 (m), 2.6-3.1 (m), 4.05 (m), 4.2 (m), 5.3 (m ), 5.4 (m), 6.6-7.4 (m). 9,11-dihydroxy-15-methoxy-16-p-fluorophenoxy-13-thia-17,18,19,20-tetra-1-nor-prostenoic acid IR; 1210, 1505, 1710, 2100, 2900, 3700 cm -1: 1.1-2.6 (m), 2.95 (m), 3.50 (s), 3.75 (m), 4.0 (m), 4.10 (mä, 5.40 (m), 5.60 (m), 6.85 (d), 6.95 (d) - Example gel 3. Analogous to Example 1 are from the corresponding The 9-oxo- compounds obtained by reaction with NaBH 4 9,11,1S-trihydroxy-15-methyl-16-m-chlorophenoxy-13-thia-17,18,19,20--tetranor-5-prostenic acid IR; 1600, 1710, 2900, 3400 cm -1; NMR: 1.4; 4.2; 4.95; 5.45; 6.7-7.3. 9,11,15-trihydroxy-15-methyl-17- phenyl-13-thia-18,19,20-trinor-5-prostenic acid, IR: 1600, 1700, 2950, 3400 cm -1; NMR: 1.35; 4.18; 5.42; 7.22. 9,11,15-trihydroxy-15-methyl-17-m-chlorophenyl-13-thia-18,19,20-trinor-5-prostenoic acid, IR; 1050, 1240, 1600, 1710, 2900, 3400 cm -1 NMR : 1.32; 4.0 - 4.3; 5.35; 7.0 - 7.2 9,11,15-trihydroxy-15-methyl-17-m-trifluoromethylphenyl-13-thia-1 1 18 19,20-Trinor-5-prostenoic acid, IR; 1720, 3450 cm -1; NMR: 1.35; 5.25; 5.48; 7.45.
De efterföljande exemplen avser farmaceutiska beredningar, som innehåller föreningar med den allmänna formeln I respektive farmakologiskt ofarliga salter därav; Exempel A: Tabletter En blandning, bestående av 30 g av natriumsaltet9,11J5- tnfiwdroxi-15-metyl-l6-p-fluorofenoxi-13-tia-17,18,19,20- tetranor-5-pnxmensyra, 50 g laktos, 16 g majsstärkelse, 2 g cellulosa- pulver och 2 g magnesiumstearat pressas pà vanligt sätt till tablet- ter, på så sätt att varje tablett innehåller 30 mg av det verksamma ämnet. 10 15 20 25 30 7809051-1 12 Exempel B: Drageer Analogt med Exempel A pressas tabletter, som därefter på van- ligt sätt överdrages med ett skikt bestående av socker, majsstärkel- se, talk och dragant. 2 Analogt är tabletter och dragéer erhållbara, som innehåller en eller flera av de övriga verksamma ämnena med formeln I respek- tive fysiologiskt ofarliga syraadditionssalter därav.The following examples relate to pharmaceutical preparations containing compounds of the general formula I and to pharmacologically harmless salts thereof; Example A: Tablets A mixture consisting of 30 g of the sodium salt 9,11J5-trihydroxy-15-methyl-16-p-fluorophenoxy-13-thia-17,18,19,20-tetranor-5-punchmenic acid, 50 g of lactose, 16 g of corn starch, 2 g of cellulose powder and 2 g of magnesium stearate are compressed into tablets in the usual way, so that each tablet contains 30 mg of the active substance. Example 15: Dragees In analogy to Example A, tablets are pressed, which are then usually coated with a layer consisting of sugar, corn starch, talc and tragacanth. 2 Analogously, tablets and dragees are available which contain one or more of the other active substances of the formula I or their physiologically harmless acid addition salts.
Jämförelseförsök För undersökning av verkan av föreliggande föreningar såsom luteolytika underkastades föreliggande föreningar 9«,11q,1S- trihydroxi-16-m-klorfenoxi-13-tia-17,18,19,20-tetranor-5-cis- -prostensyra (dubbelracemat) och 9w,11q,15M-tríhydroxi-16-m-klor- fenoxi-13-tia-17,18,19,20-tetranor-S-cis-prostensyra (racemat) i jämförelse med det kända luteolytikumet PGFZM (9x,11i,15«-tri- hydroxí-5-cis, 13-transprostadiensyra) efterföljande undersökningar: a) Dräktighetsavbrottsförsök på hamstrar SPF-hamstrar med en vikt av ca 200 g användes. Alla djur var i rum med konstant temperatur och placerades i en ljus-mörkerrytm av 14:10 timmar.Comparative Experiments To investigate the efficacy of the present compounds as luteolytics, the present compounds were subjected to 9 «, 11q, 1S-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-cis--prostenic acid (double racemate). ) and 9w, 11q, 15M-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-S-cis-prostenic acid (racemate) in comparison with the known luteolytic PGFZM (9x, 11i, 15 «-tri-hydroxy-5-cis, 13-transprostadienoic acid) the following studies: a) Termination tests on hamsters SPF hamsters weighing about 200 g were used. All animals were in constant temperature rooms and were placed in a light-dark rhythm of 14:10 hours.
På föröstrusdagen sammansattes honorna med hanarna med visad fertilitet. Kunde man nästa dag i vaginalutstrykningen påvisa sperma, togs djuret i försöket. Dagen för det positiva spermie- påvisandet gällde såsom 1:a dräktighetsdagen. På 6:e gestations- dagen tillfördes hamstrarna subkutana ínjektioner av försöks- substanserna med en volym av 0,2 mm. Föreningarna var lösta í DMSO.On the day of pre-pregnancy, the females were composed with the males with shown fertility. If the next day in the vaginal smear could show semen, the animal was taken in the experiment. The day for the positive sperm detection was considered as the 1st day of pregnancy. On the 6th day of gestation, the hamsters were given subcutaneous injections of the test substances with a volume of 0.2 mm. The compounds were dissolved in DMSO.
Dissektion av djuren skedde på 9:e dagen. Uterí avlägsnades ooh antalet levande foster resp. míkrobrester fastställdes. Färgen hos corpus luteum vid ytan av ovariet bedömdes under preparatmikro- skop. Ljus corpus luteum gällde såsom frisk (jfr LABHSETWAR, A, P.; (1971), Nature, 230, 528-529).Dissection of the animals took place on the 9th day. The uterus was removed ooh the number of living fetuses resp. microbial residues were determined. The color of the corpus luteum at the surface of the ovary was assessed under a specimen microscope. Light corpus luteum was considered healthy (cf. LABHSETWAR, A, P .; (1971), Nature, 230, 528-529).
Resultaten är sammanställda i efterföljande tabell: 10 15 Z0 ZS 7809051 '-1 Förening Dos per Antal behand- Antal av hamstrar' Antal av hamst- hamster lade hamstrar med uppnått av- rar med ljus Qag) brott Corpus luteum PGFZ w 1 o 5 o 0 25 3 3 3 9u,lhï,1S«-tri- 0,4 7 2 2 hydroxi-16-m-klor- fenoxi-13-tia-17, Û'8 10 5 4 l8,19,20-tetra- 1,6 10 5 5 nor-5-cis-prosten- syra (racemat) 3'Z 2 2 2 Tabellen visar, att föreliggande förening redan i en dosering av 0,8 På per djur hos hälften av försöksdjuren leder till avbrott av dräktigheten: en dos av 3,2 pg per djur åstadkommer hos alla försöks- djuren ett dräktighetsavbrott. Vid föreliggande förening ligger den 100% verksamma dosen, dvs dosen, som hos alla försöksdjuren leder till avbrott av dräktigheten, följaktligen mellan 0,8 och 3,2,ug per djur.The results are summarized in the following table: 10 15 Z0 ZS 7809051 '-1 Compound Dose per Number of treatments- Number of hamsters' Number of hamsters- hamsters laid hamsters with achieved avrar with light Qag) crime Corpus luteum PGFZ w 1 o 5 o Hydroxy-16-m-chlorophenoxy-13-thia-17,''8 10 5 4 l8,19,20-tetra- 1.6 10 5 5 nor-5-cis-prostenic acid (racemate) 3'Z 2 2 2 The table shows that the present compound already at a dosage of 0.8 Pa per animal in half of the experimental animals leads to termination of pregnancy : a dose of 3.2 pg per animal causes a cessation of pregnancy in all experimental animals. In the present compound, the 100% effective dose, i.e. the dose which in all experimental animals leads to termination of pregnancy, is consequently between 0.8 and 3.2 .mu.g per animal.
Såsom luteolytikum känd PGF2u'visar däremot vid en dosering av 10 pg per djur inte någon som helst verkan; först vid en dosering av 25/ug per djur uppnås hos alla försöksdjuren ett avbrott av dräktígheten.On the other hand, as a luteolytic known PGF2u ', at a dose of 10 pg per animal does not show any effect; only at a dosage of 25 .mu.g per animal is an interruption of pregnancy achieved in all experimental animals.
Föreliggande uppfinning uppvisar följaktligen minst den 10-faldiga verkan av känd PGF2“¿ b) Försök för luteolys, östrus- och ovulatíonssynkroníseríng på unga kossor.Accordingly, the present invention exhibits at least the 10-fold effect of known PGF2 ¿b) Attempts at luteolysis, oestrus and ovulation synchronization on young cows.
Unga kossor i åldern 1-3 år, som ännu inte kalvat, men dock minst hade uthärdat en brunst, ifrágakom i försöket. I början undersöktes alla djuren avseende fullgott friskhetstíllstånd. Med hjälp av rektal palpation utvaldes djuren, vars reproduktionsorgan var normalt utvecklade. Medelst en vasektomerad tjur testades de unga kossorna sex gånger dagligen på en inhägnad gårdäng på brunstför- hållande. uteslutande djur med entydigt palpabel corpus luteum behandlades. Palpatoriska undersökningar av ovarii och uterus genomfördes tre gånger i veckan och vid väntad brunsttidpunkt ofta även dagligen för att kunna följa follikelmognande, ovulation, bildning och återbildníng av corpus luteum. 10 15 7809051-1 14 En intramuskulär engångsinjektíon tíllfördes på den 7:e dagen eller senare, inte dock efter den 12:e dagen av brunstcykeln. Därvid gällde dagen såsom dag 1, vid vilken den vasektomerade tjuren för första gängen reagerade på brunstförhållandet.Young cows aged 1-3 years, which have not yet calved, but at least had endured a heat, were included in the experiment. Initially, all animals were examined for complete freshness. Using rectal palpation, the animals whose reproductive organs were normally developed were selected. By means of a vasectomized bull, the young cows were tested six times a day on a fenced farm meadow in heat condition. exclusively animals with unambiguously palpable corpus luteum were treated. Palpatory examinations of the ovary and uterus were performed three times a week and at the expected time of oestrus often also daily in order to monitor follicular maturation, ovulation, formation and regeneration of the corpus luteum. 10 15 7809051-1 14 A single intramuscular injection was given on the 7th day or later, but not after the 12th day of the oestrus cycle. In this case, the day was the same as day 1, at which the vasectomized bull for the first time reacted to the heat ratio.
Verkan fastställdes med hjälp av följande kriterier: a) Återbildning av corpus luteum inom loppet av 2 dager b) Inträdande av brunsten 3-5 dager efter injektionen och förnyad brunst efter 21 dagar.Efficacy was determined using the following criteria: a) Reconstruction of the corpus luteum within 2 days b) Occurrence of oestrus 3-5 days after injection and renewed oestrus after 21 days.
Resultaten är sammanställda i efterföljande tabell: Förening - Dos Antal behand- Antal av de unga Gränsdos . Gu 3 lade unga kossor kossorna med luteo- g lytisk verkan Üng) PGFZM 5 ^-5 10 2 9%,11w,15-trí- 2,5 1 ñvz 5 hydroxi-16-mfklor- S 2 * 2 = fenoxi-13-tia- -17,18,19,20-tetra- nor-5-cis-prosten- syra (dubbel- racemat) 9u,11v<,15=<-tri- 2,5 hydroxi-16-mfklor- fenoxi-13-tia-17,18, 5 5 5 52'5 l9,20-tetranor-S- 10 4 4 -cis-prostensyra (racematl Resultaten av detta försök visar, att föreliggande förening redan i en dos av 2,5 mg per djur uppvisar en 100-procentig verkan, dvs vid alla behandlade djur åstadkommer en luteolys. Gränsdosen är fö1j~ aktligen 3 2,5 per djur.The results are summarized in the following table: Association - Dose Number of treatment- Number of young Border dose. Gu 3 laid young cows the cows with luteo- g lytic effect Üng) PGFZM 5 ^ -5 10 2 9%, 11w, 15-tri- 2,5 1 ñvz 5 hydroxy-16-mfchlor- S 2 * 2 = phenoxy-13 -thia- -17,18,19,20-tetra-nor-5-cis-prostenic acid (double-racemate) 9u, 11v <, 15 = <- tri-2,5-hydroxy-16-m-chloro-phenoxy- 13-thia-17,18, 5 5 5 52'5 19,20-tetranor-S-4 4 -cis-prostenic acid (racemate) The results of this experiment show that the present compound already in a dose of 2.5 mg per animals show a 100% effect, ie in all treated animals a luteolysis is achieved.The limit dose is actually 3 2.5 per animal.
Känd PGFZN åstadkommer däremot först i en dosering av 10 mg per djur vid alla behandlade djur en hnßolys; vid en dosering av S mg per djur visar sig endast vid 66% av de behandlade djuren luteo- 'lytiska verkningar. lFöreliggande föreningar uppvisar följaktligen i detta försök minst den 4-faldiga verkan av PGFZW. 7809051 -1 15 c) Dessutøm till förut angivna uppförda försöksdata erhölls í urvalsförsök i dräktíghetsavbrottsförsöket på hamstrar följande resultat, som styrker den överlägna verkan hos föreliggande föreningar gentemot strukturbesläktade föreningar från den svenska ansökningen 73 15426-2.Known PGFZN, on the other hand, first results in a dose of 10 mg per animal in all treated animals; at a dose of S mg per animal, luteolytic effects appear only in 66% of the treated animals. Accordingly, the present compounds show in this experiment at least the 4-fold effect of PGFZW. 7809051 -1 15 c) In addition to the previously stated experimental data, the following results were obtained in the sampling experiment in the gestation interruption experiment on hamsters, which proves the superior effect of the present compounds compared to structurally related compounds from the Swedish application 73 15426-2.
Förening A = Förening B = Förening C = Förening D Förening E Förening F 9<,11«,1S-trihydroxi-15-metyl-17-fenyl-13-tia-18,19, 20-trinor-cis-prostensyra 9<,11g;15-tríhydroxi-1S-metyl-17-fenyl-13-tia-18,19, 20-trínor-prostflnsyra 9K,11«}15-trihydroxi-15-metyl-16-m-klorfenoxí-13-tia~ 17,18,19,Z0-tetranor-5-cis-prostensyra 9%,11Q¿15 -trihydroxí-16-m-klorfenoxi-13-tia-17,18, 19,20-tetranor-5-cis-prostensyra 9x,11Q315-tríhydroxí-15-metyl-13-tia-prostansyra 9w,11w;15-trihydroxí-15-metyl-13-tia-prostansyrametyl~ ester 7809051' -1 16 Am xmmwmw om "EmwxHu> mwwxfifl ovcwnmmuaom wow mnwcwë fl uxflfioccæm 3%; 96 .wflwpm |mm: m>h:xwwc«n uwwon comm: oucfi JUN _ :N .| mom x m G14 m mom X N A Qofi OF Q rCN \( VON .| wwß X _ V m mmm X P ^ o°_ om U K xN 1 OOP WN < Nwwm x m.@=< m mom x P A fipwg ym |mfluxmnu cmu:nn>m acw mmm wwë cwuøfiu >æ wv wswm mmm Hfifiu HHH» Qmfiwpßw pxmwmw \w1 @wH@»@«Em« H m=«=E@@@m wcfiøwhßm -Emfi fi mcfiflewwwm -m~@»flHfi@»@«fi~=< mom w=H=@%@ß N-@N«mP mß =mw=fi=@m=« «~w=@>m mcficcfiwams owcmwwflflmpßmCompound A = Compound B = Compound C = Compound D Compound E Compound F 9 <, 11 «, 1S-trihydroxy-15-methyl-17-phenyl-13-thia-18,19, 20-trinor-cis-prostenic acid 9 < 11g; 15-trihydroxy-1S-methyl-17-phenyl-13-thia-18,19,20-trinor-prostanoic acid 9K, 11 «} 15-trihydroxy-15-methyl-16-m-chlorophenoxy-13-thia 1717,18,19,20-tetranor-5-cis-prostenic acid 9%, 11Q15-trihydroxy-16-m-chlorophenoxy-13-thia-17,18,19,20-tetranor-5-cis-prostenic acid 9x, 11Q315-trihydroxy-15-methyl-13-thia-prostanoic acid 9w, 11w; 15-trihydroxy-15-methyl-13-thia-prostanoic acid methyl ester 7809051 '-1 16 Am xmmwmw om "EmwxHu> mwwx fifl ovcwnmmuaw wow mnw ux flfi occæm 3%; 96 .w fl wpm | mm: m> h: xwwc «n uwwon comm: ouc fi JUN _: N. | mom xm G14 m mom XNA Qo fi OF Q rCN \ (VON. | wwß X _ V m mmm XP ^ o ° _ om UK xN 1 OOP WN <Nwwm x m. @ = <m mom x PA fi pwg ym | m fl uxmnu cmu: nn> m acw mmm wwë cwuø fi u> æ wv wswm mmm H fifi u HHH »Qm fi wpßw pxmwmw @ w1 @ @ «Em« H m = «= E @@@ m wc fi øwhßm -Em fi fi mc fifl ewwwm -m ~ @» fl H fi @ »@« fi ~ = <mom w = H = @% @ ß N- @ N «mP mß = mw = fi = @ m = «« ~ w = @> m mc fi cc fi wams owcmww flfl mpßm
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2422924A DE2422924A1 (en) | 1974-05-11 | 1974-05-11 | THIAPROSTAGLANDINE |
| DE19752513371 DE2513371C2 (en) | 1975-03-26 | 1975-03-26 | 9,11,15-trihydroxy-13-thia-5-prostenic acid derivatives and pharmaceutical preparations containing them |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| SE7809051L SE7809051L (en) | 1978-08-29 |
| SE428207B true SE428207B (en) | 1983-06-13 |
Family
ID=25767110
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7505224A SE419755B (en) | 1974-05-11 | 1975-05-06 | PROCEDURE FOR PREPARING 13-THIAPROSTAGLAND INGREDIENTS |
| SE7809051A SE428207B (en) | 1974-05-11 | 1978-08-28 | 9,11,15, -TRIHYDROXI-13-TIA-5-PROSTENIC ACID DERIVATIVES FOR USING LUTEOLYTIC AND PREPARATIONS CONTAINING THIS |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7505224A SE419755B (en) | 1974-05-11 | 1975-05-06 | PROCEDURE FOR PREPARING 13-THIAPROSTAGLAND INGREDIENTS |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | IT1120412B (en) |
| SE (2) | SE419755B (en) |
-
1975
- 1975-05-06 SE SE7505224A patent/SE419755B/en not_active IP Right Cessation
-
1978
- 1978-08-28 SE SE7809051A patent/SE428207B/en not_active IP Right Cessation
-
1979
- 1979-04-24 IT IT4883379A patent/IT1120412B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IT7948833A0 (en) | 1979-04-24 |
| IT1120412B (en) | 1986-03-26 |
| SE419755B (en) | 1981-08-24 |
| SE7505224L (en) | 1975-11-12 |
| SE7809051L (en) | 1978-08-29 |
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