NO792313L - PROCEDURE FOR PREPARING 20-METHYL-13,14-DIDEHYDRO-PGI2 DERIVATIVES - Google Patents
PROCEDURE FOR PREPARING 20-METHYL-13,14-DIDEHYDRO-PGI2 DERIVATIVESInfo
- Publication number
- NO792313L NO792313L NO792313A NO792313A NO792313L NO 792313 L NO792313 L NO 792313L NO 792313 A NO792313 A NO 792313A NO 792313 A NO792313 A NO 792313A NO 792313 L NO792313 L NO 792313L
- Authority
- NO
- Norway
- Prior art keywords
- salt
- methyl
- pgi2
- didehydro
- process according
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 40
- 150000001447 alkali salts Chemical class 0.000 claims description 10
- 159000000000 sodium salts Chemical class 0.000 claims description 7
- 238000006704 dehydrohalogenation reaction Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 7
- 238000004519 manufacturing process Methods 0.000 claims 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 8
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960001123 epoprostenol Drugs 0.000 description 6
- 238000001802 infusion Methods 0.000 description 5
- 230000000304 vasodilatating effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 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 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000002744 anti-aggregatory effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 210000004351 coronary vessel Anatomy 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000003975 mesenteric artery Anatomy 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- -1 potassium alkoxide Chemical class 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002997 prostaglandinlike Effects 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 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 1
- 108010051913 15-hydroxyprostaglandin dehydrogenase Proteins 0.000 description 1
- QLVKECUOHNDWOI-UHFFFAOYSA-N 2-oxo-1,3,2$l^{5}-diazaphosphonan-2-amine Chemical compound NP1(=O)NCCCCCCN1 QLVKECUOHNDWOI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 101710129448 Glucose-6-phosphate isomerase 2 Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 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 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
- C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Furan Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for The present invention relates to a method for
fremstilling av 20-metyl-13,14-didehydro-PGI2-derivater. preparation of 20-methyl-13,14-didehydro-PGI2 derivatives.
Forbindelsene ifølge oppfinnelsen har den følgende formel: The compounds according to the invention have the following formula:
der R er hydrogen.eller metyl og M er hydrogen eller et farma-søytisk akseptabelt kation. Gjenstand for oppfinnelsen er også farmasøytiske preparater inneholdende forbindelser med formelen (I). M er fortrinnsvis kation av et alkalimetall, f.eks. natrium eller kalium. I formelen ifølge oppfinnelsen angir den strekede linje ( ).at en substituent bundet til en ring er i a (eller endo) konfigurasjon og at en substituent bundet til en kjede er i konfigurasjon S; bølgelinjen ( ) antyder at en substituent bundet til en ring kan ha enten a (endo) konfigurasjon eller 3 (exo) konfigurasjon, og at en substituent bundet til en kjede kan ha enten R eller S konfigurasjon. Begge de individuelle konfigurasjonsisomerer, f.eks. de individuelle 16S-metyl og.16R-metylepimerer, og disses blandinger, ligger innenfor oppfinnelsens ramme. Forbindelsen ifølge oppfinnelsen where R is hydrogen or methyl and M is hydrogen or a pharmaceutically acceptable cation. Subject matter of the invention are also pharmaceutical preparations containing compounds of the formula (I). M is preferably the cation of an alkali metal, e.g. sodium or potassium. In the formula according to the invention, the dashed line ( ). indicates that a substituent attached to a ring is in a (or endo) configuration and that a substituent attached to a chain is in configuration S; the wavy line ( ) suggests that a substituent attached to a ring can have either the a (endo) configuration or the 3 (exo) configuration, and that a substituent attached to a chain can have either the R or S configuration. Both individual configurational isomers, e.g. the individual 16S-methyl and .16R-methyl epimers, and their mixtures, are within the scope of the invention. The compound according to the invention
oppnås ved dehydrohalogenering av dihalogenforbindelser med formelen (II) obtained by dehydrohalogenation of dihalogen compounds with the formula (II)
der R og M har den ovenfor angitte betydning og hver av gruppene ogX^ som kan være like eller forskjellige, er et halogenatom valgt blant brom, klor og jod, fulgt av eventuell forsalting av den oppnådde forbindelse. where R and M have the meaning indicated above and each of the groups and X^ which may be the same or different, is a halogen atom selected from bromine, chlorine and iodine, followed by possible saltation of the compound obtained.
X2 er fortrinnsvis et bromatom. Dehydrohalogenerings-reaksjonen gjennomføres fortrinnsvis ved å bringe en forbindelse med formelen (II) til reaksjon med et overskudd av et dehydrohalogeneringsmiddel valgt f.eks. blant et dimetylsulfi-nylkarbanion, et alkalisk, f.eks. natrium- eller kaliumalkoksyd, fortrinnsvis natrium- eller kaliummetoksyd, -etoksyd, -propoksyd eller - butoksyd, ved å arbeide i et inert vannfritt oppløs-ningsmiddel, fortrinnsvis valgt blant rette og forgrenede alkoholer inneholdende fra 1 til 6 karbonatomer, f.eks. metyl-, etyl-, propyl-, butyl-, isopropylalkohol, dimetylsulfoksyd og heksametylenfosforamid. X 2 is preferably a bromine atom. The dehydrohalogenation reaction is preferably carried out by reacting a compound of the formula (II) with an excess of a dehydrohalogenation agent chosen e.g. among a dimethylsulfinylcarbanion, an alkaline, e.g. sodium or potassium alkoxide, preferably sodium or potassium methoxide, -ethoxide, -propoxide or -butoxide, by working in an inert anhydrous solvent, preferably chosen from straight and branched alcohols containing from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, butyl, isopropyl alcohol, dimethyl sulfoxide and hexamethylene phosphoramide.
Reaksjonstemperaturen kan variere fra romtemperatur The reaction temperature can vary from room temperature
til kokepunktet for oppløsningsmidlet og reaksjonstiden variere fra noen minutter til flere timer. to the boiling point of the solvent and the reaction time varies from a few minutes to several hours.
Reaksjonen gjennomføres fortrinnsvis ved en temperatur innen området 20-45°G med reaksjonstider på 2 til 3 timer. The reaction is preferably carried out at a temperature within the range 20-45°C with reaction times of 2 to 3 hours.
Ved slutten av. reaksjonstiden fordampes oppløsnings-midlet av under vakuum og forbindelsene ifølge oppfinnelsen krystalliseres, fortrinnsvis fra vann- eller hydroalkoholiske oppløsninger. At the end of. during the reaction time, the solvent is evaporated off under vacuum and the compounds according to the invention are crystallized, preferably from water or hydroalcoholic solutions.
Det eventuelle forsaltningstrinnet gjennomføres på vanlig måte. Forbindelser med formelen (II) er allerede kjent og kan syntetiseres f.eks. ved en av de prosesser som er be-skrevet i tysk Offenlegungsschrift nr. 2757919 tilsvarende The possible salting step is carried out in the usual way. Compounds with the formula (II) are already known and can be synthesized, e.g. by one of the processes described in German Offenlegungsschrift no. 2757919 corresponding
belgisk patent nr. 862.514. Belgian Patent No. 862,514.
Prostacyklin eller PGI2("Prostaglandirier", 12, 6. de-sember 1976, side 915) er et kjent vasodilaterings- og anti-aggregeringsmiddel som biosyntetiseres i arteriér og lunger i pattedyr og mennesker ved å gå ut fra arakidonsyre (Gryglewski et al., "Prostaglandiner", 12, 658, 1976). Prostacyclin or PGI2 ("Prostaglandiriers", 12, 6 December 1976, page 915) is a known vasodilator and anti-aggregation agent which is biosynthesized in arteries and lungs in mammals and humans by starting from arachidonic acid (Gryglewski et al. , "Prostaglandins", 12, 658, 1976).
PGI2inhiberer platedannelse og, mer viktig, disaggre-gerer plateaggregater i blodstrømmen. Hos mennesker sirkulerer en variabel prosentandel av den totale platemengde i form av små aggregater og statistisk er antallet høyere i atheroscle-rotiske subjekter der det induseres en høy risiko for at det skal oppstå infarkt (K. K. Wu og J. C. Haak i "Lancet", 2, 923-926, 1974). PGI2 inhibits plaque formation and, more importantly, disaggregates platelet aggregates in the bloodstream. In humans, a variable percentage of the total amount of platelets circulates in the form of small aggregates and statistically the number is higher in atherosclerotic subjects where a high risk of infarction is induced (K. K. Wu and J. C. Haak in "Lancet", 2, 923-926, 1974).
Bortsett fra den vasodilaterende virkning er prostacyklin også istand til å disintegrere disse aggregater hos mennesker (A. Szezeklik et al., "Pharmacol. Res. Comm.", 1978). Forbindelsene ifølge oppfinnelsen karakteriseres ved en pre-dominans av denne disaggregerende virkning samtidig med evnen til å avspenne koronararteriene og begge disse virkninger i sterkere grad enn PGI2 eller dennes 20-metylanaloge. Apart from its vasodilatory action, prostacyclin is also able to disintegrate these aggregates in humans (A. Szezeklik et al., "Pharmacol. Res. Comm.", 1978). The compounds according to the invention are characterized by a predominance of this disaggregating effect at the same time as the ability to relax the coronary arteries and both of these effects to a stronger degree than PGI2 or its 20-methyl analogue.
På samme måte som prostacyklin og 20-mety1-prostacyklin er i tillegg forbindelsene ifølge oppfinnelsen helt frie fra prostaglandinlignende virkning og tromboksanlignende virkning, dvs. at de har en ren PGI2~lignende virkning. In the same way as prostacyclin and 20-methyl-prostacyclin, the compounds according to the invention are also completely free from prostaglandin-like action and thromboxane-like action, i.e. they have a pure PGI2-like action.
Den PGI2~lignende virkning for forbindelsene som ble prøvet ble bedømt på basis av kapasiteten til å avspenne en strimmel av en storfe koronararterie og å forhindre plateaggregering indusert ved ADP i platerik kaninplasmå. The PGI2-like activity of the compounds tested was judged on the basis of their capacity to relax a strip of a bovine coronary artery and to prevent platelet aggregation induced by ADP in platelet-rich rabbit plasma.
Den prostaglandinlignende virkning, spesielt den PGE2~lignende, ble bedømt på basis av kapasiteten til. å trekke sammen rottetykktarmen mens den tromboksanlignende virkning, spesielt den TXA2-lignende, ble fastslått ved kapasiteten til å trekke sammen en strimmel av en kaninmesenterialarterie. Virkningen av forbindelsene ifølge oppfinnelsen, spesielt av forbindelsen 13,14-didehydro-20-metyl-PGI2, ble sammenlignet med virkningen av kjente forbindelser slik som PGI2, 20-metyl-PGI2, PGE2, 11,9-epoksy-metano-analogen av PGH2(E.M.A., U 46619, Upjohn Co.), 63- og 60-20-metyl-PG^ og 63~og 6a-20-metyl, 13,14-didehydro-PGI Tabell I gir de relevante data for PGI2~, PGE2~The prostaglandin-like action, especially the PGE2~-like, was judged on the basis of the capacity to. to contract the rat colon while the thromboxane-like action, especially the TXA2-like, was determined by the capacity to contract a strip of a rabbit mesenteric artery. The action of the compounds according to the invention, especially of the compound 13,14-didehydro-20-methyl-PGI2, was compared with the action of known compounds such as PGI2, 20-methyl-PGI2, PGE2, the 11,9-epoxy-methane analogue of PGH2(E.M.A., U 46619, Upjohn Co.), 63- and 60-20-methyl-PG^ and 63~ and 6a-20-methyl, 13,14-didehydro-PGI Table I gives the relevant data for PGI2~, PGE2~
og TXA2~lignende virkninger av.de ovenfor angitte forbindelser. and TXA2-like effects of the above compounds.
En sammenligning av de eksperimentelle data som er angitt i tabell I viser viktigheten av trippelbindingen i 13,14-stilling hva angår den biologiske virkning. I forbindelsene 20-metyl-13,14-didehydro-PGI2ifølge oppfinnelsen potensieres den rene PGI2~lignende virkning sogar med henblikk på 20-metyl-PG^-analogen. A comparison of the experimental data given in Table I shows the importance of the triple bond in the 13,14 position as far as the biological action is concerned. In the compounds 20-methyl-13,14-didehydro-PGI 2 according to the invention, the pure PGI 2 -like effect is potentiated even with regard to the 20-methyl-PG 2 analogue.
Tabell'II gir visse eksperimentelle data i forbindelse med den vasodilatoriskedg antiplateaggregerende virkning in vitro og den disaggregerende virkning in vivo av forbindelsen 13,14-dehydro-20-metyl-PGI2og PGI2~og 20-mety 1-PGI2'-analogene. Table II provides certain experimental data in connection with the vasodilatory and antiplatelet-aggregating action in vitro and the disaggregating action in vivo of the compound 13,14-dehydro-20-methyl-PGI2 and the PGI2~ and 20-methyl 1-PGI2' analogs.
Den vasodilatoriske virkning av forbindelsene in vitro ble bestemt ved å bedømme i parallell deres evne til å relak-sere storfe koronararterier og kaninmesenteriearterier; til forskjell fra de to andre forbindelser er 13,14-didehydro-derivater virksomt på begge vaskulærsjikt ved samme dose. The vasodilatory action of the compounds in vitro was determined by assessing in parallel their ability to relax bovine coronary arteries and rabbit mesenteric arteries; unlike the other two compounds, 13,14-didehydro derivatives are active on both vascular layers at the same dose.
Antiplateaggregeringsvirkningen ble fastslått både i platerikt kaninplasma og i heparinisert katteblod i henhold til Gryglewski-prøven (Naunym-Schmiedeberg's Arch. Pharmacol., 302, 25-30, 1978). The antiplatelet aggregation activity was determined both in platelet-rich rabbit plasma and in heparinized cat blood according to the Gryglewski test (Naunym-Schmiedeberg's Arch. Pharmacol., 302, 25-30, 1978).
Den disaggregerende virkning in vivo ble bestemt på anestetiserte og hepariniserte katter som fikk prøveforbindel-sen ingitt ved f.eks. infusjon (R. J. Gryglewski, R. Korbut, The disaggregating effect in vivo was determined on anesthetized and heparinized cats that had the test compound administered by e.g. infusion (R. J. Gryglewski, R. Korbut,
A. Ocetkiewicz og J. Stachura, Naunya-Schmiedeberg<1>s Arch. Pharmacol., 302, 25-30, 1978). A. Ocetkiewicz and J. Stachura, Naunya-Schmiedeberg<1>s Arch. Pharmacol., 302, 25-30, 1978).
Forbindelsene ifølge oppfinnelsen ble prøvet i form The compounds according to the invention were tested in form
av de respektive alkalisalter, men tallene som er angitt i of the respective alkali salts, but the numbers indicated in
tabellene I og II henviser til ekvimolekylare mengder av de tilsvarende frie syrer. Tabell II angir potensiering av den vasodilatoriske og antiaggregerende virkning for forbindelsene ifølge foreliggende oppfinnelse i forhold til PGI2og dens 2 0-metyl-derivater. På samme måte som naturlige prostacyklin. og 20-métyl-prostacyklin danner forbindelsene ifølge oppfinnelsen i tillegg heller ikke et substrat for 15-prosta-glandindehydrogenase. Spesielt produserer 16S- og 16R-metyl-derivatene som ikke utgjør substratet for enzymet 15-hydroksy-prostaglandin dehydrogenase en plateaggregeringsinhiberende virkning som er 2 til 5 ganger større enn den for de tilsvarende som ikke er substituert i 16-stilling. På grunn av den vasodilaterende og antiaggregerende virkning er forbindelsene ifølge oppfinnelsen spesielt brukbare ved behandling av akutt myokardialinfarksjon, til å svekke angrepet av Angina Pectoris, forhindring av plateaggregering, eventuelt forbundet med hepa-rinlignende stoffer, i forhindring av aggregering under hemo-dialyse og under operasjoner uten og med kroppslig sirkulering av blod. Giftigheten av forbindelsen ifølge oppfinnelsen er heller neglisjerbar og de kan derfor brukes trygt i terapien. tables I and II refer to equimolecular amounts of the corresponding free acids. Table II indicates the potentiation of the vasodilator and antiaggregatory effect for the compounds according to the present invention in relation to PGI2 and its 20-methyl derivatives. In the same way as natural prostacyclin. and 20-methyl-prostacyclin, the compounds according to the invention also do not form a substrate for 15-prostaglandin dehydrogenase. In particular, the 16S- and 16R-methyl derivatives which do not constitute the substrate for the enzyme 15-hydroxy-prostaglandin dehydrogenase produce a plaque aggregation inhibitory effect which is 2 to 5 times greater than that of the corresponding ones which are not substituted in the 16-position. Due to the vasodilating and anti-aggregating effect, the compounds according to the invention are particularly useful in the treatment of acute myocardial infarction, to weaken the attack of Angina Pectoris, prevention of plaque aggregation, possibly associated with heparin-like substances, in the prevention of aggregation during hemodialysis and during operations without and with bodily circulation of blood. The toxicity of the compound according to the invention is rather negligible and they can therefore be used safely in therapy.
Forbindelsene ifølge oppfinnelsen kan inngis via de vanligé veier, f.eks. ved intravenøs injeksjon eller infusjon, ved subkutan eller intramuskulær injeksjon, oralt, ved sublingual absorbsjon, rektalt osv. I nødsituasjoner inngis forbindelsene fortrinnsvis ved intravenøs infusjon der man for dette formål bruker sterile buffere ved pH 8,5 - 9 som oppnås fra vandige oppløsninger inneholdende forbindelsene ifølge oppfinnelsen ved varierende konsentrasjoner, f.eks. fra 0,0005 til 0,01%. I dette tilfelle kan inngivelsen f.eks. skje gjennom en intravenøs kanyle utstyrt med en treveisvent.il og innfører f.eks. i den venstre mediankubitale vene, f.eks. ved hjelp av en automatisk sprøyte samtidig som det innføres en 5%-ig deks-troseoppløsning i den høyre vene. Hvis det velges intravenøs infusjon, varierer dosene fortrinnsvis fra 0,2 til 25 og særlig fra 0,5 til 2,0 ng/kg kroppsvekt/min. Den totale daglige dose enten ved injeksjon eller infusjon, er fortrinnsvis i størrel-sesorden 0,005 til 2 0 mg/kg der de nøyaktige doser avhenger av alder, vekt og pasientens tilstand så vel som inngivelsesvei. The compounds according to the invention can be administered via the usual routes, e.g. by intravenous injection or infusion, by subcutaneous or intramuscular injection, orally, by sublingual absorption, rectally, etc. In emergency situations, the compounds are preferably administered by intravenous infusion, where sterile buffers at pH 8.5 - 9 are used for this purpose, which are obtained from aqueous solutions containing the compounds according to the invention at varying concentrations, e.g. from 0.0005 to 0.01%. In this case, the submission can e.g. happen through an intravenous cannula equipped with a three-way valve and introduces e.g. in the left median cubital vein, e.g. using an automatic syringe while introducing a 5% dextrose solution into the right vein. If intravenous infusion is chosen, the doses preferably range from 0.2 to 25 and especially from 0.5 to 2.0 ng/kg body weight/min. The total daily dose, either by injection or infusion, is preferably in the order of 0.005 to 20 mg/kg where the exact doses depend on the age, weight and condition of the patient as well as the route of administration.
Sterile oppløsninger eller suspensjoner i vandige Sterile solutions or suspensions in aqueous
eller ikke-vandige media kan benyttes for subkutan eller intramuskulær injeksjon. Således kan f.eks. forbindelsen oppløses i sterilt vann eller i en oppløsning av lidokainhydroklorid (idet man holder pH-verdien i oppløsningen fortrinnsvis mellom 8,5 og 9), ellér i fysiologisk sammensatt oppløsning eller i et hvilket som helst av de vanlige oppløsningsmidler som benyttes for denne inngivelsestype. I slike tilfeller varierer doseringen fortrinnsvis fra 0,05 til 50 mg daglig. Som allerede angitt, kan andre inngivelsesveier velges for forbindelsene, ifølge oppfinnelsen, f.eks. kan de inngis oralt i form av or non-aqueous media may be used for subcutaneous or intramuscular injection. Thus, e.g. the compound is dissolved in sterile water or in a solution of lidocaine hydrochloride (keeping the pH value of the solution preferably between 8.5 and 9), or in a physiologically composed solution or in any of the usual solvents used for this type of administration. In such cases, the dosage preferably varies from 0.05 to 50 mg daily. As already indicated, other routes of administration may be chosen for the compounds according to the invention, e.g. they can be administered orally in the form of
tabletter, kapsler eller sirup, rektalt i form av supposito-rier, eller ved sublingual absorbsjon i form av tabletter eller lignende. Strekkmidler og bærere som benyttes for de forskjellige farmasøytiske formuleringer er de vanlige og kan f.eks. når det gjelder oral inngivelse være laktose, dekstrose, sukkrose, manitol, sorbitol, cellulose, talkum, kalsium- eller magnesiumstearat, glykoler, stivelser, gummi arabicum, traga-kantgummi, alginater, lecitin eller ellers polysorbater og laurylsulfater, fortrinnsvis av alkali- eller jordalkalimetal-ler. tablets, capsules or syrup, rectally in the form of suppositories, or by sublingual absorption in the form of tablets or the like. Excipients and carriers used for the various pharmaceutical formulations are the usual ones and can e.g. in the case of oral administration be lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, calcium or magnesium stearate, glycols, starches, gum arabic, gum tragacanth, alginates, lecithin or otherwise polysorbates and lauryl sulfates, preferably of alkali or alkaline earth metals.
De følgende eksempler illustrerer, men er ikke ment å begrense oppfinnelsen. The following examples illustrate, but are not intended to limit, the invention.
Eksempel I Example I
En oppløsning av 0,58 g 14-brom-5(S,R)-iodo-6(S,R)-20-mety 1-PGI^ i 4 ml vannfri dimetylsulfoksyd og 0,34 g natrium-tert-butoksyd hensettes i 3 timer i en atmosfære av inertgass under omrøring. Oppløsningsmidlene fordampes under et redusert trykk på 0,02 mm Hg. Resten tas opp med en støkiometrisk mengde 2N NaOH. Man oppnår krystaller av natriumsaltet av 13,14-dehydro-20-metyl-PGI2med [a]D= + 110°C (EtOH) ved avkjøling av oppløsningen til 0°C med etterfølgende filtrering. Dette til-svarer et utbytte på 80%. A solution of 0.58 g of 14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-1-PGI^ in 4 ml of anhydrous dimethyl sulfoxide and 0.34 g of sodium tert-butoxide is prepared for 3 hours in an atmosphere of inert gas with stirring. The solvents are evaporated under a reduced pressure of 0.02 mm Hg. The residue is taken up with a stoichiometric amount of 2N NaOH. Crystals of the sodium salt of 13,14-dehydro-20-methyl-PGI2 with [a]D= + 110°C (EtOH) are obtained by cooling the solution to 0°C with subsequent filtration. This corresponds to a yield of 80%.
Eksempel 2 Example 2
En oppløsning av 0,42 g 14,5(S,R)-dibromo-6(S,R)-20-metyl-PGI^ og 0,45 g kalium-tert-butoksyd i vannfri metanol holdes ved romtemperatur i 20 dager. Oppløsningsmidlene fordampes under vakuum og produktet krystalliseres fra 2N KOH/CH^OH/ vann og man oppnår natriumsaltet av 13,14-dehydro-20-metyl-PGI2A solution of 0.42 g of 14,5(S,R)-dibromo-6(S,R)-20-methyl-PGI^ and 0.45 g of potassium tert-butoxide in anhydrous methanol is kept at room temperature for 20 days . The solvents are evaporated under vacuum and the product is crystallized from 2N KOH/CH^OH/water and the sodium salt of 13,14-dehydro-20-methyl-PGI2 is obtained
med [or] = +108°C (EtOH) i et utbytte av 72%. with [or] = +108°C (EtOH) in a yield of 72%.
Den samme forbindelse kan likeledes oppnås ved reaksjon med kaliumtertbutoksyd i tertiært butanoi ved 38°C i 8 dager. The same compound can likewise be obtained by reaction with potassium tert-butoxide in tertiary butanoe at 38°C for 8 days.
Eksempel 3 Example 3
En oppløsning av 0,3 g 16S-metyl-14-bromo-5(S,R)-iodo-6(S,R)-20-mety1-PGjog 0,35 g natriumetoksyd i 4 ml etanol holdes ved 50°C i 15 dager. Oppløsningsmidlene fordampes under vakuum og resten fortynnes med 2N NaOH og avkjøles til 0°C. A solution of 0.3 g of 16S-methyl-14-bromo-5(S,R)-iodo-6(S,R)-20-methyl-PG and 0.35 g of sodium ethoxide in 4 ml of ethanol is kept at 50°C for 15 days. The solvents are evaporated under vacuum and the residue is diluted with 2N NaOH and cooled to 0°C.
Ved filtrering oppnås krystaller av natriumsaltet av 13,14-didehydro-16S, 20-dimety1-PGI2 med [ot] = +118°C (EtOH) . Natriumsaltet av 13,14-didehydro-16R,20-dimety1-PGI2 med [a]D= +102°C i etylalkohol ble oppnådd på samme måte. By filtration, crystals of the sodium salt of 13,14-didehydro-16S, 20-dimethyl-PGI2 are obtained with [ot] = +118°C (EtOH). The sodium salt of 13,14-didehydro-16R,20-dimethyl-PGI2 with [α]D= +102°C in ethyl alcohol was obtained in the same way.
Claims (13)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT25903/78A IT1099575B (en) | 1978-07-20 | 1978-07-20 | 20-METHYL-13,14-DEHYDRO-PGI2 'ITS SALTS AND ITS 16S- AND 16R-METHYL DERIVATIVES |
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| Publication Number | Publication Date |
|---|---|
| NO792313L true NO792313L (en) | 1980-01-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792313A NO792313L (en) | 1978-07-20 | 1979-07-11 | PROCEDURE FOR PREPARING 20-METHYL-13,14-DIDEHYDRO-PGI2 DERIVATIVES |
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| JP (1) | JPS5517389A (en) |
| AT (1) | AT367758B (en) |
| AU (1) | AU520750B2 (en) |
| BE (1) | BE877687A (en) |
| CA (1) | CA1183531A (en) |
| CH (1) | CH640522A5 (en) |
| CS (1) | CS208668B2 (en) |
| DE (1) | DE2922110A1 (en) |
| DK (1) | DK304479A (en) |
| FR (1) | FR2431492A1 (en) |
| GB (1) | GB2025972B (en) |
| HU (1) | HU182727B (en) |
| IE (1) | IE48593B1 (en) |
| IL (1) | IL57552A (en) |
| IT (1) | IT1099575B (en) |
| NL (1) | NL7905259A (en) |
| NO (1) | NO792313L (en) |
| SE (1) | SE446002B (en) |
| SU (1) | SU884569A3 (en) |
| YU (1) | YU152979A (en) |
| ZA (1) | ZA793123B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3029984C2 (en) | 1980-08-08 | 1983-12-15 | Grünenthal GmbH, 5190 Stolberg | 2-Oxabicyclo [3.3.0] octane derivatives and medicinal products containing them |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL51189A (en) * | 1976-02-04 | 1985-08-30 | Upjohn Co | Prostaglandin analogs |
| AU3583378A (en) * | 1977-06-06 | 1979-11-08 | Chicago The University Of | Prostacyclin analogs |
-
1978
- 1978-07-20 IT IT25903/78A patent/IT1099575B/en active
-
1979
- 1979-05-31 DE DE19792922110 patent/DE2922110A1/en not_active Withdrawn
- 1979-06-13 IL IL57552A patent/IL57552A/en unknown
- 1979-06-13 AU AU48034/79A patent/AU520750B2/en not_active Ceased
- 1979-06-14 FR FR7915298A patent/FR2431492A1/en active Granted
- 1979-06-20 AT AT0435479A patent/AT367758B/en not_active IP Right Cessation
- 1979-06-22 ZA ZA793123A patent/ZA793123B/en unknown
- 1979-06-27 YU YU01529/79A patent/YU152979A/en unknown
- 1979-07-05 NL NL7905259A patent/NL7905259A/en not_active Application Discontinuation
- 1979-07-11 NO NO792313A patent/NO792313L/en unknown
- 1979-07-13 BE BE0/196287A patent/BE877687A/en not_active IP Right Cessation
- 1979-07-19 HU HU79EA195A patent/HU182727B/en unknown
- 1979-07-19 DK DK304479A patent/DK304479A/en not_active Application Discontinuation
- 1979-07-19 SU SU792790905A patent/SU884569A3/en active
- 1979-07-19 SE SE7906234A patent/SE446002B/en unknown
- 1979-07-19 CA CA000332125A patent/CA1183531A/en not_active Expired
- 1979-07-20 JP JP9172979A patent/JPS5517389A/en active Pending
- 1979-07-20 CH CH677779A patent/CH640522A5/en not_active IP Right Cessation
- 1979-07-20 CS CS795112A patent/CS208668B2/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| IE791360L (en) | 1980-01-20 |
| GB2025972B (en) | 1982-09-15 |
| NL7905259A (en) | 1980-01-22 |
| FR2431492B1 (en) | 1982-07-16 |
| SU884569A3 (en) | 1981-11-23 |
| FR2431492A1 (en) | 1980-02-15 |
| YU152979A (en) | 1983-01-21 |
| IL57552A (en) | 1983-02-23 |
| CA1183531A (en) | 1985-03-05 |
| JPS5517389A (en) | 1980-02-06 |
| DK304479A (en) | 1980-01-21 |
| SE446002B (en) | 1986-08-04 |
| AU4803479A (en) | 1980-01-24 |
| GB2025972A (en) | 1980-01-30 |
| BE877687A (en) | 1980-01-14 |
| IT7825903A0 (en) | 1978-07-20 |
| CS208668B2 (en) | 1981-09-15 |
| IE48593B1 (en) | 1985-03-20 |
| IL57552A0 (en) | 1979-10-31 |
| ZA793123B (en) | 1980-06-25 |
| SE7906234L (en) | 1980-01-21 |
| AU520750B2 (en) | 1982-02-25 |
| AT367758B (en) | 1982-07-26 |
| ATA435479A (en) | 1981-12-15 |
| CH640522A5 (en) | 1984-01-13 |
| HU182727B (en) | 1984-03-28 |
| DE2922110A1 (en) | 1980-01-31 |
| IT1099575B (en) | 1985-09-18 |
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