DE2702368A1 - NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION - Google Patents
NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTIONInfo
- Publication number
- DE2702368A1 DE2702368A1 DE19772702368 DE2702368A DE2702368A1 DE 2702368 A1 DE2702368 A1 DE 2702368A1 DE 19772702368 DE19772702368 DE 19772702368 DE 2702368 A DE2702368 A DE 2702368A DE 2702368 A1 DE2702368 A1 DE 2702368A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- compound
- xix
- ester
- formula xix
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000003180 prostaglandins Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000004927 clay Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- -1 aliphatic hydrocarbon radical Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229910052987 metal hydride Inorganic materials 0.000 description 3
- 150000004681 metal hydrides Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 244000061944 Helianthus giganteus Species 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 229960005003 carbocromen Drugs 0.000 description 1
- KLOIYEQEVSIOOO-UHFFFAOYSA-N carbocromen Chemical compound CC1=C(CCN(CC)CC)C(=O)OC2=CC(OCC(=O)OCC)=CC=C21 KLOIYEQEVSIOOO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 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
- 150000002561 ketenes Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000003529 luteolytic effect Effects 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229960001989 prenylamine Drugs 0.000 description 1
- 239000002089 prostaglandin antagonist Substances 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical class OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Description
HOECHST AKTIENGESELLSCHAFTHOECHST AKTIENGESELLSCHAFT
Aktenzeichen: HOE 77/F 008.File number: HOE 77 / F 008.
Datum: 20.1.1977 Dr.La/RpDate: 1/20/1977 Dr.La/Rp
NEUE PROSTAGLANDIN-ANALOGE UND VERFAHREN ZU IHRER HERSTELLUNGNEW PROSTAGLANDIN ANALOGS AND METHODS FOR THEIR PRODUCTION
Zusatz zur Patentanmeldung P 24 35 331.9 (HOE 74/F 212)Addition to patent application P 24 35 331.9 (HOE 74 / F 212)
Gegenstand der Hauptpatentanmeldung P 24 35 331.9 (HOE 74/F 212) sind Prostaglandin-Derivate der allgemeinen Formel IThe main patent application P 24 35 331.9 (HOE 74 / F 212) relates to prostaglandin derivatives of the general formula I.
worin bedeuten:where mean:
12
R und R jeweils Wasserstoff oder eine Hydroxylgruppe, wobei12th
R and R are each hydrogen or a hydroxyl group, where
ι ο
R und R verschieden sind/ι ο
R and R are different /
R3 einen gesättigten oder ungesättigten, geradkettigen oder verzweigten aliphatischen Kohlenwasserstoffrest mit 1 - 8 C-Atomen, einen geradkettigen oder verzweigten Oxo-alkylrest mit 2-8 C-Atomen sowie dessen Oxime, Oximäther, A'thylenglykol- und Äthylenthioglykolacetale, einen geradkettigen oder verzweigten Hydroxyalkylrest mit 2-8 C-Atomen, wobeiR 3 is a saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon radical with 1-8 carbon atoms, a straight-chain or branched oxo-alkyl radical with 2-8 carbon atoms and its oximes, oxime ethers, ethylene glycol and ethylene thioglycol acetals, or a straight chain branched hydroxyalkyl radical with 2-8 carbon atoms, where
80983 1 /002680983 1/0026
die OH-Gruppe endständig ist, oder einen geradkettigen oder verzweigten Carboxyalkylrest mit 2-8 C-Atomen,the OH group is terminal, or a straight-chain or branched carboxyalkyl radical with 2-8 C atoms,
4 54 5
R und R zusammen Sauerstoff oder jeweils Viasserstoff oderR and R together are oxygen or in each case hydrogen or
4 5 eine Hydroxylgruppe, wobei R und R verschieden sind,4 5 is a hydroxyl group, where R and R are different,
X eine gesättigte, verzweigte Alkylengruppe mit 2-5 C-Atomen, oder einen Aryl- oder Benzylrest, die ihrerseits mit einer oder mehreren niederen Alkyl- oder Alkoxygruppen, einem oder mehreren Halogenatomen oder Trifluormethylgruppen substituiert sein können, oder einen «jO- oder ß-Furfurylrest,X is a saturated, branched alkylene group with 2-5 C atoms, or an aryl or benzyl radical, which in turn with one or more lower alkyl or alkoxy groups, one or more halogen atoms or trifluoromethyl groups can be substituted, or a «jO- or ß-furfuryl radical,
sowie die physiologisch verträglichen Salze der Verbindung der Formel I mit organischen und anorganischen Basen und ihre Ester mit aliphatischen, cycloaliphatischen oder araliphatischen Alkoholen mit 1-8 C-Atomen im Esterteil.and the physiologically acceptable salts of the compound of the formula I with organic and inorganic bases and their esters with aliphatic, cycloaliphatic or araliphatic alcohols with 1-8 carbon atoms in the ester part.
Gegenstand der Hauptpatentanmeldung ist weiterhin ein Verfahren zur Herstellung der neuen, nicht natürlich vorkommenden Analoga von Prostansäuren der Formel I, ihrej. physiologisch verträglichen Salze mit organischen und anorganischen Basen und ihrer Ester mit 1-8 Kohlenstoffatomen im Esterteil, das dadurch gekennzeichnet ist, daß manThe main patent application also relates to a process for the preparation of the new, non-naturally occurring analogs of prostanoic acids of the formula I, theirj. physiologically compatible Salts with organic and inorganic bases and their esters with 1-8 carbon atoms in the ester part, which is characterized is that one
a) eine Verbindung der Formel II a) a compound of the formula II
IIII
oder der Formel III, or of the formula III,
809831/0026809831/0026
OH'OH'
IIIIII
worin X und R jeweils die gleiche Bedeutung wie in Formel I haben, in Gegenwart starker Säuren in eine Verbindung der Formel I überführt, und gegebenenfalls die Verbindung derwherein X and R each have the same meaning as in formula I, converted in the presence of strong acids into a compound of formula I, and optionally the compound of
4 54 5
Formel I, worin R und R zusammen ein Sauerstoffatom bedeuten, als reine Epimere oder als 15-Epimerengemisch mit einem komplexen Metallhydrid reduziert zu einer Verbindung der Formel I, worin R und R nicht gleich sind und jeweils Wasserstoff oder eine Hydroxylgruppe bedeuten, oderFormula I, in which R and R together represent an oxygen atom, as pure epimers or as a mixture of 15 epimers a complex metal hydride is reduced to a compound of the formula I in which R and R are not the same and each Mean hydrogen or a hydroxyl group, or
b.) einen Alkohol der Formel IVb.) an alcohol of the formula IV
IVIV
worin R die gleiche Bedeutung wie in Formel I hat, als
Epimerengemisch oder nach Trennung der Epimeren durch sauer katalysierte Addition von 2,3 Dihydropyran in einen Tetra- wherein R has the same meaning as in formula I, as
Mixture of epimers or after separation of the epimers by acid- catalyzed addition of 2,3 dihydropyran in a tetra-
hydropyranyläther der Formel V,hydropyranyl ether of the formula V,
809831/0028809831/0028
in der X und R die gleiche Bedeutung haben wie in Formel I, überführt,in which X and R have the same meaning as in formula I, converted,
b~) den Äther der Formel V durch basenkatalysierte Esterspaltung in einen Alkohol der Formel VI,b ~) the ether of the formula V by base-catalyzed ester cleavage into an alcohol of formula VI,
YIYI
OHOH
worin X und R die gleiche Bedeutung wie in Formel I haben,
überführt,wherein X and R have the same meaning as in formula I,
convicted,
b_) den Alkohol der Formel VI mit p-Toluol-Sulfochlorid zu einem Sulfonsäureester der Formel VIIb_) the alcohol of formula VI with p-toluene sulfochloride to one Sulphonic acid esters of the formula VII
VII
O0S-O'VII
O 0 S-O '
worin X und R die gleiche Bedeutung wie in Formel I haben,
umsetzt,wherein X and R have the same meaning as in formula I,
implements,
b4) den erhaltenen Sulfonsäureester der Formel VII in Gegen-b 4 ) the obtained sulfonic acid ester of the formula VII in counter
wart von Basen zu einem ungesättigten Lacton der Formel.VIIIwart of bases to an unsaturated lactone of formula VIII
. 809831 /0026. 809831/0026
X-O-R-X-O-R-
VIIIVIII
worin X und R die gleiche Bedeutung wie in Formel I haben, umsetzt,wherein X and R have the same meaning as in formula I, implements,
k>c) das ungesättigte Lacton der Formel VIII mit einem komplexen Aluminiumhydrid in ein Lactol der Formel IX,k> c) the unsaturated lactone of the formula VIII with a complex Aluminum hydride in a lactol of formula IX,
OHOH
«As«As
IXIX
worin X und R die gleiche Bedeutung wie in Formel I haben, überführt,in which X and R have the same meaning as in formula I ,
b ) das Lactol der Formel IX mit dem Ylid aus 4-Carboxybutyl-6 b) the lactol of the formula IX with the ylid from 4-carboxybutyl-6
triphenylphosphoniumbromid in einer Lösung von Natriumhydrid in Dimethylsulfoxid zu einer Säure der Formel X,triphenylphosphonium bromide in a solution of sodium hydride in dimethyl sulfoxide to form an acid of the formula X,
HO ·HO
809831/0026809831/0026
«■'■«■ '■
worin X und R die gleiche Bedeutung haben wie in Formel I, umsetzt,wherein X and R have the same meaning as in formula I, reacts,
b_) die Verbindung der Formel X oxydiert zu einer Verbindung der Formel XI,b_) the compound of formula X oxidizes to a compound of Formula XI,
XIXI
worin X und R die gleiche Bedeutung haben wie in Formel I, undwherein X and R have the same meaning as in formula I, and
die Tetrahydropyranylätherschutzgruppe in einer Verbindung der Formel X oder XI durch saure Hydrolyse abspaltet, wobei eine Verbindung der Formel I erhilten wird, und diese gegebenenfalls in Form der reinen Epimere oder als 15-Epimerengemisch mit einem komplexen Metallhydrid reduziert zu einersplitting off the tetrahydropyranyl ether protective group in a compound of the formula X or XI by acid hydrolysis, with a compound of formula I is obtained, and this optionally in the form of the pure epimers or as a 15-epimer mixture with a complex metal hydride reduced to one
4 5 Verbindung der Formel I, worin R. und R ungleich sind und4 5 Compound of the formula I in which R. and R are not the same and
jeweils Wasserstoff oder eine Hydroxylgruppe bedeuten, oder den Alkohol der Formel XIIeach represent hydrogen or a hydroxyl group, or the alcohol of the formula XII
COOCH,
CH2OHCOOCH,
CH 2 OH
.1OCOlIH. 1 OCOlIH
XIIXII
zum Aldehyd der Formel XIIIto the aldehyde of the formula XIII
809831/0028809831/0028
^'X COOCH,^ 'X COOCH,
CH = 0CH = 0
XIIIXIII
OCONHOCONH
oxydiert,oxidized,
c_) den Aldehyd der Formel XIII mit einem Phosphonat der Formel XIV,c_) the aldehyde of the formula XIII with a phosphonate of the formula XIV,
CH5QCH 5 Q
O
.!-X-O-O
.! - XO-
XIVXIV
CH5OCH 5 O
worin X und R dieselbe Bedeutung wie in der Formel I haben, zu einer Verbindung der Formel XVwherein X and R have the same meaning as in formula I, to a compound of formula XV
\ COOCII,\ COOCII,
HKOCOHKOCO
XVXV
umsetzt,implements,
c_) die Verbindung der Formel XV mit einem komplexen Metallhydrid zu dem Epimerengemisch der Alkohole der Formel XVIc_) the compound of the formula XV with a complex metal hydride to the epimer mixture of the alcohols of the formula XVI
HNOCOHNOCO
X-O-R'X-O-R '
XVIXVI
809831/0026809831/0026
/8/8th
worin X und R die gleiche Bedeutung wie in der Formel I haben, reduziert,wherein X and R have the same meaning as in formula I, reduced,
c ) die Esterfunktion der Verbindung der Formel XVI in Gegenwart von verdünnten wäßrigen Basen verseift zu der freien Säure
der Formel XVIIc) the ester function of the compound of the formula XVI is saponified in the presence of dilute aqueous bases to give the free acid
of formula XVII
COOHCOOH
X-O-R'X-O-R '
XVIIXVII
worin X und R die gleiche Bedeutung wie in Formel I,wherein X and R have the same meaning as in formula I,
c_) die Verbindung der Formel XVII durch Erhitzen in organischen Lösungsmitteln in Gegenwart von Wasser in ein ungesättigtes Hydroxylacton der Formel XVIIIc_) the compound of formula XVII by heating in organic Solvents in the presence of water into an unsaturated hydroxylactone of the formula XVIII
XVIIIXVIII
X-O-R'X-O-R '
wobei X und R dieselbe Bedeutung wie in Formel I haben,
überführt,where X and R have the same meaning as in formula I,
convicted,
das ungesättigte Hydroxylacton der Formel XVIII als Epimerengemisch
oder nach Trennung der Epimeren durch sauer katalysierte Addition von 2,3 Dihydropyran in die Verbindung der
Formel VIIIthe unsaturated hydroxylactone of the formula XVIII as a mixture of epimers or after separation of the epimers by acid-catalyzed addition of 2,3 dihydropyran into the compound of
Formula VIII
809831/0026809831/0026
— Js —- Js -
VIIIVIII
in der X und R die gleiche Bedeutung haben wie in Formel I, überführt, und die Verbindung der Formel VIII, wie unter b,-bis bg beschrieben, in eine Verbindung der Formel I umwandelt und die nach a), b) oder c) erhaltene Verbindung der Formel I gewünschtenfalls in physiologisch verträgliche Salze oder Ester überführt.in which X and R have the same meaning as in formula I, transferred, and the compound of formula VIII, as under b, -bis bg, converted into a compound of formula I. and the compound of the formula I obtained according to a), b) or c), if desired, in physiologically acceptable salts or Ester transferred.
Die beschriebenen erfindungsgemäßen Verbindungen zeichnen sich durch spasmogene, bronchiodilatatorische, blutdrucksenkende, magensaftsekretionshemmende, luteolytische und abortive Eigenschaften aus und können daher als Arzneimittel verwendet werden.The compounds according to the invention described are distinguished through spasmogenic, bronchodilator, antihypertensive, gastric secretion inhibiting, luteolytic and abortive properties and can therefore be used as a medicine.
In weiterer Ausgestaltung der Erfindung wurde nun gefunden, daß man zu Verbindungen mit verstärkter und differenzierterer pharmakologischer Wirkung gelangt, wenn man die allylische Hydroxylgruppe am Kohlenstoffatom 15 der Verbindungen der Formel I der Hauptpatentanmeldung mit niederen Carbonsäuren verestert. Der überraschende differenzierende und Wirkungsverstärkende Einfluß der Veresterung ist besonders ausgeprägt bei den Präparaten mit blutdrucksenkender Wirkung.In a further embodiment of the invention, it has now been found that compounds with enhanced and more differentiated pharmacological action are obtained if the allylic hydroxyl group on carbon atom 15 of the compounds of the formula I of the main patent application is esterified with lower carboxylic acids. The surprising, differentiating and effect-enhancing influence of the esterification is particularly pronounced in the case of the preparations with an antihypertensive effect.
Gegenstand der Erfindung sind daher Prostaglandin-Analoge der allgemeinen Formel XIXThe invention therefore relates to prostaglandin analogs of the general formula XIX
XIXXIX
/10/ 10
809831/0026809831/0026
X, R , R und R die zur Formel I der Hauptpatentanmeldung angegebene Bedeutung haben undX, R, R and R are those given for formula I of the main patent application Have meaning and
R ein Wasserstoffatom oder eine geradkettige oder verzweigte Alkylgruppe mit einem bis zehn Kohlenstoffatomen bedeutet,R is a hydrogen atom or a straight or branched chain alkyl group of one to ten Carbon atoms means
sowie die physiologisch verträglichen Salze der Verbindungen der Formel I mit organischen und anorganischen Basen und ihre Ester mit aliphatischen, cycloaliphatischen oder araliphatischen Alkoholen mit 1-8 C-Atomen im Esterteil.and the physiologically acceptable salts of the compounds of the formula I with organic and inorganic bases and their esters with aliphatic, cycloaliphatic or araliphatic alcohols with 1-8 carbon atoms in the ester part.
Für R und X gelten als bevorzugt die in der Hauptpatentanmeldung entsprechend genannten Reste. Für R sind bevorzugt geradkettige oder verzweigte Alkylgruppen mit bis zu 4 C-Atomen.For R and X, those in the main patent application are considered preferred appropriately named residues. Straight-chain or branched alkyl groups with up to 4 carbon atoms are preferred for R.
Als Salze und Ester sind bevorzugt die in der Hauptpatentanmeldung entsprechend genannten.Preferred salts and esters are those in the main patent application appropriately named.
Gegenstand der vorliegenden Erfindung ist ferner ein Verfahren zur Herstellung der Verbindungen der Formel XIX.The present invention also relates to a process for the preparation of the compounds of the formula XIX.
Das Verfahren ist dadurch gekennzeichnet, daß man VerbindungenThe method is characterized in that one compounds
4 5
der Formel I, deren Reste R und R zusammen Sauerstoff bedeuten, durch Umsetzung mit geeigneten Acylierungsmitteln in Verbindungen
der Formel XIX überführt, und die erhaltenen Verbindungen gegebenenfalls durch Reaktion mit geeigneten Reduktionsmitteln in
solche Verbindungen der Formel XIX umwandelt, für die einer der Reste R und R eine Hydroxylgruppe und der andere ein Wasserstoff
atom bedeutet. Als Acylierungsmittel kommen die freien Carbonsäuren sowie deren reaktionsfähige Derivate in Betracht. BeiVerwendung
der -Carbonsäure führt man die Reaktion vorzugsweise in dieser Säure als Lösungsmittel bei Temperaturen zwischen 0°
und 700C durch. In einigen Fällen ist es vorteilhaft, die Reaktionslösung
zur Vermeidung von Folgereaktionen abzupuffern. (Vergl. J. E. Pike, F. H. Lincoln, W. P. Schneider, J. Org.
Chenu 3±, 3553 (1969)). ^11 4 5
of the formula I, whose radicals R and R together represent oxygen, converted into compounds of the formula XIX by reaction with suitable acylating agents, and the compounds obtained are optionally converted by reaction with suitable reducing agents into those compounds of the formula XIX for which one of the radicals R and R is a hydroxyl group and the other is a hydrogen atom. Suitable acylating agents are the free carboxylic acids and their reactive derivatives. BeiVerwendung the carboxylic acid is preferably carrying out the reaction in this acid by as solvent at temperatures between 0 ° and 70 0 C. In some cases it is advantageous to buffer the reaction solution to avoid subsequent reactions. (See JE Pike, FH Lincoln, WP Schneider, J. Org. Chenu 3 ±, 3553 (1969)). ^ 11
809831/0026809831/0026
IHIH
Zur Acylierung können ferner die entsprechenden Carbonsäurehalogenide oder Carbonsäureanhydride verwendet werden. Die Reaktion wird dann bevorzugt in aprotischen Lösungsmitteln in Gegenwart einer Base bei Temperaturen zwischen 0° und 8 00C durchgeführt. Zur Herstellung der erfindungsgemäßen Verbindungen kommt ferner noch die Umsetzung der Alkohole mit den entsprechenden Ketenen in Betracht. Diese Reaktion wird ebenfalls in aprotischen Lösungsmitteln bei Raumtemperatur durchgeführt.The corresponding carboxylic acid halides or carboxylic acid anhydrides can also be used for the acylation. The reaction is then preferably carried out in aprotic solvents in the presence of a base at temperatures between 0 ° C and 8 0 0 C. The reaction of the alcohols with the corresponding ketenes can also be used to prepare the compounds according to the invention. This reaction is also carried out in aprotic solvents at room temperature.
Zur Darstellung solcher Verbindungen der Formel XIX bei denen einer der Reste R und R eine Hydroxylgruppe und der andere Wasserstoff bedeutet, werden die nach obigem Verfahren hergestellen 15-O-Acyl-A-prostaglandine reduziert. Als Reduktionsmittel kommen hierfür vor allem komplexe Hydride in Betracht, die eine Ketogruppe zu reduzieren vermögen, ohne Ester- oder Carboxylgruppen anzugreifen. Besonders bewährt hat sich hier die Verwendung von Natriumborhydrid in Methanol/Wasser als Lösungsmittel. To represent such compounds of the formula XIX in which one of the radicals R and R is a hydroxyl group and the other Means hydrogen, the 15-O-acyl-A-prostaglandins prepared by the above process are reduced. As a reducing agent Complex hydrides which are able to reduce a keto group, without ester or carboxyl groups, are particularly suitable for this purpose to attack. The use of sodium borohydride in methanol / water as a solvent has proven particularly useful here.
Die erfindungsgemäßen Verbindungen haben wertvolle pharmakologische Eigenschaften. Sie zeichnen sich insbesondere durch blutdrucksenkende Wirkung aus, die jener der nichtacylierten Ausgangsverbindungen überlegen ist. Die für die blutdrucksenkende Wirkung unerwünschte Nebenwirkungen auf die glatte Muskulatur wurden in diesen Fällen bisher nicht beobachtet.The compounds of the invention have valuable pharmacological properties Properties. They are particularly notable for their antihypertensive effect, that of the non-acylated ones Output compounds is superior. The side effects on the smooth muscles that are undesirable for the antihypertensive effect have not yet been observed in these cases.
Aufgrund der pharmakologischen Wirkungen können die erfindungsgemäßen Verbindungen als Arzneimittel angewandt werden.Because of the pharmacological effects, the inventive Compounds are used as drugs.
Sie können in Form ihrer wäßrigen Lösungen oder Suspensionen oder auch gelöst oder suspendiert in pharmakologisch unbedenklichen organischen Lösungsmitteln wie ein- oder mehrwertige Alkoholen, z.B. Äthanol, Äthylenglykol oder Glycerin, ölen wie z.B. Sonnenblumenöl oder Lebertran, Xthern wie z.B. Diäthylenglykoldimethyläther oder auch Polyäthern wie z.B. Polyäthylenglykole oder auch in Gegenwart anderer pharmakologisch unbedenklicher Polymerträger wie z.B. Polyvinylpyrrolidon zur Anwendung gelangen. /12They can be in the form of their aqueous solutions or suspensions or else dissolved or suspended in pharmacologically acceptable ones organic solvents such as monohydric or polyhydric alcohols, e.g. ethanol, ethylene glycol or glycerine, oils such as e.g. sunflower oil or cod liver oil, xethers such as diethylene glycol dimethyl ether or also polyethers such as polyethylene glycols or in the presence of other pharmacologically safe ones Polymer carriers such as polyvinylpyrrolidone are used. / 12
. 809831/0026. 809831/0026
- .ie -- .ie -
Als Zubereitungen können die üblichen galenischen Infusionsoder Injektionslösungen und Tabletten, sowie örtlich anwendbare Zubereitungen wie Cremes, Emulsionen, Suppositorien, insbesondere auch Aerosole in Frage kommen.The usual pharmaceutical infusion or injection solutions and tablets, as well as locally applicable Preparations such as creams, emulsions, suppositories, in particular also aerosols, are possible.
Eine weitere Anwendung der neuen Verbindungen liegt in der Kombination mit anderen Wirkstoffen. Neben anderen geeigneten Substanzen gehören vor allem:Another application of the new compounds is in combination with other active ingredients. In addition to other suitable substances, the following are particularly important:
Diuretika, wie z.B. Furosemid, Antidiabetika wie z.B. Glycodiazin, Tolbutamid, Glibenclamid, Phenformin, Buformin, Metformin, Kreislaufmittel im weitesten Sinne, z.B. Coronardilatatoren, wie Chromonar oder Prenylamin, blutdrucksenkende Stoffe wie Reserpin, ch~Methyl-Dopa oder Clonidine oder Antiarrhythmika, Lipidsenker, Geriatrika und andere stoffwechselwirksame Präparate, Psychopharmaka, wie z.B. Chlordiazepoxid, Diazepam oder Meprobamat sowie Vitamine, oder Prostaglandine oder prostaglandin-ähnliche Verbindungen sowie auch Prostaglandinantagonisten,und Prostaglandin-Biosynthesehemmer, wie z.B. nicht-steroidale Antiphlogistika. Diuretics, such as furosemide, antidiabetics such as Glycodiazin, tolbutamide, glibenclamide, phenformin, buformin, metformin, cardiovascular agents in the broadest sense, including coronary dilators, such as Chromonar or prenylamine, antihypertensive agents such as reserpine, ch ~ methyl-dopa or Clonidine or antiarrhythmic agents, lipid-lowering , Geriatrics and other metabolically active preparations, psychotropic drugs such as chlordiazepoxide, diazepam or meprobamate and vitamins, or prostaglandins or prostaglandin-like compounds and also prostaglandin antagonists, and prostaglandin biosynthesis inhibitors such as non-steroidal anti-inflammatory drugs.
809831/0026809831/0026
g-Keto-lSn-formyloxy-lö.ie-dimethyl-ie-oxa-prosta-S.10.13-triensäure g-Keto-lSn-formyloxy-lö.ie-dimethyl-ie-oxa-prosta-S.10.13-trienoic acid
200 mg 16,16-Dimethyl-ie-oxa-prostaglandin A2 werden aufgenommen in 7,5 ml Ameisensäure, die zuvor durch Zugabe von 50 mg Soda etwas abgepuffert worden war. Man lässt einen Tag bei Raumtemperatur unter Feuchtigkeitsausschluss stehen. Dann nimmt man auf mit Chloroform, extrahiert die organische Phase 2 χ mit Wasser, trocknet und dampft ein. Der Rückstand wird durch Chromathographie an Kieselgel mit Cyclohexan/ Essigester/Eisessig 90/10/1 gereinigt. Man erhält 110 mg des gewünschten Produktes. DC (Cyclohexan/Essigester/Eisessig 60/40/1) Rf "* 0,70200 mg of 16,16-dimethyl-ie-oxa-prostaglandin A 2 are taken up in 7.5 ml of formic acid, which had previously been somewhat buffered by adding 50 mg of soda. It is left to stand for one day at room temperature with the exclusion of moisture. Then it is taken up with chloroform, the organic phase is extracted 2 with water, dried and evaporated. The residue is purified by chromatography on silica gel with cyclohexane / ethyl acetate / glacial acetic acid 90/10/1. 110 mg of the desired product are obtained. TLC (cyclohexane / ethyl acetate / glacial acetic acid 60/40/1) Rf "* 0.70
NMR (60 MHz, CDCl3) (<f - Werte)NMR (60 MHz, CDCl 3 ) (<f - values)
8,1 Singulett 1 H (-0-C0-H); 7,45 aufgespaltenes Dublett 1 H (CH=CH-C=O), 6,15 aufgespaltenes Dublett 1 H (=CH-C=O)f 5,15 - 5,85 Multiplett 4 H (olef. Protonen), 3,9 - 4,4 Multiplett 1 H (CH-OOCH), 3,25 Quartett 2 H, J = 7 Hz (CH2OCH2CH3), 3,1 Singulett 2 H (CH2 OEt), 0.9 - 2.6 übrige Protonen, darunter Singuletts bei 0,9 und 1,0 ppm ((CH-)-C), Triplett bei 1,15, J = 7 Hz (CH0 CH,).8.1 singlet 1H (-0-C0-H); 7.45 split doublet 1 H (CH = CH-C = O), 6.15 split doublet 1 H (= CH-C = O) f 5.15-5.85 multiplet 4 H (olefinic protons), 3 , 9 to 4.4 multiplet 1 H (CH-OOCH), 3.25 quartet 2H, J = 7 Hz (CH 2 OCH 2 CH 3), 3.1 singlet 2 H (CH 2 OEt), 0.9 - 2.6 remaining protons, including singlets at 0.9 and 1.0 ppm ((CH -) - C), triplet at 1.15, J = 7 Hz (CH 0 CH,).
809831 /0026809831/0026
Beispiel 2: V^Example 2: V ^
9-Keto-15cr-acetoxy-16,16-dimethyl-18-oxa-prosta(5.10.13) triensäure9-keto-15cr-acetoxy-16,16-dimethyl-18-oxa-prosta (5.10.13) trienoic acid
100 mg le.ie-Diraethyl-te-öxa- PGA, (hergestellt gemäß DOS 24 35 331) oder BeIg. Pat. Nr. 831.649 werden in einem Kölbchen unter Stickstoff vorgelegt. Dann tropft man innerhalb 1/2 Stunde 3 ml Essigsaureanhydrid zu und gibt zu der klaren Lösung 20 mg Kaliumcarbonat zu. Es wird 10 Stunden bei Raumtemperatur gerührt. Das Ende der Reaktion wird mittels Dünnschichtchromatogramm (Kieselgel - Elutionsmittel: Cyclohexan, Essigester, Eisessig »60 : 40 : 1) ermittelt. Nach beendeter Reaktion wird das Reaktionsgemisch in 40 ml CHCl3 aufgenommen und 3 χ mit 1.0 ml H2O eluiert. Die CHCl- -Phase wird mit MgSO. getrocknet und eingeengt. Der Rückstand wird an Kieselgel chromatographiert. (Blutionsmittel wie oben).100 mg le.ie-Diraethyl-te-öxa-PGA, (manufactured according to DOS 24 35 331) or BeIg. Pat. No. 831,649 are placed in a small flask under nitrogen. Then 3 ml of acetic anhydride are added dropwise within 1/2 hour and 20 mg of potassium carbonate are added to the clear solution. It is stirred for 10 hours at room temperature. The end of the reaction is determined by means of a thin-layer chromatogram (silica gel eluent: cyclohexane, ethyl acetate, glacial acetic acid 60: 40: 1). After the reaction has ended, the reaction mixture is taken up in 40 ml of CHCl 3 and eluted 3 χ with 1.0 ml of H 2 O. The CHCl- phase is with MgSO. dried and concentrated. The residue is chromatographed on silica gel. (Bleeding medication as above).
Dia Fraktionen 9-16 enthalten 68 mg fast farbloses Öl Rf - 0.63The fractions 9-16 contain 68 mg of almost colorless oil Rf - 0.63
0,9» 1,0 Singuletta, zusammen 6 H J - 3 Ha ( >C(CH3)2);0.9 »1.0 Singuletta, together 6 HJ - 3 Ha (> C (CH 3 ) 2 ); 1,15 Triplett 3 H J » 7 Hz (CH2CH3)I 1,5 - 2,6 Multiplett 10 H (CH2, CH); 2,0 Singulett 3 H (COCH3); 3,05 Singulett 2 H (CH2-OCH2CH3); 3,25 Quartett 2 H J = 7 Hz (-1.15 triplet 3 HJ »7 Hz (CH 2 CH 3 ) I 1.5-2.6 multiplet 10 H (CH 2 , CH); 2.0 singlet 3 H (COCH 3 ); 3.05 singlet 2 H (CH 2 -OCH 2 CH 3 ); 3.25 quartet 2 HJ = 7 Hz (-
); 3,8 -4,3 Multiplett IH (HC-O); 5,15 - 5,85 Multi-); 3.8-4.3 multiplet IH (HC-O); 5.15 - 5.85 multi
ο · · ■—ο · · ■ -
plett 4 H (olefinische Protonen); 6,15 aufgespaltenes Dublettplett 4 H (olefinic protons); 6.15 split doublet 1 H (CH=CH-C=O); 7,45 aufgespaltenes Dublett 1 H (CH=CH-C=O),1 H (CH = CH-C = O); 7.45 split doublet 1 H (CH = CH-C = O),
I I" I-III "I - I
7,5 breites Singulett 1 H (-COOH)7.5 broad singlet 1 H (-COOH)
809831/0026 ORIGINAL INSPECTED809831/0026 ORIGINAL INSPECTED
Claims (1)
v/orin X, R , R und R' die zur Formel I dor Hauptpatentanmeldung P 24 35 33 1.9 tjenannto Bedeutung haben und R ein Wasserstoff atom oder eine geradkettige oder vorzweigte AlkyLgruppe mit 1 bis 10 Kohlenstoffatomen bedeutet, sowie die physiologisch verträglichen Salze der Verbindungen der Formel I mit organischen und anorganischen Basen und ihre Ester mit aliphatischen, cycloaliphatischen oder araliphatischen Alkoholen mit 1 - 8 Kohlenstoffatomen im Esterteil.3-1 Γ )
v / orin X, R, R and R 'which have the formula I of the main patent application P 24 35 33 1.9 tjenannto meaning and R denotes a hydrogen atom or a straight-chain or branched alkyl group with 1 to 10 carbon atoms, as well as the physiologically acceptable salts of the compounds of the formula I with organic and inorganic bases and their esters with aliphatic, cycloaliphatic or araliphatic alcohols having 1-8 carbon atoms in the ester part.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772702368 DE2702368A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
| NL7714520A NL7714520A (en) | 1977-01-21 | 1977-12-29 | NEW PROSTAGLANDINE ANALOGS AND METHOD FOR THE PREPARATION THEREOF. |
| ES466005A ES466005A2 (en) | 1977-01-21 | 1978-01-16 | Analogues of prost-5,10,138-trienoic acid and process for preparing them |
| FI780169A FI780169A (en) | 1977-01-21 | 1978-01-19 | THIS FRAMEWORK FOR ANALOGUE FOR FRAMEWORK |
| LU78916A LU78916A1 (en) | 1977-01-21 | 1978-01-19 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
| AU32561/78A AU3256178A (en) | 1977-01-21 | 1978-01-19 | Prostaglandin analogs |
| SE7800689A SE7800689L (en) | 1977-01-21 | 1978-01-19 | NEW PROSTAGLAND INNALOGS AND PROCEDURES FOR THEIR MANUFACTURE |
| JP573278A JPS5392742A (en) | 1977-01-21 | 1978-01-20 | New analogue of prostaglandin and its preparation |
| ZA00780368A ZA78368B (en) | 1977-01-21 | 1978-01-20 | New prostoglandin analogs and process for their manufacture |
| DK29378A DK29378A (en) | 1977-01-21 | 1978-01-20 | PROSTAGLAND INNALOGUE AND MANUFACTURE AND USE |
| NO780226A NO780226L (en) | 1977-01-21 | 1978-01-20 | NEW PROSTAGLANDIN ANALOG AND PROCEDURES FOR THEIR PREPARATION |
| BE184546A BE863206R (en) | 1977-01-21 | 1978-01-23 | ANALOGUES OF PROSTANOIC ACIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION |
| GB2609/78A GB1577991A (en) | 1977-01-21 | 1978-01-23 | Analogues of prost-5,10,138-trienoic acid and process for preparing them |
| FR7801789A FR2378008A2 (en) | 1977-01-21 | 1978-01-23 | NEW ANALOGUES OF PROSTANOIC ACIDS, THEIR METHOD OF PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772702368 DE2702368A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2702368A1 true DE2702368A1 (en) | 1978-08-03 |
Family
ID=5999194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19772702368 Pending DE2702368A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5392742A (en) |
| AU (1) | AU3256178A (en) |
| BE (1) | BE863206R (en) |
| DE (1) | DE2702368A1 (en) |
| DK (1) | DK29378A (en) |
| ES (1) | ES466005A2 (en) |
| FI (1) | FI780169A (en) |
| FR (1) | FR2378008A2 (en) |
| GB (1) | GB1577991A (en) |
| LU (1) | LU78916A1 (en) |
| NL (1) | NL7714520A (en) |
| NO (1) | NO780226L (en) |
| SE (1) | SE7800689L (en) |
| ZA (1) | ZA78368B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4094899A (en) * | 1972-06-02 | 1978-06-13 | Pfizer Inc. | Oxaprostaglandins |
| GB1545633A (en) * | 1975-02-24 | 1979-05-10 | American Cyanamid Co | 11-deoxy substituted prostaglandins of the e and f series |
-
1977
- 1977-01-21 DE DE19772702368 patent/DE2702368A1/en active Pending
- 1977-12-29 NL NL7714520A patent/NL7714520A/en not_active Application Discontinuation
-
1978
- 1978-01-16 ES ES466005A patent/ES466005A2/en not_active Expired
- 1978-01-19 LU LU78916A patent/LU78916A1/en unknown
- 1978-01-19 AU AU32561/78A patent/AU3256178A/en active Pending
- 1978-01-19 FI FI780169A patent/FI780169A/en not_active Application Discontinuation
- 1978-01-19 SE SE7800689A patent/SE7800689L/en unknown
- 1978-01-20 DK DK29378A patent/DK29378A/en not_active Application Discontinuation
- 1978-01-20 ZA ZA00780368A patent/ZA78368B/en unknown
- 1978-01-20 NO NO780226A patent/NO780226L/en unknown
- 1978-01-20 JP JP573278A patent/JPS5392742A/en active Pending
- 1978-01-23 BE BE184546A patent/BE863206R/en not_active IP Right Cessation
- 1978-01-23 GB GB2609/78A patent/GB1577991A/en not_active Expired
- 1978-01-23 FR FR7801789A patent/FR2378008A2/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| SE7800689L (en) | 1978-07-22 |
| LU78916A1 (en) | 1978-09-28 |
| DK29378A (en) | 1978-07-22 |
| AU3256178A (en) | 1979-07-26 |
| FI780169A (en) | 1978-07-22 |
| ZA78368B (en) | 1979-01-31 |
| JPS5392742A (en) | 1978-08-15 |
| GB1577991A (en) | 1980-10-29 |
| NO780226L (en) | 1978-07-24 |
| BE863206R (en) | 1978-07-24 |
| ES466005A2 (en) | 1978-10-01 |
| FR2378008A2 (en) | 1978-08-18 |
| NL7714520A (en) | 1978-07-25 |
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| Date | Code | Title | Description |
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| OHN | Withdrawal |