DE2702366A1 - NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION - Google Patents
NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTIONInfo
- Publication number
- DE2702366A1 DE2702366A1 DE19772702366 DE2702366A DE2702366A1 DE 2702366 A1 DE2702366 A1 DE 2702366A1 DE 19772702366 DE19772702366 DE 19772702366 DE 2702366 A DE2702366 A DE 2702366A DE 2702366 A1 DE2702366 A1 DE 2702366A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- compound
- ester
- xxiii
- acid
- 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 9
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000003180 prostaglandins Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229940079593 drug Drugs 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
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 229940126601 medicinal product Drugs 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 claims 1
- 238000007796 conventional method Methods 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- -1 alkyl radical Chemical class 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 150000003555 thioacetals Chemical class 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 150000001241 acetals Chemical class 0.000 description 1
- 150000007513 acids Chemical class 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
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003524 antilipemic 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
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003182 bronchodilatating effect Effects 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
- 229960005003 carbocromen Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 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
- 229960003529 diazepam Drugs 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 150000004662 dithiols Chemical class 0.000 description 1
- 230000000694 effects Effects 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 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
- 238000005907 ketalization reaction Methods 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000003529 luteolytic effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229960001989 prenylamine Drugs 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 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
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229920002554 vinyl polymer Polymers 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
HOECHST AKTlETJCiI 'SE)^.SCHAFTHOECHST AKTlETJCiI 'SE) ^. SHAFT
Aktonzcichon: HOE 77/F 005Aktonzcichon: HOE 77 / F 005
Datum: 19.1.1977 I)r.La/KtDate: 19.1.1977 I) r.La/Kt
KEUE PROSTACLANuJH-ANALOGE WAD VERFAHRl]M ZU IHRERKEUE PROSTACLANuJH-ANALOGUE WAD PROCEDURES TO YOUR
HEESTE] ,LUNGHEESTE], LUNG
Zusatz zur Pat.entanm-ldüng Γ 24 07 186.1 (IiOE 74/1·' C43) s.ind Prostaqlcndin-Dorivuto Λι-τ al lyemeincTi Pormo] IAddendum to the patent entanm-ldüng Γ 24 07 186.1 (IiOE 74/1 · 'C43) s.ind Prostaqlcndin-Dorivuto Λι-τ al lyemeincTi Pormo] I
809831 /0024809831/0024
-JT--JT-
H HH H
CH0-CH0-C -C- CH,CH 0 -CH 0 -C -C- CH,
- CH0 - COOH- CH 0 - COOH
(D(D
in welcher bedeuten:in which mean:
R und R„ zusammen Sauerstoff oder jeweilss Wasserstoff oderR and R "together are oxygen or each is hydrogen or
eine Hydroxylgruppe, wobeia hydroxyl group, where
und R„ verschieden sind.and R "are different.
R^ einen gesättigten, geradkettigen oder verzweigten Alkylrest mit 1 bis 10 Kohlenstoffatomen, der seinerseits substituiert sein kann durch einen O-Alkylrest mit 1 bis Alkyl-C-Atomon, durch einen O-Arylrest, durch einen 0-Furylrest oder durch einen G-Benzylrest, die ihrerseits jeweils durch ein oder mehrere AlkyJgruppen mit 1-3 Kohlenstoffatomen substituiert sein können oder einen gesättigten Cycloalkylrest mit 3 bis 7 Ringgliedern oder einen Aryl- oder Furylrest, die ihrerseits durch ein oder mehrere Alkylgruppen mit 1 bis 3 Kohlenstoffatomen substituiert sein können, und ihre physiologisch verträglichen Salze mit organischen und anorganischen Basen und Ester.R ^ is a saturated, straight-chain or branched alkyl radical with 1 to 10 carbon atoms, which in turn can be substituted by an O-alkyl radical with 1 to Alkyl-C-Atomon, through an O-aryl radical, through an O-furyl radical or by a G-benzyl radical, which in turn each by one or more alkyl groups with 1-3 Carbon atoms can be substituted or one saturated cycloalkyl radical with 3 to 7 ring members or an aryl or furyl radical, which in turn by a or more alkyl groups having 1 to 3 carbon atoms can be substituted, and their physiologically acceptable salts with organic and inorganic bases and Ester.
Gegenstand des Hauptpatentes ist weiter ein Verfahren zur Herstellung von Prostaglandin-Derivaten der Formel I, das dadurch gekennzeichnet ist, daß manThe main patent also relates to a process for the preparation of prostaglandin derivatives of the formula I, which is characterized in that one
809831/0024809831/0024
a) ein Acetal der Formel IIa) an acetal of the formula II
,CU/-, ' X ■, CU / -, 'X ■
,CH- CIU - CH0 - CN II, CH- CIU - CH 0 - CN II
Cm £· Cm £
in welcherin which
X = Sauerstoff oder Schwefel und Y eine -CH-- oder eineX = oxygen or sulfur and Y a -CH-- or a
-C- Gruppe oder eine einfache Bindung bedeuten, mit einer-C- group or a single bond with a
Grignard - Verbindung der Formel III HaI-Mg-CH2-CH2-CH2-CH2-O-CH2 III,Grignard compound of the formula III Hal-Mg-CH 2 -CH 2 -CH 2 -CH 2 -O-CH 2 III,
in welcher Hai Chlor oder Brom bedeutet, zu einem Acetal-Keton der Formel IVin which Hai means chlorine or bromine, to an acetal ketone of formula IV
'CH2 X" IV 'CH 2 X " IV
,0-CH2-C), 0-CH 2 -C)
in welcher X und Y dieselbe Bedeutung wie in der Formel II haben, umsetzt,in which X and Y have the same meaning as in formula II ,
809831/0024809831/0024
b) das erhaltene Acetal-Keton der Formel IV in einer für Acetfile bzw. Thioacetale üblichen VJeise in das Aldehyd-·b) the acetal-ketone of the formula IV obtained in a for Acetfile or thioacetals are usually converted into the aldehyde
keton der Formel V
0ketone of formula V
0
—κ ν- κ ν
überführt,convicted,
c) das erhaltene Aldehydketon der Formel V einer sauer oder alkalisch katalysierten Aldolkondensation unterzieht, wobei das ungesättigte Keton der Formel VIc) the aldehyde ketone of the formula V obtained is subjected to an acidic or alkaline-catalyzed aldol condensation, wherein the unsaturated ketone of the formula VI
Π r,—λΠ r, —λ
f^Tr CH2"CH2~CH2~°"Cn2~\ / VI f ^ Tr CH 2 " CH 2 ~ CH 2 ~ °" Cn 2 ~ \ / VI
entsteht,arises,
d) das erhaltene ungesättigte Keton der Formel VI unter alkalischen Bedingungen mit Cyanidionen umsetzt, wobei das Cyanketon der Formel VIId) the unsaturated ketone of the formula VI obtained under alkaline conditions Reacts conditions with cyanide ions, the cyanetone of the formula VII
VIIVII
:n: n
erhalten wird,is obtained
e) das erhaltene Cyanketon der Formel VII mit wasserfreier alkoholischer Säure über das Iminoäthersalz der Formel VII ae) the cyanetone of the formula VII obtained with anhydrous alcoholic acid via the imino ether salt of the formula VII a
-CIU-CK.. O-CH,-CIU-CK .. O-CH,
C-OR11 C-OR 11
VII aVII a
HH-IlSHH-IlS
809831/0024809831/0024
270236S270236S
worin S ein anorganisches Säureradnkal und R einen niederen Alkylrest mit 1-5 C-Atomen bedeutet, und .anschließende Hydrolyse in die Ester der Formel VIII 0where S is an inorganic acid radical and R is one is a lower alkyl radical with 1-5 carbon atoms, and. Subsequent hydrolysis into the esters of the formula VIII 0
VIIIVIII
COOR4 COOR 4
worin R. die zur Formel VII a genannte Bedeutung hat, überführt,wherein R. has the meaning given for formula VII a, convicted,
f) den erhaltenen Ester der Formel VIII zur Abspaltung der Benzyläthergruppicrung in Gegenwart von Katalysatoren hydriert, wobei ein Ester - Alkohol der Formel IXf) the ester of the formula VIII obtained for splitting off the benzyl ether group in the presence of Hydrogenated catalysts, an ester alcohol of the formula IX
,CH2-CH2-CHp-OrI IX, CH 2 -CH 2 -CHp-OrI IX
COOR4 COOR 4
worin R- dieselbe Bedeutung hat wie in Formel VIII, erhalten wird,wherein R- has the same meaning as in formula VIII will,
g) den erhaltenen Ester-Alkohol der Formel IX zu einem Aldehyd der Formel Xg) the resulting ester alcohol of the formula IX to form an aldehyde of formula X
.CH2-CH2-CHO.CH 2 -CH 2 -CHO
COOR4 COOR 4
in der R- dieselbe Bedeutung wie in Formel VIII hat, oxydiertin which R- has the same meaning as in formula VIII, is oxidized
809831/0024809831/0024
Si -Si -
h) den erhaltenen Aldehyd der Forme] X selektiv mit ei nein Dithiol der Formel Xlh) the aldehyde obtained of the form] X selectively with ei no Dithiol of the formula Xl
XIXI
worin Y. eine -CII0- oder eine -C (CH^) „-Gruppe odei" eine einfache Bindung bedeutet, in Gegenwart saurer Katalysatoren zu einem Thioacelal der Formel XIIwherein Y. a -CII 0 - or a -C (CH ^) "group or a single bond, in the presence of acidic catalysts to a thioacelal of the formula XII
S C]IS C] I
„ 'CH2-Cl 12-CH_"'CH 2 -Cl 1 2 -CH_
COORj,COORj,
XIIXII
■S CH,■ S CH,
worin R^ dieselbe Bedeutung hat wie j.n Formel X, umsetzt,where R ^ has the same meaning as j.n formula X, converts,
i) das erhaltene Thioacetal der Formel XII durch sauer katalysierte Ketalisierung mit einem Glykol der Formel XIIIi) the thioacetal of the formula XII obtained by acidic catalyzed ketalization with a glycol of the formula XIII
XlIIXlII
worin Y- die gleiche Bedeutung hat wie der zur Formel XII genannte Rest Y1, in ein Ketal-Thioacetal der Formel XlVwhere Y- has the same meaning as the radical Y 1 mentioned for the formula XII, in a ketal thioacetal of the formula XIV
XIVXIV
COORCOOR
worin Y1 und Y„ gleich oder verschieden sein können, und dieselbe Bedeutung hat wie in Formel X, überführt,wherein Y 1 and Y "can be the same or different and have the same meaning as in formula X, converted,
809831/0024809831/0024
Y"Y "
j) das erhaltene Ketal-Thioacetal der Formel XIV mit einem komplexen Metallhydrid in aprotischen Lösungsmitteln zu einem Aldehyd der Formel XVj) the resulting ketal thioacetal of the formula XIV with a complex metal hydride in aprotic solvents to form an aldehyde of the formula XV
CIU-CII --CIICIU-CII --CII
U-CIIU-CII
ti etti et
XVXV
CHOCHO
worin Y1 und Y_ die gleiche Bedeutung haben wir in der Formel XlV, reduziert,where Y 1 and Y_ have the same meaning in the formula XlV, reduced,
k) den erhaltenen Aldehyd der Formel XV mit einem Phosphonat Formel XVIk) the obtained aldehyde of formula XV with a phosphonate formula XVI
ClI7O. CH3O-ClI 7 O. CH3O-
;T-c)i2-c-n,; Tc) i 2 -cn,
XVIXVI
worin R dieselbe Bedeutung wie in der Formel I hat, zu einem ungesättigten Keton der Formel XVIIwherein R has the same meaning as in formula I, to an unsaturated ketone of the formula XVII
809831/0024809831/0024
'Kr'Kr
XVlIXVlI
worin Y1 und Y_ die gleiche Bedeutung wie in der Formel XlV und R_ die gleiche Bedeutung wie in der Formel I haben, umsetzt,where Y 1 and Y_ have the same meaning as in formula XIV and R_ have the same meaning as in formula I,
1) das erhaltene Keton der Formel XVII mit einem komplexen Meta].lhydrid zu dein Epimerengernisch der Alkohole der Formel XVIII1) the resulting ketone of the formula XVII with a complex meta] .lhydride to form the epimeric mixture of the alcohols of the formula XVIII
XVIIIXVIII
809831/0024809831/0024
worin Y. und Y„ und R., dieselbe Bedeutung wie in Forme] XVI] haben, reduziert,where Y. and Y "and R., the same meaning as in formula] XVI] have, reduced,
m) den erhaltenen Alkohol der Formel XVIII als Epimerengemisch oder niich Trennung der Epimeren durch sauerkatalys.i orte Addition von 2,3-Dihydropyran in einen Tetrahydropyranylether der Formel XIXm) the alcohol of the formula XVIII obtained as Mixture of epimers or failure to separate the epimers Acid-catalyzed addition of 2,3-dihydropyran in one Tetrahydropyranyl ether of the formula XIX
„CH^-CH^-CJI"CH ^ -CH ^ -CJI
Ί>Ί>
XTXXTX
in der Y. und Y_ und R^ die gleiche Bedeutung haben wie Formel XVII, überführt,in which Y. and Y_ and R ^ have the same meaning as formula XVII, transferred,
η) den erhaltenen Äther der Formel XIX durch Erhitzen mit einem C1 - C.-Alkyljodid in einem polaren aprotischen Lösungsmittel in Gegenwart eines säurebindenen Mittels in einen Aldehydäther der Formel XXη) the ether of the formula XIX obtained by heating with a C 1 -C alkyl iodide in a polar aprotic solvent in the presence of an acid-binding agent in an aldehyde ether of the formula XX
CJL,CJL,
9 831/00249 831/0024
- 10 -- 10 -
worin Υ_ und R dieselbe Bedeutung wie in Formel XVlI haben, überführt,wherein Υ_ and R have the same meaning as in formula XVlI have convicted
o) den erhaltenen /\ldehydather der Forme] XX mit dem Ylid aus 4-Carboxypiopyltriphenylphosphoniumbromid in einer Lösung von Natriumhydrid in Diiviethy] sulfoxid zu einer Säure der Formel XXIo) the obtained / \ ldehydather of the form] XX with the ylid from 4-carboxypiopyltriphenylphosphonium bromide in one Solution of sodium hydride in diiviethy] sulfoxide to form a Acid of formula XXI
,. C]I0-CII0-CiI-OH-CIU-CIU-COOII,. C] I 0 -CII 0 -CiI-OH-CIU-CIU-COOII
ei dei d ti dti d
κ.κ.
worin Y„ und R die gleichen Bedeutung wie in der Formel XVlI haben, umsetzt undwherein Y "and R have the same meaning as in the formula XVlI have implemented and
p) die Tetrahydropyranylätherschutzgruppe in der erhaltenen Verbindung der Formel XXI durch .schonende, saure Hydrolyse abspaltet, wobei ein Alkohol der Formel XXIIp) the tetrahydropyranyl ether protecting group in the one obtained Compound of the formula XXI by gentle, acidic hydrolysis splits off, an alcohol of the formula XXII
C]I0-CH0-Ci]-CII-ClvyC] I 0 -CH 0 -Ci] -CII-Clvy
r. tir. ti eiegg
XXIIXXII
- 11 - - 11 -
809831/0024809831/0024
'/3'/ 3
-JkT --JkT -
in der Y und R.. dieselbe Bedeutung wie in Formel XVII
haben, erhalten wird und danach die Ketalgruppierung
in dein Alkohol der Formel XXlI entweder durch schonende sauerkatalytische Hydrolyse oder durch Umketaiisierung
in Gegenwart eines großen Überschusses an einem Keton entfernt, oder die Abspaltung beider Schutzgruppen
durch schonende saure Hydrolyse in einem Schritt durchführt und gegebenenfalls die so erhaltene Verbindung der Formel I,
worin R- und R- zusammen Sauerstoff bedeuten,in which Y and R .. have the same meaning as in formula XVII, and then the ketal group
in the alcohol of the formula XXlI removed either by gentle acid catalytic hydrolysis or by reketaiization in the presence of a large excess of a ketone, or the cleavage of both protective groups is carried out by gentle acid hydrolysis in one step and optionally the compound of the formula I thus obtained, in which R- and R- together mean oxygen,
zu einer Verbindung der Formel I, in der R. und R„ Wasserstoff oder Hydroxyl bedeuten, mit einem komplexen Metallhydrid reduziert und die Verbindungen der Formel Ito a compound of the formula I in which R. and R “hydrogen or hydroxyl, reduced with a complex metal hydride and the compounds of the formula I
gewünschtenfalls in die physiologisch verträglichen Salze oder ihre Ester überführt.if desired, converted into the physiologically acceptable salts or their esters.
Die beschriebenen erfindungsgemäßen Verbindungen zeichnen
sich durch spasmogene, bronchiodilatiitorischc, blutdrucksenkende,
magensaf tsekretionshernmende , luteolytische und
abortive Eigenschaften aus und können daher als Arzneimittel verwendet werden.The compounds according to the invention described are characterized by spasmogenic, bronchodilatory, antihypertensive, gastric juice secretion inhibiting, luteolytic and antihypertensive
abortive properties and can therefore be used as drugs.
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 I mit niederen Carbonsäuren verestert. Der überraschende differenzierende und wirkungsverstärkcnde 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 stronger and more differentiated A pharmacological effect is obtained if the allylic hydroxyl group on carbon atom 15 of the compounds I is used esterified lower carboxylic acids. The surprising differentiating and effect-enhancing influence of the esterification is particularly pronounced with preparations with antihypertensive effects.
Gegenstand der Erfindung sind daher Prostaglandin-Analoge der allgemeinen Formel XXIIIThe invention therefore relates to prostaglandin analogs of the general formula XXIII
- 12 -- 12 -
809831/0024809831/0024
1 R1 row
.CII=CH R-..CII = CH R-.
R-COR-CO
- COOH- COOH
XXIIIXXIII
12 3
worin R , R und R die zur Formel I der Hauptpatentanmeldung genannte Bedeutung haben und R ein Wasserstoffatom oder eine
geradkettige oder eine verzweigte Alkylgruppe mit bis zu
10 Kohlenstoffatomen bedeutet,12 3
in which R, R and R have the meaning given for formula I of the main patent application and R is a hydrogen atom or a straight-chain or branched alkyl group with up to 10 carbon atoms,
und ihre physiologisch verträglichen Salze mit organischen und anorganischen Basen sowie ihre physiologisch verträglichen Ester.and their physiologically acceptable salts with organic and inorganic bases as well as their physiologically compatible ones Ester.
Für R sind bevorzugt die in der Ilauptpatentanmoldung als bevorzugt genannten Reste. Für R sind bevorzug I: geradkettige oder verzweigte Alkylcjruppen mit bis zu 4 C--/itomen.For R, those in the Ilauptpatentanmoldung as are preferred preferably mentioned residues. For R, I are preferred: straight-chain or branched alkyl groups with up to 4 carbon atoms.
Als Salze und Ester sind ebenfalls bevorzugt die in der Hauptpatentanmeld>mg besonders genannten.Preferred salts and esters are those specifically mentioned in the main patent application.
Diis Verfahren zur Darstellung der erfindungsgemäßen Verbindungen ist dadurch gekennzeichnet, daß man solcheDiis method for the preparation of the invention Connections is characterized by the fact that you have such
1 21 2
Verbindungen der Formel I, deren Reste R und R zusammen Sauerstoff bedeuten, durch Umsetzung mit geeigneten Acylierungsmitteln in Verbindungen der Formel XXIII über-Compounds of the formula I, the radicals of which R and R together denote oxygen, by reaction with suitable ones Acylating agents in compounds of the formula XXIII
1 2
führt, deren Reste R und R zusammen Sauerstoff bedeuten1 2
leads, whose radicals R and R together represent oxygen
- 13 -- 13 -
809831/0024809831/0024
und diese Verbindungen gegebenenfalls reduziert zu Verbindungen der Formel XXITI, worin einer der Reste R und R eine Hydroxylgruppe und der andere ein Wasserstoffatom bedeutet.and these compounds optionally reduced to compounds of the formula XXITI, in which one of the radicals R and R is a hydroxyl group and the other is a hydrogen atom.
Als Acylierungsinittel kommen die freien Carbonsäuren sowie deren reaktionsfähige Derivate in Betracht. Bei Verwendung der Carbonsäure führt man die Reaktion vorzugsweise in dieser Säure als Lösungsmittel bei Temperaturen zwisehen 0° und 70° durch. In einigen Fällen ist es vorteilhaft, die Reaktionslösuuo; zur Vermeidung von Folgereeiktionen abzupuffern. (Vgl. J. E. Pike, F. H. Lincoln, W. P. Schneider, J. Org. Chem. 34, 3553 (1969)).The free carboxylic acids and theirs are used as acylating agents reactive derivatives into consideration. When using the Carboxylic acid, the reaction is preferably carried out in this Acid as a solvent at temperatures between 0 ° and 70 °. In some cases it is advantageous to use the reaction solution; to be buffered to avoid subsequent events. (See J. E. Pike, F. H. Lincoln, W. P. Schneider, J. Org. Chem. 34, 3553 (1969)).
Zur Acylierung können ferner die entsprechenden Carbonsäurehalogenide oder Carbonsäureanhydride verwendet werden. Die Reaktion wird dann bevorzugt in aprotisehen Lösungsmitteln in Gegenwart einer Base bei Temperaturen zwischen 0° und 80° durchgeführt. Zur Herstellung der erfindungsgemäßen Verbinddungen 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 can also be used for acylation or carboxylic acid anhydrides can be used. The reaction is then preferably carried out in aprotic solvents carried out in the presence of a base at temperatures between 0 ° and 80 °. For the production of the compounds according to the invention the reaction of the alcohols with the corresponding ketenes is also possible. This reaction will also carried out in aprotic solvents at room temperature.
Zur Darstellung solcher Verbindungen der Formel XXIIl, bei denenTo represent such compounds of the formula XXIIl, in which
1 2
einer der Reste R und R eine Hydroxylgruppe und der andere Viasserstoff bedeutet, werden die nach obigem Verfahren hergestellten
9--Keto-1 5-acyloxy-prostadi ensäurederivete 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.1 2
one of the radicals R and R is a hydroxyl group and the other is hydrogen, the 9-keto-1 5-acyloxy-prostadioenoic acid derivatives prepared by the above process are reduced. Particularly suitable reducing agents for this are complex hydrides which are able to reduce a keto group without attacking ester or carboxyl groups. The use of sodium borohydride in methanol / water as a solvent has proven particularly useful here.
Die freien Säuren der Formel XXIII können gegebenenfalls nach den üblichen Verfahren in die entsprechenden Salze oder Ester überführt werden.The free acids of the formula XXIII can optionally be converted into the corresponding salts or esters by customary processes be convicted.
- 14 -- 14 -
809831/0024809831/0024
- yi - - yi -
Die erfahrungsgemäfien Verbindungen haben wertvolle pharmakoloqi sehe Ei genschaf ten. Sie zeichnen rich insbesondere durch blutdrucksenkende Wi rkunq aus, die joner dor nichtacyliorton Ausgangsverbindungen deutlich überlegen ist. Die für die blutdrucksenkende Wirkung unerwünschten Nobenvi rkunyon auf die glätte J'usku J a tür wurde in diesen Fällen bisher nicht beobachtet. Aufgrund der pharmakologischon Wirkungen können die crfindungsgemaßon Verbindungen als Arzneiini ttel angewandt werden.The connections according to experience have valuable pharmakoloqi see properties. You draw particularly well by blood pressure lowering Wi rkunq, the joner dor nichtacyliorton Output compounds is clearly superior. The undesirable for the antihypertensive effect Nobenvi rkunyon on the smoothness J'usku J a door was in these Cases not observed so far. Due to the pharmacologicalon The compounds according to the invention can have effects be used as medicinal products.
Sie können in Form ihrer wäßrigen Lösungen oder Suspensionen oder auch gelöst oder suspendiert in pharniakologisch unbedenklichen organischen Lösungsmitteln wie ein- oder mehrwertige Alkoholen, z.B. Äthanol, Äthy.l ongl ykol oder Glyzerin, ölen wie z.B, Sonnenblumenöl odc2~ Lebertran, Zithern wie z.B. Di äthyl c -ng] yko.l dimef hyiäthor oder auch Polyäthcrn wie v.. H, Pol yäthy.l onql ykol e oder au.c:li i): Clccjenwart anderer pharmakologisch unbcdiuiklichor Polymerträger wie z.B, Polyvinyl jvyrrolidon zur Anwendung gelangen.They can be in the form of their aqueous solutions or suspensions or also dissolved or suspended in pharniacologically harmless organic solvents such as monohydric or polyhydric alcohols, e.g. Ethyl c -ng] yko.l dimef hyiäthor or also Polyäthcrn like v .. H, Pol yäthy.l onql ykol e or au.c: li i): If other pharmacologically unbecdiuiklichor polymer carriers such as, for example, polyvinyl jvyrrolidon are used.
Als Zubereitungen können die üblichen galenischen Tnfusions- oder 1 η jeJ;f i onr.l ösungon und Tabletten, sowie örtlich anwendbare Zuboj ei tiingon wie Ctcüh-s, Emulsionen, Supjjoti t ori ei« , insbesondere auch Aerosole in Frage kommen.The usual galenic infusion or 1 η perJ; fi onr solution and tablets, as well as locally applicable zuboj eiingon such as ctcüh-s, emulsions, supjoti t ori, in particular also aerosols can be used as preparations.
Eine weitere Anwendung der neuen Verbindungen liegt in de:·]- Kombination mit anderen Wirkstoffen. Neben anderen geeigneten Substanzen gehören dazu vor allem:Another application of the new compounds is the de: ·] combination with other active ingredients. Next to other suitable substances include:
Diurotika, wie: z.B. Furosemid , Anti di abet ika wie z.B. Gl y co; Ii a ζ i η , To] but amid , GJi ben el ami d , Phonf ornii η , Buforinin, Metformin, Kreislaufmittel im weitesten Sinne, z.B. Coronardilatatoren, wie Chromonar oder Prenylamin, blutdrucksenkende Stoffe wie Reserpi η , Ot.-Methyl-DopaDiurotics, such as: e.g. furosemide, anti-diabetic drugs such as e.g. Gl y co; Ii a ζ i η, To] but amid, GJi ben el ami d, Phonf ornii η, Buforinin, metformin, circulatory drugs in the broadest sense, e.g. coronary dilators, such as Chromonar or Prenylamine, Antihypertensive substances such as Reserpi η, Ot.-Methyl-Dopa
- 15 -- 15 -
80983 1 /002480983 1/0024
7T7T
oder Clonidine oder Antiarrhytmika, Lipidsenker, Goriatrika und andere Stoffwechsel v/irksame Präparate, Psychopharmaka, wie z.B. Chlord Lazepoxid, Diazepam oder Moprobamat sov;ie Vitamine, oder Prostaglandine oder prostaglandin-ähnliche Verbindungen sowie aucli Prostatjlandinantagonisten und ProsLaglandin-Diosynthesoheiimier, wie z.B. nicht-steroida Le Antiphlogistika. or clonidines or antiarrhythmics, lipid lowering agents, goriatrics and other metabolic drugs, psychotropic drugs, such as Chlord Lazepoxid, Diazepam or Moprobamat so; ie Vitamins, or prostaglandins, or prostaglandin-like ones Compounds as well as prostatlandin antagonists and proslaglandin diosynthesis inhibitors, such as non-steroidal anti-inflammatory drugs.
- 16 -- 16 -
80903 1 /002480903 1/0024
- J6 Bei spiel 1:- J6 example 1:
9-Ko Ig- 1 5^-acetoxy-16, 1 6-d i me thy 1-1 8--ο χα-pro st/ι-4 , 13-dlensäure9-Ko Ig- 1 5 ^ -acetoxy-16, 1 6-d i me thy 1-1 8 - ο χα-pro st / ι-4, 13-dlenic acid
200 nicj 9-Keto-15'-v'-hydroxy-1 6 , 1 6-diniethyl- 1 8-oxa-prosta·- 4, 13-d i ensäure werden in 10 ml absolutem Pyridin gelöst, mit 0,2 ml Acetanhydrid versatzt und H Stunden bei 65° gerührt. Anschließend lässt man abkühlen, gießt die erkaltete Lösung in eine Mischung von L'i.s und Natriuinhydrogenphoijphat. Die so gewonnene Mischung wird niohrfacli mit Äther extraliiet t . Die vereinigten Atherphasen werden getrocknet und eingedampft. Der Rückstand wird über eine Kieselgel-Gäule mit Cyelohexan/Essigester/Eisessig 80/20/1 alt; Laufmittel chroma I-hogrnphiert. Mrin erhält 110 mg och gewünschten Produktes.200 nicj 9-keto-15'-v'-hydroxy-1 6, 1 6-diniethyl- 1 8-oxa-prosta - 4, 13-dioenoic acid are dissolved in 10 ml of absolute pyridine, mixed with 0.2 ml of acetic anhydride and H hours at 65 ° touched. Then let it cool down, pour the cold solution in a mixture of L'i.s and Natriuinhydrogenphoijphat. The mixture obtained in this way is niohrfacli with ether extraliiet t. The united ether phases become dried and evaporated. The residue is over a silica gel column with cyelohexane / ethyl acetate / glacial acetic acid 80/20/1 old; Mobile phase chroma I-engraved. Mrin receives 110 mg och desired product.
DC (Kiesel gel, Laufmittel Cyclohexan/Essigester/Cisessig 60/40/1).TLC (silica gel, mobile phase cyclohexane / ethyl acetate / cisacetic acid 60/40/1).
Rf ~- 0,22Rf ~ - 0.22
NMR (60 MHz, CDCl3)NMR (60 MHz, CDCl 3 )
5,7-4,9 ppm, Multi plett 5 II5.7-4.9 ppm, multiplet 5 II
3,3 ppm, Quartett 2 II3.3 ppm, quartet 2 II
3,0 ppni/ Singulett 2 II3.0 ppni / singlet 2 II
2,5 -- 0,6 ppm, übrige Protonen mit2.5 - 0.6 ppm, other protons with
2,0 ppm, Singulett2.0 ppm, singlet
1 ,1 ppm, Triplett1.1 ppm, triplet
0,8 u.0,9 ppm, Singuletts0.8 and 0.9 ppm, singlets
- 17 -- 17 -
809ΘΊ I /0024809ΘΊ I / 0024
Beispiel 2:Example 2:
9-Keto-1 5 Cv--acetoxy-16 , 1 6-diinet liyl-18-oxa-prostn-4 ,9-keto-1 5 Cv -acetoxy-16, 1 6-diinet liyl-18-oxa-prostn-4,
sauremethy!esteracid methyl ester
28 mc} dor Verbindung aus Beispiel 1 werden in 10 ml absolutemfttber gelöst und bis zur ersten Gelbfärbung der Lösung tropfenweise bei 0° mit ätherischem Diazomethan versetzt. Man läßt noch eine Stunde bei Raumtemperatur stehen, zersetzt dann den überschuss an Diazomethan durch Zu crab« von etwas Eisessig und dampft schließlich im Vakuum ein. Man erhält 2 9 ing des gewünschten F. κ te rs. 28 ml of the compound from Example 1 are dissolved in 10 ml of absolute solution and ethereal diazomethane is added dropwise at 0 ° until the solution turns yellow. The mixture is left to stand for a further hour at room temperature, the excess diazomethane is then decomposed by adding a little glacial acetic acid and finally evaporated in vacuo. 2 9 ing of the desired F. κ te rs are obtained.
DC (Kieselgel, Laufmitte] Cyclohexan/Essigester/Eisessig
60/40/1)
Uf 0,G2TLC (silica gel, middle section] cyclohexane / ethyl acetate / glacial acetic acid 60/40/1)
Uf 0, G2
NMR (CIvCl3, GO KUt.) NMR (CIvCl 3 , GO KUt.)
5,8 -■ 5,0 ppm, 5 H, Multiplett5.8 - ■ 5.0 ppm, 5 H, multiplet
4.7 ppro, 3 H, Singu.lett 3,4 ppm, 2 11, Quartett 3,1 ppm, 2 H, Sinyu]ett4.7 ppro, 3H, singlet 3.4 ppm, 2 11, quartet 3.1 ppm, 2 H, Sinyu] ett
2.8 - 0,8 ppm, restl. Protonen, darunter2.8 - 0.8 ppm, remaining protons, below
2.1 ppm, Singulelt2.1 ppm, Singulelt
.,2 ppm, Triplett
1,0 u. 0,9 ppm, ßingulel-ts., 2 ppm, triplet
1.0 and 0.9 ppm, ßingulel-ts
- 18 -- 18 -
809831/0024809831/0024
Claims (5)
einer der Reste R und R eine Hydroxylgruppe und der andere Viasserstoff bedeutet, und gegebenenfalls eine freie Säure der Formel XXIII nach üblichem Verfahren in ein physiologisch verträgliches Salz oder einen physiologisch verträcjlichen Ester überführt.1 2
one of the radicals R and R is a hydroxyl group and the other is hydrogen, and optionally a free acid of the formula XXIII is converted into a physiologically acceptable salt or a physiologically acceptable ester by a conventional method.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772702366 DE2702366A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
| NL7714523A NL7714523A (en) | 1977-01-21 | 1977-12-29 | NEW PROSTAGLANDINE ANALOGS AND METHOD FOR THE PREPARATION THEREOF. |
| ES466004A ES466004A2 (en) | 1977-01-21 | 1978-01-16 | New analogue of prostaglandin and its preparation |
| SE7800688A SE7800688L (en) | 1977-01-21 | 1978-01-19 | NEW PROSTAGLAND INNALOGS AND PROCEDURES FOR THEIR MANUFACTURE |
| LU78909A LU78909A1 (en) | 1977-01-21 | 1978-01-19 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
| JP573078A JPS5392740A (en) | 1977-01-21 | 1978-01-20 | New analogue of prostaglandin and its preparation |
| DK29478A DK29478A (en) | 1977-01-21 | 1978-01-20 | PROSTAGLAND INNALOGUE AND THEIR MANUFACTURE AND USE |
| ZA00780366A ZA78366B (en) | 1977-01-21 | 1978-01-20 | New prostaglandin analogs and process for their manufacture |
| FR7801790A FR2378009A2 (en) | 1977-01-21 | 1978-01-23 | 15-Acyloxy-prostaglandin analogues - with hypotensive activity without undesired smooth muscle side effects (BE 24.7.78) |
| BE184545A BE863205R (en) | 1977-01-21 | 1978-01-23 | NON-NATURAL ANALOGUES OF PROSTANOIC ACIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772702366 DE2702366A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2702366A1 true DE2702366A1 (en) | 1978-08-03 |
Family
ID=5999192
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19772702366 Pending DE2702366A1 (en) | 1977-01-21 | 1977-01-21 | NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5392740A (en) |
| BE (1) | BE863205R (en) |
| DE (1) | DE2702366A1 (en) |
| DK (1) | DK29478A (en) |
| ES (1) | ES466004A2 (en) |
| FR (1) | FR2378009A2 (en) |
| LU (1) | LU78909A1 (en) |
| NL (1) | NL7714523A (en) |
| SE (1) | SE7800688L (en) |
| ZA (1) | ZA78366B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4045577A (en) * | 1971-06-17 | 1977-08-30 | Alza Corporation | Valuable medicinial prostaglandin compounds prepared from material isolated from the sea |
| ZA764727B (en) * | 1975-09-02 | 1977-07-27 | Upjohn Co | Prostanoic acid derivatives |
-
1977
- 1977-01-21 DE DE19772702366 patent/DE2702366A1/en active Pending
- 1977-12-29 NL NL7714523A patent/NL7714523A/en not_active Application Discontinuation
-
1978
- 1978-01-16 ES ES466004A patent/ES466004A2/en not_active Expired
- 1978-01-19 LU LU78909A patent/LU78909A1/en unknown
- 1978-01-19 SE SE7800688A patent/SE7800688L/en unknown
- 1978-01-20 ZA ZA00780366A patent/ZA78366B/en unknown
- 1978-01-20 DK DK29478A patent/DK29478A/en unknown
- 1978-01-20 JP JP573078A patent/JPS5392740A/en active Pending
- 1978-01-23 FR FR7801790A patent/FR2378009A2/en active Pending
- 1978-01-23 BE BE184545A patent/BE863205R/en active
Also Published As
| Publication number | Publication date |
|---|---|
| BE863205R (en) | 1978-07-24 |
| LU78909A1 (en) | 1978-09-28 |
| FR2378009A2 (en) | 1978-08-18 |
| NL7714523A (en) | 1978-07-25 |
| DK29478A (en) | 1978-07-22 |
| ES466004A2 (en) | 1978-10-01 |
| JPS5392740A (en) | 1978-08-15 |
| SE7800688L (en) | 1978-07-22 |
| ZA78366B (en) | 1979-01-31 |
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