DD210027B3 - PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES - Google Patents
PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES Download PDFInfo
- Publication number
- DD210027B3 DD210027B3 DD83252808A DD25280883A DD210027B3 DD 210027 B3 DD210027 B3 DD 210027B3 DD 83252808 A DD83252808 A DD 83252808A DD 25280883 A DD25280883 A DD 25280883A DD 210027 B3 DD210027 B3 DD 210027B3
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- group
- oxa
- dihomo
- prostaglandin
- yloxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 230000008569 process Effects 0.000 title claims abstract description 6
- -1 hydroxymethylene group Chemical class 0.000 claims abstract description 96
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 97
- 125000004429 atom Chemical group 0.000 claims description 10
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical class C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
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- 150000001408 amides Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
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- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
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- 238000003786 synthesis reaction Methods 0.000 claims 1
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- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000002615 hemofiltration Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000036593 pulmonary vascular resistance Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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Abstract
Description
K) OHK) OH
(5E)-6a-Carbaprostaglandin-I2 (5Z)-6a-Carbaprostaglandin-I2 (5E) -6a-carbaprostaglandin-I 2 (5Z) -6a-carbaprostaglandin-I 2
Aus dem sehr umfangreichen Stand der Technik der Prostacycline und ihrer Analoga weiß man, daß diese Stoff klasse aufgrund ihrer biologischen und pharmakologischen Eigenschaften zur Behandlung von Säugetieren, einschließlich Menschen geeignet ist. Ihre Verwendung als Arzneimittel stößt jedoch häufig auf Schwierigkeiten, da sie eine für therapeutische Zwecke zu kurze Wirkungsdauer besitzen.From the very extensive state of the art of prostacyclins and their analogs, it is known that this class of substances is suitable because of their biological and pharmacological properties for the treatment of mammals, including humans. Their use as a drug, however, often encounters difficulties because they have a too short duration of action for therapeutic purposes.
Ziel der Erfindung ist die Bereitstellung neuer Carbacyclinderivate mit verlängerter Wirkungsdauer und gesteigerter Selektivität. Darlegung des Wesens der ErfindungThe aim of the invention is to provide novel Carbacyclinderivate with extended duration of action and increased selectivity. Explanation of the essence of the invention
Der Erfindung liegt die Aufgabe zugrunde, neue Carbacycline mit den gewünschten Eigenschaften und Verfahren zu ihrer Herstellung aufzufinden.The invention has for its object to find new carbacyclins with the desired properties and processes for their preparation.
Gegenstand der Erfindung ist daher ein Verfahren zur Herstellung von Carbacyclinderivaten der allgemeinen Formel IThe invention therefore provides a process for the preparation of Carbacyclinderivaten of the general formula I.
ι CH9 CH 9
I * CXI * CX
A-W-D-E-R. OH 4 AWDER. OH 4
R1 den Rest OR2, wobei R2 Wasserstoff, Alkyl mit 1—4C-Atomen oder den RestR 1 is the radical OR 2 , where R 2 is hydrogen, alkyl having 1-4C atoms or the radical
oder R1 den Restor R 1 is the rest
NHR3 mit R3 als Wasserstoff oder 2,3-Dihydroxypropyl bedeuten kann, X ein Wasserstoffatom oder ein Fluoratom, A eine trans-CH=CH-oder-C=C-Gruppe, W eine Hydroxymethylengruppe, wobei die OH-Gruppe α- oder ß-ständig sein kann, D dieGruppe —C—CH_—i einegeradkettigeAlkylengruppemiti-SC-AtomenodereineverzweigteAlkylengruppeNHR 3 with R 3 as hydrogen or 2,3-dihydroxypropyl, X is a hydrogen atom or a fluorine atom, A is a trans-CH = CH- or-C = C group, W is a hydroxymethylene group, where the OH group is α- or β-substituent, the group -C-CH_-i may be a straight-chain alkylene group-SC atom or a branched alkylene group
mit 2-5 C-Atomen, 'with 2-5 C atoms, '
E eine-C=C-Gruppe oder eine-CH=CH(CH3)-Gruppe bedeuten, R4 eine Alkylgruppe mit 1—7 C-Atomen und, falls R2 die Bedeutung eines Wasserstoffatoms hat, deren Salze mit physiologisch verträglichen Basen bedeuten, welches sich dadurch auszeichnet, daß man in an sich bekannter Weise eine Verbindung der allgemeinen Formel IlE is a-C = C group or a -CH = CH (CH 3 ) group, R 4 is an alkyl group having 1-7 C atoms and, if R 2 is hydrogen, their salts with physiologically compatible bases mean, which is characterized in that in a conventional manner a compound of the general formula II
CH2OHCH 2 OH
CX (II), CX (II),
A-W-O-E-R4 OHAWOER 4 OH
worm X, R4, A, W, D und E die oben angegebenen Bedeutungen aufweisen, gegebenenfalls nach Schutz anwesender freier Hydroxygruppen mit einem Halogenketal der allgemeinen Formel IIIworm X, R 4 , A, W, D and E have the meanings given above, optionally after protection of present free hydroxy groups with a halo ketal of the general formula III
(III),(III)
wobei Hai ein Chlor-, Brom- oder Jodatom, R8 und R9 eine Alkylgruppe mit 1-10 C-Atomen oder R8 und R9 gemeinsam eine ringbildende Gruppe mit 2-1 OC-Atomen bedeuten, in Gegenwart einer Base verethert und mit Saure das Ketal spaltet und gegebenenfalls anschließend ι η beliebiger Reihenfolge Isomere trennt und/oder geschützte Hydroxygruppen freisetzt und/oder freie Hydroxygruppen verestert und verathert und/oder die Aldehydgruppe oxydiert und/oder die resultierende freie Carboxylgruppe verestert und/oder eine veresterte Carboxylgruppe verseift oder eine Carboxylgruppe in ein Amid oder mit einer physiologisch vertraglichen Base in ein Salz überfuhrtwherein Hal is a chlorine, bromine or iodine atom, R 8 and R 9 is an alkyl group having 1-10 C atoms or R 8 and R 9 together form a ring-forming group having 2-1 OC atoms, etherified in the presence of a base and with acid, the ketal cleaves and optionally subsequently ι η arbitrary sequence of isomers and / or free hydroxy groups esterified and etherified and / or oxidized the aldehyde group and / or esterifying the resulting free carboxyl group and / or an esterified carboxyl group or saponified converted a carboxyl group into an amide or with a physiologically-based base into a salt
Es wurde gefunden, daß durch Homologisierung der oberen Kette der 3-Oxa-Carbacycline eine längere Wirkungsdauer, eine größere Selektivität und eine bessere Wirksamkeit erzielt werden können Die erfindungsgemaß hergestellten Verbindungen wirken blutdrucksenkend und bronchodilatonsch Sie sind außerdem zur Vasodilatation, Inhibierung der Thrombocytenaggregation und der Magensauresekretion geeignetIt has been found that by homologation of the upper chain of 3-oxa-carbacyclins a longer duration of action, greater selectivity and better efficacy can be achieved The compounds prepared according to the invention have antihypertensive and bronchodilatating action. They are also useful for vasodilation, inhibition of platelet aggregation and gastric acid secretion suitable
Die Verbindungen der Formel I stellen sowohl (5E)-als auch (5Z)-lsomeredar Als Alkylgruppen R2 sind gerad-oderverzweigtkettige Alkylgruppen mit 1 bis4C-Atomenzu betrachten, wie beispielsweise Methyl, Äthyl, Propyl, Isopropyl, Butyl, Isobutyl, tert -ButylThe compounds of formula I represent both (5E) and (5Z) -isomeres. As alkyl groups R 2 , straight or branched chain alkyl groups having 1 to 4C atoms are contemplated, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. butyl
Als Alkylgruppe R4 kommen gerad- und verzweigtkettige Alkylreste mit1 bis 7 C-Atomen in Frage Beispielsweise genannt seien Methyl, Äthyl, Propyl, Butyl, Isobutyl, tert -Butyl, Pentyl, Hexyl, HeptylSuitable alkyl groups R 4 are straight-chain and branched-chain alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl
AlsAlkylengruppe D kommen geradkettige oder verzweigtkettige, gesattigte Alkylenreste mit 1 bis5C-Atomen in Frage Beispielsweise seien genannt Methylen, Äthylen, 1,2-Propylen, Athylathylen, Trimethylen, Tetramethylen, Pentamethylen, 1-Methyltetramethylen, 1-MethyltnmethylenSuitable alkylene groups are straight-chain or branched-chain, saturated alkylene radicals having from 1 to 5 carbon atoms. Examples which may be mentioned are methylene, ethylene, 1,2-propylene, ethylenyl, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyltnmethylene
Zur Salzbildung mit den freien Sauren (R1 = H) sind anorganische und organische Basen geeignet, wie sie dem Fachmann zur Bildung physiologisch vertraglicher Salze bekannt sind Beispielsweise seien genannt Alkalihydroxide, wie Natrium- und Kaliumhydroxid, Erdalkalihydroxide, wie Calciumhydroxid, Ammoniak, Amine, wie Athanolamin, Diathanolamin, Triathanolamin, N-Methylglucamin, Morpholm, Tns-(hydroxymethyl)-methylamin usw Die Umsetzung der Verbindung der allgemeinen Formel Il mit einem Halogenketal der allgemeinen Formel III wird bei Temperaturen von O0C bis 1000C, vorzugsweise 1O0C bis 800C, in einem aprotischen Losungsmittel oder Losungsmittelgemisch, beispielsweise Dimethylsulfoxid, Dimethylformamid, Tetrahydrofuran usw , vorgenommen Als Basen kommen die dem Fachmann fur Veratherungen bekannten Basen in Frage, beispielsweise Natriumhydrid, Kalium-tert -butylat, ButyllithiumFor salt formation with the free acids (R 1 = H), inorganic and organic bases are suitable, as are known in the art for the formation of physiologically compatible salts. Examples include alkali metal hydroxides, such as sodium and potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diathanolamine, triethanolamine, N-methylglucamine, morpholm, Tns- (hydroxymethyl) -methylamine, etc. The reaction of the compound of general formula II with a halo ketal of general formula III at temperatures of 0 0 C to 100 0 C, preferably 1O 0 C to 80 0 C, in an aprotic solvent or solvent mixture, for example, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, etc., made As bases, the well-known in the art for etchings bases are suitable, for example, sodium hydride, potassium tert-butylate, butyllithium
Die sich an die Veretherung anschließende Ketalspaltung zu den Verbindungen der allgemeinen Formel I erfolgt nach bekannten Methoden Beispielsweise wird die Ketalspaltung in einer wäßrigen Losung einer organischen Saure, wie zum Beispiel Essigsaure, Propionsäure u a ,oder in einer wäßrigen Losung einer anorganischen Saure, wie zum Beispiel Salzsaure, durchgeführt Zur Verbesserung der Löslichkeit wird zweckmaßigerweise ein mit Wasser mischbares inertes organisches Losungsmittel zugesetzt Geeignete organische Losungsmittel sind zum Beispiel Alkohole, wie Methanol und Äthanol, und Äther, wie Dimethoxyathan, Dioxan und Tetrahydrofuran Tetrahydrofuran wird bevorzugt angewendet Die Ketalspaltung wird vorzugsweise bei Temperaturen zwischen 200C und 800C durchgeführtFor example, ketal cleavage is carried out in an aqueous solution of an organic acid, such as acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as, for example Hydrochloric acid, carried out. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The ketal cleavage is preferably carried out at temperatures between 20 0 C and 80 0 C performed
Die Oxydation der Aldehydgruppe wird nach den dem Fachmann bekannten Methoden vorgenommen Als Oxydationsmittel können beispielsweise dienen Pyndiniumdichromat (Tetrahedron Letters, 1979,399), Jones-Reagenz (J Chem Soc 1953,2555) oder Platin/Sauerstoff (Adv in Carbohydrats Chem 17,169 [1962])The oxidation of the aldehyde group is carried out according to methods known to those skilled in the art. Examples of suitable oxidizing agents are Pyndinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J Chem Soc 1953, 255) or platinum / oxygen (Adv in Carbohydrate Chem 17, 1669 [1962 ])
Die Oxydation mit Pyridiniumdichromat wird bei Temperaturen von O0C bis 1000C, vorzugsweise 20°C bis 400C, in einem gegen das Oxydationsmittel inerten Losungsmittel, beispielsweise Dimethylformamid, durchgeführt Die Oxydation mit Jones-Reagenz wird bei Temperaturen von -4O0C bis +40°C, vorzugsweise 00C bis 300C, in Aceton als Losungsmittel ausgeführt Die Oxydation mit Platin/Sauerstoff wird bei Temperaturen von 00C bis 600C, vorzugsweise 2O0C bis 4O0C, in einem gegen das Oxydationsmittel inerten Losungsmittel, wie zum Beispiel Essigester, durchgeführt Die Verseifung der Carbacyclinester wird nach den dem Fachmann bekannten Methoden durchgeführt, wie beispielsweise mit basischen KatalysatorenThe oxidation with pyridinium dichromate is performed at temperatures of from 0 C to 100 0 C, preferably 20 ° C to 40 0 C, in a solvent inert to the oxidizing agent solvent, for example dimethylformamide, carried out the oxidation with Jones reagent at temperatures of -4o 0 C to + 40 ° C, preferably 0 0 C to 30 0 C, carried out in acetone as a solvent The oxidation with platinum / oxygen is at temperatures from 0 0 C to 60 0 C, preferably 2O 0 C to 4O 0 C, in one The saponification of the carbacyclin esters is carried out by the methods known to the person skilled in the art, such as, for example, with basic catalysts
Die Einfuhrung der Estergruppe-OR2 fur R1, bei welcher R2 eine Alkylgruppe mit 1 bis 4 C-Atomen darstellt, erfolgt nach den dem Fachmann bekannten Methoden Die Carboxyverbmdungen werden beispielsweise mit Diazokohlenwasserstoffen in an sich bekannter Weise umgesetzt Die Veresterung mit Diazokohlenwasserstoffsn erfolgt zum Beispiel dadurch, daß man eine Losung des Diazokohlenwasserstoffes in einem inerten Losungsmittel, vorzugsweise Diathylather, mit der Carboxyverbindung in dem gleichen oder in einem anderen inerten Losungsmittel, wie zum Beispiel Methylenchlond, vermischt Nach beendeter Umsetzung in 1 bis 30 Minuten wird das Losungsmittel entfernt und der Ester in üblicherweise gereinigt Diazoalkane sind entweder bekannt oder können nach bekannten Methoden hergestellt werden (Org Reactions Bd 8, Seiten 389-394 [1954]) Die Einfuhrung der Estergruppe -OR2 fur R1 kann auch durch Umsetzung des Carboxylatanions mit dem entsprechendenThe introduction of the ester group-OR 2 for R 1 , in which R 2 is an alkyl group having 1 to 4 carbon atoms, is carried out by methods known to those skilled in the art. The carboxy compounds are reacted, for example, with diazohydrocarbons in a conventional manner. The esterification is carried out with diazohydrocarbons for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably diathyl ether, with the carboxy compound in the same or other inert solvent, such as methylene chloride. After completion of the reaction in 1 to 30 minutes, the solvent is removed and The esters in usually purified diazoalkanes are either known or can be prepared by known methods (Org Reactions Bd 8, pages 389-394 [1954]). The introduction of the ester group -OR 2 for R 1 can also be achieved by reacting the carboxylate anion with the corresponding
Alkylhalogenidoderw Halogenketon (Hal—CH —C—Ar mit Ar als Diphenyl, erfolgenAlkylhalogenidoderw halogen ketone (Hal-CH -C-Ar with Ar as diphenyl, take place
Die Carbacyclin-Derivate der allgemeinen Formel I mit R1 in der Bedeutung einer Hydroxygruppe (R2 = H) können mit geeigneten Mengen der entsprechenden anorganischen Basen unter Neutralisierung in Salze überführt werden. Beispielsweise erhält man beim Lösen der entsprechenden Säuren in Wasser, welches die stöchiometrische Menge der Base enthält, nach Abdampfen des Wassers oder nach Zugabe eines mit Wasser mischbaren Lösungsmittels, zum Beispiel Alkohol oder Aceton, das feste anorganische Salz.The carbacyclin derivatives of general formula I with R 1 in the meaning of a hydroxy group (R 2 = H) can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization. For example, upon dissolving the corresponding acids in water containing the stoichiometric amount of the base, after evaporation of the water or after addition of a water-miscible solvent, for example, alcohol or acetone, the solid inorganic salt is obtained.
Die Herstellung der Aminsalze erfolgt in üblicher Weise. Dazu wird die Carbacyclinsäure zum Beispiel in einem geeigneten Lösungsmittel, wie Äthanol, Aceton, Diäthyläther oder Benzol, gelöst und mindestens die stöchiometrische Menge des Amins dieser Lösung zugesetzt. Dabei fällt das Salz gewöhnlich in fester Form an oder wird nach Verdampfen des Lösungsmittels in üblicherweise isoliert.The preparation of the amine salts is carried out in the usual manner. For this purpose, the Carbacyclinsäure is dissolved for example in a suitable solvent such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine added to this solution. The salt usually accumulates in solid form or is usually isolated after evaporation of the solvent.
Die funktionell Abwandlung der freien OH-Gruppen erfolgt nach den dem Fachmann bekannten Methoden. Zur Einführung der Ätherschutzgruppen wird beispielsweise mit Dihydropyran in Methylenchlorid oder Chloroform unter Verwendung eines sauren Kondensationsmittels, wie zum Beispiel p-Toluolsulfonsäure, umgesetzt. Das Dihydropyran wird im Überschuß angewandt, vorzugsweise in der 4-bis lOfachen Menge des theoretischen Bedarfs. Die Umsetzung ist normalerweise bei O0C bis 300C nach 15 bis 30 Minuten beendet.The functional modification of the free OH groups is carried out by the methods known to those skilled in the art. For the introduction of ether protecting groups, for example, is reacted with dihydropyran in methylene chloride or chloroform using an acid condensing agent such as p-toluenesulfonic acid. The dihydropyran is used in excess, preferably in 4 to 10 times the theoretical requirement. The reaction is normally complete at 0 ° C. to 30 ° C. after 15 to 30 minutes.
Die Einführung der Acylschutzgruppen erfolgt, indem man eine Verbindung der allgemeinen Formel I in an sich bekannter Weise mit einem Carbonsäurederivat, wie zum Beispiel Säurechlorid, Säureanhydrid u.a., umsetzt.The introduction of the acyl protecting groups is carried out by reacting a compound of the general formula I in a manner known per se with a carboxylic acid derivative, such as, for example, acid chloride, acid anhydride and the like.
Die Freisetzung einer funktionell abgewandelten OH-Gruppe zu den Verbindungen der allgemeinen Formel I erfolgt nach bekannten Methoden. Beispielsweise wird die Abspaltung von Ätherschutzgruppen in einer wäßrigen Lösung einer organischen Säure, wie zum Beispiel Essigsäure, Propionsäure u.a., oder in einer wäßrigen Lösung einer anorganischen Säure, wie zum Beispiel Salzsäure, durchgeführt. Zur Verbesserung der Löslichkeit wird zweckmäßigerweise ein mit Wasser mischbares inertes organisches Lösungsmittel zugesetzt. Geeignete organische Lösungsmittel sind zum Beispiel Alkohole, wie Methanol und Äthanol, und Äther, wie Dimethoxyäthan, Dioxan und Tetrahydrofuran. Tetrahydrofuran wird bevorzugt angewendet. Die Abspaltung wird vorzugsweise bei Temperaturen zwischen 200C und 800C durchgeführt.The release of a functionally modified OH group to the compounds of general formula I is carried out by known methods. For example, the cleavage of ether protecting groups in an aqueous solution of an organic acid, such as acetic acid, propionic acid, etc., or in an aqueous solution of an inorganic acid, such as hydrochloric acid, performed. To improve the solubility, a water-miscible inert organic solvent is conveniently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The cleavage is preferably carried out at temperatures between 20 0 C and 80 0 C.
Die Abspaltung der Silylätherschutzgruppen erfolgt beispielsweise mit Tetrabutylammoniumfluorid. Als Lösungsmittel sind beispielsweise geeignet Tetrahydrofuran, Diäthyläther, Dioxan, Methylenchlorid usw. Die Abspaltung wird vorzugsweise bei Temperaturen zwischen O0C und 800C durchgeführt.The splitting off of the silyl ether protective groups takes place, for example, with tetrabutylammonium fluoride. Suitable solvents are, for example tetrahydrofuran, diethyl ether, dioxane, methylene chloride, etc. The cleavage is preferably carried out at temperatures between 0 0 C and 80 0 C.
Die Verseifung der Acylgruppen erfolgt beispielsweise mit Alkali- oder Erdalkalicarbonaten oder -hydroxiden in einem Alkohol oder der wäßrigen Lösung eines Alkohols. Als Alkohole kommen aliphatische Alkohole in Betracht, wie zum Beispiel Methanol, Äthanol, Butanol usw., vorzugsweise Methanol. Als Alkalicarbonate und -hydroxide seien Kalium- und Natriumsalze genannt, bevorzugt sind jedoch die Kaliumsalze. Als Erdalkalicarbonate und -hydroxide sind beispielsweise geeignet Calciumcarbonat, Calciumhydroxid und Bariumcarbonat. Die Umsetzung erfolgt bei -1O0C bis 7O0C, vorzugsweise bei 250C.The saponification of the acyl groups is carried out, for example, with alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol. Suitable alcohols are aliphatic alcohols, such as, for example, methanol, ethanol, butanol, etc., preferably methanol. As alkali metal carbonates and hydroxides, mention may be made of potassium and sodium salts, but the potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction takes place at -1O 0 C to 7O 0 C, preferably at 25 0 C.
Die Einführung der Amidgruppe NHR3 für R1 erfolgt nach den dem Fachmann bekannten Methoden. Die Carbonsäuren der allgemeinen Formel I (R2 = H) werden zunächst in Gegenwart eines tertiären Amins, wie beispielsweise Triäthylamin, mit Chlorameisensäureisobutylester in das gemischte Anhydrid überführt. Die Umsetzung des gemischten Anhydrids mit dem Alkalisalz des entsprechenden Amids oder mit Ammoniak (R3 = H) erfolgt in einem inerten Lösungsmittel oder Lösungsmittelgemisch, wie beispielsweise Tetrahydrofuran, Dimethoxyäthan, Dimethylformamid, Hexamethylphosphorsäuretriamid, bei Temperaturen zwischen -3O0C und +600C, vorzugsweise bei O0C bis 300C.The introduction of the amide group NHR 3 for R 1 is carried out according to the methods known to those skilled in the art. The carboxylic acids of general formula I (R 2 = H) are first converted into the mixed anhydride in the presence of a tertiary amine, such as triethylamine, with isobutyl chloroformate. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R 3 = H) is carried out in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric triamide, at temperatures between -3O 0 C and + 60 0 C. , preferably at 0 0 C to 30 0 C.
Eine weitere Möglichkeit für die Einführung der Amidgruppe NHR3 für R1 besteht in der Umsetzung einer 1-Carbonsäure der allgemeinen Formel I (R2 = H), in der freie Hydroxygruppen gegebenenfalls intermediäre geschützt sind, mit Verbindungen der allgemeinen Formel IVA further possibility for the introduction of the amide group NHR 3 for R 1 consists in the reaction of a 1-carboxylic acid of the general formula I (R 2 = H), in which free hydroxy groups are optionally protected intermediates, with compounds of the general formula IV
O = C =N - R3 (IV),O = C = N - R 3 (IV),
worin R3 die oben angegebene Bedeutung hat.wherein R 3 has the meaning given above.
Die Umsetzung der Verbindung der allgemeinen Formel I (R1 = OH) mit einem Isocyanat der allgemeinen Formel IV erfolgt gegebenenfalls unter Zusatz eines tertiären Amins, wie zum Beispiel Triäthylamin oder Pyridin. Die Umsetzung kann ohne Lösungsmittel oder in einem inerten Lösungsmittel, vorzugsweise Acetonitril, Tetrahydrofuran, Aceton, Dimethylacetamid, Methylenchlorid, Diäthyläther, Toluol, bei Temperaturen zwischen -800C bis 1000C, vorzugsweise bei 00C bis 3O0C, vorgenommen werden.The reaction of the compound of general formula I (R 1 = OH) with an isocyanate of general formula IV is optionally carried out with the addition of a tertiary amine, such as triethylamine or pyridine. The reaction can be carried out without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -80 0 C to 100 0 C, preferably at 0 0 C to 3O 0 C. ,
Enthält das Ausgangsprodukt OH-Gruppen im Prostanrest, so werden diese OH-Gruppen auch zur Reaktion gebracht. Werden letztlich Endprodukte gewünscht, die freie Hydroxylgruppen im Prostanrest enthalten, geht man zweckmäßigerweise von Ausgangsprodukten aus, in denen diese durch vorzugsweise leicht abspaltbare Äther-oder Acylreste intermediäre geschütztIf the starting product contains OH groups in the prostane radical, these OH groups are also reacted. If end products are ultimately desired which contain free hydroxyl groups in the prostane radical, it is expedient to start from starting materials in which these are protected by intermediates which are preferably readily cleavable ether or acyl radicals
Die als Ausgangsmaterial dienenden Verbindungen der allgemeinen Formel Il können beispielsweise hergestellt werden, indem man in an sich bekannter Weise einen Aldehyd der Formel V(DE-OS 2845770)The compounds of the general formula II which serve as starting material can be prepared, for example, by reacting, in a manner known per se, an aldehyde of the formula V (German Offenlegungsschrift 2,845,770).
(V) CHO(V) CHO
OCO-.OCO.
mit einem Phosphonat der allgemeinen Formel Vlwith a phosphonate of the general formula Vl
(Vl),(Vl),
worin D, E und R4 die oben angegebene Bedeutung aufweisen, in Gegenwart eines Deprotonierungsmittels, wie beispielsweise Natriumhydrid oder Kalium-tert.-butylat, zu einem Keton der allgemeinen Formel VII(X = H) oder zusätzlich in Gegenwart eines Bromierungsmittels, wie beispielsweise N-Bromsuccinimid, zu einem Keton der allgemeinen Formel VII (X = Br) umsetzt. ι—wherein D, E and R 4 have the abovementioned meaning, in the presence of a deprotonating agent, such as sodium hydride or potassium tert-butoxide, to give a ketone of general formula VII (X = H) or additionally in the presence of a brominating agent, such as N-bromosuccinimide, to give a ketone of general formula VII (X = Br). ι-
P - CH„ -C-D-E-RP - CH "-C-D-E-R
(VIl)(VII)
CH=CX-C-D-E-R4 CH = CX-CDER 4
OCOPhOCOPh
Nach Reduktion der Ketogruppe mit Zinkborhydrid oder Natriumborhydrid oder Umsetzung mit Alkylmagnesiumbromid oder Alkyllithium und anschließender Epimerentrennung gelangt man zu den Verbindungen der allgemeinen Formel VIIIAfter reduction of the keto group with zinc borohydride or sodium borohydride or reaction with alkylmagnesium bromide or alkyllithium and subsequent epimer separation, the compounds of general formula VIII are obtained
/ j (VIII)/j (VIII)
^ ^ CHuCX-W-D-E-R4 ^ ^ CHucX-WDER 4
C.C.
OCO-/ 0 κ OCO- / 0 κ
Verseifung der Estergruppe, beispielsweise mit Kaliumcarbonat in Methanol, sowie gegebenenfalls Hydrierung der Doppelbindung oder gegebenenfalls Verätherung mit Dihydropyran und anschließende Abspaltung von Bromwasserstoff mit beispielsweise Kaliumtert.-butylat in Dimethylsulfoxid, Ketalspaltung mit wäßriger Essigsäure sowie gegebenenfalls funktioneile Abwandlung der freien Hydroxygruppen, beispielsweise durch Verätherung mit Dihydropyran liefert das Keton der allgemeinen Formel IX.Saponification of the ester group, for example with potassium carbonate in methanol, and optionally hydrogenation of the double bond or optionally etherification with dihydropyran and subsequent elimination of hydrogen bromide with, for example, potassium tert-butoxide in dimethyl sulfoxide, ketal cleavage with aqueous acetic acid and optionally functional modification of the free hydroxyl groups, for example by etherification with Dihydropyran provides the ketone of general formula IX.
IlIl
\ » (IX) \ "(IX)
A-W-D-E-R^,A-W-D-E-R ^
OHOH
Nach Olefinierungsreaktion mit Phosphonoessigsäuretriäthylester oder Phosphonoessigsäuretrimethylester oder Phosphonofluoressigsäuretriäthylester oder Phosphonofluoressigsäuretrimethylester und anschließender Reduktion mit Lithiumaluminiumhydrid erhält man die an der Doppelbindung isomeren Verbindungen der allgemeinen Formel II, die gegebenenfalls getrennt werden können.After olefination reaction with Phosphonoessigsäuretriäthylester or Phosphonoessigsäuretrimethylester or Phosphonofluoressigsäuretriäthylester or Phosphonofluoressigsäuretrimethylester and subsequent reduction with lithium aluminum hydride obtained on the double bond isomeric compounds of the general formula II, which may optionally be separated.
Die Herstellung der Phosphonate der allgemeinen Formel Vl erfolgt in an sich bekannter Weise durch Umsetzung des Anions von Methylphosphonsäuredimethylester mit einem Ester der allgemeinen Formel XThe phosphonates of the general formula VI are prepared in a manner known per se by reacting the anion of dimethyl methylphosphonate with an ester of the general formula X.
R8° R 8 °
worin D, E, R4 die oben genannten Bedeutungen aufweisen und R8 eine Alkylgruppe mit 1 bis 5C-Atomen bedeutet, den man gegebenenfalls aus dem entsprechenden Malonsäureester durch Alkylierung mit dem Halogenidwherein D, E, R 4 have the abovementioned meanings and R 8 is an alkyl group having 1 to 5C atoms, which is optionally obtained from the corresponding malonic acid ester by alkylation with the halide
HaI-E-R4 (Xl)HaI-ER 4 (Xl)
der allgemeinen Formel Xl mit Hai in der Bedeutung Chlor oder Brom und anschließender Decarbalkoxylierung erhalten kann. Der Ester der allgemeinen Formel X ist gegebenenfalls auch aus der Carbonsäure der allgemeinen Formel XIIof the general formula XI with shark meaning chlorine or bromine and subsequent decarboxylation can be obtained. The ester of the general formula X is optionally also from the carboxylic acid of the general formula XII
Il (XII),Il (XII),
HO-C-DHO-C-D
worin D die oben angegebene Bedeutung aufweist, durch Alkylierung mit dem Halogenid der allgemeinen Formel Xl und anschließender Veresterung zugänglich.wherein D has the meaning indicated above, accessible by alkylation with the halide of the general formula XI and subsequent esterification.
Die als Ausgangsmaterial dienenden Verbindungen der allgemeinen Formel III können beispielsweise hergestellt werden, indem man in an sich bekannter Weise einen W-Halogencarbonsäureester der allgemeinen Formel XIIIThe compounds of general formula III which are used as starting material can be prepared, for example, by reacting, in a manner known per se, a W-halocarboxylic acid ester of general formula XIII
HaI-(CH2I3-COOR10 (XIII),Hal (CH 2 I 3 -COOR 10 (XIII),
worin Hai die oben angegebene Bedeutung aufweist und R10 eine Alkylgruppe mit 1 bis 5C-Atomen bedeutet, mit Diisobutylaluminiumhydrid zum entsprechenden Aldehyd reduziert und anschließend in bekannter Weise mit einem Alkohol ketalisiert.in which shark has the abovementioned meaning and R 10 is an alkyl group having 1 to 5C atoms, reduced with diisobutylaluminum hydride to the corresponding aldehyde and then ketalisiert in a known manner with an alcohol.
Die Verbindungen dieser Erfindung wirken blutdrucksenkend und bronchodilatorisch. Sie sind weiterhin geeignet zur Hemmung derThrombozyten-Aggregation. Folglich stellen die neuen Carbacyclin-Derivate der Formel I wertvolle pharmazeutische Wirkstoffe dar. Darüber hinaus weisen sie bei ähnlichem Wirkungsspektrum, verglichen mit entsprechenden Prostaglandinen, eine höhere Spezifität und vor allem eine wesentlich längere Wirksamkeit auf. Im Vergleich zu PGI2 zeichnen sie sich durch größere Stabilität aus. Die hohe Gewerbsspezifität der neuen Prostaglandine zeigt sich bei der Untersuchung an glattmuskulären Organen, wie zum Beispiel am Meerschweinchenileum oder an der isolierten Kaninchentrachea, wo eine wesentlich geringere Stimulation zu beobachten ist als bei der Applikation natürlicher Prostaglandine vom E-, A- oder F-Typ. Die neuen erfindungsgemäß hergestellten Carbacyclin-Analoga besitzen die für Prostacycline typischen Eigenschaften, wie zum Beispiel Senkung des peripheren arteriellen und koronaren vaskulären Widerstandes, Inhibierung der Thrombozytenaggregation und Auflösung von Plättchenthromben, myocardiale Zytoprotektion und damit Senkung des systemischen Blutdruckes ohne zugleich Schlagvolumen und koronare Durchblutung zu senken; Behandlung von Schlaganfall, Prophylaxe und Therapie koronarer Herzerkrankungen, koronarer Thrombose, des Herzinfarkts, peripherer Arterienerkrankungen, Arteriosklerose und Thrombose, Prophylaxe und Therapie ischaemische Attacken des ZNS-Systems, Therapie des Schocks, Inhibierung der Bronchokonstriktion, Inhibierung der Magensäuresekretion, Zytoprotektion der Magen- und Darmschleimhaut, Zytoprotektion in der Leber und im Pankreas, antiallergische Eigenschaften, Senkung des pulmonalen vaskulären Widerstandes und des pulmonalen Blutdrucks, Förderung der Nierendurchblutung, Anwendung anstelle von Heparin oder als Adjuvans bei der Dialyse der Hämofiltration, Konservierung von Blutplasmakonserven, besonders von Blutplättchenkonserven, Inhibierung von Geburtswehen, Behandlung von Schwangerschaftstoxikose, Erhöhung der zerebralenThe compounds of this invention have hypotensive and bronchodilatory effects. They are also useful for inhibiting platelet aggregation. Consequently, the new carbacyclin derivatives of the formula I are valuable pharmaceutical active ingredients. In addition, they have a similar spectrum of activity, compared with corresponding prostaglandins, a higher specificity and especially a much longer efficacy. Compared to PGI 2 , they are characterized by greater stability. The high commercial specificity of the new prostaglandins can be seen in the examination of smooth muscle organs, such as the guinea pig ileum or the isolated rabbit, where much less stimulation is observed than in the application of natural prostaglandins of the E, A or F type , The novel carbacyclin analogues prepared in accordance with the invention possess the properties typical of prostacycline, such as lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without at the same time reducing stroke volume and coronary blood flow ; Treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral arterial disease, arteriosclerosis and thrombosis, prophylaxis and therapy ischemic attacks of the CNS system, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, cytoprotection of gastric and Intestinal mucosa, cytoprotection in the liver and pancreas, antiallergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use instead of heparin or as adjuvant in the hemofiltration dialysis, preservation of blood plasma conserves, especially of platelet preserves, inhibition of Labor pains, treatment of pregnancy toxicity, increase of cerebral
Durchblutung usw. Außerdem besitzen die neuen Carbacyclin-Derivate antiproliferative und antidiarrhoegene Eigenschaften.Circulation, etc. In addition, the new carbacyclin derivatives have antiproliferative and antidiarrhoegene properties.
Die Carbacycline dieser Erfindung können auch in Kombination, zum Beispiel mit ß-Blockern oder Diuretika, verwendet werden.The carbacyclins of this invention may also be used in combination, for example with β-blockers or diuretics.
Die Dosis der Verbindungen ist 1 bis 1 500pg/kg/Tag,wennsieam menschlichen Patienten verabreicht werden. Die Einheitsdosis für den pharmazeutischen akzeptablen Träger beträgt 0,01 bis 100mg.The dose of the compounds is 1 to 1,500 pg / kg / day when administered to human patients. The unit dose for the pharmaceutically acceptable carrier is 0.01 to 100 mg.
Bei intravenöser Injektion an wachen, hypertonen Ratten in Dosen von 5, 20 und 100μg/kg Körpergewicht zeigen die erfindungsgemäßen Verbindungen eine stärkere blutdrucksenkende und langer anhaltende Wirkung als PGE2 und PGA2, ohne wie PGE2 Durchfälle oder PGA2 kardiale Arrhythmien auszulösen.When administered intravenously to conscious, hypertensive rats at doses of 5, 20 and 100 μg / kg body weight, the compounds of the present invention show a greater antihypertensive and long-lasting effect than PGE 2 and PGA 2 without triggering cardiac arrhythmias such as PGE 2 diarrhea or PGA 2 .
Bei intravenöser Injektion an narkotisierten Kaninchen zeigen die erfindungsgemäßen Verbindungen im Vergleich zu PGE2 und PGA2 eine stärkere und erheblich langer anhaltende Blutdrucksenkung, ohne daß andere glattmuskuläre Organe oder Organfunktionen beeinflußt werden.When administered intravenously to anesthetized rabbits, the compounds of the invention compared to PGE 2 and PGA 2 show a stronger and significantly longer lasting blood pressure reduction, without other smooth muscle organs or organ functions are affected.
Für die parenterale Verabreichung werden sterile, injizierbare, wäßrige oder ölige Lösungen benutzt. Für die orale Applikation sind beispielsweise Tabletten, Dragees oder Kapseln geeignet.For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For oral administration, for example, tablets, dragees or capsules are suitable.
Die erfindungsgemäß hergestellten Wirkstoffe sollen in Verbindung mit den in der Galenik bekannten und üblichen Hilfsstoffen, zum Beispiel zur Herstellung von Blutdrucksenkern, dienen.The active compounds produced according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenics, for example for the preparation of hypotensives.
Pharmakologisch besonders wertvolle Verbindungen, die als Wirkstoff in Arzneimitteln verwendet werden, sind die folgenden erfindungsgemäß hergestellten Verbindungen:Pharmacologically particularly valuable compounds which are used as active ingredient in medicaments are the following compounds prepared according to the invention:
(5E)-(16RS)-2-Descarboxy-1 a,1 b,dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2; (5E)-(16RS)-1 a,1 b-Dihomo-ie-methyl-S-oxa-ISJSJ^IS-tetradehydro-ea-carba-prostaglandin-^; (5Z)-(16 RS)-2-Descarboxy-1 a,1 b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2; (5Z)-(16RS)-1a,1 b-Dihomo-ie-methyl-S-oxa-ISJSJSjg-tetradehydro-ea-carba-prostaglandin-^; (5 E)-(16 RS)-2-Descarboxy-1 a,1 b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2;(5E) - (16RS) -2-descarboxy-1 a, 1 b, dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 ; (5E) - (16RS) -1a, 1-b-dihomo-ie-methyl-S-oxa-ISJSi ^ IS-tetradehydro-ea-carba-prostaglandin ^; (5Z) - (16RS) -2-descarboxy-1α, 1β-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6α-carba-prostaglandin-1 2 ; (5Z) - (16RS) -1a, 1-b-dihomo-ie-methyl-S-oxa-ISJSjSjg-tetradehydro-ea-carba-prostaglandin ^; (5 E) - (16RS) -2-descarboxy-1α, 1β-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-6α-carba prostaglandin-l 2 ;
(5E)-2-Descarboxy-1 a,1 prostaglandin-l2;(5E) -2-descarboxy-1 a, 1-prostaglandin-l 2 ;
(5E)-2-Descarboxy-1 a,1 b-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetrade hy dro-6a-carba-prostagl a ndin-l2;(5E) -2-descarboxy-1α, 1β-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetrade-hydro-6a-carba-prostagl amine l 2 ;
(5E)-2-Descarboxy-1 a,1(5E) -2-descarboxy-1 a, 1
(5E)-I a,1 b-Dihomo-S-o(5E) -I a, 1 b-dihomo-S-o
(5E)-(16RS)-2-Descarboxy-18,19-didehydro-1 a,1 b-dihomo-16,19-dimethyl-2-formyl-3-oxa-6a-carba-prostaglandin-l2; (5 E)-1 a,1 b-Dihomo-16,19-dimethyl-18,1 g-didehydro-S-oxa-ea-carba-prostaglandin-^; (5 E)-(16 RS)-2-Descarboxy-13,14-didehydro-1 a,1 b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6 a-carbaprostaglandin-l2;(5E) - (16RS) -2-descarboxy-18,19-didehydro-1α, 1β-dihomo-16,19-dimethyl-2-formyl-3-oxa-6α-carba-prostaglandin-l 2 ; (5E) -1a, 1-b-dihomo-16,19-dimethyl-18,1 g-didehydro-S-oxa-ea-carba-prostaglandin ^; (5 E) - (16RS) -2-Descarboxy-13,14-didehydro-1α, 1β-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro- 6 a-carbaprostaglandin-l 2 ;
(5E)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2; (5E)-(16RS)-2-Descarboxy-13,14-didehydro-1 a,1 b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,1 g-t prostaglandin-l2;(5E) - (16RS) -13,14-didehydro-1a, 1-b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 ; (5E) - (16RS) -2-descarboxy-13,14-didehydro-1α, 1β-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,1 gt prostaglandin l 2 ;
(5E)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-16,20-dimethyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-b; (5E)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylen-6acarba-prostaglandin-l2;(5E) - (16RS) -13,14-didehydro-1a, 1-b-dihomo-16,20-dimethyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-b; (5E) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6acarba- prostaglandin-l 2 ;
(5 E)-13,14-Didehydro-1 a,1 b-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethy len-6 a-carba-prostaglandin-^; (5E)-2-Descarboxy-13,14-didehydro-1a,1 b-di(5E) -13,14-didehydro-1α, 1β-dihomo-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-6α-carba-prostaglandin - ^; (5E) -2-descarboxy-13,14-didehydro-1a, 1 b-di
prostaglandin-l2;prostaglandin-l 2 ;
(5E)-13,14-Didehydro-1a,1 b-dihomo-16,1(5E) -13,14-didehydro-1a, 1-b-dihomo-16,1
(5E)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-^;(5E) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin- ^;
(5E)-13,14-Didehydro-1a,1 b-dihomo-S-oxa-ISJSjgjg-tetradehydro-ieje^O-trimethyl-ea-carba-prostaglandin-^; (5Z)-(16RS)-2-Descarboxy-1 a-1 b-dihomo-S-fluor^-formyl-ie-methyl-S-oxa-ISJSjgjg-tetradehydro-ea-carba-prostaglandin-(5E) -13,14-didehydro-1a, 1-b-dihomo-S-oxa-ISJSjgjg-tetradehydro-ieje O-trimethyl-ea-carba-prostaglandin ^; (5Z) - (16RS) -2-descarboxy-1 a-1 b-dihomo-S-fluoro-1-formyl-i-methyl-S-oxa-ISJSjgjg-tetradehydro-ea-carba-prostaglandin
(5Z)-(16RS)-I a,1 b-Di(5Z) - (16RS) -I a, 1 b-Di
(5Z)-(16RS)-2-Descarboxy-1 a,1 b-dihomo-16,20-dimethyl-5-fluor-2-formyl-3-oxa-18,18,19,19-tetradehydro-ea-carbaprostaglandin-l2;(5Z) - (16RS) -2-descarboxy-1α, 1β-dihomo-16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-ea- carbaprostaglandin-l 2 ;
(5Z)-( 16RS)-I a,1 b-Dihomo-16,20-dimethyl-5-fluor-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^; (5Z)-2-Descarboxy-1 a,1(5Z) - (16RS) -Ia, 1-b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin ^; (5Z) -2-descarboxy-1 a, 1
prostaglandin-l2;prostaglandin-l 2 ;
(5Z)-1 a,1 b-Dihomo-5-fluor-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylen-6a,-carba-prostaglandin-l2; (5Z)-2-Descarboxy-1 a,1 b-dihomo-16,16-dimethyl-5-fluor-2-formyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^; (5Z)-1 a,1 b-Dihomo-16,16-dimethyl-5-fluor-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2; (5Z)-2-Descarboxy-1 a,1 b-dihomo-5-fluor-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-(5Z) -1a, 1b-Dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylene-6a, -carba-prostaglandin-l 2 ; (5Z) -2-descarboxy-1α, 1β-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba prostaglandin - ^; (5Z) -1a, 1b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 ; (5Z) -2-Descarboxy-1α, 1β-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6α-carba prostaglandin-
a,1 b-Dihomo-5-fluor-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-l2; (5Z)-(16RS)-2-Descarboxy-13,14-didehydro-1 a,1 carba-prostaglandin-l2; (5Z)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-(5Z)-(16 RS)-2-Descarboxy-13,14-didehydro-1 a,1 b-dihomo-16,20-dimethyl-5-fluor-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2;a, 1 b-Dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-l 2 ; (5Z) - (16RS) -2-descarboxy-13,14-didehydro-1α, 1-carba-prostaglandin-l 2 ; (5Z) - (16RS) -13,14-didehydro-1a, 1β-dihomo (5Z) - (16RS) -2-descarboxy-13,14-didehydro-1α, 1β-dihomo-16, 20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 ;
(5Z)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-5-fluor-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylen-ea-carba-prostaglandin-^;(5Z) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16- trimethylene-ea-carba-prostaglandin- ^;
(5Z)-13,14-Didehydro-1 a,1 b-dihomo-B-fluor^O-methyl-S-oxa-i 8,18,19,19-tetradehydro-16,1 e-trimethylen-ea-carbaprostaglandin-l2;(5Z) -13,14-didehydro-1α, 1β-dihomo-B-fluoro-O-methyl-S-oxa-i 8,18,19,19-tetradehydro-16,1-trimethylene-ea carbaprostaglandin-l 2 ;
(5Z)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-16,16-dimethyl-5-fIuor-2-formyl-3-oxa-18,18,19,19-tetradehydro-6acarbaprostaglandin-12;(5Z) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-6acarbaprostaglandin- 12;
(5Z)-13,14-Didehydro-1 a,1 b-dihomo-16,16-dimethyl-5-fluor-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^; (5Z)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-5-fluor-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6acarba-prostaglandin-l2;(5Z) -13,14-didehydro-1α, 1β-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin ^ ; (5Z) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl- 6acarba-prostaglandin-l 2 ;
(5Z)-13,14-Didehydro-1a,1b-dihomo-5-fluor-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-l2; (5E)-(16RS)-1 a,1 b-Dihomo-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-öa-carba-prostaglandin-lrmethylester; (5E)-(16RS)-1 a,1 b-Dihomo-16-methyl-3-oxa-18,18,1 g^-tetradehydro-ea-carba-prostaglandin-lj-carboxamid; (5Z)-(16RS)-1a,1b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-(2,3-dihydroxypropyl)-(5Z) -13,14-didehydro-1a, 1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-l 2 ; (5E) - (16RS) -1a, 1b-Dihomo-16-methyl-3-oxa-18,18,19,1 g-tetrahydro-hydroxy-carba-prostaglandin-methyl ester; (5E) - (16RS) -1a, 1b-Dihomo-16-methyl-3-oxa-18,18,1 g -tetrahydehydro-ea-carba-prostaglandin-1-y-carboxamide; (5Z) - (16RS) -1a, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 - (2,3- dihydroxypropyl) -
phenacylester;phenacyl;
(5E)-(16RS)-1 a,1 b-Dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-tris-(hydroxymethyl)-aminomethan-salz.(5E) - (16RS) -1a, 1b-Dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 -tris (hydroxymethyl) aminomethane -salt.
Wie aus der nachfolgenden Tabelle zu entnehmen ist, zeigen im Blutdrucktest an der Ratte die Homologen, die durch das erfindungsgemäße Verfahren hergestellt werden, überraschenderweise sowohl im Hinblick auf ihre Wirksamkeit als auch was ihre Wirkungsdauer betrifft, deutlich bessere Ergebnisse. Die Bishomo-Verbindungen wirken danach 2- bis 4mal stärker blutdrucksenkend bei einer wiederum deutlich längeren Wirkungsdauer von 2- bis 10mal.As can be seen from the table below, show in the blood pressure test on the rat, the homologs prepared by the method of the invention, surprisingly, both in terms of their effectiveness and in terms of their duration of action, significantly better results. The bishomo compounds then have 2- to 4-fold greater blood pressure lowering with a significantly longer duration of action of 2 to 10 times.
Tabelle: VergleichsversucheTable: Comparative experiments
* Beispiel 1 aus DD 202010=1 (p.o.)* Example 1 from DD 202010 = 1 (p.o.)
Nachstehend Angaben zur Versuchsdurchführung:Below information on the experiment:
a) Zahl der Tiere bei allen Versuchen η = 6 (männliche Ratten).a) Number of animals in all experiments η = 6 (male rats).
b) Die Meßmethodik entspricht der von J. R. Weeks, Proc. Soc. Exp. Biol. Med. 104,646 (1960), d. h., der Blutdruck wurde direkt über chronisch implantierte Katheter (Aorta abdominalis) gemessen.b) The measurement methodology corresponds to that of J. R. Weeks, Proc. Soc. Exp. Biol. Med. 104,646 (1960), d. h., the blood pressure was measured directly via chronically implanted catheters (abdominal aorta).
c) Beobachtungszeitraum der Versuche war jeweils 10 Stunden.c) Observation period of the experiments was 10 hours each.
d) Die Versuche wurden im Vergleich zu Beispiel 1 aus DD 202010 und einer Lösungsmittelkontrollgruppe durchgeführt.d) The experiments were carried out in comparison to Example 1 of DD 202010 and a solvent control group.
e) Zum p.o.-Applikationsmedium: Die Substanzen wurden in physiologischer Kochsalzlösung mit einem Zusatz von 0,085% Myrj 53 und 1 % Ethanol aufgeschwemmt bzw. gelöst. Die Lösungsmittelkontrollgruppe erhielt physiologische Kochsalzlösung mit den entsprechenden Zusätzen. Für die i. v.-lnfusion wurden die Substanzen in einer 0,9%igen NaCI-Lösung (mit einem 0,125%-Anteil an NaHCO3) gelöst.e) To the po-application medium: The substances were suspended in physiological saline solution with an addition of 0.085% Myrj 53 and 1% ethanol suspended or dissolved. The solvent control group received physiological saline with the appropriate additives. For iv infusion, the substances were dissolved in a 0.9% NaCl solution (containing 0.125% NaHCO 3 ).
f) Die applizierte Wirkstoffmenge betrug 2mg/kg.f) The applied amount of active ingredient was 2 mg / kg.
g) Der Ausgangszustand der Versuchstiere war hyperton (SH-Ratten).g) The initial state of the experimental animals was hypertonic (SH rats).
Ausführungsbeispielembodiment
Die Erfindung wird nachstehend an einigen Beispielen näher erläutert.The invention is explained in more detail below with reference to some examples.
(5E)-(16RS)-2-Descarboxy-1a,1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2 Zu einer Lösung von 700mg 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-in-yl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol in 15ml Tetrahydrofuran fügt man bei 0°C 77mg 55%ige Natriumhydridsuspension in Mineralöl und rührt 30 Minuten bei 240C unter Argon. Anschließend tropft man eine Lösung von 1,15 g2-(3-Brom-propyl)-1,3-dioxolan in 7 ml Tetrahydrofuran zu und kocht 21 Stunden am Rückfluß unter Argon. Man verdünnt mit Äther, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstandes an Kieselgel erhält man mit Hexan/Äther (7 + 3) 480mg der Oxa-Verbindung, die man mit 40 ml einer Mischung aus Essigsäure/Wasser/Tetrahydrofuran (65 + 35 + 10) 16 Stunden bei 24°C rührt. Man dampft anschließend im Vakuum ein und(5E) - (16RS) -2-descarboxy-1a, 1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin l 2 To a Solution of 700 mg of 2 - {(E) - (1 S, 5 S, 6 R, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3 S, 4RS) -4 -methyl-3- ( tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-bicyclo / 3.3.0 / octan-3-ylidene} -äthan-1-ol in 15 ml of tetrahydrofuran is added at 0 ° C 77mg 55% Sodium hydride suspension in mineral oil and stirred for 30 minutes at 24 0 C under argon. Then, a solution of 1.15 g of 2- (3-bromo-propyl) -1,3-dioxolane in 7 ml of tetrahydrofuran is added dropwise, and the mixture is refluxed for 21 hours under argon. It is diluted with ether, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with hexane / ether (7 + 3) 480mg of the oxa compound, which is stirred for 16 hours at 24 ° C with 40 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) , It is then evaporated in vacuo and
chromatographiert den Rückstand an Kieselgel. Mit Essigester/Hexan (4+1) erhält man 270 mg der Titelverbindung als farbloses Öl.the residue is chromatographed on silica gel. With ethyl acetate / hexane (4 + 1), 270 mg of the title compound are obtained as a colorless oil.
IR (CHCI3): 3600, 3420 (breit), 2970, 2862, 2730,1725,1 603, 970/cmIR (CHCl 3 ): 3600, 3420 (wide), 2970, 2862, 2730, 1725, 1 603, 970 / cm
Das für die obige Verätherung verwendete 2-(3-Brom-propyl)-1,3-dioxolan wird wie folgt hergestellt:The 2- (3-bromo-propyl) -1,3-dioxolane used for the above etherification is prepared as follows:
Zu einer Lösung von 9,6g Brombuttersäureäthylester in 595 ml Toluol tropft man langsam bei -7O0C 50ml einer 1,2molaren Lösung von Diisobutylaluminiumhydrid in Toluol, rührt 15 Minuten bei -700C und versetzt anschließend tropfenweise mit 10 ml Isopropylalkohol und 25ml Wasser. Man rührt 2 Stunden bei Raumtemperatur, filtriert, trocknet das FiItrat mit Magnesiumsulfat und engt im Vakuum bei 25°C ein. Den Rückstand löst man in 500ml Toluol, fügt 10ml Äthylenglycol und 100mg p-Toluolsulfonsäurezu und kocht 6 Stunden mit einem Wasserabscheider am Rückfluß. Anschließend verdünnt man mit 500 ml Äther, schüttelt einmal mit einer 5%igen Natriumbicarbonatlösung, dreimal mit Wasser, trocknet den organischen Extrakt mit Magnesiumsulfat und engt im Vakuum bei 300C ein. Die Destillation des Rückstandes bei 0,6Torr und 430C bis 450C liefert 6,8g 2-(3-Brompropyl)-1,3-dioxolan als farblose Flüssigkeit.To a solution of 9.6 g Brombuttersäureäthylester in 595 ml of toluene is added dropwise slowly at -7O 0 C 50 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene, stirred for 15 minutes at -70 0 C and then treated dropwise with 10 ml of isopropyl alcohol and 25 ml of water , The mixture is stirred for 2 hours at room temperature, filtered, the filtrate is dried with magnesium sulfate and concentrated in vacuo at 25 ° C. The residue is dissolved in 500 ml of toluene, added to 10 ml of ethylene glycol and 100 mg of p-toluenesulfonic acid and boiled for 6 hours with a water at reflux. Then it is diluted with 500 ml of ether, shaken once with a 5% sodium bicarbonate solution, three times with water, the organic extract is dried with magnesium sulfate and concentrated in vacuo at 30 0 C. Distillation of the residue at 0,6Torr and 43 0 C to 45 0 C provides 6.8 g of 2- (3-bromopropyl) -1,3-dioxolane as a colorless liquid.
Beispiel 2 (5E)-(16RS)-1a,1b-Dihomo-16-methyl-3-oxa-18>18/19,19-tetradehydro-6a-carba-prostaglandin-l2 Zu einer Lösung von 500 mg des nach Beispiel 1 hergestellten Aldehyds in 5 ml Pyridinfügt man 2 ml Essigsäurehydrid und läßt 18 Stunden bei Raumtemperatur stehen. Anschließend engt man im Vakuum ein, löst das erhaltene 11,15-Diacetat in 25 ml Aceton und versetzt bei 00C tropfenweise mit 2,1 ml Jones Reagens. Man rührt 30 Minuten bei 0°C, fügt 2 ml Isopropylalkohol zu, verdünnt mit Äther, schüttelt dreimal mit Wasser, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstandes an Kieselgel mit Hexan/Essigester (1 + 1) erhält man 410mg (5E)-(16RS)-1a,1b-Dihomo-16-methyl-S-oxa-ISJS.igjg-tetradehydro-ea-carba-prostaglandin-^-HJB-diacetat als farbloses Öl. IR: 3650, 3400 (breit), 2960,1 730,1 600,1 245, 968/cm.Example 2 (5E) - (16RS) -1a, 1b-Dihomo-16-methyl-3-oxa-18 > 18 / 19,19-tetradehydro-6a-carba-prostaglandin-l 2 To a solution of 500 mg of the after Example 1 prepared aldehyde in 5 ml of pyridine is added 2 ml of acetic acid hydride and allowed to stand for 18 hours at room temperature. It is then concentrated in vacuo, the resulting 11,15-diacetate dissolved in 25 ml of acetone and treated at 0 0 C dropwise with 2.1 ml Jones reagent. The mixture is stirred for 30 minutes at 0 ° C, added to 2 ml of isopropyl alcohol, diluted with ether, shaken three times with water, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel with hexane / ethyl acetate (1 + 1) gives 410 mg of (5E) - (16RS) -1a, 1b-dihomo-16-methyl-S-oxa-ISI.sigjg-tetradehydro-ea-carba- prostaglandin - ^ - HJB-diacetate as a colorless oil. IR: 3650, 3400 (wide), 2960.1 730.1 600.1 245, 968 / cm.
Zur Abspaltung der Schutzgruppen rührt man 410mg des 11,15-Diacetats in 20ml Methanol 16 Stunden bei 240C mit 520mg Kaliumcarbonat. Anschließend konzentriert man im Vakuum, säuert mit 10%iger Citronensäurelösung auf pH4 an, extrahiert dreimal mit Methylenchlorid, wäscht zweimal mit Wasser, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Den Rückstand chromatographiert man mit Essigester/Essigsäure (99,5 + 0,5) an Kieselgel. Dabei erhält man 305mg der Titelverbindung als farbloses ÖlFor deprotection is stirred 410 mg of the 11,15-diacetate in 20 ml of methanol for 16 hours at 24 0 C with 520mg potassium carbonate. Then concentrated in vacuo, acidified with 10% citric acid solution to pH4, extracted three times with methylene chloride, washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed with ethyl acetate / acetic acid (99.5 + 0.5) on silica gel. This gives 305 mg of the title compound as a colorless oil
IR: 3590, 3420 (breit), 2960, 2930, 2865, 1 720, 1 600, 970/cm. IR: 3590, 3420 (wide), 2960, 2930, 2865, 1 720, 1 600, 970 / cm.
Beispiel 3 (5Z)-(16RS)-2-Descarboxy-1a,1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2 In Analogie zu Beispiel 1 erhält man aus 320mg 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-in-yl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol 125mg der Titelverbindung als farblosesExample 3 (5Z) - (16RS) -2-Descarboxy-1a, 1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 In analogy to Example 1, 320mg of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S, 4RS) -4 -methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-yn-1-bicyclo / 3.3.0 / octan-3-ylidene} -ethan-1-ol 125 mg of the title compound as a colorless
IR: 3610, 3400 (breit), 2965, 2860, 2730,1 726,1 602, 968/cmIR: 3610, 3400 (wide), 2965, 2860, 2730.1, 726.1, 602, 968 / cm
(5Z)-(16RS)-1a,1b-Dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2In Analogie zu Beispiel 2 erhält man aus 125 mg des nach Beispiel 3 hergestellten Aldehyds 90 mg (5Z)-(16RS)-1 a,1 b-Dihomo-16-methyl-S-oxa-IS.ISjgjg-tetradehydro-ea-carba-prostaglandin-^-H.iö-diacetat. Nach Abspaltung der Schutzgruppen erhält man 57 mg der Titelverbindung als farbloses Öl(5Z) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 In analogy to Example 2, 125 mg of the aldehyde prepared according to Example 3: 90 mg (5Z) - (16RS) -1a, 1 b-dihomo-16-methyl-S-oxa-IS.sub.jgjg-tetradehydro-ea-carba-prostaglandin - ^ - H. diacetate. Cleavage of the protecting groups gives 57 mg of the title compound as a colorless oil
IR: 3600, 3410 (breit), 2960, 2866,1 718,1 600, 968/cm. IR: 3600, 3410 (wide), 2960, 2866.1, 718.1, 600, 968 / cm.
In Analogie zu Beispiel 1 erhält man aus 1,35g 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-in-yl/-bicyclo/3.3.0/-octan-3-yliden}-äthan-1-ol 610mg der Titelverbindung als farblosesIn analogy to Example 1, 1.35 g of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S, 4RS) 4-methyl-3- (tetrahydropyran-2-yloxy) -non-1-en-6-yn-1-bicyclo / 3.3.0 / octan-3-ylidene} -ethan-1-ol 610 mg of the title compound as colorless
IR: 3600, 3410 (breit), 2967, 2862, 2731,1 725,1 601,970/cmIR: 3600, 3410 (wide), 2967, 2862, 2731.1, 725.1, 601.970 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
5 a) (1 R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-/(E)-(3S,4RS)-3-hydroxy-4-methyl-non-1 -βη-β-ϊη-γΙ/^ϊογοΙο-^^.Ο/οοίβη Zu einer Suspension von 1,46g Natriumhydrid (55%ige Suspension in Öl) in 130ml Dimethoxyäthan (DME) tropft man bei 0°C eine Lösung aus 9,02g S-Methyl^-oxo-oct-S-inyl-phosphonsäure-dimethylester in 67 ml DME und rührt 1 Stunde bei 00C. Anschließend versetzt man bei -20°C mit einer Lösung aus 9,4g (1 R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-formyl-bicyclo/S.S.O/octan in 130ml DME, rührt 1,5 Stunden bei -20°C, gießt auf 600ml gesättigte Ammoniumchloridlösung und extrahiert dreimal mit Äther. Man wäscht den organischen Extrakt mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstandes an Kieselgel erhält man mit Äther/Hexan (1 + 1) 9,1g des aMß-ungesättigten Ketons als Öl. Zu einer Lösung von 9,1 g des Ketons in 300 ml Methanol fügt man bei -40°C portionsweise 5,2 g Natriumborhydrid und rührt 1 Stunde bei -4O0C. Anschließend verdünnt man mit Äther, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Durch Säulenchromatographie an Kieselgel mit Äther/Hexan erhält man zunächst 3,9g der Titelverbindung (PG-Nomenklatur: 15a-Hydroxy) sowie die polarere Komponente 3,2g der isomeren 15ß-Hydroxy-Verbindung. IR: 3600, 3400 (breit), 2942,1 711,1 603, 1 588,1 276, 968, 947/cm5 a) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6 - / (E) - (3S, 4RS) -3-hydroxy-4-methyl-non-1-βη -β-ϊη-γΙ / ^ ϊογοΙο - ^^. Ο / οοίβη To a suspension of 1.46 g of sodium hydride (55% suspension in oil) in 130 ml of dimethoxyethane (DME) is added dropwise at 0 ° C, a solution of 9.02g S-methyl ^ -oxo-oct-S-ynyl-phosphonic acid dimethyl ester in 67 ml DME and stirred for 1 hour at 0 0 C. is then added at -20 ° C with a solution of 9.4 g of (1 R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / SSO / octane in 130 ml of DME, stirred for 1.5 hours at -20 ° C, poured onto 600 ml of saturated ammonium chloride solution and extracted three times with ether. The organic extract is washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel is obtained with ether / hexane (1 + 1) 9.1 g of αMβ-unsaturated ketone as an oil. To a solution of 9.1 g of the ketone in 300 ml of methanol is added at -40 ° C in portions 5.2 g of sodium borohydride and stirred for 1 hour at -4O 0 C then diluted with ether, washed with water until neutral, dried Magnesium sulfate and evaporated in vacuo. Column chromatography on silica gel with ether / hexane initially gives 3.9 g of the title compound (PG nomenclature: 15a-hydroxy) and the more polar component 3.2 g of the isomeric 15β-hydroxy compound. IR: 3600, 3400 (wide), 2942.1 711.1 603, 1 588.1 276, 968, 947 / cm
5b) (1R,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-3-(tetΓahydropyraπ-2-yloxy)-4-methyl-non-1-en-6-iπ-yl/-/5b) (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S, 4RS) -3- (tetrahydro-2-yloxy) -4-methyl-non -1-en-6-yl-iπ / - /
Eine Mischung aus 3,6g des nach Beispiel 5a hergestellten α-Alkohols und 1,4g Kaliumcarbonat in 120ml Methanol rührt man 16 Stunden bei Raumtemperatur unter Argon. Anschließend engt man im Vakuum ein, verdünnt mit Äther und wäscht mit Sole neutral. Man trocknet über Magnesiumsulfat und dampft im Vakuum ein. Den Eindampfrückstand rührt man 16 Stunden bei Raumtemperatur mit 75 ml einer Mischung aus Essigsäure/Wasser/Tetrahydrofuran (65 + 35 + 10) und dampft anschließend im Vakuum ein. Nach Filtration des Rückstandes über Kieselgel erhält man mit Essigester/Hexan (7 + 3) 2,2g des Ketons als Öl. Eine Lösung aus 2,2g des Ketons, 2,4ml Dihydropyran und 23mg p-Toluolsulfonsäure in 75ml Methylenchlorid rührt man 30 Minuten bei O0C. Anschließend verdünnt man mit Äther, schüttelt mitverd. Natriumbicarbonat-Lösung, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Man erhält 3,4g des Bistetrahydropyranyläthers, der ohne Reinigung verwendet wird. IR: 2960, 2865,1 738, 970/cmA mixture of 3.6 g of the α-alcohol prepared according to Example 5a and 1.4 g of potassium carbonate in 120 ml of methanol is stirred for 16 hours at room temperature under argon. Then concentrated in vacuo, diluted with ether and washed with brine neutral. It is dried over magnesium sulfate and evaporated in vacuo. The evaporation residue is stirred for 16 hours at room temperature with 75 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo. After filtration of the residue over silica gel, ethyl acetate / hexane (7 + 3) gives 2.2 g of the ketone as an oil. A solution of 2.2 g of the ketone, 2.4 ml of dihydropyran and 23 mg of p-toluenesulfonic acid in 75 ml of methylene chloride is stirred for 30 minutes at 0 ° C. It is then diluted with ether and shaken with co-dilution. Sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. 3.4 g of the bistetrahydropyranyl ether are obtained, which is used without purification. IR: 2960, 2865.1, 738, 970 / cm
5c) 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-in-yl/-bicyclo/S.S.O./octan-S-ylidenJ-äthan-i-ol5c) 2 - {(E) - (1 S, 5 S, 6 R, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3 S, 4RS) -4-methyl-3- (tetrahydropyran -2-yloxy) -non-1-en-6-yl-in / -bicyclo / SSO / octan-S-ylidenJ-ethane-i-ol
Zu einer Lösung von 8,1 g Phosphonessigsäuretriäthylester in 170ml Tetrahydrofuran fügt man bei 0°C 3,5g Kalium-tertbutylat, rührt 10min, versetzt mit einer Lösung aus 9g des nach Beispiel 5 b hergestellten Ketons in 90ml Toluol und rührt 16 Stunden bei Raumtemperatur unter Argon. Man verdünnt mit 1000 ml Äther, schüttelt mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Den Rückstand filtriert man mit Hexan/Äther (3 + 2) über Kieselgel. Dabei erhält man 8,2g des ungesättigten Esters als farbloses Öl3.5 g of potassium tert-butylate are added to a solution of 8.1 g of triethyl phosphonate in 170 ml of tetrahydrofuran at 0 ° C., stirred for 10 minutes, admixed with a solution of 9 g of the ketone prepared according to Example 5 b in 90 ml of toluene and stirred for 16 hours at room temperature under argon. It is diluted with 1000 ml of ether, shaken neutral with water, dried over magnesium sulfate and evaporated in vacuo. The residue is filtered with hexane / ether (3 + 2) on silica gel. This gives 8.2 g of the unsaturated ester as a colorless oil
IR: 2950, 2870, 1 700, 1 655, 968/cm IR: 2950, 2870, 1 700, 1 655, 968 / cm
Man fügt 2,2g Lithiumaluminiumhydrid portionsweise bei 00C zu einer gerührten Lösung von 8g des vorstehend hergestellten Esters in 280 ml Äther und rührt 30 Minuten bei 00C. Man zerstört den Reagenzüberschuß durch tropfenweise Zugabe von Essigester, fügt 12ml Wasser zu, rührt 2 Stunden bei 220C, filtriert und dampft im Vakuum ein. Den Rückstand chromatographiert man mit Äther/Hexan (3 + 2) an Kieselgel. Dabei erhält man als unpolarere Verbindung 2,8g 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-in-yl/-bicyclo-/3.3.0./octan-3-yliden}-äthan-1-ol und 4,2g der Titelverbindung als farbloses Öl. IR: 3600, 3430, 2942, 2863,1 600, 972/cmIs added 2.2 g of lithium aluminum hydride portionwise at 0 0 C to a stirred solution of 8 g of the ester prepared above in 280 ml of ether and stirred for 30 minutes at 0 0 C. It will destroy the excess reagent by dropwise addition of Essigester, added to 12ml of water, stirred 2 hours at 22 0 C, filtered and evaporated in vacuo. The residue is chromatographed with ether / hexane (3 + 2) on silica gel. 2.8 g of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S, 4RS) -4 are obtained as the less polar compound -methyl-3- (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl-bicyclo- / 3.3.0- / octan-3-ylidene} -äthan-1-ol and 4.2g the title compound as a colorless oil. IR: 3600, 3430, 2942, 2863.1 600, 972 / cm
(5E)-(16RS)-1a,1b-Dihomo-16,20-dimethyl-3-oxa-18,18,19, IS-tetradehydro-ea-carba-prostaglandin-l;, In Analogie zu Beispiel 2 erhält man aus 380mg des nach Beispiel 5 hergestellten Aldehyds 305mg (5E)-(16RS)-1a,1b-Dihomo-16,20-dimethyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^-i 1,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 210mg der Titelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2962, 2865, 1 720, 1 601,970/cm(5E) - (16RS) -1a, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19, IS-tetradehydro-ea-carba-prostaglandin-1; In analogy to Example 2 is obtained from 380 mg of the aldehyde prepared according to Example 5: 305 mg (5E) - (16RS) -1a, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,1-g-tetradehydro-ea-carba-prostaglandin ^ -i 1,15-diacetate. Cleavage of the protective groups gives 210 mg of the title compound as a colorless oil. IR: 3600, 3400 (wide), 2962, 2865, 1 720, 1 601.970 / cm
prostaglandin-^prostaglandin- ^
In Analogie zu Beispiel 1 und 5 erhält man aus 0,9g 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylen-non-1-en-6-in-yl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol (hergestellt gemäß Beispiel 5a-caus 2-Oxa-3,3-trimethylen-non-5-in-phosphonsäure-dimethylester) 0,4g der Titelverbindung als farbloses Öl. IR: 3610,3400 (breit), 2968,2864,2730,1725,1602,970/cm Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:Analogously to Examples 1 and 5, from 0.9 g of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-non-1-en-6-ynyl-bicyclo / 3.3.0 / octan-3-ylidene} -äthan-1-ol (mfd according to Example 5a-caus 2-oxa-3,3-trimethylene-non-5-yn-phosphonic acid dimethyl ester) 0.4 g of the title compound as a colorless oil. IR: 3610.3400 (wide), 2968.2864, 2730.1725, 16.02.970 / cm The starting material for the title compound above is prepared as follows:
7a) 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-4,4-trimethylen-non-1-en-6-in-yl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol7a) 2 - {(E) - (1 S, 5 S, 6 R, 7 R) -7- (tetrahydropyran-2-yloxy) -4,4-trimethylene-non-1-en-6-yn-yl / bicyclo / 3.3.0 / octan-3-ylidene} -ethane-1-ol
In Analogie zu Beispiel 5c erhält man aus 3g (1R,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethyien-non-1-en-6-inyl/-bicyclo/3.3.0/-octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 470mg 2-{(Z)-(1S,5S,6R,7R)-7-(Tetra-hydropyran-2-yloxy)-4,4-trimethylen-non-1-en-6-inyl/-bicyclo/S.S.O/octan-S-ylidenJ-äthan-i -öl und 690 m der Titelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2945, 2862,1 602, 972/cmAnalogously to Example 5c, from 3 g (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R) -3- (tetrahydropyran-2-yloxy) - 4,4-trimethyl-non-1-en-6-ynyl / bicyclo / 3.3.0 / octan-3-one after chromatographic separation of isomers as a more nonpolar compound 470mg 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetra-hydropyran-2-yloxy) -4,4-trimethylene-non-1-en-6-ynyl / bicyclo / SSO / octane-S-ylidene-1-ethane-i-oil and 690 m the title compound as a colorless oil. IR: 3600, 3400 (wide), 2945, 2862.1 602, 972 / cm
Beispiel 8 (5E)-1a,1b-Dihomo-20-methyl-3-oxa-16,16-trimethylen-18,18,19,19-tetradehydro-6a-carba-prostaglandin-lz In Analogie zu Beispiel 2 erhält man aus 400 mg des nach Beispiel 7 hergestellten Aldehyds 295 mg (5E)-1a,1b-Dihomo-20-methyl-3-oxa-16,16-trimethylen-18,18,19,19-tetrahydro-6a-carba-prostaglandin-l2-11,15-diacetat. Nach Abschaltung der Schutzgruppen erhält man 220 mg der Titelverbindung als farbloses Öl. IR: 3610, 3400 (breit), 2960, 2864, 1 721, 1 602, 970/cmExample 8 (5E) -1a, 1b-Dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a-carba-prostaglandin l-z In analogy to Example 2 from 400 mg of the aldehyde prepared according to Example 7, 295 mg of (5E) -1a, 1b-dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetrahydro-6a-carbonyl prostaglandin-l 2 -11,15-diacetate. After switching off the protective groups, 220 mg of the title compound are obtained as a colorless oil. IR: 3610, 3400 (wide), 2960, 2864, 1 721, 1 602, 970 / cm
(BEJ^-Descarboxy-ia^b-dihomo-ie.ie-dimethyl^-formyl-S-oxa-i 8,18,19,ig-tetradehydro-Sa-carba-prostaglandin-^ In Analogie zu Beispiel 1 und 5 erhält man 0,5g 2-{(E)-(1 S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl/-bicyclo-/3.3.0/octan-3-yliden}-äthan-1-ol 0,28g der Titelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2965, 2732,1724,1600,970/cm(BEJ ^ -Descarboxy-ia ^ b-dihomo-he.ie-dimethyl ^ -formyl-S-oxa-i 8,18,19, ig-tetradehydro-Sa-carba-prostaglandin ^ In analogy to Example 1 and 5 0.5g of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R) -4,4-dimethyl- 3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-bicyclo- / 3.3.0 / octan-3-ylidene} -ethan-1-ol 0.28g of the title compound as a colorless oil : 3600, 3400 (wide), 2965, 2732,1724,1600,970 / cm
In Analogie zu Beispiel 2 erhält man aus 0,27g des nach Beispiel 9 hergestellten Aldehyds 180mg (5E)-1a,1b-Dihomo-16,16-dimethyl-3-oxa-18,18,19,1 g-tetradehydro-öa-carba-prostaglandin-^-i 1,15-diacetat.In analogy to Example 2, from 0.27 g of the aldehyde prepared according to Example 9, 180 mg (5E) -1a, 1b-dihomo-16,16-dimethyl-3-oxa-18,18,19,1-g-tetrahydro-ethyl are obtained -carba-prostaglandin - ^ - i 1,15-diacetate.
Nach Abspaltung der Schutzgruppen erhält man 120mg der Titelverbindung als farbloses Öl.After removal of the protective groups, 120 mg of the title compound are obtained as a colorless oil.
IR: 3600, 3400 (breit), 2962, 2865,1 720,1600,971/cmIR: 3600, 3400 (wide), 2962, 2865.1 720.1600,971 / cm
In Analogie zu Beispiel 1 und 5 erhält man aus 1,1 g 2-{(E)-(1 S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy )-6-/(E)-(3R)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl/-bicyclo-/3.3.0/octan-3-yliden}-äthan-1-ol 0,6g der Titelverbindung als farbloses Öl. IR: 3610, 3420 (breit), 2964, 2730,1 725,1 602, 972/cmAnalogously to Examples 1 and 5, 1.1 g of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - ( 3R) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl / bicyclo- / 3.3.0 / octan-3-ylidene} -äthan-1-ol 0 , 6g of the title compound as a colorless oil. IR: 3610, 3420 (wide), 2964, 2730.1, 725.1, 602, 972 / cm
(5E)-1a,1b-Dihomo-3-oxa-16,16,20-trimethyl-18,18,19,IS-tetradehydro-ea-carba-prostaglandin-^ In Analogie zu Beispiel 2 erhält man aus 0,4g des nach Beispiel 11 hergestellten Aldehyds 0,3g (5E)-1a,1b,-Dihomo-3-oxayypg^(5E) -1a, 1b-dihomo-3-oxa-16,16,20-trimethyl-18,18,19, IS-tetradehydro-ea-carba-prostaglandin In analogy to Example 2 is obtained from 0.4g of the aldehyde prepared according to Example 11 0.3 g (5E) -1a, 1b, -Dihomo-3-oxayypg ^
Nach Abspaltung der Schutzgruppen erhält man 0,22g der Titelverbindung als farbloses Öl. IR: 3610, 3400 (breit), 2964, 2864,1 721,1 600, 972/cmAfter cleavage of the protective groups, 0.22 g of the title compound is obtained as a colorless oil. IR: 3610, 3400 (wide), 2964, 2864.1, 721.1, 600, 972 / cm
(5E)-(I eRSl^-Descarboxy-IS.IS-didehydro-ia.ib-dihomo-ie.ig-dimethyl^-formyl-S-oxa-Ba In Analogie zu Beispiel 1 und 5 erhält man aus 0,7g 2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4,7-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-1,6-dienyl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol 0,4g der Titelverbindung als farbloses Öl(5E) - (I eRSl ^ -Descarboxy-IS.is-didehydro-ia.ib-dihomo-ie.ig-dimethyl ^ -formyl-S-oxa-Ba In analogy to Example 1 and 5 is obtained from 0.7g 2 - {(e) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (e) - (3S, 4RS) -4,7-dimethyl-3- (tetrahydropyran 2-yloxy) -oct-1,6-dienyl / bicyclo / 3.3.0 / octan-3-ylidene} -ethan-1-ol 0.4g of the title compound as a colorless oil
IR: 3600, 3400 (breit), 2966, 2732,1 725,1 601, 972/cm IR: 3600, 3400 (wide), 2966, 2732.1, 725.1, 601, 972 / cm
In Analogie zu Beispiel 2 erhält man aus 0,2g des nach Beispiel 13 hergestellten Aldehyds 0,14 (5E)-1a,1b-Dihomo-16,19-dimethyl-ISjg-didehydro-S-oxa-ea-carba-prostaglandin-^-HJS-diacetat.In analogy to Example 2, from 0.2 g of the aldehyde prepared according to Example 13 there are obtained 0.14 (5E) -1a, 1b-dihomo-16,19-dimethyl-ish-didehydro-S-oxa-ea-carba-prostaglandin ^ -HJS diacetate.
Nach Abspaltung der Schutzgruppen erhält man 90mg der Titelverbindung als farbloses Öl.Cleavage of the protecting groups gives 90 mg of the title compound as a colorless oil.
IR: 3600, 3410 (breit), 2960, 2860,1 720,1 601, 972/cmIR: 3600, 3410 (wide), 2960, 2860.1 720.1 601, 972 / cm
(5E)-(16RS)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,le-tetradehydro-ea-carbaprostaglandin-^(5E) - (16RS) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19, le-tetradehydro-ea-carbaprostaglandin- ^
In Analogie zu Beispiel 1 und 5 erhält man aus 0,6g 2-{(E)-(1 S,5S,6R,7R)-(7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/3.3.0/-octan-3-yliden}-äthan-1-ol 0,29g der Titelverbindung als farbloses Öl.Analogously to Examples 1 and 5, from 0.6 g of 2 - {(E) - (1S, 5S, 6R, 7R) - (7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) 4-Methyl-3- (tetrahydropyran-2-yloxy) -octa-1,6-diynyl / bicyclo / 3.3.0 / octan-3-ylidene} -ethan-1-ol 0.29g of the title compound as a colorless Oil.
IR: 3610, 3410 (breit), 2966, 2730, 2225,1 725/cmIR: 3610, 3410 (wide), 2966, 2730, 2225.1 725 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
15a) 2-{(E)-(1S,5S,6R,7R)-7-Tetrahydropyran-2-yloxy-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/S.S.O/octan-S-ylidenj-äthan-i-ol15a) 2 - {(E) - (1 S, 5 S, 6 R, 7 R) -7-Tetrahydropyran-2-yloxy-6 - / (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) - octa-1,6-diinyl / -bicyclo / SSO / octan-S-ylidenj-ethane-i-ol
In Analogie zu Beispiel 5cerhält man aus 1,8g (iR,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/3.3.0/-octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 380mg 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl)/-bicyclo/3.3.0/-octan-3-yliden}-äthan-1-ol und 610mg der Titelverbindung als Öl. IR: 3600, 3400 (breit), 2945, 2860, 2225/cmAnalogously to Example 5c, 1.8 g of (iR, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- / (3S, 4RS) -4-methyl-3-tetrahydropyran-2-yloxy are obtained ) -octa-1,6-diynyl / bicyclo / 3.3.0 / octan-3-one after chromatographic separation of isomers as a more nonpolar compound 380 mg 2 - {(Z) - (1 S, 5 S, 6 S, 7 R) -7- ( tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) -octa-1,6-diinyl) / - bicyclo / 3.3.0 / octan-3 -ylidene) -äthan-1-ol and 610 mg of the title compound as an oil. IR: 3600, 3400 (wide), 2945, 2860, 2225 / cm
Beispiel 16 (5E)-(16RS)-13,14-Didehydro-1a,1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2 In Analogie zu Beispiel 2 erhält man aus 0,4g des nach Beispiel 15 hergestellten Aldehyds 0,21 g (5E)-(16RS)-13,14-Didehydro-1 a,1 b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-11,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 150mg der Titelverbindung als farbloses Öl. IR: 3600, 3410 (breit), 2960, 2864, 2 226,1 718/cmExample 16 (5E) - (16RS) -13,14-Didehydro-1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 In analogy Example 2 gives, from 0.4 g of the aldehyde prepared according to Example 15, 0.21 g of (5E) - (16RS) -13,14-didehydro-1 a, 1-b-dihomo-16-methyl-3-oxa-18 , 18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 -11,15-diacetate. After cleavage of the protective groups, 150 mg of the title compound are obtained as a colorless oil. IR: 3600, 3410 (wide), 2960, 2864, 2 226.1 718 / cm
(5E)-(16RS)-2-Descarboxy-13,14-didehydro-1a,1 b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carbaprostaglandin-^(5E) - (16RS) -2-descarboxy-13,14-didehydro-1a, 1-b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18,18,19,1 g-tetradehydro- ea-carbaprostaglandin- ^
In Analogie zu Beispiel 1 und 5 erhält man aus 0,8g 2-{(E)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo/3.3.0/-octan-3-yliden}-äthan-1-ol 042 g der Titelverbindung als farbloses Öl.Analogously to Examples 1 and 5, 0.8 g of 2 - {(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4 are obtained -methyl-3- (tetrahydropyran-2-yloxy) -nona-1,6-diynyl / bicyclo / 3.3.0 / -octan-3-ylidene} -ethan-1-ol 042 g of the title compound as a colorless oil.
IR: 3600, 3400 (breit), 2965, 2732, 2227, 1 724/cmIR: 3600, 3400 (wide), 2965, 2732, 2227, 1 724 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
17a) (2-{(E)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo/S.S.O/octan-S-ylidenJ-äthan-i-ol17a) (2 - {(E) - (1 S, 5 S, 6 S, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-one) yloxy) -nona-1,6-diinyl / -bicyclo / SSO / octan-S-ylidenJ-ethane-i-ol
In Analogie zu Beispiel 5c erhält man aus 2,1 g (1 R,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo/3.3.0/-octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 450mg (2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol und 740mg der Titelverbindung als farbloses ÖlAnalogously to Example 5c, 2.1 g of (1R, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- / (3S, 4RS) -4-methyl-3- (tetrahydropyran -2-yloxy) -nona-1,6-diynyl / bicyclo / 3.3.0 / octan-3-one after chromatographic separation of isomers as a more non-polar compound 450 mg (2 - {(Z) - (1 S, 5 S, 6 S, 7 R ) -7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) -nona-1,6-diinyl / bicyclo / 3.3.0 / octan-3-ylidene} -äthan-1-ol and 740 mg of the title compound as a colorless oil
IR: 3600,3420 (breit), 2947, 2862, 2223/cm IR: 3600.3420 (wide), 2947, 2862, 2223 / cm
Beispiet 18Example 18
(5E)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2 In Analogie zu Beispiel 2 erhält man aus 620 mg des nach Beispiel 17 hergestellten Aldehyds 340 mg (5E)-(1 RS)-13,14-Didehydro-1a,1 b-dihomo-16,20-dimethyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^-i 1,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 260 mg der Titelverbindung als farbloses Öl. IR: 3610, 3400 (breit), 2962, 2865, 2225,1 720/cm(5E) - (16RS) -13,14-didehydro-1a, 1-b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 In Analogously to Example 2, from 620 mg of the aldehyde prepared according to Example 17, 340 mg (5E) - (1RS) -13,14-didehydro-1a, 1-b-dihomo-16,20-dimethyl-3-oxa-18 are obtained , 18,19,1 g-tetradehydro-ea-carba-prostaglandin - ^ - i 1,15-diacetate. After removal of the protective groups, 260 mg of the title compound are obtained as a colorless oil. IR: 3610, 3400 (wide), 2962, 2865, 2225.1 720 / cm
carba-prostaglandin-licarba-prostaglandin-li
In Analogie zu Beispiel 1 und 5 erhält man aus 0,41 g 2-{(E)-(1 S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-(tetrahydropyran-In analogy to Examples 1 and 5, 0.41 g of 2 - {(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) - ( tetrahydropyran
2-yloxy)-4,4-trimethylen-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol 0,18g der Titelverbindung als farbloses Öl.2-yloxy) -4,4-trimethylene-nona-1,6-diynyl / bicyclo / 3.3.0 / octan-3-ylidene} -äthan-1-ol 0.18g of the title compound as a colorless oil.
IR: 3600, 3400 (breit), 2965, 2732, 2227,1 724/cmIR: 3600, 3400 (wide), 2965, 2732, 2227.1 724 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
19a) 2-{(E)-(1S,5S,6S,7R)-7-{Tetrahydropyraπ-2-yloxy)-6-/(3S)-3-{tetrahydropyran-2-yloxy)-4/4-trimethylen-nona-1,6-diinyl/-bicyclo/S.S.O/octan-S-ylidenJ-äthan-i-ol19a) 2 - {(E) - (1 S, 5 S, 6 S, 7 R) -7- (tetrahydropyra-2-yloxy) -6 - / (3 S) -3- {tetrahydropyran-2-yloxy) -4 / 4- trimethylene-nona-1,6-diinyl / -bicyclo / SSO / octan-S-ylidenJ-ethane-i-ol
In Analogie zu Beispiel 5 c erhält man aus 3,1 g (1 R,5S,6S,7R)-7-Tetrahydropyran-2-yloxy)-6-/(3S)-3-(tetra-hydropyran-2-yloxy)-4,4-trimethylen-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 890 mg (2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3RS)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylen-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol und 1,3g der Titelverbindung als Öl. IR: 3610,3420 (breit), 2945, 2862, 2226/cmIn analogy to Example 5c is obtained from 3.1 g (1 R, 5S, 6S, 7R) -7-tetrahydropyran-2-yloxy) -6 - / (3S) -3- (tetrahydropyran-2-yloxy ) -4,4-trimethylene-nona-1,6-diynyl / bicyclo / 3.3.0 / octan-3-one after chromatographic separation of isomers as a more nonpolar compound 890 mg (2 - {(Z) - (1S, 5S, 6S , 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3RS) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-nona-1,6-diinyl / -bicyclo / 3.3. 0 / octan-3-ylidene} -äthan-1-ol and 1.3 g of the title compound as an oil: IR: 3610.3420 (wide), 2945, 2862, 2226 / cm
Beispiel 20 (BEJ-IS.^-Didehydro-ia.ib-dihomo^O-methyl-S-oxa-ISjejSjig-tetradehydro-ie.ie-trimethylen-ea-carba-prostaglandin-lz In Analogie zu Beispiel 2 erhält man aus 0,42g des nach Beispiel 19 hergestellten Aldehyds 0,32g (5E)-13,14-Didehydro-1a,1b-Example 20 (BEJ-IS.) - Didehydro-ia.ib-dihomo ^ O-methyl-S-oxa-ISjejSjig-tetradehydro-ie.ie-trimethylene-ea-carba-prostaglandin-lz In analogy to Example 2 is obtained from 0.42 g of the aldehyde prepared according to Example 19 0.32 g (5E) -13,14-didehydro-1a, 1b-
Nach Abspaltung der Schutzgruppen erhält man 210mg der Titelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2963, 2865, 2225,1 720/cmCleavage of the protective groups gives 210 mg of the title compound as a colorless oil. IR: 3600, 3400 (wide), 2963, 2865, 2225.1 720 / cm
(5E)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19,ig-tetradehydro-ea-carbaprostaglandin-^(5E) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-16,16-dimethyl-2-formyl-3-oxa-18,18,19, ig-tetradehydro-ea-carbaprostaglandin- ^
In Analogie zu Beispiel 1 und 5 erhält man aus 0,9g 2-{(E)-(1S,5S,6S,7R)-7-!Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo-/3.3.0/-octan-3-yliden}-äthan-1-öl 0,47 g der Titelverbindung als farbloses Öl.Analogously to Examples 1 and 5, from 0.9 g of 2 - {(E) - (1S, 5S, 6S, 7R) -7-! -Tetrahydropyran-2-yloxy) -6 - / (3S) -4,4 -dimethyl-3- (tetrahydropyran-2-yloxy) -octa-1,6-diynyl / bicyclo- / 3.3.0 / -octan-3-ylidene} -ethane-1-oil 0.47 g of the title compound as a colorless Oil.
IR: 3600, 3410 (breit), 2966, 2730, 2225, 1 725/cmIR: 3600, 3410 (wide), 2966, 2730, 2225, 1 725 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
21a) 2-{(E)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo-/3.3.0/-octan-3-yliden}-äthan-1-ol21a) 2 - {(E) - (1 S, 5 S, 6 S, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (3 S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy ) octa-1,6-diinyl / -bicyclo- / 3.3.0 / octan-3-ylidene} -ethane-1-ol
In Analogie zu Beispiel 5c erhält man aus 2,5g (1R, 5S, 6S, 7R)-7-Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/3.3.0/-octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 625 mg 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-äthan-1-ol und 1,1g der Titelverbindung als Öl. IR: 3600, 3400 (breit), 2946, 2865, 2 225/cmAnalogously to Example 5c, 2.5 g of (1R, 5S, 6S, 7R) -7-tetrahydropyran-2-yloxy) -6- / (3S) -4,4-dimethyl-3- (tetrahydropyran-2-one) are obtained. yloxy) -octa-1,6-diynyl / bicyclo / 3.3.0 / octan-3-one after chromatographic separation of isomers as a more non-polar compound 625 mg 2 - {(Z) - (1S, 5S, 6S, 7R) -7 - (tetrahydropyran-2-yloxy) -6- (3S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -octa-1,6-diinyl / bicyclo / 3.3.0 / octan-3- yliden} -äthan-1-ol and 1.1 g of the title compound as an oil. IR: 3600, 3400 (wide), 2946, 2865, 2 225 / cm
Beispiel 22 (BEI-ia.U-Didehydro-ia^b-dihomo-ie.iS-dimethyl-S-oxa-ie^S.ig^S-tetradehydro-ea-carba-prostaglandin-la fn Analogie zu Beispiel 2 erhält man aus 0,31 g des nach Beispiel 21 hergestellten Aldehyds 0,21 g (5E)-13,14-Didehydro-1a,1b-Example 22 (BEI-ia.U-Didehydro-ia ^ b-dihomo-he.iS-dimethyl-S-oxa-ie ^ S.ig ^ S-tetradehydro-ea-carba-prostaglandin-la fn analogous to Example 2 receives 0.31 g of (5E) -13,14-didehydro-1a, 1b, are obtained from 0.31 g of the aldehyde prepared according to Example 21.
Nach Abspaltung der Schutzgruppen erhält man 0,14g der Titelverbindung als farbloses Öl. IR: 3600,3410 (breit), 2964, 2865,2225,1720/cmAfter cleavage of the protective groups, 0.14 g of the title compound is obtained as a colorless oil. IR: 3600.3410 (wide), 2964, 2865.2225, 1720 / cm
(5E)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin-^(5E) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-2-formyl-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin- ^
In Analogie zu Beispiel 1 und 5 erhält man aus 0,8g 2-{(E)-(1 S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo-/3.3.0/octan-3-yliden}-äthan-1-ol0,31 g der Titelverbindung als farbloses Öl.Analogously to Examples 1 and 5, 0.8 g of 2 - {(E) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) -4, 4-dimethyl-3- (tetrahydropyran-2-yloxy) -nona-1,6-diynyl / bicyclo / 3.3.0 / octan-3-ylidene} -ethan-1-ol 0.31 g of the title compound as a colorless oil ,
IR: 3610, 3420 (breit), 2965, 2730, 2226,1724/cmIR: 3610, 3420 (wide), 2965, 2730, 2226, 1724 / cm
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
23a) 2-{(E)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo-/3.3.0/octan-3-yliden}-äthan-1-ol23a) 2 - {(E) - (1 S, 5 S, 6 S, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (3 S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy ) -nona-1,6-diinyl / -bicyclo- / 3.3.0 / octan-3-ylidene} -ethane-1-ol
In Analogie zu Beispiel 5c erhält man aus 1,3 g (1R,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo-/3.3.0/-octan-3-on nach chromatographischer Isomerentrennung als unpolarere Verbindung 300mg 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo-/3.3.0/octan-3-yliden}-äthan-1-ol und 430mg der Titelverbindung als ÖlAnalogously to Example 5c, from 1.3 g of (1R, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) -4,4-dimethyl-3- (tetrahydropyran- 2-yloxy) -nona-1,6-diynyl / bicyclo- / 3.3.0 / -octan-3-one after chromatographic separation of isomers as a more nonpolar compound 300mg 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -nona-1,6-diinyl / -bicyclo- / 3.3.0 / octan-3-ylidene} -äthan-1-ol and 430 mg of the title compound as an oil
IR: 3610, 3400 (breit), 2945, 2865, 2225/cm IR: 3610, 3400 (wide), 2945, 2865, 2225 / cm
In Analogie zu Beispiel 2 erhält man aus 0,16g des nach Beispiel 23 hergestellten Aldehyds 0,1 g (5E)-13,14-Didehydro-1a,1bdihomo-3-oxa-18,18,19,19-tetradehydro-16,1 e^O-trimethyl-ea-carba-prostaglandin-^-i 1,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 60mg derTitelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2965, 2864, 2224,1 718/cmIn analogy to Example 2, from 0.16 g of the aldehyde prepared according to Example 23 there are obtained 0.1 g of (5E) -13,14-didehydro-1a, 1bdihomo-3-oxa-18,18,19,19-tetradehydro-16 , 1 e ^ O-trimethyl-ea-carba-prostaglandin - ^ - 1,15-diacetate. After deprotection, 60 mg of the title compound are obtained as a colorless oil. IR: 3600, 3400 (wide), 2965, 2864, 2224.1 718 / cm
Beispiel 25 (5Z)-(16RS)-2-Descarboxy-1a>1b-dihomo-5-fluor-2-formyl-16-methyl-3-oxa-18,18>19,19-tetradehydro-6a-carba-prostaglandin-l2 Zu einer Lösung von 420 mg 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl/-bicyclo-/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol in 8ml Tetrahydrofuran fügt man bei 0°C42mg 55%ige Natriumhydridsuspension in Mineralöl und rührt 30 Minuten bei 24°C unter Argon. Anschließend tropft man eine Lösung von 630 mg 2-(3-Brompropyl)-1,3-dioxolan in 8 ml Tetrahydrofuran zu und kocht 20 Stunden am Rückfluß unter Argon. Man verdünnt mit Äther, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstandes an Kieselgel erhält man mit Hexan/Äther (3 + 2) 340 mg der Oxa-Verbindung, die man mit 30 ml einer Mischung aus Essigsäure/Wasser/Tetrahydrofuran (65 + 35 + 10) 16 Stunden bei 24°C rührt. Man dampft anschließend im Vakuum ein-und chromatographiert den Rückstand an Kieselgel. Mit Essigester/Hexan (4+1) erhält man 280 mg der Titelverbindung als farbloses Öl. IR: 3600, 3420 (breit), 2960, 2930, 2870, 2730,1 730,1 603, 970/cmExample 25 (5Z) - (16RS) -2-Descarboxy-1a > 1b-dihomo-5-fluoro-2-formyl-16-methyl-3-oxa-18,18 > 19,19-tetradehydro-6a-carbato prostaglandin-l2 To a solution of 420 mg 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3S, 4RS) -4 -methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl / bicyclo- / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-ol in 8 ml of tetrahydrofuran 55% sodium hydride suspension in mineral oil is added at 0 ° C 42mg and stirred for 30 minutes at 24 ° C under argon. A solution of 630 mg of 2- (3-bromopropyl) -1,3-dioxolane in 8 ml of tetrahydrofuran is then added dropwise, and the mixture is boiled under argon for 20 hours under reflux. It is diluted with ether, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel is obtained with hexane / ether (3 + 2) 340 mg of the oxa compound, which with 30 ml of a mixture of acetic acid / water / tetrahydrofuran (65 + 35 + 10) for 16 hours at 24 ° C. stir. It is then evaporated in vacuo and the residue is chromatographed on silica gel. With ethyl acetate / hexane (4 + 1), 280 mg of the title compound are obtained as a colorless oil. IR: 3600, 3420 (wide), 2960, 2930, 2870, 2730.1, 730.1, 603, 970 / cm
In Analogie zu Beispiel 2 erhält man aus 205 mg des nach Beispiel 25 hergestellten Aldehyds 110mg (5Z)-(16RS)-I a,1 b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-11,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 78 mg der Titelverbindung als farbloses Öl.In analogy to Example 2, from 205 mg of the aldehyde prepared according to Example 25, 110 mg (5Z) - (16RS) -I a, 1 b-dihomo-5-fluoro-16-methyl-3-oxa-18, 18, 19 are obtained , 19-tetradehydro-6a-carba-prostaglandin-l 2 -11,15-diacetate. After cleavage of the protecting groups to give 78 mg of the title compound as a colorless oil.
prostaglandin-^ In Analogie zu Beispiel 25 erhält man aus 610mg 2-{(E)-(1 S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl/-bicyclo-/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol 370 mg der Titelverbindung als farbloses Öl. IR: 3610, 3400 (breit), 2963, 2930,2868,2731,1 630,1602,971/cmprostaglandin In analogy to Example 25, 610 mg of 2 - {(E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4 are obtained -methyl-3- (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl / -bicyclo- / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-ol 370 mg of the Title compound as a colorless oil. IR: 3610, 3400 (wide), 2963, 2930, 2868, 2731, 630, 1692, 971 / cm
(5Z)-(16RSJ-1 a,1 b-dihomo-16,20-dimethyl-5-fluor-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2 In Analogie zu Beispiel 2 erhält man aus 230 mg des nach Beispiel 27 hergestellten Aldehyds 125 mg (5Z)-(16RS)-1a,1b-Dihomo-16,20-dimethyl-5-fluor-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-11,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 85 mg der Titelverbindung als farbloses Öl. IR: 3600, 3410 (breit), 2965, 2930, 2870,1720,1 602, 970/cm(5Z) - (16RSJ-1a, 1b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-12 In analogy to example 2 is obtained from 230 mg of the aldehyde prepared according to Example 27 125 mg (5Z) - (16RS) -1a, 1b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18, 18, 19, 19 tetradehydro-6a-carba-prostaglandin-l 2 -11,15-diacetate, deprotected to give 85 mg of the title compound as a colorless oil, IR: 3600, 3410 (broad), 2965, 2930, 2870, 1720, 1 602 , 970 / cm
(5Z)-2-Descarboxy-1 a,1 b-dihomo-5-fluor-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,1 ß-trimethylen-ea-carbaprostaglandin-l2 In Analogie zu Beispiel 25 erhält man aus 390mg 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylen-non-1-en-6-inyl/-bicyclo-/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol 165mg der Titelverbindung als farbloses Öl. IR: 3600,3410 (breit), 2965,2931,2870,2730,1 630,1 601,970/cm(5Z) -2-Descarboxy-1α, 1β-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,1β-trimethylene-ea -carbaprostaglandin-l 2 In analogy to Example 25, from 390 mg of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R ) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-non-1-en-6-ynyl / -bicyclo- / 3.3.0 / octan-3-ylidene} -2-fluoro-ethane-1 -ol 165mg of the title compound as a colorless oil. IR: 3600.3410 (wide), 2965.2931, 2870, 2730.1, 630.1, 601.970 / cm
In Analogie zu Beispiel 2 erhält man aus 190mg des nach Beispiel 29 hergestellten Aldehyds 105 mg (5Z)-1a,1b-Dihomo-5-fluor-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,1 e-trimethylen-ea-carba-prostaglandin-^-i 1,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 70mg derTitelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2965, 2930, 2870,1 718,1 602, 970/cmIn analogy to Example 2, from 190 mg of the aldehyde prepared according to Example 29, 105 mg of (5Z) -1a, 1b-dihomo-5-fluoro-20-methyl-3-oxa-18,18,19,19-tetradehydro-16 are obtained , 1 e-trimethylene-ea-carba-prostaglandin - ^ - i 1,15-diacetate. Cleavage of the protecting groups gives 70 mg of the title compound as a colorless oil. IR: 3600, 3400 (wide), 2965, 2930, 2870.1, 718.1, 602, 970 / cm
(5Z)-2-Descarboxy-1 a,1 b-dihomo-16,16-dimethyl-5-f luor-2-formyl-3-oxa-18,1 e.^ig-tetradehydro-ea-carba-prostaglandin-la In Analogie zu Beispiel 25 erhält man aus 0,6g 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl/-bicyclo/3.3.0/-octan-3-yliden}-2-fluoräthan-1-ol 0,27g derTitelverbindung als farbloses Öl. IR: 3610, 3420 (breit), 2966, 2930, 2868, 2732,1 730,1 602, 971/cm(5Z) -2-Descarboxy-1α, 1β-dihomo-16,16-dimethyl-5-fluoro-2-formyl-3-oxa-18,1 e ^ -tetrahydehydro-ea-carba prostaglandin In analogy to Example 25, from 0.6 g of 2 - {(Z) - (1 S, 5 S, 6 R, 7 R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3 R) 4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl / bicyclo / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-ol 0 , 27g of the title compound as a colorless oil. IR: 3610, 3420 (wide), 2966, 2930, 2868, 2732.1, 730.1, 602, 971 / cm
(5Z)-1a,1b-Dihomo-16,16-dimethyl-5-fluor-3-oxa-18,18,19, ig-tetradehydro-ea-carba-prostaglandin-lj In Analogie zu Beispiel 2 erhält man aus 220mg des nach Beispiel 31 hergestellten Aldehyds 120mg (5Z)-19,16-Dihomo-16,16-dimethyl-5-fluor-3-oxa-18,18,19,ig-tetradehydro-ea-carba-prostaglandin-^-i 1,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 92 mg derTitelverbindung als farbloses Öl. IR: 3600,3410 (breit), 2964, 2931,2870,1 720,1 601,971/cm(5Z) -1a, 1b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19, ig-tetradehydro-ea-carba-prostaglandin-1 In analogy to Example 2 is obtained from 220 mg of the aldehyde prepared according to Example 31 120 mg (5Z) -19,16-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18,18,19, ig-tetradehydro-ea-carba-prostaglandin - ^ - 1,15-diacetate. Cleavage of the protecting groups yields 92 mg of the title compound as a colorless oil. IR: 3600.3410 (wide), 2964, 2931.2870.1 720.1 601.971 / cm
(5Z)-2-Descarboxy-1 a,1 b-dihomo-5-f luor-2-formyl-3-oxa-l 8,18,19,19-tetradehydro-16,1 e^O-trimethyl-ea-carba-prostaglandin-(5Z) -2-descarboxy-1α, 1β-dihomo-5-fluoro-2-formyl-3-oxa-l 8,18,19,19-tetradehydro-16,1 e ^ O-trimethyl-ea -carba-prostaglandin-
In Analogie zu Beispiel 25 erhält man aus 0,7g 2-{(Z)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(E)-(3R)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl/-bicyclo/3.3.0/-octan-3-yliden}-2-fluor-äthan-1-öl 0,38 g der Titelverbindung als farbloses Öl. IR: 3610,3400 (breit), 2965, 2930, 2870, 2730,1 730,1 601, 970/cmBy analogy with Example 25, 0.7 g of 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (E) - (3R) -4 , 4-dimethyl-3- (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl / bicyclo / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-oil 0 , 38 g of the title compound as a colorless oil. IR: 3610.3400 (wide), 2965, 2930, 2870, 2730.1, 730.1, 601, 970 / cm
In Analogie zu Beispiel 2 erhält man aus 0,3 g des nach Beispiel 33 hergestellten Aldehyds 0,16 g (5Z)-1 a,1 b-Dihomo-5-fluor-3-oxa-18,18,19,19-tetradehydro-16,16-trimethyl-6a-carba-prostaglandin-l2-11,15-diacetat.In analogy to Example 2, from 0.3 g of the aldehyde prepared according to Example 33 there are obtained 0.16 g of (5Z) -1 a, 1 b-dihomo-5-fluoro-3-oxa-18, 18, 19, 19 tetradehydro-16,16-trimethyl-6a-carba-prostaglandin-l 2 -11,15-diacetate.
Nach Abspaltung der Schutzgruppen erhält man 0,12g der Titelverbindung als farbloses Öl.After cleavage of the protective groups, 0.12 g of the title compound is obtained as a colorless oil.
IR: 3610, 3400 (breit), 2 965, 2868,1 720,1 602,971 /cmIR: 3610, 3400 (wide), 2,965, 2868,1 720,1 602,971 / cm
carba-prostaglandin-l2In Analogie zu Beispiel 25 erhält man aus 0,41 g 2-{(Z)-(1 S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-octa-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-5-fluor-äthan-1-ol 0,2g der Titelverbindung als farbloses Öl. IR: 3600, 3410 (breit), 2966, 2731,2224,1 727/cmcarba-prostaglandin-l 2 In analogy to Example 25, 0.41 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / ( 3S, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) -octa-1,6-diinyl / bicyclo / 3.3.0 / octan-3-ylidene} -5-fluoro-ethane-1-ol 0.2 g of the title compound as a colorless oil. IR: 3600, 3410 (wide), 2966, 2731,2224,1 727 / cm
(5Z)-{16RS)-13,14-Didehydro-1a,1 b-dihomo-5-f luor-16-methyl-3-oxa-18,18,19,ig-tetradehydro-ea-carba-prostaglandin-^ In Analogie zu Beispiel 2 erhält man aus 0,2g des nach Beispiel 35 hergestellten Aldehyds.0,1 g (5Z)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-5-f luor-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^-HJS-diacetat. Nach Abspaltung der Schutzgruppen erhält man 70g der Titelverbindung als farbloses Öl. IR: 3620, 3400 (breit), 2965, 2870, 2 225,1 620/cm(5Z) - {16RS) -13,14-didehydro-1a, 1-b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19, ig-tetradehydro-ea-carba-prostaglandin In analogy to Example 2, from 0.2 g of the aldehyde prepared according to Example 35, 0.1 g of (5Z) - (16RS) -13,14-didehydro-1a, 1 b-dihomo-5-fluoro-16 is obtained -methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin - ^ - HJS-diacetate. Cleavage of the protecting groups gives 70 g of the title compound as a colorless oil. IR: 3620, 3400 (wide), 2965, 2870, 2 225.1 620 / cm
(5Z)-(16RS)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-16,20-dimethyl-5-fluor-2-formyl-3-oxa-18,18,19,19-tetradehydro-6acarba-prostaglandin-l;.(5Z) - (16RS) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19,19- tetradehydro-6acarba prostaglandin l ;.
In Analogie zu Beispiel 25 erhält man aus 0,7g 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S,4RS)-4-methyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol 0,38g der Titelverbindung als farbloses Öl. IR: 3600, 3400 (breit), 2968, 2730, 2225,1 728/cmBy analogy with Example 25, 0.7 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S, 4RS) -4-methyl -3- (tetrahydropyran-2-yloxy) -nona-1,6-diynyl / bicyclo / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-ol 0.38g of the title compound as a colorless oil , IR: 3600, 3400 (wide), 2968, 2730, 2225.1 728 / cm
(5Z)-(16RS)-13,14-Didehydro-1 a,1 b-dihomo-16,20-dimethyl-5-f luor-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2In Analogie zu Beispiel 2 erhält man aus 0,35g des nach Beispiel 37 hergestellten Aldehyds 0,18g (5Z)-(16RS)-13,14-Didehydro-1a,1 b-dihomo-16,20-dimethyl-6-fluor-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^-HJö-diacetat. Nach Abspaltung der Schutzgruppen erhält man 0,14g der Titelverbindung als farbloses Öl. IR: 3600, 3420 (breit), 2966, 2870, 2226,1 718/cm(5Z) - (16RS) -13,14-didehydro-1α, 1β-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6α-carba -prostaglandin-l 2 In analogy to Example 2, from 0.35 g of the aldehyde prepared according to Example 37, 0.18 g (5Z) - (16RS) -13,14-didehydro-1a, 1 b-dihomo-16,20- dimethyl-6-fluoro-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin - ^ - H, diacetate. After cleavage of the protective groups, 0.14 g of the title compound is obtained as a colorless oil. IR: 3600, 3420 (wide), 2966, 2870, 2226.1 718 / cm
(5Z)-2-Descarboxy-13,14-didehydro-1a,1b-dihomo-5-fluor-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylen-ea-carba-prostaglandin-lj In Analogie zu Beispiel 25 erhält man aus 1,2g 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3R)-3-(tetrahydropyran-2-yloxy)-4,4-trimethylen-nona-1,6-diinyl/-bicyclo/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol0,7g der Titelverbindung als farbloses(5Z) -2-descarboxy-13,14-didehydro-1a, 1b-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16- trimethylene-ea-carba-prostaglandin-1 In analogy to Example 25, from 1.2 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3R) -3- (tetrahydropyran-2-yloxy) -4,4-trimethylene-nona-1,6-diinyl / bicyclo / 3.3.0 / octan-3-ylidene} -2-fluoro-ethane-1- ol 0.7 g of the title compound as colorless
IR: 3620, 3420 (breit), 2970, 2731, 2224,1 730/cmIR: 3620, 3420 (wide), 2970, 2731, 2224.1 730 / cm
(5Z)-13,14-Didehydro-1 a,1 b-dihomo-S-fluor^O-methyl-S-oxa-i 8,18,19,19-tetradehydro-16,1 e-trimethylen-Sa-carbaprostaglandin-l2 In Analogie zu Beispiel 2 erhält man aus 0,6g des nach Beispiel 39 hergestellten Aldehyds 0,31 g (5Z)-13,14-Didehydro-1a,1bdihomo-5-fluor-20-methyl-3-oxa-18,18,19,19-tetradehydro-16,16-trimethylen-6a-carba-prostaglandin-l2-11,15-diacetat. Nach Abspaltung der Schutzgruppen erhält man 0,25g der Titelverbindung als farbloses Öl. IR: 3620, 3425 (breit), 2968, 2870, 2225,1 720/cm(5Z) -13,14-didehydro-1α, 1β-dihomo-S-fluoro-O-methyl-S-oxa-i 8,18,19,19-tetradehydro-16,1-trimethylene-soda; carbaprostaglandin-l 2 In analogy to Example 2 is obtained from 0.6 g of the aldehyde prepared according to Example 39 0.31 g (5Z) -13,14-didehydro-1a, 1bdihomo-5-fluoro-20-methyl-3-oxa -18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostaglandin-l 2 -11,15-diacetate. After cleavage of the protective groups, 0.25 g of the title compound is obtained as a colorless oil. IR: 3620, 3425 (wide), 2968, 2870, 2225.1 720 / cm
prostaglandin-^In Analogie zu Beispiel 25 erhält man aus 1,4g 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)octa-1,6-dünyl/-bicyclo/3.3.0/octan-3-yliden}-2-fluor-äthan-1-ol 0,65g derTiteiverbindung als farbloses Öl. IR: 3600, 3420 (breit), 2970, 2930, 2865, 2730, 2225,1 730/cmIn analogy to Example 25, from 1.4 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) -4, 4-Dimethyl-3- (tetrahydropyran-2-yloxy) octa-1,6-dinyl / bicyclo / 3.3.0 / octan-3-ylidene} -2-fluoroethane-1-ol 0.65g of the title compound as a colorless Oil. IR: 3600, 3420 (wide), 2970, 2930, 2865, 2730, 2225.1 730 / cm
In Analogie zu Beispiel 2 erhalt man aus 0,4g des nach Beispiel 41 hergestellten Aldehyds 0,22g (5Z)-13,14-Didehydro-1a,1b,-dihomo-16,16-dimethyl-5-f ^0^3-0X8-18,18,19,ig-tetra-dehydro-ea-carba-prostaglandm-lrii^ö-diacetat Nach Abspaltung der Schutzgruppen erhalt man 0,18g der Titelverbindung als farbloses Ol IR 3600, 3420 (breit), 2970, 2870, 2224,1 718/cmIn analogy to Example 2 is obtained from 0.4 g of the aldehyde prepared according to Example 41 0.22g (5Z) -13,14-didehydro-1a, 1b, -dihomo-16,16-dimethyl-5-f ^ 0 ^ 3rd -0X8-18,18,19, ig-tetra-dehydro-ea-carba-prostaglandm-lrii ^ ö-diacetate After cleavage of the protective groups, 0.18 g of the title compound is obtained as a colorless oil IR 3600, 3420 (broad), 2970, 2870, 2224.1 718 / cm
carba-prostaglandin-l2 carba-prostaglandin-l 2
In Analogie zu Beispiel 25 erhalt man aus 0,7g 2-{(Z)-(1S,5S,6S,7R)-7-(Tetrahydropyran-2-yloxy)-6-/(3S)-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-nona-1,6-dnnyl/-bicyclo/3 3 0/octan-3-yliden}-2-fluor-athan-1-ol 0,3g derTitelverbindung als farbloses Ol IR 3600, 3420 (breit), 2968, 2932, 2864, 2730, 2225,1 730/cmIn analogy to Example 25, 0.7 g of 2 - {(Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6 - / (3S) -4,4-dimethyl -3- (tetrahydropyran-2-yloxy) -nona-1,6-dinyl / bicyclo / 3 3 0 / octan-3-ylidene} -2-fluoro-athan-1-ol 0.3g of the title compound as a colorless oil, IR 3600, 3420 (wide), 2968, 2932, 2864, 2730, 2225.1 730 / cm
Beispiel 44 (5Z)-13,14-Didehydro-1a>1b-dihomo-5-fluor-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin-l2 In Analogie zu Beispiel 2 erhalt man aus 0,3g des nach Beispiel 43 hergestellten Aldehyds 0,14g (5Z)-13,14-Didehydro-1a,1b-Example 44 (5Z) -13,14-didehydro-1a > 1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carba-prostaglandin l 2 In analogy to example 2 are obtained from 0.3 g of the aldehyde prepared according to example 43 0.14 g (5Z) -13,14-didehydro-1a, 1b
Nach Abspaltung der Schutzgruppen erhalt man 0,1 g derTitelverbindung als farbloses Ol IR 3605, 3402 (breit), 2970, 2870, 2225,1 720/cmAfter cleavage of the protecting groups, 0.1 g of the title compound is obtained as a colorless oil IR 3605, 3402 (broad), 2970, 2870, 2225.1 720 / cm
Zu einer Losung von 60mg (SEMieRSi-laJb-Dihomo-ie-methyl-S-oxa-IS.ISjgjg-tetradehydro-ea-carba-prostaglandin-^ in 10 ml Dichlormethan tropft man bei O0C bis zur bleibenden Gelbfärbung eine ätherische Diazomethanlosung Nach 5 Minuten wird im Vakuum eingedampft und der Ruckstand an Kieselgel Chromatographien Mit Essigester/Hexan (4 + 1) erhalt man 40mg der Titelverbindung als farbloses Ol IR 3600, 3400 (breit), 2960,1 740, 974/cmTo a solution of 60mg (SEMieRSi-laJb-dihomo-ie-methyl-S-oxa-IS.isjgjg-tetradehydro-ea-carba-prostaglandin ^ in 10 ml of dichloromethane is added dropwise at 0 0 C until the yellowing remains an ethereal Diazomethanlosung After 5 minutes, the residue is evaporated in vacuo and the residue is chromatographed on silica gel With ethyl acetate / hexane (4 + 1), 40 mg of the title compound are obtained as colorless oil IR 3600, 3400 (wide), 2960.1 740, 974 / cm
105mg (5E)-(16RS)-1a,1b-Dihomo-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-^ werden in 3 ml Tetrahydrofuran gelost und bei 00C mit40mgTriathylamin und 45 mg Chlorameisensaureisobutylester versetzt Nach 1 Stunde wird bei O0C 10 Minuten Ammoniakgas eingeleitet, dann 1 Stunde bei 24°C belassen Anschließend wird mit 30ml Wasser verdünnt, dreimal mit je 30 ml Methylenchlorid extrahiert, die vereinigten organischen Extrakte mit 20 ml Sole geschüttelt, über Magnesi jmsulfat getrocknet und im Vakuum eingedampft105 mg (5E) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin are dissolved in 3 ml of tetrahydrofuran and dissolved at 0 0 C mit40mgTriathylamin and 45 mg Chlorameisensaureisobutylester added After 1 hour, is introduced 0 C for 10 minutes, ammonia gas at O, then 1 hour at 24 ° C left is then diluted with 30 ml of water, extracted three times with 30 ml methylene chloride, the combined organic extracts with 20 Ml brine, dried over magnesium sulfate and evaporated in vacuo
Nach Chromatographie des Ruckstandes an Kieselgel mit Methylenchlorid/Isopropanol (9 + 1) erhalt man 78mg der Titelverbindung als OlChromatography of the residue on silica gel with methylene chloride / isopropanol (9 + 1) to obtain 78 mg of the title compound as an oil
IR 3610, 3540,3400 (breit), 2960,1 670, 975/cmIR 3610, 3540.3400 (wide), 2960.1 670, 975 / cm
(5Z)-(16RS)-1a,1b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-(2,3-dihydroxypropyl)-(5Z) - (16RS) -1a, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 - (2,3- dihydroxypropyl) -
195mg (5Z)-(16RS)-1a,1b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,19 tetradehydro-6a-carba-prostaglandin I2 werden in 5ml Aceton gelost und bei 00C mit 60 mg Triathylamin und 75mg Chlorameisensaureisobutylester versetzt Nach 20 Minuten fugt man eine Losung von 260mg 1-Amino-2,3-dihydroxypropan in 8 ml Aceton und 8ml Acetonitril zu und rührt 2 Stunden bei 200C Man engt im Vakuum ein, verdünnt mit Methylenchlorid, schüttelt mit wenig Sole, trocknet die organische Phase mit Magnesiumsulfat und dampft im Vakuum ein Nach Chromatographie des Ruckstandes an Kieseigel erhalt man mit Methylenchlorid/Isopropanol (8 + 2) 160mg derTitelverbindung als farbloses Öl. IR 3600, 3400 (breit), 2935,1 645, 974/cm195mg (5Z) - (16RS) -1a, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin I 2 are dissolved in 5 ml acetone and at 0 0 C with 60 mg of triethylamine and 75mg Chlorameisensaureisobutylester added After 20 minutes, adds a solution of 260 mg of 1-amino-2,3-dihydroxypropane in 8 ml of acetone and 8 ml of acetonitrile and stirred for 2 hours at 20 0 C. the mixture is concentrated in vacuo , diluted with methylene chloride, shaken with a little brine, the organic phase is dried with magnesium sulfate and evaporated in vacuo After chromatography of the residue on silica gel is obtained with methylene chloride / isopropanol (8 + 2) 160mg of the title compound as a colorless oil. IR 3600, 3400 (wide), 2935.1 645, 974 / cm
(5Z)-(16RS)-1a,1b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2-(4-phenylphenacylester(5Z) - (16RS) -1a, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 - (4-phenylphenacyl ester
120mg (5Z)-(16RS)-Ia,1b-Dihomo-5-fluor-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-b werden in 3ml Aceton gelost und mit 90 mg ü)-Brom-4-pheny!acetophenon und 1 ml Triathylamin versetzt und über Nacht bei Raumtemperatur gerührt Man versetzt mit 100 ml Äther, schüttelt zweimal mit je 10 ml Wasser, trocknet über Magnesiumsulfat unddampftim Vakuum ein Die Reinigung erfolgt durch praparative Dunnschichtchromatographie an Kieselgelplatten, die mit Essigester entwickelt werden Man erhalt 128mg derTitelverbindung IR 3610, 2940,1 740,1 703,1 602, 974/cm120mg of (5Z) - (16RS) -la, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,1 g-tetradehydro-ea-carba-prostaglandin-b are dissolved in 3ml of acetone and 90 mg of)) -bromo-4-phenylacetophenone and 1 ml of triethylamine are added and stirred at room temperature overnight. The mixture is mixed with 100 ml of ether, shaken twice with 10 ml of water each time, dried over magnesium sulfate and evaporated in vacuo Preparative Thin Layer Chromatography on Silica Gel Plates Developed with Ethyl Acetate This gives 128 mg of the title compound IR 3610, 2940.1, 740.1, 703.1, 602, 974 / cm
(SEi-deRSl-ia.ib-Dihomo-IS-methyl-S-oxa-ieje.ig.ig-tetradehydro-ea-carba-prostaglandin-^-tns-thydroxymethyl)-aminomethan-salz(SEi-deRSl-ia.ib-dihomo-IS-methyl-S-oxa-ieje.ig.ig-tetradehydro-ea-carba-prostaglandin - ^ - tns thydroxymethyl) aminomethane salt
Zu einer Losung von 185mg (5E)-(16RS)-1a,1b-Dihomo-16 methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2in 35ml Acetonitril fugt man bei 70°C eine Losung von 60mg Tns-(hydroxymethyl)-aminomethan in 0,2ml Wasser Man laßt unter Ruhren abkühlen, dekantiert nach 16 Stunden vom Losungsmittel und trocknet den Ruckstand im Vakuum Man isoliert 160mg der Titelverbindung als wachsartige MasseTo a solution of 185mg (5E) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l 2 in 35ml acetonitrile is added 70 ° C a solution of 60mg Tns- (hydroxymethyl) -aminomethan in 0.2ml water allowed to cool with stirring, decanted after 16 hours from the solvent and the residue is dried in vacuo 160mg of the title compound isolated as a waxy mass
Claims (2)
X ein Wasserstoffatom oder ein Fluoratom,
A einetrans-CH=CH-oder-C=C-Gruppe,
W eine Hydroxymethylengruppe, wobei die OH-Gruppe α- oder ß-ständig sein kann, D dieGruppe -C-CHg- , einegeradkettigeAlkylengruppe mit 1-5C-Atomen odereineMay mean 2,3-dihydroxypropyl,
X is a hydrogen atom or a fluorine atom,
A is a trans-CH = CH or-C = C group,
W is a hydroxymethylene group wherein the OH group may be α- or β-permanently; D is the group -C-CHg-, a straight-chain alkylene group having 1-5C atoms or a group
E eine-C^C-Gruppe oder eine-CH=CH(CH3)-Gruppe bedeuten, R4 eine Alkylgruppe mit 1-7C-Atomen undbranched alkylene group with 2-5 C atoms,
E is a-C ^ C group or a -CH = CH (CH 3 ) group, R 4 is an alkyl group having 1-7C atoms and
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823226550 DE3226550A1 (en) | 1982-07-13 | 1982-07-13 | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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| JP (1) | JPS5921636A (en) |
| AT (1) | ATE67182T1 (en) |
| AU (1) | AU571841B2 (en) |
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| DD (1) | DD210027B3 (en) |
| DE (2) | DE3226550A1 (en) |
| DK (1) | DK163579C (en) |
| ES (1) | ES8403865A1 (en) |
| FI (1) | FI77645C (en) |
| GR (1) | GR78873B (en) |
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| IE (1) | IE57233B1 (en) |
| IL (1) | IL69199A (en) |
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| DE3225287A1 (en) * | 1982-07-02 | 1984-01-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3225288A1 (en) * | 1982-07-02 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| JPS59141536A (en) * | 1983-02-01 | 1984-08-14 | Sumitomo Chem Co Ltd | Novel bicyclooctane derivative and preparation thereof |
| DE3405181A1 (en) * | 1984-02-10 | 1985-08-22 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US4971987A (en) * | 1984-07-27 | 1990-11-20 | Schering Aktiengesellschaft | New carbacycline, process for their production and their use as a drug |
| DE3933523A1 (en) * | 1989-10-05 | 1991-04-11 | Schering Ag | ANTIMETASTICALLY ACTIVE AGENTS |
| EP0431571A3 (en) * | 1989-12-05 | 1992-01-02 | Sagami Chemical Research Center | Cis-bicyclo(4.3.0)non-2-ene derivatives |
| DE4104607A1 (en) * | 1991-02-12 | 1992-08-13 | Schering Ag | PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES |
| CA2382759A1 (en) | 1999-08-05 | 2001-02-15 | Teijin Limited | Agent for the remedy of neural damage having a nitrogen-containing compound as the active ingredient |
| WO2008058766A1 (en) | 2006-11-16 | 2008-05-22 | Bayer Schering Pharma Aktiengesellschaft | Ep2 and ep4 agonists as agents for the treatment of influenza a viral infection |
| EP2488168A1 (en) | 2009-10-14 | 2012-08-22 | Gemmus Pharma Inc. | Combination therapy treatment for viral infections |
| AU2014305843B2 (en) | 2013-08-09 | 2019-08-29 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| US20200368223A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Methods for inhibiting phosphate transport |
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| GB2013661B (en) * | 1978-01-26 | 1982-11-10 | Erba Farmitalia | 9-deoxy-9 -methylene isosteres of pgi2 |
| US4705806A (en) * | 1978-02-13 | 1987-11-10 | Morton Jr Douglas R | Prostacyclin analogs |
| DE3048906A1 (en) * | 1980-12-19 | 1982-07-15 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| IE54303B1 (en) * | 1981-08-19 | 1989-08-16 | Merrell Dow France | Fluorinated diaminoalkene derivatives |
| GR77976B (en) * | 1982-03-12 | 1984-09-25 | Schering Ag | |
| DE3225287A1 (en) * | 1982-07-02 | 1984-01-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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- 1982-07-13 DE DE19823226550 patent/DE3226550A1/en not_active Ceased
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- 1983-07-11 DE DE8383106792T patent/DE3382408D1/en not_active Expired - Lifetime
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- 1983-07-11 GR GR71905A patent/GR78873B/el unknown
- 1983-07-11 AU AU16718/83A patent/AU571841B2/en not_active Ceased
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- 1983-07-12 JP JP58125615A patent/JPS5921636A/en active Granted
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Also Published As
| Publication number | Publication date |
|---|---|
| GR78873B (en) | 1984-10-02 |
| FI77645C (en) | 1989-04-10 |
| EP0099538B1 (en) | 1991-09-11 |
| DK321283A (en) | 1984-01-14 |
| HU191057B (en) | 1986-12-28 |
| ATE67182T1 (en) | 1991-09-15 |
| CS235329B2 (en) | 1985-05-15 |
| NZ204875A (en) | 1986-11-12 |
| DD210027A5 (en) | 1984-05-30 |
| IE57233B1 (en) | 1992-06-17 |
| EP0099538A1 (en) | 1984-02-01 |
| DK163579C (en) | 1992-08-03 |
| JPS5921636A (en) | 1984-02-03 |
| IL69199A (en) | 1987-08-31 |
| ZA835109B (en) | 1984-08-29 |
| FI832557A0 (en) | 1983-07-13 |
| ES524058A0 (en) | 1984-04-16 |
| AU571841B2 (en) | 1988-04-28 |
| ES8403865A1 (en) | 1984-04-16 |
| IL69199A0 (en) | 1983-11-30 |
| PH25119A (en) | 1991-02-19 |
| FI77645B (en) | 1988-12-30 |
| DE3382408D1 (en) | 1991-10-17 |
| SU1316555A3 (en) | 1987-06-07 |
| AU1671883A (en) | 1984-01-19 |
| DK163579B (en) | 1992-03-16 |
| FI832557A (en) | 1984-01-14 |
| DE3226550A1 (en) | 1984-01-19 |
| CA1248525A (en) | 1989-01-10 |
| DK321283D0 (en) | 1983-07-12 |
| JPH0324457B2 (en) | 1991-04-03 |
| IE831630L (en) | 1984-01-13 |
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