DD207901A5 - PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES - Google Patents
PROCESS FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES Download PDFInfo
- Publication number
- DD207901A5 DD207901A5 DD83247723A DD24772383A DD207901A5 DD 207901 A5 DD207901 A5 DD 207901A5 DD 83247723 A DD83247723 A DD 83247723A DD 24772383 A DD24772383 A DD 24772383A DD 207901 A5 DD207901 A5 DD 207901A5
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- bicyclo
- methyl
- tetrahydropyran
- bromo
- title compound
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 230000008569 process Effects 0.000 title claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 43
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 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 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- -1 alkyl radicals Chemical class 0.000 description 30
- 239000012230 colorless oil Substances 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
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- 150000003180 prostaglandins Chemical class 0.000 description 3
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
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- 150000003815 prostacyclins Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000002633 shock therapy Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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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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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4015—Esters of acyclic unsaturated acids
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Abstract
Description
Die vorliegende Erfindung betrifft (5E)-13>14,18*18,19,19-Hexadehydro-öa-oarba-prostaglandln-Ig-derivate, deren physiologisch verträgliche Salze, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutisohe Zusammensetzungen·The present invention relates to (5E) -13> 14,18 * 18,19,19-hexadehydro-o-aa-prostaglandin-Ig derivatives, their physiologically acceptable salts, processes for their preparation and pharmaceutical compositions containing them
In der SiEM)S 2 845 770 werden Carbacyolinderivate der allgemeinen FormelIn the SiEM) S 2 845 770 Carbacyolinderivate the general formula
COOR,COOR,
A-W-D-E-R2 AWDER 2
beansprucht» in derclaimed »in the
E>, Wasserstoff, Alkyl, Cycloalkyl, Aryl oder einenE>, hydrogen, alkyl, cycloalkyl, aryl or a
heterocyclischen Best bedeuten kann, A[ eine -CH2-CH2-J trans-CHsCH- oder -CSG-Gruppe,heterocyclic Best, A [ a -CH 2 -CH 2 -J trans -CHsCH or -CSG group,
2222
W eine freie oder funktionell abgewandelte Hydroxy-W is a free or functionally modified hydroxy
OH : methylengruppe oder c 3OH: methylene group or c 3
eine freie oder funktionell abgewandelte -C- Gruppe, wobei die OH-Gruppe <£-ständig ist, D und E gemeinsam eine direkte Bindung odera free or functionally modified -C group, wherein the OH group < -, D and E together are a direct bond or
7723 77723 7
D ßiiie gerädköttige oder verzweigte gesättigte oder Ungesättigte Alkylengruppemit 1 -^ 1Ö O^Atoinenv ^ die gegebenenfalls durch Fluoratome substituiertAnd (b) the submerged or branched saturated or unsaturated alkylene group containing 1 -> 1-o-oxybenzoyl optionally substituted by fluorine atoms
E eine Sauerstoffatom oder eine -C=C-Bindung oder eine direkte Bindung,E is an oxygen atom or a -C = C bond or a direct bond,
\ . ' : ' ' . . \. ' :''. ,
Rg eine Alkyl-, Cycloalkyl-, oder eine gegebenenfallsRg is an alkyl, cycloalkyl, or an optionally
substituierte Aryl- oder eine heterocyclische Gruppe, " ' .', ." · .. ' /'': ' ' . ', ' . "-.' :,:-. ^ '; .·substituted aryl or heterocyclic group, ''. ', . · .. '/'':''.','."-.' :,: -. ^ '; .
R^ eine freie oder funktionell abgewandelte Hydroxygruppe, und falls R> die Bedeutung eines Wasserstoff atoms hat, deren Salze' mit physiologisch verträglichen Basen bedeuten.R ^ is a free or functionally modified hydroxy group, and if R> has the meaning of a hydrogen atom whose salts mean 'with physiologically compatible bases.
Die Verbindungen besitzen die für Prostacycline typischen Eigenschaften, wie z. B. Senkung des peripheren arteriellen und koronaren vaskuläreh Widerstandes, Inhibierung der Thrombozytenaggregation und Auflösung von Plattchenthromben, myocardiale Zytoprotektion und damit Senkung des systemischen Blutdrucks* ohne zugleich Schlagvolumen und koronare Durchblutung zu senken, Behandlung von Schlaganfall, Prophylaxe und Therapie koronarer Herzerkrankurigen,koronarer Thrombose, des Herzinfarkts, peripherer Arterienerkrankungen, Arteriosklerose und Thrombose, Therapie des Schocks, Inhibierung der Bronchokonstriktion, Inhibierung der Magensäuresekretion, Zytoprotektion der Magen- und Darmschleimhaut, antiallergische Eigenschaften, Senkung des pulmonaren vaskulären Widerstandes und des pulmonaren 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 zerebralen Durchblutung etc. Außerdem besitzen die neuen Prostaglandinanalogä antiproliferative Eigenschaften.The compounds have the properties typical for Prostacycline such. B. Reduction 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 to reduce stroke volume and coronary blood flow, treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, myocardial infarction, peripheral arterial disease, atherosclerosis and thrombosis, shock therapy, bronchoconstriction inhibition, inhibition of gastric acid secretion, gastric and intestinal mucosal cytoprotection, 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 toxics e. Increase in cerebral blood flow, etc. In addition, the new prostaglandin analogues possess antiproliferative properties.
24 77 2 3 724 77 2 3 7
->βν-> βν
$1 854 11 14.7·83$ 1 854 11 14.7 · 83
Unter den in der DK»QS 2 845 770 beanspruchten Verbindungen zeigten die (5E)~13f14,18,1ß,19,19-Hexadehydro-6a-oarbaprostaglandin-I2-VerbIndungen als blutdrucksenkende Mittel und Thrombozyten-aggregationshenimende Mittel derartig herausragende Eigenschaften, daß damit die Dosierung weiter herabgesetzt werden kann» wodurch auch unerwünschte Nebenwirkungen noch stärker zurückgedrängt werden· Die (5E)-13|14,18,18,19, 19-Hexadehydxo-6a-carba-prostaglandin-I2-Verbindungen sind in der D^-OS 2 845 770 nicht namentlich beschrieben. Verbindungen mit A als -GsC-Gruppe werden gegenüber den anderen Verbindungen, in denen A eine -OH2-GH2- oder trena-GHaOH-Gruppe bedeutet, nicht herausgestellt«Among the compounds claimed in DK »QS 2,845,770, the (5E) ~ 13 f 14,18,1β, 19,19-hexadehydro-6a-oarbaprostaglandin I 2 compounds as antihypertensive agents and platelet aggregation-producing agents showed such outstanding Characteristics that the dosage can be further reduced thereby »which also unwanted side effects are pushed back even more · The (5E) -13 | 14,18,18,19,19-hexadehydoxo-6a-carba-prostaglandin-I 2 compounds are in D ^ -OS 2 845 770 not described by name. Compounds with A as a -GsC group are not exposed to the other compounds in which A represents an -OH 2 -GH 2 or trena-GHaOH group. «
Die Nomenklatur der Verbindungen basiert auf einem Vorschlag von Morton und Brokaw (J· Org. Chem· 44, 2280 £^97^7 )· (5E)-6a-0arba-prostaglandin-I2 hat danach folgende Strukturformell . ,-' '. : '; .."' . ;; .- "y _' : ;';;-:\ . '^ i;-:': : ''/' ' ν Ä'^y/^ ...The nomenclature of the compounds is based on a proposal by Morton and Brokaw (J · Org. Chem · 44, 2280 £ ^ 97 ^ 7) * (5E) -6a-0arba-prostaglandin-I 2 then has the following structure Formally. , - ''. : '; .. "'. ;;- " y _ ':;';; - : \. '^ i ; - : ':: '' / '' ν Ä '^ y / ^ ...
OHOH
OHOH
2477 2 3 7 -^- β-,2477 2 3 7 - ^ - β-,
14.7.8314/7/83
Ziel der Erfindung 1st die Bereitstellung von neuen Garbooyollnderlyaten mit höherer Spezlfltät und längerer Wirksamkeit^ · / ; ·..- ; ;';. .' ; : ..... ;..;; '' . :. .. '" The aim of the invention is the provision of new Garbooyollnderlyaten with higher Spezlfltät and longer efficacy ^ · /; · ..-; ; ';. . '; : .....; ..; ''. :. .. '"
Der Erfindung liegt die Aufgabe zugrunde, neue Carbooyclinderlvate mit den gewünsohten Eigenschaften und Verfahren zu Ihrer Herstellung auf zuf Inden·It is an object of the present invention to provide novel carbohydrate derivatives having the desired properties and processes for their preparation.
Erflndungsgemäß werden (5E)-13,14,18,1B,19,19-fiexade0ydro-6a-carba-prostaglandin-I2-Derivate der allgemeinen Formel I hergestellt { '' ^'-li':'- ~'-^\-:'r;.' '-.''. ". ' - ": . :...'-'. According to the invention, (5E) -13,14,18,1B, 19,19-fiexade-hydro-6a-carba-prostaglandin-I 2 derivatives of the general formula I are prepared {'''''-'''''' \ -: 'r ; . ''-.''.".'-" :. : ...'- '.
2477 23 72477 23 7
-sr --sr -
COOHCOOH
worinwherein
R , R , R , R. ein Wasserstoffatom oder eine Alkyl-, .1.2 3 ^R, R, R, R is a hydrogen atom or an alkyl, .1.2 3 ^
gruppe mit 1 - 5 C-Atomen,group with 1-5 C atoms,
R_ eine Alkylgruppe mit 1 - 5 C-Atomen bedeuten,R_ is an alkyl group having 1 to 5 C atoms,
sowie deren Salze mit physiologisch verträglichen -. Basen. " / ' ·' ..- /· / ' : ·.·... .;, .'., . -. ' and their salts with physiologically acceptable. Bases. "/ '·' ..- / · / ' : ·. · ....;,.'.,. -. '
Als Alkylgruppen R' , R_, R-, R· , R1* kommen gerad- und verzweigtkettige Alkylreste mit 1-5 Kohlenstoffatomen in Betracht wie beispielsweise Methyl, Äthyl, Propyl, Butyl, Isopropyl, Isobutyl, Pentyl. Bevorzugte Reste sind Methyl, Äthyl, Propyl und Isopropyl, insbesondere Methyl und Äthyl.Suitable alkyl groups R ', R_, R-, R *, R 1 * are straight-chain and branched-chain alkyl radicals having 1-5 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Preferred radicals are methyl, ethyl, propyl and isopropyl, in particular methyl and ethyl.
Zur Salzbildung sind anorganische und organische Basen geeignet, wie sie dem Fachmann zur Bildung physiologisch verträglicher Salze bekannt sind. Beispielsweise genannt seien Alkalihydroxide, wie Natrium- und Kaliumhydroxid, Erdalkalihydroxid wie Calciumhydroxid, Ammoniak, Amine, wie Äthanolamin, Diäthanolamin, Triäthanolamin, N-Methylglucamin, Morpholin, Tris-(hydröxymethyl)-methylamin usw.For salt formation, inorganic and organic bases are suitable, as are known to those skilled in the formation of physiologically acceptable salts. Examples which may be mentioned are alkali metal hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxide such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
' 7;fr V 1*7.83 ' 7 , for V 1 * 7.83
Pharmakologisca besonders wertvoll sind beispielsweise die folgenden erfindungsgemäß hergestellten Verbindungen«Pharmacologisca particularly valuable are, for example, the following inventively prepared compounds «
dro»6a-oäfba-prostaglandln-X2;dro "6a-oäfba-prostaglandln-X2;
dehydro-6a-oarba-prostaglandtn--l2i ,dehydro-6a-oarba-prostaglandtn - l2i,
C5E)-(16RS)-2O-.Ithyl-.13114^idebydro-16-.methyl-18i18f 19,19-tetradehydro-6a~carba-prostaglandlii~l2i (5B)-13»14-Dldebydro-16f16-dtmethyl-18,18,19t19-tötradehydro-6a~oarba-prostaglandin-*l21 C5E) - (16RS) -2O-ethyl-.13 1 14 ^ idebydro-16-methyl-18 i 18 f 19,19-tetradehydro-6a ~ carba-prostaglandi ~ l2i (5B) -13 »14-dibdebydro -16 f-16 dtmethyl-18,18,19t19-tötradehydro-6a ~ oarba-prostaglandin l2 * 1
(5E)-13 914-Didebydro-18,18,19»19-tetradehydro-16,16t20-trlmethyl-öa-qarha-prostaglandln-i-Igi(5E) -13 9 14-Didebydro-18,18,19 »19-tetradehydro-16,16t20-trlmethyl-δ-qarha-prostaglandin-i-Igi
( 5E) -13,14-Didehydro--18'.t 18,19,19«-tetradehydro-6a-earbaprofltaglandtn-Igi(5E) -13.14-Didehydro - 18 '. t 18,19,19-tetradehydro-6a-earbaprofltagagtn-Igi
(5E) -(16RS)-13,1M)tdebydro-16-metayl-i8,18 f 19,19-tetradehydro~6a-oarba-prostaslandln-I2-tris (hydroxymethyl) -aminome-(5E) - (16RS) -13,1M) tdebydro-16 Metayl i8,18-f 19,19-tetradehydro-6a ~ oarba-prostaslandln-I 2-tris (hydroxymethyl) -aminome-
24 77 2 3 724 77 2 3 7
Die Erfindung betrifft ferner ein Verfahren zur Herstellung der erfindungsgemäßen Prostacyclinderivate der allgemeinen Formel I, dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel II .The invention further relates to a process for the preparation of Prostacyclinderivate invention of the general formula I, characterized in that a compound of general formula II.
(II),(II)
H=CBr-CH C- C C=C-R_H = CBr-CH C-C C = C-R_
= 5= 5
ÖTHP 0THP ÖTHP 0THP
worin R , R-, R-, R., R_ die oben angegebenen Bedeutungen aufweisen und THP den Tetrahydropyranylrest bedeutet mit einem Wittig-Reagenz der Formel IIIwherein R, R, R, R, R_ have the meanings given above and THP is the tetrahydropyranyl radical with a Wittig reagent of the formula III
Ph P=CH-(CH2) -C^ <=> . (III),Ph P = CH- (CH 2 ) -C ^ <=>. (III)
worin Ph eine Phenylgruppe bedeutet, umsetzt und anschließend Isomere trennt, Schutzgruppen abspaltet und gegebenenfalls die Carboxylgruppe mit einer physiologisch verträglichen Base in ein Salz überführt.wherein Ph represents a phenyl group, and then reacts isomers separated, cleaves off protective groups and optionally the carboxyl group with a physiologically acceptable base in a salt.
Die Umsetzung der Verbindung der allgemeinen Formel II mit dem Wittig-Reagenz der Formel III, das man aus dem entsprechenden Phosphoniutnsalz mit Methansulfinylmethylnatrium oder Methansulfinylmethylkalium oder Kalium-tert.-butylat in Dimethylsulfoxid oder Dimethylsulfoxid-Tetrahydrofurangemischen herstellt, wird bei Temperaturen von 0 °C bis 100 C, vorzugsweise 20 °.C bis 60 C, in einem aprotischen Lösungsmittel oderThe reaction of the compound of the general formula II with the Wittig reagent of the formula III, which is prepared from the corresponding Phosphoniutnsalz with Methansulfinylmethylnatrium or Methansulfinylmethylkalium or potassium tert-butoxide in dimethyl sulfoxide or dimethyl sulfoxide-tetrahydrofuran mixtures, at temperatures from 0 ° C to 100 C, preferably 20 ° C to 60 C, in an aprotic solvent or
2477 23 7 -i-2477 23 7 -i
Lösungsmittelgemisch, vorzugsweise Dimethylsulfoxid, Dimethylformamid oder Tetrahydrofuran, vorgenommen. Die Trennung der dabei erhaltenen Z- und E-konfigurierten Olefine erfolgt auf übliche Art, beispielsweise durch Säulen- oder Schichtchromatographie. Bei der vorstehend beschriebenen Wittig-Olefinierung erfolgt gleichzeitig unter Abspaltung von Bromwasserstoff die Bildung der 13,1^-Acetylenbindung·Solvent mixture, preferably dimethyl sulfoxide, dimethylformamide or tetrahydrofuran made. The separation of the Z- and E-configured olefins thus obtained is carried out in the usual way, for example by column or layer chromatography. In the Wittig olefination described above, the formation of the 13,1 ^ -acetylene bond takes place simultaneously with elimination of hydrogen bromide.
Die Schutzgruppenabspaltung wird 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 20 C und 30 C durchgeführt.The deprotection is carried out in an aqueous solution of an organic acid, such as, for example, acetic acid, propionic acid, and the like. or in an aqueous solution of an inorganic acid such as hydrochloric acid. 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 C and 30 C.
Die Carbonsäuren der allgemeinen Formel I 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 Base enthält, nach Abdampfen des Wassers oder nach Zugabe eines mit Wasser mischbaren Lösungsmittels, zürn Beispiel Alkohol oder Aceton, das feste anorganische Salz. Zur Herstellung eines Aminsalzes wird die PG-Säure in einem geeigneten Lösungsmittel, beispielsweise 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 üblicher Weise isoliert.The carboxylic acids of general formula I can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization. For example, when the corresponding acids are dissolved in water containing the stoichiometric amount of 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. To prepare an amine salt, the PG acid is dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. The salt usually accumulates in solid form or is isolated by evaporation of the solvent in a conventional manner.
7723 77723 7
Die als Ausgangsmaterial dienenden Verbindungen der allgemeinen Formel II können beispielsweise hergestellt werden, indem man in an sich bekannter Weise einen Aldehyd der Formel IV (DE-OS 28 45 770)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 IV (German Offenlegungsschrift No. 2,845,770).
(IV)(IV)
oco-OCO
tnit einem Phosphonat der allgemeinen Formel Vwith a phosphonate of the general formula V
O O R1 FOOR 1 F
v Il Il \/-v Il Il \ / -
>P-CH„-C C-> P-CH "-C" C "
CsC-R.CsC-R.
(V)(V)
worin R1 , Rp, R_, R· und R1. die oben angegebenen Bedeutungen aufweisen, in Gegenwart eines Deprotonierungsmittels, wie beispielsweise Natriumhydrid oder Kaliumtert.-butylat und eines Bromierungsmittels, wie beispielsweise N-Bromsuccinimid, zu einem Keton der allgemeinen Formel VI umsetzt.wherein R 1 , Rp, R_, R · and R 1 . have the meanings given above, in the presence of a deprotonating agent such as sodium hydride or potassium tert-butoxide and a brominating agent such as N-bromosuccinimide, to give a ketone of the general formula VI.
OCOOCO
CH=CBr-C —-C C CCH = CBr-C - C C C
(VI)(VI)
24 77 23 724 77 23 7
4c4c
Nach Reduktion der Ketogruppe mit Natriumborhydrid und gegebenenfalls Epimerentrennung, Verseifung der Estergruppe beispielsweise mit Kaliumcarbonat in Methanol und Ketalspaltung/tnit wäßriger Essigsäure sowie gegebenenfalls Epimerentrennung gelangt man zum Keton der allgemeinen Formel VIIAfter reduction of the keto group with sodium borohydride and optionally epimer separation, saponification of the ester group, for example with potassium carbonate in methanol and ketal cleavage / with aqueous acetic acid and optionally epimer separation, the ketone of general formula VII is obtained
(VII)(VII)
CH=CBr-CH-C——— C—-CH = CBr-CH-C --- C--
ÖH OHOH OH
Die Verätherung der Hydroxylgruppen mit Dihydropyran in Gegenwart katalytischer Mengen p-Toluolsulfonsäure liefert die Verbindungen der allgemeinen Formel II.The etherification of the hydroxyl groups with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid provides the compounds of general formula II.
Die Herstellung der Phosphonate der allgemeinen Formel Y erfolgt in an sich bekannter Weise durch Umsetzung eines Alkylhalogenids (herstellbar aus dem entsprechenden Alkohol durch Halogenierung) der allgemeinen Formel VIII-The preparation of the phosphonates of the general formula Y is carried out in a manner known per se by reacting an alkyl halide (preparable from the corresponding alcohol by halogenation) of the general formula VIII-
HaI-C-C=C-R (VIII)Hal-C-C = C-R (VIII)
mit dem aus dem Phosphonat der allgemeinen Formel IX erzeugten Dianions, «with the dianion produced from the phosphonate of general formula IX, "
XP— CH- C-—^C — H (IX) X P - CH - C - ^ C - H (IX)
/ 2 CH 0// 2 CH 0 /
247723 7 -S- 247723 7 -S-
worin R., R„, R-, R. und R. die oben angegebenen Bedeutungen aufweisen.wherein R., R ", R-, R and R have the meanings given above.
Einen weiteren Zugang zu den Phosphonaten der allgemeinen Formel V besteht in der Umsetzung des Anions von Methyl-·; phosphonsauredimethylester mit einem Ester der allgemeinen Formel XAnother access to the phosphonates of the general formula V consists in the reaction of the anion of methyl ·; Phosphonsauredimethylester with an ester of the general formula X.
Ο R R R R.Ο R R R R.
I ^x/2 \3 /k I ^ x / 2 \ 3 / k
C C CSC-R- (X)C C CSC-R- (X)
5 · . · 5 ·. ·
worin R , R0, R-, R^ und R- die oben angegebenen Bedeutungen aufweisen und Rg eine Alkyl gruppe mit 1-5 C-Atomen bedeutet, den man aus dem entsprechenden Malonsäureester durch Alkylierung mit dem Halogenid der allgemeinen Formel VIII und anschließender Decarbalkoxylierung erhalten kann. Der Ester der allgemeinen Formel X ist auch aus der Carbonsäure der allgemeinen Formel XIwherein R, R 0 , R-, R ^ and R- have the meanings given above and Rg is an alkyl group having 1-5 C-atoms, which is obtained from the corresponding malonic acid ester by alkylation with the halide of the general formula VIII and subsequent Decarbalkoxylierung can receive. The ester of the general formula X is also from the carboxylic acid of the general formula XI
0 R1 R0 0 R 1 R 0
Il N^ /2 HO-C C H (XI)Il N ^ / 2 HO-C CH (XI)
worin R und R2 die oben angegebenen Bedeutungen aufweisen durch Alkylierung mit dem Halogenid der allgemeinen Formel VIII und anschließender Veresterung zugänglich.wherein R and R 2 have the meanings given above accessible by alkylation with the halide of the general formula VIII and subsequent esterification.
Die Verbindungen dieser Erfindung wirken blutdrucksenkend und bronchodilatorisch. Sie sind weiterhin geeignet zur , Hemmung der Thrombozyten-Aggregation. Folglich stellen die neuen Prostacyclin-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. ImThe compounds of this invention have hypotensive and bronchodilatory effects. They are also suitable for inhibiting platelet aggregation. Consequently, the new prostacyclin 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. in the
24 7 7 2 3 724 7 7 2 3 7
Vergleich zu PGI„ zeichnen sie sich durch größere Stabilität aus* Die hohe Gewebsspezifität der neuen Prostaglandine zeigt sich bei der Untersuchung an glattmuskulären Organen, wie z. B, am Meerschweinchenileum oder an der isolierten Kaninchentrachea, wo eine wesentlich geringere Stimulation zu beobachten ist als bei der V Applikation natürlicher Prostaglandine vom E-, A- oder F-Typ. ' ' ' " '. .' ' ' ' ... VCompared to PGI "they are characterized by greater stability * The high tissue specificity of the new prostaglandins is evident in the examination of smooth muscle organs, such. B, guinea pigile or isolated rabbit trachea, where significantly less stimulation is observed than with V application of natural E, A or F type prostaglandins. '''"'.''' ... V
Die neuen Carbacyclin-Derivate besitzen die für Prostacycline typischen Eigenschaften, wie z. B. Senkung des peripheren arteriellen und koronaren vaskularen Widerstandes, Inhibierung der Thrombozytenaggregation und Auflösung von Plattchenthromben, myocardiale Zytoprotektion und damit Senkung des systemischen Blutdrucks 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 ischaemischer Attacken , des ZNS-Systems, Therapie des Schocks, Inhibierung der Bronchokonstriktion, Inhibierung der Magensäüresekretion , Zytoprotektion der Magen- und Darmschleimhaut, Zytoprotektion in der Leber und im Pankreas; antiallergische Eigenschaften, Senkung des pulmonaren vaskularen Widerstandes und des pulmonaren Blutdrucks, Förderung der Nierendurchblütung, Anwendung anstelle von Heparin oder als Adjuvans bei der Dialyse der Hämofiltration, Konservierung von Blutplasmakonserven, besonders von Blutplättchenkonserven, Inhibierung von Geburtswehen, Behandlung von Schwangerschaftstoxxkose, Erhöhung der zerebralen Durchblutung etc. Außerdem besitzen die neuen Carbacyclin-Derivate antiproliferative Eigenschaften. Die Carbacycline dieser Erfindung können auch in Kombination, z. B. mit ß-Blockerh oder Diuretika, verwendet werden. ,The new carbacyclin derivatives have the properties typical for Prostacycline, such. B. Reduction of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and resolution of platelet thrombi, myocardial cytoprotection and thus lowering the systemic blood pressure without simultaneously 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 of ischemic attacks, 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 circulation, use instead of heparin or adjuvant in the hemofiltration dialysis, preservation of blood plasma preserves, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxcosis, increase of cerebral blood flow etc. In addition, the new carbacyclin derivatives have antiproliferative properties. The carbocyclines of this invention may also be used in combination, e.g. B. with ß-Blockerh or diuretics used. .
24 77 2 3 724 77 2 3 7
Die Dosis der Verbindungen ist 1 - 1500 /Ug/kg/Tag, wenn sie am menschlichen Patienten verabreicht werden. Die Einheits«. dosis für den pharmazeutischen aksseptablen Träger beträgt 0,01 - 100 mg.The dose of the compounds is 1-1500 / ug / kg / day when administered to the human patient. The unity «. dose for the pharmaceutically acceptable carrier is 0.01-100 mg.
Bei intravenöser Injektion an wachen, hypertonen Ratten in Dosen von 5» 20 und 100 /Ug/kg Körpergewicht zeigen die erfindungsgemäßen Verbindungen eine stärkere blutdrucksenkende und länger anhaltende Wirkung als PGrE2 und PGA2, ohne wie PGE2 Durchfälle oder PGA2 kardiale Arrhythmien auszulösen.When injected intravenously in awake, hypertonic rats in doses of 5 »20 and 100 / Ug / kg body weight of the compounds of the invention exhibit a stronger hypotensive and longer lasting effect than PGrE 2 and PGA 2, without 2 diarrhea or PGA trigger as PGE 2 cardiac arrhythmias ,
Bei intravenöser Injektion an narkotisierten Kaninchen zeigen die erfindungsgemäßen Verbindungen im Vergleioh 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 show in comparison to PGE 2 and PGA 2 a stronger and significantly longer-lasting blood pressure reduction, without affecting other smooth muscle organs or organ functions.
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 Erfindung betrifft damit auch Arzneimittel auf Basis der Verbindungen der allgemeinen Formel I und üblicher Hilf3- und Trägerstoffe.The invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and excipients.
Die erfindungsgemäßen Wirkstoffe sollen in Verbindung mit den in der Galenik bekannten und üblichen Hilfsstoffen z. B. zur Herstellung von Blutdruoksenkern dienen.The active compounds according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenics, for. B. serve to produce Blutdruoksenkern.
Die Erfindung sird nachstehend an einigen Beispielen näher erläutert.The invention will be explained in more detail below with reference to some examples.
2477 23 72477 23 7
Beispiel 1 ' Example 1 '
(5E)-(16RS)-13,14-Didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2 (5E) - (16RS) -13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I 2
Zu einer Lösung von 9,4g 4-Carboxybutyltriphenylphosphoniumbromid in 20 ml Dimethylsulfoxid und 7,δ ml Tetrahydrofuran fügt man bei 5 C innerhalb von 45 Minuten 4,75 g Kalium-tert.-butylat und rührt 45 Minuten bei 5 °C nach. Zur roten Ylenlösung fügt man eine Lösung von 1,83 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-/13S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl7-bicyclo/3·3»07octan-3-on in 3 ml Tetrahydrofuran und rührt k Stunden bei kO C. Das Reaktionsgemisch wird auf Eiswasser gegossen, mit 35 %iger Zitronensäurelösung auf pH 4-5 angesäuert und dreima'l mit Methylenchlorid extrahiert. Die organische Phase wird mit Sole geschüttelt, über Magnesiumsulfat getrocknet und im Vakuum eingedampft. Den Rückstand reinigt man durch Chromatographie an Kieselgel Mit Hexan/Essigester (3 + 2) erhält man zunächst 18.0 mg des 5Z-konfigurierten Olefins sowie als polarere Komponente 680 mg (5E)-(16RS)-13,14-Didehydro-16-methyl-18,18,19,19-tetradehydro-oa-carba-prostaglandin-Ig-i1 j 15-t>is-(tetrahydro-pyranyläther) als farbloses 01. IR(CHCl ): 3500 (breit), 2940, 2860, 2225, 1710, i44O/cm.To a solution of 9.4 g of 4-carboxybutyltriphenylphosphonium bromide in 20 ml of dimethyl sulfoxide and 7, δ ml of tetrahydrofuran is added at 5 C within 45 minutes 4.75 g of potassium tert-butoxide and stirred for 45 minutes at 5 ° C after. To the red solution of Ylen is added a solution of 1.83 g (IR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / 13S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-7-bicyclo / 3 · 3 »07octan-3-one in 3 ml of tetrahydrofuran and stirred for k hours at kO C. The reaction mixture is poured onto ice water, with 35 % citric acid solution acidified to pH 4-5 and dreima'l extracted with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel. Hexane / ethyl acetate (3 + 2) initially gives 18.0 mg of the 5Z-configured olefin and, as the more polar component, 680 mg (5E) - (16RS) -13,14-didehydro-16-methyl -18,18,19,19-tetradehydro-oa-carba-prostaglandin-Ig-i1 j 15-t> is- (tetrahydropyranyl ether) as colorless 01. IR (CH 2 Cl 2): 3500 (wide), 2940, 2860, 2225, 1710, i44O / cm.
Zur Schutzgruppenabspaltung rührt man 680 mg des vorstehend erhaltenen Olefinierungsprodukts mit 25 ml einer Mischung aus Essigsäure/Wasser/Tetrahydrofuran (65/35/IO) 20 Stunden bei 25 C. Anschließend dampft man im Vakuum ein und chromatographiert den Rückstand an Kieselgel. Mit Essigester/ Essigsäure (99,9 + 0,1) erhält man 345 mg der Titelverbindung als farbloses Öl. ' IR: 36OO, 3400 (breit), 2930, 2225, 1710, 16Ο3, 1020/cm.For deprotection, 680 mg of the olefination product obtained above are stirred with 25 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) for 20 hours at 25 ° C. Subsequently, the mixture is evaporated in vacuo and the residue is chromatographed on silica gel. With ethyl acetate / acetic acid (99.9 + 0.1) gives 345 mg of the title compound as a colorless oil. 'IR: 3600, 3400 (wide), 2930, 2225, 1710, 16Ο3, 1020 / cm.
77 2 3 7 -β- 77 2 3 7 -β-
Dag Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:Dag starting material for the above title compound is prepared as follows:
a) (iR,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-/riiRS)-2-brom-^-methyl-3-oxo-oct-1-en-6-inyl7-bicyclo/3»3«07 octana) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / i- iRS) -2-bromo-1-methyl-3-oxo-oct-1-ene-6 inyl-7-bicyclo / 3 »3« 07 octane
Zu einer Suspension von 1,81 g Natriumhydrid in 1 80 ml Dimethoxyäthan tropft man bei 0 C eine Lösung von 10,5 g 3-Methyl-2-oxo-hept-5-in-phosphonsäuredimeithylester in 70 ml Dimethoxyäthan, rührt 1 Stunde bei 0 C und fügt dann 7,^ g fein gepulvertes N-Bromsuccinimid hinzu. Man rührt 30 Minuten bei 0 C, versetzt mit einer Lösung aus 11,4 g (1R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-formyl-bicyclo/3·3«07-octan in 90 ml Dimethoxyäthan und rührt 2 Stunden bei 0 C, Das Reaktionsgemisch gießt man auf gesättigte Ammonium chloridlösung und extrahiert" mit Äther. Man wäscht den organischen Extrakt mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstands an Kieselgel erhält man mit Hexan/Äther (3 + 2) 8,2 g des ungesättigten Ketone als farbloses Öl.To a suspension of 1.81 g of sodium hydride in 1 80 ml of dimethoxyethane is added dropwise at 0 C, a solution of 10.5 g of 3-methyl-2-oxo-hept-5-yn-phosphonsäuredime i methyl ester in 70 ml Dimethoxyäthan, stirred Hour at 0 C and then added 7, ^ g finely powdered N-bromosuccinimide. The mixture is stirred for 30 minutes at 0 C, treated with a solution of 11.4 g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 · 3 07-octane in 90 ml of dimethoxyethane and stirred for 2 hours at 0 C. The reaction mixture is poured into saturated ammonium chloride solution and extracted with ether The organic extract is washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in vacuo After chromatography of the residue on silica gel With hexane / ether (3 + 2), 8.2 g of the unsaturated ketone are obtained as a colorless oil.
IR: 2930, 2880, 1712, 1688, 16O2, 1595, 1^50, 1275, 945/cm.IR: 2930, 2880, 1712, 1688, 16O2, 1595, 1 ^ 50, 1275, 945 / cm.
b) ( iR,5S,6R,7R)-7-Hydroxy-6-/r3S,4tRS)-2-brom-3-hydroxy-b) (iR, 5S, 6R, 7R) -7-hydroxy-6- / r3S, 4tRS) -2-bromo-3-hydroxy
^·3.07octan-3-on^ · 3.07octan-3-one
Zu einer Lösung von 5,9 g des nach Beispiel 1 a) hergestellten Ketons in 1^0 ml Methanol fügt man bei -^O 0G portionsweise 2,5 g Natriumborhydrid und rührt 30 Minuten bei -Ί0 C. Anschließend verdünnt man mit Äther, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein.To a solution of 5.9 g of the ketone prepared according to Example 1 a) in 1 ^ 0 ml of methanol are added at - portionwise 2.5 g of sodium borohydride ^ O 0 G and stirred for 30 minutes at -Ί0 C. Then it is diluted with ether , washed neutral with water, dried over magnesium sulfate and evaporated in vacuo.
2477 23 72477 23 7
Das Rohprodukt (15-Epimerengemisch) löst man in 200 ml. Methanol, fügt ,2,5 g Kaliumcarbonat zu und rührt 17 Stunden bei 23 C 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.The crude product (15-Epimerengemisch) is dissolved in 200 ml. Methanol, added, 2.5 g of potassium carbonate and stirred for 17 hours at 23 C under argon. Then concentrated in vacuo, diluted with ether and washed with brine neutral. It is dried over magnesium sulfate and evaporated in vacuo.
Den Eindampfrückstand rührt man 16 Stunden bei Raumtemperatur mit 300 ml einer Mischung aus Essigsäure/ Wasser/Tetrahydrqfuran (65/35/10) und dampft anschließend im Vakuum ein. Durch Säulenchromatographie an Kieselgel mit Äther/Methylenchlorid erhält man zunächst 1,6 g des 15ß-konfigurierten Alkohols sowie als polarere Komponente 2,1 g der Titelverbindung (pG-Nomenklatur 15a-Hydroxy) als farblose,Öle. IR: 3600, 3^30 (breit), 296O, 2920, 2870,1738, 1 6OO, l^OO/cm. .The evaporation residue is stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid / water / tetrahydrqfuran (65/35/10) and then evaporated in vacuo. Column chromatography on silica gel with ether / methylene chloride initially gives 1.6 g of the 15β-configured alcohol and, as the more polar component, 2.1 g of the title compound (pG nomenclature 15a-hydroxy) as colorless oils. IR: 3600, 3 ^ 30 (broad), 296O, 2920, 2870, 1738, 1 6OO, 1 OO / cm. ,
c) (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-/T3S,^RS) 2-brom-''i-methyl-3-(tetrahydropyran-2-yloxy)-oct-1 -en-6-inyl7-bicyclo/3·3«07octan-3-onc) (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / T3S, ^ RS) 2-bromo - '' i-methyl-3- (tetrahydropyran-2-yloxy) - oct-1-ene-6-ynyl-7-bicyclo / 3x3 -7octan-3-one
Eine Lösung aus 1,6 g des nach Beispiel 1 b) hergestellten α-Alkohols, 16 mg p-Toluolsulforisäure und 1,5 g Dihydropyran in 50 ml Methylenchlorid rührt man 35 Minuten bei 0 C. Anschließend verdünnt man mit Äther, schüttelt mit verdünnter Natriumbicarbonat-Lösung, wäscht mit Wasser neutral, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Chromatographie des Rückstands an Kieselgel erhält, man mit Hexan/Äther (7+3) 2,17 g der Titelverbindung als farbloses ÖlA solution of 1.6 g of the α-alcohol prepared according to Example 1 b), 16 mg of p-Toluolsulforisäure and 1.5 g of dihydropyran in 50 ml of methylene chloride is stirred for 35 minutes at 0 C. Then diluted with ether, shaking with dilute Sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel gives, with hexane / ether (7 + 3) 2.17 g of the title compound as a colorless oil
-IR: .2940, 287O, 1735, 1450, 1120, IO18, 965/cm. -IR: .2940, 287O, 1735, 1450, 1120, IO18, 965 / cm.
247723 7 -4- 247723 7 -4-
( 5E) - (16RS) -1 3,1 *t~Didehydro-16 ,20-dimethyl-1 8,1 8,19,19-tetradehydro-oa-carba-prostaglandin-I,,(5E) - (16RS) -1 3.1 * t ~ didehydro-16, 20-dimethyl-1 8,1 8,19,19-tetradehydro-oa-carba-prostaglandin-I,
In Analogie zu Beispiel 1 erhält man aus 1,6 g (iR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/r3S,ilRS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl7-bicyclo/3.3.07octan-3-on 6^0 mg (5E)-(16RS)-13,1 *i-Didehydro-i6,20-dimethyl-i8,i8,19,19-tetradehydro-6acarba-prostaglandin~Io-11,15-bis-(tetrahydro-pyranylather)In analogy to Example 1, 1.6 g of (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / r3S, i- lRS) -2-bromo-4-methyl-3 are obtained - (tetrahydropyran-2-yloxy) -non-1-en-6-ynyl-7-bicyclo / 3.3.07octan-3-one 6 ^ 0 mg (5E) - (16RS) -13,1 * i-didehydro-i6, 20-dimethyl-i8, i8,19,19-tetradehydro-6acarba-prostaglandin ~ I o -11,15-bis (tetrahydropyranyl ether)
im» , in the" ,
als farbloses Öl. J as a colorless oil. J
IR: 3500 (breit), 29^2, 2860, 222Ί, 1710/cm.IR: 3500 (wide), 29 ^ 2, 2860, 222Ί, 1710 / cm.
Nach Abspaltung der Schutzgruppen gemäß Beispiel 1 erhält man 0,3 g der Titelverbindung als farbloses ÖL·. IR: 3600, 3350 (breit), 2932, 222*1, 1710, i6O2/cm.After cleavage of the protective groups according to Example 1, 0.3 g of the title compound are obtained as a colorless oil. IR: 3600, 3350 (wide), 2932, 222 * 1, 1710, i6O2 / cm.
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
a) (iR,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-/t/tRS,2-brom-^-methyl-3-oxo-non-1-en-o-inylZ-bicyclo/^.3·θ7 octana) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / t / tRS, 2-bromo-1-methyl-3-oxo-non-1-en-o-inylZ -bicyclo / ^. 3 · θ7 octane
In Analogie zu Beispiel la) erhält man aus 6 g 3-Methyl-2-oxo-oct-5-inyl-phosphonsäure-dimethylester 3,7 g N-Bromsuccinimid und 5,6 g (1R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-formyl-bicyclo/3·3.07octan Ί,Ο g des ungesättigten Ketons als farbloses Öl.In analogy to Example la), 3.7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) are obtained from 6 g of dimethyl 3-methyl-2-oxo-oct-5-ynylphosphonate. 3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 · 3.07octane Ί, Ο g of the unsaturated ketone as a colorless oil.
IR: 2935, 2883, 1713, 1687, 16O2, 1596, 1275, 9**7/cm„IR: 2935, 2883, 1713, 1687, 16O2, 1596, 1275, 9 ** 7 / cm "
b) (1R,5S,6R,7R)-7-Hydroxy-6-/r 3S,^RS)-2-brom-3-hydroxyk-methyl-non-1-en-6-inyl7-bicyclo/3·3·θ7octan-3-onb) (1R, 5S, 6R, 7R) -7-hydroxy-6- / 3S, ^ RS) -2-bromo-3-hydroxy k -methyl-non-1-en-6-ynyl-7-bicyclo / 3 · 3 · θ7octan-3-one
In Analogie zu Beispiel 1b) erhält man aus 3 g des nach Beispiel 2 a) hergestellten Ketons nach Reduktion mit 1,3 g Natriumborhydrid, Verseifung mit 1,2 g Kaliumkarbonat und anschließender Ketal spaltung mit I5O ml einer Mischung aus Essigsäure/Wasser/Tetrahydrofuran 1,2 g der Titelverbindung ( 15<x-Hydroxy) als farbloses Öl, IR: 361Ο, 3*i00 (breit), 296O1 2870, 1739, i600/cm.In analogy to Example 1b) obtained from 3 g of the ketone prepared according to Example 2 a) after reduction with 1.3 g of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent Ketal cleavage with I5O ml of a mixture of acetic acid / water / tetrahydrofuran 1.2 g of the title compound (15 <x-hydroxy) as a colorless oil, IR: 361Ο, 3 * i00 (broad), 296O 1 2870, 1739, i600 / cm.
2477 2 3 72477 2 3 7
c) (iR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-/r3St^RS)-2»brom-4-raethyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl7-bicyclo/3·3«o7octan-3-on 'c) (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- / r3S t ^ RS) -2-bromo-4-ethyl-3- (tetrahydropyran-2-yloxy) -none 1-en-6-ynyl-7-bicyclo / 3x3 "octoctan-3-one"
In Analogie zu Beispiel 1 c) erhält man aus 0,78 g des nach Beispiel 2b) hergestellten Diols und 0,7 g Dihydropyran 1,1 g der Titelverbindung als farbloses Öl. IR: 2940, 2872, 1736, 1450, 1120, 965/cm.In analogy to Example 1 c), from 0.78 g of the diol prepared according to Example 2b) and 0.7 g of dihydropyran 1.1 g of the title compound as a colorless oil. IR: 2940, 2872, 1736, 1450, 1120, 965 / cm.
(5E) - (1 6RS)-20-Äthyl-1 3, 14-didehydro-16-methyl- 18,1 8,1 9,19-tetradehydro-6a-carba-prostaglandin-Ip(5E) - (1 6RS) -20-ethyl-1 3, 14-didehydro-16-methyl-18,1,8,1,19,19-tetradehydro-6a-carba-prostaglandin-Ip
In Analogie zu Beispiel 1 erhält man aus 2 g (1R,5S,6R,7R) 7-(Tetrahydropyran-2-yloxy)-6-/Γ3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2ryloxy)-dec-1-en-6-inyl7-bicyclo/3·3·θ7-octan-3-on 900 mg (5E)-(16RS)-20-Äthyl-13,14-didehydro-16-methyl-18,18,19 »19-tetradehydro-6a-carba-prostagl_andin-I2-11,15-bis-(tetrahydropyranyläther) als farbloses Öl. IR: 35OO (breit), 2948, 2862, 2220, 1708/cm.In analogy to Example 1, from 2 g (1R, 5S, 6R, 7R) of 7- (tetrahydropyran-2-yloxy) -6- / Γ3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran- 2ryloxy) -dec-1-en-6-ynyl-7-bicyclo / 3x3x7-octan-3-one 900 mg (5E) - (16RS) -20-ethyl-13,14-didehydro-16-methyl- 18,18,19 "19-tetradehydro-6a-carba-prostagl_andin-I 2 -11,15-bis (tetrahydropyranyl ether) as a colorless oil. IR: 3500 (wide), 2948, 2862, 2220, 1708 / cm.
Nach Abspaltung der Schutzgruppen gemäß Beispiel 1 erhält man 420 mg der Titelverbindung als farbloses Öl. IR:. 3.6.00, 336Ο (breit), 2930, 2858, 2220, 17Ο8, i60i/cm.After removal of the protective groups according to Example 1, 420 mg of the title compound are obtained as a colorless oil. IR :. 3.6.00, 336Ο (wide), 2930, 2858, 2220, 17Ο8, i60i / cm.
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
a) (iR,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-/t4RS)-2-brotn-4-methyl-3-0x0-dec-^1-en-6-inyl7bicyclo/3· 3·θ7 octan ,a) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- / t4RS) -2-bromo-4-methyl-3-oxo-dec-1-en-6-ynyl-7-bicyclo / 3 · 3 · θ7 octane,
In Analogie zu Beispiel 1 a) erhält man aus 6,25 g 3-Methyl-2-oxo-non-5-inyl-phosphonsäure-dimethylester, 3,7 g N-Bromsuccinimid und 5,6 g (1R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoy.loxy-6-formyl-bicyclo/3.3.07octan 4,5 g des ungesättigten Ketons als farbloses Öl. IR: 2940, 288Ο, 1712, 1688, 1601, 1592, 1275» 948/cm.In analogy to Example 1 a) is obtained from 6.25 g of 3-methyl-2-oxo-non-5-ynyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R , 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3.3.07octane 4.5 g of the unsaturated ketone as a colorless oil. IR: 2940, 288Ο, 1712, 1688, 1601, 1592, 1275 »948 / cm.
247723 7 ' .£.. 247723 7 '. £.
b) (iR,5S,6R,7R)-7-Hydroxy-6-/r3S,ilRS)-2-brom-3-hydroxy 4-methyl-dec-i-en-ö-iny^-bicyclo/;?. 3«9.7octan-3-onb) (iR, 5S, 6R, 7R) -7-hydroxy-6- / 3S, i- lRS) -2-bromo-3-hydroxy 4-methyl-dec-1-en-6-ynylbicyclo; ?. 3 "9.7octan-3-one
In Analogie zu Beispiel 1 b) erhält man aus k g der nach Beispiel 3 a) hergestellten Ketons nach Reduktion mit Natriuraborhydrid, Verseifung mit Kaliumcarbonat und anschließender Ketalspaltung mit Essigsäure/Wasser/ Tetrahydrofuran (65/35/10) 1,5 g der Titelverbindung ( 15o£r-Hydroxy) als farbloses ÖlIn analogy to Example 1 b) is obtained from k g of the prepared according to Example 3 a) ketone after reduction with Natriuraborhydrid, saponification with potassium carbonate and subsequent Ketalspaltung with acetic acid / water / tetrahydrofuran (65/35/10) 1.5 g of the title compound (15o r-hydroxy) as a colorless oil
IR: 361Ο, 3400 (breit), 2955, 2868, 1738, 1601/ctn. IR: 361Ο, 3400 (wide), 2955, 2868, 1738, 1601 / ctn.
c) (iR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy-6-/r3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-dec-1-en-6-inyl7-bicyclo/3·3»07octan-3-onc) (iR, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy-6 / r3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -dec-1 -en-6-inyl7-bicyclo / 3 x 3 "07octan-3-one
In Analogie zu Beispiel 1 c) erhält man aus 1,2 g des nach Beispiel 3 b) hergestellten Diols 1,8i g der Titelverbindung als farbloses Öl. IR: 29^2, 2868, 1738, 1^50, 1125, 960/cm.In analogy to Example 1 c) obtained from 1.2 g of the diol prepared according to Example 3 b) 1.8 g of the title compound as a colorless oil. IR: 29 ^ 2, 2868, 1738, 1 ^ 50, 1125, 960 / cm.
d) 3-Methyl-2-oxo-non-5-inyl-phosphonsäure-dimethylesterd) 3-methyl-2-oxo-non-5-ynyl-phosphonic acid dimethyl ester
Zu einer Lösung von 15»8 g Natrium in 340 ml Äthylalkohol tropft man bei 20 C 120 g Methylmalonsäurediäthylester. Nach 30 Minuten tropft man 135 g 1-Brom-2-hexin (hergestellt aus Hex-2-in-1-öl mit Phosphortribrotnid in Pyridin) zu und erhitzt 16 Stunden unter Rückfluß. Anschließend filtriert man, wäscht den Rückstand mit Methylenchlorid und engt im Vakuum ein. Den Rückstand löst man in 500 ml Methylenchlorid, schüttelt zweimal mit je 50 ml Wasser, trocknet über Magnesiumsulfat und engt im Vakuum ein. Den Rückstand destilliert man im Vakuum bei 1k Torr und 148 - 152 °C. Man erhält als Destil des alkylierten Methylmalonsäureesters, den man in 1200 ml Dimethylsulfoxid und 12 ml Wasser mit 52 g Lithiumchlorid 4,5 Stunden unter Rückfluß erhitzt. Anschließend gießt man auf 5 1 Eiswasser, extrahiert mit Äther, schüttelt den Extrakt mit Wasser, trocknet über Magnesiumsulfat und engt im Vakuum ein.To a solution of 15 8 g of sodium in 340 ml of ethyl alcohol is added dropwise at 20 C 120 g Methylmalonsäurediäthylester. After 30 minutes, added dropwise 135 g of 1-bromo-2-hexyne (prepared from hex-2-in-1 oil with phosphorus tribrotnide in pyridine) and heated under reflux for 16 hours. Then filtered, the residue is washed with methylene chloride and concentrated in vacuo. The residue is dissolved in 500 ml of methylene chloride, shaken twice with 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is distilled in vacuo at 1 k Torr and 148 - 152 ° C. The distillates of the alkylated methylmalonic acid ester are refluxed for 4.5 hours in 1200 ml of dimethyl sulphoxide and 12 ml of water with 52 g of lithium chloride. It is then poured into 5 1 of ice water, extracted with ether, the extract is extracted with water, dried over magnesium sulfate and concentrated in vacuo.
2477 2 3 72477 2 3 7
Die Destillation des Rückstandes liefert bei 94 -96 C und 14 Torr 95 g 2-Methyl-oct-4-insäureäthylester als farblose Flüssigkeit.The distillation of the residue provides at 94-96 C and 14 Torr 95 g of 2-methyl-oct-4-cyanate as a colorless liquid.
Zu einer Lösung von 176 g Methanphosphonsäuredimethylester in 2 1 Tetrahydrofuran tropft man 640 ml einer 1,5 M Butyllithiumlösung in Hexan bei -70 °C. Nach 15 Minuten fügt man langsam eine Lösung von 90 g 2-Methyl-oct-4-insäureäthylester in 300 ml Tetrahydrofuran zu. Man rührt 4 Stunden bei -70 C, neutralisiert mit Essigsäure und dampft im Vakuum ein. Man versetzt den Rückstand mit 200 ml Wasser, extrahiert dreimal mit je 500 ml Methylenchlorid, schüttelt den Extrakt mit 100 ml Wasser, trocknet über Magnesiumsulfat und engt im Vakuum ein;. Die Destillation des Rückstandes liefert bei 0,35 Torr und 126 - 128 0C 80 g der Titelverbindung als farblose Flüssigkeit.640 ml of a 1.5 M butyllithium solution in hexane are added dropwise at -70 ° C. to a solution of 176 g of dimethyl methanephosphonate in 2 l of tetrahydrofuran. After 15 minutes, slowly add a solution of 90 g of ethyl 2-methyl-oct-4-amino acid in 300 ml of tetrahydrofuran. The mixture is stirred for 4 hours at -70 C, neutralized with acetic acid and evaporated in vacuo. The residue is combined with 200 ml of water, extracted three times with 500 ml of methylene chloride each time, the extract is extracted by shaking with 100 ml of water, dried over magnesium sulphate and concentrated in vacuo. Distillation of the residue at 0.35 Torr and yields 126 to 128 0 C. 80 g of the title compound as a colorless liquid.
3eispiel 4Example 4
(5E)-13,14-Didehydro-16,16-dimethyl-18,18,19,19-tetradehydro-öa-carba-prostaglandin-I«(5E) -13,14-didehydro-16,16-dimethyl-18,18,19,19-tetradehydro-öa-carba-prostaglandin-I "
In Analogie zu Beispiel 1 erhält man aus 1,5 g (1R,5S,6R, 7-(Tetrahydropyran-2-yloxy)-6-/r3S)-2-brom-4,4-dimethyl-3 (tetrahydropyran-2-yloxy)-oct-1-en-ö-inylZ-bicyclo/^·3·θ7 octan-3-on 610 trig (5E)-13,14-Didehydro-16,16-dimethyl-1.8,18,19,19-teträdehydro-6a-carba-prostaglandin-Io-11,15-bis-(tetrahydropyran-2-yläther) als farbloses Öl. IR: 35OÖ (breit), 2944, 2862, 2222, 17O3/cm.In analogy to Example 1 is obtained from 1.5 g (1R, 5S, 6R, 7- (tetrahydropyran-2-yloxy) -6- / r3S) -2-bromo-4,4-dimethyl-3 (tetrahydropyran-2 -yloxy) -oct-1-en-6-ynylZ-bicyclo / ·3 3θ7octan-3-one 610 trig (5E) -13,14-didehydro-16,16-dimethyl-1,8,18,19, 19-tetradehydro-6a-carba-prostaglandin-I o -11,15-bis- (tetrahydropyran-2-yl-ether) as a colorless oil. IR: 35OÖ (wide), 2944, 2862, 2222, 17O3 / cm.
Nach Abspaltung der Schutzgruppen gemäß Beispiel 1 erhält man 290 mg der Titelverbindung als farbloses Öl. IR: 36ΟΟ, 34ΟΟ (breit), 293O, 2862, 1708, i600/cm.After removal of the protective groups according to Example 1, 290 mg of the title compound are obtained as a colorless oil. IR: 36ΟΟ, 34ΟΟ (wide), 293o, 2862, 1708, i600 / cm.
477 2 3 7477 2 3 7
a) (1R,5S,β«,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-(2-bromzl,%-dimethyl-3-oxo-oct-1-en-6-inyl)-bicyclo/3.3.07- oc tana) (1R, 5S, β ", 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- (2-bromo z l,% -dimethyl-3-oxo-oct-1-en-6-ynyl) -bicyclo / 3.3.07- oc tan
In Analogie zu Beispiel 1 a) erhält man aus 6,25 g 3, 3"-Dimeth.yi-2-oxo-hept -5-in-phosphonsäuredimethylester 3,7 g N-Brotnsuccinimid und 5,6 g (1R1SS1OR^R)-3,3-Äthylendioxy-7-benzoyloxy-6-fΌrmyl-bicyclo/3·3·θ7-octan 4,7 g des ungesättigten Ketons als farbloses Öl. IR: 2940, 2878, 17IO, 1688, 16Ο2, 1594, 1448, 127Ο, 944/cm.In analogy to Example 1 a) is obtained from 6.25 g of 3, 3 "-Dimeth.yi-2-oxo-hept -5-in-phosphonic acid dimethyl ester, 3.7 g of N-Brotnsuccinimid and 5.6 g (1R 1 SS 1 OR 4 R -3,3-ethylenedioxy-7-benzoyloxy-6-fluoryl-bicyclo / 3x3x7-octane 4.7 g of the unsaturated ketone as a colorless oil IR: 2940, 2878, 1710, 1688 16Ο2, 1594, 1448, 127Ο, 944 / cm.
b) ( iR,5S,6R,7R)-7-Hydroxy-6-/r3S)-2-brom-'t,4-dimethyl-3-< hydroxy-oct-1-en-6-inyl7-bicyclo/3·3»07octan-3-onb) (iR, 5S, 6R, 7R) -7-hydroxy-6- / r3S) -2-bromo-'t, 4-dimethyl-3- <hydroxy-oct-1-en-6-ynyl-7-bicyclo / 3 x 3 "07octan-3-one
In Analogie zu Beispiel 1 b) erhält man aus 4 g des nach Beispiel 4 a) hergestellten Ketons nach Reduktion mit Natriumborhydrid, Verseifung mit Kaliumcarbonat und anschließender Ketalspaltung 1 ,40 g der Titelverbindung (15a-Hydroxy) als farbloses 01In analogy to Example 1 b) is obtained from 4 g of the ketone prepared according to Example 4 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.40 g of the title compound (15a-hydroxy) as a colorless 01
IR: 36ΟΟ, 3410 (breit), 2958, 2865, 1738, i600/cm. IR: 36ΟΟ, 3410 (wide), 2958, 2865, 1738, i600 / cm.
c.) ( 1R,5S,6R,7H)-7-(Tetrahydropyran-2-yloxy)-6-/i"3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl7-bicycio/3.3.07octan-3-onc.) (1R, 5S, 6R, 7H) -7- (tetrahydropyran-2-yloxy) -6- / i "3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) oct-1-en-6-inyl7-bicyclo / 3.3.07octan-3-one
In Analogie zu Beispiel 1 c) erhält man aus 1,2 g des nach Beispiel 4 b) hergestellten Diols mit Dihydropyran 1,6 g der Titelverbindung als 01. IR: 2942, 287Ο, 1738, 145Ο, 1132, 960/cm.In analogy to Example 1c), 1.2 g of the diol prepared according to Example 4 b) with dihydropyran give 1.6 g of the title compound as 01. IR: 2942, 287Ο, 1738, 145Ο, 1132, 960 / cm.
(5E)-13,14-Didehydro-18,18,19,19-tetradehydro-i6,16,20-trimethyl-6a-carba-prostaglandin-Io (5E) -13,14-didehydro-18,18,19,19-tetradehydro-i6,16,20-trimethyl-6a-carba-prostaglandin-I o
In Analogie zu Beispiel 1 erhält man aus 1 g (1R,5S,6R,7R) 7-(Tetrahydropyran-2-yloxy)-6-/Γ3S)-2-brom-4,4-dimethy1-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl7-bicyclo/3·3·θ7-octan-3-on 400 mg (5E)-13,14-Didehydro-18,18,19,19-tetra-Analogously to Example 1, from 1 g (1R, 5S, 6R, 7R) of 7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-4,4-dimethy1-3- (tetrahydropyran- 2-yloxy) -non-1-en-6-ynyl-7-bicyclo / 3x3x7-octan-3-one 400 mg (5E) -13,14-didehydro-18,18,19,19-tetra
7 7 23 77 7 23 7
- zer -- zer -
dehydro- 1 6 ,1 6 , 2O-tr.imethyl-6a-carba-prostaglandj.n-I2-11,15-bis-(tetrahydropyranyläther) als farbloses Öl* IR:. 351-0. (breit), 2940, 2858, 2220, 1708/cm.dehydro- 1 6, 1 6, 2 O -trimethyl-6a-carba-prostaglandic-12 -11,15-bis- (tetrahydropyranyl ether) as a colorless oil * IR :. 351-0. (wide), 2940, 2858, 2220, 1708 / cm.
Nach Abspaltung der Schutzgruppe*! gemäß Beispiel 1 erhält man 41O mg der Titelverbindung als farbloses 01. IR: 36ΌΟ, 33^0 (breit), 29^0, 2832, 2220, 17O8, i600/cm.After cleavage of the protective group *! According to Example 1, 41O mg of the title compound are obtained as a colorless oil. IR: 36 °, 33 ° 0 (broad), 29 ° 0, 2832, 2220, 17O8, 1600 ° / cm.
Das Ausgangsmaterial für die obige Titelverbindung wird ; wie folgt hergestellt:The starting material for the above title compound becomes; made as follows:
a) (iR,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-(2-brom-4, V-dim ethyl-3-oxo-non-1 -en-6-inyl) -bicyclO/3. 3 ·θ7octana) (iR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- (2-bromo-4, V-dimethyl-3-oxo-non-1 -ene-6-ynyl) bicyclo / 3 system. 3 · θ7octane
In Analogie zu Beispiel 1 a) erhält man aus 12,6 g 3,3-Ditnethyl-2-oxo-oct-5-inyl-phosphonsäuredimethylester 7,4 g N-Bromsuccinimid und 11,2 g (1R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6-formyl-bicyclo/3·3·θ7-; octan 8,7 g des ungesättigten Ketons als farbloses Öl. IR: 29^6, 288O, 1712, 1687, 1601, 1594, 1272,Analogously to Example 1 a), 12.6 g of 3,3-dimethyl-2-oxo-oct-5-ynylphosphonic acid dimethyl ester give 7.4 g of N-bromosuccinimide and 11.2 g (1R, 5S , 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo / 3 x 3 x θ7- ; octane 8.7 g of the unsaturated ketone as a colorless oil. IR: 29 ^ 6, 288O, 1712, 1687, 1601, 1594, 1272,
b) (iR,5S,6R,7R)-7-Hydroxy-6-/C3S)-2-brom-A,4-dimethyl-3-· hydroxy-non-1-en-6-inyl7-bicyclo/3·3»07octan-3-onb) (iR, 5S, 6R, 7R) -7-hydroxy-6- / C3S) -2-bromo-A, 4-dimethyl-3-hydroxy-non-1-en-6-ynyl-7-bicyclo / 3 · 3 "07octan-3-one
In Analogie zu Beispiel 1 b) erhält man aus 5 g des nach Beispiel 5a) hergestellten Ketons nach Reduktion mit Natriumborhydrid, Verseifung mit Kaliumcarbonat und anschließender Ketalspaltung 1,80 g der Titelverbindung (15a-Hydroxy) als farbloses ÖlIn analogy to Example 1 b), from 5 g of the ketone prepared according to Example 5a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.80 g of the title compound (15a-hydroxy) as a colorless oil
IR: 36ΟΟ, 3404 (breiig), 2958, 2864, 1738, 1601/cm. IR: 36ΟΟ, 3404 (mushy), 2958, 2864, 1738, 1601 / cm.
c) (iR,5S,6R,7R)~7-(Tetrahydropyran-2-yloxy)-6-/r3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-non-1 enr-6-inyl7-bicyclo/3 · 3«07octan-3-onc) (iR, 5S, 6R, 7R) ~7- (tetrahydropyran-2-yloxy) -6- / r3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -non- 1 enr-6-ynyl-7-bicyclo / 3x3 -7octan-3-one
In Analogie zu Beispiel 1 c) erhält man aus 1,5 g des nach Beispiel 5 b) hergestellten Diols 2,20 g der Titelverbindung als farbloses öl. IR: 2942, 2878, 1738, 1125, 963/cm.In analogy to Example 1 c) obtained from 1.5 g of the diol prepared according to Example 5 b), 2.20 g of the title compound as a colorless oil. IR: 2942, 2878, 1738, 1125, 963 / cm.
24 77 23 724 77 23 7
(5E)-13,14-Didehydro-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I2 \(5E) -13,14-didehydro-18,18,19,19-tetradehydro-6a-carbaprostaglandin-I 2 \
In Analogie zu Beispiel 1 erhält man aus 400 mg (IR,5S,6P,7R)-7-(Tetrahydropyran-2-yloxy)-6-/Γ3S)-2-brom-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl7-bicyclo/3.3«07octan-3-on 130 mg (5E)-13 /1 4-Didehydro-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2-11,15-bis-(tetrahydropyranylether) als farbloses Öl. IR: 3500 (breit), 2948, 2862, 2226, 1708/cm.In analogy to Example 1, 400 mg (IR, 5S, 6P, 7R) -7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-3- (tetrahydropyran-2-yloxy) - oct-1-en-6-ynyl-7-bicyclo / 3.3 "-7octan-3-one 130mg (5E) -13 / 1 4-didehydro-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I 2 -11,15-bis (tetrahydropyranyl ether) as a colorless oil. IR: 3500 (wide), 2948, 2862, 2226, 1708 / cm.
Nach Abspaltung der Schutzgruppen gemäß Beispiel 1 erhält man 62 mg der Titelverbindung als farbloses IR: 361Ο, 335Ο (breit), 2930, 2862, 2226, 17Ο9, 1600/cm.After cleavage of the protecting groups according to Example 1, 62 mg of the title compound are obtained as colorless IR: 361Ο, 335Ο (broad), 2930, 2862, 2226, 17Ο9, 1600 / cm.
Das Ausgangsmaterial für die obige Titelverbindung wird wie folgt hergestellt:The starting material for the title compound above is prepared as follows:
a) (1R,5S,6R,7R)-3,3-Äthylendioxy-7-benzoyloxy-6r-(2-brom-3-oxo-oct-1-en-6-inyl)-bicyclo/3·3-07octana) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6r- (2-bromo-3-oxo-oct-1-en-6-ynyl) bicyclo / 3x3 07octan
In Analogie zu Beispiel la) erhält man aus 5»8 g 2-Oxo-hept-5-inyl-phosphonsäure-dimethylester 3»7 g N-Bromsuccinimid und 5,6 g (1R,5S,6R,7R)- ; 3,3-Äthylendioxy-7-benzoyloxy-6-formyl-bicyclo-/3«3«07octan 4,7 g des ungesättigten Ketons als farbloses Öl.In analogy to Example la) is obtained from 5 »8 g of 2-oxo-hept-5-ynyl-phosphonic acid dimethyl ester 3» 7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) - ; 3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo- / 3 "3" -07octane 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2932, 2380, 1712, 1688, 16ΟΟ, 1592, 1272, 948/cm.IR: 2932, 2380, 1712, 1688, 16ΟΟ, 1592, 1272, 948 / cm.
b) (1R,5S16R,7R)-7-Hydroxy-6-/r3S)-2-brom-3-hydroxy-oct-1-en-6-inyl7-bicyclo/3.3.07octan-3-onb) (1R, 5S 1 6R, 7R) -7-hydroxy-6- / 3S) -2-bromo-3-hydroxy-oct-1-en-6-ynyl-7-bicyclo / 3.3.07octan-3-one
In Analogie zu Beispiel 1 b) erhält man aus 4 g des nach Beispiel 6 a) hergestellten Ketons nach Reduktion mit Natriumborhydrid, Verseifung mit Kaliumcarbonat und anschließender Ketalspaltung 1,35 g der Titelverbindung als farbloses ÖlIn analogy to Example 1 b), from 4 g of the ketone prepared according to Example 6 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent Ketalspaltung 1.35 g of the title compound as a colorless oil
IR: 36ΟΟ, 3410 (breit), 2962, 2866, 1740, i60i/cm. IR: 36ΟΟ, 3410 (wide), 2962, 2866, 1740, i60i / cm.
lL!l L !
c) (IR,5S,6R,?R)-7-{Tetrahydropyran-2-yloxy)-6-/Γ 3S)-2-brom-3~(tetrahydropyran~2-yloxy)-oct-1-en-o-inyl?- bicyclo/3«3.07octan-3-onc) (IR, 5S, 6R, -R) -7- (tetrahydropyran-2-yloxy) -6- / Γ3S) -2-bromo-3 ~ (tetrahydropyran-2-yloxy) -oct-1-ene o-inyl-bicyclo / 3 «07,7-octan-3-one
In Analogie zu Beispiel 1 c) erhält man aus 1,20 g des nach Beispiel 6 b) hergestellten Diols mit Dihydropyran 1,6l g der Titelverbindung als farblosesIn analogy to Example 1 c) obtained from 1.20 g of the diol prepared according to Example 6 b) with dihydropyran 1.6l g of the title compound as a colorless
IR: 29^-5, 2882, 1739, 1125, 968/cm.IR: 29 ^ -5, 2882, 1739, 1125, 968 / cm.
(5E)-(16RS)-13,i^-Didehydro-io-methyl-ie,18,19,19-tetradehydro-öa-carba-prostaglandin-Ip-trisihydroxy- raethyl)-aminomethansalz(5E) - (16RS) -13, i ^ -Didehydro-io-methyl-he, 18,19,19-tetradehydro-öa-carba-prostaglandin-1p-tris-hydroxyethyl) -aminomethane salt
Zu einer Lösung von 358 mg (5E)-(1 ons)-13,14-Didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-ρrostaglandin-I2 in 60 ml Acetonitril gibt man bei 65 C eine Lösung von 121 mg Tris-(hydroxymethyl)-aminomethan in 0,'i ml Wasser. Unter Rühren läßt man abkühlen, nach 16 Stunden dekantiert man vom Lösungsmittel und trocknet den Rückstand bei 25 C und 0,1 Torr. Man erhält 310 mg der Titelverbindung als wachsartige Masse.To a solution of 358 mg of (5E) - (1 ons) -13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-ρrostaglandin-I 2 in 60 ml of acetonitrile is added 65 C a solution of 121 mg of tris (hydroxymethyl) aminomethane in 0, 1 ml of water. While stirring, allowed to cool, after 16 hours, decanted from the solvent and the residue is dried at 25 C and 0.1 Torr. 310 mg of the title compound are obtained as a waxy mass.
Claims (3)
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DE19823204443 DE3204443A1 (en) | 1982-02-08 | 1982-02-08 | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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EP (1) | EP0086404B1 (en) |
JP (1) | JPH0611728B2 (en) |
AT (1) | ATE24487T1 (en) |
AU (1) | AU567867B2 (en) |
CA (1) | CA1215362A (en) |
CS (1) | CS235307B2 (en) |
DD (1) | DD207901A5 (en) |
DE (2) | DE3204443A1 (en) |
DK (1) | DK156563C (en) |
ES (1) | ES8400384A1 (en) |
FI (1) | FI78064C (en) |
GR (1) | GR77967B (en) |
HU (1) | HU191197B (en) |
IE (1) | IE54554B1 (en) |
IL (1) | IL67839A0 (en) |
NO (1) | NO155729C (en) |
NZ (1) | NZ203115A (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 |
DE3408699A1 (en) * | 1984-03-08 | 1985-09-12 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
US4927963A (en) * | 1989-04-28 | 1990-05-22 | Syntex (U.S.A.) Inc. | Novel processes for the synthesis of certain bicyclo(4.2.0)octane derivatives with valuable therapeutic properties |
DE4135193C1 (en) * | 1991-10-22 | 1993-03-11 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De |
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CA1201712A (en) * | 1980-02-28 | 1986-03-11 | Paul A. Aristoff | Carbacyclin analogs |
DE3104044A1 (en) * | 1981-02-02 | 1982-08-26 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW PROSTACYCLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
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- 1982-02-08 DE DE19823204443 patent/DE3204443A1/en not_active Withdrawn
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- 1983-02-03 AT AT83101008T patent/ATE24487T1/en active
- 1983-02-03 DE DE8383101008T patent/DE3368609D1/en not_active Expired
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- 1983-02-07 AU AU11180/83A patent/AU567867B2/en not_active Ceased
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ES519627A0 (en) | 1983-11-16 |
NZ203115A (en) | 1986-03-14 |
FI78064B (en) | 1989-02-28 |
EP0086404B1 (en) | 1986-12-30 |
CS235307B2 (en) | 1985-05-15 |
NO830399L (en) | 1983-08-09 |
IE830246L (en) | 1983-08-08 |
DE3368609D1 (en) | 1987-02-05 |
ES8400384A1 (en) | 1983-11-16 |
GR77967B (en) | 1984-09-25 |
EP0086404A1 (en) | 1983-08-24 |
FI830414A0 (en) | 1983-02-07 |
JPS58146531A (en) | 1983-09-01 |
ATE24487T1 (en) | 1987-01-15 |
CA1215362A (en) | 1986-12-16 |
FI830414L (en) | 1983-08-09 |
DK156563C (en) | 1990-01-29 |
JPH0611728B2 (en) | 1994-02-16 |
AU1118083A (en) | 1983-08-18 |
ZA83851B (en) | 1983-10-26 |
FI78064C (en) | 1989-06-12 |
DK52383D0 (en) | 1983-02-08 |
SU1145926A3 (en) | 1985-03-15 |
DK156563B (en) | 1989-09-11 |
NO155729B (en) | 1987-02-09 |
IL67839A0 (en) | 1983-06-15 |
DE3204443A1 (en) | 1983-08-18 |
DK52383A (en) | 1983-08-09 |
AU567867B2 (en) | 1987-12-10 |
NO155729C (en) | 1987-05-20 |
IE54554B1 (en) | 1989-11-22 |
HU191197B (en) | 1987-01-28 |
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