CA1215362A - Carbacyclins, process for their preparation thereof, and use thereof as medicinal agents - Google Patents

Carbacyclins, process for their preparation thereof, and use thereof as medicinal agents

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Publication number
CA1215362A
CA1215362A CA000421004A CA421004A CA1215362A CA 1215362 A CA1215362 A CA 1215362A CA 000421004 A CA000421004 A CA 000421004A CA 421004 A CA421004 A CA 421004A CA 1215362 A CA1215362 A CA 1215362A
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Prior art keywords
yloxy
tetrahydropyran
tetrahydrofuran
methyl
dimethyl
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Expired
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CA000421004A
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French (fr)
Inventor
Werner Skuballa
Bernd Raduchel
Helmut Vorbruggen
Jorge Casals-Stenzel
Gerda Mannesmann
Michael H. Town
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C45/59—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 in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • 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, i.e. RP(=X)(XH)2 (X = S, 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

Abstract

ABSTRACT
Carbacyclin derivatives of general Formula I

(I), wherein R1, R2, R3, R4 represent a hydrogen atom or an alkyl group of 1-5 carbon atoms, R5 is an alkyl group of 1-5 carbon atoms, as well as the salts thereof with physiologically compatible bases; a process for the preparation thereof; and the use thereof as blood-pressure-lowering agents.

./.

Description

~S362 Specification The present invention relates to (5E)-13~14~18~1B,-l9,19-hexadehydro-6a-carbaprostaglandin I2 derivatives~ their physiologically compatible salts, a process for the prepara-tion thereof~ and pharmaceutical compositions containing same.
German Laid-Open Application [DOS] 2,845,770 claims carbacyclin derivatives of the general formula COO~ 1
2 ) 3 CH

, ,.

A-W-D-E-R~

wherein Rl is hydrogenj alkyl~ cycloalkyl~ aryl~ or a heterocyclic residue;
A is a -CH2-CH2-, trans-CH=CH-, or -C-C-group~
~ is a free or functionally modified hydroxy-methylene group or a free or functionally modified -C--group, wherein the O~l-group is in the ~-position, OH

~ r 36;~

D and E together mean a direct bond or D is a straight-chain or branched, saturated or unsaturated alkylene group of 1-10 carbon atoms optionally substituted by fluorine atoms, S E is an oxygen atom or a -C-C-bond or a direct bond, R2 is an alkyl~ cycloalkyl, optionally substituted aryl~ or heterocyclic group, R3 is a free or functionally modified hydroxy group, and~ if Rl means a hydrogen atom~ the salts thereof with physiologically compatible bases~
The compounds possess the properties typical for prostacyclins~ such asj for example~ lowering of peripheral arterial and coronary vascular resistance, inhibition of tnrombocyte aggregation, and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure, without simultaneously lowering stroke volume and coronary blood flow~ treatment for stroke, prophylaxis and therapy of coronary heart diseasej coronary thrombosis, cardiac infarction, peripheral arterial diseases, arterio-sclerosisj and thrombosis, shock therapy~ inhibition of bronchoconstriction, inhibition of gastric acid secretion and cytoprotection for gastric and intestinal mucosa; anti-allergic properties, lowering of pulmonary vascular resist-ance and pulmonary blood pressure, promotion of kidney bloodflow; utili~ation in place of heparin or as adjuvant in dialysis of hemofiltration; preservation of blood plasma stores, especially blood platelet preservest inhibition of labor, treatment of gestational toxicosis, enhancement of cerebral blood flow~ etc. Furthermore, the novel prostaglan-din analogs exhibit antiproliferative properties.
A~ong the compounds claimed in DOS 2,845,770, the (5E)-13~14~18jl8,19~19-hexadehydro-6a-carbaprostaglandin I2 cGmpounds show such outstanding properties as blood-pressure-lowering agents and agents inhibiting thrombocyte aggregation that the dose can be further reduced whereby undesirable side effects are likewise even more strongly suppressed. The (SE)-13j14~18,18,19~19-hexadehydro-6a-carbaprostaglandin I2 compounds have not been disclosed by name in DOS 2J845~770.
Compounds wherein A means a -C-C-group have not been emphasized over the other compounds wherein A is a -CH2-CH2- or trans-lS CH=CH-group.
The nomenclature of the compounds is based on a proposal by Morton and Brokaw (J. Org. Chem. 44 :2280 [1979]).
(5E)-6a-Carbaprostaglandin I2 accordingly has the following structural formula:

COOII

ll OH Oll i362 "

Accordingly, the invention concerns ~5E)-13,14~-18,18jl9,19-hexadehydro-6a-carbaprostaglandin I2 derivatives of general Formula I

COO~

/ (I) 11 .
~`

< C C-CH - C - C - C_C-R5 ~H
o}

wherein Rlj R2, R3, ~4 represent a hydrogen atom or an alkyl group of 1-5 carbon atoms;
R5 is an alkyl group of 1-5 carbon atoms, as well as the salts thereof with physiologically compatible bases suitable alkyl groups Rl~ R2; R3~ R4 t Rs are straight-chain and branched-chain alkyl residues of 1-5 carbon atoms~ such asj for example~ methylj ethyl~provyl~
butyl, isopropyl, isobutyl, pentyl. Preferred residues are methyl, ethylj propvl, and isopropyl, especially methyl and ethyl.

i36~:
g Suitable for the salt formation ar~ inorganic and organic bases as known to those skilled in the art for the preparation of physioloqically compatible salts. Examples are alkali hydroxidesj such as sodium and potassium hydroxide, alkaline earth hydroxides~ such as calcium hydroxide, ammonia, amines, such as ethanolaminej diethanolamine, triethanolamine, ~-methylglucamine, morpholine, tris~hydroxymethyl)methylamine, etc.
The invention furthermore relates to a process for the preparation of the prostacyclin derivatives of this inven-tion according to general Formula I~ characterized by reacting a compound of general Formula II

(II) =CBr_CH -\C/ \3 / 1 0~ , o r wherein Rlt R2, R3j R4j R5 have the meanings given above and THP means the tetrahydropyranyl residue, with a Wittig reagent of Formula III

Ph3P=C~-(C~)3-C ~

I S;~6~, ~, wherein Ph is a phenyl group, and subsequently separating isomers~ splitting off blocking groups~ and optionally converting the carboxy group into a salt with a physiologically compatible ~ase.
The reaction of the compound of general Formula II
with the Wittig reagent of Formula III~ which is produced from the corresponding phosphonium salt with methanesulfinyl-methyl sodium or methanesulfinylmethyl potassium or potassium tert-butylate in dimethyl sulfoxide or dimethyl sul oxide-tetrahydrofuran mixturesj is conducted at temperatures of 0-100 C, preferably 20-60 Cj in an aprotic solvent or solvent mixturej preferably dimethyl sulfoxide, dimethylforma-midej or tetrahydrofuran. The thus-obtained olefins of a Z-and E-configuration are separated in the usual way, for ex-ample by column or layer chromatography. During the afore-described Wittig olefin-forming reaction, the formation of the 13,14-acetylene bond also takes place, with hydrogen bromide being split off, at the same time.
The splitting off of the blocking groups is effected in an aqueous solution of an organic acid, such as, for example; acetic acid, propionic acid, or ~hers, or in an aqueous solution of an inorganic acid, e.g. hydrochloric acid. To enhance solubility, a water-miscibletinert organic solvent is suitably added. Organic solvents which can be used for this purpose are, for example, alcohols, such as methanol and ethanol, and ethers~ such as dimethoxyethane, dioxane~ and tetrahydrofuran. Tetrahydrofuran is preferably 12~5362 employed. The splitting-off step is preferably conduct~d at temperatures of between 20 and 80 C.
The carboxylic acids of general Formula I can be converted into salts with suitable amounts of the correspond-ing inorganic bases, with neutralization. For example~ thesolid inorganic salt is obtained when dissolving the cor-responding acids in water containing the stoichiometric quantity of the base~ after evaporation of the water or after the addition of a water-miscible solvent, e.g. alcohol or acetone. For the production of an amine salt, the PG acid is dissolved in a suitable solvent; e.g. ethanolj acetonej diethyl etherj or benzene~ and at least the stoichiometric amount of the amine is added to this solution. During this processj the salt is ordinarily obtained in the solid form or is isolated in the usual way after evaporation of the solvent.
~ he compounds of general Formula II serving as the starting materials can be preparedj for example/ by conven-tionally reacting an aldehyde of Formula IV (DOS 2,845j770) O O
~
~ (IV) r~
~ \ CHO
oCO~

~21536Z

with a phosphonate of general Formula V
3 > P-CH2-C _ C C - C-C-R5 (V) in Rl, R2, R3j R4, and R5 have the meanings given above, in the presence of a deprotonating agentj such as, for ex-amplej sodium hydride or potassium tert-butylate~ and a brominating agentj such asj for examplej N-bromosuccinimid~
to obtain a ketone of general Formula VI:

O (VI) \ CH=CBr- C --C ~ C - C _C-h5 oco-<3 After reduction of the keto group with sodium boro-hydride and optionally separation of epimers~ saponification of the ester group, for example with potassium carbonate in methanol, and ketal cleavage with aqueous acetic acid, as well as optionally epimer separation, the ketone of general Formula VII is obtained:

5a6Z

(VIl) Cll=C~r-C~-C C - C-C-R5 0~

Etherification of the hydroxy groups with dihydro-pyran in the presence of catalytic amounts of p-toluene-sulfonic acid yields the compounds of general Formula II.
The phosphonates of general Formula V are produced conventionally by reacting an alkyl halogenide (producible from the corresponding alcohol by halogenation) of general Formula VIII
R~ J~ 4 H~l-C- - C-C R (VJII) with the dianion formed from the phosphonate of general Formula IX:
CH30\ 11 R~ R~
P--CH2 --C ~ C-- H (lX) 1~ R2J R3, R4, and R5 have the meanings given above.

~S36Z
,~, Another method for obtaining the phosphonates of general Formula V resides in reacting the anion of the dimethyl ester of methylphosphonic acid with an ester of general Formula X:
il R~ / 2 1\3 /14 R60-C -- C------ C~ C-C-R5 (X) wherein Rlj R2, R3, R4j and R5 have the above-indicated meanings and R6 is an alkyl group of 1-5 carbon atoms, obtainable from the corresponding malonic acid ester by alkylating with the halogenide of general Formula VIII and subsequent decarbalkoxylation. The ester of general For-mula X is also obtainable from the carboxylic acid of general Formula XI:

o Rl R2 ~0-C \C - ~l (XI) wherein Rl and R2 have the meanings given above~
by alkylation with the halogenide of general Formula VIII and subsequent esterification.

~;~1536~:

The compounds of this invention have blood-pressure-lowerillg and bronchodilatory effects. They are furthermore suitable for inhibition of thrombocyte aggrega-tion. Consequently, the novel prostacyclin derivatives of ~ormula I represent valuable pharmâceutically active age!lts.
Moreover; they exhibit, with a similar spectrum of activity as compared with corresponding prostaglandinsj a higher specificity and, above all, a considerably longer duration of efficacy. As compared with PGI2j they are distinguished by greater stability. The high tissue specificity of the novel prostaglandins is demonstrated on studies on smooth-muscle organs, such asj for example? on the guinea pig ileum or on the isolated rabbit tracheaj where a substantially lesser stimulation can be observed than that caused by the administration of natural prostaglandins of the E, Aj or F
type.
The novel carbacyclin derivatives possess the prop-erties typical for prostacyclinsj such as; for example, lower-ing of peripheral arterial and coronary vascular resistance~
inhibition of thrombocyte aggregation~ and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering the stroke volume and coronary blood flow; treatment for stroke, prophylaxis and therapy o coronary heart disease, coronary ~5 thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system; therapy of shock, 1~536Z

inhibition of bronchoconstriction, inhibition of gastric acid secretion, cytoprotection for gastric and intestinal mucosa, cytoprotection in liver and pancreas; antiallergic proper-ties, lowering of pulmonary vascular resistance and pulmonary blood pressurei promotion of kidney blood flow~ utilization in place of heparin or as adjuvant in dialysis of hemofiltra-tion, preservation of blood plasma stores, especially blood platelet preserves~ inhibition of laborj treatment of gestational toxicosisj enhancement of cerebral blood flow, etc. Furthermore~ the novel carbacyclin derivatives possess antiproliferative properties. The carbacyclins of this in-vention can also be employed in combination with ~-blockers or diuretics, for example.
The dosage of the compounds is 1-1,500 ~g/kg/day if administered to human patients. The unit dosage for the pharmaceutically acceptabl~ vehicle is 0.01 - 100 mg.
When injected intravenously into nonanesthetized~
hypertonic rats in doses of 5~ 20t and 100 ~g/kg body weight~
the compounds of this invention show a stronger blood-pressure-lowering effect of a longer duration as compared with PGE2 and PGA2j without triggering diarrheat as does PGE2 or cardiac arrhythmias~ as does PGA2.
When injected intravenously into anesthetized - rabbits, the compounds of this invention~ as compared with PGE2 and PGA2~ exhibit a stronger blood-pressure-lowering effect of a considerably longer duration, without affecting other smooth-muscle organs or organ functions.

~53t~Z

1~
Sterilej injectable, aqueous or oily solutions are used for parenteral administration. Suitable for oral ad-ministration are; for examplej tablets~ dragees~ or capsules.
The invention consequently also relates to medicinal agents ~ased on the compounds of general Formula I
and customary auxiliary agents and excipients.
The active agents of this invention are to serve~
in conjunction with the auxiliary agents known and usual in galenic pharmacy~ for the preparation of blood-pressure-lowering agents, for example.

~;~1536;~

Example 1 (SE)-(16RS)-13~14-Didehydro-16-methyl-18,18,19,19-tetradehydro-6a-cdrbaprostaglandin I2 At 5 C~ 4.75 g of potassium tert-butylate is added within 45 minutes to a solution of 9.4 g of 4-carboxybutyl-triphenylphosphonium bromide in 20 ml of dimethyl sulfoxide and 7.8 ml of tetrahydrofuran; the reaction mixture is stirred for 45 minutes at 5 C. The redylene solution is combined with a solution of 1.83 g of (lR~5S~6R~7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S~4RS)~2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl]bicyclo[3.3.0]octan-3-one in 3 ml of tetrahydrofuran and agitated for 4 hours at 40~ C. The reaction mixture is poured on ice water, acidified with 35% citric acid solution to pH 4-5~ and extracted three times with methylene chloride. The organic phase is shaken with ~rine, dried over magnesium sulfate, and evaporated under vacuum. The residue is purified by chromatography on silica gel. With hexane/ethyl acetate (3+2), 180 mg of the 5Z-configured olefin is initially obtained~ and as the more polar component; 680 mg of (5E)-(16RS)-13~14-didehydro-16-methyl-18~18jl9,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR (CHC13): 3500 (broad)~ 2940~ 2860~ 2225 1710j 1440 cm 1 ;3&;2 To split off blocking groups, 680 m~ of the above-obtain~d olefin-for~ing product is stirred for 20 hours at 25 C with 25 ml of a mixture of acetic acid/water/tetra-hydrofuran (65/35/10). The mixture is then evaporatea under vacuum and the residue chromatographed on silica gel. With ethyl acetate/acetic acid (99.9 + 0.1)~ 345 mg of the title compound is produced as a colorless oil.
IR: 3600~ 3400 (broad)j 2930~ 2225~ 1710~ 1603 1020 cm~l.
The starting material for the above title compound is prepared as follows:

(a) (lRJ5S~6R,7R)-3~3-Ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3-oxooct-1-en-6-ynyl]bicyclo[3,3,0]octane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ At 0 C, a solution of 10.5 g of 3-methyl-2-oxohept-5-ynephosphonic acid dimethyl ester in 70 ml of di-methoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane; the mixture is stirred for one hour at 0 C and then 7.4 g of finely pulverized N-bromosuccinimide is added thereto. Agitation is continued for 30 minutes a~ 0 C; the reaction mixture is combined with a solution of 11.4 g of (lR~5S~6R~7R)-3>3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3 3.0]octane in 90 ml of dimetlloxyethane~ and stirred for 2 hours at 0 C.
The rcaction mixture is poured on saturated anunonium chloride solution and extracted with ether. The organic extract is ~5;~62 ,~, washed with water to render it neutral t dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (3+2) 8.2 g of the unsaturated ketone as a colorless oil.
IR: 2930~ 2880j 1712j 1688~ 1602; 1595, 1450, 1275, 945 cm~l.

(b) (lR~5Sj6R~7R)-7-Hydroxy-6-1(3S~4RS)-2-bromo-3-hydroxy-4-methyloct-1-en-6-ynyl]bicyclo-[3 3.0]octan-3-one ____________________________________________ At -40 Cj 2.5 g of sodium borohydride is added in incremental portions to a solution of 5.9 g of the ketone produced according to Example l(a) in 140 ml of methanol~ and the mixture is stirred for 30 minutes at -40 C.
Subsequently the mixture is diluted with etherj washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum.
The crude product (mixture of 15-epimers) is dis-solved in 200 ml of methanolj 2.5 g of potassium carbonate is added and the mixture is stirred for 17 hours at 23 C
under argon. Thereafter the mixture is concentrated under vacuumt diluted with ether~ and washed neutral with brine.
The mixture is dried over magnesium sulfate and evaporated - under vacuum.
The evaporation residue is stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid/
waterJtetrahydrofuran (65/35/10) and then evaporated under vacuum. Column chromatography on silica gel with ether/
methylene chloride yields first of all 1.6 g of the 15~-configured alcohol, as well as 2.1 g of the title compound (PG nomenclature 15~-hydroxy) as the more polar component~
in the form of colorless oils.
IR: 3600, 3430 (broad), 2960, 2920, 2870, 1738, lGOOj 1400 cm 1 tc) (lRj5Sj6R~7R)-7-(Tetrahydropyran-2-yloxy)-6-lt3S~4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl]bicyclol3.3.0]octan-3-one ____________________________________________ A solution of 1.6 g of the ~-alcohol prepared according to Example l(b)j 16 mg of p-toluenesulfonic acid, and 1.5 g of dihydropyran in 50 ml of methylene chloride is agitated at 0 C for 35 minutes. The mixture is then diluted with ether, shaken w~th dilute sodium bicarbonate so-lution, washed neutral with water, dried over magnesium sulfatej and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (7+3) 2.17 g of the title compound as a colorless oil.
IR: 2940t 2870j 1735, 1450j 1120, 1018, 965 cm ~215362 ,~, Example 2 (5E)-(16RS)-13jl4-Didehydro-16j20-dimethyl-18~18~19,19-tetradehydro-6a-carbaprostaglandin I2 ______________________________________________.___ In analogy to Example lj 1.6 g of (lR~5Sj6R,7R)-7-~tetrahydropyran-2-yloxy)-6-[(3Sj4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)non-1-en-6-ynyl]bicyclo~3.3.0]octan-3-one yields 640 mg of (SE)-(16RS~-13jl4-didehydro-16j20-dimethyl-18,18jl9jl9-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2942, 2860, 2224, 1710 cm 1.
After splitting off the blocking groups as described in Example lj 0.3 g of the title compound is obtained as a colorless oil.
IR: 3600, 3350 (broad)j 2932j 2224j 1710, 1602 cm 1 ~he starting material for the above title compound is prepared as follows:

(a) (lRs5Sj6R~7R)-3~3-Ethylenedioxy-7-benzoyloxy-6-1(4~S)-2-bromo-4-methyl-3-oxonon-1-en-6-ynyl]bicyclol3.3.0Joctane _____________________________________________ Analogously to Example l(a)j 6 g of 3-methyl-?-oxooct-5-ynylphosphonic acid dimethyl esterj 3.7 g of N-bromosuccinimide, and 5.6 g of (lR,5S,6R,7R)-3,3-ethylene-dioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane yield 4.0 g of the unsaturated ketone as a coiorless oil.
IR: 2935~ 2883, 1713J 1687j 1602~ 1596, 1275, 947 cm~l.

5~62 ,~

(b) (lRj5Sj6Rj7R)-7-~lydroxy-6-[(3S~4RS)-2-bromo-3-1lydroxy-4-methylnon-1-en-6-ynyl]bicyclo-~3.3.0]octan-3-one ______._____________________________________ Analogously to Example l(b)~ 3 g of the ketone prepared according to Example 2(a) yields, after reduction with 1.3 ~ of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent ketal splitting with 150 ml of a mixture of acetic acid/water/tetrahydrofuranl 1.2 g of the title compound (15~-hydroxy~ as a colorless oil.
IR: 3610, 3400 (broad)~ 2960j 2870, 1739, 1600 cm 1.

(c~ (lR,5S~6R~7R)-7-tTetrahydropyran-2-yloxy)-6-l(3S~4RS)-2-bromo-4-methyl-3-ttetrahydropyran-2-yloxy)non-1-en-6-ynyl]bicyclol3.3.0]octan-3-one ______________________________________________ In analogy to Example l(c)) 0.78 g of the diol produced according to Exam~le 2(b) and 0.7 g of dihydropyran yield 1.1 g of the title compound as a colorless oil.
IR: 2940t 2872t 1736, 1450, 1120, 965 cm 1.

Example 3 (5E)-(16RS)-20-Ethyl-13~14-didehydro-16-methyl-18j18jl9,19-tetradehydro-6a-carbaprostaglandin I2 Analogously to Example 1~ 2 g of (lR~5S~6R~7R)-7-tetrahydropyran-2-yloxy)-6-lt3S~4RS)-2-bromo-4-methyl-3-tetrahydropyran-2-yloxy)dec-1-en-6-ynyl]bicyclol3.3.0]octan-3-one yieldsj in the form of a colorless oil~ 900 mg of ~5~;2 C~

(5~)-(16RS)-20-ethyl-13~14-didehydro-16-methyl-18~18jl9~19-tetradehydro-6a-carbaprostaglandin I2 11~15-bisttetrahydro-pyranyl ether).
IR: 3500 (broad), 2948, 2862~ 2220, 1708 cm 1.
After the blocking groups have been split off ac-cording to Example lj 420 mg of the title compound is ob-tained as a colorless oil.
IR: 3600J 3360 (broad); 2930, 2858, 2220t 1708 1601 cm~l.

The starting material for the above title compound is prepared as follows:

(a) (lRj5S~6R~7R)-3j3-Ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3-oxodec-1-en-6-ynyl]bicyclol3.3.0]octane In analogy to Example l(a), 6.25 g of 3-methyl-2-oxonon-5-ynylphosphonic acid dimethyl ester~ 3.7 g of N-bromosuccinimide, and 5.6 g of (lP~,SS~6R,7R)-3~3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane result in 4.5 g of the unsaturated ketone as a colorless oil.
IR: 2940j 2880~ 1712; 1688, 1601, 1592, 1275, 948 cm~l.

3~Z

(b) (lRj5S~6R,7R)-7-Hydroxy-6-¦(3Sj4RS)-2-bromo-3-hydroxy-4-methyldec-1-en-6-ynyl]bicyclo~
~3.3.0]octan-3-one _____________________.__________________ ___ Analogously to Example l(b); 4 g of the ke~one prepared according to Example 3(a) yieldsj after reduction with sodium borohydridej saponification with potassium carbonatej and subsequent ketal cleavage with acetic acid/
water/tetrahydrofuran (65/35/10); 1.5 g of the title compound (15~-hydroxy) as a colorless oil.
IR: 3610, 3400 (broad), 2955, 2868, 1738 1601 cm~l.

~c) (lRj5S~6Rj7R)-7-(Tetrahydropyran-2-yloxy)-6-[(3Sj4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)dec-1-en-6-ynyl]bicyclo[3.3.0]octan-3-one ______________________________________________ In analogy to Example l(c); 1.2 g of the diol prepared according to Example 3(b) yields 1..81 g of the title compound as a colorless oil.
IR: 2942, 2868, 1738, 1450, 1125, 960 cm 1 (d) 3-Methyl-2-oxonon- 5-ynylphosphonic Acid Dimethyl Ester ________________________________________ At 20 C~ 120 g of methylmalonic acid diethyl ester is added dropwise to a solution of 15.3 g of sodium in 340 ml of ethyl alcohol. After 30 mi.nutes, 135 g of l-bromo-2-hexyne (prepaLed from hex-2-yn-1-ol with phosphorus tri-bromide in pyridine) is added dropwise thereto and the ' ~2153~iZ

mixture heated for 16 hours under reflux. The mixtùre is thereafter filteredj the residue washed with methylene chloride and concentrated under vacuum. The residue is dissolved in 500 ml of methylene chloridej shaken twice with respectively 50 ml of water, dried over magnesium sulfate; and concentrated under vacuum. The residue is distilled under vacuumat 14 torr and 148-152 C, thus obtaining as the distillate 155g of the alkylated methylmalonic acid ester which latter is heated under reflux for 4.5 hours in 1200 ml of dimethyl sulfoxide and 12 ml of water with 52 g of lithium chloride. The mixture is then poured on S 1 of ice water~ extracted with etherl the extract shaken with water, dried over magnesium sulfate, and concentrated under vacuum. Distillation of the residue yields, at 94-96 C and 14 torr, 95 g of the ethyl ester of 2-methyloct-4-ynoic acid as a colorless liquid.
At -70 Cj 640 ml of a 1.5-molar butyllithium so-lution in hexane is added dropwise to a solution of 176 g of the dimethyl ester of methanephosphonic acid in 2 1 of tetrahydrofuran. After 15 minutes~ a solution of 90 g of the ethyl ester of 2-methyloct-4-ynoic acid in 300 ml of tetrahydrofuran is gradually added thereto. The mixture is stirred for 4 hours at -70 C, neutralized with acetic acid and evaporated under vacuum. The residue is combined with 200 ml of waterj extracted three times with respectively 500 ml of methylene chloride, the extract is sha~en with 100 ml of water, dried over magnesium sulfate~ and ~is~

concentrated under vacuum. Distillation of.the residue yields, at 0.35 torr and 126-128 C, 80 g of the title compound as a colorless liquid.

Example 4 (5E~-13,14-Didehydro-16~16-dimethyl-18,18,19,19 tetradehydro-6a-carbaprostaglandin I2 ___________________________________._____________ Analogously to Example 1, 1.5 g of (lR,5S,6R,7R)-7-ttetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4~4-dimethyl-3-(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl~bicyclol3.3.0]octan-3-one yields.610 mg of (5E)-13~14-didehydro-16~16-dimethyl-18~18~19 t 1 9- tetradehydro-6a-carbaprostaglandin I2 11~15-bis(tetrahydropyran-2-yl ether) as a colorless~oil.
IR: 3500 (broad), 2944~ 2862~ 2222t 1708 cm 1 After the blocking groups have been split off ac-cording to Example 1~ 290 mg of the title compound is ob-tained as a colorless oil~
IR: 3600, 3400 (broad), 2930~ 2862, 1708, 1600 cm 1 153~

~,~

(a) (lRj5S~6R~7R)-3j3-Ethylenedioxy-7-benzoyloxy-6-(2-bromo-4~4-dimethyl-3-oxooct-1-en-6-ynyl~-bicyclol3.3.0)octane _______________________________________.______ In analogy to Example l(a)~ 6.25 g of 3,3-dimethyl-2-oxohept-5-ynephosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide~ and 5.6 y of (lRj5Sj6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3~03octane yield 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2940j 2878, 1710j 1688, 1602, 15947 1448, 1270, 944 cm 1 (b) (lR,5S~6R~7R)-7-Hydroxy-6-[(3S)-2-bxomo-4~4-dimethyl-3-hydroxyoct-1-en-6-ynyl]bicyclo-13.3.0]octan-3-one In analogy to Example l(b), 4 g of the ketone prepared according to Example 4(a) yields, after reduction with sodium ~orohydride~ saponification with potassium carbonate, and subsequent ketal splitting, 1.40 g of the title compound (15~-hydroxy) as a colorless oil.
IR: 3600, 3410 (broad)~ 2958j 2865, 1738 1600 cm~l.

S3~

(c) (11~, 5S~ 6R, 7R) -7- (Tt~trahydropyran-2-yloxy~ -6-1(3S)-2 brDmo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)oct-1 en-6-ynyl]bicyclo~3.3.0]octan-3-one In analogy to Example l(c), 1.2 g of the diol produced according to Example 4(b) yields, with dihydropyran, 1.6 g of the title compound as an oil.
IR: 2942j 2870J 1738, 1450, 1132, 960 cm 1 Example 5 10(5E)-13j14-Didehydro-18)L8jl9~19-tetradehydro-16jl6j20-trimethyl-6a-carbaprostaglandin I2 Analo~ously to E~ample 1~ 1 g of (1~j5S~6R~7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4~4-dimethyl-3-(tetrahydropyran-2-yloxy)non-1-en-6-ynyllbicyclo~3.3.0]octan-153-one yields 400 mg of ~5E)-13jl4-didehydro-18~18~19Jl9-tetradehydro-16j16,20-trimethyl-6a-carbaprostaglandin I2 11~15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3510 (broad~) 2940, 2858~ 2220, 1708 cm 1 After splitting off the blocking groups according to Example 1, 410 mg of the title compound is obtained as a colorless oil.

IR: 3600; 3340 (broad)~ 2940, 2832, 2220~ 1708 1600 cm~l.

~2~LS362 The starting material for the above title compound is prepared as follows:

(a) (lRj5S~6~j7R)-3j3-Ethylenedioxy-7-benzoyloxy-6-(2-bromo-4j4-dimethyl-3-oxonon-1-en-6-ynyl)-bicyclo~3.3.01Octane In analogy to Example l(a), 12.6 g of 3,3-dimethyl-2-oxooct-5-ynylphosphonic acid dimethyl ester~
7.4 g of N-bromosuccinimide, and 11.2 g of (lR~5S~6R~7R)-3~3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3~0]octane yield 8.7 g of the unsaturated ketone as a colorless oil.
IR: 2946, 2880~ 1712, 1687; 1601t 1594~ 1272, 948 cm (b) (lR~5SJ6R~7R)-7-Hydroxy-6-1(3S)-2-bromo-4~4-dimethyl-3-hydroxynon-1-en-6-ynyl]bicyclo-l3 3 O~octan-3-one Analogously to Example l(b), 5 g of the ketone produced according to Example 5(a) yieldsj after reduction Witil sodium borohydride~ saponification with potassium carbonate~ and subsequent ketal splitting, 1.80 g of the title compound (15~-hydroxy) as a colorless oil.
IR: 3600, 3404 (broad), 2958t 2864, 1738, 1601 cm 1.

3~ 36~

(c) (lRj5S~6R~7R)-7-(Tetrahydropyran-2-yloxy)-6-l(3S)-2-bromo-4j4-dimethyl-3-(tetrahydropvran-2-yloxy)non-1-en-6-ynyl]bicyclo[3.3.0~octan-3-one __________ _________________________________._ In analogy to Example l(c), 1.5 g of the diol prepared according to Example 5(b) produces 2.20 g of the title compound as a colorless oil.
IR: 2942, 2878, 1738? 1125, 968 cm 1 Example 6 (5E)-13jl4-Didehydro-18jl8~19jl9-tetradehydro-6a-carbaprostaglandin I2 _______________ __________~______________________ Analogously to Example lj 400 mg of (lR~5S~6R~7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydro-pyran-2-yloxy)oct-1-en-6-ynyl]bicyclol3.3.0]octan-3-one yields 130 mg of (SE)-13,14-didehydro-18,18jl9,19-tetra-dehydro-6a-carbaprostaglandin I2 llj15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2948, 2862~ 2226, 1708 cm 1 After splitting off the blocking groups as described in Example 1~ 62 mg of the title compound is obtained as a colorless oil.
IR: 3610; 3350 ~broad), 2930, 2862, 2226, 1709, 1600 cm~l.

~2~5362 The starting material for the above 'itle compound is produced as follows: -(a) ~lP~,5S~6Rj7R)-3i3-~thylenedioxy-7-benzoyloxy-6-(2-bromo-3-oxooct-1-en-6-ynyl)bicyclol3.3.0~-octane _____ _______________._________________________ Analogously to Example l(a), 5.8 g of 2-oxo-hept-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromo-succinimidej and 5.6 g of (lRj5S~6R,7R)-3j3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane yield 4~7 g of the unsaturated ketone as a colorless oil.
IR: 2932, 2880~ 1712, 168B, 1600, 1592, 1272 948 cm 1 (b) (lRj5Sj6Rj7P~)-7-Hydroxy-6-¦(3S)-2-bromo-3-hydroxyoct-l-en-6-ynyl~bicyclol3.3.0~octan-3-one ___________________________________________ Analogously to Example l(b), 4 g of the ketone prepared according to Example 6(a) yields, after re-duction with sodium borohydride, saponification with potas-sium carbonate; and subsequent ketal cleavage, 1.35 g of the title compound as a colorless oil.
IR: 3600j 3410 (broad)~ 2962, 2866, 1740, 1601 cm 1 ~2~5;36Z

(c) (lR~5S~6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl3bicyclol3.3.0~octan-3-one :~n analogy to Exam~le l~c), 1.20 g of the diol prepared according to Example 6~b) yieldst with dihydro-pyran, 1.61 g of the title compound as a colorless oil.
IR: 2945j 2882~ 1739j 112S, 968 cm 1 Example 7 (5E)-(16RS)-13jl4-Didehydro-16-methyl-18~18jl9~19-tetradehydro-6a-carbaprostaglandin I2 Tris(hydroxymethyl)aminomethane Salt At 65 C~ a solution of 121 mg of tris(hydroxy-methyl)aminomethane in 0.4 ml of water is added to a solu-tion of 358 mg of (5E)-(16RS)-13j14-didehydro-16-methyl-18,18jl9jl9-tetradehydro-6a-carbaprostaglandin I2 in 60 ml of acetonitrile. The mixture is allowed to cool under agi-tation~ decanted from the solvent after 16 hoursj and the residue is dried at 25 C and 0.1 torr~ thus obtaining 310 mg of the title compound as a waxy mass.

Claims (20)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a carbacyclin derivative of general Formula I

(I), wherein R1, R2, R3, R4 represent a hydrogen atom or an alkyl group of 1-5 carbon atoms, R5 is an alkyl group of 1-5 carbon atoms, or a salt thereof with a physiologically compatible base, which comprises reacting a compound of general Formula II
(II), wherein R1, R2, R3, R4, R5 have the meanings given above and THP means the tetrahydropyranyl residue, with a Wittig reagent of Formula III

(III), wherein Ph is a phenyl group, and subsequently separating isomers, splitting off blocking groups, and when required, converting the carboxy group into a salt with a physiolo-gically compatible base.
2. A process according to claim 1, in which the reacting of the compounds of Formulae II and III is effected at a temperature from 0°C to 100°C in an aprotic solvent.
3. A process according to claim 2, in which the reaction is effected at a temperature from 20 to 60°C in dimethyl sulfoxide, dimethy1 formamide or tetrahydrofuran.
4. A carbacyclin derivative of general Formula I

(I), wherein R1, R2, R3, R4 represent a hydrogen atom or an alkyl group of 1-5 carbon atoms, R5 is an alkyl group of 1-5 carbon atoms, or a salt thereof with a physiologically compatible base whenever prepared or produced by the process claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
5. A process according to claim 1, in which the alkyl groups are selected from methyl or ethyl.
6. A carbacyclin derivative of Formula I given in claim 1 or a salt thereof where R1, R2, R3, R4 and R5 are as in claim 1 and the alkyl groups are selected from methyl or ethyl whenever prepared or produced by the process claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)oct-l-en-6-ynyl]
bicyclo[3.3.0]octan-3-one in tetrahydrofuran and the isomers separated by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
8. (5E)-(16RS)-13,14-didehydro-16-methyl-18,18, 19,19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[3S,4RS)-2-bromo-4-methyl.-3-(-tetrahydropyran-2-yloxy)non-1-en-6-ynyl]bicyclo [3.3.0]octan-3-one in tetrahydrofuran and the isomers separa-ted by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
10. (5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 9 or an obvious chemical equival.ent thereof.
11. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3-tetrahydropyran-2-yloxy)dec-1-en-6-ynyl]bicyclo [3.3.0]octan-3-one in tetrahydrofuran and the isomers separa-ted by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
12. (5E-(16RS)-20-ethyl-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl]
bicyclol3.3.0]octan-3-one in tetrahydrofuran and the isomers separated by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
14. (5E)-13,14-didehydro-16,16-dimethyl-18,18,19, 19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 13 or an obvious chemical equivalent thereof.
15. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)non-1-en-6-ynyl]
bicyclo[3.3.0]octan-3-one in tetrahydrofuran and the isomers separated by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
16. (5E)-13,14-didehydro-13,18,19,19-tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process according to claim 1, which comprises adding potassium butylate in dimethyl sulphoxide and tetra-hydrofuran to 4-carboxybutyltriphenylphosphonium bromide and reacting the Wittig reagent so obtained with a solution of (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl]bicyclo[3.3.0]
octan-3-one in tetrahydrofuran and the isomers separated by chromatography and the ether obtained treated with a mixture of acetic acid/water/tetrahydrofuran to split off the blocking groups.
18. (5E)-13,14-didehydro-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 17 or an obvious chemical equi-valent thereof.
19. A process according to claim 7, in which the free acid obtained is reacted with an aqueous solution of tris(hydroxymethyl)aminomethane.
20. (5E)-(16RS)-13,14-didehydro-16-methyl-18,18, 19,19-tetradehydro-6a-carbaprostaglandin I2 whenever prepared or produced by the process claimed in claim 19 or an obvious chemical equivalent thereof.
CA000421004A 1982-02-08 1983-02-07 Carbacyclins, process for their preparation thereof, and use thereof as medicinal agents Expired CA1215362A (en)

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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
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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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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

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