Carbacyclins, their preparation and pharmacological use

Compounds of Formula I ##STR1## wherein X is oxygen or CH.sub.2 ; PA0 A is CH.sub.2 --CH.sub.2, trans-CH.dbd.CH or C.tbd.C; PA0 W is free or functionally modified hydroxymethylene or free or functionally modified ##STR2## and the OH groups may be in the .alpha.- or the .beta.-position; D is straight chain or branched, saturated or unsaturated hydrocarbon aliphatic of from 1 to 10 carbon atoms, which may be substituted by fluorine; PA0 E is C.tbd.C or CR.sub.3 .dbd.CR.sub.4, R.sub.3 and R.sub.4 being different and being hydrogen or alkyl of 1 to 5 carbon atoms; PA0 R.sub.1 is free or functionally modified hydroxy; and PA0 R.sub.2 is alkyl, cycloalkyl, optionally substituted aryl or heterocyclic, have valuable pharmacological properties, e.g., hypotensive and bronchodilatory characteristics. They can furthermore be used for prophylaxis and therapy of coronary infarct and as a treatment for stroke. They are produced by means of reduction of the corresponding 1-carbonic acid derivatives.

BACKGROUND OF THE INVENTION 
The present invention relates to new prostacyclin derivatives, a method for 
producing them and their use as medicines. 
In German laid-open applications DE-OS 28 45 770, 29 00 352, 29 02 442, 29 
04 655, 29 09 088 and 29 12 409, analogs of (5E)- and 
(5Z)-6a-carbaprostaglandin I.sub.2 are described. The nomenclature of the 
compounds of this invention is based on a proposal by Morton and Brokaw 
(J. Org. Chem., Vol. 44 [1979], p. 2880). In synthesizing these compounds, 
two double-bond isomers are always created. These are characterized by the 
symbols (5E) or (5Z). The two isomers of this prototype are illustrated by 
the following structural formulas: 
##STR3## 
From the very extensive prior art in prostacyclins and their derivatives, 
it is known that this class of substances is useful because of their 
biological and pharmacological properties for treating mammals, including 
humans. However, their use in medicine frequently meets with difficulties, 
because the periods of efficacy are too short for therapeutic purposes. 
All changes in structure in ongoing research have the purpose of both 
extending the period of efficacy and increasing the selectivity of 
effectiveness. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of this invention to provide such improved 
prostacyclin compounds. 
Upon further study of the specification and appended claims, further 
objects and advantages of this invention will become apparent to those 
skilled in the art. 
These objects have been achieved by this invention by replacing the 
1-carboxyl group in the 6a-carbacyclins and 6a-(3a-oxa)carbacyclins by a 
hydroxymethyl group, whereby a longer period of efficacy, greater 
selectivity and improved effectivness is attained. 
Thus, this invention relates to carbacyclin derivatives of Formula I: 
##STR4## 
wherein X is oxygen or CH.sub.2 ; 
A is CH.sub.2 --CH.sub.2, trans--CH.dbd.CH or C.tbd.C; 
W is free or functionally modified hydroxymethylene or a free or 
functionally modified 
##STR5## 
group, wherein the OH groups may be in the .alpha.-or the .beta.-position; 
D is straight- or branched-chain, optionally unsaturated, alkylene of from 
1 to 10 carbon atoms, optionally substituted by fluorine atoms or 
C.sub.1-4 alkyl, if the total content of carbon atoms is no more than 10; 
E is C.tbd.C or CR.sub.3 .dbd.CR.sub.4, wherein R.sub.3 and R.sub.4 are 
different and each is hydrogen or alkyl of 1-5 carbon atoms; 
R.sub.1 is a free or functionally modified hydroxy group; and 
R.sub.2 is alkyl, alkenyl, cycloalkyl, optionally substituted aryl or a 
heterocyclic group. 
The hydroxy groups in R.sub.1 and W may be conventionally functionally 
modified, for instance by conventional etherification or esterification. 
The free or modified hydroxy groups in W may be in either the .alpha. or 
the .beta. positions, free hydroxy groups being preferred. Suitable ether 
and acyl groups are well-known to those skilled in the art. Preferred 
groups are easily cleavable ether radicals, including tetrahydropyranyl, 
tetrahydrofuranyl, .alpha.-ethoxyethyl, trimethylsilyl, dimethyl 
tertiary-butylsilyl and tribenzylsilyl. Suitable acyl groups can be 
derived from C.sub.1-15 hydrocarbon carboxylic or sulfonic acids, e.g., 
C.sub.1 -C.sub.4 -alkanoyl radicals such as acetyl, propionyl or butyryl 
or benzoyl. 
Suitable groups for R.sub.2 include straight- and branched-chain, saturated 
and unsaturated aliphatic hydrocarbon radicals, preferably saturated, 
having from 1 to 10 and, in particular, 1 to 7 carbon atoms. These may 
optionally be substituted by optionally substituted aryl, all defined 
below for R.sub.2 per se. Examples include methyl, ethyl, propyl, butyl, 
isobutyl, tertiary-butyl, pentyl, hexyl, heptyl, octyl, butenyl, 
isobutenyl, propenyl, pentenyl, hexenyl, benzyl, and p-chlorobenzyl. Alkyl 
radicals of 1 to 4 carbon atoms are particularly preferred. 
Suitable cycloalkyl groups R.sub.2 may contain 4 to 10 and, preferably 5 or 
6 carbon atoms in the ring. The rings may be substituted by alkyl groups 
having from 1 to 4 carbon atoms. Examples include cyclopentyl, cyclohexyl, 
methylcyclohexyl and adamantyl. 
Examples of substituted or unsubstituted C.sub.6-10 -aryl groups R.sub.2 or 
as substituents of the aliphatic groups R.sub.2, include; phenyl, 
1-naphthyl and 2-naphthyl, which may each be substituted by 1 to 3 halogen 
atoms, a phenyl group, 1 to 3 alkyl groups each of 1 to 4 carbon atoms, or 
a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C.sub.1 -C.sub.4 
-alkoxy or hydroxy group. Preferred is substitution in the 3- or 
4-position on the phenyl ring by fluorine, chlorine, C.sub.1 -C.sub.4 
-alkoxy or trifluoromethyl, for example, or in the 4-position by hydroxy. 
Suitable heterocyclic groups R.sub.2 include 5- and 6-member heterocyclics, 
preferably aromatic, the preferred ones being those having one heteroatom, 
such as nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 
3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and others. 
Suitable alkylene groups D include straight-chain or branched-chain 
alkylene radicals optionally containing a double bond, but preferably 
saturated. These have 1 to 10 (together with C.sub.1 -C.sub.4 -alkyl 
substituents) and, in particular, 1 to 5 carbon atoms. They are optionally 
substituted by fluorine atoms or C.sub.1 -C.sub.4 -alkyl groups, 
particularly in the 1- or 2-position. Examples include methylene, 
flouromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, 
tetramethylene, pentamethylene, 1-methyl-tetramethylene, pentamethylene, 
1-methyl-tetramethylene, 1-methyltrimethylene, 2-methyl-trimethylene, 
2-methyl-tetramethylene. If a double bond is present, the alkylene radical 
generally has 4 to 10 carbon atoms, and it exists in the 2- or 3-position. 
The alkyl groups R.sub.3, R.sub.4 and R.sub.5 (see below) can be straight 
chain or branched and have 1 to 5 carbon atoms. Specific examples include 
the radicals already named for the alkyl R.sub.2 groups. 
The present invention furthermore relates to a method for producing the 
carbacyclin derivatives of Formula I comprising, in a manner known per se, 
reducing a compound of Formula II: 
##STR6## 
in which R.sub.1, R.sub.2, X, A, W, D and E are as defined above and 
R.sub.5 is alkyl of 1 to 5 carbon atoms or hydrogen, and, optionally, 
subsequently separating isomers and/or releasing protected hydroxy groups, 
in any sequence. 
The reduction of the compounds of Formula II can be performed with a 
conventional reducing agent known to be suitable for the reduction of 
esters or carbonic acids, such as lithium aluminum hydride, diisobutyl 
aluminum hydride, and so forth. Suitable solvents include: diethylene 
ether, tetrahydrofuran, diethylene glycol, dimethyl ether, toluol and so 
forth. The reduction is performed at temperatures from -30.degree. C. up 
to the boiling temperature of the solvent used, and preferably from 
0.degree. C. to 30.degree. C. 
The release of a functionally modified OH group to produce other compounds 
of Formula I is also effected by known methods. For example, the splitting 
of ether protective groups can be performed in an aqueous solution of an 
organic acid, such as acetic acid, propionic acid and others, or in an 
aqueous solution of an inorganic acid, such as hydrochloric acid. In order 
to improve solubility, an inert organic solvent which is miscible with 
water is advantageously added. Suitable organic solvents include alcohols, 
such as methanol and ethanol, and ether, such as dimethoxyethane, dioxane 
and tetrahydrofuran, for example. Tetrahydrofuran is preferred. Splitting 
is preferably performed at temperatures of 20.degree. C. to 80.degree. C. 
The splitting of silyl ether protective groups is effected, for example, 
with tetrabutyl ammonium fluoride or with KF in the presence of a crown 
ether. Examples of suitable solvents include tetrahydrofuran, diethyl 
ether, dioxane, methylene chloride, etc. The splitting is preferably 
performed at temperatures of 0.degree. C. to 80.degree. C. 
Many of the starting material compounds of Formula II are known; see, e.g., 
U.S. Pat. No. 4,238,414, BP's 2,014,143, 2,012,265 and 2,013,661 and U.S. 
Application Ser. No. 333,099 filed on Dec. 21, 1981, all of whose 
disclosures are incorporated by reference herein. They can be 
conventionally produced, by way of example, in a manner known per se, 
e.g., by converting an aldehyde of Formula III (see, e.g., German 
laid-open application DE-OS 28 45 770, or its U.S. equivalent Ser. No. 
086,506, whose disclosures are incorporated by reference herein) 
##STR7## 
in an olefinizing reaction, with a phosphonate of Formula IV 
##STR8## 
in which D, E and R.sub.2 are as defined above, into a ketone of Formula V 
##STR9## 
After the reduction of the keto group with zinc boron hydride or sodium 
boron hydride or reaction with alkyl magnesium bromide or alkyl lithium 
and a subsequent epimer separation and hydrogenation of the double bond or 
halogenation thereof followed by a double dehydrohalogenation, if needed, 
compounds of Formula VI are obtained 
##STR10## 
All such reactions and those mentioned below are conventional and 
discussed, e.g., in the many references cited above. 
Saponification of the ester group, for instance with potassium carbonate in 
methanol, and ketal splitting with aqueous acetic acid, as well as 
functional modification of the free hydroxy groups, if needed, for 
instance by etherification with dihydropyran, produces a ketone having 
Formula VII. 
##STR11## 
After an olefinizing reaction with phosphonoacetic acid triethyl ester or 
phosphonoacetic acid trimethyl ester and subsequent reduction with lithium 
aluminum hydride, the compounds of Formula VIII which are isomeric at the 
double bonds are obtained; these can be separated as needed. 
##STR12## 
Etherification of the alcohol VIII with a halogen acetic acid derivative of 
Formula IX 
##STR13## 
in which Hal is a chlorine or bromine atom and R.sub.5 is an alkyl radical 
of 1 to 5 carbon atoms or one hydrogen atom or an alkali metal, in the 
presence of a base, and a subsequent esterification, as needed, produces 
the compounds of Formula II, wherein X is oxygen. 
The reaction of a compound of Formula VIII with a halogen acetic acid 
derivative of Formula IX can be performed at temperatures from 0.degree. 
C. to 100.degree. C., preferably from 10.degree. C. to 80.degree. C., in 
an aprotic solvent or solvent mixture, such as dimethylsulfoxide, 
dimethylformamide, tetrahydrofuran, diethylene glycol dimethylether, etc. 
Suitable bases are those known to one skilled in the art for 
etherification purposes, such as sodium hydride, potassium tertiary 
butylate, butyl lithium and so forth. 
The starting material compounds of Formula II, wherein X is --CH.sub.2 -- 
can be produced, for instance, in a manner known per se by reacting a 
ketone of Formula VII with a Wittig reagent of the Formula X 
##STR14## 
and, as needed, subsequently separating the double-bond isomers and/or 
esterifying the free carboxyl group. 
The production of the phosphonates of Formula IV is effected in a manner 
known per se, e.g., by reacting an alkyl halide (produceable from the 
appropriate alcohol by halogenation) of Formula XI 
##STR15## 
with the diane ion created from the phosphonate of Formula XII 
##STR16## 
in which R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are hydrogen, fluorine or 
an alkyl group of 1 to 5 carbon atoms, and R.sub.2 and E are as defined 
above. 
Another means of obtaining the phosphonates of Formula IV involves reacting 
the anion of methylphosphonic acid dimethyl ester with an ester of Formula 
XIII 
##STR17## 
in which D, E and R.sub.2 are as defined above and R.sub.10 is alkyl of 1 
to 5 carbon atoms. The latter can be obtained from the appropriate malonic 
acid ester by alkylation with the halide of Formula XI and subsequent 
decarbalkoxylation. The ester of Formula XIV 
##STR18## 
is conventionally obtainable by means of alkylation with the appropriate 
alkyl halide. 
The compounds of this invention reduce blood pressure and act as 
bronchodilators. They are also suitable for vasodilation, for inhibiting 
thrombocyte aggregation and for inhibiting the secretion of gastric acid. 
The new carbacyclin derivatives of Formula I accordingly, are valuable 
pharmaceutical agents. Furthermore, with a similar spectrum of 
effectiveness in comparison with corresponding prostaglandins, they have 
greater specificity and, above all, a substantially longer-lasting 
effectiveness. In comparison with PGI.sub.2, they are distinguished by 
greater stability. The high degree of tissue-specificity of the new 
carbacyclins can be demonstrated by examining smooth-muscle organs such as 
the guinea pig ileum or the isolated trachea in rabbits, where 
substantially less stimulation is observed than upon administration of 
natural prostaglandins of the E-, A- or F-type. 
The new carbacyclins have the properties typical of prostacyclins, such as 
reduction of the peripheral arterial and coronary vascular resistance; 
inhibition of thrombocyte aggregation and dissolution of platelet thrombi; 
myocardial cell protection and thus a reduction in systemic blood pressure 
without at the same time reducing the volume per heartbeat or the 
efficiency of coronary blood circulation; treatment of heart attack; 
prophylaxis and therapy in coronary illness, coronary thrombosis, coronary 
infarct, peripheral artery diseases, arteriosclerosis and thrombosis; 
therapy for shock; inhibition of bronchoconstriction; inhibition of 
gastric acid secretion and cell protection for the mucous membranes of the 
stomach and intestines; anti-allergic properties; reduction in pulmonary 
vascular resistance and pulmonary blood pressure; promotion of efficient 
blood circulation in the kidneys; application in place of heparin or as an 
adjuvant therapy in hemofiltration dialysis, preservation of blood plasma 
components, in particular blood platelets; inhibition of labor pains and 
treatment of toxemia during pregnancy; and increasing the efficiency of 
cerebral blood circulation. The new carbacyclins furthermore have 
antiproliferative and antidiarrheagenic properties (that is, they prevent 
accumulations of fluid in the small intestines). 
Suitable effective doses of the compounds is 1 to 1500 .mu.g/kg/day, when 
used in a human patient. The standard unit dose for the pharmaceutically 
acceptable compositions of this invention is 0.01-100 mg. 
When given orally to conscious, hypertonic rats, the compounds of this 
invention exhibit a greater and longer-lasting effect in reducing blood 
pressure than PGE.sub.2 or PGA.sub.2, yet without causing diarrhea as with 
PGE.sub.2 or cardiac arrhythmias as with PGA.sub.2. 
In anesthetized rabbits, the compounds of this invention exhibit a greater 
and substantially longer-lasting effect in reducing blood pressure in 
comparison with PGE.sub.2 and PGA.sub.2, without affecting other 
smooth-muscle organs or organ functions. 
For parenteral administration, sterile, injectable, aqueous or oil-based 
solutions are used. For oral application, tablets, lozenges or capsules 
are suitable examples. 
Their administration is analogous to that of PGI.sub.2 or other PG-type 
compounds. 
The novel prostacyclin analogs of this invention are substantially more 
selective with regard to potency, as compared with known PG analogs in 
causing prostaglandin-like biological responses, and have a substantially 
longer duration of biological activity. Accordingly, each of these novel 
prostaglandin analogs is surprisingly and unexpectedly more useful than 
one of the corresponding conventional prostaglandins for at least one of 
the pharmacological purposes indicated above because it has a different 
and narrower spectrum of biological potency than the known prostaglandin, 
and therefore is more specific in its activity and causes smaller and 
fewer undesired side effects than when the prostaglandin is used for the 
same purpose. Moreover, because of its prolonged activity, fewer and 
smaller doses of the novel prostaglandin analog are frequently effective 
in attaining the desired result. 
The invention thus relates both to medicines per se based on the compounds 
of Formula I and to conventional auxiliary and carrier substances 
formulated in combination therewith. 
The substances of this invention are intended, e.g., to serve in 
combination with the conventional auxiliary substances known in the 
pharmacopeia for the production of agents for reducing blood pressure, for 
instance.

Without further elaboration, it is believed that one skilled in the art 
can, using the preceding description, utilize the present invention to its 
fullest extent. The following preferred specific embodiments are, 
therefore, to be construed as merely illustrative, and not limitative of 
the remainder of the disclosure in any way whatsoever. In the following 
examples, all temperatures are set forth uncorrected in degrees Celsius; 
unless otherwise indicated, all parts and percentages are by weight. 
EXAMPLE 1 
(5E)-(16RS)-2-Descarboxy-2-hydroxymethyl-3-oxa-16-methyl-18,18,19,19-tetrad 
ehydro-6a-carbaprostaglandin-I.sub.2 
A solution of 360 mg of 
(5E)-(16RS)-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandi 
n-I.sub.2 -methylester-11,15-bis-(tetrahydropyranyl ether) in 25 ml of 
tetrahydrofuran is added in portions at 0.degree. C. to 180 mg of lithium 
aluminum hydride and stirred for 30 minutes at 0.degree. C. Excess reagent 
is then destroyed by the drop-by-drop addition of acetic ester; 3 ml of 
water is added; the product is stirred for 1 hour, filtered and 
concentrated by evaporation in a vacuum. The result, in the form of a 
colorless oil, is 350 mg of 
(5E)-(16RS)-2-descarboxy-2-hydroxymethyl-3-oxa-16-methyl-18,18,19,19-tetra 
dehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl 
ether). 
IR (CHCl.sub.3): 3600, 3450, 2942, 2870, 1453, 1440, 972/cm. 
In order to split off the protective groups, 320 mg of the 
bis-tetrahydropyranyl ether is stirred with 30 ml of a mixture of acetic 
aid, water and tetrahydrofuran (in a proportion of 65:35:10) for 16 hours 
at room temperature and is then concentrated by evaporation in a vacuum. 
The residue is chromatographed with methylene chloride/isopropanol (at 
9:1) using silica gel. The product obtained is 162 mg of the compound of 
the above title in the form of a colorless oil. 
IR: 3600, 3430, 2999, 2922, 2860, 1600, 1455, 1430, 1105, 971/cm. 
The starting material for the above title compound is produced as follows. 
1(a) 
(5E)-(16RS)-Methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I 
.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether) 
A solution of 0.5 g of 
(5E)-(16RS)-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I 
.sub.2 -11,15-bis-(tetrahydropyran-2-yl ether) in 25 ml of methylene 
chloride is added drop by drop, while stirring at 0.degree. C., to an 
etheric diazomethane solution until there is a durable yellow coloration. 
After the solvent is distilled off, the residue is purified by 
chromatography using silica gel with hexane/ether (at 3:2) and 0.45 g of 
the title compound is obtained in the form of an oil. 
IR: 2945, 2870, 1750, 972/cm. 
EXAMPLE 2 
(5E)-2-Descarboxy-2-hydroxymethyl-3-oxa-16,16,20-trimethyl-18,18,19,19-tetr 
adehydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 280 mg of the methyl ester produced in accordance 
with Example 2e yields 268 mg of 
(5E)-2-descarboxy-2-hydroxymethyl-3-oxa-16,16,20-trimethyl-18,18,19,19-tet 
radehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl 
ether) in the form of a colorless oil. 
IR: 3600, 3430, 2940, 970/cm. 
After splitting off the protective groups as in Example 1, 120 mg of the 
title compound is obtained as a colorless oil. 
IR: 3610, 3430, 2925, 2865, 1600, 972/cm. 
The starting material for the above title compound is produced as follows. 
2(a) 3,3-Dimethyl-2-oxo-oct-5-inyl-phosphonic acid-dimethyl ester 
To a suspension of 7.1 g of sodium hydride (50% suspension in oil) in 220 
ml of absolute tetrahydrofuran a solution of 31.5 g of 
3-methyl-2-oxo-butylphosphonic acid dimethyl ester in 74 ml of absolute 
tetrahydrofuran is added in drops at 24.degree. C.; the product is stirred 
for 1.5 hours and then, at 0.degree. C., 111 ml of a 1.6 molar butyl 
lithium solution in hexane is added drop by drop and stirred for 20 
minutes. A solution of 29 g of 1-bromo-2-pentine in 44 ml of absolute 
tetrahydrofuran is then added to the above solution drop by drop, stirred 
for 3 hours at 0.degree. C., neutralized with 3N of hydrochloric acid and 
concentrated in a vacuum. 50 ml of brine is added; extraction is performed 
three times, each time with 200 ml of methylene chloride; the organic 
extract is shaken twice, each time with 50 ml of brine; the product is 
dried with magnesium sulfate and concentrated by evaporation in a vacuum. 
After distillation of the residue at 0.6 Torr and 125.degree. C., 23 g of 
the title compound is obtained in the form of a colorless liquid. 
IR: 3000, 2962, 2860, 1720/cm. 
2(b) 
(1R,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy-6-[(E)-(3R)-3-hydroxy-4,4-dim 
ethyl-non-1-en-6-inyl]-bicyclo[3.3.0]octane. 
To a suspension of 0.7 g of sodium hydride (55% suspension in oil) in 60 ml 
of dimethoxyethane (DME), a solution of 4.5 mg of the phosphonate produced 
according to Example 2a in 35 ml of DME is added drop by drop at 0.degree. 
C. and stirred for 1 hour at 0.degree. C. A solution of 4.75 g of 
(1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane 
in 60 ml of DME is added at -20.degree. C.; the product is stirred for 1.5 
hours at -20.degree. C.; saturated ammonium chloride solution is infused 
and extraction is performed with ether. The organic extract is washed with 
neutral water, dried via magnesium sulfate and concentrated in a vacuum. 
After chromatography of the residue on silica gel, there is obtained with 
ether/hexane (6:4), 4.7 g of the unsaturated ketone as an oil. 
IR: 2940, 2860, 1715, 1670, 1627, 948/cm. 
At -40.degree. C., 2.6 g of sodium borohydride is added to a solution of 
4.7 g of the ketone and 150 ml of methanol, portion wise, and this is 
stirred for 1 hour at -40.degree. C. The product is then diluted with 
ether, washed with neutral water, dried with magnesium sulfate and 
concentrated in vacuum. By means of column chromatography using silica 
gel, with ether/hexane (at 7:3), one obtains first 1.8 g of the title 
compound (PG nomenclature: 15.alpha.-hydroxy) and also, as a more-polar 
component, 1.6 g of the isomeric 15.beta.-hydroxy compound as colorless 
oils. 
IR: 3610, 3410 (wide), 2943, 1712, 1603, 1588, 970, 948/cm. 
2(c) 
(1R,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetr 
ahydropyran-2-yloxy)-non-1-en-6-inyl]-bicyclo[3.3.0]octane-3-one. 
A mixture of 1.8 g of the .alpha. alcohol produced in accordance with 
Example 2b and 0.7 grams of potassium carbonate in 60 ml of methanol is 
stirred for 16 hours at room temperature in argon. The product is then 
concentrated in a vacuum, diluted with ether and washed with neutral 
brine. It is dried via magnesium sulfate and concentrated by evaporation 
in a vacuum. The residue after evaporation is stirred for 16 hours at room 
temperature with 40 ml of a mixture of acetic acid, water and 
tetrahydrofuran (at 65:35:10) and then concentrated by evaporation in a 
vacuum. After filtration of the residue via silica gel, 1.15 g of the 
ketone is obtained with acetic acid/hexane (at 7:3); the ketone is in the 
form of an oil. 
A solution of 1.15 g of the ketone, 1.2 ml of dihydropyran and 10 mg of 
p-toluolsulfonic acid in 40 ml of methylene chloride is stirred for 30 
minutes at 0.degree. C. The product is then diluted with ether, shaken 
with dilute sodium bicarbonate solution, washed with neutral water, dried 
via magnesium sulfate and concentrated by evaporation in a vacuum. 1.65 g 
of the bis-tetrahydropyranyl ether is obtained, which is used without any 
further purification. 
IR: 2962, 2865, 1738, 972/cm. 
2(d) 
2-{(E)-(1S,5S,6R,7R)-7-Tetrahydropyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3 
-(tetrahydropyran)-2-yloxy)-non-1-en-6-inyl]-bicyclo[3.3.0]octane-3-ylidene 
}ethane-1-ol 
At 0.degree. C., 0.9 g of potassium tertiary butylate is added to a 
solution of 2.1 g of phosphonic acetic acid triethyl ester in 40 ml of 
tetrahydrofuran, stirred for 10 minutes, mixed with a solution of 2.2 g of 
the ketone produced according to Example 2c in 20 ml of toluol and stirred 
at room temperature for 20 hours. The product is diluted with 200 ml of 
ether, shaken twice with water and once with 20% caustic soda, washed with 
neutral water, dried via magnesium sulfate and concentrated by evaporation 
in a vacuum. The residue is filtered with hexane/ether (at 3:2) using 
silica gel. 1.95 g of the unsaturated ester is obtained in the form of a 
colorless oil. 
IR: 2943, 2865, 1700, 1655, 972/cm. 
0.6 g of lithium aluminum hydride is then added in portions at 0.degree. C. 
to a stirred solution of 1.95 g of the ester produced as above in 60 ml of 
ether and is stirred for 30 minutes at 0.degree. C. The excess reagent is 
destroyed by the addition, drop by drop, of acetic ester; 3 ml of water is 
added and the product is stirred for 2 hours at 20.degree. C., filtered 
and concentrated by evaporation in a vacuum. The residue is 
chromatographed with ether/hexane (at 3:2) using silica gel. There is 
obtained 0.45 g of 
2-{(Z)-(1S,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl- 
3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl]-bicyclo[3.3.0]octane-3-ylidene 
}ethane-1-ol and the less polar compound, 0.7 g of the title compound, in 
the form of colorless oils. 
IR: 3600, 3445, 2940, 2865, 1600, 972/cm. 
2(e) 
(5E)-3-Oxa-16,16,20-trimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglan 
din-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether) 
To a solution of 830 mg of the alcohol, produced according to Example 2d, 
in 13 ml of tetrahydrofuran, 170 mg of sodium hydride (a 55% suspension in 
oil) is added and stirred for 30 minutes at 24.degree. C. A solution of 
270 mg of bromoacetic acid in 4.4 ml of tetrahydrofuran is then added drop 
by drop and the result is heated for 24 hours in reflux. The result is 
cooled down, acidified with 5% sulfuric acid, subjected to extraction with 
methylene chloride, shaken with water and concentrated by evaporation in a 
vacuum. The residue is added to 100 ml of ether and subjected to 
extraction four times, each time with 20 ml of 4% caustic soda. The 
alkaline phase is acidified with 5% sulfuric acid and subjected to 
extraction with methylene chloride; the organic extract is washed three 
times with water, dried via magnesium sulfate and concentrated by 
evaporation in a vacuum. The product obtained is 640 mg of the 3-oxa acid 
as a colorless oil which is uniform in terms of thin-film chromatography 
and which is converted into the methyl ester in analogy to Example 1a. 
IR: 2945, 2865, 1748, 970/cm. 
EXAMPLE 3 
(5E)-2-Descarboxy-2-hydroxymethyl-3-oxa-16,16-dimethyl-18,18,19,19-tetradeh 
ydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 550 mg of the methyl ester produced according to 
Example 3d yields 540 mg of 
(5E)-2-descarboxy-2-hydroxy-methyl-3-oxa-16,16-dimethyl-18,18,19,19-tetrad 
ehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) 
as a colorless oil. 
IR: 3600, 3450, 2942, 2865, 972/cm. 
After splitting off the protective groups as in Example 1, 280 mg of the 
title compound is obtained as a colorless oil. 
IR: 3600, 3450, 2926, 2865, 1600, 972/cm. 
The starting material for the above title compound is produced as follows. 
3(a) 
(1R,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy-6-[(E)-(3R)-3-hydroxy-4,4-dim 
ethyl-oct-1-en-6-inyl]-bicyclo[3.3.0]-octane 
In analogy to Example 2b, 9.4 g of 
(1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]-octan 
e and 9.1 g of 3,3-dimethyl-2-oxo-oct-5-inyl-phosphonic acid-dimethyl ester 
yields 9.2 g of the unsaturated ketone. By means of reduction with sodium 
boron hydride, 3.7 g of the title compound is obtained in the form of a 
colorless oil. 
IR: 3600, 3400, 2942, 1712, 1602, 1589, 972, 949/cm. 
3(b) 
(1R,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl-3-(tetr 
ahydropyran-2-yloxy)-oct-1-en-6-inyl]-bicyclo[3.3.0]octane-3-one 
In analogy to Example 2c, 3.7 g of the .alpha. alcohol obtained as in 
Example 3a yields 3.4 g of the bistetrahydropyranyl ether as a colorless 
oil. 
IR: 2960, 2865, 1737, 970/cm. 
3(c) 
2-{(E)-(1S,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6-[(E)-(3R)-4,4-dimethyl- 
3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl]-bicyclo[3.3.0]octane-3-ylidene 
}ethane-1-ol 
In analogy to Example 2d, 3.2 g of the ketone produced as in Example 3b 
yields 1.1 g of the title compound as a colorless oil. 
IR: 3610, 3440, 2942, 2865, 1600, 970/cm. 
3(d) 
(5E)-16,16-Dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin- 
I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether) 
In analogy to Example 2e, 1 g of the alcohol produced in accordance with 
Example 3c yields 760 mg of the title compound as a colorless oil. 
IR: 2945, 2865, 1750, 972/cm. 
EXAMPLE 4 
(5Z)-(16RS)-2-Descarboxy-2-hydroxymethyl-3-oxa-16-methyl-18,18,19,19-tetrad 
ehydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 240 mg of 
(5Z)-(16RS)-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandi 
n-I.sub.2 -methyl ester-11,15-bis(tetrahydropyranyl ether), produced from 
the corresponding acid according to Example 1b, yields 240 mg of 
(5Z)-(16RS)-2-descarboxy-2-hydroxymethyl-3-oxa-16-methyl-18,18,19,19-tetra 
dehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) 
as a colorless oil. 
IR: 3610, 3450, 2943, 2865, 1453, 1440, 970/cm. 
After splitting off the protective groups as in Example 1, 165 mg of the 
title compound is obtained as a colorless oil. 
IR: 3600, 3435, 2922, 2860, 1600, 1456, 1430, 1105, 970/cm. 
EXAMPLE 5 
(5E)-(16RS)-2-Descarboxy-16,20-dimethyl-2-hydroxymethyl-3-oxa-18,18,19,19-t 
etradehydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 340 mg of 
(5E)-(16RS)-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostag 
landin-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced 
from the corresponding acid with diazomethane according to Example 1a, 
yields 335 mg of 
(5E)-(16RS)-2-descarboxy-16,20-dimethyl-2-hydroxymethyl-3-oxa-18,18,19,19- 
tetradehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl 
ether) as a colorless oil. 
IR: 3600, 3400, 2942, 2870, 972/cm. 
After splitting off the protective groups as in Example 1, 145 mg of the 
title compound are obtained in the form of a colorless oil. 
IR: 3610, 3450, 2925, 2860, 1600, 972/cm. 
EXAMPLE 6 
(5E)-(16RS)-2-Descarboxy-16,20-dimethyl-2-hydroxy 
methyl-3-oxa-19,19,20,20-tetradehydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 390 mg of 
(5E)-(16RS)-16,20-dimethyl-3-oxa-19,19,20,20-tetradehydro-6a-carba-prostag 
landin-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyran ether), produced 
from the corresponding acid with diazomethane as in Example 1a, yields 385 
mg of 
(5E)-(16RS)-2-descarboxy-16,20-dimethyl-2-hydroxymethyl-3-oxa-19,19,20,20- 
tetradehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl 
ether) as a colorless oil. 
IR: 3610, 3450, 2940, 2870, 1602, 974/cm. 
After splitting off the protective groups as in Example 1, 220 mg of the 
title compound are obtained as a colorless oil. 
IR: 3610, 3450, 2925, 2962, 1600, 1455, 1432, 1105, 974/cm. 
EXAMPLE 7 
(5E)-(15RS)-2-Descarboxy-2-hydroxymethyl-15-methyl-3-oxa-18,18,19,19-tetrad 
ehydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 180 mg of 
(5E)-(15RS)-15-methyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandi 
n-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from 
the corresponding acid with diazomethane as in Example 1a, yields 170 mg 
of (5E)-(15RS)-2-descarboxy-2-hydroxymethyl-15-methyl-3-oxa-18,18,19,19-te 
tradehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl 
ether) as a colorless oil. 
IR: 3620, 3440, 2945, 2865, 975/cm. 
After splitting off the protective groups as in Example 1, 85 mg of the 
title compound are obtained as a colorless oil. 
IR: 3620, 3450, 2925, 2865, 1602, 975/cm. 
EXAMPLE 8 
(5E)-2-Descarboxy-2-hydroxymethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-p 
rostaglandin-I.sub.2 
In analogy to Example 1, 540 mg of 
(5E)-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.sub.2 -methyl 
ester-11,15-bis-(tetrahydropyranyl ether), produced from the corresponding 
acid with diazomethane according to Example 1a, yields 530 mg of 
(5E)-2-descarboxy-2-hydroxymethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba- 
prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as a colorless 
oil. 
IR: 3600, 3420, 2942, 2865, 970/cm. 
After splitting off the protective groups as in Example 1, 290 mg of the 
title compound are obtained as oil. 
IR: 3610, 3440, 2925, 2862, 1602, 1455, 1432, 1105, 972/cm. 
EXAMPLE 9 
(5E)-(16RS)-2-Descarboxy-16,19-dimethyl-2-hydroxymethyl-3-oxa-18,19-didehyd 
ro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 290 mg of 
(5E)-(16RS)-16,19-dimethyl-3-oxa-18,19-didehydro-6a-carba-prostaglandin-I. 
sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from the 
corresponding acid as in Example 1, yields 280 mg of 
(5E)-(16RS)-2-descarboxy-16,19-dimethyl-2-hydroxymethyl-3-oxa-18,19-didehy 
dro-6a-carba-prostaglandin-I.sub.2 -11,15-bis(tetrahydropyranyl ether) as a 
colorless oil. 
IR: 3600, 3400, 2945, 2865, 974/cm. 
After splitting off the protective groups as in Example 1, 155 mg of the 
title compound are obtained as a colorless oil. 
IR: 3600, 3400, 2925, 2865, 1600, 1455, 1435, 1105, 974/cm. 
EXAMPLE 10 
(5E)-(16RS)-2-Descarboxy-2-hydroxymethyl-16-methyl-18,18,19,19-tetradehydro 
-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 400 mg of 
(5E)-(16RS)-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.su 
b.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from the 
corresponding acid with diazomethane as in Example 1a, yields 385 mg of 
(5E)-(16RS)-2-descarboxy-2-hydroxymethyl-16-methyl-18,18,19,19-tetradehydr 
o-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as a 
colorless oil. 
IR: 3610, 3450, 2945, 2865, 974/cm. 
After splitting off the protective groups as in Example 1, 235 mg of the 
title compound are obtained as a colorless oil. 
IR: 3600, 3400, 2925, 2865, 1600, 974/cm. 
EXAMPLE 11 
(5E)-2-Descarboxy-2-hydroxymethyl-16,16-20-trimethyl-18,18,19,19-tetradehyd 
ro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 550 mg of the methyl ester produced according to 
Example 11a yields 540 mg of 
(5E)-2-descarboxy-2-hydroxymethyl-16,16,20-trimethyl-18,18,19,19-tetradehy 
dro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as 
a colorless oil. 
IR: 3600, 3420, 2940, 2865, 972/cm. 
After splitting off the protective groups as in Example 1, 325 mg of the 
title compound are obtained as a colorless oil. 
IR: 3600, 3400, 2925, 2865, 1600, 972/cm. 
The starting material for the above title compound is produced as follows. 
11(a) 
(5E)-16,16,20-Trimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I. 
sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether) 
To a solution of 15 g of 4-carboxybutyltriphenylphosphonium bromide in 35 
ml of absolute dimethyl sulfoxide (DMSO), at 15.degree. C. in argon, 60 ml 
of a 1.04 molar solution of methylsulfinyl methyl sodium in DMSO is added 
drop by drop and stirred for 30 minutes at 20.degree. C. To the red ylene 
solution, a solution of 2.5 g of the ketone produced according to Example 
2c in 15 ml of absolute DMSO is added drop by drop, and the result is 
stirred for 5 hours at 45.degree. C. The reaction mixture is poured onto 
ice water, acidified with 10% citric acid solution to pH 4-5 and subjected 
to extraction three times with methylene chloride. The organic phase is 
shaken with brine, dried via magnesium sulfate and concentrated by 
evaporation in a vacuum. After chromatography of the residue using silica 
gel, the result first obtained, with ether/hexane (at 1:1), is 0.7 g of 
(5Z)-16,16,20-trimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I. 
sub. 2 -11,15-bis-(tetrahydropyran-2-yl ether), as well as the more-polar 
component, 1.2 g of 
(5Z)-16,16,20-trimethyl-18,18,19,19-tetradehyro-6a-carba-prostaglandin-I.s 
ub.2 -11,15-bis-(tetrahydropyranyl ether), in the form of colorless oils. 
IR: 3510 (wide), 2960, 2868, 1710, 974/cm. 
For the purpose of esterification, 1.2 g of the above-obtained 
(E)-configuration acid is dissolved in 60 ml of methylene chloride and 
mixed at 0.degree. C., drop by drop, with an etheric diazomethane solution 
until there is a durable yellow coloration. After evaporation of the 
solvent, the residue is purified by chromatography with silica gel and 
hexane/ether (at 3:2), yielding 1.1 g of the title compound as an oil. 
IR: 1735, 875/cm. 
EXAMPLE 12 
(5E)-2-Descarboxy-16,16-dimethyl-2-hydroxymethyl-18,18,19,19-tetradehydro-6 
a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 320 mg of the methyl ester produced according to 
Example 12a yields 305 mg of 
(5E)-2-descarboxy-16,16-dimethyl-2-hydroxymethyl-18,18,19,19-tetradehydro- 
6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as a 
colorless oil. 
IR: 3610, 3400, 2942, 2866, 974/cm. 
After splitting off the protective groups as in Example 1, 170 mg of the 
title compound are obtained as an oil. 
IR: 3600, 3450, 2928, 2865, 1602, 974/cm. 
The starting material for the above title compound is produced as follows. 
12(a) 
(5E)-16,16-Dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.sub. 
2 -methyl ester-11,15-bis-(tetrahydropyranyl ether) 
In analogy to Example 11a, 2.8 g of the ketone produced according to 
Example 3b yields 1.35 g of 
(5E)-16,16-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.sub. 
2 -11,15-bis-(tetrahydropyranyl ether) as a colorless oil. 
IR: 3500 (wide), 2962, 2870, 1712, 975/cm. 
By esterification of the above-obtained acid with etheric diazomethane 
solution according to Example 11a, 1.2 g of the title compound are 
obtained as an oil. 
IR: 1736, 975/cm. 
EXAMPLE 13 
(5E)-(16RS)-2-Descarboxy-16,20-dimethyl-2-hydroxymethyl-18,18,19,19-tetrade 
hydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 420 mg of 
(5E)-(16RS)-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin 
-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from 
the corresponding acid with diazomethane as in Example 1, yields 400 mg of 
(5E)-(16RS)-2-descarboxy-16,20-dimethyl-2-hydroxymethyl-18,18,19,19-tetrad 
ehydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) 
as a colorless oil. 
IR: 3610, 3450, 2945, 2865, 975/cm. 
After splitting off the protective groups as in Example 1, 270 mg of the 
title compound are obtained as an oil. 
IR: 3600, 3400, 2930, 2860, 1602, 975/cm. 
EXAMPLE 14 
(5E)-(16RS)-2-Descarboxy-16,20-dimethyl-2-hydroxymethyl-19,19,20,20-tetrade 
hydro-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 400 mg of 
(5E)-(16RS)-16,20-dimethyl-19,19,20,20-tetradehydro-6a-carba-prostaglandin 
-I.sub.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from 
the corresponding acid with diazomethane as in Example 1, yields 370 mg of 
(5E)-(16RS)-2-descarboxy-16,20-dimethyl-2-hydroxymethyl-19,19,20,20-tetrah 
ydro-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as 
a colorless oil. 
IR: 3600, 3450, 2950, 2862, 976/cm. 
The splitting off of the protective groups is effected in analogy to 
Example 1. 200 mg of the title compound are obtained as an oil. 
IR: 3600, 3420, 2944, 2860, 1600, 976/cm. 
EXAMPLE 15 
(5E)-(15RS)-2-Descarboxy-2-hydroxymethyl-15-methyl-18,18,19,19-tetradehydro 
-6a-carba-prostaglandin-I.sub.2 
In analogy to Example 1, 200 mg of 
(5E)-(15RS)-15-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.su 
b.2 -methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from the 
corresponding acid with diazomethane as in Example 1, yields 150 mg of 
(5E)-(15RS)-2-descarboxy-2-hydroxymethyl-15-methyl-18,18,19,19-tetradehydr 
o-6a-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as an 
oil. 
IR: 3600, 3452, 2952, 2860, 978/cm. 
The splitting off of the protective groups is effected analogously to 
Example 1. 85 mg of the title compound are obtained as an oil. 
IR: 3605, 3420, 2948, 2862, 1600, 978/cm. 
EXAMPLE 16 
(5E)-2-Descarboxy-2-hydroxymethyl-18,18,19,19-tetradehydro-6a-carba-prostag 
landin-I.sub.2 
In analogy to Example 1, 400 mg of 
(5E)-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I.sub.2 -methyl 
ester-11,15-bis-(tetrahydropyranyl ether), produced from the corresponding 
acid and diazomethane as in Example 1, yields 365 mg of 
(5E)-2-descarboxy-2-hydroxymethyl-18,18,19,19-tetradehydro-6a-carb-prostag 
landin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as oil. 
IR: 3620, 3450, 2952, 2866, 978/cm. 
Splitting off of the protective groups is done analogously to Example 1. 
The result is 185 mg of the title compound as an oil. 
IR: 3600, 3425, 2948, 2860, 978/cm. 
EXAMPLE 17 
(5E)-(16RS)-2-Descarboxy-16,19-dimethyl-18,19-didehydro-2-hydroxymethyl-6a- 
carba-prostaglandin-I.sub.2 
In analogy to Example 1, 500 mg of 
(5E)-(16RS)-16,19-dimethyl-18,19-didehydro-6a-carba-prostaglandin-I.sub.2 
-methyl ester-11,15-bis-(tetrahydropyranyl ether), produced from the 
corresponding acid with diazomethane as in Example 1, yields 430 mg of 
(5E)-(16RS)-2-descarboxy-16,19-dimethyl-18,19-didehydro-2-hydroxymethyl-6a 
-carba-prostaglandin-I.sub.2 -11,15-bis-(tetrahydropyranyl ether) as an 
oil. 
IR: 3610, 3452, 2950, 2864, 980/cm. 
Splitting off of the protective groups is effected as in Example 1. The 
result is 250 mg of the title compound as an oil. 
IR: 3600, 3420, 2946, 2858, 1602, 978/cm. 
The preceding examples can be repeated with similar success by substituting 
the generically or specifically described reactants and/or operating 
conditions of this invention for those used in the preceding examples. 
From the foregoing description, one skilled in the art can easily 
ascertain the essential characteristics of this invention, and without 
departing from the spirit and scope thereof, can make various changes and 
modifications of the invention to adapt it to various usages and 
conditions.