Note: Descriptions are shown in the official language in which they were submitted.
~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
CH3
-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
5362
-- 3 --
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
-- 1 --
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)
CH30/
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
S362
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.
