CA1246559A - Selective biologically active 7-oxo-prostacycline derivatives and process for the preparation thereof and pharmaceutical compositions containing same - Google Patents

Abstract

A B S T R A C T

Racemic and optically active 7-oxo-prostacycline derivatives of the general formula I
wherein R1 stands for hydrogen, C1-4 straight or branched alkyl or pharmacologically acceptable cation, R2 stands for hydrogen, C1-4 alkanoyl, benzoyl, or benzoyl substituted by C1-4 alkyl or halogen, and R2 can further represent tetrahydropyranyl, trialkyl silyl or alkoxy alkyl, A stands for ethylene, cis or trans-vinylene or -C=C-n may represent 2, 3 or 4.

Description

23305-1~03 The present invention relates to new biologically active compounds and process for the preparation thereof and pharmaceut-ical compositions containing same.
The new compounds can be defined ~y t7ne general formula . ~ COOR
0~
(I)

2)n oR2 wherein 1~ ~1 represents hydrogen, Cl 4 straig;lt or branched alkyl or a pharmacologically acceptable cation, R2 represents hydrogen,Cl 4 alkanoyl~ benzoyl, or benzoyl substi-tued by Cl 4 alkyl or halogen, and R can furtner represent tetra-hydropyranyl, trialkyl silyl or alkoxy alkyl, A represents ethylene, cis or trans-vinylene or -C~C-n may represent 2, 3 or 4.
The compounds of the general formula I may be in tne form of racemates or optically active derivatives.
If Rl stands for a ~harmacologically acceptable cation, ~ 20 it may represent all organic or inorganic cations whicn do not show : any detrimental/toxic/ effect at the used dosage, such inorganic t.~ lJ, ~, i ~.,, ".~l cations may be e.g. alkali metals, such as .sodiurn,po-tassium, alka-line earth metals, such as calcium, magnesium ions. Unsubstituted ammonium ions or ammonium ions substituted by organic, preferably all~yl groups are also suitable. The substituted ammonium ions may bear further substituents such as hydroxyl or amino groups which favourably act upon the solubility and crystallization prop-erties of the salts. One such preferred cation is the tris-/hydro-methyl/-ammonium ion. Cl 4 straight and brancn alkyl is referred to nereinafter can stand for metnyl, ethyl, propyl or isopropyl, preferably methyl. ~1-4 alkanoyl in the definition or R2 may stand for moieties derived frorn Cl 4 alkane carboxylic acid, such as Eormyl, propionyl, bu-tyryl, preEerably ace-tyl. Substitu-ted benzoyl may be substituted by one or more halogens, such as, fluorine, chlorine, iodine, bromine or one or more C1 4 straignt or branch alkyl.
Tile values n = 2,3 or 4 are meant to define cyclo-pentyl, cyclohexyl or cycloheptyl rings respectively.
Trialkyl silyl groups are moieties consisting of three Cl 4 straight or branched same or different alkyl groups attached to tne central silicium atom, such as trimethyl silyl, trietnyl silyl, tripropyl silyl or dirnethyl iso-propyl silyl, preferably dimenthyl-tert. butyl silyl.
Alkoxy alkyl can be defined by the formula R-O-CH2-wherein R is an alkyl group containing 1 -to 4 carbon atoms, which may be straight or branched, preferably methyl.
The compounds of the general formula I may be prepared '~

~aZ~lL655~

by a) heating a compound of the general formula oR3 COOR

' R20 --~ H 2 ) wherein Rl, R2,A andnare as defined above and R3 represen-ts hydro-gen or Cl 4 straight or branched alkyl, or any hydroxyl or carboxyl groups being protected, if necessary, or b) oxidizing a compound of the general formula l COOR
~Q ~

(III) ~ /
j ~I2) n OR
wherein Rl, R2, A and n are as defined above, any hydroxyl or car-boxyl groups being protected, if necessary, and if required remov-ing any protecting groups from the hydroxyl and/or carboxylic acid groups and if required converting an obtained compound into a pharmaceutically acceptable salt thereof.
The compound of formula II as defined above is obtained by oxidizing a compound of the general formula ~4~ 5S9 oR3 o ~ ~`' COOR
~ V) R A ~r~ 2)n wherein Rl, R , R3, A and n are as defined above.
The compounds of the general formula I are stable and selective biologically active pros-tacycline derivatives.
Prostacycline /PGI2/ the arachidonic acid metabolite which is wide spread in mammal organisms has been discovered in 1976. The substance show various pharmaceutically valuable bio-logical activities.
It inhibits the aggregation of blood platelets, it displays fibrinolytic ac-tivitiy, it dilates the respiratory trac-t and blood vessels and reduces gastric acid secretion. It shows so called cytoprotective activity in various organs, such as stomach, liver, heart, kidney, it eliminates the destructive con-sequencies of various damaginy effects occurring in said organs or it cures the organs.
There are two problems acting against the extensive use of PGI2. One is the chemlcal and biological instability, i.e.
the very short biological half-life, thus its route of administra-tion can only be a special method of treatment,e.g. it can be : ~

-4a~ 65~9 admlnistered by infusion. The other problem is the occuxrance of several side effects, which can be optionally observed next to the desired effect due to the complex biological spectrum of activity.

23305-lOO0 The preparation of 7-oxo-PGI2 derivatives which are more stable than the natural PGI2 is first disclosecl in USP 4 330 553. The chemical stability of the disclosed compounds is bet~er - e.g. they can be stored in aqueous solution as well -and their spectrum of activity is substantially the same as that of PGI2 (J. Med. Chem. 25, 105 (1982)).
The preparation of similar 7-oxo-PGI2 derivatives is described in BE-PS 890 390. The common property of the 7-oxo-~GI2 analogones mentioned above is that like the biologicalactivity of PGI2 their bioloyical activity is not selective.
The new 7-oxo-PGI2 derivatives accordiny to the invention have the same spectrum of activity as PGI2, but unexpectedly we have found that the new compound a~ts biologically more selectively khan 7-oxo-PGI2 clerivatives known from the state of art, whlle their stability is about the same.
The compounds of the general formula I are prepared as given above. The details of the embodiments of the above methods are as follows:
a) A compound of the general formula IV is oxidated in water-containing organic solvent, preferably dioxan or dimethoxy ethane by using 1.1 to 10 equivalents, preferably 1.3 to 1.5 equivalents selenium dioxide at a temperature ranging from 20 to 200 C, preferably 50 to 100 CC. The thus obtained .~r S5~

6 23305-lOOo compound of the general formula II is then heated ln the presence of an acid catâlyst in oryanic solvents, preferahly in benzene or toluene or halogenated solvents, such âS
chlorinated hydrocarbons, preferably in chloroform or dipolar aprotic solvents, such as dimethyl sulfoxide, preferably in dimethylformamide or without any solvent and -thus a compound of the general formula I is obtained. As acid catalyst p-toluene sulfonic acid or sulfuric are preferred. Compounds of the general formula II can be heated at 50 to 200 C', preferably at 60 to 90 C, by water separation or without. The preferred way is to perform the heatiny in the presence of p toluene sulfonic acid in benzene or toluene at 60 C' while a water trap is used.
The compounds of the general formula IV are known from the literature or the can be prepared by analogous methods, see e.g. Hungarian Patent No. 180 442.
b~ Accordiny to another preferred method of the invention a compound of the general formula III may be oxidated to a compound of the general formula I at a temperature ranging from 20 to 200 with 1.1 to 10 eyuivalents selenium dioxide in an anhydrous organic solvent, such as an ether type solvent, preferably dloxan or dimetho~yethâne. The reaction is preferably conducted in dioxan with 1.3 to 1.5 equivalents of selenium dioxide at 80 to 90 C.

~;

~Z~6~5~
7 23305-lO00 The compounds of the general formula III are known from the sate of art or may be prepared by analogous methods (R.F. Newton et al: ~ynthesis 19~, 4~9).
The hydroxyl groups at the positions ll a~d 15 of the StartinCJ materials of the yeneral formulae III and IV can be blocked by blockiny various acyl groups, trialkyl silyl groups, alkoxy alkyl groups ancl te~rahydropyranyl as defined above. The introduction of the bloking yroups may be carried out by methods known per se, and this may be important in order to achieve better yield. The above block:ing groups may be removed ~ if desired - from the compounds of the general formula I by methods know per se. The alkoxyalkyl groups or the tetrahydropyranyl groups may be removed hy acid hydrolysis anc1 the trialkyl silyl group be removed by potassium fluoride or also ln the presence of aci.c1. The acyl groups are hydrolysed :in a basic medium.
Those compounds of the general formula I wherein R1 stands for C1~ straiyht or branched alkyl may be converted to a salt containing a pharmacologically acceptable catlon by methods know per se. In the course of the salt formation the ester group is split off under basi.c conditions. As a base alkaline or alkaline earth metal hydroxides, alkoxides are used in aclueous or anhydrous alcoholic solutions. As a base sodium ~;

~6S~
8 233~5-1~00 methoxide and as a solvent anhydrous methanol is used.
Carboxylic aeids may be released from the aqueous solutions of the thus obtained salts by earefully aeidifying, and said earboxylie aeids can be dissolved in orgallie solvents and converted to further salts e.g. trimethonium salt by reacting same aeids with aliphatic and aromatic am:Lnes.
One eharae~eristie representative of the compounds of the general formula I is the sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-eyelopentyl-PGI2.
Tlle seleetive biologieal aetivity of these compounds may be studied by investigating the antlaggregation and hypotensive activity simultaneously. Anti-aggregation activlty was measured ln v_tro aeeording to Born (Nature, 214 927 (1962)) on human plasma enriehecl with thromboeytes in an aggregation indueed by 2~ m ADP, whereas the haemodynamic activity was obtained from the blood pressure redueing aetivity of the eompound administered in an i.v~ bolus injeetion to an anaesthetized cat oc open-ehest.

5~
9 23305-~000 ______...... _ ___ __ __ _ anti- relative hypo- relative aggregation efficiency tensive efficiency Hi/H2 IC~Ong/ml Hl activity H2 ED5a ug~k~

P~I2-Na 1 1 0.16 7-oxo-PGI2-Na 15 0.066 6.5 0.024 2.75 16,17,18,19,20 1.6 0.625 21.2 0.0075 83~3 10 pentanor-15-cyclopentyl~7-oxo-PGI2Na ,__ __ It can be seen that the cyclopentyl analog is about one hundred times more selective than prostacycline and it is considerably mo:re selec-tive than the sodlum salt of 7-oxo-PGI2 dlsclosed in US-P5 4 330 533.
A particular advantage of the compounds of. the yeneral formula I is that they can be administered orally, too.
Due to their biological activity the compounds according to the invention may be used as active ingredlents of pharmaceutlcal composltions. Sald composltions can be used for the prevention and curing diseases llke peripheral diseases of vessels (artherosclerosis obliterans, B~rger-disease, diabeticus angiopethia), for the improvement of. the circulation of the limos and for the reduction of the severeness of heart infarct and the number of mortality.

` ~Z4~65~9 23305-1~00 The pharmaceutical compositions are suitable for the reduction of the intensity and number of attacks in several types of angina diseases and for curing other circulation diseases of various types such as pulmonary hypertension and heart insufficiency. The can show a valuable effect in prevention and curing of cerebral ischaemias and can be used for curing asthma, diseases of the gastrointestinal system, such as ulcer, etc. and liver and pancreas diseases. The compositions are fur~her suitable for the prevention of the loss of blood platelets alone or combined with heparine in case of extra corporal circulation (]cidney chemodialysis, heart-lung machine). ~ further use is -the inhibition of metastais in patients suffering from tumour.
The pharmaceutical compositions accordincJ to the invention may be administered intravenously, subcutaneously, intramuscularly and orally (gastrointestinally) as well. The required amount is 0.0001 to 10 mg. per kg. of body weight.
The exact dosage depends on the severeness of the disease, on the velocity of the medicine, on the susceptibility of the patient or the organ to be treated and the response abili~y of the patient. The best way of administration and the necessary dosage can be determined by someone skilled in the art without any difficulty.
When preparing the pharmaceutical compositions 6~

the conventionally used fil].ing agentsr diluents, agents influencing the flavour and aroma, agents facili~ating formation, adjusting pH and osmotic pressure, stabili~ers, agents promoting resorption etc. and other excipients may be used. The prepared compositions may be solid (tablet.s, apsules, dragees, powders, pill5), liquid (infusion, inhalant or injectable solutlons, compress liquids, liquid medicines, drops etc.) or semi liquid ~crémes, ointments, balsams, suppositories etc.). The disclosed active ingredients may be used alone or combined with other active ingredienks.

Example~s ExamPle 1 Methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGIlx 605 mg.~1.25 mmole~ of methyl ester of 6-methoxy-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 are dissolved in a mixture of 6 ml. of dioxan and 0.5 ml. of water. 210 mg. ~1.89 mmole) of selenium dioxide are added and the reaction mixture is stirred for 2 hours. When the reaction is completed the mixture is filtered, the solvent is removed in vacuo. The residue is diluted with 50 ml. of ethyl acetate, washed with 2 x 10 ml. of water, a 5% sodium ' ~

s~
~2 23305-1000 hydroyen carbonate solution until pH = 7.5-8, then it is washed with a saturated salt solution and dried above magnesium sulpha~e. The thus obtained crude product is chromatographed on 200 g. of Reanal Kieselgel G absorbent and eluted with a 50~ mixture of hexane and ethyl acetate by short column chromatography. 380 g. of methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI
are isolated in the form of a red oil. Thin layer chromatography: R~: 0.18 (1 hexane - 1 ethyl acetate) IR (cm~l, film): 3400, 2950, 1740, 1150.

E~ ~e 2 Methyl ester of 7--oxo-ll,LS-cliace~yl-16,17,18,:L9,20--pentanor-15-cyclopentyl-PGI2 380 mg. (0.79 mmole) of methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI
are dissolved in 30 ml. of benzene and to the solution 3 mg.
of p-toluene sulfonic are aclded and the mixture is stirred at room temperature for 15 minutes and at 60 C for 3 hours. In the course of the heating a total of 5 ml. of benzene are distilled to the water trap. When the reaction is completed the reaction mixture is cooled to room temperature and stirred ~ for 2 hours with 0.6 y. of neu~ral aluminium oxide. The ; aluminium oxide is filtered, the filtrate is 5~o~
13 23305-lOoO
partially evaporated and the substance is chromatographed on 20 g. Kieselgel G adsorbent by short column chromatograplly and as eluant a 2:1 mixture of hexane ancl ethyl acetate is used.
lg9 mg. of methyl ester of 7-oxo-11,15-diacety:L-16rl7,18,19,20-pentanor--15-cyclopentyl-PG:[2 are obtained in the form of a colourless oil.
Rf= 0.43 (1 hexane - 1 ethyl acetate) IR (cml, film): 2950, 17~5, 1715, 1650, 1160.

uv~ Daa (nm~=287 log =3~96.

Example 3 Methyl ester of 7-oxo-16,17,18,19,2Q-pentanor-15-cycl.opentyl-PGI2 198 mg. (0.43 mmole) of methyl ester of 7-oxo-11,15 diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 are dissolved in 30 ml. of anhydrous methanol and to the solution 0.25 ml. of a 1 M methanolic sodium methoxide solution is added. The reaction mixture is stirred overnight at room temperature. Methanol is removed in vacuo at 0 Ca and the substance is dissolved in a mixture of 50 ml. of ether and 7 ml. of water at 0 C and after the separation of the layer the ether solution is washed with 10 ml. of saturated salt solution and stirred with 0.5 g. of neutral aluminium oxide and 0.2 g. of activated charcoal, filtered and finally dried above sodium sulphate in the presence of triethyl amine.

~, After evaporation 135 mg. of methyl ester of pure 7-oxo~
16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 are ~btained in the form of a colourless oil.
Rf = 0.36 ~1 hexane - 1 acetate) UV. ~ ~ax = 287 nm, log~ = 3.856.

Example 4 Sodium salt of 7-oxo-16,17rl8,19,20-pentanor-15-10 cyclopentyl-PGI2 220 mg. (0.63 mmole) methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 are dissolved in 10 ml. of methanol, 2 ml. o~ 1 M aqueous sodium hydrox:Lde solution are added and the mixture is stlrred at 40 C for 3 hours. Methanol is then removed in vacuo and the residue is dissolved in 20 ml. of distilled water. The aqueous solution is shaken out with 2x5 ml. of ether and the aqueous layer is acidified to pH = 6 at 0 C by adding 1 N sodium hydrogen sulphate solution and extracted with 2xlO ml. ethyl acetate.
The aqueous layer is further acidified with sodium hydrogen sulphate solution to pH = 4 at 0 C and it is extracted again with 2x2Q ml. ethyl acetate. All ethyl acetate organic layers are combined and washed with 2x5 ml. saturated salt solution.
The solution is stirred with 0.6 g. of neutral aluminium oxide and 0.2 g. of activated charcoal for 10 minutes and filtered.
20 ml. of water are added to the solution and pH is ad~usted to 7.2-7.3 4~5~

wi-th 0.1 N sodi.um hydroxide solution. The two layers are separated, and the organic layer is shaken out with 10 ml. of water. The combined aqueous layer is evaporated and driecl and thus 190 my. of sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 are obtained. In order to use the aqueous solution of the title compound the aqueous solution has not to be evaporated, the solution can be directly used.
Tlc.: the substance is developed in the form of acid, R = 0.30 ~20 benzene - 10 dioxan - 1 acetic acid) IR: (cm~l, KBr): 3500-3200, 2940, 2850, 1720, 1650, 1615.

Example 5 Sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 340 m~. (0.74 mmole) methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 are dissolved in 50 ml. of methanol and to the solution 0.5 ml. of 1 M methanolic sodium methoxide solution is added and the reaction mixture is stirred for 10 hours at room temperature. After removing part of the methanol (total volume about 20 ml.) 5 ml. of an 1 N
sodium hydroxide solution is added and the solution is stirred for 3 hours at 40 C. Methanol is distilled off in vacuo. The reaction mixture is worked up as clescrlbed in the previous Example.

'~

;S~
16 23305-~.000 E ample 6 Meth~fl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI~
To a solu~ion of 1010 mg. (2.25 mmole? 11,15-diacetyl-16,17,18,19,20-pentanor-15--cyclohexyl-PGI2 in 20 ml.
of anhydrous dioxan 374 my. (3.4 mmole) of selenium dioxide are added. The reaction mixture is stirred for 2.5 hours at 85 C~ under argon atmosphere. When the reaction is completed to the reaction mixture 1 g. of neutral aluminium oxide is aclded at room temperature and it is stirred for 15 minutes.
After the filtration of the mixture it is partially evaporated and purified by short column chromatoyraphy. As absorbent 200 y. of Kieselgel G and as eluant a 1:1 mlxture of hexane and ethyl acetate is used. 200 y. o the title product are isolated in the form of colourless oil.
R~ = 0.40 (hexane and ethyl acetate 1:1) IR: (cm~l, film) = 2950, 2860, 1740, 1715, 1650.

E~ 7 Methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclohexyl-PGI~
To a solution of 220 my. (0.46 mmole) of methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI~ in 30 ml. of anhydrous methanol 0.25 ml. of a 1 M methanolic soclium methoxide ~6S5~

solution is added. The reaction mixture is stirred overnight at room temperature under argon atmosphere. Methanol is then removed in vacuo, the substance is dissolved at 0 with a mixture of 50 ml. of ether and 7 ml. of water, the ether solution is washed with 10 ml. of a saturated sal-t solution after the sep-aration of the layers and stirred with O.S g. of neutral alum-inium oxide and 0~2 g. of active charcoal for 10 minutes and finally dried above sodium sulphate. After evaporation 148 mg.
of the title compound are obtained in the form of a colorless oil.
Rf: 0.34 /1 hexane - ~ acetone/
UV: ~maX=289 nm, 1 g~ = 3,903 E_ample 8 Tris-/hydroxymethyl/-amino-methane salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 540 mg. /1.35 mmole/ sodium salt of 7-oxo-16,17,18,19, 20-pentanor-15-cyclopentyl-PGI2 are dissolved in 10 ml. of water and the solution is acidified with 1 N sodium hydrogen sulphate solution to pH = 4 and extracted wi-th 2x20 ml. ethyl acetate.
The combined ~8~

~ ~t3~ ~

1~ 23305-1000 organic layers are shaken out with satura-ted salt solution and dried above sodium sulphate. Sodium sulphate is filtered off and then 175 my. (1.45 mmole) of tris-(hydroxymethyl)-amino-methane are added to the solution and it is stirred for 2 hours at 40 Cq and allowed to stand for 12 hours. The reaction mixture is then evapora~ed ~o dryness and thus 510 mg. of title compound are isola~ted.
Thln layer chromatography: identical with the previous compounds in acid form.
UV (EtOH): ~ ~aa= 288 nm, logs = 3.965 F~ E_e 9 Methyl ester O:e 6-hydroxyl-7-oxo--11,15-diacetyl-13,14-didehydro-16,17,18,19,20-pentanor-15~cyclohexyl-PGIl 1850 mg. (3.76 mmole~ of 6-methoxy-11,15~diacetyl-13,14-didehydro-16,17 r 18,1g,20-pentanor-15-cyclohexyl-PGIl-methyl ester are dissolved in 15 ml. dioxan and 2 ml. water and to the solution 650 mg. (5.86 mmole) of selenium dioxide are added and the reaction mixture is stirred for 2 hours at ~0 60 C'. The reaction mixture is then filtered, dioxan is removed at reduced pressure and the residue is diluted with 200 ml. of ethyl acetate. The solution is washed subsequently with 2x50 ml. of water, 5~ sodium hydrogen carbonate solution until pH = 7.5-8, saturated salt ~z~

solution, and it is driecl about magnesium sulphate. The product is isolated by short column chromatography - by using 500 g. Kieselgel G silicagel, and as eluant a 1:1 mixture of hexane and ethyl acetate in an amount oc 7'30 mg. in the form of a red oil.
Thin layer chroma~ography: Rf - 0.20 (1 hexane - 1 ethyl acetate) IR (cml, film~: 3400, 2950, 2230, 1740, 1160.

Example 10 Methyl ester of 7-oxo-11,15-diacetyl-13,14-didehydro-16,17,18,19,20-pentanor-15-cyclohexyl-PGI~
750 mg. (1.52 mmole) of 6--hydroxy--7-oxo-11,15-diacetyl-13,14-didehydro--16,17,18,19,20-pentanor-15-cyclohexyl-PGII-methyl ester are dissolved in 30 ml. of benzene and to the solution 5 mg. of p-toluene sulfonie acid are added whereafter the mixture is stirred for 15 minutes at room temperature and for 3 hours at 60-65 CQ while the solvent-wa~er is distilled off. During the reaction about 10 ml. of benzene are clistilled off. The reaction mixture is then cooled to room temperature and stirred for 3 hours with 1 g. of neutral aluminium oxide. Aluminium oxide is removed by filtration and the reaction mixture is purified by short column chromatography (100 g. of Kieselgel G silicagel, eluan~: 2 hexane - 1 ethyl acetate).

5'~3 ~ o 23305-1000 Thus 2~Ç mg. of title product are isolated in the form of colourless oil.
Thin layer chromatography: R~ = 0.56 (1 hexane - 1 e-thyl acetate) W (EtOH): ~ax =285 nm log =4.01 E~le 11 Methyl ester of 7-oxo-13,14-didehydro-10 16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 250 mg. (0.53 mmole) of methyl ester of 7-oxo-13,14-didehydro-11,15-diacetyl-16,17,1~,19,20-pentanor-15-cyclohexyl-PG]:2 are dlssolved in 50 ml. of anhyclrous methanol and to the so:lution 1 ml. (1 mmole) 1 l~l methanolic sod.ium methoxide solution is added. The reactlon mixture is allowed to stand overnight and the solvent is removed at reduced pressure at O C. The residue is dissolved in the mixture of 50 ml. of ether and 5 ml. of water, the separated organic layer is washed with 10 ml. of saturated salt solution, stirred with 0.5 g. of neutral aluminium oxide and 0.5 g.
activated charcoal for 10 minutes, filtered and dried above sodium sulphate in the presence of triethyl amine. After evaporation 143 my. title compound are obtained in the form of colourless oil.
Thin layer chromatography: Rf - 0.21 (1 hexane - 1 ethyl acetate) .~

tj55~

UV (~tOH):~ ~ax = 287 nm log~ - 3 g3 Example_12 Sodium salt of 7-oxo-13,14,clidehydro-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 113 mg. (0.31 mmole~ of methyl ester of 7-oxo-13,1~-didehydro-16,17,18,19,20-pentanor-15-cyclohexyl-PGI~ are dissolved in 7 ml. of methanol and 3 ml. of water and to the solution 2 ml. (2 mmole) 1 M aqueous sodium hydroxide solution is added and the solution is stirred for 3 hours at room temperature. Methanol is then removed at reduced pressure and to -the residue 10 ml. oE distillecl water are added. The aqueous solution is washed with 2x5 ml. of ether and ~ooled to O C an-l acidified to p~l = 5-6 by adcling about 2 ml. of ~olcl M aqueous sodium hydrogen sulphate solution and finally extracted with 2x10 ml. of ethyl acetate. The aqueous layer is further acidified with 0.1 M sodium hydrogen sulphate solution to pH = 3-4 washed with 2x20 ml. of ethyl acetate.
The combined ethyl acetate layers are washed with 2xlO ml. of saturated salt solution~ stirred for 10 minutes on 0.5 g. of neutral aluminium oxide and 0.2 g. of activated charcoal and filtered. To the filtrate 20 ml. of water are added and the pH is adjusted to 7.4-7.6 by adding 0.1 N sodium hydroxide soluti.on. The organic layer is shaken out with 10 ml. water and the combined aqueous

3~2~

layers are evaporated and thus 78 mg. of title ~ompound are obtained.
Thin layer ~hromatography. the suhstan~e is developed in the form of a~id R~ = 0.30 (20 benzene -10 dioxan - 1 acetic a~id) IR (KBr, ~ml): 3300, 2950, 2220, 1720, 1645.

Claims (39)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A racemic or optionally active 7-oxo-prostacycline of the general formula (I) wherein R1 represents hydrogen, C1-4 straight or branched alkyl or a pharmacologically acceptable cation, R2 represents hydrogen, C1-4 alkanoyl, tetrahydropyranyl, trialkyl silyl, alkoxy alkyl, benzoyl, or benzoyl substituted by C1-4 alkyl or halogen, A represents ethylene, cis or trans-vinylene or -C?C-, n may represent 2, 3 or 4.

2. The methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2.

3. The methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2.

4. The sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2.

5. The methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2.

6. The methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2.

7. The tris-(hydroxyrnethyl)-aminomethane salt of 7-oxo-16, 17,18,19,20-pentanor-15-cyclopentyl-PGI2.

8. A process for preparing a racemic or optically active 7-oxo-prostacycline of the general formula (I) as defined in claim 1, which process comprises (a) heating a compound of the general formula (II) wherein R1, R2, A and n are as defined in claim 1 and R3 represents hydrogen or C1-4 straight or branched alkyl, any hydroxyl or carboxyl groups being protected if necessary, or (b) oxidizing a compound of the general formula (III) wherein R1, R2, A and n are as defined in claim 1, any hydroxyl or carboxyl groups being protected if necessary, and if required removing any protecting groups from the hydroxyl or carboxylic acid groups and if required converting an obtained compound into a pharmaceutically acceptable salt thereof.

9. A process as claimed in claim 8 wherein the compound of formula II as defined in claim 8 is obtained by oxidizing a compound of the general formula (IV) wherein R1, R2, R3, A and n are as defined in claim 8.

10. A process as claimed in claim 9, wherein the oxidation of a compound of the general formula IV as defined in claim 9 is carried out with selenium dioxide in a water-containing solvent.

11. A process as claimed in claim 8(a), wherein the compound of the general formula II as defined in claim 8 is heated in a solvent in the presence of an acid catalyst at 50 to 200°C.

12. A process as claimed in claim 8(a), wherein the compound of the general formula II as defined in claim 8 is heated in the presence of an acid catalyst without a solvent at 50 to 200°C.

13. A process as claimed in claim 8(b), wherein the oxidation of the compound of the general formula III as defined in claim 8 is carried out with selenium dioxide in an anhydrous solvent.

14. A process as claimed in claim 10, wherein the oxidation of the compound of general formula IV as defined in claim 10 is carried out with 1.1 to 10 equivalents of selenium dioxide at 20 to 200°C in aqueous dioxan or dimethoxy ethane.

15. A process as claimed in claim 8(a), wherein the compound of the general formula II as defined in claim 8 is heated in an aromatic solvent or a halogenated and/or dipolar aprotic solvent in the presence of p-toluene sulfonic acid or sulfuric acid.

16. A process as claimed in claim 8(a), wherein the compound of the general formula II as defined in claim 8 is heated in benzene or toluene in the presence of p-toluene sulfonic acid catalyst at about 60°C.

17. A process as claimed in claim 8(b), wherein the oxidation is carried out in an ether type solvent, with 1.1 to 10 equivalents, of selenium dioxide at 20 to 200°C.

18. A process as claimed in claim 8(b) wherein the oxidation is carried out in dioxan with 1.3 to 1.5 equivalents of selenium dioxide at 80 to 90°C.

19. A process as claimed in claim 8 wherein R1 represents methyl, R2 represents acetyl, A represents trans vinylene and n is 2.

20. A process for preparing the methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 which process comprises heating the methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 with p-toluene-sulfonic acid in benzene at a temperature of about 60°C.

21. A process as claimed in claim 20, wherein the methyl ester of 6-hydroxy-7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 is prepared by oxidizing the methyl ester of 6-methoxy-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI1 with selenium dioxide in dioxan and water.

22. A process as claimed in claim 8 wherein R1 represents methyl, R2 represents hydrogen, A represents trans vinylene and n is 2.

23. A process for preparing the methyl ester of 7-oxo-16,17, 18,19,20-pentanor-15-cyclopentyl-PGI2 which process comprises removing the protecting acetyl groups from the methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 wherein the methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 is obtained by the process of claim 20.

24. A process as claimed in claim 23 wherein the protecting acetyl groups are removed by hydrolysis in a methanolic sodium methoxide solution.

25. A process as claimed in claim 8 wherein R1 represents sodium, R2 represents hydrogen, A represents trans vinylene and n is 2.

26. A process as claimed in claim 23 which comprises the further step of hydrolysing the methyl ester to prepare the sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2.

27. A process as claimed in claim 8 wherein R1 represents methyl, R2 represents acetyl, A represents trans vinylene and n is 3.

28. A process for preparing the methyl ester of 7-oxo-11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 which process comprises oxidizing 11,15-diacetyl-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2 with selenium dioxide in dioxan.

29. A process as claimed in claim 8 wherein R1 represents methyl, R2 represents hydrogen, A represents trans vinylene and n is 3.

30. A process as claimed in claim 28 which comprises the further step of removing the protecting acetyl groups to obtain the methyl ester of 7-oxo-16,17,18,19,20-pentanor-15-cyclohexyl-PGI2.

31. A process as claimed in claim 30 wherein the protecting acetyl groups are removed by hydrolysis in a methanolic sodium methoxide solution.

32. A process as claimed in claim 8 wherein R1 represents tris-(hydroxymethyl)aminomethyl, R2 represents hydrogen, A repre-sents trans vinylene and n is 2.

33. A process for preparing the tris-(hydroxymethyl)amino-methane salt of 7-oxo-16,17,18,19,20-pentanor-15-cyelopentyl-PGI2 which process comprises reacting the sodium salt of 7-oxo-16,17, 18,19,20-pentanor-15-cyclopentyl-PGI2 with tris-(hydroxymethyl)-aminomethane wherein the sodium salt of 7-oxo-16,17,18,19,20-pentanor-15-cyclopentyl-PGI2 is obtained by the process of claim 26.

34. A pharmaceutical composition which comprises a compound as claimed in claim 1, 2 or 3 in association with a suitable diluent or carrier.

35. A pharmaceutical composition which comprises a compound as claimed in claim 4, 5 or 6 in association with a suitable diluent or carrier.

36. A pharmaceutical composition which comprises a compound as claimed in claim 7 in association with a suitable diluent or carrier.

37. A process for preparing a pharmaceutical composition for use as an anticoagulant or as a trachea relaxant, which process comprises incorporating a compound as claimed in claim 1, 2 or 3 in the composition.

38. A process for preparing a pharmaceutical composition for use as an anticoagulant or as a trachea relaxant, which process comprises incorporating a compound as claimed in claim 4, 5 or 6 in the composition.

39. A process for preparing a pharmaceutical composition for use as an anticoagulant or as a trachea relaxant, which process comprises incorporating a compound as claimed in claim 7 in the composition.