NEW CARBACYCLINES, PROCESS FOR THEIR PRODUCTION AND THEIR USEAS MEDICAMENTS

SCH 808 New Carbacvclins. Process for their Production and Their Use as a Drug The invention relates to new carbacyclin derivatives, process for their production and their use as a drug. In US patent specification 4,420,632, 9-alkylated carbacyclin derivatives are described which have antithrombotic, antisecretory and bronchodilating qualities. In addition, they act to inhibit platelet aggregations. It was found that carbacyclin analogues, chain lengthened in the 9 position, with a reactive group in omega- position can be bonded to polymer carriers with only a small loss of biological activity. The compounds according to the invention are suitable for the inhibition of platelet aggregations, blood pressure reduction by vasodilation inhibition of stomach acid secretion and for the preparation of antibodies to carbacyclins after "chemieal bonding with proteins. The invention relates to carbacyclin derivatives with general formula I: v Y C R 9 - (r) A-W-D-E-R, Rt in which Yx stands for the radical -CH2-X(CH2)n-Ri or the radical n, 1 or 3, Rl, the fadica 1 "-oJ o-cttx/ , the radical -CH X '--filflj " AMD/0278a '• 9 9 -COCH-, COOR,, and R2 stands for hydrogen or alkyl with 1-10 C atoms optionally substituted with halogen, phenyl, C.-C, alkoxy or Cj-C, dialkyl amino; cycloalkyl, aryl or a 5- or 6 membered heterocyclic radical containing at least 1 heteroatom, or the radical CONHR,, with R3 standing for hydrogen or an alkanoyl or alkane sulfonyl radical each with 1-10 C atoms, R0 stands for the radical -(CH0) -R- or the radical 9 v 2'm 6 -(CH2)m-o-[Zl-(CH2)m-p-tZ2-<CH2)m-qly-R6' m = 2-20, o, p and q are less than or equal to 19, m-o £. 2, x, y = 0,1 or 2, Z1 stands for a cis-CH=CH group, a trans-CH=CH group of a -C=C group, and each of these groups must be separated at least by a methylene group from the C-9 carbon atom of the carbacyclin bicyclic compound, Z„ stands for OJiygeh, Sulfur, an NH or an N methyl group, R stands for amino, methylamino, hydroxy, carboxy or mercapto, X an oxygen atom or* a methylene group, Y hydrogen or fluorine, A a -CHCH, trans-CH=CH or -C-C group, W a free or functionally modified hydroxy methylene group or a free or functionally modified CH, - C - group, and the OH group can be in alpha or beta I OH position, AMD/027 8a - 2a - stands for the group ch2 — CH 2 o J a straight-chain, saturated alkylene group with 1-5 C atoms, a branched, saturated or a straight-chain or branched unsaturated alkylene group with 2-5 C atoms, which optionally can be substituted with fluorine atoms, o is, 1, 2 or 3 It ——3«8# • * a v •• • (4 • • E stands for a direct bond, a -C=C group or a -CH=CR7 group and R7 stands for a hydrogen atom, an alkyl group with 1-5 C atoms or halogen, R4 stands for an alkyl group with 1-10 C atoms, a cycloalkyl group with 3-10 C atoms or an aryl group optionally substituted with 6-10 C atoms, or a 5- or 6 monbered heterocyclic radical which contains at least 1 heteroaton, R5 stands for a free or runctionally modified hydroxy group and, if R2 represents a hydrogen atom, whose salts have physiologically well-tolerated bases. As alkyl groups R2, straight- or branched-chain alkyl groups with 1-10 C atoms are suitable, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. The alkyl groups R2 can optionally be substituted once or several times with halogen atoms, C1-C4 alkoxy groups, phenyl and di-C1-C4 alkylamines. Easily substituted alkyl groups are preferred. As substituents there can be mentioned, for example, fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. As preferred alkyl groups R2, there can be mentioned those with 1-4 C atoms, such as methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl. As aryl groups R2, both substituted and unsubstituted aryl groups are suitable, such as phenyl, 1-naphtyl and 2- naphtyl, which can each be substituted with 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 c atoms, a chloromethyl, f luoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C atoms. Preferred are substituents in the 3 and 4 position on the phenyl ring, for example with fluorine, chlorine, alkoxy or trifluoromethyl or With hydroxy in the 4 position. The cycloalkyl group R2 can contain 4-10 preferably and 6 carboft atoms in the ring. The rings can be substituted With alkyl groups with 1-4 Ccrbon atoms. For example, there I* %» a can be mentioned cyclopentyl, eyclohexyl, methylcyclohexyl and adamantyl. As heterocyclic groups R2, 5- and 6-inember heterocyclic compounds containing at least 1 heteroatom, preferably nitrogen, oxygen or sulfur, are suitable. For example, there can be mentioned a-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, etc. As the acid raccal R3, physiologically well-tolerated acid radicals are suitable. Preferred acids are organic carboxylic acids and sulfonic acids with 1-10 C atoms which belong to the aliphatic, cycloaliphatic, aromatic, aromatic- aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. As examples of the substituents there can be mentioned C-C—alfcyl-,. hydroxy, C1-C4 alkoxy, oxo or amino groups or halogen atoms (F, Gl, Br). For example, there can be mentioned the following carboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, tfidecylenic acid, myristic acid, pentadecylenic acid, trimethylacetic acid, diethylaeetie acid, tert-butyl acetic acid, cyclopropyl acetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyelohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid> methoxyacetic acid, ethoxyacetic acid, mono-1-, di- and trichloroacetic acid, aniinoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen, trifluoromethyl, hydroxy, alkdxy br carboxyl groups, nicotinic acid, isonicotinic acid, 2-furancarboxylic acid, cyclopentylpropionic acid. Acyl radicals with up to 4 carbon atoms are considered as especially preferred. As sulfonic aeids, methanesulfonic acid, ethanesulfonic acid, isopropanesulfonic acid, beta-chloroethanesulfonic acid, ,s •i • • r jMitanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, p-chlorobenzenesulfonic acid, N,N- dimethylarainosulfonic acid, N,N-diethylaininosulfonic acid, N,N-bis-(beta-chloroethyl)-aininosulfonic acid, N,N- diisobutylaminosulfonic acid, N,N-dibutylaininosulfonic acid, pyrrolidine-, piperidino-, piperazino-, N-methylpiperazino and morpholine-sulfonic acid are suitable, and sulfonic acids with up to 4 C atoms are especially preferred. The hydroxy groups R5 and in W can be functionally modified, for example by etherification or esterification, and the free or modified hydroxy groups in W can be in the alpha or beta position, free hydroxy groups being preferred. As ether and aeyl radicals, the radicals known to a roaii of the art are suitable. Preferred are easily cleavable ether radicals such as the tetrahydropyranyl, tetrahydrofuranyl, alpha-ethoxyethyl, trimethylsilyl, dimethyl'-tert-butyl-silyl and tri-p-benzyl-silyl radical. As acyl radicals, the same as mentioned for R3 are suitable; for example there can be mentioned acetyl, propionyl, butyryl, benzoyl. As alkyl groups R4, straight and branehed-chain, saturated and unsaturated alkyl radicals, preferably saturated and with 1-10, especially 1-4 C atoms, are suitable. For example there can be mentioned methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pefttyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, hexenyl. The cycloalkyl group R4 can contain 3-10, preferably and 6 carbon atoms in the ring. The rings can be substituted with alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopentyl, cyGlohexyl, methylcyclohexyl and adamantyl. As substituted or unsubstituted aryl groups R4 the following are suitable, fc»r example: phenyl, 1-naphthyl and I i 2-naphthyl, which can each be substituted with 1-3 halogen atoros, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C1-C4 alkoxy or hydroxy group. Substitution in the 3 and 4 position on the phenyl ring is preferred, for example with fluorine, chlorine, C1-C4 alkoxy or trifluoromethyl or in the 4 position with hydroxy. As heterocyclic groups R4, 5- and 6-meinber heterocyclic compounds which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur, are suitable. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyi, 3-pyridyl, 4- pyridyl, 3-furyl, 3-thienyl, among others. As alkylene group D, straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated with up to 5 C atoms> are suitable, which can optionally be substituted wittr fluorine atoms, 1,2 methylene, 1,l-trimethylene, 1,1-tetramethylene or 1,1-pentamethylene. Examples are: methylene, fluoromethylene, ethylene, 1,2 propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, l-merthyltetramethylene, 1-methyl trimethylene, 1,l-trimethylene ethylene, 1,l-tetramethylene ethylene. Especially preferred compounds of this invention are those with E as -0=0- or -CH=CR7, where R7 represents an alkyl group with 1-5 C atoms. As the alkyl group R7 with 1-5 C atoms, the groups just named for the alkyl group R4 are suitable. With R7 as halogen, fluorine, chlorine and bromine are meant. For Rg as -(CH2)m-R6j alkylene groups with 2 to 20 C atoms are suitable, which can still contain one or mpfe groups Zi or Z2 such as -(CH2)in_0-[Z1-(CH2)m-p]xtZ2-CH2)m qjy*"%f where m - 2-20 and o, p, and q together areie, such as, -(CH2)5-NM2, -(CH2) 6-NHCH3, -(CH2) 2-(GH2) 2-GOOH, - (CH2)2'0-(CH2h-NH2, -(CH2) 3-0-(CH2) 3-NH2, - (CH2) 2-0-(CH2) 3- 0-(CH2J2-0H, -<CHZ)3-N-(CH2)3- f : 1 t- - 7 NH2, -CH2-C=C-(CH2)2-NH2# -(CH2) 2-C=C- (CH2) 2-NH2 , -(CH2)2- C=C-(CH2)2-0-(CH2)2-SH, etc. For salt formation with the free acids (R2=H), inorganic and organic bases are suitable, such as they are known to a man of the art for the formation of physiologically well tolerated salts. For example, there can be mentioned alkali hydroxides such as sodium and potassium hydroxide, alkaline- earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanplamine, diethanolamine, triethanolamine, N- methylglucamine, morpholine, tris-(hydroxymethyl)- methylamine, etc. The invention relates further to processes for the production of carbacyclins of general formula I according to the invention, characterized in that a) a compound of general formula IV (IV) A-W-D-E-R. in which A, W, D, E, R4, R5 and Rg have the meanings already given, and With a Wittig reagent of general formula v and VI or a dianion of the formula VII <2> \ 1 (V), tl (OTOi-P-CCH-K-eoOR., (VI) (CH ) -R r 1 A (vii) c — 000° in which R2 has the meaning already given and Rg stands for the radicals -CH2-CH2-X-(CH2)n-Ri or 2 \ / R with the meanings already mentioned for X, n and R and Rn stand for bromine or chlorine, is reacted in the presence of K-tert-butylate or b) a ft#*v compound of general formula VIII, which is obtained from the corresponding 4-ester by DIBAH reduction CH2OH A-W-D-E-R, (VIII) in which A, W, D, E, R4, Rs, Rg, and Y2 have the meanings already given, optionally after protection of present free hydroxy or amino groups with a haloalkane acid derivative of general formula XX Hal-(CH) -C 2 a \ 0Rr (IX) , in which n is 1 or 3, Hal is a chlorine or bromine atom and Rg is an alkyl radical with 1-4 C atoms or an alkaline metal, is etherified in the presence of a base and, optionally, isomers are then separated in any order and/or protected hydroxy groups are released and/or free hydroxy groups esterified, etherified and/or a free carboxyl group esterified and/or an esterified carboxyl group saponified or a carboxyl group converted into an amide or with a physiologically well tolerated base .lato a salt. The reaction of the compound of general formula vm with a haloalkane acid derivative of general formula IX is performed at temperatures of 0oC to 100oC, preferably 10° to 80oC, in an aprotic solvent or solvent mixture, for example dimethyl sulfoxide, dimethyIformamide, tetrahydrofuran, etc. As basas, the bases known to a man of the art for etherifications are suitable, such as sodium hydride, potassium tert-butylate, butyllithium, etc. ~vBsi£ fen. j&Atyj&.j.Jw a&tiv k~ ls!£?.t. »j±v& £8 v," The starting compounds of formula IV are obtained by the reaction of compounds of formula II (II) A-W-D-E-R with Grignard reagents of formula III RlO-[(CH2)ra-q-z2]y-t(CH2>m-p-zl]x-(CH2)m-o-Mg-halogen (III), in which R4, R5, A, W, D, E, Zj, Z2, m, o, p, q have the indicated meanings, in the presence of copper(II) salts and by subsequent introduction of the upper side chain by Wittig reaction of the 5-ring carbonyl group and conversion of the group Ro into the group 1&q. For the group RQ' aroino groups protected by, for example, 1,1,4,4-tetramethyl-l,4- dichlorodisilylethane or by phthalic anhydride or by other typical amino groups protected by amino protection groups, and by hydroxy groups protected by tert-butyldiphenylsilyl or THP groups and by conversion into orthoesters or oxazoline- protected ca»rboxyl groups. After cleavage of the protection groups from nitrogen or after chemical conversion of the hydroxy or amide groups into amino groups, the desired substituents R6=NH2 are obtained. For this conversion of a hydroxy group into an amino group, the Mitsunobu reaction (see Synthesis 1, 1981) or the reduction of the azide to amine can be used. The saponification of the carbacyclin ester is performed according to methods known to a man of the art, for example with basic catalysts. The introduction of the ester group COOR2 for Rj, in which R2 represents an alkyl group with 1-10 C atoms, occurs according to methods known to a man of the art. The carboxyl compounds are reacted, for example, with diazohydrocarbons in a way known in the art. Esterificatitsn with diazohydrocarbons occurs, for example, by mixing a solution of diazohydrocarbon in an inert solvent, preferably in diethyl ether with the carboxyl compound in the same or in another inert solvent, for example, methylene chloride. After the reaction is finished in 1 to 30 minutes, the solvent is removed and the ester is purified in the usual way* Diazoalkanes are either known or can be produced by known methods (Org. Reactions Vol. 8, pages 389-394 (1954)). The introduction of the ester group COOR2 for R in which R2 represents a substituted or unsubstituted aryl group, occurs according to methods known to a man of the art. For example, the carboxyl compounds are reacted with the corresponding aryl hydroxy compounds with dicyelohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. As a solvent, methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, are suitable. The reaction is performed at temperatures between -30oC and +50oC, preferably at +10oC. The carbacyclin derivatives of general formula I with Ri representing a carboxyl group can be converted, with suitable amounts of the corresponding inorganic base, with neutralization, into salts. For example., by dissolving the corresponding PG acids in water which contains the stoichiometric amount of the base, the solid inorganic salt if obtained after evaporation of the water or after addition of a water-miseible solvent, for sxample, alcohol or acetone. Production of the amine salts occurs in the usual way. In addition, the PG acid is dissolved,- for example, in a suitablfa solvent such as ethanol, acetone, diethyl ether or benzene attd at least the stoichiometric amount of the artine of this solution is added. In doing so the salt usually precipitates in solid form of is isolated in the usual way after evaporation oi the solvent. I- I • • The functional modification of the free OH group occurs according to methods known to a man of the art. To introduce the ether protection group the reaction is performed with, for example, dihydropyran in methylene chloride or chloroform while using an acidic condensing agent, for example p- toluenesulfonic acid. An excess of dihydropyran is used, preferably 4 to 10 times the amount theoretically needed. The reaction is normally finished in 15 to 30 minutes at 0oC- 30oC. The introduction of the acyl protection groups occurs by reacting a compound of general formula I in a way known in the art with a carboxylic acid derivative, such as acid chloride, acid anhydride, among others. The release of a functionally modified OH group to the Gompounds of general formula I occurs according to known methods. For example, the cleavage of ether protection groups is performed in an aqueous solution of an organic acid, such as acetic acid, propionic acid, among others, or in an aqueous solution of an inorganic acid, such as hydrochloric acid. To improve the solubility, an water- miscible inert organic solvent is suitably added. Suitable organic solvents are, for example, alcohols such as methanol and ethanol,. and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran Tetrahydrofuran is preferably used. The cleavage is preferably performed at temperatures between 20oC and 80QC. The cleavage of the silyl ether protection group is performed, for example, with, tetrabutylammonium fluoride. Tetrahydrofuran, diethyl ether, dioxane, and methylene chloride, for example, are suitable as solvents. The cleavage is performed preferably at temperatures between 0oC and 80°G. Saponification Qf the acyl groups is performed, for example, with alkali or alkaline-earth carbonates or hydroxides in an alcohol ©r the aqueous solution of an alcohol. As alcohols. ff aliphatic alcohols are suitable, such as methanol, ethanol, butanol, etc, preferably methanol. As alkali carbonates and hydroxides there can be mentioned potassium and sodium salts, but the potassium salts are preferred.. As alkaline-earth carbonates and hydroxides, calcium carbonate, calcium hydroxide and barium carbonate are, for example, suitable. The reaction takes place at -10oC to 70oC, preferably at 250C. The introduction of the amide group CONHR3 for R occurs according to methods known to a man of the art. Carboxylic acids of general formula I (R2=H) are first converted, in the presence of a tertiary amine such as triethylamine, with chloroforftic acid isobutyl ester, into the mixed anhydride. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R3=H) occurs in an inert solvent or solvent mixture, such as tetrahydrofuran, dimethoxyethane, dimethylformamide, and hexamethylphosphoric acid triamide at temperatures between -30oC and +6q0C, preferably at 0oG to 30°c. A further possibility for the introduction of the amide group CONHR3 for R consists in reacting a 1-carboxylic acid of %..* I general formula I (R2=:H) , in which free hydroxy groups are protected intermediately, with compounds of general formula X r« * 0 = G = N-R3 (X), in which R3 has the above-mentioned meaning. The reaction of the compound of generai formula I (R=COOH) with an isoeyanate of generai fcirmula VIIt occurs optionally with I' W I- •TiSS*' i • • the addition of a tertiary amine, such as triethylamine or pyridine. The reaction can occur without solvent or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluene, at temperatures between -8Q0C to 100oC, preferably at 0oC to 30oC. If the starting product contains OH groups in the prostane radical, these OH groups are also reacted. If, ultimately, end products containing free hydroxy groups in the prostane radical are desired, suitably a starting product is used in which these free hydroxy groups are intermediately protected by preferably easily cleavable fether or acyl radicals. All remaining compounds of formula I can be produced according to processes described in laid-open specifications DE- OS 28 45 770, 3237 200, 33 22 893 and 34 05 181, The earbacyclins of formula I, in which Rg stands for the radical -(CH2)ro-R6 or -(CH2)m-o-[Zl-(CH2)m_p]x-[Z2-CH2)ra_q]y-R6 with R6 as NH2, NHCH3, OH, COOH, or SH group, can be bonded very well without great loss of biological activity to polymer carriers. The new earbacyclins prevent the formation of platelet aggregations on the surface of these polymer carriers, such as vascular prosthetic devices or artificial heart valves. After chemical bonding to proteins, the compounds of formula I are suitable for the preparation of antibodies to prostacyclins of general formula I. The compounds of this invention are furthermore suitable for therapy of diseases of the cardiovascular system, the stomach, the pancreas, the livier and the kidneys. They cause blood u t'-.ijjuSlJlSSSEK.ffi.L isS-A-iaWtSs i*fc£&ifci/»-»-«=K!i-i -i&sssttsisi'ui'&.i.. &*_ j-a&e&g -r pressure reduction and bronchodilation. They are additionally suitable for the inhibition of platelet aggregation. Consequently, the new carbacyclin derivatives of formula I represent valuable pharmaceutical active ingredients. Furthermore, compared with corresponding prostaglandins and prostacyclins, they exhibit higher specificity and above all a substantially longer effectiveness in the same activity spectrum. Compared to PGI2/ they are distinguished by higher stability. The high tissue specificity of the new carbacyclins is shown with the study of smooth muscle organs, such as the guinea pig ileum or the isolated rabbit trachea, where a considerably lesser stimulation can be observed than with the application of natural prostaglandins of the Ee A or F type. The new carbacyclin analogues possess qualities typical for prostacyclins, such as reduction of the peripheral arterial and coronary vascular resistancei inhibition of platelet aggregation and dissolution of platelet clots, myocardial cytoprotection, reduction of the systemic blood pressure without at the same time reducing cardiac output and cofonary blood circulation; treatment of stroke, prevention and tfrerapy tot coronary heart diseases, coronary thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prevention and therapy of ischemic attacks of the central nervous system, shock therapy, inhibition of bronchoconstriction," inhibition of stomach acid secretion and cytoprotection of the stomach and intestinal mucous membrane; eytoprotectiort in the liver, pancreas and kidneys, afltiallergie qualities, reduction of pulmonary vascular if _ d. if *~4 a* • resistance and pulmonary blood pressure, stimulation of kidney blood circulation, use instead of heparin or as an adjunct in dialysis or blood filtration, storage of blood plasma supplies, especially of blood platelet supplies, inhibition of labor pains, treatment of pregnancy toxicosis, elevation of cerebral blood circulation, treatment of asthma, etc. In addition, the new carbacyclin analogues possess antiproliferative qualities. The new carbaeyclins can also be used in combination, for example, with beta blockers or diuretics. The new carbaeyclins are furthermore distinguished by the suppression of rejection reactions and by its antimetastatic effect. With them, Botallo's duct (before operations) is kept open. They are further suitable for diarrhea treatment and to improve bowel movement. The dose of the compounds is 1-1500 inicrograms/kg/day, if they are administered to human patients. The unit dose for the pharmaceutically acceptable vehicles is 0.01-100 mg. With intravenous injection in awake, hypertonic rats in doses of 5, 20 and 100 micrograms/kg body weight, the compounds according to the invention exhibit stronger blood pressure reduction and longer lasting effects than PGE2 and PGA2 without causing, as with PGE2, diarrhea, or as with PGA2, cardiac arrhythmias. With intravenous injection in anesthetized rabbits, the compounds according to the invention exhibit, compared to PGE2 and PGAj, stronger and considerably longer lasting blood pressure reduction, without influencing other smooth muscle organs or s wxv.u a a Ay a. gtoups wxui a-s ttcoon atoms. *oc exainpie# *,»»«?«, r to • • c organ functions. For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For oral application, tablets, dragees or capsules are suitable, for example. The invention thus relates also to drugs based on compounds of general formula I and usual auxiliary agents and carriers. The active ingredients according to the invention should function in conjunction with the usual auxiliary agents known in galenicals, such as for the production of blood pressure reduction agents. The.unit dose range for the ampoule is 0.1 - 0.5 mg, for tablets 0.1-1 mg. Example 1 5- (E) -17-hydroxy-6- f (E) -3-hvdroxy-4-inethvl-oct-l~en-6-inyl 1--9- f C- amino-hexvn-bicvclor3. 3 .OVoctan-J-vlidenv-pentaic acid 221 mg (0.5 mmolj of 7alpha-tetrahydropyran-2-yl-oxy)- 6beta-[(E)-4-methyl-3-(tetrahydropyran-2-yloxy) -oct-l-en-6- inyl]-bicyclo-(3.3.0]-oct-l-en-3-one and 12 mg Of Cu(0Ac)2 * H2O in 6 ml of absolute tetrahydroduran were mixed slowly at -150C with a Grignard reagent, prepared from 670 mg (2 iranol) of 2,2,5,5-tetramethyl-l-aza-2,5-disilacyclopentane-l-hexyl bromide and 103 mg of magnesium chips in 2 ml of absolute ether, until a pitch black color was achieved after several color changes. After working up with NH4CI, the raw product was subsequently silylated according to the following formula for the starting material and the raw product, which according to TLG still eotttained 13% of the starting material, was subjected to a h I i « Wittig reaction with 10 equivalent of (4 carboxybutyl)- triphenylphosphonium bromide/potassium tert-butylate in dimethyl sulfoxide-tetrahydrofuran =2:1. After 3 hours of stirring at 30oC, it was mixed with ice water, carefully neutralized with citric acid and extracted with ether. After chromatography on silica gel, pure 5-E-isomer was obtained, which yielded the desired 5-E end product after cleavage of the protection group with AcOH-H20-THF> IR (oil film) 3400-3000 cm-1 (NH2 and OH) 1710-1600 cm-1 (acid carbonyl and carboxylate) 2, 2,5,5-tetrainethyl-aza-2,5-disilacyclopentane-l-hexyl bromide was prepared as follows: g (38.3 mmol) of 6-bromine-l-hexylamine hydrobromide and 8.25 g (38.3 mmol) of 1,2-bis(chlorodimethylsilyl)ethane were stirred in the presence of 15.9 ml (115 mmol) of triethylamine in 115 ml of methylene chloride for 3 hours at 24°, and triethylamine hydrochloride precipitated. After suctioning of the triethylamine hydrochloride and rewashing with methylene chloride, evaporation took place and the residue was absorbed in ml of dry hexane, while the remaining triethylamine hydrochloride precipitated and was filtered off. After evaporation, about 11.52 g (93.3%) was obtained, which was distilled at 92-102o/0.05 nun. The distillate is, like the raw product, slightly cloudy. H r:.. Example 2 5-(EV-c7-(tetrahvdropvran-2-vl-oxy)-6-f(E)-4-methvl-3- (tetrahvdropvran-2-vl-oxv) -oct-l-en-6-invl 1 -9- r 5-hydroxv-pentvl 1 - bicYclo-r3.3.01-octan-3-ylidens-pentaic acid To 740 mg (1-67 mmol) of 7 alpha-tetrahydropyran-2-yl-oxy)-6 beta-[ (E)-4-methyl-3-(tetrahydropyran-2-yl-oxy)-oct-l-en-6-inyl]- bicyclo[3.3.0]oct-l-e"n-'3'-one and 40.2 mg of Cu(OAc)2 • H2O in ml of absolute tetrahydrofuran was instilled in 10 minutes at - 15°, a Grignard solution produced from 3.949 g of 5-tert- butyldimethylsilyloxypentylbromide and 689 mg of magnesium chips in 15 ml of absolute ether until a pitch black color occurred. After working up, the raw product was chromatographed on a column of about 150 g of Si02 in hexane-ether and 932 mg = 86.4% pure bicyclic ketone was obtained. This 932 mg (1.445 mmol) was reacted analogously to Example 1 with excess (4- carboxybutyl)triphenylphosphonium bromide and after working up the isomeric compounds were Separated by chromatography in hexane-ether on 150 g of fine silica gel, and pure (e)- Stereoisomer was obtained. By treatment with a tetrabutylammonium fluoride solution in THF, the tert-butyl- dimethylsilyl protection group saponified oh the C-9 of the bicyclooctane skeleton selectively and the title compound formed. The reaction with acetic acid-HO-THF/SO0 then leads to the free carbacyclin derivative 5(E))7-hydroxy-6[(E)-4-methyl-3-hydroxy- oct-l-en-6-inyl3-9[5-hydroxyl-pent.yl]-bicyclo [3 .3 .0]-octan-3- ylidenj-pentaic acid. IR (oil film) 3300-3000 cm-1 (OH).1740-1710 cm-1 (acid S&fec&siltt.- carbonyl/wide/). 5-tert-butyldimethylsilyloxy-pentyl bromide was prepared as follows: 10.45 g (50 mmol) of 5-broniovaleric acid ethyl ester was reduced at 0° with 1.043 g of LiAIH4 in 100 ml of absolute tetrahydrofiirah, worked up with ice water, 2 N H2SO4 and chromatographed with pentane, 20% ether on a column with 27 5 g of silica gel, and 5.88 g of 5-bromopentyl alcohol was obtained. 7.01 g (42 mmol) of 5-broinopentyl alcohol was stirred in ml of DMF with 3.571 g of imidazole and 7.906 g (52.5 mmol) of tert-butyldimethylsilyl chloride for 2 hours at 24°, ice water added and extracted with hexane/ether 1:1, and 12.58 g of raw product was obtained, which yielded 8.93 g (75%) of the title compound in pentane after chromatography on silica gel. <-* I * AMD/0278a The claims defining the invention are as follows: Carbacyclin derivatives with general formula I: V /Y2 A R9-7—\ <i) '5 *. •.; in which '... Y, stands for the radical -CH„-X-(CH_) -R, or the 1 2 v 2'n 1 • •• —r, "••••" radieal y \ •" ' n, 1 or 3, 'lm"l R, f the radical - , the radical -CH /\ , '0"CH2VCH3 -O-CH CH3' -'COCH[3, COOR2, and R- stands for hydrogen or alkyl with 1-10 C atoms optionally substituted with halogen, phenyl, C1-C4 alkoxy or C,-C4 dialkyl amino; cycloalkyl, aryl or a 5- or 6 membered heterocyclic radical containing at least 1 heteroatom, or the radical CONHR,,, with R0 standing fpr j j hydrogen or an alkanoyl Or alkane sulfonyl radical eacti with 1-10 C atoms,