IE863130L - Bicyclo (3,3,o) octane derivatives - Google Patents

Abstract

Carbacycline derivatives of general formula (I), in which Y1 is the residue of Formula (II), R9 is the residue -(CH2)m-R6 or the residue -(CH2)m-o-[Z1-(CH2)m-p]x-[Z2-(CH2)m-q]y-R6, m = 2-20; o, p and q <= 19; x, y = 0, 1 or 2; Z1 is a cis-CH=CH-group, a trans-CH=CH-group or a -C=C-group, whereby each of these groups must be separated at least by one methyl group from the C-9 carbon atom of the carbacycline bi-cycle; Z2 is oxygen, sulphur, an NH or an N-methyl group, R6 is amino, methylamino, hydroxy, carboxy or mercapto; and process for their manufacture and their use as medicaments.

Description

59345 The invention relates to novel carbacyclin derivatives, processes for their manufacture and their use as medicaments.

US Patent 4,420,632, describes 9-alkylated carbacyclin 5 derivatives having antithrombotic, anti-secretory and bronchodilatory properties. In addition, they inhibit thrombocyte aggregation. There are known from European Patent Application EP 86 611 carbacyclins that are substituted in the 9-position by halomethyl or hydroxymethyl 10 and that contain unsaturated alkyl groups as further substituents, the double and triple bonds being arranged directly adjacent to the nucleus. Their pharmacological properties are described as anti-ulcer and anti-asthmatic.

It has been found that carbacyclin analogues with an 15 extended chain in the 9-position and with a reactive group in the a-position can be bonded to polymeric carriers with only a slight loss in biological activity. The compounds according to the invention are suitable for inhibiting thrombocyte aggregation, for lowering blood pressure by a 20 process of vasodilation and for inhibiting gastric acid secretion, and are also suitable, by chemical binding with proteins, for the production of carbacyclin antibodies.

The invention relates to carbacyclin derivatives of the general formula I: Y,\yY2 A • • • • "'tx.

A-W-D-E-S in which Yx represents the radical -CH2-X-(CH2)^-R^ or the radical n is 1 or 3 A- Rx represents the radical I , the radical -CH^ » -COCH3/ COOR2 wherein R2 may O'CHj CH3 represent hydrogen, alkyl having from 1 to 10 C-atoms optionally substituted by halogen, phenyl, Ci-C4-alkoxy 10 or by Ci-C^-dialkylamino, cycloalkyl, aryl or a heterocyclic radical, or R^ represents the radical CONHR3 wherein R3 represents hydrogen or an alkanoyl or alkanesulphonyl radical each having from 1 to 10 C-atoms, represents the radical -(CH2)m-R6 or the radical ~ (CH2 )m_0- [ Z 3.- (CH2 )m_p] x- [ Z2- (CH2 )m-q]y-R6, = 2 to 20 and p and q < 19, and y = 0, 1 or 2 represents a cis-CH=CH- group, a trans -CH=CH- group or a -C=C- group, each of which must be separated from the C-9 carbon atom of the carbacyclin nucleus by at least a methylene group, represents oxygen, sulphur, an NH- or an N-methyl-group, represents amino, methylamino, hydroxy, carboxy or mercapto, represents an oxygen atom or a methylene group, represents hydrogen or fluorine represents a -CH2-CH2-, trans-CH=CH- or -C=C- group represents a free or functionally modified hydroxy-methylene group or a free or functionally modified -C- group wherein the OH group may be in the a- or Ji-conf iguration, represents the group a straight-chain saturated alkylene group having from 1 to 5 C-atoms, a branched saturated, or a straight-chain or branched unsaturated, alkylene group having from 2 to 5 C-atoms, each of which may optionally be substituted by fluorine atoms, o is 1, 2 or 3, E is a direct bond, a -C=C- group or a -CH=CR7- group wherein R7 represents a hydrogen atom, an alkyl group having from 1 to 5 C-atoms, or halogen, R4 represents an alkyl group having from 1 to 10 C-atoms, a cycloalkyl group having from 3 to 10 C-atoms or an 10 optionally substituted aryl group having from 6 to 10 C-atoms, or a heterocyclic group, and Rs represents a free or functionally modified hydroxy group and, when R2 is a hydrogen atom, salts thereof with 15 physiologically tolerable bases.

There come into consideration as alkyl groups R2 straight-chain or branched alkyl groups having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, 20 neopentyl, heptyl, hexyl and decyl.

The alkyl groups R-, may optionally be mono- to poly-substituted by halogen atoms, C!-C4alkoxy groups, phenyl and di-Cx-C^alkylamines. Preferred are such alkyl groups that are monosubstituted.

The following may be mentioned as examples of substituents: fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy and ethoxy.

Preferred alkyl groups R2 are those having from 1 to 4 5 carbon atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl and butyl.

There come into consideration as aryl groups R2 both substituted and unsubstituted aryl groups, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, each of which 10 may be substituted by from 1 to 3 halogen atoms, a phenyl group, from 1 to 3 alkyl groups each having from 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoro-methyl, carboxy, hydroxy or alkoxy group having from 1 to 4 carbon atoms.

Preferred are substituents in the 3- and 4-positions of the phenyl ring, for example fluorine, chlorine, alkoxy or trifluoromethyl or, in the 4-position, a hydroxy group.

A cycloalkyl group R2 may contain from 4 to 10, preferably 5 or 6, carbon atoms in the ring. The rings may be 20 substituted by alkyl groups having from 1 to 4 carbon atoms. Cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl may be mentioned by way of example.

There come into consideration as heterocyclic groups R2/ 5-and 6-membered heterocycles that contain at least one hetero 25 atom, preferably nitrogen, oxygen or sulphur. 2-Furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl etc., may be mentioned by way of example.

There come into consideration as acidic radicals R3 physiologically tolerable acidic radicals. Preferred acids are organic carboxylic acids and sulphonic acids having from 1 to 10 carbon atoms that belong to the aliphatic, 5 cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids may be saturated, unsaturated and/or polybasic and/or may be substituted in the conventional manner. C1-C4-alkyl, hydroxy, C;,.-C4-alkoxy, oxo or amino groups or halogen atoms (F, CI, Br) may 10 be mentioned as examples of such substituents.

For example, the following carboxylic acids may be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, oenanthic acid, caprylic acid, pelargonic 15 acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert.-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, 20 cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and tri-chloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic 25 acids substituted by halogen, trifluoromethyl, hydroxy, alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic acid and cyclopentylpropionic acid. Especially preferred acyl radicals are those containing up to 4 carbon atoms. There come into consideration as 30 sulphonic acids, for example, methanesulphonic acid, ethanesulphonic acid, isopropanesulphonic acid, fl-chloroethanesulphonic acid, butanesulphonic acid, cyclopentanesulphonic acid, cyclohexanesulphonic acid, benzenesulphonic acid, £-toluenesulphonic acid, £-chlorobenzenesulphonic acid, N,N-dimethylaminosulphonic acid, N,N-diethylaminosulphonic acid, N,N-bis-(fi-chloroethyl)-aminosulphonic acid, N , N -5 diisobutylaminosulphonic acid, N,N-dibutylaminosulphonic acid, pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino- and morpholino-sulphonic acids, with sulphonic acids having up to 4 carbon atoms being especially preferred.

The hydroxy groups Rs and in W may be functionally modified, for example by etherification or esterification, it being possible for the free or modified hydroxy groups in W to be in the a or R configuration; free hydroxy groups are preferred.

There come into consideration as ether and acyl radicals those radicals that are known to the person skilled in the art. Preferred are readily removable ether radicals, such as, for example, tetrahydropyranyl, tetrahydrofuranyl, a-ethoxyethyl, trimethylsilyl, dimethyl-tert.-butylsilyl and 20 tri-£-benzylsilyl radicals. There come into consideration as acyl radicals those radicals that were mentioned for R3; there may be mentioned specifically, for example, acetyl, propionyl, butyryl and benzoyl.

There come into consideration as alkyl groups R4 straight-25 chain and branched, saturated and unsaturated alkyl radicals, preferably saturated alkyl radicals having from 1 to 10, especially from 1 to 4, carbon atoms.

There may be mentioned by way of example methyl, ethyl, propyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, 30 octyl, butenyl, isobutenyl, propenyl, pentenyl and hexenyl.

The cycloalkyl group R4 may contain from 3 to 10, preferably 5 or 6, carbon atoms in the ring. The rings may be substituted by alkyl groups having from 1 to 4 carbon atoms. There may be mentioned by way of example cyclopentyl, 5 cyclohexyl, methylcyclohexyl and adamantyl.

As substituted or unsubstituted aryl groups R4 there come into consideration, for example, phenyl, 1-naphthyl and 2-naphthyl each of which may be substituted by from 1 to 3 halogen atoms, a phenyl group, from 1 to 3 alkyl groups each 10 having from 1 to 4 carbon atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxy, C1-C4alkoxy or hydroxy group. Substitution in the 3- and 4-position of the phenyl ring, for example, by fluorine, chlorine, C1-C4-alkoxy or trifluoromethyl, or in the 4-position by hydroxy, 15 is preferred.

As heterocyclic groups R4 there come into consideration 5-and 6-membered heterocycles that contain at least one hetero atom, preferably nitrogen, oxygen or sulphur. There may be mentioned by way of example 2-furyl, 2-thienyl, 2-pyridyl, 20 3-pyridyl, 4-pyridyl, 3-furyl, 3-thienyl etc.

There come into consideration as alkylene groups D straight-chain or branched, saturated and unsaturated alkylene radicals, preferably saturated, having up to 5 carbon atoms which may optionally be substituted by fluorine atoms, 1,2-25 methylene, 1,1-trimethylene, 1,1-tetramethylene or 1,1-pentamethylene. There may be mentioned by way of example methylene, fluoromethylene, ethylene, 1,2-propylene, ethylethylene, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene, 1,1-30 trimethyleneethylene and 1,1-tetramethyleneethylene.

Especially preferred compounds of this invention are those in which E is -C=C- or -CH=CR7-, wherein R7 represents an alkyl group having from 1 to 5 carbon atoms.

The groups already mentioned for the alkyl group R4 come 5 into consideration as alkyl groups R7 having from 1 to 5 carbon atoms.

R-7 when representing halogen denotes fluorine, chlorine or bromine.

Where R9 is -(CH2)m-R6, there come into consideration 10 alkylene groups having from 2 to 20 carbon atoms that may in addition contain one or more Zx or Z2 groups, such as "(CH2)m_0-[Zx-(CH2)m_1P]x-[Z2-(CH2)m_^]y-R6 in which m = 2-20 and o, p and q together are -16, such as, for example, -(ch2)s-nh2, -(ch2)6-nhch3, -(ch2)2-0-(ch2)2-c00h, 15 -(ch2)2-0-(ch2)3-nh2, -(ch2)3-0-(ch2)3-nh2, -(ch2)2-0-(ch2)2-0-(ch2)2"0h, -(ch2)3-n-(ch2)3-nh2, ch3 -ch2-C=C-(ch2)2-nh2, -(ch2)2-CSC-(ch2)2-nh2, -(ch2)2-CSC-(ch2)2-o-(ch2)2-sh etc.

For salt formation with the free acids (R=H), inorganic and organic bases are suitable, such as are known to the person skilled in the art for the formation of physiologically tolerable salts. The following may be mentioned by way of example: alkali hydroxides, such as sodium and potassium 25 hydroxide, alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, n-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine etc.

The invention further relates to a process for the manufacture of carbacyclins of the general formula I according to the invention, characterised in that a) a compound of the general formula IV o A "ti A-W-D-E-R (IV), in which A, W, D, E, R4, Rs and R«> have the meanings given hereinbefore, is reacted with a Wittig reagent of the general formula V and VI or a dianion of formula VII O '11 (V), 0 (CH,0),P- C — CDO^ & (VI) (VII) wherein R2 has the meaning given and Rs represents the radical -CH2- /TT\ CH^-X-tCHaJ^-R^ or •CH2 \_/ in which X, n and Rx have the meanings given hereinbefore and R1;L is bromine or chlorine, in the presence of K-tert.-butoxide, or b) a compound of the general formula VIII, which is obtained from the corresponding 4-ester by DIBAH reduction, R5 (VIII), wherein A, W, D, E, R4, Rs, R9 and Y2 have the meanings given hereinbefore, optionally after protecting any free hydroxy or amino groups present, is etherified in the presence of a base with a haloalkanoic acid derivative of the general formula IX Hal-(CH2)n-C^ OR, (IX) wherein n is 1 or 3, Hal represents a chlorine or bromine atom and Rs represents an alkyl radical having from 1 to 4 C-atoms, or an alkali metal, and optionally, subsequently, in any order, isomers are separated and/or protected hydroxy groups are freed and/or free hydroxy groups are esterified or etherified and/or a free carboxy group is esterified and/or an esterified carboxy group is hydrolysed or a carboxy group is converted into an amide or converted by means of a physiologically tolerable base into a salt.

The reaction of the compound of the general formula VIII with a haloalkanoic acid derivative of the general formula 5 IX is carried out at temperatures of from 0°C to 100°C, preferably from 10° to 80°C, in an aprotic solvent or mixture of solvents, for example dimethyl sulphoxide, dimethylformamide, tetrahydrofuran etc. There come into consideration as bases those which are known to the person 10 skilled in the art for etherifications, for example sodium hydride, potassium tert.-butoxide, butyl lithium etc.

The starting compounds of formula IV are obtained by reacting compounds of formula II with Grignard reagents of formula III Rio"I (CH2)m_q-Za ]y-[ (CHa).n-p-Z, ](CHa)m-0-Mg-Halogen (III) in which R4, Rs, A, W, D, E, Zx, Z2, m, o, p and q have the meanings given hereinbefore, in the presence of copper(II) salts, followed by the introduction of the above side chain 20 by a Wittig reaction of the 5-ring carbonyl group and conversion of the R10 group into the Rs group. There come into consideration as the group Rxo protected amino groups, such as, for example, amino groups protected by 1,1,4,4-tetramethyl-1,4-dichlorodisilylethane or phthalic anhydride or other typical amino-protecting groups, as well as hydroxy 5 groups protected by tert.-butyldiphenylsilyl or THP-groups and also carboxyl groups that have been protected by conversion into orthoesters or oxazolines.

By removal of the protecting group from the nitrogen or chemical conversion of the hydroxy or amide groups to amino 10 groups, the desired substituent Rs = NH2 is obtained. This conversion of a hydroxy group to an amino group can be carried out using the Mitsunobu reaction (Synthesis 1, 1981) or by reduction of the azide to the amine.

Hydrolysis of the carbacyclin ester is carried out by 15 methods known to the person skilled in the art, such as, for example, with basic catalysts.

The ester group COOR2 as a meaning of Rx, wherein R2 represents an alkyl group having from 1 to 10 carbon atoms, is introduced by methods known to the person skilled in the 20 art. The carboxy compounds are reacted in a manner known per se, for example with diazo hydrocarbons. Esterification with diazo hydrocarbons is carried out, for example, by mixing a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy 25 compound in the same or in a different inert solvent such as, for example, methylene chloride. After completion of the reaction after 1 to 30 minutes the solvent is removed and the ester is purified in customary manner. Diazoalkanes are either known or can be manufactured by known methods 30 [Org. Reactions Vol. 8, pages 389-394 (1954)].

The ester group COOR2 as a meaning of Rx/ wherein R2 represents a substituted or unsubstituted aryl group, is introduced by methods known to the person skilled in the art. For example, the carboxy compounds are reacted with 5 the corresponding arylhydroxy compounds with dicyclohexyl carbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent. There come into consideration as solvents methylene chloride, ethylene chloride, chloroform, ethyl acetate and tetrahydrofuran, but 10 preferably chloroform. The reaction is carried out at temperatures of from -30°C to +50°C, preferably at +10°C.

Carbacyclin derivatives of the general formula I in which Rx represents a carboxy group can be converted into salts by neutralisation with suitable quantities of the corresponding 15 inorganic bases. For example, by dissolving the corresponding PG acids in water containing a stoichiometric amount of the base, the solid inorganic salt is obtained by evaporating off the water or by adding a water-miscible solvent, for example alcohol or acetone.

The amine salts are prepared in customary manner. For this purpose, the PG acid is dissolved, for example, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to the solution. The salt normally precipitates in 25 solid form or is isolated in customary manner after evaporation of the solvent.

Functional modification of the free OH groups is effected by methods known to the person skilled in the art. For the introduction of the ether protecting groups, a reaction is 30 carried out, for example, with dihydropyran in methylene chloride or chloroform with the use of an acid condensing agent, such as, for example, jj-toluene-sulphonic acid. The dihydropyran is used in excess, preferably in an amount that is from 4 to 10 times the theoretically required amount. At 0°C to 30°C the reaction is normally complete after 15 to 30 5 minutes.

The acyl protecting groups are introduced by reacting a compound of the general formula I in a manner known per se with a carboxylic acid derivative, such as, for example, the acid chloride or acid anhydride etc.

The freeing of a functionally modified OH group to form the compounds of the general formula I is carried out according to known methods. For example, the removal of "ether protecting groups is carried out in an aqueous solution of an organic acid, such as, for example, acetic acid, 15 propionic acid etc., or in an aqueous solution of an inorganic acid, such as, for example, hydrochloric acid. To improve the solubility, it is convenient to add a water-miscible inert organic solvent. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, 20 and ethers, such as dimethoxyethane, dioxan and tetrahydrofuran. Preferably, tetrahydrofuran is used. The removal is preferably carried out at temperatures of from 20°C to 80°C.

The removal of silyl ether protecting groups is carried out, 25 for example, with tetrabutylammonium fluoride. Suitable solvents are, for example, tetrahydrofuran, diethyl ether, dioxan, methylene chloride etc. The removal is carried out preferably at temperatures of from 0°C to 80°C.

The hydrolysis of the acyl groups is carried out, for 30 example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or an aqueous solution of an alcohol. Possible alcohols are aliphatic alcohols, such as, for example, methanol, ethanol, butanol etc., preferably methanol. As alkali carbonates and hydroxides mention 5 should be made of potassium and sodium salts, but potassium salts are preferred. Suitable alkaline earth carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is carried out at from -10°C to 70°C, preferably at 25°C.

The amide group CONHR3 as a meaning of Rx is introduced by methods known to the person skilled in the art. Carboxylic acids of the general formula I (R2=H) are first converted into the mixed anhydride with isobutyl chloroformate in the presence of a tertiary amine, such as, for example, 15 triethylamine. The reaction of the mixed anhydride with the alkali salt of the corresponding amide or with ammonia (R3=H) is carried out in an inert solvent or solvent mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide or hexamethylphosphoric 20 acid triamide, at temperatures of from -30°C to +60°C, preferably at from 0°C to 30°C.

A further possibility for the introduction of the amide group CONHR3 as a meaning of Rx consists in reacting a 1-carboxylic acid of the general formula I (R2=H), in which 25 free hydroxy groups are intermediately protected, with compounds of the general formula X 0 = C = N - R3 (X) in which R3 has the meaning given hereinbefore.

The reaction of the compound of the general formula I (R!=COOH) with an isocyanate of the general formula VIII is carried out optionally with the addition of a tertiary amine, such as, for example, triethylamine or pyridine. The 5 reaction can be carried out without solvents or in an inert solvent, preferably acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethyl ether or toluene, at temperatures of from -80°C to 100°C, preferably from 0°C to 30°C.

If the starting material contains OH groups in the prostane radical, these OH groups are also made to react. If, ultimately, end products are desired that contain free hydroxy groups in the prostane radical, then advantageously starting materials in which these groups are intermediately 15 protected by preferably readily removable ether or acyl radicals are used.

All the other compounds of formula I can be produced by processes as described in Offenlegungsschriften DE-OS 28 45 770, 32 37 200, 33 22 893 and 34 05 181.

The carbacyclins of formula I, in which R9 is -(CH2)m-R6 or -(CH2 )m-c,- [Z(CH2 Jm-p]x- [Z2-CH2 )m-q]y-R6 in which R6 is an NH2, NHCH3, OH, COOH or SH group can be very easily bonded to polymeric carriers without a significant loss of biological activity. By the use of the novel carbacyclins, 25 the formation of thrombocyte aggregates on the surfaces of those polymeric carriers,such as, for example, vascular prostheses or artificial heart valves, is prevented. By chemical bonding to proteins, the compounds of formula I are suitable for the preparation of antibodies to the 30 prostacyclins of the general formula I.

The compounds of the invention are also suitable for the treatment of disorders of the cardiovascular system, the stomach, the pancreas, the liver and the kidneys. They have blood pressure-lowering and bronchodilatory effects. Furthermore, they are suitable for inhibiting thrombocyte aggregation. Thus, the novel carbacyclin derivatives of formula I are valuable pharmaceutical active substances. In addition, while possessing a similar spectrum of activity, compared with corresponding prostaglandins and prostacyclins they exhibit a higher specificity and, especially, are effective for a substantially longer period. In comparison to PGI2 they are distinguished by greater stability. The high tissue specificity of the novel carbacyclins is demonstrated by the investigation of smooth muscle organs such as, for example, a guinea-pig ileum or isolated rabbit trachea, where far less stimulation is observed than when natural prostaglandins of the E, A or F type are administered.

The novel carbacyclin analogues possess properties typical 20 of prostacyclins, such as, for example, lowering of peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation and dissolution of platelet clots, myocardial cytoprotection, lowering of systemic blood pressure without simultaneous lowering of the 25 cardiac output and coronary circulation; treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial diseases, arteriosclerosis and thrombosis; prophylaxis and therapy of ischaemic attacks of the central 30 nervous system, therapy of shock, inhibition broncho-constriction, inhibition of gastric acid secretion and cytoprotection of the gastric and intestinal mucous membrane; cytoprotection in the liver, pancreas and kidneys, antiallergic properties, lowering of pulmonary vascular resistance and of pulmonary blood pressure, promotion of kidney circulation, use instead of heparin or as an adjunct in dialysis or haemofiltration, preservation of blood plasma stocks, in particular of blood platelet stocks, inhibition of labour, treatment of pregnancy toxicosis, increase of cerebral circulation, treatment of asthma etc. In addition, the novel carbacyclin analogues possess antiproliferative properties. The novel carbacyclins can in addition be used in combination,, for example, with fi-blockers or diuretics.

The novel carbacyclins are furthermore distinguished by the suppression of rejection reactions and by their antimetastatic action. As a result of their use, the ductus botalli is kept open (prior to operations). They are also suitable for the treatment of diarrhoea and for the improvement of bowel movements.

The dosage of the compounds is 1-1500 jjg/kg/day when administered to human patients. The unit dose for the pharmaceutical^ acceptable carrier is 0.01 to 100 mg.

On intravenous injection to conscious hypertonic rats at doses of 5, 20 and 100 vq/Viq body weight, the compounds of the invention exhibit a stronger blood pressure-lowering and longer-lasting effect than PGE2 and PGA2 without, as is the case with PGE2, causing diarrhoea or, as is the case with PGA2, causing cardiac arrhythmia.

On intravenous injection to narcotized rabbits, the compounds according to the invention in comparison with PGE2 and PGA2 exhibit a more pronounced and considerably longer-lasting lowering of blood pressure without other smooth muscle organs or organ functions being affected.

For parenteral administration sterile injectable, aqueous or oily solutions are used. For oral administration, for example tablets, dragees or capsules are suitable.

The invention thus also relates to medicaments based on 5 compounds of the general formula I and conventional adjuncts and carriers.

The active substances of the invention are intended, in combination with the adjuncts known and customary in galenical pharmacy, for example for the manufacture of blood 10 pressure-lowering agents.

The unit dosage range for ampoules is 0.1 to 0.5 mg, for tablets 0.1 to 1 mg.

Example 1 -(E)-{7-Hydroxy-6-\(E)-3-hydroxy-4-methyloct-1-en-6-15 ynyl 1—9 — 1" 6-aminohexyl 1 -bicyclof 3.3. 0 loctan-3-ylidene pentanoic acid A Grignard reagent, prepared from 670 mg (2 mmol) of 2,2,5,5-tetramethyl-l-aza-2 , 5-disilacyclopentane-l-hexyl bromide and 103 mg of magnesium filings in 2 ml of absolute 20 ether was slowly added, at -15°, to 221 mg (0.5 mmol) of 7a-tetrahydropyran-2-yloxy) - 615 - [ ( E ) - 4- methyl-3-(tetrahydropyran-2-yloxy) -oct-l-en-6-ynyl ] -bicyclo[ 3 .3.0] oct-l-en-3-one and 12 mg of Cu(0Ac)2.H20 in 6 ml of absolute tetrahydrofuran until, after various colour changes, a 25 pitch-black colour was reached.

After working up with NH4C1, the crude product corresponding to the following specification for the starting material was then silylated and the crude product, which according to TLC still contained 13 % starting material, was subjected to a 5 Wittig reaction with 10 equivalents of 4-carboxybutyl-triphenylphosphonium bromide/potassium tert.-butoxide in dimethyl sulphoxide/tetrahydrofuran (2:1). After stirring for 3 hours at 30° ice water was added and the whole was carefully neutralised with citric acid and extracted with 10 ether. Chromatography on silica gel yielded the pure 5-E-isomer which, after removal of the protecting groups with Ac0H-H20-THF, gave the desired -E-end product IR (oil film) 3400-3000 cm-1 (NH2 and OH) 1710-1600 cm-1 (acid carbonyl and carboxylate). 2,2,5,5-tetramethyl-aza-2,5-disilacyclopentane-l-hexyl bromide was prepared s follows: g (38.3 mmol) of 6-bromo-l-hexylamine hydrobromide and 8.25 g (38.3 mmol) of 1,2-bischlorodimethylsilylethane were 20 stirred for 3 hours at 24° in the presence of 15.9 ml (115 mmol) of triethylamine in 115 ml of methylene chloride, triethylamine hydrochloride being precipitated. After filtering off the triethylamine hydrochloride with suction and subsequently washing with methylene chloride, the 25 filtrate was evaporated and the residue taken up in 50 ml of dry hexane, the remaining triethylamine hydrochloride precipitating and being filtered off. After evaporation, 11.52 g (93.3 %) of product was obtained, which distilled at 92-102°/0.05 mm. The distillate, like the crude product, is 30 slightly turbid.

Example 2 -(E)-{7-(Tetrahydropyran-2-yloxy)-6-f(E)-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl1-9-\5-hydroxy-pentyl1-bicyclor3.3.01octan-3-ylidene> pentanoic acid A Grignard solution, prepared from 3.949 g of tert.-butyldimethylsilyloxypentyl bromide and 689 mg of magnesium filings in 15 ml of absolute ether, was slowly added dropwise, over a period of 10 minutes at -15°C, to 740 mg (1.67 mmol) of 7a-tetrahydropyran-2-yloxy)-6B-[ (E) -4-methyl-10 3-(tetrahydropyran-2-yloxy)-oct-l-en-6-ynyl]-bicyclo[3.3.0]oct-l-en-3-one and 40.2 mg of Cu(0Ac)2.H20 in 20 ml of absolute tetrahydrofuran until a pitch-black colour was reached. After working up, the crude product was chromatographed on a column of approximately 150 g of Si02 15 in hexane/ether, 932 mg (=86.4 %) of pure bicyclic ketone being obtained. This 932 mg (1.445 mol) was reacted with excess 4-carboxybutyltriphenylphosphonium bromide in an analogous manner to Example 1 and, after working up, the isomeric compounds were separated by chromatography on 150 20 g of fine silica gel using hexane/ether, pure (E)-stereoisomer being obtained. By treatment with tetrabutylammonium fluoride dissolved in THF, the tert.-butyl-dimethylsilyl protecting group on the C-9 of the bicyclooctane structure was selectively hydrolysed to give 25 the title compound. Reaction with acetic acid/H20/THF at 80° then gave the free carbacyclin derivative 5(E) {7-hydroxy-6-[ (E)-4-methyl-3-hydroxy-oct-l-en-6-ynyl] — 9 — [ 5 — hydroxypentyl]-bicyclo[3.3.0]octan-3-ylidene} pentanoic acid.

IR (oil film) 3300-3000 cm-1 (OH) 1740-1710 cm-1 (acid carbonyl/broad/).

-Tert-butyldimethylsilyloxypentyl bromide was prepared as follows: .45 g (50 mmol) of ethyl 5-bromovalerate were reduced at 0° with 1.043 g of LiAlH4 in 100 ml of absolute 5 tetrahydrofuran, worked up with ice-water and 2N H2S04 and chromatographed on a column of 275 g of silica gel, using pentane and 20 % ether, yielding 5.88 g of 5-bromopentanol. 7.01 g (42 mmol) of 5-bromopentyl alcohol were stirred in 20 ml of DMF with 3.571 g of imidazole and 7.906 g (52.5 mmol) 10 of tert.-butyldimethylsilyl chloride for 2 hours at 24°, ice-water was added and the whole was extracted with hexane/ether 1:1, yielding 12.58 g of crude product which after chromatography on silica gel in pentane gave 8.93 g (75 %) of the title compound.

Claims (3)

1. Carbacyclin derivatives of the general formula I v A (i) \ » R9 I A-W-D-E-R. in which Yx represents the radical -CH2-X-(CH2)„-Ri or the radical <*• 1 n is 1 or 3 Rx represents the radical I , the o-J ^O-CHx^CHj radical -CH J -COCH3, COOR2 wherein O-CHj CH3' R2 may represent hydrogen, alkyl having from 1 to 10 C-atoms optionally substituted by halogen, phenyl, Cx-C4-alkoxy or by Cx-C4-dialkylamino, cycloalkyl, aryl or a heterocyclic radical, or Rx represents the radical CONHR3 wherein R3 represents hydrogen or an alkanoyl or - 26 - alkanesulphonyl radical each having from 1 to 10 C-atoms, represents the radical -(CH2)m-R6 or the radical - ( CH2 )m-o_ [ Z 1~ ( CH2 Jm-p] jc- [ Z2- ( CH2 )m_q]y-R6 / = 2 to 20 and p and q < 19, and y = 0, 1 or 2 represents a cis-CH=CH- group, a trans -CH=CH-group or a -C=C- group, each of which must be separated from the C-9 carbon atom of the carbacyclin nucleus by at least a methylene group, represents oxygen, sulphur, an NH- or an N-methyl-group, represents amino, methylamino, hydroxy, carboxy or mercapto, represents an oxygen atom or a methylene group, represents hydrogen or fluorine represents a -CH2-CH2-, trans-CH=CH- or -C=C-group represents a free or functionally modified hydroxy-methylene group or a free or functionally modified - 27 - CH3 t -C- group wherein the OH group may be in the a- hn or fl-configuration, CH - D represents the group , a 2 o straight-chain saturated alkylene group having from 1 to 5 C-atoms, a branched saturated, or a straight-chain or branched unsaturated, alkylene group having from 2 to 5 C-atoms, each of which may optionally be substituted by fluorine atoms, o is 1, 2 or 3, E is a direct bond, a -C=C- group or a -CH=CR-7-group wherein R7 represents a hydrogen atom, an alkyl group having from 1 to 5 C-atoms, or halogen, R4 represents an alkyl group having from 1 to 10 C-atoms, a cycloalkyl group having from 3 to 10 C-atoms or an optionally substituted aryl group having from 6 to 10 C-atoms, or a heterocyclic group, and Rs represents a free or functionally modified hydroxy group, and when R2 is a hydrogen atom, salts thereof with physiologically tolerable bases. - 28 - Process for the preparation of carbacyclin derivatives of the general formula I, characterised in that, in a manner known per se, a) a compound of the general formula IV O T A-M-D-E-R. • • (IV) in which A, W, D, E, R4/ Rs and R«, have the meanings given hereinbefore, is reacted with a Wittig reagent of the general formula V and VI or a dianion of formula VII o 11 (Qi30)2?-(CH2)4-COOR2 m> (V), (CH2),-R. P\ 1 © xc —000 d (VII) wherein - 29 - R2 has the meaning given and Re represents the radical in which X, n and Rx have the meanings given hereinbefore and R^ is bromine or chlorine, in the presence of K-tert.-butoxide, or b) a compound of the general formula VIII, which is obtained from the corresponding 4-ester by DIBAH reduction, wherein A, W, D, E, R4, Rs, R9 and Y2 have the meanings given hereinbefore, optionally after protecting any free hydroxy or amino groups present, is etherified in the presence of a base with a haloalkanoic acid derivative of the general formula IX -CHa-C^-X-fCHaJ^-Ri or CH2OB Rs (VIII), 0 OR 8 (IX) wherein n is 1 or 3, Hal represents a chlorine or bromine atom and Ra represents an alkyl radical having - 30 - from 1 to 4 C-atoms, or an alkali metal, and optionally, subsequently, in any order, isomers are separated and/or protected hydroxy groups are freed and/or free hydroxy groups are esterified or etherified and/or a free carboxy group is esterified and/or an esterified carboxy group is hydrolysed or a carboxy group is converted into an amide or converted by means of a physiologically tolerable base into a salt. Medicaments containing one or more compounds according to claim 1 and conventional excipients and carriers. 5- ( E) -{7-Hydroxy-6-[(E)-3-hydroxy-4-methyloct-l-en-6-ynyl ]-9 -[6-aminohexyl]-bicyclo[3.3.0]octan-3-ylidene} pentanoic acid. i 5 - ( E ) - {7-(Tetrahydropyran-2-yloxy)-6-[(E)-4-methyl-3-(tetrahydropyran-2 - yloxy) -oct- l-en-6-ynyl ] — 9 — [ 5 — hydroxypentyl]-bicyclo[3.3.0]octan-3-ylidene} pentanoic acid. A compound substantially as hereinbefore described with reference to the Examples. A process substantially as hereinbefore described with reference to the Examples. A medicament substantially as hereinbefore described with reference to the Examples. - 31 - Dated this 28th day of November,1986 CRUICKSHANK & CO. Agents for the Applicants 1, Holies Street, 5 Dublin

2. \944

3. SPE