GB2156341A

GB2156341A - Furyl and imidazolyl derivatives of carboprostacyclins and process for their preparation

Info

Publication number: GB2156341A
Application number: GB08407792A
Authority: GB
Inventors: Nicola Mongelli; Roberto Ceserani
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1984-03-26
Filing date: 1984-03-26
Publication date: 1985-10-09
Also published as: IT1183479B; GB8407792D0; JPS60209570A; IT8519768A0; DE3507944A1; BE902013A; GB2156341B

Abstract

Compounds of formula <IMAGE> wherein R = H or C1-C12 alkyl m = 1-6 A = -CH=CH- or -C IDENTICAL C- one of R2 and R3 is H and the other is H, C1-C4 alkyl or F n = 1-3 B = furyl or imidazolyl, optionally substituted by C1-C6 alkyl and their salts are useful in therapy. The compounds have anti-ulcerogenic and antisecretory activity, platelet anti-aggregating and disaggregating activity, and vasodilatory and hypotensive or anti-hypertensive activity.

Description

SPECIFICATION Furyl and imidazolyl derivatives of carboprostacyclins and process for their preparation The present invention relates to new furyl and imidazolyl derivatives of carboprostacyclins, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.

The compounds of the invention are optically active or racemic carboprostacyclins of the following formula (I)

wherein R is hydrogen or a C1-C12 alkyl group; m is an integer of 1 to 6; A is -CH=CH- or -CC-; R1 is hydrogen or Ci-Ce alkyl; one of B2 and R3 is hydrogen and the other is hydrogen, C1-C4 alkyl or fluorine; n is an integer of 1 to 3; B is a furyl or a imidazolyl group, each optionally substituted by C1-C6 alkyl; and the pharmaceutically or veterinarily acceptable salts thereof.

The present invention includes also the pharmaceutical and veterinary compositions containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) or a salt thereof.

All the possible isomers of formula (I), both stereoisomers, e.g. cis (or Z) and trans (or E) isomers, and optical isomers, i.e. enantiomers, and diastereoisomers, and their mixtures, and the metabolites, and the metabolic precursors or bioprecursors of the compounds of formula (I) are included in the scope of the invention.

Pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) are e.g., the salts of the compounds of formula (I) wherein R is hydrogen with a pharmaceutically orveterinarily acceptable, either inorganic or organic, base.

Acceptable inorganic bases may be, for example, the hydroxides of alkali, e.g. sodium or potassium, or alkaline earth, e.g. calcium or magnesium, metals, zinc and aluminium.

Acceptable organic bases may be, for example, amines like methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, ee-phenylethylamine, (3-phenylethylamine, ethylenediamine, diethylenetriamine, and other similar aliphatic, aromatic and heterocyclic amines like piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4dimethylpiperazine, 2-methylpiperidine, hydrophilic derivatives, e.g. mono-, di- and triethanolamine, 2-amino-2-butanol, 2-amino-l-butanol, 2-amino-2-ethyl-1 3-propanediol, 2-amino-2-methyl-1 -propanol, tris (hydroxymethyl)-aminomethane, N-phenylethanol-amino, N-(p-tert-amylphenyl)-diethanolamine, ephedrine, procain, and a & ss amino acids, e.g. lysine and arginine. The invention includes also the salts of the compounds of formula (I) wherein B is a imidazolyl group with a pharmaceutically or veterinarily acceptable, either inorganic or organic, acid. Acceptable inorganic acids may be, for example, hydrohalogen acids, such as, e.g., hydrochloric or hydrobromic acid, or oxygenated acids such as, e.g., sulphuric or nitric acid.

Acceptable organic acids may be, for example, carboxylic acids such as, e.g., acetic, citric, oxalic, malic, maleic, fumaric, tartaric, methanesulfonic and ethanesulfonic acids, as well as o-and p-amino acids, e.g.

lysine and arginine.

In the formula (I) and in the following formulae a dashed line (r ) refers to a ring substituent in the o-configuration, that is below the plane of the ring, and to a bicyclo octane substituent in the endo configuration. A wedged line () on the other hand, refers to a ring substituent in the ss-configuration, that is above the plane of the ring, and to a bicyclo octane substituent in the exo configuration. A wavy line ( &num; indicates that a substituent may be either in the o- or in the ss-configuration.

In the compounds of this invention there are two possible geometric isomers arising from the configuration of the double bond exocyclic to the bicyclo octane ring depending on whether the chain linked to this double bond (chain a) is on the same side as or the opposite side from the other chain (chain to) linked to the bicyclo octane ring; in the first case, the exocyclic double bond is defined as Z, i.e. cis, in the second, it is E, i.e. trans.

The symbol ~ in formula (I) means that both geometric isomers are covered by this invention, both separately and in mixtures. Furthermore each Z or E or Z,E compound may be a racemic (#) ) compound or an optically active compound, i.e. a (+) or (-) enantiomer: when unspecified, a racemic compound is intended.

The absolute "R" or "S" configurations of the chiral centers are assigned according to the sequence- rule procedure of lUPACforthe Nomenclature of Organic Chemistry (J.O.C. 35. 9, 2849, 1970): when unspecified "R,S" mixtures are intended.

In formula (I) the alkyl groups may be branched or straight chain groups.

When R is a C1-C12 alkyl group, it is, preferably, a C1-C6 alkyl group, in particular methyl or ethyl.

When R1 is C,-C6 alkyl, methyl is preferred.

When one of R2 and P3 is C1-C4 alkyl, this is, preferably methyl.

When B is a furyl or imidazolyl group substituted by C1-C6 alkyl, the alkyl substituent is, preferably, methyl or ethyl.

Preferably B is a 24uryl or 1-imidazolyl group optionally substituted as reported above, most preferably being unsubstituted 2-furyl or 1-imidazolyl.

A preferred class of compounds of the invention comprises compounds of the above formula (I) wherein R is hydrogen or C1-C6 alkyl; m is 3; A is -CH=CH- (trans) or -C-C-. R1 is hydrogen; one of R2 and R3 is hydrogen and the other is C1-C4 alkyl; B is 2-furyl optionally substituted by C1-C6 alkyl, and the pharmaceutically or veterinarily acceptable salts thereof.

In the above preferred class of compounds of formula (I), a preferred A value is -C-C-.

The nomenclature used to identify the specific compounds falling within the invention is the same illustrated in UK patent 2013661 B. According to such nomenclature, relating to the prostacyclanoic acid structure, the compounds of the invention are referred to as 9a-deoxy-9a-methylene-prostacyclanoic acid derivatives with the addition that the prefix "Z" or "E" or "Z,E" is used to identify the configuration of the double bond exocyclic to the bicyclo octane system.

Specific examples of compounds of the invention are the following compounds in either racemic or optically active form: 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-17-(2'-furyl)-18,19,20-trinor-prostacycla-5,13 dienoic acid; 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinor- prostacycla-5,13-dienoic acid; 5(Z,E)-9a-deoxy-9a-methylene-i 1 ,i 5S-dihydroxy-i 6-S-i 6-methyl-i 7-(2'4uryl )-i 8,1 9,20-trinor-prostacycl- Sen-13-ynoic acid; 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-19-(1'-imidazolyl)-20-nor-prostacycla-5,13-dienoic acid; 5(Z,E)-9a-deoxy-9a-methylene-11α ;, 15S-dihydroxy-19-(1'-imidazolyl)-20-nor-prostacycl-5-en-13-ynoic acid, and the C1 -C6 alkyl esters and pharmaceutically or veterinarily acceptable salts thereof.

The compounds of the invention are prepared by a process comprising reacting a compound of formula (II)

wherein R1, R2, R3, n and B are as defined above, R4 is hydrogen or a hydroxy protecting group, and A' is -CH=CH-, -CC- or -CH=CZ- wherein Z is chlorine, bromine or iodine, with a Wittig reagent of formula (III) (+) (-) (R5)3P-CH-(CH2)m-COOR (III) wherein m and R are as defined above, and P5 is an aryl or C1C6 alkyl group, and, in any order, removing the protecting groups possibly present, converting, if desired, a possibly obtained salt into the corresponding free acid, and if desired, esterifying the obtained free aeid, or, if desired, saponifying an obtained compound of formula (I) wherein R is C1-C12 alkyl to give a compound of formula (I) wherein R is hydrogen, or a salt thereof, andlor, if desired, salifying a compound of formula (I), and/or, if desired separating a mixture of isomers of formula (I) into the single isomers.

When in the compound of formula (II) Y is -CH=CZ-, the halogen Z is, preferably, bromine.

When in the compound of formula (II) R4 is a hydroxy protecting group it is, for example, an ether or ester residue which may be readily split under mild conditions, for instance by acid hydrolysis. Preferred groups include silyl ether residues: for instance trialkylsilyl, e.g. trimethyl, dimethyl-tert-butyl, dimethyl-isopropyl, or dimethylethylsilyl; and also acetal and enol ether residues: for instance, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, oxathianyl, or groups as

where Alk is C,-C6 alkyl.

An ester residue may be, e.g., benzoyl.

When in the compound of formula (lli) R5 is aryl, it is, preferably, phenyl; when P5 is C,-C6 alkyl, ethyl is preferred. The reaction between a compound of formula (II) and a compound of formula (III) is preferably carried out in the presence of a solvent and, preferably, using an excess of the Wittig reagent of formula (Ill), e.g. from about 1.5 to about 5 moles of Wittig reagent per 1 mole of the compound of formula (II). The solvent may be any solvent which can, in general, be used for Wittig reactions.

Preferably it is an inert organic solvent chosen from ethers, both linear and cyclic, e.g. diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; aliphatic or aromatic hydrocarbons, e.g. n-hexane, nheptane, benzene, toluene or xylene; dialkylsulphoxides, e.g. dimethylsulphoxide; aliphatic acid dialkylamides, e.g. dimethylformamide or dimethylacetamide; halogenated hydrocarbons, e.g. dichloromethane or chloroform; and phosphoric acid triamides, hexamethylphosphoramide for example. Dimethylsulphoxide is a particularly preferred solvent. The reaction temperature may range from about -10"C to the reflux temperature of the solvent used although room temperature is particularly preferred.The reaction is normally carried out in the presence of a base which may be, for example, potassium tert.butoxide or sodium hydride and, preferably, operating under nitrogen atmosphere.

The Wittig reagent of formula (Ill) is usually generated in situ, with the above reaction conditions, from a corresponding (carboxy-alkyl)-tri-aryl phosphonium bromide or (carboxy-alkyl)-tri-alkyl phosphonium bromide.

To prepare a compound of formula (I) where A is -CH=CH-, a starting compound of formula (II) is used wherein A' is -CH=CH-; to prepare a compound of formula (I) where A is -C-C- either a compound of formula (II) where A' is -CC- or a compound of formula (II) where A' is -CH=CZ-, wherein Z is as defined above, may be used.

Preferably, however, a compound of formula (I) where A is -CC- is prepared from a compound of formula (Il) where A' is -CH=CZ-, wherein Z is as defined above, preferably bromine or iodine, in particular bromine, as, in this instance, both the triple bond formation and the alkylation with the Wittig reagent take place at the same time in an only one step. In this case it is preferred to use not less than about two moles of compound (III) per mole of compound (II). A greater excess of the Wittig reagent, up to 5 moles per mole of compound (II), may be, however, employed and in this way the reaction times can be considerably reduced.

The time required by the reaction may vary, depending upon the used reaction conditions, within the range from 0.5 to 24 hours. The removal of the hydroxy protecting groups may be carried out following known conventional procedures. For example ether residue protecting groups may be removed by mild acid hydrolysis, for instance with mono- or polycarboxylic acids, such as, e.g., acetic, formic, citric, oxalic, or tartaric, in a solvent such as, e.g., water, acetone, tetrahydrofuran, dimethoxyethane or a low molecular weight alcohol, or with a sulfonic acid such as, e.g., p-toluenesulfonic, in a low molecular weight alcohol such as, e.g., anhydrous ethanol or methanol, or with a polystyrene-sulfonic resin.For example, a 0.1-0.25 N polycarboxylic acid (e.g. oxalic or citric) is used with a suitable low-boiling solvent miscible with water and readily removable under vacuum at the end of the reaction. Silyl residues may be selectively removed in the presence of other protecting groups with F- ions in solvents such as, e.g.,tetrahydrofuran and dimethylformamide. Ester protecting groups may be removed by following typical saponification procedures.

The optional conversion of an obtained salt into the corresponding free acid and the optional esterification of the free acid, may be carried out following the usual and known procedures of the organic chemistry. The conversion of the salt to the free acid may be, e.g., carried out by acidification with an appropriate acid and the esterification may be carried out, for example, using the appropriate diazoalkane in an inert organic solvent, e.g. diethylether, ethylacetate, methylene chloride, or their mixtures at temperatures from about -10"C to about 20"C, preferably at about 0 C; or using the appropriate alkylhalide, for example in acetone or N,N-dimethylformamide in the presence of base which may be, for instance, sodium or potassium carbonate or bicarbonate.

Also the optional saponification of a compound of formula (I) wherein R is C1-C12 alkyl may be carried out by conventional procedures, for example by reaction with an aqueous solution of an alkali metal, e.g.

sodium or potassium, hydroxide or carbonate, in the presence of a water miscible solvent, e.g. dioxane, tetrahydrofuran, methanol or ethanol, preferably at room temperature. The saponification product may be recovered as a salt, e.g. alkali metal salt, or, previous possible acidification, as a free acid. The optional salification of a compound of formula (I) as well as the optional separation of a mixture of isomers into the single isomers may be carried out by usual methods known per se. In particular, for example, single isomers may be obtained from their mixture by means of, e.g., fractional crystallization from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid at low, medium or high pressure.For column and thin layer chromatography, for instance, silica gel or magnesium silicate may be used as support with a solvent such as, e.g., cyclohexane, n-hexane, benzene, methylene chloride, diethyl ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.

Thus, for example, the above illustrated reaction between a compound (Il) and a compound (III) gives a mixture of geometric isomers in that the new exocyclic double bond formed in the reaction may be Z or E: if desired, the individual geometric isomers may be separated by one of the above reported tecniques.

The compounds of formula (II) may be prepared by following known procedures, for example those described for preparing the analogous compounds in, e.g. UK patent 2012265B, UK patent 2017699B, UK patent 2013661 B, and European patent 11591.

In particular, for example, a compound of formula (il) may be obtained by the following steps: 1) reaction of a compound of formula (IV)

wherein R4 is as defined above and G is a protected carbonyl group, with a Wittig reagent of formula (V)

or with a modified Wittig reagent of formula (V a)

wherein B, n, R2, R3 and R6 are as defined above and M+ is an alkali metal, preferably sodium or potassium, anion, to obtain a compound of formula (Vl)

wherein G, R4, R2, R3, n and B are as defined above; 2) optional halogenation of an obtained compound of formula (VI) to give a compound of formula (Vll)

wherein G, P4, Z, R2, R3, n and B are as defined above;; 3) reduction or nucleophilic addition on the free oxo group of the compound (VI) or (VII) followed by optional separation of the obtained mixture of the Sand R alcohols and optional protection of the newly formed hydroxy group, to give a compound of formula (VIII)

wherein G, R4, R1, R2, R3, n and B are as defined above and Z' is Z or hydrogen; 4) optional dehydrohalogenation of a compound offormula (VIII), where Z' is Zto obtain a compound of formula (VIII a)

wherein G, R4, Rl, R2, P3, n and B are as defined above; and 5) removal of the carbonyl protecting group from G and optional removal of the hydroxy protecting groups possibly present either in a compound of formula (VIII), or in a compound of formula (Vllla).

In the compound of formula (IV) the protected carbonyl group G is a carbonyl group preferably protected as acetal orthioacetal, for example a dimethoxyacetal, a diethoxyacetal, a dimethylthioacetal, a diethylthioacetal, preferably a dimethoxyacetal, or as ketal or thioketal, for example an ethylenedioxyketal

a propylenedithioketal

a propylenedioxyketal

an ethylenedithioketal

preferably an ethylenedioxyketal.

In a compound pf formula (V) P5 is, preferably, a phenyl group.

In a compound of formula (Va) P5 is, preferably, a methyl group and M is, preferably, an alkali metal, sodium or potassium in particular.

The reaction between a compound of formula (IV) and a compound of formula (V) or (Va) may be carried out using, approximately, the same reaction conditions reported above for the reaction between a compound of formula (II) and a compound of formula (III).

The optional halogenation of a compound of formula (VI) to give a compound of formula (VII) may be carried out following known standard procedures, for example by treatment with pyridinium bromide perbromide.

Compounds offormula (VII) may also be prepared directly by reacting a compound of formula (IV) with a modified Wittig reagent of formula (V b)

wherein B, n, R2, R3, Z, M and R5 are as defined above (with R5 being, preferably, a methyl group), in the same conditions indicated for the reaction between a compound (IV) and a compound (V) or (V a).

The reduction of the free oxo group in a compound of formula (VI) or (ill), leading to a mixture of secondary S and R alcohols, may be performed by conventional method, e.g. by treatment with a mixed hydride such as, for instance, NaBH4 or LiAIH4, preferably NaBH4, with the usual reaction conditions reported in the organic chemistry for this kind of reduction. The nucleophilic addition on the free oxo group of a compound of formula (VI) or (VII), leading to a mixture of tertiary Sand R alcohols, may be carried out in a conventional way too, for example by reaction with a Grignard reagent of formula Rx MgZ wherein Rx is C-C6 alkyl and Z is a halogen atom as defined above, according to standard reaction conditions.

The separation of the obtained mixture of either secondary or tertiary Sand R alcohols may be carried out by the already indicated fractional crystallization or chromatography tecniques.

The optional protection of the newly formed hydroxy group may be carried out by any known conventional etherification or esterification procedure.

The optional dehydrohalogenation of a compound of formula (VIII) wherein Z' is Zto give a compound of formula (Vllla) may be performed by treatment with an appropriate base according to conventional procedures too, and standard procedures may be followed also for removing the carbonyl protecting group, and, if desired, the hydroxy protecting groups, in a compound of formula (VIII) or (Vlil a). In particular, mild acid hydrolysis as reported above is preferred to remove acetal orthioacetal carbonyl protecting groups.

The compounds of formula (III) and (IV) are known compounds and may be prepared by known methods e.g. those described in UK patent 2013661 B.

The compounds of formula (V), (V a) and (V b) may be prepared by a procedure analogous to that used to obtain a compound of formula (III), e.g. that described in UK patent 2013661 B for the preparation of analogous compounds. In particular, for example, a compound of formula (V) may be prepared reacting a compound of formula (IX)

wherein B, n, R2 and R3 are as defined above and Hal is a halogen atom, with an excess amount of a compound of formula (R5)3 P wherein R5 is as defined above, triphenylphosphine for instance, in an organic solvent such as, e.g., benzene, acetonitrile or diethylether, and then treating the produnct phosphonium salt with an equivalent amount of an inorganic base, e.g. NaOH or KOH.

Analogously, a compound of formula (V a) may be prepared from a compound of formula (X)

wherein R5, R2, R3, n and B are as defined above, with a suitable base carrying the M cation, which base may be, for instance, an alkali metal hydride such as, e.g., sodium or potassium hydride, an alkali metal alkoxide such as, e.g., sodium or potassium tert. butoxide, an alkali metal salt of a carboxyamide such as, e.g., N-sodioacetamide and N-sodiosuccinimide.

A compound of formula (V b) may be obtained by reacting a compound of formula (V a) with a suitable halogenating agent which may be, for example, N-bromo-succinimide, N-bromo-acetamide or N-bromophthalimide.

The compounds of formula (IX) and (X) are in turn prepared using standard methods, for example those described by Corey et al. in J. Amer. Chem. Soc. 90,3247 (1968) and 88,5654(1966).

The compounds of formula (I) exhibit substantially the same pharmacological activities known for carboprostacyclins and illustrated, for instance, in the UK patents 2012265 B, 2014143 B, 2019847 B, 2017699 B, 2013661 Band European patent 11591.

The present compounds of formula (I) form a class of carboprostacyclins which is not disclosed in UK patent 2013661 B and European patent 11591. Neither of these two patents mentions or characterises a specific compound within the scope of formula (I).

Furthermore, the compounds of the invention possess higher activity than the compounds of the prior art so that lower dosages can be used in administration with a consequent reduced incidence of the possible side effects.

In particular, the compounds of the invention are endowed with remarkable antiulcerogenic and antisecretory activity, as is proved by the fact that they were found to be active in preventing ethanol-induced, stress-induced, ASA-induced or indomethacin induced gastric ulcers [Gastroenterology 77, 761-767 (1979) and Prostaglandins and Medicine vol.5, 131-139 (1980)], and in inhibiting gastric secretion according to the method of Shay et al. [Gastroenterology 906 (1954)j.

In particular, for example, when the compound of the invention 5(Z,E)-9a-dexoy-9a-methylene-1 (x, 15S-dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinor-prostacycl-5-en-13-ynoic acid (internal code FCE 23632) was tested for its ability to inhibit ethanol-induced and indomethacin-induced gastric ulcers in rat, the ED50 values reported in the following table were obtained.

TABLE Compound Ethanol-induced gastric ulcers Indomethacin-induced gastric ulcers ED50 Fglkglos ED50 Fglkglos FCE 23632 0.92 (0.52-1.63)* 9.75 (4.22-25.7)* *The values between round brackets are the confidential limits for P=0.95.

The ED50 value represents the dose able to produce the 50% inhibition of the induced ulcers.

The data reported in the table were obtained by the herebelow indicated test procedures.

Ethanol-induced gastric ulcers Male rats 190c10 g b.w. were used, fasted for 15 hours, but given free access to water. The animals were treated orally with the test compound 5 minutes before being given ethanol 95" (2 ml/kg p.o.).

One hour after ethanol the rats were killed by cervical translocation and exsanguinated; the stomachs, clamped at the cardia and pyloric sphincter, were quickly removed, filled with saline, immersed in 0.4% formalin for 30 seconds, opened along the greater curvature and examined for ulcers according to an arbitrary score scale.

Indomethacin-induced gastric ulcers Rats weighing 190+ 10 g b.w. fasted as described above for ethanol, were used. The test compound was administrered orally, 15 minutes before indomethacin (9 mg/kg suspended in 0.5% Methocel per os). Three hours after indomethacin treatment, the rats were killed and the gastric ulcers evaluated as previously described for the ethanol-induced ulcers procedure.

In view of the above indicated activity the compounds of formula (I) can be used for treating and preventing gastric and intestinal ulcers and also for treating and preventing the excessive gastric secretion.

For the anti-ulcerogenic and anti-secretary applications the compounds of the invention can be administered, for example, by intravenous infusion or by intravenous, subcutaneous or intramuscular injection; doses for intravenous infusion range from 0.01 iig to 500 Fg/kilo/minute. The total daily dose for both injection and infusion is about 0.01-20 mg/kg, depending on the age, weight and condition of the patient and on the administration method.Also rectal administration and oral administration are useful for these kinds of applications The compounds of formula (I) show also high platelet antiaggregating and disaggregating activity as is proved, e.g., by the fact that they have been found to produce at a great extent inhibition of the platelet aggregation induced in vitro by 0.4 Fg/ml ADP in guinea pig platelet rich plasma.

The high platelet anti-aggregating and dissaggregating activity exhibited by the compounds of formula (I) indicates their use to inhibit platelet aggregation, to decrease adhesions, to prevent clot formation, and to dissolve recently-formed clots. The platelet anti-aggregating activity is also associated with a relaxation of the coronary arteries. Thus the compounds of formula (I) can be useful, e.g. in preventing and treating myocardial infarctions, and, in general, in treating and preventing thromboses, in treating conditions like atherosclerosis, arteriosclerosis, and, more generally, hyperlipidemia.

The compounds of the invention also exhibit a certain vasodilatory, i.e. hypotensive or anti-hypertensive, effect and so they may be useful for treating the syndromes caused by arterial hypertension.

The compounds of formula (I) may also be used for treating obstructive pulmonary diseases, such as, e.g., bronchial asthma, as is shown, e.g., by the fact that they have been found to be active in the bronchodilation test on the awake or anaesthetized guinea-pig [Prostaglandins and Medicine vol.2,459-466 (1979)I.

When the compounds of the invention are given as antiaggregating or disaggregating agents, the routes of administration can be the usual ones, oral, intravenous, subcutaneous, intramuscular. In emergency situations, the preferred route is intravenous, with doses that can vary, for adult humans, from 0.001 to 1.5 mg/kg/day. Thr exact dose will depend on the condition of the patient, his weight, his age and the route of administration.

The dosages and methods of administration of the compounds, when used as vasadilatory or hypotensive or anti-hypertensive agents, are about the same as those used for the anti-aggregating application.

For the treatment of the obstructive pulmonary disorders, for example bronchial asthma, the compounds of the invention can be given by different routes: orally, in the form of tablets, capsules, coated tablets or in liquid form as drops or syrups; by inhalation, as aerosols or solutions for the nebulizer; by insufflation, in powdered form. Doses of the order of 0.01-4 mg/kg can be given from 1 to 4 times a day to adult humans with the exact dose depending on the age, weight, and condition of the patient and on the route of administration. For use as anti-asthmatics, the compounds of the invention can be combined with other anti-asthmatic agents, such as sympathicomimetic drugs, e.g., isoproterenol, ephedrine, xanthine derivatives, such as theophylline and aminophylline, or corticosteroids.The toxicity of the compounds of the invention, e.g. the specific one hereabove mentioned, is quite negligible, so that they can be safely used in therapy.

As previously stated, the compounds of the invention can be given, either to humans or animals, in a variety of dosage forms, e.g., orally in the forms of tablets, capsules or liquids; rectally, in the form of suppositories; parenterally, subcutaneously or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; in the form of sterile implants for prolonged action; or intravaginally in the form, e.g., of bougies.

As already said, the invention includes pharmaceutical and veterinary compositions containing a compound of the invention and a pharmaceutically or veterinarly acceptable carrier and/or diluent. The carrier or diluent and the form of the compositions can be any conventionally used. For example, for intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous media may be used; for tissue implants, a sterile tablet or silicone rubber capsule containing, or impregnated with the compound is used.

Conventional carriers or diluents are, for example, water, gelatine, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium or magnesium stearate, glycol, starch, gum arabic, tragacanth gum, alginic acid or alginates, lecithin, polysorbate, vegetable oils.

For administration by suppositories suitable carriers may be, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. For administration by nebulizer, a suspension or a solution of the compound of the invention, preferably in the form of a salt, such as the sodium salt in water, can be used. Alternatively, the pharmaceutical preparations can be in the form of a suspension or of a solution of the compound of the invention in one of the usual liquefied propellants, such as dichloro difluoromethane or dichlorotetrafluoroethane, administered from a pressurized container as an aerosol.

When the compound is not soluble in the propellant it may be necessary to add a cosolvent, such as ethanol, dipropylene glycol and/or surfactant, to the pharmaceutical formulation.

The abbreviations THF and DMF used in the examples stand, respectively, for tetrahydrofuran and dimethylformamide. The following examples illustrate but do not limit in any way the invention. Percentages are by weight.

Example 1 To a suspension of sodium hydride (0.42 g) in dry benzene (50 ml), stirred under argon, a solution of dimethyl [2-oxo-3-S-3-methyl-4-(2'-furyl)-butyl] phosphonate (3 g) in dry benzene (30 ml) was added dropwise.

The reaction mixture was stirred for 30 minutes and then a solution of N-bromo-succinimide (2.05 g) in CH3C12 (40 ml) was added dropwise. The reaction mixture became yellow-orange and a solution of 3-oxo-3, 3-ethylenedioxy-6-exo-formyl-7-endo-benzoyloxy-bicyclo[3,3,0]octane (2.5 g) in dry benzene (20 ml) was dropped in. After 30 minutes stirring, the reaction was quenched with acetic acid (1 ml), poured into a separatory funnel, washed with NaH2PO4 (30% aqueous solution), dried over Na2SO4, filtered and concentrated under vacuum.

The residue was chromatographed on silica gel to give 2.2 g of pure 3-oxo-3,3-ethylenedioxy-6-exo-[1 trans-2'-bromo-3'-oxo-4'-S-4'-methyl-5-(2"-furyl)-pent-1 '-enyl]-7-endo-benzoyloxy-bicyclo(3,3,Ojoctane.

In similar way 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-2'-bromo-3'-oxo-7'-(1"-imidazolyl)-hept-1 '-enyl]-7endo-benzoyloxy-bicyclo[3,3,0]octane was prepared.

Example 2 To a suspension of 0.58 g of sodium hydride (80% dispersion in mineral oil) in dry benzene (40 ml) a solution of 5 g of dimethyl[2-oXo-3-S-3-methyl-4-(2'-furyl)-butyl]phosphonate in 10 ml of dry benzene was added dropwise. The mixture was stirred 30 minutes and then a solution of 3-oxo-3,3-ethylenedioxy-6-exo formyl-7-endo-benzoyloxy-bicyclo[3,3,0]octane (4.1 g) in dry benzene (10 ml) was added dropwise. After 20 minutes stirring the reaction was quenched with acetic acid (1 ml) and poured into a separatory funnel, washed with a 30% aqueous solution of NaH2PO4, dried over Na2SO4, filtered and evaporated under vacuum.

The residue was chromatographed on silica gel yielding 3.2 g of pure 3-oxo-3,3-ethylenedioxy-6-exo-[1 trans-3'-oxo-4'-S-4'-methyl-5'-(2"4uryl)-pent-1 '-enylj-7-endo-benzoyloxy-bicyclo[3,3,0]octane. In analogous way the following compounds were prepared: 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-3'-oxo-5'-(2"-furyl) pent-i '-enylj-7-endo-benzoyloxy-bicyclo[3,3,Ojoctane; and 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-3'-oxo- 7'-( 1 "-imidazolyl)-hept-1 '-enyl]-7-endo-benzoyloxy-bicyclo[3,3,Ojoctane.

Example3 To a solution of 3-oxo-3,3-ethylenedioxy-6-exo-[1'-trans-2'-bromo-3'-oxo-4'-S-4'-methyl-5'-(2"4uryl)-pent- 1 '-enyl]-7-endo-benzoyloxy-bicyclo[3,3,0]octane (29) in methanol (20 ml), sodium borohydride (0.2 g) was added at 0 C. After 30 minutes stirring at 0 C, the reaction mixture was carefully poured into 200 ml of 30% NaH2PO4 (water solution) and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatographic purification on silica gel gave 2.2 g of 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-2'-bromo-3'-R,S-3'-hydroxy- 4'-S-4'-methyl-5'-(2"-furyl)-pent-1 '-enyl]-7-endo-benzoyloxy-bicyclo[3,3,0]octane.

Example 4 A solution of 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-2'-bromo-3'-R,S-3'-hydroxy-4'-S-4'-methyl-5'-(2"- fu ryl)-pent-1 '-enylj-7-endo-benzoyloxy-bicyclo[3,3,Ojoctane (2.2 g) in a 9:1 methanol :water mixture (40 ml), was treated with K2CO3 (1 g) and the suspension was stirred for 2 hours at 500C. The methanol was evaporated and the residue was extracted with diethyl ether; the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness.Chromatographic separation on silica gel gave 0.35 g of 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-2'-bromo-3'-R-3'-hyd roxy-4'-S-4'-methyl-5'-(2"-f uryl)-pent-l '-enyl]7-endo-hydroxy-bicyclo[3,3,0]octane, and 0.6 g of 3-oxo-3,3-ethylenedioxy-6-exo-[1 '-trans-2'-bromo-3'-S-3' hydroxy-4'-S-4'-methyl-5'-(2"-furyl)-pent-1 '-enyl]-7-endo-hydroxy-bicyclo[3,3,0]octane.

Example 5 To a solution of 3-oxo-3,3-ethylenedioxy-6-exo-[1'-trans-2'-bromo-3'-S-3'-hydroxy-4'-S-4'-methyl-5'-(2"- furyl)-pent-1 '-enyl]-7-endo-hydroxy-bicyclo[3,3,0]octane (0.6 g) in acetone (20 ml), 1 N oxalic acid (10 ml) was added and the resulting solution was left at room temperature overnight. Acetone was evaporated under vacuum and the residue was extracted twice with ethyl acetate; the combined organic layers were washed with water, 5% aqueous sodium bicarbonate, water, then dried over Na2SO4, filtered and evaporated to dryness to give 0.58 g of 3-oxo-6-exo-[1 '-trans-2'-bromo-3'-S-3'-hydroxy-4'-S-4'-methyl-5'-(2"-furyl)-pent-1 enyl]-7-endo-hydroxy-bicyclo[3,3,0]octane.

Following analogous procedure and using starting materials prepared in accordance with the examples 3 and 4, the following compounds were obtained: 3-oxo-6-exo-[1'-trans-2'-bromo-3'-R-3'-hydroxy-4'-S-4'-methyl-5'-(2"-furyl)-pent-1'-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane; 3-oxo-6-exo-[1'-trans-3'-S-3'-hydroxy-5'-(2"-furyl)-pent-1'-enyl]-7-endo-hydroxy-bicyclo[3,3,0]octane; 3-oxo-6-exo-[1 '-trans-3'-R-3'-hyd roxy-5'-(2"-fu ryl )-pent-1 '-enyl]-7-endo-hydroxy-bicyclo[3,3,0]octane; 3-oxo-6-exo-[1 '-tra ns-3'-S-3'-hydroxy-4'-S-4'-methyl-5'-(2"-fu ryl )-pent-1 '-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane; 3-oxo-6-exo-[1 '-trans-3'-R-3'-hydroxy-4'-S-4'-methyl-5'-(2"-furyl)-pent-1 '-enyl]-7-endo-hydroxybicyclo[3,3,0]octane;; 3-oxo-6-exo-[1'-trans-2'-bromo-3'-S-3'-hydroxy-7'-(1"-imidazolyl)-hept-1'-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane; 3-oxo-6-exo-[1'-trans-2'-bromo-3'-R-3'-hydroxy-7'-(1"-imidazolyl)-hept-1'-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane; 3-oxo-6-exo-[1 '-trans-3'-S-3'-hydroxy-7'-(1 "-imidazolyl)-hept-1 '-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane; and 3-oxo-6-exo-[1 '-trans-3'-R-3'-hydroxy-7'-(1"-imidazolyl)-hept-1 '-enyl]-7-endo-hydroxy bicyclo[3,3,0]octane.

Example 6 To a stirred mixture of potassium tert-butoxide (2 g) and 4-carboxybutyl triphenylphosphonium bromide (4 g) dryTHF (10 ml) was added. After stirring under argon for 10 minutes, a solution of 3-oxo-6-exo-[1'- trans-2'-bromo-3'-S-3'-hydroxy-4'-S-4'-methyl-5'-(2"-fu ryl)-pent-1 '-enyl]-7-endo-hydroxybicyclo[3,3,0]octane (0.58 g) in THF (5 ml) was dropped into the ylide suspension. The whole was stirred for 30 minutes and then poured into 100 ml of NaH2PO4 (30% water solution).

The separated organic phase was evaporated to dryness and the residue was eluted on silica gel to give 0.13 g of 5(Z,E)-9a-deoxy-9a-methylene-11α, 1 5S-dihydroxy-1 6-S-1 6-methyl-i 7-(2'4uryl)-i 8,1 9,20-trinorprostacycl-5-en-13-ynoic acid, NMR (90 MHz) CDCI38 p.p.m. 0.98 (d,3H), 2.69 (m, 2H), 3.96 (m, 1 H), 4.26 (dd, 1 H), 5.23 (m, 1 H), 5.99 (d, 1 H), 6.24 (dd, 1 H), 7.26 (d, 1 H).

By analogous procedure the following compounds were prepared: 5(Z,E)-13E-9a-dexoy-9a-metylene-11α, 15S-dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinorprostacycla-5,13-dienoic acid, NMR (90MHz) CDCl3 # 6 p.p.m.: 0.96 (d,3H), 2.70 (m,3H), 3.96 (m,1 H), 4.12 (m,1 H), 5.25 (t,lH), 5.53 (m,2H), 6.03 (d,1 H), 6.31 (dd,1 H), 7.34 (d,1 H); 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-17-(2'-furyl)-18,19,20-trinor-prostacycla-5,13dienoic acid, NMR (90MHz), CDCl3 # p.p.m.: 2.71 (t,2H), 3.70 (m,1 H), 4.08 (m, 1 H), 5.24 (t,1 H), 5.55 (m,2H), 6.05 (d,1 H), 6.29 (dd,1 H), 7.32 (d,lH); 5(Z,E)-9a-deoxy-9a-methylene-i 1 a,1 5S-dihydroxy-i 9-(1 '-imidazolyl)-20-nor-prostacycl-5-en-i 3-ynoic acid, NMR (90MHz) CDCI3 e p.p.m.: 3.62 (m,1 H), 3.98 (t,2H), 4.23(m,1 H), 5.28 (m,1 H), 6.84 (bs,1 H), 7.08 (bs,1H), 7.71 (bs,1H); 5(Z,E)-13E-9a-dexoy-9a-methylene-11α, 15S-dihydroxy-19-(1'-imidazlyl)-20-nor-prostacycla-5,13-dienoic acid, NMR (90MHz) CDCl3 #p.p.m.: 3.59 (m, 1H), 3.97 (t,2H), 4.00 (m, 1H), 5.26 (m, 1H), 5.50 (m, 2H), 6.92 (bs, 1H), 7.10 (bs,1 H), 7.75 (bs,iH); 5(Z,E)-9a-deoxy-9a-methylene-11α, 15R-dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinor-prostacycl- 5-en-13-ynoic acid, NMR (90MHz) CDCl3 #p.p.m:: 0.98 (d,3H), 2.68 (m, 2H), 3.96 (m, 1H), 4.25 (dd, 1H), 5.23 (m, 1H), 5.99 (d, 1H), 6.5 (dd, 1H), 7.26 (d, 1H); 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15R-dihydroxy-16-S-16-methyl-17-(2'-furyl0-18,19,20-trinor- prostacycla-5,13,dienoicacid, NMR (90MHz) CDCl3 a p.p.m.: 0.96 (d,3H), 2.71 (m,3H), 3.96 (m, 1H), 4.12 (m, 1H), 5.24 (t, 1H), 5.53 (m, 2H), 6.03 (d, 1H), 6.32 (dd, 1H), 7.34 (d, 1H) ; 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15R-dihydroxy-17-(2'-furyl)-18,19,20-trinor-prostacycla-5,13- dienoic acid, NMR (90MHz) CDCl3 3 p.p.m.: 2.71 (t,2H), 3.71 (m,1 H), 4.08 (m,1 H), 5.25 (t,1 H), 5.55 (m,2H), 6.06 (d,1H), 6.29 (dd,1 H), 7.33 (d,1 H); 5(Z,E)-9a-deoxy-9a-methylene-11α, 15R-dihydroxy-19-(1'-imidazolyl)-20-nor-prostacycl-5-en-13ynoic acid, NMR (90MHz) CDCl3 3 p.p.m.: 3.63 (m,1 H), 3.98 (t,2H), 4.24 (m,1 H), 5.28 (m,1 H), 6.85 (bs,iH), 7.08 (bs,1 H), 7.73 (bs,1H); and 5(Z,E)-1 3E-9a-deoxy-9a-methylene-i 1α1 5R-dihydroxy-19-(1 '-imidazolyl)-20-nor-prostacycla-5,1 3-dienoic acid, NMR (9OMHz) CDCI3 3 p.p.m.: 3.59 (m, 1 H), 3.98 (t,2H), 4.02 (m,1 H), 5.26 (m,1 H), 5.52 (m,2H), 6.92 (bs,1 H), 7.12 (bs,iH), 7.75 (bs,iH).

Example 7 Dry potassium carbonate (0.28 g) was added to a solution of 5(Z,E)-9a-deoxy-9a-methylene-11α, 15S- dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinor-prostacycl-5-en-13-ynoicacid (0.5 g) and methyliodide (0.17 ml) in dry DMF (3.3 ml). The mixture was stirred at room temperature for 4 hours. The inorganic material was filtered, and the organic solution was diluted with water (20 ml) and exhaustively extracted with diethyl ether.The ethereal extracts were collected, washed with water and evaporated affording 5(Z,E)-9a-deoxy-9a-methylene-1 1 a,1 5S-dihydroxy-1 6-S-i 6-methyl-i 7-(2'-fu ryl )-1 8,1 9,20-trinor-prostacycl-5- en-13-ynoic acid methyl ester (0.45 g), NMR (90MHz) CDCl3 3 p.p.m.: 0.96 (d,3H), 2.70 (m,3H), 3.65 (s,3H), 3.97 (m, 1H), 4.25 (dd, 1H), 5.23 (m, 1H), 5.99 (d, 1H), 6.25 (dd, 1H), 7.26 (d, 1H).

In analogous fashion the methyl esters of the acids listed in example 6 were obtained.

Example 8 To a solution of sE-i 3E-9a-deoxy-9a-methylene-1 1 a,i 5S-dihydroxy-1 6-S-i 6-methyl-i 7-(2'4uryl)-i 8,19,20- trinorprostacycla-5,13-dienoic acid (0.4 g) in ethyl acetate (1 ml), a solution of D(t)ephedrine (0.16 g) in ethyl acetate (0.5 ml) was added. The cloudy solution was left 18 hours in a refrigerator. The ephedrinium salt was collected by filtration (0.45 g), m.p. 136 C (dec).

Claims

1. A compound of the following formula (I)

wherein R is hydrogen or a C1-C12 alkyl group; m is an integer of 1 to 6; A is -CH=CH- or C-C-; R1 is hydrogen or C1-C6 alkyl; one of R2 and R3 is hydrogen and the other is hydrogen, Cs-C4 alkyl or fluorine; n is an integer of 1 to 3; B is a furyl or a imidazolyl group, each optionally substituted by C1 -C6 alkyl; and the pharmaceutically or veterinarily acceptable salts thereof.

2. A compound having the formula (I) reported in claim 1 wherein R is hydrogen or C1 -C6 alkyl; m is 3; A is -CH=CH- (trans) or -C-C-; R1 is hydrogen; one of R2 and R3 is hydrogen and the other is Cs-C4 alkyl; B is 2-furyl optionally substituted by C1 -C6 alkyl, and the pharmaceutically or veterinarily acceptable salts thereof.

3. A compound of formula (I) according to claim 2 wherein A is -C--C-.

4. A compound selected from the group consisting of 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-17-(2'-furyl)-18,19,20-trinor-prostacycla-5,13- dieneoic acid; 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-16-S-16-methyl-17-(2'-furyl)-18,19,20-trinor- prostacycla-5,13-dienoic acid; 5(Z,E)-13E-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-19-(1'-imidazolyl)-20-nor-prostacycla-5,13-dienoic acid; 5(Z,E)-9a-dexoy-9a-methylene-11α, 15S-dihydroxy-19-(1'-imidazolyl)-20-nor-prostacycl-5-en-13-ynoic acid; and the C,-C6 alkyl esters and pharmaceutically or veterinarily acceptable salts thereof.

5. The compound 5(Z,E)-9a-deoxy-9a-methylene-11α, 15S-dihydroxy-16S-16-methyl-17-(2'-furyl)- 18,1 9,20-trinor-prostacycl-5-en-l 3-ynoic acid, and the C1 -C6 alkyl esters and pharmaceutically or veterinarily acceptable salts thereof.

6. A process for preparing a compound having the formula (I) reported in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof, the process comprising reacting a compound of formula (II)

wherein R1, R2, R3, n and B are as defined in claim 1, R4 is hydrogen or a hydroxy protecting group, and A' is -CH=CH, -CEC- or -CH=CZ- wherein Z is chlorine, bromine or iodine, with a Wittig reagent of formula (Ill)

wherein m and R are as defined in claim 1, and R5 is an aryl or C1-C6 alkyl group, and, in any order, removing the protecting groups possibly present, converting, if desired, a possibly obtained salt into the corresponding free acid, and, if desired, esterifying the obtained free acid, or, if desired, saponifying an obtained compound of formula (I) wherein R is C1-C12 alkyl to give a compound of formula (I) wherein R is hydrogen, or a salt thereof, and/or, if desired, salifying a compound offormula (I), and/or, if desired separating a mixture of isomers of formula (I) into the single isomers.

7. A pharmaceutical or veterinary composition containing a compound of formula (I) according to claim 1 or a pharmaceutically or veterinarily acceptable salt thereof and a pharmaceutically or veterinarily acceptable carrier or diluent.

8. A compound of formula (I) as defined in claim 1, or a pharmaceutically or veterinarily acceptable salt thereof, herein before specified other than a compound of formula (I) or salt thereof claimed in claim 4 and 5.

9. A compound of formula (i) as defined in claim 1 or a pharmaceutically or veterinarily acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

10. A compound of formula (I) or salt thereof according to claim 9 for use in treating and preventing gastric and intestinal ulcers and excessive gastric secretion.

11. A compound of formula (I) or salt thereof according to claim 9 for use as a platelet anti-aggregation and disaggregating agent.

12. A compound of formula (I) or salt thereof according to claim 9 for use as a vasodilatory or hypotensive or anti-hypertensive agent.

13. A compound of formula (I) or salt thereof according to claim 9 for use in treating obstructive pulmonary diseases.

14. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in Example 6 or 7.

15. A process for the preparation of a pharmaceutically or veterinarily acceptable salt of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in Example 8.

16. A compound offormula (II) as defined in claim 6.

17. A compound of formula (II) as defined in claim 6 hereinbefore specified.

18. A process for the preparation of a compound of formula (Il) as defined in claim 6, which process comprises: 1) reaction of a compound of formula (IV)

wherein R4 is as defined in claim 6 and G is a protected carbonyl group, with a Wittig reagent of formula (V)

or with a modified Wittig reagent of formula (V a)

wherein B, n, R2 and R3 are as defined in claim 1, R6 is as defined above in claim 5 and M is an alkali metalcation, to obtain a compound of formula (VI)

wherein G, R2, R3, R4, n and B are as defined above;; 2) optional halogenation of an obtained compound of formula (VI) to give a compound of formula (VII)

wherein G, R2, R3, R4, n and B are as defined above and Z is as defined in claim 6; 3) reduction or nucleophilic addition to the free oxo group of the compound (VI) or (VII) followed by optional separation of the obtained mixture of the Sand R alcohols and optional protection of the newly formed hydroxy group, to give a compound of formula (VIII)

wherein G, R4, R1, R2, R3, n and B are as defined above and Z' is Z or hydrogen; ; 4) optional dehydrohalogenation of a compound of formula (VIII) where Z' is Z to obtain a compound of formula (Vlil a)

wherein G, R4, Ra, R2, R3, n and B are as defined above and; 5) removal of the carbonyl protecting group from G and optional removal of the hydroxy protecting groups which may be present either in a compound of formula (VIII) or in a compound of formula (VIII a).

19. A process for the preparation of a compound of formula (II) as defined in claim 6, said process being substantially as hereinbefore described in Example 5.