SE453594B - carbacyclin analogues - Google Patents

Description

453,594 lodges to be designated by the trivial names given in N.A. Nelson's Nomenclature System, J._Med. Chem. 17: 911 (1974) for prostaglandins.

Accordingly, all of the novel prostacyclin derivatives will be referred to as 9-deoxy-PGF1-type preparations and the PGI2 derivatives will preferably be referred to as CBA1 or CBA2 derivatives.

In the formulas given, a broken line denotes connection to a ring of substituents in the "alpha" (G) configuration, i.e. below the plane of said ring. Thick solid lines denote the connection of substituents to a ring in a "beta" 95) configuration, i.e. over the plane of said ring. The use of wavy lines (AJ) denotes connection of the substituents in alpha or beta configuration or connection in a mixture of alpha and beta configurations. Alternatively, wavy lines denote either an E or Z geometric isomeric configuration or mixtures thereof.

A hydroxy group in the side chain at C-15 in the formulas is in the S or R configuration, as determined by Cahn-Ingold-Prelog Sequence Rules, J. chem. sa. 41 = 16 (1964). see also Nature 212 = 3e (1966) where the stereochemistry of prostaglines is discussed, which discussion can be applied to the new prostacyclin or carbacycline analogs of the present invention. Molecules of prostacyclin and carbacycline each have several asymmetric centers and can therefore exist in optically inactive form or in either of two enantiomeric (optically active) forms, ie dextrorotating or levorotating forms. In the way they are designed, the formula for PGI2 corresponds to that which is endogenously formed in mammalian species. In particular, the stereochemical configuration at C-8 (W), C-9 (G), C-11 (M) and C-12 Qß) refers to endogenously formed prostacyclines. The mirror image of the above prostacycle forms represents the enantiomer. Racemic forms of prostacyclin contain equal numbers of the two enantiomeric molecules.

For practical reasons, reference is made to the optically active forms of prostacycline and carbacycline. A reference to prostacyclin thus includes the form thereof which has the same absolute configuration as that obtained from mammalian species.

The term "prostacyclin-type product" is used herein to refer to cyclopentane derivatives which are useful for at least one of the pharmacological purposes for which prostacyclin is used. The formulas drawn herein denote prostacyclin-type products or intermediates used in their preparation and represent the particular stereoisomer of the prostacyclin-type product which has the same relative stereochemical configuration as the prostacyclin obtained from mammalian tissue or the particular stereoisomer of the intermediate which is useful for the preparation of the above stereoisomer of the prostacyclin-type product. The term "prostacyclin analogues" or "carbacycline analogs" denotes the stereoisomer of a prostacyclin-type product having the same relative stereochemical configuration as prostacyclin derived from mammalian tissue or a mixture consisting of the stereoisomer and the enantiomer. In particular, where a formula is used to show a prostacyclin-type product in the present specification, the term "prostacyclin analog" or "carbacycline analog" refers to a compound of this formula or a mixture of this compound and the enantiomer thereof.

Prior Art Carbacycline is closely related to previously known compounds. See, for example, Japanese Kokai 63,059 and 63,060, which are summarized in Derwent Farmdoc CPI, Nos. 48,154B / 26 and 48,1558/26. See also British Patent Specification 2,012,265 and German Offenlegungsschrift 2,900,352, summarized in Derwent Farmdoc CPI No. 54,825B / 30.

See also British Patents 2,017,699, 2,014,143 and 2,013,661.

The synthesis of carbacycline and similar compounds is reported in the chemical literature as follows: Morton, D.R. and co-workers, J. Organic Chemistry, 44: 2880 (1979); Shibasaki, M. and co-workers, Tetrahedron Letters, 433-436 (1979); Kojima, K and co-workers, Tetrahedron Letters, 3743-3746 (1978); Nicolaou, K.C. and co-workers, J. Chem. soc. Chemical Communications, 1067-1068 (1978); Sugie, A. and co-workers, Tetrahedron Letters 2607-2610 (1979); Shibasaki, M., Chemistry Letters, 1299-1300 (1979) and Hayashi, M., Chem. Easy. 1437-40 (1979) and Li, Tsung-tee, "A Facile Synthesis of 9 (O) -Methano-Prostacyclin", Abstract No. 378 (Organic Chemistry) and P.A. Aristoff, "Synthesis of 6a-Carbaprostacyclin I", Summary 455 594 Abstract 236 (Organic Chemistry) both in Abstract of Papers (Part II), Second Congress of the North American Continent, San Francisco, California (Las Vegas, Nevada), USA, 24-29, August 1980. 7-oxo- and 7-bydroxy-CBA2 compounds are apparently disclosed in U.S. Patent 4,192,891. 19-hydroxy-CBA2 compounds are disclosed in U.S. Patent Application 054,811, filed July 5, 1979. CBA2-type aromatic esters are disclosed in U.S. Patent 4,180,657. 11-deoxy-β§0 or 44J1-CBA2 compounds are disclosed in Japanese Kokai 77/24,865, published February 24, 1979.

Summary of the Invention The present invention shows in particular: (a) a carbacycline intermediate of formula VI, (b) a carbacycline analog of formula X wherein n represents 1 or 2, wherein L1 represents hydrogen or fluorine and is the same or different with the proviso that one of R 3 and R 4 represents fluorine only when the other represents hydrogen or fluorine, where M1 represents M-OHQG-H or OK-Hzß-OH, where M6 represents m-onufp-Rs or vk-nsrs-on10, where R represents hydrogen or methyl and where R 10 represents a protecting group which can be removed by acid hydrolysis, where R 7 represents -Cm fi zm-CH 3, where m represents 1, 2, 3, 4 or 5, where R 8 represents hydroxy or hydrogen, where R 15 represents hydrogen or fluorine, where R16 represents hydrogen or where R16 and R17 together represent -CH2- or R16 and R17 together represent a second valence bond between C-6a and C-9, where R17 is defined as (1) hydrogen or methyl, ~. (2) (C1-C4), where R18 represents hydrogen, hydroxy, hydroxymethyl, -OR10 or -CH2OR10. where R 10 represents a protecting group, which can be removed by acid hydrolysis. Some new prostacyclin analogues in the present application, i.e. compounds of formula X, are all named as CBA1 or CBA2 compounds due to the substitution of methylene instead of ox in the heterocyclic ring of prostacyclin and substitution. The CBA2 compounds are those which exhibit the olefinic double bond at C-5.6, while the CBA1 compounds are those which are saturated at C-5.6.

These CBA analogs where Z1 represents trans-CH2-CH = CH are described as "trans-2,3-didehydro-CBA" compounds.

These new compounds where n represents 2 are further characterized as 7α-homo-CBA compounds due to the cyclohexyl ring included in the site of the heterocyclic ring in prostacyclin. Furthermore, the new compounds are called Qß-methyl-CBA compounds when R17 represents methyl.

When R15 represents fluoro, the compounds are described as "5-fluoro-CBA".

For compounds where Y1 represents cis-CH = CH-, compounds where the M1 moiety contains a hydroxyl in alpha configuration can be named as "15- -epi-CBA" compounds. For a description of the nomenclature for identifying C-15 epimers, see U.S. Patent 4,016,184, especially columns 24-27.

The new carbacycline analogs herein contain - (CH 2) 2 - or cis-CH = CH- as the Y 1 moiety and can therefore be termed "13,14-dihydro" or "cis-13" compounds.

R7 represents a straight chain -Cm fl zm-CH3, where m has been previously defined.

The compounds may be described as "19,20-dinor", "20-nor", "20-methyl" or "20-ethyl" compounds when m represents 1, 2, 4 or 5.

The new CBA analogues here showed gerxüssa aprostacyclin-like pharmacological responses. Consequently, the new CBA analogues of formula X are useful as agents in the study, prevention, control and treatment of diseases of undesirable physiological conditions in mammals, especially humans, valuable domestic animals, pets, zoological species and laboratory animals. (eg mouse, rat, rabbit and monkey). In particular, the compounds are useful as antithrombotic agents, anti-wound agents and anti-asthma agents as set forth below. (a) Inhibition of platelet aggregation These new CBA analogues are useful when it is desired to inhibit platelet aggregation, to reduce the aggressive properties of platelets or to remove or prevent thrombi formation in mammals, including humans. For example, the compounds are useful in the treatment and prevention of myocardial infarction to treat and prevent postoperative thrombosis, to facilitate the opening of vascular grafts after surgery, to treat peripheral vascular diseases, and to treat conditions such as atherosclerosis. arteriosclerosis and blood coagulation defects due to lipemia and other clinical conditions where the underlying thiology is associated with lipidobalance or hyperlipidemia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long-term prophylaxis following myocardial infarction and stroke. For these purposes, the compounds are administered systematically, e.g. intravenously, subcutaneously, intramuscularly and in the form of sterile implants with prolonged action. In order to obtain answers quickly, especially in emergencies, intravenous administration is preferred. Doses in the range of about 0.01 to about 10 mg per body weight and day are used, the exact dose depending on the age, weight and condition of the patient or animal and on the frequency and route of administration.

Preferred dosage forms for these compounds are oral, although other non-parenteral routes (eg, buccal, rectal, sublingual) may likewise be used with parenteral route presenters. Oral dosage forms are conventionally formulated (tablets, capsules, etc.) and administered 2-4 times daily. Doses in the range of 0.05 to 100 mg per kg of body weight per day are effective.

Addition of these compounds to whole blood results in in vitro use, such as storage of whole blood for use in cardiopulmonary bypass machines.

Additional compounds containing these compounds can be circulated through organs, e.g. heart and kidneys, which are removed from a donor before transplantation. They are also useful in the preparation of platelet-rich concentrates for use in the treatment of thrombocytopenia, chemotherapy and radiation therapy. In vitro applications in 453,594 utilize doses of 0.001 - 1.0 pg per ml of whole blood. For the treatment of peripheral vascular disease, see U.S. Patent 4,103,026. (B) Reduction of gastric secretion These new CBA analogs, as set forth herein, are also useful in mammals including humans and certain useful animals, e.g. dogs and pigs to reduce and regulate gastric secretion, thereby reducing or avoiding the formation of gastrointestinal ulcers and accelerating the healing of such ulcers that already exist in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously or intramuscularly with an infusion dose in the range of from about 0.1 pg to 20 pg per kg of body weight per minute or in a total daily dose by injection or infusion in the range of from about 0. 01 to about 10 mg per kg body weight per day, the exact dose depending on the age, weight and condition of the patient or animal as well as the frequency and vagus administration.

However, it is preferred that these novel compounds be administered orally or by other non-parenteral routes. Orally used, 1-6 daily administrations were used at a dose of about 1.0 to 100 mg per kg of body weight per day. Once a wound has healed, maintenance doses may be required to prevent wounds from recurring and downward as long as the patient or animal remains asymptomatic. (c) Inhibition of NOSAC-induced damage These new CBA analogs shown herein are also useful in reducing undesirable gastrointestinal effects obtained by systemic administration of anti-inflammatory prostaglandin synthetase inhibitors and are useful for this purpose by co-administration of the prostaglandin derivative and the anti-inflammatory prostaglandin-swanetase inhibitor. See Partridge et al., U.S. Pat. No. 3,781,429, which states that the ulcerogenic effect obtained with certain non-sterile anti-inflammatory agents in rats is inhibited by co-administration of certain prostaglandins. Accordingly, these novel CBA analogs are useful, for example, in reducing undesirable effects in the gastrointestinal tract caused by systemic administration of indomethacin, phenylbutazone and acetylsalicylic acid. These are substances that have been specifically mentioned by Partridge and co-workers as non-steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, for example indomethacin, acetylsalicylic acid or phenylbutazone, is administered in some known manner to alleviate inflammatory conditions, for example in any dosage regimen on any of the known routes of systemic administration. (d) Bronchodilation (anti-asthma agent) These new analogues shown here are also useful in the treatment of asthma. For example, these compounds may be useful as bronchodilators or as inhibitors of mediator-induced bronchoconstriction, such as SRS-A and histamine, which are released from cells activated with an antigen-antibody complex. Thus, these compounds regulate seizures and facilitate breathing in conditions such as bronchial bronchitis, bronchiectasis, pneumonia and emphysema. For this purpose, the compounds are administered in different dosage forms, e.g. orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, parenthetally, subcutaneously or intramuscularly with intravenous administration being preferred in emergencies; by inhalation in the form of aerosols or solutions in spray bottles or by snuff in the form of powder. Doses in the range of about 0.01 to 5 mg per kg of body weight are used 1-4 times daily, the exact dose depending on the age, weight and condition of the patient and the frequency and route of administration. For the above use of these CBA analogs, these can be preferably combined with other anti-asthmatic agents, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone).

These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by oral inhalation route with conventional vials or by oxygen aerosolization, it is convenient to provide the present active ingredient in dilute solution, preferably in concentrations. from about one part of the drug to about 100 to 200 parts by weight of total solution. Completely conventional additives can be used to stabilize these solutions or 453 594 to provide isotonic agents, for example sodium chloride, sodium citrate, citric acid, sodium hydrogen sulfite and the like can be used. For administration as a self-propelled unit dose for administering the active ingredient in aerosol form suitable for inhalation therapy, the composition may consist of the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent. Suitable agents such as ethanol, flavors and stabilizers. Suitable means for obtaining aerosol inhalation therapy are described in U.S. Patent 3,868,691.

When X represents -COOR1, the new CBA analogs can be used for the purposes described above in the form of a free acid, in ester form or in the form of a pharmacologically acceptable salt. When the ester form is used, the ester is one of those which fall within the definition of R. However, it is preferred that the ester be alkyl of 1-12 carbon atoms. Among the alkyl esters, methyl and ethyl esters are especially preferred due to optimal absorption of the compound in the body or experimental animal system, and straight chain octyl, nonyl, decyl, undecyl and dodecyl are especially preferred for extended action.

Pharmacologically acceptable salts of the novel prostaglandin analogs of the present invention for the purposes described above are those with pharmacologically acceptable metal cations, ammonia, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are those derived from the alkali metals, e.g. lithium, sodium and potassium and from the alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron also fall within the scope of the invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary and tertiary amines. Examples of suitable iner amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, vylamethylamine adamantylamine and similar aliphatic, cycloaliphatic, araliphatic amines containing up to about 18 carbon atoms as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like as well as amines containing water-soluble hydrophilic groups, e.g. mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris- (hydroxymethyl) -aminomethane, N-phenylethanolamine, N- (p-tert.amylphenyl) -dietanolamine, galactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like. Additional useful amino salts of basic amino salts, e.g. lysine and arginine.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

Particularly preferred for biological activity are CBA2 analogs of formula X which have the same C-5 isomeric configuration as CBA2 itself.

Particularly preferred are those compounds which satisfy two or more of the above preferred properties. Furthermore, the above preferred embodiments are expressly intended to describe the preferred compounds within the scope of the general formula of the novel CBA analogs shown in the present application.

The protecting groups within the framework of R 10 are any group which can exchange a hydroxy hydrogen atom or which is neither attacked nor reactive for the reactions used in the conversion according to the present invention and which can then be exchanged for hydrogen by acid hydrolysis in the preparation of prostaglandin-type compounds. Several such protecting groups are known per se, e.g. tetrahydropyranyl and substituted tetrahydropyranyl. See, for example, E.J. Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XII Organic Synthesis, p. 51-79 (1969).

Such blocking groups which have been found to be useful include: (a) tetrahydropyranyl (b) tetrahydrofuranyl (c) a group of the formula -C (OR 11) (R 12) -CH (R 13) (R 14), where R represents alkyl of 1-18 carbon atoms, cycloalkyl of 3-10 carbon atoms, aralkyl of 7-12 carbon atoms, phenyl or phenyl substituted with 1-3 alkyl of 1-4 carbon atoms, where R12 and R13 represent alkyl of 1-4 carbon atoms carbon atoms, phenyl, phenyl substituted with 1, 2 or 3 alkyl having 1-4 carbon atoms or where R 12 and R 13 together represent - (CH 2) a - or where R 12 and R 13 together represent - (CH 2) b O- (CH 2) ) c-, where a represents 3, 4 or 5 and where b represents 1, 2 or 3 and where c represents 1, 2 or 3 and where b plus c is 2, 3 or 4 and where R 12 and R 13 may be the same or different and where R 14 represents hydrogen or phenyl. and (d) silyl groups according to R 28 defined below.

When the protecting group R 10 is tetrahydropyranyl, the tetrahydropyranyl ether derivative of each hydroxy group is obtained in CBA-type intermediates by reaction with the hydroxy-containing compound with 2,3-dihydropyran in an inert solvent, e.g. dichloromethane in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. Dihydropyran is used in large stoichiometric excess, preferably 4-100 times the stoichiometric amount. The reaction is usually complete in less than 1 hour at 20 ° C.

When the protecting group is tetrahydrofuranyl, 2,3-dihydrofuran is used in the manner described in the previous paragraph instead of 2,3-dihydropyran.

When the protecting group has the formula -C (OR11) (R12) -CH (R13) (R14), where R11, R12, R13 and R14 have been previously defined, a vinyl ether or an unsaturated cyclic or heterocyclic compound is used, e.g. . 1-cyclohexen-1-yl methyl ether or 5,6-dihydro-4-methoxy-2H-pyran.

See, e.g., Reese et al., J. American Chemical Society 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those of the dihydropyran above. R 28 is a silyl protecting group of the formula -Si (G1) 3. In some cases such silylations are general in that they silylate all the hydroxy groups in the molecule, while in other cases they are selective in that one or more hydroxy groups are silylated, at least one other hydroxy group remains unaffected. For some of these silylation processes, silyl groups within the framework of -Si (G1) 3 include trimethylsilyl, dimethylphenylsilyl, triphenylsilyl, t-butyldimethylsilyl or methylphenylbenzylsilyl. With respect to G1 are examples of alkyl, methyl, ethyl, propyl, isofbutyl, butyl, secondary butyl, butyl, pentyl and the like. Examples of aralkyl are benzyl, phenethyl, flphenylethyl, 3-phenylpropyl, dnaphthylmethyl and 2- (flphenaphthyl) ethyl.

Examples of phenyl substituted by halogen or alkyl are p-chlorophenyl, m-fluoro-phenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl and 2,4 -dichloro-3-methylphenyl.

These silyl groups are known. See, for example, Pierce "Silylation of Organic Compounds", Pierce Chemical Company, Rockford, Ill. (1968).

When silylated products according to the reaction schemes below are subjected to chromatographic purification, the use of silyl groups is known to be unstable in chromatography (eg trimethylsilyl) and should be avoided. Furthermore, when the silyl groups are selectively introduced, silylating agents are used which are available and known to effect selective silylation. For example, t-butyldimethylsilyl groups are used when selective introduction is required. Furthermore, when silyl groups are to be selectively hydrolyzed in the presence of protecting groups in accordance with R 10 or acyl protecting groups, the use of silyl groups which are readily available and known to be readily hydrolyzable with tetra-n-butylammonium fluoride can be used. A particularly useful silyl group for this purpose is t-butyldimethylsilyl, while other silyl groups (eg trimethylsilyl) are not used when selective introduction and hydrolysis are required.

Incidentally, the protecting groups as defined by R10 can be removed by mildly acid hydrolysis. For example, by reaction with (1) hydrogen chloride in methanol, (2) a mixture of acetic acid, water and tetrahydrofuran or (3) an aqueous solution of citric acid or an aqueous solution of phosphoric acid in tetrahydrofuran at temperatures below SSOC, wherein hydrolysis of the blocking group obtained.

R31 is a hydroxy-protecting group indicated above. As such, R 31 may be an acyl protecting group according to R 9, an acid hydrolyzing protecting group according to R 10, a silyl protecting group according to R 28. Acyl protecting groups according to R 9 include: (a) benzoyl (b) benzoyl substituted with 1-5 alkyl having 1-4 carbon atoms or phenylalkyl having 7-12 carbon atoms or nitro, with at most two substituents having other meanings than alkyl and the total number of carbon atoms in the substituents does not exceed 10 and that the substituents are the same or different, (c) benzoyl substituted by alkoxycarbonyl having 2-5 carbon atoms (d) naphthoyl (e) naphthoyl substituted by 1-9 alkyl having 1- 4 carbon atoms, phenylalkyl having 7-12 carbon atoms, nitro, no more than two substituents on either of the annealed aromatic rings having a meaning other than alkyl and the total number of carbon atoms in the substituents on either of the annealed aromatic rings does not exceed 10 carbon atoms and where the different substituents are the same or different or (f) alkanoyl having 2 to 12 carbon atoms.

In the preparation of these acyl derivatives of a hydroxy-containing compound, generally known methods are used. Thus, an aromatic acid of the formula RQOH, where R 9 is previously defined (eg benzoic acid), is reacted with the hydroxy-containing compound in the presence of a dehydrating agent, e.g. p-toluenesulfonyl chloride or dicyclohexylcarbodiimide or alternatively an anhydride of the aromatic acid of formula (R9) OH, e.g. benzoic anhydride.

Preferably, however, the process described in the preceding paragraph is carried out with a suitable acyl halide, e.g. R9Hal, where Hal denotes chloro, bromo or iodo. For example, benzoyl chloride is reacted with the hydroxyl-containing compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is carried out under various conditions, using generally known procedures. Generally mild conditions are used: 0-60 ° C, the reactants are contacted in a liquid medium (eg excess pyridine or an inert solvent such as benzene, toluene or chloroform). The acylating agent is used either in a stoichiometric amount or in a substantially stoichiometric excess. As examples of R 9, the following compounds are available as acids (RQOH), (R 9) 2 O or acyl chlorides (R 9 Cl): benzoyl, substituted benzoyl, e.g. (2-, 3- or 4-) methylbenzoyl, (2-, 3- or 4-) ethylbenzoyl, (2-, 3- or 4-) isopropylbenzoyl, (2-, 3- or 4-) tert .-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, phenyl (2-, 3- or 4-) toluyl, (2- , 3- or 4-) phenethylbenzoyl, (2-, 3- or 4-) nitrobenzoyl, (2,4-, 2,5- or 2,3} dinitrobenzoyl, 2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenylethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro--2-phenethylbenzoyl, mono-esterified phthaloyl, isophthaloyl or terephthaloyl, 1- or 2-naphthoyl, substituted naphthoyl, eg (2-, 3-, 4-, 5-, 6- or 7-methyl-1-mmol), (2- or 4- ) ethyl 1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, ( 3-, 4-, 5- or 8-) nitro-1-naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8-) methyl-1-naphthoyl, 4-ethyl-2-naphthoyl and (5- or 8-) nitro-2-naphthoyl and acetyl.

Benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride or the like can be used for this purpose, e.g. R9Cl compounds corresponding to the above R9 groups. If the acyl chloride is not available, it can be prepared from the corresponding acid and phosphorus pentachloride in a known manner. It is preferred that the RQOH, (R 9) 2 O or R 9 Cl reactant does not contain major hindering substituents, e.g. tertiary butyl on both ring carbon atoms near the point of carbonyl attack.

The acyl protecting group, according to R9, is removed by deacylation.

Alkali metal carbonates or hydroxides are used efficiently at ambient temperature for this purpose. For example, potassium carbonate or hydroxide in an aqueous methanol at 25 ° C is advantageously used.

R34 is defined as any arylmethyl group which can replace the hydroxyhydrogen in the intermediate in the preparation of various CBA analogs, which subsequently replaces hydrogen in the process of preparation of the respective prostacyclone analog, stably with respect to various reactions for which the R34-containing compound are exposed and introduced and then removed by hydrogenolysis under conditions which give essentially quantitative yields of the desired products. Examples of arylmethyl-hydroxyhydrogen exchange groups are (a) benzyl (b) benzyl substituted with 1-5 alkyl of 1-4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7-12 carbon atoms, wherein the different substituents are the same or different (c) -benzhydryl. (d) benzhydryl substituted with 1-10 alkyl of 1-4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylacyl of 7-12 carbon atoms with the additional condition that different substituents are the same or different on each aromatic ring ( e) trityl (f) trityl substituted with 1-15 alkyl having 1-4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl having 7-12 carbon atoms and wherein the different substituents are the same or different on each aromatic ring .

The introduction of such ether linkages into the hydroxy-containing compound, especially benzyl or substituted benzyl ether, takes place in a manner known per se, for example by reaction of hydroxy-containing compounds with benzyl or substituted benzyl halide (chloride, bromide or iodide) corresponding to the desired etern. This reaction takes place in the presence of a suitable condensing agent (eg silver oxide). The mixture is stirred and heated to 50-80 ° C. Reaction times of 4-20 hours are usually suitable.

The reaction schemes below describe processes in which the novel intermediates and final products of the present specification are prepared by the novel process. With respect to these schemes, 9 'n' L1 'M1' M6 'Rv' Re 'R1o' R1s' Rw 'E17' R1s' Rze 'X1 °° h Y have been defined above. R38 is -OR32, vate or -CHZOR31, where R32 has been previously defined. R27 is R7 except that - (CH2) 2-CH (OH) -CH3 is (CH2) 2-CH (OR10) -CH3. R37 is the same as R17 but not hydrogen.

Ac denotes acetyl. Z2 has the same meaning as Z but denotes 1 non- (Ph) - (CH2) g-. Z3 is the same as Z1 but does not denote trans- -cH2-cH = cH-.

With respect to Reaction Scheme A, a process is shown in which the known bicyclic lactone of formula XXI is converted to the carbacyclin-455 594 16 intermediate of formula XXV useful in the preparation of CBA compounds of formula X, wherein R 17 represents alkyl or R 16 and R 17 together denotes methano or a second valence bond between C-6a and C-9. With respect to Reaction Scheme A, the compound of formula XXI is converted to the compound of formula XXII by treatment with the anion of dimethyl methylphosphonate. The method of such a reaction is previously known. See Dauben et al., JACS, 97: 4973 (1975), which describes a reaction of this type.

The lactol of formula XXII is converted to the diketone of formula XXIII by oxidation methods known per se. See Collins Reagent or Jones Reagent, which can be used for this oxidative conversion. The diketone of formula XXIII is cyclized to the compound of formula XXIV by an intermolecular Horner-Emmons reaction. The chemical methodology for analog conversions is known per se. See Piers et al., Tetrahedron Letters, 3279 (1979) and Clark et al., Synthetic Communications 5: 1 (1975).

The compound of formula XXIV is converted to the new compound of formula XXV, where R16 represents hydrogen and where R37 represents alkyl by treatment with lithium dialkyl cupuprate. Lithium dialkyl cuprate is prepared in a conventional manner, e.g. by a reaction between anhydrous copper iodide in diethyl ether with an alkyllithium compound in diethyl ether and then the compound of formula XXIV is reacted, e.g. in diethyl ether.

The compound of formula XXIV is converted to the new compound of formula XXV, wherein R 16 and R 37 together represent methylene (-CH 2 -) by one of two methods. By the first method, the compound of formula XXV is prepared by treating the compound of formula XXIV with an anion of trimethyloxosulfonium iodide. See Corey et al., JACS 87: 1353 (1965). With this process, the anion is most easily created by treating trimethyloxysulfonium iodide in sodium hydride.

The second method converts the compound of formula XXIV to the compound of formula XXV, wherein R16 and R37 together represent methylene by first converting the compound of formula XXIV to the corresponding hydroxymethyl compound of formula XXVI by photochemical addition of methanol (see Bundy, Tetr. Lett. 1957 , 1975), after which the resulting hydroxymethyl compound is treated with an excess (eg two equivalents) of p-toluenesulfonyl chloride in a tertiary amine base, whereby the corresponding tosylate of formula XXVII is obtained and finally the obtained tosylate of formula XXVII is treated with a base (eg potassium t-butoxide) to give the cyclopropyl compound of formula XXV.

With respect to Reaction Scheme B, a process is reported in which a compound of formula XXXI is prepared according to the procedures of Reaction Scheme A and converted to new CBA2 analogs of formula XXXVI.

The compound of formula XXXI is converted to the compound of formula XXXVI in a manner known per se for the preparation of carbacycline.

See, for example, the above-mentioned British patents. Alternatively, the compound of formula XXXI may react with the compound of formula XXXII and thereby be gradually converted to the compounds of formulas XXXIII, XXXIV and XXXV.

The reaction between the compound of formula XXXI utilizes the compound of formula XXXII in a manner known per se. See, for example, Muersch, J., Organic Chemistry, 36: 1149 (1971) and Mulzer et al., Tetrahedron Letters, 2949 (1978). The reactants of formula XXXII are known or can be prepared in a manner known per se. See Example 4 which describes such a process for the preparation of the compound of formula XXXII. The compound of formula XXXIII is then converted to the compound of formula XXXIV by decarboxylative dehydration. Methods for this reaction are previously known. See Bsdurrnser 'and co-workers, Helv.

Chim. Acta, 58: 1450 (1975), Hara and co-workers, Tetrahedron Letters, 1545 (1975), and Mulzer and co-workers, Tetrahedron Letters, 2953 (1978) and 1909 (1979).

Finally, compounds of formula XXXV are prepared from compounds of formula XXXIV by selective desilylation. Such processes are known and suitably utilize tetra-n-butylammonium fluoride and tetrahydrofuran. See Corey et al., JACS 94: 6190 (1972).

The compound of formula XXXV is converted to various acids, esters, amides and amines of formula XXXVI in a manner known per se. Particularly useful in this regard is a process described in the above-mentioned British patent specification which describes the preparation of carbacycline analogues.

In the preparation of compounds of formula XXXVI from compounds of formula XXXV, for example, oxidation of the corresponding carboxylic acid is carried out followed by hydrolysis of each protecting group at C-11 or C-15 position in the molecule. Such carboxylic acids are then esterified in a conventional manner or amidated by conventional means. Such amides can then be reduced, for example, to the corresponding amines (X1 represents -CH2NL2L3) by reduction with lithium aluminum hydride.

See U.S. Patent 4,073,808. In the preparation of primary alcohols of formula XXXVI from compounds of formula XXXV, hydrolysis of each protecting group at C-11 or C-15 occurs directly. The hydrolysis is carried out in the manner described above, e.g. by mildly acidic conditions at elevated temperatures.

Reaction Scheme E illustrates a method by which the known compound of formula LXI is converted to the intermediate compound of formula LXIII useful in the preparation of the novel CBA2 analogs.

The process steps for the conversion of the compound of formula LXI to the compound of formula LXIII are analogous to those described for the conversions in Reaction Schemes A, B, D for the compound of formula XXI to the compounds of formulas XXXVI and LX (ie the corresponding conversion of the compound of formula formula LXI to the compound of formula LXII corresponds to the conversion in Reaction Scheme A of the compound of formula XXI to the compound of formula XXV and to the conversion of the compound of formula LXII to the compound of formula LXIII the conversion in Reaction Scheme D of the compound of formula LI to the compound of formula LX). The protecting groups R31 and R38 may, for suitability reasons, be the same or different, although such protecting groups are preferably different, whereby the hydrolysis of a protecting group according to R31 is carried out in the presence of a protecting group according to R38. Reaction Scheme F illustrates a method whereby The compound of formula LXXI prepared according to Reaction Scheme E is converted to the carbacycline analog of formula LXXII of the present invention.

In the case of Reaction Scheme F, the compound of formula LXXI is converted to the compound of formula LXXII by selective hydrolysis of the protecting group according to R31. Thereafter, the compound of formula LXXII is converted to the compound of formula LXXIII in a manner known per se, e.g. by oxidation of the primary alcohol of formula LXXII to the corresponding aldehyde, Wittig oxylacylation of the aldehyde and reduction of the resulting ketone to the secondary or tertiary alcohol corresponding to M1. As examples of various conversions applied in Reaction Scheme F, reference is made to Reaction Scheme A (Part VI) of U.S. Patent 4,107,427.

Reaction Scheme G illustrates a process by which the novel intermediate of formula LXXXI prepared according to Reaction Scheme A is converted to the isomers of formula LXXXVIII and LXXXIX by the novel C-6a and / or C-9 substituted CBA2 analogs.

Referring to Reaction Scheme G, the compound of formula LXXXIII is prepared from the ketone of formula LXXXI by a Wittig-6 »carboxyalkylation using a triphenylphosphonium compound of formula LXXXII. The Wittig reaction is carried out under conventional reaction conditions for the preparation of prostaglandin-type substances.

The compound of formula LXXXIII is then optionally subjected to hydrolysis to give the carboxylic acid products of formula X or used for the further conversions of Reaction Scheme G in ester form.

The compound of formula LXXXIII thus prepared is then preferably separated directly into C-5 isomers of formulas LXXXVIII and LXXXIX (eg by chromatography followed by hydrolysis of any protecting groups in positions C-11 or C-15 in the molecule) or alternatively converted to the ester of formula LXXXIV by conventional esterification techniques, e.g. treatment with diazomethane in ether or treatment with methyl iodide. The ester of formula LXXXIV is then reduced to the corresponding primary alcohol by reduction with a suitable reducing agent, e.g. lithium aluminum hydride in a manner known per se for the preparation of primary alcohols of the prostaglandin type, corresponding to prostaglandin esters. The compound of formula LXXXV represents a particularly suitable intermediate for easy separation of the C-5 diastereomers. Thus, the compound of formula LXXXV can be separated in a conventional manner, in the case of separation of diastereomeric mixtures, e.g. column chromatography, whereby the compounds of formula LXXXVI and LXXXVII are obtained in isomerically pure form. These primary alcohols are then converted in a conventional manner to products of the formula LXXXVIII and LXXXIX in the manner described above. Reference is made to the conversions of the compound of formula XXXV to the compound of formula XXXVI in Reaction Scheme B.

Reaction Scheme H illustrates a process by which the S-fluoro-CBA2 compounds of formula XCVII are prepared from known CBA2 intermediates of formula XCIII of known type. See e.g. British Offenlegungsschrift No. 2,014,143, in particular as regards the discussion of step (b) of Reaction Scheme A. This sulfoximine of formula XCI is converted to the fluorinated sulfoximine of formula XCII by first producing an anion of the compound of formula XCII , e.g. by treatment with n-butyllithium in hexane, and treating the resulting anion with a fluorine compound. Particularly preferred fluorine compound is perchloryl fluoride (FCIO3).

The compound of formula XCII thus prepared and the above-described known compound of formula XCIII were then used in the preparation of the compound of formula XCIV in a known manner. Here again, reference is made to step (b) of Reaction Scheme A in British Offenlegungsschrift 2,014,143.

The compound of formula XCIV thus prepared is then converted to the primary alcohol of formula XCV by hydrolysis under mild acidic conditions (eg mixtures of acetic acid, water and tetrahydrofuran) in a known manner. Thereafter, the primary alcohol of formula XCV is oxidized to the corresponding carboxylic acid of formula XCVI using conventional techniques. For example, by treatment with oxygen and an aqueous suspension of platinum oxide hydrogenated at room temperature and pressure, carboxylic acid of the formula LXXVI is obtained.

Thereafter, the compound of formula XCVI is converted to various products of formula XCVII by derivatization or conversion of the carboxyl group of the compound of formula XCVI.

The C-5 isomers of the compounds of formula XCIV-XCVII are suitably separated during some step in the process of Reaction Scheme H but are suitably and preferably separated from the diastereomeric mixture of formula XCIV. Conventional technology, e.g. column chromatography, used in the separation.

Reaction Scheme I describes an optional method whereby the known compound of formula CI is converted to the products of formula 453 594 21 CIII. According to Reaction Scheme I, the compound of formula XCII is prepared from the compound of formula XCI according to the procedure described in Reaction Scheme H to prepare the compound of formula XCVII from the compound of formula XCIII. This CBA2 intermediate of formula CII is then converted to the compound of formula CIII according to the method described in Reaction Scheme F for converting the compound of formula LXXI to the compound of formula LXXIII.

The compounds of the invention prepared according to the processes of the invention present in the form of free acids are converted into pharmacologically acceptable salts by neutralization with appropriate amounts of corresponding inorganic or organic bases, examples of which may be mentioned above cations and amines. These conversions are carried out according to several different known methods generally useful for the production of inorganic salts, ie metal or ammonium salts. The choice of method depends in part on the solubility properties of the salts to be prepared. In the case of inorganic salts, it is generally convenient to dissolve an acid of the invention in water containing a stoichiometric amount of a hydroxide, a carbonate or bicarbonate corresponding to the desired inorganic salt. By using, for example, sodium hydroxide, sodium carbonate or sodium bicarbonate, a solution of the sodium salt is obtained.

By evaporating the water or adding a water-miscible solvent of moderate polarity, e.g. a lower alkanol or a lower alkanone, the solid inorganic salt is obtained if it is the desired form.

To prepare an amine salt, an acid of the invention is dissolved in a suitable solvent of moderate or low polarity. Examples of the former are ethanol, acetone and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to the solution. If the resulting salt does not precipitate, it is usually obtained in solid form by evaporation. If the amine is relatively volatile, any excess can be easily removed by evaporation. Preferably, stoichiometric amounts of the less volatile amines are used.

Salts in which the cation is quaternary ammonium are obtained by mixing an acid according to the invention with a stoichiometric amount of the corresponding quaternary ammonium hydroxide in aqueous solution followed by evaporation of the water.

Description of the Preferred Embodiments The invention is described in more detail below with reference to the following examples: Example 1 3-oxo-7K-tetrahydropyran-2-yloxy-quinyl-3'-tetrahydropyran-2-yloxy-trans-1'- octenyl] -bicycloal, 3, Q] -oct-1: (Formula XXIV: R18 is tetrahydropyranyloxy; Y1 β-tetrahydropyranyloxy: / 5-H, L1 is'KH: ßrH, R27 is n-butyl and n is the number ) is trans-CH = CH-, M6 is See Reaction Scheme A.

A. To a stirred solution of 19 ml (170 mmol) of dimethyl methylphosphonate and 600 ml of dry tetrahydrofuran was added dropwise at -78 ° C in an argon atmosphere dropwise over 5 minutes. 110 ml (172 mmol) of 1.56 M n-butyllithium in hexane.

The resulting solution was stirred for 30 minutes. at -78 ° C, treated with 25.4 g of 3W, 5 5-dihydroxy-β- (3α-hydroxy-trans-1-octenyl) -1dr-cyclopentaneacetic acid, lactone, bis (tetrahydropyranyl) ether in 100 ml dry tetrahydrofuran dropwise over 1 hour and stirred for 1 hour at -78 ° C and 4 hours at room temperature. The reaction was then quenched by the addition of 10 mL of glacial acetic acid and the reaction mixture was diluted with 700 mL of brine and extracted with diethyl ether (3 x 700 mL). The combined ether layers were washed with 200 ml of bicarbonate and 500 ml of brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 37 g of the compound of formula XXII as an oily white solid: 3-dimethylphosphonomethyl-3- hydroxy-2-oxa-7K-tetrahydropyran-2-yloxy-xyl-3'S) -3-'-tetrahydropyran-2-yloxy-trans-1'-octenyl] -bicyclo [3,3, Q] -octane.

After recrystallization of the crude product from hexane and ether, 22.1 g of purified product of formula XXII were obtained. Thin layer chromatography on silica gel showed an Rf value in ethyl acetate of 0.22. The melting point was at s9-93 ° C. NmR absorptions were observed at 3.72 (ablett, J = 11 Hz) and 3.83 (aublet, J = 11 rmá _ characteristic: xx absorptions occurred at 3340, 1250, 1185, 1130, 1075 and 1030 cm -1.

B. To a solution of 10.0 g of the product obtained under A in 75 ml of acetone stirred in a nitrogen atmosphere at -10 ° C was added for 30 minutes. 9.0 ml 453 594 23 Jones reagent. The resulting suspension was stirred for 30 minutes. at -10 ° C and then added with 4 ml of 2-propanol. The solvents were decanted from the green residue and most of the acetone was removed under reduced pressure. The acetone concentrate was then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 8.2 g of the product of formula XXIII: 2-decarboxy-6-desbutyl-6-dimethylphosphonomethyl-6-keto-PGE1, 11,15-bis (tetrahydropyranyl ether). Chromatography of the product of formula XXIII on 600 g of silica gel eluting with 20% acetone in methylene chloride gave 4.95 g of pure product of formula XXIII. Thin layer chromatography using silica gel showed an Rf value (1 a mixture of 20% acetone in methylene chloride) of 0.22.

Characteristic NMR absorption bands were observed at 3.14 (doublet, J = 23 az) aan 3.80 (doublet, J = 11 Hz), s, 4-s, s (m) é. Characteristic IR absorption bands occurred at 1745, 1715, 1260, 1200, 1185, 1130, 1030, 970, evo cm -1.

C. A suspension of 5.37 g of the product of Example 1, Part B, 1.33 g of anhydrous potassium carbonate and 5.37 g of 10-Crown-6-ether in 200 ml of toluene was heated at 75 ° C for 6 hours in a nitrogen atmosphere. , cooled to 0 ° C and washed with 200 ml of brine, 200 ml of a 3: 1 mixture of water and brine and 200 ml of brine and dried over anhydrous sodium sulfate. Most of the solvent was removed under reduced pressure and the residue was filtered through 50 g of silica gel eluting with 250 ml of ethyl acetate to give 3.9 g of product of the formula XXIV: 3-oxo-7K-tetrahydropyranyl-2-yloxy- -3'-tetrahydropyran-2-yl-trans-1'-octenyl7bicyclo3,3, Q] -oct-1-ene. The crude product was chromatographed on 300 g of silica gel eluting with a 60:40 mixture of hexane and ethyl acetate to give 2.39 g of pure product. Thin layer chromatography using silica gel showed an Rf value of 0.22 in a 60:40 mixture of hexane and ethyl acetate. NMR absorption bands were observed at 5.18-5.86 (m) and 5.94 (broad singlet) ¿. IR absorption bands were observed at 1710 and 1632 if ”.

By applying the procedure of Example 1 but using different 3K, S-hydroxy-2-substituted-1-cyclopentaneacetic acid lactones of formula XXI, each of the various corresponding products of formula XXIV is prepared in which n is one.

Furthermore, by applying the method of Example 1 but using each of the various 3%, β-dihydroxy-2-substituted-β-cyclopentanepropionic acid, the β-lactones of formula XXI can obtain each of the various compounds of formula XXIV, in which n is two.

Furthermore, by applying the procedure of Example 1 but using each of the various 5-hydroxy-2-substituted-1G-cyclopentanalkanoic acid lactones of formula XXI, one can obtain each of the various compounds of formula XXIV in which R18 is - draws hydrogen. Finally, by applying the procedure of Example 1 but using each of the various α-hydroxymethyl-hydroxy-2-substituted-cyclopentanalkanoic acid lactones of formula XXI, each of the various compounds of formula XXIV, in which R18 represents -CH2OR10.

Example 2 3-Oxo-HM-tetrahydropyran-2-yloxy-WO 3'S) -3'-tetrahydropyran-2-yl-oxy-trans-1'-octenyl] bicyclo [3,3-zonon-1-ene '(Formula XXIV: B18, Y1, M6 and R7 defined as in Example 1 and n are the integer 2) See Reaction Scheme A.

A. A solution of 2.05 ml (18.9 mmol) of dimethylmethylphosphonate and 100 ml of dry tetrahydrofuran was stirred at -78 ° C under a nitrogen atmosphere and treated dropwise with 11.8 ml (18.9 mmol) of 1.6 molar n -butyllithium in hexane. After stirring for 30 min. at -78 ° C, the resulting mixture was treated dropwise over 25 minutes. with 4.25 g of 3W, 5M-dihydroxy-go (Bhydrohydroxytrans-1-octenyl) -1d-cyclopentane-propionic acid, β-lactone, 11,15-bis (tetrahydropyranyl ether) in 30 ml of dry tetrahydrofuran. The resulting mixture was then stirred for 1 hour at 78 ° C. The solution was then stirred at room temperature for 2 hours and added with 1.2 ml of acetic acid. The mixture was then added to 250 ml of brine and 200 ml of diethyl ether. The aqueous layer and the organic layer were separated and the aqueous layer was extracted twice with diethyl ether. The ether extracts were then washed with brine, dried over anhydrous sodium sulfate and concentrated to 5.6 g of crude compound of formula XXII as an oil: 3- (dimethyl-phosphonomethyl) -3-hydroxy-2-oxa-8K -tetra-hydropyran-2-yl-oxy-β [13'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl-7-bicyclo [α, 3,0] nonane. Chromatography on silica gel eluting with a 4: 1 mixture of ethyl acetate and acetone gave 4.1 g of a purified product of formula XXII. Characteristic NMR absorption bands were observed at 5.15-5.65 (multiplet) δ. Thin layer chromatography with silica gel gave an Rf value of 0.34 in a 4: 1 mixture of ethyl acetate and acetone. Characteristic IR absorption bands were observed at aaso, 1235 and 1030 cmq.

B. A suspension of 3.42 g of chromium trioxide and 80 ml of methylene chloride was treated with 5.8 ml of pyridine, stirred at room temperature under a nitrogen atmosphere for 30 minutes. and combined with 3 tablespoons of dry diatomaceous earth. The resulting mixture was then treated with 3.25 g of the reaction product in Part A and 8 ml of dry dichloromethane, stirred for 30 minutes. at room temperature under nitrogen, filtered through 30 g of silica gel (eluting with 200 ml of ethyl acetate and acetone 2: 1) and concentrated under reduced pressure. The residue (3.73 g) was chromatographed on 120 g of silica gel and eluted with ethyl acetate and acetone in a ratio of 4: 1 to give 2.07 g of product of the formula XXIII: 2-decarboxy-5-despropyl-6-dimethylphosphonomethyl- 5-keto-PGE1, 11,15-bis (tetrahydropyranyl ether). Characteristic IR absorption bands were observed at 1740 and 1715 cm-1.

Characteristic NMR absorption bands were observed at 3.1 (doublet, J = 23 Hz) and 3.8 (doubled, J = 11 Hz) à.

C. A suspension of 12 mg of 50% sodium hydride in mineral oil and 3 ml of diglyme was stirred at 0 ° C in an argon atmosphere. The suspension was then treated with 150 ml of the product in Part B in 3 ml of diglyme. After 1 hour, the cooling bath was removed and the resulting solution was stirred at room temperature under argon. After a total of 20 hours from the addition of the reactant of formula XXIII, the resulting solution was then added to 30 ml of water and extracted with 90 ml of diethyl ether. The ether extract was washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg) and subjected to chromatography on 10 g of silica gel eluting with hexane and ethyl acetate (1: 1). There was thus obtained 15 mg of the compound of formula XXIV: 3-oxo-8M-tetrahydropyran-2-yloxy-δ [ε3'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl] - 453 594 26 -bicyclo [2.3, Q] -non-1-ene. NMR absorption bands were observed at 4.7 (broad singlet) and 5.3-6.0 (multiplet) ¿. IR absorption band was observed at 1670 cm -1.

Alternatively, the compound of formula XXIV was prepared as follows: A solution of 150 mg of the product in Part B and 5 ml of dry tetrahydrofuran was treated at 0 ° C in an argon atmosphere dropwise with 0.5 ml of 0.52 M potassium hydride and 18-Crown. -6-ether (Aldrich Chemical Co. Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee, Wisconsin, p. 133; Pedersen, JC, JACS 92: 386 (1970) in tetrahydrofuran (prepared from 800 mg of potassium hydride and 1, 0 g of 18-Crown-6-ether in 8.7 ml of dry tetrahydrofuran) After stirring for 1 hour at 0 ° C under an argon atmosphere, the mixture was added to 30 ml of water, extracted with 90 mg of diethyl ether and the ether extract was washed with brine. was dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to chromatography on 9 g of silica gel eluting with ethyl acetate and hexane to give a product of formula XXIV (40 mg) Thin layer chromatography on silica gel showed an Rf value of 0.30 in ethyl acetate and hexane (1: 1).

Example 3 γ6-Methyl-3-oxo-7d-tetrahydropyran-2-yl-oxyda - [(3'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl] -cycloea, 3, QZ -Octane (Formula XXV: R18, Y1, M6, n, L1 and R7 defined as in Example 1, R16 is hydrogen and R37 is methyl) See Reaction Scheme A.

A suspension of 2.70 g of anhydrous copper iodide was stirred in 100 ml of anhydrous diethyl ether at -20 ° C under an argon atmosphere and treated dropwise with 20.0 ml of 1.4 M methyl lithium in ether. The resulting solution was then stirred for 15 minutes at -20 ° C and treated for 2.5 hours at -ZOOC with a solution of 2.00 g of the title product of Example 1 in 100 ml of anhydrous diethyl ether. Stirring was continued for an additional 1.5 hours at -20 ° C and the resulting mixture was added to 200 ml of 1 M anhydrous ammonium chloride. The aqueous layer and the organic layer were separated and the aqueous layer was extracted with diethyl ether (400 ml). The combined organic extracts were then washed with brine (200 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 2.4 g of the title product as a pale green oil.

Chromatography on 25 g of silica gel eluting with hexane in ethyl acetate (3: 1) gave 2.0 g of the title product as a colorless oil. Characteristic NMR absorption bands (CDCl 3) were observed at 1.19, 3.20-4.43, 4.70 and 5.2-5.9 Å. Characteristic IR absorption bands were observed at 1745, 1665, 1200, 1130. 1110, 1075, 1035, 1020, 980 and 870 cm-1. Thin layer chromatography on silica gel showed an Rf value of 0.26 in ethyl acetate and hexane (1: 3).

By known methods, each of the various novel intermediates of formula XXV could be transferred to a ¶ß-methyl-CBA2 or CBA1 compound using the methods exemplified below or known from British Laid-Open Publications 2,013,661, 2 014 143 and 2 017 699.

Example 4 5-Carboxypentanol, t-butyldimethylsilyl ether A solution of 4 g of sodium hydroxide in 100 ml of methanol and water (4: 1) was treated with 10 ml of caprolactone and stirred at room temperature under a nitrogen atmosphere. After 20 hours, the solvent was evaporated and toluene was added to give 15 g of solid, crude 5-carboxypentanol.

The resulting solid was suspended in 300 ml of dimethylformamide under a nitrogen atmosphere, cooled to 0 ° C, treated with 35 g of imidazole, stirred for 15 minutes. at 0 ° C and 15 min. at room temperature, cooled to 0 ° C and treated with 39 g of t-butyldimethylsilyl chloride.

The resulting solution was then allowed to warm to room temperature under a nitrogen atmosphere. After 26 hours, the resulting solution was treated with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol with continued stirring under a nitrogen atmosphere. After 13 hours, the suspension was acidified to pH 4 with 500 ml of 1 N hydrogen chloride solution, then saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate extracts were then washed with 1 M sodium hydroxide solution. The basic extracts were then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine and extracted with ethyl acetate. The ethyl acetate extracts were then washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 22.6 g of a yellow liquid, 5-carboxypentanol, t-butyldimethylsilyl ether. Chromatography on 800 g of silica gel eluting with ethyl acetate and hexane (1: 9 to 1: 1) gave 14.8 g of S-carboxypentanol, t-butyldimethylsilyl ether. MR absorption band was observed at 0.05 (singlet) and 0.90 (singlet) δ. IR absorption band was observed at 3000 (wide) and 1700 cm *.

By applying the procedure of Example 4 but using other lactones corresponding to the 60-carboxyalkanol compounds of formula XXXII, each of the different products of formula XXXII was prepared.

Example 5 2-Decarboxy-2- (t-butyldimethylsilyloxy) methyl-5-carboxy-6-hydroxy-1β-methyl-CBA1, 11,15-bis (tetrahydropyran) ether (Formula XXXIII: R28 is t-butyldimethylsilyl, Z 2 is - (CH 2) 3 -, n is 1 and 1116, E 18, 1137, M 6, L 1 and R 4 are defined as in Example 3) See Reaction Scheme B.

A solution of 0.58 ml of dry diisopropylamine and 20 ml of dry tetrahydrofuran at 0 ° C under an argon atmosphere was treated with 2.6 ml of 1.56 M n-butyllithium in hexane, stirred for 5-10 minutes. at 0 ° C, treated with 0.50 g of the title product of Example 4 in 5 ml of tetrahydrofuran, stirred for 15 minutes. at 0 ° C and for 1 hour at room temperature, cooled to 0 ° C, treated with 0.91 g of the title product of Example 3 in 5 ml of tetrahydrofuran and allowed to slowly warm to room temperature in an argon atmosphere. Then 130 ml of water and 20 ml of brine were added and the mixture was extracted with diethyl ether. The ether extracts were washed with 4 ml of 1 N hydrochloric acid and 150 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the title product.

Applying the procedure of Example 5 but using various other compounds of formula XXXI described after Example 1, each of the various compounds of formula XXXIII was prepared, wherein R 28 represented t-butyldimethylsilyl and Z 2 represented - (CH 2) 3 - .

Example 6 2-Decarboxy-2- (t-butyldimethylsilyloxy) methyl-Qb-methyl-CBA -bis (tetrahydropyranyl ether) 2, 11,15- (Formula XXXIV: R28, Zz. N, R18, Y1, M6, L1 and R7 defined as in Examples 1 and 5) 453 594 29 The reaction product from Example 5 (1.37 g) and 16 ml of methylene chloride were treated with 2.9 ml of dimethylformamide-dineopentyl acetal, stirred for 3 hours at room temperature in a nitrogen atmosphere, added to 160 ml ice water and 40 ml of brine and extracted with diethyl ether. The ether extracts were then washed with 150 ml of sodium bicarbonate and 150 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude title product. Chromatography on 100 g of silica gel eluting with 10% ethyl acetate in hexane gave the pure title product.

By applying the procedure of Example 6 but using various other compounds of formula XXXIII described after Example 5, each of the various products corresponding to formula XXXIV was prepared, wherein R28 represented t-butyldimethylsilyl and Z2 represented - (CH2) 3 - Example 2-Decarboxy-2-hydroxymethyl-gß-methyl-CBA2, 11,15-bis (tetrahydropyranyl) ether (Formula XXXV: Z2, n, R16, R37, R18, Y1, M6, L1 and R7 defined as in Examples 1 and 5) See Reaction Scheme B.

A solution of 0.71 g of the title product of Example 6 and 16 ml of dry tetrahydrofuran was treated at 0 DEG C. under a nitrogen atmosphere with 3.2 ml of 0.75 molar of tetra-n-butylammonium fluoride and tetrahydrofuran. When the reaction mixture was allowed to slowly warm to room temperature overnight with stirring, 1150 ml of brine was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extracts were then washed with 0.5 N potassium bisulfate solution, 100 ml of sodium bicarbonate and 100 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude title product. After filtration through 25 g of silica gel with 200 ml of ethyl acetate and hexane, 0.61 g of further purified product was obtained. Chromatography on silica gel eluting with 35% ethyl acetate in hexane gave the pure title product.

By applying the procedure of Example 7 but using various other compounds of formula XXXIV described in and after Example 6 'free (5E) and (52) acids (Formula LXXXIII) 453 594 were prepared each of the different compounds of formula XXXV, wherein Z2 represented - (CH2) 3-.

By applying the procedure of Examples 5, 6 and 7 and using different starting materials described in and after these examples and each of the different compounds of formula XXXII described in and after Example 4, each of the different compounds was prepared for the units of formula XXXV.

Example 8 2-Decarboxy-2-hydroxymethyl-36-methyl-CBA2 (Formula XXXVI: X1 is -CH 2 OH, Z 2 is - (CH 2) 3 -, R 8 is hydroxy, Y 1 is trans-CH = CH-, M 1 is O Ol-Izß-H, L.) is fl- Hz / QH and E., is n-butyl) See Reaction Scheme B.

The title product of Example 7 (0.25 g) was combined with 9 ml of acetic acid, water and tetrahydrofuran (6: 3: 1) and heated to 37-40 ° C for 2 hours. Then the resulting mixture was cooled and extracted with diethyl ether. The ether extracts were then washed with brine, dried over sodium sulfate and concentrated to give the crude title product. After chromatography on silica gel, the pure title product was obtained.

By applying the procedure of Example 7 but using each of the other primary alcohols of formula XXXV described in and after Example 7, each of the different products of formula XXXVI was prepared, wherein X1 was -CH 2 OH.

Example 9% - methyl-CBA2, methyl ester, 11,15-bis (tetrahydropyranyl ether) (Formula LXXXIV: R16 is hydrogen, R37 is methyl, Z2 is - (CH2) 3- and R18, Y1, M6, L1 and R7 defined as in Example 3) and the corresponding See Reaction Scheme G.

A. A suspension of 57% sodium hydride in mineral oil (1.90 g) was washed with hexane and treated with 130 ml of dry dimethyl sulfoxide (DMSO). The resulting suspension was heated at GSOC for 1 hour under a nitrogen atmosphere and the resulting solution was cooled to 15 ° C and treated dropwise over 15 minutes. with 10.0 g of 4-carboxy-butyltriphenylphosphonium bromide. The resulting orange solution was stirred for 15 minutes. at 10 ° C and then treated dropwise over 15 minutes. with a solution of 2.12 g of the title product of Example 3 in 20 ml of dry DMSO. The resulting solution was then stirred at room temperature under a nitrogen atmosphere for 60 hours, treated with 15 ml of water, stirred for 30 minutes at room temperature, added to 200 ml of ice water and 100 ml of brine, acidified with 1 N hydrochloric acid and extracted with 900 ml of diethyl ether. The ether extracts were then washed with 1 L of water and 200 mL of brine, dried over sodium sulfate and concentrated under reduced pressure to give 4.8 g of a yellow oil constituting the carboxylic acid of formula LXXXIII.

B. The product of formula LXXXIII and 42 ml of diisopropylethylamine in 120 ml of acetonitrile were treated at 10 ° C in a nitrogen atmosphere with 15 ml of methyl iodide and allowed to slowly warm to room temperature. The resulting suspension was then stirred for 16 hours, treated with 3.0 ml of methyl iodide, stirred for a further 2 hours, added to 500 ml of brine and extracted with 1 l of ethyl acetate. The organic extracts were then washed with 250 ml of 0.5 N potassium bisulfate, 250 ml of saturated sodium bicarbonate solution, 250 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a solid residue. This was then subjected to chromatography on 500 g of silica gel eluting with 8% acetone in hexane to give 2.25 g of the title product of formula LXXXIV. NMR absorption band (CDCl 3) was observed at 0.9, 1.05, 1.08, 3.66 3.02-4.35, 4.70 and 4.958. IR absorption bands were observed at 1730, 1670, 1645, 1200, 1165, 1135, 1080, 1035, 1020, 980 and 870 cm -1.

Thin layer chromatography on silica gel showed an Rf value of 0.46 in ethyl acetate and hexane (1: 3) and a value of 0.26 in ethyl acetate and hexane (1: 6) C. Alternatively, the isomeric reaction products of formula LXXXlII were separated in Part A of the title free acids (SE) and (52) by chromatography on acid-washed silica gel eluting with 10-30% ethyl acetate in hexane.

In addition, by applying the procedure of Example 9 but using a mono-carboxytriphenylphosphonium compound of formula LXXXII, wherein Z2 represents other than - (CH2) 3, other ketones of formula LXXXI could be converted to the corresponding esters of formula LXXXIV, 453 594 wherein Z 2 is other than - (CH 2) 3 -.

Example 10 (52) -2-Decarboxy-2-hydroxymethyl-Wβ-methyl-CBA2, 11,15-bis (tetrahydropyranyl ether) (Formula LXXXVI: R16, R37, Z2, R18, M6, L1 and R7 defined as in Example 9) and its (SE) isomer (Formula LXXXVII) See Reaction Scheme G.

A suspension of 0.16 g of lithium aluminum hydride in 45 ml of dry tetrahydrofuran was treated at 0 ° C in a nitrogen atmosphere dropwise with 1.98 g of the title product of Example 9 in 15 ml of dry tetrahydrofuran. The resulting suspension was stirred for 1 hour at 0 ° C and then for 1 hour at room temperature. The resulting mixture was then cooled to 0 ° C, added with 0.16 ml of water and 0.16 ml of 15% sodium hydroxide solution. After stirring for 1 hour at room temperature, treatment with magnesium sulphate and filtration with diatomaceous earth, rinsing with diethyl ether, a mixture was obtained which was concentrated under reduced pressure. The resulting product, 0.25 g, was chromatographed on 180 g of silica gel eluting with 30% ethyl acetate in hexane to give 1.03 g of product of formula LXXXVII and 1.06 g of a product of formula LXXXVI. For the product of formula LXXXVI, NMR absorption band (CDCl 3) was observed at 0.90, 1.09, 3.2-4.4, 4.72 and 5.0-5.9¿. IR absorption bands were observed at 3470, 1760, 1200, 1135, 1120, 1075, 1035, 1020 and 980 cm-1. Thin layer chromatography on silica gel showed an Rf value of 0.29 in ethyl acetate and hexane (35:65). For the product of formula LXXXVII, MMR absorption bands (CDCl 3) were observed at 0.90, 1.05, 3.2-4.4, 4.6-4.95 and 5.05-5.97 Å. IR absorption bands were observed at 3470, 1670, 1200, 1125, 1110, 1080, 1035, 1020 and 985 cm_1. Thin layer chromatography on silica gel showed an Rf value of 0.36 in ethyl acetate and hexane (35:65).

By applying the procedure of Example 10 but using the other esters of formula LXXXIV described after Example 9, the respective primary alcohols of formula LXXXVI and LXXXVII were prepared.

Example 11 (52) -fl b-methyl-CBA2-methyl ester (Formula LXXXVIII: X1 is -COOCH3, R8 is hydroxy, M1 is M-OH: /} H and R16, R17, L1, R7, Y1 and Zz are defined as in Example 10) 453 594 33 See Reaction Scheme G.

A. A solution of the title product of Example 10 of formula LXXXVI in 38 ml of acetone was treated at -20 ° C under a nitrogen atmosphere for 5 minutes. with 1.9 ml of Jones reagent (prepared by dissolving 133.6 g of chromium trioxide in 115 ml of concentrated sulfuric acid and diluting with water to a volume of 500 ml) was stirred for 2 hours at -20 ° C, was added with 2.3 ml isopropanol, stirred for 40 minutes. at -20 ° C, diluted with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 600 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give 1.01 g of carboxylic acid corresponding to the primary alcohol with formula LXXXVI as a pale green oil.

B. A solution of the product of Part A in 11 ml of acetonitrile was treated at 15 ° C in a nitrogen atmosphere with 4.1 ml of diisopropylethylamine and 1.5 ml of methyl iodide. The resulting suspension was then stirred at room temperature for 17 hours, treated with 0.3 ml of methyl iodide, stirred for 2 hours at room temperature, diluted with 50 ml of brine, extracted with 100 ml of ethyl acetate, washed with 50 ml of 5 M potassium bisulfate, 50 ml of sodium bicarbonate solution and 50 ml of saline, were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.02 g of the methyl ester corresponding to the carboxylic acid product of Part A.

C. A solution of the product from Part B in 56 ml of a mixture of tetrahydrofuran, water and acetic acid (1: 2: 4) was heated to 45 ° C in a nitrogen atmosphere for 3 hours, cooled, diluted with 200 ml of brine and extracted. with 400 ml of diethyl acetate. The organic extracts were then washed with 600 ml of saturated sodium bicarbonate solution and 400 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.9 g of crude product of the title compound as a yellow oil. Chromatography on 100 g of silica gel eluting with hexane and ethyl acetate (3: 7) gave 0.39 g of pure product as a colorless oil. NMR absorption band (CDCl 3) was observed at 0.89, 1.08, 3.5 ~ 4.35, 3.66 and 5.0-5.7 Å. IR absorption band was observed at 3360, 1740, 1670. 1455, 1435, 1370, 1240, 1225, 1195, 1170, 1075, 1020 and 970 cm_1. Thin layer chromatography on silica gel gave an Rf value of 0.22 in ethyl acetate and hexane (7: 3). Using the procedure of Example 11 but using the other compounds of formula LXXXVI described after Example 10, each of the various% ß-methyl-CBA2 compounds of formula LXXXVIII was prepared, wherein X1 represents - COOR1.

Example 12 (SE) -Qβ-methyl-CBA2, methyl ester (Formula LXXXIX: R16, R17, X1, Z those as in Example 11) 2, R8, _B1, M1, L1 and R7 define- See Reaction Scheme G.

A. Applying the procedure of Example 11, Part A, 0.60 g of the product of Example 10 of formula LXXXVII was converted to the carboxylic acid corresponding to the primary alcohol of formula LXXXVII in the form of 0.65 g of a green oil. A B. By applying the procedure of Example 11, Part B, the product of Part A above (0.66 g) was converted to the methyl ester corresponding to the carboxylic acid product of Part A in the form of 0.58 g of a yellow oil.

C. By applying the procedure of Example 11, Part C, the product in Part B above (0.58 g) was transferred to 0.25 g of the title product as a colorless oil. NMR absorption band (CDCl 3) was observed at 0.90, 1.05, 3.30, 3.66, 3.75-4.25 and 5.0-5.7 ¿. IR absorption bands were observed at 3360, 1740, 1670, 1455, 1435, 1250, 1225, 1195, 1170, 1075, 1020 and 970 cm-1. Thin layer chromatography on silica gel gave an Rf value of 0.22 in ethyl acetate and hexane (3: 7).

By applying the procedure of Example 12 but using other compounds of formula LXXXVII described after Example 10, each of the various products of formula LXXXIX was prepared, wherein X1 represents -COOHCH3.

Example 33 - (5Z) -Qβ-methyl-CBA2 A solution of 0.28 g of the title product of Example 11 in 8 ml of methanol was stirred at room temperature under a nitrogen atmosphere and treated with 1 ml of 8 M sodium hydroxide solution. The resulting yellow solution was then stirred for 5 hours at room temperature in a nitrogen atmosphere, diluted with 90 ml of ice and brine, acidified to pH 2 with 1 N hydrochloric acid, extracted with 360 ml of ethyl acetate, 453 594 ss washed with 120 ml of brine. was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.25 g of the crude title product. Chromatography on 30 g of silica gel eluting with the A-IX solvent system (the organic phase of an equilibrium mixture of ethyl acetate, acetic acid, cyclohexane and water, 9: 2: 5: 10) gave 0.235 g of the pure title compound. the product as a colorless oil. NMR absorption band (CDCl 3) was observed via 0.89, 1, os, 3.5-4.35, s, o-5.1 and s, os, 1n absorption band was observed at 3340, 2660, 1710, 1240, 1205, 1175, 1130, 1075, 1055, 1020 and 970 cm -1. Thin layer chromatography on silica gel showed an Rf value of 0.25 in the A-IX solvent system.

By applying the procedure of Example 13, other methyl esters prepared according to Example 11 were converted to the corresponding carboxylic acid.

Example 14 (sz) -36-methyl-cBA2 By applying the procedure of Example 13, 0.25 g of the title product of Example 12 was converted to 0.21 g of the title product as a colorless oil. NMR absorption band (CDCl 3) was observed at 0.90, 1.06, 3.5-4.3, 5.0-5.7 and 5.935. IR absorption bands were observed at 3340, 2660, 1710, 13øo, 1240, 1175, 113o, 1075, 1oss_1020 and -97o cm -1. value of 0.27 in the A-IX solvent system.

Thin layer chromatography on silica gel showed an Rf- other carboxylic acids corresponding to the compounds of formula LXXXVIII and LXXXIX, where X1 was designated -COOH-, could be prepared from corresponding reaction products of formula LXXXIII by acid hydrolysis of the tetrahydropyran-C ¿] 5Z) reaction products LXXXIII in Example 9, part C, switched to the product of formula LXXXVIII and (SE) reaction products LXXXIII in Example 9, part C, switched to products of formula LXXXI§f By applying the procedure in Example 14 but using other methyl esters of formula LXXXIX described after Example 12, the other corresponding carboxylic acids were prepared.

Example 15 26+ (t-butyldimethylsilyloxymethyl) -α-methyl-7-oxo-3d-tetrahydropyran-2-yl-oxy-bicyclo [B, 3, Q] -octane 453 594 36 (Formula LXII: 1) , R hydropyranyloxy) 31 is t-butyldimethylsilyl and R 38 is tetra- See Reaction Scheme E.

A. A solution of 40.6 g of 3Å-benzooyloxy-5K-hydroxy-β-6-hydroxy-methyl-Ä- -cyclopentaneacetic acid, α-lactone in 250 ml of dimethylformamide was treated with stirring at 0 ° C in a nitrogen atmosphere with 25 g imidazole in 28 g of t-butyldimethylsilyl chloride. The resulting solution was then stirred for 67 hours at room temperature, added to 500 ml of water, extracted with three 500 ml portions of diethyl ether, washed with 500 ml of 10% aqueous potassium bisulfate solution, 500 ml of sodium bicarbonate solution and 500 ml of brine. was dried over sodium sulfate and concentrated under reduced pressure to give 59.9 g of 30% -benzoyloxy-fl-hydroxy-ÅR »(t-butyldimethylsilyloxymethyl) -α-cyclopentaneacetic acid, du-lactone as a white solid. NMR absorption band (CDCl 3) could be observed at 0.06, 0.91, 2.1-3.12, 3.74, 4.94-5.54, 7.24-7.67 and 7.9 -8.2 <$. IR absorption bands were observed at 1780, 1720, 1600, 1585, 1490, 1270, 1255, 1180, 1115, 1100, 1070, 1050, 850, 790 and 710 cm -1. Thin layer chromatography on silica gel gave an Rf value of 0.20 in ethyl acetate and hexane (1: 4).

B. A solution of 59.1 g of the reaction product from Part A and 500 ml of absolute methanol was treated with stirring at room temperature in a nitrogen atmosphere with 35 ml of a 25% solution of sodium methoxide and methanol. The resulting reaction mixture was then stirred for 90 minutes. at room temperature and added with 9.5 ml of glacial acetic acid. The methanol was removed under reduced pressure and the resulting residue was diluted with 500 ml of saturated sodium bicarbonate solution. The resulting mixture was then extracted with two 500 ml portions of ethyl acetate, washed with 300 ml of saturated sodium bicarbonate solution in 200 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 58 g of an oily substance as Crude 3d, 5M-dihydroxy-2 - ((t-butyldimethylsilyloxymethyl) -1M-cyclopentaneacetic acid, 60-lactone. This crude product was then chromatographed on 800 g of silica gel eluting with 20-75% ethyl acetate in hexane to give the pure title product as white crystals. melting point ranges 60.5 - 62%. NMR absorption bands (CDCl 3) could be observed at 0.06, 0.90, 1.7-3.0, 3.67, 3.9-4.4 and 4.7-5, ¶3Ö. Thin layer chromatography on silica gel showed an Rf value of 0.3 in 50% ethyl acetate in hexane 453 594 37 ° C. A solution of 37.3 g of the reaction product from Part B in 400 ml of methylene chloride was treated with stirring at 0 ° C under a nitrogen atmosphere of 18 ° C. ml of dihydropyran and 0.14 g of pyridine hydrochloride. The resulting solution was stirred at room temperature for 13 hours, treated with an additional 3 ml of dihydropyran and 30 mg of pyridine hydrochloride, stirred for a further 4 hours, washed with two portions of 400 ml of saturated sodium bicarbonate solution and 400 ml of brine, dried. over anhydrous sodium sulfate and concentrated under reduced pressure to give 49 g of pale yellow oil as crude Sd-hydroxy-3-tetrahydropyran-2-yloxy-26 '(t-butyldimethylsilyloxymethyl) -10% cyclopentaneacetic acid, 4) -lactone. Chromatography on 800 g of silica gel eluting with 0-75% ethyl acetate in hexane gave 37 g of pure product as a colorless oil. NMR absorption bands (CDCl 3) could be observed at 0.05, 0.90, 1.62, 2.0-3.0, 3.6, 3.2-4.4, 4.67 and 4.8 -5.2Ö. IR absorption bands could be observed at 1780, 1255, 1175, 1160, 1116, 1080, 1035, 1020, 1005, 975, 835 and 775 cm -1. Thin layer chromatography on silica gel showed an Rf value of 0.25 in hexane and ethyl acetate (2: 1).

D. A solution of 28 ml of dimethylmethylphosphonate in 800 ml of dry tetrahydrofuran was treated at -70 ° C under a nitrogen atmosphere with 160 ml of 1.56 M n-butyllithium in hexane and stirred for 30 minutes. at -70 ° C. The resulting mixture was kept at -70 ° C and then treated dropwise over 30 minutes. with 41.7 g of the reaction product from Part C in 200 ml of tetrahydrofuran. The resulting solution was then stirred at 7070 ° C for 1 hour, allowed to warm, stirred for an additional 2.5 hours at room temperature, added with 14 ml of glacial acetic acid, added to 1 liter of brine, extracted with three 700 ml portions of diethyl ether. , washed with 500 ml of brine / solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 63 g of a yellow oil as crude 6fiP (t-butyldimethylsilyloxymethyl) -3-dimethylphosphonomethyl] -3-hydroxy 2-oxa-7K-tetrahydropyranyloxyl-bicyclo [3.9] octane. Chromatography on 800 g, silica gel eluting with 50-75% ethyl acetate in hexane gave 44.2 g of the pure title product as a colorless oil. NMR absorption bands (CDCl 3) could be observed at 0.05, 0.89, 1.23-3.02, 2.2-4.37, 4.70 and 4.99¿. IR absorption bands could be observed at 3380, 1255, 1235, 1120, 1050, 1035, ace and 775 cn fl. Frunn stratum chromatography on S111 keg gave an Rf value of 0.25 in ethyl acetate. 453 594 38 E. A suspension of 29.2 g of chromium trioxide in 700 ml of methylene chloride was treated with stirring at room temperature in a nitrogen atmosphere rapidly with 50 ml of pyridine, treated with dry diatomaceous earth, stirred for 5 minutes. and then treated with 23.9 g of the title product of Part D in 60 ml of methylene chloride. The resulting suspension was then stirred for 45 minutes. at room temperature and in a nitrogen atmosphere and filtered through 300 g of silica gel eluting with 2 liters of ethyl acetate in acetone (2: 1). Concentration under reduced pressure gave 24 g of a brownish-yellow oil, in the form of crude 3βF (t-butyldimethylsilyloxymethyl) -2Ar (2'-dimethylphosphonomethyl-2'-oxoethyl) -4-tetrahydropyranyloxy-pentanone. High pressure liquid chromatography of 12 g of the crude product on silica gel eluting with 20% acetone in methylene chloride gave 4.54 g of pure product as a colorless oil. NMR absorption band (CDCl 3) could be observed at 0.05, 0.88, 2.8-4.5, 3.77 and 4.86¿. IR absorption bands could be observed at 1745, 1715, 1255, 1130. 1105, 1060, 1025, 835, 810 and 775 cm-1. Thin layer chromatography on silica gel gave an Rf value of 0.27 in 20% acetone in methylene chloride and a value of 0.3 in ethyl acetate.

F. A degassed suspension of 0.52 g of Part E reaction product, 0.15 g of anhydrous potassium carbonate and 0.50 g of 18-Crown-6-ether in 20 ml of toluene was stirred at 75 ° C for 6 hours in a nitrogen atmosphere and was then cooled to QOC. The resulting solution was then washed successively with 20 ml of brine, a solution of 15 ml of water and 5 ml of brine and with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated to give a brown residue as a crude solution. t-Butyldimethylsilyloxymethyl-7G-tetrahydropyran-2-yl-oxybicyclo [3.3.1] oct-1-en-2-one, which was filtered through 7 g of silica gel and eluted with hexane and ethyl acetate (70 ml, 1: 1). 1) to give 0.31 g of product as an oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml / min flow rate) on silica gel eluting with hexane and ethyl acetate (3: 1) gave 0.20 g of pure product as a colorless oil. NMR absorption band (CDCl 3) for the trimethylsilyl derivative could be observed at 0.06, 0.90, 1.20-3.20, 3.20-4.85 and 5.85-SJJÄ. IR absorption bands could be observed at 1710, 1630, 1250, 1130, 1115, 1075, 1030, 965, 870, 835, 810 and 775 cm-1. Thin layer chromatography on silica gel gave an Rf value of 0.34 in hexane and ethyl acetate (2: 1). 453 594 39 G. A suspension of 0.35 g of anhydrous copper iodide in 12 ml of anhydrous diethyl ether was treated at -20 ° C in an argon atmosphere dropwise with 2.0 ml of 1.4 M methyllithium. The resulting solution was then stirred at -20 ° C for 15 minutes, treated at -20 ° C dropwise over 1.5 hours with a solution of 0.22 g of the reaction product from Part F in 12 ml of anhydrous diethyl ether. The resulting suspension was then stirred at -20 ° C for 2 hours, added to 50 ml of 1 M ammonium chloride, extracted with 150 ml of diethyl ether, washed with 50 ml of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.23 g of the crude title product as a pale yellow oil. Chromatography on 30 g of silica gel eluting with ethyl acetate and hexane (1: 4) gave 0.22 g of the pure title product as a colorless oil. NMR absorption band (CDCl 3) was observed at 0.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4 and 4.63 ° C. IR absorption bands were observed at 1745, 1255, 1135, 1110, 1095, 1075, 1035, 1020, 835 and 775 cm-1. Thin layer chromatography on silica gel gave an Rf value of 0.32 in ethyl acetate and hexane (1: 4).

Example 16 N-methyl- (1-fluoro-5-tetrahydropyranyloxypentyl) -phenylsulfoximine (Formula XCII: Z 2 is - (CH 2) 3 and R 10 is tetrahydropyranyl) See Reaction Scheme H.

Diisopropylamine (0.59 g) was dissolved in 21 ml of tetrahydrofuran and the resulting mixture was cooled to -78 ° C with stirring in an argon atmosphere. Then triphenylmethane was added for use as an indicator and a solution of n-butyllithium and hexane was added dropwise until the resulting mixture turned light brown. After stirring for another 75 minutes. the resulting mixture was treated with 1.50 g of N-methyl- (5-tetrahydropyranyloxypentyl) -phenylsulfoximine dissolved in 6 ml of dry tetrahydrofuran. The resulting mixture was then stirred for an additional 30 minutes. at -78 ° C. Then an excess of perchloryl fluoride (FC103) was bubbled through the solution for 4-5 minutes, during which time an argon flow was also bubbled through the mixture for safety reasons. The resulting mixture was then stirred for an additional 90 minutes. at -78 ° C and then the reaction mixture was added with 5% sodium bicarbonate solution. After adjusting the reaction mixture to room temperature, the mixture was diluted with an additional 5% sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.64 g of a yellow oil. Chromatography on silica gel columns in series and eluting with ethyl acetate and hexane (1: 1) gave 0.18 g of the title product of formula XCII as a mixture of diastereomers. Thin layer chromatography on silica gel gave an Rf value in ethyl acetate and hexane (1: 1) of 0.54 (the less polar isomer) and 0.45 (the more polar isomer). NMR absorption band (CDCl 3) for the less polar isomer was found at 1.2-2.15, 3.65, 3.68, 3.1-4.1, 4.4-4.8, 5.5 and 7.4-8.1Å. NMR absorption band (CDCl 3) for the more polar isomer was found at 1.15-2.20, 3.63, 3.1-4.1, 4.4s-4, ss, 5.27 and 7,4-a , 1¿.

By applying the procedure of Example 16 but using other phenylsulfoxamines of formula XCI, other fluorinated phenylsulfoxamines of formula XCII were prepared.

Example 17 5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2, 1,11,15-tris (tetrahydropyranyl ether) (Formula XCIV: R16 and R17 are both hydrogen, R10 is tetrahydropyranyl, Z2 is - (CH2) 3-, n is 1, R18 is tetrahydropyranyloxy, Y1 is trans- -CH = CH -, M6 is drtetrahydropyranyloxy96 hydrogen, R3 and R4 in the L1 moiety are both hydrogen and R7 is n-butyl) See Reaction Scheme H.

Diisopropylamine (164 mg) and triphenylmethane (1.5 mg) were dissolved in 4 ml of dry tetrahydrofuran and the resulting solution was cooled to -7B ° C under a nitrogen atmosphere. A solution of n-butyllithium and hexane was added until a pale light brown color was obtained. This solution was then stirred for another 80 minutes. Then 0.488 g of the title product of Example 16 in 4 ml of dry tetrahydrofuran was added dropwise.

Then the reaction mixture was reacted with 608 mg of 7-oxo-3-tetrahydropyran-2-yl-oxy-lo-Ål3'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl7bicyclo [§, 3, Q] octane (Formula XCIII: R16, R17, n, R18, Y1, M6, L1 and R7 are defined as in the title product) in 4 ml of tetrahydrofuran. After 4 min. the resulting mixture was added with saturated ammonium chloride solution, and ethyl acetate was then added to the reaction mixture, which was kept at -78 ° C. The resulting mixture was then allowed to warm until solids separated. Then additional ethyl acetate was added and the reaction mixture was extracted with brine. The ethyl acetate layer was then dried over sodium sulfate and concentrated under reduced pressure.

Aluminum amalgam was then prepared by reacting 0.31 g of 20 mesh aluminum with 2.5 ml of mercury chloride and subsequent washing with ethyl acetate and diethyl ether. The residue from the ethyl acetate layer (described in the previous paragraph) was dissolved in 5 ml of tetrahydrofuran and the solution was cooled to 0 ° C. This cooled solution was then treated with aluminum amalgam, 2 ml of water and 1 ml of glacial acetic acid. The resulting mixture was then stirred for 2 hours at 0 ° C and for 16 hours at 20 ° C. The reaction mixture was then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer was washed with 5% sodium bicarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 0.96 g as an oily residue. By chromatography on 100 g of silica gel eluting with 500 ml of 15% ethyl acetate in mixed hexanes, 500 ml of 25% ethyl acetate in mixed hexanes, 300 ml of 50% ethyl acetate in mixed hexanes and 800 ml of 50% acetone in methylene chloride, taken in 20 ml fractions, a less polar isomer in fractions 22-26 (80 mg) and a more polar isomer in fractions 30- 36 (74 mg) were obtained. These isomers represented the C-5 diastereoisomers of the product of formula XCIV. For the less polar isomer, NMR absorption band (CDCl 3) could be observed at 0.65-2.65, 3.15-4.15, 4.35-4.75 and 5.25-5.75a. For the more polar isomer, NMR absorption band (CDCl 3) could be observed at 0.6-2.65, 3.10-4.15, 4.40-4.7 and 5.2-5j7¿. Thin layer chromatography on silica gel gave an Rf value for the less polar isomer of 0.66 and for the more polar isomer of 0.57 in ethyl acetate and mixed hexanes (3: 7).

By applying the procedure of Example 17 but using other ketones of formula XCIII, each of the other intermediates of formula XCIV was obtained, wherein Z 2 represented - (C fl zfg-.

By applying the procedure of Example 17 but replacing each of the different fluorinated phenylsulfoximines described in Example 16, each of the different ketones of formula XCII was prepared from the different ketones of formula XCII, wherein Z - (CH2) 3-. Example 18 5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2 (more polar isomer) (Formula XCV: R16, R17, 22, n, RB, M1, L1 and R7 were defined as in Example 12) See Reaction Scheme HRS.

The title product of Example 17 (74 mg) was dissolved in 2 ml of a mixture of tetrahydrofuran, water and glacial acetic acid (2: 2: 1) and the resulting mixture was stirred under a nitrogen atmosphere. The reaction mixture was kept at room temperature for 17 hours, then at 40 ° C for 7 hours and finally at 23 ° C for a further 24 hours. The resulting mixture was then diluted with ethyl acetate, washed with 5% sodium bicarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 52 mg of crude title product. Chromatography on silica gel eluting with acetone and methylene chloride (60:40) gave 19 mg of the pure title product. NMR absorption band (CDCl 3) could be observed at 0.1 e-2, so, 2, so-3.3o, 3.3o-4.1s one s, 1-s, 9¿. 13 C-NMR ataerption pathway (cnc131 could be observed at 135.8, 133.0, 117.5 (d J = 18 Hz), 77.4.73.3, 62.6, 57.6, 41.1, 38.0, 37.2, 36.2 (d J = 5 Hz), 31.9, 31.8, 31.2, 29.5 (d J = 29 Hz), 25.2, 22.5 and Thin layer chromatography on silica gel showed an Rf value of 0.280 in acetone and methylene chloride (1: 1).

Example 19 5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2 (less polar isomer) By applying the procedure of Example 18, 85 mg of the less polar title product of Example 17 was converted to 25 mg of the pure title product. NMR absorption band (CDCl 3) could be observed at 0.5-2, s, 3.1-4.75 and s, os-s, aó. 13 c-MNR ablation bands (CDCl 3) could be observed at 137.0, 132.6, 77.0, 73.6, 62.3, 57.4, 45.5, 41.6, 36.9, 36.5, 34.4 (d J = 3.1 Hz), 32.5 (d J = 5.4 Hz), 31.8, 31.7, 29.2 (d J = 28.9 Hz ), 25.4, 22.6, 22.4 and 24.0¿.

Thin layer chromatography on silica gel gave an Rf value of 0.33 l of acetone and methylene chloride.

By applying the procedure of Examples 18 and 19 but using the other diastereomeric products described in Examples 17, 453 594 43, each of the other different diastereomers corresponding to formula XCV was prepared.

Example 20 5-Fluoro-CBA2 (more polar isomer) (Formula LXXXVI: Z2, n, R8, Y1, M1, L1 and R7 defined as in Example 18) See Reaction Scheme H.

A platinum oxide catalyst was prepared by suspending 46 mg of 85% platinum oxide in 9 ml of water and hydrogenating the resulting mixture at ambient temperature and pressure for 34 minutes. To this suspension were added 58 mg of sodium bicarbonate and 18 mg of the rubricated product of Example 18 dissolved in 2 ml of acetone. The resulting mixture was then heated to 60 ° C and oxygen was bubbled through it for 80 minutes. The reaction mixture was then filtered through diatomaceous earth and the filter cake was washed in water. The filtrate was then acidified to pH 4 with 5% sodium hydrogen sulfate solution and extracted with ethyl acetate. The organic extracts were then dried over magnesium sulfate and concentrated under reduced pressure to give 21 mg of the pure title product. NMR absorption band absorption band (CDCl 3) could be observed at 176.9, 135.5, 133.2, 118.5 (d J = 17.5 Hz), 77.7, 73.5, 57.3, 46.5 , 41.0, 38.2, 37.0, 36.2 (d J = 4.8 Hz), 32.3, 31.7, 31.1 (d J = 13.5 Hz), 28.5 (d J = 28.3 Hz), 25.2, 22.6, 21.0 and 14.0 <§. Thin layer chromatography on silica gel gave an Rf value of 0.39 in the A-IX solvent system.

Example 21 5-Fluro-CBA2 (less polar isomer) By applying the procedure of Example 20, of 24 mg of the title product of Example 19, 23 mg of the pure title product was obtained. NMR absorption band (CDCl 3) could be observed at 0, & Q, 9, 3.3-4.2 and 5.0 ~ 6.0Ö. 13 C-NMR absorption band (CDCl 3) could be observed at 176.8, 135.4, 132.9, 118.3 (d J = 18.2 Hz), 77.6, 73.4, 57.2, 46 , 3, 41.2, 37.8, 36.8, 34.6 (d J = 2.7 Hz), 32.8, 32.4, 31.7, 28.7 (d J = 28.4 Hz), 25.2, 22.6, 21.1 and 14, () Ö. Thin layer chromatography showed an Rf value of 0.50 in the A-IX solvent system.

The reaction products of Examples 20-21 were obtained as diastereomeric mixtures of the geometric isomers (SE) and (SZ). These geometric isomers are characterized here as "less polar" and "more polar" isomers based on thin layer chromatography motifs.

The isomers of these 5-fluoro-CBA2 compounds correspond to the geometric isomers (SE) and (SZ) of CBA2 itself. On the basis of the relative biological activities, the more polar 5-fluoro-CBA2 isomer gives stronger pharmacological effects and can on this basis be designated by the (52) structure, taking into account only pharmacological aspects. However, 13 C-NMR data suggest that the more polar isomer corresponds to the (SE) structure of the 5-fluoro-CBA2 compound. By applying the procedure of Examples 20-21, each of the different 5-fluoro-CBA2 diastereomers is prepared. of formula XCVI from the starting materials described in Example 19.

By further applying known procedures, each of the various 5-fluoro-CBA2 compounds described in and after Examples 19-20 could be converted to the corresponding 5-fluoro-CBA2 analogs of formula XCVII.

Example Gel 22 (52) -Ga-methyl-CBA2-adamantylamine salt The title product of Example 13 (54 mg), (5Z) -2-methyl-CBA2 in 6 ml of diethyl ether was combined with 23 mg of adamantylamine. After 10 min. a precipitate formed which was then stirred for 12 hours, decanted and concentrated under reduced pressure to give 68 mg of a solid, pure title product. Melting point range is 110-114 ° C.

Example Gel 23 (5Z) -α-methyl-CBA2, calcium salt hydrate The title product of Example 13 (0.95 g), Q6-methyl- (SZ) -CBA2, calcium oxide (0.064 g), freshly boiled water (9.2 ml) and distilled tetrahydrofuran (6 ml), combined and heated to 50 ° C in a nitrogen atmosphere with stirring for 20 minutes. The resulting mixture was then filtered, washed with tetrahydrofuran and concentrated under reduced pressure to give a residue. This was dissolved in tetrahydrofuran (10 ml) and concentrated 8 times to give a cream foam. This was then dissolved in 6 ml of tetra- a: 453,594 hydrofuran, which was dropped into anhydrous diethyl ether (95 ml). The resulting suspension was then stirred for 15 minutes. at room temperature in a nitrogen atmosphere and filtered. The filter cake was then washed with anhydrous diethyl ether and dried for 20 hours under reduced pressure at room temperature to give 0.686 g of the title product. Melting point range 101-108 ° C. After atmospheric equilibrium setting, the melting point range was 80-117 ° C. IR absorption bands were observed at 3330, 1670, 1555, 1455, 1345, 1310, 1270, 1075, 1020, 970 cm -1.

Example 24 Su-hyaroxy-δp- (sn-hyaroxy-trans-1-octenyl-tricyclo [1,3] 17-nonan-4-one, 8,3'-bis (tetrahydropyranyl ether) (Formula XXV: R18, Y1 , M6, L1, R27 and n defined as in Example 1, R16 and R37 together forming -CH2-) See Reaction Scheme A.

A. The title product of Example 1 of formula XXIV (4.0 g) and benzophenone (2 g) in 1 liter of methanol were subjected to photolysis (3500 Å lamp) for 3 hours while bubbling argon through the solution.

The methanol was then removed by concentration under reduced pressure and the residue was chromatographed on 600 g of silica gel eluting with a mixture ranging from ethyl acetate in hexane (1: 3) to 100% ethyl acetate. Compound XXVI, γb-hydroxymethyl-70F-hydroxy-α-β- (6'-hydroxy-trans-1'-octenyl) bicyclo [3.3.0] octan-3-one, 7,3'--bis (tetrahydropyranyl ether) was obtained as a white solid product (3.45 g).

After crystallization from ethyl acetate in hexane, a white solid with a melting point range of 65-70 ° C was obtained. NMR absorption band (CDCl 3) was observed at 0.89, 1.17-2.90, 2.92-4.40, 4.69 and 5.24-5.77¿.

IR absorption bands could be observed at 3420, 1730, 1200, 1125, 1110, 1070, 1040, 1020 and 970 cm -1. Thin layer chromatography on silica gel showed an Rf value of 0.29 in hexane and ethyl acetate (1: 4).

B. A solution of 0.6 g of the reaction product of Part A and 0.49 g of p-toluenesulfonyl chloride in 30 ml of pyridine was cooled to 0 DEG C. under argon for 70 hours, added to 100 ml of ice, diluted with 300 ml of water and extracted. with diethyl ether (800 ml). The ether extracts were then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure and chromatographed eluting with 50-80% hexane in ethyl acetate to give 0.49 g of the compound of formula XXVII, i.e. -oxo-7H-tetrahydropyran-2-yloxy- -gß- [Y3'S) -3'-tetrahydropyran-2-yloxy-trans-1'-octenyl7-Lß- (p-tolynesulfonyl) -oxymethyl-bicyclo [§, 3 Q] octane, as a colorless oil. NMR absorption band (CDCl 3) was observed at 0.88, 1.06-2.9, 2.45, 3.17-4.35, 4, s244, e3, 5.2-5.8, 7.37 can 7,816 IR absorption path was observed at 1740, 1600, 1360, 1200, 1190, 1175, 1130, 1110, 1075, 1035, 1020, 970 and 820 cm -1. Thin layer chromatography on silica gel showed Rf values at 0.45 or 0.26 in ethyl acetate and hexane (1: 1 or 1: 2).

C. A degassed solution of 0.49 g of the reaction product from Part B and 1 ml of t-butanol in 50 ml of dry tetrahydrofuran was treated at 0 ° C in an argon atmosphere with 0.8 ml of 1.7 M potassium t-butoxide in tetrahydrofuran.

After 5 min. the temperature of the reaction mixture was allowed to rise and the resulting brown solution was stirred for 3 hours at room temperature. Then 90 ml of brine was added and the mixture was extracted with 270 ml of ethyl acetate. The ethyl acetate extracts were then washed with 100 ml of saturated sodium bicarbonate solution, 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain 0.37 g of a brown oil and subjected to chromatography on 40 g of silica gel eluting with hexane and ethyl acetate. (2: 1) to obtain 0.32 g of the pure rubricated product of formula XXV as a colorless oil.

D. Alternatively, a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 g of trimethyloxosulfonium iodide was treated dropwise under a nitrogen atmosphere with 6 ml of dimethyl sulfoxide. The resulting gray slurry was then stirred at room temperature for 20 minutes, treated with 2.03 g of the title product of Example 1 in 4 ml of dry dimethyl sulfoxide and stirred for 2 hours at room temperature.

Stirring was then continued for 1 hour at 50 ° C, the reaction mixture was allowed to cool and diluted with 200 ml of water and then extracted with 3 portions of 100 ml of diethyl ether. The combined ether extracts were then washed with 200 ml of water, with 100 ml of brine and dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain a brown oil and subjected to chromatography on 250 g of silica gel eluting with ethyl acetate and hexane (1: 1). 2) to obtain 453 mg of the pure classified product. 453 594 47 E. For the title product prepared according to C or D above, NMR absorption band (CDCl 3) was observed at 0.25-2.75, 3.15-4.39, 4.68 and 5.2-5.8 ¿. IR absorption bands were observed at 1725, 1665, 1135, 100 °, 1040, 1020 and 980 cm -1.

The mass spectra program showed a molecular ion at 446 and thin layer chromatography on silica gel showed an Rf value of 0.30 in ethyl acetate and hexane.

Example 25 (5Z) - and (SE) -6a%,% metrmethano-CBA2 (Formula X: X1 is -COOH, Z1 is - (CH2) 3-, R15 is hydrogen, R16 and R17 together form methano, n is 1, R8 is hydroxy, Y1 is trans-CH = CH-, M1 is U-OHyb-H, L1 is M-Hnßr fi, R7 is n-butyl and C-5, C-6 positions are unsaturated) See Reaction Scheme G .

A. A suspension of 452 mg of 57% sodium hydride in mineral oil and 30 ml of dimethyl sulfoxide was heated to 6500 for 1 hour in a nitrogen atmosphere, then cooled to 17 ° C and treated for 15 minutes. with 2.39 g of 4-carboxybutyltriphenylphosphonium bromide. The resulting red solution was then stirred for 15 minutes. at 17-20 ° C, treated with a solution of 716 mg of the title product of Example 24, 6 ml of dry dimethyl sulfoxide, stirred for 43 hours at 40 ° C, cooled to 0 ° C and treated with 3.5 ml of water, stirred for 30 minutes. at 0 ° C, was added to 75 ml of water and brine (2: 1), acidified with 1 N hydrochloric acid and extracted with 225 ml of diethyl ether. The ether extracts were then washed with 375 ml of water and 75 ml of brine, dried over magnesium sulfate, concentrated under reduced pressure and chromatographed on 150 g of acid-washed silica gel eluting with 10-25% ethyl acetate in hexane to give 290 mg (SZ) -6q. , Β-methano-CBA2, 11,15-bis (tetrahydropyranyl ether), 70 mg (SE) -6β, α-methano-CBA2, 11,15-bis (tetrahydropyranyl ether) and 400 mg of a mixture of (5E) - and ( The 5Z) isomers of formula LXXXIII.

After chromatography of the isomeric mixture on 150 g of acid-washed silica gel, an additional 50 mg of the (5E) isomer and 180 mg of the (52) isomer were obtained.

For the (5Z) isomer, NMR absorption band (CDCl 3) was observed at 0.5-2.85, 3.22-4.4, 4.70, 4.9-5.75 and 10.16 IR absorption pathway was observed. 453 594 48 at 3600-3000 (wide band), 1740, 1710, 1240, 1210, 1135, .1080, 1035 1020, 980 and 870 cm-1. Thin layer chromatography on silica gel showed an Rf value of 0.27 in hexane, ethyl acetate and acetic acid (65: 34: 1).

For the (SE) isomer, NHR absorption bands were observed at 0.40-2.70.3.24, in 4.70, 5.0-5.8 and 6.320. IR absorption bands were observed at 3600-3000, 1740, 1710, 1460, 1445, 1200, 1135, 1075, 1035, 1020 and 982 cm-1.

Thin layer chromatography on silica gel showed an Rf value of 0.32 'in hexane, ethyl acetate and acetic acid (65: 34: 1).

'B. A solution of 446 mg of the (52) reaction product in Part A in 44 ml of acetic acid, water and tetrahydrofuran (6: 3: 2) was heated at 45 ° C in a nitrogen atmosphere for 3 hours, cooled, added to 200 ml of brine. extracted with 160 ml of ethyl acetate in hexane (3: 2), washed with 500 ml of brine, extracted with 120 ml of ethyl acetate and hexane (3: 2), dried over sodium sulfate, concentrated under reduced pressure to give 0.38 g of a yellow oil and chromatographed on 60 g of acid-washed silica gel eluting with 70% ethyl acetate in hexane to give 170 mg of pure (5Z) product as a colorless oil. NMR absorption bands could be observed at 0.5-2.90, 0.89, 4.05, 4.35-5.8 and 6.130. IR absorption bands were observed at 3360, 2260, 171fi, 1245, 1240, 1075, 1025 and 970 cm-1. The mass spectrogram of the tris-trimethylsilyl derivative showed a high resolution peak at 578,3653.-Thin layer chromatography on silica gel showed an Rf value of 0.30 in the A-IX solvent system (the organic phase of an equilibrium mixture of ethyl acetate, acetic acid and cyclohexane; 2: 5: 10).

C. By applying the procedure of Part B above, 90 mg of the (SE) reaction product of Part A was transferred to 46 mg of the title product (SE) as a colorless oil. NMR absorption bands were observed at 4.40-2.8, 0.89, 4.06 and 5.0-5.85 Å. IR absorption bands were observed at 3340, 2630, 1710, 1070 and 970 cm -1. The mass spectra program showed a high resolution peak at 578.3664. Thin layer chromatography on silica gel gave an Rf value of 0.32 in the A-IX solvent system.

By applying the procedure of Examples 22-24, other products of formula X could be prepared, wherein R16 and R17 represent methane from corresponding reactants of formula LXXXI according to Reaction Scheme G. 453 594 49 The above examples thus indicate methods for preparing each and one of the various CBA analogs of the invention of formula X.

Thus, according to the procedure described above, (SE) -% b-mecyl-cBA2 (5Z) -25-methyl-CBA2-compounds (SE) -5-fluoro-gb-methyl-CBA2-compounds (sz) -5-fluoro- g6-methyl-csA2-compounds (SE) -5-fluoro-CBA2-compounds (SZ) -5-fluoro-CBA2-compounds -compounds in the form of free acid or methyl ester having the following side chain substituents: 16-fluoro-1s, 1s-difluoro-13,14-didehydro-16-fluoro-13,14-didehydro-16,16-difluoro-13,14-didehydro-13,14-dihydro-16-fluoro-13,14-dihydro-1e) 1s-difluoro-13,14-alkyl-16,16-difluoro-13-cis-453 594 50 Formulas II III 51 Formulas (continued) R1s 21-X1 R 16.

R1 7 f:. _ C fl z fl ksz RAW. '6.

('CH2) n Rv: Yrt-C-Rv Ü | I H1 L1 453 594 VI 453 594 52 Reaction scheme A 0 / L 0 (lc fl znf \ xxx_ ncc-nv '.,, R1: M6' -1 Û I _P (ÛCHa) 2 H0 “z Q 'ÉCM" xxn Y1-C -1-C-R21 'IU | m "° L * oon | ° I (cu,) nc-ca, -P (ocH =) = XXIII Y; -c - c-Rz, I å É R1. 6 1 Û (f XX n XXIV Y1 “c '*” c'R27 I' I w "g till XXV _ till XXVI 453 594 53 Reaction Scheme A (cont.) Rf-a fi xxlv x 0.

R1G% ('cH3) n i 3 ”' 'xxv Y1-E - C-Rzv I n, f ..

R1I _ 0 Ho | (Lg fl wn Miu xxvl Y1 "C __ 'C" RZ7' I få i Ru 5 "om? (Lgcngn" = ° xxvn ° Y1 ~ c "__ c'R27 I 453 594 s4 Reaction Scheme B _ om (Link), now _ _ XXX1 K, // I Y1'c - C-Ra? 'II Rq' M6 L! 9 LiOC-CH-Z; -CH20R2a XXXII I Li HQ CH-Z; -CH; OR2; R16 (ßH fl n _ RJ, XXXIII Y, -C - C-Rzv r »å E. R18 6 1 \ / - A to to * XXXVI XXXIV from XXXI Reaction Scheme B (cont.) Va., R1 a -Åf fifl n Rs? -Í2:;: S- IZI x fifi ï 55: "cH20R2 ', Mø _ hæmm R1 ° (CH2) fl R”' ~ Y1 ~ c - cR ,, | u .MJ RSV! I R1a I RB Y1-C - C-Rgv II L1 Ms 'L1 Z2'x1, CH2) n Y1-C - C-Ry' II M1 L1 453 594 XXXIV XXXV XXXVI 453 594 Reaction Scheme E R16 R1v R16 R17 »gå é_ ä» 56 i vO CH2) n QI H38 RBS Q cnzoau s RED (CH =) n cnzoa fi _ Z1-X, CH2) n CH; OR31 LXI ILXII LXIII. z§-x1 rzwJcu fi n 'RW 453 594 57 Reaction scheme F z1 ° X1 m Ännu ..

R 'Lxxl 17' ücugonz., | Raa å \ 'Lxxn mogna -' I Ras Z; -X1 R1 6 (lcH2h1 RW Lxxm vccn? '“- II Ra Ü1 Lä <1 453 594 58 Reaktionsschema G 0 Ru C fl zín I RS? Y1' cíc ° ng_7 | § ' R1 '5 L1 Brc) | () P == CH-Z; -COOH LXXXII LXXXI \ / 22-coon R1¿ Qc fl2) n' R “7 Lxxx111 Y1'c“ “'c'R27. | | | _ R, - Measure 1.1 Z; -CÛÛCH; R1 = ~ ({(Ic | 1,) n = Rßv _ _ 'Lxxxav _ Y, -c - c-Ra,'.

I | I - 31: Ms' -1 \ / to Lxxxvzll and Lxxxxv ti11 Lxxxv 455 594 59 Reaction Scheme G (cont.) From LXXXIV zrcnzon RÉÄICÜÜ "new, 'Lxxxv 1-C - C-Rzv' I å i R1. 6 1 "° *. * - = ° 'Z = H n zz-crbou _ rue-Äng" Rv' Lxxxvl Lxxxvu '_Y1_E _'_ (': 'R27 Y1'c: "(': - R21 '. I m: M . L, u n. L, X1'Z'2 HH Z2 "x1 R-us (lCH fl n R-ns (iC flfl n 'RW Lxxxvm R” ~. Lxxxlx. Vvc-ca, i YfE-gR,' '151 f | u L RB 1 1 Ra 1 1 453 594 60 Reaction scheme H 0 I § - CH; -CH; -Z; -CH20R1 ° H; CN - XCI 0 å --- CH (F) -CH; -23 ~ CH ; ÛR10 XCII fl3 C @ _ 0 Rz 6 '_Å (, CH2) "R17 Y1“ C "' _ 'C" R; 1 III _. N .. “= L * XCIII F _ zz-cuzon RT 5 R11 XCV Y , -C - CR, IIIR 'J / M1 L1 till XCVI 453 594 61 Reaction Scheme H (cont. Snar »xçy F zfcoou, R' 5 - (c fl z) n I R fl xcvx y1 'cïc-Ry | II Ra M1 L * F z, -x1 R * 6 _ (ifï fl zh RW xcvn v, -ccR, IIR: M1 L1

Claims (2)

453 594 10 15 20 25 30 35 6: 2; Patent claims Carbacycline analog of the formula R1 cnz- (cuzyf-cnz-x R16 where Y represents -CH = CH- or -CHZCH2-, where m represents 1,2,3,4 or S, where n represents 1 or 2, where f represents o, 1,2 or a, where M1 represents u-omß-H or ß-oma-a, where L1 represents hydrogen or fluorine, where R8 represents hydrogen or hydroki, where R15 represents hydrogen or fluorine, where R16 represents hydrogen or together with R 17 a double bond or -CH 2 - and R 17 in addition hydrogen or methyl and where at least one of R 15, R 16 and R 17 has other meaning than hydrogen and where X, represents (1) - -COOR 1 where R 1 represents hydrogen or other alkyl with 1 -12 carbon atoms. (2) -cH oH 2 (3) -COL4, where L4 represents hydrogen or amino. Compound according to Claim 1, characterized in that it is selected from the group (SE) -5-fluoro-CBA2 (SZ) -5-fluoro-CBA2 (Sri) -9B-methyl-CBA2 * - (5Z) 9S-methyl-CBA2 (SE) -9B-methyl-CBA2, methyl ester and (52) -98-methyl, CBA2, calcium salt hydrate (SE) -6aB, 9B-methano-CBA2 (52) -6aB, 9B-methano -CBA2