MXPA01000507A

MXPA01000507A - 5-THIA-&ohgr;-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT

Info

Publication number: MXPA01000507A
Application number: MXPA/A/2001/000507A
Authority: MX
Inventors: Toru Maruyama; Shuichi Ohuchida
Original assignee: Ono Pharmaceutical Co Ltd
Priority date: 1998-07-15
Filing date: 2001-01-15
Publication date: 2002-05-09

Abstract

5-Thia-&ohgr;-substituted phenyl-prostaglandin E derivatives represented by general formula (I) wherein each symbol is as defined in the specification. Because of being capable of bonding strongly to PEG2receptors (in particular, the subtype EP4), the compounds represented by general formula (I) are expected as useful in preventing and/or treating immunologic diseases, asthma, bone dysplasia, nerve cell death, lung failure, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, shock, etc. Moreover, these compounds participate in sleep disorders and platelet aggregation and, therefore, are expected as useful in preventing/treating these diseases.

Description

ES $ DERIVATIVES OF FENILPROSTAGLANDI TO 5-TIA-OMEGA-REPLACED, PROCESS TO PRODUCE THEM AND DRUGS THAT CONTAIN THEM AS ACTIVE INGREDIENT FIELD OF THE INVENTION The present invention relates to 5-thia-substituted phenylprostaglandin E derivatives. More particularly, it relates to 5-thia-substituted phenylprostaglandin E derivatives of the formula (I) (where all the symbols are as they will be defined below). BACKGROUND OF THE INVENTION Prostaglandin E2 (abbreviated as PGE2) has been known as a metabolite in the arachidonate cascade. It has been known that PGE2 possesses cytoprotective activity, uterine contractile activity, a pain-inducing effect, a promoter effect on digestive peristalsis, an arousal effect, a suppressive effect on the secretion of Ref: 126586 gastric acid, hypotensive activity and diuretic activity, etcetera. In a recent study, it was found that the PGE2 receptor was divided into some subtypes that possessed different physical functions with respect to each other. So far four receptor subtypes are known and are termed EPi, EP2, EP3, EP4 (Negishi M. et al, J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)). The present inventors have studied to find the compound that can be specifically bound to each receptor, they have found that the compound of the present invention can bind strongly to the subtype EP4 receptor and thus achieved the present invention. It is thought that the EP4 subtype receptor is related to the inhibition of TNF-α production and an acceleration of IL-10 production. Therefore, compounds of the present invention that can inhibit subtype EP4 receptor binding are expected to be useful for the prevention and / or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus, etc., and rejection after organ transplants, etc.), asthma, abnormal bone formation, death of neuronal cells, pulmonary insufficiency, liver damage, acute hepatitis, nephritis, renal failure , hypertension, myocardial ischemia, systemic inflammatory response syndrome, pain due to ambush, sepsis, hematophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, heartburn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia in the dialysis, multiple organ failure and shock, etc. Furthermore, it is thought that the EP4 subtype receptor is related to sleep disorders and blood platelet aggregation, so that the compounds of the present invention are expected to be useful for the prevention and / or treatment of such diseases. The compounds of the present invention of the formula (I) bind weakly to the other receptor subtypes and do not express other effects, so that such compounds are expected to be an agent having few side effects. On the other hand, a large amount of modified prostaglandins are known in which the carbon atom in the fifth position of the PG skeleton has been replaced by a sulfur atom and whose carbon-A atoms of the chain? They have been modified. But among such prostaglandins, is there no publication describing prostaglandins having substituted or unsubstituted phenyl groups in the chain? of the PG skeleton. For example, in Japanese Patent Application Kokai Sho 58-198466, it is described that the following 5-thia-prostaglandin derivatives possess an activity of inhibiting platelet aggregation in the blood. That is, it is described that the 5-thia-prostaglandins of the formula (A) (wherein R1 is a hydrogen atom or an alkyl radical of 1 to 10 carbon atoms, R2 is an alkyl radical of 1 to 10 carbon atoms substituted or unsubstituted, or cycloalkyl of 5 to 6 carbon atoms, R3 and R4 are the same or different, and represent a hydrogen atom or a protective group) or non-toxic salts thereof, wherein R1 is a hydrogen atom, possess an activity inhibitory of platelet aggregation in the blood and a vasodilator activity, so that they are useful as agents for the treatment or prevention of thrombosis and are also hypertensive agents. In the present patent description, the following compound? -cyclopentyl is shown in Example 3, as a particular compound: DESCRIPTION OF THE INVENTION The present inventors have studied to find the stable compound that can bind specifically to the EP4 receptor and that can not bind to the other subtypes of EP receptors or other prostanoid receptors. From their results, they found that 5-thiaprostaglandins modified by introducing a substituted phenyl in the chain? of said prostaglandins, fulfill these purposes and, in this way, have achieved the present invention. As will be mentioned below, it was found that prostaglandin compounds in which the carbon atom at position 5 of the a chain of the PG skeleton is replaced by a sulfur atom and where a phenyl substituted with a functional group is introduced particular in the chain? of the PG skeleton, they can bind strongly to EP4, and bind weakly to the other prostanoid receptors, including the other receptor subtypes, and are stable. Thus, they have achieved the present invention. The present invention relates to (1) a 5-thia-substituted phenylprostaglandin E-thia derivative of the formula (I) (wherein R1 is a hydroxy radical, alkyloxy of 1 to 6 carbon atoms or NR6R7 (wherein R6 and R7, each independently, are a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms) R2 is a radical oxo, halogen or 0-COR8 (where R8 is an alkyl radical of 1 to 4 carbon atoms, phenyl or phenyl (alkyl of 1 to 4 carbon atoms)), R3 is a hydrogen atom or a hydroxy group, R4a and R4b, each independently, are an atom of hydrogen or an alkyl group of 1 to 4 carbon atoms, R5 is a phenyl group substituted with the. following substituents: i) from 1 to 3 of alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, alkynyloxy of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms (alkyloxy of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, phenyloxy-alkyl of 1 to 4 carbon atoms, phenyl-alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms- alkyl of 1 to 4 carbon atoms, thioalkenyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkynyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkylthio of 3 to 7 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms carbon (thioalkyl of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, thiophenyl-alkyl of 1 to 4 carbon atoms or phenyl-thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms carbon, ii) alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyl of 1 to 4 carbon atoms, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and halogen, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms- alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy or thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and halogen, iii) haloalkyl or hydroxy alkyl of 1 to 4 carbon atoms, or iv) alkyl of 1 to 4 carbon atoms and hydroxy; is a single bond or a double bond, provided that when R2 is 0-COR8, C8-C9 represents a double bond) or a non-toxic salt thereof or a diclodextrin clathrate thereof, (2) a process for produce them, and (3) a pharmaceutical composition comprising them as an active ingredient. DETAILED DESCRIPTION OF THE INVENTION In the formula (I), the alkyl radical of 1 to 4 carbon atoms represented by R 4a, R 4b, R 6, R 7b and R 8 and the alkyl of 1 to 4 carbon atoms in R 5 and R 8, mean methyl, ethyl, propyl, butyl radicals and isomers of the same. In formula (I), the alkyl group of 1 to 6 carbon atoms represented by R 1 means a methyl, ethyl, propyl, butyl, pentyl, hexyl group and isomers thereof. In formula (I), the alkenyl group of 2 to 4 carbon atoms in R 5 means a vinyl, propenyl, butenyl group and isomers thereof.

In formula (I) the alkynyl group of 2 to 4 carbon atoms in R 5 means an ethynyl, propynyl, butynyl group and isomers thereof. In the formula (I), the cycloalkyl group of 3 to 7 carbon atoms in R 5 means a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group. In the formula (I), the halogen group in R2 and R5 means fluorine, chlorine, bromine and iodine.

In the present invention, the symbol - ^ means a single bond or a double bond. In addition, unless otherwise specified, in this invention the symbol, means that the substituent attached to it is in front of the sheet, the symbol, means that the substituent that is attached to it is behind the sheet and the symbol or ^ means that there is a mixture of substituents on the front and back of the sheet or that the attached substituent may be opposite or behind the sheet, as would be clear to a person skilled in the art. Unless otherwise specified, all isomers are included in the present invention. For example, the terms alkyl, alkenyl, alkynyl, alkylene means straight or branched chain groups. In addition, isomers of double bonds, rings, fused rings (E-, Z-, cis-, trans- isomers), isomers generated by asymmetric carbon atoms (R-, S-, a-, and R-isomers) are also included in the present invention. , ß-, enantiomers, diastereoisomers), optically active isomers (D-, L-, d-, 1- isomers), polar compounds generated by the chromatographic separation (more polar compound, less polar compound), compounds at equilibrium, mixtures of the same in proportions at will and racemic mixtures. In the formula (I), the phenyl substituent (s) in R5 is / are preferably attached in the 3-position, the 3-position and the 4-position, or the 3-position and the 5-position. (I), each group (i) to (iv) as substituents or substituents of the phenyl in R5, means the following: group i) means 1, 2 or 3 alkyloxyalkyl groups, etc., group ii) means at least one alkyloxyalkyl group, etc. and at least one alkyl, alkyloxy, hydroxy or halogen group, group iii) means alkyl substituted with 1 or 2 halogen or hydroxy groups, and group iv) means at least one alkyl group and at least one hydroxy group. Among the compounds of the present invention of the formula (I), the compounds described in the examples, the compounds shown in the following tables and the corresponding esters and amides, are preferred.

TABLE 1 TABLE 3 [Sales] The compounds of the present invention of the formula (I) can be converted into the corresponding salts, by known methods. Non-toxic water-soluble salts are preferred. Suitable salts, for example, are the following: alkali metal salts (potassium, sodium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) -aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.). [Cyclodextrin clathrate] The compounds of the present invention of the formula (I) can be transformed into the corresponding cyclodextrin clathrates by the method described in the Japanese Patent Applications of Kokoku Sho 50-3362, 52-31404 or 61-512146, using a-, β- or β-cyclodextrin or a mixture thereof. The transformation into the corresponding cyclodextrin clathrates serves to increase the stability and water solubility of the compounds, and is therefore useful in pharmaceutical applications. [Processes for producing the compounds of the present invention] (a) The compounds of the formula (I) wherein R 1 is an alkyloxy group of 1 to 6 carbon atoms, i.e., the compounds of the formula (Ia) (wherein R >? - is an alkyloxy group of 1 to 6 carbon atoms and the other symbols are as previously defined) can be prepared from the compounds of the formula (119) (where R, 3- "1 is a hydrogen atom or a hydroxy group protected by a protecting group which is removed under acidic conditions, R10 is a hydroxy protecting group that is removed under acidic conditions, R5_1 is as defined for R5, provided that the hydroxy group in R5"1 is protected by a protective group that is removed under acidic conditions, and the other symbols are as previously defined) by the reaction for the removal of a protective group in acidic conditions . The hydroxy protecting group that is removed under acidic conditions includes, for example, t-butyldimethylsilyl, triphenylmethyl, tetrahydropyran-2-yl groups, and the like. Hydrolysis under acidic conditions can be carried out by known methods. It can be carried out, for example, in an organic solvent miscible with water (eg, tetrahydrofuran, methanol, ethanol, dimethoxyethane, acetonitrile or mixtures thereof, etc.) using an inorganic acid (eg, hydrochloric, phosphoric, hydrofluoric acid, hydrogen fluoride-pyridine, etc.) or an organic acid (eg, acetic acid, tosyl acid, trichloroacetic acid, etc.) at a temperature of from 0 to about 50 ° C. (b) The compounds of the formula (I) wherein R 1 is a hydroxy group, i.e., the compounds of the formula (Ib) (where all the symbols are as previously defined) can be prepared from the compounds of the formula (the) (where all symbols are as previously defined) by hydrogenolysis using an enzyme or by hydrogenolysis in alkaline conditions. Hydrogenolysis using an enzyme can be carried out by known methods. It can be carried out, for example, in organic solvents miscible with water (eg ethanol, dimethisulfoxide, etc.) and water, in the presence or absence of a buffer, using an enzyme for hydrogenolysis (esterase, lipase, etc.) to a temperature from 0 to about 50 ° C. Hydrogenolysis under alkaline conditions can be carried out by known methods. It can be carried out, for example, in an organic solvent miscible with water (eg ethanol, tetrahydrofuran (THF), dioxane, etc.) using an aqueous solution of an alkali (sodium hydroxide, potassium hydroxide, potassium carbonate, etc.) ) at a temperature of -10 to about 90 ° C. (c) The compounds of the formula (I) wherein R 1 is a radical NR 6 R 7, i.e. the compounds of the formula (le) (wherein all symbols are as previously defined) can be prepared by amidation of the compounds of the formula (Ib) (ib) (where all the symbols are as previously defined) with the compounds of the formula (III) HNR6R7 (III) (where all the symbols are like those previously defined). The amidation can be carried out by known methods. For example, it can be carried out in an inert organic solvent (THF, methylene chloride, benzene, acetone, acetonitrile or mixtures thereof, etc.) in the presence or absence of a tertiary amine. (dimethylaminopyridine, pyridine, triethylamine, etc.), using a condensing agent (1/3-dicyclohexylcarbodiimide (DCC), l-ethyl-3- [3- (dimethylamino) -propyl] -carbodiimide (EDC), etc.) a a temperature of 0 to about 50 ° C. The compounds of the formula (III) are known or can be prepared easily by known methods. The compounds of the formula (II) can be prepared by adhering to the following reaction schemes 1-5. In each reaction scheme, the symbols are as previously defined or are the following: t-Bu: t-butyl, Et: ethyl, Ms: methanesulfonyl, DMAP: dimethylaminopyridine, n-Bu: butyl normal, AIBN: 2.2 '-azobisisobutyronitrile, Ts: p-toluenesulfonyl, R2"1: halogen, Ac: acetyl, TMS: trimethylsilyl.

REACTION SCHEME 1 REACTION SCHEME 2 UBHlsec- ^ Hß) - TsCt REACTION SCHEME 3 HCOOH NH, Tsa halogenation REACTION SCHEME 4 silane (11-4) REACTION SCHEME 5 (l.}. Í V) ÍXV.I) (XVIII) • ixxii (XXID REACTION SCHEME 5 (Cont.) (XXIII) [Raw materials and reagents] Each Reaction of the Reaction Schemes can be carried out by known methods.

Reaction, the compounds of the formulas (IV), (V), (VI), (XIV), (XVI) and (XXIII) as raw materials are known or can be easily prepared by known methods. For example, the compounds of the formula (XIV) wherein R3_1 is THP, have been described in J. Am. Chem. Soc. 98, 1490 (1971). The other raw materials and reagents of the present invention are known per se or can be prepared by known methods. In each reaction of the present disclosure, the reaction products can be purified by conventional techniques. For example, the purification can be carried out by distillation at atmospheric pressure or under reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing by recrystallization. The purification can be carried out after each reaction or after a series of reactions. [Pharmacological activities] The compounds of the present invention of the formula (I) can be strongly bound and show an activity on the subtype EP4 receptor, which is one of the PGE2 receptors. For example, in a standard laboratory test such effects of the compounds of the present invention were confirmed by binding assays using cells expressing the prostanoid receptor subtypes. (i) Binding assay using cells expressing prostanoid receptor subtypes. The preparation of the membrane fraction was carried out according to the method of Sugimoto et al (J.

Biol. Chem., 267, 6463-6466 (1992)), using CHO cells expressing the prostanoid receptor subtypes (EPi, EP2, murine EP3a and EP4, and human IP). The reaction solution (200 μl) containing the membrane fraction (0.5 mg / ml), [3 H] -PGE2 was incubated for 1 hour at room temperature. The reaction was stopped by the addition of 3ml of ice cold buffer. The mixture was rapidly filtered under reduced pressure through a glass filter (GF / B). The radioactivity associated with the filter was measured by scintillation in a liquid medium. The Kd and Bmax values were determined from the Scatchard plots [Ann. N.Y. Acad. Sci. 51, 660 (1949)]. The non-specific binding was calculated as the bound amount in the presence of an excess (2.5 uM) of unlabeled PGE2. In the competition experiment for the specific binding of [3H) -PGE2 by the compounds of the present invention, [3H] -PGE2 was added at a concentration of 2.5 nM and the compound of the present invention was added at various concentrations. The following regulatory solution was used in all reactions. Regulatory solution: 10 mM potassium phosphate (pH 6.0), 1 mM EDTA, 10 mM MgCl2, 0.1 M NaCl. The constant dissociation Ki (uM) of each compound was calculated by the following equation. Ki = IC 50 / (1 + ([C] / Kd)) The results are shown in Table 4. TABLE 4 As shown in the above results, the compounds of the present invention can bind to the EP subtype receptor with great force and do not bind to the other PGE2 receptors. [Toxicity] The toxicity of the compounds of the formula (I) of the present invention is very low and, therefore, it is confirmed that these compounds are safe to be used as medicaments. For example, the maximum tolerance dose of the compound of Example 1 intravenously (i.v.) in rats was 30 mg / kg body weight, or more. INDUSTRIAL APPLICATION The compounds of the present invention of the formula (I) can bind and show the activity on the PGE2 receptor. Particularly, they bind strongly to the subtype EP4 receptor, such that they are useful for the prevention and / or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumatic arthritis and lupus erythematosus systemic, etc., and rejection of organs after transplants, etc.), asthma, abnormal bone formation, death of neuronal cells, lung failure, liver damage, acute hepatitis, nephritis, renal failure, hypertension, myocardial ischemia, inflammatory response syndrome systemic, pain due to ambulation, sepsis, hematophagic syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, heartburn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytinemiamia in dialysis, multiple organ failure and shock, etc. . Furthermore, it is thought that the EP4 subtype receptor is related to sleep disorders and platelet aggregation in the blood, so that the compounds of the present invention are expected to be useful for the prevention and / or treatment of such diseases. The compounds of the present invention of the formula (I) bind weakly to the other receptor subtypes and do not express other effects, therefore, such compounds are expected to be agents with few side effects. For the purposes described above, the compounds of the formula (I) of the present invention, non-toxic salts thereof or cyclodextrin clathrates thereof, can normally be administered systemically or locally, usually orally or parenterally (including administration in joints or subcutaneous administration, etc.). The doses to be administered are determined depending on age, body weight, symptoms, effect* * > &-the desired therapeutic, route of administration and duration of treatment, etcetera. In adult humans, the dose per person is generally between 1 μg and 100 mg orally, up to several times a day, and between 0.1 μg and 10 mg per parenteral administration (preferably intravenous) up to several times a day, or administration Continues between 1 and 24 hours a day intravenously. As mentioned above, the doses to be used depend on several conditions. Therefore, there are cases in which doses higher or lower than the previously specified ranges can be used. The compounds according to the present invention can be administered as solid compositions, liquid compositions or other compositions by oral administration, or in the form of injections, liniments or suppositories, etc. for parenteral administration. Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules. The capsules include hard gelatin capsules and soft gelatin capsules. In such compositions, one or more of the active components is mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate-aluminate. The compositions may also comprise, as in normal practice, additional substances other than inert diluents: for example lubricating agents such as magnesium stearate, disintegrating agents such as cellulose calcium glycolate and agents to aid dissolution such as glutamic acid , asparaginic acid. The tablets or pills, if desired, may be coated with films of gastric or enteric material, such as sugar, gelatin, hydroxypropylcellulose or hydroxypropylcellulose phthalate, etc., or they may be coated with two or more films. In addition, the coating can form part of the capsules of absorbable materials, for example of gelatin. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs, and the like. In such liquid compositions, one or more of the active ingredients are comprised in the inert diluent (s) commonly used in the art (eg, purified water, ethanol, etc.). In addition to inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents and preservatives. Other compositions for oral administration include spraying compositions which can be prepared by known methods and which comprise one or more active compounds. Spray compositions may comprise additional substances other than inert diluents: e.g., stabilizing agents such as sodium acid sulfate, stabilizing agents to give isotonicity, isotonic regulatory solutions such as sodium chloride, sodium citrate, citric acid. For the preparation of such spray compositions, for example, the method described in US Pat. Nos. 2,868,691 or 3,095,355 can be used. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include distilled water for injection and physiological saline. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohols such as ethanol, POLYSORBATE 80®, et cetera. Such compositions may comprise additional diluents: e.g. preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, auxiliary agents for dissolution (for example glutamic acid, acid, asparagin). These can be sterilized, for example, by filtration through a filter that retains bacteria, by the incorporation of sterilizing agents in the compositions, or by irradiation. They can also be manufactured in the form of sterile solid compositions that can be dissolved in sterile water or in some other sterile diluent for injection, immediately before use. Other compositions for parenteral administration include liquids for external use and dermal liniments, ointments, suppositories and weighings, which comprise one or more active compounds and can be prepared by known methods. BEST WAY TO CARRY OUT THE INVENTION The following Reference Examples and Examples are intended to illustrate, but not to limit, the present invention. The solvents in parentheses in the chromatographic separations and in thin layer chromatography (TLC) show the developing or eluting solvents, and the ratios of the solvents used are in volume. The solvents in parentheses in the NMR are those used for the measurement.

REFERENCE EXAMPLE 1 1 -bromo-3 -? - ethoxy? - ethylbenzene To a solution of 3-bromobenzyl bromide (15.0 g, 60 mmol) in methanol-dimethoxyethane (DME) (30 ml + 10 ml), sodium methylate (4.9 g, 90 mmol) was added in a cooling bath with ice. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water and subjected to extraction with ether. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation to obtain the title compound (12.1 g) which yielded the following physical data. TLC: Rf = 0.74 (ethyl acetate / hexane = 1: 4); NMR (CDC13): d 7.50 (s, 1H), 7.42 (dt, J = 8, 2Hz, 1H), 7.3-7.2 (m, 2H), 4.43 (s, 2H), 3.40 (s, 3H). REFERENCE EXAMPLE 2 (2S) -3- (3-methoxymethylphenyl) -l-triphenylmethoxypropan-2-ol Magnesium (1.41 g, 58 mmol) was heated to dryness in vacuo. To this was added anhydrous tetrahydrofuran (THF) (30 ml) and dibromoethane (a few drops). A solution of a compound prepared in Reference Example 1 (9.65 g, 48 mmol) in anhydrous THF (30 ml) was added dropwise over a period of 45 minutes. The solution obtained in this way was added to a suspension of cuprous iodide (0.76 g, 4 mmol) in anhydrous THF (30 ml) in an ice-cooling bath. The mixture was stirred for 30 minutes. To this mixture was added a solution of S- (-) - glycidyltrityl ether (12.7 g, 40 mmol) in anhydrous THF (30 ml). After stirring the mixture for 1 hour, it was poured into a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation to obtain the title compound (19.5 g) which yielded the following physical data. TLC: Rf = 0.29 (ethyl acetate / hexane = 1: 4); NMR (CDC13): d 7.5-7.1 (m, 19H), 4.40 (s, 2H), 4.1-3.9 (m, 1H), 3.37 (s, 3H), 3.3-3.1 (m, 2H), 2.9-2.7 (m, .2H), 2.23 (br, 1H).

REFERENCE EXAMPLE 3 (2S) -3- (3-methoxymethylphenyl) -propan-1,2-diol To a solution of a compound prepared in Reference Example 2 (19.5 g) in THF (10 ml), acetic acid (80 ml) and water (10 ml) were added. The mixture was heated for 6 hours at 60 ° C and then cooled to room temperature by the addition of water (40 ml). The precipitate was filtered. The filtrate was concentrated. The precipitate was filtered again. The oily compound obtained by the concentration of the filtrate was distilled with toluene to remove the solvent and to obtain the title compound (8.9 g) which yielded the following physical data. TLC: Rf = 0.64 (ethyl acetate / hexane = 2: 1). REFERENCE EXAMPLE 4 (2S) -3- (3-methoxymethylphenyl) -l-acetyloxypropan-2-ol A solution of a compound prepared in Reference Example 3 (8.9 g) and 2, 4, 6-collidine (10.6 ml, 80 mmol) in methylene chloride (120 ml) was cooled to -70 ° C.

I To this was added acetyl chloride (4.0 ml, 56 mmol). After stirring the mixture for 15 minutes, methanol was added. The reaction mixture was warmed to 0 ° C, washed with IN HCl and with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed by distillation to obtain the title compound (10.8 g) which presented the following physical data. TLC: Rf = 0.64 (ethyl acetate / hexane = 2: 1); NMR (CDC13) d 7.4-7.1 (m, 4H), 4.43 (s, 2H), 4.25-3.95 (m, 3H), 3.41 (s, 3H), 2.9-2.8 (m, 2H), 2.12 (s, 3H). REFERENCE EXAMPLE 5 (2S) -3- (3-methoxymethylphenyl) -1-acetyloxy-2- (2-tetrahydropyranyloxy) -propane To a solution of a compound prepared in Reference Example 4 (10.8 g) in methylene chloride (40 ml) were added dihydropyran (5.5 ml, 60 mmol) and pyridinium p-toluenesulfonate (0.50 g). The mixture was stirred for 4 hours, concentrated, diluted with ethyl acetate, washed with water and with a saturated aqueous solution of sodium hydrogen carbonate and dried over sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain the desired compound (14.0 g) which presented the following physical data. TLC: Rf 0.53 (ethyl acetate / hexane / methylene chloride = 1: 2: 2); NMR (CDC13): d 7.3-7.1 (m, 4H), 4.85-4.8 and 4.45-4.0 (, 1H), 4.43 (s, 2H), 4.25-3.85 and 3.5-3.2 (m, 5H), 3.39 (s) , 3H), 3.05-2.8 (, 2H), 2.10 and 2.08 (s, 3H), 1.9-1.4 (m, 6H). REFERENCE EXAMPLE 6 (2S) -3- (3-methoxymethylphenyl) -2- (2-tetrahydropyranyloxy) -propan-1-ol To a solution of a compound prepared in Reference Example 5 (14.0 g) in methanol (40 ml) was added an aqueous 2N sodium hydroxide solution (5 ml).

The mixture was stirred for 1 hour at room temperature.

The solvent was removed by distillation under reduced pressure. The reaction mixture was diluted with ether, washed with water and with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated.

The residual oil was purified by silica gel column chromatography, to obtain the title compound (11.0 g) which yielded the following physical data. TLC: Rf = 0.51, 0.41 (mixture of diastereomers of the THP compound, ethyl acetate / hexane = 2: 1); NMR (CDC13): d 7.3-7.1 (m, 4H), 4.85-4.8 and 4.25-4.2 (m, 1H), 4.42 (s, 2H), 4.05-3.4 (m, 5H), 3.38 (s, 3H) , 3.06 (dd, J = 14, 6 Hz, 1H), 2.85 (dd, J = 14, 8Hz, 1H), 2.8-2.7 and 2.15-2.05 (, 1H), 1.9-1.4 (m, 6H). REFERENCE EXAMPLE 7 (2S) -3- (3-methoxyphenylphenyl) -2- (2-tetrahydropyranyloxy) -propan-1-al A solution of oxalyl chloride (6.8 mL, 78 mmol) in methylene chloride (150 mL) was cooled to -78 ° C. To this was added dropwise a solution of anhydrous dimethylsulfoxide (DMSO) (11.1 ml, 156 mmol) in methylene chloride (30 ml) over a period of 15 minutes. After stirring the mixture for 15 minutes, a solution of a compound prepared in Reference Example 6 (11.0 g, 39 mmol) in methylene chloride (40 ml) was added dropwise over a period of 35 minutes. After stirring the mixture for 10 minutes, triethylamine (32 ml) was added. The mixture was warmed to -40 ° C, stirred for 45 minutes, emptied in IN HCl and extracted with an ether / hexane mixture. The organic phase was washed with water, with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, successively, and dried over sodium sulfate. The solvent was removed by distillation to obtain the title compound (11.1 g) which presented the following physical data. TLC: Rf = 0.45 (ethyl acetate / hexane = 1: 2); NMR (CDC13): d 9.75-9.0 (m, 1H), 7.3-7.1 (m, 4H), 4.8-4.75 and 4.35-4.3 (m, 1H), 4.43 (s, 2H), 4.45-4.3 and 4.1- 4.0 (m, 1H), 3.95-3.9 and 3.5-3.4 (m, 1H), 3.40 (s, 3H), 3.3-2.8 (m, 3H), 1.9-1.3 (, 6H). REFERENCE EXAMPLE 8 (3S) -1, 1-dibromo-4- (3-methoxymethylphenyl) -3- (2-tetrahydropyranyloxy) -1-butene A solution of tetrabromomethane (39.8 g, 0.12 mol) in methylene chloride (150 ml) was cooled to -20 ° C. To this solution was added a solution of triphenylphosphine (63 g, 0.24 mol) in methylene chloride (100 ml) per drop in a period of 20 minutes. The reddish-brown solution was cooled to -40 ° C. To this was added dropwise a solution of a compound prepared in Reference Example 7 (11.1 g) and triethylamine (5.6 ml, 40 mmol) in methylene chloride (40 ml). After stirring the mixture for 10 minutes, triethylamine (11.7 ml) and methanol (9.8 ml) were added. Vigorously stirring the solution gave a brown solution, which was drained in a mixture of ether / hexane. The solid product was filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (13.6 g) which presented the following physical data. TLC: Rf = 0.36 (ethyl acetate / hexane = 1: 9). REFERENCE EXAMPLE 9 (3S) -4- (3-methoxymethylphenyl) -3- (2-tetrahydropyranyloxy) -1-butyne A solution of a compound prepared in Reference Example 8 (13.5, 31.1 mmol) in anhydrous THF (90 mL) was cooled to -78 ° C. To this solution was added dropwise a solution of n-butyl lithium in hexane (1.61M, 42.5 ml, 68.4 mmol) over a period of 20 minutes. After stirring the mixture for 10 minutes, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain the title compound (8.9 g), which presented the following physical data. TLC: Rf = 0.50, 0.44 (ethyl acetate / hexane = 1: 4). REFERENCE EXAMPLE 10 (3S) -4- (3-methoxymethylphenyl) -l-butin-3-ol A compound prepared in Reference Example 9 (8.9 g) was dissolved in a solvent mixture of dioxane (10 ml) and methanol (10 ml). To this mixture was added 4N HCl-dioxane (2 ml) at room temperature. The reaction mixture was stirred for 1 hour. The mixture was diluted with water and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, successively, and dried over sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromaaphy to obtain the title compound (5.6 g) which presented the following physical data. TLC: Rf = 0.40 (ethyl acetate / hexane = 1: 2). REFERENCE EXAMPLE 11 (3S) -4- (3-methoxymethylphenyl) -3-t-butyldimethylsilyloxy-l-butyne To a solution of a compound prepared in Reference Example 10 (5.64 g, 29 mmol) and imidazole (3.0 g, 44 mmol) in N, N-dimethylformamide (DMF) (30 ml), was added t-chloride. butyldimethylsilyl (5.3 g, 35 mmol).

The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous solution of sodium chloride, successively, and dried over sodium sulfate. The solvent was removed by distillation. The residue was purified by chromaaphy on a column of silica gel, to obtain the title compound (7.82 g) which presented the following physical data. TLC: Rf = 0.73 (ethyl acetate / hexane = 1: 4); NMR (CDCl 3): d 7.3-7.1 (m, 4H), 4.5-4.45 (m, 1H), 4.44 (s, 2H), 3.37 (s, 3H), 3.0-2.95 (m, 2H), 2.41 (d , J = 2Hz, 1H), 0.83 (s, 9H), -0.02 (s, 3H), -0.08 (s, 3H). REFERENCE EXAMPLE 12 (3S) -l-? Odo-4- (3-methoxymethylphenyl) -3-t-butyldimethylsilyloxy-lE-butene To a suspension of zirconocene chlorohydride (7.81 g, 30 mmol) in anhydrous THF (15 ml), a solution of a compound prepared in Reference Example 11 (7.7 g, 25 mmol) in THF (30 ml) was added dropwise. ml) at room temperature. After stirring the mixture for 45 minutes, the reaction mixture was cooled to 0 ° C. A solution of iodide (6.43 g, 25 mmol) in THF was added dropwise. The mixture was stirred for 15 minutes at room temperature. Hexane was added. The precipitate was filtered on silica gel. The filtrate was concentrated. The residue was purified by silica gel column chromaaphy, to obtain the title compound (9.77 g) which presented the following physical data. TLC: Rf = 0.61 (ethyl acetate / hexane = 1: 9); NMR (CDCl 3): d 7.3-7.05 (m, 4H), 6.56 (dd, J = 15, 5Hz, 1H), 6.19 (dd, J = 15, 1Hz, 1H), 4.43 (s, 2H), 4.3- 4.15 (m, 1H), 3.38 (s, 3H), 2.8-2.7 (m, 2H), 0.83 (s, 9H), -0.08 (s, 3H), -0.11 (s, 3H). REFERENCE EXAMPLE 13 methyl ester of (lla, 13E, 15a) -7-hydroxy-9-oxo-ll, 15-bis (t-butyldimethylsilyloxy) -16- (3-methoxymethylphenyl) - 17,18,19,20 -tetranor-5-tiaprost-13-enoic Under an argon atmosphere, to a solution of a compound prepared in Reference Example 12 (432 mg) in anhydrous diethyl ether (5 ml), was added dropwise a solution of t-butyl lithium in pentane (1.2 ml, 1.64M) a -78 ° C. The mixture was stirred for 1 hour. To the reaction mixture was added dropwise a solution of lithium 2-thienylcyanocouplet in THF (4.8 ml, 0.25M). The mixture was stirred for 30 minutes. A solution of (4R) -4-t-butyldimethylsilyloxy-2-cyclopentenone (150 mg) in anhydrous THF (1 ml) was slowly added dropwise. The mixture was stirred for 30 minutes. After cooling the mixture to -78 ° C, a solution of 2- (3-methoxycarbonylpropylthio) -ethanol (150 mg, prepared according to the method described in Chem. Pharm. Bull., 33 (5) was added dropwise. ), 1815-1825 (1985) in anhydrous THF (1 ml) The mixture was stirred for 20 minutes, a saturated aqueous solution of ammonium chloride was added at -78 ° C. The mixture was heated to 0 ° C. The reaction mixture was extracted with hexane The extract was washed with a mixture of solvents (a saturated aqueous solution of ammonium chloride / 28% ammonium water = 4: 1) and a saturated aqueous solution of sodium chloride successively, it was dried over sodium sulfate and concentrated.The residue was purified by chromaaphy on a silica gel column. (hexane / ethyl acetate = 10: 1 -> 6: 1) to obtain the title compound (415 mg), which presented the following physical data. TLC: Rf = 0.36 (hexane / ethyl acetate = 4: 1); NMR (CDC13): d 7.3-7.05 (m, 4H), 5.68 (dd, J = 16, 5Hz, 1H), 5.50 (dd, J = 16, 5Hz, 1H), 4.43 (s, 2H), 4.35- 4.2 (m, 1H), 4.15-4.0 (m, 1H), 3.75-3.65 (m, 1H), 3.67 (s, 3H), 3.40 (s, 3H), 2.9-2.7 (m, 5H), 2.65- 2.5 (m, 3H), 2.43 (5, J = 7Hz, 2H), 2.35-2.2 (m, 2H), 2.0-1.8 (m, 2H), 0.90 (s, 9H), 0.85 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), -0.10 (s, 3H), -0.22 (s, 3H).

REFERENCE EXAMPLE 14 i methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-bis (t-butyldimethylsilyloxy) -16- (3-methoxymethyl) -17, 18, 19, 20-tetranor -5-tiaprost-7, 13-d? Enoic To a solution of a compound prepared in Reference Example 13 (415 mg) in methylene chloride (4 ml), N, N-dimethylaminopyridine (440 mg) and methanesulfonyl chloride (186 μl) were added at 0 ° C. . The mixture was stirred for 2 hours. Water was added at 0 ° C. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, with a saturated aqueous solution of potassium hydrogen sulfate and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain the title compound (346 mg) which presented the following physical data. TLC: Rf = 0.48 (hexane / ethyl acetate = 4: 1); NMR (CDCl 3): d 7.3-7.0 (m, 4H), 6.8-6.65 (m, 1H), 5.6-5.45 (m, 2H), 4.43 (s, 2H), 4.3-4.2 (m, 1H), 4.15 -4.1 (m, 1H), 3.67 (s, 3H), 3.45-3.4 (, 1H), 3.39 (s, 3H), 3.2-3.05 (m, 2H), 2.8-2.7 (, 2H), 2.6-2.2 (m, 6H), 2.0-1.8 (m, 2H), 0.85 (s, 9H), 0.83 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H), -0.12 (s, 3H), -0.22 (s, 3H). REFERENCE EXAMPLE 15 methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-bis (t-butyldimethylsilyloxy) -16- (3-methoxymethylphenyl) -17, 18, 19,20- tetranor-5- tiaprost-13-enoic To a solution of a compound prepared in Reference Example 14 (346 mg) in tributyltin hydride (3 ml), t-butyl peroxide (90 mg) was added. The mixture was stirred for 35 minutes at 100 ° C.

The reaction mixture was cooled to room temperature and purified by chromatography on a silica gel column. (hexane / ethyl acetate = 110: 1 - »10: 1) to obtain the title compound (64 mg), which presented the following physical data. TLC: Rf = 0.28 (benzene / ethyl acetate = 19: 1); NMR (CDCl 3): d 7.3-7.0 (m, 4H), 5.67 (dd, J = 15, 6Hz, 1H), 5.55 (d, J = 15, 8Hz, 1H), 4.42 (s, 2H), 4.29 ( q, J = 6Hz, 1H), 4.05 (q, J = 8Hz, 1H), 3.69 (s, 3H), 3.38 (s, 3H), 2.8-2.7 (m, 2H), 2.7-2.5 (m, 5H) ), 2.5-2.4 (m,, 3H), 2.23 (dd, J = 18, 8Hz, 1H), 2.1-2.0 (m, 1H), 1.9-1.7 (m, 4H), 0.90 (s, 9H), 0.83 (s, 9H), 0.09 (s, 3H), 0.07 '(s, 3H), -0.10 (s, 3H), -0.28 (s, 3H). EXAMPLE 1 methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost-13-enoic acid To a solution of a compound prepared in Reference Example 15 (33 mg) in acetonitrile (1.5 ml), pyridine (0.1 ml) and the hydrogen fluoride-pyridine complex (0.2 ml) was added at 0 ° C. The mixture was stirred for 2 hours at room temperature. The reaction mixture was added to a cold mixed solution (ethyl acetate / saturated aqueous sodium carbonate acid solution). The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a gel column. silica (hexane / ethyl acetate = 1: 2 → 1: 4 - »ethyl acetate), to obtain the title compound (16 g) which presented the following physical data. i TLC: Rf = 0.14 (ethyl acetate); NMR (CDC13): d 7.35-7.1 (m, 4H), 5.75 (dd, J = 16,, 6Hz, 1H), 5.52 (dd, J = 16, 8Hz, 1H), 4.42 (s, 2H), 4.4 -4.35 (m, 1H), 4.0-3.85 (m, 1H), 3.67 (s, 3H), 3.42 (s, 3H), 3.3-3.2 (m, 1H), 3.0-2.1 (m, 13H), 2.0 -1.8 (m, 3H), 1.8-1.16 (, 1H). Example 1 (1) to Example 1 (11). By the same procedure described in Reference Example 13, Reference Example 14, Reference Example 15 and Example 1, the following compounds of the present invention were obtained. Example 1 (1) Methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methyl-4-hydroxyphenyl) -17, 18,19,20-tetranor-5- tiaprost-13-enoic CCF: Rf = 0.29 (ethyl acetate); NMR (CDC13): d 6.93 (s, 1H), 6.87 (d, J = 8 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 5.71 (dd, J = 15, 7 Hz, 1H) , 5.62 (s, 1H), 5.50 (dd, J = 15, (Hz, 1H), 4.4-4.2 (m, 1H), 4.1-3.9 (m, 1H), 3.68 (s, 3H), 3.35-3.3 (br, 1H), 2.8-2.6 (, 3H), 2.6-2.4 (, 7H), 2.4-2.1 (m, 3H), 2.22 (s, 3H), 2.0-1.8 (m, 3H), 1.7-1.5 (m, 1H) Example 1 (2) Ethyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor- 5-thiaprost-13-enoic TLC: Rf = 0.31 (ethyl acetate / acetic acid = 50: 1); NMR (300 MHz, CDC13): d 7.33-7.10 (m, 4H), 5.74 (dd, J = 15, 6.2 Hz, 1H), 5.53 (ddd, J = 15, 8.5, 1.1 Hz, 1H), 4.48- 4.36 (m, 3H), 4.12 (q, J = 7.2 Hz, 2H), 3.94 (m, 1H), 3.41 (s, 3H), 2.89 (dd, J = 14, 5.4 Hz, 1H), 2.83 (dd) , J = 14, 6.9 Hz, 1H), 2.69 (ddd, J = 19, 7.6, 1.1 Hz, 1H), 2.65-2.50 (m, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.40 (t, J = 7.4 Hz, 2H), 2.38-2.13 (m, 3H), 1.96-1.82 (m, 3H), 1.76-1.61 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H). Example 1 (3) n-propylester of (lla, 13E, 15a) -9-oxo-l, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.39 (ethyl acetate / acetic acid = 50: 1); NMR (300 MHz, CDC13): d 7.33-7.09 (, 4H), 5.74 (dd, J = 15, 6.0 Hz, 1H), 5.54 (ddd, J = 15, 8.4, 0.9 Hz, 1H), 4.48-4.36 (m, 3H), 4.02 (t, J = 6.8 Hz, 2H), 3.94 (m, 1H), 3.41 (s, 3H), 2.89 (dd, J = 14, 5.4 Hz, 1H), 2.83 (dd, J = 14, 6.9 Hz, 1H), 2.69 (ddd, J = 19, 7.5, 1.0 Hz, 1H), 2.66-2.51 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.38-2.14 (m, 3H), 1.95-1.81 (m, 3H), 1.74-1.57 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). Example 1 (4) i-propyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.35 (ethyl acetate / acetic acid = 50: 1); NMR (300 MHz, CDC13): d 7.33-7.11 (m, 4H), 5.74 (dd, J = 15, 5.7 Hz, 1H), 5.54 (dd, J = 15, 8.4 Hz, 1H), 4.99 (septet, J = 6.3 Hz, 1H), 4.48-4.37 (m, 3H), 3.94 (m, 1H), 3.42 (s, 3H), 2.90 (dd, J = 14, 5.6 Hz, 1H), 2.83 (dd, J = 14, 7.1 Hz, 1H), 2.69 (dd, J = 19, 7.4 Hz, 1H), 2.63-2.52 (m, 2H), 2.49 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 2.36-2.13 (m, 3H), 1.96-1.81 (m, 3H), 1.74-1.62 (m, 1H), 1.22 (d, J = 6.3 Hz, 6H). Example 1 (5) n-Butylester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.36 (ethyl acetate / acetic acid = 50: 1) NMR (300 MHz, CDC13): d 7.33-7.11 (m, 4H), 5.75 (dd, J = 16, 6.2 Hz, 1H), 5.54 (dd, J = 16, 8.5 Hz, 1H), 4.48-4.36 (m, 3H), 4.07 (t, J = 6.6 Hz, 2H), 3.94 (m, 1H), 3.42 (s, 3H), 2.90 ( dd, J = 13, 5.6 Hz, 1H), 2.84 (dd, J = 13, 6.9 Hz, 1H), 2.69 (dd, J = 19, 7.5 Hz, 1H), 2.64-2.52 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.38-2.14 (m, 3H), 1.96-1.81 (m, 3H), 1.74-1.53 (m, 3H), 1.43-1.30 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). Example 1 (6) Methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-ethoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost-13- enoic TLC: Rf = 0.29 (ethyl acetate); NMR (300 MHz, CDC13): d 7.32-7.12 (m, 4H), 5.77 (dd, J = 15.3, 5.4 Hz, 1H), 5.53 (dd, J = 15.3, 7.78 Hz, 1H), 4.48-4.43 ( m, 3H), 3.97-3.87 (m, 1H), 3.67 (s, 3H), 3.58 (q, J = 6.9 Hz, 2H), 2.98-2.80 (m, 2H), 2.76-2.14 (m, 13H) , 1.95-1.60 (m, 3H), 1.26 (t, J = 7.2 Hz, 3H).

Example 1 (7) Methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-n-propyloxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.36 (ethyl acetate); NMR (300 MHz, CDC13): d 7.32-7.13 (m, 4H), 5.77 (dd, J = 15.3, 6.0 Hz, 1H), 5.53 (dd, J = 15.3, 8.0 Hz, 1H), 4.48-4.43 ( m, 3H), 3.97-3.89 (m, 1H), 3.67 (s, 3H), 3.47 (t, J = 6.6 Hz, 2H), 2.94-2.91 (m, 2H), 2.76-2.14 (m, 13H) , 1.92-1.50 (m, 5H), 0.95 (t, J = 7.5 Hz, 3H). Example 1 (8) t-Butyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.35 (ethyl acetate); NMR (300 MHz, CDC13): d 7.35-7.16 (m, 4H), 5.78 (dd, J = . 3, 5.1 Hz, 1H), 5.54 (dd, J = 15.3, 7.5 Hz, 1H), 4.50-4.40 (m, 3H), 4.00-3.92 (m, 1H), 3.42 (s, 3H), 2.97-2.82 (, 2H), 2.76-2.15 (m, 11H), 1.95-1.63 (m, 3H), 1.44 (s, 9H). Example 1 (9) Methyl ester of (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16-methyl-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5- tiaprost-13-enoic TLC: Rf = 0.40 (ethyl acetate); NMR (300 MHz, CDC13): d 7.36-7.11 (m, 4H), 5.76-5.60 (m, 1H), 5.56-5.42 (m, 1H), 4.48-4.37 (m, 2H), 4.29-4.20 (m, 1H), 3.96-3.75 (m, 1H), 3.67 (s, 3H), 3.43 (s, 3H), 2.96- 2.05 (, 11H), 1.97-1.60 (m, 6H), 1.37 (d, J = 8.0 Hz, 1.5 H), 1.30 (d, J = 7.2 Hz, 1.5H). Example 1 (10) (15a, 13E) -9-Oxo-15-hydroxy-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic acid methyl ester CCF: Rf = 0.60 (ethyl acetate / hexane = 2: 1); NMR (300 MHz, CDC13): d 7.3-7.1 (m, 4H), 5.7-5.6 (m, 2H), 4.44 (s, 2H), 4.4-4.3 (br, 1H), 3.68 (s, 3H), 3.41 (s, 3H), 2.9-2.75 (m, 2H), 2.7-2.3 (m, 8H), 2.3-2.0 (m, 3H), 2.0-1.5 (m, 6H). Example 1 (11) Methyl ester of (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16- (3-methyl-4-hydroxyphenyl) -17, 18,19,20-tetranor-5- tiaprost-13-enoic TLC: Rf = 0.45 (ethyl acetate); NMR (300 MHz, CDC13): d 6.99-6.82 (m, 2H), 6.75-6.68 (m, 1H), 5.73-5.54 and 5.44-5.31 (m, 3H), 4.14-3.90 (m, 2H), 3.70 (s, 3H), 2.82-2.06 (m, 14H), 1.99-1.53 (, 6H), 1.31 and 1.20 (d, J = 7.0 Hz, 3H).

REFERENCE EXAMPLE 16 Methyl ester of (9a, lla, 13E, 15a) -9-hydroxy-ll, 15-bis (t-b tildimethylsilyloxy) -16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic Under an argon atmosphere, to a solution of a compound prepared in Reference Example 15 (186 mg) in anhydrous THF (3 ml), a solution of lithium tri-s-butyl cyanide hydride in THF (320 ml) was added dropwise. μl, l.OM) at -78 ° C. The mixture was stirred for 1 hour. After adding IN HCl to the reaction mixture, it was warmed to 0 ° C and subjected to extraction with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a silica gel column (hexane / ethyl acetate = 6: 1 - »4: 1), to obtain the title compound (77 mg) which presented the following physical data. NMR (CDC13): d 7.3-7.0 (m, 4H), 5.51 (dd, J = 15, 6Hz, 1H), 5.35 (dd, J = 15, 8Hz, 1H), 4.42 (s, 2H), 4.22 ( q, J = 6Hz, 1H), 4.2-4.1 (m, 1H), 4.1-3.95 (m, 1H), 3.69 (s, .3H), 3. 38 (s, 3H), 2.8-2.7 (m, 3H), 2.7-2.4 (m, 6H), 2.3-2.15 (m, 1H), 2.0-1.8 (m, 5H), 1.7-1.5 (m, 2H), 0.88 (s, '9H), 0. 82 (s, 9H), 0.08 (s, 6H), -0.10 (s, 3H), -0.22 (s, 3H).

Example 2 Methylester of (9ß, lla, 13E, 15a) -9-chloro-l, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor-5-thiaprost-13-enoic acid 1) Under an argon atmosphere, to a solution of a compound prepared in Reference Example 16 (95 mg) in anhydrous pyridine (1.5 ml), p-toluenesulfonyl chloride (530 mg) was added at 0 ° C. The mixture was stirred for 21 hours at room temperature. To this was added ice water. After stirring the mixture, ethyl acetate was added. The reaction mixture was washed with IN HCl, with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The obtained tosyl compound was used for the next reaction without further purification. 2) Under an atmosphere of argon, to a solution of the tosyl compound obtained in anhydrous toluene (6 ml), tetra-n-butylammonium chloride (390 mg) was added rapidly. The mixture was stirred for 1 hour at 55 ° C. The reaction mixture was diluted with ethyl acetate, washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The crude product obtained was used for the next reaction without further purification. 3) To a solution of the crude product obtained in acetonitrile (3 ml), pyridine (0.2 ml) was added to the hydrogen fluoride-pyridine complex (0.4 ml) at 0 ° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was added to a solution (ethyl acetate-saturated aqueous sodium hydrogen carbonate solution) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified on a short column and then by chromatography on a silica gel column (toluene / i-propanol = 50: 1), to obtain the title compound (38 mg), which presented the following physical data. TLC: Rf = 0.42 (ethyl acetate); NMR (CDCl 3): d 7.3-7.1 (, 4H), 5.63 (dd, J = 15, 6Hz, 1H), 5.48 (dd, J = 15, 8 Hz, 1H), 4.42 (s, 2H), 4.4- 4.3 (m, 1H), 4.1-3.9 (m, 2H), 3.68 (s, 3H), 3.42 (s, 3H), 3.0-2.7 (m, 3H), 2.6-2.4 (m, 6H), 2.35- 2.1 (m, 3H), 2.1-1.8 (m, 4H), 1.8-1.6 (m, 2H). Example 2 (1) Methyl ester of (9ß, lla, 13E, 15a) -9-fluoro-11, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost- 13-enoic By the same procedure described in Reference Example 16 and Example 2, the title compound was obtained. TLC: Rf = 0.49 (hexane / ethyl acetate = 1: 3); NMR (CDCl 3): d 7.3-7.1 (, 4H), 5.66 (dd, J = 15, • 6Hz, 1H), 5.49 (dd, J = 15, 8Hz, 1H), 4.85-4.8 and 4.7-4.65 (m , 1H), 4.42 (s, 2H), 4.45-4.35 (m, 1H), 4.05-3.9 (m, 1H), 3.68 (s, 3H), 3.42 (s, 3H), 2.95-2.8 (m, 2H) ), 2.7-2.4 (m, 7H), 2.4-2.2 (m, 1H), 2.1-1.5 (m, 8H).

Example 3 Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxy-methylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic To a solution of a compound prepared in the Example 1 (16 mg) in dimethisulfoxide (1 ml), phosphate buffer (1 ml, pH 7..4) and then hepatic esterase of pig (100 μl) were added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified by adding a saturated aqueous solution of ammonium sulfate and IN HCl. The mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a column of silica gel (hexane / ethyl acetate = 1: 2, 1% acetic acid -> 1: 4, 1% acetic acid -> ethyl acetate: acetic acid = 50: 1) to obtain the title compound (13 mg), which presented the following physical data.

TLC: Rf = 0.21 (ethyl acetate / acetic acid = 19: 1); NMR (CDC13): d 7.35-7.1 (m, 4H), 5.76 (dd, J = 15, 6Hz, 1H), 5.53 (dd, J = 15, 8Hz, 1H), 5.2-4.4 (br, 3H), 4.43 (s, 2H), 4.5-4.4 (m, 1H), 3.94 (q, J = 8Hz, 1H), 3.42 (s, 3H), 3.0-2.15 (m, 13H), 2.0-1.8 (m, 2H) ), 1.8-1.6 (m, 1H). Example 3 (1) - Example 3 (8) By the same procedure described in Example 3, using the compounds prepared in Examples 1 (2) -1 (8), Example 2 and Example 2 (1), the following compounds. Example 3 (1) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methyl-4-hydroxyphenyl) -17, 18, 19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.22 (chloroform / methanol = 9: 1); NMR (CD3OD): d 6.89 (s, 1H), 6.82 (d, J = 8 Hz, 1H), 6.63 (d, J = 8 Hz, 1H), 5.64 (dd, J = 15, 7 Hz, 1H) , 5.48 (dd, J = 15, 8 Hz, 1H), 4.22 (q, J = 7 Hz, 1H), 3.99 (q, J = 8 Hz, 1H), 2.9-2.1 (m, 13H), 2.15 ( s, 3H), 1.9-1.6 (m, 3H).

Example 3 (2) Acid (9ß, lla, 13E, 15a) -9-chloro-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost-13- enoic TLC: Rf = 0.29 (chloroform / methanol = 9: 1); NMR (CDC13): d 7.25-7.05 (, 4H), 5.62 (dd, J = 15, 6 Hz, 1H), 5.45 (dd, J = 15, 8 Hz, 1H), 4.38 (s, 2H), 4.4-4.3 (m, 1H), 4.0-3.9 (m, 2H), 3.37 (s, 3H), 2.85 (dd, J = 14, 5 Hz, 1H), 2.75 (dd, J = 14, 7 Hz, 1H), 2.6-2.3 (m, 6H), 2.25- 2.05 (m, 2H), 2.0-1.9 (m, 2H), 1.9-1.8 (m, 2H), 1.7-1.6 (m, 2H). Example 3 (3) Acid (9ß, lla, 13E, 15a) -9-f luoro-11, 15-dihydroxy-16- (3-methoxymethyl phenyl) -17,18,19,20-tetranor-5-thiaprost- 13-enoic TLC: Rf = 0.51 (chloroform / methanol = 9: 1); NMR (CDCl 3): d 7.3-7.1 (m, 4H), 5.68 (dd, J = 15, 6 Hz, 1H), 5.51 (dd, J = 15, 9 Hz, 1H), 4.9-4.6 (m, 1H ), 4.44 (s, 2H), 4.42 (q, J = 6 Hz, 1H), 3.96 (q, J = 9 Hz, 1H), 3.42 (s, 3H), 3.8-2.6 (br, 3H), 2.90 (dd, J = 14, 6 Hz, | 1H), 2.82 (dd, J = 14, 6 Hz, 1H), 2.65-2.2 (m, 7H), 2.1-1.5 (, 7H). Example 3 (4) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-ethoxy-methylphenyl) -17,18,19,20-tetranor-5-thiaprost-13- enoic TLC: Rf = 0.06 (chloroform / methanol = 9: 1); NMR (300 MHz, CDC13): d 7.29-7.11 (m, 4H), 5.76 (dd, J = 15.0, 5.4 Hz, 1H), 5.53 (dd, J = 15.0, 8.1 Hz, 1H), 4.51-4.40 ( m, 3H), 3.98-3.90 (m, 1H), 3.59 (q, J = 6.9 Hz, 2H), 2.95-2.80 (m, 2H), 2.76-2.16 (m, 10H), 1.94-1.62 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H). Example 3 (5) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-n-propyloxymethylphenyl) -17, 18,19,20-tetranor-5-thiaprost-13- enoic CCF: Rf = 0.12 (chloroform / methanol = 9: 1); NMR (300 MHz, CDC13): d 7.31-7.11 (m, 4H), 5.76 (dd, J = . 3, 5.7 Hz, 1H), 5.54 (dd, J = 15.3, 8.4 Hz, 1H), 4.60-4.40 (m, 3H), 3.98-3.90 (m, 1H), 3.41 (t, J = 6.9 Hz, 2H ), 2. 95-2.16 (m, 12H), 1.94-1.59 (m, 6H), 0.95 (t, J = 7.5 Hz, 3H). Example 3 (6) Acid (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16- (3-methoxy-methylphenyl) -17, 18,19,20-tetranor-5-thiaprost-13- enoic TLC: Rf = 0.17 (chloroform / methanol = 9: 1); NMR (300 MHz, CDCl 3): d 7.36-7.11 (m, 4H), 5.76 and 5.70 (dd, J = 15.0, 8.0 Hz, 1H), 5.53 and 5.48 (dd, J = 15.0, 6.0 Hz, 1H), 4.50-4.39 (m, 2H), 4.36-4.26 (m, 1H), 3.98-3.75 (m, 1H), 3.44 (s, 3H), 3.02-1.60 (m, 17H), 1.37 and 1.30 (d, J = 7.0 Hz, 3H).

Example 3 (7) Acid (15a, 13E) -9-oxo-15-hydroxy-16- (3-methoxymethylphenyl) 17,18, 19,20-tetranor-5-thiaprost-13-enoic TLC: Rf = 0.51 (chloroform / methanol = 9: 1); NMR (300 MHz, CDC13): d 7.3-7.1 (m, 4H), 5.75-5.6 (m, 2H), 4.45 (s, 2H), 4.45-4.4 (m, 1H), 4.0-2.8 (br), 3.42 (s, 3H), 2.89 (dd, J = 14, 5Hz, 1H), 2.79 (dd, J = 14, 8 Hz, 1H), 2.7-2.3 (m, 8H), 2.3-2.0 (m, 3H) ), 2.0-1.5 (, 5H). Example 3 (8) Acid (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16-methyl-16- (3-methyl-4-hydroxyphenyl) -17, 18, 19,20-tetranor- 5-thiaprost-13-enoic TLC: Rf = 0.21 (chloroform / methanol = 9: 1); NMR (300 MHz, CDCI3-CD3OD): d 7.00.6.67 (m, 3H), 5.75-5.32 (m, 2H), 4.15-3.86 (, 2H), 3.3 (bs, 3H), 2.80-1.50 (m, 18H), 1. 33 and 1. 19 (d, J = 7. 0 Hz, 3H). REFERENCE EXAMPLE 17 4-iodobutanoic acid methyl ester "COOMe To a solution of methyl 4-chlorobutylate (145.5 g) in acetone (1100 ml), sodium iodide (320 g) was added, and the mixture was refluxed with stirring for 11 hours. The mixture was cooled to room temperature and filtered through Celite, the filtrate was concentrated under reduced pressure, and a mixture of ethyl acetate / water (500 ml + 500 ml) was added to the residue. with ethyl acetate The organic phase was washed with a saturated aqueous solution of sodium thiosulfate (300 ml) and with a saturated aqueous solution of sodium chloride, successively, and dried over anhydrous magnesium sulfate. distillation under reduced pressure to obtain the title compound (236.5 g) TLC: Rf = 0.36 (hexane / ethyl acetate = 9: 1); NMR (200 MHz, CDC13): d 3.69 (s, 3H), 3.24 ( t, J = 6.8 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 2.13 (tt, J = 7.0, 6.8 Hz, 2H).

REFERENCE EXAMPLE 18 3-Bromomethylphenylacetic acid To a solution of 3-methylphenylacetic acid (125 g) in tetrachloromethane (1660 ml), N-bromosuccinimide (148 g) and 2,2'-azobisisobutyronitrile were added.

(AIBN, 1.37 g). The mixture was refluxed with heating. After finishing the reaction, the solvent was cooled with ice. The white precipitate was filtered on a glass filter. The filtrate was washed with tetrachloromethane. The filtrate together with the washing liquid was concentrated. The obtained residue was dissolved in ethyl acetate. To this was added hexane. The mixture was crystallized to obtain the title compound (59 g). TLC: Rf = 0.58 (hexane / ethyl acetate = 1: 1 + 1% acetic acid); NMR (200 MHz, CDC13): d 7.36-7.18 (m, 4H), 4.48 (s, 2H), 3.66 (s, 3H). REFERENCE EXAMPLE 19 3-methoxymethylphenylacetic acid Under an atmosphere of argon, sodium methoxide (160 g), methanol (800 ml) was added with stirring. To this mixture was added a solution of 3-bromomethylphenylacetic acid (226 g, prepared in Reference Example 18) in methanol (3200 ml). The mixture was refluxed for 20 minutes. After the temperature of the mixture reached room temperature, the methanol was removed by distillation. The residue was poured into 2N HCl. To this was added ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated, to obtain the title compound (176.3 g). TLC: Rf = 0.58 (hexane / ethyl acetate = 1: 1 + 1% acetic acid); NMR (200 MHz, CDC13): d 7.38-7.18 (m, 4H), 4.45 (s, 2H), 3.65 (s, 2H), 3.39 (s, 3H). REFERENCE EXAMPLE 20 N-methoxy-N-methyl- (3-methoxymethylphenyl) -acetic acid amide I Under an argon atmosphere, to a solution of 3-methoxymethylphenylacetic acid (176.1 g, prepared in the Reference Example 19) in methylene chloride (2500 ml) was added successively methylmethoxyamine hydrochloride (289 g), 1-hydroxybenzotriazole (HOBt) monohydrate (166 g) and l-ethyl-3- [3- ( dimethylamino) -propyl] -carbodiimide (EDC, 284 mg). To this mixture was added N-methylmorpholine (325 ml). The mixture was stirred at room temperature. After 11 hours, EDC monohydrochloride (94.7 g) and N-methylmorpholine (54.0 ml) were added to the mixture. The reaction mixture was stirred for a further 2 hours. The mixture was filtered. The solvent was removed by distillation under reduced pressure. Water (600 ml) and ethyl acetate (600 ml) were added. After it had completely dissolved, the mixture was poured into 2N HCl (2000 ml). This mixture was filtered to remove the hydrochloride. The filtrate was separated. The organic phase was washed with 2N HCl, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, successively, and concentrated under reduced pressure, to obtain the title compound ( raw product, 200 g). TLC: Rf = 0.58 (ethyl acetate); NMR (200 MHz, CDC13): d 7.36-7.18 (m, 4H), 4.44 (s, 2H), 3.78 (s, 2H), 3.61 (s, 3H), 3.38 (s, 3H), 3.20 (s, 3H). REFERENCE EXAMPLE 21 3- (3-methoxymethylphenyl) -2-oxopropylphosphonate dimethyl Under an argon atmosphere, a solution of dimethyl methylphosphonate (DMMP, 147 g) in anhydrous toluene (1500 ml) was cooled to -74 ° C. To this solution was added n-butyl lithium (714 ml, 1.52M in hexane) in a period of 1 hour. The mixture was stirred for 1 hour. To the reaction mixture was added a solution of N-methoxy-N-methyl- (3-methoxymethylphenyl) -acetic acid amide (200 g, prepared in Reference Example 20) in anhydrous toluene. (400 ml) in a period of 30 minutes. The reaction mixture was stirred for a further 2 hours. Acetic acid (73.5 ml) was added to this mixture. The mixture was warmed to room temperature and emptied in water. The organic phase was separated. The organic phase was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (206.5 g). TLC: Rf = 0.22 (ethyl acetate); ! NMR (200 MHz, CDC13): d 7.38-7.11 (m, 4H), 4.45 (s, 2H), 3. 90 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.40 (s, 3H), 1 3. 11 (d, J = 23 Hz, 2H). REFERENCE EXAMPLE 22 (1S, 5R, 6S, 7R) -3-oxo-6-formyl-7- (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane To a solution of (SS, 5R, 6R, 7R) -3-oxo-6-hydroxymethyl-7- (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane (140.5 g, J. Am. Chem. Soc., 98, 1490 (1971)) in ethyl acetate (4100 ml), water (410 ml), sodium acetate (134.9 g), potassium bromide (6.53 g) and radical 2, 2 were added, 6,6-tetramethyl-1-piperidinyloxy (TEMPO, 2.14 g). The mixture was cooled with sodium chloride-water. The reaction mixture was stirred vigorously. To this was added dropwise a solution of 10% sodium hypochlorous acid (302 ml) which was saturated with sodium acid carbonate, in a period of 40 minutes. After concluding the reaction, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, to obtain the title compound (113.6 g). TLC: Rf = 0.60 (ethyl acetate / acetic acid = 100: 1); NMR (300 MHz, CDC13): d 9.73 (m, 1H), 5.11-5.00 (m, 1H), 4.81-4.51 (m, 2H), 3.92-3.79 (m, 1H), 3.59-3.35 (m, 2H ), 3.20-3.03 (, 1H), 2.90 and 2.87 (each dd, J = 18, 6.2 Hz and J = 18, 6.3 Hz, 1H), 2.57 and 2.44 (each dd, J = 18, 3.2 Hz and J = 18, 3.2 Hz, 1H), 2.40-2.30 (m, 1H), 1.97-1.42 (m, 7H). REFERENCE EXAMPLE 23 (SS, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3-oxo-1-butenyl) -7- (2-tetrahydropyranyloxy) -2-oxabicyclo [ 3.3.0] - octane Under an argon atmosphere, a suspension of sodium hydride (5.08 g, 62.5%) in anhydrous THF (2000 ml) was cooled with a water bath. To this was added dropwise a solution of dimethyl 3- (3-methoxymethylphenyl) -2-oxopropylphosphonate (42.7 g, prepared in Reference Example 21) in anhydrous THF (1000 ml), over a period of 15 minutes. The mixture was stirred for 1 hour.

To this was added dropwise a solution of (SS, 5R, 6S, 7R) -3-oxo-6-formyl-7- (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane (113.6 g, prepared in Reference Example 23) in anhydrous THF (800 ml). The mixture was stirred for 12 hours. Acetic acid (51 ml) was added to the reaction mixture. The mixture was emptied in water. The reaction mixture was subjected to extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title compound (143.0 g). TLC: Rf = 0.52 (hexane / ethyl acetate = 1: 1); NMR (200 MHz, CDC13): d 7.38-7.07 (m, 4H), 6.71 (m, 1H), 6.22 (m, 1H), 4.97 (, 1H), 4.68-4.51 (m, 1H), 4.44 (s) , 2H), 4.22-3.92 (, 1H), 3.88-3.34 (m, 2H), 3.81 (s, 2H), 3.40 (s, 3H), 2.88-2.03 (m, 6H), 1.98-1.32 (, 6H) ). REFERENCE EXAMPLE 24 (1S, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S-hydroxy-1-butenyl) -7- (2-tetrahydropyranyloxy) -2-oxabicyclo [ 3.3.0] -octane Under an atmosphere of argon, to a suspension of lithium aluminum hydride (13.0 g) in anhydrous THF (760 ml), an anhydrous ethanol solution (15.0 g) in anhydrous THF was added dropwise. (90 ml), in a period of 12 minutes. The mixture was stirred for 20 minutes. To this, a solution of (S) -binaphol (93.3 g) in anhydrous THF (200 ml) was added dropwise over a period of 1 hour. The mixture was stirred for 1 hour. The mixture was cooled to -72 ° C. A solution of (SS, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3-oxo-1-butenyl) -7- (2-tetrahydropyranyloxy) -2 was added dropwise. -oxabicyclo [3.3.0] -octane (30.0 g, prepared in Reference Example 23) in anhydrous THF (210 ml), over a period of 30 minutes. The mixture was stirred for 1 hour. To the reaction mixture was added dropwise methanol (75 ml) in a period of 10 minutes. The water bath was removed. Sodium tartrate (1500 ml) was added to the mixture, 0.5M) at -30 ° C. The mixture was warmed to room temperature and subjected to extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added ethyl acetate / hexane (100 ml / 230 ml). The mixture was allowed to stand overnight. The precipitated crystals were filtered. The filtrate was concentrated. The residue was purified by chromatography on a silica gel column (hexane / ethyl acetate = 1: 2 - »ethyl acetate), to obtain the title compound (23.1 g), the title compound: 15-epimor = 93.9: 6.1). TLC: Rf = 0.51 (ethyl acetate); NMR (200 MHz, CDCl 3): d 7.35-7.07 (m, 4H), 5.61 (dd, J = 16, 5.5 Hz, 1H), 5.50 and 5.48 (each dd, J = 16, 6.5 Hz and J = 16, 6.6 Hz, 1H), 4.94 (m, 1H), 4.65 (m, 1H), 4.44 (s, 2H); 4.32 (m, 1H), 4.12-3.38 (m, 3H), 3.41 (s, 3H), 2.87-2.03 (m, 8H), 1.89-1.40 (m, 6H). REFERENCE EXAMPLE 25 (1S, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S- (2-tetrahydropyranyloxy) -1-butenyl) -7- (2-tetrahydropyranyloxy) - 2-oxabicyclo [3.3.0] -octane Under an argon atmosphere, to a solution of (ÍS, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S-hydroxy-1 -butenyl) -7- (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane (114.7 g, prepared in Reference Example 24) in methylene chloride (1000 ml), dihydropyran (37.7 ml) was added and tosylic acid monohydrate (524 mg). The mixture was stirred for 1 hour. Triethylamine was added to the reaction mixture at 0 ° C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2: 1-1: 1-1: 2) to obtain the title compound (126.9 g). TLC: Rf = 0.51, 0.45 (hexane / ethyl acetate = 1: 2); NMR (200 MHz, CDC13): d 7.32-7.02 (m, 4H), 5.63-5.23 (m, 2H), 4.89 (m, 1H), 4.70-4.46 (m, 1H), 4.42 (s, 2H), 4.35-3.18 (m, 6H), 3.39 (s, 3H), 3.07-1.94 (, 8H), 1.88-1.20 (m, 12H).

REFERENCE EXAMPLE 26 (9a, lla, 15a, 13E) -6, 9-dihydroxy-11, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) 1, 2, 3, 4, 5, 17, 18, 19, 20-nonanorprost-13-ene Under an argon atmosphere, lithium aluminum hydride (7.68 g) was cooled with ice. To this solution was added anhydrous THF (500 ml). To this mixture was added dropwise a solution of (SS, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S- (2-tetrahydropyranyloxy) -1-butenyl) -7 - (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane (126.7 g, prepared in Reference Example 25) in anhydrous THF (500 ml), over a period of 1.5 hours at 2 ° C. The mixture was stirred for 10 minutes. To the reaction mixture was added diethyl ether (750 ml) and a saturated aqueous solution of sodium sulfate (70 ml). The mixture was stirred for 20 minutes at room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (133.8 g). TLC: Rf = 0.36 (ethyl acetate / acetic acid = 50: 1); NMR (200 MHz, CDC13): d 7.30-7.06 (m, 4H), 5.64-5.24 (m, 2H), 4.77-4.53 (m, 2H), 4.41 (s, 2H), 4.46-3.28 (m,, 9H). 3.39 (s, 3H), 3.09-2.68 (m, 2H), 2.50-1.94 (m, 4H), 1.91-1.17 (m, 12H). REFERENCE EXAMPLE 27 (9a, lla, 15a, 13E) -6-acetylthio-9-trimethylsilyloxy-ll, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -1,2,3,4,5 , 17,18, 19,20-nonanorprost-13-ene Under an argon atmosphere, a solution of (9a, lla, 15a, 13E) -6, 9-dihydroxy-11, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -1,2,3,4,5,17,18,19 , 20-nonanorprost-13-ene (51.4 g, prepared in Reference Example 26) in anhydrous THF (600 ml) was cooled to -25 ° C. To this solution was added diisopropylethylamine (35.5 ml). Then mesyl chloride (11.8 ml) was added at -20 ° C, over a period of 2 minutes. The mixture was stirred for 30 minutes at -10 ° C. After the product used for the reaction had been completely consumed, 1-diisopropylethylamine (35.5 ml) was added at -10 ° C. Trimeylsilyl trichloride (15.5 ml) was added dropwise over a period of 8 minutes. The mixture was stirred for 1 hour at -10 ° C. After concluding the reaction, potassium carbonate (84.6 g) was added to the mixture at -10 ° C and then a solution of potassium thioacetate (34.9 g) was added to the mixture.

DMF anhydrous (1200 ml) by dripping over a period of 1 hour, at -10 ° C. The mixture was stirred for 18 hours at room temperature. To this was added water (2000 ml). The mixture was extracted with a hexane / ethyl acetate (1: 1) solvent mixture. The organic phase was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, to obtain the title compound (63.5 g). TLC: Rf = 0.57, 0.53 (hexane / ethyl acetate = 2: 1). REFERENCE EXAMPLE 28 Methylester of (9a, lla, 15a, 13E) -9-hydroxy-ll, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor- 5-thiaprost-13-enoic Under an argon atmosphere, to a portion of anhydrous THF (200 ml) was added potassium t-butoxide (27.5 g). To the mixture was added dropwise anhydrous methanol (200 ml) over a period of 6 minutes. The mixture was stirred for 10 minutes. To the reaction solution was added dropwise a solution of (9 a, 11 a, 15 a, 13E) -6-acetylthio-9-trimethylsilyloxy-ll, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -1,2,3,4,5,17,18,19,20-nonanorprost- 13-ene (63.5 g, prepared in Reference Example 27) and 4-iodobutanoic acid methyl ester (55.8 g, prepared in Reference Example 17) in anhydrous THF (400 ml), over a period of 25 minutes. The mixture was stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (1000 ml) and extracted with ethyl acetate. The organic phase was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (51.3 g). TLC: Rf = 0.39 (hexane / ethyl acetate = 1: 2); NMR (300 MHz, CDC13): d 7.31-7.07 (m, 4H), 5.65-5.29, (m, 2H), 4.75-4.59 (m, 2H), 4.43 (s, 2H), 4.31-3.19 (m, 7H), 3.67 (s, 3H), 3.37 (s, 3H), 3.00-2.70 (m, 2H), 2.65-2.03 (m, 10H), 2.01-1.28 (m, 16H). REFERENCE EXAMPLE 29 Methyl ester of (lla, 15a, 13E) -9-oxo-ll, 15-bis (2-tetrahydropyranyloxy (-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5- tiaprost-13-enoic Under an argon atmosphere, to a solution of methyl ester of the acid (9a, lla, 15a, 13E) -9-hydroxy-ll, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -17.18, 19,20-tetranor-5-thiaprost-13-enoic (120.0 g, prepared in Reference Example 28) in anhydrous DMSO (500 ml), triethylamine (161 ml) was added. To this mixture was added a solution of the sulfur trioxide-pyridine complex (92.0 g) in anhydrous DMSO (300 ml), over a period of 10 minutes in a water bath. The mixture was stirred for 1 hour at room temperature. Triethylamine (161 ml) and the sulfur trioxide-pyridine complex (92.0 g) were added to the reaction mixture. The mixture was stirred. The reaction mixture was poured into a cold solution of hexane / ethyl acetate / water (500 ml / 500 ml / 2000 ml) and extracted with hexane / ethyl acetate (1: 1). The organic phase was washed with IN HCl, with water, with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was diluted with toluene to obtain the title compound (121.8 g). TLC: Rf = 0.47 (hexane / ethyl acetate = 1: 1). Example 4 Methyl ester of (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor-5-thiaprost-13-enoic acid A solution of methyl ester of the acid (9a, lla, 15a, 13E) -9-hydroxy-ll, 15-bis (2-tetrahydropyranyloxy) -16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5 -thiaprost-13-enoic (121.8 g, prepared in Reference Example 29) in a mixture of acetic acid / THF / water (480 ml / 80 ml / 240 ml), was stirred for - ,,,, - =, - 1.5 hours at 70 ° C. The reaction mixture was cooled with ice and poured into water (1000 ml). The reaction mixture was subjected to extraction with ethyl acetate. The organic phase was washed with water and with a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane -> ethyl acetate / methanol) to obtain the title compound (32.7 g). TLC: Rf = 0.29 (ethyl acetate / acetic acid = 50: 1) '; NMR (500 MHz, CDC13): d 7.29 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H ), 5.73 (dd, J = 15, 6.5 Hz, 1H), 5.53 (ddd, J = 15, 9.0 / 1.0 Hz, 1H), 4.46-4.39 (m, 2H), 4.38 (m, 1H), 3.94 ( m, 1H), 3.67 (s, 3H), 3.41 (s, 3H), 2.88 (dd, J = 14, 5.5 Hz, 1H), 2.82 (dd, J = 14, 7.3 Hz, 1H), 2.70 (ddd) , J = 19, 7.4, '1.1 Hz, 1H), 2.62-2.49 (m, 2H), 2.49 (t, J = 7.0 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 2.30 (m , 1H), 2.25 (dd, J = 19, 10, Hz, 1H), 2.18 (m, 1H), 1.93-1.83 (m, 3H), 1.72-1.63 (m, 1H).

Optical rotation: [a] D26-5 -40.3 (c = 0.625, CHCI3). REFERENCE EXAMPLE 30 (1S, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S- (2-tetrahydropyranyloxy) -1-butyl) -7- (2-tetrahydropyranyloxy) - ^ a ^ a ^ i 2-oxabicyclo [3.3.0] -octane Under an argon atmosphere, to a solution of (SS, 5R, 6R, 7R) -3-oxo-6- (4- (3-methoxymethylphenyl) -3S- (2-tetrahydropyranyloxy) -1-butanyl) -7- (2-tetrahydropyranyloxy) -2-oxabicyclo [3.3.0] -octane (100 mg, prepared in Reference Example 25) in methanol (2.0 ml), palladium on carbon (10 mg, 10%) was added. Under a hydrogen atmosphere, the reaction mixture was stirred for 2.5 hours at room temperature. The reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by column chromatography (hexane / ethyl acetate = 2: 1-1: 1) to obtain the title compound (74 mg). TLC: Rf = 0.30 (hexane / ethyl acetate = 1: 1); NMR (CDC13, 300 MHz): d 7.35-7.08 (m, 4H), 4.98-4.94 (m, 1H), 4.70-4.59 and 4.39-4.15 (m, 2H), 4.43 (s, 2H), 4.09-3.75 (m, 3H), 3.60-3.29 (m, 6H), 3.02-2.12 (m, 6H), 2.09-1.40 (m, 18H).

Example 5 Methyl ester of (lla, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor-5-thiaprostanoic acid By the same procedures described with reference to Examples 26 to 29 and Example 4, using a compound prepared in Reference Example 30, the title compound was obtained. TLC: Rf = 0.29 (ethyl acetate); NMR (300 MHz, CDC13): d 7.36-7.16 (m, 4H), 4.45 (s, 2H), 4.15-4.08 (m, 1H), 3.96-3.90 (m, 1H), 3.67 (s, 3H), 3.42 (s, 3H), 2.90-2.82 (, 1H), 2.76-2.51 (m, 6H), 2.44 (t, J = 7.5 Hz, 2H), 2.31-2.23 (m, 1H), 2.05-1.60 (m , 12H). Example 6) Acid (lla, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethyl) -17, 18, 19,20-tetranor-5-thiaprostanoic acid I I i By the same procedures described in I Example 3 using a compound used in Example I 5, the title compound was obtained. , TLC: Rf = 0.25 (chloroform / methanol = 9.1); NMR (300 MHz, CDC13): d 7.35-7.12 (m, 4H), 4.46 (s, 2H), 4.17-4.08 (m, 1H), 4.00-3.90 (m, 1H), 3.44 (s, 3H) , 2 | .91- 2.82 (m, 1H), 2.78-2.20 (m, 10H), 2.15-1.60 (m, 12H). ' i Formulation of Example 1 The following compounds were mixed, according to a conventional method, and compressed to obtain | 100 tablets, each containing 0.5 mg of the active ingredient. • Methyl ester (lla, 15a, 13E) -9-oxo-ll ^ 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic-a- 250 mg cyclodextrin (active ingredient: 50 mg). Calcium carboxymethyl cellulose 200 mg . Magnesium stearate 100 mg . Microcrystalline cellulose 9.2 g Example formulation 2 The following components were mixed following a conventional method and the solution was sterilized following a conventional method, divided into 1 ml portions in ampoules and lyophilized by a conventional method, to obtain 100 ampoules, each one containing 0.2 mg of the active ingredient. . Methylester (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic-a-cyclodextrin 100 mg (active ingredient: 20 mg). Mannitol 5 g . Distilled water 100 ml It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. A phenylprostaglandin E 5 -thia-substituted derivative of the formula (I) (characterized in that R1 is a hydroxy radical, alkyloxy of 1 to 6 carbon atoms or NR6R7 (wherein R6 and R7, each independently, are a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms), R2 is an oxo, halogen or O-COR8 radical (wherein R8 is an alkyl radical of 1 to 4 carbon atoms, phenyl or phenyl (alkyl of 1 to 4 carbon atoms)), R3 is a hydrogen atom or a hydroxy group , R4a and R, each independently, are a hydrogen atom or an alkyl group of 1 to 4 carbon atoms, R5 is a phenyl group substituted with the following substituents: i) from 1 to 3 alkyloxy groups of 1 to 4 atoms carbon-alkyl, from 1 to 4 carbon atoms,; alkenyloxy of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, alkynyloxy of 2 to 4 carbon atoms-alkyl of

1 to 4 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms (alkyloxy of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, phenyloxy-alkyl of 1 to 4 carbon atoms, phenyl-alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkenyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkynyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkylthio of 3 to 7 carbon atoms-alkyl from 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms (thioalkyl of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, thiophenyl-alkyl of 1 to 4 carbon atoms or phenyl-thioalkyl from 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, ii) alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms rbonone and alkyl of 1 to 4 carbon atoms, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and halogen, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy or thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and halogen, iii) haloalkyl or hydroxy-alkyl of 1 to 4 carbon atoms, or iv) alkyl of 1 to 4 carbon atoms and hydroxy; "*" is a single bond or a double bond, provided that when R2 is 0-COR8, C8-C9 represents a double bond) or a non-toxic salt or a dichlodextrin clathrate thereof.

2. A compound according to claim 1, characterized in that R1 is a hydroxy radical.

3. A compound according to claim 1, characterized in that R1 is an alkoxy radical of 1 to 6 carbon atoms.

4. A compound according to claim 1, characterized in that R1 is a radical NR6R7 ((wherein all symbols are as defined in claim 1.)

5. A compound according to claim 1, characterized in that R2 is an oxo radical

6. A compound according to claim 1, characterized in that R2 is a halogen radical

7. A compound according to claim 1, characterized in that R2 is a radical 0-CO8 (wherein R8 is like the defined in claim 1) •

8. A compound according to claim 1, characterized in that R5 is a phenyl radical substituted with i) from 1 to 3 alkyloxy radicals of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, alkynyloxy of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms (alkyloxy of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, phenyloxy-alkyl of 1 to 4 carbon atoms, phenyl-alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkenyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, thioalkynyl of 2 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkylthio of 3 to 7 carbon atoms-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 atoms of carbon (thioalkyl of 1 to 4 carbon atoms) -alkyl of 1 to 4 carbon atoms, thiophenyl-alkyl of 1 to 4 carbon atoms, or phenyl-thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms.

9. A compound according to claim 1, characterized in that R5 is a phenyl radical substituted with ii) alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyl of 1 to 4 carbon atoms, alkyloxy from 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy, alkyloxy of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and halogen, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and alkyl of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms carbon-alkyl of 1 to 4 carbon atoms and alkyloxy of 1 to 4 carbon atoms, thioalkyl of 1 to 4 carbon atoms-alkyl of 1 to 4 carbon atoms and hydroxy, or thioalkyl of 1 to 4 carbon atoms- alkyl of 1 to 4 carbon atoms and halogen.

10. A compound according to claim 1, characterized in that R5 is a phenyl radical substituted with iii) haloalkyl or hydroxy-alkyl of 1 to 4 carbon atoms.

11. A compound according to claim 1, characterized in that R5 is a phenyl group substituted with, iv) alkyl of 1 to 4 carbon atoms and hydroxy.

12. A compound according to any of claims 1, 2, 5 or 8, characterized in that it is selected from the group consisting of: (1) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy -16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (2) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16 - (3-ethoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (3) Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- ( 3-n-propyloxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (4) Acid (lla, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-) methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprostanoic acid, (5) Acid (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16-methyl-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, and i (6) Acid (15a, 13E) -9-oxo-15-hydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic.

13. A compound according to any of claims 1, 3.5 or 8, characterized in that it is selected from the group consisting of: (1) Methyl ester of acid (lla, 13E, 15a) -9-oxo-11, 15 -dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (2) ethyl ester of (lla, 13E, 15a) -9-oxo-11, 15 -dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (3) n-propylester of acid (lla, 13E, 15a) -9-oxo-11 , 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-, tetranor-5-thiaprost-13-enoic, (4) i-propylester of acid (lla, 13E, 15a) -9- oxo-11, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic,, (5) n-butylester of acid (lla, 13E, 15a) -9-oxo-11, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (6) Methyl ester of acid (lla, 13E, 15a) -9- xo-11, 15-dihydroxy-16- (3-ethoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (7 ) Methyl ester of (lla, 13E, 15a) -9-oxo-11, 15-dihydroxy-16- (3-n-propyloxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, (8) acid t-butylester (lla, 13E, 15a) -9-oxo-11, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13- enoic, (9) Methyl ester of (lla, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprostanoic, (10) Methyl ester of acid, 15a, 13E) -9-oxo-11,15-dihydroxy-16-methyl-16- (3-methoxymethylphenyl) -17,18,19,20-tetranor-5-thiaprost-13-enoic, and (11) (15a, 13E) -9-Oxo-15-hydroxy-16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic acid methyl ester.

14. A compound according to any of claims 1, 2, 6 or 8, characterized in that it is selected from the group consisting of: Acid (9ß, lla, 13E, 15a) -9-chloro-ll, 15-dihydroxy- 16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, and II Acid (9ß, lla, 13E, 15a) -9-fluoro-ll, 15-dihydroxy -16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic.

15. A compound according to any of claims 1, 3, 6 or 8, characterized in that it is selected from the group consisting of (9β, lla, 13E, 15a) -9-chloro-11,15-dihydroxymethyl ester. -16- (3-methoxymethylphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, and Methylester of (9ß, lla, 13E, 15a) -9-fluoro-11,15-dihydroxy acid -16- (3-methoxymethylphenyl) -17, 18, 19,20-tetranor-5-thiaprost-13-enoic.

16. A compound according to any of claims 1, 2, 5 or 11, characterized in that it is selected from the group consisting of: Acid (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy-16- (3-methyl-4-hydroxyphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, and Acid (lla, 15a, 13E) -9-oxo-ll, 15-dihydroxy-16- methyl-16- (3-methyl-4-hydroxyphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic.

17. A compound according to any of claims 1, 3, 5 or 11, characterized in that it is selected from the group consisting of: Methyl ester of (lla, 13E, 15a) -9-oxo-ll, 15-dihydroxy- 16- (3-methyl-4-hydroxyphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic, and Methylester of acid (lla, 15a, 13E) -9-oxo-ll, 15- dihydroxy-16- (3-methyl-4-hydroxyphenyl) -17, 18, 19, 20-tetranor-5-thiaprost-13-enoic.

18. A process for producing a compound of the formula (la) illustrated below, characterized in that it consists of the removal of the protecting group from a compound of the formula (II) (wherein R 1"1 is alkyloxy of 1 to 6 carbon atoms, R 3" 1 is hydroxy or hydroxy protected with a hydroxy protecting group which is removed under acidic conditions, R 10 is a protective group which is removed under acidic conditions , R5"1 is as defined for R5 in claim 1, provided that the hydroxy group in R5"1 is protected by a protecting group that is removed under acidic conditions, and the other symbols are as defined in claim 1) under acidic conditions, to obtain a compound of the formula (Ia) (wherein R3 and R5 are as defined in claim 1, and the other symbols are as previously defined).

19. A process for producing a compound of the formula (Ib) illustrated below, characterized in that it consists of the hydrogenolysis of a compound of the formula (Ia) ((wherein all symbols are as defined in any of claims 1 or 18) using an enzyme or under alkaline conditions, to obtain a compound of the formula (Ib) ((wherein all symbols are as previously defined)

20. A process for producing a compound of formula I (I) which is illustrated below, characterized in that it consists of the amidation of a compound of formula (Ib) ((wherein all symbols are as defined in claim 1) with a compound of the formula (III) HNR6R7 (III) ((wherein all symbols are as defined in claim 1) to obtain a compound of the formula (le) ((in which all the symbols are as defined above)

21. A pharmaceutical composition characterized in that it comprises a phenylprostaglandin derivative 'E 5-thia-β-substituted according to claim 1, or a non-toxic salt thereof or a cyclodextrin clatratp thereof, as the active ingredient

22. A 5-thia-substituted phenylprostaglandin E-derivative of the formula (I), as defined in claim 1, or a salt non-toxic thereof or a cyclodextrin clathrate thereof to be used for binding to the subtype EP4 receptor

23. The use of a phenylprostaglajndine E 5 -thia-substituted derivative of the formula (I), as define i in claim 1, or a The non-toxic of the same or a cyclodextrin clathrate thereof, for the manufacture of a medicament to bind to the subtype EP4 receptor. SUMMARY OF THE INVENTION The present invention relates to 5-thia-substituted phenylprostaglandin E derivadots represented by the general formula (I), where each symbol is like the one defined in the description. Because they are able to bind strongly to the PEG2 receptors (in particular, the EP4 subtype), the compounds represented by the general formula (I) are expected to be useful for preventing and / or treating immunological diseases, asthma, bone dysplasia. , death of nerve cells, pulmonary insufficiency, hepatopathy, acute hepatitis, nephritis, renal failure, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain due to ambush, sepsis, hematophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease , heartburn, systemic granulomatous, ulcerative colitis, Crohn's disease, hypercystinemia in dialysis, multiple organ failure, shock, etcetera. In addition, these compounds participate in sleep disorders and platelet aggregation and, therefore, are expected to be useful for the prevention / treatment of these diseases.