IE921543A1 - New thiopyranopyrrole derivatives, their preparation and¹pharmaceutical compositions containing them - Google Patents

Abstract

New thiopyranopyrrole derivatives of general formula (I) in which X is an oxygen atom or an NH radical, R1 is phenyl, which is optionally substituted, cyclohexadienyl, naphthyl or heterocyclyl, R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino, and n is 0, 1 or 2, in their stereoisomeric forms and their mixtures, optionally their salts when they exist and their preparation. The new derivatives according to the invention are particularly advantageous as antagonists of substance P.

Description

RHONE-POULENC RORER S.A., a French body corporate, Raymond Aron, F 92165 Antony, France. of 20 Avenue la The present invention relates to thiopyranopyrrole derivatives and their preparation and use.

Products derived from isoindole of the formula: which exhibit opium activity, have been described in United States Patent No. 4,042,707. These products exhibit no activity towards substance P.

Herbicides of the formula: in which X may be a sulphur atom, R, and R2 are hydrogen or alkyl and R is a substituted phenyl, have been described in European Patent Application 0068822.

In spite of the research carried out and in spite of the interest created [M.R. Hanley, TINS, (5) 139 (1982)], practically no product had been discovered so far which acts specifically on substance P and which has a non-peptide structure.

The present invention provides the 5 thiopyranopyrrole derivatives of formula and their salts when these exist, - in which X represents an oxygen atom or an NH radical, - Rj represents phenyl, phenyl substituted by one or more halogen atoms or hydroxyl or alkyl radicals which may be optionally substituted (by halogen atoms or by amino, alkylamino or dialkylamino radicals), or alkoxy or alkylthio radicals which may be optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals optionally substituted (by phenyl, hydroxyl or amino radicals) or by dialkylamino radicals whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members which may contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical)], or Rj represents phenyl which is substituted by amino, alkylamino or dialkylamino radicals whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulphur, - R2 represents a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, and - n is 0, 1 or 2. These compounds antagonise the effects of substance P and are as a result particularly useful in therapeutic sectors where this substance is known to play a role.

The abovementioned alkyl or acyl radicals contain 1 to 4 carbon atoms each in a linear or branched chain.

When R, contains a halogen atom, the latter may be chlorine, bromine, fluorine or iodine. When Rt represents a saturated or unsaturated, mono- or polycyclic heterocyclic radical, it may for example be thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, quinolyl, isoquinolyl or naphthyridinyl. When R, represents a phenyl which is substituted by a chain carrying a heterocycle, the latter may be pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl or thiomorpholino.

The products of formula (I) have various stereoisomeric forms, and it is to be understood that the thiopyranopyrrole derivatives of the (4aR,7aR) form or of the (4aS,7aS) form, in a pure state, or in the form of a mixture of the cis-(4aRS,7aRS) forms, are included within the scope of the present invention.

The products of the formula (I) in which n = also have axial or equatorial stereoisomers at the Soxide level. The position-1 R and S derivatives and mixtures thereof are also included within the scope of the present invention.

Furthermore, when R2 is other than hydrogen, the substituted chain on the thiopyranopyrrole has a chiral centre. It is to be understood that the stereoisomeric forms and mixtures thereof are within 20 the scope of the present invention.

According to a feature of the invention, the thiopyranopyrrole derivatives of formula (I) are obtained by reaction of the acid of formula: Rj - CH - COOH (II) I r2 IE 921543 or of a reactive derivative of this acid, in which R, and R2 are defined as above, with a thiopyranopyrrole derivative of formula: in which the symbol n is defined as above, followed, where appropriate, by conversion of the amide obtained into an amidine for which X represents an NH radical.

It is understood that the amino, alkylamino or carboxyl radicals contained in R, and/or R2 are preferably protected beforehand.

The protection is carried out using any compatible group whose introduction and removal does not affect the rest of the molecule. In particular the procedure is carried out according to the methods described by T.W. Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or by Me Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

By way of example, - the amino or alkylamino groups may be protected with the following radicals: methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbony1, trichloroethoxycarbony1, trichloroacetyl, trifluoroacetyl, chloroacetyl, trityl, benzhydryl, benzyl, allyl, formyl, acetyl, benzyloxycarbonyl or its substituted derivatives; - the acidic groups may be protected with the following radicals; methyl, ethyl, t-butyl, benzyl, substituted benzyl or benzhydryl.

Furthermore, when R2 represents a hydroxyl 10 radical, it is preferable to protect this radical beforehand. The protection is carried out for example using an acetoxy, trialkylsilyl or benzyl radical or in the form of a carbonate using a -COORa radical in which Ra is an alkyl or benzyl radical.

When the condensation of a reactive derivative of the acid of general formula (II) is carried out, the procedure is advantageously carried out using the acid chloride, the anhydride, a mixed anhydride or a reactive ester in which the ester residue is for example a succinimido, 1-benzotriazolyl, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido radical or a derivative.

The reaction is generally carried out at a temperature of between -40 and +40°C in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane, chloroform), an ether (for example tetrahydrofuran, dioxane), an ester (for example ethyl acetate), an amide (for example dimethylacetamide, dimethylformamide), or a ketone (for example acetone) or in a mixture of these solvents, in the presence of an acid acceptor such as a nitrogen-containing organic base such as for example pyridine, dimethylaminopyridine, N-methylmorpholine or k a trialkylamine (in particular triethylamine) or such as an epoxide (for example propylene oxide). It is also possible to carry out the procedure in the presence of a condensation agent such as a carbodiimide, [for example dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide], N,N'-carbonyldiimidazole or 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline or alternatively in a dilute organic medium in the presence of an alkaline condensation agent such as sodium bicarbonate, and where appropriate the amide obtained is then converted to an amidine as defined above.

The conversion of the amide of general formula (I) to an amidine for which X is an NH radical is carried out by preparing the derivative of general formula: (IV) in which Rlz R2 and n are defined as above, Y represents a chlorine atom, a methoxy or ethoxy radical and Z' represents a chloride, tetrafluoroborate, fluorosulphonate, trifluoromethylsulphonate, methyl 5 sulphate or ethyl sulphate ion, and subsequently by reacting ammonia with the derivative of general formula (IV).

The preparation of the derivative of general formula (IV) in which Y is a chlorine atom or a methoxy or ethoxy radical, is carried out by reaction of a reagent such as phosgene, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichloromethyl chloroformate, triethyl- or trimethyloxonium tetrafluoroborate, methyl or ethyl triflate, methyl or ethyl fluorosulphonate or methyl or ethyl sulphate. The reaction is carried out in a chlorine-containing solvent (for example dichloromethane, dichloroethane) or in an aromatic hydrocarbon (for example toluene) at a temperature between 0°C and the reflux temperature of the reaction mixture. The reaction of ammonia with the derivative of general formula (IV) is carried out in an anhydrous organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane) in an alcohol/chlorine-containing solvent mixture, in an ether (for example tetrahydrofuran), in an ester (for example ethyl acetate), in an aromatic solvent (for example toluene) or in a mixture of these solvents, at a temperature between -20°C and the reflux temperature of the reaction mixture.

It is not essential to isolate the derivative of general formula (IV) in order to use it in this reaction.

According to the invention, the thiopyranopyrrole derivatives of general formula (I) for which the symbol Rj is an alkoxyphenyl radical whose alkyl part is substituted or unsubstituted and the symbol R2 is other than a halogen atom or hydroxyl radical, may also be prepared from a thiopyranopyrrole derivative of general formula (I) for which R, is a hydroxyphenyl radical, by reaction in a basic medium of the corresponding halogenated derivative of general formula: Hal - R4 (V) in which Hal is a halogen atom and R4 is an alkyl radical which is optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals which are optionally substituted (by phenyl, hydroxyl or amino radicals), or a dialkylamino radical whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle as defined above in the general formula (I) ] · The reaction is generally carried out in the presence of a base such as an alkali metal hydride, hydroxide, alcoholate or carbonate, in an organic solvent such as an amide (for example dimethylformamide), an aromatic hydrocarbon (for example toluene), a ketone (for example butanone) or in a mixture of these solvents, at a temperature between 20°C and the reflux temperature of the reaction mixture.

When the radical R* carries a substituent which may interfere with the reaction, it is understood that the said substituent is protected beforehand. The protection and the removal of the protective radical are carried out according to methods described previously.

According to the invention, the thiopyranopyrrole derivatives of general formula (I) for which X is an NH radical, may also be obtained from the thiopyranopyrrole derivative of general formula (III), by reaction of a product of general formula: .MH S (VI) „-=«-cx B M . *2 5 optionally in the form of a salt, in which R, and R2 are defined as above and R5 represents an alkoxy radical containing 1 to 4 carbon atoms in a linear or branched chain, or a methylthio, ethylthio, benzylthio or alkoxycarbonylmethylthio radical.

The reaction is carried out using the derivative of general formula (VI), which is optionally prepared in situ, in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane), an ether (for example tetrahydrofuran), an aromatic hydrocarbon (for example toluene) or a nitrile for example acetonitrile, at a temperature between 0°C and the reflux temperature of the reaction mixture.

It is understood that should the radicals R, and/or R2 of the product of general formula (VI) carry substituents which may interfere with the reaction, these substituents should be protected beforehand.

According to the invention, the thiopyranopyrrole derivatives of general formula (I) for which n equals 1 or 2, may also be obtained by oxidation of the corresponding derivative of general formula (I) for which n = 0.

The oxidation is carried out according to known methods. For example, the procedure is carried out by reaction of an organic peracid (percarboxylic or persulphonic acid, especially perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid, permaleic acid, monoperphthalic acid, percamphoric or pertoluenesulphonic acid) or inorganic peracids (for example periodic or persulphuric acid).

The reaction is advantageously carried out in a chlorine-containing solvent (methylene chloride) at a temperature between 0 and 25°C. It is also possible to carry out the procedure using tert-butyl hydroperoxide in the presence of titanium tetraisopropylate.

When it is desired to obtain a product of general formula (I) for which n=2, the procedure is carried out using 2 eguivalents of oxidising agent.

The acids of general formula (II) may be prepared according to the methods described in the examples below, or by analogy with these methods.

The thiopyranopyrrole derivative of general formula (III) for which n=0 may be obtained from the corresponding derivative of general formula: (VII) in which R^ represents an allyl radical or a radical of the structure -CR„RbRc in which R, and Rb are hydrogen atoms or phenyl radicals which are optionally substituted (by a halogen atom, an alkyl, alkoxy or nitro radical) , and Rc is defined as R, and Rb or represents an alkyl or alkoxyalkyl radical, at least one of R,, Rb and Rc being a substituted or unsubstituted phenyl radical and the alkyl radicals containing 1 to 4 carbon atoms in a linear or branched chain, by removing the radical R^ by any known method which does not affect the rest of the molecule.

In particular, when Re is other than an allyl radical, the group R^ may be removed by catalytic hydrogenation in the presence of palladium. Generally, the reaction is carried out in an acidic medium, in a solvent such as an alcohol (methanol, ethanol), in water or directly in acetic acid or formic acid, at a temperature between 20 and 60°C.

When R6 is a benzhydryl or trityl radical, the removal may be carried out by treatment in an acidic medium, by carrying out the procedure at a temperature of between 0°C and the reflux temperature of the reaction mixture, in an alcohol, in an ether, in water or directly in acetic acid, formic acid or trifluoroacetic acid. The group may also be removed by reaction of vinyl chloroformate, 1-chloroethyl chloroformate or phenyl chloroformate, a product of general formula: (VIII) in which R7 is a vinyl, 1-chloroethyl or phenyl radical, being obtained as an intermediate, and then removing the radical R7 by acid treatment. The reaction of the chloroformate is generally carried out in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane, chloroform), an ether (for example tetrahydrofuran, dioxane) or a ketone (for example acetone) or in a mixture of these solvents, by carrying out the procedure at a temperature between 20°C and the reflux temperature of the reaction mixture.

The removal of the radical R7 is carried out 5 by treatment in an acidic medium for example with trifluoroacetic, formic, methanesulphonic, p-toluenesulphonic, hydrochloric or hydrobromic acid in a solvent such as an alcohol, an ether, an ester, a nitrile, a mixture of these solvents or in water, at a temperature between 0°C and the reflux temperature of the reaction mixture.

Under the conditions for removing the R7 radicals mentioned above, the thiopyranopyrrole derivative of general formula (III) is obtained in the form of a salt of the acid used, which may be used directly in the subsequent stage.

The thiopyranopyrrole derivative of general formula (VII) may be obtained by cycloaddition reaction, by reaction of a silylated derivative of general formula: R6_N\ 3 ch2r·· (IX) in which Re is defined as above, (R°)3 represents alkyl radicals or alkyl and phenyl radicals and R°° represents an alkoxy, cyano or phenylthio radical, with the 4-dehydrothiapyranone of formula: Ο (X) followed by treating the product of general formula: which is obtained, successively with phenylmagnesium 5 bromide and then with benzene in the presence of zirconium tetrachloride.

The cycloaddition reaction is carried out in the presence of a catalytic amount of an acid chosen from trifluoroacetic acid, acetic acid, methanesulphonic acid or the acids given in the references mentioned below, in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane), in an aromatic hydrocarbon, in a nitrile (acetonitrile) or in an ether, at a temperature between 0°C and the reflux temperature of the reaction mixture.

The introduction of the phenyl radicals is carried out according to the method described in greater detail in Example 1.

The silylated derivative of general formula (IX) may be obtained according to the methods described by: - Y. Terao et al., Chem. Pharm. Bull., 33 . 2762 (1985); - A. Hosomi et al., Chem. Lett., 1117 (1984); - A. Padwa et al., Chem. Ber., 119. 813 (1986) or - Tetrahedron, 41, 3529 (1985).

The thiopyranopyrrole derivative of general formula (III) for which n=l or 2 may be obtained by oxidation of the corresponding derivative of general formula (III) for which n=0 whose amine functional group has been protected beforehand, followed by removal of the protective radical.

The reaction is carried out as described above for the preparation of thiopyranopyrrole derivatives of general formula (I) for which n=l or 2, from the corresponding derivative for which n=0. The introduction and the removal of the protective radical is carried out by the usual methods which do not affect the rest of the molecule; in particular by the methods mentioned above. It is also advantageous to carry out the procedure using the product of general formula (III) for which n=0, in the form of a salt with an inorganic acid (for example hydrochloride, sulphate).

In practice, it is understood that in order to prepare a product of general formula (III) for which n=l or 2, the procedure is advantageously carried out using a thiopyranopyrrole derivative of general formula (VII) or of general formula (VIII) which is obtained in the preceding stage, it being possible for the reaction to be carried out directly on one of these protected derivatives of the product of general formula (III).

The products of general formula (III) for which n=2 may also be obtained from 3,4-dihydro-4,4-diphenyl-2Hthiapyran 1,1-dioxide of formula: (XII) by cycloaddition reaction with a product of general formula (IX), under conditions identical to those described above for the cycloaddition reaction of this product with the 4dehydrothiapyranone of formula (X), followed by removal of the protective radical under the conditions described above. 3,4-Dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide of formula (XII) may be obtained by successive oxidation of 3,4-dihydro-4,4-diphenyl-2H-thiapyran and 3,4-dihydro-4,4diphenyl-2H-thiapyran 1-oxide of formula: h5c6 /C6h5 (XIII) (Xiv) s The oxidation reaction is carried out under the conditions described above for the preparation of the products of general formula (I) . It is not essential to isolate the Soxide of general formula (XIV) in order to oxidise it to a sulphone. 3,4-Dihydro-4,4-diphenyl-2H-thiapyran of general formula (XIII) may be prepared according to or by analogy with the method described in Example 12 below.

It is understood that the thiopyranopyrrole 10 derivatives of general formula (III) , (VII) and (VIII) have several stereoisomeric forms. When it is desired to obtain a product of general formula (I) with (4aR,7aR) or (4aS,7aS) stereoisomerism, the separation of the isomeric forms is preferably carried out with respect to the derivative of general formula (III) ; it may also be carried out using the thiopyranopyrrole of general formula (I). Similarly, when a thiopyranopyrrole derivative for which n=l is prepared, the separation of the axial and equatorial isomers is preferably carried out with respect to the product of general formula (III); it may also be carried out using the thiopyranopyrrole of general formula (I).

The separation of the stereoisomers is carried out according to any known method which is compatible with the molecule. By way of example, the separation may be carried out by the preparation of an optically active salt, by reaction of L(+) or D(-) mandelic acid, or of dibenzoyltartaric acid, followed by separation of the isomers by crystallisation. The desired isomer is released from its salt in a basic medium. The separation of the axial and equatorial isomers may be carried out by chromatography or crystallisation.

The new thiopyranopyrrole derivatives of general 5 formula (I) may be purified, where appropriate, by physical methods such as crystallisation or chromatography.

Where appropriate, the new derivatives of general formula (I), for which the symbols R, and/or R2 contain amino or alkylamino substituents and/or X represents an NH radical, may be converted to the addition salts with acids. As examples of addition salts with pharmaceutically acceptable acids, there may be mentioned the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulphonates, ptoluenesulphonates, isethionates, or with substituted derivatives of these compounds).

The new thiopyranopyrrole derivatives of general formula (I) may also, where appropriate, when R2 represents a carboxyl radical, be converted to the metal salts or to the addition salts with a nitrogen-containing base, according to methods which are known per se. These salts may be obtained by reaction of a metal base (for example alkali metal or alkaline earth metal), of ammonia or an amine, with a product according to the invention, in an appropriate solvent such as an alcohol, an ether or water, or by exchange reaction with an organic acid salt. The salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or freeze-drying. As examples of pharmaceutically acceptable salts, there may be mentioned salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), ammonium salt, salts of nitrogencontaining bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, Ν,Ν-dimethylethanolamine, benzylamine, dicyclohexyl-amine, N-benzyl-0-phenethylamine, N,N'-dibenzyl-ethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).

The thiopyranopyrrole derivatives according to the present invention antagonise the effects of substance P and are therefore of potential utility in the field of analgesia, and the treatment of inflammation, asthma, and allergies, and for their effects on the central nervous system, on the cardiovascular system, as antispasmodics, on the immune system, and on the stimulation of lachrymal secretions.

The products according to the invention exhibit an affinity for substance P receptors at doses of between 10 and 2000 nM according to the technique described by C.M.

Lee et al., Mol. Pharmacol., 23., 563-69 (1983).

Furthermore, it has been demonstrated that the compounds of the invention have a substance P-antagonising effect. In the technique described by S. Rose11 et al., Substance P, Ed. by US Von Euler and B. Pernow, Raven Press, New York (1977), pages 83 to 88, the compounds of the invention which were studied proved to be active at doses of between 20 and 2000 nM.

Substance P is known to be involved in a certain number of pathological domains: see, for example: - Agonists and antagonists of substance P, A.S. Dutta Drugs of the future, 12 (8), 782 (1987); - Substance P and pain: an updating, J.L. Henry, TINS, 3(4), 97 (1980); - Substance P in inflammatory reactions and pain, S. Rosell, Actual. Chim. Ther., 12th series, 249 (1985) ; - Effects of Neuropeptides on Production of Inflammatory Cytokines by Human Monocytes, M. Lotz et al., Science, 241. 1218 (1988); - Neuropeptides and the pathogenesis of allergy, Allergy, 42, 1 to 11 (1987); - Substance P in Human Essential Hypertension, J.

Cardiovascular Pharmacology, 10 (suppl. 12), 5172 (1987) .

The thiopyranopyrrole derivatives of the invention show an analgesic activity according to the technique of Siegmund E. et al., Proc. Soc. Exp. Biol. Med., 95, 729 (1957), as illustrated by the following figures for two products described in the Examples below.

Product of Example No. EDS0 mg/kg p.o. Example 7 3 Example 10 1.7 Using the technique of A. Saria et al., Arch. 5 Pharmacol., 324. 212-218 (1983) adapted to mice, it has been found that the thiopyranopyrrole derivatives of formula I show an inhibitory effect of the increase in capillary permeability brought about by septide (agonist of substance P), which is evidence of anti10 flammatory activity, as illustrated by the following figures for two products described in the Examples below: Product of Example No. ED5o mg/kg s.c. Example 8 0.05 Example 10 <0.1 Injection of substance P into animals produces hypotension. When studied by the technique of C.A. Maggi et al., J. Auton. Pharmac., Ί_, 11-32 (1987), the compounds of the invention show an antagonistic effect in rats towards this hypotension. In particular, the products administered at a dose of 1 mg/kg i.v./min, for 5 min, produce antagonism of the hypotension induced by an i.v. injection of 250 mg/kg of substance P, as illustrated by the following figures for two products described in the Examples below.

Product of % inhibition of Example No. hypotension Example 8 100 Example 10 100 The thiopyranopyrrole derivatives according to the present invention are not toxic. When administered to mice by the subcutaneous route at a dose of 40 mg/kg or by the oral route at a dose of 100 mg/kg, they did not produce toxic effects.

The following products are of particular interest: - 6-{[(3-dimethylamino-2-propoxy)phenyl]acetyl}-4,420 diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, - 6-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl)acetyl)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, - 6-[(S)-2-(2-methoxyphenyl)propionyl]-4,4-diphenylIE 921543 perhydrothiopyrano[2,3-c]pyrrole 1-oxide, - 6-{2-[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole, in their stereoisomeric forms and mixtures thereof.

The following Examples illustrate the present invention. In the examples it is to be understood, unless specifically stated, that the proton NMR spectra were established at 250 MHz in dimethyl sulphoxide; the chemical shifts are expressed in ppm.

EXAMPLE 1 N,N'-Carbonyldiimidazole (1.18 g) is added to a solution of 2-dimethylaminophenylacetic acid (1.16 g) in dry dichloromethane (20 cc). The mixture is stirred for 30 minutes at +5°C and then a solution of (4aRS,7aRS)15 4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole hydrochloride (2.0 g) and triethylamine (1.83 cc) in dichloromethane (20 cc) is added. The reaction mixture is stirred for 1 hour at 20°C and is then washed with water (2 x 50 cc) and dried over magnesium sulphate. The solution is filtered, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (60/40 by volume), and collecting fractions (60 cc). Fractions 6 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallised from an acetonitrile and diisopropyl oxide mixture. The crystals are drained and dried. (4aRS,7aRS)-6-[(2-Dimethylaminophenyl)acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole (2.16 g) is obtained in the form of a white solid; m.p. = 163 °C. (4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano15 [2,3-c]pyrrole hydrochloride may be prepared in the following manner: (4 aRS,7 aRS) -4,4-d ipheny1-6-v iny1oxycarbony1perhydrothiopyrano[2,3-c]pyrrole (4.35 g) is treated with a 5.7 N solution of hydrochloric acid (30 cc) in dry dioxane for 30 minutes at 20°C. The solution is concentrated to dryness under reduced pressure (2.7 kPa), the residue is taken up in ethanol (150 cc) the resulting solution is refluxed for 30 minutes and then concentrated to dryness. The solid obtained is washed with ethyl ether (50 cc), drained and dried. (4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride (3.64 g) is obtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, cm'1) : 3060, 3030, 3000, 2250, 1600, 1495, 1580, 1450, 755, 710, 700.

Proton NMR spectrum (DMSO-d6, main signals): 2.2 to 2.9 5 (mt, 4H, CH2 at 2 and CH2 at 3); 2.4 and 3.3 (2mt, 2H, CH2 at 5); 3.08 (d, J=12.5, ΙΗ, 1H at 7); 3.7 (mt, 1H, H at 4a); 4.16 (t, J=5, 1H, H at 7a); 7.1 to 7.5 (mt, 10 H, aromatics). (4 aRS,7 aRS)-4,4-Diphenyl-6-vinyloxycarbonyl10 perhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: Vinyl chloroformate (1.72 cc) is added to (4aRS,7aRS) -6-benzyl-4,4-diphenylperhydroth iopyrano[2,3-c]pyrrole (6.2 g), in 1,2-dichloroethane (50 cc).

The mixture is refluxed for 15 minutes and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 25 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions (60 cc). Fractions 5 to 16 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in diisopropyl oxide (70 cc), the suspension is filtered, the solid drained and dried. (4aRS,7aRS)-4,4-Diphenyl6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole (4.35 g) is obtained in the form of a white solid; m.p. = 160’C. 6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole (4.35 g) is obtained in the form of a white solid; m.p. = 160*C. (4aRS,7aRS)-6-Benzyl-4,4-diphenylperhydro5 thiopyrano[2,3-c]pyrrole may be prepared in the following manner: Zirconium tetrachloride (43.7 g) is added to a solution of (4RS,4aSR,7aRS)-4-hydroxy-4-phenyl-6benzylperhydrothiopyrano[2,3-c]pyrrole (12.2 g) in benzene (180 cc). The reaction mixture is refluxed for 1 hour and then brought to 20’C and diluted with dichloromethane (200 cc). A 4N aqueous solution of sodium hydroxide (150 cc) is added to the resulting cooled solution. The suspension obtained is filtered, the filtrate is decanted, the organic phase is washed with a saturated aqueous solution of sodium chloride (200 cc), dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 5.2 cm, height 39 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions (125 cc). Fractions 19 to 32 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallised from diisopropyl oxide (200 cc), the crystals are drained and dried. (4aRS,7aRS)-6-Benzyl-4,4diphenylperhydro-thiopyrano[2,3-c]pyrrole (6.2 g) is obtained in the form of orange-coloured crystals; m.p. = 130’C. (4RS,4aSR,7aRS)-4-Hydroxy-4-phenyl-6benzylperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: A solution of (4aRS,7aSR)-6-benzyl-4oxoperhydrothiopyrano[2, 3-c]pyrrole (21.15 g) in anhydrous ethyl ether (150 cc) is added over 30 minutes to a solution of phenylmagnesium bromide prepared from bromobenzene (19.8 cc) and dry magnesium (4.52 g) in anhydrous ethyl ether (120 cc). The reaction mixture is stirred at the reflux temperature for 3 hours and then for 20 hours at 20’C. The mixture, to which ethyl ether (200 cc) has been added, is stirred with a saturated aqueous solution of ammonium chloride (600 cc). The aqueous phase is extracted with ethyl ether (200 cc), the two pooled ethereal extracts are washed with a saturated aqueous solution of sodium chloride (2 x 300 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35’C. (4RS,4aSR,7aRS)-4-Hydroxy-4-phenyl6-benzylperhydrothiopyrano[2,3-c]pyrrole (12.2 g) is obtained in the form of a white solid; m.p. = 137’C. (4aRS,7aSR)-6-Benzyl-4-oxoperhydrothio25 pyrano[2,3-c]pyrrole may be prepared in the following manner: Trifluoroacetic acid (5 drops) is added to a solution of 4-dehydrothiapyranone (20 g) and N-butoxyIE 921543 methyl-N-trimethylsilylmethylbenzylamine (54 cc) in anhydrous dichloromethane (100 cc) and the mixture is stirred for 4 hours while maintaining the temperature at 20’C. The reaction mixture is stirred with potassium carbonate (5 g), filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 9.2 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and then with the cyclohexane and ethyl acetate mixture (75/25 by volume), and collecting fractions (250 cc). Fractions 35 to 56 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). (4aRS,7aSR)-6-Benzyl-415 oxoperhydrothiopyrano[2,3-c]pyrrole (24 g) is obtained in the form of a yellow oil.

Infrared spectrum (CC14 solution, characteristic bands, cm'1): 3090, 3070, 3025, 2925, 2850, 2800, 2730, 1710, 1600, 1585, 1495, 1475, 1450, 700.

Proton NMR spectrum (CDC13, main signals): 2.42 (dd, J=10 and 7, IH, IH at 7); 2.66 (mt, 2H, CH2 at 5); 3.05 (mt, IH, H at 4a); 3.1 (dd, J=10 at 7.5, IH of CH2 at 7); 3.61 (s, 2H, N-CH2-Ar) ; 3.8 (dt, J=7.5 and 7, IH, H at 7a); 7.15 at 7.35 (mt, 5H aromatics).

EXAMPLE 2 By carrying out the procedure as in Example 1, using [2-(l-pyrrolidinyl)phenyl]acetic acid hydrobromide (1.85 g) and (4aRS,7aRS)-4,4-diphenylperhydrothiopyranof 2,3-c] pyrrole hydrochloride (2.0 g), (4aRs, 7aRS )-6-( 12-( 1-pyrrolidiny1) pheny 1 ] acetyl) -4,4 -diphenylperhydrothiopyranof 2,3-c] pyrrole (0.90 g) is obtained in the form of white crystals; m.p. = 166’C.

EXAMPLE,! λ solution of phenylacetyl chloride (1.15 cc) in dichloromethane (25 cc) is added over 5 minutes to a solution, cooled to O’C, of (4aRS,7aRS)-4,4-diphenyl10 perhydrothiopyrano[2,3-c]pyrrole hydrochloride (2.63 g) and triethylamine (2.42 cc) in di chloromethane (25 cc) . After stirring for one hour at O’C and one hour at 20*C, dichloromethane (20 cc) is added. The reaction mixture is washed with distilled vater (2 x 100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclochexane and ethyl acetate mixture (80/20 by volume) and collecting fractions (125 cc). Fractions 19 to 26 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). (4aRS,7aRS)-6-Phenylacetyl4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole (0.87 g) is obtained in the form of a white solid; m.p. = 210*C. EXAMPLE 1 Ethyl chloroformate (0.58 cc) is added to a solution of 2-hydroxyphenylacetic acid (0.92 g) in dry dichloromethane (30 cc). After stirring for 15 minutes at 20 *C, the mixture is cooled to -15’C and triethylamine (0.85 cc) is added. After stirring for 2 hours at -15’C, a suspension of (4aRS,7aRS)-4,45 diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride (2 g) and triethylamine (1.70 cc) in dichloromethane (30 cc) is added over 20 minutes. After stirring for 20 hours at 20’C, the reaction mixture is washed with IN hydrochloric acid (50 cc), a saturated aqueous solution of sodium chloride (50 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from dichloromethane (20 cc), the crystals are washed with diisopropyl oxide, drained and dried under reduced pressure (2.7 kPa). (4aRS,7aRS)-4,4-Diphenyl-6-[(2hydroxypheny1) acetyl]perhydrothiopyrano[2,3-c]pyrrole (1.02 g) is obtained in the form of white crystals; m.p. = 248’C.

EXAMPLE 5 Ν,Ν'-Carbonyldiimidazole (1.13 g) is added to a solution, cooled to 0’C, of 2-methoxyphenylacetic acid (1.16 g) in dry dichloromethane (20 cc). The mixture is stirred for 40 minutes at 0’C and then a solution of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano25 [2,3-c]pyrrole hydrochloride (2.15 g) and triethylamine (0.9 cc) in dichloromethane (20 cc) is added. The reaction mixture is stirred for one hour at 0’C and it is then washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with ethyl ether (30 cc), diisopropyl oxide (30 cc) and it is then dried under reduced pressure (2.7 kPa). (4aRS,7aRS)-4,4-Diphenyl-6-[(2-methoxyphenyl)acetyl]perhydrothiopyrano(2,3-c]pyrrole (2.66 g) is obtained in the form of a white solid; m.p. = 172*C. EXAHPLE__6 6-((S)-2-(2-Methoxyphenyl)propionyl]-4,4diphenylperhydrothiopyranof 2,3-c] pyrrole - mixture of the (4aR,7aR) and (4aS,7aS) forms - may be prepared by carrying out the procedure as described in Example 5, using (S)-2-(2-methoxyphenyl) propionic acid (0.89 g) and (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride. 6-((S)-2-(2-Methoxyphenyl)propionyl]-4,4-diphenylperhydrothiopyrano(2,3-c]pyrrole - mixture of the (4aR,7aR) and (4aS,7aS) forms - (1.46 g) is obtained in the form of a white meringue.

First form: Infrared spectrum (characteristic bands, cm1): 3095, 3055, 3025, 2950, 2930, 2875, 2835, 1630, 1595, 1490, 1565, 1425, 1240, 1030, 750, 700.

Proton NMR spectrum (DMSO-d6 + CFjCOOD, at room temperature, a mixture of the two rotamers is observed; characteristic signals): 1.15 and 1.20 (2d, J=7.5, 3H, CHj)ί 2.1-2.9 (mt, 5H, 2 CH2 at 5 and 3 + H at 4a); 3.36 and 3.8 (2s, 3H, OCH3) ; 6.7 to 7.4 (mt, 14H, aromatics) Second form: Infrared spectrum (characteristic bands, cm'1): 3095, 3060, 3025, 2960, 2930, 2870, 2835, 1640, 1600, 1495, 1465, 1425, 1240, 1035, 755, 700.

Proton NMR spectrum (DMSO-d6 + CF3COOD, at room temperature, a mixture of the two rotamers is observed; characteristic signals): 1.1 and 1.18 (2d, J=7.5, 3H, CH3) ; 2.1-2.35 (mt, 2H, CH2 at 3); 2.35-3.10 (mt, 3H, CH2 at 5 + H at 4a); 3.6 and 3.8 (2s, 3H, OCH3); 3.95 and 4.02 (mt, IH, H at 7a); 6.7 to 7.4 (mt, 14H, aromatics).

(S)-2-(2-Methoxyphenyl)propionic acid may be obtained in the following manner: (S)-2-(2-Methoxyphenyl)propionic acid may be prepared by analogy with the methods described by D.A. Evans et al., Tetrahedron, 41, 5525, (1988), according to the following procedure: Lithium hydroxide (1.52 g) is added to a solution, cooled to +5’C, of (4S, 5S) -4-methyl-5-phenyl-3-[ (S) -2-(2-methoxyphenyl) propionyl]-2-oxazolidinone (4.1 g) in tetrahydrofuran (60 cc) and water (30 cc). The reaction mixture is stirred for 3 hours at this temperature and then, after re-equilibrating to room temperature, ethyl acetate is added, the mixture decanted and the aqueous phase is acidified with a IN aqueous solution of hydrochloric acid, extracted with ethyl acetate and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallised from hexane, drained and dried. (S)-2-(2-Methoxyphenyl)propionic acid (0.4 g) is obtained in the form of white crystals; m.p. = 102’C. [e]J° = +84.6· (c-l? CHClj) . (4S,5S)-4-Methyl-5-phenyl-3-[(S)-2-(2methoxy-pheny1) propionyl]-2-oxazolidinone may be obtained in the following manner: Sodium 1,1,1,3,3,3-hexamethyldisilazanate (19.1 g) is added to a solution, cooled to -50*C, of (4 S,5S) -4-methyl-5-phenyl-3-[(2-methoxypheny1) acetyl]2-oxazolidinone (10 g) in tetrahydrofuran (150 cc) and the mixture is stirred for 45 minutes at this temperature and then methyl iodide (7.72 cc) is added.

The reaction mixture is then stirred for 15 hours at room temperature and then diluted with ethyl acetate, washed with water (50 cc) and then with a saturated agueous solution of sodium chloride (50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallised from isopropyl oxide, drained and dried. (4S,5S)-4-Methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)propionyl]-2-oxazolidinone (4.2 g) is obtained in the form of a white solid. (4S,5S)-4-Methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone may be obtained in the following manner: 2-Methoxyphenylacetic acid (9.38 g) is added to a suspension of sodium hydride (1.89 g) (80% dispersion in vaseline) in dry tetrahydrofuran (200 cc), at room temperature. This suspension is cooled to -30°C, pivaloyl chloride (7.77 cc) is added and then a solution, cooled to -78°C, which is obtained by adding a 1.6 M solution of butyllithium (35.27 cc) in hexane to a solution, cooled to -78°C, of (4S,5S)-4-methyl-5-phenyl-2-oxazolidinone (10 g) in dry tetrahydrofuran (200 cc) is finally added. The reaction mixture is stirred for 45 minutes at -30°C and after re-equilibrating to room temperature, a saturated aqueous solution of ammonium chloride (200 cc) is added followed by ethyl acetate (500 cc); after decantation, the organic phase is washed with water (2 x 100 cc) and then with a saturated aqueous solution of sodium chloride (2 x 100 cc); dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040.06 mm, diameter 4.8 cm, height 36 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (85/15 followed by 80/20 by volume) and collecting fractions (50 cc). Fractions 14 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). (4S,5S)-4-Methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone (13.6 g) is obtained in the form of a yellow oil. ,e 921543 EXAMPLE 7 By carrying out the procedure according to that described in Example 8 below, using (lRS,4aRS,7aRS)-4,4diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide (1.82 g) and [(3-dimethylamino-2-propoxy)phenyl]acetic acid (1.39 g), (lRS,4aRS,7aRS)-6-{[(3-dimethylamino-2propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3c]pyrrole 1-oxide (0.3 g) is obtained in the form of white crystals; m.p. = 150°C.

(IRS,4aRS,7aRS)-4,4-Diphenylperhydrothio-pyrano[2,3c]pyrrole 1-oxide may be prepared in the following manner: 4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the IRS,4aSR,7aSR and IRS,4aRS,7aRS isomers) (3.98 g) is treated with a mixture (40 cc) of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 by volume) for 48 hours at 20°C. The solution is concentrated to dryness at 40°C under reduced pressure (2.7 kPa). The oil obtained is taken up in dichloromethane (30 cc), the solution is washed with a 2N aqueous solution of sodium hydroxide (60 cc), the aqueous phase is extracted with dichloromethane (20 cc). The organic extracts are pooled, dried over magnesium sulphate, concentrated to dryness at 40°C under reduced pressure (2.7 kPa). The residue is taken up in diisopropyl oxide and it is then concentrated to dryness at 40°C under reduced pressure (2.7 and then 0.13 kPa). (lRS,4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (3.0 g) is obtained in the form of a white meringue.

Infrared spectrum (KBr, characteristic bands, cm'1) : 3080, 3055, 3025, 2950, 2920, 2880, 2860, 1595, 1580, 1490, 1440, 1020, 760, 740, 700.

Proton NMR spectrum (DMSO-d6 + CFjCCOD, main signals) : 2.26 (broad t, J=14, IH, IH at 3); 2.42 (dd, J=10 and 9, IH, CH2 at 5); 2.55 (broad dd, J=14 and 4, IH, IH at 3); 3.68 (t, J=6, IH, H at 7a); 3.82 (d, J=14, IH, H at 7); 3.8 to 4 (mt, IH, CH at 4a); 4.15 (dd, J=14 and 6, IH, H at 7); 7.1 to 7.5 (mt, 10H aromatics). 4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the IRS,4aSR,7aSR and IRS,4aRS,7aRS isomers) may be prepared in the following manner: A solution of 3-chloroperoxybenzoic acid (2.3 g) (at 85%) in dichloromethane (20 cc) is added to a solution, cooled to 0’C of (4aRS,7aRS)-4,4-diphenyl20 6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole (4.2 g) in dry dichloromethane (30 cc). After stirring for 1.5 hours at 3°C, and 1.5 hours at 20°C, the reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate (2 x 100 cc) and then with distilled water (100 cc), dried over magnesium sulphate, concentrated to dryness at 35°C under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl oxide, drained and then dried under reduced pressure (2.7 kPa). 4,4-Diphenyl-6-tertbutyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide - (mixture of the IRS,4aSR,7aSR and IRS,4aRS,7aRS isomers) (3.98 g) is obtained in the form of white crystals which are used as they are in the next reaction. (4aRS,7aRS)-4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyranof2,3-c]pyrrole may be prepared in the following manner: Ditert-butyl dicarbonate (2.89 g) is added in fractions (0.5 g) to a suspension of (4aRS,7aRS)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride (4.0 g) and triethylamine (1.70 cc) in dry dichloromethane (60 cc), followed by 4-dimethylaminopyridine (0.15 g). The mixture is stirred for 20 hours at 20*C and then the reaction solution is washed with an aqueous solution of citric acid of pH 4 (2 x 100 cc), with water (100 cc) dried over magnesium sulphate, and concentrated to dryness at 35’C under reduced pressure (2.7 kPa). The residue is crystallised from ethyl ether, the crystals are drained and dried. (4aRS,7aRS)-4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole (4.27 g) is obtained in the form of pink crystals; m.p. = 162”C.

(IRS,4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide may also be prepared in the following manner: A solution of 3-chloroperoxybenzoic acid (15.4 g) (at 85%) in dichloromethane (400 cc) is added over 40 minutes to a solution, cooled to -3°C, of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c] 5 pyrrole (25 g) in dichloromethane (500 cc) and methanol (100 cc). After stirring for one hour at -3°C, the reaction mixture is washed with a 10% aqueous solution of potassium hydrogen carbonate (200 cc) and with this same solution (100 cc) and then dried over magnesium sulphate and concentrated to dryness at 40°C under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate (50 cc), the crystals are taken up in dichloromethane (200 cc), the solution obtained is washed with a IN aqueous solution of sodium hydroxide (75 cc) and then dried over magnesium sulphate and concentrated to dryness. The residue is crystallised from ethyl acetate (30 cc), the crystals are washed with ethyl acetate, drained and dried. (lRS,4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole l-oxide (13.6 g) is obtained in the form of white crystals; m.p. = 174’C.

EXAMPLE 8 Hydroxybenzotriazole hydrate (0.03 g) is added to a solution, cooled to O’C, of (IR*,4aR*,7aR*)25 (-)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (1.06 g) and 2-[(3-dimethylamino-2-propoxy)phenyl]acetic acid (0.81 g) in dry dichloromethane (60 cc), followed by 1-(3-dimethylaminopropyl)-3IE 921543 ethylcarbodiimide (0.77 g) . After stirring for 2 hours at 0*C and 20 hours at 20’C, the reaction mixture is washed with water (20 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 35 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions (50 cc). Fractions 8 to 19 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in dichloromethane (60 cc), the solution is washed with a IN aqueous solution of sodium hydroxide (20 cc), dried over magnesium sulphate and then concentrated to dryness.

The solid obtained is recrystallised from an ethyl acetate and ethyl ether mixture, the crystals are washed with diisopropyl oxide, drained and dried. (lR*,4aR*,7aR*) -(-) -6-(2-( (3-Dimethylamino-220 propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.99 g) is obtained in the form of a white solid; m.p. = 120’C. [at]20 = -323’ (c=0.5; acetic acid).

(IR*, 4aR*, 7aR*) -(-)-4,4-Diphenylperhydro25 thiopyrano(2,3-c]pyrrole 1-oxide may be prepared in the following manner: (S)-Mandelic acid (3.5 g) and a mixture of acetonitrile and water (99/1 by volume) (90 cc) are added to (IRS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (7.15 g). After stirring, the resulting solution is allowed to stand for 48 hours at room temperature. The crystals obtained are drained, washed with the acetonitrile-water mixture, and then dried. The crystals are taken up in boiling acetonitrile-water mixture (200 cc) and after filtration while still hot, the solution obtained is allowed to stand for 5 hours at room temperature. The crystals are drained, washed with acetonitrile (2 x 10 cc) and then dried. (lR*,4aR*,7aR*)-4,4Diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate (1.5 g) is obtained; [a]*0 = -228°, (c=0.44; acetic acid). The filtrate is allowed to stand for 20 hours at room temperature, the crystals obtained are drained, washed with acetonitrile (2x5 cc) and then dried. (IR*,4aR*,7aR*)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate (0.62 g) is obtained; [a]*0 = -230°, (c=0.45; acetic acid).

Dichloromethane (40 cc) and IN aqueous sodium hydroxide (7.0 cc) are added to (lR*,4aR*,7aR*)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)mandelate (2.06 g). The mixture is stirred for a few minutes after dissolution of the starting product, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is disintegrated in a mixture of ethyl acetate and ethyl ether, the solid is washed with diisopropyl oxide and dried. (lR*,4aR*,7aR*)-(-)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (1.14 g) is obtained in the form of a white solid; m.p. = 192*C. [a]*0 = -405*, (c=0.46; acetic acid).

EXAMPLE 9 Hydroxybenzotriazole hydrate (0.03 g) is added to a solution, cooled to +5°C, of (IRS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.69 g) and ([3-(1-pyrrolidinyl)-210 propoxy]phenyl)acetic acid (0.68 g) in dry dichloromethane (25 cc), followed by a solution of 1(3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride (0.5 g) in dry dichloromethane (20 cc). After stirring for 2 hours at +5°C and 20 hours at ’C, the reaction mixture is washed with distilled water (2 x 50 cc) and dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 32 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate, acetic acid and water mixture (80/20/20 by volume) and collecting fractions (25 cc). Fractions 21 to 50 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate (8 cc), the crystals are washed with ethyl acetate and diisopropyl oxide and then dried. (lRS,4aRS,7aRS)-6{{[3-(1-pyrrolid inyl) -2-propoxy]phenyl}acetyl)-4,4IE 921543 diphenylperhydrothiopyrano-[ 2,3-c] pyrrole 1-oxide (0.45 g) is obtained in the form of beige crystals; m.p. 126‘C.

EXAMPLE -LQ Hydroxybenzotriazole hydrate (0.06g) and 1-(3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.01 g) are added to a solution, cooled to about O’C, of (IR*, 4aR*, 7aR*) -(-)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (1.43 g) and (S)-2-(2-methoxy10 phenyl)propionic acid (0.83 g) in dry dichloromethane (100 cc) . After stirring for 2 hours at O’C and 2 hours at 20’C, the reaction mixture is washed with water (50 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in acetonitrile, the crystals are drained, washed several times with ethyl ether and then dried.

(IR*, 4aR*, 7aR*) -6-[ (S)-(-)-2-(2-Methoxyphenyl ) propionyl) -4,4-diphenylperhydrothiopyrano20 [2,3-c]pyrrole 1-oxide (1.56 g) is obtained in the form of white crystals? m.p. = 170’C. [a]*0 = -316’C (c=0.50; acetic acid).

EXAMPLE. 11 By carrying out the procedure as described in Example 1 above, using 2-dimethylaminophenylacetic acid (0.49 g), N,N'-carbonyldiimidazole (0.50 g), triethylamine (0.70 cc) and (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c)pyrrole 1,1-dioxide hydrochloride (1.0 g), (4aRS,7aRS)-6-(2-dimethylaminophenyl)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (0.55 g) is obtained in the form of white crystals; m.p. = 226’C.

EXAMPLE 12 Triethylamine (0.35 cc) and a solution of phenylacetyl chloride (0.17 cc) in dichloromethane (5 cc) is added to a suspension, cooled to 0’C, of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]10 pyrrole 1,1-dioxide hydrochloride (0.46 g) in dichloromethane (10 cc). After stirring for 1 hour at 0’C and then 1 hour at 20°C, the reaction mixture is diluted with dichloromethane (10 cc), washed with distilled water (2 x 30 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallised from ethyl ether (30 cc), the crystals are drained and dried. (4aRS,7aRS)-4,4-Diphenyl-6-phenylacetylperhydro thiopyrano[2,3-c]pyrrole 1,1-dioxide (0.50 g) is obtained in the form of white crystals.

Infrared spectrum (characteristic bands, cm'1): 3050, 3025, 2970, 2930, 1880, 1630, 1595, 1495, 1455, 1425, 1330, 1305, 1140, 1120, 765, 755, 700, 510.

Proton NMR spectrum (DMSO-d6 + CF3CCOD, main signals, a mixture of the two rotamers is obtained at room temperature): 2.48 (mt, 1H, CH2 at 3); 2.8 (mt, ΙΗ, 1H at 5); 3.39 and 3.65 (s and ab J=14, 2H, N-CO-CH2) ; 6.S to 7.6 (mt, 15H, aromatics). (4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride may be prepared in the following manner: (4aRS,7aRS)-4,4-Diphenyl-6-vinyloxycarbonyl 5 perhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (0.58 g) is treated with a 5.7 N solution of hydrochloric acid (25 cc) in dry dioxane for 30 minutes while making lukewarm. The reaction solution is concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. The residue is taken up in ethanol (15 cc), the solution obtained is refluxed for 30 minutes and it is then concentrated to dryness. The solid obtained is washed with ethyl ether, drained and dried. (4aRS,7aRS)-4,4Diphenyl-perhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride (0.46 g) is obtained in the form of a white solid.

Infrared spectrum (characteristic bands, cm'1) : 3055, 3030, 2970, 2935, 2825, 2300, 1600, 1495, 1462, 1335, 1315, 1300, 1140, 1120, 770, 760, 710, 595, 505.

Proton NMR spectrum (DMSO-d6 + CFjCCOD, main signals): 3.84 (ab, 2H, CH2 at 7); 4.0 (mt, IH, H at 4a); 4.27 (mt, IH, H at 7a); 7.1 to 7.6 (mt, 10H, aromatics). (4aRS,7aRS)-4,4-Diphenyl-6-vinyloxycarbonyl perhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide may be prepared in the following manner: Vinyl chloroformate (0.16 cc) is added to a solution of (4aRS,7aRS)-6-benzyl-4,4-diphenylperhydro thiopyrano[2,3-c]pyrrole 1,1-dioxide (0.7 g) in 1,2-dichloroethane (10 cc). The mixture is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. The crystalline solid is washed with ethyl ether, drained and then dried. (4aRS,7aRS)-4,4-Diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (0.58 g) is obtained in the form of white crystals.

Infrared spectrum (characteristic bands, cm'1) : 3080, 3055, 3025, 2990, 2970, 2925, 2885, 1715, 1645, 1595, 1580, 1495, 1415, 1330, 1300, 1150, 1140, 1125, 945, 865, 755, 700, 510.

Proton NMR spectrum (DMS0-d6 + CF3COOD, main signals): 2.5 to 3.45 (mt, 6H, CH2 at 5, at 2 and at 3); 3.8 to 4.2 (mt, 4H, CH2 at 7, H at 4a and H at 7a); 4.46 and 4.72 (broad 2d, J=6 and J=14, 2xlH, CH=CH2) ; 7.0 (dd, J=14 and 6, IH, OCH=); 7.1 to 7.6 (mt, 10H, aromatics). (4aRS,7aRS)-6-Benzyl-4,4-diphenylperhydrothiopyranof2,3-c]pyrrole 1,1-dioxide may be prepared in the following manner: Trifluoroacetic acid (2 drops) is added to a solution of 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide (1.3 g) and N-butoxymethyl-Ntrimethylsilylmethylbenzylamine (1.75 cc) in anhydrous dichloromethane (12 cc) and the mixture is stirred for minutes at 30°C. N-Butoxymethyl-N-trimethylsilylmethylbenzylamine (1.75 cc) and trifluoroacetic acid (2 drops) are again added and the mixture is stirred for 2 hours at 35°C. This last operation is again repeated and after stirring for 1 hour, potassium carbonate (1 g) is added. The suspension is filtered, the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (80/20 by volume) and collecting fractions (30 cc). Fractions 20 to 28 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). (4aRS,7aRS)-6-Benzyl-4,4diphenylperhydrothiopyrano-[2,3-c]pyrrole 1,l-dioxide (0.7 g) is obtained in the form of white crystals; m.p. = 186’C. 3,4-Dihydro-4,4-diphenyl-2H-thiapyran . 1,l-dioxide may be prepared in the following manner: A solution of 3-chloroperoxybenzoic acid (1.12 g) (at 85%) in dry dichloromethane (25 cc) is added to a solution of 3,4-dihydro-4,4-diphenyl-2H20 thiapyran 1-oxide (1.47 g) in dry dichloromethane (15 cc). After stirring for 20 hours at 20’C, the reaction mixture is washed with a 10% aqueous solution of sodium thiosulphate (50 cc) and then with a saturated aqueous solution of sodium hydrogen carbonate (50 cc). The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The crystalline residue is washed with ethyl ether, drained, and dried under reduced pressure (2.7 kPa). 3,4-Dihydro-4,4-diphenyl-2Hthiapyran 1,1-dioxide (1.3 g) is obtained in the form of white crystals; m.p. = 166’C. 3,4-Dihydro-4,4-diphenyl-2H-thiapyran 1-oxide 5 may be prepared in the following manner: By carrying out the procedure as above, using 3,4-dihydro-4,4-diphenyl-2H-thiapyran (2.05 g) and 3-chloroperoxybenzoic acid (1.67 g) (at 85%), 3.4- dihydro-4,4-diphenyl-2H-thiapyran l-oxide (1.9 g) is obtained in the form of a white solid; m.p. = 130°C. 3.4- Dihydro-4,4-diphenyl-2H-thiapyran may be prepared in the following manner: Acetic anhydride (3.95 cc) is added to a suspension of 4,4-diphenyltetrahydrothiapyran 1-oxide (2.7 g) in anhydrous toluene (30 cc). The mixture is refluxed for 20 hours and concentrated to dryness at 60°C under reduced pressure (2.7 kPa and then 0.13 kPa). The oily residue is crystallised from diisopropyl oxide, the crystals are drained and dried. 3,4-Dihydro-4,4-diphenyl-2H-thiapyran (2.1 g) is obtained in the form of white crystals? m.p. = 78°C. 4.4- Diphenyltetrahydrothiapyran 1-oxide may be prepared in the following manner: A solution of 3-chloroperoxybenzoic acid (20.3 g) (at 85%) in dichloromethane (300 cc) is added over 40 minutes to a solution, cooled to 0’C, of 4.4- diphenyltetrahydrothiapyran (25.4 g) in dichloromethane (130 cc). After stirring for 2 hours at 0’C, a 5% aqueous solution of potassium hydrogen carbonate (250 cc) is added to the mixture and then stirred for 15 minutes. The organic phase is again washed with the potassium hydrogen carbonate solution (250 cc) and it is then dried over magnesium sulphate, concentrated to dryness (after verifying the absence of peroxides), under reduced pressure (2.7 kPa). 4,4-Diphenyltetrahydrothiapyran 1-oxide (26.9 g) is obtained in the form of a white solid; m.p. = 122°C. 4,4-Diphenyltetrahydrothiapyran may be prepared in the following manner: Sodium sulphide nonahydrate (100 g) is added to a suspension of 3,3-diphenyl-l,5-bis(methanesulphonyl oxy) pent ane (140.8 g) in 1-butanol (1400 cc).

The mixture is refluxed for 2 hours and then cooled to about 20’C, and water (1000 cc), ethyl acetate (500 cc) and dichloromethane (500 cc) are then added. After stirring, the organic phase is separated, washed successively with water (1000 cc), IN hydrochloric acid (500 cc), a saturated aqueous solution of sodium hydrogen carbonate (500 cc) and water (1000 cc), and then dried over magnesium sulphate and concentrated to dryness at 60’C under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are washed with diisopropyl oxide, drained and dried. 4,4-Diphenyltetrahydrothiapyran (76 g) is obtained in the form of white crystals; m.p. = 134’C. 3,3-Diphenyl-l,5-bis(methanesulphonyloxy)IE 921543 pentane may be prepared in the following manner: A solution of methanesulphonyl chloride (62 cc) in dichloromethane (100 cc) is added over 10 minutes to a solution, cooled to -20°C, of 3,3-diphenyl-l,5-pentanediol (95 g) (prepared according to P. EILBRACHT et al., Chem. Ber. 118. 825-839 (1985)) in dichloromethane (950 cc) and triethylamine (113 cc). After stirring for 2 hours at 2O’C, the reaction mixture is washed with water (2 x 500 cc), the organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallised from ethyl ether, the crystals are washed with ethyl ether, drained and dried. 3,3-Diphenyl-l,5-bis(methanesulphonyloxy)pentane (140 g) is obtained in the form of white crystals; m.p. = 99’C.

EXAMPLE 13 A solution of (4aRS,7aRS)-4,4-diphenyl-6-[2(2-hydroxyphenyl) acetyl]perhydrothiopyrano[2,3-c]20 pyrrole (1.4 g) in a mixture of dimethylformamide, toluene and anhydrous tetrahydrofuran (15/10/5.5 by volume) is added over 30 minutes to a suspension of sodium hydride (0.12 g) in anhydrous toluene (10 cc). A solution of N-(3-chloropropyl)-Ν,Ν-dimethylamine (3 g) in anhydrous toluene (10 cc) is added to the solution obtained heated to 35°C. The reaction mixture is refluxed for 15 minutes, stirred at 20°C for 20 hours, then diluted with ethyl acetate (100 cc) and then washed with distilled water (2 x 150 cc) and brine (100 cc). The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa). (4aRS,7aRS)-6-{2-[2-(3dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole (1.18 g) is obtained in the form of beige crystals; m.p. = 130°C.

EXAMPLE 14 Triethylamine (1.16 cc) is added dropwise to a suspension of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride (1.5 g) and l-ethoxy-l-imino-2-(2-methoxyphenyl)ethyl hydrochloride (0.95 g) in 1,2-dichloroethane (15 cc).

After stirring for 20 hours at 20°C, dichloromethane (30 cc) is added to the mixture and then washed successively with water (100 cc) and a 5% aqueous solution of potassium carbonate (100 cc). The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from an acetonitrile and diisopropyl oxide mixture. The crystals are washed with acetonitrile and then with diisopropyl oxide, drained and dried. (4aRS,7aRS)-6-[lImino-2-(2-methoxyphenyl)-ethyl]-4,425 diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide (0.83 g) is obtained in the form of white crystals; m.p. = 240°C. lE 921543 EXAMPLE 15 A solution of 3-chloroperoxybenzoic acid (0.88 g) (at 85%) in dichloromethane (15 cc) is added to a stirred solution, cooled to 0°C, of (4aRS,7aRS)-6-[(2-dimethyl5 aminophenyl)acetyl]-4,4-diphenylperhydro-thiopyrano[2,3c]pyrrole (1.88 g) in dichloromethane (30 cc). The reaction mixture is stirred for 2 hours at 0°C, washed with a saturated aqueous solution of sodium bicarbonate (2 x 30 cc) and then with water (30 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The yellow oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate and methanol mixture (98/2 by volume) and collecting fractions (60 cc). Fractions 9 to 32 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallised from acetonitrile (10 cc), the crystals are drained, filtered and dried. (lRS,4aSR,7aSR)-6-[(2-Dimethyl20 aminophenyl)-acetyl]-4,4-diphenylperhydrothiopyrano-[2,3c]pyrrole 1-oxide (0.93 g) is obtained in the form of white crystals; m.p. = 204°C.

Fractions 33 to 50 are pooled and concentrated to dryness and then the residue is purified by chromatography under the same conditions as above (eluent ethyl acetate and methanol 94/6 by volume).

Fractions 76 to 86 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from acetonitrile, the crystals are drained and dried. (lRS,4aRS,7aRS)-6-[(2-Dimethylaminophenyl) acetyl]-4,4-diphenylperhydrothiopyrano5 [2,3-c]pyrrole 1-oxide (0.28 g) is obtained in the form of a white solid; m.p. = 190*C.

(IRS,4aRS,7aRS)-6-[(2-Dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide may also be prepared in the following manner: (IRS,4aSR,7aSR)-6-((2-Dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (2.46 g) in a mixture (25 cc) of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 by volume) is stirred for 48 hours at 20°C. The solution is then neutralised at 10’C with a 4N aqueous solution of sodium hydroxide (20 cc). The decanted organic phase is washed with distilled water (50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 30°C. The oily residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 34 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions (25 cc). Fractions 72 to 92 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 40*C. The residue is crystallised from ethyl acetate, the crystals are washed with diisopropyl oxide, and then drained and dried.

(IRS,4aRS,7aRS)-6-[(2-Dimethylaminophenyl)acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (1.08 g) is obtained in the form of white crystals; m.p. = 190*C.

EXAMPLE 16 A solution of 3-chloroperoxybenzoic acid (0.83 g) (at 85%) in dichloromethane (15 cc) is added to a solution, cooled to O’C, of (4aRS,7aRS)-6-{[2-(1pyrrolidinyl) phenyl]acetyl)-4,4-diphenylperhydrothio10 pyrano[2,3-c]pyrrole (1.85 g) in dichloromethane (30 cc). After stirring for 1 hour at O’C and 2 hours at room temperature, the reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate (50 cc) and then with water (2 x 30 cc). The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in a mixture of concentrated hydrochloric acid and dioxane (19 cc) (1/2 by volume). After stirring for 48 hours at 20’C, 4N sodium hydroxide (15 cc) is added to the resulting solution and then extracted with dichloromethane (30 cc). The organic phase is washed with water (40 cc) and then dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 40 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions (25 cc). Fractions 100 to 119 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are drained and dried.

(IRS,4aSR,7aSR)-6-{[2-(1-Pyrrolidinyl) phenyl]acetyl)5 4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.11 g) is obtained in the form of a white solid; m.p. = 190*0.

EXAMPLE 17 By carrying out the procedure as in Example 10 16, pooling and concentrating to dryness the chromatographic fractions 123 to 148, a residue is obtained which is crystallised from ethyl acetate. The crystals are drained, washed with ethyl acetate and diisopropyl oxide and dried. (IRS,4aRS,7aRS)-6-{[2-(115 Pyrrolidinyl)phenyl]acetyl)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.39 g) is obtained in the form of a white solid; m.p. = 198°C.

EXAMPLE 18 Trifluoroacetic acid (0.15 cc) is added to a solution of (4aRS,7aRS)-6-{2-[2-(3-dimethylaminopropoxy) phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole (0.5 g) in dry dichloromethane (5 cc), and then cooled to 0*C. After stirring for 30 minutes at O’C, a solution of 3-chloroperoxybenzoic acid (at 85%) in dichloromethane (10 cc) is added dropwise. The reaction mixture is stirred for 2 hours at O’C, then diluted with dichloromethane (10 cc) and then washed with IN sodium hydroxide (20 cc) and a saturated aqueous solution of sodium chloride (20 cc). The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under a nitrogen pressure of 1 bar with an ethyl acetate, acetic acid and water mixture (80/10/10) and collecting fractions (25 cc). Fractions 13 to 21 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from an ethyl acetate and diisopropyl oxide mixture, the crystals are drained and dried.

(IRS,4aSR,7aSR)-6-(2-[2-(3-Dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]15 pyrrole (0.13 g) is obtained in the form of a beige solid; m.p. = 146°C.

EXAMPLE 19 By carrying out the procedure as described in Example 15 above, using (4aRS,7aRS)-4,4-diphenyl-620 phenylacetylperhydrothiopyrano[2,3-c]pyrrole (0.99 g) and 3-chloroperoxybenzoic acid (0.49 g), (IRS,4aSR,7aSR)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.54 g) is obtained after chromatography in the form of white crystals; m.p. = 217*C.

EXAMPLE20 By carrying out the procedure as described in Example 15 above, using (4aRS,7aRS)-4,4-diphenyl-6IE 921543 phenylacetylperhydrothiopyrano[2,3-c]pyrrole (0.99 g) and 3-chloroperoxybenzoic acid (0.49 g) , (IRS,4aRS,7aRS)-4,4-diphenyl-6-phenylacetylperhydrothiopyranof2,3-c]pyrrole 1-oxide (0.17 g) is obtained after chromatographic purification in the form of white crystals? m.p. = 226’C.

EXAMPLE 21 By carrying out the procedure as in Example 15 above, using (4aRS,7aRS)-4,4-diphenyl-6-[(2-methoxy10 phenyl)acetyl]perhydrothiopyrano[2,3-c]pyrrole (0.95 g) and 3-chloroperoxybenzoic acid (0.43 g) (at 85%), (IRS,4aSR,7aSR)-6-[(2-methoxyphenyl)acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (1.0 g) is obtained after chromatographic purification in the form of a white solid; m.p. = 240’C, as well as (IRS,4aRS,7aRS)-6-[(2-methoxyphenyl) acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.15 g), in the form of a white solid; m.p. = 254’C.

EXAMPLE 22 A solution of 3-chloroperoxybenzoic acid (0.69 g) (at 85%) in dichloromethane (15 cc) is added to a solution, cooled to 0’C, of 6-[(S)-2-(2-methoxyphenyl) propionyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole, mixture of the (4aR,7aR) and (4aS,7aS) forms, (1.46 g) in dichloromethane (15 cc). After stirring for 3 hours at +5’C, the reaction mixture is washed with a saturated aqueous solution of sodium bicarbonate (30 cc) and with water (2 x 30 cc), and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated for 48 hours at 20*C with a concentrated hydrochloric acid and dioxane mixture (1/2 by volume).

The resulting solution is washed with a 4N aqueous solution of sodium hydroxide (12 cc), with water (20 cc), and it is then concentrated to dryness at 40°C under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.02-0.045 mm, diameter 3.6 cm, height 40 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions (60 cc). Fractions 22 to 42 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 6-[(S)-2-(2-Methoxyphenyl)propionyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, mixture of the (lR,4aR,7aR) and (lS,4aS,7aS) forms, (0.4 g) is obtained in the form of a white solid. Infrared spectrum (characteristic bands, cm'1) : 3060, 3025, 2970, 2935, 2880, 2840, 1640, 1595, 1490, 1460, 1445, 1425, 1245, 1020, 755, 705.

Proton NMR spectrum (the mixture of the two rotamers of each form is observed at room temperature; characteristic signals): 1.2-1.4 (mt, 3H, CH3) ; 3.41, 3.60 and 3.87 (3s, 3H, OCHj) ; 6.5 to 7.4 (mt, 14H aromatics).

EXAMPLE 23 By carrying out the procedure as in Example 22, pooling and evaporating to dryness the chromatographic fractions 13 to 20, a residue is obtained which is crystallised from acetonitrile. The crystals are drained, washed with acetonitrile and diisopropyl oxide and then dried. 6-[(S)-2-(2-Methoxyphenyl) propionyl ]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide - mixture of the (lR,4aS,7aS) and (lS,4aR,7aR) forms - (0.02 g) is obtained in the form of a white solid.

Infrared spectrum (characteristic bands, cm'1) : 3060, 3030, 3000, 2970, 2935, 2880, 2840, 1640, 1595, 1490, 1485, 1460, 1445, 1420, 1370, 1240, 1050, 1040, 1030, 755, 705.

Proton NMR spectrum (DMSO-d6 + CF3COOD, a mixture of the two rotamers is obtained at room temperature; characteristic signals): 1.1-1.3 (mt, 3H, CH3) ; 3.35 and 3.81 (2s, 3H, OCHj) ; 6.7 to 7.5 (mt, 14H aromatics). EXAMPLE 24 A solution of (4aRS,7aRS)-6-[(2-methoxy20 phenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c] pyrrole (0.443 g) in dichloromethane (4.0 cc) is added to a solution, placed under a nitrogen atmosphere, of titanium tetraisopropylate (0.3 cc) in dichloromethane (10 cc) and water (0.018 cc). The mixture is cooled to -20°C and then a 70% aqueous solution of tertbutylhydroperoxide (0.16 cc) is added. After stirring for 6 hours at -20°C, the tert-butylhydroperoxide solution (0.01 cc) is added to the white suspension obtained. After 1 hour 30 minutes at -20°C, water (2.0 cc) is added to the reaction mixture and the gel obtained is filtered. The dichloromethane phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from acetonitrile, the crystals are taken up in dichloromethane and the solution obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar with ethyl acetate and then with an ethyl acetate and methanol mixture (90/10 by volume) and collecting fractions (30 cc). Fractions 5 and 6 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). (4aRS,7aRS)-6-[(215 Methoxyphenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,l-dioxide (0.06 g) is obtained in the form of a white solid; m.p. = 258°C. Fractions 24 and 25 are pooled and concentrated to dryness.

(IRS,4aSR,7aSR)-6-((2-Methoxyphenyl)acetyl]-4,420 diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (0.26 g) is obtained, after crystallisation from acetonitrile, in the form of a white solid; m.p. = 240°C.

The present invention also provides pharmaceutical compositions consisting of a product of general formula (I) or a salt, when these exist, optionally in combination with any other pharmaceutically compatible product, which may be inert or physiologically active. The compositions according to the invention may be used parenterally, orally, rectally or topically.

The sterile compositions for parenteral 5 administration which may be used in particular in the form of perfusions are preferably aqueous or nonaqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic esters for injections, for example ethyl oleate or other suitable organic solvents may be used as solvent or vehicle. These compositions may also contain adjuvants, in particular wetting, isotonising, emulsifying, dispersing and stabilising agents. Sterilisation may be performed in a number of ways, for example by asepticising filtration, by incorporating sterilising agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in a sterile medium for injection.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cacao butter, semisynthetic glycerides or polyethylene glycols.

Tablets, pills, powders or granules may be used as solid compositions for oral administration. In these compositions, the active product according to the invention (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch. These compositions may also comprise substances other than diluents, for example a lubricant such as magnesium stearate.

Emulsions which are pharmaceutically acceptable, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used as liquid compositions for oral administration. These compositions may also comprise substances other than diluents, for example wetting, sweetening or flavouring products.

The compositions for topical administration may be for example creams, pomades or lotions.

In human therapy, the products according to the invention may be particularly useful in the treatment of pain of traumatic, post-surgical, menstrual, or cephalic origin, in the treatments of anxiety, psychoses, Parkinson's disease, schizophrenia and Alzeimer's disease, in muscle-relaxant treatment, in the treatment of spasmodic, painful and inflammatory manifestations of the digestive tracts (ulcerative colitis, irritable colon syndrome, Crohn's disease), of the urinary tracts (cystitis) and of the respiratory tracts (asthma, rhinitis) or in gynaecology and in the treatment of migraines. The new thiopyranopyrrole derivatives are also useful in the treatment of rheumatoid arthritis and in disorders due to the perturbation of the immune system, in the treatments of dermatological inflammations such as psoriasis, herpes, urticarias, eczemas, photodermatitis and in eye or dental inflammatory disorders.

The products according to the invention may also find an application in the treatments of cardiovascular disorders such as hypotension.

The doses depend on the desired effect and on the duration of treatment. For an adult, they are generally between 0.25 and 1500 mg daily in graded doses.

Generally, the physician will determine the dosage which he judges to be most appropriate according to the age, the weight and all the other factors specific to the individual to be treated.

The following example illustrates a composition according to the invention.

Example Tablets of active product having the following composition are prepared according to the usual technique: (IRS,4aRS,7aRS)-6-{{[3-(1-Pyrrolidinyl) 2-propoxy]phenyl}acetyl}-4,4-dipheny1perhydrothiopyrano[2,3-c]pyrrole 1-oxide...............................

Starch mg 83 mg Silica................................ 30 mg Magnesium stearate.................... 3 mg

Claims (13)

1. Thiopyranopyrrole derivatives of the formula: 5 in which - X represents an oxygen atom or an NH radical, - R t represents phenyl, phenyl substituted by one or more halogen atoms or hydroxyl or alkyl radicals which may be optionally substituted (by halogen atoms or by 10 amino, alkylamino or dialkylamino radicals), or alkoxy or alkylthio radicals which may be optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals optionally substituted (by phenyl, hydroxyl or amino radicals) or by dialkylamino 15 radicals whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members which may contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl 20 radical)], or R, represents phenyl substituted by amino, alkylamino or dialkylamino radicals whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above, or R, represents a cyclohexadienyl, naphthyl or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulphur, - R 2 represents a hydrogen or halogen atom or a 5 hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, and 10 - n is 0, 1 or

2. , the abovementioned alkyl and acyl radicals being linear or branched and containing 1 to 4 carbon atoms each, in their stereoisomeric forms and mixtures thereof, and their salts when these exist. 15 2. 6-{[(3-Dimethylamino-2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide in its stereoisomeric forms and mixtures thereof.

3. 6-{{[3-(l-Pyrrolidinyl)-2-propoxyΙΣΟ phenyl}acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide in its stereoisomeric forms and mixtures thereof.

4. 6-[(S)-2-(2-Methoxyphenyl)propionyl]4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide in 25 its stereoisomeric forms and mixtures thereof.

5. 6-{2-[2-(3-Dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole in its stereoisomeric forms and mixtures thereof.

6. A method of preparing a thiopyranopyrrole derivative according to claim 1, which comprises reacting an acid of formula: R,-CH- COOH 1 I *2 in which Rj and R 2 are as defined in claim 1, or a reactive derivative of this acid, with a thiopyranopyrrole derivative of formula: in which n is as defined in claim 1, and the amide obtained is then optionally converted into an amidine in which X represents an NH radical and the product obtained is optionally converted into a salt when such 15 exists.

7. A method of preparing a thiopyranopyrrole derivative according to claim 1, in which R, represents an alkoxyphenyl radical whose alkyl part is optionally substituted, R 2 is other than a 20 hydroxyl radical, and n and X are as defined in claim 1, which comprises reacting a halogenated derivative of formula: R,-Hal in which R, is an alkyl radical which is optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals which are optionally substituted (by phenyl, hydroxyl or amino radicals), or a dialkylamino radical whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle as defined in claim 1 above] and Hal is a halogen atom, with a thiopyranopyrrole derivative according to claim 1, in which R, is a hydroxyphenyl radical, followed, where appropriate, by removal of the hydroxylprotecting radical and optionally converting the product obtained into a salt when such exists.

8. A method of preparing a thiopyranopyrrole derivative according to claim 1, in which X is an NH radical and R,, R 2 and n are as defined in claim 1, which comprises reacting a compound of formula: MB -B.-CH-C optionally in the form of a salt, in which Rj and R 2 are as defined in claim 1 and R 5 represents a linear or branched alkoxy radical containing 1 to 4 carbon atoms or a methylthio, ethylthio, benzylthio or alkoxycarbonylmethylthio radical, with a thiopyranopyrrole derivative of formula: in which n is as defined in claim 1, and optionally converting the product into a salt, when such exists.

9. A method of preparing a thiopyranopyrrole derivative according to claim 1, in which n equals 1 or 5 2, which comprises oxidizing a corresponding derivative according to claim 1 in which n equals 0, and optionally converting the product obtained into a salt when such exists.

10. A method of preparing a thiopyranopyrrole 10 derivative according to claim 1 substantially as described in any one of Examples 1 to 24.

11. A thiopyranopyrrole derivative according to claim 1, when prepared by a process as claimed in any one of claims 6 to 10. 15

12. A pharmaceutical composition which contains at least one product according to one of claims 1 to 5 or 11, combined with one or more compatible and pharmaceutically acceptable adjuvants or diluents.

13. A composition according to claim 12 20 substantially as hereinbefore described.