EP0587673A1 - Derivatives of thiopyranopyrrole and preparation thereof - Google Patents

Abstract

New thiopyranopyrrole derivatives of general formula (I) in which R is hydrogen, allyl or a radical of structure: -CRaRbRc in which Ra and Rb are hydrogen atoms or phenyl radicals possibly substituted (by halogen, alkyl, alkyloxy or nitro), and Rc is defined as Ra and Rb or represents an alkyl or alkyloxyalkyl radical, at least one of Ra, Rb and Rc being a substituted or unsubstituted phenyl radical, and n = 0 to 2, in their stereoisomeric forms and their mixtures, possibly their salts when they exist and their preparation. The new derivatives according to the invention are particularly advantageous as synthesis intermediates.

Description

 NOVEL THIOPYRANOPYRROLE DERIVATIVES AND THEIR PREPARATION

The present invention relates to new thiopyranopyrrole derivatives of general formula

as well as their salts when they exist, useful as intermediates for the preparation of thiopyranopyrrole derivatives antagonists of the effects of substance P.

In the US patent 4,042,707 were described products derived from the isoindole of general formula:

having an opiate activity.

These products have no activity with respect to substance P and are also not used for the synthesis of such products.

In European application 0068822, herbicides corresponding to the general formula have been described:

in which X can be a sulfur atom, R ₁ and R ₂ are hydrogen or alkyl and R is substituted phenyl.

So far, despite the research carried out and despite the interest aroused [M.R. Hanley, TINS, (5) 139 (1982)], there had practically been no product acting specifically on substance P and having a non-peptide structure, this is why the thiopyranopyrrole derivatives of general formula (I) are of considerable interest insofar as they allow access to such products. In the general formula (I), the symbol R represents a hydrogen atom, an allyl radical or a radical of structure:

- CR _a R _b R _c (la) in which R _a and R _b are hydrogen atoms or phenyl radicals optionally substituted (by a halogen atom, an alkyl, alkyloxy or nitro radical), and R _c is defined as R _a and R _b or represents an alkyl or alkyloxyalkyl radical, at least one of R _a , R, _b and R _c being a substituted or unsubstituted phenyl radical, and the symbol n represents an integer from 0 to 2 .

It is understood that the alkyl radicals mentioned above contain 1 to 4 carbon atoms in a straight or branched chain.

The products of general formula (I) have different steroisomeric forms; it is understood that thiopyranopyrrole derivatives of form (4aR, 7aR) or form (4aS, 7aS) in the pure state, or in the form of a mixture of the cis forms (4aRS, 7aRS), fall within the scope of the present invention.

In addition, the products of general formula (I) for which n = 1 also have axial or equatorial steroisomers at the level of the S-oxide. It is understood that the R and S derivatives in position -1 as well as their mixtures also come within the scope of the present invention. According to the invention, the thiopyranopyrrole derivative of general formula (I) can be obtained by treatment of the derivative of general formula:

in which R 'is defined as R except for representing the hydrogen atom, successively by a phenylmagnesium halide, then by benzene in the presence of zirconium tetrachloride, optionally followed by the elimination of the protective radical R' if one wants to obtain a product for which R is a hydrogen atom, and / or followed where appropriate by the oxidation of the product obtained, to obtain a thiopyranopyrrole derivative for which n = 1 or 2.

The treatment of the thiopyranopyrrole derivative of general formula (II) is carried out according to the usual methods. The treatment with a phenyl magnesium halide is advantageously carried out by means of phenyl magnesium bromide, in an ether (ethyl ether for example) at a temperature between 20 ° C. and the reflux temperature of the reaction mixture. Treatment with benzene in the presence of zirconium tetrachloride is carried out at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.

Where appropriate when it is desired to eliminate the radical R ′, one operates by any known method which does not affect the rest of the molecule.

In particular when R 'is other than an allyl radical, the group R' can be eliminated by catalytic hydrogenation in the presence of palladium. Generally, the reaction is carried out in an acid 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 R 'is a benzhydryl or trityl radical, the elimination can be carried out by treatment in an acid medium, operating at a temperature 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 R ′ can also be eliminated by causing vinyl chloroformate, 1-chloroethyl chloroformate or phenyl chloroformate to act, passing through a product of general formula:

 in which R "is a vinyl, 1-chloro ethyl or phenyl radical, then by elimination of the radical R" by acid treatment. The action of chloroformate is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example) or a ketone (acetone for example) or in a mixture of these solvents, operating at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

The elimination of the radical R "is carried out by treatment in an acid medium, for example with trifluoroacetic, formic, methanesulfonic, p.toluenesulfonic, 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 eliminating the radicals R "mentioned above, the thiopyranopyrrole derivative of general formula (I) is obtained directly in the form of a salt of the acid used.

When it is desired to obtain a thiopyranopyrrole derivative of general formula (I) for which n equals 1 or 2, the oxidation reaction is carried out by any known method for oxidation sulfides to sulfoxides or sulfones, which does not alter the rest of the molecule, on the product for which the amino function is protected. For example, the operation is carried out by the action of an organic peracid (percarboxylic or persulfonic acid, in particular perbenzoic acid, 3-chloro perbenzoic acid, 4-nitro perbenzoic acid, peracetigue acid, pertrifluoroacetic acid, performic acid, permaleigic acid, monoperphthalic acid, percamphoric or pertoluenesulfonic acid) or mineral peracids (for example periodic or persulfuric acid). The reaction is advantageously carried out in a chlorinated solvent (methylene chloride) at a temperature between 0 and 25 ° C. It is also possible to operate by means of tert-butyl hydroperoxide in the presence of titanium tetia-isopropylate.

When we want to obtain a product of general formula (I) for which n = 2, we operate using 2 equivalents of oxidizing agent.

If necessary, the choice, the establishment and the elimination of the amino protective radical are carried out according to the usual methods which do not affect the rest of the molecule; in particular, we operate according to the methods described by T.W. Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

It is also advantageous to operate from the product of general formula (I) for which n = 0 in the form of a salt with a mineral acid (hydrochloride, sulphate for example).

In practice, it is understood that to prepare a product of general formula (I) for which n = 1 or 2 and for which R is a hydrogen atom, it is advantageous to carry out the oxidation before elimination of the protective radical R '. According to the invention, the thiopyranopyrrole derivative of general formula (I) for which n = 2 can also be obtained from 3,4-dihydro-4,4-diphenyl-1,1 2H-thiapyranne of formula:

by reaction, of cycloaddition with a silylated derivative of general formula:

 in which R 'is defined as above, (R °), represents alkyl radicals or alkyl and phenyl radicals and R °° represents an alkyloxy, cyano or phenylthio radical, optionally followed by the elisiination of the protective radical R' in the conditions described above, if we want to obtain a derivative of general formula (I) for which R is a hydrogen atom.

The cycloaddition reaction is carried out in the presence of a catalytic amount of an acid chosen from trifluoroacetic acid, acetic acid, methanesulfonic acid or the acids cited in the references mentioned below, in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane for example), 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 thiopyranopyrrole derivative of general formula (II) can be obtained by cycloaddition reaction by the action of a silylated derivative of general formula (V) on dehydrothiapyranone-4 of formula:

under conditions identical to those described above for the cycloaddition reaction of this product on the sulfone of formula (IV).

The silylated derivative of general formula (V) can 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 3,4-dihydro-4,4-diphenyl-1,1-dioxide 2H-thiapyranne of formula (IV) can be obtained by successive oxidation of the 3,4-dihydro-4,4-diphenyl 2H-thiapyranne and the 3-dihydro, 4-diphenyl-4,4 oxide-1 2H-thiapyranne of formulas:

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 S-oxide of general formula (VIII) to oxidize it to sulfone.

The 3,4-dihydro-4,4-diphenyl 2H-thiapyranne of general formula (VII) can be prepared according to or by analogy with the method described below in Example 5.

It is understood that the thiopyranopyrrole derivatives of general formula (I), (II) and (III) have several steroisomeric forms. The separation of the (4aR, 7aR) or (4aS, 7aS) steroisomers is advantageously carried out at the level of the derivative of general formula (I). The separation of the steroisomers is carried out according to any known method compatible with the molecule. For example, the separation can be carried out by preparing an optically active salt, by the action of L (+) or D (-) mandelic acid, or of dibenzoyltartaric acid, then separation of the isomers by crystallization. . The desired isomer is released from its salt in basic medium.

The separation of the axial and equatorial isomers can be carried out by chromatography or crystallization.

According to the invention, the new thiopyranopyrrole derivatives of general formula (I) are useful for the preparation of derivatives which antagonize the effects of substance P and correspond to the general formula:

in which - n is defined as above,

- the symbol X represents an oxygen atom or an NH radical,

- the symbol R ₁ represents a phenyl radical optionally substituted by one or more halogen atoms or hydroxy radicals, alkyl which can be optionally substituted (by halogen atoms or amino, alkylamino or dialkoylamino radicals) alkyloxy or alkylthio which can optionally be substituted [by hydroxy, amino, alkylamino or dialkoylamino radicals optionally substituted (by phenyl, hydroxy or amino radicals), or dialkoylamino, the alkyl parts of which form, with the nitrogen atom to which they are attached, a heterocycle at 5 to 6 links which may contain another heteroatom chosen from oxygen, sulfur or nitrogen, optionally substituted by an alkyl, hydroxy or hydroxyalkyl radical)], or substituted by amino, alkylamino, dialkoylamino radicals, the alkyl parts of which can form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl or heterocyclyl radical mono or polycyclic, saturated or unsaturated containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur, and

- the symbol R ₂ represents a hydrogen or halogen atom or a hydroxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkoylaminoalkyl, alkyloyloxy, alkylthio, acyloxy, carboxy, alkyloxycarbonyl, dialkoylaminoalkylcarbonyl, aminocarbonyl, aminocarbonyl alkyl or acyl cited above containing 1 to 4 carbon atoms in a straight or branched chain.

 In the general formula (IX) above, when R contains a halogen atom, the latter can be chosen from chlorine, bromine, fluorine or iodine;

when R ₁ represents a saturated or unsaturated mono or polycyclic heterocyclyl radical, for example it can be chosen from thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazol , quinolyl, isoquinolyl, or naphthyridinyl; when R ₁ represents phenyl substituted by a chain carrying a heterocycle, the latter can be chosen from pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl or thio-morpholino; moreover, when the symbol R ₂ is other than the hydrogen atom, the chain substituted on the thiopyranopyrrole has a chiral center, it is understood that the steroisomeric forms and their mixtures also fall within the scope of the general formula (IX).

The thiopyranopyrrole derivatives of general formula (IX) can be obtained by the action of the acid of general formula:

or a reactive derivative of this acid, in which R ₁ and R ₂ are defined as above, on a thiopyranopyrrole derivative of general formula (I) for which R is a hydrogen atom and n is defined as above, followed where appropriate, the transformation of the amide obtained into an amidine for which X represents an NH radical.

It is understood that the amino, alkylamino or carboxy radicals contained in R ₁ and / or R ₂ are preferably previously protected.

Protection is effected by any compatible group, the establishment and elimination of which does not affect the rest of the molecule. In particular, according to the methods mentioned above.

For exemple,

- the amino or alkylamino groups can be protected by methoxycarbonyl, ethoxycarbonyl, t.butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichlorethoxycarbonyl, trichloracetyl, trifluoroacetyl, chloracetyl, trityl, benzhydryl, benzyl, alkyyloxycarbonyl radicals;

- the acid groups can be protected by methyl, ethyl, t.butyl, benzyl, substituted benzyl or benzhydryl radicals.

In addition, when R ₂ represents a hydroxy radical, it is preferable to protect this radical beforehand. The protection is carried out for example by an acetoxy, trialkylsilyl, benzyl radical, or under form of a carbonate by a radical -COORa in which Ra is an alkyl or benzyl radical.

 When the condensation of a reactive acid derivative of general formula (X) is carried out, the operation is advantageously carried out using acid chloride, anhydride, a mixed anhydride or a reactive ester. in which the remainder of the ester is for example a succinimido radical, benzotriazolyl-1, 4-nitro phenyl, 2,4-dinitro phenyl, pentachlorophenyl or phthalimido or a derivative.

The reaction is generally carried out at a temperature between -40 and + 40 ° C, in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), a ester (ethyl acetate for example), an amide (dimethylacetamide, dimethylformamide for example), or a ketone (acetone for example) or in a mixture of these solvents, in the presence of an acid acceptor such as a base organic nitrogenous, such as for example pyridine, dimethylaminopyridine, N-methylmorpholine or a trialkoylamine (in particular triethylamine) or such as an epoxide (propylene oxide for example). It is also possible to operate in the presence of a condensing agent such as a carbodiimide, [for example dicyclohexylcarbodiimide or (3-dimethylamino propyl) -1 ethyl-3 carbodiimide), NN'-carbonyldiimidazole or ethoxy- 2 ethoxycarbonyl-1 dihydro-1,2 quinoline or else in a hydroorganic medium, in the presence of an alkaline condensing agent such as sodium bicarbonate, then the amide obtained is converted where appropriate into an amidine as defined above.

The transformation of the amide of general formula (IX) into an amidine for which X is an NH radical is carried out by preparing the derivative of general formula:

in which R ₁ , R ₂ and n are defined as above, Y represents a chlorine atom, a methoxy or ethoxy radical and Z represents a chloride, tetrafluoroborate, fluorosulfonate, trifluoromethylsulfonate, methylsulfate, or ethylsulfate ion, then by causing it to act ammonia on the derivative of general formula (XI).

The preparation of the derivative of general formula (XI) in which Y is a chlorine atom or a methoxy or ethoxy radical is carried out by the action of a reagent such as phosgene, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichloromethyl chloroformate, triethyl (or trimethyl) oxonium tetrafluoroborate, methyl (or ethyl) triflate, methyl (or ethyl) fluorosulfonate or sulfate methyl (or ethyl). The reaction is carried out in a chlorinated solvent (dichloromethane, dichlorethane for example) or in an aromatic hydrocarbon (toluene for example), at a temperature between 0 ° C. and the reflux temperature of the reaction mixture. The action of ammonia on the derivative of general formula (XI) is carried out in an anhydrous organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane for example), in an alcohol-chlorinated solvent mixture, in an ether ( tetrahydrofuran for example), 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 mixture reactive.

It is not essential to have isolated the derivative of general formula (XI) to use it in this reaction. The acids of general formula (X) can be prepared according to the methods described below in the examples, or by analogy with these methods.

The thiopyranopyrrole derivatives of general formula (IX) for which X is an NH radical can also be obtained from the thiopyranopyrrole derivative of general formula (I) for which R is a hydrogen atom, by the action of a product of general formula

optionally in the salt state, in which R ₁ and R ₂ are defined as above and R ₁ represents an alkyloxy radical containing 1 to 4 carbon atoms in a straight or branched chain or a methylthio, ethylthio, benzylthio or alkyloxycarbonylmethylthio radical.

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

It is understood that, in the event that the radicals R ₁ and / or R ₂ of the product of general formula (XII) carry substituents which can interfere with the reaction, the latter must be protected beforehand. The new thiopyranopyrrole derivatives of general formula (I) as well as the derivatives of general formula (IX) to which they lead can be purified if necessary by physical methods such as crystallization or chromatography. Where appropriate, the new derivatives of general formula (I) or the derivatives of general formula (IX) for which the symbols R ₁ and / or R ₂ contain amino or alkylamino substituents and / or X represents an NH radical, may be transformed into addition salts with acids. As examples of addition salts with acids, there may be mentioned the salts formed with mineral acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, p.toluenesulfonates, isethionates, or with substitution derivatives of these corrosives).

Substance P is known to be involved in a number of pathological areas:

 - Agonists and antagonists of substance P, A.S. Dutta Drugs of the futur, 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 Essentiel Hypertension, J. Cardiocascular Pharmacology, 10 (suppl. 12), 5172 (1987). The thiopyranopyrrole derivatives of general formula (IX) which antagonize the effects of substance P may find application in the fields of analgesia, inflammation of asthma, allergies, on the central nervous system, on the cardiovascular system, as an antispasmodic, or on the immune system, as well as in the area of stimulation of lachrymal secretions.

Indeed, these products show an affinity for the substance P receptors at doses between 10 and 2000 nM depending on the technique described by CM Lee et al., Mol. Pharmacol., 23, 563-69 (1983).

In addition, it has been shown to be an antagonistic effect of substance P, using various products. In the technique described by S. Rosell et al., Substance P, Ed. By US Von Euler and B. Pernow, Raven Press, New-York (1977), pages 83 to 88, the products studied have been shown to be active at doses between 20 and 2000 nM.

Furthermore, the thiopyranopyrrole derivatives according to the present invention do not exhibit any toxicity, they have been shown to be non-toxic in mice by the subcutaneous route at a dose of 40 mg / kg or by the oral route at a dose of 100 mg / kg.

Of particular interest are the following products:

 - Diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole;

- 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole;

 - Diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1;

 - 4,4-Diphenyl vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole;

 - 4,4-diphenyl-1-oxide tert-butyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole;

as well as their salts, their steroisomeric forms and their mixtures.

The following examples, given without limitation, illustrate the present invention.

In the examples which follow, it is understood that, unless otherwise mentioned, the proton NMR spectra were made at 250 MHz in dimethylsulfoxide; chemical shifts are expressed in ppm. Example 1

4.35 g of 4,4-diphenyl vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) are treated with 30 cm ³ of a 5.7 N solution of hydrochloric acid 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 150 cm ³ of ethanol, the resulting solution is brought to reflux for 30 minutes, then is concentrated to dryness. The solid obtained is washed with 50 cm ³ of ethyl ether, drained, dried.

3.64 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) are 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-d-, main signals): 2.2 to 2.9 (mt, b

4H, CH ₂ in 2 and CH ₂ in 3); 2.4 and 3.3 (2mt, 2H, CH ₂ in 5); 3.08 (d,

J = 12.5, 1H, 1H in 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, aromatic).

The 4,4-diphenyl vinγloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) can be prepared as follows: A 6.2 g of 6,4-benzyl-4,4-diphenyl perhydrothiopyrano [2, 3-c] pyrrole¬

(4aRS, 7aRS), in 50 cm ³ of 1,2-dichloroethane, 1.72 cm ³ of vinyl chloroformate is added. The mixture is brought to reflux for

15 minutes then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.04 mm-0.06 mm, diameter 25 cm), eluting under a pressure of 0.6 bar of nitrogen, with a mixture of cyclohexane and acetate ethyl (90/10 by volume), collecting 60 cm ³ fractions. Fractions 5 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in 70 cm ³ of diisopropyl ether, the suspension is filtered, the solid drained and dried. We obtain 4.35 g of 4,4-diphenyl vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole (4aRS, 7aRS), in the form of a white solid, melting at 160 ° C.

6,4-Benzyl-4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) can be prepared as follows: To a solution of 12.2 g of 4-hydroxy-4-phenylbenzyl- 6 perhydrothiopyrano [2,3-c] pyrrole- (4RS, 4aSR, 7aRS) in 180 cm of benzene, 43.7 g of zirconium tetrachloride are added. The reaction mixture is brought to reflux for 1 hour then brought to 20 ° C. and diluted with 200 cm ³ of dichloromethane. To the resulting cooled solution, 150 cm ³ of a 4N aqueous sodium hydroxide solution are added. The suspension obtained is filtered, the filtrate is decanted, the phase

 3

organic is washed with 200 cm of saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a column of silica gel (0.04 mm-0.06 mm, diameter 5.2 cm, height 39 cm), eluting under a nitrogen pressure of 0.6 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume), collecting fractions of 125 cm ³ . Fractions 19 to 32 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 200 cm ³ of diisopropyl ether, the crystals are wrung, dried. 6.2 g of 6-benzyl-4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) are obtained in the form of orange crystals, melting at 130 ° C.

4-hydroxy-4-phenylbenzyl-6 perhydrothiopyrano [2,3-clpyrrole- (4RS, 4aSR, 7aRS) can be prepared as follows:

To a solution of phenylmagnesium bromide prepared from

19.8 cm ³ of bromobenzene and 4.52 g of dry magnesium, in 120 cm ³ of anhydrous ethyl ether, a solution of

21.15 g of 6-benzyl-4-oxo perhydrothiopyrano [2,3-c] pyrrole (4aRS, 7aSR) in 150 cm ³ of anhydrous ethyl ether. The reaction mixture is stirred at reflux temperature for 3 hours, then for 20 hours at 20 ° C. The mixture, supplemented with 200 cm ³ of ethyl ether, is stirred with 600 cm ³ of saturated aqueous solution ammonium chloride. The aqueous phase is extracted with 200 cm ³ of ethyl ether, the two ethereal extracts combined are washed twice with 300 cm ³ of saturated aqueous sodium chloride solution then dried over jnagmesium sulfate and concentrated to dryness under reduced pressure (5 , 4 kPa) at 35 ° C. 12.2 g of 4-hydroxy-4-phenyl-benzyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4RS, 4aSR, 7aRS) are obtained in the form of a white solid, melting at 137 ° C.

Benzyl-6 oxo-4 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aSR) can be prepared as follows: To a solution of 20 g of dehydrothiapyrannone-4 and 54 cm ³ of N-butoxymethyl N trimethylsilylmethyl benzylamine in 100 cm ³ of anhydrous dichloromethane, 5 drops of trifluoroacetic acid are added and the mixture is stirred for 4 hours, maintaining the temperature at 20 ° C. The reaction mixture is stirred with 5 g of potassium carbonate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is chromatographed on a column of silica gel (0.04 mm-0.06 mm, diameter 9.2 cm), eluting under a pressure of 0.6 bar of nitrogen, with a mixture of cyclohexane and ethyl acetate (90/10 by volume), then with the cyclohexane and acetate mixture ethyl (75/25 by volume), collecting 250 cm ³ fractions. Fractions 35 to 56 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 24 g of 6-benzyl-4 oxo-perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aSR) are obtained in the form of a yellow oil. Infrared spectrum (CCI ₄ solution, characteristic bands, cm ^-1 ):

3090, 3070, 3025, 2925, 2850, 2800, 2730, 1710, 1600, 1585, 1495, 1475, 1450, 700.

Proton NMR spectrum (CDCl ₃ , main signals): 2.42 (dd, J = 10 and

7.1H, 1H in 7); 2.66 (mt, 2H, CH ₂ in 5); 3.05 (mt, 1H, H at 4a); 3.1 (dd, J = 10 and 7.5, 1H of CH ₂ in 7); 3.61 (s, 2H, N-CH ₂ -Ar); 3.8 (dt,

J = 7.5 and 7.1H, H in 7a); 7.15 to 7.35 (mt, 5H aromatic). Example 2

3.98 g of 4,4-diphenyl-1-oxide tertiobutyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole (mixture of isomers 1RS, 4aSR, 7aSR and 1RS, 4aRS, 7aRS) are treated with 40 cm ³ of a mixture 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 30 cm ³ of dichloromethane, the solution is washed with 60 cm ³ of 2N aqueous sodium hydroxide solution, the aqueous phase is extracted with 20 cm of dichloromethane. The organic extracts are combined, dried over magnesium sulphate, concentrated to dryness at 40ºC under reduced pressure (2.7 kPa). The residue is taken up in diisopropyl ether, then concentrated to dryness at 40 ° C under reduced pressure

(2.7 then 0.13 kPa). 3.0 g of diphenyl-4,4 oxide-1 perhydrothiopyrano [2,3-c] pyrrole (1RS, 4aRS, 7aRS) are 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-d ₆ + CF ₃ CCOD, main signals): 2.26 (wide t, J = 14, 1H, 1H in 3); 2.42 (dd, J = 10 and 9, 1H, CH ₂ in 5);

2.55 (broad dd, J = 14 and 4, 1H, 1H in 3); 3.68 (t, J = 6.1H, H at 7a); 3.82 (d, J = 14, 1H, H at 7); 3.8 to 4 (mt, 1H, CH in 4a); 4.15 (dd, J = 14 and 6, 1H, H at 7); 7.1 to 7.5 (mt, 10H aromatic). 4,4-diphenyl-1-oxide tert-butyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole (mixture of isomers 1RS, 4aSR, 7aSR and 1RS, 4aRS, 7aRS) can be prepared as follows:

To a solution cooled to 0 ° C. of 4.2 g of diphenyl-4,4 tertiobutyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) in 30 cm ³ of dry dichloromethane, a solution of 2.3 g of 3-chloro peroxybenzoic acid (85%) in 20 cm ³ of dichloromethane. After 1.5 hours of stirring at 3 ° C and 1.5 hours at 20 ° C, the reaction mixture is washed twice with 100 cm ³ of saturated aqueous sodium bicarbonate solution, then with 100 cm of distilled water , dried over magnesium sulfate, concentrated to dryness at 35 ° C under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl ether, drained, then dried under reduced pressure (2.7 kPa). 3.98 g of diphenyl-4,4 oxide-1 tertiobutyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole- (mixture of isomers 1RS, 4aSR, 7aSR and 1RS, 4aRS, 7aRS) are obtained in the form of crystals blanks used as is in the following reaction.

Diphenyl-4,4 tert-butyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4 to RS, 7aHS) can be prepared in the following way:

To a suspension of 4.0 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and 1.70 cm ³ of triethylamine in 60 cm ³ of dry dichloromethane, in 0.5 g fractions, 2.89 g of ditert-butyl dicarbonate then 0.15 g of 4-dimethylamino pyridine. The mixture is stirred for 20 hours at 20 ° C. and then the reaction solution is washed with 2 times 100 cm ³ of aqueous citric acid solution of pH 4, with 100 cm ³ of water, dried over magnesium sulfate, concentrated to dryness at 35 ° C under reduced pressure (2.7 kPa). The residue is crystallized from ethyl ether, the crystals are drained, and dried. 4.27 g of 4,4-diphenyl-tert-butyloxycarbonyl-6 perhydrothiopyrano [2, 3-c] pyrrole- (4aRS, 7aRS) are obtained in the form of pink crystals, melting at 162 ° C.

Diphenyl-4,4 oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) can also be prepared as follows:

To a solution cooled to -3 ° C of 25 g of 4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole (4aRS, 7aRS) in 500 cm of dichloromethane and 100 cm ³ of methanol, a solution of 15.4 g of 3-chloro peroxybenzoic acid (85%) in 400 cm ³ of dichloromethane. After one hour of stirring at -3 ° C, the reaction mixture is washed with 200 cm ³ of an aqueous solution of potassium hydrogen carbonate at 10% and 100 cm ³ of this same solution, then dried over magnesium sulfate, and concentrated to dryness

40 ° C under reduced pressure (2.7 kPa). The residue is crystallized in

50 cm ³ of ethyl acetate, the crystals are taken up in 200 cm ³ of dichloromethane, the solution obtained is washed with 75 cm ³ of a 1N aqueous sodium hydroxide solution then dried over magnesium sulphate and concentrated to dry. The residue is crystallized from 30 cm of ethyl acetate, the crystals are washed with ethyl acetate, drained and dried. 13.6 g of diphenyl-4,4 oxide-1 perhydro-thiopyrano [2,3-c] pyrrole (1RS, 4aRS, 7aRS) are obtained; in the form of white crystals, melting at 174 ° C.

Example 3

To 7.15 g of 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole (1RS, 4aRS, 7aRS) is added 3.5 g of mandelic acid- (S) and 90 cm ³ of a mixture of acetonitrile and water (99/1 by volume). After stirring the resulting solution is left for 48 hours at room temperature. The crystals obtained are drained, washed with with an acetonitrile-water mixture, then dried. The crystals are taken up by

200 cm of the boiling acetonitrile-water mixture and after hot filtration, the solution obtained is left for 5 hours at temperature

 3 ambient. The crystals are drained, washed twice with 10 cm of acetonitrile, then dried. 1.5 g of 4,4-diphenyl-1-oxide-perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) are obtained.

[α] ²⁰ _D = -228 °, (c = 0.44; acetic acid). The filtrate is left for 20 hours at room temperature, the crystals obtained are drained, washed twice with 5 cm ³ of acetonitrile, then dried. 0.62 g of 4,4-diphenyl-1-oxide-perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) is obtained. [α] ²⁰ D = -230 °, (c = 0.45; acetic acid). To 2.06 g of mandelate- (S) of diphenyl-4,4 oxide-1 perhydrothiopyrano- [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) 40 cm ³ of dichloromethane and 7 are added. , 0 cm ³ of 1N aqueous sodium hydroxide. The mixture is stirred for a few minutes after dissolution of the starting product, the organic phase is dried on magnesium sulfate, 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 ether, and dried. 1.14 g of (-) - 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) are obtained in the form of a white solid melting at 192 ° C. [α] ²⁰ D = -405 °, (c = 0.46; acetic acid).

Example 4

To 32.3 g of diphenyl-4,4 oxide-1 perhydrothiopyrano {2,3-c] pyrrole- (1RS, 4aRS, 7aRS) 15.8 g of (+) - mandelic acid (S) are added and 750 cm of a mixture of acetonitrile and water (99/1 by volume) then 5.0 cm ³ of water. After lukewarm, the solution obtained is left for 48 hours at room temperature. The crystalline suspension is filtered, the dry concentrated filtrate gives a meringue which is taken up in 200 cm ³ of the boiling acetonitrile-water mixture. The solution obtained is left for approximately 20 hours at room temperature. The crystals are drained, washed with acetonitrile, dried, then taken up again with 200 cm ³ of an acetonitrile-water mixture (98/2 by volume). The resulting solution is left for approximately 20 hours at room temperature. The crystals are wrung, dried. 9.4 g of (+) - mandelate- (S) of 4,4-diphenyl-oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) are obtained; [α] D = + 337 °, (c = 0.45; acetic acid).

To 9.2 g of (+) - mandelate- (S) of 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) is added 100 cm ³ of dichloromethane and 30 cm ³ of 1N aqueous sodium hydroxide. The mixture is stirred for 10 minutes, the organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is disintegrated in a mixture of ethyl acetate and diisopropyl ether, the solid is washed with diisopropyl ether and dried. 5.6 g of (+) - 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) are obtained in the form of a white solid melting at 198 ° C. [α] ²⁰ D = + 434 °, (c = 0.45; acetic acid). Example 5

0.58 g of 4,4-diphenyl-vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) is treated with 25 cm ³ of a 5.7 N acid solution hydrochloric acid in dry dioxane for 30 minutes while warming up. The reaction solution is concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. The residue is taken up in 15 cm ³ of ethanol, the solution obtained is brought to reflux for 30 minutes, then is concentrated to dryness. The solid obtained is washed with ethyl ether, drained, and dried. 0.46 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) 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-d ₆ + CF ₃ CCOD, main signals): 3.84

(ab, 2H, CH ₂ in 7); 4.0 (mt, 1H, H at 4a); 4.27 (mt, 1H, H at 7a); 7.1 to 7.6 (mt, 10H, aromatics).

4,4-diphenyl-vinyloxycarbonyl-6 perhydrothiothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) can be prepared as follows:

To a solution of 0.7 g 6-benzyl-4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) in 10 cm ³ of 1,2-dichloro ethane is added 0 , 16 cm of vinyl chloroformate.

The mixture is brought to reflux for 2 hours 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. 0.58 g of 4,4-diphenyl-vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) 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 (DMSO-d ₆ + CF ₃ COOD, main signals): 2.5 to 3.45 (mt, 6H, CH ₂ in 5, in 2 and in 3); 3.8 to 4.2 (mt, 4H, CH ₂ in 7, H in 4a and H in 7a); 4.46 and 4.72 (2d wide, J-6 and J-14, 2 × 1H, CH = CH ₂ ); 7.0 (dd, J = 14 and 6, 1H, OCH =); 7.1 to 7.6 (mt, 10H, aromatics).

Benzyl-6-diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) can be prepared in the following way:

To a solution of 1.3 g of 3,4-dihydro-4,4-diphenyl-1,1-dioxide 2H-thiapyran and 1.75 cm ³ of N-butoxymethyl N-trimethylsilylmethyl benzylamine in 12 cm ³ of anhydrous dichloromethane, 2 drops of trifluoroacetic acid are added and the mixture is stirred for 30 minutes at 30 ° C. 1.75 cm ³ of N-butoxymethyl N-trimethylsilylmethyl benzylamine and 2 drops of trifluoroacetic acid are again added and the mixture is stirred for 2 hours at 35 ° C. This last operation is repeated again, and after 1 hour of stirring, 1 g of potassium carbonate is added. The suspension is filtered, the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3.2 cm ³ , height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 30 cm ³ fractions. Fractions 20 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of 6-benzyl-4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) is obtained in the form of white crystals, melting at 186 ° C.

3,4-dihydro-4,4-diphenyl-1,1-dioxide 2H-thiapyran can be prepared as follows:

To a solution of 1.47 g of 3,4-dihydro-4,4-diphenyl-1-oxide 2H-thiapyranne in 15 cm of dry dichloromethane, a solution of 1.12 g of 3-chloro-peroxybenzoic acid is added (to 85%) in 25 cm ³ of dry dichloromethane. After 20 hours of stirring at 20 ° C, the reaction mixture is washed with 50 cm ³ of a 10% aqueous solution of sodium thiosulfate then with 50 cm ³ of saturated aqueous sodium hydrogencarbonate solution. 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, dried under reduced pressure (2.7 kPa). 1.3 g of 3,4-dihydro-4,4-diphenyl-1,4-dioxide-2H-thiapyran are obtained in the form of white crystals, melting at 166 ° C.

3,4-dihydro-4,4-diphenyl-1-oxide 2H-thiapyran can be prepared in the following manner: By operating as above, starting from 2.05 g of 3,4-dihydro-4,4-diphenyl 2H-thiapyran and 1.67 g of 3-chloro-peroxybenzoic acid (85%), 1.9 g of 3,4-dihydro-4,4-diphenyl-4-oxide-2H-thiapyran are obtained, in the form of '' a white solid melting at 130 ° C. The 3,4-dihydro-4,4-diphenyl 2H-thiapyranne can be prepared as follows:

To a suspension of 2.7 g of 4,4-diphenyl-1-oxide tetrahydrothiapyranne in 30 cm of anhydrous toluene is added 3.95 cm ³ of acetigue anhydride. The mixture is brought to reflux for 20 hours and concentrated to dryness at 60 ° C. under reduced pressure (2.7 kPa then

0.13 kPa). The oily residue is crystallized from diisopropyl ether, the crystals are drained and dried. 2.1 g of 3,4-dihydro-4,4-diphenyl 2H-thiapyran are obtained in the form of white crystals, melting at 78 ° C. 4,4-diphenyl-1-oxide tetrahydrothiapyran can be prepared as follows:

To a solution cooled to 0 ° C of 25.4 g of 4,4-diphenyl tetrahydrothiapyran in 130 cm ³ of dichloromethane is added in 40 minutes a solution of 20.3 g of 3-chloro-peroxybenzoic acid (85%) in 300 cm ³ of dichloromethane. After 2 hours of agitation at

0 ° C, 250 cm ³ of an aqueous solution are added to the mixture 5% potassium hydrogencarbonate then stir for 15 minutes. The organic phase is washed again with 250 cm of the potassium hydrogen carbonate solution, then is dried over magnesium sulphate, concentrated to dryness (after checking for the absence of peroxides), under reduced pressure (2.7 kPa) . 26.9 g of 4,4-diphenyl-1-oxide tetrahydrothiapyran are obtained in the form of a white solid, melting at 122 ° C.

The 4,4-diphenyl tetrahydrothiapyran can be prepared in the following way: To a suspension of 140.8 g of 3.3-diphenyl-3,3 bis methanesulfσnyloxy-1,5 pentane in 1,400 cm ³ of butanol-1 is added 100 g of sulfide sodium nonahydrate. The mixture is heated at reflux for 2 hours then cooled to approximately 20 ° C., then added with 1000 cm ³ of water, 500 cm ³ of ethyl acetate, 500 cm ³ of dichloromethane. After stirring, the organic phase is separated, washed successively with 1000 cm ³ of water, 500 cm ³ of 1N hydrochloric acid, 500 cm ³ of saturated aqueous sodium hydrogencarbonate solution, 1000 cm of water, then dried over magnesium sulfate and concentrated to dryness at 60 ° C under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate, the crystals are washed with diisopropyl ether, drained, and dried. 76 g of 4,4-diphenyl tetrahydrothiapyran are obtained in the form of white crystals, melting at 134 ° C.

The diphenyl-3,3 bis methanesulfonyloxy-1,5 pentane can be prepared as follows:

To a solution cooled to -20 ° C of 95 g of diphenyl-3,3 pentane diol-1,5 (prepared according to P. EILBRACHT et al. Chem. Ber. 118, 825-839

(1985)) in 950 cm ³ of dichloromethane and 113 cm ³ of triethylamine, a solution of 62 cm ³ of methanesulfonyl chloride in 100 cm of dichloromethane is added over 10 minutes. After 2 hours of stirring at 20 ° C, the reaction mixture is washed with 2 times 500 cm ³ of water, the organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallized from ethyl ether, the crystals are washed with ethyl ether, wrung and dried. 140 g of diphenyl-3,3 bis methanesulfonyloxy-1,5 pentane are obtained in the form of white crystals, melting at 99 ° C. The products according to the invention can lead to thiopyranopyrrole derivatives of general formula (IX) by operating as in the following examples:

Usage example 1

To a solution of 1.16 g of 2-dimethylamino-phenylacetic acid in 20 cm ³ of dry dichloromethane, 1.18 g of

N, N'-carbonyldiimidazole. The mixture is stirred for 30 minutes at + 5 ° C. and then a solution of 2.0 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and 1.83 cm ³ of triethylamine in 20 cm ³ of dichloromethane. The reaction mixture is stirred for 1 hour at 20 ° C. then is washed twice with 50 cm of water and dried over magnesium sulfate. The solution is filtered, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a column of silica gel (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume), collecting 60 cm ³ fractions. Fractions 6 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallized from a mixture of acetonitrile and diisopropyl ether. The crystals are wrung, dried. 2.16 g of [(2-dimethylamino phenyl) acetyl] -6-4,4-diphenyl-perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) are obtained in the form of a white solid melting at 163 ° vs.

Usage example 2

By operating as in the example of use 1 from 1.85 g of hydrobromide of acid ((pyrrolidinyl-1) -2 phenyl) acetic, and of 2.0 g of hydrochloride diphenyl-4,4 perhydrothiopyrano [ 2,3-c] pyrrole- (4aRS, 7aRS), we obtain 0.90 g of {[(pyrrolidinyl-1) -2 phenyl] acetyl} -6-4,4-diphenyl perhydro-thiopyrano [2,3-c] pyrrole- (4aRS, 7aRS), in the form of white crystals melting at 166 ° C.

Example of use 3

To a solution cooled to 0 ° C. of 2.63 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and of 2.42 cm of triethylamine in 25 cm of dichloromethane, a solution of 1.15 cm of phenylacetyl chloride in 25 cm ³ of dichloromethane is added over 5 minutes. After stirring one hour at 0 ° C and one hour at 20 ° C, 20 cm of dichloromethane are added. The reaction mixture is washed twice with 100 cm ³ of distilled water, dried over magnesium sulphate, then concentrated to dryness under reduced pressure (2.7 kPa).

The oil obtained is chromatographed on a column of silica gel

(0.04-0.06 years, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume), collecting fractions of 125 cm ³ . Fractions 19 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.87 g of 6-phenylacetyl-4,4-diphenyl-perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) is obtained in the form of a white solid, melting at 210 ° C. Example of use 4

To a solution of 0.92 g of 2-hydroxyphenyl acetic in 30 cm of dry dichloromethane, 0.58 cm ³ of ethyl chloroformate is added.

After 15 minutes of stirring at 20 ° C, the mixture is cooled to -15 ° C and 0.85 cm ³ of triethylamine is added. After 2 hours of stirring at -15 ° C, a suspension of 2 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and

1.70 cm ³ of triethylamine in 30 cm ³ of dichloromethane. After stirring for 20 hours at 20 ° C., the reaction mixture is washed with 50 cm ³ of 1N hydrochloric acid, 50 cm of saturated aqueous sodium chloride solution and then dried over magnesium sulfate, and concentrated to dryness under reduced pressure ( 2.7 kPa). The residue is crystallized from 20 cm ³ of dichloromethane, the crystals are washed with diisopropyl ether, drained and dried under pressure reduced (2.7 kPa). 1.02 g of 4,4-diphenyl [(2-hydroxyphenyl) acetyl] -6 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) are obtained in the form of white crystals, melting at 248 ° C. .

Example of use 5 To a solution cooled to 0 ° C of 1.16 g of 2-methoxyphenylacetic acid in 20 cm ³ of dry dichloromethane, 1.13 g of N, N'-carbonyldiimidazole are added. The mixture is stirred for 40 minutes at 0 ° C. and then a solution of 2.15 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and 0.9 cm of triethylamine is added. 20 cm ³ of dichloromethane. The reaction mixture is stirred for one hour at 0 ° C. and is then washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with 30 cm ³ of ethyl ether, 3C cm ³ of diisopropyl ether, then is dried under reduced pressure (2.7 kPa). 2.66 g of 4,4-diphenyl are obtained

[(2-methoxy phenyl) acetyl] -6 perhydrothiopyrano [2,3-c] pyrrole¬

(4aRS, 7aRS), in the form of a white solid, melting at 172 ° C.

Example of use 6 Le ((2-methoxy phenyl) -2 propionyl- (S)] - 6 diphenyl-4,4 perhydrothiopyrano [2, 3-c] pyrrole-mixture of the forms (4aR, 7aR) and (4aS, 7aS) can be prepared by operating as described in Example 5, starting from 0.89 g of (2-methoxyphenyl) -2 propionic acid (S) and 4,4-diphenyl hydrochloride perhydrothiopyrano [2 , 3-c] pyrrole (4aRS, 7aR≤) to obtain 1.46 g of [(2-methoxyphenyl) -2 propionyl- (S)] - 6 4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole-mixture of the forms (4aR, 7aR) and (4aS, 7aS) in the form of a white meringue.

First form:

Infrared spectrum (characteristic bands, cm ^-1 ): 3.095, 3055, 3025, 2950, 2930, 2875, 2835, 1630 1595, 1490, 1565, 1425, 1240, 1030, 750, 700. Proton NMR spectrum (DMSO-d ₆ + CF ₃ COOD, at room temperature, there is the mixture of the two rotamers, characteristic signals): the ¹⁵ and 1.20 (2d, J = 7.5, 3H, CH ₃ ); 2.1-2.9 (mt, 5H, 2 CH ₂ at 5 and 3 + H at 4a); 3.36 and 3.8 (2s, 3H, OCH ₃ ); 6.7 to 7.4 (mt, 14H, aromatic).

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 K4N spectrum (DMS0-d ₆ + CF COOD, at room temperature, the mixture of the two rotamers is observed; characteristic signals): 1.1 and 1.18 (2d, J = 7.5, 3H, CH ₃ ) ; 2.1-2.35 (mt, 2H, CH ₂ in 3); 2.35-3.10

(mt, 3H, CH ₂ in 5 + H in 4a); 3.6 and 3.8 (2s, 3H, OCH ₃ ); 3.95 and 4.02 (mt, 1H, H at 7a); 6.7 to 7.4 (mt, 14H, aromatic). The (2-methoxyphenyl) -2 propionic- (S) acid can be obtained in the following manner:

(2-methoxyphenyl) -2-propionic acid (S) can be prepared, by analogy with the methods described by DA Evans et al., Tetrahedron, 44, 5525, (1988), according to the following procedure: A a solution cooled to + 5 ° C of 4.1 g of 4-methyl-5-phenyl

[(2-methoxy phenyl) -2- (S) -propionyl] -3 oxazolidinone-2- (4S, 5S) in

60 cm 3 of tetrahydrofuran and 30 cm ³ of water, 1.52 g of lithium hydroxide are added. The reaction mixture is stirred for 3 hours at this temperature, then, after returning to ambient temperature, ethyl acetate is added, it is decanted, the aqueous phase is acidified with a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from hexane, drained and dried. 0.4 g (2-methoxyphenyl) -2 propionic acid (S) is obtained under the form of white crystals melting at 102 ° C. [a] ²⁰ D = + 84.6 °; (c = 1; CHCl ₃ ).

4-methylphenyl-5 [(2-methoxyphenyl) -2- (S) -propionyl] -3 oxazolidinone-2- (4S, 5S) can be obtained in the following way: In a solution cooled to -50 ° C of 10 g of methyl 4-phenyl-5 [(methoxy-2 phenyl) -acetyl] -3 oxazolidinone-2- (4S, 5S) in 150 cm ³ of tetrahydrofuran, 19.1 g of hexamethyl-1 are added, 1,1,3,3,3 sodium disilazanate, stirred 45 minutes at this temperature, then added 7.72 cm of methyl iodide. The reaction mixture is then stirred for 15 hours at room temperature, then diluted with ethyl acetate, washed with 50 cm ³ of water, then with 50 cm ³ of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from isopropyl ether, drained and dried. 4.2 g of 4-methylphenyl-5 [(2-methoxy-phenyl) -2- (S) -propionyl] -3 oxazolidinone-2- (4S, 5S) are obtained in the form of a white solid.

4-methylphenyl-5 (2-methoxyphenylacetyl) -3 oxazolidinone-2- (4S, 5S; can be obtained as follows: From a suspension of 1.89 g of sodium hydride (80% dispersion in petrolatum) in 200 cm of dry tetrahydrofuran, 9.38 g of 2-methoxyphenylacetic acid is added at room temperature. This suspension is cooled to -30 ° C, 7.77 cm ³ of pivaloyl chloride is added, then finally adding a solution cooled to -78 ° C obtained by adding a solution of 35.27 cm ³ of butyllithium

1.6 M in hexane to a solution cooled to -78 ° C of 10 g of 4-methyl-5-phenyl-oxazolidinone-2- (4S, 5S) in 200 cm ³ of dry tetrahydrofuran. The reaction mixture is stirred 45 minutes at -30 ° C, then after returning to room temperature, 200 cm ³ of a saturated aqueous ammonium chloride solution are added, then 500 cm ³ of ethyl acetate; after decantation the organic phase is washed twice with 100 cm ³ of water, then twice with 100 cm ³ of a saturated aqueous sodium chloride solution; dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel

(grain size 0.04-0.06 mm, diameter 4.8 cm, height 36 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (85 / 15 then 80/20 by volume) and collecting 50 cm ³ fractions. Fractions 14 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 13.6 g of methyl 4-phenyl-5 (2-methoxy-phenyl cetyl) -3 oxazolidinone-2- (4S, 5S) are obtained in the form of a yellow oil.

Example of use 7

By operating according to the procedure of Example 8 below, from 1.82 g of 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole (1RS, 4aRS, 7aRS) and 1 , 39 g of [(3-dimethylamino-2-propoxy-2) phenyl] acetic acid, 0.3 g of {[(3-dimethylamino-propoxy-2) phenyl] acetyl} -6 4,4-diphenyl oxide-1 is obtained perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) in the form of white crystals melting at 150 ° C.

Example of use 8 To a solution cooled to 0 ° C of 1.06 g of (-) - 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R ^* , 4aR ^* , 7aR ^* ) and 0.81 g of [(3-dimethylamino-2-propoxy-2) phenyl] -2 acetic acid in 60 cm ³ of dry dichloromethane, 0.03 g of hydroxybenzotriazole hydrate is added, then 0.77 g (3-dimethylamino-propyl) -1 ethyl-3-carbodiimide hydrochloride. After 2 hours of stirring at 0 ° C and 20 hours at 20 ° C, the reaction mixture is washed with 20 cm ³ of water then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.4 cm ³ , height 35 cm), eluting under a pressure of 0.6 bar of nitrogen with a mixture of ethyl acetate, acetic acid and water (60/10/10 by volume) and collecting 50 cm ³ fractions. Fractions 8 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 60 cm of dichloromethane, the solution is washed with 20 cm of 1N aqueous sodium hydroxide solution, dried over magnesium sulphate, then concentrated to dryness. The solid obtained is recrystallized from a mixture of ethyl acetate and ethyl ether, the crystals are washed with diisopropyl ether, drained, and dried. 0.99 g of (-) - {[(3-dimethylamino-2-propoxy) phenyl] -2 acetyl} -6 4-diphenyl-4,4-oxide-1 perhydrothiopyrano [2, 3-c] pyrrole- (1R ^* ) are obtained ^. , 4aR ^* , 7aR ^* ) in the form of a white solid, melting at 120 ° C. [a] ²⁰ D = -323 °; (c = 0.5; acetic acid). Example of use 9

To a solution cooled to + 5 ° C of 0.69 g of 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) and 0.68 g of acid

{[(pyrrolidinyl-1) -3 propoxy-2] phenyl} acetic acid in 25 cm ³ of dry dichloromethane, 0.03 g of hydroxybenzotriazole hydrate is added, then a solution of 0.5 g of hydrochloride

(3-dimethylamino propyl) -1 ethyl-3 carbodiimide in 20 cm of dry dichloromethane. After 2 hours of stirring at + 5 ° C and 20 hours at 20 ° C, the reaction mixture is washed twice with 50 cm ³ of distilled water and dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2, 7 kPa). The residue obtained is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.4 cm ³ , height 32 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture ethyl acetate, acetic acid, and water (80/20/20 by volume) and collecting 25 cm ³ fractions. Fractions 21 to 50 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 8 cm ³ of ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl ether and then dried. 0.45 g of {{[(pyrrolidinyl-1) -3-propoxy-2] phenyl} acetyl} -6 diphenyl-4,4-oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) in the form of beige crystals melting at 126 ° C. Example of use 10

To a solution cooled to approximately 0 ° C. of 1.43 g of (-) - 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *), and 0.83 g (2-methoxyphenyl) -2 propionic acid (S) in 100 cm ³ of dry dichloromethane, 0.06 g of hydroxybenzotriazole hydrate and 1.01 g of (dimethylamino hydrochloride) are added -3 propyl) -1 ethyl-3 carbodiimide. After 2 hours of stirring at 0 ° C and 2 hours at

20 ° C, the reaction mixture is washed with 50 cm of water and then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile, the crystals are drained, washed several times with ethyl ether, then dried.

1.56 g of (-) - (2-methoxyphenyl) -2 propionyl- (S)] - 6 4-diphenyl-4,4-oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR) are obtained. *, 7aR *) in the form of white crystals melting at 170 ° C. [α] ²⁰ D = -316 °;

(c = 0.50; acetic acid). Example of use 11

By operating as described previously in Example 1, starting from

0.49 g of 2-dimethylamino phenylacetic acid, 0.50 g of N, N'-carbonyldiimidazole, 0.70 cm ³ of triethylamine and 1.0 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2 , 3-c] pyrrole dioxide-1,1- (4aRS, 7aRS), we obtain 0.55 g of [(2-dimethylamino phenyl) -6 4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole dioxide- 1,1- (4aRS, 7aRS), in the form of white crystals melting at 226 ° C. Example of use 12

To a suspension cooled to 0 ° C. of 0.46 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) in 10 cm ³ of dichloromethane, 0.35 cm ³ of triethylamine, and a solution of 0.17 cm ³ of phenylacetyl chloride in 5 cm ³ of dichloromethane. After 1 hour of stirring at 0 ° C and then 1 hour at 20 ° C, the reaction mixture is diluted with 10 cm ³ of dichloromethane, washed twice with 30 cm ³ of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 30 cm ³ of ethyl ether, the crystals are drained and dried. 0.50 g of 4,4-diphenylphenylacetyl-6 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) 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-d ₆ + CF ₃ CCOD, main signals, at room temperature the mixture of the two rotamers is observed): 2.48 (mt, 1H, CH ₂ in 3); 2.8 (mt, 1H, 1H in 5); 3.39 and 3.65 (s and ab

J = 14.2H, N-CO-CH ₂ ); 6.9 to 7.6 (mt, 15H, aromatic).

Example of use 13 To a suspension of 1.5 g of 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrroledioxide-1,1- (4aRS, 7aRS) and 0.95 g of hydrochloride 1-ethoxy-1-imino (2-methoxy-phenyl) -2 ethyl in

15 cm ³ of 1,2-dichloroethane, 1.16 cm ³ of triethylamine are added dropwise. After 20 hours of stirring at 20 ° C, 30 cm ³ of dichloromethane are added to the mixture and then washed successively with

100 cm ³ of water and 100 cm ³ of 5% aqueous potassium carbonate solution. The organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile and diisopropyl ether. The crystals are washed with acetonitrile then with diisopropyl ether, drained, and dried. 0.83 g of imino-1 (2-methoxy-phenyl) -2 6-ethyl-4,4-diphenyl-perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) is obtained in the form white crystals melting at 240 ° C.

Claims

1 - New thiopyranopyrrole derivative characterized in that it corresponds to the general formula:

 in which the symbol R represents a hydrogen atom, an allyl radical or a radical of structure:

- CR _a R _b R _c in which R _a and R _b are hydrogen atoms or phenyl radicals optionally substituted (by a halogen atom, an alkyl, alkyloxy or nitro radical), and R _c is defined as R _a and R _b or represents an alkyl or alkyloxyalkyl radical, at least one of R _a , R _b and R _c being a substituted or unsubstituted phenyl radical, and the symbol n represents an integer from 0 to 2, it being understood that the aicoyl radicals mentioned above contain 1 to 4 carbon atoms in a straight or branched chain, as well as its stereoisomeric forms and its salts when they exist.

2 - Diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole, as well as its salts, in its stereoisomeric forms and their mixtures.

3 - Diphenyl-4,4 oxide-1 perhydrothiopyrano [2,3-c] pyrrole, as well as its salts, in its stereoisomeric forms and their mixtures.

4 - Diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1, as well as its salts, in its stereoisomeric forms and their mixtures.

5 - Diphenyl-4,4 vinyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole, in its stereoisomeric forms and mixtures thereof. 6 - Diphenyl-4,4 oxide-1 tert-butyloxycarbonyl-6 perhydrothiopyrano [2,3-c] pyrrole, in its stereoisomeric forms and their mixtures.

7 - Process for the preparation of a new thiopyranopyrrole derivative according to claim 1, characterized in that a derivative of general formula is treated:

in which R 'is defined as R in claim 1 with the exception of representing the hydrogen atom, successively by a phenyl-magnesium halide, then by benzene in the presence of zirconium tetrachloride, then optionally eliminates from the radical protector R 'if one wants to obtain a product for which R is a hydrogen atom, and / or, where appropriate, oxidizes the product obtained, to obtain a thiopyranopyrrole derivative for which n = 1 or 2, then separates optionally the steroisomers and optionally transforms the product obtained into a salt when they exist.

8 - Process for preparing a thiopyranopyrrole derivative according to claim 1, for which the symbol n is equal to 1 or 2, characterized in that one oxidizes a thiopyranopyrrole derivative according to claim 1, for which the symbol n is equal to 0, and the amino function of which, where appropriate, is protected beforehand, by any known method for the oxidation of sulfides to sulfoxides or sulfones, which does not alter the rest of the molecule, then if appropriate, if we want to obtain a product for which R is the hydrogen atom, eliminates the protective radical, optionally separates the steroisomers and optionally transforms the product obtained into a salt when they exist.

9 - Process for the preparation of a thiopyranopyrrole derivative according to claim 1, for which the symbol n is equal to 2, characterized in that a cycloaddition reaction of a silylated derivative of general formula is carried out:

in the laguelle in which R ′ is defined as above, (R °) ₃ represents alkyl radicals or alkyl and phenyl radicals and R °° represents an alkyloxy, cyano or phenylthio radical, on 3,4-dihydro-4-diphenyl, 4 di-oxide-1,1 2H-thiapyranne of formula:

 optionally followed by the elimination of the protective radical R ', if it is desired to obtain a thiopyranopyrrole derivative according to claim 1 for which R is a hydrogen atom, then optionally separates the steroisomers and optionally transforms the product obtained into a salt when they exist.

10- Use of a product according to claim 1 for the preparation of a thiopyranopyrrole derivative of general formula:

in which

- the symbol n is an integer from 0 to 2,

- the symbol X represents an oxygen atom, or an NH radical, - the symbol R ₁ represents a phenyl radical optionally substituted by one or more halogen atoms or hydroxy radicals, alkyl which can be optionally substituted (by halogen atoms or amino, alkylamino or dialkoylamino radicals) alkyloxy or alkylthio which can optionally be substituted [by hydroxy, amino, alkylamino or dialkoylamino radicals optionally substituted (by phenyl, hydroxy or amino radicals), or dialkoylamino, the alkyl parts of which form, with the nitrogen atom to which they are attached, a heterocycle at 5 to 6 links which may contain another heteroatom chosen from oxygen, sulfur or nitrogen, optionally substituted by an alkyl, hydroxy or hydroxyalkyl radical)], or substituted by amino, alkylamino or dialkoylamino radicals, the alkyl parts of which may form with l nitrogen atom to which they are attached, a heterocycle as defined above, or represents a radic al cyclohexadienyl, naphthyl or heterocyclyl mono or polycyclic, saturated or unsaturated containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulfur, and

- the symbol R ₂ represents a hydrogen or halogen atom or a hydroxy, alkyl, aminoalkyl, alkylaminoalkyl, dialkoylaminoalkyl, alkyloyloxy, alkylthio, acyloxy, carboxy, alkyloxycarbonyl, dialkoylaminoalkylcarbonyl, aminocarbonyl, aminocarbonyl alkyl and acyl mentioned above being straight or branched and containing 1 to 4 carbon atoms, in its steroisomeric forms or their mixtures, as well as its salts when they exist.