Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to new thiopyranopyrrole derivatives of general formula:
• R 1 and R 2 are hydrogen or alkyl and R is substituted phenyl.
• 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
• R 2 represents a hydrogen or halogen atom or a hydroxy, alkyl, aminoalkyl, alkyllaminoalkyl, dialkoylaminoalkyl, alkyloyloxy, alkylthio, acyloxy, carboxy, alkyloxy radical carbonyl, dialkoylaminoalkylcarcaryl, benzyloxycarbonyl, amino, acylamino or alkyloxycarbonylamino and
• - n is an integer from 0 to 2.
• alkyl or acyl radicals mentioned above contain 1 to 4 carbon atoms in a straight or branched chain.
• R 1 contains a halogen atom
• the latter can be chosen from chlorine, bromine, fluorine or iodine.
• R 1 represents a saturated or unsaturated mono or polycyclic heterocyclyl radical, for example it may be chosen from thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazc , quinolyl, isoquinolyl, or naphthyridinyl.
• R 1 represents phenyl substituted by a chain carrying a heterocycle
• the latter can be chosen from pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl or thiomorpholino.
• 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, one operates according to the methods described by TW Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or by Me Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).
• amino or alkylamino groups can be protected by methoxycarbonyl, ethoxycarbonyl, t.butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichlorethoxycarbonyl, trichlor radicals acetyl, trifluoroacetyl, chloroacetyl, trityl, benzhydryl, benzyl, allyl, formyl, acetyl, benzyloxycarbonyl or its substituted derivatives;
• the acid groups can be protected by methyl, ethyl, t.butyl, benzyl, substituted benzyl or benzhydryl radicals.
• R 2 represents a hydroxy radical
• R 2 represents a hydroxy radical
• the protection is carried out, for example, by an acetoxy, trialkylsilyl or benzyl radical, or in the form of a carbonate by a -COORa radical in which Ra is an alkyl or benzyl radical.
• the operation is advantageously carried out using acid chloride, anhydride, a mixed anhydride or a reactive ester.
• 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 (tetrahydrofufan, 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).
• an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), an ether (tetrahydrofufan, dioxane for example
• 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, if necessary, the amide obtained is converted into an amidine as defined above.
• 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,
• 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 acting l ammonia on the derivative of general formula (IV).
• 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.
• a chlorinated solvent dichloromethane, dichlorethane for example
• an alcohol-chlorinated solvent mixture in an ether ( tetrahydrofuran for example), in an ester (for example ethyl acetate), in an aromatic solvent (toluene for example) or in a mixture of these solvents, at a temperature between -20 ° C and the reflux temperature of the reaction mixture.
• the thiopyranopyrrole derivatives of general formula (I) for which the symbol R 1 is an alkyloxyphenyl radical in which the alkyl part is substituted or not and the symbol R 2 is other than a halogen atom or hydroxy radical can also be prepared from a thiopyranopyrrole derivative of general formula (I) for which R 1 is a hydroxyphenyl radical, by action in basic medium of the corresponding halogen derivative, of general formula:
• the reaction is generally carried out in the presence of a base such as a hydride, a hydroxide, an alcoholate, or an alkali metal carbonate, in an organic solvent such as an amide (for example dimethylformamide), an aromatic hydrocarbon ( toluene for example), a ketone (butanone for example) or in a mixture of these solvents, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.
• a base such as a hydride, a hydroxide, an alcoholate, or an alkali metal carbonate
• organic solvent such as an amide (for example dimethylformamide), an aromatic hydrocarbon ( toluene for example), a ketone (butanone for example) or in a mixture of these solvents, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.
• the radical R 4 carries a substituent which can interfere with the reaction, it is understood that the latter is previously protected.
• the protection and removal of the protective radical is carried out according to the methods described above.
• the thiopyranopyrrole derivatives of general formula (I) for which X is an NH radical can also be obtained from the thiopyranopyrrole derivative of general formula (III), by the action of a product of general formula:
• R 1 and R 2 are defined as above and R 5 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 (VI) 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 0oC and the reflux temperature of the reaction mixture.
• the oxidation is carried out according to known methods. For example, one operates by the action of an organic peracid (percarboxylic or persulfonic acid, in particular perbenzoic acid, 3-chloro perbenzoic acid, 4-nitro perbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid, acid permaleic, monoperphthalic acid, percamphoric or pertoluenesulfonic acid) or mineral peracids (for example periodic or persulfuric acid).
• an organic peracid percarboxylic or persulfonic acid, in particular perbenzoic acid, 3-chloro perbenzoic acid, 4-nitro perbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid, acid permaleic, mono
• 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 tetra-isopropylate.
• Kg represents 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 radical, alkyloxy or nitro), 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 alkyl radicals containing 1 to 4 carbon atoms in a straight or branched chain, by elimination of the radical R 6 , by any known method which does not affect the rest of the molecule.
• R 6 is other than an allyl radical
• the R 6 group can be eliminated by catalytic hydrogenation in the presence of palladium.
• 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 60oC.
• R 6 is a benzhydryl or trityl radical
• elimination can be carried out by treatment in an acid medium, operating at a temperature between 0oC and the reflux temperature of the reaction mixture, in an alcohol, in an ether, in the water or directly in acetic acid, formic acid or trifluoroacetic acid.
• the R 6 group can also be eliminated by causing vinyl chloroformate, 1-chloroethyl chloroformate or phenyl chloroformast to act, passing through a product of general formula:
• R 7 is a vinyl, 1-chloroethyl or phenyl radical
• 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 20oC and the reflux temperature of the reaction mixture.
• a chlorinated solvent dichloromethane, dichlorethane, chloroform for example
• an ether tetrahydrofuran, dioxane for example
• ketone acetone for example
• the elimination of the radical R 7 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.
• the thiopyranopyrrole derivative of general formula (III) is obtained in the form of the salt of the acid used which can be used directly in the subsequent step.
• the thiopyranopyrrole derivative of general formula (VII) can be obtained by cycloaddition reaction by the action of a silylated derivative of general formula:
• (Ro) 3 represents alkyl radicals or alkyl and phenyl radicals and Roo represents an alkyloxy, cyano or phenylthio radical, on dehydrothiapyranone-4 of formula:
• 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.
• an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane for example)
• an aromatic hydrocarbon in a nitrile (acetonitrile) or in an ether
• the phenyl radicals are set up according to the method described in more detail in Example 1.
• the silylated derivative of general formula (IX) can be obtained according to the methods described by:
• the 3,4-dihydro-4,4-diphenyl-1,1-dioxide 2H-thiapyranne of formula (XII) 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:
• thiopyranopyrrole derivatives of general formula (III), (VII) and (VIII) have several forms stereoisomers.
• the separation of the isomeric forms is preferably carried out at the level of the derivative of general formula (III); it can also be implemented from the thiopyranopyrrole of general formula (I).
• the separation of the axial and equatorial isomers is preferably carried out at the level of the product of general formula (III); it can also be implemented from the thiopyranopyrrole of general formula (I).
• the separation of the stereoisomers is carried out according to any known method compatible with the molecule.
• 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.
• the new thiopyranopyrrole derivatives of general formula (I) can be purified if necessary by physical methods such as crystallization or chromatography.
• the new derivatives of general formula (I) for which the symbols R 1 and / or R 2 contain amino or alkylamino substituents and / or X represents an NH radical can be converted into addition salts with acids .
• addition salts with pharmaceutically acceptable acids there may be cited 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 compounds).
• the new thiopyranopyrrole derivatives of general formula (I) can also, where appropriate, when R 2 represents a radical because boxy, be transformed into metallic salts or into addition salts with a nitrogenous base, according to the methods known per se.
• These salts can be obtained by the action of a metal base (for example alkaline or alkaline earth), ammonia or an amine, on a product according to the invention, in a suitable solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid.
• a suitable solvent such as an alcohol, an ether or water
• the salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or lyophilization.
• salts with alkali metals sodium, potassium, lithium
• alkaline earth metals magnesium, calcium
• the ammonium salt the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine , triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-b-phenethylamine, NN'-dibenzylethylenediamine, diphenylenediamine, benzhyldrylamine, quinine, choline, arginine, lysine).
• nitrogenous bases ethanolamine, diethanolamine, trimethylamine , triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-b-phenethylamine, NN'-dibenzylethylene
• the new thiopyranopyrrole derivatives according to the present invention 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 system cardiovascular, as an antispasmodic, or on the immune system, as well as in the field of stimulation of lachrymal secretions.
• the products according to the invention show an affinity for the 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).
• Substance P is known to be involved in a number of pathological areas:
• the injection of substance P in animals causes hypertension.
• the products studied in the technique of C.A. Maggi et al., J. Auton. Pharmac, 2, 11-32 (1987) show an antagonistic effect in the rat vis-à-vis this hypotension.
• the products administered at a dose of 1 mg / kg i.v./ran, for 5 min cause an antagonism of the hypotension induced by an i.v. injection of 250 mg / kg of substance P.
• 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.
• 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.
• 4,4-diphenyl hydrochloride perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) can be prepared as follows: 4.35 g of 4,4-diphenyl-vinyloxycarbonyl-6 perhydrothiopyrano are treated [2, 3-c] pyrrole- (4aRS, 7aRS) per 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 of ethanol, the resulting solution is brought to reflux for 30 minutes, then is concentrated to dryness.
• 4-hydroxy-4-phenyl-6-benzyl perhydrothiopyrano [2,3-c] pyrrole- (4RS, 4aSR, 7aRS) can be prepared as follows:
• the oil obtained is chromatographed on a column of silica gel (0.04-0.06 mm, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar by 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.
• reaction mixture After stirring for 20 hours at 20 ° C., the reaction mixture is washed with 50 cm 3 of 1N hydrochloric acid, 50 cm 3 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 reduced pressure (2.7 kPa).
• Infrared spectrum (characteristic bands, cm -1 ): 3095, 3055, 3025, 2950, 2930, 2875, 2835, 1630 1595, 1490, 1565, 1425, 1240, 1030, 750, 700.
• Infrared spectrum (characteristic bands, cm -1 ): 3095, 3060, 3025, 2960, 2930, 2870, 2835, 1640, 1600, 1495, 1465, 1425, 1240, 1035, 755, 700.
• (2-Methoxyphenyl) -2 propionic acid (S) can be prepared, by analogy with the methods described by D.A Evans et al., Tetrahedron, 44, 5525, (1988), according to the following procedure:
• Infrared spectrum (KBr, characteristic bands, cm -1 ): 3080, 3055, 3025, 2950, 2920, 2880, 2860, 1595, 1580, 1490, 1440, 1020, 760, 740, 700.
• Diphenyl-4,4 oxide-1 tertiobutyloxycarbonyl-6 perhydrothiopyrano [2, 3-c] pyrrole (mixture of isomers 1RS, 4aSR, 7aSR and 1RS, 4aRS, 7aRS) can be prepared as follows:
• the reaction mixture is washed twice with 100 cm 3 of saturated aqueous sodium bicarbonate solution, then with 100 cm 3 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).
• Diphenyl-4,4 tert-butyloxycarb ⁇ nyl-6 perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) can be prepared as follows:
• Diphenyl-4,4 oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) can also be prepared as follows:
• reaction mixture After 2 hours of stirring at 0oC 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).
• (-) - 4,4-diphenyl-1-oxide perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aS *) can be prepared as follows: A 7.15 g of 4-diphenyl , 4 oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) 3.5 g of mandelic acid- (S) and 90 cm of a mixture of acetonitrile and water are added (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 in 200 cm 3 of the boiling acetonitrile-water mixture and after hot filtration, the solution obtained is left for 5 hours at room temperature. The crystals are drained, washed twice with 10 cm 3 of acetonitrile, then dried. 1.5 g of 4,4-diphenyl-1-oxide-perhydrothiopyrano [2,3-c] pyrrole- (1R *, 4aR *, 7aR *) are obtained.
• reaction mixture is washed twice with 50 cm 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).
• reaction mixture After 2 hours of stirring at 0 ° C and 2 hours at 20 ° C, the reaction mixture is washed with 50 cm of water 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.
• the oil obtained is crystallized from 30 cm 3 of ethyl ether, the crystals are wrung, 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
• Diphenyl-4,4 hydrochloride perhydrothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) can be prepared as follows:
• 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 .
• 4,4-diphenyl-vinyloxycarbonyl-6 perhydrothiothiopyrano [2,3-c] pyrrole dioxide-1,1- (4aRS, 7aRS) can be prepared as follows:
• 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.
• Benzyl-6-diphenyl-4,4 perhydrothiopyrano [2,3-c] pyrrole dioxide1,1- (4aRS, 7aRS) can be prepared in the following way:
• 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).
• 3,4-dihydro-4,4-diphenyl-1,1,2-dioxide 2H thiapyran are obtained in the form of white crystals, melting at 166 ° C.
• the 3,4-dihydro-4,4-diphenyl-1-oxide 2H-thiapyranne can be prepared as follows:
• the 3,4-dihydro-4,4-diphenyl 2H-thiapyranne can be prepared as follows:
• the organic phase is washed again with 250 cm 3 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 as follows:
• 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
• the reaction mixture is heated at reflux for 15 minutes, stirred at 20 ° C for 20 hours, then diluted with 100 cm 3 of ethyl acetate, then washed twice with 150 cm 3 of distilled water and 100 cm of brine .
• the organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa).
• the residue is crystallized from diisopropyl ether, the crystals are wrung, dried under reduced pressure (2.7 kPa).
• the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa).
• the yellow oil obtained is chromatographed on a column of silica gel (0.04 mm-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar, using a mixture of ethyl acetate and methanol (98/2 by volume), collecting 60 cm fractions.
• Fractions 9 to 32 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallized from 10 cm of acetonitrile, the crystals are drained, filtered and dried.
• the organic phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 19 cm 3 of a mixture of concentrated hydrochloric acid and dioxane 0/2 by volume. After 48 hours of stirring at 20 ° C, the resulting solution is added with 15 cm 3 of 4N sodium hydroxide, then extracted with 30 cm 3 of dichloromethane. The organic phase is washed with 40 cm 3 of water and then dried over magnesium sulfate and concentrated to dryness.
• the residue is chromatographed on a column of silica gel (0.04-0.06 mm, diameter 3.6 cm, height 40 cm), eluting under a nitrogen pressure of 0.8 bar, by mixing acetate ethyl and methanol (95/5 by volume), collecting 25 cm 3 fractions. Fractions 100 to 119 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from ethyl acetate, the crystals are drained, dried.
• Example 16 By operating as in Example 16, by combining and concentrating the chromatographic fractions 123 to 148 to dryness, a residue is obtained which is crystallized from ethyl acetate. The crystals are drained, washed with ethyl acetate and diisopropyl ether and then dried. 0.39 g of ⁇ [(pyrrolidinyl-1) -2 phenyl] acetyl ⁇ -6 diphenyl-4,4 oxide-1 perhydrothiopyrano [2,3-c] is obtained pyrrole- (1RS, 4aRS, 7aRS) in the form of a white solid, melting at 198 ° C.
• the residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under a pressure of 1 bar of nitrogen with a mixture of ethyl acetate , acetic acid and water (80/10/10) and collecting 25 cm 3 fractions. Fractions 13 to 21 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of ethyl acetate and diisopropyl ether, the crystals are drained and then dried.
• Example 15 By operating as described previously in Example 15, starting from 0.99 g of 4,4-phenyl-6-phenylacetyl perhydrothiopyrano [2,3-c] pyrrole- (4aRS, 7aRS) and 0.49 g of 3-chloro peroxybenzo ⁇ que acid, 0.17 g of diphenyl-4,4 phenylacetyl-6 oxide-1 perhydrothiopyrano [2,3-c] pyrrole- (1RS, 4aRS, 7aRS) is obtained after chr ⁇ raatographic purification white crystals melting at 226 ° C.
• the reaction mixture is washed with 30 cm 3 of saturated aqueous sodium bicarbonate solution and with 2 times 30 cm of water, 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 mixture of concentrated hydrochloric acid and dioxane (1/2 by volume).
• the resulting solution is washed with 12 cm 3 of aqueous 4N sodium hydroxide solution, with 20 cm 3 of water, then is concentrated to dryness at 40 ° C under reduced pressure.
• the residue is chromatography on a silica gel column (particle size
• Example 22 By operating as in Example 22, by combining and evaporating the chromatographic fractions 13 to 20 to dryness, a residue is obtained which is crystallized from acetonitrile. The crystals are drained, washed with acetonitrile and diisopropyl ether and then dried. 0.02 g of [(2-methoxyphenyl) -2 propionyl- (S)] - 6 4-diphenyl-4,4-oxide-1 perhydrothiopyrano [2,3-c] pyrrole-mixture of the forms (1R, 4aS, 7aS) and (1S, 4aR, 7aR) as 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.
• the white suspension obtained is added with 0.01 cm of solution of tert-butyl hydroperoxide. After 1 hour 30 minutes at -20 ° C., 2.0 cm 3 of water are added to the reaction mixture, the gel obtained is filtered. The dichloromethane phase is dried over magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa).
• the present invention also relates to the pharmaceutical compositions consisting of a product of general formula (I) or a salt when they exist, optionally in combination with any other pharmaceutically compatible product, which may be inert or physiologically active.
• the compositions according to the invention can be used parenterally, orally, rectally or topically.
• the sterile compositions for parenteral administration which can in particular be used in the form of infusions are preferably aqueous or non-aqueous solutions, suspensions or emulsions.
• solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
• compositions can also contain adjuvants, in particular wetting agents, isoeonizers, emulsifiers, dispersants and stabilizers.
• Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.
• compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• solid compositions for oral administration tablets, pills, powders or granules can be used.
• the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
• These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.
• compositions for oral administration pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
• the compositions for topical administration can be, for example, creams, ointments, or lotions.
• the products according to the invention can be particularly useful in the treatment of pain of traumatic, post-surgical, menstrual, cephalic origin, in the treatment of anxiety, psychosis, Parkinson's disease, schizophrenia, Alzeimer's disease, in muscle relaxant treatments, in the treatment of spasmodic, painful and inflammatory manifestations of the digestive tract (ulcerative colitis, irritable bowel syndrome, Crohn's disease), urinary tract (cystitis) and respiratory tract (asthma, rhinitis) or in gynecology and in the treatment of migraines.
• the new thiopyranopyrrole derivatives are also useful in the treatment of rheumatoid arthritis and in disorders due to dysregulation of the immune system, in the treatment of inflammations in dermatology such as psoriasis, herpes, urticaria, eczema, photodermatoses and in inflammatory ocular or dental disorders.
• the products according to the invention can also find an application in the treatment of cardiovascular disorders such as hypotension.
• the doses depend on the desired effect and on the duration of the treatment. For an adult, they are generally between 0.25 and 1500 mg per day in staggered doses. In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.
• Example 1 illustrates a composition according to the invention.
• Active product tablets having the following composition are prepared according to the usual technique:

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