EP0794944A1 - Perhydroisoindolderivate als substanz p antagonisten - Google Patents

Perhydroisoindolderivate als substanz p antagonisten

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Publication number
EP0794944A1
EP0794944A1 EP95941161A EP95941161A EP0794944A1 EP 0794944 A1 EP0794944 A1 EP 0794944A1 EP 95941161 A EP95941161 A EP 95941161A EP 95941161 A EP95941161 A EP 95941161A EP 0794944 A1 EP0794944 A1 EP 0794944A1
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EP
European Patent Office
Prior art keywords
phenyl
methoxy
radical
cyanomethyl
mixture
Prior art date
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Ceased
Application number
EP95941161A
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English (en)
French (fr)
Inventor
Daniel Achard
Jean-François Peyronel
Michel Tabart
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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Publication of EP0794944A1 publication Critical patent/EP0794944A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new derivatives of perhydroisoin- dole of general formula:
  • R- represents a phenyl radical optionally substituted by one or more halogen atoms or hydroxy, alkyl radicals which can be optionally substituted (by halogen atoms or amino, alkylammo or dialkoylammo radicals), alkyloxy or alkylthio which can be optionally substituted [ by hydroxy, amino, alkylammo or dialkylammo radicals optionally substituted (by phenyl, hydroxy or amino radicals), or dialkoylammo, the alkyl parts of which form, with the nitrogen atom to which they are attached, a 5 to 6-membered heterocycle which can contain another heteroatom chosen from oxygen, sulfur or nitrogen, optionally substituted by an alkyl, hydroxy or hydroxyalkyl radical), or substituted by amino, alkylam or dialkylammo radicals in which the alkyl parts can form with nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexa
  • the syrribole R2 represents a hydrogen or halogen atom or a hydroxy, alkyl, amino, aminoalkyl, alkyllaminoalkyl, dialkoylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy radical, alkyloxycarbonyl, dialkoylaminoalkyloxycarbonyl, benzyloxycarbonyl or acylamino,
  • R3 represents a phenyl radical optionally substituted in position -2 by an alkyl or alkyloxy radical containing 1 or 2 carbon atoms, hydroxy or by a fluorine atom, or disubstituted by trifluoromethyl radicals, and
  • R4 represents an alkyl radical containing 1 or 2 carbon atoms substituted by a halogen atom or by a cyano, az do or cyanamido radical
  • R are identical or different and represent a hydrogen atom, an alkyl or phenyl radical.
  • alkyl or acyl radicals mentioned above contain (unless special mention) 1 to 4 carbon atoms in a straight or branched chain.
  • or R4 contains a halogen atom
  • the latter can be chosen from chlorine, bromine, fluorine or iodine.
  • R- represents a mono or polycyclic heterocyclyl radical, saturated or msaturated, by way of example it can be chosen from thienyl, furyl, pyridyl, dithimyl, dolyl, isoindolyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, isidazolyl, pyrrolyl, triazolyl quinolyle, isoquinolyle, or naphty ⁇ d yle.
  • R- represents phenyl substituted by a chain carrying a heterocycle
  • the latter can be chosen from pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl, thiomorpholmo.
  • the perhydroisomdole derivatives of general formula (I) can be obtained by the action of the acid of general formula:
  • R 4 is an azidoalkyl radical, optionally transforms this radical into a cyanoaminoalkyl radical.
  • and / or R2 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, we operate according to the methods described by TW Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or by Me O ie, Protective Groups Organic Chemistry, Plenum Press (1973).
  • amino or alkylammo groups may be protected by methoxycarbonyl, ethoxycarbonyl, t.butoxycarbonyl, allyloxycarbonyl, vmyloxycarbonyl, trichlorethoxycarbonyl, trichloroacetyl, trifluoroacetyl, chloracetyl, benzylaryl, ethyl acetyl, benzyl acrylate radicals its substituted derivatives;
  • the acid groups can be protected by ethyl, ethyl, t.butyl, allyl, benzyl, substituted benzyl or benzhydryl radicals.
  • the operation is advantageously carried out using acid chloride, anhydride, a mixed anhydride or a reactive ester.
  • the remainder of the ester is a succinimido radical, optionally substituted benzotr ⁇ azolyl-1, n ⁇ tro-4 phenyl, 2,4-dinitro-phenyl, pentachlorophenyl or phthalimido.
  • the reaction is generally carried out at a temperature between
  • an organic solvent such as a chlorinated solvent (dichloromethane, d chlorethane, chloroform for example), a hydrocarbon (toluene for example), an ether (tetrahydrofuran, dioxane for example), an ester (ethyl acetate for example), an amide (dimethylacetamide, dimethylfor amide for example), or a ketone (acetone for example) or in a mixture of these solvents, in the presence of an acceptor of acid such as an organic nitrogenous base such as, for example, pyridme, dimethylammopyridine, N-methylmorphol or an alkylamide (in particular triethylamine, dopropylethylamine) or such as an epoxide (propylene oxide for example).
  • a chlorinated solvent dichloromethane, d chlorethane, chloroform for example
  • a hydrocarbon toluene for example
  • an ether tetrahydro
  • a condensing agent such as a carbodumide, [for example dicyclohexyl-caibodumide or (d ⁇ méthylam ⁇ no-3 propyl) -1 ethyl-3 carbodumide], NN '-carbonyldumidazole or the 2-ethoxy-1-ethoxycarbonyl-1,2-hydro-olein or else in a hydroorganic medium, in the presence of an alkaline condensing agent such as sodium bicarbonate.
  • a condensing agent such as a carbodumide, [for example dicyclohexyl-caibodumide or (d ⁇ méthylam ⁇ no-3 propyl) -1 ethyl-3 carbodumide], NN '-carbonyldumidazole or the 2-ethoxy-1-ethoxycarbonyl-1,2-hydro-olein or else in a hydroorganic medium, in the presence of an alkaline condensing agent such as sodium bicarbon
  • the preparation of the amine is generally carried out by hydrogenation in the presence of palladium or palladium hydroxide on carbon in an organic solvent such as an alcohol (ethanol for example), an amide (dimethylformamide for example), an ether ( tetrahydrofuran for example), at a temperature between 20 and 80 ° C
  • an organic solvent such as an alcohol (ethanol for example), an amide (dimethylformamide for example), an ether ( tetrahydrofuran for example), at a temperature between 20 and 80 ° C
  • the reaction of cyanogen halide is carried out in a solvent such as an ether (tetrahydrofuran for example), an aromatic solvent (toluene for example), an alcohol (ethanol for example) at a temperature between 0 and 50 ° vs.
  • a solvent such as an ether (tetrahydrofuran for example), an aromatic solvent (toluene for example), an alcohol (ethanol for example) at a temperature between 0 and 50 ° vs.
  • R'4 represents a sulfonyloxy radical and n represents 1 or 2, by the action of an alkali cyanide, sodium azide or an alkali halide to obtain the derivative for which R4 is respectively cyanoalkyl, azidoalkyl or haloalkyl, then optionally transforms the product obtained for which R4 is azidoalkyl to a product for which R 4 is cyanoammoalkyl, or else optionally transforms the product obtained for which R4 is haloalkyl into a product of general formula (I) for which R4 is cyanoalkyl or azidoalkyl.
  • the radical R ′ 4 can be p.toluenesulfonyloxy or methanesulfonyloxy.
  • the reaction is carried out in particular by the action of potassium or sodium cyanide in an organic solvent such as in particular dimethyl sulfoxide , at a temperature between 20 and 80 ° C.
  • the reaction is carried out by the action of sodium azide, in an organic solvent such as an amide ( dimethylformamide, dimethylacetamide for example) at a temperature between 10 and 50 ° C.
  • an alkali halide such as for example lithium bromide, chloride of lithium, potassium fluoride, potassium iodide ...
  • a solvent such as an alcohol (ethanol, methanol ...), a glycol (ethylene glycol, diethylene glycol ...), a ketone (acetone %), an ether (tetrahydrofuran, etc.) or a mixture of solvents, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.
  • the reaction is carried out under conditions analogous to the preparation of the cyanoalkyl or azidoalkyl derivatives from the corresponding sulfonyloxyalkyl derivative.
  • the iso dole derivative of general formula (III) can be obtained from the perhydroisoindole derivative of general formula:
  • R5, R3, R'4 and n are defined as above and R5 is a protective radical, by analogy with the process for the preparation of perhydroisoindole derivatives of general formula (I) from a derivative of general formula (IV), then elimination of the protective radical R5.
  • the protective radical 5 can be any amino protective group which is compatible with the reaction and the establishment and elimination of which does not alter the rest of the molecule.
  • alkyloxycarbonyl benzyloxycarbonyl or benzyl groups
  • allyl formyl, chloracetyl, trichloracetyl, trifluoroacetyl, vinyloxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, chloro-1 ethoxycarbonyl or chlorocarbon groups.
  • reaction is carried out under conditions identical to those described above for the preparation of the derivatives of general formula (I).
  • subsequent elimination of the radical R5 is carried out according to known methods which do not affect the rest of the molecule; in particular according to the methods described by T.W. Greene, Protective Groups in Organic Synthesis, A. Wiley - Interscience Publication (1981), or by Me Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).
  • the perhydroisoindole derivative of general formula (V) can be obtained by the action of an organometallic compound of general formula:
  • R3 is defined as above, and M represents lithium, a radical MgX or CeX2 for which X is an atom halogen, on the corresponding derivative of perhydroisoindolone of general formula:
  • R, R ' 4 , R5 and n are defined as above.
  • the reaction is carried out in an anhydrous medium, under the usual reaction conditions of the organometallic compounds with a ketone, which do not affect the rest of the molecule.
  • the operation is carried out in an anhydrous ether (for example tetrahydrofuran or ethyl ether) optionally in the presence of anhydrous cerium chloride at a temperature between -78 and 30 ° C.
  • the perhydroisoindole derivative of general formula (VII) can be obtained by the action of a sulphonic acid derivative of structure R'4-H on the hydroxylated derivative of general formula:
  • the reaction is carried out in particular by the action of the acid chloride, in an organic solvent such as a halide (dichloromethane, dichlorethane, chloroform for example) in the presence of an organic nitrogenous base as mentioned above (triethylamme for example) .
  • an organic solvent such as a halide (dichloromethane, dichlorethane, chloroform for example)
  • an organic nitrogenous base as mentioned above (triethylamme for example) .
  • perhydroisoindolone derivative of general formula (VIII) can be prepared as described below in the examples and by analogy with the methods described in patent application EP 429 366. It is understood that, depending on the nature of the substituents R desired, it will be necessary to start from the cyclohexenone suitably substituted.
  • the perhydroisoindole derivative of general formula (IV) can be obtained by the action of a sulfonic acid derivative of structure R'4-H on the corresponding hydroxylated derivative of general formula:
  • , R 2 , R3 and n are defined as above.
  • reaction is carried out under conditions analogous to those described for obtaining the perhydroisoindolone of general formula (VII).
  • the perhydroisoindole derivative of general formula (IX) can be obtained by the action of an acid of general formula (II) or its reactive derivative, on the perhydroisoindole derivative of general formula:
  • R, R3 and n are defined as above.
  • reaction is carried out by analogy with the preparation of the products according to the invention by condensation of an acid of general formula (II) on a perhydroisoindole derivative of general formula (III).
  • the perhydroisoindole derivative of general formula (X) can be obtained by the action of an organometallic compound of general formula (VI) on the corresponding derivative of perhydroisoindolone of general formula (VIII) whose hydroxy radical in position 6 can be protected beforehand, operating by analogy with the preparation of the derivatives of general formula (V), then release of the protective radicals according to the usual methods that do not alter the rest of the molecule.
  • reaction is carried out under the conditions described for obtaining the product of general formula (V) and as described in more detail in the examples. If necessary, the protection of the hydroxy radical in position 6 can be carried out according to known methods.
  • the separation can be carried out by preparing an optically active salt, by the action of L (-t) or D (-) mandelic acid, or of dibenzoyltart ⁇ que or ditoluoyltartrique acid, then separation of the isomers by crystallization.
  • the desired isomer is released from its salt in basic medium.
  • Another alternative may also be, if necessary, to operate directly from an enantiomer of the starting cyclohexenone.
  • the perhydroisoindole derivatives of general formula (III) are new products which also fall within the scope of the present invention.
  • the isoindole 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 ⁇ and / or R 2 contain amino or alkylammo substituents, or the intermediates of general formulas (III), or (X) can be transformed into salts d addition with acids.
  • addition salts with pharmaceutically acceptable acids mention may be made of 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 isoindole derivatives of general formula (I) can also, where appropriate, when R represents a carboxy radical, be transformed into metal salts or into addition salts with a nitrogenous base, according to 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, a ether or water, or by exchange reaction with a salt of an organic acid.
  • a metal base for example alkaline or alkaline earth
  • ammonia or an amine on a product according to the invention
  • a suitable solvent such as an alcohol, a 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
  • oterrous alkali metals magnesium, calcium
  • the ammonium salt the salts of nitrogenous bases (ethanolamme, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl- ⁇ -phenethylamme, NN'-dibenzylethylene-diam e, diphenylenediamme, benzhyldrylamine, quinine, quinine, quinine leuc e, dibenzylamine).
  • the new isomdole derivatives according to the present invention which antagonize the effects of substance P can find application in the fields of analgesia, inflammation, asthma, allergies, on the nervous system central, on the cardiovascular system, as an antispasmodic, as an antiemetic, 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 0.3 and 1000 nM according to the techniques adapted from DG Payan et al., J. of immunology, 133 (6), 3260-5 (1984): Stereospecif c receptors for substance P on cultured human IM-9 lymphoblasts and from Me Pherson et al., J. Pharmacol. Meth., 14, 213 (1985): Analysis of radioligand binding expenments.
  • Substance P is known to be involved in a number of pathological areas:
  • Example 1 1 Example 5 3-30 Example 9 3-30
  • isoindole derivatives according to the present invention do not exhibit any toxicity, they have been shown to be non-toxic in mice at a dose of 40 mg / kg by the subcutaneous route.
  • the present invention also relates to the synergizing association consisting of at least one NK1 receptor antagonist of general formula (I) and at least one NK2 receptor antagonist.
  • Neurok ine A The effects of neurok ine A are mediated mainly by NK2 receptors.
  • Neurokmine A is involved in many pathologies such as pain transmission, arthritis, asthma, inflammatory phenomena, psychoses, blood pressure disorders, bladder disorders, cystitis ...
  • NK2 receptor antagonists are known and described in particular and without limitation in patent applications EP 428 434, EP 474 561, EP 512 901, EP 515 240, FR 2 678 267, WO 92/19254 or WO 93/14084.
  • NK2 receptor antagonists may in particular be derivatives of the class of arylalkylamines, the class of ⁇ -substituted polypeptides or of the class of piperidine derivatives ...
  • NK2 receptor antagonists of the arylalkylamine class can be products of structure:
  • NK2 receptor antagonist Y N- iCH 2 ) m — C— (CH 2 ) p — N — T- (CH 2 ) q ⁇ Z Ar and among these products a specific NK2 receptor antagonist is more particularly described by X. Emonds-Alt et al., Life Science, j> 0, PL 100 to PL 106 (1992).
  • NK2 receptor antagonists of the class of ⁇ -substituted polypeptides can be products of structure:
  • radicals can be residues of amino acids.
  • NK2 receptor antagonists of the class of piperidine derivatives can for example be products of structure:
  • the reaction mixture is cooled to 20 ° C, diluted with 300 cm 3 of water and then extracted with twice 50 cm 3 of ethyl acetate.
  • the organic phase is then washed with 150 cm 3 of water, 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 0.06-0.20 mm, diameter 4.4 cm, height 50 cm), eluting under a pressure of 0.2 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and by collecting 120 cm 3 fractions.
  • (2-methoxy-phenyl) -4 [(2-methoxy-phenyl) -2 propionyl- (S)] -2 tosyloxymethyl-6 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6R, aR) can be prepared as follows: To a solution of 23.2 g of hydroxymethyl-6 (2-methoxy-phenyl) -4 [(2-methoxy-phenyl) -2 propionyl- (S)] -2 perhydro ⁇ somdolol-4- (mixture of the 2 diastereoisomers 3aR, 4R , 6S, 7aS, S and 3aS, 4S, 6R, 7aR, S) and with 14.9 cm 3 of triethylamine in 300 cm 3 of dichloromethane, 20.1 g of p.toluenesulfonyl chloride are added.
  • reaction mixture is washed with 150 cm 3 of water and 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 0.06-0.20 mm, diameter 8.0 cm, height 45 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 500 cm 3 fractions. Fractions 14 to 17 are concentrated to dryness under reduced pressure.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3560 + 3510, 3425, 3110 + 3070, 2930, 2890, 2860, 2840, 1635, 1600 + 1580 + 1495, 1460 + 1430, 1360, 1240, 1190 + 1180, 1100, 1060, 1035, 965, 815, 760, 670, 580 + 560.
  • Infrared spectrum (characteristic bands in cm -1 ): 3480, 3425, 3110 + 3070, 2930, 2880, 2840, 1625, 1600 + 1585 + 1495 + 1490, 1460, 1410, 1240, 1110, 1080, 1060, 1030 , 970, 750.
  • Hydroxymethyl-6 (2-methoxy-phenyl) -4 perhydro ⁇ somdolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3420, 3075, 2920, 2880, 1595, 1575, 1485, 1460, 1235, 1055, 1030, 755.
  • Benzyl-2-hydroxymethyl-6 (2-methoxy-phenyl) -4 perhydroisoindolol- 4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3560, 3420, 3060, 3025, 3005, 2910, 2850, 2800, 1590, 1575, 1495, 1480, 1230, 1055, 1030, 755, 735, 700.
  • Acetoxymethyl-6 benzyl-2 perhydro ⁇ soindolone-4- (3aRS, 6SR, 7aSR) can be prepared as follows:
  • CCI4 Infrared spectrum
  • characteristic bands cm -1 : 3105, 3090, 3065, 3030, 2920, 2795, 1745, 1712, 1605, 1585, 1495, 1455, 1425, 1365, 1240, 1035, 700.
  • Acetoxymethyl-5 cyclohexene-2 one-1 can be prepared according to the method described by DIPAKRANJAN MAL and Coll, J. Chem. Soc. Perkin Trans. 1, 309, (1994).
  • (2-methoxyphenyl) -2-propionic acid (S) can be prepared, by analogy with the methods described by DA Evans et al., Tetrahedron, 4_4, 5525, (1988), according to the following procedure :
  • 4-methylphenyl-5 [(2-methoxyphenyl) -2- (S) -propionyl] -3 oxazolinidone-2- (4S, 5S) can be obtained in the following way: To a solution cooled to -50 ° C of 10 g of 4-methylphenyl-5 [(2-methoxyphenyl) -acetyl] -3 oxazol ⁇ d ⁇ none-2- (4S, 5S) in 150 cm of tetrahydrofuran is added 19.1 g of sodium hexamethyl-1, 1, 1, 3, 3.3, disilazanate, the mixture is stirred for 45 minutes at this temperature, then 7.72 cm of methyl iodide are added. The reaction mixture is then stirred for 15 hours at room temperature, then diluted with
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3430, 3110 + 3070 + 3025, 2950, 2880 + 2890, 2855, 2840, 2825, 2250, 1625, 1600 + 1585 + 1495 + 1485, 1450, 1250, 1105, 1060, 1090, 1025, 960, 755, 587.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6RS, 7aSR) can be prepared as follows:
  • the cyanomethyl-6 (2-methoxy-phenyl) -4 perhydroiso-mdolol-4- (3aRS, 4RS, 6RS, 7aSR) hydrochloride obtained is taken up in 400 cm 3 of dichloromethane and after addition of 160 cm 3 of 4N sodium hydroxide, organic phase is washed with 300 cm 3 of water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa).
  • 103 g of cyanomethyl-6 (2-methoxy-phenyl) -4 perhydroiso- ⁇ ndolol-4- ((3aRS, 4RS, 6RS, 7aSR) are obtained in the form of a yellowish white solid.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3345, 2980, 2950, 2950, 2785 + 2760 + 2470 + 2410, 2240, 1600, 1575, 1485, 1460, 1435, 1240, 1100, 1060, 1025, 950, 765.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 perhydro- ⁇ somdolol-4- (3aRS, 4RS, 6RS, 7aSR) trifluoroacetate can be prepared by treating a solution of 8.5 g of cyanomethyl-6 (2-methoxyphenyl) ) -4 tert-butyl-oxycarbonyl-2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, RS, 6RS, 7aSR) in 170 cm 3 of dichloromethane per 12.6 cm 3 of trifluoroacetic acid, at 20 C C for 4 hours.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ somdolol-4- (3aRS, 4RS, 6RS, 7aSR) can be prepared as follows:
  • (2-methoxy-phenyl) -4 tert ⁇ obutyloxycarbonyl-2 tosyloxymethyl-6 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows: To a suspension cooled to + 5 ° C.
  • tertiary butyloxycarbonyl-2 tosyloxymethyl-6 perhydro ⁇ so ⁇ ndolone-4- (3aRS, 6SR, 7aSR) can be prepared as follows:
  • Infrared spectrum (CC1 4 ), characteristic bands (cm -1 ): 2980, 2930, 2900, 1720, 1700, 1600 + 1495, 1480, 1455, 1405, 1395, 1365, 1190 + 1180, 1165, 1110, 1100 +1020, 980, 880, 825, 670 + 570 + 555.
  • Hydroxymethyl-6 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ so ⁇ ndolone-4- (3aRS, 6SR, 7aSR) can be prepared by hydrogenation at atmospheric pressure for two hours from a suspension brought to 50 ° C of 513 g of 6-acetoxymethyl-benzyl-2 perhydro ⁇ so ⁇ ndolone-4- (3aRS, 6SR, 7aSR) and 103 g of 20% palladium hydroxide on black in 5.13 liters of ethanol and 157 cm 3 of 35% hydrochloric acid. The reaction mixture is then filtered, concentrated to dryness under reduced pressure (2.7 kPa).
  • the organic phase is washed cold with 2.5 liters of a 3% aqueous citric acid solution, with two liters of water, two liters of brine, then dried over magnesium sulfate and concentrated to dryness under reduced pressure.
  • 22 liters of methanol, 6.6 liters of water and 660 g of sodium carbonate are added to the red oil obtained.
  • the mixture is stirred at 60 ° C for 2 hours then 20 hours at 20 ° C.
  • concentration at reduced volume the mixture is extracted with 3 liters and 1.5 liters of ethyl acetate, the extracts are washed with 4 times a liter of brine then dried over magnesium sulphate and concentrated to dryness under pressure scaled down.
  • 3aRS, 6SR, 7aSR 6-hydroxymethyl tert-butyloxycarbonyl-2 perhydro ⁇ so ⁇ ndolone-4-
  • CCI4 Infrared spectrum
  • characteristic bands cm -1 : 3635, 3440, 2980, 2920 + 2930, 2880, 1720, 1695 + 1680, 1480, 1455 + 1445, 1405, 1395 + 1365, 1240, 1165, 1110, 1060 + 1050, 875.
  • Cyanomethyl-6 [(2-methoxy-6, phenyDacetyl] -2 (2-methoxy-phenyl) - 4 perhydro ⁇ so ⁇ ndolol-4 (3aRS, 4RS, 6RS, 7aSR) can be prepared in operating according to the method described in Example 2, from 0.5 g of cyanomethyl-6 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aRS, 4RS, 6RS, 7aSR), 50 cm 3 of dichloromethane, 0.05 g of hydroxybenzotriazole hydrate, 0.34 g of (2,6-dimethoxy-6 phenyl) acetic acid, and 0.37 g of (3-dimethylamino propyl) -1 ethyl-3 carbodumide.
  • (2,6-dimethoxyphenyl) acetic acid can be prepared according to the method of F. E. KING and M. F. GRUNDON., Chem. Soc. Transactions, 3547 - 3552 (1950).
  • reaction mixture is washed with twice 50 cm 3 of water, 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 4.8 cm, height 44 cm), eluting under a pressure of 0.4 bar of nitrogen, with a mixture dusopropyl ether and ethyl acetate (75/25, then 60/40 then 50/50 by volume and ending with ethyl acetate), and collecting fractions of 125 cm 3 .
  • Fractions 65 to 73 are concentrated to dryness under reduced pressure (2.7 kPa).
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3410, 3110 + 3065 + 3030, 2930, 2880, 2835, 2245, 1630, 1600 + 1590 + 1495, 1450 + 1435, 1240, 1120 + 1110, 1060 + 1050, 1025, 960, 755, 700.
  • Cyanomethyl-6 [(2-hydroxyphenyl) -2 propionyl- (S)] -2 (methoxy-2 phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR) can be prepared by hydrogenation under atmospheric pressure for 2 hours of a suspension of 0.59 g of cyanomethyl-6 [(2-benzyloxy-phenyl) -2 propionyl- (S)] -2 (2-methoxy-phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR) and 0.06 g of 20% palladium hydroxide on carbon black in 30 cm 3 of ethanol.
  • N- [(2-benzyloxyphenyl) -2- (S) propionyl] camphor-2, 10-sultame- (1R, 2S) can be prepared as follows:
  • reaction mixture is extracted with 80 cm 3 of ethyl acetate, the organic phase is washed twice with 25 cm of a saturated aqueous ammonium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 39 cm), eluting under a pressure of 0.3 bar of nitrogen with dichloromethane and collecting 25 cm fractions. Fractions 21 to 53 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from dusopropyl ether.
  • N- [(2-benzyloxy phenyl) -acetyl] camphor-2, 10-sultame- (1R, 2S) can be prepared in the following way:
  • Cyanomethyl-6 (2-methoxyphenyl) -4 perhydroiso-mdolol-4- (3aS, 4S, 6S, 7aR) hydrochloride can be prepared as described in Example 2, starting from 28.7 g of cyanomethyl- 6 (2-methoxy-phenyl) -4 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ somdolol-4- (3aS, 4S, 6S, 7aR), 230 cm 3 of dioxane, 70 cm 3 of 6N hydrochloric dioxane.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3330, 2975, 2950, 2915 + 2855, 2840, 2770 + 2745 + 2460 + 2380, 2245, 1595, 1570, 1480, 1455 + 1465, 1435, 1420, 1240, 1100, 1050, 1020, 955, 775 + 760.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ somdolol-4- (3aS, 4S, 6S, 7aR) can be prepared as described in Example 2, starting from 42 g of (2-methoxyphenyl ) -4 tert-butyloxycarbonyl-2 tosyloxymethyl-6 perhydro ⁇ somdolol-4- (3aS, 4S, 6R, 7aR), 200 cm 3 of dimethylsulfoxide, and 7.7 g of potassium cyanide.
  • (2-methoxy-phenyl) -4 tert-butyloxycarbonyl-2 tosyloxymethyl-6 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6R, 7aR) can be prepared by operating as described in Example 2, starting from 2-methoxyphenylmagnesium bromide (prepared from 30 cm 3 of bromo-2 anisole and 5.8 g of magnesium), 200 cm 3 of tetrahydrofuran, 55.6 g of tert-butyloxycarbonyl-2 tosyloxymethyl-6 perhydroisoindolone-4- (3aS, 6R, 7aR ), and 300 cm 3 of tetrahydrofuran.
  • 2-methoxyphenylmagnesium bromide prepared from 30 cm 3 of bromo-2 anisole and 5.8 g of magnesium
  • 200 cm 3 of tetrahydrofuran 55.6 g
  • the tertiary butyloxycarbonyl-2 tosyloxymethyl-6 perhydro ⁇ somdolone-4- (3aS, 6R, 7aR) can be prepared by operating as described in example 2, starting from 35 g of hydroxymethyl-6 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ so ⁇ ndolone-4- (3aS , 6R, 7aR), of 350 cm 3 of dichloromethane, 36.4 cm 3 of triethylam e, and 49.5 g of paratoluene-sulfonyl chloride.
  • Hydroxymethyl-6 tert ⁇ obutyloxycarbonyl-2 perhydro ⁇ so ⁇ ndolone-4- (3aS, 6R, 7aR) can be prepared by hydrogenating at atmospheric pressure for 2 hours, a mixture of 34 g of acetoxymethyl-6 benzyl-2 perhydro ⁇ somdolone-4- (3aS , 6R, 7aR), 6 g of palladium hydroxide on black, 140 cm 3 of ethanol, 12 cm 3 of 35% hydrochloric acid. The reaction mixture is then filtered, concentrated to dryness under reduced pressure (2.7 kPa).
  • Acetoxymethyl-6 benzyl-2 perhydro ⁇ somdolone-4- (3aS, 6R, 7aR) can be prepared by operating according to the method described in Example 1, starting from 80 g of 5-acetoxymethyl-2-cyclohexene one-1 - (R), 168 g of N-butoxymethyl N-trimethylsilylmethyl benzylamine, 800 cm 3 of dry dichloromethane, and 5 drops of trifluoroacetic acid. 83 g of 6-acetoxymethyl-2-benzyl-perhydro ⁇ so ⁇ ndolone-4- (3aS, 6R, 7aR) are obtained, after chromatographic purification, in the form of an oil used as it is in the next step.
  • 5-acetoxymetyl cyclohexè ⁇ e-2 one-1- (R) can be prepared as follows:
  • Example 4 By operating as described in Example 4, starting from 1.61 g of cyanomethyl-6 hydrochloride (2-methoxyphenyl) -4 perhydroiso- mdolol-4- (3aS, 4S, 6S, 7aR), 50 cm 3 of dichloromethane, 0.70 cm 3 of triethylamme, 1.21 g of (2-benzyloxy-phenyl) acetic acid, 0.02 g of hydroxybenzotriazole hydrate, and 1.05 g of (3-methylpropyl propyl) - 1 ethyl-3 carbodumide.
  • Cyanomethyl-6 [(2-hydroxyphenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR) is obtained by operating as described in Example 4, starting from 1.3 g cyanomethyl-6
  • Cyanomethyl-6 [(d ⁇ chloro-3, 4 phenyl) acetyl] -2 (methoxy-2 phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 5 , from 0.65 g of cyanomethyl-6 hydrochloride (2-methoxy-phenyl) -4 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR), 0.28 cm 3 of triethylamme, 0.41 g of 3,4-phenylacetic acid, 5 mg of hydroxybenzotriazole hydrate, and 0.42 g of (3-methylamino-propyl) -1 ethyl-3 carbodumide.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3410, 3070, 2930, 2885 + 2850, 2835, 2245, 1630, 1600 + 1580 + 1560 + 1485 + 1470, 1460 + 1435, 1235, 1130, 1105, 1030, 960, 875 + 810, 755.
  • Cyanomethyl-6 [( ⁇ ndolyl-3) acetyl] -2 (2-methoxyphenyl) -4 perhydro- ⁇ so ⁇ ndolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 5, from 0.65 g of cyanomethyl-6 (2-methoxy-phenyl) -4 hydrochloride perhydro ⁇ somdolol-4- (3aS, 4S, 6S, 7aR), 0.35 g of 3-indolyl acetic acid, 0.05 g of hydroxybenzotriazole hydrate, 0.28 cm 3 of triethylamme, and 0.42 g of (d ⁇ méthylam ⁇ no-3 propyl) -1 ethyl-3 carbodumide.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3535, 3430, 3230, 3105 + 3080 + 3055 + 3025, 2960, 2925 + 2905, 2880, 2855, 2840, 2250, 1630, 1583 + 1490, 1460, 1432, 1340, 1285, 1240 + 1235, 1115 + 1105, 1025, 955, 750 + 745.
  • the crude product is chromatographed on a column of silica gel (particle size 0.06-0.20 mm, diameter 4 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen in a mixture of acetate ethyl and cyclohexane (50/50 by volume) and collecting 120 cm 3 fractions. Fractions 4 to 16 are concentrated to dryness under reduced pressure (2.7 kPa). 4.55 g of [tertiobutyloxycarbonylamino-2 phenyl-2 acetyl- (S)] -2 cyanomethyl-6 (2-methoxy-phenyl) -4 perhydroisomdolol-4- (3aS, 4S, 6S, 7aR) are obtained. the shape of a whitish meringue.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3410, 3380 + 3300, 3075 + 3055 + 3025 + 3005, 2965 + 2950 + 2935, 2910 + 2885 + 2860, 2835, 2245, 1640, 1600 + 1580 + 1485, 1545, 1460 + 1445, 1245, 1105, 1030, 970, 755, 700.
  • Example 14 By operating according to the procedure of Example 14 below, starting from 0.63 g of 6-cyanomethyl-4-phenyl-hydrochloride-4-isoindolol-4- (3aRS, 4RS, 6RS, 7aSR) hydrochloride and 0, 39 g of 2-methoxyphenylacetic acid, 0.56 g of cyanomethyl-6 phenyl-4 is obtained (2-methoxyphenylacetyl) -2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6RS, 7aSR) in the form of a white meringue.
  • Infrared spectrum (characteristic bands in cm -1 ): 3580, 3400, 2980 + 2950, 2890, 2855, 2840, 2250, 1635, 1605 + 1580 + 1495, 1450, 1250, 1115, 1050, 1035, 970.
  • 6-cyanomethyl-4-phenyl hydrochloride perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6RS, 7aSR) can be prepared as follows:
  • Cyanomethyl-6 phenyl-4 tert-butyloxycarbonyl-2 perhydroisoindolol- 4- (3aRS, 4RS, 6RS, 7aSR) can be prepared as follows:
  • P-Toluenesulfonyloxymethyl-6 phenyl-4 tert-butyloxycarbonyl-2 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • the organic phase is washed with 20 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, then 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 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and d ethyl acetate (80/20 by volume) and collecting 25 cm 3 fractions. Fractions 16 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • P-Toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 (2-methoxyphenylacetyl) -2 perhydro ⁇ somdolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • P-Toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 [(2-methoxy-phenyl) -2 propionyl- (S)] -2 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6R, 7aR) can be obtained in this way next : To a solution of 1.17 g of hydroxymethyl-6 (2-fluoro-phenyl) -4 [(2-methoxy phenyl) -2 propionyl- (S)] -2 perhydro ⁇ so ⁇ ndolol-4- (3aS, 4S, 6R, 7aR ) in 30 cm 3 of dichloromethane is added, at room temperature, 4.2 g of p-toluenesulfonyl chloride, then 3.1 cm 3 of triethylamme.
  • reaction mixture is stirred at this temperature for 18 hours, then washed with 2 times 25 cm 3 of water, then with 25 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 is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 25 cm), eluting under a pressure of 0.8 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm 3 fractions. Fractions 22 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • reaction mixture is stirred for 18 hours at room temperature, then 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 is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.5 cm, height 29 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 75 cm 3 fractions. Fractions 81 to 99 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • Hydroxymethyl-6 (2-fluoro-phenyl) -4 hydrochloride-indolol-4- (3aRS, 4RS, 6SR, 7aSR) hydrochloride can be obtained as follows:
  • Hydroxymethyl-6 (fluoro-2 phenyl) -4 tert-butyloxycarbonyl-2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • reaction mixture is then stirred for 48 hours at room temperature, then it is treated with 50 cm 3 of a saturated aqueous ammonium chloride solution, extraction is carried out with 200 cm 3 of ethyl acetate, the organic phase is washed with 100 cm 3 of a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue is chromatographed on silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 75 cm 3 fractions.
  • Example 13 By operating according to the procedure of Example 13, starting from 1.67 g of p-toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 (2-benzyloxy-phenylacetyl) -2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6RS, 7aSR) and 0.104 g of potassium cyanide, 0.35 g of cyanomethyl-6 (2-fluoro-phenyl) -4 (2-benzyloxyphenylacetyl) -2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6SR, is obtained) 7aSR) in the form of a pink meringue.
  • Infrared spectrum characteristic bands in cm -1 : 3430, 3080 + 3040, 2925, 2890, 2855, 2790 + 2745 + 2640, 2250, 1625, 1600 + 1490 + 1485, 1460, 1255, 1210, 1100, 1040 , 970, 760.
  • P-Toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 (2-benzyloxyphenylacetyl) -2 perhydro ⁇ somdolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • Example 13 By operating according to the procedure of Example 13, starting from 0.72 g of hydroxymethyl-6 (2-fluoro-phenyl) -4 (2-benzyloxyphenylacetyl) -2 perhydro ⁇ so ⁇ ndolol-4- (3aRS, 4RS, 6SP , 7aSR), 0.55 g of p-toluenesulfonyl chloride and 0.4 cm 3 of triethylamme, after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2), 4 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume), 0.51 g of p-toluenesulfonyloxymethyl- 6 (2-fluoro phenyl) -4 (2-benzyloxyphenylacetyl) -2 perhydro ⁇ so ⁇ ndolol-4- (3
  • reaction mixture is stirred at room temperature for 18 hours, then the organic phase is washed with 10 cm 3 of water, then with 10 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dry under reduced pressure (2.7 kPa).
  • the residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with acetate ethyl and collecting 25 cm 3 fractions. Fractions 18 to 50 are combined and then concentrated to dryness under reduced pressure (2.7 kPa).
  • P-Toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 [(pyrrolidinyl- 1) -2 phenylacetyl] -2 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • Example 13 By operating according to the procedure of Example 13, starting from 0.2 g of 6-hydroxymethyl (2-fluoro-phenyl) -4 [(pyrrolidinyl-1) -2 phenylacetyl] -2 perhydroisoindolol-4- (3aRS , 4RS, 6SR, 7aSR), 0.168 g of p-toluenesulfonyl chloride and 0.124 cm 3 of triethylamine, 0.07 g of p-toluenesulfonyloxymethyl-6 (2-fluoro-phenyl) -4 [(pyrrolidinyl-1) is obtained ) -2 phenylacetyl) -2 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) in the form of a white meringue.
  • Example 14 By operating according to the procedure of Example 14, from 0.73 g of hydroxy ⁇ ethyl-6 hydrochloride (2-fluoro-phenyl) -4 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) and from 0 , 68 g of (pyrrolidinyl-1) -2 phenylacetic acid, 0.2 g of hydroxymethyl-6 (2-fluoro-phenyl) -4 [((pyrrolidinyl-1) -2 phenylacetyl] -2 perhydro-isoindolol- is obtained 4- (3aRS, 4RS, 6SR, 7aSR) in the form of a white meringue.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3400, 3070, 2925, 2880, 2835, 2095, 1625, 1600 + 1580 + 1495 + 1480, 1460, 1435, 1285, 1245 + 1235, 1105, 1050, 1030, 960, 755.
  • (2-methoxy-phenyl) -4 [(2-methoxy-phenyl) acetyl] -2 tosylmethyl-6 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3430, 3075, 3000-2875, 2835, 1620, 1605, 1495, 1485, 1460, 1435, 1245, 1055, 1030, 750.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3410, 3200, 3070, 2925, 2880, 2840, 2215, 1620, 1600 + 1490 + 1 80, 1460, 1435, 1285, 1245 + 1235, 1105 , 1050, 1030, 960, 755.
  • Aminomethyl-6 (2-methoxy phenyl) -4 [(2-methoxy phenyl) acetyl] -2 perhydroisoindolol-4- (3aRS, 4RS, 6SR, 7aSR) can be prepared as follows:
  • the combined organic extracts are then washed with 20 cm 3 of brine, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 1.5 cm, height 35 cm), under a pressure of 0.1 bar of nitrogen, eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 25 cm 3 fractions.
  • Fractions 15 to 22 are concentrated to dryness and then the residue is concrete in dusopropyl ether.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3560 + 3430, 3110 + 3070, 2970 + 2935, 2885, 2835, 1625, 1600 + 1585 + 1 90, 1460 + 1435, 1250, 1105, 1060 , 1030, 1020 + 1000, 960, 795, 755.
  • Cyanomethyl-6 (2-methoxy phenyl) -4 [2-phenyl propionyl- (S)] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared as follows:
  • reaction medium After 20 hours of stirring at 20 ° C, the reaction medium is washed twice with 30 cm 3 of water, dried over magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa).
  • the residue obtained is chromatographed on a silica gel column (particle size 0.04 - 0.063 mm, height 32 cm, diameter 2.8 cm), eluting under a pressure of 0.6 bar of nitrogen, with a mixture of cyclohexane and ethyl (50/50 by volume), and collecting 25 cm 3 fractions. Fractions 19 to 35 are concentrated to dryness under reduced pressure (2.7 kPa).
  • Cyanomethyl-6 [(2-fluoro phenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxy-phenyl) -4 hydrochloride-isoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.155 g of acid ( 4-fluoro phenyl) acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(2-tolyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in the example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-isoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.147 g of acid orthotolylacetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(3-thienyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 perhydro-isoindolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.140 g of thienyl acid 3 acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g hydroxybenzotriazole hydrate, and 0.210 g (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 [2-methoxy-2-phenyl acetyl- (S)] -2 (2-methoxy-phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, starting with 0.32 g of cyanomethyl-6 (2-methoxy-phenyl) -4 hydrochloride-isoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.170 g 2-methoxy-2-phenylacetic acid, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1 ethyl-3 hydrochloride carbodumide. After chromatographic purification is obtained (silica gel 0.06
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3600 3250 3073; 3030, 2940; 2886; 2853, 2838, 2244, 1635, 1600; 1582; 1486; 1452; 1438, 1452, 1236, 1105, 1029, 759, 700.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(2-thienyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.32 g of cyanomethyl-6 (2-methoxy-phenyl) -4 hydrochloride-isoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.14 g of acid 2-thienyl acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 [(2,3-dimethoxy phenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride perhydro-isoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.196 g of (2,3-dimethoxy phenyl) acetic acid, 0.21 cm 3 of diisopropyl ⁇ ethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • the (2,3-dimethoxyphenyl) acetic acid can be prepared according to the method described by W. WENNER., J. Org. Chem, 548 (1950).
  • Example 28 [(2-Chloro-phenyl) acetyl] -2 cyanomethyl-6 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-isoindolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.17 g 2-phenyl acetic acid, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 (methoxy-2 phenyl) -4 phenylacetyl-2 perhydro-isoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, starting from 0.32 g of cyanomethyl-6 hydrochloride (2-methoxy-phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0.140 g of phenylacetic acid, 0.21 cm 3 diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 [(3,4-dimethoxy phenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.200 g (3,4-dimethoxyphenyl) acetic acid, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1 ethyl-3 hydrochloride carbodumide.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3600 3250, 3075, 2937; 2886, 2836, 2243, 1622, 1592; 1516; 1485; 1456; 1436, 1556, 1236, 1027, 788, 760.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(2-trifluoromethyl phenyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.200 g of acid ( trifluoromethyl-2 phenyl) acetic, 0.21 cm 3 of diisopropylethyl- amino, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(4-methoxy-phenyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.166 g of acid
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3600 3250, 3070, 2937; 2884, 2836, 2243, 1620, 1582; 1513; 1485; 1454; 1438, 1454, 1245, 1030, 812, 757.
  • Cyanomethyl-6 (2-methoxy phenyl) -4 [(3-methoxy phenyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.166 g of acid ( 3-methoxyphenyl) acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino-propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 [(3-fluoro phenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.155 g of acid ( 4-fluoro phenyl) acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Cyanomethyl-6 [(4-fluoro phenyl) acetyl] -2 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21 , from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.155 g of acid ( 4-fluoro phenyl) acetic, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.210 g of (3-dimethylamino propyl) -1-ethyl-3-carbodumide hydrochloride.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3600 3250, 3070; 3050, 2931; 2885, 2840, 2244, 1624, 1582; 1510; 1485; 1454; 1437, 1554, 1234, 1027, 816, 758.
  • Cyanomethyl-6 [(3,4-difluoro phenyDacetyl] -2 (2-methoxyphenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.32 g of cyanomethyl-6 (2-methoxyphenyl) -4 hydrochloride-indolol-4- (3aS, 4S, 6S, 7aR) hydrochloride, 25 cm 3 of dichloromethane, 0.17 g 3,4-difluoro-phenylacetic acid, 0.21 cm 3 of diisopropylethylamine, 0.01 g of hydroxybenzotriazole hydrate, and 0.21 g of (3-dimethylamino-propyl) hydrochloride-3 ethyl-carbodumide
  • chromatographic purification sica gel 0.06 - 0.200 mm, elution with a mixture
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3600; 3250, 3072, 2940; 2880; 2850, 2838, 2243, 1625, 1581; 1515; 1485; 1453; 1437, 1453, 1235, 1028, 757.
  • Cyanomethyl-6 [2-hydroxy-phenyl-2 acetyl- (S)] -2 (methoxy-2 phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR), can be prepared by operating as it is described in Example 1, from 1.4 g of cyanomethyl-6 hydrochloride (2-methoxy phenyl) -4 perhydroiso- indolol- (3aS, 4S, 6S, 7aR), 40 cm 3 of dichloromethane, 0 , 66 g of S- (+) -mandelic acid, 0.02 g of hydroxybenzotriazole hydrate, 0.88 cm 3 of diisopropylethylamine, and 0.93 g of (3-dimethylamino propyl) -1 ethyl hydrochloride -3 carbodumide.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(2-methoxy-phenyl) -2 propionyl- (R)] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as it is described in Example 5, from 0.57 g of cyanomethyl-6 (2-methoxy-phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR), 30 cm 3 of dichloromethane, 0.20 cm 3 of diisopropylamine, 0.36 g of (methoxy-2 phenyl) -2- (R) - propionic acid, prepared according to T.
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3410, 3060, 2930, 2830, 2245, 1620, 1600 + 1580 + 1490, 1240, 1030, 755.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(2-pyridyl) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 9, from 0.57 g of cyanomethyl-6 (2-methoxy phenyl) -4 perhydroisoindolol-4-
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 [(pyridyl-3) acetyl] -2 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 9, from 0.57 g of cyanomethyl-6 (2-methoxy phenyl) -4 perhydroisoindolol-4-
  • Infrared spectrum (KBr), characteristic bands (cm -1 ): 3420, 3060 + 3030, 2945, 2850, 2840, 2245, 1640, 1600 + 1580 + 1485, 1240, 1030, 790, 760, 705.
  • Cyanomethyl-6 (2-methoxy-phenyl) -4 ⁇ [((pyrrolidinyl-1) -3 propoxy] - 2 phenyl ⁇ acetyl ⁇ -2 perhydro ⁇ soindolol-4- (3aS, 4S, 6S, 7aR) can be prepared by operating as described in Example 21, from 0.35 g of cyanomethyl-6 (2-methoxy phenyl) -4 perhydroisoindolol-4- (3aS, 4S, 6S, 7aR), 25 cm 3 of dichloromethane, 0 , 22 cm 3 of diisopropylethylamine, 0.32 g of ⁇ [(pyrrolidinyl-1) -3 propoxy] -2 phenyl ⁇ acetic acid, 0.01 g of hydroxybenzotriazole hydrate, and 0.26 g of hydrochloride of (dimethylamino-3 propyl) -1 ethyl-3 carbodumide.
  • the oily residue obtained is chromatographed on an alumina column (particle size 100 mesh, height 30 cm, diameter 4.5 cm), eluting under a pressure of 0.7 bar of nitrogen with a mixture of cyclohexane and acetate ethyl (75/25 by volume) and collecting 100 cm 3 fractions. Fractions 1 to 6 are concentrated to dryness under reduced pressure (2.7 kPa). 2.9 g of ⁇ [(pyrrolidinyl-1) -3 propoxy] -2 phenyl ⁇ acetic acid are obtained in the form of a thick oil.
  • Benzyl ⁇ [(pyrrolidinyl-1) -3 propoxy] -2 phenyl ⁇ acetate can be prepared as follows: To a solution 5.3 g of benzyl [(bromo-3 propoxy) -2 phenyl] acetate in 100 cm 3 of acetonitrile, 2.06 g of potassium carbonate, 0.5 g of sodium iodide and 1.25 cm 3 of pyrrolidine are added. After 3 hours of heating to 90 ° C., the mixture is cooled to room temperature, added with 50 cm 3 of water and then diluted with 50 cm 3 of dichloromethane.
  • Benzyl [(bromo-3 propoxy) -2 phenyl] acetate can be prepared according to the following procedure:
  • the oil obtained is chromatographed on a column of silica gel (particle size 0.06 - 0.200 mm, height 30 cm, diameter 5 cm), eluting with a mixture of cyclohexane and ethyl acetate (95/5 in volumes) and collecting 100 cm 3 fractions. Fractions 18 to 28 are concentrated to dryness under reduced pressure (2.7 kPa). 2.0 g of benzyl [(bromo-3 propoxy) -2 phenyl] acetate are obtained in the form of an oil.
  • Benzyl [(hydroxy-2) phenyl] acetate can be prepared by operating according to the following procedure: A suspension of 22.6 g of 2-hydroxyphenyl acetic acid, 0.5 g of para.toluene acid sulfonic in 15.5 cm 3 of benzyl alcohol is brought to reflux for three hours. 2 g of 3S active carbon are added, the suspension is filtered on a supercel and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa). Benzyl 30 * * (2-hydroxy) phenyl] acetate is obtained in the form of crystals. Mp K - 104 ° C.
  • the present invention also relates to the pharmaceutical compositions constituted by 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 by parenteral, oral, sublingual, rectal, topical, transdermal, ocular, intranasal or aerosol for pulmonary purposes.
  • 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 d, can be used. other suitable organic solvents.
  • These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating into the composition sterilizing agents, 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, senuptic glycerides or polyethylene glycols.
  • compositions for oral administration tablets, pills, powders or granules can be used.
  • the active product according to the invention (optionally combined with another pharma-ceutically compatible product) 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 it is possible to use pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil.
  • inert diluents such as water or paraffin oil.
  • These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.
  • compositions for topical administration can be, for example, creams, ointments, or lotions.
  • compositions for ocular administration may be instillations.
  • compositions for intranasal administration can be pharmaceutically acceptable solutions or powders intended for drops or sprays.
  • compositions can also be aerosols.
  • the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, serum or any other pharmaceutically acceptable vehicle.
  • the active principle is finely divided and combined with a water-soluble solid diluent or vehicle with a particle size of 30 to 80 ⁇ m, for example dextran, mannitol or lactose.
  • the products according to the invention can be particularly useful in the treatment of pain of traumatic, post-surgical, menstrual, cephalic origin, in cluster headache and in the treatment of migraines.
  • the new isoindole derivatives are also useful in the treatment of inflammation in rheumatology, 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, photodermatosis, burns and in inflammatory dental or ocular disorders and in the area of lachrymal secretions; they are also useful in the treatment of spasmodic, painful and inflammatory manifestations of the digestive tract (ulcerative colitis, irritable bowel syndrome, Crohn's disease), urinary tract (urinary hyperreflexia, cystitis) and respiratory tract (asthma , bronchial hypersecretion, chronic bronchitis, rhinitis
  • the products according to the invention can also find application in the treatment of neurological diseases, Parkinson's disease, Alzheimer's disease, in the treatment of inflammatory and / or autoimmune and / or demyelinating diseases of the central and / or peripheral nervous system ( multiple sclerosis, Guillain-Barré syndrome, encephalopathies of viral origin ...), in neurological syndromes in relation to plasma extravasation (edema of the spinal cord, cerebral edema ”), in relation to the blood-brain barrier or in any spastic neurological syndrome (muscle relaxant treatments).
  • the products according to the invention can also be useful in the treatment of anxiety, psychosis, schizophrenia, Huntington's disease or in the treatment of cardiovascular disorders such as hypotension.
  • Another application can also be the treatment of gynecological disorders, the treatment of disorders linked to poor growth regulation (dwarfism, secondary hypothrophies to chronic childhood diseases, osteoporosis, development of grafts).
  • 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.
  • 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.
  • Active product tablets having the following composition are prepared according to the usual technique: - [2-amino-2-phenyl acetyl- (S)] -2 cyanomethyl-6 (2-methoxy-phenyl) -4 perhydroisoindolol-4- ( 3aS, 4S, 6S, 7aR) 25 mg
  • Active product tablets having the following composition are prepared according to the usual technique:
  • Active product tablets having the following composition are prepared according to the usual technique: - azidomethyl-6 (2-methoxy-phenyl) -4 [(2-methoxy-phenyl) -2 propionyl- (S)] -2 perhydroisoindolol-4 - (3aS, 4S, 6R, 7aR) 25 mg

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EP95941161A 1994-11-30 1995-11-29 Perhydroisoindolderivate als substanz p antagonisten Ceased EP0794944A1 (de)

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FR9414345A FR2727411B1 (fr) 1994-11-30 1994-11-30 Nouveaux derives de perhydroisoindole, leur preparation et les compositions pharmaceutiques qui les contiennent
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PCT/FR1995/001577 WO1996016939A1 (fr) 1994-11-30 1995-11-29 Derives de perhydroisoindole comme antagonistes de la substance p

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