AU653033B2 - Novel derivatives of thiopyranopyrrole, their preparation and pharmaceutical compositions containing them - Google Patents

Description

OPI DATE 30/12/92 APPLN. ID 19140/92 AOJP DATE 11/02/93 PCT NUMBER PCT/FR92/00431 AU92 19140 DEMANDE INTERNATIONALE PUBLIEE EN YtRTU DU TRAITE DE COOPERATION EN MATIERE DE BREVETS (PCT) (21) Nurnro de la demande internationale: PCT/FR92/00431 (74) Mandataire: LOBJOIS, Franqoise; Rh6ne Poulenc Roret Direction Brevets, 20, avenue Raymond-Aron, F- (22) Datc de d~p6t international: 15 rnai 1992 (15.05.92) 92165 Antony C~dex (FR).

Donn~cs relatives h la prioriti: (81) Etats d~sign~s: AT (brevet europ~en), AU, BE (brevet euro- 91/06037 17 mal 1991 (17.05.9 1) FR p~en), CA, CH (brevet europ~en), CS, DE (brevet europ~en), DK (brevet europ~en), ES (brevet europ~en), Fl, FR (brevet europ~en), GB (brevet europ~en), GR (brevet (71) D~posant (pour tous les Etats dksig3~s sauf US): RHONE europ~en), HU, IT (brevet europ~en), JP, KR, LU (bre- POULENC RORER S.A. [FR/FR]; 20, avenue Ray- vet europ~en), MC (brevet europ~en), NL (brevet euromond-Aron, F-92 160 Antony p~en), NO, PL, RU, SE (brevet europ~en), US.

(72) Inveitteurs; et Inventeurs/D~posants (US settlement) ACHARD, Daniel Publi~e [FR/FR]; 26, rue Adrien-Tessier, F-94320 Thiais Avec rapport de rechzerche internationale.

MOUTONNIER, Claude [FR/FR]; 3, rue Auguste-Rodin, F-92350 Le Plessis-Robinson TABART, Michel [FR/FR]; Tour Ath~nes, 75, rue du Javelot, F-75013 Paris TRUCHON, Alain [FR/FR]; 73, rue Henri- Gorjus, F-69004 Lyon PEYRONEL, Jean-Frangois [FR/FR]; 6, parc dArdenay, F-91 120 Palaiseau (54) Title: NOVEL DERIVATIVES OF THIOPYRANOPYRROLE, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM ,(54)Titre: NOUVEAUX DERIVES DU THIOPYRANOPYRROLE, LEUR PREPARATION ET LES COMPOSITIONS PHARMAGEUTIQUES QUI LES CONTIENNENT }1 5

C

6

_C

6 171 N -c-CH-Ri (1) (57) Abstnrt Novel derivatives of thiopyranopyrrole of general formula in which X is an oxygen atom or an NH radical, R, is optionally substituted phenyl, or cyclohexadienyl, naphthyl, or heterocyclyl, R 2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino, and n is 0, 1 or 2, in their stercoisomer forms and mixtures thereof, and possibly the salts if they ex~ist, and preparation thereof. The novel derivatives of the invention are particularly interesting as P substance antagonists.

(57) Abr~g6 Noveaux d~riv~s de thiopyranopyrrole de formule g~n~rale dans laquelle X est un atome d'oxyg~ne ou un radical NH, R, est plifnyle 6v mtelement substitu6, cyclohexadi~nyle, naphtyle, ou h~t~rocyclyle, R 2 est H, halog~ne, OH, alcoyle, aminoalcoyle, alcoyianiinoalcoyle, dialcoylaminoalcoyle, alcoyloxy, alcoylthio, acyloxy, carboxy, alcoyloxycarbonyle 6ventuellement substitu6, benzyloxycarbonyle, amino ou acylamino, et n est 0, 1 ou 2, sous leurs formes st6r~oisom6res et leurs m6langes, 6ventuellement leurs sels lorsqu'ils existent et leur preparation. Les nouveaux d~riv~s scion l'invention sont particu- 1iirement int~ressants comme antagonistes de la substance P.

I d I WO 92/20685 1 PCT/FR92/00431 NEW THIOPYRANOPYRROLE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

The present invention relates to new thiopyranopyrrole derivatives of the general formula:

HC

6 C 6

H

X

N--C--CH--R

I (i) (0) n and their salts when these exist, which antagonise the effects of substance P and are as a result particularly useful in the therapeutic sectors where this substance is known to play a role.

Products derived from isoindole of the general formula:

C

6

H

N--R

H

which exhibit opium activity, have been described in American Patent 4,042,707.

These products exhibit no activity towards substance P.

Herbicides of the general formula:

V*^

1 0 1 2 R 1 R2 O

N-P

A

in which X may be a sulphur atom, R, and R 2 are hydrogen or alkyl and R is a substituted phenyl, have been described in European Patent Application 0068822.

In spite of the research carried out and in spite of the interest created Hanley, TINS, 139 (1982)], practically no product had been discovered so far which acts specifically on substance P and which has a nonpeptide structure; accordingly, the thiopyranopyrrole derivatives of general formula (I) are of great interest.

In the general formula the symbol X represents an oxygen atom or an NH radical, the symbol R, represents a phenyl radical which is optionally substituted by one or more halogen atoms or hydroxyl or alkyl radicals which may be optionally substituted (by halogen atoms or amino, alkylamino or 'dialkylamino radicals) alkoxy or alkylthio radicals which may be optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals optionally substituted (by phenyl, hydroxyl or amino radicals) or by dialkylamino radicals whose alkyl parts form with the nitrogen atom to which they are attached, a

I

3 heterocycle with 5 to 6 members which ay/ contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical)], or which is substituted by amino, alkylamino or dialkylamino radicals whose alkyl parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulphur, the symbol R, represelts a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylaminoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, and n is an integer from 0 to 2.

It is understood that the abovementioned alkyl or acyl radicals contain 1 to 4 carbon atoms in a linear or branched chain.

When RI contains a halogen atom, the latter may be chosen from chlorine, bromine, fluorine or iodine.

When Ri represents a saturated or unsaturated, mono- or polycyclic heterocyclic radical, it may for example be chosen from thienyl, furyl, pyridyl, dithiinyl, indolyl, isoindolyl, thiazolyl, t 4 isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, quinolyl, isoquinolyl or naphthyridinyl.

When RI represents a phenyl which is substituted by a chain carrying a heterocycle, the latter may be chosen from pyrrolidinyl, morpholino, piperidinyl, tetrahydropyridinyl, piperazinyl or thiomorpholino.

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

The products of the general formula for which n 1 also have axial or equatorial stereoisomers at the level of the S-oxide. It is understood that the position-i R and S derivatives and mixtures thereof are also included within the scope of the present invention.

Furthermore, when the symbol R 2 is other than the hydrogen atom, the substituted chain on the thiopyranopyrrole has a chiral centre, it is understood that the stereoisoniric forms and mixtures thereof are also included within the scope of the present invention.

According to the invention, the thiopyranopyrrole derivatives of general formula (I) may be obtained by reaction of the acid of general formula:

(II)

CH- COOH

R

2 or of a reactive derivative of this acid, in which R 1 and R 2 are defined as above, with a thiopyranopyrrole derivative of general formula:

H

5

C

6 C 6

H

H (III)

S

(0) n in which the symbol n is defined as above, followed, where appropriate, by conversion of the amide obtained to an amidine for which X represents an NH radical.

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

The protection is carried out using any compatible group whose introduction and removal does not affect the rest of the molecule. In particular the procedure is carried out according to the methods described by T.W. Greene, Protective Groups in Organic o 'I' 6 Synthesis, A. Wiley Interscience Publication (1981), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

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

Furthermore, when R 2 represents a hydroxyl radical, it is preferable to protect this radical beforehand. The protection is carried out for example using an acetoxy, trialkylsilyl or benzyl radical or in the form of a carbonate using a -COORa radical in which Ra is an alkyl or benzyl radical.

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

r 1 1. 1 7 The reaction is generally carried out at a temperature of between -40 and +40°C in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane, chloroform), an ether (for example tetrahydrofuran, dioxane), an ester (for example ethyl acetate), an amide (for example dimethylacetamide, dimethylformamide), or a ketone (for example acetone) or in a mixture of these solvents, in the presence of an acid acceptor such as a nitrogen-containing organic base such as for example pyridine, dimethylaminopyridine, N-methylmorpholine or a trialkylamine (in particular triethylamine) or such as an epoxide (for example propylene oxide). It is also possible to carry out the procedure in the presence of a condensation agent such as a carbodiimide, [for example dicyclohexylcarbodiimide or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide], N,N'-carbonyldiimidazole or 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline or alternatively in a dilute organic medium in the presence of an alkaline condensation agent such as sodium bicarbonate, and where appropriate the amide obtained is then converted to an amidine as defined above.

The conversion of the amide of general formula to an amidine for which X is an NH radical is carried out by preparing the derivative of general formula:

H

5

C

6

C

6

H

S I I

R

2 (0) n in which R 2 and n are defined as above, Y represents a chlorine atom, a methoxy or ethoxy radical and Z" represents a chloride, tetrafluoroborate, fluorosulphonate, trifluoromethylsulphonate, methyl sulphate or ethyl sulphate ion, and subsequently by reacting ammonia with the derivative of general formula

(IV).

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

I

9 (for example dichloromethane, dichloroethane) in an alcohol-chlorine-containing solvent mixture, in an ether (for example tetrahydrofuran), in an ester (for example ethyl acetate), in an aromatic solvent (for example toluene) or in a mixture of these solvents, at a temperature between -20°C and the reflux temperature of the reaction mixture.

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

According to the invention, the thiopyranopyrrole derivatives of general formula (I) for which the symbol R, is an alkoxyphenyl radical whose alkyl part is substituted or unsubstituted and the symbol R 2 is other than a halogen atom or hydroxyl radical, may also be prepared from a thiopyranopyrrole derivative of general formula for which R 1 is a hydroxyphenyl radical, by reaction in a basic medium of the corresponding halogenated derivative of general formula: Hal R4 (V) in which Hal is a halogen atom and R 4 is an alkyl radical which is optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals which are optionally substituted (by phenyl, hydroxyl or amino radicals), or a dialkylamino radical whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle as defined above in the general formula The reaction is generally carried out in the presence of a base such as an alkali metal hydride, hydroxide, alcoholate or carbonate, in an organic solvent such as an amide (for example dimethylformamide), an aromatic hydrocarbon (for example toluene), a ketone (for example butanone) or in a mixture of these solvents, at a temperature between 0 C and the reflux temperature of the reaction mixture.

When the radical R 4 carries a substituent which may interfere with the reaction, it is understood that the said substituent is protected beforehand. The protection and the removal of the protective radical are carried out according to methods described previously.

According to the invention, the thiopyranopyrrole derivatives of general formula (I) for which X is an NH radical, may also be obtained from the thiopyranopyrrole derivative of general formula (III), by reaction of a product of general formula: k2

NP

(VI)

optionally in the form of a salt, in which R I and R 2 are defined as above and Rs represents an alkoxy radical containing 1 to 4 carbon atoms in a linear or branched chain, or a methylthio, ethylthio, benzylthio or alkoxycarbonylmethylthio radical.

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

It is understood that should the radicals R, and/or R 2 of the product of general formula (VI) carry substituents which may interfere with the reaction, these substituents should be protected beforehand.

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

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

I

12 peracids (for example periodic or persulphuric acid).

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

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

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

The thiopyranopyrrole derivative of general formula (III) for which n=0 may be obtained from the corresponding derivative of general formula:

H

5

C

6

C

6

H

S(VII)

NR

6 in which R, represents an allyl radical or a radical of the structure -CRaRbRc in which R a and Rb are hydrogen atoms or phenyl radicals which are optionally substituted (by a halogen atom, an alkyl, alkoxy or nitro radical), and R. is defined as R, and Rb or represents an alkyl or alkoxyalkyl radical, at least one of Rb and Re being a substituted or unsubstituted phenyl radical and the alkyl radicals Vts v ^LSr I I 13 containing 1 to 4 carbon atoms in a linear or branched chain, by removing the radical R 6 by any known method which does not affect the rest of the molecule.

In particular, when R 6 is other than an allyl radical, the group R. ma" be removed by catalytic hydrogenation in the presence of palladium. Generally, the reaction is carried out in an acidic medium, in a solvent such as an alcohol (methanol, ethanol), in water or directly in acetic acid or formic acid, at a temperature between 20 and 60 0

C.

When R 6 is a benzhydryl or trityl radical, the removal may be carried out by treatment in an acidic medium, by carrying out the procedure at a temperature of between 0 C and the reflux temperature of the reaction mixture, in an alcohol, in an ether, in water or directly in acetic acid, formic acid or trifluoroacetic acid. The group R 6 may also be removed by reaction of vinyl chloroformate, 1-chloroethyl chloroformate or phenyl chloroformate, a product of general formula:

M

5

C

6

C

6

H

N-COOR 7

(VIII)

S

in which R 7 is a vinyl, 1-chloroethyl or phenyl radical, being obtained as an intermediate, and then by removing the radical R 7 by acid treatment. The reaction of the 1 14 chloroformate is generally carried out in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane, chloroform), an ether (for example tetrahydrofuran, dioxane) or a ketone (for example acetone) or in a mixture of these solvents, by carrying out the procedure at a temperature between 20 0 C and the reflux temperature of the reaction mixture.

The removal of the radical R 7 is carried out by treatment in an acidic medium for example with trifluoroacetic, formic, methanesulphonic, p-toluenesulphonic, hydrochloric or hydrobromic acid in a solvent such as an alcohol, an ether, an ester, a nitrile, a mixture of these solvents or in water, at a temperature between 0 C and the reflux temperature of the reaction mixture.

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

The thiopyranopyrrole derivative of general formula (VII) may be obtained by cycloaddition reaction, by reaction of a silylated derivative of general formula:

NCH

2 Si(R 0 3

(IX)

R

6 N I X CH2Roo

Q

in which R 6 is defined as above, (RO) 3 represents alkyl radicals or alkyl and phenyl radicals and ROO represents an alkoxy, cyano or phenylthio radical, with the 4-dehydrothiapyranone of formula: 0

(X)

S

followed by treating successively the product of general formula: 0

(XI)

NR6

S

which is obtained, with phenylmagnesium bromide and then with benzene in the presence of zirconium tetrachloride.

The cycloaddition reaction is carried out in the presence of a catalytic amount of an acid chosen from trifluoroacetic acid, acetic acid, methanesulphonic acid or the acids given in the references mentioned below, in an organic solvent such as a chlorine-containing solvent (for example dichloromethane, dichloroethane), in an aromatic 4 16 hydrocarbon, in a nitrile (acetonitrile) or in an ether, at a temperature between 0 C and the reflux temperature of the reaction mixture.

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

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

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

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

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

The products of general formula (III) for which n=2 may also be obtained from 3,4-dihydro- 4,4-diphenyl-2H-thiapyran 1,1-dioxide of formula:

H

5

C

6 C 6

H

(XII)

0 0 by cycloaddition reaction with a product of general formula under conditions identical to those described above for the cycloaddition reaction of this product with the 4-dehydrothiapyranone of formula followed by removal of the protective radical R 6 under the conditions described above.

3,4-Dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide of formula (XII) may be obtained by successive oxidation of 3,4-dihydro-4,4-diphenyl- 6 18 2H-thiapyran and 3,4-dihydro-4,4-diphenyl-2H-thiapyran 1-oxide of formula:

H

5

C

6

C

6

H

5

H

5

C

6

C

6 (XIII) (XIV)

S

s II 0 The oxidation reaction is carried out under the conditions described above for the preparation of the products of general formula It is not essential to isolate the S-oxide of general formula (XIV) in order to oxidise it to a sulphone.

3,4-Dihydro-4,4-dphenyl-2H-thiapyran of general formula (XIII) may be prepared according to or by analogy with the method described in Example 12 below.

It is understood that the thiopyranopyrrole derivatives of general formula (III), (VII) and (VIII) have several stereoisomeric forms. When it is desired to obtain a product of general formula with (4aR,7aR) or (4aS,7aS) stereoisomerism, the separation of the isomeric forms is preferably carried out with respect to the derivative of general formula (III); it may also be carried out using the thiopyranopyrrole of general formula Similarly, when a thiopyranopyrrole derivative for which n=l is prepared, the separation of the axial and equatorial isomers is preferably carried out with respect to the product of general formula (III); it may also be carried out using the thiopyranopyrrole of general formula The separation of the stereoisomers is carried out according to any known method which is compatible with the molecule. By way of example, the separation may be carried out by the preparation of an optically active salt, by reaction of or mandelic acid, or of dibenzoyltartaric acid, followed by separation of the isomers by crystallisation. The desired isomer is released from its salt in a basic medium. The separation of the axial and equatorial isomers may be carried out by chromatography or crystallisation.

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

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

The new thiopyranopyrrole derivatives of general formula may also, where appropriate, when R 2 represents a carboxyl radical, be converted to the metal salts or to the addition salts with a nitrogencontaining base, according to methods which are known per se. These salts may be obtained by reaction of a metal base (for example alkali metal or alkaline earth metal), of ammonia or an amine, with a product according to the invention, in an appropriate solvent such as an alcohol, an ether or water, or by exchange reaction with an organic acid salt. The salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or freeze-drying. As examples of pharmaceutically acceptable salts, there may be mentioned salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), ammonium salt, salts of nitrogen-containing bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, *N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-b-phenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, benzhyldrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).

The new thiopyranopyrrole derivatives 21 according to the present invention which antagonise the effects of substance P may find an application in the fields of analgesia, inflammation, asthma, allergies, on the central nervous system, on the cardiovascular system, as antispasmodic, or on the immune system, as well as in the domain of the stimulation of lachrymal secretions.

Indeed, the products according to the invention exhibit an affinity for substance P receptors at doses of between 10 and 2000 nM according to the technique described by C.M. Lee et al., Mol.

Pharmacol., 23, 563-69 (1983).

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

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

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

The study of a number of products has demonstrated in particular that the new thiopyranopyrrole derivatives exhibit an analgesic activity according to the technique of Siegmund E. et al., Proc. Soc. Exp. Biol. Med., 95, 729 (1957).

t Example No. EDs 5 mg/kg p.o.

Example 7 3 Example 10 1.7 The study of a number of thiopyranopyrrole derivatives of general formula according to the technique of A. Saria et al., Arch. Pharmacol., 324, 212-218 (1983) adapted to mice, has made it possible to demonstrate an inhibitory effect of the increase in capillary permeability brought about by septide (agonist of substance which is evidence of an antiflammatory activity: y Product of ED 50 mg/kg s.c.

Example No.

Example 8 0.05 Example 10 <0.1 Injection of substance P into animals produces hypotension. The products studied in the technique of C.A. Maggi et al., J. Auton. Pharmac., 1, 11-32 (1987) exhibit an antagonistic effect in rats towards this hypotension. In particular, the products administered at a dose of 1 mg/kg i.v./min, for 5 min, produce antagonism of the hypotension induced by an i.v. injection of 250 mg/kg of substance P.

Product of inhibition Example No. of hypotension Example 8 100 Example 10 100 Moreover, the thiopyranopyrrole derivatives according to the present invention are not toxic, they proved to be nontoxic 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 following products are of particular interest: 6-{[(3-dimethylamino-2-propoxy)phenyl]acetyl}-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, 6-{{[3-(l-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, 6-[(S)-2-(2-methoxyphenyl)propionyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, 6-{2-[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole, in their stereoisomeric forms and mixtures thereof.

The following examples, which are given with no limitation being implied, illustrate the present invention.

In the examples below, it is understood, unless specifically stated, that the proton NMR spectra were established at 250 MHz in dimethyl sulphoxide; the chemical shifts are expressed in ppm.

EXAMPLE 1 1.18 g of N,N'-carbonyldiimidazole are added to a solution of 1.16 g of 2-dimethylaminophenylacetic acid in 20 cm 3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5 0 C and then a solution of g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano- [2,3-c]-pyrrole hydrochloride and 1.83 cm 3 of triethylamine in 20 cm 3 of dichloromethane is added. The reaction mixture is stirred for 1 hour at 20 0 C and is then washed twice with 50 cm 3 of water and dried over magnesium sulphate. The solution is filtered, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (60/40 by volume), and collecting fractions of 60 cm 3 Fractions 6 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallised from an acetonitrile and diisopropyl 1C oxide mixture. The crystals are drained and dried.

2.16 g of (4aRS,7aRS)-6-[(2dimethylaminophenyl)acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid* melting point 163°C.

(4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano- [2,3-c]pyrrole hydrochloride may be prepared in the following manner: 4.35 g of (4aRS,7aRS)-4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole are treated with 30 cm 3 of a 5.7 N solution of hydrochloric acid in dry dioxane for 3U minutes at 20°C. The solution is concentrated to dryness under reduced pressure (2.7 kPa), the residue is taken up in 150 cm 3 of ethanol, the resulting solution is refluxed for 30 minutes and then concentrated to dryness. The solid obtained is washed with 50 cm 3 of ethyl ether, drained and dried. 3.64 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride are obtained in the form of a white solid.

Infrared spectrum (KBr, characteristic bands, 3060, 3030, 3000, 2250, 1600, 1495, 1580, 1450, 755, 710, 700.

Proton NMR spectrum (DMSO-d 6 main signals): 2.2 to 2.9 (mt, 4H, CH, at 2 and CH, at 2.4 and 3.3 (2mt, 2H, CHz at 3.08 J=12.5, 1H, 1H at 3.7 (mt, 1H, H at 4a); 4.16 J=5, 1H, H at 7a); 7.1 to (mt, 10 H, aromatics).

(4aRS,7aRS)-4,4-Diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: 1.72 cm 3 of vinyl chloroformate are added to 6.2 g of (4aRS,7aRS)-6-benzyl-4,4diphenylperhydrothiopyrano-[2,3-c]pyrrole, in 50 cm 3 of 1,2-dichloroethane. The mixture is refluxed for minutes and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 25 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 60 cm 3 Fractions 5 to 16 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is triturated in 70 cm 3 of diisopropyl oxide, the suspension is filtered, the solid drained and dried. 4.35 g of (4aRS,7aRS)-4,4diphenyl-6-vinyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 160 0

C.

(4aRS)-6-Benzyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: 43.7 g of zirconium tetrachloride are added to a solution of 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy-4phenyl-6-benzylperhydrothiopyrano[2,3-c]pyrrole in 180 cm 3 of benzene. The reaction mixture is refluxed for 1 hour and then brought to 20 0 C and diluted with 200 cm 3 of dichloromethane. 150 cm 3 of a 4N aqueous solution of sodium hydroxide are added to the resulting cooled solution. The suspension obtained is filtered, the filtrate is decanted, the organic phase is washed with 200 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 5.2 cm, height 39 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and collecting fractions of 125 cm 3 Fractions 19 to 32 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallised from 200 cm 3 of diisopropyl oxide, the crystals are drained and dried. 6.2 g of (4aRS,7aRS)-6-benzyl-4,4diphenylperhydro-thiopyrano(2,3-c]pyrrole are obtained in the form of orange-coloured crystals; melting point 130 0

C.

(4RS,4aSR,7aRS)-4-Hydroxy-4-phenyl-6benzylperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: A solution of 21.15 g of (4aRS,7aSR)-6benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole in 150 cm 3 of anhydrous ethyl ether is added over 30 minutes to a solution of phenylmagnesium bromide prepared from 19.8 cm 3 of bromobenzene and 4.52 g of dry magnesium in 120 cm 3 of anhydrous ethyl ether. The reaction mixture is stirred at the reflux temperature for 3 hours and then for 20 hours at 20 0 C. The mixture, to which 200 cm 3 of ethyl ether has been added, is stirred with 600 cm 3 of a saturated aqueous solution of ammonium chloride.

The aqueous phase is extracted with 200 cm 3 of ethyl ether, the two pooled ethereal extracts are washed twice with 300 cm 3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35 0 C. 12.2 g of (4RS,4aSR,7aRS)-4-hydroxy- 4-phenyl-6-benzylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 137°C.

(4aRS,7aSR)-6-Benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: drops of trifluoroacetic acid are added to a solution of 20 g of 4-dehydrothiapyranone and 54 cm 3 of N-butoxy-methyl-N-trimethylsilylmethylbenzylamine in 29 100 cm 3 of anhydrous dichloromethane and the mixture is stirred for 4 hours while maintaining the temperature at 20 0 C. The reaction mixture is stirred with 5 g of potassium carbonate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 9.2 cm), eluting under a nitrogen pressure of 0.6 bar, with a cyclohexane and ethyl acetate mixture (90/10 by volume) and then with the cyclohexane and ethyl acetate mixture (75/25 by volume), and collecting fractions of 250 cm 3 Fractions to 56 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 24 g of (4aRS,7aSR)-6benzyl-4-oxoperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a yellow oil.

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

Proton NMR spectrum (CDCl., main signals): 2.42 (dd, J=10 and 7, 1H, 1H at 2.66 (mt, 2H, CH 2 at 3.05 (mt, 1H, H at 4a); 3.1 (dd, J=10 at 7.5, 1H of CH, at 3.61 2H, N-CH 2 3.8 (dt, J=7.5 and 7, 1H, H at 7a); 7.15 at 7.35 (mt, 5H aromatics).

EXAMPLE 2 By carrying out the procedure as in Example 1, using 1.85 g of [2-(l-pyrrolidinyl)phenyl]acetic acid hydrobromide and 2.0 g of (4aRS,7aRS)-4,4diphenyl-perhydrothiopyrano[2,3-c]pyrrole hydrochloride, 0.90 g of (4aRS,7aRS)-6-{[2-(1pyrrolidinyl)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of white crystals; melting point 166 0

C.

EXAMPLE 3 A solution of 1.15 cm' of phenylacetyl chloride in 25 cm 3 of dichloromethane is added over minutes to a solution, cooled to 0°C, of 2.63 g of (4aRS,7aRS)-4,4-diphenyl-perhydrothiopyrano[2,3,c] pyrrole hydrochloride and 2.42 cm 3 of triethylamine in cm 3 of dichloromethane. After stirring for one hour at 0°C and one hour at 20°C, 20 cm 3 of dichloromethane are added. The reaction mixture is washed twice with 100 cm 3 of distilled water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.5 cm, height 26 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclochexane and ethyl acetate mixture (80/20 by volume) and collecting fractions of 125 cm 3 Fractions 19 to 26 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.87 g of (4aRS,7aRS)-6-phenylacetyl-44,4-diphenylperhydrothiopyrano pyrrole is obtained in the form of a white solid; melting point 210 0

C.

EXAMPLE 4 0.58 cm 3 of ethyl chloroformate is added to a solution of 0.92 g of 2-hydroxyphenylacetic in 30 cm 3 of dry dichloromethane. After stirring for 15 minutes at 20 0 C, the mixture is cooled to -15 0 C and 0.85 cm 3 of triethylamine is added. After stirring for 2 hours at 15 0 C, a suspension of 2 g of (4aRS,7aRS)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 1.70 cm 3 of triethylanine in 30 cm 3 of dichloromethane is added over 20 minutes. After stirring for 20 hours at 20 0 C, the reaction mixture is washed with 50 cm 3 of 1N hydrochloric acid, a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from 20 cm 3 of dichloromethane, the crystals are washed with diisopropyl oxide, drained and dried under reduced pressure (2.7 kPa). 1.02 g of (4aRS,7aRS)-4,4-diphenyl- 6-[(2-hydroxyphenyl)acetyl]perhydrothiopyrano[2,3-c] pyrrole are obtained in the form of white crystals; melting point 248 0

C.

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

2.66 g of (4aRS,7aRS)-4,4-diphenyl-6-((2-methoxyphenyl)acetyl]perhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 172 0

C.

EXAMPLE 6 6-[(S)-2-(2-Methoxyphenyl)propionyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole mixture of the (4aR,7aR) and (4aS,7aS) forms may be prepared by carrying out the procedure as described in Example using 0.89 g of (S)-2-(2-methoxyphenyl)propionic acid and (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride. 1.46 g of methoxyphenyl)-propionyl]-4,4-diphenylperhydrothiopyrano [2,3-c]-pyrrole mixture of the (4aR,7aR) and (4aS,7aS) forms are obtained in the form of a white meringue.

First form: Infrared spectrum (characteristic bands, 3095, 3055, 3025, 2950, 2930, 2875, 2835, 1630, 1595, 1490, 33 1565, 1425, 1240, 1030, 750, 700.

Proton NMR spectrum (DMSO-d 6

CF

3 COOD, at room temperature, a mixture of the two rotamers is observed; characteristic signals): 1.15 and 1.20 (2d, J=7.5, 3H, CH3); 2.1-2.9 (mt, 5H, 2 CH, at 5 and 3 H at 4a); 3.36 and 3.8 (2s, 3H, OCH 3 6.7 to 7.4 (mt, 14H, aromatics).

Second form: Infrared spectrum (characteristic bands, 3095, 3060, 3025, 2960, 2930, 2870, 2835, 1640, 1600, 1495, 1465, 1425, 1240, 1035, 755, 700.

Proton NMR spectrum (DMSO-d 6

CF

3 COOD, at room temperature, a mixture of the two rotamers is observed; characteristic signals): 1.1 and 1.18 (2d, J=7.5, 3H,

CH

3 2.1-2.35 (mt, 2H, CH 2 at 2.35-3.10 (mt, 3H,

CH

2 at 5 H at 4a); 3.6 and 3.8 (2s, 3H, OCH 3 3.95 and 4.02 (mt, 1H, H at 7a); 6.7 to 7.4 (mt, 14H, aromatics).

(S)-2-(2-Methoxyphenyl)propionic acid may be obtained in the following manner: (S)-2-(2-Methoxyphenyl)propionic acid may be prepared by analogy with the methods described by D.A. Evans et al., Tetrahedron, 44, 5525, (1988), according to the following procedure: 1.52 g of lithium hydroxide are added to a solution, cooled to +5 0 C, of 4.1 g of (4S,5S)-4-methyl-5-phenyl-3-[(S)-2-(2methoxyphenyl)-propionyl]-2-oxazolidinone in 60 cm 3 of tetrahydrofuran and 30 cm 3 of water. The reaction mixture is stirred for 3 hours at this tempetature and then, after re-equilibrating to room temperature, ethyl acetate is added, the mixture decanted and the aqueous phase is acidified with a 1N aqueous solution of hydrochloric acid, extracted with ethyl acetate and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is rerystallised from hexane, drained and dried. 0.4 g of methoxyphenyl)propionic acid is obtained in the form of white crystals; melting point 102°C. +84.6° CHC1 3 (4S,5S)-4-Methyl-5-phenyl-3-[(S)-2-(2methoxy-phenyl)propionyl]-2-oxazolidinone may be obtained in the following manner: 19.1 g of sodium 1,1,1,3,3,3hexamethyldisilazanate are added to a solution, cooled to -50oC, of 10 g of (4S,5S)-4-methyl-5-phenyl-3-[(2methoxyphenyl)acetyl]-2-oxazolidinone in 150 cm 3 of tetrahydrofuran and the mixture is stirred for minutes at this temperature and then 7.72 cm 3 of methyl iodide are added. The reaction mixture is then stirred for 15 hours at room temperature and then diluted with ethyl acetate, washed with 50 cm 3 of water and then with cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallised from isopropyl oxide, drained and dried. 4.2 g of (4S,5S)-4methyl-5-phenyl-3-[(S)-2-(2-methoxyphenyl)-propionyl]- 2-oxazolidinone are obtained in the form of a white solid.

(4S,5S)-4-Methyl-5-phenyl-3-(2-methoxyphenylacetyl)-2-oxazolidinone may be obtained in the following manner: 9.38 g of 2-methoxyphenylacetic acid are added to a suspension of 1.89 g of sodium hydride dispersion in vaseline) in 200 cm 3 of dry tetrahydrofuran, at room temperature. This suspension is cooled to -30°C, 7.77 cm 3 of pivaloyl chloride are added and then a solution, cooled to -78 0 C, which is obtained by adding 35.27 cm 3 of a 1.6 M solution of butyllithium in hexane to a solution, cooled to -78 0

C,

of 10 g of (4S,5S)-4-methyl-5-phenyl-2-oxazolidinone in 200 cm 3 of dry tetrahydrofuran is finally added. The reaction mixture is stirred for 45 minutes at -30°C and after re-equilibrating to room temperature, 200 cm 3 of a saturated aqueous solution of ammonium chloride are added followed by 500 cm 3 of ethyl acetate; after decantation, the organic phase is washed twice with 100 cm 3 of water and then twice with 100 cm 3 of a saturated aqueous solution of sodium chloride; dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 36 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture (85/15 followed by 80/20 by volume) and collecting fractions of 50 cm 3 Fractions 14 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 13.6 g of (4S,5S)-4-methyl- 5-phenyl-3-(2-methoxy-phenylacetyl)-2-oxazolidinone are obtained in the form of a yellow oil.

EXAMPLE 7 By carrying out the procedure according to that described in Example 8 below, using 1.82 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 1.39 g of [(3-dimethylamino-2propoxy)phenyllacetic acid, 0.3 g of (1RS,4aRS,7aRS)-6- {([(3-dimethylamino-2-propoxy)phenyl]acetyl}-4,4diphenylperhydrothiopyrano[2,3-c]pyrole 1-oxide is obtained in the form of white crystals; melting point 150 0

C.

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

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

Proton NMR spectrum (DMSO-d 6

CF

3 CCOD, main signals): 2.26 (broad t, J=14, 1H, 1H at 2.42 (dd, J=10 and 9, 1H, CH 2 at 2.55 (broad dd, J=14 and 4, 1H, 1H at 3.68 J=6, 1H, H at 7a); 3.82 J=14, 1H, H at 3.8 to 4 (mt, 1H, CH at 4a); 4.15 (dd, J=14 and 6, 1H, H a.t 7.1 to 7.5 (mt, 10H aromatics).

4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the 1RS,4aSR,7aSR and 1RS,4aRS,7aRS isomers) may be prepared in the following manner: A solution of 2.3 g of 3-chloroperoxybenzoic acid (at 85%) in 20 cm' of dichloromethane is added to a solution, cooled to 0 C of 4.2 g of (4aRS,7aRS)-4,4diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano [2,3-c]pyrrole in 30 cm 3 of dry dichloromethane. After

I

38 stirring for 1.5 hours at 3 0 C, and 1.5 hours at 20 0

C,

the reaction mixture is washed twice with 100 cm 3 of a saturated aqueous solution of sodium bicarbonate and then with 100 cm 3 of distilled water, dried over magnesium sulphate, concentraced to dryness at under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl oxide, drained and then dried under reduced pressure (2.7 kPa). 3.98 g of 4,4-diphenyl-6-tertbutyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (mixture of the 1RS,4aSR,7aSR and 1RS,4aRS,7aRS isomers) are obtained in the form of white crystals which are used as they are in the next reaction.

(4aRS,7aRS)-4,4-Diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano[2,3-c]pyrrole may be prepared in the following manner: 2.89 g of ditert-butyl dicarbonate are added in fractions of 0.5 g to a suspension of 4.0 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3c]pyrrole hydrochloride and 1.70 cm 3 of triethylamine in cm 3 of dry dichloromethane, followed by 0.15 g of 4-dimethylaminopyridine. The mixture is stirred for 20 hours at 20°C and then the reaction solution is washed with twice 100 cm 3 of an aqueous solution of citric acid of pH 4, with 100 cm 3 of water, dried over magnesium sulphate, and concentrated to dryness at 39 under reduced pressure (2.7 kPa). The residue is crystallised from ethyl ether, the crystals are drained and dried. 4.27 g of (4aRS,7aRS)-4,4-diphenyl-6-tertbutyloxycarbonyl-perhydrothiopyrano[2,3-c]pyrrole are obtained in the form of pink crystals; melting point 162 0

C.

(1RS,4aRS,7aRS)-4,4-Diphenylperhydrothiopyranol2,3-c]pyrrole 1-oxide may also be prepared in the following manner: A solution of 15.4 g of 3-chloroperoxybenzoic acid (at 85%) in 400 cm 3 of dichloromethane is added over 40 minutes to a solution, cooled to of 25 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole in 500 cm 3 of dichloromethane and 100 cm 3 of methanol, After stirring for one hour at -3 0 C, the reaction mixture is washed with 200 cm 3 of a 10% aqueous solution of potassium hydrogen carbonate and with 100 cm 3 of this same solution and then dried over magnesium sulphate and concentrated to dryness at 40 0

C

under reduced pressure (2.7 kPa). The residue is crystallised from 50 cm 3 of ethyl acetate, the crystals are taken up in 200 cm 3 of dichloromethane, the solution obtained is washed with 75 cm 3 of a IN aqueous solut of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. The residue is crystallised from 30 cm 3 of ethyl acetate, the crystals are washed with ethyl acetate, drained and dried.

13.6 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothio- .7

S

pyrano [2,3-c]pyrrole 1-oxide are obtained in the form of white crystals; melting point 174 0

C.

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

0.99 g of (1R*,4aR',7aR')-(-)-6-{2-[(3-dimethylamino-2- 41 propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 120°C. [C]j -3230 acetic acid).

(1R*,4aR*,7aR*)-(-)-4,4-Diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide may be prepared in the following manner: g of (S)-mandelic acid and 90 cm 3 of a mixture of acetonitrile and water (99/1 by volume) are added to 7.15 g of (1RS,4aRS,7aRS)-4,4diphenylperhydrothio-pyrano[2,3-c]pyrrole 1-oxide.

After stirring, the resulting solution is allowed to stand for 48 hours at room temperature. The crystals obtained are drained, washed with the acetonitrilewater mixture, and then dried. The crystals are taken up in 200 cm 3 of boiling acetonitrile-water mixture and after filtration while still hot, the solution obtained is allowed to stand for 5 hours at room temperature.

The crystals are drained, washed twice with 10 cm 3 of acetonitrile and then dried. 1.5 g of (1R*,4aR*,7aR*)- 4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-mandelate are obtained; -228°, (c=0.44; acetic acid). The filtrate is allowed to stand for hours at room temperature, the crystals obtained are drained, washed twice with 5 cm 3 of acetonitrile and then dried. 0.62 g of (1R',4aR',7aR')-4,4- Diphenylperhydrothio-pyrano[2,3-c]pyrrole 1-oxide mandelate is obtained; [a]c 0 -2300, (c=0.45; acetic

I

42 acid).

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

EXAMPLE 9 0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5 0 C, of 0.69 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.68 g of {[3-(1-pyrrolidinyl)-2propoxy]phenyl}acetic acid in 25 cm 3 of dry dichloromethane, followed by a solution of 0.5 g of 1l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride in 20 cm 3 of dry dichloromethane. After stirring for 2 hours at +5 0 C and 20 hours at 20°C, the reaction mixture is washed twice with 50 cm 3 of distilled water and dried over magnesium sulphate and then concentrated to dryness under reduced pressure 43 (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 32 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate, acetic acid and water mixture (80/20/20 by volume) and collecting fractions of 25 cm 3 Fractions 21 to 50 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from 8 cm 3 of ethyl acetate, the crystals are washed with ethyl acetate and diisopropyl oxide and then dried. 0.45 g of (1RS,4aRS,7aRS)-6-{{[3-(1-pyrrolidinyl)-2propoxy]phenyl}acetyl}-4,4-diphenylperhydrothiopyrano- [2,3-c]pyrrole 1-oxide is obtained in the form of beige crystals; melting point 126 0

C.

EXAMPLE 0.06 g of hydroxybenzotriazole hydrate and 1.01 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride are added to a solution, cooled to about 0 C, of 1.43 g of (1R*,4aR*,7aR*)-(-)-4,4-diphenylperhydrothiopyrano-[2,3-c]pyrrole 1-oxide and 0.83 g of (S)-2-(2-methoxy-phenyl)propionic acid in 100 cm 3 of dry dichloromethane. After stirring for 2 hours at 0 C and 2 hours at 20 0 C, the reaction mixture is washed with cm 3 of water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in acetonitrile, the crystals are drained, washed several times with ethyl ether and then dried.

I K. f 44 1.56 g of methoxy-phenyl)propionyl]-4,4-diphenylperhydrothiopyrano-[2,3-c]pyrrole 1-oxide are obtained in the form of white crystals; melting point 170°C. -316°C (c=0.50; acetic acid).

EXAMPLE 11 By carrying out the procedure as described in Example 1 above, using 0.49 g of 2-dimethylaminophenylacetic acid, 0.50 g of N,N'-carbonyldliimidazole, 0.70 cm 3 of triethylamine and 1.0 g of (4aRS,7aRS)-4,4diphenylerhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride, 0.55 g of (4aRS,7aRS)-6-(2dimethylamino-phenyl)-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 226 0

C.

EXAMPLE 12 0.35 cm 3 of triethylamine and a solution of 0.17 cm 3 of phenylacetyl chloride in 5 cm 3 of dichloromethane are added to a suspension, cooled to 0 C, of 0.46 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1,1-dioxide hydrochloride in cm 3 of dichloromethane. After stirring for 1 hour at 0 C and then 1 hour at 20 0 C, the reaction mixture is diluted with 10 cm 3 of dichloromethane, washed twice with 30 cm 3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallised from 30 cm 3 of ethyl ether, the crystals are drained and dried. 0.50 g of (4aRS,7aRS)-4,4-diphenyl-6phenylacetylperhydro-thiopyrano[2,3-c]pyrrole 1,1dioxide 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, a mixture of the two rotamers is obtained at room temperature): 2.48 (mt, 1H, CH 2 at 2.8 (mt, 1H, 1H at 3.39 and 3.65 (s and ab J=14, 2H, N-CO-CH 2 6.9 to 7.6 (mt, 15H, aromatics).

(4aRS,7aRS)-4,4-Diphenylperhydrothiopyrano- [2,3-c]pyrrole 1,1-dioxide hydrochloride may be prepared in the following manner: 0.58 g of (4aRS,7aRS)-4,4-diphenyl-6vinyloxycarbonyl-perhydrothiopyrano[2,3-c]pyrrole 1,1dioxide is treated with 25 cm 3 of a 5.7 N solution of hydrochloric acid in dry dioxane for 30 minutes while making lukewarm. The reaction solution is concentrated to dryness under reduced pressure (2.7 kPa) at 50 0

C.

The residue is taken up in 15 cm 3 of ethanol, the solution obtained is refluxed for 30 minutes and it is then concentrated to dryness. The solid obtained is washed with ethyl ether, drained and dried. 0.46 g of (4aRS,7aRS)-4,4-diphenyl-perhydrothiopyrano[2,3-c] 1,1dioxide hydrochloride is obtained in the form of a white solid.

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

Proton NMR spectrum (DMSO-d, CF 3 CCOD, main signals): 3.84 (ab, 2H, CH2 at 4.0 (mt, 1H, H at 4a); 4.27 (mt, 1H, H at 7a); 7.1 to 7.6 (mt, 10H, aromatics).

(4aRS,7aRS)-4,4-Diphenyl-6-vinyloxycarbonylperhydrothiothiopyrano[2,3-c]pyrrole 1,1-dioxide may be prepared in the following manner: 0.16 cm 3 of vinyl chloroformate is added to a solution of 0.7 g of (4aRS,7aRS)-6-benzyl-4,4diphenylperhydro-thiopyrano[2,3-c]pyrrole 1,1-dioxide in 10 cm 3 of 1,2-dichloroethane. The mixture is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa) at 50*C. The crystalline solid is washed with ethyl ether, drained and then dried. 0.58 g of (4aRS,7aRS)-4,4-Diphenyl-6vinyloxycarbonylperhydro-thiopyrano[2,3-c]pyrrole 1,1dioxide is obtained in the form of white crystals.

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

Proton NMR spectrum (DMSO-d 6

CF

3 COOD, main signals): 2.5 to 3.45 (mt, 6H, CH, at 5, at 2 and at 3.8 to 4.2 (mt, 4H, CH, at 7, H at 4a and H at 7a); 4.46 and 4.72 (broad 2d, J=6 and J=14, 2xlH, CH=CH,); 7.0 (dd, J=14 and 6, 1H, OCH=); 7.1 to 7.6 (mt, 10H, aromatics).

(4aRS,7aRS)-6-Benzyl-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide may be prepared in the following manner: 2 drops of trifluoroacetic acid are added to a solution of 1.3 g of 3,4-dihydro-4,4-diphenyl-2Hthiapyran 1,1-dioxide and 1.75 cm 3 of N-butoxymethyl-Ntrimethylsilylmethylbenzylamine in 12 cm 3 of anhydrous dichloromethane and the mixture is stirred for minutes at 30 0 C. 1.75 cm 3 of N-butoxymethyl-Ntrimethylsilyl-methylbenzylamine and 2 drops of trifluoroacetic acid are again added and the mixture is stirred for 2 hours at 35°C. This last operation is again repeated and after stirring for 1 hour, 1 g of potassium carbonate is added. The suspension is filtered, the filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 35 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (80/20 by volute) and collecting fractions of 30 cm 3 Fractiont 20 to 28 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (4aRS,7aRS)-6-benzyl-4,4diphenylperhydrothiopyrano-[2,3-c}pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 186 0

C.

3,4-Dihydro-4,4-diphenyl-2H-thiapyran 1,1-dioxide may be prepared in the following manner: A solution of 1.12 g of 3-chloroperoxybenzoic acid (at 85%) in 25 cm 3 of dry dichloromethane is added to a solution of 1.47 g of 3,4-dihydro-4,4-diphenyl-2Hthiapyran 1-oxide in 15 cm 3 of dry dichloromethane.

After stirring for 20 hours at 20 0 C, the reaction mixture is washed with 50 cm 3 of a 10% aqueous solution of sodium thiosulphate and then with 50 cm 3 of a saturated aqueous solution of sodium hyd:ogen carbonate. The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The crystalline residue is washed with ethyl ether, drained, and dried under reduced pressure (2.7 kPa). 1.3 g of 3,4-dihydro-4,4-diphenyl- 2H-thiapyran 1,1-dioxide are obtained in the form of white crystals; melting point 1664C.

3,4-Dihydro-4,4-diphenyl-2H-thiapyran 1-oxide may be prepared in the following manner: By carrying out the procedure as above, using 2.05 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran and 1.67 g of 3-chloroperoxybenzoic acid (at 1.9 g of 3,4-dihydro-4,4-dipheyl-2H-thiapyran i-oxide are obtained in the form of a white solid; melting point 130 0

C.

3,4-Dihydro-4,4-diphenyl-2H-thiapyran may be prepared in the following manner: 3.95 cm 3 of acetic anhydride are added to a suspension of 2.7 g of 4,4-diphenyltetrahydrothiapyran 1-oxide in 30 cm 3 of anhydrous toluene. The mixture is refluxed for 20 hours and concentrated to dryness at under reduced pressure (2.7 kPa and then 0.13 kPa). The oily residue is crystallised from diisopropyl oxide, the crystals are drained and dried.

2.1 g of 3,4-dihydro-4,4-diphenyl-2H-thiapyran are obtained in the form of white crystals; melting point 78 0

C.

4,4-Diphenyltetrahydrothiapyran 1-oxide may be prepared in the following manner: A solution of 20.3 g of 3-chloroperoxybenzoic acid (at 85%) in 300 cm 3 of dichloromethane is added over 40 minutes to a solution, cooled to 0 C, of 25.4 g of 4,4-diphenyltetrahydrothiapyran in 130 cm 3 of dichloromethane. After stirring for 2 hours at 0°C, 250 cm 3 of a 5% aqueous solution of potassium hydrogen carbonate are added to the mixture and then stirred for minutes. The organic phase is again washed with 250 cm 3 of the potassium hydrogen carbonate solution and it is then dried over magnesium sulphate, co. trated to dryness (after verifying the absence of per ',des), under reduced pressure (2.7 kPa). 26.9 g of 4,4-diphenyltetrahydrothiapyran 1-oxide are obta\ in the form of a white solid; melting point 122 0

C.

4,4-Diphenyltetrahydrothiapyran may be prepared in the following manner: 100 g of sodium sulphide nonahydrate are added to a suspension of 140.8 g of 3,3-diphenyl-1,5bis(methane-sulphonyloxy)pentane in 1400 cm 3 of 1-butanol. The mixture is refluxed for 2 hours and then cooled to about 20 0 C, and 1000 cm 3 of water, 500 cm 3 of ethyl acetate and 500 cm 3 of dichloromethane are then added. After stirring, the organic phase is separated, washed successively with 1000 cm 3 of water, 500 cm 3 of IN hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and 1000 cm 3 of water, and then dried over magnesium sulphate and concentrated to dryness at 60°C under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are washed with diisopropyl oxide, drained and dried. 76 g of 4,4-diphenyltetrahydrothiapyran are obtained in the form of white crystals; melting point 134 0

C.

3,3-Diphenyl-1,5-bis(methanesulphonyloxy)pentane may be prepared in the following manner: A solution \f 62 cm 3 of methanesulphonyl chloride in 100 cm 3 of dichloromethane is added over minutes to a solution, cooled to 2 0 0 °C o 95 g of 3,3-diphenyl-1,5-pentanediol (prepared according to P.

EILBRACHT et al., Chem. Ber. 113, 825-839 (1985)) in 950 cm 3 of dichloromethane and 113 cm 3 of triethylamine.

After stirring for 2 hours at 20°C, the reaction mixture is washed with twice 500 cm 3 of water, the organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallised from ethyl ether, the crystals are washed with ethyl ether, drained and dried. 140 g of 3,3-diphenyl-1,5bis(methanesulphonyloxy)pentane are obtained in the form of white crystals; melting point 99 0

C.

EXAMPLE 13 A solution of 1.4 g of (4aRS,7aRS)-4,4diphenyl-6-[2-(2-hydroxyphenyl)acetyl]perhydrothiopyrano[2,3-c]-pyrrole in a mixture of dimethylformamide, toluene and anhydrous tetrahydrofuran (15/10/5.5 by volume) is added over 30 minutes to a suspension of 0.12 g of sodium hydride in 10 cm 3 of anhydrous toluene. A solution of 3 g of N-(3chloropropyl)-N,N-dimethylamine in 10 cm 3 of anhydrous toluene is added to the solution obtained heated to 0 C. T| .':action mixture is refluxed for 15 minutes, stirred at -o°C for 20 hours, then diluted with 100 cm 3 of ethyl acetate and then washed twice with 150 cm 3 of distilled water and 100 cm 3 of brine. The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from diisopropyl oxide, the crystals are drained and dried under reduced pressure (2.7 kPa).

1.18 g of (4aRS,7aRS)-6-{2-[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenyl-perhydrothiopyrano[2,3c]pyrrole are obtained in the form oC beige crystals; melting point 130 0

C.

EXAMPLE 14 1.16 cm 3 of triethylamine are added dropwise to a suspension of 1.5 g of (4aRS,7aRS)-4,4diphenylperhydrothio-pyrano[2,3-c]pyrrole 1,1-dioxide hydrochloride and 0.95 g of 1-ethoxy-l-imino-2-(2methoxyphenyl)ethyl hydrochloride in 15 cm 3 of 1,2dichloroethane. After stirring for 20 hours at 20 0

C,

cm 3 of dichloromethane are added to the mixture and then washed successively with 100 cm 3 of water and 100 cm 3 of a 5% aqueous solution of potassium carbonate.

The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from an acetonitrile and diisopropyl oxide mixture. The crystals are washed with acetonitrile and then with diisopropyl oxide, drained and dried. 0.83 g of (4aRS,7aRS)-6-[l-imino-2-(2-methoxyphenyl)-ethyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of white crystals; melting point 240 0

C.

EXAMPLE A solution of 0.88 g 3-chloroperoxybenzoic acid (at 85%) in 15 cm 3 of dichloromethane is added to a stirred solution, cooled to 0 C, of 1.88 g of (4aRS,7aRS)-6-[(2-dimethylaminophenyl)acetyl]-4,4diphenylperhydro-thiopyrano[2,3-c]pyrrole in 30 cm 3 of dichloromethane. The reaction mixture is stirred for 2 hours at 0°C, washed twice with 30 cm 3 of a saturated aqueous solution of sodium bicarbonate and then with cm 3 of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The yellow 53 oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate and methanol mixture (98/2 by volume) and collecting fractions of 60 cm 3 Fractions 9 to 32 are pooled and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallised from cm 3 of acetonitrile, the crystals are drained, filtered and dried. 0.93 g of (1RS,4aSR,7aSR)-6-((2dimethyl-aminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano-[2,3-c]pyrrole 1-oxide is obtained in the form of white crystals; melting point 204 0

C.

Fractions 33 to 50 are pooled and concentrated to dryness and then the residue is purified by chromatography under the same conditions as above (eluent ethyl acetate and methanol 94/6 by volume). Fractions 76 to 86 are pooled and, concentrated to clyness under reduced pressure (2.7 kPa). The residue is crystallised from acetonitrile, the crystals are drained and dried. 0.28 g of (IRS,4aRS,7aRS)-6-[(2dimethyl-aminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano-[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 190 0

C.

(1RS,4aRS,7aRS)-6-[(2-Dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide may also be prepared in the following manner: 2.46 g of (1RS,4aSR,7aSR)-6-[(2dimethylaminophenyl)-acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide in 25 cm 3 of a mixture of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 by volume) is stirred for 48 hours at 0 C. The solution is then neutralised at 10°C with 20 cm 3 of a 4N aqueous solution of sodium hydroxide. The decanted organic phase is washed with 50 cm' of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 30°C. The oily residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 34 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions of 25 cm 3 Fractions 72 to 92 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) at 400C. The residue is crystallised from ethyl acetate, the crystals are washed with diisopropyl oxide, and then drained and dried. 1.08 g of (1RS,4aRS,7aRS)-6-[(2dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide are obtained in the form of white crystals; melting point 190 0

C.

EXAMPLE 16 A solution of 0.83 g of 3-chloroperoxybenzoic acid (at 85%) in 15 cm 3 of dichloroiethane is added to a solution, cooled to 0 C, of 1.85 g of (4aRS,7aRS)-6- {[2-(l-pyrrolidinyl)phenyl]acetyl}-4,4diphenylperhydrothio-pyrano[2,3-c]pyrrole in 30 cm 3 of dichloromethane. After stirring for 1 hour at 0 C and 2 hours at room temperature, the reaction mixture is washed with 50 cm 3 of a saturated aqueous solution of sodium bicarbonate and then with twice 30 cm 3 of water.

The organic phase is dried over magnesium sulphate, 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 dioxiane (1/2 by volume). After stirring for 48 hours at 20 0

C,

cm 3 of 4N sodium hydroxide are added to the resulting solution and then extracted with 30 cm 3 of dichloromethane. The organic phase is washed with 40 cm 3 of water and then dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 40 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions of 25 cm 3 Fractions 100 to 119 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from ethyl acetate, the crystals are drained and dried.

0.11 g of (1RS,4aSR,7aSR)-6-{[2-(l-pyrrolidinyl)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano- [2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 190 0

C.

EXAMPLE 17 By carrying out the procedure as in Example 16, pooling and concentrating to dryness the chromatographic fractions 123 to 148, a residue is obtained which is crystallised from ethyl acetate. The crystals are drained, washed with ethyl acetate and diisopropyl oxide and dried. 0.39 g of (1RS,4aRS,7aRS)- 6-{[2-(1-pyrrolidinyl)phenyl]acetyl}-4,4diphenylperhydrothio-pyrano[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 198 0

C.

EXAMPLE 18 0.15 cm 3 of trifluoroacetic acid is added to a solution of 0.5 g of (4aRS,7aRS)-6-{2-[2-(3dimethylamino-propoxy)phenyl]acetyl}-4,4diphenylperhydrothiopyrano-[2,3-c]pyrrole in 5 cm 3 of dry dichloromethane, and then cooled to 0 C. After stirring for 30 minutes at 0°C, a solution of 3chloroperoxybenzoic acid (at 85%) in 10 cm 3 of dichloromethane is added dropwise. The reaction mixture is stirred for 2 hours at 0 C, then diluted with 10 cm 3 of dichloromethane and then washed with 20 cm 3 of 1N sodium hydroxide and 20 cm 3 of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under a nitrogen pressure of 1 bar with an ethyl acetate, acetic acid and water mixture (80/10/10) and collecting fractions of 25 cm 3 Fractions 13 to 21 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from an ethyl acetate and diisopropyl oxide mixture, the crystals are drained and dried. 0.13 g of (1RS,4aSR,7aSR)-6-{2-[2-(3-dimethylaminopropoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of a beige solid; melting point 146 0

C.

EXAMPLE 19 By carrying out the procedure as described in Example 15 above, using 0.99 g (4aRS,7aRS)-4,4diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole and 0.49 g of 3-chloroperoxybenzoic acid, 0.54 g of (1RS,4aSR,7aSR)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained after chromatography in the form of white crystals; melting point 217 0

°C

EXAMPLE By carrying out the procedure as described in Example 15 above, using 0.99 g of (4aRS,7aRS)-4,4diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole and 0.49 g of 3-chloroperoxybenzoic acid, 0.17 g of (1RS,4aRS,7aRS)-4,4-diphenyl-6-phenylacetylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained after chromatographic purification in the form of white crystals; melting point 226°C.

EXAMPLE 21 By carrying out the procedure as in Example above, using 0.95 g of (4aRS,7aRS)-4,4-diphenyl-6- [(2-methoxy-phenyl)acetyl]perhydrothiopyrano[2,3-c]pyrrole and 0.43 g of 3-chloroperoxybenzoic acid (at 1.0 g of (1RS,4aSR,7aSR)-6-[(2methoxyphenyl)acetyl]-4,4-diphenylperhydrothiopyrano- [2,3-c]pyrrole 1-oxide is obtained after chromatographic purification in the form of a white solid; melting point 240°C, as well as 0.15 g of (1RS,4aRS,7aRS)-6-[(2-methoxyphenyl)acetyl]-4,4diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, in the form of a white solid; melting point 254 0

C.

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

The resulting solution is washed with 12 cm 3 of a 4N aqueous solution of sodium hydroxide, with 20 cm 3 of water, and it is then concentrated to dryness at under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.02-0.045 mm, diameter 3.6 cm, height 40 cm), eluting under a nitrogen pressure of 0.8 bar with an ethyl acetate and methanol mixture (95/5 by volume) and collecting fractions of 60 cm 3 Fractions 22 to 42 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.4 g of 6-[(S)-2-(2-methoxyphenyl)propionyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, mixture of the (1R,4aR,7aR) and (1S,4aS,7aS) forms, is obtained in the form of a white solid.

Infrared spectrum (characteristic bands, cm1): 3060, 3025, 2970, 2935, 2880, 2840, 1640, 1595, 1490, 1460, 1445, 1425, 1245, 1020, 755, 705.

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

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

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

Proton NMR spectrum (DMSO-d 6

CF

3 COOD, a mixture of the two rotaiers is obtained at room temperature; characteristic signals): 1.1-1.3 (mt, 3H, CH 3 3.35 and 3.81 (2s, 3H, OCH 3 6.7 to 7.5 (mt, 14H aromatics).

EXAMPLE 24 A solution of 0.443 g of (4aRS,7aRS)-6-[(2methoxy-phenyl)acetyl]-4,4-diphenylperhydrothiopyrano- [2,3-c]-pyrrole in 4.0 cm 3 of dichloromethane is added to a solution, placed under a nitrogen atmosphere, of 0.3 cm 3 of titanium tetraisopropylate in 10 cm 3 of dichloromethane and 0.018 cm 3 of water. The mixture is cooled to -20 0 C and then 0.16 cm 3 of a 70% aqueous solution of tert-butylhydroperoxide is added. After stirring for 6 hours at -20 0 C, 0.01 cm 3 of the tertbutylhydroperoxide solution is added to the white suspension obtained. After 1 hour 30 minutes at -20 0

C,

cm 3 of water are added to the reaction mixture and the gel obtained is filtered. The dichloromethane phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised from acetonitrile, the crystals are taken up in dichloromethane and the solution obtained is chromatographed on a silica gel column (particle "l 4.c 61 size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar with ethyl acetate and then with an ethyl acetate and methanol mixture (90/10 by volume) and collecting fractions of 30 cm 3 Fractions 5 and 6 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.06 g of (4aRS,7aRS)-6-[(2-methoxyphenyl)acetyl]-4,4-diphenylperhydrothio-pyrano[2,3-c]pyrrole 1,1-dioxide is obtained in the form of a white solid; melting point 258 0 C. Fractions 24 and 25 are pooled and concentrated to dryness. 0.26 g of (1RS,4aSR,7aSR)-6-[(2methoxyphenyl)acetyl]-4,4-diphenylperhydrothiopyrano- [2,3-c]pyrrole 1-oxide is obtained, after crystallisation from acetonitrile, in the form of a white solid; melting point 2401C.

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

The sterile compositions for parenteral administration which may be used in particular in the form of perfusions are preferably aqueous or nonaqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oilsv in

I

62 particular olive oil, organic esters for injections, for example ethyl oleate or other suitable organic solvents may be used as solvent or vehicle. These compositions may also contain adjuvants, in particular wetting, isotonising, emulsifying, dispersing and stabilising agents. Sterilisation may be performed in a number of ways, for example by asepticising filtration, by incorporating sterilising agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in a sterile medium for injection.

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

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

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

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

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

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

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

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

The following example, given with no limitation being implied, illustrates a composition according to the invention.

Example Tablets of active product having the following composition are prepared according to the 15 usual technique: (1RS,4aRS,7aRS)-6-{{[3-(1-Pyrrolidinyl)- 2-propoxy]phenyl}acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 25 mg 20 83 mg 30 mg Magnesium 3 mg Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

%f

Claims (14)

1. New thiopyranopyrrole derivative characterised in that it is of the general formula: H 5 C 6 C 6 O X II N--C--CH--R S R 2 (0) n in which the symbol X represents an oxygen atom or an NH radical, the symbol R, represents a phenyl radical which is optionally substituted by one or more halogen atoms or hydroxyl or alkyl radicals which may be optionally substituted (by halogen atoms or amino, alkylamino or dialkylamino radicals) alkoxy or alkylthio radicals which may be optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals optionally substituted (by phenyl, hydroxyl or amino radicals) or by dialkylamino radicals whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle with 5 to 6 members which may contain another heteroatom chosen from oxygen, sulphur or nitrogen, optionally substituted by an alkyl, hydroxyl or hydroxyalkyl radical)], or which is substituted by amino, alkylamino or dialkylamino radicals whose alkyl a. parts may form with the nitrogen atom to which they are attached, a heterocycle as defined above, or represents a cyclohexadienyl, naphthyl or a saturated or unsaturated, mono- or polycyclic heterocyclic radical containing 5 to 9 carbon atoms and one or more heteroatoms chosen from oxygen, nitrogen or sulphur, the symbol R 2 represents a hydrogen or halogen atom or a hydroxyl, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkylthio, acyloxy, carboxyl, alkoxycarbonyl, dialkylam.inoalkoxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkoxycarbonylamino radical, and n is an integer from 0 to 2, the abovementioned alkyl and acyl radicals being linear or branched and containing 1 to 4 carbon atoms, in its sterecisomeric forms or mixtures thereof, as well as its salts when these exist.

2. 6{ (3-Dimethylamino2-propoxy)phenyl]> acetyl}-4 ,4-diphenylperhydrothiopyrano [2,3-c ]pyrrole 1-oxide in its stereoisomeric forms and mixtures thereof.

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

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

6-{2-(2-(3-Dimethylaminopropoxy)- phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]- pyrrole in its stereoisomeric forms and mixtures thereof. 6. Method of preparing a new thiopyranopyrrole derivative according to Claim 1, characterised in that an acid or a reactive derivative of the acid of general formula: Ri-- CH- COOH R 2 in which R, and R 2 are as defined in Claim 1, is reacted with a thiopyranopyrrole derivative of general formula: H 5 C 6 C 6 H (0) n in which the symbol n is as defined in Claim 1, and then optionally converting thk amide obtained to an amidine for which X represents an NH radical and optionally converting the product obtained to a salt when these exist.

7. Method of preparing a thiopyranopyrrole derivative according to Claim 1, for which the symbol Ri represents an alkoxyphenyl radical whose alkyl part is optionally substituted, the symbol R, is other than a hydroxyl radical and the symbols n and X are as defined I I in Claim 1, characterised in that a halogenated derivative of general formula: R 4 -Hal in which R, is an alkyl radical which is optionally substituted [by hydroxyl, amino, alkylamino or dialkylamino radicals which are optionally substituted (by phenyl, hydroxyl or amino radicals), or a dialkylamino radical whose alkyl parts form with the nitrogen atom to which they are attached, a heterocycle as defined in Claim 1 above] and Hal is a halogen atom, is reacted with a thiopyranopyrrole derivative according to Claim 1, for which R, is a hydroxyphenyl radical, followed, where appropriate, by remrval of the hydroxyl-protecting radical and optionally conve.ting the product obtained to a salt when these exist.

8. Method of preparing a thiopyranopyrrole derivative according to Claim 1, for which X is an NH radical and the symbols Ri, R, and n are as defined in Claim 1, characterised in that a product of general formula: R,-CH-C I R; optionally in the form of a salt, in which Ri and R 2 are as defined in Claim 1 and R 5 represents a linear or branched alkoxy radical containing 1 to 4 carbon atoms or a methylthio, ethylthio, benzylthio or I I 69 alkoxycarbonylmethylthio radical, is reacted with a thiopyranopyrrole derivative of general formula: C 6 C 6 H NH S (0) n in which n is as defined in Claim 1, and then, when these exist, optionally converting the product to a salt.

9. Method of preparing a thiopyranopyrrole derivative according to Claim 1, for which n equals 1 or 2, characterised in that the corresponding derivative according to Claim 1 for which n equals 0, is oxidised and then the product obtained is optionally converted to a salt when these exist. Pharmaceutical composition characterised in that it contains at least one product according to one of Claims 1 to 5, in a pure state or combined with one or more compatible and pharmaceutically acceptable adjuvants or diluents. 'f -X IfV'

11. A thiopyranopyrrole derivative according to claim 1 substantially as hereinbefore described with reference to anyone of the examples.

12. A method according to any one of claims 6 to 9 substantially as hereinbefore described with reference to any one of the examples.

13. A composition according to claim 10 substantially as hereinbefore described with reference to any one of the examples. DATED this 21st day of July, 1994. RHONE-POULENC RORER S.A. By Its Patent Attorneys DAVIES COLLISON CAVE e 9*. 0 t o oo. *o 94MOl,p:\opcrccl9I140rospV,7 p I INTERNATIONAL SEARCH REPORT International application No. PCT/FR 92/00431 A. CLASSIFICATION OF SUBJECT MATTER C07D495/04; A61K31/40; //(C07D495/04, 335:00, 209:00) According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Ejectronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. EP, A, 0 058 567 see abstract EP, A, 0 093 805 see abstract US, A, 4 042 707 cited in the column 31, EP, A, 0 068 822 cited in the see abstract (WARNER-LAMBERT CO.) 25 August 1982 (WARNER-LAMBERT CO.) 16 November 1983 RIPKA) 16 August 1977 application table I 1,10 1,10 1 1 (ROHM AND HASS application CO.) 5 January 1983 Further documents are listed in the continuation of Box C. SI See patent family annex. Special categories of cited documents: document defining the general state of the art which is not considered to be of particular relevance earlier document but published on or after the international filing date 1" document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified) document referring to an oral disclosure, use, exhibition or other means 7" document published prior to the international filing date but later than the priority date claimed later document published after the international filing dateor priority date and not in conflict with the application but cited to understand the principle or theory underlying the invention document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone document of particular relevance; the claimed invention cannot be considered to involve an Inventive step when the document is combined with one ormore othersuch documents, such combination being obvious to a person skilled in the art document member of the same patent family lte of the actual completion of the international search Date of mailing of the international search report 21 August 1992 (21.08.92) 7 September 1992 (07.09.92) tnme and mailing address of the ISA/ EUROPEAN PATENT OFFICE PCamile No. PCT/ISA/210 (second sheet) (July 1992) Authorized officer I Telephone No. F I 1, ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. FR 9200431 SA 60083 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international s9arc rrp The members are as contained in the European Patent Office EDP file onpo The European Patent Office is in no way liable for theve particulars which ame merely given for the purpose of information, 2 1/08/92 Patent document Publication Patent family Publication cited in search report dole meniber(s) dat: e 7 EP-A-0058567 25-08-82 AT-T- EP-A, B JP-A- US-A- 8619 0093805 57158758 4503043

15-08-84

16-11-83

30-09-82 05-03-85 EP-A-0093805 16-11-83 AT-T- 8619 15-08-84 EP-A,B 0058567 25-08-82 JP-A- 57158758 30-09-82 US-A- 4503043 05-03-85 US-A-4042707 16-08-77 None EP-A-0068822 05-01-83 US-A- 4439229 27-03-84 JP-A- 58013567 26-01-83 sw]Fervmore dets about this stmex: vv Official Journal of the Europoan Patent Office, No. 12182 titarlM DE RECH-ERCHE INTERNATIONALE Demande internattonaJe ro PCT/ FR 92/00431 i. CL.ASSEMENT DE LINVENTION Isietars syvbos de classificaion &ant appables, Its initquer tou-. Scion la ciassficauon tnenauonale its brevets (CIS) ou 1 12 tols scion ia ciasstficaion flationai et la CMB CIB 5 C07D495/04; A61K31/40; //(C07D495/04,335:00,209:00) 0DOMAINES SUR LESQUEIS LA RECUfERCAE A PORTE Do~~fehtsafon iatntmais consultee' Systine de 4f-%ifjcuon jSyvuboles de c~iafiation CIB 5 C070 Docu entagton conksuitke auts qua ia docuamentaion mininta. dinis mesiart o6~ ism id cuaments (ont parts des domaines sur iesqll9 1z rechierche apre A EP,AfC 058 567 (WARNER-LAMBERT CO.) 25 AoOt 1982 1,10 voir abrdgd A EP,A,O 093 805 (WARNER- LgERT CO.) 16 Novembre 1,10 1983 voir abrdgd A US,A,4 042 707 RIPKA) 16 Aot~t 1977 1 citd clans la demande colonne 31, tableau I A EP 5 A,O 068 822 (ROHM AND HAAS CO.) 5 Janvier 1 1983 cite dans la dernande voir abrdgd catkones sp~esido id ocuments w4=1 inoameat attiiitur ptabui poestneurenant i la dte do i*t *A doausrt i~iolunt ri4 in. ornaw~ala u Ii il t pnoniti cc ttSappataSIat ps W owst ifiawa comingpuU a o la toth~e, i 1&uz ds Ixchnaique Perunant, mais 01i pour, cOmPmsnrt coudkr come artcu~krnea petinntIt pnacaps eta is tiian co"Msutun js bass ic I'In%'atUon 'C iocume at anterteur, miii puW16 i la. isis is diyt inivusa- dooaaat paruaalismunt paruntar Vinwotson rswnl- b05a4ala u carte data gict. be ut ame coasiii* cocmm. Dotrnii CI comme L iosail poumat lat an inixe fur Ua reenicaio do izpliqiant Uas actrvi ifmav priort ou ens pouar ibtter la date is pubUcatin itate documen part iusaat pertinci rI'nvetion seven- doumts o rkate i un titfi riO n it at iuya*lnu sdcmn s sos bo U4 osm CE EUOPE taus BREVETS CHRISTIA HAstrsate dcmnsS 40atr, at liameat pul a idt do. 9551entotL asnl tn ywai orUepesao atr ANNEXE AU RAPPORT DE RECHERCHE INTERNATIONALIE RELATIF A LA DEMANDE INTERNATIONALE NO. FR SA 9200431 60083 La prisente annexe indiqueesm be dI.anJe dc brevets rciatifs: aux documents brevets citis dans Ic rap port do rtcbercie internationaie visedesur Lesdits memabres sont conteiws au ilider informatique do 'O~ffice europien des brevets i Ia date du Lesa rnegnements fournis soot donncs i titre indicatif et n'engagent paslas responsabiliti do P'Office curopien des brevems 2 1/08/92 Document brevet dti Date dc Memobre(s) do as Date do au rapport do recbarw'c p;ulication famifle do brevet(s) publication EP-A-0058567 25-08-82 AT-T- EP-A, B JP-A- US-A- 8619 0093805 57158758 4503043 15-08-84 16-11-83 30-09-82 05-03-85 EP-A-0093805 16-11-83 AT-T- 8619 15-08-84 EP-A,B 0058567 25-08-82 JP-A- 57158758 30-:09-82 US-A- 4503043 05-03-85 US-A-4042707 16-08-77 Aucun EP-A-0068822 05-01-83 US-A- 4439229 27-03-84 JP-A- 58013567 26-01-83 Pour tout remeilfemm coomuuax cct amme :voir Journal Officiel do romie eszropica des brevets, No.12/82