Derived from alcadienes, their preparations, drugs the container and intermediate products

The present invention relates to derivatives of formula:

processes for their preparation, medicaments containing them and intermediates useful in preparing them.

...... In the formula (I-), represents hydroxy or acetoxy, F.; R.₂ ^ represents a hydrogen atom, a carboxyl radical, alkoxycarbonyl, phenyl or benzoyl and

. either RG is a radical - alkylthio or alkoxy and

represents a radical naphthoyl, benzoyl or benzoyl substituted with one or more halogen atoms, one or more alkyl radicals, alkoxy, phenyl, phenoxy, piperidino, dimethylamino or hydroxy or positions by a radical -3 and -4 isopropylenedioxy,

- either the R ^ represents an alkoxycarbonyl radical, cycloalkyloxycarbonyl which the cycloalkyl portion contains 3 to 6 carbon atoms or cyano and R ^ represents an alkyl radical (1 to-8c), naphthyl, optionally substituted by a radical phényie phenoxy, phenyl, naphthyl or benzoyl, an alkylthio radical, naphtylméthanethio, benzylthiopropionic optionally substituted by one or more alkyl radicals or trifluoromethyl, phenyl or phenoxy, a phenylthio radical optionally substituted by a halogen atom or an alkoxy radical, a radical naphthylthio groups, or cycloalkylthio phénéthylthio,

- either the R - and R. together form aveib the carbon atom 3, 4

which they are attached form a cycles of formulae:

wherein R ^ represents a hydrogen atom or an alkoxy radical and X is a methylene radical or a sulfur atom, with the proviso that, when R ^ represents a acetoxy radical, the R ^ cannot represent a benzoyl radical substituted by one or more hydroxy radicals, that, unless otherwise specified mentions, in the definitions above and those that will be mentioned hereinafter, the alkyl and alkoxy radicals, and alkyl and alkoxy portions contain 1 to 4 carbon atoms in straight or branched chain and that the invention also relates to the tautomeric forms of the aforementioned products, when R ^ represents a hydroxyl radical.

According to the invention, the products of formula (I-) wherein Rj is the hydroxyl radical, the R ^ represents a hydrogen atom or an alkoxycarbonyl radical, phenyl or benzoyl and the other symbols are as defined above can be prepared by acidic hydrolysis of the enamines of formula:

wherein R ^ to re-press: th a hydrogen atom or a radical

alkoxycarbonyl, benzoyl or phenylated, R_ and R_ represent of b/

alkyl radicals or R, and R " together form with the nitrogen atom/b.

which they are attached flax ' hêtérocycle as the piperidine ring or the morpholine ring, the R ^ ^ and R have the same meaning as in the formula (I-).

It is advisable to carry out this hydrolysis in the presence of 1 to 5 equivalents of a mineral acid IN to 12n, optionally in the presence of a water-miscible solvent, at a temperature ranging from 20 °c to 100 °c. As mineral acid, there may be mentioned hydrochloric, sulfuric and broffihydric and as solvent, alcohols (methanol, ethanol, isopropanol, propanol), tetrahydrofuran or dioxane.

These enamines, except the dimethylamino-2 cyano 5 phenyl~5 pentadiene-to-2.4 pentadienoate, are novel and form part of the invention.

The enamines of formula (III) may be prepared by the action of a salt of the formula:

V HAS

NR

^H 3^C

/

(ni)

in which THE R ^_{the R}R_grams and R₇ have the same meaning as in formula (III) and X represents LF ^, LC, ClO ^, brr, on an activated methylene compound of R ^ - HC₂ - R.₄ for which R₃ and have the same meaning as in formula (III).

This reaction is carried out in the presence of a base including among many methoxide, ethoxide or sodium or potassium tert-butoxide, in the corresponding alcohol at a temperature of between 20 °c and the boiling temperature of the solvent. Can also be used as a basis a lithium compound such as methyllithium, butyllithium, lithium diisopropylamide in an inert solvent such as tetrahydrofuran or diethyl ether at a temperature between -78 °c and the boiling temperature of the solvent.

Vinamidinium salts of formula (II) may be

prepared by action of a secondary amine MST ^ the R " wherein R, and R ^ o/b have the same meaning as in formula (III), on the

products of formula:

^{OF OC} 2^H 5

^H 3^C VBE1

dW

(IV)

^H 3^C

wherein R₂ and X have the same meaning as in formula (II).

The reaction is preferably performed in a solvent, such as chlorinated web chloroform, methylene chloride or web - poly-1.2 ethane, at a temperature between 0 °c and the boiling temperature of the solvent.

The compounds. of formula (VI) may be obtained by application or adaptation of the method described by R. GOMPPER et, - Angew. Mal. Int.. DE. Eng., 17, 760 - 3 (1978) '. This method includes reacting a salt of alkyloxonium triethyloxonium tetrafluoroborate as, on an enamine of formula:

(V.)

wherein has the same meaning as that. in formula (VI).

The reaction is, preferably, conducted in a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 20 °c and the boiling temperature of the solvent.

The compounds, of formula (V-) can be obtained by applying or adapting methods described by r.f.. Abdullatif Abdulla et al. Tetrahedron' 35.1675 and 1734 (1979). These methods include reacting a dîalkylacétal of n, n-dimethylformamide with a compound HC ^ - ^ for co-R, wherein R is £has the same meaning as in the formula (V-).

Many compounds of formula R a-CH R, are known.

3 - z 4

Among them, include has-methoxyacetphenone (rr.b. MOFFET and ai, 92. Synthesis ., 3, 562, 1955), 1 'a tetralone (7 Beil, 370), the methoxy-6 oxô-to-1 tetrahydro-1, 2, 3, 4 naphthalene (Beil 9 (2), 889), propionitrile (2 Beil, 245), the décanenitrile (Beil 2,356), the benzylcyanure (Beil 9>441), the indanone and 2 (Beil 7, 363), ethyl phenylacetate (Beil 9, . 434), the biphénylacétonitrile and 4 (US Patent 3,780 065), web phenoxy-3 benzylcyanure ('d. MATTHIES et, Briefs. Pharm., 316, 598 - 608, 1938), the benzoyl 3 benzylcyanure (has. Was going et, J ' the MED. Mal. Chem. Plastic strips in sections, 9 (4), 381 - 389, 1974).

The compounds of formula RG represents a-Ch R ^ novel may be obtained by application or adaptation of methods described for known compounds and methods described below and in the examples..

The compounds of formula RG represents a-Ch R ^ wherein RG is an alkoxycarbonyl radical or cyano and R ^ represents a phenylthio optionally substituted by a halogen atom or an alkoxy radical, a radical naphtyltbio, banzylthio optionally substituted by one or more alkyl radicals or trifluoromethyl, phenyl or phenoxy, a radical phénéthylthio, cycloalkylthio, alkylthio or naphtylméthanethio are obtainable by condensation of a thiol or thiolate RG are s-to RG wherein RG is a phenyl radical optionally substituted by a halogen atom or an alkoxy radical, a naphthyl radical, benzyl optionally substituted with one or more alkyl radicals or trifluoromethyl, phenyl or phenoxy, an allyl radical, alkyl, or phenethyl naphtylmethylene and RG represents sodium, potassium, lithium or a hydrogen atom on a compound of formula X-Ch rg wherein X represents a halogen atom and RG has the same meaning as before.

When RG is sodium, potassium or lithium, the reaction is preferably carried out in a solvent such as an alcohol (methanol, ethanol, isopropanol, propanol), the diraéthylformamide, tetrahydrofuran or diethyl ether, at a temperature between 0 °c and the boiling temperature of the solvent. The antibiotics the rg-s-rg can be obtained by the action of a base such as methoxide, ethoxide or tert-butoxide. sodium or potassium or a lithium base such as butyllithium on the corresponding sulfide.

When RG is the hydrogen atom, the reaction is preferably carried out in a. solvent such as mêthanol, ethanol, propanol ., 1 'isopropyl alcohol, the diraéthylformamide, tetrahydrofuran, diethyl ether or a chlorinated solvent (methylene chloride, ethane di'di' chloro-a 1.2}, in the presence of a tertiary base such as a trialcoylaaine, the diaza 1.8 the bicyclo [5.4.0] undecene. above 7 or the diaza 1.5 the bicyclo [4.3.0.] nonene and 5.

The thiols for which R represents a benzyl radical

THE O•

substituted by an alkyl, trifluoromethyl, phenyl or phenoxy may be obtained from the corresponding halide of Rg - x with RG has as defined hereinbefore and X represents a halogen atom by the action of sodium suifhydrate by methods known per se such as those described by market by, an advanced Biologique joining technology, 1977, P 374 (the second editing). The rg-X-halides can be obtained by applying or adapting methods described by J Ashby and al, its occurrence, 2 (1), 33 - 38, 1981, D et MATTHIES, Briefs. Apotex,, 316, 598 - 608, 1983, J. L. Rideout and al, the MED J. Chem.; 1489, 1983 and in Beil. 5, 364, 384 and 373.

The compounds of formula R ^ ^ - ^ - C. R. wherein

represents an alkoxycarbonyl radical and R ^ benzylthiopropionic represents a radical which is optionally substituted by phenyl, phenoxy, alkyl or trifluoromethyl are obtainable by condensation of ethyl mercaptoacetate on a compound formula X-R de_1Q wherein X represents a halogen atom and R ^ g represents a benzyl radical optionally substituted by a phenyl, phenoxy, alkyl or trifluoromethyl.

The reaction formulae.' performs preferably in a solvent such as alcohol (mêthanol, ethanol, isopropanol, propanol), the diraé -

- thylformamide, tetrahydrofuran or diethyl ether, in the presence of a base such as méthÿlate, ethoxide or sodium or potassium tert-butoxide or lithium base such as butyllithium on the ethyl mercaptoacetate at a temperature between 0 °c and the boiling temperature of the solvent<. - "•'

The compounds of formula R ^ ^ - ^ - R-OH wherein R ^ - nts.' feel an alkoxycarbonyl radical. or cycloalkyloxycarbonyl Rÿ and represents an alkyl {1 a-8c), naphthyl, phenyl optionally substituted with a phenoxy radical, pbényle, naphthyl © Û benzoyl, an alkylthio radical, naphtylméthanethio, benzylthiopropionic optionally substituted by one or more alkyl radicals or trifluoromethyl, phenyl. or phenoxy, a phenylthio radical optionally substituted by a halogen atom or an alkoxy radical, a radical napthylthio, phénéthylthio cycloalkylthio or can be prepared by esterification of the corresponding acids by... known processes such as those described by market by, an advanced Biologique joining technology, 1977, e. 363 - 367 (the second editing).

Preferably, the esterification is carried out using an alcohol in the presence of a mineral acid.

Acids for which R ^ - represents a phenyl radical optionally substituted by a phenoxy radical, phenyl, naphthyl or benzoyl, may be obtained by application or adaptation of methods described by D. MATTHIES et, Briefs. Pharm., 316, 598 - 608', 1983; A was going et, €. The MED J. Mal. Chem. Plastic strips in sections ., 9 (4), 381 - 389, 1974 and R.M. SHAFIF et, J Apotex. IBS, 952 - 955, 1969.

Acids for which R represents a carboxy radical ^ ^ and R represents an alkylthio, naphtylméthanethio, benzylthiopropionic unun.ou more radicals optionally substituted by alkyl residue or an IFFT luorométhyle ., phenyl or phenoxy group, a phenylthio radical optionally substituted by a halogen atom or an alkoxy radical, a radical naphthylthio groups, or cycloalkylthio phénéthylthio can be prepared by hydrolysis of the ethyl esters or corresponding cyano derivatives previously described by methods known per se such as those described by market by, an advanced Biologique joining technology, 1977, P 349 - 354 (the second editing).

The compounds of formula

Ch2 - r4 wherein R ^ nts - alkylthio and perceives a radical represents a radical naphthoyl, benzoyl or benzoyl substituted with one or more halogen atoms, one or more alkyl radicals, alkoxy, phenyl, phenoxy, hydroxyl, piperidino, dimethylamino or at positions by a radical -3 and -4 isopropylenedioxy may be prepared by action of a j-ANS ^ R-compounds for which R ^ j represents an alkyl radical, with a halide of formula R ^ ^ - ch-X in which R ^ has the same meaning as above and X represents a halogen atom. This reaction is preferably carried out in an alcohol such as methanol or strip 1' ethanol at a temperature between .20 °c and 60 °c.

The chloride of formula R ^ - ^ ch-Cl in which R ^ is a benzoyl radical substituted with piperidine may be prepared by action of titanium chloride>grown on the dibromo derivative of R ^ - ^ ar ch brr ^ for which R has the same meaning as before, in the presence of a mineral acid such as hydrochloric acid to a tempéiature of about 100 °c.

The compound of the R fcrmule ^ - ^ ar ch brr can be obtained by action of a mixing bromine-acid, hydrobromic on the corresponding ketone derivative, preferably th 20 °c.

The other novel halides of formula R ^ - ^ - ch-X can be prepared by halogenation of compounds of R ^ - ^ ch-corresponding by per se known methods such as those described by market by, an advanced Biologique joining technology, 1977, e. 537 - 39 (the second editing) or by adaptation of methods. preparation of halogênures known.

The compounds of R ^ - ANS can be obtained by the action of a base such as sodium ethoxide or méthylete on the corresponding thiol.

■compounds of formula R ^ ^ - ^ - R-OH wherein Ris ^ an alkoxy radical and R represents a radical naphthoyl, benzoyl or benzoyl substituted with one or more atoms of halogè babies or one or more radicals phényie, phenoxy, hydroxyl, piperidino, dimethylamino, or at positions by a radical -3 and -4 isopropylenedioxy can be provided by applying or adapting the method described by R.B. MOFFET and Al, BRGs synthesis..., 3, 562 (1955).

The compounds of formula:

wherein RG is hydrogen unun.atome or an alkoxy radical and X is of. sulfur may be obtained by heating the acid benzylthioacetic radical optionally substituted with alkoxy in a solvent such as nitrobenzene, in the presence of an acid such as polyphosphoric acid at a temperature between 50 °c and 180 °c..

According to the invention, the products of formula (I-) wherein Rj represents a hydroxy group, where R represents an alkoxycarbonyl radical 00 and the other symbols are as defined above can also be prepared by acid hydrolysis of the enamines of formula:

(SEEN

wherein R ^ represents a ' alkoxycarbonyl radical, the R ^ ^ and R have the same meaning as in the formula (I-).

This hydrolysis can carried out under the same conditions that the hydrolysis of the enamine of formula (III).

■lo

The formula (IV) énamînes can be obtained by action of a dialkyl acetal of n, n diméthyl£ormamide on a corresponding acid of formula (I-) wherein represents the carboxyl radical, the R ^ represents the. hydroxy radical, where R and R are defined^4 as previously. It is carried out preferably in a chlorinated solvent such as chloroform or dichlororaéthàne at a temperature close to 20 °c.

The enamines of formula {-VI) are novel and form part of the invention.

According to the invention, the products of formula (I-) wherein Rj represents a hydroxyl radical, the R ^ represents the carboxyl radical and the other symbols are as defined above, may be prepared by saponification of the ester of formula corresponding enol:

(VII)

wherein R ^ represented an alkoxycarbonyl radical and R ^, are defined as above.

Preferably, this reaction is carried out using % to 10 equivalents of soda or potash - 4n IN to optionally in the presence of an inert solvent miscible with water such as methanol, ethanol, propanol, 1' isopropanol or tetrahydrofuran, at a temperature between 20 °c and 50 °c.

According 1 'a, - the products of formula (I-) wherein represents an acetoxy radical and the other symbols are as defined above, it being understood that R ^ cannot represent a radical benzdyle substituted by one or more hydroxy radicals, can be obtained by the action of acetyl chloride on 1' corresponding enol of formula ' (the I) in which R represents a hydroxy group ^. This reaction is preferably carried out in an inert solvent such as tetrahydrofuran in the presence of an acid acceptor such as triethylamine at a temperature of about 20 °c.

The reaction mixtures obtained by the various methods described above are treated according to routine methods physical (evaporation, extracting, distilling, crystallization, chromatography) or chemical.

The compounds of formula (I-) have valuable pharmacological properties. These compounds inhibit 5 a-lipoxygenase and are therefore useful as anti-inflammatory, as protecting agents especially on the gastrointestinal tract and for the treatment of asthma, allergic diseases, psoriasis, rheumatoid arthritis and fibrotic conditions such as liver fibrosis.

Inhibition of 5 a-lipoxygenase was determined on cells in the methods RBL and 1 of M.m., STEINHOFF et, B.B.B., 618, 28 - 34, 1980 and BA JAKSCHIK et, J. Agric. Chem.,

257, 5346, 1982. In this test, the CI__WITH (Meters) to compounds of formula

-5 _ 7⁵⁰

(I-) is between 10 and 10..

These compounds are also active on cells of PMN according the method of H. SAFAYHI et, Pharmacol. Hyg ., 34 (15),

2691-4, 1985. In this test, the IC_rC _ (meters) to compounds of formula (I-)

-5 _ 7 DEGREES.

is between 10. and 10.

The products of formula (I-) exhibit low - borne

cited. Their LD_C " is greater than 100 mg/kg orally in the at

mouse.

Are of particular interest:

- the compounds of formula (I-) wherein

- either Rj represents a hydroxyl radical, the R ^ represents an alkoxycarbonyl radical, where R represents an alkylthio ^ ^ and R represents a benzoyl radical substituted by a halogen atom, a piperidino radical, two hydroxy radicals or at positions -3 and

-4 isopropylenedioxy by a radical;

O"

- either represents hydroxy or acetoxy, the R ^ represents a hydrogen atom, a carboxyl radical, - alcoxycarbo

nyle or phenyl, where R, and R represents an alkoxycarbonyl radical.

•- 3, 4 represents a radical optionally substituted by benzylthiopropionic alkÿlthio or an alkoxy radical

- and the tautomeric forms of these products when represents a hydroxyl radical.

Are of interest■' particular, the following products:

^2 - hydroxy acid phéhylthio-to-5 ethoxycarbonyl-to-5 pentadiene-to-2.4 oxque,

- (chlorophenyl 4 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate,

hydroxy 2 - methylthio-5 oxo 6 (piperidino-4 phênyl) -6 hexadiene and 2.4 pentadienoate,

hydroxy 2 - (methoxy-4 phénylthioj-to-5 hexadiene and 2.4 diçate of dièthyle,

benzyithio-a 5 - hydroxy 2 hexadiene and 2.4 dièthyle dioate

- phenylthio-2 liydroxy-to-5 pentadiene-to-2.4 pentadienoate,

5 - acetoxy-2phénylthio ^ hexadiene and 2.4 dièthyle dioate

- oxo 5 phényi-to-5 phenylthio-2 pentene-2 pentadienoate,

- hydroxy 2 (isopropylenedioxy-to-3.4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate,

- hydroxy 2 methoxy-5 oxo 6 phenyl-6 hexadiene and 2.4 pentadienoate, •

hydroxy 2 - methylthio-5 hexadiene and 2.4 dièthyle dioate,

hydroxy 2 - ethylthio-5 hexadiene and 2.4 dièthyle dioate.

The following examples, non-limiting exemplary, shows how the invention may be misemise.en practical.

EXAMPLE 1

Has an ethanolic solution of 17 grams of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 dioate diethyl, . added, in 10 min, maintaining a temperature close to 20 °c has, 211 cm3 of both in an aqueous sodium hydroxide solution. The mixture is maintained at a temperature close to 20 °c during 2 hours 15 minutes and then is brought to pH 1 using an aqueous solution of hydrochloric acid in vivo.

Ethanol reaction is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa gauge). After addition of 100 cm3 of water, the mixture is extracted by 2 times 150 cm3 of ethyl acetate. The ' organic phase is dried on anhydrous magnesium sulfate and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The solid thus obtained is recrystallized in a mixture of isopropyl and CEA tonitoni.trile (50 - 55 in volumes) boiling.

This provides 9.5 g of hydroxy 2 phenylthio-5 ethoxycarbonyl-5 pentadiene-to-2.4 oïgue melts at 172 °c.

EXAMPLE 2 ■

To a solution of 60 g of dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate 340 cm3 in diethyl ethanol, is added, in 10 min, the EH maintaining the temperature at about 40 °c, 344 cm3 of aqueous solution of hydrochloric acid in vivo. The resulting slurry is cooled to a temperature of about 20 °c and is held 30 minutes at this temperature. The precipitate is filtered, washed 3 times with water and dried at 50 cm3 20 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge) in the presence of phosphorus pentoxide. Obtained 54 g of a crystalline solid. 13 g of this solid are recrystallized in isopropyl oxide 30 cm3 boiling, this provides 10 grams of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 dioate diethyl melts at 98 °c.

The dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl can be obtained as follows:

THE O -

I-■■

0895?

To a solution of ethyl phénylthioacétate 68.7 grams of 100 g of n-die tétrafluarobbrate - {dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium in 120 cm3 of ethanol, are added dropwise, confectioneries drop, in 50 minutes and maintaining the temperature at about 20 °c, 210 cm3 of an ethanolic solution of sodium ethylate 2:00. The reaction mixture is maintained 2 hours 20 minutes at a temperature close to 20 °c then the solvent is distilled off under reduced pressure (20 mm of mercury; 2.7 kPa gauge) to 40 °c.

The residue is taken up by 1000 cm3 of distilled water and extracted 3 times 300 cm3 of ethyl acetate. After washing with water, the organic extracts are dried over anhydrous magnesium sulfate and concentrated to dry under reduced pressure (20 mm of mercury; 2.7 kPa gauge).

After recrystallization from boiling isopropyl oxide 150 cm3, obtained 107 g of a solid that melts at 70 °c.'

15 g of this soli - -? are chromatographed on a column of 6 cm diameter subcontinent 450 g of silica with a mixture Cyclohexaneacetate ethyl {80 - 20 by volume) as. eluent. The first fraction of 800 cm3 is removed then collecting fractions of 100 cm3. 4 11 To inspecting the fractions are pooled and concentrated to dry 4 40 °c ernment reduced pressure (20 mm of mercury. ? 2.7 kPa gauge). After recrystallization from boiling isopropyl oxide 40 cm3, 13.2 g of obtained diraéthylamino-to-2 phenylthio-5 hexadiene and 2.4 dioate diethyl melts at 76 °c.

The tetrafluoroborate n - (dimethylamino-3 éthoxycarbonyl-to-3 propenylidene) n-methyl méthanaminium obtainable in the_:

as follows:

To a solution of tetrafluoroborate chlororaethylenic 1007 g n-de - (ethoxy-3 éthoxycarbonyl.-to-3 propenylidene) n-methyl méthanaminium, is. adds, in 1 hour 20 min, at a temperature of about 20 °c, a solution of diraéthylamine chloromethylenic of 233 cm3. Then sinks R4II slowly into the reaction medium 2000 cm3 anhydrous ethyl ether and then filtered off the crystallized product and dried under reduced pressure {.20 mm mercury; 2.7 kPa gauge) at a temperature of about 20 °c.

This provides 925 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium melts at 102 °c.

The tetrafluoroborate n - (ethoxy-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium can be obtained as follows:

To a solution of 862 chloromethylenic triethyloxonium tetrafluoroborate g of cooled to 10 °c and passing a stream of argon, is added, in 3 hours, 675 g of dimethylamino-4 oxo 2 butene-3 pentadienoate by keeping the temperature at about 10 °c. The reaction medium is then stirred 5 hours at a temperature close to 20 °c. The solution of n - chloromethylenic (ethoxy-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium thus obtained is stored under an atmosphere of argon and used immediately in the subsequent syntheses.

The dimethylamino-4 oxo 2 butene-3 pentadienoate can be obtained as follows:

2100 G of diethyl acetal-n, n-dimethylformamide cooled to a temperature of about 5 °c, added 2 hours, 1500 g of ethyl pyruvate by maintaining the temperature 5 °c about th. The mixture is then stirred 3 hours at a temperature close to 20 °c. Ethanol reaction is evaporated dry and the residue obtained is beaten by 12 liters of diethyl ether and 30 g of black 3s then filtered over supercel. The residue is taken up by 500 cm3 of water, the organic phase is extracted with dichloromethane 3 times 2000 cm3, dried on sodium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury;

2.7 kPa gauge). The oil obtained is purified by distillation

(Εb " < - 146 and 149 degrees Celsius). This provides 695 g of dimethylamino-4 U-, immHg

oxo 2 butene-3 pentadienoate used in the raw state into the .SYn -

subsequent manuscripts.

The phénylthioacétate ethyl can be obtained as follows:

One of 1,400 cm3 has 2 Μ ethanolic solution of sodium ethoxide, is added, dropwise, in 10 min, at a temperature close to 20 °c, 300. g of thiophenol. Then insert 454 g of ethyl bromoacétatë by keeping the temperature at about 10 °c. The precipitate obtained is filtered and the ethanolic solution is concentrated to residual secà ' 40 °c under reduced pressure (20 Nfld mercury; 2.7 kPa gauge). Distilled and obtains 352g phénylthioacétate of ethyl whose boiling point is 125 °c under 0.75 mm of mercury (0.1 kPa gauge).

EXAMPLE 3

To a solution of 21 g of dimethylamino-2 (oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2] and 4 butene-2 pentadienoate in 150 cm3

•ethanol maintained under reflux, is added for 2 min in, 70 cm3 of an aqueous solution of hydrochloric acid in vivo. The mixture is immediately cooled to a temperature of about 20 to 30 °c and 1' ethanol reaction is distilled at 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The resulting slurry is diluted. 50 cm3 by water and extracted by 2 times 50 cm3 - ethyl acetate after washing with water and drying 50 cm3, the organic phase is concentrated® to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The solid obtained after recrystallization in a mixture of isopropyl ethyl chloroacetate oxide (90 - 10 by volume) boiling, obtained 11.2 grams of hydroxy-a 2 (oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate melts at 117 °c.

The dimethylamino-2 (oxo 1 tetrahydro-1, 2, 3, 4 naphtylidè-to-η℮ and 2) -4 butene-2 pentadienoate can be obtained as follows:

With a mixture of 100 g of n - tetrafluoroborate (disai-to-thylamino-to-3 ethoxycarbonyl-3 propenylidene) n-methyl raéthanaminiua in 500 cm3 210 cm3 of ethanol and ethanol solution of 2m sodium ethylate, is added, dropwise, in 45 min, at a temperature of around 15 °c, 51 grams of has-tetralone. The mixture is maintained for 1 hour 45 minutes at a temperature of about 20° g and then is heated for 4 hours 45 minutes to 70 °c.

Ethanol reaction is evaporated to dry and the oil obtained is " beaten with 4 times 300 cm3 ethyl ether. The ethereal extracts are concentrated to dryness under reduced pressure (20 mm of mercury;

2.7 kPa gauge). After recrystallization of the solid obtained in 60 cm3 of a mixture of isopropyl and ethyl acetate (90 - 10 by volume) 17.5 g of boiling is obtained dimethylamino-2 (oxo 1 tetrahydro-1, 2, 3, 4 naphtylidene-to-r2) -4 butene-2 pentadienoate melts 84°^C. .

EXAMPLE 4

To a solution of 13 g of phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate in 100 cm3 of ethanol, is added, in 10 minutes and maintained at reflux, 53 cm3 both in an aqueous solution of hydrochloric acid. The mixture is immediately cooled and ethanol reaction is concentrated at 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The resulting slurry is diluted by 100 cm3 of distilled water and extracted by 3 times 100 cm3 of diethyl ether. After washing with water, the organic extracts are concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). After recrystallization of the solid obtained in boiling isopropyl oxide 45 cm3, 10.2 g of obtained phenyl-6 oxo 6 hydroxy 2 methylthio 5 hexadiene and 2.4 pentadienoate melts at 86 °c.

The phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate can be obtained as follows:

to a solution of 26 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl willwill méthanaminiura and 30 grams of has-to-méthylthioacétophénone in ethanol 100 cm3 maintained ' at around 25 °c, is added, dropwise, in 30 min, 54 cm3 2m ethanolic solution of sodium ethoxide. The mixture is kept for 2 hours 10 minutes at a temperature close to 25 °c then ethanol reaction is removed by distillation at 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). After recrystallization of the residue in 100 cm3 boiling isopropyl oxide, 19.2 g of obtained phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate melts at 78 °c.

Can be obtained has a-œéthylthioacétophénone as follows:

To a solution of 199 grams of has-bromoacetophenone in 500 cm3 of ethanol, is added ", in 1 hour 30 min /•by small portions and at a temperature close to 20 °c, 70 g of sodium méthanethiolate die. . The mixture is kept for 2 hours 30 minutes at a temperature close to 20 °c. The solid is suspended. is willed. mined by filtration and 1' ethanol reaction is removed by evaporation. 40 °c to dry under reduced pressure (20 mm of mercury;

2.7 kPa gauge). The oily residue is taken up by 400 cm3 of diethyl ether, the organic phase is washed 4 times with 200 cm3 of water, dried and concentrated to dry to 40° g under reduced pressure (20 mm of mercury; 2.7 kPa gauge). After distillation, obtained 98 grams of has-to-méthyltbioacétophénone distilling to 100 and 102 °C under a pressure of 0.2 mm of mercury (0,027 kilopascals)..

EXAMPLE 5

To a solution of 21.3 g of dimethylamino-2 cyano 5 phenyl-5 pentadiene-to-2j4 pentadienoate in 27 cm3 ethanol maintained under reflux, is added, in 3 min, 87 cm3 solution, aqueous hydrochloric acid in vivo. The mixture is cooled to a temperature of about 10 °c and the precipitate obtained is filtered ., 15 cm3 washed by ethanol and dried.. this provides 12.1 grams of hydr'hydr' oxÿ-to-2 cyano 5 phenyl-5 pentadiene-to-2.4 ethyl paste melts at 189 °c.

The dimethylamino-2 cyano 5 phenyl-5 pentadiene-to-2.4 'pentadienoate .'d' ethyl can be prepared as follows:

.. Operation is carried out as' to the example 2. for the preparation of the dimethylamino-2 - phenylthio-5 hexadiene and 2.4 dioate diethyl from 57.2 g of n - tetrafluoroborate (dimethylamino-3 ethoxy-cairbonyl-a 3 n-methyl propènylidènejméthanaminium, of. 105 cm3®•a 2m ethanolic solution of sodium and of éthylâte. 23.4 - grams of benzyl cyanide. 36.1 g of obtained dimêthylam'dimêthylam' ino-to-2 cÿano-to-5 phenyl-5 pentadiene-to-2.4 pentadienoate melts at 67⁰ C..

EXBMPLg e

Has an agitated solution of 6.3 g of (1 ·ή· diméthyleainométhyr) -3 oxo 2 phenylthio-5 hexene and 4 dioate (6) and (1) ethyl ethyl■70 cr3 in ethanol, heated 15 minutes to 50 * c, 34 ca3 is added an aqueous solution of hydrochloric acid noreal. Stirring continued 2 hours at a attachment suppressing neighbor, of 20 * c. The solution is concentrated to dry to 40 * theS under reduced pressure (20■■of sercure; 2.7 kPa gauge). The residue is washed with water and taken up by 100 cm3 of dichloromethane. The organic phase is dried over anhydrous magnesium sulfate ., filtered and concentrated to dry 40 °c under reduced pressure (20 mm of sercure; 2.7 kPa gauge). The oil obtained is recrystallized in boiling isopropyl oxide 60 cm3. This provides 2.7 grams of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 dioate (6) (1) ethyl and methyl melts at 112 °c.

The (dimethylamino methylene) -3 oxo 2 phenylthio-5 hexene and 4 dioate (6) (1) ethyl and methyl can be obtained as follows:

8 g of hydroxy 2 phenylthio-5 ethoxycarbonyl-5 pentadiene-to-2.4 oic acid, . obtained according to example 1, 7.2 cm3 of dimethylacetal of n, n-dimethylformamide and 80 cm3 of dich1orométhane 2 hours are stirred at a temperature close to 20 °c. The solution is concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The residue obtained is dissolved in 100 cm3 of a mixture of cyclohexane and ethyl acetate (90 - 10 by volume). The solution is poured onto 500 g of silica contained in a colonne.de 5 cm in diameter. By eluting with a mixture of cyclohexane and ethyl acetate (90 - 10 by volume) and the eluate is concentrated to dry to corresponding 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). This gives 5.6 g of (dimethylamino methylene) ^ oxo 2 - phenylthio-5 hexene and 4 dioate (6) (1) ethyl and methyl melts at 118 °c.

EXAMPLE 7

Operation is carried out as in example 3, from 4.2 g of diraéthylamino-to-2 (methoxy-6. oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate, 19.1 cm3 of an aqueous solution of hydrochloric acid In and die. 19 cm3 dléthanol. The mixture is heated for 5 minutes to boiling and then cooled at a temperature close to 20 °c. After purification by recrystallization from boiling ethanol 120 cm3, obtained 3.4 grams of hydroxy-a 2 (methoxy-6 oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate melts at 175 °c..

The dimethylamino-2 (methoxy-6 oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate 'ethyl can be prepared in the following manner:'

Operation is carried out as in example 3 for the preparation of the diraéthylamino-a 2. (ojfb-to-1 tétrahvdro-a 1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate, from 14.3 g of n - têtrafluoroborate (dimethylamino-3 prbpenylidene êthoxycarbonyl. and 3) n-methyl méthanaminium, of 30 cm3 2m of an ethanolic solution of sodium ethylate and 8.8 g of methoxy-6 oxo 1 tetrahydro-1, 2, 3, 4 72 cm3 naphthalene in ethanol. After purificaHon by column chromatography of silica with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent. and precipitation. in 150 cm3 metal oxide|ethyl, 7.2 g of obtained dimethylamino-2 (oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate melts at 123 °c.

EXAMPLE 8

RN operates as corresponding to example 3, from 3.8 grams' of dimethylamino-2 (oxo 2 dihydro 2.3 indenylidene L) -4 butene-2 pentadienoate, of 20 cm3 of one-to-aqueous hydrochloric acid solution 20 cm3 In and ethanol. The mixture is heated 10 minute. to a® temperature of about 60 °c and then is cooled to about 20 °c.

After purification by chromatography on silica column with a whereinfrom cyclohexane and ethyl acetate (70 - 30 by volume) as eluent and recrystallization in 52 cm3 of a mixture of cyclohexane and ethanol (90 - 10 by volume) boiling, obtained 1.5 grams of hydroxy-a 2 (oxo 2 dihydro 2.3 indenylidene L) -4 butene-2 pentadienoate flux 137 °c.

The dimethylamino-2 (oxo 2 dihydro 2.3 indenylidene L) -4 butene-2 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 3 for the preparation of the dimethylamino-2 (oxo 1 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate, from 14.3 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, solution of 31.2 cm3 1, 6m of butyllithium in 1' hexane and 6.6 grams of indanone and 2 100 cm3 in tetrahydrofuran at a temperature close to 0 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent and recrystallization from boiling isopropyl oxide 70 cm3, 4.9 g of obtained dimethylamino-2 (oxo 2 dihydro 2.3 indenylidene and 1) -4 butene-2 pentadienoate melts at 93 and 95 degrees Celsius.

EXAMPLE 9

Operation is carried out as in example 3, from 16.8 g of dimethylamino-2 (oxo 1 thia 3 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate, 120 cm3 of an aqueous solution of hydrochloric acid 120 cm3 In and ethanol. The mixture is stirred for 15 hours at a temperature close to 20 °c. After purification by chromatography on silica column with dichloromethane as eluent and recrystallization from 40 cm3 of isoprdpanol boiling, obtained 1.5 grams of hydroxy-a 2 (oxo 1 thia 3 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4 butene-2 pentadienoate melts at 152 °c>

. 22;

L-&; diméthyIainino-a 2' (oxo-I-thia 3 téttét.rahydro L, 2, 3, 4naph-to-tylityli.dèhe and 2) -4 butene-2, rethinking ethyl can be prepared in the following manner:

Operation is carried out as in example 3 for the preparation of the dimethylamino-2 (oxo 1 naphthylidene and 2 tetrahydro-1, 2, 3, 4} 4 - butene-2 pentadienoate, from 15.2 grams of n - detétrafluoroborate (dimèthylamino-to-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, of ' 35 cm3 éthanoligue 2m solution of sodium ethylate and 8.7 grams of oxo-to-1 thia 3 tetrahydro-1, 2, 3, 4 naphthalene in 160. cm3 and of ethanol. 13 G of obtained dimethylamino-2 (oxo 1 thia 3 tetrahydro-1, 2, 3, 4 naphthylidene and 2) -4. butene-2 pentadienoate used raw in subsequent syntheses.

1 'oxo-to-1 thia 3 tetrahydro-1, 2, 3, 4 naphthalene can be prepared according to the following process :'■

975 cm3 nitrobenzene and 292.5 g of polyphosphoric acid are heated at a temperature of around 70 °c. 97.5 g of benzylthioacetic acid are added to the medium ' reaction. Is left under stirring for 26 hours and then cooled to about 70 °c to about 20 °c. 4000 cm3 of a saturated aqueous solution of sodium bicarbonate. sodium and 4000. cm3 ' of dichlorométhâne are added to the solution. The organic phase is decanted and the aqueous phase is extracted 2 times by 200 cm3 of dichlorométhâne. The organic phases are combined, dried on sulfate. anhydrous magnesium, filtered and evaporated at 40 °c under reduced pressure (20 mm of mercury;

2.7 kPa gauge). The residue is dissolved in 80 cm3, a mixture of cyclohexane and ethyl acetate. (85 - 15 volumes) and the solution is poured onto 2 kg of silica contained in a 9 cm diameter column. By eluting with a mixture of cyclohexane and ethyl acetate (85 - 15 volumes). ; the eluate corresponding to 40 °c is concentrated to dryness under reduced pressure (20 mm of mercury; .2, 7 kPa gauge). This provides 10 grams of oxo-to-1 thia 3 tetrahydro-1, 2, 3, 4 naphthalene used raw in subsequent syntheses.

Benzylthioacetic acid may be prepared in the following manner:

500 cm3 of an aqueous sodium hydroxide solution in-cooled to a temperature of about 5 °c are added in 1 hour to 70 g of bromoacetic acid. The resulting mixture is added to a solution of. 50. g phénylméthanethiol, of 500 cm3. aqueous solution. de soda 1n in 500 cm3 of tetrahydrofuran and heated to about 100 °c for 90 mins. The mixture is cooled to a temperature of about 5 °c. 100 Cm3 is added an aqueous solution of hydrochloric acid and then 3000 cm3 12n of dichloromethane 30 min. The organic phase is decanted, the aqueous phase is extracted by, 2 times 200 cm3 of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated to dry to 40 °c under reduced pressure (20 mm of mercury;

2.7 kPa gauge). The residue is recrystallized in boiling cyclohexane 50 cm3. 40.5 G acid obtained benzylthioacetic 58 and 60° melts.

EXAMPLE 10

Operation is carried out as in example 2, from 6 g of dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (1) de-ethyl and methyl (6) and 30 cm3 of a 12n aqueous hydrochloric acid solution. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from cyclohexane boiling 50 cm3, obtained 4.3 grams of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 dioate (1) and (6) ethyl methyl melts at 85 °c.

The dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (1) and (6) ethyl methyl may be prepared in the following manner:

5...

Operation is carried out as to 1' exempt 2 ottoman preparing the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from;

of 8.6 g of tétrafluoroboraté... of the n -•(diméthyIamino-to-3 ethoxycarbonyl-3 propenylidene) n méthyI willwill méthanaminiura, . a solution of 18.7 cm3 of 5.1>6 m of butÿllithium in hexane and 5.5 g of: methyl phénylthioacétate 50 cm3 in tetrahydrofuran at a temperature close to 0 °c. After purification by chromatography on silica column with dichloromethane as eluent and recristallisat '90 cm3.de ion in boiling cyclohexane derivatives, obtained 6.8 grams Ig diméthyiamino-to-2 phenylthio-'hexadiène 5 a-2.4 dioate (1) and (6) ethyl methyl melts at 75 °c.

The phénylthioacétate methyl can be prepared as follows:

16 g of phenylthioacetic acid, 0.26 cm3 solution 15 aqueous sulfuric acid in methanol 80 cm3 36n are heated to boiling for 24 hours. After cooling to about

•20 °c, added to the reaction medium 1 gm. potaspotas.sium carbonate. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dry under reduced pressure 20 to 50 °c. (20 mm of mercury; 2.7 kPa gauge). The oil is dissolved in 20 cm3 of a mixture of cyclohexane and ethyl acetate (b0 and 50 by volume) and ' the solution is poured onto 700 g of silica contained in/a 7 cm diameter column. By eluting with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume); the corresponding éluàt z5 is concentrated to dry under reduced pressure to 40 °c, (2.0 mm of mercury; 2, 7 - kilopascals). This gives 11 g of methyl phénylthioacétate used has raw in subsequent syntheses.

Operation is carried out as to 1' example 4, from 7.8 g of (chlo-a 30 a ro-4 phenyl) -6 dimethylamino-2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate 33 cm3 and an aqueous solution of hydrochloric acid in ethanol thein 300 cm3. The mixture is heated and then cooled 5 minutes to boil at a temperature close to 20 °c.

After purification by recrystallization from cyclohexane 70 cm3 boiling, 5.6 g of obtained (chloro 4 phenyl) -6 hydrqxy and 2 oxo 6 aéthylthio-to-5 hexadiene and 2.4 pentadienoate melts at 88 °c.

The (chloro 4 phénylj-to-6 dimethylamino-2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 11.3 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 19.7 cm3 2m of sodium ethylate and 7.9 grams of has-methylthio-chloro 4 86 cm3 acetophenone in ethanol. After purification by recrystallization from cyclohexane 130 cm3 boiling, 7.8 g of obtained (chloro 4 phenyl) -6 dimethylamino-2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 93 °c.

Has a-raéthylthio platinic 4 acetophenone may be prepared in the following manner:

Has an agitated solution of 11.7 grams of has-bromo-chloro 4 100 cm3 acetophenone in methanol, is added, in 15 min, 3.5 g of méthanethiolate sodium at a temperature close to 20 °c and shaking for 2 hours is allowed at the same temperature. The reaction mixture is evaporated to dry at 50 °c under reduced pressure (20' mm of mercury; 2.7 kPa gauge). The residue obtained is dissolved in 50 cm3 of dichloromethane, the organic phase dried over anhydrous magnesium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). This provides 9.9 grams of has-methylthio-chloro 4 acetophenone used raw in subsequent syntheses.

A CTO operates as corresponding to example 4 from 4.1 g of will say-to-thylamino-to-2 (methyl-4 phenyl) methylthio 5 -6 oxo 6

pentadienoate and an aqueous solution of 18.5 cm3 Large ehlorhydric In in 18.5 cm3 ethanol * the mixture is heated to boiling and then 5 ninutes cooled to a temperature close to the d © © 20° g. After purification by recrystallization from cyclohexane 35 cm3 boiling, obtained 2.9 grams of hydroxy-a 2 (methyl-4 phenyl} 6 - oxo 6 aéthylthio-to-5 hexadiene and 2.4 pentadienoate flux th ' of c/8®.

The dimethylamino-2 (methyl-4 phenyl) -6 aéthylthio-the Exe-s-hexadiene and 2.4 pentadienoate may be prepared manièresuivante:

Operation is carried out as in example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate confectioneries from 23.4 g of tetrafluoroborate î3 - (will say thvla-to-Mino-to-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanarainiua, D.®40.8 cm3 etoanolic 2m solution of sodium ethylate, and 14.7 grams of has-methylthio méttvl-a 4 163 cm3 acetophenone in ethanol. After purification on silica column with a mixture of cyclohexane acetate (50 - 50 by volume) étlyle as eluent and recrystallization from boiling cyclohexane 65 cm3, 5.9 g of obtained dimethylamino-2 (methyl-4 phenyl) methylthio 5 -6 of oxo-s-hexadiene and 2.4 pentadienoate melts at 98 °c.

Has-methylthio-methyl 4 acetophenone may be prepared in the following manner:

Operation is carried out as to 1 'example 4 for the preparation of 1 'a-methylthio acetophenone; to an agitated solution of 20.8 grams of has-bromo-methyl-4 195 cm3 of acetophenone in néthanol, added, in 30 min, 6.8 g of sodium méthanethiolate, at a temperature close to 20 °c and shaking for 2 hours is allowed at the same temperature. The result is 16.5 grams of has-to-aéthylthioraê-to-polyethylene resins and 4 acetophenone used raw in subsequent syntheses.

EXAMPLE 12

EXAMPLE 13

Operation is carried out as to the example 4 from 6.1 g of dimethylamino-2 (raéthoxy-to-4 phenyl) methylthio 5 -6 oxo 6 h @ xadièn @ - 2, 4 pentadienoate 26.2 cm3 and an aqueous solution of hydrochloric acid in ethanol thein 26.2 cm3. The mixture is heated to boiling 5 minutes and then cooled to a temperature close to® the d®20 °c. After purification by recrystallization from boiling isopropyl oxide 35 cm3, obtained 2.7 grams of hydroxy-a 2 (methoxy-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate melts at 88 °c.

The dimethylamino-2 (methoxy-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate from 13.9 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 24.2 cm3 2m of sodium ethylate and 9.5 grams of has-methylthio methoxy-4 97 cm3 acetophenone in ethanol. After purification on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 6.1 g of obtained dimethylamino-2 (methoxy-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate used raw in subsequent syntheses.

Has-methylthio methoxy-4 acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-methylthio acetophenone from an agitated solution of 11, 5 grams of has-bromo-methoxy-4 acetophenone in 100 cm3 methanol, added 15 min méthanetbiolate 3.5 g of sodium at a temperature close to 20 °c and is left under stirring for 12 hours at this temperature. This provides 9.5 grams of has-methylthio methoxy-4 acetophenone used raw in subsequent syntheses.

EXAMPLE 14

Operation is carried out as to the example 4 from 23.5 g of dimethylamino-2 methylthio 5 oxo 6 (piperidino-4 phenyl) - O hsxa diene 2.4 pentadienoate and 139 cm3 hydrochloric acid In in 139 cm3 of ethanol. The mixture is stirred 16 hours at a temperature close to 20 °c. After purification by chromatography on silica column with dichloromethane as eluent, the oil obtained is dissolved in 20 cm3 of a mixture of cyclohexane and ethyl acetate (50 - 50 by volume); the eluate corresponding to 40 °c is concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The residue is recrystallized in 100 cm3 oxide isopropyls boiling. The result is 3 grams of hydroxy-a 2 methylthio 5 oxo 6 (piperidino-4 phenyl) -6 hexadiene and 2.4 pentadienoate melts at 65 °c.

The dimethylamino-2 methylthio 5 oxo 6 (piperidino-4 phenyl) -6 hexadiene and 2.4 pentadienoate can be obtained as follows:

Operation is carried out as in example 4 for thereby preparing the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 34.4 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminiua, an ethanol solution of 60 cm3 2m of sodium ethylate and 30 grams of has-methylthio piperidino-4 300 cm3 acetophenone in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent and recrystallization from boiling isopropanol 150 cn3, obtained 27 g of dimethylamino-2 aéthylthio-to-5 oxo 6 (piperidino-4 phenyl) -6 hexadiene and 2.4 pentadienoate melts at 113 °c.

Piperidino-4 has-methylthio acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of pure © 1¹ has-methylthio acetophenone. Has an agitated solution of 67 grams of has-chloro-acetophenone in piperidino-4 670 cm3 roêthanol'd®, is added, in 90 min, 20.1 g of méthanethiolate sodium to a® temperature close to 20 °c and the stirring is continued for 3 hours at the same temperature. After purification by recrystallization from 1400 cm3 of a mixture of hexane and cyclohexane (90 - 10 by volume) boiling, obtained 55 grams of has-methylthio acetophenone piperidino-4 melts at 66 °c.

Has-chloro-piperidino-4 © acetophenone can be prepared in the following manner:

Has an agitated solution of 124 grams of has, has' a-bromo acetophenone in piperidino-4 990 cm3 of a 12n aqueous hydrochloric acid solution, . 620 cm3 added titanium chloride III in aqueous solution at 15%. The solution is heated to boiling for 2 hours 30 minutes and cooled at a temperature close th 20 °c. The reaction mixture is alkalinized to pH 11 by 900 cm3 of an aqueous sodium hydroxide solution and taken up by 10n 750 cm3 dichloromethane and filtered. The organic phase is decanted, washed with 2 times 200 cm3 of water, dried on sodium in amorphous®, filtered and evaporated to dry to 40 °c under reduced pressure (20 Ata-mercury; 2.7 kPa gauge). The residue is recrystallized in boiling isopropanol 400 cm3. Obtained 67 grams of has-chloro-piperidino-4 acetophenone melts at 125 °c.

Has, has' a-bromo acetophenone piperidino-4 may be prepared in the following manner:

Has an agitated solution of 99.5 g of piperidino-4 200 cm3 acetophenone in an aqueous solution of hydrobromic acid 8, 6n, added, in 40 min, at a temperature close to 20 °c, a mixture of 50 cm3 of bromine and hydrobromic cyclopentan-® 75 cm3. while maintaining the temperature at about 20 °c. Stirring is maintained 2 hours at the same temperature. The reaction mixture is filtered, the filter cake washed by water 300 cm3. The solid is crushed and resumed by 800 cm3 of diehlorosaéthane.

The resulting solution is alkalized to pH 11 by 200 cm3 sodium ion and resumed by 600 cm3 of water. The organic phase is decanted, dried on anhydrous magnesium sulfate, filtered and evaporated to dry to 40 °c under reduced pressure (20 mm of mercury ;

2.7 kPa gauge). The residue is recrystallized in boiling ethanol 2160 cm3. Obtained... 124 grams of has, has' a-bromo acetophenone piperidino-4 melts at 134 °c.

EXAMPLE 15

Operation is carried out as to the example 5•from 12.5 g of cyano 5 dimethylamino-2 phenylthio-5 pentadiene-to-2.4 pentadienoate 51.7 cm3 and an ethanol solution of hydrochloric 4n. The mixture is heated and cooled 3 mins to boil at a temperature close to 20 °c. After purification by recrystallization from boiling isopropyl oxide 55 cm3; 3.2 g of obtained cyano 5 hydroxy 2 phenylthio-5 pentediene-to-2.4 pentadienoate ' melts at 112 °c..

Cyano 5 dimethylamino-2 phenylthio-5 pentadiene and 2.4. pentadienoate may be prepared in the following manner:

Operation is carried out as in the example 5 from 97 g of tetrafluoroborate n-de - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 170 cm3 2m of sodium ethylate and 50.5 g of phénylthioacétonitrile in 700 cm3 of ethanol. After, recrystallization purification ' in 250 cm3 boiling isopropanol, 21.4 g of obtained diraéthylamino-to-2 pénylthio-to-5 pentadiene-to-2.4 pentadienoate melts at 88 °c.

The phénylthioacétonitrile may be prepared in the following manner:

A. an agitated solution, of 20 g of thiophenol and 90 cm3 ethanol solution.. 2m of sodium ethylate, added, at a temperature close to 5° e, 45 min during, - 11.4 cm3'd® chloroacetonitrile. Stirring is maintained 5 hours at a® temperature close to 20 °c. The reaction mixture is filtered, the filtrate is evaporated to dry at 50 °c under vacuum (20 mm of mercury;

2.7 kPa gauge). The residue is dissolved in 30 cm3 of a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) and the solution is poured onto 1000 g of silica contained in a 6.5 cm diameter column. By eluting with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent. 14.5 G of obtained phénylthioacétonitrile used raw in subsequent steps.

EXAMPLE 16

Operation is carried out as to the example 2 from 10 g of (chloro 4 phenylthio) -5 dimethylamino-2 hexadiene and 2.4 dioate diethyl, 39 cm3 of an aqueous solution of hydrochloric acid in ethanol 39 cm3 inches. The mixture is heated and then cooled 2 minutes to boil at a temperature close to 20 °c. After purification by recrystallization from cyclohexane 135 cm3 boiling, 6.8 g of obtained (chloro 4 phenylthio) -5 hydroxy 2 hexadiene and 2.4 dioate diethyl melts at 84 °c.

The (chloro 4 phenylthio) -5 dimethylamino-2 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 14.3 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, of 25 cm3 2m of an ethanolic solution of sodium ethylate and 11.5 g of (chloro 4 phenylthio) ethyl acetate in ethanol 100 cm3. This provides 19 g of (chloro 4 phenylthio) -5 dimethylamino-2 hexadiene and 2.4 dioate diethyl used raw in subsequent steps.

The (chloro 4 phenylthio) ethyl acetate can be prepared as follows:

Operation is carried out as to 1' example 2 for the preparation of the ethyl phénylthioacétate, from 16.7 g of ethyl bromoacetate, an ethanol solution of 50 cm3 2m of sodium ethylate and 14.5 g of platinic 4 thiophênol. This gives 20.7 g of (chloro 4 phenylthio) acetate. ethyl used raw in subsequent steps.

EXAMPLE 17

Operation is carried out as to the example 2 from 10 g of dimethylamino-2 (methoxy-4 phenylthio) -5 hexadiene and 2.4 dioate 39.5 cm3 diethyl and an aqueous solution of hydrochloric acid in ethanol thein 39.5 cm3. The mixture is heated and cooled 3 minutes to boil at a temperature close to 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent and crystallizing recrista 105 cm3 in boiling cyclohexane, obtained the I of hydroxy-a 2 6 (methoxy-4 phenylthio) -5 hexadiene and 2.4 dioate diathyle melts at 88 °c.

The diméthylaminc-to-2 (methoxy-4 phenylthio) -5 hexadiene and 2.4 dioate diethyl can iîre prepared in the following manner:

Operation is carried out as to 1' example 2 for the preparation of the dimethylamino-2 phenylthio -5 hexadiene and 2.4 dioate diethyl, from 17.2 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, of 30 cm3 2m of an ethanolic solution of sodium ethylate and 13.6 g of (methoxy-4 phenylthio) ethyl acetate in ethanol 136 cm3. After purification by recrystallization from boiling isopropyl oxide 110 cm3, 8.4 g of obtained dimethylamino-2 (methoxy-4 phenylthio) -5 hexadiene and 2.4 dioate diethyl melts at 78 °c.

The (methoxy-4 phenylthio) ethyl acetate can be prepared as follows:

Operation is carried out as in example 2 for the preparation of the ethyl phénylthioacétate, from 11.7 g of ethyl bromoacetate, of 35 cm3 2m of an ethanolic solution of sodium ethylate and 10 g of methoxy-4 thiophenol. The result is 13.6 g of (methoxy-4 phenylthio) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 18

Operation is carried out as in example 2, from 10 g of benzylthiopropionic-to-5 dimethylamino-2 hexadiene and 2.4 dioate 41.3 cm3 diethyl and an aqueous solution of hydrochloric acid in ethanol thein 41.3 cm3. The mixture is heated and then cooled 2 minutes to boil at a temperature close to 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (30 - 70 by volume) as eluent, 6.3 g of obtained hydroxy 2 benzylthiopropionic-to-5 hexadiene and 2.4 dioate diethyl (melting point < 40 °c) [rf=0, 6; thin layer chromatography silica gel; eluent: cyclohexane-ethyl acetate (30 - 70 by volume)].

The benzylthiopropionic-to-5 dimethylamino-2 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 15.7 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanamihium, an ethanol solution of 27.5 cm3 2m of sodium ethylate and 11.6 g of ethyl benzyltbioacétate 110 cm3 in ethanol. The result is 19.2 g of benzylthiopropionic-to-5 dimethylamino-2 hexadiene and 2.4 dioate diethyl used raw in subsequent steps.

The benzylthioacétate ethyl may be prepared

following manner: "

Tl■■■

Operation is carried out as in example 2 for the preparation of the ethyl phénylthioacétate, from 16.7 g of ethyl bromoacetate, of 50 cm3 - a "' 2m ethanolic solution of sodium ethylate and 11.7 cm3 benzyl mercaptan. The result is 19.4 g of ethyl benzylthioacétate raw used in subsequent steps.

EXAMPLE 19

Operation is carried out as to the example 2 from 5.1 grams of allylthio-to-5 dimethylamino-2 hexadiene and 2.4 dioate 24.4 cm3 diethyl and an aqueous solution of hydrochloric acid. In 24.4 cm3 of ethanol. The mixture is heated and cooled 3 minutes to boil at a temperature close to 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (75 - 25 by volume) as eluent, obtained 2.3 grams of allylthio-to-5 hydroxy 2 hexadiene and 2.4 dioate diethyl as a yellow oil [rf=0, 2; thin layer chromatography silica gel; eluent: cyclohexane-ethyl acetate (75 - 25 by volume)].

The allylthio-to-5 dimethylamino-2 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 5.5 g of n - tetrafluoroborate (dimethylamino-3 éthoxycarbonyl-to-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 9.7 cm3 2m of sodium ethylate and 3.1 g of ethyl allylthioacétate 31 cm3 in ethanol. This provides 5.1 grams of allylthio-to-5 dimethylamino-2 hexadiene and 2.4 dioate diethyl used raw in subsequent steps.

The allylthioacétate - ethyl can be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the ethyl phénylthioacétate 16.7 g of from ethyl bromoacetate, an ethanol solution of 50 cm3 2m of sodium ethylate and 7.7 cm3 " of allylmercaptan. After purification by chromatography on silica column with cyclohexane as eluant, 3.1 g of allylthioacétate obtained ethyl used raw in subsequent steps.

EXAMPLE 20

operation is carried out as to the example 2 from 9.3 g of dimethylamino-2 ethoxycarbonyl-5 tridecadiene-to-2.4 pentadienoate 40 cm3 and an aqueous solution of hydrochloric acid in ethanol 40 cm3 inches. The mixture is heated and then cooled 5 minutes to boil at a temperature close to 20 °c. After purification by recrystallization from petroleum ether 100 cm3 40 - 65 degrees, obtained 3.9 grams of éthoxycarbonyl-to-5 hydroxy 2 tridecadiene-to-2.4 pentadienoate melts at 58 °c.

The dimethylamino-2 ethoxycarbonyl-5 tridecadiene-to-2.4 pentadienoate may be prepared in the following manner:

To a solution stirred. 5.6 cm3 of diisopropylamine, 37.5 cm3 1, 6m solution of n-butyllithium in 1' 30 cm3 hexane and tetrahydrofuran, is added, at a temperature close to -78 °c, in 10 min, 10 g of ethyl-n-decanoate. Stirring is maintained 30 minutes at the same temperature is then added 14.3 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl. méthanaminium and maintains the stirring 3 hours at a temperature close to -78 °c. After gradual heating to about 20 °c, added to the reaction medium 4 g of ammonium chloride dissolved in 50 cm3 of water. Added 200 cm3 of dichloromethane and 100 cm3 of water and settle upon the organic phase. The aqueous phase is washed with 2 times 50 cm3 of dichloromethane.

N-■^tB _ The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated at 40 °c under reduced pressure (20 mm of mercury > 2.7 kPa gauge). The residue is dissolved in 30 cm3 of a mixture of cyclohexane and ethyl acetate (60 - 40 by volume) and the resulting solution is poured onto 600 g.de silica contained in a column of 7 cm in diameter. By eluting with a mixture of cyclohexane and ethyl acetate (60 - 40 by volume) and the eluate is concentrated to dry to 40 °c under reduced pressure (20 mm of mercury;

2.7 kPa gauge). The result is 9.8 g of dimethylamino-2 ethoxycarbonyl-5 tridecadiene-to-2.4 pentadienoate used to 1' raw state in subsequent syntheses.

Lë n-décànoate ethyl can be prepared in the following manner:

17.2 ' g of n-decanoic acid, 3 cm3 of an aqueous solution of sulfuric acid and 300 cm3 36n ethanol are heated 4 hours to boiling. After cooling at a temperature close to 20 °c, the solution is concentrated to dry at 50 °c under vacuum (20 mm of mercury; 2.7 kPa gauge) and then the residue is taken up by 200 cm3 of dichloromethane. The organic phase is washed with 2 times 100 cm3 of a saturated aqueous solution of sodium bicarbonate,, decanted, dried on anhydrous magnesium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). This gives 18 g of the n-decanoate ethyl used raw in subsequent syntheses.

EXAMPLE 21

Operation is carried out as to - the example 2, from 5 g of D-PLA-to-thylamino-a 5. phenylthio-2 pentadiene-to-2.4 ethyl rethinking 108 cm3 and an aqueous solution of hydrochloric acid in ethanol.. 90 cm3 in the mixture is heated and then cooled 2 minutes to boiling to. a temperature close to 20 °c. After purification by recrystallization from a mixture of cyclohexane•15 cm3 and ethyl acetate (50 - 50 by volume) boiling, obtained 1.5 grams of hydroxy-a 5 phenylthio-2 pentadiene-to-2.4 pentadienoate flux. to 120 °C.

- ' Λ O

The dimethylamino-5 phenylthio-2 pentadiene-to-2.4 pentadienoate may be prepared in the following manner:

Has an agitated solution of 25.1 g of ethyl phénylthioacétate 280 cm3 in ethanol maintained under nitrogen atmosphere, is added, at a temperature close to 20 °c, 15 minute period, 64 cm3 2m of an ethanolic solution of sodium ethoxide. Stirring is maintained 30 minutes at the same temperature and then 20.8 g of chloride of n - (diméthylaraino-to-3 propenylidene) n-methyl méthaneminium are added. The reaction medium is stirred 15 hours at a temperature close to 20 °c. The mixture is concentrated to dryness under reduced pressure to 40 °c (20 mm of mercury; 2.7 kPa gauge) and taken up by 200 cm3 of water. The precipitate formed is filtered, washed by water 50 cm3 and recrystallized in boiling ethanol 125 cm3. 18.1 G of obtained dimethylamino-5 phenylthio-2 pentadiene-to-2.4 pentadienoate melts at 128 °c.

The chloride of n - (dimethylamino-3 propenylidene) n-methyl méthanaminium can be prepared according to the method described by V. Nair and S.R. Cooper pair, J 92. Chem., 46, (1981) 4759.

EXAMPLE 22

To a solution of 5 g of stirred of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 2.4 cm3 dioate diethyl and triethylamine in tetrahydrofuran 45 cm3, penetrated by a stream of nitrogen, is added, at a temperature of about 20 °c during 5 min and, 1.2 cm3 of acetyl chloride. Stirring is maintained 2 hours at the same temperature. The mixture is resumed by 100 cm3 100 cm3 of water and dichloromethane. The organic phase is decanted and the aqueous phase is extracted with 2 times 50 cm3 of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The oil obtained is dissolved in 10 cm3 of a mixture of cyclohexane and ethyl acetate (70 - 30 in volumes) and poured onto 300 g of silica, contained in a column of 4 cm in diameter.

By eluting with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) and the eluate is concentrated to dry to corresponding 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). Obtained 4.5 gms of acétoxy-to-2 phenylthio-5 hexadiene and 2.4 dioate. diethyl as an oil reddish|rf=0, 50; thin layer chromatography silica gel; eluent cyclohexane ethyl acetate (70 - 30 by volume)].

EXAMPLE 23

Operation is carried out as in example 2, from 4.5 g of dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (1) and (6) ethyl cyclohexyl and 0.5 cm3 of an aqueous solution of hydrochloric acid in tetrahydrofuran 12n 5ô cm3. The solution is stirred 15 hours at a temperature of about 20 °c. After purification by recrystallization DAA ^ 70' cm3•cyclohexane boiling, obtained 2.3 grams of hydroxy-a 2■>hénylthio-to-5 hexadiene and 2.4 dioate (1) and (6) ethyl cyclohexyl melts at 110 °c.

The diméthylaminc-to-2 phenylthio-5 hexadiene and 2.4 dioate (1) and (6) ethyl cycjohexyle can be prepared in the following manner:

The flight operation is carried out as for the preparation of example 2 dimethylamino-2 phenylthio-5 dioate diethyl iexadiènè and 2.4, from 13.7 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, solution of 33.1 cm3 1, 6m in 1' hexane and n-butyllitbium and 12 g of cyclohexyl phénylthioacétate 150 cm3 in tetrahydrofuran. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate. (80 - 20 by volume) as eluent, 9.7 g of obtained diméthylamino.-a 2 phenylthio-5 hexadiene and 2.4 dioate (1) and (6) ethyl cyclohexyl used to 1' raw state in subsequent steps.

The phénylthioacétate cyclohexyl may be prepared in the manner Injury Control; nts:

Operation is carried out as to the example 20 for the preparation of ethyl n-decanoate, from 20 g of phenylthioacetic acid 0.32 cm3 and an aqueous solution of sulfuric acid in 100 cm3 36n of cyclohexanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent, obtained 29 g of cyclohexyl phénylthioacétate raw used in subsequent steps.

EXAMPLE 24

Operation is carried out as to the example 2 from 3.5 g of diraé-to-thylamino-to-5 phenyl-5 phenylthio-2 pentadiene-to-2.4 pentadienoate 17 cm3 and an aqueous solution of hydrochloric acid in ethanol thein 17 cm3. The solution is heated and then cooled 2 minutes to boil at a temperature close to 20 °c. After purificâr except by chromatography on silica column with dichloromethane as eluent, . obtained 1.7 grams of oxo-to-5 phenyl-5 phenylthio-2 pentene-2 pentadienoate as a yellow oil (the RF=Q-, 40;

thin layer chromatography silica gel; eluent:

dichlororaéthane).

' The dimethylamino-5 phenyl-5 phenylthio-2 pentadiene-to-2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, 15.4 g of from tetrafluoroborate. n - (dimethylamino-3 phenyl-3 propenylidene) n-methyl méthanaminium, 26.5 cm3 of 2m solution of sodium ethylate and 10.4 g of ethyl phénylthioacétate 150 cm3 in ethanol. After purification by chromatography on silica column with dichloromethane as eluent, 9.7 g of obtained dimethylamino-5 phenyl-5 phenylthio-2 pentadiene-to-2.4 pentadienoate melts at 99 °c.

N - tetrafluoroborate (diméthyiamino-to-3 phenyl-3 propenylidene) n-methyl méthanaminium can be prepared in the following manner:

Operation is carried out as to 1 'example 2 for the preparation of the n-tétraflûoroborate - (ethoxy-3; ethoxycarbonyl-3 propenylidene) n-methyl méthanaminiumtétraflûoroborate due and n - (dimethylamino-3 ethoxycarbonyl-3' propenylidene) n-methyl méthanaminium, from 10.1 g of (dimethylamino-2 ethenyl) - L-phenyl ketone, of 12.3 g of tétraflûoroborate of triethyloxonium and 5 cm3 dimethylamine in 50 cm3 of dichloromethane. After purification by recrystallization from boiling isoprppanol of 100 cm3, 15.4 g of tétraflûoroborate obtained n - (dimethylamino-3 phenyl-3 propenylidene) n-methyl méthanaminium melts at 136 °c.

The (dimethylamino-2 ethenyl) -! phenyl ketone may be prepared according to the method " described by H. BRADERECK, f effarberger and H. BOTSCH, mal. Berv 97, 3397 (1964). _

EXAMPLE 25

Operation is carried out as in example 2, from 4.6 g of dimethylamino-2 phenyl-5 hexadiene and 2.4 dioate 28 cm3 diethyl and an aqueous solution of hydrochloric acid in ethanol 28 cm3 inches. The solution is stirred to. a temperature close to 20 °c during 15 hours. After purification by recrystallization from cyclohexane 35 cm3 boiling, obtained 1.8 grams of hydroxy-a 2 phenyl-5 hexadiene and 2.4 dioate diethyl melts at 107 °c.

The dimethylamino-2 phenyl-5 hexadiene and 2.4 dioate diethyl can be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2>4 dioate diethyl, from de.10 tétraflûoroborate g of n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium,: of 21 cm3 ethanplic 2m solution of sodium ethylate and 5.6 cm3 of ethyl phênylacétate 100 cm3 in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent, 4.6 g of obtained dimethylamino-2 phenyl-5 hexadiene and 2.4 dioate diethyl used raw in subsequent steps.

EXAMPLE 26

Operation is carried out as in example 4, from 4.9 g of diraéthylamino-to-2 (isopropylenedioxy-to-3.4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate 20 cm3 and an aqueous solution of hydrochloric acid in ethanol 20 cm3 inches. The mixture is heated and then cooled 5 minutes to boil at a temperature close to 20⁹ C. purification by recrystallization, in 70 cm3 boiling isopropyl oxide, obtained 1.1 grams of hydroxy-a 2 (isopropylenedioxy-to-3.4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate melts at 134 °c.

The dimethylamino-2 (isopropylenedioxy-to-3.4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 7.2 g of n - tetrafluoroborate (dimethylamino-3 éthoxycarbonylr-to-3 propenylene) n-methyl méthanaminium, of 12.5 cm3 2m of an ethanolic solution of sodium ethylate and 6 g of dimethyl-2.2 (methylthio 2 acetyl) phenylalkyl-to-1.3 -5 50 cm3 in ethanol. After purification on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 3.9 g of obtained dimethylamino-2 (isopropylenedioxy-to-3.4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate used raw in subsequent syntheses.

The dimethyl-2.2 (methylthio 2 acetyl) -5 phenylalkyl and 1.3 may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-to-méthylthioacétophénone, from an agitated solution of 14.9 g (bromo 2 acetyl) dimethyl-2.2 -5 phenylalkyl-to-1.3 150 cm3 in methanol. Added, in 5 min, 3.8 g of sodium méthanethiolate, at a temperature close to 20 °c and allowed to stir 15 hours at the same temperature. This gives 11 g of dimethyl-2.2 (methylthio 2 acetyl) -5 phenylalkyl-to-1.3 used raw in subsequent syntheses.

The (bromo 2 acétyi) -5 phenylalkyl-I-dimethyl-2.2, 3 can be prepared in the following manner:

Has an agitated solution of 5.8 grams of acétyl-to-5 dimethyl 2; 2 phenylalkyl and 1.3 in 100 cm3 of carbon tetrachloride, added 5 min, 1.5 cm3 bromine at a temperature close to 20 °c and allowed to stir 15 hours at the same temperature. The reaction mixture is not resumed 150 cm3 of water. The organic phase is decanted, dried on anhydrous magnesium sulfate, filtered and evaporated to dry to 40 °c under reduced pressure (20 mm of mercury;

2.7 kPa gauge). 7.1 G of obtained (bromo 2 acetyl) dimethyl-2.2 -5 relief pattern zodibxole-to-1.3 used raw to in subsequent syntheses.

The acéty1-to-5 'diméthyl-to-2.2 phenylalkyl-to-1.3 can be prepared according to' the method ' described by G. Benoit and B millets, Miniature bull. Share. Chem. FR 1960, 638.

EXAMPLE 27

Operation is carried out as to 1¹ example 4, from 1.9 g of (dihydroxy 3.4 phenyl) -6 dimêthylamino and 2 oxo 6 methylthio 5 hexadiene and 2.4 - pentadienoate 10.8 cm3 and an aqueous solution of hydrochloric acid in ethanol thein 10.8 cm3. The mixture is heated and then cooled 5 minutes to boil at a temperature close to 20 °c. After purification by exodentate in 100 cm3 isopropyl oxide, 0.6 g of obtained (dihydroxy 3.4 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 156 °c.

The (dihydroxy 3.4 phenyl) -6 dimethylamino-2 mêthylthio-to-5 oxo 6 hexadiènet2, 4 pentadienoate may be prepared in the following manner:

Operation is carried out as to L/example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, 11.4 from tétraflüoroborate g of n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, de60 cm3 2m ethanolic solution of sodium ethylate and 7.9 g of (methylthio 2. acetyl) - 4. pyrocatechol 60 cm3 in ethanol.

After purification on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 2.4 g of obtained (dihydroxy 3.4 phenyl) -6 dimethylamino-2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 144 °c.

The (methylthio 2 acetyl) -4 pyrocatechol can be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-to-méthylthioacétophénone, from an agitated solution of 18.6 g of (chloro 2 acetyl) 200 cm3 -4 pyrocatechol in methanol. Added, in 15 min, 7 g of sodium méthanethiolate, at a temperature close to 20 °c and allowed to stir 3 hours at the same temperature. This gives 14.5 g of (methylthio 2 acetyl) melts at 107 °c -4 pyrocatechol.

EXAMPLE 28

Operation is carried out as in example 4, from 8 g of dimethylamino-2 methoxy-5 oxo 6 phenyl-6 hexadiene and 2.4 pentadienoate 40 cm3 and an aqueous solution of hydrochloric acid in ethanol 40 cm3 inches. The mixture is heated and then cooled 5 minutes to boil at a temperature close to 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent and recrystallization from boiling isopropyl oxide 70 cm3, obtained 4 grams of hydroxy-a 2 methoxy-5 oxo 6 phenyl-6 hexadiene and 2.4 pentadienoate melts at 84 °c.

The dimethylamino-2 methoxy-5 oxo 6 phenyl-6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, 11.4 from tetrafluoroborate g of n - (dimethylamino-3 propénylidsne ethoxycarbonyl-3) n-methyl méthanaminium, 20 cm3 of 2m ethanol solution of sodium ethylate and 6 grams of has-methoxyacetphenone 50 cm3 in ethanol.

VV-after purification by chromatography on silica column with a mixture of ethyl acetate and dichlororaéthane (50 - 50 by volume) as eluent, 8.1 g of obtained dimethylamino-2 methoxy-5 oxo 6 phenyl-6 hexadiene and 2,4' pentadienoate used to 1' raw state in subsequent syntheses.

Has a-methoxyacetophenone is prepared by RBB MOFFETT and R " L-. SHRINER, 92. Synthesis. 3, 562 (1955).

EXAMPLE 29

Operation is carried out as in example 2, from 5 g of dirné-to-thylamino-to-2 (bênzylthiométhÿl and 4) -5 hexadiene and 2.4 dioate diethyl, 20 cm3 of a 12n aqueous hydrochloric acid solution and 20 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling petroleum ether 84 cm3, obtained 3.2 grams of hydroxy-a 2 (methyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 66 °c.

The diméthylaminc-to-2 (methyl-4 bênzylthio) -5 hexadiene and 2.4 dioate diéthylè can be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 diéthylè dioate, 5.7 from tétrafluqroborate g of n - (dimethylamino-3 prppenyiidene ethoxycarbonyl-3) n-methyl mêthanaminium, an ethanol solution of 10 cm3 2m of sodium ethylate and 4.5 g of (methyl-4 bênzylthio) acetate D.^{the R} ethyl 50 cm3 in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, obtained 5 g of dimethylamino-2 (methyl-4 benzylthiopropionic) -5 hexadiene and 2.4 diéthylè dioate, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (methyl-4 bênzylthio) ethyl acetate can be prepared as follows:

Has an agitated solution of 37.5 cm3 2m ethanolic solution of sodium ethoxide and ethanol 50 cm3, penetrated by a stream of nitrogen, added 15 min, 8.5 cm3 of mercapto-2 ethyl acetate at a temperature close to 20 °c. Allowed to stir 15 minutes at the same temperature and then added 20 min 13.9 grams of has-bromo-p xylëne at a temperature close to 20 °c. Stirring is maintained 60 minutes at this temperature and then the reaction mixture is evaporated to dry at 50 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The residue obtained is dissolved in 100 cm3 of dichloromethane, the organic phase dried over anhydrous magnesium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). This provides 15.6 g of (methyl-4 benzylthiopropionic) ethyl acetate used in the raw state in subsequent syntheses.

EXAMPLE 30

Operation is carried out as in example 2, from 6 g of dimethylamino-2 (phenyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 20.5 cm3 of a 12n aqueous hydrochloric acid solution and 40 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling isopropanol 70 cm3, obtained 4.25 grams of hydroxy-a 2 (phenyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 133 °c.

The dimethylamino-2 (phenyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, 5.7 from tetrafluoroborate g of n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 10 cm3 2m of sodium ethylate and 5.7 g of (phenyl-4 benzylthiopropionic) ethyl acetate in 50 cm3 of ethanol.

After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent, 6 g of obtained dimethylamino-2 (phenyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (phenyl-4 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to 1' example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 10.25 g of chloromethyl-4 biphenyl, of 25 cm3 2îj ethanol solution of sodium ethylate and 6.1 g of mercapto 2 ethyl acetate in ethanol 150 cm3. This provides 13.1 g of phenyl-4 benzylthiopropionic ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 31

Operation is carried out as in example 2, from 7 g of dimethylamino-2 (phenoxy-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 23 cm3 of an aqueous solution of hydrochloric acid and ethanol 46 cm3 12n. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20^{the P} c.. After purification by chromatography on silica column with dichloromethane as eluent, obtained 4.5 grams of hydroxy-a 2 (phenoxy-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, in the form of a yellow oil (rf=0, 2; thin layer chromatography silica gel; eluant: dichloromethane).

The dimethylamino-2 (phenoxy-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner. 9.ï

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, 5.7 from tetrafluoroborate g of n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 10 cm3 2m of sodium ethylate and 6.1 g of (phenoxy-3 benzylthiopropionic) ethyl acetate in 50 cm3 of ethanol.

After purification by chromatography, on silica column with a mixture of cyclohexane and ethyl acetate ' (50 - 50 by volume) as eluent, obtained 7 grams. of dimethylamino-2 (phenoxy-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, of windings in the form of yellow oil, used in the raw state into the subsequent syntheses

The (phenoxy-3 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 21.5 g of chloromethyl-1 phenoxy-4 benzene, of 50 cm3 éthanoligue 2m solution of sodium ethylate and 12.2 grams de mercaptoimidazole 2 ethyl acetate in 200 cm3 of ethanol. The result is 28.8 g of (phenoxy-3 benzylthiopropionic) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 32

Operation is carried out as in example 4, from 6.9 g of dimethylamino-2 mëthylthio and 5 (naphthyl-2) -6 oxo 6 hexadiene and 2.4 pentadienoate, 29 cm3 of an aqueous solution of hydrochloric acid and ethanol 12n 29 cm3. The mixture is heated 5 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from diisopropyl oxide 300 cm3 boiling, OH-obtains 2.7 grams of hydroxy-a 2 methylthio 5 (naphthyl-2) -6 oxo 6 hexadiene and 2.4 pentadienoate melts at 117 °c.

The dimethylamino-2 methylthio 5 (naphthyl-2) -6 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, 10.6 from tetrafluoroborate g of n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 18.5 cm3 2m of sodium ethylate and 8 g of (methylthio 2. acetyl) -2 naphthalene in 50 cm3 of ethanol.

0■⁴ After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, obtained 5 g of dimethylamino-2 methylthio 5 (naphtÿl and 2) -6 oxo 6 hexadiene and 2.4 pentadienoate, an orange oil formed under, used in the raw state into jetproof subsequent syntheses.

The (methylthio 2 acetyl) -2 naphthalene can be prepared as follows:

Operation is carried out as in example 4 for the preparation of 1 'a-to-aéthylthio acetophenone, 12.5 g of from (bromo 2 acetyl) -2 naphthalene and 3.5 g of sodium in 100 cm3 méthanethiolate ethanol. This gives 8 g of (methylthio 2 acêtyl) -2 naphthalene used raw in subsequent syntheses.

EXAMPLE 33

Operation is carried out as to 1' example 4, from 3.4 g of dimethylamino-2 (phenoxy-3 phenyl) -5 hexadiene and 2.4 dioate diethyl, 13 cm3 of an aqueous solution of hydrochloric acid and ethanol 13 cm3 12n. The mixture is heated 5 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from 100 cm3 oxide - diisopropyl boiling, obtained 2.7 grams of hydroxy-a 2 (phenoxy-3 phenyl) -5 hexadiene and 2.4 dioate diethyl melts at 108 °c.

The dimethylamino-2 (phenoxy-3 phénylj-to-5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 7.6 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 13.3 cm3 2m of sodium ethylate and 6.8 g (phenoxy-3 phenyl) ethyl acetate in 70 cm3 of ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 3.4 g of obtained dimethylamino-2 (phenoxy-3 phenyl) -5 hexadiene and 2.4 dioate die diethyl, . in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (phenoxy-3 phenyl) ethyl acetate may be prepared in the following manner:

11.5 g acid (phenoxy-3 phenyl) acetic acid, an aqueous solution 3 cm3 .'d ' acid sulfuric 36n 200 cm3 in ethanol are boiled during 72 hours. After cooling to about 20 °c, the reaction mixture is concentrated to dryness under reduced pressure to 50 °c (20 mm of mercury; 2.7 kPa gauge). The oil is dissolved in 300 cm3 dichloromethane; the organic phase is washed by 150 cm3 of water, dried on anhydrous magnesium sulfate, filtered and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The residue is dissolved in 20 cm3 of a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) and the solution is poured onto 400 g of silica contained in a column of 5 cm in diameter. By eluting with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) and the eluate is concentrated to dry corresponding à,40 °C under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The result is 7.4 g of (phenoxy-3 phenyl) ethyl acetate used in the raw state into the subsequent syntheses.

The acid (phenoxy-3 phenyl) acetic acid can be prepared according to the method described by d.. and cqllMATTHIES, archarch.pharm. 604 (1983).

EXAMPLE 34

Operation is carried out as in example 2, from 7.3 g of dimethylamino-2 (trifluoromethyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 25.5 cm3 of a 12n aqueous hydrochloric acid solution and 50 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling petroleum ether 60 cm3, obtained 4.2 grams of hydroxy-a 2 (trifluoromethyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 73 °c.

'•IV to the dimethylamino-2 {trifluoromethyl-4 bènzylthio) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as to 1' example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, 5.7 from tetrafluoroborate g of n - (dimethylamino-3 êthoxycarbonyl-to-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 50 cm3 2m of sodium ethylate and 5.6 g of (trifluoromethyl-4 bènzylthio) ethyl acetate in 50 cm3 of ethanol. This gives 7.3 g of dimethylamino-2 (trifluoromethyl-4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (trifiudrômëthyl and 4 - bènzylthio) ethyl acetate can be prepared as follows:

It takes place ' as to the example 29 for the preparation of the (methyl-4 bènzylthio) ethyl ATEs CEA, 9.8 g of from chloromethyl-1 trifluoromé hly-to-4 benzene, ethanol solution of 25 cm3 2m of sodium ethylate and 6.1 g of mercapto 2 120 cm3 ethyl acetate in ethanol. This provides 12.2 g of (trifluoromethyl-4 bènzylthio) ethyl acetate used in the raw state into the subsequent syntheses. '

EXAMPLE 35

Operation is carried out as in example 4, from 9 g of dimethylamino-2 (GBP fluoro-to-4 phenyl) 6 - -6 méthyïthio-to-5 οχο hexadiene and 2.4 pentadienoate, of 36 cm3 solution ' 12n aqueous hydrochloric acid and ethanol 100 cm3. The mixture is heated 5 minutes to boil piifs is cooled to a temperature of about 20 °c. After ijurification by recrystallization from boiling cyclohexane 50 cm3, 3.2 g of obtained (fluoro 4 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 95° g.

The dimethylamino-2 (fluoro .phényl 4) -6 methylthio-5 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 21 cm3 2m of sodium ethylate and 6.5 grams of has-methylthio fluoro 4 100 cm3 acetophenone in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 9 g of obtained dimethylamino-2 (fluoro 4 phenyl) -6 méthylthiô-to-5 oxo 6 hexadiene and 2.4 pentadienoate, as an orange oil, used in the raw state into the subsequent syntheses.

The fluoro-4 has-methylthio acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of 1 'a-methylthio-to-2 acetophenone, from 25 g of P-fluoro-acetophenone and 10.3 g of sodium méthanethiolate 130 cm3 in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, obtained 21.9 grams of has-methylthio fluoro 4 acetophenone used raw in subsequent syntheses.

EXAMPLE 36

Operation is carried out as in example 4, from 7.7 g of dimethylamino-2 (bromo 4 phenyl} 6 - methylthio-5 oxo 6 hexadiene and 2.4 pentadienoate, 25 cm3 of an aqueous solution of hydrochloric acid and ethanol 80 cm3 12n. The mixture is heated 5 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 and then 50 - 50 by volume) as eluent and recrystallization from cyclohexane boiling 40 cm3, 2.5 g of obtained (bromo 4 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 84 °c.

The dimethylamino-2 (bromo 4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner / :.

Operation is carried out as to 1' example 4, for the preparation of the phenyl-6 oxo 6 méthylméthyl.thio and 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 10 g of n - tetrafluoroborate (dimethylamino-to-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 21 cm3 of an ethanol solution of 2m éthylaie sodium and ' 8.6 grams of has-methylthio bromo 4 100 cm3 acetophenone in ethanol. After purification by recrystallization from cyclohexane 100 cm3, 7.7 g of obtained dimethylamino-2 (bromo 4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate melts at 107 °c.

Bromo 4 has-methylthio acetophenone. can be prepared in the following manner -:

Operation is carried out as in example 4 for the preparation of has-methylthio acetophenone, from 30g of p-bromo-acetophenone and of 7.6 g of sodium in 100 cm3 méthanethiolate ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and dichloromethane (50 - 50 by volume) as eluent, obtained from cx-methylthio 22.4 g of bromo 4 acetophenone used raw in subsequent syntheses.

EXAMPLE 37

Operation is carried out as to 1' example 4, from 2.7 g of dimethylamino-2 (biphenylyl and 4) -6 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate, 10.7 cm3 of an aqueous solution of hydrochloric acid and ethanol 12n 10.7 cm3. The mixture is heated 5 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from diisopropyl oxide 100 cm3 boiling, obtained 1.1 grams of hydroxy-a 2 (biphenyl-yl-4) -6 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 125 °c. '

The dimethylamino-2 (biphenylyl and 4) -6 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate can. be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 6 g of n - tetrafluoroborate (dimethylamino-3 propenylldene ethoxycarbonyl-3) n-methyl méthanaminium, an ethanol solution of 10.5 cm3 2m of sodium ethylate and 5.1 grams of has-methylthio phenyl-4 150 cm3 acetophenone in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 2.8 g of obtained dimethylamino-2 (biphenylyl and 4) -6 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate, as an orange oil, used in the raw state into the subsequent syntheses.

Has-methylthio phenyl-4 acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-methylthio acetophenone, from 9.6 grams of has-bromo-phenyl-4 acetophenone and 2.4 g of sodium in 100 cm3 méthanethiolate ethanol. Obtained 5.1 grams of has-methylthio phenyl-4 acetophenone, melts at 92 °c, used in the raw state into the subsequent syntheses.

EXAMPLE 38

Operation is carried out as in example 2, from 22.8 g of dimethylamino-2 phénéthylthio-to-5 hexadiene and 2.4 dioate diethyl, 120 cm3 of an aqueous solution of hydrochloric acid 12n and 120 cm3 of ethanol. Le. mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent and recrystallization from boiling cyclohexane 140 cm3, obtained 13.2 grams of hydroxy-a 2 phénéthylthio-to-5 hexadiene and 2.4 dioate diethyl melts at 50 °c.

The dimethylamino-2 phénéthylthio-to-5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as to 1' example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 20 g.de tetrafluoroborate n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 42 cm3 of an ethanol solution of sodium ethylate 2m 15.7 g of phénéthylthio and ethyl acetate in 200 cm3 of ethanol. The result is 22.8 g of dimethylamino-2 phénéthylthio-to-5 hexadiene and 2.4 dioate diethyl, as an orange oil, used in the raw state into the subsequent syntheses.

The phénéthylthio ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate ', from 20 g of (brorao and 2 ethyl) benzene, of 25 to-cm3 ethanol solution 2m degradation evaluation. thylate sodium and 13 grams of mercapto-2 ethyl acetate in ethanol 150 cm3. This results phénéthylthio 21.7 g of ethyl acetate used to 1.' raw state in subsequent syntheses.

EXAMPLE 39 •

With an ethanolic solution of 2.8 grams of hydroxy-a 2 phé'phé' néthylthio-to-5 hexadiene and 2.4 dioate diethyl, added, in 10 min, . by maintaining at a temperature close to 20 °c, 32 cm3 of both in an aqueous sodium hydroxide solution. The mixture is maintained at a temperature close to 20 °c during 15 minutes and then is brought to pH 1 using an aqueous solution of hydrochloric acid in vivo.

Ethanol reaction is evaporated under reduced pressure (20 mm of mercury; 2.7 kPa gauge). After addition of 80 cm3 of water, the mixture is extracted by 2 times 80 cm3 of ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate and concentrated to dry to 40 °c under reduced pressure (20 mm of mercury; 2.7 kPa gauge). The solid thus obtained is recrystallized in a mixture of cyclohexane and ethyl acetate (98 - 2 by volume) boiling. This gives 1 g of hydroxy 2 ethoxycarbonyl-5 phénéthylthio-to-5 pentadiene-to-2.4 oic acid melts at 111 °c.

•ii "■.

EXAMPLE 40

Operation is carried out as in example 2, from 11.5 g of dimethylamino-2 (naphthyl-2 alkylthio) -5 hexadiene and 2.4 dioate diethyl, of 58 cm3 a, 12n aqueous hydrochloric acid solution and 100 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling petroleum ether 50 cm3, obtained 2 grams of hydroxy-a 2 (naphthyl-2 alkylthio) -5 hexadiene and 2.4 dioate diethyl melts at 90 °c.

The diméthylaroino-to-2 (naphthyl-2 alkylthio) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as to the example. 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 21 cm3 of an ethanol solution of sodium ethylate 2m 12.9 g of and (naphthyl-2 alkylthio) ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with a mixture of ethyl acetate and cyclphexane (50 - 50 by volume) as éluânt, 11.5 g of obtained dimethylamino-2 (naphthyl-2 alkylthio) -5 hexadiene and 2.4 dioate diethyl, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (thio-naphthyl-2) ethyl acetate can be prepared as follows:

Operation is carried out as in example 2 for the preparation of the phenylthio ethyl acetate, from 15 g of naphthyl-2 mercaptane, 48 cm3 of an ethanol solution of sodium ethylate 2m 15.7 g of de ethyl bromoacetate in 150 cm3 of ethanol. The result is 16.67 g of (naphthyl-2 alkylthio) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 41

Operation is carried out as in example 39, from 2 grams of hydroxy-a 2 (naphthyl-2 alkylthio) -5 hexadiene and 2.4 dioate diethyl, of 80 cm3 of an aqueous sodium hydroxide solution 100 cm3 In and ethanol. Is obtained by precipitation in ethanol 1.5 g of hydroxy 2 ethoxycarbonyl-5 (naphthyl-2 alkylthio) -5 pentadiene-to-2.4 oic acid melts at 182 °c.

EXAMPLE 42

operation is carried out as in example 2, from 2.2 g of dimé-to-thylaffiino-to-2 (naphthyl L) -5 hexadiene and 2.4 dioate diethyl, 12 cm3 of a 12n aqueous hydrochloric acid solution and 50 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization, 30 cm3 Dup boiling cyclohexane, obtained 0.8 grams of hydroxy-a 2 (naphthyl L) -5 hexadiene and 2.4 dioate diethyl melts at 99 °c.

The diméthylaminc-to-2 (naphthyl-1) -5 hexadiene and 2.4 dioate diethyl préparf may be as follows:

It is performed as confectioneries 2 the example for the preparation of the dimethylamino-2 phénylthic-to-5 hexadiene and 2.4 dioate diethyl, from 10 g of tétraf ' joroborate n - (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 26 cm3 of 2m ethanol solution of sodium ethylate and 7.5 g of (nadph-to-the Thyl L) -2 ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) boiling, 2.2 g of obtained dimethylamino-2 (naphthyl-1) -5 hexadiene and 2.4 dioate diethyl, as an oil, yellow, used in the raw state into the subsequent syntheses.

EXAMPLE 43

Operation is carried out as in example 4, from 5.5 g of dimethylamino-2 (dimethylamino-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate, 38 cm3 of a 12n aqueous hydrochloric acid solution and 50 cm3 of ethanol. The mixture is heated 5 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (60 - 40 by volume) boiling, 3.9 g of obtained (dimethylamino-4 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate as brown oil (rf * 0, 2; carrier: silica gel;

eluent: hexane/ethyl acetate 60 - 40 by volume).

The dimethylamino-2 (dimethylamino-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 8.6 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, of 15 cm3 2m of an ethanolic solution of sodium ethylate and 5.8 grams of has-methylthio dimethylamino-4 60 cm3 acetophenone in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent, 5.5 g of obtained dimethylamino-2 (dimethylamino-4 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate, as an orange oil, used in the raw state into the subsequent syntheses.

Dimethylamino-4 has-methylthio acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-methylthio acetophenone, from 12.5 grams of has-bromo-dimethylamino-4 acetophenone and 3.6 g of sodium méthanethiolate 65 cm3 in ethanol. Obtained 9.7 grams of has-methylthio diméthylaraino-to-4 acetophenone, melts at 65 °c, used in the raw state into the subsequent syntheses.

EXAMPLE 44

Operation is carried out as in example 4, from 14 g of dimethylamino-2 (benzoyl 3 phenyl) -5 hexadiene and 2.4 dioate diethyl, 52.3 cm3 of an aqueous solution of hydrochloric acid and ethanol 12n 52.3 cm3. 5 Minutes and the mixture is heated, boiled and then is cooled to a temperature of about 2q °C. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (50 - 50 by volume) as eluent and recrystallization from boiling isopropanol 100 cm3, obtained 2.3 grams of hydroxy-a 2 (benzoyl 3 phenyl) -5 hexadiene and 2.4 dioate diethyl melts at 105 °c.

The dimethylamino-2 (benzoyl 3' phenyl) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation of the phenyl-6 οχο methylthio 5 6 - dimethylamino-2 hexadiene and 2.4 pentadienoate, from 17.8 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminiun, of 31.3 cm3. 2m of an ethanolic solution of sodium ethylate and 16.8 g of (benzoyl 3 phenyl) ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with dichloromethane as eluent, obtained 14 g of dimethylamino-2 (benzoyl 3 phenyl) -5 hexadiene and 2.4 dioate diethyl, under ' form of a yellow oil, used in the raw state into the subsequent syntheses.

The (benzoyl 3 phenyl) ethyl acetate may be prepared in the following manner:

Operation is carried out as in the example 33 for the preparation of the (phenoxy-3 phenyl) ethyl acetate, from 16.6 g acid (benzoyl 3 phenyl) acetic 2 cm3 and an aqueous solution of sulfuric acid in ethanol 36n 2ô0 cm3. 16.8 G of•obtained (benzoyl 3 phenyl) ethyl acetate, in the form of brown oil, used in the raw state into the subsequent syntheses.

The acid (benzoyl 3 phenyl) acetic acid can be prepared according to the method described by G. COMISSO et, gazzgazz.chim.ïtal.

80, vol.110, 123 (1977).

EXAMPLE 45

Operation is carried out as in example 4, from 4.2 g of dimethylamino-2 (biphenylyl-a 3) -5 hexadiene and 2.4. diethyl dioate, 17 cm3 of an aqueous solution of hydrochloric acid and ethanol 17 cm3 12n. The mixture is heated 5 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by chromatography on silica column with dichloromethane as eluent and recrystallization from boiling cyclohexane 75 cm3, 0.7 g of obtained (biphenylyl-a 3) -5 hydroxy 2 hexadiene and 2.4 dioate diethyl melts at 95 °c.

The dimethylamino-2 (biphenylyl-a 3) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 4, for the preparation, of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 8 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 14 cm3 of an ethanol solution of sodium ethylate 2m 6.7 g of and (biphenylyl-a 3) - L-ethyl acetate in ethanol 30 cm3. After purification by chromatography on silica column with dichloromethane as eluent, 4.2 g of obtained dimethylamino-2 (biphenylyl-a 3) -5 hexadiene and 2.4 dioate diethyl, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (biphenylyl-a 3) - L-ethyl acetate may be prepared in the following manner:

Operation is carried out as in the example 33 for the preparation of the (phenoxy-3 phenyl) ethyl acetate, from 6.8 g acid (biphenylyl-a 3) acetic and 0.5 cm3 of a sulfuric acid aqueous solution 50 cm3 36n in ethanol. 6.8 G of obtained (biphenylyl-a 3) - L-ethyl acetate, in the form of brown oil, used in the raw state into the ISS subsequent syntheses.

Acid acetic (biphenylyl-a 3) can be prepared according to the method described by G. SAMs et, J Apotex. Science, vol.58, no. 8, 953 (1969).

EXAMPLE 46

Operation is carried out as to 1' example 2, from 9.5 g of diraéthylamino-to-2 (methyl-2 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 50 cm3 of an aqueous solution of acid chlorhydridriqüe 12n and 100 cm3 of ethanol. The mixture is heated to boiling and then ii min is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling cyclohexane 100 cm3, obtained 6.9 grams of hydroxy-a 2 (methyl-2 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 95 °c.

The dimethylamino-2 (methyl-2 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as to 1' example 2 for the preparation of the phenylthio-5 diméthÿlamino-to-2 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 prbpenylidene ethoxycarbonyl-3) n-methyl méthanaminium, 21 cm3 of 2m ethanolic solution of sodium ethylate and 7.9 g of (methyl-2 benzylthiopropionic) ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent, 9.5 g of obtained dimethylamino-2 (methyl-2 benzylthiopropionic) -5 hexadiene and 2 ,4dioate diethyl, in the form of a yellow oil, used in the raw state into the syntheses. subsequent..

The (methyl-2 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 10 g of bromomethyl-2 toluene, 30 cm3 of 2m ethanolic solution of sodium ethylate and 6, 5g of mercapto-2 ethyl acetate in ethanol 100 cm3. This gives 8.9 g of (methyl-2 benzylthiopropionic) ethyl acetate used in the raw state into the subsequent syntheses.'

EXAMPLE 47

Operation is carried out as in example 2, from 8.8 g of dimethylamino-2 (isopropyl 4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 44 cm3 of an aqueous solution of hydrochloric acid 12 n *t of 100 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from cyclohexane boiling 50 cm3, OH-obtains 5.6 grams of hydroxy-a 2 (isopropyl 4 benzylthiopropionic) -5 hexadiene and 2.4 dioate 86° g diethyl melts.

The dimethylamino-2 (isopropyl 4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 21 cm3 2m of sodium ethylate and 8.8 g of (isopropyl 4 benzylthiopropionic) ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent, 8.8 g of obtained dimethylamino-2 (isopropyl 4 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, as an orange oil, used in the raw state into the subsequent syntheses.

The (isopropyl 4 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 15 g of bromomethyl-1 isopropyl 4 benzene, ethanol solution of 49 cm3 2m of sodium ethylate and 9.8 g of mercapto 2 ethyl acetate in ethanol 150 cm3. This gives 17.9 g of (isopropyl 4 benzylthiopropionic) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 48

Operation is carried out as in example 4, from 7.3 g of dimethylamino-2 (chloro 3 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 pentadienoate D.¹ ethyl, 30.9 cm3 of an aqueous solution of hydrochloric acid and 62 cm3 of éthartol 12n. The mixture is heated and then 5 min & boiling is cooled to a temperature of about 20 °c.

After purification by recrystallization from cyclohexane 71 cm3 boiling, 6.6 g of obtained (chlorophenyl 3 phenyl) -6 hydroxy 2 methylthio 5 oxo 6 hexadiene and 2.4 pentadienoate melts at 90 °c.

The dimethylamino-2 (chloro 3 phenyl) methylthio 5 -6 oxo 6 hexadiene and 2.4 dioate diethyl can be prepared as follows

It is carried out - as to the example 4, for the preparation of the phenyl-6 oxo 6 methylthio 5 dimethylamino-2 hexadiene and 2.4 pentadienoate, from 11.5 g of n - tetrafluoroborate (dimethylamino-3 P-ethoxycarbonyl-3 openylidene) n-methyl mëthanaminium, 20 cm3 of 2m ethanol solution of sodium ethylate and 8 grams of has-to-mâthylthio platinic 3 CA ètophénone 80 cm3 in ethanol. After purification chromate graphy on silica column with a mixture of cyclohexane th^- ethyl acetate (50 - 50 by volume) as eluent, 7.3 g of obtiert is dimethylamino-2 (ohloro-to-3 phenyl) methylthio 5 -6 0:3 -6 hexadiene and 2.4 pentadienoate, under•form of oil of orange, used to 1_; ' raw state in subsequent syntheses.

Has-methylthio-chloro 3 acetophenone may be prepared in the following manner:

Operation is carried out as in example 4 for the preparation of has-methylthio acetophenone, from 22.3 grams of has-bromo-chloro 3 acetophenone and 6.8 g of sodium méthanethiolate 223 cm3 in ethanol. This gives 17.3 grams of has-methylthio-chloro 3 acétûphénone used raw in subsequent syntheses.

EXAMPLE 49

Operation is carried out as in example 2, from 11 g of dimethylamino-2 (methyl-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 58 cm3 of a 12n aqueous hydrochloric acid solution and 100 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as éiuant and recrystallization from cyclohexane boiling. 17 cm3, obtained 6.6 grams of hydroxy-a 2 (methyl-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 78 °c.

The dimethylamino-2 (methyl-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 21 cm3 of an ethanol solution of sodium ethylate 2 Μ 7.9 g of and (methyl-3 benzylthiopropionic) ethyl acetate in ethanol 100 cm3. Is. obtains 11 g of dimethylamino-2 (methyl-3 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, as a brown oil, used in the raw state into the subsequent syntheses.

The (methyl-3 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 15 g of bromomethyl-3 toluene, ethanol solution of 44.5 cm3 2m of sodium ethylate and 9.7 g of mercapto 2 ethyl acetate in 100. cm3 of ethanol. This provides 14.4 g of. (methyl-3 benzylthiopropionic) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 50

Operation is carried out as in example 2, from 21.9 g of dimethylamino-2 methylthio 5 a-hexadiene and 2.4 ' dioate diethyl, 114 cm3 of an aqueous solution of hydrochloric acid and ethanol 110 cm3 12n. The mixture, 5 minutes to boil is heated and then is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling cyclohexane 100 cm3, obtained 9.7 grams of hydroxy-a 2 methylthio 5 hexadiene and 2.4 dioate diethyl melts at 80 °c.

The dimethylamino-2 methylthio 5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 28.6 grams de tètrafluoroborate n - (dimethylamino-3 ethoxy-carbûnyl-to-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 50 cm3 2m of sodium ethylate and 13.4 g of methylthio ethyl acetate in ethanol 180 cm3. This provides 21.9 g of dimethylamino-'méthylthio 2 and 5 hexadiene and 2.4 dioate diethyl, as a brown oil, used in the raw state into the syntheses' subsequent.

The methylthio ethyl acetate can be prepared as follows:

Operation is carried out as in example 1 for the preparation of the phenylthio ethyl acetate, from die 7 g of methane thiolate sodium and 16.7 g of ethyl bromoacetate in 80 cm3 of ethanol. This results in 13.4 g of methylthio ethyl acetate used in the raw state into the subsequent syntheses.

; - The V " (of LKR -•

60 cm3 of a 12n aqueous hydrochloric acid solution and 100 cm3 of ethanol. The mixture is stirred 15 minutes at a temperature of about 20 °c. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent and recrystallization from boiling cyclohexane 22 cm3, obtained 4.4 grams of hydroxy-a 2 ethylthio-5 hexadiene and 2.4 dioate diethyl melts at 65 °c.

The dimethylamino-2 ethylthio-5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 21 cm3 of an ethanol solution of sodium ethylate 2m and 5.2 g of ethylthio ethyl acetate in ethanol 100 cm3. This gives 8.5 g of dimethylamino-2 ethylthio-5 hexadiene and 2.4 dioate diethyl, as a red oil, used in the raw state into the subsequent syntheses.

The ethylthio ethyl acetate can be prepared as follows. :

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 10.5 g of iodoethane, an ethanol solution of 37 cm3 2m of sodium ethylate and 8.1 g of mercapto 2 ethyl acetate in ethanol 100 cm3. The result is 6.9 g of ethylthio ethyl acetate used in the raw state into the syntheses, later.

EXAMPLE 51

Operation is carried out as to 1' example 2, from 8.5 g of

dimethylamino-2 ethylthio-5 hexadiene and 2.4 dioate diethyl, of

EXAMPLE 52

Operation is carried out as in example 2 -, from 4, 7g of dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (6) and (1) ethyl tert-butyl, 25 cm3 of a 12n aqueous hydrochloric acid solution and 50 cm3 of ethanol. The mixture is heated 1 minute to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from 88 cm3 of a mixture of petroleum ether and diisopropyl ether (50 - 50 by volume) boiling, obtained 3 grams of hydroxy-a 2 phenylthio-5 hexadiene and 2.4 dioate (6) and (1) ethyl tert-butyl melts at 113 °c.

The dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (6) and (1) ethyl tert-butyl can be prepared in the following manner:

Operation is carried out as to 1 'example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 4.05 g of n - tetrafluoroborate (dimethylamino-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanaminium, a solution of 8.8 cm3 1, 6m of butyllithium in of 1' 2.8 g of hexane and ethyl phénylthioacétate 65 cm3 in tetrahydrofuran. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent, 2.6 g of obtained dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate (6) and (1) ethyl tert-butyl melts at 85 and 88°.

The tetrafluoroborate n - (dimethylamino-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanamihium can be obtained as follows:

Operation is carried out as in example 2 for the preparation of the tetrafluoroborate n - (dimethylamino~3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, from 5.2 g of n - tetrafluoroborate (ethoxy-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanaminium and 1.1 cm3 dimethylamine dissolved in 8 cm3 of•dichlorométhané. After separation by filtration, 4.1 g of tetrafluoroborate is obtained n - (dimethylamino-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanaminium melts at 137 °c.

The tetrafluoroborate n - (ethoxy-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanaminium can be obtained as follows:

Operation is carried out as in example 2 for the preparation of the tetrafluoroborate n - (ethoxy-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, 3.3 g of from dimethylamino-4 oxo 2 butene-3 pentadienoate T-butyl of 3.62 g of triethyloxonium tetrafluoroborate in 20. cm3 of dichloromethane. The solution of n - ethylenic■chlorine (ethoxy-3 T-butyloxycarbonyl 3 propenylidene) n-methyl méthanaminium thus obtained is stored under an atmosphere of argon and used immediately in the subsequent syntheses.

The diméthylaraino-to-4 oxo 2 butene-3 pentadienoate T-butyl can be obtained as follows:

Operation is carried out as in example 2 for the preparation of the dimethylamino-4 oxo 2 butene-3 pentadienoate, 9.7 from pyruvate-g of T-butyl diethyl acetal of 11.4 g of n, n-dimethylformamide. After purification by chromatography on silica column with ethyl acetate as eluent and recrystallization from diisopropyl ether 50 cm3 boiling, 3.3 g of obtained dimethylamino-4 oxo 2 butene-3 T - pentadienoate: butyl melts at 93 °c.

T-butyl pyruvate can be prepared according to the method described by H.C. Brownian et, J 92. CHEM., 50, 1384 (1950).

EXAMPLE 53

Operation is carried out as in example 2, from 10 g of dimethylamino-2 H-butylthio-to-5 hexadiene and 2.4 dioate diethyl, 63 cm3 of a 12n aqueous hydrochloric acid solution and 100 cm3 of ethanol. The mixture is kept 1 hour at a temperature of about 20 °c. After purification by chromatography on silica column with dichloromethane as eluent, obtained 5.6 grams of hydroxy-a 2 n-butylthio-to-5 hexadiene and 2.4 dioate diethyl melts at 37 °c.

The_{the I}/3iaéthylamino and 2; rbutylthio-to-5 h'h' exadiene-to-2.4 dioate diethyl may be prepared de: 1a as follows;

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 éthoxycar, bônyl-to-3 propenylidene) K BéthylBéthanaœiniuiB, solution of 17.5 cm3, ethanoiic, 2m of sodium ethylate and 6.16 g of n-butylthio 60 cm3 ethyl acetate in ethanol. The result is 10 g of dimethylamino-2 n-butylthio-to-5 hexadiene and 2.4 dioate diethyl, souswformeunefbuilè of reddish, used in the raw state into the subsequent syntheses.

N-tert-butylthio ethyl acetate can be prepared as follows:

Operation is carried out as to 1 'example 2 for the preparation of the phénylthioacétate, 'd' from 10.7 cm3 ethyl n-butylmercaptan, of 50 cm3 ethanoiic 2m solution of sodium ethylate and 16.7 g of bi " ethyl aoacétate 100 cm3 in ethanol. NC is thus ' 5.4 g of n-butylthio ethyl acetate used state of BN T into the subsequent syntheses.

EXAMPLE 54

On. operates as ee 1' example 2, from 9.8 g of dimethylamino-2 iso-5 hexadiene and 2.4 dioate diethyl, 63 cm3 of an aqueous solution of hydrochloric acid and 98 cm3 12n ethanol. The mixture is stirred 1 hour at a temperature of about 2q °C. After purification by recrystallization from boiling pentane 90 cm3 is obtained 5.3 grams of hydroxy-a 2 iso-5 hexadiene and 2.4 dioate diethyl melts at 68 °c.

Web dimethylamino-2 iso-5. hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

" - h-V -■

Operation is carried out as to 1' example 2 for the preparation of the dimethylamino-2, phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 17.5 cm3 2m of sodium ethylate and 5.7 g of isopropylthio 57 cm3 ethyl acetate in ethanol. The result is 9.8 g of diméthylaraino-to-2 iso-5 hexadiene and 2.4 dioate diethyl, in the form of a reddish oil, used in the raw state into the subsequent syntheses.

The isopropylthio ethyl acetate can be prepared as follows: operation is carried out as in example 2 for the preparation of the ethyl phénylthioacétate, from 9.3 cm3 of isopropylmercaptan, an ethanol solution of 50 cm3 2m of sodium ethylate and 11.1 cm3 of ethyl bromoacetate in 100 cm3 of ethanol. This results isopropylthio 14 g of ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 55

It is performed and as to the example 24, from 4.5 g of dimethylamino-5 phenyl-5 phénéthylthio-to-2 pentadiene-to-2.4 pentadienoate, 23.6 cm3 of an aqueous solution of hydrochloric acid and 45 cm3 12n ethanol. The mixture is stirred 3 hours at a temperature of about 20 °c. After purification by chromatography on silica column with dichloromethane as eluent, obtained 2.8 grams of oxo-to-5 phenyl-5 phénéthylthio-to-2 pentene-2 pentadienoate as a yellow oil (rf=0, 4; carrier: silica gel; eluent:

dichloromethane).

The dimethylamino-5 phenyl-5 phénéthylthio-to-2 pentadiene-to-2.4 pentadienoate may be prepared in the following manner:

it is carried out to the example 24 qomme for the preparation of the dimethylamino-5 phenyl-5 phenylthio-.pentadiène 2 and 2.4 pentadienoate, 5.8 from tetrafluoroborate g of n - (dimethylamino-3 phenyl-3 propenylidene) n-methyl ' méthanaminium, of 10 cm3 2m of an ethanolic solution of sodium ethylate and 4.5 g of 50 cm3 phénéthylthio ethyl acetate in ethanol. After purification by column chromatography of silica with dichloroaéthane as eluent, 4.5 g of obtained dinéthylamino-to-5 phenyl-5 phénéthylthio-to-2 pentadiene-to-2.4 pentadienoate, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

EXAMPLE 56

Operation is carried out as in example 2, from 4 g of dimethylamino-5 benzoyl 5 phenylthio-2 pentadiènè-to-2.4 pentadienoate, 21 cm3 of an aqueous solution of hydrochloric acid and 40 cm3 12m of ethanol. The mixture is heated 3 minutes to boiling and then is cooled to a temperature of about 20 °c. After purification by recrystallization from cyclohexane 70 cm3 boiling, obtained 2.9 grams of hydroxy-a 5 oxo 6 phenyl-6 phenylthio-2 hexadiene and 2.4 pentadienoate melts at 110 °c.

The dimethylamino-5 benzoyl 5 phenylthio-2 pentadiene-to-2.4 pentadienoate may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 5 g of n - tetrafluoroborate (diraéthylamino-to-3 benzoyl 3 propenylidene) n-methyl méthanaminium, an ethanol solution of 7.9 cm3 2m of sodium ethylate and 3.1 g of ethyl phénylthioacétate 50 cm3 in ethanol. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent, 4.1 g of obtained dimethylamino-5 benzoyl 5 phenylthio-2 pentadiene-to-2.4 pentadienoate melts at 58 °c.

The tetrafluoroborate n - (dimethylamino-3 benzoyl 3 propenylidene) n-methyl méthanaminium can be prepared as follows:

Operation is carried out as in example 24 for preparing tetrafluoroborate n - (dimethylamino-3 phenyl-3 propenylidene} n métbylmétbanaminium, 9.3 g of (dimethylamino-2 éttaényl} - L-phenyl-3 to propanedione-a 1.2, of 10.3 g of triethyloxonium tetrafluoroborate and 3.2 cm3 dimethylamine•140 cm3 in dichloromethane. After precipitation in 30 cm3 of ethyl acetate, 5 g of tetrafluoroborate is obtained n - (dimethyl-amiho-to-3 benzoyl 3 propenylidene) n-methyl méthanaminium melts at 140 °c.

The (dimethylamino-2 ethenyl) - L-phenyl-3 to propanedione and 1.2 may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-4 oxo 2 butene-3 pentadienoate, from 25 g of phenyl-1 to propanedione and 1.2 and 28.3 g of diethyl acetal of n, n-dimethylformamide. After purification by chromatography on silica column with ethyl acetate as eluent, 9.3 g of obtained (dimethylamino-2 ethenyl) - L-phenyl-3 melts at 88 °c to propanedione and 1.2.

EXAMPLE 57

Operation is carried out as in example 2, from 6.4 g of diméthylamino-to-2 (trimethyl-2, 4, 6 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, 32 cm3 of an aqueous solution of hydrochloric acid and ethanol 80 cm3 12n. The mixture is stirred 90 minutes at a temperature of about 20 °c. After purification by recrystallization from boiling cyclohexane 100 cm3, obtained 4.28 g of hydroxy-a 2 (trimethyl-2, 4, 6 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl melts at 122 °c.

The dimethylamino-2 (trimethyl-2, 4, 6 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phénylthiô-to-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl mèthanaminium, of 21 cm3 etbanolic 2m solution of sodium ethylate and 8.8 g of (trimethyl-2, 4, 6 benzylthiopropionic) ethyl acetate in ethanol 80 cm3. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (70 - 30 by volume) as eluent, 6.44 g of obtained dimethylamino-2 (trimethyl-2, 4, 6 benzylthiopropionic) -5 hexadiene and 2.4 dioate diethyl, as a hiiile yellow, used in the raw state into the subsequent syntheses.

The (trimethyl-2, 4, 6 benzylthiopropionic) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, from 10.25 g of benzyl chloride trimethylammonium 2, 4, 6, a solution of 32.5 cm3 etbanolic éthyïate 2m of sodium and 7.1 g of mercapto 2 ethyl acetate in ethanol 150 cm3. This gives 11 g (trimethyl-2, 4, 6 benzylthiopropionic) ethyl acetate used in the raw state into the subsequent syntheses.

EXAMPLE 58 ;

Operation is carried out as in example 2, from 9 g of dimethylamino-2 (naphthyl-2 méthanethio) -5 hexadiene and 2.4 dioate diethyl, 42 cm3 of a 12n aqueous hydrochloric acid solution and 100 cm3 of ethanol. The mixture is heated to boiling and then the I min is cooled to a temperature of about 20 °c. After purification by recrystallization from boiling cyclohexane 100 cm3, obtained 7g hydroxy~2 (naphthyl-2 méthanethio) -5 hexadiene and 2.4 dioate diethyl melts at 88 °c.

The dimethylamino-2 (naphthyl-2 méthanethio) -5 hexadiene and 2.4 dioate diethyl may be prepared in the following manner:

ΐ γ ·ν ' -

Operation is carried out as in example 2 for the preparation of the dimethylamino-2 phenylthio-5 hexadiene and 2.4 dioate diethyl, from 10 g of n - tetrafluoroborate (dimethylamino-3 ethoxycarbonyl-3 propenylidene) n-methyl méthanaminium, an ethanol solution of 21 cm3 2m of sodium ethylate and 9.1 9 of (naphthyl-2 méthanethio) ethyl acetate in ethanol 100 cm3. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent, obtained 9 g.de dimethylamino-2 (naphthyl-2 méthanethio) -5 hexadiéne-to-2.4 dioate diethyl, in the form of a yellow oil, used in the raw state into the subsequent syntheses.

The (naphthyl-2 méthanethio) ethyl acetate can be prepared as follows:

Operation is carried out as to the example 29 for the preparation of the (methyl-4 benzylthiopropionic) ethyl acetate, 20 g of from bromomethyl-2 naphthalene, of 5.1 g of sodium hydride at 50% oil dispersion of petrolatum and 10.9 g of mercapto 2 ethyl acetate 200 cm3 in tetrahydrofuran. After purification by chromatography on silica column with a mixture of cyclohexane and ethyl acetate (80 - 20 by volume) as eluent, obtained 12 g of (naphthyl-2 methylthio) ethyl acetate used in the raw state into the subsequent syntheses.

The medicaments according to the invention consist of a compound of formula (I in) in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which can be inert or physiologically active. These demounting drugs can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, can be used tablets, pills, powders (gelatin capsules, tablets) or granules. In these compositions,, the active principle according to the invention is mixed with one or more diluents

inert, like starch, a cellulose, sucrose, lactose or silica.

Q. ^ These compositions may also comprise substances other than diluents ^ for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

As liquid compositions for oral administration, may be used solutions, suspensions, emulsions, syrups and elixirs containing pharmaceutically acceptable diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.

The sterile compositions for parenteral administration, can be preferably non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water may be employed, the lycol propylene copolymers, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. In CTS compositions can also contain adjuvants, in particul IERs of. wetting agents, isotonicity, emulsifiers, dispersants and stabilizers. The sterilization can be in a number of ways, for example by filtration sanitizing, by incorporating the composition of the sterilizing agents, by irradiation or by heating. They may also be prepared in the form of compositions " sterile solid that can be dissolved at the time of 1' use in a sterile injectable medium..

Flame lengths, for rectal administration are suppositories or rectal capsules ., which contain in addition to the active product excipients such as cocoa butter, semisynthetic glycerides or dice polyéthylèneglÿcolSi

The compositions for topical administration may be for example creams, ointments, lotion, eye drops, mouthwashes, nasal drops or aerosols.

In human therapeutics, the compounds of the invention are particularly useful as anti-inflammatory, as protecting agents especially on the diarrheogenic tract, and for the treatment of asthma, allergic diseases, psoriasis, rheumatoid arthritis and fibrotic conditions such as liver fibrosis.

The doses depend on the desired effect, the duration of treatment and the administration route used; they are generally between 0.1 g and 5g per day orally for an adult with unit doses ranging from 20 to 200 mg of active ingredient..

In general, the physician will determine the appropriate dosage based on the age, weight and all the other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:

Prepared, as usually, of capsules of 50 mg of active product having the following composition:

- hydroxy 2. methylthio-5 oxo 6 (piperidino-4 phenyl) -6 hexadiene and 2.4 pentadienoate 50 mg

- a cellulose 18 mg

55 mg of lactose -

- colloidal silica 1 mg

- carboxymethyl starch 10 mg

- 10 mg of talc

- magnesium stearate 1 mg SUCH AS B

Prepared, as usually, of tablets containing 50 mg of active product having the following composition:

- hydroxy 5 phênylthio-to-2 pentadiene-to-2.4 rethinking ethyl... 50 milligram

- lactose-....................., .., 4... 104 mg

- a cellulose 40 mg

povidone - 10 mg

- carboxyméthyland donation 22 mg sodium

- talcum.............. 4 . 10 mg

- magnesium stearate 2 mg

- colloidal silica...................... 2 mg mixture d¹ hydroxymethylcellulose, glycerin, oxide

titanium (72 - 3, 5 - 24.5) - 1 q.s. ad terminated 245 mg film-coated tablet

E.G. C

Prepared " injectable solution containing 10 mg of active product having the following composition:

hydroxy 2 - phenylthio-5 éthoxycarbony1 and 5

pentadiene-to-2.4 oïqûe... 10 mg

benzoic acid - - Υ...., ·. .... ν·........ 80 mg

benzylic alcohol -.................. '............ 0.06 cm3

- sodium benzoate: .............. 80 mg

- ethanol to 95% ......., ............................... 0.4 cm3

- sodium hydroxide......... "................. 24 mg

- prolpylene glycol. ............ I-1.6 cm3

- water. " qs p * 4 cm3