WO1982003860A1 - Derivatives of 1,4-thiazane-carboxylic acid,preparation and utilization thereof and compositions containing same - Google Patents

Abstract

Derivatives of 1,4-thiazane-3-carboxylic acid represented by the formula I, wherein R1? and R2? are hydrogen, an alkyl radical or a phenyl nucleus substituted or not or form a cycloalkyl radical; R3? is a hydroxyl group, OR9? group, wherein R9? may have different significations; R4? is hydrogen, alkyl or CONH2?, R3? and R4? forming a hydantoin cycle, R5? and R6? representing hydrogen, alkyl, phenyl substituted or not; R7? is hydrogen, alkyl, particularly dimethyl, phenyl substituted or not, and the salts of those compounds.$(6,)$as well as the pharmaceutical compositions containing them and the intermediaries for their preparation, having the formulas II, III, IV:$(7,)$.

Description

 "1, 4-t hiazane-carboxylic acid derivatives, their preparation and use as well as the compositions containing these derivatives". - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

The subject of the present invention is derivatives of 1,4-thiazane-carboxylic acid as well as the salts of these compounds, their methods of preparation as well as pharmaceutical compositions containing at least one of these derivatives and their method of use

The derivatives of the innovation correspond to the general formula I:

in which :

R ₁ and R ₂ which may be the same or different, represent hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ or a phenyl ring, optionally substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ or by a linear or branched alkoxy radical C ₁ , C _2, C ₃ or C ₄ ,

R ₁ and R ₂ may form, with the neighboring carbon atom, a cycloalkyl of 3, 4, 5, 6, 7 or 8 carbon atoms of which one or more carbon atoms may optionally be replaced by a sulfur atom, .. oxygen or by an SO, SO ₂ or NR _{8 group} in which R ₈ represents hydrogen, a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical, a phenyl ring or a benzyl group. R ₃ re present in te: - a hydroxyl group an OR ₉ group in which R ₉ represents a linear or branched alkyl group C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ ,

C ₈ , C ₉ , C _{1 0} , C ₁₁ , C ₁₂ or a group or a

group in which R ₁₀ represents hy

drogen or an alkyl radical C ₁ or C ₂ and R ₁₁ represents a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C5 ' ^C 6 ^{, C} 7, ^C 8, ^C 9, ^C 10, ^C 11, ^C 12

a group in which R ₁₂ and R _13, which can

be the same or different, represent hydrogen, a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical, a 3-phthalidyl group or a 1- (2,5-dioxopyrrolidinyl) -1-ethoxy group

R ₄ represents a hydrogen atom, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ or a linear or branched acyl group C ₁ , C ₂ , C ₃ , C ₄ , C _5, C ₆ , C ₇ or C ₈ or a CONH ₂ group,

R ₃ and R ₄ may form with the neighboring carbon and nitrogen atoms a hydantoin ring, R ₅ and R ₆ , which may be the same or different, represent hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ , a phenyl ring optionally substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched C ₁ alkyl radical , C ₂ , C ₃ or C ₄ or by a linear or branched alkoxy radical C ₁ , C ₂ , C ₃ or C ₄ , ung rou pe CH ₂ COOR _{1 4 in} which R ₁₄ represents hydrogen, a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical. R ₇ represents hydrogen, a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical or a gem radical. dimethyl or a phenyl ring optionally substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical or by a linear or branched C ₁ alkoxy radical , C ₂ , C ₃ or C ₄ , n can have the values 0, 1 or 2.

If R ₁ , R ₂ , R ₄ , and R ₇ , represent hydrogen and if

R ₃ represents a hydroxyl group or a linear or branched C ₁ -C ₄ alkyl radical,

R ₅ or R ₆ do not represent hydrogen, a linear or branched C ₁ -C ₄ alkyl radical or a phenyl ring.

According to a preferred form of the invention, its subject is the compounds of formula I in which: R ₁ and R ₂ which may be identical or different, represent hydrogen, a linear or branched alkyl radical C ₁ - C ₄

R ₃ represents a hydroxyl group, a group OR ₉ in which Rg represents a linear or branched C ₁ -C ₄ alkyl group, a group ^ or a group

10 in which R ₁₀ represents hydrogen or a methyl radical and R ₁₁ represents a linear or branched C ₁ -C ₈ alkyl radical.

R ₄ represents hydrogen or a methyl group.

R ₅ and R ₆ which may be the same or different, represent hydrogen, a linear or branched C ₁ -C ₄ alkyl group or a CH ₂ COOR _{14 group} in which R ₁₄ represents hydrogen or a C alkyl group ₁ -C ₂ ,

R ₇ represents hydrogen; n can have the values 0 or 1.

A preferred class of the compounds of formula I is that in which R ₁ and R ₂ represent hydrogen or a methyl group, R ₃ represents a hydroxyl group or an OR ₉ group in w hich R ₉ rep res e te te g rou pe al kyl eli naa re or rami fi ed

C ₁ -C ₄ ,

R ₄ represents hydrogen or a methyl group, R ₅ represents hydrogen and R ₆ represents a linear or branched C ₁ -C ₄ alkyl group, R ₇ represents hydrogen, n can have the v-lcurs 0 or 1.

Examples of compounds according to the invention are: 2,2,5-methyl-1,4-thiazane-3-carboxylic acid, 1-oxide,

- 2,2,5-trimethyl-1,4-thiazane-3-ethyl carboxylate, 1-oxide,

- 2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid, - 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (pivaloyloxy) ethyl, 1- oxide,

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of (octyloxycarbonyl) methyl, 1-oxide,

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (ethyloxycarbonyl) ethyl, 1-oxide,

- 5-butyl-2,2-dimethyl-1,4-thiazane-3-carboxylic acid,

- 2,2-dimethyl-5-isopropyl-1,4-thiazane-3-carboxylic acid

- 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid,

- 3-carboxy-2,2-dimethyl-1,4-thiazane-5-ethyl acetate.

If the derivatives according to formula I are in the form of addition salts with acids, they can be transformed according to usual methods, into their free base or into salts with other acids.

The most commonly used salts are non-toxic, pharmaceutically usable acid addition salts formed with suitable inorganic acids, for example hydrochloric acid, acid su! furic or acid phosphoric or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, aral iphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric acids , ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesul fonique, ethanesulfonic, pantothenic, toluenesulfonic, sulfanilic, cyclohexyl aminyl, cycl ohexyl friendyl -hydroxypropionic, β-hydroxybutyric, oxalic, malonic, galactaric, gaiacturonic.

These salts can also be derived from natural or unnatural amino acids such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, etc ...

When R ₃ represents an OH group, the present invention also covers the salts formed between this carboxylic acid function thus obtained in formula I and bases such as sodium, potassium, lithium, ammonium or magnesium hydroxide , calcium as well as internal salts (zwitterions).

The compounds of formula I may have one or more asymmetric centers and are capable of existing in the form of optical isomers, racemates or diastereoisomers; all of these forms are part of the present invention. The optical isomers can be obtained by stereospecific or sterëosël ecti ve synthesis or by resolution of racemates according to conventional methods for example by formation of diastërëo salts isomers by the action of optically active acids, such as tartaric, diacetyl tartaric, tartranilic, dibenzoyl tartaric, dito iuoyltartrique and separation of the mixture of diastereoisomers for example by crystallization or chromatography, then release of the optically active bases from these salts. The optically active compounds of formula I can also be obtained using optically active starting materials. The mixtures of diastereoisomers can be separated in the same way as the diastereoisomeric salts mentioned above.

Thrombotic, arterial and venous affections are currently a cause of mortality and especially of very important morbidity in Western countries.

The products of the invention allow a new therapeutic approach, different from that of substances acting on the functions of blood platelets on the one hand and that of fibrinolytic enzymes, on the other hand.

The increase in the fibrinolytic activity of the blood, following an increase in synthesis and / or release of the natural activators of fibrinolysis resulting from the oral or parenteral administration of the products of the invention makes it possible to envisage uses important therapeutic in greater safety conditions. Thus, the prevention of deep vein thromboses and their often fatal consequences of pulmonary embolism could be obtained by oral treatment administered before and in the weeks following unsafe surgical procedures.

The prevention of thromboses complicating phlebitis of the superficial veins, primary or secondary to periods of prolonged immobilization of patients, can also be considered.

The products of the invention can also be used in circumstances where a fall in the fibrinolytic activity of the blood occurs, for example, after surgery, during general anesthesia or in the case of diabetes treated with insulin.

Finally, alone or in combination with substances inhibiting the adhesion and aggregation of blood platelets, the products of the invention are indicated for the prevention of recurrent arterial or venous thrombotic accidents. We know, in fact, that in patients who have suffered from cerebral or coronary thrombosis (myocardial infarction), the risk of relapse justifies the application of preventive therapy.

The products of the invention are active orally, which allows easy use, and can be administered for long periods, in contrast to current fibrinolytic substances, since they are devoid of enzymatic activity, are not immunogenic and act through activators normally found in the body. Their use, alone or in combination with substances that inhibit blood platelets, allows a new approach to the treatment and prevention of arterial and venous thrombosis.

The present invention also claims pharmaceutical compositions containing, as active ingredient, at least one compound of general formula I and / or one of its salts with a pharmaceutical excipient. These compositions are presented so that they can be administered orally, rectally or parenterally. Thus, for example, the compositions for oral administration can be liquid or solid and presented in the form of tablets, capsules, granules, powders, syrups or suspensions; such compositions include the additives and excipients generally used in galenic pharmacy, inert diluents, disintegrating agents, binding agents and lubricating agents, such as lactose, starch, talc, gelatin, stearic acid, silicic acid, magnesium stearate , polyvinylpyrrol idone, calcium phosphate, calcium carbonate, etc.

Such formulations can be made so as to prolong the disintegration and, consequently, the duration of action of the active ingredient.

The aqueous suspensions, the emulsions and the oily solutions are made in the presence of softening agents, such as dextrose or glycerol, perfuming agents, such as vanillin, for example, and may also contain thickening agents, wetting agents , preservatives.

The emulsions and oily solutions are made in an oil of vegetable or animal origin and may contain emulsifying, perfuming, dispersing, softening and antioxidant agents.

For parenteral administration, sterile water, an aqueous solution of polyvinyl pyrrol idone, peanut oil, ethyl oleate, etc. are used as the vehicle. These aqueous injectable solutions or oily oils may contain thickening, wetting, dispersing and gelling agents. The compounds according to the invention are prepared according to methods which form part of the present invention and defined below. In the cases where the processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which are necessary before preparation, also form part of the present invention.

According to a first way of proceeding, a vinyl thioether of formula II obtained according to the method described by

A.I. Virtaneπ et al., In Acta Chem. Scand., 1966, 20, 1163-1185, is cyclized to derivative III according to the scheme:

R _1, R ₂ , R _3, R _4, R _5, R ₆ , R ₇ and n have been defined previously

Cyclization is preferably carried out in a basic medium. The base can be organic such as the triethyl amino, pyridine, N, N-dimethyl anil or mineral such as, for example, the hydroxides of alkali metals such as sodium or potassium hydroxide or alternatively hydroxide d 'ammonium.

When the base used is an organic base, the solvent will preferably be an inert organic solvent such as chlorinated solvents such as chloroform or dichloromethane, aromatic or aliphatic hydrocarbons such as benzene, toluene or the various fractions of petroleum ether or also solvents such as acetonitrile, N, N-dimethylformamide or dimethyl sulfoxide. When the base is mineral, the solvent used will preferably be water and the concentration of the basic solution will be from 0.01 N to 10 N and advantageously from 0.2 N to 2 N.

The reaction takes place at a temperature between 0 ° C and the reflux temperature of the solvent. However, it can be very advantageous to work at a temperature close to ambient temperature, especially when the reagents or the products contain a preponderant stereoisomer which risks s' i sover if the conditions used are too harsh.

Another way of proceeding consists in carrying out a cyclization starting from a cysteinyl derivative obtained according to the method described by J.F. Carson et al. in J. Org. Chem. 29, 2203 (1964), according to the following diagram

In this scheme, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and n have been defined previously and X represents a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or an easily removable group such as, for example, a tosyl or mesyl group. If the cyclization takes place in a basic medium, the conditions described for the first process can be applied in the present case.

If the cyclization takes place in an acid medium, then a mineral or organic acid is used such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, formic acid, l 'acetic acid.

It is also possible to use dehydrating agents such as, for example, phosphorus hemipentoxide, concentrated sulfuric acid, a carbodiimide such as dicyclohexylcarbodiimide.

These reactions are generally carried out in inert organic solvents such as chlorinated solvents such as chloroform, dichloromethane, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether or also in solvents such as dimethyl sulfoxide or N, N-dimethyl formamide. The reaction takes place at a temperature between room temperature and the reflux temperature of the chosen solvent.

According to another way of proceeding, a cysteine derivative IV is cyclized by reaction with an α-halogen ketone V; an unsaturated cyclic compound VI is thus formed which is then reduced to derivative VII according to the scheme:

R ₁ , R ₂ , R ₃ , R ₅ and R ₇ have been defined above and Y represents a halogen atom such as chlorine, bromine or iodine.

The first step of the process takes place in an inert organic solvent such as alcohols such as methanol, ethanol, propanol, ethers such as dioxane or tetrahydrofuran or in solvents such as dimethyl sulfoxide, N, N-dimethylformamide or in aromatic hydrocarbons such as benzene or toluene.

As bases, it is possible to use alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal alcoholates such as, for example, sodium or potassium methanolate, sodium or potassium ethanolate or sodium or potassium t.butanolate.

The reaction takes place at a temperature between tre - 20 ° C and the reflux temperature of the solvent; it is advantageous to work at a temperature between 0 ° C and room temperature.

It is possible, with advantage, to add to the reaction mixture a dehydrating agent such as, for example, molecular sieve.

The derivative VI can be isolated and purified, or the crude mixture can be used directly for the reduction step.

The reduction of imine VI takes place in the presence of hydrogen and of a hydrogenation catalyst such as platinum, platinum oxide or palladium on carbon in a solvent such as methanol, ethanol, acetate. ethyl or glacial acetic acid and this at ordinary pressure and more advantageously at higher pressure or by an alkali metal hydride such as sodium borohydride in a solvent such as methanol or aluminum hydride and lithium in a solvent such as ether or tetrahydrofuran.

Generally, this reduction takes place at room temperature but depending on the reactivity of the system it can sometimes be advantageous to heat the reaction mixture or to cool it.

An acid such as, for example, hydrochloric acid, sulfuric acid or acetic acid can sometimes ca ta l yser the reaction.

For the production of sulfoxides, agents such as iodine and bromine can be used in water or in the presence of acetate ions or in complex with pyridine, peracids such as peracetic, monoperphthalic or m-chloroperbenzoic acids , N-halosuccinimides such as N-bromosuccinimide, hypochlorites such as sodium, t.butyl or i.propyl hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of anhydride acetic acid or in the presence of vanadium hemipentoxide in t.butanol, nitrates, such as acetyl nitrate or ammonium and cerium nitrate, oxides such as chromium (VI) oxide in pyridine or l vanadium hemipentoxide in the presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, singlet or triplet oxygen, acids such as nitric acid, chromic acid or Caro acid or other agents such as sulfuryl chloride, 1-chlorobenzotriazole, l a chloramine, N-chloro-nylon 66, iodobenzene dichloride, iodosobenzene, iodobenzene diacetate, N-chlorotriazole, 2,4,4,6-tetrabromocyclohexadienone or chloroauric acid (HAuCl ₄ ). These oxidation reactions will be carried out in solvents such as, for example, water, acetic acid, chloroform, dichl oromethane, carbon tetrachloride, methanol, t.butanol or acetone.

To obtain sulfones, it will be useful to use agents such as hydrogen peroxide preferably in the presence of zirconium salts, peracids such as peracetic, monoperphthalic and m-chloroperbenzoic acids (in the case of oxidation with peracids, we will use advantageously catalysts based on transition metals), potassium permanganate in acid or basic medium, sodium or potassium dichromate, osmium tetroxide, selenium oxide, t.butyl hypochlorite , nitric acid, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by electrochemical oxidation. These reactions will be carried out in solvents such as water, acetic acid, chloroform, dichl oromethane, methanol, ethanol, isopropanol, t-butanol, dioxane or acetone.

In certain cases, it may be advantageous to carry out the oxidation reactions described above on compounds in which the functions sensitive to the oxidizing agent used have been protected.

The cyclization, reduction and oxidation steps described below can also be part of a continuous process that does not require the isolation of any intermediates.

It should be noted that the transformation of derivative I where n = 0 into derivative I where n = 1, 2 can be carried out at any stage of the development of the 1,4-thiazane cycle.

The introduction of the substituent when R ₄ represents a linear or branched alkyl group C ₁ -C ₈ acyl or linear or branched C ₁ -C ₈ takes place by alkylation or acylation of the amine according to the scheme:

R ₁ , R ₂ , R _3, R _4, R ₅ , R ₆ , R ₇ and n have been defined previously.

Z represents a halogen atom such as chlorine, bromine or iodine or an easily removable group such as, for example, a tosyl or mesyl group.

The reaction advantageously takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or dichloromethane, aliphatic aromatic hydrocarbons such as benzene, toluene or petroleum ether alcohols such as methanol and ethanol or even l 'acetoni trile and ethers. The temperature is between room temperature and the reflux temperature of the reaction mixture. The reaction can be carried out, with profit, in the presence of organic base such as pyridine, triethylamine or N, Nd i raëthyl an il ine or of mineral base such as hydroxides, carbonates and bicarbonates of alkali or alkali metals ino-earthy or finely pulverized lime.

The alkyl derivative can also be obtained by reduction of the corresponding acyl derivative according to conventional methods.

The introduction of substituent R ₄ = CONH _{2 is} effected conventionally by reaction of the derivative VIII with an isocyanate of an alkali metal or of ammonium, according to the scheme:

In this scheme, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , and n have been defined previously, M represents a monovalent cation such as sodium, potassium, lithium or ammonium ions

The reaction is conventionally carried out in water at a temperature between normal temperature and the reflux temperature.

Hydantoin XI is obtained by heating the derivative X where R ₃ represents a hydroxyl group in an aqueous solution of acid.

In this scheme, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and n have been defined previously.

The acid used is a mineral acid such as halogenated hydracids such as hydrochloric acid, hydrobromic acid hydroiodic acid or nitric acid, sulfuric acid or even phosphoric acid.

The reaction mixture is generally brought to a temperature close to the reflux temperature of the solution

The transformation of derivatives in which R ₃ represents a hydroxyl group into derivatives in which R ₃ represents an OR ₉ group, is a reacti on

of esterification.

The esterification of an acid is a very general reaction which can occur in many ways. Conventionally, the acid and the alcohol are reacted in the presence of an acid catalyst such as hydrochloric acid or sulfuric acid or p.toluenesulfonic acid. This reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in large excess. The solvent can be either one of the reactants or an inert organic solvent such as chlorinated hydrocarbons such as chloroform or carbon tetrachloride or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. The temperature is between the normal temperature and the reflux temperature of the reaction mixture.

Another way of proceeding is to distil the water as soon as it forms using an appropriate device. The reaction conditions are identical to those of

above, except that one of the reagents should not be used in large excess.

The hydrolysis of the ester takes place under conditions similar to the esterification reaction but, in this case, one of the reagents, in this case water, is used in very large excess. The catalysis and temperature conditions are the same as for esterification.

The transformation of derivatives in which R ₃ represents a hydroxyl group or groups such as OR ₉ ,

or derivatives in esquel s R ₃ , represented by

feel a group is a classic reaction and

very well documented in chemistry and which can be carried out according to several processes illustrated below.

For example, the carboxylic acid can be placed in the presence of the amine, the pyrolysis of the salt thus formed leads to the amide, as does the action of a dehydrating agent such as P ₂ O ₅ .

Another way of proceeding consists in transforming the carboxylic acid into an acid halide and then into an amide by the action of an amine. The conversion of acid to acid halide is often done without solvent with thionyl chloride, phosphorus pentachloride or phosphorus oxychloride. The corresponding bromides can also be used. For the reaction to be complete, it is often useful to heat the reaction mixture to a temperature between 50 and 150 ° C. If a solvent is useful for the course of the reaction, it will be an inert organic solvent such as hydrocarbons such as benzene, toluene or petroleum ether or ethers such as diethyl ether.

The reaction between the acid halide and the amine is done by cooling the reaction mixture to a temperature between 0 ° C and -50 ° C, by introducing an excess of amine (at least 2 equivalents or at least 1 equivalent of amine and at least 1 equivalent of a tertiary organic base such as, for example, triethylami). Conventionally, the acid chloride is added to the amine in solution in an inert organic solvent such as those defined above or also in solution in water. Yet another way of proceeding consists in reacting a carboxylic acid and an amine in the presence of a coupling reagent as used, for example, in peptide synthesis. There are currently a lot of coupling reagents such as, for example, dicycl ohexylcarbodiimide, N-ethyl-N ', 3-dimethyl-aminopropylcarbodiimide, phosphines, phosphites, silicon or titanium tetrachloride or EEDQ.

The aminolysis of an ester is conventionally carried out either in water or in an inert organic solvent. As an example of a solvent that can be used, there may be mentioned an aromatic hydrocarbon such as benzene or toluene; an aliphatic hydrocarbon such as hexane or petroleum ether, a halogenated hydrocarbon such as dichloromethane or chloroform.

The presence of a strong base may be essential in the case of reaction with slightly basic or sterically hindered amines. The above reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent.

Depending on the conditions used, the hydrolysis of an amide

derivative in which R ₃ represents a group, can

lead to a carboxylic acid or to esters

All the methods described above allow easy access to the 1,4-thiazane derivatives of the invention. However, the composition of the mixture of diastereoisomers obtained varies according to the process used. The fractionation of these mixtures of diastereoisomers is carried out conventionally in organic chemistry. Below are given detailed examples of the preparation of some derivatives of the invention. These examples are mainly intended to further illustrate the particular characteristics of the methods according to the invention.

Example No. 1. Acid 2,2-dimethyl-1,4-thiazane-3-carboxylic acid. 1º) S- (2-hydroxyethyl) -penicillamine. To a solution of 14.9 g (0.10 mole) of fine icillin in 75 ml of 2 N aqueous sodium hydroxide, maintained under an inert atmosphere (N ₂ ), a solution of dropwise is added, with good stirring. 17.5 g (0.14 mole) of 2-bromoethanol in 100 ml of ethanol. At the end of the addition, sufficient ethanol is added again to obtain a homogeneous medium and then the mixture is stirred at room temperature for 24 hours. After neutralization with concentrated hydrochloric acid, the majority of the alcohol is evaporated under reduced pressure and the volume is brought to 300 ml with water. The resulting solution is fixed on a column of resin of the Dowex 50 type, conditioned in acid form. The resin is washed with water and then eluted with 3 liters of 3N ammonia. The eluate is evaporated to dryness. 50 ml of water and 500 ml of ethanol are added to the residue. The solid is then filtered and recrystallized from 1 sopropanol. 9.0 g (47%) of white solid are thus obtained. Mp 148-150 ° C.

2) S- (2-chloroethyl) -penicinamine (hydrochloride).

A mixture of 9.0 g (47 mmol) of the above product and 350 ml of 38% hydrochloric acid is heated for 7 hours using a bath maintained at 95 ° C. It is evaporated to dryness under reduced pressure and the residue is recrystallized from 1 sopropanol. 8.9 g (78%) of homogeneous product in thin layer chromatography on silica (eluent: BuOH / AcOH / H ₂ O: 13: 3: 5) - Rf. 0.59.

3) 2,2-dimethyl-1,4-thiazane-3-carboxylic acid. 6.7 g (27 mmol) of the above chloride are dissolved in 450 ml of N, N-dimethylformamide then 50 ml of triethylamine are added before heating the mixture, for 2.5 h. by means of a bath maintained at 95 ° C. It is then evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of water and the solution is percolated on 250 ml of resin of the Dowex 50 type. It is washed with water and then eluted with 1.5 l of ammonia. The residue is concentrated under reduced pressure to a volume of 400 ml, the resulting solution then being treated overnight with 100 ml of resin of the Amberlite IRC 50 type conditioned in acid form. After filtration of the resin, the solution is concentrated to a volume of 30 ml. The crystals which have appeared are filtered and redissolved in 10 ml of water. The progressive addition of 40 ml of acetone causes the reprecipitation of the final product. Weight: 3.1 g (66%). Mp 320 ° C (dec).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure. Elementary analysis: C H N% ca l culated 48.0 7.5 8.0

% found 47.9 7.4 7.9

Example No. 2. 2,2,5- (R, S) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid. 1 °) S-allylpênicillamine.

To a suspension of 7.5 g (50 mmol) of laminated penicil in 50 ml of ethanol, a solution of 6.6 g (4.1 ml; 55 mmol) of allyl bromide in 50 is added slowly and simultaneously. ml ethanol and 35 ml soda aqueous 2 N, keeping the temperature of the medium below 20 ° C. At the end of the addition, the mixture is still stirred for approximately 2 hours, checking the disappearance of the starting thiol (thin layer of silica; eluent BuOH / AcOH / H ₂ O 12: 3: 5; revelation with ninhydrin).

The solution is neutralized by means of concentrated hydrochloric acid and then it is concentrated until a solid appears. The volume is brought to 300 ml with water and the solution obtained is percolated on a column of resin of the sulfonic type (Amberlite IR 120) conditioned in acid form. The resin is washed with water and then eluted with 1 l of 1 N ammonia. The eluate is evaporated to dryness and the solid res i of e l is recrystallized from isopropanol. 7.8 g (82%) of product are thus obtained. M. 182-184 ° C.

2) S- (2-bromopropyl) -penicillamine - hydrobromide.

The product from the previous step (7.8 g; 41 mmol) is added with stirring to 300 ml of a 40% solution of hydrobromic acid in acetic acid. After 3 days of stirring, the reaction medium is evaporated to dryness under reduced pressure. The residue is then stirred in ether and filtered. The resulting solid is used as is in the next step. Weight: 14.2 g (99%). Mp 106-108 ° C.

3) 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid. The above product (14.2 g; 40 mmol) is added to 500 ml of DMF containing 50 ml of triethylamine. The mixture is heated for 2.5 hours in a water bath maintained at 90 ° C; then evaporated to dryness under reduced pressure. The residue is dissolved in 400 ml of water and the solution is percolated on 500 g of sulfonic resin (Amberlite IR 120) packaged in acid form. The resin is washed with 2 l of water; then eluted with 2 1 of 1N ammonia. The eluate is evaporated to dryness under reduced pressure and the residue, dissolved in 500 ml of water, is stirred with 50 ml of carboxylic resin (Amberlite IRC 50) packaged in the form acid. It is filtered, then the aqueous phase is evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of a 2: 1 mixture of aceton and water and the solution is placed in the fridge. After 3 days, the crystals which have appeared are filtered. After washing with acetone and drying, 3.7 g (45%) of product are thus obtained. M. 290 ° C (dec). The IR, NMR and mass spectra confirm the structure of the cyclized product.

The Karl-Fisher analysis indicates the presence of 8.7% water. Elementary analysis: C H N

% calculated 46.4 8.3 6.8% found 46.1 8.5 6.4

The product appears homogeneous when examined by chromatography on a thin layer of silica, after elution using a butanol / acetic acid / water mixture 12: 3: 5. After silylation, chromatography in the vapor phase reveals however the presence two epimers in equal proportions.

Example No. 3. 2,2,5- (S) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid, 1- (R, S) -oxide. The recrystallization mother liquors and the acetone for washing the product of the previous example, carefully stored, are evaporated to dryness under reduced pressure. The residual white solid is recrystallized from ethyl acetate. The resulting solid is then triturated in acetone and then recrystallized from a mixture of acetone. and water. This gives 0.57 g (7% relative to the hydrobromide of S (2-bromopropyl) -penicillamine) of the acid 2,2,5- (S) -trimethyl-1,4-thiazane-3- (S) -carboxylic 98% enriched.

M. 328 ° C (dec.).

[α] _D ²⁰ = 131 ° (C = 0.5; water)

Ana l yse é l éme nta i re H N

% ca l cu l é 50 .8 7.8 7.4% found 50. 5 8.0 7.7

The above sulfide is dissolved in 10 ml of acetic acid to which 0.4 ml of 30% hydrogen peroxide is added. The mixture is stirred for 24 hours at room temperature then is concentrated under reduced pressure until a syrup is obtained. 25 ml of acetone are added and the mixture is stored overnight at 5 ° C. The crystalline balance is filtered and redissolved in 10 ml of water. The solution is concentrated until a syrup is obtained. The above treatment is repeated and then provides 0.29 g (47%) of white solid consisting of a mixture of two epimeric sulfoxides.

Mp 230 ° C (dec).

The I.R. spectra of R.M.N. and mass are in agreement with the expected structure.

The Karl-Fisher analysis indicates the presence of 2.2% of water. Elementary analysis: C H N

% calculated 45.8 7.5 6.7% found 45.6 7.4 6.9

Example No. 4. 2,2,5- (R) -trimethyl-1,4-thiazane- 3- (S) -carboxylic acid. To a suspension of 5 g (33.6 mmol) of D-penicillamine in 28 ml of water, 3.25 ml (40.3 mmol) of freshly redistilled chl oroacetone is added, with stirring. When the medium has become homogeneous, the reactor is immersed in an ice bath. A 20% aqueous sodium hydroxide solution is then added dropwise to pH 5.3, without the temperature exceeding 10 ° C, then dropwise and ensuring that the temperature does not exceed 30 ° C , a solution of 1 g (26.4 mmol) of sodium borohydride in 5 ml of basified water. At the end of the addition, the mixture is stirred for an additional hour at room temperature. 37% aqueous hydrochloric acid is then added slowly until pH 5.0. The final medium is evaporated to dryness under reduced pressure and the residue is added with 50 ml of absolute ethanol. The insoluble material is filtered and the filtrate is evaporated to dryness under reduced pressure. The residual colorless oil is redissolved in 10 ml of water. Evaporated to dryness under reduced pressure. The resulting white solid is mixed with 10 ml of water and the mixture is heated to reflux until dissolved. The solution is left to crystallize by storage for 4 h at room temperature and then overnight at 5 ° C. The solid is filtered and dried. Weight: 4.3 g (20.7 mmol; 62%). Mp 310 ° C (dec). [α] _D ²⁰ = + 93 ° (C = water).

The Karl-Fîsher analysis indicates the presence of 8.7% of water. The spectra I.R., from R.M.N. and mass are in agreement with the expected structure. The HPLC analysis testifies to the homogeneity of the final product.

Elementary analysis: C H N

% calculated 46.4 8.3 6.8% found 46.3 8.3 6.9 Analysis in a thin layer of silica, the product has an R _F of 0.69 after elution with a methanol / acetic acid / chloroform 6: 1: 4 mixture. Example No. 5. 2,2,5- (R) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid, 1- (R) -oxide. A solution of 3.5 g (16.7 mmol) of the product of the preceding example is produced in 17 ml of an acetic acid / water mixture 1: 1 and then it is cooled in an ice bath. 1.94 ml of 30% hydrogen peroxide are added dropwise with stirring over 5 minutes. At the end of the addition, the mixture is stirred for 8 hours, maintaining the cooling bath, then for 10 hours, at ambient temperature. It is evaporated to dryness under reduced pressure, at a temperature not exceeding 60 ° C. The residual oil is dissolved in 10 ml of water and the solution is evaporated to dryness under reduced pressure. The operation is repeated until a solid is obtained. This is then dissolved in 6 ml of water. 15 ml of acetone are added slowly, with stirring. The mixture is stirred for 1 hour at room temperature and filtered. A first jet of the desired sulfoxide is thus obtained. A second jet is obtained by cooling the mother liquors to 10 ° C., by adding 10 ml of acetone and then filtering after 15 minutes of crystallization. Total weight: 2.2 g (9.9 mmol; 59%). Mp 246 ° C (dec). [α] _D ²⁰ = -3.5 ° (C = 1; HCl 1 N). The IR, NMR and mass spectra are in agreement with the expected structure.

Analysis of the corresponding hydrochloride by the X-ray method confirms the absolute structure. The Karl-Fisher analysis indicates the presence of 8.2% of water. Elementary analysis: C H N% calculated 43.0 7.7 6.3

% found 43.2 7.6 6.4 Examined in a thin layer of silica, the product has an Rp of 0.42 after elution with a methanol / acetic acid / chloroform 6: 1: 4 mixture. HPLC analysis confirms the homogeneity of the product. Example No. 6. 2,2,5- (R) -trimethyl-1,4-thiazide-3- (S) -carboxylic acid, 1- (S) -oxide (hydrochloride) acid. The mother liquors of crystallization of the second jet of the product of the previous example, carefully preserved, are evaporated to dryness under reduced pressure. The residue, which weighs 1.3 g, is dissolved in 10 ml of water which is brought to pH 1 using 37% aqueous hydrochloric acid. The solution is concentrated until a wet weight of 3.0 g is obtained and this residue is stored overnight at 5 ° C. The solid is filtered, which has a rotary power of 79 ° in water. The crystals are dissolved in 10 ml of water and evaporated under reduced pressure until a syrup is obtained. 1.5 ml of acetone are added and the mixture is stored overnight at 5 ° C. We filter. The rotary power of the solid is 84 °. A new crystallization operation provides a product of sufficient purity. Weight: 0.22 g (0.9 mmol; 5% relative to the product of Example No. 4 used). M. 275 ° C.

[α] _D ²⁰ = + 85 ° (C = 1; water) + 73 ° (C = 1; HCl 1 N). The IR, NMR and mass spectra are in agreement with the expected structure.

Karl-Fisher analysis indicates the presence of 0.5% water. Elementary analysis: C H N

% calculated 39.8 6.7 5.8

% found 39.8 6.7 5.9

HPLC analysis indicates a purity of 99.5%.

Example No. 7. 2,2,5- (R) -trimethyl-1,4-thiazide-3- (S) -carboxylic acid, 1,1-dioxide.

5 g (22.4 mmol) of the product of Example 5 are dissolved in 300 ml of 0.5 N aqueous sulfuric acid. A solution of 2.5 g of potassium permanganate in 300 ml of water. At the end of the addition, the mixture is stirred for 2 h at room temperature, then added 12 ml of formic acid. Filtered, and then 1 is added ^"aqueous barium hydroxide 0.5N until the end of the precipitation. Was filtered and pass the filtrate through an ion exchange resin column of strong acid-type, packaged in the form

The resin is washed until the effluent is neutral and then eluted with 3 N ammonia. The eluate is concentrated under reduced pressure, until a volume of approximately 100 ml is obtained. The resulting ammonium salt solution is then percolated on a column of resin of the weak acid type. The filtrate is evaporated under reduced pressure until a syrup is obtained to which 15 ml of acetone are added. The mixture is stirred for 2 hours and then filtered. Weight: 2.7 g (11.6 mmol; 52%). Mp 232 ° C (dec).

[α] _D ²⁰ = + 2 ° (C = 1; HCl 1 N).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure.

Karl-Fisher analysis indicates the presence of 6.2% water. Elementary analysis: C H N

% calculated 40.7 7.1 5.9% found 40.7 7.3 5.9 Examined in a thin layer of silica, the product has an R _F of 0.38 after elution with a butanol / acetic acid / water mixture 5: 2: 3.

Example No. 8. 5-methyl-1,4-thiazane-3-carboxylic acid, hydantoin. 3.9 g (24.0 mmol) of 5-methyl-1,4-thiazide-3-carboxylic acid and 2.3 g (28.8 mmol) of potassium isocyanate are successively added to 25 ml of 'water. The mixture is heated to boiling and then brought to room temperature. The solution of 5-methyl-4-ureido-1,4-thiazane-3-carboxylic acid thus obtained is then added with 34 ml of 10% aqueous hydrochloric acid. It is concentrated under reduced pressure to a volume of approximately 20 ml. The mixture is stirred for 1 hour at room temperature and then filtered. The solid is finally recrystallized from water. Weight: 2.5 g (13.4 mmol; 56%).

F. 189 ^β C (dec).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure.

Elementary analysis: C H N

% calculated 45.2 5.4 15.0% found 44.9 5.5 15.1

Example No. 9. 1-Ethoxycarbonylethyl, 1-oxide (oxalate) 2,2,5-trimethyl-1,4-thiazane-3-carboxylate. A solution of 3.7 g (17.4 mmol) of the product of Example No. 5 in 37 ml of water is added with a 0.5 N solution of aqueous potassium hydroxide, until the pH reaches a value of 9. The resulting solution is evaporated to dryness under reduced pressure. The residue is suspended in 40 ml of DMF. Then added dropwise, 3.2 g (17.6 mmol) of ethyl 2-bromopropιonate. The medium is stirred for 48 hours at room temperature then is diluted with 100 ml of water before being extracted with chloroform. The organic extract is dried and then evaporated to dryness under reduced pressure. The residual oil is taken up in 50 ml of ethanol and is then added with a solution of 1.6 g (17.6 mmol) of oxalic acid in the minimum of the same solvent. The mixture is stirred for 30 minutes and filtered. The solid thus obtained is recrystallized from ethanol. 4.3 g (10.5 mmol; 64%) of pure product are obtained. M. 196 ° C (dec).

The IR, NMR and mass spectra are in agreement with the expected structure. The Karl-FîsFer analysis indicates the presence of 3.1% water. Elementary analysis CHN

% calculated 44.1 6.5 3.4

% found 44.1 6.7 3.3

Chromatographed in a thin layer of silica, the product has an Rp of 0.52 after elution using a butanol / acetic acid / water mixture 5: 2: 3.

Example No. 10. 1, 5-valoyloxyethyl, 1-oxide (oxalate) 2,2,5-trimethyl-1,4-thiazide-3-carboxylate. A solution of 3.7 g (16.4 mmol) of product of Example No. 5 in 37 ml of water is added with a 0.5 N solution of aqueous potassium hydroxide, until the pH reaches the value of 9. The resulting solution is evaporated to dryness under reduced pressure. The residue is suspended in 40 ml of DMF. 2.9 g (17.6 mmol) of 1-chloroethyl pivalate are added dropwise and with good stirring. At the end of the addition, stirring is continued for 48 h at 40 ° C. The resulting medium is diluted with 100 ml of water and is then extracted with chloroform. The organic extract is dried and then evaporated to dryness under reduced pressure. 50 ml of ethanol are added to the residue, followed by a solution of 1.6 g (17.6 mmol) of oxalic acid in the minimum of the same solvent. The mixture is stirred for 30 minutes and then the precipitate which has formed is filtered. This is finally purified by recrystallization from ethanol. 4.2 g (9.9 mmol; 60%) of white crystalline solid are obtained. Mp 214 ° C (dec).

The I.R., R.M.N and mass spectra are in agreement with the expected structure. Elementary analysis: C H N

% calculated 48.2 6.9 3.3% found 48.1 7.2 3.2

Chromatography in a thin layer of silica, the product has an R _F of 0.65 after elution using a butanol / acetic acid / water mixture 5: 2: 3.

Example No. 11. Methyl 2,2,5-trimethyl-1,4-thiazane-3-carboxylate (hydrochloride).

A solution of 32.2 g of potassium hydroxide in 640 ml of methanol is cooled to 0-5 ° C. 47.9 g (0.24 mole) of hydrochloride of the methyl ester of penicillamine are added, then dropwise, 25.0 g of chloroacetone. The mixture is stirred for 1 hour at the initial temperature and then the medium is brought to pH 6.5 using ethanolic hydrochloric acid. 6.2 g of sodium borohydride are then added in small portions. At the end of the addition, the mixture is stirred for an additional 1 hour, always at the same temperature. The excess hydride is destroyed by adding concentrated hydrochloric acid and then the solution is neutralized with 1% aqueous hydrogen carbonate. The aqueous solution is extracted with chloroform. The extracts are dried and then evaporated to dryness under reduced pressure. The residual oil is dissolved in a mixture consisting of 50 ml of methanol and 350 ml of ether. The addition of hydrochloric acid in saturated solution in ether causes the precipitation of a solid hydrochloride. This is filtered and reprépcipitë twice from its methanol solution by addition of ether. Weight: 17.2 g (30%). Mp 204 ° C (dec).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure. Elementary analysis: C H N

% calculated 45.1 7.6 5.8% found 45.1 7.7 5.8 Example No. 12. 2,2,4,5-Tetramethyl-1,4-thiazane-3-carboxylic acid. 1.68 g (20 mmol) of sodium bicarbonate and 1.5 g (0.66 ml; 10.5 mmol) of methyl iodide are successively added to a solution of 2.1 g (10 mmol) of 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid in 50 ml of methanol. The resulting medium is stirred at room temperature for 24 hours and then heated to reflux temperature for the same period of time. It is evaporated to dryness under reduced pressure and the residue is taken up in 100 ml of water. The solution thus obtained is passed over a column of ion-exchange resin of the strong acid type, packaged in H® form. The resin is washed with water until the effluent is neutral and is then eluted with 1N ammonia. The eluate is evaporated to dryness under reduced pressure. The residual white solid is recrystallized from ethyl acetate. 1.4 g (6.8 mmol; 68%) of pure product are thus obtained. M.201 ° C (dec). The IR, NMR and mass spectra are in agreement with the expected structure.

Elemental analysis: CHN% calculated 53.2 8.4 6.9% found 52.8 8.5 7.0 Chromatographed in a thin layer of silica, the product has an R _F of 0.60 after elution with methanol.

Example No. 13. 5-n acid. butyl-2,2-dimethyl-1,4-tiazane¬

3-carboxylic acid (hydrochloride). 7.5 g (50 mmol) of D-penicillamine are added to 40 ml of water maintained at a temperature between 0 and 5 ° C. With good stirring, 9.5 g (53 mmol) of 1-bromo-2-hexanone are added dropwise and simultaneously on the one hand, in approximately 10 minutes, and on the other hand, 25 ml (50 mmol) ) 2 N aqueous sodium hydroxide, in 30 minutes about. At the end of the addition, the stirring and the temperature are maintained for an additional 1 hour, then the temperature is adjusted to approximately 15 ° C. 50 ml of methanol are added and then slowly a solution of 1.5 g (39 mmol) of sodium borohydride in 9 ml of basified water. The medium is allowed to return to room temperature and then extracted with chloroform. The organic extract is dried and then evaporated to dryness under reduced pressure. The residual red oil is taken up in 50 ml of isopropyl ether to which sufficient ethanol is added to obtain a solution. Then hydrochloric ether is added until the end of precipitation and then enough ethanol so that the red-brown mass gives a beige solid. Filtered, washed with isopropyl ether and dissolved hot in ethanol. Ethyl ether is added until persistent cloudiness and then allowed to cool. The crystals are collected and purified a second time. Weight: 8.0 g (30 mmol; 60%). Mp 225 ° C (dec).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure.

Elementary analysis: C H N

% calculated 49.3 8.3 5.2% found 49.5 8.2 5.5

Chromatographed the silica in a thin layer, the product has an R _F of 0.62, after elution with a butanol / acetic acid / water mixture 5: 2: 3.

Example No. 14. 5-Methyl-2-phenyl-1,4-thiazane-3-carboxylic acid (hydrochloride). 1 g (4.3 mmol) of threo-β-phenyl cystene hydrochloride is dissolved in 12 ml of water. The solution is cooled in an ice bath and then the pH is brought to 7.0 using 20% aqueous sodium hydroxide. 0.42 g (4.5 mmol) is added of freshly redistilled chloroacetone. After stabilization of the pH for 30 minutes, 2N aqueous sodium hydroxide is added until neutral. Stirring is continued for 1 hour still in an ice bath, then a solution of 0.13 g (3.4 mmol) of sodium borohydride in 2 ml of basic water is added. A colorless and clear solution is obtained, the pH of which is 9.1. The mixture is stirred for 1 hour, leaving to return to room temperature. The pH is brought to 6.0 using aqueous hydrochloric acid at 37%. It is evaporated to dryness under reduced pressure. The suitably dried residue is taken up in 10 ml of ethanol to which 2 ml of 22% ethanolic hydrochloric acid are added. The mixture is stirred for 15 minutes and then evaporated to dryness under reduced pressure. The residue is recrystallized twice from a 4: 1 isopropanol / ethanol mixture. Weight: 0.66 g (2.4 mmol; 56%). Mp 248 ° C (dec).

The spectra I.R., from R.M.N. and mass are in agreement with the expected structure. Elementary analysis: C H N

% calculated 52.6 5.9 5.1% found 52.3 5.9 5.4

Example No. 15. 2,2,5- (R) -trimethyl-1,4-thiazane-3- (S) -carboxylic acid, 1- (R) -oxide.

(without isolation of intermediary). To a suspension of 10 g (67 mmol) of (D) -pë n icil lamine in 56 ml of water at room temperature, 7.4 g (80 mmol) of freshly distilled chloroetone are added with good stirring. After 2 h of reaction, 20% aqueous sodium hydroxide is added until pH 5.3 (temperature ≤ 20 ° C). A solution of 2 g (50 mmol) of sodium borohydride in 10 ml of water is added dropwise to the reaction medium (temperature ≤ 30 ° C). After 1 hour of reaction, the solution is acidified by adding 50 ml of acetic acid. The reaction medium is cooled (0 ° C ≤ temperature ≤ 5 ° C) and 2.4 g (0.74 mole) of 30% hydrogen peroxide is added dropwise to it. The temperature is maintained between 0 ° C and 5 ° C for 8 hours and then at 20 ° C for 4 hours.

It is concentrated under reduced pressure. The residue is taken up in 40 ml of ethanol; the suspension is filtered and the ethanolic solution is added with good stirring to 240 ml of ethyl acetate. It is left to crystallize at 20 ° C. for 1 hour. The precipitate is drained and washed with acetone. The crude amino acid is crystallized from a H ₂ O / acetone mixture 1: 4. 7.4 g (33.3 mmol; 54%) of a white crystalline solid identical to the product of Example 5 are thus obtained.

Table I given below groups the derivatives of the above examples as well as other derivatives of the invention prepared according to the above processes.

(1): it is most often a decomposition temperature. The value entered corresponds to the start of the phenomenon.

(2): all the products mentioned give a C.H.N. correct,

(3): hydrated product,

(4): hydrochloride.

(5): free base or zwitterion.

(6): oxalate.

(7): mixture of isomers whose components, separated, appear further in the table,

(8): configuration of the asymmetry centers: l- (R) -3- (S) -5- (R).

(9): configuration of asymmetry centers: l- (S) -3- (S) -5- (R).

(10): configuration of asymmetry centers: l- (R) -3- (S) -5- (R)

(11): configuration of asymmetry centers:

3- (S) -5- (S).

(12): configuration of asymmetry centers:

1- (R, S) -3- (S) -5- (S).

(13): pht means 3-phthalidyl.

(14): pyr signified 2, 5-dioxo-1-pyrrol idinyl.

(15): configuration of asymmetry centers:

3- (R) -5- (S).

(16): configuration of asymmetry centers:

1- (S) -3- (R) -5- (S).

(17): configuration of asymmetry centers:

3- (S) -5- (R).

(18): hemi-chl orhydrate. The products of the invention were subjected to a series of pharmacological tests, the methodology of which is described below. The results of these tests are shown in Table II in which the numbers in the first column correspond to the numbers in the first column in Table I.

The LD ₅₀ are calculated according to the method of Lichtfîeld and Wîlcoxon (J. Pharmacol. Exp. Ther. £ 6, 99, 1949) and expressed in mg / kg. The products are administered orally to mice.

The effect on behavior is studied using a method derived from that of S. Irwîn (Gordon Res. Conf. On Médicinal Chem., 133, 1959). The substances, suspended in a mucilage containing 1% of tragacanth, are administered orally by means of an intragastric probe to groups of 5 male mice (CDl, Charles River strains, fasting for 18 hours), The doses tested depending on the activity observed range from 3000 to 3 mg / kg.

Behavior is studied 2, 4, 6 and 24 hours after treatment. Observation is extended if symptoms persist at this time. Mortalities are recorded during the 14 days following treatment.

None of the products tested induced abnormal behavior in the mouse or proved to be toxic.

Determine the effect on fibrinolytic activity on bleeding time and on blood loss.

The test substance, suspended in a mucilage containing 1% of tragacanth, is administered to rats orally at a dose of 30 mg / kg. Blood is taken 1 hour or 3 hours after treatment. The plasma is separated by centrifugation and the euglobulins are precipitated.

The fibrinolytic activity is determined according to the method of Astrup and Mullertz (Arch. Biochem. Biophys. 1952, 40, 346).

50 μl of a solution of eugl obulins in a vëronal buffer containing 0.25% of gelatin are deposited on 0.08% fibrin plates. After an 18 hour incubation at 37 ° C, the diameter of the lysis zone is measured.

A score is assigned according to the ratio of fibrinolytic activity of the treated rats and that of the rats having received a placebo. The meaning is as follows: Score 4: coefficient of increase in fibrinolytic activity from 0.51 to 0.99. Score 5: coefficient of increase in fibrinolytic activity from 1 to 1.5.

Score 6: coefficient of increase in fibrinolytic activity from 1.6 to 2. Score 7: coefficient of increase in fibrinolytic activity from 2.1 to 2.5. Score 8: coefficient of increase in fibrinolytic activity from 2.6 to 3. Score 9: coefficient of increase in fibrinolytic activity •> 3.1. To determine the bleeding time, the tail of the rats, maintained at room temperature for 2 hours, is cleaned with ether and incised with a scalpel 2 mm from the end; bleeding time, expressed in seconds, is measured 1 hour or 3 hours after treatment.

The blood is collected on a filter paper. The amount of blood lost is determined by weighing the filter paper before and after the blood is collected.

The coefficient of increase in bleeding time is the ratio between the bleeding time of treated rats and that of rats given a placebo.

A score of 3 means an increase coefficient from 0.79 to 0.89.

A score of 4 means an increase coefficient of

0.9 to 1.09. A score of 5 means an increase coefficient from 1.1 to 1.11. A score of 6 means an increase coefficient of

1.12 to 1.22. A score of 7 means an increase coefficient of

1.23 to 1.33. A score of 8 means an increase coefficient from 1.34 to 1.44.

A score of 9 means an increase coefficient ≥ 1.45.

The coefficient of increase in blood loss is the ratio between the amount of blood lost by the treated rats and that lost by the control rats. A score of 3 means an increase coefficient ≤ 0.5 A score of 4 means an increase coefficient of

0.51 to 0.99. A score of 5 means an increase coefficient of

1 to 1.5. A score of 6 means an increase coefficient of

1.6 to 2. A score of 7 means an increase coefficient of

2.1 to 2.5. A score of 8 means an increase coefficient of

2.6 to 3. A score of 9 means an increase coefficient ≥ 3.1.

Two products of the invention were the subject of a more in-depth evaluation: these are derivative 7 and derivative 12 (free base of derivative 7 in hydrated form).

Compound 7 was the subject of a 1 month toxicity study in rats and monkeys. This study has shown that its tolerance is perfect up to the dose of 300 mg / kg / day.

The toxicity of compound 12 is excellent: the LD ₅₀ is greater than 8 g / kg in mice and in rats. In monkeys, it is perfectly tolerated up to the dose of 800 mg / kg.

After oral administration of derivative 7 to groups of 4 rabbits at doses of 2.5 to 50 mg / kg, an increase in the fibrinolytic activity of the blood is observed proportional to the dose administered. This increase is, for example, 3 times, 90 minutes after the administration of 5 mg / kg. This effect manifests itself with repeated administrations; thus, treatment with 10 mg / kg, 2 times a day for 21 days raised the fibrinolytic activity of the blood to a value 3 times higher than that of the controls.

As an intravenous infusion of derivative 12 at doses of 3 or 5 mg / kg / 10 min. for 2 hours, a 2.8-fold increase in fibrinolytic activity is observed from 10 to 30 minutes after the start of the infusion until at least 3 hours after the end of the infusion.

The activity of compound 12 has also been demonstrated in rats and monkeys, after oral administration. Finally, in humans, oral administration of 100 to 800 mg causes an increase, proportional to the dose, of the fibrinolytic activity of the blood.

For the administration of the new compounds of the invention, the daily dose will be from 50 mg to 2 g orally and from 10 mg to 1 g by injection or by intravenous infusion.

The products of the invention can be used in various pharmaceutical forms. The examples which follow are not limiting and relate to the galenical formulations containing an active product of the invention designated by the letter A and which can be, for example:

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide.

- 2,2,5-trimethyl-1,4-thiazane-3-ethyl carboxylate, 1-oxide. - 2,2,4,5-tetramethyl-1,4-thiazide-3-carboxylic acid.

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (pivaloyl oxy) ethyl, 1-oxide.

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of (octyloxycarbonyl) methyl, 1-oxide. - 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (etyloxycarbonyl) ethyl, 1-oxide. - a-cide 5-butyl-2,2-dimethyl-1,4-thiazane-3-carboxylic

- 2,2-dimethyl-5-isopropyl-1,4-thiazane-3-carboxylic acid.

- 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid.

- ethyl 3-carboxy-2,2-dimethyl-1,4-thiazane-5-acetate,

Capsules

50 mg

Starch Sta RX 100 mg Microcrystalline cellulose 60 mg Lactose extra fine, crystals 132 mg Colloidal silica 2 mg Hydrogenated castor oil 6 mg

100 mg

Bicalcium phosphate 95 mg Starch sodium glycolate 32.5 mg Colloidal silica 2 mg Magnesium stearate 0.5 mg

Tablets

At 500 mg

Mannitol 95 mg

Polyvi nyl pyrrol idone 27 mg

Polyethylene glycol 6000, powder 8 mg

At 300 mg

Starch 60 mg

Lactose 130 mg

Ethylcellulose low viscosity 20 mg

Talc 5 mg

Aerosil 5 mg Suppository.

A 500 mg α-tocophërol 10 mg

Witepsol H 15 (semi-glyceride) 2600 mg

Injectable solutions.

At 20 mg

Sodium chloride 2.5 mg

Citric acid / sodium citrate buffer ad pH 4.8 water for injectables ad 1 ml.

50 mg

Propylene glycol 300 mg Ethyl alcohol 50 mg water for injectables ad 1 ml

Capsule containing 100 mg of compound A and 300 mg of acetylsal icylic acid. A 100 mg acetylsalicylic acid 300 mg ethylcellulose 60 mg lactose 40 mg aerosil 8 mg magnesia stearate 8 mg

Tablet containing 300 mg of compound A and 50 mg of dipyridamol

A 300 mg dipyridamol 50 mg hypromellose 25 mg starch 100 mg calcium stearate 8 mg Tablet containing 200 mg of compound A and 100 mg of suloctidil

A 200 mg suloctidil 100 mg tween 80 8 mg ethylcellulose 22 mg lactose 40 mg starch 71 mg magnesia stearate 9 mg

Claims

CLAIMS.

1. Derivative of 1,4-thiazane-3-carboxylic acid of general formula I

in which: R ₁ and R ₂ , which may be the same or different, represent hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ or a phenyl ring, optionally substituted by a d atom halogen such as fluorine, chlorine or bromine, a linear or branched alkyl radical C _1, C _2, C ₃ or C ₄ or a linear alkoxy or branched C _1, C _2, C ₃ or C _4, R ₁ and R ₂ can form, with the neighboring carbon atom, a cycloalkyl of 3, 4, 5, 6, 7 or 8 carbon atoms of which one or more carbon atoms may optionally be replaced by a sulfur atom, d oxygen or by a group SO, SO ₂ or NR ₈ in which R ₈ represents hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ , a phenyl ring or a benzyl group.

Rg represents:

- a hydroxyl group

- A group OR ₉ in which R ₉ represents a linear or branched C ₁ , C ₂ alkyl group. C ₃ , C _4, C ₅ , C ₆ , C _7,

C ₈ , C _9, C ₁₀ , C ₁₁ , C ₁₂ OR a group or a

group in which R _1Q re pre s in te of hydro

gene or an alkyl radical C ₁ , or C ₂ and R ₁₁ represents a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ , C ₁₂ ,

- a group in which R ₁₂ and R1 ₁ 13 _3, which can

be the same or different, represent hydrogen, a linear or branched C ₁ , C ₂ , C ₃ alkyl radical or

a 3-phthalidyloxy group or a 1- (2,5-dioxopyrrolidinyl) -1-ethoxy group,

R ₄ represents a hydrogen atom, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ , a linear or branched acyl group C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ or a CONH ₂ group,

R ₃ and R ₄ can form with the neighboring carbon and nitrogen atoms a hydantoin ring,

R ₅ and R ₆ , which may be the same or different, represent hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ , a possible phenyl nucleus! ement _^ substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ or by a linear or branched alkoxy radical C _1, C ₂ , C ₃ or C _4, a CH ₂ COOR _{14 group} in which R ₁₄ represents hydrogen, a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ ,

R ₇ represents hydrogen, a linear or branched C ₁ , C ₂ , C ₃ or C ₄ alkyl radical, a gem radical. dimethyl or a phenyl ring optionally substituted by a halogen atom such as fluorine, chlorine or bromine, by a linear or branched alkyl radical C ₁ , C ₂ , C ₃ or C ₄ or by a linear or branched alkoxy radical C ₁ , C ₂ , C ₃ or C ₄ , n can have the values 0, 1 or 2, if R ₁ , R ₂ , R ₄ and R ₇ represent hydrogen and if R ₃ represents a hydroxyl group or a linear or branched alkyl radical C ₁ - C ₄ ,

R ₅ and R ₆ do not represent hydrogen, a linear or branched C ₁ - C ₄ alkyl radical or a phenyl ring, as well as the salts of these compounds formed with pharmaceutically usable acids and bases.

2. Derivative according to claim 1, characterized in that, in the general formula I, R ₁ - and R ₂ which may be identical or different, represent hydrogen or a methyl group.

3. Derivative according to either of the claims

1 or 2, characterized in that, in the general formula I, Rg represents a hydroxyl group, a group OR ₉ in which R ₉ represents a linear or branched C ₁ -C ₄ alkyl radical, an OCH-COOR- _{j group} , or an OCHOCOR group ^

^R 10 ^R 10 in which R ₁₀ represents hydrogen or a methyl radical and R ₁₁ represents a linear or branched C ₁ - C ₈ alkyl radical.

4. Derivative according to any one of claims 1 to 3, characterized in that, in the general formula I, R ₄ represents hydrogen or a methyl radical.

5. Drift according to any one of claims 1 to 4, characterized in that, in the general formula I, R ₅ and R ₆ , which may be identical or different, represent hydrogen, a linear or branched alkyl group C ₁ - C ₄ or a CH ₂ COOR _{14 group} in which R ₁₄ represents hydrogen or a C ₁ - C ₄ alkyl group.

6. Derivative according to claim 5, characterized in that, in the general formula I, R ₅ represents hydrogen and R ₆ represents a linear or branched C ₁ -C ₄ alkyl group

7. Derivative according to any one of claims 1 to 6, characterized in that, in the general formula I, n has the values 0 or 1.

8. A derivative according to claim 1, characterized in that it is chosen from the group formed by the compounds:

- 2, 2,5-trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide,

- ethyl 2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 1-oxide,

- 2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid,

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (pivaloyloxy) ethyl, 1-oxide,

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of (octyloxycarbonyl) methyl, 1-oxide,

- 2,2,5-trimethyl-1,4-thiazane-3-carboxylate of 1- (ethyloxycarbonyl) ethyl, 1-oxide,

- 5-butyl-2,2-dimethyl-1,4-thiazane-3-carboxylic acid,

- 2,2-dimethyl-5-isopropyl-1,4-thiazane-3-carboxylic acid,

- 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid,

- 3-carboxy-2,2, -dimethyl-1,4-thiazane-5-ethyl acetate

9. Intermediate products, in particular for the preparation of the derivatives according to any one of the preceding claims, corresponding to formulas II, III and VI:

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₅ R ₆ , R ₇ and n have the meanings given above.

10. Derivative as described above, in particular in the examples given in the description.

11. Process for the preparation of 1,4-thiazane-3-carboxylic acid derivatives and its salts, characterized in that a compound of formula II, of formula III or of compounds of formulas IV and V is cyclized, so as to obtain a comçosë corresponding to formula I:

in these formulas R ₁ to R ₇ and n have the meanings given above, the intermediate product resulting from the cyclization then being subjected to a reduction so as to obtain the derivative corresponding to formula I, the latter or the intermediate product, as well as the derivatives of formula I obtained from the compounds of formulas II and of formulas IV and V being optionally subjected to oxidation, alkylation or acylation by the substituent R ₄ , or a substitution of this substituent R ₄ by a group CONH ₂ followed by cyclization with the substituent R ₃ when the latter represents a hydroxyl group, so as to obtain a hydantoin group.

12. Method according to claim 11, characterized in that a derivative of formula is cyclized in basic medium

II

^" BURS-A WIPO

13. Method according to claim 12, characterized in that an organic or inorganic base is used such as, for example, triethylamine, N, N-dimethylanil ine, pyridine, alkali metal hydroxides or hydroxide ammonium.

14. Method according to claim 11, characterized in that a derivative of formula III is cyclized, in basic or dehydrating medium

in which X represents a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or an easily removable group such as, for example, a tosyl or mesyl group.

15. Method according to "claim 11, characterized in that a derivative of 5,6-dihydro-2H-thiazine VI

is reduced to 1,4-thiazane of formula I, optionally followed by oxidation to obtain the corresponding sulfoxide or sulfone.

16. The method of claim 15, characterized in that the derivative VI is prepared by reaction between a cysteine derivative IV

and an α-halogenone YCH -CORg in which Y represents

smells of a halogen atom such as chlorine, bromine or iodine.

17. Method according to claim 11, characterized in that, for the preparation of a derivative of formula I in which R ₄ represents a linear or branched alkyl radical C ₁ - C ₄ or linear or branched acyl C ₁ - C ₄ , an amine of formula I in which R ₄ is hydrogen is subjected to alkylation or acylation in basic medium by a reagent R ₄ Z in which Z represents a halogen atom such as chlorine, bromine or iodine or an easily removable group such as, for example, a tosyl or mesyl group.

18. Process according to claim 11, characterized in that, for the preparation of a derivative of formula I in which R ₄ represents a radical CONH ₂ , a derivative of formula I is reacted in which R ₄ represents hydrogen, with a reagent of formula MNCO in which M represents a monovalent cation such as sodium, potassium, lithium or ammonium ions.

19. The method of claim ll, characterized in that, for the preparation of a derivative of formula I, in which R ₃ and R ₄ form with the neighboring carbon and nitrogen atoms a hydantoin ring, a compound of formula I, in which Rg represents a hydroxyl group and R ₄ represents a group CONH ₂ , in an acid medium with optional heating.

20. Method according to claim 11, characterized in that, for the preparation of a derivative of formula I, in which n = 1 or 2, a derivative of formula I is treated where n = 0 with an oxidizing agent.

21. The method of claim 20, characterized in that the oxidation is carried out at any stage of the development of the 1,4-thiazane ring.

22. Method according to claim 11, characterized in that a derivative of formula I is transformed in which R ₃ represents a hydroxyl group in a derivative in the equel R ₃ represents a group OR ₉ ,

by es tëri fi cati on

23. The method of claim 11, characterized in that a derivative of formula I is transformed in which Rg represents a hydroxyl group, an OR ₉ group, or into a derivative in which R ₃ re

presents a group by amidation.

WHERE

24. The method of claim 11, characterized in that a derivative of formula I in which R ₃ represents an OR ₉ group, or is transformed

10

derivative in which R ₃ represents a hydroxyl group

or a group by hydrolysis or aminolysis.

25. The method of claim 11, characterized in that a derivative of formula I in which R ₃ represents

a group is transformed into a derivative in which

Rg represents a hydroxyl group or an OR ₉ group, or by hydrolysis or alcoholysis

26. Process for the preparation of 1,4-thiazane-3-carboxylic acid derivatives and its salts, as described above, in particular in the examples given in the description.

27. Pharmaceutical composition in particular for the treatment and prevention of certain affections of the circulatory system, such as venous or arterial thrombosis, characterized in that it comprises at least one of the compounds of formula I or one of its salts, associated with one of the appropriate pharmaceutical excipients or éveπtasllemient to other therapeutic agents such as anti-aggregating pi aquettaires.

28. Composition according to claim 27, characterized in that it is in the form of dragees, tablet granules, capsules, solutions, syrups, emulsions or suspensions containing conventional additives or excipients. in galenic pharmacy.

29. Compos i ti on according to claims 27 or 28, characterized in that it comprises at least one of the derivatives according to formula I in solution, in particular in sterile water or in peanut oil or ethyl oleate.

30. A method of using the derivatives according to formula I, in particular for the treatment and prevention of certain affections of the circulatory system, such as venous or arterial thromboses, characterized in that they are administered at daily doses of 50 mg to 2 g orally and 10 mg to 1 g by injection or intravenous infusion.