LU83327A1 - PROCESS FOR THE PREPARATION OF 1,4-THIAZINE DERIVATIVES, THEIR USE AND COMPOSITIONS CONTAINING SUCH DERIVATIVES - Google Patents

Description

I "! 1.

The subject of the present invention is derivatives of 1,4-thiazane 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 invention correspond to the general formula I: (0)

»N R

R7 / S \ / Kl 7 T ^ 2

! J R_ I

i 5 R5 r 0 4 in which: i Rj and R2j which may be the same or different, represent j of hydrogen, a linear or branched alkyl radical C ^, C2, C ^ or or a phenyl ring, R ^ and R2 may form with the neighboring carbon atom a 3 to 8-membered ring optionally interrupted by a sulfur or oxygen atom or by an SO, SO2 or NRg group in which Rg represents hydrogen, a linear alkyl radical or branched Cj, C2, C3 or; _, a phenyl ring or a benzyl group / I ^ Rg represents: I - a hydroxyl group - an ORg group in which RQ represents a linear or branched alkyl group Cj, C21 Cg,, Cg, Cg, Cy, Cg, Cg, C ^ q, C ^ j, C ^ »j or a group Q-CH-COÛRjj in which R ^ q represents * Ko j ej the hydrogenated or a methyl radical and represents a linear or branched alkyl radical Cj, C2, Cg,, Cg, Cg, Cy, Cg, Cg, CCC L10 'Lll' 12 / R12 î- - an N group in which R, 9 and Rn, which may be

\ n i - IO

K13 // identical or different, represent hydrogen, a jjj} linear or branched alkyl radical C., Zr C ^ or C. / $ J- C ô J.

2.

* · Represents an atony of hydrogen, a linear alkyl radical! or branched C2> C3, C ^, Cg, Cg, Cy, Cg or a group CONHg; j Rg and R ^ can form with the neighboring carbon and nitrogen atoms a hydantoin ring, Rg and Rg, which can be identical or different, represent hydrogen, a linear or branched alkyl radical Cj, C ^, C ^, C ^, Cg, Cg, Cy, Cg, Cg, Clg,

Ci j, Cj2 "a phenyl ring, a group C1 ^ COQRj ^ in which R ^ I represents a linear or branched alkyl radical Cj, C ^, Cg or C ^.

j Ry represents hydrogen, a linear or branched alkyl radical Cj, C ^, Cg or C ^.

| n can have the values 0, 1 or 2.

! If Rj, R2. R4 and Ry represent hydrogen and if Rg represents a hydroxyl group or a linear or branched C ^ -C ^ alkyl radical,

Rg and Rg do not represent hydrogen, a linear or branched C ^ -C ^ alkyl radical or a phenyl ring.

i; According to a particular form of the invention, this relates to the I compounds of formula I in which:

Rj and R2 <which may be the same or different, represent hydrogen, a linear or branched C ^ -C ^ alkyl radical.

'Rg represents a hydroxyl group R ^ j represents hydrogen, a group CONH25 R3 and R ^ can form with the neighboring carbon and nitrogen atoms a ring j hydantoin.

Rg represents hydrogen, a linear or branched alkyl group! . C1 "C4 \ Rfi and R? Which may be the same or different, represent hydrogen \ or a linear or branched alkyl radical C.-C.

! n can have the values 0 or 1.

I A preferred class of the compounds of formula I is that in which I Rj and R2 represent a methyl group

Rg represents a hydroxyl group R ^ 'represents hydrogen or forms with Rg and the neighboring carbon and nitrogen atoms a hydantoin ring Rg represents hydrogen, or a methyl group

Rg and R7 which may be the same or different, represent hydrogen; or a linear or branched C ^ -C ^ alkyl radical. 1

'n can have the values 0 or 1. J

Examples of compounds according to the invention are: I

f * ifl-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide // m -1 'hydantoin of 5-methyl-1,4-thiazane-3 acid -carboxylic // m 1 [fmi i. 1 3.

ί i-2,2-dimethyl-1,4-thiazane-3-carboxylic acid -1 '2,2-dimethyl-1,4-thiazane-3-carboxylic acid, l-oxide-acid 2 , 2,5-trimethyl-1,4-thiazane-3-carboxylic.

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

The most commonly used salts are addition salts of acids, in particular addition salts of non-toxic acids, pharmaceutically usable, formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic acids, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, 'maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, pan-thotene , sulfonic, sulfonic, cyclohexylaminosulfonic, stearic, al gi ni que, 'ß-hydroxypropioni que, ß-hydro-xybutyric, oxalic, malonic, gaiactarique, gaiacturonique. i These salts can also be derived from natural amino acids or i! not like lysine, glycine, arginine, ornithine, as paragine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, etc ...

i -, When R3 represents an OH group, the present invention also covers the salts formed between this carboxylic acid function and bases such as sodium hydroxide, potassium potassium, lithium, ammonium, magnesium, calcium as well as internal salts (zwitterions).

/ /

The compounds of formula I have at least one asymmetric carbon atom and therefore exist in the form of fl // 4 isomers.

optical or racemic; all these forms are part of the present invention. The optical isomers can be obtained by resolution of the racemates according to conventional methods, for example by formation of diastereoisomeric salts by the action of optically active acids, such as tartaric, diacetyltartaric, tartranic, dibenzoyltartaric, ditoiuoyltartric acid and separation of the mixture of diastereoisomers! for example by crystallization or chromatography, then released! ration of optically active bases from these salts. The optically active compounds of formula I can also be obtained using optically active starting materials.

: i

Thrombotic, arterial and venous disorders are currently a cause of mortality and especially of very significant 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 ; important therapeutic uses in greater safety conditions. Thus, the prevention of deep vein thrombosis j: J and their often fatal consequences of pulmonary embolism could be obtained by i. oral treatment administered before and in weeks j: following risky surgical procedures, u i; "! The prevention of thromboses complicating phlebitis of the veins, superficial, primary or secondary to periods of prolonged immobilization of the patients, can also be considered.

Finally, alone or in combination with substances inhibiting / adhesion and aggregation of blood platelets, the products.ij / of the intervention are indicated for the prevention of! $ i // .. 4 5.

! j,; Recurrent arterial or venous thrombotic accidents.

I We know, in fact, that in patients who have suffered dj I from a 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, unlike current fibrinolytic substances, since they are devoid of activity. enzymatic, are not immunogenic and act by the intermediary of activators normally present in the organism, it - Their use, alone or in association with substances ir! platelet inhibitors, allows a new,

It approaches the treatment and prevention of arterial and venous thrombosis.

! / - \ ί

S

u * 1 i • -j; ·}!

S

! , ίι; î i .if} "il - if • ï i! ... 6.

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 and one of i its esters with a pharmaceutical excipient. These compositions are presented so that they can be administered orally, rectally or parenterally.

5; Thus, for example, the compositions for administration by! - oral route 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 , polyvinylpyrrolidone, 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.

(| Emulsions and oily solutions are made in an oil | of vegetable or animal origin, and may contain emulsifying perfuming, dispersing, softening and anti-oxidant agents.

i -5 fi% ï | For parenteral administration, the vehicle used is

Yes

If sterile water, an aqueous solution of pol yvi nyl pyrrol idone, archid oil, ethyl oleate, etc ... These f aqueous or oily injectable solutions may contain / | j thickening, wetting, dispersing and gelling agents ^ / Ιί. t 7.

The compounds according to the invention are prepared according to methods which form part of the present invention and defined below. In cases where these processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which serve for their preparation, also form part of the present invention.

According to a first way of proceeding, a vinylthioether of formula II obtained according to the method described by A.I. Virtanen et al. in Acta Chem. Scand. 1966, 20, 1163-1185, is cyclized to derivative III according to the scheme: d R1 CORi (OVi Ri r2 ~ t / —-— (3 SC-CH-COR, / \ I K2NH-R4 - "f >>" - 5

C / / "* D

r / \ - R5 "7.R6 5 7 i R6 l · I„ ni! I R2 "R3> R4> R5> R5" Ry and n have been defined previously.

ï Cyclization is preferably carried out in basic medium 1. The base can be organic, such as triethylamine, pyridine, Η, Ν-dimethylaniline or mineral, for example, alkali metal hydroxides such as sodium or potassium hydroxide or ammonium hydroxide. .

j When the base used is an organic base, the solvent will be: preferably an inert organic solvent such as solvents: = chlorinated 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-dimethyl- <formamide or dimethylsulfoxide. When the base is mineral I, the solvent used will preferably be water f I and the concentration of the basic solution is 0.01 N at / y 10 h and aibntcgeuseent from 0.2 S to 2 K. // / v / 'Ö.

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 reactants or the products contain a preponderant stereoisomer which risks being isomerized if the conditions used are too harsh.

Another way of proceeding consists in carrying out a cyclization starting from a derivative of IV cysteine obtained according to the method described by J.F. Carson et al. in J ,. Org. Chem. 2 £, 2203 (1964), according to! diagram.

R, R, COR, n Y_i_ c, r r / '5or3 / \ 27 ~ \ (O) n-S v NHR /, _ / \! '\ I 4 - ^ (0) n - S n-R4 CH-C-Rr \ / R R "> - R7 R6. R7 R6 K5

IV III

In this scheme, Rj, R2, R3 »R '^, Rg, Rg, R7 and n have been defined above and X represents a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or a group easily removable such as, for example, a tosyle or mesyl group.

; If the cyclization takes place in a basic medium, the conditions described j ‘for the first process can be applied in the present case.

If the cyclization is carried out in an acid medium, then a mineral or organic acid is used such as hydrochloric acid, 1 'hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, formic acid, acetic acid.

I - 7 j i Dehydrating agents such as, for example, t can also be used.

! Phosphorus hemipentoxide, concentrated sulfuric acid, a carbon; diimide such as dicyclohexylcarbodiimide.

These reactions are generally carried out in organic solvents /! inert as chlorinated solvents such as chloroform, dichlof i romethane, aromatic or aliphatic hydrocarbons such as j / y · petroleum ether or in solvents such as dimethylsulfoxide or N, Ν-dimethylformamide.

The reaction takes place at a temperature between room temperature and the reflux temperature of the chosen solvent.

! I

; i According to another way of proceeding, a cysteine derivative V is, cyclized with an α-halogen ketone VI, there thus forms ji an unsaturated cyclic compound VII which is then reduced to π P - derivative III according to the scheme: ; HS-C - CH - C0R3 + Y-CH-C0-R5 R2 R2 nh2 r7 r ^ n ^ cor3 I: v vi seen it! i! : i: Ù reduction i; -t

V

i:

F, VV

i *; R2 i rX n ^ cor ^ I 5 H 3 im

Rj, R2 "R3, Rg and Ry have been previously defined and Y represents a halogen atom such as chlorine, bromine or iodine.

K

The first stage 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 dimethylsulfoxide, Ν, Κ-dimethyV formamide or in aromatic hydrocarbons such as ben //

‘Zene or toluene. f V

"* 10.

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

The reaction takes place at a temperature between -20oC | and the reflux temperature of the solvent; we work advantageously

Isement 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.

Ί

Derivative VII can be isolated and purified, or the crude mixture can be used directly for the reduction step.

I The reduction of imine VII takes place in the presence of hydrogen ί I and a hydrogenation catalyst, such as platinum, oxide | of platinum or palladium on carbon in a solvent such as Γ methanol, ethanol, ethyl acetate or acetic acid! »Glacial and that at ordinary pressure and more advantageously at higher pressure or by an alkali metal hydride | like sodium borohydride in a solvent like methanol or aluminum hydride and lithium in a solvent like i "; ether or tetrahydrofuran.

... As a rule, 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 the I

cool.

"

An acid such as, for example, hydrochloric acid, sulfuric acid or acetic acid can sometimes catalyze the reaction. ! // · i! 6f |

\ i /. J

I 11.

For the production of sulfoxides, agents such as iodine and bromine can be used in water or in the presence of acetate S ions or in complex with pyridine, peracids such as peracetic, monoperphthalic or m- chloro-perbenzoic, N-halosuccinimides such as N-bromosuccini- | mide, hypochlorites such as t.butyl or ipropyl soda hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or in the presence of hemipentoxide of vanadium in t.butanol, nitrates, i such as acetyl nitrate or ammonium and cerium nitrate, i | oxides such as chromium (VI) oxide in pyridine or! 1 vanadium hemipentoxide in the presence of oxygen or hemi- | nitrogen pentoxide, peroxides, ozone, singlet or triplet oxygen, acids such as nitric acid, chromic acid or Caro acid or others agents such as sulfuryl chloride, 1-chlorobenzotriazole, chloramine, N-chloro-nylon 66, 1eich dichloride iodobenzene, iodosobenzene, diacetate iodobenzene, N-chlorotriazole, 2,4 , 4,6-tetrabromocyclohexadienone or chloroauric acid 1 (HAuCl ^). These oxidation reactions will take place in solvents such as, for example, water, acetic acid, chloroform, i dichloromethane, carbon tetrachloride, methanol, i! t.butanol or acetone.

i h

For the production of sulfones, agents such as hydrogen peroxide are preferably used, preferably in the presence of salts. zirconium, peracids such as peracetic, monoperphthalic and m-chloroperbenzoic acids (in the case of peracid oxidation, catalysts based on transition metals will advantageously be used), potassium permanganate in an acid medium. basic, sodium or potassium dichromate, osmium tetroxide, selenium oxide, t.butyl hypochlorite, nitric acid, ozone, oxygen, advantageously in 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, 1 'sopropanol, t-butanol, dioxane or acetone. j ^ J · '12.

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.

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

i! *; The introduction of the substituent R ^ when it represents a linear or branched alkyl group Cj-C ^ is done by alkylation of the amine according to the scheme:

Ri yCORo R "R, COR, (0) -S N-H + M -" (0) -S N-R4 w, w, ", 's 5" i' t 5

III VIII

1.

Rp R2 »Kg, R4, Rç, Rg, R7 .and n have been defined previously.

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

j The reaction advantageously takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or chloromethane, aliphatic aromatic hydrocarbons such as benzene, toluene or petroleum ether, h alcohols such as methanol and ethanol or even acetonitrile and them! ethers. The temperature is between ambient 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, tri êt hy 1 ami ne or fi, Ν-dimethylani 1 i ne or inorganic base such as hydroxides, carbonates and bicarbonates of alkali metals or no-earth alkali or finely pulverized lime .

The introduction of the substituent = CONl · ^ takes place conventionally | by reaction of derivative III with an isocyanate of an alkali metal or ammonium, according to the scheme! • R, COR. R, COR.

(°) n “s ^ + MNC0 -> (Q) n- ^ I R7 R6 R5 R7 R6 R &

III IX

In this scheme, Rj, R2 * R3, Rg, Rg, Ay 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 I comprised between the normal temperature and the reflux temperature.

Hydantoin X is obtained by heating the derivative IX where R3 represents I a hydroxyl group in an aqueous acid solution.

! · - '? _ / 1 R. s./1 / 0R3 / 1 /> 9 \ r2 / \ (0) -S N-CONH, -S-> (0) -S N ^; W, W “j R7 R6 5 Ry dream R5 IX x j · || In this scheme, Rj, R ^, R ^, Rg, Rg, Ry and n have been defined above j | demment.

! 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. , i \ /.

!! / * ·: 14.

ii! ί j All the methods described above allow easy access I 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 chemistry

He . organic.

Below are given detailed examples of the preparation of some derivatives of the invention. The main purpose of these examples is to further illustrate the particular characteristics! methods according to the invention. .

/

J

î k -i i g! & 15.

J

Example No. I: 2,2-Dimethyl-1,4-thiazane-3-carboxylic acid.

1) S- (2-Hydroxyethyl) -penici11 amine.

To a solution of 14.9 g (0.10 mole) of penici 11 ami ne in 75 ml of 2N aqueous sodium hydroxide, maintained under an inert atmosphere (N ^), is added, drop by drop and with good stirring / a solution 17.5 g (0.14 mole) of 2-bromoethanol in 100 ml of ethanol. After the addition, add enough ethanol to obtain a homogeneous medium and then stir at room temperature for 24 hours after neutralization using concentrated hydrochloric acid "evaporate most of the alcohol 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 ammonia 3 N. 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 isopropanol. 9.0 g (47%) of white solid are thus obtained.

Mp 148-150 ° C.

2e) S- (2-chloroethyl) -penicillamine (hydrochloride).

he

A mixture consisting of 9.0 g (47 mmol) of the preceding product 1 and 350 ml of 38% hydrochloric acid is heated for 7 h using a bath maintained at 95 ° C. It is evaporated to dryness under reduced pressure and the residue is recrystallized from isopro-panol. 8.9 g (78%) of homogeneous product are obtained by chromatography on a thin layer of silica (eluent: BuOH / AcOH / H2O 13: 3: 5) Rf 0.59.

3) 2,2-dimethyl-1,4-thiazane-3-carboxylic acid.

5.7 g (27 mmol) of the above chloride are dissolved in 450 ml of N, N-dimethylformamide and 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 solution I is percolated on 250 ml of resin of the Dowex 50 type. The mixture is washed with water and then eluted with 1.5 l of 1.5 N ammonia. 'eluate is' / concentrated under reduced pressure to a volume of 400 ml,! tf 16.

1 the resulting solution then being treated overnight * with 100 ml of resin of the Amberlite IRC 50 type conditioned under

Jf] acid form. After filtration of the resin, the solution is concentrated to a volume of 30 ml. We filter the crystals | appeared and redissolved them in 10 ml of water. The addition of progress- | 40 ml acetone siv.reprecipitation of the product | final. Weight: 3.1 g (66%). Mp 320 ° C (dec).

<. The IR, NMR and mass spectra are in agreement with the expected structure.

I Elementary analysis: C H N

1 C, H ,, N09S% calculated 48.0 7.5 8.0 I i 16 c% found 47.9 7.4 7.9 i

Example 2: 2,2,5-Trimethyl-1,4-thiazane-3-carboxylic acid.

î | 1 °) S-A1lylpénicillami ne.

• i i!

AT

! To a suspension of 7.5 g (50 mmol) of penicillamine in 50 ml of ethanol is added slowly and simultaneously a solution of 6.6 g (4.1 ml; 55 mmol) of allyl bromide in 50 ml of ethanol and 35 ml of 2N aqueous sodium hydroxide, keeping the temperature of the medium below 20 ° C. At the end of the addition, the mixture is stirred again for approximately 2 hours, checking the disappearance of the starting thiol (thin layer of silica; eluent BuOH, AcOH, 1 ^ 0 i 12: 3: 5; revelation with ninhydrin ).

s The solution is neutralized by means of concentrated hydrochloric acid I r and then it is concentrated until a solid appears. The volume is brought to 300 ml with water and the solution obtained, it is percolated on a column of resin of the sulfonic type | (Amberlite IR 120) packaged in acid form. The resin is washed with water and then eluted with 1 1 of 1N ammonia.

, The eluate is evaporated to dryness and the residual solid is recrystallized from isopropanol. r i

7.8 g (82%) of product are thus obtained. Mp 182-184 ° C.

17.

2Û) 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 1 in acetic acid. After 3 days of agitation, we evaporate! the dry reaction medium under reduced pressure. The residue! ' is then stirred in ether and filtered. The resulting solid j is used as it is in the next step.

j Weight: 14.2 (99%). M 106-108 ° C.

: i:] i 3 °) 2,2,5-Trimethyl-1,4-thiazane-3-carboxylic acid.

i The preceding product (14.2 g; 40 mmol) is added to 500 ml; of DMF containing 50 ml of triethy1 ami ne.

I 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 over 500 g of sulfonic resin (Amberlite IR 120) conditioned I in acid form. The resin is washed with 2 liters of water; then i · i ni \\ eluted with 2 1 ammonia 1 N. The eluate is evaporated to dryness under reduced pressure and the residue, dissolved in 500 ml of water i; is stirred with 50 ml of .carboxylic resin (Amberl iteIRC 50) * packaged in acid form. We filter, then evaporate it; ’Dry aqueous phase under reduced pressure. The residue is dissolved in 50 ml of a 2: 1 mixture of acetone and water and the solution is placed in the fridge. After 3 days, the crystals which have appeared are filtered ii iii. After washing with acetone I and drying, 2.8 g (34%) of product are thus obtained. F.290eC (dec).

î! - = The compound is homogeneous when examined by TLC (eluent: • Ί

BuOH / AcOH / HrjO 12: 3: 5). The IR, NMR and mass spectra confirm the structure of the cyclized product.

i Elementary analysis: C H N

K i C8H15N02S -H2 °% calculated 46.4 8 · 3 6.8 / r% found 46.1 8.5 6.4 i / '/ i.

P i.

i 38.

f [Example # 3: 1, 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid-oxide.

• n To the solution of 7.2 g (35 mmol) of the previous product in 80 ml i | J acetic acid, joust / 1/2 hour apart, 6 fractions; 0.5 ml of 30% hydrogen peroxide. At the end of the addition, we main- | is restless overnight. Evaporate to dryness under pressure | reduced then the residue is chromatographed on 400 g of silica, eluting with a BuOH / AcOH / H ^ O 5: 2: 3 mixture. The first elution product is discarded and the second is dissolved in a 3.5: 1 mixture of acetone and water. The solution, kept in the fridge, j crystallizes slowly. 4.5 g of solid are filtered and then | dissolved in 200 ml of 2N hydrochloric acid. The solution is concentrated under reduced pressure until it has a slight consistency and then acetone is added. The crystals of chlorhy-1 drate which appeared are filtered, washed with acetone and dried. Weight: 4.4 g (51%). F 190-194 ° C (dec).

I *

The Spectra I.R., from R.M.N. and mass corroborate the structure of the cyclic sulfoxide. The product is homogeneous when it is | examined in TLC (eluent: BuOH / AcOH / I ^ O 5: 2: 3). Rf 0.34.

Elementary analysis C H N

C8H15N03S · HC1 · 3/2 H2 °% calculated 38 * 3 6 · 8 5 · 6 | *% found 38.5 6.4 5.5 1 Example n ° 4: 2, 2,5-Trimethyl-1,4-thiazane-3-carboxylate of I methyl.

1 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 I of the methyl ester of penicamine are added, then, dropwise, I 25.0 g of chloroacetone. The mixture is stirred for 1 h at the initial temperature I and then the medium is brought to pH 6.5 using acid | hydrochloric ethanolic. 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 h, always at the same temperature. /

The excess hydride is destroyed by adding hydrochloric acid // '- //

-, concentrated and then the solution is neutralized with 1 hydrogen carbon

19.

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 reprecipitated twice from its methanolic solution by addition of ether.

Weight: 17.2 g (30%). F. 204aC (dec.)

The IR, NMR and mass spectra are in agreement with the expected structure.

Elementary analysis: C H N

CgH17 N02S .HCl% calculated 45.1 7.6 5.8% found 45.1 7.7 5.8

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

TABLE I.

0

* n R

-R2

Kff'L JL

d ^ COR ..

Kr "3.

N ° Ri Ro Ro Ρλ Rl Rc Rt n F (° C) Recrystallization solvent (1) 1 CH ^ CH ^ OH HHHH 0 320 (dec) acetone / water 2 CH3 CH3 OH HHHH 1 242 (dëc) (2) isopropanol / water 3 CH3 CH3 OH H CH3 HH 0 290 (dècJ2 ^ acetone / water 4 CH3 CH3 OH H CH3 HH 1 190 (dec) ™ acetone / water 5 HH -NH-C0- CH3 HH 0 189-191 water 6 CH3 CH3 QQi3 H CH3 HH 0 204 (dec methanol-ether / ^ -l—- - '-f' - '* * "' ........... / / / / (1) all products mentioned give an elementary analysis C, H, N / f / correct. (If (2) hydrate.

The compounds of the invention were subjected to a series of biochemical and pharmacological evaluation tests.

co.

The DLçq are calculated according to the method of Lichtfield and Wilcoxon (J. Pharmacol. Exp. Ther. 915.95, 1949) and expressed in mg / kg. The I products are administered orally to mice.

(The effect on behavior is studied using a method derived from that of S. Irwin (Gordon Res. Conf. On Medicinal Chem., 133, 1959). The substances, suspended in a mucilage containing 1% of tragacanth, are administered orally using an intragastric probe to groups of 5 male mice (CD1, Charles River strains, fasting for 18 hours).

If the quantity of substance available allows, the doses are 3000, 1000 and 300 mg / kg. In the case where this last dose is active, the effect of the drug is examined at 100, 30, 10 and, possibly, 3 mg / kg. The behavior is studied 2,4,6 and 24 hours after treatment. Observation is extended if symptoms persist at this time. Mortalities I are recorded during the 14 days following treatment.

None of the products tested induced abnormal behavior in the mouse or proved to be toxic; products 1 to 6 thus have LD ^ -g greater than 3,000 mg / kg.

1, Determination of fibrinolytic activity.

I The test substance is administered intravenously or orale I 'orally to anesthetized rabbits. Blood is taken at time t0, then l 1, 3, 5, 10, 15, 20, 30, 60 and 120 minutes after intra-injection! venous drug or at times 30, 60, 90, 120, 135, 150, 1165, 180 and 240 minutes after oral administration.

The plasma is separated by centrifugation and the euglobulins are | precipitated.

*;

T

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

150 μl of a solution of euglobulins in a veronal buffer containing 0.25% of gelatin are placed on plates of

0.08% fibrin. After an incubation of 18 hours at 37 ° C, the / Y

/ // The diameter of the lysis zone is measured. / // i / k

The results are expressed in the form of an increase coefficient of the activity compared to the time tO, at the time of the peak.

In this test, product 4 was found to be particularly active.

21.

i j i! ! · For the administration of the new compounds of the invention, the j · daily dose will be 50 mg to 2 g orally and 10 mg fl - ~ d to 500 mg by intravenous infusion.

The products of the invention can be used in various dosage forms. The examples which follow are not limita-1 tives and relate to the galenical formulations containing an active product of the invention designated by the letter A and which can! be, for example: -i ü - 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide.

H

i - hydantoin of 5, methyl-1,4-thiazane-3-carboxylic acid.

| - 2,2-dimethyl-1,4-thiazane-3-carboxylic acid.

| - 2,2-dimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide.

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

* dd Capsules.

I, i A 50 mg I Starch Sta RX 100 mg! Microcrystalline cellulose 60 mg I Extra fine lactose, crystals 132 mg 1 ^ (Colloidal silica 2 mg

Hydrogenated castor oil 6 mg I A 100 mg d; Dicalcium phosphate 95 mg! Starch glycolate sodium 32.5 mg

Colloidal silica 2 mg, f, Magnesia stearate 0.5 mg / f /; // if 22.

Tablets.

| i At 500 mg | Mannitol 95 mg f | Polyvinylpyrrol idone 27 mg 1 Polyethylene glycol 6000, powder 8 mg | ...

! At 300 mg: Starch 60 mg! Lactose 130 mg § „Ethylcel1ulose low viscosity 20 mg | Talc 5 mg I „Aerosil 5 mg * Solutions for injection.

i - _ - - At 20 mg? | i Sodium chloride 2.5 mg citric acid / sodium citrate buffer ·· ad pH 4.8 water for injectables ad 1 ml.

"-i * § A 50 mg if Propyleneglycol 300 mg I Ethyl alcohol 50 mg i water for injectables ad 1 ml.

i Capsule dosed at 100 mg of compound A and 300 mg of acetylsalicyic acid.

At 100 mg (acetylsalicylic acid 300 mg ethylcellulose 60 mg | u lactose 40 mg r / I aerosil 8 ma I magnesia stearate 8 mg fj ^ f 23.

i i I. Tablet containing 300 mg of compound A and 50 mg of dipyridamol.

A 300 mg dipyridamol 50 mg hypromellon 25 mg starch 100 mg calcium stearate 8 mg i

Tablet containing 200 mg of compound A and 10Q mg of suloctidil.

A 200 mg suloctidil 100 mg tween 80 8 mg I ethyl! 1ulose 22 mg /; / i lactose. 40 m. j starch 71 mg / / / / magnesia stearate 9 mg j s i

/ V

t * i i '

Claims (20)

1. 1,4-Thiazane derivative of general formula I: j <?> Ni R7V / S \ xRl 1 s'r2] R67 \ n ^ cr „IR * ï4 S 3 j] * I j„ in which: i ; Rj and R2> which may be the same or different, represent f of hydrogen, a linear or branched alkyl radical C ^, C ^, C ^ or C4 or a phenyl ring, | Rj and R2 can form with the neighboring carbon atom a ring l | from 3 to 8 members, possibly 1 ement interrupted by an atom of sulfur, oxygen or by a group SO, SO2 or NRg in which I Rg represents hydrogen, a linear or branched alkyl radical C ^, C2> C3, C4, a phenyl ring or a benzyl group, Rg represents: * - - a hydroxyl group - an ORg group in which Rg represents a linear or branched alkyl group Cj, C2, Cg, C ^, Cg, Cg, C ^ , Cg, Cg, Cjq, Cjj or C ^ 2 or a group Û-CH-COüRjj in which Rjq represents I R10 I of hydrogen or a methyl radical and Rjj represents an alkyl radical. linear or branched C ^, C2, Cg, C ^, Ct, Cg, Cy, *: Cg, Cg, C jo, C j j or C12; t ^ R - a group N 12 in which R] 2 and Rj3, which may be Χβ13 identical or different, represent hydrogen, a j ^ linear or branched alkyl radical C ^, C2, Cg or C ^, / j R4 represents a hydrogen atom, a linear alkyl radical / (f * H '. 25. "* or branched C}, C. ,, Cg,, C ^, Cg, Ιη, Cß or a group C0NH2; and R ^ j can form with the neighboring carbon and nitrogen atoms a hydantoin ring Rg and Rg, which can be identical or different, represent hydrogen, a linear or branched alkyl radical Cj, C2, C3> C4, Cg, Cg, C ?, Cg, Cg, C1Q, Cn »j Cj2, a phenyl ring, a CH ^ COOR ^ group in which Rj4 i represents a linear or branched alkyl radical Cj, Cg, Cg or!; R7 represents hydrogen, a linear alkyl radical or Î: * · ji branched Cj, C2> Cg, C ^ ', | in can have the values 0, 1 or 2) If Rj, R2> and R ^ represent hydrogen and if Rg represents a hydroxyl group or a linear alkyl radical i (or branched Cj - C ^, Rg and Rg do not represent hydrogen, | A linear or branched alkyl radical C, - C. or a phenyl ring * il: i H y jj as well as the salts of these compounds formed with acids and | pharmaceutically usable bases. 2. Derivative according to claim 1, characterized in that, in the general formula I, Rj and Rg, which may be identical or different, represent a methyl or ethyl group. ! " 3. A derivative according to any one of claims 1 and 2,; characterized in that, in the general formula I, Rg and R ^, which may be the same or different, represent hydrogen, a methyl group or an ethyl group. u ji 4. Derivative according to any one of claims 1 to 3, characterized in that, in the general formula I, Rg and R ^^ |: which may be identical or different represent an alkyl group C ^ -C ^ . c s 5, derivative according to any one of claims 1 to 3, characterized in that, in the general formula I, Rg and which may be identical or different represent an i- j alkyl group - Cg. / (/! 6. Derivative according to any one of claims 1 to 3 // // i characterized in that, in the general formula I, Rg and Rjj / jf I which may be the same or different represent an iß ,,, _v / f. 26. • · 7. A derivative according to claim 4, characterized in that, in the general formula I, Rg and / or Rjj represent a group! methyl or ethyl. i • i \ 8. Derivative according to any one of claims II to 7, characterized in that R ^ represents an alkyl group Cj-C ^. 9. Derivative according to any one of claims 1 to 7, characterized in that R ^ represents an alkyl group - Cg. 10. A derivative according to claim 8, characterized in that! * j IR ^ represents a methyl or ethyl group. 11. Derivative according to any one of claims 1 to 10, characterized in that Rg, R12> R13 and / or represent a methyl or ethyl group. \, j 12. Derivative according to claim 1, characterized in that it j | is chosen from the group formed by the compounds: j - 2, 2, 5-trimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide. î - hydantoin of 5-methyl-1,4-thiazane-3-carboxylic acid. I - 2,2-dimethyl-1,4-thiazane-3-carboxylic acid. ; i - 2,2-dimethyl-1,4-thiazane-3-carboxylic acid, 1-oxide. here - 2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid it 5 11! 13. Derivatives, in particular for the preparation of derivatives according to j | any one of the preceding claims / corresponding to I formulas II, IV and VII: if I fl C0-R3 Çi_'C ° -r3 Ri ï (Q \ S ^ H-R4 (q) s yNH'R * ï - i R7 R6 R7 R6 II IV VII / i / in which R ^, R9, Rg,, RF, Rg, Ry and n have the meanings / IV J cations given above. \ ^ ί »* 27. 14. Process for the preparation of 1,4-thiazane derivatives and its salts, characterized in that a compound of formula II, of formula IV or the compounds of formulas V and VI is cyclized. r COR / cor3 K2 C — CH J £ C - CH, ηλ A \ h-R- fn. {NH-R. (°) nln 4 (O) nS 4 \ / 5 V. / C — C CH - C - Pc / II 5: “7 6 R7 R6 II IV Y HS VBC \ ^ R1 Rb - c * j ^ ®2 Il C-ÇOR O / 3. H2N VI V "in these formulas Rj to R ^ 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 corresponding derivative of formula I, the latter or the intermediate product, as well as the derivatives of formula I obtained from the compounds of formulas II and III possibly being subjected to oxidation, alkylation by the substituent R ^, or a substitution of this substituent by a CGNi ^ group followed by cyclization with the substituent when the latter represents a hydroxyl group therein, so as to obtain a / j hydantoin group. / DD η ‘! 2b. . " 15. Process for the preparation of 1, 4-thiazane derivatives and its salts, characterized in that a derivative of formula II is cyclized / in a basal medium: n? 1 ^ OK K2 ^ C - CH J • "" „ -sy * "" \ / R5 c —c / N: r7 r6 Π 16. A method according to claim 15, characterized in that an organic or inorganic base is used such as, for example, triethy1 ami ne, 1 a N, Ν-dimethylami ne, pyridine, alkali metal hydroxides or 1 ' ammonium hydroxide. 17. Process for the preparation of 1,4-thiazane derivatives and its salts, characterized in that a derivative of formula IV R, ^ COR, pii - ύ i K2 is cyclized, in an acidic or dehydrating medium, C - CH, (W iv; (0) n - s ^ 4 4 CH — C - Rc (I lit r 4 r7 Rr a - 7 b I î- in which X represents a halogen atom such as chlorine, II · *. Bromine or 1 iodine, a hydroxyl group or a faci group - ement * can be eliminated as, for example, a tosyl or mesyl group. "1 d, 18 · Process for the preparation of 1,4-thiazane derivatives, characterized in that a derivative of 5,6-dihydro-2H- thiazine VII R / S-Jl 7. p rnp R5 luk3 VII j is reduced to 1,4-thiazane of formula lf and then optionally L ely oxidized to obtain the sulfoxide or sulfone cor- IM 2 9. γ IV Process according to Claim Ib, characterized in that the derivative VII is prepared by reaction between a cysteine derivative V? 1 HS - C - CH - COR, II Ί r2 nh2 V and an a-halogenocetone YCH-COR ^ in which Y represents * 7 a halogen atom such as chlorine, bromine or iodine. 20. The method of claim 19 »characterized in that the reaction between the cysteine derivative V and 1 1 α-ha1ogeno-ketone is carried out in basic medium. · 21. A process for the preparation of 1,4-thiazane derivatives- characterized in that, for the preparation of a derivative of formula I in which R ^ represents a linear or branched C ^ -C ^ alkyl radical, an amine of formula III to an alkylation in basic medium. COR ^ R2 / H (0) -S NH III WR R7 R6 5 by a reagent R ^ Z in which Z represents a halogen atom such as chlorine,. Bromine or iodine, or an easily removable group such as, for example, a tosyle or mesyle group. 22. Process for the preparation of 1,4-thiazane derivatives-characterized in that ^ for the preparation of a derivative of formula I in which R. represents a radical CONH „, a derivative III is reacted with a reagent of formula MKCG in. _. _. / / / which M represents a monovalent cation such as scoium ions / / potassium, lithium or ammonium. 'Jf Ύ · 30. i * 23. Process for the preparation of 1,4-thiazane derivatives-characterized in that, for the preparation of a derivative of formula I in which and together with the neighboring carbon and nitrogen atoms a hydantoin cycle, a drift of form; mule “l * 1 COR, U - · / -c0NH2 IX; '' Rz R6 K5, | in which represents a hydroxyl group, is placed in the middle. Acidic and possibly heated. !, i - 24. Process for the preparation of 1,4-thiazane-j derivatives; 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. 25. The process as claimed in claim 24, characterized in that the oxidation is carried out at any stage of the preparation of the 1,4-thiazane ring. \ 26. Pharmaceutical composition, characterized in that it comprises at least one of the compounds of formula I or one of its salts, fl r associated with one of the appropriate pharmaceutical excipients or - optionally with other therapeutic agents such as ! antiplatelet agents. r- 27. A composition according to claim 26, characterized Î, in that it is in the form of dragees, granules, tablets, capsules, solutions, syrups, emulsions or suspensions containing conventional additives or excipients in pharmaceutical pharmacy. 28. Composition according to Claim 26, characterized in that it comprises at least one of the derivatives according to formula I in solution, in particular in sterile water or in an oil such as peanut oil or l 'ethyl oleate / //; 1/0 31. 29. Process for the use of the derivatives according to formula I,! characterized in that they are administered in daily doses! 50 mg to 2 g orally and 10 ni g to 500 mg as an intravenous infusion. 30. A method of using the derivatives of formula I in the treatment and prevention of certain affections of the circulatory system, such as venous and arterial thromboses. I _. / rUr-hre * ------- ^ i λ Ä —...... P0 · * 2 ^ - ~ c · .- er.cripticn - g ... -ï claims; /. - description * · ε r. 1 rd-.τς f'-ir.chen 1