NL8220153A - 1,4-THIAZANCARBONIC ACID DERIVATIVES, THEIR PREPARATION AND USE, AND THE COMPOSITIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

& t>. 31,483 0 2 2 0 '!; 5 '"-—— / _____ Tr / TW-pl.

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

The subject of the present invention is 1,4-thiazancarboxylic acid derivatives as well as the salts of these compounds, their preparation methods as well as the pharmaceutical compositions containing at least vanη of these derivatives and their method of use. The derivatives of the invention correspond to the general formula I: <?> "R ........ - R7 f1 I Γ2 I 1" 1 i 3: 5 R, b in which: and R2, which may be identical or different, hydrogen, a straight or branched C 1, C 2, C 2, C 3 or C 1 alkyl group or a phenyl core, optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight or branched C 1, C 2, C 3, or C 1 alkyl group or with a straight or branched C 1, C 2, C 2, or C 3 alkoxy group, represent R 15 and R 2 with the adjacent nitrogen atom a cycloalkyl group may form of 3, 4, 5, 6, 7 or 8 carbon atoms, of which one or more carbon atoms may be replaced by a sulfur or oxygen atom or an SO, SO 2 or NRg group, wherein Rg is hydrogen, represents a straight or branched C 1, C 2, C 3 or C 4 alkyl group, a phenyl core or a benzyl group.

R3 represents: - a bydroxyl group, - a 0R <} - group, in which R9 is a straight or branched (4-, C2-, ^ 3 “> C4—, C3—, Cg—, Cy—, Cg—, C9— , Cjq -, C 1 -, C - - group or a 0-CH-C00R - - group or a 0CH - 0C0R] - - group R10 represents R10, where R 2 represents hydrogen or a C 1 - or C 2 - alkyl group and R 1 represents a straight or branched C 1, C 2, C 3, C 4, C 5, Cg, C 7, Cg, C 9, C 6, Cj, C 12 alkyl group, 8220153 / r12 2 - an N group, in which and R13 »which may be identical or different, R13 • represent hydrogen or a straight or branched C], C2, C3 or C4 group, - a 3- phthalidyloxy group or a 1- (2,5-dioxopyrrolidinyl) -1-ethoxy-5 group R4 represents a hydrogen atom, a straight or branched Cj, C2, C3, C4, C5, Cg, C7 or Cg alkyl group or a straight or branched C ^, ¢ 3, C3, C4, C5, Cg, C7 or Cg acyl group or a C0NH2 ~ group for, R3 and R4 may be attached to the adjacent carbon and nitrogen atoms form a hydantoin, R5 and Rg, which may be identical or different hydrogen, a straight or branched C 1, 3, C 3, C 4, C 5, C 5, C 7 or C 6 alkyl group, a phenyl group optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight or branched C 1, C 2, C 3, or C 4 alkyl group or a straight or branched C 1, C 2, C 3, or C 4 group, a C 1 CO 2 CO 1 group, wherein R 4 is hydrogen, a straight or represents branched C 1, C 2, C 3 or C 4 alkyl group.

R7 represents hydrogen, a straight or branched C 1 -C 2, C 2, C 3 or C 4 -alkyl group or a gem. dimethyl group or a phenyl core, optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight or branched C 1, 3, C3 or C 4 alkyl group or a straight or branched C 2, C 2, C 3 , or C4 -alkoxy group for, 25n can have the values 0, 1 or 2.

When R 1, R 2, R 4 and R 7 represent hydrogen and when R 3 represents a hydroxyl group or a straight or branched C 1 -C 4 alkyl group, R 5 or R 8 do not represent hydrogen, straight or branched C 1 -C 4 alkyl group or a phenyl core in front of.

According to a preferred form of the invention it is subject to the compounds of formula I, wherein: R 1 and R 2, which may be identical or different, represent hydrogen, a straight or branched C 1 -C 4 alkyl group, R 3 represents a hydroxyl group an ORg group, wherein R9 represents a straight or branched C1 -C4 alkyl group, a 0-CH-C00Rii group or a 0-CH-0C0Rn group R10 R10 8220153 3, wherein R ^ represents hydrogen or a methyl group and R 11 represents a straight or branched C 1 -C 6 alkyl group.

R4 represents hydrogen or a methyl group.

R5 and Rg, which may be identical or different, represent hydrogen, a straight or branched C 1 -C 6 alkyl group, or a C 1 -COO 6 group, wherein R 4 represents hydrogen or a Ογ-Οχ alkyl group , R7 represents hydrogen; n can have the values 0 or 1.

A preferred class of the compounds of formula I is those in which R 1 and R 1 represent hydrogen or a methyl group, R 3 represents a hydroxyl group or an ORg group, wherein R 9 represents a straight or branched C 1 -C 4 alkyl group, R 4 hydrogen represents a methyl group, R 5 represents hydrogen and R 9 represents a straight or branched C 1 -C 6 alkyl group, R 7 represents hydrogen, n may have the values 0 or 1.

Examples of compounds according to the invention are: 2,2,5-trimethyl-1,4-thiazan-3-carboxylic acid 1-oxide, ethyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate 1-oxide, 2,2,4,5-tetramethyl-1,4-thiazan-3-carboxylic acid, 1- (pivaloyloxy) ethyl-2,2,5-trimethyl-1,4-thiazan-3-carboxylate-1,4 -oxide, 25 (octyloxycarbonyl) methyl-2,2,5-trimethyl-1,4-thiazan-3-carboxylate-1-oxide, 1- (ethyloxycarbonyl) ethyl-2,2,5-trimethyl-1,4- thiazan-3-carboxylate-1-oxide, 5-butyl-2,2-dimethyl-1,4-thiazan-3-carboxylic acid, 2,2-dimethyl-5-isopropyl-1,4-thiazan-3-carboxylic acid 1,5-methyl-2-phenyl-1,4-thiazan-3-carboxylic acid, ethyl 3-carboxy-2,2-dimethyl-1,4-thiazan-5-acetate.

When the derivatives of the formula I are in the form of addition salts with acids, they can be converted to their free base or to salts with other acids by customary methods.

The most commonly used salts are the addition salts of non-toxic pharmaceutically usable acids formed with suitable inorganic acids, for example hydrochloric, sulfuric or phosphoric acid or with suitable organic acids, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carbon or sulfonic acids, 8220153 4 4 e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranric acid -5 acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, (3-hydroxy-propionic acid, β-hydroxybutyric acid, oxalacturic acid, malic acid .

These salts may also come from natural or non-natural amino acids such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, etc.

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

The compounds of formula I may have έέ or more asymmetric centers and may exist 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 stereoselective synthesis or by cleavage of the racemates by conventional methods, for example by formation of diastereoisomeric salts by the action of optically active acids such as tartaric acid, diacetyl tartaric acid, tartranilic acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid and separation of the mixture of diastereoisomers, for example, by crystallization or chromatography, followed by release of the optically active bases from these salts.

The optically active compounds of the formula I can be obtained using optically active starting materials. The mixtures of diastereoisomers can be separated in the same manner as the above diastereoisomeric salts.

Thrombotic, arterial and venous diseases are currently a very important cause of mortality and, above all, disease in Western countries.

The products according to the invention allow a new therapeutic approach different from that of the substances which act on the functions of the platelets on the one hand and those of the fibrinolytic enzymes on the other. The promotion of the fibrinolytic activity of the blood, as a result of the promotion of the synthesis and / or the release of natural activators of the fibrololysis resulting from the administration by oral or parenteral route of the products of the invention makes it possible to consider important therapeutic applications under the greatest safety conditions. Thus, the occurrence of the deep vein thromboses and their often fatal consequences, which are the pulmonary emboli, can be obtained by oral treatment before and during the weeks following risky surgical procedures.

The occurrence of thromboses complicating the vein inflammation of the superficial, primary or secondary veins with prolonged immobilization periods of the patients may also be considered.

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

Finally, the products of the invention, alone or together with substances that inhibit platelet adhesion and aggregation, are indicated for the prevention of recurrent thrombotic, arterial or venous disease manifestations. After all, it is known that in patients suffering from cerebral or coronary thrombosis (heart market) the risk of collapse justifies the application of a preventive therapy.

The products of the invention are active by the oral route, which permits easy application and can be administered for long periods, unlike the topical brinolytic substances, because they are devoid of enzymatic activity, not immunogenic be and act through normal activators present in the organism.

Their use, alone or in combination with platelet inhibitors, allows a new approach to treatment and to the prevention of arterial and venous thromboses.

The present invention also claims pharmaceutical compositions which contain as active ingredient at least one compound of the general formula I and / or one of its salts with a pharmaceutical excipient. These compositions were provided such that they can be administered by the oral, rectal or parenteral route.

8220153 7 6

For example, the compositions for oral administration may be liquid or solid and provided in the form of tablets, capsules, granules, powders, syrups or suspensions; such compositions contain the additives and extenders commonly used in galenic pharmacy, inert diluents, disintegrants, binders and lubricants such as lactose, amidone, talc, gelatin, stearic acid, silicic acid, magnesium stearate, polyvinylpyrrolidone, calcium phosphate, calcium carbonate, etc.

Such formulations can be effected to extend the disintegration and consequently the duration of action of the active principle.

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

The oily emulsions and solutions are formulated in an oil of vegetable or animal origin and may contain emulsifying agents, perfuming agents, dispersing agents, sweetening agents and antioxidants.

For the parenteral administration, sterile water, an aqueous solution of polyvinylpyrrolidone, salad oil, ethyl oleate, etc. are used as the carrier. These aqueous or oily injectable solutions may contain thickeners, wetting agents, dispersants and gelling agents.

The compounds of the invention are prepared according to methods which are part of the present invention and are defined below. In the event that the methods give rise to the production of new intermediates, these new compounds, as well as the processes that serve their preparation, are also part of the present invention.

In a first embodiment, a vinyl thioether of formula II is obtained according to the method described by A.I. Virtanen 35 et al., In Acta Chem. Scand., 1966, _20, 1163-1185 cyclized to derivative I according to the scheme: 8220153 7 / h „co-R, R1 P0r3 r2? C-ch zT \ '“' "Λ Λ 4 - (0) "'\ Γ *

. xc = cv J ~ rH

h Re R7 Rg

II I

R1, R2> R4, R5, Rg, R7 and n have been previously defined.

The ringing is preferably effected in a basic medium.

The base can be organic such as triethylamine, pyridine, N, N-dimethylaniline or inorganic such as, for example, the hydroxides of alkali metals such as sodium hydroxide or potassium hydroxide or ammonium hydroxide.

When the base used is an organic base, the solvent will preferably be an inert organic solvent such as the chlorinated solvents such as chloroform or dichloromethane, aromatic or aliphatic hydrocarbons such as benzene, toluene or the various fractions of petroleum ether or 00k solvents such as acetonitrile, Ν, Ν-dimethylformamide or dimethyl sulfoxide. When the base is inorganic, the solvent used will preferably be water and the concentration of the basic solution will be 0.01 N to 10 N and suitably from 0.2 N to 2 N.

The reaction proceeds at a temperature between 0 ° C and the reflux temperature of the solvent. However, it can be very advantageous to operate at a temperature near the ambient temperature, especially when the reagents or products contain a predominant stereoisomer, which is likely to isomerize when the conditions used are too drastic.

Another way of proceeding is to accomplish a cyclization from a cysteine derivative III obtained according to the method described by J.F. Carson et al. In J.

Org. Chem. 29 ^, 2203 (1964) according to the following scheme: 8220153 7 8

Ro R. .COR, R i pod V- ^ c / 3 / \ HR / \ (0) „- S X NHR4 -► (0) n-S N-R4> -? - r5. V-ar R7 R6 R7 R6 5

III I

In this scheme, R 1, R 2, R 3, R 4, R 5, R 5, R 7 and n are defined above 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.

When the cyclization is carried out in basic medium, the conditions described for the first method can be applied in the present case.

When the cyclization is carried out in an acid medium, an inorganic or organic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, formic acid, acetic acid is used.

Desiccants such as, for example, phosphorus hemipentoxide, concentrated sulfuric acid, a carbodiimide such as the dicyclohexylcarbodiimide can also be used.

These reactions are generally conducted 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 in solvents such as dimethyl sulfoxide or N, N dimethylformamide.

The reaction proceeds at a temperature between ambient temperature and the reflux temperature of the selected solvent.

According to another mode of operation, a cystine derivative IV is cyclized by reaction with an α-halo ketone V; thus an unsaturated cyclic compound VI is formed, which is subsequently reduced to the derivative VII according to the scheme: 8220153 9 W1

Λ R η ~ Y

1 ^ k a ς ρ * R ο HS-C - CH - COR, + Y-CH-CO-Rr X * ιΐ 3.5 m ^^ COR-3 r2 nh2 R7 Rj 3

IV V VI

i reduction! - S. R1

RlXX

VI! 2, ^^ cor3 -

5 H

R 1, R 2, R 3, R 5 and R 7 are previously defined eti Y represents a halogen atom such as chlorine, bromine or iodine.

The first step of the process proceeds 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, Ν, Ν-dimethylformamide or in aromatic hydrocarbons such as benzene or toluene.

As bases, one can use alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal alkoxide such as, for example, sodium or potassium methanolate, sodium or potassium ethanolate or sodium or potassium tert-butoxide.

The reaction proceeds at a temperature between -20 ° C and the reflux temperature of the solvent; one operates efficiently at a temperature between 0 ° C and ambient temperature.

Advantageously, a dehydrating agent such as, for example, a molecular sieve, can be added to the reaction mixture.

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

The reduction of the imine VI is carried out in the presence of 8220153 hydrogen and a hydrogenation catalyst such as platinum, platinum oxide or palladium on carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid and sheet at normal pressure or more efficiently at elevated pressure or additionally with an alkali metal hydride such as sodium boron hydride in a solvent such as methanol or lithium aluminum hydride in a solvent such as ether or tetrahydrofuran.

As a general rule, this reduction proceeds at ambient temperature, but depending on the reactivity of the system it may sometimes be advantageous to heat or cool the reaction mixture.

An acid such as, for example, hydrochloric acid, sulfuric acid or acetic acid can sometimes catalyze the reaction.

To obtain sulfoxides, agents can be used such as iodine, bromine in water or in the presence of acetate ions or also as a complex with pyridine, peracids such as peracetic acid, monoper-15 phthalic acid or m-chloroperbenzoic acid, N-halogen succinimides such as N-bromosuccinimide, hypochlorites such as sodium, tert-butyl or iso-propyl hypochlorite, periodates such as sodium periodate, hydrogen peroxide in the presence of acetic anhydride or in the presence of vanadium hemipentoxide in tert-butanol, nitrates such as acetyl nitrate or cerium ammonium nitrate, oxides such as chromium (VI) oxide in pyridine or vanadium hemipentoxide in the presence of oxygen or nitrogen hemipentoxide, peroxides, ozone, oxygen in the singlet or triplet state, acids such as nitric acid, chromic acid or caroic acid or other agents such as sulfuryl chloride, 1-chlorobenzotriazole, chloramine, 25 N-chloro-nylon 66, iodobenzene dichloride, iodobenzene, iodobenzene acetate, N-chlorotriazole, 2,4,4 , 6-tetrabromocyclohexadienone or tetrachloroacidic acid (HAUCI4). These oxidation reactions will take place in solvents such as, for example, water, acetic acid, chloroform, dichloromethane, carbon tetrachloride, methanol, t-butanol or 30 tons.

To obtain the sulfones, one will advantageously use agents such as hydrogen peroxide, preferably in the presence of zirconium salts, peracids such as peracetic acid, monoperphthalic acid and m-chloroperbenzoic acid (in the case of oxidation with peracids, catalysts based on transition metals will advantageously be used - len), potassium permanganate in acid or basic medium, sodium or potassium bichromate, osmium tetroxide, selenium oxide, tert.butyl hypochlorite, nitric acid, ozone, oxygen, advantageously in the presence of iridium or rhodium salts, iodobenzene dichloride, periodic acid or by elic acid trochemical oxidation. These reactions will proceed in solvents such as water, acetic acid, chloroform, dichloromethane, methanol, ethanol, isopropanol, t-butanol, dioxane or acetone.

In certain instances it may be effective to carry out the oxidation reactions described above on compounds in which the functions sensitive to the oxidizing agent used will be protected.

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

It should be noted that the conversion of the derivative I, in which n = 0 to the derivative I in which n = 1, 2 can be effected at any stage of the processing of the 1,4-thiazane ring.

The introduction of the substituent R 4, when it is a straight or branched C 1 -C 8 alkyl group or straight or branched C 1 -C 8 acyl group, proceeds by alkylation or acylation according to the scheme: R, C 0 R 3 d COR, (0) nS NH + R4Z - ^ (°) n-3 Vr4 r7 r6 r5 * 5

VIII IX

R1, R2, R3, R4, R5, R7 and n have been defined above.

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 proceeds in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or dichloromethane, aromatic or aliphatic hydrocarbons such as benzene, toluene or petroleum ether, alcohols such as methanol or ethanol or acetonitrile and ethers. The temperature is between ambient temperature and the reflux temperature of the reaction mixture. The reaction can advantageously be carried out in the presence of an organic base such as pyridine, triethylamine or Ν, Ν-dimethylaniline or an inorganic 822015 * 12 / base such as the hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals or finely powdered lime.

The alkylated derivative can be obtained by reduction of the corresponding acylated derivative by known methods.

The introduction of the substituent R4 = COM2 is usually effected by reaction of the derivative. VIII with an alkali language or ammonium isocyanate according to the scheme:

VIII X

R1 C0R3 R]. COR, * zj— \ ^ {(0) n-S NH + MNCO-— (0) -S N-C0NH2

) —A5 WA

R7 R6 R7 R6 5 10 In this scheme R 1, R 2, R 3, R 5, R 5, R 7 and n are defined above, M represents a monovalent cation such as the sodium, potassium, lithium or ammonium ions.

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

The hydantoin XI is obtained by heating the derivative X, wherein R3 represents a hydroxyl group, in an acidic aqueous solution.

0 Λ / C0R3 / R1 / R2 7 \ H + \ T \

(0) -S N-C0NH2-► (OL-S n-A

, V. (W;

Ry r6 5 R7 R6 K5

20 X XI

In this scheme n Rj, R2, R3, R5, R5, R7 and n are defined above.

The acid used is an inorganic acid such as halogenated 8220153 hydrogen acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide or nitric acid, sulfuric acid or phosphoric acid.

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

The conversion of the derivatives in which R3 represents a hydroxyl group to derivatives in which R3 represents an OR9, OCHCORN or OCH-0C0Rn R10 R10 group is an esterification reaction.

The esterification of an acid is an acidic general reaction which can take place in many ways. Usually, the acid and alcohol are reacted in the presence of an acidic catalyst such as hydrochloric or sulfuric acid or p-toluenesulfonic acid. This reaction is advantageously carried out under anhydrous conditions and one of the reagents is used in great excess. The solvent can be either one of the reagents 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 mode of operation is to distill the water from its formation using a suitable device. The reaction conditions are identical to those described above with the exception that one of the reagents must not be used in excess.

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

The conversion of the derivatives, in which R3 represents a hydroxyl group or groups of the groups such as OR9 CHCORN or OCH-0C0Rn R10 R10, into derivatives in which R3 represents a r12 N is a conventional and very well-conducted chemistry. argued reaction, which can be accomplished by various methods explained below.

8220153 14

For example, the carboxylic acid can be used in the presence of the amine, the pyrolysis of the salt thus formed leads to the amide as well as the action of a dehydrating agent such as the p2 ° 5 * 5. Another mode of implementation consists of converting the carboxylic acid to acid halide , then to the amide by action of an amine. The conversion of the acid to acid halide often takes place without solvent with the thionyl chloride, phosphorus pentachloride or the phosphorus oxychloride. The corresponding bromides can also be used. In order for the reaction to be complete, it is often useful to heat the reaction mixture at a temperature between 50 and 150 ° C. When a solvent is useful in the course of the reaction, it will be an inert organic solvent such as the hydrocarbons such as benzene, toluene or petroleum ether or the ethers such as diethyl ether.

The reaction between the acid halide and the amide takes place under cooling of the reaction mixture at a temperature between 0 ° C and -50 ° C, while adding an excess of amine (at least 2 equivalents to at least 1 equivalent of amine and at least 1 equivalent of a tertiary organic base such as, for example, triethylamine). Typically, the acid chloride is added to the amine in solution in an inert organic solvent, as defined above, or in aqueous solution.

Yet another mode of operation is to react a carboxylic acid and an amine in the presence of a coupling reagent as used, for example, in peptide synthesis. In fact, there are very many coupling reagents such as, for example, the dicyclohexylcarbodiimide, the N-ethyl-N ', 3-dimethylaminopropylcarbodiimide, the phosphines, the phosphites, the silicon or titanium tetrachloride or the EEDQ.

The aminolysis of an ester is usually carried out either in water or in an inert organic solvent. As an example of a useful solvent, mention may be made of 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 can be indispensable in the case of reaction with weakly basic or sterically hindered amines. The foregoing reaction can be carried out at a temperature between the ambient temperature and the reflux temperature of the solvent.

A1 depending on the conditions used, the hydrolysis of an amide, a derivative in which R3 represents a -R12 N group, may lead to a carboxylic acid or to esters.

All of the above-described methods 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 method used. The fractionation of these mixtures of diastereoisomers is carried out in a manner customary for organic chemistry.

Detailed examples of the preparation of some derivatives of the invention are given below. The purpose of these examples is, in particular, to illustrate more the particular features of the methods of the invention.

Example I. 2,2-dimethyl-1,4-thiazan-3-carboxylic acid. le) S- (2-hydroxyethyl) penicillamine.

To a solution of 14.9 g (0.10 mol) of penicillamine in 75 ml of 2 N aqueous sodium hydroxide, maintained under an inert atmosphere (¾), a solution of 17.5 g is added dropwise and with good stirring. (0.14 mol) 2-bromoethanol in 100 ml of ethanol. At the end of the addition, sufficient ethanol is added to obtain a homogeneous environment, then it is stirred at ambient temperature for 24 hours. After neutralizing by means of concentrated hydrochloric acid, the majority of the alcohol is evaporated under reduced pressure and the volume is made up to 300 ml with water. The resulting solution is bound on a Dowex 50 resin column conditioned in acid form. The resin is washed with water, then eluted with 3 liters of 3 N 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 off and recrystallized from isopropanol. 9.0 g (47%) of a white solid are thus obtained. Melting point 148-150 ° C.

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

A mixture consisting of 9.0 g (47 mmol) of the previous product and 350 ml of 38% hydrochloric acid is heated for 7 hours by means of a bath maintained at 95 ° C. The mixture is evaporated to dryness under reduced pressure and the residue is recrystallized from isopropanol. 8.9 g (78%) of a homogeneous product are obtained by chromatography on 8220153 16 a thin silicon dioxide layer (eluent: BuOH / AcOH / H2O: 13: 3: 5) - Rf. 0.59.

3e) 2,2-dimethyl-1,4-thiazan-3-carboxylic acid.

6.7 g (27 mmol) of the previous chloride are dissolved in 450 ml of Ν, Ν-dimethylformamide, then 50 ml of triethylamine are added before the mixture is stirred at 95 ° C for 2.5 hours. maintain heated bath. It is then evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of water and the solution is filtered over 250 ml of Dowex 50 resin. It is washed with 10 water and then eluted with 1.5 l of ammonia. The eluate is concentrated to a volume of 400 ml under reduced pressure, the resulting solution is then treated overnight with 100 ml of Amberlite IRC 50 resin, conditioned in acid form. After filtration of the resin, the solution is concentrated to a volume of 30 ml. The appeared crystals 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%). Melting point 320 ° C (dec.).

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

Elemental Analysis: C Η N

% calculated 48.0 7.5 8.0% found 47.9 7.4 7.9.

Example II. 2,2,5 - (R, S) -trimethyl-1,4-thiazan-3 (S) -carboxylic acid.

Le) S-allylpenicillamine.

A suspension of 7.5 g (50 mmole) of penicillamine in 50 ml of ethanol is added slowly and simultaneously to a solution of 6.6 g (4.1 ml; 55 mmole) of allyl bromide in 50 ml of ethanol and 35 ml of 2N aqueous sodium hydroxide. droxide while maintaining the temperature of the environment below 30 ° C. At the end of the addition, stirring is continued for about 2 hours, checking the disappearance of the starting thiol (thin-layer silica; eluent BuOH / AcOH / 2 O 12: 3: 5; development with the ninhydrin).

The solution is neutralized by means of concentrated hydrochloric acid, then it is concentrated to the appearance of a solid. The volume is brought to 300 ml with water and the resulting solution is filtered through a sulfonic acid type resin column (Amberlite IR 120) conditioned in the acid form. The resin is washed with water and then eluted with 1 1 1 N ammonia. The 40 eluate is evaporated to dryness and the residual solid is recrystallized from 8220153 17 isopropanol.

7.8 g (82%) of the product are thus obtained.

Melting point 182-184 ° C.

2e) S- (2-bromopropyl) -penicillamine - bromohydrate.

The product from the previous step (7.8 g; 41 mmol) is added with stirring to 300 ml of a 40% hydrogen bromide solution in acetic acid. After stirring for 3 days, the reaction medium is evaporated to dryness under reduced pressure. The residue is then stirred in ether and filtered. The solid obtained is used as such in the next 10 steps.

Weight: 14.2 g (99%).

Melting point 106-108 ° C.

3rd) 2,2,5-trimethyl-1,4-thiazan-3-carboxylic acid.

The previous product (14.2 g; 40 mmol) is added to 500 ml of DMF containing 50 ml of triethylamine. The mixture is heated on a water bath kept at 90 ° C for 2.5 hours; then evaporated to dryness under reduced pressure. The residue is dissolved in 400 ml of water and the solution is filtered over 50 g of sulfonic acid resin (Amberlit IR 120), conditioned in acid form. The resin 20 is washed with 2 liters of water; it is then eluted with 2 1 1 N 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 acid resin (Amberlite IRC 50), conditioned in acid form. It is filtered, then the aqueous phase is evaporated to dryness under reduced pressure. The residue 25 is dissolved in 50 ml of a 2: 1 mixture of acetone and water and the solution is placed in the refrigerator. After 3 days, the crystals that have appeared are filtered off. After washing with acetone and drying, 3.7 g (45%) of product are thus obtained.

Melting point 290 ° C (dec.).

The IR, NMR and mass spectra confirm the structure of the ring-closed product.

The Karl-Fisher analysis indicates the presence of 8.7% water. Elemental Analysis: C Η N

% calculated 46.4 8.3 6.8 35% found 46.1 8.5 6.4.

The product appears homogeneous when examined by chromatography on a thin silicon dioxide layer after elution with a mixture of butanol / acetic acid / water 12: 3: 5. After silylation, however, chromatography in the vapor phase brings the presence of two epimers in equal amounts. to the light.

8220153 18

Example III. 2,2,5- (S) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid, 1- (R, S) -oxide.

The mother liquors of the recrystallization and the acetone of washing the product of the previous example, carefully preserved, are evaporated to dryness under reduced pressure. The residual white solid is recrystallized from ethyl acetate. The solid obtained is then triturated with acetone, then recrystallized from a mixture of acetone and water. 0.57 g (7% based on the bromohydrate of S (2-bromopropyl) -penicillamine) 2,2,5- (S) -trimethyl-1,4-thiazan-3- (thus obtained) S) -carboxylic acid enriched to 98%.

Melting point 328 ° C (dec.).

[Α] 25D = 131 ° (C = 0.5; water).

Elemental Analysis: C Η N

15% Calculated 50.8 7.8 7.4% found 50.5 8.0 7.7.

The previous sulfide is dissolved in 10 ml of acetic acid, to which 0.4 ml of 30% hydrogen peroxide is added. The mixture is stirred at ambient temperature for 24 hours, then concentrated under reduced pressure to obtain a syrup. 25 ml of acetone are added and the mixture is left at 5 ° C overnight. The crystalline solid is filtered off and redissolved in 10 ml of water. The solution is concentrated to obtain a syrup. The preliminary treatment is repeated to give 0.29 g (47%) of a white solid consisting of a mixture of two epimed sulfoxides.

Melting point 230 ° C (dec.).

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

The Karl-Fisher analysis indicates the presence of 2.2% water.

Elemental Analysis: C Η N

% calculated 45.8 7.5 6.7% found 45.6 7.4 6.9.

Example IV. 2,2,5- (R) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid.

To a suspension of 5 g (33.6 mmol) D-penicillamine in 28 ml water, 3.25 ml (40.3 mmol) of freshly distilled chloroacetone are added with stirring. When the environment has become homogeneous, the reactor is immersed in an ice bath. A 20% solution of sodium hydroxide in water is then added dropwise to a pH 40 of 3.5 without the temperature exceeding 10 ° C, then dropwise and ensuring that the temperature is not 30. ° C, a solution of 1 g (26.4 mmol) of sodium borohydride in 5 ml of alkalized water. At the end of the addition, the mixture is stirred at ambient temperature for another §§ hour. 37% hydrochloric acid containing water is then slowly added to a pH of 5.0. The final medium is then evaporated to dryness under an anhydrous pressure and 50 ml of absolute ethanol are added to the residue. The insoluble component is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residual uncolored oil is redissolved in 50 ml of water. It is evaporated to dryness under reduced pressure. The white solid obtained is mixed with 10 ml of water and the mixture is heated to solution under reflux. The solution is allowed to crystallize by storage at ambient temperature for 4 hours, then at 5 ° C overnight. The solid is filtered off and dried.

15 Weight: 4.3 g (20.7 mmol; 62%).

Melting point 310 ° C (dec.).

[<X] D = + 93 ° (C = 1; water).

The Karl-Fisher analysis indicates the presence of 8.7% water. The IR, NMR and mass spectra are in accordance with the expected structure. The HPLC analysis shows the homogeneity of the final product.

Elemental Analysis: C Η N

% calculated 46.4 8.3 6.8% found 46.3 8.3 6.9.

Analyzed with a thin layer of silicon dioxide, the product has an Rf of 0.69 after elution with a mixture of methanol / acetic acid / chloroform 6: 1: 4.

Example V. 2,2,5- (R) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid, 1- (R) -oxide.

A solution of 3.5 g (16.7 mmol) of the product of the previous example in 17 ml of a mixture of acetic acid / water 1: 1 is obtained, then it is cooled in an ice bath. 1.94 ml of 30% hydrogen peroxide is added dropwise with stirring over 5 minutes. At the end of the addition, stirring is maintained for 8 hours while 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 to obtain a solid. It is then dissolved in 6 ml of water. 8220153 is slowly added with stirring 15 ml of acetone. The mixture is stirred at ambient temperature for ½ hour and filtered. A first portion of the desired sulfoxide is thus obtained. A second portion was obtained by cooling the mother liquors at 10 ° C with the addition of 10 ml of acetone, followed by filtration after 15 minutes of crystallization. Total weight: 2.2 g (9.9 mmol; 59%).

Melting point 246 ° C (dec.).

[Α] D = -3.5 ° (C = 1.1N HCl).

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

The analysis of the corresponding chlorohydrate by the X-ray method allows confirmation of the absolute structure.

The Karl-Fisher analysis indicates the presence of 8.2% water.

15 Elemental Analysis: C Η N

% calculated 43.0 7.7 6.3% found 43.2 7.6 6.4.

When tested with a thin layer of silica, the product has an Rf of 0.42 after elution with a mixture of methanol / acetic acid / chloroform 6: 1: 4.

The HPLC analysis confirms the homogeneity of the product. Example VI. 2,2,5- (R) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid, 1- (S) -oxide (chlorohydrate).

The crystallization mother liquors of the second portion of the product of the previous example, carefully stored, 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 a pH of 1 by means of hydrochloric acid containing 37% water. The solution is concentrated to obtain a wet weight of 3.0 g and this residue is stored overnight at 5 ° C. The solid, which has a rotational power of 79 ° in water, is filtered off. The crystals are dissolved in 10 ml of water and evaporated under reduced pressure to obtain a syrup. 1.5 ml of acetone are added and the mixture is left at 5 ° C overnight. It is filtered. The rotational power of the solid is 84 °. A new crystallization operation provides a product of sufficient purity. Weight: 0.22 g (0.9 mmol; 5% based on the product of Example IV used).

Melting point 275 ° C.

[Cx] D = + 85 ° (C = 1; water) + 73 ° (C = 1; 1 N HCl).

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

The Karl-Fisher analysis indicates the presence of 0.5% water. Elemental Analysis: C Η N

% calculated 39.9 6.7 5.8 5% found 39.9 6.7 5.9.

The HPLC analysis indicates a purity of 99.5%.

Example VII. 2,2,5- (R) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid, 1,1-dioxide.

5 g (22.4 mmol) of the product of Example V are dissolved in 300 ml of 0.5 N sulfuric acid containing 0.5 N. A solution of 2.5 g of potassium permanganate in 300 ml of water is then added over 2 hours. At the end of the addition, the mixture is stirred at ambient temperature for 2 hours, then 12 ml of formic acid are added. It is filtered, then 0.5 N aqueous barium hydroxide is added until the end of the precipitation. The filtrate is filtered and passed through an ion exchange resin column of the strongly acidic type, conditioned in the H + form. The resin is solidified to the neutrality of the effluent, then eluted with 3 N ammonia. The eluate is concentrated under reduced pressure to obtain a volume of about 100 ml. The solution of the resulting ammonium salt is then filtered through a weak acid type resin column. The filtrate is evaporated under reduced pressure to obtain a syrup to which 15 ml of acetone are added. It is stirred for 2 hours, then it is filtered.

25 Weight: 2.7 g (11.6 mmol; 52%).

Melting point 232 ° C (dec.).

[<x] q ° = + 2 ° (C = 1.1N HCl).

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

The Karl-Fisher analysis indicates the presence of 6.2% water. Elemental Analysis: C Η N

% calculated 40.7 7.1 5.9% found 40.7 7.3 5.9.

When tested with a thin layer of silicon dioxide, the product 35 has an Rf of 0.38 after elution with a mixture of butanol / acetic acid / water 5: 2: 3.

Example VIII. 5-methyl-1,4-thiazan-3-carboxylic acid, hydantoin.

3.9 g (24.0 mmol) of 5-methyl-1,4-thiazan-3-carboxylic acid and 2.3 g (28.8 mmol) of potassium isocyanate are added successively to 25 ml of water. 40 The mixture is heated to boiling and then returned to ambient temperature 8220153 22. To the aidus solution of 5-methyl-4-hour-indo-1,4-thiazan-3-carboxylic acid is then added 34 ml of 10% aqueous hydrochloric acid. Concentrate under reduced pressure to a volume of about 20 ml. The mixture is stirred for about one hour at ambient temperature, then it is filtered. The solid is finally recrystallized from water. Weight: 2.5 g (13.4 mmol; 56%).

Melting point 189 ° C (dec.).

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

10 Elemental analysis: C Η N

% calculated 45.2 5.4 15.0% found 44.9 5.5 15.1.

Example IX. 1-ethoxycarbonylethyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide (oxalate).

To a solution of 3.7 g (17.4 mmol) of the product of Example V in 37 ml of water is added a solution of 0.5 N aqueous potassium hydroxide until the pH reaches 9. The resulting solution is evaporated to dryness under reduced pressure. The residue is suspended in 40 ml of DMF. 3.2 g (17.6 mmol) of ethyl 2-bromopropionate are then added dropwise. The medium is stirred at ambient temperature for 48 hours, then diluted with 100 ml of water before being extracted with chloroform. The organic extract is dried, then evaporated to dryness under reduced pressure. The residual oil is taken up in 50 ml of ethanol, then a solution of 1.6 g (17.6 mmol) of oxalic acid in the minimum of the same solvent is added. It 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.

8220153 • f 23

Melting point 196 ° C (dec.)

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

The Karl-Fisher analysis indicates the presence of 3.1% water.

5 Elemental analysis: C Η N

% calculated 44.1 6.5 3.4% found 44.1 6.7 3.3.

Chromatographed on a thin silicon dioxide layer, the product has an Rf of 0.52 after elution by means of a mixture of bu-10-tanol / acetic acid / water 5: 2: 3.

Example X. 1-pivaloyloxyethyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide (oxalate).

To a solution of 3.7 g (16.4 mmol) of the product of Example V in 37 ml of water, an aqueous solution of 0.5 N potassium hydroxide is added until the pH reaches 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 with good stirring. At the end of the addition, the stirring treatment is maintained at 40 ° C for 48 hours. The resulting medium is diluted with 100 ml of water, then extracted with chloroform. The organic extract is dried, 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, then the precipitate which is formed is filtered. This is finally purified by recrystallization from ethanol. 4.2 g (9.9 mmol; 60%) of a crystalline white solid are obtained.

Melting point 214 ° C (dec.).

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

Elemental Analysis: C Η N

% calculated 48.2 6.9 3.3% found 48.1 7.2 3.2.

Chromatographed on a thin silicon dioxide layer, the product has an Rf of 0.65 after elution by means of a mixture of butanol / acetic acid / water 5: 2: 3.

Example 11. Methyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate (chlorohydrate).

40 A solution of 32.2 g of potassium hydroxide in 640 ml of methanol is cooled to -5 ° C 8220153 24. 47.9 g (0.24 mol) of the chlorohydrate of the methyl ester of penicillamine are added, then 25.0 g of chloroacetone are added dropwise. It is stirred for 1 hour at the initial temperature, then the medium is brought to a pH of 6.5 by means of ethanolic hydrochloric acid. 6.2 g of sodium borohydride in small amounts are then added. At the end of the addition, stirring is continued for 1 hour, always at the same temperature. The excess hydride is destroyed by addition of concentrated hydrochloric acid, and the solution is then neutralized with 10% aqueous hydrogen carbonate. The aqueous solution is extracted with chloroform. The extracts are dried, 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 the saturated hydrochloric acid solution in the ether causes the precipitation of a solid chlorohydrate.

This is filtered and reprecipitated with two repetitions of its methanolic solution by addition of ether.

Weight: 17.2 g (30%).

Melting point 204 ° C (dec.).

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

Elemental Analysis: C Η N

% calculated 45.1 7.6 5.8% found 45.1 7.7 5.8.

Example XII. 2,2,4,5-tetramethyl-1,4-thiazan-3-carboxylic acid.

1.68 g (20 mmol) of sodium hydrogen carbonate and 1.5 g (0.66 ml; 10.5 mmol) of methyl iodide are added successively to a solution of 2.1 g (10 mmol) of 2.2.5 trimethyl-1,4-thiazan-3-carboxylic acid in 50 ml of methanol. The resulting medium is stirred at ambient temperature for 24 hours, then it is heated at the reflux temperature for the same period of time. The mixture 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 an ion exchange resin column of the strongly acid type conditioned in the H + form. The resin is washed with water to neutrality of the effluent, then it is eluted with 1 35 N ammonia. The eluate is evaporated to dryness under reduced pressure. The remaining solid is recrystallized from ethyl acetate. 1.4 g (6.8 mmol; 68%) of pure product are obtained on this free form.

Melting point 201 ° C (dec.).

40 The IR, NMR and mass spectra are in accordance with the expected structure 8220153.

Elemental Analysis: C Η N

% calculated 53.2 8.4 6.9% found 52.8 8.5 7.0.

Chromatographed on a thin silicon dioxide layer, the product has an Rf of 0.60 after elution with methanol.

Example XIII. 5-n-butyl-2,2-dimethyl-1,4-thiazan-3-carboxylic acid (chlorohydrate).

7.5 g (50 mmol) of D-penicillamine are added to 40 ml of water, which was kept at a temperature between 0 and 5 ° C. While stirring well, 9.5 g (53 mmol) of 1-bromo-2-hexanone are added dropwise and simultaneously, on the one hand, in about 10 minutes and, on the other hand, 25 ml (50 mmol) of 2 N aqueous sodium hydroxide in about 30 minutes. At the end of the addition, the stirring treatment and the temperature are maintained for an additional 1 hour, then the temperature is adjusted to about 15 ° C. 50 ml of methanol are added, then gradually a solution of 1.5 g (39 mmol) of sodium borohydride in 90 ml of alkalized water. The medium is allowed to warm to ambient temperature and then extracted with chloroform. The organic extract is dried, then evaporated under reduced pressure. The remaining red oil is taken up in 50 ml of diisopropyl ether, to which sufficient ethanol is added to obtain a solution. Hydrochloric acid ether is then added until the end of the precipitation, then sufficient ethanol until the reddish brown mass gives a beige solid. It is filtered, washed with diisopropyl ether and dissolved warm in ethanol. Diethyl ether is added to permanent cloudiness, then allowed to cool. The curled houses are recovered and purified a second time.

Weight: 8.0 g (30 mmol; 60%).

30 Melting point 225 ° C (dec.).

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

Elemental Analysis: C Η N

% calculated 49.3 8.3 5.2 35% found 49.5 8.2 5.5.

Chromatographed on a thin silicon dioxide layer, the product has an Rf of 0.62, after elution with a 5: 2: 3 butanol / acetic acid / water mixture.

Example XIV. 5-methyl-2-phenyl-1,4-thiazan-3-carboxylic acid 40 (chlorohydrate).

8220153 26

1 g (4.3 mmol) of treo-g-phenylcysteine chlorohydrate are dissolved in 12 ml of water. The solution is cooled on an ice bath, then the pH is adjusted to 7.0 using 20% aqueous sodium hydroxide. 0.42 g (4.5 mmol) of fresh redistilled chloroacetate-5 tons are added. After stabilizing the pH for 30 minutes, 2 N aqueous sodium hydroxide is added to neutrality. The ice bath is still stirred for 1 hour, then a solution of 0.13 g (3.4 mmol) of sodium borohydride in 2 ml of alkalized water is added. An uncoloured and transparent solution 10 of which the pH is 9.1 is obtained. The mixture is stirred for 1 hour and allowed to come to ambient temperature. The pH is adjusted to 6.0 by means of 37% aqueous hydrochloric acid. It is evaporated to dryness under reduced pressure. The suitably dried product is taken up in 10 ml of ethanol, to which 2 ml of 22% ethanolic hydrochloric acid are added. It is stirred for 15 minutes, then it is evaporated to dryness under reduced pressure. The residue is recrystallized from a 4: 1 isopropanol / ethanol mixture with two repetitions.

Weight: 0.66 g (2.4 mmol; 56%).

Melting point 248 ° C (dec.).

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

Elemental Analysis: C Η N

% calculated 52.6 5.9 5.1% found 52.3 5.9 5.4.

Example XV. 2,2,5- (R) -trimethyl-1,4-thiazan-3- (S) -carboxylic acid, 1- (R) -oxide (without intermediate isolation).

To a suspension of 10 g (67 mmol) (D) -penicillamine in 56 ml of water at ambient temperature, 7.4 g (80 mmol) of freshly distilled chloroacetone are added with good stirring. After a reaction for 2 hours, 20% rs aqueous sodium hydroxide is added to a pH of 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 3030 ° C). After a reaction of 1 hour, the solution is acidified by adding 50 ml of acetic acid. The reaction medium (0 ° C.temperature ^ 5 ° C.) is cooled and 2.4 g (0.74 mmol) of 30% hydrogen peroxide are added dropwise. The temperature is maintained between 0 ° C and 5 ° C for 8 hours, then at 20 ° C for 4 hours.

It is concentrated under reduced pressure. The residue is taken up in 40 ml of methanol, the suspension is filtered and the ethanolic 8220153 27 solution is added with good stirring to 240 ml of ethyl acetate. It is allowed to crystallize at 20 ° C for 1 hour. The precipitate is filtered off and washed with acetone. The crude amino acid is crystallized from a mixture of 1: 4 / acetone 1: 4. Thus, 7.4 g (33.3 mmol; 54%) of a white crystalline solid identical to the product of Example V are obtained.

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

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rH ____ 0 M · nj P CO w Η Μ <Ω \ Ω 8220153 33 (1): It usually concerns a decomposition temperature. The informed value corresponds to the beginning of the phenomenon.

(2): All listed products give a correct elemental analysis C.H.N.

5 (3): Hydrated product.

(4): Chlorohydrate.

(5): Free base or zwitterion.

(6): Qxalate.

(7): Mixture of isomers whose components, separated, appear further 10 in the table.

(8): Configuration of the asymmetry centers: 1- (R) -3- (S) -5- (R).

(9): Configuration of the asymmetry centers: 1- (S) -3- (S) -5- (R).

15 (10): Configuration of the asymmetry centers: 1- (R) -3- (S) -5- (R).

(11): Configuration of the asymmetry centers: 3- (S) -5- (S).

(12): Configuration of the asymmetry centers: 20 1- (R, S) -3- (S) -5- (S).

(13): pht means 3-phthalidyl.

(14): pyr means 2,5-dioxo-1-pyrrolidinyl.

(15): Configuration of the asymmetry centers: 3- (R) -5- (S).

25 (16): Configuration of the asymmetry centers: 1- (S) -3- (R) -5- (S).

(17): Configuration of the asymmetry centers: 3- (S) -5- (R).

(18): Hemi chlorohydrate.

The products of the invention have been subjected to a series of pharmacological tests, the method of which is described below. The results of these tests were reported in Table II, in which the numbers of the first column correspond to the numbers of the first column of Table I.

The LD50 have been calculated according to the method of Lichtfield and

Wilcoxon (J. Pharmacol. Exp. Ther. 99, 1949) and expressed in mg / kg. The products were administered to the mice orally.

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 gum solution of 1201 tragacanth gum were administered by oral wagon through an intragastric zone in groups of 5 male mice (CD1, Charles RLver strain, sober for 18 hours).

The dosages tested as a function of the observed activity range from 3000 to 3 mg / kg.

Behavior is studied 2, 4, 6 and 24 hours after treatment. Perception continues when the symptoms persist at that time. The deaths were recorded over the 14 days following treatment. None of the tested products induce an abnormal behavior in the mouse, nor do they prove to be toxic.

8220153 35

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Determination of the effect on fibrinolytic activity, on bleeding time and on blood loss.

The substance to be studied, suspended in a gum solution of 1% tragacanth gum, is administered to rats orally at a dose of 30 mg / kg. Blood will be drawn 1 hour or 3 hours after treatment. The plasma is separated by centrifugation and the euglobulins are precipitated.

Fibrinolytic activity is determined by the method of Astrup and Mullertz (Arch. Biochem. Biophys. 1952, 40, 346).

50 µl of a solution of euglobulins in a veronal buffer containing 0.25% gelatin are plated on 0.08% fibrin plates. After an incubation of 18 hours at 37 ° C, the diameter of the lysis zone is measured.

A score is assigned as a function of the ratio of the brinolytic activity of the treated rats and that of rats receiving a placebo. The meaning is the following:

Score 4: increase coefficient of fibrinolytic activity from 0.51 to 0.99.

Score 5: increase coefficient of the fibrinolytic activity from 1 to 1.5.

Score 6: increase coefficient of fibrinolytic activity from 1.6 to 2.

Score 7: increase in efficiency of the fibrinolytic activity from 2.1 to 2.5.

25 Score 8: increase coefficient of fibrinolytic activity from 2.6 to 3.

Score 9: increase coefficient of the fibrinolytic activity ^, 3.1.

To determine the bleeding time, the tail of the rats, which have been kept at ambient temperature for 2 hours, is moistened with ether and cut with the scalpel to 2 mm from the end; the 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 blood collection.

The increase coefficient of the bleeding time is the ratio between the bleeding time of the treated rats and that of the rats receiving placebo,

A score of 3 means an increase coefficient from 0.79 to 40 0.89.

8220153 39

A score of 4 means an increase coefficient of 0.9 to 1.09.

A score of 5 means an increase coefficient of 1.1 to 1.11.

A score of 6 means an increase coefficient from 1.12 to 1.22.

5 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 increase coefficient of 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.

20 A score of 9 means an increase coefficient ^ 3.1.

Two products of the invention have been the subject of deeper appreciation: they are derivative 7 and derivative 12 (free base of derivative 7 in hydrated form).

Compound 7 has been the subject of a 1-month toxicity study in the rat and monkey. This study has shown that its tolerance is complete up to the dose of 300 mg / kg / day.

The toxicity of compound 12 is excellent: the LD50 is greater than 8 g / kg in the mouse and rat. In the monkey it is completely tolerated up to the dose of 800 mg / kg.

After oral administration of the derivative 7 to groups of 4 rabbits at the doses of 2.5 to 50 mg / kg, an increase in fibrinolytic activity of the blood is observed, which is proportional to that of the administered dose . This increase is, for example, threefold 90 minutes after the administration of 5 mg / kg.

This effect manifests itself during repeated administrations: thus treatment with 10 mg / kg twice a day for 21 days increases the fibrinolytic activity of the blood by a value three times better than that of the control tests.

Intravenous perfusion of the derivative 12 at doses of 3 or 5 40 mg / kg / 10 min for 2 hours, an increase of 2.8 times the 8220153 40 fibrinolytic activity is observed from 10 to 30 minutes after the start of the perfusion for at least 3 hours after the end of the perfusion.

The activity of the compound 12 has also been revealed in the rat and monkey after oral administration. Finally, in humans, the oral administration of 100 to 800 mg effects an increase in proportion 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 to 2 g orally and from 10 mg to 10 1 g by injection or intravenous perfusion.

The products of the invention can be used in various galenic forms. The examples that follow are not limiting and relate to the galenic formulations containing an active product of the invention denoted by the letter A and which may be, for example, 2,2,5-trimethyl-1,4-thiazan-3 -carboxylic acid, 1-oxide. ethyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide.

2.2.4.5-Tetramethyl-1,4-thiazan-3-carboxylic acid.

1- (pivaloyloxy) ethyl-2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxi-20 de.

(octyloxycarbonyl) methyl-2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide.

1- (ethyl oxycarbonyl) ethyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide, 5-butyl-2,2-dimethyl-1,4-thiazan-3-carboxylic acid.

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

5-methyl-2-phenyl-1,4-thiazan-3-carboxylic acid. ethyl 3-carboxy-2,2-dimethyl-1,4-thiazan-5-acetate.

Gelatin capsules.

30 A 50 mg amidone Sta RX ^ 100 mg microcrystalline cellulose 60 mg very fine lactose crystals 132 rag colloidal silica 2 mg 35 hydrogenated castor oil 6 mg A 100 mg bicalcium phosphate 95 mg sodium lumidone glycolate 32.5 mg colloidal silicon 2 mg 8220153 41 magnesium stearate .

Tablets.

A 500 mg mannitol 95 mg 5 polyvinylpyrrolidone 27 mg polyethylene glycol 6000 powdered 8 mg A 300 mg amidone 60 mg lactose 130 mg 10 ethyl cellulose with low viscosity 20 mg talc 5 mg aerosil 5 mg.

Suppository.

A 600 mg 15 α-tocopherol 10 mg

Witepsol H 15 (semi-glyceride) 2600 mg.

Injectable solutions.

A 20 mg sodium chloride 2.5 mg 20 citric acid / sodium citrate buffer to pH 4.8 water injection to 1 ml.

A 50 mg propylene glycol 300 mg ethanol 50 mg 25 water for injection ad 1 ml.

Gelatin capsule dosed to 100 mg of the compound A and 300 mg of acetylsalicylic acid.

A 100 mg acetylsalicylic acid 300 mg 30 ethyl cellulose 60 mg lactose 40 mg aerosil 8 mg magnesium stearate 8 mg.

8220153 42

Tablet dosed up to 300 mg of compound A and 50 mg of dipyridamole. A 300 mg dipyridamole 50 mg hypromellose 25 mg 5 amidone 100 mg calcium stearate 8 mg.

Tablet dosed with 200 mg of compound A and 100 mg of suloctidil. A 200 mg suloctidil 100 mg 10 tween 80 8 mg ethyl cellulose 22 mg lactose 40 mg amidone 71 mg magnesium stearate 9 mg.

8220153

Claims (34)

C3-, C4-, C5-, Cg-, C7-, Cg-, C9-, C ^ o ~> cll “» Ciz alkyl group or an O-CH-COOR ^ group or an OCH-OCORn group R10 represents R10, wherein R ^ represents hydrogen or a C 1-8 or C 2- alkyl group and R 8 represents a straight or branched C 1 -C 2 -C 3 -C 3 C4, C5, Cg, C7, Cg, C9, C ^ q, Cjj, Cj ^ alkyl group, ^ R12 - an N group, wherein R12 and R13, which are identical or far - ^ R13 may be different, represent hydrogen, a straight or branched C1, C2, C3 or C4 alkyl group, 30. a 3-phthalidyloxy group or a 1- (2,5-dioxopyrrolidinyl) -1-ethoxy- 8220153 group R 4 represents a hydrogen atom, a straight or branched C 1 -C 2, C 3, C 4, C 5, C 5, C 7 or C 6 alkyl group, a straight or branched C 1 -C 2, C 3, C 4 - C5, Cg, C7 or Cg acyl group or 5 represents a C0NH2 group, R3 and R4 with the adjacent carbon and nitrogen atoms may form a hydrogenation ring, R5 and Rg, which may be identical or different, hydrogen, a straight or branched C 1, C 2, C 3, C 4, C 5, C 5, C 7 or C 6 alkyl group, a phenyl core optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight or branched Οχ, C2, C3, or C4 ~ alkyl group or with a straight or branched Οχ, C2 ~, C3, or C4 alkoxy group, a C H ^ COOR ^ group, where R14 is hydrogen, a straight or branched Cj-, C 2 -C 3 or C 4 -alkyl group, R 7 hydrogen, a straight or branched C 1 -O 2, C 3 or C 4 group, a gem. dimethyl group or a phenyl core, optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight or branched C 1, C 2, C 3 or C 4 alkyl group or with a straight or branched C 1, C 2, C 2, C 3 or represents C 4 alkoxy group, n may 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 straight or branched C 1 -C 4 alkyl group, R 5 or R 9 no hydrogen, a straight or branched C 1 -C 4 alkyl group or a phenyl core, as well as the salts of these compounds formed with pharmaceutically suitable 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 one or more of claims 1 or 2, characterized in that in the general formula I R3 is a hydroxyl group, an ORg group, in which R9 is a straight or branched C1 -C4 alkyl group, an OCH -COOR 1 - group or an OCHOCOR 2 - - group R 10 represents R 10, wherein R 1 represents hydrogen or a methyl group and R 1 represents a straight or branched C 1 -C 8 alkyl group. 8220153 Derivative according to one or more of claims 1 to 3, characterized in that in the general formula I 84 represents hydrogen or a methyl group. Derivative according to one or more of claims 1 to 4, characterized in that in the general formula I R5 and Rg, which may be identical or different, are hydrogen, a straight or branched C1 -C4 alkyl group or represent a C 1 -C 20 C 12 group, wherein hydrogen represents a C 1 -C 2 alkyl group. 6. Derivative according to claim 5, characterized in that in the general formula I R 5 represents hydrogen and R 1 represents a straight or branched C 1 -C 4 alkyl group. Derivative according to one or more of claims 1 to 6, characterized in that in the general formula I n has the values 0 or 1. Derivative according to claim 1, characterized in that the derivative 15 is selected from the group formed by the compounds: 2.2.5-trimethyl-1,4-thiazan-3-carboxylic acid, 1-oxide, ethyl 2,2, 5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide, 2.2.4.5-tetramethyl-1,4-thiazan-3-carboxylic acid, 1- (pivaloyloxy) ethyl 2,2,5-trimethyl-1, 4-thiazan-3-carboxylate, 1-oxi-20de, (octyloxycarbonyl) methyl 2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide, 1- (ethyl oxycarbonyl) ethyl 2,2 1,5-trimethyl-1,4-thiazan-3-carboxylate, 1-oxide, 5-butyl-2,2-dimethyl-1,4-thiazan-3-carboxylic acid, 2,2-dimethyl-5-isopropyl- 1,4-thiazan-3-carboxylic acid, 5-methyl-2-phenyl-1,4-thiazan-3-carboxylic acid, ethyl-3-carboxy-2,2-dimethyl-1,4-thiazan-5-acetate. 9. Intermediates, in particular for the preparation of the derivatives of έ§η or more of the preceding claims, corresponding to formulas II, III and VI: 8220153 i-^ -3 ^ CO- R 1, R 2 / C 2 R 2 -C-CH 2 S 4, Ir A, 6 II III VI wherein R 1, R 2, R 3, H 4, R 5, R 5, R 7 and n have the meanings given above. 10. Derivative as described above, especially in the examples given herein. 11. A process for the preparation of 1,4-thiazan-3-carboxylic acid derivatives and their salts, characterized in that a compound of formula II, formula III or compounds of formulas IV and V is made to close ring-10 such that a compound responds the formula I gives:? 1 ^ COR,? 1 .COR. R2-C-CH 0 Rz-c-CH J, 0) ns Vr4 («)" - ('VR4: T =. L \ h_C-Rr / VD II 3 R? R6 R? ^ II III κγ I Hs \ r r7-hc: ^ c ^ 1 7.xr2 r5 - c + 2 0 CH-COR. / h2n 15. IV in these formulas R1 to R7 and n have the meanings indicated above 8220153, wherein the intermediate obtained from the cyclization is then subjected to a reduction to obtain the derivative corresponding to the formula I, this last derivative or intermediate, as well as the derivatives of formula I obtained from the compounds of formulas II and formulas IV and V are optionally subjected to an oxidation, an alkylation or an acylation by the substituent R4, or a substitution of this substituent R4 by a group CONH2 followed by cyclization with the substituent R3 when the latter represents a hydroxyl group, to obtain a hydantoin group. 12. Process according to claim 11, characterized in that in a basic medium a derivative of formula II is cyclized. R i ll. COR.,; Ro-C-CH J j / \. NH-R- (0 n 5 / II 13. Process according to claim 12, characterized in that an organic or inorganic base is used, such as, for example, triethylamine, Ν, Ν-dimethylaniline, pyridine, alkali metal hydroxides or ammonium hydroxide. 14. Process according to claim 11, characterized in that in a basic or dehydrating medium a derivative of formula III R, XOR-1/0 R2-C - CH (0) n '^ Γ * 311 r5' is used. 1. b R7 R6 is cyclized, wherein X represents a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or an easily eliminable group such as, for example, a tosyl or mesyl group. 15. Process according to claim 11, characterized in that a 5,6-dihydro-2H-thiazine derivative VI 8220153 R2 r6 'h / A'cor3 VI is reduced to 1,4-thiazan of formula I, optionally followed by an oxidation to obtain the corresponding sulfoxide or sulfone. 16. Process according to claim 15, characterized in that the derivative VI is prepared by reaction between a cystene derivative IV R1 HS - C - CH - COR3 II r2 nh2 IV 10 and an α-halo ketone YCH-COR5 in which Y is a halogen atom such as f r7 represents chlorine, bromine or iodine. Process according to claim 11, characterized in that for the preparation of a derivative of the formula I, wherein R 4 represents a straight or branched C 1 -C 4 alkyl group or a straight or branched C 1 -C 18 group, an amine of the formula I, wherein R4 is hydrogen, in an alkaline medium subject to an alkylation or an acylation, with a reagent R4Z, 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 . Process according to claim 11, characterized in that for the preparation of a derivative of the formula I, in which R4 represents a C0NH2 group, a derivative of the formula I, in which R4 represents hydrogen, is reacted with a reagent of the formula MNCO wherein M represents a monovalent cation such as the sodium, potassium, lithium or ammonium ions. Process according to claim 11, characterized in that for the preparation of a derivative of the formula I, wherein R3 and R4 form a hydantoination with the adjacent carbon and nitrogen atoms, a 8220153 compound of the formula I, wherein R3 represents a hydroxyl group and R4 represents a C0NH2 group, in an acidic medium under optional heating. 20. Process according to claim 11, characterized in that for the preparation of a derivative of the formula I, wherein n = 1 or 2, a derivative of the formula I, in which n = 0 is treated with an oxidizing agent. 21. Process according to claim 20, characterized in that the oxidation is carried out at an indifferent walk stage of the processing of the 1,4-thiazane ring. Process according to claim 11, characterized in that a derivative of the formula I, in which R3 represents a hydroxyl group, is converted by esterification into a derivative in which R3 represents an OR9, OCHCOORjj or OCHOCORn group. R10 R10 23. Process according to claim 11, characterized in that a derivative of the formula I, in which R3 represents a hydroxyl group, an OR9, OCHCORO or OCHOCOR1 group, is converted by amidation R10 R10 to a derivative in which R3 represents a / r12 represents N group. r13 24. Process according to claim 11, characterized in that a derivative of the formula I, in which R3 represents an OR9, OCHCOORij or OCHOCOR ^ group, is converted by hydrolysis or R10 R10 aminolysis into a derivative in which R3 is a hydroxyl group or represents a ^ -R12 N group. ^ 13 25. A process according to claim 11, characterized in that a derivative of the formula I, in which R3 represents an / r12 N group, is converted by hydrolysis or alcoholysis to r13 to a derivative in which R3 represents a hydroxyl group or an OR9-, OCHCO2 group. OGHOCOR ^ group. R10 R10 26. A process for the preparation of 1,4-thiazan-3-carboxylic acid derivatives and their salts, as described above, in particular in the examples given herein. 8220153 < Pharmaceutical composition in particular for the treatment and prevention of certain circulatory system diseases, such as venous or arterial thromboses, characterized in that the composition comprises at least one of the compounds of the formula I 5 or ££ contains one of its salts together with ££ one of the appropriate pharmaceutical excipients or optionally other therapeutic agents such as antiplatelet agents. 28. A composition according to claim 27, characterized in that the composition is in the form of dragees, granules, tablets, 10 capsules, solutions, syrups, emulsions or suspensions containing additives or excipients customary for the pharmaceutical industry. . 29. A composition according to claim 27 or 28, characterized in that the composition contains at least one of the derivatives of the formula 15. in solution, in particular in sterile water or in peanut oil or ethyl oleate. 30. Method of using the derivatives of the formula I, in particular for the treatment and prevention of certain disorders of the organs of the circulatory system, such as venous or arterial thromboses, characterized in that they are administered with daily doses of 50 mg to 2 mg by the oral route and 10 to 1 g by injection or by intravenous perfusion. ******** 8220153