NO824398L - 1,4-TIAZANAN CARBOXYLIC ACID DERIVATIVES, PREPARATION AND USE OF THESE AND MIXTURES IN WHICH THESE DERIVATIVES ARE PRESENT - Google Patents

Description

The present invention relates to a 1,4-thiazancarboxyl derivative and salts of these compounds, methods for the production of these and pharmaceutical mixtures in which at least one of these derivatives is present, and methods for application of them.

in ! i '•'The derivatives according to the invention have the general formula !

in which j'R^ and R2/ which may be the same or different, is hydrogen, J ^a straight-chain or branched C^, C^, or alkyl residue j 'or a phenyl nucleus which is optionally substituted with a ; i^halogen atom such as fluorine, chlorine or bromine, with a straight chain; or branched , , C., or alkyl residue or with a j straight-chain or branched C.^, C 2 , or alkoxy acid residue, \ .R-^ and R 2 can together with the adjacent carbon atom form ;a

cycloalkyl radical with 3, 4, 5, 6, 7 or 8 carbon atoms, in which

one or more carbon atoms may optionally be substituted

■ I<1>i with a sulfur or oxygen atom or with a group SO, SO^ or NR^, in which Rg is hydrogen, a straight chain or for-;

'branched C^, C^ r or alkyl residue, a phenyl nucleus or benzyl group, j

, i 1 i ■ I i

R3 is in the case of a hydroxyl group<;->!a group ORg, in which Rg is a linear or branched C1-1,C-12 alkyl group, a group O-CH-COOR^ or a group j

,OCH OCOR^-j^, j-^where R, n is hydrogen or a C, or C alkyl-jio I residue and R.^ is a straight-chain or branched C^-C-^alkyl residue,- 1

I.I

i<1>Irest, i

j- a group

i ■ 1

in

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, in which R. „ and R , , 12 13, which can be! .

!

in ili! ke or different, is hydrogen or a straight chain

■or branched C^-C^- alkyl residue, or

i-jen 3-phthalidyloxy group or a 1-(2,5-dioxopyrrolidinyl)-jl-j-ethoxy group, I. jR^ is a hydrogen atom, a straight-chain or branched C^-Cg jalkyl residue, a straight-chain or branched C^-Cg acyl groupjor a group CONI-^ ,^R^ and R^ can form a hydantoin ring with the adjacent carbon and nitrogen atoms, | in iRj. and R 8 , which may be the same or different, is hydrogen; ^a straight-chain or branched C^-C^alkyl residue, a phenyl nucleus optionally substituted with a halogen atom such as fluorine, chlorine, or bromine, with a linear or branched C-^-C^alkyl residue<:>or with a straight-chain or branched C -^-C^alkoic acid residue, .or a group CI^COOR-^, where R.^is hydrogen or a ■ 'straight chain or branched C-C. alkyl residue, i i 14- i ,R^ is hydrogen, a straight-chain or branched C^-C^ alkyl- j Irest, a gem-dimethyl residue or a phenyl nucleus optionally sub-,

; 1 " ■ i i

.substituted with a halogen atom, such as fluorine, chlorine or bromine, jwith a straight-chain or branched C₁-C₄alkyl radical or with j;a straight-chain or branched C₁-C. alkoc acid rest, and i

! i n can have the value 0, 1 or 2. ,

If R^, R^, R^ and R^ are hydrogen and if R^ is a hydroxyl group or a straight-chain or branched C-^-C^ alkyl residue, ,' is not Rj. and R 8 hydrogen, a straight chain or branched C 2 -; 'C4. alkyl residue or a phenyl ring.

According to a preferred embodiment of the invention, this is a compound of formula I in which R, and R„, which may be the same or different, means hydrogen or a straight

IN

'chained or branched C₁-C₂-alkyl radical, R₂ means a hydroxy-jSyl group, a group ORg in which R₂ means a straight-chain or] is '.branched C₂C₂-alkyl group, a group O-CH-COOR or a

j 14 ' i 11

Igroup 0-CH-OCOR, , in which R, „ Rn _

In i 111010

!<R>10

i j means hydrogen or a methyl residue and R^^ means a straight-chain or branched C^-Cq alkyl residue, R^ means hydrogen or a simple methyl group, R and R^, which may be the same or different, means hydrogen, a straight-chain or branched C, -C. alkyl-14 in ;

residue or a group Cf-^COOR^ in which R-^ means hydrogen or a C -C_ alkyl group, R-, means hydrogen and n can have the value

i 11 1"* i ; 0 !i ; or 1... 1ii

A preferred class of compounds of formula I is that; in which R^ and R^ mean hydrogen or a methyl group, R^ meansj a hydroxyl group.or a group OR^ in which R^ means a j j straight-chain or branched C^-C^-alkyl group, R^ means hydrogen or a methyl group, R,- means hydrogen and Rg means a<1>straight-chain or branched C-^-C^ alkyl group, R^ means hydrogen and n can have the value 0 or 1.

• 1 !

Examples of compounds according to the invention are: l 1-oxo-2,2,5-trimethyl-1,4-thiazan-3-carboxylic acid, ethyl 1-oxo-■2,2,5-trimethyl-1,4-thiazan- 3-carboxylate, 2,2,4,5-tetramethyl-;

1,4-thiazane-3-carboxylic acid, 1-(pivaloyloxy)-ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, (octyloxycarbonyl)-methyl l-oxo-2, 2,5-trimethyl-1,4-thiazane-3-carboxylate, 1-(ethoxycarbonyl)-ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 5 -butyl-2,2-dimethyl-1,4-thiazane-3-carboxylic acid j 2,2-dimethyl-5-isopropyl-1,4-thiazan-3-carboxylic acid, 5-methyl-: i 2-phen<y>1-1,4-thiazan-3-carboxylic acid and ethyl 3-carboxy- 2, 2-dimethyl-1,4-thiazan-5-acetate.

If the derivatives according to formula I are present in the form of acid j

IN

. addition salts, they can by usual methods be transferred i to-j i

IN

corresponding free bases or in salts with other acids'. | in

! The most commonly used salts are pharmacologically tolerable, non-toxic acid addition salts which are formed with suitable inorganic acids, e.g. hydrochloric, sulfuric or phosphoric acid, or I ! |me' d suitable organic acids such as aliphatic, cvkloalikfa! tisk'e, li'. Aromatic, araliphatic or heterocyclic carboxylic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, gluceronic acid, malic acid , fu-j maric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenyl-acetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminesulfonic acid, stearic acid, Aligic acid, (3-hydroxy-ipropionic acid, (3-hydroxybutyric acid, oxalic acid, malonic acid, galactic acid and galacturonic acid. These salts can also be derived[

i from natural or synthetic amino acids such as lysine, j glycine, arginine, ortitin, asparagine, glutamine, alanine, valine!, threonine, serine. leucine, cysteine etc. j

If R^ is a group OH, the present invention also covers salts formed between the resulting carboxylic acid group in formula I and bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, magnesium hydroxide and calcium hydroxide, and also the internal salts<1>

(zwitterions)_ . |

i The compounds of formula I may have one or more centers of asymmetry and may exist in the form of optical isomers, racemates or diastereoisomers; which forms are all subject to the present invention. The optical isomers can be prepared: by stereospecific or stereoselective synthesis or also 1 by resolution of the racemates according to the usual method, e.g. by forming diastereoisomeric salts by reaction with optically active acids such as tartaric acid, diacetyltartaric acid,: j tatranilic acid, digenzoyltartaric acid and ditolyoyltartaric acid, separate ! the mixtures of diastereisomers, e.g. by crystallization ■or chromatography, and then release the optically active | ■bases from these salts. The optically active compounds with j

! jigfoaI nrmgesml atI ekrain aloegrs. to Blfra■' enmdsintgielnle es of by that asbterurkoe ismoperte isk can actadive iul!tl- esj

! = i I in the same way as the diastereomeric salts mentioned above.

jArterial and venous thrombosis disorders often constitute a very j important cause of death and cause deaths in particular in western j jcountries. The products according to the invention open a new therapeutic! 'way which is different on the one hand from the compounds that affect platelet functions and on the other hand from the action of the fibrinolytic enzymes. The increase in the fibrinolytic activity of the blood following an increase in the synthesis and/or release of natural activators of fibrinolysis, resulting from oral or<p>arenteral administration of the products according to the present invention, enables important tera-

in peutic application under safer conditions. Thus, in deep venous thrombosis, its often fatal consequences, namely, pulmonary embolism, could be avoided by an oral treatment before and in the weeks after surgical interventions, which involve risk. IN

in i

i It is also possible to prevent, thrombosis complicating phlebi<i>tt in primary or secondary surface veins during periods of long immobilization of patients. The products according to the invention can also be used under conditions where a drop in fibrinolytic activity in the blood takes place, such as e.g. after a surgical intervention, under general anesthesia or in cases of; diabetes treated with insulin. To. finally, either alone or in conjunction with substances that inhibit the adhesion and aggregation of the platelets, the <p>roducts according to the invention are suitable for preventing recurrent arterial or venous

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thrombosis attack. Thus, it is known in patients after;

a cerebral or coronary thrombosis (myocardial infarction)

that the risk of recurrence justifies the use of preventive treatment.

.i i The products according to the invention are active after oral administration, which makes them easy to use, and they can be given over; long periods of time in contrast to the often fibrinolytic substances, as they lack enzymatic activity, are not immuno-

'■ geI ne and works through activators that are normally present; the organism. Their use alone or in conjunction with jsubstances that prevent platelet aggregation enablesj in a new way to treat and prevent arterial and venous! , thrombosis.

l i The above invention also requires pharmaceutical mixtures, which as active ingredient contain at least one j1 compound with the general formula I and/or one of its i!i

.salts with a pharmaceutical carrier. These compositions are formulated so that they can be given orally, rectally or parenterally.

<!/>'Thus, e.g. the compositions for oral administration may be liquid or solid and may be given in the form of tablets, capsules, granules, powders, syrups or suspensions; and such mixtures include additives and excipients that are generally used in galenic pharmacy, inert diluents, explosives, binders and lubricants such as lactose, starch, talc, gelatin, stearic acid, silicic acid, magnesium stearate, polyvinylpyrrolidone, calcium phosphate, calcium carbonate etc. 1.

Such formulations can be prepared to prolong the bursting reaction and consequently the duration of action of the active ingredient.

The aqueous suspensions, emulsions and the oil solution are prepared in the presence of sweeteners such as dextrose or glycerin and flavoring agents such as e.g. vanilla, and may also contain thickeners, wetting agents and preservatives.

The oil-active emulsions and solutions are prepared in a vegetable or animal oil and may contain emulsifiers, flavourings, dispersants, sweeteners and antioxidants.

I: sterile water, an aqueous solution of polyvinylpyrrolidone, I in peanut oil, ethyl oleate, etc. used as a carrier for parenteralj in administration. These aqueous or oily injectables; The solutions may contain thickeners, wetting agents, dispersing agents and gelling agents. j

I! IN

i The compounds according to the invention are produced according to methods which form part of the present invention) and : which are defined below. In cases where the methods give rise to the production of new intermediate products, these new intermediate products and also the method used in their production form part of the present opip-

invention. in \i

r<!>

. According to a first method, a vinylthioete is cyclized. with formula II prepared according to the method described by A.L. Virtanen et al. in Acta Chem. Scand., 1966 , _20, ! 1.163-1.185 is cyclized according to the reaction equation

The cyclization is preferably carried out in a basic environment, the base

. can be organic such as triethylamine, pyridine or N,N-dimethylaniline or inorganic such as e.g. alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or

in also ammonium hydroxide.

If the base used is an organic base, the solvent will preferably be an inert organic solvent such as chlorinated solvents such as chloroform or ethylene chloride, aromatic or aliphatic hydrocarbons such as benzene, toluene or the various petroleum ether fractions, or also solvents such as acetonitrile, N,N-dimethylformamide or dl-methylsulfoxide. If the base is inorganic, the solvent used will preferably be water and the concentration of it in the basic solution will be 0.01 N to 10 N and preferably 0.3 N to 2 N. The reaction takes place at a temperature between 0°C and the solvent reflux temperature. However, it may be advantageous to carry out the reaction near room temperature,! especially if the reactant or products contain an usta-bdrial ssttieskre eobiseotmiengr eslosm erl. one is isomerized if it is used for j

Another method consists in carrying out cyclization of a cystein derivative III prepared according to the method described by J.F. Carson et al. in J. Org. Chem. _29, 2 , 203 (1964) according to the following reaction equation:

In the ionic equation of this reaction, R^, R^ , R^ , R^ , R^ , Rg , R-, and n have the above meanings and X is a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or a group, which can be easily removed, such as e.g. a tosyl or mesyl group.

If the cyclization is carried out in a basic medium, the conditions described for the first method can be used in the present case.

If the cyclization is carried out in an acidic medium, a mineral or organic acid is used, such as hydrochloric, hydrobromic, hydrogen iodide, phosphoric, sulfuric, formic or acetic acid.' ! £>e! t is also possible to use de' hydration agents such as f1 . eg phosphorus pentoxide, concentrated sulfuric acid or a carbodiimide such as dicyclohexylcarbodiimide.

IN

These reactions are generally carried out in inert organic solvents such as chlorinated solvents such as chloroform or methylene chloride, aromatic di aliphatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene or petroleum ether, or also solvents such as dimethylsulfoxide or N,N-dimethylformamide . The reaction takes place at a j j temperature between room temperature and the reflux temperature of the solvent in question. j j

In i

i According to another method, a cysteine derivative IV is cyclized by reaction with an α-halogen ketone V; whereby an unsaturated: cyclic compound VI' is formed, which is then reduced and \ j gives derivative VII according to the reaction equation: ;

in'

IN

<R>l'R2 'R4' R5°g R7 are defined above and Y is a halogen atom such as chlorine, bromine or iodine.

in i

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

The bases that can be used are alkali metal hydroxides such as sodium hydroxide or potassium hydroxide or alkali metal alcoholates such as e.g. sodium methanolate or potassium meta-,

'<!>i nolate, sodium ethanolate or potassium ethanolate or sodium t-butanolate or potassium t-butanolate.<;>

i The reaction takes place at a temperature between -20^C and i<j>j the reflux temperature of the solvent; and it is preferably carried out at a temperature between 0 o C and room temperature. in

A dehydrating agent such as e.g. a molecular sieve • ! can advantageously be added to the reaction mixture.

in

i Derivative VI can be isolated and purified, or alternatively the crude reaction mixture can be used directly in the reduction step.

The imine VI is reduced in the presence of 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 this is carried out at normal pressure and preferably at a higher pressure, or also by means of an alkali metal hydride such as sodium borohydride, in a solvent such as methanol or by means of lithium aluminum hydride in a solvent such as ether or tetrahydrofuran..

In general, the reduction takes place at room temperature, | but depending on the reactivity of the system it may sometimes be advantageous to heat the reaction mixture or to cool it. | j An acid such as e.g. hydrochloric acid, sulfuric acid or acetic acid! can sometimes catalyze the reaction.

i To prepare sulfoxides it is possible to use reagents such as iodine, bromine in water or in the presence of acet ions!.

i or also complexed by pyridine, peracids such as peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, N-halogen succinimides such as N-bromosuccinimide, hypochlorite such as sodium hypochlorite or t-butyl or i-propyl hypochlorite, j j

periodates such as sodium periodates, hydrogen peroxide in the vicinity

• ■ 'in the presence of acetic anhydride or in the presence of vanadium pentoxide in t-butanol, nitrates such as acetyl nitrate or cerium

in ammonium nitrate, oxides such as chromium (VI).oxide in pyridine, vanadium pentoxide in the presence of oxygen, or nitrogen j pentoxide, peroxides, ozone, oxygen in the singlet or triplet state,' acids such as nitric acid, chromic acid or Caro's acid, or also other reagents such as sulfuryl chloride, ; i 1-chlorobenzotriazole, chloramine, N-chloro-nylon 6,6, iodobenzene'' dichloride, iodosobenzene, iodobenzene diacetate, N-chlorotriazole, ! 2,4,4,6-tetrabromocyclohexadienone or chloroauric acid (HAuCl^). These oxidation reactions will be carried out in solvents such as e.g. water, acetic acid, chloroform, methylene chloride, carbon tetrachloride, methanol, t-butanol or acetone.

To prepare sulfones, it would be advantageous to use reagents such as hydrogen peroxide, preferably in the presence of zirconium salts, peracids such as peracetic acid, monoperthalic acid and m-chloroperbenzoic acid (in the case of oxidation with peracids, catalysts based on transition metals would be used with advantage) potassium permanganate in acidic or basic medium, sodium dichromate or potassium dichromate, osmium tetroxide, selenium oxide, t-butyl hypochlorite, nitric acid, ozone, oxygen, with advantage in the presence of. iridium salts or rhodium-; salts, iodobenzene dichloride or periodic acid, or use, electrochemical oxidation. These reactions will be carried out in solvents such as water, acetic acid, chloroform, methylene-.

' I chloride, methanol, ' ethanol, isopropanol, t-butanol, dioxane ' Ii I 1 acetone .j<1>or acetone....'

In certain cases, it may be advantageous to carry out oxidation

! IN

the oxidation reactions described above on compound Ir' in which the groups sensitive to the oxidizing agent are protected. il i l ! in! In the cyclization, the reduction oxidation step described below can also form part of a continuous process that does not require the isolation of any intermediate.

It should be pointed out that the transfer of the derivative I in which n = 0 to the derivative I in which n = 1 or 2 can be carried out at every step in the preparation of the 1,4-thiazan ring. in

When the substituent R. is a straight-chain or branched C-^; -Cg.!i alkyl group or a straight-chain or branched C-^-Cg acyl-j group, it is introduced by alkylation or acylation of the amine according to the reaction equation:

L

R^, R^, R^, R^, R^, Rg, R_, and n are as indicated above.

Z is a halogen atom such as chlorine, bromine or iodine, or a group, which can be easily removed, such as e.g. tosyl or mesyl group.

The reaction usually takes place in an inert organic solvent such as chlorinated hydrocarbons such as chloroform or

In methylene chloride, aromatic or allphatic hydrocarbons<:>such as benzene, toluene or petroleum ether, alcohols such as methanol and

<;>me1 etalnloom l, roemltleemr poegrsata . uar ceog tonrietakrisl ionog sbelatendrein.. gTeenms pettriallbtuakreen løplsiIg-geri temperature. The reaction can advantageously be carried out in the presence of an organic base such as pyridine, triethylamine or N,N-dimethylaniline, or an inorganic base such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates or finely powdered lime.

The alkylated derivative can also be prepared by reducing the corresponding acylated derivative according to usual methods.

i The substituent R^ = CONH^ is easily introduced by reacting the derivative VIII with an alkali metal isocyanate or ammonium isocyanati

i i or isocyanate according to the reaction equation: j

IN

In this reaction's ionic equation, R^, R^, R3 ' ^5 ' Rg ' have R and ri

the meanings given above, and M is a monovalent cation -! such as sodium, potassium, lithium or ammonium ions.

The reaction is easily carried out in water at a temperature between room temperature and reflux temperature.

The hydanthioin XI is prepared by heating derivative X in which <\>R^ is a hydroxyl group in an aqueous solution of acid.

in •

i!I

' ' ..... 1 . IN

in

In this reaction equation R^, R2 , R^, R,., R^R^and n have in front

■ indicate meaning. The acid used is a mineral acid such as halogen-containing hydrogen acids such as hydrochloric acid, hydrogen bromide or hydrogen iodide, or nitric acid, sulfuric acid or also phosphoric acid.

i The reaction mixture is generally heated to a temperature close to the reflux temperature of the solution. '

The transfer of the derivative in which R^ is a hydroxyl group to

derivatives in which R 1 is a group

ocori; l

is an esterification reaction. The esterification of an acid is a very general reaction that can take place in many ways. The acid and alcohol react easily in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid. This reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in large excess. Solution! the agent can either be one of the reactants or an inert organic solvent such as chlorinated hydrocarbons, such as chloroform or carbon tetrachloride or an aromatic or aliphatic hydrocarbon such as benzene, toluene or petroleum ether. The temperature range is between normal temperature and the reflux temperature of the reaction mixture.

IN

Another method consists in distilling the water as soon as|l Idea! t is formed by using a suitable apparatus. The reaction conditions are similar to those described above, except that it is not necessary that one of the reactants be used in large excess. j

ij ,The hydrolysis of the ester is carried out. under similar conditions to the above reaction, but in this case one of the reactants, namely water, is used in very large excess. Catalyst I and temperature conditions are the same as for the esterification.

in

i i The transfer of the derivatives in which R^ is a hydroxyl group !

or groups such as

or i i i-! ■ i i i to derivatives in which R^is a group

is a comb

in réak-i i

tion which is very well described in chemistry and which can be carried out according to several methods which are described below]

E.g. the carboxylic acid can be brought into contact with the amine, and the pyrolysis of the salt thereby formed leads to the amide in the same way as the action of a dehydrating agent so

as P.0r.

Z d■

in

Another method consists in transferring the carboxylic acid to the acid halide and then to the amide by reaction of an amine. The transfer of the acid to the acid halide is often carried out without a solvent using thionyl chloride, phosphorus pentachloride or phosphorus oxychloride. The corresponding bromides<!>can also be used. In order for the reaction to proceed completely, it is often necessary to heat the reaction mixture to a temperature between 50 and 150°C. If a solvent is necessary to carry out the reaction, this will be an inert organic solvent such as hydrocarbons, such as benzene, toluene or petroleum ether, or ethers such as diethyl ether.

The reaction of the acid halide with the amine is carried out while cooling the reaction mixture to a temperature between 0°C and -50°C, an excess amine is introduced (at least 2 equivalents or at least 1 equivalent of amine and at least 1 equivalent of a tertiary organic base such as e.g., triethylamine) . The acid chloride is preferably added to a solution of the amine in an inert organic solvent such as those indicated above, or also in water.

Still another method consists in reacting a carboxylic acid and an amine in the presence of a coupling agent such as, for example, is used in peptyl synthesis. Many times there is an enormous ! number of coupling means such as e.g. dicyclohexylcarbodiimide;, N-ethyl-N<1->3-dimethylaminopro<p>yl-carbodiimide, phosphines, phos- i . in fitter, silicon tetrachloride or tetanus tetrachloride or!! EEDQ!.

The aminolysis of an ester is easily carried out either in water or in an inert organic solvent. Examples that can be mentioned in solvents that can be used are an aromatic hydrocarbon such as benzene or toluene, an aliphatic hydrocarbon such as. In hexane or petroleum ether, or a halogenated hydrocarbon such as methylene chloride or chloroform.

The presence of a strong base can be decisive in the reaction of amines with low basicity or sterically hindered amines.' The above reaction can be carried out at a temperature between room temperature and the reflux temperature of the solvent.

in

i Depending on the conditions used, the hydrolysis of an amide,

namely a derivative in which R is a group

lead to one.

carboxylic acid or to esters.

All of the methods described above provide the best access

to the 1,4-thiazan derivatives according to the invention. However; the conversion of the mixture of diastereoisomers obtained is varied depending on the method used. Fractionation, of these mixtures of diastereoisomers, is carried out in a conventional

' 1 way within organic chemistry.

Detailed examples of the preparation of a few derivatives according to the invention are given below. The purpose of with these examples is especially to give a further illu-jSt; reration of the special characteristics of the method

•according to the invention. |

in EXAMPLES

in

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Example 1 2,2-dimethyl-1,4-thiazane-3-carboxylic acid. !

' i :lo j) S- ( 2- hydroxyethyl)- penicillamine j'

A solution of 17.5 g (0.14 mol) of 2-bromoethanol in 100 ml of ethanol is added dropwise with good stirring to a solution of 14.9 g!

.(0.10 mol) penicillamine . in 75 ml of 2 N aqueous sodium hydroxide solution which is kept under an inert atmosphere (N„). When the addition has finished, further ethanol is added in one ; sufficient amount to give a homogeneous medium and the medium j is then stirred at room temperature for 24 hours. After'neutra! Li-,i sering with concentrated hydrochloric acid, most of the avl is evaporated in the alcohol under reduced pressure and the volume is filled up to [300; :ml with water. The resulting solution is bound to a column of the resin Dov/ex 50 type, which is conditioned. in the acid worm'. The resin is washed with water and then eluted with 3 1 3N ammonia solution. The eluate is evaporated to dryness. The remainder is treated|with 50 ml of water and 500 ml of ethanol. The solid is filtered there, then from and recrystallized from isopropanol. This, gives!

9.0 g (47%) white solid. Temp. 148-150°C.'

2?) S-(2-chloroethy1)-penicillamine (hydrochloride)

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

in

3°) 2,2-dimethyl-1,4-thiazane-3-carboxylic acid;

Dissolve 6.7 g (27 mmol) of the above-mentioned chloride in 450 ml |

N,N-dimethylformamide, 50 ml of triethylamine are then added and: the mixture is heated for 2.5 hours using a bath at 95°C. The mixture is then evaporated to dryness under reduced pressure. The residue is dissolved in 75 ml of water and the solution is allowed to flow through 250 ml of resin of the Dowex 50 type. The resin is washed with water and eluted with 1.5 1 ammonia solution. The eluate is evaporated! under reduced pressure to a volume of 400 ml, the resulting solution is then treated overnight with 100 ml of resin j

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of Amberlite LRC 50 type, which is conditioned in the acid form. After the resin has been filtered off, the solution is concentrated to a volume of 30 ml. The crystals formed are filtered from °9 and dissolved in 10 ml of water.* Gradual addition of 40 ml of acetone results in precipitation of the final product. Weight: 3.1 g (6.6%) j j Melting point: 320°C (decomposition). j j

in i

in •

<!>I'.R., N.M.R. and the mass spectrum is consistent with the expected structure.

■ 1 Example no. 2 2,2,5-(R,S)-trimethyl-1,4-thiazan-3-(S)- >

carboxylic acid

1°) S-allylpenicillamine i

A solution of 6.6 g (4.1 ml, 55 mmol) of allyl bromide in 50 ml of ethanol and 35 ml of 2 N aqueous sodium hydroxide solution is added slowly and simultaneously with a mixture of 7.5 g (50 mmol) of penicillamine in 50 ml of ethanol, the temperature of the medium is kept below 20°C. When the addition ends, the mixture is stirred for a further 2 hours while testing for the disappearance of the starting thiol

(thin layer of silica; eluent: BuOH/AcOH/H' 2 O: 12:3:5, development with ninhydride). The solution is neutralized using concentrated hydrochloric acid and concentrated until a solid ■ appears. The volume is approx. 300 ml of water and the solution obtained is filtered in a column of resin

.of sulphonic acid type (Amberlite IR 120), in acid form. The resin is washed with water and then eluted with 1 1 1 N ammonium

solution. The eluate is evaporated to dryness and the solid

i is recrystallized from isopropanol. This gave 7.8 g (82%) of product. M.p.: 182-184°C.

] o i ; !2! ' ) S-(2-bromopropyl)-pencillamine hydrobromide in \

.The product from the previous procedure (7.8 g, 41 mmol) to

'• • '-.ii

■ add, while stirring, to 300 ml of a 40% strong solution of hydrogen bromide in acetic acid. After stirring for 3 days, the reaction is evaporated to dryness under reduced pressure. The residue is then stirred in ether and filtered off. The resulting solid is used as in subsequent steps. Weight: 14.2 g (99%) Mp: 106-108°C.

3o. 2, 2, 5-trimethyl-l,. 4- thiazan- 3- carboxylic acid in !.

: i

<.>i

<1>The above-mentioned product (14.2 g; 40 mmol) is added to 500 ml of DMF containing 50 ml of triethylamine. The mixture is heated 2.5; hours in a water bath at 90°C, then evaporated to dryness below; reduced pressure. The residue is dissolved in 400 ml of water and the solution is filtered through 500 g of sulphonic acid resin (Amberlite IR 120) diluted in acid form. The resin is washed with 2 1 water; is then eluted with 2 1 1 N ammonium solution. The eluate is evaporated to dryness under reduced pressure and the residue is dissolved in 500 ml of water, stirred with 50 ml of carboxylic acid resin (Amberlite IRC 50) conditioned in acid form. The resin is filtered off and the aqueous phase is evaporated to dryness 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 a refrigerator. After 3 days the crystals that emerge are filtered off. After washing with

■acetone and drying yield 3.7 g (45%) of the product.

Temp. 290°C (decomposition)

I.R., N.M.R. and mass spectra confirm the structure of the crystallized product.

The Karl-Fisher analysis indicates the presence of 8.7% water.

jThe product is found to be homogeneous when examined by !chromatography on a thin layer of silica after slurrying with a mixture of butanol/acetic acid/water: 12:3:5. After silylation, however, vapor phase chromatography shows the presence of two epimers in equal proportions. j 11<;>i ' Example No. 3 1-(R,S)-oxo-2,2,5-(S)^-trimethyl-1,4-thiazan-3-(S)-carboxylic acid. I 'The mother liquors from recrystallization and acetone from washingj of : the product according to the above example, which is taken! well cared for is evaporated to dryness under reduced pressure. The white solid residue is recrystallized from ethyl acetate. The resulting solid is then ground in acetone and then recrystallized from a mixture of acetone and water. This1 gave 0.57 g (7% relative to S-(2-bromopropyl)-pencillamine hydro- , bromide) of 98% saturated 2,2,5-(S)-trimethyl-1,4-thiazan-3-( S)-.carboxylic acid. Mp: 328°C (decomposition) [^q0 = 131° (C = 0.5; water) .

The above-mentioned sulphide is dissolved in 10 ml of acetic acid and 0.4 ml of 30% strong hydrogen peroxide is added. The mixture is stirred for 24 hours at room temperature and is thus concentrated under reduced pressure until a syrup is obtained. 25 ml of acetone is added to the mixture and kept overnight at 5°. The crystalline solid is filtered and dissolved again in 10 ml of water. The mixture is concentrated until a syrup is obtained. The above treatment is repeated and 0.29 g (47%) of a white solid consisting of a mixture of two epimeric sulfoxides is obtained. Temp. 230 o G ' ' Ij i 1 (' cleavage).' ' I.R., N.M.R. and mass spectra are consistent with the expected structure. II

in

in

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

in !

Example No. 4 2,2,5-(R)-trimethyl-1,4-thiazan-3-(S)-in carboxylic acid. IN

; in •

3.25 ml (40.3 mmol) of freshly distilled chloroacetone is added and stirred to a suspension of 5 g (33.6 mmol) of D-penicillamine in 28 ml of water. When the medium is homogeneous, the reactor is placed in an ice bath. A 20% strong aqueous sodium hydroxide mixture is added dropwise until the pH is 5.3 without the temperature exceeding 10 C and the solution of 1 g (26.4 mmol) sodium borohydride in 5 ml of water containing a base is thus added dropwise, taking care to that the temperature does not exceed 30°C. When the addition is over, the mixture is stirred for a further hour at room temperature. 37% strong aqueous hydrochloric acid is added slowly until the pH is 5.0. The product is evaporated to dryness under reduced pressure and the residue is treated with 50 ml of absolute ethanol. The insoluble material is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue, which is a colorless oil, is dissolved again in 10 ml of water. The solution is evaporated to dryness under reduced pressure. The resulting white solid is mixed with 10 ml of water and the mixture is heated under reflux until the solid dissolves. The solution is allowed to crystallize for 4 hours at room temperature and overnight at 5°C. The solid material is filtered off and dried.

Weight: 4.3 g (20.7 mmol; 62%). Temp. 310°C (decomposition).

[a]^° = + 93° (C 1; water).

IN

The Karl-Fisher analysis indicates the presence of 8.7% water.

IN

I.R., N.M.R. and the mass spectra consist of the expected structural dr. Analyzes by high-pressure liquid chromatograph show homogeneity

the nature of the resulting product.

IN

When the product is analyzed on a thin layer of silica, it has an Rf of 0.6 9 after elution with a mixture of methanol/acetic acid/chloroform: 6:1:4. : i

Example No. 5 1-(R)-oxo-2,2,5-(R)-trimethyl-1,4-thiazan-

. 3-(S)-carboxylic acid. in

i<[>j A solution of 3.5 g (16.7 mmol) of the product according to the previous example in 17 ml of a mixture of acetic acid/water: 1:1 is made and then cooled in an ice bath. 1.94 ml of 30% strong hydrogen peroxide is added drop by drop over the course of 5 minutes. under' stirring. When the addition is over, the mixture is stirred for 8 hours in the cooling bath and then for 10 hours at room temperature. It is evaporated to dryness under reduced pressure at a temperature not exceeding 60°C. The residual oil dissolves again

in •

in 10 ml of water and the mixture is evaporated to dryness under reduced pressure. The operation is repeated until a solid substance is obtained. This is then dissolved in 6 ml of water. Add 15 ml of acetone slowly while stirring. The mixture is stirred for 1 hour at room temperature and filtered. This gave a yield of the desired sulfoxide. Another benefit is obtained by cooling mother-; the liquids to 10°C while adding 1.0 ml of acetone and then filtering the mixture after a crystallization time of 15 min. Total weight: 2.2 g (9.9 mmol, 59%). Temp. 246°C (decomposition).

[α]p° 13.5° (C 1, 1 N HCl) .

t i

IN

in 1 in

il:R., N.M.R. and mass spectra consist of expected structure.

IN

; !<1>[Analyze the corresponding hydrochloride by the X-ray method

i ii makes it possible to confirm the absolute structure. j il I iKarl-Fisher analysis indicates the presence of 8.3% water. in

IN

During the investigation on a thin layer of silicon showed ! j in the product an Rf of 0.4 2 after slurrying with a mixture of' in methanol/acetic acid/chloroform: 6:1:4. I i I-l I !<!.>Analyses by high-pressure liquid chromatography confirm the product's! in homogeneity. ; : i Example No. 6 1-(S)-oxo-2,2,5-(R)-trimethyl-1,4-thiazan- 3-(S)-Carboxylic acid (hydrochloride) . The mother liquors from the crystallization of the second resulting product of the previous example which have been carefully taken care of, are evaporated to dryness under reduced pressure. The rest that weigh; 1.3 g is dissolved in 10 ml of water and the solution is given pH 1 with the help of 37% strong aqueous hydrochloric acid. The solution is concentrated until a wet weight of 3.0 g is obtained and the residue is kept overnight at 5°C. The solid is filtered off; it has an optical rotation of 79° in water. The crystals are dissolved in 10 ml of water and the solution is evaporated to dryness under reduced pressure until a syrup is obtained. 1.5 ml of acetone is added and the mixture is kept overnight at 5°C. It is filtered. The optical rotation of the solid is 84°. A further crystallization operation produces a product of sufficient purity. Weight: 0.22 g (0.9 mmol; 5% relative to the product in example 4 is used) Mp. 275°C. j [a]p°= +85° (C=-1; water), + 73° (C = 1; IN HC1). I I I.'. R., N.M.R. and the mass spectra have the expected structure l j iKarl-Fisher analysis indicates the presence of 0.5% water.<1>I

'■'•<!.!>.Analysis by high-pressure liquid chromatography indicates a purity of 99.5%. : i i I

■ Example No. 7 1,1-dioxo-2,2,5-(R)-trimethyl-1,4-thiazan-3-(S)-carboxylic acid.

'■!..- I

<!>in ; Dissolve 5 g (22.4 mmol) of the product in example 5 in 300 ml of 0.5 N aqueous sulfuric acid. A solution of 2.5 g of calcium permanganate in 300 ml of water is added over a period of 2 hours. When the addition stops, the mixture is stirred for 2 hours at room temperature and 12 ml of formic acid is then added. The mixture is filtered and 0.5 N aqueous barium hydroxide solution is added until precipitation ends. The mixture is filtered and the filtrate is transferred to a column of strong acid type ion exchange resin, conditioned in H form. This resin is washed until the effluent is neutral and then slurried with 3 N ammonium solution. The eluate is concentrated under reduced pressure until a volume of approx. 100 ml. The resulting solution of ammonium cumic salts is filtered in a resin column with a weak acid type.: The filtrate is evaporated under reduced pressure until an acid is obtained and 15 ml of acetone is added to the syrup. The mixture is stirred for 2 hours and then filtered. Weight: 2.7 g (11.6 mmol; 52%) M.p.: 232°C (decomposition). [a]^° = +2° (C = 1; 1 N HC1)., 1. R., N.M.R. and the mass spectra have the expected structure.

The Karl-Fischer analysis indicates the presence of 6.2% water.

I •When examined on a thin layer of silica, the product j •gets an Rf of 0.38 after slurrying with a mixture of butanol/ j acetic acid/water : 5:2:3. • j \ ii Example No. 8 Hydantoin of 5-methyl-1,4-thiaza.n-3-carboxylic 1-acid. i j '3.9 g (24.0 mmol).5-methyl-1,4-thiazan-3-carboxylic acid and 2.3 j g 1 (28.8 mmol) potassium isocy"anat are gradually added to 25 ml i|i water The mixture is heated to the boiling point and brought back to room temperature. in aqueous hydrochloric acid. The mixture is concentrated under reduced pressure to a volume of about 20 ml. It is stirred for 1 hour at room temperature and then filtered. The solid is recrystallized from water. Weight: 2.5 g (13.4 mmol; 56%). Temp. 189°C (decomposition). in I.R., N.M.R. and the mass spectra have the expected structure.

Example No. 9 1-ethoxycarbonylethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate (oxalate).

A solution of 3.7 g (17.4 mmol) of the product in Example 5

in 37 ml of water is treated with a 0.5 N solution of aqueous potassium hydroxide until a pH of 9 has been reached. The resulting solution is evaporated to dryness under reduced pressure. The rest

i is suspended in 40 ml DMF. 3.2 g (17.6 mmol) of ethyl 2-bromopropionate are added dropwise. The product is stirred for 48 hours1 at room temperature and diluted with 100 ml of water and extracted with chloroform. The organic extract is dried and evaporated

IN

to dryness under reduced pressure. The oil residue is taken up in 50 ml! ethyl alcohol and then treated with a solution of 1.6 g (17.6 mmol I) of oxalic acid in the smallest amount of the same agent. The mixture is stirred for 30 min and filtered. The precipitated solid is then recrystallized from ethanol. This gives 4.3 g (10.5 mmol; 64%) of pure product. M.p.: 196 C (s- splitting).

1

in I'.R.,N.M.R. and the mass spectra have the expected structure.

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

in ..li

in

When the product is chromatographed on a thin layer of silica, it obtains an Rf of 0.52 after washing with a mixture of butanol/acetic acid/water: 5:2:3.

Example No. 10 1-pivaloyloxyethyl-1-oxo-2,2,5-trimethyl-[

1,4-thiazan-3-carboxylate (oxalate).

A solution of 3.7 g (16.4 mmol) of the product according to example 5 in 37 ml of water is treated with a 0.5 N solution of aqueous potassium hydroxide until the pH reaches a value of 9. The resulting mixture 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 then added dropwise with good stirring. When the addition ceases, stirring continues for 48 hours at 40°C. The resulting medium is slurried with 100 ml of water and then extracted with chloroform. The organic extract is dried and evaporated to dryness under reduced pressure. The residue is treated with 50 ml of ethanol and then with a mixture of 1.6 g (17.6 mmol) of oxalic acid in the smallest amount of the same agent. The mixture is stirred for 30 min and the precipitate that forms is filtered off. It is finally purified by recrystallization from ethanol. This gave 4.2 g (9.9 mmol; 60%) of white crystalline solid. Melting point: 214°C (decomposition).

! IN

<I>!.R.', N.M.R. and the mass spectra have the expected structurel

IN

i ■ ! When the product is chromatographed on a thin layer of silica, it obtains an Rf of 0.65 after suspension using a j mixture of butanol/acetic acid/water: 5:2:3. Example No. 11 Methyl 2,*2',5-trimethyl-1,4-thiazan-3-carboxylate (hydrochloride). A solution of 32.2 g of potassium hydroxide in 640 ml of methanol is cooled to 0-5 C. 47.9 g (0.24 mol) of the hydrochloride of penicillamine ethyl ester is added and 25.0 g of chloroacetone is then added dropwise. . The agent is stirred for 1 hour at room temperature and brought to pH 6.5 using a mixture of hydrogen chloride in ethanol. 6.2 g of sodium borohydride are then added, in small portions. When the addition ceases, the mixture is stirred in; a further 1 hour at the same temperature. The excess hydride is destroyed by adding concentrated hydrochloric acid and the solution is then neutralized with 10% strong aqueous bicarbonate solution. The aqueous solution is extracted with chloroform. The extracts are dried and then evaporated to dryness under reduced pressure. The oil residue is dissolved in a mixture consisting of 50 ml: methanol and 350 ml ether. The addition of saturated hydrogen chloride solution in ether causes precipitation of a solid hydrochloride. This is filtered off and reprecipitated twice from a methanol solution by adding ether. Weight: 17.2 g (30%). Temp. 204°C (decomposition). ! I.R., N.M.R. and the mass spectra have the expected structure. Example No. 12 2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid. | j i 'i<!>1.6 8 g (20 mmol) sodium bicarbonate and 1.5 g (0.66 ml; 10.5 mmol) methyl iodide are added stepwise to a solution jav 2.1 g (10 mmOl) 2, 2,5-trimethyl-1,4-thiazane-3-carboxylic acid in 50 ml of methanol. The resulting mixture is stirred at room temperature for 24 hours and heated at reflux temperature for a corresponding period of time. It is evaporated to dryness under reduced pressure and the residue is dissolved in 100 ml of water. The j j solution obtained is transferred to a column of ion mixer resin of \ strong acid type, conditioned in H"<5> form. The resin is washed with water until the effluent is neutral and washed with 1 N ammonium solution. The eluate is evaporated to dryness under reduced pressure 1 The white solid residue is recrystallized from ethyl acetate. This gives 1.4 g (6.8 mmol; 68%) of pure product. M.p. 201°C (dec.). I.R., N.M.R. and mass spectra have the expected structure.

When the product is chromatographed on a thin layer of silica

it gets an Rf of 0.6 after washing with methanol.

Example No. 13 5-n-butyl-2,2-dimethyl-1,4-thiazan-3-carbox-'

syllic acid (hydrochloride).

7.5 g (50 mmol) of D-penicillamine is added to 40 ml of water at 1

a temperature between 0 and 5°C. The following is added drop by drop at the same time while stirring well: on. on one side 9.5 g (53 mmol) of l-bromohexan-2-one during 10 min. and on the other side 25 ml (50 mmol) of 2 N aqueous sodium hydroxide solution during 30 min. After the addition is complete, stir for a further j 1 hour at the same temperature and the temperature is then set to i i approx. 15°C. 50 ml of methanol are added and a mixture of 1.5 g '•

IN

(39 mmol) of sodium borohydride in 9 ml of water containing a base!

j is added slowly.. The mixture is left at room temperature and-

' is then extracted with chloroform. The organic extract j is dried and then evaporated to dryness under reduced pressure. The red oil residue is poured into 50 ml of diisopropyl ether and ethanol is added in a sufficient amount to obtain a solutionJ

One. solution of hydrogen chloride in ether is added until i

in the precipitation ends and ethanol is then added in a sufficient

in quantity to turn the brown-red mass into a beige solid. This is filtered off, washed with diisopropyl ether and dissolved in hot ethanol. Ethyl ether is added until the solution becomes cloudy and it is allowed to cool. The crystals are collected and cleaned once more. Weight: 8.0 g (30 mmol; , 60%). Melting point: 225°C (decomposition). j.

in I.R., N.M.R. and the mass spectra have the expected structure.

When the product is chromatographed on a thin layer of silica

it gets an Rf of 0.6 2 after washing with a. mixture of<1>

butanol/acetic acid/water: . 5:2:3. in.

Example No. 14 5-methyl-2-phenyl-1,4-thiazane-3-carboxylic acid

(hydrochloride).

1 g (4.3 mmol) of threo-(3-phenylcysteine hydrochloride) is dissolved in 12 ml of water. The solution is cooled in an ice bath and the pH is brought to 7.0 using 20% strong aqueous sodium hydroxide solution. 0.42 g (4 .5 mmol) freshly redistilled chloroacetone is added. After stabilization of the pH for 30 minutes, 2 N water is added;

dig hydroxide solution until the solution is neutralized.'(

The mixture is stirred for a further 1 hour, still in an ice bath and

the solution consisting of 0.13 g (3.4 mmol) of sodium borohydride in 2 ml of water containing a base is added. This gives a'

k: leaves colorless solution with a pH of 9.1. This is stirred for 1 hour as room temperature is reached. The pH is brought to 6.0 using 37% strong aqueous hydrochloric acid. The mixture is evaporated to dryness under reduced pressure. The residue, sufficiently dried, is taken up in 10 ml of ethanol and 2 ml of a 22% strong solution of hydrogen chloride in ethanol is added. The mixture is stirred for 15 min.j and evaporated to dryness under reduced pressure. The rest recrystallized

I . is lysed twice from a mixture of isopropanol/ethanol: j 4:1. Weight: 0.66 g (2.4 mmol; 56%). Temp. 248<Q>C (cleavage). j

i',

I.R., N.M.R. and the mass spectra have the expected structure.

i i i ! . in

IN

Example No. 15 1-(R)-oxo-2,2,5-(R)-trimethyl-1,4-thiazine-<!>

3-(S)-carboxylic acid (without isolation of the intermediate)..

7.4 g (80 mmol) of freshly distilled chloroacetone are added with good stirring to a suspension of 10 g (67 mmol) of (D)-penicillamine in 56 ml of water at room temperature. After a reaction time of 2 hours, a 20% strong aqueous sodium hydroxide mixture is added until the pH is 5.3 (temperature 20°C). A solution of 2 g (50 mmol) of sodium borohydride in 10 ml of water is added dropwise to the reaction medium (temperature <;30°C). After a reaction time of 1 hour, the mixture is acidified by adding;

50 ml acetic acid. The reaction medium is cooled (0°C 4 temp i. ^ 5°C) and 2.4 g (0.74 mol) of 30% hydrogen peroxide is added dropwise. show. The temperature is kept between 0°C and 5°C for 8 hours and then

in

at 20 C for 4 hours. The mixture is concentrated under reduced pressure. The residue is taken up in 40 ml of ethanol, the suspension is filtered and 240 ml of ethyl acetate is added to the ethanol solution with good stirring. The product is allowed to crystallize at 20°C for 1 hour. The precipitate is filtered off and washed with acetone. Pure ammonium acid is crystallized from a mixture of i

jH 2 O/acetone: 1:4. This gave 7.4 g (33.3 mmol; 54%) of ethyl !white crystalline solid identical to the product in ! example 5. il

■ i

in i

in

■Table I below shows the derivatives from the above-mentioned examples i together with other derivatives according to the invention, j produced in accordance with the above-mentioned methods.

IN

(1) this is most often a decomposition temperature.

j The noted value corresponds to the beginning of the phenomenon!.

(2) all the mentioned products give a correct C.H.N. elemental analysis. i (3) hydrated product (4) hydrochloride Ii (5) free base or zwitterion (6) oxalate (7) mixture of isomeric, separated components as shownI' at the end of the table in (8) configuration at the center of asymmetry: l-(R )-3-(S)-(R) . I (9) configuration at the center of asymmetry: i 1- (S) -3- (S)-5- (R) 'j (10) configuration at the center of asymmetry: 1-(R)-3-(S)-5-( R) i

(11) configuration at the center of asymmetry:

3-(S)-5-(S)

(12) configuration at the center of asymmetry: 1-(R,S)-3- (S)-5- (S)

(13) ft... shows 3-phthalidyl

(14) pyr shows 2,5-dioxo-1-pyrrolidiny1

(15) configuration of the asymmetric center: 3-(R)-5-(S) (16) configuration of the asymmetric center: 1-(S)-3-(R)-5-(S)

(17) configuration at the center of asymmetry:

3-(S)-5-(R)

(18) hemi-hydrochloride.

■ The products according to the invention were subjected to a series of 'pharmacological trials', the methodology of which is described below. i The results of these tests are listed in Table li, in which the numbers in the first column correspond to the numbers in the first column of Table I.

i<1>i LD q is calculated according to the method of Lichtfield and Wilcoxon '

(J. Pharmacol. Exp. Ther.. 9J5, 99, 1949) and expressed in mg/kg. The products are given orally to mice.<1>j i i The effect on behavior is studied using a method derived from S. Irwin (Gordon Res. Conf. on Medicinal ' Chem., 133, 1959). The substances suspended in a porridge containing 1% tragacanth gum are given orally by means of an intra-gastric tube to groups of 5 male mice (CD1 strain, Charles River, fasted for 18 hours). The doses tested as a function of the observed activity ranged from 3,000 to <1>

3 mg/kg. The behavior is studied 2, 4, 6 and 24 hours after treatment the ling. The observation is extended if the symptoms persist at this time. Mortality is recorded within 14 days of treatment. None of the examined products induced abnormal behavior in mice or proved to be toxic.

Determination of the effect on the fibrinolytic activity, \

. bleeding time and blood loss:

in 5 in

■The substance to be examined is given dissolved in a porridge such as j

; i contains 1% tragacanth gum orally to rats in a dose of 30 mg/kg. A blood sample is taken 1 hour to 3 hours after hairdressing. Plasma is separated by centrifugation and the euglobulins are precipitated. The fibrinolytic activity is determined according to the method of Astrup and Mullertz (Arch. Biochem. Biophys. 1952,

.40, 346). 50 µl of a solution of uglobulins in a veronal buffer containing 0.25% gelatin is deposited on dishes as I

IN

contains a 0.08% suspension of fibrin. After an incubation time of 18 hours at 37°C, the diameter of the light zone is measured.

A grade is given as a function of the ratio between the fibrinolytic activity of the treated rats and the rats given a placebo. The meanings are as follows:

in

To determine the bleeding time, the tail of the rats kept at room temperature for 2 hours is cleaned with ether and cut 2 mm

.from the end with a scalpel; as the bleeding time expressed in seconds is measured 1 hour or 3 hours after the treatment. The blood is collected on a filter paper. The blood loss is determined by

to weigh the filter paper before and after collecting the blood. '

in

The coefficient of increase in the bleeding time is the ratio between the bleeding time of treated rats and rats that have received a placebo. A grade of 3 corresponds to an increase coefficient of 0.79-0.89.

i ■ A grade of 4 corresponds to an increase coefficient of | I0.9-1.09. I A grade of 5 corresponds to an increase coefficient of 1.1- J1.11. I A grade of 6 corresponds to an increase coefficient of 1.12-4 1.22. j. i A grade of 7 corresponds to an increase coefficient of 1.23-1.33. li<i>A grade of 8 corresponds to an increase coefficient of 1.34-j j 1.44. ! A grade of 9 equates to an increase coefficient of £1.45.

The coefficient of increase in blood loss is the ratio between the amount of blood lost in . treated rats and that lost in the control rats.

A grade of 3 corresponds to an increase coefficient of 0.5. A grade of 4 corresponds to an increase coefficient of 0.51-0.99. A grade of 5 corresponds to an increase coefficient of 1-1.5.

A grade of 6 corresponds to an increase coefficient of 1.6-2.

A grade of 7 corresponds to an increase coefficient of 2.1-2.5. A grade of 8 corresponds to an increase coefficient of 2.6-3. A grade of 9 corresponds to an increase coefficient of 3.1.'

Two products according to the invention were the subject of a more detailed investigation: these are derivative 7 and derivative 12 (free base of derivative 7 in hydrated form).

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

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

After oral administration of derivative 7 to groups of 4 rabbits in doses of 2.5-50 mg/kg, an increase in the fibrinolytic activity of the blood is observed - which is proportional to the administered dose. This increase is e.g. 3 times |90 ! my. after administration of 5 mg/kg. This effect is evident after repeated administration; thus, treatment with 10 mg/kg 2 times a day for 21 days increases the fibri-i

in nolytic activity of the blood to 3 times greater than |

in such for the controls.

in ;

After intravenous perfusion of derivative 12 in doses of 3 or 5 mg/kg/10 min. for 2 hours a 2.8-fold increase j is observed

in the fibrinolytic activity from 10-30 min. after the start of perfusion up to at least 3 hours after the end of perfusion. '

The activity of compound 12 was also demonstrated for rats and monkeys after oral administration. Finally, oral administration of 100-800 mg to humans causes a dose-proportional increase in blood fibrinolytic activity.

For administration of the new compounds according to the invention, the daily dose will be 50 mg - 2 g given orally and 10 mg -lg given by injection or by intravenous perfusion.

The products according to the invention can be used in different galenic forms. The examples that follow entail . no limitation and relates to a galenic formulation containing an active product according to the invention which is denoted by the letter A and e.g. can be: l-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid, ethyl l-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 2, 2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid, 1-(pivaloyl-oxy)-ethyl 1-oxo-2,2,5-trimethyl-1)4-'

IN

thiazan-3-carboxylate, (octyloxycarbonyl)-methyl l-oxo-2,2,5-trimethyl-1,4-thiazan-3-carboxylate, 1-(ethoxycarbonyl)-ethyl l-oxo-2 , 2 , 5- trimethyl-1, 4-thiazane-3-carboxylate, 5-butyl-j-2,2-dimethyl-1,4-thiazane-3-carboxylic acid, 2,2,-dimethyl-5-iso-propyl-1, 4 -thiazan-3-carboxylic acid, 5-methyl 1-2-phenyl-1, 4-thi a-; zan.-3-carboxylic acid or ethyl 3-carboxy-2,2-dimethyl-1; 4- i thiazan-5-acetate. j j

in

Oh damn pills

' Injectable solutions Coated pills containing a 100 mg dose of compound A and a 300 mg dose of acetylsalicylic acid Tablets containing a . 300 mg dose of compound A and a 50 mg dose of dipyridamole

1 Tablet containing a 200 mg dose of compound A and a

i , 100 mg dose of suloctidil. j

in i

Claims (3)

I I. 1. 1,4-thiazan-3-carboxylic acid derivative with the gene- ■ proper formula I i ! where <!> ■ and R 2 which may be the same or different means- hydrogen, a straight chain or branched, C^, C^. or alkyl residue or a phenyl nucleus optionally substituted with a halogen atom such as fluorine, chlorine or bromine, with a straight-chain or branched , , or alkyl residue or with a straight-chain or branched C₁ -C₂ alkoxy acid residue, R^ and R2 together with the adjacent carbon atom can form a ; cycloalkyl group with 3,4,5,6,7 or 8 carbon atoms in which one or more carbon atoms may optionally be replaced by a sulfur or oxygen atom or by a group .SO, SO2 or NRg in which Rg means hydrogen, a straight-chain or branched C-^-C^ alkyl residue, a phenyl nucleus or a benzyl group, R^ means - a hydroxyl group - a group 0Rq in which R„ means a straight chain or branched C-^ -C^ alkyl group, a group or a group where R^q means hydrogen or C-^ or C2 alkyl residue and R^ means a straight-chain or branched C^-C^2 alkyl residue, ; where <R> ^2°9 R, -. which can be ' j same or different means hydrogen or a straight-chain ;or branched C^ -C^ alkyl residue or | -■. a 3-phthalidyloxy group or a 1-(2,5-dioxo-1pyrrolidinyl)-1-ethoxy group, Imeans a hydrogen atom or a straight-chain or branched C-j_~C8 alkyl residue, a straight-chain or branched c-| __cg acyl residue or a group' • CONH; I 1 <R>^ and R^ can form a hydantoin ring with the adjacent carbon and nitrogen atoms, <;> R^ and Rg which may be the same or different means hydrogen, a straight-chain or branched C^-Cg alkyl residue, a phenyl nucleus optionally substituted with a halogen atom such as fluorine, -chlorine or bromine, with a straight-chain or branched C-^-C^j ■alkyl residue or with a straight-chain or branched C-C.] carboxylic acid residue, or a group CP^ COOR^^ in which R 4 means hydrogen or a straight-chain or branched C^- C^ alkyl residue,! R-, means hydrogen, a straight-chain or branched C₁-C₂ alkyl residue, a gemdimethyl residue or a phenyl nucleus optionally substituted by a halogen atom such as fluorine, chlorine or bromine with a straight-chain or branched C₁-C₂. alkyl residue or a straight-chain or branched C₁-C₄ carboxylic acid residue, and n may have the value 0, 1 or 2; if R^ , R^ R^ and R^ mean hydrogen and if R^ means a hydroxyl group or a straight-chain or branched C^-C^ -alkyl residue, R^ and Rg do not mean hydrogen, a straight-chain or branched C^-C^ alkyl residue or a phenyl ring, and salts of these compounds formed with pharmaceutically acceptable acids and bases. 2. Derivative according to claim .1, characterized in that in the general formula I, R^ and R^, which may be the same or different, mean hydrogen or a methyl group. 3. Derivative according to one of the preceding claims or 2, | ' ■ / i ' characterized in that in the general formula i i i I, a hydroxyl group, a group OR^ in which Rg denotes the straight-chain or branched C-^-C^ alkyl residue, a groupj or a group where R^ q means :hydrogen or a methyl residue and R^^ means- a straight-chain or branched C^-Cg alkyl residue. ! ! J1 I 4. Derivative according to one of claims 1-3, character-; distinguished by the fact that in the general formula I R 1 means hydrogen or a methyl residue. ' i i i • in I ,5. Derivative according to one of claims 1-4, character- raised by the fact that in the general formula I means R,-! and Rg which may be the same or different, hydrogen, a straight- ' chained or branched C 1 -alkyl group or a group! <!> CH^COOR^^ where R^^ means hydrogen or a C^-^ alkyl group. 6. Derivative according to claim 5, characterized in that in the general formula I, R< - means hydrogen and ;R^ means a straight-chain or branched C 1 -C 2 -alkyl group. in • 7.. Derivative. according to one of claims 1-6, characterized in that in the general formula I n has the value 0 or 1. 8. Derivative according to claim 1, characterized in that it is selected from the group consisting of the following; connections: 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylic acid, ethyl 1-oxo-2,2,5-trimethyl-1,4-thiazane-3-carboxylate, 2,2,4,5-tetramethyl-1,4-thiazane-3-carboxylic acid, 1-(pivaloyloxy)-ethyl j 1-oxo-2, 2, 5-trimethyl-1, 4-thiazan-3-carboxylate, (octyloxy-^-carbonyl)-methyl- 1-oxo-2,2,5-trimethyl-1,4-thiazan- 3- carboxylate, 1-(ethoxycarbonyl)-ethyl 1-oxo-2,2,5-trimethyl-'; 1,4-thiazan-3-carboxylate, 5-butyl 1-2,2-dimethyl-1,4-thiazan-3-j carboxylic acid, 2,2,-dimethyl-5-isopropyl-1,4-thiazan-3- IN '■ 1 jcarboxylic acid and ethyl 3-carboxy-2,2-dimethyl-1,4-thiazan-5- i! acetate. | 9L Between <p> products, especially for the preparation of the I derivatives according to each of the preceding claims, characterized in that they have the formulas I, III and VI: 1 in which R^ -R^ and n have the meanings indicated above. ' 10. Derivative as described above, especially in the specified examples in the description. 11. Process for the production of derivatives of 1,4-thiazan-3-carboxylic acid and its salts, characterized in that a compound of formula II, a compound of formula III or compounds of formula IV and V are cyclized to a compound corresponding to formula I in which formulas R -R^ and n have the meanings indicated above. the intermediates resulting from the cyclization are then reduced to give derivatives corresponding to formula I, the latter or the intermediate, and also the derivatives of formula I obtained from the compounds of formula II and of formulas IV and V optionally, optionally oxidized, alkylated or acylated with the substituent R^ , or this substituent R^ is replaced by a group CONH^ followed by cyclization with the substituent R^ , which if the latter means a hydroxyl group gives a hydantoin group. 12. Method according to claim 11, characterized in that a derivative with formula II is cyclized in a basic medium. ; i <!> 113. Method according to claim 12, characterized in that an organic or inorganic base is used, such as e.g. triethylamine, N,N-dimethylaniline, pyridine, alkali metal hydroxides or ammonium hydroxide. in j H <:> 14. Method according to claim 11, characterized in that a derivative with formula III ! j in i wherein C means a halogen atom such as chlorine, bromine or iodine, a hydroxyl group or a group that can be easily removed, such as a tosyl or mesyl group, cyclized in a basic or dehydrating medium. i 15. Method according to claim 11, c a r a c t e r i- ' i i cert in that a 5,6-dihydro-2-H-thiazine derivative V of formula IV is reduced to 1,4-thiazane of formula I, and this is optionally followed by oxidation to give the corresponding sulfoxide or sulfon. 16. Method according to claim 15, character! in other words, the derivative VI is produced by reacting a cysteine derivative IV in in with an α-halogen ketone YCH-COR^, in which Y represents j a halogen atom such as chlorine, bromine or iodine. [ 17. Process according to claim 11, characterized in that to prepare a derivative of formula I in which means a straight-chain or branched C 1 -C 2 -alkyl residue or a straight-chain or branched C 1 -C . acyl-residue;, in alkylates or acylates an amine of formula I in which R^ is hydrogen in a basic medium with a reactant R^ Z in which Z <1> means a halogen atom such as chlorine, bromine or iodine, or. a group that can be easily removed such as e.g. a tosyl or mesyl group. 18. Process according to claim 11, characterized in that in order to prepare a derivative of formula I in which R^ means a residue GONI^ , a derivative of formula I in which R^ means hydrogen is reacted with a reactant of formula MNCO in which M means a monovalent cation such as sodium, potassium, lithium or ammonium ion. 19. Method according to claim 11, characterized by: in order to prepare a derivative of formula I in which R^ and R^ form a hydantoin ring with the adjacent carbon and nitrogen atoms, a compound of formula I is placed in which R^ denotes a hydroxyl group and R^ means a group CONI^ , in et. acidic medium with heating if necessary. \ 20. Method according to claim 11, characterized in that in order to prepare a derivative with formula ]i! wherein n = 1 or 2, treat a derivative of formula I- i Ihyori n = 0 with an oxidizing agent. j ! j i 21. Method according to claim 20, character ji-; ;s' e r t in that the oxidation is carried out on any .step in the preparation of 1,4-thiazane ring. j li in '22. Method according to claim 11, characterized in that a derivative of formula I in which R 3 n means I one; . hydroxyl group is transferred to a derivative in which R, means one group OR^ , in by esterification. in in '23. Method according to claim 11, characterized in that a derivative of formula I in which R^ means a hydroxyl group or a group OR^ , OCI-LCOOR ^ or' OCHOCOR,, Rin In 1 x Lu ' <R> in is transferred in a derivative in which R^ means a group by amidation.24. Method according to claim 11, characterized in that a derivative of formula I in which R^ means a group OR^, is transferred in a derivative in which R 1 means a hydroxyl group or a group or by hydrolysis or aminolysis. in I 25. Method according to claim 11, characterized in that a derivative of formula I in which R 1 means a group I li i is transferred in a derivative in which a hydroxy yl-!I means j i li 'group or a group ORg, i j or IN 1 ! 1 'by hydrolysis or alcoholysis. j j i"" : I i 26. Procedure for the production of derivatives avl ! 'i 1,4-thiazan-3-carboxylic acid and its salts, as described] 1 'above, especially in the examples given in the description. '. in i 27■ . Pharmaceutical mixtures, especially for treatment and the like .! prevention of certain disorders in the circulation, such as venous i or arterial thrombosis, characterized by the fact that it comprises at least one of the compounds of formula I or one of its salts in association with one of the suitable pharmaceutical excipients, or if necessary with other 'therapeutic agents such as agents that inhibit platelet-, aggregation. 28. Mixture according to claim 27/characterized in that it is in the form of coated tablets, <1> granules, tablets, capsules, solutions, syrups, emulsions or suspensions containing additives or excipients that are common in galenic pharmacy. '29. Mixture according to claim 27 or 28, characterized in that it comprises at least one of the derivatives according to formula I i; solution, especially in sterile water or in peanut oil or ethyl oleate. 30. Method using the derivative according to formula i I, especially in the treatment or prevention of certain disorders' in the circuit, such as venous or arterial thrombosis, ! characterized in that doses of 50 mg to 2 g are administered orally daily and administered by injection; In 'sering or by intra* venous perfusion' tion on daily doses of lo mg -lg.