LU82738A1 - DERIVATIVES OF AMINOTHIOLS, THEIR PREPARATION AND USE AS WELL AS COMPOSITIONS CONTAINING THESE DERIVATIVES - Google Patents

Description

• V '* .., · # \ ·: · · ... "4 *" ·, · * ’. I · * · ’·.” /: 1> 1.

The present invention relates to amino thiol derivatives of general formula (I) R, R.. Ä, i 1 iob R2-C - CH - NC 'SR4 ^ R6 (I) in which - - Rj represents hydrogen or a linear or branched alkyl radical - R2 represents hydrogen or a linear lower alkyl radical or branched Cj, C2, Cg or C ^.

- Rj and R2 can form with the neighboring carbon atom a cycloalkyl radical Cg-Cg.

- Rj represents hydrogen or a linear or branched lower alkyl radical C ^, C2 or Cg.

- R4 represents hydrogen, a linear or branched lower alkyl radical, C2 or Cg, a linear or branched lower alkanoyl radical Cg, C2, Cg or C4, a linear or branched alkanoylthio radical Cg, C2 or C3, an alkyloxycarbonylthi radical linear or branched lower Cj, C2 or C3, a linear or branched Cth-CgQ alkylthio radical.

R 5 ^ 6 "which may be the same or different, represent ·.

- hydrogen, - a linear or branched alkyl radical Cg-Cg6, - a linear or branched alkyl radical C2, C3, C4, C5 or C-substituted by - a hydroxyl, carboxylic, alkoxycarbonyl group, linear or branched Cg, ' C2 or C3, - a naphthyl group, - a phenyl, phenoxy, phenyl or benzyloxy ring mentioned: -1 adorned substituted by one or more halogen atoms such as chlorine, by one or more linear or branched alkyl radicals

Cj, C2, C3 or C4, by one or more linear or branched alkyloxy radicals C ,, or C. ,, 1 C 3 - un nroiiriPffiPriT a U · η v υ nu a 1 l- u 1 f h î r. i <**, ~ - * w ..- ~ ^ ^ x z ^ r i i 1t t 2.

- an alkylamino group Cj, C2, C3 or optionally substituted by a phenyl, phenoxy or cycloalkyli group C3, 1 C g or Cg, 1 - a phenoxyacetyl group, \ - a linear or branched alky1carboxamido group Cj, C2, C3,, Cçj or Cg optionally substituted by a phenyl or phenoxy ring, - a cycloalkylcarboxamido group C ^, C ^, Cg, Cg, Cy or (- a cycloalkyl radical C ^ -Cg, - a linear or branched alkenyl radical C3 ~ Cjg, - a linear or branched alkynyl radical C ^ -C ^ q,; - R5 and Rg can form with the neighboring nitrogen atom a heterocyc '· such as piperidine, pyrrolidine, morpholine, piperazine optionally substituted in position 4 by a benzyl group, a linear or branched alkyl group Cj, C2, C3 or, or a phenyl ring which may itself be substituted by one or more halogen atoms such as fluorine and chlorine, linear or branched alkyl radicals Cj, Cg, or Cg, linear or branched lower alkoxy radicals Cj, C2 or C3.

- R ^ and Rg may form a thiazolidine ring optionally substituted in position 2 by 1 or 2 linear or branched lower alkyl groups Cj, C2 or or a thiazolidinone ring.

Rj. R2> R * p R5 and Rg cannot simultaneously represent hydrogen.

The present invention also covers the symmetric disulfides, in this case R ^ is represented by the formula 1 'in which

i fl f 3 A

l Ro - C - CH - N () d I \

S- T

(I ‘) R], R3 R R5 and Rg have been defined previously, and the disulfides formed with sulfur amino acids such as, in particular, o-nicillamine and cysteine. '• </, · (3.

Included among the products of the invention are the non-toxic and pharmaceutically usable salts of these derivatives.

With profit, the present invention covers the derivatives of formul- (I) in which: - R1 represents hydrogen or a linear or branched alkyl radical CpCg; - Rg represents hydrogen or a lower, linear or branched alkyl radical Cp Cp C3 or Cp - Rj and R2 can form with the neighboring carbon atom a radical, cycloalkyl C5-Cg; *! - Rg represents hydrogen or a linear or branched lower alkyl radical Cp C2 or C3; j - R ^ represents hydrogen, a linear lower alkyl radical j or branched Cp C2 or Cg, a linear lower alkanoyl radical! or branched Cp C2, Cg or Cp an al koxycarbonyl thi o lower · linear or branched Cp C2 or Cg radical, a linear or branched alkylthio radical Cj-Cp - Rg and Rg which may be the same or different, represent - hydrogen , - a linear or branched alkyl radical C1 C12 '- a linear or branched alkyl radical C2, Cg or substituted by - a phenyl ring substituted by one or more halogen atoms such as chlorine, by one or more methyl or methoxy radicals , - a linear or branched alkoxy or alkylthio group Cp C2,

Cg or C ^ ,, - a linear or branched al kyl carboxami do group Cp Cp Cg, Cp Cg or Cg optionally substituted with a phenyl ring or (phenoxy, - a cycloal kyl ca rboxarni do C3, Cp Cg, Cg, C-, or CP.

- Rg and Rg can form with the neighboring nitrogen atom a heterocycia such as piperidine, pyrrolidine, morpholine, pipërazine optionally substituted in position 4 by a benzyl group, a methyl radical or by a phenyl ring which can itself be substituted because one or more halogen atoms such as fluorine and chlorine, linear or branched lower alkyl radicals C,, C2 or C3, of · / / * i- v "" · »» · · * · ». ’” · F ”· · * · I '! ϊ linear or branched lower alkoxy radicals, C2 or C3, (- R4 and Rg may form a thiazolidine ring optionally substituted in position 2 by one or two methyl radicals or a thiazolidinone ring, as well as symmetrical disulfides or formed with amino acids sulfur such as, in particular, the penici 11 ami ne and the cystéi

Preferred are the products of the invention which correspond to formula (I) in which: - R 1 and R 2 represent hydrogen or linear or branched lower alkyl radicals C · ^, C 2 »C3 or C4; i - Rj and R2 can form, with the neighboring carbon atom, a cycloalkyl radical Cg-Cg, - R3 represent hydrogen or a methyl radical, - R4 represents hydrogen, a linear re or branched lower alkanoyl radical C ^, C2, C3 or C4,! - Rg represents hydrogen or a linear or branched lower alkyl radical, C2> C3 or C ^, j - Rg represents: - a linear or branched alkyl radical C ^ -Cg-, - a linear alkyl radical or branched C2, C3 or C4 may be substituted by a phenoxy or phenylthio or phenoxy or phenylthio group substituted by one or more chlorine atoms or by one or more methyl or methoxy radicals; - R4 and Rg can form a thiazolidine ring optionally substituted in position 2 by one or two methyl radicals or a thi azol ring i.di none.

The present invention advantageously covers the derivatives of formula 1 in which: - Rls R2 and R3 represent hydrogen or metal radicals, - represents hydrogen; - Rg represents hydrogen; · - Rg represents a linear or branched alkyl radical C2, Cg c- l, which can be substituted by a phenoxy or phenyl group? · Or phenoxy or phenylthio substituted by one or more etc · - · of chlorine or by one or more methyl or methox radicals, // 6 /. \ .1 '.w .. rf c.

A particular class of products is composed by the derivatives of formula (I) in which: - Rj and R ^ represent a methyl radical; - R3, R4 and R5 represent hydrogen; - R- represents a phenoxyethyl group the nucleus of which may optionally be substituted by one or more halogen atoms such as chlorine or one or more methyl or methoxy radicals.

Examples of compounds according to the invention are: 2-methyl-1- (2-phenoxyethylamino) -2-propanethiol, 2-methyl-1- (2-p.tolyloxyethylamino) -2-propanethiol, 2-methyl-1- (2-p.chlorophenoxyethylamino) -2 ~ propanethiol, 2-methyl-1- (2-benzyloxyethylami no) -2-propanethiol, bis- [2-methyl-1- (2-phenoxyethylamino) -2-propyl disulfide] , bis- [2-methyl-l- (2-m.chlorophenoxyethylamino) -2-propyl 2-methyl-1-n.octylamino-2-propanethiol, 2-methyl-ln.dodecylamino-2-propanethiol disulfide, 2 -methyl-1- (2-phenylethylami no) -2-p ropanethiol.

3- (2-mercapto-2-methylpropylami no) propanoic acid. j

The derivatives of formula (I) can be obtained in the form of salts; especially hydrochlorides or sulfates. We can transform it! derivatives of formula (1), according to usual methods, in free bases or in salts with other organic or inorganic acids. ! i

According to the invention, it is more particularly of addition salts of non-toxic acids, pharmaceutically usable formed av! · ,. suitable inorganic acids. For example: hydrochloric acid, sulfuric acid or phosphoric acid or with suitable c ganic acids, such as aliphatic acids, cycl oal i phati que-; aromatic, araliphatic or heterocyclic, carboxylic or sul! foniques, for example formic, acetic, propionieue, su j kinique, glycolic, gluconic, lactic, malic, tatric, c i t r i c j ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic j glutamic, benzoic, anthranic, hydroxybenzoic, salicylic acid. i i

phenylacetic, man ical, emboniou, methanesul func., ethcr.es- · - j nique, pan cnc tén i q ue, such as uênesul fom que, sulfanilique, cycl onexy! a .7 'J

i nosul fonique, stéarique, al gi ni que -hydroxypropi oni que, b-hydroxyou | lyrical, oxalic, maloni.que, gaiactarique, gai acturonioue. These are '| can also ceriver of natural amino acids or ncr-, ro ~~ e 's j l.'sine, cl vein, ‘a rm ni ne, i’ orni tr. i r. e, asparagine, la! "V.

. : y v i. · Β · î The products of the invention may contain one or! several asymmetry centers.

Products that have an asymmetry center can be in the form of optical antipodes or in the form of a mixture, racemic or not. Their separation into enantiomers $ | can be carried out by the formation of diastereoisomeric salts.

* For the products of the invention having two centers of asymmetry, ί two racemates can be obtained corresponding respectively to the erythro and threo configurations; these two racemates | can be resolved by conventional methods, for example by formation of diastereoisomeric salts by the action of optically active acids, such as tartaric, diacetyltartaric tartranic, dibenzoyltartaric, ditoiuyltatrique and separation of the mixture of diastereoisomers by crystallization, distillation, chromatography, then release of the optically active bases from these salts.

For the products of the invention having 3 centers of asymmetry, 8 optical isomers can be obtained. The same processes can be. applied for the resolution of these mixtures.

The derivatives of the invention can therefore be used either in the form of mixtures containing several diastereoisomers whatever their relative proportions, or in the form of pairs of enantiomers in equal proportions (racemic mixture) or not, or also in the form of optically pure compounds. 1

The derivatives of the invention are endowed with hypolipi- | demiant, antithrombotic, antiarthritic and antimitotic.

| These properties make it possible to envisage the use of the products of the invention in the treatment of cardiovascular diseases such as hypercholesterolemia, thrombotic disorders and atherosclerosis, for the treatment of rheumatoid arthritis and for the treatment of cancerous conditions.

The present invention also claims pharmaceutical compositions containing, as active ingredient, at least one compound of the general formula (I) and / or a salt with a pharmaceutical excipient. These compositions are pre-.

so that they can be administered because

Oral _ recta 1 P _ njwntürjlo nu tnm'ni'P / 7.

Thus, for example, the compositions for oral administration can be liquid or solid and presented in the form of tablets, dragees, coated tablets, capsules, granules, powders, syrups or suspensions. Dry oral forms include the additives and excipients generally used in pharmaceutical dosage forms, inert diluents, disintegrating agents, binding agents and lubricating agents, such as lactose, starch, talc, gelatin, stearic acid, cellulose and derivatives, acid. silicic, magnesium stearate, polyvinylpyrrolidone, calcium phosphate, calcium carbonate, ... etc.

Such preparations can be carried out so as to prolong the disintegration and therefore the duration of action of the active ingredient.

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

The emulsions and oily solutions are made in an oil of vegetable or animal origin and may contain perfuming, dispersing, softening and antioxidant emulsifying agents. For parenteral administration, sterile water, an aqueous solution of polyvinylpyrrolidone, peanut oil, 11 or 1 ethyl acetate, etc., are used as the vehicle. These aqueous or oily injectable solutions may contain thickening, wetting, dispersing and gelling agents.

The compositions intended for the topical administration route can be semi-solid or liquid and presented in the form of hydrophobic fatty bases, hydrophilic fatty bases, emulsified bases, pastes, gels and lotions. They include the additives and excipients generally used in galenic pharmacy, surfactants, solvents, thickeners, / *

iS

i 1 ‘8.

1 · is emollients, antioxidants, preservatives such as sorbitan derivatives, ethers of cetyl alcohol, J alginic acid, propylene glycol, glycerin, sorbitol, i I cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, 3 propyl gal 1ate, benzyl alcohol, esters of p-hydroxybenzoic acid, ...

Λ *

Several methods make it possible to synthesize the products of the invention. These methods, illustrated below, also form part of the invention.

A first method consists in transforming, by reduction, an amide, an imine or an iminium salt corresponding to an aminothiol derivative: according to formula (I). This process more particularly consists in subjecting an aldehyde, a ketone or an acid corresponding to a sulfurization, a condensation with an amine and a reduction until the said derivative is obtained.

According to a first variant of this process, an aldehyde or a ketone is treated with a sulfurization reagent, then condensed with a primary amine and the imine (II) thus obtained is reduced to amine.

The diagram below illustrates this process.

h? 3 -,. ? 3 H2NR5 Rl? 3 R? - C - C = 0 lulf-ÎLa-l! - ° V R? - C - C = 0 -R - C-C = N-Rr t I 2 | 2 i b X SR? SR? (Π) reduction î R, Ro f; , 1 | 3 i R, - C - CH - NHRr —- 1 i 2.5

SH

! R ^, R ,,, Rj and Rg have the meanings given above. *.

j X represents hydrogen or an easily removable group such as chlorine, bromine, tosyle or mesyl groups, Ry represents · i of hydrogen or the SOgNa group.

The carbon-sulfur bond is formed using sulfiding agents such as, for example, sodium hydrosulfite (Na ^ SoOg, spdium hydrogen sulfide (NaSH) or * monochloride ce scuxre / (S2C1,). Sj 9.

* In the latter case, we obtain a symmetrical disulfide of formula (Γ! OR, R, 0

! He I 1 I 1 II

j Ro-C-C-S-S-C-C-R, ”^ I j o | r2 r2 I (ΙΠ)

The sulfurization reaction is carried out in an inert organic solvent such as a chlorinated solvent, an aliphatic or aromatic hydrocarbon, an alcohol, an ether or a nitrile.

The temperature is between the ordinary temperature and the reflux temperature of the chosen solvent.

i 5 i | The conversion to imine is done conventionally in one! inert organic solvent chosen, for example, from alcohols, | chlorinated solvents, aromatic or aliphatic hydrocarbons and in general under acid catalysis, by introducing, for example 1, into the reaction mixture a catalytic amount of p-toluene sulfonic acid or organic or mineral acid. Imine as well; obtained is then reduced according to methods well documented in the literature.

This reduction can be carried out in the usual way, for example by hydrogenation in the presence of a catalyst, such as palladium on carbon, Raney nickel or platinum, in the presence of a solvent, such as methanol or ethanol, and this at ordinary pressure or at high pressure, or by the action of alkali metal hydrides such as sodium borohydride, in a solvent such as methanol or ethanol preferably at low temperature or aluminum hydride and lithium in ether or tetrahydrofurant preferably at low temperature, or by the action of an aluminum alcohol, such as aluminum isopropylate, and this in a solvent such as isopropanol, most advantageously at reflux thereof or by the action of diborane in these same solvents.

When a disulfide is formed in the first step, it can be transformed into thiol for example, under the action of a phosphine such as tributylphospnine. This reaction is carried out in an inert organic solvent such as a chlorinated solvent, an alcohol, an ether or a hydrocarbon and at a temperature between the ordinary temperature and the reflux temperature of the solvent.

A second variant of this process consists in combining an eicéhyc or a ketone of formula (IV) with a secondary amine to form 10.

** * · ”.

• »> vy.

.. · $ ** · .-. * / · R t '* ·' - ·. i ·.

a minimium salt and reduce it to an amine. The diagram j below illustrates this variety.

h h? 1? 3, / s R? - C - C = 0 + HNR, R, -R „- C - C = ti + -, ά I 3 0 CI \ S R 7 SR7 Rg reduction

Ri Rn Rr il I d / o R, - C - CH - IK - * - 1 SH R6

Rl * R2 ’R3 * R5 * R6 and R7 Have the meanings given above.

The condensation of the aldehyde or of the ketone (IV) with the secondary amine is conventionally carried out in an inert organic solvent chosen for example from alcohols, chlorinated solvents, aromatic or aliphatic hydrocarbons and advantageously under acid catalysis by introducing, for example, in the reaction mixture a catalytic amount of p-toluenesulfonic acid or organic or mineral acid. It is also advantageous to introduce the secondary amine in the form of a salt, for example in the form of the hydrochloride.

The iminium salt is then reduced to an amine under the action of a reducing agent such as, for example, lithium and aluminum hydride - in tetrahydrofuran hearing ether.

According to a third variant, an amide (V) conventionally obtained from acid or amine via acid chloride is first treated with a sulfurization agent and then reduced to aminothiol according to the diagram: ..... ..

□ r r * η sulfurization R, - C - C .R- R2 'f - Cv / R5 - Z' \ / = H i X R * i n „reduction i Π / i

R ry ~ C - C Π O K P: R r S

QU * »* I · / - I 11.

ί; Rj, R2, R5 and Rg have the meanings given above, X represents hydrogen or an easily removable group such as chlorine, bromine, tosyl ^ or mesyl groups, represents hydrogen or the SOjNa group.

? ! The carbon-sulfur bond is formed using sulfiding agents such as, for example, sodium hyposulfite (^ 252 () 3), sodium hydrogen sulfide (NaSH) or sulfur monochloride (SgClg). In the latter case, a symmetrical disulfide of formula (VII) is obtained

Rr OR, R, Ç Rr b. Il I 1 I 1 II, 5: ^ N-c-c-s-s-c-c-rr / * · \ R6 R2 R2 R6 (VII)

The sulfurization reaction is carried out in an inert organic solvent such as a chlorinated solvent, an aliphatic or aromatic hydrocarbon, an alcohol, an ether or a nitrile. The temperature is between the ordinary temperature and the reflux temperature of the chosen solvent.

i J The amide (VI) is then reduced in the usual way, for example by hydrogenation in the presence of a catalyst such as palladium "j on carbon, Raney nickel or platinum, in the presence of a ! solvent, such as methanol or ethanol, and this at regular pressure! high pressure, or by the action of metal hydrides such as aluminum and lithium hydride in ether or tetrahydrofuran, or by the action of diborane in the same solvents.

When a disulfide is formed in the first step, it can be transformed into thiol by action, for example of a phosphine like tributylphosphine. This reaction is carried out in an inert organic sclvar such as a chlorinated solvent, an alcohol, an ether or a hydrocarbon and at a temperature between I · * '“' \ m ':' · e. *; i *

k * „,; " ·* . VS

i, t I. . 1 •> ’t Τ '" "* ··" · "", ·· J. / 12.

ordinary temperature and the reflux temperature of the solvent.

It is also possible to introduce, into a derivative of formula (I), substituents Rg and Rg, other than hydrogen, on the nitrogen atom, and the substituent on the sulfur atom by alkylation or by acylation.

a) alkylation on the nitrogen atom R1 R3 R 2 R3 R, - C - CH - NH? . "2 - f - tH - NHR5 <- 1 ^ deprotecti on

SQ

Rj, R2, R3 and Rg have the meanings given above and Q represents the substituent or a protecting group for the thiol function, X represents an easily removable group such as a halogen such as chlorine, bromine and iodine or tosyle groups and mésyle. A list of protecting groups for the thiol function can be found in specialized works such as, for example, "Protective Groups in Organic Chemistry Ed. J.F.W. Mc OMIE, Plenum Press (1973).

The alkylation of the amine is conventionally carried out in an inert organic solvent such as a chlorinated solvent, an aromatic or aliphatic hydrocarbon, an alcohol or an ether and, advantageously at the reflux temperature of the solvent. The presence of base, organic or inorganic, such as sodium hydroxide or triethylamine in the reaction mixture, facilitates the reaction and increases the yield.

b) acylation on the nitrogen atom

? 1? 3 -, v R 'CO y h h J

R2 - Ç - CH - NHj ^ VotecUon - R2 - Ç - CH - NH - i - Rg

SQ SH I

(VIII) jrédt ftior

R1 R3 I

R P - C - CH - N H - R5 „_!

SH

13.

Γ *. · *, * ·. ! R ^ and Rg have the meanings given above, Q represents the group R ^ or a group protecting the thiol function, Y represents an easily removable group such as, for example 'chlorine, bromine, or even the group R ^ COO . represents ί the substituent R5 whose chain is shorter by an atom of! carbon. A list of the protective groups of the thiol function can be found for example in the book to which 1 mention is made above.

i

S

The acylation is conventionally carried out in an inert organic solvent such as a chlorinated solvent, an aromatic or aliphatic hydrocarbon or an ether and, advantageously at the reflux temperature of the solvent. The basic, organic or inorganic mixture in the reaction mixture facilitates the reaction and increases the yield.

The reduction of the amide (VIII) can be carried out in the usual manner, for example by hydrogenation in the presence of a catalyzing catalyst, such as palladium on carbon, Raney nickel or 1 of platinum, in the presence of a solvent, such as methanol or etha- i! nol, and this at ordinary pressure or at high pressure, or by the action of metal hydrides such as aluminum hydride and lithium in ether or tetrahydrofuran, or by the action of diborane in the same solvents.

i c) alkylation on the sulfur atom.

: h? 3 / R5 R4X fl>? 3 / R5

Ro - C - CH - R9 - C - CH - en

Ci x c, s.

SH XR6 SR, X

R 1, R 1, R 5 and R 5 have the meanings given above and X represents an easily removable group such as, for example, a halogen atom such as chlorine, bromine or iodine or a tosyl or mesyl group. ^ - / i 14 ..

The alkylation is conventionally carried out in an inert organic solvent such as a chlorinated solvent, an aromatic or aliphatic hydrocarbon, an alcohol or an ether and, advantageously, at the reflux temperature of the solvent. The basic presence, organized; that or mineral, in the reaction mixture facilitates the reaction and increases the yield.

According to another way of proceeding, an episulphide of formula; (IX) is reacted with an amine according to the general scheme:

Ri R, Ri R0 Rc 11 13 11 13 yS 5

R, - C - CH + HNRCR / - - »R9 - C - CH - N

V SH ^ Rg (IX)

Rj, R2 »R3» R5 and Rg have the meanings given above. Depending on the reagents used, the episulphide can be opened at atmospheric pressure or at a pressure higher than atmospheric pressure, at ordinary temperature or at an elevated temperature, or else by catalysis with Ag ions. The reaction can be carried out with or without a solvent. If a solvent is used, it can be water or an inert organic solvent such as an aromatic or aliphatic hydrocarbon, a chlorinated solvent or an ether. Advantageously, the presence of tertiary amine has a favorable influence on the course of the reaction which takes place in this case, with advantage, at a temperature between 25 and 100 ° C. · ([. Μ · · · - · ** ι. Ί d · 15 ·

Yet another way of proceeding is illustrated by the diagram below.

:, 'j fl? 3 Ts „H fl f3 HNR5R6 1 r9-c - ch - OH -> - R9 - C - CH ---» - (I) ά 1 c I i 2 S-COORg \ i 1 \ κ xc m ô (κι)

Rj, R ^, Rg, Rg and Rg have the meanings given above and Rg represents a lower alkyl group

Cl ”C3‘

A thiolcarbonate of formula (X) is treated with an acid in an inert organic solvent, such as an aliphatic or aromatic hydrocarbon or a chlorinated solvent or an ether.

The acid is preferably organic such as p-toluene sulfonic acid (TsOH) or methanesulfonic acid. The reaction temperature is higher than normal temperature and preferably close to the boiling point of the chosen solvent. The derivative (XI) thus obtained is then treated with an amine at reflux of an inert organic solvent to give the products of the invention.

According to a last way of proceeding, a derivative of 2-mercaptoethanol (XII) is esterified with an acid and then treated with an amine according to the scheme.

fl h fl? 3 R2-C - CH - OH + RgCOOH - R2 ~ C - CH - OCORg -

SH SH

R5

'(XII) (XIII) HNX

fl? 3 ^ R, j k6 R ~ -C - CH - N - 'ÎH // [/ / _ · ^ ’·: t ·”, V ‘·. · I. '}: "."'. · · · * '", L · 16.

R1, R2 "R3" Rg, Rg have the meanings given above and Rg represents a group such that it makes the acyloxy group easily removable. For example, Rg may be a tri-h a1omethyl group such as the trifluoromethyl or tri ch 1oromethyl group. The esterification is conventionally carried out in an inert organic solvent chosen, for example, from aromatic solvents, chlorinated solvents or ethers and preferably at reflux of the solvent. It is advantageous to remove the water as soon as it forms, for example by azeotropic distillation. The ester (XIII) is then heated in an inert organic solvent as mentioned above in the presence of an excess of amine to form the products of the invention.

Below are given detailed examples of the preparation of some aminothiol derivatives according to the invention. These examples are mainly intended to further illustrate the specific characteristics of the methods according to the invention. / j ‘17.

i

Example No. 1 2-methyl-1 - (2-phenoxyethylamino) -2-propanethiol, hydrochloride I (derivative No. 3 of Table I).

f a - To 650 ml of carbon tetrachloride, 817 ml (9 mol to 648.9 g) of isobutyraldehyde are added with stirring. The mixture is heated to 50 ° C before slowly adding 360 ml (4.5 moles ·, 135.0 g) of sulfur monochloride. The reaction is exothermic. At the end of the addition, the temperature of the medium is maintained at 40 ° C for 48 hours. The solvent is then evaporated under reduced pressure and then the residue is distilled. The main fraction is collected between 94 and 100 ° C, for a pressure of 0.8 Torr. A second i distillation round provides 365 g (1.8 mole; 40¾) of α, α'-dithiodiisobutyraldehyde.

b- A mixture consisting of 20.6 g (0.1 mole) of the preceding product, 27.4 g (0.2 mole) of 2-phenoxyethylamine and 130 ml of isopropanol is heated for 1.5 h at temperature reflux. The resulting medium is evaporated to dryness under reduced pressure. The residue is taken up in hexane. An insoluble material is filtered and the filtrate is in turn evaporated.

A diiminodisulfide is thus obtained which is used as it is in the next step.

j c- In a 1 liter reactor, 7.6 g (0.2 mole) of hydride | and aluminum are suspended in 250 ml | anhydrous ether. While stirring, a solution is then added; of the previous product in 250 ml of the same solvent, at a rate such as a slight reflux sets in then persists. At the end of the addition, reflux is maintained by heating for an additional 2 hours. The mixture is allowed to cool and then the excess hydride is destroyed.

T I

18.

The organic phase, dried, is brought into contact with gaseous hydrochloric acid and dry until the end of the precipitation which occurs. The hydrochloride is filtered, washed thoroughly with ether and then dried at reduced pressure. After recrystallization from a mixture of ethyl acetate and benzene, 38.5 g (0.15 mol; 75%) of the expected compound are obtained.

F. ' 139.9 ° C.

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

Elementary analysis: C H N

C12HigN0S.HCl% shim. 55.1 7.7 5.4 P.M. 261.82% rev. 55.4 7.7 5.2

Example No. 2 2-methyl -1- (2-p.tolyloxyethylami no) -2-propanethi ol, hydrochloride (derivative No. 11 of Table I).

This compound is obtained according to the procedure described in Example No. 1, by replacing 2-phenoxyethylamine with 2-p.tolyloxyethylamine.

Yield: 56%. Mp 115.2 ° C (AcOEt).

Elementary analysis: C H N

C13H21N0S.HC1% shim. 56.6 8.0 5.1 P.M. 275.84% tr. 56.6 8.1 5.0

Example 3

Bis [[2-methyl-1- (2-phenoxyethylami no) -2-propyl] disulfide, dihydrochloride (derivative No. 14 of Table I).

This disulfide is obtained at the expense of the product resulting from the operation given under b- in Example No. 1.

A solution of 16.1 g (35 mmol) of crude diiminodisulfide in 90 ml of ethanol is heated to 60 ° C. and then slowly added with a solution of 4.0 g (105 mmol) of sodium borohydride in 105 ml of the same solvent. At the end of the addition, the mixture is heated at reflux for two hours. Then we pour the 'r /! '' 19.

• ‘'. **. ·? '• f t *.

• * ·. t. . , · ·, Medium, returned to room temperature, on 350 q of crushed ice. The aqueous phase is extracted with chloroform. The organic extract is evaporated to dryness under reduced pressure. The evaporative residue I is dissolved in ether and the solution is brought into contact. £ with gaseous hydrochloric acid and dry. The salt that has | precipitate is filtered and then recrystallized from propanol.

Weight: 11.8 g (23 mmol; 66%). Mp 181.8 ° C.

The IR, NMR and mass spectra corroborate the structure of the expected disulfide.

Elementary analysis:

C H N

C24H36N2 ° 2S2 * 2HC1% calc * 55.3 7‘3 5.4 P.M. 521.62% rev. 55.6 7.2 5.0

Example No. 4 5,5-Dimethyl-3- (2-phenoxyethyl) -2-thiazolidinone (derivative No. 23 of Table I).

10.5 g (40 mmol) of 2-methyl-1- (2-phenoxyethylamino) -2-propanethiol hydrochloride are dissolved in 100 ml of methanol to which 11.0 ml (8.0 g; 80 mmol) are added of triethylami ne. The mixture is stirred for 15 minutes and then evaporated to dryness under reduced pressure.

The residue, taken up in ether> is filtered and the filtrate is, in turn, evaporated to dryness under reduced pressure. The product obtained, suitably dried, is dissolved in 250 ml of toluene, which is further added with 8.0 ml of triethylami before being mixed with 250 ml of aqueous sodium hydrogencarbonate solution. Then stirred vigorously while slowly adding 34 ml (65 mmol) of a 20% solution of phosgene in toluene.

When the addition is complete, the mixture is stirred for an additional 2 hours. The organic phase is decanted, dried and then evaporated to dryness under reduced pressure. The residue consists of a dark oil which spontaneously crystallizes.

Recrystallization from n-heptane 'then provides a white solid weighing 5.2 g (21 mmol .; 53%} F. 51.3 ° C.

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20.

Elementary analysis CH N

C13H17N02S 62.1 6 · 8 5 * 6 P.M. 251.35 62.2 6.8 5.5

Example 5.

Bis - [(2-phenoxyacetamido) ethyl disulfide] (derivative No. 19 of Table I).

A mixture of 11.3 g (50 mmol) of cystamine dihydrochloride, 50 ml of chloroform and 42 ml (30.3 g; 300 mmol) of triethylami is only slowly added with a solution of 20.5 g ( 120 mmol) of phenoxyacetyl chloride in 50 ml of chloroform. The medium is further stirred for 2 hours and then successively extracted with 25 ml of water, 25 ml of 10¾ aqueous solution of sodium hydrogen carbonate and 25 ml of water. It is dried over magnesium sulphate and then evaporated to dryness under reduced pressure. Finally, the residue is recrystallized from isopropanol.

Weight: 17.4 g (41 mmol; 82%) F. 110.2 ° C.

The IR, NMR and mass spectra verify the structure of the expected product.

Elementary analysis CH N

C20H24N204S2% shim. 57.1 5.8 6.7 P.M. 420.56% rev 57.2 5.6 6.6

Example n ° 6 3- (2-methyl-2-mercapto-butylamino) propanoic acid (derivative n ° 5 of table I).

a - 36.9 g (150 mmol) of 1-amino-2-benzylthio-2-methylbutane hydrochloride are mixed with 200 ml of isopropanol and 62 ml of triethylamine. The mixture is stirred while slowly adding 23.0 g (150 mmol) of 3-bromopropanoic acid. When the addition is complete, the mixture is heated for 2 hours at reflux temperature.

The medium, returned to ambient temperature, is evaporated to dryness under reduced pressure. The residue is partitioned between this water and chloroform. The organic phase is dried / and evaporated. The residue is taken up in a little acetone, which causes a white solid to form. (//, * V 'V).

*; · / ’; ^ · '

Weight: 19.0 g (68 mmol; 45%). Mp 140.9 ° C.

The NMR spectrum agrees with the structure of 3- (2-methyl-2-benzylthi obutylami no) propanoic acid.

ijb - To 200 ml of liquid ammonia, 8.4 g (30 mmol) of the preceding product, with sufficient metallic sodium, is added at a temperature between -50 and -60 ° C, in small successive portions, so that the blue coloration is persistent.

At this point, add the quantity of ammonium chloride allowing the medium to discolor, then, after removing the cooling bath, the ammonia is evaporated.

30 ml of water are added and gradually acidified until; pH 2, under a nitrogen atmosphere. It is carefully evaporated to dryness under reduced pressure and then the residue is taken up in acetonitrile. The addition of ether causes precipitation of a white solid which is filtered, washed thoroughly with ether and dried.

Weight: 2.4 g (11 mmol; 37%). Mp 117.2 ° C.

Examination of the IR, NMR and mass spectra confirms the structure of the expected product.

Elementary analysis C H N

C8H17N02S * HC1 42.2 8.0 6.2 ί P.M. 227.76 42.3 7.8 6.1!

The melting points and the recrystallization solvents of derivatives prepared according to the invention are included in /; / y following table I: / y /// /% 22.

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Lj> C32I o 3 O Ö O (J ΰ Û ° un lo r- »co cr> o * - · cnj co ^ ^ ^ <5- -CT« 5Γ LO LO LT, LP LO _n ^ / 4 1 '17 (1) the recrystallization solvent is given in parentheses.

3 | (2) the elementary analyzes were carried out for the elements I C, Hs N and are in accordance with the theoretical values.

! (3) Sym is the indication of a symmetrical disulfide. / I A / (4) hydrochloride. /// | (5) free base. If> (6) hydrobromide. / 'f ‘\ · ·, i * I,: · ·' 28 ·; In Table II, the numbers given in column 1 correspond to the numbers in column 1 of Table I.

The results given in Table II are obtained under the following conditions: 1) Acute toxicity in mice.

The substances suspended in a mucilage containing 1% of tragacanth, are administered orally by means of an intragastric probe to groups of 5 male mice (strain CD1, Charles River, fasting for 18 hours). If the quantity of substance available allows, the doses are 3000, 1000 and 300 mg / kg. In case this last dose: is active, the effect of the drug is examined at 100, 30, 10 and possibly 3 mg / kg. Mortalities are recorded within 14 days of treatment. The LD50s are calculated according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther., 96, 99, 1949) and expressed in mg / kg.

2) Inhibition of platelet aggregation.

The turbidimetric method described by 6.V.R. Born and M.J. Cross (J. Physiol., 168, 178-195, 1973) is used.

The plasma rich in human platelets is preincubated for 4 minutes before the introduction of the inducer (Thrombofax).

The variations in optical transmission are recorded over a period of 10 minutes in an "Upchurch" agrometer. The test is carried out in duplicate, in the presence of a drug or of the corresponding solvent and the results noted in percentage of inhibition of the maximum amplitude of aggregation compared to the controls.

3) Inhibition of lipolysis

Epididymal fat is removed from fasted rats.

Fragments of adipose tissue (+ 150 mg) are incubated in the Krebs-Ringer buffer containing 3 "of bovine serum albumin and the substance to be studied. A reference sample is taken after an incubation of 30 minutes at 37 ° C. Norepinephrine is used to induce lipolysis.

The level of free amino acids is measured after 20 minutes of incubation (Duncombe W.G., Clin. Chim. Acta, 8, 122, 1964). / J ί '(.,; 29 f ι j î

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4) Inhibition of cholesterol bipsynthesis.

Rat liver homogenates are prepared and incubated in a suitable medium. Aliquots are incubated for 60 minutes with 1- C acetate and the test compound. After saponification of the medium, the sterols are extracted with petroleum ether and the dry residue is precipitated with digitonin in an al-acetone solution. The 14 C content of the precipitate dissolved in pyridine is measured by liquid scintillation counting according to the method described by N. Bûcher (J. Biol. Chem. 222, 1-15, 1956). - '5) Inhibition of collagen degradation.

After incubation at 37 ° C. of the collagen in the presence of collagenase in a medium buffered to pH 7.2, in the presence or in the absence of a drug, the released amino acids are detected by colorimetric reaction with ninhydrin and measurement absorbance at 570 nm.

In addition, more in-depth experiments were carried out on a particular product of the invention: the CP 430 AP (compound No. 3 in Table I).

A preliminary study was carried out in Rhesus monkeys rendered dyslipemic by administration of a diet containing 14 "of butter and 1 mg of cholesterol / Kcal. These animals developed hypercholesterolemia, without modifying the triglyceride level. Two monkeys with hypercholesterolemia at approximately 400 mg / 100 ml received an oral administration of 30 mg / kg of CP 430 AP every day for two weeks.

The blood samples were taken on days 8, 12 and 15, d as well as before the start and 7, 14 and 21 days after replacing the treatment with a placebo.

The total cholesterol, free and esterified and the cholesterol a as well as the triglycerides, were determined on these samples.

The results are given in tables III and IV annexed.

/ ♦ /

Under these conditions, the CP 430 AP seems to significantly reduce the hypercholesterolemia of the two monkeys and does not alter /// '' I 33.

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The cholesterol esterification ratio is not changed, which makes it possible to exclude a hepatotoxic effect.

i The CP 430 AP inhibits cholesterol biosynthesis in vitro.

| This activity can be demonstrated on rat liver homogenates incubated in the presence of labeled acetate or labeled mevalonate. The inhibitory effect of CP 430 AP is manifested - 5-4 feste between 3.10 and 10 M. The inhibition is similar for the two precursors tested, which indicates that the activity of the product is exerted beyond the formation mevalonate and is therefore more specific than that of clofibrate.

This inhibitory effect of CP 430 AP is found when the product is administered orally to rats, at a dose of 200 mg / kg, two hours before the liver is removed. In this case, the inhibition observed is 35¾.

The CP 430 AP, in vitro, inhibits the breakdown of collagen by collagenase. The inhibition is 61% at the concentration of 10 “3M.

In vitro, the CP 430 AP inhibits the aggregation of human platelets induced by Thrombofax. The inhibition is total 1 -4 at the concentration of 2.10 M.

i

In mice, the LD 50 of the CP 430 AP is 950 mg / kg orally (confidence limit for p = 0.95: 637-1415 mg / kg); intraperitoneally the LD50 is 300 mg / kg (confidence limit 171-527 mg / kg).

The study of the toxicity of CP 430 AP by repeated administration in rats has been undertaken. Administered at a dose of 100 mg / kg /! daily by the oral route, every day for 3 weeks, in rats \ SD, it does not induce any mortality or any macroscopic lesion i and did not affect the main blood parameters. This / / dose therefore appears to have no major toxic effect.

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The active compounds of the invention can be administered in combination with various pharmaceutical excipients and this by oral, parenteral or rectal route.

For oral administration, dragees, granules, tablets, capsules, tablets and capsules with controlled release of the active principle, sublingual tablets, solutions, syrups, emulsions containing additives or excipients conventional in galenic pharmacy will be used. For parenteral administration, sterile water or an oil, such as peanut oil or ethyl oleate, will be used. For administration: rectal, suppositories or rectal capsules will be used.

These active compounds can be used alone or in combination with other active products having a similar or different activity.

The products of the invention can be used in various forms. The examples which follow are not limiting and relate to the galenical formulations containing as active product, hereinafter designated by the reference "A", one of the following compounds: 2-methyl-1- (2-phenoxyethyl no) -2-propanethi ol 2-methyl-l- (2-p.tolyloxyethylamino) -2-propanethiol 2-methyl-l- (2-p.chl orophenoxyethylamino) -2-oropanetniol 2-methyl-1- (2-benzyloxyethylamino) -2- bis - [2-methyl-1- (2-phenoxyethylamino) -2-propyl] disulfide propanethiol.

3- (2-mercapto-2-methyl-propylami no) propanoic acid.

bis-r2-methyl-l- (2-m.chloropnenoxyetny1amlno) -Z-propyl], 2-methyl-ln.octylamino-2-propanethiol, 2-methyl-ln.dodecylamino-2-propanethiol disulfide -methyl-I - ^^ - phenylethylaminoJ-Z-propanethiol. ^. / r I · 37.

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! Comp n mes I - A 250 mg soluble starch 50 mg; cellulose mid crocri s tall i ne 150 mg j lecithin 30 mg i gelatin 25 mg talc 8 mg i magnesium stearate 7 mg - A 500 mg lecithin 50 mg lactose 100 mg magnesium stearate 10 mg i j Capsules | - At 200 mg; lactose 200 mg 'polyvinylpyrrolidone 20 mg magnesium stearate 5 mg

Suppose you are - At 800 mg

Witepsol H15 ad 3500 mg

Injectable ampoules - At 100 mg to be dissolved immediately in

NaCl 40 mg

NaHSOg 20 mg distilled water for injectables ad 10 ml

Creams' 5g

Polymerized acrylic acid, 1 g carbopol 940 type) tri ethanol amine qs ad pH 5 / aqua purificata ad 100 q // '/ 4 ¥ 3a A 5 q stearic alcohol 25 g petroleum jelly 20 g propylene glycol 5 g polyoxyl 40 stearate 5 g p. methyl hydroxybenzoate 0.02 g p.propyl hydroxybenzoate 0.01 g water ad 100 g - Witepsol H15: mixture of glycerides partially or fully esterified.

Depending on the case, the route of administration, the nature of the activity sought and of the specific compound used, the derivatives according to the invention are administered in daily doses of 100 to 2500 mg and, by intravenous injection, the derivatives according to invention are administered in doses / from 5 to 100 mg. AT

/ "

Claims (29)

2. Derivatives according to claim 1, characterized in that in formula I: - R ·, represents hydrogen or a linear or branched C1-Cn alkyl radical, - R2 represents hydrogen or an alkyl.adical lower, linear or branched C g 'C0, C- or C4, / "// 4 i» 1 41. - Rj and R2 can form with the neighboring carbon atom a »cycloalkyl radical Cg-Cg,! - R3 represents hydrogen or a linear or branched lower alkyl radical Cj, C2 or C3; | - R. represents hydrogen, a linear or branched lower alkyl radical | ^ | C ^, C2 or C3, a linear lower alkanoyl radical or branched Cj, C2, C3 or C ^, a linear or branched lower koxycarbonyl thio radical Cj, C2 or C3 a linear or branched alkylthio radical C ^ -Cg, - Rg and Rg which may be identical or different, represent:: - hydrogen, - a linear or branched alkyl radical Cj-Cj. ,, - a linear or branched alkyl radical C2, C3 or C ^, substituted by: - a ring phenyl substituted by one or more halogen atoms such as chlorine, by one or more methyl or methoxy radicals, - a linear or branched alkoxy or alkylthio group Cj, C2 »C3 or C ^, - a linear or branched alkylcarboxamido group Cj , C2, C3, C4, Cg or Cg optionally substituted by a phenyl or phenoxy ring, - a cycloalkylcarboxamido group C ^, C ^, Cg, Cg, Ζη i or Cg. | - Rg and Rg can form with the neighboring nitrogen atom a hetero ring such as piperidine, pyrrolidine, morpholine, piperrazine optionally substituted in position 4 by a benzyl group, a methyl radical or by a phenyl ring which can itself be substituted by one or more halogen atoms such as fluorine and chlorine, linear or branched lower alkyl radicals C ^, C2 or C3, alkoxy radicals. linear or branched C ^, C2 or C3, - and Rg can form a thiazoli dine ring optionally substituted in position 2 by one or two methyl radicals or a thiazolidinone ring, as well as symmetrical disulfides or those formed with sulfur-containing amino acids such as, in particular, the peni ci 11 ami r · ^ and cysteine. / /> •. · '· 1, \ ·. ·. * »'1 4 * ί ·, J' · '* · 42. 3. Derivatives according to claim 1 characterized in that in formula I: - Rj and R2 represent hydrogen or linear or branched lower alkyl radicals Cj, C3 or C ^, - Rj and R3 can form, with the neighboring carbon atom, a Cg-Cg cycloalkyl radical, - R3 represents hydrogen or a methyl radical, - represents hydrogen, a linear or branched lower alkanoyl radical Cl5 C2, C3 or C4; - Rg represents hydrogen or a linear or branched lower alkyl radical Cj, C2, C3 or C ^, 7 - Rg represents: - a linear or branched alkyl radical C ^ -Cg, - a linear or branched alkyl radical C2, C3 or which may be substituted by a phenoxy or phenylthic or phenoxy or phenylthio group substituted by one or more chlorine atoms or by one or more methyl or methoxy radicals, - R ^ and R5 may form a thiazolidine ring optionally substituted in position 2 by a or two methyl radicals or a thiazolidinone ring. 4. Derivatives according to claim 1, characterized in that in formula I: - Rj, R3 and R3 represent hydrogen or methyl radicals, I - R ^ represents hydrogen, - Rg represents hydrogen, - Rg represents a linear or branched alkyl radical C2, C3 or which may be substituted by a phenoxy or phenylthio or phenoxy or phenylthio group substituted by one or more chlorine atoms or by one or more methyl or methoxy radicals. 5. Derivatives according to claim 1, characterized in that in formula I: - R-1 and R2 represent a methyl radical; - R3, and Rg represent hydrogen, / - Rg represents a Dhênoxyëtnvle group whose novau ^ ': / $ * t \ • 43. may be substituted by one or more halogen atoms * such as chlorine or one or several methyl or εί radicals | methoxy. P 6. Derivative according to any one of claims 1 to 3, characterized in that, in formula I, R ^, Rg and Rg represent an alkyl radical C ^ -C ^. 7. Derivative according to claim 1, characterized in that, in formula I, Rj, Rg and Rg represent an alkyl radical C5 "C10 · 8. A derivative according to claim 1, characterized in that, in formula I, Rg and Rg represent an alkyl radical C11 ~ C16 ’ 9. A derivative according to any one of claims 1 and 2, characterized in that, in formula I, represents an alkylthio C ^ -Cg. 10. Derivative according to claim 1, characterized in that, in formula I, R4 represents a C5 "C10 * J alkylthio 11. Derivative according to any one of claims 1 to 3, characterized in that, in formula I , R- ^ and R £ form, with the neighboring carbon atom, a cycloalkyl radical Cg or Cfi. II * 1 12. Derivative according to claim 1, characterized in that, in formula I, Rg and Rg represent a cycloalkyl radical! Cg or Cg, an alkenyl or alkynyl radical Cg, C ^, Cg or Cg. 13. A derivative according to claim 1, characterized in that, in formula I, Rg and Rg represent an alkenyl or alkynyl radical Cg-C1Q. 14. A derivative according to claim 1, characterized in that, in formula I, Rg and Rg represent an alkenyl radical / r _ r · S / -π iô · // ί / ". .44. 15. A derivative according to any one of claims 1 to 5, characterized in that it is chosen from the group formed by the following compounds: .2-methyl-l- (2-phenoxyethylamino) -2-propanethiol, 2- methyl-1- (2-p.toiyloxyethylamino) -2-propanethiol, 2-methyl-1- (2-p. chlorophenoxyethyl.amino) -2-p ropanethiol, 2-nié thyl.-l- (2-benzyloxyethylamino) -2-p ropanethiol, bis- [2-methyl-1- (2-phenoxyethylamino) -2-propyl disulfide. bis-r2-inethyl-1 disulphide - (2-m. chlorophenoxyethyl amino) -2-pro-pylej, - 2-methyl-1-n.octylamino-2-propanethiol, 2-methyl-ln.do decylamino -2-propanethiol, 2-methyl-1- (2-phenylethylamine no) -2-propanethiol. 3- (2-mercapto-2-methylpropylamino) propanoic acid. 16. Derivative as described above, in particular in the examples given in the description. 17. Process for the preparation of aminothiol derivatives according to any one of the preceding claims, characterized in that it consists in transforming, by reduction, an amide,. an imine or an iminium salt corresponding to an aminothiol derivative according to formula I. 18. Method according to claim 17, characterized in that it consists in subjecting an aldehyde, a ketone or an acid corresponding to a sulfurization, a condensation with an amine and a reduction until the said derivative is obtained. i 19. The method of claim 18, characterized in; that an aldehyde bearing on carbon has a sulfur residue is treated with an amine and then reduced to an aminothiol derivative. , i 20. The method of claim 18, characterized in that an amide which bears on the carbon has a sulfur residue is / reduced to an aminothiol derivative. AT/ / / * . _ y,. . he.,.-.· ·. -! i t * * - »^. 21. Process for the preparation of aminothiol derivatives according to | any one of claims 1 to 16, characterized in 1 that it consists in subjecting to a reaction with a compound RX I, or R'cC0Y a derivative of 1 has formula: * v fl f3 R2 - C - CH - NH2 SQ in which Rj to Rg and Rg have the meanings given - in any one of claims 1 to 16, Q represents the substituent or a protecting group for the thiol function, R'g represents the substituent Rg whose chain is shorter of a carbon atom, X represents an easily removable group, such as a halogen, such as chlorine, bromine, iodine, or tosyl or mesyl groups, Y represents an easily removable group such as, for example example, chlorine, bromine or even the R'gCOO group, until obtaining, after possible reduction, a compound of formula: * fl f 3 R, - C - CH - NHR, i ~ £ | t>; sh » 22. Process for the preparation of aminothiol derivatives according to any one of claims 1 to 16. characterized in that it consists in subjecting to a reaction with a compound R4X a derivative of the formula: fl h / R5 R2 - C - CH - SH XR6 in which R ·, to R ,, Rg and Rg have the meaning cario-s given in any one of claims i = 16 e: X represents an easily eliminated group, such as a nalo-gene, such as chlorine, bromine, iodine, or grouoes / tosyle or mesyle, so as to obtain an aminothicl This formula /? > IM · U ' 23. Process for the preparation of solvent aminothiol derivatives any one of claims 1 to 16, characterized in that it consists in putting an episulphide of formula \? Ih R0 - C - CH in reaction with an amine of the type HNRCR ^ of c \ / oo S so as to obtain a corresponding aminothiol derivative. 24. Process for the preparation of aminothiol derivatives according to any one of claims 1 to 16, characterized in that a 2-oxathiolanone of formula: fl? 3 Rg - C - CH is treated with an amine of the NHR ^ type Rg, from S 0 V 0 so as to obtain the corresponding aminothiol derivative of formula (I). 25. The method of claim 24, characterized in that it consists in reacting a thiolcarbonate of formula 1 Pl h - C - CHj - OH with an acid, such as S-COORg p-toluenesulfonic acid or methanesulfonic acid, so as to form 2-oxathiul anone, the latter being mransfc, into a corresponding aminothiol derivative of formula (I sc - s V action of an amine. " 26. Process for the preparation of derivatives of friend nothi ois Sî. '. vs't any of claims 1 to i £, characterized / / s ♦ ·} „'', i '' * ·"> '/' \ '' * * * -r / „h? 3 | R2 - C - CH - OCORg, in which at R3 have the meanings! SK? *% Û V j- given above and Rg is a group such that it makes the I acyloxy group easily removable, such as a tri group fluoromethyl or trichloromethyl, is treated with an amine of the HNR ^ Rg type. 27. A method according to claim 26, characterized in that it consists in esterifying a 2-mercaptoethanol derivative of formula R1? 3 R2 - C - CH - OH with a compound of the RgCOOH type until SH ester is obtained cited above, and to treat the latter with an amine of the hnr5r6 type. ! 28. Process for the preparation of aminothiol derivatives such as I * | described above, in particular in the examples given. \ i 29. Pharmaceutical composition comprising, as active product, at least one of the derivatives according to any one of claims 1 to 16; associated with at least one excipient and / or optionally with at least one other therapeutic agent. 30. Pharmaceutical composition having a half ante hypolipi, antithrombotic, antiarthritic and antimitotic activity, characterized in that it comprises, as active product, at least one of the derivatives according to any one of claims 1 to 16, associated with at least one appropriate excipient and / or at least one other therapeutic agent. 31. Pharmaceutical composition based on * aminothiols according to any one of claims Γ to 16, characterized in that the administration takes place by oral, parenteral, reft.h? - // fl! I f. Γ; "î Γ1 Ί r </ // \ · \% · '. t s J â i 32. Method of using the derivatives according to any one of claims 1 to 16, or of the compositions according to reven-I dications 29 to 31, characterized in that the derivatives I of friend nothiο 1 s are administered by the oral at daily doses of 100 to 2,500 mg and intravenously at daily doses of 5 to 100 mg. £ „. | Drawings: - = rr .. „. pages pages of which .... pope of carding paoes of description: ounces of claims - '' '"I descriptive abbreviation Luxembourg, le 2 g ;;; j: 1350 ^^ Le ^^^ dated: Charles München K \ | it ? ti ï iis