NL8103993A - AMINOTHIOL DERIVATIVES, PREPARATION AND USE THEREOF, AND PREPARATIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

t? S * * N.0.30382 - 1 -

Aminothiol derivatives, preparation and use thereof, and preparations containing these derivatives.

The present invention relates to amino thiol derivatives of the general formula 1, wherein R 1 represents hydrogen or a straight or branched alkyl group with 1 to 10 carbon atoms, R 2 represents hydrogen or a straight or branched alkyl group with 1 to 4 carbon atoms, R 1 represents and R2 with the adjacent carbon atom form a cycloalkyl group of 3-8 carbon atoms, R10 hydrogen, a straight or branched alkyl group of 1-3 carbon atoms, a straight or branched alkanoylthio group of 1-3 carbon atoms, a straight or branched alkyloxycarbonyl thio group with 1-3 carbon atoms, a straight or branched alkylthio group with 1-10 carbon atoms or a sulfur containing -tent group having the structure - (S) -CRjR ^ CE ^ -NR ^ Rjj, where n = 1 or 2 R and Rg, which may be the same or different, hydrogen, a straight or branched alkyl group of 1 to 16 carbon atoms, a straight or branched alkyl group of 2 to 6 carbon atoms, substituted with a hydroxy group, carboxyl group, straight or branched an alkoxycarbonyl group with 1-3 carbon atoms, a naphthyloxy group, a phenyl, phenoxy, phenylthio or benzyloxy group, optionally substituted with one, two or more halogen atoms, such as chlorine, with one, two or more straight or branched alkyl groups of 1-4 carbon atoms or of one, two or more straight or branched alkyloxy groups of 1-4 carbon atoms, a straight or branched alkoxy or alkylthio group of 1-4 carbon atoms, 8103993 * * ... -2- an alkylamino group of 1-4 carbon atoms, optionally substituted with a phenyl group, a straight or branched chain alkylcarboxamido group of 1-6 carbon atoms, optionally substituted with a phenyl-5 or phenoxy group or a cycloalkylcarboxamido group of 3-8 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, a straight or branched alkenyl group of 3-16 carbon atoms, or a straight or branched alkynyl group of 3-8 carbon atoms, R 1 and R 1 with the adjacent nitrogen atom may form a heterocyclic ring, such as piperidi ne, pyrrolidine, morpholine or piperazine, optionally substituted in the 4-position with a benzyl group, a straight or branched chain alkyl group with 1 to 4 carbon atoms or a phenyl group, which may itself be substituted with one, two or more halogen atoms such as fluorine or chlorine, straight or branched alkyl groups having 1-3 carbon atoms, and / or straight or branched alkoxy groups having 1-3 carbon atoms, Rg and Rl a thiazolidine ring, optionally substituted in the 2 position with one or two straight or branched alkyl groups with 1-3 carbon atoms or a thiazolidinone ring can form and R 2, R 2, R 3, and R j cannot simultaneously represent hydrogen.

In the present description, the word "branched" denotes both tertiary and quaternary carbon atoms.

The products of the invention include the non-toxic and pharmaceutically applicable salts of these derivatives. Advantageously, the present invention protects the derivatives of formula I, wherein R 1 represents hydrogen or a straight or branched alkyl group with 1 to 8 carbon atoms, R 2 represents hydrogen or a straight or branched alkyl group with 1 to 4 carbon atoms,

R1 and R2 with the adjacent carbon atom form a cycloalkyl group with 5 or 6 carbon atoms, R1 hydrogen, a straight or branched alkyl group with 1-3 carbon atoms, a straight or branched alkoxycarbonylthio-40 group with 1-3 carbon atoms, a straight or branched alkyl-8103993 \ ii-3-thio group having 1 to 5 carbon atoms or a -S-CR 1 R 3 -CH 1 NR 3 R 1 group which forms symmetrical disulfides, and R 4, which may be the same or different, hydrogen, 5 a straight or branched alkyl group of 1-12 carbon atoms, a straight or branched alkyl group of 2-4 carbon atoms, substituted with one with one, two or more halogen atoms, such as chlorine, with one, two or more methyl or methoxy groups substituted phenyl core a straight or branched chain alkoxy or alkylthio group of 1 to 4 carbon atoms, a straight or branched chain alkylcarboxamido group of 1 to 6 carbon atoms, optionally substituted with a phenyl-15 group or a cycloalkylcarboxamido group of 3 to 8 carbon atoms, R 1 and R 9 with the adjacent nitrogen atom can form a heterocyclic ring, such as piperidine, pyrrolidine, morpholine or piperazine optionally substituted in the 4-position with a benzyl group, a methyl group or a phenyl group, which may itself be substituted with one, two or more halogen atoms, such as fluoro and chloro, straight or branched alkyl groups of 1-3 carbon atoms or straight or branched alkoxy groups of 1-3 carbon atoms, Rg and Rl a thiazolidine ring, optionally substituted in the 2-position with one or two methyl groups or a thiazoli dinon ring.

Preference is given to products according to the invention which correspond to the formula I, wherein R 1 and R 2 represent hydrogen or straight or branched chain alkyl groups with 1 to 4 carbon atoms, R 2 and R 2 with the adjacent carbon atom represent a cycloalkyl group with 5 or 6 carbon atoms, R 3 represents hydrogen, R 3 represents hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, R 5 represents a straight or branched alkyl group of 1 to 8 carbon atoms, a straight or branched alkyl group of 2 to 4 carbon atoms, which may be substituted are substituted with a phenoxy or phenylthio-40 group or a phenoxy or phenylthio group with 8103993 ft- * - 4 - one, two or more chlorine atoms or with one, two or more methyl or methoxy groups, and a thiazolidination, optionally substituted in the 2-position with one or two methyl groups or form a thiazoli-5 dinon ring.

The present invention preferably relates to the derivatives of the formula 1, wherein R 1 and R 2 represent hydrogen or methyl groups, R 1 represents hydrogen, R 4 represents hydrogen, R 1 represents a straight or branched chain alkyl group having 2-4 carbon atoms, which optionally substituted with a phenoxy or phenylthio group or a phenoxy or phenylthio group substituted with one, two or more chlorine atoms or with one, two or more methyl or methoxy groups.

A particular group of compounds consists of derivatives of the formula 1, wherein R 1 and R 2 represent a methyl group, R 1 and R 2 represent hydrogen, R 1 represents a phenoxyethyl group, in which the core may be optionally substituted with one, two or more halogen atoms such as chlorine or one, two or more methyl or methoxy groups.

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-benzyloxyethylamino) -2-propanethiol, bis-C2-methyl-1- (2-phenoxyethylamino) 2-propyl] disulfide, bis-C2 -methyl-1- (2-m-chlorophenoxyethylamino) 2-propyl] disul-30-fide, 2-methyl-1-octylamino-2-propanethiol,.

2-methyl-1- (2-phenylethylamino) -2-propanethiol, 2-methyl-1-dodecylamino-2-propanethiol, 3- (2-mercapto-2-methylpropylamino) propanoic acid, 35 2-methoxycarbonyldithio-2-methy1- 1- (2-phenoxyethylamino) propane.

The derivatives of the formula 1 can be obtained in the form of salts, in particular the chlorohydrates or the sulfates. The derivatives of formula (I) can be converted to free bases or salts by conventional methods according to conventional methods, using other organic or inorganic acids.

According to the invention, these are in particular non-toxic, pharmaceutically applicable acid addition salts formed with suitable inorganic acids. For example hydrogen chloride, sulfuric or phosphoric acid or with suitable organic acids such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carbon or sulfonic acids, for example formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, hydroxybenzoic acid, salicylic acid, phenylacetic acid, mandelic acid., embonic acid, methanesulfonic acid, ethanesulfonic acid toluene sulfonic acid, sulanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, g-hydroxypropionic acid, β-hydroxybutyric acid, oxalic acid, malonic acid, galactaic acid and galacturonic acid. These salts can also be derived from natural or non-natural amino acids such as lysine, glycine, arginine, ornithine, asparagine, glutamine, alanine, valine, threonine, serine, leucine, cysteine, etc.

The products of the invention may contain one or more asymmetric centers.

The products, which have an asymmetric center, can be in the form of optical antipodes or in the form of a racemic or non-racemic mixture. Their enantiomeric separation can be performed by formation of the diastereoisomeric salts.

Among the products according to the invention, which have two a-30 symmetrical centers, one can obtain two racemates, resp. match the erythro and threo configurations; these two racemates can be separated by conventional methods, for example, by formation of diastereoisomeric salts by the action of optically active acids, such as tartaric, diacetyl tartaric, tartranilic, dibenzoyl tartaric, ditoluyl tartaric acid and separation of the mixture of diastereoisomers by crystallization, distillation, chromatography followed by release of the optically active bases from these salts.

40 Among the products of the invention which are three asynchronous 8103993 V * * *

V

Possessing 6 centers, one can obtain eight optical isaners. The same methods can be used for the cleavage of these mixtures.

Thus, the derivatives of the invention may be either in the form of mixtures containing different diastereoisomers which are in relative proportions, or in the form of couples of enantiomers in equal (racemic mixture) or non-equal proportions, or the form of optically pure compounds.

The derivatives of the invention are endowed with hypolipid-10, anti-antibiotic, anti-arrhythmic, anti-antibiotic, anti-hypertensive, vasodilating and immunomodulatory activities.

These properties make it possible to consider the use of the products of the invention in the treatment of cardiovascular diseases such as hypercholesterolemia, traribotic disorders and athero sclerosis, for the treatment of rheumatoid arthritis, for the treatment of cancerous conditions and for the treatment of hypertension and, in particular, for the prevention of vascular lesions accompanying the hypertension.

The present invention also relates to pharmaceutical preparations, which contain as active ingredient at least one compound of the general formula 1 and / or a salt with a pharmaceutical excipient. These preparations are presented in such a way that they can be administered by oral, rectal, parenteral or topical route.

For example, the preparations for oral administration may be liquid or solid and presented in the form of pills, dragees, coated pills, capsules, granules, powders, syrups or suspensions. The dry oral forms contain additives and extenders generally used in galenic pharmacy, inert diluents, disintegrants, binders and lubricants such as lactose, amidone, talc, gelatin, stearic acid, cellulose and derivatives, silicic acid, magnesium stearate, polyvinylpyrrolidone, calcium phosphate, calcium carbonate, etc.

Such preparations can be carried out in such a way that the disintegration and consequently the duration of action of the active principle is prolonged.

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

The oily emulsions and solutions are made in an oil of vegetable or animal origin and may contain emulsifying agents, perfuming agents, dispersing agents, emollients and antioxidants. For the parenteral administration, sterile water, an aqueous solution of polyvinylpyrrolidoiv peanut oil, ethyl oleate, etc. are used as the carrier. These aqueous or oily injectable solutions may contain thickeners, wetting agents, dispersing agents and gelling agents.

The compositions intended for topical administration may in part be solids or liquids and are in the form of hydrophobic fat bases, hydrophilic fat bases, emulsified bases, pastes, gels and lotions. They contain additives and extenders commonly used in galenic pharmacy, surfactants, solvents, thickeners, emollients, antioxidants, preservatives such as sorbitan derivatives, cetyl alcohol ethers, alginic acid, propylene glycol, glycerol, sorbitol , cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, propyl gallate, benzyl alcohol, p-hydroxybenzoic acid esters, etc.

Various methods allow the synthesis of the products of the invention. These methods, explained below, are also part of the invention. In the event that these processes give rise to the preparation of new intermediates, these new compounds, as well as the processes used for their preparation, form. also part of the present invention.

A first method consists of the conversion by reduction of an amide, an imine or a corresponding iminium salt to an aminothiol derivative of the formula 1. More particularly, this method consists of subjecting an aldehyde, a ketone or a corresponding acid to a sulfur, a condensation with an amine and a reduction to 40 to obtain the respective derivative.

8103993 * Λ - 8 -

According to a first variant of this method, an aldehyde is treated with a sulfurizing reagent, then condensed with a primary amine and the imine of the formula II thus obtained is reduced to amine.

The reaction comparison with Fig. 1 illustrates this method.

] * 2 and have the meanings given above, X represents hydrogen or an easily removable group such as chlorine, bromine, tosyl or methyl groups and Rg represents hydrogen or the group SO 2 Na.

The carbon-sulfur bond is formed using sulfurizing agents such as, for example, sodium hyposulfite (^ 282 () 2), sodium hydrogen sulfide (NaSH) or sulfur mono chloride (S2CI2).

In the latter case, a symmetrical disulfide of the formula III is obtained.

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 ambient temperature and a temperature at which the selected solvent is refluxed.

The conversion to imine is carried out in the usual manner in an inert organic solvent, for example selected from alcohols, chlorinated solvents, aromatic or aliphatic hydrocarbons and generally under acid catalysis, for example by adding a catalytic amount of p-toluenesulfonic acid in the reaction mixture or an organic or inorganic acid. The imine thus obtained is then reduced according to methods described in the literature.

This reduction can be carried out in the usual manner, 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 at ordinary pressure or elevated pressure, or by action of alkali metal hydrides such as sodium borohydride, in a solvent such as methanol or ethanol, preferably 40 at low temperature, or aluminum lithium hydride in ether or 8103993 * - 9 - tetrahydrofuran, preferably at low temperature, or by action of an aluminum alkoxide, such as aluminum isopropoxide in a solvent such as isopropanol, most efficiently with diboran in these same solvents.

When a first stage disulfide is formed, it can be converted to thiol, for example, by the action of a reducing agent, such as, for example, phosphines, such as tributylphosphine, or hydrides such as lithium aluminum hydride. 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 ambient temperature and the reflux temperature of the solvent.

A second variant of this method consists of the condensation of an aldehyde of formula 4 with a secondary amine to form an iminium salt and the reduction of the latter to amine.

The reaction comparison with Fig. 2 illustrates this variant.

R ^, R-2, R ^, R5 and Rg have the meanings given above.

The condensation of the aldehyde of formula IV with the secondary amine is carried out in the usual manner in an inert organic solvent, for example selected from the alcohols, the chlorinated solvents, the aromatic or aliphatic hydrocarbons and expediently under acid catalysis, for example in the reaction mixture. catalytic amount of 2-toluenesulfonic acid or an organic or inorganic acid. Man. can also advantageously supply the secondary amine in the form of a salt, such as, for example, in the form of the chlorohydrate.

The iminium salt is then reduced to amine by the action of a reducing agent such as, for example .. ... lithium aluminum hydride in ether or tetrahydrofuran.

According to a third variant, an amide of formula 5 is conventionally obtained from the acid and the amine via the acid chloride, first treated with a sulfurizing agent, and then reduced to aminothiol according to the reaction equation of Fig. 3.

11, R2, R ^ and Rg have the meanings given above -40 sen, X represents hydrogen or an easily removable 8103993-10 group, such as chlorine, bromine, tosyl or mesyl groups and Rg represents hydrogen or the group SO ^ After before.

The carbon-sulfur bond is formed using sulfurizing agents such as, for example, sodium hyposulfite (Na2S2O2), sodium hydrogen sulfide (NaSH), or sulfur monochloride (S2C12). In the latter case, a symmetrical disulfide of formula 7 is obtained.

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 ambient temperature and the temperature at which the selected solvent is refluxed.

The amide of formula 6 is then reduced in the usual manner, 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 at ordinary pressure or elevated pressure either by action of metal hydrides such as aluminum lithium hydride in ether or tetrahydrofuran, or by action of diboranin the same solvents.

When a first stage disulfide is formed, it can be converted to thiol by the action of, for example, a reducing agent, such as, for example, phosphines, such as tributylphosphine, or hydrides such as lithium aluminum hydride. 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 ambient temperature and the temperature at which the solvent is refluxed. It is also possible to introduce substituents R ^ and R 1, other than hydrogen, on the nitrogen atom and the substituent R ^ on the sulfur atom in a derivative of the formula 1 by alkylation or by acylation.

A) alkylation of the nitrogen atom: see the reaction equation with fig. 4.

R 2 R 2 and have the meanings given above and Q represents the substituent R 1 or a protecting group of the thiol function, X represents an easily removable group such as a halogen, for example chlorine, bromine or 8103993 s. 11 - * * iodine, or tosyl or mesyl groups. A list of thiol function protecting groups can be found in specialized works such as, for example, "Protective Groups in Organic Chemistry", Ed. J.F.W. Mac Omie, Plenum 5 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 conveniently at the reflux temperature.

The presence of an organic or inorganic base such as sodium hydroxide or triethylamine in the reaction mixture facilitates the reaction and improves the yield.

b) acylation to the nitrogen atom:. 15 see the reaction equation with fig. 5.

and R2 have the meanings given above, Q represents the group R1 or a protecting group of the thiol function, Y represents an easily removable group such as, for example, chlorine, bromine or the group R'4COO.

R'4 represents the substituent R4, the chain of which is a carbon atom shorter. For example, a list of protecting groups of the thiol group can be found in the aforementioned book.

The acylation is carried out conventionally in an inert organic solvent such as a chlorinated solvent, an aromatic or aliphatic hydrocarbon or an ether and expediently at the reflux temperature of the solvent. The presence of an organic or inorganic base in the reaction mixture facilitates the reaction and improves efficiency.

The reduction of the amide of formula 8 can be carried out in the usual manner, 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 in ordinary pressure or elevated pressure, either by action of metal hydrides such as aluminum and lithium hydride in ether or tetrahydrofuran or by action of diborane in the same solvents.

c) alkylation at the sulfur atom: 40 see reaction comparison with Fig. 6.

8103993 - 12 - * *

Rj ^ I ^ / Rgri ^ © η Rg have the meanings given above and X represents an easily removable group such as e.g. a halogen atom, such as chlorine / bromine or iodine or a tosyΙοί mesyl group.

The alkylation is carried out conventionally in an inert organic solvent, such as a chlorinated solvent, an aromatic or aliphatic hydrocarbon, an alcohol or an ether, and conveniently at the reflux temperature. The presence of an organic or inorganic base in the reaction mixture facilitates the reaction and improves efficiency.

In another mode of operation, an episulfide of formula 9 is reacted with an amine according to the reaction comparison of Figure 7.

15 and R ^ have the meanings given above. Depending on the reagents used, the opening of the episulfide can be carried out at atmospheric pressure or at a pressure higher than atmospheric pressure, at ambient temperature or at elevated temperature or by catalysis with Ag + ions. The reaction can be carried out with or without solvent . When a solvent is used, it can be water or an inert solvent such as an aromatic or aliphatic hydrocarbon, a chlorinated solvent or an ether. The presence of tertiary amine advantageously influences the course of the reaction, which in that case advantageously proceeds at a temperature between 25 and 100 ° C.

A variant of this other mode of implementation is illustrated by the reaction scheme with Fig. 8.

Rj ^ Rj / Rj and Rg have the meanings given above 30 and Ry represents an alkyl group having 1-3 carbon atoms.

A thiol carbonate of formula 10 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-toluenesulfonic acid (TsOH) or methanesulfonic acid. The reaction temperature is higher than ambient temperature and preferably approaches the boiling point of the selected solvent. The derivative of formula 11 thus obtained is then treated with an amine under reflux of the inert organic solvent to obtain the products of the invention.

8103993 - 13 -

In a final embodiment, a 2-mer captoethanol derivative of formula 12 is esterified with an acid, then treated with an amine according to the reaction equation of FIG. 9.

R1 # R2, and R ^ have the meanings given above and Rg represents a group which makes the acyloxy group easily removable. For example, Rg may be a trihalomethyl group such as the trifluoromethyl or trichloromethyl group. The esterification is carried out in the usual manner in an inert organic solvent, for example selected from the aromatic solvents, the chlorinated solvents or the ethers and preferably under reflux of the solvent. It is effective to remove the water from its formation, for example, by azeotropic distillation. The ester of formula 13 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.

Example I

2-methyl-1- (2-phenoxyethylamino) -2-propanethiol, chlorohydrate (derivative no. 3 of Table A).

a. 817 ml (9 mol; 648.9 g) of isobutyraldehyde are added to 650 ml of carbon tetrachloride 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 mixture is maintained at 40 ° C for 48 hours. The solvent is then evaporated under reduced pressure, then the residue is distilled. The main fraction is recovered between 94 and 100 ° C, at a pressure of 0.1 kPa. A second distillation gives 365 g (1.8 mol; 40%) of α, α-dithiodiisobutyraldehyd.

b. A mixture consisting of 20.6 g (0.1 mole) of the previous product, 27.4 g (0.2 mole) of 2-phenoxyethylamine 35 and 130 ml of isopropanol is heated for 1.5 hours at the reflux temperature is heated.

The resulting medium is evaporated to dryness under reduced pressure. The residue is taken up in hexane. An insoluble component is filtered off, then the filtrate in turn evaporated to dryness. Man thus obtains a diimino disulfide, which is taken as such in the next step.

8103993 "- 14 - c. 7.6 g (0.2 mol) of lithium aluminum hydride are suspended in 250 ml of anhydrous ether in a 1 l reactor. A solution of the precursor product is then added with stirring. in 250 ml of the same solvent at a rate such that a slight refluxing will occur, which will persist. At the end of the addition, the reflux heating treatment is maintained for an additional 2 hours. It is then allowed to cool and the excess hydride is destroyed.

The dried organic phase is contacted with gassing and dry hydrogen chloride until the end of the predL titration which results. The chlorohydrate is filtered, washed extensively with ether and then dried under 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. Melting point 139.9 ° C.

The IR? NMR and mass spectra are consistent with the structure.

Elemental analysis:

20 C Η N

C12H19NOS, HCl% calc * 55.1 7/7 5.4 mole wt. 261.82%. 55.4 7.7 5.2

Example II.

2-methyl-1- (2-p-tolyoloxyethylamino) -2-propanethiol, chloro-25 hydrate (derivative no. 11 of Table A).

This compound is obtained according to the method described in Example I by replacing 2-phenoxyethylamine with 2-p-tolyloxyethylamine.

Yield: 56% - melting point 115.2 ° C (ethyl acetate).

30 Basic analysis:

C Η N

C13H21NOS, HCl% calc 56/6 8.0 5.1 mole wt. 275.84%. 56.6 8.1 5.0

Example III.

1- (2-p-chlorophenoxyethylamino) -2-methyl-2-propanethiol, chlorohydrate (derivative no. 13 of Table A).

This compound is obtained by the method described in Example 1, replacing 2-phenoxyethylamine with 2-p-chlorophenoxyethylamine.

40 Efficiency: 54% - melting point 141.5 ° C (ethyl acetate).

8103993 - 15 -

Elemental analysis:

C Η N

C 12 H 18 ClNO S * HCl% ber * 48.7 6.5 4.7 mol. Wt. 296.26%. 48.6 6.5 4.6 5 Example IV.

Bis- [2-methyl-1- (2-phenoxyethylamino) -2-propyl] disulfide, dichlorohydrate (derivative no. 14 of Table A).

This disulfide is obtained at the expense of the product obtained in the under b. repeated treatment.

A solution of 16.1 g (35 mmol) of crude diiminodisulfide in 90 ml of ethanol is heated to 60 ° C, then slowly a solution of 4.0 g (105 mmol) of sodium borohydride in 150 ml of the same solvent added.

After the addition, the mixture is heated under reflux for 2 hours. The mixture, which has reached ambient temperature, is then poured onto 350 g of crushed ice. The aqueous phase is extracted with the aid of chloroform. The organic extract is evaporated to dryness under reduced pressure. The evaporation residue is dissolved in ether and the solution is contacted with gaseous and dry hydrogen chloride. The precipitated salt is filtered and then recrystallized from propanol.

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

The IR, NMR and mass spectra correspond to the expected disulfide structure.

Elemental analysis:

C Η N

C24H36N2 ° 2S2 * 2HC1% calc * 55.3 7.3 5.4 mole wt. 521.62%. 55.6 7.2 5.0 30 Example V.

3- (2-methyl-2-mercaptobutylamino) propanoic acid (derivative no. 5 of Table A).

a. 36.9 g (150 mmol) of 1-amino-2-benzylthio-2-methylbutane chlorohydrate 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, heat for 2 hours at the reflux temperature. The mixture, which has reached ambient temperature, is evaporated to dryness under reduced pressure. The residue is partitioned between water and chloroform. The organic phase is dried and evaporated. The residue is taken up in little acetone, leading to the formation of a white solid.

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

The NMR spectrum is consistent with the structure of the 3- (2-methyl-2-benzylthiobutylamino) propanoic acid.

b. 8.4 g (30 mmol) of the product obtained above are added to 200 ml of liquid ammonia at a temperature between -50 and -60 ° C, then sufficient sodium-10 metal, in small successive quantities, so that the blue discoloration is permanent. At this time, the amount of ammonium chloride, which allows the environmental decolorization, is added, then, after removing the cooling bath, the ammonia is evaporated. 30 ml of water are added and the pH is gradually adjusted to> 2 under a nitrogen atmosphere. The mixture is evaporated carefully to dryness and the residue is taken up in acetonitrile. The addition of ether causes the precipitation of a white solid, which is filtered, washed carefully with ether and dried.

Weight: 2.4 g (11 mmol - 37%). Melting point 117.2 ° C.

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

Elemental analysis:

25 C Η N

C8H17NO2S.HC1% calc. 42.2 8.0 6.2 mol. Wt. 227.76%. 42.3 7.8 6.1

Example VI.

1- (4-Benzyl-1-piperazinyl) -2-propanethiol, dichlorohydrate 30 (derivative no. 32 of Table A).

A mixture consisting of 4.5 g (60 mmol) of propylene sulfide and 10.5 g (60 mmol) of N-benzylpiperazine is stirred at 60 ° C for 20 hours. The temperature of the mixture is brought to 100 ° C in 3 hours and maintained at this value for an additional 1 hour. The reactor is then placed under reduced pressure (0.05 kPa) overnight. 150 ml of ether are added to the residue, followed by ether containing hydrochloric acid until the precipitation thus produced. It is filtered and recrystallized from crystallization to constant melting point (215 ° C) in ethanol.

8103993 - 17 -

12.8 g (40 mmol, 67%) of the expected dichlorohydrate are obtained in this way, the identity of which is confirmed by examination of the IR, NMR and mass spectra. Elemental analysis:

5 C Η N

C14H22N2S * 2HC1% calc * 52.0 7.5 8.7 mole wt. 323.33%. 51.9 7.2 8.5

Example VII.

5,5-dimethyl-3- (2-phenoxyethyl) -2-thiazolidinone 10 (derivative no. 23 of Table A).

10.5 g (40 mmol) of 2-methyl-1- (2-phenoxyethyl-amino) -2-propanethiol chlorohydrate are dissolved in 100 ml of methanol, to which 11.0 ml (8.0 g; 80 mmol) of triethylamine are then added. adds. 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 in turn evaporated to dryness under reduced pressure. The product obtained, dried appropriately, is dissolved in 250 ml of toluene, to which an additional 8.0 ml of triethylamine has been added before being mixed with 250 ml of an aqueous solution of sodium hydrogen carbonate. It is then stirred vigorously with the slow addition of 34 ml (65 mmol) of a 20% solution of phosgene in toluene. When the addition is finished, stirring is continued for 2 hours. The organic phase is decanted and then evaporated to dryness under reduced pressure.

The residue forms a dark oil, which recrystallizes spontaneously. The recrystallization from n-heptane then gives a white solid, 5.2 g weight (21 mmol; 53%. Melting point 51.3 ° C).

The structure of the cyclization product is verified by examining IR, NMR and mass spectra. Elemental analysis:

C Η N

C13 H17 NO2 S% calc. 62.1 6.8 5.6 mole wt. 251.35%. 62.2 6.8 5.5

Example VIII.

2-methoxycarbonyldithio-2-methyl-1- (2-phenoxyethylamino) propane, chlorohydrate (derivative no. 24 of Table A).

40 In an inert atmosphere (oxygen-free nitrogen) 8103993 -18-.

9.8 g (77 mmol) of methoxycarbonylsulfenyl chloride are dissolved in 600 ml of methanol. The solution, which is stirred and cooled to 0 ° C, is added over 30 minutes to a solution of 15/7 g (60 mol) of the product of Example I in 300 ml of the previous solvent. After the addition, stirring is continued for 30 minutes before the mixture is allowed to come to ambient temperature.

Evaporation takes place under a reduced pressure. The remaining syrup crystallizes after a stay in the refrigerator. The mixture is crystallized successively from benzene and isopropanol. 10.6 g (30 mmol; 50 ¾) of the expected disulfide are obtained in this way, as confirmed by examination of the IR, NMR and mass spectra. Melting point 104.1 ° C. Elemental analysis:

15 C Η N

C14H21NO3S2 * HCl% ber * 47.8 6/3 4.0

Mol. Wt. 351.92%. 47.9 6.3 3.9

The melting points and recrystallization solutions of the preparations prepared according to the invention are listed in Table A below.

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The products according to the invention have been subjected to a series of biochemical pharmacological tests, the method of which is described below. The results of these tests are reported in Table B, the numbers of column 1 5 of which correspond to the numbers of column 1 in Table A.

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Explanation of the tests, the results of which are shown in Table B.

1. Acute toxicity in the mouse.

The substances suspended in a 1% mucus gum mucus are administered orally by way of an intragastric zone in groups of 5 male mice, which are fasting for 18 hours. Mortalities are recorded for 14 days following treatment.

The LDjjq are calculated by the method of Litchfield 10 and Wilcoxon (J. Pharmacol. Exp. Ther. 9 (5, (1949) 99)) and expressed in mg / kg.

2. Inhibition of platelet aggregation.

Platelet aggregation is measured by the cloudiness method described by G.V.R. Born and M.J. Cross 15 (J. Physiol., 168, 178-195 (1973)). The citrate-treated human platelet-rich plasma is preincubated for 3 min prior to addition of the inducer.

The optical transmission variations are recorded over a 10 min period in a "Chronolog" agrego-20 meter. The test is performed in duplicate in the presence of the product or the corresponding solvent. The results are recorded as an inhibition percentage of the maximum aggression amplitude relative to the control tests. The concentration of the product (expressed in micromoles) - 6 25 (jaM or 10 M)) which induces 50% inhibition of the plate sagregation under the test conditions (CI ^ q) is calculated from the results obtained at six different concentrations.

3. Vasodilating activity.

The peripheral vasodilating activity of the products is measured in the anesthetized dog in the area of the femoral artery circulation. For this purpose, the femoral vein, from which the side walls are tied off, is doused with constant flow by means of blood drawn from the aorta.

Thus, the perfusion pressure, measured in the area of the femoral artery, varies as a function of the resistance of the overgrowth area. The products tested and the corresponding solvents are injected directly into the cycle at a dose of 30 µg / kg. Therefore, when the blood flow rate is kept constant at 40, a vasodilation is measured by 8103993 * &% - 34 - a decrease in perfusion pressure. This is expressed in numerical value relative to the action of the papaverine, which is considered as reference. 4 products injected per group. In case of interest, the products are tested at other dosages under the same conditions.

The vasodilating activity is rated as follows: 0: inactive <10 mm Hg reduction * 10 1: 1/3 of the activity of papaverine, 2: 2/3 of the activity of papaverine, 3: activity equal to that of papaverine, 4 : activity greater than that of papaverine.

4. Inhibition of cholesterol biosynthesis.

A) Homogeneous rat liver product.

Homogeneous rat liver products are prepared and incubated in a suitable environment. Aliquots are incubated with 1 C acetate and the test compound at a concentration of 10 M for 14 min. After sterilization of the medium, the sterols are extracted through petroleum ether and the dry residue is precipitated by digi - 14 tonine in an alcohol-acetone solution. The C content of the precipitate dissolved in pyridine is measured by counting by liquid scintillation according to the method described by N. Bucher (J. Biol. Chem. 222, (1956), 1-15): the results are expressed as inhibition percentage . b). Fibroblast culture.

When the cells are confluent, the culture medium is eliminated and replaced with 10 ml of new medium, 14 ml containing 100 µl C acetate and the product to be tested at a concentration of 5.10. The boxes are incubated at 37 ° C for 2 hours. After incubation, the synthesis of cholesterol is determined by measuring the radioactivity associated with the cholesterol C purified from the culture medium (Stoffel and Klotzbücher, Hoppeseler Zs. Physiol. Chemie 359, (1978) 199-209). .

The amount of proteins in the cells is measured according to the Folin method. The results are expressed in cpm cholesterol per pg proteins.

40 5. Inhibition of Collagen Breakdown.

8103993 - 35 -

After incubation of the collagen at 37 ° C in the presence of collagenase in a pH-buffered environment of 7.2 in the presence of a drug at the concentration of _10 M or in the absence of the drug, the 5 released amino acids are detected by colorimetric reaction with ninhydrin and the absorbance is measured at 570 mm.

6. Inhibition of lipolysis.

Epididymal fat is taken from fasted rats.

Fragments of the adipose tissue (+ 150 mg) are incubated in the Krebs-Ringer buffer, containing 3% bovine serum albumin and the test substance at the concentration of 10 M. A reference sample is taken after a 30 min incubation at 37 ° C. The norepinephrine is used to induce lipolysis. The amount of free amino acids is measured after incubation for 20 min (Duncombe W.G., Clin. Chim.Acta. 8, (1964), 122); results are expressed as percent inhibition.

Products 7, 13, 16, 17, 18 and 19 were found to be active in this test.

7. Anti-spasmodic activity.

The antispasmodic activity of the tested substances is investigated with respect to the contractions of the ileum of the guinea pig generated by histamine and acetylcholine.

These experiments make it possible to demonstrate an antihistamine, anticholinergic or musculotropic activity.

The reaction to the contracting agent (submaximal concentration) is obtained every 5 min before and after the injection of increasing concentrations of the tested products (10 to 10 M). The percentage of inhibition is calculated under the influence of the products tested and the theoretical concentration, which produces an inhibition of 50%, is graphically determined for each experiment. These values are expressed in 35 log CI50 (M). In this test, products 9, 14, 15 and 21 are distinguished in particular, with a value of Cl 2 greater than 6.

8. Inhibition of DDL recovery by human fibroblasts.

40 The human skin fibroblasts are cultured 8103993-36-.

τ 9 according to the method of Ross (J. Cell. Biol. 5 (), (1971), 170-186). The low density lipoprotexan (LDL) are prepared from human plasma by preparation / ultracentrifugation. They are isolated with the J according to the method of Bilheimer et al. (Biochemica Biophysica Acta 260, (1972), 212).

The measurement of the binding of the LDL is carried out according to the method of Chait et al. (Proced. Nat. Acad. Sci., In pressure).

In view of the experiment, the culture medium is eliminated and replaced with 2 ml new medium containing 5 µg / ml ° J LDL. After 24 hours of incubation at 37 ° C, the cells and the environment are separated. The cells are washed, then incubated in the presence of 4 mg / ml dextran sulfate. The reactivity of the above product allows measurement of the bond.

The cells are then dissolved in 0.1NaOH; an even part is counted (uptake).

125

Finally, the degradation of the J LDL is determined by measuring the radioactivity of the J associated with the free tyrosine in the culture medium.

Products 3, 7, 13, 18, 25, 27, 34, 44 and 48 have shown themselves to be particularly active in this test.

9, Immunomodulating activity.

The immunomodulatory activity is measured in mice C 57BL / 10 sensitized by intrapedial injection ....... of whooping cough vaccine.

After 15 days, an intramuscular injection is performed into the lumbar region.

Four days later, the animals are sacrificed and the hock ganglia are opened and weighed. The treatments are from the 13th day to. administered by a tube on the 18th day.

The products are tested at a dose equivalent to 50 mg / kg of D.penicillamine. Under these conditions, the penicillamine inhibits the weight gain of the hock ganglion of the sensitized side (2.53 + 0.12 mg in the treated with respect to 4.16 + 0.24 mg in the control animals).

In this test, the products 2, 3, 13, 14, 18, 19 8103993 • f - 37 - 27, 30 and 35 exhibit an activity equivalent to that of the D.penicillamine.

In all these tests, it appears that compounds 3, 14, 18 and 33 react favorably in the majority of the 5 tests. On the other hand, it has also been found that compound 24 exhibits anti-cancer activity. This activity has been proven in the animal inoculated with cancerous cells and treated orally with the product of the invention.

It is noted that numerous products according to the invention have an important vasodilating activity.

The compound 18 and especially the compound 24 have an extremely important activity (from the dosage of 0.1 µg / kg) and especially of a very long duration (up to 30 minutes after the intra-bacterial injection).

A more in-depth valuation has been made at compound 3.

Thus, it has been found that this compound has anti-hypertensive activity in the spontaneously hypertensive-induced rat: administered orally at a dose of 60 mg / kg in rats whose systolic pressure is between 180 and 220 mm Hg. a reduction in pressure brought about in the order of 30-50 mm Hg.

It has also been found that this product administered to the rat orally at doses of 50 and 10 mg / kg, increases the release of prosacycline through the blood vessels. The test is performed according to the method described by Villa et al. In British J. Haematol. 42, (1979), 425-431.

The compound No. 3 also has very beneficial effects in preventing certain arterial wall reactions during the development of hypertension, in rats rendered hypertensive by the method of Goldblatt (renal artery contraction); -35 taken that: during the preventive administration, from the day of the surgical intervention, the product exerts a significant meaningful effect on the aorta: the product reduces hypertrophy, the levels of ADN, of collagen 40 and of cholesterol and the product reduces the synthesis of 8103993 * - 38 -

V

proteins and collagen. There is no similar effect in normal rats.

During the curative administration to 1 month of pre-hypertensive rats, compound No. 3.5 typically reduces blood pressure and cholesterol in the aorta.

Because of all these experimental results, the properties of the products of the invention make their application .....

possible in the therapy of: 10 1) cardiovascular diseases such as hypertension and atherosclerosis, 2) rheumatic diseases, 3) cancer, 4) autoimmune diseases.

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

For oral administration, dragees, granules, tablets, capsules, pills and capsules with controlled release of the active principle will be used, sublingual pills, solutions, syrups, emulsions containing additives or excipients customary in galenic pharmacy. Sterile water or an oil such as groundnut oil or ethyl oleate will be used for parenteral administration. Suppositories or rectal capsules will be used for rectal administration.

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

The products of the invention can be used in various forms. The examples that follow are non-limiting and relate to galenic formulations containing as active product, hereinafter referred to by reference "A", one of the following compounds: 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-benzyloxyethylamino) -2-propanethiol.

40 bis- [2-methyl-1- (2-phenoxyethylamino) -2-propyl disulfide.

8103993 * - 39 - 3- (2-mercapto-2-methylpropylamino) propanoic acid.

bis- [2-methyl-1- (2-m-chlorophenoxyethylamino) -2-propyl] disulfide.

2-methyl-1-n-octylamino-2-propanethiol.

2-methyl-1-n-dodecylamino-2-propanethiol.

2-methyl-1- (2-phenylethylamino) -2-propanethiol. 2-methoxycarbonyldithio-2-methyl-1- (2-phenoxyethylamino) propane.

Pills 10 A 250 mg soluble amidone 50 mg microcrystalline cellulose 1-50 mg lecithin 30 mg gelatin 25 mg 15 talc 8 mg magnesium tartate 7 mg A 500 mg lactose 100 mg magnesium tartate 10 mg 20 Gelatin capsules A 200 mg lactose 200 mg polyvinylpyrrolidone 20 mg magnesium stearate 5 mg 25 Suppositories A 800 mg

Witepsol H15 ad 3600 mg

Injectable ampoules A 100 mg 30 to be randomly dissolved in:

NaCl 40 mg

NaHSOg 20 mg distilled water for injections ad 10 ml 8103993 '- 40 -

Creams A 5 g polymerized acrylic acid (type carbopol 940) 1 g 5 triethanolamine qs ad pH 6 aqua purificata ad 100 g A 5 g stearyl alcohol 25 g petrolatum 20 g 10 propylene glycol 5 g polyoxyl 40 stearate 5 g methyl p-hydroxybenzoate 0.02 g propyl p-hydroxybenzoate 0.01 g water ad 100 g 15 Witépsol H 15: partially or fully esterified mixture of glycerides.

Depending on the case, the route of administration, the nature of the intended activity and of the compound used specifically, the derivatives of the invention are used with daily doses of 100-2500 mg and by intravenous injection, the derivatives of the invention are administered at doses of 5 -100 mg.

8103993

Claims (30)

1. Aminothiol derivatives of the general formula 1, wherein hydrogen represents a straight or branched chain alkyl group with 1 to 10 carbon atoms, 2. Derivative according to claim 1, characterized in that in formula 1 R 1 represents hydrogen or a straight or branched alkyl group with 1 to 5 carbon atoms. Derivative according to claim 1, characterized in that in formula 1 R 1 represents a straight or branched alkyl group with 6-10 carbon atoms. Derivative according to claim 1, characterized in that in formula 1 R 1 represents a straight or branched chain alkyl group having 4-8 carbon atoms. Derivative according to claim 1, characterized in that in formula 1 R 1 represents hydrogen or a methyl group. R 2 represents hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, R 1 and R 2 with the adjacent carbon atom may form a cycloalkyl group of 3-8 carbon atoms, R 8 hydrogen, a straight or branched alkyl group of 1 to 3 carbon atoms a straight or branched chain alkanoylthio group of 1-3 carbon atoms, a straight or branched chain alkyloxycarbonyl thio group of 1-3 carbon atoms, a straight or branched chain alkyl group of 1-10 carbon atoms or a sulfurized group of the structure - (S) n-CR1R2 " CII2 "'NR4R5" wherein n = 1 or 2, 15 represents R4 and Rg, which may be the same or different, hydrogen, a straight or branched alkyl group having 1 to 16 carbon atoms, 20. a straight or branched alkyl group having 2-6 carbon atoms substituted with: a hydroxyl group, carboxyl group, straight or branched chain alkoxycarbonyl group with 1-3 carbon atoms, a naphthyloxy group, a phenyl, phenoxy, phenylthio or benzyloxy group, optionally substituted with one, two or more halo atoms such as chlorine, having one, two or more straight or branched chain alkyl groups of 1-4 carbon atoms, having one, two or more straight or branched chain alkyloxy groups of 1-3 carbon atoms, a straight or branched chain alkoxy or alkylthio group of 1-4 carbon atoms an alkylamino group with 1-4 carbon atoms, optionally substituted with. a phenyl group, a straight or branched alkyl carboxamido group of 1-6 carbon atoms, optionally substituted with a phenyl or phenoxy ring, a cycloalkylcarboxamido group of 3-8 8103993 \ - 42 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, a straight or branched alkenyl group with 3-16 carbon atoms, a straight or branched alkynyl group with 3-6 carbon atoms, R4 and R5 with the adjacent nitrogen atom may form a heterocyclic ring, such as piperidine, pyrroline, morpholine, piperazine, optionally on the 4-position substituted with a benzyl group, a straight or branched alkyl group with 1-4 carbon atoms or a phenyl group, which may itself be substituted with one, two or more halogen atoms, such as fluorine and chlorine, straight or branched alkyl groups with 1 -3 carbon atoms, straight or branched alkoxy groups of 15 1-3 carbon atoms, R3 and R4 a thiazolidine ring, optionally substituted in the 2-position with one or two straight or branched alkyl groups with 1-3 carbon atoms or a thiazolidinone ring, Derivative according to claims 1 to 5, characterized in that in formula 1 R 2 represents hydrogen or a methyl group. Derivative according to claims 1-6, characterized in that in formula 1 R 1 represents an ethanoylthio group, a methoxycarbonylthio group or a straight or branched chain alkylthio group having 40 1-8 carbon atoms. 8103993% - 43 - 5 8. Derivative according to claims 1-7, characterized in that in formula 1 R4 and Rg, which may be the same or different, are hydrogen, a straight or branched chain alkyl group with 1-8 carbon atoms, a cycloalkyl group with 5-8 carbon atoms, a straight or branched alkenyl group of 3-12 carbon atoms, a straight or branched alkynyl group of 4-6 carbon atoms. 9. Derivative according to claims 1-7, characterized in that in formula 1, R 1 and R 1, which may be the same or different, represent a straight or branched alkyl group with 2-4 carbon atoms, substituted with: a hydroxyl group, carboxyl group, straight or branched alkoxycarbonyl group with 1-3 carbon atoms, a phenyl, phenoxy, phenylthio or benzyloxy core, optionally substituted with one or two chlorine atoms, with one, two or more straight or branched alkyl groups of 1-3 carbon atoms, having one or two straight or branched chain alkoxy or alkylthio groups of 1-3 carbon atoms. 10. Derivative according to claims 1-7, characterized in that in formula 1, R 4 and R 4, which may be the same or different, an alkylamino group with 1-4 carbon atoms, optionally substituted with a phenyl core, or a straight or branched alkylcarboxamido group having 1-4 carbon atoms, optionally substituted with a phenyl or phenoxy nucleus. 11. Derivative according to claims 1-7, characterized in that in formula 1, R 4 and R 4 form a heterocyclic ring with the adjacent nitrogen atom, such as piperidine, pyrrolidine, morpholine, piperazine, optionally substituted in the 4-position with a benzyl group, a phenyl group, optionally substituted with a chlorine atom. 12. Derivative according to claims 1-7, characterized in that R4 represents hydrogen and R1 represents a phenoxyethyl group, the phenyl core of which may optionally be substituted with one or two chlorine atoms or with one or two methyl methoxy groups. Derivative according to claims 1-7, characterized in that R4 represents hydrogen or an ethyl group. Derivative according to claims 1-13, characterized in that the derivative is selected from the group consisting of the 8103993 "- 44 - following compounds: 2-methyl-1- (2-phenoxyethylamino) -2-propanethiol, 2 -methyl-1- (2-p-tolyloxyethylamino) -2-propanethiol, 2-methyl-1- (2-p-chlorophenoxyethylamino) -2-propanethiol, 5 2-methyl-1- (2-benzyloxyethylamino) -2- propanethiol, bis- [2-methyl-1- (2-phenoxyethylamino) -2-propyl] disulfide, bis-2-methyl-1- (2-m-chlorophenoxyethylamino) -2-propyl] disulfide, 2 -methyl-1-octylamino-2-propanethiol, 10 2-methyl-1-dodecylamino-2-propanethiol, 2-methyl-1- (2-phenylethylamino) -2-propanethiol, 3- (2-mercapto-2-methylpropylamino) propanoic acid, 2-methoxycarbonyldithio-2-methyl-1- (2-phenoxyethylamino) propane. 15. Derivative as described above, in particular in the examples given in the description. 16. Process for preparing aminothiol derivatives according to any one of the preceding claims, characterized in that an amide, an imine or a corresponding iminium salt is converted by reduction into an aminothiol derivative according to formula 1. 17. Process according to claim 16, characterized in that an aldehyde or a corresponding acid is subjected to a sulfur, a condensation with an amine and a reduction to obtain said derivative. 18. Process according to claim 17, characterized in that an aldehyde containing a sulfurized residue on the α-carbon atom is treated with an amide and then reduced to an aminothiol derivative of the formula 1. - 30 Process according to claim 17, characterized in that an amide containing a sulfurized residue on the α-carbon atom is reduced to an aminothiol derivative of the formula 1. 20. Process according to claims 17-19, characterized in that when a disulfide is formed during the aforementioned sulfurization, the latter is converted into thiol, for example under the action of a reducing agent such as phosphine, such as tributylphosphine or hydrides such as lithium or aluminum hydride. R 1, R 2, R 3 / R 4 and R 4 cannot simultaneously represent hydrogen, as well as non-toxic and pharmaceutically acceptable salts of these derivatives. 21. Process for the preparation of aminothiol derivatives 8103993-45 according to any one of claims 1-20, characterized in that a derivative of the formula 14 is reacted with a compound R 1 X or R 1 COY, wherein R 1 , R2 and R4 have the meanings given in any one of claims 1-15, Q represents the substituent Rg or a protecting group of the thiol function, R'4 represents the substituent whose chain with a carbon atom is shorter, X an easily removable group, such as a halogen, for example chlorine, bromine, iodine or tosyl or mesyl groups, Y represents an easily removable group, such as, for example, chlorine, bromine or the group R 1 COO • to obtain, after any reduction 3 of a compound of the formula 15. 22. A process for the preparation of aminothiol derivatives according to any one of claims 1-21, characterized in that a derivative of formula 16 is reacted with a compound RgX, wherein R 1, R 2, Rg, R 1 and R 5 are the any of claims 1-15 have given meanings and X represents an easily removable group such as a halogen, for example chlorine, bromine, iodine or tosyl or mesyl groups, whereby an aminothiol of formula 1 is obtained. 23. A process for preparing aminothiol derivatives according to any one of claims 1-15, characterized in that an episulfide of formula 9, a 2-oxathiolanone of formula 11 or an ester of formula 13 is reacted with an amine of the type HNR ^ Rg to obtain a corresponding aminothiol derivative. 24. Process according to claim 23, characterized in that a thiol carbonate of formula 10 is reacted with an acid, such as for example p-toluenesulfonic acid or methanesulfonic acid, whereby the 2-oxathiolanone is obtained and the latter is converted into an aminothiol derivative of formula 1 under the action of an amine of the NHR-Rg type. 25. Process according to claim 23, characterized in that a 2-mercaptoethanol derivative of the formula 12 is esterified with a compound of the type RgCOOH to obtain the aforementioned ester and the latter is treated with an amine of the type NHR-R, -. 26. Process for the preparation of aminothiol derivatives 8103983-46 - v. as described above, especially in the examples given. 27. A pharmaceutical composition containing as active product at least one of the derivatives of any one of claims 1-15 together with at least one excipient and / or optionally at least another therapeutic agent. 28. Pharmaceutical composition with an antihypertensive, vasodilating, hypolipidemic, antithrombotic, immunomodulatory, antiarrhythmic and / or antimitotic activity, characterized in that the active product composition comprises at least one of derivatives according to any one of claims 1-15. with at least one suitable excipient and / or at least one other therapeutic agent. The method of use of the derivatives according to any one of claims 1-15 or the aminothiol-based pharmaceutical preparation according to any one of claims 27 or 28, characterized in that the administration is by oral, parenteral, rectal or topical route. Method of use of the derivatives according to any one of claims 1-15 or the preparations according to claims 27 or 28, characterized in that the aminothiol derivatives are administered orally with daily doses of 100-2500 mg and intravenously with daily doses of 5 -100 mg. / 8103993