FR2842522A1 - New dithiobis-(3-aminobutane-1-sodium sulfonate) derivatives useful in the treatment of hypertension and related disorders - Google Patents

Abstract

4,4'-dithiobis-(3-aminobutane-1-sodium sulfonate) (I) and 4,4'-dithiobis[-3-aminobutane-1-(2,2-dimethyl propyl sulfonate)] (II) are new. ACTIVITY : Hypotensive; Cardiant; Antidiabetic; Ophthalmological. MECHANISM OF ACTION : None given.

Description

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 The subject of the present invention is novel compounds, processes for the preparation of these compounds, pharmaceutical formulations comprising these compounds, and the use of these compounds in therapy. The present invention relates in particular to compounds which are useful in the treatment and prevention of primary and secondary arterial hypertension, stroke, myocardial ischemia, heart and kidney failure, myocardial infarction, peripheral vascular disease, diabetic proteinuria, syndrome X and glaucoma.

 High blood pressure is a condition whose causes are generally unknown. Extrinsic factors that may participate include obesity, a sedentary lifestyle, excessive intake of alcohol or salt, and stress. Intrinsic factors suggested as contributing factors include fluid retention, activity of the sympathetic nervous system, and constriction of blood vessels.

High blood pressure can contribute directly or indirectly to diseases of the heart, peripheral and cerebral vascular system, brain, eye and kidney.

 Treatment of high blood pressure includes the use of diuretic agents, adrenergic blocking agents, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium blockers and direct vasodilators. It is desirable to identify additional compounds for the treatment of high blood pressure.

 The present inventors have identified novel compounds which are effective in reducing high blood pressure and which, therefore, are useful in the treatment of high blood pressure and the diseases to which it contributes indirectly and directly.

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 Accordingly, the present invention includes the following compounds: 4,4'-dithiobis- (3-aminobutane-1-sodium sulfonate) bis-hydrochloride; 4,4'-dithiobis- (3-aminobutane-1-sulfonate 2,2-dimethylpropyl) bis-trifluoroacetate.

 In another aspect, the present invention describes a method for the prevention or treatment of high blood pressure and indirectly and directly related diseases, comprising administering a therapeutically effective amount of a compound of the present invention. In another aspect, the present invention provides pharmaceutical compositions comprising one or more compounds of the present invention, preferably in combination with a pharmaceutically acceptable diluent or carrier.

 In another aspect, the present invention provides one or more compounds of the present invention for use in therapy, and in particular in human medicine.

 In another aspect, the present invention provides the use of one or more compounds of the present invention for the production of a medicament for the treatment of high blood pressure and indirectly and directly related diseases.

 In another aspect, the present invention provides a method of treating a patient suffering from high blood pressure and indirectly and directly related diseases, comprising administering a therapeutically effective amount of one or more compounds of the present invention .

 Figure 1 demonstrates the effect of the compound of Example 1 on blood pressure in hypertensive rats.

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 The present invention provides methods for the prevention or treatment of high blood pressure and diseases to which high blood pressure contributes directly or indirectly. These diseases include diseases of the heart, peripheral and cerebral vascular system, brain, eye and kidney. In particular, diseases include primary and secondary hypertension, stroke, myocardial ischemia, heart failure and kidney failure, myocardial infarction, peripheral vascular disease, diabetic proteinuria, syndrome X and glaucoma.

 As used herein, the term "compound of the present invention" means a compound described above or one of its pharmaceutically acceptable salts or solvates.

 Those skilled in the art will recognize that stereocenters exist in the compounds of the present invention. Accordingly, the present invention includes all possible stereoisomers and geometric isomers of the compounds of formula (I) and includes not only racemic compounds but also the optically active isomers. When a compound of formula (I) is desired in the form of a single enantiomer, it can be obtained by resolution of the final product or by stereospecific synthesis from the isomerically pure starting material or from any suitable intermediate . The resolution of the final product, of an intermediate or of a starting material can be carried out by any suitable method known in this field. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. In addition, in cases where tautomeric forms of the compounds of formula (I) are

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 possible, the present invention is intended to include all the tautomeric forms of the compounds.

 The specialist in organic chemistry will note that many organic compounds can form complexes with solvents in which they have been caused to react or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". The solvates of the compound of formula (I) fall within the scope of the present invention.

 The specialist in organic chemistry will also note that many organic compounds can exist in more than one crystalline form. For example, the crystalline form can vary from one solvate to another. Thus, all crystalline forms of the compounds of the present invention or their pharmaceutically acceptable solvates are included within the scope of the present invention.

 Those skilled in the art will also appreciate that the compounds of the present invention can also be used in the form of one of their pharmaceutically acceptable salts or solvates. Physiologically acceptable salts of the compounds of the present invention include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium salts. More specific examples of suitable acid salts include the salts formed with hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic acids. , malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic,

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 naphthalene-2-sulfonic, benzenesulfonic, hydroxy-naphthoic, hydroiodic, malic, steric, tannic, etc.

Other acids such as oxalic acid, although not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically salts acceptable.

More specific examples of suitable basic salts include the sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N, N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine salts. , ethylenediamine, N-methylglucamine and procaine. References below to a compound according to the present invention relate to both the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.

 The compounds of the present invention and their pharmaceutically acceptable derivatives are suitably administered in the form of pharmaceutical compositions.

These compositions can be conveniently presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The support (s) must be "acceptable" in the sense that they must be compatible with the other ingredients of the formulation and they must not be harmful to the subject receiving them.

 Although it is possible to therapeutically administer the compounds of the present invention as the crude chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.

 Accordingly, the present invention further provides a pharmaceutical formulation comprising a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof in association with one or more pharmaceutically supported carriers.

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 acceptable and, optionally, other therapeutic and / or prophylactic ingredients.

 The formulations include those suitable for oral, parenteral (including subcutaneous, for example by injection or by means of a depot, intradermal, intrathecal, intramuscular, for example by depot, and intravenous), rectal and topical administration ( including dermal, oral and sublingual) or in a form suitable for administration by inhalation or insufflation, although the most suitable route may depend, for example, on the condition and condition of the recipient. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy field. All of the methods include the step of combining the compounds ("active ingredients") with the carrier which includes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately associating the active ingredient with liquid vehicles or finely divided solid supports or else with these two types of supports and then, if necessary, by shaping the product into the desired formulation. .

 Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets, particularly for pediatric administration), each containing a predetermined amount of the ingredient active; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or in the form of an oil-in-water liquid emulsion or a water-in-liquid emulsion

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 oil. The active ingredient can also be presented in the form of a bowl, an electuary or a paste.

 A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free flowing form such as a powder or granules in a suitable machine, optionally in admixture with other conventional excipients such as binders (e.g. syrup, gum arabic, gelatin, sorbitol, tragacanth, starch mucilage, polyvinylpyrrolidone or hydroxymethylcellulose), fillers (e.g. lactose, sucrose, microcrystalline cellulose, corn starch , calcium phosphate or sorbitol), lubricants (e.g. magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g. potato starch or sodium starch glycolate) or wetting agents such as sodium lauryl sulfate. Molded tablets can be prepared by molding in a suitable machine a mixture of the sprayed compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated to cause the slow or controlled release of the active ingredient therein. The tablets can be coated by methods well known in the art.

 Alternatively, the compounds of the present invention can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions or emulsions, syrups or elixirs, for example. In addition, formulations containing these compounds can be presented as dry products intended for reconstitution with water or another suitable vehicle before use. These liquid preparations may contain conventional additives such as

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 suspending agents, for example sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; emulsifying agents such as lecithin, sorbitan mono-oleate or gum arabic; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid. These preparations can also be formulated in the form of suppositories, containing for example conventional excipients for suppositories such as cocoa butter or other glycerides.

 Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the chosen recipient; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. The formulations can be presented in single dose or multiple dose containers, for example ampoules and hermetically sealed bottles, and can be stored in the freeze-dried state (freeze-dried) requiring only the addition of a sterile liquid vehicle, for example water for injections, immediately before use. Extemporaneous injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the type described above.

 Formulations for rectal administration may be presented as suppositories with

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 usual supports such as cocoa butter, hard fat or polyethylene glycol.

 Formulations for topical administration in the oral cavity, for example for oral or sublingual administration, include tablets comprising the active ingredient in a flavored excipient such as sucrose and gum arabic or gum tragacanth, and lozenges comprising the active ingredient in an excipient such as gelatin and glycerol or sucrose and gum arabic.

 For topical administration to the epidermis, the compounds can be formulated in the form of creams, gels, ointments or lotions or in the form of a transdermal patch.

 The compounds can also be formulated as preparations for deposition. These long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or else by intramuscular injection.

Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example in the form of an emulsion in an acceptable oil) or ion exchange resins, or in the form of very poorly soluble derivatives, for example in the form of a very slightly soluble salt.

 For intranasal administration, the compounds of the present invention can be used, for example, in the form of an atomizing liquid, a powder or drops.

 For administration by inhalation, the compounds according to the present invention are suitably delivered in the form of an aerosol emitted by spraying by a pressure container or a nebulizer, by means of a suitable propellant, for example 1.1 , 1,2-trifluoroethane (HFA 134A) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), dioxide of

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 carbon or other suitable gas. In the case of a pressurized aerosol, the exact dose can be determined by installing a valve intended to deliver a measured quantity. The capsules and cartridges consisting, for example, of gelatin, intended for use in an inhaler or insufflator can be formulated so as to contain a mixture of powders consisting of a compound of the present invention and a suitable powdered excipient such as than lactose or starch.

 In addition to the ingredients particularly mentioned above, the formulations can comprise other agents conventional in this field in relation to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

 Those skilled in the art will note that a reference in this specification to treatment extends to prophylaxis as well as to the treatment of established diseases or symptoms. In addition, it should be noted that the amount of a compound of the present invention required for use in treatment varies depending on the nature of the condition being treated and the age and condition of the patient and will ultimately be left to the discretion of the attending physician or veterinarian. In general, however, the doses used for the treatment of an adult human patient are usually in the range of 0.02 to 5000 mg per day, preferably 1 to 1500 mg per day. The desired dose can be conveniently presented as a single dose or divided into several doses administered at appropriate intervals, for example as two, three, four or more than four secondary doses per day. The formulations in accordance with the present invention may contain 0.1 to 99% of the active ingredient, suitably 30 to 95% for the

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 tablets and capsules and 3 to 50% for liquid preparations.

 The compound of the present invention for use in the present invention can be used in combination with one or more other therapeutic agents, for example beta-adrenergic receptor blockers, calcium channel blockers, thiazide diuretics , angiotensin receptor blockers and angiotensin converting enzyme inhibitors. Thus, the present invention provides in a further aspect the use of a combination comprising a compound of formula (I) and an additional therapeutic agent in the treatment of arterial hypertension.

 When the compounds of the present invention are used in combination with other therapeutic agents, the compounds can be administered successively or simultaneously by any suitable route.

 The above-mentioned combinations can be suitably presented for use in the form of a pharmaceutical formulation and, thus, pharmaceutical formulations comprising an association corresponding to the above definition together optimally with a pharmaceutically acceptable carrier or excipient constitute a further aspect of the present invention. The various constituents of these associations can be administered successively or simultaneously in separate or combined pharmaceutical formulations.

 When combined in the same formulation, it will be appreciated that the two compounds must be stable and compatible with each other and the other constituents of the formulation and can be formulated for administration. When formulated separately, they can be supplied in any formulation

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 suitable, conveniently in a manner known for such compounds in this field.

 When a compound of the present invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that administered when the compound is used alone. The appropriate doses will be readily determined by those skilled in the art.

 The compounds of the present invention can be prepared by means of the following examples which are not to be construed as limiting the present invention.

Example 1: 4,4'-dithiobis- (3-amino-butane-1-sodium sulfonate) bis-hydrochloride Step 1: Synthesis of 2-amino-4-chloro-1-ethoxycarbonylpropane hydrochloride

A solution of 20 g of L-homoserine in 50 ml of absolute ethanol was cooled to 0 C and 121 ml (10 equivalents) of SOC12 were added dropwise.

The mixture was warmed to room temperature and then heated to reflux for 8 hours. The solution was evaporated in vacuo and the residue was treated with Et20.

The precipitate was filtered and washed three times with Et20.

White solid substance: 31.2 g (92%). Rf (CH2Cl2 / MeOH / AcOH: 7/3 / 0.5) 0.59.

Step 2: Synthesis of ethyl 2-tert-butoxycarbonylamino-4-chlorobutanoate

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The preceding compound (31.2 g) dissolved in 80 ml of DMF, was cooled to -10 ° C., then a solution of (BOC) 20 (37.1 g) in 80 ml of DMF and 23.8 ml of Et3N has been added. The mixture was stirred at room temperature overnight. The solution was evaporated in vacuo and the residue was partitioned between H2O and Et2O. The organic phase was washed, dried over Na2SO4, filtered and evaporated in vacuo. Beige solid substance: 40.7 g (99%).

Rf (EtOAc / n-Hex: 3/1) 0.66.

Step 3: Synthesis of 3-tert-butoxycarbonylamino-3-ethoxycarbonylpropane-1-sodium sulfonate

The above compound (10.8 g) was dissolved in a mixture of 150 ml of dioxane / 150 ml of H2O and 6.1 g of NaI and 25.6 g of Na2SO3 were added. The mixture was heated at reflux for 15 hours, then evaporated in vacuo. The residue was dissolved in EtOH (250 ml). The precipitate was removed and the filtrate was evaporated in vacuo. A white powder was obtained; 12 g (89%). Rf (CH2Cl2 / MeOH: 8/2) 0.18.

Step 4: Synthesis of sodium 3-tertiobutoxycarbonylamino-4hydroxybutane-1-sulfonate

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The previous ester (10 g) was dissolved in 125 ml of absolute EtOH and 125 ml of anhydrous THF, then 5.1 g of anhydrous LiCl and 4.9 g of NaBH4 were added. The mixture was stirred for 17 hours at room temperature. Acetic acid (60 ml) was added at 0 ° C and the mixture was evaporated in vacuo. The crude product was purified by chromatography on silica gel using an 8/2 EtOAc / MeOH mixture as eluent. White solid substance: 7.16 g (82%). Rf (EtOAc / MeOH: 7/3) 0.32.

Step 5: Synthesis of 4-acetylsulfanyl-3-tertiobutoxycarbonylaminobutane-1-sodium sulfonate

A solution of 13 g of triphenylphosphine in anhydrous THF (170 ml) was cooled to 0 C and 10 ml of diisopropyl azodicarboxylate were added. The solution was stirred for 45 minutes at the same temperature. A solution of the above alcohol (7 g) in THF (125 ml) + DMF (40 ml) was added and was followed, 15 minutes later, with 4 ml of CH3COSH and the mixture was stirred for overnight at room temperature. After evaporation in vacuo, the residue was dissolved in EtOAc and washed with NaHCO3 solution (10%), H2O and brine and was dried over Na2SO4.

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 After evaporation, an n-hexane / EtOAc mixture was added and the precipitate was removed. The filtrate was evaporated and the residue was purified by chromatography on silica gel using as eluent an n-Hex / EtOAc mixture in the ratio 4: 1. Oily product: 8.4 g (80%).

Rf (CH2C12 / MeOH. 8/2) 0.20.

Step 6: Synthesis of 4,4'-dithiobis- (3-aminobutane-1-sodium sulfonate) bis-hydrochloride.

 350 mg of the above compound were heated to reflux with 15 ml of 6N HCl for 3 hours. The solution was evaporated in vacuo and the residue was dissolved in an EtOH / H2O mixture in the ratio 1/4 and was treated with an iodine solution until a persistent yellow color was observed. The solution was evaporated and the final compound was precipitated with Et2O. Highly hygroscopic white solid: 200 mg (80%).

Example 2: 4,4'-dithiobis- (3-aminobutane-1-sulfonate-2,2-dimethylpropyl) bis-trifluoroacetate Step 1: Benzyloxycarbonyl-L-homocystine

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L-homocystine (5 g) was dissolved in a mixture (80 ml) of dioxane / H2O. At 0 C and with stirring, 1.52 g (2.1 equivalents) of NaOH and a solution of 7.8 g (2.4 equivalents) of benzyl chloroformate in 40 ml of dioxane were added. The pH was maintained at 9 by adding a 1 M NaOH solution.

After stirring for 2.30 hours at room temperature, 100 ml of H 2 O was added and the white precipitate was subjected to extraction with Et 2 O (2 x 50 ml). The aqueous phase was acidified to pH 1 and the precipitate was extracted with EtOAc (4 x 80 ml). The organic phase was washed, dried over Na2SO4, filtered and evaporated in vacuo. White solid substance: 10.2 g (100%).

Step 2: Benzyloxycarbonyl-L-ethyl homocystinate

Z-L-homocystine (10 g) was dissolved in 150 ml of absolute EtOH. A solution of 1 ml SOC12 in CH2Cl2 (17 ml) was added at 0 ° C and the mixture was heated at reflux for 4 hours. The mixture was evaporated in vacuo and the residue was dissolved in CH2Cl2.

The organic phase was washed, dried over Na2SO4, filtered and evaporated in vacuo. Yellow paste: 9 g (80%).

Rf (EtOAc / cHex: 1/1) 0.59.

Step 3: ethyl 2-benzyloxycarbonylamino-4- (2,2-dimethylpropyl) - 1-sulfonylbutanoate

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The preceding compound (9 g) was dissolved in a mixture of CC14 / EtOH and Cl2 gas was bubbled through the mixture for 45 minutes. After evaporation under vacuum, a yellow paste was obtained which was dissolved in 200 ml of CH2Cl2. Then, 3.48 g of neopentyl alcohol and 5.85 ml of Et3N were added. The mixture was stirred overnight, evaporated in vacuo and purified by chromatography on silica gel, using as eluent an EtOAc / cHex mixture in the ratio 1/4. 11.2 g of a white solid were obtained (90%). Rf (EtOAc / cHex: 1/4) 0.16.

Step 4: ethyl 2-tert-butoxycarbonylamino-4- (2,2-dimethylpropyl) -1-sulfonylbutanoate

The above compound (5.2 g) was dissolved in 30 ml of EtOAc and a solution of 4.07 g of BOC20 in 30 ml of EtOAc and 400 mg of a 10% Pd / C catalyst were added . The mixture was stirred under H2 pressure of 250 kPa at 40 C for 48 hours. The mixture was filtered through Celite and the organic phase was evaporated in vacuo (100%). Rf (EtOAc / cHex: 1/4) 0.79.

Step 5: 3-tert-butoxycarbonylamino-4-hydroxybutane-1 (2,2-dimethylpropyl) sulfonate

The above compound (2.44 g) was dissolved in 120 ml of a THF / EtOH mixture in the 50/50 ratio. The

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 solution was cooled to -10 ° C under an inert atmosphere and 1.09 g (4 equivalents) of LiCl and 0.97 g (4 equivalents) of NaBH4 were added. After 15 minutes at -10 ° C., the mixture was stirred at room temperature for 60 hours. Then 20 ml of AcOH was added and the mixture was evaporated in vacuo. The residue was dissolved in 400 ml of EtOAc, washed with water and brine and dried over Na2SO4. The crude product was purified by chromatography on silica gel using as eluent an EtOAc / MeOH / cHex mixture in the ratio 1/1/4 (Rf 0.20). 2.1 g (99%).

Step 6: 3-tert-butyloxycarbonylamino-4-acetylsulfanyl-butane-1-(2,2-dimethylpropyl) sulfonate BocHN # SC (O) CH3
SO3CH2tBu
The preceding compound (0.965 g) in 10 ml of CHCl3 was cooled to -10 ° C. and 1.07 ml of Et3N and 0.44 ml of CH3SO2Cl in 4 ml of CHCl3 were added successively. The mixture was stirred at room temperature for 1.5 hours. Then 40 ml of CHCl 3 were added and the organic phase was washed at 0 ° C. with a 10% solution of NaHCO 3, H 2 O, 1 N HCl, H 2 O and brine and was dried over Na 2 SO 4. After filtration and evaporation, the crude product (Rf (EtOAc / AcOH / cHex: 1/1/4) = 0.41) was dissolved in 15 ml of DMF and, at -10 ° C., an amount of 0.65 g from CH3COSK has been added. The mixture was stirred for two days at room temperature. The solvent was evaporated in vacuo and an orange residue was obtained.

 Chromatography on silica gel: eluent EtOAc / cHex in the ratio 1/4 (Rf = 0.15); white solid: 0.64 g (57%).

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Step 7: 4,4'-dithiobis- (3-tertiobutyloxycarbonylaminobutane-1-sulfonate) of 2,2-dimethylpropyl

The above compound (0.25 g) was dissolved in an EtOH / THF mixture in the ratio 2/1. Then 60 mg of NaOH dissolved in 1 ml of H2O were added. The mixture was stirred while bubbling O2 through it for 12 hours.

After evaporation in vacuo, the residue was dissolved in a mixture of 40 ml of H20 / 40 ml of EtOAc and was acidified to pH 1. The organic phase was isolated, washed, dried over Na2SO4, filtered and evaporated in vacuo. White solid substance: 0.178 g (80%). Rf (EtOAc / MeOH / cHex: 1/1/4) 0.28.

Step 8 Bis-trifluoroacetate of 4,4'-dithiobis- (3 aminobutane-1-sulfonate) of 2,2-dimethylpropyl
The above disulfide (0.17 g) was dissolved in 6 ml of CH2Cl2 and 6 ml of CF3CO2H were added. The mixture was stirred at room temperature for 2 hours and evaporated in vacuo. The residue was washed with Et20.

White solid substance 0.17 g (100%). Rf (CH2Cl2 / MeOH: 7/3) 0.47.

EXAMPLE OF BIOLOGICAL ACTIVITY Effect on blood pressure in rats
Rats rendered hypertensive with a salt of deoxycorticosterone acetate (DOCA) were obtained from Pham, I. et al. (1993) J. Pharmacol. Exp. Ther.

265, 1339-1347, with the following modifications: under pentobarbital anesthesia, a unilateral nephrectomy was performed in male Wistar Kyoto rats (300 g) and a 50 g pellet of DOCA was implanted

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 skin. After surgery, the rats were fed conventional rat food and the drinking water was supplemented with 0.9% NaCl and 0.2% KCl.

Hypertension appeared 3 weeks after surgery.

 For the recording of arterial blood pressure, the rats which received the DOCA salt were anesthetized with sodium pentobarbital (50 mg / kg ip, Sentravet Laboratory, Plancoët, France), a femoral artery catheter (PEso ) filled with heparinized physiological serum (250 U / ml) was inserted, then was passed under the skin and taken out at the nape of the neck. A flexible metal spring was attached to the rat's skull and neck and connected to two-channel ball joints mounted directly above the cage. This configuration allowed the free movement of the rat inside the cage.

Then each rat received an intramuscular injection of 0.1 ml of penicillin-streptomycin (50,000 IU / ml, Boehringer Mannheim, GmbH - Germany) and was left for recovery for at least 24 hours before the experiment. The mean arterial blood pressure was recorded continuously throughout this experiment using a COBE CDX III pressure transducer (Phymep, Paris, France) connected to the MacLab system (Phymep, Paris, France) consisting of a MacLab technological unit and Chart software running on a MacIntosh computer.

 The compound of Example 1 was administered to rats by oral gavage in water at 15 mg / kg. As shown in Figure 1, the mean arterial blood pressure was reduced by 3680 Pa, 4.5 hours after administration.

 The application of which this description and the claims are a part may be used as a basis of priority with respect to any subsequent application. The claims of such an application

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 may be intended for any new feature or combination of new features described in this specification. These claims may be in the form of product, composition, process or use claims and may include, by way of example and not limitation, one or more of the following claims.

Claims (4)

1. A compound characterized in that it is chosen from: sodium 4,4'-dithiobis- (3-aminobutane-1-sulfonate) hydrochloride; 4,4'-dithiobis bis-trifluoracetate - ((2,2-dimethylpropyl) 3-aminobutane-1-sulfonate).  2. Compound according to claim 1, characterized in that it is intended to be used in therapy.  3. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1.  4. Use of a compound according to claim 1, characterized in that it is intended for the production of a medicament for the treatment of arterial hypertension and of indirectly or directly related diseases.