EP1572692A1

EP1572692A1 - Enantiomer (-) of tenatoprazole and the therapeutic use thereof

Info

Publication number: EP1572692A1
Application number: EP03814481A
Authority: EP
Inventors: Suzy Charbit; Avraham Cohen; Hervé FICHEUX; Michel Homerin; François SCHUTZE; Alain Taccoen
Original assignee: Sidem Pharma SA
Current assignee: Sidem Pharma SA
Priority date: 2002-12-16
Filing date: 2003-12-16
Publication date: 2005-09-14
Also published as: NZ540663A; JP2006513230A; CN1726214A; US20060194832A1; RU2310652C2; WO2004060891A1; MXPA05006419A; AU2003300627B2; KR20140022437A; JP5230897B2; US7652034B2; NO331505B1; CN100345849C; KR20050088184A; PL215162B1; FR2848555B1; KR20120087886A; RU2005122465A; BR0317328A; CA2509899A1

Abstract

The invention relates to enantiomer (-) of tenatoprazole. The inventive enantiomer (-) of tenatoprazole, or (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4,5-b]pyridine exhibits improved pharmacocinetic properties which make it possible to use a once a day posology of a drug for relevant indications. Said invention can be used for curing digestive pathologies.

Description

ENANTIO ERE (-) OF TENATOPRAZOLE AND ITS APPLICATION IN THERAPEUTICS

The present invention relates to tenatoprazole, and more particularly an enantiomer of tenatoprazole, a process for its preparation, as well as its use in human or veterinary therapy. Tenatoprazole, i.e. 5-methoxy-2- [[((4-metho-xy-3, 5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4, 5-b] pyri- dine, is described in patent EP 254,588. It is one of the drugs considered to be proton pump inhibitors, that is, drugs which inhibit the secretion of gastric acid and are useful for the treatment of gastric and duodenal ulcers. It can also be used in the treatment of gastroesophageal reflux, digestive hemorrhages and dyspepsias, because of its relatively long elimination half-life, as indicated in French patent application FR 02.13113.

The first known derivative of the proton pump inhibitor series is omeprazole, described in patent EP 005,129, which has inhibitory properties for gastric acid secretion, and is widely used as an anti-ulcer in human therapy.

In addition to omeprazole, other proton pump inhibitors are well known and mention may be made in particular of rabeprazole, pantoprazole and lansoprazole, all of which have a structural analogy, and which belong to the group of pyridinyl-methyl- sulfinyl-benzimidazoles. These compounds are sulfur oxides having an asymmetry at the level of the sulfur atom and are therefore generally present in the form of a racemic mixture of two enantiomers.

Various formulations have been proposed to improve the properties or activity of proton pump inhibitors. In the case of omeprazole, for example, application WO 01.28558 describes a stable liquid formulation obtained in forming in situ the sodium or potassium salts in solution in polyethylene glycol, by the action of a hydroxide on one omeprazole. The drug thus formulated can be used in the usual indications of proton pump inhibitors.

Like omeprazole and other suifoxides with a similar structure, tenatoprazole has an asymmetric structure and can therefore be in the form of the racemic mixture or its enantiomers. Thus, it can exist in the form of its two enantiomers having the configurations R and S, or (+) or (-), respectively.

Recent work has shown that, unlike all other proton pump inhibitors such as, for example, omeprazole or lansoprazole, and unexpectedly, tenatoprazole has a markedly prolonged duration of action, resulting from a plasma half-life about 7 times higher. Thus, the medical data collected show that tenatoprazole brings a level of symptom relief and scarring of gastric lesions higher than that of other drugs belonging to the same therapeutic class of proton pump inhibitors, which then allows its effective use. in the treatment of atypical and esophageal symptoms of gastroesophageal reflux, digestive hemorrhage and dyspepsia, as indicated above.

The studies carried out by the applicant have made it possible to show that each of the two enantiomers contributes in a different way to the properties of tenatoprazole and that the two enantiomers (+) and (-) have significantly different pharmacokinetic properties. Thus, it is possible to isolate these enantiomers and to prepare drugs having specific activities and different pharmacokinetic profiles. It thus becomes possible to use each of these enantiomers more effectively in indications specific for the treatment of perfectly identified pathologies.

A subject of the present invention is therefore the (-) configuration enantiomer of tenatoprazole, and its use in human or veterinary therapy.

A subject of the invention is also a pharmaceutical composition comprising the (-) enantiomer of tenatoprazole combined with one or more pharmaceutically acceptable excipients and carriers. The invention also relates to a pharmaceutical composition comprising (-) -tenatoprazole in combination with one or more antibiotics.

A subject of the invention is also the use of the (-) enantiomer of tenatoprazole in the manufacture of a medicament for the treatment of digestive pathologies where an inhibition of acid secretion must be intense and prolonged for the treatment of symptoms and gastroesophageal reflux lesions, digestive bleeding resistant to other proton pump inhibitors, as well as for the treatment of these diseases in multi-drug patients.

A subject of the invention is also the use of the (-) enantiomer of tenatoprazole in the manufacture of a medicament providing a significant improvement in wound healing as well as an increase in the speed of normalization of the histological modifications of gastric lesions in animal or man, and therefore a sharp decrease in recurrences of esophagitis.

A further subject of the invention is the use of the (-) enantiomer of tenatoprazole for the manufacture of a medicament having improved pharmacokinetic properties allowing a dosage of a single medicament intake per day in the relevant indications, as indicated below, in particular for the eradication of Helicobacter pylori in the treatment of duodenal ulcers, which require two taken, morning and evening, with other proton pump inhibitors.

The (-) enantiomer of tenatoprazole can be used in the form of a salt, in particular an alkali or alkaline earth metal salt, and for example in the form of a sodium, potassium, lithium, magnesium or calcium salt. These salts can be obtained from the (-) enantiomer of the previously isolated tenatoprazole, by salification reaction according to a usual method of the technique, for example by action of basic mineral reagents comprising alkaline or alkaline counter-ions earth.

The (-) enantiomer of tenatoprazole corresponds to (-) - 5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] sufinyl] imidazo [4, 5- b] pyridine, and can be represented by the following general formula:

According to a preferred method of preparation, the (-) enantiomer of tenatoprazole can be obtained enantioselective under good conditions of yield and purity, by enantioselective oxidation of the corresponding sulfide in the presence of a specific catalyst based on vanadium. Such a process is described in French patent application 0303914. The sulfide used as starting material is a known product which can be prepared by various methods described in the literature, and for example by the methods described in patents EP 254,588 and EP 103.553. The oxidant used in the process of the invention is preferably a peroxide, for example hydrogen peroxide. According to an advantageous embodiment, hydrogen peroxide at high concentration, for example greater than 30%, is used. According to the process of the invention, the catalyst can be chosen from catalysts such as an oxo-vanadium V complex and for example vanadium acetylacetonate. Such catalysts are commercially available.

A ligand such as a Schiff base derived from a substituted salicylic aldehyde and a chiral amino alcohol is preferably used in combination with the catalyst. A very particularly preferred ligand is 2,4-di-tert-butyl-β- [1 --- hydroxymethyl-2-methyl-propylimino) -methyl] -phenol. Under the operating conditions, the ligand and the metal catalyst form an asymmetric complex where the metal is oxidized by the oxidant.

The reaction can be carried out in a solvent, in a neutral or weakly basic medium, for example in methanol, tetrahydrofuran, dichloromethane, acetonitrile or toluene. The base used, where appropriate, can be a tertiary amine such as pyridine, di-isopropylethylamine or triethylamine. The oxidation reaction is easily carried out cold or at room temperature. The (-) enantiomer of tenatoprazole of the present invention can be readily obtained in optically pure form by the above process.

By "optically pure form" is meant that the (-) enantiomer is substantially free of (+) enantiomer or includes only traces thereof. If appropriate, base salification is then carried out in an appropriate solvent, to form a salt, in particular an alkali or alkaline earth metal salt.

This shape can be determined by optical rotation measurements according to the usual techniques. For example, a 0.25% solution of the desired enantiomer (50 g of sample per 20 ml of solvent) dissolved in DMF or in acetonitrile can be prepared using a polarimeter of the commonly used type (Jobin Yvon). Thus, the optical rotation angle of (-) -tenatoprazole is levorotatory in dimethylformamide and in acetonitrile, and its melting point is 127-130 ° C (decomposition).

The (-) enantiomer of tenatoprazole can also be obtained in optically pure form by well known techniques, using an appropriate separation method, for example by preparative column chromatography, such as chiral chromatography or HPLC.

The principle of the chiral chromatography method is based on the difference in affinity between the enantiomers (+) and (-) and the chiral selector of the stationary phase. This method makes it possible to separate the enantiomers with a good yield.

If necessary, the racemic mixture which can be used as starting material can be obtained by known methods, for example according to the method described in patent EP 254,588. Thus, it can be prepared by treating with an oxidizing agent, such as a perbenzoic acid, the corresponding sulfide originating from the condensation of a thiol and a pyridine, preferably in the presence of a base such as potassium hydroxide in a suitable solvent, for example ethanol, hot.

The known method of separation of enantiomers from the racemic by high performance liquid chromatography (HPLC) makes it possible to isolate the (-) enantiomer with excellent purity (chiral purity: min. 98.8% of area).

The studies carried out have shown that the (-) isomer prepared according to the invention has the S configuration, and, consequently, that the (+) isomer has the R configuration. Pharmacological study

In vivo studies in rats: measurement of the volume and pH of gastric secretion.

The pharmacological effects of the two (-) and (+) isomers of tenatoprazole were studied in vivo in rats in the pylorus ligation model. This well-established and validated model consists of pre-treating the animals at different times (10, 16 and 20 h) before ligation of the pylorus, then measuring the volume and pH of the gastric secretions, 4 h after ligation.

Significant differences are then observed between the two isomers as indicated below. Thus, 10 h after administration, the (-) isomer remains pharmacologically active. It increases the pH by 49% (p <0.01) and decreases the acidity by 55% (p <0.01) compared to the control group, while the effect of the (+) isomer is not more meaningful.

In vivo studies in dogs: evaluation of the antisecretory effect. The antisecretory effect of the (-) and (+) isomer of tenatoprazole was observed in dogs by measuring the intragastric pH after administration of 10 mg / kg / day for 6 days. 24-hour pH profiles were performed the first two days, the βth day of administration, and two days after stopping treatment. These pH values were compared to the basal pH measured before the administration of the product.

It has thus been shown that the (-) and (+) isomers inhibit gastric secretion in dogs. However, a significant effect is observed from the first day of administration only in the case of the (-) isomer, and it occurs maintains two days after stopping the administration of the product.

The results corresponding to a holding time at pH> 3 and pH> 4 for 24 hours, expressed in percent, are described below.

In vivo studies in rats: evaluation of the healing time and the increase in the normalization of histological changes in lesions.

Other in vivo experiments carried out in rats have shown that the time to healing of ulcerative lesions was significantly improved by the administration of the (-) enantiomer of tenatoprazole, compared with the effects obtained with the (+) isomer. . Thus, the effect observed with the (-) enantiomer appears one day before that of the (+) enantiomer. Such a difference is unexpected, and, in addition, it is accompanied by a significant increase in the quality of wound healing due to an increase in the normalization of histological changes, when the (-) enantiomer is administered. These modifications consist of a reduction in lesions, resulting in complete morphological healing of the esophageal epithelium.

Such pharmacological effects of the (-) enantiomer on both quantitative and qualitative improvement, results in a significant decrease in the number of recurrences of esophagitis. Pharmacokinetic study:

Unexpectedly, the studies carried out on the enantiomer prepared as indicated above have revealed pharmacokinetic properties which are fundamentally different from those of the classic proton pump inhibitors, and those of the (+) enantiomer of tenatoprazole, allowing to consider its use in specific therapeutic indications.

Thus, the (-) isomer of tenatoprazole differs significantly from other proton pump inhibitors by its pharmacokinetic properties, as shown by the studies described below. This characteristic is essential because it makes it possible to make available to the practitioner a medicament specifically adapted to the effective treatment of specific pathologies.

More particularly, the unexpected pharmacokinetic properties of the (-) isomer appeared during in-depth studies of pharmacokinetics and metabolism Given the variability of the pharmacokinetic parameters, in particular AUCo- i _nf (area under the curve) and tι _{/ 2} ( elimination half-life), some subjects have been genotyped to identify the type of metabolizer, slow or fast, to which they belong.

It is important to note that a major problem with the metabolism of proton pump inhibitors is that they are mainly metabolized by the cytochrome CYP2C19, which is under the control of chromosome 10, and thus they exhibit a genetic polymorphism. ie a variable activity depending on the type of patient population. This results in variable plasma levels as well as a susceptibility to possible harmful drug interactions, depending on the individual. In vitro studies of pharmacokinetic properties and metabolism:

In vitro metabolism studies on cytochromes that metabolize tenatoprazole have shown a significant difference in the behavior of the two isomers (-) and (+) with regard to the rate of metabolism, as shown in the table below.

In this table, the value of Vmax is the maximum metabolic rate, measured in pmol / min per pmol of cytochrome. Vmax (-) is the value of Vmax for the (-) enantiomer of tenatoprazole.

These results make it possible to conclude that the (-) enantiomer is metabolized much more slowly than the (+) enantiomer, ie approximately 7 times slower. Consequently, it can be deduced that the (-) enantiomer of tenatoprazole has a much longer mean presence time (MRT) in the human body, compared with the (+) enantiomer.

In addition, it has been shown that different cytochromes are involved in the metabolism of tenatoprazole.

The (-) enantiomer is mainly metabolized by the cytochrome CYP3A4, which can compensate for a deficiency or blockage of the cytochrome CYP2C19. The (+) enantiomer is metabolized by two pathways, mainly CYP2C19, and to a lesser extent CYP2A4.

In addition, it clearly appears that homozygous subjects with a mutation in exon 5 leading to the CYP2C19 * 2 / * 2 genotype, have pharmacokinetic characteristics totally different from the standard population. These homozygous subjects have a very weak metabolic activity affecting CYP2C19 responsible in part for the metabolism of tenatoprazole. Plasma analysis showed that these subjects had a very significant increase in the (+) isomer versus the (-) isomer. These subjects are called slow metabolizers.

Conversely, fast metabolizing subjects, characterized by the CYP2C19 * 1 / * 1 genotype, have a higher concentration of (-) isomer than (+) isomer, as shown in the table below.

Given the possible saturation of CYP2C19, it can be deduced that the potential risk of drug interactions will be greatly reduced by the administration of the (-) enantiomer.

In vivo studies of pharmacokinetic properties and metabolism:

Other studies in dogs have shown that administration of the (-) enantiomer of tenatoprazole results in a difference in metabolic rates leading to a significantly longer half-life for the (-) enantiomer of tenatoprazole by comparison with the (+) enantiomer.

Clinical study :

A pharmacokinetic study was carried out to assess the difference in pharmacokinetic characteristics between the (-) isomer of the invention and the (+) isomer. This study was carried out on Caucasian subjects after acute and repeated administration (7 days) of tenatoprazole. It was then found, after 7 days of treatment, that the Plasma concentration of the (-) isomer changes linearly with dose, as does AUC, which is predictive of the subject's gastric pH, and therefore of drug activity. On the contrary, the evolution of the plasma concentration of the (+) isomer is not linear, and therefore does not allow to predict the efficacy and tolerance of the drug. In addition, the variability of pharmacokinetic parameters between subjects is significantly lower with the (-) isomer compared to the (+) isomer. In another study, it was shown that the elimination half-life of the (+) isomer in slow metabolizing subjects (deficient in CYP 2C19 activity) is approximately 4 times longer than that of the isomer. (-) as shown in the following table.

As a result, the (-) enantiomer offers much better predictability of its action, which also makes it possible to predict and limit the risks of drug interaction when the patient is polymedicated. Thus, the overall conclusion of the above studies is that the (-) enantiomer of tenatoprazole has better efficacy and better tolerance, which avoids the risk of side reactions.

All these unexpected results lead to proposing the isolation and administration of a single isomer of tenatoprazole, the (-) enantiomer which has the following advantages: - a reduction in inter-subject variability hence better use of the product with a more homogeneous response rate to treatment in all patients, - better impregnation of the product, because the speed of elimination is slower and the mean time of presence in the body (MRT) is longer, - a decrease in the number of drug interactions with potentially co-administered drugs. In fact, the (-) isomer is metabolized by two pathways, cytochromes 2C19 and 3A4, which makes it possible to compensate for a possible deficit or blockage of cytochrome 2C19,

- simple use in all types of patients, whether slow or fast metabolizers. In fact, the (-) isomer in the slow metabolizing subject will be metabolized by CYP3A4, which makes it possible to obtain uniform pharmacokinetic parameters, whatever the genotype of the patients, whether they are slow or rapid metabolizers,

- an improved efficacy / safety profile in all types of patients in the treatment of digestive diseases such as atypical and esophageal symptoms of gastroesophageal reflux, digestive hemorrhages and dyspepsias,

- an improved healing time as well as an increase in the return to normal of histological changes in gastric lesions. Furthermore, the isolation of the (-) enantiomer made it possible to determine a pharmacokinetic profile different from that of the racemic, in particular an average plasma half-life of between 10 and 12 hours approximately for the (-) enantiomer for doses from 10 mg to 80 mg. Conversely, we know that the racemic has an average plasma half-life of around 7 hours in this range of doses.

These unexpected properties of the (-) enantiomer of tenatoprazole, and more particularly its specific pharmacokinetic and metabolic parameters, show that the (-) enantiomer of tenatoprazole can be advantageously used in the treatment of digestive pathologies where it is necessary to obtain inhibition of intense and prolonged acid secretion, such as endo-brachy-esophagus

(Barrett's esophagus) which represent pre-cancerous disorders linked to gastroesophageal reflux for which the Risk of esophageal adenocarcinoma is directly proportional to the frequency, severity and duration of episodes of gastroesophageal reflux.

The (-) enantiomer of tenatoprazole is also suitable for the treatment of Zollinger-Ellison syndrome and other acid hypersecretion syndromes, and the treatment of atypical and esophageal symptoms of gastroesophageal reflux disease, digestive hemorrhage resistant to other pump inhibitors. protons, as well as for the treatment of these diseases in polymedicated patients, in particular in patients receiving treatments involving the administration of several drugs, and more particularly elderly patients, in order to avoid incidents linked to an interaction drug. The (-) enantiomer of tenatoprazole can also be used, preferably in combination with one or more antibiotics, in the treatment of ulcers in the event of infection by Helicobacter pylori, in particular for the eradication of Helicobacter pylori to promote healing of the duodenal ulcer and to prevent any recurrence.

The (-) enantiomer of tenatoprazole, in the treatment of the pathologies indicated above, and very particularly in the treatment of endo-brachy-esophagus (esophagus of

Barrett) and Zollinger-Ellison and gastroesophageal reflux, digestive hemorrhages, can be administered in the usual forms adapted to the chosen mode of administration, for example by oral or parenteral route, preferably by oral or intravenous route .

It is possible, for example, to use formulations of tablets or capsules containing the (-) enantiomer of tenatoprazole as active ingredient, or alternatively oral solutions or emulsions or solutions for parenteral administration containing a tenatoprazole salt with a pharmaceutically acceptable carrier. usual. The enantiomer salt (-) of tenatoprazole can be chosen, for example, from sodium, potassium, lithium, magnesium or calcium salts.

By way of example, an appropriate formulation of tablets containing 30 mg of the (-) isomer of tenatoprazole combined with pharmaceutically acceptable carriers and excipients, at least one of which confers on the formulation of gastro-resistant properties, is indicated below. below:

(-) -tenatoprazole 30.0 mg lactose 40.0 mg aluminum hydroxide 17.5 mg hydroxypropylcellulose 8.0 mg talc 4.5 mg titanium dioxide 5.0 mg magnesium stearate 2.0 mg excipients q.s.p. 160.0 mg

An example of a gastric-resistant enteric capsule formulation (capsule containing acetophthalate derivatives, or a polyvinylpyrrolidone, or acrylic resins) of size 2, containing 40 mg of (-) isomer of tenatoprazole is indicated below:

(-) -tenatoprazole 40.0 mg lactose 200.0 mg magnesium stearate 10.0 mg

The dosage is determined by the practitioner depending on the patient's condition and the severity of the condition. It is generally between 10 and 120 mg, preferably between

10 and 80 mg, (-) enantiomer of tenatoprazole per day. For example, it can be administered at a dose of 1 to 2 unit doses, for example tablets, each containing 10 to 80 mg, preferably 15 or 20 to 40 or 60 mg, of active ingredient per day. for a period of time which can be between 4 and 12 weeks, in the case of an attack or maintenance treatment. In the case of a pediatric form suitable for young children, for example in the form of an oral solution, the unit dose may be more low, for example 2 or 5 mg. In severe conditions, it may be effective to administer the drug first intravenously and then orally. The invention also has the advantage of allowing effective sequential treatment by simple administration of a single tablet dosed at 60 or 90 mg per week.

One of the advantages of the present invention is to allow the treatment of the pathologies indicated above with a dosage limited to a single dose of drug per day, including in the treatment of duodenal ulcer resulting from infection by Helicobacter pylori , unlike conventional drugs, including conventional proton pump inhibitors which require two daily doses. An example of preparation of the (-) enantiomer of tenatoprazole is described below in order to illustrate the present invention.

Example

3 L of dichloromethane are introduced into a 5 L flask, followed by 360 g of 5-methoxy-2- [[4-methoxy-3, 5-dimethyl] -2-pyridyl) methyl] thio] imidazo [4, 5- b] pyridine. The mixture is left stirring at room temperature for 30 min.

700 ml of acetonitrile, 5.22 g of 2,4-di-tert-butyl-6- [li? -Hydroxy-methyl-2-methyl-propylimino) -methyl] are successively introduced into a 2 L flask. -phenol, then 2.90 g of vanadyl acetylacetonate. The mixture is stirred in air at room temperature. After 30 min of stirring this solution is added to the previous one.

To this mixture, with stirring, 135 L of 30% hydrogen peroxide are added for 20 h at room temperature. After separation of the aqueous phase, the organic phase is washed twice with water, then dried and concentrated under reduced pressure. 283 g of the desired enantiomer are obtained, with an enantiomeric excess greater than 80% (yield 75%). We performs two successive recrystallizations from a methanol / water or DMF / ethyl acetate mixture and one obtains

1 enantiomer with an enantiomeric excess greater than 99%. T _F : 127.5 ° C [α] _D : -186.6 (DMF)

UV spectrum (methanol-water): λ _max : 272 n, 315 nm.

Infrared (KBr): 3006, 1581, 1436, 1364, 1262 cm ^"1 .

¹³ C NMR (KOH, reference: 3- (sodium trimethylsilyl) -1-propanesulf onate) δ (ppm): 13.2; 15.0; 56, 6; 60.8; 62.6; 107.2; 129.5; 130.4; 131.9; 135.1; 150.5; 151.4;

156.9; 160.7; 163.0; 166.6.

^X H NMR (DMSO d _6, reference: TMS) δ (ppm): 2.20 (s, 6H), 3.70 (s, 3H), 3.91 (s, 3H), 4.69 to 4, 85 (m, 2H), 6.80 (d, J 8.5 Hz,

1H), 7.99 (d, J 8.5 Hz, 1H), 8.16 (s, H), 13.92 (s, 1H).

Claims

1. (-) -tenatoprazole, or (-) -5-methoxy-2- [[(4-metho-xy-3, 5-dimethyl-2-pyridyl) methyl] sulfinyl] imidazo [4, 5-b ] pyridine or a salt thereof, substantially free of the (+) enantiomer.

2. Pharmaceutical composition, characterized in that it comprises (-) -tenatoprazole, or (-) -5-methoxy-2- [[(4-methoxy-3, 5-dimethyl-2-pyridyl) methyl] sulfinyl ] imidazo- [4, 5-b] pyridine or a pharmaceutically acceptable salt thereof, substantially free of the (+) enantiomer, and one or more pharmaceutically acceptable excipients or carriers.

3. Composition according to claim 2, characterized in that the (-) -tenatoprazole is in the form of an alkali or alkaline earth metal salt.

4. Composition according to claim 3, characterized in that the (-) -tenatoprazole is in a salt chosen from sodium, potassium, lithium, magnesium and calcium salts.

5. Composition according to any one of claims 2 to 4, characterized in that it is in the form of a unit dose containing 10 to 80 mg of active principle.

6. Composition according to claim 2, characterized in that it comprises (-) -tenatoprazole in combination with one or more antibiotics.

7. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the treatment of digestive pathologies.

8. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of digestive pathologies where an inhibition of acid secretion must be intense and prolonged.

9. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of endo-brachy-esophages (Barrett's esophages) , atypical and esophageal symptoms of gastroesophageal reflux, and digestive hemorrhage resistant to other proton pump inhibitors.

10. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of digestive pathologies, gastroesophageal reflux, and hemorrhages digestive, in multi-drug patients.

11. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, in combination with one or more antibiotics for the manufacture of a medicament for the treatment of ulcers duodenal resulting from infection with Helicobacter pylori.

12. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the manufacture of a medicament for the prevention or treatment of recurrences of esophagitis.

13. The use of (-) -tenatoprazole substantially free of the (+) enantiomer, or of a pharmaceutically acceptable salt, for the manufacture of a medicament having improved pharmacokinetic properties.