WO2000031071A1

WO2000031071A1 - 2-alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazole-4-carboxaldehyde acetal derivatives, their preparation and use

Info

Publication number: WO2000031071A1
Application number: PCT/EP1999/008991
Authority: WO
Inventors: Rafael Foguet; Lluis Anglada; Aurelio Sacristán; Josep M. Castelló; José A. Ortiz
Original assignee: Ferrer Internacional SA
Current assignee: Ferrer Internacional SA
Priority date: 1998-11-24
Filing date: 1999-11-22
Publication date: 2000-06-02
Anticipated expiration: 2001-05-24
Also published as: ES2154191A1; AR021343A1; AU1272800A; PA8485801A1; ES2154191B1

Abstract

The present invention relates to 2-Alkyl-5-halo-3-[2'-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxaldehyde acetal derivatives of general formula (I), wherein R is an alkyl radical having 1 to 6 carbon atoms, X is a halogen atom and R1 and R2 are either alkyl radicals having 1 to 4 carbon atoms or form in conjunction with the carbon atom to which they are bound a 3- to 6-membered cycle, and n is 0 or 1, as well as pharmaceutically acceptable salts thereof. These compounds are useful in the management of hypertension.

Description

2-ALKYL-5-HALO-3- [2 ^• - (TETRAZOL-5-YL) -BIPHENYL-4-YLMETHYL] -

3H-I IDAZOLE-4-CARBOXALDEHYDE ACETAL DERIVATIVES, THEIR

PREPARATION AND USE

DESCRIPTION

The present invention relates to new 2-alkyl-5-halo-3- [2 ' ~ (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H-imidazole-4- carboxaldehyde acetal derivatives which are useful for the management of hypertension.

US Patent 5,138,069 discloses the preparation and antihypertensive properties of 2-butyl-4-chloro-l- [ [2 ' - (1H- tetrazol-5-yl) [1,1' -biphenyl] -4-yl] methyl-lH-imidazole-5- methanol (Losartan, WHO-INN) on the basis of its capacity of blocking angiotensin II receptors.

The present invention relates to 2-Alkyl-5-halo-3- [2 ' - (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H-imidazole-4- carboxaldehyde acetal derivatives of general formula (I) :

0) wherein R is an alkyl radical having 1 to 6 carbon atoms, X is a halogen atom and R_x and R₂ are either alkyl radicals having 1 to 4 carbon atoms or form in conjunction with the carbon atom to which they are bound a 3- to 6-membered cycle, and n is 0 or 1, as well as pharmaceutically acceptable salts thereof.

The term "alkyl radical" designates a lower alkyl radical having 1 to 6 and preferably up to 4 carbon atoms . Said radical may be a straight chain or branched radical .

Preferred examples include methyl, ethyl, n-propyl, i- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, etc.

The term "halogen atom" includes a fluorine, chlorine, bromine and iodine atom, a chlorine atom being preferred.

The term "3- to 6-membered cycle" designates cycloalkyl radicals having 3 to 6 and preferably up to 4 carbon atoms in the ring moiety. The cycle may be unsaturated or preferably saturated. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Particularly preferred is cyclobutyl. Together with the [1, 3] dioxan-2-yl moiety to which said cycles are attached, they form spiro units.

A preferred example of said spiro unit is 6,8- dioxaspiro [3 , 5] -non-7-yl . For n = 0 a [1, 3] dioxolan-2-yl moiety and for n = 1 a [1, 3] dioxan-2-yl moiety is formed.

The term "pharmaceutically acceptable salt" designates substitution salts of the present derivatives which can be obtained with pharmaceutically acceptable inorganic bases, in particular hydroxides. Preferred examples of inorganic salts include metal salts such as sodium, potassium, calcium, magnesium salts etc.

Particularly preferred examples include alkali metal salts, in particular potassium salts.

The term "compound" as used hereinafter includes the present derivatives as well as pharmaceutically acceptable salts thereof.

Preferred embodiments of the present invention are compounds wherein R is butyl, in particular n-butyl; X is chlorine; n is 0; and/or n is 1 and R_x and R₂ are both methyl or R_x and R₂ form in conjunction with the carbon atom to which they are bound a 4-membered saturated cycle; R is an alkyl radical having 4 carbon atoms at most, X is a halogen atom and R_x and R₂ are either alkyl radicals having 4 carbon atoms at most or form in conjunction with the carbon atom to which they are bound a 4-link cycle at most, and n is 0 or 1. The present invention also relates to a process for preparing the compounds of formula (I) as defined above, which comprises reacting an intermediate of the formula (ID :

(M) wherein R and X are as defined for (I) , with a diol of the formula (III) :

HO (CR,R₂)n

HO J

(III)

wherein R_1# R₂ and n are as defined for (I) , in the presence of a trialkyl chlorosilane, optionally followed by a salification with the corresponding base in order to obtain the pharmaceutically acceptable salt .

Preferred embodiments of said process are wherein the trialkyl chlorosilane is trimethyl chlorosilane; and/or the base is the hydroxide. For example, the compounds of the present invention may be obtained by acetalization of the aldehyde function which is present in 2-alkyl-5-halo-3- [2 ' - (tetrazol-5-yl) -biphenyl- 4-ylmethyl] -3H-imidazole-4-carboxaldehyde intermediates of general formula (II) according to the process shown in Scheme 1 :

(I)

Scheme 1 In turn, 2-alkyl-5-halo-3- [2 ' - (tetrazol-5-yl) -biphenyl-4- ylmethyl] -3H-imidazole-4-carboxaldehyde intermediates (II) may be obtained according to the process described by David J. Carini y col. (J. Med. Chem . 34, 2525-2547, 1991).

( 1 -Hydroxymethyl - cyclobutyl ) -methanol intermediate ( III , R_XR₂ : - (CH₂) ₃- , n=l ) may be obtained from 1 , 1- cyclobutan- dicarboxylic acid under the conditions described by J . Das and S . Chandrasekaran (Synthetic Communications 20 (6) , 907- 912 , 1990 ) .

The present invention also relates to a pharmaceutical composition comprising as active ingredient (s) at least one compound as defined above and a pharmaceutically acceptable carrier. Optionally, other therapeutic ingredient (s) may be present .

Pharmaceutically acceptable carriers are well known in the art. The present compositions include those in a form suitable for oral, rectal, parenteral (including subcutaneous, intramuscular, intravenous and intraperitoneal) administration.

Compositions suitable for oral administration are advantageous and may be in the form of descret units such as capsules, sachets, tablets or lozenges; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or water-in-oil emulsion.

The compositions may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. Commonly, said preparation includes a step of bringing the active ingredient into association with the carrier.

The compounds of the present invention are angiotensin II antagonists and they are useful for the management of hypertension in man and mammals. Thus, the present invention also relates to the use of at least one compound as defined above for preparing a pharmaceutical composition for the treatment of hypertension. Treatment means treating patients, in particular mammals and preferably humans in need of such a treatment by administering to said patients an effective amount of at least one compound as defined above, if necessary together or concomitantly with one or more other therapeutically active components.

The present compounds have advantages over Losartan as evidenced in the following pharmacological tests: a) Effect on arterial blood pressure in furosemide- pretreated conscious rats after oral administration Following activation of the renin-angiotensin system, endogenous angiotensin II is the substrate responsible for the generation of hypertension, mostly because of vasoconstriction by AT_X vasoreceptor stimulation. The assessment of antihypertensive agents inhibiting the endogenous stimulation of AT., receptors is performed in experimental models. Normotensive animals are administered with repeated subcutaneous injection of furosemide provoking the release of renin by renal juxtaglomerular cells, which results in the formation of angiotensin I from its angiotensinogen. Angiotensin I is converted by its conversion enzyme in angiotensin II, which is a substrate of potent vasoconstrictive action and is responsible for the generation of hypertension.

For the practical performance of this experiment, male Sprague-Dawley normotensive rats were used. The animals were subcutaneously injected with furosemide at doses of 10 mg/kg on two consecutive days, and from that time (2nd day; time 0) they were deprived of water and food. At 4 h the test compounds were administered orally, and an arterial blood sample was collected for determination of baseline hematocrit. Then mean arterial blood pressure (MABP) , being ABP = (SABP + DABP) /2 (SABP = Systolic arterial blood pressure; DABP = Diastolic arterial blood pressure) , was measured at the beginning of the experiment (baseline) and at every hour. The compound used as a standard was losartan potassium. Losartan at an oral dose of 3 mg/kg decreased remarkably the MABP after 1 h of the administration down to a maximum of 14.8 mmHg at 5 h, the baseline value being 126 ± 10.3 mmHg, which corresponds to an 11.7% reduction in comparison with baseline value.

At an oral dose of 10 mg/kg, losartan potassium decreased the MABP down to a maximum of 26 mmHg at 5 h, the baseline value being 119.3 ± 9.77 mmHg, which corresponds to a 21.8% reduction in comparison with baseline value.

The compound of Example 6 at an oral dose of 3 mg/kg produced a significant continual reduction to the MABP in comparison with baseline value already since 1 h and down to 21.0 mmHg at 5 h, which corresponds to a 17.3% reduction versus baseline value of 121.3 ± 3.72 mmHg.

At an oral dose of 10 mg/kg, the compound of Example 6 reduced significantly the MABP in comparison with baseline value already since 1 h and down to 29.3 mmHg at 5 h. This reduction corresponds to 25.38% versus baseline value of 118.2 ± 7.24 mmHg.

According to the results obtained in furosemide-pretreated conscious rats, it is observed that the antihypertensive effect of the compound of Example 6 by the oral route is higher than that of losartan potassium both at a dose of 3 mg/kg (« 1.5 times) and at a dose of 10 mg/kg A 1.2 times) . b) Effect on furosemide- and angiotensin II-induced hyperdipsia in rats after oral administration The repeated subcutaneous administration of furosemide provokes the activation of the renin-angiotensin- aldosterone system (RAAS) , which results in a slight increase of arterial blood pressure and, in addition, in the induction of thirst (dipsogen effect) . The combination of both pretreatments (furosemide plus angiotensin II) by subcutaneous route increases the RAAS-related dipsogen effect.

For the practical performance of this experiment, male Sprague-Dawley rats weighing 170-200 g under fasting and deprived of water were used. Furosemide was administered twice (26 h and 4 h) at the dose of 10 mg/kg/s.c. each before starting (90 m) the water consumption reading. Test compounds were administered orally on the 2nd day 4 hours earlier. Angiotensin II was administered subcutaneously at the dose of 200 μg/kg (2 x 100 μg/kg; bilateral) half an hour before starting (90 m) the water consumption reading.

Under these experimental conditions, the 25% inhibitory dose (ID₂₅) resulted in an ID₂₅ = 7.47 mg/kg for the compound of Example 2, and an ID₂₅ = 1.86 mg/kg for the compound of Example 6. The standard compound, losartan potassium, showed an ID₂₅ = 14.2 mg/kg. It can, therefore, be concluded that in this experiment the compound of Example 2 is nearly 2 times more potent than losartan potassium, and the compound of Example 6 is 7 times more potent than losartan potassium.

c) Effect on arterial blood pressure in conscious rats with renal hypertension after oral administration The surgical operation applied according to the technique of Cangiano et al. (total ligature of left renal artery) (J. Pharmacol . Exp . Ther. 208, 310-313, 1978) provokes an evident activation of RAAS within 7-8 days postoperation. For the practical performance of this experiment, male Sprague-Dawley rats with mean weight of 270.7 + 18.8 g were used. The rats were allowed to remain in the animal facilities for a 5-6 day recovery period. Four hours prior to drug administration, food was withdrawn. One hour prior to drug administration, recording (polygraph) of mean arterial blood pressure (MABP) was started. After 1 h the initial mean arterial blood pressure (MABP₀) was measured. An arterial blood sample was collected for determination of baseline hematocrit . Then, test compounds were orally administered. Thus, MABP (SABP + DABP) /2 and baseline MABP₀ of each animal were measured at 5 h of treatment. The reduction rate of MABP at 5 h was adopted as the efficacy measurement of compounds. Likewise, the effect duration was observed by means of a final evaluation at 22 h. In losartan potassium treated animals at 3 mg/kg and 10 mg/kg p.o., the MABP₀ (176.0 ± 23.05 and 174.0 ± 18.2 mmHg, respectively) was reduced to a mean value of 50.3 mmHg (28.6% decrease) and 73.2 mmHg (42.05% decrease) respectively at 5 h. Following administration of the compound of Example 6 at 3 mg/kg and 10 mg/kg p.o., the MABP₀ (169.1 ± 15.65 and 163.6 ± 29.9 mmHg respectively) was reduced to a mean value of 49.4 mmHg (29.2% decrease) and 59.1 mmHg (36.1% decrease) respectively at 5 h.

The compound of Example 6 showed a similar profile to that of losartan potassium. However, the antihypertensive effect of the compound of Example 2 was reached 1 h more rapidly and more significantly than with losartan potassium (p< 0.05) at single oral doses of 10 mg/kg.

These findings are of great therapeutic importance and allow the use of the compounds of the present invention as antihypertensive agents.

Example 1; 5-{4 ' - [2-n-butyl-4-chloro-5- (5, 5-dimethyl- [1,3]

dioxan-2-yl) -imidazole-1-ylmethyl] -biphenyl-2-yl } -tetrazol

To a 250-ml flask provided with a magnetic stirrer, a reflux cooler and an inert atmosphere operating device were placed: 1.38 g (13.2 mmoles, 2.2 eq.) of 2, 2 -dimethyl propanodiol, 2.53 g (6 mmoles, 1 eq.) of 2-n-butyl-5- chloro-3- [2 ' - (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H- imidazole-4-carboxaldehyde and 35 ml of dry methylene chloride. Under a nitrogen atmosphere, 2.87 g (26.4 mmoles, 4.4 eq.) of trimethyl chlorosilane and 5 ml of methylene chloride were added. The reaction mixture was refluxed for 72 hours (always under inert atmosphere) . Thereafter, the mixture was allowed to temper, 60 ml of a 5% sodium bicarbonate aqueous solution were added, stirred for 15 min and the two phases were decanted. The aqueous phase was removed with 40 ml of methylene chloride, and the collected organic phases were washed with 2 x 50 ml of sodium' chloride saturated solution and 50 ml of water. The organic phase was dried over magnesium sulphate and evaporated to yield 3.91 g of an amorphous solid which corresponds basically to a mixture of the reaction product and hexamethyl disiloxane. Crystallization of this solid in 100 ml of ethyl ether gave 2.64 g of product (86% yield) . 'H-NMR (DMSO-d₆) δ 7.80-7.44 (m, 4H) , 7.05 (d, 2H, J= 8.1

Hz), 6.80 (d, 2H, J= 8.1 Hz), 5.43 (s, 1H) , 5.40 (s, 2H) , 3.60 (d, 2H, J=10.5 Hz), 3.50 (d, 2H, J=10.5 Hz), 2.21 (t, 3H, J=7.5 Hz), 1.42 (m, 2H) , 1.18 (m , 2H) , 1.06 (s, 3H) , 0.78 (t, 3H, J= 7.5 Hz), 0.73 (s, 3H) .

Example 2 ; 5-{4 ' - [2-n-butyl-4-chloro-5- (5, 5-dimethyl- [1,3]

dioxan-2-yl) -imidazole-1-ylmethyl] -biphenyl-2-yl} -tetrazol potassium salt

To a 100-ml flask provided with a magnetic stirrer, a pH monitoring electrode and a cooling bath are placed: 2.59 g (5.10 mmoles) of the product obtained in Example 1 and 50 ml of water. To the formed suspension, which was allowed to stand at the temperature of about 20°C, 5 ml (5 mmoles) of 1M KOH were slowly added. The resultant solution was freeze-dried to give 2.79 g of product (100% yield). 'H-NMR (DMSO-d₆) δ 7.56-7.25 (m, 4H) , 7.08 (d, 2H, J= 8.1 Hz), 7.01 (d, 2H, J= 8.1 Hz), 5.61 (s, 1H) , 5.41 (s, 2H) , 3.7-3.6 (m,4H), 2.36 (t, 3H, J= 7.5 Hz), 1.36 (m, 2H) , 1.20 (m, 2H) , 1.14 (s, 3H) , 0.75 (t, 3H, J= 7.5 Hz), 0.72 (s, 3H) . IR(KBr) υ 3400, 2920, 1459, 1256, 1094, 1020 and 1010 cm¹.

Example 3 ; 5-{4 ' - [2-n-butyl-4-chloro-5- (6, 8-dioxa-

spiro [3 , 5] non-7-yl) -imidazole-1-ylmethyl] -biphenyl-2-yl } - tetrazol

To a 100-ml flask provided with a magnetic stirrer, a reflux cooler and an inert atmosphere operating device were placed: 1.13 g (9.7 mmoles, 2.2 eq.) of (1-hydroxymethyl- cyclobutyl) -methanol , 1.86 g (19.4 mmoles, 2 eq.) of 2-n- butyl-5-chloro-3- [2 ' - (tetrazol-5-yl) -biphenyl-4-ylmethyl] - 3H-imidazole-4-carboxaldehyde and 25 ml of dry methylene chloride. Then, 2.11 g (19.4 mmoles, 4.4 eq.) of trimethyl chlorosilane were added, and the reaction mixture was heated at reflux under a nitrogen atmosphere for 72 hours . Thereafter, the mixture was allowed to temper, 45 ml of a 5% sodium bicarbonate aqueous solution were added, stirred for 15 min and the two phases were decanted. The aqueous phase was removed with 2 x 25 ml of methylene chloride, and the collected organic phases were washed with 2 x 30 ml of sodium chloride saturated solution and 30 ml of water. The organic phase was dried over magnesium sulphate and evaporared to dryness to yield 2.57 g of an amorphous solid which corresponds basically to a mixture of the reaction product and hexamethyl disiloxane. Crystallization of this solid in 65 ml of ethyl ether gave 2.06 g of product (90% yield) . ^XH-NMR (DMS0-d₆) δ 7.81-7.42 (m, 4H) , 7.04 (d, 2H, J= 8.1 Hz), 6.74 (d, 2H, J= 8.1 Hz), 5.42 (s, 1H) , 5.25 (s, 2H) , 3.91 (d, 2H, J= 11.4 Hz), 3.53 (d, 2H, J=11.4 Hz), 2.18 (t, 2H, J= 7.8 Hz), 1.89 (m, 4H) , 1.53 (m, 2H) , 1.48 (m, 2H) , 1.2-1.08 (m,2H), 0.77 (t, 3H, J= 7.8 Hz). IR (KBr) υ 2950, 1490, 1270, 1090 and 1080 cm^"1. Melting point: 193-194.1 °C

Example 4 : 5- {4 ' - [2-n-butyl-4-chloro-5- (6, 8-dioxa-

spiro [3 , 5] non-7-yl) -imidazole-1-ylmethyl] -biphenyl-2 -yl } - tetrazol potassium salt

To a 100-ml flask provided with a magnetic stirrer, a pH monitoring electrode and a cooling bath are placed: 1.90 g (3.66 mmoles) of the product obtained in Example 3 and 40 ml of water. To the formed suspension, which was allowed to stand at the temperature of about 20°C, 3.66 ml (3.66 mmoles) of IM KOH were slowly added. The resultant solution was freeze-dried to give 2.02 g of product (100% yield) . 'H-NMR (DMSO-d₆) δ 7.58-7.26 (m,4H) , 7.08 (d, 2H J= 8.4 Hz) ,

6.8 (d, 2H, J= 8.4 Hz), 5.63 (s, 1H) , 5.34 (s, 2H) , 4.02 (d, 2H, J= 11.4 Hz) , 3.66 (d, 2H, J= 11.4 Hz) , 2.34 (t, 2H, J= 7.5 Hz) , 2.0-1.75 (m, 4H) , 1.5 (m, 2H) , 1.48 (q, 2H) , 1.25-1.1 (m, 2H) , 0.75 (t, 3H, J= 7.5 Hz) .

IR (KBr) υ 2950, 2910, 1490, 1250, 1090 and 1010 cm^"1.

Example 5; 5- [4 ' - (2-n-butyl-4-chloro-5- [1, 3] dioxolan-2-yl-

imidazole-1-ylmethyl) -biphenyl- 2 -yl] -tetrazol

To a 250-ml flask provided with a magnetic stirrer, a reflux cooler and an inert atmosphere operating device were placed: 1.64 g (26.4 mmoles, 2.2 eq.) of ethylene glycol , 5.05 g (12 mmoles, 1 eq.) of 2-n-butyl-5-chloro-3- [2 ' - (tetrazol-5-yl) -biphenyl-4-ylmethyl] -3H-imidazole-4- carboxaldehyde and 65 ml of dry methylene chloride. Under a nitrogen atmosphere, 5.74 g (52.8 mmoles, 4.4 eq.) of trimethyl chlorosilane and 10 ml of methylene chloride (this latter is used to wash out the trimethyl chlorosilane) were added. The reaction mixture was refluxed for 72 hours (always under inert atmosphere) . Thereafter, the mixture was allowed to temper, 120 ml of a 5% sodium bicarbonate aqueous solution were added, stirred for 15 min and the two phases were decanted. The aqueous phase was removed with 50 ml of methylene chloride, and the collected organic phases were washed with 2 x 100 ml of sodium chloride saturated solution and 100 ml of water. The organic phase was dried over magnesium sulphate and evaporared to dryness to yield 6.11 g of an amorphous solid which corresponds basically to a mixture of the reaction product and hexamethyl disiloxane. Crystallization of this solid in a mixture of 150 ml of cyclohexane and 50 ml of absolute ethanol gave 4.56 g of product (82% yield). ^XH-NMR (DMS0-d₆) δ 7.80-7.42 (m,4H), 7.05 (d, 2H, J= 8.4

Hz), 6.82 (d, 2H, J= 8.4 Hz), 5.78 (s, 1H) , 5.1 (s, 2H) , 3.82 (m, 4H) , 2.34 (t, 2H, J= 7.2 Hz), 1.5 (m, 2H) , 1.23 (m, 2H) , (m,2H), 0.8 (t, 3H, J= 7.2 Hz).

IR (KBr) υ 2980, 1583, 1466, 1260, 1049 and 954 cm^"1. Melting point: 111-113 °C

Example 6 ; 5- [4 ' - (2-n-butyl-4-chloro-5- [1, 3] dioxolan-2-yl-

imidazole-1-ylmethyl) -biphenyl -2 -yl] -tetrazol potassium salt

To a 100-ml flask provided with a magnetic stirrer, a pH monitoring electrode and a cooling bath are placed: 4.26 g (8.37 mmoles) of the compound of Example 5 and 80 ml of water. To the formed suspension, which was allowed to stand at the temperature of about 20°C, 8.33 ml (8.33 mmoles) of IM KOH were slowly added. The resultant solution was freeze-dried to give 4.27 g of product (100% yield) . ^XH-NMR (DMS0-d₆) δ 7.39-6.80 (m, 4H) , 6.64 (d, 2H, J= 8.1

Hz), 6.49 (d, 2H, J= 8.1 Hz), 5.58 (s, 1H) , 4.76 (s, 2H) , 3.5 (s, 4H) , 2.07 (t, 3H, J= 7.8 Hz), 1.08 (q, 5H) , 0.78 (sext, 2H) , 0.38 (t, 3H, J= 7.8 Hz). IR (KBr) υ 2920, 1459, 1257, 1083, 1046 and 762 cm^"1.

Example 7 : Coated tablet formulation

5- [4 ' - (2-n-Butyl-4-chloro-5- [1, 3] dioxolan-2-yl- imidazole-1-ylmethyl) -biphenyl-2-yl] -tetrazol potassium salt 50 mg Lactose dihydrate 40 mg

Pregelatinized starch 8 mg

Microcrystalline cellulose 150 mg

Magnesium stearate 2 mg

Hydroxypropylmethylcellulose 6 cps 9 mg Titanium dioxide 1 mg

Claims

1. 2 -Alkyl - 5-halo-3 - [2 ' - (tetrazol- 5-yl) -biphenyl -4-

ylmethyl] -3H-imidazole-4-carboxaldehyde acetal > derivatives of general formula (I) :

(I) wherein R is an alkyl radical having 1 to 6 carbon atoms, X is a halogen atom and R and R₂ are either alkyl radicals having 1 to 4 carbon atoms or form in conjunction with the carbon atom to which they are bound a 3- to 6-membered cycle, and n is 0 or 1, as well as pharmaceutically acceptable salts thereof.

2. The compounds according to claim 1, wherein R is n-

butyl .

3. The compounds according to claim 1, wherein X is

chlorine .

4. The compounds according to claim 1, wherein n is 0.

5. The compounds according to claim 1, wherein n is 1 and R-_L and R₂ are methyl .

6. The compounds according to claim 1, wherein n is 1 and

R-_L and R₂ form in conjunction with the carbon atom to which they are bound a 4-membered saturated cycle.

7. The compounds according to claim 1, wherein the pharmaceutically acceptable salts are potassium salts.

8. A pharmaceutical composition comprising at least one compound as defined in any of the preceding claims and a pharmaceutically acceptable carrier.

9. The use of a at least one compound as defined in any of claims 1 to 7 for preparing a pharmaceutical composition for the treatment of hypertension.

10. A process for preparing the compounds of formula (I)

as defined in any of claims 1 to 7, which comprises reacting an intermediate of the formula (II) :

(II) wherein R and X are as defined for (I) , with a diol of the formula (III) :

HO (CR,R₂)n HO^

(III) wherein R_1# R₂ and n are as defined for (I) , in the presence of a trialkyl chlorosilane, optionally followed by a salification with the corresponding base in order to obtain the pharmaceutically acceptable salt.

11. The process according to claim 10, characterized in

that the trialkyl chlorosilane is trimethyl chlorosilane.

12. The process according to claim 10, characterized in

that the base is the hydroxide.