FR2578544A1 - Antihypertension spirocyclic compounds - Google Patents

Abstract

Compounds corresponding to the expanded formula: and their pharmaceutically acceptable salts. These compounds have an antihypertension activity.

Description

ANTI-HYPERTENSIVE SPIRO-CYCLIC COMPOUNDS
The present invention relates to compounds, their pharmaceutically acceptable salts and pharmaceutical preparations made therefrom, useful in the treatment of hypertension in subjects suffering from hypertension.

et leurs sels d'addition aux acides, leurs sels de métaux alcalins et leurs sels de métaux alcalino-terreux pharmaceutiquement acceptables, dans laquelle
Q est Y-C(O)-C*H(R1)-NH-, -NH2,
R1-C(O)-S-(C*H(R1))0-1-, ou HS-(C*H(R1))0-1 ;;
Y1 et Y2 sont indépendamment -OH, -OR, ou -NR1R2
un des indices x et y est égal à 1 et l'autre est égal à 0
R, R1, R2, R4 et R5 sont indépendamment l'hydrogène, un alkyle en C1-C8, un aryle ayant jusqu'à 12 atomes de carbone, un aryl -alkyle dans lequel la partie aryle a jusqu'à 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle en C3-C10, un cyclo alkylaryle condensé en C8-C12, un groupe hétérocyclique ou un groupe alkylamino substitué ayant 1 à 6 atomes de carbone
A, B et E sont indépendamment H, un halogène, -OH, -OR, -CF3, -NR1R21 -C(O)Y1' -S02R, ou S02NR1R2 pourvu qu'au moins deux des radicaux A, B et E ne soient pas H
X1est-(CH2)a-, -(CH2)b @(CH2)c-,
CCH2)bCCO)(CH2)c,. ou -(CH2)bCH(R3) (CH2)C-;
X2est - (CH2)d-, - (CH2)e S(CH2)f-,
-(CH2)e C(O) (CH2)f-, ou -(CH2)e CH(R3) (CH2)f- ;
pourvu que a et d soient chacun 0-4 ; b, c, e et f soient chacun 0-3 ; (a+d) soit 2-4 ; (a+e+f) soit 1-3 ; (b+c+d) soit 1-3 ; et (b+c+e+f) soit 0-2 ; et
R3 est -OH, un phényle ou un groupe alkyle ou alcoxy ayant jusqu'à 6 atomes de carbone
dans laquelle les groupes alkyle, cycloalkyle, aryle et aryl-cycloalkyle condensé peuvent porter des substituants choisis parmi le groupe constitué d'un alcoxy en
C1-C6, d'un alkyle en C1-C6, de -CF3, -OH, -SH, halogène, -NO2 et -COOR.In general, the present invention relates to compounds corresponding to formula (1)

and their acid addition salts, their alkali metal salts and their pharmaceutically acceptable alkaline earth metal salts, wherein
Q is YC (O) -C * H (R1) -NH-, -NH2,
R1-C (O) -S- (C * H (R1)) 0-1-, or HS- (C * H (R1)) 0-1 ;;
Y1 and Y2 are independently -OH, -OR, or -NR1R2
one of the indices x and y is equal to 1 and the other is equal to 0
R, R1, R2, R4 and R5 are independently hydrogen, C1-C8 alkyl, aryl having up to 12 carbon atoms, arylalkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a C3-C10 cycloalkyl, a C8-C12 condensed alkylaryl cyclo, a heterocyclic group or a substituted alkylamino group having 1 to 6 carbon atoms
A, B and E are independently H, halogen, -OH, -OR, -CF3, -NR1R21 -C (O) Y1 '-S02R, or S02NR1R2 provided that at least two of the radicals A, B and E are not not H
X1 is- (CH2) a-, - (CH2) b @ (CH2) c-,
CCH2) bCCO) (CH2) c ,. or - (CH2) bCH (R3) (CH2) C-;
X2 is - (CH2) d-, - (CH2) e S (CH2) f-,
- (CH2) e C (O) (CH2) f-, or - (CH2) e CH (R3) (CH2) f-;
provided that a and d are each 0-4; b, c, e and f are each 0-3; (a + d) or 2-4; (a + e + f) or 1-3; (b + c + d) or 1-3; and (b + c + e + f) either 0-2; and
R3 is -OH, phenyl or an alkyl or alkoxy group having up to 6 carbon atoms
wherein the condensed alkyl, cycloalkyl, aryl and aryl-cycloalkyl groups may carry substituents selected from the group consisting of alkoxy in
C1-C6, C1-C6 alkyl, -CF3, -OH, -SH, halogen, -NO2 and -COOR.

et R2 est de préférence
NH2(CH2)4
A est -NH2 ; -OH ; un phénoxy ; un alcoxy ayant jusqu'à 6 atomes de carbone ; -SO2NR1R2 dans lequel R1 et R2 sont l'hydrogène, un méthyle, ou un alkyle en C2-C3, et de préférence tous deux l'hydrogène
B est un halogène, et de préférence un chloro ; ou -CF3 ; et E est un halogène ou l'hydrogène.Preferred substituents within the scope of the present invention include those in which
Y1 and Y2 are independently hydroxy or alkoxy containing up to 8 carbon atoms
R1 is H; an alkyl having 1 to 8 carbon atoms; phenyl-alkyl in which the alkyl has 1 to 4 carbon atoms, and preferably phenetyl; or An indanyl, for example a 2-indanyl;
R2 is H; an alkyl having 1 to 8 carbon atoms; or an alkyl group having 1 to 8 carbon atoms, which is substituted by an amino or by an amino derivative such as -NH-C (NH2) = NH, or

and R2 is preferably
NH2 (CH2) 4
A is -NH2; -OH ; phenoxy; an alkoxy having up to 6 carbon atoms; -SO2NR1R2 in which R1 and R2 are hydrogen, methyl, or C2-C3 alkyl, and preferably both hydrogen
B is halogen, and preferably chloro; or -CF3; and E is halogen or hydrogen.

 The ring formed by X1, X2, and the atoms to which they are linked, contains a total of 5, 6 or 7 atoms. In a preferred embodiment, X1 and X2 are both -CH2-, thus forming a proline ring. X1 or X2 may other substituted by a group R3 which is preferably -OH or a C1-C6 alkyl. Preferred substituents for R4 and R5 are -H, or alkyl having 1 to 2 carbon atoms.

 The alkyl groups include straight or branched chain groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, iso-amyl, hexyl, and the like. Halogen "means chloro, bromo, iodo and fluoro.

 Preferred substituents for R1 and / or R2 also include cycloalkyl groups, aryl groups, heterocyclic groups, and fused aryl-cycloalkyl groups, as defined herein, any of which may be further related to the main chain of the molecule (1) directly or through an alkylene bridge - (CH2) n - where n is a number of .1: -à. 6. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, or norbornyl. Preferred condensed aryl and aryl-cycloalkyl groups include phenyl, indolyl, indolino, indanyl, naphthyl, tetrahydronaphtyl, and decahyd. Preferred heterocyclic groups include the pyridyl, quinoleyl, isoquinoleyl, tetrahydroquinoleyl, tetrahydroisoquinoleyl, decahydroquinoleyl, decahydroisoquinoleyl, pyrrolidyl, pyrrolyl, morpholinyl, furyl, tetrahydro-furyl, furyluryl, benzimidyl group.

Preferred aryl alkyl substituents include benzyl and phenethyl groups. Preferred substituents over the alkyl, cycloalkyl, aryl and aryl-cycloalkyl substituents
condensates include C1-C6 alkyl and alkoxy,
-CF3, -OH, -NH21 phenoxy, -NR1R2, -COOH, -CN, -SH, a
halogen, -NO2, and COOR, and in particular a COO-alkyl
in Cl C6.

Compounds according to formula (1) can
contain asymmetric centers on the marked carbon atoms: C =. Each of these carbon atoms can have a
configuration (R) or (S), preferably (S). In the
preferred compounds, the spiro carbon is (S) or (R) and the other asymmetric carbons are in the (S) configuration.

Individual optical diastereoisomers as well as
mixtures of these are considered to fall within the
field of the invention. The invention also covers in
particular of the compounds (S, S, S, S) and (S, S, S, R) and
mixtures thereof; as well as compounds (S, S, S)
and (S, S, R) and mixtures thereof. When the fashions
synthetic operating systems provide diastero products
isomers, the desired diastereoisomeric product can be
separated by conventional chromatography methods or
of fractional crystallization.

puis oxydation du groupe @ CHOH en C=O et réaction de ce produit avec le composé (4)

The compounds corresponding to formula (1) may other
prepared by coupling of compounds corresponding to the formulas
(2) and (3)

then oxidation of the group @ CHOH to C = O and reaction of this product with the compound (4)

The two groups -NH2 react with the group C = O to form the desired spiro bond. The various substituents on compounds (2), (3) and (4) have been defined above.

Specialists will realize that the coupling of compounds (2) and (3) can be carried out by conventional peptide bonding techniques, for example in the presence of a coupling agent such as DCC (N, N'-dicyclohexylcarbodiimide) or CDI (N, N'-carbonyldiimidazole). It may also be preferable to transform the -COOH group of the compound (2) into -C (O) Cl, then react the intermediate obtained with the compound (3). It is also possible, preferably, to transform the compound (2) into the corresponding N-carboxyanhydride (NCA) by letting (2) react with phosgene, then react the N-carboxyanhydride obtained with the compound (3) to give the You can also prepare the amino spiro ester by first reacting (4) with the ketone derived from (3) by oxidation, then reacting (2) with the spiro amino ester obtained by one any of the above pathways (NCA; acid chloride; or active ester-peptide coupling) to give the desired intermediate. We will also realize that the nitrogen atom which is between the carbon atoms to which
R1 and R2 are attached can be protected by a blocking group such as the 2,2,2-trichlorethoxycarbonyl group or the benzyloxycarbonyl group. The protective group is then removed, preferably after the compounds (2), (3) and (4) have been combined. Other nitrogen atoms, in substituents such as NH2 (CH2) 4-, must be protected and seeded in a similar manner. Similarly, Y1 and Y2 are preferably transformed into ethoxy, into t-butoxy or benzyloxy, before the intermediates are reacted. If the free acid is desired, it is obtained subsequently by elimination of the esterifying group in a known manner.

 The compounds of the present invention in which one of Y1 and Y2 is -OH and the other is alkyl, such as methoxy or ethoxy, are preferably prepared by reacting the compounds (2) and (3) As indicated above above, in which one of the radicals Y1 and Y2 is the desired alkyl ester, and the other is an easily separated ester group, such as t-butoxy. The amide intermediate thus prepared is oxidized and reacted with (4) to give the corresponding intermediate, which, by gentle acid hydrolysis, gives the desired monoesters-monoacids.

 When Q contains sulfur, the preferred synthetic route is via the acid chloride.

The compounds of the present invention form salts with various mineral and organic acids and bases which also belong to the field of the invention. These salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases, for example dicyclohexylamine salts,
N-methyl-D-glucamine, salts with amino acids such as arginine, lysine and the like. It is likewise possible to prepare salts with mineral and organic acids, for example HCl, HBr, H2SO4, H3PO4, as well as methanesulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, malic acid, citric acid, fumaric acid and camphrosulfonic acid.

Physiologically acceptable non-toxic salts are preferred, although other salts are also usable, for example to isolate or purify the product.

 The salts can be formed by conventional means, for example by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvar.t or n! I.liell in which salt is insoluble, or in a solvent such as water, which is then removed in vacuo by lyophilization, or by exchanging the cations of an existing salt for another cation on an appropriate ion exchange resin.

 The action of the enzyme renin on angiotensinoqene, a pseudoglobulin from human plasma, produces the decapeptide angiotensin I. Angiotensin I is transformed by the enzyme transforming angiotensin (ACE) into the octapeptide angiotensin II. The latter is a vasopressive substance which has been implicated as a causative agent in various forms of hypertension in various species of mammals, for example the rat and the dog. The compounds falling within the scope of the invention which are involved in the renin-angiotensin I-arHgi.otensin II sequence inhibit the enzyme transforming angiotensin I, and therefore are useful for reducing or relieving hypertension.

 Furthermore, the compounds within the scope of the present invention which possess diuretic activity promote the relief of hypertension by promoting diuresis and therefore are useful for the treatment of congestive heart failure. The compounds falling within the scope of the invention can also simultaneously possess an ACE inhibiting activity and a diuretic activity, which is particularly unexpected in view of the fact that this simultaneous activity cannot be predicted from the compounds of the prior art. Thus, by administration of a composition containing a compound of formula (1) or a combination thereof or their pharmaceutically acceptable salts, hypertension is relieved in species of mammals which suffer therefrom. A single dose, or preferably two to four divided doses per day, provided on the basis of about 0.1 to 100 mg / kg per day, preferably about 1 to 50 mg / kg per day is suitable for reducing blood pressure. The substance is preferably administered orally, but a parenteral route such as a subcutaneous, intramuscular, intravenous or intraperitoneal route can also be used.

 The compounds of the invention can be used to achieve the reduction of blood pressure by formulating one or more of them in compositions such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound or mixture of compounds corresponding to formula (1) or their physiologically acceptable salts are mixed with a vehicle, support, excipient, binder, preservative, stabilizer, perfume, etc. physiologically acceptable, in unit dose form as claimed by established pharmaceutical practice. The amount of active substance in these compositions or preparations is such that an appropriate dose is obtained within the indicated range.

 As examples of the adjuvants which can be incorporated into tablets, capsules, etc., there may be mentioned: a binder such as tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin; a fragrance such as peppermint, sassafras essence or cherry essence.

When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid excipient such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dose unit.

For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabeno as preservatives, a color and a perfume such as a cherry or orange fragrance.

 The sterile compositions for injection can be formulated in accordance with conventional pharmaceutical practice, by dissolving or suspending the active substance in a vehicle such as water for injection, a natural vegetable oil such as sesame oil, coconut oil peanut oil, cottonseed oil, etc. or a synthetic fatty vehicle such as ethyl oleate, and the like. Buffers, preservatives, antioxidants, and the like can be incorporated if necessary.

 Particular embodiments of the invention are illustrated in the following examples.

A. 4-Hydroxy- ethyl ester hydrochloride
L-proline
To a solution of ethyl ester of N-Cbz-4-hydroxy
L-proline (3.29 g) in 40 ml of ethanol, 6 ml of ethanol saturated with BCl gas is added, then 10% palladium on carbon (0.50 g). The mixture is hydrogenated in a Parr hydrogenator at 207 to 276 kPa for 3 hours.

The solution is filtered through Celait and is applied under vacuum, which gives 2.09 g of the crystalline product.

B. N- [N - [(1S) -1- (ethoxycarbonyl) 3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanyl] -4-hydroxy-L-proline ethyl ester
A N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanine (5.94 g, 13.07 mmol) in 50 ml of meffQibne chloride, under nitrogen, oxalyl chloride (5.70 ml, 65.33 mmol) is added, followed by N, N-dimethylformamide (20 μl). The solution is stirred for 3.5 hours and concentrated in vacuo. The residue is diluted with 30 ml of methylene chloride and cooled in an ice bath while it is under N2. To this solution, a mixture of 4-hydroxy-Lproline ethyl ester hydrochloride (1.96 g, 10.05 mmol) and triethylamine is added in successive portions.
(6.99 ml, 50.25 mmol) in 40 ml of methylene chloride.

When the addition is complete, the solution is slowly warmed to room temperature, stirred for 18 hours and concentrated in vacuo. The residue is dissolved in ether and washed with water, 10% hydrochloric acid, 1N sodium hydroxide and brine, and dried over magnesium sulfate, then concentrated under vacuum. Chromatography of the residue by HPLC using 50% ethyl acetate in hexanes as eluents provides 2.44 g (41%) of the oily product.

C. N-1N ethyl ester - [(1S) -1- (ethoxycarbonyl) - 3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl] -L-alanyl]
L-prolin-4-one.

 To a solution of ethyl ester of N- (N - ((ÎS) -1- (ethoxycarbonyl) -3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanyl] -4-hydroxy -L-proline (2.21 g, 3.71 mmol) in 30 ml of methylene chloride, pyridinium chlorochromate (PCC) (1.60 g, 7.43 mmol) is added.

The mixture is stirred for 28 hours and additional PCC (1.60 g) is added. The mixture is stirred for 72 hours and the solution of the solid residue is decanted. The residue is triturated with ether. The combined organic solutions are passed through a pad of silica gel. By concentrating the filtrate under vacuum, 2.1 g (95%) of the oily product are obtained, which is used without further purification.

D. Spirof (7) -sulfonamyl-6-chloro-3 ethyl ester! 4-dihydro-2H-1,2,4-benzothiadiazineu dioxide) - 3,4 '- [N- [N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -N (2,2,2 -trichlorethoxycarbonyl) -L-alanyl] L-proline]]
To a solution of ethyl ester of N- [N - [(ÎS) -1- (ethoxycarbonyl) -3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanyl] -L-prolin -4-one (1.01 g, 1.70 mmol) and 1-amino-3-chloro-4,6-benzenedisulfamide (0.511 g, 1.79 mmol-) in 15 ml of ethanol, 2 ml of ethanol saturated with gaseous HCl. The solution is heated to 650C for 1.5 hours and concentrated in vacuo. The residue is chromatographed by HPLC using 60% ethyl acetate in hexane as diluent, which gives the solid product.

E. Spiro ethyl ester hydrochloride [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine l, l-dioxide) -3,4'-tN- E (1S) -l-tethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline]]
To a spirot ethyl ester solution (7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine1,1-dioxide) -3,4 '- [N- [N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanyl] -Lproline]] (0.55 g) in 7 ml of acetic acid freezing, zinc powder (1.5 g) is added. The mixture is stirred at room temperature for 1.1 hours, filtered through Celite and gaseous HCl is added to the filtrate. The solution is concentrated in vacuo and the residue is triturated with 20% ethyl acetate in ether, which gives the crystalline product, having the following structural formula

EXAMPLE 2
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '- [N [N- r (ls) -l- (hydroxyearbonyl) -3-phenylpropyl] -L-alanyl] -L- proline j
To a solution of spiro ethyl ester hydrochloride [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '- [ N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -L-proline]] (0.60 g) in 5 ml of ethanol, aqueous sodium hydroxide is added (8.3 ml of a 1N solution). The solution is stirred at room temperature for 20 hours, acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The organic bottles are washed in brine, dried over MgSO 4 'and then concentrated in vacuo. By trituration of the residue with 50% ethyl acetate in ether, 0.51 g of the crystalline product pf 1980C is obtained. (Dec.).

The following compounds, which fall within the scope of the invention, are prepared by the procedures used in Examples 1 to 2
EXAMPLE 3
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3, 4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -Lproline]] (in formula (1): a = d = y = l; x-0).

EXAMPLE 4
Spiror dihydrochloride (7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N- α - [( 1S) -1- (hydroxycarbonyl) -3-phenylpropyl] -L-lysyl] -L-proline]] (formula (1): a = d = y = 1; x-0).

EXAMPLE 5
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3,4dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N - [(1S) -1 - (ethoxycarbonyl) -3-phenylpropyl] -L-valyl] -L prolineJ] (formula (1): a = d = ly = l; x-0).

EXAMPLE 6
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3,4dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N - [(1S) -1 - (hydroxycarbonyl) -3-phenylpropyl] -L-phenyl alanylJ-L-prolineJ] (formula (1): a - dy = 1; x-0).

EXAMPLE 7
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3,4dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N - [(1S) -1 - (hydroxycarbonyl) -3-methylbutyl] -L-alanyl] -Lproline J] (formula (1): ady-x1; x-0).

EXAMPLE 8
Spiro hydrochloride [(7-sulfonamyl-6-chloro-3,4dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N - [(1S) -1 - (ethoxycarbonyl) -1- (2,3-dihydro-1H-inden-2-yl) methyl] -L-alanyl] -L-proline]] (formula (1) a = d = y = 1; x = O).

EXAMPLE 9
Spiro acid hydrochloride [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '[N- [N- [ (1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -Lpipecolinique J] (formula (1): a = 2, d = y = l; x = 0).

EXAMPLE 10
Spiro acid hydrochloride [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,5 '[N- [N- [ (1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -L-alanyl] -Lpipécolinique] J (formula (1): d = 2, a = y = l,
EXAMPLE 11
Spiro acid dihydrochloride [(7-sulfonamyl-6-chloro-3, 4-dihydro-2H-1,2,4-benzothiadiazine-l, l-dioxide) -3,42-
NN - [(1S) -1- (hydroxycarbonyl) -3-phenylpropyl] -L-lysyl] -Lpipécolinique]] (formula (1): a = 2, dy = 1; x-0).

EXAMPLE 12
Spiro acid hydrochloride [(7-sulfonamyl-6-chloro-3, 4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,5'- [N- [N- [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl-L-alanyl] -Lhomopipécolinique]] (formula (1): a = 3, d = y = l; x-0).

EXAMPLE 13
Spiro acid dihydrochloride [(7-sulfonamyl-6-chloro-3, 4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4'- [N- [N- α - [(1S) -1- (hydroxycarbonyl) -3-phenylpropy] -L-lysyl] -L- homopipecolinic]] (formula (1): a = 3, d = y = l; s = 0).

EXAMPLE -14
Spiro acid hydrochloride [(7-sulfonamyl-6-chloro-3, 4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4'- [N- [N- [(1S) -1- (hydroxycarbonyl) -1- (2,3-dihydro-1H-inden-2-yl) methyl] -L-alanyl] -L-homopipecolinic]] (formula (1): a = 3 , dyl; x = 0).

EXAMPLE 15
Spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4, -benzo thiadiazine-l, l-dioxide) -3,4'-iN- (3-mercapto-2- methyl-propanoyl) -L-proline (formula (1): a = d = y = l, x = 0)
EXAMPLE 16
Spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide)) - 3,4 '- [N- (3-trimethylacetylthio-2-methylpropanoyl ) -L-prolineJf (formula (1): a = d = y = l, x = 0).

Claims (23)

1. Compound corresponding to the formula

 their acid addition salts, their pharmaceutically acceptable alkali metal and alkaline earth metal salts. C1-C6, -CF3, -OH, -SH, halogen, -NO2 and -COOR; and  in which the condensed alkyl, cycloalkyl, aryl and aryl-cycloalkyl groups can carry substituents chosen from the group consisting of an alkoxy in  R3 is hydroxy, phenyl, C1-C6 alkyl or C1-C6 alkoxy  provided that a is 0-4, b is 0-3, c is 0-3, d is 0-4, e is 0-3, f is 0-3, (a + d) or 2-4, (a + e + f) either 1-3, (b + c + d) or 1-3, and (b + c + e + f) is 0-2; and  - (CH2) eC (O) (CH2) f-, or - (CH2) e CH (R3) (CH2) f-;  X2 is - (CH2) d-, - (CH2) e S (CH2) f-,  - (CH2) bC (O) (CH2) c-, or - (CH2) b CH (R3) (CH2) c-;  X1 is - (CH2) a-, - (CH2) bS (CH2) c-,  A, B and E are independently hydrogen, halogen, hydroxy, -CF3, -OR, -NR1R2, -C (O) Y1, -SO2R, or -SO2NR1R2 provided that at least two of the radicals A, B and E are not hydrogen  R, R1, R2, R4 and R5 are independently hydrogen, a C1-C8 alkyl radical, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 atoms carbon and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or an alkyl group having 1 to 6 carbon atoms which is substituted by -NH2, -NH-C (NH2) = NH2, or -NC = NCH = CHCH = N  one of the indices x and y is equal to 1 and the other is equal to 0;  Y1 and Y2 are independently -OH, -OR or -NR1R2;  R1-C (O) -S- (C * HR1)) 0-1-, or HS- (C * H (R1)) 0-1-;  Q is Y1 - C (O) -C * H (R1) -NH -, - NH2  in which  2. A compound or salt according to claim 1, wherein the spiro carbon atom is in the (S) or (R) configuration and the other asymmetric carbon atoms are in the (S) configuration.  3. A compound or salt according to claim 1, wherein R4, R5 and E are hydrogen.  4. A compound or salt according to claim 3, wherein X1 is - (CH2) a and X2 is - (CH2) d--  5. A compound or salt according to claim 4, wherein Y1 and Y2 are independently -OH or C1-C8 alkoxy.  6. A compound or salt according to claim 5, wherein R1 is hydrogen, alkyl, aryl, aryl-alkyl, or condensed aryl-cycloalkyl; and R2 is hydrogen, alkyl, aryl-alkyl, condensed aryl-cycloalkyl, or amino-substituted alkyl.  7. A compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2R4-benzOthiadiazine-1,1-dioxide) 3,4 '- [N - [(1S) -1- (ethoxycarbonyl) -3 phenylpropyl -L-alanyl II-proline and its acid addition salts, its salts with alkali metals and pharmaceutically acceptable alkaline earth metals.  8. A compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadia zine-l, 1-dioxide) 3,4'-lN -tN-a [(lS) -lS ydroxycarbonyl) -3 phenylpropyl] -L-lysyl] -L-proline]] and its acid addition salts, its salts with alkali metals and pharmaceutically acceptable alkaline earth metals .  9. A compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) 3,4 '- [N - [N - [(1S) -1- (ethoxycarbonyl) -3phenylpropyl] -L-valyl] -L-proline]] and its acid addition salts, its salts with alkali metals and pharmaceutically alkaline earth metals acceptable.  10. Compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzOthiadiazine-1,1-dioxide) 3,4'- [N- [N - [(1S) -1- (hydroxycarbonyl) -3phenylpropyl] -L-phenylalanyl] -L-proline]] and its acid addition salts, its salts with alkali metals and alkali metals- pharmaceutically acceptable earthy.  11. A compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzOthiadiazine-1,1-dioxide) 3,4'- [N- [N - [(1S) -1- (hydroxycarbonyl) -3 methylbutylJ-L-alanylJ-L-prolineJ] and its acid addition salts, its salts with alkali metals and pharmaceutically alkaline earth metals acceptable.  12. Compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro 2H-1,2,4-benzothiadiazine-1,1-dioxide) 3,4 '- [ N- [N - [(1S) -1- (ethoxycarbonyl) -1 (2,3-dihydro-1H-inden-2-y) methyl] -L-alanyl-L-proline]] and its addition salts with acids, its salts with alkali metals and icalino-earth metals which are pharmaceutically acceptable.  13. A compound according to claim 6 which is spiro acid [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) 3,4'- [N- [N - [(1S) -1- (ethoxycarbonyl) -3phenylpropyl] -L-alanyl] -L-pipecolinic]] and its acid addition salts, its salts with alkali metals and alkali metals- pharmaceutically acceptable earthy.  14. Compound according to claim 6 which is spiro acid [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadi @ zine-1,1-dioxide) 3,5 '- [N- [N - [(1S) -1- (ethoxycarbonyl) -3phenylpropyl] -L-alanyl] -L-pipecolinic]] and its acid addition salts, its salts with alkali metals and metals pharmaceutically acceptable alkaline earth.  15. Compound according to claim 6 which is spiro acid [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadi @ zine-1,1-dioxide) -3, 4 '- [N- [N- α - [(1S) -1- (hydroxycarbonyl) -3- phenylpropyl] -L-lysyl] -L-pipecolinic]] and its addition salts with acids, its salts with pharmaceutically acceptable alkali metals and alkaline earth metals.  16. A compound according to claim 6 which is 1a spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) 3,5 '- [N - [N - [(1S) -1- (ethoxycarbonyl) -3phenylpropyl] -L-alanyl] -L-homopipecolinic]] and its acid addition salts, its salts with alkali metals and pharmaceutically alkaline earth metals acceptable.  17. A compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadia zine-1,1-dioxide) 3,4 '- [ N- [N- α - [(1S) -1- (hydroxycarbonyl) -3- phenylpropyl] -L-lysyl] -L-homopipecolinic]] and its acid addition salts, its salts with alkali metals and pharmaceutically acceptable alkaline earth metals.  18. Compound according to claim 6 which is spiro acid [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadia zine-1,1-dioxide) -3,4 '- [N [N [(1S) -1- (hydroxycarbonyl) -1 (2,3-dihydro-1H-inden-2-yl) methyl] -L-alanyl] -L-colinic homopiped]] and its salts addition to acids, its salts with alkali metals and pharmaceutically acceptable alkaline earth metals.  19. Compound according to claim 6 which is spiro  [(7-snlfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadia  zine-1,1-dioxide) -3,4 '- [N- (3-mercapto-2-methylpropanoyl) L-proline]] and its acid addition salts, its salts with alkali metals and pharmaceutically acceptable alkaline earth metals.  20. Compound according to claim 6 which is spiro [(7-sulfonamyl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide) -3,4 '- [ N- (3-trimethylacetylthic-2-methylpropanoyl) -L-proline || and its acid addition salts, its salts with pharmaceutically acceptable alkali metals and alkaline earth metals  21. Pharmaceutical preparation cosprenast an amount effective as a hypertensive of a compound or salt according to claim 1, associated with a pharmaceutically acceptable excipient.  22. Process for the preparation of the alkyl ester of N- [N - [(1S) -1- (ethoxycarbonyl) -3-phenylpropyl] -N- (2,2,2trichlorethoxycarbonyl) -L-alanyl] -L- proline-4-one consisting in reacting N - [(1S) -1- (ethoxycarbonyl) -3- phenylpropyl-N- (2,2,2-trichlerethoxyearbonyl] -L-alanine and alkyl ester of 4-hydroxy -L-proline, then oxidizing the product obtained with an oxidizing agent.  23. Process for the preparation of the alkyl ester of spiro [(7-sulfanomoyl-6-chloro-3,4-dihydre-2H-1,2,4benzo-thiadiazine-1,1-dioxide) -3,4 '- [N- [N [(1S) - (ethexycarbonyl) -3-phenylpropyl] -N- (2,2,2-triohlerethoxycarbenyl) -L-alenyl] -L-proline]] consisting in reacting 1- amino-3-chloro-4,6-benzenedisolfamide with the alkyl ester of N = [N- [(1S) ethoxycarbonyl) 3 phenyl propyl] -2- (2,2,2-trichlorethoxycarbonyl) -L-alanyl] -Lproline-4-one.