FR2561243A1 - SULFAMIDES ANTIHYPERTENSEURS - Google Patents

Abstract

COMPOUND RESPONDING TO FORMULA (1): (CF DRAWING IN BOPI) AND THEIR ADDITIONAL SALTS TO ACIDS, THEIR ALKALINE METAL SALTS AND THEIR PHARMACEUTICALLY ACCEPTABLE ALKALINE-EARTH METAL SALTS. THESE COMPOUNDS OR SALTS ARE ACTIVE AGAINST HYPERTENSION.

Description

SULFAMIDES ANTIHYPERTENSEURS

  The present patent application relates to compounds,

  pharmaceutically acceptable salts thereof, and

  pharmaceutical preparations made from these

  ci, useful in the treatment of hypertension in subjects with hypertension.

  In general, the present invention

  takes compounds of formula (1) (1)

R2 O S02NH2

ili G (1)

Q-C * -CN CH

I I I

k3 CH Z Ai

Y20C X A2

  and their acid addition salts, their

  alkali metals and their alkali metal salts

  pharmaceutically acceptable salts, wherein Q is Y -C (O) -C H (R4) -NH-, -NH2,

1 4

  R5-C (O) -S-C H (R4) n-, or HS- (C H (R4)) n-; y1 and Y2 are independently - OH, -OR or -NR1R2; Z is -O-, -S-, -N (R) -, or -S (O) -; n is zero or one; R, R1, R2, R3, R4 and R5 are independently hydrogen, C1-C8 alkyl, aryl having up to 12 carbon atoms, aryl-alkyl wherein the aryl portion has up to carbon and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms,

  a fused cycloalkylaryl having 8 to 12 carbon atoms

  bone, a heterocyclic group or an alkyl having 1 to 6

  carbon atoms, which is substituted by -NH2, -NH-C-

I I

  (NH2) = NH2, or -N-C = NCH = CHCH = N; or R4 may be G '- (CH2) 1-6-X1- (CH2) 1-6, wherein G' is aryl having up to 12 carbon atoms or fused arylcycloalkyl having 8 to 12 carbon atoms, and X1- is -S-, -O-, -NH-, or -S (O) -; X is an alkylene bridge having a length of 1, 2 or 3 carbon atoms, optionally substituted with hydroxy, phenyl, C1-C6 alkyl or C1-C6 alkoxy; A1 and A2 are independently halogen, -OH, -OR,

  -CF3, -NR1R, -C (O) Y1, -SO2R, or -SO2NR1R, where A2 is hydrogen;

  gene; wherein the fused alkyl, cycloalkyl, aryl, and arylcycloalkyl groups may bear substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, -CF3, -OH, SH, halogen, -NH2, -NO2, -CPPR, -NH-C (NH2) = NH, and -NC = NCH = CHCH = N; provided that when Q contains a sulfur atom, R5 is not amino-substituted alkyl; and provided that when Q contains a sulfur atom, and A1 is chloro, A2 is hydrogen, Z is -S-, X is -CH2-, n is one, R2 is hydrogen or alkyl; unsubstituted C1-C6 and R3 and R4 are hydrogen, and the group -SO2NH2 and A1 are respectively at meta and para positions relative to the point at which the G-ring is attached to the heterocyclic ring, R5 is then (CH3) 3CCH2 -, (CH3) 3C-, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part of 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having from 8 to 12 atoms

  of carbon, or a heterocyclic group.

  Preferred compounds according to the present invention include those wherein: Y1 and Y2 are independently hydroxy, or alkoxy containing up to 8 carbon atoms; R1 and R2 are independently and preferably hydrogen or C1-C8 alkyl; R2 is H; C1-C8 alkyl; or an alkyl group having 1 to 8 carbon atoms, which is substituted by an amino or an amino derivative such that -NH-C (NH2) = NH, or -N- C = NCH = CHCH = N; and R2 is preferably methyl or

NH2 (CH2) 4-;

  R3 is preferably hydrogen; R4 is H; an alkyl having 1 to 8 carbon atoms; and a phenyl-alkyl wherein the alkyl has 1 to 4 carbon atoms, and preferably a phenethyl; or indanyl, for example 2-indanyl; R5 is preferably (CH3) 3CCH2- or (CH3) 3C- when Q contains a sulfur atom; A1 is a halogen; -OH; a phenoxy; an alkoxy having up to 6 carbon atoms; and preferably a chloro, and most preferably a para-chloro relative to the point at which the G-ring is attached to the heterocyclic ring; A2 is a halogen, and preferably a chloro; -OH; NH2; an alkoxy having up to 6 carbon atoms; COOR;

  or CF3; or hydrogen. The sulfamoyl group is preferably

  in the meta position with respect to the point at which G is

attached to the heterocyclic ring.

  The alkyl groups contain straight and branched chain groups including methyl, ethyl,

  propyl, isopropyl, butyl, isobutyl, tert-

  butyl, amyl, isoamyl, hexyl, and the like.

  By "halogen" is meant chloro, bromo, iodine and

a fluoro.

  Preferred substituents for R 1 and / or R 2 also include cycloalkyl groups, aryl groups, heterocyclic groups, and fused aryl-cycloalkyl groups, as defined herein, any of which may be connected to the chain. of the molecule (1) directly or through an alkylene bridge - (CH2) n - there is a number from 1 to 6. Preferred cycloalkyl groups

  cyclopropyl, cyclobutyl, cyclopropyl,

  pentyl, cyclohexyl, cycloheptyl, adamantyl, or norborn-

  nyle. The aryl and aryl-cycloalkyl condensed groups

  Examples include phenyl, indolyl, indolino, indanyl, naphthyl, tetrahydronaphthyl, and decahydronaphthyl. Preferred heterocyclic groups include pyridyl, quinolyl, isoquinolyl,

  tetrahydroquinolyl, tetrahydroisoquinolyl, decahydro-

  neryl, decahydroisoquinolyl, pyrrolidyl, pyrrolyl,

  morpholinyl, furyl, tetrahydrofuryl, furfuryl, benzine

  midazolyl, thienyl and imidazolyl. Aryl substituents

  Preferred alkyls include benzyl and phenethyl groups.

  Preferred substituents on the fused alkyl, cycloalkyl, aryl and aryl-cycloalkyl substituents include C1-C6 alkyl and alkoxy, -CF3, -OH, -NH2, phenoxy, -NR1R2, -COOH, -CN, -SH. , a halogen, -NO2, and COOR, and

  preferably a COO-C 1 -C 6 alkyl.

  Compounds according to formula (1) may contain asymmetric centers on carbon atoms labeled as follows: C * and at one or more carbon atoms in the ring formed by X and Z. Each of these carbon atoms may have a configuration (R) or (S). In the preferred compounds, the asymmetric carbon in Q and the carbon atom to which Q is attached in formula (1) are in the (S) configuration. Asymmetric carbons in the heterocyclic ring are in the (R) or (S) configuration. Individual optical diastereoisomers as well as mixtures thereof are considered within the scope of the invention. When diastereoisomeric products result

  synthetic procedures, the diastereo-

  desired isomer can be separated by chromatographic methods.

  classical fractional crystallization or crystallization.

  The compounds corresponding to formula (1) may be prepared by coupling a compound corresponding to the formulas

(2) and (3).

R 0 S02NH2

Q-C * -COH + HN - CH -

j I I R2 CH Z Al

Y20C X A2

(2) (3)

  wherein R 2, R 3, X, Y 2, Z, A 1 and A 2 are such that

defined above.

  The compound of formula (3) may be prepared, for example, by reacting an appropriately substituted aldehyde G-CH = O with a compound of the formula H 2 N -CH (COY 2) -X-ZH so that the groups

  amino terminals and -ZH form a ring with the carbon-

  aldehyde. Specialists will realize that the coupling

  compounds (2) and (3) can be carried out by means of

  conventional peptide bonding systems, for example

  presence of a coupling agent such as DCC (N, N'-

  dicyclohexylcarbodiimide) or CDI (N, N'-carbonyl-

  diimidazole). It may also be preferable to convert the -COOH group of the compound (2) to -C (O) Cl, then to make

  react the intermediate obtained with the compound (3).

  It is also possible, preferably, to convert the compound (2) into the corresponding Ncarboxyanhydride (NCA) leaving

  (2) react with the phosgene, then react the N-carboxy-

  anhydride obtained with the compound (3) to give the product

the desired intermediary.

  It will be further appreciated that the nitrogen atom which is between the carbon atoms to which R4 and R2 are attached must be protected with a blocking agent such as

  2,2,2-trichloroethoxycarbonyl, or benzyloxycarbonyl.

  The protecting group is then eliminated, preferably

  after the compounds (2) and (3) have been linked together.

  Other nitrogen atoms, in substituents such as NH2 (CH2) 4-, must be protected and then deprotected in a similar manner. Similarly, Y 1 and Y 2 are preferably converted to ethoxy, t-butoxy or benzyloxy before the intermediates are reacted. If you wish

  free acid, it is obtained later by eliminating

  nation of the esterifying group in a known manner.

  Compounds of the present invention wherein one of Y1 and Y2 is OH and the other is alkyl, such as methoxy or ethoxy, are preferably prepared by reacting compounds (2) and (3) as indicated herein. above, in which one of Y1 and Y2 is the desired alkyl ester, and the other is an easily cleaved ester group such as t-butoxy. The intermediate amide thus prepared gives

  monoesters-monoacids desired by acid hydrolysis me-

  swum. When Q contains sulfur, the synthesis process

  preferred is that by the acid chloride.

  The compounds of the present invention form salts with various inorganic 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 salts and

  potassium (which are preferred), alkali 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 inorganic and organic acids, for example HCl, HBr, H 2 SO 4, H 3 PO 4,

  as well as methanesulphonic acid, toluenesulphoni-

  that, maleic acid, acetic acid, malic acid,

  citric acid, fumaric acid and camphoric acid

  sulfonic acid. Non-toxic salts physiologically acceptable

  tables are preferred, although other salts are also

  useful, for example to isolate or purify the product.

  The salts may 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 base or the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such

  water, which is then removed under vacuum or

  philization, or by exchanging the cations of a salt that is

  for another cation on a resin exchange

ions.

  The action of the renin enzyme on angiotensinogen,

  a pseudoglobulin from human plasma, produces the decapep-

  tide angiotensin I. Angiotensin I is converted by the angiotensin-converting enzyme (ACE) into octapeptide angiotensin II. The latter is an active vasopressor agent that has been implicated as a causative agent in various forms of hypertension in various mammals, for example rats and dogs. Compounds entering the field

  of the invention which intervene in the renin-

  -angiotensin I-angiotensin II inhibit the trans-

  angiotensin I, and therefore are useful for

  reduce or relieve hypertension.

  In addition, 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. Thus, by administering a composition containing a compound or combination of compounds of formula (1) or

  their pharmaceutically acceptable salts, the hyper-

  tension in the mammalian species that suffer from it. A

  single dose, or preferably two to four doses

  divided patients provided on the basis of about 0.1 to 100 mg / kg per day, preferably about 1 to 50 mg / kg

  a day is appropriate for lowering blood pressure.

  The substance is preferably administered orally, but a parenteral route such as subcutaneous, intramuscular, intravenous or intraperitoneal routes may also be used. The compounds of the invention may be used to effect 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 2 to 500 mg of a compound or mixture of compounds of formula (1) or of their physiologically acceptable salts are mixed with a vehicle, carrier, excipient, binder, preservative, stabilizer, perfume, physiologically acceptable, in the form of unit of dosage as claimed by the established pharmaceutical practice. The amount of active substance in these compositions or preparations is such that an appropriate dose is obtained in

the indicated interval.

  Examples of adjuvants that can be incorporated

  resins in tablets, capsules, etc., include: a binder such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, etc. ; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a fragrance such as mint

  peppery, 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 carrier such as a fatty oil. Various other materials may be present as coatings or to modify

  in another way the physical form of the unit of dose.

  For example, the tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as an agent

  sweetener, methyl and propyl paraben as

  a dye, and a perfume such as a cherry scent

or orange.

  Sterile injection compositions can be

  in accordance with standard 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, cotton qraine oil, etc. or in a synthetic fatty vehicle such as ethyl oleate, etc. Buffers, preservatives,

  antioxidants, etc. can be incorporated if necessary.

  Particular embodiments according to the invention

  are illustrated by the following examples.

EXAMPLE 1

  A. 2-chloro-5-methylaniline A suspension of iron powder (440 g, 7.88 moles) in water (333 ml) was heated until it became

  hot in a bain-marie, and then remove the bath.

  4-Chloro-3-nitrotoluene (39.6 g, 0.231 mol) is added

  stirring vigorously, then concentrated HC1 (9.25 ml).

  Within 5 minutes, 4-chloro-3-nitro-

  toluene (201.4 g, 1.174 mol). Concentrated HCl (46.2 ml) was added in successive fractions over the next 20 minutes, and the mixture was then heated in a water-bath for

  1 hour. Remove the bath and add a solution of hydro-

  sodium hydroxide (18.5 g, 0.462 mol) in water (37 ml).

  The solution is filtered while hot and the black precipitate is extracted several times with boiling ether, the extracts being added to the filtrate. The extract / filtrate mixture is separated; the organic layer is washed with water and brine and then dried (Na 2 SO 4) and concentrated

  to get a black oil that solidifies quickly.

Yield: 193.5 g (97.2%).

  B. 4-Chloro-3-chlorosulfonyltoluene Concentrated HCl (22.5 mL) was added to a solution of 2-chloro-5-methylaniline (9.9 g, 70 mmol) in acetic acid (108 mL) . The mixture is cooled in an ice bath and sodium nitrite (5.3 g, 77 mmol) is added

  in water (6.5 ml) for 1 minute.

  A second solution is prepared by adding CuCl 2 .2H 2 O (2.8 g) / H 2 O (4 ml) to 38 ml of SO 2/34% HOAc at 0 ° C. This solution is cooled on an ice bath to introduction of the diazonium salt solution above for 5 minutes. The ice bath is removed and the mixture is stirred for 2 hours, filtered and poured into water (500 ml). The precipitate is filtered, washed with water and dried in vacuo to give 13.9 g.

(88%) of product.

  C. 4-Chloro-3-sulphamoyltoluene 4-Chloro-3-sulphonyltoluene is added in portions

  (128.3 g, 0.57 mol) to anhydrous ammonium (1200 ml) at -78 ° C.

  The mixture is maintained at -78 ° C. for 6 hours, the ammonium is evaporated overnight. Water is added to the residue and the resulting sludge is filtered. The precipitate is recrystallized from ethanol to give 103.6 g (88%) of

whitish solid.

  D. N-Acetyl-2-chloro-5-diacetoxymethylbenzenesulfonamide 4chloro-3-sulfamoyltoluene (16.7 g, 81 mmol) was added to acetic anhydride (127 ml) / acetic acid (128 ml), followed by sulfuric acid (19.0 ml). The solution is cooled to 5 ° C. and chromium oxide is added

  (VI) (22.4 g) for 1 hour, during which time the temperature

  The stirring of the solution was maintained below 10 ° C. The stirring was continued for a further hour, the mixture was poured onto ice (500 g) and the precipitate was filtered off.

  and washed with water in 30 minutes. Recrystallization

  This gives 14.8 g (50%) of a solid, m.p. 161-163 C.

  E. 4-chloro-3-sulfamoylbenzaldehyde

  Refluxed for 1 hour of N-acetyl-2-chloro

  -diacetoxymethylbenzenesulfonamide (57.5 g, 0.158 mole) in 2N HCl (170 mL) / ethanol (365 mL) and then concentrated in vacuo to a reduced volume. The precipitate is filtered and washed with water to give 33.8 g (97%) of product.

  F. Ethyl-2- (4-chloro-3-sulfamoylphenyl) Carboxylate

4 (R) -thiazolidine

  L-ethyl ester hydrochloride is added

  cysteine (2.78 g, 15 mmol) in water (5.6 ml) at 4-

  chloro-3-sylfamoylbenzaldehyde (3.29 g, 15 mmol) in hot ethanol (30 ml) and heated for 15 minutes on a steam bath, and allowed to stand overnight. The mixture is adjusted to pH 4.5 with sodium bicarbonate solution and concentrated in vacuo. The residue is separated between saturated NaHCO 3 solution and ethyl acetate. The organic layer is removed,

  washed with brine and dried (Na2SO4).

  The concentration gives a product (4.9 g, 94%) as an oil.

  G. N- [N - [(1S) -1-Ethoxycarbonyl) ethylcarboxylate

  3-phenylpropyl] -N- [2,2,2-trichloroethoxycarbonyl] -L-alanyll

  2- (4-Chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine Oxalyl chloride (4.04 g, 31.8 mmol) is added

  N - [(1S) -1-ethoxyxarbonyl-3-phenylpropyl] -N- [2,2,2-

  trichloroethoxycarbonyl] -L-alanine (5.09 g, 11.2 moles) in

  methylene chloride (71 ml), followed by N, N-dimethyl-

  formamide (76 pil). The solution is concentrated under vacuum

  4 hours. The residue is dissolved in CH 2 Cl 2 (25 ml) and added in portions for 10 minutes to

  2- (4-chloro-3-sulfamoylphenyl) -4 (R) ethyl carboxylate

  thiazolidine (3.93 g, 11.2 mmol) and triethylamine (1.25 g, 12.3 mmol) in CH 2 Cl 2 (150 ml) at 0 ° C. The solution is stirred overnight and then concentrated. under vacuum. The residue is dissolved in ethyl acetate, washed with 1N hydrochloric acid, NaHCO 3 solution and brine, dried (Na 2 SO 4) and concentrated to an oil. Purification

  HPLC gives 2.4 g (27%) of pure product.

  H. N- [N - [(1S) -1-Ethoxycarbonyl) ethylcarboxylate

  3-phenylpropyl] -L-alanyl] -2- (4-chloro-3-sulfamoyl-phenyl) -

  4 (R) -thiazolidine A suspension of zinc powder (2.11 g,

  32.2 mmol), ethyl carboxylate of N- [N - [(1 S) -1-etboxy-

  carbonyl-3-phenylpropyl-N- [2,2,2-tricholorethoxycarbonyl]

  L-alanyl] -2- (4-chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine (1.88 g, 2.39 mmol) and acetic acid (12.8 ml) for 4 hours, then it is filtered on Celite, the Celite being well washed with tetrahydrofuran. The filtrate and washings are combined and concentrated under vacuum to remove most of the THF, and the residue is poured into water. The mixture is extracted with ethyl acetate and the organic layer is washed with saturated NaHCO 3 solution and brine, dried (Na 2 SO 4) and concentrated to form a

  foam (1.28 g, 87%). A pure product is obtained by purification.

CLPH.

EXAMPLE 2

  N- [N - [(iS) -1-carboxy-3-phenylpropyl] -1-L-alanyl] -2-

  (4-Chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid Sodium hydroxide (0.21 g, 5.3 mmol) was added

  in water (0.60 ml) to ethyl carboxylate N- [N - [(1S) -

  1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -2- (4-chloro-3-

  Sylfamoylphenyl) -4 (R) -thiazolidine in methanol (5.2 ml) and stirred for 1.5 hours. The mixture is concentrated to remove methanol and 1.00N hydrochloric acid (5.2 ml) is added. The resulting precipitate is filtered, washed with water and recrystallized from ethanol.

  aqueous yielding 0.44 g (65%) of product, m.p. 161-163 C.

EXAMPLE 3

  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-

  (4-chloro-3-sulfamoyl-phenyl) -4 (R) -oxazolidinecarboxylique,

EXAMPLE 4

  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-

  (4-chloro-3-sulfamoyl-phenyl) -4 (S) -tetrahydro-1,3-thiazine

carboxylic acid.

EXAMPLE 5

  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-

  (4-Chloro-2-hydroxy-5-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

EXAMPLE 6

  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-

  (2-Amino-4-chloro-5-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

EXAMPLE 7

  N- [N-α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -2-

  (4-Chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

EXAMPLE 8

  N- [2- (3,3-dimethylbutyrylthio) propionyl] -2- (4-

  chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

EXAMPLE 9

  N- [N - [(1S) -1-carboxy-1- (2-indanyl) methyl] -L-

  alanyl] -2- (4-chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

EXAMPLE 10

  N- [2- (2,2-dimethylpropionylthio) propionyl] -2-

  (4-Chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid.

Claims (15)

  1. Compound having formula (1) PR2 0 S02NH2 (1) i II Q-C * -CN - C H I! I L X R3 CH Z AI Y20C X A2   and their acid addition salts, their metal salts   alkali and their alkaline earth metal salts   maceutically acceptable, wherein Q is Y1-C (O) -CH (R4) -NH-, -NH2, R5-C (O) -SC H (R4) n-, or HS- (CH (R4)) not; Y1 and Y2 are independently - OH, -OR or -NR1R2; Z is -O-, -S-, -N (R) -, or -S (O) -; n is zero or one; R, R1, R2, R3, R4 and R5 are independently hydrogen, C1-C8 alkyl, aryl having up to 12 carbon atoms, aryl-alkyl wherein the aryl portion has up to carbon and the alkyl part with 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms,   a fused cycloalkylaryl having 8 to 12 carbon atoms   bone, a heterocyclic group or an alkyl having from 1 to 6   carbon atoms, which is substituted by -NH2, -NH-C-   (NH2) NH2, or -N-C = NCH = CHCH =; or R can be G '- (CH 2) 1 -6-X- (CH 2) 16, wherein G' is an aryl having up to 12 carbon atoms or a fused arylcycloalkyl having 8 to 12 carbon atoms, and -X1- is -S-, -O-, -NH-, or -S (O) -; X is an alkylene bridge having a length of 1, 2 or 3 carbon atoms, optionally substituted with hydroxy, phenyl, C1-C6 alkyl or C1-C6 alkoxy; A1 and A2 are independently halogen, -OH, -OR,   -CF3, -NR1R, -C (O) Y1, -SO2R, orSO2O2NR1R, where A2 is hydrogen;   gene; wherein the fused alkyl, cycloalkyl, aryl, and arylcycloalkyl groups may bear substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, -CF3, -OH, SH, halogen, -NH2, -NO2, -COOR, -NH-C (NH2) = NH, and -NC = NCH = CHCH = N; provided that when Q contains a sulfur atom, R5 is not amino-substituted alkyl; and provided that when Q contains a sulfur atom, and A1 is chloro, A2 is hydrogen, Z is -S-, X is -CH2-, n is one, R4 is hydrogen, or unsubstituted C1-C6 alkyl and R3 and R4 are hydrogen, and -SO2NH2 and A1 are respectively at the meta and para positions relative to the point at which the G-ring is attached to the heterocyclic ring, R5 is then (CH3) 3CCH2-, (CH3) 3C-, an arylalkyl in which the aryl part   has up to 10 carbon atoms and the alkyl part of 1 to   6 carbon atoms, a cycloalkyl of 3 to 10 carbon atoms, a fused cycloalkylaryl of 8 to 12 atoms   of carbon, or a heterocyclic group.   2. Compound or salt according to claim 1, characterized   in that Q does not contain sulfur.   3. Compound or salt according to claim 2, characterized   in that R2 is not hydrogen and R3 is hydrogen.   4. Compound or salt according to claim 2, characterized in that A1 is a halogen.   5. Compound or salt according to claim 3, characterized   in that R2 is methyl or NH2 (CH2) 4.   6. Compound or salt according to claim 5, characterized in that R4 is phenethyl.   7. Compound or salt according to claim 5, characterized in that R4 is an indanyl.   8. A compound according to claim 6 which is a carboxy   N- [N - [(1S) -1-Ethoxycarbonyl-3-phenylpropyl] L -alanyl] -2- (4-chloro-3-sulfamoylphenyl) -4- (R) -thiazolidine ethylate   or N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-   (4-Chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid;   or N- [N-KlS) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-   (4-Chloro-3-sulfamoylphenyl) -4 (R) -oxazolidine carboxylic acid; or N [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -2-   (4-chloro-3-sulfamoyl-phenyl) -4 (S) -tetrahydro-1,3-thiazine   carboxylic acid; or N- [N - [(1S) -1-carboxy-3-phenyl]   propyl] -L-alanyl] -2- (4-chloro-2-hydroxy-5-sulfamoyl-phenyl) -   4 (R) -thiazolidine carboxylic acid; or N- [N - [(1S) -l-   carboxy-3-phenylpropyl] -L-alanyl] -2- (2-amino-4-chloro-5-   sulfamoylphenyl-5 (R) -thiazolidine carboxylic acid; or the acid   N- [N-a - [(1S) -l-carboxy-3-phenylpropyl] -L-lysyl] -2- (4-chloro-   3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid; or the acid   N- [N - [(1S) -l-carboxy-1- (2-indanyl) methyl] -L-alanyl] -2- (4-   chloro-3-sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid; and its acid addition salts, its metal salts   alkaline and its alkaline earth metal salts acceptable.   9. Compound or salt according to claim 1, characterized   in that Q contains a sulfur atom.   10. Compound or salt according to claim 9, characterized   in that n is one and R is not hydrogen.   11. Compound or salt according to claim 9, characterized in that n is zero.   12. Compound or salt according to claim 9, characterized in that A2 is not hydrogen 13. Compound or salt according to claim 9, characterized in that Z is not -S-.   The compound of claim 1 which is acid   N- [2- (3,3-diméthylbutyrylthio) propionyl] -2- (4-chloro-3-   sulfamoyl) -4 (R) -thiazolidinecarboxylic acid; or the acid   N- [2- (2,2-dimethylpropionylthio) propionyl -2- (4-chloro-3-   sulfamoylphenyl) -4 (R) -thiazolidine carboxylic acid, and its acid addition salts, alkali metal salts and its   alkaline earth metal salts pharmaceutically acceptable.   15. CoinosJ or salt for pharmaceutical preparation   against hypertension according to any one of the claims   1 to 14 in combination with a pharmaceutical carrier- acceptable.