GB2155927A - Sulfonamide antihypertensives - Google Patents

Abstract

Compounds of formula (1> <IMAGE> and their pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts, wherein Q is Y1-C(O)-@H(R4)-NH-, -NH2, 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, C1-8 alkyl, C6-12 aryl, aryl-alkyl (wherein aryl is C6-10 and alkyl is C1-6), C3-10 cycloalkyl, fused C8-12 cycloalkylaryl, heterocyclic, or C1-6alkyl group which is substituted with -NH2, -NH-C(NH2)=NH, or -N-C=NCH=CHCH=N; or R4 can be G'-(CH2)1-6-X1-(CH2)1-6- wherein G' is C6-12 aryl or fused C8-12 arylcycloalkyl, and -X1- is -S-, -O-,-NH-, or -S(O)-; X is a C1-3 alkylene bridge which is 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, or A2 is also hydrogen; wherein the alkyl, cycloalkyl, aryl and fused aryl-cycloalkyl groups may be further substituted are useful in the treatment of hypertension and congestive heart failure.

Description

SPECIFICATION Sulfonamide antihypertensives This application relates to compounds, their pharmaceutically acceptable salts, and pharmaceutical preparations made therefrom, having utility in the treatment of hypertension in subjects suffering therefrom.

Broadly stated, the present invention comprises compounds of the formula (1):

and their pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts, wherein o is Y1-C(O)-C*H(R4)-NH-, NH2, R5C(O)S(C*H(R4))n, or HS -(C*H(R4))-; Y1 andY2 are independently -OH, -OR, or -NR1R2; Zis -O-, -S-, -N(R)-, or -S(O)-; n is zero or one;; R, R1, R2, R3, R4 and R5 are independently hydrogen, alkyl having 1 to 8 carbon atoms, aryl having up to 12 carbon atoms, aryl-alkyl wherein the aryl moiety has upto 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, fused cycloalkylaryl having 8 to 12 carbon atoms, heterocyclic, or an alkyl group having 1 to 6 carbon atoms which is substituted with -NH2, -NH-C-(NH2)=-NH2, or-N-C=NCH=CHCH=N; or R4 can be G -(CH2)1.6-X1-(CH2)16-, 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 1,2 or 3 carbon atoms long which is optionally substituted with hydroxy, phenyl, C1C6 alkyl, or C1-C6 alkoxy; A1 and A2 are independently halogen, -OH, -OR, -CF3, -NR1R, -C(O)Yr, -SO2R, or -SO2NR1R, orA2 is hydrogen; wherein the alkyl, cycloalkyl, aryl, and fused arylcycloalkyl groups may carry substituents selected from the group consisting of alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, -CF3, -OH, -SH, halogen, -NH2, -NO2, -COOR, -NH-C(NH2=NH, and -N-C=NCH=CHCH-N; provided that when Q contains a sulfur atom, R5 is not amino-substituted alkyl;; and provided further that when 0 contains a sulfur atom, A1 is chloro, A2 is hydrogen, Z is -S-, X is -CH2, n is one, R2 is hydrogen or unsubstituted C1 -C6 alkyl and R3 and R4 are hydrogen, and the -SO2NH2 group and An are respectively in the meta and para positions with respect to the point at which the ring G is attached to the heterocyclic ring, then R5 is (CH3)3CCH2-,(CH3)3C-, aryl-alkyl wherein the aryl moiety has up to 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, fused cycloalkylaryl having 8 to 12 carbon atoms, or heterocyclic.

Preferred compounds within the scope of the present invention include those wherein Y1 and Y2 are independently hydroxy or alkoxy containing up to 8 carbon atoms; Rand R1, independently, are preferably hydrogen orC1-C8 alkyl; R2 is H; alkyl having 1 to 8 carbon atoms; or an alkyl group having 1 to 8 carbon atoms which is substituted with amino or an amino derivative such as -NH-C(NH2)=NH, or -N-C=NCH=CHCH=N; and R2 is more preferably methyl or NH2(CH2)W; R3 is preferably hydrogen; R4 is H, alkyl having 1 to 8 carbon atoms, and phenyl-alkyl wherein the alkyl has 1 to 4 carbon atoms, and more preferably phenethyl; or indanyl, e.g., 2-indanyl; R6 is preferably (CH3)3CCH2- or (CH3)3C- when Q contains a sulfur atom; A1 is halogen; -OH; phenoxy; alkoxy having up to 6 carbon atoms; and preferably chloro, and more preferably chloro in the para-position relative to the point at which the ring G is attached to the heterocyclic ring; A2 is halogen, and more preferably chloro; -OH;-NH2; alkoxy having up to 6 carbon atoms; -COOR; or CF3; or hydrogen. The sulfamoyl group is preferably in the meta-position relative to the point at which G is attached to the heterocyclic ring.

The alkyl groups include straight-chained and branched groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, amyl, iso-amyl, hexyl, and the like. By "halogen" is meant chloro, bromo, iodo, and fluoro.

Preferred R1 and/or R2 substituents also include cycloalkyl groups, aryl groups, heterocyclic groups, and fused aryl-cycloalkyl groups, as defined herein, any of which can be connected to the main chain of the molecule (1 ) directly or thorough an alkylene bridge -(CH2)n- wherein n is 1 to 6. The preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, or norbornyl. The preferred aryl and fused aryl-cycloalkyl groups include phenyl, indolyl, indolino, indanyl, naphthyl, tetrahydronaphthyl, and decahydronaphthyl.Preferred heterocyclic groups include pyridyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, pyrrolidyl, pyrrolyl, morpholinyl, furyl, tetrahydrofuryl, furfuryl, benzimidazolyl, thienyl, and imidazolyl. Preferred arylalkyl substituents include benzyl and phenethyl. Preferred substituents on the alkyl, cycloalkyl, aryl, and fused aryl-cycloalkyl substituents include alkyl and alkoxywith 1 to 6carbon atoms, -CF3, OH, -NH2, phenoxy, -NR1R2,-COOH, -CN, -SH, halogen, -NO2, and COOR, particularly COO-C, 6 alkyl.

Compounds according to formula (1) can contain asymmetric centers at the carbon atoms marked thus: C*, and at one or more carbon atoms in the ring formed by X and Z. Each of these carbon atoms can have an (R) or an (S) configuration. In the preferred compounds the asymmetric carbons in 0, and the carbon atom to which Q is attached in the formula (1), are in the (S) configuration. The asymmetric carbons in the heterocyclic ring are in the (R) or (S) configuration. Individual optical diastereoisomers as well as mixtures thereof are considered to be within the scope of this invention. When diastereoisomeric products result from the synthetic procedures, the desired diastereoisomeric product can be separated by conventional chromatographic or fractional crystallization methods.

The compounds of formula (1) can be prepared by coupling compounds of formulas (2) and (3)

wherein 0, R2, R3, X, Y2, Z, A1 and A2 have the meanings defined herein.

Compound (3) can be prepared, for example, by reacting a suitably substituted aldehyde G-CH=O with a compound of the formula H2N -CH(COY2)-X-ZH so that the terminal amino and -ZH groups cyclize with the aldehyde carbon.

It will be recognized by those skilled in this art that the coupling of compounds (2) and (3) can be carried out by conventional peptide linkage techniques, e.g., in the presence of a coupling agent such as DCC (N,N'-dicyclohexylcarbodiimide) or CDI (N,N'-carbonyldiimidazole). Alternatively, one may prefer to convert the -COOH group of compound (2) to -C(O)CI, and then react the resulting intermediate with compound (3).

Alternatively one may preferably convert the compound (2) to the corresponding N-carboxyanhydride (NCA) by allowing (2) to react with phosgene, and then react the resulting N-carboxyanhydride with compound (3) to yield the desired intermediate.

It will further be recognized that the nitrogen atom which is between the carbon atoms to which R4 and R2 are attached can be protected with a blocking group such as 2,2,2-trichloroethoxycarbonyl, or benzyloxycarbonyl. The protecting group is subsequently removed, preferably after compounds (2) and (3) have been joined together. Other nitrogen atoms, in substituents such as NH2(CH2)4-, should be protected and then deprotected in a similar manner. Similarly, Y1 and Y2 are preferably converted to ethoxy, t-butoxy, or benzyloxy, before the intermediates are reacted. If the free acid is desired, it is subsequently obtained by removal of the esterifying group in a known manner.

The compounds of the present invention in which Y1 and Y2 is -OH and the other is alkoxy, such as methoxy or ethoxy, are preferably made by reacting compounds (2) and (3) as shown 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 amide intermediate thus prepared yields the desired monoester-monoacids upon a mild acid hydrolysis.

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

The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred), alkaline earth metals salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine and the like. Also, salts with organic and inorganic acids may be prepared, e.g., HCI, HBr, H2SO4, H3PO4, as well as methanesulfonic, toluenesulfonic, maleic, acetic, malic citric, fumaric and camphorsulfonic acids. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.

The salts may be formed by conventional means, as 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 solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying, or by exchanging the cations of an existing salts for another cation on a suitable ion exchange resin.

The action of the enzyme renin on angiotensinogen, a pseudoglobulin, in blood plasma, produces the decapeptide angiotensin I. Angiotensin I is converted by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II. The latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs. The compounds within the scope of this invention which intervene in the renin-to-angiotension l-to-angiotensin II sequence inhibit angiotensin I converting enzyme and therefore are useful in reducing or relieving hypertension.

Furthermore, the compounds within the scope of the present invention which possess diuretic activity promote relief from hypertension by promoting diuresis, and consequently have utility in treating congestive heart failure. Thus, by the administration of a composition containing one or a combination of compounds of formula (1) or pharmaceutically-acceptable salts thereof, hypertension in the species of mammal suffering therefrom is alleviated. A single dose, or preferably two to four divided daily doses, provided on a basis of about 0.1 to 100 mg per kilogram per day, preferably about 1 to 50 mg per kilogram per day, is appropriate to reduce blood pressure. The substance is preferably administered orally, but a parenteral route such as subcutaneously, intramuscularly, intraveneously or intraperitonealy can also be employed.

The compounds of the invention can be utilized 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 of formula (1 ) or physiologically acceptable salts(s) thereof is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, 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 magneisum stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, 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 parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate, and the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.

Specific embodiments of the invention are illustrated in the following Examples.

Example 1 A. 2-Chloro-5-methylaniline A suspension of powdered iron (440) g, 7.88 mol) in water (333 ml) was heated until hot in a boiling water bath, and the bath was then removed. 4-Chloro-3-nitrotoluene (39.6 g, 0.231 mol) was added with vigorous stirring, followed by concentrated HCI (9.25 ml). In 5 min. more 4-chloro-3-nitrotoluene (201.4 g, 1.174 mol) was introduced. Concentrated HCI (46.2 ml) was added in portions over the next 20 min., then the mixture was heated in the water bath for 1 hr. The bath was removed and a solution of sodium hydroxide (18.5 g, 0.462 mol) in water (37 ml) was added. The solution was filtered hot and the black precipitate was extracted several times with boiling ether, the extracts being added to the filtrate.The extract/filtrate mixture was separated; the organic layer was washed with water and brine, then dried (Na2SO4 and concentrated to a dark oil which soon solidified.

Yield: 193.5 g (97.2%).

B. 4-Chloro-3-chlorosulfonyltoluene Concentrated HCI (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 was cooled in an ice bath and sodium nitrite (5.3 g, 77 mmol) in water (6.5 ml) was added over 1 min.

A second solution was prepared by adding CuCI2-2H2O (2.8 g)/H2O (4 ml) to 38 ml of 34% SO2/HOAc at 0 C.

This was cooled in an ice bath as the above diazonium salt solution was introduced over 5 min. The ice bath was removed and the mixture was stirred 2 hr., then filtered and poured into water (500 ml). The precipitate was filtered, washed with water and dried in vacuo to give 13.9 g of (88%) product.

C. 4-Chloro-3-sulfamoyltoluene 4-Chloro-3-chlorosulfonyltoluene (128.3 g, 0.57 mol) was added in portions to anhydrous ammonia (1200 ml) at -78 C. The mixture was held at -78" for 6 hours, then the ammonia was allowed to evaporate overnight.

Water was added to the residue and the resulting slurry was filtered. The precipitate was recrystallized from ethanol to give 103.6 g (88%) of an off-white solid.

D. N-A cetyl-2-chloro-5-diacetoxymethylbenzenesulfonamide 4-Chioro-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 was cooled at 5"C and chromium (VI) oxide (22.4 g) was added over 1 hr. during which the solution temperature was kept less than 10"C. Stirring was continued an additional hour, the mixture was poured onto ice (500 g) and, in 30 min. the precipitate was filtered and washed with water. Recrystallization gave 14.8 g (50%) of a solid, m.p. 161-163C.

E. 4- Chlaro-3-suifamo yibenzaldeh yde N-Acetyl-2-chloro-5-diacetoxymethylbenzene-sulfamonamide (57.5 g, 0.158 mol) was refluxed for 4 hrs. in 2N HCI (170 methanol (365 ml), then concentrated to a small volume in vacuo. The precipitate was filtered and washed with water to give 33.8 g (97%) of product.

F. Ethyl-2-64-chloro-3-sulfamoylphenyl)-4{R)-thiazolidine carboxylate L-Cysteine ethyl ester hydrochloride (2.78 g, 15 mmol) in water (5.6 ml) was added to 4-chloro-3sulfamoylbenzaldehyde (3.29 g, 15 mmol) in warm ethanol (30 ml) and heated 15 min. on the steam bath, then allowed to stand overnight. The mixture was adjusted to pH 4.5 with sodium bicarbonate solution, then concentrated in vacuo. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate.

The organic layer was removed, washed with brine and dried (Na2SO4). Concentration provided the product (4.9 g, 94%) as an oil.

G. Ethyl N-[N-J( 15)- 1-eth axycarb an yl-3-ph 1-ethoxycarbonyl-3-phénylpropyl]- chloro-3-sulfamoylphenyl)-46R)-thiazolidine carbaxylate Oxalyl chloride (4.04 g, 31.8 mmol) was added to N-[(1 S)-1 -ethoxycarbonyl-3-phenylpropyl]-N [2,2,2- trichloroethoxycarbonyl]-L-alanine (5.09 g, 11.2 mmol) in methylene chloride (71 ml), followed by N,N-dimethylformamide (76 ul). In 4 hrs. the solution was concentrated in vacua.The residue was dissolved in CH2Cl2 (25 ml) and added in portions over 10 min. to ethyl 2-(4-chloro-3-sulfamoylphenyl)-4(R)thiazolidine-carboxylate (3.93 g, 11.2 mmol) andtriethylamine (1.25 12.3 mmol) in CH2CI2 (150 ml) at O"C.

The solution was stirred overnight, then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCI, saturated NaHCO3 solution and brine, then dried (Na2SO4) and concentrated to an oil.

Purification by HPLC gave 2.4 g (27%) pure product.

H. Ethyl N-[N-f(lS)- 1-eth oxycarb on yl-3-phen ylprop y-L-alan yl]-2-(4-chloro-3-suIfam o ylphen yl)-4(RI- thiazolidinecarboxylate A suspension of powdered zinc (2.11 g, 32.2 mmol), ethyl N-[N-[(1 S)-1 -ethoxycarbonyl-3-phenylpropyl]-N [2,2,2-trichloroethoxycarbonyl]-L-alanyl ]-2-(4-chloro-3-su If amoyl phenyl )-4(R)-thiazolidinecarboxylate (1.88 g, 2.39 mmol) and acetic acid (12.8 ml) was stirred 4 hr., then filtered through celite (RTM), the celite being washed well with tetrahydrofuran. The filtrate and washings were combined and concentrated in vacuo to remove most of the THF, and the residue was poured into water.The mixture was extracted with ethyl acetate and the organic layer was washed with saturated NaHCO3 solution and brine, then dried (Na2SO4 and concentrated to a foam (1.28 g, 87%). Pure material was obtained by HPLC purification.

Example 2 N-fN-[( 1S)- I- Carb oxy-3-phen ylprop y-l-alan yl]-2-(4-chloro-3-su/fam o ylphen yll-4(R)-thiazolidinecarboxylic acid Sodium hydroxide (0.21 g, 5.3 mmol) in water (0.60 ml) was added to ethyl N-[N-[(1S)-1-ethoxycarbonyl-3- phenylpropyl]-L-alanyl]-2-(4-chloro-3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylate in methanol (5.2 ml) and stirred 1.5 hour. The mixture was concentrated to remove methanol and 1.00 N HCI (5.2 ml) was added.

The resulting precipitate was filtered, washed with water and recrystallized from aqueous ethanol to give 0.44 g (65%) product, m.p. 161-163C.

Example 3 N-[N-[(1 S)-1 -carboxy-3-phenylprnpylj-L-alanylj-2-(4-chlorn-3-sulfamoylphenyl)-4(R)-oxazolidine- carboxylic acid.

Example 4 N-[N-[(1 S)-1 -carboxy-3-phenylpropyl]-L-ala nyl]-2-(4-chloro-3-su If amoyl phenyl ,3thiazinecarboxylic acid.

Example 5 N-[N-[(1 S)-1 -carboxy-3-phenylpropyl]-L-alanyl]-2-(4-chloro-2-hydroxy-5-sulfamoylphenyl)-4(R)- thiazolidinecarboxylic acid.

Example 6 N-[N-[(1 S)-1 -carboxy-3-phenylpropyl]-L-alanyl]-2-(2-amino-4-chloro-5-sulfamoylphenyl)-4(R)- thiazolidinecarboxylic acid.

Example 7 N-[N-a-[(1 S)-1 -carboxy-3-phenylpropyl]-L-iysyl]-2-(4-chloro-3-sulfamoylphenyl)4(R)-thiazolidine- carboxylic acid.

Example 8 N-[2-(3,3-dimethyIbuWrylthio)prnpionyIj-2-(4-chIorn-3-suIfamoylphenyl)A(R)thiazolidinecarboxyIic acid Example 9 N-[N-[(1 S)-1 -carboxy-1 -(2-indanyl)methyl]-L-alanyl]-2-(4-chloro-3-su If amoylphenyl)-4(R)- thiazolidinecarboxylic acid.

Example 10 N-[2-(2,2-dimethyl propionylth io) propionyl]-2-(4-ch loro-3-su If amoylphenyl)-4(R)-th iazolidineca rboxylic acid.

Claims (23)

1. Acompound of the formula (1 )

and their pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts, wherein o is Y1-C(O)*H(R4)-NH, -NH2, R5-C(O)-S(C H(R4))n, or HS-(C'H(R4)-; 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, alkyl having 1 to 8 carbon atoms, aryl having up to 12 carbon atoms, aryl-alkyl wherein the aryl moiety has up to 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, fused cycloalkylaryl having 8 to 12 carbon atoms, heterocyclic, or an alkyl group having 1 to 6 carbon atoms which is substituted with -NH2-,-NH-C(NH2)=NH2, or -N-C=NCH-CHCH=N; or R4 can be -(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)-;; Xis an alkylene bridge 1,2 or 3 carbon atoms long which is optionally substituted with hydroxy, phenyl, C1-C6 alkyl, or C,-C6 alkoxy; A1 and A2 are independently halogen, -OH, -OR, -CF3, NR1R, -C(O)Y1, -SO2R, or -SO2NR1R, orA2 is hydrogen; wherein the alkyl, cycloalkyl, aryl and fused aryl-cycloalkyl groups may carry substituents selected from the group consisting of alkoxy with 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, -CF3,-OH, -SH, halogen, -NH2, -NO2, -COOR, -NH-C(NH2)=NH, and -N-C=NCH=CHCH=N; provided that when 0 contains a sulfur atom, R6 is not amino-substituted alkyl;; and provided further 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 unsubstituted C1 -C6 alkyl, and R3 and R4 are hydrogen, and the -SO2NH2 group and A1 are respectively in the meta and para positions with respect to the point at which the ring G is attached to the heterocyclic ring, then R5 is (CH3)3CCH2-,(CH3)3C-, aryl-alkyl wherein the aryl moiety has up to 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, fused cycloalkylaryl having 8 to 12 carbon atoms, or heterocyclic.

2. A compound or salt according to Claim 1 wherein 0 does not contain sulfur.

3. A compound or salt according to Claim 2 wherein R2 is not hydrogen, and R3 is hydrogen.

4. A compound or salt according to Claim 2 wherein A1 is halogen.

5. A compound or salt according to Claim 3 wherein R2 is methyl or NH2(CH2)4-

6. A compound or salt according to Claim 5 wherein R4 is phenethyl.

7. A compound or salt according to Claim 5 wherein R4 is indanyl.

8. A compound according to Claim 6 which is ethyl N-[N(1 S)-1 -ethoxycarbonyl-3-phenylpropyl]-L- alanylj-2-(4-chloro-3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylate and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

9. A compound according to Claim 6 which is N-[N-[(1S)-l -carboxy-3-phenylpropyl]-L-alanyl]-2-(4- chloro-3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

10. A compound according to Claim 6 which is N-[N-[(1S)-1-carboxy-3-phenylprnpyl]-L-alanyl)-2-(4 chloro-3-sulfamoylphenyl)-4(R)-oxazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

11. A compound according to Claim 6 which is N-[N-[(1 S)-1-carboxy-3-phenylpropyl]-L-alanyl]-2-(4- chloro-3-sulfamoylphenyl)-4(S)-tetrahydro-1 ,3-thiazinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

12. A compound according to Claim 6 which is N-[N-[(1 S)-1 -carboxy-3-phenylpropyl]-L-alanyl]-2-(4chloro-2-hydroxy-5-sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

13. Acompound according to Claim 6which is N-[N-[(1S)-1-carboxy-3-phenylpropyl]-L.alanyl]-2-(2.

amino-4-chloro-5-sulfamoylphenyl-5(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

14. A compound according to Claim 6 which is N-[N-a-[(1 S)-l -carboxy3-phenyl propyl]-l-lysyl]-2-(4- chloro-3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

15. A compound according to Claim 7 which is N-[N-[(1S)-l -carboxy-l -(2-indanyl)methyl]-L-alanyl ]-2-(4- chloro-3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

16. A compound or salt according to Claim 1 wherein 0 contains a sulfur atom.

17. A compound or salt according to Claim 16 wherein n is one, and R4 is not hydrogen.

18. A compound or salt according to Claim 16 wherein n is zero.

19. A compound or salt according to Claim 16 wherein A2 is not hydrogen.

20. A compound or salt according to Claim 16 wherein Z is not -S-.

21. A compound according to Claim 18 which is N-[2-(3,3-dimethylbutyrylthio)propionylj-2-(4-chloro-3- sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

22. A compound according to Claim 18 which is N-[2-(2,2-dimethylpropionylthio)propionyl]-2-(4-chloro- 3-sulfamoylphenyl)-4(R)-thiazolidinecarboxylic acid, and its pharmaceutically acceptable acid addition, alkali metal, and alkaline earth metal salts.

23. An antihypertensive pharmacetical preparation compound or salt as in any of Claims 1-22 in combination with a pharmaceutically acceptable carrier.