PHOSPHINYLALKANOYL IMINO ACIDS

Abstract: Phosphinylalkanoyl imino acids containing a 1,2,4-benzothiadiazine-1,1-dioxide moiety and useful in the treatment of hypertension.

Description: PHOSPHINYLAL ANOYL AMINO ACIDS The present invention relates to phosphinyl- al anoyl i ino acids. Compounds of this invention are useful as antihypertensives, in the treatment of congestive heart failure, and in the treatment of glaucoma. Compounds of this invention may have diuretic and/or angiotensin converting enzyme (ACE) inhibitory activity. More particularly, this invention relates to compounds represented by the following formula I wherein X is Ila lib Y is -S- or -0- ; D is -CO-NH- or a bond; m, n, and r are independently 0-4; x is 1-4; p and q are independently 0 or 1, provided that the sum of p and q is 1 or 2; s is 2 or 3; t is 1-3; R is hydrogen, lower alkyl, halogen-substituted lower alkyl, cycloloweralkyl, cycloloweralkyl-(CH 2 ) u -, or CgH 5 -(CH ) v - wherein u is 1-4 and v is 0-4; R is hydroxy, alkoxy having from 1 to 8 carbon atoms, phenylloweralkoxy, allyloxy, R -Q w - (CH )y-0-, wherein Q is oxygen or sulfur, w is 0 or 1 and y is 2 to 4, -OCH(R 10 )-OCO-alkyl wherein the alkyl has from 3 to 8 carbon atoms, -OCH(R 10 )-OCO-phenyl wherein the phenyl may be substituted with group T defined below, 1-glyceryl, R is R or heterocycloloweralkyl; R is hydrogen or lower alkyl; A C R and R are independently hydrogen, lower alkyl or cycloloweralkyl, or R and R J together with the carbon atoms to which they are attached form a 5- or 6- member_ed ring; R and R are independently hydrogen, lower alkyl or cycloloweralkyl, or R and R' together with the nitrogen and carbon atoms to which they are attached form a 4-, S~, 7- or 8-membered ring; R 8 is R1 , amino, hydroxylamino, mono- or di- substituted amino wherein the substituents are lower alkyl, phenyl or phenylloweralkyl, and wherein the phenyl may be substituted with group T defined below; q R is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2- naphthyl; T is halogen, hydroxy, t ifluoro ethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trifluoromethyl, lower alkoxy or lower alkyl; R is hydrogen or alkyl having from 1 to 8 carbon atoms; R" L1 is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenylloweralkyl wherein phenyl may be substituted by group T; R 4 - *11 is hydrogen or lower alkyl; R is chloro or trifluoromethyl; or a pharmaceutically acceptable salt thereof. When X is formula Ha, a preferred group is characterized by R and R , together with the carbons to which they are attached, forming a five or six-membered ring. When X ' is formula lib, compounds wherein each Y is sulfur and s is 2 are preferred. For compounds wherein X is lid, a preferred group is represented by values of 0 and 1 for p and q, respectively. Formulae Ha and lib represent preferred structures for group X. Compounds wherein Z is formula Ilia are much preferred,, with those wherein A is -(CH 2 ) m -h f-(CH 2 ) r -D- being more- preferred. Especially preferred are those compounds wherein Z is of formula Ilia and wherein m and r are not zero. When Z is formula Ilia and A is not a bond, n is preferably 0 or 1. Also ' preferred are compounds wherein the phenylene group in A is 1,4- phenylene. Another group of preferred compounds is those wherein R 13 is chloro. Also preferred are compounds wherein Z is formula IHb wherein B is a bond. More preferred are compounds wherein Z is of formula IHb, B is*a bond and 2 R is hydrogen; especially preferred are those compounds wherein B is a bond, R is hydrogen and n is 5. Examples of preferred compounds of formula I are as follows: especially wherein 2 is benzyl, R3 is methyl and n is 4; especially wherein R 2 is benzyl, R 3 is methyl, and n is 4; especially wherein R is phenyl, R is n-butyl or phenylethyl, r is hydrogen or methyl, n is 3, and X is cyclopentyl glycine (i.e., X is of formula He wherein R is cyclopentyl, and R 7' and R°fl are hydrogen) ; especially wherein r is 0 , n is 1 or 3 and is not zero; especially wherein m is not 0 and the sum of r and n is 3 or 4. As used herein, "lower alkyl" means straight or branched chain hydrocarbon radicals of from 1 to 6 carbons, e.g. methyl, ethyl, propyl, isopropyl, butyl, t- butyl, pentyl and hexyl. Similarly, "lower alkoxy" means straight or branched alkoxy radicals having from 1 to β carbon atoms, e.g. methoxy, ethoxy, propoxy, butoxy, isobutoxy, pentoxy and hexyloxy. "Halogen" means fluorine, chlorine and bromine. "Heterocyclo" radicals include 5- or 6-membered aliphatic or aromatic rings containing 3 to 5 carbon atoms and 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen, e.g. imidazolyl, thiazolyl, pyridyl and morpholinyl; all positional isomers (e.g. 2-, 3- or 4-pyridinvl) are included. Compounds of the present invention may exist in various stereoisomeric forms. Preferred stereoisomers are those in which the absolute configuration at carbon atoms adjacent to both a nitrogen and a carbonyl group corresponds to the absolute configuration of ct-amino acids. All stereoisomeric, diastereoisomeric and raceraic forms are within the scope of the present invention. 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, e.g. sodium and potassium salts, and alkaline earth metal salts, e.g. calcium and magnesium salts. Salts with organic bases may also be prepared, e.g., N-methylglucamine, lysine and arginine salts. Those compounds with a basic substituent e.g., pyridinyl, may form salts with organic and inorganic acids, e.g. HCl, HBr, H 2 S0 4 , H3PO4, ethanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. The non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g. in isolating or purifying the product. The alkali metal salts are preferred, especially the sodium salt. The salts may be formed by conventional means, as by reacting the free acid or 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 exchanging the cations of an existing salt for another cation on a suitable ion exchange resin. The compounds of the formula I can also be regarded as having the formula E-W where E and W are moieties that build up a compound of formula I and are united by an amide bond (CO-N or S0 2 ~N). Thus, E and W can have values qiven in the following table, where Z and Z" 1 denote the benzothiadiazine nucleus of the groups of formulae Ilia and IHb respectively, such that Z .S0 2 -NH-A- is formula Ilia and Z .B is formula IHb, the central part of formula I, namely - is denoted by L, and the various symbols (A, B, R, R , X, Z, m, n, r and x) are as defined in formula I: W Z-L-CO- -X The invention therefore provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises reacting an acid of the formula E-Off or an amide-forming derivative thereof, under amide- forming conditions with an amine of the formula H-W or with an amide-forming derivative thereof, and isolating the product of the formula I as such or as a pharmaceutically acceptable salt thereof; where Ξ and ~~ are as hereinabove defined. When the acid E-OH and amine H-W themselves are used in- this process, the amide-forming conditions are conveniently provided by a dehydrating agent, e.g., a σarbodiimide. Preferred embodiments of this process will now be described, in particular for the preparation of compounds of the formulae Ia-Ie hereinabove defined. Compounds of formula la (i.e. wherein Z is of formula IHb and B is a bond) can be prepared by condensing an acid of formula IV with an amino acid derivative of formula V: -) la wherein R, R 1 , R 2 , R 3 , R 13 , x and n are as defined above. The reaction is carried out in an inert solvent such as dimethylformamide (DMF) in the presence of a condensing agent such as l,l'-σarbonyldiimidazole. The reaction is preferably carried out in an inert atomosphere at a temperature of 0-25°C. Compounds of formula IV can be prepared by known methods, for example as shown in the following flow diagram for compounds wherein R, R 2, R3 and R8 are hydrogen and n is 4: l,l'-carbonyl- xla + v iimidazole > la Compounds of formula V, VI, VII and IX are known in the art or may be prepared by well-known methods. Compounds of formula lb (wherein Z is of formula IHb and B is -(CH 2 ) r -CO-NH-) may be prepared by condensing a benzothiadiazinyl acid of formula XII with an aminoalkylphosphinyl compound of formula XIII: XIII wherein R, R J R^ R 3 , R 13 , n and X are as defined above, under conditions similar to those described for preparing compounds of formula la. Compounds of formulae XII and XIII are both known in the art, or may be prepared by readily available methods. To prepare compounds of formula Ic (wherein Z is of formula Ilia and A is a bond) a benzothiadiazinyl sulfonyl chloride of formula XIV may be reacted with an aminoalkylphosphinyl compound of formula XIII: wherein R , R and ~ \ J - J are as defined above. Reaction conditions are again similar to those for preparing compounds of the formula la. Compounds of formula XIV may be prepared from known starting materials using procedures well-known in the art. For example, when R 2 is phenylethyl, R3 is hydrogen and R J is chloro, a sulfonyl chloride of formula XlVa may be obtained by reacting a disulfonyl chloride of formula XV with aqueous ammonia at low temperature (dry-ice/acetone bath) in a solvent such as 1, 2-dimethoxyethane (DME) in the presence of a base such as triethyla ine to obtain a sulfonamide of formula XVI, followed by reaction of the sulfonamide with phenyl- propanal in a solvent such as DME and in the presence of an acid such as p-toluenesulfonic acid: XV XVI XlVa For compounds of formula Id (i.e. wherein Z is of formula Ilia and A is -(CH 2 ) m —Λ)— (CH 2 ) r -D- and wherein D is -CO-NH-) an acid of formula XVII may be reacted under the conditions described above with an aminoalkylphosphinyl compound of formula XIII: wherein R " ~ , R ~ \, Rι ~, m and r are as defined above. Compounds of formula XVII may be prepared by known methods; for example compounds of formula XVIIa wher.ein m is 1, r is 0, the phenylene group is 1,4- phenylene, R is chloro and R and R J are as defined above, may be prepared as follows: XIX XIX -h XIV XVIIa Compounds of formula e (i.e. wherein Z is of formula Ilia, A is -(CH 2 ) m — fj—(CH 2 ) r -D and wherein D is a bond) may be prepared by condensing an acid of formula XXI with an amino acid of formula V, again under conditions similar to those described for compounds of formula la: XXI wherein R, R 1 , R 2 , R 3 , R 13 , X, m, n and r are as defined above. Acids of formula XXI may be prepared from known starting materials using known methods. For example, compounds of formula XXIa wherein R, R x and R are hydrogen, R is chloro, the phenylene group is 1,4- phenylene, r is 0, m is 1, n is 4, and R , R and X are as defined above, may be prepared as follows: χ H XXIII (EtO) 2 -P-CH 2 - ftC-0-Et XXVII deprotect Compounds of formulae XXII and XXIII are known or may be prepared by known methods. The known coupling methods above may include phosphinyl group protection during the coupling reaction, for example with protecting groups such as alkyl, e.g. ethyl, and benzyl groups, followed by their removal to Q yield compounds of formula I. Furthermore, the COR function wherein R 8 is OH may be protected by removable ester groups such as benzyl, ethyl, t-butyl, tri ethylsilylethyl and the like. The following Preparations and Examples further illustrate the preparation of compounds of this invention. PREPARATION 1 6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETHYL)-2H-1,2,4-BENZO- THIAPIAZINE-7-SULFONYL CHLORIDE, S,S-DIOXIDE A. Dissolve 5 g 4-amino-6-chloro-l,3-benzenedisulfonyl chloride in 20 ml DME, cool in a dry-ice/acetone bath and add 2 ml triethylamine. Add dropwise 25% ammonium hydroxide in water (1 ml) in DME (4 ml) , stir in a dry- ice/acetone bath for 1 hour, allow to warm to room temperature, and stir for 90 min. Dilute the resultant reaction mixture with ethyl acetate, wash with 4% aqueous HCl, water and brine, dry over MgSO^ and evaporate to obtain a solid residue. B. Combine 13.6 g of the sulfonamide prepared in Step A, 6.57 g 3-phenyl-propanal, 25 ml DME and 20 mg p-toluene- sulfonic acid and stir at room temperature under N for 3 hours. Evaporate the solvent, dissolve the resultant residue in 250 ml ethyl acetate, wash with 100 ml saturated aqueous NaHC03 and 100 ml brine, then dry over MgSO^, filter and evaporate the solvent to obtain the crude title compound. Purify the crude residue by precipitation in CH 2 C1 2 ; mp. 167.0-167.5°C. PREPARATION 2 3-BϋTYL- -CHLORO-3,4-DIHYDRO-2H-l,2-4-BENZOTHlADlAZINE-7- SULFONYL CHLORIDE, S,S-DIOXIDE Combine 90 g of the sulfonamide prepared in Preparation 1 Step A, 36 ml valeraldehyde, 0.3 g p-toluenesulfonic acid and 400 ml DME and stir at room temperature for 20 hours. Evaporate the solvent, extract and precipitate the resultant residue as described in Preparation 1 Part B to obtain the title compound, m.p. 161-162°C. PREPARATION 3 CIS,SYN-OCTAHYDRO-lH-INDOLE-2(S)-CARBOXYLIC ACID, PHENYLMETHYL ESTER A. Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml of trifluoroacetic acid. Add 2.05 g of platinum oxide and hydrogenate the mixture at 345 kPa (50 lb/in ) at room temperature. Filter the mixture and concentrate the filtrate _in_ vacuo to give a residue. Suspend the residue in ether and treat with cold dilute sodium hydroxide solution. Dry the organic layer over magnesium sulfate and concentrate it to give octahydro-lH-indole-2- carboxylic acid, ethyl ester, a pale yellow oil. B. Dissolve 116 g d-10-camphorsulfonic acid in 1 liter of warm ethyl acetate and add a solution of 86 g of the product of part A in 1 liter of ethyl acetate. Allow the mixture to crystallize, heat to reflux, cool to room temperature, and filter. Recrystallize the filter cake from a mixture of 500 ml isopropanol and 1800 ml ethyl acetate, filter and dry the crystals to obtain cis,syn- octahydro-lH-indole-2(S)-carboxylic acid, ethyl ester, d- 10-camphorsulfonate, m.p. 192-193°C. C. Heat the product of Part B (107.6 g) and d-10- camphorsulfonic acid (6.35 g) in benzyl alcohol- (270 ml) at 105°C under vacuum for 6 hours or until TLC (silica, elute neutralized sample with ethyl ether) indicates reaction is complete. Pour the resultant residue into ethyl ether, seed and stir to obtain a precipitate. Filter off the precipitate, wash with ethyl ether (2 x 500 ml) and dry the resultant residue under vacuum to obtain cis,syn-octahydro-lH-indole-2(S)-carboxylic acid, phenylmethyl ester, d-10-camphorsulfonate, m.p. 114- 118°C. D. Suspend the product of Part C (150 g) in ethyl ether (1500 ml), add IN aqueous NaOH (300 ml) and stir until the solid dissolves. Separate the organic layer and wash the aqueous layer with ethyl ether (2 x 200 ml). Combine the organic layer, wash with brine, dry over Na 2 Sθ4 and evaporate the solvent to obtain the title compound. PREPARATION 4 CIS,SYN-OCTAHYDRO-lH-INDOLE-2(S)-CARBOXYLIC ACID, (1,1- DIMETHYLETHYL) ESTER A. Dissolve the product of Preparation 3 (77 g) in absolute ethanol (900 ml), add 4% Pd/C (10 g) and hydrogenate at room temperature at an initial pressure of -I8¬ 60 p.s.i. After 3 hours, filter off the catalyst and wash with hot methanol. Evaporate the combined filtrate and wash jui vacuo, triturate the resultant residue in ethanol (100 ml) , chill the solution, then filter and air dry the resultant precipitate to obtain -a residue of the free carboxylic acid, m.p. 269-270°C. B. Suspend the product of Part A in dioxan (400 ml) and cone. H2SO4 (40 ml) , add isobutylene (300 ml) and shake in a Parr shaker for 28 hours. Pour the resultant reaction mixture into 50% aqueous NaOH (150 ml) in 500 ml ice water and extract with ethyl ether (3 x 500 ml) . Wash the combined organic extracts with water, then brine. Dry the organic layer over a 2 Sθ4 and evaporate the solvent to obtain the title compound. The following Examples illustrate the preparation of compounds of formula I. Evaporating and drying were generally effected in vacuo. EXAM E 1 N-C [ [5-[6-CHLORO-3,4-DIHYDRO-2-METHYL-7- [ (PHENYLMETHYL) AMINOSULFONYL]-2H-1, 2 , 4-BENZOTHIADI ZIN-3- YL1 PENTYL] HYDROXYPHOSPHINYL] CΞTYL] -N-CYCLOPE TYLGLYCINE , S , S-DIOXIDE A) 4-Amino-6-Chloro-3- (Methylaminosulfonyl) Benzene- sulfonyl Chloride Cool a solution of 4-amino-6-chloro-l, 3- benzenedisulfonyl chloride (32.3 g) in tetrahydrofuran (THF, 150 ml) to -78°C under a nitrogen atmosphere. Add a solution of 1.45 Molar methylamine in benzene (100 ml) containing triethylamine (10.1 g) dropwise with stirring over 45 minutes. After the addition is complete, stir at room temperature for 3 hours. Evaporate off the solvent and partition the residue between ethyl acetate (EtOAc) (500 ml) and 10% aqueous citric acid (50 ml). Separate the organic layer and wash with saturated aqueous aHCθ3 (100 ml) followed by brine (100 ml). Dry the solution over a 2 Sθ4, filter and evaporate off the solvent. Triturate the residue with ether (100 ml) and collect the product by filtration. Dry at room temperature to give the title compound, m.p. 153-155°C; R f (silica gel; CH 2 Cl 2 :EtOAc,97:3) =0.40. B) 4-Amino-6-Chloro-N 3 -Methyl-N 1 - (Phenylmethyl) Benzene- 1,3-Disulfonamide Cool a solution of the product of Part A (8.0 g) in THF (50 ml) to 0°C under a nitrogen atmosphere and add a solution of benzylamine (5.36 g) and triethylamine (5.0 g) dropwise with stirring over 10 minutes. Stir at room temperature for 16 hours and evaporate off the solvent. Partition the residue between EtOAc (250 ml) and 10% aqueous citric acid. Separate the organic layer and wash with water (25 ml) followed by brine (25 ml). Dry the solution over Na 2 S0 4 , filter and evaporate off the solvent. Purify the product by chromatography on a silica gel column eluting with 3% EtOAc in CH 2 C1 . Combine fractions containing the desired product and evaporate off the solvent to obtain the title compound, m.p. 151-152.5°C; R f (silica gel; CH 2 Cl 2 ;ΞtOAc, 97:3)=0.20. C) 3-(5-Bromoρentyl )-6-Chloro-3,4-Dihydro-2-Methyl-7- [(Phenylmethyl)Aminosulfonyl] -2H-1, 2,4-Benzothiadiazine S,S-Dioxide Add acetic acid (HOAc) (50 ml) to the product of Part B (5.00 gm) and heat the mixture at 100°C until a clear solution forms. Cool the solution to 50°C and immediately add 6-bromohexanal (4.50 gm) followed by 12 N aqueous HCl (2 drops). Stir at room temperature for 16 hours. Collect the solid product by filtration and wash with cold HOAc (10 ml) followed by ether (50 ml). Dry the product at room temperature to obtain the title compound, m.p. 141-142°C. R f (silica gel; CH 2 Cl 2 :EtOAc, 97:3)=0.35. D) [[5-[6-Chloro-3,4-Dihydro-2-Methyl-7- [(Phenylmethyl) minosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl] Pentyl] Ethoxyphosphinyl]Acetic Acid, Ethyl Ester, S,S- Dioxide Heat the product of Part C (2.93 g) to 70°C under an argon atmosphere and add ethyl (diethoxyphosphino)acetate (3.20 g) with stirring. Heat under an argon atmosphere at 120°C for 1 hour with stirring. Increase the temperature to 180°C and maintain this temperature for 3 hours. Remove volatile material under vacuum and chromatograph the residue on a silica gel column elutinq with 3% CH3OH in EtOAc. Combine the desired fractions and evaporate off the solvent to obtain the title compound; Rg (silica qel; EtOAc:CH 3 OH, 97:3)=0.50. E) [[5-[6-Chloro-3,4-Dihydro-2-Methyl-7- [(Phenylme hyl)Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl] Pentyl]Hydroxyphosphinyl]Acetic Acid, Ethyl Ester, S,S-Dioxide Dissolve the product of Part D (2.50 g) in dry CH 2 C1 (30 ml) at- room temperature under an argon atmosphere. Add bromotrimethylsilane (5.0 ml) and stir for 3 hours at room temperature. Evaporate off the solvent and excess bromotrimethylsilane. Partition the residue between EtOAc (100 ml) and water (25 ml). Separate the organic layer and wash with brine (25 ml). Dry the organic layer over Na 2 S0 4 , filter and evaporate off the solvent. Chromatograph the product on a LH-20 Sephadex column eluting with CH 3 OH. Combine the desired fractions and evaporate off the solvent to obtain the title compound; f (silica gel; CH 2 C1 2 :CH 3 0H: HOAc, 8:1:1)=0.50. F) [[5-[6-Chloro-3,4-Dihydro-2-Methyl-7- [(Phenylme h l) minosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl]Pentyl]Hydroxyphosphinyl]Acetic Acid, S,S-Dioxide Cool a solution of the product of Part E (1.45 g) in THF (10 ml) to 0°C and add 0.50 N aqueous NaOH (15.0 ml). Stir at room temperature for 18 hours, then evaporate off the solvent. Partition the residue between ethyl acetate (50 ml) and 1 N aqueous HCl (10 ml). Separate the organic layer and wash with water (15 ml) followed by brine (15 ml). Dry the organic solution over a 2 S0 4 , filter, and evaporate off the solvent to obtain the title compound; R^ (silica gel; CH 2 Cl 2 :CH 3 0H:H0Ac, 8:1:1)=0.20. G) N-[ C [5-[6-Chloro-3,4-Dihydro-2-Methyl-7- [ (Phenylmethyl) Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl]Pentyl]Hydroxyphosphinyl] Acetyl]-N-Cyclopentylglycine, (1,1-Dimethylethyl) Ester, S,S-Dioxide Cool a solution of the product of Part F (0.60 gm) in dry N,N-dimethylformamide (DMF) (10 ml) to 0°C under an argon atmosphere and add 1,1'- carbonyldiimidazole (0.26 gm) with stirring. After 45 minutes, add triethylamine (0.20 ml) and N-cyclopentyl- glycine, (1,1-dimethylethyl) ester (0.31 gm) . Stir at 0°C for one hour, then for 18 hours at room temperature. Evaporate off the solvent and partition the residue between EtOAc (30 ml) and 10% aqueous citric acid (10 ml) . Separate the organic layer and wash with water (10 ml) followed by brine (10 ml). Dry the organic solution over Na 2 S0 4 , filter, and evaporate off the solvent. Chromatograph the residue on a LH-20 Sephadex column eluting with CH3OH. Combine the desired fractions and evaporate off the solvent to obtain the title compound; R f (silica gel; CH C1 2 :CH 3 0H:H0AC, 8:1:1) =0.40. H) N-[[[5-[6-Chloro-3, -Dihydro-2-Methyl-7- [ (Phenylmethyl) Aminosulfonyl]-2H-1,2, 4-Benzothiadiazin-3- yl] entyl ] Hydroxyρhosphinyl] Acetyl ] -N-Cyclopentylglycine , S ,S-Dioxide Cool a solution of the product of Part G (0.40 gm) in CH 2 C1 2 (5 ml) to 0°C under an argon atmosphere and add trifluoroacetic acid (5.0 ml) with stirring. Stir at room temperature for 18 hours. Evaporate off the solvent and excess trifluoroacetic acid. Partition the residue between EtOAc (25 ml) and water (5 ml) . Separate the organic layer and wash with brine. Dry the solution over a s0 4, filter, and evaporate off the solvent. Chromatograph the residue on a C-18 reverse-phase silica qel column eluting with a linear gradient of CH 3 OH/H 0 (60% →- 100% CH 3 OH) containing 0.2% trifluoroacetic acid. Combine the desired fractions and evaporate off the solvent to give 0.32 qm of the title compound. Rg (silica gel, CH 2 Cl 2 :CH 3 OH:HOAc,8: 1: 1)=0.30. EXAMPLE 2 1"[ C [4-C [ [6-CHL0R0-3,4-DIHYDR0-2-METHYL-7- [(PHENYLMETHYL)AMINOSULFONYL]-2H-1,2,4-BENZOTHIADIAZIN-3- YL]ACETYL]AMINO] BUTYL] HYDROXYPHOSPHINYL]ACETYL]-CIS,SYN- OCTAHYDRO-lH-INDOLE-2(S)-CARBOXYLIC ACID, S,S-DIOXIDE A) 6-Chloro-3,4-Dihydro-2-Methyl 7- [(Phenylmethyl)Aminosulfonyl]-2H-1,2,4-Benzothiadiazine- 3-Acetic Acid, Ethyl Ester, S,S-Dioxide Add the product of Example 1, Part B (3.0 gm) and ethyl 3,3-diethoxy-propionate (1.56 g.) to HOAc (50ml). With stirring, add 12 _N_ aqueous HCl (2 drops) and heat the mixture at 100°C until a clear solution forms. Stir at room temperature for 16 hours. Collect the solid product by filtration, wash with cold HOAc (20 ml) and dry to obtain the title compound. R^ (silica gel, CH 2 Cl 2 :EtOAc; 97:3)=0.40. B) 6-Chloro-3,4-Dihydro-2-Methyl-7- [ (Phenylmethyl)Aminosυlfonyl] -2H-1, 2,4-Ben2othiadiazine- 3-Acetic Acid, S,S-Dioxide Add THF (10 ml) to the product of Part A (1.90 g) and cool in an ice bath. With stirring, add 0.50 _N_ aqueous NaOH (8.0 ml) dropwise. Stir at 0° to 5°C for 20 hours. Evaporate off the solvent and partition the residue between EtOAc (150 ml) and 0.5 _N_ aqueous HCl (30 ml). Separate the organic layer and wash with water ' (30 ml) followed by brine (30 ml). Dry the organic solution over Na 2 S0 4 , filter and evaporate off the solvent to obtain the title compound, m.p. 141-145°C. C) l-[ [ [4-f[[6-Chloro-3,4-Dihydro-2-Methyl-7- [ (Phenylmethyl)AminosulfonylJ-2H-1, 2 , 4-Benzothiadiazin-3- yl]Acetyl]Amino]Butyl]Hydroxyphosphinyl]Acetyl]-cis,syn- Octahydro-lH-Indole-2(S)-Car oxylic Acid, (1,1- Dimethylethyl)ester, S,S-Dioxide Dissolve the product of Part B (0.46 gm) in DMF (20 ml) and cool the solution to 0°C under a nitrogen atmosphere. Add 1,1'-carbonyldiimidazole (0.016 gm) and stir at 0°C for 1 hour. Dissolve l-[[(4- arainobutyl)hydroxyphosphinyl]acetyl]-cis,syn-octahydro- lH_-indole-2(S)-carboxylic acid, (1,1-dimethylethyl)ester (0.37 gm) (See Example 3, Parts A-G) in DMF (25 ml) containing triethylamine (0.10 gm) and add this solution dropwise with stirring to the above cold solution. Stir at 0°C for 1 hour, then at room temperature for 18 hours. Evaporate off the solvent and partition the residue between EtOAc (50 ml) and 10% aqueous citric acid (1.5 ml). Separate the organic layer and wash with water (10 ml) followed by brine (10 ml) . Dry the organic solution over Na 2 S0 4 , filter and evaporate off the solvent. Purify the product by chromatography on a LH-20 Sephadex column, eluting with CH3OH. Combine fractions containing the desired product and evaporate off the solvent to obtain the title compound. D. 1-[ [ [4- [ [ [6-Chloro-3,4-Dihydro-2-Methyl-7- [ (Phenylmethyl) Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl]Acetyl]Amino]Butyl]Hydroxyphosphinyl]Acetyl]-cis,syn- Octahydro-lH-Indole-2 (S)-Carboxylic Acid, S,S-Dioxide. Dissolve the product of Part C in CH 2 C1 2 (15 ml) and cool to 0°C under a nitrogen atmosphere. Add trifluoroacetic acid (10 ml) and stir at 0°C for 1 hour followed by 13 hours at room temperature. Evaporate off the solvent and excess trifluoroacetic acid. Partition the residue between EtOAc (50 ml) and water (10 ml). Separate the organic layer and wash with brine. Dry the organic solution over Na 2 S0 4 , filter and evaporate off the solvent. Purify the product by chromatoqraphy on a C-18 reverse-phase silica gel column, eluting with a linear- gradient of CH 3 OH/H 2 0 (60% ÷100% CH3OH) containing 0.2% trifluoroacetic acid. Combine the desired fractions and evaporate off the solvent to obtain the title compound. EXAMPLE 3 1-[ [ [4-[ [ [6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETH L)-2H- 1,2,4-BENZOTHIADIAZIN-7-YL]SULFONYL] MINO]BUTYL]HYDROXY¬ PHOSPHINYL]ACETYL]-CIS,SYN-OCTAHYDRO-lH-INDOLΞ-2(S)- CARBOXYLIC ACID, S,S-DIOXIDE A) [Ethoxy-[4-[2,3-Dihydro-l,3-Dioxo-lH-Isoindol-2- yl]Butyl]Phosphinyl]Acetic Acid, Ethyl Ester Heat 12.5 gm of ethyl (diethoxyphosphino)- acetate with 16.9 qm of N-(4-bromobutyl)phthalimide in a melt at 180° for 5 hours under a nitrogen atmosphere. After cooling, chromatograph the mixture on a silica gel column, eluting with a gradient of 1% to 2% CH3OH in EtOAc. Isolate the major product by evaporation of the solvent from the combined fractions to obtain the title compound. R f (silica qel; EtOAc:CH 3 OH, 99:1)=0.40. B) [(4-Aminobutyl)Hydroxyphosphinyl]Acetic Acid Add the product of Part A (30.7 g) to a mixture of 90 ml HOAc, 90 ml 48% HBr, and 45 ml H 2 0 and heat at reflux with"stirring for 22 hours. Concentrate the solution to half volume and cool to give a precipitate of o_-phthalic acid. Obtain a second crop by further concentration. Concentrate the filtrate to dryness, take it up in 100 ml water, refilter, and extract thoroughly with ether. Evaporate the aqueous layer to dryness in vacuo to give a residue. Take up the residue in water and charge- to a column of Bio-Rad AG 50W-X3(H + ) cation exchange resin (900 g). Wash the column with deionized water until, no further bromide ion is detected in the eluate (Ag 03 test). Elute the column with 10% pyridine in water to give, after solvent removal, the title compound, m.p. 238°C (dec) . Rf (silical gel; BuOH:AcOH:H 2 0, 3:1:1) = one spot near origin, ninhydrin positive. Mass spectrum [FAB]: M+l ion at M=196. C) [4-f C (Phenylmethoxy)Carbonyl]Amino]Butyl]- Hydroxyphosphinyl]Acetic Acid. Suspend 1.99 g of the product of Part B in 25 ml dry CH3CN, add 10.5 g (10.8 ml) of bis (tri ethyl- silyl)trifluoroaceta ide and stir at room temperature until solids dissolve (approx. 1 hr). Add 2.9 ml benzyl σhloroformate and continue stirring at room temperature overnight. Quench the reaction with 10 ml water, then dissolve the product in excess 5% aqueous NaHO^. Extract the resultant solution with Ξt 2 0 (3X), acidify the aqueous layer with 10% aqueous HCl, and extract with EtOAc (3X). Wash the combined extracts with water, dry over MgS0 4 and evaporate the solvent to obtain a residue. R f (silica gel; BuOH:HOAc:H 2 0, 3:1:1) =0.4. Recrystallize the product from EtOAc to obtain the title compound, m.p. 98-101°C, FAB mass spec M/e=330 (M + H) . D) 1- [ C [ 4- [ [ ( Phenylmethoxy ) Carbonyl ] mi no ] Butyl ] - Hydroxyphosphinyl ] Acetyl ] -ci s , syn-Octahydro-lH-Indόle- 2 (S) -Car boxyl ic Acid , (1 , 1-Dimethylethyl ) Ester . Treat 4.0 g of the product of Part C in 25 ml dry THF at 10°C with 1.95 g of 1,1-carbonyldiimidazole. After 30 min., add 3.4 g cis,syn-octahydro-lH-indole- 2 (S) -carboxylic acid, (1, 1-dimethylethyl) ester in 5 ml THF. Stir the resultant solution overnight at room temperature. Remove THF in vacuo, and partition the residue between EtOAc and H 2 0. Wash the organic layer with 5% aqueous KHS0 4 , then extract with 5% Na 2 HP0 4 (5X). Wash the combined extracts with Et 2 0, then acidify with cold dilute HCl. Add the precipitate to EtOAc, wash with water and dry over MgS0 4 : Rf (silica gel; BuOH:flθAC:H 2 0, 3:1:1)=0.8; FAB mass spec M/e=537 (M+H); M/e=481 (M-isobutylene) . E) 1- [ C (4-Aminobutyl)Hydroxyphosphinyl] Acetyl]-cis,syn- Q ctahydro-lH-indole-2 (S) -Carboxylic Acid, (1,1-Dimethyl¬ ethyl) Ester Hydrogenate the product of Part D (1.7 g) at about 140 kPa (20 psi) over 0.5 g 5% Pd/C in 100 ml absolute ethanol for a total of 5 hours. TLC (silica gel; BuOH:HOAc:H 2 0,- 3:1:1) shows one spot near origin, ninhydrin positive. Remove catalyst, and evaporate the solvent _in_ vacuo to obtain a residue. FAB mass spec M/e=403 (M+H) . F) 1- C [ [4- [ [ [6-Chloro-3,4-Dihydro-3- (2-Phenylethyl)-2H- 1, 2, 4-Benzothiadiazin-7-yl]Sulfonyl]Amino]Butylj- Hydroxyphosphinyl]Acetylj-Cis,Syn-Octahydro-lH-indole- 2 (S)-Carboxylic Acid, (1,1-Dimethylethyl) Ester, S,S- Dioxide Dissolve 0.91 g of the product of Part E, 0.95 g of 6-chloro-3,4-dihydro-3-(2-phenylethyl)-2H- 1, 2, 4-benzothiadiazine-7-sulfonyl chloride, S,S-dioxide and 0.7 ml triethylamine in 25 ml dry THF. Stir overnight at RT. Filter off triethylamine HCl. Remove THF in vacuo. Dissolve the resultant residue in water and acidify with a cold 5% KHSO4 solution. Extract with ethyl acetate (3X), wash the extracts with water and dry over MgS04» Evaporate the solvent to obtain a residue. Chromatograph the resultant residue on a Lfl-20 Sephadex Column, eluting with methanol. Combine the desired fractions to obtain the title compound. FAB mass spec M/e=731 (M-isobutylene) . G) l-[ [ [4-[ [ [6-Chloro-3,4-Dihydro-3-(2-Phenylethyl)-2H- 1, 2,4-Benzothiadiazin-7-yl]Sulfonyl] Amino]Butyl]- Hydroxyphosphinyl]Acetyl]-cis,syn-Octahydro-lH-Indole- 2(S)-Carboxylic Acid, S,S-Dioxide Dissolve 1.02 g of the product from Part F in 25 ml CH 2 C1 2 , add 3 ml trifluoroacetic acid and stir overnight at room temperature. Wash the solution with water (4X), once with 5% aqueous citric acid, and again with water. Dry the organic phase over MgS0 4 and evaporate the solvent to obtain a residue. Chromatograph the residue on an LH-20 Sephadex column eluting with CH3OH to obtain the title compound. FAB mass spec M/e=731 (M + 1) . ΞXAMPLE 4 !-[[ [4-[[4-[ [ [ [6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETHYL)-2H- 1, 2, 4-BENZ0THIADIAZIN-7-YL] SULFONYL] AMINO]- METHYL] BENZOYL] AMINO] BUTYL] HYDROXYPHOSPHINYL] ACETYL] - CIS,SYN-OCTAHYDRO-lH-INDOLE-2(S) -CARBOXYLIC ACID, S,S- DIOXIDE A) 4-Cyanobenzoic Acid, (1,1-Dimethylethyl) Ester • Dissolve 22.1 g 4-cyanobenzoic acid and 28.2 ml t-butanol in 500 ml DMF. Add 9.15 g 4- (dimethylamino) - pyridine and 31.5 g 1- (3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride. Stir the mixture overnight at room temperature. Remove the DMF in vacuo, and partition the resultant residue between ethyl acetate and water. Wash the organic layer successively with cold 0.5N aqueous HCl, water, 5% aqueous aHCθ and brine. Dry the organic layer over MgSθ4 and evaporate the solvent to obtain the title compound, m.p. 75-8°C; R (silica gel; 5% EtOAc in hexane)=0.3; IR 2240 cm -1 ; 1730 cm -1 . B) 4- (Aminomethyl) Benzoic Acid, (1,1-Dimethylethyl) Ester Dissolve 10.1 g of the product of Part A in EtOH (100 ml) saturated with anhydrous NH 3 . Add 3.0 g 5% Rh on alumina and hydrogenate at 410 kPa (60 psi) overnight at room temperature. Remove the catalyst and evaporate the solvent to give the title compound. TLC (silica gel; EtOAc) shows one major spot near origin, ninhydrin positive. C) 4-[[[ [6-Chloro-3,4-Dihydro-3-(2-Phenylethyl)-2H- 1,2,4-Benzothiadiazin-7-yl]Sulfonyl]Amino]Methyl]Benzoic Acid, (1,1-Dimethylethyl)Ester, S,S-Dioxide Add 10.53 g 6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H-1,2,4-benzothiadiazine-7- sulfonylchXoride, S,S-dioxide to a stirred mixture of the product- of: Hart B (5.2 g) and 7.7 ml triethylamine in 50 ml dry; THE ' a±: 0°C. Stir the mixture at room temperature for 72 hours-.. Filter off the triethylamine HCl, and evaporate the solvent. Take up the resultant residue in EtOAc (800 ml) and wash with water, 0.5N cold aqueous HCl, 5% aqueous aHC^ and brine. Dry the organic layer over gSθ4, concentrate to about 300 ml and cool. Collect the solids and wash with cold EtOAc to give the title compound, m.p. 210°C (dec.) Rf (silica gel; 50% hexane in EtθAc)=0.5. FAB mass spec: M/e=592 (M) ; M/e=536 (M-isobutylene) . D) 4-[ [ [ [6-Chloro-3,4-Dihydro-3-(2-Phenylethyl)-2H- 1,2,4-Benzothiadiazin-7-yl]Sulfony]Amino]Methyl]3enzoic Acid, S,S-Dioxide Add 6.0 g of the product of Part C to a mixture of 50 ml acetic acid and 5 ml trifluoroacetic acid. Stir for 2 hours at room temperature, then pour into water and collect the precipitate. Water wash the precipitate and dry to give a residue, m.p. 248-251°C (dec.) FAB mass spec; M/e=563 (M) . Ξ) 1-[ [ [4-[ [4-C [ [ [6-Chloro-3,4-Dihydro-3-(2- Phenylethyl)-2H-1,2,4-Benzothiadiazin-7- yl]Sulfonyl]Amino]Methyl]Benzoyl]Amino]Butyl]Hydroxy- phosphinyl]Acetyl]-cis,syn,-Octahydro-1H-indole-2(S)- Carboxylic Acid, (1,1-Dimethylethyl) Ester, S,S-Dioxide Dissolve 2.4 g of the product of Part D in a mixture of 30 ml THF and 3 ml DMF and add a solution of l,l*-carbonyldiimidazole (0.73 g) in 5 ml THF. After 10 minutes, add a solution of 1.81 g of the product of Example 3, Part E in 10 ml DMF, and stir at room temperature overnight. Remove the solvents in vacuo at 40°C. Partition the resultant residue between 5% aqueous NaHCθ3 and EtOAc. Separate the layer containing the desired product (as determined by TLC), dissolve it in a large volume of EtOAc, dry over MgSθ4, and evaporate the solvent. Chromatograph the resultant residue on a Sephadex LH-20 column, eluting with methanol to obtain the title compound; R (silica gel; CH 2 Cl2:HOAc:CH 3 OH, 85:7.5:7.5) =0.2. FAB mass spec M/e=943 (M+Na) . F) 1-[ [ [4-[ [4-[ [ [ [6-Chloro-3,4-Dihydro-3-(2- Phenylethyl)-2H-l,2,4-Benzothiadiazin-7- 1]Sulfonyl]Amino]Methyl]Benzoyl]Amino]Butyl]Hydroxyphos- phinyl]Acet l]-cis,syn-Octahydro-lH-indole-2(S)- Carboxylic Acid, S,S-Dioxide Dissolve 0.92 g of the product of Part E in 3 ml TFA and stir at room temperature for 5 hours. Pour the product into ice water and separate the precipitate. Take up the precipitate in EtOAc, wash with water until neutral to pH paper, dry over MgS0 4 and evaporate the solvent to obtain a residue. Dissolve this residue in excess 5% NaHC0 3 solution, filter, and re- precipitate with 3N aqueous HCl. Collect the solids, wash and air dry. Dry further in vacuo over P2O5 to obtain the title compound. FAB mass spec: M/e ,= 8o4 (M) . E AM E 5 1- [ [ [5-[4-[ [ [ (3-BUTYL-6-CHLORO-3, 4-DIHYDRO-2H-1, 2 , 4- BENZOTHlADlAZIN-7-YL) SULFONYL] AMINO]METHYL] PHENYL]- PENTYL] HYDROXYPHOSPHINYL] ACETYL]-CIS,SYN-OCTAHYDRO-lH- INDOLE-2(S)-CARBOXYLIC ACID, S,S-DIOXIDE A) l-Bromo-5- ( 4-Cyanophenyl ] -4-Pentene Add (4-cyanophenylmethyl) triphenylphosphonium bromide (27.25 g) to dry THF (65 ml) and cool to -20°C under an argon atmosphere. With stirring, dropwise add 65 ml of a solution of 1 molar lithium bis (trimethylsilyl)amide in THF, maintaining the temperature at -20°C. Stir for 30 minutes at -20°C; then for 30 minutes at 0°C. Cool to -20°C and add freshly distilled 4-bromobutanal (10.50 g) dropwise with stirring. Stir at -20 β C for 1 hour, then at room temperature for 16 hours. Remove the solid material by filtration and wash with THF. Evaporate off the solvent from the filtrate and purify the resultant residue by chromatography on silica gel, eluting with CH 2 Cl 2 :hexane (4:1) . Combine the desired fractions and evaporate off the solvent to obtain the title compound. B) l-Bromo-5- (4-Cyanophenyl) Pentane Dissolve 5.0 gm of the product of Part A in EtOH (120 ml) and add platinum oxide (0.30 g) . Hydrogenate at atmospheric pressure with stirring until one equivalent of hydrogen is consumed. Remove the catalyst by filtration and evaporate off the solvent from the filtrate to obtain the title compound. C) [ [5- (4-Cyanophenyl) entyl]Ethoxyphosphiny] Acetic Acid, Ethyl Ester Heat the product of Part B (3.50 g) to 70°C under an argon atmosphere and add ethyl (diethoxy- phosphino)acetate (4.00 g) dropwise with stirring. Heat with stirring at 120°C for 1 hours, then increase the temperature to 180°C and stir at this temperature for 3 hours. After cooling, purify the product by chromatography on silica gel, eluting with EtθAc:MeOH (97:3). Evaporate off the solvent from the desired fractions to obtain the title compound. D) [ [5-[4- (Aminomethyl) Phenyl]Pentyl]- Ethoxyphosphinyl] Acetic Acid, Ethyl Ester, Hydrochloride Dissolve 1.70 g of the product of Part C in EtOH (20 ml) containing 8.40 ml of a 4.0 molar solution of anhydrous HCl in dioxan. Add 10% Pd/C (0.1% g) and hydrogenate at 410 kPa (60 psi) for 6 hours. Remove the catalyst by filtration and evaporate off ,fche solvent from the filtrate to obtain the title compound. E) C [5-[4-[ [ C (3-Butyl-6-Chloro-3,4-Dihydro-2H-l, 2, 4- Benzothiadiazin-7-yl) Sulfonyl] Ami o]Methyl] Phenyl]- Pentyl]Ethoxyphosphinyl] Acetic Acid, Ethyl Ester, S,S- Dioxide Dissolve 2.0 g of the product of Part D in DMF (20 ml) and cool to -10°C under a nitrogen atmosphere. With stirring, add triethylamine (3.1 ml) and 3-butyl-6- chloro-3,4-dihydro-2H-l, 2,4-benzothiodiazine-7- sulfonylchloride, S_,Sr-dioxide (3.3 g). Allow the reaction mixture to warm to room temperature and stir for 16 hours. Evaporate off the solvent and partition the residue between EtOAc (60 ml) and 5% aqueous citric acid (10 ml) . Separate the organic phase and wash with 5% aqueous citric acid (10 ml) followed by water (10 ml), and brine (10 ml). Dry the organic solution over Na 2 Sθ4, filter and evaporate off the solvent. Purify the resultant residue by chromatography on silica gel, elutinq with CH 2 Cl 2 :EtOAc (7:3). Evaporate off the solvent from the desired fractions to obtain the title compound. F) [ [5-[4-[ [ [ ( 3-Butyl-6-Chloro-3,4-Dihydro-2H-l ,2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]Methyl] Phenyl]- Pentyl]Hydroxyphosphinyl]Acetic Acid, Ethyl Ester, S,S- Dioxide Dissolve 1.70 g of the product of Part E in CH 2 C1 (30 ml) and cool the solution to 0°C under an argon atmosphere. Add bromotrimethylsilane (5.0 ml) with stirring, allow to warm to room temperature and stir for 3 hours. Evaporate off the solvent and excess bromotrimethylsilane. Partition the residue between EtOAc (70 ml) and water (15 ml). Separate the organic layer and wash with brine (15 ml). Dry the organic solution over Na 2 Sθ4, filter and evaporate off the solvent to obtain the title compound. R (silica gel; CH 2 Cl 2 :CH 3 OH:HOAC, 8:1:1)=0.25. G) C [5- [4- [ [ [( 3-Butyl-6-Chloro-3,4-Dihydro-2H-l,2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]Methyl]- Phenyl]Pentyl] Hydroxyphosphinyl] cetic Acid, S,S-Dioxide Dissolve 1.52 g of the product of Part F in THF (15 ml) and cool to 0°C. With stirrinq, add dropwise 0.5 _N_ aqueous NaOH (14.0 ml) and keep at 0° to 5°C for 18 hours. Evaporate off the solvent and partition the residue between EtOAc (80 ml), and 10% aqueous citric acid (10 ml). Separate the orqanic layer and wash with water (10 ml) followed by brine (10 ml). Dry the organic solution over a 2 S04, filter and evaporate off the solvent to obtain the title compound. H) 1-[ [ [5- [4- [ C [( 3-Butyl-6-Chloro-3, 4-Dihydro-2H-l,2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]Methyl] Phenyl]- Pentyl] Hydroxyphosphinyl]Acetyl]-cis,syn-Octahydro-lH- Indole-2(S)-Carboxylic Acid, (1, 1-Dimethylethyl)Este , S,S-Dioxide Dissolve 1.30 g of the product of Part G in DMF (15 ml) and cool to 0°C under a nitrogen atmosphere. Add l,l'-carbonyldiimidazole (0.37 g) and stir at 0°C for 1 hour. With stirrinq, add triethylamine (0.30 ml) and cis,syn-octahydro-lH_-indole 2(S)-carboxylic acid, (1,1- dimethylethyl) ester (1.70 g). Stir for 1 hour at 0°C, then at room temperature for 10 hours. Evaporate off the solvent and partition the residue betwen EtOAc (75 ml) and 10% aqueous citric acid (15 ml). Separate the organic phase and wash with water (15 ml) followed by brine (15 ml). Dry the organic solution over Na S04, filter and evaporate off the solvent.. Purify the product by chromatography on a LH-20 Sephadex column, eluting with CH3OH. Combine the desired fractions and evaporate off the solvent to obtain the title compound. Rf (silica gel; CH 2 C1 2 :CH 3 OH:HOAc, 8:1:1)=0.40. I) l-[ [ [5-[4-[ [ [(3-Butyl-6-Chloro-3,4-Dihydro-2H-l,2,4- Benzothiadiazin-7-yl )Sulfonyl]Amino]Methyl] Phenyl]- Pentyl] Hydroxyphosphinyl]Acetyl] cis,syn-Octahydro-lH- Indole-2(S)-Carboxylic Acid, S,S,-Dioxide, Hydrate Dissolve 1.32 g of the product of Part H in CH 2 C1 2 (15 ml) and cool to 0°C under a nitrogen atmosphere. Add trifluoroacetic acid (12 ml) and stir at 0°C for 1 hour, then at room temperature for 16 hours. Evaporate off the solvent and excess trifluoroacetic acid. Partition the residue between EtOAc (60 ml) and water (10 ml). Separate the organic Iphase and wash with brine. Dry the organic solution over Na 2 S0 4 , filter and evaporate off the solvent. Purify the resultant residue by chromatography on a C-18 reverse-phase silica gel column, eluting with a linear gradient of CH 0H/H 2 0 (60% 100% CH3OH) containing 0.2% trifluoroacetic acid. Combine the desired fractions and evaporate off the solvent to obtain the title compound. R (silica gel; CH 2 Cl 2 :CH 3 0H:H0Ac, 8:1:1)=0.20. EXAMPLE 6 N-[ C [4-[ [(3-BUTYL-6-CHL0R0-3,4-DIHYDRO-2H-1,2,4- BENZOTHIADIAZIN-7-YL)SULFONYL]AMINO]-4- PHENYLBUTYL]HYDROXYPHOSPHINYL]ACETYL]-N- CYCLOPENTYLGLYCINE, S,S-DIOXIDE A) S-(Methoxyimino)-benzenebutanoic acid Add 3-benzoylpropionic acid (17.82 g) and methoxylamine hydrochloride (9.18 g) to pyridine (250 ml) and heat under a nitrogen atmosphere with stirring at 90°C for 18 hours. Evaporate off the solvent and add water (50 ml) to the residue. Cool the mixture in an ice bath and add 6 N aqueous HCl dropwise with stirring to pH 3. Extract the mixture with EtOAc (3 x 100 ml) and wash the combined organic extracts with 1 N aqueous HCl (50 • ml) followed by brine. Dry the EtOAc solution over Na 2 S0 4 , filter and evaporate off the solvent to obtain the title compound. B) δ-Aminobenzenebutanol Cool to -10°C a solution of product of Part A (20.70 g) in THF (100 ml) under a nitrogen atmosphere. Add dropwise with stirring a 1 molar solution of borane in THF (350 ml) over one hour while maintaining the temperature -at -10°C. Stir at -10°C for one hour, then at room temperature for one hour. Heat the solution at reflux for 18 hours under a nitrogen atmosphere. Cool to -10°C and add water (75 ml) dropwise with stirring over one hour. Stir at 0° for one hour, then 18 hours at room temperature. Evaporate off the solvent and cool the residue in an ice bath. Add 50% aqueous NaOH (60 g) to the residue dropwise with stirring. Heat the solution at reflux for 4 hours. After cooling, extract the mixture with ether (3 x 250 ml). Wash the combined extracts with water (50 ml.) followed by brine (50 ml). Dry the solution over Na 2 S0 , filter and evaporate off the solvent to a volume of 75 ml. Collect the crystalline product by filtration and vacuum dry at room temperature to give the title compound, m.p. 72-75°C. C) 6-Phenyl-l,3-Dihydro-l,3-Dioxo-2H-Isoindole-2-Butanol Heat a solution of δ-aminobenzenebutanol (7.32 g), phthalic anhydride (6.57 g) and 4-(dimethyl- amino)pyridine (0.050 g) in dioxan (100 ml) under a nitrogen atmosphere at reflux for one hour. Evaporate off the solvent at atmospheric pressure and heat the residue at 155°C under a nitrogen atmosphere for two-and- a-half hours. After cooling, dissolve the residue in EtOAc (400 ml). Wash the solution with 10% aqueous citric acid (50 ml) followed by saturated aqueous NaHC0 3 (50 ml) and brine (50 ml). Dry the organic layer over Na 2 Sθ4, filter and evaporate off the solvent to obtain the title compound. D) 2-(4-Bromo-l-Phenylbutyl)-lH-Isoindole-1,3(2H)-Dione Cool in an ice bath a solution of triphenylphosphine (19.56 g) in dry CH C1 2 (100 ml) under a nitrogen atmosphere. Add carbon tetrabromide (12.37 g) and stir the solution for 10 minutes with cooling. Add a solution of -the product of Part C (10.0 g) in dry CH 2 C1 2 (100 ml) dropwise with stirring. Stir in an ice bath for one hour and then for 18 hours at room temperature. Remove the insoluble material by filtration and evaporate off the filtrate to a volume of 50 ml. Chromatograph the mixture on a silica gel column, eluting with CH 2 C1 2 . Combine the desired fractions and evaporate off the solvent to obtain the title compound, m.p. 88-91°C. E) [Ethoxy-[4-[2,3-Dihydro-l,3-Dioxo-lH-Isoindol-2-yl]- 4-Phenylbutyl]Phosphinyl] Acetic Acid, Ethyl Ester Add ethyl (diethoxyphosphino)acetate (100 ml) to the product of Part D (8.10 g) under an argon atmosphere and heat at 120°C with stirring for one hour. Increase the temperature to 180°C and stir at this temperature for 3 hours. After cooling, chromatograph the residue on a silica gel column, eluting with EtOAc:CH 2 Cl 2 (l:l) . Combine the desired fractions and evaporate off the solvent to obtain the title compound. F) [ (4-Amino-4-Phenylbutyl)Hydroxyphosphinyl] Acetic Acid Add the product of Part E (2.50 g) to a solution of HOAc (11 ml) , 33% HBr/HOAc (11 ml) and water (5 ml) and heat with stirring at reflux for 16 hours. Evaporate off the solvents and add water (50 ml) to the residue. Extract with ether (2 x 30 ml) and add the aqueous phase to a column of AG50WX8(H + ) ion-exchange resin (100 ml). Elute with water (200 ml) followed by 10% pyridine in water. Combine the desired fractions and evaporate off the solvent to obtain the title compound. R f (silica gel; CHCl 3 :CH 3 OH:NH 4 OH, 27:11:2.6) =0.20 (ninhydrin positive) . G) [ [4-[ [ (3-Butyl-6-Chloro-3,4-Dihydro-2H-l, 2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]-4-Phenylbutyl]- Hydroxyphosphinyl]Acetic Acid, S,S-Dioxide Add CH 3 CN (25 ml), bis (trimethylsilyl) tri- fluoroacetamide (4.10 g) and triethylamine (0.40 g) to the product of Part F (1.10 g) under a nitrogen atmosphere. Stir at room temperature for one hour. Add 3-butyl-6-chloro-3,4-dihydro-2H_-l,2,4-benzothiadiazine-7- sulfonyl chloride, S,S-dioxide (2.25 g) and stir at room temperature for 16 hours. Evaporate off the solvent and extract and purify the resultant residue as described in Example 1, Part C to obtain the title compound. Rf (silica gel; CH 2 Cl 2 :CH 3 OH:HOAc; 7.5:1:1.5) =0.40. H) N-[[[4-[[ (3-Butyl-6-Chloro-3,4-Dihydro-2H-l,2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]-4-Phenylbutyl]- Hydroxyphosphinyl]Acetyl]-N-Cyclopent lglycine, (1,1- Dimethylethyl) Ester, S,S-Dioxide Add 1,1'-carbonyldiimidazole (0.26 g) to a solution of the product of Part G (0.80 g) in DMF (10 ml) at 0°C under an argon atmosphere. Stir at 0°C for 1 hour, then add triethylamine (0.20 ml) followed by N- σyclopentylglycine, (1,1-dimethylethyl) ester (0.31 gm) . Stir at 0°C for 1 hour, then at room temperature for 16 hours. Evaporate off the solvent, extract and purify the resultant residue as described in Example 1, Part G to obtain the title compound; Rf (silica gel; CH 2 Cl 2 :CH 3 OH:HOAc, 8:1:1) =0.40. I) N-[ [ [4-[ [ (3-Butyl-6-Chloro-3,4-Dihydro-2H-l, 2,4- Benzothiadiazin-7-yl)Sulfonyl]Amino]-4-Phenyl utyl]- Hydroxyphosphinyl]Acetyl]-N-Cyclopentylglycine, S,S- dioxide Dissolve the product of Part H (0.50 g) in CH 2 C1 2 - (5 ml), cool the solution to 0°C and add tri aLuσroacetic acid (5 ml) with stirring. Allow the ssDl tLαπ to warm to room temperature and stir for 16 Hours-.. Evaporate off the volatile materials and dissolve the residue in EtOAc (30 ml). Wash the solution with water (10 ml) followed by brine (10 ml). Dry the organic solution over Na Sθ4, filter and evaporate off the solvent. Triturate the residue with ether, collect the solid product by filtration and dry at room temperature to obtain 0.30 g of the title compound. Rf (silica gel; CH 2 Cl 2 :CH 3 OH:HOAC, 8:1:1) =0.20. EXAMPLE 7 1-[ [ [5-[6-CHLORO-3,4-DIHYDRO-2-METHYL-7-[ (PHENYLMETHYL)- AMINOSULFONYL]-2H-1,2,4-BENZOTHIADIAZIN-3-YL] ENTYL]- [ (2,2-DIMETHYL-l-OXOPROPOXY)METHOXY]PHOSPHINYL] CETYL]- CIS,SYN-OCTAHYDRO-lH-INDOLE-2(S)-CARBOXYLIC ACID, S,S- DIOXIDE A. l-[ [ [5-[6-Chloro-3,4-Dihydro-2-Methyl-7- [ (Phenylmethyl) Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- y1]Pent l]Hydroxyphosphinyl]Acetyl]-cis,syn-Octahydro-1H- Indole-2(S)-Carboxylic Acid, Phenylmethyl Ester, S,S- Dioxide Following the procedure of Example 1, Part G, substitute 0.41 g of cis,syn-octahydro-lH_-indole-2(_S_)-carboxylic acid, phenylmethylester for N-cyclopentylglycine, (1,1- di ethylethyl)ester to obtain the title compound. B. 1-[[ [5-[6-Chloro-3,4-Dihydro-2-Methyl-7-[ (Phenyl¬ methyl) Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl]Pentyl] [ (2,2-Dimethyl-l-Oxoρropoxy)Methoxy]- Phosphinyl]Acetyl]-cis,syn-Octahydro-lH-Indole-2 (S) - Carboxylic Acid, Phenylmethyl Ester, S,S-Dioxide Dissolve 0.20 g of the product of Part A in DMF (20 ml) containing triethylamine (0.03 g) . Add chloromethyl pivalate (0.05 g) and stir at room temperature for 18 hours. Evaporate off the solvent and partition the residue between EtOAc and water. Separate the organic layer and wash with saturated aqueous NaHC0 3 , 10% aqueous citric acid and brine. Dry the organic phase over Na 2 Sθ4, filter and evaporate off the solvent. Chromatograph the residue on silica gel eluting with EtOAc. Combine the desired fractions and evaporate off the solvent to obtain the title compound. C. Dissolve the product of Part B in EtOH (30 ml) and add 10% Pd/C (0.25 g). Hydrogenate at atmospheric pressure with stirring until one equivalent of hydrogen is consumed. Filter off the catalyst, and evaporate off the solvent to obtain the title compound. EXAMPLΞ 8 1-C [ [4-[6-CHLORO-3,4-DIHYDRO-2-METHYL-7-[ (PHENYL¬ METHYL) AMINOSULFONYL]-2H-1,2,4-BENZOTHIADIAZIN-3- YL]BUTYL]HYDROXYPHOSPHINYL]ACETYL]-CIS,SYN-OCTAHYDRO-1H- INDOLE-2(S)-CARBOXYLIC ACID, [ (2,2-DIMETHYL-l- OXOPROPOXY)METHYL] ESTER, S,S-DIQXIDE A. 1-C (Phenylmethoxy)Carbonyl]-cis,syn-Octahydro-1H- Indole-2(S)-Carboxylic Acid, Ethyl Ester Add cis,syn-octahydro-l : H_-indole-2 (S)-carboxylic acid, ethyl ester d-10-camρhorsulfonate (8.01 g) (See Preparation 3, Part B) to THF (50 ml) and cool to 0°C under a nitrogen atmosphere. Add triethylamine (2.28 ml) with stirring, followed by benzyloxycarbonyl chloride (2.86 ml) dropwise and further triethylamine (2.28 ml). Stir the mixture at 0°C for 4 hours, then at room temperature for 16 hours. Evaporate off the solvent and partition the residue between EtOAc (250 ml) and water (50 ml) . Separate the organic layer and wash with saturated aqueous NaHC0 3 (50 ml) followed by water (50 ml) and brine (50 ml). Dry the organic layer over Na 2 Sθ4, filter and evaporate off the solvent to obtain the title compound as a syrup. B. 1-[ (Phenylmethoxy)Carbonyl]-cis,syn-Octahydro-1H- Indole-2(S)-Carboxylic Acid Dissolve 7.00 g of the product of Part A in THF (30 ml) and cool to 0°C. Add IN aqueous NaOH (21.3 ml) and stir at 0°C for 3 hours, then at room temperature for 16 hours. Evaporate off the solvent and add water (150 ml) to the residue. Extract with ether (2 x 100 ml) and acidify the aqueous solution to pH 3 with IN HCl. Extract with EtOAc (2 x 75 ml) and wash the combined EtOAc extracts with water (25 ml) followed by brine (25 ml) . Dry the organic layer over Na 2 Sθ4, filter and evaporate off the solvent to obtain the title compound. C. 1-[ (Phenylmethoxy)Carbonyl]-cis,syn-Octahydro-1H- Indole-2(S)-Carboxylic Acid [ (2,2-Dimethyl-l- Oxopropoxy)Methyl] Ester Dissolve the product of Part B (1.40 g) in THF (30 ml) and cool to 0°C under a nitrogen atmosphere. Add triethylamine (0.50 g), chloromethyl pivalate (0.77 g) and tetrabutylammonium iodide (0.10 g) and stir at room temperature for 48 hours. Evaporate off the solvent and partition the residue between EtOAc (100 ml) and 10% aqueous citric acid (25 ml) . Separate the organic layer and wash with water followed by saturated aqueous NaHCθ3, water and brine. Dry the organic layer over Na 2 Sθ4, filter and evaporate off the solvent. Purify the product by chromatography on silica gel eluting with CH 2 Cl 2 :hexane (1:1). Combine the desired fractions and evaporate off the solvent to obtain the title compound. D. Cis,syn-Octahydro-lH-Indole-2(S)-Carboxylic Acid, [ (2,2-Dimethyl-l-Oxopropoxy)Methyl] Ester, p- Toluenesulfonate Dissolve 0.86 g of the product of Part A in EtOAc (20 ml) containing p-toluenesulfonic acid monohydrate (0.39 g). Add 10% Pd/C (0.020 g) and hydrogenate at 310 kPa (45 psi) for one hour. Remove the catalyst by filtration and evaporate off the solvent. Dry the product at room temperature to obtain the title compound. E. [4-C [6-Chloro-3,4-Dihydro-2-Methyl-7-[ (Phenylmethyl)- Aminosulfonyl]-2H-l,2,4-3enzothiadiazin-3-yl]Butyl]- Hydroxyphosphinyl]Acetic Acid, S,S-Dioxide Using the procedure described in Example 1, Parts A-F, substituting 5-bromopentanal for 6-bromohexanal in Part C, prepare the title compound. F. 1-[ [ [4-[6-Chloro-3,4-Dihydro-2-Methyl-7-[ (Phenyl¬ methyl)Aminosulfonyl]-2H-1,2,4-Benzothiadiazin-3- yl]Butyl]Hydroxyphosphinyl]Acetyl]-cis,syn-Octahydro-1H- Indole-2(S)-Carboxylic Acid, [ (2,2-Dimethyl-l- Oxopropoxy) ethyl] Ester, S,S-Dioxide Dissolve 0.69 g of the product of Part D and 0.88 g of the product of Part E in 7 ml DMF. Stir the solution at room temperature while adding 0.21 g hydroxybenzotriazole hydrate, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 0.23 ml triethylamine. Stir at room temperature overnight, remove the DMF ^Lri vacuo and partition the resultant "residue between ethyl acetate and water. Wash the organic phase successively with water, 5% citric acid, and water again. Dry the organic layer over MgS0 4 and evaporate the solvent to obtain a residue. Chromatograph the residue on a Sephadex LH-20 column, eluting with CH3OH. Combine the desired fractions and evaporate the solvent to obtain the title compound. R [silica gel; BuOH:HOAc:H 2 0, 3:1:1]=0.7; FAB Mass spec: M/e=845 (M+) . EX MP E 9 1-[ [[4-[6-CHLORO-3,4-DIHYDR0-2-METHYL-7-[ (PHENYLMETHYL)- AMINOSULFONYL]-2H-1,2,4-BENZOTHIADIAZIN-3-YL]BUTYL]- HYDROXYPHOSPHINYL] ACETYL]-CIS,SYN-OCTAHYDRO-lH-INDOLE- 2(S)-CARBQX MIDE, S,S-PIOXIDE A. 1-[ (Phenylmethoxy)Carbonyl]-cis,syn-Octahydro-1H- Indole-2- (S)-Carboxamide Dissolve the product of Example 8, Part B (6.06 g) in DMF (100 ml) and cool the solution to 0°C under a nitrogen atmosphere. Add l,l'-carbonyldiimidazole (3.70 g) and stir at 0°C for one-half hour, then at room temperature for 1 hour. Cool the solution to -20°C and add concentrated aqueous NH4OH (50 ml) with stirring. Stir at -20°C for 1 hour, then at room temperature for 2 hours. Evaporate off the solvent and excess NH4OH. Partition the residue between EtOAc (100 ml) and 10% aqueous citric acid. Separate the organic layer and wash with saturated aqueous NaHC03 followed by brine. Dry the organic solution over Na 2 Sθ , filter and evaporate off the solvent to obtain the title compound. B. Cis,syn-Octahydro-lH-Indole-2(S)-Carboxamide Dissolve the product of Part A (4.00 g) in EtOH (30 ml) and add 10% Pd/C (0.10 g) . Hydrogenate at 410 pKa (60 psi) on a Parr apparatus for one-and-a-half hours at room temperature. Remove the catalyst by filtration and evaporate off the solvent from the filtrate. Dry the product at room temperature to obtain the title compound, m.p. 116-118°C. C. Substituting the product of Part 3 for the N-cyclo- pentylglyσine ester, carry out the procedures of Example 1, Parts G and H, to obtain the title compound. Using the procedures described above and substituting the appropriate starting materials, prepare the following compounds: l-[[ [5-[6-chloro-3,4-dihydro-2-methyl-7- [ (phenylmethyl)aminosulfonyl]-2H_-1,2,4-benzothiadiazin-3- yl]pentyl]hydroxyphosphinyl]acetyl]-(S)-proline, S,S- dioxide. 7-[[[5-[6-chloro-3,4-dihydro-2-methyl-7- [ (phenylmethyl)aminosulfonyl]-2H_-1,2,4-benzothiadiazin-3- yl]pentyl]hydroxyphosphinyl]acetyl]-l,4-dithia-7- azaspiro[4.4]nonane-8(S)-carboxylic acid, S,S-dioxide. 1-C [ [4-[ [ [6-chloro-3,4-dihydro-2-methyl-7- [ (phenylmethyl)aminosulfon l]-2H-l,2,4-benzothiadiazin-3- yl]acetyl]amino]butyl]hydroxyphosphinyl]acetyl]- (S)- proline, S,S-dioxide. 7-[ [ [4-[ [ [6-chloro-3,4-dihydro-2-methyl-7- [ (phenylmethyl)aminosulfonyl]-2H_-1,2,4-benzothiadiazin-3- yl]acetyl]amino]butyl]hydroxyphosphinyl]acetyl]-1, 4- dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, S,S- dioxide. 1-[ [ [4-[ [ [6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H_-1,2,4-benzothiadiazin-7-yl]sulfonyl]- amino]butyl]hydroxyphosphinyl]acetyl]- (S)-proline, S,S- dioxide. 7-[ [ [4-[ [ [6-chloro-3,4-dihydro-3-(2- ρhenylethyl)-2H_-l,2,4-benzothiadiazin-7-yl]sulfonyl]- a inolbutyl]hydroxyphosphinyl]acetyl]-1,4-dithia-7- azaspiro[4.4]nonane-S(S)-carboxylic acid, S,S-dioxide. 1-[ [ [ -[ [4-[ [ [[6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H_-1,2,4-benzothiadiazin-7-yl]sulfonyl]- amino]methyl]benzoyl]amino]butyl]hydroxyphosphinyl]acetyl] -(S)-proline, S,S-dioxide. 7-[ [ [4-[ [4-[ [ [[6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H_-l,2,4-benzothiadiazin-7-yl]sulfonyl]- amino]methyl]benzoyl]amino]butyl]hydroxyphosphinyl]acetyl] -1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, S,S-dioxide. l-[[ [5-[4-[[[ (3-butyl-6-chloro-3,4-dihydro-2_H- 1,2,4-benzothiadiazin-7-yl)sulfonyl]amino]methyl]phenyl]- pentyl]hydroxyphosphinyl]acetyl]- (S)-proline, S,S- dioxide. 7-[ [ [5-[4-[ [ [ (3-butyl-6-chloro-3,4-dihydro-2_H- 1,2,4-benzothiadiazin-7-yl)sulfonyl]amino] ethyl]phenyl]- pentyl]hydroxyphosphinyl]acetyl]-1,4-dithia-7- azaspiro[4.4]nonane-8(S)-carboxylic acid, S,S-dioxide. l-[ [[4-[ [ (3-butyl-6-chloro-3,4-dihydro-2_H- 1,2,4-benzothiadiazin-7-yl)sulfonyl]amino]-4-phenyl- butyl]hydroxyphosphinyl]acetyl]- (S)-proline, S,S-dioxide. 7-[[[4-[[ (3-butyl-6-chloro-3,4-dihydro-2H.- 1, 2, 4-benzothiadiazin-7-yl)sulfonyl]amino]-4-phenyl- butyl]hydroxyphosphinyl]acetyl]-l,4-dithia-7-azaspiro- [4.4]nonane-8(S)-carboxylic acid, S,S-dioxide. These compounds, for which test results are given in the following Table, can also be prepared by analogous methods from analogous starting materials: A. 1-[ [ [ [6-chloro-3,4-dihydro-2-methyl-7- (aminosulfonyl)-2H-l,2,4-benzothiadiazin-3- yl]methyl]hydroxyphosphinyl]acetyl]-cis,syn-octahydro-lH- indole-2(S)-carboxylic acid, S,S-dioxide. 3. 1-[ [[2-[ [4-[ [ [ [6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H-1,2,4-benzothiadiazin-7- yl]sulfonyl]amino]methyl]benzoyl]amino]ethyl]hydroxy¬ phosphinyl]acetyl]-cis,syn-octahydro-lH-indole-2(S)- carboxylic acid, S,S-dioxide. C. l-[ [ [2-[6-chloro-3,4-dihydro-2-methyl-7- (aminosulfonyl)-2H-1,2,4-benzothiadiazin-3- yl]ethyl]hydroxyphosphinyl]acetyl]-cis,syn-octahydro-lH- indole-2(S)-carboxylic acid, S,S-dioxide. D. l-[ [ [4-[6-chloro-3,4-dihydro-2-methyl-7- [(phenylmethyl)aminosulfonyl]-2H-1,2, -benzothiadiazin-3- yl]butyl]hydroxyphosphinyl]acetyl]-cis,syn-octahydro-lH- rndolei-2(S)-carboxylic acid, S,S-dioxide. E. 1-[[ [2-[ [4-[[ [ [6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H-l,2,4-benzothiadiazin-7- yl]sulfonyl]amino]methyl]benzoyl]amino]-(3- phenyl)propyl]hydroxyphosphinyl]acetyl]-cis,syn- octahydro-lH-indole-2(S)-carboxylic acid, S,S-dioxide. F. l-[ [[5-[6-chloro-3,4-dihydro-2-methyl-7- [(phenylmethyl)aminosulfonyl]-2H-1,2,4-benzothiadiazin-3- yl]pentyl]hydroxyphosphinyl]acetyl]-cis,syn-octahydro-lH- indole-2(S)-carboxylic acid, S,S-dioxide. G. l-[[[4-[6-trifluoromethyl-3,4-dihydro-2- methyl-7-[(phenylmethyl)aminosulfonyl]-2H-1,2,4- benzothiadiazin-3-yl]butyl]hydroxyphosphinyl]acetyl]- cis,syn-octahydro-lH-indole-2(S)-carboxylic acid, S,S- dioxide. H. 1-[ [ [4-[ [ [6-chloro-3,4-dihydro-3-butyl-2H- 1,2,4-benzothiadiazin-7-yl]sulfonyl]amino]-(4- phenyl)butyl]hydroxyphosphinyl]acetyl]-cis,syn-octahydro- lH-indole-2(S)-carboxylic acid, S,S-dioxide. I. 1-[ C [4-[ [4-[ [ [ [6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H-l,2,4-benzothiadiazin-7- yl]sulfonyl]amino]methyl]benzoyl]amino]butyl]hydroxy¬ phosphinyl]acetyl]-cis,syn-octahydro-lH-indole-2(S)- carboxylic acid, S,S-dioxide. J. l-[[[4-[[[4-[[[[6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H-l,2,4-benzothiadiazin-7- yl]sulfonyl]amino]methyl] henyl]sulfonylamino]butyl] hydroxy-phosphinyl] acetyl] -cis,syn-octahydro-lH-indole- 2(S)-carboxylic acid, S,S-dioxide. The followinq Table gives results in natriuresis tests and in ACE inhibition tests for the above-identified compounds A-J: Natriuresis ACE Inhibition Compound Na(uEq) Route I°so ( pk) A 426 iv 2.4 B 398 iv 1.8 C 239 iv 1.5 D 602 iv 0.3 E 397 iv 1.9 F 244 iv 0.2 G 54 iv 0.1 H 150 po .0.1 I 491 iv 0.4 J 62 iv 0.1 Natriuresis is the increase in Na excretion, over control, when the druq is administered at 30mq/kg. This is reported in u equivalents of Na . ACE inhibition is reported as the dose (administered iv) that reduces the b.p. of exogenously administered Angiotensin II. The D^ Q is reported as the mg/kq dose that reduces the Angiotensin response to 50% of the level before drug administration. Test animal is the rat. The compounds of the invention are - ■ substantially non-toxic at therapeutic doses. The compounds of this invention are useful in view of their pharmacoloqical properties. In particular, they possess activity as antihypertensive agents, as evidenced by their ability to reduce blood pressure in mammals in which the blood pressure has become abnormally elevated. For example, compounds of this invention lower blood pressure in the spontaneously hypertensive rat (SHR) model. Compounds of .this invention may show activity as diuretic agents. Since compounds of this invention may also act as inhibitors of angiotensin convertinq enzyme, it is contemplated that they may be used in treating other cardiovascular disorders, for example congestive heart failure, in the same manner as other ACE inhibitors such as captopril and enalapril. In addition, compounds of this invention may be used in the treatment of glaucoma by topical application. The compounds of this invention can be combined with pharmaceutical carriers and, administered in a variety of well-known pharmaceutical forms suitable for oral, parenteral or subcutaneous administration to provide compositions useful in the treatment of cardiovascular disorders and particularly mammalian hypertension. The daily antihypertensive dose of the compounds of this invention will be typically in the ranqe of about 1 to about 25 mg/kg of mammalian weight, administered in single or divided doses. The exact dose to be administered is determined by the attending clini¬ cian and is dependent upon the potency of the adminis¬ tered compound, i.e. where the particular compound lies within the above range, as well as upon the age, weight and condition of the patient. Generally, in treating humans having hyper¬ tension, the compounds of this invention may be adminis¬ tered to patients in need of such treatment in dosage ranqe of about 5 to about 500 mq per patient # qenerally given several times a day, thus providing a total daily dose of from about 5 to about 2000 mg per day. The antihypertensive compositions containing the compounds of this invention will preferably contain from about 5 to about 250 mg of the active compound per dosage unit. The compositions of the present invention are most preferably administered orally. Typical formulations for oral administration are those such as tablets, capsules, syrups, elixirs or suspensions. Typical injectable formulations include solutions and suspensions. Also contemplated are mechanical delivery systems, e.g. transdermal dosage forms. The typical acceptable pharmaceutical carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalσium phosphate and triσalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anioniσ surfactants; ethylene glycol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed cereal solids; and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations. In the following examples the preferred "active ingredient" is N-[ [5- [ [6-chloro-3,4-dihydro-2-methyl-7- [ (phenylmethyl)aminosulfonyl]-2_H-1,2,4-benzothiadiazin-3- yl]pentyl]hydroxyphosphinyl]acetyl]-N-cyclopentylglycine, S,S-dioxide, but if desired this compound may be replaced by equally effective quantities of other compounds within formula I, in particular by a compound A-J for which test results are included hereinabove. EXAMPLE 10 Capsule Amount (mg) Active ingrr&dient 250.0 125.0 Lactose 173.0 86.5 Corn Starch 75.0 37.5 Magnesium Stearate 2.0 1.0 500.0 250.0 Blend the active ingredient, lactose, and corn starch until uniform; then blend the magnesium stearate into the resulting powder. Encapsulate the mixture into suitably sized two-piece hard gelatin capsules. EXAMPLE 11 Tablet Amount (mg) Active Ingredient 250.0 125.0 Lactose 161.0 80.5 Corn Starch 12.0 6.0 tablets) 120. ml 60 ml (evaporates) (evaporates) Corn Starch 75.0 37.5 Magnesium Stearate 2.0 1.0 500.0 250.0 Blend the active ingredient with the lactose until uniform. Blend the smaller quantity of corn starch with the water and add the resulting corn starch paste, then mix until a uniform wet mass is formed. Add the remaining corn starch to the remaining wet mass and mix until, uniform granules are obtained. Screen the granules throαgh a suitable milling machine, using a 6.2 mm. (3/4 inch) stainless steel screen. Dry the milled granules in a suitable drying oven until the desired moisture content is obtained. Mill the dried granules through a suitable milling machine using a 16 mesh stainless steel screen. Blend in the magnesium stearate and compress the resulting mixture into tablets of desired shape, thickness, hardness and disintegration. EXAMPLE 12 Injectable Solution mg/ml Active ingredient 5.00 Methyl p_-hydroxybenzoate 0.80 Propyl p_-hydroxybenzoate 0.10 Disodium Edetate 0.10 Citric Acid Monohydrate 0.08 Dextrose 40.0 Water for injection qs. ad 1.0 ml Dissolve the p_-hydroxybenzoates in a portion of water for injection at 60-70°C and cool the solution to 25-25°C. Charge and dissolve all other excipients and the active ingredient. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers. Similarly, substitute other compounds of the present invention to prepare other compositions of the present invention.

Claims: Claims: 1. A compound represented by the formula R 0 0 I II II Z-CH- (CH 2 ) n -P-CH 2 -C-X k 1 wherein X is Ha- lib Y is -S- or -0-; Z is A is -(CH 2 ) m — j] (CH 2 ) r -D-, -(CH 2 ) χ -C0-NH- or a bond; B is -(CH 2 ) (CH- ) r -D-, -(CH 2 ) r -CO-NH- or a bond; D is -CO-NH- or a bond; m, n, and r are independently 0-4; x is 1-4; p and q are independently 0 or 1, provided that the sum of p and q is 1 or 2; s is 2 or 3; t is 1-3; R is hydrogen, lower alkyl halogen-substituted lower alkyl, cycloloweralkyl, cycloloweralkyl-(CH 2 ) u , or CgH5~(CH 2 ) v -, wherein u is 1-4 and v is 0-4; R 1 is hydroxy, alkoxy having from 1 to 8 carbon q atoms, phenylloweralkoxy, allyloxy, R J -Q W -(CH 2 ) -0-, wherein Q is oxygen or sulfur, w is 0 or 1 and y is 2 to 4, -OCH(R 10 )-OCO-alkyl wherein the alkyl has from 3 to 8 carbon atoms, -OCH(R 10 )OCO-phenyl wherein the phenyl may be substituted with group T defined below, 1-glyceryl, R is R or heterocycloloweralkyl; R 3 is hydrogen or lower alkyl; R and R are independently hydrogen, lower alkyl or cycloloweralkyl, or R 4 and R5 together with the carbon atoms to which they are attached form a 5- or 6- membered ring; R 6 and R7 are independently hydrogen, lower alkyl or cycloloweralkyl, or Rfi and 7 together with the nitrogen and carbon atoms to which they are attached form a 4-, 6-, 7- or 8-membered ring; R is R , amino, hydroxylamino, mono- or di- substituted amino wherein the substituents are lower alkyl, phenyl or phenylloweralkyl, and wherein the phenyl may be substituted with qroup T defined below; R^ is phenyl, substituted phenyl wherein the substituents are chosen from qroup T, 1-naphthyl or 2- naphthyl; T is halogen, hydroxy, trifluoromethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trifluoromethyl, lower alkoxy and lower alkyl; R 10 is hydrogen or alkyl havinq from 1 to 8 carbon atoms; R is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenylloweralkyl wherein phenyl may be substituted by group T; - -s R ώ is hydrogen or lower alkyl; R iJ is chloro or trifluoromethyl; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein Z is represented bbyy ffoorrmmuullaa IIIHlaa aamnd A is -(CH 2 ) m -^^-(CH 2 ) r -D- or -(CH 2 ) χ -C0-NH-. 3. A compound of claim 1 wherein Z is represented by formula IHb and B is -(CH 2 ) r -CO-NH- or a bond. 4. A compound of claim 7 wherein Z is represented by formula IHb and B is - (CH 2 ) m-ζ - (CH 2 ) r- D -* 5. A compound of claim 1 wherein X is represented by formula lib and Y is -S-. 6. An antihypertensive pharmaceutical composition comprising an antihypertensive effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier. 7., A method for reducing blood pressure in hypertensive mammals which comprises administering to a hypertensive mammal a antihypertensively effective amount of a compound of claim 1. 8. A method for reducing blood pressure in an hypertensive mammals which comprises administering to a hypertensive mammal a pharmaceutical composition of claim 6. 9. A process for the preparation of a compound of formula I defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises reacting an acid of the formula E-OH or an amide-forming derivative thereof, under amide-forming conditions with an a ine of the formula H-W or with an amide-forming derivative thereof, and isolating the product of the formula I as such or as a pharmaceutically acceptable salt thereof; where E and W are as defined as in the followinq Table: W Z-L-CO- -X wherein Z 1 and Z2 denote the benzothi.adi.azm. e nucleus of the groups of formulae Ilia and IHb respectively, such that Z .S0 2 -NH-A- is formula Ilia and Z .B is formula IHb, the central part of formula I, namely - is denoted by L, and the symbols A, B, R, R , X, Z, m, n, r and x and the formulae Ilia and IHb are as defined in claim 1.

Inventors: CZARNIECKI MICHAEL F, WITKOWSKI JOSEPH T, CZARNIECKI, MICHAEL, F., WITKOWSKI, JOSEPH, T.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1986
Main classification: C07F9
IPC codes: C07F9