CARBOXYALKYLDIPEPTIDES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: Novel carboxyalkyldipeptides, their preparation and pharmaceutical compositions containing them. The novel dipeptides are represented by general formula (I), where A is selected from formula (II), with n, p and q being specified values from 0 to 2, B is -[J]-[L]-[M]-; D is formula (III), E is -NH-, -O-, -S-, or -CH2-; G is formula (IV) or -SO2-; J is -(CH2)s- or -((CH2)t-W-; where L is chemical bond, specified alkyl, aryl or heterocyclic moieties, M is -(CH2)u- or -((CH2)t-X-(CH2)v)- where n and v are 0-5 and X is -NR<9>-, -O-, -S-, formula (V) or formula (VI), R<1> and R<2> are hydrogen, lower alkyl or lower acyl; R<3> is hydrogen, lower alkyl, haloloweralkyl, phenylloweralkyl, (cycloalkyl)lower alkyl, aminomethyl, lower alkylaminomethyl, phenylloweralkylaminomethyl, (cycloalkyl)loweralkylaminomethyl, loweralkylthiomethyl, haloloweralkylthiomethyl, 2-, 3- or 4-pyridylloweralkyl, 2-, 4- or 5-thiazolylloweralkyl, 2-, 4- or 5-1H-imidazolylloweralkyl, 1-imidazolylloweralkyl, 1-morpholinoloweralkyl or hydroxyphenylloweralkyl; R<4> is chlorine or CF3; R<5> is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl; R<7> is hydrogen, lower alkyl or aminoloweralkyl; R<6> and R<8> are hydroxy or specified substituted hydroxy groups. The compounds exhibit angiotensin converting enzyme inhibitory activity and/or diuretic activity.

Description: CARBOXYALKYLDIPEPTIDES, THEIR PREPARATION AND PHARMACEU ICA COMPOSITIO S CONTAINING THEM This invention relates to novel carboxyalkyl¬ dipeptides, to their preparation and to pharmaceutical compositions containing them. More particularly, this invention relates to carboxyalkyldipeptides in which the dipeptide moiety is joined through a sulfonamido group to a diuretic moiety. The compounds of the present invention exhibit angiotensin converting enzyme inhibitory activity and/or diuretic activity. Compounds of this invention are indicated as being useful in the treatment of hypertension, congestive heart failure and glaucoma. In accordance with one of its aspects, the present invention provides novel compounds of the general formula I R 6 C D] and the pharmaceutically acceptable salts thereof, wherein: A IS I la lib He lid He 1 is 1 or 2; n is 0 or 1; p and q are 0, 1 or 2, provided that iiT" structures lib and He the sum of p and q is 1 or 2, and that in formula lid, p is not 0; B is -[J]-[L]-[M]-; E is -NH-,-0-, -S-, or -CH 2 -? 0 G is -c- or -S0 2 -; J is -(CH 2 ) S - or -((CH 2 ) t - )-; L is a chemical bond, cis- or trans- lower alkene, lower alkyne, -Z-aryl-, -aryl-Z-, -Z-cycloalkyl-, -cycloalkyl-Z-, a 5- or 6-membered heterocyclic radical comprising 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from N, 0 and S, or a R 5 -substituted heterocyclic radical, wherein aryl is and wherein w is 1, 2 or 3; M is -(CH 2 ) U - or -((CH 2 ) t -X-(CH 2 ) v )-; X and Z are independently a chemical bond, 0 0 -NR 9 -, -0-, -S-, -CNH- or -NHC-; s, u and v are independently 0-5; t is 1-5; • j Q R , R* and ^ are independently hydrogen, lower alkyl or lower acyl; R 3 is hydrogen, lower alkyl, haloloweralkyl (in particular halo- and di-haloloweralkyl) phenylloweralkyl, (cycloalkyl) lower alkyl, aminomethyl, lower alkylamino- methyl, phenylloweralkylaminomethyl, (cycloalkyl) lower- alky laminomethyl, loweralkylthiometh l, haloloweralky 1- thiomethyl, 2-, 3- or 4-pyridylloweralkyl, 2-, 4- or 5- thiazolylloweralkyl, 2-, 4- or 5-1^-imidazolylloweralkyl, 1-imidazolylloweralkyl, 1-morpholinoloweralkyl or hydroxyphenylloweralkyl; R is chlorine or CF3; R 5 is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl; R is hydrogen, lower alkyl or aminoloweralkyl; R and R are independently hydroxy, alkoxy having from 1 to 8 carbon atoms, benzyloxy, allyloxy, R -Q r -(CH 2 ) m -0-, wherein Q is oxygen or sulfur, r is 0 or 1 and I m is 2 to 4, -OCH-OCO-alkyl wherein the alkyl has from 3 to 8 carbon atoms, -OC fH 1 C 1 O-phenyl wherein the phenyl may be substituted with group T defined below, 1-glyceryl, R 10 is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2- naphthyl; T is halogen, hydroxy, trif luoromethyl , lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trif luoromethyl, lower alkoxy or lower alkyl; R 1 is hydrogen or alkyl having from 1 to 8 carbon atoms; R" is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenyl lower alkyl wherein phenyl may be substituted by group T; • j R J is hydrogen or lower alkyl; provided that if L is alkene or alkyne, J is -(CH 2 ) S - wherein s is 1-5; provided that if L is -Z-aryl- or -Z-cycloalkyl-, J is -(CH 2 ) S - wherein s is 2-5; provided that if L is alkene, alkyne, -aryl-Z- or -cycloalkyl-Z-, M is -(CH 2 ) U - wherein u is 1-5; provided that if s and u are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); and provided that if s and v are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); with the further provision that when D is of formula IHb and R is hydrogen, B is not -(CH 2 )4~ and that when D is of formula ' Illb and R is hydrogen or lower alkyl, B is not -(CH 2 ) g -aryl-(CH 2 ) t -X-(CH 2 ) y - wherein s is 0 or 1, t is 1, v is 0 to 2 and X is a bond, -0-, or -S-. When A is formula lib or He, the preferred sum of p and q is 1; when A is of formula lid, preferred values for each of p and q are 1 with n being zero. Preferably, A is Ha or lib where p is o and q is 1. D is preferably of the formula Ilia; R 4 being preferably chlorine and G being preferably -S0 -. R ώ is • i preferably hydrogen and R J preferably phenylethyl, (cyclopentyl)methyl, chloromethyl, dichloromethyl, 2- pyr id inyl ethyl, butyl, pentyl or trifluoroethyl- thiomethyl. For B, preferred values are of the formula CH 2 _ -Ca bondor -o-]-CCH 2 _ 1-2 i.e., where J is -(CH 2 ) - and s is 0-1, L is a bond or -Z-aryl- wherein Z is a bond, and M is -((CH ) t -X-(CH 2 ) v ) , wherein t is 1, v is 1-2, and X is a bond or -0-. For compounds wherein L is a heterocyclic radical, thiazolyl rings joined to the rest of molecule at the 2,4 and 2,5 positions are preferred. A preferred value for E is -NH-. Preferred values of R 7 are hydrogen, methyl and β Q aminobutyl and for R and R preferred values are hydroxy, ethoxy, methoxy, phenoxyethoxy , 1-glyceryl, pivaloyloxyalkyloxy , and -OCH2- IH — C IHg A preferred group of compounds are those represented by the general formula • 5 wherein R is phenylethyl, ehloromethyl, dichloromethyl, butyl, pentyl, (cyclopentyl)methyl, trifluoroethyl- thiomethyl or 2-pyridinylethyl. Specifically preferred compounds of the general formula I include: l-[[2-(S)-[[l(S)-carboxy-5-[[6-chloro-3-chloromethyl-3,4- dihydro-2lϊ_-l,2,4-benzothiadiazin-7-yl] sulfonylamino]- pentyl] amino]-l-oxopropyl]- [2S-(2a, 3aα, 7aα)]-octahydro- lji^indole-2-carboxylic acid, J3_,j3_-dioxide, 1- [2- (S )- [ [1- (S )-carboethoxy-2- [4- [ [ [β-chloro-3 , 4- dihydro-3-(2-phenylethyl)-2H_-l,2,4-benzothiadiazin-7- yl] sulfonyl-amino] methyl] phen lmethoxy] ethyl] am ino]-l- oxopropyl]- [2S- [2α, 3aα, 7aα)]-octahydro-lH--indole-2 . - carboxylic acid, jS^E- dioxide, 1- [2- (S )- [ [1- (S )-carboxy-2- [4- [ [ [6-chloro-3, 4-dihydro-3- (2-phenylethyl)-2jj-l,2,4-benzothiadiazin-7- 1] sulf ony lamino] -methyl] phen lmethoxy ] ethyl] amino] -1 oxopropyl]-[2S-2α, 3ao, car boxy lie acid, jS^j^- dioxide, N- [2-( j- [ [3- [4- [ [ [6-chloro-3 , 4-dihydro-3- (2- phenylethyl)- 2Et_-l,2,4-benzothiadiazin-7-y 1] sulf ony 1- amino ] me thy 1 ] phen 1 ] -1 - (S) - ( ethox car bony 1 ) buty 1] a ino ] - 1-oxopr opy 1 ] - ( S_) -pr ol ine-S ,S-dioxide , and l-[N_-[3-[4-[[[6-chloro-3,4-dihydro-3-[2-pyridylethyl)-2jl_- l,2,4-benzothiadiazin-7-yl]-sulfonyl]aminoraethyl] pheny 1]- 1 (j>_)-(ethoxycarbonyl)-propyl]- (S)-alanyl] -cis ,syn- octahydroindole-2(^_)-carboxylic acid S,S-dioxide. 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 6 carbon atoms, e.g. methoxy, ethoxy, propoxy , butoxy, iso- butoxy , pentoxy and hexyloxy. "Halogen" means fluorine, chlorine and bromine. "Lower acyl" means organic radicals obtained by removing the hydroxy 1 group from the corresponding carboxylic acid of from 1 to 6 carbons, e.g. formyl, acetyl, propionyl and butyryl. "Lower alkene" means unsaturated hydrocarbon radicals of from 2 to 6 carbon atoms having one double bond, e.g. vinylene propenyl, butenyl, pentenyl and hexenyl, wherein the double bond may be present anywhere in the chain, e.g. 1- or 2-propenyl, 1-, 2- or 3-butenyl. Similarly, "lower alkyne" means a hydrocarbon radical of from 2 to 6 carbon atoms having one triple bond, e.g. ethynylene, propynyl, butynyl, pentynyl and hexynyl, wherein the triple bond may be present anywhere in the chain, e.g. 1- or 2- propynyl, 1-, 2- or 3-butynyl. Examples of heterocyclic radicals are: τ H τ> y . Λ . O.Ό Compounds of the instant invention include various stereoisomers. Preferred stereoisomers are those in which the absolute configuration at carbon atoms adjacent to both a nitrogen and a carbonyl group corresponds most closely to the absolute configuration of L-amino acids. The compounds of this invention form acid addition salts with various inorganic and organic acids and cationic salts with bases. Cationic 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 be prepared, e.g., N-methylglucamine, lysine and arginine. Typically acid additional salts may be formed with such organic and inorganic acids, as HCl, HBr, H 2 S04, H3PO4, methanesulfonic acid, toluenesulfonie 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. Acid addition salts (e.g. HCl and maleate) are preferred, especially the hydrochloride. 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. Compounds of formula I may be prepared by several routes using methods known in the art. For example, compounds of formula I can be prepared by condensing an acid of formula IV, or a reactive derivative thereof, with an amino acid of the formula V, or a reactive derivative thereof: [E]-CH-C-OH + H[A]-C0R 8 ■ > I wherein R A 1 ,R6 , R 7 , R 8 , D, B, E and A are as defined for formula I. The reaction may be carried out in an inert solvent such as dimethylformamide (DMF) in the presence a condensing agent such as l-(3-dimethylaminopropy l)-3- ethyl carbodiimide hydrochloride (DEC) and 1-hydroxy- benzotriazole, and where the compound of formula IV is in the form of a salt in the presence of a base such as triethylamine. The reaction is preferably carried out in an inert atmosphere at a temperature of 0-25°C. Compounds of formula V are known in the art, or may be prepared by methods well known to those skilled in the art. Compounds of formula IV may be prepared for example from the reaction of a sulf ony 1 chloride of formula VI and an a ine of formula VII: VI VII wherein D, B, E, R A i, R a° and R7 are as defined above and R 1 is a readily removable ester protecting group such as t-butyl, benzyl or trimethylsilylethyl. The reaction is carried out at 0-5 β C in a solvent such as tetrahydrofuran (THF) . Compounds of formula VI may be prepared from known starting materials using procedures well known in the art. For example, when D is of the formula Ilia • 3 wherein G is S0 2 and R is phenylethyl, the sulfonyl chlorides of formula VI may be obtained by reacting a disulfonyl chloride of formula VIII with aqueous ammonia at low temperature (dry -ice-ace tone bath) in a solvent such as 1 , 2- dimethoxy ethane (DME) in the presence of a base such as triethylamine to obtain a sulfonamide of formula IX, 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: VIII IX VI (wherein R 2 =H, R -phenylethyl, G l = ~ so 2~ ) Similarly, when D is of formula IHb, the sulfonyl chlorides of formula VI may be obtained by well known procedures. A typical reaction scheme was follows: Compounds of formula VII are prepared from known starting materials using methods known in the art. A typical reaction scheme is shown below for compounds of formula VHb, wherein R is hydrogen, R is 7 lower alkyl, R is methyl, J is -(CH 2 )-, L is phenyl, M is -CH 2 -0-CH 2 -, E is -NH-, and R 14 is as defined above: Details of the above typical reaction scheme are disclosed in Example 1, Parts A-E. In the above reaction scheme, the trif late reagent, i.e. t-butyl 2(S)-(trifluoromethanesulfonyloxy )- propionate, reacts by nueleophillic displaement with the o-aminoacid ester to give a high yield of the correspond¬ ing specific diastereomer of the resulting monoamino dicarboxylic acid ester. Compounds of formula VII d, wherein M is (CH 2 ) and R , R , R , R , J, L and E are as described above for formula VHb, may be prepared as follows: The above reaction scheme is exemplified in Parts A-C of Example 3. A typical reaction scheme for the preparation of compounds of formula VHf wherein L is a bond, J is -(CH 2 ) S - and M is -(CH ) U )- wherein the sum of s and u is 4, and R , R , R , R and E are as described above for formula VHb is as follows: Vila f Example 5 provides details of this procedure. Alternatively, intermediates of formulae Vila or Vile may be used to prepare compounds of formula I as follows: The R protecting groups (e.g. t-butoxy- carbonyl) of compounds of formulae Vila or VIIc may be removed, e.g. by trifluoroacetic acid, and the nitrile reacted with an amino acid derivative of formula V under the conditions described on page 7. The resulting nitrile can then be reduced to the corresponding amine, e.g., by hydrogenation, which amine can then in turn be coupled to a sulfonyl chloride of formula VI by conventional methods. Similarly, intermediates of formula Vile (i.e., compounds of formula VII wherein B is alkyl) may be deprotected at the carboxylic acid group and condensed with the amino acid derivative of formula V as described above, then deprotected at the amino group, e.g. by hydrogenation, and the resultant amine reacted with a sulfonyl chloride of formula VI by conventional methods. Another method for preparing compounds of formula IV is that exemplified below for preparing compounds wherein D is of formula Ilia wherein G is -S0 2 -, J is -CH 2 -, L is -aryl-Z- wherein aryl is phenyl 0 and Z is -C '--NH-, M is -CH 2 -, E i .s -NH-, R x 1 is hydrogen, R is ethyl, R is methyl, and R , R and R are as defined above: is -SO.- " i C cr CO,-t-Bu Example 7 incorporates the above procedure, Another method for the preparation of compounds of formula I comprises condensing an amine of the formula X: with a sulfonic acid of the formula Via: [D]S0 2 0H, or a reactive derivative thereof, such as the acid chloride, wherein R^ 1 , R __ , R 7 , R 8 , B, D, E and A are as defined above. The reaction may be carried out in an inert solvent such as tetrahydrofuran in the presence of a proton acceptor such as N-methylmorpholine. The reaction is preferably carried out in an inert atmosphere at a temperature of 0-25 °C. Compounds of formula X may be. prepared by well known methods, for example to obtain compounds wherein B is -CH 2 -C 6 H 5 -(CH 2 ) 2 -, E is -NH- and R 1 , R 6 , R 7 and R 8 are as defined above, compounds of formula VII (c) may be deprotected at the terminal carboxy group and then condensed with an amino acid of formula V: O C CHH,j mM HCl, dloxan∑ "' ' *Λγ" ■ v== H H H XI xz∑ The nitrile of formula XII is reduced to an amine of formula X, e.g. by hydrogenation. Compounds of formula I ma also be prepared by condensing an aldehyde of formula XIII (or a reactive derivative thereof, e.g., an acetal) with an amino- sulfonamide of formula XIV: XIV wherein R , R , R , R , R , R , B, E and A are as defined above. The reaction is carried out in an inert solvent such as tetrahydrofuran in the presence of p-toluene- sulfonic acid. The reaction is preferably carried out in an inert atmosphere at a temperature of 0-80°C. Compounds of formula XIII are known in the art or may be prepared by known methods. Compounds of formula XIV can also be prepared by known methods, for example a sulfonamide of formula IX can be reacted with an amine of formula VII to obtain a compound of formula XV: X wherein R 1 , R 4 , R 6 , R 7 , R 14 , B and E are as defined above. The protecting group R is then removed e.g., by treating with hydrochloric acid in a solvent such as dioxane. The resultant product is condensed with an amino acid of formula V under conditions similar to those described above for the reaction of compounds of formulae IV and V to obtain a compound of formula XIV. Yet another process for the preparation of the compounds of the formula I wherein X is sulfur comprises condensing a halide of the general formula XV [D]-S0 2 -N-J-L-(CH 2 ) t -Hal XV, R 1 with a thiol of the general formula XVI R 6 C 1 =0 R 7 7 XVI, H-S- (CH, i. ) „ V-CH- [E ] -CH-C j ,- [A] -COR B 0 where R , R , R , R , A, E, J, L, t and v are as defined for formula I and Hal represents halogen, preferably bromine. The reaction is preferably carried out in an inert medium at a temperature of 0-25°C. Compounds of the formula XV may be prepared by well known methods. Illustrative of such methods, is the following specific reaction scheme: Compounds of general formula XVI may also be prepared by known methods, the following specific reaction scheme being illustrative of such methods: COOMβ d The known coupling methods above include amino group protection during the coupling reaction , for example with protecting groups such as N-formyl , N-t- butoxycarbonyl ( t-Boc) and N-carbobenzyloxy (Cbz ) groups , followed by their removal to y ield compounds of formula q q I. Furthermore, the COR function wherein R is OH may be protected by removable ester groups such as benzyl, ethyl, t-butyl, trimethylsilylethyl and the like. The more complex esters at R (i.e., R is other than hydroxy or alkoxy) are most conveniently prepared by esterifying compounds compounds of formula I wherein R 6 is hydroxy and R 8 is a protected hydroxy, e.g. benzyloxy, with the appropriate reagents, e.g. ehloromethyl pivalate in the presence of base, to obtain the corresponding pi valoyloxy methyl ester; the benzyl group is then removed by conventional means, e.g. catalytic hydrogenation. The following procedures and examples further illustrate the preparation of compounds of this invention. PREPARATION 1 t-BUTYL 2 ( S )- (TRIFLUOROMETHANESULFO YLOXY ) PROPRIONATE (Trif late Reagent) A. Add 2(S)-(p-toluenesulfonyloxy )propionic acid (4.4 g) to a cold solution of 10ml of isobutylene and 0.4 ml of concentrated sulfuric acid in 30 ml of methylene chloride in a pressure vessel, seal, and agitate at room temperature for 48 hours. Pour into 50 ml of 15% sodium carbonate solution, dry over magnesium sulfate and concentrate to obtain t-butyl 2(j3_)-(p-toluenesulfonyl- oxy) propionate as an oil (NMR δ 1.37). Distilled material (Kugelrohr, 120°) has [ ]D 26 = -45.9° (EtOH, c=l). B. Combine the product of part A (100 g) with acetic acid (40.0 g) and triethylamine (67.2 g) in 200 ml of dry DMF. Heat at 65° for 20 hours. Partition with 21 each ether and water, and wash the ether with citric acid, then with dilute sodium bicarbonate soultion. Dry and concentrate the ether solution to obtain t-butyl 2(jU- acetoxypropionate as a colorless liquid, bp 50°C/0.1 mm. C. Combine the product of part B (62,6 g) with ethylenediamine (11.6 g) and heat at 70° for 24 hours, allow to cool, add 300 ml ether and filter. Wash the ether with water, 10% citric acid, and then with sodium bicarbonate solution. Dry and concentrate the ether solution to leave a colorless oil. Crystallize from hexane at -20° to give t-butyl 2(RJ )-hydroxypropionate as white needles, m.p. 41-2°C. D. Combine the product of part C (10 g) with pyridine (6 ml) in 100ml methylene chloride. Cool to -70 °C, and add dropwise over a period of about 45 minutes a solution of trifluoromethanesulfonic anhydride (13.5 g) in 20 ml methylene chloride, maintaining the temperature below -15°C. Stir at -20°C for 30 min. Add ether and wash successively with water, 4 of aq HCl, sat'd NaHCO β and brine. Dry and concentrate the organic layer to obtain the title compound. PREPARATION 2 6-CHLORO-3 , 4-DIHYDRO-3- ( 2-PHEN YLETHYL ) -2H-1 , 2 , 4-BENZO- THIAD AZINE-7 -SULFONYL CHLORIDE 1,1-DIOXIDE A. Dissolve 5g 2-chloroaniline-3, 5-disulphonyl chloride in 20ml DME, cool to in a dry- ice/acetone both and add 2ml triethylamine. Add dropwise 25% ammonium hydroxide in water (1ml) in DME (4ml), stir at 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% aq HCl, water and brine, dry over MgSO^ and evaporate to obtain a solid residue. B. Combine 13.6g of the sulfonamide prepared in Step A, β.57g phenyl propanal, 25ml DME and 20mg p-tolulene- sulfonic acid and stir at room temperature under N 2 for 3 hours. Evaporate the solvent, dissolve the resultant residue in 250ml ethyl acetate, wash with 100ml sat'd aq. NaHCO j , and 100ml 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. PRE PART ION 3 CIS,SYN-OCTAHYDROINDOLE-2(S)-CARBOXYLIC ACID, t-BUTYL ESTER A. Dissolve the product of Preparation 4 (77g) in absolute ethanol (900 ml), add 5% Pd/C (lOg) and hydrogenate at room temperature at an initial pressure of 60 p.s.i. After 3 hours, filter off the catalyst and wash with hot methanol. Evaporate the combined filtrate and wash in vacuo, triturate the resultant residue in ethanol (100 ml), chill the solution, then filter and air dry the resultant precipitate to obtain a residue, m.p. 269-270°C. B. Suspend the product of Part A in dioxane (400 ml) and cone. H^O^ (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 the organic layer over Na 2 S0 4 and evaporate the solvent to obtain the title compound. PREPARATION 4 CIS,SYN-OCTAHYDROINDOLE-2(S)-CARBOXYLIC ACID BENZYL ESTER A. Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml of trif luoroacetic acid. Add 2.05 g of platinium oxide, hydrogenate the mixture at 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 ethyl octahydroindole-2- carboxylate,a pale yellow oil. B. Dissolve 116 g 10-d-camphorsulfonic acid in 1 liter of warm ethyl acetate and add a soultion 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 2-(S)- carboethoxy-cis,syn-octahydroindole, d-10- camphorsulfonate, m.p. 192-193 °C. C. Heat the product of Part B (107.6g) and d-10- camphor-sulfonic acid (6.35g) in benzyl alcohol (270 ml) at 105 β C under vacuum for 6 hours or until TLC (silica, elute neutralize sample with ethyl ether) indicates reaction is complete. Pour the resultant residue into ethyl ether, seed and stir to obtain a precipitate. Filter the precipitate, wash with ethyl ether (2 x 500 ml) and dry the resultant residue under vacuum to obtain 2- (S) -benzyl oxy-_cis_, syn-octahydro-indole , d-10- camphorsulfonate, m.p. 114-118°C. D. Suspend the product of Part C (150g) 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 a 2 SO^ and evaporate the solvent to obtain the title compound. PREPARATION 5 6-CHLORO-3 , 4-DIHYDRO-3- (CHLOROMETHYL ) -2H-1 ,2,4- BENZOTHIADIAZINE-7 -SULFONYL CHLORIDE 1,1-DIOXIDE A. Dissolve the sulfonamide prepared in Part A of Preparation 2 (20 g) in dry DME (100 ml), add chloro- acetaldehyde dimethyl acetal (10 ml) and p-toluene- sulfonic acid and reflux for 3 hours or until TLC (silica, 3% ethyl acetate in CH 2 C1 ) indicates reaction is complete. Evaporate the solvent, dissolve the resultant residue in ethyl acetate, wash with saturated NaHCO j , then brine and concentrate to half volume. Refrigerate overnight, filter the resultant precipitate, wash in hexane, filter and dry to obtain the title compound . EXAMPLE 1 1- [2-(S )- [ [1-(S )-CARBOETHOXY-2- [4- [ [ [6-CHLORO-3 , 4- DIHYDRO-3- ( 2-PHEN YLETHYL )-2H-l , 2 , 4-BE ZOTHIADIAZ IN-7- YL ] S ULFON YLAMINO ] METHYL ] PHEN YLMETHOXY ] ETHYL ] AMINO ] -1 OXOPROPYL]-[2S-[2α, 3aα, 7aα ) ] -OCTAHYDRO-lH-INDOLE-2- CARBOXYLIC ACID, S,S-DIOXIDE A. To 10.4 g NaH (50% in mineral oil, washed with hexane) in 50 ml DMF at 0-5 °C, add dropwise over a 1 hour period 20g of N-a-t-butoxycarbonyl-L-serine in 350 ml DMF. Stir at room temperature for 1 hour, then at 45° for 1 hour. Cool the reaction mixture to 0-5 °C and add dropwise over 30 minutes 21.3 g of p-cyanobenzylbromide in 100 ml DMF. Stir at 0°C for 80 minutes, add 30 ml water, stir and filter. Concentrate the filtrate and partition between ethyl acetate and sat'd. aq. aHC03/H 2 0. Wash the aqueous phase with ethyl acetate ,adjust to pH 7.5 with 6N HCl and concentrate to approximately 100 mis. B. To the product of Step A, add 60 ml methanol, 40 ml ethyliodide, and 4 g NaHCOg. S ir under a nitrogen atomsphere for 72 hours, evaporate the solvent in vacuo and partition the residue between 800 ml ethyl acetate and 800 ml water. Separate the organic layer, and extract the aqueous layer with ethyl acetate; combine the organic extracts, wash with brine, dry over MgS0 4 , filter and evaporate the solvent. Purify the resultant residue by High Pressure Liquid Chromatography (HPLC) using 2 Prep 500 ςartidges and eluting with 21% ethyl acetate in hexane. Combine the desired fractions and evaporate the solvent to obtain a residue. FAB mass spec m/e - 349 ( M+H ) . C. Cool 2 g of the product of Step B to 0-5 °C and add dropwise 25 ml trifluoroacetic acid. Let stand until TLC (silica, elute with hexane: ethyl acetate) indicates no starting material is left. Add ethyl acetate, then evaporate the solvent in vacuo. Dissolve the resultant residue in ethyl ether, and wash with IN aqueous NaOH; backwash the aqueous phase with ether, combine the ethereal extracts, dry over K 2 Cθ 3 and evaporate the solvent to obtain a residue. D. Cool 1.6 g trif late reagent (Preparation 1) in 10 ml CH 2 C1 2 to 0°C. Add dropwise 1.1 g of the product of Step C and 1.2 g of PROTON SPONGE ® (1,8-bis ( dimethylamino)- naphthalene, Aldrich Chemical Co., Milwaukee, WI) in 20 ml CH 2 C1 2 . Monitor reaction by TLC, adding 1,8-bis- (dimeth la ino) naphthalene and trif late reagent as necessary. Filter the resultant precipitate with the aid of ethyl acetate, evaporate the solvent, and purify the resultant residue by column chromatography, eluting with 30% ethyl acetate in hexane. FAB mass spec m/e = 377 (M+H). E. Dissolve 2.5 g of the product of Step D in 50 ml ethanol saturated with NH 3 , add 1.25 g 5% Rh/Al 2 0 3 and hydrogenate at 60 psi for 4 hours. Filter the resultant mixture through celite with the aid of ethanol, then evaporate the solvent in vacuo to obtain a residue. F. Cool to 0°C 2.5 g of the product of Step E in 25 ml dry THF and add dropwise 3.3 g 6-chloro-3 ,4-dihydro-3-(2- phenylethyl)-2H-l, 2,4-benzothiadiazine-7-sulfonyl chloride 1,1-dioxide in 20 ml dry THF. Stir at 0°C for 1 hour, then add 0.6 ml N,N-diisopropylethylamine and stir at room temperature for 2 hours. (Reaction may be monitored by TLC [silica; elute with hexane: ethyl . acetate]). Add the reaction mixture to ethyl acetate ,wash with 4% aq. HCl, sat'd NaHCOg and brine, then dry over MgSO^ and evaporate the solvent in vacuo. Purify the resultant residue by HPLC: dissolve the residue in acetone:ethyl acetate:hexane (20:35:45) and separate on 2 Prep 500 cartridges using acetone:ethyl acetate: exane (5.5:36.5:58) as mobile phase. Monitor eluent by TLC (silica; elute with acetone: ethyl acetate :hexane [6:39:55]), combine the desired fractions and evaporate the solvent in vacuo to obtain a residue. FAB mass spec m/e = 766 (M+H). G. Stir 2.9 g of the t-butyl ester of Step F in 40 ml HCl/dioxane overnight; pass nitrogen through the solution to evaporate the solvent and obtain the free acid. H. Dissolve 2.9 g of the product of Step G in 6 ml DMF, add 1. lg cis ,syn-octahydro-lH-indole-2(S)carbox lic acid, t-butyl ester and 700 mg 1-hydroxybenzotriazole. Cool to 0°C, add 0.7 ml triethylamine and 900 mg l-(3-dimethyl- aminopropyl)-3-ethyl carbodiimide hydrochloride and stir overnight. Evaporate the solvent in vacuo, take up the residue in ethyl acetate, and wash with water, 4% aq. HCl, sat'd aq. NaHCO^, and brine. Dry the organic layer over MgSO^, filter and evaporate to obtain a residue. Purify said residue by HPLC using 2 Prep 500 cartridges and methanol: ethyl acetate: hexane (5.25:36:58.75) as mobile phase (residue dissolved in methanol: ethyl acetate: hexane [10:35:55]). Combine the desired fractions as determined by TLC and evaporate the solvent. Rechromatograph the resultant residue by HPLC using acetone: ethylacetate: hexane (10:40:50) as mobile phase, combining the desired fractions and evaporating the solvent to yield the title compound as a t-butyl ester. FAB mass spec m/e = 917 (M+H). I. Stir 1.5 g of the product of Step H in 20 ml dioxane saturated with HCl overnight; pass nitrogen through the solution to evaporate the solvent. Purify the resultant residue on Dowex Ag 50 2X (H form) , eluting with (ethanol: water [1: 1] ) :pyridine (95:5). Combine desired fractions as determined by TLC (silica; CH 2 Cl 2 :MeoH:AcOH [90:5:3]) and evaporate the solvent to obtain the title compound. FAB mass spec m/e = 861 (M+H). EXAMPLE 2 l-[2-(S)-[[l-(S)-CARBOXY-2-[4-[[[6-CHLORO-3,4-DIHYDRO-3- (2-PHENYLETHYL)-2H-l,2,4-BENZOTHIADIAZIN-7- YL]SULFONYLAMINO] METHYL] PHENYLMETHOXY] ETHYL] AMINO]-! OXOPROPYL]-[2S-(2α, 3aα, 7aα) ] -OCTAHYDRO-1H-INDOLE-2- CARBOXYLIC ACID, S,S-DIOXIDE. A. Treat the product of Example 1, Step G in a manner similar to that described in Example 1, Step H, first paragraph, substituting cis,syn-octahydro-lH-indole-2(S)- carboxylic acid, benzyl ester camphorsulfonate salt (see Preparation 4, Part C) for the t-butyl ester. Purify the resultant residue by column chroma¬ tography on 100 g silica eluted with CHCI3:ethyl acetate. Combine the desired fractions as determined by TLC (silica; elute with CH 2 C1 2 :methanol:acetone [93:2:5]) and evaporate the solvent to obtain a residue. Further purify the residue on a sephadex column (350g) . FAB mass spec m/e = 951 (M+H). B. Suspend 450 mg of the diester obtained in Step A in 2 ml water. Add 2 ml IN aq. NaOH and stir overnight at room temperature. Adjust to pH 6-7 with IN HCl, filter the resultant solid and dry under vaccum to obtain the title compound. FAB mass spec m/e = 833 (M+H). EXAMPLE 3 1- [2- (S )- [ [3- [4- [ [ [6-CHLORO-3,4-DIHYDRO-3-( 2-PHE YL- ETHYL)-2H-l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYLAMINO- METH YL] PHENYL ]-l-(S)- (ETHOXYCARB ON YDPROPYL] AMINO ] -1- OXOPROPYL]-[2S-(2α, 3aα, 7aα] -OCTAHYDRO-lH-INDOLE-2- CARBOXYLIC ACID, S,S -DIOXIDE HYDROCHLORIDE A. 2-Amino-4-(4-cyano) phen Ibutanoic acid, ethyl ester Reflux 2- (4-cyano) phenylethyl bromide (23 gm) , the p-chlorobenzaldimine of ethyl glycinate (21 gm) , tetra-n-butylammonium bromide (10 gms) and freshly ground fine potassium carbonate powder (42 gms) in acetonitrile (150 mis) with mechanical stirring under nitrogren for 12 hours . Cool the mixture, filter off the solid and wash the filter cake with ethyl acetate (3 x 150 mis). Wash the combined filtrate with water (2 x 100 mis) and evaporate the solvent in vacuo. Stir the residue vigorously with THF (200 mis) and 2N HCl (200 mis) at room temperature for 2 hours. Wash the aqueous phase with ethyl acetate, basify with solid potassium carbonate to pH 9 and extract with ethyl acetate to give the title compound of Part A. B. N- [1-(S)~ (Ethoxy carbonyl) -3- (4-cyano) heny 1]-(S )- alanine, t-butyl ester Slowly add the product of Part A (9 gms) " and PROTON SPONGE® (17.2 gm) in dry dichlorome thane (80 mis) dropwise into a stirred solution of triflate reagent (22 gm) in dry dichlorome thane (40 mis) cooled in an acetone-ice bath. Stir at room temperature overnight. Filter the resultant precipitate and wash the filter cake with ethyl acetate (5 x 100 ml). Wash the combined filtrate with 10% citric acid (3 x 100 ml); sodium bicarbonate (sat'd, 2 x 100 ml), and saturated brine (2 x 100 ml). Dry the solution over potassium carbonate in the presence of triethyl amine (5 mis), and remove the solvent in vacuo. Chroma tograph the resultant residue ( hexane :EtOAc:CH 2 Cl 2 [8:1:1], 1% Et 3 N; 500 gm silica gel; 230-400 mesh) to obtain the title compound of Part B. C. N-[3-(4-Aminomethyl)phen l-l-(S )-( ethoxy car bony 1) propyl]-(S)-alanine, t-butyl ester Hydrogenate a mixture of the product of Part B (2 g), hydrogen chloride (0.2 gm) and 10% Pd/C (0.4 gm) in absolute ethanol (100 ml) at 50 psi for 5 hours. Filter the resultant mixture through celite. Evaporate the solvent to obtain the hydrogen chloride salt of the title compound of Part C. D. Add N-methylmorpholine (0.5 ml) to a solution of the product of Part C (1 gm) in dry THF (20 mis) cooled in acetone-ice bath (-5°C). Add the sulfonyl chloride of Preparation 2 (1.3 gm) and stir the resulting mixture at room temperature overnight. Dilute the resultant reaction mixture with ethyl acetate (400 ml), wash with 0.5N HCl (100 ml), saturated NaHC0 3 (2 x 100 ml), and brine (2 x 100 ml). Dry the solution over MgS0 4 and remove the solvent in vacuo. Purify the resultant residue by chromatography [400 gm silica gel, 230-400 mesh; first hexane:EtOAc:CH Cl 2 , 4:1:1, then hexane: EtOAc:CH 2 Cl 2 , 1:1:1] to obtain a residue. E. Add the product of Part D (1.76 gm) to 5.5 M HCl in dioxane (50 ml) and stir the resulting mixture at room temperature overnight. Evaporate the solvent in vacuo, triturate the solid residue with ether, and remove the solvent in vacuo to obtain a residue (hydrogen chloride salt) . F. Treat the product of part E in a manner similar to that described in Example 1, Part H, first paragraph, substituting N-methylmorpholine for triethylamine to obtain a residue. Purify the resultant residue by chromatography [400 gm silica gel 230-400 mesh; .hexane: EtOAc:CH 2 Cl , 1:2:1] to obtain the t-butyl ester of the title compound. G. Stir the product of Part F (0.9 gm) in 5.5 M HCl/dioxane (40 mis) at room temperature for 2 hours. Remove the solvent in vacuo, triturate the product with ether, and dry in vacuo to obtain the title compound of Example 3. FAB mass spec m/e=845 (M + H) EXAMPLE 4 1- [2- (S )- [ [1- (S )-CARBOXY-3- [4- [ [ [6-CHLORO-3 , 4-DIHYDRO-3- (2-PHENYLETHYL)-2H-l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYL- A INO] METHYL ]PHENYL]-PROPYL] AMINO] -1- OXOPROPYL]-[2S-(2α,3aα,7aα)]-OCTAHYDRO-lH-INDOLE- 2-CARBOXYLIC ACID, S.,S- DIOXIDE Dissolve the product of Example 3 (0.85 gm) in methanol (2 mis) and cool to 0°C under nitrogen. Add IN sodium hydroxide (5 mis) portionwise. Refrigerate the mixture overnight. Acidify the resultant mixture with acetic acid, evaporate to dryness, and purify the residue by chromatography on a C-18 medium pressure reverse-phase column to yield the title compound of Example 4. EXAMPLE 5 1- [ [2- (S )- [5- [ [6-CHLORO-3-CHLOROMETHYL-3 , 4-DIHYDRO-2H- l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYLAMINO]-l-(S)- (ETHOXYCARBO YL)PENTYL]AMINO]-l-OXOPROPYL]-[2S- ( 2α , 3aα ,7act ) ] -OCTAHYDRO-lH-IHDOLE-2-CARBOXYLIC ACID, S,S-DIOXIDE A. Combine N ε Cbz lysine, ethyl ester (30.0 g) , t-butyl bromo propionate (44.78 g) , triethylamine (14.8 ml) and DMF (120 ml) and stir under nitrogen at 75 °C until TLC shows no starting material present. Evaporate the solvent, dilute the resultant residue with water and extract with ethyl ether. Wash the organic layer with brine, dry over MgS0 4 , filter and evaporate the solvent in vacuo. Purify the resultant residue by column chromatography on 1,100 g silica gel (60-200 mesh), eluting with ether :hexane (50: 50+75: 50) . Combine the desired fractions and evaporate the solvent in air. Further purify the resultant residue by HPLC using 2 Prep 500 cartridges and eluting with ether :hexane. Combine desired fractions, dry over MgS0 4 and evaporate the solvent in air to obtain a residue. B. Combine 20% Pd(OH) 2 /C (21. lg) and anhydrous ethanol (25 ml) in a Parr shaker bottle, add the product of Part A (16.5 g) in ethanol (55 ml) and hydrogenate overnight under 60 p.s.i. H 2 . Filter the resultant solution over filter paper and celite and evaporate the solvent to obtain a residue. C. Dissolve the sulfonyl chloride prepared in Preparation 5 (2.4 g) in dry DME (15 ml). Add triethylamine (1 ml) and the product of Part B of this Example (2 g) in DMF (10 ml) and stir for 1 hour, or until TLC (silica, 10% MeOH in CH 2 C1 2 ) indicates no starting material is left. Add the resultant solution to ethyl acetate, wash with water, saturated NaHC0 3 and brine, dry over MgS0 and evaporate the solvent in vacuo. Purify the resultant residue on a Sephadex LH20 column to obtain a residue. FAB mass spec m/e = 632 (M+H) . D. Treat the product of Part C in a manner similar to that described in Example 1, Part G. E. Treat the product of Part D in a manner similar to that described in Example 1, Part H, first paragraph, substituting the camphorsulfonate salt of the benzyl ester of the octahydroindole (see Preparation 4 Part C) for the t-butyl ester. Purify the resultant residue on a sephadex LH20 column, combine the desired fractions and evaporate the solvent. Dissolve the resultant residue in ethyl acetate, add dioxane saturated with HCl and evaporate the solvent to obtain the benzyl ester of the title compound. FAB mass spec m/e = 817 (M+H). F. Dissolve the product of Part E (600 mg) in acetic acid saturated with hydrogen bromide (6 ml). After 5 hours, evaporate the solvent and purify the resultant residue on a Sephadex LH20 column. Combine the desired fractions as determined by TLC (silica, MeOH:CH 2 Cl 2 :acetic acid, 10:90:4) and evaporate the solvent to obtain the title compound. FAB mass spec m/e = 726 (M+). EXAMPLE 6 l-[[2-(S)-[l-(S)-CARBOXY-5-[[6-CHLORO-3-CHLOROMETHYL- 3 , 4-DIHYDRO-2H-1 , 2, 4-BENZOTHIADIAZ I -7 -YL] SULFONYLAMINO] PENTYL]AMrNO]-l-OXOPROPYL]-[2S-(2α,3aα,7aα)]- OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID, S_,S_-DIOXIDE Add the product of Example 5, Part E (benzyl ester) to IN aqueous NaOH (4 ml) and water (4 ml) and stir overnight. Add IN HCl (4 ml) and ethanol. Charge the resultant solution to Dowex Ag 50 cation exchange resin by stirring batehwise for 20 minutes (60 ml resin, pre-washed with ethanol: water, 1:4). Prepare a column from the loaded resin, elute the column with ethanol: water (1:4) until the elute is pH 6, then elute with ethanol/water:pyridine (95:5). Combine the desired fractions as determined by TLC (silica, ethanol: water, 9:1). Further purify the resultant product on a Sephadex LH 20 column. Combine the desired fractions and evaporate the solvent to obtain the title compound. FAB mass spec m/e + 698 (M+H). EXAMPLE 7 N-[2-[[4-[[[6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETHYL)- 2H-l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYLAMINO]METHYL] PHENYL]CARBONYL]AMINO-l-(S)-(ETHOXYCARBO YL)ETHYL]-(S)- ALANYL-(S)-PROLINE, S_,S-DIOXIDE A. Dissolve 4-cyanobenzoic acid, t-butyl ester (11.34 g) in ethanol (100 ml) saturated with anhydrous NH 3 , add 5% Rh/Al 2 0 3 (120 g) and hydrogenate in a Parr apparatus at 60 p.s.i. at room temperature for 2 3/4 hours. Filter the resultant solution through celite and evaporate the solvent to obtain a residue. B. Dissolve the product of Part A (11.27 g) in dry THF (100 ml) add N,N,-diisopropylethyl amine (8.44 g) and cool to 0°C in an ice bath. Add dropwise, slowly and with stirring, the sulfonyl chloride prepared in Prepara¬ tion 2 (27.51 g) and let stand at 0°C for 35 minutes. ' ~~ Remove the ice bath and stir at room temperature for 2 1/2 hours or until TLC (silica, CH 2 Cl 2 :MeOH, 95:5) shows the reaction to be complete. Evaporate the solvent to obtain a residue. C. Cool to 0°C a solution of the product of Part B (3.00 g) in CH 2 C1 2 (25 ml) and add, slowly and with stirring, trifluoroacetic acid (25 ml). Stir for 30 minutes at 0 β C, then at room tempeature for 2 1/4 hours or until TLC (as in Part B) shows the reaction to be complete. Evaporate the solvent to obtain a residue. D. Dissolve trif late reagent as prepared in Preparation 1 (3.31 g) in CH 2 C1 2 (75 ml) and cool to 0°C; add, slowly and with stirring a solution of PROTON SPONGE® (4.24 g) and N-βCbz-2,3-diaminopropionate, ethyl ester (2.00 g) in CH 2 C1 2 (75 ml). Stir at 0°C for 15 hours. Extract the solution with 10% citric acid (2x), then sat'd. NaHC0 3 (2x), dry the organic layer over MgS0 , filter and evaporate the solvent. Purify the resultant residue by flash chromatography, eluting with CH 2 Cl 2 :EtOAc (88:12). Combine the desired fractions and evaporate the solvent. Dissolve the Cbz-diester (0.5 g) in ethanol (25 ml) containing 20% Pd(OH) 2 /C (0.15 g) and hydrogenate in a Parr apparatus at 50 p.s.i. at room temperature for 1 hour. Filter .the resultant solution through celite and evaporate the filtrate in vacuo. Combine the resultant residue (0.33 g) and the product of Part C (0.59 g) in dry DMF (7 ml), cool to 0°C and add slowly 1-hydroxybenzotriazole (0.18 g) followed by N-methyl morpholine (0.13 g) , then by DEC (0.25 g) . Stir the mixture for 20 min. at 0°C, then at room temperature for 16 hours or until TLC (silica, ethanol: methanol, 85:15) indicates the reaction to be complete. Dilute the reaction mixture with CH 2 C1 2 and extract with saturated NaHC0 3 , then with 10% aqueous citric acid. Dry the organic layer with MgS0 4 , filter and evaporate the solvent in vacuo to obtain a residue. E. Dissolve the product of Part D (0.75 g) in CH 2 C1 2 (5 ml) and cool to 0°C. Add, slowly and with stirring, trifluoroacetic acid (5 ml) and stir at 0°C for 30 minutes, then at room temperature for 4 hours or until TLC (silica, CH 2 Cl 2 :MeOH, 90:10) indicates no starting material is left. Evaporate the solvent. Purify the resultant residue by ion exchange chromatography on Biorad AG50-W-X2 resin (100-200 mesh, hydrogen form) previously equilibrated in ethanol: water. Elute with ethanol :water:pyridine, combine the desired fractions and evaporate the solvent to obtain a residue. F. Treat the product of Part E in a manner similar to that described in Example 3, Parts F and G, substituting proline, t-butyl ester for the octahydro-ljϊ-indole to obtain the title compound. FAB mass spec m/e = 873 (M+) . EXAMPLE 8 N-[5-[[6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETHYL)-2H- l,2,4-BENZOTHIADIAZIN-7-YL] SULFON YLAMINO]-l-(S )- (METHOXYCARBONYL)PENTYN-3-YL]-(S)-ALANYL-(S)- PROLINE , S_, S-DIOXIDE , HYP ROC HLORIDE A. Titrate a solution of diazomethane in ether into a solution of l-amino-l-(S)-carboxy-5-( t-butoxycarbonyl amino )-3-pentyne (4 g) in ethanol (200 ml) until a yellow color remains. Evaporate the solvent to obtain 1-amino- l-(s)-methoxy car bony 1-5- ( t-butoxycar onylamino)-3- pentyne. B. Add the product of Part A (4 g) and PROTON SPONGE® (5 g) in dichloromethane (15 ml) dropwise to. a stirred solution of triflate reagent (6.5 g) (See Preparation 1) in dichloromethane (10 ml) at -10 °C. Stir the solution and slowly allow to warm to room temperature over 2 h. Filter the reaction mixture through celite, washing thoroughly with ethyl acetate. Wash the combined organic solution with 10% citric acid (3x), saturated sodium bicarbonate (2x) and brine (2x) , dry over MgS0 4 and evaporate the solvent. Chroma tograph on silica gel, eluting with ethyl acetate: hexane (1:4) containing 1% triethylamine to obtain 1- (S)-methoxy car bony 1-5- ( t- butoxycarbonylamino)pentyn-3-yl-(S)-alanine, t-butyl ester. C. Add the product of Part B (3.5 g) to a stirred solution of 4M HCL in dioxane (25 ml) at 0° and stir for 0.5 hours. Evaporate the solvent and triturate the residue with ether to obtain l-(S)-methoxycarbonγl-5- amino-pentyn-3-yl-(S)-alanine, t-butyl ester, hydrochloride. D. Add N-methylmorpholine (1.5 g) to a solution of the product of Part C (2.9 g) in tetrahydrofuran at 0°. Add 6-chloro-3 , 4-dihy dro-2- ( pheny lethy 1 ) -2H-1 ,2,4- benzothiadiazine-7-sulfonyl chloride, J3_, ^-dioxide (3.9 g) (See Preparation 2) and stir the resulting mixture at room temperature overnight. Dilute the reaction mixture with ethyl acetate, wash with 0.5 N HCl (lx), saturated sodium bicarbonate (2x) , and brine (lx), dry over MgS0 4 and evaporate the solvent. Chroma tograph on silica gel, eluting with ethyl acetate: dichloromethane to obtain a residue. E. Add the product of Part D (4.8 g) to a 4M solution of HCL in dioxane (100 ml) and stir the resulting mixture at room temperature overnight. Evaporate the solvent then triturate the residue with ether to obtain a residue. F. Treat the product of Part E in a manner similar to that described in Example 3, Part F, first paragraph, substituting (S)-proline, t-butyl ester for the octahydro-lH-indole, to obtain a residue. Purify the resultant residue by chromatography on silica gel, eluting with ethyl acetate:CH 2 Cl 2 . Combine the desired fractions and evaporate the solvent to obtain a residue. G. Treat the product of Part F in a manner similar to that described in Example 3, Part G to obtain the title compound. EXAMPLE 9 N-[S-[[6-CHLORO-3,4,-DIHYDRO-3-(2-PHENYLETHYL)-2H- l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYLAMINO]-l-(S)- METHOXYCARBO YL)- (E )-PENTEN-3-YL] - (S )-ALANYL-(S )- PROLINE, S_, S-DIOXIDE,HYDROCHLORIDE A. Add a solution of l-N-acetylamino-l-(S)-carboxy-5- ( t-butoxycarbonylamino)-3-pentyne (5 g) in tetrahydrofuran (20 ml) dropwise to a stirred solution of sodium (1.2 g) in liquid ammonia (1.2 L). After 2 h, add ammonium hydroxide and water. Remove the ammonia, dissolve the residue in ethyl acetate, wash with 0.5N HCl (2x) and brine (3x) , dry over MgS0 4 and evaporate the solvent. Purify by precipitation from dichloromethane as the DCHA salt of (E_)-l-N-acetylamino-l-carboxy-5-(_t_- butoxy-carbonylamino)-3-pentene. B. Add cobalt chloride hexahydrate (50 mg) and Acylase I (aminoacylase from porcine kidney, grade 1, available from Sigma Chemical Co., St. Louis, MO) (100 mg) to a stirred solution of the product of Part A (3.5 g) in O.lM, pH 7.5 phosphate buffer (120 ml) at 38°. After 16 hours, remove the protein with activated carbon and filter through celite. Adjust pH of the solution to 2.75 and remove the unreacted isomer by washing with ethyl acetate (3x). Adjust the pH to 6.5 and evaporate the solvent. Remove the salt from the residue by dissolving in ethanol (100 ml) and filtering through celite. Evaporate the solvent to obtain (j -1 -am ino-1- (£»_)- carboxy-5-( t-butoxycarbonylamino)-3-pentene. C. Substitute the product of Part B (i.e., the 3- pentene compound) for the 3-pentyne compound in the procedure of Example 8, Parts B to G to obtain the title compound. EXAMPLE 10 1- [2- (S )- [ [2- [4- [ [ [6-CHLORO-3-CHLOROMETHYL-3, 4- DIHYDRO-2H-l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYLAMINO]- METHYL]PHENYL-l-(S)-(ETHOXYCARBONYL)PROPYL] AMINO ]- 1-OXOPROPYL] - ( 2S-( 2α , 3aα ,7aα ) ] -OCTAHYDRO-1-H- I DOLE-2-CARBOXYLIC ACID, T-BUTYL ESTER, S,S-DIOXIDE A. To lg of the compound of Example 3, part B, in THF, add HCl-saturated dioxane (30 ml). Stir the mixture at room temperature for 5 hours under an inert atmosphere. Evaporate the solvent to obtain a dry foam as a hydrochloride salt. B. Combine 3g of the product of Part A with 2.5g of octahydroindole-t-butyl ester (Preparation 3) in the manner described in Example 3, Part F to obtain 1-[2(S)- [ [ p- cyanopheny 1-1 (S)-( ethoxy car bony Dpropyl] amino] -1- oxopropyl]-[2S-(2α,3aα ,7aα)]-octahydro-lH-indole-2- carboxylic acid, t-butyl ester. FAB mass spec. M/e=501 (M + ). C. Hydrogenate 2.5g of the product of Part B in 150 ml of ethyl alcohol containing 5 ml of saturated HCl/dioxane at 55 psi in the presence of 500 mg of 10% Pd on C for 20 hours. Filter the resultant reaction mixture through celite to obtain 2.6g of amine. D. Combine 850 mg of the product of Part C with 600 mg of 6-chloro-3-chloromethy 1-3 , 4- di hydro- 2^1 ,2,4- benzothiadiazin-7-sulfonyl chloride, ^_,j3_- dioxide in 5ml of THF containing 0.8 ml of N-methylmorpholine and let stand overnight at room temperature. Dilute with EtOAC, wash with saturated NaCl, and evaporate the solvent. Purify the resultant residue by chromatography on Si0 2 with CH 2 Cl 2 /EtOAC as eluant to produce 700 mg of title compound. FAB mass spectrum shows M/e=844 (M + ). EXAMPLE 11 N- [N- [4- [4- [ [ [ [6-CHLORO-3,4-DIHYDRO-3- [2- (2-PYRIDI YL )- ETHYL ] -2H-1 , 2 , 4-BENZOTHIADIAZ IN-7-YL ] SULFON YL- AM INO] METHYL] PHENYL ]-l-(S )-ETHOXYCARBON YL )PROPYL] - (S)-ALANYL-(S)-PROLINE, T-BUTYL ESTER, S_,S-DIOXIDE A. To 6g of the amine of Example 3, Part C, in 25 ml of DME cooled with an ice-bath, add 1.9 ml of N- methylmorpholine. To this mixture add 5g of 4-amino-2- chloro-5-sulfonamidobenzenesulfonyl chloride in 25 ml of DME. Stir the reaction overnight with cooling under an inert atmosphere. Concentrate the resultant reaction mixture and partition the residue between EtOAc and H 2 0. Separate the organic layer and evaporate the solvent. Purify the resultant residue by chromatography on Si0 using EtoAc/Hexanes as eluant to obtain 5g of an oil. FAB mass spectrum M/e=633 (M + ). B. Treat the product of Part A in a manner similar to that described in Example 10, Part A, to yield a dry foam. FAB mass spectrum M/e=614 (M + ) . C. Combine 1.6g of the product of Part B with 490 mg L-Proline, t-butyl ester in the present of 9 ml of DMF, 380 mg 1-hydroxybenzotriazole, 1.14 ml N-methylmorpholine and 550 mg DEC. Stir the reaction overnight, then extract and purify the resultant product as described in Example 3, Part F, using EtoAc/Hexanes as eluent to obtain a residue, FAB mass spectrum M/e=730 M + . D. In 7 ml THF, combine the amino-sulphonamide obtained in Part C with 360 mg of (2-pyridiny Dpropanal and 10 mg of p-toluenesulfonic acid and stir for 24 hours at room temperature in an inert atmosphere. Concentrate the reaction mixture and partition the resultant residue between EtOAc and water. Separate the organic phase, wash with dilute NaHS0 3 , saturated NaHC0 3 , saturated NaCl and dry with MgS0 . Evaporate the solvent and chroma tograph the residue on Si0 2 using EtOAc as eluant to obtain 350 mg of the title compound. Mass spectrum, M/e=899 (M + ). EXAMPLE 12 l-[N-[2-[4-[[[6-CHLORO-3,4-DIHYDRO-3-(2-PHENYLETHYL)- 2H-l,2,4-BENZOTHIADIAZIN-7-YL]SULFONYL]AMINOMETHYL]- TH IAZOL-2-YLMETHYLTHIO]-l(S)-(METHOXYCARB ON YL) ETHYL ] - (S)-ALANYL]-CIS,SYN-OCTAHYDROI DOLE-2(S)-CARBOXYLIC ACID, S,S-DIOXIDE A) E thy 1-4 -Aminome thy lthiazole-2-Car boxy late 1. Ethyl- thizaole-4 -Car boxy late Combine ethylbromopyruvate (19.5 g, 100 mmole) in 50ml EtOH and thioformamide (4.27 g, 70 mmole) in 10 ml EtOH and stir at room temperature overnight. Pour into IN HCl (100 ml) and extract with 190 ml die thy 1 ether. Separate the aqueous layer and treat with an excess of solid sodium bicarbonate. Extract the aqueous layer with diethylether (2 x 150 ml), dry over MgS0 4 and evaporate the' solvent to obtain the title compound of Part A(l) as a syrup. Recrystallize from hexanes to obtain white needles, m.p. 52-54°C. 2. 2-Carboamide-Thia zole Treat 5.0 g of the product of Part A(l) with 100 ml of concentrated ammonium hydroxide solution overnight. Purge with 2 for 2 hours and remove the solvent to obtain a crude product. Recrystallize using ethylacetate/pet ether to obtain the title compound, m.p. 122-124°C. 3. 4-Cy ano-Thia zole Dissolve the product of Part A(2) (2.0 g, 14.50 mmoles) in 20 ml of dry CH 2 C1 and cool in an ice bath. Add trifluoroacetic anhydride (3.65 g, 16.50 mmoles) and stir at room temperature for 3 hours. Evaporate the solvent and recrystallize from ethylacetate/pet ether to obtain the title compound, m.p. 54-56°C. 4. E thy 1-4 -Cyanothia zole- 2-Car boxy late Cool diisopropyl amine (4.04 g, 40.0 mmoles) in dry THF in an ice bath under nitrogen. Add n-butyl lithium (40 ml, 40 mmoles) and stir at 0°C for 15 min. Cool the resultant reaction mixture to -78 °C and add a solution of the product of part A(3) (4.0 g, 36.36 mmoles) in 20 ml THF. Stir the reaction mixture at -78 °C for 30 minutes, add ethylchloro- formate (3.93 g, 36.36 mmoles) and slowly warm the reaction mixture to room temperature. Add aqueous ammonium chloride and evaporate the solvent. Add CH 2 C1 2 (300 ml) to the resultant residue, wash with water, dry over MgS0 4 and evaporate the solvent to obtain the title compound. Purify the product by column chromatography using ethylacetate/pet ether. 5. Ethy 1-4 -Aminomethylthiazole-2-Car boxy late Cool a disiamylborane (17.50 mmoles) solution in an ice bath under nitrogen. Add the product of Part A(4) (1.5 g, 8.24 mmoles) in 10 ml of dry THF and let stand at 0°C for 2 days. Pour the reaction mixture into ice cold IN HCl and extract with die thy 1 ether. Separate the aqueous layer, treat with sodium bicarbonate, extract with 2 x 100 ml ethyl acetate, dry over MgS0 and evaporate the solvent to obtain the title compound. Use without further purification in Part B. B. l-N-[2-[4-[6-Chloro-3,4-Dihydro-3-(2-Phenylethyl)- 2H-1, 2,4,-Benzothiadiazin-7-yl] Sulfonyl] Aminomethyl] -2- Carboethoxythiazole, S,S-Dioxide Combine the product of Preparation 2 (1.2 mmoles) and the product of Part A (1.0 mmoles) in dry DMF (1.0 ml) and cool in an ice bath. Add dropwise triethyl amine (1.5 mmoles). Stir the resulting reaction mixture at room temperature for 16 hours. Evaporate the solvent under high vacuum, take up the residue in ethylacetate (100 ml), wash with water, dry over MgS0 4 and evaporate the solvent. Purify the resultant residue by column chromatography. C. l-[N-[2-[4-[6-Chloro-3,4-Dihvdro-3-(2-Phenylethyl)- 2H-1 , 2,4-Benzothiadiazin-7-yl] Sulfonyl]Aminomethyl] -2- Hy droxyme thy lthia zole, S,S-Dioxide Dissolve the product of Part B (1.0 mmole) in 25 ml dry THF and cool to -40 °C under nitrogen. Add LiALH 4 (1.5 mmole) and stir the resultant mixture at -40 °C for 1 hour. Add Na 2 S0 4 : 10H 2 O, filter, dry over MgS0 4 and evaporate the solvent to obtain the title compound. D. 1- [N- [2- [4- [6-Chloro-3 , 4-Dihydro-3- ( 2-Pheny lethy 1 )- 2H-1 ,2,4-Benzothiadiazin-7-yl]Sulfonyl]Aminomethyl]-2- Bromomethylthiazole, S,S-Dioxide Combine carbon tetrabromide (1.1 mmoles) and triphenyl phosphine (1.1 mmoles) in dry DMF (5 ml) at 0°C under nitrogen and stir at 0°C for 1/2 hour. Add a solution of the product of Part C (1.0 mmoles) in dry DMF (3 ml) and stir the reaction mixture at 0°C for 1 - 2 hours. (Check progress of reaction by TLC). Pour the resultant mixture into ice cold water, extract with diethyl ether (2 x 150 ml), dry over MgS0 4 and evaporate the solvent. Purify the resultant residue by column chromatography . E » Bis[ [ [l-(S)-(Methoxycarbonyl)-Ethyl]-(S)-Alanyl]- Cis ,Syn-Octahydroindole-2(S)-tert-Butoxycarbonyl]- disulphide 1. Cool a solution of L-cysteine (7.20 g, 0.027 moles) in 50 ml dry CH 2 C1 2 in an ice bath under N . Add N- methylmorpholine (16.8 g, 0.16 moles), then add a freshly prepared solution of triflate reagent (0.161 moles) (Preparation 1) in 200 ml CH C1 2 dropwise over 2 hours. Stir the resulting reaction mixture overnight at room temperature. Wash the reaction mixture with 2 x 100 ml of water, then 2 x 100 ml of brine, dry over MgS0 , and evaporate the solvent. Column chromatograph the resultant residue using 40% ethyl acetate:60% pet ether to obtain a syrup. 2. Cool a solution of the product of Part E(l) in 50 ml dioxane in an ice bath. Add 150 ml of a solution of saturated dioxane: HCl and stir at room temperature for 3 hours. Reduce the volume of the reaction mixture to 50 ml and add 150 ml of ethyl acetate to precipitate the product as the hydrochloride salt. 3. Cool a solution of the product of Part E(2) (1.0 mmole) in 10 ml dry DMF in an ice bath. Add 1- hydroxybenzotriazole hydrate (2.2 mmoles), 1- ( dimethylaminopropyl)-3-ethyl-carbodiimide (3.0 mmole) and 2-carboxy-perhydroindole t-butyl ester (2.3. mole) (Preparation 3) and stir the resulting solution at 0°C. Add triethylamine dropwise (6.0 mmoles) and stir the resulting reaction mixture over-night at room temperature. Evaporate the solvent, dissolve the residue in 200 ml of ethylacetate, wash with water, brine, and dry over MgS0 4 . Evaporate the solvent and column chromatograph the resultant residue using 60% ethylacetate: 40% pet ether. F. Cool 5 ml of dry methanol in an ice bath under nitrogen, add sodium borohydride (10.0 mmole) and stir at 0°C for 10 minutes. Add the product of Part E (0.60 mmoles) in 5 ml dry methanol and stir the resulting mixture for 5 minutes at 0°C. Add the product of Part D (1.2 mmoles) in 5 ml THF, warm the mixture to room temperature and stir at room temperature for 2 hours. Evaporate the solvent and take up the resultant residue in ethylacetate. Extract with 10% citric acid, NaHC0 solution and brine, dry over MgS0 4 and evaporate the solvent. Chromatograph the residue to obtain the t-butyl ester of the title compound of Example 12. G. Treat the product of Part F in a manner similar to that described in Example 3, Part G, to obtain the title compound. Mass spectrum m/e = 925 (M+) . In a similar manner, using appropriate starting materials and reagents, the following compounds may be prepared: 1- [2- (S )- [ [1- (S )-carboxy-2- [4- [ [ [6-chloro-3- (cyclopentylmethyl)-3,4-dihydro-2H_-l,2,4-benzothiadiazin- 7-yl] sulf ony lamino] methyl] phenylmethoxy] ethyl] amino] -1- oxopropyl]- [2S-(2α, 3aα, 7aα) ]-octahydro-lH_-indole-2- carboxylic acid, _S,j3^ dioxide 1- [2- (S )- [ [1- (S )-carboxy-2- [4- [ [ [6-chloro-3- ( dichlorome thy 1) -3 ,4-dihydro-2H--l, 2,4-benzothiadiazin-7- yl] sulfony lamino] methyl] phenylmethoxy] ethyl] amino] -1- oxopropyl]- [2S-(2α, 3ao, 7aα)]-octahydro-ljH*--indole-2- carboxylic acid, ^,^-dioxide l-[2-(S)-[[l-(S)-carboxy-3-[4-[[[6-chloro-3,4- dihydro-3-(2-phenylethyl)-2jH > -l,2,4-benzothiadiazin-7- yl] sulf ony lamino] methyl] phenyl] propyl] amino] -1- oxopropyl]- [2S-(2α, 3aα, 7act) ]-octahydro-lji^indole-2- car boxy lie acid, _S_,_S- dioxide 1- [2- (S )- [ [1- (S )-carboxy-3- [4- [ [ [6-chloro-3- (cyclopentylmethyl)-3,4-dihydro-2H-l ,2,4-benzothiadiazin- 7-yl] sulf ony lamino] methyl] phen l] propyl] amino] -1- oxopropyl]-[2S-(2α, 3ao, 7aα)]-octahydro-lH_-indole-2- carboxylic acid, j3_,^- dioxide l-[2-(S)-[[l-(S)-carboxy-3-[4-[[[6-chloro-3- ( dichlor omethy 1 ) -3 , 4-dihy dr o-2II_-l , 2 , 4-benzothiadia z in-7- yl] sulfony lamino] methyl] phenyl] propy 1] amino] -1- oxopropyl]-[2S-(2α, 3aα, 7aα)]-octahydro-lH_-indole-2- carboxylic acid, J3j3---dioxide l-[2-(S)-[[l-(S)-carboxy-2-[4-[[[6-chloro-3,4- dihydro-3-(2-phenylethyl)-2-H_-l,2,4-benzothiadiazin-7-yl]- sulfony lamino] methyl] phenyl] ethyl] amino] -1-oxopropyl] - [2S-(2o, 3aα, 7aα ) ]-octahydro-lH_-indole-2-carboxylic acid, _S_,^-dioxide N- [1-(S )-carboxy-3- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( 2- pheny lethy 1 ) -2I_-1 , 2 , 4-benzothiadia zin-7-y 1] sulfony 1- amino] methyl] phenyl] propyl] -(S)-alanyl-(S )-proline, jjj^S- dioxide N-[l-(S)-carboxy-3-[4-[[[6-chloro-3- ( cyclopentylme thy 1) -3, 4-dihy dro-2H_-l, 2,4-benzothiadiazin- 7-yl] sulf ony lamino] methyl] pheny 1] propyl] -(S)-alanyl-(S )- proline, ,jS*-- dioxide N-[l-(S)-carboxy-3-[4-[[[6-chloro-3- ( dichlor omethy 1 ) -3 , 4-dihy dro-2H_-l , 2 , 4-benzothiadia zin-7- yl] sulfony lamino] methyl] phenyl] propyl]-(S)-alanyl-(S )- proline, ^,J5-dioxide N-[l-(S)-carboxγ-2-[4-[[[6-chloro-3,4-dihydro-3-(2- phen lethyl)-2E[_-l,2,4-benzothiadiazin-7- l] sulfonyl- amino] methyl] phenyl] ethyl] -(S)-alanyl-(S)-proline, ^ϋ dioxide N- [1-(S )-carboxy-3- [4- [ [ [6-chloro-3 , 4-dihy dr o-3- ( 2- pheny lethy 1 ) -2li_-l , 2 , 4-benzothiadia z in-7- yl] sulf ony lamino] methyl] henyl] propyl] - (S )-alany 1- (S )- ( 4- cyclohexyl) proline, jS^S-^dioxide 7-N- [2-(S )- [ [l-(S)-carboxy-3- [4- [ [ [6-chloro-3 , 4- dihydro-3-(2-phenylethyl)-2H_-l,2,4-benzothiadiazin-7- yl] sulfony lamino] methyl] phenyl] propyl] amino] -1- oxopropyl] -1 , 4-dithia-7-azaspiro [4.4] nonane-8- (S )- carboxylic acid, ,jj--- dio ide l-[2-(S)-[[l-(S)-carboxy-3-[4-[[[6-chloro-3,4- dihydro-3-(2-phenylethyl)-2]_-l,2,4-benzothiadiazin-7- yljsulf ony lamino] methyl] phenyl] propyl] amino] -1- oxopropyl]-lH_-2,3-dihydroindole-2-(S)-carboxylic acid _S_,^- dioxide 1- [2- (S )- [ [2- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2- phenylethγl)-2]i > -l,2,4-benzothiadiazin-7- yl] sulfony lamino] methyl] henylmethoxy] -1-(S )- [ (2,2- dimethy l-l,3-dioxolan-4-yl)methoxycarboxy 1] ethyl] amino] - 1-oxopropyl]- [2S-(2o, 3aα, 7aα)] -octahydro-lH 7 indole-2- carboxylic acid, j^^S*-- dio ide 1- [2-(S )- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( 2- phenylethyl)-2H_-l,2,4-benzothiadiazin-7- yl] sulf ony lamino] methyl] phenyl] -1-(S)- [ (2,2-dimethyl-l ,3- dioxolan-4-yl)methoxycarbonyl] propyl] amino] -1-oxopropyl]- [2S-(2α, 3ao, 7aα) ] -octa hydro- lH--indole-2-carboxy lie acid, j3_,J3-- dioxide 1- [2-(S )- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( 2- pheny lethy 1 ) -2^-l , 2 , 4-benzothiadia z in-7-y 1] sulfony 1- amino] me thy 1 ] pheny 1 ] -1 - ( S ) - ( ethoxy car bony 1 ) pr opy 1 ] amino ] - 1-oxopropy 1]- [2S-(2α, 3aα, 7aα) ]-octahydro-lH---indole-2- carboxylic acid, ^5_,j3--- dioxide N- [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pheny lethy 1 ) - 2II_-1 , 2 , 4-benzothiadia z in-7- yl] sulfony lamino] ethyl] pheny 1]-1-(S)- ( e thoxy car bony 1 ) propy 1 ] - ( S ) -alany 1- ( S ) -pr ol ine , .§_,___" dioxide N-[3-[4-[[[6-chloro-3,4-dihydro-3-(2-phenylethyl)- 2H_-l,2,4-benzothiadiazin-7- yl] sulf ony lamino] methyl] phenyl] -1-(S)- [(2- phe noxy ) e thoxy carbony 1] propy 1 ] - ( S ) -alany 1- ( S ) -pr ol ine , .S_,^- dioxide. N- [3- [4- [ [ [6-chloro-3 , 4-dihy dr o-3- ( 2-pheny lethy 1 )- 21^-1 , 2 , 4-benzothiadia z in-7- yl] sulfony lamino] methyl] phenyl] -1-(S )- [ (2, 3- dihydroxy )propoxy carbony 1] propyl] - (S )-alanyl-(S )-proline, .S ϋ dioxide. N- [3- [4- [ [ [6-chloro-3-( cyclopenty lmethyl)-3 , 4- dihydro-2H_-l, 2,4-benzothiadiazin-7-y 1] sulfony 1- amino] ethyl] phenyl] -1-(S)- (ethoxy carbonyl) propyl] - (S )- alanyl-(S)-proline, jS^S- dioxide N-[3-£4-[[[6-chloro-3,4-dihydro-3-(2-phenylethyl)- 2jϊ_-l,2,4-benzothiadiazin-7- yl] sulf ony lamino] methyl] pheny l]-l-(S)-[ (2 ,2-dimethy 1-1, 3- dioxolan-4-yl)me thoxy carbonyl] propyl] -(S)-alanyl-(S) - proline, _S_,j5- dioxide N- [3- [4- [ [ [6-chloro-3-( cyclopenty lmethy l)-3 ,4- dihy dr b-2H_-l , 2 , 4-benzothiadia zin-7-y 1] sulf ony lamino] methyl] phenyl] -1-(S)- [(2,2-dimethyl-l,3-dioxolan-4- yDmethoxy carbonyl] propy l]-(S)-alanyl-(S)-proline, j3.,.S_- dioxide N-[3-[4-[ [ [6-chloro-3-(cyclopentylmethyl)-3,4- dihy dro-2l^l,2,4-benzothiadiazin-7-yl] sulfony lamino]- me thy 1 ] phenyl] -1-(S)- [ (2-phenoxy) ethoxy carbonyl] propy 1] - (S)-alanyl-(S)-proline, 5_,S_- dio ide N- [3- [4- [ [ [6-chloro-3- (cyclopenty lmethy l)-3 , 4- dihydro-2Ii_-l,2,4-benzothiadiazin-7-yl] sulfonylamino]- methyl] henyl] -1-(S)- [ ( 2, 3-dihydroxy )propoxy carbonyl ]- propy l]-(S)-alanyl-(S) -proline, _S_, _-dioxide l-[2-[[2-[[4-[[[4-chloro-3-[[ (pheny lmethy 1) amino] sulfonyl] phenyl] sulfony lamino] methyl] phenyl] me thoxy ] -1- (S )- (ethoxy carbony 1) ethyl] amino] -1-oxopropy 1] - [2S- ( 2α,3aα,7aα) ] -octahydro-lJH^indole-2-carboxylic acid l-[2-[[2-[[4-[[[4-chloro-3-[[(phenylmethyl)amino]- sulfonyl] phenyl] sulfony lamino] methyl] pheny 1] me thoxy ] -1- ( S ) - ( car boxy ) ethy 1 ] amino ] - 1 -oxopr opy l]-[2S-(2o,3ao,7aα)] octahydro-lH---indole-2-carboxylic acid N-[2-[ [4-[ [ [4-chloro-3-[ [( pheny lmethy 1) amino] - sulfonyl] phenyl] sulfony lamino] methyl] phenyl] me thoxy ] -1- (S)-( ethoxy carbonyl) ethyl]- (S)-alanyl-(S)-proline N-[2-[[4-[[ [4-chloro-3-[ [ (pheny lmethy 1) amino] - sulfon l] -phenyl] sul f ony lamino] me thy 1] phenyl] me thoxy ]-l - (S)-(carboxy ) ethyl] -(S)-alanyl- (S)-proline l-[2-[[2-[[4-[[[3-(amino)sulfonyl-4- chloropheny 1] sulfony lamino] me thy 1] heny 1] me thoxy ] -1- ( S ) - (ethox carbonyl) ethyl] amino] - 1-oxopr opy 1]- [2S- (2α,3aα,7aα)]-octahydro-lH*--indole-2-carboxγlic acid 1- [2- [ [2- [ [4- [ [ [3- (amino ) sulf ony 1-4- chlorophenyl] sulfony lamino] methyl] pheny 1] me thoxy ]-l-(S )- (car boxy ) ethyl ] amino] -1-oxopropyl]- [2S-(2α,3aα,7ao)]~ octahydro-liϊ -indole-2-carboxylic acid N- [2- [ [4-[ [ [3- (amino) sulfony 1-4-chloropheny 1] - sulfony lamino] methyl] phenyl] me thoxy] -1-(S)- ( ethoxy carbonyl) ethyl] -(S)-alanyl-(S)-proline N- [2- [ [4- [ [ [3-(amino)sulfonyl-4-chlorophenyl]- sulf ony lamino] me thy 1] phenyl] me thoxy 3-1- (S )- (ethoxy carbonyl) ethy l]-(S)-lysyl-(S ) -proline N- [2- [ [4- [ [ [3-(amino) sulfony 1-4-chlorophenyl]- sul f ony lamino] me thy 1] heny 1] me thoxy ] -1- ( S ) - ( car boxy ) ethyl] - (S )-alany 1-(S ) -proline N- [2- [ [4- [ [ [3-(amino)sulfony 1-4-chlorophenyl]- sulfony lamino] methyl] phenyl] me thoxy ]-l-(S)- (car boxy )- ethyl]- (S)-lysyl-(S)-proline N- [2- [ [4- [ [ [3-(amino) sulfony 1-4 -chlorophenyl] - sulf ony lamino] methyl] phenyl] me thoxy ]-l-(S )-[ (2,2- dimethyl-l-oxopropoxy )methoxycarbonyl] ethyl] -(S )-alanyl- (S) -proline N- [3- [4- [ [ [6-chloro-3 , 4-dihy dro-2H_-l ,2,4- benzothiadiazin-7- 1] sulfony lamino] methyl] heny 1] -1- (S )- (ethoxy carbonyl) propyl]- (S)-alanyl-(S)-proline, _S_, S^- dioxide N- [3- [4- [ [ [6-chloro-3 , 4-dihy dr o-2H_-l ,2,4- benzo thiadiazin-7-yl] sulf ony lamino] me thy 1] pheny 1]-1-(S) - [2 , 2-dimethy 1-1 -oxopr opoxy )methoxy carbony 1] propyl] - (S )- alanyl-(S) -proline, S j ^-dioxide N- [3- [4- [ [ [6-chloro-3 , 4-dihy dr 0-2^-1 ,2,4- benzothiadiazin-7-yl] sulfony lamino] meth l] pheny 1]-1- (S )- (ethoxycarbonyl)propyl]-(S)-lysyl-(S)-proline , ^, S-- dioxide N-[l-(S)-carboxy-3-[4-[ [ [6-chloro-3, 4-dihy dro-2H_- 1, 2,4-benzothiadiazin-7- l] sulf ony lamino] methyl] - phenyl] propyl]-(S)-alanyl-(S)-proline, S>_, J3_-dioxide N-[l-(S)-carboxy-3-[4-[[[6-chloro-3,4-dihydro-2H_- l,2,4-benzothiadiazin-7-yl] sulf ony lamino] methyl] phenyl]- propyl]-(S)-lysyl-(S)-proline, _S, ^-dioxide N- [l-(S)-carboxy-3-[4-[ [ [6-chloro-3-chloromethyl- 3,4-dihydro-2K -l,2,4-benzothiadiazin-7-yl] - sulfony lamino] methyl] phenyl] propyl]- (S )-alanyl-(S)- proline, j5_, _S^dioxide N-[l-(S)-carboxy-3-[4-[ [ [6-chloro-3-chloromethyl- 3 , 4-dihy dro-2ji_-l , 2 , 4-benzothiadia zin-7-y 1] - sulfony lamino] methyl] henyl] propy l]-(S)-lysyl-(S )- proline, £>_, ^-dioxide N- [3- [4- [ [ [6-chloro-3-chloromethy 1-3 , 4-dihy dro-2*H_- l,2,4-benzothiadiazin-7-yl] sulfony lamino] methyl] phenyl] - 1-(S )- [2 , 2-dimeth 1-1 -oxopropoxy )methoxy carbonyl] ropy 1] - (S)-alanyl-(S)-proline, S_, jv-dioxide N- [3- [4- [ [ [6-chloro-3-chloromethyl-3 , 4-dihy dro- 2 - 1, 2, 4-benzothiadiazin-7-yl] sulf ony lamino] methyl] pheny 1] - l-(S)-( ethoxy carbonyl) propyl] -(S)-alanyl-(S)-proline , _S_, ^-dioxide 1- [2-(S )- [ [2- [4- [ [ [6-chloro-3-chloromethy 1-3 , 4- dihydro-2H_-l,2,4-benzothiadiazin-7- l] sulfony lamino] - methyl] pheny lme thoxy ] -1-(S )- (ethoxy carbony 1 ) ethyl] amino] - l-oxopropyl]-[2S-(2o,3aα,7aα) ]-octahydro-lH_-indole-2- carboxylic acid, ^5_, ^-dioxide 1- [2- (S )- [ [1-(S )-carboxy-2- [4- [ [ [6-chloro-3- chlor omethy 1-3 , 4-dihy dro-2^-1 , 2 , 4-benzothiadia zin-7-y 1] - sulfony lamino] methyl] phenyl] ethyl] amino] -1-oxopropyl] - [2S-(2α,3aα,7ao) ]-octahγdro-lH---indole-2-carboxy lie acid, jS_, j^-dioxide l-[2-(S)-[[l-(S)-carboxy-2-[4-[[[6-chloro-3- chloromethyl-3,4-dihydro-2lϊ_-l,2,4-benzothiadiazin-7-yl]- sulf on lamino] methyl] henylmethoxy] ethyl] amino] -1- oxopropyl]- [2S-(2α,3aα,7aα) ]-octahγdro-lH---indole-2- carboxylic acid, _S_, ^-dioxide • l-[2-(S)-[[l-(S)-carboxy-2-[4-[[[6-chloro-3,4- dihydr 0-2^1 ,2,4-benzothiadiazin-7-yl] sulfony lamino] - methyl] phenylmethoxy] ethyl] amino] -1 -oxopr opy 1]- [2S- (2α,3ao,7ao)]-octahydro-l^-indole-2-carboxylic acid, _S_, _-dioxide N- [l-(S)-carboxy -5- [6-chloro-3, 4-dihy dro-2H_-l, 2,4- benzothiadiazin-7-y 1] sulf ony lamino] entyn-3-y 1] - (S ) - alanyl-(S)-proline, _S_, _S-dioxide N- [5-[6-chloro-3,4-dihydro-2H_-l,2,4-benzothiadiazin- 7-y 1] -sulfony lamino] -l-(S)-( ethoxy carbony l)pentyn-3-yl] - (S ) -a lanyl-(S) -proline, S j ^-dioxide l-[4-carboxy-5-[4-[ [ [6-chlor o-3-( cyclopenty lmethy 1)- 3, 4-dihy dro-2H_-l, 2,4-benzothiadiazin-7-yl] s ulf ony lamino ]- methyl] phenylmethoxy] -1-oxopentyl] -octa hydro- lH-indole-2= carboxylic acid, j3_, ^-dioxide N- [2-(S )- [1-(S )-carboxy-3- [4- [ [ [6-chloro-3 , 4- dihydro-3-(2-phenylethyl)-2H_-l,2,4-benzothiadiazin-7- yl] sulfony 1-amino] methyl] phenyl] propoxy]-l-oxopropyl] - (S)-proline, j^, ^-dioxide N-[N-[3-[5-[[[[6-chloro-3,4-dihydro-3-(2- phenylethyl)-2ji l, 2, 4-benzothiadiazin-7-yl] sulfonyl] - amino]methy 1] -lH_-imidazol-2-y 1] -l-( ethoxy carbony 1)- propyl]-(S)-alanyl-(S )-proline, _S_,j3--- dioxide N-[N-[3-[5-[[[[6-chloro-3,4-dihydro-3-(2- pheny lethy D-2JJ---1, 2,4-benzothiadiazin-7-yl] sulfony 1]- amino] me thy 1 ] -2- thia zoly 1 ] -1- ( e thoxy car bony 1 ) propy 1 ] - ( S ) - alanyl-(S)-proline, _S_,j3--- dioxide 1- [N- [2- [4- [ [ [3-buty l-6-chloro-3 , 4-dihy ro-2jJ_-l ,2,4- benzothiadiazin-7-y 1] sulfonyl] aminomethy 1] thiazol-2- y lmethylthio] -JL (S )- (me thoxy carbony 1 ) ethy 1] - (S )-alanyl- (S)-proline, J3_,S-dioxide N-[l-(S)-carboxy-4-[4-[ [ [ [6-chloro-3 , 4-dihy dro-3-( 2- pheny lethy l)-2J3--l,2, ' 4-benzothiadiazin-7-yl] sulfonyl] - amino] methyl] phenyl] butyl] -(S)lysyl-(S)-proline, .§.,.§ 7 dioxide 7- [2-(S_)- [ [1-(S )-carboxy-4- [4- [ [ [3-buty 1-6-chloro- 3, 4-dihy dro-2jϊ_-l,2,4-benzothiadiazin-7- l] sulfonylamino]- methyl] phenyl] utyl] amino] -l-oxopropyl]-l, 4-dithia-7- azaspiro[4.4]-nonane-8-(S)-carboxylic acid, ^,S-dioxide N- [1-(S )-ethoxy carbony 1-4- [4- [ [ [ [6-chloro-3 , 4- dihy dro-3- ( 2-pheny lethy 1 ) -2H_-1 , 2 , 4-benzothiadiazin-7- yl] sulfonyl] -amino] methyl] phenyl] butyl]-(S)-lysyl-(S)- proline, S_,j3^dioxide 1- [2-(S )- [ [1-(S )-carboxy-4- [4- [ [ [6-chloro-3 , 4- dihydro-3-(2-phenylethyl)-2H_-l,2,4-benzothiadiazin-7-yl]- sulfony lamino] methyl] phenyl] butyl] amino] -1-oxoproply] - (S)-proline, ^,^_-dioxide l-2-(S)-[[3-[4-[[[6-chloro-3,4-dihydro-3-(2- pyridinyl)-ethyl-2H_-l,2,4-benzothiadiazin-7- y 1] s ulf ony lamino] e thy 1 ] -pheny 1 ] -1- ( S ) - ( e thoxy carbony 1 ) - propyl] amino] -l-oxopropyl-[2S-(2o,3ao,7aα) ] -octa hydro- 1H-- indole-2-carboxylic acid, j3_,£^-dioxide 1- [2-(S )- [ [1-(S )-carboxy-4- [ [ [3-buty l-6-chloro-3 , 4- dihydro-2JJ_-l, 2,4-benzothiadiazin-7-yl] sulfony lamino]- methyl] phenyl] butyl] amino] -1-oxopropyl] - [2S- ( 2α,3aα,7aα) ]-octahydro-lji--indole-2-carboxylic acid, S J S - dioxide N- [3- [4- [ [ [3-buty l-6-chloro-3 , 4-dihy dro-2H.-l ,2,4- benzo-thiadiazin-7-yl] sulfonyl] aminomethy 1] phenyl] -1-(S )- ( ethoxycarbon l ) propyl] - (S )-alany 1- (S ) -proline , j3 / .S- dioxide N- [2- (S )- [ [4- [4- [ [ [3-buty l-6-chloro-3 , 4-dihy dro-2H_- 1, 2,4-benzothiadiazin-7-yl] sulfony lamino] methyl] phenyl]- 1- (S )- ( ethoxy carbony 1 ) butyl] - (S )-ala y 1- (S )-prol ine , S j §^- dioxide 1- [2- (S )- [ [4- [4- [ [ [6-chloro-3 , 4-dihy dro-3-buty 1-2H_- l,2,4-benzothiadiazin-7-yl] sulfony lamino] methyl] phenyl]- 1-(S)- (ethoxy carbonyl) butyl] am ino]-l -oxopr opy 1]- [2S- (2o,3aα,7aα)]-octahydro-lH^indole-2-carboxylic acid, S,S- dioxide N- [2- [4- [ [ [3-buty 1-6 -chloro-3 , 4-dihy dr 0-21^-1 ,2,4- benzothiadiazin-7-yl] sulfonyl] aminomethy 1] pheny I e thoxy ]- 1-(S )- (ethoxycarbonyl) ethyl- (S )-alany 1- (S )-prol ine , j3,i - dioxide - [2- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pheny lethy 1 ) - 2j_-l, 2,4-benzothiadiazin-7-y 1] sulfonyl] aminomethy 1]- phenylmethylthio]-l-(S)-(ethoxy carbonyl) ethyl] - (S )- alanyl-(S)-proline, S,S-dioxide N- [2- [4- [ [ [6-chloro-3 , 4-dihy dro-3-buty 1-2^-1 ,2,4- benzothiadiazin-7-yl] sulfony 1] aminomethy 1] pheny 1- me thy lthio] -1- (S )- (me thoxy carbony 1 ) ethy 1] - (S )-alany 1- (S ) ■ proline, j3,S- dioxide N-[2-[4-[[[6-chloro-3,4-dihydro-3-chloromethyl-2H_- 1, 2, 4-benzothiadiazin-7-yl] sulfonyl] am inome thy 1] heny 1- me thy lthio] -l-(S)-( e thoxy carboxyl) e"thyl-(S)-alanγ 1-(S )- proline, 5_,j3---dioxide N- [2- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( cyclopenty 1) - methy 1-2IT-1 , 2 , 4-benzothiadiazin-7-y 1] sulf ony 1] amino¬ methy 1] pheny lmethy lthio ]-l-(S)-( ethoxycarbonyl) ethyl— (S) • alanyl-(S)-proline, j3,S- dioxide 1- [2- [ [2- [ [4- [ [ [ [3-buty l-6-chloro-3 , 4-dihy dro-2H_- 1, 2,4-benzothiadiazin-7-yl] sulfonyl] amino] methyl] phenyl]- methy lthio] -l-( ethoxy carbonyl) eth l] amino-1-oxopropyl- [2S-(2α,3aα,7aα)]-octahydro-lH---indole-2-carboxylic acid, .S_,S- dioxide N- [N- [3- [5- [ [ [ [6-chloro-3 , 4-dihy dro-3- (2-pheny 1- e thy 1 ) -2jϊ^l , 2 , 4-benzothiadia z in-7-y 1] sulf ony 1] amino] - methy l]-2-pyridiny l]-l-( ethoxy carbonyl) propy 1]-(S)- alanyl]-(S)-proline, J5_,S-di oxide N-[N-[N-[3-[2-[[[[6-chloro-3,4-dihydro-3-(2-phenyl- ethyl)-2]_-l,2,4-benzothiadiazin-7-y 1] sulfonyl] amino] - methy l]-5-pyridinyl]-l-(ethoxy carbonyl) propy 1]-(S )- alanyl]-(S) -proline, £5_,S^dioxide N- [N- [3- [4-[[[[6-chlor o-3, 4-dihy dro-3-(2-pheny 1- ethyl)-2jϊ^l,2,4-benzothiadiazin-7-yl] sulfonyl] amino] - methyl] -2-thia zoly l]-l-( ethoxy carbony l)propyl]-(S )- alanyl]-(S)-proline, _S_,^-dioxide N- [N- [3- [4- [ [ [ [6-chloro-3,4-dihydro-3- (2-phenyl- ethyl)-2jH-l,2,4-benzothiadiazin-7-yl] sulfonyl] amino] - me thy l]-2-oxa zoly l]-l-e thoxy carbonyl) propy l]-(S)-alany 1] - (S)-proline, _S,jS--- dioxide N-[N-[4-[4-[[[[6-chloro-3,4-dihydro-3-[2-(2- pyridinyl)ethyl]-2E_-l,2,4-benzothiadiazin-7- γl] sulfonyl] amino] methyl] phenyl] -l-(S)-( ethoxy car bonyl)- butyl]-(S)-alanyl]-(S) -proline, js_,S_--di oxide N- [N- [3- [5- [ [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pheny 1- ethy 1)-2H_-1, 2, 4-benzothiadiazin-7-yl] sulfonyl] amino] - methy 1] -ljJ-imidazol-2-y 1] -1- ( ethoxycarbonyl ) propy 1] - (S ) - alanyl-(S)-proline, j3_,£v--di oxide N- [N- [3- [5- [ [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pheny 1- ethy 1 ) -2JH_-1 , 2 , 4-benzothiadia z in-7-y 1] sulfony 1] amino] - methy l]-2-thiazolyl]-l-( ethoxy carbonyl) propy 1]-(S )- alanyl-(S) -proline, _S_,£5^dioxide N_- [2-(^)- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( 2- phenylethyl)-2j_-l,2,4-benzothiadiazin-7-yl] sulfony 1- amino] methyl] phenyl] -1-(J5_)- (ethoxycarbonyl) buty 1] amino] - l-oxopropyl]-(S) -proline S,S-dioxide 1- [2- (S_)- [ [1- (j3_)-carboxγ-3- [4- [ [ [6-chloro-3 , 4- dihy dro-3- ( 2-pheny lethy l-2Iϊ_-l , 2 , 4-benzothiadia zin-7- yl] sulfony lamino] methyl] phenyl] butyl] amino] -1-oxopropyl]- [ 2- (S) - ( 2o , 3aα , 7ao ) ] -oc tahy dr o-lH--- indole-2-carboxy lie acid, S,S-dioxide l-[2-(SJ-[[3-[4-[[[6-chloro-3,4-dihydro-3-(2-phenγl- ethyl)-2jϊ > -l,2,4-benzothiadiazin-7-yl] sulfonyla-nino]- methyl] phenyl] -1-(S_)- ( ethoxycarbonyl) butyl] amino] -1- oxopropy 1] - [2S- ( 2α , 3aα , 7aα ) ] -octahy dro-lH^ indole-2- carboxylic acid, S,S-dioxide l-[2-(_S_)-[[l-(_S_)-carboxy-3-[4-[[[6-chloro-3,4- dihy ro-3- ( 2-pheny lethy 1 ) -2H 1 , 2 , 4-benzothiadia zin-7- yl] sulfony lamino] methyl] phenyl] propyl] amino] -1- oxopropyl]-(S_) -proline, S,S-dioxide l-[2-(S_)-[[3-[4-[[[-6-chloro-3,4-dihydro-3-(2- phenylethyl)-2H_-l,2,4-benzothiazin-7-yl] sulfonylamino]- methyl] phe nyl]-l-(jj>_) -(ethoxy car bony 1) propy 1] amino ]-l - oxopropyl ] - ( S_) -pr ol ine , S , S , -dioxide l-[2-(j>J-[[l-(S_)-carboxy-3-[4-[[[6-chloro-3,4- dihy dro-3- ( chloromethy 1 ) -2H j -l , 2 , 4-benzothiadia zin-7- yl] sulfony lamino] methyl] phenyl] propyl] amino] -1- oxopropy 1 ] - [2- (S)-( 2α , 3aα , 7aα ) ] -octahy dro-l-H^ indole-2- carboxylic acid, S,S-dioxide 1- [2- (S )- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3-( chloro¬ methy l)-2jϊ_-l, 2, 4-benzothiadiazin-7-yl] sulfony lamino] - methyl] phe nyl]-l-(S)- (ethoxy car bonyDpropy 1] amino] -1- oxopropy 1] - ( 2S--- ( 2o , 3aα , 7ao ) ] -oc tahy dr o-l-jjj- indole-2- carboxylic acid, S,S-dioxide 1- [ , - [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pyr idy 1- ethy 1 ) -2ϊl_-l , 2 , 4-benzothiadia zin-7-y 1] -sulf ony 1] amino- methyl] phenyl]-l (^_)-(ethoxycarbonyl)-propyl]-(^_)-alanyl]- cis ,synoctahydroindole-2 (S)-carboxylic acid, S,S-dioxide l-[N-[2-[4-[[[6-chloro-3,4-dihydro-3-(2-phenyl- ethyl)-2jϊ_-l, 2,4-benzothiadiazin-7-y l]-sulfony 1] amino- methyl] thiazol-2-ymethylthio] -l(j3_)- (me thoxy carbony 1)- ethyl]-(j3_)-analyl] cis ,syn-octahydroindole-2(S_)-tert. butoxy carbonyl, S,S-dioxide 1- [N- [2- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2-pheny 1- ethyl)-2EI_-l,2,4-benzothiadiazin-7-yl]-sulfonyl] amino- methyl] thiazol-2-ymethylthio]-l (JS_) -(me thoxy car bony 1 )- ethy l]-^S_)-alanyl] -cis ,syn-octahy droindole-2(S_)- carboxylic acid, S,S-dioxide 1- [N- [2- [4- [ [ [6-chloro-3,3-dihydro-3- ( 2- pheny lethy 1 ) -2JH-1 , 2 , 4-benzothiadia zin-7-y 1] - sulfonyl] aminomethy 1] thiazol-2-ymethy lthio] -1 (S )- carboxyethy 1] - (j3_)-alany 1-cis ,syn-octahydroindole-2 (S - carboxyl acid S,S-dioxide 1- [N- [2- [4- [ [ [6-chloro-3 , 3-dihydro-3- ( 2- phenylethyl)-2jJ_-l,2,4-benzothiadiazin-7-yl]- sulfonyl] aminomethyl] thia zol-l-y lmethy lthio] -1 (S)- carboxyethyl]-(^_)-alanyl]-cis ,syn-octahydroindole-2(^_)- carboxylic acid, S,S-dioxide The compounds of this invention are useful in view of their pharmacological properties. In particular, representative compounds of the invention possess activity as ant ihy per tensive 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. The hypertensive activity of the compounds of the invention is illustrated by reference to the following compounds for which the activity of the compounds in the spontaneously hypertensive rat was measured using the methodology of D.J.S. Chiv, S. Vemulapalli and A. Barnett J. Pharm. Pharmacol., 37, 105- 109 (1985). Compound A: N- [2- (S_)- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3- ( 2- phenylethyl)-2KI_-l,2,4,-benzothiadiazin-7-yl] sulfonyl- am ino ] me thy 1 ] phe ny 1 ] - 1 - ( S_) - ( ethoxy carbony 1 ) buty 1 ] am ino ] - l-oxopropyl]-(S)-proline-S,S-dioxide Compound B: 1- [N- [2- [4- [ [ [6-chloro-3 , 4- di hydro- 3 -buty 1-2H_-1 ,2,4- benzothiadiazin-7-yl] sulfonyl] aminoethyl] heny lmethy 1- thio]-l (S )- (me thoxy carbonyl) -ethy l]-(S)-alanyl] -cis, syn- octahydroindole-2(j3_)-carboxylic acid S,S-dioxide For compound A at a dose of 30 mpk a reduction in mean blood pressure measured over a period of 5 hours, of 27 mm Hg was obtained and for Compound B, at a dose of 10 mpk, a reduction of 22 mm Hg was obtained. Representative compounds of this invention also exhibit activity as diuretic agents. Further, they exhibit angiotensin converting enzyme inhibitory activity and are thus contemplated for use in treating 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 or parenteral 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 range 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 individual. "" "" 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 range of about 5 to about 500 mg per patient generally given several times a day, thus giving 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 herein are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch tapioca starch and potato starch; cellulose and der ivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvmylpyrrolidone, polyvinyl alcohol; stearic acid; 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 anionic surfactants; eth lene gylcol polymers; beta- cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other non-toxic compatible fillers, binders, dis integrants, buffers, preservatives, anti- oxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations. In their opthalmological use, the compounds of this invention are typically administered as topical preparations such as solutions, suspensions, ointments and solid inserts. Formulations of these compounds may contain from 0.00001 to 1.0%, preferably 0.00001 to 0.1%, and especially 0.00001 to 0.001% of medicament. Other concentrations may be employed provided the dose is effective in lowering intraocular pressure. As a unit dosage form, between 0.005 meg to 0.5 mg, preferably 0.005 meg to 50 meg, and especially 0.005 meg to 0.5 meg of the active compound is applied to the human eye, generally on a daily basis. Individual dosage requirements are variable; however, and must be administered by the attending clinician on the basis of the severity of the disease and the condition and response of the patient. To prepare suitable dosage forms, the active compounds may be conveniently admixed with a non-toxic pharmaceutically acceptable carrier suitable for topical ophthalmolgic administration. When topically administered to the eye, the compounds of the invention reduce intraocular pressure (IOP). For example, 1- [2-(S)-carboxy-5- [ [6-chloro-3- chloromethyl-3,4-dihydro-2lϊ_-l,2,4-benzothiadiazinyl-7- yl] sulf ony lamino] -pentyl] amino] -l-oxopropyl]-2S-[2α, 3a α, 7aα) ] -octahy dro-lj indole-2-carboxy lie acid, j3_,j3^dioxide caused falls in IOP of a magnitude similar to those produced by the anti-glaucoma agent timolol when each were administered at concentrations of 0.001 and 0.5 (w/v%), respectively, and tested by the following procedure: Male New Zealand white rabbits having a normal IOP are conditioned to the laboratory setting for at least one 4 hour period before being used to study drug effects. A Makay-Marq applanation tonometer is used to measure IOP. Readings, in mm Hg, are taken in triplicate and the average is recorded. Rabbits are restrained in a cloth sack 2 minutes prior to IOP determination. The left lower eyelid is retracted to form a pouch and 1 drop of a local anesthetic is irrigated over the cornea. The lower eyelid is then held closed over the eye for about 1 minute. Corneal anesthesia is repeated before each set of IOP determinations. Readings are taken just before dosing with drug (0 time) and at hourly intervals thereafter. Drugs are administered in 50 ul volume in the same manner as the anesthetic. As to the toxic ity of the compounds of the invention, they are non-toxic at the therapeutic dose. In the following examples the "active ingredient" is 1- [2(S )- [ [1 (S)-carboxy-2- [4- [ [ [6-chloro- 3,4-dihydro-3-(2-phenylethyl)-2jlτ'l,2,4-benzothiadiazin-7- yl) sulf ony lamino] methyl] phenylmethoxy] e thy 1] amino] -1- oxopropyl]- [2(S)-(2α, 3a , 7aα) ]-octahydro-lH---indole-2- carboxylic acid, ^_,j>--- dio ide. It is contemplated. however, that this compound may be replaced by equally effective quantities of other compounds within the scope of formula I. EXAMPLE 13 Capsule Amoun t (mq) Active ingredient 250. .0 125. ,0 Lactose 173. 0 86. ,5 Corn Starch 75. .0 37. ,5 Magnesium Stearate 2. .0 1. ,0 500.00 500.00 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 14 Tablet Amount (mg) Active Ingredient 250.0 125.0 Lactose 161.0 80.5 Corn Starch 12.0 6.0 Water (per thousand tablets) 120. ml 60. ml (evaporates) (evaporates) Corn Starch 75.0 37.5 Magnesium Stearate 2.0 1.0 500.00 250.0 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 through a suitable milling machine, using a 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 disintergration. EXAMPLE 15 Inj ectable Solution mg/ml Act ive ingredient 5. , 00 Methyl jDrhydroxybenzoate 0. 80 Propyl _ - hydroxy be nzoa te 0. , 10 Disodium Edeta te 0. , 10 C i tric Acid Monohydra te 0. , 08 Dextrose 40.0 Wa ter for inj ection qs . ad, 1. , 0 ml Dissolve the _p_-hydroxybenzoates in a portion of water for inj ection 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 , f ilter it through a sterilizing membrane and f ill into ster ile conta iners . Similarly, substitute other compounds of the present invention to prepare other compositions of the present invention. EXAMPLE 16 Topical Ophthamological Solution mg/ml Active Ingredient 10. 0 Dibasic Sodium Phosphate 10. 4 Monobasic Sodium Phosphate 2. 4 Chlorobutanol 5. 0 Hydroxypropyl methylcelluose 5. 0 Sterile Water q. s . ad 1. 0 ml l.OH NaOH q.s . ad pH 7.4 Mix the ingredients under sterile conditions and using standard techniques to obtain the ophthamological solution.

Claims: CLAIMS: 1. A compound of the general formula I R and the pharmaceutically acceptable salts thereof, wherein: 1 is 1 or 2; n is 0 or 1; p and q are 0, 1 or 2, provided that in structures lib and He the sum of p and q is 1 or 2, and that in formula Hd, p is not 0; Ilia IHb E is -NH-,-0-, -S-, or -CH 2 -; 0 II G is -C-; or -S0 2 ~; J is -(CH 2 ) S - or -((CH 2 ) t -W)-; L is a chemical bond, cis- or trans-lower alkene, lower alkyne, -Z-aryl-, -aryl-Z-, -Z-cycloalkyl-, -cycloalkyl-Z-, a 5- or 6-membered heterocyclic radical comprising 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from N, O and S, or a R^-substituted heterocyclic radical, wherein aryl is wherein w is 1, 2 or 3; M is -(CH 2 ) U - or -((CH 2 ) t -X-(CH 2 ) v )-; O 0 II ll W is -CNH- or -NHC-; X and Z are independently a chemical bond, Q H 0 H -NR 9 -, -0-, -S-, -CNH- or ' -NHC-; s, u and v are independently 0-5; t is 1-5; It 1 . R 2 and R 9 are independently hydrogen, lower alkyl or lower acyl; * 3 R is hydrogen, lower alkyl, haloloweralkyl, phenylloweralkyl, ( cycloalkyl) loweralkyl, aminomethy 1, loweralky laminomethyl , phenyl lower a Ik laminomethyl, (cycloalkyl) lower alky laminome thy 1, loweralkylthiomethyl, haloloweralkylthiomethyl, 2-, 3- or 4-pyridylloweralkyl , 2-, 4- or 5-thiazolylloweralkyl, 2-, 4- or 5-lH_- imidazolylloweralkyl, 1-imidazolylloweralkyl, 1- morpholinoloweralkyl or hydroxyphenylloweralkyl; R 4 is chlorine or CF 3 ; R is hydrogen, halogen, lower alkyl, lower acyl, lower alkoxy, haloloweralkyl or phenylloweralkyl; R 7 is hydrogen, lower alkyl or aminoloweralkyl; and R° are independently hydroxy, alkoxy having from 1 to 8 carbon atoms, benzyl, allyl, R -Q r - (CH 2 ) m -0-, wherein Q is oxygen or sulfur, r is O or 1 and R 11 I m is 2 to 4, -OCH-OCO-alky 1 wherein the alkyl has from R 11 I 3 to 8 carbon atoms, -OCHCO-phenyl wherein the phenyl may be substituted with group T defined below, 1-glyceryl, R 10 is phenyl, substituted phenyl wherein the substituents are chosen from group T, 1-naphthyl or 2- naphth l; T is halogen, hydroxy, trif luoromethyl, lower alkoxy, lower alkyl, 2-furanyl, 3-furanyl, 2-thienyl, 3- thienyl, phenyl and substituted phenyl wherein the substituents are chosen from halogen, hydroxy, trif luoromethyl, lower alkoxy or lower alkyl; RH is hydrogen or alkyl having from 1 to 8 carbon atoms; R is hydrogen, lower alkyl, unsubstituted or substituted phenyl and substituted or unsubstituted phenyl lower alkyl, wherein phenyl may be substituted by group T; R 13 is hydrogen or lower alkyl; provided that if L is alkene or alkyne, J is -(CH 2 ) g - wherein s is 1-5; provided that if L is -Z-aryl- or -Z-cycloalkyl-, J is -(CH 2 ) S - wherein s is 2-5; provided that if L is alkene, alkyne, -aryl-Z- or -cycloalkyl-Z-, M is -(CH 2 ) U - wherein u is 1-5; provided that if s and u are each zero, L is aryl or cycloalkyl (i.e. Z is a bond); and provided that if s and v are each zero, L is aryl or cycloalkyl (ie. Z is a bond); with the further provision that when D is of formula Hlb and R 1 is hydrogen, B is not -(CH 2 ) 4 ~; and that when D is of formula II lb and R is hydrogen or lower alkyl, B is not -(CH 2 ) s -aryl-(CH 2 ) t -X-(CH 2 ) v - wherein s is 0 or 1, t is 1, v is 0 to 2 and X is a bond, -0-, or -S-. 2. A compound as claimed in claim 1, wherein L is a chemical bond, cis- or trans-lower alkene, lower alkyne, -Z-aryl-, -aryl-Z-, -Z-cycloalky 1-, or -cycloalkyl-Z-, where aryl is and cycloal wherein w is 1, 2 or 3, and 3 R is hydrogen, lower alkyl, haloloweralkyl, phenylloweralkyl, (cycloalkyl)lower alkyl, aminomethyl, lower alkylaminomethyl, phenylloweralkylaminomethyl, or (cycloalkyl)loweralkylainomethyl, loweralkylthiomethyl haloloweralkylthiomethyl, the remaining substituents being as defined for formula I. 3. A compound as claimed in claim 1 or claim 2, wherein A is of the formula Ha, lib wherein p is zero and q is 1, or Hd wherein p and q are each 1 and n is zero. 4. A compound as claimed in any one of the preceding claims, wherein D is of the formula Ilia wherein G is -S0 2 - and R 4 is chlorine. 5. A compound as claimed in claim 4, wherein in 9 3 the moiety D, R Λ is hydrogen and R is phenylethyl (cyclopent Dmethyl, ehloromethyl, dichloromethyl, 2- pyr idin lethy 1, butyl, pentyl or trifluoroethylthiomethyl. 6. A compound as claimed in any one of the preceding claims, wherein E is -NH-. 7. A compound as claimed in any one of the preceding claims, wherein R is hydrogen, methyl < £ o aminobutyl and R° and R° are hydroxy. 8. A compound as claimed in any one of the preceding claims wherein B is of the formula: -C bondor -0-]-[CH 2 _ l-2 9. A compound as claimed in claim 1 selected from: 1- [ [2- (S )- [ [1 (S )-carboxy-5- [ [6-cloro-3-chloromethy 1-3 , 4- dihydro-2ϊ_-l,2,4-benzothiadiazin-7- yl] sulfony lamino] pentyl] amino] -1-oxopropyl]- [2S- (2o,3aα,7aα) ]-octahydro-lH-indole-2-carboxylic acid, S_,S_- dioxide, 1- [2-(S )- [ [1-(S )-carboethoxy-2- [4 [ [ [6-chloro-3 , 4-dihy dro- 3- ( 2-pheny lethy 1 ) -2H_-1 , 2 , 4-benzothiadia zin-7-y 1] sulf ony 1- a inojmeth l] hen lmethoxy] ethyl] amino] -1-oxopropyl]- [2S- [2α,3aα,7aα]-octahydro-lH^indole-2-carboxylic acid, .§_,.§_.- dioxide. l-[2-(S)-[ [1- (S)-carboxy-2- [4- [ [ [6-chloro-3, 4-dihy dro-3- ( 2-pheny lethy 1) -2^1,2, 4-benzothiadiazin-7-y 1] sulf ony 1- amino] meth l] phenylmethoxy] eth l] amino] -1 oxopropyl]- [2S- 2ct,3aα,7aα)] -octahydro-lH---indole-2-carboxylic acid, S_,S-- dioxide, N- [2-( _)- [ [3- [4- [ [ [6-chloro-3 , 4-dihy dro-3- (2-phenyl- ethy 1)-2H_-1, 2,4-benzothiadiazin-7-yl] sulfony lamino]- methyl] pheny 1] -1- (_§_)- (ethoxycarbonyl ) buty 1] amino] -1- oxopr opy l]-(J3_)-proline-S,S- dioxide, and l-[t3_-[3-[4-[ [ [ 6-chloro-3, 4-dihy dro-3-(2-pyr idy lethy 1)-2JH_- 1, 2,4-benzothiadiazin-7-yl]-sulfony l]aminoethy 1] phenyl]- 1 (S)- ( ethoxycarbonyl ) -propyl] - S_)-analy 1] -cis ,syn- octahydroindole-2(S_)-carboxylic acid S,S-dioxide. 10. A process for the preparation of a compound as claimed in claim 1, in which process the symbols A, B, D, E, J, L, R 1 , R 4 , R 6 , R 7 , R 8 , t and v, unless otherwise stated, are as defined in claim 1, which process comprises: A: condensing an acid of the general formula IV, or a reactive derivative thereof. with an amino acid of the general formula V, or a reactive derivative thereof. H[A]-COR 8 (V), or B: condensing an amine of the general formula X, with a sulfonic acid of the general formula Via , or a reactive der ivative thereof . [D] . S0 2 OH (Via), or C: condensing an aminosulfonamide of the general formula XIV, with an aldehyde of the general formula XIII: R 3 -CHO, or a reactive derivative thereof, or D: condensing a halide of the general formula XV [D]-S0 2 -N-J-L-(CH) t -Hal (XV), R 1 where Hal represents halogen , with a thiol of the general formula XVI H-S-CH 2 ) -C- [A ] -COR ft° XVI , said process being followed, if desired, by a step of esterification or de-esterification, the so-obtained compound of the general formula I being isolated in free form or in the form of a pharmaceutically acceptable salt. 11. A pharmaceutical composition which comprises a compound as claimed in claim 1 in association with a pharmaceutically acceptable carrier. 12. A pharmaceutical composition as claimed in claim 11 in the form of topical opthalmologically acceptable composition for reducing and controlling elevated intraocular pressure associated with glaucoma. 13. A pharmaceutical composition as claimed in claim 11 or 12 in the form of dosage units.

Inventors: ANDREWS DAVID ROY, GAETA FEDERICO CARLOS AREJOLA, ANDREWS, DAVID, ROY, GAETA, FEDERICO, CARLOS, AREJOLA
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1985
Main classification: C07K5
IPC codes: A61K31, A61K38, C07D207, C07D209, C07D215, C07D217, C07D417, C07D495, C07K1, C07K5, C07K14