CARBOXYALKYL DIPEPTIDES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The compounds of the present invention are com­ pounds of the formula and the pharmaceutically acceptable esters and salts there­ of wherein R¹ and R² independently are hydrogen or lower alkyl; the group is one of the structures II to VIII specified the description, one of R³, R⁴ and R⁵ is a group wherein Z is selected from Z¹ to Z¹⁰ being as in the description and the other of the groups R³, R⁴ and R⁵ are as also defined. The compounds are useful as hypertensive agents, in the treatment of congestive heart failure and glaucoma. Their preparation and phar­ maceutical compositions are disclosed.

Description: Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them. The present invention relates to carboxyalkyl dipeptides substituted with groups containing one sulfamoyl group. The compounds are useful as antihypertensive agents, in the treatment of congestive heart failure and glaucoma. Carboxyalkyl dipeptides which are useful as inhibitors of angotensinconverting enzyme and as antihypertensive acents are known from the published European patent applications Nos. 12401 and 50800. The compounds of the present invention are compounds of the formula EMI1.1 and the pharmaceutically acceptable esters thereof and the pharmaceutically acceptable salts of the free compounds and the esters, wherein R1 and R2 independently are hydrogen or lower alkyl; the group EMI2.1 one of the structures II to VIII EMI2.2 EMI3.1 (wherein B is a saturated or aromatic ring) or EMI3.2 one of R3, R4 and R5 is a group Z-(CH2)0-6-, wherein z has one of the following values Z1 to Z10 Z1: EMI4.1 Z2: EMI4.2 Z3: EMI4.3 Z4: EMI4.4 Z5: EMI4.5 Z6: EMI4.6 Z7: EMI5.1 Z8: EMI5.2 Z9: EMI5.3 Z10: : EMI5.4 wherein R8 is C1 or CF3; R6 is hydrogen or halogen; 7 is hydrogen, halogen, carboxy, hydroxy or amino; R9 and R10 are independently hydrogen, lower alkyl or halolower alkyl and R9 can also be phenyl or phenyl lower alkyl, R11 is hydrogen or lower alkyl; R12 is hydrogen, lower alkyl or phenyl lower alkyl; whereby when R3 is the group Z-(CH2)0-6-, then R3 is Z1-(CH2)1-6-, Z2-(CH2)1-6-, Z3-(CH2)1-6-, Z4-CH2-, Z5-(CH2)1-6-, Z6-(CH2)1-6-, Z7-(CH2)1-6-, Z8-(CH2)1-6-, Z9-(CH2)1-6-, or Z10-(CH2)1-6-, R4 is lower alkyl, benzyl, benzyloxy, benzylthio, phenoxy, or phenylthio, R5 is hydrogen; and the group EMI6.1 one of the structures 11 to VIII; and when R4 is the group Z-(CH2)0-6-, then R4 si Z1-(CH2)0-6-, Z2-(CH2)0-6-, Z3-(CH2)0-6-, Z4-(CH2)0-6-, Z5-(CH2)0-6-, Z6-(CH2)0-6-, Z7-(CH2)0-6, Z8-(CH2)0-6-, Z9-(CH2)0-6- or Z10-(CH2)0-6-and 7 is hydrogen, lower alkyl or amino lower alkyl and R5 is hydrogen; and the group EMI6.2 one of the structures II to VIII; and when R5 is the group Z-(CH2)0-6-, then R5 is Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, or Z10, R3 is hydrogen, lower alkyl or amino lower alkyl and R4 is lower alkyl, benzyl, benzyloxy, benzylthio, phenoxy or phenyl thio; and the group EMI8.1 one of the structures II to VII. One embodiment of the present invention comprises compounds of formula I, its esters and salts, wherein R4 is the group Z-(CH2)0-6-. Among these compounds certain groups of compounds are preferred: .) compounds, wherein the group EMI8.2 the group of formula II, IV (wherein B is a saturated ring) or VIII, preferably R being hydrogen; .) compouds, wherein R4 is Z-(CH2)0-6-, Z being Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, or Z10; .) compounds, wherein R4 is Z1-(Ch2)2 or 3-, Z2-(CH2)2 or 3-, Z3-(CH2)2 or 3-, Z5-(CH2)2 or 3-, Z7-(CH2)2 or 3-, Z8-(CH2)2 or 3-, Z9-(CH2)2 or 3- or Z10-(CH2)2 or 3-; .) compounds wherein R4 is Z4; .) compounds, wherein R1 and R2 are hydrogen; .) compounds, wherein R6 is hydrogen and R7 is hydrogen or hydroxy; .) compounds, wherein R9 and R10 are independently hydrogen or methyl; ; .) compounds, wherein R8 is chloro; .) compounds, wherein R3 is methyl; .) compounds, wherein R1 and R2 are independently hydrogen or lower alkyl (preferably hydrogen), the group EMI9.1 the group of formula II or IV, wherein B is a saturated ring and R is hydrogen, R4 -is Z -(CH2)3-, Z2-(CH2)3- or Z4, R6 and R7 are hydrogen and R8 is chloro; and R3 is hydrogen; lower alkyl or amino lower alkyl (preferably methyl); .) of particular interest are compounds, wherein R1 and 2 R are hydrogen, the group EMI9.2 the group of formula TV wherein B is a saturated ring, and R5 is hydrogen, R4 is Z -(CH2)3- or Z2-(CH2)3-, wherein R is hydrogen, R7 is hydrogen or hydroxy, and R8 is chloro, and R3 is methyl, preferably in the form of its mono-or-di-ethyl ester. Also the analogous compounds, wherein the group EMI9.3 are preferred. Another embodiment of the present invention comprises compounds of formula I, its esters and salts, wherein R3 is the group Z7-(CH2)0-6-. Among these compounds the following groups of compounds are preferred: .) compounds, wherein the group EMI9.4 the group of formula II, IV (wherein B is a saturated ring) or VIII; .) compounds, wherein R3 is Z1-(CH2)4-, Z2-(CH2)4-, Z3-(CH2)4-, Z4-CH2-, Z5-(CH2)4-, Z6-(CH2)4-, Z7-(CH2)4-, Z8-(CH2)4-, Z9-(CH2)4- or Z10-(CH2)4-; .) compounds, wherein R1 and R2 are hydrogen; .) compounds wherein R6 is hydrogen and R7 is hydrogen or hydroxy; .) compounds, wherein R9 and R10 are independently hydrogen or methyl; .) compounds, wherein R8 is chloro; ) compounds, wherein R4 is benzyl or ethyl; ; .) compounds, wherein R1 and R2 are independently hydrogen or lower alkyl (preferably hydrogen), the group EMI10.1 the group of formula II or IV, wherein B is a saturated ring, and R5 is hydrogen, R3 is Z -(CH2)4-, Z2-(CH2)4- or Z4-CH2-, R6 and R7 are hydrogen and R8 is chloro and R4 is EMI10.2 -CH2-(S)m- wherein m is zero or 1, .)of particular interest are compound, wherein R1 and R2 are hydrogen, the group EMI10.3 the group of formula IV, wherein B is a saturated ring and R5 is hydrogen, R3 is Z1-(CH2)4- or Z2-(CH2)4-, wherein R6 and R7 are hydrogen, R8 is chloro; and R4 is benzyl, preferably in the form of its mono-ordi-ethyl ester. Also the analogous compounds, wherein the group EMI11.1 are preferred. Another embodiment of the present invention comprises compounds of formula I, its esters and salts, wherein R5 is the group Z (CH2)0-6-. Among these compounds the following groups of compounds are preferred: .) compounds, wherein the group EMI11.2 the group of II, VI (wherein B is an aromatic ring), or TV (wherein B is a saturated ring); .) compounds, wherein the group EMI11.3 .) compounds, wherein R5 is Z1, Z2, Z3, Z5, Z7, Z8, Z9 or Z10; .) compounds wherein R1 and R2 are hydrogen; .) compounds, wherein R6 is hydrogen and R7 is hydrogen or hydroxy; .) compounds, wherein R9 and R10 are independently hydrogen or methyl; .) compounds, wherein This chloro; .) compounds, wherein R is methyl; .) compounds, wherein R4 is benzyl or ethyl; ; .) compounds, wherein R1 and R are independently hydrogen or lower alkyl, the group EMI12.1 formula III, IV, V, VI or VII, wherein m is zero or 1 and R5 and R7 are hydrogen and R8 is chlor, and R is hydrogen or lower alkyl (preferably methyl). The lower alkyl groups; except where noted otherwise, include straight and branched chain hydrocarbon radicals from one to six carbon atoms, or example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclohexyl and the like. The compounds of this invention form esters. In these esters the hydroxy group of the carboxy groups shown in formula I can be replaced by the same or by different groups which are selected from alkoxy having from 1 to 8 carbon atoms, phenoxy, phenylalkyloxy having from 7 to 10 carbon atoms, -OCR2OCO-alkyl having from 3 to 8 carbon atoms, -OCH2CO-phenyl, -O(CH2)k-O- phenyl wherein k is 1 or 2 and the phenyl ring may be substituted by halogen, hydroxy, trifluormethyl, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms (the phenyl group preferably containing one substituent) and -O(CH2)k-O-naphthyl wherein k is 1 or 2. Preferred are alkyl esters (the alkyl group being defined as above) and aryl esters, especially the ethyl and benzyl esters. Of particular interest are the monoesters wherein the carboxy group attached to the group EMI13.1 in the free form. The compounds of tis invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts (which are preferred) , alkaline earth metal salts like the calcium and magnesium salts, sa'ts with organic bases e.g., dicyclohexylamine salts, N-methyl-D- glucamine, salts with amino acids like arginine, lysine and the like. Also, salts with orGatlic and inorganic acids may be prepared, e.g., HCl, HBr, H2SO4, H3PO4, methanesulfonic acid, toluensulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating of purifying the product. This invention includes all possible stereoisomers of the compounds. Preferred stereoisomers are those in which the absolute configurations at each of the three carbon atoms bonded to both a nitrogen and a carbonyl group corresponds most closely to the absolute configuration of L-aminoacids. The preferred compounds contain a cis, syn-octahydro-lH-indole-2(S)-carboxylic acid moiety or a 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid moiety. Non limiting examples of preferred compounds of the present invention are: 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoyl)benzenesulfonaminopentyl)-(S)-alanyl}-cis, synoctahydro-1H-indole-2(S)-carboxylic acid, 1-{N-[1(S)-ethoxycarbonyl-5-(5-chloro-3-sulfamoyl)benzamidopentyl-(S)-alanyl}-cys, syn-octahydro-1Hindole-2 (5)-carboxylic acids, 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-2[hydroxy 5-sulfamoyl)-benzamidopentyl]-(S)-alanyl]-cis, syn octahydro-1H-indole-2(S)-carboxylic acid, 1-{N&alpha;-[1(S)-ethoxycarbonyl-3-phenylpropyl)-N#-[(4- chloro-3-sulfamoyl)benzensulfonyl]-(S)-lysyl} cys, syn-octahydro-1H-indole-2(S)-carboxylic acid, 1-{N&alpha; ;-[1(S)-ethoxycarbonyl-3-phenylpropyl)-N#-[(4- chloro-3-sulfamoyl)benzoyl]-(S)-lysyl}-cys, syn octahydro-1H-indole-2(S)-carboxylic acid, 7-(4-chloro-3-sulfamoylbenzamido)-2-{N-[1(S) ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl} 1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-2-HYDROXY-5-SULFAMOYL PHENYL)CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN OCTAHYDRO-1H-INDOLE-2(S)-CARBOXYLIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-(N-METHYL, SULFAMOYL) PHENYL]CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CYS, SYN OCTAHYDRO-1H-INDOLE-2(S)-CARBOXYLIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-SULFAMOYL PHENYL) CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN-OCTAHYDRO1H-INDOLE-2(S)-CARBOXYLIC ACID, 1-[N-[1(S)-ETHOXYCARBONYL-5[[t4-CHLORO-2-AMINO-5- SULFAMYLPHENYL)-CARBONYL]AMINO]PENTYL]-(S)ALANYL]-CIS, SYN OCTHADYDRO-1H-INDOLE-2(S)CARBOXYLIC ACID 1-{N-[1(S)-ethoxycarbonyl-5-[5-chloro-4-oxo-6-sulfamyl2-phenyl-1,2,3,4-tetrahydro quinazolin-3-yl]pentyl]-(S)alanyl]-cis, syn-octahydro-1H-indole-2(S) carboxylic acid or the corresponding EMI16.1 acids or esters, respectively. The compounds of the present invention can be produced by one or more of the methods and subroutes depicted in the following equations. Reactive groups not involved in the reactions described below such as amino and carboxy groups may be protected by methods standard in peptide chemistry prior to the coupling reactions and subsequently deprotected to obtain the desired products. Racemates, if obtained by these processes, can be resolved by standard techniques such as column chromatography or fractional crystallization A. For the preparation of compounds of formula I, wherein R is hydrogen a @@@@compound (AIA) is condensed with a dipeptide ( XX ) under reduction. EMI17.1 In these compounds A, R , R , R and R5 are as defined above and Pr stands for a free or a protected (e.g. by esterification) hydroxy group. The ketocompound (xix) can be condensed with the dipeptide (XX ) in aqueous solution, optimally near neutrality, or in a suitable organic solvent (for example CH30H) in the presence of a reducing agent such as for example sodium cyanoborohydride to give directly the desired compound I (wherein R1 is hydrogen). Alternatively, the intermediate Schiff base, enamine, or aminol may be catalytically reduced to yield product I, for example, by hydrogen in the presence of palladium on carbon (e.g. 10% palladium on carbon) or of Raney nickel. The ratio of diasteriomeric products formed may be altered by the choice of catalyst. B. Alkylation of a dipeptide ( XX ) by means of a compound of formula (XXI ) EMI18.1 wherein X is chloro, brooc, iodo, alkanesulfonyloxy or arenesulfonyl- oxy, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group. The reaction can be carried out under basic conditions in water or in an organic solvent. C. Condensation of an aminoacid (XXII) with an aminoacid (XXIII) EMI18.2 XXII XXIII A, RÚ, Rê, R , R4, R5 are as defined above for compounds formula I and Pr stands for a free or protected (e.g. esterification) hydroxy group. This reaction is well known from peptide chemistry. The reaction can be carried out in the presence of a condensing agent such as for example dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) and N,N-disuccinimidyl carbonate in CH3CN. While, as mentioned above1 reactive groups (e.g. hydroxy groups) are protected before the coupling reaction is carried out, the amino group of compound (XXIII) can be activated, e.g. by means of tetraethyldiphosphit and/or the carboxy group of compound (XXII) can be activated via the intermediacy oS active esters such as that derived from l-hydroxybenzotriazole, its mixed anhydride (derived from a chlorocarbonic acid ester), its azide or dicyclohexylcarbodiimide. This process is of particular use for the preparation of compounds wherein the R3, R4 or R5 contains or is z1, especially wherein R4 is or contains Z1. D. Condensation of an amino compound (XXIV) with a ketocompound (XXV) EMI19.1 under the conditions described for process A. A, RÚ, Rê, R , R4, R5 are as defined above for compounds formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group. E. Alkylation of an amino compound (XXIV) by means of a compound (XXVI) EMI20.1 wherein X is chloro, bromo, iodo, alkynesulfonyloxy or arenesulfonyloxy, A, RÚ, Rê, R , R4, R5 are as defined for compound of fornula I, and Pr stands for a free or protected (e.g. by esterification) hydroxy group. The reaction can be carried out under the conditions described for process B. F. For the preparation of compounds of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6, wherein Z is Z5, Z6, Z7, Z8, Z9 or Z10 preferably Z7, Z8 or Z9: Condensation of Åa peptide of the general formula (XXX) with a compound containing the desired group (XXXI) EMI20.2 1 2 wherein R , R and A are as defined for formula I, Pr is a protected hydroxy group, W3, W4 and W5 are defined like R4 and R5 respectively with the difference that one of W , W4 and W5 contains an NH2-goup instead of the respective Z5 to z10- group; ; and W6 is z5, z6, z7 z8 z9 or z10 The reaction can be carried out in an inert organic solvent, e.g. an alcohol, (preferably ethanol) at reflux temperature. This reaction may be exemplified by the following Reaction Scheme: EMI21.1 G. For the preparation of compounds of formula I, wherein one of R3, R4 and R5is a group 'Z-(CH2)0-6-, wherein Z is zÚ, z2 or Z3: condensation of a peptide of formula XXXII with an appropriately substituted compound of formula XXXIII EMI21.2 wherein RÚ, Rê and A are as defined for formula I, Pr is a protected hydroxy group, W7, W8 and W9 are defined like R , R4 and R5 respectively, with the difference z nce that one of W7 , W8 and W9 contains an NH2-group instead of the respective Z zÚ, zê or Z group, and W10 is EMI22.1 This condensation can be exemplified by the following Reaction Scheme: EMI22.2 The reaction can be carried out in a suitable solvent (e.g. THF, pyridine or mixture THF and triethylamine), usually between 0 C and room temperature. H. For the preparation of compounds of formula I, wherein one of R3, R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z4: condensation of a peptide of formula (XXXVII) with a 3-halomethylbenzothiadiazine (XXXVIII) EMI23.1 1 2 wherein R , R and A are as defined for formula I, Pr is a protected hyedroxy group, W11, W12 and W13 are defined like R , R4 and R5 respectively with the difference that one of W11, W12 and W13 contains a -SH-group instead of the respective Z -group, and Hal is halogen, preferably chloro. The reaction is carries out in a suitable solvent (e.g. DMF), preferably in the presence of triethylamine. I. For the preparation of compounds of formula I, wherein one of R , R4 and R5 is a group z-(CH2)0-6-, wherein Z is Z5 or Z6: condensation of a peptide of formula XXXIX with a compound of formula XXXX EMI24.1 wherein RÚ, Rê, R9, R10 and A are as defined for formula I, Pr is a protected hydroxy group, W14, W15 and W16 are defined liked R , R4 and R5 respectively with the difference that one of W14, W15 and W16 contains the group EMI24.2 respect ively instead of the group Z5 or Z6 respectively. The reaction can be carried out in an inert organic solvent, e.g. an alcohol preferably ethanol, under acidic conditions (e.g. by addition of a hydrochloric acid) at reflux temperature. The starting compounds in these reactions can be prepared according to known methods. The compound of formula XXII, wherein R1 is hydrogen can for example be prepared by reacting a keto compound *(XIX) with on aminoacid (XXVII) EMI25.1 according to the condition described in process A. Alternatively, the compound of formula XXII can be prepared by condensing XXIV with a keto acid (XXVIII) EMI25.2 or by condensing EMI25.3 EMI26.1 under the conditions described for process B (X being as defined in process B). The compound XXII can also be prepared analogously to process G described ab-ove. The starting compound (XXXVII) of process H can for example be prepared from a correspondign compound wherein the respective group W11, W12 or W13 is -SCHC6H5 by reduction with sodium in liquid ammonia. The above processes are followed by setting free protected groups by known methods. Protected carboxy groups, e.g. when, for example,protected by removable ester groups (e.g. Pr being alkoxy, (methoxy, ethoxy, tert. butyloxy) nitrobenzyloxy or benzyloxy,) are set free by hydrolysis or hydrogenation. (Reductive cleavage of a compound, wherein one of the protecting groups (Pr) is benzyloxy and the other protecting group is alkoxy will yield a compound, wherein the benzyloxy group has been replaced by hydroxy but the alkoxy group has not been replaced.) Hydrolysis can be carried out under acidic conditions (using e.g. a halogen hydracid or trifluoroacetic acid), under basic conditions or by means of photochemical hydrolysis. The amino group(s) can be protected by protecting groups such as for example formyl, t-butoxycarbonyl, carbobenzyloxy, triphenylmethyl and nitrophenylsulfenyl. These groups can be removed under acidic conditions, e.g. by means of a halogenhydroacid and/or trifluoroacetic acid. Esters obtained by the above processes can also be transesterified. For example, ethyl esters can be converted to the corresponding benzyl esterwith b3uyl alcohol under acidic conditions. As mentioned before the compounds of this invention exist in diastereoisomeric forms or in mixtures thereof. The above described syntheses can utilize racemates, enanti amersl or diastereomers as starting materials. Enantiomeric intermediates may be obtained by resolution methods known in the art. When diastereomeric products result from the synthetic procedures, the diastereomeric products can be separated by conventional chromatographic or franctional crystallization methods (e.g. described in the European published application No. 12401). The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts ( which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases e.g., dicyclohexylamine salts, N-methyl D-glucamine, salts with amino acids like arginine, lysine and the like. Also, salts with organic and inorganic acids may be prepared, e.g., HC1, HBr, R2S04, B3PO4, methanesulfonic acid, toluensulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid. The non-toxic physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product. The salts may be formed by conventional means, as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin. The compounds of this invention are useful as antihypertensive agents in mammals, including humans, in which the blood pressure has become abnormally elevated. The compounds of the present invention can be combined with pharmaceutical carriers and administered in z 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 effective dose (ED50) of the compounds of this invention will typically be in the range of about 0.01 to about 30mg/kg, preferable of about 0.1 to about lOmg/kg, of mammalian weight, administered in single or divided doses. The exact aose to be adIrinistered is dependent upon where the particular compound lies within the above quoted range, as well as upon the age, weight and condition of the individual. Generally, in treating humans, the compounds of this invention may be administered to patients in need of such treatment in a dosage range of 5 to 500mc per patient generally given several times, thus giving a total daily dose of from 5 to 2000mg per day. The composition containing the compounds of this invention will preferably contain from about 5 to 250mg of the active compound per dosage unit. These compositions 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 suspentsions. The typical acceptable pharmaceutical carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tri calcium phosphates sodium sulfate; calcium sulfate, polyvinylpyrrolidone, 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; ethylene glycol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavoring agents, and -the like commonly used in pharmaceutical formlations. The following examples illustrate the preparation of the compounds of the present invention. The diasteromers prepared as setforth below may be isolated by column chromatography or by fractional crystallization. In the examples below octahydroindole-2(S)-carboxylic acid refers to cis,syn-octahydroindole-2(S)-carboxylic acid, also named 3a(S), 7a(S)-octahydroindole-2(S)carboxylic acid. Example 1 1-{Na-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro- 3-sulfamoyl)benzenesulfonyl]-(S)-lysyl}-cis,syn-octahydro lH-indole-2 (5)-carboxylic acid A. Stir a suspension of 24.0g of Ng-benzyloxycarbonyl-(S)- lysine and 36.Og of ethyl 2-oxo-4-phenylbutanoate acid in 2500ml of absolute ethanol at room temperature for 24 hours. Add 16.0g of sodium cyanoborohydride and stir the resulting mixture at room temperature for 48 hours. Add 80ml of water and stir the resulting mixture at room temperature for 72 hours. Concentrate this mixture in vacuo at 300C to give a white residue. Suspend the residue in 1200ml of ice water, add concentrated hydrochloric acid to maintain pH 2-4, and stir this mixture for 2 hours. Absorb this aqueous solution on-2000ml of XAD-2 (Rohm & Haas Co.) resin. Elute the resin with 16,000ml of water and then with 8000ml of absolute ethanol. Concentrate the ethanol solution and chromatograph the residue on a column of silica gel (3000ml, 60200 mesh) eluting with chloroform : isopropanol : 7% ammcnium hydroxide 1:1:1 (organic layer) to give a white resdue. Chromatograph this residue on a column of silica gel (3000ml), eluting with chloroform : isopropanol : 7% ammonium hydroxide 1:1:1 (organic layer) to give fractions A, B, C, and D. Absorb fraction B on a column of silica gel (1500ml), eluting with chloroform : isopropanol : 7% ammonium hydroxide 1:1:1 (organic layer) to give N -benzyloxy carbonyl-NG-[l(S)-carboethoxy-3-(phenyl)propyl]-(S)-lysine, a white solid, [&alpha;]D26+6.1# (ethanol), m.p. 114-115 C. B. Cool a solution of l.9g of the product of part A and 1.3g of cis,syn-octahydro-1H-indole-2(S)-carboxylic acid benzyl ester in 24ml of dimethylformamide to 0 C under nitrogen. Add dropwise a solution of 0.9 of diphenyl phosphorylazide in 6ml of dimethylformamide, followed by a solution of 0,7 ml of N-methylmorpholine in 6m1 of dimethylformamide, also added dropwise, and stir at room temperature for 18 hours. Pour the reaction solution into water, adjust to pH 8 with 1N NaOH, and extract with ether. Dry the ether layer over magnesium sulfate, and concentrate under vacuum to a yellow oil. Chromatograph the oil on silica gel (100 ml, 60-200 mesh), eluting with hexane ethyl acetate (1:2) to give 1-#Na-[1(S)-carboethoxy-3- (phenyl) propyl) --benzyloxy-carbonyl- (S) lysYlJ-cis ,syn- octahydro-1H-indole-2(S)-carboxylic acid, benzyl ester, a yellow oil. C. Dissolve 1.60 g of the product of part B in 150ml of absolute ethanol. Add 0.75g of 10% palladium-on-charcoal and hydrogenate the mixture at 50 psi at room temperature. Filter the reaction mixture and concentrate the filtrate in vacuo to give 1-#Na-[1(S9-ethoxycarbonyl-3-(phenyl)propyl- (S)-lysyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid hydrate, a white foam, [#]D26 -42.5 (ethanol). D. To 4.9 g of 1-#Na-[1(S)-[ethoxycarbonyl-3-phenylpropyl]- (S)-lysyl}-cis,svn-octahyro-lH-indole-2(S)-carboxylic acid in 200ml of tetrahydrofuran and 2g of triethylamine at 0-50C, add 2. ig of 4-chloro-3-sulfamoylbenzenesulfonl chloride and stir the resulting mixture at room temperature. Concentrate the resulting mixture in vacuo and chromatograph the residue on an Lobar RP-8, size B column (E. Merck) using acetonitrile : water as eluant to give the title compound. Example -2 1-#Na-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro- 3-sulfamoyl)benzoyl]-(S)-lysyl]-cis,syn-octahydro-1H-in dole-2 (S) -carboxylic acid Treat 4.9 g of 1--#Na[1(S)-ethoxycarbonyl-3-phenylpropyl]- (S)-lysyl#-cis,sin-octahydro-1H-indole-2(S)-carboxylic acid (obtainable as described in Example 1A to 2C) in 200ml of tetrahydrofuran and 2.Og of triethylamine at O-5 C with 2.2 g of 4-chloro-3-sulfamoyl-benzoyl chloride and stir the resulting mixture at room temperature. Concentrate the resulting mixture in vacuo and chromatograph the resin idue on a Labor RP-8, size B column (E. Merck) using acetonitrile : water as eluant to give the title compound. Example 3 1-#Na-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro3-sufamoyl)benzenesulfonyl-(S)-lysyl#-(S)-proline Substitute 2.17g of 1-#Na-[1(S)-ethoxycarbonyl-3-phenyl- propyl]-(S)-lysyl3- (S)-proline for the respectively substituted octahydro-1H-indole-2(S)-carboxylic acid in Example 1D to obtain the title compound. Example 4 1-#Na-[1(S)-Ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro3-sufamoyl)benzoyl]-(S)-lysyl#-(S)-proline Substitute 2.17 g of 1-#Na-[1(S)-ethoxycarbonyl-3-phenyl- propyl]-(S)-lysyl#-(S)-proline for the respectively substituted octahydro-lH-indole-2(S)-carboxylic acid in Ex ample 2 to obtain the title compound. Example 5 l-IN-[1(S) -Carboxy-3-phenylpropyl] --[ (4-chloro-3-sulf- amoyl)benzenesulfonyl]-(S)-lysyl-cis,syn-octahydro-lH indole-2 (S) -carboxylic acid A. To a solution of l.lOg of 1-{Na[1(S)-ethoxycarbonyl- 3-phenylpropyl]-(S)-lysyl#-cis,syn-octahydro-1H-indole-2(S)- carboxylic acid (prepared as in Example 1) in 100 ml of methanol at 0-50C, add 2.0ml of 2.5N sodium hydroxide solution and stir at room temperature for 24 hours. Add 20ml of water, concentrate to one-half volume, and stir 24 hours. Concentrate this solution in vacuo and absorb on AG 50W-X2 (100-200 mesh, hydrogen form, Bio-Rad resin) (50ml). Place said 50ml of resin on an additional 300ml of resin, elute the resin with 1200ml of water, and then elute with 4% pyridine in water to yield carboxy-3-phenylpropyl]-(S)-lysyl#-cis,syn-octahydro-1H- indole-2(S)-carboxylic acid, a white solid, m.p. 165-166 [&alpha;]D26-8-2 (ethanol). B. Treat 2.45g of the product of Step A with 1.45g of 4chloro-3-sulfamoylbenzenesulfonyl chloride as described in Example 1D to give the title compound. Example 6 [1(S)-Carboxy-3-phenylpropyl]-N#-[(4-chloro-3-sulfamovl)benzOyl-(S)-lysyli-cis,ssn-octahydro-lH-indole-2(S)- carboxylic acid Treat 2.45g of the product from Example 5A with l.lg of 4-chloro-3-sulfamoylbenzoyl chloride as described in Example 2 -to give the title compound. Example 7 1-fN- rl (S) -Carboxy-3-phenylpropylj-S- (3- (6-chloro-3,4- dihydro-7-sulfamoyl-1,2,4-benzothiadiazinyl-1,1-dioxide) methyl]-(R)-cysteinyl$-cis,syn-octabydro-lE-indole-2(S)- carboxylic acid A. Stir 10.5g of S-benzyl-L-cysteine and ll.Og og 2-oxo4-phenylbutyric acid, ethyl ester in lOO0ml of absolute ethanol at room temperature for 24 hours. Add. 5.28g of sodium cyanoborohydride and stir the resulting mixture at room temperature for 48 hours. Concentrate this mixture in vacuo at 30 C to give a white residue. Suspend the residue in ice-water, add concentrated hydrochloric acid to maintain pH 2-4, and stir this mixture for 1 1/2-2 hours. Absorb this aqueous solution on XAD-2 (Rohm & Haas Co.) resin. Elute the resin with water and then with absolute ethanol. Concentrate the ethanol solution and chromatograph the residue on a column of silica gel using chloroform : isopropanol : 7% ammonium hydroxide i:l:l (organic layer) to give N-[l(S)-carboethoxy-3-phenylpropyl]-S-benzyl- (R)-cysteine. s. Treat 4.0g of the product of part A and 2.6g of cis,syn octahydro-lR-indole-2(S)-carboxylic acid, benzyl ester in 10ml of dimethylformamide at 0 under nitrogen with a solution of 2.75g of diphenylphosporylazide in l.0g of Nmethylmorpholine in 10ml of dimethylformamide, and stir at room temperature for 18 hours. Pour the reaction solution into water, adjust to pH 8 with 1N, NaOH, and extract with ether. Wash the combined ether layers with aqueous sodium chloride solution, dry the ether layer over magnesium sulfate, filter, and concentrate in vacuo to give a residue. Chromatograph this residue -on silica gel (60-2.00 mesh) using hexane : ethylacetate to give -I-N-[l(S)-ethoxy- carbonyl-3-phenylpropyl]-S-benzyl-(R)-cysteinyl3-cistsyn- octahydro-lH-indole-2- (S) -carboxylic acid, benzyl ester. C. Stir the product of part B in 50m1 of a 15-20% solution of hydrobromic in acetic acid under nitrogen for 2 hours, then concentrate to dryness under vacuum at room temperature. Triturate the resultant residue with ether to obtain 1-{N- [1(S)-(ethoxycarbonyl-3-phenylpropyl]-s-benzyl-(R)-cys teinyl#-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, hydrobromide. D. React 1.5g of the product from part C in methanol with 3.0ml of 2.5N sodium hydroxide at room temperature for 24 hours and concentrate the resulting mixture in vacuo at room temperature. Absorb the residue on AG 50W-X2 (100200 mesh, hydrogen form, Bio-Rad) resin. Elute the resin with water and then elute with 4% pyridine in water to yield l-iN-[l(S)-carboxy-3-phenylpropyl]-S-benzyl-(R)-cysteinyl}- cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, hydrobromide. E. Treat 1.0g of product form part D with 0.05g of sodium in 100ml of liquid ammonia. Evaporate and concentrate the resulting mixture to give 1-{N-[1(S)-sulfamoyl-1,2,4-benzylthiadiazine-1,1-dioxide (R)-cysteinylciS,syn-octahydro-1H-indole-2(S)-carboxylic acid as the sodium salt. F. React 0.4g of the product from Step E in 20ml of dimethylformamide with 0.36g of 2-bromomethyl-6-chloro-3,4dihydro-7-sulfamoyl-1,2,4-benzothiadizine-1,1-dioxide and triethylamine. Concentrate the resulting mixture and chromatograph on an AG 50W-X2 column eluting with 4% pyridine in water to give-the title compound. Example 8 1-{N-[1(R)-Carboxy-2-[S-((3-(6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazinyl-1,1-dioxide)methyl))thio] ethyla3-(S)-alanyl}-c-is,ssn-octahydro-lH-indole-2(S)-car- boxylic acid A. Stir lOOg of S-benzyl-L-cysteine ethyl ester hydrochloride, 132g of benzyl pyruvate, and lOg of 3A molecular sieves in 8 liters of ethanol for 18 hours under nitrogen. Add dropwise a solution of 52g of sodium cyanoborohydride in lOOml of ethanol, stir at room temperature for 24 hours, filter, then concentrate the filtrate at room temperature under vacuum. Suspend the resultant residue in lOOml of water and 50Oml of ether and adjust the mixture to pH 8 with 1N HC1. Wash the organic layer with saturated sodium chloride solution, dry over sodium sulfate, and filter. Adjust the filtrate to pH 2 with 3M ethereal HC1, decant the supernatant, wash the resulting oily precipitate with 200ml of ether, and mix with saturated aqueous sodium bicarbonate to obtain a solution of pH 8. Extract the mixture with 1 liter of ether, dry the ether layer over sodium sulfate and concentrate at room temperature to give N-[l(R)-carboethoxy 2- (benzylthio)ethyl)- (R,S) -alanine, benzyl ester, an amber oil. Thin layer chromatography in ethyl acetate : hexane (15:85) may be used to separate the two isomers (isomer A at Rf = 0.36, and isomer B at Rf = 0.28), or the procedure may be continued on the mixture. B. Add 50g of the product of part A to 1800ml of a 15-20t solution of hydrobromic-acetic acid and heat at 500C for 20 hours. Concentrate the resultant mixture to dryness under vacuum, and wash the resultant oily residue with ether until free of acetic acid to produce N-[l(R)-carboxyethyl-2(benzyl- thio)ethyl]-(R,S)-alanine hydrobromide, an amber oil. C. Cool a solution of 50.5g of the product of part B and 33.4g of cis,syn-octahydroindole-2(S)-carboxylic acid benzyl ester in 1 liter of dimethylformamide to 0 C under nitrogen, add dropwise a solution of 35.5g of diphenylphosphorylazide in 1 liter of dimethylformamide, followed by a solution of 33.4g of N-methylmorpholine in 200ml of dimethylformamide, also added dropwise, and stir at room temperature for 18 hours. Pour the reaction solution into 3 liters of water, adjust- to pH 8 with 1N NaOH, and extract with 4 x 1 liter of ether. Wash the combined ether layers with 1 liter of aqueous sodium chloride, dry the ether layer over magnesium sulfate, filter, and concentrate under vacuum to an amber oil. Chromatograph the resultant oil on 2kg of silica gel (60200 mesh) using ether : hexane (90:10). Collect components having Rf 0.38 and Rf 0.61 as indicated by thin layer chromatography on silica gel eluted with ether. The isomer with Rf 0.61 is 1-{N-[1(R)-carboethoxy-2-(benzylthio)ethyl]-(S)- alanyl#-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid, benzyl ester. D. Stir 0.70g of the (S)-alanyl product of part C and 25ml of a 15-20% solution of hydrobromic-acetic aicd under nitnXn for 2 hours, then concentrate to dryness under vacuum at room temperature. Triturate the resultant residue with ether and filter to obtain 1- -[l(R)-carboethoxy-2-(benzylthio)- ethyl-(S)-alanyl3-cis,n octahydro-1H-indole-2 (S)-carbo- xylic acid, hydrobromide as a tan solid, m.p. 124-1250C. E. To a solution of 10.6g of the product of Step D in 500ml of methanol, add 24ml for 2 SN sodium hydroxide solution and stir at room temperature for 24 hours. Concentrate this solution in vacuo and absorb on AG 50W-2 (Bio-Rad) resin (100-200 mesh, hydrogen form). Elute the resin with water and then elute with 4% pyridine in water to yield [1(R)-carboxy-2-( benzylttio)ethyl]- (S) alanyl-cis,yn-octa- hydro-lH-indole-2(S)-carboxylic acid. F. Treat 4.22g of the product of Step E with 0.23g of sodium in 200ml of liquid ammonia. Evaporate the ammonia and absorb the residue on AG 50W-2 (Bio-Rad) resin (100-200 mesh, hydrogen form). Elute the resin with water and then elute with 4% pyridine in water to yield 1-{N-[l(R)-carboxy-2- (mercapto)ethyl]-(S)-alanyl}-cis,syn-octahydro-lH-indole- 2(S)-carboxylic acid. G. React 2.2g of the product of Step F in 20 ml of dimethylformamide with 2.4g of 3-bromomethyl-6-chloro-3,4-dihydro 7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide and triethylamine. Concentrate the resulting mixture to give the title compound. Example 9 1- {N- (1(S) -Ethoxycarbonyl-5- (4-chloro-3sulfainoyl) -benzene- sulfonaminopentyl)-(S)-alanyl#-cis,syn-octahydro-1H-indole- 2 (S)-carboxylic acid A. Dissolve 27.0g of ethyl indole-2-carboxylate in 250ml of trifluoroacetic acid. Add 2.OSg of platinium oxide, hydrogenate the mixture at 50 lb/in2 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--c.arboxylate, a pale yellow oil. B. Dissolve 116g of l0-d-camphorsulfonic acid in 1 liter of warm ethyl acetate and add a solution of 86g 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 500ml of isopropanol and 1800ml ethyl acetate, filter and dry the crystals to obtain 2-(S)-carboethoxy cis syn-octahydro-lH-indole, d-10-camphorsulfonate, m.p. 192-1930C. C. Slurry 10g of the product of part B in 1 liter of ether, adjust to pH 11 with aqueous sodium hydroxide, and stir for 5 minutes. Wash the organic layer with sodium chloride solution, dry over magnesium sulfate, filter, and evaporate in vacuo at room temperature to obtain 2(S) carboethoxy-cis,syn-octahydro-lH-indole as a colorless oil. Dissolve the resultant oil in SOml of methynol containing 23ml of 1N sodium hydroxide, stir at 250C for 30 minutes, adjust to pH 7 with 1N hydrochloric acid, and evaporate the solvent to give cis,syn-octahydro-lH-indole-2(S)-carboxylic acid. D. Cool 23ml of benzyl alcohol to OOC under nitrogen and add 5.95g of thionyl chloride dropwise over 15 minutes, maintaining the temperature at OOC. Add the product of part C, stir for 1 hour at OOC, then stir for 24 hours at room temperature. Pour the resulting mixture into 500ml of ether, stir 1 hour under nitrogen, then allow to stand under nitrogen until the solution is clear. Decant the supernatant, wash the precipitate with 25ml ether, then slurry the precipitate in 200ml ether and adjust to pH 8-9 with 1N sodium hydroxide. Stir 5 minutes, wash-the organic layer with sodium chloride solution, dry over magnesium sulfate, filter and evaporate in vacuo at room temperature to obtain cis,syn-octahydroindole-2(S)-carboxylic acid, benzyl ester as a colorless oil (TLC in ether: one spot, Rf 0.3). E. To 26g of the product of Step D in lOOml of dichloromethane and 7.8ml of pyridine add ll.Og of pyruvoyl chloride and stir the resulting mixture at room temperature. Extract the reaction mixture with water and dry the organic layer over magnesium sulfate. Concentrate the dichloromethane solution in vacuo and distill the residue to give l-pyr-uvoyl-cis,syn-octahydro-lH-indole-2(S)-carboxylic acid, benzyl ester. F. To 20g of the product from Step E in 400ml of ethanol, add 2.0g of 10% palladium-on-charcoal and hydrogenate at 50 psi at room temperature. Filter ther resulting mixture and concentrate the filtrate in vacuo to give 1pyruvoyl--cis , syn-octahydro-lH-indole-2 (S) carboxylic acid. G. React 6.20g of N#-(benzyloxycarbonyl)-L-lysine ethyl ester in 20 ml of tetrahydrofuran with 4.8 g of 1-pyruvoyl-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid and add 20 ml of molecular sieves 4A Rohm anr Haas). Stir the resulting mixture for 4 hours, add 12g of sodium cyanoborohydride in 20ml of methanol and stir the reaction mixture 20 hours. Filter, concentrate to dryness, and partition the residue between water and dichloromethane. Absorb the aqueous phase on strong acidic ion-exchange resin and elute with 4% pyridine in water to give 1-#N-[1(S)-ethoxycarbonyl-5-benzyloxycarbonylaminopentyl)-(R,S)- alanyl#-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid. Separate the isomers on a column of silica gel using CHCl3 : isopropanol : 7% ammonium hydroxide 1:1:1 (organic) as eluant to give 1- N-[1(S) ethoxycyrbonyl-5-benzyloxycarbonylaminopentyl] EMI43.1 cis,syn-octahydro-1H-indole-2(S)-carboxylic acid. H. Hydrogenate the product from Step G in 300ml of ethanol using lg of 10% palladium-on-charcoal at 50 psi at room temperature. Filter the mixture and concentrate the filtrate to give 1- I1(S)-ethoxycaronyl-5-aminopentyl]- (S)-alanyli-cis,syn-octahvdro-lH-indole-2(s)-carboxylic acid. I. React 1.01g of the product of Step H in 20ml of tetrahydrofuran and 0.25g of triethylamine with 0.75g of 4chloro-3-sulfamoylbenzensulfonyl chloride and stir the resulting mixture at room temperature. Concentrate the resulting mixture invacuo and chromatograph the residue on a Lobar RP-8 (E. Merck) size B column using acetonitrile water as eluant to give the title compound. Example 10 [1(S)-Ethoxycarbonyl-5-(4-chloro-3-sulfamoyl-benzamido pentyl3-(S)-alanyl}-cis,syn-octahydro-lH-indole-2tS)-car- boxylic acid Treat 1.01 g of 1#N-[(S)-ethoxycarbonyl-5-aminopentyl]- (S)-alanyl-cis,svn-octahydro-lH-indole-2(S)-carboxylic acid, obtained according to Example 9H, in 20ml of tetrahydrofuran and 0.25g of triethylamine with 0.55g of 4chloro-3-sulfamoylbenzoyl chloride and stir the resulting mixture at room temperature. Concentrate the resulting mixture in vacuo and chromatograph the residue on a Lobar RP-8 W. Merck) size B column using acetonitrile : water as eluant to give the title compound. Example 11 1-#N-[1(S)-Carboxy-5-(4-chloro-3-sulfamoyl)benzamidopentyl]- (S)-alanyl#-cis,syn-octyhydro-1H-indole-2(S)-carboxylic acid A. To 4.04 g of 1-#N-]1(S)-ethoxycarbonyl-5-aminopentyl]- (S)-alanyl#-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid in 100ml of methanol : water 1:1 add 8ml of 2.5N NaOH at o-50C and then stir the resulting mixture at room temperature for 24 hours. Concentrate the resulting mixture and absorb on AG 50W-2 (Bio-Rad) resin (100-200 mesh, hydrogen form). Elute the resin with water, and then elute with 4% pyridine in water to yield 1-#N-[1(S)-carboxy-5-aminopentyl]- (S)-alanyl#-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid. B. React 0.95g of the product from Step llA with 0.55g of 4-chloro-3-sulfamoylbenzoyl chloride as described in Example 10 to give the title compound. Example 12 l- & -El(S)-Carboxy-5-(4-chloro-3-sulfamoyl)benzenesulE- onamidopentyl]-(S)-alanyl#-cis,syn-octahydro-1H-indole- 2(S)-carboxylic acid Treat 0.95g of the product from Example llA with 0.75g of 4-chloro-3-sulfamoylbenzenesulfonyl chloride as described in Example 91 to give the title compound. Example 13 1-#N-[(S)-Ethoxycarbonyl]-5-(chlore-3-sulfamoyl]benzensulfoamidopentyl]-(R,S)-alanyl#-proline A. Make a solution of NL-benzyloxycarbonyl-L-lysine ethyl ester hydrochloride (2.94g) in water (lOml) basic with 15ml of saturated aqueous potassium bicarbonate and extract with CH2Cl2. Dry the extract over M=SO4 and concentrate to dryness. Dissolve the residue, NK-benzyloxycarbonyl lysine ethyl ester, in tetrahydrofuran (20ml) and pyruvoylproline (555mg) and add powdered No. 4A molecular sieves (1.0 g). Stir the mixture at room temperature for 4 hours. Add sodium cyanoborohydride (630mg) in lml of methanol over 2 hours and stir the mixture overnight. Filter the mixture, concentrate to dryness, and partition the residue between water (lOml) and CR2 Cl2 (15ml). Absorb the aqueous phase on strong acid ion-exchange resin and elute with 4% pyridine in water to yield 470mg of lN-[l(S)-ethoxycarbonyl-5- benzyloxycarbonylaminopentyl]-(R,6)-alanylS -S-proline. Remove the protecting group by hydrogenation in ethanol water 1:1 over 10% Pd/C catalyst at 40 psi. Filter the mixture and take the filtrate to dryness. Chromatograph the residue in methanol on an LH-20 column to give the desired 1-#N[1(S)-ethoxycyrbonyl-5-aminopentyl]-(R,S)- alanyl#-(S)-proline. B. Condense 0.90g of the product from Step A with 0.75g of 4-chloro-3-sulfamoylbenzenesulfonyl chloride as described in Example 91 to give the title compound. Example 14 1-#N-[1(S)-Ethoxycarbonyl-5-(4-chloro-3-sulfamoyl)-benzamidopentyl]-(R,S)-alanyl#-(S)-proline React 0.90g of the product of Example 13A with 0.55g of 4-chloro-3-sulfamoylbenzoylchloride as described in Example 10 to give the title compound. Example 15 1-#N-[1(S)-Carboxy-5-(4-chloro-3-sulfamoyl)benzenesulfoamidopentyl]-R,S)-alanyl#-(S)-proline A. Treat 3.50 g of the product of Example 13A in 100ml of methanol : water 1:1 with 8.Oml of 2.5N NaOH as described in Example 11A to giveN-C1(S)-carboxy-5-aminopentyll- (R,S)-alanyl#-(S)-proline. B. Condense 0.80g of the product of Step A with 0.75g of 4-chloro-3-sulfamoylbenzenesulfonyl chloride as described in Example 91 to give the title compound. Example 16 [-#N-[(S)-Carboxy-5-(4-chloro-3-sulfamoyl)benzamidopentyl] (R,S)-alanyl#-(S)-proline React 0.80g of the product of Example 15A with 0.55g of 4-chloro-3-sulfamoylbenzoyl chloride as described in Example 10 to give the title compound. Example 17 ?- (4-Chloro-3-sulfamoylbenzamido)-24 N-[l(S)-carboxy-3- phenylpropyl]-(S)-alanyl#-1,2,3,4-tetrahydroisoquinoline- 3(S)-carboxylic acid A. Dissolve 1,2,3 ,4-tetrahydro-7-nitroisoquinoline-3 (S) - carboxylic acid ethyl ester (0.1 mole) in ethanol and add the solution to 10% palladium on carbon (1.0g) in a hydrogenation bottle. Hydrogenate the mixture at 30 psi, at room temperature until the reduction is complete as indicated by thin layer chromatography. Remove the catalyst by filtration and evaporate the solvent under reduced pressure to obtain 7-amino-1,2, 3,4-tetrahydroisoquinoline-3-(S)- carboxylic acid ethyl ester. (The preparation of 1,2,3,4-tetrahydro-7-nitroisoquino- line-3(S)-carboxylic acid is described in US patent 4,064,274.) B. Treat 7-amino-1,2,3,4-tetrahydroisoquinoline-3(S)- carboxylic acid ethyl ester (Step A) (0.1 mole) with benzyl alcohol (0.5 mole) and ±-toluenesulfonic acid (0.22 mole) in toluene at reflux overnight. Evaporate the solvent under reduced pressure to obtain the ±-toluenesulfonic acid salt of the product. Add this salt to aqueous sodium bicarbonate solution with stirring. Extract the mixture with chloroform, dry the extract with magnesium sulfate and evaporate the solvent under reduced pressure to obtain 7-amino-l,2 ,3,4-tetrahydroisoquinoline-3 acid acid benzyl ester. C. Add a solution of 4-chloro-3-sulfamoylbenzoyl chloride (0.1 mole) in tetrahydrofuran to a solution of product of Step B in tetrahvdrofuran containing triethylamine (0.1 mole). When the reaction is complete as indicated by thin layer chromatography, remove the triethylamine hydrochloriae by filtration and evaporate the solvent at reduced pressure. Purify the residue by chromatography to obtain 7-(4-chloro3-sulfamoylbenzamido)-1,2,3,4-tetrahydroisoquinoline-3(S)carboxylic acid benzyl ester. D. Cool a solution of N-±l(S)-carboethoxy-3-phenylpropyl)- (S)-alanine (0.01 mole) and the benzyl ester (0.01 mole) from Step C in dry dimethylformamide to OOC. .Add N-methylmorpholine (0.01 mole) with stirring, then add dropwise, with stirring, a solution of diphenylphosphoryl azide (0.01 mole) in dry dimethylformamide while maintain the temperature at 0tC. Stir the reaction for one hour at 0 C and overnight at room temperature. Dilute the mixture with ethyl acetate and wash with aqueous sodium bicarbonate. Dry the organic solution with magnesium sulfate and evaporate the solvent under reduced pressure. Purify the residue by chromatography to give 7-(4-chloro-3-sulfamoylbenzamido)- 2-iN-[l(S)-carboethoxy-3-phenylpropyll-(S)-alanyl3-1,2,3,4- tetrahydrois.oquinoline-3- (S)-carboxylic acid benzyl ester. E. Add a solution of 0.01 mole of the benzyl ester from Step D in ethanol to 10% palladium on charcoal (0.5g) in a hydrogenation bottle. Hydrogenate the mixture -at 60 psi, at room temperature until removal of benzyl group is complete as indicated by thin layer chromatography. Remove the catalyst by filtration and evaporate the solvent under reduced pressure to obtain 7-(4-chloro-3-sulfamoylbenz amido)-2- b -rl(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl}- 1,2,3,4-tetrahydrosoquinoline-3(S)-carboxylic acid. F. Stir a solution of 0.01 mole of the product from Step E in water containing sodium hydroxide (0.022 mole) at room temperature until the reaction is complete as indicated by thin layer chromatography. Add methanol to the reaction and then add 0.022 equivalents of Dowex-50(H+) with stirring. Remove the resin by filtration and evaporate the solvent under reduced pressure. Purify the product by chromatography to obtain the tittle compound. Example 18 7-(4-Chloro-3-sulfamoylbenzenzenesulfonamido)-2-#N-[1(S)carboxy-3-phenylpropyl]-(S)-alanyl#-1,2,3,4-tetrahydro- isoquinoline-3(S)-carboxylic acid A. Follow the procedure of Example 17C using 4-chloro-3sulfamoylbenzenesulfonyl chloride in place of 4-chloro-3sulfamoylbenzoyl chloride to obtain 7-(4-chloro-3-sulfamoylbenzoyl chloride to obtain 7-(4-chloro-3-sulfamoylbenzene- sulfoamido)-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid benzyl ester. B. Couple the product from Step A with N-[l(S)-carboethoxy- 3-phenylpropyl]-(S)-alanine following the procedure of Example 17D. Chromatograph the crude product to obtain 7-(4-chloro-3-sulfamoylbenzenesulfonamido)-2-tN-rl(S)- carboethoxy-3-phenylpropyl)-(S)-alanyl#-1,2,3,4-tetrahydro- isoguinoline-3(S)-carboxylic acid benzyl ester. C. Subject the benzyl ester from Step B to hydrogenolysis as described in Example 17E to obtain 7-(4-chloro-3 sulfamoylbenzenesulfonamido)-2-#N-[1(S)-carboethoxy-3phenylpropyl]-(S)-alanyl2-1,2,3,4-tetrahydroisOquinoline- 3(S)-carboxylic acid. D. Treat the product from Step C with aqueous sodium hydroxide followed by Dowex-50(H+) as described in Example 17F to obtain the title compound. Example 19 5-(4-Chloro-3-sulfamoylbenzamido)-lJ;Er-ll(s)-carboxy-2- phenylpropyl]-(S)-alanyl}-octahydro-1H-indole-2-carboxylic acid A. Following the procedure of Example 17A, substitute 5-nitroindole-2-carboxylic acid ethyl ester for 1,2,3,4 tetrahydro-7-nitroisoquinoline-3(S)-carboxylic acid ethyl ester to obtain 5-aminoindole-2-carboxylic acid ethyl ester. B. Dissolve 5-aminoindole-2-carboxylic acid ethyl ester in trifluoroacetic acid containing PtO2. Hydrogenate at 60 psi on a Parr shaker for 24 hours. Distill the trifluoroacetic acid at reduced pressure and dissolve the residue in ethyl acetate. Filter and adjust to pH 9 with 1N NaOH. Dry the organic layer over MgSO4 and distill the solvent at reduced pressure to obtain 5-aminooctahydro-lH-indole-2carboxylic acid ethyl ester. C. Following the procedure of Example 17B, substitute 5-aminooctahydro-lH-indole-2-carboxylic acid ethyl ester for 7-amino-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid ethyl ester to obtain 5-aminooctahydro-lH-indole-2carboxylic acid benzyl ester. Analogously following the procedures of Examples 17C, 17D, 17E and 17F obtain 5-(4-chloro-3-sulfamoylbenzamido)octa- hydro-1H-indole-2-carboxylic acid benzyl ester, 5-(4-chloro-3-sulfamoylbenzamido)-l-i- 1(S)-carboethoxy- 3-phenylpropyl]-(S)-alanyl}-octahydro-1H-indole-2-carboxylic acid benzyl ester, 5-(4-chloro-3-sulfamoylbenzamido)-1-{N-[1(S)-carboethoxy3-phenylpropyl]-(S)-alanyl}-octahydro-1H-indole-2-carboxylic acid and the title compound. Example 20 5-(4-Chloro-3-sulfamoolbenzenesulfonamido)-lA N-tv S)- carboxy-3-phenylpropyl) - (S) -alanyl -octahydro-lH-indole- 2-caroxylic acid A. Following the procedures of Example 18A, substitute 5aminooctahydro-lH-indole-2-carboxylic acid benzyl ester for 7-amino-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid benzyl ester and 4-chloro-3-sufamoylbenzenesulfonyl chloride for 4-chloro-2-sulfamoylbenzoyl chloride to obtain 5-(4-chloro-3-sulfamoylbenzenesulfonamido)-octahydro-lHindole-2-carboxylic acid benzyl ester. B. Following the procedures of Examples 17D, 17E and 17F obtain 5-(4-chloro-3-sulfamoylbenzamido) [l(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl-octahydro-lH- indole-2-caroxylic acid benzyl ester, 5-(4-chloro-3-sulfamoylbenzenesulfonamido) -1AN- [1(S)- carboethoxy-3-phenylpropyl]-(S)-alanyl}-octahydro-1Hindole-3-carboxylic acid and the title compound. Example 21 1-{N-[1(S)-Ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenzamido)pentyl]-(S)-alanyl}-cis,syn-octahydro lH-indole-2 (S) -carboxylic acid hydrochloride A. N-[1(S)-ethoxycarbonyl-5-(benzyloxycarbonylamino) pentyl) - (S) -alanine. Dissolve 17g of N-[1(S)-ethoxycarbonyl-5-(benzyloxy- carbonylamino)pentyl]-(S)-alanine, t-butyl ester in 150ml of trifluoroacetic acid at 50C. .Stir at room temperature for.5hr. and then concentrate at room temperature in vacuo. Triturate the residue with ether and dry under vacuum to give the title compound.. B. 1-{N-[1(S)-ethoxycarbonyl-5-(benzyloxycarbonylamino) pentyl]-tS)-alanyl}-cis,sYn-octahydro--lH-indole-2(S)- carboxylic acid benzyl ester. In 5ml of DMF, dissolve 0.7g of N-[1(S)-ethoxycarbonyl- 5-(benzyloxycarbonylamino)pentyl]-(S)-alanine, 0.325g of cis,syn-octahydro-1H-indole-2(S)-carboxylic acid benzyl ester, 0.24g of 1- (3-dimethylaminopropyl) -3-ethyl- carbodiimide hydrochloride, and 0.20g of l-hydroxybenzotriazole. Stir this solution under nitrogen for 18 hr. and then concentrate at room temperature in vacuo. Partition between ether and water. Dry the organic layer (MgSO4) and concentrate at room temperature in vacuo to give the title compound. C. 1-{N-[1(S)-ethoxycarbonyl-5-aminopentyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)-carboxylic acid. In 80ml of ethanol dissolve 3.7g of l-kN-[l(S)-ethoxy carbonyl-5-(benzyloxycarbonylamino)pentyl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S)-carboxylic acid benzyl ester. To this add lg of 20% palladium hydroxide on carbon. Hydrogenate this mixture at 60 psi for 18 br. Filter and concentrate at room temperature in vacub. Triturate the oily residue with ether and filter to give the title compound, m.p. 160 C (decomp.), [&alpha;]D26-40.7 (MEOR). D. 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenzamido)pentyl]-(S)-alanyl}-cis,syn-octahydro-1Hindole-2(S)-carboxylic acid hydrochloride. Dissolve 0.7g of 1- [1(S)-ethoxycarbonyl-5-aminopentyll- (S)-alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid and 0.4g of triethyl amine in 40ml of tetrahydro furan and cool to 50C. To this solution add dropwise a solution of 0.48g of 4-chloro-3-sulfamoylbenzoyl chloride in 20ml of tetrahydrofuran. Stir for 1 hr. at 50C and 1 hr. at 250C. Filter and concentrate in vacuo. Dissolve the residue in 200ml of dichloromethane and acidify with HCl-gas. Decant and triturate the residue several times with dichloromethane to give the title compound, m.p. 185 C, [&alpha;]D26-20 (MEOH). Example 22 1-{N-[1(S)-Ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenz amido) pentyl-(S) -alanvl)-cis,syn-octahydro-ls-indole- 2(S)-carboxylic acid A. N-[1(S)-ethoxycarbonyl-5-(benzyloxycarbonylamino) pentyl]-(S)-alanine, t-butyl ester. Dissolve 60g of NE-benzyloxycarbonyl-(S)-lysine, ethyl ester and 90g of t-butyl bromopropionate and 22g of trethylamine in 200ml of DMF. Heat this soution at 700C for 18 hr. Concentrate in vacuo and dissolve the residue in ethyl acetate. Wash organic layer with water and brine. Dry organic layer (MgS04) and concentrate in vacuo. Chromatograph the residue on silica gel (100-200 mesh) using ether : hexane (1:1) as solvent. Elute SR-isomer and then the title compound. Thin layer chromatography in ether : hexane 1:1 shows the SR-isomer at 0.2 and the SS-isomer at 0.1 B. N-El(S) -ethoxyzarbonyl-5-aminopentyl]-(S)-alanine t-butyl ester. Dissolve lOg of N-[1(S)-ethoxycarbonyl-5-(benzyloxy- carbonylamino)pentyl]-(S)-alanine, t-butyl ester in 40ml of ethanol. Add 3.0g of 20% palladium hydroxide on carbon. Hydrogenate at 60 psi for 18 hr. Filter and concentrate in vacuo to give title compound. C. N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenz amido)pentyl) - (S) -alanine, t-butyl ester. Dissolve lOg of N-I1(Sf-ethoxycarbonyl-5-aminopentyl]- (S)-alanine, t-butyl ester in SOml of THF. Add 0.3g of triethylamine. Cool to 50C under nitrogen. Add, dropwise, with stirring a solution of 0.8g of 4-chloro-3sulfamoyl benzoyl chloride in 30ml of THF. Warm to room temperature and stir for 10 hr. Filter and concentrate in vacuo. Dissolve residue in ethyl acetate and wash with water and brine. Dry organic layer (MgSO4) and concentrate in vacuo to give the title compound. Purify by chromatography on silica gel using ethyl acetate as eluant. D. N[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenzamido)pentyl]-(S)-alanine, hydrochloride. Dissolve 0.75g of N-[1(S)-ethoxycarbonyl-5-(4-chloro-3- sulfamoylbenzamido)pentyl]-(S)-alanine, t-butyl ester in 10ml of dioxane saturated with HCl gas. Keep at room temperature 18 hr. Concentrate in vacuo and triturate the residue with ether to give title compound; E. 1-{N-[l(S)-ethoxyc2rbonyl-5-(4-chloro-3-sulfamoylbenz- amido) pentyl) - (S) -alanylj -cis ,sn-octahydro-lR-indole- 2(S)-carboxylic acid, benzyl ester. In 20ml of DMF dissolve 0.75g of N-[l(S)-ethoxycarbonyl5-(4-chloro-3-sulfamoylbenzamido)pentyl-(S)-alanine HCl, 0.39g of cis, syn-octahydro-1H-indole-2(S)-carboxylic acid benzyl ester, 0.40g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide HC1, 0.23g of l-hydroxybenzotriazole and 0.15g of N-methyl morpholine. Stir under nitrogen for 18 hr., concentrate at room temperature (0.03 mm) and partition residue between ethyl acetate and water. Dry organic layer (MgSO4) ) and concentrate in vacua to give an oil Chromatograph the oil on silica gel using ethyl acetate as eluant to give the title compound. F. 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoylbenzamido)pentyl)-(S)-alanyl}-cis, syn-octahydro-1H-indole2(S)-carboxylic acid. Dissolve 0.05 g of 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro3-sulfamoylbenzamido)pentyl-(S)-alanyl}-cis, syn-octahydro1H-indole-2(S)-carboxylic acid benzyl ester in 5m1 of 20% HBr in glacial acetic acid and a low to stand for 4 hr. Concentrate at room temperature (0.03 mm) and triturate witi ether to yield product in the form of its hydrobromide salt. Generate the free base by dissolving the hydrobro- me salt in 20% aqueous ethanol and absorbing on a strongly acidic ion exchange column (Bio-Rad AG 50W-XZ). Elute with pyridine: water 4:96 and concentrate eluant in vacuo to yield title compound, Generate HCl salt of title compounc b adding title compound to dichloromethane and HCl es tc give title compound in the form of its hydrochloride, m.p. 185 C [c]D26-20 (MeOH). Example 23 Treat the benzyl ester from example 1,-C with N-carbo benzoxlf-alonine-M-hpdroxysuccinimide ester (0.10 mole) in cimethylformamide at room temperature. When the reaction is complete as indicated by thin layer chromatography, evaporate the solvent at reduced pressure. Add ethyl acetate and wash with aqueous sodium bicarbonate solution. Dry -the organic solution with magnesium sulfate and evaporate the solvent at reduced pressure. Purify the residue by chromatography. Dissolve this product in ethanol and add the solution to 108 palladium on charcoal (l.Og) in a hydrogenation bottle, Hydrogenate the mixture at 30 psi, until the reaction is complete as indicated by thin layer chromatography. Filter the mixture and evaporate the solvent at reduced pressure to give 7-(4-chloro-3-sulfamoylbenzamido)-2-[(S)-alanyl]-1,2,3,4-tetrahydroisoquinoline 3(5) -carboxylic acid. Dissolve - (4-chloro-3-sulfamoyl- benzamido)-2-[(S)-alanyl]-1,2,3,4-tetrahydroisoquinoline 3(S)-car.hox lic acid (0.10 mcle) in lOOml of absolute ethanol and add 2-oxo-4-phenylbutyric acid, ethyl ester (0.30 mole). Add 50ml of 3 Angstrom molecular sieve pellets and stir the resulting mixture at room temperature for 18 hrs. Filter the mixture and treat the filtrate with sodium cyanoborohydride (0.30 mole) at room temperature for 2 hrs. Concentrate the mixture under reduced pressure, dilute the oil with dilute hydrochloric acid and stir at room temperature for one hour. Absorb the aqueous solution on XAD-2 resin (Rohm & Haas Co.). Elute the resin with water and then with methanol. Concentrate the methanol solution and purify the residue by chromatography to obtain 7-(4-Chloro-3-Sulfamoylbenzamido)-2-N-[1(S) Carboethoxy-3-Phenylpropyl]-(S)-Alanyl-1,2,3,4 Tetrahvdroisoauincline-3- (S) -Carboxvlic Acid Example 24 Add ethyl 2-bromo-4-phenylbut2noate (0.10 mole) to a solution of 7-(4-chloro-3-sulfamoylbenzamido-2-[(S) al2nyl3-1,2,3,'-tetrahvcrosioauinoline-3(S)-carboxylic acid (0.10 mole) and triethylamine (0.20 mole) in 200ml of dimethylformamlde and heat the mixture at 700C for 18 hrs. Remove the solvent at reduced pressure and purify the residue by ion-exchange chromatography to give the product as a mixture of diostereoisomers. Purify this mixture by chromatography to obtain 7-(4-Chloro-3-Sulfamoylbenzamido)-2- N-[1(S) Carboethoxy-3-Phenylpropyl)-(S)-Alanyl-1,2,3,4 Tetrahydroisoquinoline-3-(S)-Carboxylic Acid Example 25 [1(S)-ethoxycarbonyl-5-[3-hydroxy-3-(4-chloro 3-sulfamoylphenyl) phthalimidine-2-yl) pentyl) - (S) - alanyl}-cis, syn-octahydro-1H-indole-2(S) carboxylic acid. Dissolve 3.4 g (0.01 mole) of 3-hydroxy-3-(4-chloro EMI57.1 <tb> 3-sulfamylphthalilimidine, <SEP> 4g <SEP> (0.01 <SEP> mole) <SEP> of <SEP> 1-{N <tb> [1(S)-ethoxycarbonyl-5-amino-pentyl]-(S)-alanyl} cis, syn-octahydro-1H-indole-2-(S) carboxylic acid and 2g (0.01g) of p-toluenesulfonic acid monohydrate in 10 ml of N,N-dimethylformamide. Stir at 25 C for 2 days then concentrate at room temperature under vacuum. Chromatograph the crude product on an acid ion exchange column (Dowex-50) using water followed by 4% aqueous pyridine followed by chromatography on Sephadep LH-20 (methanol) to obtain the product. Example 26 1-{N-[1(S)-ethoxycarbonyl-5-[7-chloro-4-oxo-6sulfamyl-2-phenyl-1,2,3,4-tetrahydro quinazolin-3yl]pentyl]-(S)-alanyl]-cis, syn-octahydro-1H-indole 2 (S) carboxylic acid hydrochloride. Dissolve 3.8g (0.01 mole) of 6-chloro-7-sulfamyl- isotoic anhydride and 4g (0.01 mole) of 1-{N-[1(S) ethoxycarbonyl-5-aminopentyl]-(S)-alanyl}-cis, synoctahydro-1H-indole-2-(S)-carboxylic acid in 20 ml of pyridine. Stir mixture until gas evolution stir (3 hrs). Concentrate at room temperature under vacuum. Chroma- tograph the crude product on an acid ion exchange column (Dowex-5O) using water followed by 48 aqueous pyridine to obtain 1- [1(S) -ethoxycarbonyl-5- [[4-chloro-2- amino-5-sulfamylphenyl)carbonyl]amino]pentyl]-(S)alanyl} cis,syn-octahydro-lE-indole-2(S) carboxylic acid. HCl salt m.p. 180 C(d) [&alpha;]D26=-16.6 (methanol C=0.7) Dissolve the above intermediate in 20ml of acetic acid and add 2g (0.02 mole) of benzaldehyde. Stir for 3 days and concentrate at room temperature under vacuum. Chromatograph the residue on a strong acid on exchange column (Dwex-50) using water followed by 4% aqueous pyridine. Concentrate under vacuum and dissolve the residue in ethanol ether. Crucify with HCl gas and dilute with ether to cause -the product to precipitate as a white solid. m.p. 1800C(d) The following compounds exemplify the compounds of formula I, which can be prepared according to the described processes and the examples. Other esters and the corresponding free acids are equally important. EMI59.1 EMI59.2 <SEP> b <tb> <SEP> R5 <tb> No. <SEP> z <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> 1 <SEP> C1 <SEP> NCH <SEP> i <tb> <SEP> --NNN---CH <tb> <SEP> tcl'b) <SEP> < <tb> 3 <SEP> ij¯ <tb> <SEP> Cl <tb> <SEP> 0 <tb> <SEP> .4 <SEP> I' <tb> <SEP> · <tb> <SEP> 41 <SEP> Cl <tb> <SEP> -N <tb> EMI60.1 <tb> <SEP> 5 <tb> <SEP> R <tb> No. <SEP> -- <SEP> Z <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> 0 <tb> <SEP> N-- <SEP> 5 <tb> <SEP> Of <tb> <SEP> IzN <SEP> - <SEP> I <tb> <SEP> Cl <SEP> -- <SEP> -Ca <tb> <SEP> 6 <SEP> CI <SEP> 0 <SEP> · <tb> <SEP> H2N)·10 <tb> <SEP> OH, <tb> <SEP> B2NS02 <SEP> o <SEP> F <tb> <SEP> CI <tb> <SEP> a <SEP> I <tb> <SEP> H2N502 <SEP> J <SEP> - <SEP> EMI61.1 <tb> <SEP> R5 <tb> <SEP> No. <SEP> j <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> 9 <SEP> b¯ <tb> <SEP> 9 <SEP> -N <tb> <SEP> 10 <SEP> X <SEP> P2 <SEP> m > <SEP> 5O2-SH <SEP> ^ <tb> <SEP> -N <tb> <SEP> 'Cl <tb> <SEP> 11 <SEP> F <SEP> N5 <tb> <SEP> -N <SEP> CR <tb> <SEP> Cl' <tb> <SEP> 0 <tb> <SEP> II <tb> <SEP> 12 <SEP> < <SEP> (· <tb> <SEP> NI <tb> <SEP> -N-CH <tb> <SEP> 0 <tb> <SEP> II <tb> <SEP> 13 <tb> OH <tb> <SEP> hun <tb> <SEP> H <SEP> 2N <SEP> 02 <SEP> - <SEP> -N <SEP> CR <tb> <SEP> Cl <tb> EMI62.1 <tb> <SEP> z,R5 <tb> No. <tb> <SEP> CR, <tb> <SEP> CI <SEP> 0 <tb> <SEP> 14 <SEP> iN- <SEP> n <tb> <SEP> H,N <tb> <SEP> Cl <SEP> OH, <tb> <SEP> 15 <SEP> N <tb> <SEP> = <SEP> CR <SEP> H <SEP> SO, <tb> <SEP> 'Cl <tb> <SEP> H,NSO, <SEP> O <tb> <SEP> 17 <tb> <SEP> - <SEP> N <SEP> - <SEP> CH <SEP> EMI63.1 <tb> <SEP> R5 <tb> <SEP> X <SEP> z <SEP> -YR2 <tb> NSO\2502 <SEP> NH <SEP> - <SEP> CR2 <tb> 18 <SEP> NH <SEP> -- <SEP> 1 <tb> <SEP> S <tb> <SEP> -N-CR <tb> <SEP> 7 <tb> <SEP> 19 <SEP> · <tb> <SEP> Cl <SEP> -N-CH <tb> <SEP> 0 <tb> <SEP> 22 <SEP> r <tb> <SEP> Ii <SEP> 7 <tb> <SEP> 20 <SEP> (Ni. <tb> <SEP> Cl <SEP> -N-CH <tb> 0 <tb> <SEP> I <SEP> N <SEP> 21 <SEP> M-- <SEP> 7 <tb> <SEP> l <SEP> H2N <SEP> 4 <SEP> | <tb> <SEP> H2N02 <SEP> <tb> <SEP> Cl <tb> <SEP> Cm <SEP> 0 <SEP> -N <tb> <SEP> 1 <SEP> CX <SEP> | <SEP> 5As <tb> <SEP> ---NNN----CH- EMI64.1 <tb> <SEP> R5 <tb> No. <SEP> Z <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> 23 <tb> <SEP> -N-CH <tb> <SEP> Cl <SEP> Th <tb> 24 <SEP> WI <tb> <SEP> j <SEP> 1 <SEP> B2NS <SEP> X <SEP> O <tb> EMI65.1 EMI65.2 <tb> <SEP> 5 <tb> <SEP> R <tb> <SEP> No. <SEP> z <SEP> -NR <tb> No. <SEP> a <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> 25 <SEP> ¸',' <SEP> 1 <tb> <SEP> Ci <tb> <SEP> 0 <tb> <SEP> 26 <tb> <SEP> 26 <SEP> I' <SEP> I <tb> <SEP> Cl <SEP> N <SEP> -N--CR <tb> <SEP> 0 <tb> <SEP> N <SEP> 27 <tb> <SEP> OH <tb> <SEP> S2N0 <tb> <SEP> Cl <SEP> -N <tb> <SEP> Cl <tb> <SEP> N <tb> <SEP> 28 <tb> <SEP> H2NSO2 <SEP> A <SEP> ---- <SEP> CH <tb> EMI66.1 <tb> <SEP> 'R5 <tb> <SEP> No. <SEP> z <SEP> y <tb> <SEP> -N <SEP> - <SEP> N <SEP> R2 <SEP> \ <tb> <SEP> oil <tb> <SEP> H2NSO2 <SEP> H <tb> 1 <SEP> 2 <SEP> 0 <tb> <SEP> Cl <tb> <SEP> 30 <tb> <SEP> H2NSO2O <SEP> <tb> <SEP> I <tb> <SEP> 31 <tb> <SEP> Cl <SEP> ,N-CH <tb> <SEP> I <tb> <SEP> f,NS3, <SEP> I <SEP> I <tb> <SEP> 33 <tb> EMI67.1 <SEP> W <tb> <SEP> .RS <tb> <SEP> No. <SEP> z <SEP> 1 <tb> <SEP> 2 <tb> <SEP> It <SEP> - <SEP> C <SEP> sFms <tb> <SEP> JN-- <SEP> S <SEP> S <tb> <SEP> -N <SEP> CH <tb> <SEP> -N-CE <tb> <SEP> 35 <SEP> $ <SEP> CI <tb> <SEP> 7 <tb> i <SEP> H2N <SEP> 3 <SEP> Nss <SEP> H <SEP> <tb> <SEP> Cl <tb> <SEP> Cl <SEP> 0 <SEP> iTh <tb> <SEP> 36 <tb> <SEP> H2SO2 <SEP> ol <SEP> -N-CH <tb> <SEP> OH <tb> <SEP> SIT <tb> <SEP> - <SEP> Ns?a; <SEP> N <SEP> S <SEP> S <tb> <SEP> ---N- <SEP> --CH <tb> EMI68.1 <tb> <SEP> IR5 <tb> <SEP> No. <SEP> Z <tb> <SEP> Cl <SEP> Th <tb> 38 <SEP> 38 <tb> <SEP> n=N502 <SEP> Ï <SEP> N <SEP> -CH <tb> <SEP> 2 <SEP> I <tb> <SEP> - <tb> <SEP> 39 <SEP> Cl <SEP> -N <tb> <SEP> 40 <SEP> n <SEP> rm <tb> <SEP> , <SEP> ¯ <SEP> .. <SEP> ¯ <tb> <SEP> 41, <SEP> > <SEP> n <SEP> Fm <tb> <SEP> I <tb> <SEP> Cl <tb> <SEP> C <tb> <SEP> fi <tb> <SEP> 2 <SEP> r <tb> <SEP> '4,2 <SEP> jJ <tb> <SEP> CI <SEP> -N-CH EMI69.1 <tb> <SEP> [ <SEP> A <SEP> q <tb> No <SEP> Z <SEP> -N- <SEP> C2 <tb> <SEP> 0 <tb> <SEP> 43 <SEP> N- <tb> <SEP> OH <SEP> (· <tb> <SEP> H2 <SEP> 02 <SEP> <tb> <SEP> cl <tb> <SEP> 0 <tb> <SEP> cm <tb> <SEP> 1 <tb> <SEP> 2 <tb> <SEP> 45 <SEP> N- <tb> <SEP> 1 <tb> <SEP> 46 <SEP> n <tb> <SEP> 1: <SEP> -N-CR <tb> <SEP> ': <SEP> ''S0 <SEP> 0 <tb> <SEP> 2 <SEP> 2 <tb> EMI70.1 EMI70.2 <tb> <SEP> 5 <tb> No. <SEP> ¯ < <tb> <SEP> 1 <tb> <SEP> 47 <SEP> \ <SEP> < <SEP> Nh <SEP> <tb> <SEP> B <tb> 48 <SEP> )·i5O2-NH <tb> HQ <tb> 49 <tb> <SEP> C1' <SEP> I <tb> <SEP> H2NS02 <SEP> o <SEP> n <tb> <SEP> C·3¸1IINH <tb> <SEP> 51 <tb> EMI71.1 EMI71.2 <tb> <SEP> 5 <tb> <SEP> R <tb> <SEP> No. <SEP> z <SEP> -r)(C <tb> <SEP> H2N502 <SEP> O2 <tb> <SEP> NH <tb> <SEP> M. <SEP> Z <SEP> N <SEP> CR2 <tb> <SEP> 52 <SEP> Cl <SEP> NHH2S <SEP> ¯¯ <SEP> --CH <tb> <SEP> H2N50 <SEP> 2?2 <tb> <SEP> 53 <SEP> NH <SEP> (m <tb> C1 <SEP> C1 <SEP> < H < <SEP> CH2- <SEP> 5 <SEP> - <SEP> | <tb> EMI72.1 EMI72.2 <tb> <SEP> 5 <tb> <SEP> R <tb> No. <SEP> R3 <SEP> N <SEP> - <SEP> Ail <tb> <SEP> -N <SEP> - <SEP> CR2' <tb> <SEP> H2N502 <SEP> W <SEP> 2- <SEP> NH-(CH2)4-C0---NH-(CH2) <SEP> 4 <tb> <SEP> 54 <tb> <SEP> Cl <tb> <SEP> H <SEP> CI <SEP> 0 <SEP> -WH-(CH2)4 <tb> <SEP> 55 <tb> <SEP> 56 <SEP> H2 <SEP> <SEP> 2 <SEP> /CH2 <SEP> - <SEP> NH <SEP> (CH2)4 <SEP> A <tb> <SEP> -N-CH <tb> H <SEP> NSO <tb> 57 <SEP> 2{jO <SEP> · <tb> <SEP> CI <SEP> i <SEP> ss <SEP> H2 <SEP> CH2 <SEP> -N-CH EMI73.1 <tb> <SEP> No. <SEP> R3 <tb> <SEP> H2NS02 <SEP> C <tb> <SEP> C <tb> <SEP> II <tb> <SEP> 58 <SEP> }%J)$iN)(CH2) <SEP> 4 <tb> <SEP> CI <SEP> H <SEP> CH <tb> <SEP> H2NS02 <SEP> o <tb> <SEP> 59 <tb> <SEP> 0 <tb> \N--( <SEP> I <SEP> N-(CH2)4 <tb> <SEP> OH <tb> <SEP> 60 <SEP> 3 <SEP> t <SEP> (CH <SEP> ) <tb> <SEP> /f <tb> <SEP> H,NSO, <SEP> C1E <tb> <SEP> 61 <SEP> O <SEP> - <SEP> N <SEP> - <SEP> CH <SEP> 4 <tb> EMI74.1 <tb> 5 <tb> No. <SEP> (K <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> OH <tb> <SEP> Cl <tb> <SEP> 62 <SEP> N <SEP> - <SEP> (CH2)4 <SEP> - <SEP> (cm2) <SEP> A <tb> <SEP> C <tb> <SEP> 63 <SEP> %iN-(CH2)4 <tb> <SEP> H2N <SEP> SO2 <SEP> 0 <tb> <SEP> -N--CR <tb> <SEP> LL <SEP> 0 <tb> <SEP> 64 <SEP> -NH- <SEP> (CH2) <SEP> p <tb> <SEP> CF3 <SEP> N <SEP> CH <tb> <SEP> H <SEP> NSO <SEP> 0 <tb> <SEP> 22 <SEP> II <tb> <SEP> 65 <SEP> \N- <SEP> (CH,) <SEP> 4 <SEP> C\ <tb> <SEP> 3 <SEP> -N-CR'- <tb> <SEP> H2NSO2 <tb> <SEP> 66 <SEP> t <SEP> O-NH-(CH2)4 <tb> <SEP> Cl <SEP> OH <SEP> CR EMI75.1 <tb> <SEP> 5 <tb> <SEP> R <tb> <SEP> No. <SEP> R <SEP> N <SEP> - <SEP> R3 <tb> <SEP> 2 <tb> <SEP> 67 <SEP> H2NS( <SEP> S <SEP> CO <SEP> - <SEP> NH- <SEP> 4 <SEP> [· <tb> <SEP> Cl <SEP> C1 <SEP> - <SEP> N- <SEP> CH <tb> <SEP> H <SEP> NSO <tb> <SEP> 2S02-Nr-(CH2)4 <tb> <SEP> 68 <SEP> Cl <SEP> 2 <SEP> K <tb> <SEP> Cl <SEP> CH <tb> <SEP> H2NSO2 <SEP> CH <SEP> 4 <SEP> n <tb> 69 <SEP> -- <SEP> ¸i/2 <SEP> K <tb> <SEP> Cl <SEP> --NN <tb> <SEP> H <SEP> NSO <tb> <SEP> 2X·H <tb> <SEP> 70 <tb> <SEP> C1 <SEP> A <SEP> CH---SS-- <SEP> CH2- <SEP> N----CCH EMI76.1 <tb> <SEP> R5 <tb> No. <SEP> R3 <SEP> N < <SEP> 7% <tb> <SEP> 2 <tb> <SEP> H2NS020CII <tb> 71 <SEP> ----CffE <tb> <SEP> Cl <SEP> H <SEP> -N-CE- <tb> <SEP> H2NS02 <SEP> 2 <tb> <SEP> 72 <SEP> $1:5CH2) <SEP> 4 <tb> <SEP> Cl <SEP> -N--CE- <tb> <SEP> I <tb> .(CH, <SEP> I <SEP> N,-(CH2)4 <tb> <SEP> OH <tb> <SEP> 73 <SEP> / <SEP> \- <SEP> rm <tb> <SEP> H <tb> <SEP> H2N502 <tb> <SEP> Cl <tb> <SEP> 1 <SEP> WN(CH2 <SEP> ) <SEP> -7tH <tb> <SEP> H2N502 <SEP> 0 <tb> EMI77.1 <tb> No. <SEP> R3 <SEP> R5 <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> 2 <tb> <SEP> OH <tb> <SEP> Cl <tb> <SEP> 75 <SEP> X <SEP> CH2)4 <SEP> | <SEP> n <SEP> rm <tb> <SEP> 2NS2 <SEP> 0 <SEP> H <tb> <SEP> 76 <SEP> ;¸iN-(CH2) <SEP> 4 <tb> <SEP> E,NSOZ <SEP> O <SEP> CH- <tb> <SEP> 77 <SEP> Li <tb> <SEP> H <tb> <SEP> H2NSO2 <tb> <SEP> 78 <SEP> $JN(CH2) <SEP> 4 <SEP> '· <tb> <SEP> Cl <SEP> NHCH <SEP> -N- <SEP> CH <tb> <SEP> 3 <tb> <SEP> H2N502 <tb> <SEP> 79-C--iHH- <SEP> (CH, <SEP> ) <SEP> 4 <tb> <SEP> Cl <SEP> OH <SEP> CH EMI78.1 <tb> <SEP> No. <SEP> R3 <SEP> fy <tb> <SEP> -N- <SEP> CR2 <tb> <SEP> .¯ <SEP> . <tb> <SEP> 80 <SEP> H2N <SEP> X <SEP> z <SEP> CON <SEP> ¸! <SEP> cm <SEP> 2 <tb> <SEP> Cl <tb> <SEP> - <SEP> N---CH <tb> <SEP> . <SEP> .¯ <SEP> ¯ <tb> <SEP> S <SEP> (CH2) <SEP> q- <SEP> 5 <tb> <SEP> 81 <SEP> cm <tb> <SEP> Cl <tb> <SEP> -N-CH <tb> <SEP> H2NSO <SEP> 2CH-NH-(CH <tb> <SEP> 24 <tb> <SEP> S <SEP> S <tb> <SEP> 82 <SEP> H2NS <SEP> K <tb> <SEP> CI <tb> <SEP> -N-CH <tb> <SEP> 83 <SEP> '7 <tb> 83 <SEP> ¸11NH <SEP> S <SEP> 5 <tb> <SEP> ClH2-S-CI12 <tb> <SEP> m <tb> EMI79.1 <tb> <SEP> R5 <tb> <SEP> No. <SEP> R3 <tb> <SEP> -N <SEP> - <SEP> R <SEP> <tb> <SEP> 2 <tb> <SEP> H2NS020 <tb> <SEP> 7 <tb> 84 <SEP> < <SEP> ï <SEP> ·-(CH2) <SEP> S <tb> <SEP> Cl <SEP> H <tb> <SEP> . <tb> <SEP> H <SEP> 2NS <SEP> 02 <SEP> 2 <tb> <SEP> 85 <SEP> Cl <SEP> N <SEP> -(CH2)4 <SEP> S <SEP> S <tb> <SEP> ci1 <tb> <SEP> 0 <tb> <SEP> 86 <SEP> (CH2)4 <SEP> m <tb> <SEP> 86)2/ <tb> <SEP> 86 <tb> <SEP> H2N502 <SEP> -N---CH <tb> <SEP> C1 <tb> <SEP> C1 <SEP> O <tb> <SEP> 87 <SEP> \I(/N <SEP> (CH2)4 <SEP> s <SEP> S <tb> <SEP> H2NS <SEP> 2 <SEP> - <SEP> N <SEP> --CH EMI80.1 <SEP> T <tb> No. <SEP> R3 <SEP> R5 <tb> <SEP> &num;CR <tb> <SEP> 2 <tb> <SEP> OH <tb> <SEP> Cl <SEP> 17 <tb> <SEP> 88 <SEP> JN---(CR2) <SEP> ss <SEP> S <SEP> S <tb> <SEP> H2NSO2 <SEP> O <SEP> - <SEP> N <SEP> <tb> <SEP> Cl <SEP> sim <tb> <SEP> 89 <SEP> -(CH7) <SEP> S\ys <tb> <SEP> H2NS02 <SEP> lo <SEP> . <SEP> --h' <SEP> CR <tb> <SEP> H2N502?1 <SEP> '7 <tb> <SEP> 90 <SEP> -NH-(CH2) <SEP> 4 <SEP> X <SEP> 5 <tb> <SEP> CF3 <SEP> -N-CR <tb> <SEP> RN <SEP> O2 <SEP> m <tb> <SEP> S <SEP> a <tb> <SEP> 91 <SEP> 1 <SEP> (CR2)4 <tb> <SEP> N <tb> <SEP> C1 <SEP> HCR3 <SEP> -N--CR <tb> <SEP> CI <SEP> II <tb> <SEP> m <tb> <SEP> C---NH-(CE2)4 <tb> 92 <SEP> N <tb> <SEP> X <SEP> t <SEP> <SEP> ( <SEP> OR <tb> EMI81.1 EMI81.2 <tb> <SEP> 5 <tb> <SEP> No. <SEP> R3 <SEP> -rf: <tb> <SEP> 2 <tb> <SEP> H <SEP> NS <SEP> CO---NH- <SEP> (CH2)4 <SEP> ) <SEP> <SEP> 93 <SEP> C1 <SEP> 24 <tb> <SEP> Cl <tb> <SEP> - <SEP> N-CH <tb> <SEP> H2NS102NH <SEP> (CR24 <tb> <SEP> 94 <tb> <SEP> C1 <tb> <SEP> NH <SEP> 0 <tb> 95 <SEP> {iO·H <SEP> (¸ <tb> <SEP> Cl <SEP> NH,H2S <SEP> CH2 <SEP> - <SEP> -N-CH EMI82.1 <tb> <SEP> 5 <tb> No. <SEP> R3 <SEP> ThCR2 <tb> <SEP> H2NSO2 <SEP> CC--NH- <SEP> (CR2)4 <tb> <SEP> 96k <tb> Cl <SEP> -N-CR <tb> <SEP> N---- <SEP> CH- <tb> 97 <SEP> H2Ni <SEP> W <SEP> ¯n <tb> <SEP> H <tb> <SEP> 98 <SEP> 2 <tb> <SEP> 98 <SEP> NH <tb> <SEP> Cl <SEP> NH <SEP> --s--cH2 <SEP> - <SEP> ¯¯¯¯¯¯¯H <tb> <SEP> H <SEP> NSO <SEP> CC--NH- <SEP> (CR <SEP> S <SEP> 8 <tb> <SEP> 99 <SEP> 24 <SEP> 24 <tb> <SEP> Cl <SEP> k$ <tb> <SEP> -N---CR EMI83.1 <tb> <SEP> No. <SEP> R3 <SEP> f;;?,R <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> H2NSO2 <SEP> So <SEP> ---nrH- <SEP> (CR <tb> 100 <SEP> ;j2 <SEP> 24 <tb> <SEP> N <SEP> - <SEP> CH <tb> <SEP> H2 <SEP> I <SEP> 1 <tb> <SEP> 101 <SEP> $,1NH <SEP> Ss <tb> Cl <SEP> NH <SEP> H' <SEP> 2-S <SEP> CH2 <SEP> 8 <SEP> I <tb> EMI84.1 EMI84.2 <tb> <SEP> Z <tb> <SEP> Z <tb> <SEP> BZN <SEP> CO-NH <tb> 102 <tb> <SEP> CI <SEP> ---N- <SEP> H <tb> <SEP> z <tb> <SEP> HZN <SEP> 0-NH <SEP> 2 <tb> 103 <tb> <SEP> Cl <SEP> - <SEP> H, <tb> <SEP> F- <SEP> CR2-NR- <SEP> z <tb> 104 <tb> <SEP> --- <SEP> N----CCH- <tb> 105 <SEP> R2NS{1ONR <SEP> · <tb> <SEP> C1 <SEP> BCl <SEP> A <SEP> H2 <SEP> | <tb> EMI85.1 <tb> <SEP> No. <SEP> Z <SEP> Z <tb> <SEP> 2 <tb> <SEP> H2NSO <SEP> 0 <tb> <SEP> 106 <SEP> . <SEP> 7 <tb> Cl <SEP> H <SEP> - <SEP> CH <tb> <SEP> H2NS <SEP> 0202 <SEP> z <tb> <SEP> z <tb> <SEP> 107 <tb> <SEP> Cl <tb> <SEP> ocs <tb> <SEP> 0 <tb> <SEP> N- <SEP> z <tb> <SEP> ,OH <tb> <SEP> 108 <tb> <SEP> H2N502 <SEP> -N---CH <tb> <SEP> C1 <tb> 109 <SEP> Cl <SEP> 0N- <SEP> · <tb> <SEP> H2NS00 <SEP> -N--CR <tb> <SEP> 2 <tb> EMI86.1 <tb> No. <SEP> Z <tb> -N <SEP> - <SEP> CR2 <tb> <SEP> OR <tb> <SEP> Cl <tb> 110 <SEP> H2 <SEP> OH <tb> 2NO2No <tb> <SEP> H <SEP> - <SEP> N---CH- <tb> <SEP> Cl <tb> <SEP> Z <SEP> N,I0N, <SEP> · <tb> <SEP> -N---CH <tb> <SEP> H <SEP> Z <tb> <SEP> 112 <SEP> C---NH- <tb> <SEP> CF3 <SEP> -N-CH <tb> <SEP> H2NS02 <SEP> 1t <SEP> Z <tb> <SEP> 113 <tb> <SEP> ClR <SEP> CR3 <SEP> -N- <SEP> CR <tb> <SEP> H, <SEP> N <SEP> z <tb> 114 <SEP> --NHH- <tb> <SEP> Cl <SEP> OR <tb> EMI87.1 <tb> <SEP> 1 <tb> No. <SEP> -N <SEP> z <tb> <SEP> -N <SEP> <tb> 115 <SEP> R2NSO2WI <SEP> CO---NH- <SEP> ss <tb> <SEP> Cl <SEP> -N-CH <tb> <SEP> H2NSO <SEP> ,N <tb> <SEP> 116 <tb> <SEP> C1 <tb> <SEP> HM <SEP> Z <tb> <SEP> 2 <SEP> /CH <SEP> 2-NR- <SEP> z <tb> <SEP> 117 <tb> <SEP> C1 <SEP> IT <tb> <SEP> H <tb> 118 <SEP> Ii <SEP> 5 <SEP> 0NH <tb> <SEP> Cl <SEP> NH012S <tb> EMI88.1 <tb> <SEP> z <tb> <SEP> No, <SEP> Z <SEP> 4 <tb> <SEP> 0 <tb> <SEP> 119 <SEP> ¸ <tb> <SEP> C1 <SEP> H <SEP> ¯¯¯¯¯¯¯¯¯¯ <tb> <SEP> H2NSO2 <SEP> 2 <tb> <SEP> 120 <tb> <SEP> o <tb> <SEP> I <tb> OH <SEP> toy <SEP> Z <tb> <SEP> 121 <SEP> SO2 <tb> <SEP> Cl <tb> 122 <SEP> n <tb> EMI89.1 <tb> <SEP> 7 <tb> No. <SEP> z <tb> <SEP> -N <SEP> - <SEP> CRIZ' <tb> <SEP> I <tb> <SEP> OH <tb> <SEP> 123 <SEP> Cm$1 <SEP> N- <SEP> WI <tb> <SEP> H2N <SEP> 020 <SEP> - <SEP> CH-- <tb> <SEP> Cl <SEP> z <tb> <SEP> 124 <SEP> N- <SEP> · <tb> <SEP> H2NSO <SEP> 2',io' <SEP> H <tb> <SEP> H2NS02 <SEP> o <tb> <SEP> 125 <SEP> %1C11-NR <SEP> z <tb> <SEP> CF3 <SEP> NCH <tb> <SEP> H2NSO2 <tb> <SEP> NN <tb> <SEP> 126 <SEP> 'NHA\CH <tb> <SEP> C1 <tb> <SEP> H2NSO20 <tb> <SEP> 127 <SEP> )t <SEP> NH <SEP> - <SEP> A <tb> <SEP> Cl <SEP> J <SEP> OH <tb> EMI90.1 <tb> <SEP> f <tb> <SEP> I <SEP> /I <tb> <SEP> -N <SEP> - <SEP> CR No. <SEP> z <tb> <SEP> H2N502 <SEP> CC-NH- <SEP> y <tb> <SEP> 141 <SEP> Cl¸I <tb> <SEP> z <tb> <SEP> I <SEP> IT <tb> <SEP> 1422-H-Q <tb> <SEP> z <tb> <SEP> H2NS\02 <SEP> CH, <SEP> LH <tb> <SEP> 143 <SEP> ¸' <tb> <SEP> Cl <SEP> --N <tb> <SEP> . <tb> <SEP> NR <tb> <SEP> 144 <SEP> Cl1 <SEP> NH <SEP> H <SEP> -S- <SEP> -N <tb> <SEP> 2 <tb> EMI91.1 <tb> <SEP> I <tb> <SEP> No. <tb> <SEP> z <tb> <SEP> H2NSO <SEP> 0 <tb> <SEP> 2 <tb> <SEP> 145 <SEP> /C, <SEP> 0 <tb> <SEP> NN <SEP> -N <tb> <SEP> Cl <SEP> H <tb> <SEP> N <tb> <SEP> z <tb> <SEP> 2 <SEP> 2 <tb> <SEP> 14' <tb> <SEP> C,,R <SEP> -N <tb> <SEP> COS <tb> <SEP> -1( <tb> <SEP> OR <tb> 147 <SEP> N <SEP> I <tb> <SEP> 147 <SEP> -N <tb> <SEP> Nc <tb> <SEP> ., <tb> <SEP> 148 <SEP> C¸)ON <SEP> -N <tb> <SEP> N <tb> <SEP> H2N502 <SEP> 0 <tb> EMI92.1 <tb> No. <tb> <SEP> 2 <tb> <SEP> OH <SEP> z <tb> <SEP> Cl <tb> <SEP> 149 <SEP> - <SEP> N <tb> <SEP> H2N020 <SEP> -N <tb> <SEP> z <tb> <SEP> X <SEP> mN <SEP> 4 <tb> <SEP> O <SEP> \C <tb> <SEP> Z <tb> NH <tb> <SEP> 151 <SEP> CF3N <tb> <SEP> R2N <SEP> 02 <tb> <SEP> 152 <SEP> N <tb> <SEP> N <SEP> 'I <SEP> N <SEP> <tb> <SEP> Cl <SEP> H <SEP> C113 <SEP> -N <tb> <SEP> I,CH3 <SEP> 0 <SEP> A <tb> <SEP> 153 <SEP> eNH <SEP> C <SEP> j <tb> <SEP> Cl <SEP> OH <SEP> -N <tb> EMI93.1 EMI93.2 <tb> <SEP> Na, <SEP> Z <SEP> Z <tb> No. <SEP> z <tb> <SEP> ¯. <tb> <SEP> z <SEP> CO-NH <tb> <SEP> 154 <tb> <SEP> Cl <SEP> - <SEP> N-CR <tb> <SEP> H <SEP> NSO <tb> <SEP> z <tb> <SEP> 155 <SEP> H2N <SEP> - <SEP> H <tb> <SEP> z <tb> <SEP> H2NSO2 <SEP> CC--NH <tb> <SEP> 156. <tb> <SEP> Cl <SEP> -N <tb> <SEP> C1 <SEP> 02-NH <tb> <SEP> 157 <tb> <SEP> H? <tb> <SEP> Cl <SEP> C <tb> EMI94.1 EMI94.2 <tb> <SEP> 5 <tb> 'No. <SEP> R3 <SEP> -J%j <tb> <SEP> 158 <SEP> \ <SEP> 2R2N502)1 <SEP> C0-NH-(CH2) <SEP> 4 <SEP> · <tb> <SEP> Cl <SEP> CH <tb> <SEP> H2N502 <SEP> 02-NH-(CH2)4 <tb> <SEP> 159)1 <tb> <SEP> N <tb> <SEP> I <tb> <SEP> 160 <SEP> E <SEP> eNH(CH2 <SEP> ) <SEP> 2 <tb> <SEP> CF3 <SEP> N F <tb> <SEP> 3 <tb> <SEP> \(CH2)4 <SEP> 161 <SEP> A <SEP> i <SEP> j <tb> <SEP> CI <SEP> OH <SEP> CR EMI95.1 <tb> <SEP> 5 <tb> <SEP> t <SEP> R5 <tb> No. <SEP> R3 <tb> <SEP> R, <tb> 162 <SEP> 22 <tb> <SEP> Cl <tb> <SEP> ---- <SEP> cH <tb> <SEP> H <SEP> O <tb> <SEP> HZN <SEP> /SOa(cH,) <SEP> 4 <tb> <SEP> 163 <SEP> · <tb> <SEP> C1 <SEP> . <SEP> ---hLL- <SEP> CH <tb> <SEP> H2NS <tb> <SEP> 164 <tb> <SEP> CF3 <SEP> ---NNNN----Cf3 <SEP> CF3 <tb> <SEP> LN <tb> <SEP> O-NH-(CH2) <SEP> 4 <tb> <SEP> 165 <tb> <SEP> -N-CR <tb> <SEP> . <tb> 166 <SEP> q <SEP> ," <tb> EMI96.1 <tb> <SEP> 5 <tb> No. <SEP> R3 <SEP> 2 <tb> <SEP> /L <SEP> S <SEP> Fm <tb> 167 <tb> <SEP> Cl <SEP> -N---CH <tb> <SEP> i <SEP> 0 <SEP> Fm <tb> 168 <SEP> \ <SEP> NH-(CH2)4- <SEP> L <tb> <SEP> CF3 <SEP> -N----CH <tb> <SEP> ,1 <SEP> Fm <tb> <SEP> (cm,) <SEP> 2 <SEP> 8 <tb> 169 <SEP> < <SEP> NH <SEP> (CH2)4- <SEP> S <SEP> M <SEP> S <tb> <SEP> C1 <SEP> OH <SEP> NCH <tb> EMI97.1 EMI97.2 <tb> <SEP> 5 <tb> No. <SEP> R3 <SEP> !%air <tb> <SEP> X <SEP> - <SEP> > <SEP> <tb> <SEP> H2NSO2 <SEP> E2E <SEP> CO--NH-(CH2) <SEP> 4 <tb> 170 <tb> Cl <tb> <SEP> CH <tb> <SEP> H2Nso2- <SEP> -NH---(CH2) <SEP> 4 <tb> 171 <tb> <SEP> Cl <SEP> -H <tb> <SEP> H, <SEP> NSO <tb> <SEP> 2 <SEP> 4 <tb> <SEP> 172 <tb> <SEP> CP3 <tb> <SEP> H2-N02 <tb> <SEP> 173 <SEP> ; <SEP> O---NH-(CH2)4- <SEP> (¸ <tb> <SEP> CR EMI98.1 <tb> <SEP> 5 <tb> No. <SEP> R <SEP> Th <tb> <SEP> ¯¯¯ <SEP> , <tb> 174 <tb> <SEP> C1 <SEP> g <SEP> CH <tb> <SEP> sr\t <SEP> (CH,) <tb> <SEP> 2 <SEP> 2 <SEP> 0 <tb> 175 <SEP> n <tb> <SEP> Cl <SEP> CE <tb> <SEP> H2NSu02 <SEP> o <tb> <SEP> o <SEP> I <tb> 176 <SEP> )fNH(CH2 <SEP> 1 <SEP> n <tb> <SEP> CF3 <SEP> H <tb> <SEP> E2NS02 <tb> 177 <SEP> 1 <SEP> tNH(CH2) <SEP> 4' <SEP> ! <tb> <SEP> I <SEP> L24: <tb> 177 <tb> <SEP> Cl <SEP> H <SEP> CR <tb> <SEP> f:th' <SEP> CD--NH- <SEP> I <SEP> I <tb> D8 <SEP> H <SEP> NY <SEP> WCONE <SEP> (CH2) <SEP> 4 <SEP> 1 <SEP> W <SEP> X <tb> <SEP> CH EMI99.1 <tb> <SEP> S <tb> No. <SEP> R3 <SEP> fwRR <tb> <SEP> 2 <tb> <SEP> H2.'SO <SEP> So <SEP> -NH-(CH2)4-, <SEP> Fm <tb> 179 <SEP> | <SEP> i21 <SEP> 9 <tb> <SEP> C1 <SEP> - <SEP> N----CH <tb> <SEP> R2N502 <SEP> 0 <SEP> Fm <tb> 180 <SEP> H-(CH2)4-' <SEP> S <tb> <SEP> H2NS02 <SEP> 71 <tb> 181 <SEP> IE <SEP> (CH2)4 <tb> <SEP> Cl <SEP> OH <tb> EMI100.1 EMI100.2 <tb> <SEP> 5 <tb> <SEP> No. <SEP> R3R5 <tb> <SEP> 2 <tb> <SEP> ?- <SEP> CO---NH-(CH2) <SEP> 4' <tb> <SEP> 182 <SEP> j <SEP> Cl1 <tb> <SEP> CR <tb> <SEP> H2NSO2 <SEP> 02-NH-(CR2) <SEP> 4 <tb> <SEP> C1 <SEP> N-- <SEP> R- <tb> <SEP> C1 <SEP> H <tb> <SEP> (CR2) <SEP> | <tb> <SEP> 184 <tb> <SEP> CF3 <tb> <SEP> H2NS02 <tb> <SEP> 185 <SEP> )t <SEP> \oH <SEP> I <SEP> 1 <SEP> C <SEP> · <tb> Cl <SEP> OR <SEP> I <SEP> CH <SEP> -N-CR- <SEP> I <tb> EMI101.1 <tb> <SEP> 5 <tb> No. <SEP> R3 <SEP> ?fR2R <tb> 186 <SEP> H2NS <SEP> t <SEP> CO <SEP> - <SEP> NH- <SEP> (CH2)4 <SEP> -, <tb> <SEP> Cl <SEP> CR <tb> <SEP> . <tb> 187 <SEP> Cl <SEP> ¯¯ <SEP> Fm <tb> <SEP> cl <SEP> "f <tb> <SEP> H2N <tb> 188 <SEP> ji <SEP> -NH-(CH2)4 <tb> <SEP> H <tb> <SEP> CF3 <tb> <SEP> HN <tb> <SEP> 0-NR-(CR2)4 <tb> 189 <SEP> I <SEP> Km <tb> <SEP> ci <SEP> c <SEP> OH <tb> <SEP> H2NSO2 <SEP> CC-NH-(CH2) <SEP> 4 <SEP> ml <tb> 190 <SEP> HiN5 <SEP> WCONH(CH2) <SEP> 4 <SEP> 58 <SEP> f <tb> <SEP> Cl <tb> EMI102.1 <SEP> 5 <tb> No. <SEP> R3 <tb> <SEP> 2 <tb> <SEP> R3 <SEP> -N <SEP> < <SEP> R2- <SEP> 1 <tb> <SEP> H2 <SEP> 02-NH-(CH2)4 <SEP> 71 <tb> <SEP> S <tb> 191 <tb> <SEP> Cl <SEP> -N-CH <tb> <SEP> H2N502 <tb> <SEP> 2 <SEP> 4 <SEP> {i" <tb> 192 <tb> <SEP> CF3 <SEP> NCH <tb> <SEP> R2NSO2 <SEP> 2 <tb> 193 <SEP> NH-(CH2)4- <SEP> 4 <SEP> 5 <tb> <SEP> 1%"' <tb> <SEP> Cl <SEP> OH <SEP> N- <SEP> CH <tb> EMI103.1 EMI103.2 <tb> <SEP> 5 <tb> <SEP> 'No'. <SEP> R3 <tb> <SEP> -N <SEP> - <SEP> CR2 <tb> <SEP> H2N502 <SEP> CNH-(CH2) <SEP> 4 <tb> <SEP> 194 <SEP> c1NI <tb> 194 <SEP> C1 <SEP> -- <SEP> N----CCH- <tb> <SEP> 195 <SEP> H2S,1O2NH( <SEP> CH2) <SEP> <tb> <SEP> Cl <tb> <SEP> H2NSO2? <tb> <SEP> 196 <SEP> NH-(CH2) <SEP> <tb> <SEP> CF3 <SEP> N <SEP> CH <tb> <SEP> H <SEP> 'NSO <tb> <SEP> 197 <SEP> 2)1NR-(CR2) <SEP> 4 <tb> <SEP> CI <SEP> OH <SEP> CR EMI104.1 <tb> <SEP> 5 <tb> <SEP> No. <SEP> R3 <tb> <SEP> 1R, <SEP> I <tb> <SEP> 198 <SEP> H2NS$OtCON-I <SEP> (CH2) <SEP> 4! <SEP> LI <tb> C,l <SEP> c <SEP> - <SEP> CR <tb> R2N502 <SEP> 502-NH- <SEP> 4 <tb> 199 <SEP> ¸i <SEP> ¯LI <tb> <SEP> Cl <SEP> CR <tb> <SEP> H2N02 <SEP> 0 <tb> <SEP> 200 <SEP> I <SEP> 1-NH-(CR2)4- <SEP> ,j <tb> <SEP> CF3 <SEP> H <tb> <SEP> R2N502 <tb> <SEP> 201 <SEP> ¸ <SEP> 1 <SEP> l-(CH2)4- <SEP> LI <tb> Cl <SEP> H <SEP> CR <tb> <SEP> 202 <SEP> 'H2N502 <SEP> 1CNH-(CH2) <SEP> 4 <SEP> si7i <tb> <SEP> Cl <SEP> . <tb> <SEP> CH EMI105.1 <tb> <SEP> H2NS02 <SEP> So <SEP> -NH-(CR2)4- <SEP> Fm <tb> <SEP> o. <SEP> R <SEP> N < <tb> <SEP> 2 <SEP> o <SEP> -NH <tb> <SEP> 203, <tb> <SEP> C1 <SEP> SCH <tb> <SEP> R2NSO2 <tb> <SEP> 204 <SEP> -NH-(CH2) <SEP> 4 <tb> <SEP> CF3, <SEP> Nt <SEP> CII <tb> . <tb> <SEP> H <SEP> .N <tb> <SEP> 205 <SEP> CNH-(CH2)4 <tb> C1 <SEP> OH <SEP> N <SEP> CH EMI106.1 EMI106.2 <tb> <SEP> No. <SEP> Z <SEP> t <SEP> Z <tb> <SEP> -N <SEP> - <SEP> CRZI <tb> . <SEP> . <tb> <SEP> H2NS02 <SEP> CNH- <SEP> I <SEP> z <tb> <SEP> 206 <tb> <SEP> Cl <tb> <SEP> ---N- <SEP> H <tb> <SEP> H2NSO <SEP> 0-NH <tb> <SEP> 207 <tb> <SEP> Cl <SEP> -N <SEP> H <tb> <SEP> 208 <SEP> H2NSO;1?1 <SEP> · <tb> <SEP> CF3 <SEP> -N- <SEP> C}H <tb> <SEP> H2N502 <SEP> z <tb> 209H- <tb> <SEP> Cl <SEP> OH <tb> <SEP> -N- <SEP> CH EMI107.1 <tb> No. <SEP> - <SEP> < <SEP> 2 <tb> <SEP> ¯ <tb> 210 <SEP> R2NS1CNH <SEP> | <tb> <SEP> . <tb> <SEP> H2NS02 <SEP> 02-NH <tb> <SEP> 211 <tb> <SEP> Cl <SEP> -N---- <SEP> CR <tb> <SEP> H2NSO2 <tb> <SEP> 212 <SEP> h <SEP> sA, <tb> <SEP> CF3 <SEP> -N----CH <SEP> CF <SEP> 3 <SEP> wCH <tb> <SEP> H <SEP> NSO <tb> <SEP> )I <tb> <SEP> 213 <SEP> > <SEP> N1 <tb> <SEP> C1 <SEP> OR <tb> EMI108.1 EMI108.2 <tb> No. <SEP> N <SEP> - <SEP> CR2 <tb> <SEP> z <tb> <SEP> L <SEP> CC---NH <tb> <SEP> 214 <tb> <SEP> Cl <SEP> H <SEP> N----C <tb> <SEP> z <tb> <SEP> 215 <SEP> H2NSa3f <SEP> 2-NR <tb> <SEP> 215 <tb> <SEP> H2NSO <SEP> Z <tb> <SEP> 216 <tb> <SEP> CF3 <SEP> -N-CR <tb> <SEP> z <tb> <SEP> H2N502?t <tb> <SEP> 217 <SEP> $1NH <tb> <SEP> Cl <SEP> OH <tb> <SEP> -N----CH EMI109.1 <SEP> No. <SEP> Z <SEP> Z <tb> <SEP> No. <SEP> t <SEP> Z <tb> <SEP> W,N <SEP> ,C--NH--- <SEP> Z <tb> <SEP> 218 <tb> <SEP> Cl <tb> <SEP> H <SEP> - <tb> <SEP> 219 <SEP> 2 <SEP> W <tb> <SEP> 219 <tb> H2 <SEP> NSO, <tb> <SEP> 2 <SEP> \L <SEP> O <tb> <SEP> 220 <tb> <SEP> CF3 <tb> <SEP> H2NSO2 <tb> <SEP> 221 <SEP> XNH <SEP> ss <tb> <SEP> Cl <SEP> j <SEP> OH <tb> EMI110.1 EMI110.2 <tb> <SEP> Z <tb> <SEP> Z <tb> <SEP> H2NSO2 <SEP> CO--NH <tb> <SEP> 222 <tb> <SEP> Cl <SEP> --- <SEP> N---CH <tb> <SEP> N-- <SEP> 0 <SEP> 2-NH <tb> <SEP> 223 <tb> <SEP> CI <tb> <SEP> 224 <SEP> > <SEP> NH <SEP> - <SEP> A <tb> CF3 <SEP> -N---- <SEP> CR <tb> <SEP> H2NSO2 <SEP> z <tb> 225 <SEP> ·;11NR <tb> <SEP> Cl <SEP> OR <tb> <SEP> -N-CH-- EMI111.1 <tb> No. <SEP> Z <tb> <SEP> HN <SEP> -NH--- <SEP> Z <tb> <SEP> C1 <SEP> ' <SEP> , <SEP> N--- <SEP> C'' <tb> <SEP> f3 <SEP> ,N <tb> <SEP> 227 <tb> <SEP> Cl <tb> <SEP> No <SEP> cE <tb> <SEP> H2NS02 <SEP> o <tb> <SEP> 2 <tb> <SEP> 228 <SEP> N <tb> <SEP> CF3 <SEP> ---aT---- <SEP> M <SEP> CE <tb> <SEP> H2NSO2 <tb> EMI112.1 EMI112.2 <tb> <SEP> No. <SEP> /R <tb> No. <SEP> Z <SEP> A <tb> <SEP> Z <tb> <SEP> H2NS02 <SEP> CO--NH <tb> <SEP> 230 <SEP> ¸' <tb> <SEP> 230 <SEP> C1 <tb> <SEP> Z <tb> <SEP> z <tb> <SEP> H2N502 <SEP> SO <SEP> 2-NH <tb> <SEP> 231 <tb> <SEP> Ar+ <tb> <SEP> H2NSO <tb> <SEP> 232 <tb> <SEP> 233 <SEP> ·;11NH <SEP> I <tb> <SEP> C1 <SEP> OR <tb> EMI113.1 v <SEP> Z <SEP> -N/tR2- <SEP> | <tb> <SEP> 2 <tb> <SEP> H2NS02 <SEP> CC---NH <tb> 234 <tb> <SEP> C1 <SEP> -N----CH <tb> <SEP> H <tb> <SEP> 2-N <SEP> H N CH <tb> 235 <tb> <SEP> C1 <tb> NH- <tb> 236 <tb> <SEP> CF3 <tb> <SEP> 3 <tb> <SEP> 1-NH <tb> 237 <tb> <SEP> Cl <SEP> OH <SEP> H The following examples of formulation describe in detail compositions that are illustrative of the present invention. It will be apparent to those skilled in the art that many modifications, both of materials and methods, may be practiced without departing from the purpose and intent of this disclosure. In the formulation - examples the active ingredients are as follows: Active ingredient A: [1(S)-ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro3-sulfamoyl)benzenesulfonyl]-(S)-lysyl-cis,syn-octahydro- 1H-indale-2(S)-carboxylic acid. Active ingredient B: lANL[l(R)-carboxy-2-[S-((3-(6-chloro-3,4-dihydro-7-sulf- amoyl-1,2,4-benzothiadiazinyl-1,1-dioxide)methyl))thio] ethyl]]-(S)-alanyl}-cis, syn-octahydro-1H-indole-2(S)carboxylic acid. Active ingredient C: 7-(4-chloro-3-sulfamoylbenzamido)-2-C"-[1(S)-carboethoxy- 3-phenylpropyll-(S) -alany:J -1,2,3,4-tetrahydroisoquinoline- 3(S)-carboxylic acid. Formulation 1 Capsule Amount (mug) Active ingredient A 250.0 =- 125.0 Lactose 173.0 8 6. 5 Corn Starch 75.0 37.5 Magnesium Stearate 2.0 1.0 500.0 250.0 Blend the active ingredient, lactose and corn starch until uniform; then blend the magnesium stearate into the resulting powder.. Encapsulate the mixture into suitably sized two-piece hard gelatin capsules. Formulation 2 Tablet Amount (mg) Active ingredient A 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. o 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 disintegration. Formulation 3 Injectable Solution mg/ml Active ingredient A 5.00 Methyl p-hydroxybenzoate 0. 80 Propyl p-hydroxybenzoate 0.10 Disodium Edetate 0.10 Citric Acid Monohydrate 0.08 Dextrose 40.0 Water for injection qs. ad. 1.0 ml Dissolve the E°hydroxybenzoates in a portion of water for injection at 60-700C and cool the solution to 25-350C. Charge and dissolve all other excipients and the active ingredient. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers. Formulation 4 Capsule Amount (mg) Active ingredient B 250.0 125.0 Lactose 173.0 86.5 Corn Starch 75.0 37.5 Magnesium Stearate 2.0 1.0 500.0 250.0 Blend the active ingredient, lactose and corn starch until uniform; then blend the magnesium stearate into the resulting powder. Encapsulate the mixture into suitably sized two-piece hard gelatin capsules. Formulation 5 Tablet Amount (mug) Active ingredient B 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 1.0 500.0 250.0 Blend the active ingredient with the lactose until uniform. Blend the smaller quantity of corn starch with the water and add the resulting corn starch paste, then mix until a uniform wet mass is formed. Add the remaining corn starch to the remaining wet mass and mix until uniform granules are obtained. Screen the granules 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 disintegration. Formulation 6 Injectable Solution -- Active ingredient B 5.00 Methyl p-hydroxybenzoate 0.80 Propyl p-hydroxybenzoate 0.10 Di sodium Edetate 0.10 Citric Acid Monohydrate 0.08 Dextrose 40.0 Water for injection qs. ad. 1.0 ml Dissolve the p-hydroxybenzoates in a portion of water for injection at 60-70vC and cool the solution to 25-35'C. Charge and dissolve all other excipients and the active ingredient. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers. Formulation 7 Capsule Amount (mg) Active ingredient C 250.0 125.0 Lactose 173.0 86.5 'Corn Starch 75.0 37.5 Magnesium' stearate . '2.0 1.0 500.0 250.0 Blend the active ingredient, lactose and corn starch until uniform; then blend the magnesium stearate into the resulting powder. Encapsulate the mixture into suitably sized two-piece hard gelatin capsules. Formulation 8 Tablet Amount (mg) Active ingredient C 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 1.0 500.0 250.0 Blend the active ingredient with the lactose until uniform. Blend the smaller quantity of corn starch with the water and add the resulting corn starch paste, then mix until a uniform wet mass is formed. Add the remaining corn starch to the remaining wet mass and mix until uniform granules are obtained. Screen the granules 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 disintegration. Formulation 9 Injectable Solution mg/ml Active ingredient C 5.00 Methyl p-hydroxybenzoate 0.80 Propyl p-hydroxybenzoate 0.10 Disodium Edetate 0,10. Citric Acid Monohydrate 0.08 Dextrose 40.0 Water for injection qs. ad. 1.0 ml Dissolve the ±-hydroxybenzoates in a portion of water for injection at 60-700C and cool the solution to 25-35'C. Charge and dissolve all other excipients and the active ingredient. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers

Claims: We claim: 1) A compound of the formula EMI121.1 the pharmaceutically acceptable esters thereof and the pharmaceutically acceptable salts of the foregoing, wherein RÚ and Rê independently are hydrogen or lower alkyl; the group EMI121.2 one of the structures II to VIII EMI121.3 EMI122.1 (wherein B is a saturated or aromatic ring) or EMI122.2 one of R3, R4 and R5 is a group Z-(CH2)0-6 wherein Z has one of the following values Z to Z10: zl EMI123.1 Zê: EMI123.2 Z : EMI123.3 4 EMI123.4 5 EMI123.5 Z6: EMI124.1 Z7: EMI124.2 Z8: EMI124.3 9 EMI124.4 Z10: EMI125.1 wherein R is Cl or Cr3; R6 is hydrogen or halogen; is hydrogen, halogen, carboxy, hydroxy or amino; and R10 are independently hydrogen, lower alkyl or halo 9 lower alkyl and R can also be phenyl or phenyl lower alkyl; R11 is hydrogen or lower alkyl; R12 is hydrogen, lower alkyl or phenyl lower alkyl; ; whereby when R3 is the group Z-(CH2)-0-6-, then is ZÚ-(CH2)1-6-, Zê-(CH2)1-6-, Z -(CH2)1-6-, Z4-CH2-, Z6-(CH2)1-6-, Z6-(CH2)1-6-, Z7-(CH2)1-6-, Z8-(CH2)1-6-, Z9-(CH2)1-6-, or Z10-(CH2)1-6-, R4 is lower alkyl, benzyl, benzyloxy, benzylthio, phenoxy, or phenylthio, R5 is hydrogen; and the group EMI125.2 one of the structures II to VIII; and when R4 is the group Z-(CH2)-0-6-, then 1 2 3 Z4-(CH2)-0-6-, Z5-(CH2)-0-6-, Z6-(CH2)-0-6-, Z7-(CH2)-0-6-, Z8-(CH2)-0-6-, Z9-(CH2)-0-6-, or Z10-(CH2)-0-6- and 3 R3 is hydrogen, lower alkyl or amino lower alkyl and R5 is hydrogen; and the group EMI126.1 one of the structures II to VIII; and when R5 is the group Z-(CH2)-0-6-, then R5 is ZÚ, Zê, Z , Z4, Z5, Z6, Z7, Z8, Z9 or Z10, R3 is hydrogen, lower alkyl or amino lower alkyl and R4 is lower alkyl, benzyl, benzyloxy, benzylthio, phenoxy or phenylthio; and the group EMI126.2 one of the structures II to VII, preferably being in the form of the free di-carbonic acid or in the form of its aklyl ester, the alkyl group containing 1 to 6 carbon atoms, especially in the form of its monoester wherein the carboxy group attached to the group EMI126.3 in the free form, preferably all former compounds being the stereoisomer in which the absolute configurations at each of the three carbon atoms bonded to both a nitrogen and a carbonyl group corresponds most closely to the absolute configuration of L-aminoacids. 2) A compound accordung to claim 1, wherein R4 is a group Z-(CH2)-0-6- as defined in claim 1, wherein Z preferably is ZÚ, Zê, Z , Z5, Z7, Z8, Z9 or Z10; R4 preferably being ZÚ-(CH2)2 or 3-, Zê-(CH2)2 or Z -(CH2)2 or 3-, Z5-(CH2)2 or 3-, Z7-(CH2)2 or 3 Z8-(CH2)2 or 3-, Z9-(CH2)2 or 3-, or Z10-(CH2)2 or and wherein preferably the group EMI127.1 the group of formula II, IV (wherein B is a saturated ring) or VIII, preferably R5 being hydrogen. 3) X compound according to claim 1 or 2, wherein R1 and R2 are hydrogen, and/or when Z is of the formula IX, X or XI R6 is hydrogen and R7 is hydrogen or hydroxy, and/or when Z is of the formula XIII or XIV R9 and R10 are independently hydrogen or methyl, and/or R8 in the de finition of the moiety Z is chloro, and/or R3 is methyl. 4) A compound according to claim 1 or 2, wherein R1 and Rê are hydrogen, the group EMI128.1 the group of formula IV, wherein B is a satu rated ring and R is hydrogen, R4 is Z -(CR2)3- or Zê-(CH2)3-, wherein R is hydrogen, is hydrogen or hydroxy, and R8 is chloro; and R3 is methyl, preferably being 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoyl) benzenesulfonaminopentyl]-(S)-alanyl}-cis, syn octahydro-1H-indole-2(S)-carboxylic acid, 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoyl) benzamidopentyl]-(S)-alanyl}-cis, syn-octahydro-1H indole-2(S)-carboxylic acidr or 1-{N-[(1(S)-ethoxycarbonyl-5-(4-chloro-2-hydroxy 5-sulfamoyl) -benzamidopentyl) - (S)-alanyl}-cys ,nwsn- octahydro-1H-indole-2(S)-carboxylic acid, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-2-HYDROXY-5-SULFAMOYL PHENYL)CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN OCTAHYDRO-1H-INDOLE-2(S)-CARBOXYLIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-(N-METHYL SULFAMOYL) PHENYL]CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN OCTAHYDRO-1H-INDOLE-2(S)-CARBOXYZIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-SULFAMOYL PHENYL) CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN-OCTAHYDRO lH-INDOLE-2 (S ) -CARBOXYLIC ACID in the free form or in the form of its ester, preferably in the form of its mono-or-di-ethyl ester. 5) A compound according to claim 1, wherein R is a group Z-(CH2)0-6- as defined in claim 1, preferably ZÚ-(CH2)4-, Zê-(CH2)4-, Z -(CH2)4-, Z4-(CH2)4-, Z5-(CH2)4-, Z6-(CH2)4-, Z7-(CH2)4-, Z8-(CH2)4-, Z9-(CH2)4- or Z10-(CH2)4-, and wherein the group EMI129.1 preferably the group of formula II, IV (wherein B is a saturated ring) or VIII. 6) 6) A compound according to claim 5, wherein RÚ and are hydrogen, and/or Z is of the formula IX, X or is hydrogen and R7 is hydrogen or hydroxy, and/or when Z is of the formula XIII or XIV R9 and R10 are independent ently hydrogen or methyl, and/or R8 in the definition of the moiety Z is chloro, and/or R4 is benzyl or ethyl. 7) A compound according to claim 5, wherein RÚ and are hydrogen, the group EMI129.2 the group of formula IV, wherein B is a saturated ring and R5 is hydrogen, R is ZÚ-(CH2)4- or Zê-(CH2)4-, wherein R6 and R7 are hydrogen, and R8 is chloro, and R4 is benzyl, preferably being 1-{N&alpha;-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro- 3-sulfamoyl]benzenesulfonyl]-(S)-lysyl}-cis, synoctahydro-1H-indole-2(S)-carboxylic acid or 1-{N&alpha;-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N#- [(4-chloro-3-sulfamoyl)benzoyl-(S)-lysyl}-cis, synoctahydro-1H-indole-2(S)-carboxylic acid in the free form or in the form of its ester, preferably in the form of its mono-or-di-ethyl ester. 8) A compound according to claim 1, wherein R5is a group Z-(CH2)0-6- aS defined in claim 1, preferably being ZÚ, Zê, Z , Z5, Z6, Z7, Z8, Z9 or Z10, wherein the group EMI130.1 preferably the group of formula II, VI (wherein B is an aromatic ring), or IV (wherein B is a saturated ring), preferably EMI130.2 9) A compound according to claim 8, wherein R1 and R2 are hydrogen, and/or when Z is of the formula IX, X or XI R6 is hydrogen and R7 is hydrogen or hydroxy, and/or when Z is of the formula XIII or XIV R9 and R10 are independently hydrogen or methyl, and/or R8 in the definition of the moiety Z is chloro, and/or R3 is methyl and/or R4 is benzyl or ethyl, the compound preferably being 7-{4-chloro-3-sulfamoylbenzamido)-2-{N-[1(S) ethoxycarbonyl-3-phenylpropyl)-(S)-alanyl} 1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid or the corresponding 1-S-carboxy-compound. 10) Process for the preparation of a compound of formula I as defined in any one of claims l:to 9, characterized in that the compound is prepared by an appropriate process selected from the following processes a to i: a) for the preparation of a compound of formula I, wherein R1 is hydrogen: condensation of a ketocompound (XIX) with a depeptide (XX) under reduction EMI131.1 wherein A, Rê, R , R4 and R5 are as define above and Pr stands for a free for a protected hydroxy group; b) alkylation of a dipeptide (XX) by means of a compound of formula (XXI) under basic conditions EMI132.1 wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy, A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected hydroxy group; c) condensation of an aminoacid (XXII) with an aminoacid (XXIII) in the presence of a condensing agent EMI132.2 wherein A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I, and Pr stands for a free or protected (e.g. by esterification) hydroxy group; d) condesation of an amino compound (XXIV) with a keto compound (XXV) EMI132.3 under the conditions described for process a wherein A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group; e) alkylation of an amino compound (XXIV) by means of a compdund (XXVI) EMI133.1 wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy, A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group, under the conditions described for process b; f) for the preparation of a compound of formula I, wherein one of R3, R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z5, Z6, Z7, Z8, Z9 or Z10, preferably Z7, Z8 or Z : condensation of z peptide of the general formula (XXX) with a compound containing the desired group (XXXI) EMI133.2 wherein R1, R2 and A are as defined for formula I, Pr is a protected hydroxy group W , W4 and W5 are defined like R3, R4 and R5 respectively with the difference that one of W3, W4 and W5 contains an NH2-group instead of the respective Z5 to Z10-group; and W6 is Z5, Z6, Z7, Z8, Z9 or Z10; g) for the preparation of 2 compound of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is ZÚ, Zê, or Z3: condensation of a peptide of formula XXXII with an appropreately substituted dompound of formula XXXIII EMI134.1 wherein R1, R and A are as defined for formula I, Pr is a protected hydroxy group, W , W8 and w are defined like R3, R4 and R5 respectively, with the difference that one of w7, w and W9 contains an NH2-group instead of the respective Z1, Z2 or Z3 group, and WIO is EMI134.2 h) .f or the preparation of a compound of formula I, 5 wherein Z is Z4: condensation of a peptide of formula (XXXVII) with a 3 halomethylbenzothiadiazine (XXXVIII) EMI135.1 1 2 wherein R , R and A are as defined for formula I, Pr is a protected hydroxy group, WÚÚ, Wl2 and W13 are defined like R , R4 and R5 respectively with the difference that one of WÚÚ, W12 and W13 contains a -SH-group: instead of the re respective Z4-group, and Hal is halogen, preferably chloro; i) for the preparation ofa compound of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z5 or Z6: condensation of a peptide of formula XXXIX with a compound of formula XXXX EMI136.1 wherein RÚ a2 R9 R10 and A are as defined for formula I, P is a protected hydroxy group, W14, W15 5 and W16 re de- fined like R , R4 and R5 respectively with the difference that one of W14 , W15 and W16 contains the group EMI136.2 respect ively instead of the group Z5 or Z6 respectively; ; followed by removal of the protecting groups, if necessary, to yield the desired product, and if desired, converting a so obtained compound of formula I into its ester and/or setting free the compound of formula I from its ester or preparing a salt thereof and, if desired, isolating tne preferred isomer. 11) A pharmaceutical composition comprising a compound of the general formula I or pharmaceutically acceptable salt or ester thereof as defined in any one of claims 1 to 9 or obtained according to a process of claim 10. Claims for Austria 1) Process for the preparation of compound of the formula EMI138.1 the pharmaceutically acceptable esters thereof and the pharmaceutically acceptable salts of the foregoing, wherein RÚ and Rê independently are hydrogen or lower alkyl; the group EMI138.2 is one of the structures II to VIII EMI138.3 EMI138.4 EMI139.1 (wherein B is a saturated or aromatic ring) or EMI139.2 one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z has one of the following values ZÚ to Z10: ZÚ: EMI140.1 Zê: EMI140.2 Z : EMI140.3 Z4: EMI140.4 Z5: EMI140.5 Z6: EMI141.1 Z7: EMI141.2 Z8: EMI141.3 9 EMI141.4 Z10: EMI142.1 wherein R8 is Cl or CF3; R6 is hydrogen or haloge R is hyarocen o: halogen; R7 is hydrogen, halogen, carboxy, hydroxy or amino; R9 and R10 are independently hydrogen, lower alkyl or halolower alkyl and R9 can also be phenyl or phenyl lower alkyl; RÚÚ is hydrogen or lower alkyl; RÚê is hydrogen, lower alkyl or phenyl lower alkyl; whereby when R is the group Z-(CH2)0-6-, then R is ZÚ-(CH2)1-6-, Zê-(CH2)1-6-, Z3-(CH2)1-6-, Z4-CH2-, Z5-(CH2)1-6-, Z6-(CH2)1-6-, Z7-(CH2)1-6-, Z8-(CH2)1-6-, Z9-(CH2)1-6-, or Z10-(CH2)1-6-, R4 is lower alkyl, benzyl, benzyloxy, benzyloxy, phenoxy, or phenylthio, is hydrogen; EMI142.2 one of the structure II to VIII; and when R4 is the group Z-(CH2)0-6-, then R4 is ZÚ-(CH2)0-6-, Zê-(CH2)0-6-, Z -(CH2)0-6-, Z4-(CH2)0-6-, Z5-(CH2)0-6-, Z6-(CH2)0-6-, Z7-(CH2)0-6-, Z8-(CH2)0-6-, Z9-(CH2)0-6- or Z10-(CH2)0-6- and R is hydrogen, lower alkyl or amino lower alkyl and 5 k hydrogen; an-A the g=' EMI143.1 one of the structures II to # and when P is the group :-(cz2)O-6-, then R is Z , Z z3 z z5 z6 z7 Z Z8, Z9 or Z10, R is hydrogen, lower alkyl or amino alkyl and R4 is lower alkyl, benzyl, benzyloxy, benzylthio, phenoxy or phenylthio; ; and the EMI143.2 one of the structures II to VII, preèraoly being in the form of the free di-carbonic acid or in the form of its aklyl ester, the alkyl group containing 1 to 6 carbon atoms, especially in the form of its monoester wherein the carboxy group attached to the group EMI143.3 in the free form, preferably all former compounds being the stereoisomer in which the absolute configurations at each of the three carbon atoms bonded to both a nitrogen and a carbonyl group corresponds most closely to the absolute configuration of L-aminoacids, characterized in that the com pound is prepared by an appropriate process selected from the following processes a to i: a) for the preparation of a compound of formula I, wherein R1 is hydrogen: condensation of a ketocompound (XIX) with a depeptide (XX) under reduction EMI144.1 wherein A, Rê, R , R4 and R5 are as defined above and Pr stands for a free or a protected hydroxy group; b) alkylation of a dipeptide (XX) by means of a compound of formula (XXI) under basic conditions EMI144.2 wherein X is chloro, bromo, iodo, alkanesulfonyloxy or crenesunfonynoxy, A, R, R, R, R, R5 are as defined above for compounds of formula I and Pr stands for a free or protected hydroxy group; ; c) condensation of an aminoacid (XXII) with an aminoacid (XXIII) in the presence of a condensing agent EMI145.1 wherein A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I, and Pr stands for a free or protected (e.g. by esterification) hydroxy group; d) condesation of an amino compound (XXIV) with e keto compound (XXV) EMI145.2 under the conditions described for process wherein A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group; e) alkylation of an amino compound (XXIV) by means of a compound (XXVI) EMI145.3 wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy, A, RÚ, Rê, R , R4, R5 are as defined above for compounds of formula I and Pr stands for a free or protected (e.g. by esterification) hydroxy group, under the concitions described fo process b; f) for the preparation of a compound or formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z5, Z6, Z7, Z8, Z9 or Z10, preferably Z7, Z8 or Z9: condensation of a peptide of the general formula (XXX) with a compound containing the desired group (XXXI) EMI146.1 wherein Rl, R2 and A are as defined for formula I, Pr is a protected hydroxy group W , W4 and W5 are defined like R , R4 and R5 respectively with the difference that one of W , W4 and W5 contains an NH2-group instead of the respective Z5 to Z10-group; and W6 is Z5, Z6, Z7, Z8, Z9 10 or Z ; g) for the preparation of a compound of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is ZÚ, Zê or Z : condensation of a peptide of formula XXXII with an appropreately substituted compound of formula XXXIII EMI147.1 wherein RÚ, Rê and A are as defined for formula I, Pr is a protected bydroxy group, h', W8 and 99 are defined like R3, R4 and R5 respectively, with the difference that one of W7, W8 and W9 contains an NH2-group instead of the respective Z1 Z2 cr Z3 group, and w is EMI147.2 h) for the preparation of a compound of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z4; condensation of a peptide of formula (XXXVII) with a 3 halomethylbenzothiadiazine (XXXVIII) EMI148.1 wherein RÚ, Rê and A are as defined for formula I, Pr is a protected hydroxy group, WÚÚ, WÚê and WÚ are defined like R , R4 and R5 respectively with the difference that one of WÚÚ, WÚê and WÚ contains a -SH-group instead of the re spective Z4-group, and Hal is halogen, preferably chloro; i) for the preparation of a compound of formula I, wherein one of R , R4 and R5 is a group Z-(CH2)0-6-, wherein Z is Z Or Z6: condensation of a peptide of formula XXXIX with a compound of formula XXXX EMI148.2 wherein XÚ, Rê, R9, R10 and A are as defined for formula I, Pr is a protected hydroxy group, W14, W15 and W16 are defined like R , R4 and R5 respectively with the difference that one of W14, W15 and W16 contains the group EMI149.1 respect ively instead of the group Z5 or Z6 respectively; followed b removal of the protecting groups, if necessary, to yield the desired product, and if desired, converting a so obtained compound of formula I into its ester and/or setting free the compound of formula; from its ester or preparing a salt thereof and, if desired, isolating the preferred isomer. 2) Process according to claim 1, characterized in that a compound is prepared, wherein R4 is a group Z-(CH2)0-6- as defined in claim 1, wherein Z preferably is ZÚ, Zê, Z , Z5, Z7, Z8, Z9 or Z10; R4 preferably being ZÚ-(CH2)2 or 3-, Zê-(CH2)2 or Z -(CH2)2 or 3-, Z5-(CH2)2 or 3-, Z7-(CH2)2 or 3 Z8-(CH2)2 or 3-, Z9-(CH2)2 or 3-, or Z10-(CH2)2 or and wherein preferably the group EMI150.1 the group of formula II, IV (wherein B is a saturated ring) or VIII, preferably R being hydrogen. 3) Process according to claim 1 or 2, characterized in that a compound is prepared, wherein RÚ and Rê are hydrogen, and/or when Z is of the formula IX, X, or XI R6 is hydrogen and R7is hydrogen or hydroxy, and/or when Z is of the formula XIII or XIV R9 and R10 are independently hydrogen or methyl, and/or R8 in the definition of the moiety Z is chloro, and/or R3is methyl. 4) Process according to claim 1 or 2, characterized in that a compound is prepared, wherein RÚ and Rê are hydrogen, the group EMI150.2 the group of formula IV, wherein B is a saturated ring and R5 is hydrogen, R4 is ZÚ-(CH2)3- or Zê-(CH2)3-, wherein R6 is hydrogen, R7 is hydrogen or hydroxy, and R8 is chloro; and R3 is methyl, preferably being 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoyl)benzenesulfonylaminopentyl]-(S)-alanyl]-cis, synoctahydro-1H-indole-2(S)-carboxylic acid, 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-3-sulfamoyl)benzamidopentyl]-(S)-alanyl}-cis, syn-octahydro-1Hindole-2(S)-carboxylic acid, or 1-{N-[1(S)-ethoxycarbonyl-5-(4-chloro-2-hydroxy 5-sulfamoyl)-benzamidopentyl)-(S)-alanyl}-cis, syn octahydro-1H-indole-2(S)-carboxylic acid, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-2-HYDROXY-5-SULFAMOYL PHENYL)CARBONYL)AMINO]PENTYL)-(S)-ALANYL}-CIS, SYN OCTAHYDRO-lE-INDOLE-2 (S ) -CARBOXYLIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-(N-METHYL SULFAMOYL) PHENYL]CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN OCTAEHYDRO-1H-INDOLE-2(S)-CARBOXYLIC ACID, 1-{N-[1(S)-CARBOXY-5-[[(4-CHLORO-3-SULFAMOYL PHENYL) CARBONYL]AMINO]PENTYL]-(S)-ALANYL}-CIS, SYN-OCTAHYDRO lE-INDOLE-2 (5)-CARBOXYLIC ACID in the free form or in the form of its ester, preferably in the form of its mono-or-di-ethyl ester. 5) Process according to claim 1, characterized in that a compound is prepared1 wherein R3 is a group z-(CH2)0-6- as defined in claim 1, preferably ZÚ-(CH2)4-, Zê-(CH2)4-, Z -(CH2)4-, Z4-(CH2)4-, Z5-(CH2)4-, Z6-(CH2)4-, Z7-(CH2)4-, Z8-(CH2)4-, Z9-(CH2)4- or Z10-(CH2)4-, and wherein the group EMI152.1 preferably the group of formula II, IV (wherein B is a saturated ring) or VIII. 6) Process according to claim 5, characterized in that a compound is prepared, wherein RÚ and Rê are hydrogen, 6 and/or Z is of the formula IX, X or XI, R6 is hydrogen and R7is hydrogen or hydroxy, and/or when ,Z is of the formula XIII or XIV R9 and R10 are independently hydrogen or methyl, and/or R8 in the definition of the moiety Z is chloro, and/or R4 is benzyl or ethyl. 7) Process accordina to claim 5, characterized in that a compound is prepared, wherein R1 and R2 are hydrogen, the group EMI152.2 the group of formula IV, wherein B is # group -N - C- is the group of formula IV, wherein B is # # saturated ring and R5 is hydrogen, R is ZÚ-(CH2)4- or Zê-(CH2)4-, wherein R6 and R are hydrogen, and R8 is chloro, and R4 is benzyl, preferably being 1-{N&alpha;-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N#-[(4-chloro- 3-sulfamoyl)benzenesulfonyl)-(S)-lysyl}-cis, syn oc=ahydro-1E-indole-2(S)-carboxylic acid or 1-{N&alpha; ;-[1(S)-ethoxycarbonyl-3-phenylpropyl]-N#- [(4-chloro-3-sulfamoyl)benzoyl-(S)-lysyl}-cis, syn octahydro-1H-indole-2(S)-carboxylic acid in the free form or in the form of its ester, preferably in the form of its mono-or-di-ethyl ester. 8) Process according to claim 1, characterized in that a compound is prepared, wherein R5is a group Z-(CH2)0-6 as defined in claim 1, preferably bein ZÚ, Zê, Z , Z5, Z7 Z8, Z9 or Z10; wherein the group EMI153.1 preferably the group of formula II, VI (wherein B is an aromatic ring), or IV (wherein B is a saturated ring), preferably EMI153.2 9) Process according to claim 8, characterized in that a compound is prepared, wherein R1 and R2 are hydrogen, and/or when Z is of the formula IX, X or XI R6 is hydrogen and R7 is hydrogen or hydroxy, and/or when Z is of the formula XIII or XIV R and R10 are independently hydrogen or methyl, and/orR8 in the definition of the moiety Z is chloro, and/or R3 is methyl and/or R4 is benzyl or ethyl, the compound preferably being 7- (4-chloro-3-sulfamoylbenzamido) -2-;N- [1 (S) - ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl}1,2,3, 4-tetrahydroisoquinoline-3 (S) -carboxylic acid or the corresponding I-S-carboxy-compound. 10) Process for the preparation of a pharmaceutical composition comprising a compound of the general formula I or pharmaceutically acceptable salt or ester thereof as defined in any one of claims 1 to 9, characterized in that active ingredient is brought into a form suitable for therapeutic application.

Inventors: DOLL, RONALD J., GOLD, ELIJAH H., NEUSTADT, BERNARD R., SMITH, ELIZABETH M., WITKOWSKI, JOSEPH T., YEHASKEL, ALBERT S.
Applicants: SCHERING CORPORATION
Application year: 1983
Main classification: C07K5
IPC codes: A61K38, C07K5