Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them

Abstract: Disclosed are novel carboxyalkyl dipeptides which are useful as inhibitors of angiotensinconverting enzyme and as antihypertensive agents, having the formula and the pharmaceuticallv acceptable salts thereof, wherein R and R⁶ are for example hydroxy, lower alkoxy or aryllower-­ 4 alkoxy; R¹ is for example hydrogen, alkyl, lower alkoxy or aryloxy; R² and R⁷ are the same or different and are hydrogen or lower alkyl; R³ is for example lower alkyl or phenyl lower alkyl; R⁴ and R⁵ are selected from hydrogen, lower alkyl and Z, or R⁴ and R⁵ taken together form a group represented by Q, U, V, Y, D or E wherein wherein X¹ and X² independent of each other are O, S or CH₂, R⁸ and R⁹ independent of each other are lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl having 3 to 8 carbon atoms, hydroxy lower alkyl or -(CH₂) n Ar, wherein n is 0, 1. 2 or 3 or R⁸ and R⁹ taken together form a bridge W, wherein W is a single bond or a methylene bridge or a substituted methylene bridge when at least one of X¹ and X² is methylene, or W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms; with the proviso that at least one of R⁴ and R⁵ is Z; wherein L is O or S. The compounds can be prepared according to known methods such as for example by condensation of an aminoacid XXI with an aminoacid XVII

Description: The present invention relates to carboxyalkyl dipeptides which are useful as inhibitors of angiotensin-converting enzyme and as antihypertensive agents. Carboxyalkyl dipeptides which are useful as inhibitors of angiotensin-converting enzyme and as anti-hypertensive agents are known from the published European patent application No. 12401. The compounds of the present invention are compounds of the formula and the pharmaceutically acceptable salts thereof, wherein R and R⁶ are the same or different and are hydroxy, lower alkoxy, lower alkenyloxy, dilower alkylamino lower alkoxy (e.g. dimethylaminoethoxy), acylamino lower alkoxy (e.g. acetylaminoethoxy), acyloxy lower alkoxy (e.g. pivaloyloxyethoxy), aryloxy (e.g. phenoxy), arylloweralkoxy (e.g. benzyloxy), amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino (e.g. benzylamino), or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R¹ is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated (e.g. allyl) alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, (e.g. phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio (e.g. phenylthio), substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl; R² and R⁷ are the same or different and are hydrogen or lower alkyl; R³ is hydrogen, lower alkyl, phenyl lower ally, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower ally (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, guanadino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl; R⁴ and R⁵ taken together form a group represented Q or U, wherein; Q is wherein X¹ and X² independent of each other are O, S or CH₂, R⁸ and R⁹ taken together form a bridge W, wherein W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl, and aryl lower alkyl groups. p is 0, 1 or 2, q is 0, 1 or 2, with the proviso that the sum of p and q must be 1, 2 or 3, with the proviso that if p is 0 then X¹ and X² must be methylene; U is ,wherein W is a methylene bridge or a substituted methylene bridge when at least one of X¹ and X² is methylene, or W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted methylene bridge or said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, (except that W may also be a methylene bridge when X¹ and X² are oxygen or sulfur), X¹ and X² are as defined above, p is 0, 1 or 2, q is 0, 1 or 2, with the proviso that the sum of p and q is 1 or 2, and with the proviso that if p is 0, X¹ must be CH₂, excluding compounds wherein U is wherein p is zero or 1 and q is 1; As will be seen from the above descriptions of the compounds of the present invention, when R⁴ and R⁵ form a group Q or U, these groups, taken together with the nitrogen' to which R⁴ is attached and the carbon to which R⁵ is attached, form various ring systems. Included among these ring systems are the following: R⁸ and R⁹ in the group Q form a bridge W, as described above, whereby the following ring system is formed: Each of the rings in the structures shown above will have at least four members. The values of p and q, and the chosen definition of W in the rings drawn above will determine whether any of the aforesaid rings will have 5 or 6 or more members. Another embodiment of the present invention comprises compounds of the formula wherein R⁸, R⁹, X¹, X², p and q are as defined above for the group Q and wherein R, R¹, R², R³, R⁶ and R⁷ are as defined above. Non-limiting examples of compounds of the formula III are compounds wherein X¹ and X² are methylene, R⁸ and R⁹ taken together form the bridge W, and p, q, and W are as defined above, especially wherein W is an ethylene bridge; wherein p and q are each 1, or wherein p is 0 and q is 2; compounds, wherein X¹ and X² are S, and R⁸, R⁹, p and q are as defined above, especially compounds wherein R⁸ and R⁹ taken together form an ethylene bridge and p and q are as defined above, preferably are each 1 or p is 1 and q is 2. Another embodiment of the present invention comprises compounds of the formula wherein X¹, X², W, p and q are as defined above for the group U and R, R¹, R², R³, R⁶ and R⁷ are as defined above. Non-limiting examples of compounds of the formula VI are compounds, wherein X¹ and X² are methylene and W is methylene and p and q are as defined above, especially wherein p is 0 and q is 1 and wherein p is 0 and q is 2; compounds, wherein X¹ and X² are methylene and W is ethylene and p and q are as defined above, especially wherein p is 1 and q is 0 and wherein p is 0 and q is 2; compounds wherein X¹ and X² are methylene and W is trimethylene and p and q are as defined above, especially wherein p is 0 and q is 1; compounds wherein X¹ and X² are methylene and W is methylene, ethylene or trimethylene substituted with one or two lower alkyl groups and p and q are as defined above, especially wherein p is 0 and q is 1; compounds, wherein X¹ and X² are O, W is methylene and p and q are as defined above. In the above described compounds R, R¹, R² R³, R⁶ arid R⁷ can be exemplified as follows: R¹ is substituted lower alkyl, wherein the substituent is unsubstituted or lower-alkyl-substituted aryl, aralkyloxy or aralkylthio, in particular R¹ is substituted lower alkyl, wherein the substituent is aralkyloxy or aralkylthio, especially benzyloxy or benzylthio; R and R⁶ are the same or different and are hydroxy or lower alkoxy, especially R is hydroxy, methoxy or ethoxy and R⁶ is hydroxy, ethoxy or benzyloxy; R² and R⁷ are hydrogen; R³ is hydrogen, lower alkyl or phenyl lower alkyl, especially hydrogen, methyl or benzyl. Preferred subclasses of the present invention are aminoacyl-azabicycloalkane carboxylic acids, more preferably alanyl azabicycloalkane carboxylic acids and most preferably N-(alkoxycarbonyl alkylalanyl)-azabicycloalkane carboxylic acids. Other preferred subclasses of the present invention are N-(alkoxycarbonyl-aralkyloxyalkyl) dipeptides and N-alkoxycarbonyl-aralkylthio-alkyl) dipeptides. Particularly preferred are N-(alkoxycarbonyl-aralkylthioalkyl)-alanyl aminoacids, and most preferred are N-(alkoxycarbonyl-aralkylthioalkyl)-alanyl azacycloalkane carboxylic acids and the corresponding azabicycloalkane carboxylic acids. The aforementioned compounds of the formula I, as defined above, include all possible stereoisomers. Acyl includes ―OC―R¹², wherein R¹² is lower alkyl, lower alkenyl or aryl. The lower alkyl, lower alkenyl or lower alkynyl groups except where noted otherwise are represented by any of the variables including straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like. Cycloalkyl groups (containing 3 to 8 carbon atoms) include bridged and non-bridged groups. The aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxybenzyl and the like. Halo means chloro, bromo, iodo or fluoro. Aryl where it appears in any of the radicals except where noted otherwise represents phenyl or naphthyl. Heteroaryl groups where they appear include for example pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazolyl and thiazolyl. The R₁ and R₃ substituted lower alkyl moieties are exemplified by groups such as HO―CH₂―, HS―CH₂―, H₂N―(CH₂)₄―, CH₃―S―(CH₂)₂―, H₂N―(CH₂)₃―, In the compounds of the formula I , the carbon atoms to which R¹, R³ and R⁵ are attached may be asymmetric . The compounds accordingly exist in diastereoisomeric forms or in mixtures thereof. In general, the aminoacid part-structures, i.e., of Formula I are preferred in the configuration most similar to that of natural L-amino acids. Usually, natural L-amino acids are assigned the S -configuration. A notable exception is the natural amino acid L-cysteine which is assigned the R -configuration. 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 condensations described below such as amino, carboxy, mercapto, etc., may be protected by methods standard in peptide chemistry prior to the coupling reactions and subsequently deprotected to obtain the desired products. In other words, in the formula of the following description of the processes R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above for Formula I, including suitable protection. A. For the preparation of compounds of formula I, wherein R² is hydrogen a ketocompound (XIII) is condensed with a dipeptide (XIV) under reduction. The ketocompound (XIII) can be condensed with the dipeptide ( XIV ) in aqueous solution, optimally near neutrality, or in a suitable organic solvent (for example, CH₃OH) in the presence of a reducing agent such as for example sodium cyanoborohydride to give directly the desired compound I. 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 choice of catalyst. B. Alkylation of a dipeptide (XIV) by means of a compound XXII wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy. The reaction can be carried out under basic conditions in water or in an organic solvent. C. Condensation of an amino compound (XVIII) with a keto-compound (XIX) under the conditions described for process A. D. Alkylation of an aminocompound ( XVIII ) by means of a compound XXIII. wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy. The reaction can be carried out under the conditions described for process B. E. Condensation of an aminoacid XXI with an aminoacid XVII 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 dicyclohexylcarbodiumide (DCC), diphenylphosphoryl azide (DPPA) and N,N-disuccinimidyl carbonate in CH₃CN. While, as mentioned above, reactive groups (in R, R¹, R³, R⁴, R⁵ and R⁶) are protected before the coupling reaction is carried out, the amino group of compound XVII can be activated, e.g. by means of tetraethyldiphosphit and/or the carboxy group of compound XXI can be activated via the intermediacy of active esters such as that derived from 1-hydroxybenzotriazole, its mixed anhydride (derived from a chlorocarbonic acid ester), its azide or dicyclohexylcarbodiimide. The starting compounds in this reaction are known compounds and/or can be prepared according to known methods. The compound of formula XXI, wherein R² is hydrogen can for example be prepared by reacting a keto compound XIII with an amino acid XV according to the conditions described in process A. Alternatively compound XXI can be prepared by condensing XVIII with a ketoacid XX or by condensing XV and XXII or XVIII and XXIV under the conditions described for process B above (X being as defined in process B). It is evident that a compound of formula I obtained by any one of processes A to E can be transformed into another compound of formula I by methods known in the art. The above processes are followed by setting free protected groups by known methods. Protected carboxy groups, e.g. when R and R⁶ are for example alkoxy (methoxy, ethoxy, tert.butyloxy), nitrobenzyloxy or benzyloxy, are set free by hydrolysis or hydrogenation. (Reductive cleavage of a benzyl ester / (where R⁶ is benzyloxy and R is alkoxy) will yield compounds of formula I wherein R is alkoxy and R⁶ is hydroxy, and where R⁶ is alkoxy and R is benzyloxy, will yield compounds of formula I wherein R is hydroxy and R⁶ is alkoxy). 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. In the special case of R¹ bearing an alpha-amino substituent, the carbonyl and amino groups can be conveniently protected as a beta-lactam function. This kind of protection can be removed by known methods, e.g. as described above for the hydrolysis. In the compounds of formula I , the carbon atoms to which R¹, R³ and R⁵ are attached may be asymmetric. The compounds accordingly exist in diastereoisomeric forms or in mixtures thereof. The above described syntheses can utilize racemates, enantiomers 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 fractional crystallization methods. 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., HCl, HBr, H₂SO₄, H₃PO₄, methanesulfonic acid, toluenesulfonic 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 have useful pharmacological properties. They are useful in the treatment of high blood pressure. The compounds of the present invention can be combined with pharmaceutical carriers and administered in a variety of well known pharmaceutical forms suitable for oral or parenteral administration to provide compositions useful in the treatment of cardiovascular disorders and particularly mammalian hypertension. The dosage of the compounds of this invention will typically be in the range of about 0.01 to about 30 mg/kg, preferably about 0.1 to about 10 mg/kg, of mammalia weight, administered in single or divided doses. The exact dose to be administered 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 500 mg per patient generally given several times, thus giving a total daily dose of from 5 to 2000 mg per day. Also, the compounds of this invention may be given in combination with diuretics or other antihypertensives. Typically, these are combinations whose individual dosages range from one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Examples of such diuretics or other antihypertensives are hydrochlorothiazide, ethacrynic acid, amiloride, furosemide, propanolol, timolol, methyldopa and chlorothiazide. The composition containing the compounds of this invention will preferably contain from about 5 to about 250 mg 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 suspensions. 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 tricalcium phosphate; 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; nonionic, 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 formulations. The following examples illustrate the preparation of the compounds of the present invention. The diasteromers prepared as set forth below may be isolated by column chromatography or by fractional crystallization. Preparations 1 to 5 illustrate details of suitable analogy processes. The products of preparations 1 to 5 are excluded from the claimed subject matter. In the preparations 1 to 5, 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. Preparation 1 1-[N-(1-Carbomethoxy-3-phenylpropyl)-(S)-alanyl]octahydroindole-2(S)-carboxylic acid A. Dissolve 27.0 g of ethyl indole-2-carboxylate in 250 ml of trifluoroacetic acid. Add 2.05 g 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 dried over magnesium sulfate and concentrate it to give ethyl octahydroindole-2-carboxylate, a pale yellow oil. The oil should immediately be used in the following step. B. To a solution of 10.0g of ethyl octahydroindole-2-carboxylate (prepared in as shown in paragraph A of this preparation) in 400 ml of ethyl acetate add 17.0 g of N-benzyl-oxycarbonyl-(S)-alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concentrate it in vacuo . Place the residue on a column of silica gel (3000 g, particle size 0.25―0.074 mm, (60―200 mesh)) and elute with chloroform:ethyl acetate 10:1 to give 1-[N-benzyloxycarbonyl-(S)-alanyl]-octahydroindole-2(R)-carboxylic acid ethyl ester, a colorless oil [α] 26 / D +22.0° (ethanol) and 1-[N-benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid ethyl ester, a colorless oil [α] 26 / D -96.4° (ethanol). C. To a solution of 3.22 g of 1-[N-benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid, ethyl ester in 150 ml of methanol, add 20 ml of 2.5 N sodium hydroxide and stir the mixture at room temperature for 18 hours. Concentrate the mixture under nitrogen, dilute the residue with ice-water and then make the mixture acidic with concentrated hydrochloric acid. Extract the aqueous solution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic phase and place it on a column of silica gel (500 g., particle size 0.25―0.074 mm, (60―200 mesh)). Elute with chloroform:glacial acetic acid 9:1 to give 1-[N-benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid, a white solid [α] 26 / D -62.1° (ethanol), m.p. 58.60°. D. Dissolve 1.70 g of 1-[N-Benzyloxycarbonyl-(S)-alanyl]octahydroindole-2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 g 10% palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. Filter the mixture and concentrate in vacuo to give 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid, a white solid [α] 26 / D -18.5° (ethanol), m.p. 163―165°. E. Dissolve 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared in paragraph D of this preparation) in 100 ml of absolute methanol. Add 1.10 g 2-oxo-4-phenylbutyric acid, ethyl ester and 20 ml of 3 Angstrom molecular sieve pellets, and stir the resulting mixture at room temperature for eighteen hours. Filter the reaction mixture and treat the filtrate with 0.68 g sodium cyanoborohydride at room temperature for two hours. Concentrate the mixture under nitrogen and dilute the oil with dilute hydrochloric acid and stir at room temperature for one hour. Absorb the aqueous solution on 200 ml of an XAD―2 (Rohm & Haas Co. resin). Elute the resin with 2000 ml of water and then with 2000 ml of methanol. Concentrate the methanol solution and place the residue on a column of silica gel (400 g, 60―200 mesh) and elute with chloroform:isopropanol:7% ammonium hydroxide 1:1:1 (organic layer) to give 1[N(1-ethoxycarbonyl-3-phenylpropyl)-(S)-alanyl)octahydroindole-2(S)-carboxylic acid, a white solid [α] 26 / D -45.2° (ethanol), m.p. 71―73°. Preparation 2 1-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]octahydroindole-2(S)-carboxylic acid To a solution of 1-[N-(1-carbomethoxy-3-phenylpropyl)-(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in preparation 1) in methanol, add 2.5 N sodium hydroxide. After three hours, concentrate the reaction mixture and absorb it on an XAD―2 resin column and elute with water and then with methanol. Concentrate the methanol eluant to give a residue and absorb this residue on a silica gel column and elute with chloroform:methanol:14% ammonium hydroxide 1:1:1. Concentrate the desired eluant fractions to obtain the title compound. Preparation 3 1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-octahydroindole-2(S)-carboxylic acid Following the procedure of Preparation 1, but modifying step E to use ethanol as reaction solvent, prepare 1-[N-(1(R,S)-carboethoxy-3-phenylpropyl)-(S)-alanyl-octahydroindole-2(S)-carboxylic acid. Chromatograph this material on an RP―8 reversed-phase column using acetonitrile:0.2N NH₄OAc 40:60 (pH 8.6) as eluent to obtain the title compound as a solid [α] 26 / D = -45.3° (ethanol). Preparation 4 1-{N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl}-3a(S),7a(S)-octahydroindole-2(S)-carboxylic acid A. To a 100 ml three-neck flask, equipped with a thermometer, dropping funnel, magnetic stirrer and ice bath, 23 ml (0.21 mole) of benzyl alcohol was added and cooled to 0°C under N₂. SOCl₂ (5.95 g, 3.7 ml, 0.05 mole) was added dropwise over 15 min, maintaining the temperature at ca . 0°C. Cis,syn -perhydroindole-2(S)-carboxylic acid (ca. 0.21 mole) was added and the mixture was stirred at ca . 0°C for 1 hour and then for 24 hours at room temperature. The resulting mixture was poured into 500 ml of ether, stirred under N₂ for 1 hour and then allowed to stand under N₂ until it was no longer cloudy. The mixture was decanted and the oily precipitate was washed with 25 ml of ether, then slurried in 200 ml of ether followed by addition of 1N NaOH to pH 8―9. The mixture was stirred for 5 minutes, and the organic layer was then washed with brine, dried over MgSO₄, filtered and evaporated in vacuo at room temperature to give 2-(S)-benzyloxycarbonyl- cis,syn -octahydroindole as a colorless oil (t)c (ether) one spot, R f ∼0.31. B. To a 5 l flask equipped with a magnetic stirrer, dropping funnel and N₂ inlet tube, was added a solution of 190 g (0.92 mole) of ethyl 2-oxo-4-phenyl butanoate, and 258 g (0.734 mole) of S-alanine benzylester p-toluenesulfonate in 1.4 l of EtOH. This yellow solution was stirred for 2 hours under N₂. A solution of 17.7 g (0.282 mole) of NaBH₃CN in 550 ml of EtOH was then added, with stirring, over 90 minutes. The solution was stirred overnight and concentrated to dryness in vacuo at room temperature. The residue was partitioned between 500 ml of H₂O and 2 l of ether and the ether layer was dried over MgSO₄ and filtered. To this solution, 1.3M ethereal HCl was added to pH 4. The ether and excess HCl were then removed in vacuo at room temperature. The residue was slurried in 250 ml of ether and diluted with 750 ml of hexane. The supernatent was decanted from the resulting precipitate. The precipitate was washed with two 300 ml portions of ether as above. The residue was then triturated with 300 ml of ether and filtered under N₂ to give a white solid. This was slurried in ether and made basic with saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄, filtered and concentrated in vacuo at room temperature to give a yellow oil. This oil was dissolved in 510 ml of EtOAc, to which was added a hot solution of 40.5 g of maleic acid in 895 ml of EtOAc. After cooling to room temperature the resulting precipitate was filtered and recrystallized from EtOAc to give hemimaleate as a white solid, mp 127―128°C, [α] 26 / D 0° (c=1 % H₂O) [tlc (cyclohexane: EtOAc ― 85:15) shows one spot R f ∼0.30) after neutralization]. 7.0 g (.015 mole) of the so obtained product was slurried in EtOAc and made basic with saturated aqueous NaHCO₃. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated in vacuo at room temperature to give the product as a colorless oil. This was dissolved in 100 ml of EtOH containing 0.7 g of 10% Pd/C. The mixture was hydrogenated in a Parr shaker under pressure for 2 hours. After filtration, the solvent was removed in vacuo at room temperature to afford 4.0 g (82%) of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-(S)-alanine as a white solid, mp 147―148°C, [α] 26 / D +24.8° (c=1% MeOH) [R f ∼0.1 (EtOAc:MeOH:HOAc ― 100:1:1)]. C. To a 50 ml three-neck flask equipped with a dropping funnel, thermometer, magnetic stirrer and an ice bath, a solution of 0.23 g of 2-(S)-benzyloxycarbonyl- cis - syn -octahydroindole and 0.25 g (0.0009 mole) of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-(S)-alanine in 5.0 ml of DMF was added and cooled under N₂ to 0°C. With stirring, 0.14 g (0.00135 mole) of N-methylmorpholine was added, followed by dropwise addition (5 min) of a solution of 0.25 g (0.0009 mole) of diphenylphosphorylazide in 5 ml of DMF, (temperature of mixture maintained at 0―10°C). The solution was stirred at this temperature for 1 hour and then at room temperature overnight. Saturated aqueous NaHCO₃ was added to the light yellow solution to pH 8. It was then extracted with ether, dried over MgSO₄, filtered and evaporated in vacuo at room temperature to give 0.43 g of crude product as a yellow oil. This was preadsorbed on 1 g of coarse (particle size 0.25―0.074 mm) ((60―200 mesh) silica gel and then gravity filtered through 40 g of coarse silica gel (60―200 mesh) with ca . 300 ml of ether. 1-[N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl]- cis - syn -octahydroindole-2-(S)-carboxylic acid benzyl ester was obtained as a colorless oil. D. 0.20 g (0.00038 mole) of the so obtained product was dissolved in 50 ml of EtOH containingg 0.04 g of 10% Pd/C. The mixture was hydrogenated in a Parr shaker at 60 psi (rt) for 2 hours. The mixture was filtered and the filtrate was evaporated in vacuo at room temperature to yield the title compound as a colorless oil. Preparation 5 1-{N-[1(S)-carboethoxy-3-phenylpropyl]-(S)-alanyl}-3a(S),7a(S)-octahydroindole-2(S)-carboxylic acid N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-(S)-alanine (400 mg, 0.0014 mole) (obtainable according to preparation 4 step B) was dissolved in 40 ml of dry CH₃CN containing 0.417 g (0.0014 mole) of N,N-disuccinimidyl carbonate. Dry pyridine (0.10 ml, 0.0014 mole) was added and the solution was stirred at room temperature under N₂ overnight. Cis , syn -perhydroindole-2(S)-carboxylic acid (0.0014 mole) and 0.25 ml Et₃N were then added and the mixture was stirred overnight. The solvent was evaporated in vacuo at room temperature to give a yellow gum. This was chromatographed on 100 g silica gel (tlc grade ― EtOAc:MeOH:HOAc ― 100:1:1) to afford the title compound as its acetate salt (gum). Example 1 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]decahydroquinoline-2(S)-carboxylic acid Use ethyl decahydroquinoline-2-carboxylate (prepared by hydrogenation of quinoline-2-carboxylic acid in glacial acetic acid with platinum oxide followed by esterification in ethanol) in place of ethyl octahydroindole-2-carboxylate in Preparation 1B. Continue the sequence of reactions described in Preparation 1) to obtain the title compound. Example 2 1-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]decahydroquinoline-2(S)-carboxylic acid As described in Preparation 2, treat 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]decahydroquinoline-2-carboxylic acid (prepared as described in Example 1) with sodium hydroxide to obtain the title compound. Example 3 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]octahydroisoihdole-1(S)-carboxylic acid A. Heat cis -octahydroisoindole (prepared by reduction or cis -hexahydrophthalimide in tetrahydrofuran with lithium aluminum hydride) and mercuric acetate in 10% aqueous acetic acid under reflux for twenty hours to give cis -hexahydro-Δ¹-isoindole. Dissolve this compound in water and treat with potassium cyanide followed by 2N hydrochloric acid at 0° for two hours and at room temperature for twenty hours to give 1-cyano- cis -octahydroisoindole. Heat this cyano compound in 6N hydrochloric acid under reflux for 6 hours followed by concentration of the reaction mixture and absorption of the residue on an XAD―2 resin column. Elute with methanol to obtain cis -octahydroisoindole-1-carboxylic acid. B. Use ethyl cis -octahydroisoindole-1-carboxylate (prepared by esterification with ethanol of the acid prepared in paragraph A next above) in place of ethyl octahydroindole-2-carboxylate in Preparation 1B through 1E to give the title compound. Example 4 2-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]octahydroisoindole-1(S)-carboxylic acid As described in Preparation 2 treat N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]octahydroisoindole-1(S)-carboxylic acid (prepared as described in Example 3) with sodium hydroxide to obtain the title compound. Example 5 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid A. Substitute octahydrocyclopenta[b]pyrrole (prepared by reduction of 2-ketooctahydrocyclopenta[b]-pyrrole in tetrahydrofuran with lithium aluminum hydride) for octahydroisoindole in Example 3A to obtain octahydrocyclopenta[b]pyrrole-2-carboxylic acid. B. Use ethyl octahydrocyclopenta[b]pyrrole-2-carboxylate (prepared by esterification with the ethanol of the acid prepared as described in paragraph A) in place of ethyl octahydroindole-2-carboxylate in the procedure described in paragraphs B through E of Preparation 1 to give the title compound. Example 6 1-(N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]octahydrooyclopenta[b]pyrrole-2(S)-carboxylic acid As described in Preparation 2, hydrolyze the ester (prepared as described in Example 5) with sodium hydroxide to obtain the title compound. Example 7 5-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2,2-dimethyl-octahydro-1,3-dioxolo[4,5-c]pyrrole-4(S)-carboxylic acid Heat 1-benzyloxycarbonyl-3,4-dihydroxy-(S)-proline [preparable from reaction of 3,4-dihydroxy-(S)-proline in 2N sodium hydroxide with benzyl chloroformate in ether] with 2,2-dimethoxy propane in dimethylformamide and p-toluenesulfonic acid to obtain 5-benzyloxycarbonyl-2,2-dimethyloctahydro-1,3-dioxolo[4.5-c]pyrrole-4(S)-carboxylic acid. Hydrogenate this compound in methanol with palladium on carbon to give 2,2-dimethyloctahydro-1,3-dioxolo[4,5-c]pyrrole-4(S)-carboxylic acid. React this compound with N-benzyloxycarbonyl-(S)-alanine, N-hydroxysuccinimide ester as described in Preparation 1B―E to isolate the title compound. Example 8 7-[N-(carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid A. Dissolve 7.0 g of 1-benzyloxycarbonyl-4-keto-(S)-proline methyl ester in 75 ml of glacial acetic acid. Add 0.7 g of p -toluenesulfonic acid and 2.8 g of 1,2-ethanedithiol and heat under reflux with stirring for eighteen hours. Add the reaction mixture to saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (300 g, 60―200 mesh) and elute with hexane:ethyl acetate (1:1) to give 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester, a yellow oil having [α] 26 / D -12.6° (dioxane). B. Dissolve 3.0 g of 7-benzoyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture dropwise to diethyl ether at 0―5°C to give 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester hydrobromide, a brown solid m.p. 156―158°. C. Dissolve the 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester, hydrobromide from paragraph B in 0.1 N NaOH and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate in vacuo to give 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester (1.35 g). Dissolve the latter in 100 ml of ethyl acetate and treat with 2.07 g of N-benzyloxycarbonyl-(S)-alanine, N -hydroxysuccinimide ester. Stir the reaction mixture at room temperature for eighteen hours and concentrate in vacuo . Place the residue on a column of silica gel (300 g, 60―200 mesh) and elute with hexane:ethyl acetate 4:1 to obtain 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester, a yellow oil [α] 26 / D -14.8° (ethanol). D. Dissolve 1.05 g of 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester in 100 ml of methanol. Add 10 ml of 2.5N sodium hydroxide and stir the mixture at room temperature for sixteen hours. Concentrate the mixture under nitrogen, dissolve the oil in 0.1 N sodium hydroxide and dilute with ice water. Extract the aqueous solution with ethyl acetate. Acidify the aqueous solution with concentrated hydrochloric acid and then extract with ethyl acetate. Dry the organic phase over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (100 g, 60―200 mesh) and elute with chloroform:glacial acetic acid 19:1 to obtain 7-[N-benzyloxycarbonyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, [α] 26 / D -15.8° (ethanol). E. Dissolve 1.4 g of 7-[N-benzyloxycarbonyl-(S)-alanyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid in 20 ml of 20% hydrobromic acid in glacial acetic acid and stir the mixture at room temperature for 2 hours. Add the mixture dropwise to diethyl ether at 0―5°C to give 7-[(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]-nonane-8(S)-carboxylic acid hydrobromide which is used immediately in the process described in paragraph F below. F. Dissolve the 7-[(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, hydrobromide (prepared in paragraph E next above) in 100 ml of absolute methanol. Add 0.5 g of 2-oxo-4-phenylbutyric acid, ethyl ester and 10 ml of 3Å molecular sieve pellets and stir the mixture at room temperature for eighteen hours. Filter the reaction mixture and treat the filtrate with 0.30 g of sodium cyanoborohydride at room temperature for two hours. Concentrate the mixture under nitrogen and dilute the oil with 5% hydrochloric acid to pH 2 to 4 and stir at room temperature for one hour. Adjust the pH of the solution to pH 8 with 2.5N sodium hydroxide solution and absorb the solution in 150 ml of a XAD―2 resin. Elute the resin with 800 ml of water and then with 800 ml of methanol. Concentrate the methanol solution, place the residue on a column of silica gel (100 g, 60―200 mesh) and elute with chloroform:isopropanol:7% ammonium hydroxide 1:1:1 (organic layer) to obtain 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, a white solid, m.p. 56―60°C, [α] 26 / D -25.5° (ethanol). Example 9 7[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonan-8(S)-carboxylic acid Hydrolize 0.18 g of 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 8) in 600 ml of methanol with 10 ml of 2.5N sodium hydroxide, concentrate the reaction mixture and absorb it on an XAD―2 resin column and elute with water and then with methanol. Concentrate the methanol eluant to give a residue and absorb this residue on a silica gel column (100 g, 60―200 mesh). Elute the column with chlooroform:methanol: 14% ammonium hydroxide 1:1:1 and concentrate the desired eluant fractions to obtain the title compound. Example 10 7-[N-(1-carbomethoxy-3-methylthiopropyl)-(R,S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid A. Couple 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, methyl ester (prepared as described in Example 8) with pyruvic acid using dicyclohexylcarbodimide and triethylamine in dioxane to yield, after isolation and hydrolysis of the ester, 7-pyruvoyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. B. Condense 7-pyruvoyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid and (S)-methionine, methyl ester with sodium cyanoborohydride in methanol at pH 7 for three days at room temperature followed by chromatography on a XAD―2 resin column, using methanol as eluant, to obtain the title compound. Example 11 7-[N-(1-carboxy-3-methylthiopropyl)-(R,S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid Treat 7-[N-(1-carbomethoxy-3-methylthiopropyl)-(R,S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 10) with sodium hydroxide in methanol as described in Example 9) to yield the title compound. Example 12 7-{N-[1-carbomethoxy-2-(3-indolyl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid Use 7-pyruvoyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 10) and condense with tryptophan methyl ester in the presence of sodium cyanoborohydride using the method described in Example 10) to obtain the title compound. Example 13 7-{N-[1-carboxy-2-(3-indolyl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid Hydrolize 7-{-N-[1-carbomethoxy-2-(3-indolyl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 12) with sodium hydroxide as described in Example 9) to yield the title compound. Example 14 7-{N-[1-carbomethoxy-2-(1H-imidazol-4-yl)ethyl]-(R,S)alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid As described in Example 10, react 7-pyruvoyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 10) and (S)-histidine, methyl ester in the presence of sodium cyanoborohydride to obtain the title compound. Example 15 7-{N-[1-carboxy-2-(1H-imidazol-4-yl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid Treat 7-{N-[1-carbomethoxy-2-(1 H -imidazolyl-4-yl)-ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]-nonane-8(S)-carboxylic acid (prepared as described in Example 14) with sodium hydroxide as described in Example 9) to yield the title compound. Example 16 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid A. As described in Example 8, react 1-benzyloxycarbonyl-4-keto-(S)-proline, ethyl ester (prepared from the acid by esterification in ethanol) with 1,2-ethanedithiol to obtain 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester, a yellow oil [α] 26 / D - 21.0° (ethanol). B. Convert 2.22 g of 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester (prepared as described in paragraph A) to 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester as described in Example 8 and couple this compound with 1.5 g of N-benzyloxycarbonylglycine, N-hydroxysuccinimide ester as described in Example 8) to yield 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester, a yellow oil [α] 26 / D - 21.0°. C. Hydrolize 1.43 g of 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester (prepared as described in paragraph B next above) with sodium hydroxide as described in Example 8 to obtain 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. a colorless oil, [α] 26 / D - 7.9°. D. Treat 0.95 g of the acid obtained in the process described in paragraph C next above with 20% hydrobromic acid in glacial acetic acid as described in Example 8) obtain 7-glycyl-1,4-dithia-7-azaspiro[4.4]-nonane-8(S)-carboxylic acid, hydrobromide [α] 26 / D - 18.7° E. As described in Example 8, couple 0.76 g of 7-glycyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, hydrobromide (prepared as described in paragraph D next above) with 0.50 g of 2-oxo-4-phenylbutyric acid, ethyl ester to obtain 7-[N-(1-carboethoxy-3-phenylpropyl)-glycyl]-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid. Example 17 7-[N-(1-carboxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid As described in Example 9, hydrolize 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]-nonane-8(S)-carboxylic acid (prepared as described in Example 31) with sodium hydroxide to give the title compound. Example 18 7-(N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.5]decane-8(S)-carboxylic acid A. Dissolve 1-benzyloxycarbonyl-5-hydroxy-(S)-pipecolic acid (prepared from 5-hydroxy-(S)-pipecolic acid in 2N sodium hydroxide solution treated with benzylchlorformate in diethyl ether) in acetone and treat with Jones reagent to obtain 1-benzyloxycarbonyl-5-keto-(S)-pipecolic acid. Then esterify in methanol to give the respective methyl ester. B. Substitute 1-benzyloxycarbonyl-5-keto-(S)-pipecolic acid, methyl ester as the keto-ester in Example 8 and follow the procedure described to obtain the title compound. Example 19 7-[N-(1-carboxy-3-phenylpropyl(-(S)-alanyl]-1,4-dithia-7-azaspiro[4.5]decane-8(S)-carboxylic acid Hydrolize 7[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.5]decane-8(S)-carboxylic acid (prepared as described in Example 18) with sodium hydroxide and isolate the title compound using the procedure described in Example 9. Example 20 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-azaspiro[4.4]nonane-2(S)-carboxylic acid. A. Condense nitrocyclopentane (prepared from bromocyclopentane and sodium nitrite) and acrolein in tetrahydrofuran in the presence of sodium hydride to obtain 3-(1-nitrocyclopentyl)propionaldehyde. Treat this aldehyde with p-toluene-sulfonic acid in methanol and isolate 3-(1-nitrocyclopentyl)propionaldehyde dimethyl acetal. Hydrogenate this compound with Raney nickel. Isolate 3-(1-aminocyclopentyl)propionaldehyde dimethylacetal and dissolve in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give 1-azaspiro[4.4]-Δ¹-nonane. B. Substitute 1-azaspiro[4.4]-Δ¹-nonane (from paragraph A) for cis-hexahydro-Δ¹-isoindole in Example 3A to obtain 1-azaspiro[4.4]nonane-2-carboxylic acid. C. Use 1-azaspiro[4.4]nonane-2-carboxylic acid, ethyl ester prepared by esterification of the acid (obtained as described in paragraph B) in methanol in place of octahydroindole-2-carboxylic acid, ethyl ester in Preparation 1B through 1E to obtain the title compound. Example 21 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2-azaspiro[4.4]nonane-3(S)-carboxylic acid A. Reduce 2-(1-cyanocyclopentylacetaldehyde diethyl acetal (preparable from 3-cyanopropionaldehyde diethyl acetal and 1,4-dibromobutane in tetrahydrofuran in the presence of sodium hydride) with lithium aluminum hydride to yield 2-(1-aminomethylcyclopenryl)acetaldehye, diethyl acetal. Dissolve this compound in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give Δ²-2-azaspiro[4.4]nonane. B. Substitute Δ²-2-azaspiro[4.4]nonane (prepared as described in paragraph A for cis -hexahydro-Δ¹-isoindole in Example 3A to yield 2-azaspiro[4.4]nonane-3-carboxylic acid. C. As described in Preparation 1B through 1E, substitute 2-azaspiro[4.4]nonane-3-carboxylic acid, ethyl ester (preparable by esterfication of the acid from paragraph B in ethanol) for octahydroindole-2-carboxylic acid, ethyl ester to obtain the title compound. The following compounds exemplify the compounds of formula I, which can be prepared according to the described processes: 1-[N-(1-carbomethoxy-3-phenylpropyl)-(S)-alanyl]-decahydrocyclohepta[b]pyrrole-2(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-thia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 1-[N-(1-carbomethoxy-3-phenylpropyl)-(S)-alanyl]-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid; 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-octahydrocyclopenta[c]pyrrole-2(S)-carboxylic acid; 1-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydrocyclopenta[c]pyrrole-2(S)-carboxylic acid; 1-[N-(1-carbomethoxy-3-phenylpropyl)-(S)-alanyl)-decahydroquinoline-2(S)-carboxylic acid; 1-[N-(1-carboxy-3-phenylpropyl)glycyl]-decahydroquinoline-2(S)-carboxylic acid; 1-[N-(1-carboethoxy-3-p-chlorophenylpropyl)-(S)-alanyl]-decahydroquinoline-2(S)-carboxylic acid; 1-[N-(1-carboxy-2-phenylethyl)-(S)-alanyl]-octahydroisoindole-1(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-2,2-dimethyloctahydro-1,3-dioxolo[4,5-c]pyrrole-4(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,4-dioxino[2,3-c]pyrrole-5(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,3-dithiolo[4,5-c]pyrrole-4(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,4-dithiino[2,3-c]pyrrole-5(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-2,2-dimethyloctahydro-1,3-dioxolo[4,5-c]pyridine-6(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-decahydro-1,4-dioxino[4,5-c]pyridine-7(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,3-dithiolo[4,5-c]pyridine-6(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-decahydro-1,4-dithiino[2,3-c]pyridine-7(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,3-dioxolo[4,5-c]pyridine-4(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-decahydro-1,4-dioxino[2,3-c]pyridine-5(S)-carboxylic acid; 5-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-octahydro-1,3-dithiolo[4,5-c]pyridine-4(S)-carboxylic acid; 6-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-decahydro-1,4-dithiino[2,3-c]pyridine-5(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-p-chlorophenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboxy-3-p-chlorophenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboxy-2-phenoxyethyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carbomethoxy-3-methylthiopropyl)-(R,S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboxy-3-methylthiopropyl)-(R,S)-alanyl]-1,4.dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-{N-[1-carboethoxy-2-(3-indolyl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-{N-[1-carboxy-2-(3-indolyl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-{N-[1-carboethoxy-2-(1H-imidazol-4-yl)ethyl]-(R,S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carbomethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dioxa-7-azaspiro[4.4]nonane-8(S)carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-6,10-dioxa-2-azaspiro[4.5]decane-3(S)carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-6,10-dithia-2-azaspiro[4.5]decane-3(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dioxa-7-azaspiro[4.4]nonane-6(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-6,10-dioxa-2-azaspiro[4.5]decane-1(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-6(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-6,10-dithia-2-azaspiro[4.5]decane-1(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dioxa-7-azaspiro[4.5]decane-8(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.5]decane-8(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,5-dithia-8-azaspiro[5.5]undecane-9(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dioxa-8-azaspiro[4.5]decane-7(S)-carboxylic acid; 9-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,5-dioxa-9-azaspiro[5.5]undecane-8(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-8-azaspiro[4.5]decane-7(S)-carboxylic acid; 9-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,5-dithia-9-azaspiro[5.5]undecane-8(S)-carboxylic acid: 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-azaspiro[4.5]decane-2(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2-azaspiro[4.5]decane-3(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2-azaspiro[4.5]decane-7(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-7-azaspiro[4.5]decane-8(S)-carboxylic acid; 2-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2-azaspiro[5.5]undecane-3(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-8-azaspiro[4.5]decane-7(S)-carboxylic acid; 3-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-3-azaspiro[5.5]undecane-2(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-7-azaspiro[4.4]nonane-6(S)-carboxylic acid; 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-7-azaspiro[4.5]decane-8(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-8-azaspiro[5.5]undecane-9(S)-carboxylic acid; 8-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-8-azaspiro[4.5]decane-7(S)-carboxylic acid; 9-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1-oxa-9-azaspiro[5.5]undecane-8(S)-carboxylic acid; 7-[N-(1-carboethoxy-2-benzyloxyethyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 7-[N-(1-carboethoxy-2-benzylthioethyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; 1-[N-(1-carboethoxy-2-benzyloxyethyl)-(S)-alanyl]decahydrocyclohepta[b]pyrrole-2(S)-carboxylic acid; 1-[N-(1-carboethoxy-2-benzylthioethyl)-(S)-alanyl]-decahydrocyclohepta[b]pyrrole-2(S)-carboxylic acid; 7-[N-(1(S)-carboethoxy-3-phenylpropyl-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid; [α] 26 / D = -39.0° 7-[N-(3-phenyl-1-ethoxycarbonylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-(S)-carboxylic acid; [α] 26 / D = -2.4° (ETOH) 1-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-perhydrocyclopenta[b]pyrrole-2-( )-carboxylic acid; [α] 26 / D = -5.8° (ETOH) 1-[N-1-carboethoxy-3-phenylpropyl)-(S)-alanyl]-perhydrocyclopenta[b]pyrrole-2-( )-carboxylic acid. The following examples describe in detail composition 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. Formulation 1 Capsule Amount mg Active ingredient 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 tow-piece hard gelatin capsules. Formulation 2 Tablet Amount (mg) Active ingredient 250.0 125.0 Lactose 161.0 80.5 Corn Starch 12.0 6.0 Water (per thousand tablets) 120 ml (evaporates) 60 ml (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 coorn 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 opf desired shape, thickness, hardness and disintegration. Formulation 3 Injectable Solution mg/ml Active ingredient 5.00 Methyl- p -hydroxybenzoate 0.80 Propyl- p -hydroxybenzoate 0.10 Disodium Edetate 0.10 Citric Acid Monohydrate 0.08 Dextrose 40.0 Water for injection qs. ad. 1.0 ml Dissolve the p -hydroxybenzoates in a portion of water for injection at 60―70°C and cool the solution to 25―35°C. Charge and dissolve all other excipients and the active ingredient. Bring the solution to a final volume, filter it through a sterilizing membrane and fill into sterile containers.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula or a pharmaceutically acceptable salt thereof, wherein R and R⁶ are the same or different and are hydroxy, lower alkoxy, lower alkenyloxy, dilower alklylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R¹ is hydrogen, alkyl of from 1 to 10 carbon atoms, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxy carbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy, aralkylthio group is substituted with a group selected from halo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano, or sulfamoyl; R² and R⁷ are the same or different and are hydrogen or lower ally; R³ is hydrogen, lower ally, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower ally. acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkyl thio lower alkyl; R⁴ and R⁵ taken together form a group represented by Q or U, wherein; Q is wherein X¹ and X² independent of each other are O, S or CH₂, R⁸ and R⁹ taken together form a bridge W, wherein W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl lower alkyl groups, p is 0, 1 or 2, q is 0. 1 or 2, with the proviso that the sum of p and q must be 1, 2 or 3, with the proviso that if p is 0 then X¹ and X² must be methylene; U is , wherein W is a methylene bridge or a substituted methylene bridge when at least one of X¹ and X² is methylene, or W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted methylene bridge or said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, (except that W may also be a methylene bridge when X¹ and X² are oxygen or sulphur), X¹ and X ² are as defined above, p is 0, 1 or 2, q is 0, 1 or 2, with the proviso that the sum of p and q is 1 or 2, and with the proviso that if p is 0. X¹ must be CH₂, excluding compounds wherein U is wherein p is zero or 1 and q is 1. A compound according to claim 1, wherein R⁴ and R⁵ taken together form the group Q, wherein X¹ amd X² are methylene, R⁸ and R⁹ taken together form the bridge W, W preferablky being an ethylene bridge, and wherein p and q are each 1 or wherein p is 0 and q is 2; or wherein X¹ and X² are S, and R⁸ and R⁹ taken together form an ethylene bridge and p and a preferably are each 1 or p is 1 and q is 2. A compound according to claim 1, wherein R⁴ and R⁵ taken together form the group U, wherein X¹ and X² are methylene and W is methylene and p preferably is zero and a preferably is 1 or 2; or wherein X¹ and X² are methylene and W is ethylene and wherein preferably p is 0 and q is 2 or p is 1 and q is 0; or wherein X¹ and X² are methylene and W is trimethylene and wherein preferably p is 0 and q is 1; or wherein X¹ and X² are O, W is methylene and p and q are as defined in claim 1. A compound according to any one of claims 1 to 3, wherein R¹ is substituted lower alkyl; wherein the substituent is unsubstituted or lower-alkyl-substituted aryl, aralkyloxy or aralkylthio, R¹ preferably being substituted lower alkyl, wherein the substituent is aralkyloxy or aralkylthio, preferably benzyloxy or benzylthio. A compound according to any one of claims 1 to 4, wherein R and R⁶ are the same or different and are hydroxy, lower alkoxy or aryllower alkoxy; R² and R⁷ are hydrogen; and R³ is hydrogen, lower alkyl or phenyl lower alkyl, preferably R being hydroxy, methoxy or ethoxy; R⁶ being hydroxy, ethoxy or benzyloxy; R² and R⁷ being hydrogen; and R³ being hydrogen, methyl or benzyl. A compound according to claim 2, wherein X¹ and X² are S, R⁸ and R⁹ taken together form an ethylene bridge and p and q are each 1, R¹ is phenethyl, R and R⁶ are the same or different and are hydroxy or ethoxy, R² and R⁷ are hydrogen and R³ is hydrogen or methyl. A compound according to claim 6, which is 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, 7-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)carboxylic acid or 7-[N-(1-carboxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. A compound according to any one of claims 1 to 7, wherein the aminoacid part structures have the S-configuration. A compound according to claim 7 or 8, which is 7-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. Process for the preparation of a compound of formula I as defined in any one of claim 1 to 9, characterized in that the compound is prepared by an appropriate process selected from the following processes (whereby in the following formulae R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined for formula I, including suitable protection): a) for the preparation of compounds of formula I wherein R² is hydrogen) condensation of a ketocompound (XIII with a dipeptide (XIV) under reduction b) alkylation of a dipeptide (XIV) by means of a compound (XXII) wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy; c) condensation of an amino compound (XVIII) with a ketocompound (XIX) under reduction d) alkylation of an amino compound (XVIII) by means of a compound (XXIII) wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy; e) condensation of an aminoacid (XXI) with an aminoacid (XVII) 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 another compound of formula I, and, if desired, preparing a salt thereof and, if desired, isolating the preferred isomer. A pharmaceutical composition useful in the treatment of hypertension, comprising a compound of the general formula I as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, preferably in admixture with a suitable pharmaceutically acceptable carrier or excipient. Claims for the following Contracting State : AT Process for the preparation of a compound of the general formula or a pharmaceutically acceptable salt thereof, wherein R and R⁶ are the same or different and are hydroxy, lower alkoxy, lower alkenyloxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino; aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R¹ is hydrogen, alkyl of from 1 to 10 carbon atoms, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxy carbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy, aralkylthio group is substituted with a group selected from halo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano, or sulfamoyl; R² and R⁷ are the same or different and are hydrogen or lower alkyl; R³ is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl. acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkyl thio lower alkyl; R⁴ and R⁵ taken together form a group represented by Q or U, wherein; Q is wherein X¹ and X² independent of each other are O, S or CH₂, R⁸ and R⁹ taken together form a bridge W, wherein W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, p is 0, 1 or 2, q is 0. 1 or 2, with the proviso that the sum of p and q must be 1, 2 or 3, with the proviso that if p is 0 then X¹ and X² must be methylene; U is , wherein W is a methylene bridge or a substituted methylene bridge when at least one of X¹ and X² is methylene, or W is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted methylene bridge or said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, (except that W may also be a methylene bridge when X¹ and X² are oxygen or sulphur), X¹ and X² are as defined above, p is 0, 1 or 2, q is 0, 1 or 2, with the proviso that the sum of p and q is 1 or 2, and with the proviso that if p is 0. X¹ must be CH₂, excluding compounds wherein U is wherein p is zero or 1 and q is 1; characterised in that the compound is prepared by an appropriate process selected from the following processes (whereby in the following formulae R, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined for formula I, including suitable protection): a) for the preparation of compounds of formula I wherein R² is hydrogen) condensation of a ketocompound (XIII with a dipeptide (XIV) under reduction b) alkylation of a dipeptide (XIV) by means of a compound (XXII) wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy; c) condensation of an amino compound (VIII) with a ketocompound (XIX) under reduction d) alkylation of an amino compound (XVIII) by means of a compound (XXIII) wherein X is chloro, bromo, iodo, alkanesulfonyloxy or arenesulfonyloxy; e) condensation of an aminoacid (XXI) with an aminoacid (XVII) 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 another compound of formula I, and, if desired, preparing a salt thereof and, if desired, isolating the preferred isomer. Process according to claim 1, characterized in that a compound of formula I is prepared wherein R⁴ and R⁵ taken together form the group Q, wherein X¹ amd X² are methylene, R⁸ and R⁹ taken together form the bridge W, W preferably being an ethylene bridge, and wherein p and q are each 1 or wherein p is 0 and q is 2; or wherein X¹ and X² are S, and R⁸ and R⁹ taken together form an ethylene bridge and p and q preferably are each 1 or p is 1 and q is 2. Process according to claim 1, characterized in that a compound of formula I is prepared wherein R⁴ and R⁵ taken together form the group U, wherein X¹ and X² are methylene and W is methylene and p preferably is zero and q preferably is 1 or 2; or wherein X¹ and X² are methylene and W is ethylene and wherein preferably p is 0 and q is 2 or p is 1 and q is 0; or wherein X¹ and X² are methylene and W is trimethylene and wherein preferably p is 0 and q is 1; or wherein X¹ and X² are O, W is methylene and p and q are as defined in claim 1. Process according to any one of claims 1 to 3, characterized in that a compound of formula I is prepared wherein R¹ is substituted lower alkyl; wherein the substituent is unsubstituted or lower-alkyl-substituted aryl, aralkyloxy or aralkylthio, R¹ preferably being substituted lower alkyl, wherein the substituent is aralkyloxy or aralkylthio, preferably benzyloxy or benzylthio. Process according to any one of claims 1 to 4, characterized in that a compound of formula I is prepared wherein R and R⁶ are the same or different and are hydroxy, lower alkoxy or aryllower alkoxy; R² and R⁷ are hydrogen; and R³ is hydrogen, lower alkyl or phenyl lower alkyl, preferably R being hydroxy, methoxy or ethoxy; R⁶ being hydroxy, ethoxy or benzyloxy; R² and R⁷ being hydrogen; and R³ being hydrogen, methyl or benzyl. Process according to claim 2, characterized in that a compound of formula I is prepared wherein X¹ and X² are S, R⁸ and R⁹ taken together form an ethylene bridge and p and q are each 1, R¹ is phenethyl, R and R⁶ are the same or different and are hydroxy or ethoxy, R² and R⁷ are hydrogen and R³ is hydrogen or methyl. Process ccording to claim 9, characteized in that a compound is prepared which is 7-[N-(1-carboethoxy-3-phenylpropyl)-(S)-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, 7-[N-(1-carboxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)carboxylic acid or 7-[N-(1-carboxy-3-phenylpropyl)glycyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. Process according to any one of claims 1 to 7, characterized in that a compound is prepared wherein the aminoacid part structures have the S-configuration. Process according to claim 7 or 8, characterized in that a compound is prepared which is 7-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid. Process for preparing pharmaceutical compositions useful in the treatment of hypertension, characterized in that a compound of the general Formula I as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, is brought into a form suitable for pharmaceutical administration.

Inventors: GOLD ELIJAH H, NEUSTADT BERNARD R, SMITH ELIZABETH M, GOLD, ELIJAH H., NEUSTADT, BERNARD R., SMITH, ELIZABETH M.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1981
Main classification: C07K5
IPC codes: C07K1, A61P43, C07K14, A61P9, C07K5, A61K38, C12N9