CYCLOALKYL-SUBSTITUTED GLUTARAMIDE ANTIHYPERTENSIVE AGENTS

Abstract: Compounds of the formula: Wherein A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated; R¹ is H or (C₁-C₄)alkyl; R and R⁴ are H, (C₁-C₆)alkyl, C₃-C₇ cycloalkyl, benzyl, or an alternative biolabile ester-forming group; Y is either a direct bond or an alkylene group of from 1 to 6 carbon atoms; R² is H, aryl, heterocyclyl, R⁶CONR⁵-, R⁷NR⁵CO-, R⁷NR⁵SO₂- or R⁸SO₂NR⁵-, with the proviso that Y is not a direct bond when R² is H, aryl or heterocyclyl; wherein R⁵ is H, (C₁-C₆)alkyl or aryl(C₁-C₆)alkyl; R⁶ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula R⁹R¹⁰R¹¹C- wherein R⁹ is H, OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl, R¹²CONH-, R¹²SO₂NH- or (R¹³)₂N-; R¹⁰ and R¹¹ are H or (C₁-C₆)alkyl; or R¹⁰ is H and R¹¹ is amino(C₁-C₆)alkyl, imidazolylmethyl, aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl or methylthio(C₁-C₆)alkyl; or the two groups R¹⁰ and R¹¹ form a 3 to 6 membered carbocyclic ring or a pyrrolidine or piperidine ring which may optionally be substituted by amino, (C₂-C₄)alkanoyl or aroyl; R¹² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; each R¹³ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl or the two groups R¹³ form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C₁-C₄)alkyl-piperazinyl group; R⁷ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula R¹⁰R¹¹R¹⁴C- wherein R¹⁰ and R¹¹ are as previously defined and R¹⁴ is (R¹³)₂NCO-, R¹²OCH₂- or R¹⁵OCO, wherein R¹² and R¹³ are as previously defined and R¹⁵ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or aryl(C₁-C₆)alkyl; and R⁸ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; R³ is a group of the formula: wherein R¹⁶ is H, halo, 4-OH, 4-(C₁-C₆ alkoxy), 4-(C₃-C₇ cycloalkoxy) 4-(C₂-C₆ alkenyloxy), 4-[(C₁-C₆ alkoxy)carbonyloxy], 4-[(C₃-C₇ cycloalkoxy)carbonyloxy], or 3-(C₁-C₄ alkyl)SO₂NH-; and R²⁰ is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₆ alkanoyl or halo; or R³ is a group of the formula: wherein said groups may optionally be substituted in the fused benzene ring by C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halo or CF₃; are antihypertensive agents of utility in the treatment of hypertension, heart failure and renal insufficiency.

Description: This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders, including hypertension and heart failure. According to the specification of our European patent application 274234, we disclose certain cycloalkyl-substituted glutaramide derivatives which are inhibitors of the zinc dependent neutral endopeptidase E.C.3.4.24.11 and which are thereby able to potentiate the biological effects of atrial natriuretic factor and in particular, are natriuretic, antihypertensive and diuretic agents of value in the treatment of various cardiovascular disorders. The compounds of the present invention are also inhibitors of the enzyme E.C.3.4.24.11 and, in addition, they are also able to inhibit angiotensin converting enzyme, a further enzyme which is involved in the control of blood pressure. The compounds thus have a dual pharmacological action through inhibiting two key enzymes involved in blood pressure control which makes them particularly useful in the treatment of various forms of hypertension and associated cardiovascular disorders, e.g. congestive heart failure and glaucoma. The compounds are of the formula: wherein: A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated; R¹ is H or (C₁-C₄)alkyl; R and R⁴ are each independently H, (C₁-C₆)alkyl,(C₃-C₇) cycloalkyl, benzyl, or an alternative biolabile ester-forming group; Y is either a direct bond or an alkylene group of from 1 to 6 carbon atoms which may be straight or branched chain; R² is H, aryl, heterocyclyl, R⁶CONR⁵-, R⁷NR⁵CO-, R⁷NR⁵SO₂ or R⁸SO₂NR⁵-, with the proviso that Y is not a direct bond when R² is H, aryl or heterocyclyl; wherein R⁵ is H, (C₁-C₆)alkyl or aryl(C₁-C₆)alkyl; R⁶ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R⁹ is H, OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl, R¹²CONH-, R¹²SO₂NH- or (R¹³)₂N-; R¹⁰ and R¹¹ are each independently H or (C₁-C₆)alkyl; or R¹⁰ is H and R¹¹ is amino(C₁-C₆)alkyl, imidazolylmethyl, aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl or methylthio(C₁-C₆)alkyl; or the two groups R¹⁰ and R¹¹ are joined together to form, with the carbon atom to which they are attached, a 3 to 6 membered carbocyclic ring or a pyrrolidine or piperidine ring which may optionally be substituted by amino, (C₂-C₄)alkanoyl or aroyl; R¹² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl (C₁-C₆)alkyl; each R¹³ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl or the two groups R¹³ are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C₁-C₄)alkyl-piperazinyl group; R⁷ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R¹⁰ and R¹¹ are as previously defined and R¹⁴ is (R¹³)₂NCO-, R¹²OCH₂- or R¹⁵OCO, wherein R¹² and R¹³ are as previously defined and R¹⁵ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or aryl(C₁-C₆)alkyl; and R⁸ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; R³ is a group of the formula: wherein R¹⁶ is H, halo, 4-OH, 4-(C₁-C₆ alkoxy), 4-(C₃-C₇ cycloalkoxy), 4-(C₂-C₆ alkenyloxy), 4-[(C₁-C₆ alkoxy)carbonyloxy], 4-[(C₃-C₇ cycloalkoxy)carbonyloxy], or 3-(C₁-C₄ alkyl)SO₂NH-; and R²⁰ is H,(C₁-C₄)alkyl, (C₁-C₄) alkoxy, (C₂-C₆) alkanoyl or halo; or R³ is a group of the formula: wherein said groups may optionally be substituted in the fused benzene ring by (C₁-C₄) alkyl, (C₁-C₄) alkoxy, OH, halo or CF₃; and pharmaceutically acceptable salts thereof and bioprecursors therefor. In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms may be straight or branched-chain. The term aryl as used herein means an aromatic hydrocarbon group such as phenyl or naphthyl which may optionally be substituted with, for example, one or more OH, CN, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, carbamoyl, aminosulphonyl, amino, mono or di(C₁-C₄ alkyl) amino or (C₁-C₄ alkanoyl)amino groups. Halo means fluoro, chloro, bromo or iodo. The term heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which, unless otherwise stated, may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with for example, one or more halo, C₁-C₄ alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(C₁-C₄ alkyl)amino or (C₁-C₄ alkanoyl)amino groups. Particular examples of heterocycles include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, piperidino, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindolinyl, quinolyl, quinoxalinyl, quinazolinyl and benzimidazolyl, each being optionally substituted as previously defined. The compounds of formula (I) may contain several asymmetric centres and thus they can exist as enantiomers and diastereomers. The invention includes both the separated individual isomers as well as mixtures of isomers. The pharmaceutically acceptable salts of the compounds of formula (I) containing an acidic centre are those formed with bases which form non-toxic salts. Examples include the alkali or alkaline earth metal salts such as the sodium, potassium or calcium salts or salts with amines such as diethylamine. Compounds having a basic centre can also form acid addition salts with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate,phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate tosylate and lauryl sulphate salts. The term bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I). Examples include biolabile ester derivatives and amide or amino acid derivatives of the compounds of formula I. A preferred group of compounds of the formula (I) are those wherein A is (CH₂)₄ and R¹ is H, i.e. compounds of the formula (II) wherein R, R², R³ and R⁴ are as previously defined for formula (I): Also preferred are those compounds of formulae (I) and (II) wherein R and R⁴ are both H (diacids) as well as biolabile mono and di-ester derivatives thereof wherein one or both of R and R⁴ is a biolabile ester-forming group. The term biolabile ester-forming group is well understood in the art as meaning a group which provides an ester which can be readily cleaved in the body to liberate the corresponding diacid of formula (I) wherein R and R⁴ are both H. A number of such ester groups are well known, for example in the penicillin area or in the case of the ACE-inhibitor antihypertensive agents. In the case of the compounds of formulae (I) and (II) such biolabile pro-drug esters are particularly advantageous in providing compounds of the formula (I) suitable for oral administration. The suitability of any particular ester-forming group can be assessed by conventional animal or in vitro enzyme hydrolysis studies. Thus, desirably for optimum effect, the ester should only be hydrolysed after absorption, accordingly, the ester should be resistant to hydrolysis by digestive enzymes before absorption but should be readily hydrolyzed by, for example, gut-wall, plasma or liver enzymes. In this way the active diacid is released into the bloodstream following oral absorption. In addition to lower alkyl esters (particularly ethyl) and benzyl esters, alternative biolabile esters include alkanoyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted derivatives thereof, aroyloxyalkyl esters, arylesters, aralkylesters, haloalkyl esters and hydroxyalkyl esters including ketal derivatives thereof, wherein said alkanoyl or alkyl groups have from 1 to 8 carbon atoms and are branched or straight chain and said aryl groups are phenyl, naphthyl or indanyl optionally substituted with one or more C₁-C₄ alkyl, C₁-C₄ alkoxy or C₁-C₄ alkoxycarbonyl groups or halo atoms. Thus examples of R and R⁴ when they are biolabile ester groups include ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxyethyl, pentanoyloxyethyl, acetoxyethyl, acetoxybenzyl, pentanoyloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl. In one preferred aspect of the invention, the group R³ is 4-hydroxybenzyl and the carbon atom to which it is attached is of (S) stereochemistry; the group NHCH(R³)CO₂R⁴ being derived from L-tyrosine. Also preferred are compounds wherein R³ is 4-methoxybenzyl or 3-methanesulphonamidobenzyl. In further aspects of the invention R² is H and Y is (CH₂)₃ or R² is phenyl and Y is (CH₂)₂. In another aspect of the invention R² is R⁶CONR⁵ and Y is CH₂, R³ is 4-hydroxybenzyl, 4-methoxybenzyl or 3-methanesulphonamidobenzyl and R⁶ is of formula R⁹R¹⁰R¹¹C-, wherein R⁹ is (R¹³)₂N-, R¹²SO₂NH- or R¹²CONH-, R¹¹ is amino(C₁-C₆)alkyl and R¹⁰ is H. Particularly preferred are compounds of the formula (I) wherein Y is CH₂ and R² is R⁶CONH- and R⁶CO is (S)-lysyl or N² substituted (S)-lysyl (wherein R⁹ is NH₂, R¹²CONH or R¹² SO₂NH, R¹¹ is 4-aminobutyl and R¹⁰ is H). Preferred substituents for R¹² are methyl and phenyl. Particularly preferred individual compounds of the invention include N-[1-(2(S)-carboxy-3-(S)-lysylaminopropyl)-1-cyclopentanecarbonyl]-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-methanesulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-2-furoyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-4-methoxyphenylalanine, N-[1-(2-carboxy-3-(S)-lysylaminopropyl-1-cyclopentanecarbonyl]-3-methanesulphonamidophenylalanine, N-{1-[2-carboxy-3-(N²-methanesulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-3-methanesulphonamidophenylalanine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-3-methanesulphonamidophenylalanine, and N-{1-[2(S)-carboxy-3-(N²-phenylsulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl }-(S)-tyrosine, and salts and biolabile ester derivatives thereof. The compounds of formula (I) are prepared by a number of different processes: a) One procedure involves the synthesis of a partially protected cycloalkyl-substituted glutaric acid derivative which is coupled to an amino acid ester derivative to give the desired glutaramide. Any reactive groups in R² and R³ may require protection during the coupling step and such protecting groups are removed in the final stage of the process. The synthetic route is illustrated in the following reaction scheme wherein A and R¹ are as previously defined, R 2′ and R 3′ are as defined for R² and R³ with any reactive groups therein protected if necessary and R¹⁷ and R¹⁸ are as defined for R and R⁴ excluding H, or they are conventional carboxylic acid protecting groups: The reaction of the compounds of formula (III) and (IV) is achieved using conventional amide coupling techniques. Thus in one process the reaction is achieved with the reactants dissolved in an organic solvent, e.g. dichloromethane, using a diimide condensing agent, for example 1-ethyl-3-(dimethylaminopropyl)-carbodiimide, or N,N′-dicyclohexylcarbodiimide, advantageously in the presence of 1-hydroxybenzotriazole and an organic base such as N-methylmorpholine. The reaction is generally complete after a period of from 12 to 24 hours at room temperature and the product is then isolated by conventional procedures, i.e. by washing with water or filtration to remove the urea biproduct and evaporation of the solvent. The product may be further purified by crystallisation or chromatography, if necessary. The compounds of formula (V) include compounds of formula (I) wherein R and R⁴ are C₁-C₆ alkyl or benzyl. The diesters of formula (V) are subsequently reacted to give the monoester or diacid derivatives of formula (I) wherein one or both of R and R⁴ are H. The conditions used will depend on the precise nature of the groups R¹⁷ and R¹⁸ present in the compound of formula (V) and a number of variations are possible. Thus for example when both of R¹⁷ and R¹⁸ are benzyl, hydrogenation of the product will yield the diacid of formula (I) wherein R and R⁴ are both H. Alternatively if one of R¹⁷ and R¹⁸ is benzyl and the other is alkyl, hydrogenation will yield a monoester product. This can then be hydrolysed, if desired, to again yield the diacid product. When one of R¹⁷ and R¹⁸ is t-butyl, treatment of the compound of formula (V) with trifluoroacetic acid or hydrogen chloride yields the corresponding acid. If some other carboxylic acid protecting group is used for R¹⁷ or R¹⁸ then clearly appropriate conditions for its removal must be employed in the final step to give the ester or diacid product of formula (I). For example when R¹⁷ or R¹⁸ is trimethylsilylethyl it may be removed by treatment with tetrabutylammonium fluoride. Any protecting groups present in R 2′ and R 3′ must also be removed and this may be performed concominantly with removal of protecting groups present in R¹⁷ and R¹⁸ or as a separate step using procedures appropriate to the particular protecting group employed. Thus, for example when R 2′ contains a substituted or protected amino group (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) the compounds may be converted to the free amines by hydrogenation or hydrolysis as appropriate. (b) In an alternative process, compounds of the formula (I) wherein R² is R⁶CONR⁵- or R⁸SO₂NR⁵- are prepared by a process which involves reacting an amine of the formula: wherein A, Y, R¹, R³, R⁵, R¹⁷ and R¹⁸ are as previously defined; with a carboxylic acid or sulphonyl chloride of the formulae: R⁶CO₂H or R⁸SO₂Cl respectively, or a reactive derivative of the carboxylic acid, wherein R⁶ and R⁸ are as previously defined, and wherein any reactive groups therein are optionally protected, to yield for example a compound of the formula: wherein R 6′ is as previously defined for R⁶ with any reactive groups therein optionally protected; and subsequently removing any protecting groups, if present and, if desired hydrolysing the ester product to yield the compounds of formula (I) wherein R and R⁴ are H. Similarly, reaction with the sulphonyl chloride yields the corresponding sulphonamides. The reaction of the amine of formula (VI) and compound of formula R⁶CO₂H or R⁸SO₂Cl is achieved using conventional amide coupling techniques as previously described or, in the case of the sulphonyl compounds, by reaction with the corresponding sulphonyl chloride. Subsequent removal of protecting groups is achieved using appropriate procedures as previously described. The amines of formula (VI) are prepared following the same procedure outlined in process (a) above but using an acid of formula (III) wherein R 2′ is a protected amine of formula R¹⁹NR⁵- wherein R⁵ is as previously defined and R¹⁹ is an amino-protecting group. Thus, in one variant of this process the coupling reaction with the amino acid derivative is achieved using a compound of formula (III) wherein R² is R¹⁹R⁵N- and R¹⁹ and R⁵ are both benzyl. Alternatively R¹⁹ and R⁵ are both S-α-methylbenzyl to enable the S-isomer of the compound of formula (V) to be isolated. Hydrogenation of the coupled product of formula (V) gives the amine of formula (VI) wherein R⁵ is H. This is then reacted with, for example a protected lysine derivative of formula R⁶CO₂H (wherein R 6′ is R⁹R¹⁰R¹¹C-, R⁹ is protected amino or R¹²CONH-, R¹²SO₂NH-, R¹⁰ is N-protected-4-aminobutyl and R¹¹ is H), deprotection of the resulting product yields the corresponding product of formula (I) wherein R⁶CO is (S)-lysyl or N²-substituted-(S)-lysyl. (c) Compounds of the formula (I) wherein R² is R⁷NR⁵CO- or R⁷NR⁵SO₂ are prepared in an exactly analogous manner to that described above but starting with a carboxylic acid or sulphonic acid of the formula: or wherein A, Y, R¹, R³, R¹⁷ and R¹⁸ are as previously defined, and reacting with an amine of the formula R⁷R⁵NH, followed by removal of protecting groups if present and, if desired, hydrolysing or hydrogenating the ester product to yield the compounds of formula (I) wherein R and R⁴ are H. (d) In a further variant of these processes, the coupling is achieved using a compound of the formula (IV) wherein R 3′ is of formula: Subsequent reduction of the nitro group, followed by sulphonation of the product with a sulphonyl halide of the formula (C₁-C₄)alkyl SO₂Cl yields the corresponding compound of formula (V) wherein R 3′ is Compounds of the formula (I) wherein one or both of R and R⁴ is a biolabile ester-forming group are prepared following similar procedures to those outlined above using the appropriate ester group for R or R⁴. As well as removing any protecting group which may be present in R 2′ , a number of chemical transformation reactions are possible on the final mono-ester or diacid products as previously described. In each case the product may be obtained as the free carboxylic acid or it may be neutralised with an appropriate base and isolated in salt form. Appropriate coupling and protecting methods for all of the above steps and alternative variations and procedures will be well known to those skilled in the art by reference to appropriate text books and to the examples provided hereafter. The starting spiro-substituted glutaric acid mono esters of formula III may be prepared as described in our European patent application 274234. The amino acid esters of formula (IV) are generally known compounds which are either commerically available or they may be prepared by standard methods in accordance with literature precedents. As previously mentioned, the compounds of the invention are potent inhibitors of the neutral endopeptidase (E.C.3.4.24.11). This enzyme is involved in the breakdown of a number of peptide hormones including, in particular the breakdown of atrial natriuretic factor (ANF). Thus, the compounds of the invention, by preventing the degradation of ANF by endopeptidase E.C.3.4.24.11, can potentiate its biological effects and the compounds are thus diuretic, natriuretic and antihypertensive agents of utility in a number of disorders including hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia. Activity against neutral endopeptidase E.C.3.4.24.11 is assessed using a procedure based on the assay described by J. T. Gafford, R. A. Skidgel, E. G. Erdos and L. B. Hersh, Biochemistry , 1983, 32 , 3265-3271. The method involves determining the concentration of compound required to reduce by 50% the rate of release of radiolabelled hippuric acid from hippuryl-L-phenylalanyl-L-arginine by a neutral endopeptidase preparation from rat kidney. As previously mentioned, the compounds of the invention are also inhibitors of angiotensin converting enzyme. As such they are useful in treating a further variety of conditions for which ACE inhibitors are known to be useful including limitation of ischaemic damage to the myocardium, protection of the kidney against hyperfiltration damage, prevention or reversal of left ventricular hypertrophy, memory enhancement, control of cognitive function, dementia, and preventing reocclusion following coronory angioplasty or coronory artery bypass surgery. Their activity against this enzyme is assessed using a modified procedure based on the assay described by Rohrbach, M.S., Anal. Biochem., 1978, 84 , 272. The method involves determining the concentration of compound required to reduce by 50% the extent of release of radiolabelled hippuric acid from hippuryl-L-histidyl-L-leucine by angiotensin converting enzyme isolated from the rat kidney. Inhibitory activity is also measured in vivo following intravenous injection to anaesthetised rats using the methods described by I. L. Natoff et al, Journal of Pharmacological Methods, 1981, 5 , 305 and by D. M. Gross et al, J. Pharmacol. Exp. Ther., 1981, 216 , 552. The dose of inhibitor required to reduce the pressor response produced by intravenous injection of angiotensin I (50 ng bolus) by 50% is determined. The activity of the compounds as diuretic agents is determined by measuring their ability to increase urine output and sodium ion excretion in saline loaded conscious mice. In this test, male mice (Charles River CD1, 22-28 g) are acclimatised and starved overnight in metabowls. The mice are dosed intravenously via the tail vein, with the test compound dissolved in a volume of saline solution equivalent to 2.5% of body weight. Urine samples are collected each hour for two hours in pre-weighed tubes and analysed for electrolyte concentration. Urine volume and sodium ion concentration from the test animals are compared to a control group which received only saline. The antihypertensive activity of the compounds is evaluated by measuring the fall in blood pressure following oral or intravenous administration to salt depleted, diuretic primed, spontaneously hypertensive rats, salt depleted renally hypertensive dogs, or DOCA/salt hypertensive rats. For administration to man in the curative or prophylactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds will generally be in the range of from 3-1500 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly, or in multiple doses, once or several times a day. Dosages for intravenous administration would typically be within the range 1 to 500 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. For human use, the compounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The compounds may be co-administered with other agents as may be beneficial for the control of blood pressure or the treatment of cardiac conditions or renal insufficiency. Thus for example they may be co-administered with digitalis or another cardiac-stimulant drug or with an alpha-blocker, beta-blocker, exogenous ANF or with a potassium channel activator or another diuretic agent as shall be determined by the physician as appropriate to the particular patient or disease state. Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a compounds of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for us in medicine, in particular in the treatment of hypertension, congestive heart failure or renal insufficiency in a human being. The preparation of the compounds of the invention and of intermediates for use in their preparation is illustrated by the following Examples. EXAMPLE 1 N-[1-(2-t-Butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentanecarbonyl]-O- t-butyl-(S)-tyrosine-t-butyl ester To an ice cold solution of 1-(2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentane carboxylic acid (12.7 g, 27 mmole) in dry dichloromethane (100 ml) was added 1-hydroxybenztriazole (4.2 g, 31 mmole), and 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (7 g, 36 mmole) and the resulting solution stirred at 0°C for 30 minutes. To this solution was added O-t-butyltyrosine t-butyl ester (8.4 g, 28.6 mmole) and N-methylmorpholine (5.25 g, 52 mmole) and the solution allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the resultant mobile oil was dissolved in methylene chloride and washed with water (2 x ), 2M hydrochloric acid and saturated aqueous sodium bicarbonate (1 x) dried (MgSO₄), and the solution filtered and evaporated to yield the crude product as a gum. Recrystallisation from n-hexane gave the title compound as a solid (13 g, 69%), m.p. 82-87°C. A further batch of material was obtained by evaporation of the supernatant liquors and further recrystallisation. Found: C,74.12; H,8,69; N,3.87. C₄₅H₆₂N₂O₆ requires C,74.34; H,8.59; N,3.85%. EXAMPLES 2-38 The following compounds were prepared following the general procedure of Example 1 starting with the appropriate carboxylic acid and coupling to the appropriate aminoacid ester. Unless otherwise stated the group -NHCH(R³)CO₂R⁴ is derived from the naturally occurring amino acids having S stereochemistry. Examples 33-35 are the separated isomers having S,S stereochemistry. EXAMPLE 39 1-(2-Benzyloxycarbonylpentyl)-1-cyclopentanecarbonyl-3-methanesulphonamido-(R,S)-phenylalanine benzyl ester (a) A mixture of 1-(2-benzyloxycarbonylpentyl)-1-cyclopentanecarbonyl-3-nitro-(R,S)-phenylalanine benzyl ester (3 g, 499 mmole), zinc dust (7 g, 107 mmole) and ammonium chloride (7 g, 131 mmole) in methanol (200 ml) was heated under reflux for 24 hours. The solvent was removed under reduced pressure, the residue basified to pH 12 by the addition of 2N sodium hydroxide solution and the resulting mixture extracted with ethyl acetate (3 x 75 ml). The combined extracts were washed with brine, dried (MgSO₄) and the solvent evaporated to yield 1-(2-benzyloxycarbonylpentyl)-1-cyclopentanecarbonyl-3-amino-(R,S)-phenylalanine benzyl ester as an oil (2.36 g). (b) Methane sulphonyl chloride (0.56 g, 0.49 mmole), and pyridine (0.039 g, 0.49 mmole) were added to a solution of the amine from part (a) above (0.236 g, 0.41 mmole) in dichloromethane (5 ml) and the solution stirred at room temperature for 1 hour. The solution was diluted with dichloromethane (50 ml), washed with citric acid (1N, 3 x 5 ml), saturated aqueous sodium bicarbonate solution (3 x 5 ml) and water, dried and the solvent evaporated under reduced pressure. The resulting oil was chromatographed on silica gel eluting with dichloromethane followed by a mixture of dichloromethane and methanol (98:2) to give the title product as a viscous oil (0.17 g). EXAMPLE 40 1-(2-t-Butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentanecarbonyl-3-methanesulphonamido-(R,S)-phenylalanine ethyl ester The procedure of Example 39 was followed starting with 1-(2-t-butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentanecarbonyl-3-nitro-(R,S)-phenylalanine ethyl ester (from Example 5) to yield the title compound as an oil (3.17 g, 72%). EXAMPLE 41 1-(2-Carboxypentyl)-1-cyclopentanecarbonyl-3-methanesulphonamido-(R,S)-phenylalanine A solution of 1-(2-benzyloxycarbonylpentyl)-1-cyclopentanecarbonyl-3-methanesulphonamido-(R,S)-phenylalanine benzyl ester (0.16 g) in ethanol (5 ml) and water (1 ml) was hydrogenated over palladium on charcoal catalyst (10%, 0.016 mg) at a pressure of 30 p.s.i. (2 bar) and room temperature for 3 hours. The catalyst was removed by filtration and the solvent evaporated to yield a foam. Trituration with diethyl ether followed by drying under vacuum gave the title product as a glass (0.45 g). Found: C,55.37; H,6.97; N,5.69. C₂₂H₃₂N₂O₇. 0.5 H₂O requires C,55.33; H,6.96; N,5.87%. EXAMPLES 42-46 The following compounds were prepared by catalytic hydrogenation of the corresponding benzyl ester following the procedure of Example 41. EXAMPLE 47 N-[1-(2-Carboxy-4-phenylbutyl)-1-cyclopentanecarbonyl]-(S)-tyrosine A solution of N-[1-(2-benzyloxycarbonyl-4-phenylbutyl))-1-cyclopentanecarbonyl-(S)-tyrosine methyl ester (0.8 g, 1.47 mmole) in methanol (8 ml) was hydrogenated over 10% palladium on charcoal (100 mg) under an atmosphere of hydrogen (25 p.s.i., 1.7 bar) at room temperature for 2 hours. The reaction mixture was filtered through an 'arbacel' pad and evaporated to dryness. The residue was re-dissolved in aqueous sodium hydroxide (0.5 M, 10 ml) and stirred at room temperature for 2 hours. The reaction mixture was washed with diethyl ether and acidified to pH 1 with aqueous hydrochloric acid (10%). The aqueous phase was extracted with diethyl ether (x 2) and the combined organic phases dried (Na₂SO₄) and evaporated to yield the title product as a foam (0.27 g, 40%). Found: C,67.24; H,6.85; N,3.26. C₂₆H₃₁NO₆. 0.25 H₂O requires C,67.54; H,6.97; N,3.03%. EXAMPLES 48-55 The following compounds were prepared by catalytic hydrogenation followed by hydrolysis of the resulting mono ester following the procedure of Example 47. EXAMPLE 56 N-[1-(3-Aminopropyl-2-(S)-t-butyloxycarbonyl)-1-cyclopentanecarbonyl]-O-t-butyl-(S)-tyrosine t-butyl ester N-[1-(2-t-Butyloxycarbonyl-3-dibenzylaminopropyl)-1-cyclopentanecarbonyl]-O-butyl-(S)-tyrosine t-butyl ester (from Example 1, 19 g) was dissolved in an ethanol:water mixture (8:1, 300 ml) and hydrogenated under an atmosphere of hydrogen (60 p.s.i., 4.1 bar) at room temperature, over 20% palladium hydroxide on carbon (2 g). After 24 hours, the solution was filtered through a solkafloc pad, and the filtrate evaporated to yield an oil which crystallised. This was triturated with hexane, chilled and filtered to yield the pure enantiomer title compound as a solid (6 g, 42%) m.p. 122-127°C. Found: C,67.90: H,9.33; N,5.08. C₃₁H₅₀N₂O₆ requires C,68.09; H,9.22; N,5.12%. EXAMPLES 57-78 The following compounds were prepared from the corresponding dibenzylaminopropyl starting material following the procedure of Example 56. EXAMPLE 79 N-[1-(2-(S)-t-Butyloxycarbonyl-3-N-methylaminopropyl)-1-cyclopentane-carbonyl]-O-t-butyl-(S)-tyrosine t-butyl ester a) A stirred solution of N-[1-(3-aminopropyl-2-(S)-t-butyloxycarbonyl)-1-cyclopentanecarbonyl]-O-t-butyl-( S)-tyrosine t-butyl ester (2.0g, 1 equiv) and N-methylmorpholine (0.55 g, 1.5 equiv) in dry dichloromethane (17 ml) was cooled in ice and trifluoroacetic anhydride (1.0 g, 1.3 equiv) in dichloromethane (3 ml) added dropwise over 20 minutes. The solution was stirred for 30 minutes at which time a further aliquot of trifluoroacetic anhydride (0.5 g) was added and the solution stirred for a further 30 minutes. The reaction mixture was diluted with diethyl ether (10 ml), washed with water (2 x 10 ml), dilute hydrochloric acid (2 x 10 ml) , dried (MgSO₄) filtered and the solvent evaporated to yield N-[1-(2-(S)-t-butyloxycarbonyl-3-trifluoroacetamidopropyl)-1-cyclopentane-carbonyl]-O-t-butyl-(S)-tyrosine t-butyl ester as a yellow gum (2.2 g, 94%) b) Dry potassium carbonate (1 g, 2.0 equiv) was added to a cooled and stirred solution of the above product (2.2 g, 1.0 equiv) and methyl iodide (2.0 g; 0.9 ml, 4.0 equiv) in dry dimethylformamide (10 ml) and the mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (10 ml), dilute hydrochloric acid (5 x 5 ml), dried (MgSO₄), filtered and the solvent evaporated to yield the 3-N-methyltrifluroacetamide derivative as a yellow gum (1.95 g, 87%). c) Sodium hydroxide (0.14 g, 1.2 equiv) was added to an ice-cooled and stirred solution of the above trifluoracetamide (1.94 g, 1.0 equiv) in ethanol (10 ml), and the reaction allowed to warm to room temperature for an hour. The reaction mixture was concentrated by evaporation under reduced pressure and diluted with a mixture of ethyl acetate (20 ml) and water (5 ml). The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (10 ml). The combined organic extracts were dried (MgSO₄), filtered and the solvent evaporated to yield an oil which crystallised on standing. Recrystallisation from hexane gave the title product (1.24 g, 75%), m.p. 105-109°C. Found: C, 68.85; H,9.41; N,4.90. C₃₂H₅₂N₂O₆ requires C, 68.54; H,9.35; N,4.99%. EXAMPLE 80 N-{1-[3-Carboxy-2(R,S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine ethyl ester a) A solution of 1-[3-benzyloxycarbonyl-2-t-butyloxycarbonylpropyl]-1-cyclopentanecarboxylic acid (2.55 g, 6.53 mmole) in dry dichloromethane (40 ml) cooled to 0°C, was treated with 1-hydroxybenztriazole (0.97 g, 7.18 mmole); N-methylmorpholine (0.86 g, 8.32 mmole), and 1-ethyl-3-(dimethylaminopropyl)-carbodimide (1.63 g, 8.32 mmole), and the mixture stirred at 0°C for 10 minutes. O-t-Butyl-(S)-tyrosine-ethyl ester (1.73 g, 6.53 mmole) was added, and the reaction allowed to warm to room temperature and stirred overnight. The solvent was then removed from the reaction under reduced pressure and the resultant gum allowed to stand for a further 48 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was separated and then washed with water (2 x 30 ml), saturated brine (30 ml), dried (MgSO₄), filtered, and the solvent evaporated to yield the crude product as an oil. Chromatography over silica gel, eluting with mixtures of hexane and diethyl ether gave N-{1-[3-benzyloxycarbonyl-2(R,S)-t-butyloxycarbonylpropyl]-1-cyclopentane} carbonyl-O-t-butyl-(S)-tyrosine ethyl ester as a yellow oil (2.56 g, 60%). Found: C,69.31; H,8.49; N,2.49. C₃₇H₅₁NO₈ requires C,69.67; H,8.06; N,2.20%. b) The above product (2.48 g, 3.89 mmole) was dissolved in an ethanol;water mixture (9:1,66 ml) and hydrogenated at room temperature under an atmosphere of hydrogen (60 p.s.i., 4.1 bar) over 10% palladium on carbon (250 mg) for 5 hours. The reaction mixture was filtered through a solkaflok pad, and the filtrate evaporated to dryness. The residue was azeotroped with dichloromethane (3x) to yield the crude product as white foam. Charomatography over silica gel, eluting with mixtures of hexane and ethyl acetate gave the title compound as a white foam (1.83 g, 86%). Found: C,65.48; H,8.33; N,1.92. C₃₀H₄₅NO₈ requires C,65.79; H,8.28; N, 2.56%. EXAMPLE 81 N-{1-[3-(N²,N⁶-Dibenzyloxycarbonyl-(S)-lysylamino)-2(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester A solution of N-[1-(3-aminopropyl-2(S)-t-butyloxycarbonyl)-1-cyclopentanecarbonyl]-O-t-butyl-( S)-tyrosine-t-butyl ester (from Example 56, 0.4 g, 0.73 mmole) in dry dichloromethane (10 ml) cooled to 0°C, was treated with 1-hydroxybenztriazole (0.13 g, 0.88 mmole), and 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (0.21 g, 0.88 mmole) and the mixture stirred at 0°C for 30 minutes. N²,N⁶-Dibenzyloxycarbonyl-(S)-lysine (0.33 g, 0.80 mmole) was added, and the reaction allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with methylene chloride (5 ml) and washed with water (2 x 10 ml), dilute hydrochloric acid (1 M, 2 x 10 ml), aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried (MgSO₄), filtered and the solvent evaporated to yield the crude product as an oil. Chromatography over silica gel, eluting with mixtures of hexane and ethyl acetate gave the title compound as a foam (0.55 g, 85%). Found: C,67.47; H,7.99; N,5.74. C₅₃H₁₄N₄O₁₁ requires C,67.49; H,7.91; N,5.94%. EXAMPLES 82-144 The following compounds were prepared following the procedure of Example 81 using the appropriate amine of Examples 56 to 79 and coupling with the appropriate amino acid. Z indicates the benzyloxycarbonyl N-protecting group and BOC indicates the t-butyloxycarbonyl group. Unless otherwise indicated R² and R³ are derived from the naturally occurring amino acids having S stereochemistry. Examples 85-91, 107, 108, 118-141 and 143 are derived from the appropriate amine of formula (VI) from Examples 76-78 having S stereochemistry. EXAMPLES 145-150 The following compounds were prepared according to the method of Example 81 using the appropriate amine. EXAMPLES 151-152 The following compounds were prepared according to the method of Example 81 starting with the N-methyl amine of Example 79. Examples 153-156 The following compounds were prepared by the method of Example 81 starting with the acid of Example 80 and coupling with the appropriate amine. EXAMPLE 157 N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino)-2(R,S)-trimethylsilylethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester A solution of N-{1-[3-(N⁶-t-butyloxycarbonyl-(S)-lysylamino-2(R,S)-trimethylsilylethoxycarbonyl propyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester, (2.5 g, 3.1 mmole) in ice-cold dichloromethane (50 ml) was treated with pyridine (1.25 g, 15.8 mmole) and methanesulphonyl chloride (860 mg, 7.5 mmole) and stirred overnight at room temperature. The solvents were removed under reduced pressure and the residue partitioned between between ethyl acetate and dilute citric acid. The combined extracts were washed with dilute aqueous sodium bicarbonate and brine, dried and evaporated to give a yellow foam which was ehromatographed on silica gel eluting with a mixture of hexane, ethyl acetate and methanol (80:20:5) to give the title product as a colourless foam (1.92 g, 69%). Found: C,58.64; H,8.50; N,6.01. C₄₄H₇₆N₄O₁₁S Si requires C,58.89; H,8.54; N,6.24%. EXAMPLE 158 The fully resolved material was prepared in identical fashion to the above Example starting with the S,S,S isomer to give N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butoxycarbonyl-(S)-lysylamino)-2(S)-trimethylsilylethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl(S)-tyrosine-t-butyl ester. Found C,59.20; H,8.60; N,6.23%. EXAMPLE 159 N-{1-[3-(N⁶-Benzyloxycarbonyl-N²-methanesulphonyl-(S)-lysylamino)-2-(R,S)-ethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine ethyl ester The above procedure was followed starting with the corresponding N⁶-benzyloxycarbonyl derivative to give the title product. Found: C,56.61, H,6.80, N,6.67. C₃₈H₅₄N₄O₁₁S (0.75 CH₂Cl₂) requires C,55.50; H,6.67; N,6.88%. EXAMPLE 160 N-{1-[3-(N⁶-t-Butoxycarbonyl-N²-acetyl-(S)-lysylamino) 2(S)-trimethylsilyl-ethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-3-methanesulphonamido-(S)-phenylalanine t-butyl ester The procedure of Example 157 was followed but using the appropriate diester and reacting with acetyl chloride instead of methanesulphonyl chloride to give the title N²-acetyl derivative as a colourless foam. EXAMPLE 161 N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino-2(R,S)-carboxypropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester A solution of N-{1-[3-(N²-methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino-2(R,S)-trimethylsilylethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine- t-butyl ester (1.80 g, 2.0 mmole) in tetrahydrofuran (20 ml) was treated with a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 3 ml, 3.0 mmole) and heated to 60°C under nitrogen. The solvent was removed under reduced pressure, the residue partitioned between ethyl acetate and dilute citric acid, the combined extracts washed with brine, dried and the solvent evaporated to give a foam which was chromatographed on silica gel eluting with ethyl acetate, methanol, hexane, (4:1:5) to give the pure title product as a foam (1.17 g 74%). Found: C,57.49; H,7.89; N,6.93. C₃₉H₆₄N₄O₁₁S. H₂O requires C,57.46; H,8.16, N,6.87%. EXAMPLE 162 The fully resolved material was prepared in identical fashion to the above from the S,S,S isomer produced in Example 158 to give N-{1-[3-(N²-methanesulphonyl-N⁶-t-butoxycarbonyl-(S)-lysylamino-2(S)-carboxypropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester. Found:C,59.01; H,8.21; N,6.87. C₃₉H₆₄N₄O₁₁S requires C,58.77; H,8.09; N,7.03% EXAMPLE 163 N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino)-2(R,S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysyl-amino)-2(R,S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-tbutyl-(S)-tyrosine ethyl ester (2.21 g, 2.68 mmol) was dissolved in acetone (5.5 ml) and then a 1N aqueous solution of sodium hydroxide (5.36, 5.38 mmol) was added. After stirring for 10 minutes at room temperature the solution was acidified to pH4 with aqueous citric acid (10%). The acetone was then removed on a rotary evaporator and the residue extracted with ethyl acetate (50 ml). The organic phase was separated, washed with saturated brine, dried over magnesium sulphate and the solvent removed under reduced pressure to yield the title compound as a white foam (1.89 g, 88%). Found: C,58.49; H,8.01; N,6.64. C₃₉H₆₄N₄O₁₁S requires C,58.77; H,8.09; N,7.03%. EXAMPLE 164 N-{1-[3-N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino-2-(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine The procedure of Example 163 was followed using the resolved starting material for Example 143 to yield the title compound. Found: C,58.17; H,8.09; N,6.42. C₃₉H₆₄N₄O₁₁S (0.66 H₂O) requires C,57.89; H,8.14; N,6.93%. EXAMPLE 165 N-{1-[3-(N⁶-Benzyloxycarbonyl-N²-methanesulphonyl-(S)-lysylamino)-2-(S)-carboxypropyl]-1-cyclopentanecarbonyl}-O-benzyl-(S)-tyrosine benzyl ester a) Aqueous sodium hydroxide (1N, 9.2 ml, 1 eq) was added to a solution of 1-(3-bis(S)-α-methylbenzyl)amino-2-(S)-butoxycarbonylpropyl)-cyclopentane carboxylic acid (4.5 g, 1 eq) in aqueous ethanol (9:1, 80 ml), and the resultant mixture hydrogenated over 20 % palladium hydroxide (0.5 g) at 60 p.s.i. (4.1 bar) and room temperature overnight. A further 0.5 g of catalyst was added and the hydrogenation continued for a further five hours when t.l.c. indicated the reaction was complete. The catalyst was removed by filtration and the reaction mixture evaporated under reduced pressure. The residue was azeotroped twice with dichloromethane and the amine product finally taken up in dichloromethane and used directly in the next reaction. b) To an ice cold solution of N²-trichloroethoxycarbonyl-N⁶-benzyloxycarbonyl-(S)-lysine (4.17 g) in dry dichloromethane (20 ml) was added 1-hydroxy-benztriazole (1.49 g), and 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (4.46 g) and the resulting solution stirred at 0°C for 30 minutes. To this was added a solution of 1-(2-(S)-t-butoxycarbonyl-3-aminopropyl)-cyclopentane carboxylic acid sodium salt in dichloromethane (10 ml) from part (a), and the reaction allowed to warm to room temperature and stirred overnight. The reaction was evaporated to dryness and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the organic phase washed with water (2 x 10 ml), 1N hydrochloric acid (2 x 10 ml), aqueous sodium bicarbonate, brine and then dried (MgSO₄), filtered, and evaporated to yield the crude product as an oil. This was chromatographed over silica gel (160 g) eluting with mixtures of hexane and ethyl acetate. The desired fractions were combined, concentrated then azeotroped with toluene to yield the pure product as a foam (4.28 g, 66%). c) The activated ester of this material (4.63 g in dichloromethane (20 ml) was prepared as described in part (b), and treated at 0°C with a solution of O-benzyl-(S)-tyrosine benzyl ester tosylate salt (3.48 g) and N-methyl-morpholine (1.33 g) in dichloromethane (20 ml). The reaction was allowed to warm to room temperature and stirred overnight. The solution was then evaporated to dryness, the residue dissolved in ethyl acetate and washed with water (2 x 10 ml), 1N hydrochloric acid (2 x 10 ml), aqueous sodium bicarbonate, brine, dried (MgSO₄), filtered and evaporated to yield the crude product as an oil (8.02 g). This was chromatographed over silica gel (130 g), eluting with mixtures of hexane and ethyl acetate. The appropriate fractions were combined and evaporated to yield the pure coupled product as a foam (4.32 g, 68%). d) To a cooled solution of the product from part (c) (4.32 g) in acetic acid (25 ml) was added activated zinc dust (4 g) in one portion, and the reaction allowed to warm to a room temperature and stirred. After 90 minutes, the solid residue was removed by filtration, and washed with water. The combined filtrate and washings were evaporated under reduced pressure, and the residue azeotroped with toluene (x3), and then taken up in ethylacetate and washed with aqueous sodium bicarbonate. The organic layer was dried, filtered and evaporated to yield the amine product as a gum. e) To a stirred solution of the amine from part (d) (3.38 g), and N-methylmorpholine (0.48 g) in dry dichloromethane (20 ml), cooled to 0°C was added methanesulphonyl chloride (0.49 g), and the reaction mixture allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane (20 ml) and washed with water (2 x 10 ml), 0.1 M hydrochloric acid (10 ml), brine and dried (MgSO₄), filtered and evaporated to yield the crude sulphonamide as a foam (4 g). This was chromatographed over silica gel (65 g) eluting with mixtures of hexane and ethyl acetate to give the desired N²-methanesulphonyl product as a foam (2.9 g, 79%). f) Trifluoracetic acid (15 ml) was added dropwise to a stirred solution of the product from part (e) (2.87 g), and anisole (0.4 g) in dry dichloromethane (15 ml), cooled to 0°C. After 3 hours, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with aqueous sodium bicarbonate (2 x 10 ml), 0.1M hydrochloric acid, and brine, dried (MgSO₄), filtered and evaporated to yield the crude product as a yellow oil (3.5 g). This was chromatographed over silica gel (60 g) eluting with mixtures of hexane and ethyl acetate, with 1% acetic acid, to yield the title acid as a foam (2.6 g, 97%). A portion of this material was converted to the caesium salt, using aqueous ethanolic caesium carbonate. Found: C,54.81; H,5.70; N,5.21. C₄₈H₅₇N₄O₁₁S Cs requires: C,55.92; H,5.57; N,5.43%. EXAMPLE 166 N-{1-[3-(N⁶-Benzyloxycarbonyl-N²-methanesulphonyl-(S)-lysylamino)-2-(S)-pivaloyloxymethoxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-benzyl-(S)-tyrosine benzyl ester Pivaloyloxymethylchloride (0.12 g) was added to a stirred solution of the caesium salt from Example 165 (0.55 g) in dry dimethylformamide (6 ml) and the reaction stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (5 x 10 ml), 1N hydrochloric acid (2 x 10 ml), aqueous sodium bicarbonate (10 ml), brine and dried (MgSO₄), filtered and evaporated to yield the crude product as a pale yellowish oil (0.7 g). Chromatography over silica gel (12 g) eluting with mixtures of hexane and ethylacetate, gave the title ester as a foam (0.465 g, 88%). EXAMPLES 167-170 The following products were prepared by the method of Example 166 using the caesium salt of Example 165 and reacting with the appropriate chloride. EXAMPLE 171 N-{1-[3-(N⁶-Benzyloxycarbonyl-N²-methanesulphonyl-(S)-lysylamino)-2-(S)-indanyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-benzyl-(S)-tyrosine benzylester 1-Ethyl-3-(dimethylaminopropyl)-carbodiimide (0.28 g) was added to a solution of the acid from Example 165(f) (1.0 g) and hydroxybenztriazole (0.17 g) in dichloromethane (25 ml) cooled to 0°C. After 10 minutes, N-methyl morpholine (0.42 g), indanol (0.42 g) and dimethylaminopyridine (10 mg) were added , and the mixture stirred for 72 hours. The reaction mixture was diluted with dichloromethane, washed with water (2 x 10 ml), 2M hydrochloric acid (2 x 10 ml, brine (10 ml), dried (MgSO₄), filtered and evaporated to yield the crude product as an oil. This was chromatographed over silica gel, eluting with mixtures of ethyl acetate and hexane, to yield the title indanyl ester as a foam (0.93 g, 69%). EXAMPLE 172 N-{1-[3-(N⁶-t-Butyloxycarbonyl-N²-methanesulphonyl-(S)-lysylamino)-2(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine 5-indanyl ester The above procedure was followed starting with the acid of Example 164 to give the tyrosine 5-indanyl ester as a foam. Found: C,62.37; H,8.04; N,5.93. C₄₈H₇₂N₄O₁₁S requires: C,63.13; H,7.95; N,6.14%. EXAMPLE 173 N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino)-2(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-ethoxycarbonyl-(S)-tyrosine-ethyl ester. Ethyl chloroformate (0.1093 g, 1.007 mmol) was added to an ice-cooled solution of N-{1-[3-(N²-methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino)-2-(S)-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine-ethyl ester (0.7041 g, 0.916 mmol), triethylamine (0.2781 g, 2.75 mmol and 4-dimethylaminopyridine (0.0112 g in dry dichloromethane (20 ml). After 30 minutes the ice-cooling was removed and the reaction stirred overnight at room temperature. The solvent was then evaporated under reduced pressure and the residual oil partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (50 ml). The phases were separated and the organic phase washed with saturated sodium bicarbonate solution (50 ml), then with saturated brine, (50 ml) and was finally dried over magnesium sulphate, before removing the solvent under reduced pressure to give the crude product as an oil. Chromatography over silica gel, eluting with mixtures of dichloromethane and diethyl ether gave the title compound as a white foam (0.367 g, 48%). Found: C,56.68; H,7.36; N,6.65. C₃₉H₆₄N₄O₁₃S requires C,56.50; H,7.78; N,6.76%. EXAMPLE 174 N-{1-[3-(N²-Methanesulphonyl-N⁶-t-butyloxycarbonyl-(S)-lysylamino)-2-(R,S)-t-butoxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-cyclohexyloxycarbonyl-(S)-tyrosine-cyclohexyl ester The title compound was prepared in an analogous manner to Example 173 but starting with Example 116 and reacting with cyclohexyl chloroformate to give the title product as a white foam (1.672 g, 81%). Found: C,60.69; H,8.16; N,6.14. C₄₈H₇₆N₄O₁₃S requires C,60.73; H,8.07; N,5.90%. EXAMPLE 175 N-{1-[2-(S)-t-Butyloxycarbonyl-3-(N⁶-t-butyloxycarbonyl-N²-ethyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S)-tyrosine-t-butyl ester. Sodium cyanoborohydride (45 mg) was added in one portion to a stirred, ice cold solution of N-{1-[2-(S)-t-butyloxycarbonyl-3-(N⁶-t-butyloxycarbonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl-O-t-butyl-(S)-tyrosine-t-butyl ester (507 mg) and acetaldehyde (31 mg) in aqueous ethanol (80%, 10 ml) and the pH adjusted to 5 with 1N hydrochloric acid. The resulting solution was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The phases were separated and the organic phase washed with a little aqueous sodium bicarbonate, dried (MgSO₄), filtered and evaporated. The residue was chromatographed over silica gel, eluting with mixtures of hexane and ethyl acetate containing 1% diethylamine to yield the title compound as an oil (370 mg, 64%) Rf 0.55 (silica; CH₂Cl₂, CH₃OH, NH₄OH; 90:10:1). EXAMPLE 176 N-{1-[3-(N²,N⁶-Dibenzyloxycarbonyl-(S)-lysylamino)-2(S)-carboxypropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine Hydrogen chloride gas was passed through a stirred, ice cold solution of N-{1-[3-(N²,N⁶-dibenzyloxycarbonyl-(S)-lysylamino)-2-t-butyloxycarbonylpropyl]-1-cyclopentanecarbonyl}-O-t-butyl-(S) - tyrosine-t-butyl ester (from Example 81, 0.445 g, 0.47 mmole), and anisole (0.765 g, 7.1 mmole) in dry dichloromethane (10 ml) until saturation was achieved. A precipitate formed. After stirring for 1.5 hours, the solvent was evaporated under reduced pressure, and the residue azeotroped with dry dichloromethane. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The phases were separated, and the organic phase washed with two further portions of aqueous sodium bicarbonate. The combined aqueous phases were re-extracted with diethyl ether, and then acidified with 1M hydrochloric acid to pH. 2. The aqueous phase was extracted with ethyl acetate (2 x ) and the combined organic phase dried (MgSO₄), filtered and the solvent evaporated to yield a foam, which was azeotroped with methylene chloride to yield the title compound as a solid foam (0.325 g, 89%). Found: C,62.81; H,6.68; N,6.92. C₄₁H₅₀N₄O₁₁ 0.4 CH₂Cl₂ requires C,61.17; H,6.33; N,6.93%. EXAMPLE 177 N-[1-(2(S)-Carboxy-3-(S)-lysylaminopropyl)-1-cyclopentane carbonyl]-(S)-tyrosine The product from Example 176 (0.247 g, 0.32 mmole) was dissolved in an ethanol:water mixture (9:1, 20 ml) and hydrogenated at room temperature under an atmosphere of hydrogen (60 p.s.i., 4.1 bar) over 10% palladium on carbon (100 mg) overnight. The reaction mixture was filtered through a solkaflok pad, and the filtrate evaporated to dryness. The residue was azeotroped with dichloromethane (3 x ) to yield the title compound as a foam (0.12 g, 74%). Found: C,56.87; H,7.76; N,10.36. C₂₅H₃₈N₄O₇ 0.65 H₂O requires C,57.93; H,7.64; N,10.81%. EXAMPLES 178-213 The following compounds were prepared following the deprotection procedures of Examples 176 and 177 as appropriate starting with the corresponding t-butyl or benzyl ester/t-butyloxycarbonyl or benzyloxycarbonyl protected compound. Unless otherwise stated compounds derived from lysine and tyrosine are of (S) stereochemistry. Examples 178-187, 203 and 204 are derived from the resolved compounds having S,S stereochemistry. EXAMPLES 214-245 The following compounds were prepared from the appropriate t-butyl or benzyl ester/t-butoxycarbonyl or benzyloxycarbonyl protected compound by treatment with HCl and or hydrogenation following the procedure of Examples 176 and 177 as appropriate. Lysine derivatives are of (S) stereochemistry unless otherwise stated. EXAMPLES 246-259 The following compounds were prepared from the appropriate t-butyl or benzyl ester/t-butoxycarbonyl or benzyloxycarbonyl protected compound by treatment with HCl and/or hydrogenation following the procedures of Examples 176 and 177 as appropriate. Moities derived from lysine and tyrosine are of (S) stereochemistry unless otherwise stated. Examples 249, 251, 252, 258 and 259 are fully resolved S,S,S isomers. EXAMPLES 260-263 The following compounds were prepared by deprotection of the corresponding N-butyloxycarbonyl or N-benzyloxycarbonyl derivative following the procedure of Example 176 or 177 starting with the appropriate S,S,S isomer. EXAMPLE 264 N-{1-[3-(N²-Acetyl-(S)-lyslyamino)-2-carboxypropyl]-1-cyclopentanecarbonyl}-3-methanesulphonamido-(R,S)-phenylalanine A solution of N-{1-[3-N²-acetyl-(S)-lysylamino-2-carboxypropyl]-1-cyclopentanecarbonyl}-3-methanesulphonamido-(R,S)-phenylalanine ethyl ester (from Example 195, 0.21 g) in ethanol (10 ml) was treated with sodium hydroxide solution (5 ml 2N) and the solution stirred at room temperature for 3½ hours. The reaction mixture was poured onto a column of a strongly acidic ion-exchange resin, which was washed to neutrality and the product subsequently eluted with aqueous pyridine (3%). Evaporation of the product containing fractions gave the title dicarboxylic acid as a glass (0.092 g, 46 %), m.p. 160-164°C. Found: C,51.32; H,6.86; N,10.75. C₂₈H₄₃N₅O₉S (1.5 H₂O) requires C,51.52; H,7.10; N,10.73%. EXAMPLES 265-273 The following products were prepared following the procedure of Example 264 starting with the appropriate ethyl ester. Examples 267 and 273 are resolved compounds having S,S,S, stereochemistry. EXAMPLE 274 N-{1-[3-(N²-Methanesulphonyl-(S)-lysylamino)-2-(S)-carboxypropyl]-1-cyclopentanecarbonyl}-3-methanesulphonamido-(S)-phenylalanine The title compound was prepared from Example 259 in the following manner: The N²-methanesulphonyl group was introduced using the procedure of Example 157 to yield the N²-methanesulphonyl derivative as an oil. Found: C,52.09; H,7.75; N,7.32. C₄₁H₇₁N₅O₁₂S₂Si (1.5 H₂O) requires C,52.09; H,7.89; N,7.41%. The trimethylsilyethyl protecting group was removed using the procedure of Example 161 to yield the monoacid as a white foam. Found: C,51.81; H,7.30; N,7.95. C₃₆H₅₉N₅O₁₂S₂ (H₂O) requires C,51.72; H,7.35; N,8.37%. And finally the title diacid was prepared from the monoacid by treatment with HCl using the procedure of Example 176 and was obtained as a white powder. Found: C,45.65; H,6.70; N,8.59. C₂₇H₄₃N₅O₁₀S₂ (1 HCl, 0.75 ethyl acetate, 1.5 H₂O) requires C,45.53; H,6.75; N,8.85%. EXAMPLE 275 N-{1-[3-(S)-Lysylamino-2-(S)-carboxypropyl]-1-cyclopentanecarbonyl}-3-methanesulphonamido-(S)-phenylalanine The title compound was prepared from Example 150 in the following manner: The trimethylsilyethyl protecting group was removed using the procedure of Example 161 to yield the monoacid as a white foam. Found: C,57.66; H,7.17; N,7.62. C₄₃H₆₃N₅O₁₂S(H₂O) requires C,57.89; H,7.34; N,7.85%. Further deprotection using the procedure of Example 176 gave the diacid as a white foam. Found; C,51.02; H,6.46; N,8.33. C₃₄H₄₇N₅O₁₀S (HCl, 2.5H₂O) requires C,51.09; H,6.68; N,8.76%. The benzyloxycarbonyl group was then removed using the procedure of Example 177 to give the title compound as a white powder. R f 0.17 (methyl isobutylketone, water, acetic acid, 2:1:1). EXAMPLE 276 N-{1-[3-(N²-Methanesulphonyl-(R,S)-(1-imidazolyl)alanylamino)-2-(S)-carboxypropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine N²-Methanesulphonyl-(R,S)-(1-imidazolyl)alanine was coupled to N-[1-(3-aminopropyl-2(S)-t-butyloxycarbonyl)-1-cyclopentanecarbonyl]-O-t-butyl-( S)-tyrosine t-butyl ester (Example 56) using the procedure of Example 81 to give the product as a white foam. Found: C,59.46; H,7.90; N,9.04. C₃₈H₅₉N₅O₉S requires C,59.89; H,7.80; N,9.19%. This material was deprotected by treatment with the HCl using the procedure of Example 176 to give the title compound as a white powder. R f 0.30 (methyl isobutylketone, water, acetic acid 2:1:1) EXAMPLE 277 N-{1-[3-(N²-Methanesulphonyl-N²-methyl-(S)-lysylamino)-2-carboxypropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine N⁶-Benzyloxycarbonyl-N²-methanesulphonyl-N²-methyl-lysine was coupled to N-[1-(3-aminopropyl-2(S)-t-butyloxycarbonyl)-1-cyclopentanecarbonyl]-O-t-butyl-( S)-tyrosine t-butyl ester (Example 56) using the procedure of Example 81 to give the product as a white foam. Found: C,62.40; H,8.17; N,6.30. C₄₇H₇₂N₄O₁₁S requires C,62.64; H,8.05; N,6.22%. Deprotection of this material following the procedures of Examples 176 and 177 gave the title compound. Found C,50.26; H,7.17; N,8.60. C₂₇H₄₂N₄O₉S (2.5 H₂O) requires C,50.37; H,7.36; N,8.70%. EXAMPLE 278 N-{1-[3-(N²-Methanesulphonyl-(S)-lysylamino)-2-(S)-carboxypropyl]-1-cyclopentanecarbonyl}-S-tyrosinamide The title compound was prepared from Example 164 by coupling with ammonia using the procedure of Example 171 to give the primary amide as a white foam. Deprotection of this material with HCl using the procedure of Example 176 gave the title compound as a white powder. Found: C,53.02; H,7.38; N,11.26. C₂₆H₄₁N₅O₈S (0.45 H₂O) requires C,52.76; H,7.14; N,11.83%. EXAMPLE 279 N-{1-[3-(N²-Methanesulphonyl-(S)-lysylamino)-2-(1-(R,S)-isobutyryloxyethoxy)carbonylpropyl-1-cyclopentantecarbonyl}-(S)-tyrosine The title compound was prepared in the following manner. Alkylation of the product of Example 161 with 1-(R,S)-isobutyryloxyethyl chloride using the procedure of Example 166 gave the protected ester a white foam. Found: C,57.36; H,7.91; N,5.74. C₄₅H₇₄N₄O₁₃S (0.5CH₂Cl₂) requires C,57.30; H,7.93; N,5.88%. Deprotection of this product with HCl using the procedure of Example 176 gave the title ester as a white powder. Found: C,51.32; H,7.25; N,6.86. C₃₂H₅₀N₄O₁₁S (HCl, H₂O) requires C,51.02; H,7.09; N,7.43%. EXAMPLE 280 N-{1-[3-(N²-Methanesulphonyl-(S)-lysylamino)-2-(1-(R,S)-benzoyloxyethoxy)carbonylpropyl]-1-cyclopentanecarbonyl}-(S)-tyrosine The title compound was prepared by alkylation of the product of Example 161 with 1-(R,S)-benzyloxy-ethyl chloride using the procedure of Example 166 to give the protected ester derivative. Deprotection of this material with HCl using the procedure Example 176 gave the title ester as a white powder. Found: C,54.82; H,6.57; N,7.01. C₃₅H₄₇N₄O₁₁S (HCl) requires C,54.72; H,6.30; N,7.29%.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound having the formula-: and pharmaceutically acceptable salts thereof and bioprecursors therefor wherein: A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated; R¹ is H or (C₁-C₄)alkyl; R and R⁴ are each independently H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, benzyl, or an alternative biolabile ester-forming group; Y is either a direct bond or an alkylene group of from 1 to 6 carbon atoms which may be straight or branched chain; R² is H, aryl, heterocyclyl, R⁶CONR⁵-, R⁷NR⁵CO-, R⁷NR⁵SO₂- or R⁸SO₂NR⁵-, with the proviso that Y is not a direct bond when R² is H, aryl or heterocyclyl; wherein R⁵ is H, (C₁-C₆)alkyl or aryl(C₁-C₆)alkyl; R⁶ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R⁹ is H, OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl, R¹²CONH-, R¹²SO₂NH- or (R¹³)₂N-; R¹⁰ and R¹¹ are each independently H or (C₁-C₆)alkyl; or R¹⁰ is H and R¹¹ is amino(C₁-C₆)alkyl, imidazolylmethyl, aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl or methylthio(C₁-C₆)alkyl; or the two groups R¹⁰ and R¹¹ are joined together to form, with the carbon atom to which they are attached, a 3 to 6 membered carbocyclic ring or a pyrrolidine or piperidine ring which may optionally be substituted by amino, (C₂-C₄)alkanoyl or aroyl; R¹² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; each R¹³ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl or the two groups R¹³ are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C₁-C₄)alkyl-piperazinyl group; R⁷ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R¹⁰ and R¹¹ are as previously defined and R¹⁴ is (R¹³)₂NCO-, R¹²OCH₂- or R¹⁵OCO, wherein R¹² and R¹³ are as previously defined and R¹⁵ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or aryl(C₁-C₆)alkyl; and R⁸ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; R³ is a group of the formula: wherein R¹⁶ is H, halo, 4-OH, 4-(C₁-C₆ alkoxy), 4-(C₃-C₇ cycloalkoxy),4-(C₂-C₆ alkenyloxy), 4-[(C₁-C₆ alkoxy)carbonyloxy], 4-[(C₃-C₇ cycloalkoxy)carbonyloxy], or 3-(C₁-C₄ alkyl)SO₂NH-; and R²⁰ is H,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₂-C₆)alkanoyl or halo; or R³ is a group of the formula: wherein said groups may optionally be substituted in the fused benzene ring by (C₁-C₄)alkyl, (C₁-C₄)alkoxy, OH, halo or CF₃. A compound as claimed in claim 1 wherein A is (CH₂)₄ and R¹ is H having the formula: A compound as claimed in claim 1 or claim 2 wherein one of R and R⁴ is a biolabile ester-forming group. A compound as claimed in claim 3 wherein said biolabile ester-forming group is selected from ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxyethyl, pentanoyloxyethyl, acetoxyethyl, acetoxybenzyl, pentanoloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl. A compound as claimed in claim 4 wherein said biolabile ester group is pivaloyloxymethyl. A compound as claimed in any one of claims 1 to 5 wherein R³ is 4-hydroxybenzyl, 4-methoxybenzyl, or 3-methanesulphonamidobenzyl, and the carbon atom to which it is attached is of (S) stereochemistry. A compound as claimed in any one of claim 1 to 5 wherein Y is CH₂. A compound as claimed in any one of claims 1 to 7 wherein R² is a group of the formula R⁶CONR⁵. A compound as claimed in claim 8 wherein R⁶ is of formula R⁹R¹⁰R¹¹C- wherein R⁹ is (R¹³)₂N-, R¹²SO₂NH- or R¹²CONH- wherein R¹² and R¹³ are as previously defined, R¹¹ is amino(C₁-C₆)alkyl and R¹⁰ is H. A compound as claimed in claim 9 wherein R⁶CO is (S)-lysyl or N² substituted-(S)-lysyl of formula R⁹R¹⁰R¹¹CO- wherein R⁹ is NH₂, R¹²CONH or R¹²SO₂NH and R¹² is as previously defined, R¹¹ is 4-aminobutyl and R¹⁰ is H. A compound as claimed in claim 10 wherein R⁶CO is (S)-lysyl, N²-methanesulphonyl-(S)-lysyl, N²-phenylsulphonyl-(S)-lysyl or N²-acetyl-(S)-lysyl. A compound as claimed in claim 1 selected from-: N-[1-(2(S)-carboxy-3-(S)-lysylaminopropyl)-1-cyclopentanecarbonyl]-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-methanesulphonyl-(S)lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-2-furoyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-4-methoxyphenylalanine, N-[1-(2-carboxy-3-(S)-lysylaminopropyl-1-cyclopentanecarbonyl]-3-methanesulphonamidophenylalanine, N-{1-[2-carboxy-3-(N²-methanesulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-3-methanesulphonamidophenylalanine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-3-methanesulphonamidophenylalanine, and N-{1-[2(S)-carboxy-3-(N²-phenylsulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, and pharmaceutically acceptable salts and biolabile ester derivatives thereof. A pharmaceutical composition comprising a compound of the formula (I) or (II) as claimed in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier. A compound of the formula (I) or (II) as claimed in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, particularly for the treatment of hypertension, heart failure or renal insufficiency. The use of a compound of the formula (I) or (II) as claimed in any one of claims 1 to 12, or of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertension, heart failure or renal insufficiency. Claims for the following Contracting States : ES, GR A process for preparing a compound having the formula-: wherein: A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated; R¹ is H or (C₁-C₄)alkyl; R and R⁴ are each independently H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, benzyl, or an alternative biolabile ester-forming group; Y is either a direct bond or an alkylene group of from 1 to 6 carbon atoms which may be straight or branched chain; R² is H, aryl, heterocyclyl, R⁶CONR⁵-, R⁷NR⁵CO-, R⁷NR⁵SO₂- or R⁸SO₂NR⁵-, with the proviso that Y is not a direct bond when R² is H, aryl or heterocyclyl; wherein R⁵ is H, (C₁-C₆)alkyl or aryl(C₁-C₆)alkyl; R⁶ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R⁹ is H, OH, (C₁-C₆)alkoxy, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl, R¹²CONH-, R¹²SO₂NH- or (R¹³)₂N-; R¹⁰ and R¹¹ are each independently H or (C₁-C₆)alkyl; or R¹⁰ is H and R¹¹ is amino(C₁-C₆)alkyl, imidazolylmethyl, aryl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl or methylthio(C₁-C₆)alkyl; or the two groups R¹⁰ and R¹¹ are joined together to form, with the carbon atom to which they are attached, a 3 to 6 membered carbocyclic ring or a pyrrolidine or piperidine ring which may optionally be substituted by amino, (C₂-C₄)alkanoyl or aroyl; R¹² is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; each R¹³ is H, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl or the two groups R¹³ are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C₁-C₄)alkyl-piperazinyl group; R⁷ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl, heterocyclyl(C₁-C₆)alkyl or a group of the formula: wherein R¹⁰ and R¹¹ are as previously defined and R¹⁴ is (R¹³)₂NCO-, R¹²OCH₂- or R¹⁵OCO, wherein R¹² and R¹³ are as previously defined and R¹⁵ is (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl or aryl(C₁-C₆)alkyl; and R⁸ is (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heterocyclyl or heterocyclyl(C₁-C₆)alkyl; R³ is a group of the formula: wherein R¹⁶ is H, halo, 4-OH, 4-(C₁-C₆ alkoxy), 4-(C₃-C₇ cycloalkoxy), 4-(C₂-C₆ alkenyloxy), 4-[(C₁-C₆ alkoxy)carbonyloxy], 4-[(C₃-C₇ cycloalkoxy)carbonyloxy], or 3-(C₁-C₄ alkyl)SO₂NH-; and R²⁰ is H,(C₁-C₄) alkyl, (C₁-C₄)alkoxy(C₂-C₆)alkanoyl or halo; or R³ is a group of the formula: wherein said groups may optionally be substituted in the fused benzene ring by (C₁-C₄)alkyl, (C₁-C₄)alkoxy, OH, halo or CF₃; which process comprises removing one or both of the ester-forming or protecting groups R¹⁷ and R¹⁸, or if both are protecting groups, removing both protecting groups, and removing any further protecting groups in R 2′ and R 3′ from a compound of the formula: wherein A and R¹ are as previously defined, R 2′ and R 3′ are as defined for R² and R³ with any reactive groups therein optionally protected and R¹⁷ and R¹⁸ are as defined for R and R⁴ excluding H, or they are conventional carboxylic acid protecting groups; and optionally forming a pharmaceutically acceptable salt of the product. A process as claimed in claim 1 wherein the groups R¹⁷ and R¹⁸ are independently selected from benzyl, t-butyl, C₁-C₂ alkyl and trimethylsilylethyl and said groups are removed by catalytic hydrogenation, treatment with hydrogen chloride or trifluoroacetic acid, aqueous hydrolysis or treatment with tetrabutylammonium fluoride respectively. A process as claimed in claim 1 or claim 2 wherein A is (CH₂)₄ and R¹ is H having the formula: wherein R, R², R³ and R⁴ are as previously defined. A process as claimed in claim 1 or claim 2 wherein one or R¹⁷ and R¹⁸ is a biolabile ester forming group, and said group is not removed. A process as claimed in claim 4 wherein said biolabile ester forming group is selected from ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-onyl)methyl, cyclohexylmethyl, cyclohexylcarboxyethyl, cyclohexylacetoxyethyl, propionyloxyisobutyl, hexanoyloxyethyl, pentanoyloxyethyl, acetoxyethyl, acetoxybenzyl, pentanoloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl. A process as claimed in claim 5 wherein said biolabile ester group is pivaloyloxymethyl. A process as claimed in any one of claims 1 to 6 wherein R³ is 4-hydroxybenzyl, 4-methoxybenzyl, or 3-methanesulphonamidobenzyl, and the carbon atom to which it is attached is of (S) stereochemistry. A process as claimed in any one of claim 1 to 6 wherein Y is CH₂. A process as claimed in any one of claims 1 to 8 wherein R² is a group of the formula R⁶CONR⁵. A process as claimed in claim 9 wherein R⁶ is of formula R⁹R¹⁰R¹¹C- wherein R⁹ is (R¹³)₂N-, R¹²SO₂NH- or R¹²CONH- wherein R¹² and R¹³ are as previously defined, R¹¹ is amino(C₁-C₆)alkyl and R¹⁰ is H. A process as claimed in claim 10 wherein R⁶CO is (S)-lysyl or N² substituted-(S)-lysyl of formula R⁹R¹⁰R¹¹CO- wherein R⁹ is NH₂, R¹²CONH or R¹²SO₂NH and R¹² is as previously defined, R¹¹ is 4-aminobutyl and R¹⁰ is H. A process as claimed in claim 11 wherein R⁶CO is (S)-lysyl, N²-methanesulphonyl-(S)-lysyl, N²-phenylsulphonyl-(S)-lysyl or N²-acetyl-(S)-lysyl. A process as claimed in claim 1 wherein said compound of formula I produced is selected from-: N-[1-(2(S)-carboxy-3-(S)-lysylaminopropyl)-1-cyclopentanecarbonyl]-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-methanesulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-2-furoyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-4-methoxyphenylalanine, N-[1-(2-carboxy-3-(S)-lysylaminopropyl-1-cyclopentanecarbonyl]-3-methanesulphonamidophenylalanine, N-{1-[2-carboxy-3-(N²-methanesulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-3-methanesulphonamidophenylalanine, N-{1-[2(S)-carboxy-3-(N²-acetyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-3-methanesulphonamidophenylalanine, and N-{1-[2(S)-carboxy-3-(N²-phenylsulphonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}-(S)-tyrosine, and pharmaceutically acceptable salts and biolabile ester derivatives thereof.

Inventors: DANILEWICZ, JOHN CHRISTOPHER, DR., JAMES, KEITH, DR., KOBYLECKI, RYSZARD JUREK, DR.
Applicants: PFIZER INC., PFIZER LIMITED
Application year: 1989
Main classification: C07C237
IPC codes: A61P9, A61P15, C07C271, A61K31, C07F7, C07D233, C07C233, C07C235, C07D207, C07D317, A61P43, C07C311, C07D231, A61P3, C07C323, C07D521, C07D307, A61P13, C07C237, C07D209, C07D213, A61P27, A61P7