CYCLOALKYL-SUBSTITUTED GLUTARAMIDE DIURETIC AGENTS

Abstract: Compounds of formula (I), wherein A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring; B is (CH2)m wherein m is an integer of from 1 to 3; each of R and R<4> is independently H, C1-C6 alkyl, benzyl or an alternative biolabile ester-forming group; R<1> is H or C1-C4 alkyl; R<2> is C1-C6 alkyl substituted by C1-C4 alkoxy, aryl or aryloxy and R<5> is defined to include a range of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and substituted alkyl groups including in particular methoxyethyl, 2-methoxyethoxymethyl, N<2>-substituted-S-lysylaminomethyl, R-alanylaminomethyl and (2-amino-2-methyl-propanoyl) aminomethyl; are atriopeptidase inhibitors of utility in the treatment of hypertension, heart failure, renal insufficiency and other disorders.

Description: Cycloalkyl-substituted Glutaramide Diuretic Agents This invention relates to a series of cyclo___-cyl--substituted glt-taramide derivatives which are diuretic agents having utility in a variety of therapeutic areas inclnding the treatment of various c-_u__dicwascular disorders such as hypertension, heart failure and renal insufficiency. According to the specification of our European patent applications EP-A-0274234 and EP-A-0343911 we describe and claim certain cyclc-_l_<yl-substitu_ted gluterainide derivatives as diuretic agents. The present invention provides further related ∞πpαunds having an extended substituent group in the ε_ιdnocyclθ-__lc_ ec____x_)-__γlate ring. The σcπpσunds are inhibitors of the zinc-dependent, neutral endopeptidase E.C.3.4.24.11. This enzyme is involved in the breakdown of several peptide hormones, ir_cluding atrial natriuretic factor (ANF) , which is secreted by the heart and vdiich has potent vasodilatory, diuretic and natriuretic activity. Thus, the compounds of the invention, by .uihibiting the neutral endcpeptidase E.C.3.4.24.11, can potentiate the biological effects of ANF, and in particular the ccπpoun s are diuretic agents having utility in the treatment of a number of disorders, including hypertension, heart failure, angina, renal insufficiency, pr__Tienstrual syndrome, cyclical oedema, Meniέres disease, hyperε&dosteronism (primary and secondary) pulmonary oedema, ascites, and hypercalciiiria. In addition, because of their ability to potentiate the effects of ANF the cxπpounds 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 -xaπpαunds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, e ilepsy, affective disorders, dementia and geriatric confusion, obesity and g-ustrointestinal disorders (especially diarrhoea and irritable bowel syndrome) , the modulation of gastric acid secretion and the treatment of hyperreninaemia and leukemia. The ccxπpcunds of the present invention are of the formula: (I) wherein A cxxπpletes a 4 to 7 meaiibered carbocyclic ring which may be saturated or moιx -_msat'urated and which may optionally be fused to a further satαjrated or --^saturated 5 or 6 membered carbocyclic ring ; B is (Cfr ) wherein m is an integer of from 1 to 3; each of R and R 4 i .s independently H, C.-C alkyl, benzyl or an alternative biolabile ester-forming group; R 1 is H or C--C 4 alkyl; 2 . R is C- ^ -Cg alkyl substituted by C-.-C. alkoxy, aryl or aryloxy; 5 . and R is C j -Cg alkyl, C-,-C 6 alleπyl, C -C alkynyl, C--G- cycloalkyl, or C -CL cycdoalHryl, 5 or R is C,-C 6 alkyl substituted by halo, hydroxy, C--C alkoxy, C--C 6 a3_-θxy(C.-C 6 )alkoxy, C -C_ cycloalkyl, C_-CL cydoalkenyl, aryl, aryloxy, heterocyclyl, -NE * TR , →-3. 8 COR 9 , -NR 8 S0 2 R 10 , 5 . or R is C,-Cg alkyl substituted by a group of the formula: R 12 11 " 13 HNR OO-C-R ,12 R 13 11 14 -CX-WR -C- 6 7 wherein R and R are each independently H, Cy-C alkyl, C_-<_L cycloalkyl, aryl, a__yl(C,-C )alkyl, C -C 8 alkαxyalkyl, or heterocyclyl; or the two groups R and R are taken together with the nitrogen to which they are attached to form a pryrrolidinyl, piperidino, morpholino, piperazinyl or N-(CL-C 4 )-__kyl-piper_tzinyl grcup; Q R is H or Cy-C. alkyl; g , R is Cy-C. alkyl, CSL, aryl, aryl(C.-C )alkyl, aryl(C,-C.)alko>cy, heteorcyclyl, C.-C alkoxy or NETR 6 7 wherein R and R are as previcusly defined; R is C.-C. alkyl, C--CL cycioalkyl, aryl or heterocyclyl; R is H, Cy-Cg alkyl, aryl or C -CL cycloalkyl; R 12 is R n <_ONR 11 -, R 1:L S0 2 NR 1:L -, ^^N-CO^) -, or R 0-, wherein each R is as previously defined above; 13 14 R and R are each independently H or C,-C β alkyl; or 13 14 R is H and R is -C alkyl which is substituted by CH, C--C 4 alkoxy, SH, SCH-, OC0NH-, NH-00-, C0 2 H, guanidino, aryl, or heterocyclyl; 13 14 or the two groups R and R are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered cai ocyclic ring which may be saturated or ιrorx ^unsaturated and which may optionally be substituted by C.-C alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring; or R is H, and R and R are linked to form a 2-(N-COR -4-_αιιirκ3pyιτoli-__nyl) group; R 15 is R 16 R 17 Nαo-, R 1:L oαo-, R 1*l Oα_ 2 - or heterocyclyl, wherein R is as previously defined above; 16 17 R and R are each independently H or Cy-C 8 alkyl; and p is 0 or an integer of from 1 to 6; and p-___-maceutically acxeptable 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 hydrocarbcai group such as phenyl, naphthyl or bipheπyl which may optionally be si±istituted with one or more OH, CN, CF_, C.-C. alkyl, C-.-C. alkoxy groups or halo atoms. Halo means fluoro, chloro, brcmo or iodo. The term heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur (_ontaining heterocyclic group which, unless σtherwise 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, C,-C. alkyl, hydroxy, carbamqyl, benzyl, oxo, amino or mono or di-(C.-C, alkyl)amino or (C.-C. alkancyl)amino groups. Particular exaπples of heterocycles include pyridyl, pyraziπyl, pyr_i_midiπyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furaπyl, te * t---_ιyd__Ofuraπyl, tetrahydrcpyranyl, diσxaπyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindoliπyl, quinolyl, quinαxaliiψl, quinazoliπyl and benzimidazolyl, each being optionally substituted as previously defined. The coπpounds of formula (I) may contain several asymmetric centres and thus they can exist as enaπticmers and diaste__eαmers. The invention includes both πiixtures and the separated individual isα^s. *. ^^ents *». a,* ∞ Have c or t»_» geometry relative to the amide att_achmeπt. The pharmaceutically acceptable salts of the coitpounds of formula (I) coritaining an acidic centre are those formed with bases which form non-toxic salts. Examples include the alkali metal salts such as the sodium, potassium or calcium salts or salts with amines such as diethylamine. Ccaπpσunds 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, suσcinate and tartrate salts. The term biαpreαxrsor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the coπpound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a ccnpound of the formula (I) . A preferred group of coπpcunds of the foπtula (I) are those wherein A is (CH-)., R is H and B is (CH-)_, i.e. coπpcunds of 2 4 5 the formula (II) below wherein R, R , R and R are as previously defined for formula (I) : (ID Also preferred are those compounds of formulae (I) and (II) 4 . . . wherein R and R are both H (diacids) as well as biolabile mono 4 and di-ester derivatives thereof wherein one or both of R and R is a biolabile est__r-forming group. The term biolabile ester-forming group is well -...derstood in the art as meaning a group which provides an ester which can be readily cleaved in the body to liberate the corresponding diacid 4 of formula (I) wherein R and R 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-irihibitor eur±-iΛypertensive agents. In the case of the (_caτpcunds of formulae (I) and (II) such biolabile pro-drug esters are particularly advantageous in providing cxxipcunds of the formula (I) suitable for oral administration. The suitability of any particular ester-fo ing 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, acxxjrdingly, the ester should be resistant to hydrolysis before absorption by digestive enzymes but should be readily hydrolysed by, for example, 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, suitable biolabile esters include a_______y-yloxyalkyl esters, includi g alkyl, cycloalkyl and aryl substituted derivatives thereof, aryloxyalkyl esters, εtroyloxyalkyl esters, arylalkylojQTalkyl esters, arylesters, aralkylesters, and haloalkyl esters wherein said alkancyl 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 C--C alkyl or C.-C. alkoxy groups or halo atoms. 4 Thus exaπples of R and R when they are biolabile ester-forming groups other than ethyl and benzyl include: 1-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, l-(2-ethylpropionyloxy)ethyl, l-(2,4-dime1_hy__oenzcylo}y)ethyl, 1- (benzσyloxy)benzyl, l-(benzoyloxy)ethyl, 2-methyl-l-prcpionyloxy- prcpyl, 2,4,6-trimethy__oeaτzcylc«ymethyl, l-(2,4,6-trimethyl- benzyloxy)ethyl, pivaloyloxymethyl, phenethyl, pherpropyl, 2,2,2- trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butyl- phenyl, [5-(4-methyl-l,3- ioxolen-2-onyl)]methyl and 5-indaπyl. Compounds of the formulae (I) and (II) wherein R is benzyl or 4 . . . t-butyl and R is ethyl are valuable intermediates for the preparation of the diacids wherein R and R are both H. 5 . In a further preferred group of compounds R is methylene substituted by a group of the formula -NHαX-R **" ^ 1" ^ 14 ' particularly where R 12 is Nf^, R 1:L <-ONH- or R i:L SO NH-, R 13 is H and 14 . . R is -(OL) NH_. Particularly preferred are such groups derived 5 from S-lysine; thus especially preferred R substαtutents of this type include N^-ac_» * tyl-S-ly_yla_α rκ_aιιet_hyl, IT-methanesulphoπyl-S- lysyl-amincmethyl, N^-phenylsulphonyl-S-lysyl-a_ιdncιnethy. l and _- * T-cyclc__utylca_±»nyl-S-ly_y^ . 5 . In further groups of preferred -xanpounds R is C--C fi alkyl 5 . substituted by C--C 8 alkoxy, particularly methαxyethyl; or R is Cy- alkyl substituted by .-C- alkox (C.-C 6 )alkoxy, particularly 5 2-methyoxyethoxymethyl; or wherein R is .-C 6 alkyl substituted by - HCDCR 1 ^ 1 ^ 14 wherein R 12 is NIL, R 13 is Oi- and R 14 is H or OL inclviding in particular R-alanyl-am.i_nc-neth.yl and (2-amino-2- methylprcpanoyl)aminoroethyl. 2 . R is preferably phenyl, benzyl, phenethyl, methoxyprqpyl or ethoxypropy1. Particularly preferred individual cc-ipcunds of the invention include: 2S-(N^-ifet_hanesulphonyl-S-lysylam_i_ncιι«thyl)-3-{1-[cis-4- carbo.xy-3-cis{3-ethoxypropyl}-cyclohexyl)carbamσyl]cyclcpentyl}- propanoic acid. 2-(w -methanesulphoryl-S-lysylaπdrκ_-i^thyl)-3-{l-[(cis-4- c-__bQxy-3-c___s-phe-_-sthyl-cyclohexyl)carbamoyl]cyclopentylJpropanoic acid, 2S-(2-methoxyethoxymethyl)-3-{l-[(cis-4-carbojy-3-cis-{3- etho_qφixpyl}cyclche-yl)carbamoyl]cyclopentylJprαpanoic acid and 2S-(2-iiethoxyet--αxymethyl)-3-{l-[(c___s-4-cs_rbαxy-3-cis-{3- π»et_hcxxyp-rcpyl)-_yclc--e-yl)carbaπκ_yl]^ acid, and biolabile ester derivatives thereof. The cαrpcunds of formula (I) are prepared by a number of different processes. The basic p_τ_c-_3ure involves the synthesis of a partially protected cycloa_J<yl-sι_bstituted glutaric acid derivative which is coupled to an amine to give the desired glutaramide. The carboxylic acid group in the amine, if free, or 5 . . . any reactive groups m R , 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 scheme 1 wherein A, B, 1 2 5* 5 R and R are as previously defined, R is as defined for R with 18 19 any reactive group therein protected if necessary and R and R 4 are as defined for R and R excluding H, or they are conventional carboxylic acid protecting groups: Scheme 1 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. dichlorotnethane, using a diimide condensing agent, for example l-ethyl-3-(diπethylamincpropyl)- carbodiimide, or N,N'-dicyclche_<ylcarrχ__xiiimide, 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 * fc-_πperature and the product is then isolated by conventional procedures, i.e. by w__=hing with water or filtration to remove the urea biproduσt and evaporation of the solvent. The product may be further purified by cxrystallisation or chromatography, if necessary. The cσπpcunds of 4 formula (V) include σcapcunds of formula (I) wherein R and R are Cy-C alkyl or benzyl. In seme cases the coupled product, in protected form, may be subjected to conventional c_hemical transformation reactions to allcw preparation of further cctrpcunds of formula (V) . Thus for 5' example σαrpcunds of formula (V) wherein R contains an ester group may be hydrolysed or hydrogenated to generate the carboxylic acid which may be further reacted, for example with an amine, to give amide derivatives. 5 " Similarly coπpcunds wherein R contains a s-_-_ ituted or protected amino group (for example a be____yl_m_Lno, di_benzylamino, b-_r___yloxy-_3_±3rylaιι no or group) may be converted to the free amines by hydrogenation or protonolysis as appropriate. The amines produced may be further reacted, thus for example reaction with a sulphoπyl halide yields the corresponding sulphonamides, acylaticn with an acid chloride or anhydride yields the corresponding amides, reaction with an isocyaπate yields urea derivatives and reaction with a chlorofornate yields the alkoxy- carboπylamino and products respectively. All these transformations are entirely conventional and appropriate conditions and reagents for their performance will be well known to those skilled in the art as will other variations and possibilities. The diesters of formula (V) may be further reacted to give the monoester of diacid derivatives of formula (I) wherein one or 4 . . both of R and R are H. The conditions used will depend on the 18 19 precise nature of the groups R and R present in the compound of formula (V) and a number of variations are possible. Thus for 18 19 example when both of R and R are benzyl, hydrogenation of the 4 product will yield the diacid of formula (I) wherein R and R are 18 19 both H. ternatively if one of R and R is benzyl and the other is alkyl, hydrogenation will yield a monoester product. This can be hydrolysed, if desired, again to yield the diacid 18 19 product. When one of R and R is t-butyl, treatment of the cxxπpcund of formula (V) with trifluoroacetic acid yields the 18 19 cx>rresporκ_ing acid. The diester product wherein R and R are benzyl or lower alkyl can also be treated with trimethylsilyl iodide to produce the dicarboxylic acid product. If some other 18 19 carboxylic acid protecting group is used for R or R then clearly appropriate conditions for its removal must be employed in the final step to give the ester or diacid product of formula 5 . (I) . In the case where the ring A or the substitueπt R is unsaturated, the deprotectiαn must be effected by non-reductive 4 . methods, thus for example if either of R and R is benzyl, they may be removed by treatment with trimethylsilyl iodide. As well as removing any protecting group which may be present 5 1 . . . in R , 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. In a variant of the above procedure, coπpcunds of the formula C Q Q O "1 n (I) wherein R is C -C 6 alkyl substituted by -NR OOR , -MR SO^ , *« VV* or ^rfVV* - pepy _ a pr∞ss which involves acylating or sulphonylating a ccsπpσund of the formula: (VI) 20 8 11 18 19 wherein R is as defined for R or R , R and R are as previously defined and Y is a C--C fi alkyl group; by reaction with an acid of the formula R 9 00-,H, R 10 SO 3 H, R *L2 R 13 R 14 O00 2 H, or 12_13 14 . . . R R CS0 3 H, or an activated derivative thereof. The resulting amide or sulphonamide product is then d-protected if required and the diester product cleaved to yield the carboxylic acids of 4 formula (I) wherein R and R are each H as previously described. The ccmpcunds of formula (VI) are prepared following the procedures shown in scheme 1 but using a cciipound of formula (III) 5 1 . . 5' having R as a protected amine derivative. Thus, for example R can contain a bis-(___)-ph€a_ lethylamά_no substituent. Hydrogearation of the coupled product gives the corresponding free 20 . amine of formula (VI) wherein R is H and Y is CH-,. This route is of particular value for the preparation of compounds having 2(S) stereoc-iemistry in the glutaramide backbone. The starting cyclca_l_kyl-subst_ituted glutaric acid mono esters of formula III may be prepared as described in cur European patent applications EP-A-0274234, 89305180.5 and 89304698.7. The amines of formula (IV) are generally novel cx-αpσunds (particularly when the subε^tueπts have defined sterecxΛemistry) and they are prepared by appropriate synthetic procs_dures in accordance with literature precedents. Thus in one p_roσedure the t-orresponding ketone is converted to the amine via reduction of the oxime. In an alternative process the corresponding alcohol is reacted with methyl toluenesulphonate in the presence of diethyl diazodicarboxylate and triphe^lphosphine; the resulting 4-met_hy_I_benzer_esulphαπyloxy derivative is reacted with sodium azide and the product reduced to yield the amine. These procedures are Lllustrated in the Preparations give hereafter. 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 standard text books and to the examples provided hereafter. As previously mentioned, the coπpcunds of the invention are potent inhibitors of the neutral endcpeptidase (E.C.3.4.24.11). This enzyme is involved in the breakdown of a number of peptide hormones and, in particular it is involved in the breakdown of atrial natriuretic factor (ANF) . This hormone consists of a family of related natriuretic peptides, secreted y the heart, of which the major c__ra_lat-ing form in humans is known to be the 28 amino-acid peptide referred to as < -hANP. Thus, by preventing the degradation of ANF, by endcpeptidase E.C.3.4.24.11, the compounds of the invention can potentiate its biological effects and the cc-cpcunds are thus diuretic and natriuretic agents of utility in a number of disorders as previously described. 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 coπpcund required to reduce by 50% the rate of release of radiolabelled hippuric acid from hippuryl-L- by a neutral endcpeptidase preparation from rat kidney. 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 CDl, 22-28 g) are acclimatised and starved σverni t in metabcwls. 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 cαnoeπtraticai. Urine volume and sodium ion concentration from the test animals are compared to a control group which received only saline. For actadnistration to man in the curative of prophylactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds will generally be in the range of from 4-800 mg daily for an average adult patient (70 kg) . Thus for a typical adult patient, individual tablets or capsules contain from 2 to 400 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 actai-iistration would typically be within the range 1 to 400 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 actadnistered alone, but will generally be adπLnistered 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 coπt____ning 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 coi-taining flavouring or colouring agents. They may be injected parenterally, for example, intravenously, int_rarnι___cularly or s-fl-αitanecusly. For pareπteral 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 isσtαnic with blood. The coπpcunds may be actadnistered alone but may also be actadnistered together with such other agents as the physician shall direct to optimise control of blood pressure or to treat congestive heart failure, renal insufficiency or other disorders in any particular patient in accordance with established medical practice. Thus the compounds can be c»-adm_i_n_i^tered with a variety of ca__diσv___κ_ular agents, for example with an ACE inhibitor such as captcpril or enalapril to facilitate the control of blood pressure in treatment of hypertension; or with digitalis, or another cardiac stimulant or with an ACE inhibitor, for the treatment of congestive heart failure. Other possibilities include cx>-actadnistration with a calcium antagonist (e.g. nifedipine, amlodopine or diltiazem) a beta-blocker (e.g. atenolol) or an alpha-blocker (e.g. prazosin or doxazosin) as shall be determined by the physician as appropriate for the treatment of the particular patient or condition involved. In addition to the above, the txπpcunds may also be adm istered in conjunσticai with exogenous ANF, or a derivative thereof or related peptide or peptide fragment having diuretic/natriuretic activity or with other ANF-gene related peptides (e.g. as described by D. L. Vesely et al, Biochem. Biophys. Res. Ccmm., 1987, 143, 186). Thus in a further aspect the invention provides a pii--maσeutical composition comprising a ccπpcund of the formula (I) , or a ptørmaσeutically acceptable salt thereof or bioprecursor therefor, together with a p-_-__macoutically acceptable diluent or carrier. The invention also includes a compound of the formula (I) , or a p-___cmacoutically acceptable salt thereof or bicprecursor therefor, for use in medicine, particularly for use as a diuretic agent for the treatment of hypertension, congestive heart failure or renal insufficiency in a human being. The invention ___urther includes the use of a compound of the formula (I) for the manufacture of a medicament for the treatment of hypertension, heart failure, angina, renal insufficiency, preinenstrual syndrome, cyclical oedema, Menieres disease, hyper_ dosteronism, pulmonary oedema, ascites, hyperoaciuria, glaucoma, asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity. gastrointestinal disorders (including diarrhoea) , hype-___eninaemia, leukemia, and the modulation of gastric acid secretion. The preparation of the coπpcunds of the invention will now be more particularly illustrated by reference to the following experimental exaπples, in which Preparations 1-8 describe preparation of the starting amines of formula (IV) and Exaπples 1-45 describe preparations of compounds of the formula (I) . The purity of coπpcunds was routinely monitored by thin layer c_hromatography using Kferck Kieselgel 60 F_ 54 plates. Solvent system ss-1 was a mixture of dic-__loromethane, methanol and glacial acetic acid (90:10:1) , ss-2 was the upper phase of a mixture consisting of methyl iso-butyl ketone, glacial acetic acid and water (2:1:1) , and ss-3 was a mixture of ethyl acetate and hexane (1:1). " Tl-Nuclear magnetic reasonanσe spectra were recorded using a Nicolet QE-300 spectrαieter and were in all cases consistent with the proposed structures. FREPARATIO 1 c-4-Amino-c-2-(2-pheπylethyl)cyclcAexane-r-1-carboxylic acid ethyl ester hydrochloride i. 4-Oxo-2-(2-τ_heπylethyl)<-yclohex-2-ene carboxylic acid ethyl ester An 80% dispersion of sodium hydride in oil (307 mg, 10 mmole) was added under nitrogen to an ice cold stirred πdxture of 3-oxo-5-phenyl pentanoic acid ethyl ester (28.4 g , 129 mmole) and absolute ethanol (1 ml) . Methyl vinyl ketone (10.7 ml, 129 mmole) was then added dropwise over half an hour with continued ice cooling and, after stirring for an hour at room teπperature, acetic acid (1.4 ml), pyrrolidine (775 g), ethanol(17 ml) and water (2 ml) were added. After refluxing for 2 hours, the solvent was evaporated under vacuum and the residue dissolved in diethyl ether. Washing sequentially with 2N hydrochloric acid, water, saturated aqueous sodium bicarbonate and water, drying over MgSO and evaporation gave a yellcw liquid (34.6 g) . Chroriatography on silica gel (600 g) eluting with a mdxture of diethyl ether and hexane (1:3 by volume) gave the required enone as a clear liquid (18.54 g,) Rf 0.35 (1:1 diethyl ether:hexane) . Found: C,74.88; H,7.40. j -^O. j requires C,74.97; H,7.40%. ii. 4-Oxo-cis-2-(2-τAιenylethyl)σclohc-xanecarfaoxylic acid ethyl ester The enone (18.44 g, 6.76 mmole) from part (i) in ethanol (80 ml) conttaining 2N hydrochloric acid (3 ml) was hydrogenated over 5% palladium on charcoal catalyst (500 mg) at 50 p.s.i. (3.45 bar) pressure. After three hours a further amount of catalyst (250 mg) was added and reduction was cxsntinued for a further two hours. The suspension was filtered through Avicel and the filtrate evaporated under vacuum. The residual oil was dissolved in diethyl ether, washed with saturated aqueous sodium bic___bαnate and water, dried over MgSO. and evaporated to give a clear liquid (18.52 g) . Chromatography on silica gel (600 g) , eluting with an increasing proportion of diethyl ether in hexane (2:8 - 4:6) gave the required ketone as a liquid. (16.78 g,90%). Rf 0.4 (1:1 diethyl ether:hexane) . iii. 4-^thoχyi_r_d_no--c:i_s-2-(2-pheny^ carboxylic acid ethyl ester The above ketone (3.02 g, 11 mmole), methoxylamine hydrochloride (1.19 g, 14.3 mmole) and sodium acetate (1.17 g; 14.3 mmole) were refluxed for five hours in ethanol (50 ml) . the solvent was evaporated under vacuum, the residue taken up in diethyl ether and washed with saturated aqueous sodium bicarbonate followed by water. Drying over MgSO. and evaporation under vacuum gave the 0-methyl oxime as an oil (3.32 g, 99%) Rf 0.55 and 0.66 (1:1 diethyl ether, hexane). Found: C,71.23; H,8.33; N,4.88. C-^^.. requires C,71.26; H,8.30; N,4.62%. iv. c -4-Butoxyc--_t_faonylaπdno-c-2-(2-pheπylethyl)-cvclchexane- r-1-carboxylic acid ethyl ester Trifluroaσetic acid (4.2 ml, 54 mmole) in dry tetxcύydrofuran (10 ml) was added dropwise with ice cooling to a stirred suspension of sodium borohydride (2.04 g, 54 iπmole) in dry tetrahydrofuran. The teπperature was kept between 5 and 10°C and after stirring for fifteen minutes the 0-^nethylca me from part (iii) (3.28 g; 10.8 mmole) in tetrahydrofuran (10 ml) was added dropwise over ten minutes. The temperature rose to 20 C and, after stirring for five hours, water was very carefully added with ice cooling and the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate, the combined organic extracts washed with saturated salt solution, dried over MgSO and evaporated to give a gum (3.25 g) . The crude amine was dissolved in methylene chloride (50 ml) (2.2 g, 21.6 mmole) and di-t-butyl dicarbonate (4.7 g, 21.6 mmole) were added and the mixture allowed to stand at room temp-Stature for 48 hours. The solvent was evaporated under vacuum, the residue partitioned between diethyl ether and water and the organic extract washed sequentially with 0.5N hydiochloric acid, water, saturated aqueous sodium bicarbonate and water. Drying over MgSO. and evaporation gave a gum (3.9 g) . The required cis- coπpound was separated from the minor more polar trans-isomer by c±iromatography on silica gel (400 g) . Elution with a mixture of diethyl ether in hexane (3:7 by volume) gave the protected amine as an oil (1.94 g, 48%). Rf 0.35 (3:7 diethyl ether:hexane) . Found: C,70.43; H,8.75; N,3.45. C ^ H-.- O. requires C,70.37; H,8.86; N,3.73%. v. c-4-Amino-c-2-(2-ϋheπylethyl)cyclohexane-r-1-carboxylic acid ethyl ester hydrochloride An ice cold stirred solution of the above ester (1.94 g, 5.17 itmole) in diethyl ether was saturated with hydrogen chloride. After three hours the solvent was blown off with nitrogen and the residue triturated with diethyl ether and collected by filtration giving the title amine salt as a white solid (1.44 g, 89%) . m.p. 213-214°C. Rf 0.5 (ss-1). Found; C,65.84; H,8.74; N,4.43. C 17 H 25 N0 2 .HC1 requires C,65.48; H,8.40; N,4.49%. PREPARATION 2 c-4-Amino-c-2-(3-roethoχypropyl)cyclohexane-r-1-carboxylic acid ethyl ester hydrochloride The procedure of Preparation 1 was followed but using 3-oxo-6-roethoxy-hexanoic acid ethyl ester as the starting material in part (i) to give the title amine as white solid, m.p. 206-208°C. Rf 0.2 (ss-1) . Found: C,55.15; H,9.11; N,5.34. C L3 H 25 0 3 . HCl, 0.2 H-,0 requires C,55.09; H,9.39; N,5.94%. PREPARATION 3 c^4-Amd_rκ_>-c'-2-(3-ethoχyprαpγl)c^^ acid ethyl ester hydrochloride The procedure of Preparation 1 was followed but using 3-c_xcr-6-et_hc_xyhexa-X-ic acid ethyl ester as the starting material in part (i) to give the title amine as a white solid, m.p. 201-203°C. Rf 0.2 (ss-1). Found: C,55.50; H,9.52; N,4.33. C 1 ^l 27 iX> 3 .HCl.0.5H-.0 requires C,55.52; H,9.65; N,4.63%. - •• REPARAπC-l 4 c^-4-Amir -_^2-(2-ι -3wlethyl)c_^^ acid methyl ester hydrochloride A solution of the ethyl ester from Preparation 1 (1.4 g; 4.48 πmole) in dry methanol (50 ml) was saturated with hydrogen chloride and heated at 55 to 60°C for four days and then refluxed for a further 3 days. Hydrogen chloride was periodically introduced to maintain saturation. The solution was evaporated to dryness under vacuum, the residue dried azexstropically with methylene chloride, and the residue triturated with diethyl ether to give the methyl ester as a white pcwder (1.29 g, 97%) m.p. 202-4°C. Rf 0.15 (SS-1) . Found: C,63.70; H,8.13; N,4.74. C L NO . HCl.0.25 H^O requires C,63.56; H,8.17; N,4.63%. FREPARA3TON 5 c-4-Amino-t-2- (2-theπylethyl) cvclohexane-r-1-carbσxylic acid ethyl ester i. cis-7- (2-Hιeπylethyl) -1 ,4-dioxaspiror4.5 * |decane-8- carboxylic acid ethyl ester The ketone of Preparation 1 part ii (10.97 g; 40 mmole) , ethylene glycol (2.73 g, 44 mmole) and 4-toluenesulphonic acid (100 mg) were refluxed in benzene (80 ml) using a Dean-Stark water trap. After eic£ιt hours the solution was cooled, diluted with diethyl ether and washed sequentially with saturated aqueous sodium bicarbonate and water. Drying over MgSO . and evaporation under vacuum gave a clear liquid (12.22 g, 96%) Rf 0.32 (3:7, diethyl ether, hexane) . Found: C,71.45; H,8.30. T Q H 2 6 0 4 requires C,71.67; H,8.23%. ii. trans-7-(2-Phenylethyl)-1.4-dioxaspiror4.5 * )decane-8 carboxylic acid ethyl ester Potassium t-butoxide (1.9 g, 17 mmole) was added to a solution of the above ester (12.17g, 38.2 mmole) in dry t-butanol (90 ml) and the mixture refluxed under nitrogen for forty eight hours. Neutralisation with 2N hydrochloric acid and evaporation under vacuum gave a light brcwn oil which was dissolved in diethyl ether and washed with water. Drying over MgSO. and evaporation gave an oil (12.09 g) which was cdi-omatographed on silica gel (600 g) . Elutions with a mixture of diethyl ether and hexane (3:7 by volume) gave the required trans-iscmer as an oil (8.44 g, 69%) . Rf 0.29 (3:7 diethyl ether, hexane). Found: C,71.60; H,8.14. C gELgO. requires C,71.67; H,8.23%. iii. 4-Oxo-t_rans-2-(2-phe--yl-^yl)cy^ acid ethyl ester The above ester (8.40 g, 26.4 mmole) was refluxed in IN sulphuric acid (50 ml) amd ethanol (70 ml) . After three hcurs most of the ethanol was evaporated off under vacuum, water was added and the suspension extracted with diethyl ether. The organic extract was washed sequentially with water, saturated aqueous sodium bicarbonate and water, dried over MgSO and evaporated under vacuum to give a clear oil (6.46 g, 89%) Rf 0.38 (1:1 diethyl ether, hexane). Found: C,74.25; H,8.07. c y~- l 2 2°3 requires C,74.42; H,8.08%. iv. t-2-(2-Eheπylethyl)-c -4-i3henfy___methylamin--cyclohe-^^ 1-carbσxylic acid ethyl ester 3A molecular sieve (3 g) was added to a stirred solution of the ketone from part iii (3.2 g, 11.66 mmole) and benzylamine (1.27 ml, 11.66 mmole) in ethanol (15 ml) . After three and a half hours at room temperature, the solution was pipetted off into a dry hydrogenation vessel washing the sieves with a little ethanol (2x5 ml) . Pla * tiπum oxide (500 mg) was added and the reduction ccπpleted in three hours at 50 p.s.i. (3.45 bar) . The mixture was filtered through arbaσel, evaporated under vacuum and the residual liquid <_hroπatographed on silica gel (200 g) . Elution with increasing proportions of ethyl acetate in hexane (7:3 - 1:1 by volume) gave the required cis-isomer as a clear oil (3.17 g, 74%) Rf 0.3 (ss-3) Found: C,78.85; H,8.53; N,4.86. C-.^ ^ NO, requires C,78.86; H,8.55; N,3.83%. v. c-4-Amino-t-2-(2-pheπylethyl)cyclohexane-r-1-carboxylic acid ethyl ester A solution of the above amine (3.13 g, 8.56 mmole) in ethanol (80ml) containing IN hydrochloric acid (9.42 ml, 9.42 mmole) was hydrogenated over 20% palladium hydroxide and charcoal catalyst (600 mg) at 50 p.s.i. (3.45 bar) pressure. Further amounts of catalyst (500 mg) were added after six and twenty four hours. After a further twenty two hours the suspension was filtered through arbacel and the filtrate evaporated to dryness under 29 vacuum. The residue was __ecrystallised from a mixture of ethanol and diethyl ether to give the required amine as a white solid (2.03 g, 76%) m.p. 175-7°C. Rf 0.25 (ss-1) . Found: C,64.42; H,8.50; N,4.52. C ^JfO^ HCl.0.251^0 requires C,64.54; H,8.44; N,4.43%. o-4-Aπd_τo-o-2-τ-heπylcvclc-^^ acid methyl ester hydrochloride i. 4-Oxo-2-pherylc-yclc_ ex-2-ene-carboxylic acid methyl ester 2-Hydιxc<y-4-oxo-2-pherylcyclchexane carboxylic acid methyl ester (17.5 g, 70.48 mmole) [J. Org. Chem. , 39 2427 (1974) ] was stirred for 15 minutes at 80 C with polyphosphoric acid (17.5 g) . On cooling the mixture was partitioned between ethyl acetate and water. The organic extract was washed sequentially with water, saturated aqueous sodium bicarbonate and water, dried over MgSO and on evaporation gave an oil. c_hromatography on silica gel eluting with increasing proportions of ethyl acetate in hexane (2:8 - 3:7 by volume) gave the required coπpound as a golden oil (9.0 g, 56%) Rf 0.5 (ss-3) . ii. 4-0xo-2-pherylcyclc>hexarκ3carfaoχylic acid mether ester The enone of part 1 (9.0 g, 39.08 mmole) in methanol (40 ml) containing 2N hydrochloric acid (1.5 ml) was hydrogenated over 5% palladium on charcoal catalyst at 50 p.s.i. (3.45 bar) . After three hours the suspension was filtered through Arbacel and evaporated to dryness under vacuum. The residual oil was chromatographed on silica gel (400 g) . Elution with increasing proportions of ethyl acetate in hexane (2:8 - 4:6 by volume) gave the required ketone as a white solid (4.04 g, 49%) Rf 0.55 (ss-3) Found: C,72.39; H,6.95. C^H^O j requires C,72.39; H,6.94%. iii. €>-4-H-Λ-roxy-c^-2-i3heπylc^clohe acid methyl ester Sodium borohydride (2.33 g, 61.51 mmole) was added in small portions to a stirred solution of the ketone of part ii (3.78 g, 16.27 mmole) in methanol (80 ml) , keeping the teπperature belcw 5 C. After fifteen minutes the solvent was evaporated under vacuum, the residue dissolved in methylene chloride and washed with saturated salt solution. Drying over MgSO and evaporation under vacuum gave a white solid. C_hromatography on silica gel (250 g) eluting with diethyl ether in hexane (1:1 by volume) gave the required ester as a foam (2.93 g, 77%). Found: C,71.84; H,7.82. C 14 H-gO requires C,71.77; H,7.74%. iv. t-4-(4-Methy__-er_ze_ne_-Ulphorτyloxy)-c^2-phenylcyclohexane-r-l carboxylic acid methyl ester Diethyl diazodicarboxylate (4.08 g, 23.47 mmole) in tetrahydrofuran (10 ml) was added under nitrogen to a stirred solution of the ester of part iii (4.4 g, 18.78 mmole) , triphenylphosphine (6.16 g, 23.47 mmole) and methyl 4-toluene sulphonate (4.37 g, 23.47 mmole) in tetrahydrofuran (60 ml) keeping the teπperature between 5 and 10 C. After stirring oveuπiight at room tenpeα^ture the mixture was re-cooled to 0°C and further amounts of triphenylphosphine (1.23 g, 4.7 mmole) and methyl 4-toluene sulphonate (874 mg, 4.7 mmole) were added followed by diethyl diazodicarboxylate (816 mg, 4.7 mmole) . After stirring at room temperature for a further four hours, the mixture was evaporated to a small volume, the residue redissolved in methylene chloride and applied directly to a silica gel (400 g) c-ironatography column. Elution with iiicreasing proportions of ethyl acetate in hexane (1:9 - 3:7 by volume) gave the required 4-toluenesulphonate as an oil (3.45g, 47%). Rf 0.45 (4:1 ethyl acetate, hexane) Found: C,64.71; H,6.26. C_,-H_ 4 O g S requires; C,64.93; H,6.23%. v. c^4-Azido-c^2-ph€a'-ylcyclch€--ane^^ acid methyl ester Sodium azide (1.16 g, 17.76 mmole) was added to a stirred solution of the 4-toluenesulphαnate from part iv (3.45 g, 8.88 mmole) in dimethylfoππamide, and the mixture was stirred at 60°C for eighteen hours. On cooling water was added and the suspension extracted with diethyl ether. The organic extract was washed with water, dried over MgS0 4 and evaporation gave a clear oil which was chrαmatographed on silica gel (300 g) . Elution with increasing proportions of ethyl acetate in hexane (1:20 - 1:4 by volume) gave the azide as waxy solid (2.11 g, 92%). Rf 0.55 (4:1 hexane, ethyl acetate). Found: C,65.20; H, 6.60; N,15.32. C_.H._N O requires C, 64.85; H,6.61; N,16.20%. vi. c>-4-Aπd_nc -c-2-i-h-3τylc clciιexane-^^ acid methyl ester hydrochloride The azide from part v (2.1 g, 8.1 m mmole) in methanol (50 ml) was hydrogenated over 10% palladium on charcoal catalyst (210 mg) at 50 p.s.i. (3.45 bar) . After two and a quarter hours the mixture was filtered through a short arbacel column and evaporated under vacuum. The residue was dissolved in ethyl acetate and acidified with IN hydrogen chloride in diethyl ether. The precipitated salt was filtered and washed with ethyl acetate to give the title amine salt as a white solid (1.88 g, 94%) m.p. 255-6°C (dec). Rf 0.2 (ss-1). Found: C,62.64; H,7.74; N,5.74. C 14 H 19 0 2* HC1 re( 3 uires C,62.33; H,7.47; N,5.19%. EKEPARATTON 7 c 3-Amino-c>-5^ph€aιy.l_meth^ acid methyl ester hydrochloride i. c_-3-5-te_±-_- tyldimethylsilyloxy cyclohexane-cis-1.3- dicarfaoxylic acid dimethyl ester t-Butyldimeτ_hylsilyl chloride (16.58 g, 110 mole) in dry methylene chloride (65 ml) was added dropwise ever half an hour to a stirred solution of cis-3-hy-__oj^cyclciiexane-cis-l,3- dicarbσxylic acid dimethyl ester (21.5 g, 99 nmole) [J. Org. Chem. , 38, 1726 [1973] , triethylcunine (11.13 g, 110 mmole and 4-dimethyl-___dncpyridine (488 mg, 4 mmole) in methylene chloride (80 ml) , with ice cooling keeping the temperature between 5 and 10 C. After standing overnight at room temperature further amounts of t-rbityldimethylsilyl chloride (1.6 g) , rxiethylamine (1.1 g) and d_imethylam_i_r_opyridine (450 mg) were added and stirring continued for sixty-eight hours. The mixture was then washed sequentially with water, satxirated aqueous ammonium chloride and water, dried over M S0 4 and evaporated under vacuum to give a liquid (34.4 g) which was chrt_matographed on silica gel (600 g) . Elution with a mixture of diethyl ether in hexane (1:3 by volume) gave the required product as a liquid (32.6 g, 99%) Rf 0.3 (1:3 diethyl ether, hexane) . Found: C,57.89; H,9.20. C. -HL-O^i requires C,58.15; H,9.15%. ii c__^-5-tert-Butyldi_πethylsilγloxycyclchexane-cis-l.3- dicarfaoxylic acid mono-methyl ester IN Sodium hydroxide (94 ml) was added to an ice cooled solution of the above diester (30.87 g, 93.4 mmole) in methanol (500 ml) . The mixture was stirred at 5°C for 3 hours and then allowed to stand at room temperature for eighteen hours. Most of the solvent was evaporated off under vacuum, water was added and the suspension extracted with diethyl ether to recover xinreacted diester (3.86 g) . The aqueous phase was acidified with 2N hydrochloric acid, extracted with diethyl ether, and the organic extract washed with water, dried over MgSO and evaporated under vacuum to give a clear gum (25.5 g) . Chromatography on silica gel (500 g) eluting with a mixture of diethyl ether in hexane (7:3 by volume) gave the required mono-ester as thick oil (20.0 g, 68%) . Rf 0.75 (diethyl ether). Found: C,56.75; H,8.71. C -H^O Si requires C,56.93; H,8.92%. iii c-3-teart-Butyldi_nrethyls:^ r-1-carfaoxylic acid methyl ester A 1M solution of diborane in tetrahydrofuran (59 ml) was added dropwise under nitrogen to a stirred solution of the mono ester from part ii (17.0 g, 53.72 mmole) in tetrahydrofuran keeping the temperature at -5 C. The mixture was allowed to warm up to room temperature and after four hours a further amount of lM diborane solution (10.7 ml) was added and the mixture allowed to stand for eighteen hours. The solvent was evaporated under vacuum, diethyl ether was added and the solution washed sequentially with saturated salt solution, saturated aqueous sodium bicarbonate solution and again with saturated salt solution. Drying over MgS0 4 and evaporation under vacuum gave a clear oil whic was chromatographed on silica gel (500 g) . Elution with a mixture of ethyl acetate and hexane (1:1 by volume) gave an oil (15.18 g, 93%). Rf 0.42 (ss-3). Found: C,59.24; H,9.67. <_-._H_ 0.Si requires C,59.56; H,10.0%. iv. c-3-tert-ButyldiιrelAylsilyloχy-c^ oxymethyl)cyclche-<ane-r-l-carfaoχylic acid methyl ester 4-ifethy.U-enzenesulphQnyl chloride (14.18 g, 74.39 mmole) was added to an ice cold stirred solution of the ester from part iii (15.0 g, 49.59 mmole) in dry pyridine (130 ml) . After stirring at room tenperature for twenty four hours the πdxture was poured onto ice, extracted with diethyl ether and the extract washed sequentially with 2N hydrochloric acid, water, _κ_turated aqueous sodium bicarbonate solution and water. Drying over MgS0 4 and evaporation under vacuum gave an oil (22.0 g) which was C-ir-aiatographed on silica gel (600 g). Elution with increasing proportions of ethyl acetate in hexane (1:9 - 1:4 by volume) gave the required product as an oil (21.78 g, 96%). Rf 0.3 (4:1 hexane, ethyl acetate. Found: C,57.66; H,7.96. C.J SSi requires C,57.86; H,7.95%. v. c-~3-t-=-_ -Butyld_jnethylsilyloχy-c^ σclohe-__uτe-_>-l-carboχylic acid methyl ester 2M Ehenyl lithium in cyclchexa_ne-ether (7:3) (24.5 ml, 49 mmole) was added under rdtrogen to a stirred suspension of cuprous iodide (4.67 g, 24.5 lαmole) in dry diethyl ether (50 ml) keeping the teπperature belcw 5°C. The resulting dark green solution was stirred at room teπperature for one and three quarters of an hour, cooled to -70 C and a solution of the ester from part iv (3.7 g, 8.1 mmole) in ether (10 ml) and cyclchexane (40 ml) added dropwise. The teπperature was maintained belcw -60°C during the addition, and then reduced to -70°C for fifteen mii-Utes. The mixture was then allowed to warm up to room temperature, stirred for an hour and the reaction quenched with saturated aqueous ammonium chloride with iσe cooling. The organic phase was washed with saturated salt solution, dried over MgS0 4 and on evaporation under vacuum gave an oil. Chrcmatogrcphy on silica gel, eluting with increasing proportions of diethyl ether in hexane (1:20 - 1:10 by volume) gave the .required title product (1.4 g, 48%) Rf 0.2 (1:9 diethyl ether, hexane) . vi. t-3-(4Hfethylbenzenesul^oπyloxy)-c^3-T-he3W-_ethyl cyclc^exane-ι_^-l-carboxylic acid methyl ester 40% Aqueous hydrofluoric acid (0.5 ml, 10 mmole) was added to a stirred solution of the above ester (3.6 g, 9.93 mmole in acetonitrile (40 ml) . After an hour the solution was diluted with diethyl ether, washed with saturated aqueous sodium bi<_a__bonate solution and water, dried over MgS0 4 and evaporated under vacuum to give the required alcohol as a clear oil (2.36 g, 96%) . Rf 0.2 (1:1 diethyl ether hexane). The product (2.39 g, 9.62 mmole) was treated as described in Preparation 6, part iv to give the • trans-4-methylbenzene sulphonate title coπpcund as a pale yellow gum (2.44 g, 63%). Rf 0.4 (1:1 diethyl ether hexane). Found: C,65.59; H,6.54; C-.-.H^OgS requires C,65.65; H,6.51%. vii c-~3- π o-<^5-ιA-gτv-__m-±hylc-ycl-^ acid methyl ester hydrochloride The txans-4--iethy-_J3enzenesulphσnate from part iv (2.41 g, 5.99 mmole) was treated with sodium azide as described in Preparation 6, part v to give the corresponding azide as an oil (1.44 g, 88%) , Rf 0.72 (1:1 diethyl ether, hexane) . The azide (1.41 g, 5.16 mmole) was then reduced as described in Preparation 6, part vi to give the .required amine salt as a foam (1.44 g, 99%), Rf 0.2 (ss-1). Found: C,63.31; H,7.76; N,4.56. C JL N0-..HC1 requires C,63.48; H,7.81; N,4.94% PREPARATION 8 carboxylic acid methyl ester hydrochloride i 3-Oxo-4-phenylπethyle3τε--yclchexanecarroxylic acid πethyl ester A mdxture of ethyl(-trimethylsilyl) acetate (16.01 g, 99.9 mmole) and 3-o-_-X-yclohea__nec-_dx)xylic acid methyl ester (13.0 g, 83.24 mmole) was slcwly added dropwise under nitrogen to a stirred solution of 1.0M tetrabutylcfflimαnium fluoride in tetrahydrofuran (2.78ml) keeping the temperature between 0 and 10 C. The resulting pale brown solution was stirred at room tempeaature for seventeen hours, further amounts of tetø___u_tyl-__ππcnium fluoride (0.3 ml) and ethyl(trimethylsilyl) acetate (5 ml) were added and after three hours the reaction was shewn to be completed by n.m.r. The mixture was diluted with n-4ιexane (50 ml) , stood over 3A molecular sieves for an hour, filtered and the solvent evaporated under vacuum to give the silylenol ether as a golden oil (19.97 g, 100%) . The silylenol ether product in dry methylene chloride (50 ml) , was added dropwise under nitrogen to a stirred suspension of titanium tetrachloride (9.15 ml, 83.24 mmole) in benzaldehyde (9.31 ml, 91.56 mmole) and dry methylene chloride (250 ml) at -70°C. The mixture was allowed to warm up to room temperature over eighteen hours and quenched with water (100 ml) with iσe cooling. The organiσ phase was washed with water, dried over MgSO and evaporated under vaσuum. The residue was c_roπatograpahed on silica gel, eluting with increasing proportions of ethyl acetate in hexane (1:4 - 3:7 by volume) to give the .required product as a pale solid (6.89 g, 34%) m.p. 73-5°C. Rf 0.25 (4:1 hexane, ethyl acetate) . Found: C,73.20; H,6.54. c^gH^O j . O.liy) requires C,73.2l; H,6.63%. ii. 3-Oxc.-cis-4-τ-heπy.l__αethylcyc^^ acid methyl ester The enone from part i (6.55 g, 26.8 mπole) in methanol (152 ml) and water (8 ml) was hydrogenated over 5% palladium on (-harcoal catalyst (750 mg) at 20 p.s.i. (1.4 bar). After three hours the suspension was filtered and on evaporation under vacuum the residue was c_h_rcιnatographed on silica gel (600 g) . Elution with increasing proportions of ethyl acetate in hexane (1:4 - 3:7 by volume) gave the trans-isoroer as a white solid m.p. 54-5°C. Rf 0.35 (1:4 ethyl acetate, hexane) . Found: C,73.11; H,7.46. C._H- 8 0 3 requires C,73.15; H,7.37%. Further elution gave the more polar cis-iscroer as a white solid m.p. 71-2°C. Rf 0.25 (1:4 ethyl acetate, hexane). Found: C,72.8l; H,7.4l. -J -O requires: C,73.15; H,7.37%. iii. 3-Methoxyiπdrάo-cis-4-ι teπy-__πethyl(^cl-h---ane carboxylic acid methyl ester The σis-iscmer from part ii above (1.9 g, 7.71 mmole) on treatment with methoxylamine hydrochloride as described in Preparation 1 part iii gave the title required Cr-πethyloxime as a clear oil (2.0 g, 94%). Rf 0.4 and 0.45 (4:1 hexane, ethyl acetate). Found: C,69.53; H,7.69; N,4.94. C--H_-H0 requires C,69.79; H,7.69; N,5.09%. iv. c and t-3-(tert-Butoχyca_±o:r_ylaπd-ro^ cvclchexane-r-1-carbαxylic aσid methyl ester The 0-methyl oxime from part iii (1.97 g, 7.15 mmole) on treatment as described in Preparation 1, part iv gave the title product as a mixture of cis and trans-iscπers which were separated by ciircmatcgraphy on silica gel (300 g) eluting with increasing proportions of ethyl acetate in hexane (1:3 - 3:7 by volume) . The trans-isoroer was obtained as a gum (680 mg, 27%) . Rf 0.5 (1:4, hexane, ethyl acetate). Found: C,68.84; H,8.17; N,3.91. C.-IL-NO. ι_equires C,69.14; H,8.41; N,4.03%. The cis-isσmer was also obtained as a gum (345 mg, 14%). Rf 0.45 (1:4 hexane, ethyl acetate). Found: C,67.55; H,8.08; H,3.80, CJim.0.5 IL0 requires C,67.39; H,8.48; N,3.93%. v. t-3-Aπd_no-c^-4-pheπyImethylcyclc^ aσid methyl ester hydrochloride The trans-iscπer from part iv (650 mg, 1.87 mmole) on treatment with HCl as described in Preparation 1, part v gave the title salt as a gum (533 mg, 99%). Rf 0.25 (ss-1). Found: C,62.41; H,7.78; N,4.77. C^-H^KE^. HCl.0.251^0 requires C,62.49; H,7.87; N,4.86%. methyl ester hydrochloride The cis-iscπer from part iv (325 mg, 0.94 mmole) on treatment with HCl as described in Preparation 1, part v, gave the title salt as a gum (263 mg, 99%). Rf 0.25 (ss-1). Found: C,59.45; H,7.44; N,4.77. C j -H^NO-,. HCl. 1^0 requires C,59.69; H,8.0l; N,4.64% EXAMPLE 1 3-(1-[(cis-4-Ethoχycarboπyl-cis-3- 2-phenylethyl )σyclohexyl^- carbamoyl1cyclopentyl)-2-(2-methoχyethyl)prooanoic aσid benzyl ester l-Et_hyl-3-(3-di_nethyl_urdncp:ropy^ hydrochloride (460 mg, 2.4 mmole) was added to an iσe σold stirred solution of 3-(l-car_xaxycy<_lcp-aτtyl)-2-(2-me^ aσid benzyl ester (EP-A-0274234) (401 mg, 1.2 mmole) , c>-4-amdno-c-2-(2- pheaπylethyljcyclc-hexane-i^l-carbojςlic aσid ethyl ester hydrochloride (343 mg, 1.1 mmole) , l-hydroxybenzotriazole (162 mg, 1.2 mmole) and N-methyl-morpholine (354 mg, 3.5 mmole) in dry methylene chloride (15 ml). After half an hour the mixture was allowed to attain room teiiperature and stirred for twenty hours. The solvent was evaporated under vacuum and the residue partitioned between diethyl ether and water. The organiσ extract was washed sequentially with water, 2N hydrochloriσ aσid, water, saturated aqueous sodium bicarbonate and water. Drying (MgSO ) and evaporation under vacuum gave an oil (640 mg) , which was ch__oπatographed on siliσa gel (50 g) eluting with a mixture of diethyl ether and hexane (7:3 by volume) to give the required diester as a colourless oil (550 mg, 85%). Rf 0.32 (7:3 diethyl ether, hexane). Found: C,73.23; H,8.37; N,2.12. C.J1 JO. requires C,73.07; H,8.35; N,2.37%. EXAMPIES 2-5 The following compounds were prepared following the piocsdure of Example 1 using the appropriate amine of formula (IV) . EXAMPIES 6-7 The following σcπpcunds were prepared following the procs≡dure of Example 1 but using 3-(l-caι±oxyσyσlcpentyl)-2 (S)-(2-methoxy- ethoxymethyl)proparιoic aσid t-butyl ester (EP application no. 89304698.7) as the starting material and coupling with the appropriate amine of formula (IV) . C_> H I KYAMPTiRS P.-- ? The following compounds were prepared following the p_rcσedure of Example 1 but using 2S-(N^-benzylαxycarboπyl-N -t-butyloxy- σa_±oι_ l-S-ly_yl__ιdncπethyl)-3-[l-(l-ca__±oxycyclcpeαιtyl)]propanoic aσid t-butyl ester (EP application 89305180) as the starting material and coupling with the appropriate amine of formula (IV) . CBZ NH C0 2 R EXAMPLE 13 2(S N -t-Butoxyc_a_±>αnyl-S-lvsyl-aπdno-n-_th.yl)-3-f1-fσis-4 ethoxyca_t±oπyl-cis-3-(3-et_hoxypropyl)σyσlcheχyl)σarbaπoyl ** σyσlo- pentyllpropanoic aσid t-butyl ester The diester of Example 8 (734 mg, 0.85 πole) in methanol (18 ml) and water (2 ml) was hydrogenated at room teπperature for three hours over 5% palladium on charcoal catalyst (75 mg) at 50 p.s.i. (3.45 bar) pressure. The suspension was filtered tihrcugh arbacel, and evaporation of the solvent under reduced pressure gave the title product as a white foam (630 mg, 100%) . Rf 0.66 (ss-1). Found: C,63.22; H,9.73; H,7.17. ^-Α -ff - 9 requires C,62.78; H,9.70; 7.71%. FyAM TJ-y. - Δ-T7 The following coπpαunds were prepared from Exaπples 9-12 by hydrogenation follcwing the pioσedure of Example 13. EXAMPLE 18 methyl)-3-(l-[(σis-4-ethoxyσarboπyl-σis-3-f3-ethoxypropylIcvσlo- hexyl)oarbaπoyl]σyσlopentylIpropanoiσ aσid t-butyl ester Methanesulphonyl chloride (0.14 ml, 1.8 mmole) was added dropwise to an ice cold stirred solution of the amine from Example 13 (601 mg; 0.83 mmole) and N-methyiLmoi-pholine (0.2 ml, 1.8 mmole) in dry methylene chloride (8 ml) . The solution was stirred at 10 C for 3 hours and the reaction mixture then quenched with saturated aqueous sodium hydrogenσarbonate. The organiσ phase was separated, the aqueous phase extracted with methelene chloride and the combined extracts dried over MgS0 4 . Evaporation under vacuum gave a gum which was c_hromatographed on siliσa gel (100 g) eluting with increasing proportions of ethyl acetate in hexane starting with a 1:1 mixture and finally with neat ethyl aσetate. Evaporation of relevant fractions gave the required product as a foam (576 mg, 87%). Rf 0.56 (ss-1). Found: C,58.66; H,8.91; N,6.65. C 3g H 72 N 4 0 1 -S requires C,58.18; H,9.0l; N,6.96%. XΆ- TF^ I C,-- - The follcwing coπpcunds were prepared in a similar manner to Example 18, using the appropriate amine of Exaπples 14 to 17 and reacting with the appropriate sulphαπyl chloride or acyl chloride to yield the N^-substituted-lysyl derivative. 12 R CO R 4 / EXAMPIE 24 2S- (bis- (IS ) -Ihenylethyl 1 amincπethyl > -3- f 1- rσis-4-ethoxy- σarfaoπyl-σis-3- (3-methoχypropyl) cyclohexyl^ carbamoyl * . cyclopentyl ) - prσpanoiσ aσid t-butyl ester 2S- {bis- [IS) -Pherylethyl ] aπdioπethyl } -3- (1-carbσxy- cyσlcpea_ιtyl)p_ropanoiσ aσid and c_^4-amdnc -c>-2-(3^orethoxypropyl)- cyclc_hexane-_c L-ca_rroxyliσ aσid ethyl ester (from Preparation 2) were coupled as described in Example 1 to give the title diester as a gum. Rf 0.1 (4:1 hexane, ethyl aσetate) Found: C,73.19; H,9.13; N,4.01. requires C,73.26; H,9.15; N,3.97%. EXAMPIE 25 2S-(bisf f!S)-Ihenylethyl1amdrκ_methγl>-3-(ir (cis-4-ethoχy- σarboπyl-σis-3- (2-^pheπylethyl) σvσlohexyU carbamoyl 1 cyclopentyl >- propanoiσ aσid t-butyl ester The title compound was prepared as described in Example 24 above using cj-4-amdno-c>-2-(2-pherylethyl)cyc-lc_hexane-r-l- σarboxyliσ aσid ethyl ester hydrochloride (from Preparation 1) as the amine component to yield the product as a white foam. Rf 0.55 (ss-3) . Found: C,76.11; H,8.74; N,4.25. C 47 H 64 N 2 0 5 , 0.251^0 requires C,76.12; H,8.77; N,3.77%. EXAMPIE 26 2S-(Amdnomethyl)-3-(1-r(σ_i^-4-ethoxyσarboπyl-cis-3-(3-πethoχy- propyl)CT * clcfoexyl)ca__±>anoyl]cycl^^ acid t-butyl ester The diester from Example 24 above (992 mg, 1.4 mmole) in ethanol (20 ml) was hydrogenated over 20% palladium hydroxide on charcoal catalyst at 60 p.s.i. (4.1 bar) pressure. After twenty four hours the suspension was filtered through a short arbaσel column and the solvent was evaporated under vacuum. The residue was dried azeotropiσally with methylene chloride to give the title amine as a thick oil. (690 mg, 99%) Rf 0.35 (ss-1) Found: C,65.69 H,9.88; N,5.19. C^H gNOg requires C,65.29; H,9.74; N,5.64%. EXAMPIE 27 2S-(Aminomethyl)-3-f1- [(σis-4-ethoxycarboπyl-cis-3-(2-phenyl- ethyl)cyσlchexyl)carr-_-ioyl1σyσlσps-ityl>P-C-ip--^ aσid t-butyl ester The product of Example 25 was hydrogenated as described in Example 26 above to yield the title compound as a gum. Rf 0.35 (ss-1) Found: C,69.00; H,8.80; N,4.88. 31 H 4 8 N 2 0 5* °* 6 H ? 0 requires C,69.00; H,9.19; N,5.19. EXAMPIE 28 2S- (N^-Methanesulphoπyl-N -t-butoxyca_rbonyl-S-lysyl-am_i_no- methyll 3-(l-r (σis-4-ethoxycarboπyl-σis-3-(3-ιre^ hexyl)caι±>amoyl1C ^σlcpentyl>propanoiσ aσid t-butyl ester N-methylmorpholine (0.34 ml, 3.06 mmole) was added to an iσe cooled stirred mixture of the product from Example 26 (690 mg, 1.39 mmole) w -methanesulphonamido -t-butcκycar_>αnyl-S-lys_j-3 (406 mg, 1.39 mmole) , l-hydroxybenzotxiazole (188 mg, 1.39mmole) and l-ethyl-3-(3-d_i_πethylam___ hydrochloride (586 mg, 3.06 mmole) in dry methylene chloride (10 ml) . After six hours the mixture was diluted with methylene chloride (20 ml) washed with water and dried over MgSO . Evaporation of the solvent under vaσuu and c_h_txHiatography on siliσa gel, eluting with increasing proportions of ethyl aσetate in hexane (50 - 90%) and finally with 5% ethanol in ethyl aσetate gave the required product as a cream foam (880 mg, 81%) . Rf 0.2 (ss-3) Found: C,58.07; H,9.06; N,6.74. C^H^N^^S requires C,58.33; H,8.79; N,6.98%. EXAMPIE 29 2S-(N-t-Butyloxycar-oriyl-R-alanylaminoroethyl)-3-(1-[(σis-4- ethoχyσarfaoπyl-σis-3-(2-phenylethyl)cvclohexyl)σarbamoyllσvσlo- pentyllpropanoic acid t-butyl ester The procedure of Example 28 was followed starting with the amine of Example 27 and coupling with N-t-bui_yloxyσa_±o_πyl-R- alanine to yield the title product as a foam. Rf 0.5 (ss-1) . Found: C,67.22; H,8.86; N,5.66. 3 g H 6 x N 3 0 o requires C,66.92; H,8.78; N,6.00%. EXAMPLE 30 2- TN- (2-t-Butyloxycarbonylamdno-2-^ιethylprop-_ )yl) amdno- roethyll -3-( 1- r (σ_i_s-4-ethoxyσarboπyl-σis-3- (2-pheπylethyl) σyσlo- hexyl)c_arbaiioyllc_vclcx_)entyl)P-t_opanoic acid t-butyl ester The procedure of Example 28 was followed starting with the amine of Example 27 and coupling with 2-t-butyloxyσa_±onyl_αnino- 2-πethyl-propanoiσ aσid to give the title produσt as a foam. Rf 0.48 (ss-1) . Found: C,67.06; H,8.94; N,5.81. C. -H„N_0_ requires 4U Do J o C,67.29; H,8.89; N,5.89% EXAMPIE 31 2S-(N^-^fet-_i__res-_lphonyl-S-l-ysyl-am___nc-_et^ -3-f1-f(cis-4- carroχy-σis-3-{2-phenγlethyl)σyσlohexyl)σai±iaπoyllσyσlσpentyl>- propanoiσ aσid Trifluoroaσetiσ aσid (5 ml) was added to an iσe cold solution of 2S-(N^-ιnet__anesulphαnyl- I -t-_>utoxy-a__bonyl-S-ly_yl-a_αd_no- methyl)-3-{l-[(c___s-4-et-_oxyca_rboιyl-<:is-3-(2-phe-_ le_hyl)cycle— he-yl)ca_ι±)__τκ_yl]cyclcp--i-yl}prqp-α-Diσ aσid-t-butyl ester (from Example 19) (445 mg, 0.53 mmole) in dry methylene chloride (5 ml) . The solution was allowed to warm to room temperature and after three hours evaporated to dryness under vaσuum. The residue was dried azeσtrcpiσally twiσe with toluene and dissolved in IN sodium hydroxide, the solution was stirred at 40-55°C for sixty eight hours, cooled and passed dcwn a sulphαnic acid ion-exchange column. Elution with 10% aqueous pyridine and evaporation of the relevant fractions gave a foam which was crushed under acetonitrile and filtered to give a white powder (279 mg, 80%) Rf 0.25 (ss-2) Found: C,58.66; H,7.92; N,8.49. C. N0.S re-quires: C,59.06; H,7.74; N,8.6l%. EXAMPIES 32-37 The follcwing compounds were prepared from the appropriate N -t-butyloxycarboπyl protected diester of Examples 18, 20-23 or 28 by treatment with trifluoroacetic acid followed by alkaline hydrolysis following the procedure of Example 31. 12 R 00 EXAMPLES 38-39 The follcwing coπpounds were prepared from the diesters of Examples 29 and 30 by treatment with trifluoroaσetiσ aσid followed by alkaline hydrolysis following the proσedure of Example 31. EXAMPLE 40 3-(l-rσ_-3-4-Ca_±oxy-σis-3- 2-pheaτylethyl>cyσlΦexyl)- carbamoyl]cyclopentyl>-2-(2-methoxyethyl)propanoiσ aσid The diester of Example 1 (510 mg, 0.86 mmole) in ethanol (25 ml) and water (10 ml) was hydrogenated at room temperature for three hours over 10% palladium on charcoal catalyst (100 mg) at 50 p.s.i. (3.45 bar) pressure. The mixture was filtered through a short Avicel column and the solvent evaporated under reduσed pressure. The monoester thus obtained was dissolved in IN sodium hydroxide and the solution heated to 65°C under a nitrogen atmosphere for two days. On σooling the solution was extracted with diethyl ether, the aqueous phase acidified with 2N hydrochloric acid and extracted with diethyl ether. The organiσ phase was washed with water, dried over MgS0 4 and evaporated under reduσed pressure to give the required title diaσid as a white foam, (300 mg, 75%). Rf 0.62 (ss-1) Found: C,68.17; H,8.45; N,2.95. C 2? H 3g 0 6 requires C,68.47; H,8.30; N,2.96%. EXAMPIES 41-44 The follcwing coπpσunds were prepared from the appropriate diester of Exaπples 2 to 5 by hydrogenation followed by alkaline hydrolysis following the procedure of Example 40. C0 2 H EXAMPIE 45 2S-(2--fethoxyethoχymethγl)-3(1-r(cis-4-carboxy-cis-3-f3-methoxy- pr-pyl)σyσlches_y)c-a_ι±aιroyl1cvσlopeπtyl pr^^ acid Trifluoroacetic acid (5 ml) was added to an iσe cold solution of the diester of Example 6 (480 mg; 0.77 mmole) in dry methylene chloride (3 ml) . After standing at room temperature for three hcurs the solution was evaporated to dryness under vacuum and the residue was dried azeσtrσpically with toluene. The residual oil was dissolved in diethyl ether, washed with water (x9) and the resulting mono-ester extracted into IN sodium hydroxide solution (2 x 10 ml) . The aqueous extraσt was heated at 65-70°C under nitrogen for 24 hours, cooled saturated with salt, acidified with σonσentrated hydrochloriσ acid and extracted with ethyl acetate. The organic extract was washed with water, dried over MgSO and on evaporation gave the required diacid as a gum (320 mg 88%) . Found: C,60.55; H,8.54; N,2.80, C /P A T HS ' °- 4H 2° r& S-- J --- i C,60.20; H,8.80; N,2.93%. EXAMPIE 46 2S-(2-Methoχyethoxymethyl)-3-f1-f(σis-4-σarfaoxy-σis-3-(3-ethoxy- propyl )cylohexyl)carbamoyl1σyσlopentylIpropanoiσ acid The title product was prepared from the diester of Example 7 as described in Example 45 above and was obtained as a gum. Found: C,61.26; H,8.66; N,2.83. C NO . 0.3H_0 requires C,61.15; H,8.95; N,2.85%

Claims: CLAIMS 1. A ∞mpσund having the formula: - (I) wherein A completes a 4 to 7 membered σarbocyσliσ ring which may be saturated or πono-unsaturated and which may optionally be fused to a further saturated or -msaturated 5 or 6 membered σarbocycliσ ring; B is (CH„) wherein m is an integer of from 1 to 3; 2 m 4 . each of R and R is independently H, C--C alkyl, benzyl or an alternative biolabile ester-forπdng group; H or C,-C alkyl; R2 i.s C.-C- alkyl substituted by C--C, alkoxy, aryl or aryloxy; 5 and R is C-.-C 6 alkyl, C 2 ~C alkenyl, C -C alkynyl, C -CL cyσloalkyl, or C -CL cycloalkenyl, or R 5 i.s C.. -C, alkyl substituted by halo, hydroxy, C,-C fi alkoxy, C-.-C- alkoxy(C.-C )alkoxy, C -CL cycloalkyl, C -CL cycloalkenyl, aryl, aryloxy, heterocyclyl, -NRTl , -NR 8 00R 9 , -NR 8 S0 2 R 10 , -CONRT* 7 or R 6 R 7 N-(C -C Jalkojy; 5 . or R is C.-C- alkyl substituted by a group of the formula: E 12 R 15 - -j wherein R and R are each independently H, C--C alkyl, C--CL σyσloalkyl, aryl, aryl(CyCL)alkyl, C -C alkoxyalkyl, 6 7 or heterocyσlyl; or the two groups R and R are taken together with the nitrogen to which they are attached to form a pyrrolidiirl, piperidino, morpholino, piperazinyl or N-(C.-C )alkyl-piperazinyl group; R 8 is H or C.-C alkyl; 9 . R is C j -C^ alkyl, CF 3 , aryl, aryl(CyC alkyl, aryl(C -C alkoxy, heterocyclyl, C.-C alkoxy or NRTl wherein R and R are as previously defined; R is Cy-C alkyl, -C_ cycloalkyl, aryl or heterocyclyl; R is H, C,- 6 alkyl, aryl or C 3 -C_ cycloalkyl; R 12 is R 11 CX * »1R 11 -, R i:L S0 2 NR i:i* -, R l6 R l7 N-(CH 2 ) -, or R 0-, wherein each R is as previously defined above; 13 14 R and R are each independently H or C,-C alkyl; or 13 . 14 . . . R is H and R is C,-C fi alkyl which is substituted by OH, Cy-C. alkoxy, SH, SOi., NIL, aryl(C--C )alkyl- CX-ONH-, NELO0-, CO H, guanidino, aryl, or heterocyclyl; 13 14 . . or the two groups R and R are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered carboσycliσ ring which may be saturated or monc)-u-τsaturated and which may optionally be substituted by C.-C 4 alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring; or R 13 is H, and R12 and R14 are linked to form a 2-(N-COR -4-amdnopy__rolidinyl) group; R 15 is R 16 R 17 NCO-, R i:L OCO-, R^OCH-.- or heterocyclyl, wherein R is as previously defined above; 16 17 R and R are each independently H or C--C alkyl; and p is 0 or an integer of from 1 to 6; and pharmaceutically acceptable salts thereof and bioprecursors therefor. 2. A compound according to σlaim 1 wherein A is (OL) , R is H and B is (CH_)_ having the formula- (ID wherein R, R 2, R4 and R5 are as previously defined. 4 3. A compound as σlaimed in σlam 1 or σlaim 2 wherein R and R are both H. 4. A ccπpcund as claimed in claim 1 or claim 2 wherein one or both of R and R is a biolabile ester-forming group and said group is ethyl, benzyl, l-(2,2-diethylbutyryloxy)ethyl, 2-ethyl- propionyloxymethyl, l-(2-ethylpropionyloxy)ethyl, l-(2,4-dimethyl- benzoyloxy)ethyl, 1- (benzσylαxy)benzyl, l-(benzoyloxy)ethyl, 2-methyl-l-propioryloxyprcpyl, 2,4,6-tr__τ^ * _hylbea_-oyloxymethyl, l-(2,4,6-trimethy___benzyloxy)ethyl, pivalcyloxymethyl, phenethyl, pherpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butylpheryl, [5-(4-methyl-l,3-dioxolen- 2-onyl)]methyl or 5-indanyl. 5 5. A compound according to any one of claims 1 to 4 wherein R is methylene sι_ιbstituted by a group of the formula 12_13 14 12 . 11 11 13 . -MHOOCRTl R , Where R ls NE^, R O0NH- or R S0 2 NH-, R IS H and R 14 is -(0_ 2 ) 4 ___ 2 . 6. A cxaipound according to σlaim 5 wherein R is tr-aσetyl-S- lysylamdromethyl, N^-methane_n_ιlphonyl-S-ly-yl-__τdncmethyl, N^phenyls-__phonyl-S-lysyl-am_i_noπethyl or JN -σyσlobutylσarbonyl-S- lysyl-amiromethyl . 7. A compound according to any one of claims 1 to 4 wherein R 5 is methoxyethyl or 2-me * t_hoxyethoxymethyl. 8. A compound according to any one of claims 1 to 4 wherein R 5 is C χ -C 6 alkyl substituted by -NHC0CR 12 R 13 R 14 wherein R 12 is ^, R 13 is CH- and R 14 is H or O^. 9. A compound aσσording to any one of σlai s 1 to 8 wherein R 2 is phenyl, benzyl, phenethyl, πethαxypropyl or ethoxypropyl. 10. A σcxipσund according to σlaim 1 wherein said compound is 2S-(N^-^ethane-=ulphonyl-S-ly^lamdnomethyl) -3-{l-[σis-4- σarboxy-3-σis { 3-ethoxypropyl } -cyclchexyl) carbamoyl] cyσlcpentyl } - propanoiσ aσid; 2-(N^-methanesulphoι l-S-lysylamdncπethyl) -3-{l-[ (σis-4- c^ι±oxy-3-c_i_s-pheretlιyl-cyσlchexyl) carbamoyl] cyclopentyl }propanoic aσid; 2S- (2-methoxyetiιoxymethyl) -3-{ 1- [ (σis-4-carboxy-3-cis-{ 3- ethoxyp_rcρyl}cyσlc)he-<yl)c-a__bamo^ acid or 2S-(2-methoxyeiΛoxymethyl) -3-{l-[ (σis-4-σarboxy-3-σis-{3- methoxypropylj-cyσlαhexyl) carbamoyl] cyclopentyl }propanoiσ acid, or a biolabile ester derivative thereof. 11. A process for preparing a ccπpound of the formula (I) as claimed in σlaim 1 which comprises subjecting a compound of the formula-: R I 18 19 4 wherein R and R are as defined for R and R exσluding H, or 5 1 they are conventional σarboxyliσ aσid protecting groups and R is 5 . . . . • • as defined for R with any reactive groups therein optionally pro * tected; to a hydrolysis and or hydrogenation and/or other deprotection 5 1 reaction to remove any protective group present in R and to remove one or both of R- 1 - 8 and R 1 ^ to yield the corresponding 4 dicarboxylic acid of formula (I) wherein R and R are both H, or to yield the corresponding mono-ester produσt wherein one of R and 4 . . . . R is H and the other is a biolabile ester-forming group; and optionally forming a pharmaceutically acceptable salt of the product. 18 19 12. A process as σlai ed in σlaim 11 wherein R and R are selected from t-butyl, ethyl and benzyl and said groups are removed by txeatment with trifluoroacetic acid, aqueous alkali or catalytic hydrogenation respectively, to yield the coπpσund of 4 formula (I) wherein R and R are both H. 13. A pharmaσeutiσal composition comprising a compound of the formula (I) or (II) as claimed in any one σlaims 1 to 10 or a pharmaceutically acceptable salt thereof or biopreσursor therefor, together with a pharmaceutically acceptable diluent or carrier. 14. A cαπpound of the formula (I) or (II) as σlaimed in any of σlaims 1 to 10 or a phaπtaσeutiσally acceptable salt thereof or bioprecursor therefor, for use in medicine, particularly for the treatment of hypertension, heart failure or renal insufficiency. 72 15. A process for preparing a compound having the formula-: (I) wherein A ccanpletes a 4 to 7 membered σ_u±>ocyσlic ring whic±i may be saturated or πono-unsaturated and which may optionally be fused to a further saturated or urisaturated 5 or 6 membered carbocyclic ring; B is ( H^) wherein m is an integer of from 1 to 3; 4 . each of R and R is independently H, C.-C alkyl, benzyl or an alternative biolabile ester-forming group; R is H or ^-C alkyl; R2 i.s C -C^ alkyl substituted by C,-C. alkoxy, aryl or aryloxy; and R 5 i.s C--C alkyl, C--C alkenyl, C -C alkynyl, C -CL cycloalkyl, or C -CL cyσloalkenyl, or R 5 is C,-C- alkyl substituted by halo, hydroxy, Cy- alkoxy, C--CL alkoxy(C.-C )alkoxy, C -CL cycloalkyl, 67 C -CL cycloalkenyl, aryl, aryloxy, heterocyclyl, -NR R , -NR 8 C0R 9 , -NR 8 S02R 10 , -C0NR 6 R 7 or R 6 R ? N-(C, -Co alkoxy; or R 5 i .s C^-C f - alkyl substituted by a group of the formula: ,12 R 13 -O0NR 11-C'-R14 6 7 wherein R and R are each independently H, C--C alkyl, C -CL cyσloalkyl, aryl, aryl(C.-C )alkyl, C -C alkoxyalkyl, 6 7 or heterocyclyl; or the two groups R and R are taken together with the nitrogen to which they are attached to form a yrrolidinyl, piperidino, morpholino, piperazinyl or N-(C--C 4 )alkyl-piperazinyl group; R is H or Cy-C alkyl; R 9 is C -C 4 alkyl, CF 3 , aryl, a_ryl(Cy-C 4 )_ιl-lcyl, aryl(C.-C )alkoxy, heterocyclyl, C.-C alkoxy or NR R 6 7 wherein R and R are as previously defined; R is C,-C alkyl, C -CL cycloalkyl, aryl or heterocyclyl; R is H, Cy-C alkyl, aryl or C -CL cycloalkyl; R 12 is R 11 0CNR 11 -, R U S0 2 NEC L1 - f R l6 R 17 N-(CH 2 ) -, or R 0-, wherein each R is as previously defined above; 13 14 R and R are each independently H or C,-C alkyl; or 13 . 14 . . . R is H and R is Cy-C 8 alkyl which is substituted by OH, Cy-c alkoxy, SH, SCH j , __!-, OO0NH-, __LCO-, 00 H, guanidino, aryl, or heterocyclyl; 13 14 . . or the two groups R and R are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered carbocyclic ring which may be saturated or moro-unsatαirated and which may optionally be substituted by C.-C 4 alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring; or R is H, and R and R are linked to form a 2-(N-COROl-4-amirκ__pyrrolidinyl) group; R 15 is R 16 R 17 NC0-, K-^-oαo-, Εt 11 O H 2 - or heterocyclyl, wherein R is as previously defined above; R 16 and R17 are each independently H or C. -C alkyl; and p is 0 or an integer of from 1 to 6; which comprises subjecting a coπpσund of the formula 18 19 4 wherein R and R are as defined for R and R exσluding H, or 5' . they are conventional carboxylic acid protecting groups and R is 5 . . . as defined for R with any reactive groups therein optionally protected; to a hydrolysis and/or hydrogenation and/or other deprotection 5' reaction to remove any protective group present in R and to 18 19 remove one or both of R and R to yield the corresporriing dicarboxylic acid of formula (I) wherein R and R are both H, or to yield the corresponding mono-ester product wherein one of R and 4 . R is H and the other is a biolabile ester-forming group; and optionally forming a pharmaceutically acceptable salt of the product. 18 19 16. A process as claimed in claim15 wherein R and R are selected from t-butyl, ethyl and benzyl and said groups are removed by treatment with trifluoroacetiσ acid, aqueous alkali or catalytic hydrogenation respectively, to yield the compound of 4 formula (1 ) wherein R and R are both H. 17. A process according to claiml5 wherein A is (OI-) 4 , R is H and B is (CH_)- to give a compound having the formula-: (II) wherein R, R 2 , R 4 and R 5 are as previously defined. 18. A process according to claim 15 wherein R is ϊT-acetyl-S- lysylamJJT nethyl, ^-methanesul^onyl-S-lysylamdrrarnethyl, N^- phenyls-dphonyl-S-ly_ylamd_r_σmet_hyl or N -cyclcbutylcarbonyl-S- ly_yl__τdnc_methyl . 19. A process according to claim 15 wherein R 5 i .s methoxyethyl or 2-ι_ethoxyethoxymethyl . 20. A process according to claim15 wherein R is C,-C, alkyl 1 o substituted by -NHCOCR 12 R 13 R 14 wherein R 12 is NH^, R 13 is d^ and R 14 is H or CH 3 . 2 21. A process according to claim 15 wherein R is phenyl, benzyl, phenethyl, πethoxypropyl or ethoxypropyl. 22. A process according to claim 15 wherein said compound of formula (I) produced is-: 2S- (N^-methanesι_ phonyl-S-lysylam_i_nατeth.yl) -3-{ 1- [cis-4- carboxy-3-cis { 3-ethoxypropyl } -cycldhexyl) carbamoyl ] cyclopentyl } - prqpanoic acid; 2- (N^-irethane-sulphonyl-S-ly^lamiiiomethyl ) -3- { 1- [ (cis-4- c-___boxy-3-c___s-pheατethyl-cyσld exyl) carbamoyl] cyσlopentyl Jpropanoiσ acid; 2S- (2-methoxyethojymethyl) -3- { 1- [ (cis-4-carboxy-3-cis- { 3- ethθ5ςyprcpyl}cyσlche.^l)ca_dDamoyl]cyclcp--ityl}propanoic aσid or 2S- (2-methoxyethoxymethyl) -3-{ 1- [ (σis-4-carboxy-3-cis- { 3- methoxypropyl}-cyclche_-yl) carbamoyl] cyclopentyl Jpropanoic acid, or a biolabile ester derivative thereof.

Inventors: DANILEWICZ JOHN CHRISTOPHER, DANILEWICZ, JOHN, CHRISTOPHER
Applicants: PFIZER, PFIZER LTD, PFIZER LIMITED, PFIZER, INC.
Application year: 1990
Main classification: C07C271
IPC codes: C07C235, C07C237, C07C271, C07C311