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; R is H, C1-C6 alkyl, benzyl or an alternative biolabile ester-forming group; R<1> is H or C1-C4 alkyl; R<2> is H, OH, C1-C4 alkyl, C1-C4 alkoxy, halo or CF3; R<3> is CH2OH or CO2R<4> where R<4> is as defined for R; and R<5> is defined to include a range of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and substituted alkyl groups including in particular methoxyethyl, S-lysylamino-methyl, N<2>-acetyl-S-lysylaminomethyl and N<2>-methanesulphonyl-S-lysyl-aminomethyl, are atriopeptidase inhibitors of utility in the treatment of hypertension, heart failure, renal insufficiency and other disorders

Description: "Cycloal kyl -substituted glutaramide diuretic agents 1 This invention relates to a series of c_ycloalkyl-su__st±t rted glutaramide derivatives which are diuretic agents having utility in a variety of therapeutic areas including the treatment of various ca_τlicjva_κ_ular disorders such as hypertension, heart failure ε_nd renal __ns_-fficiency. Acxx>rd__ng to the .specification of our European patent applications EP-A-0274234 and EP-A-0343911 we describe and claim certain cycloa-^l-substituted glutaramide derivatives as diuretic agents. The present invention provides further related compounds having a 2,3-d__hydroindene substituent. The cxxnpcunds are inhibitors of the z__rx ependent, neutral endopeptidase E.C.3.4.24.11. This enzyme is involved in the breakdown of several peptide hormones, inclτ_.ing atrial natriuretic factor (ANF) , which is secreted by the heart and which has potent vasodilatory, diuretic and natriuretic activity. Thus, the <x_πpαunds of the invention, by -_r_h_Lbiting the neutral endopeptidase E.C.3.4.24.11, can potentiate the biological effects of ANF, and in particular the σonpcunds are diuretic agents having utility in the treatment of a number of disorders, __r_cluding hypertension, heart failure, angina, renal ÷Lnsufficiency, p_reme_nst_rual εϊyndro e, cyclical oedema, Menieres disease, (pr__mary and secondary) pulmonary oedema, ascites, and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the c__trpounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral erriαpeptidase E.C.3.4.24.11 the compcunds of the inventica may have activity in other therapeutic areas ircluding for example the treatment of asthma, ..nflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastroiirtestinal disorders (especially diarrhoea and irritable bcwel syndrome) , the modulation of gastric acid secretion and the t__eatment of hyperreninaemia and leukaemia. The cc_πpσunds of the present invention are of the formula: (I) wherein A cc_npletes a 4 to 7 ιι___ribered c______ocyclic ring which may be .saturated or _ro_x3- _n_»turated and which may optionally be fused to a further saturated or unsaturated 5 or 6 ιr_=mbered csarbocyclic ring ; R is H, .-C alkyl, benzyl or an alternative biolabile eεter-forming group; R 1 is H or C j -^ alkyl; K * is H, OH, C.-C alkyl, C.-C alkoxy, halo or CF ; R 3 i .s 3L0H or CO R 4 wherein R 4 i .s as previously defined for R; and R 5 i.s .-C- alkyl, C -C_ a__kenyl, C 2 -C 8 alkynyl, C -C_ cycloalkyl, or C -C_ cycloalkerryl, or R 5 i.s C,-C fi alkyl substituted by halo, hydrσxy, C.-C-. alkoxy, ,-C 6 al__o__y(C, : 6 )--lkoxy, C -C, cycloalkyl, C -C^ cycloalkerryl, aryl, aryloxy, __eterocyclyl, -NRT. , -NR 8 O0R 9 , -NR 8 S0 2 R 10 , -CONR 7 or 5 . or R is C--C 6 alkyl substituted by a group of the forxπula: R 13 A* 6 V wherein R and R are each __r_dependeπtly H, -C, alkyl, C -C cycloalkyl, aryl, arylC -C.) alkyl, C_-C 6 alkoxy__Lkyl, 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 pyrrolidirfyl, piperidino, morpholino, piperazinyl or N-(C, : 4 )alkyl-piperazinyl group; R 8 is H or C.-C. alkyl; 9 . R is C,- alkyl, CF , aryl, aryl(C,-C 4 )alkyl, aryl(C.-C )alkoxy, heterocyclyl, G.-C, alkoxy or NR R _ 7 wherein R and R are as previously defined; R is C--C alkyl, j -C cycloalkyl, aryl or heterocyclyl; R is H, j -Cg alkyl, aryl or C.-C-. cycloalkyl; R 12 is R-^O-NR 11 -, R^^ R 11 -, R 16 R 17 H- (CH -, 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 6 alkyl which is substituted by OH, j - 4 alkoxy, SH, SCH-, NH-, aryl(C,-c )alkyl- CX23NH-, N_LCX>-, 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 ιr_em__ered car±ocyclic ring which may be _»turated or ir_or.o-ur_3ato_rated and which may optionally be substituted by C.-C alkyl or fused to a further 5 or 6 iΛembered saturated or unsaturated c-a__bbcyclic ring; 13 12 14 . or R is H, and R and R are linked to form a 2-(N-00R -4-aminopyr_Olidiπyl) group; R 15 is R 16 R 17 NOO-, R 0CO-, 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 pliarmaσeutically 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 brar_hed-ci_a-_n. The term aryl as used herein means an arαtatic l-ydrocarbon group such as phenyl, naphthyl or biphenyl which may qptionally be substituted with one or more CH, CN, CF,, C.-C alkyl, C.-C alkoxy groups or halo atoms. Halo means fluoro, chloro, bro o 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, C.-C alkyl, hydroxy, carbamcyl, benzyl, oxo, amino or mono or di-(C,-C a__kyl)aiπino or (C,-C alkanσyl)amino groups. Barticular examples of heterocycles include pyridyl, pyrazinyl, pyrimidiπyl, pyridaziπyl, pyrrolyl, __midazolyl, pyrazolyl, triazolyl, tetrazolyl, furaπyl, tet-^ydrofuranyl, tet-3hyd_xpyr__nyl, diαxaπyl, thienyl, oxazolyl, isαxazolyl, thiazolyl, indolyl, isoindoliryl, quinolyl, quinoxaliπyl, quinazolinyl and benzimidazolyl, each being optionally substituted as previously defined. The compounds of formula (I) may contain several asymmetric c_entres and thus they can exist as enantiomers and diasterec_ners. The invention includes both mixtures and the separated individual iscaxters. The phaiiraσeutically acceptable salts of the <_x__r cunds of formula (I) cont-aining 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. Con cunds having a basic centre can also form acid addition salts with pharmaceutically acceptable acids. Examples include the hydrochloride hydrob_x_rιide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts. The term bioprecursor in the above definition means a Ehaπra<_eutic-_____y acceptable biologically degradable derivative of the cxxπpαund of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a c_c_πpσund of the formula (I) . A preferred group of cαtpounds of the foriπula (I) are those 1 2 wherein A is (CH_) 4 and R and R are H, i.e. compounds of the 3 5 • formula (II) below wherein R, R and R are as previously defined for formula (I) : RO-C (ID Also preferred are those compounds of formulae (I) and (II) 4 3 . 4 . wherein R and R (when R is CO R ) are both H (diacids) as well as biolabile mono and di-ester derivatives thereof wherein one or 4 . both of R and R is a biolabile ester-forming group. The term biolabile ester-forming group is well underetood in the art as meaning a group which provides an ester which can be readily cleaved in the __ody to liberate the corresponding diacid 4 of foππula (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-__r_hibitor antiliypertensive agents. In the case of the cc_rpounds of fαππulae (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 anim__l or in vitro enzyme hydrolysis studies. Thus, desirably for opt__mum effect, the ester should only be hydrolysed after absorption; a_x_ordingiy, 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 a__kyl esters (particularly ethyl) and benzyl esters, suitable biolabile esters include alkancyloxya_Lkyl esters, __nclι_ding alkyl, cycloalkyl and aryl substituted derivatives thereof, arylαxyal_kyl esters, c__τ_ylσxyalkyl esters, a_.yla__kyloxyalkyl esters, arylesters, aralkylesters, and haloalkyl esters wherein said alkancyl groups have from 2 to 8 carbon atoms and said alkyl groups have from 1 to 8 carbon atoms and are branched or straight chain and said aryl groups are phenyl, naphthyl or indairyl optionally .substituted with one or more C.-C alkyl or C -C εdj-oxy groups or halo atoms. 4 Thus examples of R and R when they are biolabile ester-fo__ming groups other than ethyl and benzyl include: 1-(2,2-diethylbutyryloxy)ethyl, 2-ethylpropionylo.ymethyl, 1-(2-ethylpropionyloxy)ethyl, 1-(2,4-dimethylbenzσyloxy)ethyl, l-(benzcyloxy)benzyl, 1-(benzoyloxy)ethyl, 2-methyl-l- propiorryloxypropyl, 2,4,6-tr__u^thy__benzoylαxy_r_ethyl, l-(2,4,6- 1_r__π_et±ιyl-ber__ylαxy)ethyl, pivalαyloxyrnethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4- dimethylpherryl, 4-t-butyl-phenyl, 5-(4-ιnethyl-l,3-<_io___ yπyl- 2-onyl)methyl and 5-indarryl. Ccitpσunds of the formulae (I) and (II) wherein R is benzyl or 4 . . . t-butyl and R is ethyl are valuable irrtermediates for the 4 preparation of the diacids wherein R and R are both H. 5 . In a .further preferred group of conpounds R is methylene substituted by a group of the formula -NHO0CR j R ' particularly where R 12 is NF^, R i:L O0NH- or R X1 S0 2 NH-, R 13 is H and 14 . R s -(αL) 4 NH_. Particularly preferred are such groups derived 5 from S-lysme; thus especially preferred R εajbεtitutents of this type include S-lysyl-_-__inc_ιethyl, _r-acj_tyl-S-lysyl-_m__rarjethyl and N -_r__t-_anes__lph__τyl-S-lysyl-_-u__nα . 5 . In further groups of preferred C-trpcunds R is C.-C alkyl, or C_-Cg alkyl s__bstituted by .-C 6 alkoxy, particularly 5 . roet__oxyethyl; or R is C.-C alkyl substituted by phenyl. Particularly preferred individual compounds of the invention include: 2-{l-[2(S)-c___r__oxy-3-(S-lysyl--cn^ ra_.tonyl-_a_i_o}-2,3-dihydra__^ acid, 2-{l-[2 (S)- arbc_ςy-3-(N^-_r_εt____πesulpho_ l-S-lysylε_(ni^ prppyl ] cyclcperrtylc_--_ix_r^l--π no } -2 , 3-dihydιπ3__ndene-2-carboxylic acid, and 2-{l-[2(S)-ca_±x_κy-3-(-^-_ι*eth--nesulp^ - propyl]c_yclcpentylc_-__i_o_yl__m__^ ,3-dihydroindene and biolabile ester derivatives thereof. The ccmpσunds of formula (I) are prepared by a number of different processes. The basic pra_*___ture involves the synthesis of a partially protected cycloalkyl-s-_c>_rt tuted 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 in R , may require protection during the coupling step and such protecting groups are removed in the final stages of the process. The synthetic route is illustrated in Scheme 1 wherein A, R and R 2 are as previ.ously defined, R5' i.s as def.ned for R5 with any reactive group therein protected if necessary, R 18 is as defined for R excluding H, or is a conventional carboxylic acid protecting group, and R 3' is either OLOH or CC R19 wherein R19 is 4 as previously defined for R excluding H or is a c_c_wentιonal carbojylic acid protecting group: 11 (I) The reaction of the ccπpounds of formula (III) and (IV) is achieved using ∞riventional amide coupling techniques. Thus in one process the reaction is achieved with the reactants dissolved in an organic solvent, e.g. ά_.chlo_ _methane, using a diimide condensing agent, for example l-etJπyl-3-(d__nethylaminc rc_3yl)- cs_Q±)cχ±Limide, or N,N'-dicyclohe_^lc3_iχιd_ _mide, advantageously in the presence of l-hydroxybenzotriazole and an organic base such as 4-πrethylmorpholine. The reaction is generally complete after a period of frcan 12 to 24 hours at room tertperatαire and the product is then isolated by conventional procedures, i.e. by washing with water or filtration to remove the urea by-product and evaporation of the solvent. The product may be further purified by crystallisation or c_τj natogτ_φhy, if necessary. The compounds of 4 formula (V) include cs-Xtpcunds of formula (I) wherein R and R are C,-C fi alkyl or benzyl. In seme cases the coupled product, in protected form, may be subjected to conventional chemical transformation reactions to allow preparation of further α_rπpcunds of foriπula (V) . Thus for example cαtpounds of foππula (V) wherein R 5' contains an ester group may be hydrolysed or hycLrogenated to generate the carboxylic acid which may be further reacted, for example with an amine, to give amide derivatives. 5* Similarly coπpounds wherein R contains a substituted or protected amino group (for example a benzylεαnino, d__berι_γlamino, ben∑yloxycarbαr lamino or t-butylαxyca_±χ__ lamino group) may be cxϊπverted to the free ermines 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, acylation with an acid chloride or anhydride yields the corresponding amides, reaction with an isocyanate yields urea derivatives and reaction with a chloroformate yields the carbamate products respectively. All these transformations are entirely conventional and appropriate conditions and reagents for their performance will be well kncwn to those skilled in the art as will other variations and possibilities. 3• . ig The diesters of forrπula (V) wherein R is COR may be further reacted to give the onoester of diacid derivatives of 4 formula (I) wherein one or both of R and R are H. The conditions used will depend on the precise nature of the groups R 18 and R19 present in the compound of formula (V) and a number of variations 18 19 are possible. Thus for example when both of R and R are benzyl, hydrogenation of the product will yield the diacid of 3 . 4 4 formula (I) wherein R is O R and R and R are both H. 18 19 Alternatively 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 product. When 18 19 one of R and R is t-butyl, treatment of the cαπpound of formula (V) with trifluoroacetic acid yields the cx)_rrespor__t_ng 18 19 acid. The diester product wherein R and R are benzyl or lower alkyl can also be treated with trimethylsilyl iodide to produce the dicarbojcylic acid product. If some other c_a__bo_ylic acid 18 19 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 foriπula (I) . In the case 3' . . . where R is CflLOH a single deprotection step is required to produce the σc_πpcunds of formula (I) using dqprotection methods as 18 appropriate to the particular R group present in the co_πpσund of 5 formula (V) . In the case where the ring A or the -substituent R is ur-saturated, the deprotection 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 1_rimethylsilyl iodide. As well as re_tκ_ving any protecting group vdiich 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 carixxxylic acid or it may be neutralised with an appropriate base and isolated in salt form. In a variant of the above p_n_x_*_*_ure, compounds of the formula (I) wherein R 5 is .-C alkyl sut-stitoted by ' -NR 8 COR 9 , -NR 8 SO R 10 , -NR 11 OOCR :L2 R 13 R 14 or -NR 11 S0 2 CR :L2 R l3 R 14 are prepared by a process which involves acylating or sulphonylating a compound of the 20 8 11 18 3' wherein R is as defined for R or R , R and R are as previously defined and Y is a ,-C 6 alkyl group; by reaction with an acid of the formula R 9 C0 2 H, R 10 SO 3 H, R 12 __r L3 I_ W oαo 2 __, or R jR R CSO_H, or an activated derivative thereof. The resulting amide or sulphαnamide product is then deprotected if required and the mono- or diester product cleaved to yield the carboxylic acids 3 . of formula (I) wherein R is H and R is CELOH or O0 2 H as previously described. The c_oπpσunds of formula (VI) are prepared following the procedures shown in Scheme 1 but using a α_mpound of formula (III) 5 1 . 5 1 having R as a protected amine derivative. Thus, for example R can contain a b__s-[(__S)-phenylethyl]c_fj_i_ιc_r3thyl substituent. Hydrogenation of the coupled product gives the corresponcling free 20 amine of formula (VI) wherein R is H and Y is OL. This route is of particular value for the preparation of cχ__npounds having 2(S) stereochemistry in the glutaramide backbone. The starting cycloa-Lkyl-sul-Stituted glutaric acid mono esters of formula HI may be prepared as described in our European patent applications EP-A-0274234, 89305180.5 and 89304698.7. The amines of formula (IV) are generally known cα_pσunds or they are prepared by appropriate synthetic procedures in accordance with literature precedents. Thus in one procedure the 3 . compounds of formula (IV) wherein R is CELOH may be prepared by reduction of the corresponding acid, or lower alkyl ester for example using sodium borohydride. 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 compounds of the invention are potent .Inhibitors of the neaitral endopeptidase (E.C.3.4.24.11) . This enzyme is involved in the breakdown of a rrumber 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 by the heart, of which the major circulating form in humans is kncwn to be the 28 amino-acid peptide referred to as alpha-hANP. Thus, by preventing the degradation of ANF, by endopeptidase E.C.3.4.24.11, the compounds of the invention can potentiate its biological effects and the ccanpσunds 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. ErrJos and L.B. Hersh, Biochemistry. 1983, 32, 3265-3271. The method involves det_erι_in__ng the c_oιx_entratiαn of <___t_pσund required to reduce by 50% the rate of release of radiolabelled hippuric acid from hippuryl- - pherrylalanyl- -εugjjiine by a neutral endopeptidase preparation from rat kidney. The activity of the craπpounds as diuretic agents is deterinined by measuring their ability to increase urine output and sodium ion excretion in saline loaded conscious mice, m this test, male mice (Charles River CDl, 22-28 g) are acclimatised and starved crvernight in itretabσwls. 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 cxaiceπtration. Urine volume and sodium ion concentration from the test animals are <xmpared to a cxontrol group which received only saline. For adrninistration to man in the curative or prophylactic t-reatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the cxmpcunds 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 adπiiriistration singly, or in multiple doses, once or several times a day. Dosages for .Intravenous adr_tinistration 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 __πvention. For human use, the compounds of the formula (I) can be administered alone, but will generally be c_-_ιι_ι_istered in admixture with a p___u_maceutical carrier selected with regain to the intended route of administration and standard pέiarmaσeutical practice. For example, they may be adrDinistered 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 cx^taiiiing flavouring or colouring agents. They may be injected parenterally, for example, irrtravenously, __ntr__rιtuscularly 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 ∞πpαunds may be administered alone but may also be adπ_i_istered 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 acx_αtf_anσe with established medical practice. Thus the cc pcunds can be cx_^adrninistered with a variety of c_a_rdiσvascular agents, for example with an ACE inhibitor such as captqpril or enalapril to facilitate the control of blood pressure in treatment of hypertension; or with digitalis, or another cardiac stimulant, or with an ACE __nhibitor, for the treatment of congestive heart failure. Other * possibilities include α_^adm__r_istration with a calcium antagonist (e.g. nifedipine, amlodopine or diltiazem) a bete-blcx_ker (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 cxsnpounds may also be adrrώiistered in conjunction with exogenous ANF, or a derivative thereof or related peptide or peptide fragment having diuretic/natriuretic activity or with other ANF-^ene related peptides (e.g. as described by D. L. Vesely et al, Biochem. Bicphys. Res. Comm., 1987, 143, 186). Thus in a further aspect the invention provides a phaπtaceutical composition comprising a compound of the formula (I) , or a piiarmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a ccaπpσund of the formula (I) , or a p__a_nιac__utically acceptable salt thereof or bioprecursor 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 further includes the use of a compound of the formula (I) for the _ι_anufac_ture of a medicament for the treatment of hypertension, heart failure, angina, renal insufficiency, preπ_=n_rt_rual syndrome, cyclical oedema, Mesnieres disease, hyperaldosteronism, pulmonary oedema, ascites, hypercalciuria, glaucoma, asthma, Jnflεαπmation, pain, epilepsy, affective disorders, dementia and geriatric confusion, Obesity, gastrointestinal disorders (..ncluding diarrhoea) , hyperrε_r_ir_aemia, leukaemia, and the modulation of gastric acid secretion. The preparation of the compounds of the invention will now be more particularly illustrated by reference to the following experimental Examples. The purity of cxxrpcunds was _xut_inely monitored by thin layer chromatography using Merck Kieselgel 60 F 4 plates. " TMJuclear magnetic reasonanσe spectra were recorded using a Nicolet QE-300 spectrometer and were in all cases consistent with the proposed structures. EXAMPIE 1 2-f1-T2(R.S)-Ca__ooxy-4-t-herfy_-butyl1c-V^loent^ 2.3-dJhydro-_nderre-2-ca_±oxylic acid (a) 2-Amino-2.3-d__hvd--θ--ndene-2-carboxylic acid, benzyl ester A mixture of 2-_ααino-2,3-<i_hydrτj__ndene-2-carboxylic acid hydrochloride (R. M. Pinder, B. H. Butcher, D. A. Buxton and D J Hcwells, J. Med. Chem., 1971, 14, 892), (11.33 g, 0.053 m) , benzyl alcohol (27.5 ml, 0.27 m), para-toluenesulphonic acid monohydrate (12.1 g, 0.064 m) and benzene (150 ml) was boiled under reflux with continuous removal of water using a Dean-Stark trap. After 48 hours, further quantities of benzyl alcohol (27.5 ml, 0.27 m) and benzene (100 ml) were added, and the reaction allowed to continue under reflux for a further 72 hours. The cool reaction mixture was diluted with diethyl ether and the resulting white precipitate collected by filtration and washed with diethyl ether. The crude tosylate salt was then dissolved in water and this solution basified with IM aqueous sodium hydroxide solution, then extracted with ethyl acetate. The c_ombined extracts were washed with saturated brine, dried (anhydrous N_ S0 4 ) and filtered. Evaporation under vacuum of the filtrate gave an oil (7.6 g, 53.6 %) which solidified at room temperature σver-night. Crystallisation of a sample from hexane afforded the pure product as a white solid, m.p. 55-55.5°C. Found: C,75.98; H,6.38; N,5.18. C 17 H 17 N0 2 requires C,76.38; H,6.41; N,5.24 (b) 2-fl-[2(R.S)-Ε hoxycarbonyl-4-pheπyl_-utyl1σyclcpeπtyl- ca_iχ3nylc_-ino)-2,3-d--hvd-X)--r_den acid, benzyl ester Qxalyl chloride (470 mg, 3.74 mmol) was added at room temperature to a stirred solution of l-[2(R,S)-etiιoxycarbonyl-4- phenylbutyl]cyclopentane carboxylic acid (600 mg, 1.87 mmol) in dry dici__orcB_et__a__e (10 ml) ∞__taining dry dimethylfor amide (2 drops). After 2 hours the solvent was removed under vacuum and the residual oxalyl chloride evaporated azeσtrcpically using dry dichloi πethane (3 x 10 ml). The crude acid chloride was dissolved in dry dicinlor nethane (15 ml) , then the resulting solution added dropwise to a stirred, ice-cold solution of the product from step (a) (500 mg, 1.87 mmol) and dry triethylε-αiine (210 mg, 2.06 mmol) in dry dichlo_x-_eth__ne (25 ml) ; stirring was c_o__tiπued for 1 hour at 0 C, then for 16 hours at room temperature. The reaction mixture was diluted with dichloix-nethane (60 ml) , washed successively with water, IM hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, dried (anhydrous Na_S0 ) and filtered. Evaporation under vacuum of the filtrate afforded a brown gum (880 mg) which was purified by clirematography on silica gel using an ethyl acetate in hexane elution gradient (0-25%) . Evaporation under vacuum of the appropriate fractions provided the required product as a clear oil, which subsequently formed a white waxy solid; (__ystallisation from diethyl ether-hexane gave the pure product (437 mg, 41.1%), m.p. 89-90°C. Found: C,76.21; H,7.22; N,2.48. C 36 H 41 0_ reqlires C,76.16; H,7.28; N,2.47%. 2-(l-f2 fR.S) -Car-_oxy-4-phe_-y_i ιtyl1cvclope^ 2 f 3-dJhyd_-o__r_derre-2-<-a-±)θxylic acid (c) A IM aqueous solution of sodium hydroxide (5 ml, 5 mmol) was added at room temperature to a stirred solution of the above product (430 mg, 0.76 mmole) in 1,4-diαxan (10 ml) and methanol (2.5 ml) . After 5 days, the reaction mixture was diluted with water (40 ml) , its pH adjusted to 7 with 2M hydrochloric acid, and the organic solvents removed by evaporation under vacuum. The resulting xαixture was washed with diethyl ether, acidified to pH 2 with 2M hydrochloric acid, then extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried (c-rihydrcus Na_SO ) , filtered, and evaporated under vacuum. Crystallisation of the residue from ethyl acetate-hexane gave the required product as a white solid (200 mg, 56.6%) . Found: C,71.30; H,6.88; N.3.25. ^^-NO.; 0.17 (H-OO-C-Hg requires C,71.59; H,7.02; N,3.02%. EXAMPLE 2 2- f 1- T 2 ( R. S ) -Carfaoxy-4-iι_5thc_xybutyl 1 c_vclσpentylcarfaonyl- a_nino)-2.3-dihvdro--nderre-2-carboxylic acid (a) 2-(l-r2 (R.S) -Benzyloxyca_tonyl-4-inethoxybutyl1 c^clopentyl- car-_onyl_αr_L--o)-2,3-^:il ydro acid, benzyl ester The procedure of Example 1(b) was followed using 1-[2 (R,S)- berizylo.yca_±x3-T/l-4-_r>eto^ carboxylic acid (334 mg, 1 mmole) and 2-_mιino-2 , 3-d__hydroindene-2-carboxylic acid benzyl ester (267 mg, 1 mmol) , to furnish the required diester (430 mg, 72.5%) . Found: C,72.95; H,7.03 ; N,3.08. C- Ji .NO ; 0.5 H_0 requires C,72.75; H,7.14; N,2.36%. (b) 2-11- [2 (R. S) -Ca_toxy-4-ιret oxy__utyl1 C TC!^ _anino>-2 ,3-d--hyd--0--r_dene-2-ca-±oxyli^ acid A solution of the above product (390 mg, 0.67 mmol) in ethanol (20 ml) was hydrogenated over 10% palladium on charcoal (39 mg) at 15 p.s.i. (1 bar) and room tetrperature for 1 hour. The catalyst was removed by filtration through a pad of Arboσel (upper) and Hyflo (lower) , then the filtrate evaporated under vacuum, and residual ethanol removed azeσtropically with dic___Lo_xmet_hane to provide the required product as a white solid (235 mg, 87.2%), m.p. 142-144°C. Found: C,65.17; H,7.29; N,3.32. C^^-NOg requires C,65.49; H,7.25; N,3.47%. EXΑMPIE 3 2-{ l-r2 (R.S. -Carboxy-3-f S-lvsyle-m-_no)prepyllC-yclopentyl- carbQrτylamiικ.ϊ-2.3-dihydro.J de acid (a) 2-Amino-2.3-d_hydro_ndener-2-<S-rboxylic acid, ethyl ester, hvdrochloride A stirred, ice-cold solution of 2-amino-2 , 3-dihydroindene-2- carbcoylic acid hydrochloride (2.48 g, 11.6 mmol) in absolute ethanol was saturated with dry hydrogen chloride. The resulting suspension was stirred at room tetrperature overnight, then warmed to 40 C and treated further with dry hydrogen chloride until a clear solution was obtained (2 hours) . After a further 4 hours at 40 C, the reaction mixture was evaporated to dryness under vacuum, then the residue crystallised from ethanol-diethyl ether to give the pure product (2.41 g, 85.8%) , m.p. 189-193°C. Found: C,59.74; H,6.69; N,5.76. C 12 H 15 N °2 ; HC1 rec 3 uires C,59.63; H,6.67; N,5.79%. (b) 2-UT2(R.S)-tert-Butoxyca_ix> -- yl-3-(d--benzyl cyclcpeπtylcarborf/lair-lno )-2.3-dJhydro:lnde--^2-c-U_boχylic acid. ethyl ester To a stirred, ice-cold solution of 2(R,S)-tert-b-rtoxycarboιτyl- 3-(diber__yl-_c_i_x3)p_π_pylcyclcpentane carboxylic acid hydrochloride (7.84 g, 0.016 m), 1-hydroxybenzσtriazole (2.16 g, 0.016 m) and 4-_tethy__mo_.p__oline (4.86 g, 0.048 m) in dry dic__lo_π__nethane (100 ml) was added l-(3-d__rrethylaιr__r_cp_xpyl)-^ hydrochloride (6.13 g, 0.032 m) ; stirring was continued for 1 hour at 0 C, then for 16 hours at room tetrperature. The dic±loi methane was removed by evaporation under vacuum at room teirperature, and the residue partitioned between diethyl ether and water. The ether phase was separated, washed with water, dried (arihydrcus Na SO and filtered; subsequent evaporation under vacuum at room temperature of the filtrate provided the crude activated ester (9.33 g, 95.4%) as a hemi-solvate with dichlo_x-r*at-hane, of sufficient purity for further progression. To a stirred solution of this activated ester (3.24 g, 5.3 iπmol) in dry didhlorcmethane (40 ml) at 0°C was added 2-ε_mino-2,3-d__hyd_oirώer.e-2-ca_boxylic acid ethyl ester (1.09 g, 5.3 mmol) and 4-dirnetoyla__ir-cpyridi_-e (0.71 g, 5.8 mmol). After 0.5 hours the solvent was removed by evaporation under vacuum and the resulting viscous oil allcwed to stand at room temperature for 3 days before partitioning between diethyl ether and water. The ether phase was separated, washed with water, dried (anyhdrous MgSO and filtered. Evaporation under vacuum of the filtrate furnished an oil which was purified by ciircmatography on silica gel using a dic lo_rj_r_ethane in hexane elution gradient (20-100%) . Evaporation of the appropriate fractions provided the required product (2.10 g, 61.2%). Found: C,73.92; H,7.88; N,4.55. C JhL. N_0 0.5 H-O requires C,74.15; H,7.94; N,4.33%. (c) 2-(l-r3-Atr__no-2(R.S)-tert-butoxyca-±oπylp-π-pyl]cyclopentyl-- ca__borryl-_mino)-2.3-d--hvdro--nder_--2-car^ acid, ethyl ester A solution of the above diester (2.7 g, 4.2 mmol) in a mixture of ethanol (6 ml) and water (0.5 ml) was hydrogenated over 20% palladium hydroxide on c_harcoal (270 mg) at 50 p.s.i. (3.45 bar) and room temperature for 16 hours. The catalyst was removed by filtration through a pad of Arbooel (upper) and Hyflo (lower) , then the filtrate evaporated under vacuum, and residual solvents removed azeotropically with dichlorαπethane, to afford the required product (1.92 g, 99.6%). Pound: C,67.64; H,8.44; N,5.89. C2-H--N20- r__guires C,68.09; H,8.35; N,6.11%. (d) 2-(l-r2(R.S)-tert-B-rtylαχyc_-iΦonyl-3-fN^. N -di-benzyloxy- dihydro__r_3ene-2-ca_i-oxylic acid, ethyl ester l-(3-Dir_et__ryla__i_.oprc yl^ hydrochloride (944 mg, 4.92 mmol) was added to a stirred solution of the above c-tnine (1.13 g, 2.46 mmol), l-hydroxytønzotriazole (322 mg, 2.46 mmol) , W , N -di-ben__yloxycarbcnyl-S-lysine (1.02 g, 2.46 mmol) and 4-_rιethyl_rorpholrne (746 mg, 7.38 mmol) in dry diciiloromethane (25 ml) at 0 C. Stirring was continued for 0.5 hours at 0°C, then for 16 hours at room tetrperature, before removal of the solvent under vacuum. The residue was partitioned between diethyl ether and water, then the ether phase washed with IM hydrochloric acid and water, dried (anhydrous N- SO ) and filtered. Evaporation under vacuum of the filtrate, followed ty <_h_xπatcgraphy of the residual oil on silica gel using a diethyl ether in hexane elution gradient (0-50%) , gave the required product (1.30 g, 61.8%) . Found: C,67.31; H,7.40; N,6.09. c 48 H 62 N 4°ιo rec J^ es C,67.42; H,7.31; N,6.55%. (e) 2-(l-r2(R.S)-Carfaoχy-3-ftT. N -di-benzyloxycai±onyl-S-lysyl- arαino)propyl1(-yclocerr_yl(_a-A>oπyl--α-ino1-2.3-d__hydroindene-2- carboxylic acid, ethyl ester Trifluoroacetic acid (5 ml) was added dropwise to a stirred solution of the above product (1.28 g, 1.5 mmol) in dry dichlo_x_methane (10 ml) at 0 C. The ice-bath was removed, stirring continued for 1 hour at room temperature, then the reaction mixture evaporated under vacuum. The crude product was dissolved in ethyl acetate and residual trifluoroacetic acid removed by washing the solution with saturated aqueous sodium bicarbonate .solution. Drying (-_r_hydrous Na_S0 4 ) , filtration and evaporation under vacuum of the ethyl acetate solution, followed by azecrtrcpic removal of residual solvent with dici_lorcroetha__e, afforded the required product (1.12 g, 90.4%). Found: C,63.85; H,6.66; N,6.59. requir s C,63.98; H,6.96; N,6.78%. (f) 2-(l-f2(R.S)-CarbQxy-3-rs-lysylarni_io)propyl1cvclocentyl- carroιryl-_nιino)-2.3-lihvd^ acid, ethyl ester A solution of the above product (1.10 g, 1.33 mmol) in a inixture of ethanol (7 ml) and water (0.5 ml) was hydrogenated over 10% palladium on charcoal (110 mg) at 60 p.s.i. (4.1 bar) and room temperature for 16 hours. Work-up as described above for Example 2 (b) provided the required product as a beige foam (740 mg, 98.9%). Found: C,59.98; H,7.56; N,9.52. C 2 _H 42 N 4 0_; 1.75 I^O requires C,59.82; H,8.16; N,9.97%. (g) 2-(l-r2 ,S)-Carroχy-3-(S-lysylcar-i->^ c r_x>rτyl_mιir>o}-2.3-cuVhydro.^ acid A solution of the above ester (700 mg, 1.24 mmol) in IM aqueous sodium hydroxide solution (7.5 ml, 7.5 mmol) was allowed to stand at room t_3-iperature for 16 hours, then loaded onto a column of strongly acidic ic_ι-exc_hange resin. The column was washed to neutrality using distilled water, then eluted with 5% aqueous pyridine. Evaporation under vacuum of the appropriate foactions gave a glass which was dissolved in di tilled water; freeze drying of this aqueous solution provided the required product (370 mg, 55.4%). Found: C,57.58; H,7.95; N,10.31. C-gH-gN^O-; 2H-0 requires C,57.97; H,7.86; N,10.40%. EXAMPLE 4 2-(l-r3-(N^-AQetγl-S-ly5yl_-mino) -2 (R.S) -caιtoxypropyllcyclo- pentylci-u±onylamino }-2.3-dihydroi-x3e -- e-2-carfaoχylic acid The prcx_edure of Example 3 was followed but using N^-aoetyl-N -ten∑ylαxycarbonyl-S-lysine in step (d) . Deprotection gave the title cc_rpound. Found: C,58.30; H,7.58; N,10.07. C 28 H 40 N 4°7 ; 1 * 75 ^2° ra 3 u Lres C,58.36; H,7.61; N,9.72%. EXAMPLE 5 2-(l-f2 (R.S) -Carboxy-3-fN -irethanesulphoπyl-S-lysylcffliino) - propyl ] <_vclσpentylca_jx>nylaιri--no ) -2.3-d_hydrτ_i-_r_aer-e-2-<_arboχylic acid The procedure of Example 3 was followed but using N - ber__yloxyca___x-_yl--^-_ret_r^ in step (d) . Deprotection gave the title compound. Found: C,53.99; H,7.13; N,9.31. C 27 H 4 _N 4 0gS; H-0 requires C,54.17; H,7.07; N,9.36%. EXAMPLE 6 2- f 1- \2 (S) -Carboxy-3- ( S-lvsyl-mtino) propyl ] cyclopentyl- c rborrylam-JK>)-2,3-dihydro:_ndei^ acid (a) 2-(l-r2 fS)-i^rt-__-rtoxycarboπyl-3-( fS.S>-al-ha, alpha - diιnet-hyld-±)er-zyla-πino Iprooyll cvclopentylcarbonylctmino 1-2.3- d-Jhydroindene-2-carboxylic acid, ethyl ester The procedure of Example 3 was followed but using 1-{2(S)- tert-buto__ycarboπyl-3-[ (S,S) -alpha, alpha -l-d-_met_ιyldi__enzyl- a__ino)prcpyl]cyclopentane carboxylic acid in step (b) to give the title product, in 79.1% yield. Found: C, 75.45; H,8.30; N,4.0l. C 42 H 54 N 2°5 re£ 3 uires C,75.64; H,8.16; N,4.20%. (b) ca-±o_τylcgr-ino>-2,3-dihydro--r_dene-2-c^^ acid, ethyl ester Hydrogenation of the above product as described in Example 3 (c) gave the 2(S) isσmer of the amine in 99.1% yield. Rf (silica) 0.50 (dichlo-xmethar-er-iriethanol, 9:1) . (c) 2-(l-f2 (S) -Ca-±oxy-3-(S-lysylam-_rκ_0p. yl1 carboirylamino ) -2 , 3-<3__ yd-^3indene-2-carboxylic acid The above amine was coupled to , N -^-ben_yloxycarbo_ryl-S- lysine following the p_xχ_-_κ_ure of Example 3 (d) and the product deprotected as described in Example 3 steps (e) to (g) to give the title compound. Found: C,56.71; H,7.48; N,9.16. CJLJ O ; 2 .5 H_0 requires C,57.02; H,7.91; N,10.23%. EXAMPLE 7 2-(l-f2 (S) -Carfaoxy-3-(N^-_ret-r_-uτes-d]±ior-yl-S-lysylc- ^ - prσpyl 1 cyclcp__ntyl(^]±onyl--mino ) -2.3-dihyd_ro--nder-&-2-carfaoxylic acid The procedure of Example 6 was followed but using N - berLzylαxy-carboπyl-w -metlianesulphoπyl-S-lysine in the coupling step to give the title compound. Found: C,53.60; H,7.27; N,8.82. C 27 H 4O N 4 0 8 S ; 1 * 5 ^2° rec 3 uires C,53.36; H,7.13; N,9.22%. EXAMPLE 8 hvdroxymethyl-2 , 3-d-_hydroindene (a) 2-Arr-Lr-D-2-hydroxyitiethyl-2.3-ό__hydroindene A solution of 2-a___Lrκ_>-2,3-d__hydro__r_deι-^ ethyl ester, hydrochloride (1.7 g, 7.03 mmol) in 50% aqueous ethanol (15 ml) , was added drcpwise to a stirred, ice-cold solution of sodium borohydride (1.11 g, 29.4 mmol) in 50% aqueous ethanol (35 ml), then the reaction mixture heated under reflux for 3 hours. The bulk of the ethanol was removed by evaporation under vacuum, and the residual suspension saturated with sodium chloride then extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried (anhydrous MgSO , filtered and evaporated under vacuum. Crystallisation of the resulting white solid (1.05 g) from ethyl aσetate-hexane afforded the required product (0.99 g, 84.8%), m.p. 89.5-90.5°C. Found: C,72.32; H,8.02; N,8.17. C-^H-^ O; 0.15 I^O requires C,72.39; H,8.08; N,8.44%. (b) 2-(1T (R.S)-Berayloxycartoπylpentyl cyclopentylcarrorrlamino )- 2-hvdrαxy_ι>et_ιyl-2.3-dihydro-_ndene l-(3-Dimethyla__ir-_propyl)-3-ethylca_±odi__^ hydrochloride (767 mg, 4 mmol) was added to a stirred, ice-cold mixture of 1- [2(R,S)-benzyloxyca_±onylperftyl]cyclcpentane carboxylic acid (637 mg, 2 mmol) , 1-hydroxybenzσtriazole (270 mg, 2 mmol) , 4-methylι_orpholine (202 mg, 2 mmol) , the product ..ram step (a) above (332 mg, 2 mmol) and dry dichloromethane (10 ml) . Stirring was continued for 0.5 hours at 0 C, then for 24 hours at room temperature. The dichlσrarr thane was removed by evaporation under vacuum, and the residue partitioned between diethyl ether and water. The ether phase was separated, washed with water, IM hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, then dried (arfiydrcus MgSO and filtered. Evaporation under vacuum of the filtrate furiiished an oil which was purified by c3rrc_ratography on silica gel using diethyl ether-hexane (1:1) as eluent. Evaporation under vacuum of the appropriate fractions provided the required product (180 mg, 19.0%). Found: C,73.75; H,7.84; N,3.06. C 2g H 37 N0 4 ; 0.5 I^O requires C,73.69; H,8.10; N,2.96%. (c) 2-U-T2(R,S)-C&ri-oxypentyllcyclσcentyl^ hydroxymethyl-2.3-dihvdroindene A solution of the above product (170 mg, 0.36 mmol) in a irdxture of etiianol (20 ml) and water (1 ml) , was hydrogenated over 5% palladium on charcoal at 50 p.s.i. (3.45 bar) and room tetrperature, to give the title product as a white solid (115 mg, 83.5%), m.p. 126-128°C, after trituration with diethyl ether- hexane (1:1). Found: C,69.04; H,8.15; N,3.63. c 2 2 H 3i N0 4 ; °- 5 H o 0 requires C,69.08; H,8.43; N,3.66%. EXAMPLE 9 2- ( 1- f 2 ( R , S ) - _a_±oxy-4-r__ery_-butyl 1 cyclopentylcarborrylcm no > - 2-hydroxymethyl-2 , 3-dJhydroindene (a) 2-(l-f 2 (R.S) -Benzyloxycar__o -- yl-4-phe -- ylta caitonylamino )-2-hydroxymethyl-2.3-dihvdroindene The procedure of Example 8(b) was followed using 1-[2 (R,S)- benzylo_ycaι±ιo_yl-4-p_-ery__butyl]cyclcpentan^ acid as starting material and allowing the reaction xrrixture to .stand at room teπperature for a further 5 days. The required product was obtained as an oil (19.9%) . Rf (silica) 0.15 (diethyl ether- hexane, 1:1) . (b) 2-f l-[2 (R.S) -Ca_±oxy-4-i-he -- y_Jxrtyl1 cycles 2-hydroxymethyl-2.3-d-_hydroindene Hydrogenation of the above product as described in Example 8 (c) , followed ty chromatography on silica gel using ethyl acetate as eluent and evaporation under vacuum of the appropriate fractions, followed by trituratiαn of the residue with diethyl et-her-hexane (1:4) , gave the required product (62.4%) as a white solid, m.p. 140-143°C. Found: C,73.76; H,7.62; N,3.12. C 27 H 33 0 4 ; 1/4 H_0 requires C,73.69; H,7.67; N,3.18%. EXAMPLE 10 caj±oirylamino ) -2-hvdroxymethyl-2.3-d_hydroindene (a) 2-(l-f 2 (R.S) -tert-B_rtoχyca-±onyl-3-(d-±)eατ--Vl_m-ij )l cyclσpentylcail-oi.yl.αnino ) -2-hydroxymethyl-2.3- .ihvdroindene 4 Methy__morpholine (1.78 g, 17.6 irarol) was added to a stirred solution of the N-hydroxy__enzσt_riazole-derived activated ester hemi-solvate with dicMoroxnethane of 2(R,S)-tert-_x_to_yca_±oπyl-3- (diben_ylaιr_ino)prcρylcyclcpentane carboxylic acid (Example 3b) (9.78 g, 16 mmol) and 2-__π___rκ_^2-hyd_o_cy-rethyl-2,3-d__hydr^ (2.65 g, 16 mmol) in dry dichloromethane (50 ml) at room teπperature. After 2 hours the .solvent was resmoved by evaporation under vacuum and the residue allowed to stand at room tetrperature for 2 days before being partitioned between diethyl ether and water. The ether phase was separated, washed with water, dried (aiϊhydrous MgSO and filtered. Evaporation under vacuum of the filtrate, followed by purification of the residue by c_r re_ratography on silica gel using a dic_hlo_xsrethane in hexane elution gradient (20-100%) , afforded the required product (3.30 g, 33.6%) . Found: C, 75.09; H,8.02; N,4.69. C 3 8 H 48 N 2 0 4 , °- 2 CR l 2 requires C,74.75; H,7.95; N,4.57%. (b) 2-(l-r3-Arπino-2 (R.S) -tert-b_ιtoχyc_a_±onylpr- yl1cyclcpentyl- carroπylaπ nol-2-hvdιoxymethyl-2.3-clihydroindene The above product was hydrogenated as described in Example 3 (c) to give the title amine in 98.2% yield. Found: C,68.96; H,8.88; N,6.63. C^H-gN^ requires C,69.20; H,8.71; N,6.73%. (c) 2-(l-r2 (R,S)-tert-Butoxycarbonyl-3-(N^. N -di-benzyloxy- carfaoriyl-S-lysylaπ-ino) propyl ] cyclσpentylcarronylamino > -2-hvdroxy- methyl-2 , 3-d__hydroindene The above aαriine was coupled to w , N -d__r_enzyloxycarbonyl-S- lysine following the pι χ_edure of Exairple 3 (d) but using a gradient of diethyl ether-hexane (1:8 to 1:1) followed by ethyl acetate as eluents for (_hro-rat_ographic purification to give the product in 62.0% yield. Found: C,67.59; H,7.53; N,6.75. C 46 H 60 N 4 O g requires C,67.96; H,7.44; N,6.89%. (d) 2-(l-r2 (R.S)-Carboxy-3-f_r . N -di-ben_yloxycarbonyl-S-lvsyl- c-O-inol propyl 1 cyclcpentylca_JX3nyl-_π-i-no ) -2-hydroxymethyl-2.3- dihydroindene A stirred, ice-cold solution of the above product (1.24 g, 1.52 mmol) in dry dichlσ_τ__ret_hane (20 ml) was saturated with dry hydrogen chloride. After a further 2 hours at 0 C, the reaction mixture was evaporated under vacuum and the residue azeotroped with dic-l-loixmethane to provide the title product as a white foam (1.05 g, 85.3%) . Found: C,64.28; H,6.83; N,7.21. C^Hg^O. ; 1.5 H-0 requires C,64.35; H,7.07; N,7.15%. (e) 2-(l-f 2 (R.S) -Ca_jx3xy-3-fS-lvsylam_no)P-^_cryl1cyclopentyl- carboπyl-_mirκ3>-2-hyd-roxyιr_5thyl-2 , 3-dihγdroindene The above product was hydrogenated following the procedure of Example 3 (f) to give the required title acid as a white foam (79.7%) . Found: C,61.20; H,8.14; N,10.41. C^ -H^N^; 1.25 H_0 .requires C,61.09; H,8.38; N,10.96%. EXAMPLE 11 2-( 1- [2 (S) -Carboxy-3- (N^-roet-r_-_f>es-ar-horr7l-S-lV-syla-r--no) - propyl 1 cyclop_Ωtylcarfcoιτyl-mύno ) -2-hydroxymethyl-2.3-diJ vdroindene The procedure of Example 10 was followed but losing the N-hydroxybenzotriazole-derived activated ester of 2(S)-tert- butyloxycarbonyl-3-[ (S,S) -alpha, alpha -dimet_hyld__benzylε_π_ino]- propylcyclopentane carboxylic acid as starting material in step (a) and coupling with N -tert-butyloxyca-±onyl-^-iretliane- sulphonyl-S-lysine in step (c) . Deprotection as previously described gave the product which was dissolved in a little distilled water and freeze dried to give the title product as a white solid. Found: C,51.50; H,7.38; N,8.67. C 2? H N 0^; HC1; 1.5 IL0 requires C,51.46; H,7.36; N,8.89%.

Claims: 34 CLAIMS 1. A coiipound having the formula-: (I) wherein A completes a 4 to 7 irembered carbocyclic ring which may be saturated or ιtorκ_^unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring ; R is H, C.-C alkyl, benzyl or an alternative biolabile est_r-forming group; R is H or C,- alkyl; R is H, OH, C,-C alkyl, C.-C alkoxy, halo or CF ; 3 . 4 . 4 . R is CH OH or COR wherein R is as previously defined for R; 5 . and R is C,-C 6 alkyl, C 2 -C β alkenyl, C -C alkynyl, C -C_ cycloalkyl, or C -C_ cycloalkenyl, or 5 . R is C,- alkyl substituted by halo, hydroxy, C,-C. 1 o 1 6 alkoxy, C,-C 8 alkoxy(C.-C.)alkoxy, C..-G, cycloalkyl, β 7 C -C_ cycloalkenyl, aryl, aryloxy, heterocyclyl, -NR R , -NR 8 O0R 9 , -NR 8 S0 2 R 10 , -CONR 6 R 7 or R 6 R 7 N-(C,-C )alkoxy; or ,D R is C.-C alkyl su__βtituted ty a group of the formula: R 12 11 13 -NR CO-C-R R 13 11 14 -CONR -C-R wherein rf ._, »' «.____ i__,«_π__yH, C^ __,!, c 3 ^ cycloalkyl, 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 pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C,-C 4 )a__kyl-piperazinyl group; g R is H or C--C 4 alkyl; R is C,-^ alkyl, CF , aryl, aryl(C.-C )alkyl, 67 aryl(C,-C 4 )alkoxy, ..eterocyσlyl, C.-C alkoxy or NR R fi 7 wherein R and R are as previously defined; R is C.-C alkyl, C -C cycloalkyl, aryl or heterocyclyl; R is H, alkyl, aryl or C.- - cycloalkyl; R 12 Ol, ,11 ,n_ i ,16-.17. is R OONR -, R SO.NR -, R R N-(OL) -, or R 0-, wherein each R is as previously defined above; R 13 and R14 are each independently H or C,-C- alkyl; or 13 14 . . R is H and R is C,-C_ alkyl which is substituted by CH, CL-C alkoxy, SH, SCH-, OCONH-, NH-CO-, CO H, guanidino, aryl, or heterocyclyl; 13 14 . . or the two groups R and R are joined together to form, with the cai±on atom to which they are attached, a 5 or 6 irembered carbocyclic ring which may be saturated or irono-unsaturated and which may optionally be substituted by C.-C alkyl or fused to a further 5 or 6 membered saturated or unsat_urated carbocyclic ring; 13 . 12 14 . or R is H, and R and R are linked to form a 2-(N-00R -4-airdnopyrrolid__nyl) group; R 15 is R 16 R 17 NOC-, R i:L 0OO-, R 11 0CH 2 - or heterocyclyl, wherein R is as previously defined above; 16 17 R and R are each independently H or C,-C fi alkyl; and p is 0 or an integer of from 1 to 6; and pharmaceutically acceptable salts thereof and bicprecursors therefor. 2. A compound according to claim 1 wherein A is (CH_) and R 2 and R are H having the foirmula R0 2 C (ID 3 5 . . wherein R, R and R are as previously defined for formula (I) . 3. A coirpound as claimed in claim 1 or claim 2 wherein R is H, R 3 is CO R 4 and R 4 is H. 3 . 4. A compound as claimed in claim 1 or claim 2 wherein R is 4 4 CO R and one or both of R and R is a biolabile ester- farming group and said group is ethyl, benzyl,1-(2,2-diethyl- butyryloxy)-ethyl, 2-etnylpropicΩyloxy_rethyl, l-(2-ethyl- propionyloxy)ethyl, 1-(2,4-dimethy__benzoyloxy)ethyl, l-(benzoyloxy)benzyl, l-(benzσyloxy)ethyl, 2-methyl-l- propionylσxypropyl, 2,4,6-tr__αv_!thyl-benzcylc_<ymethyl, 1- (2,4,6-t_r__tr_sthyl-ben_yloxy)ethyl, piv_-loylo__ymet_hyl, phenethyl, pherpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethyl- phenyl, 4-t-butyl-phenyl, 5-(4-πethyl-l,3^c_ioxDlerryl-2-oπyl)- ethyl or 5-indanyl. 5 5. A compound as claimed in any one of claims 1 to 4 wherein R 12 13 14 is methylene substituted by a group of the formula -NHOOCR R R , and R 12 is ^, R i:L C0NH- or R n S0 2 H-, R 13 is H and R 14 is 6. A coπpound as claimed in any one of claims 1 to 4 wherein R 5 is C_-Cg alkyl, C--C alkyl substituted by C,-C 6 alkoxy or C,-C alkyl substituted by phenyl. 7. A compound according to claim 1 wherein said compound is-: 2-{1-[2(S)-carboxy-3-(S-lysyl__π_ino)propyl]cyclcpentyl- c_a_±onylamino)-2,3-dihydroindene-2-carrojyli^ acid, 2-{l-[2(S)-ca___oxy-3-(_^-ιretha_esulphonyl^ - propyl]cyclcpentylcai±onylamino}-2,3-d__hydro>_-ndene-2-carboxylic acid, or 2-{1-[2(S)-carboxy-3-(N^-met- -riSS-aphoryl-S-lysyla-rd-no)- propyl]cyclopentylcartonylc-mi-no)-2-hyd_roxy_rethyl-2,3- dihydroindene; or a biolabile ester derivatives thereof. 8. A process for preparing a coπpound of the formula (I) as claimed in claim 1 which comprises subjecting a coirpound of the formula-: 1 2 . . 5 » . wherein A, R and R are as previously defined, R is as defined for R 5 with any reactive group therein protected if necessary, R18 is as defined for R excluding H, or is a conventional carboxylic acid protecting group, and R 3' is either OLOH or 00 R19 wherein R 19 i.s as previ.ously defi.ned for R4 excludi.ng H or is a conventional carboxylic acid protecting group; to a hydrolysis and/or hydrogenation and/or other deprotection reaction to remove any protective group present in R 5 1 and to 18 19 remove one or both of R and R , if present, to yield the coirresponding 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 R4 i.s H and the other is a biolabile ester-fonning group; or in the case where is CΑ M, to yield the πor-O-carboxylic acid where R is H; and optionally forrαing a pharmaceiitically acceptable salt of the product. 9. A process for preparing a compound of the fσππula (I) 5 o q o 1n wherein R is C.- alkyl _su__st_ituted by -NR COR , -M SO , →K 11∞α12τ_r13R14 or -NR11S0 2 CR12T_.13R14 which comprises acylating or s_ phor_ating a compound of the formula: wherein R ,20 is as defined for R or R ,11, R-J8 a„nd R are as previously defined and Y is a C.-C alkyl group; by reaction with an acid of the formula R 9 00 2 H, R l0 SO_H, R l2 R 13 R 14 OCO-H, or R 1 ^. 3 R CSO H, or an activated derivative thereof, followed by deprotection if reqired and hydrogenation or hydrolysis of the mono- or diester product to yield the carboxylic acid of formula 3 . (I) wherein R is H and R is C_L0H or COJH, and optionally forming a pharxriaceutically acceptable salt of the product. 10. A process as claimed in claim 8 or claim 9 wherein R 18 and R19 are __rdependently selected from t-butyl, ethyl and benzyl and said groups are removed by t_reatment with trifluoroacetic acid, aqueous alkali or catalytic hydrogenation respectively, to yield 4 the compound of formula (I) wherein R and R (if present) are both H. 11. A ph-Lπraceutical composition comprising a compound of the formula (I) or (II) as claimed in airy one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier. 12. A cc_rpσund of the formula (I) or (II) as claimed in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, particularly for the treatment of hypertension, heart failure or renal insufficiency. 13. A process for preparing a cx pcund having the fomula- (I) wherein A completes a 4 to 7 membered c_arbocyclic ring which may be .saturated or mαno-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 irrSiribered carbocyclic ring ; R is H, C, -C 6 alkyl, benzyl or an alternative biolabile ester-forming group; R is H or C.-C alkyl; 2 . R is H, OH, C.-C alkyl, -. - . alkoxy, halo or CF ; 3 . 4 . 4 . R is CH_OH or CO R wherein R is as previously defined for R; and R is C.-C alkyl, C -C, alkenyl, C -c alkynyl, C -C cycloalkyl, or C -C_ cycloalkenyl, or 5 . R is C j -C alkyl .substituted by halo, hydroxy, C_-C alkoxy, C -C j cycloalkyl, C -C_ cycloalkerryl, aryl, aryloxy, heterocyclyl, -NR ,6 R- , -NR 8 C0R 9 , -NR 8 S0 2 R 10 , -CONR 6 R 7 or R 6 R 7 N-(C. -C )alkoxy; 5 or R is C,-C alkyl sul_stι1_uted by a group of the formula: R 12 11 13 -NR- L 00-C-R R 13 __■ 7 wherein R and R are each independently H, C.-C alkyl, C--C_ cycloalkyl, 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 pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C,-C )al_kyl-piperazinyl group; R 8 is H or C--C 4 alkyl; R 9 is C j -C^ alkyl, CF 3 , aryl, aryl(C-^C 4 )alkyl, £? 7 aryl(C.-C alkoxy, heterocyclyl, C.-C alkoxy or NR R 6 7 wherein R and R are as previously defined; R is ,- 4 alkyl, C -C cycloalkyl, aryl or heterocyclyl; R is H, C-^-C. alkyl, aryl or C.-C. cycloalkyl; R 12 is R 11 C0NR 11 -, R-^SO NR 11 -, 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 fi alkyl; or R13 is H and R14 i.s C.-C alkyl whi.ch i.s substi.tuted by CH, C- T -CJ alkoxy, SH, SCH_, N^, arylfC -C )alkyl- OO0NH-, NH^CO-, CO H, guanidino, aryl, or het_erocyclyl; or the two groups R 13 and R14 are j.oi.ned together to form, with the carbon atom to which they are attached, a 5 or 6 membered carbocyclic ring which may be saturated or mono-unεatorated and vftiich may optionally be substituted by ,-C 4 alkyl or fused to a further 5 or 6 ιr___tibered saturated or unsatorated c_arbocyclic ring; or R is H, and R and R are linked to form a 2-(N-C0R -4-c_mincpyrrolidiπyl) group; R 15 is R 16 R 17 NOO-, R 0CO-, R^OCH-- or heterocyclyl, wherein R is as previously defined above; 16 17 R and R are each independently H or C_-C 6 alkyl; and p is 0 or an integer of from 1 to 6; which comprises subjecting a cαrpound of the formula: 1 2 . . 5' wherein A, R and R are as previously defined, R is as defined cr TO for R with any reactive group therein protected if necessary, R is as defined for R excluding H, or is a conventional carboxylic 3* . . 19 acid protectαng group, and R is either CH_OH or CO R wherein 19 . 4 . . R is as previously defined for R excluding H or is a conventional carboxylic acid protecting group; 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 , if present, to yield the 4 corresponding dicarboxylic acid of formula (I) wherein R and R are both H, or to yield the corresporxling mono-ester product 4 . wherein one of R and R is H and the other is a biolabile 3' . ester-fonning group; or in the case where R is <_H OH, to yield the mono-ca_±o3ylic acid where R is H, and optionally forming a j_r__rmaceutically acceptable salt of the product. 14. A process for preparing a ccmpcund of the formula (I) *. fl Q R lπ wherein R is Cy-C alkyl sajbstituted ty -NR COR , -NR SO R , -NR 11 C0CR 12 R 13 R 14 or -NR 11 S0 2 CR :L2 R 13 R 14 which comprises acylating or sulphorating a compound of the formula: 20 8 11 18 ' wherein R is as defined for R or R , R and R are as previously defined and Y is a C -Cg alkyl group; ty reaction with an acid of the formula R 9 00 2 H, R 10 S0 3 H, R 12 R 13 R 14 C00 2 H, or 12_13 14 R T. R CSO H, or an activated derivative thereof, followed by deprotection if required and hydrogenation or hydrolysis of the mono- or diester product to yield the carboxylic acid of formula 3 . (I) wherein R is H and R is CfLOH or CT H; and optionally forming a pharmaceutically a∞eptable salt of the product. 18 15. A process as claimed in claimB or claim14 wherein R and 19 R are independently selected from t-butyl, ethyl and benzyl and said groups are removed by treatment with trifluoroacetic acid, aqueous alkali or catalytic hydrogenation respectively, to yield the compound of formula (I) wherein R and R (if present) are both H. 16. A process according to claimB or claim wherein A is (O ) . 1 2 . and R and R are H to give a compound having the formula R0 2 C (II) 3 5 . . wherein R, R and R are as previously defined for formula (I) . 17. A process as claimed in claim B or claim14 wherein R is H, R 3 is C0 2 R 4 and R 4 is H. 18. A process as claimed in claim __3wherein R is methylene substituted by a group of the formula -NHCOCR 12 R 13 R 14 , and R 12 is NH_, R i:L O0NH- or R i:L S0 2 NH-, R 13 is H and R 14 is -(OL) .NEL. 5 7. A process as claimed in claim 1 wherein R is C_-C fi alkyl, C,-C alkyl εajbstituted ty C-. 'C alkoxy or C,-C alkyl substituted by pheryl. 19. A process acoording to claim 13 wherein said compound of formula (I) produced is-: 2-{l-[2 (S) -car±o_y-3-(S-lysyl__nino)p_π_pyl]cyclcpentyl- ca-±onylam__r _»}-2,3-d_-hydroi_^ acid, 2- { 1- [ 2 (S ) -carboxy-3- (_ -metharres_ phonyl-S-ly_yla_r_ino) - propyl] cyclcpentylcarbonyla_r no} -2 , 3-&ihydroindene-2-carboxylic acid, or 2-{ 1- [2 (S) -carbαxy-3- (N^-_ret_n__αιe_5ulphoryl-S-lysyl__r__i_rκ_») - propyl ] cyclcpentylc-u±»_yl-_mino ) -2-hydro_ymethyl-2 , 3- dihydroindene; or a biolabile ester derivatives thereof.

Inventors: BARNISH IAN THOMPSON, BROWN DAVID, DANILEWICZ JOHN CHRISTOPHER, KEITH JAMES, BARNISH, IAN, THOMPSON, BROWN, DAVID, DANILEWICZ, JOHN, CHRISTOPHER, KEITH, JAMES
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1990
Main classification: C07C235
IPC codes: C07C233, C07C235, C07C237, C07C311