CA2072126A1 - Cycloalkyl-substituted glutaramide diuretic agents - Google Patents

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; R1 is H or C1-C4 alkyl; R2 is H, OH, C1-C4 alkyl, C1-C4 alkoxy, halo or CF3; R3 is CH2OH or CO2R4 where R4 is as defined for R; and R5 is defined to include a range of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and substituted alkyl groups including in particular methoxyethyl, S-lysylamino-methyl, N2-acetyl-S-lysylaminomethyl and N2-methanesulphonyl-S-lysyl-aminomethyl, are atriopeptidase inhibitors of utility in the treatment of hypertension, heart failure, renal insufficiency and other disorders

Description

-~ W091tlO~ PCr/EP90/02156 ,; . .~, ~. ...
"Cycloalkyl-substituted glutaramide diuretic agents Ihis invention relates to a series of eyel ~ l~substitNted glutaramide derivatives which are diuretic ager~ts having utility in a variety of therapeutie areas ineluding the treatment of various eardiovascular disorders such as hyFe~t~sion, heart failure and ranal insuffieiency.
Ascording to the specification of our Eurcpean patent applica~ions E$-A-0274234 and EP-A-0343911 we describe and claim ce~tain cycloalkyl-substituted glutaramide derivatives as diuretic agents. The present invention pr w ides further rela~ed ca~çounds having a 2,3-dihydroindene substituent.
Ihe c=wpcunds are inhibitors of the zinc-depe ment, neutral endopeptidase E.C.3.4.24.11. This enz~me is invol~ed in the breakdown of several peptide hormones, including atrial natriuretic factor (ANF), which is secreted by the heart and which has potent vascdilatory, diuretic and natriuretic activity. Thus, the cc~pcunds of the invention, ~y inhibiting the neutral endo~epkidase E.C.3.4.24.11, can pokentiate the biologi~Al effects of ANF, and in particular the c~w}Y~nds are diuretic agents having utility in the treatment of a n~c~er of disorders, including hypertension, hsart failure, an~ina, renal insufficiency, pre=enstrual sy~drcme, cyclical oedema, Menieres disease, hyperaldosteronism (primary and secondary) pulmonary ~edema, ascites, and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the ccr~ccunds have utility in the treatment of glauc~ma. As a further result of their ab;lity to inhibit the ~eutral endopepkidase E.C.3O4.24.11 , . . r ~, : . ' '. ,' :' `
' ': ' WO 91t10644 PCT/EP90/02156 ~ 212`~

the ccnpc~nds of the m vention ~ay have activity in cther therapeutic areas including for example the tre~tment of asth~a, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastr~in~estinal disorders (especially diarrhoea and irritable kowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia and leukaemia.
Ihe ccmçoonds of the present invention are of the formula:

/9~ R

~ CHCH2~ B

(I) ~herein A co~pletes a 4 to 7 mem~ered carbocyclic rLng which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or : unsaturated 5 or 6 m~mbered carbocyclic ring ;
R is H, Cl-C6 alkyl, benzyl or an altErnative biolabile ester-formung group;
Rl is H or ~ -C4 aIkyl;
R2 is H, OH, Cl-C~ alkyl, Cl-C4 alkoxy, halo or CF3;

, , . .

:, . ~': ' : . .

~. WO 91/10644 ~ ~ 2 ~ 7~ 2 ~ 2 ~ PCI`/EP90/02156 3 . 4 R is CH2~1 or C~02R ~ere~n R is as previously defined for R;
and R5 is C1~6 a~yl~ C2 6 al~l~ C2~6 a~l, C3-C7 cyc:lo~l, or C3-C7 cycloaL~ryl, or R5 is Cl-C6 alkyl substituted ~y halo, hydro~, Cl C:6 aL~coxy, Cl-C6 alkoxy(Cl-C6)a~, C3~7 cycloalJ~l, C3~7 cycloalk~yl, aryl, arylo~, hetero~lyl, -~R6R, --NR8COR, --~R S02R , {X~R6R7 or R6R7N--(C~ a~co~;
or R5 is Cl{:6 allcyl substituted by a grol~p of the :Eorn~lla:
Rl~
_NRll l R13 NR SO2 C R or {~Rll_C_R

: " - . . ~
' ~ ~ i. .

W O 91/10644 2 0 7 21~ ~ PCT/EP90/02156 ~

4 .
wherein R and R7 are each in1ependently H, Cl-C4 alkyl, C
cycloalkyl, aryl, aryl(Cl-C4)alkyl, C2~C6 alk ~ l, or heterccyclyl; or the two grcup6 R6 and R7 are taken together with the nitrogen to which they are at~ched to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(Cl-C4)alkyl-piperazinyl group;
R is H or Cl-C4 alkyl;

R is Cl--C4 aIkyl~ CF3, aryl, aryl(Cl-C4)alkyl~
aryl(Cl-C4)alkoxy, heterccyclyl, ~ -C4 alkoxy or NR R
wherein R6 and R7 are as previGusly defined;
R10 is Cl-C4 alkyl, C3-C7 cycloalkyl, aryl or heterocyclyl;
Rll is H, Cl-C6 alkyl, aryl or C3-C7 cycloalkyl;
R is RllcoNRll_, RllsO NRll_ R1 ~17N (CH
Rl10-, wherein each * l is as previausly defined above;
R13 and R14 are each independently H or Cl-C6 alkyl; or R13 is H and R14 is Cl-C6 alkyl which is substituted by OH, ~ -C4 aIkoxy, SH, SCH3, N~ , aryl(Cl-C6)aIkYl :
OCONH-, NH2CO-, 002H, guanidino, aryl, or heterocyclyl;
or the two groups R13 and R14 are joined together to form, with the car~on atom to which they are attached, a 5 or 6 n~ red carbocyclic ring which may 'ae saturated or monG-unsaturated and which may opkionally be ,,;

2 b~ 2 1 2 6 PCI/EP90/02156 .. .

substituted ~y C~{~4 a~l or fus~d to a :Eur~er 5 or 6 memb~ saturated or unsaturated car~ocyclic rir~;
or R13 ~.s H a~3. R12 and. R14 are lir~ced to form a 2- (N{r)Rll-4-arir~r~lidinyl) grwp;
R15 is R16R17Ncx~_ RlloCI~_, Rlloc~2_ or he~clyl, ~erein Rll is as previously defined abave;
R16 a~ *7 are ea~h ~epe~ently H or C1~6 al~l;
and p is O or an integer of f m m 1 to 6;
and pbarmaceutically acceptable ~lts thereof ~nd bicprec~rsors therefor.
In the above definition, unless ctherwise indicated, alkyl groqpe having three or more carbon atLms may be straight or ~ranched-chain. The term aryl as used herein mYans an arcmatic h~h3x~lrbon group such as pbenyl, naphthyl or bip enyl which may opkionally be substitu~ed with one or more OH, CN, CF3, ~ -C4 alkyl, ~ -C4 aIkDxy groups or halo atoms. Halo means fluor~, chloro, bramo or iodo.

.~ . . . . . ... .
:. ~.. . .
, : , ,., , ., ., : , , ,, :-, , ,: . - ,, W O 91/10644 2 0 7 ~1 ~ 6 PCT/EPgO/02156 m e term heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur contaim ng heterocyclic group which, unless otherwise stated, may be saturated or unsaturated an~ which may optionally include a further oxygen or one to t~rnee nitrogen atoms in the ring and which may optionally be kenzo ~1 or s~bstituted with for example, one or more halo, ~ -C4 alkyl, hydroxy, c ~ l, benzyl, oxo, am m o or mono or di~ C4 alkyl)amuno or ~ -C4 a ~ l)amono grcups. Parti~l æ examples of heterocycles mclude pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, te~rahydrofuranyl, tetrahyoLopyranyl, dioxanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindolinyl, quinolyl, qum oxal myl, quinazolinyl and benzimidazolyl, each bleing optionally substituted as previously defined.
The cowpcunds of formula ~I) may contain several asymmetric centres and thus they can exist as enantio~ers and diastere~mYrs.
m e invention includes both mixtures and the separated individual is ~ s.
Ihe pbarma oeutically acceptable salts of the c~DFIurds of formula (I) containing an acidic centre are those formed with bases which ~orm non-toxic salts. Examples include the alkali m~etal salts such as the sodi~m, potassium or calcium salts or salts with amines such as diethylamine. CcnlYunds having a ba~sic centre can also form acid addition ~lts with pharma oe utically aoceptable acids. Examples include the hydrochloride hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, a oetate, citrate, fumarate, gluconate, lactate, . ~ .. ..
, .. . . . . .
: :
:

.~ W 0 91/10644 2~0:~ 2 1 2 6 PCT/EP90/02156 : :, maleate, succinate and tartrate salts.
The term bioprecursor in the above defLnition means a pharma oe utically accEptable biologically degradable derivative of the compcund of formula tI) which, upon admini~ration to an c~nimal or human being, is converted in the body to produ oe a ocmpound of the formLla ~I).
A preferred grcup of ccnpounu`s of the for~l1a (I) are those wherein A is ( ~ )4 and Rl and R2 are H, i.e. ccmpGunds of the formula (II) below wherein R, R3 and R5 are as previcusly defi~ed for formula (I):

R Q

/

(II) : Also preferred are those a=poY n~s of formulae (I) and (II) wherein R and R4 (when P~3 is 002R4) are both H (diacids) as well as biolabile no .~n~ di-ester derivatives thereof wherein one or ~oth of R and R4 is a biolabile ester-forming group.
'.~ 'rhe term biolabile ester-forming group is well understood in the art as m~aning a group which provides an ester which can be readily cleaved in the body to likerate the corresponding diacid of formwla (I) wh~rein R and R4 are both H. A number of such /

.. ..

... . ..
,, . , ,. ,.~ .

W O 91/10644 2 0 i ~ PCT/EP90/02156 .~.
""' 1.

ester grcups are well kncwn, for example in the penicillin area or in the case of the ACE-inhibitor antihypextensive agents.
In the case of the ccmpcunds of formulae (I) and (II) such biolabile prordrug esters are particularly adva~tagecus in providing compcAnds of the form~la (I) suitable for oral ad=uristration. The suitability of any parti~llar ester-formung ~ p can be assessed by conventional animal or in v tr~ enzyme hydrolysis studies. muS, desirably for optinn~o effect, the ester shculd only be hydrolysed after absorption; accordingly, the ester should be resistant to hydrolysis before absorption by digestive enz~mes but should be readily hydrolysed by, for example, liver enzymes. In this way the active diacid is released into the blccKb~ naam following oral absorpkion.
In aA~;tion to lcwer alkyl esters (particul æly ethyl) and benzyl esters, suitable biolabile esters include alkannyloxyalkyl esters, including alkyl, cyclc~lkyl and aryl substituted derivatives thereof, aryloxyalkyl esters, arcyloxyalkyl ester.s, arylalkyloxyalkyl esters, arylesters, aralkylesters, and haloaIkyl esters wherein said alkanoyl grcups have from 2 to 8 carbon atoms and said aIkyl groups have ~rc~ l to 8 carbon atams and are ~branche~ or straight chain and said aryl grcups are phenyl, naphthyl or indanyl optionally substituted with one or more ~ -C4 alkyl or Cl-C4 aIkoxy groups or halo atcms.
~muS examples of R and R4 when they are biolabile : ester-forming grcups okher than ethyl and ~enzyl include: ¦
l-(2,2-diethyIbutyryloxy)ethyl, 2-ethylpropionyloxymethyl, .-1-(2-ethylprcpionyloxy)ethyl, l-(2,4~dimethylbenzoyloxy)ethyl, 207~2~
;~ W O 91/10644 ~ PCTlEPgO/021~6 l-(benzoyloxy)benzyl, l-(benzoylcxy~ethyl, 2-methyl-l-prcpionyloxyprcpyl, 2,4,6-trimethylben20ylo~nnethyl, l-(2,4,6-trimethyl-benzyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluor~ethyl, l- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butyl-phenyl, 5-(4-methyl-l,3-dioxalyny1-2-ony1)methyl and S-inlanyl.
Crmpounds of the formulae (I) and (II) wh ~ R is benzyl or t-butyl and R4 is ethyl are valuable Lntermediates for the preparation of the diacids wherein R and R4 are bcth H.
In a fur~her preferred group of o~mpcunds R5 is methylene substituted by a gr~up of the formLla -NHCCCR ~ 13R14' particularly where R12 is NH2, RllCONH- or RllSO NH R13 R14 is -(CH2)4 ~ . Particularly preferred are such gro~ps derived fram S-lysine; thus especi~ preferred R5 suksti~utents of ~his type include S-lysyl-amincnm*hyl, N2-a oetyl-S-lysyl ~ ethyl and N2~tha~1phonyl-S-lysyl-z i~e~yl.
In further groups of preferred oa pounds R5 is ~ -C6 alkyl, or cl-c6 allcyl substituted }~ -c6 aL~y, partiallarly methoxyethyl; or R5 is ~ -C6 alkyl substituted by phenyl.
Particularly pre~erred individual o~mpoun~s o~ the mvention include:
2-~1-[2(S) car ~ xy-3-(S-lysylam~ propyl] ~ ~ l-carbonylamino~-2,3-dihydr3indene-2-carboxylic acid, ~ 2~ [2(S)-carboxy-3-(~ -methanesulphonyl-S-lysylami~o)-::~ p ~ pyl]cyclo ~ lcar~onylamino}-2,3 dihydroir~en ~ 2 car~oxylic acid, and ,~
:
:, ::;, ~ :
.: .
.

WO 91/10644 2 ~ 7 2 i 2 ~ PCT/EP90/02156 2~ [2(S)-car~oxy-3-(N2-methanesulphonyl-S-lysylamuno)-propyl]c~clopentylcarbonylamino~-2-hydroxymethy:L-2,3-dihydroindene and biolabile ester derivatives thereof.
The cocFcLnds of formula (I) are prepared ]Dy a number of different processes. The basic prooedure involves the synthesis of a partially pr ~ d cycloaIkyl-substitutad glutaric acid derivative which is coupled to an amine to gi~e the desired glutaramide. ~he carboxylic acid group in the amine, if free, or any reactive groups in R , may ~ protection during the coupling step and such protecting groups are removed in the final stages of the prccess.
The synthetic ro~te is illustrated in Scheme 1 wherein A, Rl and R2 are as previously defined, R5 is as defined for R5 with .
any reacti~e graup therein prokected if necsssary, R18 is as defined for R excluding H, or is a conventional carboxylic acid protecting grcup, and R3 is either CH2OH or 002Rl9 wherein R19 is as previously defined for R4 excluding H or is a conventional car~oxylic acid protecting gr w p:

.

'...................... ' ' WO 91/10644 2 a 7 212 6 Pcr/EP9o/a2l56 . I . . . ~ ' .

Sc~l~me I

CUCU2 / \ C0211 + H,,N ~R

R O2C (III) (IV) \ C~C~z~ \CONa ~ R3 R O2C (V) , ~1, .
(I) .
Ihe reaction of the ccmpconds of formula (III) and (IV) is achieved using conventional amide ccuplLng techniques. Ihus in one process the reaction is achieved with the reactants dissolved in an organic solvent, e.g. dichlorcmethane, us mg a diimide condensing agent, for example l-ethyl-3-(dimethylamlnopropyl)-carbcdiimide, or N,N'-dicyclohexylcarbodiimide, advantageously in the presence of l-hydroxyben2otriazole and an o ~ c kase such as 4-methylm~rpholine. The reaction is generally complete after a period of fr~m 12 to 24 hours at roam temperature and the product is then isolated by conventional proo dures, i.e. by washi~g with water or fil~ration to rem~ve the urea by-product and evaporation of the solvent. The product may ~e further purified by .. . .. .

wo gl/10~44 2 0 7 212 6 PCT/EP90/02156 crystallisation or chrcmatography, if ne~essary. m e ccnpoonds of formula (V) mclude ccmpcon~s of formLla (I) wherein R and R are -C6 alkyl or benzyl.
In scme cases the coupled product, in prx~ted form, may be subjected to conventional chemical transformati.on reactions to allow preparation of further compounds of formula ~V). Thus for example ccmpc~nds of formula ~V) wherein R5 contains an ester gr3up may be hy~rolysed or hydrogenated to generate the carboxylic acid which may be further reacted, for example with an amune, to give amide deri~atives.
Similarly oompoands wherein R5 contains a substituted or protected amino group (for example a benzylam mo, dibenzylam mo, benzyloxycarbonylamino or t-butyloxycarbonylamino group) may be converted to the free am m es by hydrogenation or protonolysis as apprDpriate. qhe amines produced may be further reacted, thus for example reaction with a sulphonyl halide yields the c~rresponding sulphonamides, acylation with an acid chloride or anhydride yields the correspond~^ng 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 o~her variations and possibilities.
The diesters of formula (V) wherein R3 is 0~2Rl9 may be further reacted to give the monoester of diacid derivatives of formula (I) wherein one or both of R and R4 are H. The conditions used will depend on the precise nature of the groups R18 a~d R
present in the compcund of formLla (V) and a number of variations ., ' ' ~ :

~ WO 91tlO644 ~ 2 0 7 212 6 PCT/EP90/02156 are possible. Thus for example when bcth of R and R19 are benzyl, hydroge~ation of the product will yleld the diacid of formula (I) wherein R3 is 002R4 and R and R are both H.
Alternatively if one of R18 and Rl9 is benzyl and the other is alkyl, hydrogenation will yield a monoester product. This can be hydr3lysed, if desired, again to yield the diacid product. When one of R18 and Rl9 is t-butyl treatment of the compound of formula (V) with trifluoroacetic acid yields the correspondi~g acid. The diester product wherein R18 and Rl9 are benzyl or lcwer alkyl can also be treated with trimethylsilyl iodide to produce the dicarboxylic acid product. If some other carboxylic acid protecting group is used for R18 or Rl9 then clearly appropriate conditions for its removal must be employed in the final step to give the ester or diacid product of formula (I). In the case where R3 is ~ OH a single deprokection step is requlred to produce the ccmpcunds of formLla (I) using deprotection ~ethods as app m priate to the particular R18 group present in the compound of form~la (V). In the case where the ring A or the substituent R5 is unsaturated, the deprotection must be eff~cted by non-reductive meth~, thus for example if either of R and R is benzyl, they may be remcved by treatment with trimethylsilyl iodide.
As well as removing any protect m g group which may be present in R5 , a number of chemical transforma~ion reactions are possible on the final mono-ester or diacid pro~ucts as previcusly de æ ribed. In each case the product ~ay be o~btained as the free carboxylic acid or it may be neutralised with an appropriate base and isolated in c~lt form.

- ,: , t ' ' ~ ' " :' ,' ' . .

wo gl/10644 - `2 0 7 2 i 2 6 PCTIEP90/02156 ._ In a variant of the above procedure, o~om ds of the formula (I) wherein RS is ~ -C6 alkyl substituted by -NR OOR , -NR S02R
NRllcocR12R13Rl4 or _NRllso2CRl2Rl3Rl are prepared by a procesS
w~Lich involves acylating or sulFhonylating a compound of the formula: ~ ~ R2 ~ ~Y ''' ~ R20NH Y / \ U ~ 3' ., CHCH2 R 02C / ~ I~

wherein R20 is as defined for R8 or Rll, R18 and R3 are as previcusly defined and Y is a ~ -C6 alkyl group; by reaction with an acid of the formula R9Oo2H, A OSO3H, R12Rl3Rl4CCo2H~ or R12R13 * 4CSo3H, or an activated derivative thereof. The resulting amide or ~-1phonamide product is then deprotEcted if required and the monc- or diester pro*uct cleaved to yield the carbcxylic acids of formula (I) wherein R is H and R3 is CH2OH or ~02H as previcusly d~scribed.
The corpcunds of formula (VI) are prepared following the procGdures shown in Scheme l but using a compcund of formula (III) having R5 as a protected amune derivative. Thus, for example R5 can contain a bis-[(lS)-phenylethyl}amuncmethyl substituent.
Hydrogenation of the coupled product gives the corresponding free amune of formLla (VI) wherein R20 is H and Y is ~ . mis r3ute is of partic~lar value for the pr2paration of carpounds having 2(S) stereochemistry in the glutaramide backbone.

... . . .

:: , ~` ~ '' ':

W O 91/10644 i . PCT/EP90/02156 ~t 2~72~26 i; ' The starting cycloaIkyl-substituted glutaric acid m~no esters of formula III may be pxepared as described in our ~ n ~patent applications EP-A-0274234, 89305180.5 and 8~304698.7.
m e amines of formula ~IV) are generally 'hn3wn ccnpcunds or they are prepared by appropriate synthetic ]prcoeduras in acoordance with literature precedents. Ihus ~n one p ~ e the cYmpcunds of formula (IV) wherein R is CH20H maY be preparsd by ion of the corresponding acid, or lower alXyl ester for example using sodium b~rchydride.
~ xc~priate ca~plir~ and pxatectir~ methods for all of 'che above steps and alternative variations arx~ proo~ures will be well }~awn to those ~dcilled in t~e art by ref~rence to stan~ard text booXs and to the ex~les provided hereafter.
As previa~sly n~Ttiaa~d, the co~rds of the inverltion are pctent inh~bitors of the neutral endcpeptid~se (E.C.3.4.24.11).
l~is enzyme is involved in the breakda~ of a ~ of peptide hormones anld, in particular, it is iTn~olved in the breahdc~n of atrial natriuretic factor (ANF). I~is hormone consists of a family of related natriuretic peptides, secreted by the heart, of which the major circulatLng form in humans is known to be the 28 amino,acid peptide referrad to as alpha-hANP. Thus, by preventLng the degradation of ANF, by end~peptidase E.C.3.4.2~.11, the ccnçounds of the invention can potentiate its biolugical effects and the crnpcunds are thus diuretic and natriure~ic agents of t utility in a ~ r of disorders as previously described.
Activity aga mst neutral endcpeptidase E.C.3.4.24.11 is a ~ using a prooedure based on the assay described by J.T.
Gafford, R.A. Skidgel, E.G. Erdos and L.B. Hersh, Bioche~Lstry, .
,~ , .
:.

' 1983, 32, 3265-3271. The methcd mvolves determ mQrg the concentration of ccmpound required to reduoe by 50% ~he rate of release of radiolabelled hippuric acid fram hippuryl-Ir phenylalanyl-~,arginine by a neutral endopept.idase preparation from rat kidney.
Ihe activity of the ccmpcon~s as diuretic agents is determined by measuring their ability to increase urine cutput and .cn~;um ion excretion in saline loaded conscious mloe. In thLis test, male mioe (Charles River CDl, 22-28 g) are acclimatised and starved overnight in metab3wls. The mioe are dosad intravenKusly via the ta;l ve m, with the test compound dissolved in a volu~e of saline solution equivalent to 2.5% of body weight. Urine samples are collected each hour for two hours in pre-weighed tubes and analysed for electrolyte concentration. Urine volume and sodium ion c~ncentration from the test a ~ s are ccmpared to a control group which receiYed only saline.
For admlnistration to man in the curative or prcphylactic treatm~nt of hypertension, congestive heart failure or ren21 insufficiency, oral dosages of the ccmpcurds will generally be in the range of from 4-800 mg daily for an average adult patient (70 kg). Thus for a typical adh~t patient, individual tablets or capsules contain from 2 to 400 mg of active compound, in a suitable pharma oeutically acceptable vehicle or carrier for adminuatration singly, or in mLltiple doses, once or several tLmes a day. Do6ages for intravenous ad~inist~ation w~uld typically be within the range 1 to 400 mg per single dose as required. In practi oe the physician will determ m e the actual dosage which will be mLst suit3ble for an individual patient and it will ~aly with .

~_ W O 91/10644 PCT/EP90/02156 the age, weight and response of the parti~llar patient. Ihe above dosages are exemplary of the average case but there can, of ccurse, be indivi~lal in=tan oes where higher or lower dk~tge ranges are merited, and stlch are within the so3pe of this invention. -- For human use, the conpcunds of the for~Lla (I) can be admd~L~i~ereI alone, but will generally be adn~ ered in : admixture with a pharmaceutical carrier selected with regard to .~ the intended route of admdristration and ~tandard p ~ acY~ttical practi oe. For example, they ~ay be administered orally Ln the ~- form of tablets contaimng such excipients as starch or lactose, or in capsules or ~vules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavcuring or oolouring agents. qhey may be injected p~rerterally, for example, intravencusly, mtr~m=sc=larly or sL~x~rt mecusly. For p~renteIa1 administration, they are best used in the form of a sterile aqueous solu~ion which may contain cther mL~d~n~es, for ~xample, enough salts or gluc~se to make the solution isotonic with blood.
The c~cpw nds may be administered alone ~ut may also be administered t~gether with such other agents as the physician shall direct to optimise control of blood pressu~e or to treat congestive heart failure, renal insufficiency or ~ther disor~ers in any particular patient in accordance with established mYdical practi oe . muS the cccpcun~s can ~e co-acrcuIustered with a variety of cardiovascular agenks, for example with an A OE
inhibitor such as captopril or enalapril to facilitate the contr~l of blood pressure m treatment of hypertension; or with digitalis, W O 91t10644 PCT/EP90/02156 ~

..

or ancther cardiac stimLlant, or with an ACE inhibitor, ~or the treatment of congestive heart failure. Okher possibilities m clude co-administration ~ith a calcium antagonist (e.g.
nifedipine, amlodcpine or d;ltiazem) a beta-kllocker (e.g.
atenolol) or an alpha-blocker (e.g. prazosin or doxazosin) as shall be detçrmined by the physician as a~prc~riate for the treatment of the particular patient or c~ndition involved.
In addition to the above, the cccpcunds may also be adnu~L~ibered in conjunction 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 pharma oe utical cc~o6ition ccmprising a compound of the formLla (I), or a pharmaoe utically acceptable calt thereof or bic~recursor therlefor, together with a pharma oe uti~lly acceptable diluent or carrier.
m e invention also include~ a ccmpcund of the fornula (I), or a pharmaceutically aooeptable salt thereof or bioprecursor therefor, for use in mdicine, partia~larly for use as a diuretic agent for the treatment of hypertension, congestive heart failure or renal lnsufficiency in a human being.
The invention further includes the use of a compcund of the fornLla (I) for the manufacture of a nedicament for the treatment of hypertension, heart failure, angina, renal insufficiency, premln=tIual syndrome, cyclical oedema, M~niëres disease, hyperaldost2r~nism, pulmanary oedema, ascites, hypercalciuria, - ~ .. . :.,, . : -,. :: ~ . . ~: . . . . ; 1 :. ., ~ W O 91/10644 2 ~ ~ 21% 6 PCT/EP90/02156.

glaucGma, asthma, inflammatio~l, pain, epilepsy, affective disoxders, de~entia ~ d geriatric confusion, ~esity, gastrointes*inal disDrders (including diarrhoeia), hyperTeninaemia, leuXaemia, and the m~dulation of gastric acid secretion.
m e preparation of the compcunds of the m vention will now be more particularly illustrated by reference to the following experimental Examples. Ihe purity of ccmpcun~s was rcutinely moni~ored by thin layer chromatcgraphy using Merck Kieselgel 60 F254 plates. ~-Nuclear magnetic r2asonance spectra were recorded using a Nicolet QE-300 spYctrcmeter and were in all cases consistent with the prcpos2d structures.

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W O 91/10644 2 0 7 212 6 PCT/EP90/02156 ~ ~

~. , 2-~1 r 2(R~S)-CarboxY-4-Phen~IkUtyl~c~ClC~nty_carbonylamm o~-2 3-dihydroindene-2 ~ oxy1ic acid (a) 2-Amino-2 3-dihvdr~indene-2-carboxy1ic ac:id, benzyl ester A mixture of 2-amuno,2,3-dihydr~indene-2-~rboxylic acid hydrochloride (R. M. Pinder, B. H. Butcher, D. A. Buxt~n and D J
Hc~ells, J. M~d. Chem., 1971, 14, 892), (11.33 g, 0.053 m), benzyl alcx~hol (27.5 ml, 0.27 m), para-toluenesulphonic acid monchydrate (12.1 g, 0.064 m) and benzene (150 ml) ~as koiled under reflux wi~h continuous removal of water usLng a Dean Stark trap. After 48 hours, further quantities of benzyl alc~hol (27.5 ml, 0.27 m) ~nd benzene (100 ml) were added, and the reaction allowed to oontinue under reflux for a further 72 hours. ~he cool raaction mixture was diluted wi~h diethyl ether and the ~esulting white precipitate collected by filtration and washed wi~h diethyl ether. The crude tosylate salt was then dissolved in water and this solution kasified with IM aqueous sodi~m hydroxide solution, then extrac~ed with ethyl aoetate. The combined extracts were washed with saturated br~e, dried (anhy~ra2s Na2S04) and filtered. Evaporation under vacu~n of the f-ltrate gave an oil (7.6 g, 53.6 %) which solidified at room ~erature over-night.
~rystallisation of a san~le fmm hexane afforded th~ pure pr~duct as a ~hite solid, m.p. 55-55.5 &. Found: C,75.98; H,6.38; N,5.18.
C17H17N02 re~uires C,76.38; H,6.41: N,5.24%.

i ; . : . . , :

. WO 91/10644 2 ~17 212 6 PCr/EP9OtO2156 (b) 2~ 2(R.S)-Ethox~or~ 4-pher~l lcycl~pentyl-car~onyla~nino)-2,3 dihv~roindene 2 car~oxy1ic acid, b~zvl ester C~alyl chloride (470 ~, 3.74 mnol) was ac~ded at ro~n t~tl~re to a stirred solution of 1-~2(R,S~--etho~ycar~onyl-4-pheny~utyl]~ycl~ta~ car~oxylic acid (600 ~, 1.87 mm:~l) in dry dichlor~neff~ar~ (10 ml) contain~ng dry dimethylform~nide (2 drops). After 2 hGurs the solvent was removed under vacuum and the residLal oxalyl chloride evap~rat0d azeotropically using dry dichlorRmet ~ (3 x 10 ml).
The crude acid chloride was dissolved in dry dichloro~ethane (15 ml), then the resulting solution added dropwise to a stirred, ice-cold solution of the product frcm step (a) (500 mg, 1.87 mmol) and dry triethylamune (210 mg, 2.06 mmol) in dry dichlorome~hane (25 ml); stirring was continued for 1 hcur at 0C, then for 16 hours at rocm temperature. me reaction ~ e was dilu~ed with dichloromethane (60 ml), washed suocessively with wa~r, IM
hydrochloric acid, water, saturated aqueous sodi~m bicarbonate solution and watex, dried (anbydrous Na25Q4) and filtered, Evaporation under vacuum of the filtrate afforded a brswn gum (880 mg) which was purified by chromatography on silica gel using an ethyl a oe tate in hexane elution gradient ~0-25%). hvaporation under vacuum of the appropriate fractions provided the re~uired product as a clear oil, which subsequently formed a white waxy solid; crystallisation fr~m diethyl ether-hexane gave the pure product (437 mg, 41.1%), m.p. 89-90 C. Found: C,76.21; H,7.22;
36H41N05 requires C,76.16; H,7.28; N,2.47%

::
., ., : .

W O 9l/l0644 2 q 7 2 i ~ 6: PCT/EP9U/02156 2-11-r2(R S)-CarboxY-4-PhenYIbutvllcycloPentvlcarbonYlaminol-2,3-dihydroindene-2-carkoxy1ic acid (c) A IM aguecus solution of sodium hydro~ide (5 ml, 5 mmol) was added at roum temperature to a stirred sol~tion of the above product (430 mg, 0.76 mmole) in 1,4-dioxan (10 ml) and methanol (2.5 ml). After 5 days, the reaction mixt~re was diluted with water (40 ml~, its pH adjusted to 7 with 2M hY~rcchloric acid, and the orga~ic solvents re~oved by evaporation under vacuum. The result m g ~ e was washed with diethyl ether, acidified to pH 2 with 2M hydrochloric acid, then extracted with ethyl acetate. q~e ccmbined 2xtracts were washed with saturated brine, dried (anhydr~us Na2S04), filtered, and evaporated under vacuum.
Crystallisation of the residue fram ethyl acetate-hexane gave the required product as a white solid (200 mg, 56.6%). Fcund:
C,71.30; H,6.88; N.3.25. C2 ~ 1NO5; 0-17 CH3oO2C2H5 requires C,71.59; H,7.02; N,3.02%.
EX~MP$E 2 2-fl- r 2fR~s~-carboxy-4-methoxybutyl~cyclGpentylcarbon amino~-2,3-d~hydrGindene-2-carboxylic acid ~a) 2-~l-r2fR,S)-Benzvloxycarbonvl-4-m~thoxYbutvllcvclopentyl-carbonylamunol-2,3-dihvdroinclene-2-carboxvlic acid, benzyl ester qhe procedure of Example l(b) was followed using 1-[2(R,S)-ben2yloxycarbonyl-4-methoxybutyl~cyclcpe~tane carboxylic acid (334 mg, 1 mmole) and 2-amlno-2,3-dihydroindene-2-carboxy1ic acid ~enzyl ester (267 mg, 1 mmol), to furnish the reglired diester (430 mg, 72.5%). Found: C,72.95; H,7.03; N,3.08. C36H41N06; 0.5 0 requlres C,72.75; H,7.14; N,2.36%.

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~ W O 91/10644 2 ~ ~ 21;2 ~ PCT/EP90/02156 (b) 2~ [2(R,S~-Carboxy-4-methoxybutyllcYclo~entylcarbonvl-amino~-2L3-dihydroindene-2-carboxylic acid A solution of the above pro*uct (390 mg, 0.67 mmol) Ln ethanol (20 ml) was hydrogenated over 10% palladium on c ~
~39 m~) a~ 15 p.s.i. (1 ~ar) and room ~ ablre for 1 hour. The catalyst was removed by filtration thraugh a pad of Px~ccel (upper) and Hyflo (lower), then the filtrate evaporatd un~er vac~m, and residual ethanol removed azectrcpically with dichloromethane to provide the r ~ d product as a white solid (235 mg, 87.2%), m.p. 142-144C. Found: C,65.17; H,~.29; N,3.32.
C22~ gNO6 requires C~65.49; H,7.25; N,3.47%.
EX~MPLE 3 2~ r2tR,S)-CarboxY-3-~S-lysvlamino)proPyllcyclop~t carbonYlaminol-2,3-dihydroinBene-2-carkoxYlic acid (a) 2-Amino-2,3-dihydroindene-2-carbox~1ic acid, ethYl ester, hydrochloride A stirred, ice-oold solution of 2-amino-2,3-dihydroindene-2-carboxYlic acid hYdroLhloride ~2.48 g, 11.6 mmol) in absDlute ethanol was satuxated with dry hYdrogen chloride. The resulting s ~ ion was stirred at r w m temperat~re overni~ht, then warmed to 40C and treated further with dry hydrogen chloride until a cl OE solution was obtained (2 hours). After a further 4 hcurs at 40 & , the reaction mixture was evaporated to dryness under vacuum, then the residue crystallised frcm e~hanol-diethyl ether to give the pure product (2.41 y, 85.~%), m.p. 189-193 &. Found: C,59.74;
H,6-69; N,5-76- C12H1 ~ 2; HCl reguires C,59.63; H,6.67; N,5.79%.

- . .. .":
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wo gl/10644 ~ 6 ` PCT/EPgO/02156 (b) 2-~lr2(R,S)-tert-ButoxvcarbonY1-3-(dibenzYlamlno)propyl cycl~e~tvlcarbonvlamlno~-2.3-dihYd-r-oindene-2-{arboxylic acid, ethyl ester To a stirred, ice-cold solution of 2(R,S)-tert-butoxycarbonyl-3-(dibenzylamuno)propylcyclopentane carboxylic acid h~dLcchloride ~7.84 g, 0.016 m), l-hydroxybenzokriazole (2.16 g, 0.016 m) and 4-methylmorpholLne (4.86 g, 0.048 m) in dry di ~Lorcmethane (lO0 nL'L) was added 1-(3-dimethylamuncpropyl)-3-ethylcarbodii~ide hydrcchloride (6.13 g, 0.032 m); stirring was contLnued for 1 hour a~ o&, then for 16 hours at roGm temperatuxe. The dic~iLoromethane was removed by evaporation under vacuum c~t roam temperature, and the residue partitioned between diethyl ether c~nd water. The ether phase was separated, washed with water, dried (anhydrcus N ~S04) and P~L~ered; subsequent evaporation un~er vacuum at room temperature of the filtrate provided the crude activated ester (9.33 g, 95.4%) ~ a hemi-solvate with dic~loro~ethane, of sufficient purity for further pr ~ i~n.
To a stirred solution of this activated ester (3.24 g, 5.3 1) in dry dic~loromethane (40 nl) at 0C was added 2-amuno-2,3-dihydroindene-2-carboxylic acid ethyl ester (1.09 g, 5.3 mmol) and 4-dimethylaminopyridine (0.71 g, 5.8 mmol). After 0.5 hc~rs the solvent was removed by evaporation under vacuum and the resulting ViscGus oil allowed to stand at room temperature for 3 days before partitio m ng between diethyl ether and water. m e ether p~a~e was separated, washed with water, dried (anyh1m us MgS04) and f;ltered. Evaporation under vacuum of the filtra~e furnished an oil which was purified by chromatograFhy on silica gel using a dichlorcmethane in hexane elution gradient (20-100%).

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W O 91/10644 ' . PCT/EP90/02156 Evaporation of the apprcpriate fractions prcvided the required product ~2.10 g, 61.2%). Fcund: C,73.92; ~,7.88; N,4.55.

C40HsoN2os 0 5 H20 ~ C,74.15; H,7.94; N,4.33%.
(c) 2~ r3-p~2 (R~s)-~-~oxy~m~:Lp~-cvcl~tvl-carbonvlamino~-2.3-dih~droindene-2-carboxylic acid, ethyl ester A solution of the above diester t2.7 g, 4.2 mmol) in a mixture of ethanol (6 ~L) and water (0.5 ~L) was hy*rogenated over 20% paLl~d;um hydraxide on ch2u~xx~L (270 mg) at 50 p.s.i. (3.45 bar) and room temperat~re for 16 hcurs. Ihe catalyst was removed by f~LLL~tion through a pad of ~ L (upper) and Hyflo (lower), then the filtrate evaporated under vacuum, and resi~ ~1 solvents rem~ved azeotrcpically with dichlorcmethane, to affor~ the required product (1.92 g, 99.6%). Found: C,67.64; H,8.44; N,5.89.
C2 ~38N205 requires C,68.09; H,8.35; N,6.11%.
(d) 2-~1-r2(R.S)-tert-Butyloxycarbonyl--3-~ , N6--di-benzyloxy-carbon~l-S-lysyl-aminoLer~Eyllcyclcpent~1carbony1ami~o~-2,3-dihYdroindene-2-carboxy1ic acid. ethyl ester 1-(3-Dimethyl ~ r~py1)-3-ethylcarbodiimide hydrochloride (944 mg, 4.92 mmol) was added to a stirred solution of the above amine (1.13 g, 2.46 mmol), l-hydroxybenzotriazole t322 mg, 2.46 mmol), N2, N6-di-kenzyloxycar~onyl-S-lysine (1.02 g, 2.46 mmol) and 4-methylmorpholine ~746 mg, 7.38 mmol) in dry ,dichloromethane (25 ml) at 0C. Sti~ring was continued for 0.5 hGurs at o&, then for 16 hcurs at room temperature, before ~ of the solvent under vacuum. Ihe resi*ue was partitiuned between diethyl ether and w~ter, then the ether phase washRd with lM hydrochloric acid and water, dried (anhydrcus Na2S04) and filtera~. Evap~ration under v,cuum of the filtrate, followed by chromatcgraphy of ~e , : . :
:, .: , .
:
, W O 91/10644 ? ~ ~ 2 i 2 ~ PCT/EP90/02l$6 _ i . 26 residual oil on silica gel ~ing a diethyl ether in hexane elution gradient (0-50%), gave the required product tl.30 g, 61.8%).
FOund c,67.31; H,7.40; N,6-09- C48H62N410 neqUIres C'67 42;
H,7.31; N,6.55%.
(e) 2~ r2(R.S~-Carbo~v-3-(N2, N6-di-benzyloxycarbonyl-S-ly~yl-amino)proEyl~ycloEentylcarbonylamino~-2.3-dih~droindene-2-carboxylic acid, ethYl ester Trifluoroa oetic acid (5 ml) was added dropwise to a stirred solution of the above pro*uct (1.28 g, 1.5 mmol) in dry dichloromethane (10 ml) at 0C. The ice-kath was removed, stirring continued for 1 hour at room temperature, then the reaction mixbure evaporated under vacuulm. The crude product was dissolved in ethyl a oe tate and nesidual trifluoroacetic acid removed by washing th2 solution with sa~urated aqueous sodium bicarbonate solution. Drying (anhydrcus Na2S04), f;ltration a~d evaporation under vacuum of the ethyl acetate solution, followed by azeotropic remcNal of residual solvent with dichlom methane, affor,ded the required prcduct (1.12 g, 90.4%). Found: C,63.85;

H~6-66; N~6-59- c44H54N40l0; 1-5 H2~ reqUlres C,63 ss; H,6.g6;
N,6.78%.
~f) 2-~1-[2(R.S) ~ v-3-(S-lvsylamino~PropYllcYclcpe~tyl-carbonYlaminol-2,3-dihydroindene-2-carb~xylic acid, e~h~l ester A solution of the abcve product (1.10 g, 1.33 mmol) in a n~aure of ethanol (7 ml) and water (0.5 ml) was hy*rogenated over 10% palladium on charccal (110 mg) at 60 p.s.i. (4.1 bar) an~ rocm temperature for 16 hours. Wbrk-up as described above for Exawple 2 (b) pr wided the required product as a beige foam (740 mg, 98~9%). Foun~: C,59.98; H,7.56; N,9.52. C28H42N406; 1.75 H20 requires C,59.82; H,8.16; N,9.97%.

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- `` WO 91/10644 2 0 7 212 ~ PCI/EP90/02156 (g) 2~ r2!R,S)~ar~oxy-3-~S-lysYlamino)pr~llcyclcpe car~lamino~-2,3 dihydroin~ 2 car~cy1ic acid A solution of the above ester (700 m~, 1.24 ~ ) in lM
aq~ s sodium hy~roxide solution (7.5 ml, 7.5 ~1) was allcr~ed to stand at n~n t~nperature for 16 halrs, t:hen loaded onto a col~ of strorP~ly acidic iorre~a~e resin. ~e col~ was aqueous pyridine. Evaporation un~er vacuum of the appropriate fractior~ gave a glass whi~h was dissolved in distilled water;
freeze drying of this aqueous solution provided t~e required product (370 mg, 55.4%). Found: C,57.58; H,7.95; N,10.31.
c26H38N4o6; 2H2 ~ es C,57.97; H,7.86; N,10.40%.
EX~MPLE 4 2~ r 3- (N -Asetyl-S-lys~la~ino)-2(R,S)-carboRvpeoRyllcyclo-entvlcarbonvlamino~-2,3-dihYdroindene-2-carbox~lic acid m e procedure of EXample 3 was followed but using N2-aoe~l-N6-be~loxyOE~o~l-S-lysioe ~ step (d)o Deprs~tection gave the title ccmpound. Fcund: C,58.30; H,7.58; N,10.07.
C28H40N4o7; 1-75 H2 ~ C,58.36; H,7.61; N,9.72%.
EX~MPLE 5 2-11- r 2 (R, S) ~oxv-3- (N2-metharl~lPhorlvl-s~ amino) -prc~yllcvclo~entvlcarbonvlam m o~-2,3-dihvdroindene-2-carboxylic acid The procedure of Example 3 was followed ~ut using N6-yloxycarbonyl-N2-methanesulphonyl-S-lysine in step (d).
Deprokection gave the title compound. Found C,53.99; H,7~13;
N,9.31. C27H40N~08S; ~ 0 requires C,54.17; H,7.07; N,9036%-,. . : :. . ,:
. :, .:
, W O 91/10644 2 0 7 2 i 2 ~ PCT/EP90/02156 _ I

~ 6 2-f 1-r2(S~ 3-rS-l~vlaminolp~ vcl~l-OE bonvlamino)-2,3-dihy~rnindene-2-carboxylic acid (a) 2-(l-r2(S~-tert-Butoxycarbonyl-3-lLs~s)-allpha~ alFhal_ dimethvldibenzYlamino~prcPvllcyclopentYlcarbonvlamlno~-2,3-d~h ~ dene-2-carboxv1ic acid, ethyl ester The p ~ e of Example 3 was followed but using 1-~2(S)-terk-butoxycarbony1-3-[(S,S)-alpha, alphal-l-dimethyldibenzyl-amino)prDpyl]cyclcpentane carboxylic acid m stqp (b) to give the title pr~duct, in 79.1% yield. Fcund: C, 75.45; H,8.30; N,4.01.

42 54 2 5 ~ s C,75.64; H,8.16; N,4.20%.
(b) 2-~1-r3-Aminc-2tS~-tert-butoxYcarbon~lprcpyllcyclopentYl-ca~bonylamino)-2,3-dihy~roindene-2-carbox~lic acid, ethYl ester ~ ydrogenation of the above product as described in Example 3(c) gave the 2(S) iscmer of the amone in 99.1% yield. Rf (silica) 0.50 (dichloromet ~ methanol, 9:1).

(c) 2-(1-r2(S) ~ oxy-3-tS-lys~lam~no)p ~ pyllcvcl ~ entyl-carbonylamino~-2.3-dihv~roindene-2 ~ oxYlic acid The abave amine was ccupled to ~ , N6-di-benzyloxYcarbonyl-S-lys m e following the prooedure of Example 3(d) and the product deprotected as described in EXample 3 steps (e) t~ (g) to give the title compcund. Fw nd: C,56.71; H,7.48; N,9.16. C26H38N406; 2.5 H20 requires C,57.02; H,7.91; N,10.23%.

. . WO 91/10644 ~ 0 7 ? 12 6 PCr/EP90/02156 . .

EX~MPLE 7 2-f 1- r 2 (S) ~box~-3- (N2-met:ha~onyi S-lysYlamino) -pr ~ l]cyclc~pentylcar~orvlamino!- ~ indene 2 ~ xylic acid me p ~ e of EXample 6 was followed hut using N6~
benzyloxy-car~onyl-N2-methanesulphonyl-S-lys~e m the cGupling step to give the title compound. Found: C,53.60; H,7.27; N,8.82.
C27H40N48S; 1-5 ~2 ~ C,53.36; H,7.13; N,9.22%.
EX~MPIE 8 2-~ 1-[2(R,S)-Carboxypentvl]cYclcPentylcarbonYlamino~-2-hy~r~xymethyl-2,3-dihydr3indene (a) 2-Amino-2-h ~ ethyl-2 3-dihvdroindene A solution of 2-am m o-2,3-dihydroindene-2-carboxylic, ethyl ester, hy~rochloride (1.7 g, 7.03 mmol) in 50% aqueous ethanol (15 ml), was added dropwise to a stirred, ice-cold solution of sodium borohydride (1.11 ~, 29.4 mmol) in 50% aqueuus ethanol (35 ml), then the reaction mixture heated under reflux for 3 hours.
The buIk of the ethanol wa~ rem3ved by evaporation under vacuum, and the residLal suspension saturated with sodium chloride then extracted with ethyl a oetate. The combined extracts were washed with saturated brine, dried (anhydrous MgS04), filtered anl evaporated under vacuum. Crystallisation of the resulting white solid (1.05 g) from ethyl acetate-hexane afforded the reguired product (0.99 g, 84.8%), m~p. 89.5-90.5 &. Fcund: C,72.32;
H,8.02; N,8.17. ~ oH13NO; 0.15 H20 requlres C,72.39; H,8.08;
N,8.44%.
(b) 2-~l[(R S)-BenzyloxycarbonylFentyl1cycloDentylcarbon~lam m o)-2-hyd3~yme~hyl-2 ? 3-dih~noindene : ~ . .. . i : . ~ ~ - . . .. .
.

wo gl/10644 2 Q 7 ~1~ 6 PCT/EP90/02l56 1-(3-Dimethylanunoprcpyl)-3-ethylcarbodilmide hydrochlor.ide (767 mg, 4 mmol) was add~d to a stirred, ice-oold n~bure of 1-[2(R,S)-b~nzyloxycartonylpentyl]cyclopentane carha~ylic acid (637 mg, 2 mmol), l-hydroxyben20triazole (270 mg, 2 mmol), 4-methylmorpholine (202 mg, 2 ~mol), the product from step (a) above (332 mg, 2 mmol) and dry dichloromethane (10 ml)0 Stirring was continued for 0.5 hours at 0C, then for 24 hcurs at rcom temperat~re.
Ihe dichlorcmethane was removed by evaporation under vacuum, and the residue partitioned between diethyl ether and water. m e ether phase was separated, washed with water, lM hydrcchloric acid, water, saturated aqueous sodium bicarbonate solution and water, then dried (anhydrous M~S04) and filtered. Evaporation under vac~um of the filtrate furniah d an oil which was p~rified by chromatography on silica gel using diethYl ether-hexane (1:1) as eluent. Evaporation under vacuum of the appr~priate fractions provided the required prcduct (180 mg, 19.0%). Fo~nd: C,73.75;
H,7-84; N,3-06. C29H37N04; 0.5 ~ o ~ s C,73.69; H,8.10;
N,2.96%.
(c) 2-(1-r2~R.S~-CarboxYpentYllcycloPentYlcarbonylamino~-2-hYdroxvn~thyl-2,3-dihYdroindene A solution of the above pro*uct (170 m3, 0.36 mmol) in a mixture of ethanol (20 ml) and water (1 ml), was hydrogenated over 5% palladium on c ~ at 50 p.s.i. (3.45 bar) and room temperature, t~ give the title prc~uct as a white solid ~115 mg, 83.5%), m.p. 126-128 & , after trituration with diethyl ether-hexane (1:1). Found: C,69.04; H,8.15; N,3.63. C22H31N04; 0.5 ~ 0 requires C,69.08; H,8.43; N,3.66%.

~-. W 0 91/10644 2 0 7 212 6 PCT/EP90/0215b ~ _9 2~ 2(R,S!~o~ 4~1b~11~nb~1~ylam~no~-2-hydrDxymethyl-2,3-dihydroindene (a) 2-~1-r2fR,S)-BenzyloxycarbonYl-4-ph y ~utyl~cvclcpentyl carbonvlamino~-2-h ~ ethvl-2,3-dihvdroi~ne Ihe prooedure of Example 8(b) was followed using 1-[2(R,S)-benzyloxycarkonyl-4-phenyIbutyl]cyclcF(rldooYaaraoxylic acid as starting material and allowing the reaction mixture to stand at room temperature for a further 5 days. The ~ d product was oktained as an oil (19.9%). Rf (silica) 0.15 (diethyl ether-hexane, 1:1).
(b) 2-(1- r 2fR.S)-Carboxv-4-Phenylbutyllc~clopentYlcar~on~lamin~)-2-hvdroxYmethyl-2,3-dihydroindene Hydrogenation of the above product as described in Example 8(c), followed by chromQtograFhy on silica gel using ethyl aoetate as eluent and evaporation under vacuum of the apprcpriate fractions, followed by trituration of the residue with diethyl ether-hexane (1:4), gave the required product (62.4%) as a white solid, m.p. 140-143C. Fo~n~: C,73.76; H,7.62, N,3.12.
C2 ~33N4; V4 H20 eqyIres C,73.69; H,7.67; N,3.18%.
EX~MPIE lQ
2-~1-r2~R,SI ~ ox~-3-~S-lvsvlamino!Propyl~cyclopentvl-/
carbonylamino~2-hydroxymethyl-2.3-dihydroindene (a~ 2-~1-r2(R S)-tert-Butox~carbonyl-3-(d~benzylamino)prceyll cyclocentylcarbonylamuno~-2-hydr~xvmethyl-2~3-dihydroind~ne 4-M~thylmorphol m e (1.78 g, 17.6 ~mol) was added to a stirred solution of the N-hydrcxyberzotriazole-derived activated ester ,~
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.. . .

W 0 91/t0644 .~ PCT/EP90/021~6 ,~

hemi-solvate with dichloromethane of 2(R,S)-tert-butoxycar~ony1-3-( ~ ylamino)propylcyclopentane carhoxylic acid (Ex2mple 3b) (9.78 g, 16 1) and 2-amino-2-hydroxymethyl-2,3-dihydroindene (2.65 g, 16 1) m dry dichloromethane (50 ml) at room temperature. After 2 hours the solvent was removed by evaporation under vacuum and the residue allowed to s ~ d a~ room te~perature for 2 days be~ore being partitioned between~diethyl ether and water. Ihe ether pbase was separated, washed with water, dried (anhydrcus Mg504) and filtered. Evaporation under vacuum of the filtrate, followeol ~y purification of the residue by chr~matography on silica gel using a dichlorcmethane in hexane elution gradient (20-100%), afPorded the required product (3.30 g, 33.6%). Found: C,75.09; H,8.02; N,4.69. C38H48N204, 0.2 CH2C12 requires C,74.75; H,7.95; N,4.57%.
(b) 2~ 3-Amino-2(R.S!-~ert-butoxycarbonYlprcpYl~cyclopent carbonYlaminol-2-hYdroxvmethyl-2.3-dihydroindene Ihe abcve product was h~drogenated 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- C24H36N204 reguires C,69.20; H,8.71; N,6.73%.

(C) 2-fl-r2 ~,S)-te~t-ButoxYcar~on~yl-3-(N2~ N6-di-b ~ ylox~
carbonyl-S-lysylamino)pro~y~lcyclo~entYlcarbonylamunol-2-hydroxy-m~thyl-2 3-dih~lroindene m e above amine was coupled to N2, N6~dibenzyloxycarbonyl-S-lysine following the prooedure of Example 3(d) but using a gradient of diethyl ether-hexane (1:8 to 1:1) followed by eth~l a oe tate as eluents for chromatographic purification to give the product in 62.0% yield. Found: C,67.59; H,7.53; N,6.75.
C46H6~M409 requires C,67.36; H,7.44; N,6.89%.

, ' ' ' ' ' ' . .

~- ~ wo gl/10644 2 0 ~ 2 ~ 2 ~ PCT/EP9OtO2156 ~ ~.

(d) 2~ r 2(R,S)-Car~oxy-3-t~ , N6-di-ben2Yloxycarbonyl-S-lysyl-amino~propyl]cyclcpentylcarbonylamInol-2-hydr3xymethyl-2,3-dihydroindene A stirred, ice-cold solution of the above product (1.24 g, 1.52 mmol) in dry dichloromethane (20 ml) was saturated with dry hydrogen chloride. After a further 2 hours at 0C, the re~ction ~ e was evaporated under vacuum and the residue azeotroped with dichlor~methane to provide the title prcduct as a white fo~m (1.05 g, 85.3%). Fcun~: C,64.28; H,6.83; N,7.21. C42HS2N409; 1.5 H20 requires C,64.3S; H,7.07; N,7.15%.
(e) 2~ 2(R,S)-Carkoxv-3-(S-lysYl ~ )proPvllc~cloPentyl-car~onylamino~-2-h,vdroxymeth~rl-2,3-dih~vdroindene The above product was hydrogenated following the prooedure of Example 3(f) to give the required title acid as a white foam (79.7%). Fcund: C,61~20; H,8.14; N,10.41. C26H40N405; 1.25 H20 requires C,61,09; H,8.38; N,10.96%.
' ~ME~E 11 2 - ~ 1- r 2 ~ s ! -Carbo~y-3-(N2-~ethanesulphonyl-S-lYsvlamlno)-,, DropyllcvclopentYlcarbonvlamln3)-2-hY ~ ~hvl-2.3-dihvdro mdene m e prooedure of Example 10 was followed but using the N-hYdroxy~enzokriazole-derived activated ester of 2(S)-tert-butyloxycaxbonyl-3-[(S,S)-alpha, alphal-dimethyldiben~yla D o]-propylcyclopentane carboxylic acid as startLng material in step (a) and ooupling with N6-tert-~utyloxycarbonyl-~ -methane-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 produc~ as a white solid. ~ound: C,51.50; H,7.38; N,8.67. C27H42N407S; HCl;
1.5 ~ O requires C,51.46; H,7.36; N,8.89%.

Claims (19)

34

1. A compound having the 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;
R1 is H or C1-C4 alkyl;
R2 is H, OH, C1-C4 alkyl, C1-C4 alkoxy, halo or CF3;
R3 is CH2OH or CO2R4 wherein R4 is as previously defined for R;
and R is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkenyl, or R5 is C1-C6 alkyl substituted by halo, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, aryl, aryloxy, heterocyclyl, -NR6R7, NR8COR9 -NR3SO2R10, -CONR6R7 or R6R7N-(C1-C6)alkoxy;

or R5 is C1-C6 alkyl substituted by a grcup of the formula:

or wherein R6 and R7 are each independently H, C1-C4 alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C4)alkyl, C2-C6 alkoxyalkyl, or heterocyclyl; or the two groups R6 and R7 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-C4)alkyl-piperazinyl group;
R8 is H or C1-C4 alkyl;
R9 is C1-C4 alkyl, CF3, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)alkoxy, heterocyclyl, C1-C4 alkoxy or NR6R7 wherein R6 and R7 are as previously defined;
R10 is C1-C4 alkyl, C3-C7 cycloalkyl, aryl or heterocyclyl;
R11 is H, C1-C6 alkyl, aryl or C3-C7 cycloalkyl;
R12 is R11CONR11-, R11SO2NR11-, R16R17N-(CH2)p-, or R11O-, wherein each R11 is as previously defined above;
R13 and R14 are each independently H or C1-C6 alkyl; or R13 is H and R14 is C1-C6 alkyl which is substituted by OH, C1-C4 alkoxy, SH, SCH3, NH2, aryl(C1-C6)alkyl-OCONH-, NHCO-, CO2H, guanidino, aryl, or heterocyclyl;
or the two groups R13 and R14 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 mono-unsaturated and which may optionally be substituted by C1-C4 alkyl or fuel to a further 5 or 6 membered saturated or unsaturated carbocyclic ring;
or R13 is H and R12 and R14 are linked to form a 2-(N-COR11-4-aminopyrrolidinyl) group;
R15 is R16R17NCO- R11OCO-, R11OCH2- or heterocyclyl, wherein R11 is as previously defined above;
R16 and R17 are each independently H or C1-C6 alkyl;
and p is 0 or an intiger of from 1 to 6;
and pharmaceutically acceptable salts thereof and bioprecursors therefor.

2. A compound according to claim 1 wherein A is (CH2)4 and R1 and R2 are H having the formula (II) wherein R, R3 and R5 are as previously defined for formula (I).

3. A compound as claimed in claim 1 or claim 2 wherein R is H, R3 is CO2R4 and R4 is H.

4. A compound as claimed in claim 1 or claim 2 wherein R3 is COR4 and one or both of R and R4 is a biolabile ester-forming group and said group is ethyl, benzyl,1-(2,2-diethyl-butyryloxy)-ethyl, 2-ethylpropionyloxymethyl, 1-(2-ethyl-propionyloxy)ethyl, 1-(2,4-dimethylbenzoyloxy)ethyl, 1-(benzoyloxy)benzyl, 1-(benzoyloxy)ethyl, 2-methyl-1-propionyloxypropyl, 2,4,6-trimethyl-benzoyloxymethyl, 1-(2,4,6-trimethyl-benzyloxy)ethyl, pivaloyloxymethyl, phenethyl, phenpropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethyl-phenyl, 4-t-butyl-phenyl, 5-(4-methyl-1,3-dioxolenyl-2-onyl)-methyl or 5-indanyl.

5. A compound as claimed in any one of claims 1 to 4 wherein R5 is methylene substituted by a group of the formula -NHCOCR12R13R14, and R12 is NH2, R11CONH- or R11SO2NH-, R13 is H and R14 is -(CH2)4NH2.

6. A compound as claimed in any one of claims 1 to 4 wherein R5 is C1-C6 aIkyl, C1-C6 alkyl substituted by C1-C6 alkoxy or C1-C6 alkyl substituted by phenyl.

7. A compcund according to claim 1 wherein said compound is-:
2-{1-[2(S)-carboxy-3-(S-lysylamino)propyl]cyclopentyl-carbonylamuno}-2,3-dihydroindene-2-carboxylic acid, 2-{1-[2(S)-carboxy-3-(N2-methanesulphonyl-S-lysylamino)-propyl]cyclopentylcarbonylamino)-2,3-dihydroindene-2-carboxylic acid, or 2-{1[2(S)-carboxy-3-(N2-methanesulphonyl-S-lysylamino)-propyl]cyclopentylcarbonylamino)-2-hydroxymethyl-2,3-dihydroindene; or a biolabile ester derivatives thereof.

8. A process for preparing a compound of the formula (I) as claimed in claim 1 which comprises subjecting a compound of the formula-:

(V) wherein A, R1 and R2 are as previously defined, R5' is as defined for R5 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 R3' is either CH2OH or CO2R19 wherein R19 is as previously defined for R4 excluding 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 R5' and to remove one or both of R18 and R19, if present, to yield the corresponding dicarboxylic acid of formula (I) wherein R and R4 are both H, or to yield the corresponding mono-ester product wherein one of R and R4 is H and the other is a biolabile ester-forming group; or in the case where R3' is CH2OH, to yield the mono-carboxylic acid where R is H; and optionally forming a pharmaceutically acceptable salt of the product.

9. A process for preparing a compound of the formula (I) wherein R5 is C1-C6 alkyl substituted by -NR8COR9, -NR8SO2R10, -NR11COCR12R13R14 or -NR11SO2R12R13R14 which comprises acylating or sulphonating a compound of the formula:
(VI) wherein R20 is as defined for R8 or R11, R18 and R3' are as previously defined and Y is a C1-C6 alkyl group; by reaction with an acid of the formula R9CO2H, R10SO3H, R12R13R14COO2H, or R12R13R14CSO3H, 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 (I) wherein R is H and R3 is CH2OH or CO2H, and optionally forming a pharmaceutically acceptable salt of the product.

10. A process as claimed in claim 8 or claim 9 wherein R18 and R19 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 R4 (if present) are both H.

11. A pharmaceutical composition comprising a compound of the formula (I) or (II) as claimed in any 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 compound 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 compound having the 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;
R1 is H or C1-C4 alkyl;
R2 is H, OH, C1-C4 alkyl, C1-C4 alkoxy, halo or CF3;
R3 is CH2OH or CO2R4 wherein R4 is as previously defined for R;
and R5 is C1-C6 alkyl, C2-6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, or C3-C7 cycloalkenyl, or R5 is C1-C6 alkyl substituted by halo, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, aryl, aryloxy, heterocyclyl, -NR6R7, -NR8COR9, -NR8SO2R10, -CONR6R7 or R6R7N-(C1-C6)alkoxy;

or R5 is C1-C6 alkyl substituted by a group of the formula:

or wherein R6 and R7 are each independently H, C1-C4 alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C4)alkyl, C2-C6 alkoxyalkyl, or heterocyclyl; or the two groups R6 and R7 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C1-C4)alkyl-piperazinyl group;
R8 is H or C1-C4 alkyl;
R9 is C1-C4 alkyl, CF3, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)alkoxy, heterocyclyl, C1-C4 alkoxy or NR6R7 wherein R6 and R7 are as previously defined;
R10 is C1-C4 alkyl, C3-C7 cycloalkyl, aryl or heterocyclyl;
R11 is H, C1-C6 alkyl, aryl or C3-C7 cycloalkyl;
R12 is R11CONR11-, R11SO2NR11-, R16R17N-(CH2)p-, or R11O-, wherein each R11 is as previously defined above;
R13 and R14 are each independently H or C1-C6 alkyl; or R1 is H and R1 is C1-C6 alkyl which is substituted by OH, C1-C4 alkoxy, SH, SCH3, NH2, aryl(C1-C6)alkyl-OCONH-, NH2CO-, CO2H, guanidino, aryl, or heterocyclyl;
or the two groups R13 and R14 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 mono-unsaturated and which may optionally be substituted by C1-C4 alkyl to a further 5 or 6 membered saturated or unsaturated carbocyclic ring;
or R13 is H and R12 and R14 are linked to form a 2-(N-COR11-4-aminopyrrolidinyl) group;
R15 is R16R17NCO-, R11OCO-, R11OCH2- or heterocyclyl, wherein R11 is as previously defined above;
R16 and R17 are each independently H or C1-C6 alkyl;
and p is 0 or an integer of from 1 to 6;
which comprises subjecting a compound of the formula:

(V) wherein A, R1 and R2 are as previously defined, R5' is as defined for R5 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 R3' is either CH2OH or CO2R19 wherein R19 is as previously defined for R4 excluding 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 R5' and to remove one or both of R18 and R19, if present, to yield the corresponding dicarboxylic acid of formula (I) wherein R and R4 are both H, or to yield the corresponding mono-ester product wherein one of R and R4 is H and the other is a biolabile ester-forming group; or in the case where R3' is CH2OH, to yield the mono-carboxylic acid where R is H, and optionally forming a pharmaceutically acceptable salt of the product.

14. A process for preparing a compound of the formula (I) wherein R5 is C1-C6 alkyl substituted by -NR8COR9, -NR8SO2R10, NR11OCOR12R13R14 or -NR11SO2CR12R13R14 which comprises acylating or sulphonating a compound of the formula:

(V) wherein R20 is as defined for R8 or R11, R18 and R3' are as previously defined and Y is a C1-C6 alkyl group; by reaction with an acid of the formula R9CO2H, R10SO3H, R12R13R14CCO2H, or R12R13R14CSO3H, 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 (I) wherein R is H and R3 is CH2OH or CO2H; and optionally forming a pharmaceutically acceptable salt of the product.

15. A process as claimed in claim 13 or claim 14 wherein R18 and R19 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 R4 (if present) are both H.

16. A process according to claim 13 or claim 14 wherein A is (CH2)4 and A and R2 are H to give a compound having the formula (II) wherein R, R3 and R5 are as previously defined for formula (I).

17. A process as claimed in claim 13 or claim 14 wherein R is H, R3 is CO2R4 and R4 is H.

18. A process as claimed in claim 13 wherein R5 is methylene substituted by a group of the formula -NHCOCR12R13R14, and R12 is NH2, R11CONH- or R11SO2NH-, R13 is H and R14 is -(CH2)4NH2.
7. A process as claimed in claim 1 wherein R5 is C1-C6 alkyl, C1-C6 alkyl substituted by C1-C6 alkoxy or C1-C6 alkyl substituted by phenyl.

19. A process according to claim 13 wherein said compound of formula (I) produced is-:
2-{1-[2(S)-carboxy-3-(S-lysylamino)propyl]cyclopentyl-carbonylamino}-2,3-dihydroindene-2-carboxylic acid, 2-{1-[2(S)-carboxy-3-(N2-methanesulphonyl-S-lysylamino)-propyl]cyclopentylcarkonylamino}-2,3-dihydroindene-2-carboxylic acid, or 2-{1-[2(S)-carboxy-3-(N2-methanesulphonyl-S-lysylamino)-propyl]cyclopentylcarbonylamino)-2-hydroxymethyl-2,3-dihydroindene; or a biolabile ester derivatives thereof.