PT96446A - PROCESS FOR THE PREPARATION OF UTILIZED CYCLOALKYL SUBSTITUTED GLUTARAMIDE DERIVATIVES AS DIURETIC AGENTS - Google Patents

Description

This invention relates to a set of derivatives of q 1 u. substituted cycloalkyl derivatives which are diuretic agents having utility in a number of therapeutic areas including the treatment of various cardiovascular disorders such as bed s. hypertension, cardiac insufficiency and renal failure,

According to the specification of our European patent applications EP-A-0274234 and EP-A-343411 we describe and claim certain cycllaalkyl substituted glutaramide derivatives as diuretic agents. The present invention provides additional related compounds having a 23 3-dihydroindene. involved in; Xndo O 13 ct or- heart and what diuretic and peptídii

The compounds are inhibitors of the neutral endopeptidase inhibitor of zinc EC3, 4.24.1 decomposition of various atrial natriuretic hormones (ANF>), which is secreted by the heart and which exhibits potent vasodilatation, natriuretic activity. the neutral endopeptidase E "C" 3, 4, 24, 113 the compounds of this invention can potentiate the biological effects of ANF, and in particular, the compounds are diuretic agents which are useful in treating a number of disorders, including hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclic edema, Meniere's disease, hyperaldosteronism (primary and secondary), pulmonary edema, ascites and hypercalciuria. In addition, the compounds of the present invention are useful in the treatment of glaucoma by virtue of its ability to potentiate the effects of ANF. As a further corollary of its ability to inhibit enda- to E.C., 3.4.24.11, the compounds of the present invention- may have activity in other therapeutic areas, including for example asthma treatment, inflammation. pores3 epilepsy3 disorders of geriatric, obesity-endangering states (especially irritable diarrhea) 3 a. modulation of the secretion of the disease * 3 *? The disorders of Qastrast and Qastrastin gut syndrome and the treatment of hyper reninemia and leukemia of the present invention have the formula

(I) wherein a 4 to 7 membered cyclic ring which may be saturated or mono-unsaturated and which may optionally be condensed with another saturated carbocyclic or 5-membered ring or unsaturated R3 is H, C1 -C6 alkyl, benzyl or. an alternative biolabile ester forming group is lithium or C1-4 alkyl; is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkyl, i = 4 · i h · q.

R " ' Râ,, is CHâ,ƒOH or COâ,, -; C 1 -C 10 -alkyl, C 1 -cycloalkyl, C 1 -cycloalkyl, C 1 -cycloalkyl, C 1 -cycloalkyl, C 1 -C 10 cycloalkyl, aryl, aryl, aryl, heteroaryl, heteroaryl, cyclohexyl, cyclohexyl, cyclohexyl, cyclohexyl, R7, R6, R7, NR6, R7, NR6, R7, R 1, R 2, -CONR 2, R 2,

R * " is alkyl or substituted by a group of the formula

R

R 1 '', i 3 P 14

-NR11 SO2 -. 1-4-Nk δϋ_-0 · -Η

And H are each independently of the other pendant: H, H; (I.e. C 1 -C 4 -cycloalkyl, C 1 -C 5 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl; W 5 ώ · w or. heterocyclyl or unsubstituted or substituted with one or more substituents selected from the group consisting of halogen,

- b pyrrolidinyl; piperidino, morpholino, piperazinyl or N-C1-6 alkyl, -piperazinyl, H or C1-6 alkyl, R 'is C1-4 alkyl, aryl. aryl-C 1 -C 4 alkoxy, haterocyclyl, C 1 -C 6 alkoxy, or. NR R '| wherein R " and R 'are as defined above.

1 W R & C 1 -C 10 -alkyl, C 1 -C 10 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl,

R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, R 1 and R 2 are each independently H or alkyl; and R 3 is C 1-4 alkyl, which is 1 to 4; * NH4 -aryl, DUH & substituted by OH, ci 1 L Ο λ 2 L * * | b i

QpW / 1 t? Wwi

-CH 2 CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH - - - - - - - - - - - - - - - - or the two R " 14 and 14 hours. to the other for the C 10 -C 10 atom which are 1, 2, 3, 4, 5, 6, 6, 6, 6, 7, 8, 10, 12, 12, 008 gas is optionally substituted by a C1 -C4 alkyl group with one or more other substituents. Or saturated or unsaturated C 1 -C 4 -alkyl,

OR 1 - c. R 1 is H, and R 1 and R 2 are as defined above; are joined to form a 2-CN-CO-R 1 - 4-aminopyridinyl group) R 15 is R 17 R 17 COO-s R 11, or an integer from 1 to 6 and the six pharmaceutically acceptable salts thereof and bioprecursors to form a compound of formula (I).

In the above definitions, unless otherwise expressed? alkyl groups having three or more. more pyridyl atoms a straight or branched chain. The term CO₂CH₂ is the same as that used for a hydrocarbyl group CD · ·Μ. C 1 -C 4 -alkoxy such as phenyl, naphthyl or bi-phenyl, which may optionally be substituted with, for example, one or more OH, CN, CF 2, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Or halo atoms. Halo is fluoro, chloro, bromo or iodo. The term heterocyclyl means a 5- or 6-membered heterocyclic group containing nitrogen, oxygen or sulfur which, unless otherwise indicated, may be saturated or unsaturated and which may optionally include another oxygen atom or a three nitrogen atoms in the ε ring which may be optionally benzofused or substituted with for example one or more halo, C 1 -C 4 alkyl, hydroxy, carbamoyl, benzyl groups. oxo. amino or mono- or di-C1-4 alkyl, C1-4 alkyl or C1-4 alkoxy. 4-ynyl; amino. Particular examples of heterocyclics include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl, dioxanyl, thienyl, oxazolyl, isaxazolyl, thiazolyl , indolyl, isoindolyl. ............... $ · /. , λ quinolyl, quinazoline, quinazalinyl, and benzimidazolium, each of which has been factually substituted, such a precursor was fiduciant. The compounds of the formula (I) may be asymmetric and thus may be used as diastereomeric forms of the invention including the isocyanates and the like mixtures.

The pharmaceutically acceptable salts of the compounds of the formula < 1 > In an acidic environment, the bases are non-toxic. Examples of such metal salts are such as sodium, potassium or calcium salts or salts with amines such as diethylamine. Compounds having a basic center may also form acid addition salts with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrabroeide, sulfate or phasulfate, phosphate or the like salts. hydrogensphosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate. The above example radiates a biologically digestible after ad mini s to an organism. The term b-ioprecursor in the definition of the compound of the formula (1) is pharmaceutically acceptable, which animal or human is converted to a compound of formula (I)

A preferred group is C (O) R 4 and R 5 and R 6 are H, is as defined for formula (I) and compounds are those in which A is the compound of formula (II) wherein R 1, ;

The term biolabile ester forming group is well understood in the art to mean a group which provides an ester which can be cleaved rapidly in the organism in order to release the corresponding diacid of formula (I) in which R1 and R2 are - both H, A series of these ester groups is well known, for penicillin

Preferred are those compounds of 4Ά and (11 em in which R R and R í when R ê is CF ^) are both; as well as their mono- and di-4-diastereoisomeric derivatives, both of R and F ' a group consisting of the esters of the general formula (I) (d) (c) (d) which is an example in the penicillin area or in the case of ACE inhibitor antihypertensive agents A - suitability of any one can be evaluated through in vitro or in vitro for hydrolysis

In the case of the compounds of formula (I), these prodrug esters are especially advantageous in that they provide compounds of formula (I) suitable for oral administration of an isomeric form

Thus, to obtain a desirably optimum effect, it should only undergo hydrolysis following its absorption, by J ϊ

The ester should therefore be resistant to hydrolysis before being absorbed by the digestive enzymes, but should undergo rapid hydrolysis, for example, liver enzymes. In this way, the active diacid will be released into the bloodstream following oral absorption.

In addition to the lower alkyl esters, especially the ethyl esters of the benzyl esters, suitable biolabile esters include alkanoyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted derivatives thereof, arylalkyl esters, aroyl oxacyl esters, esters aryl esters, aralkyl esters and haloalkyl esters, wherein said alkanoyl groups contain from 2 to 8 carbon atoms and said alkyl groups contain from 1 to 8 carbon atoms, carbon and have a linear or branched chain. branched, and said aryl groups represent phenyl, naphthyl or indanyl, optionally substituted by one or more C1 -C6 alkyl or C1 -C4 alkyl groups or halo atoms.

Thus, examples of R and R " when they represent biolabile ester-forming groups, with ethyl and benzyl ethers, inclusive. (2,2,2-diphenylmethyl) -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2-ethylpropyl) 2,4-dimethylbenzoylamino) ethyl, 1- (benzoyloxy) benzyl, N-benzoyloxy) ethyl, 2-methylpropionyl, propyl, 2,4,6-trichlorobenzoyloxymethyl , 1- (2,4,6-tri-methylbenzyloxylsyl, pivaloyloxymethyl, phenethyl, phenopropyl, 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4-dimethylphenyl, 4-t-butyl -phenyl, 5- (4-methyl-1,3-dienioxalin-2-onyl) methyl and 5-indanyl.

The compounds of formula (I) and (II) wherein R 1 is benzyl or t-butyl and R 4 is ethyl are valuable intermediates for the preparation of diacids wherein R 1 and R 2 are both H. (1) and (2) and (3) are as defined in claim 1, wherein R 1 and R 3 are as defined in claim 1, A compound of the formula: ## STR1 ## in which R 1 represents a hydrogen atom or a group selected from the group consisting of hydrogen, halogen, -U) =. In particular, those groups derived from 3-lysines, especially preferred R-5 substituents of this type, include N-acetyl-N-acetyl-B-1-isoxymethyl or N-B-ather -alkyl, - (C 1 -C 4) alkenyl, - C 1 -C 4 -alkyl, - C 1 -C 4 -alkyl, - C 1 -C 4 alkenyl; ie t i 1 o § or where ΉρΙλΟ'Ξ- h - =. f · *! By phenyl, represents C1-C1-4 alkyl,

Particularly preferred individual compounds of the invention

€ j-C. (S) -carbamoyl-3- (S-1-sylamino) propyl] penylcarbonylamino-3,3,3-dihydroindene-2-carboxylic acid

2-C 1 -C 2 Cl 3) - (-) - methanesulfonyl-iso-1-amino) propyl] propylcarbonylamino} -2,2-dihydroinden-2-carboxylic acid

AC .1. ti Q

-yl-L-α-cysrbic < / RTI > N '-isthane-sulfonyl; amino) propyl] cyclopentylcarbonylamino} -2-hydroxyethylidene-2-carboxylic acid, its biolabile ester derivatives of a

The cu ί ϊ tions of the formula; I) series of different processes are prepared p > The basic meo procedure

with partially protected cycloalkyl which is coupled with an amine to give the desired glutamide the carboxylic acid group in the amine, if free, or any rotative groups in R " 5 may require protection during the coupling step and these orotech groups are removed in the final stages of the process. i

in which X is as previously defined is as defined for K "with any reactive group protected therein, if n is 1-is as defined for E excluding H, or is a group of riu, κ conventional carhoxylic acid, and R '' is either Cu, E ', wherein E-4 as previously defined is R' excluding H, or is a conventional carboxylic protecting group .

Cf-woH pâfâ acid

and "

Scheme 1

The reaction of the compounds of formula (III) and (IV) is achieved using standard amide coupling techniques. Thus, in one process, the reaction is achieved with the reactants dissolved in an organic solvent, for example dichloromethane, The compounds of the invention may be prepared by the following methods: 1-hydroxyethylbenzoate, 1-hydroxybenzotriazole, N-dicyclohexane, 1-hydroxybenzoetanethanol, an organic base reaction is generally complete; 24 hours at room temperature such as 4-methylmorpholine. THE . after a period of 12 to 12 days, the product is then treated with 14

in order to remove by-product urea e. evaporation of the solvent, the product may further be purified by crystallization or chromatography, if necessary. Compounds of formula (V) include compounds of formula (I) wherein R 1 and R 2 are C 1 -C 4 alkyl or benzyl.

In some cases the coupled product in protected form may be subjected to conventional chemical conversion reactions to allow the preparation of other compounds of formula < v). Thus, for example compounds of formula (V) in W? t which K contains an ester moiety may be hydrolyzed or hydrogenated to generate the carboxylic acid which is subsequently reacted, for example with an amine, to give amine derivatives.

| ~ tvJ

J

Similarly, compounds in which α contains a substituted or protected amino group (e.g. a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) may be converted to the free amines by, for example, hydrogenation or protonolysis, as appropriate. The amines produced can then be reacted in this way, for example, the reaction with a sulfonyl halide produces the corresponding sulfonamides, the acylation with an or acid anhydride yields the corresponding amides, the reaction with an isocyanate yields urea derivatives and the reaction with a chloroformate produces carbamate products, respectively. All such transformations are entirely conventional and the conditions and reagents suitable for their execution should be well known to those skilled in the art, as well as other variations and possibilities.

The diesters of formula (v) wherein R " and may be reacted to give the monoester of the diacid derivatives of formula (I) in which one or both of?

The conditions used will depend on the H and K groups of nature present in the compound of formula (I). being possible a series of variations. Thus, for example, when both R1 and R2 are benzyl, the hydrogenation of the product will provide the desired dilute with the formula ## STR1 ## wherein R 2 is CO 2 R 3 and R 4 is - .4

And Q are both Alternatively, if one of R1 and R2 is trifluoromethyl. the hydrolysis will produce a monoester product, which can then be hydrolyzed, if desired, again to give the desired product. When one of R " and R " * is t-butyl, treating the compound of formula (V) with trifluoroacetic acid the corresponding monosaccharide in which R 2 and R 3 are benzyl or lower alkyl may also be treated with trimethylsilyl iodide to give the dicarboxylic acid product. If any other carboxylic acid protecting group is used for Râ 'or Râ', then the most suitable conditions for its removal at the end, in B.sup.B, must be clearly chosen to form the ester (I) and R 2 - (R 2) 2 and R 3 and R 4 are as defined in claim 1, wherein R 1 and R 2 are independently selected from the group consisting of: as appropriate for the particular R " group present in the compound of formula (V). In case 5, wherein ring A or substituent R is unsaturated, deprotection should be by non-reducing methods, thus, for example, if any of R and R '" for benzyl, they may be removed by treatment with trimethylsilyl iodide *

In addition to the removal of any protecting groups optionally present in n ' , a series of chemical transformation reactions can still be carried out on the monoester or the final products. di-acetic acid as previously described. In each the product may be obtained in the form of carboxylic acid or it may be neutralized with an appropriate base isolated in the form of its. In this case,

In a variant of the above-mentioned procedure, compounds of formula (I), wherein R 2 is C 1 -C 8 substituted by -OR 8, -NRUSa, R 1, -NR 11 CQCR or X i. A process involving sulfonylation of a compound of formula (I)

12-13-14, where: R 1, R 2, R 3 and R 4 are as hereinbefore defined. p ".p. 1 H X CO-jH j R " SQ-H π jL · S0US derivatives

OfH R li

wherein R " " is as defined in R or R represents t.B. as defined above is defined by reaction with an acid of the formula with one of its toluene amide, and is the monovaleric acid of the formula wherein R1 is hydrogen; H or O, nH = R 1, R 2, R 3, R 4, R 5, R 5, CH 3, or activated. sulfonamide is then cleaved to give as a pre-ester. V1

X 'and X: X *

The compounds of the formula (III) are reacted with the compounds of formula (III) with Rw and Rb and Rb are as defined above. as protected amino derivative. &quot; Thus, for example, R3 may contain a bis-substituent. (S) -phenylethylaminomethyl. The hydrolysis of the coupled product gives rise to the corresponding free amine of formula (VΪ), wherein R '&quot; represents H and Y is CH 2. of synthesis is of particular importance in the preparation of compounds having the stereochemical configuration 2 <S) in their glutinamide base structure =

Cycloalkyl-substituted gyrocarboxylic acid monoester esters of formula III may be prepared as described in our European patent applications EF-A-@274.23458-30058 = 3 s 89304683 = 7 =

In general? the mestres of formula. (I) are known compounds or may be prepared by means of appropriate synthetic procedures in accordance with the teachings contained in the corresponding literature. In a procedure, the compounds of formula (IV) can be prepared by reduction of the corresponding acid or the lower alkyl ester using, for example, sodium borohydride. Appropriate coupling and protection methods for all the foregoing and such alternate variations and procedures will be well known to those skilled in the art with reference to the standard textbooks and examples provided hereinbelow = iai as previously mentioned ? the compounds of the invention are potent neutral endopeptidase inhibitors (E, &quot; =

This enzyme is involved in the decomposition of

A number of particular peptidomers are involved in the decomposition of fsetor Π B. t Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ. t Γ .1. which are the same as those of the present invention, of which the form of polyamide is selected from the group consisting of polyethylene glycol, SC .1.dS μυΓ iisf Ui ptejj tiuSO ds 2c &gt; 3 .Ti i. η d-á c i d o s referred to as alpha-hfiNR. Thus, by avoiding the degradation of ANF5 by the endopeptidase E.C.3.4.24.i1? the compounds of the invention may potentiate their biological effects and the compounds are thus diuretic and natriuretic agents with utility in a number of disorders as described therewith. The endopeptidase-centered activity E.C.3.4.24 * 11 is evaluated using a procedure based on the assay described by 3. T. Bafford, R.A., Bkidgel, E.B. Erdos and L.B. Hersh. 1 UR? Determining the concentration of the compound required to reduce the rate of release of the radiolabeled hippuric acid from hypurl-L-phenylalanyl- L-arginine by means of a neutral endopeptidase preparation from the rat kidney. The activity of the compounds as diuretic agents is determined by measuring their ability to enhance sodium elimination in conscious mice. In this test, male male mice were selected from the group consisting of mice, mice, mice, mice and cats. 4 life in a body weight volume ΐΜΈ: - ΐΜΈ--X X r a a Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor Hor The test compound of claim 1 wherein the test compound is collected from previously weighed samples and analyzed - The volume of urine and urine volume at 2 to 5% of the urine volume are one-by-one

; The sodium ion concentration of the test animals is compared to a control group which only received the saline solution.

For administration a. humans in the curative or prophylactic treatment of hypertension, congestive heart failure or. In renal insufficiency, the compound oral dosages will generally range from 4-80 mg per day for a mean adult patient C70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 2 to mg of the compound DS of the cases where they are active in a pharmaceutically suitable carrier or excipient for single administration, or in multiple doses, one or more The dosages for intravenous administration will typically range from 1 to 4 mg per single dose as required. In practice the physician will determine the actual dosage which will be most appropriate for a given individual and will vary with the individual's age, weight and response in particular. The above indicated dosages are examples of the average cases but it may of course be necessary to administer more or less high doses, cases falling within the scope of this invention.

For human use, the compounds of formula (I) may be administered alone, but in general they will be admixed with a carrier having the standard administration route. pharmaceutical carrier selected from the desired and practiced &gt; can be administered orally in the form of tablets containing excipients such as the medicament or capsules or the like. It is also possible to isolate the cells with excipients, or in the form of suspensions containing flavoring or coranic agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a better aqueous solution in the form of an i

which may contain other substances per or glucose sufficient to make the solution is blood, e.g. isomeric CD. is set forth in the following examples with an inhalation inhibitor to control the pres- sure. 5 or with digitalis OU, Q utrc? ACh pain, shortness of breath. The w ith th e w ithin g th e w ith C ions; 2 in), a beta-1 blocker (for example, the patient-medically prescribed drug and the use thereof) may contain 1 exogenous ANF or a pharmaceutically acceptable salt thereof. one of which has one or more peptides

The compounds may be administered alone but may also be administered together with other agents indicated by the physician in order to optimize blood pressure control or to treat congestive heart failure, renal insufficiency or other disorders in any particular patient according to the practice; Thus, the compounds may be co-administered with cardiovascular agents, such as captopril or enalapril for fa < in the treatment of cardiac hypertension, or with an inhibition of cardiac failure include co-administration with an example of nifedipine, amlodipine or i (for example atenolal) or a blocking agent. or dosage form) as appropriate for treating particular individuals.

In addition to the foregoing diuretic / natriuretic activity or those with the ANF gene (for example as described by D.L Vesely et al., Biochem. Biaphys. Res., Comm., 19S7, 145-186) =

In another aspect the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a bioprecursor

ο · | for? B?,? -SC 2? together with a pharmaceutical diluent or carrier. The invention also includes a compound of the formula CI &gt; 5 or one of yours. pharmaceutically acceptable salt / sl or a biop reccursor for such purposes for use in medicine. in particular in congestive treatment or hypertension insufficiency, renal insufficiency in a human being The present invention further comprises the use of a compound of formula (I) for the preparation of a medicament in the treatment of hypertension, cardiac, intracellular, cardiac, intraepithelial, cardiac, intraepithelial, cardiac, to epilepsies with fusing (e.g., hyperaldosteronism, pulmonary edema, glaucoma), inflammation of the lungs, affective disorders, dementia and inflammation, obesity, gastric acid secretion. The preparation of the compounds of the present invention will now be illustrated in more detail by the following experimental examples. The purity of the compounds was routinely evaluated by thin layer chromatography using Merck plates KieseXgel 6 € &gt; F.- NMR spectra were recorded using a proposed Micolet spectrophotometer,

EXAMPLE 1 2-C 1 -C 2 (R 2 S) -carbothiol-4-phenylbutyl-3-cyclopentadecane-3-carboxylic acid 2-methyl-2,3-dihydroindene-2-carboxylic acid 2 -amino-23-dihydroindehyde-2-carboxy. (a)

is ester

A mixture of 2-amino-2,3-dihydroinden-2-carboxylic acid hydrochloride <M> Pinder, B, H, Bubeber, D, A = Buxton and D,> 3 = Howells , 3 * Med * Chem *, 1971, 14 * 892), &lt; 11.33 g. 1 æL. : η U ml, 0.27 m &gt; , &gt; monohydrate &lt; 12.1 g, 0.064 m) and benzene &lt; 150 ml) under reflux with a continuous dialysis solution of 50-53 m). The use of the active ingredient in the preparation of the compound of the formula The filtrate was evaporated under reduced pressure to give the title compound as a white powder. ·. What a day to go. the other * From h & Kjdi η * gave rise to an anchor, p * Γ * - j i-1 ς λ-J: _ and 'Dean-Stark device' After 48 hours, additional amounts of benzyl alcohol D, 27 m &gt; and benzene &lt; The reaction mixture was diluted with diethyl ether, and the resulting white precipitate was collected by filtration and washed with diethyl ether (10 ml) and the reaction was allowed to continue under reflux for an additional period of 72 hours. The crude tosylate salt was then dissolved in water and this solution was basified with 1M aqueous sodium hydroxide solution, then extracted with ethyl acetate. The combined extracts were washed with saturated brine, dried, Na2 SO4

A vacuum of the filtrate gave pure product as a solid

Found

C 17 '1', N0, Rc, C, 75.98; H, 6.38; N, 5.9, 76.38, H, 6.415 N 5 5 = 4, 4, &gt;; Ibb 'w'

&lt; ml) containing the solvent was evaporated. ml) and dichloromethane was added in 1 portion of the product; sec.). The title compound was prepared according to the procedure described in Example 1.

Oxalyl chloride (470 mg, 3.74 mmol) at room temperature was added to a stirred solution of 1-C2- (R5S) -ethoxycarbonyl-4-phenylphthalethylpentanoic carboxylic acid (470 mg, 3.74 mmol) (2 drops). After 2 hours, it was removed in vacuo and the residual oxalyl chloride azeotropically using dry dichloromethane (3 g, 3 mmol) was dissolved in dichloromethane (50 ml). 50 ° C for 1 hour at 6 ° C, followed for 1 hour at the diluted temperature with water and bicarbonate of vaporization under inert aqueous hydrogen chloride and water of ambient dioxide. The reaction mixture (60 ml), washed successively with water, saturated aqueous solution of dried (Na2 SO4), filtered and evaporated to give a brown gum on silica gel chromatography on a g-rad The reaction is carried out in the form of an ether and the t in particular, a single copy of the manuscript; The residue was purified by silica gel (hexane / hexane / hexane / hexane / hexane / hexane / hexane / hexane / hexane / hexane / hexane / (437 mg, 4.11%). The title compound was prepared as a white solid (437 mg, 4.11%) as a pale yellow solid. 1. i; H 3/322 s L p p 7A 1 A * r Ur? iOj (4), 47% (t ϋ

(c) 2 - (11-1,5 (R, S) -carboxy-4-phenoxyphenylcarbonylamino) -2,3-dihydroinden-2-carboxylic acid (430 mg, 0.76 mmol) in 1,4-dioxane (100 ml) was added dropwise at -78 ° C. After 5 days, the reaction mixture (40 ml) was adjusted to pH 7. The pH was adjusted to pH 7 with stirring at room temperature. The fl uoride of the solution was washed with ether and pH 2 L. The crude product was dried over sodium sulfate, dried over sodium sulfate, and evaporated to dryness. (SO2). The crystallization of the residue from

A solution of the product (<10 ml) and methanol (2 ml) was diluted with 2M hydrochloric acid. Evaporation under vacuum evaporated under vacuo ethyl acetate-hexane gave the required product as a white solid (200m, 5% -6%). H, 5.45; (I.e. EXAMPLE 2 2- (R) = S) -carbamoyl-2-hydroxybutyl-1-cyclopentylcarbamoylamino-3-2,5-dihydro- 2-carboxylic acid tert-butyl ester. (A) Z-11-LV (R, S) -benoyl &gt;: arylcarbonyl-4-tolyl-cylohexanecarboxylate. -1,2,3-dihydrazin-2-carboxylic acid. bsnclic ester

Using 2-amino-2'-3-di-12 (R, S) -benzo [1,4] -methyl-butyric acid (334 mg, 1 mol) The title compound was prepared according to the procedure of Example 1 (h) in order to give the required amount (430 mg, 72%) as a white solid.

The title compound was prepared from the title compound as a white solid (0.8 g) as a white powder. Found: C 24 H 32 NO 3: 2-yl) -2,3-dihydronaphthalene-2-carboxylic acid (2-carboxy-4-methoxybenzyl) cyclopentyl] amino] -2,3-

A solution of the previous product &lt; 390 mg, δ, 67 mmol &gt; in ethanol <20 ml) was hydrogenated over 10% palladium on charcoal at the commercial temperature <30 min) at 1 hour. The residue was removed in vacuo. d Uíft Ξι B ln; ; Arfc ocel < SiVi is followed by 3.00 5.00: evaporated over a period of 1 hr. 3.Z: isotropic with dichloromethane in the form i, 2θ5 n '; Cj U. r; mp: 42-44 ° C.

Found: C 77.07, N 6, 65.70; H, 3.47; N, 3.68.

2- (C 1 -C 2) -carboxyl-5- (S-1-isylamino) propyl] cyclopentenylcarbonylamino] -2,5-dihydroindoline-2-carboxylic acid arykyl, ethyl, hydroxymethyl, straight

A stirred, ice-cooled solution of 2 "amino-2,3-dihydro-2-propoxy-2-carboxylic acid) in absolute ethanol was saturated with hydrochloric acid 48.4 g, was stirred at room temperature overnight, then warmed to 40 ° C and then treated with dry hydrogen chloride to give a white solid. After 2 hours at 40 ° C the reaction mixture was evaporated to dryness in vacuo, then the residue was crystallized from ethanol-diethyl ether to give pure product C2.41 g, 5.8%), mp 189-193 ° C.

Found: C, 59.74: [Î »m] 3 [β9]: N = 5 = 76 = C1 = H1 = .N0, HCl = N, 5.79% (b): Î ± -carbonyl-3- (dibenzyloxy) prooxycarbonylamino-2,3-dihydro-2 H -benzoic acid. ico ester To a stirred solution cooled with 2N hydrochloric acid R 3, S) -tert-buto &gt; icar bon 1 -3- < benzimidazol-3-yl] -amide; procylcyclopentane-carboxylic acid (7.84 g, 16 m), 1-hydroxybenzotriazole (2.16 g, 16 m), 4-hydroxyethylmorpholine (4.8 g, (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.13 g, 0.32 m) was added and the stirring was continued for 1 hour at Θ ° C for 16 hours at. The dichloromethane was removed by evaporation under vacuum at room temperature, and the residue was partitioned between diethyl ether and water. The ether layer was washed with water, dried. The reaction mixture was stirred at &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; and evaporated in vacuo at room temperature. 9.33 g, 95.4%) as a hemi-solvate with dichloromethane, of sufficient purity relative to è. ρ rossecu tion,

To a stirred solution of the activated ester (5.3 g, 5.3 mmol) in dry dichloromethane (40 ml) at 0 ° C was added (1.0 g, 0.3 mmol) and 4-dimethylaminopyridine (7.0 g, After 8 mmol), an oil was removed which was purified by silica gel over elution with hexane (20% -6%), elution in hexane (20% -6%), dried (MgSOO) The solvent was removed by evaporation in vacuo and the resulting viscous oil was allowed to stand at ambient temperature for 3 days before being partitioned between diethyl ether and water, A The ether layer was separated, washed with dry water (MgSO4, anhydrous) and filtered. Evaporation of the crude product in vacuo

Found: Found: C = C = C = C = C = C = C = C = C = C = 7, 8, 8, 9, 10, 11, 12, 13, 7S, 5S, 5S, 7S, 5S, 5S, 5S, 5S, 5S, 5S, 5S, 5S, 7S, 2,5-dihydroindene-2-carboxylic acid, monohydrate (5 ml) in 5 ml) was added dropwise over t coal i. . C 27 mg &gt; (a) for the duration of the operation, and (b) The catalyst was removed by the Arbocel (upper) and lower (Hyflo) pad), then the filtrate was evaporated in vacuo, and the residual solvents were azeotroped with dichloromethane of &quot; In order to provide the required product &lt; 1592 g of the desired product &lt; / RTI &gt; C, 6.77; H, 8.44; N, 5.89; Found: C, 68.509; H, 8.44; (D) 2-C 1 -C 2 (R, S) -tert-butyloxycarbonyl-5 - [(N, N '-dibenzyl) carbonyl] -3- -yl) amino) propyl] cyclopentylcarbonylamino] -2,3-dihydroxyphenyl] -2-carbo-gt; (4-methoxyphenyl) propionic acid ethyl ester <944 mg, 4.92 mmol) was added to a stirred solution of the above amine (1.13 g, 2.46 mmol), 5-hydroxybenzo [46 mmol), N '-dimethylbenzylaniline-S-1-isine

J

(2 g, 2.46 mmol) and 4-methylmorpholine <746 mg; 7.38 mmol) in dry dichloromethane (25 ml) at 0 ° C. Stirring was continued for 1 hours at &gt; ° C then 16 hours at room temperature. before removal of the solvent in vacuo, the residue was partitioned between diethyl ether and water, then the ether phase was washed with 1M hydrochloric acid and water, dried (Na2 SO4) and filtered. Evaporation of the filtrate in vacuo , followed by chromatography of the residual oil on silica gel using a gradient elution of ethyl ether in hexane (50%), provided the required product &lt; 1 &gt; 8%),

Found: C, 67.31; H, 7.44; N, 6.9;

(5 ml) was added dropwise 5 to a stirred solution of the previous product Cl, 28 g, 1.5 mmol) in dry dichloromethane (10 ml) at 0øC . The ice bath was removed by stirring for 1 hour at room temperature, then the reaction mixture was evaporated in vacuo. The crude product was dissolved in ethyl acetate and trifluoroacetic acid was removed by washing the solution with saturated aqueous solution dried (Na2 SO4), filtration and evaporation in vacuo of the ethyl acetate solution, followed by the aseotropic removal of the residual solvent with dichloromethane, provided the required product C , 12 g «9» 4 »4»,

Buuer C, 6-5, b'3 H, 6 66 | C, 63.33; H, 6.96;

J C f &gt; (3-carboxy-3-B-lysylamino) prop-1-one. 1,2,3-dihydroindene-2-carboxylic acid ethyl ester. 11 c d

A s-o 1 u. of the previous product &lt; (1.0 g, 1.53 mmol) in an ethanol mixture <7 ml) and water <0.5 ml was hydrogenated over 10% palladium on charcoal (160 mg) at 60 (0.1 bar) and at ambient temperature for 1 hr., the workup as described above for ε θ 2 &lt; b &gt; The product required under a. a foam of QBQ0 <740 mg, 98.9%),

Found r m w n = i-2B '42 vaA s * · C, 59.90 | H, 6.52; H, 8.165 N. 5-

aqueous hydrous solution; (a) (b) (b) (b) (b) (b) (b) (b) (b) (b) ) in DMF (3 ml) was stirred at room temperature for 5 hrs at reflux temperature for 1 hour. The fractions were prepared by chromatography on silica gel with dichloromethane and evaporated to dryness by freezing of this aqueous solution. to the required product.

Found: 1, 2, 3, 4, 5, 5, and 10 10, D requires C-1 H5 7 ' EXAMPLE 4

2-Cyclohexylcarbamoyl) -2,3-dihydro-2-hydroxy-2- (R, S) -carboxypropyl] -cyclopentylcarbonylamino} -2,3- ca.

Was the procedure followed? N, N'-acetyl-N-benzyloxycarbonylation gave the product in C ,, - - -; The reaction mixture was cooled to 0 ° C. The reaction mixture was stirred at reflux for 1 hour and then cooled to -78 ° C. c, 583-30; H, R1. 58. A solution of the title compound as a white solid (0.8 g) in dichloromethane (50 ml). N, 10 s Θ 7 7 3 61 ρ N, 9.72%

EIOPL0-5

2- (N-Bis-trifluoromethylphenyl) -2- (1- (S) -1- (1- (S) followed the procedure of Example 3 but using

The title compound was obtained in the same manner as described above. The deprotecting gave the title product. 1 H-NMR (CDCl 3):?

Found: C, 53.99; H, 7.13; N, 9.31. C27 H4 F4 N4 O4 S2 O requires C, 54.17; Η, 7, β7; N, 9.36%, EXEHFlu 6 acid ..... 2-C 1 -C 2 &lt; S) -carboxy-3- (S -benzoylamino) propyl] cyclopentane. ......... 2-carboxylic acid (2-chloro-2-pyridyl) -6- (8,8-dihydroxyphenyl) -2- -5Î ± -dihydroimidazole-2-carboxylic acid ethyl ester, ethyl ester

The procedure of Example 3 was followed but using the desired acid. - tert-butoxycarbonyl; S, S) -Î ± -Î ± -Î ± -Î ± -Î ± -β-1Î ± -difluoromethyl) -propyl] cyclopentane carboxylic acid in step (b) to give the title product in 79%

Found: C, 54.54; C, 75.64; H, 8.30; H, 0.16; N, 4.01 = N, 4.20%, 4

Hydrolysis of the above product as described in Example 3 (C) gave the amine isomer (2: 9) of the amine in 99.1% yield): (silica): δ56 (dichloromethane-methanol, 9: 1). 2-Carboxyloxy-2-carbamoyl-2-carboxylic acid (2-chloroethyl) amide; oxime coupled to N, N -dimethylethylcarbamoyl-S-1-isine following the procedure of Example 3 &lt; t &gt; and the product was deprotected as described in Example 3 steps (e) at &lt; g) to give the title product &lt; RTI ID = 0.0 &gt;

Found; C₂,, HJ OO;; 2nd place 4th

C, 56.71; H, 7.48; N 2.5H2O requires C, 57.02; H, 7.91; EXAMPLE 7

62 (S) -carboxy-3- (methanesulfonyl-5-isylamino) propylcyclopentylcarbonylamino-2,3-dihydro-indene-2-carboxylic acid

J

The procedure of Example 1 was followed but using N α -benzyloxycarbonyl-γ-methanesulfonyl-S-isine in the coupling step to give the title product -3.50 (3H, m); 4 "7 1 X * π 5 / Ç 2. *«: 5 N5 Q t

Found

 € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡

. ' A

-Am x η α-2-hi d γοκ xms Lx 1 ~ 2, .5-d ± 1-hydroxycin

A solution of 2-amino-2,3-dihydro-2-inden-2-carboxylic acid, ethyl ester. (1.7 g, 7.03 mmol) in 5% NaOH (15 ml) was added dropwise to a stirred, ice-cooled, of sodium borohydride (1.11 g, 29.4 mmol) in 5% aqueous ethanol (35 ml), and then the reaction mixture was heated under reflux for 3 hours. The combined extracts were washed with saturated brine, dried (anhydrous MgSO 4), filtered and evaporated in vacuo. Crystallization from ethanol was then added and the filtrate was evaporated under reduced pressure. of the resulting white solid (130 g) from ethyl acetate-hexane provided the required product (0.99 g, 84.8%),

J

Found: 9.1 H-U requires C, 72.32; H, 8.02; SM, 8.17. C, 72.39; Η, 8, Θ8? N, 8.44%, (b> 2-fluoro-2-hydroxy-2-hydroxy-2-hydroxybenzoyl) -cyclopentyl- of 1,1'-dimethylaminopropyl) -3-ethylcarbodiimide (0.6 g) cooled with hydrochloric acid to give the same mixture of each of 1-12 R, 8 '' - , 2 mmol added, 1-hydroxybenzotriazole (27 mg, 2 mmol), 4-methylmorpholine (2 mg, Λ Vt> -wV * &quot; (a): (1): The product of the dry dichloromethane product (1 ml), A stirring was continued for 1 hour at 0 ° C, and the mixture was stirred for 24 hours at ambient temperature under reduced pressure. and water ? in vacuo of the sample medium. The residue was dried over sodium sulfate and water, and the ether phase washed with saturated aqueous sodium bicarbonate and water. Evaporation in vacuo of the filtrate gave an oil which was chromatographed on silica gel using diethyl ether-hexanoic acid and dried (MgSOâ, "). as eluent. Evaporation under vacuum of the appropriate fractions provided the required product &lt; 18Θ mg, 95%)

H, 7.84; H, 3.61; H, 8.9; M, 2.967. Found: C, 2-hydroxy-imidazo [2,3-dihydroindene

A solution of the above product (17 μm, 36 mmol) in a mixture of ethanol (20 ml) and water (1 ml) was hydrogenated over palladium-on-wet. has; perature ambi oh the form of; (3.45 bar) and then trituration with diethyl ether-hexane (10 ml)

The title compound was prepared from the title compound as a white solid (0.53 g, 0.05 mol) as a pale yellow oil. 1 H NMR (CDCl3): .delta. 1, 3, 4, 6, 4, 6, 6, 6,

EXAMPLE 9 Dihydro-inden-1-yl) -benzoylaminoethylamino-2-hydroxy-2-hydroxy- Γ.2 &lt; RB) -Benzenesulfonyl-4-oen-1-butoxycarbonylamino] -hexahydro-1H-indazole-4-carboxylic acid

The procedure was continued as in Example 1 (2R, yl) -benzyl] carbonyl] benzoic acid as starting material at ambient temperature. The required product under Example B (b) was obtained using 4-phenylbuty1cyclopentanoic acid and the mixture was allowed to react for a further five days. The title compound was prepared as an oil (19.9%). (if 1 ic * (iàfpf

1-hexanediol H (b) L (R, S) -carboxy-4-butenylbutylcyclopentylcarboxylic acid benzyl ester; 1-Hydrogenation of the above product as described in Example S (c) = followed by 1 H NMR (DMSO-d 6):? chromatography on silica using ethyl acetate as eluent and evaporation in vacuo of the appropriate fractions, followed by trituration of the resin with diethyl ether-hexane (4: 4). y gave rise to the required product

J = 62.42) under the fortin of a white solid.1 H NMR (300 MHz, CDCl3):? 5 H "7" 6-2 s N 5 3 yes 2 «; 1/4 H.-JJ requires C, T &quot; (1), (2), (3) and (5).

ε: ΕΝΡ Ιίί · Γ. 1- [2 (R, S) -carbamoyl] (3- (5-isylamino) propyl] cyclopentylcarbonyl] r 2-yl] -3- [ (R) -5- (tert-butoxycarbonyl) -3- (di-benzoimidazol-1-yl) propyl] cyclopentylcarbonylamino- 2-hydroimethylimino

To a stirred solution of the hemi-solvate with dichloromethane of the activated ester derived from 2 (R, S) -tert-butoxycarbonyl-3-carboxylic acid N-hydroxybenzotriazole (9.78 g, 16 mmol) 2-amine-2-hydroxy-3-thienyl-2,3-dihydroindene (2.65 g, 16 mmol) in dry dichloromethane (50 ml) at room temperature after 2 hours the solvent was removed by evaporation in vacuo and the residue was allowed to evaporate.

The residue was partitioned between diethyl ether and water, dried (MgSOâ, ") and filtered. Evaporation of the filtrate in vacuo followed by purification of the residue by means of gel chromatography silica using a dichloromethane / hexane hexane gradient (20-100%) provided the required product C3.3 &gt; g, 33.6%).

Found; CRHSNN °O ^N tiO /N tiH? CNH₂O °H? CNH₂O °N °O °N ° 4 4 4 4 4 4 4 4 4 4 4 4 4. --- ???????????????? C. and to τ? «« l y y y y y y l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Tij J /

and the results are shown in Fig. 4 'raker' was hydrogenated at a temperature of about -20.degree. amine in epi q Γ Θ. f 0 with 98.2% of C3 or C6 H5 O2, B, 88; N H 6 H 6 O 3 P 3 O 3 H 3 N 3 C f 3/3% (ic) 2-H-2 (R &quot; -tert-Eutox icsrbon-1-yl) -N-dihydroxy-N-diisopropylcarboxamide 1-yl) -hydrazine; The above amine was coupled to ethyl acetate as the inode a. , the title compound is obtained. following the procedure of Example 3 (d) but using a gradient of diethyl ether-hexane (1: 8 to 1: 1) followed by chromatography (1: 1)

J

Found: C, H, H, J = 6.6Hz, C = 6.4, 9.5 H, 7.33; 3 H, 7, 44 and N, 6.89. S &gt; -Ce. 2-carboxylic acid (2-chloro-3-methylphenyl) benzoate. (2.46 ml) in dry dichloromethane (2 ml) was dried over sodium sulfate, dried over sodium sulfate, dried over sodium sulfate, with dry hydrogen chloride. After another 2 hours he was submitted to a. The reaction mixture was evaporated in vacuo and the residue was stripped with dichloromethane to give

A 5% w / w 5% w / w. N, 7.15%. Γ Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο *

Found, δ = 1.5 H2 O requires H 2 O 3. 4 * 7 &quot; * &lt; £. &lt; RTI ID = 0.0 &gt; (e) &lt; / RTI &gt; 2-Cyclopropylmethyl] -amide The above product was hydrogenated following the procedure of Example 3 (f) to give the required title compound as a white foam (79.7%).

1 H-NMR (300 MHz, CDCl 3)?  € ƒâ € ƒâ € ƒ25.5 K, 20.44 ° C requires C, 61.09; H? S 3 38% Ns 10, v &amp;%

EXAMPLE: 1-C2 (S) -Car boκi

1-yl) amino] propionic acid ethyl ester 2-hydroxymethyl-2,2-dihydroxydene

J

The procedure of &lt; empid Iβ but using activated ester derived from N-hydronibenzotriazole of acid 2 &lt; S &gt; (S = S) -alpha, alfadimethylbenzylamino-3-propylcyclopentane-2-carboxylic acid as starting material in step (a) and coupling with Θ. The small amount of distilled and dried water was obtained in the same manner as described in Example 1.

Oh

The results are shown in Table 1. The results are shown in Fig.

Claims (2)

(I) in which fi completes a 4- to 7-membered carbocyclic ring which may be saturated or mono-unsaturated which may optionally be fused to another saturated or unsaturated carbocyclic 5- or b-membered ring R is H 3 C C --C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna-C alterna- is H, OH, C1-4 alkyl, C1-6 alkoxy or halo. CF-, s X η · * X '-r * &amp; Wherein R 'is as previously defined. defined for Rp or cycloalkyl is C1 -C6 alkyl, substituted by halo, hydrosec, alkoxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy, C1-6 alkoxy, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, . /? -NR & COR &quot; ? -NRâ,,SOâ, ", Râ,"; f, -CO. RaR / N-C? -C? (s). or R is C 1 -C 6 alkyl substituted by a group of the formulas 1 &gt; · J R! j 1-X-3 r -__ c &gt; - C--C R-C R-C R-C R-alkyl; SO, -R 1 ', OR 14 -NR 13 R 13; Wherein R 6 and H 'are each independently H, C 1-6 alkyl, C 1-6 cycloalkyl, aryl, C 1-6 alkyl; aryl-C 10-C 10-C 10-alkyl-C 10-C 10-C 10-C 10-C 10-C 10-C 10-C 10-C 10-C 10-C 10- OR. R1 and R2 groups are taken together with the groups to which they are attached to form a pyrrolidinyl, piperidin, morpholino, piperazinyl or N- (C1 -C4) alkyl group. R 9 is H or alloyl LR. R1 is C1 -C4 alkyl, CF7, aryl, arylC4 -C4 alkyl, arylC4 -C4 alkoxy, heterocyclyl, C1-6 alkoxy, or NR4: Wherein R 1 and R 2 are as previously defined; R 1 and R 2 are as defined above; R3 is C1-4 alkyl, cycloalkyl, C1-4 alkyl, C4-C6 cycloalkyl, heterocyclyl, C1-6 alkyl, C1-6 alkyl, C1-6 alkyl, Râ,,SOâ,ƒ, NRâ,,11, Râ, â, â,, wherein each Râ, Z n b as back | 1. 1 or 2, R 2, R 2, R 2, R 3, R 4, X * 8 * ~ "- K o K is an ad hoc n o r t h e m e n t h H OU Ί lo 0. -0. R 4 is H or Ra is C 4 -C 4 alkyl; C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, guanidino, aryl. the R 'and F' &quot; and or in the waroc: ic &gt; i.e., or the aox; 5.U bound to each other to form, with the carbon atom to which they are attached, a 5- or 6-membered carbocyclic ring, which may be saturated or mono-unsubstituted. with another SB ring either unsaturated or unsaturated? And K is rL and R is a bond. (2- (N-CORA) -4-aminopyrrolidino) is R 11 R 11, R 11, R 15, R 16, R 11, R 11, R 1 and R 2 are each C 1 -C 6, or an integer of 1 to 6, and of the pharmaceutically acceptable salts thereof, characterized in that a compound of formula (V )s Wherein A, R and F 'are as previously defined, R 2 is as defined for. R com with any reactive groups therein protected, if necessary, &quot; is as defined for R excluding) -L or is a conventional carboxylic acid protecting group and R '= is or CHOHOH or CO-R &quot; is as previously defined for K 'excluding H, or is a conventional carboxylic acid protecting group to a hydrolysis ε / α hydrogenation and / or other deprotonation reaction in order to remove any protecting group present in R For the production of the corresponding dicarboxylic acid of the formula (I) wherein R and R 'are both H, or to produce the corresponding mono -ester wherein one of R 2 and R 3 is H and the other is a Formula CI &gt; (VI) ## STR4 ## or to provide the acylation (VI). c * sv $ fc U '£. of R'_! qpr CH_OH? R1 is H; and R 2 forms an acetyl group. The process according to any one of the preceding claims, wherein R 1 and R 2 are as defined in claim 1, Or a compound of the formula ## STR4 ## or a compound of formula ## STR4 ## or a compound of formula wherein R 1 is as defined for R 1 and R 1 and R 2 is as previously defined and Y is a C 1-4 alkyl group by reaction with an acid of formula  € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ the product of the mono- or tri-ester product to produce formula (I) wherein R 1 is H and R 2 is hydrogen or C 1 -C 4 -alkoxy, CH? OH or CQ? H?, and optionally a pharmaceutically acceptable salt is claimed in the form of a pharmaceutically acceptable salt thereof. to be independently of each other are selected from t-butyl, ethyl benzyl and said groups are removed with trifluoroacetic acid and aqueous alkali. The present invention provides a process for the preparation of a compound of the formula: IJ = where F; and F (if present) are both. A process according to claim 1 or claim 2, characterized in that A is &lt; CH &gt; R 1 and R 2 are 2 4 H 5 in order to provide a compound having the formula (11) Ro2c (II) wherein R? Ff &quot; 'and R:' 'f are CDSTi | Q above inert O 0 T f orula &lt; I) 5a-F * &quot; rc cc s only according to king vintíic king action ** 7 character X X &quot; R ser is H₂O, and R qu is H₂O, and R qu is hydrogen. SST I IAB B I in C H H, C H I H, C H, C H, -CH 2 CH 2, CH) formula H .............. - - - v &gt; &quot; &gt; &gt; &gt; 5 &gt; / 2: = t i 'f &quot; The compound according to claim 1, wherein the compound of formula (I) carac * &quot; tered by R 'ΒΒΓ alULtilD L ·. alkyl substituted by C alco-C alco alkoxy, or C alquilo-C su alkyl having the formula: ???????? The compound according to claim 1, wherein said compound of formula (I) is produced by 2- (1-E2 (S) -carbamoyl-3-isylamino) -1-cyclopentyl- aminocarbonylamino] -2,3-dihydroindene-2-carboxylic acid are 2-yl. 2-Carboxy-1-amino-3-oxo-2-methyl-3-dihydro-1H-imidazol-1-yl) 1-ene-2-carboxylic acid or (1-isoglino) propyl] -dibenzo [2,1-c] [2 (S) -carbamoyl] -3- (N, 3-hydroxy-2-methyl-2,1-a] b-SX or the derivatives thereof are good Jane of 199 : 1 J J. PEREIRA DA CRUZ Official Agent for Industrial Property RUA V1CT0R CORDON, 10-A 3, * 1200 LISBOA