PT96863A - PROCESS FOR THE PREPARATION OF UTILIZED CYCLOALKYL SUBSTITUTED GLUTARAMIDE DERIVATIVES AS ANTI-HYPERTENSIVE AGENTS - Google Patents

Description

f f

This invention relates to a series of cycloalkyl substituted glutamine derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders such as hypertension and heart failure.

According to the specification of our European patent application 274234, we disclose certain cycloalkyl-substituted giutaramide derivatives; which are inhibitors of the neutral zinc-dependent endopeptidase EC3.4.24, are thus capable of potentiating the biological effects of atrial natriuretic facirier, and in particular the compounds are natriuretic, anti- hypertensives and diuretics that are useful in the treatment of various cardiac disorders. In our European patent application No. 83308740.3, we disclose compounds which are inhibitors of the EC3.4.24.11 enzyme, and, in addition, they have the ability to inhibit the angiotensin converting enzyme CACE), another enzyme that is involved in the control of pressure blood. The compounds thus possess a dual pharmacological action by inhibiting the two major enzymes involved in controlling blood pressure, which makes them useful for the treatment of various forms of hypertension and cardiovascular disorders, for example insufficiency · Cardiac and glaucoma.

According to the present invention there are provided other related compounds having as the atriopeptidase and AGE inhibitors of the formula;

V

THE

2 R -Y \ J R3 / C \ /

(I) wherein: R 2 is hydrogen; A carbocyclic ring of & or 6-membered heterocycle which may be saturated or mono-unsaturated; Y is an alkylene group of from 1 to 3 carbon atoms, which may be straight chain or branched; R " R4 is H or C1 -C4 alkyl; and R4 is each independently hydrogen, C1-6 alkyl, benzyl, or an ester forming biolabile group ; R " is hydroxy, (C1 -C6) alkoxy, hydroxy (C2 -C8) alkoxy, (C1 -C6) alkoxy, (C1 -C4) alkoxy, C1 -C4 alkoxy. CΙ -C -Calkyl, CΙ -C 4alkyl, CΙ) )alkyl, C!) )alkyl, C!) )alkyl, C!) )alkyl, C!) )alkyl, C!) ~alkyl, C!) ~alkyl, N, N, N, N ', N', N ', N', N ', C (= C 1 -C 4), C (O) (C1 -C2) alkyl, (C1 -C2) cycloalkyl, (C1 -C2) cycloalkyl, (C1 -C6) cycloalkyl, Z-. on what; A 4 is O, SCO) or NCR '·) and nR- is H, C1-4 alkyl, -C > or C1-4 alkyl); 1 4 A 4 or. A compound of the formula: wherein Y may also be a direct bond where R 1 is (C 1 -C 4) alkyl, C 1 -C 4 alkoxy, (C1 -C4) alkyl. > ami-2 < / RTI > (C,-C)) alkoxy, C)-C al alkoxy, C)-C) alkoxy, C)-C) alkoxy, (C1 -C4) alkoxy or (C1 -C4) alkanoyloxy

Q or. R " " is a group of the formula ROO- wherein R 'is a 1-piperidines or i-pipersEin group, any of which may be optionally substituted by OH; C? -C? Alkyl; or hKR ")! or

R 1, is a group of the formula K 2 CuMKr " in what

R 6 as pre-determined 5 and

R 1a is (Re > 2N, alk (C 1 -C 4) alkyl, C 1 -C 4 -alkyl, or substituted phenyl and the substituents are C 1 -C 4 alkyl, R 2 is a group of the formulas: wherein R 1, R 2, R 3, R 4 and R 5 are independently selected from the group consisting of:

- CH, 14 2 ι r

(C1 -C4) alkoxy (C1 -C4) alkoxy (C1 -C4) alkoxycarbonyl, ) 4 - (C ^-C l) alkoxycarbonyl-1,4-cycloalkoxy < 0 > -carbonyloxy, or 3-alkyl > C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, is a group of the formula:

wherein said groups may optionally be substituted on the benzene ring condensed by alkyl, -CN > 4-alkoxy < C ..-C, > 5 OH; halo or CR4,; R4 is each H, C1-10 alkyl, aryl C1-4 alkyl, or the two R6 groups are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-alkyl group (O, O -). 4-piperazinyl; R '' '' is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxy, C1-C4 alkoxy, (O) -alkyl, or morpholinylmethyloxy, or R 4 '' ' and â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ and â € ƒâ € ƒâ € η is Ο, 5. or 2, and their pharmaceutically acceptable salts and bio-drivers for that purpose.

In the foregoing definitions, unless otherwise expressed, alkyl groups having three or more carbon atoms may have a straight or branched chain. The term "aryl" as used herein means an aromatic hydrocarbon group such as phenyl, naphthyl or biphenyl, which may be substituted factually with, for example, one or more OH, CN groups; C1-4 alkyl, C1-6 alkoxy, halo, carbamoyl, amino-sulfonyl, amino, mono- or di (C1-6) -alkylamino, (alkane-4-yl) Amino, amino (C, -ilalkyl), C) di dialkylamino, C)) aminoalkylamino, C)) aminoalkylamino, C)) aminoalkylamino, 4 14 1 4 -a 1 qu i .1. (C1-C4) -alkyl, or a C1-C4 alkyl group, or a C1 -C6 alkyl group. There are 1 or 1 4 λ 4 n · ·. Fluoro, chloro, bromo or iodo. The term heterocyclyl means a B 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 ring atoms and which may be optionally benzofused or substituted with for example one or more halo, C1-6 alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di- yl G, -G, > amino or Ca-1-carboxylic acid. Particular examples of heterocyclyls include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, dihydrohydrofuranyl, tetrahydrofuranyl, dioxanyl, iienyl, exazolyl, isoxazolyl, thiazolyl, indolyl, isoindoyl, quinoxalinyl, quinazolinyl and benzimidazolyl, each of which is optionally substituted as defined hereinbefore.

I

The compounds of formula (1) may contain several asymmetric centers and thus they may exist as enantiomers and as diasignomers. The invention includes both separate individual isomers and mixtures of isomers.

Pharmaceutically acceptable salts of the compounds of formula (I) containing an acidic center are formed with bases which form non-toxic salts. Examples include alkali or alkaline earth metal salts 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, hydrobromide, sulfate or sulfosucrate salts, phosphate or hydrogensophosphate, acetate, citrate, fumarate, gluconate, lactate, magnesium, succinate, tartrate, iodide or sulfur sulfate. The term bioprecursor in the above definition means a derivative of the biologically degradable, pharmaceutically acceptable compound of formula (I), which upon administration to an animal or human is converted into the organism in order to produce a compound of formula Cl). Examples include biolabile ester derivatives or amide or smino acid derivatives of the compounds of formol 1.

A preferred group of compounds are those in which A is CCH3, R3 and R'1 is H, i.e. compounds of the formula (II) wherein R1, R ', R' and R 'are as previously defined for formula (I); ί »ί»

(II) Preferred are those compounds of the formulas (I) to (II): wherein R 1 and R 2 are both H (diacids) as well as their mono- and diethyl esters, wherein one or both of R and R 2 is a group formed of bioavailable esters. The term "bio-bi ester ester group" is well understood in the art to mean an ester-providing group which can be cleaved rapidly in the organism in order to release the corresponding diacid of formula (I) wherein R4 and R4 are both H A number of such ester groups is well known, for example in the penicillin area or in the case of the ACE antihypertensive agents.

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. The suitability of any particular ester former may be assessed by standard studies; in animals or in vitro, for enzymatic hydrolysis. Thus, in order to obtain a desirable and optimal effect, the ester should only undergo hydrolysis following its absorption; therefore, the ester should be resistant to hydrolysis prior to being absorbed by the digestive enzymes, but should be readily hydrolysed, for example, by the hepatic enzymes. In this way.7.s-a; the precipitated dioxide will be released into the bloodstream. following oral absorption.

In addition to the lower alkyl esters of especially the ethyl esters), and the benzyl esters, suitable biolaphic esters include alkanoyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted derivatives thereof, aryloxyalkyl esters, aroyloxyalkyl esters, esters of ara-1-quinoxyalkyl, aryl esters, aromatic esters, haioalkyl esters and dihydroxyalkyl esters, including their stereoisomers, wherein said alkanoyl and alkyl groups contain from 1 to 18 carbons and have a straight or branched chain, and said aryl groups are phenyl, naphthyl or indanyl, each more preferably substituted by one or more C 1 -C 4 alkyl groups. , alkoxy CH-C, or alkoxycarbonyl. 4 .1. or halo atoms. x 14 4

Thus, examples of R 1 and R 2 when they represent biolabile ester forming groups include ethyl, indanyl, iso -propyl, n-butyl, sec-butyloxy, t-butyl, C 1 -C 6 -alkoxy, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-C4-methyl-1, 3-dideoxalen-2-onx1) methyl, cyclohexyl, cyclohexyl, carboxyethyl, hexenoyloxyethyl, pentanoyloxyethyl, acethoxyethyl, acetoxybenzyl, pentanoyloxybenzyl, cyclohexyloxycarbonyloxyethyl, butyloxycarbonyloxyethyl, isobutyloxycarbonylethyl and ethoxycarbonyloxyethyl groups. q

In a preferred aspect of the invention, the R " is 4-hydroxybenzyl, and the carbon atom to which it is attached has the stereochemistry (8-j being the group NHCHCR "

L-t-s. rosinas Also preferred are those compounds wherein R " represents 4-methoxybenzyl. Y is preferably C1-6 alkyl, C1-4 alkoxy, C1-6 alkoxy, C1-6 alkoxy, C1-6 alkoxy, C1-4 alkoxy, (1)

In the same way, specific and preferred examples include 4-ethoxystyrene and 2-methoxyxyoxypropoxy. Also preferred are those compounds wherein R 'Y represents aminoalkyl (C1 -C4). A specific and preferred example of this type is 8-amino-octyl.

In another preferred group of compounds, representa is 21 1 f) c; c, CH 2 ', and R 3' is of the formula R " ' wherein R '' is H. Preferred are the examples wherein R 'represents substituted phenyl, particularly when said substituent represents, (CHâ, ... or â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ. ... 3 (0> (where n repre- xxxxnx sits 0, .1, or 2).

Thus, specific and preferred compounds of the invention include; N- (2 (S) -carboxy-4- (2-methoxyethoxyphenyl) -1-cyclopentaneoconsulfonyl) (8) -tyrosine, N- 1- (2 (S) -carboxy-4- ethoxybutyl) -1-cyclopentanecarbonyl-13- (8) -trienes: N, E-C2 -C12, S-carboxy-10-aminodecyl-1-cyclopentanecarbonyl- (3) -tyrosine, and NE "(2) -carboxy-3- (4-aminomethylbenzamido) propyl 13-1-cyclopentenone-carbonyl-3- (S) -yrosine,

Compounds of formula (I> gt; are prepared by a number of different processes! a) A process involves the synthesis of a partially protected cycloalkyl-substituted gutaric acid derivative which is coupled with an amine in the manner of. the desired gelatine is obtained. Any reactive groups in R 2 and R 3 may require protonation during the coupling step and such leaving groups are removed in the final step of the process. The synthetic route is illustrated in the reaction scheme which follows in which h; V and R " are as previously defined, R 's R " as defined for R 2 and R 3 with any reactive groups protected therein. If necessary, R 2 and R 3 are as defined for R 1 and R 2 excluding H or conventional protecting groups of carboxylic acid; I * 2 'R-Υ

R 2, R 3.

RX2C17

(III) ψ

CHCH

, 3 '(V) • co2r 18 (IV)

c ° 2R

The reaction of the compounds of the formula < RTI ID = 0.0 > (IV) is achieved using conventional amide couplite techniques. Thus, in one process, the reaction is carried out with the reagents dissolved in an organic solvent, for example dichloromethane by using a diimide condensing agent, for example 1-ethyl-3-1-diethylaminopropylcarbodiimide, or N, N-dicyclohexylcarbodiimide , advantageously in the presence of 1-hydroxybenzoylazole and an organic base such as N-methylmorpholine The reaction is generally complete after a period of from 12 to 24 hours at room temperature and the product is then isolated by convection procedures, i.e. by washing with water or filtration to remove the by-product urea and 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 6 alkyl or benzyl. .1. 4

The diesters of the formula (CM) may be reacted to give monoester derivatives or diacid derivatives of formula IV > wherein one or both of R and R is H. The conditions used will depend on the precise nature of the R " '" and RAU 'present in the compound of formula (V) and a number of variations are possible. Thus, for example, when both R1 and R2 are benzyl, hydrogenation of the product will provide the diacid of formula (I) wherein R3 and R4 are both H. Alternatively if one of R ' '' 'and R *' " ' for benzyl, and the other is alkyl, the hydrogenation will produce a monoester product. This can then be hydrolyzed, if desired, again to give the diacid product. When one of R 1 and RAW is t-butyl, treatment of the compound of formula CV) with trifluoroacetic acid provides the corresponding acid. If any other carboxylic acid protecting group is used for RAf or RA '" then the most suitable conditions for removal in the final step will need to be clearly chosen so as to form the product ester or diacid of formula (Cl). For example, when R 2 'or R 3' is trimetylated, it can be removed by treatment with tetrafluoroboride fluoride. butyl ammonium chloride. Any protecting groups present in R1 and R " should also be removed and this can be carried out concomitantly with the removal of the groups of formula present in R and RA "or as a separate step using appropriate procedures with respect to the particular preparation group used. Thus, for example, when R " '" (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino) group, the cosolvents may be converted to the free amines by hydrogenation or hydrolysis, as appropriate. (b) In an alternative process, compounds of formula (1) wherein R '" is prepared by reacting an amine of the formula

• A C 6 ·

-NH-Y CHCH-R17o2c-

Wherein A, Y, R 1, R 2, R 3 and R 4 are as defined in claim 1, with a carboxylic acid or acid chloride of the formulas: Wherein R 1 '' is as previously defined, and wherein any reactive groups present therein are optionally protected, in order to provide, for example, a compound of the formulas

R "10 'I R COM

R 1

R CHCH.

(VII) wherein R1 is as previously defined for R1C; with any reactive groups present therein optionally protected? and,

and the hydrolysis of the ester product to give the compounds of formula (1) wherein R 1 and R 2 are H. The reaction of the amine of formula VI) and of the acid of formula R 2 'is obtained using standard amide coupling techniques as previously described. In the case where it represents R '" 1 > ..., N, the acid chloride can be prepared in A%. first, by reacting the amine with phosg- nium; the subsequent reaction with amine of formula (VI) affords products of Formula (VI). Subsequent removal of the protecting groups is accomplished using appropriate procedures as previously described.

The amines of formula (VI) are prepared following the same procedure outlined in the above-mentioned process (a), but using an acid of the formula (III) in which R 2 'represents a protected amine Thus, in a variant of this process, the coupling reaction with the amino acid derivative is achieved by using a compound of formula (III) wherein R 2 represents dibenzylamino or di (alpha-methylbenzylamino). (VI) wherein R '' is H. c) Certain compounds of formula (I) are better prepared by routes involving the coupling of a precursor stage so as to provide a derivative diester of the formula (V) type, which is then subjected to a chemical transformation reaction to give the desired particular group R 2.

Thus, for example, the coupling process may be > be carried out using an acid of formula (III) wherein H 'represents halo (e.g. bromo). This can then be 17

reacted with color! an amine of the formula (R) ..... MH to give a compound of the formula: if compounds in which R 1 is R 1 -) -, - N, or a compound of the formula I where R ' represents N, .. Subsequent reduction of the azide group by means of catalytic hydrogenation; either the protected product or the deprotected diacid, that of the corresponding aisin of the formula CI > where R " represents NH 4 -

In another variation, an acid of formula (III) 2 'is used wherein R " Y- represents 2-propenyl. Reaction of the coupled product of formula (V) with an alkanoyl, or an alkoxide (in the presence of mercuric acetate and potassium iodide) gives the 3-iodo-2-C1-6 alkoxy derivative CC, -C. > 3-propyl, or subsequent reduction, for example with tributyl hydride) gives the corresponding compound of formula CV) in which Y represents propyl, * *: »I R ': " represents a C1 -C4 alkyl group; or a C1-C4 alkoxy-alkoxy bonded in the 2-position. In another variation of this process the iodine intermediate can be reacted with a heterocyclic compound, for example imidazole) to give the compound of formula (V) O 7 'C; 7 where R " " ' is of the formula R " CH, R 'is heterocyclyl-

IOCC1, -C3) and R " ' represents the C1 -C4 alkyl; . 1 4 1 · :: · a

The compounds of the formula (II) wherein Z is present and represents SCO) or SCO may of course be prepared by oxidation of the corresponding thio derivatives in which Z represents S. Oxidation may be carried out either on the protected protected diester of formula V) or the deprotected diacid product. Appropriate reagents will be well known to those skilled in the art but, for example, excess methachloroxybenzoic acid may be used in order to obtain the corresponding sulfones CZ = SO2, or equimolar amount of sodium metaperiodium such that the sulfoxides (Σ = SG) were obtained.

Appropriate reagents and conditions for all the above transformations will be well known to those skilled in the art by reference to standard textbooks and the examples provided hereinbelow. Further variations and possibilities for the convenient synthesis of the range of substituents R "will also be apparent to those skilled in the art. The foregoing are representative of some variations which are possible.

The compounds of formula (I) wherein either (1) or both of R4 and R4 and a bilellabile ester armor group are prepared following similar procedures to those outlined above using the appropriate ester group for R4 or R4.

In the same manner as removal of any propionic group which may be present in R "; a number of chemical reaction reactions are possible on the monoester or diacid end products as previously described. In each case the product may be obtained as the free carboxylic acid or may be neutralized with a suitable base and isolated as the salt. Appropriate coupling and protrusion methods for all of the above steps and alternative variations and processes will be well known to those skilled in the art with reference to the standard textbooks and examples provided hereinbelow.

The spiro-substituted starting glutaric acid monoesters of formula (III) may be prepared as described in the European patent application 274234 ·. Amino acid esters of formula (d) are generally known compounds which are either commercially available or can be prepared by standard methods according to literature precedents.

As was previously mentioned, the compounds of the invention are potent inhibitors of neutral endopeptidases (E.3.3.4.24). This enzyme is involved in the decomposition of a number of peptide hormones, in particular it is involved in the decomposition of the airial nairiurético facior (ANF). Thus, by avoiding the degradation of ANF, through the endopeptidase E.C.3.4.24.1i, the compounds of the invention may potentiate their biological effects and the compounds are thus diuretic agents; natriuretic and antihypertensive agents useful in a number of disorders including hypertension; heart failure angina; renal insufficiency; premenstrual syndrome, cyclic edema, Meniere's disease, hyperaldosteronism (primary and secondary), and hyparcalciuria. In addition, because of their ability to potentiate the effects of ANF, the compounds have utility in the treatment of glaucoma. As a further corollary of its ability to inhibit the neutral endopeptidase EC3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including, for example, the treatment of asthma, inflammations, pain states, epilepsy, affective disorders, dementia, conditions (especially diarrhea and irritable bowel syndrome), modulation of gastric acid secretion, and in the treatment of hyper-reninemia. Acivity against endopeptidase E.C.3.4.24.I1 is evaluated using a procedure based on the assay described by J. Ϊ. Safford, R.A. Skidgsl, E. 6. Erdos and L .. 8. Hersh, B1.ochem 1, 1383, 32, 3265-3271. The method involves determining the concentration of the compound required to reduce the rate of release of the radiolabeled hippuric acid from hippuryl-L-phenylalanyl-L-arginine by 50% by means of a neutral endopsytid preparation from the kidney of rat

As mentioned above, the compounds of the invention are also inhibitors of the angiotensin converting enzyme. As far as they are useful in the treatment of a variety of other states for which ACE inhibitors are known to be useful including limiting ischemic damage to the myocardium, protecting the kidney against hyperphi1 damage prevention, or cancellation of left ventricular hypertrophy, improvement of memory, cognitive function control, dementia, and prevention of recurrence following coronary angioplasty or coronary artery bypass surgery. Its activity against this enzyme is evaluated using a modified procedure based on the assay described by Rohrbach, et al., Anal. Biochem., 1378, 84, 272. The method involves determining the concentration of the compound that is required to reduce the extent of the release of radiolabeled hippuric acid from hipuryl-L-histidine-L-leucine by of the angiotensin converting enzyme isolated from the rat kidney. Inhibitory activity is also measured in vivo following intravenous injection into anesthetized rats using the methods described by IL-Na, et al., Journal of Pharmacolial Methods, 1381, 5, 305 and by 0. M. Sross et al. al., J. Pharmol. Exp. Ther., 1981, 216, 552. έ determined the dose of inhibitor that is required to inhibit the vasoconspiratory response produced by intravenous injection of angiotensin I (50 ng æg in 50%.

The acidity of the compounds as diuretic agents is determined by measuring their ability to increase urine output and sodium ion excretion in conscious saline-loaded mice. In this test, male mice (Charles River CDI, 22--283) are acclimatized and fasted in metal containers. Mice are injected intravenously into the caudal vein, the issie compound being dissolved in a volume of saline equivalent to 2.5Âμ of body weight. The urine samples are collected one hour at a time for two hours in pre-weighed tubes and analyzed for electrolytic concentration. Urine volume and sodium ion concentration of test animals are compared to a control group which only received saline. The antihypertensive activities of the compounds are evaluated by measuring the following blood pressure drop by oral or intravenous administration to diuretic, spontaneously hypertensive, salt-deficient rats, to salt-deficient, renally hypertensive dogs, or hypertensive rats with DOCfi / salt.

For administration to humans in the curative or prophylactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds will generally range from 3-1500 mg per day for an average adult patient (70 kg >. Thus for a typical adult patient , individual tablets or capsules contain from 1 to 500 mg of the acyl compound in a pharmaceutically suitable carrier or excipient for single administration or in multiple doses once or several times a day Dosages for intravenous administration will typically range from 1 to 50 mg per In practice the physician will determine the actual dosage that will be most appropriate for a particular individual and it will vary.

with age, weight and response of that particular individual. The foregoing dosages are exemplary of the average cases but there may of course be instances where more or less high doses need to be administered, and such cases are within the scope of this invention.

For human use, the compounds of formula (I) may be administered alone, but in general they will be administered in admixture with a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or as elixirs or suspensions containing flavoring or coloring agents . They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenomic administration, they are best used under a. form of a sterile aqueous solution which may contain other substances, for example, sufficient salts or glucose to render the solution isotonic with blood.

The compounds may be coadministered with other agents as is beneficial for the control of blood pressure or for the treatment of cardiac disorders or renal failure. Thus the compounds may be coadministered with digitalis or with another cardiac stimulant drug or with an alpha blocker, a beta-bioqueador, exogenous AIMF or with a potassium ketal activator or other diuretic agent as determined by the physician as set forth suitable for the treatment of the patient and particular disease situation.

Thus in a further aspect the invention provides a pharmaceutical composition comprising a compound of formula C 1 > or a pharmaceutically acceptable salt thereof or a bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier. The invention also includes a compound of formula (I) or (II). " > , or a pharmaceutically acceptable salt thereof or a bioprecursor for that purpose, for use in medicine, in particular in the treatment of hypertension, CB.rdis.cs. congestive or renal failure in a human. The preparation of the compounds of the present invention and intermediates used in their preparation is illustrated by the following Examples. Thin layer chromatography was performed on silica plates using the following solvent systems: ethyl acetate, hexane, 1: 1. 1 Css 1); ethyl acetate, hexane, 1.38 (s, 2); methyl-isobutyl-ceiona, water, acetic acid, 2: 1); cyclohexane, hexane, 3.76 (4: 4), ethyl acetate (5: 5); diethyl ether (Cs 6); dichloromethane, methanol, acetic acid, 80: 20: 1 (Cs 7); diethyl ether, hexane, 1: 8); hexane, ethyl acetate, 4.1 CSS 9); or 1: acetic acid, water, 12: 3: Cs 10). EXAMPLE 1 Allyl-2-yl-2 (2H) -pyrrolidin-

A &lt; 3 &gt; (3.0 g, 12.38 mmol) in dry tetrahydrofuran (10 ml) was added to a stirred solution of lithium diisopropylammonium (26 mmol) ) in a mixture of hexane (10.4 ml) and tetrahydrofuran (45 ml) at -70 ° C under nitrogen. After 1 hour a solution of 2-iodo-1-ethoxyethane (4.95 g, 24.8 mmol) in dry tetrahydrofuran (.3 ml) was added, keeping the temperature at -70 ° C . After one hour at that temperature, the solution is allowed to warm to room temperature overnight and is left for an additional period of two days. The mixture was then acidified to pH 2 with 2N hydrochloric acid, and extracted with ether. The organic extract was washed with brine, dried (Na2 SO4) and the solvent evaporated to give the crude acid which was chromatographed on silica. Elution with increasing proportions of ethyl acetate in hexane <4 to neat ethyl acetate) gave an oil (2.5 g, 55%). Rf 0.15 (hexane, ethyl acetate, 4: 1).

Found; C, 65.10; H, 9.36.

The following compounds were prepared by the cleavage of 1-carboxy-cyclopentyl-propesnoic acid i-propionic ester using the appropriate bromo or iodo compound following the procedure of Example 1.

V, &quot;, J Example 2-y-Isolated Form T.L.C. The title compound was prepared from the title compound as a white oil, mp 258 DEG-30 DEG C. Analysis% (Theoretical in parentheses) CΗN 2 oil 64.43 8; 82 1 0 -OCH --Rf 0.3 / (64.02 9.05) (ss 1) 3 ch30 (gh2) 64.24 9.90 Rf 0.45 (64.49 9.74) (ss 1) 4 CH 30 CH 2 CH = CHCH 2 (CH 2) 2 oil 62.36 8.83 Rf 0.45 (62.62 8.95) (ss 1) (O-2 mole CH 2 Cl 2) 0.5 - - (ss 2)

BOC = i-butoxycarbonyl Fr 5 = dimethyl-t-butoxycarbonyl FXEMPI .0 3

(RS) -t-butoxycarbonyl-1-oxo-1,3-dihydro-1-carboxy

Thrombocyzinium azide &lt;0.79; carboxylic acid added as a solution in dichloromethane (1 ml) was added to a solution of 1-CSCF (S) -butyloxycarbonyl-10-bromodecyl, β-cyclopentane-carboxylic acid &lt; , 1.4 g, 3 mmol &gt; in chloroform. A few crystals of potassium iodide were added and the resulting mixture was refluxed for 2 days. The sculpture

was cooled. (20 ml), washed with water (2 x 20 ml), dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel using a gradient of ethyl acetate: hexane to give the title compound as an oil (0.63 g, 54%), c 53.84, H 3.41, N 3.22, requires C, 53.77 H, 3.43, N, 10.52%

Found; C21 H37 N3 O4, Rf 0.9 (ethyl acetate).

EXAMPLE 10 is in the presence of a compound of formula (I).

A mixture of 1- (2R) -8-t-butoxycarbonyl-4 "-peninyl) cyclopentane carboxylic acid &lt; EP-A-0274234, Example 44) (28.24 g, 0.1 mmol) and (O- pseudoephedrine was recrystallized three times from hexane to give a white crystalline solid (18.3 g, 42%) m.p. 105.5 ° C-107.5 ° C, 2F, ν ... + 20 (C = 1.07, methanol) The above salt was dissolved in ether and washed with 1N hydrochloric acid and saturated brine, dried (MgSO)), and evaporated to dryness. evaporation gave the required R acid as an oil (11.9 g). R, 0.7 (ethyl acetate, hexane, 1 L). Π ΐ ΐ * - -11.80C-35.50C (c = 1.03, methanol).

Ester, dg ...... feb (x, y) -car bon.1.1 -4-pentenyl 13-

Anhydrous potassium carbonate (13.5 g, 98 mmol) was added in one portion to a stirred, ice-cooled solution of 1 '(RS) -1-butoxycarbonyl-4'-methylpiperazine- (10.95 g, 38 mmol) and benzyl bromide (6.6 g, 38 mmol) in dry dimethylformamide (30 mL). After 3 hours the reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). The organic phase was separated and washed with additional portions of water (x 20 ml), hydrochloric acid (5 x 20 ml), brine (1 x 10 ml), dried (MgSO 4), and the filtered solution Evaporated to afford the title compound as an oil (14.14 g, 98%). This oil was used without further purification. 0.86 (ethyl acetate, toluene, 1.4). EXAMPLE 12 4-Oxobeu-3-carboxylic acid [1- (2-trifluoromethylphenyl) -1-

Osmium tetroxide (56 mg, 0.2 mmol) was added as a 2.5% w / v solution in i-butanol (2.25 ml) to a stirred solution of 1-benzyl ester (8.25 g, 22 mmol) in acetonitrile (60 ml) and water (10 ml) at room temperature. After 30 minutes, the brown solution was treated with sodium metaperiodate (10 g, 47 mmol) in one portion. Stirring was continued for 18 hours and then the suspended solid was filtered and washed with water, the small portion of acetonitrile. The filtrate was evaporated to the dark residue and was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to give the title compound as an oil (3.77 g, 45%). %). 0.58 (diethyl ether, petrol, 1N). (RS) -tert-butoxycarbonyl-3 (R) -hydroxy-

Lico.

Potassium permanganate (7.6 g, 48 mmol) was slowly added as a solution in water (48 ml) to a stirred solution of 1- [2 (RS) -t- butoxycarbonyl-4-oxobuid. (51 g, 12 mmol) in t-butanol (70 ml) and sodium dihydrogenphosphate (20 ml). The resulting mixture was stirred vigorously for 30 minutes. The excess oxidant was destroyed by the addition of solid sodium metabisulfite &lt; 8 g &gt;. The brown suspension was filtered, and the filter pad was washed with ethyl acetate (50 mL). The filtrate was separated into two phases and the aqueous phase was extracted with ethyl acetate (30 ml). The combined organic solutions were dried (Na2 SO4), filtered and evaporated to give the title compound as an oil (4.52 g, 36%). R0.7 (ss 5). To an ice-cooled solution of 4-t-butoxycarbonylaminomethylhexanecarboxylic acid (0.589 g, 2.74 mmol) in dichloromethane (0.5 g, 2.74 mmol) in dichloromethane was added 1-hydroxyphenyl azazoles (0.405 g, 31.02 mmol), 1-ethyl-3-dimethyl-3-aminopropyl-carbodiimide (0.634 g , 3.67 mmol) and N-methylmorpholine (0.360 g, 3.67 mmol) were added and the resulting solution was stirred at 0Â ° C for 30 minutes.The tert -butyl ester of NCI-O-methylpiperidine (S) -t-butoxycarbonyl-4-cyclopentaneconsulfonyl-O-t-butyl-C1-4-tyrosine was added to this solution and stirred at room temperature for 24 hours. the resulting oil was dissolved in ethyl acetate (50 ml) and washed with 2M hydrochloric acid (60 ml), saturated aqueous sodium bicarbonate (2 x 60 ml) and saturated brine (50 ml), dried (Na2 SO4) <W · filtered and evaporated to obtain The crude product is obtained in the form of an oil. Chromatography on silica gel using dichloromethane / ether diethyl ether. The eluent gave the title compound (1.635 g, 73%) as a white foam. 0.62 (dichloromethane, diethyl ether, 1: 1).

Found: C, 67.62; H, 8.47; N, 5.26. C44 H66 N8 O9 requires C, 67.76; H, 8.40; N, 5.33%.

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The following examples were prepared following the procedure of Example 14, using the appropriate carboxylic acid derivative of the formula: &lt; R10

0, C (S.

Example No - * 10 Isolated Form Analysis% (Theoretical in parentheses) T.L.C. * CHN 15 foam 69.21 8.70 5.65 <cV2ncyO- Rf 0.38 (69.55 8.68 5.93) (ss 3) 16 foam 67.57 8.22 3.94 CH3SCH2 -> V Rf 0.85 (67.25 8.08 4.02) (ss 5) 17 CH 3 SO 2 NH foam 58.52 8.00 5.39 (s): (58.78 8.13 5.56) - 18 CH 3 OCH 2 CH 2 OCH 2 foam 64.70 8.89 3.69 CH 3 CH 2 CHOCH 0.29 (64.37 8.96 3.66) (ss 5): Found: C, 65.78; 1, 2, 3, 4, 5, 6, 8, 8, 9, 10, 12, 13, ) -Thiophene-4-carboxylate (762 mg, 3.38 mmol) was added to an ice-cooled stirred mixture of 1- (626 mg, 1.93 mmol), O-methyl t-butyl ester (<8) was obtained as a white solid. (263 mg, 1.39 mmol) in dry methylene chloride (M-methylmorphs &lt; 0.44 mL, 3.38 mmol) 10 ml). After standing at room temperature for 16 hours, the mixture was diluted with methylene chloride, washed with water, dried (Na2 SO4) and evaporated under reduced pressure to give an oil. Chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate (4: 1) gave the pure diester (375 mg, 83%) as an oil.

Found! C, 67.54; H, 8.74; N, 2.1.3. C8 H49 N07 • 0:28 HPr. Cm-1: C, 67.42; H, 3.03; N, 2.53%. i.xi.gkoe, .20z.2a

The following examples were prepared as described hereinbefore using the appropriate cyclopentane carboxylic acid of Examples 1-6 and 8-10 in the coupling step together with the title compound. amine of formula (IV).

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EXAMPLE 30 Sodium-4-oxo-4-oxo-2-methyl-3-oxopentane-carfonate (882 mg, 2.08 mmol) was added to a stirred solution of the diester of Example 28 (832 mg, 1.6 mmol) in dichloromethane in 2-methoxyethanol (4 ml) After 20 hours at ambient temperature, 2% sodium hydroxide (3.6 ml) was added followed by potassium iodate (2.3 g, 17.0 mmol) dissolved in water < The mixture was diluted with water, extracted with diethyl ether, and the extract washed with water. Drying over MgSO4 and evaporation gave an oil, which was dissolved in carbon tetrachloride. The mixture was then filtered, evaporated under reduced pressure and the residue chromatographed on silica, eluting with a mixture of diethyl ether and hexane (4: 6) gave the title product as a colorless oil. of an oil (820 mg, 51%), 0.35 (diethyl ether, hexane, i.e.). The title compound was prepared according to the procedure described in Example 1. The title compound was prepared from Example 25 using the procedure of Example 30 above. The product was obtained as an oil (57% yield). 0.28, (diethyl ether, hexane, 1.1).

Found: C, 55.80; H, 6.39; N, 1.32. IR (KBr): requires: C, 55.23; H, 7.30; N, 1.35.

(S) -Ct-butoxycarbonyl) -4- (S-methylethyl) -1H-imidazo [1,2-a] pyrimidin-4-yl] (0.5 g, 1.86 mmol) was added to a solution of the title compound as a white solid. iodo compound of Example 30 &lt; 580 mg, 0.78 mmol) in dry tetrahydrofuran <10 mL). After heating at 50Â ° C for 16 hours, the solution was diluted with diethyl ether, washed with dilute potassium fluoride solution (<4) and then with saturated salt solution. Drying (MgSO4). and evaporation under reduced pressure gave an oil which was chromatographed on silica. Elution with a mixture of diethyl ether and hexane &lt; 1! 1 &gt; gave the required product as an oil (41.0 mg, 83%). Rf 0.32 (ether / hexane = 1). C, 68.00; H, 8.25; t, 2.25. Found: C, 68.21; H, 9.38; N, 2.21%

EXAMPLE 33 N-Cl- (2 (S) - [tert-butoxycarbonyl-1-tert-butyl ester]). -4- (2-methoxyphenyl) -2- S.) -1 i r 05 i na

A solution of the iodo compound of Example 31 &lt; 430 mg, 0.6 mmol) in ethyl acetate &lt; 30 ml) containing triethylamine (67 mg, 0.66 mmol) was hydrogenated over 10% palladium on charcoal at room temperature environment and the pressure of SO psi &lt; 3.45 bar). The mixture was filtered, the solvent evaporated and the residue chromatographed on silica gel to give the title compound as an oil &lt; 300 mg, 35%) E, 0.2 &lt; hexane, 1: 1. EXAMPLE 34 (1) Compounds of the general formula (I) are prepared by the following steps: (a) (b) - one. a) Mercuric acetate (737 mg, 2.5 mmol) was added to a solution of d. (1.14 g, 2.21 mmol) in dry methanol (5 mL). After stirring at room temperature for 2 hours, 2N sodium hydroxide (5.5M) was added followed by potassium iodide (1.83 g, 11.05 mmol) dissolved in water (2.5 mL). Water was added and the mixture was extracted. gives. with ether. The organic extract was washed with water, dried (MgSO4) and evaporated to give an oil, which was dissolved in carbon tetrachloride. Iodine (558 mg, 2.2 mmol) was added and after stirring at 0 ° C under nitrogen for 1.5 hours, the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with a mixture of diethyl ether and hexane (4: 5) to give N- [1- (2 (S) - (t -butoxycarbonyl) -5-iodo-4-methoxypentene. 1-cyclopentanecarbonyl-3- (3) -O-methyl-tyrosine as an unstable oil (1.27 g, 85%). Rf 0.37 (diethyl ether, hexane, 1: 1) which was used in the next step. ) A solution of the above iodide &lt; 620 mg, 0.92 mmol) and imidazole (627 mg, 9.2 mmol) in acetonitrile (12 mL) was refluxed for 24 hours. Evaporation of the solvent under reduced pressure gave a gum, which was chromatographed on silica. The elution with an ethanol ethylester and ethyl acetate < 1 ; 19 &gt; gave the title product as a yellow oil. (Ethanol, ethyl acetate, 9 g.

Found; Found: C, 66.05; H, 8.22; N, 6.80. C34 H5 N3 O7 requires C, 66.53; H, 3.37; N, 6.85%

The bromo compound of Example 23 was dissolved in dichloromethane (50 ml) and the title compound (1.2 g, 1.88 mmol) and morpholine (650 mg, 7.5 mmol) were heated at 50 ° C in dimethylformamide (15 ml) containing potassium iodide (120 mg). After 20 hours, water was added and the mixture was extracted with ethyl acetate. Washing with water, drying (MgSO4) and evaporation gave an oil (1.2 g) which was chromatographed on silica. Gradient elution starting with dichloromethane, ethyl acetate (7: 3) to pure ethyl acetate and finally ethyl acetate, ethanol (35%) gave the required compound as a gum (1: 0 g> Rf 0.3 (hexane, diethyl ether, 1: 1).

Found! C, 68.10; H, 9.50; N, 4.14. CHHHKK] requires C, 68.03; R, 9.37; N, 4.30%

The title compound was prepared from the title compound as a white solid, mp 218-221øC. 1 H NMR (DMSO-d 6):?

Fosgánio (72 mg, 0.7 mmol) as a 1.2.5% w / v solution in toluene (0.6 ml) was added in one portion to a stirred and cooled solution of diethylamine (85 mg, 65 mmol) and N -methylmorinoline (73 mg, 0.7 mmol) in methylene chloride (10 mL). After stirring at 0 ° C for 4 hours, nitrogen was bubbled through the solution to remove excess phosgene. To this solution at room temperature was added N-methylmorpholine (73 mg, 0.7 mmol) and N- (3-aminopropyl) -2-2- (3-methoxybutoxy) carbonyl) -1-cyclopentanecarbonyl-3-tert-butyl- (S) -pyrimidine (360 mg, 0.65 mmol) as a solution in methylene chloride (3 ml). After stirring at room temperature overnight, the solvent was evaporated and the residue was dissolved in ethyl acetate (100 ml).

This solution was washed with water (2x5ml), hydrochloric acid, 1.H (2x5ml), saturated sodium bicarbonate solution (1x5ml), brine (1x5ml), dried (Na2 SO4) , filtered and evaporated. The residual oil was chromatographed on silica gel using a gradient of methylene chloride and methanol saturated with aqueous ammonia. the title compound was obtained as an oil (32 mg, 32%). R, 0.67 (ethyl acetate). EXAMPLE 37 of 2 (RS) -1-butoxycarbonyl-3- [4- ~ p i -

E. &Lt; / RTI &gt; &lt; / RTI &gt; -1. i-LSãinã. a) The 4-pipsridone was coupled to the benzyl ester of α-C2 (RS-i-butoxycarbonyl-3-carhoxymethyl-1-cyclopentanemicarboxylic acid (Example 13) using The title compound was prepared as in Example 14 (a) to give the title compound as a white crystalline solid.1H NMR (CDCl3) cyclopentane-carboxylic acid. b) The above compound was dissolved in a similar mixture of water (3 x) and hydrogenated at room temperature under an atmosphere of hydrogen (60 p.s., 4.1 bar) over 10% palladium on carbon for 3 hours. The reaction mixture was filtered, the filtrate evaporated to dryness. The residue was subjected to azeotroping with dichloromethane to provide 3- (4-keto-1-piperidin-1-yl) carbonyl) -propyl] -1-cyclopentane carboxylic acid as a foam, 0.21 g (ethyl acetate).

Found: C, 62.42; H, 8.02; N, 3.67. C34H50N2U8 Γ cr; L-100 C 62.37; H, 8.13; N, 3.67%. c) The above acid was coupled with the o-methyl ester of O-methyl- (3) -irosine following the procedure of Example 13 to give the title product as a foam, 0.71 (ethyl acetate). 43

EXAMPLE 3S Ester ......... of .......... of ...... NHIJ · - (2 <RS) - t-butoxycarbonyl. 4-hydroxy-1 - [[1-cyclopentyl] carbamoyl] methyl] -1,2,3,4-

Hydrochloric acid (4M) was added to an ice-cooled solution of (R) -1- (RS) -1-phenoxycarbonyloxy-3-4- (1-piperidyl) carbonyl (400 mg, 0.6 mmol) in ethanol (3 ml) and water <1 g (1 mmol) ; 2 ml) was added to adjust the pH of the solution to between 4 and 6. Further eanol was added as needed to keep the solution homogeneous. To the above solution was added sodium cyanoborohydride &lt; 45 mg, 07 mmol) in one portion. The resulting mixture was allowed to warm to room temperature overnight. Ethanol was evaporated and the aqueous residue partitioned between ethyl acetate &lt; 20 ml) and water &lt; 20 ml). The organic phase was separated and washed with water (1 x 10 ml), 1M hydrochloric acid <2 x 10 ml), saturated sodium bicarbonate solution <1 x 10 ml), brine <1 x 10 ml) , dried (Na2 SO4), and filtered. 0

The filtrate was evaporated and the residue was chromatographed on silica gel eluting with a gradient of ethyl acetate and hexane to give the title compound as a gum <160 mg, 33%). R <0.23 <ethyneacetate). 44 gXEnPL.RTM. 39 ESSIL-__ kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn kn (1-propyl) -1-chloropentano-3 (S) - &quot; tyrosine

Sodium cyanoborohydride (60 mg, 0.03 mmol) was added in one portion to an ice-cooled stirred mixture of tert-butyl (2 (R) -t-butoxycarbonyl, 1-3- (S) -triresin (550 mg, 0.9 mmol) in dichloromethane (5 ml) was added dropwise, of Example 37, anhydrous sodium acetate (730mg, 9mmol) and dimethylamine hydrochloride (360mg, 4.5mmol) in dry methanol (100ml) was added dropwise.The mixture was allowed to warm to room temperature After 24 hours, The organic layer was separated and washed with water (1 x 10 mL), saturated sodium bicarbonate solution (2 x 10 mL), and extracted with ethyl acetate (50 mL) 15 ml), brine (1 x 10 ml), dried (MgSO 4) and filtered. The filtrate was evaporated and the crude residue was chromatographed on silica gel to give the title product as a white solid. gum (313 mg, 54%), Rf 0.32 (ss 3) .alpha.-oxime ester of ...... t-bu (N-α-CC-C &-C &-C &-C &-C &-C &-C &-C &-C &-C &-C &-C &-

To a stirred solution of N, N-diisopropylethyl ester (8 g), was added 90% Mstachloroperoxyphossoic acid (0.29 g, 1.5 mmol) in one portion (S) -thiomorphine (Example 16, 0.33 g, 0.01 mole) in dichloromethane 0.5 mmol) in t

The solution was allowed to warm to room temp. overnight, the solvent was evaporated and the residue was dissolved in EtOAc (2 ml). This solution was cooled to 0 ° C. washed saturated sodium bicarbonate solution <2x10 ml)? aqueous solution of 1% sodium carbonate (1 x 10 ml), brine (1 x 100 ml), dried in vacuo, and evaporated to give the title compound as a foam white (0.39 g, 100%) = R * 0.66 (ethyl acetate)

Found: C, 63.21; H, 7.4; M = 3.45, 58 = C4 H5 NNR * • 09S * H2 O = C5 63 = 13? B, 7.94; N, 3, 8% = t-butyl, from ____N-ti- <2 < S) -t-butonicarnbonyl-3- (2 (3) -methano-tagosulfonyl) -propionamide. -carbonylethyl-S-f-butyl I - &lt; S) -ethylamine The title compound was prepared from Example 17 by oxidation with methanoperoxybenzoic acid following the procedure of Example 4, which was obtained in the form of a solution of ethyl acetate: =

Found: C, 59.9; H, 7.47; N = 5.58. ^ requires C, 50 = 39; Hs 7.8®? N, 5.33% (t-Butoxycarbonyl) -4- (4-hydroxymethyl) propyl] amino] -2- (t-butoxycarbonyl) -4- (4-hydroxymethyl)

Tetrabutylammonium fluorate was added in (2.1 g) at 1 ° C under nitrogen to a stirred solution of the product of

Example 29 (800 mg, 1.08 mmol) in tetrahydrofuran (10 ml).

After stirring at r.t. for 2 hours, the mixture was partitioned between ethyl acetate, washed with 0N hydrochloric acid followed by water, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, with increasing proportions of ethyl acetate in hexane (from 3.7 to 1: 1) to give a clear oil (610 mg, 30%). , ethyl acetate, 1.1 g, 63.47, H, 8.01, N, 2.31, c, 63.03, H, 8.21, N, 2.24%

Found requires:. <B b 1 ·.:? EXAMPLES AND CHARACTERISTICS OF THE INVENTION

Di-t-Butyldimidicarboxylate (333 mg, 1.03 mmol) and tr. (402 mg, 1.53 mmol) at .1.0 ° C under nitrogen was added dropwise to a stirred solution of the product of Example 42 (640 mg, 1.023 mmol) in tetrahydrofuran (30 mL). (0.24 ml, 1.03 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise and the mixture was stirred for 20 hours at room temperature. The mixture was then evaporated to dryness, the residue was pre-absorbed on silica and chromatographed. Elution with increasing proportions of ethyl acetate in hexane (from 5.35 to 114) afforded the required product as a clear gum (166 mg, 20%), 0.55 (hexane, ethyl acetate, ! i &gt;.

Trifluoroacetic acid (3.5 ml) was added to a solution of 4-C2-methoxysilyloxy) pentyloxy-N, N-diisopropylsulfonyl- Tyrosine Ca from Example 32, 330 mg, 0.62 mmol) was added as a white solid. and anisole C 33 S mg, 3.2 mmol) in dry methylene chloride (0.5 ml). After standing at 0 ° C overnight the solution was evaporated to dryness under reduced pressure and azeotroped with toluene. The residual gum was dissolved in ether and the product was extracted with sodium hydroxide (10 ml). The basic exchanger was then acidified with concentrated hydrochloric acid, saturated with salt and extracted with ethyl acetate. Wash with brine, dry CH₂Cl₂) and evaporation gave

a glass. which was crushed to give a powder (275 mg). 0.52 (ss 7). Found: C, 61.18; H, 7.521; N, 2.33. c24h35no8. 0, 1 ΟΗ ΟΟ ΟΟ ΟΟ Ο Ο Ο Η Η requer requer. 0.25 H2 O: C, 61.20; H, 7.54; N, 2.32% EXAMPLES 45-53

The following compounds were prepared from the corresponding t-butyl ester derivative of O-methyl or O-tert-butyroline, where appropriate by treatment with trifluoroacetic acid following the procedure of Example 44. Examples 43 , 50, 52, 53 were purified by means of ion exchange chromatography using Dowex AS SOW-X8 resin and eluting with &amp;% aqueous pyridine. Exims Si and 52 are the summers 28.

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The title compound was prepared as a white solid, mp 218-221 ° C. 1 H NMR (CDCl3): νmax-1-carboxylic acid The resulting solution was cooled with toluene-2-carboxylic acid tert -butyl ester (3: 1) to give (4-methoxyphenyl) -pyrimidin-4-yl) -pyrimidin-4-yl) -pyrimidin-4-yl} -cyclopentane-2-carboxylic acid tert-butyl ester ) until saturation is reached. The resulting solution was allowed to stand overnight at 0 ° C. The solvent and excess hydrogen chloride were evaporated under reduced pressure and the residue partitioned between ethyl acetate (19 ml) and saturated sodium bicarbonate solution (2 x 5 ml). The combined aqueous extracts were washed with ether (2 x 5 ml) and acidified to pH 3 with concentrated hydrochloric acid in the presence of ethyl acetate (15 ml). The acidic layer was separated and dried with ethyl acetate (5 ml). The combined organic solutions were dried (MgSOâ, "), filtered and evaporated to give the title compound as a white solid &lt; 140 mg, 78%).

Found; C, 47.32; H, 5.86; N, 6.39. C₂HHNNN₂O1N₂S · 0.75 H₂O requires C, 47.71; H, 6; 17; N, 6.68%.

The following compounds were prepared from the corresponding t-butyl protected compounds by treatment with hydrogen chloride following the procedure given in Example 54.

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(S) -Car-carboxy-3-methoxy- 1: 1). Zn, Zn, Zn,

An ice-cooled solution of the diester of Example 28 (1.4 g) and snisole (3.0 g) in dry methylene chloride (20 ml) was saturated with hydrogen chloride gas. After 30 minutes the mixture was left The residue was chromatographed using silica gel and eluted with dichloromethane, methanol, acetic acid (95: 5: 0.51) to afford the title compound as a white solid. The product was dissolved in ethanol (2 ml) and dioxane (2 ml) was hydrolyzed with 1N sodium hydroxide (6 ml). After standing at ambient temperature for 2 hours at least one portion of the solvent was evaporated under reduced pressure, water was added, the mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate.Routing with water, drying (MgSO4) and evaporation gave the title compound as a white solid of an oil, E. 0.18 (bs 7%).

Found: C, 60.45; H, 7.43; N, 3.36. Example 1 For C 20 H 20 N 3 O requires C, 60.58; H, 7.40; N, 3.07%. X * 2! EXAMPLE 65 N-C1- (2 (PS) -carbonyloxy) -1- (O-azidodecyl) -1-cyclopentane-3-one. . The title compound was prepared by partitioning. of Example 7 by treatment with hydrogen chloride followed by alkaline hydrolysis following the procedure of Example 64 above. the product was. obtained as a gum. 0.73 (ss 3). EXAMPLE 65 (Â ±) -L-Amino-2 (R) - (-) - The title compound was prepared from the acid derivative of Example SS by means of hydrogenation, following the procedure of Example 37 (part b). The product was obtained as a foam. Rf 0.1, S3 (ss 3).

Found! C, 64.10; H, 8.49; , 4.73. C. C, 64.30; H, 8, Si; H, 5.8. ΕλΟ! Ε1 · 0..67. N '- (2-Carboxy) -3' - (4'-methanesulfonylmethyl) benzoylamino] propyl] -3- (3-methoxyphenyl) To a cooled solution of sodium metaperiodate (39.0 mg, 0.18 mmol) in water (2 ml) was added to γ-E1 · (4-methylamino) benzoylamino] propyl] carbonyl] oxy] butyldimethylsilyloxycarbonyl] oxy] ethyl] (87 mg, 0.16 mmol) as a solution in methanol (3 ml) was added methanol as necessary to give a homogeneous solution.The reaction mixture was allowed to stir at 0 ° C methanol was evaporated and the aqueous residue diluted with water (5 ml), saturated with solid sodium chloride and extracted with ethyl acetate (6 x 5 ml) .The combined organic extracts were dried ( Filtered, and evaporated to give the title compound as a white solid (71 mg, 80%). 3).

Found! Found: C, 57.07; H, 6.26; N, 4.54. 0.25 H2O requires C, 56.75; H, 6; 15; N, 4.63%

EXAMPLE 3 3-4-Methoxypent- A) The procedure of Example 34 was followed but using N-methylpiperazine in step (b). (4-methyl-piperazin-1-yl) -4-methoxy-4- (4-methylpiperazin- (S) -tyrosine as a gum 0.19 (methanol, dichloromethane, acetic acid, 10130; 1 H-NMR (CDCl3):?

Found: C, 67.01; H, 3.12; N, 6.42. 1.36. 53.33. Requires C, 66.35; H, 3.21; N, 6.51%. B) Deproportionation of the above diester trifluoroacetic acid following the procedure of Example 44, followed by ion exchange chromatography gave the title diacid as a white powder. Rf 0.15 Css 3 &gt; .

Found: C, 62.68; H, 8.37; N, 7.76. To a solution of t-butyl 2-bromomethylacrylamide (2.0 g, 9.00 mmol) in 2-methoxy oxime (30 ml) at room temperature was added potassium carbonate (2.69 mmol, 18 mmol) in one portion and the mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with distilled water (100 ml) and extracted with dichloromethane (100 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2 x 50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with ethyl acetate / hexane to provide t-butyl S-methoxyethoxy-S-methoxyethoxymethyl-propionic acid as a yellow oil (1.947 g , 74%). 0.33 (ethyl acetate / hexane-1).

Found: C, 57.67; H, 9.85. Requires C, 57.51; H, 9.55%. b &gt; T-Butyl β-methoxyethoxy &quot; -2-methoxyethoxymethyl-propionate (1.60 g, 5.47 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0 ° C. The solution was saturated with hydrogen chloride and stirred for 3 hours at 0 ° C. Evaporation of the solvent under reduced pressure gave the title compound as an oil (1.292 g, 100%). requires

Found; C10 H20 O6 · -07 CH2 Cl2 C, 49.90; H, 8.41. C, 49.93; H, 8.38%. PREPftRAkgO ....... 2

4 = 12, 1, 2, 3, 4, 5, 6, 8, A solution of 4-methoxybutanoyl iodide (3.64 g, 34.3 mmol) in dry tetrahydrofuran (<20 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride &lt; 1 g, 34.3 mmol, 80% dispersion in oil) in dry tetrahydrofuran &lt; 8 ml) keeping the temperature at 10 ° C. The resulting mixture was stirred & The reaction mixture was stirred at room temperature for 1 h, cooled to 10 ° C. 1,3,2-dioxathioane-2,2-dioxide (4.77 g, 33.4 mmol) in dry tetrahydrofuran (30 ml) was added. After a final stirring of 1 hour, solid sodium bicarbonate (7 g) was added with stirring at room temperature to afford the title compound as a white solid (0.25 mL, 34.3 mmole), followed by cooling with concentrated sulfuric acid. The residue was partitioned between ethyl acetate and saturated saline.The organic extract, after washing with brine, dried (MgSOâ, "), dried (MgSOâ,") and evaporated to dryness &gt; and evaporation gave 2- (4-methoxybutyloxy) ethane (4.54 g, 88%), Rf 0.25 (hexane, ethyl acetate, 1: 1).

Found! C, 54.38; H, 10.55. C_H1 ... 0 ...,. 0.25 Η, -. 0 requires C, 55.06; H, 10.83%. b) 4-Methoxybenzenesulfonyl chloride (17.52 g, 31.30 mmol) was added to a stirred, ice-cooled solution of the alcohol of part (a) (4.54 g, 30.63 mmol) and N-methylmorpholine Cio, 44 mL, 94.36 mmol) in dry methylene chloride <100 mL). After standing at 0 ° C for 20 hours, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica eluting with increasing proportions of ethyl acetate at 60 ° C.

hexane to give 4-methylbenzenesulfonium as an oil. c &gt; Was. To a stirred solution of the above product (7.31 g, 24.17 mmol) in dimethylacetamide (30 mL) was added sodium iodide (7.25 g, 48.35 mmol) and the After cooling, water was added and the product was extracted with ether. The organic extract was washed successively with water, dilute sodium thiosulfate solution and water, dried (MgSO4) and evaporated to dryness. evaporated to give the product as an oil (5.85 g, 94%), 0.45 (hexane, ethyl acetate, 1: 1).

Found; C, 32.23; H, 5.51. I0. requires C, 32.56; H, 5.86%. . ???????????????????????????????????????????????????????????????????????????????????????? The title compound was prepared from 4-hydroxypyridine-1-carboxylic acid t-butyl ester following the procedure of Preparation 2 and was obtained as a clear oil. Rf 0.4 (hexane, ethyl acetate, 4.11 g).

Found; Found: C, 40.94; H, 6.20; N, 3.33. Requires C, 40.58; H, 6.24; N, 3.34% PREPARATION 4 1-Chloro-2-iodo-4-methoxy-2-.beta.-a) Dimethyl-t-butyldipyloxy} ethanol (5.29 g, 30% yield) (20 ml) was added dropwise under nitrogen to a stirred suspension of sodium hydride (300 mg, 30 mmol, 80% dispersion in oil) in dry tetrahydrofuran (80 ml). After stirring at room temperature for one hour, 3-bromo-4-methoxy-2-huene (5.0 g, 300 mmol) in dry tetrahydrofuran (20 ml) was added dropwise with ice-cooling . The mixture was then stirred at room temperature overnight, cooled in ice, and ether (100 ml) was added, followed, sequentially, by water (100 ml). The organic phase was washed with water, dried (Na2 SO4) and evaporated to the crude product which was chromatographed on silica. Elution with a mixture of hexane and ethyl acetate (3: 1) gave a pale yellow volatile oil (4.6 g, 53%).

1M Tetrabutylammonium fluoride in tetrahydrofuran (33.7 mmol) was added to a stirred, ice-cooled solution of the previous product (4.39 g, 16.33 mmol) in tetrahydrofuran ( After stirring at room temperature overnight, ether was added and the mixture was washed with 0.1 N hydrochloric acid and water.The aqueous washings were saturated with salt and extracted with ethyl acetate (3 x 3.00 The combined organic extracts were washed with saturated brine, dried (MgSO,), and evaporated to a yellow oil (30.8 g). Chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (1: 1) gave 2- (4-methoxy-2-butenoxy) ethylene as an oil (3.53 g, 85%), 0.34 (hexane , ethyl acetate, 313). The above product was reacted with 4-methylbenzenesulfonyl chloride, followed by sodium iodide, following the procedure of Preparation Kta). to give the title compound as a pale yellow oil. RE 0.34 (hexanes, ethyl acetate, 1.1).

Found; C, 32.47; H, 5.04. C..H..0 ..., 7 requires C, 32; 83: H, 5.12.

4-hydroxytetrahydropyran (8.0 g, 70.33 mmol) was saturated with hydrogen chloride gas at øC, was added 5-chloro-4- was added with stirring, and hydrogen chloride was introduced for an additional 4 hours. The resulting sediment was then diluted with an ether-hexane mixture (hexane, 0.50 ml), dried over MgSO4 and the solvent was evaporated under reduced pressure. Distillation gave a clear oil, eg 100-110 ° C / 10 torr 0.3.3 pa>, which was used directly. PREPARATION 6 (-) - (2-Iodo) ethoxy) -4- (diterti-1-t-butylsulfonylmethyl) benzene Alpha, 4-bis (Pimethyl-1-t-butylsilyloxy) toluene.

Imidazols (43.34 g, 0.724 mol) and dimethyl t-butylsilyl chloride (54.62 g, 0.362 mol) were successively added under nitrogen at 1 ° C to a stirred solution of 4-hydroxy- (0.1 g, 0.121 mol) of dry dimethylformamide (55 ml). After stirring at room temperature for 24 hours, water was added and the mixture was stirred for 1 hour. extracted with ether. The extract was washed with water, dried (MgSO4) and evaporation gave an oil, which was chromatographed on silica gel. The hexane solution is then .; with a mixture of ether in hexane (.5: 35) gave the desired product; to a clear oil (36.35 g, 85%). b &gt; 4ζ1Ρ1πιιΜΙτι1 ^

(4-fluorophenyl) amide (76.85 ml) was added dropwise at 0 ° C to a stirred solution of the product of part (a) (27.1 g, 76.8 mmol in dry tetrahydrofuran (1.00 ml) After a further 30 minutes a solution of ammonium chloride was added and the mixture was extracted with ether The extract was washed with water, dried (MgSO 4) 4 Chromatography on silica gel, eluting with increasing proportions of ethyl acetate in hexane gave the required product as a clear oil (4.4 g, 23%). hexane, ethyl acetate, 4: 1).

Found; C, 64.26; H, 3.57. C, ..., ..., ..., θi. 0.25 H2O requires C, 64.28; H, 3.34%. 1, 2, 3, 4, 5, (2-methoxyphenyl) -4- (dimethylamino) ethyl] -1-oxazolidin-1-yl]

Sodium hydride (5.15 mg, 17.6 mmol, 80% dispersion in oil) was added under nitrogen at room temperature to a stirred solution of the phenol. of part (b) (4.03 g, 17.16 mmol) in dry dimethylformamide (30 mL). The mixture was warmed to 30 ° C for 30 minutes, cooled and 2- (4-methyl-1-benzenesulfonyloxy) -ethioethane (3.11 ml , 17.16 mmol). The mixture was then reheated to 60 &lt; JC for 3 hours, cooled, diluted with water and extracted with ether. The organic extract was washed with water, dried (MgSO4) and the solvent was evaporated under reduced pressure. Chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (1: 9) gave the required compound as a waxy solid (2.48 g, 47%).

Found; C, 59.64; H, 8.19. Found: C, 59.87; H, 8.37%. x -. · λ * '. d) 1- (2-methoxyethoxy) -4- (1-methyl-1-thienyl) oxime 1) - Μώεμώω.

A mixture of sodium iodide (2.44 g, 16.28 mmol) and the chloro compound of part (c) (2.45 g, 8.14 mmol) was refluxed in acetone for 3.5 days. The residue was chromatographed on silica gel, eluting with a mixture of ether and hexane (1: 1). The residue was partitioned between ethyl acetate and dichloromethane. The title compound was obtained as a white solid (2.71 g, 85%) as eluent to afford the title compound as a white solid (0.8 g, 85%). The title compound was prepared from the title compound as a white solid, mp 218-221øC. 1 H-NMR (CDCl 3):? a) To an ice-cooled solution of 1- (2-t-butyloxycarbonyl-3-dibenzylaminopropyl) -1-cyclopentane carnoxylic acid (12.7 g, 27 mmol) in dry dichloromethane (100 ml) was 1-hydroxy-benzotriazole (4.2 g, 31 mmol), and 1-ethyl-3-dimethylaminopropyl) -carboxamide (7 g, 36 mmol) was added and the resulting solution was stirred at r.t. 0C for 30 minutes. To this solution 65 was. of O-t-butylamine (0.81 g, 28.6 mmol) and t-butylmorpholine (5.25 g, 52 mmol) were added. allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the resulting mobile oil was dissolved in methylene chloride and washed with

water (2x), 2M hydrochloric acid and saturated sodium bicarbonate solution (1x), dried (H2O3), and the solution filtered and evaporated to give the crude product as a gum. Recrystallization from n-hexane gave N-α-1- (2-t-butyloxycarbonyl-3-dibenzylaminopropyl) cyclopentanecarbonyl-3-tert-butyl ester -8,8 '' tyrosine as a solid (13 g, 69%); mp 82-87 ° C. An additional batch of material was obtained by evaporation of supernatant liquids and subsequent recrystallization.

Found: C, 74.12; H, 8.69; N, 3.87. Câ, â, ... Hâ, â, ‡ Oâ, "requires C, 74.34; H, 8.59; N, 3.85%. b) t-Butyl ester of methyl 1- (2-i-butyloxycarbonyl-3-dibenzylaminopropyl) -1-cyclopentanecarbonyl-O-t-butoxy- (g) was dissolved in a mixture of ethanolic water (8: 1, 300 ml) and hydrogenated under a hydrogen atmosphere (60 psi, 4.1 bar) at room temperature over argon hydroxide 20% palladium on carbon (2 g). After 24 hours, the solution was filtered through a pad of Solkafloc, and the filtrate was evaporated to give an oil, which crystallized. This was triturated with hexane, cooled and filtered to give a pure (6 s, 42%) pure pyranomer (M.P. 122: -127Â ° C. in under and Found! Found: C, 67.90; H, 9.33; N, 5.08. C 31 H 10 N 2 O 6, SqUS C, 68.09; H, 9.22; N, 5.12%.

Claims (1)

IS Claims. A process for the preparation of a compound having the formula &lt; I &gt;; ? R "-y. (I) A is a 5 or 5 membered carbocyclic ring which may be saturated or unsaturated. V is an alkylene group of from 1 to 9 carbon atoms, which may be straight chain or branched; R "is H or C1-4 alkyl; R4 are each independently H, C1 -C4 alkyl, C1 -C4 cycloalkyl, benzyl, or an ester forming biolabile alternative group; R4 is hydroxy, C1-6 alkoxy, hydroxy, C1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, R 1, R 2, R 3, R 4, R 5, R 4, R 5, R 4, , CR *>, Na 1 queni 1 oxy &lt; tb &gt;, &lt; / RTI &gt; C "-C, &gt;-Z-; aryl-Z-, wherein Z is O; SCO) or NCR5) and n R6 'is H, C1 -C7 alkyl) or C1 -C4 aryl (C1 -C6) alkyl; R 1 is a group of the formula wherein Y may also be a direct linkage and wherein; R1 is C1-6 alkyl, C1-6 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, (C1 -C6) alkoxy, or aryl, and R4 is (C1 -C4) alkoxy, (C1 -C6 alkoxy) alkoxy, hydroxy-alkoxy (Câ, -Câ, ...) or a hydroxyalkyl group is a group of the formula wherein: R 'is a group .tp. or any of which may optionally be substituted by 1 to 1 substituents selected from the group consisting of halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, halogen, , is a group of the formula wherein R 1 and R 2 are as previously defined, and R 2 is (R 1 -) - (C1 -C4) alkoxy, (C1 -C4) alkyl, R2, R3, R4, R4, R4, & Substituted phenyl wherein the substituent is CR 1 -C 8 -alkyl, - (C 1 -C 4 -alkyl) - or C 1 -C 4 -alkyl 4 (S) - (4-SCO) - (Cal-C--C)) alkenyl group is a group of the formula; * er * what! R &quot; '&quot;' is H; balloon, 4-OH, 4-alkoxy ("Cp); 4-cycloalkoxy (C 1 -C 7 -1; 4-alkenyloxy); (C1 -C6) alkoxycarbonyl, (C1 -C6) alkoxycarbonyl, (C1 -C6) alkoxycarbonyl, or C1-6 alkoxycarbonyl, and Râ, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â, â,, â, or R '&quot;' is a group of the formula: -CU 7 wherein said groups may be factually substituted on the benzene ring condensed with (C1 -C4) alkyl. C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, (C -C-C_) alkyl group or the two R grupos groups are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, pentasaccharide or N-alkyl (C -C-C -C) (C 1 -C 6) -alkyl or C 1 -C 4 alkanoic acid, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl, R 2 and R 3 are as defined in claim 1 wherein R 1, R 2, R 3, R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 4) alkoxycarbonyl and C 1 -C 4 alkoxy (C 1 -C 4) alkoxy and C 1 -C 4 alkoxy is 1, 2 or 3, and a salt thereof Accordingly, the compound of formula (V) may be present in a pharmaceutically acceptable carrier. 1 o · '·' where A, Y and R &quot; are as defined anterchlorments, R &quot; &quot; and R '&quot; are as defined for FR &quot; s R &quot; ' with any reactive groups therein protected, if necessary, and R '! and are 4 such as ros. det: f.n: fdo for R and R 'excluding H, or are conventional carboxylic acid protecting groups; to a hydrolysis and / or hydrogenation and / or other deprotecting reaction in order to remove any protecting group present in R ': &quot; And either to remove both of R1 and R2 to provide the corresponding A compound of Formula (I). wherein K and R 'are both H, or to remove one of R' 1 'and to produce the corresponding - 70-1 Monoester product wherein one of R 1 and R 2 is H and the other is a bioa-cleyl ester-forming group; and a pharmaceutically acceptable salt of the product optionally forms. 2ã. A process according to claim 1, wherein R 1 is t-butyl and R 2 is t-butyl, said groups being removed by treatment with anhydrous trifluoroacetic acid or to yield the corresponding cyclic acid of formula (1), wherein R4 and R4 are both H. The process according to claim 1, wherein R 1 is t-butyl and R 2 is C 1 -C 4 alkyl, and said groups are removed by treatment with anhydrous trifluoroacetic acid or with chloride (I), wherein R1 and R2 are both H. A process according to claim 1, characterized in that the compound of formula (I) wherein R 1 and R 2 are hydrogen, R 2 is 4-hydroxybenzyl and the carbon atom to which it is attached is stereochemically (S>), or R 4 is 4-methoxyphenylene. The substituent R 1 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, (C1 -C6) alkoxy (C1 -C6) alkyl, - (C1 -C6) alkyl, - (C1 -C6) Wherein R 'is substituted phenyl and said substitutents are as previously defined in the formula i. Yeah. A process according to claim 1, characterized in that the compound of formula (I) produced is: / 1 - N * -III *, * *. * &gt; * Ϊ́ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ ΐ. C X C 1 The PCVF Τ · ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ ΊΟ m i N "- (2 (S) -carboxy-4-yloxybutyl) -cyclopentadecybromide-3 (S) -tetrahydrofuran-2 (R) (S) - (+) - aminodecyl) cyclohepentanecarbonyl: (S) - (+) -. 4 &quot; 1 ! (I.e. &gt; · · · · · s s s s s s s s s · · · · '! HOC-9-one. i, see & RUA VtCTOR CORDON, 10-A 3. «1200 LISBOA