IE920504A1 - Cyclopentane-derived glutaramide antihypertensive agents - Google Patents

Cyclopentane-derived glutaramide antihypertensive agents

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Publication number
IE920504A1
IE920504A1 IE920504A IE920504A IE920504A1 IE 920504 A1 IE920504 A1 IE 920504A1 IE 920504 A IE920504 A IE 920504A IE 920504 A IE920504 A IE 920504A IE 920504 A1 IE920504 A1 IE 920504A1
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alkyl
ethyl
formula
methyl
compound
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IE920504A
Inventor
David Brown
Alan John Collis
John Christopher Danilewicz
Keith James
Ryszard Jurek Kobylecki
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Pfizer Ltd
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Publication of IE920504A1 publication Critical patent/IE920504A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of formula (I), wherein R<1> and R<2> are each independently H or a biolabile ester-forming group, and either or both of OR<1> and OR<2> may optionally be replaced by NH2; R<3> is (a), wherein R<5> is H or methyl, R<6> is H or halo, and n is O or 1; (b) CH2OR<7>, wherein R<7> is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, (C1-C4 alkoxy)C1-C6 alkyl, (C1-C4 alkoxy)C3-C6 alkenyl, (halo)C3-C6 alkenyl, (C3-C7 cycloalkyl)C1-C6 alkyl or (CF3)C1-C6 alkyl; (c) wherein, R<8> is CH2OH, CH2OCH3, OCH(R<5>)CH2OH or OCH2CH2OCH3 and R<5> is a previously defined; (d) or (e) (C1-C4 alkoxy)C3-C6 alkenyl or (C1-C4 alkoxy)-C2-C6 alkyl; and R<4> is H or hydroxy; and pharmaceutically acceptable salts thereof, are diuretic and natriuretic agents having utility in the treatment of hypertension, heart failure, renal insufficiency and other disorders.

Description

CYCLOPENTANE-DERIVED GLUTARAMIDE ANTIHYPERTENSIVE AGENTS This invention relates to a series of cyclopentyl-substituted glutaramide derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders, including hypertension and heart failure.
According to the specification of our European patent application 0358398, we disclose certain cycloalkyl-substituted glutaramide derivatives vhieh are inhibitors of the zinc dependent enzymes neutral metalloendcpeptidase (E.C. 3.4.24.11) and angiotensin converting enzyme. Thus these compounds have a dual pharmacological action by inhibiting two key enzymes involved in blood pressure control, which makes them particularly useful in the treatment of various forms of hypertension and associated cardiovascular disorders, e.g. congestive heart failure and glauccma.
The present invention includes further novel cyclopentylsubstituted glutaramide diacids which also possess said dual enzyme inhibitory activity. More specifically the invention provides biolabile (and thus prodrug) monoester, diester, monoamide, diamide and monoester-monoamide derivatives of the compounds, which have improved oral bioavailability profiles over those of the bioprecursors disclosed in EP-A-0358398. That is, after oral administration of the prodrugs disclosed herein, significantly enhanced systemic levels of the derived diacids are achieved. Without wishing to be bound by any particular mechanism of action, this is thought, at least in part, to be due to their improved resistance to breakdown by gastrointestinal enzymes, which allows the compounds to be more fully absorbed before —2— conversion to the active diacid species takes place. Ihe compounds are of the formula: 2 . · . wherein R and R are each independently H or a biolabile 2 ester-forming group, and either or both of OR and OR may optionally be replaced by Nt^; R3 is (a) θ R5 R . 6 . wherein R is H or methyl, R xs H or halo, and n is 0 or 1; (b) o^or7 , wherein R is C,- C3~Cg alkynyl, cycloalkyl, (C^-C^ alkoxy)C^-Οθ alkyl, (C^-C4 alkoxy)C^-C^ alkenyl, (halo)C3-C6 alkenyl, (C -C? cycloalkyl)C^-Οθ alkyl or (CF3)C]L-C6 alkyl; -3wherein R8 is CH25)CH2OH or 5 .
OCH_C3LOCH_ and R is as previously defined; (d) <*2 or (e) alkoxy) C3~C6 alkenyl or (C^-C^ alkoxy) C2~C6 alkyl; . and R is H or hydroxy; and include pharmaceutically acceptable salts thereof.
In the above definitions halo means fluoro, chloro, bromo or iodo. Alkyl groups having three or more carbon atoms, and alkenyl or alkynyl groups having four or more carbon atoms, may be straight or branched-chain.
The term biolabile ester-forming group is well understood in the art as meaning a group which provides an ester which can be readily cleaved in vivo to liberate the corresponding acid.
In the case of the compounds of formula (I), such biolabile mono- or diester prodrugs are particularly advantageous in providing compounds of the formula (I) suitable for oral administration. The suitability of any particular ester-forming group can be assessed by conventional in vivo animal or in vitro enzyme hydrolysis studies. Thus desirably, for optimum effect, the ester should only be hydrolysed after absorption is complete. Accordingly, the ester should be resistant to premature hydrolysis by digestive enzymes before absorption, but should be productively hydrolysed by, for example, gut-wall, plasma or liver enzymes. In this way, the active diacid is released into the bloodstream following oral absorption of the prodrug. —4— Suitable biolabile esters include alkyl, alkanoyloxyalkyl, cycloalkanoyloxyalkyl, arcyloxyalkyl and alkoxycarbonyloxyalkyl esters, including cycloalkyl and aryl substituted derivatives thereof, aryl esters, cycloalkyl esters, haloalkyl esters, oxoalkyl esters, dihydroxyalkyl esters including ketal derivatives thereof, pyridyl esters and [4-(5-alkyl or 5-ary 1-1,3-dioxolen-2onyl]methyl esters, wherein said alkanoyl or alkyl groups may contain from 1 to 8 carbon atoms and be branched or straight chain, said cycloalkyl groups may contain from 3-8 carbon atoms and said cycloalkanoyl groups from 4-8 carbon atoms wherein both are optionally benzo-fused, and said aryl groups are phenyl, naphthyl or indanyl optionally substituted with one or more C^-C4 alkyl, alkoxy or alkoxycarbonyl groups or with halo atoms.
. . Thus examples of R and R when they are biolabile ester-forming groups include C^-C^ alkyl, C5-C? cycloalkyl, (cyclohexy 1)alkyl, (phenyl) Cj-C3 alkyl, 1-(C2~C5 alkanoyloxy)C-^-C^ alkyl, 1-(C5~C6 cycloalkylacetoxy) C1~C4 alkyl, cycloalkylcarboxy)C^-C^ alkyl, l-(2-indanylcarboxy)C1-C4 alkyl, 1-(benzoyloxy) C-^-C4 alkyl, 3-phthalidyl, 1-(C^-C4 alkoxycarbonyloxy)C^-C^ alkyl, [4-(5-(0^-^ alkyl]-l,3-dioxolen-2onyl) ]methyl, acetonyl, indanyl and pyridyl.
Preferred biolabile ester-forming groups are methyl, ethyl, (3-cyclohexyl)propyl, (3-phenyl)propyl, pivaloyloxymethyl, 1(cyclohexy lacetoxy) ethyl, 1-(cyclohexylcarboxy)ethyl, 1-(2indany lcarboxy) ethyl, 1- (benzoyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl and [4-( 5-methy 1-1,3-dioxolen-2-onyl) ] methyl.
Ihe invention also includes amide derivatives (wherein either -51 2 or both of OR and OR are replaced by NH_). Such compounds are also bioprecursors to the dicarboxylic acids and their suitability too may be assessed as indicated above.
Ihe compounds of the formula (I) contain three or more asymmetric centres and thus they can exist as enantiomers or diastereoisomers. Ihe invention includes both the separated individual isomers as well as mixtures of isomers. The preferred stereoisomers are those derived from either (S)-proline or 4(R)~ hydroxy-(S)-proline, in which each of the terminal carboxylic acid/ester/amide groups is attached to an asymmetric carbon atom of (S)-configuration.
Also included in the invention are radiolabelled derivatives of compounds of the formula (I) which are suitable for biological studies.
The pharmaceutically acceptable salts of the compounds of formula (I) containing an acidic centre are those formed with bases which form non-toxic salts. Examples include the alkali or alkaline earth metal salts such as the sodium, potassium or calcium salts, or salts with amines such as diethylamine.
Compounds having a basic centre can also form acid addition salts with pharmaceutically acceptable acids. Exanples include the hydrochloride, hydrobrcmide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, citrate, tartrate, lactate, fumarate, maleate, succinate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Preferred compounds are prodrug mono or diesters of compounds . 3 . of the formula (I) wherein R is benzyloxymethyl (0-benzyl serine -6— derivates), l-(2-butenyl)oxymethyl, 1-(4-methoxy-2-butenyl )oxy4 . methyl or 2-chloro-2-propenyloxymethyl. R is preferably H. . 1 . 2 Preferred mono-esters are those wherein R is H and R is methyl, (3-phenyl)propyl or (3-cyclchexyl)propyl, and preferred diesters are those wherein R·^ is pivaloyloxymethyl, l-(cyclohexylacetoxy)ethyl, 1-(cyclohexyIcarboxy)ethyl, l-(2-indanyIcarboxy)ethyl, 1(benzoyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl or [4-(5-methy1-1,32 . dioxolen-2-onyl]methyl, and R is ethyl.
It will be appreciated fron the foregoing discussion that the biologically active species in vivo are the diacids, that is 3 ccarpourhs of the formula (I) wherein both R and R are H, and R and R are as previously defined for the formula (I). Thus these diacids form a further preferred aspect of the invention.
Ihe ccmpounds of the fornula (I) can be prepared by a number of methods using the coupling and protective procedures of aminoacid chemistry. One procedure involves coupling of a suitably N-protected proline or 4-hydroxyproline derivative of the formula 4..9 (II), wherein R is as previously defined and R is a conventional amino acid N-protecting group such as t-butoxycarbonyl, 2,2,2trichloroethoxycarbonyl or benzyloxycar bony1, with an amine of the 1’ 2’ formula (III), wherein R and R are as previously defined for R1 and R2 respectively but are not H, and R10 is as defined for R3 with any reactive groups therein optionally protected, to provide a compound of the formula (IV) as shown in the following reaction scheme: (IV) The reaction of the ccnpounds of formula (II) and (III) is achieved using conventional amide coupling techniques. Thus in one process the reaction is achieved with the reactants dissolved in an organic solvent, e.g. dichlorcmethane, using a diimide condensing agent, for example l-ethyl-3-(dimethylaminopropyl) carbodiimide, or Ν,Ν'-dicyclohexylcarbodiimide, advantageously in the presence of 1-hydroxybenzotriazole and an organic base such as N-methylmorpholine. Ihe reaction is generally complete after a period of from 12 to 24 hours at room temperature and the product is then isolated by conventional procedures, i.e. by washing with water, or filtration, to remove the urea by-product and evaporation of the solvent. Ihe product may be further purified by crystallisation or chromatography if necessary.
In an alternative analogous procedure, the diester products of formula (IV) may be obtained by coupling compounds of formulae: CV) h2n^r O' or2‘ (VI) and the reaction is achieved following similar procedures to those described above.
Ihe diesters of formula (IV) are subsequently deprotected to give the diester, monoester or diacid derivatives of formula (I).
Ihe conditions used will depend on the precise nature of the 1' 2' . groups R and R in the eonpound of formula (IV) and a number of 1’ variations is possible. Thus, for exanple, when one of R and ’ R is t-butyl and the other is alkyl, treatment of the eonpound of formula (IV) with hydrogen chloride or trifluoroacetic acid . 1' 2' yields a monoalkyl ester of formula (I) wherein one of R and R 1' is H and the other is alkyl. Alternatively, when both of R and · . . . .
R are t-butyl, said acid deprotection affords a diacid of 1 2 formula (I) wherein R and R are both H. As an alternative carboxylic acid protecting group, benzyl may be employed instead of t-butyl. In such cases, catalytic hydrogenation removes the benzyl groups (s) to furnish either the monoester or diacid as -9required.
A further variation is that in which a monoester of formula . 1 . 2 .
(I), wherein R is H and R is a biolabile ester-forming group, is 1 2 converted to a diacid of formula (I), wherein both R and R are H, by base hydrolysis, e.g. using an aqueous sodium or potassium hydroxide medium. . 1 2 Amides wherein either or both of OR and OR are replaced by NH^ are obtained by starting with the appropriate amide derivative corresponding with formula (III), (V) or (VI) in the coupling 1' 2' . step, that is wherein either of OR or OR is NH2 or both of OrI and OR2 are Ni^.
Depending on the protection/deprotection strategy employed, further conventional deprotection steps may be required to remove . . 10 R and/or any protecting groups present in R .
Required diester prodrugs Which are not directly accessible from compounds of formula (IV) may be obtained from monoesters of 1' 2' formula (IV) wherein either R or R is H. This may be achieved for example ty alkylation of an alkali metal, preferably caesium, salt of the monoacid with the required alkyl halide, preferably brcsnide or iodide, or by coupling of the monoacid with an alcohol or phenol by conventional techniques as described above. Further deprotection steps, e.g. to remove R and/or any protecting group contained in R10, are carried out as appropriate to afford 1 2 . compounds of formula (I) wherein neither R nor R is H.
Thus certain novel compounds of the formula (IV), wherein 1' 2' R and R are each independently selected from t-butyl or benzyl, are useful intermediates for the preparation of compounds of the formula (I) and also form part of the invention. -10The compounds of formula (I) may be isolated as, for example, hydrochloride or sodium salts directly from the previous deprotection step. Alternatively, they may be converted to other pharmaceutically acceptable acid addition, alkali metal or alkaline earth metal salts by routine procedures.
Appropriate coupling, protection and deprotection methods for all of the above steps and alternative variations and procedures will be well known to those skilled in the art by reference to relevant text-bocks and to the examples provided hereafter.
Ihe proline derivatives of formula (II) are either commercially available or preparable by standard methods in accordance with literature precedent. Ihe amines of formula (III) may be prepared by analogy with processes described in EP-A-0358398 using the aminomethylglutaric acid derivative of 1' formula (VII), wherein R is benzyl or 1(S)-phenylethyl and R is as previously defined, and the appropriate α-amino ester of 10 2 * formula (VI) , wherein R and R are as previously defined, to afford the coupled product of the formula (VIII), followed by catalytic hydrogenolytic removal of the RX1 groups as shown in the following reaction scheme: H N .R10 H2N R10 CT OR2 (VI) I (y OR2* (VIII) am The ccmpounds of formula (V) are preparable according to processes described in EP-A-0358398, by coupling the sodium salt of 1-(2-t-butoxycarbony1-3-aminopropyl)cyclopentane carboxylic acid with the proline fragment (II).
Ihe novel α-amino esters of formula (VI) may be prepared from commercially available N-protected α-amino acid derivatives such cis those of glycine, serine or tyrosine by established methods in accordance with literature precedent. For example, standard alkylation of the serine alcoholic hydroxyl group provides ether derivatives, whilst Mitsunobu or Heck modification of the tyrosine phenolic hydroxyl group or its trifluoromethanesulphonyl -12derivative respectively leads to a variety of 4-alkoxy or 4-alkyl phenylalanine derivatives, which are also obtainable by C-benzylation of glycine derivatives using the asymmetric alkylation procedure developed by O'Donnell et al. Subsequent N-deprotection then affords the compounds of formula (VI).
As previously mentioned, the prodrugs of the invention offer an oral bioavailability advantage in the systemic delivery of the potent, dual inhibitor diacids of the formula (I) derived 12 . . therefrom wherein R and R are H. These diacids are potent inhibitors of the neutral endopeptidase (E.C.3.4.24.11). This enzyme is involved in the breakdown of a number of peptide hormones including, in particular, the breakdown of atrial natriuretic factor (ANF). Thus the diacids of the invention, by preventing the degradation of ANF by endopeptidase E.C.3.4.24.11, can potentiate its biological effects and the compounds are thus diuretic, natriuretic and antihypertensive agents of utility in a number of disorders including hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Menieres disease, hyperaldosteronism (primary and secondary) and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF, the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity, gastrointestinal disorders (especially diarrhoea and -13irritable bowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia.
Activity against neutral endopeptidase E.C.3.4.24.11 is assessed using a procedure based on the assay described by J. T. Gafford, R. A. Skidgel, E. G. Erdos and L. B. Hersh, Biochemistry. 1983, 32, 3265-3271. Ihe method involves determining the concentration of caipound required to reduce by 50% the extent of release of radiolabelled hippuric acid from hippuryl-L-phenylalanyl-L-arginine by a neutral endopeptidase preparation from rat kidney.
Ihe diacids of the invention are also inhibitors of angiotensin converting enzyme. As such they are useful in treating a further variety of conditions for which ACE inhibitors are known to be useful including limitation of ischaemic damage to the myocardium, protection of the kidney against hyperfiltration damage, prevention or reversal of left ventricular hypertrophy, memory enhancement, control of cognitive function, dementia, and preventing reocclusion following coronary angioplasty or coronary artery bypass surgery. Their activity against this enzyme is assessed using a modified procedure based on the assay described by M.S. Rohr bach, Anal. Biochem., 1978, 84, 272. The method involves determining the concentration of eonpound required to reduce by 50% the extent of release of radiolabelled hippuric acid from hippuryl-L-histidyl-L-leucine by angiotensin converting enzyme isolated from rat kidney.
Inhibitory activity is also measured in vivo following intravenous injection to anaesthetised rats using the methods described by I. L. Natoff et al.. Journal of Pharmacological -14Methods, 1981, 5, 305 and by D. M. Gross et al.. J. Pharmacol.
Exp. Ther., 1981, 216. 552. The dose of inhibitor required to reduce the pressor response produced by intravenous injection of angiotensin I (50 ng bolus) by 50% is determined.
The activity of the diacids as diuretic agents is determined by measuring their ability to increase urine output and sodium ion excretion in saline loaded conscious mice. In this test, male mice (Charles River CD1, 22-28 g) are acclimatised and starved overnight in bowls. The mice are dosed intravenously via the tail vein, with the test compound dissolved in a volume of saline solution equivalent to 2.5% of body weight. Urine samples are collected each hour for two hours in pre-weighed tubes and analysed for electrolyte concentration. Urine volumes and sodium ion concentrations from the test animals are compared with those of a control group which received only saline.
The antihypertensive activity of the prodrugs of the invention and the diacids derived therefrom is evaluated by measuring the fall in blood pressure, following oral or intravenous administration respectively, to salt-depleted, diuretic primed, spontaneously hypertensive rats, salt-depleted renally hypertensive dogs, or DOCA/salt hypertensive rats.
The systemic bioavailability of diacid obtained after oral administration of a prodrug of the invention is determined, e.g. in rat, by measuring the fraction of the biologically active dose recovered via the urine (measured by in vitro assay of neutral endopeptidase activity as previously described) and comparing it with the corresponding fraction after an equivalent dose of the corresponding diacid, when administered by the intravenous route. —15— Altematively plasma concentrations of diacid are measured in dog following oral administration of the prodrug and again compared with the corresponding values obtained after the intravenous administration of an equivalent dose of the corresponding diacid.
For administration to man in the curative or propy lactic treatment of hypertension, congestive heart failure or renal insufficiency, oral dosages of the compounds of the invention will generally be in the range of from 3-1500 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules oontain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier for administration singly, or in multiple doses, once or several times a day. Dosages for intravenous administration would typically be within the range 1 to 500 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. Ihe above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
For human use, the ccnpounds of the formula (I) can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, -16or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution vhieh may contain other substances, for example enough salts or glucose to make the solution isotonic with blood.
The compounds may be co-administered with other agents as may be beneficial for the control of blood pressure or the treatment of cardiac conditions or renal insufficiency. Thus, for example, they may be co-administered with digitalis or another cardiac stimulant drug, an alpha-blocker, a beta-blocker, exogenous ANF, a potassium channel activator or another diuretic agent, as shall be determined by the physician as appropriate to the particular patient or disease state.
Thus, in a further aspect, the invention provides a pharmaceutical ccrnposition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
Ihe invention also includes a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either, for use in medicine.
Ihe invention further includes the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either, for the manufacture of a medicament for the treatment of hypertension, heart failure or renal insufficiency. -17The invention yet further includes a method for the propy lactic or curative treatment of hypertension, heart failure or renal insufficiency in a human being, which comprises administering to said human being an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either.
Ihe preparation of the compounds of the invention and of the intermediates for use in their preparation are illustrated by the following Examples and Preparations. The purity of the compounds was routinely monitored by thin layer chromatography (TLC) using Merck Kieselgel 60 ^54 Piates 31x1 the following solvent systems (SS): hexane/ethyl acetate, 4:1 hexane/diethyl ether, 1:1 hexane/ethyl acetate, 1:1 hexane/diethyl ether, 6:4 hexane/diethyl ether, 1:4 hexane/diethyl ether, 3:7 ethyl acetate/ethanol, 9:1 ethyl acetate dichloromethane/methanol/acetic acid, 80:20:1 isobutyl methyl ketone/acetic acid/water, 2:1:1 (upper phase) hexane/ethyl acetate, 1:4 ethyl acetate/ethanol, 19:1 hexane/diethyl ether, 4:1 dichlorcmethane/methanol, 9:1 diethyl ether /dichlorcmethane, 1:1 -1816 diethyl ether hexane/ethyl acetate, 6:4 hexane/diethyl ether, 4:6 dichloromethane/methanol/ammonia, 90:10:1 hexane/2-propanol/ammonia, 90:10:0.5 dichloronethane/ethanol/acetic acid, 90:10:1 dichlorcmethane/methanol/acetic acid, 90:10:1 n-butanol/water/acetic acid, 12/5/3 dichloromethane/methanol/acetic acid, 40:10:1 ethyl acetate/toluene, 1:1 dichloromethane/methanol/acetic acid/hexane, 90:10:1:150 ^-Nuclear magnetic resonance (nmr) spectra were recorded using a Nicolet QE-300 or Brucker AC-300 spectrometer and were in all cases consistent with the structures of the compounds described hereinafter. -19EXAMPLE 1 N— f 1—1 3- ΓΝ-t-Butoxvcarbonyl- f S) -proly lamino! -2 (S) -t-butoxycarbonvlpropyiycyclopentanecarbonyl 1 -0-benzyl- (S) -serine methyl ester To a stirred, ice-cold solution of l-{3-[N-t-butoxycarbonyl- (S) -proly lamino] -2 (S) -t-butoxy carbonylpropyl}cyclopentane carboxylic acid (Preparation 80, 351 mg, 0.75 mmol) in dichloromethane (15 ml) were added, sequentially, 1-hydroxybenzotriazole (122 mg, 0.90 mmol), N-methylmorpholine (265 mg, 2.62 mmol), l-ethyl-3-(3-dimethylamincprcpyl)carbodiimide hydrochloride (287 mg, 1.50 mmol) and, 0.25 hour later, 0-benzyl-(S)-serine methyl ester hydrochloride (202 mg, 0.82 mmol). The ice bath was removed, stirring continued for 24 hours, then the reaction mixture was evaporated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (50 ml), then the organic phase separated, washed successively with 2M hydrochloric acid (2 x 30 ml), saturated aqueous sodium bicarbonate solution (30 ml) and saturated brine (30 ml), dried (MgSOp and filtered. Evaporation under vacuum of the filtrate provided a foam (546 mg) which was purified by chromatography on silica gel, using 30% ethyl acetate in hexane as eluent, to afford the title compound as a white foam (409 mg, 83%). Rf 0.54 (SS 15) and 0.24 (SS 3), [α]θ5 -18° (c = 0.1, MeOH). Found: C,63.35; H,8.l2; N,6.23.
C35H53N3°9 C,63.71; H,8.10; N,6.37%. -20EXAMPLES 2-40 The following Examples were obtained according to the method of Example 1 using l-{3-[N-t-butoxycarfoonyl-(S)-prolylamino-2(S)t-butoxycarbonylpropy1) cyclopentane carboxylic acid and the appropriate α-amino ester of formula (VI) from the Preparations section. a Ό r-7 co co σι >7 in r-' Γ' ί? ιη Γ* rd in VO vo CM ιή ιή ιή in ιή ιή ιή ιή ιή in o\o brack ω •Η ω £ Η al in 8.59 8.59 8.30 8.45 7.96 7.80 7.83 7.80 8.62 8.77 C (theoretic co n CM Ί1 co VO Γ CM t CO Γιο π- f- rco o in ιή vo vo ιή ιή Ό νο vo vo KO KO VO vo Rf 0.45 (SS 3) 0.57 (SS 16) 0.38 (SS 16) (8 SS) 99*0 0.44 (SS 3) 0.67 (SS 16) cm > Pi2(cidzid)kd- 9 9 0 CM 0 CM ? jS η , Ρί & ί ί £ ί £ ^CM af1 £ ί sT £ (N OJ •τ' ? ψ V ? ? φ Ι-Η No. CM cn in Ό Γ VO Γ* in 6.67 6.71) 6.45 6.59) 5.58 5.63) 42 48)c KO o σι σι d ko in in ιή in σ> CO Ol KO co σι 0- «—1 O' rd O' 00 cn KO co KO oi in cn Γ0 rd o • • • · • 9 • · • • • • co 00 co co 00 CO CO 00 O' 00 00 co in O' rd σι -* O' o KO rd -4· o rd σ> σι sj· cn rd co co o co • • · • • • · • • • oi OJ *4· << *4· <4· KO in KO KO KO KO KO KO KO KO KO KO vo VO VO Z—*» in z—». vo z—. in ¢0 CO KO co σι r-l co co co vo CO Ol r- co KO cn co co cn o 8 d ω • o % d$ o co • o o |£ £ £ CO co CO £ z—% Z—X. z—*» in in s Ol Ol a U1 Ω tF1 a ft n CM Ol a a u VJ VJ -c —c V 9r 1 1 co co D co OJ OJ if δ Ol ί ^Ol Ol a o M CM o OJ f <3 W f b=d Ol JH a Ed *Τί q Π o 0 o o o af ? J af OJ ? af ? oi co 'f in KO O' 00 OJ Ol Ol OJ OJ OJ Ol -26tf) CO η vo vo σι σ co o co σ n CM vo VO •O’ • CM VO vo M o CO w W in CM in cn CM CM vo vo r-~ • co o vo • co o· in O r-l VO vo o in vo rf CM o cn vo in vo vo cm σ M* VD * · co co r-l O’ CM CM vo vo o co VO in CM v in cm *—i « · VO vo co CM • CO o o CO VO CM r-l O • « O’ Ό* VO vo vo co co o $ in cm [· VO vo r—I rvo co vo Γ co • · co co σ r-l • <—I vo CM O' • r—I VO in co co o $ n CN rH o o UXT1ws o o in h CM · · K ο o co r> cn m co’ Λ υ -27EXftMPTES 41-45 Ihe following compounds were prepared following the coupling procedure of Example 1 but using the appropriate N-protected proline derivative of formula (V) (see Preparations 81 and 82) and coupling to the appropriate α-amino ester or amide derivative of formula (VI). 0.40 0.25 -29EXAMPLE 46 N-< 1- Γ 3-Benzvloxycarbonylamino-2 (S) -t-butoxvcarbonvlpropyl 1 cyclopentanecarbonyll-O-benzvl-fS)-serine (3-phenyl)propyl ester Ihis was obtained by the procedure of Exanple 1 using 1- [3-benzyloxycarbonylamino-2 (S) -t-butoxycarbony lpropy 1] cyclopentane carboxylic acid (Preparation 83) and the product of Preparation 38 to provide the title eonpound, Rf 0.52 (SS 3). Found: C,67.25; H,7.44; N,3.89. ' 1,50 re£3u^res C,67.65; H,7.61; N,3.85%.
EXAMPLE 47 N—f 1- Γ 3-Amino-2 ( S) - t-butoxycarbony lpropy 11 cvclopentanecarbonyl )--0benzvl-(S)-serine (3-phenvl)propyl ester This was obtained frean Exanple 46 by Method C (catalytic hydrogenation - see Preparation 37) to provide the title eonpound, Rf 0.67 (SS 10). Found: C,69.54; H,8.45; N,4.66. C33H46N2C>6 requires C,69.93; H,8.18; N,4.94%.
EXAMPLE 48 N-Γ 1—f 2 (S) -t-Butoxycarbonvl-3-rN-t-butoxvcarbonvl-4 (R) -hvdroxy( S) -prolvlaminolpropyllcvclopentanecarbonyll -0-benzyl- (S) -serine (3-phenyl)propyl ester This was obtained from N-t-butoxycarbonyl-4(R)-hydroxy-(S)proline and Exanple 47 using the coupling methodology of Exanple 1, Rf 0.61 (SS 8), Found: C,65.91; H,7.73; N,5.31. C43H61N3°1O requires C,66.22; H,7.88; N,5.39%. -30EXAMPLE 49 Ν- Γ1—f 3- (N-Benzyioxycarbonvl- (S) -prolvlamino) -2 (S) -carboxypropyiy-l-cvcIopentanecarbonvll-O-benzvl-fS)-serine ethvl ester The title compound was prepared from Example 43, by trifluoroacetic acid deprotection (see deprotection Method A, Example 76) and was obtained as a white foam, Rf 0.68 (SS 10). Found: C,64.92; H,6.90; N,6.13. θ35Η45Ν3Οθ requires C,64.49; H,6.96; N,6.45%.
EXAMPLE 50 Ν- Γ1—f 3- (N- (2,2,2-Trichloroethoxvcarbonvl- (S) -pro ly lamino) -2(S) -carboxypropyl > -l-cyclopentanecarbonyl l -O-benzyl- (S) -serine ethyl ester Prepared from Example 44 as described above to give the title product as a white foam, Rf 0.39 (SS 14). Found C,51.31; H,5.61; N,5.86. C30H40N3Cl3Og; 0.5 1^0 requires C,51.33; H,5.89; N,5.98%.
EXAMPLE 51 Ν- Γ1—f 3- (N-t-Butoxycarbonvl- (S) -prolvlamino) -2 (S) -carboxypropyl } -1-cvclopentanecarbonvl 1 -0- ί trans-4-methoxvbut-2-envl 1 - (S) serine ethvl ester A stirred solution of N-[l-{3-(N-t-butoxycarbonyl-(S)proly lamino) -2 (S) -t-butoxycarbonylpropyl}-l-cyclopentanecarbonyl}-0-[trans-4-methoxybut-2-enyl]-(S)-serine ethyl ester (1.13 g, 1.69 mmol) in dry dichloromethane (20 ml) at -5°C was saturated with anhydrous hydrogen chloride. After five hours the reaction was degassed with nitrogen, the solvent evaporated under -31vacuum and the residual foam dried azeotropically with dichlorcmethane. This crude product was dissolved in a solution of sodium bicarbonate (0.427 g, 5.076 mmole) in water (20 ml) and the resulting solution cooled to 15°C. A solution of di-t-butyldicarbonate (0.739 g, 3.384 mmol) in dioxan (20 ml) was added dropwise with stirring and the resulting mixture allowed to warm to rocm temperature. After eighteen hours the reaction was evaporated under vacuum to lew volume, diethyl ether (20 ml) and water (20 ml) were added and the aqueous layer separated, washed with diethyl ether and then acidified to pH 2 with 2N hydrochloric acid. Ihe crude product was extracted with ethyl acetate (3 x 30 ml) and the combined extracts were washed with brine, dried (MgSC>4) and evaporated under vacuum. Azeotropic treatment of the residue with dichlorcmethane gave the required product cis a colourless foam (960 mg, 92%), Rf 0.55 (SS 22). Found: C,58.62; H,7.97; N,7.04. c30H49N3o10 squires C,58.90; H,8.07; N,6.87%.
EXAMPTFS 52-53 Ihe following compounds were prepared from Examples 38 and 39 using the procedure described above for Example 51. o OEt -3 2- Example No. R3 Rf Analysis % (theoretical in brackets) C H N 52 -CH2OCH2CH=CHCH3 0.56 59.24 8.16 7.35 (SS 22) (59.41 8.17 7.17)a 53 -O^OO^Eh 0.53 51.31 5.61 5.86 (SS 22) (51.33 5.89 5.98)b a. 0.25 H20 b. 0.50 HjO EXAMPLE 54 Ν-Γ1-13-(N-Benzvloxvcarbonvl-(S) -prolvlamino) -2 fS) -pivalovloxymethoxycarbonvlpropyl) -1-cyclopentanecarbonvl 1 -0-benzyl- (S) serine ethvl ester N- [l-{ 3-(N-Benzyloxycarbonyl-(S) -prolylamino) -2 (S) -carboxypropyl } -l-cyclopentanecarbonyl ] -0-benzyl- (S) -serine ethyl ester (Example 49, 0.648 g, 0.99 mmol) was dissolved in acetonitrile (10 ml) and water (5 ml) added. Aqueous caesium carbonate (12%) was added until the pH was 8, the resulting solution evaporated under vacuum and then the residue azeotroped with toluene (4 x 10 ml) . The resulting foam was dissolved in Ν,Ν-dimethylacetamide (5 ml) —33and pivaloyloxymethylchloride (0.298 g, 1.98 mmol) added to the stirred solution. After 16 hours at rocxn temperature the solvent was removed under vacuum and the residue partitioned between diethyl ether (100 ml) and 2M hydrochloric acid (50 ml). The ether layer was separated, washed successively with 2M hydrochloric acid (2 x 25 ml) and saturated brine (25 ml), dried (MgSOp and filtered. Evaporation under vacuum of the filtrate afforded the crude product which was purified by column chromatography (40 g silica, eluent 30% ethyl acetate in hexane) to give the title compound as a white foam, Rf 0.61 (SS 15).
Found C,64.50; H,7.33; N,5.43. requires C,64.29; H,7.24; N,5.49%.
EXAMPTFS 55-71 Ihe following Examples were prepared using the procedure described above hy reaction of the caesium salt of the appropriate monoester with the appropriate chloride of formula R1—Cl, except that for Example 67 the corresponding alkyl iodide was used and for Examples 59, 61 and 68 the corresponding alkyl bromides were used.
R OEt -36CO vo o o VO vo co <-< co o· r~ d ΟΟ σ co in vo co co in σ o· co o « « in vo in vo r-l CM co co σ vo o vo μo vo co o in vo in in o rCM O’ co co vo co • Cl vo vo • CM VO Cl vo r-l vo r~ tri in Ονο o VO Γin co co in CM CM vo vo ι—I m U CM CM-1 CM KUH VO Cl O ci cn -37ΕΧΆΜΡΙΕ 72 N- Γ1-(3-ΓΝ- (2,2,2-Tri Deprotection of Example 45 with trifluoroacetic acid according to Method A (Example 76), followed by conversion of the monocarboxylic acid product to its caesium salt and reaction with (l-isobutyryloxy) ethyl chloride following the procedures described above, gave the title ccnpound as a white foam, Rf 0.44, 0.51 (SS 8). Found: C,52.63; H,6.2l; N,7.15. C34H47N4O^0Cl3 requires C,52.48; H,6.09; N,7.20%.
EXAMPTFS 73-75 Ihe following esters were prepared from the appropriate acid and amine starting materials using the carbodiimide coupling described in Example 1.
O -38<λ« ω Η 2: .5 Μ* ιή ΓΜ* ιη σ νο σ σι νό νο ο Γη* ι—I Γ> σι νο Γη» • Γ sr νο ιή σ ιή ιη η Tf νο • . ιη ιη η ΓΓιη ΓIE 920504 -39EXAMPLE 76 (DEFROTECTION METHOD A) N-(1-Γ 2(S) -Carboxy-3 (S) -prolvlaminopropyl 1 cyclopentanecarbonvl) 4 -hydroxymethyl- (S) -phenylalanine- f3-phenyl) propyl ester Trifluoroacetic acid (6 ml, 78 mmol) was added to a stirred, ice-cold solution of Example 13 (458 mg, 0.6 mmol) and anisole (973 mg, 9 mmol) in dichloromethane (6 ml). After 14 hours at 0°C, the reaction mixture was evaporated under vacuum and the residue azeotroped with toluene (3 x 20 ml) then dissolved in water (5 ml). The aqueous solution was washed with diethyl ether (2 x 50 ml), then subjected to ion-exchange chromatography (AG50W-X8 resin) using water and then 8% aqueous pyridine as eluents. Evaporation under vacuum of the appropriate (ninhydrin positive) fractions afforded the title compound as a white powder (210 mg, 55%), Rf 0.40 (SS 10). Found: C,66.26; H,7.46; N,6.85. C34H45N3O?; 0.50 H^O requires C,66.21; H,7.52; N,6.81%.
EXAMPLES 77-104 The following Examples were obtained from the corresponding diester using the appropriate deprotection Method A, (trifluoroacetic acid, see above), B, (hydrogen chloride, described under Preparation 36), C, (catalytic hydrogenation, described under Preparation 37), D (formic acid, described under Preparation 24) or E (zinc in acetic acid, described under Preparation 66) to give the monoester products. a I 7.20 7.27)a 6.95 7.23)b 6.72 6.83)c 6.29 6.40)d 6.52 6.64)e lysis % H al in brae 8.07 8.19 7.03 7.45 7.75 7.67 6.98 6.99 7.35 7.33 3 ·Η 1 O il 62.31 (62.36 56.12 (55.80 60.54 (60.50 i i 62.24 (62.27 64.67 (64.53 % 0.30 (SS 10) 0.31 (SS 10) 0.28 (SS 10) 0.37 (SS 10) o CO rd in d 0.30 (SS 10) n ? CM ef ef ? 9 & ί ί ^CM ef ?s £ ^CM ^CM af* ? £ CM CM ? Method CQ CQ ca CQ CQ CQ 0 r-1 F > Γ- CO t- σ r- O CO i—1 CO CM CO KO vo vo o- ,60 ,7l)h .39 .51)1 O' > VO vo in in OJ VO H OJ vo n vo O' vo << n vo O' O' P P VO VO co o o in vo in CO cm cn OJ M· vo vo σ σ in in in in 0.45 (SS 10) 0.29 (SS 29) 0.15 (SS 22) 0.40 (SS 23) 0.24 (SS 22) 0.40 (SS 22) m s OJ ? ef if G CO i 1 £ rn ef cn δ CM δ °C CO δ OJ ef ro δ OJ δ Ϊ w i co m Poj 0Γ- δ CM ? o if CM ? 8 af* ? o if CM ? CQ CQ CQ < CQ 97 CO cn σ σ o o rH rd O rd OJ o rd σ> >—*. X—X ιη η Ο 1—1 > σι 'vf IO • · • · ιη ιη Ό IO co κο co r- <Ν CM σ t-~ • · • · νο νο O' o~ <Η CO σι in VD Ό Cl sf • · • « 9f o o in in VO Ό CJ Cl in ci σι ci o o • cn • «3 o cn o cn £ co £ co ^*»k □ 1 o 1 s’ if Cl ^CJ S'· ? CQ W CO o o c—I rH Ο Ο Ο Cl aiW Θ ο o in in in t-' ο ο ci η ό o afhfo o if CJ Cl d 6 in O oj cj in _ ro o · · h Q ο o U ® in ·' .. .- Ο Ο ·~ _ OHHHIflWHHlflHHNO NJ υ o · · ο ο · ο o · ci Xffi KKr-IOKWr-IWKr-lW (0 Λ ϋ Ό Φ Ή &>£! ·Η -I—l X c-Η g —45EXAMPTES 105-123 Ihe following compounds were prepared by deprotection of the corresponding N-protected proline diester compound to give the following diester products. N-Trichloroethoxycarbonyl derivatives were deprotected following deprotection method E (zinc in acetic acid) and N-t-butyloxycarbonyl derivative were deprotected using deprotection method B (hydrogen chloride).
S -46o\o (fl •Ή fl •y I .s •rH I fl o in <-i • cn o cn o cn rH M· • cn o cn <0 in 3 cn cm • · vo vo in cm vf CM Γ- Γcm in σ> cn in in o O rH d cn o co m tn vo vo o in cn o r- r<· co m o r- rin in o m· <-i cn • cn o cn o vo o O CM vo vo cn cn η· Γvo vo .-1 Γιο Γνό vo in in cn CM cn cn co CM CM CM cn cn -48-<ΓΓ η σι η μ· ιη co co η co ιο ιο t-~ Γσ «-ι ιή ιή in in CM o CM m • ω o ω 2? co ci rd η co η ι-H μ· • « co co co r~ in co co in in in CM o CM CM σι Γη ιη ιο ιο in ο σι μ ιο γin o io in in in O CM o CM CM Ui W «Γ σι 5i n· \ο ιή ιή <-Ι Γγ~ σι • « Γ- Γco o co o • · ΙΟ Γtn m in n • o CM CM £ δΓ κ ci σι rd ιή ιή CM CM <—I CM « « co co CM O cm in • · σι σι in in σ\ cn ό OJ OJ «τ Γ— r—I ο η ιή ιο <· ιο <-t CM σι σι CM • · σι σι in in CM KO CM cn « W o ω O O O1OJ OJ XKH in oj ήοδ Ό φ U-i CM CJ CM CM X n n io o o »—t I—I I-1 U U U XXX co rH σι <—f rH O OJ OJ OJ OJ m OJ —49EXAMPTES 124-126 These amides were obtained directly, in the case of Examples 124 and 125, by N-deprotection of the corresponding trichloroethoxycarbonyl proline precursors (Examples 74 and 72 respectively) using zinc and acetic acid (Method E). Example 126 was obtained from Example 45 in two stages, whereby Method E was followed by trifluoroacetic acid deprotection of the t-butyl ester (Method A). 0 or nh2 Exanple No. R1 Rf Analysis % (Theoretical in brackets) C H N 124 0.56 60.85 6.93 7.38 oy (SS 23) (60.60 6.78 8.19)a 125 ch 1 3 0.53 47.85 5.90 7.06 1 (CH3) 2CHOO2CH- (SS 23) (48.45 6.56 7.29)b 126 H 0.38 58.29 7.48 10.66 (SS 23) (58.24 7.62 10.87)c a. 0.5 CH Cl b. 0.75 ZnCl?; 2IV0 c. 1.5 HO -50— EXAMPLE 127 N- Γ1—f 2 (S) -Carboxy-3-Γ 4 (R) -hydroxy- (S) -prolylamino 1 propyllcyclopentanecarbonyll-O-benzyl-f SI-serine (3-phenyl) propyl ester This was obtained from Example 48 by reaction with hydrogen chloride in dichloromethane (deprotection Method B) to furnish the title compound, Rf 0.45 (SS 10). Found: C,60.78; H,6.88; N,6.22. C34H45N3°10' «Cl; requires C,60.21; H,7.13; N,6.20%.
EXAMPLE 128 N—f 1Γ 2 (S) -Carboxy-3- (S) -prolylamincpropyll cyclopentanecarbonviy-Obenzyl- (S)-serine 1M Aqueous sodium hydroxide solution (1.5 ml, 1.5 mmol) was added to a stirred solution of Example 77 (171 mg, 0.30 mmol) in 1,4-dioxan (2 ml). After 48 hours the pH of the solution was adjusted to 8 using dilute hydrochloric acid, then the solution subjected to ion-exchange chromatography (AG50 resin) using water and then a 1-10% aqueous pyridine gradient as eluents.
Evaporation under vacuum of the appropriate (ninhydrin positive) fractions, followed by freeze drying of an aqueous solution of the residue, furnished the title conpound as a white powder (108 mg, 70%), Rf (SS 10). Found: C,59.52; H,7.19; N,8.28. ; H20 requires C,59.15; H,7.35; N,8.28%. —51EXAMPTES 129-148 The following Examples were obtained by hydrolysis of the appropriate ester following the procedure of Example 128. . . 4 Examples 129-147 are unsubstituted (S)-proline derivatives (R H) while Example 148 is the 4 (R)-hydroxy-(S)-proline derivative (R4 = OH) derived from Example 127. -53cm cn in in oo co ι—I CO ο o cr> σι ϋ t- sr cn m* • · σι σι I— rtf o CM CO 00 in in ι—I ι—I d σι o\° .2« .5 o co ko r• a > Γσι -41 41 oo • · Γ- Γin cn o in « · 00 ΓCM O ko σ r-V cn o r-l CM co oo co oo rd o • a KO KO in in ί-- cn CM r-l d > in in CM CM ko σι • · KO KO in in P- O 't CO • · CM r-l in in co -4* •4· in d d in in CM CO CM O o c/3 CM cn cm o o $ CM CO CM O d c8 o C* I—ί CJ d c/5 r~ CM CM if cn ί o CM ? co δ CM s O if CJ ? co co co in co VO co > co -54Φ η vo l—l r—1 • · σ> σ r— co VO Γr- Γt—ι σ co σ co co ιο co in σ r- r— Ό vo ίη co σ • · co co r- i—i n in » « r- r~ in i-t Γ- ι—I r— σ . · Γ- Γo in oo n in co ιο co Γ- Γ— « · r- ΓΊ-Ι r— in n in σ σ η co ι—I ι—1 « « r— Γη n σ in in in in in co rH O σ σ in in n r~ r-l cm • · vo vo in in ο n r- o in vo tn in co co σ o in νό in in <—I vo r-l O ri t-i in in CM σ cm o • cn o cn CM Γ- CM O o $ o η h CM o ¢8 CM r- cm o o c8 CM n cm o o c8 CM CO CM o o cn co n CM <—( fN Ο Ο O CNf niW1 διηο in in ο o n γμ fN • · · fN · «ffi rd Ο Ο Κ Ο O CN nJ Λ Ο Ό (1) -5 6EXAMPTES 149-158 Examples 149-153 were obtained from the appropriate precursor N-protected proline diester derivatives (Examples 29-33 respectively) by catalytic hydrogenation (deprotection Method C) followed by treatment of the resulting monoacids with hydrogen chloride (deprotection Method B).
Examples 154-156 were obtained from similar precursors (Examples 36, 35 and 40 respectively) using hydrogen chloride treatment only (deprotection Method B).
Examples 157-158 are the result of three successive deprotection steps from their analogous precursors (Examples 41 and 42 respectively): base hydrolysis of the (3-phenyl)propyl ester group according to the method of Example 128, but using routine extraction procedures rather than ion-exchange chromatography to isolate the monoacid, followed by Method B and finally Method C. 0.26 (SS 22) 0.26 (SS 22) 0.18 (SS 22) 0.10 (SS 10) 0.13 (SS 10)£hdzhd- ?r ΐ if a X CM m δ S CM *~CM s o CM ? 2 af ? ί £ 1 ί ί 2 154 155 156 157 158 o af in d U u ffi X <ύ Λ -59FREPARATION 1 N-t-Butoxycarbonyl-O-benzyl-(S)-serine methyl ester N-t-Butoxycarbonyl-O-benzyl-(S)-serine (2.34 g, 7.9 mmol) was added to a stirred suspension of anhydrous potassium carbonate (2.19 g, 15.8 mmol) in dimethylformamide (25 ml), followed by iodcmethane (1.34 g, 9.4 mmol). After 48 hours at rocan temperature, the reaction mixture was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (50 ml). Ihe organic phase was separated, washed successively with 2M hydrochloric acid (50 ml), saturated aqueous sodium bicarbonate solution (50 ml) and saturated brine (50 ml), then dried (MgSOp and filtered. Evaporation under vacuum of the filtrate gave the required product as a colourless oil (2.40 g, 97%), Rf 0.57 (silica; SS 1). Found: C,62.18; H,7.48; N,4.63. requires C,62.11; H,7.49; N,4.53%.
REPARATIONS 2-5 The following Preparations were effected according to the procedure of Preparation 1 using the appropriate α-amino acid derivative and alkyl halide.
,OCH2Ph CH .CH BuOCONH' co2r (S) Preparation No.1 R2 R5 Rf Analysis % C (theoretic H al in bi N rackets) 2 H 0.65 (SS 2) 69.68 (69.70 7.48 7.56 3.55 3.39) 3 -^(0^0^)2 H 0.62 (SS 3) 4 -<*3 (R)CH3 0.59 (SS 3) 5 H 0.60 (SS 3) 62.45 (62.27 7.79 7.84 4.10 4.27)a a. 0.25 1^0 PREPARATION 6 N-t-Butoxycarbonyl-O-benzvl-(S)-serine cyclohexyl ester To a stirred solution of N-t-butoxycarbonyl-O-benzyl-(S)serine (5.00 g, 16.9 mmol) and cyclohexanol (3.39 g, 33.8 mmol) in dichloromethane (50 ml) at 0°C were added, sequentially, 1hydroxybenzotriazole (2.75 g, 20.3 mmol), N-methylmorpholine (4.27 g, 42.3 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.22 g, 22.0 mmol) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol). Ihe ice bath was removed, then the reaction mixture was stirred for 24 hours at room temperature and evaporated under vacuum. Ihe residue was partitioned between ethyl acetate (200 ml) and 2M hydrochloric acid (100 ml), then the -61organic phase was separated, washed successively with 2M hydrochloric acid (2 x 100 ml), saturated aqueous sodium bicarbonate solution (2 x 100 ml) and saturated brine (100 ml), dried (MgSO^) and filtered. Evaporation under vacuum of the filtrate provided an oil (5.47 g), which was purified chromatographically using silica gel (200 g) and an 8:2 mixture of hexane:ether as eluent. Evaporation under vacuum of the appropriate fractions afforded the title compound as a colourless oil (1.74 g, 27%), Rf 0.62 (silica; SS 2), [a]25 -63.0’ (c = 0.1, MeOH). Found: C,66.61; H,8.34; N,3.71. C requires C,66.81; H,8.28; N,3.71%.
PREPARATIONS 7-9 The following Preparations were effected according to the procedure of Preparation 6 using N-t-butoxycarbonyl-O-benzyl-(S)serine and the appropriate alcohol or phenol.
BuOCONH CH CH (S) OCH2Ph co2r Preparation No. R2 Rf Analysis % C (theon H atical in N brackets) 7 w 69.73 (70.05 7.11 7.10 3.35 3.40) 8 0.66 (SS 3) 69.70 (70.05 7.16 7.10 3.49 3.40) 9 0.53 (SS 2) 68.69 (68.70 8.92 8.89 3.70 3.34) PKEPARATION 10 N-t-Butoxycarbonvl-O-benzyl-fS)-serine amide N-t-Butoxycarbonyl-O-benzyl-(S)-serine (10.0 g, 34 mmol) was added to a stirred suspension of ammonium bicarbonate (8.0 g, 102 mmol) and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (10.05 g, 41 mmol) in chloroform (80 ml). After 48 hours at room temperature the solvent was removed under vacuum and the residue partitioned between ethyl acetate (200 ml) and 2N hydrochloric acid (50 ml). The ethyl acetate phase was separated, washed with saturated sodium bicarbonate (50 ml) then brine (20 ml), dried (MgSO4), then filtered. Evaporation under vacuum of the filtrate followed by crystall isation of the residue from ethyl acetate/hexane gave the title conpound as a crystalline white solid. Found: C,61.38; H,7.35; N,9.48. ci^2N2°4 C,61.20; H,7.53; N,9.51%. —63— PREPARATION 11 N-Benzyloxycarbonvl-O-f2-methaxvethvl) - (S')-tyrosine t-butvl ester Diethyl azodicarboxylate (4.4 ml, 28 mmol) was added under nitrogen to a stirred, ice-cold solution of N-benzyloxycarbonyl(S)-tyrosine t-butyl ester (5.2 g, 14 mmol), triphenylphosphine (7.34 g, 28 mmol) and 2-methoxyethanol (3.3 ml, 42 mmol) in dry tetrahydrofuran (30 ml). Ihe ioe bath was removed, then the reaction mixture was stirred for 24 hours at roam temperature and evaporated under vacuum. Ihe residue was digested with a hot 1:1 mixture of ether and hexane, then the supernatant solution was chromatographed on silica gel (500 g) using a 1:1 mixture of ether and hexane as eluent. Evaporation under vacuum of the required fractions furnished the title oonpound as an oil (5.8 g, 95%), Rf 0.30 (silica; SS 2).
PREPARATIONS 12-13 The following Preparations were effected according to the procedure of Preparation 11 using N-benzyloxycarbonyl-(S)-tyrosine and the appropriate alcohol. —64— Preparation No.r14 Rf Analysis % C (theoret; H Leal in 1 N ^rackets) 12 -οα^σ^οα^Βι 0.25 (SS 4) 71.21 (71.27 6.92 6.98 2.83 2.77) 13 -oc^cH^a^oci^rh 0.42 (SS 2) 71.74 (71.65 7.15 7.18 2.75 2.70) EREPARATION 14 N-Benzyloxycarbonyl-O-trifluoromethanesulrhonyl- (S) -tyrosine tbutyl ester To a stirred solution of N-benzyloxycarbonyl-(S) -tyrosine tbutyl ester (2.22 g, 5.97 nmol) in dichlorcmethane (20 ml) at -78 °C were added, sequentially , triethylamine (1.21 g, 11.94 mmol) and N-phenyl trifluorcmethanesulphoninu.de (2.13 g, 5.97 mmol). The cooling bath was removed, then the reaction mixture was stirred for 24 hours at room temperature and evaporated under vacuum. Ihe residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (100 ml), then the organic phase separated, washed with saturated aqueous sodium bicarbonate solution (50 ml) and saturated brine (50 ml), dried (MgSO4) and filtered. Evaporation under vacuum of the filtrate gave an oil, vhieh was purified by chromatography on silica gel (100 g) using an elution gradient of hexane:ether: diethylamine (90:10:1 to 50:50:1). Evaporation under vacuum of the required fractions provided the title oonpound as a white -6525 crystalline solid (2.45 g, 82%), m.p. 48-49°C, [a] -33° (c = D 0.1, MeOH). Found: C,52.51; H,4.76; N,2.76. C EjNC^S requires C,52.47; H,4.80; N,2.78%.
PREPARATION 15 N-Benzvloxvcarbonyl-4-hvdroxvmethvl-fS) -phenylalanine t-butyl ester (i) N-Benzvloxycarbonyl-4- f2-ethoxycarbonyl-l-ethenyl- (S) -phenylalanine t-butyl ester A solution of the product of Preparation 14 (12.99 g, 25.8 mmol), ethyl acrylate (5.6 ml, 51.6 mmol), triethylamine (16 ml) and bis (triphenylphosphine) palladium (II) chloride (1.05 g, 1.5 mmol) was stirred under nitrogen at 100-110°C for 18 hours. Evaporation under vacuum followed fcy dilution of the residue with water gave a suspension which was extracted with a 1:1 mixture of hexane and ether. The organic extract was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated brine, then dried (MgSO4) and filtered. Evaporation under vacuum of the filtrate gave a yellow oil (11.5 g) which was chromatographed on silica gel (600 g) using a 3:2 mixture of hexane and ether as eluent. Evaporation under vacuum of the appropriate fractions afforded the required olefin as a viscous oil (8.42 g, 72%), Rf 0.42 (SS 2). Found: C, 69.10; H,6.99; N,3.07. requires C,68.86; H,6.89; N,3.09%. -66(ii) N-Benzyloxycarbonyl-4-(2-ethoxvcarbonyl-l, 2-dihvdroxvethvl) (S)-phenylalanine t-butyl ester To a stirred solution of the previous product (8.42 g, 18.56 mmol) in a mixture of acetone (30 ml) and water (8 ml) were added, sequentially, N-methylmorpholine-N-oxide (3.78 g, 28 mmol) and a 2.5% solution of osmium tetroxide in t-butanol (1.5 ml). After 18 hours acetone (50 ml) was added, the reaction mixture evaporated under vacuum then the residue chromatographed on silica gel (500 g) using a 4:1 mixture of ether and hexane as eluent. Evaporation under vacuum of the appropriate fractions furnished the required diol as a gum (8.62 g, 95%), Rf 0.25 (SS 5). Found: C,64.33; H,6.72; N,3.00. C^gH^NOg requires C,64.05; H,6.82; N,2.87%. (iii) N-Benzyloxycarbonvl-4-fonnyl-(S)-phenylalanine t-butyl ester A solution of the previous product (8.61 g, 17.7 mmol) in ether (200 ml) was vigorously stirred with a solution of sodium periodate (7.55 g, 35.3 mmol) in water (150 ml) for 20 hours. The ether phase was separated, washed with water, dried (MgSC>4) and evaporated under vacuum to provide an oil (7.03 g) which, after chromatography on silica gel using a 1:1 mixture of hexane and ether as eluent, gave the required aldehyde as a clear oil (6.68 g, 99%), Rf 0.30 (SS 2). Found: C,68.80; H,6.54; N,3.68. ^2^5^5 re£3U3res c,68.9l; H,6.57; N,3.65%. (iv) Title eonpound Sodium borohydride (330 mg, 8.7 mmol) was added to a stirred, ice-cold solution of the previous product (6.67g, 17.4 mmol) in ethanol (60 ml). After 10 minutes the reaction solution was —67— acidified to pH 6 with IM hydrochloric acid, then evaporated under vacuum. The residue was partitioned between ether and water, then the organic phase separated, washed successively with IM hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated brine, dried (MgSOp and filtered.
Evaporation under vacuum of the filtrate provided an oil which was chromatographed on silica gel using a 7:3 mixture of ether and hexane as eluent. Evaporation under vacuum of the appropriate fractions afforded the required alcohol as an oil (6.6 g, 98%), which solidified on chilling. Rf 0.33 (SS 6), [a]25 +47.8° (c = D 1.04, O^Cl^. Found: C,68.21; H,7.09; N,3.66. C2^2^5 requires C,68.55; H,7.06; N,3.63%.
PREPARATION 16 N-Benzvloxvcarbonvl-4-hvdroxvmethvl- (S) -phenylalanine (3-phenyl) propyl ester The t-butyl ester group of the product of Preparation 15 was dealkylated by Method B described in Preparation 36, then the resulting acid was realkylated using (3-phenyl) propyl bromide according to the method of Example 54 to give the title compound as an oil, Rf 0.25 (SS 6). Found: C,72.35; H,6.42; N,3.12. C27H29NO5 requires C,72.46; H,6.53; N,3.13%.
PREPARATION 17 N-t-Butoxycarbonyl-O- (4-fluorobenzvl) - (S) -serine Sodium hydride (80% dispersion in oil; 2.25 g, 75.05 mmol) -68was added under nitrogen to a stirred solution of N-t-butoxycarbonyl-(S)-serine (7.0 g, 34.11 mmol) in dry tetrahydrofuran (150 ml) at 0°C. Ihe ice-bath was removed, stirring continued for 4 hours, then a solution of 4-fluorobenzyl chloride (5.42 g, 37.5 mmol) in dry tetrahydrofuran (50 ml) was added dropwise.
After a further 15 hours more sodium hydride (0.51 g, 17.0 mmol) was added followed, 4 hours later, by more 4-fluorobenzyl chloride (2.47 g, 17.0 mmol). The reaction mixture was stirred for a further 20 hours and then, after destruction of excess sodium hydride using 2-propanol, evaporated under vacuum. The residue was dissolved in water (70 ml), then the solution washed with ether and acidified to pH 3.5 with 2M hydrochloric acid.
Exhaustive extraction with ethyl acetate, washing of the combined extracts with water, followed by evaporation under vacuum of the dried (MgSC>4) extracts, provided an oil (6.3 g). Purification of the oil by chromatography on silica gel using an elution gradient of ethyl acetate:hexane (from 50:50 to 100:0), followed by elution with ethanol:ethyl acetate (10:90), furnished the required product as a colourless solid (1.95 g, 18%), Rf 0.40 (SS 7). Found: C,55.16; H,5.74; N,4.06. C^H^FNOS; 0.20 requires C,55.27; H,6.22; N,4.24%.
PREPARATIONS 18-22 The following Preparations were effected according to the procedure of Preparation 17 using the appropriate alkylating agents. For Preparations 19 and 20, N-t-tutoxycarbonyl-(S) homoserine was the starting material. -69R' t __CH BuOCONH---co2h (S) Preparation No. R3 Rf 18 Cl 0.30 (SS 8) 19 -a^a^oa^Fh 0.40 (SS 8) 20 -(0^0(¾¾ 0.25 (SS 6) 21 -a^oa^c = ch 0.3 (SS 7) 22 -^20¾^ <*2 0.48 (SS 7) —70— PREPARATION 23 N-Trirhenylmethvl-O-2-propenyl-(S)-serine ethvl ester 40% Aqueous sodium hydroxide solution (0.87 ml, 8.66 mmol) was added at 10 °C to a stirred solution of N-triphenytmethyl-Sserine ethyl ester (2.5 g, 6.66 nmol), allyl bromide (886 mg, 7.32 mmol) and benzyltriethylammonium chloride (1.51 g, 6.66 mmol) in dichlorcmethane (10 ml). Ihe mixture was allowed to warm to room temperature and stirred overnight. Dichlorcmethane was added, then the solution washed with water, dried (Mgsop and filtered.
Evaporation under vacuum of the filtrate gave an oil which was chrcmatographed on silica, eluting with a 4:1 mixture of hexane and ethyl acetate, to give the pure product as a colourless oil (2.14 g, 77%), Rf 0.52 (SS 1), [a]25 + 52.3 (c = 0.99, at,Cl ) . z z D Found: C,76.94; H,7.10; N,3.25. ^7^9^3^ 0.1 requires C,76.76; H,6.94; N,3.30%.
PREPARATION 24 (DEPROTECTION METHOD D) 0-(2-Propenvl)-(S)-serine ethyl ester A solution of the above product (1.0 g, 2.4 mmole) in formic acid (15 ml) was allowed to stand at room tenperature for 5 hours. Ihe solvent was then evaporated under vacuum and the residue dried azeotropically with acetonitrile. The resulting white solid was dissolved in water (15 ml) and the solution extracted with diethyl ether. The aqueous phase was basified to pH 9 with sodium carbonate, extracted with ethyl acetate (x 3) and dichlorcmethane (x 2), and then the combined organic extracts dried (MgSO4) and filtered. Evaporation under vacuum of the filtrate gave the pure -71product as an oil (319 mg, 76%), Rf 0.29 (SS 21). Found: C,55.98; H,8.80; N7.99. CgH^^NOj requires C,55.47; H,8.73; N,8.09%.
PREPARATIONS 25-29 Ihe following compounds were prepared from the corresponding N-trityl-(S)-serine ester by alkylation under phase transfer conditions followed by formic acid deprotection as described in the above Preparations. Preparations 25 to 28 are 2 (3-phenyl)propyl esters (R =((3^)3Ph), Preparation 29 is the ethyl ester (R2 = O^Cftj).
CH-.
(S) h2n CO2R2 Example No. R3 Rf Analysis % (Theoretical in brackets) C H N 25 -α^οσ^αΜΗα^οα^ E 0.54 (SS 22) 66.06 (66.42 7.89 8.20 4.47 4.56) 26 -a^oa^cfrCHCitj E 0.45 (SS 22) 61.34 (61.24 7.80 7.71 4.46 4.46)a 27 -0^0(09 3°¾ 0.42 (SS 22) 64.84 (65.06 8.49 8.53 4.80 4.74) 28 -t^OC^CC^OC^ ch2 0.35 (SS 8) 66.39 (66.43 7.92 8.20 4.57 4.56) 29 _ 0.35 (SS 22) a. HCl —72— FREPARATIONS 30-35 The following Preparations were effected according to the procedure of Example 54 using (3-phenyl) propyl bromide with the respective products of Preparations 17-22. r3tBuOCONH-^^' CHco2 (CH2) 3Ph (S) . Prep. No. R3 Rf Analysis % C (theoretic H al in bn N ickets) 30 'σΙ20σ^θΗΡ 0.35 (SS 1) 66.64 (66.80 7.09 7.01 3.23 3.25) 31 Cl 0.30 (SS 1) 32 -(cn^oc^ih 0.40 (SS 1) 33 -(^)30(^)2% 0.25 (SS 6) 58.07 (58.11 9.26 9.40 4.89 4.84) 34 -CH2OCH2OaCH 0.38 (SS 1) 66.56 (66.46 7.56 7.53 3.92 3.83) 35 -aqoa^caq a,2 0.51 (SS 1) 66.50 (66.82 8.30 8.28 3.81 3.71) -73PREPARATION 36 (DEPROTECTION METHOD B) O-Benzvl-(S)-serine methvl ester hydrochloride A stirred, ice-cold solution of the product of Preparation 1 (2.05g, 66.3 mmol) in dichloromethane (50 ml) was saturated with hydrogen chloride. After a further 3 hours at 0°C, the reaction mixture was evaporated under vacuum and the residual solid azeotroped with dichlaronethane (3 x 30 ml) to afford the title ccmpound as a white pcwder (1.67 g, 97%), Rf 0.60 (SS 9), [a]25 D +21° (c = 0.1, MeOH). Found: C,54.14; H,6.54; N,5.75. Ci;lH15NO3; HCI requires C,53.77; H,6.56; N,5.70%.
PREPARATION 37 (DEPROTECTION METHOD C) 0-(2-MethoxyethvI)-(S)-tyrosine t-butvl ester A solution of the product of Preparation 11 (5.4 g) in a mixture of ethanol (40 ml) and water (10 ml) was hydrogenated over % palladium on charcoal at 50 psi (3.45 bar) for 2 hours. The reaction mixture was filtered, the filtrate evaporated under vacuum and the residual oil chromatographed on silica gel (300 g) using a 1:39 mixture of ethanol and ethyl acetate as eluent..
Evaporation under vacuum of the required fractions afforded the title caipound as a clear oil (3.07 g, 82%), Rf 0.30 (SS 8), [a]^5 D + 10.1° (C = 1.63, a^Cip. Found: c,64.67; H,8.54; N,4.63. C16H25NO4 requires C,65.06; H,8.53; N,4.74%. -74FREPARATIONS 38-55 Ihe following Preparations were effected using deprotection Methods A, B or C, with the corresponding N-protected amino acid ester starting material. Method A is described under Example 76 (trifluoroacetic acid), Method B is described under Preparation 36 (hydrogen chloride) and Method C is described under Preparation 37 (hydrogenation).
H2N co2r -75CM <β in co σ σ in in σ σ νό νό σ σ in co • · VO VO η σ co ο α3 fi ef ef ?r fi ί ί co co cn σ -Μ* μ· νο • · Μ* Μ1 Ο ι—Ι σ ο • · Γ- co σ σ co νο • · σ σ ιη ιη σ ιη CM ef e Cl CO σ Μ* Ο Γ- ι—) νό νό Ο Ί· Γ- νο CM CM VO VO σ γμ· η νο νο ιη ο <ο ιη ιη νο νο ο η ι-ι <· $ ο ιη <-ι ιη ό $ ο Ο 1-4 ιη • ω ο ιη if Pi o ΊΤ CM CM co CQ CM V fi Ci af ? CQ cn tr Φ n cn in 3? CO ΓΊ cn σι in in O' 00 m σ> Ol Ol O' co O' > co co 00 KO σι σι CN cn CO 00 co 00 vo vo ko ko CM Ol KO Ol M* CM 4* 4* 0. (SS o c8 ΓΟ £ z—> co ί 1 i=ef d A ? δ ί CQ a •4* in in in o rH « o in o Ol OJ • · o o dd a a sP o o in Spo o ·« oi « o o sP r—l « o (J xJ ϋ T3 φ tp -79PREPARATION 56 O-Benzvl-(S)-serine amide This was obtained in 97% yield as the hydrochloride salt by subjecting N-t-butoxycarbonyl-O-benzyl-(S) -serine amide (Preparation 10) to deprotection Method B; Rf 0.48 (SS 10). Found: C,52.10; H,6.45; N,11.89. CpOH14N2°2' HCl retlaires C,52.06; H,6.55; N,12.14%.
PREPARATION 57 N- C2,2,2-Trichloroethoxycarbanvl) -aziridine-2 (S) -carboxylic acid benzyl ester a) Trifluoroacetic acid (40 ml) was added dropwise over 10 minutes to a stirred, ice-cooled solution of N-trityl-aziridine2-carboxylic acid benzyl ester (10 g, 1.0 eq) in methanol/ chloroform (1:1, 40 ml) and the reaction mixture stirred for 1.5 hours, when the reaction was complete (by TLC). The reaction mixture was evaporated under vacuum to yield a crystalline residue which was partitioned between diethyl ether (100 ml) and water (50 ml). The aqueous phase was extracted with diethyl ether (2 x) and the organic phases combined. The aqueous phase was neutralised with sodium bicarbonate and reextracted with ether. The combined ether extracts were dried (MgSO4), filtered and evaporated to yield an oil (3.93 g). b) A solution of the oil from part (a) (3.39 g) in dichlorcmethane (30 ml) was treated with 2,2,2-trichloroethylchloroformate (4.7 g, 1.0 eq) followed by N-methylmorpholine (2.5 g, 1.1 eq). The resulting solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (70 ml); -80this solution was washed with water ( 3 x 50 ml), hydrochloric acid (2M, 2 x 50 ml), saturated aqueous sodium bicarbonate solution (2 x 30 ml) and brine (1 x 20 ml), then dried (MgSO*) and filtered. Evaporation under vacuum of the filtrate gave the crude product as a pale yellcw oil, which was chrcmatographed on silica gel, eluting with mixtures of hexane and ethyl acetate (from 1-10% of ethyl acetate), to yield the pure title compound as an oil (6.8 g, 81%), [a]D - 20° (c = 0.1, MeOH). Found: C,43.58; H,3.50; N,3.86. C13H12C13NO4 requires C,44.28; H,3.43; N,3.97%.
PREPARATION 58 N- (2,2,2-Trichloroethoxvcarbonvl) -O- (2-fcutynvl) - (S) -serine benzyl ester Boron trifluoride etherate (1 drop) was added to a solution of 2-butyn-l-ol (0.206 g, 2eq) and (S)-N-(2,2,2-trichloroethoxycarbonyl)-aziridine-2-carboxylic acid benzyl ester (0.52 g, 1.0 eq) in dry dichlorcmethane (3 ml) and the reaction stirred for 1 hour at room tenperature. Ihe solvent was evaporated under vacuum, the residue dissolved in ethyl acetate (20 ml) and the solution washed with water (2 x 10 ml), hydrochloric acid (2M, 2 x 10 ml), saturated aqueous sodium bicarbonate solution (1 x 10 ml) and brine (1 x 10 ml), then dried (MgSO4) and filtered.
Evaporation under vacuum of the filtrate gave an oil which was chrcmatographed over silica gel, eluting with mixtures of hexane and ethyl acetate (from 1 to 4% of ethyl acetate) to yield the title conpound as an oil (48 g, 77%), [α]θ -10° (c = 0.1, MeOH).
Rf 0.7 (SS 2). Found: C,48.01; H,4.15; N,3.30. C^H^C^NOg requires C,48.30; H,4.29; N,3.31%. -81PREPARATIONS 59-65 The following compounds were pr^sared according to the method described above: CH C13CCH2O2CNH CO2CH2Ph (S) Prep. No. R3 .Rf Analysis % (Theoretical in brackets) C H N 59 0.81 (SS 2) 47.64 (47.85 4.94 5.19 3.02 3.28) 60 ^°-O 0.40 (SS 1) 48.56 (49.28 5.06 5.05 3.10 3.19) 61 -^001(013)2 0.44 (SS 1) 46.38 (46.56 4.84 4.88 3.36 3.39) 62 -o^ocho^ cf3 0.40 (SS 1) 41.58 (41.18 3.83 3.67 3.06 3.00) 63 0.35 (SS 1) 40.44 (39.80 3.51 3.34 3.06 3.10) 64 0.42 (SS 1) 48.20 (48.07 5.23 4.75 3.32 3.29) 65 0.47 (SS 6) 43.05 (43.04 5.49 5.68 3.60 3.59) -82FREPARATION 66 (DEPROTECTION METHOD E) O-(2-Butvnyl)-(S)-serine benzyl ester Zinc dust (500 mg) was added in one portion to a solution of N-(2,2,2-trichloroethoxycarbonyl) -0-(2-butynyl) - (S) -serine benzyl ester (0.44 g, 1.0 eq) in acetic acid (25 ml) and the mixture stirred at rocsn temperature for 1.5 hours. The zinc was removed by filtration and washed with acetic acid, then the filtrate evaporated under vacuum and the residue azeotroped with toluene. The residue was dissolved in ethyl acetate (20 ml) and the solution washed with saturated aqueous sodium bicarbonate solution (10 ml); the resultant precipitate of sodium acetate was removed by filtration and the filtrate washed again with saturated aqueous sodium bicarbonate solution. The organic phase was extracted with \ hydrochloric acid (2M, 2 x 100 ml), then the combined extracts overlaid with ethyl acetate and neutralised with solid sodium bicarbonate. The organic layer was separated and the aqueous phase reextracted with ethyl acetate, then the combined organic phases dried (MgSO^) and filtered. Evaporation under vacuum of the filtrate provided the title compound as a yellow oil (200 mg, 78%), Rf 0.71 (SS 19).
PREPARATIONS 67-73 The following compounds were prepared by treatment with zinc in acetic acid according to the method described above: CO2CH2Ph Preparation No. R3 Rf 67 ^0(¾) Λ 0.62 (SS 19) 68 <^0 0.18 (SS 20) 69 ^001(01,)2 0.18 (SS 20) 70 -οι,οακΜ, CF3 0.17/0.20 (SS 20) 71 -Οί,οσ^ 0.18 (SS 20) 72 -O^OOL,- 0.18 (SS 20) 73 -0¾0¾ 0.31 (SS 22) -84FREPARATION 74 4-Methoxvroethvl-(S)-phenylalanine t-butvl ester To a vigorously stirred solution of sodium hydroxide (11.5 g, 0.29 mol) in water (23 ml) were added, sequentially, a solution of (4-methoxymethyl)benzyl bromide (3.1 g, 14.4 mmol) in dichlorcmethane (30 ml), N-diphenylmethylene glycine t-butyl ester (4.26 g, 14.4 mmol) and N-berizylcinchonidinium chloride (1.21 g, 2.9 mmol). After 2.5 hours the reaction mixture was diluted with dichlorcmethane (100 ml), then the organic phase separated, washed to neutrality with water, dried (MgSO*) and evaporated under vacuum to provide an oil (7.2 g). Chromatography on silica gel (600 g) using a 4:1 mixture of hexane and ether as eluent afforded a white solid (473 g, 76%) which, on crystallisation from hexane, yielded racemic material (1.71 g), m.p. 8l-82°C. Further chromatography of the crystallisation mother liquor on silica gel using the same eluent gave the required (S)-enantiomer cis a clear oil (2.44 g, 39%), Rf 0.30 (SS 13), [a]25 -145° (c = 1.08, D CH2C12). Found: C,77.93; H,7.2l; N,3.23. C^H^NC^ requires C,78.29; H,7.27; N,3.26%.
A solution of this product (2.3 g, 5.56 mmol) in ether (50 ml) was vigorously stirred with a mixture of 0.5M hydrochloric acid (12.2 ml) and water (40 ml). After 9 hours the aqueous phase was removed and the ether phase treated two further times in the same way. The combined aqueous phases were basified with IM aqueous sodium hydroxide solution and extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated under vacuum to give an oil (960 mg) which was chromatographed on silica gel, using ethyl acetate as eluent, to afford the title compound -85as a clear oil (860 mg, 59%), Rf 0.35 (SS 8), (a]25 + 9.7° (c = D 1.65, a^Cl^. Found: C,67.73; H,8.54; N,5.1O. C15H23NO3 requires C,67.90; H,8.74; N,5.28%.
PREPARATION 75 0-n-Propyl-fS)-serine ethvl ester a) N-(Triphenylmethyl)-0-(2-propenyl)-(S) -serine ethyl ester (Preparation 23, 1.0 g, 2.4 nmol), dissolved in ethanol (36 ml) and water (4 ml), was hydrogenated over 5% palladium on charcoal (300 mg) at 50 p.s.i. (3.45 bar) and roam temperature. After three hours the mixture was filtered through a short arbacel column and the filtrate, on evaporation under vacuum, gave a clear oil (916 mg). Chromatography on silica gel, eluting with a 1:4 mixture of ethyl acetate and hexane gave N-triphenylmethyl-0n-propyl-(S)-serine ethyl ester (697 mg, 69%). Found: C,78.13; H, 8.96; N,3.31. C 1»3 requires 0,77.66; H,7.48; N,3.35%. b) The above intermediate (667 mg, 1.6 mmol) was dissolved in a I. 7% solution of concentrated hydrochloric acid in acetone (30 ml); after five hours a further amount (5 ml) of the above acid solution was added to complete the reaction. After a further half hour the mixture was evaporated under vacuum and the residue dried azeotropically with dichlorcmethane. Trituration with diethyl ether and filtration gave the required product as a white solid (247 mg, 73%), Rf 0.19 (SS 22). Found: C,45.56; H,8.23; N,6.50.
C H C1NO requires C,45.39; H,8.57; N,6.62%. o lo J -86PREPARATION 76 3-r2-(R,S)-Tetrahvdrofurvn-(S)-alanine (3-phenyl) propyl ester a) 3- (2-Furyl)-(S) -alanine (prepared by the method of Η. K. Chenault et al, J. Amer. Chem. Soc., 1981, 111. 6354) was reacted with di-t-butyl dicarbonate to give N-t-butoxycarbonyl-3-(2furyl)-(S)-alanine as a colourless oil, Rf 0.6 (SS 21). b) Ihe previous product (3.0 g, 0.12 mol) in ethyl acetate (40 ml) was hydrogenated over platinum oxide (200 mg) at 60 p.s.i. (4.1 bar) and roan temperature for 2 hours, when uptake was complete. The catalyst was removed by filtration, the filtrate evaporated under vacuum and the residue chromatographed on silica gel eluting with a mixture of dichloromethane, methanol, acetic acid and hexane (90:10:1:150) to give N-t-butoxycarbonyl-3[ (2-(R,S)-tetrahydrofuryl) ]-(S)-alanine (2.04 g) as a mixture of two diastereoisomers, Rf 0.20 (SS 26). c) Alkylation of the previous product with (3-phenyl) propyl bromide following the procedure of Preparation 1, followed by removal of the N-t-butoxycarbonyl protecting group with hydrogen chloride, gave the title compound as a colourless oil, Rf 0.30 (SS 22).
PREPARATION 77 (S)-trans 1-(4-Ethoxv-2-butenvl) glycine methvl ester hydrochloride a) n-Buty 1 lithium (3.15 ml, 7.875 mmol, 2.5M in hexane) was added dropwise over 10 minutes under nitrogen to a stirred solution of 2,5-dihydro-3,6-methoxy-2(R)-(2-propyl)pyrazine (1.38 g, 7.49 mmol) in dry tetrahydrofuran, whilst keeping the -87temperature below -68°C. After 15 minutes a solution of trans l-bromo-4-ethoxy-2-butene (1.34 g, 7.49 mmole) in tetrahydrofuran (5 ml) was added over 10 minutes at -78 °C. The reaction mixture was then allcwed to warm to room temperature overnight, being kept initially at -78°C for at least 5 hours. The solvent was removed under vacuum and the residue partitioned between diethyl ether and water. The organic phase, on drying (MgSO^) and evaporation, gave a golden oil (1.35 g, 65%) which was stirred with 0.25M hydrochloric acid (42.8 ml) for 24 hours. The mixture was evaporated under vacuum and the residue dried azeotropically with dichloromethane followed by toluene.
Di-t-butyl dicarbonate (3.13 g, 14.34 mmol) was added to an ice-cooled solution of the above mixture of esters (2.02 g) and N-methy lmorpholine (1.58 ml) in dry dichloromethane (35 ml), and the resulting solution stood at room temperature for 4 days. The solvent was removed under vacuum and the residue partitioned between diethyl ether and water. The organic phase was washed sequentially with water, IM hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, then dried (MgSO^) and filtered. Evaporation under vacuum of the filtrate gave a yellcw liquid (1.34 g) which was chromatographed on silica gel; elution with increasing proportions of diethyl ether in hexane gave N-t-butoxycarbonyl-2(S)-trans l-(4-ethoxy-2-butenyl) glycine methyl ester as an oil (565 mg, 41%), Rf 0.38 (SS 2). Found: C,58.29; H,8.50; N,5.2l. requires C,58.51; H,8.77; N,4.87%. [a] + 18.6° (c = 1.07, CH2Cl2). -88b) A stirred, ice-cold solution of the above product (492 mg, 1.7 mmol) in dry diethyl ether (15 ml) was saturated over 1.5 hours with hydrogen chloride gas. After being stirred at 0°C for a further 3 hours, the solution was evaporated under vacuum and the residue dried azeotropically with dichlaronethane (x3) to give the title product as a pale yellow foam (320 mg, 84%), Rf 0.32 (SS 14). Found: C, 47.17; H,7.79; N,6.40. CgHlgClNO3. 0.05 CH2Cl2 requires C,47.68; H,7.56; N,6.14%.
PREPARATION 78 (S)-trans l-(4-Methoxv-2-butenvl) glycine methvl ester hydrochloride This was similarly prepared following the procedures described above and was obtained as a white pcwder Rf 0.30 (SS 22). Found: C,45.17; H,7.54; N,6.71. CgHj^NCK^; 0.2 1^0 requires C,45.05; H,7.75; N,6.57%.
PREPARATION 79 2(S)—(4—Methoxy—1—butyl)glycine methvl ester This compound was obtained iron the previous product (free base), according to Preparation 75a, as a yellow oil, Rf 0.15 (SS 22).
PREPARATION 80 l-{3-fN-t-Butoxycarbonvl-(S)-prolylamino1-2(S)-t-butoxycarbonylpropyl)cvclopentane carboxylic acid N-t-Butoxycarbonyl-(S)-proline 4-nitrophenyl ester (2.89 g, -898.59 mmol) was added to a stirred suspension of l-[3-ainino-2(S)-tbutoxycarbonylpropyl] cyclopentane carboxylic acid sodium salt (EP-A-358398; 1.70 g, 5.90 mmol) in dry dichloromethane (30 ml). After 24 hours the reaction mixture was evaporated under vacuum and the residue allowed to stand for a further 24 hours before being partitioned between ethyl acetate (200 ml) and 2M hydrochloric acid (100 ml). Ihe organic phase was separated, washed successively with 2M hydrochloric acid (2 x 50 ml), saturated aqueous sodium bicarbonate solution (4 x 50 ml), more 2M hydrochloric acid (50 ml) and saturated brine (50 ml), dried (MgSO4), filtered, and the filtrate evaporated under vacuum. The resulting yellow oil (4.59 g) was purified by chromatography on silica gel (200 g), using an elution gradient of 1% acetic acid in ethyl acetate / 0 to 10% methanol, to furnish the title compound cis a cream foam (1.096 g, 40%), Rf 0.53 (SS 14), [a]2^ -161° (c = D 0.1, MeOH). Found: C,61.20; H,8.81; N,5.43. c24H40N2°7 requires C,61.51; H,8.60; N,5.98%.
PREPARATIONS 81-82 Ihe following compounds of formula (V) were prepared from the appropriate proline derivatives using the procedure described above for Preparation 80. —90— Preparation No. R9 Rf Analysis % (Theoretical in brackets) C H N 81 0.25 (SS 8) 64.75 (64.52 7.60 7.62 5.53 5.57) 82 (ci) 300^003- 0.50 (SS 21) 48.74 (48.58 5.85 6.12 5.69 5.15) PREPARftTIQN 83 1- Γ 3-Benzyloxvcarbonvlamino-2 (S) -t-butoxycarbony lpropyl 1 cyclopentane carboxylic acid To a stirred, ice-cold suspension of l-[3-aitiino-2(S)-tbutoxycarbonylpropyl ] cyclopentane carboxylic acid sodium salt (1.0 g, 3.4 mmol) in dry dichlorcmethane (15 ml) were added, sequentially, N-methy lmorpholine (0.4 ml, 4.0 mmol) and Nbenzyloxycarbony loxysuccinind.de (930 mg, 3.75 mmol). After 1 hour the ice bath was removed and stirring was continued for 24 hours. The reaction mixture was evaporated under vacuum, then the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with 1M hydrochloric acid and water, dried (MgSO4) and filtered. Evaporation under vacuum of the filtrate provided an oil (1.4 g) which was purified by chromatography on silica gel, using a 7:3 mixture of ether and hexane as eluent, to give the title ccnpound as a gum (900 mg), Rf 0.50 (SS 2). -91Bioloqical activity The following Table illustrates the dual in vitro enzyme inhibitory activities for a range of the compounds of the invention.
EXAMPLE NUMBERIC50 <M> ANGIOTENSIN CONVERTING ENZYME (ACE) NEUTRAL METALLOENDOPEPTIDASE (E.C. 3.4.24.11) 86 87 92 128 130 131 133 134 136 137 138 144 145 1.3 X 10? 1.4 X 10 T 2.6 X 10 ® 1.6 X 10 g 4.0 X 10 β 3.7 x 1O‘“ 3.2 x 10 * 1.6 x 10 ° 1.5 X 10 “ 1.4 x 10 * 2.4 x 10 ® 6.6 X 10 * 1.1 X 10 3.0 x 10“® 2.0 X 10 ° 2.0 X 10 ° 4.1 X 10 ° 1.8 x io : 4.8 x 10 J 4.0 X 10 “ 3.4 xlO J 1.5 X 10 “ 3.6 X 10° 3.2 X 10 ® 3.3 X 10 “ 4.1 x 10 Safety profile The prodrugs of the invention have been tested orally in rat at doses up to 10 mg/Kg and the diacids of the invention have been tested intravenously in rat at doses up to 10 mg/Kg. No signs of adverse acute toxicity were observed.

Claims (29)

1. A compound of formula: 12 . wherein R and R are each independently H or a biolabile 1 2 ester-forming group, and either or both of OR and OR may optionally be replaced by NH^· R 3 is (a) £Η<αφ η οα^-#Υ^ 6 R 5 R 5 6 . wherein R is H or methyl, R is H or halo, and n is 0 or 1; (b) O^OR 7 wherein R 7 is Ο-^-Οθ alkyl, C 3 ~C 6 alkenyl, C 3 ~Cg alkynyl, C^-C? cycloalkyl, (C^-C^ alkoxy)C^-C^ alkyl, (C-j-C alkoxy)C 3 -C g alkenyl, (halo)C 3 ~C 6 alkenyl, (C^-C? cycloalkyl)C^-Cg alkyl or (CF 3 )C 3 -C 6 alkyl; R wherein R 8 is CE^OO^, 5 jCS^CM or OCH 2 CH 2 OCH 3 and R is as previously defined; -93(d) or (e) alkoxy) C^-C^ alkenyl or (C 1 ~C 4 alkoxy)C_-C^ alkyl; 2. Ό 4 and R is H or hydroxy; and pharmaceutically acceptable salts thereof. 1 2
2. A compound as claimed in claim 1 wherein R and R are each independently selected from H, C^-Cg alkyl, Cg-C.? cyeloalkyl, (cyclohexyl) C^-C., alkyl, (phenyl)C^-C 3 alkyl, 1-(C 2 ~C 5 alkanoy loxy) C^-C 4 alkyl, l-(Cg-Cg cycloalky lacetoxy)C^-C^ alkyl, 1-(C 5 -C 7 eyeloalkyIcarboxy)C 1 ~C 4 alkyl, 1-(2-indanyIcarboxy)C-j-C^ alkyl, 1-(benzoyloxy)alkyl, 3-phthalidyl, 1-((^-04 alkoxycarbonyloxy)Cj-Cj alkyl, [4-(5-(0^-(^ alkyl]-l,3-dioxolen-2onyl) ]methyl, acetonyl, indanyl and pyridyl. . 1 2
3. A ccnpound cis claimed in claim 2 wherein R and R are each independently selected from H, methyl, ethyl, (3-cyclchexyl)propyl, (3-phenyl) propyl, pivaloyloxymethyl, l-(cyclohexylacetoxy)ethyl, l-(cyclohexylcarboxy)ethyl, 1-(2-indanyIcarboxy)ethyl, 1-( benzoy loxy) ethyl, l-(ethoxycarbony loxy) ethyl or [4-(5-methyl-l, 3-dioxolen-2-onyl) ]methyl.
4. A compound as claimed in claim 3 wherein R is benzy loxymethyl, 1-(2-butenyl)oxymethyl, l-(4-methoxy-2-butenyl)oxymethyl or 2-chloro-2-propenyloxymethyl, and R is H. . . 1 . 2 .
5. A compound as claimed in claim 4 wherein R is H, and R is methyl, (3-phenyl)propyl or (3-eyelohexyl)propyl. -946. A conpound as claimed in claim 4 wherein is pivaloyloxymethyl, 1-(cyclohexylacetoxy) ethyl, 1-(cyclohexy Icarboxy) ethyl, l-(2-indanyIcarboxy)ethyl, l-(benzoyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl or [4-(5-methyl-l,3-dioxolen-2-onyl) ]methyl, 2 . and R is ethyl. . . 1 2
6. 7. A compound as claimed in claim 1 wherein both R and R are H.
7. 8. A conpound as claimed in claims 1 to 7 wherein the preferred stereoisomer is of formula:
8. 9. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
9. 10. A conpound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either, for use in medicine.
10. 11. The use of a conpound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either, for the manufacture of a medicament for the treatment of hypertension, heart failure or renal insufficiency.
11. 12. A compound of formula: -95R 9 OYl . 1' 2' ... 12 wherein R and R are as defined in claim 1 for R and R . 1’ 2' . . respectively but are not H, and CR and CR are as defined xn . 1 2 4 . . . 9 . claim 1 far CR and CR , R is as defined in claim 1, R is a conventional amino acid N-protecting group and R^° is as defined in claim 1 for R with any reactive groups therein optionally protected. 1’ 2' 12. 13. A ccmpound as claimed in claim 12 wherein R and R are each independently selected frcm t-butyl and benzyl. -9614. A process for the preparation of a compound of formula: wherein
12 . . R and R are each independently H or a biolabile 1 2 ester-forming group, and either or both of OR and OR may optionally be replaced by r 3 is (a) R 5 F wherein R 5 is H or methyl, R 6 is H or halo, and n is 0 or 1; (b) O^OR 7 wherein R is C^-C g alkyl, c 3~Cg alkenyl, C 3 -O 6 alkynyl, ^-0^ cycloalkyl, (Cj-C^ alkoxy)Cj-Cg alkyl, ( C |~C 4 alkoxy)C^-C^ alkenyl, (halo)C 3 -C 6 alkenyl, cycloalkyl)C^-Οθ alkyl or (CF 3 )0^-0^ alkyl; < C > “2^0^ θ R wherein R 8 is O^OH, CH2OCH3, OCH(R 5 )CH2OH or 5 OCH„CH_OCH_ and R is as previously defined; -97 2 or (e) (C^-C^ alkoxy) C^-Cg alkenyl or (C-^-C^ alkoxy)C_-C- alkyl; 2 o
4 . and R is H or hydroxy; or a pharmaceutically acceptable salt thereof, which comprises 9 10 removing R , any protecting group present in R , and optionally 1* either one or both of any biolabile ester-forming groups R and 2' R which may be present, from a ccnpound of formula: 4 9 wherein R is as previously defined, R rs a conventional amino acid N-protecting group, R 10 is as defined for R 3 with any 1' 2 1 reactive groups therein optionally protected, and R and R are 12 1' 2' cis defined for R and R but are not H, and OR and OR are as
12 . defined for OR and CR , and optionally isolating as, or forming, a pharmaceutically acceptable salt of the product. 1 2
15. A process as claimed in claim 14 wherein R and R are each independently selected from H, Cj-C 5 alkyl, cycloalkyl, -98(cyclahexyl)C-^-C^ alkyl, (phenyl)C^-C^ alkyl, 1-(C 2 “C 5 alkanoyloxy)C^-C^ alkyl, 1-(0^-0^ cycloalkylacetoxy)C-^-C^ alkyl, l-fCg-Cy cycloalkylcarboxy) C^-C 4 alkyl, 1-{2-indanylcarboxy)C^-C^ alkyl, 1-(benzoyloxy)C^-C^ alkyl, 3-phthalidyl, 1-(C 1 -C 4 alkoxycarbonyloxy)C^-< 4 alkyl, [4-(5-[Gj-C 4 alkyl]-l,3-dioxolen-2onyl) ]methyl, acetonyl, indanyl and pyridyl. . . . 1 2
16. A process as claimed in claim 15 wherein R and R are each independently selected frcm H, methyl, ethyl, (3-cyclohexyl)propyl, (3-phenyl)propyl, pivalcyloxymethyl, l-(cyclchexylacetoxy) ethyl, 1- (cyclohexylcarboxy) ethyl, 1- (2-indanylcarboxy) ethyl, 1-(benzoyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl or [4-(5methyl-1,3-dioxolen-2-onyl) jmethyl. 1 . 2 .
17. A process as claimed in claim 16 wherein R is H, and R is methyl, (3-phenyl)propyl or (3-cyclchexyl) propyl.
18. A process as claimed in claim 16 wherein R 1 is pivalcyloxymethyl, 1- (cyclohexylacetoxy) ethyl, 1- (cyclohexylcarboxy) ethyl, 1-(2-indanylcarboxy)ethyl, 1-(benzoyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl or [4-(5-methyl-l,3-dioxolen-2-onyl) ]2 . methyl, and R is ethyl.
19. A process as claimed in any one of claims 14 to 18 wherein R is t-butoxycarbony 1, benzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl and is removed by acidolysis, hydrogenolysis and treatment with zinc in glacial acetic acid respectively.
20. A process for the preparation of a ccmpound of formula (I) 1 2 3 4 ... wherein both R and R are H and R and R are as defined in claim 13. 14, or a pharmaceutically acceptable salt thereof, vhieh comprises 1 . 2 . subjecting a compound of formula (I) wherein R is H, R is a 3 4 biolabile ester-forming group and R and R are cis defined in -99claim 14 to base hydrolysis and optionally isolating as, or forming, a pharmaceutically acceptable salt of the product. • ' 3
21. A process cis claimed in any one of claims 14 to 20 wherein R is benzyloxymethyl, 1-( 2-butenyl) oxymethyl, l-(4-methoxy-24 butenyl) oxymethyl or 2-chloro-2-propenyloxymethyl, and R is H.
2 2. A process as claimed in any one of claims 14 to 2l wherein the preferred stereoisomer of the product is of formula: and that of the precursor intermediate is of formula: 100
23. A compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt thereof, which is specifically hereinbefore mentioned.
24. A process for the preparation of a compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples and Preparations.
25. A compound of the formula I given and defined in claim 1 or a pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in any one of claims 15-22 or 24.
26. A pharmaceutical composition according to claim 9, substantially as hereinbefore described.
27. Use according to claim 10, substantially as hereinbefore described.
28. Use according to claim 11, substantially as hereinbefore described.
29. A compound of the formula IV given and defined in claim 12, which is specifically hereinbefore mentioned.
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