WO1992014706A1 - Agents anti-hypertenseurs a base de glutaramide derive de cyclopentane - Google Patents

Agents anti-hypertenseurs a base de glutaramide derive de cyclopentane Download PDF

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Publication number
WO1992014706A1
WO1992014706A1 PCT/EP1992/000321 EP9200321W WO9214706A1 WO 1992014706 A1 WO1992014706 A1 WO 1992014706A1 EP 9200321 W EP9200321 W EP 9200321W WO 9214706 A1 WO9214706 A1 WO 9214706A1
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alkyl
ethyl
compound
formula
methyl
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Inventor
David Brown
Alan John Collis
John Christopher Danilewicz
Keith James
Ryszard Jurek Kobylecki
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Pfizer Ltd Great Britain
Pfizer Inc
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Pfizer Ltd Great Britain
Pfizer Inc
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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

Definitions

  • 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.
  • the present invention includes further novel cyclopentylsubstitaited 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 cxarnpounds, which have unproved 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 conversion to the active diacid species takes place.
  • R 1 and R 2 are each independently H or a biolabile
  • OR 1 and OR 2 may optionally be replaced by NH 2 ;
  • R 3 is (a)
  • R 5 is H or methyl, R 6 is H or halo, and n is 0 or 1;
  • R 7 is C 1 -C 6 alkyl, C 3 -C 6 alkenyl
  • R 8 is CH 2 OH, CH 2 OCH, OCH(R 5 )CH 2 OH or
  • R 4 is H or hydroxy
  • 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.
  • 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.
  • biolabile mono- or diester prodrugs are particularly advantageous in providing compounds of the formula (I) suitable for oral
  • ester-forming group can be assessed by conventional in vivo animal or in vitro enzyme hydrolysis studies.
  • the ester should only be hydrolysed after absorption is complete.
  • 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.
  • Suitable biolabile esters include alkyl, alkanoyloxyalkyl, cycloalrcanoyloxyalkyl, aroyloxyalkyl and alkoxycarbonyloxyalkyl esters, including cycloalkyl and aryl substituted derivatives thereof, aryl esters, cycloalkyl esters, haloalkyl esters,
  • Qxoalkyl esters dihydroxyalkyl esters including ketal derivatives thereof, pyridyl esters and [4-(5-alkyl or 5-aryl-1,3-dioxolen-2- onyl]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 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 4 alkoxycarbonyl groups or with halo atoms.
  • ester-forming groups include C 1 -C 5 alkyl, C 5 -C 7 cycloalkyl,
  • alkanoyloxy C 1 -C 4 alkyl
  • Preferred biolabile ester-forming groups are methyl, ethyl, (3-cyclohexyl)propyl, (3-phenyl)propyl, pivaloylojcyitiethyl, 1-(cyclohexylacetoxy) ethyl, 1-(cyclohexylcarboxy) ethyl, 1-(2-indanylcarboxy)ethyl, 1-(benzoyloxy)ethyl, 1-(ethoxycarbonyloxy)-ethyl and [4-(5-methyl-1,3-dioxolen-2-onyl) ]methyl.
  • the invention also includes amide derivatives (wherein either or both of OR 1 and OR 2 are replaced by NH 2 ). Such compounds are also bioprecursors to the dicarboxylic acids and their suitability too may be assessed as indicated above.
  • the compounds of the formula (I) contain three or more asymmetric centres and thus they can exist as enantiomers or diastereoisomers.
  • the 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.
  • radiolabelled derivatives of c ⁇ tpounds 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.
  • 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 die-thylamine.
  • Co ⁇ pounds having a basic centre can also form acid addition salts with pharmaceutically acceptable acids.
  • acids include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, citrate, tartrate, lactate, fumarate, maleate, succinate, gluconate, methanesulphonate, berizenesulphonate and p-toluenesulphonate salts.
  • Preferred compounds are prodrug mono or diesters of compounds of the formula (I) wherein R 3 is benzyloxymethyl (O-benzyl serine derivates) , 1-(2-butenyl)oxymethyl, 1-(4-methoxy-2-butenyl)oxymethyl or 2-chloro-2-pro penyloxymethyl.
  • R 4 is preferably H.
  • Preferred mono-esters are those wherein R 1 is H and R 2 is methyl
  • R 1 is pivaloyloxymethyl, 1-(cyclohexylacetoxy)- ethyl, 1-(cyclchexylcarboxy)ethyl, 1-(2-indanylcarboxy)ethyl, 1- (benzoyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl or [4-(5-methyl-1,3- dioxolen-2-onyl]methyl, and R 2 is ethyl.
  • the biologically active species in vivo are the diacids, that is compounds of the formula (I) wherein both R 1 and R 2 are H, and R 3 and R 4 are as previously defined for the formula (I).
  • these diacids form a further preferred aspect of the invention.
  • the compounds of the formula (I) can be prepared by a number of methods using the coupling and protective procedures of amino-acid chemistry.
  • One procedure involves coupling of a suitably
  • R 4 is as previously defined and R 9 is a conventional amino acid N-protecting group such as t-butoxycarbonyl, 2,2,2txichloroethoxycarbonyl or benzyloxycarbonyl, with an amine of the formula (III) , wherein R 1 ' and R 2 ' are as previously defined for R 1 and R 2 respectively but are not H, and R 10 is as defined for R 3 with any reactive groups therein optionally protected, to provide a compound of the formula (IV) as shown in the following reaction scheme:
  • the reaction of the compounds of formula (II) and (III) is achieved using conventional amide coupling techniques.
  • the reaction is achieved with the reactants dissolved in an organic solvent, e.g. dichloromethane, using a diimide condensing agent, for example 1-ethyl-3-(dimethylaminopropyl)-carbodiimide, or N,N'-dicyclohexylcarbodiimide, advantageously in the presence of 1-hydroxybenzotriazole 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 conventional procedures, i.e. by washing with water, or filtration, to remove the urea by-product and evaporation of the solvent.
  • the product may be further purified by crystallisation or chromatography if necessary.
  • diester products of formula (IV) may be obtained by coupling compounds of formulae:
  • the diesters of formula (IV) are subsequently deprotected to give the diester, monoester or diacid derivatives of formula (I).
  • the conditions used will depend on the precise nature of the groups R 1' and R 2' in the compound of formula (IV) and a number of variations is possible.
  • treatment of the compound of formula (IV) with hydrogen chloride or trifluoroacetic acid yields a monoalkyl ester of formula (I) wherein one of R 1' and R 2' is H and the other is alkyl.
  • a further variation is that in which a monoester of formula (I), wherein R 1 is H and R 2 is a biolabile ester-forming group, is converted to a diacid of formula (I), wherein both R 1 and R 2 are
  • NH 2 are obtained by starting with the appropriate amide derivative corresponding with formila (III), (V) or (VI) in the coupling step, that is wherein either of OR 1' or OR 2' is NH 2 or both of
  • OR 1' and OR 2' are NH 2 .
  • Required diester prodrugs which are not directly accessible from compounds of formula (IV) may be obtained from monoesters of formula (IV) wherein either R 1' or R 2' is H. This may be achieved for exanple by alkylation of an alkali metal, preferably caesium, salt of the monoacid with the recjuired alkyl halide, preferably bromide 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 9 and/or any protecting group contained in R 10 , are carried out as appropriate to afford compounds of formula (I) wherein neither R 1 nor R 2 is H.
  • novel compounds of the formula (IV), wherein R 1' and R 2' 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.
  • the compounds of formula (I) may be isolated as, for example, hvdrochloride or sodium salts directly from the previous
  • deprotecticn step may be converted to other pharmaceutically acceptable acid addition, alkali metal or alkaline earth metal salts by routine procedures.
  • the compounds of formula (V) are preparable according to processes described in EP-A-0358398, by coupling the sodium salt of l-(2-t-butoxycarbonyl-3-aminopropyl)cyclopentane carboxylic acid with the proline fragment (II).
  • novel ⁇ -amino esters of formula (VI) may be prepared from commercially available N-protected ⁇ -amino acid derivatives such as those of glycine, serine or tyrosine by established methods in accordance with literature precedent.
  • N-protected ⁇ -amino acid derivatives such as those of glycine, serine or tyrosine
  • standard alkylation of the serine alcoholic hydroxyl group provides ether derivatives
  • Mitsunobu or Heck modification of the tyrosine phenolic hydroxyl group or its trifluoromethanesulphonyl derivative respectively leads to a variety of 4-alkoxy or 4-alkyl phenylalanine derivatives, which are also obtainable by
  • 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 therefrom wherein R 1 and R 2 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).
  • 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 c ⁇ ipounds 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,
  • the compounds Menieres disease, hyperaldosteronism (primary and secondary) and hypercalciuria.
  • the compounds because of their ability to potentiate the effects of ANF, the compounds have utility in the treatanent of glaucoma.
  • the compounds of the invention may have activity in other therapeutic areas iricluding for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity, gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome) , the modulation of gastric acid secretion and the treatment of hyperrerdnaemia.
  • the 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. Rohrbach, Anal. Biochem., 1978, 84, 272. The method involves de-termining the concentration of compound required to reduce by 50% the extent of release of radiolabelled hippuric acid from Mppuryl-I ⁇ histictyl-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 Methods, 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.
  • male mice (Charles River CDl, 22-28 g) are acclimatised and starved overnight in bowls. Ihe 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
  • the systemic bioavailability of diacid obtained after oral administration of a prodrug of the invention is deterinined, e.g. in rat, by measuring the fraction of the biologically active doserecovered 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.
  • 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.
  • 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) .
  • individual tablets or capsules contain 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.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case taut there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the compounds 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.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected
  • parenterally for exanple intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose to make the solution isotonic with blood.
  • the 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.
  • 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 de-termined by the physician as appropriate to the particular patient or disease state.
  • the invention provides a
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either, for use in medicine.
  • the 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.
  • the invention yet further includes a method for the
  • Example 1 The following Examples were obtained according to the method of Example 1 using 1- ⁇ 3-[N-t-butoxycarbonyl-(S)-prolylamino-2(S)-t-butoxycarbarylpropyl ⁇ cyclopentane carboxylic acid and the appropriate ⁇ -amino ester of formula (VI) from the Preparations section.
  • 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 room temperature. After eighteen hours the reaction was evaporated under vacuum to low 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. The crude product was extracted with ethyl acetate (3 ⁇ 30 ml) and the combined extracts were washed with brine, dried (MgSO 4 ) and evaporated under vacuum.
  • Example 67 the corresponding alkyl iodide was used and for Examples 59, 61 and 68 the corressponding alkyl bromides were used.
  • Example 45 Deprotection of Example 45 with trifluoroacetic acid according to Method A (Example 76), followed by conversion of the monocarrojsylic acid product to its caesium salt and reaction with (1-isobutyryloxy)ethyl chloride following the procedures described above, gave the title compound as a white foam, Rf 0.44, 0.51 (SS 8). Found: C,52.63; H,6.21; N,7.15. C 34 H 47 N 4 O 10 Cl 3 requires C,52.48; H,6.09; N,7.20%.
  • esters were prepared from the appropriate acid and amine starting materials using the carbodiimide coupling described in Example 1.
  • 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 ⁇ 20 ml) then dissolved in water (5 ml). The aqueous solution was washed with diethyl ether (2 ⁇ 50 ml), then subjected to ion-exchange chromatography
  • N-Trichloroethoxycarbonyl derivatives were deprotected following deprotection method E (zinc in acetic acid) and N-t-butyloxycarro ⁇ yl derivative were deprotected using deprotection method B (hydrogen chloride) .
  • 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).
  • Example 77 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-di ⁇ xan (2 ml) . After 48 hours the pH of the solution was adjusted to 8 using dilute hydrochloric acid, then the solution subjected to ioii-exchange ciir ⁇ natography (AG50 resin) using water and then. a 1-10% aqueous pyridine gradient as eluents.
  • Examples 149-153 were obtained from toe appropriate precursor N-protected proline diester derivatives (Examples 29-33).
  • Examples 157-158 are the result of three successive
  • 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
  • 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) . The ice bath was removed, then the reaction mixture was stirred for 24 hours at room temperature and evaporated under vacuum.
  • HCl requires C,53.77; H,6.56; N,5.70%.
  • dichlorcmethane (30 ml) was treated with 2,2,2-trichloroethylchlorofornate (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 tenperature and stirred overnight.
  • the solvent was evaporated under vacuum and the residue dissolved in ethyl acetate (70 ml); this solution was washed with water ( 3 ⁇ 50 ml) , hydrochloric acid (2M, 2 ⁇ 50 ml) , saturated aqueous sodium bicarbonate solution (2 ⁇ 30 ml) and brine (1 ⁇ 20 ml) , then dried (MgSO 4 ) and filtered.
  • Zinc dust 500 mg was added in one portion to a solution of
  • N-(2,2,2-trichloroethoxycarbonyl)-O-(2-butynyl)-(S)-serine benzyl ester (0.44 g, 1.0 eq) in acetic acid (25 ml) and the mixture stirred at room temperature for 1.5 hours.
  • the zinc was removed by filtration and washed with acetic acid, then the filtrate evaporated under vacuum and toe residue azeotroped with toluene.
  • the catalyst was removed by filtration, toe filtrate evaporated under vacuum and the residue chromatographed on silica gel eluting with a mixture of dichlorometoane, methanol, acetic acid and hexane (90:10:1:150) to give N-t-butoxycarbonyl-3- [ (2-(R,S)-te-trahydrofuryl) ]-(S)-alanine (2.04 g) as a mixture of two diastereoisomers, Rf 0.20 (SS 26) .
  • n-Butyllithium (3.15 ml, 7.875 mmol, 2.5M in hexane) was added dropwise over 10 miinutes 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 temperature below -68°C.
  • a solution of trans 1-bromo-4-ethoxy-2-butene (1.34 g, 7.49 mmole) in tetrahydrofuran (5 ml) was added over 10 minutes at -78°C.
  • reaction mixture was then allowed to warm to room tenperature overnight, being kept initially at -78°C for at least 5 hours.
  • the solvent was removed under vacuum and toe residue partitioned between diethyl ether and water.
  • the organic phase on drying (MgSO 4 ) and evaporation, gave a golden oil (1.35 g, 65%) which was stirred wito 0.25M
  • N-t-Butoxycarbonyl-(S)-proline 4-nitrophenyl ester (2.89 g, 8.59 mmol) was added to a stirred suspension of 1-[3-amino-2(S)-t-butoxycartonylpropyl]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.
  • the organic phase was separated, washed successively with 2M hydrochloric acid (2 ⁇ 50 ml), saturated acjueous sodium bicarbonate solution (4 ⁇ 50 ml), more 2M hydrochloric acid (50 ml) and saturated brine (50 ml), dried (MgSO 4 ), filtered, and the filtrate evaporated under vacuum.
  • N-methylmorpholine 0.4 ml, 4.0 mmol
  • N- benzyloxycarbonyloxysuccinimide 930 mg, 3.75 mmol
  • 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 (MgSO 4 ) and filtered.
  • 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.

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Abstract

Composés de la formule (I) dans laquelle R1 et R2 représentent chacun indépendament H ou un groupe formant ester-biolabile, et OR1 et/ou OR2 peuvent être facultativement remplacés par NH¿2; R?3 a la formule (a) dans laquelle R5 représente H ou méthyle, R6 représente H ou halo, et n représente O ou 1; (b) CH¿2?OR?7 où R7¿ représente alkyle C¿1?-C6, alcényle C3-C6, alkynyle C3-C6, cycloalkyle C3-C7, alkyle C1-C6(alcoxy C1-C4), alcényle C3-C6 (alcoxy C1-C4), (halo)alcényle C3-C6, alkyle C1-C6(cycloalkyle C3-C7) ou alkyle C1-C6 (CF3); la formule (c) dans laquelle R?8¿ représente CH¿2?OH, CH2OCH3, OCH(R?5)CH¿2OH ou OCH2CH2OCH3 et R5 a la notation ci-dessus définie; la formule (d) ou (e) alcényle C¿3?-C6(alkoxy C1-C4) ou alkyle C2-C6 (alkoxy C1-C4); et R?4¿ représente H or hydroxy; et les sels pharmaceutiquement acceptables desdits composés. Lesdits composés constituent des agents diurétiques et natriurétiques présentant une utilité dans le traitement de l'hypertension, de l'insuffisance cardiaque, de l'insufisance rénale ainsi que d'autres troubles.
PCT/EP1992/000321 1991-02-19 1992-02-12 Agents anti-hypertenseurs a base de glutaramide derive de cyclopentane Ceased WO1992014706A1 (fr)

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GB9103454.6 1991-02-19
GB919103454A GB9103454D0 (en) 1991-02-19 1991-02-19 Therapeutic agents

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939455A (en) * 1997-03-11 1999-08-17 Beacon Laboratories, Inc. Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
US6130248A (en) * 1996-12-30 2000-10-10 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
US6140319A (en) * 1999-03-29 2000-10-31 Bristol-Myers Squibb Co. Vasopeptidase inhibitors to treat angina pectoris
JP2006511575A (ja) * 2002-12-23 2006-04-06 ファイザー・インク エンドペプチダーゼ阻害剤としてのシクロペンチル置換グルタルアミド化合物
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
WO2009127546A1 (fr) 2008-04-16 2009-10-22 F. Hoffmann-La Roche Ag Activateurs de pyrrolidinone glucokinase
WO2009145816A3 (fr) * 2008-04-01 2010-02-25 The University Of North Carolina At Chapel Hill Nouveaux dérivés substitués par n-benzylamide d'acide 2-(acylamido)acétiques et acides 2-(acylamido)propioniques : agents neurologiques puissants
US7687553B2 (en) 2004-08-27 2010-03-30 Schwarz Pharma Ag Method for treating bone cancer pain or chemotherapy induced pain
US7875652B2 (en) 2001-03-21 2011-01-25 Ucb Pharma Gmbh Method and composition for treating pain or tinnitus aureum
WO2011009845A1 (fr) 2009-07-23 2011-01-27 F. Hoffmann-La Roche Ag Activateurs de la glucokinase à base de pyridine
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
US8008351B2 (en) 2004-04-16 2011-08-30 Ucb Pharma Gmbh Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
US8053476B2 (en) 2001-03-20 2011-11-08 Ucb Pharma Gmbh Method for treating peripheral neuropathic pain
WO2011157682A1 (fr) 2010-06-17 2011-12-22 F. Hoffmann-La Roche Ag 3 -oxo-3, 9 -dihydro- 1h-chroméno [2, 3 -c] pyrroles convenant comme activateurs de glucokinase
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
US8829033B2 (en) 2009-09-23 2014-09-09 The University Of North Carolina At Chapel Hill N-benzylamide substituted derivatives of 2-(acylamido)acetic acid and 2-(acylamido)propionic acids: potent neurological agents
US9095557B2 (en) 2006-06-15 2015-08-04 Ucb Pharma Gmbh Anticonvulsant combination therapy
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique
JP2023099607A (ja) * 2018-11-07 2023-07-13 中外製薬株式会社 Ｏ－置換セリン誘導体の製造方法

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EP0274234A2 (fr) * 1986-12-11 1988-07-13 Pfizer Limited Glutaramides spiro-substitué comme agents diurétiques
EP0358398A1 (fr) * 1988-09-05 1990-03-14 Pfizer Limited Glutaramides cycloalkyl substitués comme agents antihypertensifs

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EP0274234A2 (fr) * 1986-12-11 1988-07-13 Pfizer Limited Glutaramides spiro-substitué comme agents diurétiques
EP0358398A1 (fr) * 1988-09-05 1990-03-14 Pfizer Limited Glutaramides cycloalkyl substitués comme agents antihypertensifs

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Title
Journal of Medicinal Chemistry, vol. 13, no. 2. March 1970, N.C. CHATURVEDI et al.: "Analogs of angiotensin II. I. Solid phase synthesis", pages 177-181, see entire publication *
Journal of Medicinal Chemistry, vol. 15, no. 8, 1972, M.C. KHOSLA et al.: "Synthesis of some analogs of angiotensin II as specific antagonists of the parent hormone", pages 792-795, see entire publication *

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6130248A (en) * 1996-12-30 2000-10-10 Bar-Ilan University Tricarboxylic acid-containing oxyalkyl esters and uses thereof
US5939455A (en) * 1997-03-11 1999-08-17 Beacon Laboratories, Inc. Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
US6140319A (en) * 1999-03-29 2000-10-31 Bristol-Myers Squibb Co. Vasopeptidase inhibitors to treat angina pectoris
US8053476B2 (en) 2001-03-20 2011-11-08 Ucb Pharma Gmbh Method for treating peripheral neuropathic pain
US7875652B2 (en) 2001-03-21 2011-01-25 Ucb Pharma Gmbh Method and composition for treating pain or tinnitus aureum
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
US8796331B2 (en) 2002-01-17 2014-08-05 Novartis Ag Methods of treatment and pharmaceutical composition
US8101659B2 (en) 2002-01-17 2012-01-24 Novartis Ag Methods of treatment and pharmaceutical composition
JP2006511575A (ja) * 2002-12-23 2006-04-06 ファイザー・インク エンドペプチダーゼ阻害剤としてのシクロペンチル置換グルタルアミド化合物
US8008351B2 (en) 2004-04-16 2011-08-30 Ucb Pharma Gmbh Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
US7687553B2 (en) 2004-08-27 2010-03-30 Schwarz Pharma Ag Method for treating bone cancer pain or chemotherapy induced pain
US8536137B2 (en) 2004-08-27 2013-09-17 Ucb Pharma Gmbh Methods for treating nucleoside-induced pain
US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
US11642329B2 (en) 2005-11-09 2023-05-09 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
EP3685833A1 (fr) 2005-11-09 2020-07-29 Novartis AG Composé comprenant un arb et un nepi
US9388134B2 (en) 2005-11-09 2016-07-12 Novartis, Ag Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl)-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
US8877938B2 (en) 2005-11-09 2014-11-04 Novartis Pharmaceuticals Corporation Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
US9446011B2 (en) 2006-06-15 2016-09-20 Ucb Pharma Gmbh Anticonvulsant combination therapy
US9095557B2 (en) 2006-06-15 2015-08-04 Ucb Pharma Gmbh Anticonvulsant combination therapy
WO2009145816A3 (fr) * 2008-04-01 2010-02-25 The University Of North Carolina At Chapel Hill Nouveaux dérivés substitués par n-benzylamide d'acide 2-(acylamido)acétiques et acides 2-(acylamido)propioniques : agents neurologiques puissants
US8933065B2 (en) 2008-04-01 2015-01-13 The University Of North Carolina At Chapel Hill N-benzylamide substituted derivatives of 2-(acylamido)acetic acid and 2-(acylamido)propionic acids: potent neurological agents
WO2009127546A1 (fr) 2008-04-16 2009-10-22 F. Hoffmann-La Roche Ag Activateurs de pyrrolidinone glucokinase
WO2011009845A1 (fr) 2009-07-23 2011-01-27 F. Hoffmann-La Roche Ag Activateurs de la glucokinase à base de pyridine
US8829033B2 (en) 2009-09-23 2014-09-09 The University Of North Carolina At Chapel Hill N-benzylamide substituted derivatives of 2-(acylamido)acetic acid and 2-(acylamido)propionic acids: potent neurological agents
WO2011157682A1 (fr) 2010-06-17 2011-12-22 F. Hoffmann-La Roche Ag 3 -oxo-3, 9 -dihydro- 1h-chroméno [2, 3 -c] pyrroles convenant comme activateurs de glucokinase
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
EP3943084A1 (fr) 2012-08-24 2022-01-26 Novartis AG Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique
JP2023099607A (ja) * 2018-11-07 2023-07-13 中外製薬株式会社 Ｏ－置換セリン誘導体の製造方法
US12312297B2 (en) 2018-11-07 2025-05-27 Chugai Seiyaku Kabushiki Kaisha O-substituted serine derivative production method
JP7685551B2 (ja) 2018-11-07 2025-05-29 中外製薬株式会社 Ｏ－置換セリン誘導体の製造方法

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GB9103454D0 (en) 1991-04-03

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