EP0594588A1 - Agents antihypertensifs au glutaramide substitue par cycloalkyle - Google Patents

Agents antihypertensifs au glutaramide substitue par cycloalkyle

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Publication number
EP0594588A1
EP0594588A1 EP91903839A EP91903839A EP0594588A1 EP 0594588 A1 EP0594588 A1 EP 0594588A1 EP 91903839 A EP91903839 A EP 91903839A EP 91903839 A EP91903839 A EP 91903839A EP 0594588 A1 EP0594588 A1 EP 0594588A1
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EP
European Patent Office
Prior art keywords
alkyl
alkoxy
formula
group
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP91903839A
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German (de)
English (en)
Inventor
John Christopher Danilewicz
Keith James
Alan John Collis
David Brown
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Pfizer Inc
Original Assignee
Pfizer Ltd
Pfizer Inc
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Publication of EP0594588A1 publication Critical patent/EP0594588A1/fr
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
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    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are antihypertensive agents having utility in the treatment of various cardiovascular disorders, including hypertension and heart failure.
  • A completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
  • Y is an alkylene group of from 1 to 9 carbon atoms which may be straight or branched chain;
  • R 1 is H or (C 1 -C 4 )alkyl; R and R 4 are each independently H, (C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or an alternative biolabile ester-forming group; R 2 is hydroxy , (C 1 -C 6 )alkoxy, hydroxy (C 2 -C 6 ) alkoxy, (C 1 -C 6 ) alkyl-
  • R 6 is H, (C 1 -C 4 )alkyl or aryl(C 1 -C 4 )alkyl; or R 2 is a group of the formula R 7 R 8 CH- in which case Y may also be a direct link and wherein R 7 is (R 5 ) 2 N(C 1 -C 4 ) alkyl, (C 1 -C 4 )- alkoxy(C 2 -C 4 )alkylaminomethyl, heterocyclyl(C 1 -C 4 )alkyl or aryl and R 8 is (C 1 -C 8 ) alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 6 )alkoxy,
  • R 2 is a group of the formula R 9 CO- wherein R 9 is a 1-piperidine or 1-piperazine group, either of which may optionally be
  • R 2 is a group of the formula R 10 CONR 6 - wherein R 6 is as previously defined, and R 10 is (R 6 ) 2 N, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkyl, R 11 R 12 CH-, or substituted phenyl wherein the substituent is
  • R 3 is a group of the formula:
  • R 13 is H, halo, 4-OH, 4-(C 1 -C 6 alkoxy),
  • R 14 is H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 2 -C 6 ) alkanoyl or halo; or R 3 is a group of the formula:
  • each R is H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 ) alkyl or the two groups R 5 are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C 1 -C 4 )alkyl-piperazinyl group;
  • R is (C 1 -C 4 )alkyl-S(O) n NH- or (C 1 -C 4 )alkanoylamino and R 12 is (C 1 -C 4 )alkyl-S(O) n (C 1 -C 4 ) alkyl or morpholinomethyl or R 11 and R 12 are both morpholinomethyl or (C 1 -C 4 )alkoxy(C 1 -C 4 )alkoxy(C 1 -C 4 )- alkyl; n is 0, 1 or 2 and pharmaceutically acceptable salts thereof and bioprecursors therefor.
  • alkyl groups having three or more carbon atoms may be straight or branched-chain.
  • aryl as used herein means an aromatic hydrocarbon group such as phenyl or naphthyl which may optionally be substituted with, for example, one or more OH, CN, CF 3 , (C 1 -C 4 ) alkyl, (C 1 -C 4 )alkoxy, halo, carbamoyl, aminosulphonyl, amino, mono or di(C 1 -C 4 alkyl)amino, (C 1 -C 4 alkanoyl)amino, amino (C 1 -C 4 )alkyl, di(C 1 -C 4 alkyl)amino(C 1 -C 4 )alkyl, or (C 1 -C 4 ) alkyl-S(O) n - (C 1 -C 4 )alkyl groups.
  • Halo means fluoro, chloro, bromo or iodo.
  • heterocyclyl means a 5 or 6 membered nitrogen, oxygen or sulphur containing heterocyclic group which, unless otherwise stated, may be saturated or unsaturated and which may optionally include a further oxygen or one to three nitrogen atoms in the ring and which may optionally be benzofused or substituted with for example, one or more halo, (C 1 -C 4 )alkyl, hydroxy, carbamoyl, benzyl, oxo, amino or mono or di-(C 1 -C 4 alkyl)amino or (C 1 -C 4 alkanoyl)amino groups.
  • heterocycles include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, piperidino, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, indolyl, isoindolinyl, quinolyl,
  • the compounds of formula (I) may contain several asymmetric centres and thus they can exist as enantiomers and diastereomers.
  • the invention includes both the separated individual isomers as well as mixtures of isomers.
  • 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.
  • acids include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate tosylate and lauryl sulphate salts.
  • bioprecursor in the above definition means a pharmaceutically acceptable biologically degradable derivative of the compound of formula (I) which, upon administration to an animal or human being, is converted in the body to produce a compound of the formula (I).
  • examples include biolabile ester derivatives and amide or amino acid derivatives of the compounds of formula I.
  • a preferred group of compounds of the formula (I) are those wherein A is (CH 2 ) 4 and R 1 is H, i.e. compounds of the formula (II) wherein R, R 2 , R 3 and R 4 are as previously defined for formula (I):
  • R and R 4 are both H (diacids) as well as biolabile mono and di-ester derivatives thereof wherein one or both of R and R 4 is a biolabile ester-forming group.
  • biolabile ester-forming group is well understood in the art as meaning a group which provides an ester which can be readily cleaved in the body to liberate the corresponding diacid of formula (I) wherein R and R 4 are both H.
  • a number of such ester groups are well known, for example in the penicillin area or in the case of the ACE-inhibitor antihypertensive agents.
  • biolabile pro-drug esters are particularly advantageous in providing compounds of the formula (I) suitable for oral
  • the ester should only be hydrolysed after absorption, accordingly, the ester should be resistant to hydrolysis by digestive enzymes before absorption but should be readily hydrolyzed by, for example, gut-wall, plasma or liver enzymes. In this way the active diacid is released into the bloodstream following oral absorption.
  • biolabile esters include
  • alkanoyloxyalkyl esters including alkyl, cycloalkyl and aryl substituted derivatives thereof, aroyloxyalkyl esters, arylesters, aralkylesters, haloalkyl esters and hydroxyalkyl esters including ketal derivatives thereof, wherein said alkanoyl or alkyl groups have from 1 to 18 carbon atoms and are branched or straight chain and said aryl groups are phenyl, naphthyl or indanyl optionally substituted with one or more (C 1 -C 14 ) alkyl, (C 1 -C 14 ) alkoxy or
  • R and R 4 when they are biolabile ester groups include ethyl, indanyl, isopropyl, n-butyl, sec-butyl, t-butyl, cyclohexyl, benzyl, phenethyl, phenpropyl, acetonyl, glyceryl, pivaloyloxymethyl, 5-(4-methyl-1,3-dioxolene-2- onyl)methyl, cyclohexylt ⁇ ethyl, cyclohexylcarboxyethyl,
  • the group R 3 is
  • the substituent R 2 Y is preferably (C 1 -C 6 )alkoxy(C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 4 ) alkyl.
  • R 2 Y is preferably (C 1 -C 6 )alkoxy(C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy(C 1 -C 6 )alkoxy(C 1 -C 4 ) alkyl.
  • Particular and preferred examples include ethoxyethyl and 2-(methoxyethoxy)- propyl.
  • R 2 Y is amino(C 4 -C 9 )alkyl.
  • a particular and preferred example of this type is 8-amino- octyl.
  • Y is CH 2 and R 2 is of formula R 10 CONR 6 - wherein R 6 is H.
  • R 10 is substituted phenyl particularly when said substituent is H 2 NCH 2 -, (CH 3 ) 2 NCH 2 - or CH 3 S(O) n CH 2 - (wherein n is
  • the reaction of the compounds of formula (III) and (IV) 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 biproduct and evaporation of the solvent.
  • the product may be further purified by
  • the compounds of formula (V) include compounds of formula (I) wherein R and R 4 are C 1 -C 6 alkyl or benzyl.
  • the diesters of formula (V) are subsequently reacted to give the monoester or diacid derivatives of formula (I) wherein one or both of R and R 4 are H.
  • the conditions used will depend on the precise nature of the groups R 17 and R 18 present in the compound of formula (V) and a number of variations are possible. Thus for example when both of R 17 and R 18 are benzyl, hydrogenation of the product will yield the diacid of formula (I) wherein R and R 4 are both H. Alternatively if one of R 17 and R 18 is benzyl and the other is alkyl, hydrogenation will yield a monoester product.
  • R 2' and R 3' must also be removed and this may be performed concominantly with removal of protecting groups present in R 17 and R 18 or as a separate step using procedures appropriate to the particular protecting group employed.
  • R 2' contains a substituted or protected amino group (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) the compounds may be converted to the free amines by hydrogenation or hydrolysis as appropriate.
  • R 10 is as previously defined, and wherein any reactive groups therein are optionally protected, to yield for example a compound of the formula:
  • R 10' is as previously defined for R 10 with any reactive groups therein optionally protected; and subsequently removing any protecting groups, if present and hydrolysing the ester product to yield the compounds of formula (I) wherein R and R 4 are H.
  • the reaction of the amine of formula (VI) and acid of formula R CO 2 H is achieved using conventional amide coupling techniques as previously described.
  • the acid chloride may be prepared by first reacting the amine with phosgene; subsequent reaction with the amine of formula (VI) yields the urea products. Subsequent removal of protecting groups is achieved using appropriate procedures as previously described.
  • the amines of formula (VI) are prepared following the same procedure outlined in process (a) above but using an acid of formula (III) wherein R 2' is a protected amine.
  • the coupling reaction with the amino acid derivative is achieved using a compound of formula (III) wherein R 2 is dibenzylamino or di(alpha-methylbenzyl)amino .
  • the coupling process may be performed using an acid of formula (III) wherein R 2' is halo (e.g. bromo). This may then be reacted with an amine of formula (R 5 ) 2 NH to yield the compounds wherein R 2' is (R 5 ) 2 N-, or with an azide to give compounds wherein R 2' is N 3 . Subsequent reduction of the azide group by catalytic hydrogenation, either on the protected product or on the deprotected diacid, gives the corresponding amine of formula (I) wherein R 2 is NH 2 .
  • an acid of formula (III) is used wherein R Y- is 2-propenyl.
  • oxidation may be performed either on the protected diester formula (V) or on the deprotected diacid product.
  • the product may be obtained as the free carboxylic acid or it may be neutralised with an appropriate base and isolated in salt form.
  • the starting spiro-substituted glutaric acid mono esters of formula (III) may be prepared as described in our European patent application 274234.
  • the amino acid esters of formula (IV) are generally known compounds which are either commercially available or they may be prepared by standard methods in
  • the compounds of the invention 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).
  • ANF atrial natriuretic factor
  • 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, hyperaldosteroneism (primary and secondary) and hypercalciuria.
  • 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 and gastrointestinal disorders
  • the compounds 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 coronory angioplasty or coronory artery bypass surgery. Their activity against this enzyme is assessed using a modified procedure based on the assay described by Rohrbach, M.S., Anal. Biochem., 1978, 84, 272. The method involves determining the concentration of compound 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 the 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
  • mice Male mice (Charles River CDl, 22-28 g) are acclimatised and starved overnight in metabowls. 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 volume and sodium ion concentration from the test animals are compared to a control group which received only saline.
  • the antihypertensive activity of the compounds is evaluated by measuring the fall in blood pressure following oral or intravenous administration to salt depleted, diuretic primed, spontaneously hypertensive rats, salt depleted renally
  • oral dosages of the compounds 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 but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this
  • the compounds of the formula (I) can be administered alone, but will generally be administered in
  • 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 example, 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 or with an alpha-blocker, beta-blocker, exogenous ANF or with a potassium channel activator or another diuretic agent as shall be determined by the physician as appropriate to the particular patient or disease state.
  • the invention provides a
  • composition comprising a compound of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compounds of the formula (I) or (II), or a pharmaceutically acceptable salt thereof or
  • bioprecursor therefor for use in medicine, in particular in the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
  • R 1 9 dimethyl-t-butylsilyl
  • Tetramethylguanidinium azide (0.7 g, 6 mmol) was added as a solution in chloroform (10 ml) to a solution of 1-[2(RS)-t- butoxycarbonyl-10-bromodecyl]-1-cyclopentane carboxylic acid (1.4 g, 3 mmol) in chloroform (10 ml). A few crystals of potassium iodide were added and the resulting mixture was refluxed for 21 ⁇ 2 days. The cooled reaction mixture was then diluted with chloroform (20 ml) and washed with water (2 x 20 ml), dried (MgSO 4 ), filtered and evaporated. The residue was chromatographed on silica gel using a gradient of ethyl acetate and hexane to give the title compound as an oil (0.69 g, 54%). Found: C,63.84;
  • Osmium tetroxide (56 mg, 0.2 mmol) was added as a 2.5% w/v solution in t-butanol (2.25 ml) to a stirred solution of 1-[2(RS)- t-butoxycarbonyl-4-pentenyl]1-cyclopentane carboxylic acid benzyl ester (8.25 g, 22 mmol) in acetonitrile (60 ml) and water (10 ml) at room temperature. After 30 minutes, the black-brown solution was treated with sodium metaperiodate (10 g, 47 mmol) in one portion. Stirring was continued for 18 hours and then the suspended solid was filtered and washed with a small portion of acetonitrile.
  • Examples 25 and 26 are the 2(R) isomers
  • Example 28 is the 2(S) isomer.
  • Tributyltin hydride (0.5 ml, 1.86 mmol) was added to a solution of the iodo compound from Example 30 (590 mg, 0.78 mmol) in dry tetrahydrofuran (10 ml). After heating at 55°C for 16 hours, the solution was diluted with diethyl ether, washed with dilute potassium fluoride solution (x4) and then with saturated salt solution. Drying (MgSO 4 ) and evaporation under reduced pressure gave an oil which was chromatographed on silica. Elution with a mixture of diethyl ether and hexane (1:1) gave the required product as an oil (410 mg, 83%). Rf 0.32 (ether/hexane 1:1).
  • Example 17 The title compound was prepared from Example 17 by oxidation with metachloroperoxybenzoic acid following the procedure of Example 40 and was obtained as a foam.
  • Rf 0.63 ethyl acetate. Found: C,56.09; H.7.47; N.5.58.
  • C H N S requires C,56.39; H,7.80; N,5.33%.
  • triphenylphosphine (402 mg, 1.53 mmol) were added at 10°C under nitrogen to a stirred solution of the product of Example 42 (640 mg, 1.023 mmol) in tetrahydrofuran (6 ml). Diethyldiazodicarboxylate (0.24 ml, 1.53 mmol) in tetrahydrofuran (2 ml) was slowly added dropwise and the mixture stirred for 20 hours at room temperature. The mixture was then evaporated to dryness, the residue preabsorbed on silica and chromatographed.
  • Trifluoroacetic acid (5 ml) was added to an ice cold solution of N-[1- ⁇ 2(S)-t-butoxycarbonyl)-4-(2-methoxyethoxy)pentyl ⁇ -cyclo- pentanecarbonyl]-O-t-butyl-(S)-tyrosine t-butyl ester (from
  • Example 32 390 mg, 0.62 mmol) and anisole (998 mg, 9.2 mmol) in dry methylenechloride (5 ml). After standing at 0°C overnight the solution was evaporated to dryness under reduced pressure and dried azeotropically with toluene. The residual gum was dissolved in ether and the product was extracted with IN sodium hydroxide (10 ml). The basic extract was then acidified with concentrated hydrochloric acid, saturated with salt and extracted with ethyl acetate. Washing with brine, drying (MgSO 4 ) and evaporation gave a glass which was crushed to a white powder (275 mg) . Rf 0.52 (ss 7). Found: C.61.22; H,7.52; N.2.99. C 24 H 35 NO 8 , 0.1 CH 3 CO 2 C 2 H 5 , 0.25 H 2 O requires C.61.20; H,7.64; N,2.92%.
  • Example 49, 50, 52 and 53 were purified by ion-exchange chromatography using Dowex AG 5OW - X8 resin and eluting with 5% aqueous pyridine.
  • Examples 51 and 52 are the 2S isomers.
  • Examples 55-58 and 62 are 2S isomers.
  • Example 65 The title compound was prepared from the azido derivative of Example 65 above by hydrogenation, following the procedure given in Example 37 (part b). The product was obtained as a foam Rf 0.59, (ss 3). Found: C.64.10; H,8.49; N,4.73. C 26 H 40 N 2 O 6 . 0.5 H 2 O requires 0,64.30; H,8.51; N,5.76%.
  • N-methylmorpholine (5.25 g, 52 mmole) and the solution allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure and the resultant mobile oil was dissolved in methylene chloride and washed with water (2 x ), 2M

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Abstract

On décrit des composés de formule (I), où A complète un anneau carbocyclique à 5 ou 6 branches qui peut être saturé ou mono non saturé; Y est un groupe alkylène ayant entre 1 et 9 atomes de carbone; R1 est H ou (C1-C4)alkyle; R et R4 sont H, (C1-C6)alkyle, (C3-C7)cycloalkyle, benzyle, ou un autre groupe biolabile formant des esters; R2 est défini pour inclure une série de groupes substituants comprenant (C1-C6)alkoxy, (C1-C4)alkoxy-(C1-C6)alkoxy et divers substituants à substitution d'alkyle, amino, à substitution d'amino, aryle et hétérocyclyle liés directement ou par O, S(O)n, NR6, CO ou CONR6, où R6 est H, (C1-C4)alkyle ou aryle(C1-C4)alkyle et n est 0, 1 ou 2; R3 est un groupe de la formule (II), où R13 est H, halo, 4-OH, 4-(C1-C6alkoxy), 4-(C3-C7 cycloalkoxy), 4-(C2>-C6 alkényloxy), 4-[(C1-C6alkoxy)carbonyloxy], 4-[(C3-C7 cycloalkyloxy)carbonyloxy], ou 3-(C1-C4 alkyl)SO2NH-; et R14 est H, (C1-C4)alkyle, (C1-C4alkoxy, (C2-C6alkanoyle ou halo; ou R3 est un groupe de formule (III) où lesdits groupes peuvent être substitués facultativement dans l'anneau de benzène fusionné par (C1-C4)alkyle, (C1-C4)alkoxy, OH, halo ou CF3; ou ils sont des inhibiteurs d'atriopeptidase utiles dans le traitement de l'hypertension et d'insuffisance cardiaque.
EP91903839A 1990-02-26 1991-02-14 Agents antihypertensifs au glutaramide substitue par cycloalkyle Withdrawn EP0594588A1 (fr)

Applications Claiming Priority (3)

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GB9004260 1990-02-26
GB909004260A GB9004260D0 (en) 1990-02-26 1990-02-26 Therapeutic agents
PCT/EP1991/000296 WO1991013054A1 (fr) 1990-02-26 1991-02-14 Agents antihypertensifs au glutaramide substitue par cycloalkyle

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CA (1) CA2073450A1 (fr)
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GB (1) GB9004260D0 (fr)
IE (1) IE910615A1 (fr)
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US5298492A (en) * 1992-08-04 1994-03-29 Schering Corporation Diamino acid derivatives as antihypertensives
US5208236A (en) * 1992-09-23 1993-05-04 Schering Corporation N-(acylaminomethyl)glutaryl amino acids and use
US5432186A (en) * 1993-11-16 1995-07-11 Ciba-Geigy Corporation Cyclic amino acid derivatives
ATE193706T1 (de) * 1993-11-16 2000-06-15 Novartis Ag Zyklische aminosäure-derivate mit ace und nep inhibierender aktivität
EP1233013B1 (fr) * 1999-11-18 2007-02-28 Ajinomoto Co., Inc. Nouveaux derives de la phenylalanine
WO2002079143A1 (fr) 2001-03-28 2002-10-10 Pfizer Limited Derives de guataramide n-phenpropylcyclopentyl-substitues utilises comme inhibiteurs nep pour fsad
US6660756B2 (en) 2001-03-28 2003-12-09 Pfizer Inc. N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
US7045653B2 (en) 2002-12-23 2006-05-16 Pfizer, Inc. Pharmaceuticals

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KR880007441A (ko) * 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
GB2218983A (en) * 1988-05-27 1989-11-29 Pfizer Ltd Spiro-substituted glutaramides as diuretics
GB8812597D0 (en) * 1988-05-27 1988-06-29 Pfizer Ltd Therapeutic agents
GB8820844D0 (en) * 1988-09-05 1988-10-05 Pfizer Ltd Therapeutic agents

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FI923780A (fi) 1992-08-21
CA2073450A1 (fr) 1991-08-27
IE910615A1 (en) 1991-08-28
PT96863A (pt) 1991-11-29
FI923780A0 (fi) 1992-08-21
WO1991013054A1 (fr) 1991-09-05
GB9004260D0 (en) 1990-04-18

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