EP0513016A1 - Agents diuretiques a base de glutaramide a substitution cycloalkyle - Google Patents

Agents diuretiques a base de glutaramide a substitution cycloalkyle

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Publication number
EP0513016A1
EP0513016A1 EP91901493A EP91901493A EP0513016A1 EP 0513016 A1 EP0513016 A1 EP 0513016A1 EP 91901493 A EP91901493 A EP 91901493A EP 91901493 A EP91901493 A EP 91901493A EP 0513016 A1 EP0513016 A1 EP 0513016A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
group
aryl
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.)
Withdrawn
Application number
EP91901493A
Other languages
German (de)
English (en)
Inventor
John Christopher Danilewicz
David Brown
James Keith
Ian Thompson Barnish
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP0513016A1 publication Critical patent/EP0513016A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—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 ring other than a six-membered aromatic ring of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are diuretic agents having utility in a variety of therapeutic areas including the treatment of various cardiovascul ar disorders such as hypertension, heart failure and renal insuffici ency.
  • EP-A-0274234 and EP-A-0343911 we describe and claim certain cycloalkyl-substituted glutaramide derivatives as diuretic agents.
  • the present invention provides further related compounds having a 2,3-d-hydroindene substituent.
  • the compounds have utility in the treatment of glaucoma.
  • the compounds of the invention may have activity in other therapeutic areas ircluding for example the treatment of asthma, innflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders
  • the compounds of the present invention are of the formula:
  • R is H, C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group
  • R 1 is H or C 1 -C 4 alkyl
  • R 2 is H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo or CF 3 ;
  • R 3 is CH 2 OH or CO 2 R 4 wherein R 4 is as previously defined for R;
  • R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl,
  • R 5 is C 1 -C 6 alkyl substituted by halo, hydroxy, C 1 -C 6 .
  • R 5 is C 1 -C 6 alkyl substituted by a group of the formula:
  • R 6 and R 7 are each inde pendently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, aryl, aryl (C 1 -C 4 )alkyl, C 2 -C 6 alkoxyal kyl, or heterocyclyl; or the two groups R 6 and R 7 are taken together with the nitrogen to which they are attached to form a pyrrolidirfyl, piperidino, morpholino, piperazinyl or N-(C 1 -C 4 )alkyl-piperazinyl group;
  • R 8 is H or C 1 -C 4 alkyl
  • R 8 is C 1 -C 4 alkyl, CF 3 , aryl, aryl(C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkoxy, heterocyclyl, C 1 -C 4 alkoxy or NR 6 R 7 wherein R 6 and R 7 are as previously defined;
  • R 10 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, aryl or heterocyclyl;
  • R 11 is H, C 1 -C 6 alkyl, aryl or C 3 -C 7 cycloalkyl
  • R 12 is R 11 CONR 11 -, R 11 SO 2 NR 11 -, R 16 R 17 N- (CH 2 ) p -, or
  • R 11 O-, wherein each R 11 is as previously defined above;
  • R 13 and R 14 are each independently H or C 1 -C 6 alkyl
  • R 13 is H and R 14 is C 1 -C 6 alkyl which is substituted by
  • R 15 is R 16 R 17 NCO-, R 11 OCO-, R 11 OCH 2 - or heterocyclyl, wherein R 11 is as previously defined above;
  • R 16 and R 17 are each independently H orC 1 - C 6 alkyl; and p is 0 or an integer of from 1 to 6;
  • alkyl groups having three or more carbon atoms may be straight or branched-chain .
  • aryl as used herein means an arotatic hydrocarbon group such as phenyl, naphthyl or biphenyl which may optionally be substituted with one or more OH, CN, CF 3 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy groups or halo atoms.
  • 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, carbamcyl, 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, imiidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl,
  • the compounds of formula (I) may contain several asymmetric centres and thus they can exist as enantiomers and diastereomers .
  • the invention includes both mixtures and the separated individual 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.
  • bases which form non-toxic salts.
  • examples include the alkali 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. Examples include the hydrochloride
  • hydrobromide sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts.
  • bioprecursor in the above definition means a pharmaceu tically 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).
  • a preferred group of compounds of the formula (I) are those wherein A is (CH 2 ) 4 and R 1 and R 2 are H, i.e. compounds of the formula (II) below wherein R, R 3 and R 5 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 before absorption by digestive enzymes but should be readily hydrolysed by, for example, liver enzymes. In this way the active diacid is released into the bloodstream following oral absorption.
  • suitable biolabile esters include alkancyloxyalkyl esters, including alkyl, cycloalkyl and aryl substituted
  • alkancyl groups have from 2 to 8 carbon atoms and said alkyl groups have from 1 to 8 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 4 alkyl or C 1 -C 4 alkoxy groups or halo atoms.
  • ester-forming groups other than ethyl and benzyl include:
  • phenpropyl 2,2,2-trifluoroethyl, 1- or 2-naphthyl, 2,4- dimethylphenyl, 4-t-butyl-phenyl, 5-(4-methyl-1,3-dioxalynyl - 2-onyl)methyl and 5-indarryl.
  • R 5 is methylene substituted by a group of the formula -NHCOCR 12 R 13 R 1 4 , particularly where R 12 is NH 2 , R 11 CONH- or R 11 SO 2 NH-, R 13 is H andR 14 is -(CH 2 ) 4 NH 2 .
  • Particularly preferred are such groups derived from S-lysine; thus especially preferred R 5 substitutents of this type include S-lysyl-aminomethyl , N 2 -acetyl-S-lysylaminome thyl andN 2 -methanesulphonyl-S-lysyl-aminomethyl.
  • R 5 is C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by C 1 -C 6 alkoxy, particularly
  • Particularly preferred individual compounds of the invention include:
  • the compounds of formula (I) are prepared by a number of different processes.
  • the basic procedure involves the synthesis of a partially protected cycloalkyl-substi tuted glutaric acid derivative which is coupled to an amine to give the desired glutaramide.
  • the carboxylic acid group in the amine, if free, or any reactive groups in R 5 may require protection during the coupling step and such protecting groups are removed in the final stages of the process.
  • 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 4-methylmorpholine.
  • 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 4-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.
  • the compounds of formula (V) include compounds of formula (I) wherein R and R 4 are
  • the coupled product in protected form, may be subjected to conventional chemical transformation reactions to allow preparation of further compounds of formula (V).
  • compounds of formula (V) wherein R 5' contains an ester group may be hydrolysed or hydrogenated to generate the carboxylic acid which may be further reacted, for example with an amine, to give amide derivatives.
  • R 5' contains a substituted or protected amino group (for example a benzylamino, dibenzylamino, benzyloxycarbonylamino or t-butyloxycarbonylamino group) may be converted to the free amines by hydrogenation or protonolysis as appropriate.
  • the amines produced may be further reacted, thus for example reaction with a sulphonyl halide yields the corresponding sulphonamides, acylation with an acid chloride or anhydride yields the corresponding amides, reaction with an isocyanate yields urea derivatives and reaction with a chloroformate yields the carbamate products respectively. All these transformations are entirely conventional and appropriate conditions and reagents for their performance will be well known to those skilled in the art as will other variations and possibilities.
  • the diesters of formula (V) wherein R 3' is CO 2 R 19 may be further reacted to give the monoester of 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 18 and R 19 present in the compound of formula (V) and a number of variations are possible. Thus for example when both of R 18 and R 19 are benzyl, hydrogenation of the product will yield the diacid of formula (I) wherein R 3 is OX 2 R 4 and R and R 4 are both H.
  • R 18 and R 19 are benzyl and the other is alkyl
  • hydrogenation will yield a monoester product. This can be hydrolysed, if desired, again to yield the diacid product.
  • R 18 and R 19 is t-butyl
  • treatment of the compound of formula (V) with trifluoroacetic acid yields the c orresponding acid.
  • the diester product wherein R 18 and R 19 are benzyl or lower alkyl can also be treated with trimethylsilyl iodide to produce the dicarboxylic acid product. If some other carboxylic acid protecting group is used for R 18 or R 19 then clearly appropriate conditions for its removal must be employed in the final step to give the ester or diacid product of formula (I).
  • R 5' can contain a bis-[(1S)-phenylethyl]aminomethyl substituent.
  • the starting cycloalkyl-substituted glutaric acid mono esters of formula III may be prepared as described in our European patent applications EP-A-0274234, 89305180.5 and 89304698.7.
  • the amines of formula (IV) are generally known compounds or they are prepared by appropriate synthetic procedures in accordance with literature precedents.
  • the compounds of formula (IV) wherein R 3 is CH 2 OH may be prepared by reduction of the corresponding acid, or lower alkyl ester for example using sodium borohydride.
  • 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 and, in particular, it is involved in the breakdown of atrial natriuretic factor (ANF).
  • ANF atrial natriuretic factor
  • This hormone consists of a family of related natriuretic peptides, secreted by the heart, of which the major circulating form in humans is kncwn to be the 28 amino-acid peptide referred to as alpha-hANP.
  • the compounds of the invention can potentiate its biological effects and the compounds are thus diuretic and natriuretic agents of utility in a number of disorders as previously described.
  • mice Male mice (Charles River CD1, 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 c ompared to a control group which received only saline.
  • oral dosages of the compounds will generally be in the range of from 4-800 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 2 to 400 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 400 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 regain to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regain 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 administered alone but may also be administered together with such other agents as the physician shall direct to optimise control of blood pressure or to treat congestive heart failure, renal insufficiency or other disorders in any particular patient in accordance with established medical practice.
  • the compounds can be co-administered with a variety of cardiovascular agents, for example with an ACE inhibitor such as captopril or enalapril to facilitate the control of blood pressure in treatment of hypertension; or with digitalis, or another cardiac stimulant, or with an ACE inhibitor, for the treatment of congestive heart failure.
  • a calcium antagonist e.g.
  • nifedipine, amlodopine or diltiazem a bete-blocker (e.g.
  • Atenolol or an alpha-blocker (e.g. prazosin or doxazosin) as shall be determined by the physician as appropriate for the treatment of the particular patient or condition involved.
  • an alpha-blocker e.g. prazosin or doxazosin
  • the compounds may also be any organic compound.
  • the compounds may also be any organic compound.
  • the invention provides a
  • pha ⁇ taceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I), or a pharmaceutically acceptable salt thereof or bioprecursor therefor, for use in medicine, particularly for use as a diuretic agent for the treatment of hypertension, congestive heart failure or renal insufficiency in a human being.
  • the invention further includes the use of a compound of the formula (I) for the manufacture of a medicament for the treatment of hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Mesnieres disease, hyperaldosteronism, pulmonary oedema, ascites, hypercalciuria, glaucoma, asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity,
  • gastrointestinal disorders including diarrhoea
  • hyperreninaemia including diarrhoea
  • leukaemia including diarrhoea
  • modulation of gastric acid secretion including diarrhoea, hyperreninaemia, leukaemia, and the modulation of gastric acid secretion.
  • the crude acid chloride was dissolved in dry dichloromethane (15 ml), then the resulting solution added dropwise to a stirred, ice-cold solution of the product from step (a) (500 mg, 1.87 mmol) and dry triethylamine (210 mg, 2.06 mmol) in dry dichloromethane (25 ml); stirring was continued for 1 hour at 0oC, then for 16 hours at room temperature.
  • the reaction mixture was diluted with dichloromethane (60 ml), washed successively with water, 1M hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water, dried (anhydrous Na 2 SO 4 ) and filtered.
  • Example 1(b) The procedure of Example 1(b) was followed using 1-[2 (R,S)- benzyloxycarb onyl-4- methoxybutyl]cyclopentane carboxylic acid (334 mg, 1 mmole) and 2-amino-2,3-di hydroindene-2-carboxylic acid benzyl ester (267 mg, 1 mmol) , to furnish the required diester (430 mg, 72.5%) . Found: C,72.95; H,7.03 ; N,3.08. C 3 6 H 41 NO 6 ; 0.5 H 2 O requires C,72.75; H,7.14; N,2.36%. (b) 2- ⁇ 1-[2 (R,S)-Carboxy-4-methoxy butyl]cyclopentylcarbonyl- amino ⁇ -2 ,3-di hydroi n dene-2-carboxylic acid
  • Trifluoroacetic acid (5 ml) was added dropwise to a stirred solution of the above product (1.28 g, 1.5 mmol) in dry
  • Example 3 The procedure of Example 3 was followed but using N 6 - ben zyloxyca rbo nyl-N 2 -methanesulponyl-S-lysine in step (d) .
  • Example 3 The procedure of Example 3 was followed but using 1- ⁇ 2(S)- tert-butoxycarbonyl-3-[(S,S)-alpha, alpha 1 -1-dimethyldibenzyl- amino)prcpyl]cyclopentane carboxylic acid in step (b) to give the title product, in 79.1% yield. Found: C, 75.45; H,8.30; N,4.01. C 42 H 54 N 2 O 5 requires C,75.64; H,8.16; N,4.20%.
  • Example 8(b) The procedure of Example 8(b) was followed using 1-[2 (R,S)- benzyloxycarbonyl-4-phenylbutyl]cyclopentanecarboxylic acid as starting material and allowing the reaction mixture to stand at room temperature for a further 5 days. The required product was obtained as an oil (19.9%) . Rf (silica) 0.15 (diethyl ether- hexane, 1:1) .
  • Example 10 The procedure of Example 10 was followed but losing the N-hydroxybenzotriazole-derived activated ester of 2(S)-tert- butyloxycarbonyl-3-[(S,S)-alpha, alpha 1 -dimethyldibenzylamino]- propylcyclopentane carboxylic acid as starting material in step (a) and coupling with N 6 -tert-butyloxycarbonyl-N 2 -methane- sulphonyl-S-lysine in step (c). Deprotection as previously described gave the product which was dissolved in a little distilled water and freeze dried to give the title product as a white solid. Found: C,51.50; H,7.38; N,8.67. C 27 H 42 N 4 O 7 S; HCl; 1.5 H 2 O requires C,51.46; H,7.36; N,8.89%.

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Abstract

L'invention se rapporte à des composés représentés par la formule: (I); où: A complète une chaîne fermée carbocyclique à 4-7 éléments, qui peut être saturée ou mono-insaturée et qui peut éventuellement être fusionnée à une autre chaîne fermée carbocyclique à 5 ou 6 éléments saturée ou insaturée; R représente H, un alkyl C1-C6, un benzyle ou un groupe formant ester biolabile alternatif; R1 représente H ou un alkyl C1-C4; R2 représente H, OH, un alkyl C1-C4, un alkoxy C1-C4, un halo ou CF3; R3 représente CH2 OH ou CO2R4, où R4 est identique à R défini ci-dessus; et R5 est défini comme pouvant comporter une gamme de groupes alkyle, alkényle, alkynyle, cycloalkyle, cycloalkényle et alkyle substitué contenant en particulier un méthoxyéthyle, un S-lysylaminométhyle, un N2-acétyle-S-lysylaminométhyle et un N2-méthanesulphonyle-S-lysylaminométhyle. Ces composés constituent des inhibiteurs de l'atriopeptidase, utiles dans le traitement de l'hypertension, des défaillances cardiaques, de l'insuffisance rénale et d'autres troubles.
EP91901493A 1990-01-12 1990-12-11 Agents diuretiques a base de glutaramide a substitution cycloalkyle Withdrawn EP0513016A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909000725A GB9000725D0 (en) 1990-01-12 1990-01-12 Therapeutic agents
GB9000725 1990-01-12

Publications (1)

Publication Number Publication Date
EP0513016A1 true EP0513016A1 (fr) 1992-11-19

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Application Number Title Priority Date Filing Date
EP91901493A Withdrawn EP0513016A1 (fr) 1990-01-12 1990-12-11 Agents diuretiques a base de glutaramide a substitution cycloalkyle

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Country Link
EP (1) EP0513016A1 (fr)
JP (1) JPH0645581B2 (fr)
CA (1) CA2072126A1 (fr)
FI (1) FI922410A (fr)
GB (1) GB9000725D0 (fr)
IE (1) IE910083A1 (fr)
PT (1) PT96446A (fr)
WO (1) WO1991010644A1 (fr)

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GT199900044A (es) * 1998-04-10 2000-09-14 Procedimientos para preparar haluros de fenoxifenilsulfonilo.
PA8469301A1 (es) 1998-04-10 2000-09-29 Pfizer Prod Inc Procedimientos para la preparacion de acidos hidroxamicos.
PA8469601A1 (es) 1998-04-10 2000-09-29 Pfizer Prod Inc Procedimiento para alquilar sulfonamidas impedidas estericamente
US20020052370A1 (en) * 2000-07-06 2002-05-02 Barber Christopher Gordon Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
US20020028799A1 (en) * 2000-07-06 2002-03-07 Naylor Alasdair Mark Treatment of male sexual dysfunction
US6660756B2 (en) 2001-03-28 2003-12-09 Pfizer Inc. N-phenpropylcyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase
RS75303A (en) * 2001-03-28 2006-12-15 Pfizer Limited N-phenpropylcyclopentyl-substituted glutaramide derivatives as nep inhibitors for fsad
BRPI0717657A2 (pt) 2006-10-19 2013-12-24 Hoffmann La Roche Compostos, processo para a preparação de um composto, composição farmacêutica que o compreende, usos de compostos, métodos para o tratamento e profilaxia de diabetes, obesidade, distúrbios alimentares, displidemia e hipertensão e profilaxia de diabetes do tipo ii

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KR880007441A (ko) * 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
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Also Published As

Publication number Publication date
GB9000725D0 (en) 1990-03-14
IE910083A1 (en) 1991-07-17
FI922410A0 (fi) 1992-05-26
WO1991010644A1 (fr) 1991-07-25
CA2072126A1 (fr) 1991-07-13
FI922410A (fi) 1992-05-26
PT96446A (pt) 1991-10-15
JPH0645581B2 (ja) 1994-06-15
JPH05502231A (ja) 1993-04-22

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