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WO1990009374A1 - Agents diuretiques de glutaramide a substitution cycloalcoyle - Google Patents

Agents diuretiques de glutaramide a substitution cycloalcoyle Download PDF

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Publication number
WO1990009374A1
WO1990009374A1 PCT/EP1990/000220 EP9000220W WO9009374A1 WO 1990009374 A1 WO1990009374 A1 WO 1990009374A1 EP 9000220 W EP9000220 W EP 9000220W WO 9009374 A1 WO9009374 A1 WO 9009374A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
compound
aryl
formula
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.)
Ceased
Application number
PCT/EP1990/000220
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English (en)
Inventor
John Christopher Danilewicz
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 Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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 Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Publication of WO1990009374A1 publication Critical patent/WO1990009374A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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 cardiovascular disorders such as hypertension and heart failure.
  • A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring;
  • B is (CH 2 ) m wherein m is an integer of from 1 to 3:
  • each of R and R 4 is independently H, C 1 -C 6 alkyl, benzyl or an alternative biolabile ester-forming group;
  • R is H or C 1 -C 4 alkyl
  • R and R 3 are each independently H, OH, C 1 -C 4 alky] or C 1 -C 4 alkoxy; and R 5 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl(C 2 -C 6 alkynyl), C 2 -C 6 cycloalkyl, C 3 -C 7 cycloalkenyl, C 1 -C 6 alkoxy, -NR 6 R 7 , -NR 8 COR 9 , -NR 8 SO 2 R 9 or a saturated heterocyclic group;
  • C 1 -C 6 alkyl substituted by one or more substituents chosen from halo, hydroxy, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkoxy, C 1 -C 6 alkoxy( C 1 -C 6 alkoxy),
  • C 3 -C 7 cycloalkyl C 3 -C 7 cycloalkenyl, aryl, aryloxy, aryloxy(C 1 -C 4 alkoxy), heterocyclyl, heterocyclyloxy,
  • R 6 and R 7 are each independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl (optionally substituted by hydroxy or
  • R 8 is H or C 1 -C 4 alkyl
  • R 9 is C 1 -C 4 alkyl, CF 3, aryl, aryl(C 1 -C 4 alkyl), aryl(C 1 -C 4 alkoxy), heterocycyl, C 1 -C 4 alkoxy or N R 6 R 7 wherein R 6 and R 7 are as previously defined;
  • R 10 is C 1 -C 4 alkyl, aryl, heterocyclyl or N R 6 R 7 wherein R 6 and R 7 are as previously defined;
  • R 11 is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, aryl or heterocyclyl;
  • R 12 is H or C 1 -C 4 alkyl;
  • the compounds are inhibitors of the zinc-dependent, neutral endopeptidase E.C.3.4.24.11. This enzyme is involved in the breakdown of several peptide hormones, including artrial
  • natriuretic factor which is secreted by the heart and which has potent vasodilatory, diuretic and natriuretic activity.
  • ANF neutral endopeptidase
  • the compounds can potentiate the biological effects of ANF and, in particular, the compounds are diuretic agents having utitility in the treatment of a number of disorders, including hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oderaa, Nenieres disease, hyperaldostercneism (primary and secondary) and hypercalciura.
  • a particularly preferred group of compounds of the formula (I) identified in EP-A-0274234 are those wherein A is (CH 2 ) 4 , R 1 is H and B is (CH 2 ) 2 , i.e. compounds of the formula (II) wherein R, R 2 , R 3 , R 4 and R 5 are as previously defined for formula(I):
  • R, R 3 , R 4 and R 5 are as previously defined and R 2 is a C,-alkyl group.
  • R 2 is a C,-alkyl group.
  • 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 or (C 1 -C 4 alkanoyl)amino 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, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl,
  • the compounds of formula (II) 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 (II) containing an acidic centre are those formed with bases which form non-toxic salts. Examples include 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 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).
  • 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 (II) wherein R and R 4 are both H.
  • a number of such ester groups are described in EP-A-0274234 and include for example
  • Preferred compounds of the invention are those compounds of the formula (II) wherein R and R 4 are both H (diacids) as well as biolabile mono and diester derivatives thereof wherein one or both of R and R 4 is a biolabile ester group.
  • the group R 5 is preferably n-propyl, 2-methoxyethoxymethyl,
  • Particularly preferred individual compounds of the invention include-:
  • the compounds of formula (II) are prepared following the synthetic procedures outlined in EP-A-0274234.
  • the basic procedure involves the synthesis of a partially protected cyclopentyl-sub ⁇ tituted glutaric acid derivative (III) which is coupled to cyclohexylamine derivative (IV).
  • the carboxylic acid 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 stage of the process.
  • the route is
  • R 5 ' is as -defined for R 5 with any reactive group therein protected if necessary and R 13 and R 14 are as defined for R and R 4 excluding H, or they are conventional caboxylic acid protecting groups.
  • N-t-butyloxycarbonyl derivative to enable separation of the cis and trans isomers by chromatography.
  • the major product, the a ll cis isomer was deprotected and used in the coupling reaction.
  • the ketal derivative of the ketone is isomerised by treatment with a strong base to give the trans isomer and the keto group again converted to the amine by, in this case, reaction with methoxylamine followed by reduction.
  • chromatography of the N-t-butyloxycarbonyl derivative enabled the cis isomer to be separated from the trans isomer for use in the subsequent coupling steps.
  • the coupling 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)-carbodiiraide, or N,N'-dicyclohexylcarbodiimide, advantageously in the presence of 1-hydroxybenzotriazole and an organic base such as N-methylmorphoJine.
  • a diimide condensing agent for example 1-ethyl-3-(dimethylaminopropyl)-carbodiiraide, or N,N'-dicyclohexylcarbodiimide, advantageously in the presence of 1-hydroxybenzotriazole and an organic base such as N-methylmorphoJine.
  • 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 crystallisation or
  • the diesters of formula (V) may be further reacted to give the monoester or diacid derivatives of formula (II) wherein one or both of R and R 4 are H.
  • the conditions used will depend on the precise nature of the groups R 13 and R 14 present in the compound of formula (V) and a number of variations are possible.
  • R 13 and R 14 are benzyl
  • hydrogenation of the product will yield the diacid of formula (I) wherein R and R 4 are both H.
  • R 13 is benzyl and R 14 is alkyl
  • hydrogenation will yield a monoester product. This can then be hydrolysed, if desired, again to yield the diacid product.
  • treatment of the compound of formula (V) with trifluoroacetic acid yields the corresponding acid.
  • 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 product may be obtained as a mixture of isomers or diastereoisomers and these may be separated by conventional methods.
  • 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 we have discovered that it is involved in the breakdown of atrial natriuretic factor (ANF).
  • ANF atrial natriuretic factor
  • 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 compared to a control group which received only saline .
  • oral dosages of the compounds will generally be in the range of from 3-700 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 1 to 150 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 5 to 500 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • 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 cr 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 invention provides a
  • composition comprising a compound of the formula (II), or a pharmaceutically acceptable salt thereof or
  • the invention also includes a compound of the formula (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.
  • Trifluoroacetic acid (10.2 ml, 0.13 mmole) in dry tetrahydrofuran (20 ml) was added dropwise under nitrogen to a stirred suspension of sodium borohydride (5.0g; 0.13 mmole) in dry tetrahydrofuran (120 ml). The temperature was kept between 10-20°C with ice cooling and after 15 minutes a solution of the above ester (6.75 g; 26.4 mmole) in tetrahydrofuran (20 ml) was added. The temperature rose to 33°C and brief cooling was required to return the temperature to 20°C. After 4 hours water was carefully added, with ice cooling, followed by diethyl ether.
  • the crude product was chromotographed on silica and the two diastereoisomers were separated by elution with a mixture of diethyl ether:hexane: toluene (10:7:3).
  • Example 3 The procedure of Example 3 was followed but using the trans-isomer of the amine from Example 2.
  • C 30 H 3 NO 7 requires C,66.76; H,9.90; N,2.60%.
  • Example 5 The product of Example 5 was deprotected following the procedure of Example 4 to yield the title diacid product, a mixture of diastereoisomers, as a gum (99%). Found: C,63.28; H,9.15; N,3.07. C 24 H 41 NO 7 requires C,63.27; H,9.07; N,3.07%.
  • Oxalyl chloride (1.55 g; 12.2 mmole) was added to a stirred solution of 3-(1-carboxycyclopentyl)-2-(2-methoxyethyl)propanoic acid benzyl ester(2.04 g; 6.1 mmole) in dry methylene chloride containing two drops of dimethylformide. After 2 hours the mixture was evaporated to dryness under reduced pressure.
  • Example 7 The above diester from Example 7 (1.03g; 1.89 mmole) was dissolved in a mixture of ethanol (25 ml) and water (10 ml) and hydrogenated over 10% palladium on carbon (200 mg) at room temperature and 50 psi (3.4 bar). After 1.5 hours the mixture was filtered through avicel and evaporated to dryness. The residual gum was dissolved in 1N sodium hydroxide and the solution was kept under nitrogen at 50°C for two days. Further 1N sodium hydroxide (10 ml) was added and hydrolysis continued for 24 hours. On cooling the solution was acidified with 2N hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried (MgSO 4 ) and evaporated to give the title product as a white foam (660 mg;

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

Abstract

L'invention concerne des composés de formule (II), dans laquelle R et R4 représentent chacun indépendamment H, alcoyle contenant 1 à 6 atomes de carbone, benzyle ou un autre groupe formant des esters biolabiles; R2 représente un groupe alcoyle à quatre atomes de carbone; R2 représente un groupe alcoyle contenant 4 atomes de carbone; R3 représente H, OH, alcoyle ou alkoxy contenant 1 à 4 atomes de carbone; et R5 est défini pour comprendre une gamme de groupes alcoyle, alkenyle, alkynyke, anylalkynyle, cycloalcoyle, cycloslkinyle, alkoxy, amino, amino substitué, amido, sulfonamido et alcoyle substitué; ainsi que leurs sels pharmaceutiquement acceptables. Lesdits composés constituent des agents utiles dans le traitement de l'hypertension, des insuffisances cardiaques, rénales ainsi que d'autres troubles.
PCT/EP1990/000220 1989-02-18 1990-02-09 Agents diuretiques de glutaramide a substitution cycloalcoyle Ceased WO1990009374A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8903740.2 1989-02-18
GB898903740A GB8903740D0 (en) 1989-02-18 1989-02-18 Therapeutic agents

Publications (1)

Publication Number Publication Date
WO1990009374A1 true WO1990009374A1 (fr) 1990-08-23

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PCT/EP1990/000220 Ceased WO1990009374A1 (fr) 1989-02-18 1990-02-09 Agents diuretiques de glutaramide a substitution cycloalcoyle

Country Status (6)

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AU (1) AU5179790A (fr)
GB (1) GB8903740D0 (fr)
GR (1) GR900100109A (fr)
IL (1) IL93354A0 (fr)
PT (1) PT93179A (fr)
WO (1) WO1990009374A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
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
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0274234A2 (fr) * 1986-12-11 1988-07-13 Pfizer Limited Glutaramides spiro-substitué comme agents diurétiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0274234A2 (fr) * 1986-12-11 1988-07-13 Pfizer Limited Glutaramides spiro-substitué comme agents diurétiques

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796331B2 (en) 2002-01-17 2014-08-05 Novartis Ag Methods of treatment and pharmaceutical composition
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
US8101659B2 (en) 2002-01-17 2012-01-24 Novartis Ag Methods of treatment and pharmaceutical composition
EP3685833A1 (fr) 2005-11-09 2020-07-29 Novartis AG Composé comprenant un arb et un nepi
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
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
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
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
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
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

Also Published As

Publication number Publication date
IL93354A0 (en) 1990-11-29
AU5179790A (en) 1990-09-05
PT93179A (pt) 1990-08-31
GR900100109A (el) 1991-06-28
GB8903740D0 (en) 1989-04-05

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