WO2010024772A1 - Inhibiteurs d'aspartyl protéases - Google Patents

Inhibiteurs d'aspartyl protéases Download PDF

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WO2010024772A1
WO2010024772A1 PCT/SE2009/050976 SE2009050976W WO2010024772A1 WO 2010024772 A1 WO2010024772 A1 WO 2010024772A1 SE 2009050976 W SE2009050976 W SE 2009050976W WO 2010024772 A1 WO2010024772 A1 WO 2010024772A1
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mmol
compounds
formula
title compound
methoxy
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PCT/SE2009/050976
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Christer Sahlberg
Christian Sund
Daniel Wiktelius
Oscar Belda
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as renin. It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their use in the preparation of a medicament or their use in therapy.
  • Renin is an aspartyl protease with a high substrate specificity, its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogento angiotensin I (Ang I), which thereafter is further processed to the active peptide hormone angiotensin II (Ang II) by the less specific angiotensin-converting enzyme (ACE). Ang II increases blood pressure both directly by arterial vascoconstriction and indirectly by liberating the sodium-ion-retaining hormone aldosterone. Ang II is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, while the role of AT2 is still unknown.
  • Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. Inhibition of the enzymatic activity of renin leads to a reduction in the formation of Ang I, and as a consequence, a smaller amount of Ang II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
  • ACE inhibitors and ATI blockers have been accepted to treat hypertension and ACE inhibitors are used for renal protection in the prevention of congestive heart failure and myocardial infarction.
  • the rationale to develop renin inhibitors is the specificity of renin. Renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.
  • renin inhibitors With good oral bioavailability and long duration of action are required.
  • the present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties.
  • the compounds of the present invention exhibits advantageous metabolic stability as determined in human liver microsomes (HLM).
  • renin inhibitors which can be represented by the formula (I):
  • Q is trifluoromethyl, Cs-C ⁇ cycloalkyl, phenyl, p-fluorophenyl, pyridyl, thiazolyl, furyl, thienyl or
  • R 3 is Ci-Cealkyl
  • R 4 is Ci-Cealkyl
  • W is cyano or fluoro; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R is attached has the stereochemistry shown in structure (Ia):
  • the chiral centre to which the group R 4 is attached typically has the configuration shown in structure (Ib) below:
  • the configuration corresponds typically to that of an L-amino acid.
  • the chiral centre to which the hydroxy group is attached typically has the configuration as shown in structure (Id) below:
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in structure (Ie):
  • R 3 is Ci-C ⁇ alkyl, preferably ethyl or isopropyl.
  • R 4 is Ci-C ⁇ alkyl, preferably isopropyl or more preferably sec. butyl.
  • Q is as stated above.
  • Q is p-fluorophenyl, 2-pyridyl, 5-thiazolyl or cyclopropyl, more preferably Q is p-fluorophenyl.
  • W is as stated above.
  • W is fluoro
  • the compound is not any of:
  • 'Ci-Coalkyl' defines a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2- methyl-1 -butyl, 2-methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like.
  • ' Cs-C 6 Cy cloalkyl' defines a saturated carbocyclic ring having 3, 4, 5 or 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • cyclopropyl i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 3 - C ⁇ Cycloalkyl is cyclopropyl.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 -CsCyC loalkoxycarbonyloxyCi-C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci -C ⁇ alkoxycarbonyloxy ethyl esters for example 1-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylamino acetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acids and the like
  • organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (
  • hydroxybutanedioic acid tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, />toluenesulfonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, jV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • the TV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally.
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (T) per se, the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the N-oxides, salts, as the possible stereoisomeric forms thereof.
  • the present invention also includes isotope- labelled compounds of formula I or any subgroup of formula I, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature.
  • isotopes that may be incorporated into the compounds of formula I or any subgroup of formula I, include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 Cl, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 I, 124 I, 125 I and 131 I.
  • isotopes of hydrogen such as 2 H and 3 H (also denoted D for deuterium and T for tritium respectively)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 O, 17 O and 18 O
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 O will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
  • Isotopically labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotopically labelled reagent or starting material instead of the corresponding non-isotopically labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, TV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, TV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, to stabilize or to reduce adverse conditions associated with RAS activity, such as or related to hypertension, heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties and are modulators of the renin-angiotensin system, in particular they are inhibitors of the natural enzyme renin and may be used in the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or profylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the invention further provides a method of treating a disease or condition known to be related to the renin-angiotensin system which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate, prodrug, TV-oxide, quaternary amine, metal complex, or stereochemically isomeric form thereof, as hereinbefore defined.
  • the invention also provides a method of treating diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • compositions of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • a representative example are other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha- adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • beta- adrenergic antagonists alpha- adrenergic
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron Lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid such as sulphuric acid, in the presence of methanol.
  • the achieved free secondary hydroxy group can then be reductively removed effected for instance by transformation of the hydroxy group into a thiocarbonyl group by reaction with thiocarbonyl diimidazole (TCDI) followed by reductive removal of the formed thiocarbonyl group using for instance conditions such as tributyltin hydride the presence of a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like to give the 2,3-dideoxy glycoside (Ic).
  • a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like
  • Ic 2,3-dideoxy glycoside
  • Oxidative cleavage of the methyl ether performed for example by oxidation with m- chloroperbensoesyra or the like in the presence of BF3-etherate, gives the lactone (Id).
  • the ring substituent R 3 can then be introduced for example by treatment of the lactone with a base such as LDA or equivalent followed by reaction with a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like of the desired alkyl radical, thus providing the ⁇ -alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like of the desired alkyl radical, thus providing the ⁇ -alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of s
  • the primary hydroxy group of the afforded diol (If) can then be selectively alkylated for example by activation of the hydroxy group with dibutyltinoxide followed by reaction with a desired alkylating agent Q'-(CH 2 ) n -Lg wherein Q' is a disubstituted phenyl moiety and Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the O-alkylated lactone (Ig).
  • a desired alkylating agent Q'-(CH 2 ) n -Lg wherein Q' is a disubstituted phenyl moiety and Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the O-alkylated lactone (I
  • the substituent (2'-(CH 2 )- can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al., Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the alcohol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol Q'-(CH 2 )-OH.
  • Replacement of the hydroxy group of the secondary alcohol (Ig) by azide with concomitant inversion of the stereochemistry may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (Ih).
  • a leaving group for example a derivative of sulphonic acid like a triflate or tosylate or the like
  • sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (Ih).
  • the azide moiety can be introduced by treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate, in combination with triphenylphosphine, followed by reaction with azide for example DPPA, in a solvent like THF.
  • the linear amino compound (2b) can be achieved by opening of the lactone (Ih) with a desired amino derivative (2a) in the presence of a coupling agent for example 2-hydroxypyridine and a base like isopropyl diethylamine. Reduction of the azide using conditions compatible with the group (CH 2 )-Q ⁇ for example hydrogenation at atmospheric pressure in the presence of Lindlar Catalyst or equivalent then provides the amino derivative (2c).
  • a coupling agent for example 2-hydroxypyridine and a base like isopropyl diethylamine.
  • Amino derivatives (2a) to be used for the opening of the lactone in the scheme 2 above are commercially available or they can be prepared by the skilled person according to literature procedures. An example of their preparation is illustrated in scheme 3.
  • a suitably protected amino acid (3a), carrying the desired side chain R can be coupled to the amine W-Ph-CH 2 -NH 2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloro formate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used thus providing the amide.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • Y is a leaving group or OH
  • Pg 1 and Pg 2 are orthogonal protecting groups
  • the azide derivative (4a), prepared for example as outlined in scheme 2, wherein Pg 1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide group using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlars catalyst or the like in the presence Of BoC 2 O to provide the boc protected derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group provides the primary alcohol (4c).
  • a protecting group Pg 2
  • Suitable protecting groups for the above route will be recognized by the skilled person and a numerous of useful protecting groups are described in Greene "Protective Groups in Organic Synthesis", John Wiley and sons, New York (1981).
  • benzyl can be used as Pg 1 and acetyl as Pg 2 .
  • the disubstituted benzyl group can then be introduced as described above.
  • reaction of the primary alcohol (4c) with an alkylating agent Q '-CH 2 -Lg wherein Q' is the disubstituted phenyl moiety and Lg is a leaving group such as halide like a bromide, chloride or iodide or a derivative of sulphonic acid such as a triflate or mesylate or the like in the presence of a base like NaH or the like, or alternatively, a trichloroacetimidate of a desired group, Q'-CH 2 -O- C( NH)Cl3 may be reacted with the primary alcohol (4c) in the in the presence of a Lewis acid such as BFsOEt 2 .
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • the disubstituted benzyl moiety may be introduced by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, QJ-CH 2 -OH, as described above.
  • Suitable reactions that can be used for the introduction of the substituent Q are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q is reacted with the bromo derivative (6b) in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative (6b) is reacted with a double bond of the desired group Q in the presence of a Pd catalyst such as Pd(PPli3)4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • Reduction of the ester function of compound 6c using any convenient reduction method known in the art, such as treatment with DIBAL-H, provides benzylic alcohol (6d).
  • the afforded alcohol can then either be used directly in the coupling to the primary hydroxy group of the lactone (If) or the linear compound (4c) employing the Mitsunobu conditions, or the hydroxy group can be transferred to a leaving group, such as a halide like bromide by treatment with for instance bromine or tetrabromomethane in the presence of triphenylphosphine, and subsequently coupled to the primary hydroxy group of the lactone (If) or the linear compound (4c) as described above.
  • a leaving group such as a halide like bromide by treatment with for instance bromine or tetrabromomethane in the presence of triphenylphosphine
  • the substituent Q of the benzene ring may be introduced after coupling of the benzyl moiety to the primary hydroxy group of the lactone (If), as illustrated in scheme 7.
  • Scheme 8 shows an alternative route to compounds of the invention, starting from Garner's aldehyde.
  • Lg is a leaving group Pg is a protecting group
  • the group Q-CH 2 can then be introduced using any suitable method such as any of those described above. For example, a trichloroimidate of the desired group Q-CH 2 in the presence of TMS triflate can be used.
  • the lactone may then be opened either directly with a desired amine as described above to give the amide (8h), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (8g). Protection of the hydroxy group, using any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group, followed by coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethylamine, and finally removal of the hydroxy protecting group provide the amide (8h).
  • any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group
  • coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethyl
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • Step b) Imidazole- 1-carbothioic acid 0 ⁇ 5-0.2-bis-benzyloxyethyl)-2-methoxytetrahydrofuran- 3-yli ester Q- lfr)
  • Step b) 4-Cyclopropyl-3-(3-methoxy-propoxy)-benzoic acid methyl ester (Ib) Cyclopropylboronic acid pinacol ester (0.75 g, 4.46 mmol) was stirred in H 2 O (0.8 mL) in the presence Of KsPO 4 (2.36 g, 11.1 mmol) for 15 min. The mixture was diluted with toluene (18 mL) and bromo derivative Ia was added. The mixture was degassed, and palladium(II)acetate (116 mg, 0.51 mmol) and tricyclohexylphosphine was added. The mixture was heated to 100 0 C, and stirred for 24 h. Evaporation and purification by column chromatography (gradient elution with hexanes/THF 30:1 - 4:1) gave the title compound (0.88 g, 88%). GC/MS:[M+ ion at 264.
  • Step d) 4-Bromomethyl-l-cvclopropyl-2-(3-methoxy-propoxy)-benzene (Id) The benzyl alcohol Ic and triphenylphosphine (1.05 eq.) was dissolved in DCM and the solution was stirred and cooled to 0 0 C on an ice bath. A solution of tetrabromo methane (1.1 eq.) in DCM was added dropwise after which the cooling bath was removed and stirring was continued for 2 h. Additional triphenylphosphine (0.13 eq.) was added and stirring was continued for 2 h. of SiO2 was added and the solvent was evaporated. The product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 50:1 - 20:1) which gave the title compound (73%).
  • Step f) 5- ( 1 -Azido-2-[4-cyclopropyl-3-(3-methoxy-propoxy)-benzyloxyl-ethyl
  • Example 1 step c which gave the title compound (2.60 g, 95%).
  • the benzyl alcohol 2a (2.60 g, 9.45 mmol) was reacted according to the procedure described in Example 1 step d, which gave the title compound (2.62 g, 82%) after purification by column chromatography (gradient elution with hexanes/ethyl acetate 30:1 - 1 :1).
  • a microwave reactor tube was charged with bromide 2d (50 mg, 0.106 mmol), pyridine-3- boronic acid (17 mg, 0.138 mmol), l,l '-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex ((dppf)2PdCl2) (4.3 mg, 5.3 ⁇ mol), 3.8 mL of a 5:2:1 mixture of 1,4-dioxane, ethanol and 2 M K3PO4 solution. The mixture was degassed by 5 cycles of vacuum/ ⁇ , and subsequently heated to 140 0 C for 15 min in the microwave reactor.
  • the tube was sealed and heated to 120 0 C for 18 h after which the tube was allowed to cool and opened to release pressure and more methyl 2-chloro- 2,2-difluoroacetate (3 mL), KF (80 mg), and CuI (250 mg) were added, the mixture was degassed and heated again for 18 h. Three further additions of methyl 2-chloro-2,2- difluoroacetate were made during the following 48 h. The mixture was diluted with Et 2 O (25 mL) and filtered through Celite which was washed with Et 2 O (25 mL).
  • Step b) [3 -(3 -Methoxy-propoxy)-4-trifluoromethyl-phenvH -methanol (3b)
  • the methyl ester 3a (0.60 g, 2.05 mmol) was reduced according to the procedure described in Example 1 step c, which gave the title compound along with some minor impurities (0.52 g). The afforded compound was used as such in the next step.
  • the benzyl alcohol 3b was reacted according to the procedure described in Example 1 step d, the product was purified by column chromatography (gradient elution with hexanes/ethyl acetate 100:1 - 5:1) which gave the title compound (199 mg, 23% over two steps).
  • Alcohol 3d (169 mg, 0.388 mmol) and PPh 3 (133 mg, 0.505 mol) were dissolved in dry THF (15 mL), cooled to -15 0 C, and stirred.
  • DIAD 107 ⁇ L, 0.544 mmol
  • DPPA 117 ⁇ L, 0.544 mmol
  • the lactone 3e 44 mg, 0.096 mmol
  • the reaction mixture was diluted with DCM (10 mL) and IM HCl (10 mL).
  • the bromide 2c (100 mg, 0.225 mmol), 2-tributylstannylthiazol (141 ⁇ L, 0.45 mmol), dichloro- bis(tricyclohexylphosphine)palladium(II) (25 mg, 0,033 mmol), CuI (9 mg, 0.045 mmol), LiCl (38mg, 0.898 mmol), 1,4-dioxane (1.5 mL), and DMF (0.2 mL) were mixed in a microwave reactor tube, which was sealed, thoroughly degassed, and heated in a microwave reactor for 1 h at 165 0 C. The mixture was diluted with MeCN (25 mL) and filtered through a syringe filter.
  • the filtrate was extracted with isohexane (5 x 5 mL) and the isohexane extracts were discarded.
  • the MeCN phase was evaporated and the residue redissolved in Et 2 O (5 mL), EtOAc (5mL), and H 2 O (20 mL).
  • the phases were separated and the aqueous phase was extracted with a 1 : 1 Et 2 O/EtOAc mixture (3 x 7 mL).
  • the combined organic phases were washed with H 2 O (2 x 7 mL) and brine (7 mL) and evaporated.
  • Alcohol 4a (40 mg, 0.089 mmol) was dissolved in DCM (1 niL) and pyridine (14 ⁇ L, 0.178 mmol) was added, and the solution cooled to -20 0 C. Trifluoromethanesulfonic anhydride (19 ⁇ L, 0.11 mmol) was added, and the reaction was stirred for 10 min. Cooling was maintained while reaction was concentrated in vacuo. The residue was cooled to -78 0 C and DMF (1 mL) was added dropwise. NaN 3 (0.178 mmol, 12mg) was added (one portion), and the reaction was allowed to warm to -5 0 C for 1 h.
  • Step d) 5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-thiazol-2-yl-benzyloxy "
  • the crude reaction mixture from step 4c was diluted with MeOH (30 mL) and was reacted as described in Example 1 step i which gave a diastereomeric mixture containing the title compound in 47% yield total yield from 4a. Separation of the diastereomeric mixture by preparative HPLC (NH 4 OAc - MeCN gradient) gave the title compound (10.3 mg). Purity according to HPLC was > 95%. LC/MS [M+H] + 687.4.
  • the bromide 2c was coupled to 2-tributylstannylpyridine (145 ⁇ L, 0.45 mmol) according to the procedure described in Example 4 step a.
  • the reaction was worked up by dilution with EtOAc (5 mL), Et 2 O (5 mL), and sat aq NaHCO 3 (15 mL), followed by filtration, and the phases were separated.
  • the aqueous phase was extracted with a 1 :1 Et 2 OZEtOAc mixture (3 x 10 mL), and the combined organic extracts were washed with aq sat NaHCO 3 (2 x 5 mL), dried (MgSO 4 ), filtered and evaporated.
  • the lactone 6b (32 mg, 0.068 mmol) was reacted with he amine Ig according to the procedure described in Example 1 step h.
  • the product was isolated from the reaction mixture by preparative HPLC (NH 4 OAc - MeCN gradient) as a mixture of diastereomers along with some minor impurities and was used as such in the next step.
  • Step d) 5-Amino-4-hydroxy-2-isopropyl-6-[3-(3-methoxy-propoxy)-4-pyridin-2-yl-benzyloxy
  • the crude reaction mixture from Example 6 step c was reacted as described in Example 1 step i which gave the title compound as a diastereomeric mixture (43% total yield from 6b).
  • the title compound was isolated by preparative HPLC (NH 4 OAc - MeCN gradient) which yielded 9.9 mg. Purity according to HPLC was > 95%. LC/MS [M+H] + 681.4.
  • Step c) 5-Amino-6-r4-cvclopropyl-3-(3-methoxy-propoxy)-benzyloxyl-4-hydroxy-2-isopropyl- hexanoic acid ri-(4-cvano-benzylcarbamoyl)-2-methyl-butyl "
  • Azide 9b was reacted as described in Example 1 step i. Purification by preparative HPLC (NH 4 OAc - MeCN gradient) gave the title compound (8.0 mg, 50%). Purity according to HPLC was > 95%. LC/MS [M+H] + 651.4.
  • the diol 10a was alkylated with the benzyl bromide derivative Id according to the procedure described in Example 1 step e.
  • Silica gel column chromatography (gradient Q - 1 A - I - 2%EtOH/DCM) gave the title compound (81 mg, 74%).
  • the procedure described for the preparation of intermediate I- Ie was followed but using iodoethane instead of iodopropane, subsequent removal of the benzyl groups as described in intermediate 1 , step f, gave the title compound.
  • the diol 1 Ia (50.5 mg, 0.29 mmol) was alkylated with the benzyl bromide derivative Id according to the procedure described in Example 1 step e.
  • Step c) 5- ⁇ 1 -azido-2-r4-cvclopropyl-3-(3-methoxy-propoxy)-benzyloxyl-ethvU -3-ethyl-dihydro- furan-2-one (l ie)
  • step e The procedure described for the preparation of intermediate 1, step e was followed but using 1- iodopropane instead of 2-iodopropane, followed by removal of the benzyl groups as described in intermediate 1 , step f, which gave the title compound.
  • Step b) 5- (2-[4-cyclopropyl-3-(3-methoxy-propoxy)-benzyloxyl- 1 -hydroxy-ethyll -3-propyl- dihydro-furan-2-one (12b)
  • the lactone 12a (54.6 mg, 0.29 mmol) was alkylated with the bromo derivative Id according to the procedure described in Example 1 step e.
  • Silica gel column chromatography (gradient 0 - 1 A - 1 - 2%EtOH/DCM) gave the title compound (62 mg, 53%).
  • Step a) 5- (2-[4-Cyclopropylethynyl-3-(3-methoxy-propoxy)-benzyloxyl- 1 -hydroxy-ethyll -3- isopropyl-dihydro-furan-2-one (13a)
  • 13c) A mixture of compound 13b (17 mg, 0.0374 mmol)], the amine Ig (50 mg), 2-hydroxypyridine (50 mg) and DIPEA (150 ⁇ l) was heated at + 70° C for 3 days. The reaction mixture was evaporated and the residue purified by preparative LC/MS which gave 18 mg of the title compound. LC/MS confirmed the structure with a M+l ion at 694.
  • 14b To a solution of compound 14a (10 mg, 0.014 mmol) in methanol (2 ml) was added water (2 drops) and triphenylphosphine (4 mg, 0.015 mmol). The reaction mixture was then stirred at + 50 °C for about 24 hours. The reaction mixture was evaporated and the residue purified on preparative HPLC using a Phe column to give about 1.1 mg (11%) of the title compound.
  • LC/MS confirmed the structure with a M+l ion at 675.
  • FRET Fluorescence Resonance Energy Transfer
  • EDANS aminoethylaminonaphtalene sulphonate
  • Dabcyl 4'-dimethylaminoazobenzene
  • Arg-Glu(ED ANS)-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-Lys(D ABCYL)- Arg Sigma-Aldrich.
  • the cleavage site by human renin is the peptide bond between Leu and VaI. The compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed.
  • the substrate was prepared at a 20 ⁇ M stock solution in DMSO.
  • To each well of a 96-well polypropylene plate was added the enzyme containing assay buffer (90.0 ⁇ l) and inhibitor of different concentrations (1 ⁇ l). To controll wells were added DMSO (1 ⁇ l) instead of inhibitor.
  • the renin enzyme was preactivated by incubation at 37 0 C for 20 min whereafter the reactions were started by addition of substrate, 10 ⁇ l/well, thus giving a total volume of 100 ⁇ l/well and a substrate concentration of 2 ⁇ M.
  • the assay was performed during 20 min at 37 0 C.
  • the total concentration of DMSO was not above 1 %.
  • Product fluorescence emission filter 340 nM, excitation filter 500 nM
  • the Ki was determined by Prism Software.
  • Activity of the inhibitors was determined by measuring the fluorescence at ⁇ g X 340nm and ⁇ em 500nm.
  • Percent inhibition is calculated as follows: % Inhibition is equal to the (Fluorescence ⁇ , inhibitor - Fluorescence &aC £gr ⁇ w); divided by the (Fluorescence mmus m h ⁇ to r - Fluorescence &aC £gr ⁇ w);
  • Table 1 shows the Ki- value expressed in nM for a representative selection of compounds according to the invention when tested in an renin enzyme assay such as the one described above.
  • Category A indicates ⁇ 0.1 nM inhibition
  • category B indicates 0.1 - 1 nM inhibition
  • category C indicates > 1 nM:

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle Q représente un groupe trifluorométhyle, cycloalkyle en C3-C6, phényle, p-fluorophényle, pyridyle, thiazolyle, furyle, thiényle ou (cycloalkyl en C3-C6)éthynyle ; R3 représente un groupe alkyle en C1-C6 ; R4 représente un groupe alkyle en C1-C6 ; W représente un groupe cyano ou fluoro ; ou un de leurs sels, hydrates ou N-oxydes pharmaceutiquement acceptables. Les composés de l'invention sont des inhibiteurs d'aspartyl protéases telles que la rénine et sont utiles notamment pour le traitement d'affections associées à des activités du système rénine-angiotensine (RAS), telles que l'hypertension, l'insuffisance cardiaque et l'insuffisance rénale.
PCT/SE2009/050976 2008-08-29 2009-08-28 Inhibiteurs d'aspartyl protéases WO2010024772A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2551260A1 (fr) 2011-07-28 2013-01-30 Chemo Ibérica, S.A. Procédé chimique pour l'ouverture de composés cycliques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) * 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
WO2002040007A1 (fr) * 2000-11-17 2002-05-23 Novartis Ag Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
WO2008107365A1 (fr) * 2007-03-02 2008-09-12 Medivir Ab Nouveaux composés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559111A (en) * 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides
WO2002040007A1 (fr) * 2000-11-17 2002-05-23 Novartis Ag Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
WO2008107365A1 (fr) * 2007-03-02 2008-09-12 Medivir Ab Nouveaux composés

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2551260A1 (fr) 2011-07-28 2013-01-30 Chemo Ibérica, S.A. Procédé chimique pour l'ouverture de composés cycliques
WO2013014191A1 (fr) 2011-07-28 2013-01-31 Chemo Iberica, S. A. Procédé chimique pour ouvrir des composés cycliques

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