WO2009138122A1 - Purine derivatives further comprising a mercapto-acylamino group as neutral endopeptidase inhibitors - Google Patents

Purine derivatives further comprising a mercapto-acylamino group as neutral endopeptidase inhibitors Download PDF

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WO2009138122A1
WO2009138122A1 PCT/EP2008/055941 EP2008055941W WO2009138122A1 WO 2009138122 A1 WO2009138122 A1 WO 2009138122A1 EP 2008055941 W EP2008055941 W EP 2008055941W WO 2009138122 A1 WO2009138122 A1 WO 2009138122A1
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alkyl
alkoxy
heterocyclyl
aryl
compound
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Vincenzo Tschinke
Mauro Napoletano
Thomas Haack
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Novartis AG
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Novartis AG
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Priority to CA2723922A priority Critical patent/CA2723922A1/en
Priority to PCT/EP2008/055941 priority patent/WO2009138122A1/en
Priority to EA201001765A priority patent/EA201001765A1/en
Priority to KR1020107028071A priority patent/KR20110009704A/en
Priority to EP08759614A priority patent/EP2303883A1/en
Priority to BRPI0822879A priority patent/BRPI0822879A2/en
Priority to JP2011508800A priority patent/JP2011520817A/en
Priority to CN2008801301403A priority patent/CN102076688A/en
Priority to AU2008356436A priority patent/AU2008356436A1/en
Publication of WO2009138122A1 publication Critical patent/WO2009138122A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A61P9/04—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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

Definitions

  • the present invention relates to puhnones substituted at least at one carbon atom of the ring, to processes for their preparation and to the use of the compounds as medicaments, in particular as neutral endopeptidase (NEP) inhibitors, in particular to medicaments containing such a compound.
  • NEP neutral endopeptidase
  • NEP inhibitors and their uses are disclosed, for example, in EP 0364767 A1.
  • properties directed towards better bioavailability are, for example, increased absorption, metabolic stability or solubility, or optimized lipophilicity.
  • Properties directed towards a better safety profile are, for example, increased selectivity against drug metabolizing enzymes such as the cytochrome P450 enzymes or increased selectivity against other vasoactive zinc metalloproteases such as angiotensin converting enzyme (ACE) and aminopeptidase P (APP).
  • ACE angiotensin converting enzyme
  • APP aminopeptidase P
  • A is monocyclic Cs-s-cycloalkyl or monocyclic, saturated heterocyclyl, each of which are either unsubstituted or substituted by 1 -3 Ci -8 -alkoxy, Ci -8 -alkyl, halogen, hydroxy or oxo;
  • R 1 is H, Ci- 8 -alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci -8 -alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkyl, aryl, aryl-Ci-s- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-S- alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo; where the aryl or heterocyclyl moieties are unsubstituted or substituted; where the thiol group is unprotected or protected with a protecting group R a , which is hydrolyzed under physiological conditions to liberate the compound of formula (I); disulfide derivatives derived from the compounds of formula (I) and salts of a compound of formula (I), preferably pharmaceutically acceptable salts thereof.
  • Thiol protecting groups R a are for example acyl or sulfonyl groups, which are unsubstituted or substituted with one or more halogen (fluoro or chlorine), hydroxy, N,N-di- Ci-s-alkyl-amine, morpholine or Ci-s-alkoxy, or N,N-di-Ci-C 4 -alkylaminocarbonyl.
  • Acyl radicals are preferably alkanoyl radicals, more preferably Ci-s-alkanoyl radicals such as formyl, acetyl, fluoroacetyl, chloroacetyl, dimethylaminoacetyl, or aroyl radicals such as benzoyl. Further suitable thiol protecting groups may be identified using test systems available and known to the person skilled in the art.
  • alkyl and alkoxy radicals which may be linear or branched
  • Ci-S- alkyl and Ci-s-alkoxy radicals such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy and t-butoxy respectively.
  • Ci-s-Alkylenedioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy.
  • Cycloalkyl is a saturated, cyclic or polycyclic hydrocarbon radical having 3-12 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl and adamantyl.
  • cycloalkyl may denote a monocyclic radical having 3-8 and preferably 5 or 6 ring carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Aryl may denote mono- or polycyclic aromatic radicals, which may be mono- or poly- substituted in the aryl moiety, for example phenyl, substituted phenyl, naphthyl or substituted naphthyl.
  • substituents on such aryl radicals are acetamidinyl- Ci-s-alkyl, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyl)-Ci- 8 -alkoxy-Ci- 8 -alkylamino, C 2-8 -alkenyl, C2-8-alkenyloxy, Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbony
  • heterocyclyl except for residue A denotes mono- or polycyclic, saturated and unsaturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S or N, for example from 1 to 4 nitrogen and/or 1 or 2 sulfur and/or 1 or 2 oxygen atoms and which may be mono- or polysubstituted, especially mono- ,di- or trisubstituted. Additionally, the term heterocyclyl may include the above mentioned oxo-substituted radicals.
  • unsaturated heterocyclyl radicals are benzo[1 ,3]dioxolyl, benzofuranyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, dihydrobenzofuranyl, 1 ,3-dihydro- benzoimidazol, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, 1 ,4-dihydro-benzo[d][1 ,3]oxazin, dihydro-2H-benzo[1 ,4]thiazinyl, 3,4-dihydro-1 H- quinazolin, 3,4-dihydro-1 H-quinolin, 2,3-dihydroindolyl, dihydro-1 H-pyr
  • saturated heterocyclyl except for residue A may denote 3-16 membered mono- or bicyclic, saturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S, or N, for example from 1 to 4 nitrogen and/or 1 or 2 sulfur or oxygen atoms.
  • 3-8 membered especially preferred 5- or 6-membered monocyclic radicals, which may be condensed to a 3-8 membered, carbocyclic or heterocyclic ring.
  • Another preferred group of saturated heterocyclic radicals are bicyclic radicals possessing a spirocyclic or bridged ring skeleton.
  • Preferred heterocyclic radicals in heterocyclyl or heterocyclyl-Ci-s-alkyl except for residue A are possessing per ring 1 nitrogen, oxygen or sulfur atom, 1 -2 nitrogen atoms and 1 -2 oxygen atoms or 1 -2 nitrogen atoms and 1 -2 sulfur atoms, whereby, per ring, at least 1 carbon atom, preferentially 1 -7 carbon atoms are present.
  • Heterocyclyl radicals which comprise a nitrogen atom may be linked either via the N atom or via a C atom to the remainder of the molecule.
  • monocyclic, saturated heterocyclyl may denote 3-8 membered monocyclic, saturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S or N, for example from 1 to 2 nitrogen and/or 1 or 2 sulfur and/or 1 or 2 oxygen atoms.
  • Prefered are 4-7 membered, especially preferred are 5- or 6-membered monocyclic radicals.
  • Preferred heterocyclic radicals are possessing per ring 1 nitrogen, oxygen or sulfur atom, whereby, per ring, at least 2 carbon atoms, preferentially 2-7 carbon atoms are present.
  • Substituent may comprise substituents mentioned before, such as Ci -8 -alkyl, C 2-8 -alkenyl, C 2 - 8 -alkinyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl- Ci-s-alkyl, C 6- i8-aryl, C 7- i8-aralkyl, heterocyclyl, heterocyclyl-Ci-s-alkyl, heteroaryl-Ci -8 - alkyl, tri-Ci -8 -alkyl-silyl, and Ci -8 -acyl.
  • saturated heterocyclyl radicals are azepanyl, azetidinyl, aziridinyl, 3,4- dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl, dioxanyl, [1 ,4]dioxepanyl, dioxolanyl, 4,4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxy- methylpyrrolidinyl, 4-hydroxypiperidinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 1 -methylpiperidinyl, 1 -methylpyrrolidinyl, morpholinyl, oxathianyl, oxepanyl, 2-oxo- azepanyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, 2-oxo-piperidinyl, 4-oxo-
  • saturated bicyclic heterocyclyl radicals are 2,5-dioxa- bicyclo[4.1.0]heptanyl, 2-oxa-bicyclo[2.2.1]heptanyl, 2-oxa-bicyclo[4.1.0]heptanyl, 3-oxa-bicyclo[4.1.0]heptanyl, 7-oxa-bicyclo[2.2.1]heptanyl, 2-oxa- bicyclo[3.1.0]hexanyl, 3-oxa-bicyclo[3.1.0]hexanyl, 1 -oxa-spiro[2.5]octanyl, 6-oxa- spiro[2.5]octanyl or 3-oxa-bicyclo[3.3.1]nonanyl.
  • Heterocyclyl radicals may be unsubstituted or mono- or polysubstituted, for example mono- or disubstituted.
  • substituents on such heterocyclyl radicals are Ci-6-alkanoyl, C2-6-alkenyl, C2-6-alkinyl, Ci-6-alkoxy, Ci-6-alkoxy-Ci-6-alkoxy, Ci-6- alkoxy-Ci-e-alkyl, Ci-6-alkoxycarbonylamino-C2-6-alkoxy, Ci -6 -alkoxycarbonylamino- Co-6-alkyl, Ci -6 -alkyl, Ci-e-alkylcarbonylamino, Ci-e-alkylcarbonylamino ⁇ -e-alkoxy, Ci-e-alkylcarbonylamino-Ci-e-alkyl, Ci -6 -alkylcarbonyloxy, Ci -6 -alkylenedioxy, optionally N-mono
  • polyhalogen-Ci- 6 -alkyl denotes Ci-s-alkyl radicals which may be substituted by 2-8 halogen, for example trifluoromethyl etc.
  • halo-Ci-s-alkyl for R 2 may denote mono- or polyhalogenalkyl, such as chloro- methyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, monofluoroethyl and pentafluoroethyl.
  • Ci-s-alkyl in the residues aryl-Ci-s-alkyl and heterocyclyl-Ci-s-alkyl may be linear or branched and preferably, the alkyl group is a Ci -6 -alkyl and more preferably a Ci -4 - alkyl group, such as methylene, ethylene, 1 ,2- or 1 ,3-propylene and 1 ,2-, 1 ,3- or 1 ,4- butylene.
  • Halogen or halo denotes, for example, fluorine, chlorine or bromine.
  • Salts are primarily the pharmaceutically acceptable or nontoxic salts of compounds of formula (I).
  • pharmaceutically acceptable salts encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • Salts of compounds having salt-forming groups are in particular acid addition salts, salts with bases, or, in the presence of a plurality of salt-forming groups, in some cases also mixed salts or internal salts.
  • Such salts are formed, for example, from compounds of formula (I) with an acidic group, for example a carboxyl or sulfo group, and are, for example, the salts thereof with suitable bases such as non-toxic metal salts derived from metals of group Ia, Ib, Ha and Hb of the Periodic Table of the Elements, for example alkali metal, in particular lithium, sodium, or potassium, salts, alkaline earth metal salts, for example magnesium or calcium salts, and also zinc salts and ammonium salts, including those salts which are formed with organic amines, such as optionally hydroxy-substituted mono-, di- or trialkylamines, in particular mono-, di- or tri(lower alkyl)amines, or with quaternary ammonium bases, e.g.
  • suitable bases such as non-toxic metal salts derived from metals of group Ia, Ib, Ha and Hb of the Periodic Table of the Elements, for example alkali metal, in particular lithium,
  • methyl-, ethyl-, diethyl- or triethylamine mono-, bis- or tris(2- hydroxy(lower alkyl))amines, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, N,N-di(lower alkyl)-N- (hydroxy(lower alkyl))amine, such as N,N-di-N-dimethyl-N-(2-hydroxyethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides such as tetrabutyl- ammonium hydroxide.
  • the compounds of the formula I having a basic group, for example an amino group may form acid addition salts, for example with suitable inorganic acids, e.g. hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, e.g. orthophosphohc acid or metaphosphohc acid, or pyrophosphoric acid with replacement of one or more protons, or with organic carboxylic, sulfonic or phosphonic acids or N-substituted sulfamic acids, e.g.
  • suitable inorganic acids e.g. hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, e.g. orthophosphohc acid or metaphosphohc acid, or pyrophosphoric acid with replacement of one or more protons
  • Salts obtained may be converted to other salts in a manner known per se, acid addition salts, for example, by treating with a suitable metal salt such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt which forms is insoluble and thus separates out of the reaction equilibrium, and base salts by release of the free acid and salt reformation.
  • a suitable metal salt such as a sodium, barium or silver salt
  • the compounds of formula (I), including their salts, may also be obtained in the form of hydrates or include the solvent used for the crystallization.
  • the compounds of formula (I) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example a hydrogen atom by deuterium.
  • the compounds of formula (I) may be prepared according to known or analogous preparation processses such as disclosed in the literature (e.g. WO2002/092622) (Scheme 1 ). Details on the specific preparation variants can be taken from the examples.
  • a further object of the invention is a process for the preparation of compounds of formula (I) according to Scheme 1 , and novel intermediates according to general formulae as given in Scheme 1.
  • the compounds of formula (I) have at least one asymmetric carbon atom and may therefore be in the form of optically pure enantiomers, mixtures with predominantly one enantiomer or racemates, or -when at least one additional asymmetric carbon atom is present- be in the form of diastereomers, diastereomeric mixtures, diastereomehc racemates, mixtures of diastereomeric racemates or as meso compounds.
  • the invention encompasses all of these forms. Diastereomeric mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary procedures, for example by column chromatography, thin- layer chromatography, HPLC and the like.
  • the compounds of formula (I) may also be prepared in optically pure form.
  • the separation into antipodes can be effected by procedures known per se, either preferably at an earlier synthetic stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid and separation of the diastereomeric salts by fractional crystallization, or preferably at a relatively late stage by dehvatizing with a chiral auxiliary building block, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bonds to give the chiral auxiliary.
  • the pure diastereomeric salts and derivatives may be analysed to determine the absolute configuration of the piperidine present with common spectroscopic procedures, and X-ray spectroscopy on single crystals constitutes a particularly suitable procedure.
  • the configuration at individual chiral centres in a compound of formula (I) may be inverted selectively.
  • the configuration of asymmetric carbon atoms which bear nucleophilic substituents, such as amino or hydroxyl may be inverted by second-order nucleophilic substitution, if appropriate after conversion of the bonded nucleophilic substituent to a suitable nucleofugic leaving group and reaction with a reagent which introduces the original substituents, or the configuration at carbon atoms having hydroxyl groups can be inverted by oxidation and reduction, analogously to the process in the European patent application EP-A-O 236 734.
  • the reactive functional modification of the hydroxyl group and subsequent replacement thereof by hydroxyl with inversion of configuration is also advantageous.
  • the compounds of formula (I) also include compounds where one or more atoms are replaced by their stable, non-radioactive isotopes (for example hydrogen by deuterium).
  • Prodrug derivatives of the compounds described in the present context are derivatives thereof which, on in vivo application, release the original compound by a chemical or physiological process.
  • a prodrug may be converted to the original compound, for example, when a physiological pH is attained or by enzymatic conversion.
  • Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O- acyl derivatives of thiols, alcohols or phenols, and the acyl group is as defined in the present context.
  • ester derivatives which are converted by solvolysis in physiological medium to the original carboxylic acid
  • prodrugs are selected from compounds of formula I, wherein the hydrogen atom of thiol group is substituted by a protective group R a , which is split off in a physiological environment, such as Ci-Cs-acyl (the term acyl may include residues from carboxylic and sulfonic acids), N,N-di-Ci-C 4 -alkylamino- carbonyl (dimethylaminocarbonyl) and Ci-C ⁇ -alkoxycarbonyl (methoxy-, ethoxy- or t-butoxycarbonyl).
  • a protective group R a which is split off in a physiological environment
  • acyl the term acyl may include residues from carboxylic and sulfonic acids
  • N,N-di-Ci-C 4 -alkylamino- carbonyl dimethylaminocarbonyl
  • Ci-C ⁇ -alkoxycarbonyl methoxy-, ethoxy- or t-butoxycarbonyl
  • a certain compound in this invention also encompasses its prodrug derivative and salt form, where these are possible and appropriate.
  • the compounds of the formula (I) also include compounds that have been nitrosated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen.
  • the nitrosated compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for nitrosating compounds are described in WO 2004/098538 A2.
  • the compounds of the formula (I) also include compounds that have been converted at one or more sites such that a nitrate-ester-containing linker is attached to an existing oxygen and/or nitrogen.
  • Such "nitroderivatives" of the compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for converting compounds into their nitroderivatives are described in WO 2007/045551 A2.
  • Neutral endopepetidase 3.4.24.11 also called neprilysin, enkephalinase, common acute lymphoblastic leukemia antigen or CD10 is a zinc-containing metallo- protease that cleaves specific biologically active peptides.
  • NEP is widely distributed in the body and has been purified from kidney, brain and intestinal tissues.
  • Several peptides have been identified as substrates for NEP in vitro; however, the distribution of this peptidase and that of its potential substrates is likely to impart functional selectivity to NEP in vivo. Pharmacological inhibition of NEP affects the metabolism of the peptides and thus enhances their biologic function.
  • NEP participates in the hydrolysis of Met- and Leu- enkephalin. These peptides have the ability to mediate analgesia. Hence, inhibition of NEP has been demonstrated to yield an anti-nociceptive activity (Chipkin et al., J. Pharmacol. Exp. Ther. 1988; 245:829-838).
  • NEP participates in the degradation of natriuretic peptides and bradykinin.
  • the natriuretic peptides ANP, atrial natriuretic peptide, BNP, brain natriuretic peptide, CNP, C-type natriuretic peptide and urodilatin mediate diuretic, natriuretic, anti-inflammatory, antifibrotic and anti-mitogenic actions.
  • Bradykinin regulates the tonus of vascular smooth muscle tissues.
  • NEP participates in the degradation of CGRP, calcitonin gene- related peptide, a potent vasodilator that plays an important role in the initiation, progression and maintenance of hypertension via interactions with pro-hypertensive systems, including renin-angiotensin-aldosterone system, sympathetic nervous system and endothelin system; and via anti-hypertrophy and anti-proliferation of vascular smooth muscle cells.
  • the decrease in CGRP synthesis and release contributes to the elevated blood pressure.
  • inhibition of NEP may potentiate the effects of CGRP and its compensatory depressor role in the development of hypertension (Deng and Li, Peptides 2005; 26:1676-1685).
  • NEP participates in the catabolism of vasoactive intestinal peptide.
  • Vasoactive intestinal peptide increases genital blood flow resulting in increased vaginal, labial and clitoral blood flow.
  • inhibition of NEP potentiates the activity of vasoactive intestinal peptide and is useful for the treatment of female sexual arousal disorder (FSAD) (Pryde et al., Journal of Medicinal Chemistry 2006; 49:4409-4424).
  • FSAD female sexual arousal disorder
  • NEP participates also in the degradation of incretin glucagon-like peptide-1.
  • Glucagon-like peptide 1 has insulinotropic activity in the pancreas and may also regulate food consumption.
  • inhibition of NEP enhances glucose-dependent insulin release, reduces food consumption and is useful for the treatment of diabetes, insulin resistance and obesity.
  • NEP inhibitors have led to intensive drug discovery efforts.
  • Several selective NEP inhibitors of various chemical classes have been discovered and some have been tested clinically.
  • the ability of the herein described compounds of formula (I) to inhibit NEP activity can be shown for example by an in vitro assay that determines the hydrolysis of a fluorogenic substrate by NEP derived from rat kidney cortex membranes using a modified procedure of Orlowski and WiIk (Biochemistry, 1981 ; 20:4942-50).
  • the incubation mixture of 100 ⁇ l contains:
  • test compound is dissolved in DMSO at a concentration of 1 mM prior to serial dilution with assay buffer containing.
  • concentrations in the incubation mixture range between 10 ⁇ M and 1 nM.
  • the incubation mixture is incubated for 45 min at 30 0 C.
  • the hydrolysis product, 7-amido-4-methylcoumarin is quantified by fluorescence (A ecc :355 nm; ⁇ em :460 nm) using Victor V 2 detector (Perkin Elmer). Examples of in vitro NEP inhibition:
  • a higher inhibiting activity corresponds to a lower IC 5 O value.
  • NEP inhibitory activity of herein disclosed compounds of formula (I) can also be shown for example by an ex vivo assay that determines the hydrolysis of a fluorogenic substrate by NEP derived from rat kidney homogenate using a modified procedure of Orlowski and WiIk (Biochemistry, 1981 ; 20:4942-50).
  • Male spontaneous hypertensive rats (SHR) of 11 -14 weeks of age are subjected in groups of 3 to i.v. administration of test compound or vehicle.
  • the test compound is applied in a volume of 1.0 ml at a concentration ranging between 2 to 20 ⁇ mol/kg body weight.
  • mice Five to fifteen minutes after the tail vein injection the animals are sachfied and their kidneys are removed for homogenization in a TRIS-buffered Thton-X100 solution.
  • the NEP activity in the homogenate is measured in a mixture of 100 ⁇ l containing
  • IC50 values are calculated by fitting a 4-parameter logistic curve to the recorded %lnhib at specific test article concentrations according to following nonlinear equation:
  • c is the inflection point (EC50 or IC50) for the curve respectively the negative log of the compound concentration giving a half-maximal effect ie. if Y is halfway between the lower and upper asymptotes X equals c.
  • b is the slope-factor in the region of the IC50 or Hill coefficient. The sign of b is positive when the response increases with increasing dose and is negative when the response decreases with increasing dose (inhibition).
  • the investigations take place in pre-catheterized (carotid artery) male rats (300 g ⁇ 20%) that can move freely throughout the study.
  • the compound is administered intravenously and orally (gavage) in separate sets of animals.
  • the applied doses for oral administration may range from 0.5 to 50 mg/kg body weight; the doses for intravenous administration may range from 0.5 to 20 mg/kg body weight.
  • Blood samples are collected through the catheter before compound administration and over the subsequent 24-hour period using an automated sampling device (AccuSampler, DiLab Europe, Lund, Sweden). Plasma levels of the compound are determined using a validated LC-MS analytical method. The pharmacokinetic analysis is performed on the plasma concentration-time curves after averaging all plasma concentrations across time points for each route of administration.
  • Typical pharmacokinetics parameters to be calculated include: maximum concentration (C ma ⁇ ), time to maximum concentration (t max ), area under the curve from 0 hours to the time point of the last quantifiable concentration (AUCo-t), area under the curve from time 0 to infinity (AUCo-inf), elimination rate constant (K), terminal half-life (t /2 ), absolute oral bioavailability or fraction absorbed (F), clearance (CL), and Volume of distribution during the terminal phase (Vd).
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are responsible for more than 95% of the drug metabolizing activity in humans.
  • liver systems e.g. hepatocytes, microsomes
  • cofactors are self-sufficient and the natural orientation and location for linked enzymes is preserved.
  • a simpler screening tool is advantageous.
  • the cDNAs for the common CYP450s have been cloned and the recombinant human enzymatic proteins have been expressed in a variety of cells. Use of these recombinant enzymes provides an excellent way to quickly assess specific enzyme inhibition activities and/or confirm results identified in microsomes.
  • the metabolic properties (inhibition constants on human cytochrome P450 isoforms) of the compounds described herein can be tested in vivo using the following protocol:
  • the enzymatic reaction is monitored in the presence of different concentrations of test compound (serial dilution) and compared to maximal enzyme activity (control : no test compound).
  • inhibition can occur by three different mechanisms: (1 ) competitive inhibition, (2) noncompetitive inhibition, and (3) mechanism-based inhibition.
  • the inhibition strength is dependent on the concentration of test compound. Testing the CYP450 enzyme activity over a test compound concentration range identifies the test compound concentration at which half maximal enzyme inhibition is observed (IC 5 O concentration).
  • the inhibitory potential of a test compound can be tested with ready to use kits (CYP450 High Throughput Inhibitor Screening kit, e.g. CYP1A2/CEC, #459500, BD Biosciences, Franklin Lakes, NJ USA), which are available for all of the five above-mentioned major CYP isoforms.
  • kits CYP450 High Throughput Inhibitor Screening kit, e.g. CYP1A2/CEC, #459500, BD Biosciences, Franklin Lakes, NJ USA
  • recombinant human CYP450 isoforms expressed in insect cells are incubated with isoform specific, fluorogenic substrates in the presence of different test compound concentrations. Enzymatic activity converts the fluorogenic substrate into a fluorochrome product, the concentration of which is measured with a fluoro- spectrophotometer. Fluorescence is directly proportional to enzyme activity.
  • a compound is tested at 2 nM to 33 ⁇ M concentration range in a phosphate buffer (50 mM, pH 7.4) containing a glucose 6-phosphate dehydrogenase/NADP/NADPH regeneration system and a suitable fluorogenic substrate: e.g. 3-cyano-7- ethoxycoumahn (CYP1A2).
  • a suitable fluorogenic substrate e.g. 3-cyano-7- ethoxycoumahn
  • the following substances can be used: furafylline (CYP1A2), sulfaphenazole (CYP2C9), tranylcypromine (CYP2C19), quinidine (CYP2D6) and ketoconazole (CYP3A4).
  • the reaction is started by the addition of 2.5 nM (final concentration) CYP450 isozyme, incubated at 37°C for 15 to 45 minutes, and then terminated by the addition of 187.5 mM ths-hydroxy-aminomethane base/acetonitrile (20/80, v/v).
  • the amount of generated fluorochrome is then determined by fluorescence spectroscopy with suitable exitation and emission wavelength settings: e.g. 410 nm excitation and 460 nm emission wavelength (CYP1A2).
  • assays using human liver microsomes e.g. BD Biosciences, #452161
  • a CYP isoform-specific standard substrate e.g.
  • midazolam for CYP3A4/5) as described by R. L. Walsky and R. S. Obach in Validated assay for human cytochrome p450 activities; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Groton, Connecticut; Drug Metabolism and Disposition: (2004)32, 647-660, can be used.
  • a test compound inhibits CYP3A enzyme activity for example, hydroxylation of midazolam by human liver microsomes at varying test compound concentrations is monitored. Hydroxy-midazolam production is directly proportional to enzyme activity and can be determined by liquid chromatography-tandem mass spectrometry.
  • microsomal assay can be run without and with a 15 min pre-incubation of microsomes with test compound prior to the addition of standard substrate.
  • Test compounds or their metabolite(s) that have the potential to irreversibly modify the P450 enzyme will have a stronger inhibitory effect after preincubation.
  • a typical standard assay using the human liver microsome assay compounds are tested at 10 nM to 50 ⁇ M concentration range in a phosphate buffer (100 mM potassium phosphate, 3.3 mM MgCI 2 , pH 7.4) containing a NADPH regeneration system (glucose 6-phosphate dehydrogenase, NADP, NADPH) and 10 ⁇ M substrate (e.g. midazolam for CYP3A4/5) and 0.1 mg/mL microsomal protein.
  • a NADPH regeneration system glucose 6-phosphate dehydrogenase, NADP, NADPH
  • 10 ⁇ M substrate e.g. midazolam for CYP3A4/5
  • the same substances as described above can be used (e.g. ketoconazole (CYP3A4/5)).
  • the samples are centrifuged at 3,500 g for 60 min at 4°C to separate precipitated protein.
  • the supernatant is mixed with acetonitrile/water (50/50, v/v), and then directly analyzed for compound content with LC/MSMS.
  • Metabolic stability of herein disclosed compounds of formula (I) can be a factor influencing their bioavailability. Metabolic stability can be tested for example by determination of the hepatic intrinsic microsomal clearance using the procedure of Obach (Drug Metabolism and Disposition, 1999; 27(11 ):1350-1359).
  • Preferred inventive compounds are those of the general formula (IA)
  • a further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • A is monocyclic Cs-s-cycloalkyl which is either unsubstituted or substituted by 1 -3 Ci-8-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
  • R 1 is H, Ci-s-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci -8 -alkyl, aryl, aryl-Ci -8 - alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-S- alkoxy, carboxy, halogen, hydroxy or oxo; and
  • R 3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
  • a further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • A is monocyclic, saturated heterocyclyl which is either unsubstituted or substituted by 1 -3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
  • R 1 is H, Ci- 8 -alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 2 is Ci-8-alkoxy-Ci-8-alkoxy-Ci-8-alkyl, Ci- 8 -alkoxy-Ci- 8 -alkyl, Ci- 8 -alkyl, aryl, aryl-Ci- 8 - alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-8-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s- alkoxy, carboxy, halogen, hydroxy or oxo; and R 3 is H, Ci-s-alkyl-annino, aryl-Ci-s-alkyl-annino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-8-alkyl in Ci-s-alkyl-annino, aryl-C
  • a further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • A is monocyclic C 5-7 -cycloalkyl or monocyclic, saturated heterocyclyl, having one heteroatom selected from the group comprising O, S or N; each of which are either unsubstituted or substituted by 1-3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo; very particularly preferably cyclohexyl, cyclopentyl or tetrahydropyran-4-yl.
  • Another preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • R 1 is H, Ci-s-alkyl.or aryl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl or aryl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 1 is particularly preferred H, Ci -8 -alkyl or aryl-C 2-4 -alkyl, wherein Ci -8 -alkyl in Ci-s- alkyl or aryl-C2 -4 -alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
  • An additional preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • R 2 is Ci-s-alkoxy-Ci-s-alkyl, Ci -8 -alkyl, aryl or aryl-Ci -2 -alkyl, wherein Ci -2 -alkyl in aryl- Ci-2-alkyl is unsubstituted or substituted with 1-3 Ci -8 -alkoxy, carboxy, halogen, hydroxy or oxo; very particularly preferably benzyl, isopropyl, 2-methoxyethyl, methyl or propyl.
  • a further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
  • R 3 is H or Ci-s-alkyl-amino; very particularly preferably H, methylamino, ethylamino, propylamine or butylamino.
  • the compounds of formula (I), or preferably of formula (IA), and their pharmaceutically useable salts may find use as medicaments, for example in the form of pharmaceutical preparations. Accordingly, this invention is also directed to a pharmaceutical composition comprising a compound of formula (I), or preferably of formula (IA), and a pharmaceutically acceptable carrier or diluents.
  • the pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, or trans- dermally, for example in the form of ointments or patches.
  • enterally such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions
  • nasally for example in the form of nasal sprays, rectally, for example in the form of suppositories, or trans- dermally, for example in the form of ointments or patches.
  • the administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
  • the compounds of formula (I), or preferably of formula (IA), and pharmaceutically useable salts thereof may be processed with pharmaceutically inert, inorganic or organic excipients.
  • excipients used for example for tablets, coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
  • Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
  • Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
  • Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc.
  • Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
  • the pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
  • the herein disclosed compounds of formula (I), or preferably of formula (IA), and pharmaceutically useable salts thereof, by inhibiting the neutral endopeptidase EC.3.4.24.11 can have beneficial effects in the treatment of a number of disorders, including hypertension (including malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary types of hypertension), primary and secondary pulmonary hypertension, primary and secondary aldosteronism, oedema, salt retention, ascites, peripheral vascular resistance, arterial hypertrophy, vascular disorders including peripheral vascular disease, peripheral occlusive disease, intermittent claudication, migraine and Raynaud's disease, luminal hyperplasia, restenosis after coronary or peripheral angioplasty, heart failure including acute or chronic diastolic and congestive heart failure, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, myocarditits, pericarditis,
  • the compounds of the invention may have activity in other therapeutic areas including for example the treatment of glaucoma, cataracts, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), erectile dysfunction, female sexual dysfunction, male sexual dysfunction, sexual desire and arousal disorders, genital sensation and sensitivity disorders, orgasmic disorders, vaginal and clitoric blood flow disorders, sexual pain disorders, endometriosis, pelvic inflammatory disease,
  • the compounds of the invention should treat asthma, inflammation, leukemia, pain, epilepsy, pain, depression, psychotic conditions, affective disorders, cognitive disorders such as Alzheimer's disease and dementia and geriatric confusion, premenstrual syndrome, cerebral ischemia, stroke, subarachnoid hemorraghe, traumatic brain injury, cerebral vasospasm, cerebral ischemias, stroke, subarachnoid haemorrhage, migraine, traumatic brain injury, cerebral vasculitis, inflammatory neuropathies and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), liver disease, cirrhosis, hepato-renal syndrome, Crohn's disease, wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion and cystic fibrosis.
  • the compounds of the invention are useful in the treatment of hypertension and hypertension-derived pathologies of the cardiovascular and renal system.
  • one or more blood pressure-lowering active ingredients as such for example: renin inhibitors such as aliskiren, or compounds disclosed in WO 2005/090305, WO 2006/005741 , WO 2006/095020, WO 2006/103275, WO 2006/103277 and WO 2007/031558, etc.; angiotensin Il receptor blockers such as candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, etc.;
  • renin inhibitors such as aliskiren, or compounds disclosed in WO 2005/090305, WO 2006/005741 , WO 2006/095020, WO 2006/103275, WO 2006/103277 and WO 2007/031558, etc.
  • angiotensin Il receptor blockers such as candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, etc.
  • ACE inhibitors such as quinapril, ramipril, trandolapril, lisinopril, captopril, enalapril etc.
  • calcium antagonists such as nifedipine, nicardipine, verapamil, isradipine, nimodipine, amlodipine, felodipine, nisoldipine, diltiazem, fendiline, flunahzine, perhexiline, gallopamil etc.
  • diuretics such as hydrochlorthiazide, chlorothiazide, acetazolamide, amilohde, bumetanide, benzthiazide, etacrynic acid, furosemide, indacrinone, metolazone, triamterene, chlortalidone, etc.
  • aldosterone receptor blockers such as spironolactone, eplerenone
  • HMR 1776 HMR 1776; ⁇ - and ⁇ -receptor blockers such as phentolamine, phenoxybenzamine, prazosin, doxazosin, terazosin, carvedilol, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol etc.; sympatholytics such as methyldopa, clonidine, guanabenz, reserpine (ii) one or more agents having inotropic activity, as such for example: cardiac glycosides such as digoxin, ⁇ -receptor stimulators such as dobutamine, thyroid hormone such as thyroxine; (iii) one or more agents having antidiabetic activity, as such for example: insulins such as insulin aspart, insulin human, insulin lispro, insulin glargine and further fast-, medium- and long-acting insulin derivatives and combinations insulin sensitizers such as ros
  • HMG-CoA reductase inhibitors such as lovastatin, fluvastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin etc.; fibrate derivatives such as fenofibrate, gemfibrozil etc.; bile acid-binding active ingredients such as colestipol, colestyramine, colesevelam; cholesterol absorption inhibitors such as ezetimibe; nicotinic acid such as niacin; (vi) one or more anti-inflammatory agents, such as, for example, non-selective cyclooxygnease-1/2 inhibitors such as acetyl salicylic acid, ibuproven, diclofenac, paracetamol, mefenamic acid, indometacin, naproxen etc.; selective cyclooxygenase-2 inhibitors such as celcoxib, rofecoxib, lumiracoxib, etohcoxib etc.;
  • the dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case.
  • Another object of the invention is a method of delivering a compound of formula (I), or preferably of formula (IA), to a host, comprising administering to a host an effective amount of a compound of formula (I), or preferably of formula (IA).
  • a further object of the invention is the use of the a compound of formula (I), or preferably of formula (IA), for the manufacture of a medicament useful in the of inhibition of the neutral endopeptidase EC.3.4.24.11.
  • the starting matehal(s) is(are) prepared as follows : a) Thioacetic acid S-US)-I -H -(6-oxo-6,9-dihvdro-1 H-purin-8-yl)-cvclopentyl- carbamoyli-2-phenyl-ethyl) ester
  • the starting material(s) is(are) prepared as follows : a) Thioacetic acid S-((S)-2-methyl-1 -f 1 -(6-oxo-1 -propyl-6,9-dihvdro-1 H-purin-8-vD- cyclopentylcarbamoyli-propyl) ester

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Abstract

Substituted heterocycles of the general formula (I) with the residues A, R1, R2 and R3 as explained in detail in the description are described. The compounds are suitable in particular as neutral endopeptidase inhibitors and are highly potent.

Description

PURINE DERIVATIVES FURTHER COMPRISING A MERCAPTO-ACYLAMINO GROUP AS NEUTRAL ENDOPEPTIDASE
INHIBITORS
FIELD OF THE INVENTION
The present invention relates to puhnones substituted at least at one carbon atom of the ring, to processes for their preparation and to the use of the compounds as medicaments, in particular as neutral endopeptidase (NEP) inhibitors, in particular to medicaments containing such a compound.
BACKGROUND OF THE INVENTION
Various NEP inhibitors and their uses are disclosed, for example, in EP 0364767 A1. However, there is still a need for highly potent and selective active compounds. In this context, the improvement of a compound's pharmacokinetic properties, resulting in better oral bioavailability, and/or it's overall safety profile are at the forefront. Properties directed towards better bioavailability are, for example, increased absorption, metabolic stability or solubility, or optimized lipophilicity. Properties directed towards a better safety profile are, for example, increased selectivity against drug metabolizing enzymes such as the cytochrome P450 enzymes or increased selectivity against other vasoactive zinc metalloproteases such as angiotensin converting enzyme (ACE) and aminopeptidase P (APP).
DETAILED DESCRIPTION OF THE INVENTION
The invention therefore provides substituted heterocycles of the general formula (I)
Figure imgf000002_0001
wherein A is monocyclic Cs-s-cycloalkyl or monocyclic, saturated heterocyclyl, each of which are either unsubstituted or substituted by 1 -3 Ci-8-alkoxy, Ci-8-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-8-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkyl, aryl, aryl-Ci-s- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-S- alkoxy, carboxy, halogen, hydroxy or oxo;
R3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo; where the aryl or heterocyclyl moieties are unsubstituted or substituted; where the thiol group is unprotected or protected with a protecting group Ra, which is hydrolyzed under physiological conditions to liberate the compound of formula (I); disulfide derivatives derived from the compounds of formula (I) and salts of a compound of formula (I), preferably pharmaceutically acceptable salts thereof.
Thiol protecting groups Ra are for example acyl or sulfonyl groups, which are unsubstituted or substituted with one or more halogen (fluoro or chlorine), hydroxy, N,N-di- Ci-s-alkyl-amine, morpholine or Ci-s-alkoxy, or N,N-di-Ci-C4-alkylaminocarbonyl. Acyl radicals are preferably alkanoyl radicals, more preferably Ci-s-alkanoyl radicals such as formyl, acetyl, fluoroacetyl, chloroacetyl, dimethylaminoacetyl, or aroyl radicals such as benzoyl. Further suitable thiol protecting groups may be identified using test systems available and known to the person skilled in the art.
Examples of alkyl and alkoxy radicals, which may be linear or branched, are Ci-S- alkyl and Ci-s-alkoxy radicals such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, and methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy and t-butoxy respectively. Ci-s-Alkylenedioxy radicals are preferably methylenedioxy, ethylenedioxy and propylenedioxy. Cycloalkyl is a saturated, cyclic or polycyclic hydrocarbon radical having 3-12 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, bicyclo[2.2.2]octyl and adamantyl. Ci-8-alkyl radicals in aryl-Ci-8-alkyl, heterocyclyl- Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, aryl-Ci-s-alkyl and heterocyclyl-Ci-8-alkyl and in other substituents, which may be linear or branched, are, for example, methylene, ethylene, 1 -methylmethylene, propylene, methyl- ethylene, 1-ethylmethylene, 1 ,1-dimethylmethylene, 2-methylpropylene, 2-methyl- butylene, 2-methylbutyl-2-ene, butyl-2-ene, butyl-3-ene, propyl-2-ene, tetra-, penta- and hexamethylene.
In case of A, the term cycloalkyl may denote a monocyclic radical having 3-8 and preferably 5 or 6 ring carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl may denote mono- or polycyclic aromatic radicals, which may be mono- or poly- substituted in the aryl moiety, for example phenyl, substituted phenyl, naphthyl or substituted naphthyl. Examples of substituents on such aryl radicals are acetamidinyl- Ci-s-alkyl, acyl-Ci-s-alkoxy-Ci-s-alkyl, (N-acyl)-Ci-8-alkoxy-Ci-8-alkylamino, C2-8-alkenyl, C2-8-alkenyloxy, Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, (N-Ci-s-alkoxyJ-Ci-s-alkylaminocarbonyl-Ci-s-alkoxy, (N-Ci-8- alkoxy)-Ci-8-alkylaminocarbonyl-Ci-8-alkyl, Ci-s-alkoxy-Ci-s-alkyl-carbamoyl, Ci-S- alkoxy-Ci-s-alkyl-carbonyl, Ci-s-alkoxy-Ci-s-alkyl-carbonylamino, Ci-s-alkoxy-Ci-s-alkyl- heterocyclyl, 2-Ci-8-alkoxy-Ci-8-alkyl-4-oxo-imidazol-1 -yl, θ-alkoxy-aminocarbonyl-Ci-s- alkoxy, Ci-s-alkoxy-aminocarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonyl, Ci-s-alkoxycarbonyl- Ci-s-alkoxy, Ci-s-alkoxycarbonyl-Ci-s-alkyl, Ci-s-alkoxycarbonylamino-Ci-s-alkoxy, Ci-8- alkoxycarbonylamino-Ci-s-alkyl, Ci-8-alkoxycarbonylphenyl, Ci-8-alkyl, (N-Ci-8-alkyl)- Ci-8-alkoxy-Ci-8-alkyl-carbamoyl, (N-Ci-s-alkylJ-Ci-s-alkoxy-Ci-s-alkyl-carbonylamino, (N-Ci-s-alkylJ-Ci-s-alkoxy-carbonylamino, (N-Ci-8-alkyl)-Co-8-alkylcarbonylamino-Ci-8- alkoxy, (N-Ci-s-alkylJ-Co-s-alkylcarbonylamino-Ci-s-alkyl, (N-Ci-8-alkyl)-Ci-8-alkyl- sulfonylamino-Ci-s-alkoxy, (N-Ci-s-alkylJ-Ci-s-alkylsulfonylamino-Ci-s-alkyl, Ci-s-alkyl- - A - amidinyl, optionally N-mono or N,N-di-Ci-8-alkylated amino, Ci-8-alkylamino-C2-8- alkoxy, di-Ci-8-alkylannino-C2-8-alkoxy, Ci-s-alkylannino-Ci-s-alkyl, di-Ci-s-alkylamino- Ci-s-alkyl, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy, di-Ci-s-alkylanninocarbonyl-Ci-s-alkoxy, Ci-s-alkylanninocarbonyl-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkylanninocarbonyl-Ci-s-alkyl, di- Ci-s-alkylanninocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonylamino-Ci-s-alkoxy, Ci-8- alkylanninocarbonylannino-Ci-8-alkyl, Ci-s-alkyl-carbannoyl, di-Ci-s-alkyl-carbannoyl, Co-8- alkylcarbonylamino, Co-β-alkylcarbonylamino-Ci-s-alkoxy, Co-s-alkylcarbonylamino-Ci-s- alkyl, Ci-s-alkylcarbonyloxy, Ci-s-alkylcarbonyloxy-Ci-s-alkoxy, Ci-s-alkylcarbonyloxy- Ci-s-alkyl, Ci-s-alkylenedioxy, Ci-s-alkyl-sulfonyl, Ci-s-alkylsulfonyl-Ci-s-alkoxy, Ci-S- alkylsulfonyl-Ci-s-alkyl, Ci-s-alkylsulfonylannino-Ci-s-alkoxy, Ci-s-alkylsulfonylamino- Ci-s-alkyl, aryl-Ci-8-alkanoyl, aryl-Co-s-alkoxy, aryl-Co-s-alkyl, arylamino, aryloxy, arylthio, benzoyloxy-Ci-8-alkoxy, benzyloxy, carbamoyl-Co-s-alkoxy, carbamoyl-Co-s- alkyl, carboxy, carboxy-Ci-8-alkoxy, carboxy-Ci-s-alkoxy-Ci-s-alkyl, carboxy-Ci-8-alkyl, cyano, cyano-Ci-s-alkoxy, cyano-Ci-s-alkyl, Cs-s-cycloalkyl-Ci-s-alkanoyl, C3-8-cyclo- alkylcarbonylannino-Ci-8-alkoxy, Cs-s-cycloalkylcarbonylamino-Ci-s-alkyl, cyclopropyl- Ci-s-alkoxy, cyclopropyl-Ci-s-alkyl, CN-dinnethylhydroxylannino-Ci-s-alkyl, dioxolanyl- Ci-s-alkoxy, halogen, halogen-Ci-s-alkoxy, halogen-Ci-s-alkyl, heterocyclyl, hetero- cyclyl-Ci-s-alkanoyl, heterocyclyl-Ci-s-alkoxy, heterocyclyl-Ci-s-alkoxy-Ci-s-alkoxy, heterocyclyl-Ci-s-alkoxy-Ci-s-alkyl, heterocyclyl-Ci-s-alkyl, heterocyclylamino, hetero- cyclyloxy, heterocyclylthio, hydroxy, hydroxy-C2-8-alkoxy, hydroxy-C2-8-alkoxy-Ci-8- alkoxy, hydroxy-C2-8-alkoxy-Ci-8-alkyl, hydroxy-Ci-8-alkyl, (N-hydroxy)-Ci-8-alkyl- aminocarbonyl-Ci-8-alkoxy, (N-hydroxyJ-Ci-s-alkylaminocarbonyl-Ci-s-alkyl, hydroxy- Ci-s-alkylphenyl, (N-hydroxy)-aminocarbonyl-Ci-8-alkoxy, (N-hydroxy)-aminocarbonyl- Ci-s-alkyl, hydroxybenzyloxy, methylendioxybenzyloxy, methoxybenyloxy, O-methyl- oximyl-Ci-8-alkyl, nitro, 2-oxo-oxazolidinyl-Ci-s-alkoxy, 2-oxo-oxazolidinyl-Ci-s-alkyl or pyridylcarbonylamino-Ci-s-alkyl.
The term heterocyclyl except for residue A denotes mono- or polycyclic, saturated and unsaturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S or N, for example from 1 to 4 nitrogen and/or 1 or 2 sulfur and/or 1 or 2 oxygen atoms and which may be mono- or polysubstituted, especially mono- ,di- or trisubstituted. Additionally, the term heterocyclyl may include the above mentioned oxo-substituted radicals. Examples of unsaturated heterocyclyl radicals are benzo[1 ,3]dioxolyl, benzofuranyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl, quinoxalinyl, dihydrobenzofuranyl, 1 ,3-dihydro- benzoimidazol, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, dihydro-3H-benzo[1 ,4]oxazinyl, 1 ,4-dihydro-benzo[d][1 ,3]oxazin, dihydro-2H-benzo[1 ,4]thiazinyl, 3,4-dihydro-1 H- quinazolin, 3,4-dihydro-1 H-quinolin, 2,3-dihydroindolyl, dihydro-1 H-pyrido[2,3- b][1 ,4]oxazinyl, 1 ,1 -dioxo-dihydro-2H-benzo[1 ,4]thiazinyl, furyl, imidazolyl, imidazo[1 ,5-a]pyridinyl, imidazo[1 ,2-a]pyrimidinyl, indazolyl, indolyl, isobenzofuranyl, isoquinolyl, [1 ,5]naphthyridyl, oxazolyl, 1 -oxido-pyridyl, 2-oxo-benzoimidazolyl, 3-oxo- 4H-benzo[1 ,4]oxazinyl, 2-oxo-benzooxazolyl, 3-oxo-4H-benzo[1 ,4]thiazinyl, 2-oxo- dihydro-benzo[e][1 ,4]diazepinyl, 2-oxo-1 ,3-dihydro-benzoimidazol, 2-oxo-dihydro- benzo-[d][1 ,3]oxazinyl, 2-oxo-3,4-dihydro-1 H-quinazolin, 2-oxo-3,4-dihydro-1 H- quinolin, 4-oxo-dihydro-imidazolyl, 2-oxo-1 ,3-dihydroindolyl, 1 -oxo-3H-isobenzo- furanyl, 2-oxo-1 H-pyrido[2,3-b][1 ,4]oxazinyl, 2-oxo-1 ,3,4,5-tetrahydro- benzo[b]azepin, 2-oxo-tetrahydro-benzo[e][1 ,4]diazepinyl, 4-oxo-3H-thieno[2,3- d]pyrimidinyl, 5-oxo-4H-[1 ,2,4]triazinyl, phthalazinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, 1 H-pyrrolizinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, 1 H-pyrrolo[2,3-b]pyridyl, pyrrolyl, 1 ,3,4,5-tetrahydro- benzo[b]azepin, tetrahydroquinolinyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, 1 ,1 ,3-trioxo-dihydro-2H- 1 lambda*6*-benzo[1 ,4]thiazinyl, [1 ,2,3]triazolo[1 ,5-a]pyridinyl or [1 ,2,4]triazolo[4,3- a]pyridinyl.
The term saturated heterocyclyl except for residue A may denote 3-16 membered mono- or bicyclic, saturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S, or N, for example from 1 to 4 nitrogen and/or 1 or 2 sulfur or oxygen atoms. Preferred are 3-8 membered, especially preferred 5- or 6-membered monocyclic radicals, which may be condensed to a 3-8 membered, carbocyclic or heterocyclic ring. Another preferred group of saturated heterocyclic radicals are bicyclic radicals possessing a spirocyclic or bridged ring skeleton. Preferred heterocyclic radicals in heterocyclyl or heterocyclyl-Ci-s-alkyl except for residue A are possessing per ring 1 nitrogen, oxygen or sulfur atom, 1 -2 nitrogen atoms and 1 -2 oxygen atoms or 1 -2 nitrogen atoms and 1 -2 sulfur atoms, whereby, per ring, at least 1 carbon atom, preferentially 1 -7 carbon atoms are present. Heterocyclyl radicals which comprise a nitrogen atom may be linked either via the N atom or via a C atom to the remainder of the molecule.
In case of A, the term monocyclic, saturated heterocyclyl may denote 3-8 membered monocyclic, saturated heterocyclic radicals having one or more heteroatoms selected from the group comprising O, S or N, for example from 1 to 2 nitrogen and/or 1 or 2 sulfur and/or 1 or 2 oxygen atoms. Prefered are 4-7 membered, especially preferred are 5- or 6-membered monocyclic radicals. Preferred heterocyclic radicals are possessing per ring 1 nitrogen, oxygen or sulfur atom, whereby, per ring, at least 2 carbon atoms, preferentially 2-7 carbon atoms are present.
A heteroatom N in heterocyclyl may comprise NH or N-substituent and additionally -N= in unsaturated heterocyclyl. Substituent may comprise substituents mentioned before, such as Ci-8-alkyl, C2-8-alkenyl, C2-8-alkinyl, C3-8-cycloalkyl, C3-8-cycloalkyl- Ci-s-alkyl, C6-i8-aryl, C7-i8-aralkyl, heterocyclyl, heterocyclyl-Ci-s-alkyl, heteroaryl-Ci-8- alkyl, tri-Ci-8-alkyl-silyl, and Ci-8-acyl.
Examples for saturated heterocyclyl radicals are azepanyl, azetidinyl, aziridinyl, 3,4- dihydroxypyrrolidinyl, 2,6-dimethylmorpholinyl, 3,5-dimethylmorpholinyl, dioxanyl, [1 ,4]dioxepanyl, dioxolanyl, 4,4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxy- methylpyrrolidinyl, 4-hydroxypiperidinyl, 3-hydroxypyrrolidinyl, 4-methylpiperazinyl, 1 -methylpiperidinyl, 1 -methylpyrrolidinyl, morpholinyl, oxathianyl, oxepanyl, 2-oxo- azepanyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, 2-oxo-piperidinyl, 4-oxo- piperidinyl, 2-oxo-pyrrolidinyl, 2-oxo-tetrahydro-pyhmidinyl, 4-oxo-thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydro- thiophenyl, tetrahydrothiopyranyl, thiepanyl or thiomorpholinyl. Examples for saturated bicyclic heterocyclyl radicals are 2,5-dioxa- bicyclo[4.1.0]heptanyl, 2-oxa-bicyclo[2.2.1]heptanyl, 2-oxa-bicyclo[4.1.0]heptanyl, 3-oxa-bicyclo[4.1.0]heptanyl, 7-oxa-bicyclo[2.2.1]heptanyl, 2-oxa- bicyclo[3.1.0]hexanyl, 3-oxa-bicyclo[3.1.0]hexanyl, 1 -oxa-spiro[2.5]octanyl, 6-oxa- spiro[2.5]octanyl or 3-oxa-bicyclo[3.3.1]nonanyl.
Heterocyclyl radicals may be unsubstituted or mono- or polysubstituted, for example mono- or disubstituted. Examples of substituents on such heterocyclyl radicals are Ci-6-alkanoyl, C2-6-alkenyl, C2-6-alkinyl, Ci-6-alkoxy, Ci-6-alkoxy-Ci-6-alkoxy, Ci-6- alkoxy-Ci-e-alkyl, Ci-6-alkoxycarbonylamino-C2-6-alkoxy, Ci-6-alkoxycarbonylamino- Co-6-alkyl, Ci-6-alkyl, Ci-e-alkylcarbonylamino, Ci-e-alkylcarbonylamino^-e-alkoxy, Ci-e-alkylcarbonylamino-Ci-e-alkyl, Ci-6-alkylcarbonyloxy, Ci-6-alkylenedioxy, optionally N-mono or N,N-di-Ci-6-alkylated amino, aryl, optionally N-mono or N,N-di- Ci-6-alkylated carbamoyl, carbonylamino, carbonylamino-C2-6-alkoxy, carbonylamino- Ci-6-alkyl, optionally esterified carboxy, cyano, Cs-s-cycloalkoxy, halogen, heteroaryl, heterocyclyl, hydroxy, nitro, oxid, oxo, polyhalogen-Ci-6-alkoxy or polyhalogen-Ci-6- alkyl.
The term polyhalogen-Ci-6-alkyl denotes Ci-s-alkyl radicals which may be substituted by 2-8 halogen, for example trifluoromethyl etc.
The term halo-Ci-s-alkyl for R2 may denote mono- or polyhalogenalkyl, such as chloro- methyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, monofluoroethyl and pentafluoroethyl.
Ci-s-alkyl in the residues aryl-Ci-s-alkyl and heterocyclyl-Ci-s-alkyl may be linear or branched and preferably, the alkyl group is a Ci-6-alkyl and more preferably a Ci-4- alkyl group, such as methylene, ethylene, 1 ,2- or 1 ,3-propylene and 1 ,2-, 1 ,3- or 1 ,4- butylene.
Halogen or halo denotes, for example, fluorine, chlorine or bromine. Salts are primarily the pharmaceutically acceptable or nontoxic salts of compounds of formula (I). The term "pharmaceutically acceptable salts" encompasses salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Salts of compounds having salt-forming groups are in particular acid addition salts, salts with bases, or, in the presence of a plurality of salt-forming groups, in some cases also mixed salts or internal salts.
Such salts are formed, for example, from compounds of formula (I) with an acidic group, for example a carboxyl or sulfo group, and are, for example, the salts thereof with suitable bases such as non-toxic metal salts derived from metals of group Ia, Ib, Ha and Hb of the Periodic Table of the Elements, for example alkali metal, in particular lithium, sodium, or potassium, salts, alkaline earth metal salts, for example magnesium or calcium salts, and also zinc salts and ammonium salts, including those salts which are formed with organic amines, such as optionally hydroxy-substituted mono-, di- or trialkylamines, in particular mono-, di- or tri(lower alkyl)amines, or with quaternary ammonium bases, e.g. methyl-, ethyl-, diethyl- or triethylamine, mono-, bis- or tris(2- hydroxy(lower alkyl))amines, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, N,N-di(lower alkyl)-N- (hydroxy(lower alkyl))amine, such as N,N-di-N-dimethyl-N-(2-hydroxyethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides such as tetrabutyl- ammonium hydroxide. The compounds of the formula I having a basic group, for example an amino group, may form acid addition salts, for example with suitable inorganic acids, e.g. hydrohalic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid with replacement of one or both protons, phosphoric acid with replacement of one or more protons, e.g. orthophosphohc acid or metaphosphohc acid, or pyrophosphoric acid with replacement of one or more protons, or with organic carboxylic, sulfonic or phosphonic acids or N-substituted sulfamic acids, e.g. acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid, isonicotinic acid, and also amino acids, for example the alpha-amino acids mentioned above, and also methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate, glucose 6-phosphate, N-cyclohexylsulfamic acid (with formation of the cyclamates) or with other acidic organic compounds such as ascorbic acid. Compounds of formula (I) having acidic and basic groups may also form internal salts.
Salts obtained may be converted to other salts in a manner known per se, acid addition salts, for example, by treating with a suitable metal salt such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt which forms is insoluble and thus separates out of the reaction equilibrium, and base salts by release of the free acid and salt reformation.
The compounds of formula (I), including their salts, may also be obtained in the form of hydrates or include the solvent used for the crystallization.
For the isolation and purification, pharmaceutically unsuitable salts may also find use.
The compounds of formula (I) also include those compounds in which one or more atoms are replaced by their stable, non-radioactive isotopes; for example a hydrogen atom by deuterium.
The compounds of formula (I) may be prepared according to known or analogous preparation processses such as disclosed in the literature (e.g. WO2002/092622) (Scheme 1 ). Details on the specific preparation variants can be taken from the examples. A further object of the invention is a process for the preparation of compounds of formula (I) according to Scheme 1 , and novel intermediates according to general formulae as given in Scheme 1.
Figure imgf000011_0001
The compounds of formula (I) have at least one asymmetric carbon atom and may therefore be in the form of optically pure enantiomers, mixtures with predominantly one enantiomer or racemates, or -when at least one additional asymmetric carbon atom is present- be in the form of diastereomers, diastereomeric mixtures, diastereomehc racemates, mixtures of diastereomeric racemates or as meso compounds. The invention encompasses all of these forms. Diastereomeric mixtures, diastereomeric racemates or mixtures of diastereomeric racemates may be separated by customary procedures, for example by column chromatography, thin- layer chromatography, HPLC and the like.
The compounds of formula (I) may also be prepared in optically pure form. The separation into antipodes can be effected by procedures known per se, either preferably at an earlier synthetic stage by salt formation with an optically active acid, for example (+)- or (-)-mandelic acid and separation of the diastereomeric salts by fractional crystallization, or preferably at a relatively late stage by dehvatizing with a chiral auxiliary building block, for example (+)- or (-)-camphanoyl chloride, and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bonds to give the chiral auxiliary. The pure diastereomeric salts and derivatives may be analysed to determine the absolute configuration of the piperidine present with common spectroscopic procedures, and X-ray spectroscopy on single crystals constitutes a particularly suitable procedure.
It is possible for the configuration at individual chiral centres in a compound of formula (I) to be inverted selectively. For example, the configuration of asymmetric carbon atoms which bear nucleophilic substituents, such as amino or hydroxyl, may be inverted by second-order nucleophilic substitution, if appropriate after conversion of the bonded nucleophilic substituent to a suitable nucleofugic leaving group and reaction with a reagent which introduces the original substituents, or the configuration at carbon atoms having hydroxyl groups can be inverted by oxidation and reduction, analogously to the process in the European patent application EP-A-O 236 734. Also advantageous is the reactive functional modification of the hydroxyl group and subsequent replacement thereof by hydroxyl with inversion of configuration.
The compounds of formula (I) also include compounds where one or more atoms are replaced by their stable, non-radioactive isotopes (for example hydrogen by deuterium).
Prodrug derivatives of the compounds described in the present context are derivatives thereof which, on in vivo application, release the original compound by a chemical or physiological process. A prodrug may be converted to the original compound, for example, when a physiological pH is attained or by enzymatic conversion. Prodrug derivatives may, for example, be esters of freely available carboxylic acids, S- and O- acyl derivatives of thiols, alcohols or phenols, and the acyl group is as defined in the present context. Preference is given to pharmaceutically useable ester derivatives which are converted by solvolysis in physiological medium to the original carboxylic acid, for example lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or disubstituted lower alkyl esters such as lower co-(amino, mono- or dialkylamino, carboxyl, lower alkoxycarbonyl)-alkyl esters or such as lower α-(alkanoyloxy, alkoxycarbonyl or dialkylaminocarbonyl)-alkyl esters; as such, pivaloyloxymethyl esters and similar esters are utilized in a conventional manner. In a preferred embodiment, prodrugs are selected from compounds of formula I, wherein the hydrogen atom of thiol group is substituted by a protective group Ra, which is split off in a physiological environment, such as Ci-Cs-acyl (the term acyl may include residues from carboxylic and sulfonic acids), N,N-di-Ci-C4-alkylamino- carbonyl (dimethylaminocarbonyl) and Ci-Cβ-alkoxycarbonyl (methoxy-, ethoxy- or t-butoxycarbonyl).
Owing to the close relationship between a free compound, a prodrug derivative and a salt compound, a certain compound in this invention also encompasses its prodrug derivative and salt form, where these are possible and appropriate.
The compounds of the formula (I) also include compounds that have been nitrosated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The nitrosated compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for nitrosating compounds are described in WO 2004/098538 A2.
The compounds of the formula (I) also include compounds that have been converted at one or more sites such that a nitrate-ester-containing linker is attached to an existing oxygen and/or nitrogen. Such "nitroderivatives" of the compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for converting compounds into their nitroderivatives are described in WO 2007/045551 A2.
Neutral endopepetidase 3.4.24.11 (NEP), also called neprilysin, enkephalinase, common acute lymphoblastic leukemia antigen or CD10 is a zinc-containing metallo- protease that cleaves specific biologically active peptides. NEP is widely distributed in the body and has been purified from kidney, brain and intestinal tissues. Several peptides have been identified as substrates for NEP in vitro; however, the distribution of this peptidase and that of its potential substrates is likely to impart functional selectivity to NEP in vivo. Pharmacological inhibition of NEP affects the metabolism of the peptides and thus enhances their biologic function. In the central nervous system, NEP participates in the hydrolysis of Met- and Leu- enkephalin. These peptides have the ability to mediate analgesia. Hence, inhibition of NEP has been demonstrated to yield an anti-nociceptive activity (Chipkin et al., J. Pharmacol. Exp. Ther. 1988; 245:829-838).
In the heart, kidney and vasculature, NEP participates in the degradation of natriuretic peptides and bradykinin. The natriuretic peptides ANP, atrial natriuretic peptide, BNP, brain natriuretic peptide, CNP, C-type natriuretic peptide and urodilatin mediate diuretic, natriuretic, anti-inflammatory, antifibrotic and anti-mitogenic actions. Bradykinin regulates the tonus of vascular smooth muscle tissues. Hence, inhibition of NEP has been demonstrated to lower blood pressure, to improve peripheral arterial disease, to increase diuresis, to be cardioprotective and anti-atherosclerotic as well as protective against ischemic infarcts and endothelial dysfunction (Mukassam-Daher, Expert Opinion Therapeutic Targets 2006; 10:239-252).
In sensory nerves, NEP participates in the degradation of CGRP, calcitonin gene- related peptide, a potent vasodilator that plays an important role in the initiation, progression and maintenance of hypertension via interactions with pro-hypertensive systems, including renin-angiotensin-aldosterone system, sympathetic nervous system and endothelin system; and via anti-hypertrophy and anti-proliferation of vascular smooth muscle cells. The decrease in CGRP synthesis and release contributes to the elevated blood pressure. Hence, inhibition of NEP may potentiate the effects of CGRP and its compensatory depressor role in the development of hypertension (Deng and Li, Peptides 2005; 26:1676-1685).
In addition, NEP participates in the catabolism of vasoactive intestinal peptide. Vasoactive intestinal peptide increases genital blood flow resulting in increased vaginal, labial and clitoral blood flow. Hence, inhibition of NEP potentiates the activity of vasoactive intestinal peptide and is useful for the treatment of female sexual arousal disorder (FSAD) (Pryde et al., Journal of Medicinal Chemistry 2006; 49:4409-4424). NEP participates also in the degradation of incretin glucagon-like peptide-1. Glucagon-like peptide 1 has insulinotropic activity in the pancreas and may also regulate food consumption. Hence, inhibition of NEP enhances glucose-dependent insulin release, reduces food consumption and is useful for the treatment of diabetes, insulin resistance and obesity.
These potential therapeutic applications for NEP inhibitors have led to intensive drug discovery efforts. Several selective NEP inhibitors of various chemical classes have been discovered and some have been tested clinically.
The ability of the herein described compounds of formula (I) to inhibit NEP activity can be shown for example by an in vitro assay that determines the hydrolysis of a fluorogenic substrate by NEP derived from rat kidney cortex membranes using a modified procedure of Orlowski and WiIk (Biochemistry, 1981 ; 20:4942-50). The incubation mixture of 100 μl contains:
Figure imgf000015_0001
The test compound is dissolved in DMSO at a concentration of 1 mM prior to serial dilution with assay buffer containing. The final compound concentrations in the incubation mixture range between 10 μM and 1 nM. The incubation mixture is incubated for 45 min at 300C. The hydrolysis product, 7-amido-4-methylcoumarin, is quantified by fluorescence (Aecc :355 nm; λem :460 nm) using Victor V2 detector (Perkin Elmer). Examples of in vitro NEP inhibition:
Figure imgf000016_0001
* A higher inhibiting activity corresponds to a lower IC5O value.
The NEP inhibitory activity of herein disclosed compounds of formula (I) can also be shown for example by an ex vivo assay that determines the hydrolysis of a fluorogenic substrate by NEP derived from rat kidney homogenate using a modified procedure of Orlowski and WiIk (Biochemistry, 1981 ; 20:4942-50). Male spontaneous hypertensive rats (SHR) of 11 -14 weeks of age are subjected in groups of 3 to i.v. administration of test compound or vehicle. The test compound is applied in a volume of 1.0 ml at a concentration ranging between 2 to 20 μmol/kg body weight. Five to fifteen minutes after the tail vein injection the animals are sachfied and their kidneys are removed for homogenization in a TRIS-buffered Thton-X100 solution. The NEP activity in the homogenate is measured in a mixture of 100 μl containing
Figure imgf000016_0002
that is incubated for 45 min at 300C. Subsequently, the hydrolysis product, 7-amido- 4-methylcoumarin, is quantified by fluorescence (Aecc :355 nm; λem :460 nm) using Victor V2 detector (Perkin Elmer).
The percentage of inhibited NEP activity by compounds of formula (I) is calculated as follows:
%lnhib = Spl ~ B_ x lOO
Cont - B where: • SpI is fluorescence measured in the well
• B is fluorescence measured in blank wells
• Cont is fluorescence measured in the control wells
IC50 values are calculated by fitting a 4-parameter logistic curve to the recorded %lnhib at specific test article concentrations according to following nonlinear equation:
Figure imgf000017_0001
The equation is fit to sigmoidal concentration-repsonse curves where
• Y is the observed response as dependent variable
• X is the test compound concentration as independent variable
• c is the inflection point (EC50 or IC50) for the curve respectively the negative log of the compound concentration giving a half-maximal effect ie. if Y is halfway between the lower and upper asymptotes X equals c.
• a is the limiting response as X approaches zero.
• d is the background effect or effect at infinite X concentration.
• b is the slope-factor in the region of the IC50 or Hill coefficient. The sign of b is positive when the response increases with increasing dose and is negative when the response decreases with increasing dose (inhibition).
The bioavailability of the compounds described herein can be tested in vivo using the following protocol:
The investigations take place in pre-catheterized (carotid artery) male rats (300 g ± 20%) that can move freely throughout the study. The compound is administered intravenously and orally (gavage) in separate sets of animals. The applied doses for oral administration may range from 0.5 to 50 mg/kg body weight; the doses for intravenous administration may range from 0.5 to 20 mg/kg body weight. Blood samples are collected through the catheter before compound administration and over the subsequent 24-hour period using an automated sampling device (AccuSampler, DiLab Europe, Lund, Sweden). Plasma levels of the compound are determined using a validated LC-MS analytical method. The pharmacokinetic analysis is performed on the plasma concentration-time curves after averaging all plasma concentrations across time points for each route of administration. Typical pharmacokinetics parameters to be calculated include: maximum concentration (Cmaχ), time to maximum concentration (tmax), area under the curve from 0 hours to the time point of the last quantifiable concentration (AUCo-t), area under the curve from time 0 to infinity (AUCo-inf), elimination rate constant (K), terminal half-life (t/2), absolute oral bioavailability or fraction absorbed (F), clearance (CL), and Volume of distribution during the terminal phase (Vd).
Five major metabolizing CYP450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are responsible for more than 95% of the drug metabolizing activity in humans.
The goals in evaluating in vitro drug metabolism are:
(1 ) to identify all of the major metabolic pathways that affect the test compound and its metabolites, including the identification of the specific enzymes responsible for metabolism and elucidation of the intermediates formed; and
(2) to explore and anticipate the effects of the test drug on the metabolism of other drugs and the effects of other drugs on its metabolism.
The most complete picture for hepatic metabolism can be obtained with intact liver systems (e.g. hepatocytes, microsomes), in which the cofactors are self-sufficient and the natural orientation and location for linked enzymes is preserved. However, when many compounds have to be tested simultaneously, a simpler screening tool is advantageous. The cDNAs for the common CYP450s have been cloned and the recombinant human enzymatic proteins have been expressed in a variety of cells. Use of these recombinant enzymes provides an excellent way to quickly assess specific enzyme inhibition activities and/or confirm results identified in microsomes. The metabolic properties (inhibition constants on human cytochrome P450 isoforms) of the compounds described herein can be tested in vivo using the following protocol:
To assess the inhibitory activity towards CYP450 enzymes, the enzymatic reaction is monitored in the presence of different concentrations of test compound (serial dilution) and compared to maximal enzyme activity (control : no test compound). In principle, inhibition can occur by three different mechanisms: (1 ) competitive inhibition, (2) noncompetitive inhibition, and (3) mechanism-based inhibition. In any case, the inhibition strength is dependent on the concentration of test compound. Testing the CYP450 enzyme activity over a test compound concentration range identifies the test compound concentration at which half maximal enzyme inhibition is observed (IC5O concentration).
For screening purposes, the inhibitory potential of a test compound can be tested with ready to use kits (CYP450 High Throughput Inhibitor Screening kit, e.g. CYP1A2/CEC, #459500, BD Biosciences, Franklin Lakes, NJ USA), which are available for all of the five above-mentioned major CYP isoforms. In such kits, recombinant human CYP450 isoforms expressed in insect cells are incubated with isoform specific, fluorogenic substrates in the presence of different test compound concentrations. Enzymatic activity converts the fluorogenic substrate into a fluorochrome product, the concentration of which is measured with a fluoro- spectrophotometer. Fluorescence is directly proportional to enzyme activity. In a typical standard assay using the CYP450 High Throughput Inhibitor Screening kit, a compound is tested at 2 nM to 33 μM concentration range in a phosphate buffer (50 mM, pH 7.4) containing a glucose 6-phosphate dehydrogenase/NADP/NADPH regeneration system and a suitable fluorogenic substrate: e.g. 3-cyano-7- ethoxycoumahn (CYP1A2). As control inhibitors, the following substances can be used: furafylline (CYP1A2), sulfaphenazole (CYP2C9), tranylcypromine (CYP2C19), quinidine (CYP2D6) and ketoconazole (CYP3A4).
The reaction is started by the addition of 2.5 nM (final concentration) CYP450 isozyme, incubated at 37°C for 15 to 45 minutes, and then terminated by the addition of 187.5 mM ths-hydroxy-aminomethane base/acetonitrile (20/80, v/v). The amount of generated fluorochrome is then determined by fluorescence spectroscopy with suitable exitation and emission wavelength settings: e.g. 410 nm excitation and 460 nm emission wavelength (CYP1A2). Alternatively and/or complimentary, assays using human liver microsomes (e.g. BD Biosciences, #452161 ) in combination with a CYP isoform-specific standard substrate (e.g. midazolam for CYP3A4/5) as described by R. L. Walsky and R. S. Obach in Validated assay for human cytochrome p450 activities; Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Groton, Connecticut; Drug Metabolism and Disposition: (2004)32, 647-660, can be used. To determine whether a test compound inhibits CYP3A enzyme activity, for example, hydroxylation of midazolam by human liver microsomes at varying test compound concentrations is monitored. Hydroxy-midazolam production is directly proportional to enzyme activity and can be determined by liquid chromatography-tandem mass spectrometry. Additionally, the microsomal assay can be run without and with a 15 min pre-incubation of microsomes with test compound prior to the addition of standard substrate. Test compounds or their metabolite(s) that have the potential to irreversibly modify the P450 enzyme will have a stronger inhibitory effect after preincubation.
In a typical standard assay using the human liver microsome assay, compounds are tested at 10 nM to 50 μM concentration range in a phosphate buffer (100 mM potassium phosphate, 3.3 mM MgCI2, pH 7.4) containing a NADPH regeneration system (glucose 6-phosphate dehydrogenase, NADP, NADPH) and 10 μM substrate (e.g. midazolam for CYP3A4/5) and 0.1 mg/mL microsomal protein. As control inhibitors, the same substances as described above can be used (e.g. ketoconazole (CYP3A4/5)). If pre-incubation of the compound is desired, all assay components except substrate are mixed and incubated for 15 minutes at 37°C. After that period, substrate is added to the assay mix and then incubation at 37°C is continued for 15 minutes. Without pre-incubation, all assay components are mixed simultaneously and then incubated at 37°C for 15 minutes. Termination of the enzymatic reaction is achieved by the addition of a HCOOH/acetonitrile/H2O (4/30/66, v/v/v) solution. Samples are then incubated in the refrigerator (4 ± 2°C) for 1 h ± 10 min to increase protein precipitation. Directly before analysis by LC/MSMS, the samples are centrifuged at 3,500 g for 60 min at 4°C to separate precipitated protein. The supernatant is mixed with acetonitrile/water (50/50, v/v), and then directly analyzed for compound content with LC/MSMS.
Evaluation of the data from either experimental setup is then done as follows: the fraction of remaining activity at a specific compound concentration versus the activity in the control as a function of compound concentration is used to compute IC5O values. This is done by fitting a 4-parameter logistic function to the experimental data set.
Metabolic stability of herein disclosed compounds of formula (I) can be a factor influencing their bioavailability. Metabolic stability can be tested for example by determination of the hepatic intrinsic microsomal clearance using the procedure of Obach (Drug Metabolism and Disposition, 1999; 27(11 ):1350-1359).
The definitions of the substituents of the preferred compounds mentioned below are not to be regarded as closed, but rather parts of these definitions may be exchanged with one another or with the definitions given above or omitted in a sensible manner, for example to replace general by more specific definitions. The definitions are valid in accordance with general chemical principles, such as, for example, the common valences for atoms.
Preferred inventive compounds are those of the general formula (IA)
Figure imgf000021_0001
where A, R1, R2 and R3 are each as defined above for the compounds of the formula (I). A further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
A is monocyclic Cs-s-cycloalkyl which is either unsubstituted or substituted by 1 -3 Ci-8-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-s-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-8-alkyl, aryl, aryl-Ci-8- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-S- alkoxy, carboxy, halogen, hydroxy or oxo; and
R3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
A further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
A is monocyclic, saturated heterocyclyl which is either unsubstituted or substituted by 1 -3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-8-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-8-alkoxy-Ci-8-alkoxy-Ci-8-alkyl, Ci-8-alkoxy-Ci-8-alkyl, Ci-8-alkyl, aryl, aryl-Ci-8- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-8-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s- alkoxy, carboxy, halogen, hydroxy or oxo; and R3 is H, Ci-s-alkyl-annino, aryl-Ci-s-alkyl-annino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-8-alkyl in Ci-s-alkyl-annino, aryl-Ci-8-alkyl-amino or in heterocyclyl-Ci-s-alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
A further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
A is monocyclic C5-7-cycloalkyl or monocyclic, saturated heterocyclyl, having one heteroatom selected from the group comprising O, S or N; each of which are either unsubstituted or substituted by 1-3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo; very particularly preferably cyclohexyl, cyclopentyl or tetrahydropyran-4-yl.
Another preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
R1 is H, Ci-s-alkyl.or aryl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl or aryl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo; R1 is particularly preferred H, Ci-8-alkyl or aryl-C2-4-alkyl, wherein Ci-8-alkyl in Ci-s- alkyl or aryl-C2-4-alkyl is unsubstituted or substituted with 1-3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
An additional preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
R2 is Ci-s-alkoxy-Ci-s-alkyl, Ci-8-alkyl, aryl or aryl-Ci-2-alkyl, wherein Ci-2-alkyl in aryl- Ci-2-alkyl is unsubstituted or substituted with 1-3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo; very particularly preferably benzyl, isopropyl, 2-methoxyethyl, methyl or propyl. A further, preferred group of compounds of formula (I), or more preferably of formula (IA) and the salts thereof, preferably the pharmaceutically acceptable salts thereof, are compounds in which
R3 is H or Ci-s-alkyl-amino; very particularly preferably H, methylamino, ethylamino, propylamine or butylamino.
The compounds of formula (I), or preferably of formula (IA), and their pharmaceutically useable salts may find use as medicaments, for example in the form of pharmaceutical preparations. Accordingly, this invention is also directed to a pharmaceutical composition comprising a compound of formula (I), or preferably of formula (IA), and a pharmaceutically acceptable carrier or diluents.
The pharmaceutical preparations may be administered enterally, such as orally, for example in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatine capsules, solutions, emulsions or suspensions, nasally, for example in the form of nasal sprays, rectally, for example in the form of suppositories, or trans- dermally, for example in the form of ointments or patches. The administration may also be parenteral, such as intramuscular or intravenous, for example in the form of injection solutions.
To prepare tablets, coated tablets, sugar-coated tablets and hard gelatine capsules, the compounds of formula (I), or preferably of formula (IA), and pharmaceutically useable salts thereof, may be processed with pharmaceutically inert, inorganic or organic excipients. Such excipients used, for example for tablets, coated tablets and hard gelatine capsules, may be lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof etc.
Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, etc.
Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.
Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, bile acids, lecithin, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.
The pharmaceutical preparations may additionally also comprise preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavourings, salts for altering the osmotic pressure, buffers, coatings or antioxidants. They may also comprise other therapeutically valuable substances.
Thus, the herein disclosed compounds of formula (I), or preferably of formula (IA), and pharmaceutically useable salts thereof, by inhibiting the neutral endopeptidase EC.3.4.24.11 , can have beneficial effects in the treatment of a number of disorders, including hypertension (including malignant, essential, reno-vascular, diabetic, isolated systolic, or other secondary types of hypertension), primary and secondary pulmonary hypertension, primary and secondary aldosteronism, oedema, salt retention, ascites, peripheral vascular resistance, arterial hypertrophy, vascular disorders including peripheral vascular disease, peripheral occlusive disease, intermittent claudication, migraine and Raynaud's disease, luminal hyperplasia, restenosis after coronary or peripheral angioplasty, heart failure including acute or chronic diastolic and congestive heart failure, left ventricular dysfunction, endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, myocarditits, pericarditis, endocarditis, supraventricular and ventricular arrhythmias, atrial fibrillation, cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, atherosclerosis including coronary arterial disease, myocardial infarction and its sequelae, cerebrovascular disease including embolic and thrombotic stroke, angina pectoris including unstable and stable forms, acute and chronic renal disease including diabetic and non-diabetic forms, renal fibrosis, polycystic kidney disease, chronic kidney disease, renal failure conditions such as nephrotic syndrome, diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease and end-stage renal disease (ESRD), kidney transplants, urinary tract disorders, lupus nephritis, insulin resistance, type 2 diabetes, diabetic complications, obesity, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, metabolic syndrome, obesity, cyclical oedema, Menieres disease and hypercalciuria.
In addition, the compounds of the invention may have activity in other therapeutic areas including for example the treatment of glaucoma, cataracts, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), erectile dysfunction, female sexual dysfunction, male sexual dysfunction, sexual desire and arousal disorders, genital sensation and sensitivity disorders, orgasmic disorders, vaginal and clitoric blood flow disorders, sexual pain disorders, endometriosis, pelvic inflammatory disease,
Also, the compounds of the invention should treat asthma, inflammation, leukemia, pain, epilepsy, pain, depression, psychotic conditions, affective disorders, cognitive disorders such as Alzheimer's disease and dementia and geriatric confusion, premenstrual syndrome, cerebral ischemia, stroke, subarachnoid hemorraghe, traumatic brain injury, cerebral vasospasm, cerebral ischemias, stroke, subarachnoid haemorrhage, migraine, traumatic brain injury, cerebral vasculitis, inflammatory neuropathies and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), liver disease, cirrhosis, hepato-renal syndrome, Crohn's disease, wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion and cystic fibrosis. In a preferred embodiment, the compounds of the invention are useful in the treatment of hypertension and hypertension-derived pathologies of the cardiovascular and renal system.
The compounds described herein and their pharmaceutically usable salts can be used in combination with
(i) one or more blood pressure-lowering active ingredients, as such for example: renin inhibitors such as aliskiren, or compounds disclosed in WO 2005/090305, WO 2006/005741 , WO 2006/095020, WO 2006/103275, WO 2006/103277 and WO 2007/031558, etc.; angiotensin Il receptor blockers such as candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, etc.;
ACE inhibitors such as quinapril, ramipril, trandolapril, lisinopril, captopril, enalapril etc.; calcium antagonists such as nifedipine, nicardipine, verapamil, isradipine, nimodipine, amlodipine, felodipine, nisoldipine, diltiazem, fendiline, flunahzine, perhexiline, gallopamil etc.; diuretics such as hydrochlorthiazide, chlorothiazide, acetazolamide, amilohde, bumetanide, benzthiazide, etacrynic acid, furosemide, indacrinone, metolazone, triamterene, chlortalidone, etc.; aldosterone receptor blockers such as spironolactone, eplerenone; aldosterone synthesis inhibitors such as fadrozole, FAD286 etc.; endothelin receptor blockers such as bosentan, avosentan, darusentan, ambrisentan, atrasentan, enrasentan, tezosentan, sitaxentan, clazosentan etc.; phosphodiesterase inhibitors such as amrinone, iodenafil, sildenafil, vardenavil, tadalafil; direct vasodilators such as dihydralazine, minoxidil, pinacidil, diazoxide, nitroprusside, flosequinan etc.; guanylcyclase activators such as BAY 41 -2272, BAY 63-2521 , BAY 58-2667,
HMR 1776; α- and β-receptor blockers such as phentolamine, phenoxybenzamine, prazosin, doxazosin, terazosin, carvedilol, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol etc.; sympatholytics such as methyldopa, clonidine, guanabenz, reserpine (ii) one or more agents having inotropic activity, as such for example: cardiac glycosides such as digoxin, β-receptor stimulators such as dobutamine, thyroid hormone such as thyroxine; (iii) one or more agents having antidiabetic activity, as such for example: insulins such as insulin aspart, insulin human, insulin lispro, insulin glargine and further fast-, medium- and long-acting insulin derivatives and combinations insulin sensitizers such as rosiglitazone, pioglitazone; sulphonylureas such as glimepiride, chlorpropamide, glipizide, glyburide etc.; biguanides such as metformin; glucosidase inhibitors such as acarbose, miglitol; meglitinides such as repaglinide, nateglinide; dipeptidyl protease IV inhibitors such as sitagliptin, vildagliptin, denagliptin etc.; (iv) one or more obesity-reducing ingredients, as such for example: lipase inhibitors such as orlistat; appetite suppressants such as sibutramine, phentermine; (v) one or more lipid-lowehng active ingredients, such as, for example,
HMG-CoA reductase inhibitors such as lovastatin, fluvastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin etc.; fibrate derivatives such as fenofibrate, gemfibrozil etc.; bile acid-binding active ingredients such as colestipol, colestyramine, colesevelam; cholesterol absorption inhibitors such as ezetimibe; nicotinic acid such as niacin; (vi) one or more anti-inflammatory agents, such as, for example, non-selective cyclooxygnease-1/2 inhibitors such as acetyl salicylic acid, ibuproven, diclofenac, paracetamol, mefenamic acid, indometacin, naproxen etc.; selective cyclooxygenase-2 inhibitors such as celcoxib, rofecoxib, lumiracoxib, etohcoxib etc.; glucocorticoids such as cortisone, hydrocortisone, prednisolone, betamethasone, triamcinolone, dexamethasone etc.; and other agents which are suitable for the treatment of high blood pressure, heart failure or vascular disorders associated with diabetes and renal disorders, such as acute or chronic renal failure, in humans and animals. Such combinations can be used separately or in products which comprise a plurality of components.
The dose may vary within wide limits and has of course to be adapted to the individual circumstances in each individual case. In general, for oral administration, a daily dose of about 3 mg to about 3 g, preferably about 10 mg to about 1 g, for example about 300 mg, per adult (70 kg), divided into preferably 1-3 individual doses which may, for example, be of equal size, may be appropriate, although the upper limit specified may also be exceeded if this should be found to be appropriate; typically, children receive a lower dose according to their age and body weight.
Another object of the invention is a method of delivering a compound of formula (I), or preferably of formula (IA), to a host, comprising administering to a host an effective amount of a compound of formula (I), or preferably of formula (IA).
A further object of the invention is the use of the a compound of formula (I), or preferably of formula (IA), for the manufacture of a medicament useful in the of inhibition of the neutral endopeptidase EC.3.4.24.11.
EXAMPLES
The examples which follow illustrate the present invention. All temperatures are reported in degrees Celsius, pressures in mbar. Unless stated otherwise, the reactions take place at room temperature. The abbreviation "Rf = xx (A)" means, for example, that the Rf value xx is obtained in the solvent system A. The ratio of the solvents relative to one another is always reported in parts by volume. Chemical names of end products and intermediates were obtained with the aid of the program AutoNom 2000 (Automatic Nomenclature).
HPLC gradient on X-Terra RP18 (5 μm); column: 4.6 x 50 mm; T = 500C; Detection:
UV @ 220nm:
95% H2O715% CH3CN* to 5% H2O795% CH3CN* in 0.8 minutes + 8.7 minutes
(1.2 ml/min);
* containing 0.1 % formic acid
The following abbreviations are used:
AI(CH3)3 trimethylaluminum
CDMT 2-Chloro-4,6-dimethoxy-1 ,3,5-triazine [3140-73-6]
CH2CI2 dichloromethane
CHCI3 chloroform
CH3CN acetonitrile Cy cyclohexane
DCC dicyclohexylcarbodiimide
DIBAL diisobutylaluminium hydride
DMF N,N-dimethylformamide
DME 1 ,3-dimethoxyethane
EDC-HCI N-ethyl-N'-(3-dimethylaminopropyl)carbodiinnide hydrochloride [25952-53-8]
Et3N triethylamine
Et2O diethylether
EtOAc ethyl acetate
EtOH ethanol h hour(s)
HBr hydrobromic acid
HCI hydrochloric acid
H2O water
HOAc acetic acid
HOBt 1 -hydroxybenzotriazole hydrate [123333-53-9]
MeOH methanol min minute(s) m.p. melting point (temperature)
N2 nitrogen
Na2CO3 sodium carbonate
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaOH sodium hydroxide
Na2SO4 sodium sulphate
NH4CI ammonium chloride
NH4Br ammonium bromide
NMP 1 -methyl-2-pyrrolininone
Rf ratio of distance which a substance travels to distance of the eluent front from the start point in thin layer chromatography
Rt retention time of a substance in HPLC (in minutes)
RT room temperature (23°C) TFA trifluoroacetic acid
THF tetrahydrofuran
WSC'HCI 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [25952-53-8]
Example 1
(S)-2-Mercapto-N-[1 -(6-oxo-6, 9-dihvdro-1 H-purin-8-yl)-cvclopentyl1-3-phenyl- propionamide
1.0 mmol of thioacetic acid S-{(S)-1-[1 -(6-oxo-6,9-dihydro-1 H-purin-8-yl)-cyclopentyl- carbamoyl]-2-phenyl-ethyl} ester is dissolved in DMF. 1.5 ml of 1 M NaOH is added at 00C and the solution is stirred at RT under N2 atmosphere for 4 h. 1 M HCI is added until pH 3 is reached and the solvent is evaporated. Water is added and the mixture is extracted with CH2CI2 under N2 atmosphere. The organic layer is collected, dried over Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified chromatography to afford the title compoundas a white solid. Rt = 4.07.
The starting matehal(s) is(are) prepared as follows : a) Thioacetic acid S-US)-I -H -(6-oxo-6,9-dihvdro-1 H-purin-8-yl)-cvclopentyl- carbamoyli-2-phenyl-ethyl) ester
A solution of 1.0 mmol of (R)-2-bromo-N-[1 -(6-oxo-6,9-dihydro-1 H-purin-8-yl)- cyclopentyl]-3-phenyl-propionamide in DMF at 00C is treated in one portion with 1.5 mmol of potassium thioacetate. The mixture is stirred for 1 h at 00C, than poured on icecold H2O, and extracted with EtOAc (3X). The combined organic phases are dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified chromatography to afford the title compound as a white solid. Rf = 0.35 (CH2CI2-MeOH 100:5); Rt = 4.37.
b) (R^-Bromo-N-ri -rG-oxo-G.g-dihvdro-I H-purin-δ-vD-cvclopentyll-S-phenyl- propionamide
1.1 mmol of CDMT is added to a stirred mixture of 1.0 mmol of 8-(1 -amino-cyclo- pentyl)-1 ,9-dihydro-purin-6-one and 1.0 mmol of (R)-2-bromo-3-phenyl-propionic acid [42990-55-6] in CH3CN at 00C under N2 atmosphere. A solution of 1.5 mmol of N-methylmorpholine in CH3CN is added dropwise. After 3 h at RT, the reaction is triturated with water, the solid is filtered and dried in vacuo. The title compound is used in the next step without further purification. Rf = 0.4 (CH2CI2-MeOH 90:10); Rt = 4.37.
c) 8-(1 -Amino-cvclopentyl)-1 ,9-dihvdro-purin-6-one
To a mixture of 1.0 mmol of 1 -(2,2,2-trifluoro-acetylamino)-cyclopentanecarboxylic acid (4-amino-6-oxo-1 ,6-dihydro-pyhmidin-5-yl)-amide in 5 ml of dioxane is added 5 ml of 10% NaOH. The mixture is stirred at 1000C for 24 h, than diluted with H2O and neutralized with cone. HCI. The solvent is evaporated under reduced pressure and the residue is triturated with MeOH, filtered and dried in vacuo. The title compound is obtained as white solid. Rf = 0.3 (CH2CI2-MeOH-HOAc 80:20:1 ); Rt = 0.56.
d) 1 -(2,2,2-Thfluoro-acetylamino)-cvclopentanecarboxylic acid (4-amino-6-oxo-1 ,6- dihvdro-pyrimidin-5-yl)-amide
To a mixture of 0.5 mmol of 5,6-diamino-3H-pyhmidin-4-one hemisulfonat [102783- 18-6] in 15 ml of DMF under N2 atmosphere at RT is added 1.0 mmol DBU. After 1 hour 1.0 mmol of 1 -(2,2,2-thfluoro-acetylamino)-cyclopentanecarboxylic acid [151159-24-9] 1.05 mol of HOBt (1.67g, 2.1 eq) and 1.05 mol of WSOHCI are added. The mixture is stirred overnight and then the solvent is evaporated under reduced pressure. The residue is treated with isopropyl alcohol and then solvent is evaporated under reduced pressure. The residue is purified chromatography to afford the title compound as as pale yellow solid. Rf = 0.5 (CH2CI2-MeOH-HOAc 90:10:1 ); Rt = 2.40.
The following compounds are prepared in an analogous manner to the process described in Example 1 :
4 (S^-Mercapto-S-methyl-N-ri-fe-oxo-e.g-dihvdro-I H-purin-δ-vD-cvclopentyli- butyramide using (R)-2-bromo-3-methyl-butyric acid [76792-22-8] instead of(R)-2-bromo-3- phenyl-propionic acid in step b. 2 (S)-2-Mercapto-3-methyl-N-π -(6-oxo-1 -propyl-6,9-dihvdro-1 H-purin-8-vD- cvclopentyli-butyrannide
1.0 mmol of thioacetic acid S-{(S)-2-methyl-1 -[1 -(6-oxo-1 -propyl-6,9-dihydro-1 H- purin-8-yl)-cyclopentylcarbamoyl]-propyl} ester is dissolved under N2 atmosphere in 10 ml of degassed ethanol. The mixture is cooled to 00C and treated with 3 ml of 1 N NaOH. The reaction is stirred under N2 for 3 h at RT. The mixture is cooled to 00C and the pH is taken to 5-6 with 10% HCI. The solvent is concentrated by evaporation and the residue partitioned between H2O and Et2O. The organic layer is collected and the solvent evaporated. The obtained solid is triturated with petroleum ether to afford the title compound as a white solid. Rt = 4.36.
The starting material(s) is(are) prepared as follows : a) Thioacetic acid S-((S)-2-methyl-1 -f 1 -(6-oxo-1 -propyl-6,9-dihvdro-1 H-purin-8-vD- cyclopentylcarbamoyli-propyl) ester
According to the procedure described in Example 1 a, (R)-2-bromo-3-methyl-N-[1 -(6- oxo-1 -propyl-θ.θ-dihydro-I H-purin-δ-ylJ-cyclopentyll-butyramide is used to afford the title compound as an off-white solid. Rf = 0.25 (CH2CI2-MeOH 100:3); Rt = 4.57.
b) (R)-2-Bromo-3-methyl-N-π -(6-oxo-1 -propyl-6,9-dihvdro-1 H-purin-8-yl)-cvclo- pentyli-butyramide
According to the procedure described in Example 1 b, 8-(1-amino-cyclopentyl)-1 - propyl-1 ,9-dihydro-purin-6-one and (R)-2-bromo-3-methyl-butyric acid [76792-22-8] are used to afford the crude title compound which is used in the next step without further purification.
c) 8-(1 -Amino-cvclopentyl)-1 -propyl-1 ,9-dihvdro-purin-6-one
According to the procedure described in Example 1 c, 1 -(2,2,2-thfluoro-acetylamino)- cyclopentanecarboxylic acid (4-amino-6-oxo-1-propyl-1 ,6-dihydro-pyrimidin-5-yl)- amide is used to afford the title compound as an off-white solid. Rf = 0.3 (CH2CI2- MeOH-HOAc 80:20:1 ); Rt = 1.01. d) 1 -(2,2,2-Trifluoro-acetylamino)-cvclopentanecarboxylic acid (4-amino-6-oxo-1 - propyl-1 ,6-dihvdro-pyrimidin-5-yl)-amide
To a mixture of 1.0 mmol of 5,6-diamino-3-propyl-3H-pyrimidin-4-one) and 1.0 mmol of 1 -(2,2,2-trifluoro-acetylannino)-cyclopentanecarboxylic acid [151159-24-9] in 25 ml of acetonitrile, 1.0 mmol of coupling reagent CDMT and finally 3.2 ml of NMP are added and the reaction mixture is stirred for 4 h at RT. The reaction mixture is poured into water and the resulting precipitate is filtrated to yield the title compound as a white solid. Rf = 0.5 (CH2CI2-MeOH 100:5); Rt = 3.10.
e) 5,6-Diamino-3-propyl-3H-pyhmidin-4-one
A mixture of 1.0 mmol of 6-amino-5-nitro-3-propyl-5H-pyhmidin-4-one and 2.0 mmol of SnCI2 in 7 ml of EtOH is heated to reflux overnight. 5% aqueous NaHCO3 is added and the aqueous phase is extracted with EtOAc (3X). The combined organic phases are dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography to afford the title compound as a white solid Rf = 0.25 (CH2CI2-MeOH 100:5).
f) 6-Amino-5-nitro-3-propyl-5H-pyhmidin-4-one
A mixture of 1.0 mmol of 6-amino-5-nitro-pyhmidin-4-ol [36746-26-6] in 5 ml of DMF and 1.3 mmol of Cs2COs is heated to 600C for 1 h. 1.2 mmol of 1 -iodopropane are then added at RT and the mixture is stirred at RT overnight. Water is added and the aqueous phase is extracted with EtOAc (3X). The combined organic phases are dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified chromatography to afford the title compound as a white solid. Rf = 0.4 (CH2CI2-MeOH 100:5); Rt = 2.03.
The following compounds are prepared in an analogous manner to the process described in Example 2:
3 (S)-N-π -d -Benzyl-6-oxo-6,9-dihvdro-1 H-purin-8-yl)-cvclopentvn-2-mercapto-
3-methyl-butyramide using benzyl bromide instead of 1-iodopropane in the step f. White solid; Rf = 0.3 (CH2CI2-MeOH 100:2); Rt = 5.15. 5 (S)-2-Mercapto-N-H -(6-oxo-1 -propyl-6,9-dihvdro-1 H-purin-8-yl)-cvclopentyl1- 3-phenyl-propionamide using (R)-2-bromo-3-phenyl-propionic acid [42990-55-6] instead of (R)-2-bromo-3- methyl-butyric acid in step b. White solid; Rt = 4.95.
6 (S)-N-π -d -Benzyl-6-oxo-6,9-dihvdro-1 H-purin-8-yl)-cvclopentvn-2-mercapto- 3-phenyl-propionannide using (R)-2-bromo-3-phenyl-propionic acid [42990-55-6] instead of (R)-2-bromo-3- methyl-butyric acid in step b and benzyl bromide instead of 1 -iodopropane in the step f. White solid; Rt = 5.62.
7 (S)-N-ri-(2-Ethylamino-6-oxo-6,9-dihvdro-1 H-purin-8-yl)-cvclopentyl1-2- mercapto-3-methyl-butyrannide using 5,6-diamino-2-ethylamino-3H-pyrimidin-4-one [28690-88-2] instead of 5,6- diamino-3-propyl-3H-pyrinnidin-4-one in step d.
8 (S)-N-H -[1 -(3-Chloro-benzyl)-6-oxo-6,9-dihvdro-1 H-purin-8-yll-cvclopentyl)-2- mercapto-3-nnethyl-butyrannide using 1 -bromonnethyl-3-chloro-benzene [766-80-3] instead of 1 -iodopropane in the step f.

Claims

1. A compound of the formula (I)
Figure imgf000036_0001
wherein
A is monocyclic Cs-s-cycloalkyl or monocyclic, saturated heterocyclyl, each of which are either unsubstituted or substituted by 1 -3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-s-alkyl, aryl-Ci-8-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-8-alkyl, aryl, aryl-Ci-8- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-8- alkoxy, carboxy, halogen, hydroxy or oxo;
R3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo; where the aryl or heterocyclyl moieties are unsubstituted or substituted; where the thiol group is unprotected or protected with a protecting group Ra, which is hydrolyzed under physiological conditions to liberate the compound of formula (I); a disulfide derivative derived from the compound of formula (I) or a salt of a compound of formula (I), preferably a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , which corresponds to formula (IA)
Figure imgf000037_0001
wherein A, R1, R2 and R3 are each as defined according to claim 1 , where the thiol group is unprotected or protected with a protecting group Ra, which is hydrolyzed under physiological conditions to liberate the compound of formula (IA); a disulfide derivative derived from the compound of formula (IA) or a salt of a compound of formula (IA), preferably a pharmaceutically acceptable salt thereof.
3. A compound according to claims 1 or 2, wherein the group Ra is an acyl or sulfonyl group, which is unsubstituted or substituted with one or more halogen, hydroxy, N1N- di-Ci-s-alkyl-amine, morpholine or Ci-s-alkoxy, or is N,N-di-Ci-C4-alkylaminocarbonyl.
4. A compound according to claims 1 or 2, wherein heterocyclyl A denotes a 3-8 membered heterocyclic radical having one or more heteroatoms selected from the group comprising O, S or N.
5. A compound according to claims 1 or 2, wherein A is monocyclic C5-7-cycloalkyl or monocyclic, saturated heterocyclyl, having one heteroatom selected from the group comprising O, S or N; each of which are either unsubstituted or substituted by 1-3 Ci-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo.
6. A compound according to claim 5, wherein A is cyclohexyl, cyclopentyl or tetrahydropyran-4-yl.
7. A compound according to claims 1 or 2, wherein R1 is H, Ci-s-alkyl or aryl-Ci-s- alkyl, wherein Ci-8-alkyl in Ci-8-alkyl or aryl-Ci-8-alkyl is unsubstituted or substituted with 1 -3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo.
8. A compound according to claims 1 or 2, wherein R1 is H, Ci-s-alkyl or aryl-C2-4- alkyl, wherein alkyl in Ci-s-alkyl or aryl-C2-4-alkyl is unsubstituted or substituted with 1 -3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo.
9. A compound according to claims 1 or 2, wherein R2 is Ci-s-alkoxy-Ci-s-alkyl, Ci-s- alkyl, aryl or aryl-Ci-2-alkyl, wherein alkyl in aryl-Ci-2-alkyl is unsubstituted or substituted with 1-3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo
10. A compound according to claim 9, wherein R2 is benzyl, isopropyl, 2-methoxy- ethyl, methyl or propyl.
11. A compound according to claims 1 or 2, wherein R3 is H or Ci-s-alkyl-amino.
12. A compound according to claim 11 , wherein R3 is H, methylamino, ethylamino, propylamine or butylamino.
13. A compound of formula (I) or (IA), according to claims 1 or 2, or a salt thereof, preferably a pharmaceutically acceptable salt thereof, wherein
A is monocyclic Cs-s-cycloalkyl which is either unsubstituted or substituted by 1 -3 Ci-8-alkoxy, Ci-8-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-8-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-8-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkyl, aryl, aryl-Ci-s alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-S- alkoxy, carboxy, halogen, hydroxy or oxo; and R3 is H, Ci-s-alkyl-annino, aryl-Ci-s-alkyl-annino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-annino, aryl-Ci-8-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
14. A compound of formula (I) or (IA), according to claims 1 or 2, and a salt thereof, preferably a pharmaceutically acceptable salt thereof, wherein
A is monocyclic, saturated heterocyclyl which is either unsubstituted or substituted by 1 -3 Ci-s-alkoxy, Ci-8-alkyl, halogen, hydroxy or oxo;
R1 is H, Ci-s-alkyl, aryl-Ci-s-alkyl, carboxy, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in Ci-s-alkyl, aryl-Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo;
R2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkyl, aryl, aryl-Ci-s- alkyl, halo-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-s-alkyl in aryl- Ci-s-alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci-s- alkoxy, carboxy, halogen, hydroxy or oxo; and
R3 is H, Ci-s-alkyl-amino, aryl-Ci-s-alkyl-amino or heterocyclyl-Ci-s-alkyl-amino, wherein Ci-s-alkyl in Ci-s-alkyl-annino, aryl-Ci-s-alkyl-amino or in heterocyclyl-Ci-s- alkyl-amino is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, carboxy, halogen, hydroxy or oxo.
15. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , or a compound of formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2, and a pharmaceutically acceptable carrier or diluents.
16. A method of delivering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , or a compound of formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2 to a host, comprising administering to a host an effective amount of a compound of formula (I), or preferably of formula (IA).
17. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , or a compound of formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2 for the manufacture of a medicament useful in the inhibition of the neutral endopeptidase EC.3.4.24.11.
18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , or a compound of formula (IA) or a pharmaceutically acceptable salt thereof according to claim 2 useful in the inhibition of the neutral endopeptidase EC.3.4.24.11.
PCT/EP2008/055941 2008-05-15 2008-05-15 Purine derivatives further comprising a mercapto-acylamino group as neutral endopeptidase inhibitors Ceased WO2009138122A1 (en)

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CA2723922A CA2723922A1 (en) 2008-05-15 2008-05-15 Purine derivatives further comprising a mercapto-acylamino group as neutral endopeptidase inhibitors
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EA201001765A EA201001765A1 (en) 2008-05-15 2008-05-15 DERIVATIVES OF PURIN, ADDITIONALLY CONTAINING A MERCAPTOACYLAMINO GROUP, AS NEUTRAL ENDOPEPTIDASE INHIBITORS
KR1020107028071A KR20110009704A (en) 2008-05-15 2008-05-15 Purine derivatives further comprising a mercapto-acylamino group as a neutral endopeptidase inhibitor
EP08759614A EP2303883A1 (en) 2008-05-15 2008-05-15 Purine derivatives further comprising a mercapto-acylamino group as neutral endopeptidase inhibitors
BRPI0822879A BRPI0822879A2 (en) 2008-05-15 2008-05-15 purine derivatives also containing a mercapto-acylamine group as neutral endopeptidase inhibitors
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EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

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EP2567959A1 (en) 2011-09-12 2013-03-13 Sanofi 6-(4-Hydroxy-phenyl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

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