EP2291351A1 - Alpha-mercaptoamides - Google Patents

Alpha-mercaptoamides

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Publication number
EP2291351A1
EP2291351A1 EP08750117A EP08750117A EP2291351A1 EP 2291351 A1 EP2291351 A1 EP 2291351A1 EP 08750117 A EP08750117 A EP 08750117A EP 08750117 A EP08750117 A EP 08750117A EP 2291351 A1 EP2291351 A1 EP 2291351A1
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EP
European Patent Office
Prior art keywords
alkyl
alkoxy
heterocyclyl
aryl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08750117A
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German (de)
English (en)
Inventor
Mauro Napoletano
Thomas Haack
Vincenzo Tschinke
Stjepan Jelakovic
Robert Mah
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Novartis AG
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Novartis AG
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Publication date
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Publication of EP2291351A1 publication Critical patent/EP2291351A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to alpha-mercapto-amides, to processes for their preparation and to the use of the compounds, 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 WO 1997/011717.
  • 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-s-alkoxy, Ci-s-alkyl, halogen, hydroxy or oxo;
  • R 1 is Ci- 8 -alkyl, aryl-Ci-s-alkyl, 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, 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 -8 -alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci -8 -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; 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 give the compound of formula (I); disulfide derivatives derived from the compound 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 -8 -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 -8 -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 -8 -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 to 7 ring carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclo- hexyl, 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-acylJ-Ci-s-alkoxy-Ci-s-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 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 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 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- i 2 -cycloalkyl, C 3- i 2 -cycloalkyl- Ci-s-alkyl, C ⁇ -i ⁇ -aryl, C 7- i8-aralkyl, heterocyclyl, heterocyclyl-Ci-s-alkyl, heteroaryl-Ci-s- alkyl, tri-Ci-s-alkyl-silyl, and Ci-12-acyl.
  • saturated heterocyclyl radicals are azepanyl, azetidinyl, azihdinyl, 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,
  • Heterocyclyl radicals may be unsubstituted or mono- or polysubstituted, for example mono- or disubstituted.
  • substituents on such heterocyclyl radicals are Ci-6-alkanoyl, C 2- 6-alkenyl, C 2- 6-alkinyl, Ci -6 -alkoxy, Ci-e-alkoxy-Ci-e-alkoxy, Ci -6 - alkoxy-Ci-e-alkyl, Ci-6-alkoxycarbonylamino-C2-6-alkoxy, Ci -6 -alkoxycarbonylamino- Co-6-alkyl, Ci-6-alkyl, Ci-6-alkylcarbonylannino, Ci-e-alkylcarbonylamino ⁇ - ⁇ -alkoxy, Ci-e-alkylcarbonylannino-Ci-e-alkyl, Ci-6-alkylcarbonyloxy, Ci-6-alkylenedioxy, optionally N-mono or
  • polyhalogen-Ci- 6 -alkyl denotes Ci- 6 -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 chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, monofluoroethyl and pentafluoroethyl.
  • Ci- 8 -alkyl in the residues aryl-Ci -8 -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.
  • methyl-, ethyl-, diethyl- or triethylamine mono-, bis- or tris(2-hydroxy(lower alkyl))amines, such as ethanol-, diethanol- or triethanol- amine, 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-hydroxy- ethyl)amine, or N-methyl-D-glucamine, or quaternary ammonium hydroxides such as tetrabutylammonium 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. orthophosphoric acid or metaphosphoric 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. orthophosphoric acid or metaphosphoric acid, or pyrophosphoric acid with replacement of one or more protons, or with organic carboxylic, sulfonic or phosphonic acids or N-
  • 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.
  • 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 solvates, incorporating a solvent used in the crystallization process.
  • 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 in a similar manner to the preparation processses disclosed in the literature (WO 2002/09262) (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, diastereo- meric 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 derivatizing 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 pipehdine 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
  • 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 ⁇ -(alkanoyl- oxy, alkoxycarbonyl or dialkylaminocarbonyl)-alkyl esters; as such, pivaloyloxymethyl esters and similar esters are utilized in a conventional manner.
  • 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 endopeptidase 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).
  • 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.
  • 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.
  • 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).
  • 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 fluoro- genic 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 sacrified and their kidneys are removed for homogenization in a TRIS-buffered Triton-X100 solution.
  • the NEP activity in the homogenate is measured in a mixture of 100 ⁇ l containing
  • hydrolysis product 7-amido-4-methylcoumahn
  • fluorescence A ecc :355 nm; ⁇ em :460 nm
  • Victor V 2 detector Perkin Elmer
  • IC 5 O values are calculated by fitting a 4-parameter logistic curve to the recorded %lnhib at specific test article concentrations according to following nonlinear equation: a — d
  • 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).
  • a higher inhibiting activity corresponds to higher % lnhib value.
  • the investigations take place in pre-cathetehzed (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-mf), elimination rate constant (K), terminal half-life (ty 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).
  • test compound serial dilution
  • maximal enzyme activity control : no test compound.
  • inhibition can occur by three different mechanisms: (1 ) competitive inhibition, (2) non-competitive 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 (IC50 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-ethoxy- coumarin (CYP1A2).
  • a suitable fluorogenic substrate e.g. 3-cyano-7-ethoxy- coumarin
  • 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 centhfuged 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 is monocyclic Cs-s-cycloalkyl which is either unsubstituted or substituted by 1-3
  • R 1 is Ci-s-alkyl, aryl-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci -8 - alkyl in Ci -8 -alkyl, aryl-Ci -8 -alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci -8 -alkoxy, halogen, hydroxy or oxo; and
  • R 2 is Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci -8 -alkoxy-Ci -8 -alkyl, Ci -8 -alkyl, aryl, aryl-Ci -8 - alkyl, halo-Ci -8 -alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci -8 -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.
  • A is monocyclic, saturated heterocyclyl which is either unsubstituted or substituted by
  • R 1 is Ci- 8 -alkyl, aryl-Ci -8 -alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci -8 - alkyl in Ci -8 -alkyl, aryl-Ci -8 -alkyl or in heterocyclyl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, halogen, hydroxy or oxo: and
  • 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.
  • 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.
  • Particularly preferred groups A are cyclohexyl, cyclopentyl or tetrahydropyran-4-yl.
  • 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 1 is Ci- 8 -alkyl, aryl-Ci -8 -alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci -8 - 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, halogen, hydroxy or oxo; R 1 is particularly preferred aryl-C2-4-alkyl, heterocyclyl or wherein C2 -4 -alkyl in aryl-C2 -4 - alkyl or in heterocyclyl-C2 -4 -alkyl is unsubstituted or substituted with 1 -3 Ci-s-alkoxy, halogen, hydroxy or oxo.
  • R 2 is Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkyl, aryl or a ryl -Ci-s-alkyl wherein Ci-s-alkyl in aryl-
  • Ci-s-alkyl is unsubstituted or substituted with 1-3 Ci -8 -alkoxy, carboxy, halogen, hydroxy or oxo;
  • R 2 is benzyl, isopropyl, 2-methoxyethyl, methyl or propyl.
  • 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 ⁇ - 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 rosiglitazone, pi
  • 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.; gluco
  • 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 material(s) is(are) prepared as follows : a) Thioacetic acid S- ⁇ (S)-2-methyl-1 -[1 -O-phenyl-propylcarbamovD-cvclopentyl- carbamoyli-propyl) ester
  • the starting material(s) is(are) prepared as follows : a) 1 -Amino-3-(4-methoxy-phenyl)-propan-2-ol hydrochloride
  • the starting matehal(s) is(are) prepared as follows : a) Thioacetic acid S-((S)-2-methyl-1 - ⁇ 1 -r3-(2-methyl-benzooxazol-6-yl)- propylcarbamovH-cvclopentylcarbamovD-propyl) ester
  • the starting material(s) is(are) prepared as follows : a) 4-(3-Methoxy-benzylH1 ,3,51triazin-2-ylamine
  • Example 3 using thioacetic acid S-((S)-1 - ⁇ 1 -[2-hydroxy-3-(4-methoxy-phenyl)-propyl- carbamoyl]-cyclopentylcarbamoyl ⁇ -2-methyl-propyl) ester instead of thioacetic acid
  • the starting material(s) is(are) prepared as follows : a) Thioacetic acid S-((S)-1 -11 -r2-hvdroxy-3-(4-methoxy-phenyl)-propylcarbamoyl1- cvclopentylcarbamoyl)-2-methyl-propyl) ester
  • the title compound is prepared in an analogous manner to the process described in Example 3a using 1 -((S)-2-bromo-3-methyl-butyrylamino)-cyclopentanecarboxylic acid [2-hydroxy-3-(4-methoxy-phenyl)-propyl]-amide instead of 1-((S)-2-bromo-3- methyl-butyrylamino)-cyclopentanecarboxylic acid [3-(2-methyl-benzooxazol-6-yl)- propyl]-amide.
  • the title compound is obtained from the residue by flash chromatography (SiO 2 60F) as a white solid.
  • the title compound is prepared in an analogous manner to the process described in Example 1 b using 2-(tert-butyl-dimethyl-silanyloxy)-3-(4-methoxy-phenyl)-propyl- amine instead of 1-amino-cyclopentanecarboxylic acid (3-phenyl-propyl)-amide and 1 -((S)-2-bromo-3-methyl-butyrylamino)-cyclopentanecarboxylic acid. [248262-45-5] instead of (R)-2-bromo-3-methyl-butyric acid [76792-22-8].
  • the crude compound is triturated with hexanes to afford the title compound as a white solid.

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Abstract

L'invention porte sur des amides substitués représentés par la formule générale (I), dans laquelle les résidus A, R1 et R2 sont tels qu'expliqués en détail dans la description. Les composés sont très puissants et sont appropriés en particulier comme inhibiteurs de l'endopeptidase neutre.
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