WO2009135526A1 - Alpha-mercapto-amides - Google Patents

Alpha-mercapto-amides Download PDF

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Publication number
WO2009135526A1
WO2009135526A1 PCT/EP2008/055594 EP2008055594W WO2009135526A1 WO 2009135526 A1 WO2009135526 A1 WO 2009135526A1 EP 2008055594 W EP2008055594 W EP 2008055594W WO 2009135526 A1 WO2009135526 A1 WO 2009135526A1
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Prior art keywords
alkyl
alkoxy
heterocyclyl
aryl
compound
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PCT/EP2008/055594
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French (fr)
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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Priority to AU2008355852A priority Critical patent/AU2008355852A1/en
Priority to BRPI0822880A priority patent/BRPI0822880A2/en
Priority to CA2723550A priority patent/CA2723550A1/en
Priority to JP2011507794A priority patent/JP2011520797A/en
Priority to KR1020107027350A priority patent/KR20110004472A/en
Priority to CN2008801301418A priority patent/CN102076662A/en
Priority to MX2010012139A priority patent/MX2010012139A/en
Priority to PCT/EP2008/055594 priority patent/WO2009135526A1/en
Priority to EP08750117A priority patent/EP2291351A1/en
Publication of WO2009135526A1 publication Critical patent/WO2009135526A1/en
Anticipated expiration legal-status Critical
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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
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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

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

Description

Alpha-mercapto-amides
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Various NEP inhibitors and their uses are disclosed, for example, in WO 1997/011717. 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
(I) 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 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;
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-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 Ra, 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 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-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.
Examples of alkyl and alkoxy radicals, which may be linear or branched, are 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. Ci-s-alkyl radicals in aryl-Ci-s-alkyl, heterocyclyl- Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkoxy-Ci-s-alkyl, aryl-Ci-8-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-dimethylnnethylene, 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 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. Examples of 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, 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-8- alkoxy-Ci-s-alkyl-carbonyl, Ci-s-alkoxy-Ci-s-alkyl-carbonylamino, Ci-8-alkoxy-Ci-8-alkyl- heterocyclyl, 2-Ci-8-alkoxy-Ci-8-alkyl-4-oxo-imidazol-1 -yl, 6-alkoxy-aminocarbonyl-Ci-8- 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-S- alkoxycarbonylamino-Ci-s-alkyl, Ci-s-alkoxycarbonylphenyl, Ci-s-alkyl, (N-Ci-s-alkyl)- Ci-s-alkoxy-Ci-s-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-alkyO-Ci-s-alkylsulfonylamino-Ci-s-alkyl, Ci-8-alkyl- amidinyl, optionally N-mono or N,N-di-Ci-8-alkylated amino, Ci-8-alkylamino-C2-8- alkoxy, di-Ci-8-alkylamino-C2-8-alkoxy, Ci-s-alkylamino-Ci-s-alkyl, di-Ci-s-alkylamino- Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s-alkoxy, di-Ci-s-alkylaminocarbonyl-Ci-s-alkoxy, Ci-s-alkylaminocarbonyl-Ci-s-alkoxy-Ci-s-alkyl, Ci-s-alkylaminocarbonyl-Ci-s-alkyl, di- Ci-s-alkylaminocarbonyl-Ci-s-alkyl, Ci-s-alkylaminocarbonylamino-Ci-s-alkoxy, Ci-S- alkylaminocarbonylamino-Ci-s-alkyl, Ci-8-alkyl-carbamoyl, di-Ci-s-alkyl-carbamoyl, C0-S- alkylcarbonylamino, Co-s-alkylcarbonylamino-Ci-s-alkoxy, Co-s-alkylcarbonylamino-Ci-s- alkyl, Ci-8-alkylcarbonyloxy, Ci-s-alkylcarbonyloxy-Ci-s-alkoxy, Ci-s-alkylcarbonyloxy- - A -
Ci-s-alkyl, Ci-s-alkylenedioxy, Ci-s-alkyl-sulfonyl, Ci-s-alkylsulfonyl-Ci-s-alkoxy, Ci-S- alkylsulfonyl-Ci-s-alkyl, Ci-s-alkylsulfonylamino-Ci-s-alkoxy, Ci-s-alkylsulfonylamino- Ci-s-alkyl, aryl-Ci-s-alkanoyl, aryl-Co-8-alkoxy, aryl-Co-8-alkyl, arylamino, aryloxy, arylthio, benzoyloxy-Ci-s-alkoxy, benzyloxy, carbamoyl-Co-8-alkoxy, carbamoyl-Co-β- alkyl, carboxy, carboxy-Ci-8-alkoxy, carboxy-Ci-s-alkoxy-Ci-s-alkyl, carboxy-Ci-8-alkyl, cyano, cyano-Ci-8-alkoxy, cyano-Ci-8-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, O.N-dimethylhydroxylamino-Ci-s-alkyl, dioxolanyl- Ci-s-alkoxy, halogen, halogen-Ci-8-alkoxy, halogen-Ci-8-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-s-alkyl, (N-hydroxy)-Ci-8-alkyl- anninocarbonyl-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- oxinnyl-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]pyhdinyl, imidazo[1 ,2-a]pyhmidinyl, 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-isobenzofuranyl, 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]pyrinnidinyl, 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, tetrahydro- quinoxalinyl, 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, 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-i2-cycloalkyl, C3-i2-cycloalkyl- Ci-s-alkyl, Cβ-iβ-aryl, C7-i8-aralkyl, heterocyclyl, heterocyclyl-Ci-s-alkyl, heteroaryl-Ci-s- alkyl, tri-Ci-s-alkyl-silyl, and Ci-12-acyl.
Examples for 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-piperidinyl, 2-oxo-pyrrolidinyl, 2-oxo-tetrahydro-pyhmidinyl, 4-oxo-thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, 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-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^-θ-alkoxy, Ci-e-alkylcarbonylannino-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-alkyl- ated carbamoyl, carbonylamino, carbonylamino-C2-6-alkoxy, carbonylamino-Ci-6-alkyl, optionally esterified carboxy, cyano, C3-8-cycloalkoxy, halogen, heteroaryl, hetero- cyclyl, hydroxy, nitro, oxid, oxo, polyhalogen-Ci-6-alkoxy or polyhalogen-Ci-6-alkyl.
The term polyhalogen-Ci-6-alkyl denotes Ci-6-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 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). 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 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. acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucahc 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-phospho- glycerate, 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 solvates, incorporating a solvent used in the crystallization process.
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 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.
Figure imgf000010_0001
(PG = Boc, Cbz)
Figure imgf000010_0002
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.
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-(alkanoyl- oxy, 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 endopeptidase 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. 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 imgf000015_0002
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 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 μmol/kg body weight. 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 μl containing
Figure imgf000016_0001
that is incubated for 45 minutes at 300C. Subsequently, the hydrolysis product, 7-amido-4-methylcoumahn, 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:
SpI - B
%lnhib = ■ 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
IC5O 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
Y = + d
1 +
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).
Examples of NEP inhibitory activity:
Figure imgf000017_0001
* A higher inhibiting activity corresponds to higher % lnhib value.
The bioavailability of the compounds described herein can be tested in vivo using the following protocol:
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 (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-mf), elimination rate constant (K), terminal half-life (ty2), 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) non-competitive 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 (IC50 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-ethoxy- coumarin (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 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.
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 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
(IA) where A, R1 and R2 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 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
R2 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 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-8-alkoxy, Ci-8-alkyl, halogen, hydroxy or oxo;
R1 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
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.
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. 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
R1 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; R1 is particularly preferred aryl-C2-4-alkyl, heterocyclyl or
Figure imgf000022_0001
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. 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
R2 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; In particular, R2 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. 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: AcOH acetic acid CH2Cb dichloromethane CHCI3 chloroform CH3CN acetonitrile Cy cyclohexane
DCC dicyclohexylcarbodiimide
DIBAL diisobutylaluminium hydride
DMF N,N-dimethylformamide
EDOHCI 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
K2CO3 potassium carbonate
MeI methyl iodide
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
NH3 ammonia
NH4CI ammonium chloride
NH4Br ammonium bromide
Pd2(dba)3 ths(dibenzylideneacetone)dipalladium [51364-51 -3]
Pd(OAc)2 palladium acetate
P(tert-Bu)3 tri-tert-butyl phosphine
P(o-tolyl)3 tri-o-tolyl-phosphine
Ra/Ni Raney-nickel 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
1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid (3-phenyl- propyD-amide
1.0 mmol of thioacetic acid S-{(S)-2-methyl-1 -[1 -(3-phenyl-propylcarbamoyl)- cyclopentylcarbamoyl]-propyl} ester is dissolved under N2 atmosphere in 15 ml of EtOH, with gentle heating. The mixture is cooled to 00C and 3 ml of 1 N NaOH is added. The reaction is stirred under N2 for 4 h at RT. After this time the pH is taken to 2-3 with 10% HCI. The solvent is concentrated by evaporation and the residue partitioned between H2O (5 ml) and CH2CI2 (5 ml). The organic layer is collected, dried with Na2SO4 and the solvent is evaporated under reduced pressure. The obtained solid is triturated with petroleum ether to afford the title compound as a white solid. Rf = 0.30 (Cy-EtOAc 7:3); Rt = 6.22.
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
A suspension of 1.0 mmol of 1 -((R)-2-bromo-3-methyl-butyrylamino)-cyclopentane- carboxylic acid (3-phenyl-propyl)-amide and 1.5 mmol of potassium thioacetate in 7 ml of DMF is stirred at room temperature for 48 h. The solvent is concentrated by evaporation and the residue is dissolved in 15 ml of H2O and extracted first with ether (10 ml) and then with EtOAc (10 ml). The combined organic layers are dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by Varian Mega Bond Elut (Sl), eluting with Cy-EtOAc 9:1 -» 7:3 to afford the title compound as a white solid (after triturating with ether). Rf = 0.33 (Cy-EtOAc 1 :1 ); Rt = 6.29.
b) 1 -((R)-2-Bromo-3-methyl-butyrylamino)-cvclopentanecarboxylic acid (3-phenyl- propyD-amide
A solution of 1.0 mmol of 1 -amino-cyclopentanecarboxylic acid (3-phenyl-propyl)- amide, 1.0 mmol of (R)-2-bromo-3-methyl-butyric acid [76792-22-8] and 1.1 mmol of DMAP in 5 ml Of CH2CI2 is cooled to 00C. 1.1 mmol of WSC-HCI is added and the reaction mixture is stirred at RT for 24 h. After this time, the mixture is partitioned between H2O (2 x 10 ml) and CH2CI2. The organic layer is dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by Varian Mega Bond Elut (Sl) eluting with Cy-EtOAc 95:5 to afford the title compound as a white solid. Rf = 0.40 (Cy-EtOAc 1 :1 ); Rt = 6.27.
c) 1 -Amino-cvclopentanecarboxylic acid (3-phenyl-propyl)-amide
1.0 mmol of [1 -(3-phenyl-propylcarbamoyl)-cyclopentyl]-carbamic acid tert-butyl ester is dissolved in 6 ml of a solution of CH2CI2/TFA 1 :1. The reaction mixture is stirred at RT for 15 h. The solvent is evaporated under reduced pressure to afford the title compound as a yellow oil. Rf = 0.30 (CH2CI2-MeOH 1 :1 ); Rt = 2.82.
d) [1 -(3-Phenyl-propylcarbamoyl)-cvclopentvH-carbamic acid tert-butyl ester
A solution of 1.0 mmol of 3-phenyl-1 -propylamine [2038-57-5], 1..0 mmol of 1 -tert- butoxycarbonylamino-cyclopentanecarboxylic acid [35264-09-6] and 1.1 mmol of DMAP in 5 ml of CH2CI2 is cooled to 00C. 1.1 mmol of WSC-HCI is added and the reaction mixture is stirred at RT for 48 h. After this time, the mixture is partitioned between H2O (2 x 10 ml) and CH2CI2. The organic layer is dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by Biotage Flash Chromatography (Sl, 40+M) eluting with Cy-EtOAc 8:2 to afford the title compound as a white solid. Rf = 0.42 (Cy-EtOAc 1 :1 ); Rt = 6.52.
The following compounds are prepared in an analogous manner to the process described in Example 1 : 2 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [3-(4- methoxy-phenvD-propyli-annide using 3-(4-methoxy-phenyl)-propylannine [36397-23-6] instead of 3-phenyl-1 -propylamine in step d. Off-white solid; Rf = 0.38 (Cy-EtOAc 1 :1 ); Rt = 6.13.
11 1 -((S)-2-Mercapto-3-methyl-butyrylannino)-cvclopentanecarboxylic acid [3-(4- fluoro-phenvD-propyli-annide using 3-(4-fluoro-phenyl)-propylamine [101488-65-7] instead of 3-phenyl-1 - propylamine in step d. The title compound is identified based on the Rf value.
12 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [3-(4- chloro-phenvD-propyli-amide using 3-(4-chloro-phenyl)-propylamine [18655-50-0] instead of 3-phenyl-1 -propylamine in step d. The title compound is identified based on the Rf value.
5 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [2- methoxy-3-(4-methoxy-phenyl)-propyH-amide using 1 -amino-3-(4-methoxy-phenyl)-propan-2-ol hydrochloride instead of 3-phenyl- 1 -propylamine in step d. White solid; Rf = 0.29 (Cy-EtOAc 1 :1 ); Rt = 5.95.
The starting material(s) is(are) prepared as follows : a) 1 -Amino-3-(4-methoxy-phenyl)-propan-2-ol hydrochloride
A mixture of 1.0 mmol of 1 -(3-azido-2-methoxy-propyl)-4-methoxy-benzene and 18 mg of Pd/C in 5 ml of MeOH is hydrogenated at 30 psi for 4 h. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and HCI/EtOAc is added. The solvent is evaporated under reduced pressure and the residue is tritured with Et2O and filtred. The title compound is obtained as white solid. Rf = 0.52 (BuOH- AcOH-H2O = 3:1 :1 ); Rt = 1.94.
b) 1 -(3-Azido-2-methoxy-propyl)-4-methoxy-benzene
2.1 mol of NaH (60% dispersion in oil) is added portionwise to a solution of 1.0 mol of 1 -azido-3-(4-methoxy-phenyl)-propan-2-ol [845910-13-6] in 7 ml of dry DMF.The mixture is stirred at RT for 2 h. 2.1 mol of MeI in 2 ml of dry DMF is added dropwise. The reaction is stirred at RT overnight. The solvent is evaporated; brine is added and the mixture is extracted with EtOAc (3X). The combined organic layers are dried with Na2SO4 and the solvent is evaporated under reduced pressure. The residue is purified by by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf = 0.50 (EtOAc-petroleum ether = 20:80); Rt = 5.93.
6 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid heptylamide using heptylamine [111 -68-2] instead of 3-phenyl-1 -propylamine in step d. White solid; Rf = 0.22 (Cy-EtOAc 7:3); Rt = 6.74.
Example 3
1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [3-(2-methyl- benzooxazol-6-yl)-propyl1-amide
1.0 mmol of thioacetic acid S-((S)-2-methyl-1-{1 -[3-(2-methyl-benzooxazol-6-yl)- propylcarbamoyl]-cyclopentylcarbamoyl}-propyl) ester is dissolved under N2 atmosphere in 10 ml of degassed ethanol. The mixture is treated with 3.0 ml of 1 N NaOH. The reaction is stirred under N2 at RT for 3 h. The mixture is cooled to 00C and the pH is taken to 5-6 with 10% HCI. The solvent is evaporated under reduced pressure and the residue is partitioned between H2O and CH2CI2. The organic layer is collected,dhed with Na2SO4 and the solvent evaporated under reduced pressure. The obtained solid is triturated with petroleum ether to afford the title compound as a white solid. Rt = 5.56.
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
150 mmol of potassium salt of thioacetic acid is added to a supension of 1.0 mmol of 1 -((S)-2-bromo-3-methyl-butyrylamino)-cyclopentanecarboxylic acid [3-(2-methyl- benzooxazol-6-yl)-propyl]-amide in 10 ml DMF under nitrogen at 00C. The reaction mixture is stirred for 30 min after which it is brought up to RT and stirred again for 48 h. The reaction solution is concentrated in under reduced pressure, partitioned between Et2O and water and extracted with EtOAc (3X). The combined organic layers are washed with NaHCO3 and brine, dried with Na2SO4 and evaporated under reduced pressure. The crude product is purified by Varian Mega Bond Elut (Si) eluting with petroleum ether/EtOAc from initial 2:8 to a mixture of 8:2 to afford the title compound as colorless oil. Rf = 0.53 (EtOAc); Rt = 5.60.
b) 1 -((S)-2-Bromo-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [3-(2-methyl- benzooxazol-6-yl)-propyl1-amide
A solution of 0.66 mmol of 1 -((S)-2-bromo-3-methyl-butyrylamino)- cyclopentanecarboxylic acid methyl ester [248263-14-1], 1.0 mmol of 3-(2-methyl- benzooxazol-6-yl)-propylamine hydrochloride and 1.3 mmol of thethylamine in 5 ml of toluene under nitrogen at 00C is treated with 1.3 mmol of thmethylaluminum (2M in toluene). The mixture is stirred for 1 h ar RT, the for 2 h at 600C. The reaction mixture is poured onto a mixture of 1 N NaOH and ice and extracted with EtOAc (1X) and CH2CI2 (4X). The combined organic layers are dried with Na2SO4 and evaporated under reduced pressure. The title compound is obtained from the residue by flash chromatography (SiO2 60F) as a white solid. Rf = 0.47 (EtOAc); Rt = 5.69.
c) 3-(2-Methyl-benzooxazol-6-yl)-propylamine hydrochloride
1.0 mmol of 3-(2-methyl-benzooxazol-6-yl)-acrylonitrile is taken up in 45 ml of EtOH and 5 ml of 30% NH3 solution and subjected to hydrogenation at 35 psi for 2 h using 35 mg of 30%w/w Ra/Ni. The mixture is filtered through a short plug of Hyflow and the filtrate is evaporated. The residue is treated repeatedly with a mixture of CH2CI2 and EtOH and evaporated to remove residual water. The crude compound is dissolved in a small amount of EtOAc and HCI/EtOAc is added. The solvent is removed by evaporation and the residue is tritured with Et2O and filtred. The resulting white solid is washed with CH2CI2 and diethyl ether and dried in vacuo. Rf = 0.43 (CH2CI2-MeOH-25%NH3 80:20:2); Rt = 1.08.
d) 3-(2-Methyl-benzooxazol-6-yl)-acrylonitrile
A mixture of 1.0 mmol of 6-bromo-2-methyl-benzooxazole [151230-42-1], 2 mmol of acrylonitrile, 1.0 mmol of sodium acetate, 0.1 mmol of Pd(OAc)2 and 0.2 mmol of P(o-tolyl)3 in 3 ml of DMF under N2 atmosphere is treated at 1500C for 1 h in the microwave. The reaction is filtered through a short plug of Hyflow. The solvent of the filtarate is concentrated by evaporation. The title compound is obtained from the residue by chromatography on Varian Mega Bond Elut (Si) eluting with EtOAc to a mixture of petroleum ether/EtOAc 10:1 to afford the title compound as a mixture of cis and trans geometric isomers. Rf = 0.15 (CH2CI2-MeOH 100:2); Rt = 4.48.
The following compounds are prepared in an analogous manner to the process described in Example 3:
7 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid (5- ethyl-H .3.41thiadiazol-2-yl)-amide using 5-ethyl-[1 ,3,4]thiadiazol-2-ylamine [14068-53-2] instead of 3-(2-methyl-benzo- oxazol-6-yl)-propylamine in step b. White solid; Rf = 0.53 (petroleum ether-EtOAc 60:40); Rt = 3.24.
8 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [4-(3- methoxy-benzylH1 ,3,51triazin-2-yl1-amide using 4-(3-methoxy-benzyl)-[1 ,3,5]triazin-2-ylamine instead of 3-phenyl-1 -propylamine in step b. The title compound is identified based on the Rf value.
The starting material(s) is(are) prepared as follows : a) 4-(3-Methoxy-benzylH1 ,3,51triazin-2-ylamine
A mixture of 1.0 mmol of N-formylguanidine [4471 -51-6] and 2 mmol of (3-methoxy- phenyl)-acetonitrile [104-47-2] is heated to 2000C for 6 h. The reaction mixture is cooled to RT, poured in H2O and extracted with EtOAc. The organic layer is dried with Na2SO4 and the solvent is concentrated by evaporation. The residue is purified by by flash chromatography (SiO2 60F) to afford the title compound as a brown solid. Rf = 0.57 (CH2CI2-MeOH-25%NH3 = 90:10:1 ).
9 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid (1 H- pyrazol-4-yl)-amide using 1 H-pyrazol-4-ylamine [28466-26-4] instead of 3-phenyl-1 -propylamine in step b. The title compound is identified based on the Rf value. 10 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid (1- ethyl-1 H-pyrazol-4-yl)-amide using 1 -ethyl-1 H-pyrazol-4-ylamine [876343-24-7] instead of 3-phenyl-1 -propylamine in step b. The title compound is identified based on the Rf value.
13 1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [3-(2- methyl-benzothiazol-5-yl)-propyl1-amide using (E)-3-(2-methyl-benzothiazol-5-yl)-acrylonitrile [03983-98-8] instead of 3-(2- methyl-benzooxazol-6-yl)-acrylonitrile in step c. The title compound is identified based on the Rf value.
Example 4
1 -((S)-2-Mercapto-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [2-hvdroxy-3-
(4-methoxy-phenyl)-propyl1-amide
The title compound is prepared in an analogous manner to the process described in
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
S-((S)-2-methyl-1 -{1 -[3-(2-methyl-benzooxazol-6-yl)-propylcarbamoyl]-cyclopentyl- carbamoyl}-propyl) ester. White solid. Rf = 0.19 (petroleum ether-EtOAc 50:50).
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 (SiO2 60F) as a white solid. Rf = 0.23 (petroleum ether-EtOAc 40:60); Rt = 5.38. b) 1 -((S)-2-Bromo-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [2-hvdroxy- 3-(4-methoxy-phenyl)-propyl1-annide
A solution of 1.0 mmol of 1 -((S)-2-bromo-3-methyl-butyrylamino)-cyclopentane- carboxylic acid [2-(tert-butyl-dimethyl-silanyloxy)-3-(4-nnethoxy-phenyl)-propyl]-annide in 5 ml of THF is mixed with 2.0 mmol of tetrabutylammonium fluoride (1 M solution in THF), and the solution is stirred at RT for 10 h. The reaction solution is then diluted with water and extracted with CH2CI2 (2X). The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure. The title compound is obtained from the residue by flash chromatography (SiO2 60F) as a white solid. Rf = 0.23 (petroleum ether-EtOAc 40:60); Rt = 5.37.
c) 1 -((S)-2-Bromo-3-methyl-butyrylamino)-cvclopentanecarboxylic acid [2-(tert-butyl- dimethyl-silanyloxy)-3-(4-methoxy-phenyl)-propyH-amide
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. Rf = 0.80 (hexanes-EtOAc 50:50); Rt = 7.88.
d) 2-(tert-Butyl-dimethyl-silanyloxy)-3-(4-methoxy-phenyl)-propylamine
A mixture of 1.0 mmol of [2-azido-1 -(4-methoxy-benzyl)-ethoxy]-tert-butyl-dimethyl- silane and 150 mg of Pd/C 10% in 5 ml of MeOH is hydrogenated at 30 psi for 1 h. The catalyst is filtered off and the filtrate is evaporated. The crude title compound is obtained from the residue as a coulorless oil. Rf = 0.25 (petroleum ether-EtOAc 70:30).
e) [2-Azido-1-(4-methoxy-benzyl)-ethoxy1-tert-butyl-dimethyl-silane
A solution of 1.0 mmol of 1 -azido-3-(4-methoxy-phenyl)-propan-2-ol [845910-13-6] and 1.03 mmol of imidazole in 5 ml of DMF at 00C is treated with 1.2 mmol of tert- butyl-dimethyl-silyl chloride, and the solution is stirred at RT for 10 h. The reaction solution is then poured on water and extracted with EtOAc (2X). The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure. The title compound is obtained from the residue by flash chromatography (SiO2 60F) as a coulorless oil. Rf = 0.83 (petroleum ether-EtOAc 10:90).

Claims

Claims
1. Compound of the formula (I)
Figure imgf000039_0001
(I) 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 Ci-s-alkyl, aryl-Ci-s-alkyl, heterocyclyl or heterocyclyl-Ci-s-alkyl, wherein Ci-S- 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;
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; 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 give 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 corresponding to formula (IA)
Figure imgf000039_0002
(IA) wherein A, R1 and R2 are each defined according to claim 1.
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-8-alkyl, halogen, hydroxy or oxo.
6. A compound according to claim 5, wherein A is cyclohexyl, cyclopentyl or tetra- hydropyran-4-yl.
7. A compound according to claims 1 or 2, wherein R1 is Ci-s-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.
8. A compound according to claim 7, wherein R1 is aryl-C2-4-alkyl, heterocyclyl or heterocyclyl-C2-4-alkyl, 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.
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-s-alkyl wherein Ci-s-alkyl in aryl-Ci-s-alkyl is unsubstituted or substituted with 1 -3 Ci-s-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
A is monocyclic, saturated heterocyclyl which is either unsubstituted or substituted by
1 -3 Ci-8-alkoxy, Ci-8-alkyl, halogen, hydroxy or oxo;
R1 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
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.
12. 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.
13. 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).
14. 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.
15. 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.
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