WO2008107365A1 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

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Publication number
WO2008107365A1
WO2008107365A1 PCT/EP2008/052416 EP2008052416W WO2008107365A1 WO 2008107365 A1 WO2008107365 A1 WO 2008107365A1 EP 2008052416 W EP2008052416 W EP 2008052416W WO 2008107365 A1 WO2008107365 A1 WO 2008107365A1
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mmol
methyl
alkyl
hydroxy
title compound
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PCT/EP2008/052416
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English (en)
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Oscar Belda
Christian Sund
Vladimir Ivanov
Daniel Wiktelius
Christer Sahlberg
Bertil Samuelsson
Åsa ROSENQUIST
Fredrik WÅNGSELL
Ingemar KVARNSTRÖM
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Medivir Ab
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Publication of WO2008107365A1 publication Critical patent/WO2008107365A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • This invention relates to novel compounds having inhibitory activity on aspartyl proteases such as renin. It further concerns pharmaceutical compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions and their use in the preparation of a medicament or their use in therapy.
  • Renin is an aspartyl protease with a high substrate specificity, its only known substrate is angiotensinogen. Renin cleaves the N terminus of circulating angiotensinogento angiotensin I (Ang I), which thereafter is further processed to the active peptide hormone angiotensin II (Ang II) by the less specific angiotensin-converting enzyme (ACE). Ang II increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-ion-retaining hormone aldosterone. Ang II is known to work on at least two receptor subtypes called ATI and AT2. ATI seems to transmit most of the known functions of Ang II, while the role of AT2 is still unknown.
  • Modulation of the RAS represents a major advance in the treatment of cardiovascular diseases. Inhibition of the enzymatic activity of renin leads to a reduction in the formation of Ang I, and as a consequence, a smaller amount of Ang II is produced. The reduced concentration of that active peptide hormone is a direct cause of the hypotensive effect of renin inhibitors.
  • ACE inhibitors and ATI blockers have been accepted to treat hypertension and ACE inhibitors are used for renal protection in the prevention of congestive heart failure and myocardial infarction.
  • the rationale to develop renin inhibitors is the specificity of renin. Renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATI blockers with regard to efficacy in blocking the RAS and in safety aspects.
  • renin inhibitors Only limited clinical experience has been created with renin inhibitors because of their insufficient oral activity. The clinical development of several compounds has been stopped because of this problem together with the high cost of goods. Only one compound has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7, 493; Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required.
  • the present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties. Compound 38 on page 4547 of Hanessian et al J. Med.
  • Chem., 2006, 4544-4567 describe the boc-protected peptido mimetic derivative l-benzylsulfanylmethyl-4-(l-butylcarbamoyl-2- methyl-propylcarbamoyl)-2-hydroxy-pentyl]carbamic acid tert-butyl ester, used as an intermediate in the preparation of macrocyclic peptidomimetic BACE inhibitors.
  • Compound 38 is outside the scope of the claims presented below and there is no suggestion that such intermediates could find utility as renin inhibitors.
  • Q is aryl or heterocyclyl
  • Ra is H or Ci-C 4 alkyl
  • R 1 is hydrogen, d-C ⁇ alkyl, Co-C 3 alkanediylC 3 -Cycycloalkyl or Co-C 3 alkanediylaryl, Co-
  • R 2 is hydrogen or Ci-C ⁇ alkyl
  • X' is hydrogen, fluoro, hydroxy, amino or Ci-C ⁇ alkoxy
  • X" is hydrogen, or when X' is fluoro, then X" may also be fluoro;
  • R 3 is Ci-Cealkyl
  • R 4' is Ci-Cealkyl
  • R 4 is H or Ci-C ⁇ alkyl
  • R 4 and R 4 together with the carbon atom to which they are attached define a Cs-C ⁇ Cycloalkyl
  • W is C 3 -Cycycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl moiety is optionally substituted with fluoro, methyl or methoxy; wherein aryl is independently phenyl, naphthyl, or phenyl fused to Cs-C ⁇ cycloalkyl or Cs-C 6 cycloalkenyl; heterocyclyl is independently a 5 or 6 membered, saturated, partially unsaturated or heteroarylic ring containing 1 to 3 heteroatoms independently selected from S, O and N, the ring being optionally fused with a benzene ring; wherein each Ci-C ⁇ alkyl, aryl and heterocyclyl moiety above (including those in composite expressions such as alkoxy or alkanediylaryl), unless otherwise specified is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected
  • Ci-C 4 alkyl a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C 4 alkyl or fluoro), Co-C3alkanediylaryl*, Co ⁇ alkanediylheterocyclyl*, C2-C3alkenyldiylC3-
  • the compounds of the invention are generally potent inhibitors of renin and thus the invention further provides the use of a compound of the formula I or a pharmaceutically acceptable salt, hydrate or N-oxide thereof for the treatment or prophylaxis of disorders mediated by the RAS, such as hypertension, heart failure and renal insufficiency .
  • the compounds of general formula (I) have several centres of chirality, conveniently the compounds display at least 75%, preferably at least 90%, such as in excess of 95%, enantiomeric purity at each of the chiral centres.
  • the chiral centre whereto the group R 3 is attached has the stereochemistry shown in structure (Ia):
  • Preferred compounds of formula (I) are those having the stereochemistry indicated in the structure of formula (Ie):
  • R 3 is Ci-C ⁇ alkyl, preferably ethyl or more preferably isopropyl.
  • R 4 is Ci-C ⁇ alkyl, preferably isopropyl or more preferably sec. butyl.
  • R 4 " is preferably hydrogen.
  • R4' and R4" together define a spiro-cycloalkyl group, for example cyclopentyl or cyclobutyl or preferably cyclopropyl.
  • X' is fluoro, or more preferably hydroxy.
  • X is hydrogen
  • a further embodiment of the invention are compounds of formula (I) or any subgroup of formula (I) wherein X' and X" are both fluoro.
  • R 1 is hydrogen, Ci-C ⁇ alkyl, Co-C 3 alkanediylC 3 -Cycycloalkyl, Co- Csalkanediylaryl or Co-C 3 alkanediylheterocyclyl, wherein each Ci-C ⁇ alkyl, cycloalkyl, aryl and heterocyclyl moiety is optionally substituted with one, two or three substituents independently selected from halo, haloCi-C 4 alkyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, hydroxy and cyano.
  • R 1 Convenient values for R 1 include hydrogen, optionally substituted phenyl, optionally substituted benzyl and optionally substituted Ci-C ⁇ alkyl.
  • R 1 is hydrogen, Ci-C ⁇ alkyl or optionally substituted benzyl, especially hydrogen, methyl, ethyl or isopropyl.
  • R 1 is optionally substituted heteroarylCi-C 4 alkyl, such as heteroarylmethyl, especially where the heteroaryl is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy), cyano or halo (preferably fluoro) groups.
  • heteroarylCi-C 4 alkyl such as heteroarylmethyl
  • the heteroaryl is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as with 1 or 2 Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C
  • R 1 is pyridylCi-C 4 alkyl or thiazolylCi-C 4 alkyl. Further configurations for R 1 include phenylethyl, which is optionally substituted with a sulphonamide group such as methanesulphonamide or N-methyl methanesulphonamide.
  • R 1 in general are as defined above.
  • Representative values include Ci-C 4 alkyl such as methyl; halo such as fluoro; haloCi-C 4 alkyl such as fluoromethyl and trifluoromethyl; and cyano.
  • R 1 is Co-C3alkanediylaryl or Co-C3alkanediylheterocyclyl
  • the optional substituent(s) to the aryl or heterocyclyl moiety are conveniently in the para and/or ortho position.
  • favoured configurations for R 1 according to this embodiment are phenyl or benzyl substituted in the para position.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl, or preferably R 2 is hydrogen.
  • Z is O.
  • Z is NRa, wherein Ra is hydrogen or Ci-C 3 alkyl, preferably hydrogen or methyl.
  • the group Q is bonded either directly to Z, i.e. n is 0, or Q is bonded via a methylene, ethylene or propylene moiety, i.e. n is 1, 2 or 3 respectively.
  • Q is bonded directly to Z or via an ethylene moiety, i.e. n is 0 or 2.
  • Q is bonded via a methylene moiety, i.e. n is 1.
  • Q is aryl or heterocyclyl, optionally substituted with one, two or three substituents independently selected from Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from Co-C3alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C2-Cealkenyl, C 2 -C6alkynyl, C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyC 0 - C 3 alkyl, hydroxy, hydroxyCi-C 4 alkyl, cyano, azido, Ci-C 4 alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrroli
  • the optional substituent (s) to Q include Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from Co-C 3 alkanediylaryl, amino, carbamoyl, amido and Ci-C4alkoxyamido), C3-Cycycloalkyl, Ci-C4alkoxy, halo, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCo-C3alkyl, hydroxy, hydroxyCi-C4alkyl, cyano, azido, Ci-C4alkylcarbonyl, carbamoyl, amino, amido, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with Ci-C 4 alkyl or fluoro), Co-C 4 alkyl
  • Q is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl.
  • Q is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • heterocyclyl groups for Q include pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, any of which may be substituted as defined above, such as 1 or 2 with C1-C4 alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl, preferably methoxypropoxy) or halo (preferably fluoro) groups.
  • C1-C4 alkyl preferably methyl
  • Ci-C4alkoxy preferably methoxy
  • Ci-C4alkoxyCi-C3alkoxyCo-C3alkyl preferably methoxypropoxy
  • halo preferably fluoro
  • Typical values for Q include optionally substituted 5 or 6 membered aryl or heterocyclyl, preferably phenyl or pyridyl.
  • a further typical value for Q is optionally substituted naphthyl.
  • Optional substituents to Q are as defined above. Representative values include substituents independently selected from Ci-C 4 alkyl, C 3 -Cycycloalkyl, Ci-C 4 alkoxy, Ci-C 4 alkoxy-Ci- C 6 alkoxyCo-C 3 alkyl, halo and haloCi-C 4 alkyl.
  • favoured values for the optional substituents for Q include cyclopropyl, methoxy- ethoxy, fluoro, optionally substituted phenyl and benzyl, more favoured substituents are chloro, methyl or methoxy-propoxy.
  • substituents to Q include Co-C 3 alkanediylaryl which aryl is optionally substituted, Co-C3alkanediylheterocyclyl and Co-C3alkanediylheteroaryl.
  • Typical heterocyclyl and heteroaryl include, but are not limited to, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, morpholinyl and especially furyl, thienyl, thiazolyl and pyridyl.
  • Q is a mono-substituted 6-membered ring, wherein the substituent is preferably in one of the meta positions or in the para position.
  • Q is para-substituted phenyl.
  • Q is meta-substituted phenyl.
  • Q include phenyl which is substituted with methoxypropoxy, and phenyl which is mono- or disubstituted with chloro.
  • Q include phenyl which is substituted with phenyl or substituted phenyl such as fluoro- or chlorophenyl, cycloalkyl such as cyclopropyl, Ci-C ⁇ alkyl such as methyl, ethyl or isopropyl, or pyridyl.
  • a further embodiment for the optional substituents to Q is benzyl which is substituted at the benzylic position.
  • Suitable substituents for the benzylic position includes for example amino, amido or alkoxyamido such as Ci-C4alkylamino or tert-butoxycarbonylamino.
  • R 5 is Ci-C 4 alkyl, Ci-C 4 alkylcarbonyl or Ci-C 4 alkyloxycarbonyl and R 5 is hydrogen, methyl or especially phenyl.
  • Q is disubstituted 6-membered ring with the substituents in the two meta positions or with one substituent in the meta position and the other in the para position.
  • Preferred substituents to Q according to this embodiment are independently chloro, methoxypropoxy and methyl.
  • Q is phenyl, optionally substituted with one or two substituents independently selected from methyl, cyclopropyl, fluoro, chloro and 3-methoxy-propxy.
  • Q is phenyl, substituted in one of the meta positions and/or in the para position.
  • Suitable configurations for Q include phenyl which is substituted in the meta position with Ci-C4alkoxy-Ci-C4alkoxy, and in the para position with Ci-C4alkyl, cyano or halo.
  • More suitable configurations for Q include phenyl which is substituted in the meta position with 3-methoxy-propoxy and in the para position with methyl, ethyl, cyano, fluoro, chloro or bromo.
  • Q include phenyl which is substituted in one of the meta positions with Ci-C4alkoxy-Ci-C4alkoxy, such as methoxypropoxy and/or in the para position with optionally substituted heteroaryl or optionally substituted phenyl.
  • More suitable configurations for Q include phenyl which is substituted in one of the meta positions with 3-methoxy-propoxy and/or in the para position with pyridyl, thienyl or furyl or with optionally substituted phenyl, such as p-fluorophenyl.
  • the group W is bonded either directly to the amide nitrogen, i.e. m is 0, or W is bonded via a methylene or ethylene moiety, i.e. m is 1 or 2 respectively. In favoured embodiments of the invention W is bonded via a methylene moiety, i.e. m is 1.
  • W is Ci-C ⁇ alkyl, C 3 -Cycycloalkyl, aryl or heterocyclyl which is optionally substituted with one, two or three substituents.
  • W is an optionally substituted mono or bicyclic aryl moiety such as phenyl or naphthyl, preferably optionally substituted phenyl.
  • W is an optionally substituted mono- or bicyclic ring containing 1 , 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulphur.
  • Representative monocyclic rings according to this embodiment include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like
  • representative bicyclic rings include quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the mono and bicyclic rings is optionally substituted.
  • W is unsubstituted C3-C7 cycloalkyl, such as cyclopropyl.
  • a C3-C7 cycloalkyl W can be substituted, for example with fluoro, methyl or methoxy;
  • W is a monocyclic 5- or 6-membered ring.
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • W is optionally substituted phenyl.
  • W is phenyl which is substituted with fluoro chloro, methyl or cyano and the substituent is preferably in the para position.
  • the substituents are preferably in the two meta positions or in the meta and para positions.
  • Preferred optional substituents to W include one or two substituents independently selected form halo such as fluoro or chloro; C 3 -Cycycloalkyl such as cyclopropyl; haloCi-Csalkyl such as fluoromethyl and trifluoromethyl; Ci-C ⁇ alkyl such as methyl, ethyl and isopropyl.
  • halo such as fluoro or chloro
  • C 3 -Cycycloalkyl such as cyclopropyl
  • haloCi-Csalkyl such as fluoromethyl and trifluoromethyl
  • Ci-C ⁇ alkyl such as methyl, ethyl and isopropyl.
  • 'd-dalkyl' as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl. Methyl is typically preferred in many applications.
  • Ci-C 4 alkyl radicals encompasses Ci-C 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl- 1 -butyl, 2-methyl- 1-pentyl, 2-ethyl-l -butyl, 3-methyl-2-pentyl, and the like.
  • Ci-C ⁇ alkyl is Ci-C 4 alkyl.
  • C 2 -C 6 alkenyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1-propenyl, 2- propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like.
  • C 2 -Cealkenyl is C 2 -C 4 alkenyl.
  • C 2 -C 6 alkynyl' as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 2 -Cealkynyl is C 2 -C 4 alkynyl.
  • 'C 0 -C 3 alkanediyr defines a bond (Co) or a bivalent straight or branched saturated hydrocarbon chain having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1 ,2-propanediyl, and the like, especially methylene.
  • 'C 2 -C 3 alkenediyr defines a bivalent straight or branched hydrocarbon chain having one double bond and having 2 or 3 carbon atoms such as, for example, ethenylene, 1,3-propenediyl, 1 ,2-propenediyl, and the like, especially vinylene.
  • 'C 2 -C 3 alkynediyr defines a bivalent hydrocarbon chain having 2 or 3 carbon atoms and a triple bond, i.e. ethynylene and propynylene.
  • Ci-C ⁇ alkoxy of interest include but are not limited to methoxy, ethoxy, n-propoxy and isopropoxy.
  • Ci-C4-alkoxy or Co-C3-alkoxy has the corresponding definition, adjusted as necessary for C number.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • the term 'haloCi-C4alkyl' as a group or part of a group, is meant to include mono- and polyhalo substituted Ci-C4alkyl, in particular Ci-C4alkyl substituted with one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Preferred is trifluoromethyl.
  • the halogen atoms may be the same or different.
  • the carbon atom to which the oxo is linked is a saturated carbon.
  • Ci-C ⁇ alkyl as a group or part of a group, unless the context suggests otherwise, includes NH 2 , NHCi-C ⁇ alkyl or N(Ci-C6-alkyl)2, wherein in the amino definitions each Ci-C ⁇ alkyl is especially Ci-C4alkyl variants. Included are also radicals wherein the two Ci-C ⁇ alkyl groups of the N(Ci-C6-alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholniyl.
  • 'Co-C 3 alkanediylaryl' as applied herein is meant to include an aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a C 5 - C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above.
  • aryl moiety such as a phenyl or naphthyl or a phenyl fused to a Cs-C ⁇ cycloalkyl (for example indanyl), or a C 5 - C ⁇ cycloalkenyl which aryl is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanedi
  • Suitable aryl groups include but are not limited to phenyl, naphtyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C4alkyl, C 1 - C 4 alkoxy, C 3 -C 7 cycloalkyl, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi- C4alkoxyCo-C3alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co- Csalkanediylaryl, Co-C 3 alkanediylheteroaryl,
  • 'C 2 -C 3 alkenediylaryl and 'C 2 -C 3 alkynediylaryl have the corresponding meanings, adjusted just for the link to the aryl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • 'Co-C3alkanediylheterocyclyl' as applied herein is meant to include a 5-6 membered saturated, partly unsaturated or unsaturated heterocyclic ring containing 1 to 3 heteroatoms each independently selected from nitrogen, oxygen and sulphur, the ring being optionally fused with a benzene ring.
  • heterocyclyl groups include but are not limited to pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, thiazolidinyl, thiadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, azetidinyl, piperidinyl,
  • the ring system is optionally substituted with one, two or where valence allows three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 3 -Cycycloalkyl, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi-C 4 alkoxyCo-C 3 alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, Co ⁇ alkanediylaryl, Co-C 3 alkanediylheteroaryl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co
  • 'Heterocyclyl' has the corresponding meaning, i.e. where the Co-C3alkanediyl linkage is absent.
  • 'C 2 -C 3 a lkenediylheterocyclyl and 'C 2 -C 3 alkynediylheterocyclyl have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C 3 alkenediyl' and 'C 2 -C 3 alkynediyl
  • aryl and heterocyclyl moieties within the scope of the above definitions are thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6 membered ring fused to a 5 or 6 membered ring.
  • heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • Cycloalkyl' as applied herein is meant to include a C 3 -Cycycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which is directly bonded (i.e. Co) or through an intermediate methylene, ethylene, 1 ,2-propanediyl or 1,3-propanediyl group as defined for Ci-C3alkanediyl above.
  • the cycloalkyl group may contain an unsaturated bond.
  • the cycloalkyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, C 1 - C 4 alkyl, Ci-C 4 alkoxy, haloCi-C 4 alkyl, Ci-C 4 alkoxyCi-C 4 alkyl, Ci-C ⁇ alkanoyl, amino, amido, carbamoyl, azido, oxo, mercapto, nitro Co ⁇ alkanediylaryl, Co ⁇ alkanediylheterocyclyl, it being understood that heterocyclic and carbocyclic moieties in the Co-C3alkanediylaryl or Co- C3alkanediylheterocyclyl substituent may itself be substituted as provided herein but typically not with a further Co-C 3 alkanediylaryl or Co-C 3 alkanediylheterocyclyl. 'C 3 Cv
  • 'C 2 -C 3 alkenediylcarbocyclyl and 'C 2 -C 3 alkynediylcarbocyclyl have the corresponding meanings, adjusted just for the link to the carbocyclyl moiety as defined for 'C 2 -C 3 alkenediyr and 'C 2 -C 3 alkynediyl
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1- pentyl, 2-pentyl and 3-pentyl.
  • each definition is independent.
  • the term 'compounds of formula (I)', or 'the present compounds' or similar terms it is meant to include the compounds of formula (I), their prodrugs, TV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
  • prodrug' as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy and/or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydro lysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, Cs-CscycloalkoxycarbonyloxyCi- C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-C ⁇ alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)- N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric acids and the like; or organic acids such as, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, / ⁇ -aminosalicylic, pamoic acids and the like.
  • Acid addition salt forms can be converted to the free base form by treatment with an appropriate base.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) or any of the subgroups of compounds of formula (I), as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates and the like.
  • 'quaternary amine' as used above and hereinafter defines the quaternary ammonium salts which the compounds of formula (I) or any of the subgroups of compounds of formula (I), are able to form by reaction between a basic nitrogen of a compound of formula (I) or any of the subgroups of compounds of formula (I), and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called iV-oxide.
  • the compounds according to the invention may contain one or more asymmetrically substituted carbon atoms, asymmetric or chiral centre.
  • the presence of one or more of these asymmetric centres in compounds according to the invention can give rise to stereochemically isomeric forms, stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, both in pure form and mixed with each others, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
  • stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates.
  • the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by application of art-known procedures (cf. Advanced Organic Chemistry: 3rd Edition: author J March, pp 104-107).
  • enantiomers may be separated from each other using known procedures including, for example, formation of diastereomeric mixtures by reaction with a convenient optically active auxiliary species followed by separation of the diastereomers, using for instance selective crystallisation, and finally cleavage of the auxiliary species.
  • optically active auxiliary species are optically active acids and bases such as tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the compound will preferably be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I) may have metal binding, chelating or complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • the invention relates to the compounds of formula (I) or any subgroup of compounds of formula (I) per se, the prodrugs, iV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the iV-oxides, salts, as the possible stereoisomeric forms thereof.
  • the invention further relates to methods for the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I), the prodrugs, JV-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, its intermediates, and the use of the intermediates in the preparation of the compounds of formula (I) or any subgroup of compounds of formula (I).
  • the invention also relates to the use of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof, for the manufacture of a medicament.
  • the invention relates to the use of a of a compound of formula (I) or any subgroup of compounds of formula (I), or a prodrug, iV-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form thereof in therapy.
  • the term 'therapy' also includes 'prophylaxis' unless there are specific indications to the contrary.
  • the terms 'therapeutic' and 'therapeutically' should be construed accordingly.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of any of the subgroups of formula (I) or a pharmaceutically acceptable salt thereof as specified herein, and a pharmaceutically acceptable adjuvant, diluent or carrier for administration to a subject in need thereof.
  • a therapeutically effective amount in this context is an amount sufficient to act in a prophylactic way against, to stabilize or to reduce adverse conditions associated with RAS activity, such as or related to hypertension, heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, in affected subjects or subjects being at risk of being affected.
  • the invention further relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable adjuvant, diluent or carrier with a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) as specified herein, or a pharmaceutically acceptable salt or a solvate, prodrug, N-oxide, quaternary amine, metal complex or stereochemically isomeric form thereof as specified herein.
  • the compounds of formula (I) or any of the subgroups of formula (I) have enzyme inhibiting properties and are modulators of the renin-angiotensin system, in particular they are inhibitors of the natural enzyme renin and may be used in the treatment and/or prophylaxis of diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other
  • the invention relates to a method for the treatment and/or prophylaxis of diseases or conditions which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or profylaxis of the above mentioned diseases, said method comprising administering to a patient a pharmaceutically active amount of a compound of formula (I) or any of the subgroups of formula (I).
  • the invention further provides a method of treating a disease or condition known to be related to the renin- angiotensin system which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, a solvate, prodrug, iV-oxide, quaternary amine, metal complex, or stereochemically isomeric form thereof, as hereinbefore defined.
  • the invention also provides a method of treating diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • diseases or conditions such as or related to the above mentioned (e.g. hypertension) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or any of the subgroups of formula (I) or a pharmaceutically acceptable salt, or solvate thereof as hereinbefore defined.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of formula I/salt/so lvate (active ingredient) may be in the range from 0.001 mg/kg to 75 mg/kg, in particular from 0.5 mg/kg to 30 mg/kg. This daily dose may be given in divided doses as necessary.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • DMPK parameters of the compounds of the invention are measured by conventional assays.
  • the advantageously high permeability of the invention can be assayed in the Caco-2 cell line which is commercially available and widely used in the literature.
  • the advantageosuly high bioavailability can be assayed by conventional oral dosing in appropriate animal models such as rat or cynomolgus, followed by blood sampling (measured by MS) at defined time intervals to monitor the apperance of the compounds, ie absorption.
  • Absolute bioavailability is measured in the conventional manner by reference to the time course/ AUC of an IV or IP dose of the compound, typically at 1/10 th the dose.
  • the advantageously low hepatic and other metabolism can be gauged with commercially available hepatocytes, such as XEN-025 or 1037.
  • the advantageously low P450 metabolism is measured with supersomes (Gentest Corp, USA) that is baculovirus infected insect cells transfected with human P450 iso forms, including CYP 1A2, CYP2A6, CYP2C9-Arg 144, CYP219, CYP2D6Val 374 and CYP34A, typically with P450 reductase, whereby th involvement of a given iso form in the metabolism of the test compound is determinted by UV HPLC or MS.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, iV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • the oral delivery route, particularly capsules or tablets is favoured.
  • composition of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • a representative example are other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • beta- adrenergic antagonists alpha-adrenergic antagonists
  • Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the isopropylidene derivative (Ia) achieved for example as described in Tetrahedron Lett., 1987, 28, 1143, can be transferred into the methyl glycoside (Ib) by acidic hydrolysis of the acetal group effected by treatment with a suitable acid such as sulphuric acid, in the presence of methanol.
  • the achieved free secondary hydroxy group can then be reductively removed effected for instance by transformation of the hydroxy group into a thiocarbonyl group by reaction with thiocarbonyl diimidazole (TCDI) followed by reduction of the formed thiocarbonyl group using for instance conditions such as tributyltin hydride the presence of a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like to give the 2,3-dideoxy glycoside (Ic).
  • a radical initiator like azobis-(2-methylpropyonitrile) (AIBN) or the like
  • Ic 2,3-dideoxy glycoside
  • Oxidative cleavage of the methyl ether performed for example by oxidation with m-chloroperbensoesyra or the like in the presence of BF3-etherate, gives the lactone (Id).
  • the ring substituent R 3 can then be introduced for example by treatment of the lactone with a base such as LDA or equivalent followed by reaction with a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like, thus providing the ⁇ -alkylated lactone (Ie).
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like
  • a suitable alkylating agent such as an alkyl halide like an alkyl bromide or alkyl iodide or a derivative of sulphonic acid such as a mesylate, triflate or tosylate or the like
  • the primary hydroxy group of the lactone (If) can be selectively alkylated for example by activation of the hydroxy group with dibutyltinoxide followed by reaction with a desired alkylating agent Q-(CH 2 ) D -Lg wherein Lg is a suitable leaving group such as a halide like bromide or iodide in the presence of tetrabutylammonium bromide or the like thus forming the ether derivative (2a).
  • the substituent Q-(CH 2 )D can be introduced by using the Mitsunobu conditions (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al, Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706) i.e. reaction of the alcohol (If) with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine followed by displacement with a desired alcohol.
  • Replacement of the hydroxy group of the secondary alcohol (2a) by azide may then be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b).
  • a leaving group for example a derivative of sulphonic acid like a triflate or tosylate or the like
  • sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (2b).
  • the azide moiety can be introduced by treatment of the alcohol with diisopropyl azodicarboxylate or any other suitable azodicarboxylate, in combination with triphenylphosphine, followed by reaction with azide for example DPPA, in a solvent like THF.
  • the linear amino compound (2e) can then be achieved by opening of the lactone with a desired amino derivative (2c) in the presence of a coupling agent for example 2-hydroxypyridine and a base like isopropyl diethylamine.
  • Reduction of the azide using conditions compatible with the (CH 2 ) n -Q group, for example hydrogenation at atmospheric pressure in the presence of Lindlar Catalyst or equivalent.
  • an alkylating agent R 1 -Lg wherein Lg is a leaving group such a halide like chloride, bromide or iodide or a derivative of sulphonic acid such as a mesylate or a triflate or the like, optionally in the presence of a base, or alternatively an N- substituent may be introduced by reaction with an al
  • Lactones useful for the synthesis of compounds of formula (I) wherein Z is S or NH and n is 1 or 2 can be prepared from the diol If for example by a Mitsunobu reaction with a thiol or amino derivative respectively, as illustrated in scheme 2B.
  • the primary hydroxy group of the lactone (If) can be converted to a thioether or an amine for example by transforming it into a leaving group followed by displacement of the formed leaving group with the desired group Q-(CH 2 )D-S or Q-(CH 2 )D-NRa.
  • a convenient method to effect this transformation is by way of a Mitsunobu reaction, i.e. reaction of the hydroxy group with an azodicarboxylate such as DIAD or the like in the presence of triphenylphosphine or the like followed by displacement with a desired thiol or amine to provide the thioether (2Ba) or the amine derivative (2Bb) respectively.
  • an azide derivative such as sodium azide or DPPA in the Mitsunobu reaction with the alcohol (If)
  • a further alternative to obtain the amino derivative (2Bb) is to selectively oxidize the primary hydroxy group of the alcohol (If) to the corresponding aldehyde, effected for example by treatment with Dess-Martin periodinane or by any other suitable oxidation reagent, followed by a reductive amination with the desired amino derivative Q-(CH 2 ) n -NHRa in the presence of a reducing agent like NaCNBH 3 . Replacement of the secondary hydroxy group with azide, opening of the lactone and finally reduction of the azide as described above, then provides the linear compounds (2Bc and 2Bd).
  • Compounds wherein the group Q is linked directly to a sulphur or nitrogen atom i.e. an intermediate for the preparation of compounds of formula (I) wherein Z is S or NRa and n is O, may be prepared by transformation of the primary hydroxy group of the diol (If) into a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloromethane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with a desired thiol Q-SH or a amine Q-NHRa optionally in the presence of a base.
  • a leaving group such as a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like
  • An alternative method for the preparation of compounds wherein Z is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Compounds wherein Z is NRa and n is 0 may alternatively be achieved by oxidation of the primary hydroxy group of the diol (If) followed by a reductive amination with a desired aniline derivative Q-NRa in the presence of a suitable catalyst like NaCNBH 4 or the like.
  • the oxidation can be performed either at the last step of the synthesis or on any suitable intermediate.
  • Many suitable methods for this oxidation are described in the literature for example a peroxyacid such as AcOOH, mCPBA can be used.
  • Amino derivatives (2c) to be used for the opening of the lactone in the scheme 2 above are commercially available or they can be prepared by the skilled person according to literature procedures.
  • an amino derivative useful for the preparation of compounds of formula (I) wherein Y is NH can be prepared from a suitably protected amino acid carrying the desired side chain R 4 R 4 , as illustrated in scheme 3.
  • the amino acid (3a), carrying the desired side chain R 4 R 4 can be coupled to the amine W- (CH 2 )Hi-NH 2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloroformate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used thus providing the amide.
  • DIEA ethyldiisopropylamine
  • N-methylmorpholine in a solvent like dimethyl formamide
  • amino derivatives useful for the preparation of compounds of general formula (I) wherein Y is S can be prepared by transforming the amino acid (3 a) into an activated acid derivative such as the acid chloride or an activated ester such as the p-nitrophenyl ester or pentafluoroester, followed by reaction with a desired thio derivative SH-(CH 2 ) m -W.
  • activated acids and esters are well known to a person skilled in the field of organic synthesis and are exensively described in the literature.
  • the acid chloride can be prepared by treatment of the acid with POCI3 or phosgene or the like in the presence of a base like pyridine.
  • the azide derivative (4a), prepared for example as outlined in scheme 2, wherein Pg 1 is a hydroxy protecting group for example a benzyl group can be transformed to the corresponding amine by reduction of the azide group using any convenient reduction method such as hydrogenation in the presence of a suitable catalyst, such as Lindlars catalyst or the like in the presence of BoC 2 O to provide the boc protected derivative (4b). Protection of the secondary hydroxy group, using a protecting group (Pg 2 ) which is orthogonal to the one used for the primary hydroxy group (Pg 1 ), followed by removal of the primary hydroxy protecting group using the appropriate conditions according to the group used, such as for example catalytic hydrogenation in the case of a benzyl group provides the primary alcohol (4c).
  • a protecting group Pg 2
  • Suitable protecting groups for the above route will be recognized by the skilled person and a numerous of useful protecting groups are described in Greene "Protective Groups in Organic Synthesis", John Wiley and sons, New York (1981).
  • benzyl can be used as Pg 1 and acetyl as Pg 2 .
  • the group (CH 2 ) n -Q can then be introduced as described above.
  • Trichloroacetimidates are conveniently prepared by reaction of the corresponding alcohol with trichloroacetonitrile in the presence of a base like NaH.
  • Z' in scheme 4 is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (4c) with a desired alcohol, Q-(CH 2 ) n -OH, thiol, Q-(CH 2 ) n -SH or amine Q-(CH 2 ) n -NHRa respectively as described above.
  • Z' is S or NRa
  • a leaving group for example a derivative of sulphonic acid such as a triflate, tosylate or the like which subsequently is displaced by a with a desired thiol Q-(CH 2 ) n -SH or amine Q-(CH 2 ) n-NHRa optionally in the presence of a base.
  • An alternative method for the preparation of compounds wherein Z' is S and n is 0 is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • Substituted phenyl and heteroaryl derivatives Q-(CH 2 ) n - used in the schemes above are commercially available or they may be prepared according to literature procedures.
  • a method to prepare a substituted phenyl derivative useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with aminomethyl or amidomethyl and derivatives thereof is illustrated in scheme 5.
  • the hydroxy protected cyanobenzyl derivative (5 a) can be prepared by protection of commercially available cyanobenzyl alcohol, illustrated herein as 3 -cyanobenzyl alcohol, with a suitable protecting group, for example a trityl or monomethoxy trityl group using standard conditions well known in the art.
  • R 5 is H can be achieved by direct reduction of the cyano group to the methyl amino group using for instance LAH or diborane or the like, followed by protection of the afforded primary amine as previously described. Removal of the hydroxy protecting group using standard conditions such as treatment with acid in the case of trityl or monomethoxy trityl group provides the alcohol (5c). The afforded alcohol (5c) can then be used in the coupling to the primary alcohol of the lactone Ig or the linear compound 4c employing for example the Mitsunobu conditions as described in scheme 2 and 4 respectively.
  • the hydroxy group of the alcohol (5 c) can be transformed into a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromo derivative (5d), or the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence of a base for example pyridine. Subsequently, the afforded compound can be coupled to the primary alcohol of the lactone If or the linear compound 4c as described in scheme 2 and 4 respectively.
  • a leaving group such as a bromide for example by treatment with bromine or carbontetrabromide in the presence of triphenylphosphine or the like thus affording the bromo derivative (5d)
  • a suitable sulphonylating agent such as a sulphonic halide or anhydride optionally in the presence
  • Scheme 6 illustrates an example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) wherein Q is phenyl which is substituted with an alkoxy-alkoxy group.
  • Q' is aryl, heteroaryl or an unsaturated group
  • Suitable reactions that can be used for the introduction of the substituent Q' are for instance the Stille reaction, wherein a tin derivative, such as a trialkyltin derivative, of the desired group Q' is reacted with the bromo derivative 6Ac in the presence of Pd(O), or the Heck coupling reaction wherein the bromo derivative 6Ac is reacted with a double bond of the desired group Q' in the presence of a Pd catalyst such as Pd(PPtLs) 4 PdCl 2 or Pd(OAc) 2 and a base such as triethylamine, potassium carbonate or the like.
  • a Pd catalyst such as Pd(PPtLs) 4 PdCl 2 or Pd(OAc) 2
  • a base such as triethylamine, potassium carbonate or the like.
  • Scheme 7 shows an alternative route to compounds of the invention, starting from Garner's aldehyde.
  • the group Q-(CH 2 ) n can then be introduced using any suitable method such as any of those described above. For example, a trichloroimidate of the desired group Q-(CH 2 ) n in the presence of TMS triflate will provide the ether derivative (7f) i.e. Z' is O.
  • the lactone may then be opened either directly with a desired amine as described above to give the amide (7h), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (7g). Protection of the hydroxy group, using any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group, followed by coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethylamine, and finally removal of the hydroxy protecting group provide the amide (7h).
  • any conventional protecting group for example a silyl group such as a tert-butyl dimethylsilyl group
  • coupling of the acid to a suitable amine using standard peptide coupling conditions such as using a coupling agent like EDAC in the presence of HOBt and a tertiary amine like triethyl
  • the hydroxy group of compound (4a) can be replaced by two fluoro atoms by oxidizing the hydroxy group to a keto group using any convenient method such as using a reagent like Dess Martin periodinane or oxone® (potassium monopersulphate triple salt) or any other suitable oxidizing agent, followed by treatment of the afforded keto compound with a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable fluorinating conditions, yields the difluoro compound (8a).
  • a fluorinating agent like DAST or Deoxofluor or the like in a solvent like dichloromethane as described e.g. by Singh, R. P. and Shreve, J. M. in Synthesis, 17, 1999, p. 2561-2578, or any other suitable flu
  • the monofluoro compound (8c) with the desired stereochemistry can be obtained by first inverting the stereochemistry at the steric centre whereto the hydroxy group is attached which can be performed for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and reagents like DIAD and PI13P followed by hydrolysis of the afforded p-nitrobenzoic ester by treatment with sodium methoxide or the like, and then subject the afforded inverted alcohol to fluorinating conditions such as treatment with DAST or deoxofluor as described above.
  • scheme 8 illustrates the replacement of the hydroxy group with fluoro or difluoro as the last step of the synthesis, the skilled person will realise that this transformation alternatively may be performed at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • RV is R1 or an N-protecting group
  • the configuration of compound (9a), prepared as described above has to be inverted, for example as described in scheme 8.
  • the inverted alcohol (9b) can then be subjected to Mitsunobu conditions, i.e.
  • the azido derivative (9c) can be achieved by transformation of the hydroxy group to a derivative of sulphonic acid like a mesylate, triflate, tosylate or the like by treatment with the appropriate sulphonylating agent in a solvent like for instance pyridine or dichloro methane optionally in the presence of triethylamine or the like, followed by displacement of the leaving group with sodium azide or the like.
  • Reduction of the azide using any conventional reduction method such as hydrogenation in the presence of a suitable catalyst, or treatment with triphenylphosphine provides the corresponding amine (9d)
  • scheme 9 illustrates the conversion of the hydroxy group to an amine as the last step of the synthesis, the skilled person will realise that this transformation is also applicable at any other suitable stage of the synthesis for example on any of the intermediates described above.
  • any functional groups present on any of the constituent compounds used in the preparation of the compounds of the invention are appropriately protected where necessary.
  • functionalities on the natural or non-natural amino acids are typically protected as is appropriate in peptide synthesis.
  • Suitable protecting groups are described in Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) and “The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosure of which are hereby incorporated by reference.
  • reaction mixture was cooled to 0 0 C and lithium aluminium hydride (450 mg) was added as a slurry in THF (18 ml), and the suspension was stirred at r.t. for Ih and then refluxed for 1 h.
  • the reaction mixture was cooled to 0 0 C and water (0.55 ml), 10%NaOH (0.55 ml) and water (1,84 ml) were added successively.
  • the resulting suspension was filtered through Celite, and the solid was washed with THF and DCM. The filtrate was evaporated and the residue partitioned between DCM and water.
  • the organic extract was dried by sodium sulfate and then evaporated.
  • Triflic anhydride (224 ⁇ l) dissolved in DCM (1.2 ml) was added dropwise under nitrogen to a stirred DCM (5.8 ml) solution cooled at 0 0 C of the alcohol 1Oe (281 mg, 0.67 mmol) and pyridine (0.16 ml). The mixture was stirred at 0 0 C for 1 h. The mixture was poured into a chilled 5% NaHSO 4 solution and extracted with DCM. The organic extract was dried through sodium sulfate and evaporated on rotavapor below r.t.
  • N,N-diisopropylethyl amine (36 ml, 200 mmol) in dichloromethane (5 ml) was then added to the reaction mixture -45 0 C during 30 min whereafter the reaction mixture was allowed to warm to 0 0 C during 10 min.
  • the reaction mixture was then transferred to a separation funnel charged with ice-cold 1 M HCl solution (130 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried and concentrated which gave the title compound (7.89 g, 99%). The residue was used in the next step without further purification.
  • the isopropyl lactone 12g (204 mg, 0.624 mmol) was treated with TFA - H 2 O (5 ml, 9:1), stirred at room temperature for 1 h, and then concentrated under vacuum. The residue was dissolved in a mixture of dioxane and a 10% solution of sodium carbonate (10 ml, 1 :1, pH ⁇ 8). BoC 2 O (204 mg, 0.936 mmol) was added in portions and the mixture was stirred at room temperature for 2 h. Dioxane was then removed under vacuum and the aqueous phase was extracted with dichloro methane, dried and concentrated.
  • N-Methylmorpholine (3 eq) and isobutylchloro formate (1 eq) was added to a stirred solution of Boc-valine (40 mg) in THF (ImI) at -15 0 C was.
  • the reaction was stirred at -15 0 C for one minute and then the appropriate amino derivative (1 eq) was added as a solution in DMF (ImI).
  • the reaction was then warmed to room temperature during a period of 30 min.
  • the solution was diluted with ethyl acetate and washed with sat. NaHCOs (aq) and concentrated in vacuo.
  • the residue was taken up in a solution of ImI 4M HCl in dioxane, stirred for one hour and then concentrated in vacuo to give the HCl salt of the amine.
  • the title compound was prepared according to general Method A, using 4-chloro benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using 4-methoxy benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using 3,4-dichloro benzylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using C-pyridin-3-yl- methylamine as amino derivative in step a.
  • the title compound was prepared according to general Method A, using C-pyridin-4-yl- methylamine as amino derivative in step a.
  • Azodicarboxylic acid dipiperidide (505 mg, 2 mmol) and PPh 3 (524 mg, 2 mmol) were added to a solution of 23a (166 mg, 1 mmol) and 3-methoxypropan-l-ol (95.7 ⁇ l, 1 mmol) in CH 2 Cl 2 (10 ml) and the resulting mixture was stirred under N 2 for 17 h. The reaction mixture was then concentrated under vacuum and the residue was taken into EtOAc and washed with 10% aq. citric acid and brine. The organic phase was dried (Na 2 SO 4 ) and the solvent evaporated to give the crude product that was purified by flash chromatography on silica gel (Hex:EtOAc 10:1) to give 96 mg (40%) of the title compound.
  • Trifluoro-methanesulfonic acid 1 (4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-2-[3-(3-methoxy- propoxy)-4-methyl-benzyloxy]-ethyl ester (28a)
  • Example 30 The procedure described in Example 30 was followed but using thiazole-4-carbaldehyde instead of acetaldehyde, which gave the title compound (40% yield).
  • Example 8 The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (24% yield).
  • Example 8 The procedure described in Example 8 was followed but using 4-pyridinecarboxaldehyde instead of acetone, which gave the title compound (19% yield).
  • Example 30 The procedure described in Example 30 was followed but using 3-pyridinecarboxaldehyde instead of acetaldehyde, which gave the title compound (45% yield).
  • Example 30 The procedure described in Example 30 was followed but using thiazole-2-carbaldehyde instead of acetaldehyde, which gave the title compound (10% yield).
  • Triphenylphosphine (5.25 g, 20 mmol) and azodicarboxylic dipiperidine (5.04, 20 mmol) were added to a solution of 2-chloro-5-methyl-phenol (1.43 g, 10 mmol) and 3-methoxy- propan-1-ol (1 mL, 10 mmol) in CH 2 Cl 2 (100 mL).
  • the reaction mixture was stirred at r.t. 16 h and the evaporated into SiO 2 gel.
  • the title compound was purified by flash chromatography on silica gel (Hep:EtOAc 20:1) to give 2.0 g (80%).
  • N-Bromosuccinimide (284 mg, 1.6 mmol) and benzoyl peroxide (11 mg, 0.034 mmol) were added to a solution of 37a in CCU (6 mL) and the resulting suspension was refluxed for 1 h.
  • the reaction mixture was filtered through SiO 2 using Hep: EtOAc 10:1 as eluent. Evaporation of the solvent afforded 304 mg of the title compound (78% yield).
  • Methanesulfonyl chloride (0.47 mL, 6.07 mmol) was added to a solution of 40a (Ig, 6.06 mmol) and pyridine (1 mL, 12.4 mmol) in CH 2 Cl 2 (6 mL) at 5 0 C. The reaction mixture was then stirred at r.t. for 17 h. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel (Hep:EtOAc 2.5:1) to give 1.1 g (75%) of the title compound.
  • Triphenylphosphine (2.66 g, 10.16 mmol) and azodicarboxylic dipiperidine (2.56, 10.16 mmol) were added to a solution of 46a (1.0 g, 5.08 mmol) and 3-ethoxypropan-l-ol (0.59 mL, 5.08 mmol) in CH 2 Cl 2 (25 mL).
  • the reaction mixture was stirred at r.t. 16 h and then evaporated into SiO 2 gel.
  • the residue was purified by flash chromatography on silica gel (Hep:EtOAc 20:1 to 2.5:1) to give title compound 0.70 g (49%).
  • Example 30 The procedure described in Example 30 was followed but using lH-Indole-3-carbaldehyde instead of acetaldehyde, which gave the title compound (27% yield).
  • step g The procedure described in example 1 step g was followed but using 4-fluorobenzylamine instead of benzylamine, which gave the title compound in a yield of 78%.
  • Triphenylphosphine (0.44 g, 1.7 mmol) was dissolved in DCM (10 ml). Bromine (85 ⁇ l, 1.7 mmol) was added and the reaction mixture stirred for 5 min and then the obtained solution was added to [4-ethyl-3-(3-methoxy-propoxy)-phenyl] methanol (0.4 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue purified on silica gel using hexanes 9 and ethyl acetate 1 as eluent to give 0.45 (87%) of the title compound. LC/MS confirmed the correct structure with characteristic double peaks at 289 (M+l) and 306 (M+NH 4 ).
  • step g The procedure described in example 1 step g was followed but using 4-(2-aminoethyl)- morpholine instead of benzylamine, which gave the title compound (65%).
  • Example 1 step h The procedure described in Example 1 step h was followed but using the bromide 23 d instead of benzyl bromide, whereafter the procedure described in Example 1 step i was followed, which gave the title compound (35%).
  • the lactone 60b was opened with the amine 48a according to the procedure described in
  • Example 49 step h whereafter the azide function was reduced according to the procedure described in Example 49 step i, which gave the title compound (63%)
  • the methyl ester 61b (0.73 g, 3.01 mmol) was dissolved in heptane (10 mL) and the solution was cooled to 0 0 C and stirred. DIBAL-H (9.0 mL of a 1.0 M solution in hexane, 9.0 mmol) was added dropwise. The reaction was quenched after 30 min by careful dropwise addition of 3 M HCl (10 niL). The mixture was diluted with Et 2 O (40 mL) and 1 M HCl (20 niL) and the layers were separated.
  • Example 1 step h The procedure described in Example 1 step h was followed but using 4-bromomethyl-l- fluoro-2-(3-methoxy-propoxy)-benzene (0.50 g, 1.80 mmol) instead of benzyl bromide, which gave 0.60 g (96%) of the title compound after column chromatography (elution with hexanes/ethyl acetate 10:1 - 2:1 with 1% MeOH throughout).
  • the lactone 6If (102 mg, 0.249 mmol), amine 48a (238 mg, 1.00 mmol), 2-hydroxypyridine (95 mg, 1.00 mmol) and DIPEA (48 ⁇ L, 0.275 mmol) were stirred and heated to 70 0 C for 3 days.
  • the mixture was cooled to room temperature and 3 mL of t-BuOMe was added to yield a brown suspension which was heated to 50 0 C and sonicated for 5 min, then centrifuged at 3500 rpm at 7 0 C for 12 min after which the supernatant was siphoned off. This process was repeated thrice to yield the title compound after drying in vacuo (55 mg, 34%).
  • Example 61 step d The procedure described in Example 61 step d was followed using benzyl alcohol 62a (2.60 g, 9.45 mmol) instead of 61c to yield the title compound (2.62 g, 82%) after purification by column chromatography (gradient elution with hexanes/ethyl acetate 30:1 - 1 :1).
  • Example 61 step g The procedure described in Example 61 step g was followed using lactone 62d (90 mg, 0.19 mmol) instead of 6 If.
  • the product was purified by sonication, centrifugation and siphoning off the supernatant as described in Example 1 step g using 1 mL of MeOH, t-BuOMe, MeCN, and t-Bu OMe in sequence which gave 36 mg (27%) of the title compound.
  • the product was purified by column chromatography (gradient elution from 100% DCM to

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Abstract

L'invention porte sur des composés représentés par la formule I dans laquelle Q représente aryle ou hétérocyclyle, chacun étant facultativement substitué; Z représente O, S, Nra ou S(=O)p; Y représente NH, NHNH, CH2NH, O, S ou S(=O)p; n vaut 0, 1, 2 ou 3; m vaut 0, 1 ou 2; p vaut 1 ou 2; Ra représente H ou un alkyle en C1-C4; R1 représente l'hydrogène, alkyle en C1-C6, alcanediyl en C0-C3-cycloalkyle en C3-C7, alcanediyl en C0-C3-aryle ou alcanediyl en C0-C3-hétérocyclyle; R2 représente hydrogène ou alkyle en C1-C6; X' représente hydrogène, fluoro, hydroxy, amino ou alcoxy en C1-C6; X' représente hydrogène, ou lorsque X' représente fluoro, X' peut également représenter fluoro; R3 représente alkyle en C1-C6; R4' représente alkyle en C1-C6; R4' représente H ou alkyle en C1-C6; ou R4' et R4' conjointement avec l'atome de carbone auquel ils sont attachés définissent un cycloalkyle en C3-C6; W représente alkyle en C1-C6, cycloalkyle en C3-C7, aryle ou hétérocyclyle, chacun étant facultativement substitué; ou un sel, hydrate ou N-oxyde pharmaceutiquement acceptable de ces composés. Les composés de l'invention sont des inhibiteurs des aspartyl protéases telles que la rénine et sont entre autres utiles pour le traitement d'états associés à des activités du système rénine-angiotensine (RAS), telles que l'hypertension, l'insuffisance cardiaque et l'insuffisance rénale.
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WO2010024772A1 (fr) * 2008-08-29 2010-03-04 Medivir Ab Inhibiteurs d'aspartyl protéases
EP2403839A2 (fr) * 2009-03-06 2012-01-11 The University of North Carolina At Chapel Hill Mimétiques de neurotrophine et leurs utilisations
EP2498782A1 (fr) * 2009-11-12 2012-09-19 Pharmatrophix Inc. Formes cristallines de composés mimétiques de neurotrophines et leurs sels
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts

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Title
S. HANESSIAN ET AL: "Structure.based desigh and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)", JOURNAL OF MEDICINAL CHEMISTRY., vol. 49, no. 15, 2006, USAMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 4544 - 4567, XP002449025 *
SHU-HUI CHEN ET AL: "P3 Cap modified Phe-Ala series BACE inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 1, 2004, GBOXFORD, pages 245 - 250, XP002449033 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
WO2010024772A1 (fr) * 2008-08-29 2010-03-04 Medivir Ab Inhibiteurs d'aspartyl protéases
EP2403839A2 (fr) * 2009-03-06 2012-01-11 The University of North Carolina At Chapel Hill Mimétiques de neurotrophine et leurs utilisations
EP2403839A4 (fr) * 2009-03-06 2014-05-28 Univ North Carolina Mimétiques de neurotrophine et leurs utilisations
EP2498782A1 (fr) * 2009-11-12 2012-09-19 Pharmatrophix Inc. Formes cristallines de composés mimétiques de neurotrophines et leurs sels
EP2498782A4 (fr) * 2009-11-12 2014-03-12 Pharmatrophix Inc Formes cristallines de composés mimétiques de neurotrophines et leurs sels
US9271986B2 (en) 2009-11-12 2016-03-01 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
EP3470402A1 (fr) * 2009-11-12 2019-04-17 Pharmatrophix Inc. Formes cristallines de composés mimétiques de la neurotrophine et leurs sels
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US11225467B2 (en) 2009-11-12 2022-01-18 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts

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