WO2009053277A1 - Inhibiteurs de l'aspartyle protéase - Google Patents

Inhibiteurs de l'aspartyle protéase Download PDF

Info

Publication number
WO2009053277A1
WO2009053277A1 PCT/EP2008/063802 EP2008063802W WO2009053277A1 WO 2009053277 A1 WO2009053277 A1 WO 2009053277A1 EP 2008063802 W EP2008063802 W EP 2008063802W WO 2009053277 A1 WO2009053277 A1 WO 2009053277A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
methyl
hydroxy
mmol
compound according
Prior art date
Application number
PCT/EP2008/063802
Other languages
English (en)
Inventor
Christian Sund
Christer Sahlberg
Oscar Belda
Original Assignee
Medivir Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivir Ab filed Critical Medivir Ab
Publication of WO2009053277A1 publication Critical patent/WO2009053277A1/fr

Links

Classifications

    • 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
    • C07D213/60—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 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07C237/04—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 the carbon skeleton being acyclic and saturated
    • C07C237/06—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 the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C07C237/04—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 the carbon skeleton being acyclic and saturated
    • C07C237/08—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 the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • 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
    • C07C237/04—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 the carbon skeleton being acyclic and saturated
    • C07C237/10—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 the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

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.
  • the renin-angiotensin system is an endocrine system involved in regulation of long-term blood pressure and fluid electrolyte balance in mammals.
  • One of the enzymes involved in the RAS is renin, which 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.
  • the present invention concerns inhibitors of renin which exhibit beneficial potency, selectivity and/or pharmacokinetic properties.
  • renin inhibitors represented by the formula (I):
  • A is selected from the partial structures Al, A2 and A3;
  • Ry and Ry' are both hydrogen, or Ry and Ry' together with the nitrogen atom to which they are attached form a cyclic amine such as morpholine, piperidine, piperazine or pyrrolidine;
  • L is NHNH, CH 2 NH, O or S
  • Q is aryl or heterocyclyl
  • m is 0, 1 or 2;
  • n is 0, 1, 2 or 3;
  • p is independently 1 or 2;
  • q is 0 or 1 ;
  • Ra is H or Ci-C 4 alkyl
  • R 1 is hydrogen, Ci-C ⁇ alkyl, C 3 -CycycloalkylCo-C3alkyl, arylCo-Csalkyl or heterocyclylCo-
  • R 2 is hydrogen or Ci-C ⁇ alkyl
  • X' is hydrogen, fluoro, hydroxy, NRaRb or Ci-C ⁇ alkoxy
  • X" is hydrogen, or when X' is fluoro, then X" may also be fluoro;
  • R 3 is Ci-C 6 alkyl
  • R 4' is Ci-C 6 alkyl
  • R 4 is H or Ci-C ⁇ alkyl; or R 4 and R 4 together with the carbon atom to which they are attached define a Cs-C ⁇ cycloalkyl;
  • W is Ci-C ⁇ alkyl, C 3 -Cycycloalkyl, aryl or heterocyclyl; 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 arylalkyl), unless otherwise specified is optionally substituted with one, two or where valence allows three substituents independently selected from Ci-C4alkyl (optionally substituted with one or two substituents independently selected from aryl*Co-C 3 alkyl, NRaRb, amido and
  • A is selected from the structures Al, A2 and A3 shown below:
  • the invention includes compounds having any of the structures I-Al, I-A2 and I- A3 shown below:
  • 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):
  • R , 3 is Ci-C ⁇ alkyl, preferably ethyl or more preferably isopropyl.
  • R 2 is Ci-C ⁇ alkyl such as methyl or ethyl.
  • R 2 is hydrogen.
  • the chiral centre to which X' and X" are attached has typically the configuration as shown in structure (Ic) below:
  • X' is preferably fluoro, or more preferably hydroxy.
  • X" is preferably hydrogen.
  • a further embodiment of the invention includes compounds of formula (I) or any subgroup of formula (I) wherein X' and X" are both fluoro.
  • H R 4 is d-C ⁇ alkyl, preferably isopropyl or more preferably sec. butyl.
  • R 4 " is preferably hydrogen.
  • R 4 and R 4 together define a spiro-cycloalkyl group, for example cyclopentyl or cyclobutyl or preferably cyclopropyl.
  • compounds are includes wherein A is Al, thus providing compounds of general formula (I-Al):
  • compounds of general formula (I) are included wherein q is 0 or 1, i.e. compounds according to structures (I-Ala) and (I-Alb) respectively.
  • Preferred compounds according to this embodiment are those wherein q is 1, i.e. compounds of formula (I-Alb).
  • Preferred compounds of formula (I) wherein A is Al and q is 0 orl are those having the stereochemistry indicated in the structure of formula (1-AIa') and (1-AIb') respectively:
  • Typical embodiments of the invention where A is Al include compounds wherein q is 0 and Y is NH, NHNH, CH 2 or CH 2 NH, thus giving compounds having the structures shown below:
  • Preferred structures according to these embodiments are those wherein Y is NH, i.e. compounds of formula I-Alc.
  • A is Al
  • Y is NH, NHNH, CH 2 , or CH 2 NH
  • Preferred structures according to these embodiments are those wherein Y is NH, i.e. compounds of formula I-Alg.
  • A is Al
  • Y is O or S
  • compounds are includes wherein A is A2, thus providing compounds of general formula (I-A2):
  • L is NHNH, CH 2 NH, O or S.
  • L is CH 2 NH and more preferably NHNH, thus giving compounds having the structures I-A2a and I-A2b respectively as shown below.
  • compounds of formula I wherein A is A have the stereochemistry as indicated in structure I-A2' below.
  • compounds are includes wherein A is A3, thus providing compounds of general formula (I -A3)
  • compounds are included wherein q is 0 or 1, i.e. compounds having the structures I-A3a and I-A3b respectively.
  • Ry and Ry' together with the nitrogen atom to which they are attached, form a cyclic amine, for example morpholine, piperidine, piperazine or pyrrolidine.
  • Suitable values for R 1 include hydrogen, optionally substituted phenyl, optionally substituted benzyl and optionally substituted Ci-C ⁇ alkyl.
  • R 1 is hydrogen, or optionally substituted Ci-C ⁇ alkyl or benzyl, more preferably R 1 is hydrogen, methyl, ethyl or isopropyl.
  • R 1 is optionally substituted 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 Ci-C 4 alkyl (preferably methyl), Ci-C 4 alkoxy (preferably methoxy), Ci- C4alkoxyCi-C3alkoxyCo-C3alkyl, (preferably methoxypropoxy), cyano or halo (preferably fluoro).
  • 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 Ci-C 4 alkyl (preferably methyl), Ci-C 4 alkoxy (preferably methoxy), Ci- C4alkoxyCi-C3alkoxyCo-C3alkyl, (preferably methoxypropoxy), cyano or halo (preferably fluoro).
  • 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 arylCo-Csalkyl or heterocyclylCo ⁇ alkyl
  • 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.
  • 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-C3alkandiylaryl, NRaRb, amido and C 1 - C4alkoxyamido), C3-Cycycloalkyl, Ci-C4alkoxy, Ci-C4alkoxyCi-C3alkyl, Ci-C4alkoxyCi- C 4 alkoxyCo-C 3 alkyl, halo, haloCi-C 4 alkyl, hydroxy, hydroxyCi-C 4 alkyl, cyano, azido, C 1 - C 4 alkylcarbonyl, NRaRb, amido, a cyclic amine selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl (any of which cyclic amines being optionally substituted with
  • Q is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • the heterocyclyl moiety contain 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • Representative bicyclic rings according to this embodiment include naphthyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl each of which is optionally substituted wherein each of the bicyclic rings is optionally substituted.
  • a typical value for Q is naphthyl or optionally substituted naphthyl.
  • Q is phenyl or 5 or 6-membered heterocyclic ring, any of which is optionally substituted with one two or three substituents.
  • the heterocyclyl moiety contain 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 phenyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like.
  • heterocyclyl groups include 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 substituents independently selected from Ci-C4alkyl (preferably methyl), Ci-C4alkoxy (preferably methoxy), C 1 - C4alkoxyCi-C3alkoxyCo-C3alkyl, (preferably methoxypropoxy) or halo (preferably fluoro or chloro).
  • Ci-C4alkyl preferably methyl
  • Ci-C4alkoxy preferably methoxy
  • C 1 - C4alkoxyCi-C3alkoxyCo-C3alkyl preferably methoxypropoxy
  • halo preferably fluoro or chloro
  • Optional substituents to Q are as defined above. Representative values include Ci-C4alkyl, C3- Cycycloalkyl, Ci-C4alkoxy, Ci-Csalkoxy-Ci-C ⁇ alkoxy, halo, haloCi-C4alkyl.
  • Currently favoured values according to these configurations for the optional substituents to Q include cyclopropyl, methoxy-ethoxy, fluoro, more favoured substituents are chloro, methyl or methoxy-propoxy.
  • Typical Co-C3aryl and Co-Csheterocyclyl include, but are not limited to, phenyl, benzyl, pyrrolyl, pyrrolinyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyrazinyl, morpholinyl and especially furyl, thienyl, thiazolyl and pyridyl.
  • Q is 6-membered ring, which is substituted in one of the meta positions and/or in the para position.
  • Q is meta- or para-substituted phenyl or, preferably, Q is phenyl which is substituted in one of the meta-positions and in the para-position.
  • Suitable configurations for Q include phenyl which is substituted in one of the meta positions with Ci-C4alkoxyCi-C4alkoxy such as 3-methoxy-propoxy, and in the para position with Ci- C4alkyl such as methyl or ethyl, cyclopropyl, halo such as fluoro or chloro, or cyano.
  • Q include phenyl which is substituted in one of the meta positions with Ci-C4alkoxyCi-C4alkoxy, such as 3-methoxy-propoxy and/or in the para-position with optionally substituted phenyl, preferably p-fluorophenyl, or optionally substituted heteroaryl, preferably pyridyl, thienyl or furyl.
  • 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, methoxy-propoxy and methyl.
  • W is bonded either directly to Y, 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 any of which is optionally substituted with one, two or three substituents.
  • W is optionally substituted Ci-C ⁇ alkyl such as methyl, ethyl or isopropyl.
  • Preferred substituents to W according to this embodiment include hydroxy and halo such as mono-, di- or trifluoro.
  • a favoured embodiment of the invention include compounds wherein A is Al, q is 0, Y is NH and W is optionally substituted Ci-C ⁇ alkyl preferably butyl or isobutyl.
  • W is an optionally substituted bicyclic aryl or heterocyclyl moiety.
  • Representative bicyclic rings include naphthyl quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolinyl isoindolinyl.
  • W is an optionally substituted monocyclic ring, such as optionally substituted phenyl, Cs-C ⁇ cycloalkyl or monocyclic heterocyclyl.
  • the heterocyclic ring according to this embodiment typically contains 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, independently selected from nitrogen, oxygen and sulphur.
  • monocyclic heterocyclyl include pyridyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl and morpholinyl and the like, each of which is optionally substituted.
  • W is an optionally substituted monocyclic aryl, heterocyclyl or cycloalkyl, more preferably W is cyclopropyl or phenyl.
  • a typical embodiment for W include optionally substituted phenyl, wherein the optional substituents are selected from fluoro, chloro, methyl and cyclopropyl.
  • a favoured embodiment of the invention include compounds wherein A is Al, q is 1 and W is optionally substituted phenyl, pyridyl or pyrimidinyl.
  • W is a substituted 6-membered ring
  • the ring is preferably mono substituted with the substituent in the meta or para position.
  • Preferred configurations according to this embodiment include meta or para substituted phenyl, for example p-fhioro phenyl.
  • 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.
  • Ci-C ⁇ alkyl means an alkyl group having from 1 to 6 carbon atoms.
  • Preferred alkyl groups for use in the invention are Ci-C ⁇ alkyl groups, i.e. alkyl groups having from 1 to 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert.butyl, pentyl, hexyl and the like.
  • the alkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • alkenyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon double bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkenyl means an alkenyl group having from 2 to 6 carbon atoms).
  • Preferred alkenyl groups for use in the invention are C 2 - C ⁇ alkenyl groups, i.e. alkenyl groups having from 2 to 6 carbon atoms.
  • alkenyl groups include ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), isopropenyl, butenyl, and the like. Unless otherwise indicated the alkenyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 2 -C n alkynyl' as a group or part of a group defines a straight or branched chain hydrocarbon radical having saturated carbon-carbon bonds and at least one carbon-carbon triple bond, and having the number of carbon atoms designated, (e.g. C 2 -Cealkynyl means an alkynyl group having from 2 to 6 carbon atoms).
  • Preferred alkynyl groups for use in the invention are C 2 -C 6 alkynyl, i.e. alkynyl groups having from 2 to 6 carbon atoms.
  • alkynyl groups include, ethynyl, propynyl, propynyl, butynyl, and the like, especially propynyl. Unless otherwise indicated the alkynyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 3 -C n cycloalkyl as a group or part of a group defines a saturated cyclic hydrocarbon radical having the number of carbon atoms designated, e.g. Cs-C ⁇ cycloalkyl means a cycloalkyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl cyclopentyl, cyclohexyl and the like, especially cyclopropyl.
  • the cycloalkyl group is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • C 3 -C n 'CycloalkylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with a C 3 - C n 'Cycloalkyl moiety, wherein C 3 -C n 'Cycloalkyl and C m -C n alkyl are as defined for C 3 - C n cycloalkyl and C m -C n alkyl respectively above.
  • Preferred C 3 -C n 'CycloalkylC m -C n alkyl groups for use in the invention are C 3 -CycycloalkylCo-C 3 alkyl, i.e. the cycloalkyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • C3-C n 'CycloalkylC2-C n alkenyl and C3-C n 'CycloalkylC2- C n alkynyl groups for use in the invention are C 3 -C n 'CycloalkylC 2 -C 3 alkenyl and C 3 - C n 'CycloalkylC 2 -C 3 alkynyl, i.e. the C 3 -C n 'Cycloalkyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • C 3 -C n cycloalkenyl as a group or part of a group defines a cyclic hydrocarbon radical having one double bond and having the number of carbon atoms designated, e.g. C3- C ⁇ cycloalkenyl means a cycloalkenyl group having 3, 4, 5 or 6, carbon atoms.
  • Exemplary cycloalkenyl groups include cyclobutenyl cyclopentenyl, cyclohexenyl and the like. Unless otherwise indicated the cycloalkenyl moiety is optionally substituted with 1 or 2, or where valence permits up to 3, substituents.
  • Ci-C n alkyl is as defined for C m -C n alkyl above.
  • Preferred alkoxy groups for use in the invention are Ci-C ⁇ alkoxy, i.e. alkoxy groups having from 1 to 6 carbon atoms.
  • Exemplary alkoxy groups include but are not limited to methoxy, ethoxy n-propoxy and isopropoxy, and the like.
  • 'halo' is generic to fluoro, chloro, bromo and iodo. Fluoro is typically preferred in many applications.
  • 'haloC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with one or more halogen atoms, 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.
  • halogen atoms may be the same or different.
  • 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(C 1 - C6-alkyl)2 together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  • Included are also radicals wherein the two Ci-C ⁇ alkyl groups of the dialkylcarbamoyl together with the nitrogen atom to which they are attached form a saturated cyclic amine such as pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • Aryl' as a group or part of a group as applied herein represents 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.
  • suitable aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Unless otherwise indicated the aryl and/or its fused cycloalkyl moiety is optionally substituted with 1 or 2, or where valence allows up to 3 substituents.
  • 'ArylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with an aryl moiety, wherein aryl and C m -C n alkyl are as defined above.
  • Preferred arylC m -C n alkyl groups for use in the invention are arylCo-Csalkyl, i.e. the aryl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • arylC2-C n alkenyl and arylC2-C n alkynyl groups for use in the invention are arylC 2 - Csalkenyl and arylC 2 -C 3 alkynyl, i.e. the aryl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • ⁇ eterocyclyl' as applied herein is meant to include a saturated, partially unsaturated or aromatic 4-7 membered monocyclic ring or a 8-12 membered bicyclic ring, which monocyclic or bicyclic ring contains 1, 2, 3 or 4 heteroatoms independently selected from S, O and N.
  • 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,
  • HeterocylylC m -C n alkyl' represents a C m -C n alkyl radical which is substituted with a heterocyclyl moiety, wherein heterocyclyl and C m -C n alkyl are as defined above.
  • Preferred heterocyclylC m - C n alkyl groups for use in the invention are heterocyclylCo-Csalkyl, i.e. the heterocyclyl moiety is directly bonded (i.e. Co) or bonded through a methyl, ethyl, n-propyl or isopropyl group.
  • heterocyclylC 2 -C n alkenyl' and 'heterocyclylC 2 -C n alkynyl' have the corresponding meanings, adjusted just for the link to the heterocyclyl moiety as defined for 'C 2 -C n alkenyl' and 'C 2 -C n alkynyl respectively.
  • Preferred heterocyclylC 2 -C n alkenyl and heterocyclylC 2 -C n alkynyl groups for use in the invention are heterocyclylC 2 -C 3 alkenyl and heterocyclylC 2 -C 3 alkynyl, i.e. the heterocyclyl moiety is bonded through an ethenyl, propenyl, ethynyl or propynyl group respectively.
  • Heteroaryl' as applied herein means an aromatic heterocyclyl moiety.
  • 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.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl is independently optionally substituted with 1 or 2, or where valence permits up to 3, substituents independently selected from: Ci-C 4 alkyl (optionally substituted with one or two substituents independently selected from aryl*Co-C 3 alkyl, NRaRb, amido and Ci-C4alkoxyamido), C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cyclolkyl, Ci-C 4 alkoxy, Ci-C 4 alkoxyCi-C 3 alkyl, Ci-C 4 alkoxyCi- C 6 alkoxyCo-C 3 alkyl, halo, haloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, polyhaloCi-C 4 alkyl, poly
  • 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, iV-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 hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci-C ⁇ alkoxymethyl esters for example methoxymethyl, Ci-C ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, 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-methoxycarbonyloxy ethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown will give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylamino acetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) or any subgroup of compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulphuric, 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 nontoxic metal or amine addition salt forms by treatment with an appropriate organic or inorganic base.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • Base addition salt forms can be converted to the free acid form by treatment with an appropriate acid.
  • the term 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 trifluoromethanesulphonates, alkyl methanesulphonates, and alkyl p-toluenesulphonates.
  • 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 stereospecif ⁇ cally.
  • the compound When a specific stereoisomer of a compound is desired, the compound will preferably be synthesized by stereospecific 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, JV-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, N-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.
  • the compounds of formula (I) and pharmaceutically acceptable salts, solvates, prodrugs, TV-oxides, quaternary amines, metal complexes, or stereochemically isomeric forms thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of formula (I) /salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.10 to 70 %w/w, of active ingredient, and, from 1 to 99.95 %w/w, more preferably from 30 to 99.90 %w/w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
  • a representative tablet within the scope of the pharmaceutical composition of the invention could have a mass of 500 - 1500 mg with a loading of active ingredient in the range 35 - 75%, with the balance being excipients, such as binders, disintegrants, antioxidants and the like.
  • compositions of this invention may be administered in standard manner for the disease or condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • compositions of this invention may also contain, or be co- administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more of the diseases or conditions referred to hereinabove.
  • a representative example are other pharmacologically active compounds such as ACE-inhibitors, neutral endopeptidase inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta- adrenergic antagonists, alpha- adrenergic antagonists and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 ibeta-hydroxy steroid dehydrogenase type 1 inhibitors and soluble guanylate cyclase activators.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • beta- adrenergic antagonists alpha- adrenergic
  • the compounds of the present invention and intermediates useful for the synthesis of these compounds are prepared by methods and techniques known to those skilled in the art.
  • the general schemes below illustrate typical synthetic routes to the compounds of the invention and to intermediates thereof.
  • Alternative routes which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes and the preparative examples below.
  • Scheme 1 illustrates a synthetic route to a lactone which is a useful intermediate in the preparation of compounds of formula (I).
  • the 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 glucoside (Ic).
  • a radical initiator like azobis- (2-methylpropyonitrile) (AIBN) or the like
  • Ic 2,3-dideoxy glucoside
  • 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
  • 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 (IAa).
  • 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 primary hydroxy group of the lactone (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 secondary hydroxy group of the alcohol (IAa) by azide may be effected by transforming the hydroxy group to a leaving group, for example a derivative of sulphonic acid like a triflate or tosylate or the like by subjecting the alcohol to sulphonylating conditions such as treatment with the appropriate anhydride or halide optionally in the presence of a base, for instance pyridine, followed by displacement of the leaving group with azide for example sodium azide, thus giving the azide derivative (IAb).
  • a leaving group for example a derivative of sulphonic acid like a triflate or tosylate or the like
  • a base for instance pyridine
  • 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 compound (IAd) is then be achieved by opening of the lactone with a desired nucleophile (IAc) as described herein below.
  • 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
  • Opening of the lactone (IAb) with hydroxide such as lithium hydroxide provides the linear hydroxy acid (2Aa). Protection of the afforded secondary alcohol using any suitable hydroxy protecting group known in the art, followed by a Mitsunobu reaction with a desired alcohol HO- (CH 2 ) m -W or thiol HS-(CH 2 ) m -W and finally removal of the hydroxy protecting group, provides compounds esters and thioesters (2Ac) which subsequently can be reduced to the corresponding amine and optionally N-alkylated as described above to yield compounds of formula (I) wherein Y is O or S respectively and q is 0.
  • Amino derivatives (2a) to be used for the opening of the lactone (IAb) in scheme 2 are available commercially or they can easily be prepared by the skilled person according to literature procedures.
  • an appropriate amine can be prepared for example as illustrated in scheme 3.
  • the amino acid (3a), carrying the desired side chain R > 4'r R > 4" can be coupled to an amine W- (CH 2 )Hi-NH 2 using any convenient method for peptide coupling known in the art.
  • a coupling agent like HATU or isobutylchloro formate in the presence of a tertiary amine such as ethyldiisopropylamine (DIEA) or N-methylmorpholine in a solvent like dimethyl formamide can be used, thus providing the amide.
  • the amine 3b can be achieved by coupling of a suitably amino protected amino alcohol (3a), carrying the desired substituents R 4 and R 4 , to the amine W-(CH 2 )Hi-NH 2 using for example the Mitsunobu conditions, or the amino alcohol group can be oxidized to the corresponding amino aldehyde by treatment with a suitable oxidation agent such as Dess Martin periodinane or the like, followed by reaction with the amine W-(CH 2 ) m -NH2 in a reductive amination reaction, thus affording the amine (3b). Subsequent removal of the N-protecting provides the amine (3b).
  • a suitable oxidation agent such as Dess Martin periodinane or the like
  • the amino alcohol (3Aa) can be oxidized to the corresponding amino aldehyde by treatment with a suitable oxidation agent such as Dess Martin periodinane or the like, followed by reaction with the hydrazine derivative (3Ab) in a reductive amination reaction, to give the N,N'-dialkylated alkylated hydrazine derivative.
  • a suitable oxidation agent such as Dess Martin periodinane or the like
  • the hydrazine derivative (3Ab) in a reductive amination reaction to give the N,N'-dialkylated alkylated hydrazine derivative.
  • Removal of the amino protecting group using the appropriate conditions according to the protecting group used, such as acidic treatment in the case of a boc group, then gives the hydrazine containing amine (3Ac).
  • 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 5.
  • 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 (5a) or the amine derivative (5b) 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 (5b) 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 ) D -NHRa in the presence of a reducing agent like NaCNBH 3 .
  • a reducing agent like NaCNBH 3
  • 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 0, 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 nBu3P.
  • 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.
  • the azide derivative (6a), prepared for example as outlined in e.g. scheme IA, 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 (6b).
  • a suitable catalyst such as Lindlars catalyst or the like in the presence Of BoC 2 O to provide the boc protected derivative (6b).
  • 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 (6c).
  • 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). For example 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.
  • Compounds wherein Z' is O, S or NRa may be prepared by a Mitsunobu reaction of the primary alcohol (6c) 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.
  • An alternative method for the preparation of compounds wherein Z' is S and n is O is to react the diol (If) with a desired diphenyl disulphide derivative in the presence of nBusP.
  • hydroxy protected cyanobenzyl derivative (7a) 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 (7c). The afforded alcohol (7c) 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 (7c) 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 bromoderivative (7d), 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 6c as described in scheme 2 and 6 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 bromoderivative (7d
  • the hydroxy group can be transformed into a derivative of sulphonic acid by reaction with a suitable sulphonylating agent such as
  • Scheme 8 illustrates an example to another substituted phenyl derivative, useful for the preparation of compounds of formula (I) wherein Q is phenyl substituted with an alkoxy-alkoxy group.
  • Scheme 9 shows an alternative route to compounds of the invention, starting from Garner's aldehyde. 9h
  • 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 (9f) i.e. Z' is O.
  • the lactone may then be opened either directly with a desired amine as described above to give the amide (9i), or alternatively, the lactone may be opened by treatment with hydroxide such as lithium hydroxide, thus affording the acid (9g). 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 (9h).
  • 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 (6a) 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, to yield the difluoro compound (10a).
  • 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 fluor
  • the stereochemistry at the steric centre whereto the hydroxy group is attached first has to be inverted.
  • the inversion can be achieved for example by subjecting the alcohol to a Mitsunobu reaction with for instance p-nitrobenzoic acid and an azodicarboxylate like DIAD in the presence OfPh 3 P followed by hydrolysis of the afforded p-nitrobenzoic ester by treatment with sodium methoxide or the like.
  • the afforded inverted alcohol (1 Ib) is then subjected to fluorinating conditions such as treatment with DAST or Deoxofluor as described above.
  • scheme 10 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.
  • R1' is R1 or an N-protecting group
  • the azido derivative (1 Ic) 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 (l id)
  • 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.
  • 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.
  • N-methylmorpholine (0.5 mL, 4.55 mmol) was added to a solution of Boc-Ile-OH (1 g, 4.32 mmol) in THF (10 mL) at -20 0 C under N 2 .
  • the mixture was allowed to stir for 10 min. and then ⁇ obutylchloroformate (0.59 mL, 4.55 mmol) was added dropwise keeping the temperature below -14 0 C.
  • the reaction mixture was allowed to stir for 20 min. and aniline (0.44 mL, 4.78 mmol) was then added dropwise keeping the temperature below -20 0 C. After the addition was completed the reaction mixture was allowed to warm to r.t. Stirred at r.t. until LC-MS showed full conversion.
  • reaction mixture was diluted with toluene and washed with 2 M HCl and H 2 O.
  • the organic phase was dried (Na 2 SO 4 ) and the solvent evaporated to give a solid that was dissolved into THF:toluene (1.5:3 niL).
  • the resulting solution was cooled to 0 0 C under N 2 and then treated carefully with 70% w/w RedAl (6.9 mL, 24 mmol). After the addition was completed the reaction mixture was stirred at 40 0 C for 21 h then cooled down to 0 0 C and carefully quenched with 5 M NaOH (10 mL). Stirred 20 min at r.t. and then the product extracted into toluene.
  • step a The procedure described in example 4 step a was used but using 3,5-dimethylaniline instead of aniline which afforded the title compound (54%).
  • 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 ).
  • Example Ih The procedure described in Example Ih was followed using 4-bro mo methyl- l-ethyl-2-(3- methoxy-propoxy)-benzene (0.45 g, 1.6 mmol) instead of benzyl bromide, which gave the title compound (0.48 g, 78%).
  • step a The procedure described in example 4 step a was used but using 3-aminopyridine instead of aniline which afforded the title compound (12%).
  • the lactone 2f was opened according to the procedure described in example 4 step b but using the amine 12a instead of 4a which afforded the title compound (30%).
  • the lactone 2f was opened according to the procedure described in example 4 step b but using the amine 13a instead of 4a which afforded the title compound (20%).
  • lactone 2f was opened according to the procedure described in example 4 step b but using (7i?-2iS)-norephedrine instead of 4a which afforded the title compound (25%).
  • the lactone 2f was opened according to the procedure described in example 4 step b but using 16a instead of 4a, which afforded the title compound (15%).
  • the lactone 2f was opened according to the procedure described in example 4 step b but using
  • Example 10 step a The procedure described in Example 10 step a was followed but using 4-fluoro-3-hydroxy- benzoic acid methyl ester (0.69 g, 4.06 mmol) instead of 4-bromo-3-hydroxy-benzoic acid methyl ester, which gave the title compound (0.76 g, 77%) after silica gel column chromatography (gradient elution with hexanes/ethyl acetate 20:1 - 6:1).
  • the methyl ester 20b (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 mL). The mixture was diluted with Et 2 O (40 mL) and 1 M HCl (20 rnL) and the layers were separated.
  • Example 1 step g The procedure described in Example 1 step g 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). LC/MS [M+H] + 385, [M+Na] + 407.
  • the lactone 2Of was opened according to the procedure described in example 4 step b but using the amine (25'-35)-2-amino-3-methyl-pentanoic acid amide instead of 4a, which afforded the title compound (57%).
  • the product was purified by flash chromatography on SiO 2 gel (eluent heptane:EtOAc 10:1 to 2.5:1) to give 0.26 g of the protected amine which was taken into a 1 M HCl solution in MeOH and stirred at r.t. until full deprotection was achieved.
  • the reaction mixture was concentrated under vacuum and the residue was partitioned between 2 M NaOH and CH 2 Cl 2 .
  • the phases were separated and the aqueous phase was extracted with CH 2 Cl 2 .
  • the combined organic extracts were dried (Na 2 SO 4 ) and the solvent evaporated to give 152 mg (24%) of the title compound.
  • the lactone 2Of was opened according to the procedure described in example 4 step b but using the amine 22a instead of 4a, which afforded the title compound (31%).
  • step b The procedure described in Example 21, step b was followed but using 4-chlorobenzenesulfonyl chloride instead of TsCl, which gave the title compound.
  • the lactone 2Of was opened according to the procedure described in example 4 step b but using the amine (5)-2-methyl-l-butylamine instead of 4a, which afforded the title compound (40%).
  • the lactone 2Of was opened according to the procedure described in example 30 step a but using ethylamine instead of methylamine which afforded the title compound (55%).
  • 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-l-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. Purification of the afforded residue by flash chromatography on silica gel (Hep:EtOAc 20:1) gave the title compound (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 34a 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).
  • 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 lactone 37e (40 mg, 0.079 mmol) was dissolved in isobutylamine (1 ml) and stirred at 70 °C for 16 hours. The volatile matter was evaporated on rotavapor and the residue was partitioned between DCM and 5% citric acid. The organic extract was dried through sodium sulphate and evaporated. Silica gel column chromatography (gradient 0 - Vi - 1 - 1 /4EtOH/DCM) gave the title compound (43 mg, 93%). MS mlz 582.3 (M+H) + .
  • Example 38a A solution of example 38a (47 mg) in methanol (50 ml) was hydrogenated at atmospheric pressure in an H-Cube instrument using Lindlars catalyst as the catalyst. The reaction mixture was evaporated and 50 mg of the title product was obtained with a LC purity at 230 nm of 94.5%. LC/MS confirmed the structure with a M+l ion at 524.0.
  • 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 43e (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.
  • FRET Fluorescence Resonance Energy Transfer
  • EDANS aminoethylaminonaphtalene sulphonate
  • Dabcyl 4'-dimethylaminoazobenzene
  • Arg-Glu(ED ANS)-Ile-His-Pro- Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg Sigma- Aldrich.
  • the cleavage site by human renin is the peptide bond between Leu and VaI. The compounds were tested at a range of concentrations whereas the enzyme and substrate concentrations were fixed.
  • the substrate was prepared at a 20 ⁇ M stock solution in DMSO.
  • To each well of a 96-well polypropylene plate was added the enzyme containing assay buffer (90.0 ⁇ l) and inhibitor of different concentrations (1 ⁇ l). To control wells were added DMSO (1 ⁇ l) instead of inhibitor.
  • the renin enzyme was preactivated by incubation at 37 0 C for 20 min whereafter the reactions were started by addition of substrate, 10 ⁇ l/well, thus giving a total volume of 100 ⁇ l/well and a substrate concentration of 2 ⁇ M.
  • the assay was performed during 20 min at 37 0 C.
  • the total concentration of DMSO was not above 1 %.
  • Product fluorescence emission filter 340 nM, excitation filter 500 nM
  • the Ki was determined by Prism Software.
  • Activity of the inhibitors was determined by measuring the fluorescence at ⁇ e X 340nm and ⁇ em 500nm.
  • Percent inhibition is calculated as follows: % Inhibition is equal to the (Fluorescence ⁇ inhibitor - Fluorescence ⁇ C £gro»«rf); divided by the (Fluorescence mmus inhibitor - Fluorescence ⁇ C £ g ro»«rf);
  • Table 1 shows the Ki- value expressed in nM for a representative selection of compounds according to the invention when tested in a renin enzyme assay such as the one described above.
  • Category A indicates ⁇ 50 nM inhibition
  • category B indicates 51 - 200 nM inhibition
  • category C indicates > 200 nM:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle A est choisi parmi des structures partielles A1, A2 et A3 ; Ry et Ry' sont tous deux hydrogène, ou Ry et Ry' forment ensemble avec l'atome d'azote auquel ils sont liés une amine cyclique telle que morpholine, pipéridine, pipérazine ou pyrrolidine; L est NHNH, CH2NH, O ou S; Y est NH, NHNH, NHC(=O), S(=O)2NH, NHS(=O)2, CH2, CH2NH, O, S or S(=O)p; Q est aryle ou heterocyclyle; Z est O, S, NRa ou S(=O)p; m est 0, 1 ou 2; n est 0, 1, 2 ou 3; p est indépendamment 1 ou 2; q est 0 or 1; Ra est H ou C1-C4alkyle; R1 est hydrogène, C1-C6alkyle, C3-C7cycloalkylC0-C3alkyle, arylC0-C3alkyle ou heterocyclylC0-C3alkyle, R4'' est H ou C1-C6alkyle; ou un sel, hydrate ou N-oxyde de ceux-ci pharmaceutiquement acceptables. Les composés selon l'invention sont des inhibiteurs de l'aspartyle protéase telles que la rénine, et sont entre autres utiles pour le traitement de conditions associées aux activités du gène RAS, telles que l'hypertension, l'insuffisance cardiaque et l'insuffisance rénale.
PCT/EP2008/063802 2007-10-25 2008-10-14 Inhibiteurs de l'aspartyle protéase WO2009053277A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07119316 2007-10-25
EP07119316.3 2007-10-25
EP08104635 2008-07-04
EP08104635.1 2008-07-04

Publications (1)

Publication Number Publication Date
WO2009053277A1 true WO2009053277A1 (fr) 2009-04-30

Family

ID=40276105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/063802 WO2009053277A1 (fr) 2007-10-25 2008-10-14 Inhibiteurs de l'aspartyle protéase

Country Status (1)

Country Link
WO (1) WO2009053277A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148775A1 (fr) * 2006-06-23 2007-12-27 Daiichi Sankyo Company, Limited Composé à chaîne aminée

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007148775A1 (fr) * 2006-06-23 2007-12-27 Daiichi Sankyo Company, Limited Composé à chaîne aminée

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HANESSIAN S 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, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 49, no. 15, 2006, pages 4544 - 4567, XP002449025, ISSN: 0022-2623 *
MEALY N E ET AL: "ALISKIREN FUMARATE ANTIHYPERTENSIVE", DRUGS OF THE FUTURE, BARCELONA, ES, vol. 26, no. 12, 2001, pages 1139 - 1148, XP009017211, ISSN: 0377-8282 *

Similar Documents

Publication Publication Date Title
FI112472B (fi) Menetelmä terapeuttisesti aktiivisten substituoitujen atsaheterosyklikarboksyylihappojen valmistamiseksi
IE903957A1 (en) Aromatic amine compounds, their method of preparation and¹pharmaceutical compositions in which they are present
IL108507A (en) Phenyl Sulfonamides are converted, their preparation and pharmaceutical preparations containing them
US20050222146A1 (en) N-substituted-n-sulfonylaminocyclopropane compounds and pharmaceutical use thereof
WO1999029686A1 (fr) Nouveaux composes
WO2008107365A1 (fr) Nouveaux composés
US20030105099A1 (en) Novel compounds and compositions as cathepsin inhibitors
US7718646B2 (en) Cyclohexyl(alkyl)propanolamines, preparation method and pharmaceutical compositions containing same
KR20040093123A (ko) Ｎｋ1 길항제
AU2005314601A1 (en) Indane amides with antiproliferative activity
WO2008119772A1 (fr) Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases
EP1615629B1 (fr) Inhibiteurs de la peptide deformylase
WO2009053277A1 (fr) Inhibiteurs de l'aspartyle protéase
WO2008119773A1 (fr) Dérivés d'amide utilisés en tant qu'inhibiteurs d'aspartyl-protéases
EP1005493B1 (fr) Inhibiteurs de proteases antiviraux
US10577356B2 (en) Beta-arrestin-biased cannabinoid CB1 receptor agonists and methods for making and using them
JP2014517812A (ja) アダマンチル基を有するスルファミド誘導体及びこれの薬剤学的に許容可能な塩
EP1658274A2 (fr) Inhibiteurs de la cathepsine s
AU2941200A (en) 1,3,4-oxadiazole derivatives and process for producing the same
JP5797662B2 (ja) ５−アミノ−４−ヒドロキシペントイルアミド
WO2008135488A1 (fr) Inhibiteurs de l'aspartyle protéase
US7384970B2 (en) Inhibitors of cathepsin S
WO2010024772A1 (fr) Inhibiteurs d'aspartyl protéases
EP1534267A1 (fr) Derives de pyrrolidine inhibiteurs de tryptase
MXPA00005327A (en) Novel compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08842633

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08842633

Country of ref document: EP

Kind code of ref document: A1