WO2006059304A2 - Nouveaux derives bicycliques - Google Patents

Nouveaux derives bicycliques Download PDF

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Publication number
WO2006059304A2
WO2006059304A2 PCT/IB2005/054008 IB2005054008W WO2006059304A2 WO 2006059304 A2 WO2006059304 A2 WO 2006059304A2 IB 2005054008 W IB2005054008 W IB 2005054008W WO 2006059304 A2 WO2006059304 A2 WO 2006059304A2
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
compound
mmol
substituted
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PCT/IB2005/054008
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English (en)
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WO2006059304A3 (fr
Inventor
Olivier Bezencon
Christoph Boss
Daniel Bur
Olivier Corminboeuf
Walter Fischli
Corinna Grisostomi
Lubos Remen
Sylvia Richard-Bildstein
Thierry Sifferlen
Thomas Weller
Dwight Macdonald
Daniel Mckay
David A. Powell
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Actelion Pharmaceuticals Ltd
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Publication of WO2006059304A2 publication Critical patent/WO2006059304A2/fr
Publication of WO2006059304A3 publication Critical patent/WO2006059304A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the invention relates to novel compounds of the formula (I).
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.
  • renin-angiotensin II the biologically active angiotensin II (Ang II) is generated by a two-step mechanism.
  • the highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II by the less specific angiotensin-converting enzyme (ACE).
  • Ang II is known to work on at least two receptor subtypes called ATi and AT2. Whereas ATi seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown.
  • ACE inhibitors and ATi blockers have been accepted to treat hypertension (Waeber B. et al, "The renin-angiotensin system: role in experimental and human hypertension", in Birkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1986, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S).
  • ACE inhibitors are used for renal protection (Rosenberg M. E. et al, Kidney International, 1994, 45, 403; Breyer J. A.
  • renin inhibitors The rationale to develop renin inhibitors is the specificity of renin (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645).
  • the only substrate known for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin.
  • ACE can also cleave bradykinin besides Ang I and can be by-passed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Konili Z. H.
  • 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 with good oral bioavailability and long duration of action are required.
  • the first non-peptide renin inhibitors were described which show high in vitro activity (Oefner C. et al., Chem. Biol., 1999, 6, 127; Patent Application WO 97/09311; Marki H. P. et al., Il Farmaco, 2001, 56, 21).
  • the development status of these compounds is not known.
  • the present invention relates to the identification of renin inhibitors of a non-peptidic nature and of low molecular weight. Described are orally active renin inhibitors of formula (I) which have a long duration of action and which are active in indications beyond blood pressure regulation where the tissular renin-chymase system may be activated leading to pathophysiologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, and possibly restenosis. So, the present invention describes these non-peptidic renin inhibitors of formula (I).
  • the present invention relates to novel compounds of the formula (I),
  • W represents phenyl, substituted by V in para position
  • V represents alkylenoxy or alkylenedioxy, wherein alkylenoxy can be oriented in both possible ways;
  • U represents phenyl or mono-, di-, tri- or tetra- substituted phenyl, wherein the substituents are independently selected from halogen, -CF 3 , -OCF 3 -CH 2 OH and alkyl;
  • T represents -CO-N(R 1 )-;
  • M represents phenyl or pyridinyl, wherein these two radicals can be mono- or di- substituted, wherein the substitutents are independently selected from alkyl; alkoxy; -OCF 3 ; -CF 3 ; hydroxy-alkyl; halogen; alkyl-O-(CH 2 ) 0 - 4 -CH 2 -; alkyl-O-(CH 2 ) 2 .
  • R 1 represents alkyl or cycloalkyl, especially cyclopropyl
  • J represents hydrogen or alkyl
  • any reference to a compound of formula (I) is to be understood as referring also to optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and meso-forms, as well as salts (especially pharmaceutically acceptable salts) and solvent complexes (including hydrates) of such compounds, and morphological forms, as appropriate and expedient.
  • alkyl in the definitions of formula (I) - if not otherwise stated - the term alkyl, alone or in combination with other groups, means saturated, straight or branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms, i.e. Ci-C 4 -alkyl.
  • alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl.
  • the methyl, ethyl and isopropyl groups are preferred.
  • alkoxy refers to an R-O- group, wherein R is an alkyl.
  • alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert- butoxy.
  • alkylenoxy refers to an -L-O- group, wherein L is an alkylene.
  • alkylenoxy groups are methylenoxy, ethylenoxy, propylenoxy, iso-propylenoxy, iso- butylenoxy, sec-butylenoxy and tert-butylenoxy.
  • alkylenedioxy refers to an -O-L-O- group, wherein L is an alkylene. Examples are oxymethylenoxy, oxyethylenoxy, oxypropylenoxy, oxy-iso-propylenoxy, oxy-tert-butylenoxy, etc.
  • alkylene alone or in combination with other groups, means straight or branched divalent chain groups with one to seven carbon atoms, preferably one to four carbon atoms.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 7, preferably 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, palmoic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, p-toluenesulfonic acid, salicylic acid, succinic acid, trifluoroacetic acid, and the like that are non toxic to living organisms or, in case the compound of formula (I) is acidic in nature, with an inorganic base like an alkali or earth alkali
  • the compounds of the formula (I) can contain two or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, or meso-forms.
  • the present invention encompasses all these forms. Mixtures may be separated in a manner known per se, e.g. by column chromatography, thin layer chromatography, HPLC or crystallization.
  • Very preferred compounds are compounds of formula (I) wherein T represents -CONR 1 -; R 1 represents cycloalkyl, especially cyclopropyl; Q represents methylene; and M represents phenyl, or mono- or di-substituted phenyl, wherein the substituents are independently selected from CH 3 O(CH 2 ) 2 _ 3 -, halogen, and -CF 3 .
  • Especially preferred compounds are further compounds of formula (I) wherein V is propylenoxy; U represents phenyl which is tri- substituted with halogen; T represents -CONR 1 -, wherein R 1 is cyclopropyl; Q represents methylene; M represents phenyl which is di-substituted with halogen; and J represents alkyl, especially methyl.
  • the compounds of formula (I) are useful for 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 diseases related to the renin-angiotensin system.
  • diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia,
  • the compounds of formula (I) are especially useful for the treatment and/or prophylaxis of hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin- angiotensin system, in particular to a method for the treatment or prophylaxis of the above-mentioned diseases, said methods comprising administering to a patient a pharmaceutically active amount of a compound of formula (I).
  • a further aspect of the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier material.
  • These pharmaceutical compositions may be used for the treatment and/or prophylaxis of the above-mentioned diseases.
  • the pharmaceutical compositions can be used for enteral, parenteral, or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
  • the invention also relates to the use of a compound of formula (I) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above- mentioned diseases.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Compounds of formula (I) or the above-mentioned pharmaceutical compositions are also of use in combination with 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, 1 lbeta-hydroxysteroid dehydrogenase type 1 inhibitors, soluble guanylate cyclase activators and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • aldosterone antagonists angiotensin II receptor antagonists
  • endothelin receptors antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • the present invention also relates to pro-drugs of a compound of formula (I) that convert in vivo to the compound of formula (I) as such. Any reference to a compound of formula (I) is therefore to be understood as referring also to the corresponding pro- drugs of the compound of formula (I), as appropriate and expedient.
  • the compounds of formula (I) can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
  • the dipeptide B is prepared (Scheme 1) using known chemistry (H. Hiemstra et al., J. Org. Chem., 2003, 68, 4486). Removal of the Boc-protecting group and simultaneous cyclization leads to diketopiperazine C, which is then reprotected to compound D. Partial reduction to compound E allows the second cyclization to take place and leads to compound F. Compound F is then oxidized to compound G, which is then acylated to compound H (Majewski, M; et al.; J. Org. Chem., 1995, 60, 5825).
  • the vinylic triflate of compound H can be prepared using standard conditions and leads to compound J (Scheme 2).
  • a carbon-carbon coupling catalysed by a transition metal typically a Pd- or a Co-complex, leads to a compound of type K, wherein the substituent R a stands for a precursor for the group U-V as defined in formula I. After manipulations this compound is transformed into a compound of type L. Hydrolysis of the ester leads to compound of type M, and for instance amide coupling leads then to a compound of type N.
  • a compound of type N can be deprotected to a final compound as described in formula (I), by simple cleavage of the methoxycarbonyl protecting group.
  • HPLC- or LC-MS-conditions (if not indicated otherwise): Analytic: Zorbax 59 SB Aqua column, 4.6 x 50 mm from Agilent Technologies.
  • TPAP (0.74 g) and N-methylmorpholine (3.95 g; 33.7 mmol) was added successively to a sol. of compound F (6.15 g; 27.0 mmol) in acetone (328 mL). The black mixture was stirred at rt for 1 h, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH 2 Cl 2 MeOH 20:1) yielded the title compound (4.55 g 75%).
  • EIA Enzyme immuno assay
  • the solution was then filtered with a Syringe filter, 0.45 ⁇ m (Nalgene, Cat. No. 194- 2545).
  • the conjugate can be stored in polypropylene tubes in 0.05% sodium azide at 4 0 C for at least 12 months.
  • Microtiter plates (MPT384, MaxiSorpTM, Nunc) were incubated overnight at 4 0 C with 80 ⁇ l of Ang I (l-10)/BSA conjugate, diluted l:100'000 in PBS IX in a teflon beaker (exact dilution dependent on batch of conjugate), emptied, filled with 90 ⁇ l of blocking solution [0.5% BSA (Sigma A-2153) in PBS IX, 0.02% NaN 3 ], and incubated for at least 2 h at rt, or overnight at 4 0 C.
  • 96 well MTP (MaxiSorpTM, Nunc) were coated with 200 ⁇ l conjugate and blocked with 250 ⁇ l blocking solution as above, except that the blocking solution contained 3% BSA.
  • the plates can be stored in blocking solution at 4 0 C for 1 month.
  • Ang I-EIA in 384 well MTP
  • the Ang I (l-10)/BSA coated MTP were washed 3 times with wash buffer (PBS IX, 0.01% Tween 20) and filled with 75 ⁇ l of primary antibody solution (anti-Ang I antiserum, pre-diluted 1:10 in horse serum), diluted to a final concentration of lilOO'OOO in assay buffer (PBS IX, ImM EDTA, 0.1% BSA, pH 7.4). 5 ⁇ l of the renin reaction (or standards in assay buffer) (see below) were added to the primary antibody solution and the plates were incubated overnight at 4 0 C.
  • the plates were washed 3 times with wash buffer and then incubated for 1 h at rt with substrate solution [1.89mM ABTS (2.2'- azino-di-(3-ethyl-benzthiazolinsulfonate)] (Roche Diagnostics, 102 946) and 2.36mM H 2 O 2 [30%, (Fluka, 95300] in substrate buffer (0.1M sodium acetate, 0.05M sodium dihydrogen phosphate, pH 4.2). The OD of the plate was read at 405 nm in a microplate reader (FLUOStar Optima from BMG). The production of Ang I during the renin reaction was quantified by comparing the OD of the sample with the OD of a standard curve of Ang 1(1-10), measured in parallel.
  • substrate solution 1.89mM ABTS (2.2'- azino-di-(3-ethyl-benzthiazolinsulfonate)] (Roche Diagnostics, 102 946)
  • the renin assay was adapted from an assay described before (Fischli W. et ah, Hypertension, 1991, 18:22-31) and consists of two steps: in the first step, recombinant human renin is incubated with its substrate (commercial human tetradecapeptide renin substrate) to create the product Angiotensin I (Ang I). In the second step, the accumulated Ang I is measured by an immunological assay (enzyme immuno assay, EIA). The detailed description of this assay is found below.
  • EIA enzyme immuno assay
  • the EIA is very sensitive and well suited for renin activity measurements in buffer or in plasma. Due to the low concentration of renin used in this assay (2 fmol per assay tube or 10 pM) it is possible to measure inhibitor affinities in this primary assay down to low pM concentration.
  • Test compounds were dissolved and diluted in 100% DMSO and 2.5 ⁇ l added to the premix, then incubated at 37 0 C for 3 h. At the end of the incubation period, 5 ⁇ l of the renin reaction (or standards in assay buffer) were transferred into EIA assays (as described above) and Ang I produced by renin was quantified. The percentage of renin inhibition (Ang I decrease) was calculated for each concentration of compound and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC 50 ). The ICso-values of all compounds tested are below 100 nM. However, selected compounds exhibit a very good bioavailability and are metabolically more stable than prior art compounds.
  • the examplified compound displays an IC 50 - value below 10 nM.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention porte sur de nouveaux dérivés bicycliques et sur leur utilisation comme ingrédients actifs dans la préparation de compositions pharmaceutiques. Cette invention porte également sur des processus de préparation des composés, des compositions pharmaceutiques contenant un ou plusieurs de ces composés et, notamment, sur leur utilisation comme inhibiteurs de la rénine.
PCT/IB2005/054008 2004-12-01 2005-12-01 Nouveaux derives bicycliques WO2006059304A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2004/013610 WO2006058546A1 (fr) 2004-12-01 2004-12-01 Nouveaux dérivés de lactame en tant qu’inhibiteurs de la rénine
EPPCT/EP2004/013610 2004-12-01

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WO2006059304A2 true WO2006059304A2 (fr) 2006-06-08
WO2006059304A3 WO2006059304A3 (fr) 2006-10-12

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PCT/EP2004/013610 WO2006058546A1 (fr) 2004-12-01 2004-12-01 Nouveaux dérivés de lactame en tant qu’inhibiteurs de la rénine
PCT/IB2005/054008 WO2006059304A2 (fr) 2004-12-01 2005-12-01 Nouveaux derives bicycliques

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8129538B1 (en) 2007-03-28 2012-03-06 Takeda Pharmaceutical Company Limited Renin inhibitors
US8334308B2 (en) 2007-08-20 2012-12-18 Merck Sharp & Dohme Corp. Renin inhibitors
US8343968B2 (en) 2007-05-24 2013-01-01 Merck Canada Inc. Case of renin inhibitors
US8889714B2 (en) 2008-05-05 2014-11-18 Actelion Pharmaceuticals Ltd. 3,4-substituted piperidine derivatives as renin inhibitors

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096116A2 (fr) * 2003-05-02 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene
WO2004096803A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives d'azabicyclononene
WO2004096366A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives de 9-azabicyclo'3.3.1!non-6-ee a heteroatome en position 3 servant d'inhibiteurs de la renine
WO2005040165A1 (fr) * 2003-10-13 2005-05-06 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et leur utilisation en tant qu'inhibiteurs de la renine
WO2005040173A1 (fr) * 2003-10-23 2005-05-06 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine
WO2005054244A2 (fr) * 2003-12-05 2005-06-16 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine comprenant une nouvelle chaine laterale

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096803A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives d'azabicyclononene
WO2004096366A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives de 9-azabicyclo'3.3.1!non-6-ee a heteroatome en position 3 servant d'inhibiteurs de la renine
WO2004096116A2 (fr) * 2003-05-02 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene
WO2005040165A1 (fr) * 2003-10-13 2005-05-06 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et leur utilisation en tant qu'inhibiteurs de la renine
WO2005040173A1 (fr) * 2003-10-23 2005-05-06 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine
WO2005054244A2 (fr) * 2003-12-05 2005-06-16 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine comprenant une nouvelle chaine laterale

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8129538B1 (en) 2007-03-28 2012-03-06 Takeda Pharmaceutical Company Limited Renin inhibitors
US8343968B2 (en) 2007-05-24 2013-01-01 Merck Canada Inc. Case of renin inhibitors
US8334308B2 (en) 2007-08-20 2012-12-18 Merck Sharp & Dohme Corp. Renin inhibitors
US8889714B2 (en) 2008-05-05 2014-11-18 Actelion Pharmaceuticals Ltd. 3,4-substituted piperidine derivatives as renin inhibitors

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WO2006058546A1 (fr) 2006-06-08

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