WO2007034406A1 - Derives amides d'acide pyrrolidine-3-carboxylique utilises comme inhibiteurs de la renine - Google Patents

Derives amides d'acide pyrrolidine-3-carboxylique utilises comme inhibiteurs de la renine Download PDF

Info

Publication number
WO2007034406A1
WO2007034406A1 PCT/IB2006/053359 IB2006053359W WO2007034406A1 WO 2007034406 A1 WO2007034406 A1 WO 2007034406A1 IB 2006053359 W IB2006053359 W IB 2006053359W WO 2007034406 A1 WO2007034406 A1 WO 2007034406A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
compound according
independently selected
formula
Prior art date
Application number
PCT/IB2006/053359
Other languages
English (en)
Inventor
Olivier Bezencon
Christoph Boss
Daniel Bur
Olivier Corminboeuf
Corinna Grisostomi
Lubos Remen
Sylvia Richard-Bildstein
Thomas Weller
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2007034406A1 publication Critical patent/WO2007034406A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present claimed invention was made as a result of activities undertaken within the scope of a research collaboration agreement between Merck & Co., Inc., Actelion Pharmaceuticals Ltd, and Actelion Ltd. The agreement was executed on December 4, 2003.
  • 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 comprising a compound of formula (I) and especially their use as renin inhibitors in cardiovascular events and renal insufficiency.
  • renin- angiotensin system 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).
  • ACE angiotensin-converting enzyme
  • ATi seems to transmit most of the known functions of Ang II
  • AT2 the role of AT2 is still unknown.
  • 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 bypassed 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.
  • ACE inhibitors do not inhibit Chymase. Therefore, the formation of Ang II is still possible in patients treated with ACE inhibitors.
  • Blockade of the ATi receptor e.g. by losartan
  • AT 2 AT-receptor subtypes
  • 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-pep tide 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 renin inhibitors of a non-peptidic nature and of low molecular weight.
  • 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 pathophysiological ⁇ 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).
  • W is a phenyl ring (preferred) or a six-membered, non benzofused aromatic ring with one or two nitrogen ring atoms, wherein said rings are substituted by V in para position;
  • V represents a bond, -(CH 2 V, -(CH 2 ) S -A-, -CH 2 -A- (CH 2 ) r , -(CH 2 ) 2 -A-(CH 2 ) U -, -A-(CH 2 ) V -B-, -CH 2 -CH 2 -CH 2 -A-CH 2 -, -A-CH 2 -CH 2 -B-CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -A-
  • V represents the heterocyclic group , wherein this heterocyclic group is bound to the group W of formula (I) via its nitrogen ring atom;
  • a and B independently represent -O- or -S-, preferably -O-;
  • L represents a five-membered heteroaryl with two or three, preferably two, ring heteroatoms independently selected from nitrogen and oxygen, preferably an oxadiazolyl or isoxazolyl, most preferably an isoxazolyl;
  • U represents unsubstituted aryl; mono-, di-, tri- or tetra- substituted aryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and -CF 3 ; or mono-, di-, or tri- substituted heteroaryl wherein the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and -CF 3 ;
  • Q represents methylene or ethylene, preferably methylene
  • R 1 represents alkyl or cycloalkyl, preferably cycloalkyl such as especially cyclopropyl;
  • 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 solvates (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-C4-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.
  • hydroxy-alkyl alone or in combination with other groups, refers to an HO-R group, wherein R is alkyl. Examples are hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and CH 3 CH(OH)-.
  • alkoxy alone or in combination with other groups, 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.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • cycloalkyl alone or in combination with other groups, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cyclopropyl group is a preferred group.
  • aryl alone or in combination, relates to a phenyl, naphthyl or indanyl group, preferably a phenyl group.
  • heteroaryl alone or in combination, means six-membered aromatic rings with one to four nitrogen ring atoms; six-membered aromatic rings with one to three nitrogen ring atoms, wherein said rings are fused to a benzene ring; five- membered aromatic rings with one to three ring heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said rings are optionally fused to a benzene ring; a tetrazolyl ring; a thiazinyl ring; or a coumarinyl.
  • Examples of such ring systems are furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, benzothienyl, quinazolinyl and quinoxalinyl.
  • V within the present invention represents an asymmetric bivalent group
  • such a group may be connected in both possible ways to the group W and U of a compound of formula (I).
  • the beginning part of an asymmetric group V is linked to the group W of a compound of formula (I) (that means that for example the -(CH 2 ) S part of -(CH 2 ) S -A- is linked to the group W of a compound of formula (I)).
  • Salts are preferably the pharmaceutically acceptable salts of the compounds of formula (I).
  • 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, ethane sulfonic 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 alkal
  • the compounds of the formula (I) contain asymmetric carbon atoms and can 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.
  • Mixtures can be separated in a manner known per se, e.g. by column chromatography, thin layer chromatography (TLC), high performance liquid chromatography (HPLC), or crystallization.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • Compounds of the invention also include nitrosated compounds of formula (I) that have been nitrosated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfydryl condensation) and/or nitrogen.
  • the nitrosated compounds of the present invention can be prepared using conventional methods known to one skilled in the art. For example, known methods for nitrosating compounds are described in U.S. Pat. Nos. 5,380,758, 5,703,073, 5,994,294, 6,242,432 and 6,218,417; WO 98/19672; and Oae et al., Org. Prep. Proc. Int., 15(3): 165-198 (1983).
  • a group of preferred compounds of formula (I) is that wherein M represents aryl (preferably phenyl), which is especially optionally mono- or di- substituted with substituents independently selected from the group consisting of methyl, methoxy, -CF 3 , -(CH 2 ) 2 _ 3 OCH 3 , and halogen.
  • M represents aryl (preferably phenyl), which is especially optionally mono- or di- substituted with substituents independently selected from the group consisting of methyl, methoxy, -CF 3 , -(CH 2 ) 2 _ 3 OCH 3 , and halogen.
  • a further group of preferred compounds of formula (I) is that wherein Q is methylene.
  • V is -OCH 2 CH 2 O- or especially -CH 2 CH 2 CH 2 O- [preferably wherein the -CH 2 - part of -CH 2 CH 2 CH 2 O- is linked to the group W of formula (I)].
  • V represents -0-CH 2 -L-, wherein L represents isoxazolyl.
  • a further group of preferred compounds of formula (I) is that wherein U is a mono-, di-, tri- or tetra- substituted aryl (preferably a mono-, di-, or tri- substituted phenyl), wherein the substituents are independently selected from the group consisting of halogen and methyl.
  • Another group of preferred compounds of formula (I) is that wherein W is phenyl.
  • a further group of preferred compounds of formula (I) is that with an (i?)-absolute configuration at the 3-position of the pyrrolidine core structure of formula (I), and an ( ⁇ -absolute configuration at the 4-position of the pyrrolidine core structure of formula (I).
  • the present invention also relates to compounds of formula (I) wherein the meanings of one or more of the substituents and symbols as defined for formula (I), or a preferred embodiment of formula (I), are replaced by their preferred meanings as defined herein, such as those defined for the above-given preferred compounds.
  • the present invention relates to a compound of formula (I), wherein
  • W is a phenyl ring, substituted by V in para position
  • V represents -A-(CH 2 ) V -B-;
  • a and B are both -O- ;
  • U represents tri- substituted phenyl, wherein the substituents are independently selected from alkyl (preferably methyl) and halogen;
  • M represents di- substituted phenyl, wherein the substituents are independently selected from alkyl, preferably from methyl; R 1 is cycloalkyl, preferably cyclopropyl; and v is the integer 2.
  • 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 known to be related to the renin-angiotensin system.
  • diseases such as or related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal
  • 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.
  • the production of the pharmaceutical 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 and/or other drugs beneficial for the prevention or the treatment of the above-mentioned diseases such as 1 lbeta-hydroxysteroid 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
  • 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.
  • a compound of formula (I) can be prepared as described in Scheme 1. Starting from a dihydropyrrolyl derivative protected with a suitable protecting group PG (that may be changed along the synthesis) a compound of type A is prepared typically using any kind of Michael addition, often catalyzed by a transition metal. A subsequent amide coupling leads to a compound of type B, then removal of the protecting group to a compound of formula (I).
  • EIA Enzyme immuno assay
  • Angl-BSA conjugate 1.3 mg (1 ⁇ mol) of Angl [1-10 (Bachem, H-1680)] and 17 mg (0.26 ⁇ mol) of BSA (Fluka, 05475) were dissolved in 4 mL of 0.1M phosphate buffer, pH 7.4, after which 2 mL of a 1:100 dilution of glutaraldehyde in H 2 O (Sigma G-5882) was added dropwise. The mixture was incubated overnight at 4 0 C, then dialyzed against 2 liters of 0.9% NaCl, twice for 4 h at rt, followed by dialysis against 2 liters of PBS IX overnight at rt.
  • 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.
  • 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.
  • Angl-EIA in 384 well MTP
  • the Angl (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- Angl antiserum, pre-diluted 1:10 in horse serum), diluted to a final concentration of l:100'000 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 Angl during the renin reaction was quantified by comparing the OD of the sample with the OD of a standard curve of Angl(l-lO), measured in parallel.
  • substrate solution 1.89mM ABTS (2.2'-azino-di-(3-ethyl- benzthiazolinsulfonate)] (Roche Diagnostics, 102
  • renin inhibition assay IC 50 in buffer, 384 well MTP
  • 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 (Angl). In the second step, the accumulated Angl 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 Angl produced by renin was quantified. The percentage of renin inhibition (Angl decrease) was calculated for each concentration of compound and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC50).
  • the compounds of formula (I) exhibit IC50 values between 0.1 nM to 300 nM, especially between 1 nM to 30 nM.

Landscapes

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

Abstract

L'invention concerne des dérivés amides d'acide pyrrolidine-3-carboxylique et leur utilisation en tant qu'ingrédients actifs dans la préparation de compositions pharmaceutiques. L'invention concerne également des aspects associés comprenant des procédés de préparation de ces nouveaux composés, des compositions pharmaceutiques renfermant lesdits composés et en particulier, l'utilisation desdits composés comme inhibiteurs de la rénine.
PCT/IB2006/053359 2005-09-22 2006-09-19 Derives amides d'acide pyrrolidine-3-carboxylique utilises comme inhibiteurs de la renine WO2007034406A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP2005010241 2005-09-22
EPPCT/EP2005/010241 2005-09-22

Publications (1)

Publication Number Publication Date
WO2007034406A1 true WO2007034406A1 (fr) 2007-03-29

Family

ID=37733748

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/053359 WO2007034406A1 (fr) 2005-09-22 2006-09-19 Derives amides d'acide pyrrolidine-3-carboxylique utilises comme inhibiteurs de la renine

Country Status (1)

Country Link
WO (1) WO2007034406A1 (fr)

Cited By (3)

* 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
TWI452044B (zh) * 2007-06-15 2014-09-11 Mitsubishi Tanabe Pharma Corp 嗎啉衍生物
US8889714B2 (en) 2008-05-05 2014-11-18 Actelion Pharmaceuticals Ltd. 3,4-substituted piperidine derivatives as renin inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006397A2 (fr) * 1997-08-04 1999-02-11 Abbott Laboratories Antagonistes d'endotheline
WO2004043925A2 (fr) * 2002-11-08 2004-05-27 Neurogen Corporation 6-aryl pyridines substituees en 3

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999006397A2 (fr) * 1997-08-04 1999-02-11 Abbott Laboratories Antagonistes d'endotheline
WO2004043925A2 (fr) * 2002-11-08 2004-05-27 Neurogen Corporation 6-aryl pyridines substituees en 3

Cited By (3)

* 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
TWI452044B (zh) * 2007-06-15 2014-09-11 Mitsubishi Tanabe Pharma Corp 嗎啉衍生物
US8889714B2 (en) 2008-05-05 2014-11-18 Actelion Pharmaceuticals Ltd. 3,4-substituted piperidine derivatives as renin inhibitors

Similar Documents

Publication Publication Date Title
KR20090008211A (ko) 신규 아민
RU2410374C2 (ru) Новые амидные производные пиперидинкарбоновой кислоты
EP1846407B1 (fr) Acide 7-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylique cyclopropyl-(2,3-dimethylbenzyl)amide utilisé comme inhibiteur de la renine pour le traitement de l'hypertension
CA2707565A1 (fr) Inhibiteurs de la renine
US20090088457A1 (en) Primary Amines as Renin Inhibitors
EP2097377B1 (fr) Inhibiteurs de la rénine
US20110237622A1 (en) Renin inhibitors
WO2007049224A1 (fr) Nouveaux derives d'hexahydro- ou d'octahydro-cyclopenta[c]pyrrole
WO2007034406A1 (fr) Derives amides d'acide pyrrolidine-3-carboxylique utilises comme inhibiteurs de la renine
WO2007034445A2 (fr) Nouveaux derives de la piperazine
WO2006021403A1 (fr) Dérivés du bicyclononène
WO2006059304A2 (fr) Nouveaux derives bicycliques
US20110207783A1 (en) Renin inhibitors
US20060235056A1 (en) Novel 3,4-disubstituted 1,2,3,6-tetrahydropyridine derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06809336

Country of ref document: EP

Kind code of ref document: A1