WO2006063610A1 - Dérivés de diazabicyclononène substitués par des groupements hétéroaryle - Google Patents

Dérivés de diazabicyclononène substitués par des groupements hétéroaryle Download PDF

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Publication number
WO2006063610A1
WO2006063610A1 PCT/EP2004/014401 EP2004014401W WO2006063610A1 WO 2006063610 A1 WO2006063610 A1 WO 2006063610A1 EP 2004014401 W EP2004014401 W EP 2004014401W WO 2006063610 A1 WO2006063610 A1 WO 2006063610A1
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Prior art keywords
mixtures
diastereomers
racemates
substituted
compound
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PCT/EP2004/014401
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English (en)
Inventor
Olivier Bezencon
Lubos Remen
Thierry Sifferlen
Corinna Grisostomi
Sylvia Richard-Bildstein
Daniel Bur
Christoph Boss
Olivier Corminboeuf
Walter Fischli
Thomas Weller
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Actelion Pharmaceuticals Ltd
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Priority to PCT/EP2004/014401 priority Critical patent/WO2006063610A1/fr
Priority to PCT/IB2005/054276 priority patent/WO2006064484A1/fr
Priority to ARP050105314A priority patent/AR052055A1/es
Publication of WO2006063610A1 publication Critical patent/WO2006063610A1/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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to novel heteroaryl substituted tetrahydropyridine derivatives of the general 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 Q) 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 ah, "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 ctl, 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 (Oefher C. et al, Chem. Biol, 1999, 6, 127; Patent Application WO97/09311; Marki H. P. et al, E 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 long duration of action 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.
  • the present invention relates to novel heteroaryl substituted tetrahydropyridine derivatives of the general formula (I):
  • W represents 1,4-phenyl
  • V represents a substituent of the formula -E 1 -Z-E 2 -;
  • E 1 represents -0-CH 2 -; - CH 2 -CH 2 -;
  • E 2 represents a bond, -O-, -CH 2 -;
  • Z represents a five-membered heteroaryl with 2 or 3 heteroatoms
  • U represents phenyl or mono-, di-, tri- or terra- substituted phenyl, whereby the substituents are selected from the group consisting of halogen, -CF 3 , C 1-7 -alkyl or C 1 -C 7 hydroxy-lower alkyl;
  • T represents -CONR 1 -;
  • M represents phenyl, mono- or di-substituted phenyl, whereby the substituents are selected from the group consisting of C 1 . 7 -a.kyl, C ⁇ -alkoxy, -OCF 3 , -CF 3 , hydroxy-Ci- 7 -alkyl and halogen;
  • R 1 represents Q- 7 -alkyl or C 3 -C 6 cycloalkyl
  • enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, the meso-form as well as pharmaceutically acceptable salts, solvent complexes and morphological forms.
  • lower alkyl in the definitions of general formula (I) - if not otherwise stated - the term lower alkyl, alone or in combination with other groups, means saturated, straight and branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms that can be optionally substituted by halogens.
  • lower 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.
  • lower alkoxy refers to a R-O group, wherein R is a lower alkyl.
  • R is a lower alkyl.
  • lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.
  • hydroxy-lower alkyl alone or in combination with other groups refers to a HO-R group, wherein R is a lower alkyl.
  • R is a lower alkyl.
  • hydroxy-lower alkyl groups are HO-CH 2 -, HO-CH 2 CH 2 - -CH(OH)CH 3 , or HO-CH 2 CH 2 CH 2 -.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
  • cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which can be optionally mono- or multisubstituted by lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkylenoxy, lower alkylenedioxy, lower alkoxy - lower alkyl, cycloalkyl - lower alkyl, cycloalkoxy, cycloalkoxy - lower alkyl, hydroxy, halogen, -CF 3 , and OCF 3 .
  • cycloalkoxy refers to a R-O group, wherein R is a cycloalkyl.
  • Examples of cycloalkoxy groups are cyclopropoxy, cyclobutoxy, cyclopentoxy.
  • heteroaryl means five-membered aromatic rings containing two or three heteroatoms, preferably nitrogen, oxygen or sulfur.
  • Preferred are five-membered aromatic rings containing one oxygen and two nitrogen atoms; five- membered aromatic rings containing one nitrogen and one oxygen atom; five-membered aromatic rings containing two nitrogen atoms; five-membered aromatic rings containing three nitrogen atoms; five-membered rings containing two nitrogen atoms and one sulfur atom.
  • Examples of such ring systems are triazinyl, thiazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl.
  • Such rings may be adequatly substituted with lower alkyl, lower alkenyl, lower alkinyl, lower alkylene, lower alkenylene, lower alkylenedioxy, lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen, -CF 3 , -OCF 3 , another aryl, preferably phenyl or substituted phenyl, or another heteroaryl and the like.
  • V represents a substituent of the formula -E 1 -Z- E 2 - which may be connected in both possible ways to the group W and U of the compound of formula I.
  • the beginning part of the group -E'-Z-E 2 - is linked to the group W of the compound of formula I (that means, for example, that the -E ⁇ part of -E 1 ⁇ -Z-E 2 - is linked to the group W of the compound of formula I.
  • T within the present invention represents -CONR 1 - which may be connected in both possible ways to the core structure of compound of formula I.
  • CONR 1 - is linked to the core structure of compound of formula I.
  • T within the present invention represents -CONR 1 - ,wherein R 1 represents C 1-7 -alkyl or C 3 - Ce-cycloalkyl, preferably and most preferred cyclopropyl.
  • salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic 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 base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non toxic to living organisms or in case the compound of formula (I) is
  • the compounds of the general formula (I) contain two or more asymmetric carbon atoms and are prepared in form of optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and the meso-form and pharmaceutically acceptable salts thereof.
  • the present invention encompasses all these forms. Mixtures are separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC or crystallization.
  • M represents phenyl, mono- or di-substituted phenyl, wherein the substituents are selected from the group consisting of C 1-7 -alkyl, C 1-7 -alkoxy, and halogen.
  • M represents disubstituted phenyl, wherein the substituents are selected from the group consisting of C 1-7 -alkyl, C ⁇ -alkoxy, and chlorine.
  • R 1 represents a cyclopropyl group.
  • U represents a mono-, di-, or trisubstituted phenyl wherein the substituents are selected from the group consisting of halogen and C 1-7 -alkyl.
  • heteroaryl substituted diazabicyclononene derivatives of general formula (I) are those selected from the group consisting of:
  • the invention relates to a method for the treatment and/or prophylaxis of diseases which are 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, which method comprises administrating a compound as defined above to a human being or animal.
  • the invention relates to a method for the treatment and/or prophylaxis of diseases which are 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, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy.
  • the invention in another embodiment, relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin-angiotensin system as well as for the treatment of the above-mentioned diseases.
  • the invention also relates to the use of compounds of formula (I) for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.
  • a further aspect of the present invention is related to a pharmaceutical composition containing at least one five-membered heteroaryl derivative according to general formula (I) and pharmaceutically acceptable carrier materials or adjuvants.
  • This pharmaceutical composition may be used for the treatment or prophylaxis of the above-mentioned disorders; as well as for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.
  • Compounds of formula (I) and their pharmaceutically acceptable acid addition salts can be used as medicaments, e. g. in the form of pharmaceutical compositions containing at least one compound of formula (I) and pharmaceutically acceptable inert carrier material or adjuvants.
  • These 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.
  • Five-membered heteroaryl derivatives of formula (I) or the above-mentioned pharmaceutical compositions are also of use in combination with other pharmacologically active compounds comprising ACE-inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, aldosterone antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.
  • ACE-inhibitors neutral endopeptidase inhibitors
  • angiotensin II receptor antagonists aldosterone antagonists
  • endothelin receptors antagonists endothelin receptors antagonists
  • vasodilators calcium antagonists
  • potassium activators diuretics
  • sympatholitics beta-adrenergic antagonists
  • alpha-adrenergic antagonists
  • compositions can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and their pharmaceutically acceptable acid addition 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.
  • suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
  • lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules).
  • Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Suitable carrier materials for injections are, for example, water, alcohols, polyols, glycerols and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
  • Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • Heteroaryl substituted tetrahydropyridine derivatives according to formula (I) are also used in combination with other pharmacologically active compounds comprising ACE- inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin receptors antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases.
  • the amount administered to a patient of a pharmaceutically active amount of a heteroaryl substituted tetrahydropyridine derivative according to formula (I) is comprised between 2 mg and 1000 mg per day.
  • this amount is comprised between 1 mg and 500 mg per day.
  • this amount is comprised between 5 mg and 200 mg per day. All forms of prodrugs leading to an active component comprised by general formula (I) above are included in the present invention.
  • Another aspect of the invention is related to a process for the preparation of a pharmaceutical composition comprising a heteroaryl substituted tetrahydropyridine derivative of the general formula (I).
  • one or more active ingredients of the general formula (I) are mixing with inert excipients in a manner known per se.
  • heteroaryl substituted tetrahydropyridine derivatives of general formula (I) can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
  • a compound of type A in Scheme 1, wherein PG stands for a protecting group can be prepared from P-methyl-T-trifluoromethanesulfonyloxy-S ⁇ -diazabicyclop.S.ljnon- ⁇ -ene- 3,6-dicarboxylic acid 3-fert-butyl ester 6-ethyl ester (WO03/093267), and a protected 4- bromophenol derivative via a Negishi coupling, or any other coupling catalyzed by a palladium catalyst.
  • a protecting group manipulation delivers a compound of type B, then a hydrolysis of the ethyl ester yields a compound of type C.
  • An amide coupling for instance, leads then to a compound of type E, and a subsequent ether formation, via a Mitsunobu reaction, for instance, delivers a compound of type F.
  • the fragment necessary for the construction of the fragment U-V is prepared in parallel, very often following literature procedures. Final deprotection yields a compound of general formula (I).
  • segment U-V- can be prepared on the template directly, as described in Scheme 2.
  • a compound of type H can be prepared, wherein X stands for a precursor of the substituent V as described in general formula (I).
  • X can be modified along the synthesis.
  • the whole segment U-V- is constructed to yield a compound of type F. Deprotection yields a compound of general formula (I).
  • the compound is characterized at least by LC-MS and 1 H-NMR. Only the LC-MS data are given here (Zorbax SB-AQ column, 5 ⁇ m, 4.6x50 mm; eluent A: 0.04% trifluoroacetic acid in water; eluent B: acetonitrile; gradient 5% -» 100% eluent B over 1.5 min, flow 1 mL/min)
  • the enzymatic in vitro assay was performed in 384-well polypropylene plates (Nunc).
  • the assay buffer consisted of 10 mM PBS (Gibco BRL) including 1 niM EDTA and 0.1% BSA.
  • the incubates were composed of 50 ⁇ L per well of an enzyme mix and 2.5 ⁇ L of renin inhibitors in DMSO.
  • the enzyme mix was premixed at 4 0 C and consists of the following components:
  • the accumulated Ang I was detected by an enzyme immunoassay (EIA) in 384-well plates (Nunc). 5 ⁇ L of the incubates or standards were transferred to immuno plates which were previously coated with a covalent complex of Ang I and bovine serum albumin (Ang I - BSA). 75 ⁇ L of Ang I-antibodies in essaybuffer above including 0.01% Tween 20 were added and a primary incubation made at 4 0 C overnight. The plates were washed 3 times with PBS including 0.01% Tween 20, and then incubated for 2 h at rt with an antirabbit-peroxidase coupled antibody (WA 934, Amersham).
  • EIA enzyme immunoassay
  • the peroxidase substrate ABTS (2.2'-azino- di-(3-ethyl-benzthiazolinsulfonate), was added and the plates incubated for 60 min at room temperature. After stopping the reaction with 0.1 M citric acid pH 4.3 the plate was evaluated in a microplate reader at 405 nm. The percentage of inhibition was calculated of each concentration point and the concentration of renin inhibition was determined that inhibited the enzyme activity by 50% (IC50). The IC50 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.

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Abstract

La présente invention a pour objet des dérivés de diazabicyclononène substitués par des groupements hétéroaryle, des composés de structure proche desdits dérivés, ainsi que l'emploi desdits dérivés en tant que principes actifs dans l'élaboration de préparations pharmaceutiques. La présente invention a également pour objet des aspects liés à ces composés, ce qui inclut des procédés de synthèse desdits composés, des préparations pharmaceutiques comprenant un ou plusieurs desdits composés, et plus particulièrement leur emploi en tant qu'inhibiteurs de la rénine.
PCT/EP2004/014401 2004-12-17 2004-12-17 Dérivés de diazabicyclononène substitués par des groupements hétéroaryle WO2006063610A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/EP2004/014401 WO2006063610A1 (fr) 2004-12-17 2004-12-17 Dérivés de diazabicyclononène substitués par des groupements hétéroaryle
PCT/IB2005/054276 WO2006064484A1 (fr) 2004-12-17 2005-12-15 Derives d'azabicyclononene utilises en tant qu'inhibiteurs de la renine
ARP050105314A AR052055A1 (es) 2004-12-17 2005-12-16 Derivados de biciclononeno

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908763A1 (fr) * 2006-10-04 2008-04-09 Speedel Experimenta AG Composés bicycliques
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

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US8129538B1 (en) 2007-03-28 2012-03-06 Takeda Pharmaceutical Company Limited Renin inhibitors
SG192543A1 (en) 2008-05-05 2013-08-30 Merck Canada Inc 3, 4 - substituted piperidine derivatives as renin inhibitors
WO2013145666A1 (fr) 2012-03-29 2013-10-03 ソニー株式会社 Élément électroluminescent organique
US9978975B2 (en) 2012-03-29 2018-05-22 Joled Inc Organic electroluminescence device
CN107935863A (zh) * 2017-11-30 2018-04-20 厦门海乐景生化有限公司 Elagolix的关键原料化合物C的合成方法

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WO2003093267A1 (fr) * 2002-04-29 2003-11-13 Actelion Pharmaceuticals Ltd Derives de 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene et leur utilisation en tant qu'inhibiteurs de renine dans le traitement de l'hypertension, de maladies cardiovasculaires ou renales
WO2004096803A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives d'azabicyclononene
WO2004096804A1 (fr) * 2003-04-28 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine
WO2004096116A2 (fr) * 2003-05-02 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene

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CN1780663A (zh) * 2003-04-30 2006-05-31 埃科特莱茵药品有限公司 作为肾素抑制剂的新型3－位具有杂原子的9－氮杂双环壬烯衍生物
WO2004105762A1 (fr) * 2003-05-30 2004-12-09 Actelion Pharmaceuticals Ltd Utilisation medicale de derives de diazabicyclononene utilises comme inhibiteurs des proteases aspartiques parasites

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2003093267A1 (fr) * 2002-04-29 2003-11-13 Actelion Pharmaceuticals Ltd Derives de 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene et leur utilisation en tant qu'inhibiteurs de renine dans le traitement de l'hypertension, de maladies cardiovasculaires ou renales
WO2004096804A1 (fr) * 2003-04-28 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine
WO2004096803A1 (fr) * 2003-04-30 2004-11-11 Actelion Pharmaceuticals Ltd Derives d'azabicyclononene
WO2004096116A2 (fr) * 2003-05-02 2004-11-11 Actelion Pharmaceuticals Ltd Derives de diazabicyclononene

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908763A1 (fr) * 2006-10-04 2008-04-09 Speedel Experimenta AG Composés bicycliques
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

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