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WO2006058546A1 - Nouveaux dérivés de lactame en tant qu’inhibiteurs de la rénine - Google Patents

Nouveaux dérivés de lactame en tant qu’inhibiteurs de la rénine Download PDF

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Publication number
WO2006058546A1
WO2006058546A1 PCT/EP2004/013610 EP2004013610W WO2006058546A1 WO 2006058546 A1 WO2006058546 A1 WO 2006058546A1 EP 2004013610 W EP2004013610 W EP 2004013610W WO 2006058546 A1 WO2006058546 A1 WO 2006058546A1
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WO
WIPO (PCT)
Prior art keywords
renal
cardiac
lower alkyl
phenyl
mmol
Prior art date
Application number
PCT/EP2004/013610
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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
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
Priority to PCT/EP2004/013610 priority Critical patent/WO2006058546A1/fr
Priority to PCT/IB2005/054008 priority patent/WO2006059304A2/fr
Publication of WO2006058546A1 publication Critical patent/WO2006058546A1/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 five-membered heteroaryl 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 (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
  • 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 Berkenhager W. H., Reid J. L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996, 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 (Oefher C. et al, Chem. Biol, 1999, 6, 127; Patent Application WO97/09311; 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 long duration of action 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.
  • the present invention relates to novel bicyclic derivatives of the general formula (I),
  • W represents a 1 ,4-disubstituted phenyl, substituted by V in para position;
  • V represents oxy-lower alkyl; lower alkyloxy or oxy-lower alkyloxy;
  • U represents aryl or mono-, di-, tri- or tetra- substituted aryl, whereby the substituents are halogen, -CF 3 , -OCF 3i -CH 2 OH or lower alkyl;
  • T represents -CO-N(R 1 )-;
  • Q represents lower alkylene
  • M represents phenyl, mono- or di-substituted phenyl, substituted by lower alkyl, lower alkyloxy, -OCF 3 , -CF 3 , hydroxy-lower alkyl, halogen;
  • R 1 represents lower alkyl; or cycloalkyl ;
  • J represents hydrogen or lower alkyl
  • optically pure enantiomers mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and 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 alkyloxy refers to a R-O group, wherein R is a lower alkyl.
  • Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso- butoxy, sec-butoxy and tert-butoxy.
  • oxy-lower alkyl refers to a -O-R group, wherein R is lower alkyl. Examples are oxymethyl, oxyethyl, oxypropyl, oxy-iso-propyl, oxy- tert.-butyl etc.
  • Term oxy-lower alkyloxy refers to a -O-R-O- group, wherein R is lower alkylen. Examples are oxymethylenoxy, oxyethylenoxy, oxypropylenoxy, oxy- iso-propylenoxy, oxy-tert.-butylenoxy etc.
  • lower alkylene alone or in combination with other groups, means straight and branched divalent chain groups with one to seven carbon atoms, preferably one to four carbon atoms.
  • Examples of lower alkylene are methylene, ethylene, propylene or butylene.
  • 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 7 carbon atoms, preferably 3 to 6, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • 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) 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, and the meso-form and pharmaceutically acceptable salts therof.
  • Bicyclic derivatives of the general Very Very preferred compounds are compounds of formula (I) wherein W, V, U, J are as defined in general formula (I), T represents -CONR 1 - , R 1 represents cycloalkyl; Q represents methylene; M represents phenyl, mono- or di- substituted phenyl substituted with halogen, -CF 3, or -OCF 3 ,
  • enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates, and the meso- form; as well as pharmaceutically acceptable salts, solvent complexes and morphological forms.
  • An especially preferred bicyclic derivative of general formula (I) is: (rac.)-(lR*, 5S*)-7- ⁇ 4-[3-(2-chloro-3,6-difluorophenoxy) ⁇ ropyl] ⁇ henyl ⁇ -3- methyl-2-oxo-3,9-diazabicyclo[3.3.1 ]non-6-ene-6-carboxylic acid cyclopropyl- (2,3 -dichlorobenzyl)amide.
  • 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 compound 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.
  • 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, 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.
  • this amount 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.
  • 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.
  • 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, corn starch 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, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
  • the dosage of compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case.
  • Another aspect of the invention is related to a process for the preparation of a pharmaceutical composition comprising a derivative of the general formula (I). According to said process, one or more active ingredients of the general formula (I) are mixing with inert excipients in a manner known per se.
  • the compounds of general formula I can be manufactured by the methods outlined below, by the methods described in the examples or by analogous methods.
  • the vinylic triflate of compound H can be prepared using standard conditions and leads to compound J (Scheme 2).
  • R a stands for a precursor for the group U-V as defined in general formula I.
  • 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 general formula (I), by simple cleavage of the methoxycarbonyl protecting group.
  • TPAP (0.74 g) and iV-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 /Me0H 20:1) yielded the title compound (4.55 g 75%).
  • 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 mM 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°C and consists of the following components: • human recombinant renin (0.16 ng/mL) • synthetic human angiotensin(l-14) (0.5 ⁇ M)
  • the plates were washed 3 times with PBS including 0.01% Tween 20, and then incubated for 2 h at it with an antirabbit-peroxidase coupled antibody (WA 934, Amersham). After washing the plates 3 times, 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% (IC 50 ). The IC 5 o-values of all compounds tested are below 100 nM. However selected compounds exhibit a very good bioavailibility and are metabolically more stable than prior art compounds.
  • the examplif ⁇ ed compound displayed an IC 50 -value of 2.1 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)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • 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

La présente invention décrit de nouveaux dérivés de lactame, des composés proches ainsi que l’emploi de ces substances en tant que principes actifs dans l’élaboration de préparations pharmaceutiques. La présente invention a également pour objet des aspects issus des précédents en ce qui concerne la synthèse des substances, les préparations pharmaceutiques contenant l'un au moins de ces composés, et plus particulièrement leur emploi en tant qu’inhibiteurs de la rénine.
PCT/EP2004/013610 2004-12-01 2004-12-01 Nouveaux dérivés de lactame en tant qu’inhibiteurs de la rénine WO2006058546A1 (fr)

Priority Applications (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
PCT/IB2005/054008 WO2006059304A2 (fr) 2004-12-01 2005-12-01 Nouveaux derives bicycliques

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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

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PCT/IB2005/054008 WO2006059304A2 (fr) 2004-12-01 2005-12-01 Nouveaux derives bicycliques

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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
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009135299A1 (fr) 2008-05-05 2009-11-12 Merck Frosst Canada Ltd. Dérivés de pipéridine substitués en 3,4 utilisés en tant qu'inhibiteurs de la rénine

Citations (5)

* 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
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070142363A1 (en) * 2003-10-13 2007-06-21 Actelion Pharmaceuticals Ltd Novel diazabicyclonene derivatives and use thereof

Patent Citations (5)

* 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
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 (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
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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WO2006059304A3 (fr) 2006-10-12

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