WO2006079610A1 - Derives de sartane nitrooxy en tant que bloqueurs d'un recepteur d'angiotensine ii pour le traitement de maladies cardio-vasculaires et inflammatoires - Google Patents

Derives de sartane nitrooxy en tant que bloqueurs d'un recepteur d'angiotensine ii pour le traitement de maladies cardio-vasculaires et inflammatoires Download PDF

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WO2006079610A1
WO2006079610A1 PCT/EP2006/050348 EP2006050348W WO2006079610A1 WO 2006079610 A1 WO2006079610 A1 WO 2006079610A1 EP 2006050348 W EP2006050348 W EP 2006050348W WO 2006079610 A1 WO2006079610 A1 WO 2006079610A1
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Nicoletta Almirante
Alessia Nicotra
Ennio Ongini
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Nicox SA
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Nicox SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to Angiotensin II Receptor Blocker (ARB) nitroderivatives , pharmaceutical compositions containing them and their use for the treatment of cardiovascular, renal and chronic liver diseases , inflammatory processes and metabolic syndromes .
  • ARB Angiotensin II Receptor Blocker
  • angiotensin II receptor blockers a class of compounds is intended, comprising as main components
  • Olmesartan medoxomil Olmesartan medoxomil .
  • ARBs are approved only for the treatment of hypertension, the antihypertensive activity is due mainly to selective blockade of ATi receptors and the consequent reduced pressor effect of angiotensin II .
  • Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a potent direct vasoconstrictor effect .
  • angiotensin II receptor blockers have side-effects such as for example hypotension, hyperkalaemia, myalgia, respiratory-tract disorders , renal disorders , back pain, gastrointestinal disturbances , fatigue, and neutropenia (Martindale, Thirty-third edition, p . 921 ) .
  • angiotensin II Receptor Blocker nitroderivatives having an improved pharmacological activity an improved pharmacodinamic and pharmacokinetic profiles as compared to the compounds of the prior art . It has been so surprisingly found that angiotensin II receptor blocker nitroderivatives of the invention have a significantly improved overall profile as compared to native compounds both in term of wider pharmacological activity and enhanced tolerability .
  • angiotensin II receptor blocker nitroderivatives of the present invention exhibit a strong anti-inflammatory, antithrombotic and antiplatelet activity and can be furthermore employed for treating or preventing heart failure, myocardial infarction, ischemic stroke, atherosclerosis , ocular and pulmonary hypertension, hypertension, diabetic nephropathy, peripheral vascular diseases , left ventricular dysfunction and hypertrophy, liver fibrosis , portal hypertension and metabolic syndromes .
  • Obj ect of the present invention are, therefore, Angiotensin II Receptor Blocker nitroderivatives of general formula (I ) and pharmaceutically acceptable salts or stereoisomers thereof :
  • Ri is selected from the group consisting of :
  • R 2 is H, or -W 1 -Y 0 -ONO 2 wherein W 1 is -C (O) - or -C (O) O-; Yo is as reported below;
  • R 3 is H, -Y 0 -ONO 2 or -W 2 -Y 0 -ONO 2 , wherein W 2 is
  • Y 0 is as reported below; W has the following meanings : -C (O) -, -C (O) O-,
  • Wi is -C (O) -; preferably in the radical Ri of formula (Ib) , (Ic) , (Id) ,
  • R 3 is -Y 0 -ONO 2 ; more preferably when Ri is (Ia) , R 2 is H or when Ri is chosen among the radicals of formula (Ib) , (Ic) , (Id) , (Ih) or (Ii) , R 3 is H; Y and Y 0 are the same or different and are bivalent radicals having the following meanings : a)
  • C 1 -C 20 alkylene preferably C 1 -C 10 alkylene, more preferably C 3 -C 6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of : halogen atoms , hydroxy, -ONO 2 or T 0 , wherein T 0 is -OC (O) - (C 1 -C 10 alkyl) -0N0 2 or -0- (C 1 -C 10 alkyl) -0N0 2 ;
  • n is an integer from 0 to 20 , preferably n is 0 or 1 , nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, more preferably nl is 1 , n2 is 0 or 1 , preferably n2 is 0 ; c)
  • nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ,
  • R 4 is H or CH 3 ; d)
  • nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ;
  • Xi is -OC (O) -, -C (O) O-,
  • R 4 is H or CH 3 ; when Y or Y 0 are selected from the bivalent radicals of the groups b) , c ) or d) the -ONO2 group is linked to - (CH 2 ) n1 - group; g)
  • X 2 is 0 or S
  • n3, n4 and n6 are integer independently selected from 0 to 20 , preferably n3, n4 and n6 are selected from 1 to 5, more preferably n3, n4 and n6 are 1
  • n5 is an integer from 0 to 6, preferably from 0 to 4 , more preferably n5 is 0
  • R 6 is H, CH 3 or nitrooxy group, preferably R 6 is H, R 7 is CH 3 or nitrooxy group; when Y or Y 0 are selected from the bivalent radicals of the group g) the -ONO 2 group is linked to - (CH 2 ) n6 - group; when Y or Y 0 are selected from the bivalent radicals of the group h) the -ONO 2 group is linked to -CH (R 7 ) - group; i)
  • n8 is as defined a ove
  • Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
  • C 1 -C 20 alkylene refers to branched or straight C 1 -C 20 saturated hydrocarbon chain that results from the removal of two hydrogen atoms from an acyclic saturated hydrocarbon, preferably having from 1 to 10 carbon atoms such as -CH 2 -, -CH 2 -CH 2 -, - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) 5 -, - (CH 2 ) 6 - and the like .
  • C 1 -C 10 alkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms , including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, n-octyl and the like .
  • cycloalkylene refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C 1 -C 10 ) - alkyl, preferably CH 3 .
  • heterocyclic refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like .
  • Another aspect of the present invention provides the use of the compounds of formula (I ) in combination with at least a compound used to treat cardiovascular disease selected from the group consisting of : ACE inhibitors ,
  • HMGCoA reductase inhibitors beta-adrenergic blockers , calcium channel blockers , diuretics , antithrombotics such as aspirin, nitrosated ACE inhibitors , nitrosated HMGCoA reductase inhibitors , nitrosated beta-adrenergic blockers , nitrosated aspirin and nitrosated diuretics .
  • ACE inhibitors Suitable ACE inhibitors , HMGCoA reductase inhibitors , beta-adrenergic blockers , calcium channel blockers , antithrombotics and diuretics are described in the literature such as The Merck Index (13 th edition) .
  • Suitable nitrosated compounds are disclosed in WO 98/21193, WO 97/16405 and WO 98/09948.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the compounds and/or compositions of the present invention and one or more of the compounds used to treat cardiovascular diseases reported above .
  • the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I ) and stereoisomers thereof .
  • Examples of pharmaceutically acceptable salts are either those with inorganic bases , such as sodium, potassium, calcium and aluminium hydroxides , or with organic bases , such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines .
  • the compounds according to the present invention when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids .
  • organic acids are : oxalic, tartaric, maleic, succinic, citric acids .
  • inorganic acids are : nitric, hydrochloric, sulphuric, phosphoric acids . Salts with nitric acid are preferred.
  • the compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers , pure diastereomers , enantiomers mixtures , diastereomers mixtures , enantiomer racemic mixtures , racemates or racemate mixtures .
  • optically pure enantiomers pure diastereomers
  • enantiomers mixtures pure diastereomers
  • diastereomers mixtures enantiomer racemic mixtures
  • racemates or racemate mixtures enantiomer racemic mixtures
  • obj ect of the invention are also all the possible isomers , stereoisomers and their mixtures of the compounds of formula (I ) .
  • Preferred compounds are those of formula (I ) wherein R 1 is (Ie) , (If) , (Ig) , (II) , (Im) , (In) or Ri is (Ia) , (Ib) , (Ic) , (Id) , (Ih) , (Ic) wherein R 2 and R 3 are H,
  • C 1 -C 20 alkylene preferably C 1 -C 10 , more preferably C 3 -C 6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of : halogen atoms , hydroxy, -ONO2 or T 0 , wherein T 0 is -OC (O) - (C 1 -C 10 alkyl) -ONO 2 or -0- (C 1 -C 10 alkyl) -0N0 2 ;
  • T is straight or branched alkyl with from 1 to 10 carbon atoms , preferably T is CH 3 ;
  • n is an integer from 0 to 20 , preferably n is 0 or 1 , nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, more preferably nl is 1 , n2 is 0 or 1 , preferably n2 is 0 ; c)
  • nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ;
  • nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ;
  • X 2 is 0 or S
  • n3, n4 and n6 are integer independently selected from 0 to
  • n3, n4 and n6 are selected from 1 to 5, more preferably n3, n4 and n6 are 1 , n5 is an integer from 0 to 6, preferably from 0 to 4 , more preferably n5 is 0 ,
  • R 6 is H, CH 3 or nitrooxy group, preferably R 6 is H,
  • R 7 is CH 3 or nitrooxy group; when Y or Y 0 are selected from the bivalent radicals of the group g) the -ONO 2 group is linked to - (CH 2 ) n6 - group; when Y or Y 0 are selected from the bivalent radicals of the group h) the -ONO 2 group is linked to -CH (R 7 ) -; i )
  • n8 is as defined above;
  • Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
  • Another preferred compounds are those of formula (I ) wherein
  • R 1 is (Ie) , (If) , (Ig) , (II) , (Im) , (In) or Ri is (Ia) , (Ib) , (Ic) , (Id) , (Ih) , (Ic) wherein R 2 and R 3 are H,
  • W is as above reported, and Y has the following meanings : a) straight C 1 -C 10 alkylene, preferably C 3 -C 6 alkylene; b)
  • n 0 or 1
  • nl 1
  • X 2 is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 ,
  • R 6 is H
  • Another preferred compounds are those of formula (I ) wherein
  • Ri is the radical of formula (Ia) , wherein R 2 is -Wi-Y 0 -ONO 2 wherein
  • Wi is -C (O) - or -C (O) O-, preferably Wi is -C (O) -
  • Y 0 is as defined below
  • W is -C (O) -, -C (O) O-, preferably W is
  • Y and Yo are the same or different and have the following meanings : a) straight C 1 -C 10 alkylene, preferably C 3 -C 6 alkylene; b)
  • n is 0 or 1 , nl is 1 , n2 is 0 ; g)
  • X 2 is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 , R 6 is H,
  • Another preferred group of compounds are those of formula (I ) wherein
  • Ri is a radical of formula (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is -Y 0 -ONO 2 or -W 2 -Y 0 -ONO 2 wherein
  • Yo is as defined below, W is -C (O) -, -C (O) O-
  • Y and Yo are the same or different and have the following meanings : a) straight C1-C1 0 alkylene, preferably C3-C6 alkylene; b)
  • n is 0 or 1 , nl is 1 , n2 is 0 ; g)
  • R 1 is a radical of formula (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R3 is -Y 0 -ONO2 wherein Y 0 is as defined below, W is -C (O) O-
  • Y and Yo are the same or different and have the following meanings : a) straight C 1 -C 10 alkylene, preferably C 3 -C 6 alkylene; b)
  • n is 0 or 1 , nl is 1 , n2 is 0 ; g)
  • X 2 is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 , R 6 is H,
  • the daily dose of active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day .
  • the dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors , including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs .
  • the compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation or aerosol, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers , adjuvants and vehicles as desired.
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices .
  • transdermal administration such as transdermal patches or iontophoresis devices .
  • parenteral includes subcutaneous inj ections , intravenous , intramuscular, intrasternal inj ection or infusion techniques .
  • Inj ectable preparations for example sterile inj ectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents .
  • the sterile inj ectable preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent .
  • the acceptable vehicles and solvents are water, Ringer' s solution and isotonic sodium chloride .
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any- bland fixed oil may be employed including synthetic mono or diglycerides , in addition fatty acids such as oleic acid find use in the preparation of inj ectables .
  • Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols .
  • Solid dosage forms for oral administration may include capsules , tablets , pills , powders , granules and gels . In such solid dosage forms , the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch .
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents , e . g . lubricating agents such as magnesium stearate .
  • additional substances other than inert diluents e . g . lubricating agents such as magnesium stearate .
  • the dosage forms may also comprise buffering agents . Tablets and pills can additionally be prepared with enteric coatings .
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions , solutions , suspensions , syrups and elixirs containing inert diluents commonly used in the art, such as water .
  • Such compositions may also comprise adjuvants , such as wetting agents , emulsifying and suspending agents , and sweetening, flavouring and the like .
  • the compounds of the present invention can be synthesised as follows .
  • Ri is the radical of formulae ( Ie) , (If) , (Ig) , (H) or (Im) , (In) , or
  • Ri is (Ia) wherein R2 is H and the functional group -CH2-OH is protected, or
  • Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected, in presence of a inorganic or organic base/DMAP in an aprotic polar/non- polar solvent such as DMF, THF or CH 2 CI 2 at temperatures range between 0 ° to 65 °C or in a double phase system H 2 0/Et 2 0 at temperatures range between 20 ° to 4O °C; or in the presence of DMAP and a Lewis acid such as Sc (OTf) 3 or Bi (OTf) 3 in solvents such as DMF, CH 2 Cl 2 ; and then removing the protective group of the compounds obtained as described in IA) ; and optionally converting the resulting compound of general formula (I ) into a pharmaceutically acceptable salt thereof .
  • an aprotic polar/non- polar solvent such as DMF, THF or CH 2 CI 2 at temperatures range
  • Act-H (Ic) wherein Act is as above defined, by conventional esterification reaction with condensing agents as DCC EDAC HCl as well known in the literature .
  • a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF) under nitrogen in the dark at temperatures range between 20 ° to 8O °C
  • the reaction with AgNO 3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 70-180 °C for short time (1-60 min) .
  • Ri is the radical of formulae ( Ie) , (If) , (Ig) , (H) or (Im) , (In) , or
  • Ri is (Ia) wherein R 2 is H and the functional group -CH 2 -OH is protected, or Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected, with a compound of formula (Ia . i)
  • the compounds of formula (If) are obtained by reacting the commercially available compounds of formula HO-Y-HaI (If ) wherein Y and Hal are as above defined, with AgNO 3 in a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF) under nitrogen in the dark at temperatures range between 20 ° -80 °C; alternatively the reaction with AgNC> 3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between about 100-180 °C for time range about 1-60 min .
  • a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF)
  • Act-H (Ic) wherein Act is as above defined, with phosgene and derivatives such as triphosgene, in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures range between 0 ° to 65 °C .
  • Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or ( In) , or Ri is the radical of formulas (Ia) , (Ib) , (Ic)
  • Ri is (Ia) wherein R2 is H and the functional group -CH2-OH is protected, or
  • Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected, with compounds of formula (Ia . ii) ,
  • HaI-C (O) -O-Y-ONO 2 (Ia . ii) wherein Hal is an halogen atom, preferably is Cl, and Y is as above defined, in presence of a inorganic or organic base/DMAP in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0 ° to 65 °C or in a double phase system H 2 0/Et 2 0 at temperatures range between 20 ° to 4O °C; or in the presence of DMAP and a Lewis acid such as Sc (OTf) 3 or Bi (OTf) 3 in solvents such as DMF, CH 2 Cl 2 ; and then removing the protective group of the obtained compounds ; and optionally converting the resulting compounds of formula (I ) into a pharmaceutically acceptable salt .
  • aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • ii) as above defined, are obtained by reacting a compounds of formula (If) HO-Y-ONO 2 (If) and phosgene and its derivatives such as triphosgene in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0 ° to 65 °C, IC c)
  • aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or ( In)
  • Ri is the radical of formulas (Ia) , (Ib) , (Ic) (Id) (Ih) or (Ii) , wherein R 2 or R 3 are H, and wherein W is ,
  • Y is as above defined, can be obtained by a process comprising :
  • Ri is the radical of formulae ( Ie) , (If) , (Ig) , (H) or
  • Ri is (Ia) wherein R2 is H and the functional group -CH2-OH is protected, or
  • Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected, with compounds of formula (la . iii)
  • HaI-W 4 -OC (O) O-Y-ONO 2 (la . iii) wherein Hal is an halogen atom and W4 is -CH 2 - or -CH (CH 3 ) -, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0 ° to 65 °C or in a double phase system H 2 0/Et 2 0 at temperatures range between 20 ° to 4O °C; and then removing the protective group of the obtained compounds .
  • ID . a) The compound of formula (1 ) wherein Ri is (Ia) and the functional group -CH 2 -OH is protected, is obtained using method described in IA. b) .
  • Y is as above defined, can be obtained by a process comprising :
  • an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • ACt-C (O) -Y-ONO 2 (Ia) as above defined are obtained by using the method described in IA. d) .
  • Y is as above defined, can be obtained by a process comprising :
  • Y is as above reported, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0 ° to 65 °C; II .
  • a) The compounds of formula (1 ) wherein Ri is as above reported and R 3 is -Y-ONO 2 are obtained by method described in IH . b) .
  • HaI-W 4 -OC (O) O-Y-ONO 2 (la . iii) as above defined, are obtained by method described in lD . b) .
  • Y is as above defined, can be obtained by a process comprising : IL) reacting a compounds of formula (1 ) , wherein Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) and R 3 is H, with compounds of formula (la . iii)
  • Ri is the radical of formulas (Ia) , (Ib) , (Ic)
  • Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , or Ri is the radical of formula (Ia) wherein R 2 is H and the functional group -CH 2 -OH is protected, or Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected; W and Y are as above defined, Hal is an halogen atom, preferably Cl, Br, I , with AgNO 3 as described for similar transformations ; and then removing the protective group with the methods known in the art; and optionally converting the resulting compound of general formula (I ) into a pharmaceutically acceptable salt .
  • a Lewis acid such as Sc (OTf) 3 or Bi (OTf) 3 in solvents such as DMF, CH 2 Cl 2 ; IM.
  • Ri is the radical of formulas (Ia) , (Ib) , (Ic)
  • Ri is the radical (Ie) , (If) , (Ig) , (II) , (Im) or (In) , or Ri is the radical of formula (Ia) wherein R2 is H and the functional group -CH 2 -OH is protected, or
  • Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected,
  • W and Y are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between -60 ° to 65 °C; and then removing the protective group with the methods known in the art; and optionally converting the compound of formula (I ) into a pharmaceutically acceptable salt .
  • an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , or
  • Ri is the radical of formula (Ia) wherein R 2 is H and the functional group -CH 2 -OH is protected, or
  • Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R 3 is H and the functional groups -C (O) OH are protected, with compounds of formula (Im)
  • ACt-C (O) -Y-OH (Im) are obtained by reacting commercially available (Ic) Act-H (Ic) with the commercially available compounds of formula (lo)
  • ACt-C (O) -O-Y-OH (In) are obtained by reacting compounds of formula (Ie)
  • an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • the resulting solution was kept under stirring for further 4 hrs at room temperature .
  • the reaction mixture was poured into a pH 3 buffer solution (50 ml) , acidified with HCl IN to pH 3-4 and extracted with CH2CI2 (2 x 50 ml) .
  • the organic phase was washed with brine (100 ml) , dried on sodium sulfate and evaporated.
  • the resulting solution was kept under stirring for further 16 hrs at room temperature .
  • the reaction mixture was poured into a pH 3 buffer solution (50 ml) , acidified with HCl 1 N to pH 3-4 and extracted with CH 2 Cl 2 (2 x 50 ml) .
  • the organic phase was dried on sodium sulfate and evaporated.

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Abstract

L'invention concerne des nitrodérivés de bloqueurs d'un récepteur d'angiotensine II de formule (I) à activité pharmacologique élargie et à tolérabilité accrue. Ces dérivés peuvent servir au traitement de maladies cardio-vasculaires et rénales et de processus inflammatoires.
PCT/EP2006/050348 2005-01-31 2006-01-20 Derives de sartane nitrooxy en tant que bloqueurs d'un recepteur d'angiotensine ii pour le traitement de maladies cardio-vasculaires et inflammatoires Ceased WO2006079610A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009150007A1 (fr) * 2008-06-09 2009-12-17 Nicox S.A. Antagonistes des récepteurs de l’angiotensine ii
WO2010015447A1 (fr) * 2008-08-08 2010-02-11 Nicox S.A. Antagonistes des récepteurs de l'angiotensine ii
EP2194048A1 (fr) * 2008-12-02 2010-06-09 Dirk Sartor Esters de nitrate pour le traitement de maladies vasculaires et métaboliques
WO2009106470A3 (fr) * 2008-02-26 2010-06-24 Nicox S.A. Antagonistes vis-à-vis des récepteurs de l'angiotensine ii
US7880014B2 (en) 2006-12-13 2011-02-01 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
EP2377855A1 (fr) * 2010-04-19 2011-10-19 Cardiolynx AG Dérivé dinitrate du valsartanamide pour le traitement de maladies vasculaires et métaboliques
WO2011131613A1 (fr) * 2010-04-19 2011-10-27 Cardiolynx Ag Dérivés de valsartan portant des donneurs d'oxyde d'azote dans le traitement de maladies vasculaires et métaboliques
US8361994B2 (en) 2011-03-07 2013-01-29 Merck Sharp & Dohme Corp Primary amine diazeniumdiolate heterocyclic derivatives
EP2521545A4 (fr) * 2010-01-07 2015-11-18 Alkermes Pharma Ireland Ltd Promédicaments de composés hétéroaromatiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067231A1 (fr) * 1998-06-19 1999-12-29 Nicox S.A. Sels de nitrate de medicaments anti-hypertenseurs
WO2005011646A2 (fr) * 2003-07-31 2005-02-10 Nicox S.A. Derives de bloqueur du recepteur de l'angiotensine ii

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067231A1 (fr) * 1998-06-19 1999-12-29 Nicox S.A. Sels de nitrate de medicaments anti-hypertenseurs
WO2005011646A2 (fr) * 2003-07-31 2005-02-10 Nicox S.A. Derives de bloqueur du recepteur de l'angiotensine ii

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRESCHI ET AL: "New NO-Releasing Pharmacodynamic Hybrids of Losartan and Its Active Metabolite: Design, Synthesis, and Biopharmacological Properties", JOURNAL OF MEDICINAL CHEMISTRY, ASAP, 22 March 2006 (2006-03-22), published on Web, pages A - I, XP002374461 *
BRESCHI ET AL: "NO-Sartans: A New Class of Pharmacodynamic Hybrids as Cardiovascular Drugs", JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, no. 23, 2004, pages 5597-5600, XP002374434 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7880014B2 (en) 2006-12-13 2011-02-01 Merck Sharp & Dohme Corp. Angiotensin II receptor antagonists
WO2009106470A3 (fr) * 2008-02-26 2010-06-24 Nicox S.A. Antagonistes vis-à-vis des récepteurs de l'angiotensine ii
WO2009150007A1 (fr) * 2008-06-09 2009-12-17 Nicox S.A. Antagonistes des récepteurs de l’angiotensine ii
WO2010015447A1 (fr) * 2008-08-08 2010-02-11 Nicox S.A. Antagonistes des récepteurs de l'angiotensine ii
EP2194048A1 (fr) * 2008-12-02 2010-06-09 Dirk Sartor Esters de nitrate pour le traitement de maladies vasculaires et métaboliques
CN102245583A (zh) * 2008-12-02 2011-11-16 心脏林克斯股份公司 用于治疗血管和代谢疾病的西洛他唑的硝酸酯衍生物
EP2521545A4 (fr) * 2010-01-07 2015-11-18 Alkermes Pharma Ireland Ltd Promédicaments de composés hétéroaromatiques
US9580417B2 (en) 2010-01-07 2017-02-28 Alkermes Pharma Ireland Limited Prodrugs of heteraromatic compounds
WO2011131613A1 (fr) * 2010-04-19 2011-10-27 Cardiolynx Ag Dérivés de valsartan portant des donneurs d'oxyde d'azote dans le traitement de maladies vasculaires et métaboliques
CN103080095A (zh) * 2010-04-19 2013-05-01 心脏林克斯股份公司 用于治疗血管和代谢疾病的携带氮氧化物给体的缬沙坦衍生物
US8729115B2 (en) 2010-04-19 2014-05-20 Cardiolynx Ag Valsartan derivatives carrying nitrogen oxide donors for the treatment of vascular and metabolic diseases
EP2377855A1 (fr) * 2010-04-19 2011-10-19 Cardiolynx AG Dérivé dinitrate du valsartanamide pour le traitement de maladies vasculaires et métaboliques
US8361994B2 (en) 2011-03-07 2013-01-29 Merck Sharp & Dohme Corp Primary amine diazeniumdiolate heterocyclic derivatives

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