WO2006079610A1

WO2006079610A1 - Nitrooxy sartan derivatives as angiotensin ii receptor blockers for the treatment of cardiovascular and inflammatory diseases

Info

Publication number: WO2006079610A1
Application number: PCT/EP2006/050348
Authority: WO
Inventors: Nicoletta Almirante; Alessia Nicotra; Ennio Ongini
Original assignee: Nicox SA
Current assignee: Nicox SA
Priority date: 2005-01-31
Filing date: 2006-01-20
Publication date: 2006-08-03
Anticipated expiration: 2007-07-31
Also published as: AR053330A1

Abstract

Angiotensin II receptor blockers nitroderivatives of Formula (I) having wider pharmacological activity and enhanced tolerability. They can be employed for treatment cardiovascular and renal diseases and inflammatory processes.

Description

NITROOXY SARTAN DERIVATIVES AS ANGIOTENSIN II RECEPTOR BLOCKERS FOR THE TREATMENT OF CARDIOVASCULAR AND INFLAMMATORY DISEASES

* * * * * *

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 .

With the angiotensin II receptor blockers a class of compounds is intended, comprising as main components

Losartan, EXP3174 , Exp3179, Dup532 , Candesartan,

Tasosartan, Valsartan, Elisartan, Irbesartan and Olmesartan

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 .

Now, it has been reported that 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 ) .

Maria C . Breschi et al . , in Journal of Medicinal Chemistry, 47 (23) , 5597-5600 , 2004 , describes two NO- releasing Losartan of formulae 2a and 2b

and the results of an "exploratory" in vivo protocol evaluating the anthypertensive action of the compound of formula 2a in comparison with the "native" sartan and a ACE inhibitor (i . e . captopril) . In this test all the compounds had shown practically equivalent effect on the reduction of the systolic blood pressure .

It was now obj ect of the present invention to provide a new class of 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 .

In particular, it has been recognized that the 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 :

wherein :

Ri is selected from the group consisting of :

wherein

R₂ is H, or -W₁-Y₀-ONO₂ wherein W₁ is -C (O) - or -C (O) O-; Yo is as reported below;

R₃ is H, -Y₀-ONO₂ or -W₂-Y₀-ONO₂, wherein W₂ is

Y₀ is as reported below; W has the following meanings : -C (O) -, -C (O) O-,

preferably in the radical Ri of formula (Ia) when R₂ is -Wi-

Y₀-ONO₂, Wi is -C (O) -; preferably in the radical Ri of formula (Ib) , (Ic) , (Id) ,

(Ih) or (Ii) , R₃ is -Y₀-ONO₂; more preferably when Ri is (Ia) , R₂ is H or when Ri is chosen among the radicals of formula (Ib) , (Ic) , (Id) , (Ih) or (Ii) , R₃ is H; Y and Y₀ are the same or different and are bivalent radicals having the following meanings : a)

- straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀ alkylene, more preferably C₃-C₆ alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of : halogen atoms , hydroxy, -ONO₂ or T₀, wherein T₀ is -OC (O) - (C₁-C₁₀ alkyl) -0N0₂ or -0- (C₁-C₁₀ alkyl) -0N0₂;

- cycloalkylene having from 5 to 7 carbon atoms , the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms , preferably T is CH₃; b)

wherein 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)

wherein : nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ,

Xi is - (CH₂ ) ₃-0C (O) - or -CH=CH-C (O) O-, and

R₄ is H or CH₃; d)

wherein : 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-,

Y¹ is -CH=CH-, - (CH₂) ₃-, and

R₄ is H or CH₃; when Y or Y₀ are selected from the bivalent radicals of the groups b) , c ) or d) the -ONO2 group is linked to - (CH₂ ) _n1- group; g)

h)

wherein X₂ 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 , R₆ is H, CH₃ or nitrooxy group, preferably R₆ is H, R₇ is CH₃ or nitrooxy group; when Y or Y₀ are selected from the bivalent radicals of the group g) the -ONO₂ group is linked to - (CH₂) _n6- group; when Y or Y₀ are selected from the bivalent radicals of the group h) the -ONO₂ group is linked to -CH (R₇) - group; i)

wherein : n7 is an integer from 0 to 10 ; n8 is an integer from 1 to 10 ; R₈ R₉, R₁₀, R₁₁ are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R₈ R₉, R₁₀, R₁₁ are H; wherein the -ONO2 group is linked to

wherein n8 is as defined a ove;

Y² 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

The term "C₁-C₂₀ alkylene" as used herein refers to branched or straight C₁-C₂₀ 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 -CH₂-, -CH₂-CH₂-, - (CH₂) ₃-, - (CH₂) ₄-, - (CH₂) ₅-, - (CH₂) ₆- and the like . The term "C₁-C₁₀ alkyl" as used herein 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 .

The term "cycloalkylene" as used herein 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 (C₁-C₁₀) - alkyl, preferably CH₃.

The term "heterocyclic" as used herein 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 .

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 administration of the compounds above reported can be carried out simultaneously or successively .

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 .

As stated 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 .

Examples of organic acids are : oxalic, tartaric, maleic, succinic, citric acids . Examples of 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 . Within the 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 R₁ is (Ie) , (If) , (Ig) , (II) , (Im) , (In) or Ri is (Ia) , (Ib) , (Ic) , (Id) , (Ih) , (Ic) wherein R₂ and R₃ are H,

W is as above reported, and Y has the following meanings : a)

- straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀, more preferably C₃-C₆ alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of : halogen atoms , hydroxy, -ONO2 or T₀, wherein T₀ is -OC (O) - (C₁-C₁₀ alkyl) -ONO₂ or -0- (C₁-C₁₀ alkyl) -0N0₂;

- cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms , preferably T is CH₃; b)

wherein : nl is an integer from 1 to 20 , preferably nl is an integer from 1 to 6, n2 is 0 or 1 ; Xi is - (CH₂ ) ₃-OC (O) - or -CH=CH-C (O) O- R₄ is H or CH₃; d)

Xi is -OC (O) -, -C (O) O-, Y¹ is -CH=CH-, - (CH₂) S-, and R₄ is H or CH₃; when Y or Yo are selected from the bivalent radicals of the groups b) , c) , d) the -ONO₂ group is linked to - (CH₂) _n1- group; g)

h)

wherei X₂ 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 ,

R₆ is H, CH₃ or nitrooxy group, preferably R₆ is H,

R₇ is CH₃ or nitrooxy group; when Y or Y₀ are selected from the bivalent radicals of the group g) the -ONO₂ group is linked to - (CH₂) _n6- group; when Y or Y₀ are selected from the bivalent radicals of the group h) the -ONO₂ group is linked to -CH (R₇) -; i )

wherein : n7 is an integer from 0 to 10 ; n8 is an integer from 1 to 10 ; R₈ R₉, R₁₀, R₁₁ are H; wherein the -ONO2 group is linked to

wherein n8 is as defined above; Y² 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

(YIl) (Y12) (Y13)

Another preferred compounds are those of formula (I ) wherein

R₁ is (Ie) , (If) , (Ig) , (II) , (Im) , (In) or Ri is (Ia) , (Ib) , (Ic) , (Id) , (Ih) , (Ic) wherein R₂ and R₃ are H,

W is as above reported, and Y has the following meanings : a) straight C₁-C₁₀ alkylene, preferably C₃-C₆ alkylene; b)

wherein n is 0 or 1, nl is 1; g)

wherein

X₂ is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 ,

R₆ is H,

Another preferred compounds are those of formula (I ) wherein

Ri is the radical of formula (Ia) , wherein R₂ is -Wi-Y₀-ONO₂ wherein

Wi is -C (O) - or -C (O) O-, preferably Wi is -C (O) -

Y₀ 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 C₁-C₁₀ alkylene, preferably C₃-C₆ alkylene; b)

wherein n is 0 or 1 , nl is 1 , n2 is 0 ; g)

wherein

X₂ is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 , R₆ 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 R₃ is -Y₀-ONO₂ or -W₂-Y₀-ONO₂ wherein

W₂ is

Yo 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 C1-C1₀ alkylene, preferably C3-C6 alkylene; b)

wherein n is 0 or 1 , nl is 1 , n2 is 0 ; g)

wherein X₂ is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 , R₆ is H, Another preferred group of compounds are those of formula (I ) wherein

R₁ is a radical of formula (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R3 is -Y₀-ONO2 wherein Y₀ is as defined below, W is -C (O) O-

wherein n is 0 or 1 , nl is 1 , n2 is 0 ; g)

wherein X₂ is 0 or S, n3, and n6 are selected from 1 to 5, n5 is 0 , R₆ is H,

Most preferred compounds are

(4)

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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 . The term "parenteral" as used herein, 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 . Among the acceptable vehicles and solvents are water, Ringer' s solution and isotonic sodium chloride . In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose 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 . In the case of capsules , tablets and pills , 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 .

A) The compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , or R₁ is the radical of formulas (Ia) , (Ib) , ( Ic) (Id) (Ih) or (Ii) , wherein R2 or R₃ are H, and wherein W is -C (O) -, and Y is as above defined, can be obtained by a process comprising : IA) reacting compounds of formula (Ia) ACt-C (O) -Y-ONO₂

(Ia) wherein Y are as above defined and wherein Act is a carboxylic acid activating group used in peptide chemistry such as :

wherein :

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 R₃ 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 CH₂CI₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂ ; 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 .

IA. a) The compounds of formula (1 ) wherein R₁ is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , are commercially available or can be synthesised as follow :

- the compound of formula (1 ) wherein Ri is the radical of formula (Ie) is known as Elisartan and is obtained as described in EP 535420 ; - the compound of formula (1 ) wherein R₁ is the radical of formula (If) is known as Exp 3179 and is obtained as described in J. Med. Chem. , 1991 , 34 , 2525-2547 ;

- the compound of formula (1 ) wherein R₁ is the radical of formula (Ig) is known as Olmesartan medoxomil and is obtained as described in The Merck Index, Thirteenth Edition;

- the compound of formula (1 ) wherein R₁ is the radical of formula (H) is known as Tasosartan and is obtained as described in The Merck Index, Thirteenth Edition; - the compound of formula (1 ) wherein R₁ is the radical of formula (Im) is known as Irbesartan and is obtained as described in The Merck Index, Thirteenth Edition;

- the compound of formula (1 ) wherein R₁ is the radical of formula (In) is known as Candersartan Cilexetil and is obtained as described in The Merck Index, Thirteenth Edition;

IA. b) The compound of formula (1 ) wherein R₁ is (Ia) and the functional group -CH₂-OH is protected, is obtained by reacting the compound of formula (1 ) wherein R₁ is the radical (Ia) and R₂ is H by conventional reaction to insert a protective group such as BOC according to well known reaction conditions . The compound of formula (1 ) wherein Ri is the radical of formula (Ia) and R2 is H, is known as Losartan and is commercially available or is synthesised as described in The Merck Index, Thirteenth Edition; IA. c) The compounds of formula (1 ) , wherein R₁ is ( Ib) , (Ic) , (Id) , (Ih) or (Ii) and the functional groups -C (O) OH are protected, are obtained by reacting compounds of formula (1 ) wherein R₁ is the radical of formulae (Ib) , (Ic) , (Ih) or (Ii) and R₃ is H, by conventional reaction to insert a protective group such as trityl, benzyl, methyl according to well known reaction conditions ;

The compounds of formula (1 ) wherein R₁ is the radical of formula (Ib) , (Ic) (Id) (Ih) or (Ii) , wherein R₃ is H, are commercially available or can be synthesised as follow : - the compound of formula (1 ) wherein R₁ is the radical of formula (Ib) is known as Olmesartan and is obtained as described in The Merck Index, Thirteenth Edition;

- the compound of formula (1 ) wherein R₁ is the radical of formula (Ic) is known as EXP 3174 and is obtained as described in Tetrahedron Letters , 44 (2003) , 1149-1152 ;

- the compound of formula (1 ) wherein R₁ is the radical of formula (Id) is known as Dup 532 and is obtained as described in J. Org . Chem. , 1993, 58 , 4642.

- the compound of formula (1 ) wherein R₁ is the radical of formula (Ih) is known as Valsartan and is obtained as described in The Merck Index, Thirteenth Edition;

- the compound of formula (1 ) wherein R₁ is the radical of formula (Ii) is known as Candersartan and is obtained as described in The Merck Index, Thirteenth Edition; IA. d) The compounds of formula (Ia) as above defined are obtained by reacting the acids (Ib)

HOOC-Y-ONO₂ (Ib) wherein Y is as above defined, with the commercially available compounds (Ic)

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 .

IA. e) The compounds of formula (Ib) as above defined are obtained by reacting the commercially available acids of formula (Id)

HaI-Y-COOH (Id) with AgNO₃ in a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF) under nitrogen in the dark at temperatures range between 20 ° to 8O °C; alternatively the reaction with AgNO₃ 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) .

B) The compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (II) , (Im) or (In) , or R₁ is the radical of formulas (Ia) , (Ib) , ( Ic) (Id) (Ih) or (Ii) , wherein R₂ or R₃ are H, and wherein W is -C (O) O- and Y is as above defined, can be obtained by a process comprising : IB) reacting compounds of formula (1 )

wherein ; 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 R₃ is H and the functional groups -C (O) OH are protected, with a compound of formula (Ia . i)

ACt-C (O) -O-Y-ONO₂ (Ia . i) wherein Act and Y are as above defined, in presence of a inorganic or organic base/DMAP in an aprotic polar/non- polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂ ; and then removing the protective group of the compounds obtained as described in IB) ; and optionally converting the resulting compounds of formula (I ) into a pharmaceutically acceptable salt . IB . a) The compounds of formula (Ia . i) as above defined are obtained by reacting compounds of formula (Ie)

ACt-C (O) -HaI (Ie) with a compounds of formula (If)

HO-Y-ONO₂ (If) wherein Y is as above defined, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 at temperatures range between 20 ° to 4O °C, lB . b) 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 AgNO₃ 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 .

The compounds of formula (If ) are commercially available or can be obtained by method well known in the literature; lB . d) The compounds of formula (Ie) as above defined are obtained by reacting compounds of formula (Ic)

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 .

C) Alternatively, the compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or ( In) , or Ri is the radical of formulas (Ia) , (Ib) , (Ic)

(Id) (Ih) or (Ii) wherein R2 or R₃ are H, and wherein W is

-C (O) O-, and Y is as above defined, can be obtained by a process comprising :

1C) reacting compounds of formula (1 ) wherein : 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 R₃ is H and the functional groups -C (O) OH are protected, with compounds of formula (Ia . ii) ,

HaI-C (O) -O-Y-ONO₂ (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 CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂ ; and then removing the protective group of the obtained compounds ; and optionally converting the resulting compounds of formula (I ) into a pharmaceutically acceptable salt .

1C . a) The compound of formula (1 ) wherein Ri is (Ia) and the functional group -CH₂-OH is protected, is obtained as described in IA. b) . The compounds of formula (1 ) , wherein Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) and the functional groups -C (O) OH are protected, are obtained as described in IA. c) . IC b) The compounds of formula (Ia . ii) as above defined, are obtained by reacting a compounds of formula (If) HO-Y-ONO₂ (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 CH₂Cl₂ at temperatures range between 0 ° to 65 °C, IC c) The compounds of formula (If) are obtained as described in lB . b) .

D) Alternatively, the compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or ( In) , or Ri is the radical of formulas (Ia) , (Ib) , (Ic) (Id) (Ih) or (Ii) , wherein R₂ or R₃ are H, and wherein W is ,

Y is as above defined, can be obtained by a process comprising :

ID) reacting compounds of formula (1 ) wherein : 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 R₃ is H and the functional groups -C (O) OH are protected, with compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) wherein Hal is an halogen atom and W4 is -CH₂- or -CH (CH₃) -, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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 -CH₂-OH is protected, is obtained using method described in IA. b) .

The compounds of formula (1 ) , wherein Ri is (Ib) , (Ic) ,

(Id) , (Ih) or (Ii) and the functional groups -C (O) OH are protected, are obtained using the method described in

IA. c) . lD . b) The compounds of formula (la . iii) are obtained by reacting the commercially available haloalkylhalocarbonate of formula (Ig) HaI-W₄-OC (O) HaI (Ig) wherein Hal and W₄ are as above defined, with a compound of formula (If) HO-Y-ONO₂ (If) wherein Y is as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C, lD . b) The compounds of formula (If) are obtained as described in lB . b) .

E) Compounds of general formula (I ) wherein Ri is ( Ia) , wherein R₂ is -C (O) -Y-ONO₂, and wherein W is -C (O) -, and Y is as above defined, can be obtained by a process comprising :

IE) reacting compounds of formula (2b)

(2b) wherein Y is as above defined, with compounds of formula (Ia)

ACt-C (O) -Y-ONO₂ (Ia) wherein Act and Y are as above reported, in presence of a inorganic or organic base/DMAP in an aprotic polar/non- polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂. IE . a) The compounds of formula (2b) are obtained by reacting a compounds of formula (2 )

(2 )

wherein R₂ is H, with a compound of formula (Ib)

HO (O) C-Y-ONO₂ (Ib) according to the method described in the literature Maria C . Breschi et al . , Journal of Medicinal Chemistry, 47 (23) , 5597-5600 , 2004. lE . b) The compounds of formula (Ia)

ACt-C (O) -Y-ONO₂ (Ia) as above defined, are obtained by using the method described in IA. d) . lE . c) The compound of formula (Ib)

HO (O) C-Y-ONO₂ (Ib) as above defined, are obtained by using the method described in IA. e) .

F) Compounds of general formula (I ) wherein Ri is ( Ia) , wherein R₂ is -C (O) -Y-ONO₂, and wherein W is -C (O) O-, and Y is as above defined, can be obtained by a process comprising :

IF) reacting a compounds of formula (2b) above defined, with compounds of formula (Ia . i)

ACt-C (O) -O-Y-ONO₂ (Ia . i) wherein Act and Y are as above reported, in 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 or in a double phase system H₂O/Et2θ 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, CH₂Cl₂.

IF . a) The compounds of formula (2b) are obtained using method described in IE . a) . lF . b) The compounds of formula (Ia . i)

ACt-C (O) -O-Y-ONO₂ (Ia . i) as above defined, are obtained as described in IB . a) .

G) Compounds of general formula (I ) wherein Ri is (Ia) wherein R₂ is -C (O) -Y-ONO₂, and wherein W is

Y is as above defined, can be obtained by a process comprising :

IG) reacting a compounds of formula (2b) with compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) wherein Hal, W₄, Y are as above reported, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 at temperatures range between 20 ° to 4O °C;

IG . a) The compounds of formula (2b) are obtained by using method described in IE . a) .

IG . b) The compounds of formula (la . iii) HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) as above reported are obtained by using method described in lD . b) . H) Compounds of formula (I ) wherein Ri is (Ib) , ( Ic) , (Id) , (Ih) or (Ii) , wherein R₃ is -Y-ONO₂, and wherein W is -C (O) -, and Y is as above defined, can be obtained by a process comprising :

IH) reacting compounds of formula (1 ) wherein Ri is as above reported and R₃ is -Y-ONO₂, with compounds of formula (Ia)

ACt-C (O) -Y-ONO₂ (Ia) wherein Act and Y are as above reported, in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂. IH . a) The compounds of formula (Ia)

ACt-C (O) -Y-ONO₂ (Ia) as above defined are obtained by using the method described in IA. d) .

IH . b) The compounds of formula (1 ) wherein Ri is as above reported and R₃ is -Y-ONO₂ are obtained by reacting compounds of formula (1 ) , wherein Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) and R₃ is H, with compounds of formula (If) HO-Y-ONO₂ (If) wherein Y is as above reported, in presence of a condensing agent such as DCC or EDAC . IH . c) The compounds of formula (If)

HO-Y-ONO₂ (If) wherein Y is as above reported, can be prepared for example as described in Shan et al . , Journal of Medicinal Chemistry, 47 , 254-261 , 2004. I ) Compounds of formula (I ) wherein Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) , wherein R₃ is -Y-ONO2 , and wherein W is

_and

Y is as above defined, can be obtained by a process comprising :

II ) reacting compounds of formula (1 ) wherein R₁ is as above reported and R₃ is -Y-ONO2, with compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) wherein W₄ is -CH₂- or -CH (CH₃) - and Hal is an halogen atom,

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 CH₂Cl₂ at temperatures range between 0 ° to 65 °C; II . a) The compounds of formula (1 ) wherein Ri is as above reported and R₃ is -Y-ONO₂ are obtained by method described in IH . b) .

II . b) The compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) as above defined, are obtained by method described in lD . b) .

L) Compounds of formula (I ) wherein Ri is (Ib) , (Ic) , ( Id) , (Ih) or (Ii) , wherein R₃ is -W₂-Y-ONO₂, and wherein W₂ and W are

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 R₃ is H, with compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) wherein W₄ is -CH₂- or -CH (CH₃) - and Hal is an halogen atom, 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 CH₂Cl₂ at temperatures range between 0 ° to 65 °C . IL . a) The compounds of formula (la . iii)

HaI-W₄-OC (O) O-Y-ONO₂ (la . iii) wherein W₄, Hal and Y are as above reported, are obtained by method described in lD . b) .

M) Alternatively the compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or

( In) , or Ri is the radical of formulas (Ia) , (Ib) , (Ic)

(Id) (Ih) or (Ii) wherein R₂ or R₃ are H, and wherein W is

-C (O) or -C (O) O-, and Y is as above defined, can be obtained by a process comprising :

IM) reacting a compound of formula (3)

wherein : Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , or Ri is the radical of formula (Ia) wherein R₂ is H and the functional group -CH₂-OH is protected, or Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R₃ 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 AgNO₃ 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 . IM. a) The compounds of formula (3) as above defined are obtained by reacting compounds of formula (1 ) wherein 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-CH₂-0H is protected, or Ri is (Ib) , (Ic) (Id) (Ih) or (Ii) wherein R₃ is H and the functional groups -C (O) OH are protected, with compounds of formula (Ih)

ACt-C (O) -Y-HaI (Ih) or compounds of formula (11) ACt-C (O) -O-Y-HaI (11) wherein Hal is an halogen atom and Act, Y are as above defined, in presence of a inorganic or organic base/DMAP in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂ ; IM. b) The compound of formula (1 ) wherein Ri is (Ia) and the functional group -CH₂-OH is protected, is obtained using method described in IA. b) .

The compounds of formula (1 ) , wherein Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) and the functional groups -C (O) OH are protected, are obtained using the method described in

IA. c) .

IM. b) The compounds of formula (Ih)

ACt-C (O) -Y-HaI (Ih) as above defined, are obtained by reacting commercially available (Ic)

Act-H (Ic) with the commercially available compounds of formula (Id)

HO (O) C-Y-HaI (Id) by conventional esterification reaction with condensing agents as DCC EDAC HCl as well known in the literature . The compounds of formula (11)

ACt-C (O) -O-Y-HaI (11) as above defined, are obtained by reacting compounds of formula (Ie)

ACt-C (O) -HaI (Ie) which are commercially available or are obtained as described in lB . d) , with a compounds of formula (If )

HO-Y-HaI (If ) in 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 or in a double phase system H₂O/Et2θ at temperatures range between 20 ° to 4O °C;

N) Alternatively the compounds of general formula (I ) wherein Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or

( In) , or Ri is the radical of formulas (Ia) , (Ib) , (Ic)

(Id) (Ih) or (Ii) , wherein R₂ or R₃ are H, and wherein W is

IN) reacting a compounds of formula (4 ) :

(4 ) wherein :

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 -CH₂-OH is protected, or

Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R₃ 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 CH₂Cl₂ 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 .

2N) The compounds of formula (4 ) are obtained by reacting the compounds of formula (1 ) wherein

Ri is the radical (Ie) , (If) , (Ig) , (H) , (Im) or (In) , or

Ri is the radical of formula (Ia) wherein R₂ is H and the functional group -CH₂-OH is protected, or

Ri is (Ib) , (Ic) , (Id) , (Ih) or (Ii) wherein R₃ is H and the functional groups -C (O) OH are protected, with compounds of formula (Im)

ACt-C (O) -Y-OH (Im) or with compounds of formula (In)

ACt-C (O) -O-Y-OH (In) wherein Act and Y are as above defined, in presence of a inorganic or organic base/DMAP in an aprotic polar/non- polar solvent such as DMF, THF or CH2CI2 at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 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, CH₂Cl₂ ;

2N . a) The compound of formula (1 ) wherein Ri is (Ia) and the functional group -CH₂-OH is protected, is obtained as described in IA. b) . The compounds of formula (1 ) , wherein R₁ is (Ib) , (Ic) , (Id) , (Ih) or (Ii) and the functional groups -C (O) OH are protected, are obtained as described in IA. c) . 2N . b) The 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)

HOOC-Y-OH (lo) by conventional esterification reaction with condensing agents as DCC EDAC HCl as well known in the literature; The compounds of formula (In)

ACt-C (O) -O-Y-OH (In) are obtained by reacting compounds of formula (Ie)

ACt-C (O) -HaI (Ie) which are commercially available or are obtained as described in lB . d) , with a compounds of formula (lj )

HO-Y-OH (Ij ) in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between 0 ° to 65 °C or in a double phase system H₂0/Et₂0 at temperatures range between 20 ° to 40 °C;

EXAMPLES Example 1

Synthesis of 4- (nitrooxy) butanoic acid pentafluorophenyl ester

To a mixture of pentafluorophenol (3.3 g, 17.96 mmol) , 4-bromobutanoic acid (3.0 g, 17.96 mmol) and DMAP (0.440 g, 3.59 mmol) in CH₂Cl₂ (30 ml) , cooled to O °C, EDAC HCl (5.2 g, 26.94 mmol) was added in portion . The mixture was then stirred at O °C for 30 minutes . Then it was gradually warmed to room temperature and stirred for 8 hrs . Then the mixture was diluted with NaH₂PO₄ aqueous (5%, 50 ml) and acidified with HCl IN to pH 3-4. The organic phase was separated and the aqueous phase was extracted with CH₂Cl₂ (2 x 50 ml) . The organic phase was washed with brine, dried over Na₂SO₄ and evaporated to give an oil that was purified by flash chromatography (n-Hexane/EtOAc 98 : 2 ) to yield 4- bromobutanoic acid pentafluorophenyl ester (5.2 g, 86%) as a colorless oil .

A mixture of 4-bromobutanoic acid pentafluorophenyl ester (5.2 g, 15.61 mmol) and AgNO₃ ( 6.6 g, 39.03 mmol) in CH₃CN was heated at 6O °C for 5 hrs under nitrogen, in the dark .

Then the mixture was cooled, concentrated and diluted with

EtOAc . The silver salts were filtered off, the solvent evaporated. After flash chromatography purification (n- Hexane/EtOAc 95 : 5) 4- (nitrooxy) butanoic acid pentafluorophenyl ester (3.9 g, 80%) was obtained as a colorless oil .

¹H NMR (CDCl₃) δ : 4.60 (2H, t) , 2.86 (2H, t) , 2.23 (2H, m) .

Example 2

Synthesis of 4- (nitrooxymethyl) benzoic acid pentafluoro^¬ phenyl ester Starting from 4- (bromomethyl) benzoic acid (5.0 g, 23.25 mmol) and pentafluorophenol (4.3 g, 23.25 mmol) , applying the same procedure described in Example 1 , 4-

(bromomethyl) benzoic acid pentafluorophenyl ester (5.0 g, 56%) was obtained as a solid.

From 4- (bromomethyl) benzoic acid pentafluorophenyl ester (5.0 g, 13.12 mmol) and AgNO₃ (5.6 g, 32.80 mmol) , heating to reflux and applying the same procedure described in Example 1 , after flash chromatography purification (n-

Hexane/EtOAc 95 : 5) 4- (nitrooxymethyl) benzoic acid pentafluorophenyl ester (4.2 g, 88%) was obtained as a white solid. m.p. 75-76⁰C ¹H NMR (CDCl₃) δ: 8.26(2H,d) , 7.60(2H,d) , 5.50(2H,s) .

Example 3

Synthesis of 5- (nitrooxy) pentanoic acid pentafluorophenyl ester Starting from 5-bromopentanoic acid (1.0 g, 5.52 mmol) and pentafluorophenol (1.0 g, 5.52 mmol) , applying the same procedure described in Example 1 , 5-bromopentanoic acid pentafluorophenyl ester (1.5 g, 78%) was obtained as a colorless oil .

From 5-bromopentanoic acid pentafluorophenyl ester (1.5 g, 4.32 mmol) and AgNO₃ (1.8 g, 10.80 mmol) , heating to reflux and applying the same procedure described in Example 1 , after flash chromatography purification (n-Hexane/EtOAc 98 : 2 ) 5-nitrooxypentanoic acid pentafluorophenyl ester (0.72 g, 50%) was obtained as a pale yellow oil . ¹H NMR (CDCl₃) δ : 4.53 (2H, t) , 2.77 (2H, t) , 2.00-1.85 (4H, m) . Example 4

Synthesis of 2-butyl-4-chloro-l- [ [ 2 ' - ( lH-tetrazol-5-yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -5- [ ( 3-nitrooxypropyl) carbonyl- oxy] methyl-lH-imidazole To a solution 2-Butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5-methanol (Losartan) (2.13 g, 5.04 mmol) TEA (0.51 g, 5.04 mmol) and DMAP (0.62 g, 5.04 mmol) in DMF (25 ml) kept at O ⁰C, under stirring and under nitrogen atmosphere, a solution of 4- nitrooxybutanoic acid pentafluorophenyl ester (1.59 g, 5.04 mmol) (Example 1 ) in DMF (5 ml) was added. 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.

After purification with Flash chromatography of the residue (CH₂Cl₂/Me0H 98 : 2 ) the title compound was obtained as a white solid (1.48 g, 53%) . m. p . 66-68⁰C

¹H NMR (CDCl₃) δ : 7.85 (lH, d) , 7.58 (2H, m) , 7.42 (lH, d) , 7.11 (2H, d) , 6.79 (2H, d) , 5.15 (2H, s ) , 4.94 (2H, s ) , 4.42 (2H, t) , 2.53 (2H, t) ; 2.21 (2H, t) , 1.93 (2H, m) , 1.56 (2H, m) , 1.29 (2H, m) , 0.85 (3H, t) .

Example 5

2-butyl-4-chloro-l- [ [ 2 ' - ( lH-tetrazol-5-yl) [ 1 , 1 ' -biphenyl ] - 4-yl ] methyl ] - 5- [ ( 4-nitrooxybutyl) carbonyloxy] methyl-lH- imidazole

Using the same procedure described in Example 4 but starting from 2-Butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5-methanol (Losartan) (0.93 g, 2.19 mmol) and 5-nitrooxypentanoic acid pentafluorophenyl ester (Example 3) (0.72 g, 2.19 mmol) after purification with Flash chromatography of the residue (CH₂Cl₂/Me0H 98 : 2 ) the title compound (0.72 g, 60%) was obtained as a white foam.

¹H NMR (CDCl₃) δ : (CDC13) : 7.72-7.48 (4H, m) ; 7.10 (2H, d) ; 6.94 (2H, d) ; 5.24 (2H, s ) ; 5.00 (2H, s ) ; 4.44 (2H, t) ; 2.10 (2H, t) ; 1.57-1.44 ( 6H, m) ; 1.29 (4H, m) ; 0.83 (3H, t) .

Example 6

Synthesis of 2-butyl-4-chloro-l- [ [ 2 ' - ( lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -5- [ ( 4- (nitrooxymethyl) phenylcarbonyloxymethyl-lH-imidazole; Losartan 4- (nitrooxy^¬ methyl) benzoic acid ester To a solution of 2-butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5-methanol (Losartan) (3.1 g, 7.27 mmol) Sc (OTf) ₃ (0.3 g, 0.61 mmol) and DMAP (1.5 g, 12.12 mmol) in CH₂Cl₂ (25 ml) kept at - 5 °C, under stirring and under nitrogen atmosphere, a solution of 4- (nitrooxymethyl) benzoicacidpentafluorophenyl ester (Example 2 ) (2.2 g, 6.06 mmol) in CH₂Cl₂ (5 ml) was added. 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 CH₂Cl₂ (2 x 50 ml) . The organic phase was dried on sodium sulfate and evaporated.

After purification with Flash chromatography of the residue (CH₂Cl₂/Me0H 98 : 2 ) the title compound was obtained as a white solid (1.70 g, 47%) . m. p . 155 °C ¹H NMR (DMSO) δ : 7.73-7.56 (7H, m) , 7.24 (lH, d) , 7.00 (4H, m) , 5.60 (2H, s ) , 5.39 (2H, s ) , 5.28 (2H, s ) , 2.61 (2H, t) , 1.53 (2H, m) , 1.28 (2H, m) , 0.82 (3H, t)

Example 7

Synthesis of 2-butyl-4-chloro-l- [ [ 2 ' - [ 1- ( 3-nitrooxypropyl carbonyl) -tetrazol-5-yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -5- [ ( 3- nitrooxypropyl) carbonyloxy] methyl-lH-imidazole (Compound 433 ) To a solution of 2-butyl-4-chloro-l- [ [2 ' - (lH-tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -5- [ (3-nitrooxypropyl) carbonyloxy] methyl-lH-imidazole (Example 4 ) (0.5 g, 0.9 mmol) , TEA (0.125 ml 0.9 mmol) ) , DMAP (0.11 g, 0.9 mmol) in CH₂Cl₂ , cooled to 0 ⁰C, a solution of 4-nitrooxybutanoic acid pentafluorophenyl ester (Example 1 ) (0.28 g, 0.9 mmol) in CH₂Cl₂ (1 ml) was added. After 8 hrs at room temperature the reaction was refluxed for 4 hrs . Then was cooled, diluted with water, the two phases were separated and the organic phase was washed first with pH 3 buffer solution then with brine, dried and evaporated.

After Flash chromatography purification (n-Hexane/EtOAc 9 : 1 ) the title compound (0.053 g, 10%) was isolated as a white foam. IH NMR (CDC13) δ : 7.87-7.42 (4H, m) ; 7.13 (2H, d) ; 6.81 (2H, d) ; 5.15 (2H, s ) ; 4.92 (2H, s ) ; 4.42 (4H, m) ; 2.53-2.40 (4H, m) ; 2.21 (2H, t) ; 1.87-1.56 ( 6H, m) ; 1.29 (2H, m) ; 0.85 (3H, t) .

Example 8

Synthesis of 2-Butyl-4-chloro-l- [ [ 2 ' - ( 1- ( 3-nitrooxypropyl) carbonyl) -tetrazol-5-yl) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -IH- imidazole-5-carboxaldehyde (Compound 382 )

Following the same procedure described in Example 7 but starting from 2-butyl-4-chloro-l- [ [2 ' - (IH) -tetrazol-5- yl) [ 1 , 1 ' -biphenyl] -4-yl] methyl] -IH-imidazole-5- carboxaldehyde (0.38 g, 0.9 mmol) and 4-nitrooxybutanoic acid pentafluorophenyl ester (Example 1 ) (0.28 g, 0.9 mmol) the title compound (0.54 g, 12 %) was obtained as a white foam.

IH NMR (DMSO) δ : 9.61 (IH, s ) ; 7.70-7.62 (2H, m) ; 7.56- 7.50 (2H, m) ; 7.12 (2H, d) ; 6.81 (2H, d) ; 5.57 (2H, s ) ; 4.45 (2H, t) ; 2.55-2.40 (4H, m) ; 1.81-1.51 (4H, m) ; 1.27 (2H, m) ; 0.83 (3H, t) .

Claims

1. Compounds of general formula ( I ) and pharmaceutically acceptable salts or stereoisomers thereof

wherein :

Ri is selected from the group consisting of :

wherein R₂ is H, or -W₁-Y₀-ONO₂ wherein W₁ is -C (O) - or -C (O) O-;

Yo is as reported below; R₃ is H, -Y₀-ONO₂ or -W₂-Y₀-ONO₂, wherein W₂ is

Y₀ is as reported below;

W has the following meanings :

-C (O) -, -C (O) O-,

Y and Y₀ are the same or different and are bivalent radicals having the following meanings : a)

- straight or branched C₁-C₂₀ alkylene, preferably C₁-C₁₀ alkylene, more preferably C₃-C₆ alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of : halogen atoms , hydroxy, -ONO₂ or T₀, wherein T₀ is

-OC (O) - (C₁-C₁₀ alkyl) -0N0₂ or -O- (C₁-C₁₀ alkyl) -ONO₂;

- cycloalkylene having from 5 to 7 carbon atoms , the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms , preferably T is CH₃ ; b)

wherein n is an integer from 0 to 20 , nl is an integer from 1 to 20 , n2 is 0 or 1 ; c)

wherein : nl is an integer from 1 to 20 , n2 is 0 or 1 ; Xi is - (CH₂ ) ₃-OC (O) - or -CH=CH-C (O) O-, and R₄ is H or CH₃; d)

wherein : nl is an integer from 1 to 20 , n2 is 0 or 1 ;

Y¹ is -CH=CH-, - (CH₂) ₃-,

Xi is -OC (O) -, -C (O) O-, and

R₄ is H or CH₃, when Y or Y₀ are selected from the bivalent radicals of the groups b) , c) or d) the -ONO₂ group is linked to - (CH₂) _n1- group; g)

h)

wherein X₂ is 0 or S , n3 , n4 and n6 are integer independently selected from 0 to 20 , n5 is an integer from 0 to 6 , R₆ is H, CH₃ or a nitrooxy group, R₇ is CH₃ or a nitrooxy group; when Y or Y₀ are selected from the bivalent radicals of the group g) the -ONO₂ group is linked to - (CH₂) _n5- group; when Y or Y₀ are selected from the bivalent radicals of the group h) the -ONO₂ group is linked to -CH (R₇) - group; i )

wherein : n7 is an integer from 0 to 10 ; n8 is an integer from 1 to 10 ;

R₈ R₉, R₁₀, R₁₁ are the same or different , and are H or straight or branched C₁-C₄ alkyl, preferably R₈ R₉, R₁₀, R₁₁ are H; wherein the -ONO₂ group is linked to

wherein n8 is as defined above;

2. Compounds of formula ( I ) according to claim 1 wherein Y and Y₀ equal or different are selected from a) straight or branched C₁-C₁₀ alkylene, b)

wherein n is 0 or 1 , nl is 1 , n2 is 0 ; g)

wherein X₂ is 0 or S , n3 and n6 are selected from 1 to 5 , n5 is 0 , R₆ is H .

3. Compounds of formula ( I ) according to claim 1 wherein R₁ is a radical of formula ( Ia) , ( Ib) , ( Ic) , ( Id) , ( Ih) or (Ii) wherein R₂ and R3 are H .

4. Compounds of formula ( I ) according to claims 3 wherein Y is a) straight or branched C1-C10 alkylene, b)

wherein n is 0 or 1, nl is 1, n2 is 0; g)

wherein

X₂ is 0 or S, n3 and n6 are selected from 1 to 5, n5 is 0 ,

R₆ is H .

5. Compounds of formula ( I ) according to claim 1 wherein

R₁ is (Ia) wherein

R₂ is -W₁-Y₀-ONO₂ ,Wi is -C(O)-,

W is

6. Compounds of formula ( I ) according to claim 1 wherein

R₁ is ( Ia) wherein

R₂ is -W₁-Y₀-ONO₂ wherein W₁ is -C (O) - or -C (O) O-,

W is -C (0) -, -C (O) O- .

7. Compounds of formula ( I ) according to claims 5 and 6 wherein Y and Y₀ equal or different are a) straight or branched C₁-C₁₀ alkylene, b)

wherein n is 0 or 1, nl is 1, n2 is 0; g)

wherein X₂ is 0 or S , n3 and n6 are selected from 1 to 5 , n5 is 0 , R₅ is H .

8. Compounds of formula ( I ) according to claim 1 wherein R₁ is a radical of formula ( Ib) , ( Ic) , ( Id) , ( Ih) or ( Ii) , wherein R₃ is -Y₀-ONO₂, and W is

9. Compounds of formula ( I ) according to claim 1 wherein Ri is a radical of formula ( Ib) , ( Ic) , ( Id) , ( Ih) or ( Ii) wherein R₃ is -Y₀-ONO₂, and W -C (O) O-

10. Compounds of formula ( I ) according to claim 1 wherein Ri is a radical of formula ( Ib) , ( Ic) , ( Id) , ( Ih) or ( Ii) wherein R₃ is -W₂-Y₀-ONO₂, and

W₂ and W are

11. Compounds of formula ( I ) according to claims 8 to 10 wherein Y and Y₀ equal or different are a) straight or branched C₁-C₁₀ alkylene, b)

wherein n : Ls 0 or 1, nl is 1 , n2 is 0 ; g)

wherein is 0 or S, n3 and n6 are selected from 1 to 5, n5 is 0 ,

R₆ is H

12. Compound of formula ( I ) according to claims 1 to 4 selected from:

:30)

:3i)



(131)

(132)

(133)

(134)



(220)

(221)

(222)

(223)

(224)

(225)

(226)

(238)

(239)

(240)

(241)



(264)

(265)

(266)



(270)

(271)

(272)

(273)

(282)

(283)

(284)

(285)

(302)

:303)

:304)

:305)

(338)

(339)

(340)

(341)



(375)

(376)

(377)

13. Compound of formula ( I ) according to claims 5 and 7 selected from:

14. Compound of formula ( I ) according to claims 6 and 7 selected from:

15. Compound of formula ( I ) according to claims 8 and 11 selected from:

(503)

(504)

(505)

:506)

16. Compound of formula (I) according to claims 10 and 11 selected from:

17. Compound of formula ( I ) according to claims 9 and 11 selected from

18. Compounds of formula ( I ) according to claims 1 to 17 for use as medicaments .

19. Use of compound of formula ( I ) according to claims 1 to 17 , for the manufacture of a medicament for treatment or prophylaxis of cardiovascular, renal and chronic liver diseases , inflammatory processes and metabolic syndromes .

20. Use of a compound of formula ( I ) according to claims 1 to 17 for the manufacture of a medicament for treatment or prophylaxis of heart failure, myocardial infarction, ischemic stroke, atherosclerosis , ocular and pulmonary hypertension, hypertension, diabetic nephropathy, peripheral vascular diseases , left ventricular dysfunction and hypertrophy, liver fibrosis and portal hypertension .

21. Use of a compound according to claims 1 to 17 for the manufacture of a medicament having antithrombotic and antiplatelet activity .

22. A pharmaceutical composition comprising a compound of general formula ( I ) or a salt or stereoisomer thereof according to claims 1 to 17 and pharmaceutically acceptable carrier .