WO2011160974A2

WO2011160974A2 - Statin derivatives

Info

Publication number: WO2011160974A2
Application number: PCT/EP2011/059778
Authority: WO
Inventors: Laura Storoni; Annalisa Bonfanti; Francesca Benedini; Francesca Oliva; Daniela Miglietta; Ennio Ongini
Original assignee: Nicox S.A.
Priority date: 2010-06-21
Filing date: 2011-06-14
Publication date: 2011-12-29
Also published as: WO2011160974A3

Abstract

Dinitrate statins having improved pharmacological activity are described. They can be employed for treating and/or preventing several diseases, in particular acute coronary syndromes, neurodegenerative disorders as well as for reducing cholesterol levels.

Description

STATIN DERIVATIVES

The present invention relates to new statin nitroderivatives . More particularly, the present invention relates to dinitrate statins, pharmaceutical compositions containing them and their use as cholesterol-reducing drugs, as drugs having antioxidant, antithrombotic and anti-inflammatory activity, effects on endothelial function, immunosuppressive properties and for treating and/or preventing acute coronary syndromes, stroke, neurodegenerative disorders, such as Alzheimer's and Parkinson's disease as well as autoimmune diseases, such as multiple sclerosis.

Statins is a class of compounds which comprises as main components lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin (rivastatin) . Statins possess a side group that is structurally similar to HMG-CoA ( 3-hydroxy-3- methylglutaryl coenzyme A) . Fluvastatin, atorvastatin, rosuvastatin and cerivastatin are entirely synthetic compounds containing a heptanoic acid side chain, the remainders being fungal metabolites.

It is known that the various statins are inhibitors of HMG-CoA reductase, an enzyme which catalyses an early, rate-limiting step in cholesterol biosynthesis, reduce triglyceride levels and are also indicated for raising HDL- C levels (P.O. Bonetti et al., European Heart Journal (2003) 24, 225-248) .

WO 2004/105754 discloses mononitrate statins having improved pharmacological activity and enhanced tolerability and their use for treating and/or preventing several diseases . It has been so surprisingly found that the dinitrate compounds of the invention provide enhanced nitric oxide (NO) release over mononitrate analogs (WO 2004/105754). A consideration of stoichiometry leads to an expectation of a doubling of nitrite levels. Compounds of the invention when tested in vitro in a tissue-based measure of vessel relaxation, in rabbit aortic slices, show significant enhancement in EC50 (molar concentration of compound which produces 50% of the maximum possible response for that compound) compared to mononitrates which are greater than two fold (the increase expected based on the stoichiometric relationship) .

It was object of the present invention to provide new derivatives of statins having an improved pharmacological activity compared to mononitrate derivatives.

Object of the present invention are, therefore, statin nitroderivatives of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof

(I)

wherein R is selected from the group consisting of (Ila) (Ilf) :

(Ila) (lib)

( H e ) (lid)

( H e ) (Hf)

w is an integer selected between 0 and 1 ;

R¹ and R² can be equal or different and are independently selected from the group consisting of hydrogen and C₁-C4 alkyl ;

Y is selected from the group consisting of:

A) [R³-0]_p-R⁴-CH(ON0₂) - (R⁵)_n-CH(ON0₂) - [0-R⁶]_pl-R⁷

B) R⁴-CH (ON0₂) -R³-0-R⁵-CH (ON0₂) -R⁷

C) (R⁸) n-R⁹- [R³-0] _P-R⁴-CH (ON0₂) - (R⁵) ni-CH (ON0₂) - [O-R⁶] _pl-R⁷ wherein

R³, R⁴, R⁵, R⁶ and R⁸ are independently a straight or branched C₁-C₁0 alkylene;

n is an integer from 0 to 1 ;

nl is an integer from 0 to 1 ;

p is an integer from 0 to 4 ;

pi is an integer from 0 to 4 ;

R⁷ is selected from the group consisting of hydrogen and

C^-Cg alkyl;

R⁹ is a saturated, unsaturated or aromatic heterocyclic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen or sulphur. The term "Ci-Cio alkylene" as used herein refers to branched or straight chain Ci-Cio hydrocarbon, such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.

The term "Ci-Cio 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, pentyl, hexyl, octyl and the like .

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.

Preferred compounds according to the invention are the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein R is the group (lid) or (lie) .

An embodiment of the invention relates to the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein w is 1.

Preferably R¹ and R² which can be equal or different are independently selected from the group consisting of hydrogen and C¾.

Another preferred embodiment of the invention relates to the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein w is 0.

Another preferred embodiment of the invention relates the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein Y of the group A) is selected from the group consisting of:

5

Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein

Y of the roup B) is selected from the group consisting of:

Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein Y of the group C) is selected from the group consisting of:

Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above selected from the roup consisting of:

(11) (12)



(87)

Another aspect of the present invention includes the use of the compounds of formula (I) in combination with at least a compound used to treat cardiovascular diseases selected from the group consisting of: ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers, antithrombotics such as aspirin, nitrosated ACE inhibitors, nitrosated renin inhibitors, nitrosated angiotensin II receptor antagonists, nitrosated beta-adrenergic blockers and nitrosated aspirin. Suitable ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers, antithrombotics are described in the literature such as The Merck Index (13^th edition) .

Suitable nitrosated compounds are disclosed in WO 98/21193, WO 2005/011646, WO 97/16405, WO 2004/106300, WO 2004/110432 and WO 2007/045551.

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.

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 object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) . As mentioned above, object of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adiuvants and/or carriers usually employed in the pharmaceutical field.

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. Usually, total daily dose may be in amounts preferably from 1 to 500 mg. 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. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.

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 injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable 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 injectables.

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.

As previously reported, in addition to lipid lowering properties the new statin nitroderivatives possess enhanced anti-inflammatory, antiplatelet and antithrombotic effects as compared to native statins. Moreover, they can be effective also in the other pathologies such as acute coronary syndromes, stroke, peripheral vascular diseases such as peripheral ischemia, all disorders associated with endothelial dysfunctions such as vascular complications in diabetic patients and atherosclerosis, neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) , autoimmune diseases such as multiple sclerosis .

Synthesis procedure

1) The compounds of formula (I)

(I) wherein w, R, R¹, R² and Y are as above defined, can be obtained by a process comprising reacting a compound of formula (III)

(III)

wherein M is an alkali metal or alkaline earth metal such as sodium or calcium and R is as above defined;

with a compound of formula (XI)

(XI)

wherein W, R , R and Y are as above defined and Hal is CI, Br or I

The reaction is carried out in an aprotic polar/non polar solvent such as DMF, THF, toluene at a temperature ranging from -20°C to 60°C; The reaction is completed within a time ranges from 30 minutes to 24 hours.

Compounds (XI) can be prepared from the appropriate

compound of formula (X) :

Y-OH

(X)

wherein Y is as above defined, following procedures well known in the literature.

Compounds (X) are known in the literature or can be prepared by known compounds by methods well known in the art .

2) The compounds of formula (I)

(I) wherein w is 0, R, R , R and Y are as above defined, can be obtained

2.1) reacting a compound of formula (XII)

P P

(XII) wherein R is as above defined, P is a hydroxyl protecting group of formula (Xllla) :

(XHIa)

or the P groups taken together form the protecting group of formula (Xlllb) :

(XHIb)

with a compound of formula (X) Y-OH

wherein Y is as above defined,

the reaction may be carried out in presence in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) , N' - ( 3-dimethylaminopropyl ) -N-ethylcarbodiimide hydrochloride (EDAC) , N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP . The reaction is carried out in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C. The reaction is completed within a time range from 30 minutes to 36 hours; 2.2) deprotecting the compounds obtained in the step 2.1) . Fluoride ion is the preferred method for removing silyl ether protecting group. Triethylamine trihydrofluoride or tetrabutylamonium fluoride and acetic acid, in an aprotic polar/non polar solvent such as THF, at temperature ranging from -10°C to 30°C are the preferred method for removing the silyl ether group.

Compounds of formula (XII) can be prepared by hydrolysis of compounds of formula (XIV) ? P

0 0 0

o-x

(XIV)

wherein R and P are as above defined and X is selected from the formulas (IXa)-(IXb)

(IXa) (IXb) when X is (IXa) the deprotecting of the carboxylic function may be carried out by hydrogenation in presence of Pd/C in an aprotic polar/non polar solvent such as THF at temperature ranging from 0°C to 30 °C and a pressure ranging from 1 to 5 bar;

when X is (IXb) the deprotecting of the carboxylic function may be carried out with palladium tetrakis, in presence of dimedone and triphenylphosphine or in presence of morpholine, in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -10 °C to

30°C.

Compounds of formula (XIV) can be prepared by reaction of compound of formula (IV)

(IV) wherein R and X are as above defined,

- when P is (Xllla) with tertbutyldimethylchlorosilane and imidazole in in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -20 °C to 60°C; - when P groups taken together form the group (Xlllb) with 1, 3-dichloro-l, 1, 3, 3-tetraisopropyldisiloxane in presence of imidazole in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -20 °C to

60°C.

Compounds of formula (IV) can be prepared by reaction compound of formula (III)

(III)

wherein R is as above defined and M is an alkali metal or alkaline earth metal such as sodium or calcium,

with a compound of formula X-Hal wherein X is as above defined and Hal is selected from Br or CI,

the reaction may be carried out in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -80°C to 60°C.

In another embodiment of the invention, there is provided a process for the preparation of compounds of formula (I)

(I)

wherein w is 0, R, R¹, R² and Y are as above defined;

said process, as depicted in Scheme 1

(V) (vi :

(VII) (VIII)

Scheme 1 comprising

1) reacting compounds of formula (III), wherein M is an alkali metal or alkaline earth metal such as sodium or calcium and R is as above defined;

with a compound of formula X-Hal wherein X is selected from the formulas (IXa)-(IXb)

(IXa) (IXb)

and Hal is selected from Br or CI,

in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -80°C to 60°C;

2) reacting a compound of formula (IV) wherein R and X are as above defined, with 1, 3-dichloro-l, 1, 3, 3- tetraisopropyldisiloxane in presence of imidazole in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -80°C to 60°C; 3) deprotecting of the carboxylic function of compound of formula (V) wherein R and X are as above defined:

when X is (IXa) by catalytic hydrogenation in presence of Pd/C in an aprotic polar/non polar solvent such as THF at room temperature and pressure;

when X is (IXb) with palladium tetrakis, in presence of dimedone and triphenylphosphine or in presence of morpholine, in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -10 °C to 30°C;

4) reacting a compound of formula (VI) wherein R is as above defined with a compound of formula (X)

HO-Y

(X)

wherein Y is as above defined in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) , N' - ( 3-dimethylaminopropyl ) -N-ethylcarbodiimide

hydrochloride (EDAC) , N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP . The reaction is carried out in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C. The reaction is completed within a time range from 30 minutes to 36 hours; 5) deprotecting of the diol function of compound of formula (VII) wherein R is as above defined in presence of fluoride salt of alkylamine such as triethylamine trihydrofluoride or tetrabutylamonium fluoride and acetic acid, in an aprotic polar/non polar solvent such as THF, at temperature ranging from -10°C to 30°C. Another embodiment of the invention relates to compounds of formula (VI) wherein R is selected from the group consisting of (Ila)-(IIf). Another embodiment of the invention relates to compounds of formula (VI) wherein R is (lid) .

Another embodiment of the invention relates to compounds of formula (VI) wherein R is (He) .

The following examples are to further illustrate the invention without limiting it.

Example 1

Synthesis of (3R, 5R) -3, 3-dimethyl-5, 6-bis (nitrooxy) hexyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl

carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound ( 1 ) )

(1)

A) Methyl 2- ( (4R, 6R) -6- (2- (2- (4-fluorophenyl) -5-isopropyl- 3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) ethyl) -2, 2- dimethyl-1, 3-dioxan-4- l) acetate

To a solution of tert-butyl 2- ( (4R, 6R) -6- (2- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H- pyrrol-l-yl) ethyl) -2, 2-dimethyl-l, 3-dioxan-4-yl) acetate ( 2.0 g, 3.05 mmol) in MeOH (20 mL) , NaOH (0.25 g, 4.58 mmol) was added. The solution was stirred at reflux for 7 hours. The solution was concentrated under vacuum , diluted with an aqueous solution of 5 % Na¾P0₄ (100 mL) and extracted with AcOEt ( 3x200 mL) . The combined organic layers were washed with brine (2x100 mL) , dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient method calculated from TLC: n-hexane/EtOAc 8/2, Rf product: 0.15) affording the title compound (0.7 g, yield 37%).

B) 2- ( (4R, 6R) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl -4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) ethyl) -2, 2-dimethyl- 1, 3-dioxan-4-yl) acetic acid

To a solution of compound A) ( 0.74 g, 1.04 mmol) in THF (7 mL) , an aqueous solution of IN KOH (1.26 mL, 1.26 mmol) was added. The solution was stirred at reflux for 6 hours. The solution was concentrated under vacuum, diluted with an aqueous solution of 5 % Naf^PC^ (70 mL) and extracted with AcOEt ( 3x100 mL) . The combined organic layers were washed with brine (2x100 mL) , dried over Na₂S0₄ and concentrated under reduced pressure affording the title compound (0.61 g, yield 98%) .

C) 3, 3-dimethyl-5, 6-bis (nitrooxy) hexyl 2- ( (4R, 6R) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) - lH-pyrrol-l-yl) ethyl) -2, 2-dimethyl-l , 3-dioxan-4-yl) acetate

To a solution of compound B) (0.54 g, 0.9 mmol) in CH₂CI₂ (10 mL) , 6-hydroxy-4 , 4-dimethylhexane-l , 2-diyl dinitrate (0.35 g, 1.4 mmol) was added. The solution was cooled at 0°C and DMAP (22 mg, 0.18 mmol) and EDAC (0.27 g, 1.4 mmol) were added. The reaction was stirred at room temperature for 4 hours. The solution was diluted with CH₂CI₂ (30 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x60 mL) . The organic layer was washed with ¾0 (4x40 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient method calculated from TLC: n-hexane/EtOAc 7/3, Rf product: 0.46) affording the title compound (0.620 g, yield 93%) .

D) (3R, 5R) -3, 3-dimethyl-5, 6-bis (nitrooxy) hexyl 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (1))

To a suspension of p-toluensulfonic acid silica supported (0.44 g, 0.28 mmol) in methylene chloride (5 mL) cooled at 0°C, compound C) (0.21 g, 0.28 mmol) in CH₂CI₂ (10 mL) was added dropwise. The reaction was stirred at 0°C for 1 hour. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, Cartridge column FLASH 12+M™ KP-Sil, gradient method calculated from TLC: n-hexane/EtOAc 1/1, Rf product: 0.31) affording the compound (1) (0.03 g, yield 15%) . NMR (CDCI3) : 7.26-6.94 (14H, m) , 6.87 (1H, s), 5.46 (1H, m) , 4.73 (1H, dd) , 4.43 (1H, dd) , 4.24-4.05 (3H, m) , 3.97(1H, m) , 3.76 (1H, m) , 3.59 (2H, m) , 3.45 (1H, s), 2.40 (2H, d) , 1.85-1.41 (6H, m) , 1.55 (6H, m) , 1.27 (2H, t) , 1.02 (6H,s)

Example 2

Synthesis of (3R, 5R) -2- (2, 3-bis (nitrooxy) propoxy) ethyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl

carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound (2))

(2)

E) (3R, 5R) -allyl-7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl -4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5- dihydroxyheptanoate

To a solution of atorvastatin calcium salt (5.0 g, 4.33 mmol) in DMF (75 mL) , was added allyl bromine (2.1 g, 17.30 mmol) . The solution was stirred at room temperature for 72 hours. The solution was diluted with ¾0 (200mL) and extracted with EtOAc (3 x 100 mL) . The combined organic layers were washed with brine (2 x 100 mL) , dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 340 g, gradient method calculated from TLC: n-hexane/EtOAc 1/1, Rf product: 0.42) affording the title compound (2.60 g, 50%).

F) allyl 2- ( ( 6R, 8R) -8- (2- (2- (4-fluorophenyl) -5-isopropyl-3- phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) ethyl) -2,2,4,4- tetraisopropyl-1 , 3,5,2, 4-trioxadisilocan-6- l) acetate

To a solution of compound E) (3.00 g; 5.01 mmol) in DMF (30 mL) , was added imidazole (1.91 g; 28.05 mmol). A solution of 1, 3-dichloro-l, 1, 3, 3-tetraisopropyldisiloxane (3.20 mL; 10.00 mmol) in DMF (5mL) was then added dropwise. The reaction was stirred at room temperature for 20 hours. The solution was diluted with an aqueous solution of 5 % NaH₂P0₄ (50 mL) and extracted with AcOEt (3 x 25 mL) . The combined organic layers were washed with ¾0 (4 X 20 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 340 g, eluent: gradient method calculated from TLC: n- hexane/EtOAc 9/1, Rf product: 0.30) affording the title compound (3.04 g, 72%) .

G) 2- ( (6R, 8R) -8- (2- (2- (4-fluorophenyl) -5-isopropyl-3- phenyl-4- (phenylcarbamoyl) -lH-pyrrol-l-yl) ethyl) -2,2,4,4- tetraisopropyl-1 , 3,5,2, 4-trioxadisilocan-6-yl) acetic acid

To a solution of compound F) (0.83 g; 0.99 mmol) in dry CH₂CI₂ (20 mL) , was added dimedone (0.21 g; 1.48 mmol), followed by triphenylphosphine (0.39 g; 1.48 mmol) and palladium tetrakis (0.05 g; 0.04 mmol) . The solution was stirred for 3 hours and then concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 340 g, eluent: gradient method calculated from TLC: n-hexane/EtOAc 66/33, Rf product: 0.38) affording the title compound (4.67 g, 93%) .

¹H-NMR (DMSO-d^e) : 9.80 (1H, m) , 7.51 (2H, m) , 7.22 (6H, m) , 7.02 (6H, m) , 4.28 (1H, m) , 4.08-3.77 (3H, m) , 3.19 (1H, m) , 2.32 (2H, m) , 1.81-1.18 (10H, m) , 1.18-0.64 (28H) .

H) 2- (2, 3-dinitrooxypropoxy) ethyl 2- ( ( 6R, 8R) -8- (2- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) ethyl) -2, 2, 4, 4-tetraisopropyl-l, 3, 5, 2, 4- trioxadisilocan- 6- l ) acetate

To a solution of compound G) (0.64 g, 0.79 mmol) in CH₂CI₂ (8 mL) , 2-ethoxy-3- (2-nitrooxyethoxy) propyl nitrate (0.2 g, 0.79 mmol) was added. The solution was cooled at 0°C and DMAP (19 mg, 0.16 mmol) and EDAC (0.23 g, 1.2 mmol) were added. The reaction was stirred at room temperature for 6 hours. The solution was diluted with CH₂CI₂ (20 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient method calculated from TLC: n-hexane/EtOAc 7/3, Rf product: 0.45) affording the title compound (0.480 g, yield 63%).

I) (3R, 5R) -2- (2, 3-bis (nitrooxy) propoxy) ethyl 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (2))

To a solution of compound H) (0.43 g, 0.42 mmol) in dry THF (8 mL) , cooled at 0°C, acetic acid (0.18 mL, 2.86 mmol) and a 1M THF solution of TBAF (2.6 mL, 2.55 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient method calculated from TLC: n-hexane/EtOAc 4/6, Rf product: 0.25) affording the Compound (2) (0.2 g, 51%) .

¹H-NMR (DMSO-d^e) : 9.78 (1H, s), 7.51 (2H, d) , 7.21 (6H, m) , 7.01 (6H, m) , 5.58 (1H, m) , 4.91 (1H, dd) , 4.81-4.51 (3H, m) , 4.11 (2H, t) , 3.98-3.58 (7H, m) , 3.51 (1H, m) , 3.23 (1H, m) , 2.44-2.21 (2H, m) , 1.67-1.45 (4H, m) , 1.37 (6H, m) . Example 3

Synthesis of ( 3R, 5R) -(( 4R, 5R) -3-methyl-4 , 5-bis (nitrooxy) hexyl) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxy heptanoate

(Compound (3) )

(3)

J) (3R, 5R) -benzyl-7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl -4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5-dihydroxy

heptanoate

To a solution of atorvastatin calcium salt (5.0 g, 4.33 mmol) in DMF (25 mL) , was added benzyl bromine (1.54 g, 9.0 mmol) . The solution was stirred at room temperature for 48 hours. The solution was diluted with ¾0 (70 mL) and extracted with EtOAc (3 x 30 mL) . The combined organic layers were washed with brine (2 x 20 mL) , dried over a₂S0₄ and concentrated under reduced pressure. The crude (4.5 g) was used in the next step without further purification.

K) Benzyl 2- ( ( 6R, 8R) -8- (2- (2- (4-fluorophenyl) -5-isopropyl- 3-phenyl-4- (phenylcarbamoyl) -lH-pyrrol-l-yl) ethyl) -2,2,4,4- tetraisopropyl-1 , 3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound J) (2.5 g; 3.8 mmol) in DMF (20 mL) , was added imidazole (1.55 g; 22.8 mmol). A solution of 1, 3-dichloro-l, 1, 3, 3-tetraisopropyldisiloxane (2.3 mL; 7.32 mmol) in DMF (5mL) was then added dropwise. The reaction was stirred at room temperature for 24 hours. The solution was diluted with an aqueous solution of 5 % Na¾P0₄ (60 mL) and extracted with AcOEt (3 x 30 mL) . The combined organic layers were washed with ¾0 (4 X 20 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 340 g, eluent: gradient method calculated from TLC: n-hexane/EtOAc 9/1, Rf product: 0.30) affording the title compound (2.8 g, 85%).

G) 2- ( (6R, 8R) -8- (2- (2- (4-fluorophenyl) -5-isopropyl-3- phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) ethyl) -2,2,4,4- tetraisopropyl-1 , 3,5,2, 4-trioxadisilocan-6-yl) acetic acid

To a solution of compound K) (2.5 g; 3.35 mmol) in THF (30 mL) , Pd/C (0.23 g) was added. The solution was treated with hydrogen under the pressure of 4 bar and at room temperature for 5.5 hours. The reaction was filtered and concentrated under reduced pressure. The residue was (4.5 g) was crystallized from n-hexane (20 mL) affording the title compound (2.25 g, yield 84%) L) (4R, 5R) -4, 5-dinitrooxy-3-methylhexyl 2- ( ( 6R, 8R) -8- (2- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) - lH-pyrrol-l-yl) ethyl) -2, 2, 4, 4-tetraisopropyl-l, 3, 5, 2, 4- trioxadisilocan- 6- l ) acetate

To a solution of compound G) (1.15 g, 1.43 mmol) in CH₂CI₂ (15 mL) , (2R, 3R) -6-hydroxy-4-methylhexane-2, 3-diyl-di nitrate (0.40 g, 1.67 mmol) was added. The solution was cooled at 0°C and DMAP (41 mg, 0.33 mmol) and EDAC (0.48 g, 2.52 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (30 mL) and washed with an aqueous solution of 5 % aH2 P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a2 S 0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient method calculated from TLC: n-hexane/EtOAc 8/2, Rf product: 0.33) affording the title compound (1.15 g, yield 79%). M) (3R, 5R) - ( (4R, 5R) -3-methyl-4, 5-bis (nitrooxy) hexyl) 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) - lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (3)) To a solution of compound L) (1.04 g, 1.02 mmol) in dry THF (16 mL) , cooled at 0°C, acetic acid (0.41 mL, 6.72 mmol) and a 1M THF solution of TBAF (6.1 mL, 6.11 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x70 mL) . The organic layer was washed with ¾0 (4x70 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient method calculated from TLC: n-hexane/EtOAc 1/1, Rf product: 0.25) affording the compound (3) (0.31 g, 40%). ¹H-NMR (DMSO-d^e) : 9.78 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.41 (2H, m) , 4.68 (2H, dd) , 4.19-3.67 (5H, m) , 3.51 (1H, m) , 3.23 (1H, m) , 2.31 (2H, m) , 1.80-1.39 (10H, m) , 1.38 (6H, m) , 0.96 (3H, dd) .

Example 4

Synthesis of ( 3R, 5R) -2- ( ( S ) -2 , 3-bis (nitrooxy) propoxy) ethyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound (2 ) )

(2)

N) 2- ( (R) -2, 3-dinitrooxypropoxy) ethyl-2- ( (6R, 8R) -8- (2- (2 (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) - lH-pyrrol-l-yl) ethyl) -2, 2, 4, 4-tetraisopropyl-l, 3, 5, 2, 4- trioxadisilocan- 6-yl ) acetate

To a solution of compound G) (0.73 g, 0.91 mmol) in CH₂CI₂ (15 mL) , (R) 1 , 2-dinitrooxy-3- (2-hydroxyethoxy) propane (0.23 g, 1.02 mmol) was added. The solution was cooled at 0°C and DMAP (20 mg, 0.15 mmol) and EDAC (0.22 g, 1.15 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (40 mL) and washed with an aqueous solution of 5 % aH₂P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient method calculated from TLC : n-hexane/EtOAc 75/25, Rf product: 0.33) affording the title compound (0.76 g, yield 83%) .

0) (3R, 5R) -2- ( (S) -2, 3-bis (nitrooxy) propoxy) ethyl 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (2))

To a solution of compound N) (0.75 g, 0.74 mmol) in dry THF (10 mL) , cooled at 0°C, acetic acid (0.28 mL, 4.55 mmol) and a 1M THF solution of TBAF (4.2 mL, 4.2 mmol) were added. The reaction was stirred at room temperature for 6 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x70 mL) . The organic layer was washed with ¾0 (4x70 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 75/25 to n-hexane/EtOAc 20/80 during 1.4 L) affording the compound (2) (0.43 g, 75%) .

1H-NMR (DMSO-d^e) : 9.78 (1H, s), 7.51 (2H, d) , 7.21 (6H, m) , 7.01 (6H, m) , 5.58 (1H, m) , 4.93 (1H, dd) , 4.82-4.71 (2H, m) , 4.62 (1H, d) , 4.11 (2H, t) , 3.98-3.58 (7H, m) , 3.51 (1H, m) , 3.23 (1 H, m) , 2.44-2.21 (2H, m) , 1.67-1.45 (4H, m) , 1.37 (6H, m) .

Example 5

Synthesis of (3R, 5R) -( (R) -5, 6-bis (nitrooxy) hexyl) -7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3 5-dihydroxyheptanoate (Compound (4))

(4)

P) (R) -5, 6-dinitrooxyhexyl-2- ( (6R, 8R) -2,2,4, 4-tetraisopro pyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) -1H- pyrrol-l-yl) eth l) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (2.5 g, 3.16 mmol) in CH₂CI₂ (50 mL) , (R) -1, 2-dinitrooxyhexan-6-ol (0.8 g, 3.2 mmol) was added. The solution was cooled at 0°C and DMAP (154 mg, 1.2 mmol) and EDAC (1.21 g, 6.32 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (80 mL) and washed with an aqueous solution of 5 % Naf^PC^ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n-hexane to n- hexane/EtOAc 60/40 during 1.7 L) affording the title compound (2.93 g, yield 92%) .

Q) (3R, 5R) - ( (R) -5, 6-bis (nitrooxy) hexyl) 7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (4))

To a solution of compound P) (2.93 g, 2.91 mmol) in dry THF (45 mL) , cooled at 0°C, acetic acid (1.18 mL, 19.2 mmol) and a 1M THF solution of TBAF (17.5 mL, 17.5 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (150 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x100 mL) . The organic layer was washed with ¾0 (4x100 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 9/1 to n-hexane/EtOAc 20/80 during 1.4 L) affording the compound (4) (1.86 g, 70%) .

1H-NMR (DMSO-d^e) : 9.74 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.41 (1H, m) , 4.92 (1H, dd) , 4.70 (2H, m) , 4.59 (1H, d) , 3.98-3.66 (5H, m) , 3.51 (1H, m) , 3.23 (1H, m) , 2.36 (1H, dd) , 2.25 (1H, dd) , 1.83-1.39 (6H, m) , 1.38 (6H, m) .

Example 6

Synthesis of ( 3R, 5R) -3- (( S ) -2 , 3-bis (nitrooxy) propoxy) propyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound (5) )

(5)

R) 3- ( (R) -2, 3-dinitrooxypropoxy) propyl 2- ( ( 6R, 8R) -2 , 2 , 4 , 4- tetraisopropyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenyl carbamoyl) -lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan- 6-yl ) acetate

To a solution of compound G) (2.06 g, 2.57 mmol) in CH₂CI₂ (30 mL) , (R) -1, 2-dinitrooxyhexan-6-ol (0.57 g, 2.57 mmol) was added. The solution was cooled at 0°C and DMAP (94 mg, 0.77 mmol) and EDAC (0.74 g, 3.85 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 95/5 to n-hexane/EtOAc 60/40 during 1.4 L) affording the title compound (1.96 g, yield 74%) .

S) ( 3R, 5R) -3- ( ( S ) -2 , 3-bis (nitrooxy) propoxy) propyl 7- (2 fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) - pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (5)) To a solution of compound R) (1.96 g, 1.91 mmol) in dry THF (50 mL) , cooled at 0°C, acetic acid (0.78 mL, 12.64 mmol) and a 1M THF solution of TBAF (11.5 mL, 11.5 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (250 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x100 mL) . The organic layer was washed with ¾0 (4x100 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 7/3 to EtOAc during 1.4 L) affording the compound (5) (0.81 g, 58%).

¹H-NMR (DMSO-d^e) : 9.75 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.56 (1H, m) , 4.93 (1H, dd) , 4.77 (1H, dd) , 4.74 (1H, d) , 4.62 (1H, d) , 4.04 (2H, t), 3.96-3.70 (5H, m) , 3.51 (3H, m) , 3.23 (1H, m) , 2.37 (1H, dd) , 2.25 (1H, dd) , 1.79 (2H, m) , 1.67-1.39 (4H, m) , 1.38 (6H, m) .

Example 7

Synthesis of ( 3R, 5R) -3- ( (R) -2 , 3-bis (nitrooxy) propoxy) propyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenyl carbamoyl) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound (5)

(5)

T) 3- ( (S) -2, 3-dinitrooxypropoxy) propyl 2- ( ( 6R, 8R) -2 , 2 , 4 , 4- tetraisopropyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenyl carbamoyl) -lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan- 6-yl ) acetate

ON0₂

To a solution of compound G) (1.99 g, 2.57 mmol) in CH₂CI₂ (20 mL) , (S) -1, 2-dinitrooxyhexan-6-ol (0.55 g, 2.48 mmol) was added. The solution was cooled at 0°C and DMAP (91 mg, 0.74 mmol) and EDAC (0.71 g, 3.72 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 95/5 to n-hexane/EtOAc 60/40 during 1.4 L) affording the title compound (2.09 g, yield 79%) .

U) ( 3R, 5R) -3- ( (R) -2 , 3-bis (nitrooxy) propoxy) propyl 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (5))

To a solution of compound T) (1.97 g, 1.91 mmol) in dry THF (40 mL) , cooled at 0°C, acetic acid (0.78 mL, 12.64 mmol) and a 1M THF solution of TBAF (11.5 mL, 11.5 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (250 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x100 mL) . The organic layer was washed with ¾0 (4x100 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 7/3 to EtOAc during 1.4 L) affording the compound (5) (0.95 g, yield 64%).

1H-NMR (DMSO-d^e) : 9.75 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.56 (1H, m) , 4.93 (1H, dd) , 4.76 (2H, m) , 4.62 (1H, d) , 4.04 (2H, t) , 3.96-3.70 (5H, m) , 3.51 (3H, m) , 3.23 (1H, m) , 2.37 (1H, dd) , 2.25 (1H, dd) , 1.79 (2H, m) , 1.67-1.39 (4H, m) , 1.38 (6H, m) .

Example 8

Synthesis of (3R, 5R) -( (S) -5, 6-bis (nitrooxy) hexyl) -7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (4))

(4)

V) (S) 5 , 6-dinitrooxyhexyl-2- ( (6R,8R)-2,2,4,4-tetraiso propyl-8- (2 (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) - lH-pyrrol-1 yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

0₂

To a solution of compound G) (2.09 g, 2.62 mmol) in CH2C I 2 (50 mL) , (S) -1, 2-dinitrooxyhexan-6-ol (0.70 g, 3.15 mmol) was added. The solution was cooled at 0°C and DMAP (128 mg, 1.04 mmol) and EDAC (1.0 g, 5.24 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH2C I 2 (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n-hexane to n-hexane/EtOAc 60/40 during 1.7 L) affording the title compound (2.38 g, yield 90%).

W) (3R, 5R) - ( (S) -5, 6-bis (nitrooxy) hexyl) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (4))

To a solution of compound V) (2.38 g, 2.36 mmol) in dry THF (40 mL) , cooled at 0°C, acetic acid (0.96 mL, 15.57 mmol) and a 1M THF solution of TBAF (11.1 mL, 11.1 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (250 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x100 mL) . The organic layer was washed with ¾0 (4x100 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 9/1 to n-hexane/EtOAc 2/8 during 1.4 L) affording the compound (4) (1.5 g, yield 83%) .

¹H-NMR (DMSO-d^e) : 9.73 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.41 (1H, m) , 4.92 (1H, dd) , 4.70 (2H, m) , 4.59 (1H, d) , 4.01 (2H, t) , 3.98-3.66 (3H, m) , 3.51 (1H, m) , 3.23 (1H, m) , 2.31 (2H, m) , 1.80-1.39 (6H, m) , 1.38 (6H, m) . Example 9

Synthesis of (3R, 5R) -( (S) -1- ( (R) -2, 3-bis (nitrooxy) propyl) pyrrolidin-2-yl) methyl 7- (2- (4-fluorophenyl) -5-isopropyl-3- phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5-dihydroxy heptanoate (Com ound (43) )

(43)

X) ( (S) -1- ( (R) -2, 3-dinitrooxypropyl) pyrrolidin-2-yl) methyl 2- ( (6R, 8R) -2, 2, 4, 4-tetraisopropyl- 8- (2- (2-isopropyl-4 , 5- diphenyl-3- (phenylcarbamoyl) -lH-pyrrol-l-yl) ethyl) -1, 3, 5, 2, 4-trioxadisilocan-6- l) acetate

To a solution of compound G) (0.72 g, 0.9 mmol) in CH₂CI₂ (14.5 mL) , (R) -3- ( (S) -2- (hydroxymethyl) pyrrolidin-l-yl) - 1 , 2-dinitrooxypropane (0.25 g, 0.96 mmol) was added. The solution was cooled at 0°C and DMAP (22 mg, 0.18 mmol) and EDAC (259 mg, 1.35 mmol)) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with CH₂CI₂ (15 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x15 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient n-hexane/AcOEt 8/2 (75mL), from n-hexane/AcOEt 8/2 to n-hexane/EtOAc 1/1 during 520 mL, n-hexane/EtOAc 1/1 (75 mL) ) affording the title compound (0.66 g, yield 70%). Y) (3R, 5R) - ( (S) -1- ( (R) -2, 3-bis (nitrooxy)propyl)pyrrolidin- 2 -yl) methyl 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (43) )

To a solution of compound X) (0.64 g, 0.61 mmol) in dry THF (6 mL) , cooled at 0°C, acetic acid (0.24 mL, 3.99 mmol) and a 1M THF solution of TBAF (3.37 mL, 3.37 mmol) were added. The reaction was stirred at room temperature for 17 hours. The solution was diluted with AcOEt (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient n- hexane/AcOEt 1/1 (75mL) , from n-hexane/AcOEt 1/1 to n- hexane/EtOAc 1/9 during 230 mL, n-hexane/EtOAc 1/9 (230 mL) ) affording the compound (43) (0.59 g, yield 11%).

1H-NMR (DMSO-d^e) : 9.74 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.51 (1H, m) , 4.97-4.59 (4H, m) , 4.04-3.63 (5H, m) , 3.51 (1H, m) , 3.33-2.98 (3H, m) , 2.75 (2H, m) , 2.43-2.20 (3H, m) , 1.88-1.33 (8H, m) , 1.38 (6H, m) .

Example 10

Synthesis of (3R, 5R) -( (S) -2- (nitrooxy) -3- (3- (nitrooxy) propoxy) propyl ) 7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl- 4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound ( 42 ) )

ON0₂

(42) AB) (S) -2-nitrooxy-3- (3-nitrooxypropoxy) propyl 2-((6R,8R)- 2,2,4,4-tetraisopropyl-8- (2- (2-isopropyl-4, 5-diphenyl-3- (phenylcarbamoyl ) -lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxa disilocan- 6-yl ) acetate

To a solution of compound G) (0.89 g, 1.11 mmol) in CH₂CI₂ (20 mL) , (S) -2-nitrooxy-3- (3-nitrooxypropoxy) propan-l-ol (0.26 g, 1.11 mmol) was added. The solution was cooled at 0°C and DMAP (54 mg, 0.4 mmol) and EDAC (425 mg, 2.2 mmol)) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (30 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient from n-hexane/AcOEt 9/1 to n-hexane/EtOAc 1/1 during 750 mL) affording the title compound (1.0 g, yield 88%) .

AC) (3R, 5R) - ( (S) -2- (nitrooxy) -3- (3- (nitrooxy) propoxy) propyl) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-

(phenylcarbamoyl ) -lH-pyrrol-l-yl) -3, 5-dihydroxyheptanoate

(Compound ( 42 ) )

To a solution of compound AB) (1.13 g, 1.1 mmol) in dry THF (20 mL) , cooled at 0°C, acetic acid (0.41 mL, 6.6 mmol) and a 1M THF solution of TBAF (6.6 mL, 6.6 mmol) were added. The reaction was stirred at room temperature for 2 hours. The solution was diluted with AcOEt (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient from n-hexane/AcOEt 9/1 to EtOAc during 1.7 L) affording the compound (42) (0.24 g, yield 28%).

¹H-NMR (DMSO-d^e) : 9.75 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.47 (1H, m) , 4.74 (1H, dd) , 4.60 (3H, m) , 4.42-4.21 (2H, m) , 4.08-3.42 (8H, m) , 3.23 (1H, m) , 2.43 (1H, dd) , 2.30 (1H, dd) , 1.91 (2H, m) , 1.73-1.39 (6H, m) , 1.38 (6H, m) .

Example 11

Synthesis of ( 3R, 5R) -(( S ) -2 , 6-bis (nitrooxy) hexyl ) 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3 5-dihydroxyheptanoate (Compound (9))

(9)

AD) (S) -2, 6-dinitrooxyhexyl-2- ( (6R, 8R) -2, 2, 4, 4-tetra isopropyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenyl

carbamoyl) -lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan- 6-yl ) acetate

To a solution of compound G) (0.46 g, 0.58 mmol) in CH₂CI₂ (10 mL) , ( S ) -2 , 6-dinitrooxyhexanol (0.46 g, 0.58 mmol) was added. The solution was cooled at 0°C and DMAP (28 mg, 0.23 mmol) and EDAC (222 mg, 1.1 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (30 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient from n-hexane/AcOEt 9/1 to n-hexane/EtOAc 1/1 during 750 mL) affording the title compound (0.51 g, yield 87%).

AE) (3R, 5R) - ( (S) -2, 6-bis (nitrooxy) hexyl) 7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (9))

To a solution of compound AD) (0.51 g, 0.5 mmol) in dry THF (10 mL) , cooled at 0°C, acetic acid (0.19 mL, 3.05 mmol) and a 1M THF solution of TBAF (3.05 mL, 3.05 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (15 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x10 mL) . The organic layer was washed with ¾0 (4x10 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/AcOEt 9/1 to EtOAc during 1.7 L) affording the compound (9) (0.14 g, yield 36%).

1H-NMR (DMSO-d^e) : 9.74 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.28 (1H, m) , 4.72 (1H, d) , 4.61 (1H, d) , 4.51 (2H, t), 4.34 (1H, dd) , 4.17(1H, dd) , 4.03-3.66 (3H, m) , 3.51 (1H, m) , 3.23 (3H, m) , 2.34 (2H, m) , 1.78-1.21 (8H, m) , 1.36 (6H, m) . Example 12

Synthesis of ( 3R, 5R) -( (R) -2 , 6-bis (nitrooxy) hexyl ) 7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -1H- pyrrol-l-yl) -3 5-dihydroxyheptanoate (Compound (9))

(9)

AJ) (R) -2, 6-dinitrooxyhexyl-2- ( ( 6R, 8R) -2 , 2 , 4 , 4-tetraiso propyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) - lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (0.4 g, 0.5 mmol) in CH₂CI₂ (10 mL) , (R) -2-6-dinitrooxyhexanol (0.11 g, 0.5 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (192 mg, 1 mmol)) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (60 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient from n-hexane/AcOEt 9/1 to EtOAc during 750 mL) affording the title compound (0.38 g, yield 76%) . AK) (3R, 5R) - ( (R) -2, 6-bis (nitrooxy) hexyl) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (9)

To a solution of compound AH) (0.38 g, 0.37 mmol) in dry THF (6 mL) , cooled at 0°C, acetic acid (0.15 mL, 2.49 mmol) and a 1M THF solution of TBAF (2.3 mL, 2.3 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (35 mL) and washed with an aqueous solution of 5 % aH2 P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over a2 S 0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient from n-hexane/AcOEt 9/1 to AcOEt during 750 mL) affording the compound (9) (0.27 g, yield 72%) .

NMR (DMSO-d^e) : 9.74 (1H, s), 7.50 (2H, d) , 7.19 (6H, m) , 6.99 (6H, m) , 5.29 (1H, m) , 4.73 (1H, d) , 4.61 (1H, d) , 4.51(2H, t), 4.39 (1H, dd) , 4.15(1H, dd) , 4.03-3.66 (3H, m) , 3.51 (1H, m) , 3.23 (3H, m) , 2.41 (1H, dd) , 2.28 (1H, m) , 1.78-1.21 (8H, m) , 1.36 (6H, m) .

Example 13

Synthesis of (3R, 5R) - ( (S) -3, 4-bis (nitrooxy) butyl) -7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H- pyrrol-l-yl) -3 5-dihydroxyheptanoate (Compound (6))

(6)

AL) (S) -3, 4-dinitrooxybutyl-2- ( (6R, 8R) -2 , 2 , 4 , 4-tetraiso propyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) - lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (1.63 g, 2.04 mmol) in CH₂CI₂ (30 mL) , (S) -3-4-dinitrooxybutanol (0.4 g, 2.04 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (410 mg, 2.14 mmol)) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 84/16 to n-hexane/AcOEt 75/25 during 1750 mL) affording the title compound (1.15 g, yield 75%) .

AM) (3R, 5R) - ( (S) -3, 4-bis (nitrooxy) butyl ) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (6))

To a solution of compound AL) (1.5 g, 1.5 mmol) in dry THF (30 mL) , cooled at 0°C, triethylamine trihydrofluoride (1 mL, 6.17 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x50 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n- hexane/AcOEt 55/45 to n-hexane/AcOEt 3/7 during 1680 mL) affording the compound (6) (0.38 g, yield 37%).

NMR (CDC1₃) : 7.26-6.94 (14H, m) , 6.87 (1H, s), 5.41 (1H, m) , 4.79 (1H, dd) , 4.53 (1H, dd) , 4.28 (2H, t) , 4.15 (2H, m) , 3.97(1H, m) , 3.75 (1H, m) , 3.59 (1H, m) , 2.43 (2H, d) ,

2.11- (2H, m) , 1.79-1.40 (4H, m) , 1.55 (6H, m) , 1.28 (1H, m) .

Example 14

Synthesis of ( 3R, 5R) -(( S ) -2 , 3-bis (nitrooxy) propyl ) 7- (2 fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) - pyrrol-l-yl) -3, 5-dih droxyheptanoate (Compound (6))

(6)

AN) (S) -3, 4-dinitrooxybutyl 2- ( ( 6R, 8R) -2 , 2 , 4 , 4-tetraiso propyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) - lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (1.63 g, 2.04 mmol) in CH₂CI₂ (30 mL) , (S) -3-4-dinitrooxybutanol (0.4 g, 2.04 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (410 mg, 2.14 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n-hexane/AcOEt 84/16 to n-hexane/AcOEt 75/25 during 1750 mL) affording the title compound (1.15 g, yield 75%). AO) (3R, 5R) - ( (S) -3, 4-bis (nitrooxy) butyl ) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (6))

To a solution of compound AN) (1.5 g, 1.5 mmol) in dry THF (30 mL) , cooled at 0°C, triethylamine trihydrofluoride (1 mL, 6.17 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x50 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n- hexane/AcOEt 55/45 to n-hexane/AcOEt 3/7 during 1680 mL) affording the compound (6) (0.38 g, yield 37%).

NMR (CDCI3) : 7.26-6.94 (14H, m) , 6.87 (1H, s), 5.47 (1H, m) , 4.78 (1H, dd) , 4.66 (1H, dd) , 4.55 (1H, dd) , 4.30 (1H, dd) , 4.23-4.04 (2H, m) , 3.97 (1H, m) , 3.75 (1H, m) , 3.59 (1H, m) , 2.47 (2H, d) , 1.79-1.40 (4H, m) , 1.55 (6H, m) . Example 15

Synthesis of (3R, 5R) - ( (R) -2, 3-bis (nitrooxy) propyl) -7- (2- (4- fluorophenyl ) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -1H- pyrrol-l-yl) -3, 5-dihydroxyheptanoate (Compound (7))

(7)

AP) (R) -2, 3-dinitrooxypropyl 2- ( ( 6R, 8R) -2 , 2 , 4 , 4-tetraiso propyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl ) - lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (1.72 g, 2.14 mmol) in CH₂CI₂ (20 mL) , (R) -2 , 3-dinitrooxypropanol (0.39 g, 2.14 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (430 mg, 2.25 mmol)) were added. The reaction was stirred at room temperature for 6 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 85/15 to n-hexane/AcOEt 7/3 during 1750 mL) affording the title compound (1.69 g, yield 82%) .

AQ) (3R, 5R) - ( (S) -2, 3-bis (nitrooxy) propyl ) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (7)) To a solution of compound AP) (1.8 g, 1.86 mmol) in dry THF (15 mL) , cooled at 0°C, triethylamine trihydrofluoride (1.2 mL, 7.3 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x50 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n- hexane/AcOEt 55/45 to n-hexane/AcOEt 3/7 during 1740 mL) affording the compound (7) (0.31 g, yield 23%).

NMR (CDC1₃) : 7.26-6.94 (14H, m) , 6.87 (1H, s), 5.47 (1H, m) , 4.78 (1H, dd) , 4.66 (1H, dd) , 4.55 (1H, dd) , 4.30 (1H, dd) , 4.23-4.04 (2H, m) , 3.97 (1H, m) , 3.75 (1H, m) , 3.59 (1H, m) , 2.47 (2H, d) , 1.79-1.40 (4H, m) , 1.55 (6H, m) .

Example 16

(3R, 5R) - ( (R) -3, 4-bis (nitrooxy) butyl ) 7- (2- (4-fluorophenyl) 5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol-l-yl) - 3 , 5-dihydrox heptanoate (Compound (7))

(7)

AR) (R) -3, 4-dinitrooxybutyl-2- ( ( 6R, 8R) -2 , 2 , 4 , 4-tetraiso propyl-8- (2- (2-isopropyl-4 , 5-diphenyl-3- (phenylcarbamoyl) - lH-pyrrol-l-yl) ethyl) -1,3,5,2, 4-trioxadisilocan-6-yl) acetate

To a solution of compound G) (1.63 g, 2.04 mmol) in CH₂CI₂ (20 mL) , (R) -3, 4-dinitrooxybutanol (0.40 g, 2.04 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (410 mg, 2.1 mmol)) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over Na₂ S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n-hexane/AcOEt 8/2 to n-hexane/AcOEt 7/3 during 1750 mL) affording the title compound (1.32 g, yield 66%).

AS) (3R, 5R) - ( (R) -3, 4 -bis (nitrooxy) butyl) -7- (2- (4-fluoro phenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl ) -lH-pyrrol- 1-yl) -3, 5-dihydroxyheptanoate (Compound (7))

To a solution of compound AR) (1.32 g, 1.34 mmol) in dry THF (30 mL) , cooled at 0°C, triethylamine trihydrofluoride (0.87 mL, 5.3 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x50 mL) . The organic layer was washed with ¾0 (4x50 mL) and brine, then dried over a₂ S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n- hexane/AcOEt 55/45 to n-hexane/AcOEt 35/65 during 1740 mL) affording the compound (7) (0.52 g, yield 53%). NMR (CDCI3) : 7.26-6.94 (14H, m) , 6.87 (1H, s), 5.41 (1H, m) , 4.79 (1H, dd) , 4.53 (1H, dd) , 4.28 (2H, t) , 4.15 (2H, m) , 3.97 (1H, m) , 3.75 (1H, m) , 3.59 (1H, m) , 2.43 (2H, d) , 2.11 (2H, m) , 1.79-1.40 (4H, m) , 1.55 (6H, m) , 1.28 (1H, m) .

Example 17

Synthesis of (3R, 5S, E) - ( (R) -5, 6-bis (nitrooxy) hexyl) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) -3 5-dihydroxyhept- 6-enoate (Compound (47))

(47)

AT) (3R, 5S, E) -methyl 7- (4- (4-fluorophenyl) -6-isopropyl-2- N-methylmethylsulfonamido) pyrimidin-5-yl ) -3, 5-dihydroxy

To a solution of rosuvastatin calcium (1.0 g, 0.2 mmol) in MeOH (10 mL) and DMF (5 mL) , trimethylchlorosilane (0.41 g, 4 mmol) was added. The reaction was stirred at room temperature for 3 hours. The solution was diluted with AcOEt (60 mL) and washed with ¾0 (4x30 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 1/1 to n-hexane/AcOEt 3/7 during 1750 mL) affording the title compound (0.78 g, yield 78%) . AU) (3R, 5S, E) -methyl 3, 5-bis (tert-butyldimethylsilyloxy) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylmethylsulfon amido) pyrimidin-5-yl hept- 6-enoate

To a solution of compound AT) (0.9 g, 2 mmol) in DMF (10 mL) , tertbutyldimethylchlorosilane (0.64 g, 4.1 mmol) and imidazole (0.28 g, 4.2 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with H₂0 (4x40 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n-hexane/AcOEt 9/1 to n-hexane/AcOEt 75/25 during 1750 mL) affording the title compound (0.98 g, yield 68%) .

AV) (3R, 5S,E) -3, 5-bis (tert-butyldimethylsilyloxy) -7- (4- (4- fluorophenyl ) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) hept- 6-enoic acid

To a solution of compound AU) (0.4 g, 0.55 mmol) in THF (3 mL) and MeOH (2 mL) , LiOH (0.04 g, 1.65 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (50 mL) and washed with ¾0 (4x30 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient from n-hexane/AcOEt 8/2 to n-hexane/AcOEt 7/3 during 900 mL) affording the title compound (0.21 g, yield 53%). AW) (3R, 5S,E) - ( (R) -5, 6-dinitrooxyhexyl ) -3, 5-bis (tert- butyldimethylsilyloxy) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylmethylsulfonamido pyrimidin-5-yl ) hept- 6-enoate

To a solution of compound AV) (0.8 g, 1.13 mmol) in CH₂CI₂ (20 mL) , (R) -5 , 6-dinitrooxyhexanol (0.25 g, 1.13 mmol) was added. The solution was cooled at 0°C and DMAP (24 mg, 0.2 mmol) and EDAC (227 mg, 1.18 mmol)) were added. The reaction was stirred at room temperature for 5 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over a₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, gradient from n- hexane/AcOEt 8/2 to n-hexane/AcOEt 7/3 during 1450 mL) affording the title compound (0.63 g, yield 61%) .

AX) (3R, 5S,E) - ( (R) -5, 6-bis (nitrooxy) hexyl ) -7- (4- (4-fluoro phenyl) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin- 5-yl ) -3 , 5-dihydroxyhept- 6-enoate (Compound (47))

To a solution of compound AW) (0.63 g, 0.69 mmol) in dry THF (10 mL) , cooled at 0°C, tetrabutylammonium fluoride Solution 1M in THF (2.08 mL, 2.08 mmol) was added. The reaction was stirred at room temperature for 24 hours. The solution was diluted with AcOEt (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x30 mL) . The organic layer was washed with ¾0 (4x30 mL) and brine, then dried over Na₂SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: n-hexane/AcOEt 1/1 (900 mL) ) affording the compound (47) (0.21 g, yield 44%) .

NMR (CDC1₃) : 7.66 (2H, m) , 7.09 (2H, m) , 6.66 (1H, d) , 5.47 (1H, dd) , 5.29 (1H, m) , 4.75 (1H, dd) , 4.49 (2H, m) , 4.27- 4.08 (4H, m) , 3.58 (3H, s) , 3.52 (3H, s) , 3.36 (1H, m) , 2.49 (2H, m) , 1.75 (4H, m) , 1.55 (4H, m) , 1.28 (6H, m) .

Example 18

Synthesis of (3R, 5S, E) -( (S) -5, 6-bis (nitrooxy) hexyl) -7- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) -3 5-dihydroxyhept- 6-enoate (Compound (47))

(47)

AY) (3R, 5S, E) -allyl 7- (4- (4-fluorophenyl) -6-isopropyl-2- (N- methylmethylsulfonamido) pyrimidin-5-yl ) -3, 5-dihydroxyhept- 6-enoate

To a solution of rosuvastatin calcium salt (7.0 g, 7 mmol) in DMF (100 mL) , was added allyl bromine (1.7 g, 14 mmol) . The solution was stirred at room temperature for 12 hours. The solution was diluted with ¾0 (200 mL) and extracted with EtOAc (3 x 200 mL) . The combined organic layers were washed with brine (2 x 100 mL) , dried over Na?S0₄ and concentrated under reduced pressure affording the title compound (4.81 g, yield 66%).

AZ) Allyl 2- ( (6R, 8S) -8- ( (E) -2- (4- (4-fluorophenyl) -6- isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) vinyl) -2, 2, 4, 4-tetraisopropyl-l, 3, 5, 2, 4-trioxadisilocan-6- yl ) acetate

To a solution of compound AY) (3.3 g; 5.83 mmol) in DMF (15 mL) , was added imidazole (0.87 g; 12.83 mmol). A solution of 1, 3-dichloro-l, 1, 3, 3-tetraisopropyldisiloxane (1.84 g; 5.83 mmol) in DMF (5mL) was then added dropwise. The reaction was stirred at room temperature for 4 hours. The solution was diluted with an aqueous solution of 5 % NaH₂P0₄ (50 mL) and extracted with AcOEt (3 x 25 mL) . The combined organic layers were washed with ¾0 (4 X 20 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 340 g, eluent: gradient from n-hexane/EtOAc 9/1 to n- hexane/EtOAc 8/2 in 10 L) affording the title compound (1.86 g, 42%) .

BA) 2- ( (6R, 8S) -8- ( (E) -2- (4- (4-fluorophenyl) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) vinyl )-2, 2,4,4- tetraisopropyl-1 , 3,5,2, 4-trioxadisilocan-6-yl) acetic acid

To a solution of compound AZ) (0.29 g; 0.39 mmol) in dry THF (20 mL) , was added palladium tetrakis (0.27 g; 0.23 mmol) followed by morpholine (2.05 mL, 23.55 mmol) . The solution was stirred for 12 hours. The solution was diluted with AcOEt (100 mL) and washed with H₂0 (4 X 40 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure then concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n- hexane/EtOAc 7/3 to n-hexane/EtOAc 55/45 in 870 mL) affording the title compound (1.51 g, 89%) .

NMR (CDC1₃) : 7.61 (2H, d) , 7.09 (2H, d) , 6.65 (1H, d) , 5.43 (1H, d) , 4.47 (2H, dd) , 4.13 (1H, q) , 3.58 (3H, s), 3.52 (3H, s), 3.33 (1H, m) , 2.59 (2H, m) , 1.77-1.42 (5H, m) , 1.27 (6H, d) , 1.06 (24H, m) .

BB) (S) -5, 6-dinitrooxyhexyl-2- ( (6R, 8S) -8- ( (E) -2- (4- (4- fluorophenyl ) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin-5-yl ) inyl) -2, 2, 4, 4-tetraisopropyl-l, 3, 5, 2, 4- trioxadisilocan- 6- l ) acetate

To a solution of compound BA) (0.28 g, 0.39 mmol) in CH₂CI₂ (10 mL) , ( S ) -5 , 6-dinitrooxyhexanol (0.08 g, 0.39 mmol) was added. The solution was cooled at 0°C and DMAP (12 mg, 0.1 mmol) and EDAC (80 mg, 0.41 mmol)) were added. The reaction was stirred at room temperature for 5 hours. The solution was diluted with CH₂CI₂ (50 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x20 mL) . The organic layer was washed with ¾0 (4x20 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, gradient from n-hexane/AcOEt 8/2 to n-hexane/AcOEt 7/3 during 900 mL) affording the title compound (0.32 g, yield 86%). BC) (3R, 5S,E) -( (S) -5, 6-bis (nitrooxy) hexyl) -7- (4- (4-fluoro phenyl) -6-isopropyl-2- (N-methylmethylsulfonamido) pyrimidin -5-yl ) -3 , 5-dihydroxyhept- 6-enoate (Compound (47))

To a solution of compound BB) (0.32 g, 0.34 mmol) in dry THF (30 mL) , cooled at 0°C, triethylamine trihydrofluoride (0.85 mL, 5.2 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solution was diluted with AcOEt (90 mL) and washed with an aqueous solution of 5 % Na¾P0₄ (2x40 mL) . The organic layer was washed with ¾0 (4x40 mL) and brine, then dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: n-hexane/AcOEt 1/1 (900 mL) ) affording the title compound (0.21 g, yield 44%) . affording the compound (47) (0.18 g, yield 80%).

NMR (CDCI3) : 7.66 (2H, m) , 7.09 (2H, m) , 6.66 (1H, d) , 5.47 (1H, dd) , 5.29 (1H, m) , 4.75 (1H, dd) , 4.49 (2H, m) , 4.27- 4.08 (4H, m) , 3.58 (3H, s) , 3.52 (3H, s) , 3.36 (1H, m) , 2.49 (2H, m) , 1.75 (4H, m) , 1.55 (4H, m) , 1.28 (6H, m) . Example Fl : Evaluation of the effect of the compounds on vascular tone

The ability of statins dinitrate derivatives disclosed in examples 1-3, 5-8, 10, 11 and 13-16 to induce vasodilation in comparison to native statin (atovarstatin) and statins mononitrate derivatives (Compounds A and B) , was tested in vitro in isolated rabbit thoracic aorta preparations (Wanstall J.C. et al . , Br. J. Pharmacol., 134:463-472, 2001) .

Com ound A

Com ound B

Male New Zealand rabbits were anaesthetized with thiopental-Na (50 mg/kg, iv) , sacrificed by exsanguinations and then the thorax was opened and the aorta dissected. Single ring preparations (4 mm in length) of thoracic aorta were set up in physiological salt solution (PSS) at 37°C in small organ chambers (5 ml) . The composition of PSS was (mM) : NaCl 130, NaHC0₃ 14.9, KH₂P0₄ 1.2, MgS0₄ 1.2, HEPES 10, CaCl2 , ascorbic acid 170 and glucose 1.1 (95% O2 /5% CO2 ; pH 7.4) . Each ring was mounted under 2 g passive tension in 5 ml organ bath. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System. Preparations were allowed to equilibrate for 1 h, then contracted submaximally with noradrenaline (NA, 1 μΜ) and, when the contraction was stable, acetylcholine (ACh, 10 μΜ) was added. A relaxant response to ACh indicated the presence of a functional endothelium. When a stable precontraction was reached, a cumulative concentration- response curve to each vasorelaxant agent was obtained in the presence of a functional endothelium. Time intervals between different concentrations were based on the time needed to reach a full response. Moreover, the effect of the soluble guanylyl cyclase inhibitor ODQ (1-H- (1, 2, 4) - oxadiazol (4, 3-a) quinoxalin-l-one) on the dilator responses elicited by the compounds was examined preincubating the aortic rings with ODQ (10 μΜ) for 20 min. Responses to relaxing agents are expressed as a percentage of residual contraction and plotted against concentration of test compound. EC₅₀ values (EC₅₀ is the concentration producing 50% of the maximum relaxation to the test compound) were interpolated from these plots. During the experimental period, the plateau obtained with NA was stable without significant spontaneous loss of contraction in the aortic rings. Under these experimental conditions, native statin did not produce relaxation up to 100 μΜ, the curve being not different from that obtained in presence of vehicle alone .

Table 1 reports the EC₅₀ of the tested compounds, the results shown that the dinitrates of the invention showed improved EC₅₀ values in vessel relaxation assay compared to mononitrate derivatives (Compound A and B) which are greater than two fold. Furthermore, in experiments performed in presence of ODQ (10 μΜ) , the vasorelaxant responses to all the tested drugs were inhibited showing that the vasodilative effects are mediated by NO.

Example F2 : Evaluation of pharmacokinetic parameters

This study investigated the bioavailability following oral administration of the compounds of the present invention in comparison to atorvastatin. Tested compounds:

Compounds of examples 10, 11, 13 and 14;

Reference compound: Atorvastatin .

The formulations of the tested compounds were prepared on the day of dosing, immediately before of administration, by dissolving an appropriate amount of the test compound in PEG400/DMA 70/30, in order to obtain the following target concentrations :

Male Sprague Dawley Rats, age 7-9 weeks, bodyweight in the range 216-279 g at the dosing, were supplied by Charles River Italia, Calco (Italy) .

Approximately three days before dosing the rats, under anesthesia (an aqueous mixture of ketamine, xylazine and acepromazine, by subcutaneous administration) , were surgically prepared for serial blood samples collection from superior vena cava (SVC) . Rats were fitted with a flexible plastic cannula implanted in the superior vena cava via the jugular vein. Each animal was allowed approximately five days postoperative recovery period prior to dosing.

Test compounds were administered orally to each animal by gavage . Animals were fasted overnight before dosing. On the day of dosing the food was offered about 4 h post dosing. Serial blood samples (about 0.3 mL) were collected from the catheter of each SVC catheterized rat, using syringes containing Na-heparin as anticoagulant, at pre-dose, 15 min, 30 min, 1, 2, 4, 6 and 8 h post-dosing. The samples were then transferred into pre-cooled tubes (containing 7.5 L of a solution of sodium fluorure, 40 mg/mL and DICHLORVOS, 10 mg/mL, in order to inhibit plasma esterase activity, in water for injection), protected from light. The blood was centrifuged at 10000 rpm for 3 min at +4 °C to collect plasma (within 30 min from blood collection) , and plasma samples were stored at -80°C.

Plasma samples were thawed in ice bath. Plasma aliquots of 50 yL were protein precipitated in triplicate using 150 yL of acetonitrile to which were also added 10 yL of DMSO, vortex-mixed and centrifuged 10 min at 4°C at 4000 rpm. The supernatant was transferred to a clean plate and injected onto a LC-MS system. Atorvastatin, ortho and para hydroxy metabolites levels were quantified using a calibration curve (range 0.01-10 μΜ ) prepared in rat plasma, spiking an appropriate volume of working solution in 50 yL of plasma and then precipitating the proteins (see below for standard curve preparation) using 150 yL of acetonitrile, vortex-mixed and centrifuged 10 min at 4°C at 4000 rpm. The supernatant was transferred to a clean plate and injected onto a LC-MS system. Analytical conditions were as follows: Column: ACQUITY BEH Phenyl 50 x 2.1 mm (1.7y) @ 40°C

Mobile Phase: A. water + 0.1% formic acid

B. methanol + 0.1% formic acid

Flow Rate: 0.5 mL/min Gradient profile:

Time (min) : 0.0 1.0 1.5

A (%) : 60 0.0 0.0

B (%) : 40 100 100

Injection Volume 5 μΐ

Detection was performed using a Waters Quattro Micro API mass spectrometer operated in ESI+ mode. The multiple reaction monitoring (MRM) pair monitored was m/z 559.26-^ 440.2 for atorvastatin and m/z 575.16 -> 440.2 for ortho and para hydroxy metabolites. The autosampler cooler was maintained at 4°C.

The results reported in tables 2 and 3 show that the compounds of the invention have a better oral bioavailability in comparison to the native statin.

Table 2 reports a summary of pharmacokinetic parameters of the compounds of the invention and of atorvastatin following single oral administration to SD rats (dose equimolar to atorvastatin 20 mg/kg)

Table 3 reports a summary of pharmacokinetic parameters of 2-hydroxy metabolite of atorvastatin formed from the compounds of the invention following single oral administration to SD rats (dose equimolar to atorvastatin 20 mg/kg)

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof

(I) wherein R is selected from the group consisting of (Ila)- (Ilf) :

Ila) (lib)

(He) (Ilf) w is an integer selected between 0 and 1 ;

R¹ and R² can be equal or different and are independently selected from the group consisting of hydrogen and C₁-C₄ alkyl ;

Y is selected from the group consisting of:

A) [R³-0] _P-R⁴-CH (ON0₂) - (R⁵) n-CH (ON0₂) - [O-R⁶] _PL-R⁷

B) R⁴-CH (ON0₂) -R³-0-R⁵-CH (ON0₂) -R⁷

n is an integer from 0 to 1 ;

nl is an integer from 0 to 1 ;

p is an integer from 0 to 4 ;

pi is an integer from 0 to 4 ;

R⁷ is selected from the group consisting of hydrogen and

C^-Cg alkyl;

R⁹ is a saturated, unsaturated or aromatic heterocyclic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen or sulphur.

2. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 wherein R is the group (lid) or (lie)

3. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 2 wherein w is 1.

4. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 3 wherein R¹ and R² can be equal or different and are independently selected from the group consisting of hydrogen and C¾.

5. A compound of general formula (I) according to claim 1 or 2 wherein w is 0.

6. A compound of formula (I) according to anyone of the claims 1-5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y of the group A) is selected from the roup consisting of:



7. A compound of formula (I) according to anyone of the claims 1-5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y of the group B) is selected from the roup consisting of:

8. A compound of formula (I) according to anyone of the claims 1-5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y of the group C) is selected from the group consisting of:

9. A compound of formula (I) according to anyone of the claims 1-8 or a pharmaceutically acceptable salt or stereoisomer thereof selected from the roup consisting of:

82

83

(87) (88)

10. A compound of formula (I) according to claims 1-9 for use as a medicament.

11. A compound according to claims 1-9 for use as a drug having anti-inflammatory, antithrombotic and antiplatelet activity .

12. A compound according to claims 1-9 for reducing cholesterol and triglycerides levels and/or for raising HDL-C levels.

13. A compound according to claims 1-9 for use in the treatment of acute coronary syndromes, stroke, peripheral vascular diseases and all disorders associated with endothelial dysfunctions.

14. A compound according to claim 13 for use in the treatment of peripheral ischemia, vascular complications in diabetic patients and atherosclerosis.

15. A compound according to claims 1-9 for use in the treatment of neurodegenerative and autoimmune disorders.

16. A compound according to claim 15 for use in the treatment of Alzheimer's disease, Parkinson's disease and multiple sclerosis.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) and/or a salt or stereoisomer thereof according to claims 1-9.

18. A pharmaceutical composition according to claim 17 in a suitable form for the oral, parenteral, rectal, topic and transdermic administration, by inhalation spray or aerosol or iontophoresis devices.

19. A pharmaceutical composition comprising a compound of formula (I) according to claims 1-9, and at least a compound used to treat cardiovascular disease and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition according to claim 19, wherein the compound used to treat cardiovascular disease is selected from the group consisting of: ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers, antithrombotics, aspirin, nitrosated ACE inhibitors, nitrosated renin inhibitors nitrosated angiotensin II receptor antagonists, nitrosated beta-adrenergic blockers and nitrosated aspirin.

21. A pharmaceutical kit comprising the composition of claim 17 and a compound used to treat cardiovascular disease .

22. A process for the preparation of compounds of formula (I) as defined in claim 1,

wherein w is 0,

ined in claim 1, comprising the following steps: 1) reacting compounds of formula (III)

(III)

wherein M is an alkali metal or alkaline earth metal such as sodium or calcium and R is as defined in claim 1 ;

(IXa) (IXb)

and Hal is selected from Br or CI,

2) reacting a compound of formula (IV) obtained in step 1)

(IV)

wherein R and X are as above defined, with 1 , 3-dichloro- 1 , 1 , 3 , 3-tetraisopropyldisiloxane in presence of imidazole in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -80°C to 60°C;

3) deprotecting of the carboxylic function of compound of formula (V) obtained in step 2)

(V)

wherein R and X are as above defined:

when X is (IXa) by catalytic hydrogenation in presence of Pd/C in an aprotic polar/non polar solvent such as THF at room temperature and pressure; when X is (IXb) with palladium tetrakis, in presence of dimedone and triphenylphosphine or in presence of morpholine, in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -10 °C to 30°C;

4) reacting a compound of formula (VI) obtained in step 3)

(VI)

wherein R is as above defined with a compound of formula (X)

HO-Y

(X)

hydrochloride (EDAC) , N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP . The reaction is carried out in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C. The reaction is completed within a time range from 30 minutes to 36 hours; 5) deprotecting of the diol function of compound of formula (VII) obtained in step 4

(VII)

wherein R is as above defined in presence of fluoride salt of alkylamine such as triethylamine trihydrofluoride or tetrabutylamonium fluoride and acetic acid, in an aprotic polar/non polar solvent such as THF, at temperature ranging from -10°C to 30°C.

23. A compound of general formula (VI) or a pharmaceutically acceptable salt or stereoisomer thereof

(VI)

wherein R is selected from the group consisting of (Ila)- (Ilf) .

24. A compound of general formula (VI) according to claim 23 wherein R is (lid) .

25. A compound of general formula (VI) according to claim 23 wherein R is (He) .