WO2010015447A1 - Angiotensin ii receptor antagonists - Google Patents

Abstract

A compound having the structure (formula 1) wherein R is a "sartan family" moiety Z is a nitroxy carrying moiety, or a pharmaceutically acceptable salt thereof. The compounds are active against hypertension.

Description

TITLE OF THE INVENTION

ANGIOTENSIN II RECEPTOR ANTAGONISTS

BACKGROUND OF THE INVENTION U.S. Patent 5,138,069 generically and specifically describes 2-butyl-4-chloro-l-[p-

(o-lH-tetrazol-5-ylphenyl)-benzyl]imidazole-5-methanol potassium salt and 2-butyl-4-chloro-l- [(2'-lH-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. Columns 261-263 of U.S. Patent 5,136,069 describe general procedures for formulating compounds described in the patent, including capsules, tablets, injection formulations, and suspensions. U.S. Patent 5,153,197, describes the use of these compounds, alone and in combination with a diuretic, to treat a patient having hypertension.

WO2005011646 describes angiotensin II receptor blocker nitroderivatives, pharmaceutical compositions containing them and their use for the treatment of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes. The publication describes a variety of angiotensin receptor blocker compounds each of which are covalently linked in a variety of ways to a nitric oxide group. Specific examples include angiotensin receptor blockers with one covalently-linked nitric oxide group, and angiotensin receptor blockers with two independently-covalently-linked nitric oxide groups. WO2005023182 describes nitrosated and nitrosylated cardiovascular compounds, and compositions comprising at least one nitrosated and nitrosylated cardiovascular compound and optionally at least one nitric oxide donor. The cardiovascular compound which is nitrosated or nitrosylated may be an aldosterone antagonist, an angiotensin II receptor antagonist, a calcium channel blocker, an endothelin antagonist, a hydralazine compound, a neutral endopeptidase inhibitor or a renin inhibitor. The nitric oxide donor may be selected from S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, furoxans, and sydnonimines.

WO2005070868 describes combination therapy for treating cyclooxygenase-2 mediated diseases or conditions at risk of thrombotic cardiovascular events which involves administering selected cyclooxygenase-2 inhibitor in combination with a nitric oxide donating compound such as 5,6-bis(nitrooxy)hexyl acetate, 6-hydroxyhexane-l,2-diyl dinitrate, 5- hydroxypentane-l,2-diyl dinitrate, (5R)-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate, (5S)-5,6- bis(nitrooxy)hexyl 4-nitrobenzoate, (2R)-6-hydroxyhexane-l,2-diyl dinitrate, (2S)-6- hydroxyhexane-l,2-diyl dinitrate, (2S)-propane-l,2-diyl dinitrate, and (2R)-propane-l,2-diyl dinitrate. SUMMARY OF THE INVENTION

The present invention includes angiotensin II receptor antagonist nitrooxyderivatives, including 2-butyl-4-chloro- 1 - [(2 ' -( 1 -H-tetrazol-5 -yl)biphenyl-4-yl)methyl] - imidazole-5-carboxylate nitrooxyderivatives, including various pharmaceutically acceptable salts and hydrates of these forms, and pharmaceutical formulations for controlled and sustained delivery of these forms to a patient.

The salts include non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

The invention also includes a method for treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, muscle dystrophies, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system, by administering an angiotensin II receptor antagonist of the invention to a patient having one or more of these conditions.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Compounds of the invention are angiotensin II receptor antagonist nitrooxyderivatives having the general formula (I):

(I) wherein R is selected from the group consisting of (Ha)-(IIh):

Z is selected from the group consisting of:

1) R°-0N0₂, wherein R⁰ is a straight or branched Ci-Cio alkylene;

2) -(CH₂XR¹,

3) -(CH^-0-CH.-R¹, wherein

R¹ is -CH(ONO₂)R²;

R² is -CH₃ or C_1-4 alkyl; n is an integer from 1 to 6;

4) Y-R³, wherein

R³ is -CH(ONO₂)CH(ONO₂)R⁴;

R⁴ is selected from -CH₃, -CH₂CH₃ and -CH(CH₃)₂; Y is -(CH₂X _₄-(X)_{0 1}-(CH₂)_{0 4}, wherein X is -O- or -CR⁵R⁶-; and R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

5)Y-CH(ONO₂)CH₂(ONO₂), wherein Y is as above defined;

6)

wherein nl, n2, n3 and n4 are integers equal or different from one another, equal to 0 or 1; R⁷ and R⁸ are independently selected from H or CH₃;

Y¹ is -(CH₂)J- or -(CH₂)no-CH=CH- wherein n is as above defined and nO is an integer from 0 to 6, preferably nO is equal to 0;

X¹ is -O-, -S-, -SO-, -SO₂-, -OCO-, -SCO-, -OCOO-, -SCOO-, -OCONH-,

-SCONH-; Z¹ has the same meanings of Z or

wherein:

R⁹ and R¹⁰ are independently selected from H or C₁-C₄ alkyl; n5 is an integer from O to 6; n4 and X¹ are as above defined; Z² is equal to Z;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and selected for example from

(Yl) (Y2) (Y3) (Y4) (Y5)

(YlO) (YI l) (Y12) (Y13)

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-C₄ alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to four carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl 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.

In one preferred embodiment, R is selected from the group consisting of (Ha)- (Hd):

(Ik) (Hd) and all other variables are as previously defined.

In another embodiment, R is selected from the group consisting of (Hg) and (Hh):

and all other variables are as previously defined.

In another embodiment R is (Ha):

and all other variables are as previously defined.

In another embodiment, Z is selected from the group consisting of:

and ONO,

and stereoisomer thereof. In another embodiment, the compound is selected from the group of compounds in Tables -4 shown below

Table 1

Table 2

Table 3

Table 4



General Synthesis 1. The compound of general formula (I)

(I) s above defined wherein R is selected from the group consisting of (IΙa)-(IIf):

and (Hg)-(IIh):

Wherein Z is as above defined, can be obtained by a process comprising reacting a compound of formula (UIa)-(IIIf):

(Ilia) (HIb)

or of formula (HIg)-(IIIh):

with a compound of formula (IVa):

(IVa) wherein Z is as above defined, in the presence of condensing agent like DCC, EDC or other well known in the literature in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between 0⁰C to 100⁰C, eventually removing the trityl group when present following methods well known in the art.

Alternatively compounds (HIa)-(IIIh) can be first transformed into acyl chlorides or other activated carboxylic acids esters following procedures known in the literature and then reacted with compounds (IVa) in the presence of an organic or inorganic base such as TEA, pyridine or DIPEA in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between 0⁰C to 100⁰C, eventually removing the trityl group when present.

Alternatively compounds (IHa)-(IIIh) can be reacted with compounds (IVb)

(IVb)

Wherein A is chosen in the group:

in the presence of an organic or inorganic base such as CS2CO3, TEA, pyridine or DIPEA in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between O⁰C to 10O⁰C, eventually removing the trityl group when present.

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).

2. Alternatively the compound of general formula (I)

(I)

wherein Z is as above defined and R is selected from the group consisting of (Ha)-(IIh) as above defined, can be obtained by a process comprising reacting a compound of formula (HIa)-(IIIh):

(Ilia) (HIb)

with a compound of formula (IVa):

(IVa) wherein Z is as above defined, in the presence of condensing agent like DCC, EDC or other well known in the literature in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between 0⁰C to 100⁰C, optionally removing the trityl group when present following methods well known in the art.

Alternatively compounds (IHa)-(IIIh) can be first transformed into acyl chlorides or other activated carboxylic acids esters following procedures known in the literature and then reacted with compounds (IVa) in the presence of an organic or inorganic base such as TEA, pyridine or DIPEA in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between 0⁰C to 100⁰C, optionally removing the trityl group when present.

Alternatively compounds (IHa)-(IIIh) can be reacted with compounds (IVb)

(IVb) wherein A is chosen in the group:

Cl, Br, I, , CF₃SO₂O- 1

in the presence of an organic or inorganic base such as CS2CO3, TEA, pyridine or DIPEA in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, at temperatures ranging between 0⁰C to 100⁰C, optionally removing the trityl group when present.

Compounds (IVa) can be obtained by a process comprising: reacting a compound of formula (Va)

(Va) with tetraalkylammoniumborohydride (as described in Sun et al, Tetr. Lett., 43, (2002), 1161- 1164), or other boro hydrides in an aprotic polar/non polar solvent such as DMF, THF or CH2CI2, at temperatures ranging between -8O⁰C to 0⁰C. Compound (Va) can be prepared by reacting compound of formula (Vb)

(Vb) with (COCl)₂ or other reagents in an aprotic polar/non protic solvent such as DMF or CH2CI2 following methods well known in the art. Compounds (Vb) can be obtained by a process comprising reacting a compound of formula (Vc)

(Vc) by methods well known in the art such as reacting with an inorganic or organic acid such as HCl, BF₃-Et₂O or ZnBr₂ in an aprotic polar/non polar solvent such as THF, DMF or CH₂Cl₂, at temperatures ranging between -20⁰C to 25° C.

Compound of formula (Vc) can be obtained by a process comprising reacting a compound of formula (Vd)

OH

(Vd) with a reagent such as CDI, (COCl)₂ or (CIsC)₂CO in an aprotic polar/non polar solvent such as THF, DMF or CH₂Cl₂ at temperatures ranging between -50 ⁰C to 50 ⁰C. Compound (Vd) can be obtained by a process comprising reacting a compound of formula (Ve)

(Ve) in presence of an organometallic catalyst such as Rh₂(OAc)₂ or Cu(acac)₂ in an aprotic polar /non polar solvent such as THF or CH₂Cl₂ and water mixture, at temperatures ranging between 0⁰C and 100 ⁰C

Compound (Ve) can be obtained by reacting a compound of formula (Vf)

(Vf) with T0SN₃ in an aprotic polar /non polar solvent such as CH₃CN, DMF or CH₂Cl₂ in presence of an inorganic or organic base such as Cs₂CO₃, TEA or DIPEA, at temperature ranging between -

20⁰C and 100⁰C following methods well known in the art.

Compound (Vf) can be obtained by reacting a compound of formula (Vg) Z-COW

(Vg) wherein W is an halogen atom such as Cl, Br, F, or is a group such as -OMe, -OEt and Z is as above defined: i) W is an halogen atom: with commercially available Meldrum's acid, in presence of an inorganic or organic base such as pyridine or collidine or DIPEA, in an aprotic polar /non polar solvent such as DMF or CH2CI2, at a temperature ranging between 0⁰C and 120⁰C, and treating the intermediate formed with t-BuOH in an aprotic polar /non polar solvent such as DMF or toluene, at a temperature ranging between 60 ⁰C and 150 ⁰C; ii) W is -OMe or -OEt: with Lithium t-butyl acetate, prepared as known in the literature, in an aprotic polar /non polar solvent such as DMF or CH2CI2, at a temperature ranging between -80 ⁰C and 120 ⁰C.

Compound (Vg) can be prepared from compound (Vh)

Z-COOH (Vh) by procedures well known in the art. The carboxylic acids of formula (Vh), wherein Z is as above defined, are known in the literature or can be obtained from the corresponding alcohols or aldeydes known in the literature by well known oxidative procedures.

Altenatively compounds (Vh) can be obtained from the corresponding compounds of formula (Vi)

B-COOP (Vi) wherein B is selected from the group consisting of:

1) R°-0H, wherein R⁰ is a straight or branched C1-C10 alkylene;

2) (CH₂X₁R¹, 3) (CH^_n-O-CH₂-R¹, wherein

R¹ is -CH(OH)R²;

R² Is -CH_{3 O}r C₁^ aIkVl; n is an integer from 1 to 6; 4) Y-R³, wherein

R³ is -CH(OH)CH(OH)R⁴; R⁴ is selected from -CH₃, -CH₂CH₃ and -CH(CH₃)₂;

Y is -(CH₂)_M-p0_0.1-(CH2)₀^, wherein X is -O- or -CR⁵R⁶-; and R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

5)Y-CH(OH)CH₂(OH) wherein Y is as above defined;

6)

wherein nl, n2, n3 and n4 are integers equal or different from one another, equal to 0 or 1; R⁷ and R⁸ are independently selected from H or CH₃; Y¹ is -(CH₂)_n- or -(CH₂)_no-CH=CH- wherein n is as above defined and nO is an integer from 0 to 6, preferably nO is equal to 0;

X¹ is -O-, -S-, -SO-, SO₂-, -OCO-, -SCO-, -OCOO-, -SCOO-, -OCONH-, -SCONH-; B¹ has the same meanings of B or

V)

wherein: R⁹ and R¹⁰ are independently selected from H or C₁-C₄ alkyl; n5 is an integer from O to 6; n4, X¹, B 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, sulphur, and selected for example from

(YlO) (YI l) (Y12) (Y13)

(Y14) (Y15)

P is H or a carboxyl protecting group such as t-butyl, methyl, allyl, by reacting with nitric acid and acetic anhydride in a temperature range from -50 ⁰C to 0 ⁰C, or by reacting with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non polar solvent such as DMF, THF or CH2CI2 at temperatures ranging between -8O⁰C to 65 ⁰C, followed by the removal of the protecting group by methods well known in the art. Compounds (Vi) are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art.

Alternatively, compounds of formula (Vh), wherein Z is as above defined, can be obtained from the corresponding derivatives of formula (Vl)

B²-COOH (Vl) wherein B² is selected from the group consisting of: 1) R°-Hal, wherein Hal is Cl, Br, I, wherein R⁰ is a straight or branched Ci-Cio alkylene;

2) (CH₂XR¹,

3) (CH^_n-O-CH₂-R¹, wherein

R¹ is -CH(HaI)R² wherein Hal is as above defined;

R² is -CH₃ or C₁_₄ alkyl_; n is an integer from 1 to 6;

4) Y-R³, wherein Hal is as above defined R³ is -CH(HaI)CH(HaI)R⁴; R⁴ is selected from -CH₃, -CH₂CH₃ and -CH(CH₃)₂;

Y is -(CH₂)_M-p0_0.1-(CH2)₀^, wherein X is -O- or -CR⁵R⁶-; and R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C₁-C₄ alkyl; 5)Y-CH(Hal)CH₂(Hal) wherein Y and Hal are as above defined; 6)

wherein nl, n2, n3 and n4 are integers equal or different from one another, equal to 0 or 1; R⁷ and R⁸ are independently selected from H or CH₃;

Y¹ is -(CH₂)_n- or -(CH₂)no-CH=CH- wherein n is as above defined and nO is an integer from 0 to 6, preferably nO is equal to 0;

X¹ is -O-, -S-, -SO-, -SO₂-, -OCO-, -SCO-, -OCOO-, -SCOO-, -OCONH-, -SCONH-; B³ has the same meanings of B² or

V)

wherein:

R⁹ and R¹⁰ are independently selected from H or C₁-C₄ alkyl; n5 is an integer from 0 to 6; n4, X¹, B² 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, sulphur, and selected for example from

, , , , _? (Yl) (Y2) (Y3) (Y4) (YS)

(YlO) (YI l) (Y12) (Y13)

by reacting with AgNC>3 as described in the international application No. WO 2006/008196. Compounds (Vl) are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art,

Alternatively the compounds of formula (IVa) as above defined, can be obtained by a process comprising reacting compound (Via)

CL , 0

O

(Via) wherein B² is as above defined, with methods well known in the art such as reacting with AgNθ3, as described in the international application No. WO 2006/008196. Compound (Via) can be obtained by reacting compound (VIb)

Cl

O

(VIb) with tetraalkylammoniumborohydride or other borohydrides following the same procedure described for preparation of compound (Va). Compound (VIb) can be prepared from compound (VIc)

O

(VIc) following the same procedure described for preparation of compound (Va). Compound (VIc) can be obtained by reacting compound (VId)

(VId) with H₂/Pd(OH)₂ in a polar non protic / protic solvent such as EtOAc, MeOH at temperatures ranging between -20⁰C to 100⁰C, following known methods known in the art as described in Sun et al, Tetr. Lett., 43, (2002), 1161-1164), or by reacting compound (VId) with in situ generated H₂ following methods well known in the literature.

Compound (VId) can be obtained by reacting a compound of formula (VIe) z

OH (VIe)

following procedure described for compound (Vd).

Compound (VIe) wherein B² is as above defined, can be obtained by reacting a compound of formula (VIf)

^N2

(VIf) in presence of an organometallic catalyst such as Rh₂(OAc)₂ or Cu(acac)₂ as described for compound (Ve). Compound (VIf) can be obtained by reacting a compound of formula (VIg)

by methods well known in the art, as described for compound (Vf). Compound (VIg) can be obtained by reacting a compound of formula (VIh)

(VIh) wherein W is an halogen atom such as Cl, Br or F, B² is as above defined, with Meldrum's acid, as described for preparation of (Vg), treating the intermediate formed with BzOH instead of tBu- OH, in an aprotic polar /non polar solvent such as DMF or toluene, at a temperature ranging between 60⁰C and 150⁰C.

Compound (VIh), are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art.

Compound (IVb), wherein A is Cl, Br, I, can be obtained by reacting (IVa) following methods known in the arts such as treating with PPh₃ and CCU, CBr₄, CI₄ in an aprotic polar /non polar solvent such as DMF or CH2CI2, at a temperature ranging between -20 ⁰C and 6O⁰C. Compound IVb, wherein A is , CH₃-SO₂ -O-f , CF₃COO — 1 , CF₃SO₂O — |

can be obtained by reacting (IVa) following methods known in the art such as treating with tosyl chloride, mesyl chloride, triflic anhydride or trifluoroacetic anhydride in presence of an organic or inorganic base such as TEA, pyridine, DIPEA in an aprotic polar/non polar solvent such as THF, DMF or CH₂Cl₂, at temperatures ranging between -70 ⁰C to 60 ⁰C.

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

INTERMEDIATE 1

5-[5-(Hydroxymethyl)-2-oxo- 1 ,3-dioxol-4-yl]pentyl nitrate

Step A: 5-(6-bromo-l-hydroxyhexylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione

To a solution of 2,2-Dimethyl-l,3-dioxane-4,6-dione (4.6 g, 32 mmol) and Pyridine (5.1 mL, 64 mmol) in CH₂Cl₂ (100 mL) at 0 ⁰C under nitrogen, was added 6-bromohexanoyl chloride (5.2 niL, 35 mmol). The reaction was stirred at 0 ⁰C for 1 hour and then at room temperature for 2.5 hours. The solvent was removed affording the title compound which was used in the following step without further purification.

¹H-NMR (CDCl₃): 3.45 (2H, t); 3.12 (2H, t); 1.93 (2H, m); 1.76 (8H, m); 1.58 (2H, m)

Step B: Benzyl 8-bromo-3-oxooctanoate

To a solution of 5-(6-bromo-l-hydroxyhexylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (35 mmol) in Toluene (120 mL) was added benzyl alcohol (10.9 mL, 105 mmol) and the solution was refluxed for 4h. The solvent was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (n-Hexane/EtOAc 9:1) affording the title compound (6.2 g; 54.4%) as a yellow oil.

¹H-NMR (CDCl₃): 7.38 (5H, m) ; 5.20 (2H, s); 3.49 (2H, s); 3.40 (2H, t); 2.56 (2H, t); 1.88 (2H, m); 1.63 (2H, m); 1.43 (2H, m)

Step C: Benzyl 8-bromo-2-diazo-3-oxooctanoate

A solution of Benzyl 8-bromo-3-oxooctanoate (6.2 g; 19 mmol) in acetonitrile (70 mL) was cooled to 0⁰C and tosyl azide (3.8 g, 19 mmol) was added. The solution was stirred at 0 ⁰C for 0.5 hour and at room temperature for 4 hours. The solvent was evaporated and the oil was taken up with a mixture of diethyl etere/n-hexane (3/7). The solid formed was filtered off and the solvent concentrated under reduced pressure affording the title compound, that was used in the following step without further purification.

¹H-NMR (CDCl₃): 7.38 (5H, m) ; 5.30 (2H, s); 3.42 (2H, s); 2.89 (2H, t); 1.89 (2H, m); 1.68 (2H, m); 1.50 (2H, m)

Step D: Benzyl 8-bromo-2-hydroxy-3-oxooctanoate

A solution of Benzyl 8-bromo-2-diazo-3-oxooctanoate (6.7 g; 18.9 mmol) and rhodium acetate (63 mg; 0.13 mmol) in water/THF (5OmIVlOOmL) was refluxed under nitrogen for 2 hours. The solution was warmed to room temperature and the THF was evaporated. The water phase was extracted with ethyl acetate (2 x 70 mL) and the combined organic layers were washed with brine (2 x 50 mL), dried over Na₂SO₄ and concentrated to give the title compound that was used without further purification.

¹H-NMR (CDCl₃): 7.38 (5H, m) ; 5.26 (2H, q); 4.82 (IH, s); 3.37 (2H, t); 2.56 (2H, m); 1.80 (2H, m); 1.60 (2H, m); 1.35(2H, m) Step E: Benzyl 5-(5-bromopentyl)-2-oxo-l,3-dioxole-4-carboxylate

To a solution of Benzyl 8-bromo-2-hydroxy-3-oxooctanoate (6.4 g, 18.6 mmol) in CH2CI2 (80 niL) stirred at 0 ⁰C was added l,l '-carbonyldiimidazole (6 g, 37.3 mmol). The reaction was stirred a 0 ⁰C for 10 minutes then JV-ethyldiisopropylamine was added (162 μl, 0.9 mmol). The solution was stirred at room temperature overnight. The organic phase was washed with KHSO4 (5%, 2 x 50 mL), dried over Na₂SO₄ and concentrated. The crude material was purified by flash chromatography (n-Hexane:EtOAc 9/1) affording the title compound as a yellow oil (2.46 g,

¹H-NMR (CDCl₃): 7.42 (5H, m) ; 5.35 (2H, s); 3.42 (2H, s); 2.85 (2H, t); 1.87 (2H, m); 1.70 (2H, m); 1.50 (2H, m)

Step F: 5-(5-bromopentyl)-2-oxo-l,3-dioxole-4-carboxylic acid

A suspension of benzyl 5-(5-bromopentyl)-2-oxo-l,3-dioxole-4-carboxylate (2.46 g, 6.7 mmol), Palladium hydroxide 20% (233 mg, 0.33 mmol) and cyclohexene (4.7 mL, 46.7 mmol) in absolute EtOH (180 mL) was refluxed for 30 min. The palladium was filtered off on celite and the organic layer was evaporated affording the title compound as a yellow solid. The crude was used without any further purification. 1H-NMR (CDCl₃): 3.43 (2H, s); 2.89 (2H, t); 1.90 (2H, m); 1.74 (2H, m); 1.60 (2H, m)

Step G: 4-(5-bromopentyl)-5-(hydroxymethyl)-l,3-dioxol-2-one

To a solution of 5-(5-bromopentyl)-2-oxo-l,3-dioxole-4-carboxylic acid (1.7 g, 6.09 mmol) and Oxalylchloride (567 μl, 6.69 mmol) in CH₂Cl₂ (25 mL) stirred under nitrogen at 0 ⁰C, were added few drops of CH₂Cl₂. The reaction was stirred for 1 hour then the solvent was evaporated. The crude was dissolved in CH₂Cl₂ (25 mL) and the solution cooled at -78 ⁰C. Tetrabutylammonium borohydride (1.7 g, 6.7 mmol) in CH₂Cl₂ (8 mL) was dropped and the reaction was stirred at -78 ⁰C for 2 hours. The reaction was quenched with HCl (0.5N, 37 mL) and allowed to reach room temperature. The CH₂Cl₂ was removed, the crude was dissolved in EtOAc (50 mL), washed with Brine (2 x 20 mL), dried over Na₂SO₄ and concentrated. The crude was purified by silica flash chromatography (n-Hexane: EtOAc 7:3) affording the title compound as a yellow oil (1.03g, 64%).

¹H-NMR (CDC13): 4.4 (2H, d); 3.43 (2H, s); 2.49 (2H, t); 1.90 (2H, m); 1.74 (2H, m); 1.60 (2H, m) Step H: 5-[5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl]pentyl nitrate

A suspension of 4-(5-bromopentyl)-5-(hydroxymethyl)-l,3-dioxol-2-one (1.03 g, 3.96 mmol) and AgNO₃ (1.68 g, 9.9 mmol) in CH₃CN (20 mL) was treated under microwave irradiation at 90⁰C for 14 minutes. The solvent was evaporated and the crude dissolved in EtOAc (20 mL). The solid formed was filtered off on celite and the organic layer was washed with water (2 x 5 mL) and brine (1 x 5 mL). The organic phase was dried over Na₂SO₄ and evaporated to give the title compound as a yellow oil (600 mg, 61%).

¹H-NMR (CDCl₃): 4.47 (2H, t); 4.42 (2H, s); 2.49 (2H, t); 1.77 (2H, m); 1.67 (2H, m); 1.48 (2H, m)

INTERMEDIATE 2

(5V5-(5-(hydroxymethyl)-2-oxo- 1 ,3-dioxol-4-yl)pentan-2-yl nitrate

Step A: (S)-tert-butyl 5-(nitrooxy)hexanoate

To a solution OfHNO₃ (8.4 mL, 188 mmol) in Ac₂O (20 mL), cooled to 0 ⁰C, was slowly added a solution of {S)-tert-bvXy\ 5-hydroxyhexanoate (obtained as described in (Oscar Pamies and Jan-E. Backvall, J. Org. Chem. 2002, 67, 1261-1265) (5.84 g, 31 mmol) in CH₂Cl₂ (20 mL). The reaction was stirred at 0 ⁰C for 15 minutes, then poured into iced NaOH (10%). The two layers were separated and washed with H₂O, NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. The crude material was used in the following step without further purification. 1H-NMR: 5.09 (IH, m); 2.25 (2H, m); 1.69 (4H, m); 1.45 (9H, s); 1.38 (3H, d, J 6.2 Hz)

Step B: (S)-5-(nitrooxy)hexanoic acid

To a solution of (S)-tert-buty\ 5-nitrohexanoate (31 mmol) in CH₂Cl₂ (50 mL), cooled to 0⁰C, BF₃-Et₂O (5.1 mL, 40 mmol) was added and the reaction was stirred for 1 hour. The mixture was then washed with brine, dried over Na₂SO₄ and concentrated. The crude was used in the following step without further purification.

¹H-NMR: 5.11 (IH, m); 2.43 (2H, m); 1.75 (4H, m); 1.39 (3H, d, J6.2 Hz)

Step C: (S)-tert-buty\ 7-(nitrooxy)-3-oxooctanoate

To a solution of (5)-5-(nitrooxy)hexanoic acid (31 mmol) in CH₂Cl₂ (100 mL), cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂ (3.3 mL, 37.7 mmol) were added. After the gas evolution ceased, the mixture was warmed to room temperature and stirred for 30 minutes. Then it was cooled to 0⁰C and a solution of cycl-isopropylidene malonate (Meldrum's acid, 5.30 g, 46.4 mmol) and pyridine (7.5 mL, 93.2 mmol) in CH₂Cl₂ (20 mL) was added. The reaction was stirred at room temperature for 3 hours, then washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in toluene (150 mL) and tert-BuOH (6 mL) was added. The mixture was refluxed for 3 hours, then concentrated and purified by SPl BIOTAGE (eluting with EtOAC/Hexane from 2 to 20 %) affording the title compound (3.34 g, yield 39 % over three steps) as a yellow oil.

¹H-NMR: 5.08 (IH, m); 3.36 (2H, s); 2.60 (2H, m); 1.69 (4H, m); 1.49 (9H, s); 1.37 (3H, d, J 6.2 Hz)

Step D: (S)-tert-buty\ 2-diazo-7-(nitrooxy)-3-oxooctanoate To a solution of (S)-tert-buty\ 7-(nitrooxy)-3-oxooctanoate in CH₃CN, cooled to 0 ⁰C, T0SN3 (2.62 g, 13.3 mmol) and triethylamine (1.7 mL, 13.4 mmol) were added. The solution was stirred at room temperature for 24 hours, then concentrated. The residue was triturated with Et₂O/Hexane 1 :2 and filtered. The filtrate was concentrated and the residue was used in the next step without further purification. 1H-NMR: 5.11 (IH, m); 2.87 (2H, m); 1.72 (4H, m); 1.52 (9H, s); 1.37 (3H, d, J6.2 Hz)

Step E: (S)-tert-buty\ 2-hydroxy-7-(nitrooxy)-3-oxooctanoate

Rh₂(OAc)₄ (45 mg, 0.1 mmol) was added to a solution of (S)-tert-butyl 2-diazo-7-(nitrooxy)-3- oxooctanoate in THFZH₂O (90 mL, 2:1). The mixture was refluxed for 5 hours then concentrated. The residue was partitioned between EtOAc and KHSO₄ (5%). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was used in the following step without further purification. ¹H-NMR: 5.09 (IH, m); 4.65 (IH, d, J 6.4 Hz); 3.75 (IH, d, J 6.9 Hz); 2.78 (IH, m,); 2.61 (IH, m,); 1.69 (4H, m,); 1.49 (9H, s); 1.38 (3H, d, J 6.2 Hz)

Step F: (S)-tert-buty\ 5-[4-(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate To a solution of (S)-tert-buty\ 2-hydroxy-7-(nitrooxy)-3-oxooctanoate (12.1 mmol) in THF (50 niL), cooled to 0 ⁰C, N,N-carbonyldiimidazole (3.92 g, 24.2 mmol) and N₅N- diisopropylethylamine (90 μL, 0.5 mmol ) were added. The reaction was stirred at room temperature overnight, then concentrated. The residue was partitioned between NaH₂PO₄ (5%) and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAc/Hexane 2 to 20 %) affording the title compound as a pale yellow oil (2 g, 52% over three steps). 1H-NMR: 5.12 (IH, m); 2.86 (2H, m); 1.75 (4H, m); 1.57 (9H, s); 1.38 (3H, d, J5.6 Hz)

Step F: (S)-5-[4-(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid (S)-tert-buty{ 5-[4-(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate (1.3 g, 4.1 mmol) was dissolved in CH₂Cl₂ (10 mL) and to the solution, cooled to 0 ⁰C, BF₃-Et₂O (620 μL, 4.9 mmol) was added. 1 hour later the reaction was washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated affording the title compound in quantitative yield. 1H-NMR: 9.18 (IH, bs); 5.14 (IH, m); 2.93 (2H, m); 1.84 (4H, m); 1.40 (3H, d, J6.2 Hz)

Step G: (S)-5-(5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl)pentan-2-yl nitrate (5)-5-[4-(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid (4.1 mmol) was dissolved in CH₂Cl₂ and to the solution, cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂ (430 μL, 4.9 mmol) were added. The reaction was warmed to room temperature, stirred for 1 hour and concentrated. The residue was taken up three times with CH₂Cl₂, then dissolved in CH₂Cl₂ (27 mL) and cooled to - 78 ⁰C. Bu₄NBH₄ (4.9 mmol) was added and the reaction was stirred at -78 ⁰C for 2 hours, then quenched by addition of HCl (0.5 N). The reaction was warmed to room temperature and the volatiles were removed. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAc/Hexane from 7 to 60 %) affording the title compound as a pale yellow oil (553 mg, 54%). ¹H-NMR: 5.11 (IH, m); 4.45 (2H, s); 2.53 (2H, m); 1.74 (4H, m); 1.49 (9H, s); 1.39 (3H, d, J 6.2 Hz).

INTERMEDIATE 3

5-[5-(hydroxymethyl)-2-oxo- 1 ,3-dioxol-4-yT|pentane- 1 ,2-diyl dinitrate

Step A: tert-buty\ 7,8-bis(nitrooxy)-3-oxooctanoate

To a solution of 5,6-bis(nitrooxy)hexanoic acid (obtained as described in J. Med. Chem, 2005, 48(5), 1322-1329) (16 mmol) in CH₂Cl₂ (30 mL), cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂

(1.6 mL, 19 mmol) were added. After the gas evolution ceased the mixture was warmed to room temperature and stirred for 30 minutes. Then it was cooled to 0⁰C and a solution of commercial cycl-isopropylidene malonate (Meldrum's acid, 2.30 g, 15.9 mmol) and pyridine (3.8 mL, 47.7 mmol) in CH₂Cl₂ (20 mL) was added. The reaction was stirred at room temperature for 3 hours, then washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in toluene (50 mL) and tert-BuOH (4.5 mL) was added. The mixture was refluxed for 3 hours, then concentrated and purified by SPl BIOTAGE (eluting with EtOAC/Hexane from

2 to 20 %) affording title compound (2.33g, 43% yield over two steps) as a yellow oil.

¹H-NMR (CDCl₃) : 5.30 (IH, m); 4.78 (IH, m); 4.50 (IH, m); 3.36 (2H, s); 2.64 (2H, m); 1.77 (4H, m); 1.49 (9H, s).

Step B: tert-buty\ 2-diazo-7,8-bis(nitrooxy)-3-oxooctanoate

To a solution of tert-butyl 7,8-bis(nitrooxy)-3-oxooctanoate (2.33 g, 6.9 mmol) in CH₃CN, cooled to 0 ⁰C, freshly prepared TosN₃ (obtained as described in J. Org. Chem., 1994, 59(10),2707-2714; (1.37 g, 6.9 mmol) and triethylamine (0.26 mL, 2.07 mmol) were added. The solution was stirred at room temperature for 24 hours, then concentrated. The residue was triturated with Et₂O/Hexane 1 :2 and filtered. The crude was finally purified by SPl BIOTAGE (eluting with EtOAC/Hexane from 2 to 20 %) affording the title compound (2.03g, yield 29 %) as a yellow oil. ¹H-NMR (CDCl₃) : 5.31 (IH, m);4.79 (IH, m); 4.50 (IH, m); 2.91 (2H, m); 1.81 (4H, m); 1.53 (9H, s).

Step C: tert-buty\ 2-hydroxy-7,8-bis(nitrooxy)-3-oxooctanoate Rh₂(OAc)₄ (44 mg, 0.1 mmol) was added to a solution of tert-butyl 2-diazo-7,8-bis(nitrooxy)-3- oxooctanoate in THF/H₂O (120 niL, 2:1). The mixture was refluxed for 5 hours then concentrated. The residue was partitioned between EtOAc and KHSO₄ (5%). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was used in the following step without further purification. 1H-NMR (CDCl₃): 5.29 (IH, m); 4.79 (IH, m); 4.64 (IH, d); 4.50 (IH, m); 3.71 (IH, d); 2.91- 2.55 (2H, m); 1.79 (4H, m); 1.52 (9H, s).

Step D: tert-buty\ 5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate

To a solution of tert-butyl 2-hydroxy-7,8-bis(nitrooxy)-3-oxooctanoate (4.9 mmol) in CH₂Cl₂ (50 mL), cooled to 0 ⁰C, l,l '-carbonyldiimidazole (1.59 g, 9.8 mmol) and iV-ethyldiisopropylamine

(43 μL, 0.25 mmol ) were added. The reaction was stirred at room temperature overnight, then concentrated. The residue was partitioned between NaH₂PO₄ (5%) and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAc/Hexane 2 to 20%) affording the title compound as a pale yellow oil (1.3 g, 70% over three steps).

¹H-NMR (CDCl₃): 5.34 (IH, m); 4.79 (IH, m); 4.50 (IH, m); 2.89 (2H, m); 1.85 (4H, m); 1.57 (9H, s).

Step E: 5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid tert-Butyl 5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate (1.36 g, 3.59 mmol) was dissolved in CH₂Cl₂ (10 mL) and to the solution, cooled to 0 ⁰C, BF₃-Et₂O (460 μL, 3.9 mmol) was added. 1.5 hours later the reaction was washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated affording the title compound. 1H-NMR (CDCl₃): 5.34 (IH, m); 4.79 (IH, m); 4.50 (IH, m); 2.97 (2H, m); 1.85 (4H, m).

Step F : 5-[5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl]pentane-l,2-diyl dinitrate 5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid (2.4 mmol) was dissolved in CH₂Cl₂ and to the solution, cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂ (225 μL, 2.6 mmol) were added. The reaction was warmed to room temperature, stirred for 1 hour and concentrated. The residue was taken up three times with CH₂Cl₂, then dissolved in CH₂Cl₂ (27 mL) and cooled to - 78 ⁰C. Bu₄NBH₄ (2.66 mmol) was added and the reaction was stirred at -78 ⁰C for 2 hours, then quenched by addition of HCl (0.5 N). The reaction was warmed to room temperature and the volatiles were removed. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAc/Hexane from 7 to 60%) affording the title compound as a pale yellow oil (350 mg, 47%). 1H-NMR (CDCl₃): 5.34 (IH, m); 4.79 (IH, m); 4.50 (3H, m); 2.58 (2H, m); 1.85 (4H, m).

INTERMEDIATE 4

(i?)-5-(5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl)pentane-l,2-diyl dinitrate (corresponding to intermediate (3) (R) enantiomer

The compound was prepared starting from (i?)-5,6-bis(nitrooxy)hexanoic acid, following the same procedures described in Intermediate 3.

¹H-NMR (CDCl₃): 5.34 (IH, m); 4.79 (IH, m); 4.50 (3H, m); 2.58 (2H, m); 1.85 (4H, m).

INTERMEDIATE 5

5-r5-(Bromomethyl)-2-oxo- 1 ,3-dioxol-4-yllpentyl nitrate To a solution of 5-[5-(Hydroxymethyl)-2-oxo-l,3-dioxol-4-yl]pentyl nitrate (INTERMEDIATE 1) (1.0 g, 4 mmol), cooled to 0 ⁰C, PPh₃ (1.15 g, 4.4 mmol) and CBr₄ (1.59 g, 4.8 mmol) were added. The reaction was stirred at room temperature overnight, then concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAC/Hexane 10 to 40 %) affording the title compound (1.19 g, 95 %) as a clear oil.

¹H-NMR (CDCl₃): 4.49 (2H, t, J 6.5 Hz); 4.20 (2H, s); 2.50 (2H, t, J 7.3); 1.75 (4H, m); 1.53 (4H, m)

INTERMEDIATE 6

(2R)-5-[5-(hydroxymethyl)-2-oxo- 1 ,3-dioxol-4-yi^"|pentane- 1 ,2-diyl dinitrate

Step A: tert-buty\ hex-5-enoate To a solution of 5-hexenoic acid (18 g, 157.6 mmol), t-BuOH (200 ml, 2206 mmol) and DMAP

(3.85 g, 31.5 mmol) in CH₂Cl₂ (400 ml) cooled at 0⁰C, DCC (48 g 236.4 mmol) was added. The reaction was warmed to room temperature and stirred for 48h. The precipitate was filtered off and the solution concentrated. The crude material was purified by filtration on silica (500 ml, 100 A°, diameter 10 cm) eluting with n-Hexane/EtOAc (98/2) affording the title compound as a yellow oil (20 g, 75%).

¹H-NMR (CDCl₃) : 5.80 (lH,m); 5.00 (2H,m); 2.25 (2H,t); 2.10 (2H,q); 1.7 (2H,q); 1.46 (9H,s).

Step B: tert-buty\ (5R)-5,6-dihydroxyhexanoate

To a suspension of AD mix-β(165 g, 1.4 g x mmol) in H₂CVt-BuOH (500 mL/ 500 mL) cooled to 0 ⁰C, a solution of tert-butyl hex-5-enoate (20 g, 118 mmol) in CH₂Cl₂ (20 mL) was added. The reaction was stirred overnight at 5°C. EtOAc (500 ml) was added and the reaction quenched with solid Na₂S₂Os (30 g). The reaction was stirred 30 minutes at 5°C then at room temperature for 1 hour. The organic layer was separated and the aqueous phase extracted with EtOAc (3x100 mL). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated affording the title compound as an oil. The crude was used in the following step without further purification. (25 g) ¹H-NMR (CDCl₃) : 3.70 (2H,m); 3.45 (lH,m); 2.25 (2H,t); 1.7 (2H,q); 1.5 (l lH,m).

Step C: tert-buty\ (5R)-5,6-bis(nitrooxy)hexanoate

To a solution OfAc₂O (88 ml) and HNO₃ (25 ml) at O⁰C tert-butyi (5i?)-5,6-dihydroxyhexanoate (25 g, 118 mmol) in CH₂Cl₂ (10 ml) was slowly added. The solution was stirred at 0 ⁰C for 30 min, then was neutralized by pouring it into a solution of iced NaOH 10%. Further NaOH was added until the pH was neutralized. The aqueous phase was extracted with CH₂Cl₂ (3x20 ml) and the organic layer was washed with brine, dried over Na₂SO₄ and concentrated. The crude was purified by SPl BIOTAGE SNAP340 (eluting with EtOAC/Hexane from 2 to 20 %) affording title compound (18.5 g, yield 53%) as a brown oil.

¹H-NMR (CDCl₃) : 5.80 (lH,m); 4.75 (lH,m); 4.5 (lH,m); 2.3 (2H,t); 1.75 (4H,m); 1.46 (9H,m).

Step D: (5R)-5,6-bis(nitrooxy)hexanoic acid

A solution of tert-butyi (5i?)-5,6-bis(nitrooxy)hexanoate (18.5 g; 62.9 mmol) in CH₂Cl₂ (120 ml) was cooled under nitrogen to 0 ⁰C. BF₃-Et₂O (8.1 mL; 69.1 mmol) was added and the reaction was stirred 30 min at 0 ⁰C and 3 hours at room temperature. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated to give the desired product as a brown oil. The crude was used in the following step without further purifϊcation.(15g)

¹H-NMR (CDCl₃) : 5.80 (lH,m); 4.75 (lH,m); 4.5 (lH,m); 2.5 (2H,t); 1.75 (4H,m).

Step E: tert-buty\ (7R)-7,8-bis(nitrooxy)-3-oxooctanoate

To a solution of (5R)-5,6-bis(nitrooxy)hexanoic acid (62.8 mmol) in CH₂Cl₂ (60 mL), cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂ (6.5 mL, 75.3 mmol) were added. After the gas evolution ceased the mixture was warmed to room temperature and stirred for 30 minutes. It was then cooled to 0⁰C and a solution of cycl-isopropylidene malonate (Meldrum's acid, 9.10 g, 62.8 mmol) and pyridine (15 mL, 188.4 mmol) in CH₂Cl₂ (30 mL) was added. The reaction was stirred at room temperature for 3 hours, then washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in toluene (150 mL) and tert-BuOH (15 mL) was added. The mixture was refluxed for 3 hours, then concentrated and purified by BIOTAGE (eluting with EtOAC/Hexane from 2 to 20 %) affording the title compound (6.6 g, 31% yield over two steps) as a yellow oil.

¹H-NMR (CDCl₃) : 5.30 (lH,m);4.78 (lH,m); 4.50 (lH,m); 3.36 (2H,s); 2.64 (2H,m); 1.77 (4H,m); 1.49 (9H,s).

Step F: tert-buty\ (7R)-2-diazo-7,8-bis(nitrooxy)-3-oxooctanoate To a solution of tert-butyl (7R)-7,8-bis(nitrooxy)-3-oxooctanoate (6.6 g, 19.6 mmol) in CH₃CN, cooled to 0 ⁰C, freshly prepared T0SN3 (obtained as described in J. Org. Chem., 1994, 59(10),2707-2714; (4.7 g, 23.5 mmol) and triethylamine (0.75 mL, 5.88 mmol) were added. The solution was stirred at room temperature for 24 hours, then concentrated. The residue was triturated with Et₂O/Hexane 1 :2 and filtered. The crude material was purified by BIOTAGE

(eluting with EtOAC/Hexane from 2 to 20 %) affording title compound (5.94 g, yield 83 %) as a yellow oil.

¹H-NMR (CDCl₃) : 5.31 (lH,m); 4.79 (lH,m); 4.50 (lH,m); 2.91 (2H,m); 1.81 (4H,m); 1.53

(9H,s).

Step G: tert-butyl (7R)-2-hydroxy-7,8-bis(nitrooxy)-3-oxooctanoate Rh₂(OAc)₄ (72 mg, 0.16 mmol) was added to a solution of tert-butyl (7R)-2-diazo-7,8- bis(nitrooxy)-3-oxooctanoate in THF/H₂O (450 mL, 3:1). The mixture was refluxed for 5 hours then concentrated. The residue was partitioned between EtOAc and KHSO₄ (5%). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was used in the following step without further purification.

¹H-NMR (CDCl₃): 5.29 (lH,m); 4.79 (lH,m); 4.64 (lh,d); 4.50 (lH,m); 3.71 (lH,d); 2.91-2.55 (2H,m); 1.79 (4H,m); 1.52 (9H,s).

Step H: tert-butyl 5-[(4R)-4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate

To a solution of tert-butyl (7R)-2-hydroxy-7,8-bis(nitrooxy)-3-oxooctanoate (16.3 mmol) in CH₂Cl₂ (200 mL), cooled to 0 ⁰C, N,JV-carbonyldiimidazole (5.3 g, 32.6 mmol) and N,N- diethylisopropylamine (0.139 mL, 0.81 mmol ) were added. The reaction was stirred at room temperature overnight, then concentrated. The residue was partitioned between NaH₂PO₄ (5%) and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane 2 to 20%) affording the title compound as a pale yellow oil (4.3 g, 70% over two steps).

¹H-NMR (CDCl₃): 5.34 (lH,m); 4.79 (lH,m); 4.50 (lH,m); 2.89 (2H,m); 1.85 (4H,m); 1.57 (9H,s).

Step I: 5-[(4R)-4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid tert-Butyl 5-[(4R)-4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylate (4.3 g, 11.3 mmol) was dissolved in CH₂Cl₂ (130 mL) and ZnBr₂(12 g, 56.84 mmol) was added. After 48 hours at r.t. water (100 mL) was added and the reaction stirred 1 hour at r.t. The organic layer was separated and washed with brine, dried over Na₂SO₄ and concentrated. The crude material was used without further purification. 1H-NMR (CDCl₃): 5.34 (lH,m); 4.79 (lH,m); 4.50 (lH,m); 2.97 (2H,m); 1.85 (4H,m). Step L: (2R)-5-[5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl]pentane-l,2-diyl dinitrate

5-[(4R)-4,5-bis(Nitrooxy)pentyl]-2-oxo-l,3-dioxole-4-carboxylic acid (6.5 mmol) was dissolved in CH₂Cl₂ and to the solution, cooled to 0 ⁰C, DMF (0.5 mL) and (COCl)₂ (0.605 ml, 7.1 mmol) were added. The reaction was warmed to room temperature, stirred for 1 hour and concentrated. The residue was taken up three times with CH₂Cl₂, then dissolved in CH₂Cl₂ (50 mL) and cooled to -78 ⁰C. Bu₄NBH₄ (7.1 mmol) was added and the reaction was stirred at -78 ⁰C for 2 hours, then quenched by addition of HCl (0.5 N). The reaction was warmed to room temperature and the volatiles were removed. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 7 to 60%) affording the title compound as a pale yellow oil (450 mg, 23%). 1H-NMR (CDCl₃): 5.34 (lH,m); 4.79 (lH,m); 4.50 (3H,m); 2.58 (2H,m); 1.85 (4H,m).

EXAMPLE 1

(5-r5-(nitrooxy)pentyll-2-oxo- 1.3-dioxol-4-yl} -2-butyl-4-chloro- 1 -IT2'-αH-Tetrazol-5-vi)r 1.1 '- biphenyl] -4-yl]methyll - lH-Imidazole-5 -carboxylate

Step A: {5-[5-(nitrooxy)pentyl]-2-oxo-l,3-dioxol-4-yl}-2-butyl-4-chloro-l-[[2'-(l

Triphenylmethyltetrazol-5-yl) [1 , 1 '-biphenyl] -4-yl] methyl] - lH-Imidazole-5-carboxylate A solution of 2-butyl-4-chloro-l-{[2'-(l-trityl-lΗ-tetrazol-5-yl)biphenyl-4-yl]methyl}-lΗ- imidazole-5-carboxylic acid (0.340 g, 0.5 mmol) and N-methylmorpholine (140 μl, 1.2 mmol) in CH₂Cl₂ (10 ml) was cooled to 0 ⁰C. Then JV-Hydroxybenzotriazole (81 mg, 0.6 mmol) and N- dimethylaminopropyWV'-ethyl carbodiimide hydrochloride^ 15 mg, 0.6 mmol) were added and the reaction was stirred at 0 ⁰C for 30 minutes. Then 5-[5-(hydroxymethyl)-2-oxo-l,3-dioxol-4- yl]pentyl nitrate (INTERMEDIATE 1) (124 mg, 0.5 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 24 hours. The organic layer was then washed with a solution Of NaH₂PO₄ (5%), K2CO3 (5%) and brine, dried over Na₂SO₄ and concentrated. The residue was purified by SPl BIOTAGE (eluting with EtOAc/n-Hexane from 7 to 60 %) affording the title compound (0.35O g, 77%) as a pale yellow oil.

¹H-NMR (CDCl₃): 7.90 (IH, d); 7.50 (2H, m); 7.40-7.25 (1OH, m); 7.12 (2H, d); 6.98 (6H, d); 6.77 (2H, d); 5.43 (2H, s); 4.88 (2H, s); 4.39 (2H, t); 2.60-2.41(4H, m); 1.80-1.53 (6H, m); 1.48- 1.23 (4H, m); 0.88 (3H, t)

Step B : {5- [5-(nitrooxy)pentyl] -2-oxo- 1 ,3-dioxol-4-yl}-2-butyl-4-chloro- 1- [ [2 '-(lH-Tetrazol- 5-yl) [1 , 1 '-biphenyl] -4-yl] methyl] - lH-Imidazole-5-carboxylate

A suspension of {5-[5-(nitrooxy)pentyl]-2-oxo-l,3-dioxol-4-yl}-2-butyl-4-chloro-l-[[2'-(l Triphenylmethyltetrazol-5-yl)[ 1 , 1 '-biphenyl] -4-yi]methyi]- lH-Imidazole-5-carboxylate (0.560 g, 0.61 mmol) in MeOH (12 ml) was treated under microwave irradiation at 70⁰C for 40 minutes, then concentrated. The crude material was purified by SPl BIOTAGE (eluting with CH₂Cl₂/ MeOH 97:3) affording the title compound (0.300 g 70%) as a pale yellow oil. 1H-NMR (DMSO): 7.71-7.49 (4H, m); 7.07 (2H, s); 6.96 (2H, s); 5.55 (2H, s); 5.13 (2H, s); 4.47 (2H, t); 2.65-2.51 (4H, m); 1.70-1.45 (6H, m); 1.41-1.19 (4H, m); 0.82 (3H, t).

EXAMPLE 2

Step A: (S)-(5-(4-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-butyl-4-chloro-l-((2'-(2- trityl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-iimidazole-5-carboxylate

To a solution of 2-butyl-4-chloro-l-((2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-l/f- iimidazole-5-carboxylic acid (680 mg, 1 mmol) and N-methylmorpholine (280 μL, 2.5 mmol), cooled to 0 ⁰C, 4-N,Λ/-dimethylaminopyridine (3 mg, 0.02 mmol), JV-Hydroxybenzotriazole (162 mg, 1.2 mmol), Λ/-dimethylaminopropyWV'-ethyl carbodiimide hydrochloride (250 mg, 1.3 mmol) and (S)-5-(5-(hydroxymethyl)-2-oxo-l,3-dioxol-4-yl)pentan-2-yl nitrate (INTERMEDIATE 2) (250 mg, 1 mmol) were added. The reaction was stirred overnight, then washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAC/ Hexane from 20 to 80 %) affording the title compound (700 mg, 70 %) as a white foam.

¹H-NMR (CDCl₃): 7.91 (IH, m); 7.32 (12H, m);7.11 (2H, m); 6.97 (6H, m); 6.79 (2H, m); 5.43 (2H, s); 5.05 (IH, m); 4.87 (2H, s); 2.52 (4H, m); 1.62 (6H, m); 1.32 (5H, d, J 6.3 Hz); 0.89 (3H, t, J 7.3 Hz )

Step B: (S)-(5-(4-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-butyl-4-chloro-l-((2'- (2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-iimidazole-5-carboxylate

(5)-(5-(4-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-butyl-4-chloro-l-((2'-(2-trityl-2H- tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-imidazole-5-carboxylate (700 mg, 0.7 mmol) was dissolved in MeOH (14 mL) and treated under microwave irradiation (70 ⁰C for 40 minutes). The mixture was concentrated and purified by SPl BIOTAGE (eluting with MeOΗ/CΗ₂Cl₂ from 1 to

10 %) and HPLC (Column XBridge Shield RP 18 5 μm, 19 x 150 mm, WATERS,

H₂O/CH₃CN/0.1% HCOOH from 35 to 65 %) affording the title compound as a white solid (160 mg, 34 %)

¹H-NMR (CDCl₃): 8.07 (IH, m); 7.61 (2H, m); 7.45 (IH, m); 7.25 (2H, m); 6.99 (2H, m); 5.54 (2H,s); 5.06 (3H, m+s); 2.66 (4H, m); 1.73 (6H, m); 1.38 (5H, m+d, J 6.2 Hz); 0.91 (3H, t, J 7.3 Hz)

{5-r4,5-bis(nitrooxy)pentyll-2-oxo- 1 ,3-dioxol-4-yl| 1 ^-butvM-chloro- 1 -rr2'-(lfl-Tetrazol-5-yl)r 1.1 '-biphenyll-4-yllmethyll- lH-Imidazole-5- carboxylate

Step A: {5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxol-4-yl }-2-butyl-4-chloro-l-[[2'-(l triphenylmethyltetrazol-5-yl) [1 , 1 '-biphenyl] -4-yl] methyl] - lH-Imidazole-5-carboxylate

A solution of 2-butyl-4-chloro-l-{[2'-(l-trityl-lH-tetrazol-5-yl)biphenyl-4-yl]methyl}-lH- imidazole-5-carboxylic acid (640 mg, 0.97 mmol) and N-methylmorpholine (266 μL, 2.32 mmol) in CΗ2CI2 (20 mL) was cooled to 0⁰C. Then JV-hydroxybenzotriazole (157 mg, 1.16 mmol) and N-dimethylaminopropyl-N -ethyl carbodiimide hydrochloride (223 mg, 1.16 mmol) were added and the reaction was stirred for 30 minutes at 0⁰C. 5-[5-(hydroxymethyl)-2-oxo-l,3-dioxol-4- yl]pentane-l,2-diyl dinitrate (INTERMEDIATE 3) (300 mg, 0.97 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 24 hours. The organic layer was washed with a solution of NaH₂PO₄ (5%), K2CO3 (5%) and brine, dried over Na₂SO₄ and concentrated. The residue was purified by SPl BIOTAGE (eluting with EtOAc/Hexane from 7 to 60 %) affording the title compound as a pale yellow oil (0.500 g, 55%).

¹H-NMR (CDCl₃): 7.89 (IH, d); 7.5 (2H, m); 7.4-7.2 (1OH, m); 7.13 (2H, d); 6.99 (6H, d); 6.78 (2H, d); 5.43 (2H, s); 5.21 (IH, m); 4.86 (2H, s); 4.67 (IH, m); 4.38 (IH, m); 2.54 (4H, m); 1.68 (6H, m); 1.30 (2H, m); 0.88 (3H, t).

Step B: {5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxol-4-yl}

}-2-butyl-4-chloro-l-[[2'-(lH-Tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-lH-Imidazole-5- carboxylate

A suspension of {5-[4,5-bis(nitrooxy)pentyl]-2-oxo-l,3-dioxol-4-yl}-2-butyl-4-chloro-l-[[2'-(l triphenylmethyltetrazol-5-yl) [ 1 , 1 '-biphenyl] -4-yl]methyl] lH-Imidazole-5-carboxylate (0.500 g, 0.53 mmol) in MeOH (10 mL) was treated under microwave irradiation (70 ⁰C for 40 minutes) and concentrated. The crude material was purified by SPl BIOTAGE (CΗ₂Cl₂/Me0Η 97:3) affording the title compound (0.25 g, 67%).

¹H-NMR (DMSO): 7.70-7.46 (4H, m); 7.07 (2H, s); 6.96 (2H, s); 5.55(2H, s); 5.41(1H, m);

5.12 (2H, s); 4.91 (IH, m); 4.66 (2H, m); 2.60 (4H, m); 1.79-1.45 (6H, m); 1.25 (2H, m); 0.82 (3H, t).

EXAMPLE 4

The title compound was prepared by following the procedure for the synthesis of Example 3, except that in Step A the Intermediate 3 was replaced by the Intermediate 6.

EXAMPLE 5

((5-(5-(( 1 -((2 ' -(2-triphenylmethyltetrazol-5 -yl)biphenyl-4-yl)methyl)-4-(2-hvdroxypropan-2-yl)-2- propyl- lH-imidazole-5-carbonyloxy)methyl)-2-oxo- 1 ,3-dioxol-4- yl)pentyloxy)(oxo)ammonio)oxonium

STEP A: l-((2'-(2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2- hydroxypropan-2-yl)-2-propyl- lH-imidazole-5-carboxylic acid To a solution of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl l-((2'-(2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-lH-imidazole-5-carboxylate (4.00 g, 5 mmol) in dioxane (50 niL) NaOH (IM, 25 niL) was slowly added. The reaction was stirred at room temperature for 2 hours, then concentrated under reduced pressure to half volume. The mixture was then acidified to pΗ 3 with HCl (IN). The title compound was collected by filtration as a white solid (3.5 g, 99%).

¹H-NMR (DMSO): 7.76 (IH, d, J 7.4 Hz); 7.58 (2H, m); 7.34 (1OH, m); 6.99 (2H, d); 6.88 (8H, m); 5.67 (2H, s); 2.34 (2H, t); 1.48 (8H, s + m); 0.72 (3H, t, J 7.3 Hz)

STEP B: ((5-(5-((l-((2'-(2-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2- hydroxypropan-2-yl)-2-propyl- lH-imidazole-5-carbonyloxy)methyl)-2-oxo- 1 ,3-dioxol-4- yl)pentyloxy)(oxo)ammonio)oxonium

To a solution of l-((2'-(2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2- hydroxypropan-2-yl)-2-propyl-lH-imidazole-5-carboxylic acid (450 mg, 0.65 mmol) in DMF (10 InL)₁ cooled to 0 ⁰C, Cs₂CO₃ (230 mg, 0.7 mmol) and 5-[5-(Ηydroxymethyl)-2-oxo-l,3-dioxol-4- yTJpentyl nitrate (INTERMEDIATE 1) were added. The reaction was slowly warmed to room temperature and stirred overnight. It was then partitioned between EtOAc and NaH₂PO₄ (5%). The organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude material was purified by SPl BIOTAGE (eluting with EtOAC/Hexane from 20 to 80 %) affording the title compound (500 mg, 85 %) as a white foam.

¹H-NMR (CDCl₃): 7.88 (IH, d, J 7.4 Hz); 7.42 (12H, m); 7.11 (2H, d, J 8.1); 6.98 (6H, d); 6.71 (2H, d, J 8.1); 5.31 (2H, s); 4.73 (2H, s); 4.38 (2H, t, J 6.5 Hz); 2.56 (2H, t); 2.38 (2H, t, J 7.3 Hz); 1.64 (10 H, m + s); 0.92 (3H, t, J 7.3 Hz)

STEP C: ((5-(5-((l-((2'-(2H-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl- lH-imidazole-5-carbonyloxy)methyl)-2-oxo- 1 ,3-dioxol-4- yl)pentyloxy)(oxo)ammonio)oxonium

((5 -(5 -(( 1 -((2 ' -(2-triphenylmethyltetrazol-5 -yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2- propyl- lH-imidazole-5-carbonyloxy)methyl)-2-oxo- 1 ,3-dioxol-4- yl)pentyloxy)(oxo)ammonio)oxonium (500 mg, 0.54 mmol) was dissolved in MeOH (10 mL) and the solution was treated under microwave irradiation (70 ⁰C for 40 minutes). It was then concentrated and purified by SPl BIOTAGE (eluting with MeOH/ CH₂Cl₂ from 1 to 10 %) and HPLC ((Column XBridge Shield RP 18 5 μm, 19 x 150 mm, WATERS, CH₃CN/H₂O/0.1% HCOOH from 40 to 100 %)) affording the title compound as a clear gum ( 150 mg, 41 %). 1H-NMR (DMSO): 7.92 (IH, m); 7.60 (2H, m); 7.46 (IH, m); 7.14 (2H, m); 6.84 (2H, m); 5.70 (IH, bs); 5.47 (2H, s); 5.03 (2H, s); 4.49 (2H, m); 2.60 (4H, m); 1.65 (10 H, m + s); 0.95 (3H, t, J= 7.3 Hz)

EXAMPLE 6

(5-r(mtrooxy)methyl1-2-oxo- 1 J-dioxoM-vUmethyβ-butvM-chloro- 1 - ([2'-(2H -tetrazol-5- yl)biphenyl-4-yl]methyl| - lH-imidazole-5-carboxylate

STEP A 4,5-bis(bromomethyl)- 1 ,3-dioxol-2-one

NBS (19.58 g, 110 mmol) followed by AIBN (0.821 g, 5.00 mmol) were added to a stirred, room temperature mixture of 4,5-dimethyl-l,3-dioxol-2-one (5.70 g, 50 mmol) in benzene (300 mL) and the mixture was stirred at reflux for 1 h. Volatiles were removed.

Chromatography over silicaeluting with 5-55% EtOAc/hexane afforded the desired product as a yellow oil.

STEP B r5-(bromomethyl)-2-oxo- 1 ,3-dioxol-4-yll methyl nitrate

A solution of silver nitrate (475 mg, 2.80 mmol) in acetonitrile (4 mL) was added over 1 h to a stirred, 60 ⁰C mixture of 4,5-bis(bromomethyl)-l,3-dioxol-2-one (760 mg, 2.80 mmol) in acetonitrile (4 mL) and the mixture was stirred at 60 ⁰C for 5 min. The reaction mixture was filtered and concentrated. Chromatography over silica eluting with 0-60% EtOAc/hexane afforded the desired product as a colorless oil.

STEP C {5- r(nitrooxy)methyll -2-oxo- 1 ,3-dioxol-4-yl}methyl2-butyl-4-chloro- 1- { \2 '- (2H -tetrazol-5-yl)biphenyl-4-yllmethyl}-lH-imidazole-5-carboxylate

Potassium bicarbonate (88 mg, 0.883 mmol) was added to a stirred, 0 ⁰C mixture of2-butyl-4-chloro-l-{[2'-(2-trityl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl}-l/f-imidazole-5- carboxylic acid (trityl-protected E3174) (400 mg, 0.589 mmol) and [5-(bromomethyl)-2-oxo-l,3- dioxol-4-yl]methyl nitrate (299 mg, 1.178 mmol) in dimethylformamide (8 mL) and the mixture was stirred at room temperature for 3 h. The reaction was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na₂SO₄), filtered and concentrated. The residue was dissolved in methanol and heated at 60⁰C overnight. 4 M HCl in dioxane was added and reaction was filtered and concentrated. The residue was purified by preparative HPLC (Gilson; KR100-5C18 100x21.2 mm column), eluting with 10-90% acetonitrile/water + 0.1% TFA over 12 min (rt = 9.7 min), to afford a white solid. LC-MS: calculated for C27H24C1IN7O8 609.14, observed m/e 610.3 (M + H)⁺ (R_t 1.19/2 min).

IH NMR(CDCB): 7.92 (lH,d), 7.60 (lH,t), 7.52 (lH,t), 7.42 (lH,d), 7.30-7.11 (3H,m), 6.91 (2H,d), 5.49 (2H,s), 5.39 (2H,s), 5.14 (2H,s), 2.63 (2H,t), 1.66 (2H,m), 1.40-1.25 (2H,m), 0.87 (3H,t).

EXAMPLE 7

(5-(5-(nitrooxy)pentyl)-2-oxo-1.3-dioxol-4-yl)methyl 4'-((lJ'-dimethyl-2'-propyl-lH.3'H-2.5'- bibenzord1imidazol-3'-yl)methyl)brphenyl-2-carboxylate

4'-((l,7'-dimethyl-2'-propyl-lH,3'H-2,5'-bibenzo[d]imidazol-3'-yl)methyl)biphenyl-2-carboxylic acid (412 mg, 0.8 mmol), NMM (220 μL, 2 mmol), DMAP (2 mg, 0.016 mmol), and HOBt (130 mg, 0.96 mmol) were dissolved in CH₂Cl₂ (10 mL). To the solution, cooled to 0⁰C, INTERMEDIATE 1 (200 mg, 0.8 mmol) and EDAC-HCl (200 mg, 1.04 mmol) were added. The reaction was slowly warmed to r.t. and stirred for 48 h. The mixture was washed with NaH₂PO₄ (5%) and brine, dried over Na₂SO₄ and concentrated. The crude material was purified by BIOTAGE (eluting with acetone/hexane from 25 to 100 %) affording the title compound (470 mg, 78 %) as a clear oil.

¹H-NMR (CDCl₃) : 7.79 (2H,m); 7.42 (8H,m); 7.18 (2H,m); 7.07 (2H,m); 5.54 (2H,s); 4.71 (2H,s); 4.39 (2H,t); 3.88 (3H,s); 3.00 (2H,m); 2.8 (3H,s); 2.39 (2H,t); 1.92-1.37 (8H,m); 1.09 (3H,t)

EXAMPLE 8

(y)-(5-(5-(nitrooxy)pentyl)-2-oxo-1.3-dioxol-4-yl)methyl 2-(N-((2'-(l-H-tetrazol-5-yl)biphenyl-4- yl)methyl)pentanamido)-3-methylbutanoate

STEP A: (S)-(5-(5-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-(7V-α2'-q-trityl- tetrazol-5-yl)biphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate

A solution of methyl 2-(Λ/-((2'-(l-trityl-tetrazol-5-yl)biphenyl-4-yl)methyl)pentanamido)-3- methylbutanoate (0.500 g, 0.730 mmol) and NMM (200 μl, 1.820 mmol) in CH₂Cl₂ (15 mL) was cooled to 0⁰C. Then HOBt (118 mg, 0.880 mmol) and EDAC-HCl (168 mg, 0.880 mmol) were added and the reaction was stirred for 30 min at 0 ⁰C. INTERMEDIATE 1 (183 mg, 0.730 mmol) was then added and the reaction was slowly warmed to r.t. and stirred for 24 hours. The organic layer was then washed with a solution Of NaH₂PO₄ (5%), K₂CO₃ (5%) and brine, dried over Na₂SO₄ and concentrated. The crude material was purified by silica gel chromatography

(Hexane/EtOAc 7:3) affording the title compound (0.250 g, 40%) as a white solid. STEP B: (S)-(5-(5-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-(N-α2'-q-H-tetrazol-5- yl)biphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate

A suspension of (S)-(5-(5-(nitrooxy)pentyl)-2-oxo-l,3-dioxol-4-yl)methyl 2-(N-((2'-(l-trityl- tetrazol-5-yl)biphenyl-4-yl)methyl)pentanamido)-3-methylbutanoate (0.250 g, 0.29 mmol) in

MeOH (5 mL) was stirred at 70 ⁰C for 40 minutes under microwave irradiation. The organic phase was concentrated and the crude material was purified by silica gel chromatography

(CH₂Cl₂/Me0H 95:5) affording the title compound (0.100 g; 50%) as a white solid.

¹H-NMR (CDCl₃): 8.05-7.91(lH,m); 7.62-7.45 (3H,m); 7.17 (2H,m); 5.10-4.11 (6H,m); 2.71- 2.28 (6H,m); 1.75-1.25 (l lH,m); 1.02-0.93 (9H,m).

Assay on vascular tone

The ability of the compounds of the invention to induce vasorelaxation in comparison to native angiotensin II receptor blockers (ARBs), was tested in vitro in isolated rabbit thoracic aorta preparations (Wanstall J.C. et al, Br. J. Pharmacol, 134:463-472, 2001). 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. Aortic ring preparations (4 mm in length) 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, NaHCO₃ 14.9, KH₂PO₄ 1.2, MgSO₄ 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. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP 150 System. Preparations were allowed to equilibrate for Ih, and then contracted submaximally with noradrenaline (NA, 1 μM) and, when the contraction was stable, acetylcholine (ACh, 10 μM) was added. A relaxant response to ACh indicated the presence of a functional endothelium. Vessels that were unable to contract NA or showed no relaxation to Ach were discarded. When a stable precontraction was reached, a cumulative concentration-response curve to either of the vasorelaxant agents was obtained in the presence of a functional endothelium. Each arterial ring was exposed to only one combination of inhibitor and vasorelaxant. Moreover, the effect of the soluble guanylyl cyclase inhibitor ODQ (1-H-(1, 2,4)- oxadiazol(4,3-a)quinoxalin-l-one) on vasorelaxation elicited by the compounds was examined preincubating the aortic rings with ODQ (10 μM) for 20 min. Responses to relaxing agents are expressed as a percentage of residual contraction and plotted against concentration of test compound. EC50 values (where 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, the native ARBs did not produce relaxation at any of the concentration tested, the curve being not different from that built up in the presence of vehicle alone.

As shown in Table 1, the compounds of the invention were able to induce relaxation in a concentration-dependent manner. Furthermore, in experiments performed in the presence of ODQ (10 μM), the vasorelaxant responses to tested compounds were inhibited.

Table 1

Assay for antihypertensive activity (in vivo)

The ability of the compounds of the invention to decrease blood pressure was evaluated in conscious spontaneously hypertensive rats (SHRs). SHRs (250-300 g) received a single oral dose of tested compounds. Systolic blood pressure (SBP) and heart rate were monitored by telemetry for 24 hours after dosing. SBP was evaluated before (baseline) and at different time points (i.e. 2- 6, 12, 21-24 hours) following treatment by oral administration of the compounds. The data were processed both as the absolute value or as a delta between the absolute value and baseline.

The Dataquest IV telemetry system (Data Sciences International) was used for measurement of systolic pressure, diastolic pressure, mean arterial pressure, heart rate, and motor activity. The monitoring system consisted of a transmitter (radio frequency transducer model TAI lPA), receiver panel, consolidation matrix, and personal computer with accompanying software. Before the device was implanted, calibrations were verified to be accurate within ±3 mmHg. Rats were anesthetized with ketamine/xylazine/acepromazine, and the flexible catheter of the transmitter was surgically secured in the abdominal aorta just below the renal arteries. The transmitter was sutured subcutaneously. Rats were housed in individual cages after the operation. Each cage was placed over the receiver panel that was connected to the personal computer for data acquisition. The rats were unrestrained and free to move within their cages. Hemodynamic data were sampled every 2 minutes for 10 seconds.

Compared to Compound A (reference compound), the compounds of the invention provided BP lowering with extended peak effect and duration of action (see Data Table 2).

Compound A

Table 2

The angiotensin II receptor antagonists (ARBs) of the invention are useful for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, muscle dystrophies, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy, glaucoma, elevated intra-ocular pressure, atherosclerosis, restenosis post angioplasty, complications following vascular or cardiac surgery, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders, complications of treatments with immunosuppressive agents, and other diseases known to be related to the renin-angiotensin system.

The ARBs of the invention are especially useful for the treatment and/or prophylaxis of diseases which are related to hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, complications resulting from diabetes such as nephropathy, vasculopathy and neuropathy.

In one embodiment, the invention relates to a method for the treatment and/or prophylaxis of diseases, which are associated with a dysregulation of the renin-angiotensin system, in particular to a method for the treatment or prophylaxis of the above-mentioned diseases, said methods comprising administering to a patient a pharmaceutically active amount of an angiotensin II receptor antagonist of the invention.

The invention also relates to the use of ARBs of the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases. The above-mentioned ARBs of the invention are also of use in combination with other pharmacologically active compounds comprising angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, renin inhibitors (e.g. urea derivatives of di- and tri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives (U.S. Patents 5,095,119 and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Patent 5,114,937), di- and tri-peptide derivatives (U.S. Patent 5,106,835), peptidyl amino diols (U.S. Patents 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Patent 5,089,471); also, a variety of other peptide analogs as disclosed in the following U.S. Patents 5,071,837; 5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, and small molecule renin inhibitors (including diol sulfonamides and sulfϊnyls (U.S. Patent 5,098,924), N-morpholino derivatives (U.S. Patent 5,055,466), N-heterocyclic alcohols (U.S. Patent 4,885,292) and pyrolimidazolones (U.S. Patent 5,075,451); also, pepstatin derivatives (U.S. Patent 4,980,283) and fluoro- and chloro-derivatives of statone-containing peptides (U.S. Patent 5,066,643), enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren ((2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)- 5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptors antagonists, vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazocin, prazosin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g. hydralazine), lipid lowering agents (e.g., simvastatin, lovastatin, ezetimibe, atorvastatin, pravastatin), metabolic altering agents including insulin sensitizing agents and related compounds (e.g., muraglitazar, glipizide, metformin, rosiglitazone)) or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including nitroprusside and diazoxide.

The dosage regimen utilizing the angiotensin II receptor antagonists is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Oral dosages of the angiotensin II receptor antagonists, when used for the indicated effects, will range between about 0.0125 mg per kg of body weight per day (mg/kg/day) to about 7.5 mg/kg/day, preferably 0.0125 mg/kg/day to 3.75 mg/kg/day, and more preferably 0.3125 mg/kg/day to 1.875 mg/kg/day. For example, an 80 kg patient would receive between about 1 mg/day and 600 mg/day, preferably 1 mg/day to 300 mg/day, and more preferably 25 mg/day to 150 mg/day. A suitably prepared medicament for once a day administration would thus contain between 1 mg and 600 mg, preferably between 1 mg and 300 mg, and more preferably between 25 mg and 300 mg, e.g., 25 mg, 50 mg, 100 mg, 150, 200, 250 and 300 mg,. Advantageously, the angiotensin II receptor antagonists may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.5 mg and 300 mg, preferably between 0.5 mg and 150 mg, more preferably between 12.5 mg and 150 mg, e.g., 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg and 150 mg.

The angiotensin II receptor antagonists of the invention can be administered in such oral forms as tablets, capsules and granules. The angiotensin II receptor antagonists are typically administered as active ingredients in admixture with suitable pharmaceutical binders as described below. % w/w expresses the weight percent of the indicated composition constituent compared to the total composition. Suitable fillers used in these dosage forms include microcrystalline cellulose, silicifϊed microcrystalline cellulose, dicalcium phosphate, lactose, mannitol, and starch, preferably microcrystalline cellulose, dicalcium phosphate, lactose or mixtures thereof. Suitable binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, and polyvinyl pyrrolidone. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, sodium stearyl fumarate, stearic acid and the like, preferably magnesium stearate. Suitable coating compositions include aqueous dispersion or organic solution of insoluble polymers such as ethyl cellulose, cellulose aetate, cellulose acetate butyrate and acrylate copolymers commercially known as Eudragit®. Plasticizers include triethyl citrate, dibutyl sebacate, dibutyl phthalate, triacetin and castor oil. Antitacking agents include talc, kaolin, colloidal silica or mixtures thereof.

2-Butyl-4-chloro- 1 - [(2 ' -( 1 -H-tetrazol-5 -yl)biphenyl-4-yl)methyl] -imidazole-5 - carboxylic acid is the active metabolite of 2-butyl-4-chloro-l-[p-(o-lH-tetrazol-5-ylphenyl)- benzyl]imidazole-5 -methanol which is available as a monopotassium salt (also known as losartan potassium salt). Losartan potassium salt is available commercially as the active ingredient in COZAAR® (Merck & Co., Inc. Whitehouse Station, NJ). The preparation of losartan potassium salt is described in U.S. Patents 5,138,069, 5,130,439, and 5,310,928. Tetrazolylphenylboronic acid intermediates useful in the synthesis of losartan potassium salt are described in U.S. Patent 5,206,374. Additional patents which describe procedures useful for making losartan include U.S.

Patents 4,820,843, 4,870,186, 4,874,867, 5,039,814, and 5,859,258.

Claims

WHAT IS CLAIMED IS:

1. A compound having the general formula:

(I) wherein R is selected from the group consisting of (Ha)-(IIh):

Z is selected from the group consisting of:

1) R°-0N0₂, wherein R⁰ is a straight or branched Ci-Cio alkylene;

2) -(CH₂XR¹,

3) -(CH^-0-CH.-R¹, wherein

R¹ is -CH(ONO₂)R²;

R² is -CH₃ or C_1-4 alkyl; n is an integer from 1 to 6;

4) Y-R³, wherein

R³ is -CH(ONO₂)CH(ONO₂)R⁴;

R⁴ is selected from -CH₃, -CH₂CH₃ and -CH(CH₃)₂; Y is -(CH₂X _₄-(X)_{0 1}-(CH₂)_{0 4}, wherein X is -O- or -CR⁵R⁶-; and R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

5)Y-CH(ONO₂)CH₂(ONO₂), wherein Y is as above defined;

6)

wherein nl, n2, n3 and n4 are integers equal or different from one another, equal to 0 or 1; R⁷ and R⁸ are independently selected from H or CH₃;

Y¹ is -(CH₂)J- or -(CH₂)no-CH=CH- wherein n is as above defined and nO is an integer from 0 to 6, preferably nO is equal to 0;

X¹ is -O-, -S-, -SO-, -SO₂-, -OCO-, -SCO-, -OCOO-, -SCOO-, -0C0NH-,

-SCONH-; Z¹ has the same meanings of Z or

wherein:

R⁹ and R¹⁰ are independently selected from H or C₁-C₄ alkyl; n5 is an integer from O to 6; n4 and X¹ are as above defined; Z² is equal to Z;

Y² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and selected for example from

(Yl) (Y2) (Y3) (Y4) (Y5)

(YlO) (YI l) (Y12) (Y13)

,

(Y14) (Y15) or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 , wherein R is selected from the group consisting of (Ha)- (Hd):

(lie) (iid)

3. A compound of Claim 1, wherein R is selected from the group consisting of (Hg) and (Hh):

4. A compound of Claim 1 , wherein R is (Ha):

5. A compound of Claim 1, wherein Z is selected from the group consisting of:

and ONO, and stereoisomer thereof.

A compound of Claim 1, having the formula selected from the group consisting of

wherein Z is selected from the group consisting of:

7. A compound of Claim 1, having the formula selected from the group consisting of

wherein Z is selected from the group consisting of:

8. A compound of Claim 1, having the formula selected from the group consisting of

wherein Z is selected from the group consisting of:

9. A compound of Claim 1, having the formula selected from the group consisting of

wherein Z is selected from the group consisting of:

10. A compound of Claim 1, having the formula selected from the group consisting of

wherein Z is selected from the group consisting of:

11. A pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound of Claim 1, a diuretic, and a pharmaceutically acceptable carrier.

13. A method for treating hypertension in a patient which comprises administering to the patient a therapeutically effective amount of the composition of Claim 11.