65141-46-0

Basic information

• Product Name: Nicorandil
• Synonyms: n-[2-(nitroxy)ethyl]-3-pyridinecarboxamide;N-[2-(NITROOXY)ETHYL]-3-PYRIDINECARBOXAMIDE;NICORANDIL;PERISALOL;SIGMART;IKOREL;ADANCOR;2-nicotinamidoethylnitrate
• CAS NO: 65141-46-0
• Molecular Formula: C₈H₉N₃O₄
• Molecular Weight: 211.17
• EINECS: 265-514-1
• Product Categories: Pharmaceutical;Intermediates & Fine Chemicals;Pharmaceuticals;Potassium channel;Aromatics;Heterocycles;Ikorel;reagent;Cardiovascular APIs
• Mol File: 65141-46-0.mol

Chemical Properties

• Melting Point: 92°C
• Boiling Point: 350.85°C (rough estimate)
• Flash Point: 230 °C
• Appearance: white to off-white/
• Density: 1.4271 (rough estimate)
• Vapor Pressure: 1.58E-08mmHg at 25°C
• Refractive Index: 1.7400 (estimate)
• Storage Temp.: Desiccate at +4°C
• Solubility: DMSO: >10mg/mL
• PKA: pKa 空 (Uncertain)
• Merck: 14,6521
• CAS DataBase Reference: Nicorandil(CAS DataBase Reference)
• NIST Chemistry Reference: Nicorandil(65141-46-0)
• EPA Substance Registry System: Nicorandil(65141-46-0)

Safety Data

• Hazard Codes: Xn
• Statements: 22-41
• Safety Statements: 26-39
• WGK Germany: 3
• RTECS: US4667600
• Hazardous Substances Data: 65141-46-0(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Medicine:
Nicorandil is used as a prophylactic and therapeutic agent for angina, a condition characterized by chest pain due to insufficient blood flow to the heart. Its vasodilating properties help alleviate the symptoms of angina by improving blood circulation and oxygen supply to the heart muscle.
Used in Cardiac Protection:
Nicorandil is used as a cardioprotective agent, particularly in the context of ischemia and reperfusion injury. A study has demonstrated that Nicorandil can protect against stress-induced cell death in dystrophin-deficient cardiomyocytes and preserve cardiac function in the mdx mouse heart subjected to ischemia and reperfusion injury.

Preparation

Nicorandil is obtained by treating nicotinic acid chloride hydrochloride with nitro-oxy-ethyl-amine nitrate in an organic solvent.Nicorandil was synthesized from 2-aminoethanol by a four step process. In order to protect the amino group during nitration, 2-aminoethanol was first treated with phthalic anhydride. The amide formed was then nitrated using a nitrating mixture and was subsequently deprotected by reacting with hydrazine hydrate. The 2- nitroxyethylamine obtained was condensed with nicotinoyl chloride in pyridine. Treatment with aqueous sodium bicarbonate solution gave nicorandil as free base.synthesis of Nicorandil

Biochem/physiol Actions

Nicorandil is a hybrid ATP-sensitive K+ (KATP) channel opener and nicotinamide nitrate NO donor. Nicorandil selectively activates SUR2B- versus SUR2A-containing KATP channels. It enhances endothelial NO synthase expression and protects against ischemic ventricular arrhythmias. By activating potassium channels, and donating nitric oxide to activate the enzyme guanylate cyclase, Nicorandil causes activation of GMP leading to both arterial and venous vasodilatation. Nicorandil is selective for vascular potassium channels, but has no significant action on cardiac contractility and conduction.

Clinical Use

Nicorandil is used for the prevention and treatment of chronic stable angina. It is usually used when angina becomes difficult to control by other drugs and is given as an additional treatment.

Drug interactions

Potentially hazardous interactions with other drugs Avanafil, sildenafil, tadalafil and vardenafil: enhanced hypotensive effect - avoid. Riociguat: possible enhanced hypotensive effect - avoid.

Metabolism

Metabolism of nicorandil is mainly by denitration of the molecule into the nicotinamide pathway. About 20% of a dose is excreted in the urine mainly as metabolites

Mode of action

The coronary vasodilating activity of nicorandil is considered to be the consequence of the increasing cyclic GMP production by stimulating guanylyl cyclase in the coronary vascular smooth muscle, similar to other nitrates/nitrites (in vitro). In addition, other mechanisms such as hyperpolarization of the cell membrane were investigated concerning its coronary blood flowincreasing and coronary vasospasmolytic effects.The vasorelaxant effect of nicorandil in isolated blood vessels is suppressed by an ATP-sensitive K channel blocker or a guanylate cyclase inhibitor. Moreover, in a canine model of acute heart failure, the cardiac haemodynamics-improving effect of the drug (e.g. effect of increasing the aortic blood flow) was suppressed by an ATP-sensitive K channel blocker. Furthermore, the drug caused an increase in the cGMP content in isolated blood vessels. These facts suggest that the vasodilating effect of the drug is related to the effect of opening the ATP-sensitive K channel, as well as to the effect of increasing production of cGMP.

InChI:InChI=1/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12)

Synthetic route

N-(2-hydroxyethyl)nicotinamide (6265-73-2) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With nitric acid; urea; europium(III) trifluoromethanesulfonate at 70℃; for 6h; Schlenk technique;	86%
With nitric acid; propionic acid; propionic acid anhydride at 0 - 30℃; for 3.5h; Temperature;	85.9%
With nitric acid at -5℃; for 2h;	40%
Stage #1: N-(2-hydroxyethyl)nicotinamide With nitric acid; acetic anhydride; acetic acid at 15 - 22℃; Inert atmosphere; Stage #2: With ammonia In water at 5 - 35℃; for 1h; Product distribution / selectivity;

2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) + isopentyl nitrite (110-46-3) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
In 1,4-dioxane at 100℃; for 5h;	80%

2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With tert.-butylnitrite; oxygen In 1,4-dioxane at 60℃; Sealed tube; Green chemistry;	73%

tert.-butylnitrite (540-80-7) + 2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
In toluene at 100℃; for 5h;	60%

pyridine-3-carbonyl chloride hydrochloride (20260-53-1) + 2-nitroxyethylammonium nitrate (4665-58-1) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
With pyridine at 5 - 20℃; Inert atmosphere;
Stage #1: pyridine-3-carbonyl chloride hydrochloride; 2-nitroxyethylammonium nitrate With pyridine at 5 - 20℃; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In chloroform

3-pyridinecarboxylic acid ethyl ester (614-18-6) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 18 h / 20 - 55 °C 2: nitric acid / 2 h / -5 °C View Scheme

pyridine-3-carbonitrile (100-54-9) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: zinc(II) chloride / chlorobenzene / 36 h / Inert atmosphere; Reflux 2: tert.-butylnitrite; oxygen / 1,4-dioxane / 60 °C / Sealed tube; Green chemistry View Scheme

3-pyridinecarboxaldehyde (500-22-1) → N-(2-nitroxyethyl)nicotinamide (65141-46-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetra-N-butylammonium tribromide / ethanol / 1 h / 20 °C 2: 1,4-dioxane / 5 h / 100 °C View Scheme

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + salicylic acid (69-72-7) → C8H9N3O4*C7H6O3

Conditions	Yield
In water; acetonitrile Solvent;	95%
In water at 20℃; for 48h;	55.9%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + N-(2-nitroxyethyl)isonicotinamide (65141-47-1) + palladium dichloride → trans-[(2-nitroxyethyl)isonicotinamide-N'][(2-nitroxyethyl)nicotinamide-N]dichloropalladium(II)

Conditions	Yield
With conc. HCl In ethanol; water aq. soln. of PdCl2 added to a soln. of equimolar amts. of the ligands ina mixt.of EtOH:H2O (3:1) at 20-30°C; then conc. HCl added to pH 2-2.5; stirred for 2 h; ppt. filtered off, washed with water and EtOH, and dried in air; elem. anal.;	94%

potassium tetrachloroplatinate(II) (10025-99-7) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → PtCl2(C8H9N3O4)2 (203808-46-2)

Conditions	Yield
In water ppt. washing (H2O, EtOH, Et2O); elem. anal.;	92%

rhodium(II) pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → [(NC5H4C(O)NHCH2CH2ONO2)2Rh2(OOCC(CH3)3)4] (186506-79-6)

Conditions	Yield
In tetrahydrofuran room temperature, pure Ar atmosphere; soln. evapn. to 1/3, crystals filtration off, air drying, recrystn. (THF); elem. anal.;	90%

iodomethyl isopropylcarbamate (1402915-01-8) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridine-1-ium iodide (1402916-59-9)

Conditions	Yield
In acetonitrile at 20℃;	88%
In acetonitrile at 20℃;	88%

sodium tetrachloroplatinate(II) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) + N-(2-nitroxyethyl)isonicotinamide (65141-47-1) → trans-[(2-nitroxyethyl)isonicotinamide-N'][(2-nitroxyethyl)nicotinamide-N]dichloroplatinum(II) (365515-47-5)

Conditions	Yield
In ethanol; water aq. soln. of Pt complex added to a soln. of equimolar amts. of the ligands in 60% aq. EtOH at 20-30°C; stirred for 11 h; ppt. filtered off, washed with water and EtOH, and dried in air; elem. anal.;	86%

iodomethyl diisopropylcarbamate (353736-55-7) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	85%

iodomethyl 1-piperidinyl carbamate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 3-((2-(nitrooxy)ethyl)carbamoyl)-1-(((piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	84%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + ethoxycarbonyloxymethyl iodide (82619-14-5) → 1-(((ethoxycarbonyl)oxy)methyl)-3 -((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	77%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + 1-hydroxy-2-naphthoic acid (86-48-6) → nicorandil 1-hydroxy-2-naphthoic acid

Conditions	Yield
In water at 20℃; for 48h;	75.8%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + copper(ll) bromide (7789-45-9) → (NC5H4C(O)NHCH2CH2ONO2)2CuBr2 (186506-76-3)

Conditions	Yield
In tetrahydrofuran pure Ar atmosphere, stirring (3 h), volume reduction (30-40°C, 0.1 torr), cooling to 5°C; ppt. washing (CH2Cl2), vacuum drying, recrystn. (2x, THF); elem. anal.;	70.5%

copper(II) pivalate dimer + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → [(NC5H4C(O)NHCH2CH2ONO2)2Cu2(OOCC(CH3)3)4] (186506-77-4)

Conditions	Yield
In tetrahydrofuran; benzene THF soln. of ligand addn. to benzene soln. of Cu-compd., pure Ar atmosphere; volume redn., recrystn. (THF); elem. anal.;	70%

isopropyloxycarbonyloxymethyl iodide (258841-42-8) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	60%

2,5-dihydroxybenzoic acid. (490-79-9) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → C7H6O4*C8H9N3O4

Conditions	Yield
In water at 20℃; for 48h;	54.7%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + tert-butyl (iodomethyl) carbonate (184373-03-3) → 1-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
	54%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + 3-Carboxyphenol (99-06-9) → C7H6O3*C8H9N3O4

Conditions	Yield
In water at 20℃; for 48h;	42%

[Ni9(HOOCCMe3)4(μ4-O)3(μ3-OH)3(μ-O,O-OOCCMe3)(μ-O,O'-OOCCMe3)7(μ3-O,O,O'-OOCCMe3)3(μ4-O,O,O',O'-OOCCMe3)] + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (C5H4NC(O)NHCH2CH2ONO2)4Ni2((CH3)3CCOO)4(OH)*C4H8O*2H2O

Conditions	Yield
In toluene stirring (20°C, 0.5 h); evapn., extn. (THF/benzene), crystn. (5°C); elem. anal.;	40%

1-iodoethyl diisopropylcarbamate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(1-((diisopropylcarbamoyl)oxy)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium iodide

Conditions	Yield
In acetonitrile at 20℃;	35%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) + methyl iodide (74-88-4) → 1-(2-(nicotinamido)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridine-1-indole iodide

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 336h; pH=7.0 - 9.0; Solvent; Cooling with ice;	2.25%

methyl bromide (74-83-9) + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 1-(2-(nicotinamido)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridine-1-indole iodide

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide for 240h; pH=7.0 - 9.0; Darkness;	1.9%

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 2-(pyridin-3-yl)-4,5-dihydrooxazole (40055-37-6)

Conditions	Yield
In sodium hydroxide at 60℃; for 5h;	60 mg
at 60℃; for 7h; Rate constant; Mechanism; Thermodynamic data; variation of pH; Δ Eexcit;

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → 2-aminoethyl nicotinate nitrate (88598-33-8)

Conditions	Yield
With water at 70℃; for 4h;	40 mg

N-(2-nitroxyethyl)nicotinamide (65141-46-0) → Polymer, M.w. 30,000-50,000; Monomer(s): N-(2-nitroxyethyl)nicotinamide + Polymer, M.w. 1000; Monomer(s): 2-(3-pyridyl)-4,5-dihydrooxazole

Conditions	Yield
at 70℃; for 72h; Polymerization;

cobalt pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (nicorandil)Co(μ-OOCCMe3)4Co(nicorandil) (251911-24-7)

Conditions	Yield
In tetrahydrofuran; toluene THF soln. of ligand addn. to THF soln. of Co-compd., boiling (15 min), solvent complete removal, residue dissoln. in boiling toluene, volume reduction (Ar flow), slow cooling to room temperature; ppt. sepn., washing (hexane), drying (Ar flow, room temperature);

cobalt pivalate + N-(2-nitroxyethyl)nicotinamide (65141-46-0) → (nicorandil)2(OOCCMe3)Co(μ-OH2)(μ-OOCCMe3)2Co(OOCCMe3)(nicorandil)2

Conditions	Yield
In water soln. of ligand addn. to soln. of Co-compd., soln. keeping at room temperature (5 d); solvent removal; elem. anal.;

Upstream product

• 614-18-6 3-pyridinecarboxylic acid ethyl ester 
• 40055-37-6 2-(pyridin-3-yl)-4,5-dihydrooxazole 
• 100-54-9 pyridine-3-carbonitrile 
• 500-22-1 3-pyridinecarboxaldehyde 
• 110-46-3 isopentyl nitrite 
• 540-80-7 tert.-butylnitrite 
• 6265-73-2 N-(2-hydroxyethyl)nicotinamide 
• 20260-53-1 pyridine-3-carbonyl chloride hydrochloride 
• 4665-58-1 2-nitroxyethylammonium nitrate 

Downstream Products

• 40055-37-6 2-(pyridin-3-yl)-4,5-dihydrooxazole 
• 65141-45-9 nicorandil hydrochloride 

Relevant articles and documents

Preparation method of Nicodil

The invention discloses a preparation method of Nicorandil, the preparation method comprises the following steps: directly synthesizing N-(2-ethoxyl) nicotinamide by taking nicotinamide as an initial raw material through a transamidation method, and nitrifying by using a mixture of non-fuming nitric acid, acetic anhydride and concentrated sulfuric acid to obtain Nicorandil. The method simplifies the existing synthesis process, is easy and convenient to operate and is more suitable for large-scale production; meanwhile, the yield of products obtained in each step of reaction is increased, the types and the dosage of reaction reagents are greatly reduced, and the production cost is lower. The technical problems of more reaction steps, high reagent consumption, low production efficiency, serious environmental pollution, poor quality of the prepared product and low yield of the existing preparation process are solved.

Nicorandil preparation method

The invention discloses a nicorandil preparation method, which comprises the following steps: synthesis of 3-pyridyloxazolidine: under stirring, adding aminoethanol and a solid bromination reagent into an alcoholic solution of 3-pyridylaldehyde, stirring at room temperature until the 3-pyridylaldehyde is completely consumed, quenching the reaction system with a saturated sodium thiosulfate solution, extracting with ethyl acetate, and concentrating the organic phase to obtain a crude product 3-pyridyloxazolidine; and synthesis of nicorandil: dissolving the 3-pyridyloxazolidine in a solvent, adding nitrite, heating, introducing an oxygen-containing gas, stirring until the 3-pyridyloxazolidine is completely consumed, quenching with a saturated sodium sulfate solution, extracting with ethyl acetate, concentrating, adding the crude product into a 30% ethyl acetate n-hexane solution until dissloving, cooling to 10 DEG C, precipitating a solid, and filtering to obtain the nicorandil.

Practical catalytic nitration directly with commercial nitric acid for the preparation of aliphatic nitroesters

To pursue a sustainable and efficient approach for aliphatic nitroester preparation from alcohol, europium-triflate-catalyzed nitration, which directly uses commercial nitric acid, has been successfully developed. Gram scalability with operational ease showed its practicability.

Preparation method of nicorandil

The invention discloses a preparation method of nicorandil. According to the method, N-(2-hydroxyethyl)niacinamide is used as a raw material and is subjected to nitrifying under the actions of dilutenitric acid, propionic acid and propionic anhydride to obtain nicorandil. The method has the advantages of mild conditions, simple operation, stable process, cheap and easily available raw materials,high product yield, easy treatment of three wastes, small environmental pollution, and suitability for industrial large-scale production.

Highly efficient synthesis of β-nitrate ester carboxamides through the ring-opening of 2-oxazolines

A novel method for the synthesis of β-nitrate ester carboxamides using non-corrosive tert-butyl nitrite (TBN) as the nitro source and easily available oxygen as the oxidant has been developed. Variously substituted 2-oxazolines were efficiently ring-opened to deliver the corresponding products in excellent yields. Notably, this reaction provides fast access to pharmaceuticals such as nicorandil.

Synthesis, antinociceptive activity and pharmacokinetic profiles of nicorandil and its isomers

Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K+ channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.

Electronic device

PROBLEM TO BE SOLVED: To avoid breakage and display failure of a display panel when strong pressure is applied to an exterior member by releasing the charge adhering to the display panel to the ground level. SOLUTION: This electronic device includes the display panel 6 arranged between a conductive chassis 10 and exterior members 1 and 2, frames 5 and 8 that are made of conductive material and hold the display panel 6, and a reinforcement member 9 that is arranged along the outer periphery of the frames and abuts on the exterior member on the exterior member side of the display panel and frames. The frames have an extending section 8a gripped between the chassis and the reinforcement member. The chassis has a projection 10b, and the reinforcement member and the projection have engaging mechanisms 9a and 10a. The reinforcement member is arranged along the outer periphery of the frames in an elastically deformed state, and holds the engagement of the engaging mechanisms with a force caused by the elastic deformation. An elastic member 4 for pressing the frames onto the chassis is arranged between the exterior member and the frames. COPYRIGHT: (C)2010,JPOandINPIT

PROCESS FOR THE MANUFACTURE OF NICORANDIL

Disclosed is a process for the synthesis of Nicorandil (1), 2-(nicotinamide)ethyl nitrate, starting from N-(2-hydroxyethyl)nicotinamide (15), using nitration with nitric acid in the presence of acetic anhydride Said synthesis method is particularly advantageous because it solves the safety problems involved in the use of nitric acid as nitrating agent, and allows a product with excellent yields and quality to be isolated.

N'-NITROXYALKYLNICOTINAMIDES FOR THE TREATMENT OF CARDIOVASCULAR DISEASES

The invention relates to the novel N′-nitroxyalkylnicotinamide derivatives represented by the general formula I wherein R1 is C1-C4 alkyl; R2 is hydrogen. C1-C4 alkyl, CH2OH or CH2ONO2; R3 is ONO2, CH2ONO2 or OH; provided that when R3 is OH, R2 is CH2ONO2; and X? is an organic or inorganic anion; as well as pharmaceutical compositions thereof and their use as a medicament, in particular, in the treatment of diseases of the cardiovascular system.

N'-NITROXYALKYLNICOTINAMIDES FOR THE TREATMENT OF CARDIOVASCULAR DISEASES

The invention relates to the novel N'-nitroxyalkylnicotinamide derivatives represented by the general formula (I) wherein R1 is C1C4 alkyl; R2 is hydrogen, C1-C4 alkyl, CH2OH or CH2ONO2; R3 is ONO2, CH2ONO2 or OH; provided that when R3 is OH, R2 is CH2ONO2; and X- is an organic or inorganic anion; as well as pharmaceutical compositions thereof and their use as a medicament, in particular, in the treatment of diseases of the cardiovascular system.