Dipyridamole Chemical Properties

Melting point:

165-166 °C (lit.)

Boiling point:

593.96°C (rough estimate)

Density 

1.2046 (rough estimate)

refractive index 

1.6910 (estimate)

storage temp. 

room temp

solubility 

DMSO: soluble

form 

powder

pka

pKa 6.4 (Uncertain)

color 

yellow

Water Solubility 

Soluble in chloroform, methanol, dilute acids, ethanol. Slightly soluble in water.

Merck 

14,3346

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.

NIST Chemistry Reference

Pyrimidine, 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimido-(5,4-d)-(58-32-2)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26-36

WGK Germany 

2

RTECS 

KK7450000

HS Code 

29335990

Toxicity

LD50 in rats: 8.4 g/kg orally; 208 mg/kg i.v. (Takenaka)

MSDS

• Language:English Provider:2,6-Bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]pyrimidin
• Language:English Provider:SigmaAldrich

Dipyridamole Usage And Synthesis

Description

Dipyridamole (58-32-2) is a phosphodiesterase inhibitor (IC50=0.37, 0.38, 0.45, 0.9 and 4.5 μM for PDE11, 6, 10, 5 and 8 respectively.1,2 Potent equilibrative nucleoside transporter 1 (ENT1) inhibitor Ki=8.2 nM vs. 144.8 nM for ENT1 and ENT2 respectively.3 Antiplatelet activity.4

Chemical Properties

Yellow Powder

Originator

Persantine,Boehringer Ingelheim,US,1961

Uses

Dipyridamole prevents platelets sticking to the replacement heart valve and causing a blood clot on the valve. It is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease. This compound has been shown to suppress high glucose-induced osteopontin mRNA expression and protein secretion, as well as inhibit cAMP and cGMP hydrolysis. Research indicates that Dipyridamole is a non-specific nucleoside transport inhibitor with the ability to increase the effects of adenosine in sinoatrial and atrioventricular nodes. Dipyridamole is an inhibitor of ENT1 and ENT2.

Uses

Selective inhibitor of phosphodiesterase V (PDE 5); potent coronary vasodilator drug; adenosine transport inhibitor; inhibitor of platelet aggregation

Uses

A phosphodiester, cGMP, and non-specific nucleoside transport inhibitor

Uses

Dipiridamol is known as a coronary vasodilating agent, although it also possesses specific antiaggregant activity. It is used for preventing thrombo-formation after cardiac valve replacement in combination with warfarin.

Definition

ChEBI: A pyrimidopyrimidine that is 2,2',2'',2'''-(pyrimido[5,4-d]pyrimidine-2,6-diyldinitrilo)tetraethanol substituted by piperidin-1-yl groups at positions 4 and 8 respectively. A vasodilator agent, it inhibits the formation of blood clots.

Manufacturing Process

Urea may be reacted with acetoacetic ester and that product nitrated to give 5-nitro-orotec acid. That is hydrogenated, then reacted with urea and potassium cyanate to give tetrahydroxypyrimidopyrimidine. The tetrahydroxy compound is converted to the tetrachloro compound POCl3. Reaction with diethanolamine and then with piperidine gives dipyridamole.

brand name

Persantine (Boehringer Ingelheim).

Therapeutic Function

Coronary vasodilator

General Description

Dipyridamole, 2,2',2',2'''-[(4,8-di-1piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-tetrakisethanol (Persantine), may be used for coronary andmyocardial insufficiency. Its biggest use today, however, isas an antithrombotic in patients with prosthetic heart valves.It is a bitter, yellow, crystalline powder, soluble in diluteacids, methanol, or chloroform. A formulation containingdipyridamole and aspirin (Aggrenox) is currently beingmarketed as an antithromobotic.
Dipyridamole is a long-acting vasodilator. Its vasodilatingaction is selective for the coronary system; it is indicatedfor long-term therapy of chronic angina pectoris. Thedrug also inhibits adenosine deaminase in erythrocytesand interferes with the uptake of the vasodilator adenosineby erythrocytes. These actions potentiate the effect ofprostacyclin (PGI₂), which acts as an inhibitor to plateletaggregation.

Biological Activity

Coronary vasodilator; adenosine transport inhibitor. Phosphodiesterase inhibitor (IC 50 values are 0.37, 0.38, 0.45, 0.9 and 4.5 μ M? for PDE11, 6, 10, 5 and 8 respectively).

Biochem/physiol Actions

Selective inhibitor of phosphodiesterase V (PDE 5); potent coronary vasodilator drug; adenosine transport inhibitor; inhibitor of platelet aggregation.

Mechanism of action

Dipyridamole exerts its antiplatelet function by increasing cellular concentrations of cAMP via its inhibition of the degradating enzyme, cyclic nucleotide PDE3. It also blocks adenosine uptake, which acts at A2 adenosine receptors to stimulate platelet adenyl cyclase. Less common uses for this drug include inhibition of embolization from prosthetic heart valves when used in combination with warfarin (the only currently recommended use) and reduction of thrombosis in patients with thrombotic disease when used in combination with aspirin. Alone, dipyridamole has little, if any, benefit in the treatment of thrombotic conditions.

Clinical Use

Dipyridamole is a pyrimidopyrimidine derivative with vasodilatory and antiplatelet properties.

Safety Profile

Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion and subcutaneous routes. Human systemic effects cardiomyopathy including infarction. Mutation data reported. Used as a coronary vasodilator. When heated to decomposition it e

Synthesis

Dipyridamole, 2,2',2'',2'''-[(4,8-dipiperidinopirimido[5,4-d]pirimidin-2,6- diyl)-diimino]-tetraethanol (19.4.13), is easily synthesized from 5-nitroorotic acid (19.4.8), easily obtained, in turn, by nitrating of 2,4-dihydroxy-6-methylpyrimidine, which is usually synthesized by the condensation of urea with acetoacetic ether. Reduction of the nitro group in 5-nitroorotic acid by various reducing agents gives 5-aminoorotic acid (19.4.9), which is reacted with urea or with potassium cyanide to give 2,4,6,8- tetrahydroxypyrimido[5,4-d]pyrimidine (19.4.10). This undergoes a reaction with a mixture of phosphorous oxychloride and phosphorous pentachloride, which forms 2,4,6,8- tetrachloropyrimido[ 5,4-d]pyrimidine (19.4.11). Reacting the resulting tetrachloride with piperidine replaces the chlorine atoms at C4 and C8 of the heterocyclic system with piperidine, giving 2,6-dichloropyrimido-4,8-dipiperidino[5,4-d]pyrimidine (19.4.12). Reacting the resulting product with diethanolamine gives dipyridamole (19.4.13).

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: effects of adenosine enhanced and extended.
Anticoagulants: anticoagulant effect of coumarins, phenindione and heparin enhanced.

Metabolism

Dipyridamole is metabolised in the liver. Renal excretion of the parent compound is negligible (< 0.5%). Urinary excretion of the glucuronide metabolite is low (5%), the metabolites are mostly (about 95%) excreted via the bile into the faeces, with some evidence of entero-hepatic recirculation.

storage

Store at RT

References

1) Fujishige et al. (1999), Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A); J. Biol. Chem., 274 18438 2) Soderling et al. (1998), Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase; Proc. Natl. Acad. Sci. USA, 95 8991 3) Lin and Buolamwini (2007), Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibitors.; J. Med. Chem., 50 3906 4) Coccheri (2010), Antiplatelet drugs – do we need new options? With a reappraisal of direct thromboxane inhibitors; Drugs, 70 887

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