Anagrelide hydrochloride

Bezeichnung:Anagrelide hydrochloride

CAS-Nr58579-51-4

Englisch Name:Anagrelide hydrochloride

CBNumberCB8722913

SummenformelC10H8Cl3N3O

Molgewicht292.55

MOL-Datei58579-51-4.mol

Anagrelide hydrochloride physikalisch-chemischer Eigenschaften

Schmelzpunkt	>280°C
storage temp.	2-8°C
Löslichkeit	DMSO: soluble1mg/mL, clear (warmed)
Aggregatzustand	powder
Farbe	white to beige
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChI	InChI=1S/C10H7Cl2N3O.ClH/c11-6-1-2-7-5(9(6)12)3-15-4-8(16)14-10(15)13-7;/h1-2H,3-4H2,(H,13,14,16);1H
InChIKey	TVWRQCIPWUCNMI-UHFFFAOYSA-N
SMILES	C12C(Cl)=C(C=CC=1N=C1NC(=O)CN1C2)Cl.Cl
CAS Datenbank	58579-51-4(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	Xn
R-Sätze:	22-36/37/38
S-Sätze:	26
WGK Germany	3
Speicherklasse	11 - Combustible Solids
Hazard Classifications	Aquatic Chronic 4 Carc. 2 Repr. 2

Gefahreninformationscode (GHS)

Anagrelide hydrochloride Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Anagrelide hydrochloride was launched in the US for thrombocytosis (essential or associated with chronic myelogenous leukemia). The imidazoquinazoline derivative can be prepared from 2,5,6-trichloro-3,4-dihydropyrimidine via alkylation with ethyl bromoacetate followed by heating with ethanolic ammonia or treatment of N-(a-amino- 5,6-dichlorobenzyl)glycine ethyl ester with cyanogen bromide. As a result of its anti-cAMP phosphodiesterase (PDE Ⅲ) activity, Anagrelide hydrochloride was initially tested as a platelet aggregation inhibitor. However it was found that at much lower concentrations it became thrombocytopenic. While the mechanism is not fully understood, it did not shorten platelet survival nor inhibit the formation of colony-forming unitsmegakaryocytes (CFU-M) but primarily interfered with the maturation of megakaryocytes (reduction in size with altered ploidy). It did decrease peripheral vascular resistance and had a positive inotropic effect.
Chemische Eigenschaften
Off-White Powder
Originator
Roberts (US)
Verwenden
Anagrelide Hydrochloride is a phosphodiesterase inhibitor with antiplatelet activity. Used as an antithrombocythemic. Potent PDE3 inhibitor.
Verwenden
Signal Transduction Agents, Potent PDE3 inhibitor
Definition
ChEBI: The hydrochloride salt of anagrelide.
Manufacturing Process
6,7-Dicloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinozolin-2-one by substitution the bromine an equimolar quantity chlorine.
6-Chloro-7-bromo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced next way: to a solution of 1.30 g (8 mmole) of anhydrous ferric chloride in 30 ml of nitromethane was added 1.30 g (5 mmole) of solid 6- chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one and 0.80 g (5 mmole) of bromine. The system was stoppered, warmed to 50°C in an oil bath overnight, cooled to room temperature and the solvent removed in vacuo. The resulting solid was suspended in water (50 ml), the mixture was made basic (pH=10) with sodium bicarbonate and stirred at home temperature for 20 min. The solid was filtered under suction, washed with water, then isopropyl alcohol and dried yielding 1.19 g of 6-chloro-7-bromo- 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one (78% yield). Purification was effected by formation of the hydrochloride salt (mp 275°C) from acetonitrile.
6-Chloro-1,2,3,5,-tetrahydroimidazo[2,1-b]quinazolin-2-one was produced from 6-chloro-2-nitrobenzylchloride, ethylglycine hydrochloride and cyanogen bromide in 3 steps.
Trademarks
Agrylin (Shire).
Therapeutic Function
Platelet aggregation inhibitor
Allgemeine Beschreibung
Anagrelide belongs to the imidazo[2,1-b]quinazolin-2-one series of compounds.
Biologische Aktivität
Potent type III phosphodiesterase (PDE3) inhibitor (IC 50 = 36 nM). Inhibits platelet aggregation and produces potent thrombocytopenic effects via inhibition of megakaryocyte maturation.
Biochem/physiol Actions
Anagrelide is a phosphodiesterase inhibitor with antiplatelet activity (IC50 = 36 nM for inhibition of phosphodiesterase-III). Anagrelide inhibits the maturation of megakaryocytes into platelets, reducing both megakaryocyte hyperproliferation and differentiation. As a drug, anagrelide is antithrombocythemic used for the treatment of overproduction of blood platelets.
Einzelnachweise
[1] GILLESPIE E. Anagrelide: A potent and selective inhibitor of platelet cyclic AMP phosphodiesterase enzyme activity[J]. Biochemical pharmacology, 1988, 37 14: Pages 2866-2868. DOI:10.1016/0006-2952(88)90054-8
[2] E M MAZUR. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans.[J]. Blood, 1992, 79 8: 1931-1937.
[3] GUOSU WANG. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures[J]. British Journal of Pharmacology, 2009, 146 3: 324-332. DOI:10.1038/sj.bjp.0706341
[4] TIZIANO BARBUI Guido F Maria Chiara Finazzi. Front-line therapy in polycythemia vera and essential thrombocythemia[J]. Blood Reviews, 2012, 26 5: Pages 205-211. DOI:10.1016/j.blre.2012.06.002
[5] YU-GUANG CHEN. Platelet-lowering therapy with anagrelide as an adjuvant therapy for treatment of primary pulmonary neoplasm-associated extreme thrombocytosis.[J]. Japanese journal of clinical oncology, 2012, 42 8: 761-763. DOI:10.1093/jjco/hys087

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