Praziquantel

Preparation of2-(N-Phthalimidoacetyl-N-Cyclopropylmethyl)-Amino-5-Chlorobemophenone To a solution of 36.0 g (0.126 mol) of 2-cyclopropylmethylamino-5-chlorobenzophenone in 500 ml of tetrahydrofuran is added 50.7 g (0.252 mol) of phthalimidoacetyl chloride. 

The resulting solution is refluxed for 16 to 24 hours, the solvent removed under vacuum, the residual oil crystallized from 200 ml of ethanol and recrystallized from 500 ml of 80% ethanol-20% tetrahydrofuran giving 44.7 g of 2-(N-phthalimidoacetyl-N-cyclopropylmethyl)-amino-5-chlorobenzophenone, MP 163 to 164°C (75% yield). 

To a solution of 39.5 g (0.0845 mol) of 2-(N-phthalimidoacetyl-N-cyclopropylmethyl)amino-5-chlorobenzophenone in a mixture of 423 ml of chloroform and 423 ml of ethanol Is added 9.52 g (0.1903 mol) of hydrazine hydrate and 9.52 ml of water. This solution is allowed to stand at room temperature. In 3 hours a precipitate begins to form in the solution. After standing 16 to 24 hours a voluminous pulpy white precipitate forms. The solvents are removed under vacuum while keeping the temperature under 40 0 and the residue is partitioned between dilute ammonia water and ether. 

The aqueous layer Is separated and washed with ether, the ether extracted with 5% hydrochloric acid, the acidic solution is made basic with 10% sodium hydroxide and again extracted with ether. Since some spontaneous crystallization occurs in the ether, the solvent is removed without drying under vacuum and the residue is recrystallized from 35 ml of ethanol giving 18.0 g of 1-cyclopropylmethyl-5-phenyl-7-chloro-1 H-1,4-benzodiazepine-2(3H)-one, MP 145° to 146°C (65% yield), according to U.S. Patent 3,192,199. 

Chemical Name 2-(Cyclohexylcarbonyl)-1,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,Ta] Iso-quinolin-4-one 

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More then a dozen representatives of the above ring systems were introduced into the human therapy. Actisomide (2) and trequinsin (3) are used as antiarrhytmic and antihypertensive agents, respectively. Sunepitron (4), a a 2-adrenoceptor antagonist, is under clinical trials for the treatment of anxiety and depression. Representatives of the third generation of antibacterial quinolone-3-carboxylic acids the blockbluster ofloxacin (5), its levorotatory enantiomer, levofloxacin (6), and rufloxacin (7) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (8) is under development. Praziquantel (9) is widely applied for the treatment of schistosomes- and cestode-caused infection in both veterinary and human therapies (Scheme 4). 

Vilsmeier formylation of praziquantel (9) with DMF-POCI3 at 60 °C for 5 h gave 2-cyclohexylcarbonyl-3-dimethyliminiummethylene-4-chloro-1,6,7,116-tetrahydro-2//-pyrazino[2,l-u]isoquinoline salt (01PHA146). 

Praziquantel (9) was prepared by the cyclization of 4-cyclohexylcarbonyl-l-phenethyl-2-oxo-l,2,3,4-tetrahydropyrazine in cone. H2SO4 at room temperature in quantitative yield (98H(48)2279). 

One of the more interesting syntheses for the anthelmintic agent praziquantel (123)... 

Cyclomethycaine Oxyphencyclimine Tridihexethyl iodide Trihexyphenidyl HCl 2-Cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino[2,1 -a] isoquinoline Praziquantel... 

C2H3CIO2 79-11-8) see Acediasulfone Acefylline Adrafinil Adrenalone Carbocisteine Diodone Mefexamide Methoxsalen Modafinil Nitrofurantoin Pifoxime Praziquantel Propyliodone... 

C,7H, N20 93271-68-2) see Praziquantel l-cyclohexyl-5-(4-chlorobutyl)tetrazole (C, H C1N4 73963-42-5) see Cilostazol cyclohexylglyoxylic acid (CSH12O3 4354-49-8) see Cetiedil iV-cyclohexyl-AP-(2-hydroxyethyl)urea (C5HisN202 66929-46-2) see Lomustine... 

QH7N 119-65-3) see Fasudil Praziquantel 5-isoquinolinesulfonic acid (CjHiNO S 27655-40-9) see Fasudil isoquinoline-5-sulfonyl chloride... 

Figure 5.54 Structures of Praziquantel and its metabolites, cis- and fraw5-4-hydroxy-praziquantel. Reprinted from 7. Chromatogr., B, 708, Lerch, C. and Blaschke, G., Investigation of the stereoselective metabolism of Praziquantel after incubation with rat liver microsomes by capillary electrophoresis and liquid chromatography-mass spectrometry , 267-275, Copyright (1998), with permission from Elsevier Science.

The drug of choice for nematode infestations (hookworm, enterobiasis, and ascariasis) is mebendazole, while ivermectin is indicated for strongyloidiasis and praziquantel is indicated for tapeworms. 

Tapeworm infections (T. saginata and T. solium) are treated with praziquantel 5 to 10 mg/kg as a single dose (use the same dose for adults and pediatric patients).3 The treatment for cysticercosis and neurocysticercosis may include surgery, anticonvulsants (neurocysticercosis can cause seizures), and anthelmintic therapy. The anthelmintic therapy of choice is albendazole 400 mg twice daily for 8 to 30 days. The pediatric dose of albendazole is 15 mg/kg (maximum 800 mg) in two divided doses for 8 to 30 days. The doses for both adults and pediatric subjects can be repeated if necessary. Praziquantel is an alternative therapy.3... 

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