- GREEN CHEMISTRY SYNTHESIS OF THE MALARIA DRUG AMODIAQUINE AND ANALOGS THEREOF
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Methods are provided for a green chemistry one-pot synthesis of amodiaquine and amodiaquine analogs. The methods have a lower environmental impact, lower investment cost, reduced amounts of byproducts and impurities, and a shorter synthesis time, compared to current conventional synthesis methods. The methods reduce the total number of steps in the synthesis from four to five down to two, thereby simplifying production; and allow a reduced number of solvents and reagents to be used in production, thereby reducing the waste generated in the synthesis. The methods can reduce the waste to about 3-5 kilograms of waste generated per kilogram of product produced; and surprisingly improve the overall yield from 60-65% to greater than 90% as compared to the current conventional synthesis methods for amodiaquine and its analogs.
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Paragraph 0073; 0074
(2013/09/26)
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- The Effect of Fluorine Substitution on the Metabolism and Antimalarial Activity of Amodiaquine
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Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial which causes adverse side effects such as agranulocytosis and liver damage.The observed drug toxicity is believed to be related to the formation of an electrophilic metabolite, amodiaquine imine (AQQI), which can bind to cellular macro-molecules and initiate hypersensitivity reactions. 5'-Fluoroamodiaquine (5'-FAQ, 3), 5',6'-difluoroamodiaquine (5',6'-DIFAQ, 4), 2',6'-difluoroamodiaquine (2',6'-DIFAQ, 5), 2',5',6'-trifluoroamodiaquine (2',5',6'-TRIFAQ, 6) and 4'-dehydroxy-4'-fluoroamodiaquine (4'-deOH-4'-FAQ, 7) have been synthesized to assess the effect of fluorine substitution on the oxidation potential, metabolism, and in vitro antimalarial activity of amodiaquine.The oxidation potentials were measured by cyclic voltammetry, and it was observed that substitution at the 2',6'- and 4'-positions (2',6'-DIFAQ and 4'-deOH'4'-FAQ) produced analogues with significantly higher oxidation potentials than the parent drug.Fluorine substitution at the 2',6'-positions and 4'-position also produced analogues that were more resistant to bioactivation.Thus 2',6'-DIFAQ and 4'-deOH-4'-FAQ produced thioether conjugates corresponding to 2.17percent (SD: +/-0.27percent) and 0percent of the dose compared with 11.87percent (SD: +/-1.31percent) of the dose for amodiaquine.In general the fluorinated analogues had similar in vitro antimalarial activity to amodiaquine against the chloroquine resistant K1 strain of Plasmodium falciparum and the chloroquine sensitive T9-96 strain of P. falciparum with the notable exception of 2',5',6'-TRIFAQ (6).The data presented indicate that fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues ( 5 and 7) that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites.
- O'Neill, Paul M.,Harrison, Anthony C.,Storr, Richard C.,Hawley, Shaun R.,Ward, Stephen A.,Park, B. Kevin
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p. 1362 - 1370
(2007/10/02)
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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