Primaquine CAS 90-34-6
Introduction：Basic information about Primaquine CAS 90-34-6, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Primaquine Basic informationPharmacology and mechanism of action Indications Side effects Contraindications and precautions Interactions Preparations References
| Product Name: | Primaquine |
| Synonyms: | 4-amino-1-methylbutyl(6-methoxy-8-quinolyl)amine;N4-[6-Methoxy-8-quinolinyl]-1,4-pentanediamine;PRIMAQUIN;8-(4-AMINO-1-METHYLBUTYLAMINO)-6-METHOXYQUINOLINE;6-methoxy-8-(4-amino-1-methylbutylamino)quinoline;8-(4-amino-1-methylbutylamino)-6-methoxy-quinolin;n4-(6-methoxy-8-quinolinyl)-4-pentanediamine;primaquine |
| CAS: | 90-34-6 |
| MF: | C15H21N3O |
| MW: | 259.35 |
| EINECS: | 201-987-2 |
| Product Categories: | 90-34-6 |
| Mol File: | 90-34-6.mol |
Primaquine Chemical Properties
| Melting point | 25°C |
| Boiling point | bp0.2 175-179° |
| density | 1.0313 (rough estimate) |
| refractive index | 1.5600 (estimate) |
| storage temp. | Refrigerator |
| solubility | Chloroform (Slightly), Methanol (Slightly) |
| pka | pKa 3.74/9.99(H2O,t =25) (Uncertain) |
| form | Oil |
| color | Dark Yellow to Dark Orange |
| Water Solubility | 718.4g/L(25 ºC) |
| InChI | 1S/C15H21N3O/c1-11(5-3-7-16)18-14-10-13(19-2)9-12-6-4-8-17-15(12)14/h4,6,8-11,18H,3,5,7,16H2,1-2H3 |
| InChIKey | INDBQLZJXZLFIT-UHFFFAOYSA-N |
| SMILES | N(C(CCCN)C)c1c2ncccc2cc(c1)OC |
| CAS DataBase Reference | 90-34-6 |
| NIST Chemistry Reference | 1,4-Pentanediamine, n(4)-(6-methoxy-8-quinolinyl)-(90-34-6) |
Safety Information
| WGK Germany | WGK 3 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Repr. 2 |
| Hazardous Substances Data | 90-34-6(Hazardous Substances Data) |
| Toxicity | LD50 oral in mouse: 100mg/kg |
| Pharmacology and mechanism of action | Primaquine is active against primary exoerythrocytic stages of all malaria parasites. Primaquine is also effective against latent exoerythrocytic stages of P. vivax and P. ovale responsible for relapse. It possesses gametocytocidal activity against all four species of plasmodia which infect man and could theoretically be used to block malaria transmission. Primaquine has no effect on the erythrocytic stages of plasmodia unless toxic concentrations are achieved【1】. The mechanism of action of primaquine is unknown. |
| Indications | Primaquine is used for the radical treatment of P. vivax and P. ovale infections. It has also been used in large populations to avoid spread of chloroquine-resistant strains of falciparum malaria (through its gametocytocidal action). |
| Side effects | Primaquine is usually well tolerated in the therapeutic dosage of 15 mg base/day for 14 days, but abdominal pain and gastric distress are common if administered on an empty stomach [2] The severity of the gastrointestinal side effects are dose-related, and with larger doses, nausea and vomiting occurs. Rare effects include hypertension and cardiac arrhythmia [2]. The principal toxic effect of primaquine is haemolytic anaemia especially in patients with a deficiency of glucose-6-phosphate dehydrogenase (G6PD)[1]It is estimated that 200–300 million people have G6PD deficiency[3]. The acute haemolysis is seen after a latent phase of 1–3 days. Drug administration should be discontinued when a darkening of the urine (if possible check urine urobilinogen after 1–3 days) or a sudden decrease in haemoglobin levels occurs. The prognosis of this condition is good and specific treatment usually not needed [1]. In addition to haemolytic anaemia, primaquine can also cause methaemoglobinaemia and may rarely suppress bone marrow activity leading to leucopenia [2, 3]. |
| Contraindications and precautions | It is recommended not to use primaquine in patients with conditions affecting bone marrow function or on myelosuppressive medication [3]. |
| Interactions | In one study, the effect of primaquine has been studied on the metabolism of antipyrine. Primaquine (45 mg) given 2 hours before antipyrine (300 mg orally), increased antipyrinehalf-life (calculated from 0 to 24 hours) from a mean of 13 to 25 hours and decreased clearance from 3 to 1 l/h [4]. |
| Preparations | Available as primaquine phosphate: 26.3 mg phosphate equals 15 mg base. • Primaquine® (Zeneca) Tablets 13.2 mg. |
| References | 1. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Primaquine. In: Chemotherapy of Malaria, 2nd edn, edited by L.Bruce-Chwatt. Geneva: World Health Organization, pp. 61–63. 2. Primaquine. Martindale: The Extra Pharmacopoeia, 28th edn (1982). (London: Pharmaceutical Press), p. 404. 3. Primaquine. Therapeutic Drugs, edited by Sir Colin Dollery (1991). (London: Churchill Livingstone), pp. P209–P213. 4. Back DJ, Purba HS, Park BK, Ward SA, Orme ML’E (1983). Effect of chloroquine and primaquine on antipyrine metabolism. Br J Clin Pharmacol, 16, 497–502. |
| Chemical Properties | Viscous liquid. Boiling point 175-179°C (0.0266kPa), soluble in ether. Its phosphate (C15H21N3O-2H3PO4, [63-45-6]) is an orange-red crystalline powder. Melting point 197-198°C. Insoluble in chloroform or ether, soluble in water, aqueous solution shows acidic reaction. Odorless, bitter taste. |
| Uses | Antimalarial. |
| Uses | Primaquine is the most effective and most toxic drug from the whole series of known 8-aminoquinolines. It is generally used for treating exoerythrocyte forms of malaria causedby P. vivax and P. ovale. It also acts on the sexual forms of the plasmodia, which die in thehuman body upon using this drug. Primaquine is used for treating and preventing late relapses of 3- and 4-day malaria aswell as tropic malaria. Synonyms of this drug are avlon and others. |
| Uses | Primaquine is an intermediate in the synthesis of Primaquine-d3 Diphosphate (P733502). Primaquine-d3 Diphosphate is an isotope labelled Primaquine (P733500), which is an antimalarial. |
| Indications | Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanismby which 8-aminoquinolines exert their antimalarialeffects is thought to be through a quinoline–quinonemetabolite that inhibits the coenzyme Q–mediated respiratorychain of the exoerythrocytic parasite. |
| Definition | ChEBI: A N-substituted diamine that is pentane-1,4-diamine substituted by a 6-methoxyquinolin-8-yl group at N4 position. It is a drug used in the treatment of malaria and Pneumocystis pneumonia. |
| Brand name | Primaquine (Sanofi Aventis). |
| Antimicrobial activity | Primaquine is highly active against the hepatic stages of themalaria life cycle, including the latent hypnozoite stage of P.vivax. It has poor activity against erythrocytic stages of malariaparasites, other than gametocytes. The isomers have similarantiplasmodial activity but differ in toxicity. It exhibits activityagainst Pneumocystis jirovecii and, in experimental models,against Babesia spp. and the intracellular stages of Leishmaniaspp. and Trypanosoma cruzi. |
| Acquired resistance | Failure rates of up to 35% have been reported in South East Asiain patients treated with a standard course for P. vivax infections. |
| Pharmaceutical Applications | A synthetic 8-aminoquinoline, formulated as the diphosphatefor oral administration. |
| Mechanism of action | Moving the side chain from the fourth position of the quinoline ring to the eighth positioncompletely changes the compound’s spectrum of activity. Unlike the 4-substituted aminoquinolines, primaquine has practically no effect on erythrocyte forms of the malaria parasite. Its activity is limited to tissue forms of the parasite in mammals and in the mosquitoesthemselves. This makes primaquine an especially valuable drug, allowing radical recoveryand simultaneous prevention, which is usually not achieved by using erythrocyte drugs.The place of action of primaquine is the mitochondria of the malarial parasite. It seemslikely that primaquine interferes in the process of electron transfer, causing damage tomitochondrial enzymatic systems. This is expressed in the swelling and vacuolization ofthe parasite’s mitochondria. Host mitochondria are not affected. |
| Pharmacokinetics | Oral absorption: >75% Cmax 45 mg oral: 0.2 mg/L after 2–3 h Plasma half-life: 4–10 h Volume of distribution: 2 L/kg Plasma protein binding: Extensive Bioavailability is variable after oral administration. There isextensive tissue distribution. About 60% of the dose is metabolizedto carboxyprimaquine, which can reach levels 50 timesthat of the parent drug; this metabolite has a half-life of 16 h,a low tissue distribution and is detectable at 120 h. Methoxyand hydroxy metabolites are also detectable. Less than 4% ofthe original dose is excreted unchanged in urine. |
| Clinical Use | Primaquine is the only 8-aminoquinolinecurrently in use for the treatment of malaria. It is not usedfor prophylaxis. Its spectrum of activity is one of the narrowestof the currently used antimalarial drugs being indicatedonly for exoerythrocytic P. vivax malaria. To treat endoerythrocytic P. vivax, chloroquineor a drug indicated for chloroquine-resistant P. vivax isused with primaquine. In addition to its approved indication,it is also active against the exoerythrocytic stages ofP. ovale and primary exoerythrocytic stages of P. falciparum.Primaquine also inhibits the gameocyte stage that eliminates the form required to infect themosquito carrier. In vitro and in vivo studies indicate thatthe stereochemistry at the asymmetric is not important forantimalarial activity. There appears to be less toxicity withthe levorotatory isomer, but this is dose dependent andmay not be that important at the doses used to treatexoerythrocytic P. vivax malaria. Although structurally related to the cinchona alkaloids,the 8-aminoquinolines act by a different mechanism of action.Primaquine appears to disrupt the parasite’s mitochondria.The result is disruption of several processes includingmaturation into the subsequent forms. An advantage is destroyingexoerythrocytic forms before the parasite can infecterythrocytes. It is the latter step in the infectious process thatmakes malaria so debilitating. |
| Clinical Use | Primaquine is an important antimalarial because it isessentially the only drug effective against the liver (exoerythrocytic)forms of the malarial parasite. The drugalso kills the gametocytes in all four species of humanmalaria. Primaquine is relatively ineffective against theasexual erythrocyte forms. Primaquine finds its greatestuse in providing a radical cure for P. vivax and P. ovalemalaria. |
| Clinical Use | Radical cure of malaria caused by P. vivax or P. ovale Mild or moderately severe infections with Pn. jirovecii (in combination withclindamycin). Because of its gametocytocidal properties, primaquine hasbeen used rarely in a single dose to prevent the spread of chloroquine-resistant P. falciparum. |
| Side effects | Primaquine is readily absorbed from the gastrointestinaltract, and in contrast to chloroquine, it is notbound extensively by tissues. It is rapidly metabolized,and the metabolites are reported to be as active as theparent drug itself. Peak plasma levels are reached in 4 to6 hours after an oral dose, with almost total drug eliminationoccurring by 24 hours. The half-life is short, anddaily administration is usually required for radical cureand prevention of relapses. Although primaquine has a good therapeutic index,a number of important side effects are associated withits administration. In individuals with a genetically determinedglucose 6-phosphate dehydrogenase deficiency,primaquine can cause lethal hemolysis of redcells.This genetic deficiency occurs in 5 to 10% of blackmales, in Asians, and in some Mediterranean peoples.With higher dosages or prolonged drug use, gastrointestinaldistress, nausea, headache, pruritus, andleukopenia can occur. Occasionally, agranulocytosisalso has been observed. |
| Side effects | At standard doses side effects are mild: abdominal cramps,anemia, leukocytosis and methemoglobinemia. However,primaquineis often associated with serious adverse effects dueto the toxic metabolites 5-hydroxyprimaquine or 6-methoxy-8-aminoquinoline which are considered to be directly responsiblefor complications such as hemolytic anemia. Toxicity isworse in people deficient of glucose-6-phosphate dehydrogenase(G6PD) or glutathione synthetase. Adverse effects canbe further increased by the repeated administration of highdoses, due to its limited oral bioavailability. |
| Synthesis | Primaquine, 8-[(4-amino-1-methylbutyryl)amino]-6-methoxyquinoline(37.1.2.4), is made from 6-methoxy-8-nitroquinoline (37.1.2.1), which is synthesized in aSkraup reaction from 4-methoxy-2-nitroaniline and glycerol in the presence of sulfuricacid. The nitro group in this compound is reduced to make 6-methoxy-8-aminoquinoline(37.1.2.2). Alkylating the amino group with 4-bromo-1-phthalimidopentane gives 8-[(4-phthalimido-1-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.3), the hydrazinolysis of which removes the phthalimide protection, giving primaquine. |
| Veterinary Drugs and Treatments | Primaquine is considered the drug of choice for treating Babesiafelis in cats. Primaquine does not apparently “cure” the infection;repeated courses of therapy may be necessary. It may be useful intreating Hepatazoon canis in dogs or Plasmodium spp. in birds. Inhumans, primaquine is used for treatment and prophylaxis for malariaand treating Pneumocystis pneumonia. |
| References | [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1881 - 1884 [2] Arzneimittel-Forschung/Drug Research, 2010, vol. 60, # 10, p. 627 - 635 [3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 24, p. 6914 - 6917 [4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 886 - 892 [5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 886 - 892 |
Primaquine Preparation Products And Raw materials
| Raw materials | Primaquine diphosphate-->Sodium hydroxide |
| Preparation Products | Primaquine diphosphate |
