95233-18-4

Usage

Antimalarial Agent

The hydroxynaphthoquinone atovaquone, which exhibits antimalarial and anti-Pneumocystis activity, is an electron transport inhibitor that causes depletion of the ATP pool. The primary effect is on the iron flavoprotein dihydro-orotate dehydrogenase, an essential enzyme in the production of pyrimidines. Mammalian cells are able to avoid undue toxicity by use of preformed pyrimidines. Dihydro-orotate dehydrogenase from Plasmodium falciparum is inhibited by concentrations of atovaquone that are very much lower than those needed to inhibit the Pneumocystis enzyme, raising the possibility that the antimicrobial consequences might differ in the two organisms. Although atovaquone was originally developed as a monotherapy for malaria, high level resistance readily emerges in Plasmodium falciparum when the drug is used alone. Consequently, atovaquone is now combined with proguanil.

Indications

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihydroorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. Atovaquone is poorly absorbed from the gastrointestinal tract, but absorption is increased with a fatty meal. Excretion of the drug, mostly unchanged, occurs in the feces.The elimination half-life is 2 to 3 days. Low plasma levels persist for several weeks. Concurrent administration of metoclopramide, tetracycline, or rifampin reduces atovaquone plasma levels by 40 to 50%. Atovaquone has good initial activity against the blood but not the hepatic stage of P. vivax and P. ovale malaria parasites. It is effective against erythrocytic and exoerythrocytic P. falciparum, and therefore, daily suppressive doses need to be taken for only 1 week upon leaving endemic areas.When used alone, it has an unacceptable (30%) rate of recrudescence and selects for resistant organisms. It and proguanil are synergistic when combined and no atovaquone resistance is seen. This combination (Malarone) is significantly more effective than mefloquine, amodiaquine, chloroquine, and combinations of chloroquine, pyrimethamine, and sulfadoxine. In addition to using the combination of atovaquone and proguanil for the treatment and prophylaxis of P. falciparum malaria, atovaquone is also used for the treatment and prevention of P. carinii pneumonia and babesiosis therapy. Atovaquone is well tolerated and produces only rare instances of nausea, vomiting, diarrhea, abdominal pain, headache, and rash of mild to moderate intensity.

Manufacturing Process

Preparation of intermediate 4-(4-chlorophenyl)cyclohexane-1-carboxylic acid was needed at first. It was made as follows: acetyl chloride (30 g), aluminium chloride (60 g) in carbon disulfide (120 ml) were stirred at -50°C. Cyclohexen (30 g) previously cooled to -50°C was added dropwise during 10 minutes and the mixture was stirred for 60 minutes at -50°C. The solvent was decanted and 300 ml chlorobenzene was added, the so-obtained solution heated at 40°C for 3 hours with stirring, poured onto a mixture of ice and concentrated hydrochloric acid and the organic layer washed with 2 M HCl, 2 M NaOH and water, dried over anhydrous Na2SO4. The product was distilled in vacuo, the fraction boiling at 140°-154°C (0.1 mm Hg) collected, diluted with an equal volume of petroleum ether, cooled to -6°C and a stream of nitrogen gas bubbled through. 3.1 g above obtained hexahydroacetophenone was dissolved in dioxan (15 ml) and the fresh preparated hypobromite (8 ml) in a solution of NaOH (6.2 g) in water (42 ml) at 0°C was added at below 20°C. The mixture was stirred at ambient temperature for 6 hours then allowed to stand overnight. Excess hypobromite was destroyed with sodium metabisulphite, cooled and then acidified to give a colourless solid. It was filtered off, washed with water, dried and recrystallysed from ethanol to give 4-(4-chlorophenyl)cyclohexane-1- carboxylic acid, m.p. 254°-256°C. A mixture of this acid, 2-chloro-1,4- naphthoquinone and silver nitrate was added to ammonium persulfate to give the corresponding naphthoquinone which was saponificated with KOH and was yielded 2-trans-4-(p-chlorophenyl)cyclohexyl)-3-hydroxy-1,4 naphthoquinone, m.p. 216°-219°C, shown by NMR to be the pure trans isomer.

Antimicrobial activity

It is active against erythrocytic, liver and sexual stages of malaria parasites. It shows synergy with proguanil and tetracyclines in vitro. It is also active against Babesia spp. and both tachyzoites and cysts of Tox. gondii. Pn. jirovecii is sensitive in vitro at 0.1–3.0 mg/L and high doses are effective in the rat.

Acquired resistance

Point mutations on parasite cytochrome b, in particular at codon 268, cause resistance and readily occur when the drug is used alone. The rapid selection of resistance led to the development of the synergistic combination with proguanil. Failure of Pn. jirovecii prophylaxis has also been associated with cytochrome b mutations.

Pharmaceutical Applications

A hydroxynaphthoquinone. Available as the trans isomer (which is more active than the cis form) for oral use. It is insoluble in water.

Biochem/physiol Actions

Atovaquone is an anti-protozoal mitochondrial electron transport inhibitor; Antimalarial; Antipneumocystic, and has also been used to treat toxoplasmosis. It is an analog of protozoan mitochondrial protein ubiquinone, and acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket.

Mechanism of action

Atovaquone is thought to produce its antiparasitic action by virtue of its ability to inhibit the mitochondrial respiratory chain. More specifically, atovaquone is a ubiquinone reductase inhibitor, inhibiting at the cytochrome bc1 complex. This action leads to a collapse of the mitochondrial membrane potential. The compound shows stereospecific inhibition, with the trans isomer being more active than the cisisomer.

Pharmacokinetics

Oral absorption: Poor Cmax 750 mg oral: 27 mg/L (steady state) Plasma half-life: 70 h Plasma protein binding: >99% It is highly lipophilic and is poorly absorbed from the gastrointestinal tract following oral administration. Bioavailability is improved when administered with meals, particularly those with a high fat content. Steady-state plasma concentrations are up to 50% lower in AIDS patients than in asymptomatic HIV-positive cases and the elimination half-life is lower (55 h) in patients with AIDS. The concentration in CSF is <1% of the plasma level. Unlike some other naphthoquinones it is not metabolized by human liver microsomes. Combinations with co-trimoxazole (in HIV patients) and with proguanil plus artesunate in healthy adults did not produce any changes in atovaquone pharmacokinetics.

Clinical Use

3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone(Mepron) is a highly lipophilic, water-insolubleanalog of ubiquinone 6, an essential component of the mitochondrialelectron transport chain in microorganisms. Thestructural similarity between atovaquone and ubiquinonesuggests that the former may act as an antimetabolite for thelatter and thereby interfere with the function of electrontransport enzymes.Atovaquone was originally developed as an antimalarialdrug, but Plasmodium falciparum was found to developa rapid tolerance to its action. More recently, the effectivenessof atovaquone against P. carinii was discovered. Itis a currently recommended alternative to trimethoprimsulfamethoxazole(TMP-SMX) for the treatment and prophylaxisof PCP in patients intolerant to this combination.Atovaquone was also shown to be effective in eradicatingT. gondii in preclinical animal studies.The oral absorption of atovaquone is slow and incomplete,in part because of the low water solubility of the drug.Aqueous suspensions provide significantly better absorptionthan do tablets. Food, especially if it has a high fat content,increases atovaquone absorption. Significant enterohepaticrecycling of atovaquone occurs, and most (nearly 95%) ofthe drug is excreted unchanged in the feces. In vivo, atovaquoneis largely confined to the plasma, where it is extensivelyprotein bound ( 99.9%). The half-life of the drugranges from 62 to 80 hours. The primary side effect is gastrointestinalintolerance.

Clinical Use

Pn. jirovecii pneumonia; alternative therapy for mild to moderate illness (prophylaxis and treatment) Prophylaxis and treatment of malaria in combination with proguanil It has also been used in cerebral toxoplasmosis in AIDS patients and in a few cases of human babesiosis.

Side effects

Most clinical trials of atovaquone alone have involved patients with AIDS in whom adverse effects are often difficult to detect; however, more than 20% reported fever, nausea, diarrhea and rashes. There were limited changes in hepatocellular function. In malaria, in combination with proguanil, there are few reported side effects.

Veterinary Drugs and Treatments

Atovaquone (with azithromycin) appears effective in treating dogs with Babesia gibsoni (Asian genotype) infections, particularly in dogs not immunosuppressed or splenectomized. Atovaquone may be of benefit for treating pneumocystosis in dogs, but it is considered second line therapy after potentiated sulfonamides. Atovaquone (with azithromycin) may be of benefit in treating Cytauxzoon felis infections in cats (research is in progress at the time of writing).

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with rifabutin, concentration of both drugs reduced; avoid with rifampicin, concentration reduced and rifampicin concentration increased; concentration reduced by tetracycline. Antivirals: concentration reduced by efavirenz - avoid; concentration of indinavir possibly reduced; concentration of zidovudine increased. Metoclopramide: significant reduction in plasma atovaquone levels.

Metabolism

Atovaquone is poorly absorbed from the GI tract because of its poor water solubility and high fat solubility, but the absorption can be significantly increased if taken with a fat-rich meal. The drug is highly bound to plasma protein (94%) and does not enter the CNS in significant quantities. It is not significantly metabolized in humans and is exclusively eliminated in feces via the bile.

InChI:InChI=1/C22H19ClO3/c23-16-11-9-14(10-12-16)13-5-7-15(8-6-13)19-20(24)17-3-1-2-4-18(17)21(25)22(19)26/h1-4,9-13,15,26H,5-8H2

Upstream product

• 95233-37-7 trans-4-(p-chlorophenyl)cyclohexane carboxylic acid 
• 1409957-21-6 cis/trans-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxyrene-2,7(1aH,7aH)-dione 
• 153977-22-1 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone 
• 83-72-7 2-hydroxynaphtho-1,4-quinone 
• 1100053-59-5 2-[4-(4-chlorophenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-1,4-naphthoquinone 
• 1100053-58-4 trans-2-[4-(4-cyclohexyl)chlorophenyl]-1,4-naphthoquinone 
• 130-15-4 [1,4]naphthoquinone 
• 95233-37-7 (+/-)-trans-4-(4-chlorophenyl)cyclohexane carboxylic acid 
• 1010-60-2 2-chloro-1,4-naphthoquinone 
• 94015-53-9 atovaquone 
• 137732-39-9 cis-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione 
• 129719-64-8 2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-1,4-naphthoquinone 

Downstream Products

• 1445850-06-5 3-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyloxy-2-trans-[(4-chlorophenyl)cyclohexyl][1,4]naphthoquinone 
• 129700-44-3 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate 

Relevant academic research and scientific papers

Atovaquone preparation method

The invention provides an atovaquone preparation method, which comprises: carrying out condensation, hydrolysis and decarboxylation under the action of an alkali by using o-phthalic acid diester and 2-trans-[4-(4-chlorphenyl)]cyclohexyl succinic acid diester as raw materials to obtain 2-trans-[4-(4-chlorphenyl)]cyclohexyl-2,3-dihydro-1,4-naphthalenedione, carrying out a halogen substitution reaction on the 2-trans-[4-(4-chlorphenyl)]cyclohexyl-2,3-dihydro-1,4-naphthalenedione and a halogenating reagent to obtain a dihalogenated compound mixture, eliminating hydrogen halide to obtain 2-trans-[4-(4-chlorphenyl)]cyclohexyl-3-halo-1,4-naphthalenedione, and finally hydrolyzing to obtain atovaquone (I). According to the invention, the method has advantages of cheap and easily available raw materials, safe and simple process operation, low cost, little wastewater generation, safety, environmental protection, easily achieved reaction conditions, high reaction activity, high selectivity and fewside reactions, and the prepared atovaquone is few in impurity, high in purity and high in yield.

Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines

Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3-centered radical that can engage in the C-H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C-H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.

A single-pot synthesis of atovaquone: An antiparasitic drug of choice

The present article relates to a practical, economically viable, and validated at industrial scale, single-pot synthetic route for preparation of atovaquone, one of the most versatile antiparasitic drugs of choice used for the prophylaxis and treatment of diseases such as pneumocystis, toxoplasmosis, babesiosis, coccidiosis, and malaria. However, owing to the extremely poor yields of synthesis and very high doses of treatment (due to poor bioavailability) the cost of treatment with this drug is not affordable by the patients in need, particularly in the third world countries where these diseases are most prevalent. Unlike most of the reported processes which use 2-chloronaphthoquinone and pure trans-4-chlorophenyl cyclohexane carboxylic acid, our process is based on the decarboxylative alkylation of isomeric mixture of 4-chlorophenyl cyclohexane carboxylic acid with 1,4-naphthoquinone to give 42% overall yield of atovaquone, 10 times higher than from the reported process (4%) from the innovators of this drug.

''3-(5-METHYL-2-OXO-L, 3-DIOXOL-4-YL) METHYLOXY-2- TRANS-[(4-CHLORO PHENYL) CYCLOHEXYL] [1,4]NAPHTHAQUINONE -ATOVAQUONE PRODRUG

The present invention relates to atovaquone prodrug compound of formula (I). Accordingly, present invention provides a process involving condensation of Atovaquone (II) with 5-methyl-4- chloromethyl dioxalone (III) in suitable solvent system and optionally followed by distillation and crystallization to provide Atovaquone prodrug compound of formula (I) in high yields, purity, and suitable for large-scale manufacture.

IMPROVED SYNTHESIS OF 2-(4-(4-CHLOROPHENYL) CYCLOHEX-1-ENYL) -3, 4-DIHYDRONAPHTHALEN-1 (2H)-ONE; AN INTERMEDIATE FOR ATOVAQUONE

A process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- 1(2H)-one (V), key intermediate for synthesis of Atovaquone [I]. The process for preparation of compound(V) comprising of the steps of; i) Reaction of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of base in organic solvent to yield compound of formula (XIa) ii) Elimination of trifluoroacetyl functionality of compound (XIa) in organic solvent and in presence of organic base to give compound of formula (V). The invention also provides a Process for preparation of compound(XIa) comprising of the steps of; i) reaction of 2-(4-(4-chlorophenyl)-l-hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1(2H)-one (IV) with trifluro acetic anhydride in presence of organic base in organic solvent. A further process is provided for preparation of compound(V) from compound (XIa) comprising elimination reaction of trifluoroacetyl functionality compound (XIa) in organic solvent and in presence of organic base.

NOVEL METHOD FOR PREPARATION OF ATOVAQUONE

Provided is a process of preparation of 2-[trans,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy- 1,4-naphthoquinone, i.e. Atovaquone [I] which is cost effective, green, and eco-friendly process, without separation of any diastereomers or geometric isomers of intermediates obtained during the reactions. Also provided is separation of 'cis' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent. A method for converting 2-[cis,-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided. A process for preparation of compound 2-(4-(4- chlorophenyl)- 1 -hydroxy cyclohexyl)-3,4-dihydronaphthalen- 1 (2H)-one [IV] comprising condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4- chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent. The invention also encompasses a highly efficient and atomeconomic process for synthesis of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone as well as a process for synthesis of 2-[cis-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone. Further provided is a process for isomerization of cis- Atovaquone i.e. 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4- naphthoquinone to tnms-Atovaquone i.e. 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy- 1,4-naphthoquinone in presence of Lewis acid.

Process for the preparation of trans-2,3-disubstituted naphthoquinones

The invention concerns a new process for the preparation of naphthoquinones, in particular an improved process for the preparation of 2,3-disubstituted 1,4-naphthoquinones, in the trans configuration.

PROCESS FOR THE EPIMERIZATION OF ATOVAQUONE ISOMER, ATOVAQUONE INTERMEDIATES AND MIXTURE THEREOF

Provided is a process for the epimerization of the cis isomer of atovaquone, atovaquone intermediates and isomeric mixtures thereof into their corresponding trans-isomers resulting in higher yield of pure atovaquone.

NOVEL CRYSTALLINE FORMS OF ATOVAQUONE

The present invention relates to two novel and stable crystalline forms of atovaquone, to processes for their preparation and to pharmaceutical compositions comprising them. The present invention also provides crystalline particles of atovaquone having a specific surface area of from about 0.7 m2/g to about 4 m2/g, methods for the manufacture of said crystalline particles and pharmaceutical compositions comprising said crystalline particles. The present invention further provides an improved and commercially viable process for preparation of atovaquone substantially free of its undesired isomeric impurity, namely cis-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.

PREPARATION OF NAPHTHOQUINONE COMPOUNDS USING 2, 3-DIHALONAPTHOQUINONE

The present invention relates the use of 2, 3-dihalonaphthoquinone compounds of Formula (I) wherein R1 and R2 are leaving groups like halogens selected from the group comprising Cl, Br, I and F and the R1 and R2 may be the same halogen or may contain different halogen groups, or sulphonyl groups, for making napthoquinone compounds of Formula (IA) wherein X is any aryl, heteroaryl, alkyl, cyclohexyl, substituted cylohexyl groups and the like.