FIELD OF THE INVENTION:

The present invention discloses Atovaquone prodrugs, process for the preparation of said prodrugs and pharmaceutical compositions comprising Atovaquone prodrugs. Atovaquone prodrugs pharmaceutical composition offers high drug loading compared to Atovaquone and thus is suitable for administration to both pediatrics and adults at therapeutically effective concentrations. Atovaquone prodrugs can be administered alone, or co-administered as fixed dose or as separate dosage form in combinations with other drugs for prophylaxis or treatment of infections or treatment of neoplasms in humans. The pharmaceutical composition of Atovaquone prodrugs upon parenteral administration provides therapeutically effective concentration of active drug Atovaquone for long duration, thus exhibiting sustained depot effect and offering prolonged therapeutic or prophylactic benefit.

BACKGROUND OF THE INVENTION

Class II BCS drugs have high permeability but poor aqueous solubility and thus exhibit poor dissolution profile limiting its bioavailability following oral administration. In order to achieve sufficient therapeutic effect systemically, high oral dose is required to be administered to evade this limitation and achieve therapeutic concentration in systemic circulation.

Atovaquone, a hydroxy-1, 4-naphthoquinone, is a well-known anti-malarial and anti-pneumocystic drug, which is commercially available in different dosage forms as standalone or in combination with Proguanil since 1992, but the bioavailability of tablet formulations barely crosses 12% (23% under fat fed conditions) and for oral nano-sized suspension, bioavailability is about 23% (46- 48% under fat fed condition). Fatty meal helps to emulsify the drug in the lipids present in the food. Owing to its poor hydro solubility, Atovaquone dissolution is hampered in aqueous environment of the digestive tract thus limiting its bioavailability and adding to inter-patient variance. In order to achieve therapeutic levels of Atovaquone, patient is advised to eat high fatty food, and very often this turns out be non-feasible because of severity or nature of the underlying disease. Atovaquone (Formula I), chemical name being trans-2-[4-(4- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone, is a hydroxy-1, 4- naphthoquinone, an analog of Ubiquinone, with anti-pneumocystic and anti- malarial activity. It has previously been disclosed, for example, in European Patent No. 1,23,238 and 0675711 that Atovaquone is active (in-vivo and in-vitro) against Pneumocystis (carinii) jirovecii, Plasmodia, tachyzoite and cyst forms of Toxoplasma gondii, and Eimeria spp., a causative agent for Coccidiosis. Further uses of Atovaquone for Cryptosporidiosis and Babesiosis are disclosed in European patent application no. 0496729 and U.S. Pat. No. 5,559,156 respectively.

Atovaquone has been approved as standalone monotherapy for treating Pneumocystis (carinii) jirovecii infections in AIDS patients and in combination with proguanil for prophylaxis and treatment of malaria.

Atovaquone was initially granted orphan drug status in 1990 for treatment and in 1991 for prevention of Pneumocystis carinii infections in AIDS patients. Atovaquone 250mg tablet formulation (Mepron™) was approved in 1992 for treatment and prophylaxis of Pneumocystis carinii infections in AIDS patients. In 1993 Atovaquone was conferred orphan drug status for Toxoplasmosis as well but was subsequently withdrawn due to lack of clinical efficacy which was partially attributed to low bioavailability and high inter-patient variability. A nanoparticle of Mepron™ suspension with improved bioavailability was launched in 1995 and tablet formulation was then withdrawn from the market.

Numerous attempts have been made since then for increasing the bioavailability of Atovaquone for primarily focusing on particle size reduction, however, significant dissolution profile and bioavailability improvement over nanosuspension is far from reach.

US6018080A/US6649659B1 reported improving bioavailability of Atovaquone. These patents describe the effect of micronizing Atovaquone together with liquid vehicles to improve Atovaquone solubility and thereby increase its bioavailability. These patents used microfluidization process for preparing microparticles of 0.1 - 3 micron size of Atovaquone which can improve Atovaquone bioavailability almost double than solely micronizing the Atovaquone. However, the major disadvantage of microfluidization technique is high number of passes through the microfluidizer and that the product obtained contains a relatively larger fraction of microparticles. Our previously filed application W02014045307 reported Atovaquone-Proguanil complex with improved Atovaquone dissolution profile and its consequent bioavailability.

IN201621020162 revealed a process for preparation of stable nanoparticles of Atovaquone to increase solubility and dissolution rate and thereby increased bioavailability using electrospraying technique.

3484/MUM/2012 discloses atovaquone suspension of particle size d ₉₀ 10-11 μ, dso: 4-5 p and dio: 2-3 p.

2392/DEL/2008 discloses co-precipitate of Atovaquone with polyvinylpyrrolidone and colloidal silicon dioxide.

US20100099776 reveals oily suspension of atovaquone, with atovaquone particles having cho value of about 4-15 pm, for oral administration. US20100028425 discloses immediate release micronized formulation of atovaquone with 90% of the atovaquone particles have a volume diameter between 4 pm to 8 pm.

The oral bioavailability of drugs can be improved by use of bioadhesive nanoparticles, such as Poly(methylvinylether-co-maleic anhydride), -but the capability of bioadhesive nanoparticles to load highly lipophilic drug such as Atovaquone is limited. In order to minimize this drawback, one possible solution is incorporation of cyclodextrins as promoters of drug loading for the preparation of nanoparticles. W0200907996 discloses an inclusion complex of Atovaquone and cyclodextrin, wherein the molar ratio of atovaquone to cyclodextrin in the inclusion complex ranges from 1 :2 to 1:5.

Though the improvised oral formulations did increase the bioavailability of Atovaquone, they still exhibited food and fat effect and population variability to some extent. Parenteral route evades the food and population variability but due to atovaquone’ s low solubility in polar and most of non-polar solvents as well, only oily and aqueous injectable suspensions have been developed so far.

WO2017216564 claimed a 10 weight % solid drug nanoparticles formulation of atovaquone with carrier materials possessing hydrophilic polymeric and surfactant activity.

Patent application WO2018204563 disclosed intramuscular Atovaquone aqueous suspension for prophylaxis and treatment of malaria as well as other parasitic and fungal infections. The formulation is lyophilized powder of micronized atovaquone which upon injecting in form of suspension offers protection against malaria for 2 to 8 weeks, depending on the dose. The suspension formulation of Atovaquone disclosed in patent application WO2018204563 comprised of a maximum of 25% by weight of the atovaquone in suspension. The parenteral formulations typically contain from about 0.5% to about 25% by weight of the compounds in suspension. In the backdrop of same, requisite drug loading of Atovaquone in solution at a therapeutically effective concentration is challenging and thus have not been successfully met. For instance, liposomal formulation can circulate in the body for a long period of time and penetrate tissues efficiently due to its small size but drug loading is very low. Solutions containing dissolved lipophilic drug offers the flexibility of subcutaneous injection with shorter needles and less patient discomfort. Oil solution, in particular, generates a localised bolus which slowly disperses and release the drug. Viscous oils for e.g. sesame oil resist spreading and can persist longer periods (ti/2= 22 days in rabbits) without being absorbed.

Oil formulation of therapeutically effective Atovaquone drug concentrations in permissible intramuscular injectable volume as per age and weight of patient, tends to crystallize, precipitate or phase out immediately or during storage or shipping.

Thus, there exists an unmet medical need of effective methods for solubilizing atovaquone at effective therapeutic concentration in volume permissible for injection or parenteral delivery as per age and weight of patient, especially for children below 5 years of age wherein max permissible injection volume is 1.0 ml. Prodrug approach increases the solubility of therapeutically effective Atovaquone in Oil and thus offers high drug loading whilst offering a sustained depot effect for long duration of protection against indicated diseases or parasitic infections.

WO 2017/222996 disclosed C1-C30 alkyl esters or optionally substituted C2-C30 alkenyl esters, or C2-C30 alkynyl esters prodrug derivatives of Atovaquone to increase the solubility and loading of Atovaquone in oil, release the active moiety in-vivo, while exerting sustained release depot effect.

El Hage, Salome et al described the design and synthesis of 2-Carbon, 8-Carbon, 9-Carbon, 10-Carbon and 18-Carbon ester prodrug derivatives of Atovaquone. The derivatives were found to possess antimalarial activity.

El Hage, Salome et al described the design and synthesis of 2-Carbon, 6-Carbon, 9-Carbon, 10-Carbon and 18-Carbon ether prodrug derivatives of Atovaquone. The derivatives were found to possess antimalarial activity.

However, obtaining sufficient drug loading to offer effective therapeutic concentration of Atovaquone Prodrug, and thus Atovaquone in-vivo, in volume permissible for injection or parenteral delivery as per age and weight of patient, especially for children below 5 years of age wherein max permissible injection volume is 1.0 ml, is challenging which becomes the primary objective of the present invention. Further, there exists a challenge of co-formulating other anti- parasitic compounds especially polar compounds as stable clear solution with Atovaquone prodrug at therapeutically effective dose.

Accordingly, the primary objective of present invention is to develop new compounds with not only improved Atovaquone solubility profile, but also with high drug loading capacity therapeutically sufficient to offer sustained systemic bioavailability as sustained release depot for effective protection against endoparasitic, ecto-parasitic diseases including fungal diseases.

Another objective of present invention is to explore the feasibility of coformulation of Atovaquone prodrug derivatives with other anti-parasitic drugs, especially polar compounds, for prophylaxis and treatment of ecto and endoparasitic infections in humans. The co-formulated polar drug(s) solution should remain stable in solution, i.e. should not crystallize, precipitate or phase out during shipping or storage in all five ICH stability zone conditions SUMMARY OF THE INVENTION:

In line with the above objectives, on exploring various prodrug strategies, the Applicants have, surprisingly, found that C6-18 ether-acid, ether-ester, ester-acid and ester-ester prodrugs of formula- 1 offer high drug loading compared to Atovaquone and are thus suitable for administration to both pediatrics and adults at therapeutically effective concentrations. The pharmaceutical compositions of Prodrugs are suitable for administration as fixed dose or as separate dosage form in combinations with other drugs for both prophylaxis and treatment of infections or treatment of neoplasms in humans., The Pharmaceutical composition of C6-18 ether-acid, ether-ester, ester-acid and ester-ester prodrugs of formula-1 exhibited sustained depot effect when administered parenterally, preferably intramuscular, with the loaded concentration therapeutically effective to offer sustained systemic bioavailability for chemoprevention or treatment of endo-parasitic, or ecto- parasitic infections and treatment of neoplasms in humans. The disclosed invention offers the feasibility of co-formulating Atovaquone Prodrugs with other anti-parasitic drugs or anti-neoplastic drugs surprisingly polar drugs which further increase the prodrugs solubility in solution, to obtain a therapeutically effective pharmaceutical composition which is stable in all five ICH stability zone conditions.

Accordingly, in most preferred embodiment, the present invention provides prodrugs of Atovaquone of formula-I

Wherein Ri = -[C=O]x-[CH2] _y -C(O)OR2; R2 is H or lower alkyl group such as methyl, ethyl and propyl; x is 0 or 1; and y is 6 to 17. In a preferred aspect, the prodrugs of Atovaquone of formula I is selected from Formula -la and formula- lb, as shown below.

Wherein, y is 6 to 17; z = 5-16 and R2 is a lower alkyl group such as methyl, ethyl or propyl.

In an aspect, the preferred compounds are selected from a group consisting of 11- ((3-((lR, 4R)-4-(4-chlorophenyl)cy cl ohexyl)-l,4-di oxo-1, 4-dihydronaphthal en-2- yl)oxy)undecanoic acid, ethyl l l-((3-((lR,4R)-4-(4-chlorophenyl)cyclohexyl)-

1.4-dioxo- 1 ,4-dihy dronaphthalen-2-yl)oxy)undecanoate, 12-((3 -((1 R,4R)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2-y l)oxy)-12- oxododecanoic acid and l-(3-((lR,4R)-4-(4-chlorophenyl)cyclohexyl)-l,4-dioxo-

1.4-dihydronaphthalen-2-yl) 12-ethyl dodecanedioate.

In another aspect, the invention provides a process for preparation of prodrugs of Atovaquone of formula-I wherein R ₁ is R ₂ is lower alkyl group such as methyl, ethyl and propyl; and y is 6 to 17 methylene groups; the process comprising:

(Method 1): a) reacting Atovaquone with a compound of Formula-2, wherein X is a halogen, to obtain corresponding acid derivative of formula-Ic; and b) reacting the acid derivative of formula-Ic with alkanol of formula- R2OH to obtain prodrugs of Atovaquone of formula-la; or (Method 2): reacting Atovaquone with a compound of Formula-3, wherein X is a halogen, to obtain prodrugs of Atovaquone of formula-la; or (Method 3): a) reacting Atovaquone with a compound of Formula-4, wherein X is a halogen, followed by hydrolysis to obtain corresponding acid derivative of formula-id; and b) reacting the acid derivative of formula-id with alkanol of formula- R2OH to obtain prodrugs of Atovaquone of formula-Ib.

In one preferred aspect, the present invention provides process for preparation of prodrugs of Atovaquone of formula-la wherein R2 and y as defined above which comprises; a) Reacting Atovaquone with a compound of Formula-2, wherein X is a halogen, to obtain corresponding acid derivative of formula-lc; and b) Reacting the acid derivative of formula-lc with alkanol of formula- R20H to obtain prodrug s of Atovaquone of formula-la

Alternatively, prodrug s of Atovaquone of formula-la wherein R2 & y as defined above can be prepared by a process which comprises;

Reacting Atovaquone with a compound of Formula-3, wherein X is a halogen, to obtain prodrugs of Atovaquone of formula-la. In another preferred aspect the present invention provides process for preparation of prodrugs of Atovaquone of formula-Ib wherein R2 and z as defined above which comprises; a) Reacting Atovaquone with a compound of Formula-4, wherein X is a halogen, followed by hydrolysis to obtain corresponding acid derivative of formula-id; and b) Reacting the acid derivative of formula-id with alkanol of formula- R20H to obtain prodrugs of Atovaquone of formula-Ib.

In a preferred embodiment, the present invention provides a process for preparation of prodrugs of Atovaquone of formula-la and lb wherein a, b as defined above and R2 is H or a lower alkyl group such as methyl, ethyl or propyl.

In another embodiment, the present invention discloses pharmaceutical formulations comprising of compound of formula I for oral or parenteral administration.

In a preferred embodiment, the present invention provides pharmaceutical compositions with a high drug loaded solution of the compound of formula I due to higher solubility, when compared to Atovaquone, which is suitable for parenteral administration, preferably intramuscular, for sustained, depot or immediate release pharmaceutical formulation of Atovaquone Prodrugs at a loaded concentration sufficient to provide in-vivo systemic concentration of Atovaquone required for effective chemoprevention or treatment of ecto and endo-parasitic and topical fungal infections. In another preferred embodiment of the present invention the compound of formula I is administered intramuscularly as oil-solution or oil-suspension, which does not crystallize, precipitate or phase out during shipping or storage, either alone or with other co-formulated anti-parasitic compound at a concentration sufficient to provide systemic therapeutic concentration for chemoprevention or treatment of ecto and endo-parasitic and topical fungal infections.

Accordingly, one aspect of the present invention provides an oil-solution or oilsuspension formulation of Atovaquone Prodrugs suitable for parentral administration comprising of, but not limiting to, oily vehicles, such as castor oil, coconut oil, soybean oil, peanut oil, cottonseed oil, caprylic and capric triglycerides from coconut or palm seed oils, sesame oil, safflower oil, oleic acid or isopropyl myristate, non-ionic surfactants, albumin, Co-solvents, like polyethylene or propylene glycol, surfactants, to help oil to spread and emulsify Atovaquone Prodrugs; volatile vehicles like ethanol or acetone; pH stabilizers; DMSO; anti-microbials like sodium azide or formaldehyde, and preservatives.

In another aspect, the invention provides a pharmaceutical formulation of Atovaquone Prodrugs which upon intramuscular injection forms a sustained release gel depot to provide long term systemic therapeutic concentration for chemoprevention or treatment of ecto and endo-parasitic and topical fungal infections.

Accordingly in one aspect, the present invention provides formulation of Atovaquone prodrugs comprising of a drug dissolved in N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide, tetraglycol, and glycofurol to the more hydrophobic solvents such as propylene carbonate, triacetin, ethyl acetate, and benzyl benzoate.

In another aspect, the invention provides a micronized oil suspension of Atovaquone prodrugs suitable for parenteral administration at a loaded concentration sufficient to provide systemic therapeutic concentration for chemoprevention or treatment of ecto and endo-parasitic and topical fungal infections.

In yet another aspect, the present invention provides the micronized oil solution formulation of Atovaquone prodrugs suitable for parentral administration comprising of, but not limiting to, oil vehicles such as castor oil, coconut oil, soybean oil, peanut oil, cottonseed oil, caprylic and capric triglycerides from coconut or palm seed oils, sesame oil, safflower oil, oleic acid or isopropyl myristate, non-ionic surfactants, albumin, Co-solvents, like polyethylene or propylene glycol, surfactants to help oil to spread and emulsify, volatile vehicles like ethanol or acetone, pH stabilizers, DMSO, anti -mi cr obi al s like sodium azide or formaldehyde, and preservatives.

Applicants have surprisingly found that other anti-parasitic drugs can be coformulated with prodrugs of Atovaquone to offer broad spectrum protection. The Atovaquone Prodrugs non-polar oil based composition offers good solubility for Polar anti-parasitic drugs as well and polar drugs further increase the solubility of Atovaquone Prodrugs.

Accordingly, in another aspect, the present invention provides a process for preparation of the Atovaquone Prodrug formulations optionally in combination with one or more pharmaceutical active ingredients and with excipients/carriers suitable for parenteral administration to get sustained depot effect for prolonged protection against parasitic diseases. The process comprises formulating Atovaquone prodrugs in a therapeutically effective amount, with or without other antimicrobial, antiparasitic or anti-neoplastic drugs, along with permitted pharmaceutical excipients/carriers into a suitable oral or parenteral dosage form, using known techniques. The anti-parasitic drug is preferably the anti-malarial agent selected from the group comprising of artemisinin, artemisinin derivatives, proguanil, quinine, piperaquine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine or halofantrine. In another preferred embodiment of present invention, the formulation can be administered alone or with most preferred partner Proguanil as combination product, wherein Proguanil (formula II) shall be added to the formulation of compound of formula I at concentration adequate to confer effective protection or treatment against endo-parasitic, ecto-parasitic diseases including topical fungal infections.

Applicants have surprisingly found that addition of Proguanil further increases the solubility of Atovaquone prodrugs.

In another embodiment of present invention, the dosage forms prepared by the process of the present invention may be administered to a mammal in need, for prophylaxis or treatment of parasitic infection like, but not limited to Malaria, Pneumocystis carinii Pneumonia, Toxoplasmosis, Trichomoniasis, Giardiasis, Cryptosporidiosis, Filariasis, Babesiosis, schistosomiasis, clonorchiasis, opisthorchiasis, tapeworm infections, cysticercosis and hydatid disease or treatment of neoplasms.

The pharmaceutical composition of Atovaquone prodrugs either alone or in combinations with anti-parasitic or anti-neoplastic drugs can be injected twice weekly, weekly, biweekly, monthly or bimonthly depending on the systemic concentration required for to achieve desired anti-parasitic or anti -neoplastic activity of active moiety Atovaquone. BRIEF DESCRIPTION OF DRAWINGS AND TABLES:

Figure 1 depicts differential scanning calorimetry of final Product obtained in

Example 2

Figure 2 depicts differential scanning calorimetry of final Product obtained in

Example 8

Figure 3 depicts differential scanning calorimetry of final Product obtained in

Example 15

Figure 4 depicts differential scanning calorimetry of final Product obtained in

Example 21

Figure 5 shows differential scanning calorimetry of Atovaquone

Table 1 : Comparative solubility assessment- Atovaquone and Atovaquone

Prodrugs

Table 2: Atovaquone Prodrugs solubility in combination with Proguanil

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims The term "treating" means adding or combining or mixing or grinding the stated reagents or materials or the things being treated. The term "forming a solution" or "solution" means obtaining a solution of a substance in a solvent in any manner. It encompasses partial solutions. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.

The primary objective of present invention is to provide novel Prodrugs of Atovaquone, process for the preparation of said prodrugs and pharmaceutical compositions comprising Atovaquone prodrugs. Atovaquone prodrugs of present invention offer the advantage of high drug loading when compared to Atovaquone and thus is suitable for administration to both pediatrics and adults at therapeutically effective concentrations. The pharmaceutical composition of Atovaquone prodrugs upon parenteral administration provides therapeutically effective concentration of active drug Atovaquone for longer duration, thus exhibiting sustained depot effect and offering prolonged therapeutic or prophylactic benefit.

Another objective of present invention, is to provide pharmaceutical composition of Atovaquone Prodrugs either alone or in combination with other antiparasitic drugs. Atovaquone prodrugs can be administered alone, or co-administered as fixed dose or as separate dosage form in combination with other drugs for prophylaxis or treatment of infections or treatment of neoplasms in humans. The pharmaceutical composition of Atovaquone Prodrugs when administered parenterally offers complete long-term protection, against endo-parasitic infections, ecto-parasitic, including fungal infections, and therapeutically effective concentration as sustained release depot to treat neoplasms. The complete objective of the present invention is to synthesize and develop a stable pharmaceutical formulation of Atovaquone Prodrugs either alone or in combination with other antiparasitic drugs with a loading which is therapeutically sufficient to offer sustained systemic bioavailability over a long duration for effective protection against endo-parasitic, ecto-parasitic diseases including fungal diseases. The Atovaquone Prodrug and anti-parasitic drug combination in solution or suspension will remain stable and will not crystallize, precipitate or phase out during shipping or storage in all five ICH stability zones.

Accordingly, one aspect of the present invention provides prodrugs s of Atovaquone of formula-I

Wherein is H or lower alkyl group such as methyl, ethyl and propyl; x is 0 or 1; and y is 6 to 17.

In a preferred aspect, the prodrugs of Atovaquone of formula I is selected from

Formula -la and formula- lb, as shown below. Wherein, y is 6 to 17; z = 5-16 and Rr is a lower alkyl group such as methyl, ethyl or propyl.

In an embodiment, the preferred compounds are selected from a group consisting of 1 l-((3-((lR,4R)-4-(4-chlorophenyl)cyclohexyl)-l,4-dioxo-l,4- dihydronaphthalen-2-yl)oxy)undecanoic acid, ethyl l l-((3-((lR,4R)-4-(4- chlorophenyl)cyclohexyl)-l,4-di oxo- 1, 4-dihy dronaphthalen-2- yl)oxy)undecanoate, 12-((3-((lR,4R)-4-(4-chlorophenyl)cyclohexyl)-l,4-dioxo- 1, 4-dihy dronaphthalen-2-yl)oxy)-12-oxododecanoic acid and l-(3-((lR,4R)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2-y l) 12-ethyl dodecanedioate.

According to a second aspect, the present invention provides process for preparation of prodrugs of Atovaquone of formula-la wherein R2 and y as defined above which comprises; a) Reacting Atovaquone with a compound of Formula-2, wherein X is a halogen, to obtain corresponding acid derivative of formula-Ic; and b) Reacting the acid derivative of formula-Ic with alkanol of formula- R20H to obtain prodrugs of Atovaquone of formula-la.

The reaction of Atovaquone with a compound of Formula-2, wherein the halogen is selected from bromo, chloro or iodo. However preferred haolgen is bromo. The reaction may be conducted in a suitable organic solvent. The solvents are selected from ketones like methyl ethyl ketone, diethyl ketone, diisobutyl ketone; esters like ethyl acetate; and alkyl chlorides like methylene chloride and ethyl chloride. Usually, the reaction is conducted in presence of a base. Preferably the base is an inorganic base. More preferably, the base is selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal alkoxides such as potassium methoxide and potassium tertiary butoxide and carbonates such as sodium carbonate or potassium carbonate. Even more preferably, the base is selected from the group consisting of potassium hydroxide, potassium methoxide and potassium tertiary butoxide. Most preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

Typically, the reaction is conducted in the range of 0°C to the boiling temperature of the solvent used. Preferably, the reaction is performed in the temperature range of about 40-100°C. After completion of the reaction, corresponding acid derivative of formula-Ic is isolated by conventional methods.

The obtained acid derivative of formula-Ic is further converted into prodrugs of Atovaquone of formula-la by reacting with alkanol of formula- R20H.

R2 is an alkyl group that include, but are not limited to, lower alkyl groups, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl. However, the preferred group is methyl, ethyl, propyl.

The reaction is conducted in presence of an acid catalyst which include, but are not limited to, sulphuric acid, hydrochloric acid, p-toluene sulphonic acid.

Usually, the akanol reagent (R20H) is taken in excess to act as solvent as well. The reaction is conducted at reflux temperature. After completion of reaction, prodrugs of Atovaquone of formula-la is isolated by conventional methods.

Alternatively, prodrugs of Atovaquone of formula-la may, directly, be prepared by reacting Atovaquone with compound of Formula-3, wherein X, R2 and y defined as above. However preferred haolgen is bromo. The reaction may be conducted in a suitable organic solvent. The solvents are selected from ketones like methyl ethyl ketone, diethyl ketone, diisobutyl ketone; esters like ethyl acetate; and alkyl chlorides like methylene chloride and ethyl chloride.

Usually, the reaction is conducted in presence of a base. Preferably the base is an inorganic base. More preferably, the base is selected from the group consisting of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal alkoxides such as potassium methoxide and tertiary butoxide and carbonates such as sodium carbonate or potassium carbonate. Even more preferably, the base is selected from the group consisting of potassium hydroxide, potassium methoxide and tertiary butoxide. Most preferably, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

After completion of the reaction, prodrugs of Atovaquone of formula-la is isolated by conventional methods.

According to another aspect, the present invention provides process for preparation of prodrugs of Atovaquone of formula-Ib wherein R2 and z as defined above which comprises; a) Reacting Atovaquone with a compound of Formula-4, wherein X is a halogen, followed by hydrolysis to obtain corresponding acid derivative of formula-id; and b) Reacting the acid derivative of formula-id with alkanol of formula- R20H to obtain prodrugs of Atovaquone of formula-Ib. Atovaquone or Atovaquone sodium salt may be reacted with compound of Formula-4, wherein X is a halogen. Preferred halogen is chloro. This reaction is conducted in a suitable solvent. Suitable solvents include alkyl chlorides/halogenated hydrocarbons like methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform and hydrocarbons solvents like benzene, chlorobenzene, toluene, xylene. Esters like ethyl acetate and butyl acetate. However, preferred solvents are methylene chloride and ethylene dichloride.

This reaction is conducted in presence of an inorganic or organic base. Preferably the base is an inorganic base. More preferably, the base is selected from the group consisting of alkali metal hydroxide, alkali metal alkoxides and carbonates. Even more preferably, the base is selected from the group consisting of potassium hydroxide, potassium methoxide and tertiary butoxide. Most preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Preferably the base is dissolved in water and added to Atovaquone prior to addition of the compound of Formula-4.

Usually, the reaction is conducted between 10°C to ambient temperature.

After completion of reaction, corresponding acid derivative of formula-id which is converted into prodrugs of Atovaquone of formula-Ib by reacting with R20H either in presence of an acid catalyst or thionyl chloride.

Similar reaction conditions as mentioned in the step for the conversion of acid derivative of formula-Ic into formula-la may be employed for conversion of acid derivative of formula-id into prodrugs of Atovaquone of formula-Ib using acid catalyst.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) suitable for oral or parenteral administration to a human in need thereof. In preferred embodiment of present invention, the formulation is Oil based injectable clear solution or oil-suspension for parenteral administration for sustained depot or immediate release.

In another embodiment of the present invention the oil may be a vegetable oil and which may be selected from corn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil, coconut oil, soybean oil, cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof.

In a preferred embedment of the present invention the oil in the pharmaceutical formulation of compound of formula I may be sesame oil or coconut oil or a mixture thereof.

In another embodiment of present invention, the pharmaceutically acceptable excipients are selected from the group consisting of surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof.

In another embodiment of present invention, the pharmaceutical formulation of compound of formula I may comprise of solubilizers for example, but not limiting to, Dimethyl sulfoxide, Dimethylacetamide, Dimethylformamide, N-methyl pyrrolidone, benzyl alcohol or benzyl Benzoate. More preferably, the solubilizing agent is selected from N-methyl pyrrolidone or Benzyl alcohol or a mixture thereof.

In another embodiment of present invention, the pharmaceutical formulation may comprises one or more non-ionic surfactant of ester type (e.g. polyoxyethylene fatty acid esters, sorbitan fatty acid esters anhydrides), ether type (e.g., polyoxyethylene alkyl ether, polyoxyethylene alkyl phenol ether), amine type (such as polyoxyethylene fatty amine), amide type (such as polyoxyethylene alkyl amide) or mixing type (such as sorbitol anhydride fatty acid esters, polyoxyethylene ether).

In another embodiment of present invention, the pharmaceutical formulation of compound of formula I comprise of a surfactant, a suspending agent and any combinations thereof. Accordingly, the pharmaceutical formulation of compound of formula I may comprise of Synperonic® Fl 08, dodecyl sodium sulfate (SLS), Cremophor, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof.

In one embodiment of the present invention the pharmaceutical formulation may comprise of compound of formula I and solubilizing agent.

In another embodiment of the present invention the pharmaceutical formulation may comprise of compound of formula I and more than one solubilizing agent.

In another embodiment of the present invention the pharmaceutical formulation may comprise of compound of formula I and oil with solubilizing agent(s).

In another embodiment of the present invention the pharmaceutical formulation may comprise of compound of formula I in oil with solubilizing agent(s) and a non-ionic surfactant.

In another embodiment of the present invention the pharmaceutical formulation may comprise the concentration of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is formulated in Oil vehicle as solution greater than 125 mg/ml.

In another embodiment of the present invention the pharmaceutical formulation may comprise of prodrug of Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof formulated in Oil vehicle as solution at a concentration not less than 250mg/ml.

In another embodiment of the present invention the pharmaceutical formulation may comprise of compound of formula I in oil with a solubilizing agent(s), a nonionic surfactant and partner drug at a concentration sufficient to augment the activity of Atovaquone to offer complete protection against endo-parasitic, ecto- parasitic including topical fungal infections.

In another aspect, the present invention provides a process for preparation of high concentration oil-solution or oil-suspension formulation of Atovaquone Prodrug and anti-parasitic drug combination.

In a preferred embodiment of present invention, the solubilizing agent is N-methyl pyrrolidone, benzyl benzoate or Benzyl alcohol and oil is coconut or sesame oil or mixture thereof and non-ionic surfactant is cremophore.

In another embodiment of present invention, the Atovaquone Prodrug can be formulated with anti-parasitic drugs or antifungal drugs to offer complete protection against endo-parasites, ecto-parasites and fungal diseases or combined as fixed dose combinations (FDC) or co-administered with antineoplastic agents to treat neoplasms in humans. The anti-parasitic drug is anti-malarial drug.

The Atovaquone prodrug compound of formula I is selected from Atovaquone- Ether-Ester(Formula la), Atovaquone-Ester-Ester(formula lb) or Atovaquone- Ester-Acid (Id) which have 10 to 90 folds increased solubility when compared to parent drug, Atovaquone.

Accordingly, in another embodiment, the pharmaceutical formulations comprise the anti-malarial agent is Proguanil in combination with Atovaquone-Ether-Ester or Atovaquone-Ester-Ester Prodrugs, wherein, the anti-malarial agent Proguanil further increases the solubility of Atovaquone-Ether-Ester(Formula la), Atovaquone-Ester-Ester(formula lb) or Atovaquone-Ester-Acid (Id), upto 100 folds.

Atovaquone prodrugs can be preferably formulated with anti-malarial, wherein the additional antimalarial agent can be artemisinin, artemisinin derivatives, proguanil, quinine, piperaquine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine or halofantrine. The most preferred anti-malarial partner drug is proguanil and applicants have surprisingly found that the formulation of Atovaquone Prodrugs with polar anti- parasitic drug Proguanil, further increases Atovaquone prodrugs solubility.

Accordingly, in preferred embodiment of present invention, the anti -parasitic drug is Proguanil base or Proguanil HC1, wherein the formulation offers high solubility of polar anti-parasitic drug Proguanil base or Proguanil HC1 to form a stable clear solution suitable for parenteral administration.

The reservoir of pharmaceutical formulation of compound of formula I facilitates sustained release of the active moiety, i.e., Atovaquone from subcutaneous or intramuscular depots and offers prolonged protection for, but not limited to, 1-2 weeks, 2-3 weeks or 3-4 weeks, i.e., month long and so forth. The systemic bioavailability and efficacy of Atovaquone prodrug oil-solution or oil-suspension formulation, either alone or in combination with other antiparasitic agents, depends on dosing interval and volume of the pharmaceutical formulation injected along with the cumulative properties of excipients.

In another embodiment, the present invention provides the dosing schedule of injectable oil-solution or oil-suspension formulation of Atovaquone Prodrug either alone or in combination with other anti-parasitic drugs, at weekly, biweekly, monthly bimonthly or quarterly intervals. The pharmaceutical formulation can be can be administered parenterally by subcutaneous or intramuscular injection thereby atovaquone is released from the pharmaceutical composition at a rate providing an effective therapeutic concentration of systemically for extended period of time in the blood plasma of subject in need of such medication.

In another embodiment, the invention provides a method for the treatment or prevention of endo-parasitic, ecto-parasitic including topical fungal infections in a subject comprising administering to the subject effective concentration of pharmaceutical composition of compound of formula I, in association with suitable pharmaceutical excipients.

In yet another aspect, the invention discloses use of Atovaquone Prodrug either alone or in combination with other anti-parasitic drugs for treatment or prophylaxis of parasitic disease for example, but not limited to, Pneumocystis carinii Pneumonia, Toxoplasmosis, Malaria, Cysticercosis, Ascariasis, Echinococcosis, Cryptosporidiosis, Babesiosis, Ancylostomiasis, Clonorchiasis, Filariasis, Hydatid Disease, Enterobiasis, Leishmaniasis, Loiasis, Onchocerciasis, Strongyloidiasis, Taeniasis, Trichinellosis, Whipworm Infection, Trichuriasis and Trypanosomiasis.

In an another aspect, the invention discloses methods of administration of the Prodrug Atovaquone alone or in combination with other anti-parasitic drugs for treatment or prophylaxis of parasitic disease for example, but not limited to, Pneumocystis carinii Pneumonia, Toxoplasmosis, Malaria, Cysticercosis, Ascariasis, Echinococcosis, Cryptosporidiosis, Babesiosis, Ancylostomiasis, Clonorchiasis, Filariasis, Hydatid Disease, Enterobiasis, Leishmaniasis, Loiasis, Onchocerciasis, Strongyloidiasis, Taeniasis, Trichinellosis, Whipworm Infection, Trichuriasis and Trypanosomiasis, which method comprise administering Atovaquone Prodrug either alone or in combination with other anti-parasitic drugs in a therapeutically effective amount, optionally together with a pharmaceutical acceptable agent / carrier / excipients, to a subject in need thereof.

As used herein, the term “therapeutically effective amount” means and include an amount which is sufficient to produce safe and desired prophylactic or therapeutic effect in controlling the parasitic disease in a subject.

The Prodrugs of Atovaquone, according to the present invention are discernible and characterizable on basis of the Carbon and Proton NMR. The Atovaquone Prodrugs of present invention possesses entirely different physico-chemical properties compared to parent active moiety Atovaquone. Thus, Atovaquone Prodrugs of the present invention can be identified and well characterized by methods known in the art per se such as DSC, TGA, Melting Point etc. It should be understood that operator, instrument and other similar changes may result in some margin of error with respect to analytical characterization of the solid.

The DSC, NMR and TGA methods used for the identification and characterization of Atovaquone Prodrugs of the present invention are described below:

(a) Differential Scanning Calorimetry (Abbreviated as DSC)

Differential scanning Calorimetry analysis of Atovaquone Prodrugs was recorded on DSC Q20 (TA Instruments) at a temperature range from 30°C to 350°C with heating ramp 10 °C/Min. The Atovaquone Prodrugs of the present invention can well be characterized by endotherm in DSC diagram.

(b) Nuclear Magnetic Resonance Spectroscopy (Abbreviated as NMR)

Analytical characterization of the compound according to the invention was carried out by NMR Spectroscopy using an Avance III 300 MHz (Bruker) NMR. About 40.0 mg of sample was taken and dissolved in 1.0 ml CDC13. The solution obtained was transferred in clean NMR tube and scanned with the set parameters.

(c) Thermogravimetric Analysis (Abbreviated as TGA) To measure mass of a sample over time and characterize the thermal properties of Atovaquone Prodrug s, TGA was done by taking 5.0-10.0 mg of solid powder sample in platinum pan. The loaded pan containing sample was put in furnace. The instrument was equilibrated at 25.00 °C and ramped 10.00 °C/min to 335 °C.

EXAMPLES

Example 1: Preparation of 10-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)decanoic acid. Chemical Formula: C32H37C1O5. Molecular Weight: 537.0930 Preparation of 10-Bromodecanoic acid

Toluene (50 ml), 9-Decenoic acid (10 g) and AIBN (0.5g) was charged at 25- 30°C. Reaction mass was stirred at 25-30°C for 10 minutes, to obtain clear colorless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (15.84 gm) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25°C and 50 ml water added to the reaction mass. Reaction mass was stirred 45 minutes at 25°C and layers were separated. Aq. Layer was washed with toluene. Combined organic layer was washed with 2% Sodium metabisulfite solution. Again, organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. Product was light yellowish solid. Weight was 11 gm and Purity as analyzed by GC was 85%.

Charged NaHCOi (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 10-Bromodecanoic acid (5.14 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C, pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and subsequently washed with water (2x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml) and solvent distilled out. The weight obtained was 21 gm. Compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. Filtered at -10°C and washed with chilled n-Hexane (-10°C). Suck dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder of weight 2.2 g and purity 97% as estimated by HPLC.

Example 2: Preparation of ll-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)undecanoic acid. Chemical Formula: C33H39C1O5. Molecular Weight: 551.1200 Preparation of 11-Bromoundecanoic acid

Toluene (50 ml), 10-Undecenoic acid (10 gm) and AIBN (0.5 gm) was charged at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes.to obtain clear colourless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (14.65 gm) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred for 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25°C and 50 ml water added to the reaction mass. Reaction mass was stirred for 45 minutes at 25°C and layer separated. Aq. Layer was washed with toluene. The combined organic layer was washed with 2% Sodium metabisulfite solution. Again, organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. The product obtained was light yellowish solid. Net wt was 14 gm, and purity 85% as assessed by GC.

Charged NaHCO3 (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 11-Bromoundecanoic acid (5.42 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C, filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 2.6 gm and purity 97 % as assessed by HPLC. Example 3: Preparation of 12-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)dodecanoic acid. Chemical Formula: C34H41C1O5. Molecular Weight: 565.1470.

Preparation of 12-Bromdodecanoic acid

Toluene (50 ml), 11-Dodecenoic acid (10 gm) and AIBN (0.5g) was charged at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes. Reaction mass was clear colourless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (13.6 gm) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred for 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25°C and 50 ml water added to the reaction mass. Reaction mass was stirred for 45 minutes at 25°C and layer separated. Aq. layer was washed with toluene. Combined organic layer was washed with 2% Sodium metabisulfite solution. Again, organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. Product was light yellowish solid with net weight of 14gm and purity at 85% as assessed by GC.

Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 12-Bromododecanoic acid (5.7 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25-30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjust to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Thereafter, charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. Mass stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. Pure product was yellow colour powder with net weigh of 3.0 gm and purity 97% as estimated by HPLC. Example 4: Preparation of 14-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)tetradecanoic acid. Chemical Formula:

C36H45C1O5. Molecular Weight: 593.2010

Preparation of 14-Bromotetradecanoic acid

Toluene (50 ml), 13-Tetradecenoic acid (10 g) and AIBN (0.5g) was charged at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes. Reaction mass was clear colorless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (11.92 gm) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred for 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25°C and 50 ml water added to the reaction mass. Reaction mass was stirred for 45 minutes at 25°C and layer separated. Aq. layer was washed with toluene. Combined organic layer was washed with 2% Sodium metabisulfite solution. Again organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. Product was light yellowish solid with net weight of 13gm and purity of 85% as assessed by GC.

Charged NaHCOs (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 14-Bromotetradecanoic acid (6.28 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Subsequently, the reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25- 30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. The colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, final pH was 3-4. The mass was stirred for 20-30 minutes. The semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out and the net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n- Hexane (5:95). Column purified product was re-crystallized in n- Hexane at - 10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was sucked dried initially and further dried on rota evaporator under vacuum at 30- 35°C. Pure product was yellow colour powder with net weight of 3.1 g gm and Purity 97 % as assessed by HPLC.

Example 5: Preparation of 15-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)pentadecanoic acid. Chemical Formula: C37H47C1O5. Molecular Weight: 607.2280

Preparation of 15-Bromopentadecanoic acid

Toluene (50 ml), 14 -Pentadecenoic acid (10 gm) and AIBN (0.5 gm) was charged at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes. Reaction mass was clear colourless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (11.22 gm) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred for 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25 °C and 50 ml water added to the reaction mass. Reaction mass was stirred for 45 minutes at 25°C and layer separated. Aq. layer was washed with toluene. The combined organic layer was washed with 2% Sodium metabisulfite solution. Again, organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. Product was light yellowish solid with a net weight of 10 gm and purity of 85% as assessed by GC.

Charged NaHCO3 (34.3 g) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone (15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 15 -Bromopentadecanoic acid (6.57 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25- 30°C, final pH is 3-4. The mass was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight obtained was 21 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). Column purified product re-crystallized in n- Hexane at -10°C. It was filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and further the product was dried using rota evaporator under vacuum at 30-35°C. Pure product was yellow coloured powder with net weight of 3.0 g gm and purity at 97% as assessed by HPLC.

Example 6: Preparation of 16-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)hexadecanoic acid. Chemical Formula: C38H49C1O5. Molecular Weight: 621.2550

Preparation of 16-Bromohexadecanoic acid

Toluene (50 ml), 15 -Hexadecenoic acid (10 gm) and AIBN (0.5 gm) was charged at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes. Reaction mass was clear colorless solution. Reaction mass was cooled to 0±5°C. HBr in acetic acid (30%) (10.60 g) was added to the reaction mass at 0±5°C within 30 minutes. Reaction mass was stirred for 20 hrs at 0±5°C. Reaction was monitored with TLC. Reaction mass was warmed up to 25°C and 50 ml water added to the reaction mass. Reaction mass was stirred for 45 minutes at 25°C and layer separated. Aq. Layer was washed with toluene. The combined organic layer was washed with 2% Sodium metabisulfite solution. Again organic layer was washed with water (50 ml). Solvent was distilled out under vacuum at 35°C. Mass was degassed under vacuum for 3-4 hrs at 35°C. Product was light yellowish solid. The net weight was 10 gm and Purity 85% as assessed by GC.

Charged NaHCCh (34.3 gm) and water (75 ml) at 25-30°C. Reaction mass was stirred for 10 minutes at 25-30°C. Charged Atovaquone(15 gm) and MEK (60 ml) to the reaction mass at 25-30°C. Reaction mass was stirred for 10 minutes at 25- 30°C. 16-Bromohexadecanoic acid (6.86 gm) and MEK (15 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 30 minutes at 25- 30°C. Colour of reaction mass was red brown slurry. Then reaction mass was warmed to reflux. Reaction mass was refluxed for 20-25 hrs at 70-75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with acetic acid. Colour of reaction turned from red brown to yellowish. Charged 225 ml water to the reaction mass at 25-30°C, the final pH is 3-4. It was stirred for 20-30 minutes. Semisolid oily mass was filtered and washed with water (2 x 100 ml). Semi solid was dissolved in 500 ml MDC and washed with water (5 x 150 ml). Solvent was distilled out. The net weight was 17 gm. The compound was purified with column chromatography. Mobile phase was Ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was then suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The pure product was yellow coloured powder with weight of 3.2 g gm and purity of 97% as estimated by HPLC. Example 7: Preparation of ethyl 10-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)decanoate. Chemical Formula: C34H41C1O5. Molecular Weight: 565.1470

Charged 10-Bromodecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes. A clear pale yellow solution was obtained. Charged Cone. H2SO4 (0.624 gm). The pH was 1-2 as measured using pH paper. Reaction mass was refluxed for 8 hrs at 78-80°C. Reaction completion was monitored with GC.

Ethanol was distilled out under vacuum at 38-40°C. The product was oily mass with a weight of 10 gm and Purity of 95% as estimated by GC.

Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5gm) and MEK (20 ml) were charged to the reaction mass at 25-30°C. Reaction mass was stirred for 15-20 mins at 25-30°C to obtain red brown slurry mass. 10- Bromodecanoic acid ethyl ester (4.19 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70- 75°C. Reaction completion was monitored with HPLC. Reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25- 30°C. The mass was filtered and washed with water and hexane. The solid isolated weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. Final crude mass weighed 5.2 gm and was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as a mobile phase. After column chromatography, 2.1 gm material thus obtained was taken in 4 ml n-Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further the product was dried on rota evaporator under vacuum at 30-35°C. The final product was yellow coloured powder weighing 1.2 gm and having purity of 98% as determined by HPLC.

Example 8: Preparation of ethyl ll-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)undecanoate. Chemical Formula: C35H43C1O5. Molecular Weight: 579.1740

Charged 11-bromoundecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes. A clear pale yellow solution was obtained. Charged Cone. H2SO4 (0.6 gm), to maintain pH between 1-2.. Reaction mass was refluxed for 8 hrs at 78-80°C. Reaction completion was monitored with GC. Ethanol was distilled out under vacuum at 38-40°C. Product was oily mass with net weight of 10 gm and purity of 95% as assessed by GC.

Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 mins at 25-30°C to obtain red brown slurry mass. 11-Bromoundecanoic acid ethyl ester (4.4 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The hexane layer was concentrated on rota evaporator under vacuum at 35-40°C.The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n- Hexane and cooled to -10°C for 2.0 hrs. It was then filtered and washed with chilled n-hexane (-10°C); suck dried initially and subsequently the product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.4 gm and purity of 98% as estimated by HPLC. Example 9: Preparation of ethyl 12-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)dodecanoate. Chemical Formula: C36H45C1O5. Molecular Weight: 593.2010

Charged 12-Bromododecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes to obtain clear pale yellow solution. Charged cone. H2SO4 (0.56 gm) and the pH was 1-2 as tested using pH paper. The reaction mass was refluxed for 8 hrs at 78-80°C. The reaction completion was monitored with GC. Ethanol was distilled out under vacuum at 38-40°C. The Product was oily mass weighing 10 gm and Purity of 95% as estimated by GC.

Charged NaHCOs (13.8 gm) and water (25 ml) at 25-30°C. Reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) was charged to the reaction mass at 25-30°C and stirred for 15- 20 min at 25-30°C to obtain red brown slurry mass. 12-Bromododecanoic acid ethyl ester (4.6 gm) and MEK (5 ml) was charged to the reaction mass at 25-30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. Reaction mass was refluxed for 35-40 hrs at 70-75°C. Reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. Isolated solid weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml); concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.2 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.1 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C) suck dried initially and further product was dried on rota evaporator under vacuum at 30-35°C. The product was yellow coloured powder weighing 1.5 gm and purity 98% as estimated by HPLC.

Example 10: Preparation of ethyl 14-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)tetradecanoate. Chemical Formula: C38H49C1O5. Molecular Weight: 621.2550

Charged 14-Bromotetradecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes to obtain clear pale yellow solution. Then charged cone. H2SO4 (0.51 gm) and pH was 1-2 as measured by pH paper. The reaction mass was refluxed for 8 hrs at 78-80°C. The reaction completion was monitored with GC. Ethanol was distilled out under vacuum at 38-40°C. The product was oily mass weighing 10 gm and purity of 95% as estimated by GC.

Charged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 14- Bromotetradecanoic acid ethyl ester (5.03 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.3 gm (un-reacted atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography, 2.2 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then subjected to suck drying and further the product was dried on rota evaporator under vacuum at 30- 35°C. The product was yellow coloured powder with net weight of 1.5 gm and purity of 98% as estimated by HPLC. Example 11: Preparation of ethyl 15-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)pentadecanoate. Chemical Formula: C39H51C1O5. Molecular Weight: 635.2820

Charged 15-bromopentadecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes to obtain a clear pale yellow solution. Charged cone. H2SO4 (0.488 gm) and pH was 1-2 as estimated using pH paper. The reaction mass was refluxed for 8 hrs at 78-80°C. The reaction completion was monitor with GC. Ethanol was distilled out under vacuum at 38-40oC. The product was oily mass of 10 gm net weight and 95% Purity as estimated by GC

Charged NaHCCh (13.73 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 15-20 at 25-30°C to obtain red brown slurry mass. 15- Bromopentadecanoic acid ethyl ester (5.24 gm) and MEK (5 ml) charged to the reaction mass at 25-30°C. The reaction mass was stirred for 25-30 minutes at 25- 30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitor with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass was adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass was stirred for 15-20 minutes at 25-30°C. It was then fdtered and washed with water and hexane. The Solid isolated was weighed 2.5 gm (un-reacted atovaquone). The Hexane layer (containing product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.4 gm was taken for column chromatography using ethyl acetate: n- Hexane (5:95) as mobile phase. After column chromatography, 2.3 gm material thus obtained was taken in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. The product was yellow coloured powder with net weight of 1.6 gm and purity of 98% as estimated by HPLC.

Example 12: Preparation of ethyl 16-((3-((lr,4r)-4-(4- chlorophenyl)cyclohexyl)-l,4-dioxo-l,4-dihydronaphthalen-2- yl)oxy)hexadecanoate. Chemical Formula: C40H53C1O5. Molecular Weight: 649.3090

Charged 16-bromohexadecanoic acid (10 gm) and ethanol (100 ml) at 25-30°C and stirred for 10 minutes to obtain clear pale yellow solution. Charged cone. H2SO4 (0.47 gm) and pH was 1-2 as measured by pH paper. The reaction mass was refluxed for 8 hrs at 78-80°C. The reaction completion was monitored with GC. Ethanol was distilled out under vacuum at 38-40°C. The product was oily mass weighing 10 gm and purity of 95% as estimated by GC.

Charged NaHCCh (13.8 gm) and water (25 ml) at 25-30°C. The reaction mass was stirred at 25-30°C for 10 minutes to obtain white slurry mass. Atovaquone (5 gm) and MEK (20ml) charged to the reaction mass at 25-30°C. Reaction mass was stirred 15-20 at 25-30°C to obtain red brown slurry mass. 16-Bromohexadecanoic acid ethyl ester (5.45 gm) and MEK (5 ml) charged to the reaction mass at 25- 30°C. Reaction mass was stirred for 25-30 minutes at 25-30°C to obtain red brown slurry mass. The reaction mass was refluxed for 35-40 hrs at 70-75°C. The reaction completion was monitored with HPLC. The reaction mass was cooled to 25-30°C and pH of reaction mass adjusted to 3-4 with 30 ml acetic acid. 75 ml water was added and sticky oily mass stirred for 15-20 minutes at 25-30°C. It was then filtered and washed with water and hexane. The solid isolated was weighed 2.5 gm (un-reacted Atovaquone). The Hexane layer (containing the product) was washed with water (2 x 50 ml). The Hexane layer was concentrated on rota evaporator under vacuum at 35-40°C. The final crude mass weighing 5.8 gm was taken for column chromatographyusing ethyl acetate: n-Hexane (5:95) as mobile phase. After column chromatography 2.6 gm material thus obtained was take in 4 ml n-Hexane, cooled to -10°C for 2.0 hrs and then filtered and washed with chilled n- hexane (-10°C). It was then suck dried initially and dried on rota evaporator under vacuum at 30-35°C subsequently. Product was yellow coloured powder with net weight of 1.7 gm and Purity of 98% as determined by HPLC. Example 13: Preparation of 10-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)-10-oxodecanoic acid. Chemical

Formula: C32H35C1O6. Molecular Weight: 551.0760

Stepl

Step 3

Thionyl chloride (63.7 gm) was charged under nitrogen atmosphere and cooled to 0°C. Decanedioic acid (15 gm) was charged at 0°C to 5oC under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml). Parallelly, in another 4-neck round botom flask, Atovaquone (11.39 gm) and MDC (570 ml) was charged at 25-30°C. 456 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25-30°C for 4-5 hrs. The reaction mass colour was reddish brown biphasic. To the reaction mass, the above prepared Decanedioic acid chloride solution was added within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The reaction mass turned to light yellowish biphasic solution and the pH of reaction mass was 10, as estimated using pH paper. The reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The reaction mass pH was adjusted to 3-4 is using acetic acid. It was then stirred for 30 minutes and subsequently taken for layer separation. The aqueous layer was extracted with MDC (120 ml). Combined organic layer was filtered to remove un-reacted decanedioic acid. The organic layer was washed with water till the neutral pH of 7 was attained. The organic layer was taken for distillation. The crude product thus obtained was weighed 20 gm. The crude product was taken for column chromatography. The mobile phase was Methanol: MDC (1:99). The Product was pale yellow coloured powder and the net weight was 8 gm and purity 98% as estimated using HPLC.

Example 14: Preparation of ll-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)-l 1-oxoundecanoic acid. Chemical Formula: C33H37C1O6 Molecular Weight: 565.1030

Thionyl chloride (59.57 gm) was charged under nitrogen atmosphere and cooled to 0°C. Undecanedioic acid (15 gm) was charged at 0°C to 5°C under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. Reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml).

Parallelly, in another 4-neck round bottom flask, Atovaquone (10.65 gm) and MDC (533 ml) was charge at 25-30°C. 426 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25- 30°C for 4-5 hrs. Reaction mass color was reddish brown biphasic. Above prepared Undecanedioic acid chloride solution was added to this reaction mass within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The reaction mass turned to light yellowish biphasic solution and pH of reaction mass was 10 as estimated by pH paper. The reaction mass was stirred for 1.0 hr at 25±2°C. The Reaction completion was monitored with TLC and HPLC. The reaction mass pH was adjusted to 3-4 with acetic acid. It was then stirred for 30 minutes and subjected to layer separation. The aqueous layer was extracted with MDC (107 ml). Combined organic layer was fdtered to remove un-reacted Undecanedioic acid. The Organic layer was washed with water till the neutral pH of 7 is attained. The Organic layer was taken for distillation. The weight of crude product thus obtained was 22 gm. The crude product was subjected to column chromatography. Mobile phase was Methanol: MDC (1 :99). Then product was pale yellow coloured powder with net weight of 9 gm and purity of 98% as estimated by HPLC.

Example 15: Preparation of 12-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)-12-oxododecanoic acid. Chemical

Formula: C34H39C1O6. Molecular Weight: 579.1300

Thionyl chloride (56 gm) was charged under nitrogen atmosphere and cooled to 0°C. Dodecanedioic acid (15 g) was charged at 0°C to 5°C under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml).

Parallelly, in another 4-neck round bottom flask, Atovaquone (10 gm) and MDC (500 ml) was charged at 25-30°C. 400 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25- 30°C for 4-5 hrs. The reaction mass color was reddish brown biphasic. Above prepared Dodecanedioic acid chloride solution was added to this reaction mass within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The Reaction mass turned to light yellowish biphasic solution and pH of reaction mass was 10, as estimated using pH paper. Reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The reaction mass pH was adjusted to 3-4 with acetic acid. The reaction mass was then stirred for 30 minutes and subsequently subjected to layer separation. The aqueous layer was extracted with MDC (100 ml). Combined organic layer was filtered to remove un-reacted dodecanedioic acid. The Organic layer was washed with water till a neutral pH of 7 is obtained. Organic layer was then subjected to distillation. The weight of crude product thus obtained was 21 gm. The crude product was subjected to column chromatography. The Mobile phase was Methanol: MDC (1:99). The final product was pale yellow coloured powder weighing 9 gm and purity of 98% as estimated using HPLC

Example 16: Preparation of 14-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo- 1 ,4-dihydr onaphthalen-2-yl)oxy)-l 4-oxotetradecanoic acid. Chemical

Formula: C36H43C1O6. Molecular Weight: 607.1840 Thionyl chloride (49.87 gm) was charged under nitrogen atmosphere and cooled to 0°C. Tetradecanedioic acid (15 gm) was charged at 0°C to 5°C under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml).

Parallelly, in another 4-neck round bottom flask, Atovaquone (8.91 gm) and MDC (446 ml) was charged at 25-30°C. 357 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25- 30°C for 4-5 hrs. The reaction mass colour was reddish brown biphasic. Above prepared Tetradecanedioic acid chloride solution was added to this reaction mass within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. Reaction mass turned to light yellowish biphasic solution. The pH of reaction mass was 10 as estimated by pH paper. Reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The reaction mass pH was adjusted to 3-4 with acetic acid. It was then stirred for 30 minutes and subsequently subjected to layer separation. The aqueous layer was extracted with MDC (89 ml). Combined organic layer was filtered to remove un-reacted Tetradecanedioic acid. The organic layer was washed with water till the neutral pH of 7 was attained. The Organic layer was then taken for distillation. The weight of crude product thus obtained was 19 gm. Crude product was taken for column chromatography. The Mobile phase was Methanol: MDC (1 :99). The product was pale yellow coloured powder with net weight of 7gms and purity of 98% as estimated by HPLC

Example 17: Preparation of 15-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl)oxy)-15-oxopentadecanoic acid. Chemical

Formula: C37H45C1O6. Molecular Weight: 621.2110

Thionyl chloride (47.30 gm) was charged under nitrogen atmosphere and cooled to 0°C. Pentadecanedioic acid (15 gm) was charged at 0°C to 5°C under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml). Parallelly, in another 4-neck round bottom flask, Atovaquone (8.45 gm) and MDC (423 ml) was charged at 25-30°C. 338 ml 10% NaOH aq. Solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained at 25- 30°C for 4-5 hrs. The reaction mass colour was reddish brown biphasic. Above prepared Pentadecanedioic acid chloride solution was added to this reaction mass within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The reaction mass turned to light yellowish biphasic solution and pH of reaction mass was 10, as estimated using pH paper. The reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The pH of reaction mass was adjusted to 3-4 with acetic acid. It was then stirred for 30 minutes and subsequently subjected to layer separation. The aqueous layer was extracted with MDC (85 ml). Combined organic layer was fdtered to remove un-reacted Pentadecanedioic acid. The Organic layer was washed with water till the neutral pH of 7 is attained. The organic layer was then taken for distillation. The weight of crude product thus obtained was 18 gm. The crude product was taken for column chromatography. The mobile phase was Methanol: MDC (1 :99). The product was pale yellow coloured powder. The net weight was 8 gm with a purity of 98% as estimated using HPLC.

Example 18: Preparation of 16-((3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo- 1 ,4-dihydr onaphthalen-2-yl)oxy)-l 6-oxohexadecanoic acid. Chemical Formula: C38H47C1O6. Molecular Weight: 635.2380

Thionyl chloride (45 gm) was charged under nitrogen atmosphere and cooled to 0°C. Hexadecanedioic acid (15 gm) was charged at 0°C to 5°C under nitrogen atmosphere within 15 minutes. The reaction mass was warmed up to 25-30°C within 30 minutes. The reaction mass was refluxed for 3.0 hrs at 80-83°C. The reaction mass was a clear solution. The reaction mass was cooled to 25-30°C under nitrogen atmosphere and diluted with MDC (50 ml).

Parallelly, in another 4-neck round bottom flask, Atovaquone (8.04 gm) and MDC (402 ml) were charged at 25-30°C. 332 ml 10% NaOH aq. solution was added slowly to the reaction mass at 25-30°C. The reaction mass was maintained for 4-5 hrs at 25-30°C. The reaction mass color was reddish brown biphasic. Above prepared Hexadecanedioic acid chloride solution was added to this reaction mass within 30 minutes drop wise under vigorous stirring and under nitrogen atmosphere at 20±2°C. The reaction mass turned to light yellowish biphasic solution and pH of reaction mass was 10, as estimated through pH paper. The reaction mass was stirred for 1.0 hr at 25±2°C. The reaction completion was monitored with TLC and HPLC. The reaction mass was adjusted to pH 3-4 with acetic acid. It was then stirred for 30 minutes and subsequently taken for layer separation. The Aqueous layer was extracted with MDC (81 ml). Combined organic layer was fdtered to remove un-reacted Hexadecanedioic acid. Organic layer was washed with water till a neutral pH of 7 is attained. Organic layer was then taken for distillation. The weight of crude product thus obtained was 16 gm. The crude product was taken for column chromatography. The mobile phase was Methanol: MDC (1 :99). The product was pale yellow coloured powder weighing 7 gm and Purity of 98% as estimated by HPLC

Example 19: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl) 10-ethyl decanedioate. Chemical Formula: C34H39C1O6. Molecular Weight: 579.1300

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) were charged at 25-30°C. The reaction mass was cooled to 0-5°C under nitrogen atmosphere. Thionyl chloride (2.64 gm) was added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature of reaction mass was gradually increased up to 25- 30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot of 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product thus obtained was weighed 4.5 gm. The Crude product was purified with column chromatography. The mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product re-crystallized in n- Hexane at -10°C. It was filtered at -10°C and washed with chilled n-Hexane (- 10°C). It was then suck dried initially and subsequently dried on rota evaporator under vacuum at 30-35°C. The final product was pale yellow coloured powder with net weight of 2.2 g and purity of 98% as measured by HPLC.

Example 20: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo- l,4-dihydronaphthalen-2-yl) 11-ethyl undecanedioate. Chemical

Formula: C35H41C1O6. Molecular Weight: 593.1570

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) was charged at 25-30°C. The Reaction mass was cooled to 0-5°C under nitrogen atmosphere. Thionyl chloride (2.55 gm) was added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature was then gradually raised up to 25-30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product thus obtained was weighed 4.0 gm. The crude product was purified with column chromatography. The mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was then suck dried initially and subsequently dried on rota evaporator under vacuum at 30-35°C. The product was pale yellow coloured powder weighing 2.1 gm and having purity of 98% as estimated by HPLC.

Example 21: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl) 12-ethyl dodecanedioate. Chemical Formula: C36H43C1O6. Molecular Weight: 607.1840

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) was charged at 25-30°C. The reaction mass was cooled to 0-5°C under nitrogen atmosphere. Thionyl chloride (2.46 gm) was added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature was gradually raised to 25-30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot of 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product weighed 4.3 gm. The crude product was purified with column chromatography. The Mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n-Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was then suck dried initially and subsequently the product was dried on rota evaporator under vacuum at 30-35°C. The product was pale yellow coloured powder weighing 2.0 gm and having purity of 98%, as estimated by HPLC. Example 22: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl) 14-ethyl tetradecanedioate. Chemical Formula: C38H47C1O6. Molecular Weight: 635.2380

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) was charged at 25-30°C. The reaction mass was cooled to 0-5°C under nitrogen atmosphere. Thionyl chloride (2.3 gm) was added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature of reaction mass was then gradually raised to 25- 30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product was 4 gm. The crude product was purified with column chromatography. The mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and subsequently dried on rota evaporator under vacuum at 30- 35°C. The product was pale yellow coloured powder, weighing 1.8 gm and purity of 98% as estimated by HPLC. Example 23: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl) 15-ethyl pentadecanedioate. Chemical

Formula: C39H49C1O6. Molecular Weight: 649.2650

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) was charged at 25-30°C. The reaction mass was cooled to 0-5oC under nitrogen atmosphere. Thionyl chloride (2.23 gm) was added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature of reaction mass was raised gradually to 25-30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot of 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product thus obtained was weighed 4.1 gm. The crude product was purified with column chromatography. The mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and subsequently dried on rota evaporator under vacuum at 30-35°C. The final product was pale yellow coloured powder weighing 2.1 gm and purity of 98% as estimated by HPLC.

Example 24: Preparation of l-(3-((lr,4r)-4-(4-chlorophenyl)cyclohexyl)-l,4- dioxo-l,4-dihydronaphthalen-2-yl) 16-ethyl hexadecanedioate. Chemical Formula: C40H51C1O6. Molecular Weight: 663.2920

Atovaquone Ester-Acid (4 gm) and ethanol (60 ml) was charged at 25-30°C. The reaction mass was cooled to 0-5°C under nitrogen atmosphere. Thionyl chloride (2.15 gm) added drop wise to the reaction mass at 0-5°C under nitrogen atmosphere. The temperature of reaction mass was gradually raised to 25-30°C within 2.0 hrs and maintained at 25±2°C for 18 hrs. Thionyl chloride 2 ^nd lot of 1.0 gm was charged to the reaction mass at 0-5°C under nitrogen atmosphere. Reaction mass was maintained at 25±2°C for 4 hrs. The reaction completion was monitored with TLC and HPLC. The reaction mass was taken for solvent distillation. The crude product was 4.2 gm. The crude product was purified with column chromatography. The Mobile phase was ethyl acetate: n-Hexane (5:95). The column purified product was re-crystallized in n- Hexane at -10°C. It was then filtered at -10°C and washed with chilled n-Hexane (-10°C). It was suck dried initially and subsequently dried on rota evaporator under vacuum at 30-35°C. The product was pale yellow coloured powder weighing 2.1 gm, and purity of 98% as estimated by HPLC.

Example 25:

Various parenteral formulations of Atovaquone and Atovaquone prodrugs were prepared as shown in table 1 below. The solubility of these prodrugs vis-a-vis Atovaquone was assessed by solubilising the max possible quantity to offer a clear stable solution in 1.75ml of Benzyl Alcohol and 1.25ml of Sesame oil. The results have been tabulated below.

The polar partner drug Proguanil was added to assess its solubility with Atovaquone Prodrugs, Atovaquone-Ether -Ester and Atovaquone- Ester- Ester. Proguanil was solubilised completely in benzyl alcohol (1.75 ml) and Sesame oil solution (1.25ml) whilst further increasing the solubility of said Atovaquone prodrugs. The results have been summarized in table below