Title of Invention

COMPOUNDS WITH ANTIFUNGAL PROPERTIES AND PROCESS THEREOF

Abstract

The present invention relates to compounds of formula (1), its solvates and pharmaceutically acceptable salts having antifungal activity and its pharmaceutical composition comprising an effective amount of compound of formula (1). The invention also relates to a process for the preparation of said compounds by contacting the intermediate alcohol, prepared from 1,2-O-isopropylideneglyceraldehyde and substituted phenylacetates, with acid chlorides under appropriate conditions to obtain some of the preferred compounds of the invention.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule!3) 1. TITLE OF THE INVENTION: "Compounds with Antifungal properties and Process Thereof 2. APPLICANTS: (a) NAME: Council of Scientific & Industrial Research (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: Anusandhan Bhavan, Rafi Marg, New Delhi - 110 001, India. (a) NAME: FDC Limited (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 142-148, S.V. Road, Jogeshwari (W), Mumbai - 400 102, Maharashtra, India. 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Field of Invention: The present invention relates to compounds of formula (1), their solvates and pharmaceutically acceptable salts having antifungal activity. The invention also relates to a process for the preparation of said compounds and their pharmaceutical compositions comprising an effective amount of compound of formula (1) wherein R = substituted Formula (1) alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyl or halophenyl or pyrrolyl and Ri and R2 are same or different and each denotes hydrogen or halogen or alkoxy, or its solvates or salts of such compounds having at least one salt forming group. Background of the Invention: 5-Aceloxymethyl-3-aryl-2/£ 5//-furan-2-one based antifungal agents are known to exhibit anti-fungal activity against various strains of fungi. However, the occurrence of fungal infections in larger number and emergence of pathogens resistant to some of the antifungal drugs already existing in the market, makes it necessary for the development of broad spectrum antifungal agents which are effective against certain mycoses (such as aspergillosis) for which no effective treatment is available till to date. In the past decades, the frequency and types of life-threatening fungal infections have increased dramatically in immuno-compromised patients. Several factors have contributed to this rise such as the expansion of severely ill and or immuno-compromised patient populations with HIV infection, with chemotherapy induced neutropenia, and receiving immunosuppressive therapy; more invasive medical procedures, such as 2 extensive surgery and the use of prosthetic devices and vascular catheters; treatment with broad-spectrum antibiotics or glucocorticosteroids; and peritoneal dialysis or hemodialysis. This problem of increased fungal infections is accentuated by the emergence of fungal strains which are resistant to currently used antifungal agents. Major opportunistic fungal pathogens include Candida albicans, Aspergillus, Fusurian spp. Other species of Candida such as C, krusei, C tropicalis, C.glabrata are major causative agents of candidiasis. Invasive pulmonary aspergillosis is a leading cause of mortality in bone marrow transplant recipients. HIV-infected patients are particularly susceptible to mucosal candidiasis, cryptococcal meningitis. Fluconazole is the preferred broad spectrum anti-fungal agent used in treatment of fungal infections. In recent times resistance of Candida albicans the most common cause of mucosal candidiasis in HIV-infected patients, after long-term suppressive therapy, to azoles, particularly fluconazole, is a cause of increasing concern. Resistance to fluconazole in other Candida species and in Cryptococcus neoformans has also been reported. Also, fluconazole appears to be less active against the two emerging Candida species, C. glabratta and C. krusei. Infection with Aspergillus, although not common, is frequently life-threatening and fluconazole has only moderate activity against this fungus. This has necessitated the need for new antifungal agents with broad spectrum of antifungal activity, which this invention seeks to provide. Prior Art of the Invention: J. Med. Chem. 44, 2701-2706, 2001 describes antifungal agents which covers generically compounds of formula (1) of the present invention wherein R = p-C^lU or CH3 or (CH3)3C, R1=H or CI and R2=H or Br or CI or OCH3 3 Formula (1) Objects of the Invention: 1) To provide compounds of formula (1) as antifungal agents having broader spectrum of activity. 2) To provide a process for the preparation of antifungal compound of formula (1). 3) To provide a pharmaceutical composition comprising an effective amount of antifungal compound of formula (1). 4) To provide solvate or pharmaceutically acceptable salts of compounds of formula (1). Summary of the Invention: The present invention discloses new antifungal compounds represented by general formula (1), its solvate and pharmaceutically acceptable salts and its pharmaceutical composition. The invention also relates to a process for the preparation of compounds of formula (1). In the process of preparation of compounds of formula (1), the said compounds may also be obtained as its solvates or its pharmaceutically acceptable salts as desired. 4 Detailed Description of Invention: In accordance with the object, the present invention provides compound of formula (1), its solvates or pharmaceutically acceptable salts of such compound having at least one Formula (1) salt forming group wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyi or haloalkyl or halophenyl or pyrrolyl and R\ and R2 are same or different and each denotes hydrogen or halogen or alkoxy. In an embodiment of the invention preferred compounds are of formula (1), wherein R = CH3 or Ph or allyl or 2-thienyl or 3-thienyl or 4,5-dibromo-2-thienyl or 2-chloroethyl or 3-chloropropyl or 4-chlorobutyl or 3-iodophenyl or 2-pyrrolyl, R\ and R2 are same or different and each denotes H, Br, CI, F and/or methoxy, or its solvates or pharmaceutically acceptable salt of such compounds having at least one salt forming group. Another embodiment provides pharmaceutical composition comprising a compound of formula (1) or its solvates or pharmaceutically acceptable salts of such compound having at least one salt forming group together with a pharmaceutical carrier. Yet another embodiment of the invention provides a method for the treatment or prevention of a fungal infection in a substrate, said method comprises administering an effective amount of compound of formula 1 or a pharmaceutically acceptable salt of such compound having at least one salt forming group or solvate thereof as provided by the invention, to a substrate in need of such treatment or prevention. Still another embodiment provides human being or animal as substrate. 5 A pharmaceutical composition comprising compound of formula (1) or its solvate or pharmaceutically acceptable salt of such compound having at least one salt forming group for the treatment or prevention of fungal infections. A process for the preparation of compound of formula (1), or its solvate or pharmaceutically acceptable salt of such compound having at least one salt forming group, comprising the steps of: a) contacting aldehyde of formula (2) Formula (2) with phenyl acetates of formula (3) wherein Ri and R2 are same or different and each denotes H, Br, CI, F and/or methoxy in an ,COOEt Formula (3) organic solvent in presence of base to obtain compound of formula (4) wherein R1 and R2 are same or different and each denotes H, Br, CI, F and/or methoxy; EtOOC -O. RI R2 Formula (4) 6 b) contacting hydroxy ester of formula (4) with an acidic catalyst in an alcoholic or hydrocarbon solvent to obtain the alcohol of the formula (5), Formula (5) c) reacting the alcohol of the formula (5) with acid chloride (6) in suitable organic solvent in presence of a catalyst to obtain the compound of formula (1) O Formula (1) wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyi or halophenyl or pyrrolyl and R1 and R2 are same or different and each denotes hydrogen or halogen or alkoxy. d) converting the compound of formula (1) to its pharmaceutically acceptable salt by adapting conventional method. A use of a compound of formula (I) or its solvates or a pharmaceutically acceptable salt of said compound having at least one salt forming group for the preparation of a pharmaceutically acceptable composition for use in the treatment or prevention of antifungal infections. 7 A pharmaceutical composition preferably is in the form of a capsule or tablet for the treatment or prevention of fungal infection. A compound of formula (1), along with suitable pharmaceutically acceptable excipients is used for the treatment or prevention of fungal infection in human beings or animals. The compounds of present invention may be used in agrochemical composition and for prevention and treatment of plant fungal infection. The compounds of the present invention may be prepared by adapting the route depicted in scheme 1 as herein below: Scheme 1 H+, R'OH RCOCI or RCONR"R" The invention describes a process for the preparation of 5-substituted-3-aryl-2H, 5H-furan-2-ones of the formula (1). More particularly the invention describes a process for the preparation of compound of the formula (1) wherein Rj and R2 are same or different and each denotes hydrogen or halogen or alkoxy and R denotes CH3 or Ph or allyl or 2-thienyl or 3-thienyl or 4,5-dibromo-2-thienyl or 2-chloroethyl or 3-chloropropyl or 4- 8 chlorobutyl or 3-iodophenyl or 2-pyrrolyl, from 2,3-0-isopropylideneglyceraldehyde of the formula (2). Accordingly the present invention describes a process for the preparation of 5-substituted-3-aryl-2H, 5//-furan-2-ones of the formula (1) wherein Ri and R2 are same or different and each denotes hydrogen or halogen or alkoxy and R = CH3 or Ph or allyl or 2-thienyl or 3-thienyl or 4,5-dibromo-2-thienyl or 2-chloroethyl or 3-chloropropyl or 4-chlorobutyl or 3-iodophenyl or 2-pyrrolyl which comprises reacting 1,2-0-isopropylideneglyceraldehyde of the formula (2) with substituted phenyl acetate of the formula (3), wherein R1 and R2 are same or different and each denotes hydrogen or halogen or alkoxy in a suitable organic solvent in presence of a suitable base and a catalyst at temperature -78 -10 °C for a suitable period, allowing to come to room temperature, quenching with ammonium chloride solution, extracting with suitable organic solvent, removing the organic solvent, purifying by column chromatography to collect the intermediate of the formula (4), stirring with an acidic catalyst in a suitable solvent at 0-80 °C for a suitable period, purifying by column chromatography to collect the intermediate of the formula (5), reacting with a suitable acid chloride of formula (6) in a suitable solvent in presence of a base at -10 to 30 °C for a suitable period or with a suitable amide of formula (7) in organic solvent at 40 to 90 °C for a suitable period, diluting with water, extracting with suitable water immiscible organic solvent, separating the organic layer, washing with water, drying over drying agent, concentrating and purifying the product by column chromatography to collect the required compound of the formula (1), The suitable organic solvent used in the preparation of hydroxyl ester (4) is selected from the group consisting of ethers; preferably tetrahydrofuran or diethyl ether. The suitable base used in the preparation of hydroxyl ester (4) is selected from the group consisting of alkyl lithium, alkali metal hydrides and alkali metal carbonates, preferably n-butyllithium or sodium hydride. The acidic catalyst used in the preparation of alcohol of the formula (5) is selected from the group consisting of organic or inorganic acids, preferably p-toluene sulfonic acid . The suitable solvent used in the preparation of alcohol of formula (5) is selected from the group consisting of alcohols or hydrocarbons, preferably methanol or ethanol. 9 The suitable catalyst used for the preparation of the compound of formula (1) from, alcohol of formula (5) is selected from the group consisting of organic bases preferably pyridine. The suitable organic solvent used in the preparation of formula (1) is selected from the group consisting of chlorinated solvents preferably dichloromethane or chloroform. 10 Structures of some of the preferred alcohols (5) and acid chlorides (6) and/or amides (7) used to obtain preferred compounds of formula (1), by adapting scheme 1 are depicted below:: Accordingly, the present invention provides compositions of the active compounds of formula (1), comprising a compound of formula (1) together with an excipient and optionally other auxiliary agents .The compositions are not limiting to those disclosed herein and are only in the form of illustrations and compounds of the present invention can be administered in different forms, the nature of which will depend, as it is well known, upon the chosen route of administration and the nature of the pathology to be treated. Thus, solid compositions according to the present invention for oral administration include dispersible tablets, SR tablets, disintegrating granules pouches, dispersible powders, granules and capsules. In tablets, the active component is admixed with at least one inert diluent such as lactose, starch, mannitol, microcrystalline cellulose or calcium phosphate; granulating and disintegrating agents for example corn starch, gelatin, microcrystalline cellulose or polyvinylpyrrolidone; and lubricating agents for example magnesium stearate, stearic acid or talc. The tablets may be coated or uncoated or may be SR tablets. SR tablets can be also formulated by known technique to delay disintegration and absorption in the gastrointestinal tract and, thereby, provide a sustained action over a longer period. Gastric film-coated or enteric film-coated tablets can be made with sugar, gelatin, hydroxypropylcellulose, nor acrylic resins. Tablets with a sustained action may also be obtained using an excipient which provides regressive osmosis, such as the galacturonic acid polymers. Formulations for oral use may also be presented as hard capsules of absorbable material, such as gelatin, wherein the active ingredient is mixed with an inert solid diluent and lubricating agents, or pasty materials, such as ethoxylated saturated glycerides. Soft gelatin capsules are also possible wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil. Dispersible powders and granules suitable for the preparation of a suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent; a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpirrolidone, gum tragacanath, xanthan gum, gum acacia, and one or more preservatives, such as methyl or n-propyl p- 16 hydroxybenzoate. Additional excipients, for example sweetening, flavouring and coloring agents may also be present. Liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, or propylene glycol. Aqueous solutions can also be prepared using P-cyclodextrin. Such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening, flavouring, perfuming, preserving agents and buffers. Other compositions for oral administration include spray compositions, which may be prepared by known methods. The spray compositions will contain a suitable propellent. Preparations for injection, according to the present invention, for parenteral administration include sterile aqueous or non-toxic parentally-acceptable diluent or solvent. Examples of aqueous solvents or suspending media are distilled water for injection, Ringer's solution, and isotonic sodium chloride solution. Aqueous solutions can also be prepared using P-cyclodextrins, such as hydroxypropyl- P-cyclodextrin. Such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening, flavoring, perfuming, preserving agents and buffers. Other compositions for oral administration include spray compositions, which may be prepared by known methods. The spray compositions will contain a suitable propellent. Preparations for injection, according to the present invention, for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions, in a non-toxic parentally-acceptable diluent or solvent. Examples of aqueous solvents or suspending media are distilled water for injection, Ringer's solution, and isotonic sodium chloride solution. Aqueous solutions can also be prepared using P-cyclodextrin, such as hydroxypropyl- p-cyclodextrin. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or alcohols such as ethanol. These compositions may also include adjuvants such as wetting, preserving, emulsifying and dispersing agents. They may be sterilized 17 by one of the known methods or manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. When all of the components are sterile, the injectables will maintain the sterility if they are manufactured in sterile environment. Preparations for vaginal administration according to the present invention include tablets, capsules, softgels, moulded pessaries, creams, foams and vaginal douches. Vaginal tablets provide the active component in admixture with microcrystalline cellulose, pregelatinized starch, lactose, polyvidone and magnesium stearate as typical excipients. Soft gelatin capsules (softgels) can be made dispersing the active ingredient in an oily medium, for example liquid paraffin, dimethylpolysiloxane 1000 or hydrogenated soybean oil. Moulded pessaries provide the active ingredient in admixture with a suitable synthetic or semi synthetic base (such as Suppocire® or Novata® types). Low viscosity saturated C& to C\2 fatty acid glycerides and colloidal silica are also added to improve incorporation and to prevent sedimentation of the active ingredient. Vaginal creams can be prepared as emulsions, with sufficient viscosity to retain their integrity and adhere to the vaginal cavity. Neutral fats, fatty acids, waxes, mineral oils and fatty acid esters can be used as the oily phase. Water, glycerine, sorbitol solution and polyethylene glycol are suitable excipients for the aqueous phase. Non-ionic emulsifying agents like polyethylene glycol ethers may also be used, and such compositions may also contain preserving, buffering and stiffening agents. Foaming systems can be made using a foamer (dispenser) that is able to transform a solution into a foam. Such systems may include co solvents, buffers, preservatives, foam stabilizers and perfumes in an aqueous vehicle. Vaginal douches may contain co solvents, preservatives, buffers and perfuming agents in a surfactant rich aqueous solution. A compound of the invention may also administered in the form of suppositories for rectal administration of the drug, or as creams, ointments, pastes, lotions, gels, sprays, foams, aerosols, solutions, suspensions or powders for topical use. Such compositions are prepared following conventional procedures well known to those skilled in the art. 18 A compound of the invention may also be administered as a hair or body shampoo. These formulations may be prepared using suitable ionic and/or amphoteric surface-active agents such as sodium laureth sulfate, triethanolamine laureth sulfate, cocoamidopropyl betaine; thickening agents for example cocamide DEA, carbomer, sodium chloride and polyethylene glycol 6000 distearate; and optionally, emollient and superflatting agents, buffers, and preserving and perfuming agents. The dosage and frequency of dose may vary depending upon the nature and severity of the fungal disease, symptoms, age and body weight of the patient, as well as upon the route of administration. In general, the compounds of the invention will be administered orally or parenterally which can be administered as a single dose or as divided doses. The invention is illustrated with the following examples and should not be construed to limit the scope of the present invention. The features of the present invention will become more apparent from the following description of the inventive concept and the description of the preferred embodiments and appended claims. EXAMPLES General procedure: Preparation of compounds of formula (1) Example 1: Preparation of 5-aceloxymethyl-3-aryl-2/f, 5//-furan-2-ones of the formula (1) by reaction of alcohols 5 with acid chlorides 6: To a solution of 5 (1 mmole) and pyridine (1 mmole) in 10 mL of DCM was added acid chloride 6 (1.1 mmole) 0°C. The reaction mixture was stirred at room temperature for 2 h and then washed with water (2 x 10 mL), dil. HC1 (2x10 mL), water (2x10 mL), dried over anhydrous. Na2SCO4 and concentrated. The residue was purified by column chromatography to yield the compounds of formula 1. The following compounds were prepared by the procedure given above: Example 2: Preparation of 3-(3,4-dichlorophenyl)-5-benzoyloxymethyl-2//, 5//-furan-2-one (1AA) 19 COPh NCL-FDC-Gr 3-F3 1H NMR (CDCl3): 5 4.66 (d, J=5 Hz, 2H), 5.38-5.45 (m, 1H), 7.39-7.50 (m, 3H), 7.55-7.59 (m, 1H), 7.63 (bs, 1H), 7.70 (dd, J=10, 2 Hz, 1H), 7.96-8.01 (m, 3H). Example 3: Preparation of 3-(3-chlorophenyl)-5-benzoyloxymethyl-2i/, 5i/-furan-2-one (1AB) COPh NCL-FDC-Gr 3-F9 1H NMR (CDCU): 8 4.55-4.80 (m, 2H), 5.35-5.47 (m, 1H), 7.32-7.49 (m, 4H), 7.52-7.67 (m, 2H), 7.71-7.80 (m, 1H), 7.85 (bs, 1H), 7.93-8.20 (m, 2H). Example 4: Preparation of 3-(3-bromophenyl)-5-benzoyloxymethyl-2H, 5/f-furan-2-one (1AC) Br O 20 NCL-FDC-Gr3-Fll 1H NMR (CDCI3): 8 4.52-4.83 (m, 2H), 5.30-5.55 (m, 1H), 7.22-7.70 (m, 6H), 7.80 (bd, J=8 Hz, 1H), 7.95-8.20 (m, 3H). Example 5: Preparation of 3-(3-fluorophenyl)-5-benzoyloxymethyl-2H, 5H-furan-2-one (IAD) F COPh NCL-FDC-Gr 3-F25 !H NMR (CDCI3): 5 4.55-4.76 (m, 2H), 5.30-5.45 (m, 1H), 7.00-7.14 (m, 1H), 7.25-7.48 (m, 4H), 7.51-7.70 (m, 4H), 7.90-8.10 (m, 1H). Example 6: Preparation of 3-(3-bromo-4-methoxyphenyl)-5-benzoyloxymethyl-2i/, 5H-fiiran-2-one (1AE) NCL-FDC-Gr 3-F22 O 1H NMR (CDCI3): 8 3.96 (s, 3H), 4.57-4.75 (m, 2H), 5.37-5.45 (m, 1H), 6.95 (d, J=10 Hz, 1H), 7.40-7.63 (m, 4H), 7.91 (dd, J=8, 2 Hz, 1H), 8.00-8.09 (m, 3H). 21 Example 7: Preparation of 3-(3-bromophenyl)-5-acetoxymethyl-2H, 5H-furan-2-one Br Ac NCL-FDC-Gr3-F10 (1BC) 1H NMR (CDCl3): 8 2.08 (s, 3H), 4.31-4.45 (m, 2H), 5.21-5.30 (m, 1H), 7.33 (d, J=8 Hz, 1H), 7.50-7.61 (m, 2H), 7.82 (bd, J=8 Hz, 1H), 8.01 (bs, 1H). Example 8: Preparation of 3-(3-fiuorophenyl)-5-acetoxymethyl-2#, 5//-furan-2-one (1BD) F Ac NCL-FDC-Gr 3-F24 1H NMR (CDCl3): 8 2.05 (s, 3H), 4.30-4.46 (m, 2H), 5.20-5.29 (m, 1H), 7.00-7.16 (m, 1H), 7.30-7.45 (m, 1H), 7.51-7.70 (m, 3H). Example 9: Preparation of 3-(3-bromo-4-methoxyphenyl)-5-acetoxymethyl-2H, 5H-furan-2-one (1BE) 22 NCL-FDC-Gr3-F19 O 1H NMR (CDCl3): 5 2.07 (s, 3H), 3.93 (s, 3H), 4.25-4.48 (m, 2H), 5.18-5.30 (m, 1H), 6.93 (d, J=8 Hz, 1H), 7.42 (bs, 1H), 7.90 (bdd, J=8 Hz, 1H), 8.01 (bs, 1H). Example 10: Preparation of 3-(3,4-dichlorophenyl)-5- allyloyloxymethyl -2H, 5H-furan-2-one (1CA) NCL-FDC-Gr 3-146 O 1H NMR (CDCl3): 8 3.07 (d, J=8 Hz, 2H), 4.45 (d, 3=4 Hz, 2H), 5.02-5.45 (m, 3H), 5.70-5.95 (m, 1H), 7.45 (d, J=8 Hz, 1H), 7.53 (d, J=2 Hz, 1H), 7.70 (dd, J=8, 2 Hz, 1H), 7.96 (d, J=2 Hz, 1H). Example 11: Preparation of 3-(3-chlorophenyl)-5- allyloyloxymethyl -2H, 5#-furan-2-one (1CB) 23 NCL-FDC-Gr3-F14 O 1H NMR (CDC!3): 8 3.10 (d, J=6 Hz, 2H), 4.45 (d, J=4 Hz, 2H), 5.02-5.35 (m, 3H), 5.75-5.95 (m, 1H), 7.35-7.45 (m, 2H), 7.54 (d, J=2 Hz, 1H), 7.70-7.80 (m, 1H), 7.85 (bs, 1H). Example 12: Preparation of 3-(3-bromophenyl)-5- allyloyloxymethyl -2H, 5//-furan-2-one (ICC) NCL-FDC-Gr3-F16 O 1H NMR (CDC13): 8 3.11 (d, J=8 Hz, 2H), 4.40-4.50 (m, 2H), 5.05-5.30 (m, 3H), 5.70-5.95 (m, 1H), 7.25-7.40 (m, 2H), 7.54-7.60 (m, 1H), 7.81 (d, J=8 Hz, 1H), 7.99 (d, J=2 Hz, 1H). NCL-FDC-473 O 24 Example 13: Preparation of 3-(3-bromo-4-methoxyphenyl)-5-allyloyloxymethyl-2H, 5H-furan-2-one (ICE) 1H NMR (CDCU): 8 3.08 (d, J=8 Hz, 2H), 3.94 (s, 3H), 4.40 (d, J=6 Hz, 2H), 5.05-5.30 (m, 3H), 5.70-5.95 (m, 1H), 6.92 (d, J=10 Hz, 1H), 7.40 (d, J=2 Hz, 1H), 7.85 (dd, J=10, 2 Hz, 1H), 8.02 (d, J=2 Hz, 1H). Example 14: Preparation of 4-(3,4-dichlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-2-carboxylate (IDA) NCL-FDC-Gr 3-F6 O IDA 1H NMR (CDCl3): 5 4.60 (d, J=5 Hz, 2H), 5.28-5.50 (m, 1H), 7.05-7.20 (m, 1H), 7.40- 7.85 (m, 5H), 7.93 (bs, 1H). Example 15: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-2-carboxylate (1DB) NCL-FDC-Gr 3-F13 O 1H NMR (CDCl3): 8 4.64 (d, J=4 Hz, 2H), 5.33-5.42 (m, 1H), 7.07-7.18 (m, 1H), 7.33-7.45 (m, 2H), 7.55-7.61 (m, 2H), 7.70-7.95 (m, 3H). 25 Example 16: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-2-carboxylate (IDC) NCL-FDC-Gr3-F17 0 1H NMR (CDCI3): 5 4.54-4.65 (m, 2H), 5.31-5.40 (m, 1H), 7.05-7.15 (m, 1H), 7.20-7.35 (m, 1H), 7.45-7.68 (m, 3H), 7.72-7.83 (m, 2H), 7.97 (bs, 1H). Example 17: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-2-carboxylate (IDE) NCL-FDC-Gr 3-F21 O 1H NMR (CDCI3): 8 3.93 (s, 3H), 4.51-4.70 (m, 2H), 5.31-5.41 (m, 1H), 6.93 (d, J=8 Hz, 1H), 7.05-7.13 (m, 1 H), 7.48 (d, J=2 Hz, 1H), 7.59 (bd, J=6 Hz, 1H), 7.74-7.93 (m, 2H), 8.01 (d, J=2 Hz, 1H). Example 18: Preparation of 4-(3,4-dichlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-3-carboxylate (1EA) 26 NCL-FDC-Gr 3-F5 O 1H NMR (CDCl3): 8 4.63 (d, J=5 Hz, 2H), 5.35-5.45 (m, 1H), 7.25-7.35 (m, 1H), 7.40-7.53 (m, 2H), 7.60-7.75 (m, 2H), 7.95 (d, J= 2 Hz, 1H), 8.10 (d, J=2 Hz, 1H). Example 19: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-3-carboxylate (1EB) NCL-FDC-Gr 3-F12 O 1H NMR (CDCI3): 8 4.55-4.70 (m, 2H), 5.33-5.45 (m, 1H), 7.22-7.43 (m, 3H), 7.49 (d, J=8 Hz, 1H), 7.63 (bs, 1H), 7.75 (bd, J= 8 Hz, 1H), 7.85 (bs, 1H), 8.12 (d, J=2 Hz, 1H). NCL-FDC-Gr 3-F18 O 27 Example 20: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-3-carboxylate (1EC) 1H NMR (CDCI3): 5 4.52-4.65 (m, 2H), 5.35-5.43 (m, 1H), 7.25-7.35 (m, 2H), 7.45-7.58 (m, 2 H), 7.62 (d, J=2 Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.98 (bs, 1H), 8.10 (bs, 1H). Example 21: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl thiophene-3-carboxylate (1EE) NCL-FDC-Gr 3-F20 O 1H NMR (CDCI3): 5 3.85 (s, 3H), 4.40-4.62 (m, 2H), 5.23-5.33 (m, 1H), 6.84 (d, J=8 Hz, 1H), 7.18-7.28 (m, 1 H), 737-7.44 (m, 2H), 7.79 (dd, J=8, 2 Hz, 1H), 7.92 (bs, 1H), 8.03 (bs, 1H). Example 22: Preparation of 4-(3,4-dichlorophenyl)-5-oxo-2,5-d1Hydrofiiran-2-ylmethyl 4,5-dibromothiophene-2-carboxylate(lFA) NCL-FDC-Gr 3-308 O 1FA 1H NMR (CDCI3): 8 4.52-4.72 (m, 2H), 5.32-5.41 (m, 1H), 7.50 (d, J=8 Hz, 1H), 7.59 (bs, 2H), 7.72 (dd, J=8, 2 Hz, 1H), 7.97 (d, J=2 Hz, 1H). 28 Example 23: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4,5-dibromothiophene-2-carboxy late (1FB) NCL-FDC-376 O 1H NMR (CDC13): 1H8 4.50-4.71 (m, 2H), 5.30-5.40 (m, 1H), 7.29-7.43 (m, 2H), 7.57 (bs, 2H), 7.68-7.77 (m, 1H), 7.84 (bs, 1H). Example 24: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4,5-dibromothiophene-2-carboxy late (1FC) NCL-FDC-363 O 1H NMR (CDC13): 8 4.45-4.72 (m, 2H), 5.28-5.40 (m, 1H), 7.30 (t, J=8 Hz, 1H), 7.44-7.63 (m, 3H), 7.80 (d, J=8 Hz, 1H), 7.98 (s, 1H). Example 25: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4,5-dibromothiophene-2-carboxylate (1FE) 29 MeO NCL-FDC-Gr 3-340 O 1H NMR (CDCI3): 5 3.93 (s, 3H), 4.46-4.71 (m, 2H), 5.29-5.40 (m, 1H), 6.93 (d, J=8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.58 (s, 1H), 7.88 (dd, J=8,2 Hz, 1H), 8.00 (d, J=2 Hz, 1H). Example 26: Preparation of 4-(3,4-dichlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-chloropropionate (1GA) NCL-FDC-391 1H NMR (CDCI3): 6 2.79 (t, J=7 Hz, 2H), 3.72 (t, J=7 Hz, 2H), 4.49 (d, J=3 Hz, 2H), 5.23-5.34 (m, 1H), 7.48 (d, J=8 Hz, 1H), 7.57 (s, 1 H), 7.71 (d, J=8 Hz, 1H), 7.98 (bs, 1H). Example 27: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-chloropropionate (1GB) 30 NCL-FDC-460 O 1H NMR (CDCI3): 8 2.80 (t, J=6 Hz, 2H), 3.71 (t, J=6 Hz, 2H), 4.47 (d, J=3 Hz, 2H), 5.25-5.36 (m, 1H), 7.30-7.42 (m, 2H), 7.57 (bs, 1 H), 7.74 (bd, J=6 Hz, 1H), 7.85 (bs, 1H). Example 28: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-chloropropionate (1GC) Br NCL-FDC-426 O 1GC 1H NMR (CDCI3): 5 2.81 (t, J=6 Hz, 2H), 3.72 (t, J=6 Hz, 2H), 4.48 (d, J=4 Hz, 2H), 5.25-5.35 (m, 1H), 7.30 (t, J=9 Hz, 1H), 7.47-7.60 (m, 2 H), 7.81 (d, J=9 Hz, 1H), 8.00 (bs, 1H). Example 29: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-chloropropionate (1GE) 31 NCL-FDC-430 1H NMR (CDCI3): 8 2.85 (t, J=8 Hz, 2H), 3.76 (t, J=8 Hz, 2H), 3.97 (s, 3H), 4.49 (d, J=6 Hz, 2H), 5.25-5.36 (m, 1H), 6.96 (d, J=10 Hz, 1H), 7.47 (d, J=2 Hz, 1 H), 7.92 (dd, J=10, 2 Hz, 1H), 8.06 (d J=2 Hz, 1H). Example 30: Preparation of 4-(3,4-dichlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4-chlorobutyrate (1HA) NCL-FDC-Gr 3-260 O 1H NMR (CDCI3): 8 2.01-2.13 (m, 2H), 2.53 (t, J=6 Hz, 2H), 3.56 (t, J=6 Hz, 2H), 4.42 (d, J=4 Hz, 2H), 5.22-5.32 (m, 1H), 7.50 (d, J=10 Hz, 1H), 7.56 (d, J=l Hz, 1H), 7.74 (dd, J=10, 1 Hz, 1H), 7.99 (d, J=2 Hz, 1H). Example 31: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4-chlorobutyrate (1HB) 32 NCL-FDC-277 O 1H NMR (CDCl3): 8 2.05 (quintet, J=8 Hz, 2H), 2.50 (t, J=8 Hz, 2H), 3.04 (t, J=8 Hz, 2H), 4.32-4.51 (m, 2H), 5.20-5.31 (m, 1H), 7.29-7.45 (m, 2H), 7.55 (s, 1 H), 7.65-7.80 (m, 1H), 7.85 (s, 1H). Example 32: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4-chlorobutyrate (1HC) Br NCL-FDC-Gr 3-343 O 1H NMR (CDCl3): 5 2.05 (quintet, J=6 Hz, 2H), 2.52 (t, J=6 Hz, 2H), 3.56 (t, J=6 Hz, 2H), 4.41 (d, J=2 Hz, 2H), 5.20-5.32 (m, 1H), 7.31 (t, J=8 Hz, 1H), 7.45-5.63 (m, 2H), 7.82 (d, J=8 Hz, 1H), 7.98 (s, 1H). Example 33: Preparation of 4-(3-fluorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4-chlorobutyrate (1HD) 33 F NCL-FDC-Gr3-417 O 1H NMR (CDCl3): 5 2.06 (quintet, J=6 Hz, 2H), 2.53 (t, J=6 Hz, 2H), 3.56 (t, J=6 Hz, 2H), 4.32-4.56 (m, 2H), 5.20-5.45 (m, 1H), 7.05-7.25 (m, 1H), 7.35-7.51 (m, 1 H), 7.53-7.80 (m, 3H). Example 34: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 4-chlorobutyrate (1HE) NCL-FDC-Gr 3-345 O 1H NMR (CDCI3): 8 2.05 (quintet, J=6 Hz, 2H), 2.52 (t, J=6 Hz, 2H), 3.55 (t, 3=6 Hz, 2H), 3.93 (s, 3H), 4.30-4.50 (m, 2H), 5.16-5.28 (m, 1H), 6.92 (d, J=8 Hz, 1H), 7.41 (bs, 1H), 7.89 (d, J=8 Hz, 1H), 8.00 (bs, 1H). Example 35: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 5-chlorovalerate (HE) 34 1H NMR (CDCI3): 8 1.65-1.80 (m, 4H), 2.30-2.45 (m, 2H), 3.43-3.55 (m, 2H), 3.94 (s, 3H), 4.37-4.45 (m, 2H), 5.20-5.30 (m, 1H), 6.94 (d, J=8 Hz, 1H), 7.42 (bs, 1H), 7.89 (d, J=8 Hz, 1H), 8.02 (bs, 1H). Example 36: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofliran-2-ylmethyl 3-iodobenzoate (1JB) NCL-FDC-Gr 3-F 27 O 1H NMR (CDCI3): 8 4.57 (dd, J=12, 4 Hz, 1H), 4.68 (dd, J=12, 4 Hz, 1H), 5.34-5.44 (m, 1H), 7.17 (t, J=8 Hz, 1H), 7.31-7.42 (m, 2H), 7.60 (s, 1H), 7.70-7.79 (m, 1H), 7.82 (s, 1H), 7.85-8.00 (m, 2H), 8.31 (bs, 1H). Example 37: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-iodobenzoate (1JC) 35 NCL-FDC-Gr 3-F 28 O 1H NMR (CDCI3): 5 4.55-4.85 (m, 2H), 5.38 -5.55 (m, 1H), 7.23 (t, J=8 Hz, 1H), 7.35 (t, J=8 Hz, 1H), 7.52-7.75 (m, 2H), 7.80-8.18 (m, 4H), 8.37 (bs, 1H). Example 38: Preparation of 4-(3-bromo-4-methoxyphenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl 3-iodobenzoate (1JE) NCL-FDC-Gr 3-F 26 O 1H NMR (CDCI3): 8 3.93 (s, 3H), 4.48-4.71 (m, 2H), 5.29-5.40 (m, 1H), 6.90 (d, J=8 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 7.47 (bs, 1H), 7.84-8.02 (m, 4H), 8.32 (bs, 1H). Example 39: Preparation of 5-aceloxymethyl-3-aryl-2//, 5//-furan-2-ones of the formula (1) by reaction of alcohols 5 with amide 7: To a solution of benzotriazole (148 mg, 1.25 mmole), pyrrole-2-carboxylic acid (138 mg, 1.25 mmole) in 5 mL of dry THF was added 0.091 mL (1.25 mmole) of SOCl2 at -10 -0°C. The resulting mixture was stirred for 15 minutes followed by the addition of the alcohol 5 (0.81 mmole) in 2 mL of THF. The resultant mixture was refluxed under argon atmosphere for 10-20 h. The reaction mixture was diluted with 5 mL of ethyl acetate and washed with sat. Na2S04 solution (2x5 mL), water (2x5 mL) and concentrated. The 36 residue was purified by column chromatography to afford the 5-aceloxymethyl-3-aryl-2i/, 5H-furan-2-ones of the formula (1) in 20- 30% yield. The following compounds were prepared by the procedure given above: Example 40: Preparation of 4-(3-chlorophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl pyrrole-2-carboxylate (1KB) NCL-FDC-Gr 3-F 29 O 1KB 1H NMR (CDC13): 8 4.52 (d, J=4 Hz, 2H), 5.23-5.34 (m, 1H), 6.12-6.24 (m, 1H), 6.80-6.96 (m, 2H), 7.21-7.37 (m, 2H), 7.53 (bs, 1H), 7.65 (d, J=6 Hz, 1H), 7.75 (s, 1H), 9.13 (bs, 1H). NCL-FDC-Gr 3-F 30 O Example 41: Preparation of 4-(3-bromophenyl)-5-oxo-2,5-d1Hydrofuran-2-ylmethyl pyrrole-2-carboxylate (1KC) 37 1H NMR (CDCl3): 5 4.53 (d, J=4 Hz, 2H), 5.25-5.35 (m, 1H), 6.18-6.24 (m, 1H), 6.85-6.95 (m, 2H), 7.23 (t J=8 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 7.54 (d, J=2 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.91 (bs, 1H), 9.14 (bs, 1H). Example 42: Preparation of 3-aryl-5-hydroxymethyl-2#, 5//-furan-2-ones of the formula (5) Step 1: Preparation of hydroxy ester of formula (4) : To a solution of 32.5 mmoles of LDA (prepared by the addition of 20.4 mL of 1.6 molar n-BuLi to 4.98 mL of diisopropylamine in 90 mL of THF at 0°C) was added dropwise a solution of phenyl acetates of formula (3) wherein Ri and R2 are same or different and each denotes H, Br, CI, F and/or methoxy (35.8 mmole) in 20 mL of THF at -78°C. The resulting mixture was stirred at that temperature for 30 minutes followed by the addition of 8 mL of HMPA and stirred for further 20 minutes. To this mixture was added dropwise a solution of aldehyde of formula (2) (5.8 g, 32.5 mmole) in 20 mL of THF and the stirring was continued at -78°C for 1 h. The reaction mixture was allowed to warm to room temperature followed by quenching with ammonium chloride solution. The reaction mixture was diluted with 100 mL of ethyl acetate, washed with water (2 x 100 mL), 1 N HC1 solution (2 x 50 mL), water (2 x 100 mL), dried over Na2SC«4 and concentrated. The residue was purified by column chromatography to afford the hydroxy ester of formula (4) as a pale yellow pasty mass. Yield 50-60 %. Step 2: Preparation of the alcohol 5 A solution of the hydroxy ester of formula (4) (6.96 mmole) and catalyst PTSA (para-toluene sulphonic acid (50 mg) in 20 mL of distilled MeOH was stirred at 40°C for 3 days. The reaction mixture was concentrated and the residue was purified by flash column chromatography to give the alcohol of the formula (5) as a white solid. Yield 30-50 %. The following compounds were prepared by the procedure described above for the alcohol of the formula (5): Example 43: Preparation of 3-(3-chlorophenyl)-5-hydroxymethyl-2//, 5#-furan-2-one of the formula (5B) 38 NCL-FDC-Gr 3-F7 SB 1H NMR (CDCU): 6 3.84 (dd, J=14, 6 Hz, 1H), 4.04 (dd, J=14, 6 Hz, 1H), 5.10-5.25 (m, 1H), 7.28-7.45 (m, 2H), 7.61 (d, J=2 Hz, 1H), 7.71-7.80 (m, 1H), 7.85 (bs, 1H). Example 44: Preparation of 3-(3-bromophenyl)-5-hydroxymethyl-2//, 5Z/-furan-2-one of the formula (5c) NCL-FDC-Gr 3-F15 5C 1H NMR (CDC13): 5 3.78-4.10 (m, 2H), 5.10-5.20 (m, 1H), 7.27 (t, J=8 Hz, 1H), 7.51 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.98 (s, 1H). Example 45: Preparation of 3-(3-bromo-4-methoxyphenyl)-5-hydroxymethyl-2#, 5H-furan-2-one of the formula (5E) 39 39 5E lH NMR (CDCU + DMSO-de): 5 3.78-3.93 (m, 2H), 3.95 (s, 3H), 5.07-5.17 (m, 1H), 6.95 (d, J=10 Hz, 1H), 7.64 (d, J=3 Hz, 1H), 7.64 (d, J= 3 Hz, 1H), 7.87 (dd, J=10, 3 Hz, 1H), 8.08 (d, J=2 Hz, 1H). Antifungal Activity Testing: The compounds of Formula (I) and their pharmaceutically acceptable salts are antifungal agents effective to a greater or lesser extent, and useful in treating fungal infections in animals and humans, especially those caused by Calibicans, Aspergillus and Fusarium. In vitro evaluation of antifungal activity can be performed by determining the minimum inhibitory concentration. Anti-fungal susceptibility testing of these anti-fungal compounds was done by conventional method using soyabean casein digest broth. Known anti-fungal agents like Fluconazole and amphotericin-B were used as positive control. End points were determined after 48 hours visually and by using Spectrophotometer wherever necessary. Different dilutions were tried and the set of experiments. Antifungal activity of these compounds also extends to Aspergillus and Fusarium. The activity seen in compounds of Formula 1 as against these strains suggests that it exhibits broad spectrum antifungal activity. The results are enumerated in the table below: 40 o Formula (1) Description of Table: Table refers to the antifungal activity results Table 1 Sr no Code no Structure Activity against organisms In ug/ml C. albicans A. niger F.proliferatum 01 1AA Rl = R2 = CI, R = Ph 4 2 1 02 1AB R1=C1,R2 = H, R=Ph 2 2 0.5 03 1AC Rl=Br,R2 = H, R=Ph 2 4 0.5 04 IAD Rl = F, R2 = H, R=Ph 1-2 1-2 1-2 05 1AE Rl = Br, R2 = OMe, R =Ph NI till 2 NI till 2 NI till 2 06 1BC Rl = Br, R2 = H, R=Me 2 4 2 07 1BD Rl = F, R2 = H,R=Me 1-2 1-2 1-2 08 1BE Rl = Br, R2 = OMe, R =Me 2-4 4-8 8-16 09 1CA R1=R2 = C1,R = allyl 2 1 1 10 1CB R1=C1,R2 = H, R= -allyl 4 8 2 11 ICC Rl=Br,R2 = H, R= CO-allyl 4 8 2 12 ICE Rl = Br, R2 = OMe, R = -allyl 2-4 NI till 8 NI till 8 13 IDA Rl = R2 = CI, R= 2-thienyl 2 1 2 14 1DB Rl = CI, R2 = H, R=2-thienyl 2 4 1 15 IDC Rl = Br, R2 = H, R=2-thienyl 2 8 2 16 IDE Rl = Br, R2 = OMe, R=2-thienyl NI till 2 NI till 2 NI till 2 17 1EA Rl = R2 = CI, R = 3-thienyl 2 1 2 18 1EB Rl = CI, R2 = H, R = 3-thienyl 4 4 2 19 1EC Rl = Br, R2 = H, R = 3-thienyl 2 2 1 20 1EE Rl - Br, R2 = OMe, R = 3-thienyl NI till 2 NI till 2 NI till 2 21 1FA R1=R2 = C1,R =4,5-dibromo-2-thienyl NI till 4 NI till 4 NI till 4 22 1FB Rl = CI, R2 = H, R =4,5-dibromo-2-thienyl 1-2 2-4 1-2 23 1FC Rl = Br, R2 = H, R =4,5-dibromo-2-thienyl 1-2 2-4 1-2 24 FE Rl = Br, R2 = OMe, R =4,5-dibromo-2-thienyl 4-8 NI till 4 NI till 4 25 1GA Rl = R2 = CI, R= -CH2CH2C1 4 2 2 26 1GB Rl = CI, R2 = H, R= -CH2CH2C1 2 2 4 27 1GC Rl=Br,R2 = H, R= -CH2CH2CI 2 4 2 28 1GE Rl = Br, R2 = OMe, R= -CH2CH2C1 4-8 4-8 8-16 42 29 1HA Rl = R2 = CI, R=-(CH2)3C1 1-2 1-2 1-2 30 1HB Rl = CI, R2 = H, R= -(CH2)3C1 1-2 2-4 1-2 31 1HC Rl = Br, R2 = H, R= -(CH2)3C1 1-2 4-8 1-2 32 1HD Rl = F, R2 = H, R= -(CH2)3C1 1-2 1-2 1-2 33 1HE Rl = Br, R2 = OMe, R= -(CH2)3C1 NI till 4 NI till 4 NI till 4 34 HE Rl = Br, R2 = OMe, R= -(CH2)4C1 NI till 8 NI till 8 NI till 8 35 1JB R1=C1,R2 = H, R=3-iodophenyl NI till 2 NI till 2 NI till 2 36 1JC Rl = Br, R2 = H, R=3-iodophenyl 2-4 NI till 4 NI till 4 37 1JE Rl = Br, R2 = OMe, R=3-iodophenyl NI till 2 NI till 2 NI till 2 38 1KB Rl = CI, R2 = H,R=2-pyrrolyl 0.5-1 1-2 1-2 39 1KC Rl = Br, R2 = H, R=2-pyrrolyl 1-2 2-4 1-2 Main Advantages of the Invention: 1. Compounds of present invention exhibit broad spectrum anitiflingal activity. 2. Better activity against Candida strains resistant to known azoles. 3. Compounds possess activity against aspergillus and other emerging fungal pathogens. 4. Better safety profile than earlier azoles at the same time retaining its broad spectrum of activity. 43 We claim, 1. Compounds represented by formula (1) wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyl or halophenyl or pyrrolyl and Ri and R2 are the same or different, and each denotes hydrogen or halogen or alkoxy. Formula (1) 2. A compound of formula (1) according to claim 1, wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyl or halophenyl or pyrrolyl and Rj and R2 are same or different and each denotes hydrogen or halogen or alkoxy, its solvates or pharmaceutically acceptable salt of such compounds having at least one salt forming group. 3. A pharmaceutical composition comprising of the compound as claimed in claim 1 or its solvates or its pharmaceutically acceptable salt of said compound having at least one salt forming group thereof with pharmaceutically acceptable diluents or carrier thereof. 4. A method for the treatment or prevention of a fungal infection in a substrate, said method comprises administering a compound of formula 1 as claimed in claim 1 or a pharmaceutically acceptable salt of such compound having at least one salt forming group or solvate thereof to a substrate in need of such treatment or prevention. 5. The method of treatment as per claim 4, wherein the said substrate is animal or human being. 6. A pharmaceutical composition according to claim 3 for the treatment or prevention of fungal infections. 44 7. A process for the preparation of compound of formula (1) as claimed in claim 1, wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyl or halophenyl or pyrrolyl and Ri and R2 are same or different and each denotes hydrogen or halogen or alkoxy, or its solvate or its pharmaceutically acceptable salt of such compound having at atleast one salt forming group, said process comprising the steps of: a) contacting aldehyde of formula (2) with phenyl acetates of formula (3) wherein Ri and R2 are same or different and each denotes H, Br, CI, F and/or methoxy, in an XOOEt Formula (3) organic solvent in presence of base to obtain compound of formula (4) wherein Ri and R2 are same or different and each denotes H, Br, CI, F and/or methoxy, EtOOC -O. 45 b) contacting hydroxy ester of formula (4) with an acidic catalyst in alcoholic solvent to obtain the alcohol of the formula (5), Formula (5) c) reacting the alcohol of the formula (5) with acid chloride in suitable organic solvent in presence of a catalyst to obtain the compound of formula (1) O Formula (1) wherein R = substituted alkyl or alkenyl or aryl or heteroaryl or 2-thienyl or 3-thienyl or halothienyl or haloalkyl or halophenyl or pyrrolyl and R1 and R2 are same or different and each denotes hydrogen or halogen or alkoxy. d) converting the compound of formula (1) to its pharmaceutically acceptable salt by adapting conventional method. 8) A process as claimed in claim 7, wherein in step (a) the organic solvent used is selected from the group consisting of ethers; preferably tetrahydrofuran or diethyl ether. 9) A process as claimed in claim 7, wherein in step (a) the base used is selected from the group consisting of alkyl lithium, alkali metal hydrides and alkali metal carbonates, preferably n-butyllithium or sodium hydride. 46 10) A process of as claimed in claim 7, wherein in step (b) the acidic catalyst used is selected from the group consisting of organic or inorganic acids, preferably p-toluene sulfonic acid. 11) A process as claimed in claim 7, wherein in step (b) the solvent used is selected from the group consisting of alcohols or hydrocarbons, preferably methanol or ethanol to obtain the alcohol of the formula (5). 12) A process as claimed in claim 7, wherein in step (c) the catalyst used is selected from the group consisting of organic bases preferably pyridine to obtain the compound of formula (1). 13) A process as claimed in claim 7, wherein in step (c) the organic solvent used is selected from the group consisting of chlorinated solvents preferably dichloromethane or chloroform to obtain the compound of formula (1). 14) Intermediates of the formula (4) as claimed in claim 7 wherein Ri and R2 are same or different and each denotes hydrogen or halogen or alkoxy. 15) A use of a compounds of formula (1) according to any of claims 1 to 2 or its solvates or a pharmaceutically acceptable salt of said compound having at least one salt forming group for the preparation of a pharmaceutical composition for use in the treatment of antifungal infections. 16) Compounds of formula (1) as claimed in claim 1 as herein described substantially with reference to chemical formula. 17) Process for the preparation of compounds as claimed in claim I of formula (1) as herein substantially described with reference to examples. Dr. Gopakumar G.Nair Agent for the Applicant Dated this 8th day of May 2006 47 ABSTRACT The present invention relates to compounds of formula (1), its solvates and pharmaceutically acceptable salts having antifungal activity and its pharmaceutical composition comprising an effective amount of compound of formula (1). The invention also relates to a process for the preparation of said compounds by contacting the intermediate alcohol, prepared from 1,2-O-isopropylideneglyceraldehyde and substituted phenylacetates, with acid chlorides under appropriate conditions to obtain some of the preferred compounds of the invention. O Formula (1) 48

Documents:

713-MUM-2006-ABSTRACT 24-6-2008.pdf

713-mum-2006-abstract-1.jpg

713-mum-2006-abstract.pdf

713-mum-2006-cancelled pages-(24-6-2008).pdf

713-MUM-2006-CLAIMS 8-5-2006.pdf

713-mum-2006-claims(granted)-(24-06-2008).doc

713-mum-2006-claims(granted)-(24-6-2008).pdf

713-mum-2006-claims.pdf

713-mum-2006-correspondance-others.pdf

713-mum-2006-correspondance-received.pdf

713-MUM-2006-CORRESPONDENCE 24-6-2008.pdf

713-mum-2006-correspondence(24-6-2008).pdf

713-mum-2006-correspondence(ipo)-(22-8-2008).pdf

713-mum-2006-description (complete).pdf

713-MUM-2006-DESCRIPTION(COMPLETE) 8-5-2006.pdf

713-MUM-2006-FORM 1 24-6-2008.pdf

713-mum-2006-form 1(23-6-2006).pdf

713-mum-2006-form 1(8-5-2006).pdf

713-mum-2006-form 18(16-6-2006).pdf

713-mum-2006-form 2 8-5-2006.pdf

713-mum-2006-form 2(granted)-(24-06-2008).doc

713-mum-2006-form 2(granted)-(24-6-2008).pdf

713-MUM-2006-FORM 2(TITLE PAGE) 8-5-2006.pdf

713-mum-2006-form 26(4-5-2006).pdf

713-mum-2006-form 3(17-12-2007).pdf

713-mum-2006-form 3(8-5-2006).pdf

713-mum-2006-form 9(10-5-2006).pdf

713-mum-2006-form-1.pdf

713-mum-2006-form-2.doc

713-mum-2006-form-2.pdf

713-mum-2006-form-3.pdf

713-mum-2006-form-9.pdf