Title of Invention	A PROCESS FOR SYNTHESIS OF 1-ARYL-3-ARYL/HETEROARYL-3-ARYLTHIO/HETEROARYLTHIO-1-PROPANONES POSSESSING ANTIFUNGAL ACTIVITY
Abstract	A process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (F-l), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; Ar1 is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3; the said process comprising, a. reacting a compound of Formula (F-ll) wherein, R1, R2, Ar1 and Ar2 are same as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same as in Formula (F-l) in a basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent selected from group comprising chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone; b. removing the solvent after the reaction and taking the dry product in water and extracting the reaction product in aqueous solution with another organic solvent which may be same or different but selected from group as in step (a), c. removing the solvent from the extract; and d. further purifying the product obtained at stage c, using silica gel column chromatography.

Title of Invention

A PROCESS FOR SYNTHESIS OF 1-ARYL-3-ARYL/HETEROARYL-3-ARYLTHIO/HETEROARYLTHIO-1-PROPANONES POSSESSING ANTIFUNGAL ACTIVITY

Abstract

A process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (F-l), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; Ar1 is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3; the said process comprising, a. reacting a compound of Formula (F-ll) wherein, R1, R2, Ar1 and Ar2 are same as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same as in Formula (F-l) in a basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent selected from group comprising chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone; b. removing the solvent after the reaction and taking the dry product in water and extracting the reaction product in aqueous solution with another organic solvent which may be same or different but selected from group as in step (a), c. removing the solvent from the extract; and d. further purifying the product obtained at stage c, using silica gel column chromatography.

Full Text	FORM 2 THE PATENTS ACT 1970 COMPLETE SPECIFICATION (See Section 10) TITLE A process for synthesis of 1-aryl-3-aryl/heteroaryl-3-arylthio/ heteroarylthio-1-propanones possessing antifungal activity APPLICANT Dr. Akamanchi Krishnacharya Govindacharya, Division of Pharmaceutical Sciences and Technology, University Institute of Chemical Technology, Matunga, Mumbai- 400 019, State of Maharashtra, India, An Indian National. The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- ORIGINAL 697/MUMNP/2003 09/07/03 GRANTED 10/2/2004 Field of Invention: The present invention relates to a process for synthesis of 1- aryl -3-aryl / heteroaryl -3-arylthio / heteroarylthio -1-propanones having antifungal activity. This invention particularly relates to synthesis of 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones having antifungal activity against strains of Candida albicans which are sensitive as well as resistant to the marketed antifungal drug fluconazole. Background and Prior Art: Candida albicans is part of the normal flora of the mouth, intestine and vagina. It is also an opportunistic pathogen giving rise to an inflammation under a wide variety of circumstances. Infection is usually, endogenous though cross-infection may occur, as between infants in a nursery. The site affected by Candida albicans is mucosa. Less common manifestations are the secondary infections in the lower respiratory tract and urinary tract infection. It may cause septicemia with localization in meninges, endocardium, bone marrow or kidney, which may occur in patients seriously ill with other conditions. The commonest Candida infection is vaginitis or vaginal thrush. Pregnant women are particularly susceptible. Oral thrush occurs in debilitated or bottle fed infants. Infection of the skin is common in diabetes. Intestine infections occur in infants. Bronchial and pulmonary candiasis also occur but not common. Systemic infections may occur when the organism is inoculated into the tissues as in drug addicts. Candida albicans causes candiases on the skin and mucous membranes of the mouth, gastrointestinal tract, respiratory system, nervous system and urogenital organs of the man. Candiases of liver, biliary tract, pancreas and bones also occur. In number of chronic candiases septic cases are characterized by lesions into kidneys lung tissues, liver and other organs. About 90 per cent of the Candida infections in humans are due to Candida albicans. A large number of organic compounds used as drugs for the treatment of candiasis. They belong to following classes: i. Azoles- fluconazole, clotrimazole, econazole. ii. Allylamines and other squalene epoxidease inhinitors-nafitifine, terbinafine, butenafine, tolnaftate. iii. Morpholines- amorolphine. iv. Nucleosides- flucytosine. V. Antifungal antibiotics- polyene antibiotics, griseofulvin. However, the effectiveness of these drugs has gone down as certain strains of Candida albicans, have developed resistance to these drugs. Clinical failure in the treatment of systemic fungal infections is due to the emergence of resistance of the pathogenic fungal species to clinically used antifungal drugs. Resistance to fluconazole is spreading rapidly and has become major problem in late-stage AIDS patients. The development of such resistance is due to multiple mechanisms. Recently, NCIM 3446 a strain of Candida albicans has been found to be resistant to the antifungal drug fluconazole. There is a need to develop a new drug for this strain. The only way to overcome this resistance problem is to synthesize new antifungal compounds to which none of the strains of Candida albicans has ever been exposed. A look at the literature showed that 3-phenyl-1-(2-furyl)-3-phenylthio-1-proanones have been reported to be active against various fungal species like Botrytis cineria, Valsa ceratosperma, Sclerotium cepivorum and Phytophthera capsici. [Sung, Nack-Do.; Kang, Hee-Deog.; Meang, Joo-Yang.; Shin, Dong-Rin. Hanguk Nonghwa Hakhoechj, 1994, 37(4), 287-294]. However, such compounds have not been tried out for activity against Candida albicans. Object: The principle object of the present invention is to synthesize new molecules amongst 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones that will be effective in mitigating organisms of strains of Candida albicans and particularly those strains which are sensitive to the antifungal drug fluconazole like ATCC10231, or which are resistant to fluconazole like NCIM 3446. The main part of this object of the present invention is to synthesize and screen various analogues of 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones for their antifungal activity and evaluate in particular, their in vitro activity against strains of Candida albicans and particularly those strains, which are sensitive, like ATCC10231, or which are resistant, like NCIM 3446, to the antifungal drug fluconazole. Summary of the Invention: Accordingly, the present invention provides a process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (Fl), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; An is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3; the said process comprising, a. reacting a compound of Formula (F-ll) wherein, R1, R2, An and Ar2 are same as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same as in Formula (F-l) in a basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent selected from group comprising chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone; b. removing the solvent after the reaction and taking the dry product in water and extracting the reaction product in aqueous solution with another organic solvent which may be same or different but selected from group as in step (a), c. removing the solvent from the extract; and d. further purifying the product obtained at stage c, using silica gel column chromatography. Description of the Invention: The various analogues of 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones prepared are represented by general structural formula (F-1), Wherein, R1 = H or OH; R2 is selected from H, OH, OCH3, or N02; An is selected from compounds of formula (F - IV) or (F- V), wherein, R3 is selected from -H, -CI or -N02; Ar2= H or Phenyl; Ar3 is selected from compounds of formula (F - VI) or (FVII) (F - VI) (F-VII) wherein, R4 = H or -NHCOCH3, by reacting compounds of formula (F-ll) and (F-lll) according to the present invention and found to have biological activity against Candida albicans are shown in Table 1 - Of the various novel compounds represented by Formula (F-l) synthesized, following groups of compounds have been found to have antifungal activity against Candida albicans Synthesis of Specific compounds of formula (F-ll): 1,3-diaryl-2-propen-1-ones the compounds of formula (F-ll) are known as propenones or chalcones, henceforth referred as "Chalcones". Since they are not readily available, they are synthesized by conventional aldol condensation of compounds represented by formula (F-lla) and (F-llb) in which the substituents are selected as required for the synthesis of desired compound of formula (F-l). Compounds obtained by this step are not novel. Synthesis of Specific compounds of formula (F-ll): 1,3-diaryl-2-propen-1-ones the compounds of formula (F-ll) are known as propenones or chalcones, henceforth referred as "Chalcones". Since they are not readily available, they are synthesized by conventional aldol condensation of compounds represented by formula (F-lla) and (F-llb) in which the substituents are selected as required for the synthesis of desired compound of formula (F-l). Compounds obtained by this step are not novel. Chalcones of general formula (F-ll) (for details see Table 2) are prepared in the laboratory by literature methods (further details given in examples A and B) and used directly for the synthesis of novel propanones of formula (F-l). Following two methods for the synthesis of chalcones by aldol condensation are useful. i. Base catalyzed [Peter klinke, Heinz Gibian, Chemische berische. 1961, 94, 2638; Chemical abstract no. 72-121124p (Falco da, Fonseca, Luis. Bol Fac. Farm., Univ. Coimbra, Ed. Client. 1968, 28, 49-52); Chemical abstract- 72-66551y. (Druzilla.M; Kristian, P. Collec. Czech. Chem. Commun. 1969, 35 (2), 417-419)] and ii. Acid catalyzed aldol condensation. (Lyle, R.E.; Paradis.LP. J. Am. Chem. Soc. 1955, 77, 6667-6668.) In case any desired chalcone is readily available, this step in the synthesis is not required. Synthesis propanones of formula (F-l) In the second step a novel compound of the present invention 1- aryl-3-aryl/heteroaryl,-3-arylthio / heteroarylthio,-1-propanones represented by Formula (F-l) is obtained by conventional Michael addition of substituted thiophenol of formula (Fill) to the chalcone (F-ll) both having same substituents as in formula (F-l) which are either readily available or made as said in step 1 of this process.. The addition of substituted thiophenols compounds of formula (F-lll) on to chalcones of general structural formula (F-ll) is carried out in basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent, at ambient temperature. The reaction takes place in 0.5-5 hrs. (K. G. Akamanchi and U .W. Mali. Asian J. Chem. 2001, 49-59; Sharaf, Saber M; El-Sadany, Samir K; Hamed, Ezzat, A.; Elba, Mohammed E. Alexandria J. Pharm. Sci. 1991, 5 (2) 187-191). The products are isolated by extraction in suitable solvent (solvents) and purified by column chromatography over silica gel (60-120mesh) with suitable eluent system. These novel compounds are then evaluated for in vitro antifungal activity. In the process of present invention, for the Michael addition reaction, the preferred basic media were triethylamine and sodium methoxide in toluene and methanol respectively. Details of these procedures are given below. Reaction With Triethylamine As A Base: The reaction in presence of triethylamine as a base is carried out as follows: 1,3-diaryl-2-propen-1-ones of structural formula (F-ll), compounds of formula (Fill) and triethylamine were taken in the molar ratio (1) : (1.1 - 4) : (1.1 - 4) preferably, (1): (1.1): (1.1) . In three necked round bottom flask equipped with magnetic stirrer, CaCI2 guard tube and nitrogen inlet, a compound of 1,3-diaryl-2-propen-1-ones of general formula (F-ll) (0.01 mole) is taken in suitable organic solvents selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone. Toluene is solvent of choice. To this solution in the reaction flask, are added a compound of compounds of formula (F-lll) (0.011 mole) followed by triethylamine (0.011 mole) and stirred for 2-6 hours. The reaction is monitored by TLC and HPLC. (System for TLC; Ethyl acetate: Hexane:: 05-15: 95-85, by volume and HPLC system; water: Methanol:: 8-20: 92-80 by volume). On completion of the reaction, cold water (25ml) is added to the reaction mixture and product is extracted with suitable organic solvent (3 x 10 ml) selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone. Chloroform is solvent of choice. The product obtained after removing the solvent is further purified by column chromatography over silica gel (60-120mesh) with suitable eluent system such as Hexane and Ethyl acetate in varying proportion; Ethyl acetate : Hexane :: (05-15) : (95-85) by vol., preferably, (5:95) by volume. Reaction With Sodium Methoxide As A Base The reaction in presence of sodium methoxide as a base, is carried out as follows: A compound of formula (F-lll) is taken in methanol/ ethanol in the three necked round bottom flask equipped with magnetic stirrer, CaCI2 guard tube and nitrogen inlet. To the reaction mixture is added sodium methoxide (NaOCH3) in methanol and after 5 minutes chalcone of general formula (F-ll) is added slowly. Chalcones of general formula (F-ll), compounds of formula (F-lll) and NaOCH3 are taken in the molar ratio (1): (2 - 5): (2 - 5) preferably, 1: 5: 5. The reaction is stirred at ambient temperature and monitored by TLC and HPLC as in the above method. On completion of the reaction, the solvent is evaporated to dryness and ice-cold water is added to the reaction mixture and the product is extracted with suitable organic solvent selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and esters such as ethyl acetate and ketones such as like methyl isobutyl ketone. Chloroform is solvent of choice. The products are purified by column chromatography over silica gel (60-120mesh) with suitable eluent system such as Hexane and Ethyl acetate in varying proportion, Ethyl acetate : Hexane :: (05-15): (95-85) by vol. preferably 5: 95 by vol. The purity of the compounds is established by TLC, IR, NMR and HPLC. (Water: Methanol, 15:85). In vitro biological evaluation: The antifungal activity expressed as minimum inhibitory concentration (MIC) of the said compounds according to the invention has been determined by broth dilution method (Barrry, A. L.; Leo and Febigar, Philadelphia, 1976, 92-104). Concentration of compounds added was 50-250 µg/ml. The medium used was Saborauds dextrose broth. The inoculum concentration was 5 X 10 15 Colony forming units per ml. One loop full of this inoculum was used as inoculate per inoculation point. The results were interpreted after 48 hours incubation in dark conditions at room temperature. Measurement of turbidity by means of photoelectric colorimeter was done for the interpretation of the results. The fungal species used for evaluating the activity of said compounds have been 1) Candida albicans ATCC 10231 It was obtained from Haffkine Institute, Parel, Mumbai. 2) Candida albicans NCIM 3446. It was obtained from Food and Fermentation Technology division, UICT, Mumbai. Examples: The invention will now be illustrated with the help of examples. Examples are the way of illustration only and in no way restrict the scope of the invention. Examples I to XIII describes syntheses of thirteen novel compounds of the present invention, which are summarized in Table-1. In Table-2 are summarized preparations of the chalcones of formula (F-ll) required for the synthesis of each novel compound of formula (F-l) described in the examples I to XIII. Example I and XI describe the detailed procedure for the synthesis of specific compounds of formula (F-l) in which reaction medium is sodium methoxide and triethylamine respectively. Example A and B describes the preparation of chalcones in acid and basic media respectively and the example C describes the protocol for biological evaluation of the said novel compounds of formula (F-l). The results of the biological evaluation of the compounds synthesized are given in Table -3. Solvents and reagents Following solvents and reagents used in these Examples were obtained from S.D. Finechem Ltd., (L.R. Grade) Mumbai: chloroform, dichloromethane, carbon tetrachloride, benzene, toluene ethyl acetate, methyl isobutyl ketone, hexane; sodium methoxide, hydrochloric acid (30-35%), Triethylamine, Silica gel (60-120 mesh). Acetophenone, 4-nitro-acetophenone, 4-methoxy-acetophenone, 4-hydroxy-acetophenone, 2-hydroxy-acetophenone, benzaldehyde, 2-Chloro-benzaldehyde, 4-chloro-benzaldehyde, 3-Nitro-benzaldehyde, Benzophenone, Furfural Following imported chemicalcs were obtained locally. 1. Thiophenol (99+%, Lancaster) 2. 4-Acetamidothiophenol (97%, Lancaster) 3. 2-Thiophenethiol (96%, Lancaster). Example A: Preparation of Chalcone: 1-(4-nitrophenyl)-3-phenyl- 2-propen-1 -one. 4-nitroacetophenone (1 gm, 0.00606 mol,) and benzaldehyde (0.64g, 0.00606 mol), were taken in round bottom flask containing glacial acetic acid (20 ml). To it concentrated H2S04 (1 ml, 0.018 mol) was added and stirred for 2 days at room temperature. The precipitate formed was filtered off and washed with sodium bicarbonate solution and copious volume of water. The product was recrystalised from pyridine. 0.55g, yield 36%, recrystallized product directly used for the next reaction. Example B: Preparation of Chalcone: 1,3-diphenyl-2-propen-1-one Place a solution of 5.1 g of sodium hydroxide in 50 ml water and 30 ml methanol in a 200 ml round bottom flask immersed in ice-bath, provided with mechanical stirrer. Add freshly distilled acetophenone (1g, 0.0083 mol) under stirring and then add freshly distilled benzaldehyde (0.88g, 0.0083 mol,) Keep the temperature at about 25°C and stir vigorously until the reaction mass becomes so thick that the stirring is no longer effective. Stop the stirring and allow the reaction to stand overnight in refrigerator. Filter the reaction, wash the solid with cold water and dry in air. Recrystalise from methanol/water solvent system. (1.15g, yield 67 %, recrystaJJized product directly used for the next reaction) Example-C In vitro evaluation of biological activity The evaluation of the synthesized compounds for antifungal activity was carried out using broth dilution method and minimum inhibitory concentration was determined by visual comparison with the negative control tubes. Detailed test procedure 1. Stock Solutions of test compounds and standard drug- Compounds prepared in Examples I - XIII were taken as test samples along with a standard fluconazole sample. 10 mg of each test compound was dissolved in 1 ml of dimethylsulphoxide. (L.R Grade, S.D. Finechem Ltd. Mumbai) For preparing stock solution of fluconazole, 10 mg of fluconazole (sample Obtained from FDC Ltd., Mumbai) was dissolved in 1 ml of dimethylsulphoxide. 2. Test organism- The organisms employed in the in vitro testing of the compounds were Candida albicans ATCC 10231 (fluconazole sensitive) - It was obtained from Haffkine Institute, Parel (Mumbai). Candida albicans NCIM 3446 (fluconazole resistant) - It was obtained from Food and Fermentation Technology division, UICT, Mumbai. All the cultures were maintained on Saborauds agar (microbiology grade, Himedia lab. Ltd., Mumbai) medium by periodic subculturing. 3. Preparation of Inocula- Procedure for the preparation of inoculum for both the strains was same. The inoculum was prepared from a 24-hours old growth of organism on Saboraud's dextrose agar slant. With the help of sterile nichrome wire loop, the growth of the organism on slant was aseptically transferred to a tube containing sterile distilled water. The contents of the tube were then shaken properly so as to get uniform cell suspension of the organism. Optical density the inoculum was adjusted to 0.4 on the photoelectric colorimeter by using sterile distilled water, before using it as a inoculum. 4. Medium- 3 gm of Saboraud's dextrose broth (microbiology grade, Himedia lab. Ltd., Mumbai) was dissolved in 100 ml of sterile distilled water. 2 ml of this stock solution was transferred to each test tube. 5. Test proper- To 2 ml of sterile Saboraud's dextrose broth solution was taken in a test tube, 10-40 µl of the stock solution was added followed by a loop full of an authentic culture of Candida albicans ATCC 10231 and Candida albicans NCIM 3446 (corresponding to 5 X 10 15CFU/ml.). This corresponds to concentration range of 50, 100, 150, 200 µg/ml of the test compound. The tests were carried out in duplicate. Apart from putting the controls of standard drug (Fluconazole), controls with dimethyl sulphoxide (positive control) and without dimethyl sulphoxide (negative control) were also included in the test. 6. Incubation- The test tubes were put in the dark conditions at room temperature for 48 hours. At the end of incubation period, the results were interpreted by visual comparison with negative control. The lowest concentration of test compound which showed inhibitory effect on growth on visual distinction was taken as Minimum inhibitory concentration. The results are given in Table 3. Example-I: Synthesis of Fig. 1 1-(4-nitrophenyl)-3-phenyl-3-phenylthio-1-propanone. Sodium methoxide (0.0835 mol) in methanol (15 ml), was taken in a round bottom flask and to it was added thiophenol (0.0835 mol) and stirred still reaction mixture appeared clear. 1-(4-nitrophenyl)-3-phenyl-2-propen-1-one (chalcone), (0.00167 mol) prepared in Example A described above, was added to the reaction mixture gradually. The reaction progress was monitored by TLC. After 30 minutes reaction mixture was concentrated to dryness. The solid residue was dissolved with 15 ml of cold water and extracted with chloroform (2 x 25 ml). The chloroform layer was washed further with cold water (5 x15 ml). Then the combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to yield crude mixture of Michael adduct and corresponding unreacted thiophenol. It was further purified by silica gel column chromatography using mobile phase system (Hexane: Ethyl acetate; 9.5:0.5) to the pure product Yield: 69%. Melting point: 126-129°C The characteristics of the product which confirm the structure are: IR (KBr pellets): 1693,1601, 1514, 1338 (cm-1) 1H NMR (CCI4): 3.49-3.60 (d, 2H,J=7.2 Hz), 4.7- 4.92 (t, 1H, J=6.84 Hz), 7.2 (m, 10H), 7.9-8.35 (m, 4H). Examples II to XIII: In following Examples II to X, experimental procedure used was as described in Example I wherein sodium methoxide was used as base. In Examples XI to XIII, experimental procedure used was as described in Example XI wherein triethylamine was used as base. Example-ll: Synthesis of 3-(4-acetylaminophenylthio)-1-(4-nitrophenyl)-3-phenyl-1-propanone. (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 48%. (Column purification, Ethyl acetate: Hexane, 20:80) Melting point: 162-166°C The characteristics of the product which confirm the structure are: IR (KBr pellets): 3306, 1686, 1664, 1584, 1521, 1346 (cm -1) 1H NMR (CDCI3): 8 2.16 (s, 3H, -CH3), 3.57-3.68 (d, 2H, J=7.1 Hz), 4.72- 4.96 (t, 1H, J=7.1 Hz), 7.27-7.44 (m, 10H,), 7.92-8.38 (m, 4H, Ar-H). Example III: Synthesis of 3-(2-furyl)-1 -phenyl -3-(2-thienylthio)-1 -propanone. (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 59%, viscous liquid. The characteristics of the product which confirm the structure are: IR (KBr pellets); 1690, 1590, 1525, 1345(cm-1) 1H NMR (CCI4); 5 3.49-3.61 (d, 2H, J = 7.08Hz), 4.65- 4.9 (t, 1H, J =7.08 Hz), 6.1-7.29 (m, 11H). Example IV: Synthesis of 3-(2-furyl)-1-(2-hydroxyphenyl)- 3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 55%, viscous liquid. The characteristics of the product which confirm the structure are: IR (KBr pellets); 1685,1600, 1530,1340(cm-1) 1H NMR (CDCI3); 8 3.58-3.71 (d, 2H, J = 7.08Hz), 4.69-4.93 (t, 1H, J = 7.08Hz), 6.18-7.79 (m, 11H). Example V : Synthesis of 3-(3-nitrophenyl)-1 -phenyl-3- (2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 65% Melting point: 132-135°C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1695, 1600, 1535, 1335 (cm-1) 1H NMR (CCI4); 5 3.34-3.46 (d, 2H, J = 7.08Hz), 4.43-4.67 (t, 1H, J = 7.08Hz), 6.69-7.77(m, 12H) Example VI: Synthesis of 1 -(4-hydroxyphenyl) -3-(3-nitrophenyl)-3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 71% Melting point: 170-172°C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1690,1598, 1530,1330 (cm1) 1H NMR (CDCI3); 3.59-3.71 (d, 2H, J = 6.84 Hz), 4.73-4.92 (t, 1H, J = 6.80Hz), 6.81-8.1 (m, 12H) Example VII: Synthesis of 3-(2-chlorophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 68% Melting point: 118-121 °C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1685, 1600,1535, 1338 (cm1) 1H NMR (CDCI3); 5 3.67-3.77 (d, 2H, J = 6.36 Hz), 5.13-5.37 (1H, t), 6.92-8.4 (m, 11H) Example VIII: Synthesis of 3-(4-chlorophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 74% Melting point: 89-91 °C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1690, 1595, 1540, 1340 (cm1) 1H NMR (CDCI3); 5 3.59-3.71 (d, 2H, J = 7.08Hz), 4.61-4.81 (t, 1H, J = 7.18Hz), 6.98-8.37 (m, 11H). Example IX: Synthesis of 3-(3-nitrophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 69% Melting point: 135-137°C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1701,1601,1521, 1339 (cm"1) 1H NMR (CDCI3); 6 3.69-3.82 (d, 2H, J = 7.56 Hz), 4.64-4.97 (t, 1H, J = 7.56Hz), 6.92-8.38 (m, 12H) Example X: Synthesis of 1-(4-nitrophenyl)- 3-phenyl -3-(2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 73% Melting point: 101-103°C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1693, 1601, 1514,1338 (cm1) 1H NMR (CDCI3); 6 3.62-3.73 (d, 2H, J = 7.08Hz) 4.64-4.88 (t, 1H, J = 7.08Hz), 6.96-8.38 (m, 12H) Example XI: Synthesis of 1 -(4-Methoxyphenyl)-3-phenyl-3-(2-thienylthio)-1 -propanone. (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1), the reaction is described below. Fig. 3 In a three necked round bottom flask equipped with CaCI2 guard tube, nitrogen inlet and mechanical stirrer containing toluene (30ml), 1-(4-methoxyphenyl)-3-phenyl-2-propen-1-one (0.01 mol), the chalcone prepared as shown in Table 2 and 2-thiophenethiol (0.011 mol) are charged followed by triethylamine (0.011 mol). The reaction (See Fig.3) is stirred at an ambient temperature for 6 hours. The progress of the reaction is monitored by HPLC (water: methanol :: 10:90). On completion of the reaction the water (20ml) is added to the reaction mixture and the product is extracted with toluene. Toluene is evaporated to get the product. It was further purified by silica gel column chromatography using mobile phase system (Hexane: Ethyl acetate; 9.5:0.5) to the pure product Yield: 74% Melting point: 86-88°C The characteristics of the product which confirm the structure are: IR; (KBr pellets); 1694,1592,1512,1329 (cm"1) 1H NMR (CDCI3); 5 3.45-3.57 (d, 2H, J = 7.08Hz), 3.75 (s, 3H,), 4.59-4.83 (1H, t, J = 7.08Hz), 6.86-8.1 (m, 12H) In following Examples XI to XIII, experimental procedure used was as described in Example XI wherein triethylamine was used as base. Example XII: Synthesis of 1 -(2-hydroxyphenyl)-3-phenyl-3- (2-thienylthio)-1 -propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 61% viscous mass. The characteristics of the product which confirm the structure are: IR (KBr pellets); 1682, 1590, 1524, 1347 (cm-1) 1H NMR (CDCI3); 6 3.61-3.73 (d, 2H, J = 7.08Hz), 4.42-4.87 (t, 1H, J = 7.08Hz), 7.1-7.86 (m, 13H) Example XIII synthesis of 1,3, 3-triphenyl-3- (2-thienylthio)-1-propanone (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 65% Melting point: 123-125°C The characteristics of the product which confirm the structure are: IR (KBr pellets); 1691,1599, 1514,1339 (cm1) 1H NMR (CDCI3); 3.65-3.78 (d, 2H, J = 7.62 Hz) 4.42-4.97 (t, 1H, J = 7.47Hz), 7.1-8.52 (18H,m) The Minimum inhibitory concentration (MIC) of the active compounds corresponding to those obtained in Examples I - XIII were examined by the procedure as described in Example C the results are given in the Table 3. The results show that • All the compounds showed prominent activity against both the strains of Candida albicans. • Against fluconazole sensitive strain these compounds showed MIC value in the range 50-65 µg/ml the drug fluconazole was • Against fluconazole resistant strain, in which case fluconazole is totally ineffective for the inhibition of the growth of the fungi, the said compounds showed MIC value in the range 60-75 µg\ml. Advantages of the invention: • The synthesis of these compounds is very easy, straightforward and short, not incorporating any hazardous chemical. • The compounds effectively inhibit Candida albicans strain resistant to Fluconazole particularly one identified as NCIM 3446. TABLE 1: Examples I- XIII: Summary of the preparation of compounds of formula (F-l). Table 2: Summary of preparation of chalcones (F-ll) used in Examples I - XIII Table 3: MIC (µg/ml) values for active compounds of formula (F-l) synthesized in Examples I - XIII Example No. Candida albicans ATCC 10231 Candida albicans NCIM 3446 1 50 60 II 65 70 III 60 65 IV 50 60 V 60 60 VI 55 60 VII 65 70 VIII 70 75 IX 50 55 X 65 75 XI 60 65 XII 55 70 XIII 65 75 Fluconazole (Standard) 15 Does not inhibit the growth We Claim: 1. A process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (F-l), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; Ar1 is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3; the said process comprising, a. reacting a compound of Formula (F-ll) wherein, R1, R2, Ar1 and Ar2 are same as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same as in Formula (F-l) in a basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent selected from group comprising chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone; b. removing the solvent after the reaction and taking the dry product in water and extracting the reaction product in aqueous solution with another organic solvent which may be same or different but selected from group as in step (a), c. removing the solvent from the extract; and d. further purifying the product obtained at stage c, using silica gel column chromatography. 2. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, in formula (F-l), R1 = Ar2 =H, R2 =N02, An a phenyl and Ar3 = phenyl or4-acetylaminophenyl. 3. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 or 2 wherein, in formula (F-l), R2= Ar2=H, Ar1 = 2-furyl, Ar3 = 2-thienyl and R1 = H or OH 4. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, in formula (F -1), R1 = Ar2 =H, Ar1= 3-nitrophenyl, Ar3 = 2- thienyl and R2 = H or OH 5. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, in formula (F-l), R1 = Ar2 =H, R2 = NO2, Ar3 = 2-thienyl, and Ar1 is 4-chlorophenyl or 2-chlorophenyl or 3-nitrophenyl or phenyl. 6. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 or 2 wherein, in formula (F-l), Ar1 a phenyl and Ar2 =H, Ar3 = 2-thienyl, R1 =H together with R2= -OCH3, or R1 =OH together with R2= H. 7. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, in formula (F-l), R1 = R2, = H; Ar1 = Ar2 = phenyl and Ar3= 2-thienyl. 8. A process for the synthesis of compounds of formula (F-l) as claimed in any claim 1 - 7 wherein, the compounds of formula (F-ll), compounds of formula (F-lll) and triethylamine are taken in the molar ratio (1): (1.1 - 4): (1.1 - 4). 9. A process for synthesis of compounds of formula (F-l), as claimed in claim 8 wherein, the compounds of formula (F-ll), compounds of formula (F-lll) and triethylamine are taken in the molar ratio (1): (1.1): (1.1). 10. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-7 wherein, compounds of formula (F-ll), compounds of formula (F-lll) and sodium methoxide are taken in the molar ratio (1): (2 - 5): (2 - 5) when sodium methoxide is used as a base. 11. A process for synthesis of compounds of formula (F-l), as claimed in claim 10 wherein, compounds of formula (F-ll), compounds of formula (F-lll) and sodium methoxide are taken in the molar ratio (1): (5): (5) when sodium methoxide is used as a base. 12. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-11 wherein, the organic solvent used at step "a" is chosen from methanol or ethanol when the said basic medium employed is alkoxide. 13. A process for synthesis of compounds of formula (F-l), as claimed in 12 wherein, the organic solvent used at step "a" is preferably methanol when the said basic medium employed is sodium methoxide. 14. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-11 wherein, the organic solvent used at step "a" is chosen from benzene or toluene when the said basic medium employed is organic base such as triethylamine or pyridine. 15. A process for synthesis of compounds of formula (F-l), as claimed in any claim14 wherein, the organic base and the organic solvent used at step "a" is preferably triethylamine and toluene respectively. 16. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, the organic solvent used at step "b" is preferably chloroform. 17. A process for synthesis of compounds of formula (F-l), substantially as herein described in the text, examples and the drawings. dated this 9th day of July 2003 Dr. K. G.Akamanchi (Applicant)

Full Text

FORM 2
THE PATENTS ACT 1970
COMPLETE SPECIFICATION
(See Section 10)
TITLE
A process for synthesis of 1-aryl-3-aryl/heteroaryl-3-arylthio/
heteroarylthio-1-propanones possessing antifungal activity
APPLICANT
Dr. Akamanchi Krishnacharya Govindacharya,
Division of Pharmaceutical Sciences and Technology,
University Institute of Chemical Technology,
Matunga, Mumbai- 400 019,
State of Maharashtra, India,
An Indian National.
The following specification particularly describes the nature of the invention
and the manner in which it is to be performed:-

ORIGINAL
697/MUMNP/2003
09/07/03

GRANTED
10/2/2004

Field of Invention:
The present invention relates to a process for synthesis of 1- aryl -3-aryl / heteroaryl -3-arylthio / heteroarylthio -1-propanones having antifungal activity. This invention particularly relates to synthesis of 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones having antifungal activity against strains of Candida albicans which are sensitive as well as resistant to the marketed antifungal drug fluconazole.
Background and Prior Art:
Candida albicans is part of the normal flora of the mouth, intestine and vagina. It is also an opportunistic pathogen giving rise to an inflammation under a wide variety of circumstances. Infection is usually, endogenous though cross-infection may occur, as between infants in a nursery.
The site affected by Candida albicans is mucosa. Less common manifestations are the secondary infections in the lower respiratory tract and urinary tract infection. It may cause septicemia with localization in meninges, endocardium, bone marrow or kidney, which may occur in patients seriously ill with other conditions.
The commonest Candida infection is vaginitis or vaginal thrush. Pregnant women are particularly susceptible. Oral thrush occurs in debilitated or bottle fed infants. Infection of the skin is common in diabetes. Intestine infections occur in infants. Bronchial and pulmonary candiasis also occur but not common. Systemic infections may occur when the organism is inoculated into the tissues as in drug addicts. Candida albicans causes candiases on the skin and mucous membranes of the mouth, gastrointestinal tract, respiratory system, nervous system and urogenital organs of the man. Candiases of liver, biliary tract, pancreas and bones also occur. In number of chronic candiases septic cases are characterized by lesions into kidneys lung tissues, liver and other organs. About 90 per cent of the Candida infections in humans are due to Candida albicans.

A large number of organic compounds used as drugs for the treatment of candiasis. They belong to following classes:
i. Azoles- fluconazole, clotrimazole, econazole.
ii. Allylamines and other squalene epoxidease inhinitors-nafitifine, terbinafine, butenafine, tolnaftate.
iii. Morpholines- amorolphine.
iv. Nucleosides- flucytosine.
V. Antifungal antibiotics- polyene antibiotics, griseofulvin. However, the effectiveness of these drugs has gone down as certain strains of Candida albicans, have developed resistance to these drugs.
Clinical failure in the treatment of systemic fungal infections is due to the emergence of resistance of the pathogenic fungal species to clinically used antifungal drugs. Resistance to fluconazole is spreading rapidly and has become major problem in late-stage AIDS patients. The development of such resistance is due to multiple mechanisms. Recently, NCIM 3446 a strain of Candida albicans has been found to be resistant to the antifungal drug fluconazole. There is a need to develop a new drug for this strain. The only way to overcome this resistance problem is to synthesize new antifungal compounds to which none of the strains of Candida albicans has ever been exposed. A look at the literature showed that 3-phenyl-1-(2-furyl)-3-phenylthio-1-proanones have been reported to be active against various fungal species like Botrytis cineria, Valsa ceratosperma, Sclerotium cepivorum and Phytophthera capsici. [Sung, Nack-Do.; Kang, Hee-Deog.; Meang, Joo-Yang.; Shin, Dong-Rin. Hanguk Nonghwa Hakhoechj, 1994, 37(4), 287-294]. However, such compounds have not been tried out for activity against Candida albicans.
Object:
The principle object of the present invention is to synthesize new molecules amongst 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones that will be effective in mitigating organisms of strains of Candida albicans and

particularly those strains which are sensitive to the antifungal drug fluconazole like ATCC10231, or which are resistant to fluconazole like NCIM 3446. The main part of this object of the present invention is to synthesize and screen various analogues of 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones for their antifungal activity and evaluate in particular, their in vitro activity against strains of Candida albicans and particularly those strains, which are sensitive, like ATCC10231, or which are resistant, like NCIM 3446, to the antifungal drug fluconazole. Summary of the Invention:
Accordingly, the present invention provides a process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (Fl), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; An is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3;
the said process comprising,
a. reacting a compound of Formula (F-ll) wherein, R1, R2, An and Ar2 are same
as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same
as in Formula (F-l) in a basic medium using bases such as triethylamine,
pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an
organic solvent selected from group comprising chlorinated solvents such as
chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons
such as benzene, toluene, esters such as ethyl acetate and ketones such as
methyl isobutyl ketone;
b. removing the solvent after the reaction and taking the dry product in water and
extracting the reaction product in aqueous solution with another organic
solvent which may be same or different but selected from group as in step (a),
c. removing the solvent from the extract; and

d. further purifying the product obtained at stage c, using silica gel column chromatography.
Description of the Invention:
The various analogues of 1- aryl-3-aryl/heteroaryl-3-arylthio / heteroarylthio-1-propanones prepared are represented by general structural formula (F-1),

Wherein,
R1 = H or OH; R2 is selected from H, OH, OCH3, or N02;
An is selected from compounds of formula (F - IV) or (F- V),
wherein, R3 is selected from -H, -CI or -N02;
Ar2= H or Phenyl;
Ar3 is selected from compounds of formula (F - VI) or (FVII)

(F - VI) (F-VII)
wherein, R4 = H or -NHCOCH3,
by reacting compounds of formula (F-ll) and (F-lll) according to the present invention and found to have biological activity against Candida albicans are shown in Table 1 -

Of the various novel compounds represented by Formula (F-l) synthesized, following groups of compounds have been found to have antifungal activity against Candida albicans

Synthesis of Specific compounds of formula (F-ll):
1,3-diaryl-2-propen-1-ones the compounds of formula (F-ll) are known as propenones or chalcones, henceforth referred as "Chalcones". Since they are not readily available, they are synthesized by conventional aldol condensation of compounds represented by formula (F-lla) and (F-llb) in which the substituents are selected as required for the synthesis of desired compound of formula (F-l). Compounds obtained by this step are not novel.

Synthesis of Specific compounds of formula (F-ll):
1,3-diaryl-2-propen-1-ones the compounds of formula (F-ll) are known as propenones or chalcones, henceforth referred as "Chalcones". Since they are not readily available, they are synthesized by conventional aldol condensation of compounds represented by formula (F-lla) and (F-llb) in which the substituents are selected as required for the synthesis of desired compound of formula (F-l). Compounds obtained by this step are not novel.

Chalcones of general formula (F-ll) (for details see Table 2) are prepared in the laboratory by literature methods (further details given in examples A and B) and used directly for the synthesis of novel propanones of formula (F-l). Following two methods for the synthesis of chalcones by aldol condensation are useful.
i. Base catalyzed [Peter klinke, Heinz Gibian, Chemische berische. 1961,
94, 2638; Chemical abstract no. 72-121124p (Falco da, Fonseca, Luis.
Bol Fac. Farm., Univ. Coimbra, Ed. Client. 1968, 28, 49-52); Chemical
abstract- 72-66551y. (Druzilla.M; Kristian, P. Collec. Czech. Chem.
Commun. 1969, 35 (2), 417-419)] and ii. Acid catalyzed aldol condensation. (Lyle, R.E.; Paradis.LP. J. Am. Chem.
Soc. 1955, 77, 6667-6668.) In case any desired chalcone is readily available, this step in the synthesis is not required.
Synthesis propanones of formula (F-l)
In the second step a novel compound of the present invention 1- aryl-3-aryl/heteroaryl,-3-arylthio / heteroarylthio,-1-propanones represented by Formula (F-l) is obtained by conventional Michael addition of substituted thiophenol of formula (Fill) to the chalcone (F-ll) both having same substituents as in formula (F-l) which are either readily available or made as said in step 1 of this process.. The addition of substituted thiophenols compounds of formula (F-lll) on to chalcones of general structural formula (F-ll) is carried out in basic medium using bases such as triethylamine, pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an organic solvent, at ambient temperature. The reaction takes place in 0.5-5 hrs. (K. G. Akamanchi and U .W. Mali. Asian J. Chem. 2001, 49-59; Sharaf, Saber M; El-Sadany, Samir K; Hamed, Ezzat, A.; Elba, Mohammed E. Alexandria J. Pharm. Sci. 1991, 5 (2) 187-191). The products are isolated by extraction in suitable solvent (solvents) and purified by column chromatography over silica gel (60-120mesh) with suitable eluent

system. These novel compounds are then evaluated for in vitro antifungal activity.
In the process of present invention, for the Michael addition reaction, the preferred basic media were triethylamine and sodium methoxide in toluene and methanol respectively. Details of these procedures are given below. Reaction With Triethylamine As A Base:
The reaction in presence of triethylamine as a base is carried out as follows: 1,3-diaryl-2-propen-1-ones of structural formula (F-ll), compounds of formula (Fill) and triethylamine were taken in the molar ratio (1) : (1.1 - 4) : (1.1 - 4) preferably, (1): (1.1): (1.1) . In three necked round bottom flask equipped with magnetic stirrer, CaCI2 guard tube and nitrogen inlet, a compound of 1,3-diaryl-2-propen-1-ones of general formula (F-ll) (0.01 mole) is taken in suitable organic solvents selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone. Toluene is solvent of choice. To this solution in the reaction flask, are added a compound of compounds of formula (F-lll) (0.011 mole) followed by triethylamine (0.011 mole) and stirred for 2-6 hours. The reaction is monitored by TLC and HPLC. (System for TLC; Ethyl acetate: Hexane:: 05-15: 95-85, by volume and HPLC system; water: Methanol:: 8-20: 92-80 by volume). On completion of the reaction, cold water (25ml) is added to the reaction mixture and product is extracted with suitable organic solvent (3 x 10 ml) selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, esters such as ethyl acetate and ketones such as methyl isobutyl ketone. Chloroform is solvent of choice. The product obtained after removing the solvent is further purified by column chromatography over silica gel (60-120mesh) with suitable eluent system such as Hexane and Ethyl acetate in varying proportion; Ethyl acetate : Hexane :: (05-15) : (95-85) by vol., preferably, (5:95) by volume.

Reaction With Sodium Methoxide As A Base
The reaction in presence of sodium methoxide as a base, is carried out as follows:
A compound of formula (F-lll) is taken in methanol/ ethanol in the three necked round bottom flask equipped with magnetic stirrer, CaCI2 guard tube and nitrogen inlet. To the reaction mixture is added sodium methoxide (NaOCH3) in methanol and after 5 minutes chalcone of general formula (F-ll) is added slowly. Chalcones of general formula (F-ll), compounds of formula (F-lll) and NaOCH3 are taken in the molar ratio (1): (2 - 5): (2 - 5) preferably, 1: 5: 5.
The reaction is stirred at ambient temperature and monitored by TLC and HPLC as in the above method. On completion of the reaction, the solvent is evaporated to dryness and ice-cold water is added to the reaction mixture and the product is extracted with suitable organic solvent selected from chlorinated solvents such as chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and esters such as ethyl acetate and ketones such as like methyl isobutyl ketone. Chloroform is solvent of choice. The products are purified by column chromatography over silica gel (60-120mesh) with suitable eluent system such as Hexane and Ethyl acetate in varying proportion, Ethyl acetate : Hexane :: (05-15): (95-85) by vol. preferably 5: 95 by vol. The purity of the compounds is established by TLC, IR, NMR and HPLC. (Water: Methanol, 15:85).
In vitro biological evaluation:
The antifungal activity expressed as minimum inhibitory concentration (MIC) of the said compounds according to the invention has been determined by broth dilution method (Barrry, A. L.; Leo and Febigar, Philadelphia, 1976, 92-104). Concentration of compounds added was 50-250 µg/ml. The medium used was Saborauds dextrose broth. The inoculum concentration was 5 X 10 15 Colony forming units per ml.

One loop full of this inoculum was used as inoculate per inoculation point. The results were interpreted after 48 hours incubation in dark conditions at room temperature. Measurement of turbidity by means of photoelectric colorimeter was done for the interpretation of the results. The fungal species used for evaluating the activity of said compounds have been
1) Candida albicans ATCC 10231
It was obtained from Haffkine Institute, Parel, Mumbai.
2) Candida albicans NCIM 3446.
It was obtained from Food and Fermentation Technology division, UICT, Mumbai.
Examples:
The invention will now be illustrated with the help of examples. Examples are the way of illustration only and in no way restrict the scope of the invention. Examples I to XIII describes syntheses of thirteen novel compounds of the present invention, which are summarized in Table-1. In Table-2 are summarized preparations of the chalcones of formula (F-ll) required for the synthesis of each novel compound of formula (F-l) described in the examples I to XIII. Example I and XI describe the detailed procedure for the synthesis of specific compounds of formula (F-l) in which reaction medium is sodium methoxide and triethylamine respectively. Example A and B describes the preparation of chalcones in acid and basic media respectively and the example C describes the protocol for biological evaluation of the said novel compounds of formula (F-l). The results of the biological evaluation of the compounds synthesized are given in Table -3.
Solvents and reagents
Following solvents and reagents used in these Examples were obtained from S.D. Finechem Ltd., (L.R. Grade) Mumbai: chloroform, dichloromethane, carbon tetrachloride, benzene, toluene ethyl acetate, methyl isobutyl ketone, hexane; sodium methoxide, hydrochloric acid (30-35%), Triethylamine, Silica gel (60-120 mesh). Acetophenone, 4-nitro-acetophenone, 4-methoxy-acetophenone, 4-hydroxy-acetophenone, 2-hydroxy-acetophenone, benzaldehyde,

2-Chloro-benzaldehyde, 4-chloro-benzaldehyde, 3-Nitro-benzaldehyde, Benzophenone, Furfural Following imported chemicalcs were obtained locally.
1. Thiophenol (99+%, Lancaster)
2. 4-Acetamidothiophenol (97%, Lancaster)
3. 2-Thiophenethiol (96%, Lancaster).
Example A:
Preparation of Chalcone: 1-(4-nitrophenyl)-3-phenyl- 2-propen-1 -one.
4-nitroacetophenone (1 gm, 0.00606 mol,) and benzaldehyde (0.64g, 0.00606 mol), were taken in round bottom flask containing glacial acetic acid (20 ml). To it concentrated H2S04 (1 ml, 0.018 mol) was added and stirred for 2 days at room temperature. The precipitate formed was filtered off and washed with sodium bicarbonate solution and copious volume of water. The product was recrystalised from pyridine. 0.55g, yield 36%, recrystallized product directly used for the next reaction.
Example B:
Preparation of Chalcone: 1,3-diphenyl-2-propen-1-one
Place a solution of 5.1 g of sodium hydroxide in 50 ml water and 30 ml methanol in a 200 ml round bottom flask immersed in ice-bath, provided with mechanical stirrer. Add freshly distilled acetophenone (1g, 0.0083 mol) under stirring and then add freshly distilled benzaldehyde (0.88g, 0.0083 mol,) Keep the temperature at about 25°C and stir vigorously until the reaction mass becomes so thick that the stirring is no longer effective. Stop the stirring and allow the reaction to stand overnight in refrigerator. Filter the reaction, wash the solid with cold water and dry in air. Recrystalise from methanol/water solvent system. (1.15g, yield 67 %, recrystaJJized product directly used for the next reaction)

Example-C In vitro evaluation of biological activity
The evaluation of the synthesized compounds for antifungal activity was carried out using broth dilution method and minimum inhibitory concentration was determined by visual comparison with the negative control tubes. Detailed test procedure
1. Stock Solutions of test compounds and standard drug-
Compounds prepared in Examples I - XIII were taken as test samples along with a
standard fluconazole sample.
10 mg of each test compound was dissolved in 1 ml of dimethylsulphoxide. (L.R Grade, S.D. Finechem Ltd. Mumbai)
For preparing stock solution of fluconazole, 10 mg of fluconazole (sample Obtained from FDC Ltd., Mumbai) was dissolved in 1 ml of dimethylsulphoxide.
2. Test organism-
The organisms employed in the in vitro testing of the compounds were Candida albicans ATCC 10231 (fluconazole sensitive) - It was obtained from Haffkine Institute, Parel (Mumbai).
Candida albicans NCIM 3446 (fluconazole resistant) - It was obtained from Food and Fermentation Technology division, UICT, Mumbai.
All the cultures were maintained on Saborauds agar (microbiology grade, Himedia lab. Ltd., Mumbai) medium by periodic subculturing.
3. Preparation of Inocula-
Procedure for the preparation of inoculum for both the strains was same. The inoculum was prepared from a 24-hours old growth of organism on Saboraud's dextrose agar slant. With the help of sterile nichrome wire loop, the growth of the organism on slant was aseptically transferred to a tube containing sterile distilled water. The contents of the tube were then shaken properly so as to get uniform cell suspension of the organism. Optical density the inoculum was adjusted to 0.4 on the photoelectric colorimeter by using sterile distilled water, before using it as a inoculum.

4. Medium-
3 gm of Saboraud's dextrose broth (microbiology grade, Himedia lab. Ltd., Mumbai) was dissolved in 100 ml of sterile distilled water. 2 ml of this stock solution was transferred to each test tube.
5. Test proper-
To 2 ml of sterile Saboraud's dextrose broth solution was taken in a test tube, 10-40 µl of the stock solution was added followed by a loop full of an authentic culture of Candida albicans ATCC 10231 and Candida albicans NCIM 3446 (corresponding to 5 X 10 15CFU/ml.).
This corresponds to concentration range of 50, 100, 150, 200 µg/ml of the test compound. The tests were carried out in duplicate. Apart from putting the controls of standard drug (Fluconazole), controls with dimethyl sulphoxide (positive control) and without dimethyl sulphoxide (negative control) were also included in the test.
6. Incubation-
The test tubes were put in the dark conditions at room temperature for 48 hours. At the end of incubation period, the results were interpreted by visual comparison with negative control. The lowest concentration of test compound which showed inhibitory effect on growth on visual distinction was taken as Minimum inhibitory concentration. The results are given in Table 3.
Example-I: Synthesis of
Fig. 1

1-(4-nitrophenyl)-3-phenyl-3-phenylthio-1-propanone.

Sodium methoxide (0.0835 mol) in methanol (15 ml), was taken in a round bottom
flask and to it was added thiophenol (0.0835 mol) and stirred still reaction mixture
appeared clear. 1-(4-nitrophenyl)-3-phenyl-2-propen-1-one (chalcone), (0.00167
mol) prepared in Example A described above, was added to the reaction mixture
gradually. The reaction progress was monitored by TLC. After 30 minutes reaction
mixture was concentrated to dryness. The solid residue was dissolved with 15 ml of
cold water and extracted with chloroform (2 x 25 ml). The chloroform layer was
washed further with cold water (5 x15 ml). Then the combined organic layer was
dried over sodium sulfate and evaporated under reduced pressure to yield crude
mixture of Michael adduct and corresponding unreacted thiophenol. It was further
purified by silica gel column chromatography using mobile phase system (Hexane:
Ethyl acetate; 9.5:0.5) to the pure product
Yield: 69%.
Melting point: 126-129°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets): 1693,1601, 1514, 1338 (cm-1)
1H NMR (CCI4): 3.49-3.60 (d, 2H,J=7.2 Hz), 4.7- 4.92 (t, 1H, J=6.84 Hz), 7.2 (m,
10H), 7.9-8.35 (m, 4H).
Examples II to XIII:
In following Examples II to X, experimental procedure used was as described in
Example I wherein sodium methoxide was used as base.
In Examples XI to XIII, experimental procedure used was as described in
Example XI wherein triethylamine was used as base.
Example-ll: Synthesis of
3-(4-acetylaminophenylthio)-1-(4-nitrophenyl)-3-phenyl-1-propanone.
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 48%. (Column purification, Ethyl acetate: Hexane, 20:80) Melting point: 162-166°C

The characteristics of the product which confirm the structure are:
IR (KBr pellets): 3306, 1686, 1664, 1584, 1521, 1346 (cm -1)
1H NMR (CDCI3): 8 2.16 (s, 3H, -CH3), 3.57-3.68 (d, 2H, J=7.1 Hz), 4.72- 4.96 (t,
1H, J=7.1 Hz), 7.27-7.44 (m, 10H,), 7.92-8.38 (m, 4H, Ar-H).
Example III: Synthesis of
3-(2-furyl)-1 -phenyl -3-(2-thienylthio)-1 -propanone. (For starting compounds, F-ll and F-lll and reaction conditions, See Table 1). Yield: 59%, viscous liquid.
The characteristics of the product which confirm the structure are: IR (KBr pellets); 1690, 1590, 1525, 1345(cm-1)
1H NMR (CCI4); 5 3.49-3.61 (d, 2H, J = 7.08Hz), 4.65- 4.9 (t, 1H, J =7.08 Hz), 6.1-7.29 (m, 11H).
Example IV: Synthesis of
3-(2-furyl)-1-(2-hydroxyphenyl)- 3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 55%, viscous liquid.
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1685,1600, 1530,1340(cm-1)
1H NMR (CDCI3); 8 3.58-3.71 (d, 2H, J = 7.08Hz), 4.69-4.93 (t, 1H, J = 7.08Hz),
6.18-7.79 (m, 11H).
Example V : Synthesis of
3-(3-nitrophenyl)-1 -phenyl-3- (2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 65%
Melting point: 132-135°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1695, 1600, 1535, 1335 (cm-1)

1H NMR (CCI4); 5 3.34-3.46 (d, 2H, J = 7.08Hz), 4.43-4.67 (t, 1H, J = 7.08Hz), 6.69-7.77(m, 12H)
Example VI: Synthesis of
1 -(4-hydroxyphenyl) -3-(3-nitrophenyl)-3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 71%
Melting point: 170-172°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1690,1598, 1530,1330 (cm1)
1H NMR (CDCI3); 3.59-3.71 (d, 2H, J = 6.84 Hz), 4.73-4.92 (t, 1H, J = 6.80Hz),
6.81-8.1 (m, 12H)
Example VII: Synthesis of
3-(2-chlorophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 68%
Melting point: 118-121 °C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1685, 1600,1535, 1338 (cm1)
1H NMR (CDCI3); 5 3.67-3.77 (d, 2H, J = 6.36 Hz), 5.13-5.37 (1H, t), 6.92-8.4 (m,
11H)
Example VIII: Synthesis of
3-(4-chlorophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 74%
Melting point: 89-91 °C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1690, 1595, 1540, 1340 (cm1)

1H NMR (CDCI3); 5 3.59-3.71 (d, 2H, J = 7.08Hz), 4.61-4.81 (t, 1H, J = 7.18Hz), 6.98-8.37 (m, 11H).
Example IX: Synthesis of
3-(3-nitrophenyl) -1 -(4-nitrophenyl)-3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 69%
Melting point: 135-137°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1701,1601,1521, 1339 (cm"1)
1H NMR (CDCI3); 6 3.69-3.82 (d, 2H, J = 7.56 Hz), 4.64-4.97 (t, 1H, J = 7.56Hz),
6.92-8.38 (m, 12H)
Example X: Synthesis of
1-(4-nitrophenyl)- 3-phenyl -3-(2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 73%
Melting point: 101-103°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1693, 1601, 1514,1338 (cm1)
1H NMR (CDCI3); 6 3.62-3.73 (d, 2H, J = 7.08Hz) 4.64-4.88 (t, 1H, J = 7.08Hz),
6.96-8.38 (m, 12H)
Example XI: Synthesis of
1 -(4-Methoxyphenyl)-3-phenyl-3-(2-thienylthio)-1 -propanone.
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1), the reaction is described below.

Fig. 3
In a three necked round bottom flask equipped with CaCI2 guard tube, nitrogen inlet and mechanical stirrer containing toluene (30ml), 1-(4-methoxyphenyl)-3-phenyl-2-propen-1-one (0.01 mol), the chalcone prepared as shown in Table 2 and 2-thiophenethiol (0.011 mol) are charged followed by triethylamine (0.011 mol). The reaction (See Fig.3) is stirred at an ambient temperature for 6 hours. The progress of the reaction is monitored by HPLC (water: methanol :: 10:90). On completion of the reaction the water (20ml) is added to the reaction mixture and the product is extracted with toluene. Toluene is evaporated to get the product. It was further purified by silica gel column chromatography using mobile phase system (Hexane: Ethyl acetate; 9.5:0.5) to the pure product
Yield: 74%
Melting point: 86-88°C
The characteristics of the product which confirm the structure are:
IR; (KBr pellets); 1694,1592,1512,1329 (cm"1)
1H NMR (CDCI3); 5 3.45-3.57 (d, 2H, J = 7.08Hz), 3.75 (s, 3H,), 4.59-4.83 (1H, t,
J = 7.08Hz), 6.86-8.1 (m, 12H)
In following Examples XI to XIII, experimental procedure used was as described in Example XI wherein triethylamine was used as base.
Example XII: Synthesis of
1 -(2-hydroxyphenyl)-3-phenyl-3- (2-thienylthio)-1 -propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 61% viscous mass.

The characteristics of the product which confirm the structure are: IR (KBr pellets); 1682, 1590, 1524, 1347 (cm-1)
1H NMR (CDCI3); 6 3.61-3.73 (d, 2H, J = 7.08Hz), 4.42-4.87 (t, 1H, J = 7.08Hz), 7.1-7.86 (m, 13H)
Example XIII synthesis of
1,3, 3-triphenyl-3- (2-thienylthio)-1-propanone
(For starting compounds, F-ll and F-lll and reaction conditions, See Table 1).
Yield: 65%
Melting point: 123-125°C
The characteristics of the product which confirm the structure are:
IR (KBr pellets); 1691,1599, 1514,1339 (cm1)
1H NMR (CDCI3); 3.65-3.78 (d, 2H, J = 7.62 Hz) 4.42-4.97 (t, 1H, J = 7.47Hz),
7.1-8.52 (18H,m)
The Minimum inhibitory concentration (MIC) of the active compounds
corresponding to those obtained in Examples I - XIII were examined by the
procedure as described in Example C the results are given in the Table 3.
The results show that
• All the compounds showed prominent activity against both the strains of Candida albicans.
• Against fluconazole sensitive strain these compounds showed MIC value in the range 50-65 µg/ml the drug fluconazole was • Against fluconazole resistant strain, in which case fluconazole is totally ineffective for the inhibition of the growth of the fungi, the said compounds showed MIC value in the range 60-75 µg\ml.
Advantages of the invention:
• The synthesis of these compounds is very easy, straightforward and short, not incorporating any hazardous chemical.
• The compounds effectively inhibit Candida albicans strain resistant to Fluconazole particularly one identified as NCIM 3446.

TABLE 1: Examples I- XIII: Summary of the preparation of compounds of formula (F-l).

Table 2: Summary of preparation of chalcones (F-ll) used in Examples I - XIII

Table 3: MIC (µg/ml) values for active compounds of formula (F-l) synthesized in Examples I - XIII

Example No. Candida albicans ATCC 10231 Candida albicans NCIM 3446
1 50 60
II 65 70
III 60 65
IV 50 60
V 60 60
VI 55 60
VII 65 70
VIII 70 75
IX 50 55
X 65 75
XI 60 65
XII 55 70
XIII 65 75
Fluconazole (Standard) 15 Does not inhibit the growth

We Claim:
1. A process for synthesis of compounds 1- aryl-3-aryl / heteroaryl-3-arylthio / heteroarylthio-1-propanones, of formula (F-l), possessing antifungal activity, wherein, R1 is selected from H, OH; R2 is selected from H, OH, OCH3, CI, NO2; Ar2 is selected from H, Phenyl; Ar1 is selected from compounds of formula (F-IV) or (F- V) wherein, R3 is selected from -H, -NO2; Ar3 is selected from compounds of formula (F - VI) or (F- VII) wherein, R4 is selected from H, -NHCOCH3; the said process comprising,
a. reacting a compound of Formula (F-ll) wherein, R1, R2, Ar1 and Ar2 are same
as in Formula (F-l) with a compound of Formula (F-lll) wherein, Ar3 is same
as in Formula (F-l) in a basic medium using bases such as triethylamine,
pyridine, alkoxides such as sodium methoxide, sodium ethoxide, in an
organic solvent selected from group comprising chlorinated solvents such as
chloroform, dichloromethane, carbon tetrachloride, aromatic hydrocarbons
such as benzene, toluene, esters such as ethyl acetate and ketones such as
methyl isobutyl ketone;
b. removing the solvent after the reaction and taking the dry product in water and
extracting the reaction product in aqueous solution with another organic
solvent which may be same or different but selected from group as in step (a),
c. removing the solvent from the extract; and
d. further purifying the product obtained at stage c, using silica gel column
chromatography.

2. A process for synthesis of compounds of formula (F-l), as claimed in claim 1
wherein, in formula (F-l), R1 = Ar2 =H, R2 =N02, An a phenyl and Ar3 = phenyl or4-acetylaminophenyl.
3. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 or
2 wherein, in formula (F-l), R2= Ar2=H, Ar1 = 2-furyl, Ar3 = 2-thienyl and R1 = H or OH
4. A process for synthesis of compounds of formula (F-l), as claimed in claim 1
wherein, in formula (F -1), R1 = Ar2 =H, Ar1= 3-nitrophenyl, Ar3 = 2- thienyl and R2 = H or OH
5. A process for synthesis of compounds of formula (F-l), as claimed in claim 1
wherein, in formula (F-l), R1 = Ar2 =H, R2 = NO2, Ar3 = 2-thienyl, and Ar1 is 4-chlorophenyl or 2-chlorophenyl or 3-nitrophenyl or phenyl.
6. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 or
2 wherein, in formula (F-l), Ar1 a phenyl and Ar2 =H, Ar3 = 2-thienyl, R1 =H together with R2= -OCH3, or R1 =OH together with R2= H.
7. A process for synthesis of compounds of formula (F-l), as claimed in claim 1 wherein, in formula (F-l), R1 = R2, = H; Ar1 = Ar2 = phenyl and Ar3= 2-thienyl.
8. A process for the synthesis of compounds of formula (F-l) as claimed in any
claim 1 - 7 wherein, the compounds of formula (F-ll), compounds of formula (F-lll) and triethylamine are taken in the molar ratio (1): (1.1 - 4): (1.1 - 4).
9. A process for synthesis of compounds of formula (F-l), as claimed in claim 8
wherein, the compounds of formula (F-ll), compounds of formula (F-lll) and triethylamine are taken in the molar ratio (1): (1.1): (1.1).

10. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-7 wherein, compounds of formula (F-ll), compounds of formula (F-lll) and sodium methoxide are taken in the molar ratio (1): (2 - 5): (2 - 5) when sodium methoxide is used as a base.
11. A process for synthesis of compounds of formula (F-l), as claimed in claim 10 wherein, compounds of formula (F-ll), compounds of formula (F-lll) and sodium methoxide are taken in the molar ratio (1): (5): (5) when sodium methoxide is used as a base.

12. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-11 wherein, the organic solvent used at step "a" is chosen from methanol or ethanol when the said basic medium employed is alkoxide.
13. A process for synthesis of compounds of formula (F-l), as claimed in 12 wherein, the organic solvent used at step "a" is preferably methanol when the said basic medium employed is sodium methoxide.
14. A process for synthesis of compounds of formula (F-l), as claimed in any claim 1-11 wherein, the organic solvent used at step "a" is chosen from benzene or toluene when the said basic medium employed is organic base such as triethylamine or pyridine.
15. A process for synthesis of compounds of formula (F-l), as claimed in any claim14 wherein, the organic base and the organic solvent used at step "a" is preferably triethylamine and toluene respectively.
16. A process for synthesis of compounds of formula (F-l), as claimed in claim 1
wherein, the organic solvent used at step "b" is preferably chloroform.

17. A process for synthesis of compounds of formula (F-l), substantially as herein described in the text, examples and the drawings.

dated this 9th day of July 2003

Dr. K. G.Akamanchi (Applicant)

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Patent Number

205247

Indian Patent Application Number

697/MUM/2003

PG Journal Number

42/2008

Publication Date

17-Oct-2008

Grant Date

22-Mar-2007

Date of Filing

09-Jul-2003

Name of Patentee

DR. AKAMANCHI. KRISHNACHARYA GOVINDACHARYA

Applicant Address

DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, MATUNGA, MUMBAI 400 019, MAHARASHTRA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. AKAMANCHI. KRISHNACHARYA GOVINDACHARYA	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, MATUNGA, MUMBAI - 400 019, MAHARASHTRA, INDIA.
2	MR. CHAUDHARI MAHESH KISAN	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, MATUNGA, MUMBAI - 400 019, MAHARASHTRA, INDIA.
3	MR. BACHHAV YOGESHWAR GULABRAO	DEPARTMENT OF PHARMACEUTICAL SCIENCES AND TECHNOLOGY, UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, MATUNGA, MUMBAI - 400 019, MAHARASHTRA, INDIA.

PCT International Classification Number

C07D 400/4

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA