Title of Invention

"5-[2-(2,6,6,-TRIMENTHYL-CYCLOHEX-2-ENYL)-ENTHENYL]-ISOXAAZOLES"

Abstract

The present invention provides a novel 5- [2-(2,6,6- trimethyl-cyclohex-2-enyl)-ethenyl]-isoxaazoles of general formula 4 wherein X is selected from group consisting of OH, Cl, OEt, NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group. A substituted amino group is selected from the group consisting of morpholino, piperazino, N-phenylpiperazino, pyrrolidino, anisidino, anilino, p-chloroanilino and cyclohexylamino. This invention further relates to the preparation of compounds useful as antileishmanial agents

Full Text

5-[2-(2.6.6-Trimethvl-cyclohex-2-enyl)-ethenvl]-isoxaazoles FIELD OF THE INVENTION The present invention relates to 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxaazoles. This invention relates to a process for the preparation of 5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxaazole-3-carboxylic acid derivatives. This invention further relates to the preparation of compounds useful as antileishmanial agents. BACKGROUND OF THE INVENTION Leishmaniasis is an infection caused by protozoa of the genus Leishmania presenting several forms of the disease such as cutaneous (CL), mucocutaneous (MCL) and visceral leishmaniasis (VL), which can be fatal when untreated. The currently available chemotherapy for leishmaniasis is far from satisfactory. For the treatment of both visceral (VL) and cutaneous leishmaniasis (CL) pentavalent antimonials is recommended for > 50 years, has shown resistance all over India. Some of the new drugs come up in recent years for the treatment of VL including amphotericin B lipid complex and the oral drug miltefosine [S. L. Croft, K. Seifert, M. Duchene, Mol. Biochem. Parasitol. (2003), 126, 165], have other problems in the treatment. In recent years, efforts are being made to search for new molecules from the natural sources and in this endeavour diaryl heptanoids, oxygenated abietanes, diterpene quinones are showing promise as new lead molecules. Randomly designed heterocyclic ionone like molecules [Anzaldi M., Sottofattori E., Rizzetto R, di Casaleto B. G., Balbi A., Eur. J. Med. Chem. (1999), 34, 837] and some novel terpenyl 2, 4-diamino pyrimidines [Rosowsky A., Papoulis A. T., Queener S. F., J. Heterocyclic Chem.(1999), 36 723] are showing promising antimicrobial and dihydrofolate reductase inhibitory activities. Rationally designed 2, 4-diaminopyrimidines and some computer aided molecules are also giving further inputs in the leishmanial dihydrofolate reductase activity. In continuation of our studies on terpenyl pyrimidines as novel antileishmanial agents [Pandey S, Suryawanshi S. N., Gupta S, Srivastava V. M. L., Eur. J. Med. Chem. (2004), 39, 969], we have designed novel terpenyl Isooxazoles for their in-vivo antileishmanial activity. OBJECTS OF THE INVENTION Main objective of the present invention is to provide a novel 5- [2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]- isoxaazoles. Another objective of the present invention is to provide a process for the preparation of terpenyl isooxazole derivatives. More particularly present invention provides a process for the preparation of compound of general formula 4 of the drawing accompanying this specification wherein X is OH, NHOH, NHNH2, N(Na)OH, N(Na)NH2, morpholino, piperazino, N-phenylpiperazino, pyrrolidino, anisidino, anilino, p-chloroanilino and cyclohexylamino. (Formula Removed) Another object of this invention is to provide compounds useful as antileishmanial agents. SUMMARY OF THE INVENTION Accordingly the present invention provides a novel 5- [2-(2,6,6- trimethyl-cyclohex-2-enyl)-ethenyl]- isoxaazoles of general formula 4 (Formula Removed) wherein X is selected from group consisting of OH, Cl, OEt, NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group. A substituted amino group is selected from the group consisting of morpholino, piperazino, N-phenylpiperazino, pyrrolidino, anisidino, anilino, p-chloroanilino and cyclohexylamino DETAILED DESCRIPTION OF THE INVENTION Accordingly the present invention provides a process of preparation of 5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxaazoles of formula 4 wherein X is selected from group consisting of OH, Cl, OEt, NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group , process comprising; (i) refluxing a-ionone 1 with diethyl oxalate in presence of an alkali metal hydride in an aromatic solvent to give 1,3-diketone of formula 2, (ii) condensing 1,3-diketone 2 so obtained with hydroxyl amine in presence of a protic solvent at reflux temperature to obtain isooxazole of formula 3, purifying the product using standard laboratory techniques, (iii) reacting isooxazole 3 with an alkali hydroxide or hydroxyl amine, or hydrazine in a protic solvent to get the compound of formula 4 wherein X = OH or NHOH or NHNH2. optionally converting the compound of formula 4 wherein X is NHOH or NHNH2 their sodium salt by the treatment with sodium hydroxide to produce the compound of formula 4 wherein X is N(Ma)OH or N(Na)NH2 respectively, (iv) reacting compound of formula 4 wherein X = OH with oxallyl chloride in a chlorinated alkane to get compound of formula 4 wherein X = Cl followed by treatment with amines to get compound of formula 4 wherein X = amino. In an embodiment of the invention the non protic solvent used in step (i) may be selected from toluene, benzene, xylene. In a further embodiment of the invention the protic solvent used in step (ii) may be selected from methanol, ethanol, dichloromethane. In a yet another embodiment of the invention conventional chromatography method used may be such as preparative, thin layer chromatography, column chromatography. In a further embodiment of the invention the chlorinated alkanes may be selected from dichloro methane, chloroform, carbon tetra chloride, tetra chloro ethane, solvent used in step (i) may be selected from toluene, benzene, xylene. Yet in another embodiment the amines used in step (iv) may be selected from secondary amines like morpholine, piperazine, N-phenyl piperazine; aromatic amines like aniline, p-chloroaniline; aliphatic amine like cyclohexyl amine to get 4 (X = Morpholino, piperazino, N-phenyl piperazino, aniline, p-chloroanolino and cyclohexyloamino). The solvent used in chromatographic separation may be such as hexane, ethylacetate, methanol and mixture thereof. In a feature of the invention wherein the said compounds are converted to any pharmaceutically acceptable salt. The representative compounds of the formula 4 prepared by the process of the present invention are as follows: 1. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylicacid. 2. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-carboxylic acid hydroxyamide. 3. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid hydrazide. 4. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-sodio- hydroxyamide. 5. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-sodio- hydrazide. 6. Morpholin-4-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol- 3-yl}-methanone. 7. Piperazin-l-yl)-{5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol- 3-yl}-methanone. 8. 4-(Phenyl-piprazin-l-yl)-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]- isoxazol-3-yl}-methanone. 9. Piperidin-l-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol- 3-yl}-methanone. 10. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid (4-methoxy-phenyl)-amide. 11. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid phenylamide. 12. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-(4-chloro-phenyl)-amide. 13. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-cyclohexyl-amide. A pharmaceutical composition comprising the therapeutically effective amount of compound of formula 4 wherein X is selected from group consisting of OH, Cl, OEt, NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group optionally along with one or more pharmaceutically acceptable carriers, additives, lubricant and diluents. In an embodiment of the invention, wherein the additive used may be selected from the group comprising of proteins, carbohydrates, sugar, talc, magnesium state, cellulose, calcium, carbohydrate, starch-gelatin paste. In another embodiment of the invention, wherein the said composition may be useful for the treatment of leishmania. In yet another embodiment of the invention, wherein the said composition is effective to inhibit the amastigotes multiplication around 80% at a dose of 50 mg/kg. The invention as described above is illustrated by examples given below which should not however, be construed to limit the scope of the invention. Example 1 2,4-Dioxo-6-(2,6,6-trimethyl-cycIohex-2-enyl)-hex-5enoic acid ethyl ester 2 A mixture of oil free sodium hydride ( 1.25 gm, 26mmol ), diethyl oxalate ( 7.59 ml, 52 mmol ) and alpha-ionone ( 5.00 ml, 26 mmol ) in dry toluene ( 45ml )was magnetically stirred under reflux for 2hrs. It was cooled to room temperature and treated with dilute HC1 ( 13.00 ml ) water ( 30ml ) and ethyl acetate ( 80ml )and stirred for 0.5 hr. Organic portion was seperated and concentrated. The crude product after column chromatography furnished 2 as a thick liquid (4.30 gm, 65% ) Example 2 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid ethyl ester 3 To a mixture of ester 2 (1.92 gm, 5 mmol) in ethanol (10 ml) was added hydroxylamine hydrochloride was refluxed at 80° C for 2 hrs. After the removal of ethanol, the crude was taken up in ethylacetate (20 ml). The combined extract was washed with water (2 x 20 ml), brine (2 x 20 ml), dried (Na2SO4). The solvent was removed in- vacuo. The crude product thus obtained was chromatographed (SiOi, 60-120 mesh). Elution with 5 % ethylacetate in hexane furnished light yellow thick liquid which on crystallization (ether: hexane) gave 3 as a light yellow crystalline solid (0.98 gm, 68%). M.p. 55- 57° C. Example 3 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid 4 (X = OH) To a solution of ester 3 (0.578 gm, 2 mmol) in ethanol (25 ml), NaOH (0.20 gm) was added and the solution was stirred under reflux for 2 hr. After being cooled to room temperature, it was acidified with 1 N HC1. The crude product was extracted with ethylacetate and washed with water (2 x 15 ml), brine (2 x 15 ml), dried (Na2SO4) and the solvent was removed in- vacuo. The crude product thus obtained 4(X = OH) on crystallization (ether: hexane) furnished 4 as a white crystalline solid (0.478 gm, 90%). M.p. 99- 100° C. Example 4 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-carboxylic-acid hydroxyamide 4 (X = NHOH) To the suspension of hydroxylamine hydrochloride (4.65 gm, 67 mmol) in methanol (24 ml) was added solution of KOH (3.6 gm, 0.064 mmol) in methanol (24 ml). After stirring for 15 min. at room temperature, it was filtered and filtrate was added to a cooled solution of 3 in THF (10 ml) and stirred further at room temp, for 17 hrs. After completion, the reaction mixture was adjusted to acidic by CH3COOH and the crude product was extracted with ethylacetate (2 x 15 ml), and washed with H2O (2 x 15 ml), brine (2 x 15 ml), dried (Na2SO4). The solvent was concentrated to dryness to give dark brown thick liquid 4(X = NHOH) (0.23 gm, 84%). Example 5 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid hydrazide 4(X = NHNH2) Hydrazine hydrate (0.34 ml, 6.8 mmol) was added to 3 (0.50 gm, 1.70 mmol) and the reaction mixture was refluxed for 3 hr. On cooling, it was extracted with ethyl acetate (2 x 15 ml). The combined extract was washed with water (2 x 15 ml), brine (2 x 15 ml), dried (Na2SO4). The solvent was removed in- vacua. The crude product thus obtained was chromatographed (SiO2, 60-120 mesh). Elution with 3% ethylacetate in hexane furnished dark yellow thick liquid 4(X = NHNH2) (0.36 gm, 78%). Example 6 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyI)-ethenyl]-isoxazole-3-carboxylic acid- sodio- hydroxyamide 4(X = N(Na)OH) To a solution of 4(X = NHOH) (0.50 gm, 1.81 mmol) in 5 ml of water was added NaOH (0.10 gm, 2.5 mmol). The solution was concentrated to dryness to give sodium salt of 4(X = N(Na)OH) (0.49 gm, 91%). It was soluble in water. Example 7 5-[2-(2,6,6-Trimethyl-cycIohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid sodiohydrazide 4(X = N(Na)NH2) To a solution of 4c(X = NHNH2) (0.50 gm, 1.81 mmol) in 5 ml of water was added NaOH (0.10 gm, 2.5 mmol). The solution was concentrated to dryness to give sodium salt of 4(X = N(Na)NH2) (0.52 gm, 96%). It was soluble in water. Example 8 Morpholin-4-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-yl}-methanone 4 To a solution of 4(X = OH)(0.50 gm, 1.91 mmol) in CH2C12 (15 ml) was added oxallyl chloride (0.5 ml, 5.73 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacua. To the crude obtained was added morpholine (0.33 ml, 3.82 mmol) in CH2C12 (15 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in-vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacua. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 15% ethyl acetate in hexane furnished 4 as yellow oil (0.41 gm, 65%). Example 9 Piperazin-l-yI)-{5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]- isoxazol- 3-yl}-methanone 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added piprazine (0.258 ml, 3 mmol) in CH2CI2 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 15% ethyl acetate in hexane furnished 4 as light yellow oil (0.77 gm, 90%). Example 10 4-(Phenyl-piprazin-l-yl)-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-yl}-methanone 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added phenylpiprazine (0.48 ml, 3 mmol) in CH2C12 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 15% ethyl acetate in hexane furnished 4 as yellow oil (0.57 gm, 93%). Example 11 Piperidin-l-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-yl}-methanone 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added piperidine (0.26 ml, 3 mmol) in CH2C12 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 15% ethyl acetate in hexane furnished 4 as yellow oil (0.47 gm, 96%). Example 12 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxyIic acid (4-methoxy-phenyl)-amide 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added p- methoxy aniline (0.363 gm, 3 mmol) in CH2Cl2 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in-vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 10% ethyl acetate in hexane furnished 4 as a white crystalline compound (0.58 gm, 83%). Example 13 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyI]-isoxazole-3-carboxylic acid phenylamide 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added aniline (0.279 ml, 3 mmol) in CH2C12 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 10% ethyl acetate in hexane furnished 4 as a white crystalline compound (0.39 gm, 78%). Example 14 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-(4-chloro-phenyl)-amide 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2CI2 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in- vacuo. To the crude obtained was added p- chloroaniline (0.381 gm, 3 mmol) in CH2C12 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 10% ethyl acetate in hexane furnished 4 as a white crystalline compound (0.49 gm, 90 %). Example 15 5-[2-(2,6,6-Trimethyl-cycIohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid cyclohexyl-amide 4 To a solution of 4(X = OH) (0.40 gm, 1.50 mmol) in CH2C12 (10 ml) was added oxallyl chloride (0.40 ml, 3.14 mmol) drop wise and the resulting mixture stirred at room temperature for 2 hrs. Excess of oxallyl chloride was removed in-vacuo. To the crude obtained was added cyclohexylamine (0.297 ml, 3 mmol) in CH2C12 (10 ml) and stirred at room temperature for 2 hrs. After completion, it was concentrated in- vacuo and the extract was taken in CH2C12 (20 ml) followed by washing with H2O (2 x 15 ml), brine (2 x 15 ml) dried (Na2SO4) and it was concentrated in- vacuo. The crude product thus obtained was column chromatographed (SiO2, 60-120 mesh). Elution with 10% ethyl acetate in hexane furnished 4 as a white crystalline compound (0.36 gm, 70%). Example 16 Antileishmanial activity: The in- vivo leishmanicidal activity of the compounds were tested in golden hamsters (Mesocricetus auratus) infected with WHO reference strain of Leishmania Donovani (MHOM/IN/80/Dd8 strain [Gupta S., Tewari S., Bhaduri A. P., Jain G. K.,Acta Tropica, (2002), 84, 165]. Male hamsters weighing 45- 50 g were infected intracordially with 1X 107 amastigotes and the intensity of infection was assessed on day 20-25 post infection (p.i.) by spleen biopsy. Hamsters showing 5-15 amastigotes per 100 spleen cell nuclei were used for chemotherapeutic trials. The infected animals were randomized into several groups on the basis of their parasitic burdens. Usually 4-6 hamsters were used for each compound and the same numbers were kept as untreated controls. Drug treatment by intraperitoneal route was initiated after 2 days of biopsy and continued for 5 consecutive days at 50 mg/kg dose. Post treated biopsy was done on day 7 of the last drug administration and amastigotes counts were assessed by Giemsa stanning. The percentage inhibition in amastigotes multiplication was calculated using the following formula (Formula Removed) P.I. = Percent inhibition of amastigotes multiplication ANAT = Actual number of amastigotes in treated animals INAT = Initial number of amastigotes in treated animals, and TIUC = Times increase of parasites in untreated control animals. The compounds synthesized were tested in Leishmania donovani in hamster model at 50 mg/kg dose as shown in Table-1. The parent compound terpenyl isooxazole 3 showed 76% inhibition at 50 mg/kg. This initial promising result prompted us to generate a chemical library of compounds of general formula 4 as shown in Table- 1. Table-1 Antileishmanial activity of compounds against Leishmania donovani in hamsters. (Table Removed) We claim, 1. Novel 5- [2-(2,6,6- trimethyl-cyclohex-2-enyl)-ethenyl]- isoxaazoles of general formula 4 and salts thereof, (Formula Removed) wherein X is selected from group consisting of OH, Cl, OEt NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group. 2. The compound as claimed in claim 1 wherein the substituted amino group is selected from the group consisting of morpholino, piperazino, N-phenylpiperazino, pyrrolidino, anisidino, anilino, p-chloroanilino and cyclohexylamino, amide. 3. The compound as claimed in claim 1 wherein the representative compounds of general formula 4 comprising: i. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid ethyl ester ii. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3- carboxylicacid. iii. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol-3-carboxylic acid hydroxy amide, iv. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid hydrazide. v. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-sodio- hydroxyamide. vi. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-sodio- hydrazide. vii. Morpholin-4-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]- isoxazol-3 -yl} -methanone. viii. Piperazin-l-yl)-{5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol- 3-yl}-methanone. ix. 4-(Phenyl-piprazin-1 -yl)- {5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)- ethenyl]-isoxazol-3-yl}-methanone. x. Piperidin-l-yl-{5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazol- 3-yl}-methanone. xi. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid (4-methoxy-phenyl)-amide. xii. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid phenylamide. xiii. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-(4-chloro-phenyl)-amide. xiv. 5-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid-cyclohexyl-amide. xv. 5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxazole-3-carboxylic acid chloride. 4. A process of preparation of 5-[2-(2,6,6-trimethyl-cyclohex-2-enyl)-ethenyl]-isoxaazoles of formula 4 wherein X is selected from group consisting of OH, Cl, OEt, NHOH, NHNH2, N(Na)OH, N(Na)NH2 and substituted amino group as claimed in claiml, wherein the said process comprising; (i) refluxing a-ionone with diethyl oxalate in presence of an alkali metal hydride in an aromatic solvent to give 1,3-diketone of formula 2, (Formula Removed) (ii) condensing 1,3-diketone 2 so obtained with hydroxyl amine in presence of a protic solvent at reflux temperature to obtain isooxazole of formula 3, purifying the product using standard laboratory techniques, (Formula Removed) (iii) reacting isooxazole 3 with an alkali hydroxide or hydroxyl amine, or hydrazine in a protic solvent to get the compound of formula 4 wherein X = OH or NHOH or NHNH2, optionally converting the compound of formula 4 wherein X is NHOH or NHNH2 their sodium salt by the treatment with sodium hydroxide to produce the compound of formula 4 wherein X is N(Na)OH or N(Na)NH2 respectively, (Formula Removed) (iv) reacting compound of formula 4 wherein X = OH with oxallyl chloride in a chlorinated alkane to get compound of formula 4 wherein X = Cl followed by treatment with amines to get compound of formula 4 wherein X = amino. 5. A process as claimed in claim 4 wherein the aromatic solvent used in step (i) is selected from toluene, benzene, xylene. 6.A process as claimed in claim 4 wherein the protic solvent used in step (ii) is selected from methanol, ethanol, dichloromethane. 7. A process as claimed in claim 4 wherein the known method used for purification is conventional chromatography method such as preparative, thin layer chromatography, column chromatography. 8. A process as claimed in claim 4 herein the chlorinated alkanes is selected from dichloro methane, chloroform, carbon tetra chloride, tetra chloro ethane. 9. A process as claimed in claim 4 wherein the amines used in step (iv) is selected from secondary amines like morpholine, piperazine, N-phenyl piperazine; aromatic amines like aniline, p-chloroaniline; aliphatic amine like cyclohexyl amine to get the compound of formula 4 (X = Morpholino, piperazino, N-phenyl piperazino, anilino, p-chloroanolino (Formula Removed) and cyclohexyloamino). 10. A process as claimed in claim 6 wherein the solvent used in chromatographic separation is selected from group consisting of hexane, ethylacetate, methanol and mixture thereof.

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