Title of Invention	NOVEL ANALOGS OF 3-O-ACETYL-11-KETO-B-BOSWELLIC ACID
Abstract	This invention relates to analogs of 3-0-Acetyl-11-Keto-b-Boswellic acid (AKBA) that exhibit 5-Lipoxigenase inhibitory properties. These compounds may be used in pharmaceutical compositions for therapeutic applications against a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischemia. These compounds also inhibited the growth of brine shrimp in cultures, which may be considered as a positive indication for cytotoxicity and antitumor activity.

Title of Invention

NOVEL ANALOGS OF 3-O-ACETYL-11-KETO-B-BOSWELLIC ACID

Abstract

This invention relates to analogs of 3-0-Acetyl-11-Keto-b-Boswellic acid (AKBA) that exhibit 5-Lipoxigenase inhibitory properties. These compounds may be used in pharmaceutical compositions for therapeutic applications against a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischemia. These compounds also inhibited the growth of brine shrimp in cultures, which may be considered as a positive indication for cytotoxicity and antitumor activity.

Full Text	WO 2005/123649 PCT/K2OO4/0O0I76 Novel Analogs of 3-O-Acety1-ll-Keto-β-Boswellic acid This invention relates to novel structural analogs of 3-O-Acety1-ll-Keto-β-Boswellic acid (AKBA). Technical field: Presently, there has been a tremendous surge in demand for non-stercidal plant based antiflammatory agents. 5-Lipoxygenase is the key enzyme for the biosynthesis of leukotrienes and 5(S)-HETE, the important mediators for inflammatory, allergic and obstructive process, from arachidonic acid. 5-Lipoxygenase is the target enzyme for identifying inhibitors, which have potential to cope with a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischaernia. Scientists around the world have invested a major effort during the last ten years, in identifying 5-Hpoxygenase inhibitors. Gum resin of Boswellia species known as Indian frankincense has been used as an anti-inflammatory agent in Traditional Ayurvedic Medicine in India. Ancient Ayurvedic texts described its therapeutic use. Clinical trails performed by CSIR laboratories in India have shown fair to excellent results in 88% of the patients, with no adverse side effects [Singh, G.B.t Status report, anti-inflammatory drugs from plant sources (1982)]. A randomized, double blind, placebo controlled clinical trials on patients with Osteo-arthritis of knee exhibited statistically significant improvement in the pain, decreased swelling and increased knee flexion etc. [Kimmatkar, Phytomedicine 10: 5-7 (2003)]. The therapeutic effects shown by Boswellia serrata extract were comparable to those exhibited by sulfasalazine and mesalazine in patients with ulcerative colitis. (Gupta, I., et al, Eur. 1 Med Res., 3: 511-14, 1998 and Gerhardt, H., et. al, GastroenieroL 39: 11-17, 2001). The source of anti-inflammatory actions has been attributed to boswellic acids (Safayhh H., et al, Planta Medica 63, 487 - 493, 1997 and 1 Pharmacol Exp. Then 261. 1143 - 46. 1992, both the journals published from USA), a group of triterpene acids isolated from the Boswellia resin (Pardhy, R. S., et aL, Indian J.Chem.16B. 176 - 178, WO 2005/123649 PCT/IN2004/OWI76 1978). These compounds exert anti-inflammatory activity by inhibiting 5-iipoxygenase (5-LO). Immunomodulatory activity of boswellic acids had been reported by Sharrna et. al. in Phyioihcraph)' Research. (1O. 107 - 112. 1996), published from USA. A detailed study on the structural requirements for boswellic acids indicated that, of all the six boswellic acids, 3-O-acetyl-l 14;eto-β-boswellic acid, hereinafter referenced as AKBA shows most pronounced inhibitory activity against 5-LO (Sailer, E- R-, e: aL British J. Pharmacology 117. 615-618, 1996). AKBA acts by unique mechanism. in which it binds to 5-LO in a calcium-dependent and reversible manner and acts as a non-redox-type, non-competitive inhibitor (Sailer, E. R., et al., Euro. J. Biochem- 256. 364 - 368, 1998). AKBA has thus become the subject of intensive research for its potential for the treatment of chronic inflammatory disorders. The oleanane and ursane triterpenoids also gained prominence recently for their antiproliferative actions. As 5-Iipoxygenase (5-LO).is the first enzyme in the metabolic pathway leading to the formation of leukotrienes and eicosanoids thai are important in carcinogenesis process, inhibitors of 5-LO may thus have profound influence on the growth and apoptosis of various cancer lines (Yong S. Park, et. al. Planta Medico, 68, 397-401, 2002). Boswellic acids, for example inhibited several leukemia cell lines in vitro and inhibited melanoma growth and induced apoptosis (Hostanska. K., et aL Anticancer Res.f 22(5), 2853 -62. 2002). The acetyl boswellic acids were found to be unique class of dual inhibitors of human topoisomerases I and II a(Syrovets, T. et aL, , MoL PharmacoL, 58 (1), 71 - 81, 2000). A number of oleanane and ursane triterpenoids were found to be powerful inhibitors of nitric oxide production in macrophases. which can be correlated to their cancer chemoprevention activity. (Honda, T., eL al- J. Med. Chem., 43, 1866-1877). Background Art: 5-Lipoxigenase inhibitory properties of AKBA and other boswellic acids have been scientifically established. Efforts are currently being made to enrich AKBA in the natural extracts and also to synthesize structural analogs of AKBA with enhanced potency and water solubility. WO 2005/12319 PCTTN2lut OOOI'b Disclosure of tic invention: The organic sorvenr extract of The gum resin of Bosweilia serrata contain a total of six bcswellic acids. These acids are shown in figure 1, and are represented by Bl. B2. B3. B4, B5 and B6. The concentration of most active principle B2 (AKBA) amounts only in the range of 1-10%. but most typically in -the range of 2-3%. The enrichment of AKBA from natural boswellic extract has already been undertaken by the inventors and escnDed in international. patent application (PCT#03/074063.dtd 12th september 2003) and US patent application (US#2004073060. The potential usefulness of boswellic acids in general and AKBA in particular can be a great incentive ID take-up further development of these compounds in all possible aspects. The present invention, is related to development of novel structural analogs of AKBA by serri-synthesis from 11-keto-β-bosweliic add (KBA) or 3-O-acetyl-11-keto-β-boswellic acid (AKBA) for biological evaluation and to conduct structure activity relationship studies. The core objective of this invention is to obtain novel AKBA type compounds with enhanced biological activity and improved water solubility for use in therapeutic applications as anti-inflammatory, anti-arthritic and anti-tumor agents. A systematic study on the boswellic acids analog development has not been undertaken, so far, except the preparation of some afylidene analogs of 3-keto-{3-boswellic acid (Gupta, V. N. et al., Indian Drugs, 25(2), 70 - 72, 1987). The major functional moieties that can be expended to make novel structural analogs of AKBA are acetoxyl, carboxyl and enone. Two major types of compounds were primarily envisioned for the development of new analogs of AKBA. One type constitutes a group, which differ in the nature of the acyioxy group on C3 of the ring A The other group contains compounds obtained by modification of carboxyl group on C4 of the unit A. WO 2005/12364* PCT;TN2OW««O0I "6 This invention reiatss to novei structural analogs of 3-O-acetyl-l l-keto-β-boswellic acid (AKB A) having the formula. Where in R1, R2, R3, R4 and R5 are as indicated below in each of said analogs: 1. R1 = OCHO, R2 = H, R3 = COOH, • R4&R5=O 2. R1 = OCOCH2CKR2 = H, R3 = COOH, R4&R5=O 3. R1 = 5'-O-methylgalloyloxy, R2 = H, R3 = COOH, R4 & R5=O 4. R1= OCOCH2CH2COOH, R2 = H, R3 = COOH, R4 & R5=O 5. R1 = 8'.9'-Dihydro-4'-hydroxycinnamoyioxy, R2 = H, R3 = COOH, R4 & R5 = O 6. R1 = 4'-Hydroxycinnamoy!oxy, R2 = H, R3 = COOH, R4 & R5"=O 7. R1 = 3',4'-Dimethoxycinnamoyloxy, R2 = H, R3 = COOH, R4 & R5 = O 8. R1 = 3rT4r-DEiycro?o-5r-me±oxycinnamoy]oxy, R2 = H, R3 = COOH, R4 & R5 = O 9. R1 = OCOCH2NHrtsrt-BOQ; R; = H, R3 = COOCH;r R4 & R5 = O 10. R1 = OCOCH;NH:HCL R2 = H. R3 = COOH, R4 & R5 = O 11. R1 = OCOCH(CH3)MH2HCl, R2 = H, R3 = COOH, R4 & R5 = O 12. R1 = R R2 = OH? R3 = COOCH3; R4 & R5 = 0 13. R1 = Hr R2 = Br, R3 = COOCH3, R4 & R5 = O 14. R1 = CN, R2 = H, R3 = COOCH3, R4 & R5 = O 15. R1 = SH; R2 = H, R3 = COOCH3; R4 & R5 = O 16. R1 &R2 = N(OH\ R3 = COOCH3; R4 & R5 = O WO 2005 123649 PCT/K2004/000176 17.R1 &R2;=H&OCOCH3 R3 = H, R4&R5= O 18. R1 = OCOCHj. R2 = H R3 = COOCH:CH2N(CH3) 2, R4&R5 = O 19. R1 = OCOCH3- R2 = H R3 = CONH-, R4&R5=O 20. R1= OCOCH3, R2 = H, R3 = CONHKH;, R4&R5 = O 21. R1 = OCOCH3. R; = Hr R:- = CONHCH2CH=NH;5 R4&R5 = O 22. R1= OCOCH> R2 = H, R3 = CONHCHrCH:OH.R4&R5= O 23 R1 = OCOCH3, R2 = Hs R3 = CON{CH:CH;) ;NH. R4&R5 = 0 24. R1 = OCOCH3, R; = H R3 = NCO. R4 & R5 = O 25. R1 = OCOCris. R; = H R3 = NH2. R4&R5 = 0 26.R1=OCOCH35R2=H R3 = CN, R4& R5 =0 27. R1 = OH, R2 = H R3 = COOH, R4 & R5 = OH & H The structures of the individual compounds are presented below in figure 2. WO 2 Novel compounds of this invention may be prepared by the following processes. The compounds represented by 2 to 11 may be prepared by a coupling reaction between KBA or its ester with an appropriate acid counterpart using DCC (1.3-diclohexylicarbodiimide) and DMAP {4-(dimethylandno)pyridine} as coupling agent in a. suitable solvent system. This may also be accomplished by convening the acid corresponding to the acyloxy unit to the add chloride using SOCb (thionyl chloride) and then treating the acid chloride with KB A or its methyl ester, in the presence of an organic base The compounds represented by 12, 13, 14 and 15 may be prepared by displacing the 3α OH group in methyl ester of KBA by Br using PBr3 (phosphorus tribromide) and then further displacing the Br group with appropriate nucleophnic agents, such as SH', CN' etc. These reaction sequences are shown hereinafter in scheme I. The amide compounds represented by 19, 20, 21, 22 and 23 may be prepared by treating the acid chloride of AKBA with an excess of amine component in a suitable solvent system. This reaction scheme is shown in the scheme EL below. The isocyanate and amine compounds represented by the structures 24 and 25 respectively may be prepared by Hoffmann rearrangement of the amide 19. The intermediate isocyanate, 24 may be obtained by reducing the reaction time and working-up the reaction before completion. The isolation of starting materials AKBA and KBA for the semi-synthesis of the novel analogs is accomplished by the procedures known in the literatures (For example, US Patent Application # 2004073060). Preferred embodiments relating to the processes of preparing AKBA analogs mentioned in the foregoing discussion and other compounds of the subject invention are illustrated in the following examples, 1 to 27. These analogs inhibited 5-Lipoxigenase enzyme and also the growth of Brine Shrimp in cultures. wu jwcv'i 23649 PCT/PS2O04/OO0I76 Example 1 3-O-Forniyl-ll-keto-β-boswellic acid (1): To a solution of ll-keto-(3-boswellic acid (200 mg. 0.424 mmol) in DMF (2 mL), cooled in an ice water bath was slowly added phosphorous oxychloride (150 µL, 1.7 mmol). The reaction mixture was allowed to warm-up to the ambient temperature and the stirring was continued. After 2h. the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 25 mL). The combined organic extract was washed with brine, dried over "Na2SO4 and evaporated under reduced pressure. The residue was subjected to silica column chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane were monitored and those containing 3-O-forrnyI-lI-keto-P-bosweHic acid were combined and evaporated to obtain pure compound (120 mg). Melting point: 298 - 302°C; ;HNMR (CDCI3, 90 MHz): 5 0.50 - 2.50 (m, CH CH2 and CH3 signals), 5.43 (1H. br s, 3-H), 5.60 (1H, s, 12-H), 8.20 (1H, s, -OCHO); FT-IR (neat): 3400 -2700 (br), 2924, 2859, 1727, 1705, 1662, 1459, 1270, 1166 cm1. LC-MS (positive mode): m/z 499 (M+H)+, 521 (M+Na)+, 1019 (2M+Na)+. Example 2 3-0-(Chloroacetyl)-ll-keto-P-boswellic acid (2): To a solution of 11-keto-β-boswellic acid (200 mg, 0.43 mmol) in CH2CI2 (3 mL) was added chloroacetic acid (166 mg, 1.7 mmol) and DMAP (26 mg, 0.21 mmol), and the mixture was cooled in ice water. A solution of 1.75 g of DCC in 2 mL of CH2CI2 was slowly added to the reaction mixture and the stirring continued at the same temperature. After 2h. the solid was filtered and the Filtrate was poured into ice water. The mixture was extracted with ethyl acetate (2 x 25 mL). Tne combined organic layer was washed with 0.5 N HC1 (30 mL). water (30 mL) and brine (30 mL). The solvent was evaporated and the residue (250 mg) was subjected to silica column chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane were combined and the solvent evaporated to yield 3-O-(chloroacetyl)-ll-keto-β-bosweIlic acid (150 mg). Melting point: 126 - 132°C; 1H NMR (CDCI3): 5 0.81 (3H, d; J = 6.5 Hz, -CH3), 0.83 (3H, s, -CH3), 0.95 (3H, s, -CH3), 1.07 (3R s, -CH3), 125 (3H, s, -CH3), 2.11 (1H, m), 233 (1H, br t J = 12.7 Hz), 2.42 (1H, s), 2.56 (1H, d; J = 12.7 Hz), 4.09 (2R s, -CH2CI), 5.40 (1H, WO 20ft5/123641» PCTIN2Wi4'] "6 br s, 3-H). 5.56 (1H, s. 12-H); F7-IR (neat): 3400 - 2700 (br). 2927. 2S65. 1735, 1708, 1658, 1457, 1286, 1198, 992 cm-]. LC-MS (positive mode): m/z 547 (M-H)+, 569 (M+Na)+. 1115 (2M+Na2)+ Example 3 3-O-(5'-O-rnethylgalIoyI)-11-keto S-boswellic acid (3): A solution of 1 i-kso-3-boswellic acid, (0.5%10.6mmoles tri-O-methyigallic acid. (357 mg. 1.6 mmol) and DMAP (60 mg) in 5 ml of: Dichloromethane was stirred at 0°C while a solurion of DCC (330 mg. 1.6 mmol) in CH2Cl2; (3 mL) was slowly added. The reaction mixture was stirred at 0°C for 1h, and at room temp for 30 min. The reaction mixture was filtered and the filtrate diluted with CH-CI3 (40 ml) and poured in to ice-water. The mixture was acidified with 0.1 N HCl and the layers separated. The organic layer was washed with water and brine, and dried over "Na2SO4 and evaporated. The residue ((830 mg) was purified on silica column using hexane/ethyl acetate mixtures. The gal late containing fractions, obtained on elution with 15% ethyl acetate/hexane were combined and evaporated to yield 3-O-(tri-O-methylgalloyI)-l 1-keto p-boswellic acid (580 mg, 82%). To a mixture of A1C13 (590mg, 4.4 mrnol) and ClCH2CH2CI (5 mL), stirred at RT for 15 min was added dropwise during 20 min a CICH2CH2CI (2 mL) solution of 3-O-(5'-O-rnethylgalIoyI)-I I-keto S-boswellic acid (580 mg,0,87 mmol). After 3 h? the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with saturated NaHCOs9 water and brine, and then evaporated to obtain a residue, 30-(3'.5'-di-0-methyIgalioyI)-l 1-keto 3-boswellic acid (560 mg, 98%). To a cooled mixture of 3-0-(3'5'-di-O-methylgaUoyl)-l 1-keto β-boswellic acid (200 mg, 0.31 mmol) and AICI3 (200 mg, 1.5 mmol) in CICH2CH2CI (2.5 mL) was slowly added pyridine (0.25 mL 3.1 mmol). The mixture was subjected to reflux for 3.5 h. The reaction mixture was poured into ice water, acidified with dilute HCl and extracted with ethyl acetate (2x15 mL). The combined organic layer was washed with brine, dried over "Na2SO4 and evaporated. The residue was subjected to silica column WO 2005123649 PCI7LN2004/000176 chromatography using ethyl acetate/hexane mixtures. The fractions eluted with 20% and 25% ethyl acetate/hexane mixtures were evaporated to obtain 3-O-(5'-O-rnethylgalIoyI)-I I-keto β-boswellic acid (80mg, 41%). Melting point 128 - 136°C: 1H NMR (CDC13): 5 0.8 1 (3H. d: J = 6.3 Hz, -CH3), 0.84 (3R s, -CH3), 0.95 (3FL s, -CH3)? 122 (3H, s, -CHo. L23 «'3H? s. -CH3), 126 (3H, s. -CH3), 1-37 (3R sT -CH3)5 2.34 (1H. m), 2.49 (1H, s,. 2.62 (1H, d: J = 133 Hz), 3.93 (3H. s, 5'-OCH3). 5.52 (1H, brs. 3-HV5.57 (1H s, 12-H1, 7.25 OH, d; J = 1.5 Hz, 2f-H)s 7.30 (1R d; J - 1.5 Hz, 6'-H); IR (CHCi3): 3400 (br), 2926. 2S51. 1714, 1653. 1614, 1516, 1459, 1348, 1217, 1099. 1023 cm"1; LC - MS •■^negative mode) 635 (M-H)Example 4 3-O-Succinyl-ll-keto-β-boswellic Acid (4): A mixture of 1l-keto-β-boswellic acid (02 gm, 0.43 mmol), succinic anhydride (0262 gm, 2.62 mmol), DMAP (51 mg, 0.42 mmol) and pyridine ( 1mL) was stirred under reflux for 40 h. The mixture was poured into 20 ml of cold water and acidified to pH 4 with dil HC1 The solution was extracted with ethyl acetate (3 X 40ml) and the combined organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on a silica column eluting with hexane and ethyl acetate mixtures. The fractions eluted with 20% ethyl acetate/hexane were combined and evaporated to obtain the 3-O-succinyi-l l-keto-{3-bosweIlic acid (170 mg, 71%). Melting point: 172 - 176°C; 1H NMR (CD3OD): 5 0.78 (3H, d; J = 6.4 Hz, -CH3), 0.80 (3H, s, -CH3), 0.92 (3H, s, -CH3), 1.12 (3H, s, -CH3); 1.16 (3H, s, -CH3), 1.17 (3H, s, -CH3), 1.35 (3H, s, -CH3), 2.45 (1H, s), 2.46 (IR m)? 2J6 - 2.67 (4H3 m, -OCOCH2CH2COOH), 528 (1H, br s3 3-H), 5J0 (1H, s, 12-H). IR (KBr): 3600 - 2700 (br), 2926? 2855, 1735, 1708, 1656, 1456, 1417, 1385, 1202, 1164 cm"1. LC-MS (positive mode) rn/z 571 (M+H)+? 593 (M+Na)+, 609 (M+K)+. Example 5 3-0-[8',9r-Dihydro-4'-hydroxycinnamoyI]-ll-ketoβ-boswellic acid (5): 3-O-(4'-BenzyloxycinnamoyI)-l 1 -keto-β-boswellic acid: A mixture of 4-benzyloxycinnamic acid (250 mg) acid and thionyl chloride (02 ml) was reflux for 30 min. Excess thionyl chloride was removed and the residue was dried under WO 2005/123649 PCT.TN20M.'WK»l" high vacuum. The residue was dissolved In dry dichloromethane (2.5ml) and added drop by drop to a mixture of 1l-keto-β-boswellic acid (400 mg). triethyl amine (0.7 ml) and DMAP (20 mg} in dichlorethsne (5 ml) After 2 hours, the mixture was diluted with ether (60 ml) and washed with water (2 X 20ml) and brine (20 mL), dried over Na2SO4 and evaporated. The rescue was subjected to column chromatography over silica gel using hexane/ethyl acetate mixtures as rlaniselvants. The fractions eluted with8-12% ethyl keto-β-boswellic acid 160mg26%). H NMR (CDG3): 3 0.80 (3H. d: J = 5.4 Hz. -CK3), 0.82 (3H, E, -CH3; 0.95 =3.4. s. CH:3}. 1.15 (3rL s. -CH3). 1.19 T3H. s, -CH31. 1 -31 (3H, s, -CH3), 134 (3H, s, -CH3), 2.25 (JH, brt J = 10.7 Hz). 2.42 (1H, s). 2J5 (1H, brd; 13.1 Hz), 5.11 (2K, br s. -OCH3 Ph), 5.32 (1H, brs, 3-H), 5.56 (1H, s, 12-H). 6.31 (1H, d; J = 15.9 Hz, 8'-HX 6.99 (2H, d: J = 8.8 Hz, 375r-H). 7.50 (2H. d; J = 8.8 Hz, 276'-H), 7.73 (! H, d; J = 15.9 Hz. 9'-H). IR (CHCl3): 3431 (br), 2973, 2925. 2867, 1712, 1659, 1633. 1602. 1511, 1455. 1384, 1251, 1160, 999, 827, 734 cm"1: LC - MS (positive mode) m/z 729 (M+Na)+, 1435 (2M+Na)+. Deprotection: To a solution of 3-O-(4'-benzyloxycinnamoyl)-l l-keto-β-boswellc acid (100 mg) in 3 mL of ethanol in a 10 r mL R8 flask was added 10 mg of 10% palladium on carbon. The RB flask was flushed with H2 and the mixture was stirred under a positive H2 pressure using a balloon. After 24 h, the mixture was filtered over celite and the solvent evaporated. The residue was subjected to silica column chromatography using hexane/ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane yielded 3-O-(8'9'-dihydro-4-hydroxycinnamoyl)-1l-keto-β-boswe!lic acid. Melting point: 168 -171=0; 1H NMR (CDC13): 5 0.82 (3H, s, -CH3), 0.83 (3H, d: i = 7.7 Hz, -CH3), 0.95 (3H. s. -CH3), 1.08 (3H, s. -CH3), 1.10 (3H, s, -CH3), 1.17 (3H, s. -CH3), 1.34 (3H. s, -CH3), 234 (1H. s), 2.43 (1H, brd: 13.1 Hz), 2.66 - 2.58 (2H, m, -OCOCH2CI±.Ar). 2.84 - 2.96 (2H, m, -OCOCH;CH:Ar), 5.24 (1H, brs, 3-H), 5.56 (1H, s. 12-H). 6.73 (2H. d; J = 8.2 Hz, 375'-H), 7.05 (2H, d; J = 8.2 Hz, 2V6'-H): IR (CHC13): 3433 (br). 2925. 2856, 1730, 1714. 1645, 1516. 1455, 1382, 1266, 768 cm'1; LC-MS (positive) m/z 619 (M+H)+, 641 (M+Na)+ WO 2005/123649 PCT/LN2004/000176 Example 6 3-0-{4'-HydroxycinnamoyI)-ll-keto-β-boswellic acid (6):A mixture of 3-G-(4'-bsnzylicinnamoyl)-ll-keto-β-boswellic acid (190 mg. 0.I4mmol). N,N-dimethylanilline (50 µl) and A1CI3 (50mg/ 0.42 mmol} in CHZC)Z (2 m.L) was stirred at room temperature for 48 h. The reaction mixture was poured into ice water, acidified with 2N HCI. and extracted with ethyl acetate. The organic layer was washed with brine, dried ever Na2SO4 and evaporated. The residue was purified over a silica column using eihyi aceiarehexane mixtures. The fractions eluted with 30% ethyl acetate/hexane mixture yielded 3-O-(4'-hydroxycinnamoy!)-11-keto-P-boswellic acid (15 mg) after evaporation.Melting point 180 - 185°C; IR (CHCI3): 3429 (br), 2926, 2854, 1721. 1656, 1600, 1457. 1379, 1267, 1164 cm"1; LC-MS (positive) m/z 617 (M+H)+, 639 (M+Na)+ Example 7 Preparation of 3-0-(3',4'-climethoxycinnamoyI)-ll-keto- β-boswellic acid (7): A solution of 11-keto-P-boswelIic acid, (500 mg, 1.06 mmoles). 3,4-dimethoxycinnamic acid, (332 mg, 1.59 mmol) in 4 ml of dichloromethane was stirred at 0°C, and treated slowly with DCC (495 mg, 2.39 mmol) in 3 mL of dichloromethane at 0°C. Then DMAP (60 mg) was added and the stirring continued at 15 - 20°C for 2h. The reaction mixture was filtered, the mother liquor diluted with CH2CI2 (40ml), washed water (30 mL) and brine (30 mL), and dried over Na2SO4 and evaporated. The residue (1.1 g) was purified on silica column using hexane/ethyl acetate mixtures. The cinnamate containing fractions, eluted with 25 - 30% ethyl acetate/hexane were combined and evaporated to obtain 3.-O-(3',4'-dimethoxycinnamoyl)-l 1-keto-β-boswellic acid (650 mg. 91%). Melting point: 146 - 150°C; lH NMR (CDC13): 5 0.83 {3H, d; J = 6.4 Hz, -CH3), 0.86 (3H, s, -CH3), 0.97 (3H, s, -CH3). 1.22 (3H, s. -CH3), \2A (3H, s, -CH3), L28 (3H, s, -CH3), 1-32 (3H, s5 -CH3), 2.34 (1H, m), 2.49 (1H, s), 2.62 (1H, brd; J = 9.4 Hz), 3.94 (3H, s, 3' or 4'-OCH3), 3.92 (3H. s. 4r or 3r-OCH3), 5.49 (1H, brs, 3-H), 5.59 (1H, s, 12-H), 6.36 (1H, d; J = 15.9 Hz, 8'-H), 6.89 (1R d; J = 8 Hz, 5'-H), 7.08 (1H, br s, 2'-H), 7.13 (1H d: J = 8.0 Hz, 6'), 7.66 (1H, brd; J= 15.9 Hz, 9;-H); IR (CHC13): 3406(br), WO 20123649 PCT7IN2O04/OO0I76 (CHCI3): 3356 (br), 2925, 2855, 1711, 1633, 1603, 1516. 1459. 1381. 1278. 772 cm'1. LC - MS (negative) m/z 661 (M-H)". Example 9 Methyl 3-O- (N-BOC-glycyl)-ll-keto-β-boswellic acid hydrochloride (9): A mixture of 1 J-keto-β-boswellic acid methyl ester (130 mg, 0-27 mmol), N^'tert-butoxycarbonyl) giycine (61 mg. 0.34 m. moles and DCC (16 mg, 0.77 mmol) in dichioromelhane {4 ml) was cooled to 0°C- Tc this solution was added DMAP (35 mg) and the stirring continued at 0°C for I hour and at room temp for 48 h. The reaction mixture was filtered diluted with diethyl ether (40 ml) and washed with 0.1 N HC1. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica column using hexane and ethyl acetate mixtures as eluants. The fractions eluted with 14% ethyl acetate in hexane were evaporated to obtain methyl 3-O-(N-8OC-glycy!}-I I-keto-(3-bosweiiate (122 mg, 71%). Melting point: 126 - I30°C; 1H NMR (CDCI3): 5 0.80 (3H. d; J = 6.4 Hz, -CH3). 0.82 (3H, s, -CH3), 0.95 (3H, s, -CH3), 1.03 (3H, s, -CH3), 1.17 (6H, s, 2 x -CH3), 1.34 (3H, s,-CH3), I.44(9H, s,-C(CH3)3. 1-83- 1.93 (I H, m), 2.05 - 2.15 (IH, m), 2.18 - 2.28 (IH, m), 2.40 (1H, s), 2.53 (1H, brd; 13.0 Hz), 3.68 (3H, s, -OCH3), 3.94 (2H, s, 3-OCOCH2NH(CO)OC(CH3)3, 5.04 (1H, br sT 3-OCOCH2NH(CO)OC(CH3)3, 5.39 (IH. brs, 3-H), 5.54 (1H, s, 12-H). IR (KBr): 3419 (br), 2972. 2935, 2867, I729(br), 1663, 1517. 1460, 1375, 1172 cm"1 LC- MS (positive) m/z 664 (M+Na)+. 680 (M+K)+. Example 10 3-O-Glycyl-1l-keto-β-boswelIic acid hydrochloride (10): A mixture of II-keto-\|3- . boswellic acid (1 g. 2.12 mmol). BOC protected glycine (0.514 g, 3.19 mmol) and DMAP (120 mg) in dry CHaCI2 (9 mL) at 0°C was treated with DCC (0.68 g, 3.19 mmol) in CH2CI3: (4mL) under vigorous stirring. After 2 h, the reaction mixture was filtered and the filtrate was poured into ice water. The mixture was carefully neutralized with 0.1 N HCI and extracted with CH2CI2 (2 x 60 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4 and evaporated to obtain crude 3-O-(N-BOC-glycyl)-l l-keto-{3-boswellic acid (1.52 g). The residue was subjected silica column chromatography using 5 - 20% ethyl acetate/hexane mixtures as eluents. The fractions WO 2005/123649 PCT/L\2TY. eluted with 15 % and 20% ethyl acetate/hexane mixtures yielded pure 3-0-(N-B0C-glycyl-11-keto-β-bosweliic acid (13 g, 92%). K NMR (CDC!;.): 5 0.81 (3H. d: J = 6.4 Hz, -CH3). 0.S2 (3H, s. -CH3). 0.95 (3H. s. -CH3). 1.15 (2H, s. -CH3), 1.19 (3H. s, -CH3), 1.23 (3H. s, -CH3). 134 BH. s. -CH3:-. 1.44 (9H s. -C(CH3)3,2.21 - 233 (1H. ml 2.40 (1H, s), 2.55 (IH. brd -2.5 Hz). 3.94 '2H. s, 3-OCOCH:NH(CO)OC(CH3,)3, 5.06 MH. br A solution of 3-O(N-BOC-glycil-11-keto-β-boswellic acid (300 m.z) IT. I mL of CH2Ch cooled to 0°C was treated slowly with 1.5ml of 2.5 N HC3 in dioxane. After 30 min, the stirring was continued over night at room temperature. The reaction mixture was evaporated under vacuum and re-dissolved in 0.2 mL CH2CI2 and diluted with hexane (I mL). A white solid was precipitated. It was filtered, washed with hexane and dried to afford a white powder (219 mg). It was further purified over silica column using CH2CI2 and CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 yielded 3-O-glycyl-l 1-keto-p-bosweUic acid hydrochloride (I50mg). Melting point: 210 - 212°C; 1H NMR (CD3OD): 5 0.82 (3H, d; J = 6A Hz, -CH3), 0.86 (3H, s. -CH3), 0.97 (3H, s, -CH3), 1.17 (3H, s, -CH3), K21 (3H5 s, «CH3),.1.28 (3H, s. -CH3), 1.37 (3H, s, -CH3), 2.13 - 2.23 (IH, m), 2.27 - 2J8 (IH, m), 2.49 (IH, s), 2,56 (IH. brd: 13.4 Hz), 3.82 (2H. s, 3-OCOCH2NH2HCI). 5.42 (IH, brs. 3-H), 5.52 (IH. s. I2-H): IR (KBr): 3500 - 2400, 2979, 2928, 2868, 1721 (br), 1660, 1512, 1456, 1387, 1165. 1053 cm'1. LC-MS (positive ion mode): m/z 528 [(M-CI)4], 550 (M-HCI+Na) Example 11 3-O-Alanyl-ll-keto-β-boswellic acid hydrochloride (11): A mixture of il-keto-p-bosewellic acid (500 mg. 1.05 mmol), BOC protected alanine (320 mg. 1.69 nunof) and DMAP (75 mg) in dry CH-Cfe (5 mL) at 0°C in a 25 mL RB flask was treated with DCC (330 mg, 1.60 mmol) in CH2CI2 (2 mL) under vigorous stirring. After 30 min. the stirring was continued at room temperature for 2 h. The reaction mixture was filtered and the filtrate was poured into ice water. The mixture was carefully acidified or pH 5 with 0.1 N HCI. and extracted with CH2CI2 (2 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated to obtain 3-O-(N-BOC-alany)-11 WO 2005i23649 PCT/IN2004/000176 keio-H-boswellic acid. The residue (550 mg) was subjected silica column chroraiography using 5 - 20% ethyl acelate/hexane mixtures as eluents. The fractions eluted with 20% ethyl acetate/hexane mixture yielded 320 mg of pure 3-O-(N-BOC-alanyl)-11-keto-β-boswellic acid. 1H NMR (CDCI3) 5 0.81 (3H. d: J = 6.4 Hz. -CH3). 3.53 (3H. s. -CH3), 0-95 (3H. s. -CH3). 1.16 OH, s. -CH3). 1-20 (3K. s. -CH;)- 1.25 (3H. 5. -(CH3). 1.34 (3H, s, -CH3), 1.39 (3H, d: J = 7.1 Hz. 3-OCOCH CH3) NH(CO)OC(CH3)3), 1.43 (9H, s. -OCOCH CH3). 2.21 - 2.33 (1H. m). 2.40 (1H,s) 2.58 (1H. brd: 12.2 Hz), 4.27-4.42 (IH, s. 3-OCOCH(CH3);NH-,CO)OC(CH3)3, 5.3S {iH. br s. 3-OCOCH(CH3)NH(CO)OC(CH:,)3), 536 (1H. brs. 3-H). 5.56 (IH. s. 12-H); LC - MS (positive mode): m/z 655 (M+Na)+. A solution of 3-O-(N-BOC-alanyl)-l l-keto-P-boswellic acid (200 mg) in 1 mL of CH2CI2 cooled to 0°C was treated slowly with 2.5 mL of 1 M HC1 in dioxane. After 30 min, the stirring was continued over night at room temperature. The reaction mixture was concentrated and subjected to column chromatography over silica gel using CH2CI2 and CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 mixture afforded a white powder (90 mg) of 3-O-alanyl-l l-keto-J3-boswellic acid hydrochloride. Melting point: 212-214°C; 1H MMR (CD3OD): 5 0.83 (3H, d: J = 6.2 Hz. -CH3), 0.86 (3H, s, -CH3), 0.97 (3H, s, -CH3), 1.17 (3H, s, -CH3), 1.22 (3H, 5. -CH3), 125 (3H, s, -CH3); 1.38 (3H, s, -CH3), 1-58 (3H, d; J = 6.3 Hz, 3-OCOCH(CH3)NH2HCn, 2.15-2.23 (1H, m)? 2.28-2.38 (1H, m), 2.50 (1H, s), 2.56 (1H, brd; 13.4 Hz). 4.15-4:23 (IH, s, 3-OCOCHlCH3)NH2HCl), 5.39 (1H, brs, 3-H), 5.53 (1H, s, 12-H): IR (KBr): 3500- 2600, 2980. 2928. 2870, 1725, 1710, 1663, 1515, 1452, 1390, "l161. 1051 cm"1. LC-MS (positive ion mode): m/z 542 (M-CI)\ 564 (M-HCH-Na)+. Example 12 Methyl 3β-hydroxy-ll-ketours-12-en-24-oate (12): Methyl 3.11-dioxours-12-en-24-oate (100 mg) was dissolved in methanol (2 mL), cooled to 0°C and the solution was treated with NaBH4 (15 mg). After lh, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine, dried over NaSO4 and evaporated. The residue was purified over silica using ethyl WO 25.123649 PCT/IN2004/000176 0.71 mmol) in acetone (2 mL) was subjected to reflux for 2 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was evaporated and the residue was purified on silica column using hexane and ethyl acetate mixtures. The fractions elutcd with 20% ethyl acerate'hexane were combined and evaporated to yield methyl 3a-cyano-l I-ketours-12-en-24-oate (170 mg. 92%. Melting point: 150 - 152°C; 1HNMR (CDCI:.i: 5 u.Sl (3H. d: j = 5.5 Hz. -CH3). C.S2 (3H. s. -CH;0? 0.95 (3H d: J = 7.1 Hz, -CH3), 1-03 (3R s. -CH3). 1.17 (3H. s. -CH3). 1.25 (3H. s. -CH3). L25 (3H. s. -CH3\ 2.34/2.37 (!H. s\ 2.54 (IR hr m\ 3-63/3.67 (3H. s, -OCH.;). 4.91 (IR dd; J = 14.7 and 7.7 Hz, 3-H), 5.53/5.54 (IR s. 12-H); IR (KBr): 3433 (br). 2978. 2925, 2859. 1724, 1664, 1459, 1383. -1235, 1197, 980 cm'1; LC-MS (positive mode): m/z 493 (M+H)+. Example 15 Methyl 3α-thiohydroxy-ll-ketours-12-en-24-oate (15): To a solution of KSR obtained by bubbling H2S through an ethanolic solution of KOH (350 mg in 10 mL), was added methyl 3(3-bromo-l l-ketours-12-en-24-oate (500 mg, 0.94 mmol) in 2 mL ethanol. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-water and acidified with 2 N HC1 and extracted with ethyl acetate (3 x 30mL). The combined organic layer were washed with brine, dried over NajSO4 and evaporated. The residue was subjected to column chromatography over silica gei using hexane and ethyl acetate mixtures. The fractions eluted with 25% and 30% ethyl acetate/hexane mixtures were evaporated to obtain methyl 3α-thiohydroxy-11-ketours--12-en-24-oate (180 mg. 39%). Melting point: 226 - 230°C; H NMR (CDCb): 5 0.80 (3R d; J = 6.5 Hz, -CH:). 0.82 (3H,s,-CH3), 0.95 (3H,s,-CH3), 1.01 (3Rs,-CH3)s 1.15 (3R s?-CH5), 1.26 (3H. s? -CH3), 1.34 (3H, s, -CH3). 3.66 (3H, s, -CH3), 4.76 (!R t; J = 13.2 Hz, 3-H)? 5.51 (lHr s, 12-H); IR (KBr): 3430 (br), 2979, 2925, 2867, 1725, 1662. 1458, 1383, 1237, 1118,975 cm1. WO 2Mt>123649 PCT/IN2004/000176 dried under high vacuum to obtain the methyl 3-oximino-l l-ketours-12-en-24-oate (130 mg.84.4%) as white solid. Melting point: 238 - 240°C; 1H NMR (CDC!3): 5 0-78 (3H. d; j = 6.3 Hz. -CH3). 0.82 (3H. s. -CH3). 0.94 (3H; s, -CH3), 1.17 (3H. s. -CH3). 1.19 (3H. s. -CH3), 1.26 (3H. s, -CH3), 1.45 (3H, s, -CH3), 2.03 - 2.13 (1H. m). 2-23 - 2.33 (1H. ml. 234 (1H. s), 2.S4 - 2.92 (1H. m), 3.25 - 3.33 (1H, m), 3.67 (3R s. 24-COOCH;). 5.56 (1H. s. 12-H). 7.5S (1H, br s. =NOH): 1R (CHCI3;): 3435. 297?. 2923, 2862. 1732. 1544, 1457, 1386, 1262, 1230, 941 cm-1: LC - MS (positive mode) mz 498 (M+H)+. 523 (M+Na)+,1017 (2M+Na)+. Example 17 3-Acetoxy-ll-keto-24-norurs-12-ene (17): A mixture of methyl 3.11-diketours-12-en-24-oate (500 mg), lithium bromide (0.35 g) and pyridine (0.4 mL) in N,N-dimethylformamide (7 mL) was subjected to reflux over an oil bath on a magnetic stirrer. After six hours, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 2N HCI followed by water and brine, and dried over Na2SO4. The solvent was evaporated and the residue (910 mg) was subjected to silica flash chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 5% ethyl acetate/hexane were monitored by TLC and those containing the pure compound were combined and evaporated to obtain 3.11-diketo-24-norurs-12-ene as a semi solid. 1H NMR (CDCI3): 5 0.64 (1H, m), 0.80 (3H, d; J = 65 Hz, -CH3), 0.82 (3H, s, -CH3),0.94 (3H, s, -CH3), 0.99 (3H, d; 6.3 Hz, -CH3), 1.14 (3H, s. -CH3), 1.17 (3H, s, -CH3), L30 (3H, s, -CH3), 1.89 (1H, dt; 13.6 and 4.8 Hz), 2.09 (1H, dt; 13.5 and 4.8), 2.35 (IH? s)r 2.68 (IH, dt; 13.3 and 3.5), 3.09 (1H, dt; 10.1 and 5.99 Hz), 5.55 (IH, s? 12-H); IR (CHC13): 2926, 2870, 1710, 1662, 1615, 1457, 1384, 1200, 997 cm'1; LC - MS (positive mode) m/z 425 (M+H)+. 447 (M+Na)+, 871 (2M+Na)+. The 3.11-diketo-24-norurs-12-er.e (230 mg) was dissolved in methanol (5 mL) and treated with NaBH4 (27 mg). After 30 min, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL)- The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography over silica gel using hexane/ethyl acetate mixtures. The fractions eluted WO 2005/123649 PCTTN2 with 10% ethyl acetate/hexane were combined and evaporated to obtain 3-hydroxy-11-keto-24-norurs-12-ene (50 mg). It u-as dissolved in pyridine (0.1 mL) and treated with acetic anhydride (0.I mL; at room temperature. After 3 h, the mixture was soured into ice water (10 mL; and extracted with ethyl acetate (20 mL). The organic Saver was washed with brine, dried over Na2So4 and evaporated :c obtain 3-Acetoxy-l I-keto-24-norurs-12-ene.IRP-eneIRCHCI2, 2824,2859,1732,1654,1454,1379,1262,1242,975,885 cm-1:LC-MS positive mode mz 469 M+H)+491(M+Na)+ 959(2M+Na)+ Example 18 Preparation of (2'-N,N-(dimethylaminoethyl) 3-O-acetyI-ll-keto-β-bosweHate (18): A suspension of 2-N,N-dimethy1aminoethylchloride (126 mg, 0.87 mmol), 3-O-acetyi-] 1-keto-(3-boswellic acid (300 rng. 0.58 inmoles) and sodium carbonate (124 mg? 0.S97 mmol) in acetone (5 m!) was stirred under refluxed at 60°C. After 2h, the mixture was diluted with ether (30 mL) and filtered. The ether solution was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on a silica column using hexane/EtOAc and ethylacetate/melhanol mixtures. The fraction eluted with 10% methanol in ethyl- acetate gave 2'-N,N-dirnethylaminoethyi 3-O-acetyl-l l-keto-β-boswellie (153 mg, 45%). Melting point: 206-210°C; JHNMR (CDCI3): 5 0.80 (3H, d; J = 6.4 Hz. -CH3), 0.82 (3R s. -CH3), 0.94 (3H, s, -CH3), 1.02 (3R s, -CH3). 1.17 (3R s, -CH3), 1-19 (3H, s, «CH3)? 1-34 (3R s, -CH3), 2.09 (3H, s, -COCH3)3 2.41 (1H, s, 2.54 (1H, brd; 13,5 Hz), 2.91 (6H, s, 2 x N-CH3), 326 - 3.42 (2H, m. •OCH2CH2N(CH3)2)? 4.46 - 4.56 (1H, m -OCH-CH2N(CH3)2), 4.57 - 4.65 (IR m, -OCH-CH2N(CH3)2), 5.28 (1R br s, 3-H), 5.55 (IR s. I2-H): IR (KBr); 3446 (br). 2978, 2926r 2868. 1736, 1660, 1461, 1382, 1250. III3scin":: LC - MS (positive mode): m/z 584 (M+H)+ Example 19 3-O-Acetyl-ll-keto-β-boswellic acid amide (19): A mixture of 3-O-acetyl.11-keto-{3-boswellic acid (300 mg) and thionyl chloride (0-5 mL) was refluxed for Ih and the excess reagent was removed under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in THF (1.0 mL) and treated drop-wise with cone, ammonia solution (3.0 mL) at ice-cold Temp, for 5 min. and the mixture was stirred at the WO 35.123649 PCT/IN2004/000176 same temp, for 1h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed successively with 0.2 N H2SO4. water and brine and then dried over sodium sulfate. The residue (350 mg) obtained after evaporation of the solvent was chromaiographed over silica gel column using methanol and dichloromethane mixtures. The fractions eluted with 15% methanol'CH2-CI2: furnished 3-O-acetyl-l1-keto-β-bosweliic acid amide (325 mg). Melting point: 162 - I70°C. IR (KBr): 3465 (br). 2978, 2925. 2S5S. 1736. 1662. 1459, 1378. 1252. 1200. 1025 cm~!; LC - MS (positive mode): m/z 512 (M+Na)+ 534 (M^ 550 (M+K)+ 1045 (2M+Na)+. Example 20 N-(3-O-acetyI-ll-keto-P-bo^veIIoyI)-hydrazide (20): A mixture of 3-O-acetyl-I1-keto-β-boswellic acid (450 mg, 0.88 mmol) and thionyl chloride (0.62 mL) was subjected to reflux in an oil bath. After lh, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (3.0 mL) and treated slowly with hydrazine hydrate (265 mg, 5.3 mmol) at ice-cold temp, for 5 min. and the stirring was continued at the same temperature for 2h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 x 30 rnL). The combined organic layer was washed with 0.2N H2SO4 water and brine, and dried over sodium sulfate. The solution was filtered and the solvent evaporated to give the hydrazide, 20 (390 mg, 85%). Melting point: 190 - 192°C; !HNMR (CDCI3): 5 0.80 (3H d; J = 6.4 Hz, -CH3), 0.83 (3H,s-CH3),0.95(3H,s,-CH3), l.10(3H,s,-CH3), 1-15 (3H, s, -CH3), 1.20 (3H, s, -CH3), 1.35 (3H, s, -CH3), 2.09 (3H, s. CH3CO-X 2.24 - 2.34 (IK m). 2.41 (IH, s), 2.55 (IH, brd; 13.2 Hz), 3.86 (2H, brs, -CONHNH2), 5.34 (1H, brs, 3-H), 5.56 (1H, s, I2-H), 6.77 (1 H; brs, -CONHNH2); IR (KBr): 3600 - 2400 (br), 2925, 1737, 1662. 1459, 1377, 1252? 1201, 1023, 879; 808 cm"1; LC-MS (positive mode): m/z 527.6 (M+H)+, 549.6 (M+Na), 1076.1 (2M+Na)+. Example 21 N-(3-0-Acetyl -1l-ketobosweHoyI)-ethylenediamine (21): A mixture of 3-O-acetyl-l 1- keto-β-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL 9.4 mmol) was WO 2005/123649 PCTTN2 subjected to reflux on an oil. bath. After lh. the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2: (4.0 mL); and treated slowly with ethylene diamine (351 mg. 5.85 mmol) at ice-cole temperature for 5 min and the stirring was continued at the same temperature for 1h. The reaction mixture was poured into ice-cold water and extracted with ethyl ether (2 x 30 ml The combined organic layer was washed with 0_2N H2SO4 water and brine, and dried over sodium sulphate- The solution was filtered and the solvent evaporated. The residue '500 mg. yield 92%) was subjected to silica column chromatography using CH3OH/CH2CI2 m.boures.The fractions eiuted with 10% CH3OH/CH2CI2 temperature N-(3-O-acetyl-11-keto-β-boswelloyl Vethylenediamine (440 mg) as a white solid. Making point: 198 - 202°C 1HNMR (CDCI3): 5 0.80 (3H, d: J = 6.4 Hz, -CH3), 0.82 (3H. s, -CH3), 0.95 (3H, s, -CH3)5 1.12 (3H, s. -CH3), 1.17 (3Hr s; -CH3), 1.19 (3H, s, -CH3K 134 (3R s, -CH3), 2.09 (3H, s, CH3CO-), 2.24 - 2.36 (1H, m), 2.41 (IH. s), 2.54 (1H, brd; 13.2 Hz), 2.87 - 2.96 (2H, m, -CONHCH2CH2NH2,) 3.28 - 3.41 (2H. m, -CONHCH2CH2NH2,), 5.33 (IH, brs3 3-H), 5.55 (IH. s, 12-H), 6.39 (IH, brs, -CONHCH2CH2NH2); IR (KBr): 3430 (br), 2976, 2925, 2867, 1734, 1659, 1521, 1458, 1376, 1252, 1199, 1023 cm-1; LC-MS (positive mode): m/z 555 (M+H)+, 113 Example 22 N-(3-O-AcetyI-ll-keto- p-boswellie)-2-aminoethanol (22): A mixture of 3-O-acetyi-11-keto- β-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL 9.4 mmol) was subjected to reflux on an oil bath. After lh, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (4.0 mL) and treated slowly with etfaanol amine (350 uL, 5.86 mmol) at ice-cold temperature for 5 min. and the stirring was continued at the same temperature for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl ether (2 x 30 mL). The combined organic layer was washed with 0.2 N H2SO4 (40mL). water (40 mL) and brine (40 mL). and dried over sodium sulfate. The solution was filtered and the solvent evaporated. The residue (570 mg) was crystallized from CH2CI2 to obtain pure N-(3-O-acetyI-l l-keto-β-boswelloyl)-2-aminoethanol (480 WO 21KJ5/123649 PCT/IN2004/000176 mg-89%) as a white solid. Melting point: 284 - 290cC 1H KMR (CDCh): 5 0.S1 (3H. .± J = 6.4 Hz, -CH3), 0.83 (3H. s. -CH3). 0.95 (3H, s. -CH3). 1.15 (3H. s, -CH;), 1-17 (3H. s. -CH;.). i-20 (3H, s, -CH3), 1.35 (3H. s. -CH3), 2.09 (3H. s, CH5CO-). 2.26 - 2.36 (!H. m) 2.42 (1H. s), 2.56 (1H. br d; 13.2 Hz). 3.37 - 3.49 (2H, m, -CONHCH:CH;OH\ 3.67 - 3.SG CH. m. -CONHCH^CHaOH). 5.33 (!H. brs, 3-H). 5.56 (IH. s. !2-H). 6.00 (IH. brs. -CONHCH:CH;OH); IR (KBr): 3430 (br), 2978, 2933, J 726. 5662. 1633. 1530. 1458. 1372. 1245. 1200. 1070. 1027. 991 cm"': LC - MS (positive mode): nvz 556 1M-H'f. 578 (M-s-Naf. 594 (M+K)+, 1133 (2M-Na;f. Example 23 N-(3-O-AcetyI-ll-keto-β-boswelloyI)-pipcrzine (23): A mixture of 3-O-acety!-11-keto-B-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL, 9.4 mmol) was subjected to reflux on an oil bath. After Ih, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (4.0 mL) and treated slowly with piperzine (351 mg, 5.85 mmol) at ice-cold temperature for 5 min. and the stirring was continued at the same temperature for 2 h. The reaction mixture was poured into ice-coid water and extracted with ethyl ether (2 x 30 mL). The combined organic layer was washed with 0.2N H2SO4, water and brine, and dried over sodium sulfate. The solution was filtered and the solvent evaporated. The residue (620 mg) was subjected to silica column chromatography using CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 yielded pure N-(3-O-acetyl-l l-ketoboswelloyl)-piperzine (500 mg. 88%) as a white solid. Melting point 180 - 184°C 'HNMR (CDCI3): 5 0.81 (3H, d; J = 6.4 Hz. -CH3), 0.83 (3H, s, -CH3), 0.95 (3R s, -CH3), 1.225 (3H, s, -CH3), 1.232 (3H, s. -CH3). 1.25 (3H, s, -CH3), 1.33 (3H. s. -CH3), 2.11 (3H, sr CH3CO-), 2.41 (IH, s), 2.54 (IH. brd; 13.4 Hz), 2.87 -3.01 [4H, m, -CON(CH2CH2)2NH], 3.57 [IH. br m, -CON(CH2CH2)2NH). 3.58 -3.68 [2H, m; CON(CH2CH2)2NH) 3.68 -3.79 [2H, m,CON(CH2CH2)2NH), 5.55 (1H. s, 12-H), 5.55 (1H, br s, 3-H); 1R (KBr): 3433 (br), 2982, 2925, 2863, 1737, 1657. 1457, 1377, 1247, 1209, 1021 cm"1; LC-MS (positive mode): m/z 581 (M+H)~. 13 61 (2M+H)+, 1183 (2M+Na)+. WO 2005/123649 PCT.TN2O«4'(KiOI '6 Example 24 3-acetoxy-11-keto-24-norus-12-en-4-isocyanate(24): A solution of NaOH (0.065 g) in water (0.6 rnL) was cooled to 0°C and Treated with bromine (0.022 mL). After 10 min. 3-O-acetyl-l I-keto-β-boswellic acid amide (C.;5 g) in acetone (0.5 rnL) was added to the NaO3r solution and the mixture was heated at TO - 75°C for 45 min. The reaction mixture was diluted with eryl ethyl (40ml); and washed with water (20 mL) and brine (30 mL) and dried over Na2So4 The solvent was evaporated and the residue was purified over silica get using hexanelethyl acetate mixtures- Fractions eiuted with 5% and 10% ethyl acetate/hexana mixtures -were monitored and those showing a yellow colored spot were combined and evaporated to give 3α-acetoxy-l I-keto-24-norurs-12-en-4-isocyanate as a white solid (70 mg). Melting point 170 - 176°C. IR (KBr): 2926, 2856,2267, 1744, !658, 1458, 1619, 1458. 1379, 1238, 1205, 1044"cm-1; LC-MS (positive mode) m/z5I0 (M+H)+? 532 (M+Na)+, 1041 (2M+Na)+. Example 25 3a-Acetox7-4-amino-ll-keto-24-norurs-12-ene (25): A solution of NaOH (0.164 g) in water (0.8 mL) and dioxane (0.8 mL) was cooled to 0°C and treated with bromine (0.060 mL). To the resulting NaOBr solution was added, after 10 min. 3-0-acetyl 1-keto-P-bosweliic acid amide (0.4 g) in 1 mL dioxane and the mixture was heated at 65 - 75°C for 2h. The reaction mixture was poured into ice-water and the white precipitate was filtered, washed with water and dried under vacuum to obtain 3α-acetoxy-4-amino-ll-keto-24-norurs-12-ene (250 mg). The mother liquor was extracted with dichloromethane (2 x 30 mL) and the organic fever was washed with water, brine and dried over Na2SO4. The solvent was evaporated and the residue was crystallized from hexane and ethy{ acetate mixture to give a further quantity of 3a-acetoxy-4-amino-l l-keto-24-norurs-I2-ene (50 mg). Melting point: 212 - 216°C; 1HNMR (CDCI3): 5 0.83 (3H, d; J = 7.0 Hz. -CH3), 0.84 (3H, s, -CH3), 0.97 (3H5 d; J = 7.1 Hz, -CH3), 1-22 (3Hr s, -CH5). 1.32 WO 2005/123649 PCT/IN 2004/000176 Example 26 3α-AcetoxyT-4-cyano-ll-keto-24-norurs-12-ene (26): 3-0-Acetyl-l l-ketoboswellic acid amide (200 mg. 0.39 mmol) in ethylene dichloride (2 rnL) was treated with SOCK (0.04 mL 0.58 mmol) and the mixture was refluxed for 6 h. The mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water and brine, and dried over Na2So4 The solvent was evaporated and the residue (190 mg) was subjected to silica column chromatography using bexane/ethyl aceiaie mixtures. The fractions eluled with 10% hexane/erhyl acetate were evaporated to obtain 3a-acetoxy-4-cyano-l I-keto-24-norjrs-I2-ene (140 mg, 729',). Melting point: 214- 218°C; ; 'HNMR (CDC13): 5 0.8! (3H, d; J = 6.5 Hz, -CH3), 0.84 (5H, s, -CH3)? 0.95 (3R d; J = 7.1 Hz, -CH3), 1.24 (3H, s, -CH3)S 1.34 (3H, s, 2 x -CH3), 1.44 (3H, s, -CH3), 2.10 (3H, s, -OCOCHs), 2.20 (1H, m), 2.40 (1H, s), 2.67 (IH. br d; 13.6 Hz), 5.11 (IH, br s. 3-H), 5.57 (1H, s, I2-H); 1R (CHCI3): 2924. 2858, 1744, 1663, 1453, 1383, 1232, 1027; LC-MS (positive mode) m/z 494 (M+H)+, 516 (M+Na)+, 532 (M+K)+5 1009 (2M+Na)+. Example 27 ll-Hydro]cy-P-bosewellic acid (27): Lithium aluminum hydride (30 mg? 0.96 mmol) was dispersed in THF and cooled in ice water bath. A solution of 1 l-keto-β-boswellic acid (150 mg, 0.32 mmol) in THF (2 mL) was slowly added to the above dispersion and the stirring continued in the ice water bath for 2h. The reaction mixture was diluted with ethyl acetate (2 mL) and after 5 minutes it was poured in to ice water. The mixture was carefully neutralized with 1 "N HC1 and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with water, brine, dried over Na2SO4 and evaporated. The residue was purified on silica column using hexane and ethyl acetate mixtures. The fractions eluted with 25% ethyl acetate/hexane mixture yielded 11-hydroxy-β-boswellic acid (70 mg). Melting point: 152 - 160°C 1HNMR (CDC13): 5 0.80 (3H d; J = 5.6 Hz, -CH3), 0.85 (3H, s, -CH3), 0.93 (3H, s, -CH3), 1 -07 (3H, s. -CH3), 1.10 (3R s, -CH3), 1.18 (3H, s, -CH3), 1.36 (3H, s, -CH3), 1.96-2.08 (IH, m), 2.15 (IH, brd; J= 13.3), 2.19-2.31 (1H, m), 4.08 (IH, brs), 4.26 lH,dd;J = 9.1 and 2.9 Hz, 11- WO 20O5/123f>49 H), 5.18 (1H, d: J =2.9 Hz. 12-Hc FT - IR (neat): 3390. 2921, 2860, 1696. 1451. 1379. 1246. 1001 cm"1. LC-MS (negative mode): 471 (M-HT. 5-LOX ASSAY The AK.BA analogs were screened for their 5-Lipexyger.ase inhibitory potential usir.g colorirnetric method of crag a gay et al. and Biockem., 304. 42 — 46. 2002;. The assay mixture combined 50 ml phosphate buffer pH 6.3.5-lipoxygenese.various ; concentrations of test subtances and neuclic acid in a total volume of 0.5 ml after 5 min incubation of above reaction mixure 0.5ml ferric xylenol orange reagent was Added and OD was measured after two minutes at 585 nm using spectrophotometer (varian). Controls were run along with test hi a similar manner except using vehicle Instead of test substance solution. Percent inhibition was calculated by comparing absorbance of test with that of control BRINE SHRIMP LETHALITY ASSAY. Brine shrimp lethality (BSL) assay is a simple bench top bioassay developed by McLaughlin, el. al.(Studies in Natural Product Chemistry, 9. page 383, 1991 and Am. Chem. Soc. Symp. Series. 534, page 114, 1992) and the results obtained by this assay have been reported to be corroborative with the cytotoxicities determined in 9KB and 9PS cells. The procedure involves hatching Artemia salina cysts in a cone shaped vessel and collecting active nauplii after 48 hr and treating with known concentrations of test substances and vehicle (control) in tubes each tube containing 10 nauplii and checking viability/mortality after 24 hr. Percentage lethality was calculated by comparing mean values of control 2nd test sets of three tubes each, LC50 values were obtained from the graph plotted micro moiar concentration against percent lethality. The new analogs exhibited 5-Lipoxigenase inhibitory activities. The 5-Lipoxigsnase inhibitory activities of these analogs are summarized in table I. Consistent with the anti-proliferative actions reported for known bosweilic acid compounds, the analogs of the present invention inhibited the growth of Brine Shrimp in cultures, which is a possible WO 249 PCT/IN2004/000176 indication for their antitumor activity. The Brine Shrimp inhibitory activity of these compounds is summarized in table II. WO 200&123649 PCTTN2(>04' WE CLAIM: 1. Novel structural analogs of 3-O-acetyl-ll-keto-β-boswellic acid (AKBA) of the general formula I represented below. wherein R1, R2, R3, R4 and R5 are as indicated herein below in each of said analogs: 1. R1, = OCHO,R2 = H, R3 = COOH, R4&R5 = O 2. R1, = OCOCH2CI, R2 = H, R3 = COOH, R4&R5 = O 3. R1 = 5'-O-methyIgoyioxy, R2 = H, R3 = COOH, R4&R5 = O 4. R1, = OCOCH2CH2COOH, R2 = H, R3 = COOH, R4&R5 = O 5. R1 = 8',9'-Dihydro-4'-hydroxycinnamoyloxy5 R2 = H, R3 = COOH, R4 & R5 = O 6. R1 = 4'-Hydroxycinnamoyloxy, R, = IL R3 = COOIL R4&R5 = O 7. R1 = 3'54'-Dimethoxycinnamoyloxy, R2 = H, R3 = COOK R» & R5 = O 8. R1 = 3\4'-Dihydroxy-5'-methoxycinnamoloxy, R2 = H, R3 = COOK, R & R5 = O 9. R1 = OCOCH2NH(tert-BOC), R2 = H, R3 = COOCH3, R4&R5 = O 10. R1 = OCOCH2NH2KC1, R2 = H, R3 = COOH, R* & R5 = O 11. R1 = OCOCH2(CH3)NH2HC19 R2 = H, R3 = COOH, R4 & R5 = O 12. R1 = H, R2 = OR R3 = COOCH3, R4&R5 = O 13. R1 = Br, R2 = H, R3 = COOCH3, R4&R5 = O 14. R1 = CN, R2 = H, R3 = COOCH3, R4&R5 = O 15. R1, = SH, R2 = H, R3 = COOCH3, R4&R5 = O 16. R1. & R2 = N(OH), R3 = COOCH3; R4 & R4 = O IT. R1 & R2= H & OCOCH3 R3 = H, R4 & R5 = O 18. R1& OCOCH3, R2 = H R3 = COOCH2CH2N(CH3) 2, R4 & R5 = O 19. R1 = OCOCH3, R2 = H R3 = CONH., R4 & R5 = O 26. R1 = OCOCH5, R2 = H, R3 = COMCsH2, R4 & R5 = O 21. R1 = OCOCH3; R2 = H, R3 = COKBCH2CH2KH2, R^ & R5 = O 22. R1 = OCOCH3; R2= H, R3 = COIvHCH2CH2OIL R4 & R5 R4 = O 23. R1 = OC0CH3, R2 = H, R3 = CON(CH2CH2) 2KP1R4 & R5 = O 24. R1 = OCOCH3, R2 = H R3 = NCO, R4 & R5 = O 25. R1 & OCOCH3, R2 = H R3 = NH2, R4 & Rs = O 26. R1 = OCOCH3, R2 = H R3 = CN, R4 & R5 = O 27. R1 = OH, R2 = H R3 = COOH, R4 & R5 = OH«&H 2. The boswellic acid analog as claimed in claim 1 wherein R2 is formyl group, R2 is H, R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula 3. The boswellic acid analog as claimed in claim 1 -wheR1en R1 is chloroacetoxy group. R3 is H, R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula WO 2WJ5/123649 PCnN2M»4'«M1"6 4. The boswellic acid analog as claimed in claim 1 wherein R1 is 5'-0-methyl galloyloxy group, R2 is H, R3 is Carboxylic acid group and R4 and R5 taken together form a keto group, said analog 5. The boswellic acid analog as claimed in claim 1 wherein R1 is succinyloxy (OCOCH2CH2COOH) group, R2 is H R3 is caiboxylic acid group, and R4 and R5 taken together form a keto group, said analog represented by structural formula 4 6. The boswellic acid analog as claimed in claim 1 wherein R1 is 8'9'-dihydro-4'- hydroxycinnamoyloxy group. R2 is H R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula \O 2 7. The boswellic acid analog as claimed in claim 1 wherein R1 is 4'-hydroxy cinnamoyloxy group. R2 is H, R3 is carboxylic acid group and R4 and R5 taken together fom a keto group, said analog represented by structural formula 6 8. The boswellic acid analog as claimed in claim 1 wherein R1 is 3'4'- dimethoxycinnamoyl group, R2 is H, R3 is carboxylic group, R4 and R5 taken together form a keto group, said analog represented by structural formula 9. The boswellic acid analog as claimed in claim 1 wherein R1 is 3'.4'-dihydroxy- 55-methoxycinnamoyloxy group, R2 is H, R3 is carboxylic acid group and R4 and R5 taken together to form a keto group, said analog represented by structural formula WO 2005:123649 PCTTN2004'(Hile> 10. The boswellic acid analog of the formula L as claimed in claim 1. where in R1. is OCOCH2NH(tert-BOC) group, R2 is rL R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represemed by the structural formula 11. The boswellic acid analog of the formula 1 as claimed in claim 1 where in R1 is OCOCH2NH2HCI group, R2 is EL R3 is carboxylic acid group and R4 and R5 taken together to form a keto group, 12. The boswellic acid analog of the formula 1, as claimed in claim 1, where in R1 is OCOCH(CH3)NH2HC1 group, R2 is H, R3 is carboxylic acid group and R- and R5 taken together to form a keto group, as represented by the structural formula WO 2005/123649 PCT7IN 2004/000176 13. The boswellic acid analog of the formula 1 as claimed in claim 1, where in R1 is H, R2 is OIL R3 is carhoxylic acid STOUD and R4 and R5 taken together to form a keto group, as represented by the 14. The bosweilic acid analog of the formula 1 as claimed in claim 1, where in R1 is H, R2 is Br, R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula 15. The bosweilic acid analog of the formula 1, as claimed in claim 1, where in R1 is CN, R2 is H, R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula WO 2005-123649 PCTflN2Mi4Wi0r6 16. The boswellic acid analog of the formula L as claimed in claim 1. where in KL is SH, R2 is R R3 is COOCH3 23d R4 and R5 taken together to form a ksiD group, as represented by the structural: 17. The boswellic acid analog of the formula 1, as claimed in claim 1 where in R1 and R2 are taken together to form oximino [:N(OH)] group. R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula 16 18. The boswellic acid analog of the formula I, as claimed in claim 1, where in R} and R2 are OCOCH3 and K R3 is ±L and R4 and R5 taken together to form a keto group, as represented by the slruound formula ^ 1 WO 2005123649 PCT7IN2004/000176 19. The boswellic acid analog of the formula I, as claimed in claim 1, where in R1 is OCOCH3, R2 is H, R3 is COOCH2CH2N(CH3) 2 and R4 and R5 taken together 10 form a keto group, as represented by the structural formula _. LV 20. The boswellic acid analog of the formula 1, as claimed in claim 1, where in R1 is OCOCH3, R2 is H5 R3 is CONH2 and R4 and R5 taken together to form a keto group, as represented by the 21. The boswellic acid analog of the formula 1, as claimed in claim 1. where in R1 is OCOCH3, R2 is H, R3 is CONHNH2 and R4 and R5 taken together to form a keto group, as represented by the structural formula _ WO 2105 123649 PCTTN20(U'IHI'* 22. The boswellic acid analog of the formula 1. as claimed in claim 1. where in R1 is OCOCH3, R2 is H, R3 is CONHC&CHrNHi and R4 and R5 taken together to form a keto group, as represented 23. The boswellic acid analog of the formula 1. as claimed in claim 1, where in R1 is OCOCH3, R2 is H, R3 is CONHCH2CH2OH, and R4 and R5 taken together to form a keto group, as represented 24. The boswellic acid analog of the formula 1, as claimed in claim 1 where in R1 is OCOCH3, R2 is H, R3 is CON(CH2CH2) 2NH, and R4 and R5 taken together to form a keto group, as represented by the structural formula WO K/123649 PCT/TN2004/000176 25. The bosweilic acid analog of the formula I, as claimed in claim L where in R1 is OCOCH3. R2 is EL R3 is NCO and R4 and R5 taken together 10 form a keto group, as represented by the 24 26. The boswellic acid analog of the formula I, as claimed in claim 1, where in R1 is OCOCH39 R2 is H, R3 is NH2 and R4 and R5 taken together to form a keto group, as represented by the 27. The boswellic acid analog of the formula L as claimed in claim 1, where in R2 is OCOCH39 R2 is H, R3 is CN and R4 and R5 taken together to form a keto group, as represented by the WO 20G5/123649 PCTIN2(KU'(HHil"6 28. The bosweilic acid analog of the formula I. as claimed in claim 1, where in mL is OH, R2 is £L R3 is COOHby the srucnsrci formula 29. A process for prepaR1ng boswellic acid analogs represented by structural formula 2-11 compR1sing the steps of coupling 3-keto bosweilic acid (KBA) or its ester with an organic acid in the presence of 1,3-dicyclohexyl carbominide and 4- (dimethyl amino) pyR1dine as coupling agent 30. A process for prepaR1ng bosweilic acid analogs represented by structural formula 12-15 compR1sing the steps of treating methyl ester of 3 keto bosweilic acid with phosphorus tR1bromide to displace the 3 oc OH group by Br and further treating the same with a nucleophillic agent to displace the Br group with SH\ CN and the like 31. A process for prepaR1ng bosweilic acid analogs represented by structural formula 19 -23 compR1sing the step of treating fee acid chloR1de of AKBA wiih excess of amine in a solvent medium 32. A process for prepaR1ng novel analogs of 3-0-acety11-keto-β-bosweliic acid of the general formula I substantially as herein descR1bed with reference to The examples. WO 2005123649 PCTYIN2004/000176 33. A pharmaceutical composition compR1sing at least one boswellic acid analogs as claimed in claim 1 in a pharmaceutically acceptable carR1er. 34. The pharmaceutical composition as claimed in claim 33 wherein said carR1er is an aqueous or non-aqueous carR1er. 35. Use of boswellic acid analogs represented by the general formula I as anti- inflammatory and antitumor agents. 36. A method treating of inflammatory and tumor diseases compR1sing the steps of administeR1ng boswellic acid analogs of the general formula I to persons in need thereof.

Full Text

WO 2005/123649 PCT/K2OO4/0O0I76
Novel Analogs of 3-O-Acety1-ll-Keto-β-Boswellic acid
This invention relates to novel structural analogs of 3-O-Acety1-ll-Keto-β-Boswellic acid (AKBA).
Technical field:
Presently, there has been a tremendous surge in demand for non-stercidal plant based antiflammatory agents. 5-Lipoxygenase is the key enzyme for the biosynthesis of leukotrienes and 5(S)-HETE, the important mediators for inflammatory, allergic and obstructive process, from arachidonic acid. 5-Lipoxygenase is the target enzyme for identifying inhibitors, which have potential to cope with a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischaernia. Scientists around the world have invested a major effort during the last ten years, in identifying 5-Hpoxygenase inhibitors.
Gum resin of Boswellia species known as Indian frankincense has been used as an anti-inflammatory agent in Traditional Ayurvedic Medicine in India. Ancient Ayurvedic texts described its therapeutic use. Clinical trails performed by CSIR laboratories in India have shown fair to excellent results in 88% of the patients, with no adverse side effects [Singh, G.B.t Status report, anti-inflammatory drugs from plant sources (1982)]. A randomized, double blind, placebo controlled clinical trials on patients with Osteo-arthritis of knee exhibited statistically significant improvement in the pain, decreased swelling and increased knee flexion etc. [Kimmatkar, Phytomedicine 10: 5-7 (2003)]. The therapeutic effects shown by Boswellia serrata extract were comparable to those exhibited by sulfasalazine and mesalazine in patients with ulcerative colitis. (Gupta, I., et al, Eur. 1 Med Res., 3: 511-14, 1998 and Gerhardt, H., et. al, GastroenieroL 39: 11-17, 2001). The source of anti-inflammatory actions has been attributed to boswellic acids (Safayhh H., et al, Planta Medica 63, 487 - 493, 1997 and 1 Pharmacol Exp. Then 261. 1143 - 46. 1992, both the journals published from USA), a group of triterpene acids isolated from the Boswellia resin (Pardhy, R. S., et aL, Indian J.Chem.16B. 176 - 178,

WO 2005/123649 PCT/IN2004/OWI76
1978). These compounds exert anti-inflammatory activity by inhibiting 5-iipoxygenase (5-LO). Immunomodulatory activity of boswellic acids had been reported by Sharrna et. al. in Phyioihcraph)' Research. (1O. 107 - 112. 1996), published from USA. A detailed study on the structural requirements for boswellic acids indicated that, of all the six boswellic acids, 3-O-acetyl-l 14;eto-β-boswellic acid, hereinafter referenced as AKBA shows most pronounced inhibitory activity against 5-LO (Sailer, E- R-, e: aL British J. Pharmacology 117. 615-618, 1996). AKBA acts by unique mechanism. in which it binds to 5-LO in a calcium-dependent and reversible manner and acts as a non-redox-type, non-competitive inhibitor (Sailer, E. R., et al., Euro. J. Biochem- 256. 364 - 368, 1998). AKBA has thus become the subject of intensive research for its potential for the treatment of chronic inflammatory disorders.
The oleanane and ursane triterpenoids also gained prominence recently for their antiproliferative actions. As 5-Iipoxygenase (5-LO).is the first enzyme in the metabolic pathway leading to the formation of leukotrienes and eicosanoids thai are important in carcinogenesis process, inhibitors of 5-LO may thus have profound influence on the growth and apoptosis of various cancer lines (Yong S. Park, et. al. Planta Medico, 68, 397-401, 2002). Boswellic acids, for example inhibited several leukemia cell lines in vitro and inhibited melanoma growth and induced apoptosis (Hostanska. K., et aL Anticancer Res.f 22(5), 2853 -62. 2002). The acetyl boswellic acids were found to be unique class of dual inhibitors of human topoisomerases I and II a(Syrovets, T. et aL, , MoL PharmacoL, 58 (1), 71 - 81, 2000). A number of oleanane and ursane triterpenoids were found to be powerful inhibitors of nitric oxide production in macrophases. which can be correlated to their cancer chemoprevention activity. (Honda, T., eL al- J. Med. Chem., 43, 1866-1877).
Background Art:
5-Lipoxigenase inhibitory properties of AKBA and other boswellic acids have been scientifically established. Efforts are currently being made to enrich AKBA in the natural extracts and also to synthesize structural analogs of AKBA with enhanced potency and water solubility.

WO 2005/123*19 PCTTN2l*ut OOOI'b
Disclosure of tic invention:
The organic sorvenr extract of The gum resin of Bosweilia serrata contain a total of six bcswellic acids. These acids are shown in figure 1, and are represented by Bl. B2. B3. B4, B5 and B6. The concentration of most active principle B2 (AKBA) amounts only in the range of 1-10%. but most typically in -the range of 2-3%. The enrichment of AKBA from natural boswellic extract has already been undertaken by the inventors and escnDed in international. patent application (PCT#03/074063.dtd 12th september 2003) and US patent application (US#2004073060. The potential usefulness of boswellic acids in general and AKBA in particular can be a great incentive ID take-up further development of these compounds in all possible aspects. The present invention, is related to development of novel structural analogs of AKBA by serri-synthesis from 11-keto-β-bosweliic add (KBA) or 3-O-acetyl-11-keto-β-boswellic acid (AKBA) for biological evaluation and to conduct structure activity relationship studies. The core objective of this invention is to obtain novel AKBA type compounds with enhanced biological activity and improved water solubility for use in therapeutic applications as anti-inflammatory, anti-arthritic and anti-tumor agents.
A systematic study on the boswellic acids analog development has not been undertaken, so far, except the preparation of some afylidene analogs of 3-keto-{3-boswellic acid (Gupta, V. N. et al., Indian Drugs, 25(2), 70 - 72, 1987). The major functional moieties that can be expended to make novel structural analogs of AKBA are acetoxyl, carboxyl and enone. Two major types of compounds were primarily envisioned for the development of new analogs of AKBA. One type constitutes a group, which differ in the nature of the acyioxy group on C3 of the ring A The other group contains compounds obtained by modification of carboxyl group on C4 of the unit A.

WO 2005/12364* PCT;TN2OW««O0I "6
This invention reiatss to novei structural analogs of 3-O-acetyl-l l-keto-β-boswellic acid (AKB A) having the formula.

Where in R1, R2, R3, R4 and R5 are as indicated below in each of said analogs:
1. R1 = OCHO, R2 = H, R3 = COOH, • R4&R5=O
2. R1 = OCOCH2CKR2 = H, R3 = COOH, R4&R5=O
3. R1 = 5'-O-methylgalloyloxy, R2 = H, R3 = COOH, R4 & R5=O
4. R1= OCOCH2CH2COOH, R2 = H, R3 = COOH, R4 & R5=O
5. R1 = 8'.9'-Dihydro-4'-hydroxycinnamoyioxy, R2 = H, R3 = COOH, R4 & R5 = O
6. R1 = 4'-Hydroxycinnamoy!oxy, R2 = H, R3 = COOH, R4 & R5"=O
7. R1 = 3',4'-Dimethoxycinnamoyloxy, R2 = H, R3 = COOH, R4 & R5 = O
8. R1 = 3rT4r-DEiycro?o-5r-me±oxycinnamoy]oxy, R2 = H, R3 = COOH, R4 & R5 = O
9. R1 = OCOCH2NHrtsrt-BOQ; R; = H, R3 = COOCH;r R4 & R5 = O
10. R1 = OCOCH;NH:HCL R2 = H. R3 = COOH, R4 & R5 = O
11. R1 = OCOCH(CH3)MH2HCl, R2 = H, R3 = COOH, R4 & R5 = O
12. R1 = R R2 = OH? R3 = COOCH3; R4 & R5 = 0
13. R1 = Hr R2 = Br, R3 = COOCH3, R4 & R5 = O
14. R1 = CN, R2 = H, R3 = COOCH3, R4 & R5 = O
15. R1 = SH; R2 = H, R3 = COOCH3; R4 & R5 = O
16. R1 &R2 = N(OH\ R3 = COOCH3; R4 & R5 = O

WO 2005 123649 PCT/K2004/000176
17.R1 &R2;=H&OCOCH3 R3 = H, R4&R5= O
18. R1 = OCOCHj. R2 = H R3 = COOCH:CH2N(CH3) 2, R4&R5 = O
19. R1 = OCOCH3- R2 = H R3 = CONH-, R4&R5=O
20. R1= OCOCH3, R2 = H, R3 = CONHKH;, R4&R5 = O
21. R1 = OCOCH3. R; = Hr R:- = CONHCH2CH=NH;5 R4&R5 = O
22. R1= OCOCH> R2 = H, R3 = CONHCHrCH:OH.R4&R5= O
23 R1 = OCOCH3, R2 = Hs R3 = CON{CH:CH;) ;NH. R4&R5 = 0

24. R1 = OCOCH3, R; = H R3 = NCO. R4 & R5 = O
25. R1 = OCOCris. R; = H R3 = NH2. R4&R5 = 0
26.R1=OCOCH35R2=H R3 = CN, R4& R5 =0
27. R1 = OH, R2 = H R3 = COOH, R4 & R5 = OH & H
The structures of the individual compounds are presented below in figure 2.

WO 2 Novel compounds of this invention may be prepared by the following processes.
The compounds represented by 2 to 11 may be prepared by a coupling reaction between KBA or its ester with an appropriate acid counterpart using DCC (1.3-diclohexylicarbodiimide) and DMAP {4-(dimethylandno)pyridine} as coupling agent in a. suitable solvent system. This may also be accomplished by convening the acid corresponding to the acyloxy unit to the add chloride using SOCb (thionyl chloride) and then treating the acid chloride with KB A or its methyl ester, in the presence of an organic base The compounds represented by 12, 13, 14 and 15 may be prepared by displacing the 3α OH group in methyl ester of KBA by Br using PBr3 (phosphorus tribromide) and then further displacing the Br group with appropriate nucleophnic agents, such as SH', CN' etc. These reaction sequences are shown hereinafter in scheme I.
The amide compounds represented by 19, 20, 21, 22 and 23 may be prepared by treating the acid chloride of AKBA with an excess of amine component in a suitable solvent system. This reaction scheme is shown in the scheme EL below.
The isocyanate and amine compounds represented by the structures 24 and 25 respectively may be prepared by Hoffmann rearrangement of the amide 19. The intermediate isocyanate, 24 may be obtained by reducing the reaction time and working-up the reaction before completion.
The isolation of starting materials AKBA and KBA for the semi-synthesis of the novel analogs is accomplished by the procedures known in the literatures (For example, US Patent Application # 2004073060). Preferred embodiments relating to the processes of preparing AKBA analogs mentioned in the foregoing discussion and other compounds of the subject invention are illustrated in the following examples, 1 to 27. These analogs inhibited 5-Lipoxigenase enzyme and also the growth of Brine Shrimp in cultures.

wu jwcv'i 23649 PCT/PS2O04/OO0I76
Example 1
3-O-Forniyl-ll-keto-β-boswellic acid (1): To a solution of ll-keto-(3-boswellic acid (200 mg. 0.424 mmol) in DMF (2 mL), cooled in an ice water bath was slowly added phosphorous oxychloride (150 µL, 1.7 mmol). The reaction mixture was allowed to warm-up to the ambient temperature and the stirring was continued. After 2h. the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 25 mL). The combined organic extract was washed with brine, dried over "Na2SO4 and evaporated under reduced pressure. The residue was subjected to silica column chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane were monitored and those containing 3-O-forrnyI-lI-keto-P-bosweHic acid were combined and evaporated to obtain pure compound (120 mg). Melting point: 298 - 302°C; ;HNMR (CDCI3, 90 MHz): 5 0.50 - 2.50 (m, CH CH2 and CH3 signals), 5.43 (1H. br s, 3-H), 5.60 (1H, s, 12-H), 8.20 (1H, s, -OCHO); FT-IR (neat): 3400 -2700 (br), 2924, 2859, 1727, 1705, 1662, 1459, 1270, 1166 cm*1. LC-MS (positive mode): m/z 499 (M+H)+, 521 (M+Na)+, 1019 (2M+Na)+.
Example 2
3-0-(Chloroacetyl)-ll-keto-P-boswellic acid (2): To a solution of 11-keto-β-boswellic acid (200 mg, 0.43 mmol) in CH2CI2 (3 mL) was added chloroacetic acid (166 mg, 1.7 mmol) and DMAP (26 mg, 0.21 mmol), and the mixture was cooled in ice water. A solution of 1.75 g of DCC in 2 mL of CH2CI2 was slowly added to the reaction mixture and the stirring continued at the same temperature. After 2h. the solid was filtered and the Filtrate was poured into ice water. The mixture was extracted with ethyl acetate (2 x 25 mL). Tne combined organic layer was washed with 0.5 N HC1 (30 mL). water (30 mL) and brine (30 mL). The solvent was evaporated and the residue (250 mg) was subjected to silica column chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane were combined and the solvent evaporated to yield 3-O-(chloroacetyl)-ll-keto-β-bosweIlic acid (150 mg). Melting point: 126 - 132°C; 1H NMR (CDCI3): 5 0.81 (3H, d; J = 6.5 Hz, -CH3), 0.83 (3H, s, -CH3), 0.95 (3H, s, -CH3), 1.07 (3R s, -CH3), 125 (3H, s, -CH3), 2.11 (1H, m), 233 (1H, br t J = 12.7 Hz), 2.42 (1H, s), 2.56 (1H, d; J = 12.7 Hz), 4.09 (2R s, -CH2CI), 5.40 (1H,

WO 20ft5/123641» PCTIN2Wi4'] "6
br s, 3-H). 5.56 (1H, s. 12-H); F7-IR (neat): 3400 - 2700 (br). 2927. 2S65. 1735, 1708, 1658, 1457, 1286, 1198, 992 cm-]. LC-MS (positive mode): m/z 547 (M-H)+, 569 (M+Na)+. 1115 (2M+Na2)+
Example 3
3-O-(5'-O-rnethylgalIoyI)-11-keto S-boswellic acid (3): A solution of 1 i-kso-3-boswellic acid, (0.5%10.6mmoles tri-O-methyigallic acid. (357 mg. 1.6 mmol) and DMAP (60 mg) in 5 ml of: Dichloromethane was stirred at 0°C while a solurion of DCC (330 mg. 1.6 mmol) in CH2Cl2; (3 mL) was slowly added. The reaction mixture was stirred at 0°C for 1h, and at room temp for 30 min. The reaction mixture was filtered and the filtrate diluted with CH-CI3 (40 ml) and poured in to ice-water. The mixture was acidified with 0.1 N HCl and the layers separated. The organic layer was washed with water and brine, and dried over "Na2SO4 and evaporated. The residue ((830 mg) was purified on silica column using hexane/ethyl acetate mixtures. The gal late containing fractions, obtained on elution with 15% ethyl acetate/hexane were combined and evaporated to yield 3-O-(tri-O-methylgalloyI)-l 1-keto p-boswellic acid (580 mg, 82%).
To a mixture of A1C13 (590mg, 4.4 mrnol) and ClCH2CH2CI (5 mL), stirred at RT for 15 min was added dropwise during 20 min a CICH2CH2CI (2 mL) solution of 3-O-(5'-O-rnethylgalIoyI)-I I-keto S-boswellic acid (580 mg,0,87 mmol). After 3 h? the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with saturated NaHCOs9 water and brine, and then evaporated to obtain a residue, 30-(3'.5'-di-0-methyIgalioyI)-l 1-keto 3-boswellic acid (560 mg, 98%).
To a cooled mixture of 3-0-(3'5'-di-O-methylgaUoyl)-l 1-keto β-boswellic acid (200 mg, 0.31 mmol) and AICI3 (200 mg, 1.5 mmol) in CICH2CH2CI (2.5 mL) was slowly added pyridine (0.25 mL 3.1 mmol). The mixture was subjected to reflux for 3.5 h. The reaction mixture was poured into ice water, acidified with dilute HCl and extracted with ethyl acetate (2x15 mL). The combined organic layer was washed with brine, dried over "Na2SO4 and evaporated. The residue was subjected to silica column

WO 2005123649 PCI7LN2004/000176
chromatography using ethyl acetate/hexane mixtures. The fractions eluted with 20% and 25% ethyl acetate/hexane mixtures were evaporated to obtain 3-O-(5'-O-rnethylgalIoyI)-I I-keto β-boswellic acid (80mg, 41%). Melting point 128 - 136°C: 1H NMR (CDC13): 5 0.8 1 (3H. d: J = 6.3 Hz, -CH3), 0.84 (3R s, -CH3), 0.95 (3FL s, -CH3)? 122 (3H, s, -CHo. L23 «'3H? s. -CH3), 126 (3H, s. -CH3), 1-37 (3R sT -CH3)5 2.34 (1H. m), 2.49 (1H, s,. 2.62 (1H, d: J = 133 Hz), 3.93 (3H. s, 5'-OCH3). 5.52 (1H, brs. 3-HV5.57 (1H s, 12-H1, 7.25 OH, d; J = 1.5 Hz, 2f-H)s 7.30 (1R d; J - 1.5 Hz, 6'-H); IR (CHCi3): 3400 (br), 2926. 2S51. 1714, 1653. 1614, 1516, 1459, 1348, 1217, 1099. 1023 cm"1; LC - MS •■^negative mode) 635 (M-H)Example 4
3-O-Succinyl-ll-keto-β-boswellic Acid (4): A mixture of 1l-keto-β-boswellic acid (02 gm, 0.43 mmol), succinic anhydride (0262 gm, 2.62 mmol), DMAP (51 mg, 0.42 mmol) and pyridine ( 1mL) was stirred under reflux for 40 h. The mixture was poured into 20 ml of cold water and acidified to pH 4 with dil HC1 The solution was extracted with ethyl acetate (3 X 40ml) and the combined organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on a silica column eluting with hexane and ethyl acetate mixtures. The fractions eluted with 20% ethyl acetate/hexane were combined and evaporated to obtain the 3-O-succinyi-l l-keto-{3-bosweIlic acid (170 mg, 71%). Melting point: 172 - 176°C; 1H NMR (CD3OD): 5 0.78 (3H, d; J = 6.4 Hz, -CH3), 0.80 (3H, s, -CH3), 0.92 (3H, s, -CH3), 1.12 (3H, s, -CH3); 1.16 (3H, s, -CH3), 1.17 (3H, s, -CH3), 1.35 (3H, s, -CH3), 2.45 (1H, s), 2.46 (IR m)? 2J6 - 2.67 (4H3 m, -OCOCH2CH2COOH), 528 (1H, br s3 3-H), 5J0 (1H, s, 12-H). IR (KBr): 3600 - 2700 (br), 2926? 2855, 1735, 1708, 1656, 1456, 1417, 1385, 1202, 1164 cm"1. LC-MS (positive mode) rn/z 571 (M+H)+? 593 (M+Na)+, 609 (M+K)+.
Example 5 3-0-[8',9r-Dihydro-4'-hydroxycinnamoyI]-ll-ketoβ-boswellic acid (5):
3-O-(4'-BenzyloxycinnamoyI)-l 1 -keto-β-boswellic acid:
A mixture of 4-benzyloxycinnamic acid (250 mg) acid and thionyl chloride (02 ml) was
reflux for 30 min. Excess thionyl chloride was removed and the residue was dried under

WO 2005/123649 PCT.TN20M.'WK»l"
high vacuum. The residue was dissolved In dry dichloromethane (2.5ml) and added drop by drop to a mixture of 1l-keto-β-boswellic acid (400 mg). triethyl amine (0.7 ml) and DMAP (20 mg} in dichlorethsne (5 ml) After 2 hours, the mixture was diluted with ether (60 ml) and washed with water (2 X 20ml) and brine (20 mL), dried over Na2SO4 and evaporated. The rescue was subjected to column chromatography over silica gel using hexane/ethyl acetate mixtures as rlaniselvants. The fractions eluted with8-12% ethyl
keto-β-boswellic acid 160mg26%). H NMR (CDG3): 3 0.80 (3H. d: J = 5.4 Hz. -CK3), 0.82 (3H, E, -CH3; 0.95 =3.4. s. CH:3}. 1.15 (3rL s. -CH3). 1.19 T3H. s, -CH31. 1 -31 (3H, s, -CH3), 134 (3H, s, -CH3), 2.25 (JH, brt J = 10.7 Hz). 2.42 (1H, s). 2J5 (1H, brd; 13.1 Hz), 5.11 (2K, br s. -OCH3 Ph), 5.32 (1H, brs, 3-H), 5.56 (1H, s, 12-H). 6.31 (1H, d; J = 15.9 Hz, 8'-HX 6.99 (2H, d: J = 8.8 Hz, 375r-H). 7.50 (2H. d; J = 8.8 Hz, 276'-H), 7.73 (! H, d; J = 15.9 Hz. 9'-H). IR (CHCl3): 3431 (br), 2973, 2925. 2867, 1712, 1659, 1633. 1602. 1511, 1455. 1384, 1251, 1160, 999, 827, 734 cm"1: LC - MS (positive mode) m/z 729 (M+Na)+, 1435 (2M+Na)+.
Deprotection:
To a solution of 3-O-(4'-benzyloxycinnamoyl)-l l-keto-β-boswellc acid (100 mg) in 3 mL of ethanol in a 10 r mL R8 flask was added 10 mg of 10% palladium on carbon. The RB flask was flushed with H2 and the mixture was stirred under a positive H2 pressure using a balloon. After 24 h, the mixture was filtered over celite and the solvent evaporated. The residue was subjected to silica column chromatography using hexane/ethyl acetate mixtures. The fractions eluted with 10% ethyl acetate/hexane yielded 3-O-(8'9'-dihydro-4-hydroxycinnamoyl)-1l-keto-β-boswe!lic acid. Melting point: 168 -171=0; 1H NMR (CDC13): 5 0.82 (3H, s, -CH3), 0.83 (3H, d: i = 7.7 Hz, -CH3), 0.95 (3H. s. -CH3), 1.08 (3H, s. -CH3), 1.10 (3H, s, -CH3), 1.17 (3H, s. -CH3), 1.34 (3H. s, -CH3), 234 (1H. s), 2.43 (1H, brd: 13.1 Hz), 2.66 - 2.58 (2H, m, -OCOCH2CI±.Ar). 2.84 - 2.96 (2H, m, -OCOCH;CH:Ar), 5.24 (1H, brs, 3-H), 5.56 (1H, s. 12-H). 6.73 (2H. d; J = 8.2 Hz, 375'-H), 7.05 (2H, d; J = 8.2 Hz, 2V6'-H): IR (CHC13): 3433 (br). 2925. 2856, 1730, 1714. 1645, 1516. 1455, 1382, 1266, 768 cm'1; LC-MS (positive) m/z 619 (M+H)+, 641 (M+Na)+

WO 2005/123649 PCT/LN2004/000176
Example 6
3-0-{4'-HydroxycinnamoyI)-ll-keto-β-boswellic acid (6):A mixture of 3-G-(4'-bsnzylicinnamoyl)-ll-keto-β-boswellic acid (190 mg. 0.I4mmol). N,N-dimethylanilline (50 µl) and A1CI3 (50mg/ 0.42 mmol} in CHZC)Z (2 m.L) was stirred at room temperature for 48 h. The reaction mixture was poured into ice water, acidified with 2N HCI. and extracted with ethyl acetate. The organic layer was washed with brine, dried ever Na2SO4 and evaporated. The residue was purified over a silica column using eihyi aceiarehexane mixtures. The fractions eluted with 30% ethyl acetate/hexane mixture yielded 3-O-(4'-hydroxycinnamoy!)-11-keto-P-boswellic acid (15 mg) after evaporation.Melting point 180 - 185°C; IR (CHCI3): 3429 (br), 2926, 2854, 1721. 1656, 1600, 1457. 1379, 1267, 1164 cm"1; LC-MS (positive) m/z 617 (M+H)+, 639 (M+Na)+
Example 7
Preparation of 3-0-(3',4'-climethoxycinnamoyI)-ll-keto- β-boswellic acid (7): A solution of 11-keto-P-boswelIic acid, (500 mg, 1.06 mmoles). 3,4-dimethoxycinnamic acid, (332 mg, 1.59 mmol) in 4 ml of dichloromethane was stirred at 0°C, and treated slowly with DCC (495 mg, 2.39 mmol) in 3 mL of dichloromethane at 0°C. Then DMAP (60 mg) was added and the stirring continued at 15 - 20°C for 2h. The reaction mixture was filtered, the mother liquor diluted with CH2CI2 (40ml), washed water (30 mL) and brine (30 mL), and dried over Na2SO4 and evaporated. The residue (1.1 g) was purified on silica column using hexane/ethyl acetate mixtures. The cinnamate containing fractions, eluted with 25 - 30% ethyl acetate/hexane were combined and evaporated to obtain 3.-O-(3',4'-dimethoxycinnamoyl)-l 1-keto-β-boswellic acid (650 mg. 91%). Melting point: 146 - 150°C; lH NMR (CDC13): 5 0.83 {3H, d; J = 6.4 Hz, -CH3), 0.86 (3H, s, -CH3), 0.97 (3H, s, -CH3). 1.22 (3H, s. -CH3), \2A (3H, s, -CH3), L28 (3H, s, -CH3), 1-32 (3H, s5 -CH3), 2.34 (1H, m), 2.49 (1H, s), 2.62 (1H, brd; J = 9.4 Hz), 3.94 (3H, s, 3' or 4'-OCH3), 3.92 (3H. s. 4r or 3r-OCH3), 5.49 (1H, brs, 3-H), 5.59 (1H, s, 12-H), 6.36 (1H, d; J = 15.9 Hz, 8'-H), 6.89 (1R d; J = 8 Hz, 5'-H), 7.08 (1H, br s, 2'-H), 7.13 (1H d: J = 8.0 Hz, 6'), 7.66 (1H, brd; J= 15.9 Hz, 9;-H); IR (CHC13): 3406(br),

WO 20**123649 PCT7IN2O04/OO0I76
(CHCI3): 3356 (br), 2925, 2855, 1711, 1633, 1603, 1516. 1459. 1381. 1278. 772 cm'1. LC - MS (negative) m/z 661 (M-H)".
Example 9
Methyl 3-O- (N-BOC-glycyl)-ll-keto-β-boswellic acid hydrochloride (9): A mixture of 1 J-keto-β-boswellic acid methyl ester (130 mg, 0-27 mmol), N^'tert-butoxycarbonyl) giycine (61 mg. 0.34 m. moles and DCC (16 mg, 0.77 mmol) in dichioromelhane {4 ml) was cooled to 0°C- Tc this solution was added DMAP (35 mg) and the stirring continued at 0°C for I hour and at room temp for 48 h. The reaction mixture was filtered diluted with diethyl ether (40 ml) and washed with 0.1 N HC1. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica column using hexane and ethyl acetate mixtures as eluants. The fractions eluted with 14% ethyl acetate in hexane were evaporated to obtain methyl 3-O-(N-8OC-glycy!}-I I-keto-(3-bosweiiate (122 mg, 71%). Melting point: 126 - I30°C; 1H NMR (CDCI3): 5 0.80 (3H. d; J = 6.4 Hz, -CH3). 0.82 (3H, s, -CH3), 0.95 (3H, s, -CH3), 1.03 (3H, s, -CH3), 1.17 (6H, s, 2 x -CH3), 1.34 (3H, s,-CH3), I.44(9H, s,-C(CH3)3. 1-83- 1.93 (I H, m), 2.05 - 2.15 (IH, m), 2.18 - 2.28 (IH, m), 2.40 (1H, s), 2.53 (1H, brd; 13.0 Hz), 3.68 (3H, s, -OCH3), 3.94 (2H, s, 3-OCOCH2NH(CO)OC(CH3)3, 5.04 (1H, br sT 3-OCOCH2NH(CO)OC(CH3)3, 5.39 (IH. brs, 3-H), 5.54 (1H, s, 12-H). IR (KBr): 3419 (br), 2972. 2935, 2867, I729(br), 1663, 1517. 1460, 1375, 1172 cm"1 LC- MS (positive) m/z 664 (M+Na)+. 680 (M+K)+.
Example 10
3-O-Glycyl-1l-keto-β-boswelIic acid hydrochloride (10): A mixture of II-keto-|3- . boswellic acid (1 g. 2.12 mmol). BOC protected glycine (0.514 g, 3.19 mmol) and DMAP (120 mg) in dry CHaCI2 (9 mL) at 0°C was treated with DCC (0.68 g, 3.19 mmol) in CH2CI3: (4mL) under vigorous stirring. After 2 h, the reaction mixture was filtered and the filtrate was poured into ice water. The mixture was carefully neutralized with 0.1 N HCI and extracted with CH2CI2 (2 x 60 mL). The combined organic layer was washed with brine (40 mL), dried over Na2SO4 and evaporated to obtain crude 3-O-(N-BOC-glycyl)-l l-keto-{3-boswellic acid (1.52 g). The residue was subjected silica column chromatography using 5 - 20% ethyl acetate/hexane mixtures as eluents. The fractions

WO 2005/123649 PCT/L\2TY.
eluted with 15 % and 20% ethyl acetate/hexane mixtures yielded pure 3-0-(N-B0C-glycyl-11-keto-β-bosweliic acid (13 g, 92%). K NMR (CDC!;.): 5 0.81 (3H. d: J = 6.4 Hz, -CH3). 0.S2 (3H, s. -CH3). 0.95 (3H. s. -CH3). 1.15 (2H, s. -CH3), 1.19 (3H. s, -CH3), 1.23 (3H. s, -CH3). 134 BH. s. -CH3:-. 1.44 (9H s. -C(CH3)3,2.21 - 233 (1H. ml 2.40 (1H, s), 2.55 (IH. brd -2.5 Hz). 3.94 '2H. s, 3-OCOCH:NH(CO)OC(CH3,)3, 5.06 MH. br
A solution of 3-O(N-BOC-glycil-11-keto-β-boswellic acid (300 m.z) IT. I mL of CH2Ch cooled to 0°C was treated slowly with 1.5ml of 2.5 N HC3 in dioxane. After 30 min, the stirring was continued over night at room temperature. The reaction mixture was evaporated under vacuum and re-dissolved in 0.2 mL CH2CI2 and diluted with hexane (I mL). A white solid was precipitated. It was filtered, washed with hexane and dried to afford a white powder (219 mg). It was further purified over silica column using CH2CI2 and CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 yielded 3-O-glycyl-l 1-keto-p-bosweUic acid hydrochloride (I50mg). Melting point: 210 - 212°C; 1H NMR (CD3OD): 5 0.82 (3H, d; J = 6A Hz, -CH3), 0.86 (3H, s. -CH3), 0.97 (3H, s, -CH3), 1.17 (3H, s, -CH3), K21 (3H5 s, «CH3),.1.28 (3H, s. -CH3), 1.37 (3H, s, -CH3), 2.13 - 2.23 (IH, m), 2.27 - 2J8 (IH, m), 2.49 (IH, s), 2,56 (IH. brd: 13.4 Hz), 3.82 (2H. s, 3-OCOCH2NH2HCI). 5.42 (IH, brs. 3-H), 5.52 (IH. s. I2-H): IR (KBr): 3500 - 2400, 2979, 2928, 2868, 1721 (br), 1660, 1512, 1456, 1387, 1165. 1053 cm'1. LC-MS (positive ion mode): m/z 528 [(M-CI)4], 550 (M-HCI+Na) Example 11
3-O-Alanyl-ll-keto-β-boswellic acid hydrochloride (11): A mixture of il-keto-p-bosewellic acid (500 mg. 1.05 mmol), BOC protected alanine (320 mg. 1.69 nunof) and DMAP (75 mg) in dry CH-Cfe (5 mL) at 0°C in a 25 mL RB flask was treated with DCC (330 mg, 1.60 mmol) in CH2CI2 (2 mL) under vigorous stirring. After 30 min. the stirring was continued at room temperature for 2 h. The reaction mixture was filtered and the filtrate was poured into ice water. The mixture was carefully acidified or pH 5 with 0.1 N HCI. and extracted with CH2CI2 (2 x 60 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated to obtain 3-O-(N-BOC-alany)-11

WO 2005i23649 PCT/IN2004/000176
keio-H-boswellic acid. The residue (550 mg) was subjected silica column chroraiography using 5 - 20% ethyl acelate/hexane mixtures as eluents. The fractions eluted with 20% ethyl acetate/hexane mixture yielded 320 mg of pure 3-O-(N-BOC-alanyl)-11-keto-β-boswellic acid. 1H NMR (CDCI3) 5 0.81 (3H. d: J = 6.4 Hz. -CH3). 3.53 (3H. s. -CH3), 0-95 (3H. s. -CH3). 1.16 OH, s. -CH3). 1-20 (3K. s. -CH;)- 1.25 (3H. 5. -(CH3). 1.34 (3H, s, -CH3), 1.39 (3H, d: J = 7.1 Hz. 3-OCOCH CH3) NH(CO)OC(CH3)3), 1.43 (9H, s. -OCOCH CH3). 2.21 - 2.33 (1H. m). 2.40 (1H,s) 2.58 (1H. brd: 12.2 Hz), 4.27-4.42 (IH, s. 3-OCOCH(CH3);NH-,CO)OC(CH3)3, 5.3S {iH. br s. 3-OCOCH(CH3)NH(CO)OC(CH:,)3), 536 (1H. brs. 3-H). 5.56 (IH. s. 12-H); LC - MS (positive mode): m/z 655 (M+Na)+.
A solution of 3-O-(N-BOC-alanyl)-l l-keto-P-boswellic acid (200 mg) in 1 mL of CH2CI2 cooled to 0°C was treated slowly with 2.5 mL of 1 M HC1 in dioxane. After 30 min, the stirring was continued over night at room temperature. The reaction mixture was concentrated and subjected to column chromatography over silica gel using CH2CI2 and CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 mixture afforded a white powder (90 mg) of 3-O-alanyl-l l-keto-J3-boswellic acid hydrochloride. Melting point: 212-214°C; 1H MMR (CD3OD): 5 0.83 (3H, d: J = 6.2 Hz. -CH3), 0.86 (3H, s, -CH3), 0.97 (3H, s, -CH3), 1.17 (3H, s, -CH3), 1.22 (3H, 5. -CH3), 125 (3H, s, -CH3); 1.38 (3H, s, -CH3), 1-58 (3H, d; J = 6.3 Hz, 3-OCOCH(CH3)NH2HCn, 2.15-2.23 (1H, m)? 2.28-2.38 (1H, m), 2.50 (1H, s), 2.56 (1H, brd; 13.4 Hz). 4.15-4:23 (IH, s, 3-OCOCHlCH3)NH2HCl), 5.39 (1H, brs, 3-H), 5.53 (1H, s, 12-H): IR (KBr): 3500- 2600, 2980. 2928. 2870, 1725, 1710, 1663, 1515, 1452, 1390, "l161. 1051 cm"1. LC-MS (positive ion mode): m/z 542 (M-CI)\ 564 (M-HCH-Na)+.
Example 12
Methyl 3β-hydroxy-ll-ketours-12-en-24-oate (12): Methyl 3.11-dioxours-12-en-24-oate (100 mg) was dissolved in methanol (2 mL), cooled to 0°C and the solution was treated with NaBH4 (15 mg). After lh, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 20 mL). The combined extracts were washed with brine, dried over NaSO4 and evaporated. The residue was purified over silica using ethyl

WO 2**5.123649 PCT/IN2004/000176
0.71 mmol) in acetone (2 mL) was subjected to reflux for 2 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was evaporated and the residue was purified on silica column using hexane and ethyl acetate mixtures. The fractions elutcd with 20% ethyl acerate'hexane were combined and evaporated to yield methyl 3a-cyano-l I-ketours-12-en-24-oate (170 mg. 92%. Melting point: 150 - 152°C; 1HNMR (CDCI:.i: 5 u.Sl (3H. d: j = 5.5 Hz. -CH3). C.S2 (3H. s. -CH;0? 0.95 (3H d: J = 7.1 Hz, -CH3), 1-03 (3R s. -CH3). 1.17 (3H. s. -CH3).
1.25 (3H. s. -CH3). L25 (3H. s. -CH3\ 2.34/2.37 (!H. s\ 2.54 (IR hr m\ 3-63/3.67 (3H.
s, -OCH.;). 4.91 (IR dd; J = 14.7 and 7.7 Hz, 3-H), 5.53/5.54 (IR s. 12-H); IR (KBr):
3433 (br). 2978. 2925, 2859. 1724, 1664, 1459, 1383. -1235, 1197, 980 cm'1; LC-MS
(positive mode): m/z 493 (M+H)+.
Example 15
Methyl 3α-thiohydroxy-ll-ketours-12-en-24-oate (15): To a solution of KSR obtained by bubbling H2S through an ethanolic solution of KOH (350 mg in 10 mL), was added methyl 3(3-bromo-l l-ketours-12-en-24-oate (500 mg, 0.94 mmol) in 2 mL ethanol. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into ice-water and acidified with 2 N HC1 and extracted with ethyl acetate (3 x 30mL). The combined organic layer were washed with brine, dried over NajSO4 and evaporated. The residue was subjected to column chromatography over silica gei using hexane and ethyl acetate mixtures. The fractions eluted with 25% and 30% ethyl acetate/hexane mixtures were evaporated to obtain methyl 3α-thiohydroxy-11-ketours--12-en-24-oate (180 mg. 39%). Melting point: 226 - 230°C; *H NMR (CDCb): 5 0.80 (3R d; J = 6.5 Hz, -CH:). 0.82 (3H,s,-CH3), 0.95 (3H,s,-CH3), 1.01 (3Rs,-CH3)s 1.15 (3R s?-CH5),
1.26 (3H. s? -CH3), 1.34 (3H, s, -CH3). 3.66 (3H, s, -CH3), 4.76 (!R t; J = 13.2 Hz, 3-H)?
5.51 (lHr s, 12-H); IR (KBr): 3430 (br), 2979, 2925, 2867, 1725, 1662. 1458, 1383,
1237, 1118,975 cm*1.

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dried under high vacuum to obtain the methyl 3-oximino-l l-ketours-12-en-24-oate (130 mg.84.4%) as white solid. Melting point: 238 - 240°C; 1H NMR (CDC!3): 5 0-78 (3H. d; j = 6.3 Hz. -CH3). 0.82 (3H. s. -CH3). 0.94 (3H; s, -CH3), 1.17 (3H. s. -CH3). 1.19 (3H. s. -CH3), 1.26 (3H. s, -CH3), 1.45 (3H, s, -CH3), 2.03 - 2.13 (1H. m). 2-23 - 2.33 (1H. ml. 234 (1H. s), 2.S4 - 2.92 (1H. m), 3.25 - 3.33 (1H, m), 3.67 (3R s. 24-COOCH;). 5.56 (1H. s. 12-H). 7.5S (1H, br s. =NOH): 1R (CHCI3;): 3435. 297?. 2923, 2862. 1732. 1544, 1457, 1386, 1262, 1230, 941 cm-1: LC - MS (positive mode) mz 498 (M+H)+. 523 (M+Na)+,1017 (2M+Na)+.
Example 17
3-Acetoxy-ll-keto-24-norurs-12-ene (17): A mixture of methyl 3.11-diketours-12-en-24-oate (500 mg), lithium bromide (0.35 g) and pyridine (0.4 mL) in N,N-dimethylformamide (7 mL) was subjected to reflux over an oil bath on a magnetic stirrer. After six hours, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with 2N HCI followed by water and brine, and dried over Na2SO4. The solvent was evaporated and the residue (910 mg) was subjected to silica flash chromatography using hexane and ethyl acetate mixtures. The fractions eluted with 5% ethyl acetate/hexane were monitored by TLC and those containing the pure compound were combined and evaporated to obtain 3.11-diketo-24-norurs-12-ene as a semi solid. 1H NMR (CDCI3): 5 0.64 (1H, m), 0.80 (3H, d; J = 65 Hz, -CH3), 0.82 (3H, s, -CH3),0.94 (3H, s, -CH3), 0.99 (3H, d; 6.3 Hz, -CH3), 1.14 (3H, s. -CH3), 1.17 (3H, s, -CH3), L30 (3H, s, -CH3), 1.89 (1H, dt; 13.6 and 4.8 Hz), 2.09 (1H, dt; 13.5 and 4.8), 2.35 (IH? s)r 2.68 (IH, dt; 13.3 and 3.5), 3.09 (1H, dt; 10.1 and 5.99 Hz), 5.55 (IH, s? 12-H); IR (CHC13): 2926, 2870, 1710, 1662, 1615, 1457, 1384, 1200, 997 cm'1; LC - MS (positive mode) m/z 425 (M+H)+. 447 (M+Na)+, 871 (2M+Na)+.
The 3.11-diketo-24-norurs-12-er.e (230 mg) was dissolved in methanol (5 mL) and treated with NaBH4 (27 mg). After 30 min, the reaction mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL)- The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was subjected to column chromatography over silica gel using hexane/ethyl acetate mixtures. The fractions eluted

WO 2005/123649 PCTTN2 with 10% ethyl acetate/hexane were combined and evaporated to obtain 3-hydroxy-11-keto-24-norurs-12-ene (50 mg). It u-as dissolved in pyridine (0.1 mL) and treated with acetic anhydride (0.I mL; at room temperature. After 3 h, the mixture was soured into ice water (10 mL; and extracted with ethyl acetate (20 mL). The organic Saver was washed with brine, dried over Na2So4 and evaporated :c obtain 3-Acetoxy-l I-keto-24-norurs-12-ene.IRP-eneIRCHCI2, 2824,2859,1732,1654,1454,1379,1262,1242,975,885
cm-1:LC-MS positive mode mz 469 M+H)+491(M+Na)+ 959(2M+Na)+
Example 18
Preparation of (2'-N,N-(dimethylaminoethyl) 3-O-acetyI-ll-keto-β-bosweHate (18): A
suspension of 2-N,N-dimethy1aminoethylchloride (126 mg, 0.87 mmol), 3-O-acetyi-] 1-keto-(3-boswellic acid (300 rng. 0.58 inmoles) and sodium carbonate (124 mg? 0.S97 mmol) in acetone (5 m!) was stirred under refluxed at 60°C. After 2h, the mixture was diluted with ether (30 mL) and filtered. The ether solution was washed with brine, dried over Na2SO4 and evaporated. The residue was purified on a silica column using hexane/EtOAc and ethylacetate/melhanol mixtures. The fraction eluted with 10% methanol in ethyl- acetate gave 2'-N,N-dirnethylaminoethyi 3-O-acetyl-l l-keto-β-boswellie (153 mg, 45%). Melting point: 206-210°C; JHNMR (CDCI3): 5 0.80 (3H, d; J = 6.4 Hz. -CH3), 0.82 (3R s. -CH3), 0.94 (3H, s, -CH3), 1.02 (3R s, -CH3). 1.17 (3R s, -CH3), 1-19 (3H, s, «CH3)? 1-34 (3R s, -CH3), 2.09 (3H, s, -COCH3)3 2.41 (1H, s, 2.54 (1H, brd; 13,5 Hz), 2.91 (6H, s, 2 x N-CH3), 326 - 3.42 (2H, m. •OCH2CH2N(CH3)2)? 4.46 - 4.56 (1H, m -OCH-CH2N(CH3)2), 4.57 - 4.65 (IR m, -OCH-CH2N(CH3)2), 5.28 (1R br s, 3-H), 5.55 (IR s. I2-H): IR (KBr); 3446 (br). 2978, 2926r 2868. 1736, 1660, 1461, 1382, 1250. III3scin":: LC - MS (positive mode): m/z 584 (M+H)+
Example 19
3-O-Acetyl-ll-keto-β-boswellic acid amide (19): A mixture of 3-O-acetyl.11-keto-{3-boswellic acid (300 mg) and thionyl chloride (0-5 mL) was refluxed for Ih and the excess reagent was removed under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in THF (1.0 mL) and treated drop-wise with cone, ammonia solution (3.0 mL) at ice-cold Temp, for 5 min. and the mixture was stirred at the

WO 3*5.123649 PCT/IN2004/000176
same temp, for 1h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed successively with 0.2 N H2SO4. water and brine and then dried over sodium sulfate. The residue (350 mg) obtained after evaporation of the solvent was chromaiographed over silica gel column using methanol and dichloromethane mixtures. The fractions eluted with 15% methanol'CH2-CI2: furnished 3-O-acetyl-l1-keto-β-bosweliic acid amide (325 mg). Melting point: 162 - I70°C. IR (KBr): 3465 (br). 2978, 2925. 2S5S. 1736. 1662. 1459, 1378. 1252. 1200. 1025 cm~!; LC - MS (positive mode): m/z 512 (M+Na)+ 534 (M^ 550 (M+K)+ 1045 (2M+Na)+.
Example 20
N-(3-O-acetyI-ll-keto-P-bo^veIIoyI)-hydrazide (20): A mixture of 3-O-acetyl-I1-keto-β-boswellic acid (450 mg, 0.88 mmol) and thionyl chloride (0.62 mL) was subjected to reflux in an oil bath. After lh, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (3.0 mL) and treated slowly with hydrazine hydrate (265 mg, 5.3 mmol) at ice-cold temp, for 5 min. and the stirring was continued at the same temperature for 2h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (2 x 30 rnL). The combined organic layer was washed with 0.2N H2SO4 water and brine, and dried over sodium sulfate. The solution was filtered and the solvent evaporated to give the hydrazide, 20 (390 mg, 85%). Melting point: 190 - 192°C; !HNMR (CDCI3): 5 0.80 (3H d; J = 6.4 Hz, -CH3), 0.83 (3H,s-CH3),0.95(3H,s,-CH3), l.10(3H,s,-CH3), 1-15 (3H, s, -CH3), 1.20 (3H, s, -CH3), 1.35 (3H, s, -CH3), 2.09 (3H, s. CH3CO-X 2.24 - 2.34 (IK m). 2.41 (IH, s), 2.55 (IH, brd; 13.2 Hz), 3.86 (2H, brs, -CONHNH2), 5.34 (1H, brs, 3-H), 5.56 (1H, s, I2-H), 6.77 (1 H; brs, -CONHNH2); IR (KBr): 3600 - 2400 (br), 2925, 1737, 1662. 1459, 1377, 1252? 1201, 1023, 879; 808 cm"1; LC-MS (positive mode): m/z 527.6 (M+H)+, 549.6 (M+Na), 1076.1 (2M+Na)+.
Example 21
N-(3-0-Acetyl -1l-ketobosweHoyI)-ethylenediamine (21): A mixture of 3-O-acetyl-l 1-
keto-β-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL 9.4 mmol) was

WO 2005/123649 PCTTN2

subjected to reflux on an oil. bath. After lh. the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2: (4.0 mL); and treated slowly with ethylene diamine (351 mg. 5.85 mmol) at ice-cole temperature for 5 min and the stirring was continued at the same temperature for 1h. The reaction mixture was poured into ice-cold water and extracted with ethyl ether (2 x 30 ml The combined organic layer was washed with 0_2N H2SO4 water and brine, and dried over sodium sulphate- The solution was filtered and the solvent evaporated. The residue '500 mg. yield 92%) was subjected to silica column chromatography using CH3OH/CH2CI2 m.boures.The fractions eiuted with 10% CH3OH/CH2CI2 temperature N-(3-O-acetyl-11-keto-β-boswelloyl Vethylenediamine (440 mg) as a white solid. Making point: 198 - 202°C 1HNMR (CDCI3): 5 0.80 (3H, d: J = 6.4 Hz, -CH3), 0.82 (3H. s, -CH3), 0.95 (3H, s, -CH3)5 1.12 (3H, s. -CH3), 1.17 (3Hr s; -CH3), 1.19 (3H, s, -CH3K 134 (3R s, -CH3), 2.09 (3H, s, CH3CO-), 2.24 - 2.36 (1H, m),
2.41 (IH. s), 2.54 (1H, brd; 13.2 Hz), 2.87 - 2.96 (2H, m, -CONHCH2CH2NH2,) 3.28 -
3.41 (2H. m, -CONHCH2CH2NH2,), 5.33 (IH, brs3 3-H), 5.55 (IH. s, 12-H), 6.39 (IH,
brs, -CONHCH2CH2NH2); IR (KBr): 3430 (br), 2976, 2925, 2867, 1734, 1659, 1521, 1458, 1376, 1252, 1199, 1023 cm-1; LC-MS (positive mode): m/z 555 (M+H)+, 113
Example 22
N-(3-O-AcetyI-ll-keto- p-boswellie)-2-aminoethanol (22): A mixture of 3-O-acetyi-11-keto- β-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL 9.4 mmol) was subjected to reflux on an oil bath. After lh, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (4.0 mL) and treated slowly with etfaanol amine (350 uL, 5.86 mmol) at ice-cold temperature for 5 min. and the stirring was continued at the same temperature for 2 h. The reaction mixture was poured into ice-cold water and extracted with ethyl ether (2 x 30 mL). The combined organic layer was washed with 0.2 N H2SO4 (40mL). water (40 mL) and brine (40 mL). and dried over sodium sulfate. The solution was filtered and the solvent evaporated. The residue (570 mg) was crystallized from CH2CI2 to obtain pure N-(3-O-acetyI-l l-keto-β-boswelloyl)-2-aminoethanol (480

WO 21KJ5/123649 PCT/IN2004/000176
mg-89%) as a white solid. Melting point: 284 - 290cC 1H KMR (CDCh): 5 0.S1 (3H. .± J = 6.4 Hz, -CH3), 0.83 (3H. s. -CH3). 0.95 (3H, s. -CH3). 1.15 (3H. s, -CH;), 1-17 (3H. s. -CH;.). i-20 (3H, s, -CH3), 1.35 (3H. s. -CH3), 2.09 (3H. s, CH5CO-). 2.26 - 2.36 (!H. m) 2.42 (1H. s), 2.56 (1H. br d; 13.2 Hz). 3.37 - 3.49 (2H, m, -CONHCH:CH;OH\ 3.67 - 3.SG CH. m. -CONHCH^CHaOH). 5.33 (!H. brs, 3-H). 5.56 (IH. s. !2-H). 6.00 (IH. brs. -CONHCH:CH;OH); IR (KBr): 3430 (br), 2978, 2933, J 726. 5662. 1633. 1530. 1458. 1372. 1245. 1200. 1070. 1027. 991 cm"': LC - MS (positive mode): nvz 556 1M-H'f. 578 (M-s-Naf. 594 (M+K)+, 1133 (2M-Na;f.
Example 23
N-(3-O-AcetyI-ll-keto-β-boswelloyI)-pipcrzine (23): A mixture of 3-O-acety!-11-keto-B-boswellic acid (500 mg, 0.98 mmol) and thionyl chloride (0.7 mL, 9.4 mmol) was subjected to reflux on an oil bath. After Ih, the excess reagent was removed and dried under reduced pressure to give the corresponding acid chloride. This crude acid chloride was dissolved in CH2CI2 (4.0 mL) and treated slowly with piperzine (351 mg, 5.85 mmol) at ice-cold temperature for 5 min. and the stirring was continued at the same temperature for 2 h. The reaction mixture was poured into ice-coid water and extracted with ethyl ether (2 x 30 mL). The combined organic layer was washed with 0.2N H2SO4, water and brine, and dried over sodium sulfate. The solution was filtered and the solvent evaporated. The residue (620 mg) was subjected to silica column chromatography using CH3OH/CH2CI2 mixtures. The fractions eluted with 10% CH3OH/CH2CI2 yielded pure N-(3-O-acetyl-l l-ketoboswelloyl)-piperzine (500 mg. 88%) as a white solid. Melting point 180 - 184°C 'HNMR (CDCI3): 5 0.81 (3H, d; J = 6.4 Hz. -CH3), 0.83 (3H, s, -CH3), 0.95 (3R s, -CH3), 1.225 (3H, s, -CH3), 1.232 (3H, s. -CH3). 1.25 (3H, s, -CH3), 1.33 (3H. s. -CH3), 2.11 (3H, sr CH3CO-), 2.41 (IH, s), 2.54 (IH. brd; 13.4 Hz), 2.87 -3.01 [4H, m, -CON(CH2CH2)2NH], 3.57 [IH. br m, -CON(CH2CH2)2NH). 3.58 -3.68 [2H, m; CON(CH2CH2)2NH) 3.68 -3.79 [2H, m,CON(CH2CH2)2NH), 5.55 (1H. s, 12-H), 5.55 (1H, br s, 3-H); 1R (KBr): 3433 (br), 2982, 2925, 2863, 1737, 1657. 1457, 1377, 1247, 1209, 1021 cm"1; LC-MS (positive mode): m/z 581 (M+H)~. 13 61 (2M+H)+, 1183 (2M+Na)+.

WO 2005/123649 PCT.TN2O«*4'(KiOI '6
Example 24
3-acetoxy-11-keto-24-norus-12-en-4-isocyanate(24): A solution of NaOH (0.065 g) in water (0.6 rnL) was cooled to 0°C and Treated with bromine (0.022 mL). After 10 min. 3-O-acetyl-l I-keto-β-boswellic acid amide (C.;5 g) in acetone (0.5 rnL) was added to the NaO3r solution and the mixture was heated at TO - 75°C for 45 min. The reaction mixture was diluted with eryl ethyl (40ml); and washed with water (20 mL) and brine (30 mL) and dried over Na2So4 The solvent was evaporated and the residue was purified over silica get using hexanelethyl acetate mixtures- Fractions eiuted with 5% and 10% ethyl acetate/hexana mixtures -were monitored and those showing a yellow colored spot were combined and evaporated to give 3α-acetoxy-l I-keto-24-norurs-12-en-4-isocyanate as a white solid (70 mg). Melting point 170 - 176°C. IR (KBr): 2926, 2856,2267, 1744, !658, 1458, 1619, 1458. 1379, 1238, 1205, 1044"cm-1; LC-MS (positive mode) m/z5I0 (M+H)+? 532 (M+Na)+, 1041 (2M+Na)+.
Example 25
3a-Acetox7-4-amino-ll-keto-24-norurs-12-ene (25): A solution of NaOH (0.164 g) in water (0.8 mL) and dioxane (0.8 mL) was cooled to 0°C and treated with bromine (0.060 mL). To the resulting NaOBr solution was added, after 10 min. 3-0-acetyl 1-keto-P-bosweliic acid amide (0.4 g) in 1 mL dioxane and the mixture was heated at 65 - 75°C for 2h. The reaction mixture was poured into ice-water and the white precipitate was
filtered, washed with water and dried under vacuum to obtain 3α-acetoxy-4-amino-ll-keto-24-norurs-12-ene (250 mg). The mother liquor was extracted with dichloromethane (2 x 30 mL) and the organic fever was washed with water, brine and dried over Na2SO4. The solvent was evaporated and the residue was crystallized from hexane and ethy{ acetate mixture to give a further quantity of 3a-acetoxy-4-amino-l l-keto-24-norurs-I2-ene (50 mg). Melting point: 212 - 216°C; 1HNMR (CDCI3): 5 0.83 (3H, d; J = 7.0 Hz. -CH3), 0.84 (3H, s, -CH3), 0.97 (3H5 d; J = 7.1 Hz, -CH3), 1-22 (3Hr s, -CH5). 1.32
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Example 26
3α-AcetoxyT-4-cyano-ll-keto-24-norurs-12-ene (26): 3-0-Acetyl-l l-ketoboswellic acid amide (200 mg. 0.39 mmol) in ethylene dichloride (2 rnL) was treated with SOCK (0.04 mL 0.58 mmol) and the mixture was refluxed for 6 h. The mixture was poured into ice water and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water and brine, and dried over Na2So4 The solvent was evaporated and the residue (190 mg) was subjected to silica column chromatography using bexane/ethyl aceiaie mixtures. The fractions eluled with 10% hexane/erhyl acetate were evaporated to obtain 3a-acetoxy-4-cyano-l I-keto-24-norjrs-I2-ene (140 mg, 729',). Melting point: 214- 218°C; ; 'HNMR (CDC13): 5 0.8! (3H, d; J = 6.5 Hz, -CH3), 0.84 (5H, s, -CH3)? 0.95 (3R d; J = 7.1 Hz, -CH3), 1.24 (3H, s, -CH3)S 1.34 (3H, s, 2 x -CH3), 1.44 (3H, s, -CH3), 2.10 (3H, s, -OCOCHs), 2.20 (1H, m), 2.40 (1H, s), 2.67 (IH. br d; 13.6 Hz), 5.11 (IH, br s. 3-H), 5.57 (1H, s, I2-H); 1R (CHCI3): 2924. 2858, 1744, 1663, 1453, 1383, 1232, 1027; LC-MS (positive mode) m/z 494 (M+H)+, 516 (M+Na)+, 532 (M+K)+5 1009 (2M+Na)+.
Example 27
ll-Hydro]cy-P-bosewellic acid (27): Lithium aluminum hydride (30 mg? 0.96 mmol) was dispersed in THF and cooled in ice water bath. A solution of 1 l-keto-β-boswellic acid (150 mg, 0.32 mmol) in THF (2 mL) was slowly added to the above dispersion and the stirring continued in the ice water bath for 2h. The reaction mixture was diluted with ethyl acetate (2 mL) and after 5 minutes it was poured in to ice water. The mixture was carefully neutralized with 1 "N HC1 and extracted with ethyl acetate (3 x 25 mL). The combined organic layer was washed with water, brine, dried over Na2SO4 and evaporated. The residue was purified on silica column using hexane and ethyl acetate mixtures. The fractions eluted with 25% ethyl acetate/hexane mixture yielded 11-hydroxy-β-boswellic acid (70 mg). Melting point: 152 - 160°C 1HNMR (CDC13): 5 0.80 (3H d; J = 5.6 Hz, -CH3), 0.85 (3H, s, -CH3), 0.93 (3H, s, -CH3), 1 -07 (3H, s. -CH3), 1.10 (3R s, -CH3), 1.18 (3H, s, -CH3), 1.36 (3H, s, -CH3), 1.96-2.08 (IH, m), 2.15 (IH, brd; J= 13.3), 2.19-2.31 (1H, m), 4.08 (IH, brs), 4.26 lH,dd;J = 9.1 and 2.9 Hz, 11-

WO 20O5/123f>49
H), 5.18 (1H, d: J =2.9 Hz. 12-Hc FT - IR (neat): 3390. 2921, 2860, 1696. 1451. 1379. 1246. 1001 cm"1. LC-MS (negative mode): 471 (M-HT.
5-LOX ASSAY
The AK.BA analogs were screened for their 5-Lipexyger.ase inhibitory potential usir.g colorirnetric method of crag a gay et al. and Biockem., 304. 42 — 46. 2002;. The assay mixture combined 50 ml phosphate buffer pH 6.3.5-lipoxygenese.various ; concentrations of test subtances and neuclic acid in a total volume of 0.5 ml after 5 min incubation of above reaction mixure 0.5ml ferric xylenol orange reagent was Added and OD was measured after two minutes at 585 nm using spectrophotometer (varian). Controls were run along with test hi a similar manner except using vehicle Instead of test substance solution. Percent inhibition was calculated by comparing absorbance of test with that of control
BRINE SHRIMP LETHALITY ASSAY.
Brine shrimp lethality (BSL) assay is a simple bench top bioassay developed by McLaughlin, el. al.(Studies in Natural Product Chemistry, 9. page 383, 1991 and Am. Chem. Soc. Symp. Series. 534, page 114, 1992) and the results obtained by this assay have been reported to be corroborative with the cytotoxicities determined in 9KB and 9PS cells. The procedure involves hatching Artemia salina cysts in a cone shaped vessel and collecting active nauplii after 48 hr and treating with known concentrations of test substances and vehicle (control) in tubes each tube containing 10 nauplii and checking viability/mortality after 24 hr. Percentage lethality was calculated by comparing mean values of control 2nd test sets of three tubes each, LC50 values were obtained from the graph plotted micro moiar concentration against percent lethality.
The new analogs exhibited 5-Lipoxigenase inhibitory activities. The 5-Lipoxigsnase inhibitory activities of these analogs are summarized in table I. Consistent with the anti-proliferative actions reported for known bosweilic acid compounds, the analogs of the present invention inhibited the growth of Brine Shrimp in cultures, which is a possible

WO 249 PCT/IN2004/000176
indication for their antitumor activity. The Brine Shrimp inhibitory activity of these compounds is summarized in table II.

WO 200&123649 PCTTN2(>04' WE CLAIM:
1. Novel structural analogs of 3-O-acetyl-ll-keto-β-boswellic acid (AKBA) of the general formula I represented below.

wherein R1, R2, R3, R4 and R5 are as indicated herein below in each of said analogs:
1. R1, = OCHO,R2 = H, R3 = COOH, R4&R5 = O
2. R1, = OCOCH2CI, R2 = H, R3 = COOH, R4&R5 = O
3. R1 = 5'-O-methyIgoyioxy, R2 = H, R3 = COOH, R4&R5 = O
4. R1, = OCOCH2CH2COOH, R2 = H, R3 = COOH, R4&R5 = O
5. R1 = 8',9'-Dihydro-4'-hydroxycinnamoyloxy5 R2 = H, R3 = COOH, R4 & R5 = O
6. R1 = 4'-Hydroxycinnamoyloxy, R, = IL R3 = COOIL R4&R5 = O
7. R1 = 3'54'-Dimethoxycinnamoyloxy, R2 = H, R3 = COOK R» & R5 = O
8. R1 = 3\4'-Dihydroxy-5'-methoxycinnamoloxy, R2 = H, R3 = COOK, R* & R5 = O
9. R1 = OCOCH2NH(tert-BOC), R2 = H, R3 = COOCH3, R4&R5 = O
10. R1 = OCOCH2NH2KC1, R2 = H, R3 = COOH, R* & R5 = O
11. R1 = OCOCH2(CH3)NH2HC19 R2 = H, R3 = COOH, R4 & R5 = O
12. R1 = H, R2 = OR R3 = COOCH3, R4&R5 = O
13. R1 = Br, R2 = H, R3 = COOCH3, R4&R5 = O
14. R1 = CN, R2 = H, R3 = COOCH3, R4&R5 = O
15. R1, = SH, R2 = H, R3 = COOCH3, R4&R5 = O

16. R1. & R2 = N(OH), R3 = COOCH3; R4 & R4 = O
IT. R1 & R2= H & OCOCH3 R3 = H, R4 & R5 = O
18. R1& OCOCH3, R2 = H R3 = COOCH2CH2N(CH3) 2, R4 & R5 = O
19. R1 = OCOCH3, R2 = H R3 = CONH., R4 & R5 = O 26. R1 = OCOCH5, R2 = H, R3 = COMCsH2, R4 & R5 = O

21. R1 = OCOCH3; R2 = H, R3 = COKBCH2CH2KH2, R^ & R5 = O
22. R1 = OCOCH3; R2= H, R3 = COIvHCH2CH2OIL R4 & R5 R4 = O
23. R1 = OC0CH3, R2 = H, R3 = CON(CH2CH2) 2KP1R4 & R5 = O
24. R1 = OCOCH3, R2 = H R3 = NCO, R4 & R5 = O
25. R1 & OCOCH3, R2 = H R3 = NH2, R4 & Rs = O
26. R1 = OCOCH3, R2 = H R3 = CN, R4 & R5 = O
27. R1 = OH, R2 = H R3 = COOH, R4 & R5 = OH«&H

2. The boswellic acid analog as claimed in claim 1 wherein R2 is formyl group, R2 is H, R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula
3. The boswellic acid analog as claimed in claim 1 -wheR1en R1 is chloroacetoxy group. R3 is H, R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula

WO 2WJ5/123649 PCnN2M»4'«M*1"6
4. The boswellic acid analog as claimed in claim 1 wherein R1 is 5'-0-methyl galloyloxy group, R2 is H, R3 is Carboxylic acid group and R4 and R5 taken together form a keto group, said analog
5. The boswellic acid analog as claimed in claim 1 wherein R1 is succinyloxy (OCOCH2CH2COOH) group, R2 is H R3 is caiboxylic acid group, and R4 and R5 taken together form a keto group, said analog represented by structural formula

4
6. The boswellic acid analog as claimed in claim 1 wherein R1 is 8'9'-dihydro-4'- hydroxycinnamoyloxy group. R2 is H R3 is carboxylic acid group and R4 and R5 taken together form a keto group, said analog represented by structural formula

\*O 2 7. The boswellic acid analog as claimed in claim 1 wherein R1 is 4'-hydroxy cinnamoyloxy group. R2 is H, R3 is carboxylic acid group and R4 and R5 taken together fom a keto group, said analog represented by structural formula

6
8. The boswellic acid analog as claimed in claim 1 wherein R1 is 3'4'- dimethoxycinnamoyl group, R2 is H, R3 is carboxylic group, R4 and R5 taken together form a keto group, said analog represented by structural formula

9. The boswellic acid analog as claimed in claim 1 wherein R1 is 3'.4'-dihydroxy- 55-methoxycinnamoyloxy group, R2 is H, R3 is carboxylic acid group and R4 and R5 taken together to form a keto group, said analog represented by structural formula

WO 2005:123649 PCTTN2004'(*Hil*e>
10. The boswellic acid analog of the formula L as claimed in claim 1. where in R1. is OCOCH2NH(tert-BOC) group, R2 is rL R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represemed by the structural formula

11. The boswellic acid analog of the formula 1 as claimed in claim 1 where in R1 is OCOCH2NH2HCI group, R2 is EL R3 is carboxylic acid group and R4 and R5 taken together to form a keto group,
12. The boswellic acid analog of the formula 1, as claimed in claim 1, where in R1 is OCOCH(CH3)NH2HC1 group, R2 is H, R3 is carboxylic acid group and R- and R5 taken together to form a keto group, as represented by the structural formula

WO 2005/123649 PCT7IN 2004/000176
13. The boswellic acid analog of the formula 1 as claimed in claim 1, where in R1 is H, R2 is OIL R3 is carhoxylic acid STOUD and R4 and R5 taken together to form a keto group, as represented by the
14. The bosweilic acid analog of the formula 1 as claimed in claim 1, where in R1 is H, R2 is Br, R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula

15. The bosweilic acid analog of the formula 1, as claimed in claim 1, where in R1 is CN, R2 is H, R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula

WO 2005-123649 PCTflN2Mi4Wi0r6
16. The boswellic acid analog of the formula L as claimed in claim 1. where in KL is SH, R2 is R R3 is COOCH3 23d R4 and R5 taken together to form a ksiD group, as represented by the structural:
17. The boswellic acid analog of the formula 1, as claimed in claim 1 where in R1 and R2 are taken together to form oximino [:N(OH)] group. R3 is COOCH3 and R4 and R5 taken together to form a keto group, as represented by the structural formula

16
18. The boswellic acid analog of the formula I, as claimed in claim 1, where in R} and R2 are OCOCH3 and K R3 is ±L and R4 and R5 taken together to form a keto group, as represented by the slruound formula ^

1
WO 2005123649 PCT7IN2004/000176
19. The boswellic acid analog of the formula I, as claimed in claim 1, where in R1 is OCOCH3, R2 is H, R3 is COOCH2CH2N(CH3) 2 and R4 and R5 taken together 10 form a keto group, as represented by the structural formula _.

LV
20. The boswellic acid analog of the formula 1, as claimed in claim 1, where in R1 is OCOCH3, R2 is H5 R3 is CONH2 and R4 and R5 taken together to form a keto group, as represented by the
21. The boswellic acid analog of the formula 1, as claimed in claim 1. where in R1 is OCOCH3, R2 is H, R3 is CONHNH2 and R4 and R5 taken together to form a keto group, as represented by the structural formula _

WO 21*05 123649 PCTTN20(U'IH*I'*
22. The boswellic acid analog of the formula 1. as claimed in claim 1. where in R1 is OCOCH3, R2 is H, R3 is CONHC&CHrNHi and R4 and R5 taken together to form a keto group, as represented
23. The boswellic acid analog of the formula 1. as claimed in claim 1, where in R1 is OCOCH3, R2 is H, R3 is CONHCH2CH2OH, and R4 and R5 taken together to form a
keto group, as represented
24. The boswellic acid analog of the formula 1, as claimed in claim 1 where in R1 is OCOCH3, R2 is H, R3 is CON(CH2CH2) 2NH, and R4 and R5 taken together to form a keto group, as represented by the structural formula

WO *K*/123649 PCT/TN2004/000176
25. The bosweilic acid analog of the formula I, as claimed in claim L where in R1 is OCOCH3. R2 is EL R3 is NCO and R4 and R5 taken together 10 form a keto group, as represented by the
24
26. The boswellic acid analog of the formula I, as claimed in claim 1, where in R1 is OCOCH39 R2 is H, R3 is NH2 and R4 and R5 taken together to form a keto group, as represented by the
27. The boswellic acid analog of the formula L as claimed in claim 1, where in R2 is OCOCH39 R2 is H, R3 is CN and R4 and R5 taken together to form a keto group, as represented by the

WO 20G5/123649 PCTIN2(KU'(HHil"6
28. The bosweilic acid analog of the formula I. as claimed in claim 1, where in mL is OH, R2 is £L R3 is COOHby the srucnsrci formula
29. A process for prepaR1ng boswellic acid analogs represented by structural formula 2-11 compR1sing the steps of coupling 3-keto bosweilic acid (KBA) or its ester with an organic acid in the presence of 1,3-dicyclohexyl carbominide and 4- (dimethyl amino) pyR1dine as coupling agent
30. A process for prepaR1ng bosweilic acid analogs represented by structural formula 12-15 compR1sing the steps of treating methyl ester of 3 keto bosweilic acid with phosphorus tR1bromide to displace the 3 oc OH group by Br and further treating
the same with a nucleophillic agent to displace the Br group with SH\ CN and the like
31. A process for prepaR1ng bosweilic acid analogs represented by structural formula 19 -23 compR1sing the step of treating fee acid chloR1de of AKBA wiih excess of amine in a solvent medium
32. A process for prepaR1ng novel analogs of 3-0-acety11-keto-β-bosweliic acid of the general formula I substantially as herein descR1bed with reference to The examples.

WO 2005123649 PCTYIN2004/000176
33. A pharmaceutical composition compR1sing at least one boswellic acid analogs as claimed in claim 1 in a pharmaceutically acceptable carR1er.
34. The pharmaceutical composition as claimed in claim 33 wherein said carR1er is an aqueous or non-aqueous carR1er.
35. Use of boswellic acid analogs represented by the general formula I as anti- inflammatory and antitumor agents.
36. A method treating of inflammatory and tumor diseases compR1sing the steps of administeR1ng boswellic acid analogs of the general formula I to persons in need thereof.

Documents:

0805-chenp-2006 complete specification as granted.pdf

805-CHENP-2006 CORRESPONDENCE OTHERS.pdf

805-CHENP-2006 CORRESPONDENCE PO.pdf

805-CHENP-2006 FORM-2.pdf

805-CHENP-2006 FORM-3.pdf

805-CHENP-2006 FROM-18.pdf

805-CHENP-2006 POWER OF ATTORNEY.pdf

805-CHENP-2006 PETITION.pdf

805-chenp-2006-abstract.pdf

805-chenp-2006-claims.pdf

805-chenp-2006-correspondnece-others.pdf

805-chenp-2006-description(complete).pdf

805-chenp-2006-form 1.pdf

805-chenp-2006-form 3.pdf

805-chenp-2006-form 5.pdf

805-chenp-2006-pct.pdf

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Patent Number

234751

Indian Patent Application Number

805/CHENP/2006

PG Journal Number

29/2009

Publication Date

17-Jul-2009

Grant Date

15-Jun-2009

Date of Filing

06-Mar-2006

Name of Patentee

GOKARAJU, Ganga, Raju

Applicant Address

40-15-14 Brindavan Colony, Vijayawada 520 010, Andhra Pradesh

Inventors:

#	Inventor's Name	Inventor's Address
1	GOKARAJU, Ganga, Raju	40-15-14 Brindavan Colony, Vijayawada 520 010, Andhra Pradesh
2	GOKARAJU, Rama, Raju	40-15-14 Brindavan Colony, Vijayawada 520 010
3	GOTTUMUKKALA, Venkata, Subbaraju	Lakshmisurya, A-16, Nalanda Nagar, Tirupati 517 502
4	GOLAKOTI, Trimurtulu	54-16-3/6A (I Floor), Aditya Buildings, Loyola Gardens, Vijayawada 520 008.

PCT International Classification Number

C07C 61/12

PCT International Application Number

PCT/IN2004/000176

PCT International Filing date

2004-06-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA