# Patent

## Title
Amidobenzothiazoles and process for the preparation thereof

## Abstract

The present invention provides a compound of general formulae A useful as potential anti-cancer agents against human cancer cell lines and a process for the preparation thereof. Where in R, R1, R2═H, alkyl, alkoxy, halo, haloalkyl, halomethoxy, nitro and G=




Where in R, R1, R2═H, alkyl, alkoxy, halo, haloalkyl, halomethoxy, nitro and G=

## Background
FIELD OF THE INVENTION
The present invention relates to amidobenzothiazoles of general formula A




wherein R, R1, R2═H, alkoxy, halo, haloalkyl, halomethyl or nitro and

G=





and structural formula of the representative compounds are:





Present invention further relates to amidobenzothiazoles of general formula A as anticancer agents and process for the preparation thereof.
Present invention further relates to olefine, chalcone, pyrazoline, pyrazole, isoxazoline and isoxazoles linked to aminobenzothiazoles with amide bond useful as anticancer agents.
BACKGROUND OF THE INVENTION
Inhibition of tubulin polymerization is the target of many antitumoural agents known as antimitotic agents or spindle poisons colchicines, podophyllotoxins and combretastatins are representative examples of compounds that inhibit microtubule assembly by binding to tubulin. Benzothiazoles are small synthetic molecules that contain a benzene ring fused to a thiazole ring. These simple molecules have shown remarkable anti-cancer properties and some of them are undergoing, evaluation in clinical trials (Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld, P.; Fichtner, I.; Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375; Kashiyama, E.; Hutchinson, I.; Chua, M.-S.; Stinson, S. F.; Phillips, L. R.; Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 1999, 42, 4172; Hutchinson, I.; Chua, M.-S.; Browne, H. L.; Trapani, V.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2001, 44, 1446). Recently Westwell and coworkers have prepared a series of benzothiazole derivatives and evaluated for anticancer activity, One of these analogues has shown excellent anticancer activity (Mortimer, C. G.; Wells, G.; Crochard, J.-P.; Stone, E. L.; Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Med. Chem. 2006, 49, 179). Many chalcone, pyrazoline, isoxazole and isoxazoline type moieties related to combretastain A-4 showed potential biological properties particularly anticancer activity (Sylvie Ducki, David Rennison, Meiko Woo, Alexander Kendall, Jérémie Fournier Dit Chabert, Alan T. McGown, Nicholas J. Lawrence. Bioorg. Med. Chem, Vol 17, 22, 2009, 7698-7710; Regan LeBlanc, John Dickson, Toni Brown, Michelle Stewart, Hari N. Pati, Don VanDerveer, Hadi Arman, Jeff Harris, William Pennington, Herman L. Holt Jr., Moses Lee. Bioorg. Med. Chem, Volume 13, 21, 2005, 6025-6034; Marlie Johnson, Brent Younglove, Lauren Lee, Regan LeBlanc, Herman Holt Jr., Patrice Hills, Hilary Mackay, Toni Brown, Susan L. Mooberry, Moses Lee. Bioorg. Med. Chem Lett, Vol 17, 21, 2007, 5897-5901; B. A. Bhat, K. L. Dhar, S. C. Puri, A. K. Saxena, M. Shanmugavel, G. N. Qazi. Bioorg. Med. Chem Lett, Vol 15, 12, 2005, 3177-3180; Simoni, D.; Grisolia, G.; Giannini, G.; Roberti, M.; Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.; Romagnoli, R.; Invidiata, F. P.; Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.; Crosta, L.; Abbadessa, V.; DiCristina, A.; Dusonchet, L.; Meli, M.; Tolomeo, M. J. Med. Chem. 2005, 48, 723, Julia Kaffy, a Rene'e Pontikis, a, Danie'le Carrez, b Alain Croisy, Claude Monnereta and Jean-Claude Florent. Bioorg. Med. Chem. 2006, 14, 4067-4077, Gian Ceasure Tron, Tracy Pirali, Giovanni sorba, Francesca pagliai, Sara Buasacca and Armado A. Genazzani. J. Med. Chem. 2006, 49, 3033-3044. and Tracey Pirali, Sara buasacca, Lorena Beltrami, Daniela Imovilli, Francesca Paliai, Gianluca Migilio, Alberto Massrotti, Luisella Verotta, Gian Cesare Tron, Givanni Sorba, and Armado A. Genazzani. J. Med. Chem. 2006, 49, 5372-5376). Some of the heterocyclic bridged Combretastains showed an attractive profile of cytotoxicity and were able to induce apoptosis at lower concentrations.







OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide amidobenzothiazole of general formula A useful as anti-cancer agents.
Yet another object of the present invention is to provide a process for the preparation of amidobenzothiazole of general formula A.
SUMMARY OF THE INVENTION
Accordingly, present invention relates to amidobenzothiazole of general formula A




wherein R, R1, R2═H, alkoxy, halo, haloalkyl, halomethyl or nitro and

G=





In an embodiment of the present invention, chemical formulas of the representative compounds are:

    N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8e);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8f);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8v);
    N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9c);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9i);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9v);
    N1-(1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10c);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10f);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxyacetamide (10u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxyacetamide (10v);
    N1-(1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11c);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11f);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (11t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxyacetamide (11u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-1H-5-pyrazolyl]-2-methoxyphenoxyacetamide (11v);
    N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12c);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12f);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-Methoxy-5-[3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-5-isoxazolyl]-2-methoxyphenoxy}acetamide (12v);
    N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13a);
    N1-(6-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13b);
    N1-(6-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13e);
    N1-(6-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13d);
    N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13e);
    N1-(6-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13f);
    N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13g);
    N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13h);
    N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13i);
    N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13j);
    N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13k);
    N1-(5-nitro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13l);
    N1-(5-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13m);
    N1-(5-ethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13n);
    N1-(5-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13o);
    N1-(5-chloro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13p);
    N1-(5-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13q);
    N1-(5-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13r);
    N1-(5-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13s);
    N1-(5-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxy phenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13t);
    N1-(5,6-dimethyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13u);
    N1-(5,6-difluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[3-(3,4,5-trimethoxyphenyl)-5-isoxazolyl]-2-methoxyphenoxy}acetamide (13v).









TABLE 1







Showing the amidobenzothiazoles formed by reacting


compounds 7(a-v) with compounds 1-6:










Comp. No.
















7(a-v)/1-6
1
2
3
4
5
6







7a
8a
9a
10a
11a
12a
13a



7b
8b
9b
10b
11b
12b
13b



7c
8c
9c
10c
11c
12c
13c



7d
8d
9d
10d
11d
12d
13d



7e
8e
9e
10e
11e
12e
13e



7f
8f
9f
10f
11f
12f
13f



7g
8g
9g
10g
11g
12g
13g



7h
8h
9h
10h
11h
12h
13h



7i
8i
9i
10i
11i
12i
13i



7j
8j
9j
10j
11j
12j
13j



7k
8k
9k
10k
11k
12k
13k



7l
8l
9l
10l
11l
12l
13l



7m
8m
9m
10m
11m
12m
13m



7n
8n
9n
10n
11n
12n
13n



7o
8o
9o
10o
11o
12o
13o



7p
8p
9p
10p
11p
12p
13p



7q
8q
9q
10q
11q
12q
13q



7r
8r
9r
10r
11r
12r
13r



7s
8s
9s
10s
11s
12s
13s



7t
8t
9t
10t
11t
12t
13t



7u
8u
9u
10u
11u
12u
13u



7v
8v
9v
10v
11v
12v
13v










In yet another embodiment of the present invention, structural formulas of the representative compounds 8-13 (a-v) are:











































In yet another embodiment of the present invention, said compounds are useful as anti-cancer agents.
In yet another embodiment of the present invention, said compounds exhibit an in vitro anticancer activity against human cancer cell lines selected from the group consisting of leukemia cancer cell lines, non-small cell lung cancer cell lines, colon cancer cell lines, CNS cancer cell lines, melanoma cancer cell lines, ovarian cancer cell lines, renal cancer cell lines, prostate cancer cell lines and breast cancer cell lines.
In yet another embodiment of the present invention, process for the preparation of amidobenzothiazole of general formula A comprising the steps of:

    
    
        i. reacting 2-aminobenzothiazoles of formula 7a-v with a compound selected from formulae 1, 2, 3, 4, 5 and 6 in an organic solvent in the presence of EDC (1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide) and 1-hydroxy-1,2,3-benzotriazole(HOBt) at a temperature in the range of 25 to 30° C. for a period in the range of 22 to 24 hrs;
    
    






    
    
        ii. adding water in the mixture as obtained in step (i) and extracting with organic solvent and evaporating the organic solvent to obtain the resultant crude product;
        iii. purifying crude product as obtained in step (ii) by column chromatography to obtain the desired products of formulae 8a-v, 9a-v, 10a-v, 11a-v, 12a-v and 13a-v.
    
    


In yet another embodiment of the present invention, organic solvent used is selected from the group consisting of dichloromethane, chloroform or N,N-dimethylformamide.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against leukemia cancer cell lines is in the range of 0.037 to 29.9 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8a, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against non small cell lung cancer cell lines is in the range of 0.038 to 50.3 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against colon cancer cell lines is in the range of 0.046 to 94.8 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against CNS cancer cell lines is in the range of 0.045 to 18.8 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8a, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against melanoma cancer cell lines is in the range of 0.019 to 89.2 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g; 9i, 9j and 10i) used for in vitro activity against ovarian cancer cell lines is in the range of 0.033 to 91.6 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against renal cancer cell lines is in the range of 0.05 to 100 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i) used for in vitro activity against prostate cancer cell lines is in the range of 0.18 to 22.9 μM.
In yet another embodiment of the present invention, GI50 values of the compounds (8a, 8e, 8g, 8i, 8j, 9a, 9e, 9a, 9i, 9j and 10i) used for in vitro activity against breast cancer cell lines is in the range of 0.051 to 58.5 μM.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents the flow diagram for the preparation of compound 1. Wherein reagent and conditions are i) TBDMS-Cl, TEA, DMF; ii) NaBH4, MeOH; iii) LiBr, THF; iv) PPH3, toluene; v) n-BuLi, THF, −20° C., trimethoxy benzaldehyde; vi) TBAF, THF; vii) 2-bromoethyl acetate, K2CO3, DMF; viii) LiOH, THF, H2O
FIG. 2 represents the flow diagram for the preparation of compound 2.
FIG. 3 represents the flow diagram for the preparation of compound 3.
FIG. 4 represents the flow diagram for the preparation of compound 4.
FIG. 5 represents the flow diagram for the preparation of compound 5. Wherein reagent and conditions are i) NH2OH.HCl, NaHCO3, H2O ii) CH3P(Ph)3+Br−, KOtBu, THF; iii) NaOCl, Et3N, DCM; iv) TBAF, THF; v) 2-bromoethyl acetate, K2CO3, DMF; vi) THF, H2O.
FIG. 6 represents the flow diagram for the preparation of compound 6. Wherein reagent and conditions are i) NH2OH.HCl, NaHCO3, CH3OH, H2O ii) CBr4, PPh3, DCM; iii) n-BuLi, THF, −78° C.; iii) NaOCl, Et3N, DCM; iv) TBAF, THF; v) 2-bromoethyl acetate, K2CO3, DMF; vi) LiOH, THF, H2O.
FIG. 7 represents the flow diagram for the preparation of compound 8-13(a-v).


DETAILED DESCRIPTION OF THE INVENTION
The precursors 2-aminobenzothiazoles of formula 7a-v are commercially available and the precursors combretastatin, chalcone, pyrazoline, pyrazole, isoxazoline and isoxazole of formulae 1, 2, 3, 4, 5 and 6 have been prepared using literature methods or as shown in schemes (Sylvie Ducki, David Rennison, Meiko Woo, Alexander Kendall, Jérémie Fournier Dit Chabert, Alan T. McGown, Nicholas J. Lawrence. Bioorg. Med. Chem, Vol 17, 22, 2009, 7698-7710; Regan LeBlanc, John Dickson, Toni Brown, Michelle Stewart, Hari N. Pati, Don VanDerveer, Hadi Arman, Jeff Harris, William Pennington, Herman L. Holt Jr., Moses Lee. Bioorg. Med. Chem, Volume 13, 21, 2005, 6025-6034; Marlie Johnson, Brent Younglove, Lauren Lee, Regan LeBlanc, Herman Holt Jr., Patrice Hills, Hilary Mackay, Toni Brown, Susan L. Mooberry, Moses Lee. Bioorg. Med. Chem Lett, Vol 17, 21, 2007, 5897-5901; B. A. Bhat, K. L. Dhar, S. C. Puri, A. K. Saxena, M. Shanmugavel, G. N. Qazi. Bioorg. Med. Chem Lett, Vol 15, 12, 2005, 3177-3180; Gian Ceasure Tron, Tracy Pirali, Giovanni sorba, Francesca pagliai, Sara Buasacca and Armado A. Genazzani. J. Med. Chem. 2006, 49, 3033-3044. and Tracey Pirali, Sara buasacca, Lorena Beltrami, Daniela Imovilli, Francesca Paliai, Gianluca Migilio, Alberto Massrotti, Luisella Verotta, Gian Cesare Tron, Givanni Sorba, and Armado A. Genazzani. J. Med. Chem. 2006, 49, 5372-5376; Julia kaffy, Renee Pontikis, Daniele Carrez, Alain Croisy, Claude Monneret and Jean-Claude Florent. Bioorg. Med. Chem. 2006, 14, 4067-4077, Simoni, D.; Grisolia, G.; Giannini, G.; Roberti, M.; Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.; Romagnoli, R.; Invidiata, F. P.; Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.; Crosta, L.; Abbadessa, V.; DiCristina, A.; Dusonchet, L.; Meli, M.; Tolomeo, M. J. Med. Chem. 2005, 48, 723).
These new analogues of olefine, chalcone, pyrazoline, pyrazole, isoxazole and isoxazoline linked amidobenzothiazole have shown promising anticancer activity in various cancer cell lines. The molecules synthesized are of immense biological significance.
EXAMPLES
The following examples are given by way of illustration and therefore should not be construed to the present limit of the scope of invention.
Example 1
N1-(1,3-Benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8a)
To a solution of 2-aminobenzothiazole (150 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 1.0 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8a) (395 mg, 80% yield).
1H NMR (CDCl3): δ7.74-7.82 (m, 2H), 7.37-7.44 (m, 1H), 7.29 (d, 1H, J=8.3 Hz), 6.96-7.01 (d, 1H, J=8.3, 2.2 Hz), 6.93 (d, 1H, J=2.2 Hz), 6.82 (d, 1H, J=8.3 Hz), 6.46 (d, 1H, J=12.0 Hz), 6.38-4.30 (m, 3H), 4.60 (s, 2H), 4.02 (s, 3H), 3.83 (s, 3H), 3.69 (s, 6H); ESIMS: 507 (M+1)+.
Example 2
N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (8e)
To a solution of 6-fluoro-2-aminobenzothiazole (168 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid(1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using, ethyl acetate and hexane as solvent system to obtain the pure product (8e) (375 mg, 70% yield).
1H NMR (CDCl3): δ 7.71-7.76 (m, 1H), 7.47-7.53 (dd, 1H, J=8.1, 2.4 Hz), 7.13-7.20 (m, 1H), 7.00-7.04 (dd, 1H, J=8.1, 1.6 Hz), 6.93 (d, 1H, J=1.6 Hz), 6.83 (d, 1H, J=8.1 Hz), 6.46-6.51 (m, 3H), 6.44 (d, 1H, J=12.2 Hz), 4.63 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.70 (s, 6H); ESIMS: 525 (M+1)+.
Example 3
N1-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxy phenyl)-1-ethenyl]phenoxy}acetamide (8i)
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic ac id (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80% yield)
1H NMR (CDCl3): δ 8.12 (s, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.69-7.75 (m, 1H), 7.01-7.06 (dd, 1H, J=8.3, 1.7 Hz), 6.95 (d, 1H, J=1.7 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.43-6.53 (m, 1H), 4.68 (s, 2H), 3.99 (s, 3H), 3.83 (s, 3H), 3.70 (s, 6H); ESIMS: 575 (M+1)+.
Example 4
N1-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxy phenyl)-1-ethenyl]phenoxy}acetamide (8j)
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield)
1H NMR (CDCl3): δ 7.80 (d, 1H, J=8.8 Hz), 7.69 (s, 1H), 7.29-7.36 (dd, 1H, J=8.4, 2.2 Hz), 7.01-7.06 (dd, 1H, J=8.4, 1.7 Hz), 6.95 (d, 1H, J=1.7 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.42-6.53 (m, 4H), 4.65 (s, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.70 (s, 6H); ESIMS: 591 (M+1)+
Example 5
N1-(4-methyl-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetamide (9k)
To a solution of 4-methyl-2-aminobenzothiazole (164 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9k) (440 mg, 80% yield)
1H NMR (CDCl3): δ 10.71 (br s, 1H), 7.76 (d, 1H, J=15.4 Hz), 7.65-7.70 (m, 1H), 7.32-7.43 (m, 4H), 7.28 (s, 2H), 7.22-7.26 (m, 1H), 7.02 (d, 1H, J=8.4 Hz), 4.86 (s, 2H), 4.09 (s, 3H), 3.96 (s, 6H), 3.94 (s, 3H), 2.67 (s, 3H); ESIMS: 549 (M+1)+.
Example 6
N1-(6-ethoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetamide (9h)
To a solution of 6-ethoxy-2-aminobenzothiazole (194 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9h) (452 mg, 80% yield).
1H NMR (CDCl3): δ 7.75 (d, 1H, J=15.8 Hz), 7.70 (d, 1H, J=9.0 Hz), 7.36-7.41 (m, 2H), 7.29-7.34 (m, 2H), 7.25-7.28 (m, 3H), 7.01 (d, 1H, J=8.3 Hz), 4.84 (s, 2H), 4.06-4.15 (q, 2H), 4.04 (s, 3H), 3.96 (s, 6H), 3.95 (s, 3H), 1.46 (t, 3H); ESIMS: 565 (M+1)+.
Example 7
N1-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9i)
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80% yield)
1H NMR (CDCl3): δ 10.74 (br s, 1H), 8.11 (s, 1H), 7.87 (d, 1H, J=8.3 Hz), 7.64-7.74 (m, 2H), 7.28-7.40 (m, 3H), 7.22 (s, 2H), 6.99 (d, 1H, J=8.3 Hz), 4.84 (s, 2H), 4.09 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS: 603 (M+1)+.
Example 8
N1-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (9j)
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9j) (498 mg, 80% yield)
1H NMR (CDCl3): □□10.62 (br s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.66-7.73 (m, 2H), 7.27-7.39 (m, 3H), 7.24 (d, 1H, J=15.1 Hz), 7.22 (s, 2H), 6.98 (d, 1H, J=8.3 Hz), 4.83 (s, 2H), 4.07 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS: 619 (M+1)+.
Example 9
N1-(1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10a)
To a solution of 2-aminobenzothiazole (359.37 ma, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 ma, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10a) (472 mg, 80% yield)
1H NMR (CDCl3): δ 7.73-7.81 (m, 2H), 7.40 (t, 1H), 7.29 (d, 1H, J=7.3 Hz), 6.92-6.97 (m, 1H), 6.85-6.91 (m, 4H), 5.44-5.53 (dd, 1H, J=11.7, 4.5 Hz), 4.69 (s, 2H), 3.99 (s, 3H), 3.90 (s, 6H), 3.86 (s, 3H), 3.64-3.76 (dd, 1H, J=11.8, 17.3 Hz), 3.04-3.14 (dd, 1H, J=17.3, 4.5 Hz), 2.40 (s, 3H); ESIMS: 591 (M+1)+.
Example 10
N1-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10i)
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10i) (528 mg, 80% yield).
1H NMR (CDCl3): δ 10.82 (br s, 1H), 8.11 (s, 1H), 7.88 (d, 1H, J=7.9 Hz), 7.67-7.70 (m, 1H), 6.98-7.02 (dd, 1H, J=7.9, 1.6 Hz), 6.96 (s, 2H), 6.90-6.94 (m, 2H), 5.51-5.56 (dd, 1H, J=11.9, 3.9 Hz), 4.79 (s, 2H), 3.99 (s, 3H), 3.91 (s, 6H), 3.89 (s, 3H), 3.71-3.79 (dd, 1H, J=11.9, 17.5 Hz), 3.10-3.15 (dd, 1H, J=17.5, 4.7 Hz), 2.43 (s, 3H); ESIMS: 659 (M+1)+.
Example 11
N1-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (10j)
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10j) (531 mg, 80% yield).
1H NMR (CDCl3): δ 10.71 (br s, 1H), 7.79 (d, 1H, J=8.3 Hz), 7.69 (d, 1H, J=1.5 Hz), 7.29-7.34 (dd, 1H, J=9.0, 1.5 Hz), 6.98-7.02 (dd, 1H, J=8.3, 1.5 Hz), 6.96 (s, 2H), 6.89-6.94 (m, 2H), 5.50-5.58 (dd, 1H, J=11.3, 4.5 Hz), 4.77 (s, 2H), 3.98 (s, 3H), 3.91 (s, 6H), 3.90 (s, 3H), 3.69-3.81 (dd, 1H, J=18.1, 12.0 Hz), 3.08-3.17 (dd, 1H, J=17.3, 4.5 Hz), 2.43 (s, 3H); ESIMS: 675 (M+1)+.
Biological Activity
The in vitro anticancer activity studies for these amidobenzothiazoles were carried out at the National Cancer Institute, Maryland, USA.
In Vitro Cytotoxicity
The amidobenzothiazoles have been tested against sixty human tumor cell lines derived from nine cancer types (leukemia cancer cell line, non-small cell lung cancer cell line, colon cancer cell line, CNS cancer cell line, melanoma cancer cell line, ovarian cancer cell line, renal cancer cell line, prostate cancer cell line and breast cancer cell lines). For these compounds results are expressed in GI50 values of that particular cancer cell at micro molar (μM) concentration as per NCI protocol. The compounds 8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j, and 10i were evaluated for in vitro anticancer activity against sixty human tumor cells derived from nine cancer types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma cancer, ovarian cancer, renal cancer, prostate cancer and breast cancer) at concentration of μM and the results are shown in Tables 2.
The compounds 8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i exhibited an interesting profile of anti cancer activity against various cancer cell lines.







TABLE 2







In vitro cytotoxicity of compounds 8a, 8e, 8g, 8i, 8j, 9a, 9e, 9g, 9i, 9j and 10i against sixty human cancer cell lines.








Panel/Cell
GI50 values (μM conc.)


















Line
8a
8e
8g
8i
8j
9a
9e
9g
9i
9j
10i





















Leukemia













CCRF-CEM
0.078
3.70
3.87
4.27
4.12
2.09
5.73
3.55
3.37
2.5
—


HL-60(TB)
—
—
—
—
—
—
—
—
—
—
—


K-562
0.042
3.62
3.6
3.3
3.43
0.44
4.32
3.52
3.67
0.43
—


MOLT-4
0.34
3.07
3.87
3.75
4.21
3.03
29.9
3.5
4.31
2.89
—


RPMI-8226
0.15
6.36
5.43
5.48
5.83
1.09
7.35
3.02
3.84
2.02
2.21


SR
0.037
2.19
3.69
3.35
3.55
0.38
3.17
2.53
0.85
0.39
—


Non-small cell


lung


A549/ATCC
0.34
5.99
5.19
4.46
6
2.63
23.2
11.7
14.3
1.99
2.16


EKVX
0.038
5.72
5.11
6.25
7.89
5.91
38.1
50.3
30.3
5.11
4.1


HOP-62
—
5.70
23
5.22
7.09
6.11
11.7
4.11
6.57
2.12
2.2


HOP-92
0.039
5.73
6.28
2.88
2.74
1.33
2.39
2.62
4.1
2.14
1.7


NCI-H226
0.27
5.60
4.51
3.17
4.3
2.77
21.1
32.5
21.5
3.35
2.22


NCI-H23
0.11
4.26
3.91
3.9
4.39
3.4
11
5.06
3.68
2.15
3.76


NCI-H322M
—
>100
>100
5.38
>100
4.26
38.1
7.16
6.73
2.77
3.67


NCI-H460
0.052
4.36
3.73
3.55
4.11
2.64
13.5
3.32
4.06
2.43
—


NCI-H522
0.079
2.92
3.09
2.89
3.16
1.32
3.2
2.16
2
0.67
2.71


Colon


COLO-205
2.83
7.78
3.89
17.1
43.3
5.47
26.8
58.5
37.7
6.37
3.94


HCC-2998
0.37
>100
7.34
4.23
17.1
2.14
33
19.3
21.3
6.18
>100


HCT-116
0.046
4.48
3.7
3.29
3.92
2.88
15.7
3.98
3.83
1.43
2.39


HCT-15
0.048
8.19
2.89
3.24
3.23
0.49
3.96
3.34
2.68
0.4
9.26


HT29
3.16
9.63
3.34
14.9
>100
3.49
94.8
32.4
21.5
3.66
—


KM12
0.058
4.78
3.12
3.14
4.48
0.36
2.97
2.4
1.77
1.51
—


SW-620
—
65
5.1
4.65
5.65
0.62
3.84
4.07
3.82
1.08
>100


CNS


SF-268
0.18
7.23
4.31
3.85
6.01
0.95
3.78
4.16
3.28
1.2
3.84


SF-295
0.22
4.29
1.84
3.36
3.7
3.41
18.8
6.68
8.87
2.21
3.06


SF-539
0.045
4.51
2.84
2.66
2.28
0.34
2.49
2.17
2.1
0.29
1.75


SNB-19
—
>100
6.3
5.03
7.08
2.81
17.3
5.61
6.01
1.58
11


SNB-75
0.046
4.39
1.91
1.58
1.56
0.53
1.67
2.04
2.2
0.34
1.55


U251
0.048
4.33
4
3.67
3.37
0.96
6.08
3.08
3.27
0.7
3.08


Melanoma


LOX IMVI
0.067
3.23
4.17
4.01
4.77
0.52
3.37
2.59
2.88
0.47
3.36


MALME-3M
1.99
5.22
>100
>100
—
6.42
27.7
9.62
8.75
2.69
6.44


M14
0.072
6.82
4.33
3.58
4.36
3.29
10.7
3.28
3.31
1.72
—


MDA-MB-435
0.019
0.33
1.16
1.84
1.93
0.3
1.93
1.51
1.16
0.3
3.08


SK-MEL-2
0.18
8.46
4.07
3.98
3.29
5.39
100
24.2
30
4.97
—


SK-MEL-28
—
>100
4.41
3
4.57
4.61
24.1
14.4
9.47
3.31
3.56


SK-MEL-5
0.036
1.76
2.68
2.84
3.26
1.76
4.49
4.56
2.88
2.03
—


UACC-257
11
8.69
63
40
89.2
1.37
73.2
20.4
49.5
8.08
3.77


UACC-62
0.063
4.05
5.93
3.9
5.11
7.87
33.6
14.5
22.7
9.52


Ovarian


IGROV1
0.21
4.17
7
4.48
5.64
3.6
16.2
7.73
15.6
2.54
5.3


OVCAR-3
0.043
9.99
2.17
2.11
3.37
0.48
3.4
2.6
1.95
1.52
1.84


OVCAR-4
0.37
7.30
5.31
4.66
5.34
3.2
14.7
11.2
4.37
2.07
2.9


OVCAR-5
—
>100
5.89
5.98
3.12
3.54
91.6
71.7
38.9
4.76
28.2


OVCAR-8
0.25
7.15
5.28
3.86
5
2.77
10.2
3.49
3.85
1.54
3.36


NCI/ADR-
0.033
2.55
2.3
2.12
2.7
0.48
2.43
1.89
1.73
0.49
3.13


RES


SK-OV-3
0.34
8
4.69
3.29
8.42
2.54
15.2
7.32
5.08
2.16
5.75


Renal


786-0
7.3
7.12
7.52
6.96
54.3
4.12
24.7
19.4
24.6
2.26
3.58


A498
0.36
6.25
3.5
2.81
3.61
22.6
100
100
100
7.4
2.78


ACHN
0.093
3.33
7.77
4.82
8.31
3.46
12.4
4.94
7.48
1.62
2.48


CAKI-1
0.41
2.78
3.2
3.1
4.6
3.78
30.7
25.1
10.9
2.2
2.17


RXF 393
0.05
6.29
2.5
2.27
2.65
1.83
8.5
2.37
2.6
1.58
2.09


SN12C
0.37
4.61
5.75
4.43
6.42
3.02
17.4
5.19
5.41
1.74
3.31


TK-10
—
9.89
7.54
7.03
18.6
3.3
20.9
16.4
15.6
2.08
2.85


UO-31
0.58
2.56
4.31
3.59
4.37
3.07
6.83
5.31
7.8
1.61
1.93


Prostate


PC-3
0.18
6.74
4.45
4.32
5.12
3.63
22.9
12.2
12
3.14
2.92


DU-145
0.1
8.97
2.04
2.51
4.11
1.94
4.05
2.49
2.62
1.56
1.82


Breast


MCF7
0.051
2.3
2.88
3.16
2.89
1.05
3.7
3.02
3.05
1.32
4.02


MDA-MB-
0.19
9.34
5.4
3.38
5.16
2.69
12.6
5.82
7.14
2.01
3.11


231/ATCC


HS 578T
—
>100
4.15
4.18
4.33
4.75
10.5
3.72
4.81
3.08
2.48


BT-549
0.41
16.7
21.2
5.23
10.5
4.82
4.82
8.38
11.2
2.71
3.55


T-47D
1.0
3.39
4.03
4.79
3.95
4.97
58.5
14.7
15
3.08
2.75


MDA-MB-468
0.1
3.68
2.29
2.16
2.3
2.3
13.1
10.5
13.5
3.52
6.12









ADVANTAGES OF THE INVENTION


    
    
        1. The present invention provides amidobenzothiazole of general formula A useful as anticancer agents.
        2. It also provides a process for the preparation of amidobenzothiazole of general formula A.

## Claims

1. An amidobenzothiazole of formula A




Wherein:
R=H, alkoxy, halo, haloalkyl, halomethyl, or nitro,
R1=H, alkoxy, halo, haloalkyl, halomethyl, or nitro,
R2=H, halo, haloalkyl, halomethyl, or nitro, and

2. An amidobenzothiazole compound having a formula selected from the group consisting of compounds 8a-8v, 9a-9v, 10a-10v, 11a-11v, 12a-12v and 13a-13v shown below:

3. A composition having in vitro anticancer activity against human cancer cell lines selected from the group consisting of leukemia cancer cell lines, non-small cell lung cancer cell lines, colon cancer cell lines, CNS cancer cell lines, melanoma cancer cell lines, ovarian cancer cell lines, renal cancer cell lines, prostate cancer cell lines and breast cancer cell lines, comprising an amidobenzothiazole of formula A:




wherein:
R=H, alkoxy, halo, haloalkyl, halomethyl, or nitro,
R1=H, alkoxy, halo, haloalkyl, halomethyl, or nitro,
R2=H, alkoxy, halo, haloalkyl, halomethyl or nitro, and

4. A composition having in vitro anticancer activity against human cancer cell lines selected from the group consisting of leukemia cancer cell lines, non-small cell lung cancer cell lines, colon cancer cell lines, CNS cancer cell lines, melanoma cancer cell lines, ovarian cancer cell lines, renal cancer cell in claim 2, wherein the amidobenzothiazole compound is:
N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (compound 8a);
N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxy phenyl)-1-ethenyl]phenoxy}acetamide (compound 8e);
N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (compound 8g);
N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (compound 8i);
N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetamide (compound 8j);
N1-(1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (compound 9a);
N1-(6-fluoro-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetamide (compound 9e);
N1-(6-methoxy-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (compound 9g);
N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (compound 9i);
N1-(6-(trifluoromethoxy)-1,3-benzothiazol-2-yl)-2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxyphenyl)-1-propenyl]phenoxy}acetamide (compound 9j); or
N1-(6-(trifluoromethyl)-1,3-benzothiazol-2-yl)-2-{5-[1-acetyl-3-(3,4,5-trimethoxy phenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetamide (compound 10i).

5. A process for the preparation of an amidobenzothiazole compound as claimed in claim 2:
comprising the steps of:
i. reacting a 2-aminobenzothiazole of formula 7a-7v with a compound selected from formula 1, 2, 3, 4, 5 and 6 in an organic solvent in the presence of 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxy benzotriazole (HOBT) at temperature in the range of 25 to 30° C. for a period in the range of 22 to 24 hrs;








ii. adding water to the product of step (i) to form an aqueous mixture and extracting a crude product by mixing the aqueous mixture with organic solvent and then evaporating the organic solvent to obtain the crude product;
iii. purifying the crude product of step (ii) using column chromatography.

6. A process as claimed in claim 5, wherein the organic solvent used in step (i) or step (ii) is selected from the group consisting of dichloromethane, chloroform or N, N-dimethylformamide.