FIELD OF THE INVENTION
The present invention relates to Isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids as anticancer agents. Particularly, the present invention relates to Isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids of general formula A.
Where in G=
More particularly the present invention relates to 2-[4-(5-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy Phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H quinazolin-4-one, 2-[4-(5-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one, 2-(4-(5-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxy-phenyl isoxazol-3-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one, 2-(4-(5-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxy phenyl) isoxazol-5-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one, (Z)-2-(4-(5-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3 dihydroquinazolin-4(1H)-one with aliphatic chain length variations useful as anticancer(antitumour) agents. The structural formulae of these isoxazole/isoxazoline/combretastatin-dihydroquinazolinone hybrids is given below.
BACKGROUND OF THE INVENTION
Inhibition of tubulin polymerization is the target of many antitumoural agents known as antimitotic agents or spindle poisons colchicines, podophyllo-toxins and combretastatins are representative examples of compounds that inhibit microtubule assembly by binding to tubulin. 2-Aryl- and 2-styrylquinazolin-4(3H)-ones(SQZ) and 2,3-dihydro-2-aryl-1-quinazolinones (DHPQ) are compounds that possess this common structural feature for an effective interaction with tubulin. The antitumor activities of 2,3-dihydro-2-aryl-4-quinazolinones (DHPQZ) were reported around 1970 (Yale H L, Kalkstein M. Substituted nones, a new class of inhibitors of cell multiplication. J Med Chem 1967 10, 334-336, Neil, G. L.; Li, L. H.; Buskirk, H. H.; Moxlcy, T. E. Cancer Chemother. 1972, 56, 163-173. and Hamel, E.; Lin, C. M.; Plowman, J.; Wang, H. K.; Lee, K. H.; Paull, K. D. Antitumor 2,3-dihydro-2-(aryl)-4(1H)-quinazolinone derivatives. Interactions with tubulin. Biochem. Pharmacol. 1996, 51, 53-59). A more recent reevaluation of this type of compound by NCl against human tumor cell lines reconfirmed that, like colchicine, they are effective inhibitors of tubulin polymerization. Many isoxazole, isoxazoline type moieties related to combretastain A-4 showed potential biological properties particularly anticancer activity (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{grave over ( )}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 cytotoxicity and were able to induce apoptosis at lower concentrations.
OBJECTIVES OF THE INVENTION
The main objective of the present invention is to provide novel isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids useful as antitumour agents.
Yet another object of this invention is to provide a process for the preparation of novel isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a novel isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids of general formulae A
Where in G=
In an embodiment of the present invention the novel isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids of formulae A is represented by the compounds of general formulae 3a-i to 6a-i, 7a-i to 10a-i, 12a-i to 15a-i, 16a-i to 19a-i, 21a-i to 24a-i, 25a-i to 28a-i, 30a-i to 33a-i, 34a-i to 37a-i and 39a-i to 42a-i, 43a-i to 46a-i.
In yet another embodiment the isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids are represented by the group of the following compounds:
- 2-[3-Methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3a)
- 2-[3-Methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3b)
- 2-[3-Methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3c)
- 2-[3-Methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3d)
- 2-[3-Methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3e)
- 2-[3-Methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3f)
- 2-[3-Methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3g)
- 2-[3-Methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3h)
- 2-[3-Methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3i)
- 6-Chloro-2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4a)
- 6-Chloro-2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4b)
- 6-Chloro-2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4c)
- 6-Chloro-2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4d)
- 6-Chloro-2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one (4e)
- 6-Chloro-2-[3-Methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4f)
- 6-Chloro-2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4g)
- 6-Chloro-2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4h)
- 6-Chloro-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(4i)
- 6-Methyl 2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5a)
- 6-Methyl 2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5b)
- 6-Methyl 2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5c)
- 6-Methyl 2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5d)
- 6-Methyl 2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-hexyloxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5e)
- 6-Methyl 2-[3-methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5f)
- 6-Methyl 2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5g)
- 6-Methyl 2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5h)
- 6-Methyl-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(5i)
- 6-Methoxy-2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6a)
- 6-Methoxy-2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6b)
- 6-Methoxy-2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6c)
- 6-Methoxy-2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6d)
- 6-Methoxy-2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6e)
- 6-Methoxy-2-[3-methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6f)
- 6-Methoxy-2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6g)
- 6-Methoxy-2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6h)
- 6-Methoxy-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(6i)
- 2-[4-(2-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7a)
- 2-[4-(3-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7b)
- 2-[4-(4-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7c)
- 2-[4-(5-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7d)
- 2-[4-(6-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7e)
- 2-[4-(7-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7f)
- 2-[4-(8-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7g)
- 2-[4-(9-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7h)
- 2-[4-(10-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro 1H-quinazolin-4-one(7i)
- 6-Chloro-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8a)
- 6-Chloro-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8b)
- 6-Chloro-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8c)
- 6-Chloro-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro 1H-quinazolin-4-one(8d)
- 6-Chloro-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8e)
- 6-Chloro-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8f)
- 6-Chloro-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8g)
- 6-Chloro-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8h)
- 6-Chloro-2-[4-(10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(8i)
- 6-Methyl-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9a)
- 6-Methyl-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9b)
- 6-Methyl-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9c)
- 6-Methyl-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9d)
- 6-Methyl-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9e)
- 6-Methyl-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9f)
- 6-Methyl-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9g)
- 6-Methyl-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9h)
- 6-Methyl-2-[4-(10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(9i)
- 6-Methoxy-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10a)
- 6-Methoxy-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10b)
- 6-Methoxy-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10c)
- 6-Methoxy-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10d)
- 6-Methoxy-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10e)
- 6-Methoxy-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10f)
- 6-Methoxy-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10g)
- 6-Methoxy-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10h)
- 6-Methoxy-2-[4-(10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(10i)
- 2-[3-Methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12a)
- 2-[3-Methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12b)
- 2-[3-Methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12c)
- 2-[3-Methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12d)
- 2-[3-Methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12e)
- 2-[3-Methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12f)
- 2-[3-Methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12g)
- 2-[3-Methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12h)
- 2-[3-Methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-dedyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12i)
- 6-Chloro-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13a)
- 6-Chloro-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13b)
- 6-Chloro-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13c)
- 6-Chloro-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13d)
- 6-Chloro-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13e)
- 6-Chloro-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13f)
- 6-Chloro-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13g)
- 6-Chloro-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13h)
- 6-Chloro-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(13i)
- 6-Methyl-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14a)
- 6-Methyl-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14b)
- 6-Methyl-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14c)
- 6-Methyl-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14d)
- 6-Methyl-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14e)
- 6-Methyl-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14f)
- 6-Methyl-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14g)
- 6-Methyl-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14h)
- 6-Methyl-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(14i)
- 6-Methoxy-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15a)
- 6-Methoxy-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15b)
- 6-Methoxy-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15c)
- 6-Methoxy-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15d)
- 6-Methoxy-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H quinazolin-4-one(15e)
- 6-Methoxy-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15f)
- 6-Methoxy-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15g)
- 6-Methoxy-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15h)
- 6-Methoxy-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(15i)
- 2-[4-(2-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16a)
- 2-[4-(3-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16b)
- 2-[4-(4-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16c)
- 2-[4-(5-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16d)
- 2-[4-(6-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16e)
- 2-[4-(7-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16f)
- 2-[4-(8-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16g)
- 2-[4-(9-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16h)
- 2-[4-(10-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16i)
- 6-Chloro-2-[4-(2-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(17a)
- 6-Chloro-2-[4-(3-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(17b)
- 6-Chloro-2-[4-{4-(2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(17c)
- 6-Chloro-2-[4-(5-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17d)
- 6-Chloro-2-[4-(6-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17e)
- 6-Chloro-2-[4-(7-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17f)
- 6-Chloro-2-[4-(8-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17g)
- 6-Chloro-2-[4-(9-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17h)
- 6-Chloro-2-[4-(10-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(17i)
- 6-Methyl-2-[4-(2-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(18a)
- 6-Methyl-2-[4-(3-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(18b)
- 6-Methyl-2-[4-(4-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(18c)
- 6-Methyl-2-[4-(5-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18d)
- 6-Methyl-2-[4-(6-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-Methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18e)
- 6-Methyl-2-[4-(7-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18f)
- 6-Methyl-2-[4-(8-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18g)
- 6-Methyl-2-[4-(9-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18h)
- 6-Methyl-2-[4-(10-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(18i)
- 6-Methoxy-2-[4-(2-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(19a)
- 6-Methoxy-2-[4-(3-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(19b)
- 6-Methoxy-2-[4-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]=phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(19c)
- 6-Methoxy-2-[4-(5-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19d)
- 6-Methoxy-2-[4-(6-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19e)
- 6-Methoxy-2-[4-(7-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19f)
- 6-Methoxy-2-[4-(8-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19g)
- 6-Methoxy-2-[4-(9-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19h)
- 6-Methoxy-2-[4-(10-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]2,3-dihydro-1H-quinazolin-4-one(19i)
- 2-(3-methoxy-4-(2-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)ethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21a)
- 2-(3-methoxy-4-(3-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)propoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21b)
- 2-(3-methoxy-4-(4-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl) isoxazol-3-yl)phenoxy)butoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21c)
- 2-(3-methoxy-4-(5-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21d)
- 2-(3-methoxy-4-(6-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl) isoxazol-3-yl)phenoxy)hexyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21e)
- 2-(3-methoxy-4-(7-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)heptyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21f)
- 2-(3-methoxy-4-(8-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)octyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21g)
- 2-(3-methoxy-4-(9-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)nonyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21h)
- 2-(3-methoxy-4-(10-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)decyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21i)
- 6-Chloro-2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22a)
- 6-Chloro-2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22b)
- 6-Chloro-2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22c)
- 6-Chloro-2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22d)
- 6-Chloro-2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22e)
- 6-Chloro-2-[3-methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22f)
- 6-Chloro-2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22g)
- 6-Chloro-2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22h)
- 6-Chloro-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(22i)
- 6-Methyl-2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23a)
- 6-Methyl-2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23b)
- 6-Methyl-2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23c)
- 6-Methyl-2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23d)
- 6-Methyl-2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23e)
- 6-Methyl-2-[3-methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23f)
- 6-Methyl-2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23g)
- 6-Methyl-2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23h)
- 6-Methyl-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(23i)
- 6-Methoxy-2-[3-methoxy-4-(2-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24a)
- 6-Methoxy-2-[3-methoxy-4-(3-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24b)
- 6-Methoxy-2-[3-methoxy-4-(4-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24c)
- 6-Methoxy-2-[3-methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24d)
- 6-Methoxy-2-[3-methoxy-4-(6-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24e)
- 6-Methoxy-2-[3-methoxy-4-(7-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24f)
- 6-Methoxy-2-[3-methoxy-4-(8-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24g)
- 6-Methoxy-2-[3-methoxy-4-(9-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24h)
- 6-Methoxy-2-[3-methoxy-4-(10-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(24i)
- 2-(4-(2-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)ethoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25a)
- 2-(4-(3-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)propoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25b)
- 2-(4-(4-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)butoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25c)
- 2-(4-(5-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25d)
- 2-(4-(6-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)hexyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25e)
- 2-(4-(7-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)heptyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25f)
- 2-(4-(8-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)octyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25g)
- 2-(4-(7-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)heptyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25h)
- 2-(4-(8-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)octyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25i)
- 2-(4-(9-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)nonyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25h)
- 2-(4-(10-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)decyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(25i)
- 6-Chloro-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26a)
- 6-Chloro-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26b)
- 6-Chloro-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26c)
- 6-Chloro-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26d)
- 6-Chloro-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26e)
- 6-Chloro-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26f)
- 6-Chloro-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26g)
- 6-Chloro-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26h)
- 6-Chloro-2-[4-10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(26i)
- 6-Methyl-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27a)
- 6-Methyl-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27b)
- 6-Methyl-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27c)
- 6-Methyl-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27d)
- 6-Methyl-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27e)
- 6-Methyl-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27f)
- 6-Methyl-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27g)
- 6-Methyl-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27h)
- 6-Methyl-2-[4-(10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(27i)
- 6-Methoxy-2-[4-(2-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28a)
- 6-Methoxy-2-[4-(3-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28b)
- 6-Methoxy-2-[4-(4-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28c)
- 6-Methoxy-2-[4-(5-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28d)
- 6-Methoxy-2-[4-(6-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28e)
- 6-Methoxy-2-[4-(7-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28f)
- 6-Methoxy-2-[4-(8-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28g)
- 6-Methoxy-2-[4-(9-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28h)
- 6-Methoxy-2-[4-(10-{2,6-dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-3-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(28i)
- 2-(3-methoxy-4-(2-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)ethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30a)
- 2-(3-methoxy-4-(3-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)propoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30b)
- 2-(3-methoxy-4-(4-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)butoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30c)
- 2-(3-methoxy-4-(5-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30d)
- 2-(3-methoxy-4-(6-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)hexyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30e)
- 2-(3-methoxy-4-(7-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)heptyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30f)
- 2-(3-methoxy-4-(8-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)octyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30g)
- 2-(3-methoxy-4-(9-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)nonyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30h)
- 2-(3-methoxy-4-(10-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)decyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30i)
- 6-Chloro-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31a)
- 6-Chloro-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31b)
- 6-Chloro-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31c)
- 6-Chloro-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31d)
- 6-Chloro-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31e)
- 6-Chloro-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31f)
- 6-Chloro-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31g)
- 6-Chloro-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31h)
- 6-Chloro-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(31i)
- 6-Methyl-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32a)
- 6-Methyl-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32b)
- 6-Methyl-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32c)
- 6-Methyl-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32d)
- 6-Methyl-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32e)
- 6-Methyl-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32f)
- 6-Methyl-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32g)
- 6-Methyl-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32h)
- 6-Methyl-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(32i)
- 6-Methoxy-2-[3-methoxy-4-(2-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33a)
- 6-Methoxy-2-[3-methoxy-4-(3-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33b)
- 6-Methoxy-2-[3-methoxy-4-(4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33c)
- 6-Methoxy-2-[3-methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33d)
- 6-Methoxy-2-[3-methoxy-4-(6-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33e)
- 6-Methoxy-2-[3-methoxy-4-(7-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33f)
- 6-Methoxy-2-[3-methoxy-4-(8-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33g)
- 6-Methoxy-2-[3-methoxy-4-(9-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33h)
- 6-Methoxy-2-[3-methoxy-4-(10-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(33i)
- 2-(4-(2-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)ethoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34a)
- 2-(4-(3-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)propoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34b)
- 2-(4-(4-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)butoxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34c)
- 2-(4-(5-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34d)
- 2-(4-(6-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)hexyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34e)
- 2-(4-(7-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)heptyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34f)
- 2-(4-(8-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)octyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34g)
- 2-(4-(9-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl(isoxazol-5-yl)phenoxy)nonyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34h)
- 2-(4-(10-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)decyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34i)
- 6-Chloro-2-[4-(2-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35a)
- 6-Chloro-2-[4-(3-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35b)
- 6-Chloro-2-[4-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35c)
- 6-Chloro-2-[4-(5-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35d)
- 6-Chloro-2-[4-(6-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35e)
- 6-Chloro-2-[4-(7-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35f)
- 6-Chloro-2-[4-(8-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35g)
- 6-Chloro-2-[4-(9-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35h)
- 6-Chloro-2-[10-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(35i)
- 6-Methyl-2-[4-(2-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36a)
- 6-Methyl-2-[4-(3-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36b)
- 6-Methyl-2-[4-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36c)
- 6-Methyl-2-[4-(5-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36d)
- 6-Methyl-2-[4-(6-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36e)
- 6-Methyl-2-[4-(7-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36f)
- 6-Methyl-2-[4-(8-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36g)
- 6-Methyl-2-[4-(9-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36h)
- 6-Methyl-2-[10-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(36i)
- 6-Methoxy-2-[4-(2-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37a)
- 6-Methoxy-2-[4-(3-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37b)
- 6-Methoxy-2-[4-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-butyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37c)
- 6-Methoxy-2-[4-(5-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37d)
- 6-Methoxy-2-[4-(6-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37e)
- 6-Methoxy-2-[4-(7-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37f)
- 6-Methoxy-2-[4-(8-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37g)
- 6-Methoxy-2-[4-(9-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37h)
- 6-Methoxy-2-[10-(4-{2,6-dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-5-yl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(37i)
- (Z)-2-(3-methoxy-4-(2-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)ethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39a)
- (Z)-2-(3-methoxy-4-(3-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)propoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39b)
- (Z)-2-(3-methoxy-4-(4-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)butoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39c)
- (Z)-2-(3-methoxy-4-(5-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39d)
- (Z)-2-(3-methoxy-4-(6-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)hexyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39e)
- (Z)-2-(3-methoxy-4-(7-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)heptyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39f)
- (Z)-2-(3-methoxy-4-(8-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)octyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39g)
- (Z)-2-(3-methoxy-4-(9-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)nonyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39h)
- (Z)-2-(3-methoxy-4-(10-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)decyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39i)
- 6-Chloro-2-[3-methoxy-4-(2-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40a)
- 6-Chloro-2-[3-Methoxy-4-(3-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40b)
- 6-Chloro-2-[3-Methoxy-4-(4-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40c)
- 6-Chloro-2-[3-methoxy-4-(5-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40d)
- 6-Chloro-2-[3-Methoxy-4-(6-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40e)
- 6-Chloro-2-[3-Methoxy-4-(7-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40f)
- 6-Chloro-2-[3-methoxy-4-(8-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40g)
- 6-Chloro-2-[3-Methoxy-4-(9-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40h)
- 6-Chloro-2-[3-Methoxy-4-(10-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(40i)
- 6-Methyl-2-[3-methoxy-4-(2-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41a)
- 6-Methyl-2-[3-Methoxy-4-(3-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41b)
- 6-Methyl-2-[3-Methoxy-4-(4-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41c)
- 6-Methyl-2-[3-methoxy-4-(5-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41d)
- 6-Methyl-2-[3-Methoxy-4-(6-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41e)
- 6-Methyl-2-[3-Methoxy-4-(7-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41f)
- 6-Methyl-2-[3-methoxy-4-(8-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41g)
- 6-Methyl-2-[3-Methoxy-4-(9-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41h)
- 6-Methyl-2-[3-Methoxy-4-(10-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(41i)
- 6-Methoxy-2-[3-methoxy-4-(2-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42a)
- 6-Methoxy-2-[3-Methoxy-4-(3-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl-]phenoxy}-propoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42b)
- 6-Methoxy-2-[3-Methoxy-4-(4-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42c)
- 6-Methoxy-2-[3-methoxy-4-(5-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42d)
- 6-Methoxy-2-[3-Methoxy-4-(6-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42e)
- 6-Methoxy-2-[3-Methoxy-4-(7-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42f)
- 6-Methoxy-2-[3-methoxy-4-(8-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl-]phenoxy}-octyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42g)
- 6-Methoxy-2-[3-Methoxy-4-(9-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42h)
- 6-Methoxy-2-[3-Methoxy-4-(10-{2-methoxy-5-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(42i)
- (Z)-2-(4-(2-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)ethoxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43a)
- (Z)-2-(4-(3-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)propoxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43b)
- (Z)-2-(4-(4-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)butoxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43c)
- (Z)-2-(4-(5-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)pentyoxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43d)
- (Z)-2-(4-(6-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)hexyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43e)
- (Z)-2-(4-(7-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)heptyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43f)
- (Z)-2-(4-(8-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)octyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43g)
- (Z)-2-(4-(9-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)nonyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43h)
- (Z)-2-(4-(10-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)decyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43i)
- 6-Chloro-2-[4-(2-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44a)
- 6-Chloro-2-[4-(3-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44b)
- 6-Chloro-2-[4-(4-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44c)
- 6-Chloro-2-[4-(5-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44d)
- 6-Chloro-2-[4-(6-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44e)
- 6-Chloro-2-[4-(7-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44f)
- 6-Chloro-2-[4-(8-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (44g)
- 6-Chloro-2-[4-(9-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44h)
- 6-Chloro-2-[4-(10-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(44i)
- 6-Methyl-2-[4-(2-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45a)
- 6-Methyl-2-[4-(3-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-Phenyl)-vinyl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45b)
- 6-Methyl-2-[4-(4-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (45c)
- 6-Methyl-2-[4-(5-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45d)
- 6-Methyl-2-[4-(6-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45e)
- 6-Methyl-2-[4-(7-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45f)
- 6-Methyl-2-[4-(8-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45g)
- 6-Methyl-2-[4-(9-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45h)
- 6-Methyl-2-[4-(10-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(45i)
- 6-Methoxy-2-[4-(2-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46a)
- 6-Methoxy-2-[4-(3-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-propoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46b)
- 6-Methoxy-2-[4-(4-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-butoxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46c)
- 6-Methoxy-2-[4-(5-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46d)
- 6-Methoxy-2-[4-(6-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-hexyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46e)
- 6-Methoxy-2-[4-(7-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-heptyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46f)
- 6-Methoxy-2-[4-(8-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-octyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46g)
- 6-Methoxy-2-[4-(9-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-nonyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46h)
- 6-Methoxy-2-[4-(10-{2,6-dimethoxy-4-[2-(3,4,5-trimethoxy-phenyl)-vinyl]-phenoxy}-decyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(46i)
The present invention further provides a process for preparation of novel isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids of general formulae 3a-i to 6a-i, 7a-i to 10a-i, 12a-i to 15a-i, 16a-i to 19a-i, 21a-i to 24a-i, 25a-i to 28a-i, 30a-i to 33a-i, 34a-i to 37a-i and 39a-i to 42a-i, 43a-i to 46a-i which comprises
Reacting 2-[4-(n-Bromo-alkyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one of formula 2 with the compounds of formulae 1a, 1b, 11a, 11b, 20a, 20b, 29a, 29b, 38a, 38b respectively in an aprotic water miscible organic solvent, in the presence of anhydrous mild inorganic base, under room temperature for a period of about 48 hrs, followed by the removal of inorganic base by filtration and evaporating the organic solvent to obtain the resultant crude product and purifying it by column chromatography to obtain the desired products of formulae 3a-i to 6a-i, 7a-i to 10a-i, 12a-i to 15a-i, 16a-i to 19a-i, 21a-i to 24a-i, 25a-i to 28a-i, 30a-i to 33a-i, 34a-i to 37a-i and 39a-i to 42a-i, 43a-i to 46a-i respectively.
DETAILED DESCRIPTION OF THE INVENTION
The precursor dihydroquinazolinone of formula 2, has been prepared using literature method (Mann-Jen Hour, † Li-Jiau Huang, † Sheng-Chu Kuo, *, † Yi Xia, ‡ Kenneth Bastow, §Yuka Nakanishi, §Ernest Hamel, | and Kuo-Hsiung Lee*, ‡ J. Med. Chem. 2000, 43, 4479-4487). The precursors isoxazoles, isoxazolines and combretastatins of formulae 1(a&b), 11(a&b), 20(a&b), 29(a&b) and 38(a&b) have been prepared using literature methods (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 isoxazole/isoxazoline/combretastatin linked dihydro-quinazolinone hybrids have shown promising anticancer activity in various cell lines. The molecules synthesized are of immense biological significance. This resulted in design and synthesis of new congener's as illustrated in schemes 1-5 which comprise:
The ether linkage between dihydroquinazolinone of formula 2 and isoxazole/isoxazoline/combretastatins of formulae 1(a&b), 11(a&b), 20(a&b), 29(a&b) and 38(a&b)
- 1. Stirring the reaction mixtures at a temperature of 35° C. for 30 h.
- 2. Synthesis of isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrids.
- 3. Purification by column chromatography using different solvents like ethyl acetate, hexane, dichloromethane and methanol.
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
2-[3-Methoxy-4-(5-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(3d)
2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenol(1a) (359.37 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (3d) (557 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.69-3.82 (dd, 1H, J=10.7 Hz, J=16.4 Hz), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s; 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 5.63-5.73 (t, 1H, J=10.1 Hz, J=9.2 Hz), 5.77 (s, 1H), 6.57-6.61 (d, 1H, J=7.9 Hz), 6.63 (s, 1H) 6.76-6.79 (d, 1H, J=8.1 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.87 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 698.75 (M+H)−.
Example 2
2-[4-(5-{2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenoxy}pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(7d)2,6-Dimethoxy-4-[5-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-phenol (1b)
(389.15 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (7d) (583 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.69-3.82 (dd, 1H, J=10.7 Hz, J=16.4 Hz), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 5.63-5.73 (t, 1H, J=10.1 Hz, J=9.2 Hz), 5.77 (s, 1H), 6.62 (s, 2H), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 728.78M+H)+.
Example 3
2-[3-Methoxy-4-(5-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-phenyl]-2,3-dihydro-1H-quinazolin-4-one(12d)
2-Methoxy-5-[3-(3,4,5-trimethoxy-Phenyl)-4,5-dihydro-isoxazol-5-yl]phenol(11a) (359.37 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (12d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.69-3.82 (dd, 1H, J=10.7 Hz, J=16.4 Hz), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 5.63-5.73 (t, 11-1, J=10.1 Hz, J=9.2 Hz), 5.77 (s, 1H), 6.57-6.61 (d, 1H, J=7.9 Hz), 6.63 (s, 1H) 6.76-6.79 (d, 1H, J=8.1 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2Hz), 7.82-7.87 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 698.75 (M+H)+.
Example 4
2-[4-(5-{2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenoxy}-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(16d)
2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenol (11b)(389.40 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (16d) (570 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.69-3.82 (dd, 1H, J=10.7 Hz, J=16.4 Hz), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 5.63-5.73 (t, 1H, J=10.1 Hz, J=9.2 Hz), 5.77 (s, 1H), 6.62 (s, 2H), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 728.80 (M+H)+.
Example 5
2-(3-methoxy-4-(5-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(21d)
2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20a) (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (21d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.57-6.61 (d, 1H, J=7.9 Hz), 6.63 (s, 1H), 6.67 (s, 1H), 6.76-6.79 (d, 1H, J=8.1 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.87 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 696.76 (M+H)+.
Example 6
2-(4-(5-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (25d)
2,6-dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)isoxazol-3-yl)phenol (20b) (387.38 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (25d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.62 (s, 2H), 6.67 (s, 1H) 6.82-6.85 (d, 1H, J=7.7 Hz), 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 726.78 (M+H)+.
Example 7
2-(3-methoxy-4-(5-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(30d)
2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (290 (357.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (30d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.57-6.61 (d, 1H, J=7.9 Hz), 6.63 (s, 1H), 6.67 (s, 1H), 6.76-6.79 (d, 1H, J=8.1 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz) 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.87 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 696.76 (M+H)+.
Example 8
2-(4-(5-(2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one(34d)
2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (29b) (387.38 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (34d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.62 (s, 2H), 6.67 (s, 1H) 6.82-6.85 (d, 1H, J=7.7 Hz), 6.88 (s, 2H), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.74 Hz J=7.55 Hz) FABMS: 726.78 (M+H)+.
Example 9
(Z)-2-(3-methoxy-4-(5-(2-methoxy-5-(3,4,5-trimethoxystyryl)phenoxy)pentyloxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one(39d)
(Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenol (38a) (316.35 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (39d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.2 Hz), 4.10-4.16 (t, 2H, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.39 (d, 2H, J=4.4 Hz), 6.47 (s, 2H) 6.73 (d, 1H, 2.2 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz), 6.89 (d, 1H, J=2.2 Hz), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.55 Hz J=7.74 Hz) FABMS: 655.75M+H)+.
Example 10
(Z)-2-(4-(5-(2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenoxy)pentyloxy)-3-methoxy phenyl)-2,3-dihydroquinazolin-4(1H)-one(43d)
(Z)-2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenol (38b) (346.37.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one(2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (43d) (546 mg, 80% yield).
1H NMR (CDCl3): δ 1.70-1.80 (m, 2H), 1.89-2.02 (m, 4H), 3.84 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 3.89 (s, 6H), 3.94 (s, 3H), 4.02-4.08 (t, 2H, J=5.2 Hz), 4.10-4.16 (t, 21-1, J=6.4 Hz), 4.39-4.42 (bs, NH), 6.04 (s, 1H), 6.47 (s, 2H), 6.70 (s, 2H), 6.73 (d, 1H, J=2.2 Hz), 6.82-6.85 (d, 1H, J=7.7 Hz), 6.89 (d, 11-1, J=2.2 Hz), 6.90 (s, 1H), 6.94-6.97 (d, 1H, J=7.7 Hz), 7.18-7.21 (m, 2H), 7.22-7.29 (dd, 1H, J=7.5 Hz J=15.2 Hz), 7.82-7.92 (dd, 1H, J=7.55 Hz J=7.74 Hz): FABMS: 685.77M+H)+.
Biological Activity:
some of in vitro biological activity studies were carried out at the National Cancer Institute, Maryland, USA.
In Vitro Cytotoxicity
The isoxazole/isoxazoline/combretastatin linked dihydroquinazolinone hybrid (7d) has been tested against forty nine human tumour cell lines derived from nine cancer types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) as per NCI protocol. For each compound, dose response curves for individual cell lines have been measured at a minimum of five concentrations at 10 fold dilutions. A protocol of 48 h continuous drug exposure has been used, and a sulforhodamine B (SRB) protein assay was used to estimate cell viability or growth. The concentration for 50% cell growth inhibition (GI50), total cell growth inhibition (TGI, 0% growth) and 50% cell death (LC50, 50% growth) compared with the control has been calculated (Table-1). Compound 7d has been evaluated for their in vitro cytotoxicity in forty nine cell lines from nine human cancer types of lung (Hop-62, NCI-H226, NCI-H522), leukemia (K-562, SR), colon (HCT-116, HCT-15, HCC-2998), CNS(SF-539), melanoma (SK-MEL-5, MDA-MB-435, UACC-62, M14), ovarian (IGROV1), renal (A498), prostate (PC3) breast (BT-549, HS578T)origin. The results are expressed as percent of cell growth determined relative to that of untreated control cells (Table 2). The representative compound 7d has shown significant cytotoxicity against some cancer cell lines.
TABLE 1
|
|
Log10 GI50 (concentration in mol/L causing 50% growth
|
inhibition) values for quinazolinone-PBD hybrid(7d)
|
Log10 GI50
Log10 LC50
|
|
Leukemia
−6.17
−4.15
|
Non-small-celllung
−4.97
−4.00
|
Colon
−5.17
−4.00
|
CNS
−4.66
−4.00
|
Melanoma
−5.69
−4.00
|
Ovarian
−5.20
−4.00
|
Renal
−4.72
−4.00
|
Prostate
−5.39
−4.00
|
Breast
−5.82
−4.00
|
|
Each cancer type represents the average of six to eight different cancer cell lines.
|
The compound 7d exhibits a wide spectrum of activity against forty nine cell lines in nine cell panels, with GI50 value of <40 μm. In the non-small cell lung cancer panel, the growth of EKVX, NCI-H3 cell lines were affected by compound 7d with GI50 values as 0.36 and 0.38 μM respectively. The GI50 values of compound 7d against colon cancer HCC-2998, FICT-116 cell lines are 0.06 and 0.26 μm respectively. The GI50 values for compound 7d against leukemia CCRF-CEM, K-562, MOLT-4 and RPMI-8226 cell lines are 0.62, 0.37, 0.68 and 0.06 μm respectively. The GI50 values for compound 7d against melanoma SK-MEL-5, UACC-257, MDA-MB-435, and UACC-62 cell lines are 0.18, 0.29, 0.60 and 0.99 μm respectively. The GI50 values for compound 7d against ovarian IGROV1 and OVCAR-4 cell lines are 0.32 and 0.49 μM. The GI50 values for compound 7d against renal ACHN cell line is 0.95 μm The GI50 values for compound 7d against prostate PC-3 cell line is 0.74 μm. The GI50 values for compound 7d against breast MCF7, T-47D. MDA-MB-468 cell lines are 0.45, 0.30, 0.08 μm respectively.
Compound 7d exhibits activity against forty nine cell lines in nine cancer cell panels with GI50 values of <40 μm. in vitro cytotoxicity of compound 7d in selected cancer cell lines has been illustrated in Table 2. The average GI50 values for each cancer panel of compounds 7d have been illustrated in Tablet.
TABLE 2
|
|
In vitro cytotoxicity of compounds 7d in
|
forty nine cancer cell lines
|
Cancer panel/
GI50
|
cell line
(μm) 7d
|
|
Leukemia
|
CCRF-CEM
0.62
|
HL-60(TB)
12.2
|
K-562
0.37
|
MOLT-4
0.68
|
RPMI-8226
0.06
|
Non-small
|
cell lung
|
A549/ATCC
15.7
|
EKVX
0.36
|
HOP-92
15.8
|
NCI-H23
0.38
|
NCI-H460
15.1
|
NCI-H522
27.4
|
Colon
|
HCC-2998
0.06
|
HCT-116
0.26
|
HCT-15
15.9
|
KM12
10.4
|
SW-620
21.0
|
CNS
|
SF-268
20.2
|
SF-295
16.4
|
SF-539
21.2
|
SNB-19
16.6
|
SNB-75
34.2
|
U251
25.2
|
Melanoma
|
LOX IMVI
19.5
|
M14
19.8
|
Ovarian
|
IGROV1
0.32
|
OVCAR-3
12.4
|
OVCAR-4
0.49
|
OVCAR-5
31.7
|
OVCAR-8
25.7
|
SK-OV-3
38.5
|
NCI/ADRRES
10.6
|
Renal
|
786-0
31.8
|
A498
19.3
|
ACHN
0.95
|
CAKI-1
18.0
|
SN12C
39.1
|
UO-31
21.4
|
Prostate
|
PC-3
0.74
|
DU-145
22.4
|
Breast
|
MCF7
0.45
|
MDA-MB-231/ATCC
14.7
|
HS 578T
15.0
|
T-47D
0.30
|
MDA-MB-468
0.08
|
Melanoma
|
SK-MEL-28
3.24
|
SK-MEL-5
0.18
|
UACC-257
0.29
|
UACC-62
0.99
|
MDA-MB-435
0.60
|
|
The mean graph mid point values of log10 TGI and log10 LC50 as well as log10 GI50 for 7d is listed in Table-3. As demonstrated by mean graph pattern, compounds 7d exhibit an interesting profile of activity and selectivity for various cell lines. The mean graph mid points of log10 TGI and log10 LC50 have shown similar pattern to the log10 GI50 mean graph mid points.
TABLE 3
|
|
log10 GI50, log10 TGI and log10 LC50 mean graphs midpoints
|
(MG_MID) of in vitro cytotoxicity data for the compound
|
7d.against human tumour cell lines.
|
Compound
Log10 GI50
Log10 TGI
Log10 LC50
|
|
7d
−5.28
−4.18
−4.02
|
|
Significance of the Work Carried Out
The novel dihydroquinazolinone-isoxazole/isoxazoline/combretastatin hybrids that have been synthesized exhibited significant cytotoxic activity against forty nine human tumour cell lines.
ADVANTAGES OF THE INVENTION
- 1. The present invention provides a new dihydroquinazolinone-isoxazole/isoxazoline/combretastatin hybrids useful as antitumour agents.
- 2. It also provides a process for the preparation of novel dihydroquinazolinone-isoxazole/isoxazoline/combretastatin hybrids.