Figuring out the interplay between cancer and thrombosis, with thrombin and platelet GPIIb IIIa receptor as essential gamers involved in angiogenesis and metastasis, we desired to investigate no matter whether our compounds with thrombin inhibitory and GPIIb IIIa antagonistic activity are endowed with antiangiogenic exercise. Small molecule multitarget compounds with antithrombotic, antiangiogenic and possible antimetastatic exercise would present an exciting synergistic strategy in cancer treatment which has also been reported for phosphomannopentaose sulfate , a multi element mixture of phosphomannopentaose and phosphomannotetraose sulfates and relevant heparan sulfate mimetics . The sulfated oligosaccharide PI 88 is usually a potent antiangiogenic and antimetastatic agent which also inhibits thrombin but won’t aggregate platelets .
In this paper we report on the antiangiogenic exercise of two series of our multitarget compounds combining inside the very same molecule hugely overlapped pharmacophores of thrombin inhibitors and GPIIb IIIa antagonists and seek to create a rough structureeactivity Methazolamide romance. and talk about a potential mechanism liable for their inhibition of angiogenesis. The style and synthesis of 1,four benzoxazine compounds represented by general structures 1a and 1b has become described just lately . They comprise highly integrated pharmacophores of thrombin inhibitors and GPIIb IIIa antagonists . The planning of nitriles 2a,b and triazolo pyridazine analogs 2c has also been described . The synthesis of one,4 benzodioxine analogs 10a,b and 11a,b is presented in Schemes one and 2.
The response of four nitrocatechol with epichlorohydrin within the presence of sodium hydrogen carbonate in N,N dimethylformamide in accordance to a published procedure afforded methanol whereas the response of 3 with epichlorohydrin utilizing sodium hydride like a base gave the 6 nitro isomer 5a . Each nitro isomers had been reacted with 4 hydroxybenzonitrile beneath Mitsunobu disorders IOX2 to give ethers 6a and 6b which had been decreased while in the upcoming phase to amines 7a and 7b employing catalytic hydrogenation more than palladium on charcoal. The amines were benzylated employing benzaldehyde and sodium borohydride along with the resulting N benzylamines 8a and 8b acylated with ethyl oxalyl chloride to present compounds 9a and 9b. They afforded amidines 10a,b on Pinner reaction, the ester group of which was hydrolyzed towards the carboxylic acids 11a and 11b . The preparation of compounds 17a and 17b, lacking the basic benzamidine moiety is presented in Scheme 3.
The two 2H benzo oxazine derivative twelve was acetylated with acetic anhydride to give ester 13, which on catalytic reduction to amine 14 and even further benzylation with benzaldehyde or three,5 difluorobenzaldehyde afforded N benzylamines 15a and 15b.