On reviewing of literature on rapamycin and some of its derivatives; specifically used for controlling restenosis treatment, we found that the control of the restenosis after percutaneous transluminal coronary angioplasty (PTCA) still remains one of the most important limitations. Despite of early success, the occurrence of restenosis after initial PTCA is between 30 and 50%, however later years it is reduced to 20-30%, (Hamon, M. et al., Drug Therapy, 4: 291-301 (1998); Bauters C. et al., European Heart Journal, 16: 3348 (1995)). Neo-intimal hyperplasia and vascular remodelling are two major component processes considered for restenosis after PTCA, the former coming initially, the latter occurring later in the process (Hoffman, R. et al., Circulation, 94: 1247-1254 (1996); Oesterle, S. et al., American Heart Journal, 136: 578-599 (1998), Kenneth G. et al., Journal of the American collage of cardiology, 35: 583-591 (2000)).
With use of vascular remodelling process control approach, one should eliminate or reduce restenosis. This can be skilfully done by implanting a metal stent in the stenosed lumen of the arterial vessel after PTCA procedure. Coronary stents are tiny tubular scaffolds which are widely used to prevent acute reclosure or collapse of weakened vessels following angioplasty procedure. Stents are now regularly implanted in 70 to 80% of all interventional cases (Emanuele B. et Al., European Heart Journal, 24: 394-403 (2003), Schluter L. et al., Kardiovask Med., 7: 61-70 (2005).
Despite of this success, the problem of restenosis is yet to be completely understood or conquered (Hamon, M. et al., Drug Therapy, 4: 291-301 (1998); Oesterle, S. et al., American Heart Journal, 136: 578-599 (1998)) The injury in target vessel during balloon angioplasty and stent implantation procedure often induce excessive healing response, including thrombosis and cell proliferation, which eventually leads to the in-stent restenosis. There remains a need to solve the eventual renarrowing of the lumen inside the stent (i.e. restenosis) after angioplasty and stent placement experienced by many patients ((Lally C. et al., .Wiley Encyclopedia of Biomedial Engineering 2006); (Peter J. et at., Rev. Esp. Cardiol. 61: 1001-1006 (2008)).
This problem is addressed by the use of antiproliferative drugs like paclitaxel, rapamycin and its analogues as mentioned in various publications. The family of paclitaxel drug in general has cytotoxic properties hence it has limited application in the use of drug eluting stents. On the other hand drug rapamycin and its analogues are widely used for this application being non-cytotoxic (cytostatic) in nature.
In an effort to increase the potency or specificity of pharmacological action till date various structural features of rapamycin have been modified. We found number of U.S. patents such as U.S. Pat. No. 7,220,755 discloses 42-O-alkoxyalkyl rapamycin derivatives and composition comprising same, U.S. Patent. No. 2009/0209572 discloses 36-DES(3-Methoxy-4-Hydroxycyclohexyl) 36-(3-Hydroxycycloheptyl) derivatives of rapamycin, U.S. Pat. No. 7,812,155 B2 discloses process for preparing an O-alkylated Rapamycin derivatives having normal stereochemistry at the 42 position. The PCI published application 2010/0249415 A1 discloses process for preparation of Temsirolimus.
Some chemical modifications of rapamycin have been attempted in recent years. These include the preparation of O-alkylated rapamycin derivatives by Masashi Isozaki in U.S. Pat. No. 7,193,078 B2, March 2007; Pimecrolimus a rapamycin derivative by Viktor Gyollai in U.S. Pat. No. 7,279,571 B2, Oct. 2007; Tetrazole derivatives of rapamycin by Madhup Dhaon in U.S. Patent 2010/0204466 A1, August 2010 and Alkyl benzene sulfonate rapamycin derivatives by Kwang-Chung Lee in U.S. Pat. No. 7,872,122 B2, January 2011. However, these attempts were limited to manufacturing process and no further potency study of these derivatives completed. Therefore, there remains unmet need for rapamycin derivatives with improved anti-proliferative properties.
Accordingly, the object of the invention is to provide novel compounds of rapamycin which are useful as an anti-proliferative agents possessing the general structure of rapamycin wherein, the hydroxyl group in the 42-position has been modified to corresponding 42-O-(heteroalkoxyalkyl) rapamycin compounds and methods for preparing the same.