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Medical devices containing rapamycin analogs

a technology of rapamycin and analogs, applied in the field of immunomodulatory drugs, can solve the problems of ineffective systemic effects, severe limitations of the usefulness of new procedures, and inability to provide long-term solutions to procedures, and achieve the effect of reducing the rate of restenosis and reducing the vasculature restenosis

Inactive Publication Date: 2005-02-10
MOLLISON KARL W +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Coatings that are suitable for use in this invention include, but are not limited to, polymeric coatings that can comprise any polymeric material in which the therapeutic agent, i. e., the drug, is substantially soluble. The coating can be hydrophilic, hydrophobic, biodegradable, or non-biodegradable. This medical device reduces restenosis in vasculature. The direct coronary delivery of a drug such as A-179578 is expected to reduce the rate of restenosis to a level of about 0% to 25%.

Problems solved by technology

Unsatisfactory side-effects associated with cyclosporine and FK-506 such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety, including an immunosupressive agent which is effective topically, but ineffective systemically (U.S. Pat. No. 5,457,111).
While this procedure changed the practice of interventional cardiology with respect to treatment of patients with obstructive coronary artery disease, the procedure did not provide long-term solutions.
It was determined that the existence of restenotic lesions severely limited the usefulness of the new procedure.
Radiation, however, has limitations of practicality and expense, and lingering questions about safety and durability.

Method used

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  • Medical devices containing rapamycin analogs
  • Medical devices containing rapamycin analogs
  • Medical devices containing rapamycin analogs

Examples

Experimental program
Comparison scheme
Effect test

embodiments

In one embodiment of the invention is a compound of formula

In another embodiment of the invention is a compound of formula

Preparation of Compounds of this Invention

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.

The compounds of this invention may be prepared by a variety of synthetic routes. A representative procedure is shown in Scheme 1.

As shown in Scheme 1, conversion of the C-42 hydroxyl of rapamycin to a trifluoromethanesulfonate or fluorosulfonate leaving group provided A. Displacement of the leaving group with tetrazole in the presence of a hindered, non-nucleophilic base, such as 2,6-lutidine, or, preferably, diisopropylethyl amine provided epimers B and C, which were separated and purified by flash column chromatography.

Synthetic Methods

The foregoing may be better understood by reference to th...

example 1

42-Epi-(tetrazolyl)-rapamycin (Less Polar Isomer)

example 1a

A solution of rapamycin (100 mg, 0.11 mmol) in dichloromethane (0.6 mL) at −78° C. under a nitrogen atmosphere was treated sequentially with 2,6-lutidine (53 uL, 0.46 mmol, 4.3 eq.) and trifluoromethanesulfonic anhydride (37 uL, 0.22 mmol), and stirred thereafter for 15 minutes, warmed to room temperature and eluted through a pad of silica gel (6 mL) with diethyl ether. Fractions containing the triflate were pooled and concentrated to provide the designated compound as an amber foam.

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Abstract

A medical device comprising a supporting structure having a coating on the surface thereof, the coating containing a therapeutic substance, such as, for example, a drug. Supporting structures for the medical devices that are suitable for use in this invention include, but are not limited to, coronary stents, peripheral stents, catheters, arterio-venous grafts, by-pass grafts, and drug delivery balloons used in the vasculature. Drugs that are suitable for use in this invention include, but are not limited to,

Description

TECHNICAL FIELD The present invention relates to novel chemical compounds having immunomodulatory activity and synthetic intermediates useful for the preparation of the novel compounds, and in particular to macrolide immunomodulators. More particularly, the invention relates to semisynthetic analogs of rapamycin, means for their preparation, pharmaceutical compositions containing such compounds, and methods of treatment employing the same. BACKGROUND OF THE INVENTION The compound cyclosporine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. Recently, several classes of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara et al., in European Patent Application No. 184,162, published Jun. 11, 1986, disclose a number of macrocyclic compounds isolated from the genus Streptomyces, in...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61L27/00A61K31/436A61L27/34A61L27/54A61L29/00A61L29/08A61L29/16A61L31/00A61L31/10A61L31/16A61P9/10A61P31/10A61P35/00A61P37/02A61P37/06C07D498/18
CPCA61L27/34A61L27/54A61L29/085A61L29/16C07D498/18A61L31/16A61L2300/416A61L2300/426A61L2300/606A61L31/10A61P9/10A61P31/00A61P31/10A61P35/00A61P37/02A61P37/06A61L31/148A61L2300/41A61L2300/604
Inventor MOLLISON, KARL W.LECAPTAIN, ANGELA M.BURKE, SANDRA E.CROMACK, KEITH R.TARCHA, PETER J.
Owner MOLLISON KARL W
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