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Vitamin receptor binding drug delivery conjugates

A technology of vitamin receptors and conjugates, applied in the field of targeted drug delivery compositions, which can solve the problems of tumor-specific antigen difficulties and complications

Inactive Publication Date: 2006-04-19
ENDOCTYE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these approaches have been complicated by difficulties in defining tumor-specific antigens

Method used

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  • Vitamin receptor binding drug delivery conjugates
  • Vitamin receptor binding drug delivery conjugates
  • Vitamin receptor binding drug delivery conjugates

Examples

Experimental program
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Effect test

Embodiment 1

[0331]

[0332] According to the method described in P.Fuchs et al., J.Am.Chem.Soc., 1997, 119, 10004 diethylenetriamine folic acid, gamma-amide (DETA-folate), the disclosure of which is incorporated by reference In this article. This compound (100 mg) was dissolved in 2 ml of 0.1N HCl. The resulting solution was added to K 2 PtCl 4 (158 mg) in 1 ml of 0.1N HCl was stirred. 3ml of DMSO was added and stirred continuously for 3 days, the solution was filtered, and the filtrate was precipitated in acetonitrile to obtain 170mg of yellow powder;

[0333] MS (MALDI) 1249.92, 1286.27; 1 H NMR (D 2 O) δ1.05(t, 1H), 2.3(t, 2H), 3.1(t, 2H), 4.45(m, 1H), 6.65(d, 2H), 7.5(d, 2H), 8.65(s, 1H).

Embodiment 2a

[0335]

[0336] N 10 -Trifluoroacetyl-protected folate-containing peptidyl fragment N 10-TFA-Pte-Glu-Glu-Lys-OH was prepared by a polymer-supported continuous method with the Fmoc-strategy as outlined in Scheme 12. Synthesis was performed on acid-sensitive Fmoc-Lys(Boc)-Wang resin. PyBop was used as an activator to ensure efficient coupling with low equivalent weight amino acids. The Fmoc protecting group was removed after each coupling step under standard conditions (20% piperidine in DMF). Fmoc-Glu-OtBu and N 10 -TFA-Pte-OH was used as the protected amino acid building block. After the final assembly step, the peptide is cleaved from the polymer support by treatment with trifluoroacetic acid, ethanedithiol and triisopropylsilane. This reaction also results in simultaneous removal of the t-Bu and t-Boc protecting groups. The crude peptide was purified by preparative HPLC to give N 10 - TFA salt of TFA-Pte-γGlu-γGlu-Lys-OH. A solution of 81 mg (0.1 mmol) of the resu...

Embodiment 2b

[0339]

[0340] N 10 -Trifluoroacetyl-protected folate-containing peptidyl fragment N 10 - TFA-Pte-Glu-Cys-OH was prepared by a polymer-supported sequential method with the Fmoc-strategy, as outlined in Scheme 12 and described in Example 2a. Reaction of cystamine with mitomycin A (see Matsui et al., J.Antibiot.21, 189-198 (1968); Vias et al., J.Org.Chem.51, 4307-4309 (1986)) gives Disulfides of mitomycin C derivatives with free amino groups, which are coupled to levulinic acid followed by subsequent carbonyl reaction with maleimide-derived acylhydrazides. The resulting Michael acceptor with N 10 - TFA-Pte-Glu-Cys-OH reaction, after removal of the trifluoroacetyl protecting group with aqueous ammonium hydroxide solution (pH=10.0), precipitation from acetonitrile to give the final conjugate;

[0341] MS (MALDI) 1059.04, 1148.44, 1225.32, 1300.8; 1 H NMR (D 2 O) δ1.8(d, 2H), 1.9(s, 1H), 2.3(q, 1h), 2.45(q, 1H), 2.9(t, 1H), 3.3...

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Abstract

The invention describes a vitamin receptor binding drug delivery conjugate, and preparations therefor. The drug delivery conjugate consists of a vitamin receptor binding moiety, a bivalent linker (L), and a drug. The vitamin receptor binding moiety is a vitamin, or a vitamin receptor binding analog or a derivative thereof, and the drug includes analogs or derivatives thereof. The vitamin receptor binding moiety is covalently linked to the bivalent linker, and the drug, or the analog or the derivative thereof, is covalently linked to the bivalent linker, wherein the bivalent linker (L) comprises one or more spacer linkers, releasable linkers, and heteroatom linkers. Methods and pharmaceutical compositions for eliminating pathogenic cell populations using the drug delivery conjugate are also described.

Description

[0001] Cross References to Related Applications [0002] According to 35 U.S.C. § 119 (e) of the United States, this application claims protection of the U.S. patent application filed on January 27, 2003 with the title of "Vitamin-Receptor Binding Drug Delivery Conjugates" U.S. Patent Application No. 60 / 442,845, filed August 1, 2003, entitled "Vitamin Receptor Binding Vitamin Receptor Binding Drug Delivery Conjugates" is the priority of U.S. Patent Application No. 60 / 516,188. The entire disclosure of each of these applications is incorporated herein by reference. field of invention [0003] The present invention relates to compositions and methods for targeted drug delivery. More specifically, the present invention relates to vitamin receptor binding drug delivery conjugates for treating diseases caused by pathogenic cell populations, and related methods and pharmaceutical compositions. Background of the invention [0004] The mammalian immune system provides the means to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/00A61M36/14A61K47/54A61K47/64
Inventor I·R·弗拉霍夫C·P·利蒙M·A·帕克S·J·霍瓦德H·K·桑塔普拉姆A·萨特亚姆J·A·雷迪
Owner ENDOCTYE INC
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