Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same

A heterocycloalkyl compound technology, applied in the field of aziridinyl-epothilone analog conjugates and pharmaceutical compositions containing them, can solve the problem of attacking normal tissues, uneven distribution of antigens, and host toxicity drop and other issues

Inactive Publication Date: 2009-07-29
BRISTOL MYERS SQUIBB CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, anticancer drugs often attack not only tumor cells but also normal tissues, causing unwanted side effects
In addition, anticancer drugs often have solubility issues, which can make the formulation and delivery of the drug difficult, leading to the use of drugs such as solubilizer
Cytotoxicity of some anticancer drugs and / or formulation components is known to cause neuropathy or other side effects such as anaphylaxis
These adverse side effects highlight the urgent need for anticancer treatments that are selective for pathogenic cell populations and thus cause reduced host toxicity
[0006] However, as discussed in WO 2004 / 054622A1, for many years scientists have attempted to use monoclonal antibodies (mAbs) in targeted drug therapy for the delivery of chemotherapeutic agents to patients, but have been limited in particular by cleavable moieties, linkers Difficulties with clumps and drug forms released in cells
Successful tumor therapy with mAbs has been reported to be limited by insufficient penetration of the antibody into the tumor and by uneven distribution of the corresponding tumor-associated antigen in tumor tissue

Method used

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  • Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same
  • Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same
  • Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0083] As noted above, the present invention includes compounds having the following formula I:

[0084]

[0085] And include its pharmaceutically acceptable salts and / or solvates.

[0086] According to one embodiment of the present invention,

[0087] K is O;

[0088] A to C 2-4 alkylene;

[0089] B 1 is -OH;

[0090] R 2 , R 3 , R 4 and R 5 are independently hydrogen or lower alkyl;

[0091] R 6 is hydrogen or methyl;

[0092] R 13 is an optionally substituted 5- or 6-membered heteroaryl, preferably an optionally substituted thiazolyl, pyridyl or oxazolyl; and

[0093] M for -S-R 30 -O-C(=O)-, -S-R 30 -C(=O)-or-S-R 34 R 30 -O-C(=O)-, where

[0094] R 30 is lower alkylene or substituted lower alkylene; and R 34 is arylene or substituted arylene; and R 1 , R 12 , T and Q are as described elsewhere herein, for example in the Summary section above or in the Alternative Embodiments section below.

[0095] One embodiment of the invention provides compounds ...

Embodiment 1

[0232] Example 1: Folic Acid Conjugates Epothilone Analogs

[0233] As noted above in the Summary of the Invention, analogs and derivatives of folic acid are described in Vlahov. In research and development for folate receptor targeting tumor cells conjugated to epothilone and epothilone analog compounds, several compounds were conjugated to folic acid. For example, Compound AA and Compound BB are considered candidates for conjugation with folic acid.

[0234]

[0235] Compound AA Compound BB

[0236] Compound AA was active in Phase II clinical trials, and six folate moiety conjugates of Compound AA (Compounds AA.I to AA.VI) were prepared (see Figure 1) and their chemistry was optionally tested in cell culture. Stability, FR binding and FR-mediated activity.

[0237] Binding of the folate group conjugate of compound AA to FR was determined in an assay measuring the extent of displacement of radiolabeled folate from FR expressed on KB tumor cells grown to confluence. Bindi...

Embodiment 2

[0258] Embodiment 2: preparation compound J

[0259]

[0260] (S)-2-(4-((2-Amino-4-oxo-3,4-dihydropteridin-6-yl)methylamino)benzamido)-5-((S)- 3-carboxy-1-((S)-1-((S)-3-carboxy-1-((R)-1-carboxy-2-(2-(2-((2-((1S,3S , 7S, 10R, 11S, 12S, 16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl )prop-1-en-2-yl)-5,9-dioxo-4-oxa-17-aza-bicyclo[14.1.0]heptadecan-17-yl)ethoxy)carbonyl Oxy)ethyl)dithio)ethylamino)-1-oxopropan-2-ylamino)-5-guanidino-1-oxopentane-2-ylamino)-1-oxopropane -2-ylamino)-5-oxopentanoic acid

[0261] A.[1S-[1R*, 3R*(E), 7R*, 10S*, 11R*, 12R*, 16S*]]-8,8,10,12-Tetramethyl-3-[1-methanol Base-2-(2-methyl-thiazol-4-yl)vinyl]-7,11-bis[(triethylsilyl)oxy]-4,17-dioxabicyclo[14.1.0 ] Heptadecane-5,9-dione

[0262]

[0263] Triethylsilyl chloride (15.0 mL, 89.4 mmol) was added to N 2 In a stirred solution of epothilone A (5.0 g, 10.1 mmol), imidazole (3.40 g, 49.9 mmol) and DIPEA (28.5 mL, 163.6 mmol) in anhydrous DMF (100 mL) under atmosphe...

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Abstract

The present invention is directed to conjugated compounds comprising a folate, or an analog or derivative thereof, and an aziridinyl epothilone analog, as further described herein, and / or pharmaceutically-acceptable salts and / or solvates thereof, useful in the treatment of cancer or other folate-receptor associated conditions.

Description

[0001] This application claims priority to US Provisional Patent Application 60 / 808,367, filed May 25, 2006, which is hereby incorporated by reference in its entirety. technical field [0002] The present invention relates to conjugates (conjugates) of aziridinyl-epothilone analogs (aziridinyl-epothilone analogs), more specifically to folate group conjugation of aziridinyl-epothilone analogs Folate conjugates, to pharmaceutical compositions comprising said conjugates, and to methods of using said conjugates and pharmaceutical compositions. Background technique [0003] Epothilone A and Epothilone B A naturally occurring compound isolated from the fermentation product of the microorganism Sorangium cellulosum discovered by et al. (see eg WO 93 / 10121). also found 37 natural epothilone variants and related compounds produced by S. cellulosus, including epothilone C, D, E, F and other isomers and variants. See, eg, US Patent No. 6,624,310. in 1993 et al reported the cytot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P35/00
CPCC07D491/04A61K47/48107A61K47/48338C07D519/00A61K47/65A61K47/551A61P35/00C07D487/04A61K31/519
Inventor 格雷戈里·D·维特李煜辉克里斯托弗·P·利蒙艾恩特乔·R·弗拉霍夫
Owner BRISTOL MYERS SQUIBB CO
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