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Taxane anticancer agents

a technology of anticancer agents and taxane, which is applied in the field of taxane anticancer agents, can solve the problems of inability to provide preparation details and inability to predict the formation of s in vivo, and achieve the effects of preventing or reducing the appearance of sclerosis, preventing or reducing the risk of sclerosis, and significant inhibitory

Inactive Publication Date: 2002-02-07
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0060] The new products that have the general formula I display a significant inhibitory effect with regard to abnormal cell proliferation, and have therapeutic properties that make it possible to treat patients who have pathological conditions associated with an abnormal cell proliferation. The pathological conditions include the abnormal cellular proliferation of malignant or non-malignant cells in various tissues and / or organs, including, non-limitatively, muscle, bone and / or conjunctive tissues; the skin, brain, lungs and sexual organs; the lymphatic and / or renal system; mammary cells and / or blood cells; the liver, digestive system, and pancreas; and the thyroid and / or adrenal glands. These pathological conditions can also include psoriasis; solid tumors; ovarian, breast, brain, prostate, colon, stomach, kidney, and / or testicular cancer, Karposi's sarcoma; cholangiocarcinoma; choriocarcinoma; neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granulocytic lymphomas. The novel products in accordance with the invention are particularly useful in the treatment of non-Hodgkin's lymphoma, multiple myeloma, melanoma, and ovarian, urothelial, oesophageal, lung, and breast cancers. The products in accordance with the invention can be utilized to prevent or delay the appearance or reappearance, or to treat these pathological conditions. In addition, the compounds of formula I are useful in treating and / or preventing polycystic kidney diseases (PKD) and rheumatoid arthritis. The compounds of this invention may also be useful for the treatment of Alzheimer's disease. While some of the products of general formula I are of interest due to advantages over commercial taxanes following iv administration others are of interest due to their unique properties after oral administration.

Problems solved by technology

This application also does not provide details of the preparation of any C-7 deoxy taxanes which are not covered by the above mentioned U.S. patent.
However, one reference in the patent literature mentions in passing that the para hydroxy phenyl metabolite might have an improved therapeutic index despite reduced potency and thus it's formation in vivo may be fortuitous.
However, this patent does not describe the synthesis or administration of para-hydroxyphenyl taxanes nor any actual efficacy results.

Method used

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  • Taxane anticancer agents
  • Taxane anticancer agents
  • Taxane anticancer agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0089] 8

[0090] 7-Deoxy-paclitaxel. (1) The 2'-O-triethylsilyl-7-deoxy-6,7-olefin of paclitaxel (1.2 g, 1.26 mmol) prepared according to the method of Johnson et al. was dissolved in 20 mL of ethanol and 1.51 g of 10% Pd on carbon added. The solution was shaken under an atmosphere of 65 psi of hydrogen for 48 hours. The catalyst was removed by filtration and the solution concentrated to give 1.192 g of product (quant.). The product (805 mg, 0.845 mmol) in 20 mL of acetonitrile was treated at 0.degree. C. with 1N HCl (1.69 mL, 1.69 mmol) for 1 hour. The solution was diluted with ethyl acetate and washed with saturated bicarbonate and brine. The organic fraction was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel using 1:1 hexane-ethyl acetate to give 655 mg of product (83% overall yield).

[0091] ESIMS m / z 838 (M+H) IR(KBr) 3442 (br), 1733, 1715, 1243 cm-1 1H NMR (CDCl3, 300 MHz) .delta.8.15 (d, J=7.2 Hz, 2H), 7.72 (d, J=7.2 Hz, 2H), 7.63-7.31 (m, 11H)...

example 2

[0093] 9

[0094] 7-Deoxy Baccatin III. (2) To a solution of 7-deoxy paclitaxel (461 mg, 0.55 mmol) in 20 mL of methylene chloride and 0.4 mL of methanol was added Bu4NBH4 (283 mg, 1.1 mmol) and the solution stirred for 24 hours. The solution was quenched with saturated NH4CI and extracted with ethyl acetate. The solution was dried over MgSO4 and concentrated. The residue was chromatographed over silica gel using hexane-ethyl acetate (1:1) to give 249 mg of product (79%).

[0095] FABMS m / z 699 (M+Na) IR(film) 3514 (br), 1734, 1712, 1374, 1274, 1242, 1110, 1070, 1018, 754 cm-1 1H NMR (CDCl3, 300 MHz) .delta.8.09 (d, J=8.6 Hz, 2H), 7.58 (t, J=7.3 Hz, 1 H), 7.45 (t, J=7.3 Hz, 2H), 6.44 (s, 1 H), 5.59 (d, J=7.3 Hz, 1 H)m 4.93 (d, J=9.5 Hz, 1 H), 4.82 (br t, 1 H), 4.22 (ABq, J=37.0, 8.3 Hz, 2H), 3.81 (d, J=7.2 Hz, 1H), 3.27 (d, J=5.7 Hz, 1H), 2.4-1.4 (m, 6H), 2.25 (s, 3H), 2.19 (s, 3H), 1.69 (s, 6H), 1.08 (s, 3H), 1.04 (s, 3H).

[0096] Anal. Calcd for C31H38O10: C,65.25; H, 6.71; N, 0.00. Found...

example 3

[0097] 10

[0098] 4-(tert-butyldimethylsilanyloxy)benzaldehyde. (3) 4-Hydroxybenzaldehyde (20 g, 0.164 mol) was dissolved in DMF (60 ml) and stirred at RT as imidazole (22.3 g, 0.328 mol) and tert-butyidimethylsilyl chloride (32.1 g, 0.213 mol) were added. The reaction mixture was stirred for 16h. The solution was diluted with EtOAc, washed with water, brine, then dried (MgSO4) and concentrated in-vacuo to afford 24 g of crude 4-(tert-butyidimethylsilanyloxy)benzalde-hyde.

[0099] 1H NMR (CDCl3) .delta.9.87 (1H, s), 7.79-7.76 (2H, m), 6.94-6.92 (2H, m), 0.98 (9H, s), 0.22 (6H, s).

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Abstract

The present invention concerns novel 7-deoxy taxane derivatives, their use as antitumor agents, and pharmaceutical formulations.

Description

[0001] 1. Field of the Invention[0002] The present invention concerns antitumor compounds. More particularly, the invention provides novel paclitaxel derivatives, pharmaceutical formulations thereof, and their use as antitumor agents.[0003] 2. Background Art[0004] Paclitaxel is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia and the active constituent of the anticancer agent TAXOL.RTM.. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is used clinically against a number of human cancers. It is an important cancer agent both therapeutically and commercially. Numerous clinical trials are in progress to expand the increase the utility of this agent for the treatment of human proliferative diseases. The results of TAXOL.RTM. clinical studies have been reviewed by numerous authors. A ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/337A61K31/341A61P35/00C07D305/14C07D407/12
CPCC07D305/14C07D407/12A61P35/00
Inventor KADOW, JOHN F.SCHWARTZ, WENDY S.SCOLA, PAUL M.XUE, QIUFEN MAYWITTMAN, MARK D.WU, MU-JEN
Owner BRISTOL MYERS SQUIBB CO
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