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Antiangiogenic agents

an antiangiogenic agent and angiogenesis technology, applied in the field of antiangiogenic agents, can solve the problems of not being able to undergo demethylation of analogs, and achieve the effects of improving absorption, transport, biological stability, and reducing toxicity

Inactive Publication Date: 2006-06-22
ENTRE MED INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028] The present invention provides certain analogs of 2-methoxyestradiol that are effective in treating diseases characterized by abnormal mitosis and / or abnormal angiogenesis. Specifically the present invention relates to analogs of 2-methoxyestradiol that have been modified at the 2 position and the 16 position. Compounds within the general formulae that inhibit cell proliferation are preferred. Preferred compositions may also exhibit a change (increase or decrease) in estrogen receptor binding, improved absorption, transport (e.g. through blood-brain barrier and cellular membranes), biological stability, or decreased toxicity. The invention also provides compounds useful in the method, as described by the general formulae of the claims.
[0030] Since 2-methoxyestradiol is metabolized to a much less active metabolite, the present invention adds steric bulk and / or modification of electrostatic characteristics at position 16 of 2-methoxyestradiol for retarding or preventing interaction of 17β-hydroxysteroid dehydrogenases and co-factor NADP+ on this substrate. Addition of steric bulk and / or modification of electrostatic characteristics at position 16 of 2-methoxyestradiol may retard or prevent glucuronidation. It is believed that retardation or prevention of these two metabolic deactivation pathways prolongs the serum lifetime of 2-methoxyestradiol and other estrogenic compounds while retaining the desired anti-angiogenic and anti-tumor activity.
[0031] Aside from preventing the possible metabolism of 2ME2 to 2ME1, which may occur by making these steroids poor substrates for 17B-HSD (by either steric and / or electronic effects), it is not possible for these analogs to undergo the demethylation known to occur with 2ME2 since there is no methyl ether group at that position. This is desirable since it has been demonstrated that 2-hydroxyestradiol (the product of demethylation of 2ME2) has estrogenic activity.

Problems solved by technology

Aside from preventing the possible metabolism of 2ME2 to 2ME1, which may occur by making these steroids poor substrates for 17B-HSD (by either steric and / or electronic effects), it is not possible for these analogs to undergo the demethylation known to occur with 2ME2 since there is no methyl ether group at that position.

Method used

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Examples

Experimental program
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example 1

Synthesis of 2-ME Derivatives and Modifications at the 16 Position

[0079] Synthesis of the 2-ME derivatives described herein is within the capability of one ordinarily skilled in the art. A specific description of the synthesis of the 2-ME derivatives having modifications at the 2 and 6 positions and analogs discussed herein can be found in M. Cushman, H-M. He, J. A. Katzenellenbogen, C. M. Lin and E. Hamel, Synthesis, antitubulin and antimitotic activity, and cytotoxicity of 2-methoxyestradiol, and endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine binding site, J. Med. Chem., 38(12): 2042 (1995); and M. Cushman, H-M. He, J. Katzenellenbogen, R. Varma, E. Hamel, C. Lin, S. Ram and Y. P. Sachdeva, Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth, J. Med. Chem. 40(15): 2323 (1997).

[0080] The synthetic pathways used to prepare the derivatives of the...

example 2

Preparation of 3-Benzyl-2-methoxyestradiol

[0081] 2-Methoxyestradiol (10.09 g, 33.4 nmmol) and potassium carbonate (22 g, 278 mmol) were suspended in anhydrous ethanol and cooled to 0° C. Benzyl bromide (11.4 mL, 95.8 mmol) was added dropwise, and following the addition, the mixture was brought to reflux for 8 h. The solution was cooled to room temperature (rt), and the solvent was removed via rotoevap. The resulting residue was diluted with approximately 200 ml water, and washed with ethyl acetate (3×200 mL). The combined organics were washed with water (200 mL), sodium bicarbonate (saturated (satd), 200mL) and brine (200 mL). Dry with sodium sulfate, filter and roto-evaporation (rotoevap). Product was dried under vacuo with occasional gentle heating using a heat gun to give a yellowish glass (13.54 g, quanitative yield) and used without further purification.

[0082] Selected spectral data: 1H-NMR (300 MHz, CDCl3) δ 7.29-7.53 (m, 5H), 6.88 (s, 1H), 6.65 (s, 3H), 5.11 (s, 2H), 3.87 ...

example 3

Preparation of 3-Benzyl-2-methoxyestrone

[0083] Oxalyl chloride (38 mmol, 19 mL, 2M, methylene chloride) was added to anhydrous methylene chloride (25 mL) and cooled to −46° C. Methyl sulfoxide (5.40 mL, 76 mmol) was added dropwise, and the mixture was stirred for 2 minutes. 3-Benzyl-2-methoxyestradiol in methylene chloride / methyl sulfoxide (10 mL / 15 mL) and added within 5 minutes and the resulting mixture was stirred for 1 h. Triethyl amine (170 mmol, 23.5 mL) was added drop-wise, stirred 5 minutes and warmed to rt. Water (˜200 mL) was added and the mixture was washed with methylene chloride (3×200 mL). The combined organics were washed with water (200 mL), dilute HCl (1% aq., 200 mL), sodium carbonate (satd, 200 mL) and brine (200 mL). The organics were dried with magnesium sulfate, filtered and rotoevaped to give a white solid. The solid was crystallized with hot ethanol to give white crystals (9.94g, 25.5 mmol, 76% overall yield from 2-methoxyestradiol).

[0084] Selected spectra...

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Abstract

Compositions and methods for treating mammalian disease characterized by undesirable angiogenesis by administering derivatives of 2-methoxyestradiol of the general formula: wherein the variables are defined in the specification.

Description

FIELD OF THE INVENTION [0001] The present invention relates to treating disease states characterized by abnormal cell mitosis and or abnormal angiogenesis. More particularly, the present invention relates to certain analogs of 2-methoxyestradiol (2ME2) and their effect on diseases characterized by abnormal cell mitosis and / or abnormal angiogenesis. BACKGROUND OF THE INVENTION [0002] As used herein, the term “angiogenesis” means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological dama...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07J41/00C07J1/00A61K31/56
CPCA61K31/56C07J1/00
Inventor AGOSTON, GREGORY E.PRIBLUDA, VICTORTRESTON, ANTHONY M.GREEN, SHAWN J.
Owner ENTRE MED INC
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