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Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs

a technology of thalidomide and analogues, which is applied in the field of synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs, can solve the problems of increased thickness of lesion, increased risk of metastasis, and tumors progressing to large cavernous and infiltrative forms, so as to inhibit unwanted angiogenesis, inhibit angiogenesis, and be easily administered.

Inactive Publication Date: 2007-05-10
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0040] In accordance with the present invention, compositions and methods are provided that are effective in inhibiting unwanted angiogenesis. These compositions are easily administered by different routes including oral and can be given in dosages that are safe and provide angiogenic inhibition at internal sites. The present invention provides a method of treating mammalian diseases mediated by undesired and uncontrolled angiogenesis by administering a composition comprising an anti-angiogenic compound in a dosage sufficient to inhibit angiogenesis.
[0045] One object of the present invention is to provide a compound and method to inhibit unwanted angiogenesis in a human or animal.

Problems solved by technology

The onset of neovascularization leads to increased thickness of the lesion and an increased risk of metastasis.
In more severe cases, the tumors progress to large cavernous and infiltrative forms and create clinical complications.
Systemic forms of hemangiomas, hemangiomatoses, have a high mortality rate.
Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use.
In wound healing, excessive repair or fibroplasia can be a detrimental side effect of surgical procedures and may be caused or exacerbated by angiogenesis.
Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction.
The toxicity of protamine limits its practical use as a therapeutic.
Thus, there are concerns regarding its use in women of child-bearing age.
Although minimal, there are a number of side effects which limit the desirability of thalidomide as a treatment.
One such side effect is drowsiness.
In a number of therapeutic studies, the initial dosage of thalidomide had to be reduced because patients became lethargic and had difficulty functioning normally.
Another side effect limiting the use of thalidomide is peripheral neuropathy, in which individuals suffer from numbness and disfunction in their extremities.

Method used

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  • Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs
  • Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs
  • Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0111] Synthesis of 3-hydazino-thalidomide and 3-hydoxylamino-thalidomide: 3-hydoxylamino-thalidomide 3-hydazino-thalidomide was synthesized as depicted in FIGS. 1 and 2.

[0112] First, N-carboxybenzyloxy-L-gluteramide (1) was synthesized. Synthesis of N-carboxybenzyloxy-L-gluteramide (1): Into a stirring solution of carboxybenzyloxy-L-glutamine (2.8 g, 10 mmols) in 40 mL THF anhydrous, 1,1-carbonyldiimidazole (1.92 g, 12 mmols) was added. (Alternatively, carboxybenzyloxy-L-glutamine can be cyclized by N,N-Dicyclohexylcabdiimide in THF or in dichloromethane to carboxybenzyloxy-L-gluteramide). The reaction mixture was heated under reflux for 18 hours. The THF was evaporated and the product was dissolved in chloroform. The chloroform layer was washed with water and brine and dried over CaSO4 anhydrous, filtered and evaporated to give white solid. The solid product was crystallized from ethyl ether to give 2.4 grams crystalline powder (90%). 1H NMR in CDC13 confirmed the product as carb...

example 2

[0119] Synthesis of S-(−)-(3-benzyloxycarbonylamino)-glutarimide: Into a stirring solution of carboxybenzyloxy-L-glutamine (2.8 g, 10 mmols) in 40 mL THF anhydrous, 1,1-carbonyldiimidazole (1.92 g, 12 mmols) were added. The reaction mixture was heated under reflex for 18 hours. The THF was evaporated and the product was dissolved in chloroform. The chloroform layer was washed with water and brine and dried over CaSO4 anhydrous, filtered and evaporated to give white solid. The solid product was crystallized from ethyl ether to give 2.4 grams crystalline powder (90%). Alternatively, carboxybenzyloxy-L-glutamine can be cyclized by treating with SOC12 in DMF at about −70° C. to about 0° C. for 1 hour to S-(−)-(3-benzyloxycarbonylamino)-glutarimide. The reaction mixture was diluted with CHC13 and washed with 5% Na2C03, dried over Na2SO4 anhydrous, filtered, and evaporated to give 2.5 g (90%) S-(−)-(3-benzyloxycarbonylamino)-glutarimide). 1H NMR in CDC13 confirmed the product as S-(−)-(3-...

example 3

[0120] Synthesis of S-(−)-3-Amino-glutarimide.HBr: Into a solution of S-(−)-(3-benzyloxycarbonylamino)-glutarimide (1.2 g, 4.6 mmols) in 15 mL acetic acid glacial, 8 mL of 30% HBr / acetic acid solution was added at 20° C. The temperature of reaction mixture was raised to RT and stirred for 1 hour. White solid powder of S-(−)-2-Amino-gluteramide.HBr started appearing in the reaction mixture. The solid was filtered and washed with 5 mL acetic acid glacial and then with ether to give 1.8 g (80%) product. Analysis on polarimeter of product showed (−) rotation, [a]25D (c=1, water)=−37.50 and confirmed the product as S(−)-2-amino-gluteramide. 1H NMR in DMSO-D6 confirmed the product as 2-amino-L-gluteramide.HBr. 1H NMR (DMSO-D6, PPM), 11.60 (1H, s broad), 8.45 (3H, s broad), 4.4 (1H, dd, J=4.5, 3), 2.85-2.45 (2H, m), 2.25-1.90 (2H, m), m. p. 279-281° C. (lit=279° C.).

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Abstract

The present invention comprises a group of compounds that effectively inhibit angiogenesis. More specifically, nitrogen-substituted thalidomide analogs and di-substituted thalidomide analogs have been shown to inhibit angiogenesis. Importantly, these compounds can be administered orally.

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] This is a division of copending U.S. application Ser. No. 10 / 213,294, filed Aug. 6, 2002, which claims priority of U.S. Provisional Patent Application Ser. No. 60 / 310,261 filed Aug. 6, 2001, both of which are incorporated herein in their entireties by reference.TECHNICAL FIELD [0002] The present invention relates to methods and compositions for preventing unwanted angiogenesis in a human or animal. More particularly, the present invention relates to a method for preventing unwanted angiogenesis, particularly in angiogenesis dependent or associated diseases, by administration of compounds such as thalidomide and related compounds. BACKGROUND OF THE INVENTION [0003] Angiogenesis is the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and em...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/454A61K31/4523A61P9/00A61P27/02C07D401/04
CPCA61K31/454C07D401/04A61P27/02A61P35/00A61P43/00A61P9/00
Inventor TRESTON, ANTHONYSHAH, JAMSHED H.D'AMATO, ROBERT J.CONNER, BARRY P.HUNSUCKER, KIMBERLY A.ROUGAS, JOHNSWARTZ, GLENN M.PRIBLUDA, VICTOR
Owner CELGENE CORP
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