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Phthalazines derivatives, preparation method thereof, medicament composition and use

A derivative, phthalazine technology, applied in the fields of new phthalazine derivatives and their preparation methods, pharmaceutical compositions and uses, to achieve high bioavailability

Inactive Publication Date: 2007-11-28
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the above-mentioned anticancer compounds have made great contributions to the field, research continues in the field in order to improve anticancer drugs

Method used

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  • Phthalazines derivatives, preparation method thereof, medicament composition and use
  • Phthalazines derivatives, preparation method thereof, medicament composition and use
  • Phthalazines derivatives, preparation method thereof, medicament composition and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 (FVE-3)

[0049]

[0050] 0.48 grams of sodium hydride (60%) (12 mmol) and 50 milliliters of anhydrous tetrahydrofuran were placed in a 100 milliliter flask, and a solution of 1.28 grams (10 millimoles) of p-chloroaniline dissolved in 10 milliliters of anhydrous tetrahydrofuran was added dropwise with stirring , then heated to reflux for one hour, cooled to room temperature, added 2.6 grams (12 mmol) of di-tert-butoxyformic anhydride, stirred for 0.5 hours and then heated to reflux for 14 hours, cooled to room temperature, neutralized by adding saturated ammonium chloride aqueous solution, and Wash with saturated sodium bicarbonate, water, and saturated saline solution, dry over anhydrous sodium sulfate, and spin off the solvent to obtain N-tert-butoxyformyl-p-chloroaniline, which is directly used in the next reaction after drying.

[0051] 1 H NMR (400MHz, CDCl 3 ), δ (ppm) 7.32-7.22 (m, 4H, ArH), 6.48 (S, 1H, NH), 1.53 (S, 9H, CH3).

[0052] MS-FAB: M ...

Embodiment 2

[0058]

[0059] Dissolve 346 mg (1 mmol) of 1-(4-chloroanilino)-4-(4-pyridylmethylene)phthalazine in 15 mL of dry N,N-dimethylformamide, add 1 mL of anhydrous Triethylamine, then dropwise added 129 mg (1.2 mmol) of ethoxyformyl chloride and 5 ml of N,N-dimethylformamide solution, stirred at room temperature until the raw material point disappeared, poured into 100 ml of ice water, acetic acid Extracted three times with ethyl ester, combined the extracts, washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, spun off the solvent, and separated the residue by column chromatography to obtain the title product.

[0060] 1 H NMR (400MHz, CDCl 3 ), δ (ppm) 8.88 (d, 1H, J=8.0Hz, ArH), 8.00 (m, 2H, ArH), 7.85 (m, 1H, ArH), 7.60 (m, 5H, ArH), 7.02 (m , 1H, ArH), 6.78(m, 2H, ArH), 6.37(d, 1H, CH2), 5.88(S, 1H, CH2), 4.42(m, 2H, CH2), 1.41(t, 3H, CH3) .

[0061] MS-FAB: M + +1 = 419.8.

Embodiment 3

[0063]

[0064] Dissolve 346 mg (1 mmol) of 1-(4-chloroanilino)-4-(4-pyridylmethylene)phthalazine in 10 mL of dry N,N-dimethylformamide, add 1 mL of anhydrous Triethylamine, then dropwise add 163 milligrams (1.2mmol) isobutoxyformyl chloride and 5 milliliters of N, the solution that N-dimethylformamide forms, stir at room temperature until raw material point disappears, pour into 100 milliliters of ice waters, Extract with ethyl acetate three times, combine the extracts, wash with water and saturated aqueous sodium bicarbonate solution, dry over anhydrous sodium sulfate, spin off the solvent, and separate the residue by column chromatography to obtain the title product.

[0065] 1 H NMR (400MHz, CDCl 3 ), δ (ppm) 8.68 (d, 1H, ArH), 7.89 (m, 3H, ArH), 7.59 (m, 1H, ArH), 7.43 (m, 2H, ArH), 7.22 (m, 3H, ArH) , 6.90(m, 2H, ArH), 6.25(d, 1H, CH2), 5.98(S, 1H, CH2), 4.11(m, 2H, CH2), 2.05(m, 1H, CH), 0.99(d, 6H, CH3).

[0066] MS-FAB: M + +1 = 447.9.

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Abstract

The present invention discloses serial new 1-amido-4-(pyridyl-4-methylene) phthalazine derivatives and their medicinal salts, hydrates, solvolytes, precursors, precursor derivatives, and compositions, and their preparation process and pharmacological use, especially in preparing medicines for treating hypertrophic diseases, such as tumor, inflammatory rheumatism, rheumatoid diseases, etc and diseases caused by vascularization disorder, such as eye' s maculopathy, retinopathy, etc.

Description

technical field [0001] The present invention relates to a series of novel 1-amido-4-(pyridine-4-methylene)phthalazine derivatives of general formula I, its pharmaceutically acceptable salts, its hydrates and solvates, its polymorphs and Co-crystals, precursors or derivatives thereof that also have biological functions, methods for their preparation, compositions containing one or more of these compounds, and pharmaceutical uses of such compounds, especially for proliferative diseases, such as neoplastic diseases Treatment, inflammatory rheumatic and rheumatoid diseases and pain, diseases caused by neovascularization such as ocular macular degeneration and retinopathy. Background technique [0002] Currently, cancer is still one of the deadliest diseases. Chemotherapy is an important means to inhibit tumor growth and cancer cell proliferation, and make tumor regression. Most of the traditional chemotherapeutic drugs are cytotoxic drugs that directly attack DNA or inhibit its...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61K31/502A61P35/00A61P29/00A61P27/02
Inventor 冯志强陈晓光李永强付剑江
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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