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1,3-dihydro-1-oxo-2H-isobenzazole compounds as well as preparation method and use thereof

A technology for oxoisoindole and compounds, which is applied in the field of 1,3-dihydro-1-oxo-2H-isoindole compounds, their preparation and application, and can solve the problems of low bioavailability, difficulty in mass production, and half-life Short and other questions

Inactive Publication Date: 2012-07-25
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the shortcomings of antibodies and peptide drugs, such as in vivo degradation, short half-life, low bioavailability, intravenous administration, and difficulty in large-scale preparation, it is necessary to search for and discover non-peptide integrin α that can be administered orally with high efficiency and high selectivity. v beta 3 Inhibitors are one of the important fields of anti-angiogenesis and anti-tumor metastasis drug research at home and abroad

Method used

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  • 1,3-dihydro-1-oxo-2H-isobenzazole compounds as well as preparation method and use thereof
  • 1,3-dihydro-1-oxo-2H-isobenzazole compounds as well as preparation method and use thereof
  • 1,3-dihydro-1-oxo-2H-isobenzazole compounds as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of 3-(6-(3-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropionate hydrochloride (I-1) and trifluoroacetate

[0043]

[0044] step( a ): Add 2-formyl-5-nitrobenzoic acid ( 4 ) 10.0 mmol, β-phenyl-β-alanine methyl ester 12.0 mmol and methanol 80ml, stirred at room temperature for 2.0h, then slowly added NaBH under ice-water bath cooling 4 10.0 mmol, insulated and stirred for reaction (the reaction process was monitored by TLC), after the reaction was completed, the solvent was evaporated under reduced pressure, 20 ml of acetic acid was added to the residue, and the reaction was incubated at 80°C for 40 min, and 100 ml of deionized water was added to the reaction bottle, and the precipitated Solid, the filter cake was washed with aqueous sodium carbonate solution and dried to obtain 3-(6-nitro-1-oxoisoindol-2-yl)-3-phenylpropionic acid methyl ester with a yield of 90.0%, ESI- MS ( m / z , +Q): 341.0 [M+H] + ;

[0045] step( b ): Add 10.0 mmol of ...

Embodiment 2

[0050] Preparation of 3-(6-(4-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropion hydrochloride (I-2)

[0051]

[0052] Operation process is the same as embodiment 1, just step ( c ) in m-guanidinobenzoic acid hydrochloride is replaced by p-guanidinobenzoic acid hydrochloride, and the condensing agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride is used DCC was substituted to obtain 3-(6-(4-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropionate hydrochloride with a yield of 74.0%, 1 H NMR (400MHz, DMSO-d 6 ) δ: 12.42(brs, 1H, COOH), 11.01(brs, 1H, HCl), 10.64(s, 1H, CONH), 8.26(d, 1H, J =1.6Hz, Ar-H), 8.11(d, 2H, J =8.4Hz, Ar-H), 7.98(dd, 1H, J 1 =1.6Hz, J 2 =8.0Hz, Ar-H), 7.97(brs, 4H, NH 2 C(NH)NH), 7.52(d, 1H, J =8.0Hz, Ar-H), 7.33(d, 2H, J =8.4Hz, Ar-H), 7.40-7.27(m, 5H, Ar-H), 5.77(t, 1H, J =8.0Hz, CH), 4.52(d, 1H, J =17.6Hz, ArCH 2 ), 4.14(d, 1H, J =17.6Hz, ArCH 2 ), 3.13-3.02(m, 2H, CH 2 COOH); ESI-MS ( m / z ): 458.15 [M-Cl]...

Embodiment 3

[0054] 3-[6-[3-[(4,5-dihydro-1 H Preparation of -imidazol-2-yl)amino]benzamido]-1-oxoisoindol-2-yl]-3-phenylpropion hydrochloride (I-3)

[0055]

[0056] Operation process is the same as embodiment 1, just step ( c ) in m-guanidinobenzoic acid hydrochloride with 3-[(4,5-dihydro-1 H -imidazol-2-yl) amino] benzoic acid hydrochloride instead, condensing agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride replaces with DCC, obtains 3-[ 6-[3-[(4,5-dihydro-1 H -Imidazol-2-yl)amino]benzamido]-1-oxoisoindol-2-yl]-3-phenylpropion hydrochloride, yield 85.0%, 1 H NMR (400MHz, DMSO-d 6 ) δ: 12.44(brs, 1H, COOH), 10.89(s, 1H, HCl), 10.78(s, 1H, CONH), 8.58(s, 2H, NHCNH), 8.25(d, 1H, J =1.2Hz, Ar-H), 7.95(dd, 1H, J 1 =1.2Hz, J 2 =8.4Hz, Ar-H), 7.88-7.86(m, 2H, Ar-H), 7.59(t, 1H, J =8.0Hz, Ar-H), 7.53(d, 1H, J =8.0Hz, Ar-H), 7.45(d, 2H, J =8.0Hz, Ar-H), 7.41-7.28(m, 5H, Ar-H), 5.76(t, 1H, J =8.0Hz, CH), 4.50(d, 1H, J =17.6Hz, ArCH 2 ), 4.12(d, 1H, J =17.6H...

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Abstract

The invention discloses 1,3-dihydro-1-oxo-2H-isobenzazole compounds (I) and pharmaceutically acceptable salts thereof, and also discloses preparation methods for the compounds, and uses of the compounds in preparing medicines for preventing and / or treating various diseases caused by the mediation of integrin alpha v beta 3, such as tumor metastasis, tumor growth, solid tumor growth, angiogenesis, retinopathy, macular degeneration, osteoporosis, arthritis, smooth muscle cell migration and atherosclerosis symptoms or diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a class of 1,3-dihydro-1-oxygen-2 H - Isoindole compounds (I) and their pharmaceutically acceptable salts, their preparation methods, pharmaceutical compositions and preparations for the prevention or / and treatment of various factors integrin α v beta 3 Use of drugs in mediating the symptoms or diseases caused, including but not limited to tumor metastasis, tumor growth, solid tumor growth, angiogenesis, retinopathy, macular degeneration, osteoporosis, arthritis, smooth muscle cell migration, and atherosclerosis hardening etc. Background technique [0002] Angiogenesis refers to the process of generating a new vascular system from an existing vascular bed. Under normal physiological conditions, angiogenesis is strictly controlled in certain transient, specific physiological processes, such as reproduction, developmental processes, and wounds. Healing process, etc., while persis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46C07D403/12C07D405/14C07D409/14C07D401/14A61K31/4035A61K31/4178A61K31/506A61K31/4439A61P35/04A61P35/00A61P9/10A61P27/02A61P19/10A61P19/02A61P29/00A61P21/00
Inventor 邓勇金晓董黄志雄吴成龙
Owner SICHUAN UNIV
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