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A class of 1,3-dihydro-1-oxo-2h-isoindole compounds and their uses

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

Inactive Publication Date: 2016-08-17
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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  • A class of 1,3-dihydro-1-oxo-2h-isoindole compounds and their uses
  • A class of 1,3-dihydro-1-oxo-2h-isoindole compounds and their uses
  • A class of 1,3-dihydro-1-oxo-2h-isoindole compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of 3-(6-(3-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropion hydrochloride (I-1) and trifluoroacetate

[0045]

[0046] Step (a): Add 10.0 mmol of 2-formyl-5-nitrobenzoic acid (4), 12.0 mmol of β-phenyl-β-alanine methyl ester and 80 ml of methanol into the reaction flask, and stir at room temperature for 2.0 h , slowly add NaBH under cooling in an ice-water bath 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] + ;

[0047] St...

Embodiment 2

[0052] Preparation of 3-(6-(4-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropion hydrochloride (I-2)

[0053]

[0054] The operation process is the same as in Example 1, except that the m-guanidine benzo hydrochloride in the step (c) is replaced with p-guanidine benzo hydrochloride, and the condensation agent 1-ethyl-3-(3-dimethyl Aminopropyl) carbodiimide hydrochloride is replaced by DCC to obtain 3-(6-(4-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropionic acid Hydrochloride, yield 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

[0056] 3-[6-[3-[(4,5-Dihydro-1 H Preparation of -imidazol-2-yl)amino]benzamido]-1-oxoisoindol-2-yl]-3-phenylpropion hydrochloride (I-3)

[0057]

[0058] The operation process is the same as in Example 1, except that the m-guanidinobenzoic acid hydrochloride in the step (c) is treated 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 ...

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Abstract

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

Description

[0001] related application [0002] This application is a divisional application, the application number of the original application is 201210038183.7, the application date is February 21, 2012, and the invention name is "1,3-dihydro-1-oxo-2H-isoindole compound , its preparation method and use”. technical field [0003] 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 [0004] Angiogenesis refers to the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/46C07D403/12C07D405/14C07D409/14C07D401/14A61K31/4035A61K31/4178A61K31/506A61K31/4439A61P35/00A61P27/02A61P19/10A61P19/02A61P9/10A61P29/00A61P21/00
CPCC07D209/46C07D401/14C07D403/12C07D405/14C07D409/14
Inventor 邓勇金晓董黄志雄吴成龙
Owner SICHUAN UNIV
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