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

A compound, the technology of isoindole, applied in the fields of 1,3-dihydro-1-oxo-2H-isoindole compounds, their preparation and application, can solve the problems of short half-life, low bioavailability and large-scale preparation And other issues

Inactive Publication Date: 2014-07-09
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

[0041] Preparation of 3-(6-(3-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropion hydrochloride (I-1) and trifluoroacetate

[0042]

[0043] Step (a): Add 10.0mmol of 2-formyl-5-nitrobenzoic acid (4), 12.0mmol of β-phenyl-β-alanine methyl ester and 80ml of methanol into the reaction flask, and stir at room temperature for 2.0h , slowly add NaBH under cooling in an ice-water bath 4 10.0mmol, insulated and stirred for reaction (the reaction process is monitored by TLC), after the reaction, the solvent was evaporated under reduced pressure, 20ml of acetic acid was added to the residue, 80°C was incubated for 40min, and 100ml of deionized water was added to the reaction bottle, and the precipitated Solid, the filter cake was washed with aqueous sodium carbonate solution, dried to obtain 3-(6-nitro-1-oxoisoindol-2-yl)-3-phenylpropionic acid methyl ester, yield 90.0%, ESI- MS (m / z, +Q): 341.0 [M+H] + ;

[0044] Step (b): Add 10.0mmol of 3-(6-nitro-1-oxoisoindol-2-yl)-3-ph...

Embodiment 2

[0049] Preparation of 3-(6-(4-guanidinobenzamido)-1-oxoisoindol-2-yl)-3-phenylpropion hydrochloride (I-2)

[0050]

[0051] The operation process is the same as in Example 1, except that the m-guanidinobenzoic acid hydrochloride in the step (c) is replaced with p-guanidinobenzoic acid hydrochloride, and the condensing 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

[0053] 3-[6-[3-[(4,5-Dihydro-1H-imidazol-2-yl)amino]benzamido]-1-oxoisoindol-2-yl]-3-phenylpropane Preparation of hydrochloride (I-3)

[0054]

[0055] The operation process is the same as in Example 1, except that the m-guanidinobenzoic acid hydrochloride in the step (c) is 3-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid salt Salt replacement, the condensing agent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride is replaced by DCC, and 3-[6-[3-[(4,5-dihydro -1H-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=17.6Hz...

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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-oxo-2H-isoindole compounds (I) and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions and preparation methods. Prevention and / or treatment of various factor 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 by certain transient, specific physiological processes, such as reproduction, developmental processes, and wounds. Healing process, etc., while persistent...

Claims

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Application Information

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