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Isoindolone compound as well as preparation method and application thereof

A compound and composition technology, applied in the field of medicine, can solve problems such as hindering development, achieve the effects of alleviating toxic and side effects, effectively inhibiting the activity of PARP1 protease, and solving the problem of drug resistance

Active Publication Date: 2021-11-12
HEBEI KANGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, while PARP inhibitors have achieved good therapeutic effects, their limitations in the application of HRR repair-deficient tumors and the emergence of drug resistance have hindered their further development in the clinic.

Method used

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  • Isoindolone compound as well as preparation method and application thereof
  • Isoindolone compound as well as preparation method and application thereof
  • Isoindolone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of target product compound 1

[0050]

[0051] The preparation steps are as follows:

[0052] 1) Preparation of compound A-3

[0053]

[0054] 4-Bromoisoindolin-1-one (743 mg, 3.50 mmol) was dissolved in dioxane (35.0 mL) and H 2 O (3.50mL), were added 5-amino-2-fluorobenzoic acid methyl ester (800mg, 4.73mmol), Pd 2 (dba) 3 (160mg, 0.180mmol), K 3 PO 4 (2.60g, 12.3mmol) and brettphos (188mg, 0.350mmol) were reacted at 100°C for 15h. After the reaction solution was cooled to room temperature, it was filtered with diatomaceous earth, washed with ethyl acetate, dried and concentrated, and purified by column chromatography (dichloromethane:methanol=20:1) to obtain compound A-3 (white solid, 840mg, 80%) .

[0055] Compound A-3 was detected, and the detection results were as follows: 1 H NMR (400MHz, DMSO-d 6 )δ8.52(s,1H),8.13(s,1H),7.56(dd,J=6.1,3.0Hz,1H),7.41–6.83(m,5H),4.27(s,2H),3.85(s ,3H). 13 CNMR (100MHz, DMSO) δ170.6, 164.6, 164.5, 155.8 ...

Embodiment 2

[0063] Preparation of target product compound 2

[0064]

[0065] The preparation steps are as follows:

[0066] 1) Preparation of compound A-3: The preparation steps of A-3 in Example 1 were the same to obtain compound A-3.

[0067] 2) Preparation of compound A-4: The preparation steps of A-4 in Example 1 were the same to obtain compound A-4.

[0068] 3) Preparation of Compound 2

[0069] On the basis of Example 1, the difference from Example 1 is that the amine used is different, and what is used in this example is cyclobutyl (piperazin-1-yl) ketone (27.4mg, 0.170mmol), according to The synthesis steps described in Example 1 obtained the target compound 2. Flash column chromatography (dichloromethane:methanol=20:1) gave compound 2 (53.4 mg, 72%, white solid).

[0070] Compound 2 was detected, and the detection results were as follows: 1 H NMR (400MHz, Chloroform-d) δ8.17(s,1H),7.89(d,J=8.5Hz,1H),7.83(q,J=8.9Hz,1H),7.67–7.56(m,2H) ,7.49–7.43(m,2H),7.15–6.92(m,1H),4.6...

Embodiment 3

[0072] Preparation of target product compound 3

[0073]

[0074] The preparation steps are as follows:

[0075] 1) Preparation of compound A-3

[0076] The preparation steps of A-3 in Example 1 were the same to obtain compound A-3.

[0077] 2) Preparation of Compound A-4

[0078] The preparation steps of A-4 in Example 1 were the same to obtain compound A-4.

[0079] 3) Preparation of compound 3

[0080] On the basis of Example 1, the difference from Example 1 is that the amines used are different, and what is used in this example is cyclopentyl (piperazin-1-yl) ketone (28.8 mg, 0.170 mmol), according to The synthesis steps described in Example 1 obtained the target compound 3. Flash column chromatography (dichloromethane:methanol=20:1) gave compound 3 (53.6 mg, 70%, white solid).

[0081] Compound 3 was detected, and the detection results were as follows: 1 H NMR (400MHz, Chloroform-d) δ8.11(s,1H),7.99(d,J=7.5Hz,1H),7.81(q,J=8.9Hz,1H),7.67–7.56(m,2H) ,7.48–7.43(m,2H...

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Abstract

The invention provides an isoindolone compound as well as a preparation method and application thereof. The general formula of the compound or pharmaceutically acceptable salt thereof is as shown in (I), wherein R1 and R2 are independently selected from H, alkane, substituted aromatic ring group, alkyl amide or aryl amide; and n is 0 or 1. The compound or the pharmaceutically acceptable salt thereof has the effect of efficiently and reversibly inhibiting PARP1 protease activity, and is expected to relieve toxic and side effects of drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound of isoindolinone, a preparation method and an application thereof. Background technique [0002] Malignant tumor is one of the major diseases that threaten the safety of human life. At present, the treatment methods for malignant tumors mainly include surgery, radiotherapy and chemotherapy. The disadvantages of traditional antineoplastic drugs, such as high toxicity and side effects, have hindered their further clinical application. In recent years, the rapid development of small molecule targeted drugs has provided new options for the treatment of tumors [0003] The abnormality of DNA damage response pathway is an important factor leading to the occurrence and development of tumors. It can promote the rapid growth of tumor cells by promoting the accumulation of tumor driver gene mutations, the generation of tumor heterogeneity and the escape of apopto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46C07D405/12C07D401/12C07D409/12A61K31/496A61K31/454A61K31/551A61K31/4709A61P35/00A61P35/02
CPCC07D209/46C07D405/12C07D401/12C07D409/12A61P35/00A61P35/02Y02P20/55
Inventor 李金岭李金波
Owner HEBEI KANGTAI PHARMA
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