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Salt of bromine domain structural protein inhibitor and preparation method and application thereof

A technology of acid addition salts and alkyl groups, used in crystal forms and pharmaceutical compositions, the preparation of the above salts and crystal forms, and the field of salts of bromodomain structural protein inhibitors, which can solve the problem that tumor cells cannot be completely removed or completely killed. , tumor metastasis or recurrence

Pending Publication Date: 2019-12-17
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Due to the unrestricted growth, invasion and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) currently used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs

Method used

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  • Salt of bromine domain structural protein inhibitor and preparation method and application thereof
  • Salt of bromine domain structural protein inhibitor and preparation method and application thereof
  • Salt of bromine domain structural protein inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] The preparation of embodiment one formula (III) compound nitrate

[0246]

[0247] The first step: 4-bromo-7-methoxy-2-methyl-1H-pyrrolo[2,3-c]pyridine

[0248]

[0249]5-Bromo-2-methoxy-3-nitropyridine (15g, 64.3mmol) was dissolved in tetrahydrofuran (150mL), and isoallylmagnesium bromide (385mL, 192.9 mmol, 0.5 M). The reaction solution was stirred at -78°C for 3 hours, the reaction solution was quenched with saturated aqueous ammonium chloride (100 mL), the solution was extracted with ethyl acetate (100 mL×2), the organic phase was washed with saturated brine (100 mL), and anhydrous sulfuric acid Sodium dry. The organic phase was dried and spin-dried, and column separation (petroleum ether / ethyl acetate=5 / 1) gave 4-bromo-7-methoxyl-2-methyl-1H-pyrrolo[2,3-c]pyridine (5.5 g, yellow oil).

[0250] 1 H NMR (400MHz, CDCl 3 ) δ 7.80 (d, J = 5.6Hz, 1H), 7.26 (s, 1H), 4.06 (s, 3H), 2.48 (s, 3H).

[0251] The second step: 4-bromo-7-methoxy-2-methyl-1-toluenesulf...

Embodiment 2

[0290] The preparation of embodiment two formula (III) compound crystal form

[0291] Add 10.7 g of the compound of formula (III) into 18 ml of dichloromethane, and stir until it dissolves. Add 64ml of acetonitrile to the solution, stir at room temperature to precipitate a solid, stir at room temperature for 3h, filter, and rinse with 24ml of acetonitrile. Finally, the solid was dried at 35°C until constant weight, and finally an off-white solid was obtained. After testing and analysis, it has basic figure 1 The XRPD pattern shown, such as figure 2 shown in the TGA plot as well as image 3 DSC plot shown.

Embodiment 3

[0292] The preparation of embodiment trinitrate crystal form I

[0293] Weigh 40mg of the compound of formula (III), add 2mL of methanol to dissolve it, and filter it through a membrane filter. Add 96uL of 1M ethanol solution of nitric acid to the filtrate, stir at room temperature for 10min without solid formation, put the solution at 50°C and stir to volatilize. Add 2.5mL of Ethyl acetate solution until the solid was precipitated, and the solid was dried in a vacuum oven at 40°C to constant weight to obtain the nitrate salt crystal form I. After testing and analysis, it has basically Figure 4 The XRPD pattern shown, such as Figure 5 shown in the TGA graph and as Image 6 DSC plot shown.

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Abstract

The invention relates to a salt of a bromine domain structural protein inhibitor as well as a preparation method and application thereof. The invention belongs to the field of biological medicines, and relates to the salt and a crystal form of the bromine domain structural protein inhibitor as well as the preparation method and application thereof. The invention particularly relates to an acid addition salt and an acid addition salt crystal form of a compound shown as a general formula (I), a preparation method and application of a pharmaceutical composition containing a therapeutically effective amount of the salt or the crystal form. The invention discloses application of the compound serving as a BRD4 high-selectivity inhibitor to treatment of cardiovascular diseases such as cancer, inflammation, chronic liver diseases, diabetes and dyslipidemia or related diseases such as AIDS, wherein substituents in the formula (I) are as defined in the claims.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a salt, a crystal form and a pharmaceutical composition of a bromodomain structural protein inhibitor and an application thereof, as well as a preparation method of the salt and the crystal form. The invention discloses its use as a highly selective BRD4 inhibitor for treating cardiovascular diseases including cancer, inflammation, chronic liver disease, diabetes, dyslipidemia, or related diseases such as AIDS. Background technique [0002] Tumor is one of the major diseases that seriously endanger human life, and more than half of it occurs in developing countries. The overall incidence of malignant tumors in China is on the rise, and the incidence is increasing at an average annual rate of 3% to 5%. The main reasons are: aging, urbanization, industrialization, and changes in living habits. In the Chinese hospital drug market, the sales scale of antineoplastic drugs has b...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P35/02A61P29/00A61P1/16A61P3/10A61P3/06A61P9/00A61P31/04
CPCC07D471/04A61P35/00A61P35/02A61P29/00A61P1/16A61P3/10A61P3/06A61P9/00A61P31/04C07B2200/13
Inventor 詹小兰龚素娟呙临松
Owner SHANGHAI HANSOH BIOMEDICAL
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