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PRMT type-I inhibitor, and preparation method and application thereof

A compound and isomer technology, which is applied in the preparation of sulfides, amino compounds, chemical instruments and methods, etc., can solve the problems of off-target, poor cell membrane penetration, and no significant improvement in activity, etc.

Active Publication Date: 2018-12-07
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, most of the existing PRMTs targeting PRMTs are methyl donor SAM analogs, but because SAM is also a methyl donor for other methyltransferases in the body, these inhibitors lack selectivity and have serious off-target question
The first reported selective small molecule inhibitor is AMI-1, IC 50 The value is in the order of micromolar. Many other small molecule inhibitors such as DCLX069, DB75 and MHI-21, etc., have no significant improvement in the activity of these inhibitors, poor cell membrane penetration, and poor druggability of the molecular skeleton.

Method used

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  • PRMT type-I inhibitor, and preparation method and application thereof
  • PRMT type-I inhibitor, and preparation method and application thereof
  • PRMT type-I inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] The preparation of embodiment 1 PT-1 compound

[0130] Step i:

[0131]

[0132] Under nitrogen protection, o-chlorobenzaldehyde (14.6 grams, 1 equivalent), o-chlorothiophenol (30 grams, 2 equivalents) and potassium carbonate (43.8 grams, 3 equivalents) were added in DMF (200 milliliters) respectively, oil The bath was heated to 90°C overnight with stirring. All raw materials have been converted. Cool, pour into 2 liters of water, and extract 3 times with methyl tert-butyl ether. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain 23.5 g of a yellow solid product.

[0133] Step ii:

[0134]

[0135] The raw material (15 g, 1 eq) was dissolved in 200 ml of anhydrous methanol, cooled to 0°C, and sodium borohydride (3 g, 1.3 eq) was added in portions. Warm to room temperature and continue stirring for 20 minutes. Cool down to 0°C, add saturated ammonium chlori...

Embodiment 2

[0145] The preparation of embodiment 2 PT-1A oxalate

[0146]

[0147] The amine (200 mg, 1 eq) was dissolved in 1 mL of ethyl acetate, and a solution of oxalic acid (59 mg, 1 eq) in ethyl acetate (3 mL) was added dropwise, a precipitate was formed, and stirring was continued for 30 minutes. Filter, wash with ethyl acetate, collect, dry to obtain 253 mg of white solid product, characterization data: 1 H NMR (400MHz, DMSO-d 6 )δ7.66(d, J=7.6Hz, 1H), 7.57–7.51(m, 1H), 7.42(d, J=7.5Hz, 1H), 7.36–7.21(m, 4H), 6.94–6.83(m , 1H), 3.63(s, 2H), 2.92(t, J=6.4Hz, 2H), 2.59(t, J=6.3Hz, 2H), 2.11(s, 3H). Purity: 98.7%.

Embodiment 3

[0148] The preparation of embodiment 3 PT-1B tartrate compound

[0149]

[0150] Amine (100 mg, 1 eq) was dissolved in 1 mL of ethyl acetate, a solution of tartaric acid (74 mg, 1.5 eq) in ethyl acetate (2 mL) and methanol (1 mL) was added dropwise, and stirred overnight at room temperature. The resulting white precipitate was collected by filtration, washed with ethyl acetate, and dried to give 123 mg of the product as a white solid. Characterization data: 1 H NMR (400MHz, DMSO-d 6 )δ7.66(d, J=7.6Hz, 1H), 7.57–7.51(m, 1H), 7.42(d, J=7.5Hz, 1H), 7.36–7.21(m, 4H), 6.94–6.83(m , 1H), 3.96(s, 3H), 3.63(s, 2H), 2.92(t, J=6.4Hz, 2H), 2.59(t, J=6.3Hz, 2H), 2.11(s, 3H). Purity: 98.4%.

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Abstract

The invention discloses a PRMT type-I inhibitor, and a preparation method and an application thereof. The PRMT type-I inhibitor has a structure as shown in a formula I which is described in the specification. In the formula I, substituents are as defined in the specification and the claims. The compound provided by the invention can prepare a drug used for treating or preventing human and mammalian diseases associated with modulation of PRMT type-I abnormalities.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a multi-substituted protein arginine methyltransferase PRMTI-type activity-inhibiting compound, a preparation method, a pharmaceutical composition and an application thereof. Background technique [0002] Protein arginine methyltransferase PRMT can catalyze the methylation modification of many proteins including histone H4 in vivo. Arginine methylation is a ubiquitous post-translational modification in eukaryotes, involved in the regulation of numerous protein functions including histone methylation. The level of methylation is closely related to the physiological state of cells, which in turn affects the occurrence and development of diseases. Therefore, it is particularly important to regulate the methylation level in vivo. In mammals, the methylation modification of arginine is mainly completed by arginine methyltransferase PRMT. [0003] At present, there are 9 kinds of arginine...

Claims

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Application Information

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IPC IPC(8): C07C319/20C07C323/32C07C213/02C07C217/58C07D213/70C07D213/643C07C315/04C07C317/32C07C209/08C07C209/16C07C211/56C07D309/14C07D213/74C07D215/227C07D239/38C07D241/18C07D241/44C07D215/38C07D215/36C07D241/20C07D239/47C07D211/58C07D209/08C07C217/52C07C323/30A61K31/145A61K31/444A61K31/136A61K31/44A61K31/137A61K31/351A61K31/47A61K31/505A61K31/4965A61K31/498A61K31/5377A61K31/4465A61K31/404A61K31/135A61P35/00A61P35/02A61P9/00A61P25/28A61P33/06A61P31/18A61P19/06A61P3/10A61P13/12A61P11/00A61P27/02A61P25/36A61P9/12A61P21/00A61P1/16
CPCC07C211/56C07C217/52C07C217/58C07C317/32C07C323/30C07C323/32C07D209/08C07D211/58C07D213/643C07D213/70C07D213/74C07D215/227C07D215/36C07D215/38C07D239/38C07D239/47C07D241/18C07D241/20C07D241/44C07D309/14Y02A50/30
Inventor 罗成金甲谢轶谦姚志艺叶飞王晨蒋昊张元元陆文超蒋华良
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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