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A kind of acyl guanidine compound and its preparation method and application

A compound and drug technology, applied in the field of medicine, can solve problems such as insufficient intestinal absorption, limitation of dosage form and route of administration, low water solubility, etc.

Active Publication Date: 2020-11-13
天津泰普制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the low water solubility of tolvaptan and insufficient intestinal absorption, the dosage form and route of administration are subject to many restrictions

Method used

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  • A kind of acyl guanidine compound and its preparation method and application
  • A kind of acyl guanidine compound and its preparation method and application
  • A kind of acyl guanidine compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]

[0049] Add 30g of compound (II), 500ml of acetonitrile, 27g of compound (III), 29g of EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride) in the reaction flask, and heat up To reflux, react for 5h. After the reaction was completed, it was evaporated to dryness to obtain an oil. Add 500ml of water, stir vigorously, and filter to obtain the crude compound of formula (IV). The crude product was purified by flash preparative chromatography to obtain 38.2 g of compound (IV).

[0050]

[0051] Add the compound of formula (IV) above into 500ml of acetonitrile, add 27g of compound (III), 29g of EDCI in total, raise the temperature to reflux, and react for 48h. After the reaction was completed, it was evaporated to dryness to obtain an oil. Add 500ml of water, stir vigorously, and filter to obtain the crude compound of formula (I). The crude product was purified by flash preparative chromatography to obtain 45.5 g of compound (I). 1 H NMR: 8.11(d, 2H, ...

Embodiment 2

[0053] Add 30g of compound (II), 500ml of toluene, and 58g of EDCI in the reaction bottle, raise the temperature to reflux, add 54g of compound (III) in two batches, and react for 9h. After the reaction was completed, it was evaporated to dryness to obtain an oil. Add 1000ml of water, stir vigorously, and filter to obtain the crude compound of formula (I). The crude product was purified by flash preparative chromatography to obtain 49.3 g of compound (I). 1 H NMR: 8.11(d, 2H, J =8.8Hz), 7.96(d, 2H, J =8.4Hz), 7.85(d, 2H, J =84Hz), 7.39(d, 2H, J =8.4Hz),7.23(dd, 2H, J =2Hz, 6.4Hz), 6.84(d, 2H, J =8.4Hz), 5.44(br s), 4.82(s, 2H), 3.81(s, 2H), 2.91(s, 3H), 2.91(s, 3H). ESI-MS: 560.3.

Embodiment 3

[0055]

[0056] Add 100ml of thionyl chloride and 27g of compound (III) into the reaction flask, stir at reflux for 4h, evaporate to dryness, entrain with toluene, and remove thionyl chloride. Add 500ml of dichloromethane, 27g of compound (III), and reflux for 12h. Evaporated to dryness, the oil (V) was obtained, which was continued to the next step without treatment.

[0057]

[0058] Add 30g of compound (II) and 29g of EDCI to tetrahydrofuran (V) solution obtained above, reflux for 48h, stop the reaction, evaporate to dryness, add 1000ml of water and stir vigorously, filter to obtain the crude compound of formula (I). The crude product was purified by flash preparative chromatography to obtain 52.8 g of compound (I). 1 H NMR: 8.11(d, 2H, J =8.8Hz), 7.96(d, 2H, J =8.4Hz),7.85(d, 2H, J =84Hz), 7.39(d, 2H, J =8.4Hz), 7.23(dd, 2H, J =2Hz, 6.4Hz), 6.84(d, 2H, J =8.4Hz), 5.44(br s), 4.82(s, 2H), 3.81(s, 2H), 2.91(s, 3H), 2.91(s,3H). ESI-MS: 560.3.

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PUM

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Abstract

The invention discloses an acyl guanidine compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the compound. The invention also discloses a pharmaceutical composition taking the compound or pharmaceutically acceptable salt thereof as an active ingredient, and their application tothe prevention or treatment of diseases (such as hypertension, chronic congestive heart failure, antidiuretic hormone secretion disorder syndrome or hyponatremia caused by chronic heart failure / livercirrhosis / antidiuretic hormone secretion disorder) related to an arginine vasopressin V1a receptor, an arginine vasopressin V1b receptor and an arginine vasopressin V2 receptor.

Description

technical field [0001] The present invention belongs to the technical field of medicine, more specifically, it relates to a compound having an acylguanidine structure and a preparation method thereof, a pharmaceutical composition containing them and as an arginine vasopressin receptor antagonist, especially arginine Vasopressin V 2 Use of receptor antagonists. Background technique [0002] Arginine vasopressin (AVP) is a peptide hormone that regulates the reabsorption of free water, the osmotic pressure of body fluids, blood volume, blood pressure, cell contraction, cell proliferation, and adrenocortical hormone (ACTH). play an important role in secretion. Arginine vasopressin via V 1a , V 2 , and V 1b It plays a role in the regulation of three receptor subtypes. The distribution and physiological roles of AVP receptor subtypes are shown in the table below: [0003] Table 1 Distribution and physiological roles of AVP receptor subtypes [0004] [0005] Elevated AV...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C279/22C07C277/08A61K31/245A61P9/04A61P9/12A61P1/16A61P5/00A61P13/00
CPCA61P1/16A61P5/00A61P9/04A61P9/12A61P13/00C07C279/22
Inventor 陈蔚穆帅闫少杰王浩李树军张慕军雷勇胜崔轶达刘福景孙靖于玲丽周学福潘毅陈华
Owner 天津泰普制药有限公司
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