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Preparation method of 1-type receptor antagonist of novel hypertension II and application for lowering blood pressure, resisting tumors, and like

A solvent and organic solvent technology, applied in the field of medicinal chemistry, can solve the problems of toxicity, easy explosion, low oral bioavailability, etc.

Inactive Publication Date: 2010-02-03
陈志龙
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Most of the currently marketed drugs and compounds entering clinical trials contain tetrazole groups, but there are certain defects in the synthesis and metabolism of tetrazole, such as the synthesis of which requires the use of toxic and explosive azide compounds, It is easily metabolized in the form of glucuronidation in the body, resulting in a shortened existence time of the compound in the body (Drug Metab Dispos, 1993, 21: 792-799)
And when containing 2 acid groups (tetrazolium and carboxyl) in the compound, because its polarity is big, general oral bioavailability is not high, needs to form prodrug to improve oral (Bioorg Med Chem Lett, 1944,4: 201-206)

Method used

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  • Preparation method of 1-type receptor antagonist of novel hypertension II and application for lowering blood pressure, resisting tumors, and like
  • Preparation method of 1-type receptor antagonist of novel hypertension II and application for lowering blood pressure, resisting tumors, and like
  • Preparation method of 1-type receptor antagonist of novel hypertension II and application for lowering blood pressure, resisting tumors, and like

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] This compound: the preparation method of N-[4-(2-(5-oxo-1,2,4-oxadiazole) phenyl) benzyl]-N-propionyl-L-valine specifically includes the following step:

[0017] Step 1: Synthesis of (L)-valine methyl ester hydrochloride

[0018] Add 5.0mL of anhydrous methanol to a 50mL three-necked flask at room temperature, stir, slowly add 1.0mL of thionyl chloride (13.9mmol) dropwise, after the dropwise addition, stir for 30min, add 1.0g (L)-valine (8.55mmol), stirred overnight, and evaporated the solvent under reduced pressure. Recrystallized from methanol-ether (1:5) to obtain 1.35 g of a colorless needle-like solid, yield 94.8%, mp: 128-132°C.

[0019] Step 2: Synthesis of N-[4-(2-cyanophenyl)benzyl]-L-valine methyl ester

[0020] in N 2 Under protective conditions, dissolve 2.0g (L)-valine methyl ester hydrochloride (12.0mmol) in 15.0mL DMF, stir, add 5mL triethylamine (39.1mmol) dropwise, and then add 3.0g 2 '-cyano-4-bromomethylbiphenyl (11.0 mmol).

[0021] React at 70...

Embodiment 2

[0032] Embodiment 2 antihypertensive drug activity screening experiment

[0033] Experimental animals: 30 spontaneously hypertensive rats (SHR), healthy, male, purchased from Shanghai Bikai Experimental Animal Co., Ltd., certificate number: Shanghai Donghe Zhengzi No. 152;

[0034] Test drug: antihypertensive active compound N-[4-(2-(5-oxo-1,2,4-oxadiazole)phenyl)benzyl]-N-propionyl-L-valine ( Compound 1).

[0035] Positive control drug: irbesartan, the clinical dosage is 150mg / kg, assuming that the body weight is 60kg, the human dosage is 15 / 6mg / kg, which is converted into a rat dosage of 15mg / kg.

[0036] Experimental method: 30 spontaneously hypertensive rats (SHR) models were selected and divided into blank group, positive control group, and compound 1 administration group, and a small animal non-invasive blood pressure transducer was connected to MPA-HBBS after carrier amplification Type conscious free-moving animal blood pressure recording and analysis system (Shanghai...

Embodiment 3

[0044] Embodiment 3 pair mouse S 180 sarcoma activity test

[0045] Test animals: Outbred Kunming strain mice with an average weight of 18-24g, S 180 Sarcoma mice (provided by the Institute of Materia Medica, Chinese Academy of Sciences).

[0046] Drugs to be tested: compound 1, irbesartan and losartan were dissolved in a minimum amount of Tween-80 in physiological saline under aseptic conditions and diluted to 10 mg / mL solution for later use.

[0047] Compound 1 on mouse S 180 Sarcoma anti-tumor activity experiment: Subcutaneous inoculation of S 180 For sarcoma, when the tumor grows to a diameter of 4-6 mm, select mice that grow well, have no ulcers, and have a hemispherical single tumor, and randomly divide them into groups according to the same sex in the same litter, with 8 mice in each group. As a blank control, irbesartan and losartan were prepared with the same concentration solution as a positive control, and 14 days after administration, the mice were sacrificed, ...

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Abstract

The invention discloses a novel phenylaniline compound which is formed by organically connecting biphenyl with amino acid and oxadiazole and is the 1-type receptor antagonist of a novel hypertension II. The compound can be used for preparing medicines for preventing or treating diseases, such as high blood pressure, coronary heart disease, cardio-cerebral renovascular disease, splitting headache,splitting headache, and the like and can be used for effectively inhibiting the multiplication and the mobility of carcinomas in situ, such as gastric cancer, pancreatic cancer, oophoroma, prostatic cancer, lung cancer, bladder cancer, liver cancer, renal carcinoma, breast cancer, cervical carcinoma, colon carcinoma, and the like.

Description

[0001] The present invention relates to the field of medicinal chemistry, in particular to a class of drugs with the functions of preventing and treating hypertension, other cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and other diseases and effectively inhibiting various carcinomas in situ, such as breast cancer and prostate cancer. Drugs for the proliferation and migration of tumor cells such as pancreatic cancer and liver cancer. Background technique [0002] The renin-angiotensin system (RAS) is an important factor in the regulation of blood pressure and electrolyte balance. Angiotensinogen secreted by the liver is converted into angiotensin I (Ang I) under the action of renin. Ang I generates angiotensin II (Ang II) under the action of angiotensin converting enzyme (ACE). Ang II receptors mainly include Ang II type 1 receptors (AT 1 receptor), AngII type 2 receptor (AT 2 receptor) two receptor subtypes. At present, it is believed that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D271/07A61K31/4245A61P9/12A61P9/10A61P9/00A61P25/06A61P35/00A61P35/04
Inventor 陈志龙温彩红朱林锋田娟梁丽莎丁志楼达雅静
Owner 陈志龙
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