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Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity

A compound and drug technology, applied in the field of pharmaceutical compounds, to achieve excellent pharmacokinetic and metabolic properties, small dosage, and small side effects

Inactive Publication Date: 2011-05-04
苏州康益明华生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although bisphosphonic acid (salt) is an effective drug for the treatment of metastatic bone disease, bisphosphonic acid (salt) as a kind of intravenous drug has many side effects in clinical practice, including: fever, flu symptoms, arthralgia, muscular Pain, hypocalcemia, in addition to renal insufficiency, the latter is related to the dose, infusion volume, and frequency of infusion

Method used

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  • Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity
  • Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity
  • Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity

Examples

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Effect test

Embodiment 1

[0026] A phosphorus-containing compound, the chemical name is: di-1,3-dioxalyl-2,2-dideutero-1-hydroxyl-2-(1H-imidazole-1-ester)ethane-1,1 - diester diphosphates, the structural formula of which is as follows:

[0027]

[0028] Above-mentioned phosphorus-containing compound can be prepared through the following steps:

[0029] (1) Add potassium carbonate to 2-(1H-imidazol-1-ester) acetic acid and deuterated methanol, stir at room temperature for 18 hours, and concentrate to dryness. The residue was dissolved in ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-(1H-imidazol-1-ester)-dideuteroacetic acid (intermediate 1-1 ).

[0030] (2) Add phosphorus trichloride dropwise to the suspension of intermediate 1-1 and methanesulfonic acid (98-99%) under stirring, add water, reflux at 55°C for 12 hours, and cool the reaction solution to 10°C And add water slowly. The reaction solution ...

Embodiment 2

[0035] A phosphorus-containing compound, the chemical name is: tetramethyl [1-hydroxyl-2-(1H-imidazol-1-ester)-2,2-dideutero-ethane-1,1-diester) diphosphoric acid , which can be prepared as follows:

[0036]

[0037] At 0°C, add 2,2-dideutero-1-hydroxy-2-(1H-imidazol-1-ester)ethane-1,1-diester diphosphoric acid, triethylamine and pyridine to the mixture Methyl iodide was added slowly, the reaction solution was returned to room temperature and stirred at room temperature for 4 hours, and concentrated to dryness. The residue was dissolved in ethyl acetate, washed successively with dilute hydrochloric acid (1M), saturated sodium carbonate, water and saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain the product.

Embodiment 3

[0039] A phosphorus-containing compound, the chemical name is: 2-(1H-imidazole-1-ester)-1,1-bis(2-oxidation-1,3,2-cyclophosphamide-2-ester)-2,2 - ethanol, which can be prepared by:

[0040]

[0041] At 0°C, add 2,2-dideutero-1-hydroxy-2-(1H-imidazol-1-ester)ethane-1,1-diester diphosphoric acid, triethylamine and pyridine to the mixture Phosphorus oxychloride was slowly added, and the reaction solution was returned to room temperature and stirred at room temperature for 1 hour. Cool the reaction solution to 0°C, slowly add 3-aminopropanol, return to room temperature, stir for 1 hour; add water, stir for 1 hour, and concentrate to dryness. The residue was dissolved in ethyl acetate, washed successively with dilute hydrochloric acid (1M), saturated sodium carbonate, water and saturated brine. Dry over anhydrous sodium sulfate, filter, and concentrate to obtain the product.

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Abstract

The invention relates to phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity. Compared with bisphosphonates of existing structures, the compound in the invention can decrease oxidative metabolism, and increase the effective bioavailability. In addition, applying the compound for treatment of bone metabolism abnormity, can reduce the dosage and side effects. The phosphorus-containing compound in the invention is especially suitable for the treatment of hypercalcemia diseases.

Description

technical field [0001] The invention belongs to the field of medical compounds, and in particular relates to a phosphorus compound, its preparation method and its application in the preparation of drugs for abnormal bone metabolism. Background technique [0002] Metastatic bone disease is the most common serious complication in cancer patients, with 80% of multiple myeloma patients and 70% of breast and prostate cancer patients developing metastatic bone disease. According to different tumor types, the median survival time of patients with metastatic bone disease ranges from 6 to 48 months. Bone-related events such as bone pain, pathological fractures, hypercalcemia, and spinal cord compression caused by metastatic bone disease bring great pain to patients and seriously affect their quality of life. [0003] In the prior art, the most commonly used drug for treating metastatic bone disease is bisphosphonic acid (salt). Bisphosphonic acid (salt) is a kind of organic synthet...

Claims

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Application Information

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IPC IPC(8): C07F9/6571C07F9/6584C07F9/6506A61K31/665A61K31/675A61P19/08A61P3/14A61P35/04
Inventor 殷建明朱惠霖
Owner 苏州康益明华生物医药科技有限公司
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