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Phosphorus-containing compound having drug actions, and preparation and application thereof

A compound and drug technology, applied in the field of medicinal compounds, can solve problems such as renal function damage, and achieve the effects of inhibiting bone resorption, high lipophilicity, and improving lipophilicity

Inactive Publication Date: 2011-09-21
NANTONG BORUI BIOMEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although bisphosphonic acid (salt) is an effective drug for the treatment of metastatic bone disease, the existing bisphosphonic acid (salt) has many clinical side effects, including: fever, flu symptoms, arthralgia, myalgia, hypocalcemia symptoms, and damage to renal function, the latter is related to the dosage, infusion volume, and frequency of infusion

Method used

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  • Phosphorus-containing compound having drug actions, and preparation and application thereof
  • Phosphorus-containing compound having drug actions, and preparation and application thereof
  • Phosphorus-containing compound having drug actions, and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] A phosphorus-containing compound, the chemical name is: 1,1-bis[bis[(3-chlorophenyl)methoxy]phosphono]-2,2-dideutero-2-imidazol-1-yl-ethanol , its structural formula is as follows:

[0034]

[0035] Above-mentioned phosphorus-containing compound can be prepared through the following steps:

[0036] (1) Phosphorous acid was added to dicyclohexylcarbodiimide, 3-chlorobenzyl alcohol and anhydrous tetrahydrofuran, the reaction solution was cooled with a liquid nitrogen basin, stirred for 15 minutes, and ultrasonically treated for 0.5 hours. The reaction solution was filtered through celite and concentrated to dryness. The residue was dissolved in ethyl acetate, washed successively with saturated sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized to obtain 1-chloro-3-[(3-chlorophenyl ) methoxyphosphonooxymethyl]phenyl (intermediate 1-1).

[0037]

[0038] (2) At room temperature, potassium ca...

Embodiment 2

[0047] A phosphorus-containing compound, the chemical name is [1-[bis(2,2,2-trifluoroethoxy)phosphoryl]-2,2-dideutero-1-hydroxyl-2-(1H-imidazole- 1-base) ethane]-(2,2,2-trifluoroethoxy) hypophosphorous acid, its structural formula is as follows:

[0048]

[0049] Above-mentioned compound can be prepared by following steps:

[0050] (1) Add potassium carbonate to 2-(1H-imidazol-1-ester) acetic acid and deuterated methanol, stir at room temperature for 18 hours, stop the reaction, and concentrate to dryness. The residue was dissolved in ethyl acetate and the organic layer was separated. Washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2-(1H-imidazol-1-ester)-dideuteroacetic acid (intermediate 2-1).

[0051]

[0052] (2) Add phosphorus trichloride dropwise to the suspension of intermediate 2-1 and methanesulfonic acid (98-99%) under stirring, add water, reflux at 55°C for 12 ...

Embodiment 3

[0057] A phosphorus-containing compound, the chemical name is benzyloxy-(2,2-dideutero-1-dibenzyloxyphosphoryl-1-hydroxyl-2-(1H-imidazol-1-yl)ethane) times Phosphoric acid, its structural formula is as follows:

[0058]

[0059] Above-mentioned compound can be prepared by following steps:

[0060] (1), preparation of intermediate 3-1 (method is the same as in Example 2).

[0061]

[0062] (2), at room temperature and under nitrogen, slowly add to the stirred mixture of intermediate 3-1, N,N-diisopropylethylamine, tetrabutylammonium iodide and N,N-dimethylformamide Benzyl chloride, stirred for 3 days, concentrated to dryness at 35-40°C. The residue was dissolved in tert-butyl methyl ether and washed successively with water, dilute sodium bisulfite (2.5%), dilute sodium bicarbonate (2.5%), dilute hydrochloric acid (2%) and water. Dry over anhydrous sodium sulfate, filter, concentrate, and recrystallize to obtain the target product.

[0063]

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Abstract

The invention relates to a phosphorus-containing compound and application thereof. Compared with the bisphosphonate in the existing structure, the compound provided by the invention has higher lipotropism, and can reduce drug metabolism and improve effective bioavailability. When applied to the treatment of abnormal bone metabolism, the compound provided by the invention can reduce the dosage and the side effect. The phosphorus-containing compound provided by the invention has, but is not limited to, the following drug actions: improving the bone mineral density of patients with osteoporosis, reducing the fracture risk, easing the bone metastatic cancer pain, and treating bone metastasis, hypercalcemia and other diseases.

Description

technical field [0001] The present invention belongs to the field of pharmaceutical compounds, and particularly relates to a phosphorus compound, its preparation method and its application in the following medicines including but not limited to: improving the bone density of patients with osteoporosis, reducing the risk of fracture; alleviating bone metastatic cancer pain, treating tumors Diseases such as bone metastases and hypercalcemia. 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 seriou...

Claims

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Application Information

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IPC IPC(8): C07F9/6506A61K31/675A61P19/10A61P35/04A61P19/08
Inventor 殷建明朱惠霖
Owner NANTONG BORUI BIOMEDICAL
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