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Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof

A bimatoprost and derivative technology, applied in the field of deuterated drug compounds, can solve the problems of increasing the biological half-life of the compound, reducing the system clearance rate, etc., and achieve the effects of reducing toxic and side effects, mild action, and high safety

Inactive Publication Date: 2014-03-26
NANJING HUASHI NEW MATERIAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0026] (1) Reduce the system clearance rate and increase the biological half-life of the compound

Method used

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  • Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof
  • Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof
  • Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The preparation (1) of embodiment 1 deuterated substance (I1)

[0074] The methyl ester of formula II structure (R 2 is methyl) 12.5g (31mmol), 70% deuterated methylamine (30%D 2 (0) 150mL was added to a 250ml flask, stirred at room temperature for 50h, HPLC detected that the reaction of the raw materials was complete, concentrated to 80mL, neutralized with saturated aqueous sodium bisulfate to pH neutral, extracted with ethyl acetate (300mL) 3 times , washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction and concentrated to dryness, added an appropriate amount of isopropyl ether, stirred for 1 h, filtered with suction, and dried to obtain 10.0 g with a yield of 80.0%.

[0075] 1 HNMR (CDCl 3 )δ: 7.17-7.41 (Ar H -, m, 5H); 5.11-5.62 (-CH=C H -, m, 4H); 4.22-4.24(-O H , m, 3H); 3.17-3.55(C H -, m, 3H); 3.08(C H 2 -, m, 2H); 2.63(C H -, m, 1H); 2.73 (C H 2 -, m, 2H); 2.13-2.38 (C H -, m,...

Embodiment 2

[0076] The preparation (2) of embodiment 2 deuteriums (I1)

[0077] The methyl ester of formula II structure (R 2 Add 12.5g (31mmol) of methyl) and 100mL of deuterated methylamine (99%) into a 250ml flask, stir at 50°C for 30h, HPLC detects that the reaction of the raw materials is complete, concentrate to 50mL, and neutralize with a saturated aqueous solution of sodium bisulfate To neutral pH, extract with ethyl acetate (300mL) 3 times, wash with saturated sodium chloride aqueous solution 3 times, dry with anhydrous sodium sulfate, filter with suction and concentrate to dryness, add an appropriate amount of isopropyl ether, stir for 1 hour, filter with suction, After drying, 10.5 g was obtained with a yield of 82.0%.

[0078] 1 HNMR (CDCl 3 )δ: 7.25-7.41 (Ar H -, m, 5H); 5.22-5.57 (-CH=C H -, m, 4H); 4.11-4.38 (-O H , m, 3H); 3.17-3.69 (C H -, m, 3H); 3.07(C H 2 -, m, 2H); 2.85(C H -, m, 1H); 2.66(C H 2 -, m, 2H); 2.13-2.37(C H -, m, 10H); 1.57-1.83 (C H 2 -, m...

Embodiment 3

[0079] The preparation of embodiment 3 deuterated bimatoprost (I2) (1)

[0080] The methyl ester of formula II structure (R 2 Add 12.5g (31mmol) of methyl) and 100mL of deuterated ethylamine (99%) into a 250ml flask, stir at 50°C for 30h, HPLC detects that the reaction of the raw materials is complete, concentrate to 50mL, and neutralize with a saturated aqueous solution of sodium bisulfate To neutral pH, extract with ethyl acetate (300mL) 3 times, wash with saturated sodium chloride aqueous solution 3 times, dry with anhydrous sodium sulfate, filter with suction and concentrate to dryness, add an appropriate amount of isopropyl ether, stir for 1 hour, filter with suction, After drying, 10.9g was obtained with a yield of 84.3%.

[0081] 1 HNMR (CDCl 3 )δ: 7.25-7.41 (Ar H -, m, 5H); 5.22-5.57 (-CH=C H -, m, 4H); 4.11-4.38 (-O H , m, 3H); 3.17-3.69 (C H -, m, 3H); 3.01(C H 2 -, m, 2H); 2.85(C H -, m, 1H); 2.66(C H 2 -, m, 2H); 2.13-2.37(C H -, m, 10H); 1.57-1.83 (C ...

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Abstract

The invention relates to deuterated bimatoprost or a derivative thereof. A novel deuterated drug compound is formed by substituting an isotopic nuclide deuterium atom (D) for a hydrogen atom (H) contained in a bimatoprost structure and changing the chemical molecular structure and bond energy of the bimatoprost structure. The deuterated drug compound can be used for pharmacokinetic research, achieves obviously enhanced drug property and reduces the toxic side effect of a drug. The invention also relates to a preparation method and application of the deuterated bimatoprost or the derivative thereof.

Description

technical field [0001] The present invention relates to a deuterated pharmaceutical compound, its preparation method and application, in particular to a deuterated bimatoprost or its derivatives, their preparation method and application. Background technique [0002] Bimatoprost, (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpenta-1- Alkenyl]cyclopentyl]-N-ethylhept-5-enamide is considered to be the local anti-glaucoma drug with the strongest IOP-lowering effect at present. It is effective for normal people, POAG and OHT patients. Patients with POAG or OHT who are not treated with other IOP-lowering drugs or who are ineffective with other IOP-lowering drugs. [0003] In the molecular structure of organic compounds, the carbon-hydrogen structure is the most basic structure, and the carbon-hydrogen bond (C-H) formed is also the most basic chemical bond. The hydrogen bond is represented by X-H...Y, and the distance between X-Y is defined as the bond of the hyd...

Claims

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Application Information

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IPC IPC(8): C07C405/00A61K31/5575A61P17/14A61P27/04
Inventor 颜宁苏桂珍史鲁秋
Owner NANJING HUASHI NEW MATERIAL
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