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Water-soluble organic acid salt of tegaserod as well as preparation method and application of water-soluble organic acid salt

A technology of tegaserod and organic acid salts, which is applied in the fields of organic chemistry methods, preparation of organic compounds, preparation of carbamate derivatives, etc., can solve problems such as difficulty in swallowing, and achieve the effect of meeting different clinical drug needs

Active Publication Date: 2021-06-18
QINGDAO MARINE BIOPHARMACEUTICAL RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the clinically used tegaserod maleate is in the form of tablets and capsules, which cannot meet the needs of patients with dysphagia and other patients who are not suitable for using tablets, especially when developing its anti-tumor indication drugs, it needs to be considered The needs of different patients for dosage forms

Method used

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  • Water-soluble organic acid salt of tegaserod as well as preparation method and application of water-soluble organic acid salt
  • Water-soluble organic acid salt of tegaserod as well as preparation method and application of water-soluble organic acid salt
  • Water-soluble organic acid salt of tegaserod as well as preparation method and application of water-soluble organic acid salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: 3-(5-methoxy-1H-indole-3-methylene)-N-pentyl-iminoguanidine D-pyroglutamate (2a)

[0052] Add 3-(5-methoxy-1H-indole-3-methylene)-N-pentyl-iminoguanidine (1.0g, 3.3mmol) in a 100mL single-necked bottle, add 15mL methanol, stir at room temperature After completely dissolving, D-pyroglutamic acid (0.43 g, 3.3 mmol) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried to obtain crude product. Add 10 mL of ethyl acetate, stir at room temperature for half an hour, filter, collect the filter cake, and dry in a vacuum oven to obtain 1.3 g of the product.

[0053] Refining: Add 1.3g of the product to a 100mL single-necked bottle, add 20mL of diethyl ether at room temperature, stir for 0.5 hours and filter, collect the filter cake, and dry it in a vacuum oven overnight to obtain product 2a (1.2g, yield 84%). 1 H NMR (400MHz, DMSO-d 6 )δ11.47(s, 1H), 8.28(s, 1H), 7.75(s, 1H), 7.63(d, J=2.5Hz, 1H), 7.56(s...

Embodiment 2

[0054] Example 2: 3-(5-Methoxy-1H-indole-3-methylene)-N-pentyl-iminoguanidine 4-(fluorenylmethoxycarbonylamino)butyrate (2b)

[0055] Add 3-(5-methoxyl-1H-indole-3-methylene)-N-pentyl-iminoguanidine (100.0mg, 0.33mmol) into a 25mL single-necked bottle, add 5mL methanol, and stir at room temperature After it was completely dissolved, 4-(fluorenylmethoxycarbonylamino)butanoic acid (108.0 mg, 0.33 mmol) was added and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and dried to obtain crude product. Add 10 mL of petroleum ether, stir at room temperature for half an hour, filter, collect the filter cake, and dry in a vacuum oven to obtain 69 mg of the product.

[0056] Refining: Add 69 mg of the product to a 10 mL single-necked bottle, add 5 mL of ether at room temperature, stir for 0.5 hours and filter, collect the filter cake, and dry it in a vacuum oven overnight to obtain product 2b (52 mg, yield 25%). 1 H NMR (400MHz, DMSO-d 6 )δ1...

Embodiment 3

[0057] Embodiment 3: the water solubility determination of target compound

[0058] The excess compound to be tested was dissolved in water, oscillated at 37°C with a constant temperature oscillator to balance, centrifuged and filtered, and undissolved compounds were removed to obtain a saturated aqueous solution of the compound to be tested. Agilent 1260 high performance liquid chromatography was used to measure the peak area of ​​the saturated solution, and the concentration of the compound to be tested was calculated by establishing a standard curve between the concentration of the compound to be tested and the peak area.

[0059] Liquid phase detection conditions are: Agilent TC-C18 (2) column (specification 5 μm, 250x4.6mm) detection wavelength: 278nm; mobile phase: acetonitrile / water (containing 0.05% trifluoroacetic acid)=49 / 51; injection volume The column temperature is 25°C, the flow rate is 1mL / min, and the detection time is 15min.

[0060] Table 1. Solubility of so...

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Abstract

The invention provides a preparation method and application of a tegaserod water-soluble organic acid salt. Specifically, the invention provides a water-soluble organic acid salt of a compound as shown in a structural general formula (I). The organic salt can be used as a PI3K / Akt / mTOR and JAK-STAT3 signal channel inhibitor and an immunomodulator for use of developing drugs for treating tumors and inflammations. In the tegaserod organic acid salt provided by the invention, the solubility of the tegaserod D-pyroglutamate in water is greater than 600 mg / mL, and is improved by more than 3000 times compared with that of maleate. Therefore, obvious advantages are generated in the aspects of in-vivo pharmacokinetic behaviors of medicines, development of new dosage forms of the medicines and the like, and the compound can be used for improvement of a preparation process and development of the new dosage forms and has practicability. In the study of antitumor activity in mice, the tegaserod D-pyroglutamate has obvious inhibitory activity on prostatic cancer and melanoma, and the growth inhibitory activity on melanoma B16F10 reaches 50.6%.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a water-soluble organic acid salt of tegaserod, a preparation method and application thereof. Background technique [0002] Tegaserod, the chemical name is 3-(5-methoxy-1H-indol-3-yl-methylene)-N-pentyl-iminoguanidine, which belongs to the indole class with high selectivity 5-HT 4 Receptor partial agonist, can selectively interact with 5-HT in the gastrointestinal tract 4 The receptor binds and activates the receptor. Tegaserod activates 5-HT by 4 receptors to promote the release of acetylcholine, and then promote the peristalsis and secretion of the gastrointestinal tract, mainly used for the treatment of constipation-based irritable bowel syndrome (IBS). [0003] In recent years, studies have found that besides 5-HT, Tegaserod 4 In addition to being a partial receptor agonist, it also has an inhibitory effect on the JAK-STAT3 signaling pathway. At the same time...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14C07D207/28C07C271/54C07C269/06A61K31/404A61P35/00A61P29/00A61P35/02A61P19/02A61P17/00
CPCC07D209/14C07D207/28C07C269/06C07C271/54A61P35/00A61P29/00A61P35/02A61P19/02A61P17/00C07B2200/07
Inventor 江余祺杨金波徐同强李晓杨秦冲张心心宋巧玲徐文方徐锡明赵晨阳
Owner QINGDAO MARINE BIOPHARMACEUTICAL RES INST
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