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6-deoxy alpha-amino acid derivative cyclodextrin, preparation and application thereof

A derivative and amino acid technology, which is applied in the field of 6-deoxy α-amino acid derivative cyclodextrin and its preparation and application, can solve the problems of poor antagonistic effect and exclusion, and achieve stable preparation process, high yield and strong Effects of Binding and Selectivity

Active Publication Date: 2011-05-18
HANGZHOU ADAMERCK PHARMLABS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The main disadvantage of Sugammadex is that it can only antagonize the muscle relaxation antagonism caused by rocuronium bromide and vecuronium bromide. Ammonium, etc. have the disadvantage of poor reversal or antagonistic effect
[0020] The advantage is that it has better selectivity, but the structure of the compound does not include the substitution of the amino acid at the α-position and its derivatives

Method used

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  • 6-deoxy alpha-amino acid derivative cyclodextrin, preparation and application thereof
  • 6-deoxy alpha-amino acid derivative cyclodextrin, preparation and application thereof
  • 6-deoxy alpha-amino acid derivative cyclodextrin, preparation and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050]A solution of L-cysteine ​​(1.5g, 8.54mmol) in water (5ml) was added to the reaction flask, and mixed with 1M sodium bicarbonate (25.62ml) and benzyl chloroformate 1.32ml (9.41mmol). The reaction was stirred at 0°C for 4 hours, then cooled to room temperature and extracted with ether to remove excess benzyl chloroformate. The aqueous phase was acidified to PH=3 by adding hydrochloric acid, extracted with ethyl acetate, dried, and the solvent was removed to obtain the product (CD-1) with a yield of 93%.

[0051]

[0052] Weigh dry CD-16g (0.024mol), measure dehydrated 60ml DMF, add to a dry three-necked flask, stir until fully dissolved and colorless solution. The temperature of the reaction solution was lowered to -20°C under a constant temperature cooling bath, and 2.35 g (0.059 mol) of sodium hydride (60%) was slowly added in batches, protected by argon, mechanically stirred, and the temperature was controlled below -5°C. Continue to stir until no bubbl...

Embodiment 27

[0139] Dutch guinea pigs were injected with atropine 30 minutes before the operation, and after intraperitoneal anesthesia with pentobarbital sodium, the guinea pigs were fixed on the mouse board, connected to a small animal ventilator after endotracheal intubation, and the stimulation electrodes of the TOF-Watch SX muscle relaxation monitor were respectively It was connected under the skin of the left femur and posterior tibia of the guinea pig, and the left tibia was fixed on a small platform with self-made tools, and the left hind paw could move freely. The sensor was fixed on the palm of the left hind paw of the guinea pig, and the skin temperature probe was fixed on the palm of the left forepaw. Adjust 4 serial stimulations (TOF, frequency 2 Hz, wave width 0.2 ms, interval between strings 15 s), TOF stimulation voltage 5 mA; adjust the sensitivity so that T1 is stable for more than 5 min, and inject rocuronium bromide intravenously , 50mg / 5ml) 0.16mg / kg (2 times ED90 dose...

Embodiment 28

[0148] Male mice were given the compound of the present invention by tail vein injection, and the toxic reaction was observed. See Table 2 for the results.

[0149] Table 2

[0150] group

[0151] CD-30

[0152] According to literature reports, the maximum immortal dose of CN1402737's marketed product Bridion mice is 2000mg / kg, given the compounds of the present invention CD-8, CD-10, CD-19, CD-23, CD-28, CD-30 or CD-32 When the dose was 4000mg / kg, the mice were still normal, indicating that the safe dose of the compound of the present invention was doubled, and the drug safety was high.

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PUM

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Abstract

The invention provides 6-deoxy alpha-amino acid derivative cyclodextrin which is a target substance obtained by the condensation of an amino acid derivative and halogenated cyclodextrin in the presence of alkali. The 6-deoxy alpha-amino acid cyclodextrin derivatives comprise a 6-deoxy thioether alpha-amino acid derivative cyclodextrin, a 6-deoxy sulfoxide alpha-amino acid derivative cyclodextrin and a 6-deoxy sulfonyl alpha-amino acid derivative cyclodextrin. The compounds provided by the invention can be used for reversing the phenomenon of nerve muscle relaxation induced by human or animal muscle relaxants, have rapid reversing and antagonizing effects on muscle relaxation induced by the muscle relaxants, can be used for preparing medicaments with muscle relaxation antagonizing effect, have the characteristics of low production cost and wide muscle relaxation reversing and antagonizing range and have effectively increased clinical application range. More importantly, the safe dose of the compounds provided by the invention is increased by at least one time compared with the known compounds. The general formula (I) of the compounds is shown in the specifications.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to 6-deoxy α-amino acid derivative cyclodextrin and its preparation method, mainly related to 6-deoxysulfide α-amino acid derivative cyclodextrin, 6-deoxysulfoxide α-amino acid derivative Cyclodextrin, 6-deoxysulfone-based α-amino acid derivative cyclodextrin and its preparation method, as well as the use in the preparation of muscle relaxation antagonistic drugs, said compound can quickly reverse the muscle relaxation caused by muscle relaxants , and has high safety, and also has the characteristics of easy availability of reaction raw materials and low production cost. technical background [0002] In 1986, Tubashi.I. reported the synthesis of o-carboxyphenylthiocyclodextrin in J.A.C.S.; in 1995, Guillo.F. reported the synthesis of carboxymethylthiocyclodextrin; in 1996, Baer.H.H. and Santoyo-Gonzalez. F. Preparation of 2,3-dihydroxypropylthiocyclodextrin. Its structu...

Claims

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Application Information

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IPC IPC(8): C08B37/16A61K31/724A61P21/00
CPCA61K47/48A61K31/724C08B37/0012A61K9/00A61K47/40A61P21/00A61P21/02
Inventor 漆又毛
Owner HANGZHOU ADAMERCK PHARMLABS INC
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