CN101250183A

CN101250183A - Optical isomer of rebeprazole as well as preparation method and medical use thereof

Info

Publication number: CN101250183A
Application number: CNA2008101033543A
Authority: CN
Inventors: 姚勇敢
Original assignee: Beijing Rundekang Medical Technology Co Ltd
Current assignee: Beijing Rundekang Medical Technology Co Ltd
Priority date: 2008-04-03
Filing date: 2008-04-03
Publication date: 2008-08-27

Abstract

An optical isomer of rebeprazole is represented as formula I, which can be prepared by general chiral drug preparation methods as spectrum separation, asymmetry oxidation and separation. The optical isomer of rebeprazole can be used to treat digestive tract diseases, particularly to treat peptic ulcer.

Description

Optical isomer of a kind of rabeprazole and preparation method thereof, medicinal use

Technical field

The present invention relates to a kind of optical isomer of rabeprazole and preparation method thereof, medicinal use, belong to medical technical field.

Background technology

After chiral drug is meant and introduces chiral centre in the drug molecular structure, the enantiomer of a pair of in kind each other and mirror image that obtains.The physico-chemical property of these enantiomers is similar substantially, only is opticity difference to some extent, is named as R-type (dextrorotation) or S-type (left-handed), racemize respectively.The chiral drug of clinical application, except that natural and semisynthetic drug, the medicine that contains chirality of synthetic still supplies medicine based on racemic modification, accounts for more than 87% of whole synthesis of chiral medicines.And since nearly 20 years along with the going deep into of study of pharmacy work, shown the stereoselective difference of drug enantiomer, make its avidity different and cause the very big difference of pharmacological action with each acceptor.People are called excellent enantiomorph with active high enantiomorph in the chiral drug, and active enantiomorph low or non-activity is called bad enantiomorph.In many cases, bad enantiomorph does not only have drug effect, but also the drug effect of the excellent enantiomorph of meeting partial offset, sometimes even also can produce serious toxic side effects, show the complicacy of drug effect difference, also determined therapeutic index and its raceme of single enantiomer that suitable difference is arranged, the curative effect of DL-(+-) syntomycin only is half of D (-) paraxin as the well-known; The pharmaceutical activity of Proprasylyte L-isomer is bigger 100 times than D-isomer.Chiral technology has been widely applied in the exploitation of digestive system, cardiovascular diseases, cancer drug, " chirality " technology of utilization, people can reject the composition of inoperative in the medicine or toxic side effect effectively, produce homochiral medicine with single oriented structure, thereby make pharmaceutical cpd purer, curative effect is faster when the treatment disease, the course of treatment is shorter.Therefore, the research of chiral drug has become one of new side of international new drug research at present.

Rabeprazole belongs to the medicine of secretion inhibitor, is the substitute of benzoglyoxaline, no anticholinergic and anti-H2 histamine characteristic, but can be attached to the parietal cell surface by suppressing the secretion that the H+/K+-ATP enzyme comes gastric acid inhibitory.This enzyme system is counted as sour proton pump, so the generation that Sodium rabeprazole blocks hydrochloric acid in gastric juice as the proton pump inhibitor in the stomach, this effect is a dosage correlation.Animal experiment confirmation Sodium rabeprazole can be discharged from blood plasma and stomach mucous membrane after medication soon.Sodium rabeprazole is the potent inhibitor of parietal cell most advanced and sophisticated secretion film endoplasm pump (being proton pump) as benzoglyoxaline substituting agent up-to-date behind omeprazole, lansoprazole.The chemical structural formula of rabeprazole is as follows:

The rabeprazole that has gone on the market at present is a racemic modification, and the correlative study of its optical isomer is not arranged.

Summary of the invention

The present invention relates to a kind of optical isomer of rabeprazole, its chemical structure is suc as formula shown in the I:

Chemical name: (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline

The present invention also comprises the pharmaceutically acceptable metal-salt of above-mentioned optical isomer or its hydrate, solvate.Wherein the metal-salt of this optical isomer is preferably by Li ⁺, Na ⁺, K ⁺, Mg ²⁺, Ca ²⁺, Ti ⁴⁺Salt Deng the positively charged ion formation.

The invention still further relates to the preparation method of above-mentioned optical isomer or its pharmaceutically acceptable metal-salt or its hydrate, solvate, this compounds can pass through conventional chiral drug preparation method preparation such as chromatographic separation, asymmetric oxidation, fractionation and get.

Optical isomer of the present invention or its pharmaceutically acceptable metal-salt or its hydrate, solvate are mainly used in the treatment of treatment, the especially peptide ulceration of digestive tract diseases.

The optical isomer of rabeprazole can pass through conventional chiral drug preparation method preparation such as chromatographic separation, asymmetric oxidation, fractionation and get.

The optical isomer purity of rabeprazole can detect according to the following analysis method:

Chromatographic column: Chiral-AGP 100 * 4.0mm

Moving phase: phosphoric acid buffer (PH=7.0): acetonitrile=400: 70

Flow velocity: 0.5ml/min

Detect wavelength: 210nm

Embodiment

Can further describe the present invention by the following examples, yet invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.

Embodiment 1:

With 10g2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline sodium salt is suspended in the 120ml acetone; add 5.6g L-(+)-diethyl tartrate, 4g titanium isopropylate (IV), 8.2g triethylamine then; be warming up to 35～40 ℃; add 4.2gL-(+)-amygdalic acid, reaction 0.5h.Filter 50ml washing with acetone, drying.The gained solid suspension in 40ml methylene dichloride, 40ml5% sodium hydrogen carbonate solution, is stirred 0.5h, divide and get organic phase, washing, anhydrous magnesium sulfate drying.Filter, be evaporated to driedly, obtain (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline 3.6g, yield 76%.Optical purity is 99.5%e.e.Ultimate analysis: C (60.22%), H (5.96%), N (11.85%); Calculated value: C (60.09%), H (5.84%), N (11.68%).

Embodiment 2:

With 10g 2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfenyl]-[1H]-benzoglyoxaline is dissolved in the 250ml toluene, add 0.2ml water, 7.6ml L-(+)-diethyl tartrate, 5.14g titanium isopropylate (IV) then, at 50 ℃ of reaction 1h, cool to room temperature adds 2.1ml diisopropyl ethyl amine, 5.2ml80% cumyl hydroperoxide.Stirring at room reaction 2h adds 250ml toluene, with 12% ammonia extraction 3 times, and each 250ml, combining water layer, the Glacial acetic acid neutralization, concentrated, the column chromatography purifying obtains crude product.It is used acetonitrile treatment, filter, filtrate decompression is concentrated into dried, obtains (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline 4.8g, yield 46%.Optical purity is 99.0%e.e.Ultimate analysis: C (59.94%), H (5.81%), N (11.42%); Calculated value: C (60.09%), H (5.84%), N (11.68%).

Embodiment 3:

0.55g sodium hydroxide is joined in the 10ml methyl alcohol; stir 0.5h; be cooled to 0～5 ℃, add 5.0g (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline, 20ml methyl alcohol, stirring reaction 1h.Removal of solvent under reduced pressure adds the 30ml isopropyl ether, stirs 1h; be cooled to 0～5 ℃, restir 1h filters; the gained solid drying obtains (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline sodium salt 2.3g, yield 48%.Optical purity is 99.5%e.e.ESI-MS：358.2(M-Na ⁺)。

Embodiment 4:

MAGNESIUM METAL 0.13g, 0.4ml methylene dichloride are joined in the 10ml methyl alcohol stirring reaction 2h.Be cooled to 0～5 ℃, add 3.7g (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline, 10ml methyl alcohol, stirring reaction 0.5h.Then reaction mixture slowly is poured in the 70ml frozen water in batches, temperature continues to stir 1h below 10 ℃ in keeping.Filter, the 20ml washing, the gained solid is dissolved in the 20ml methyl alcohol, filters, evaporated under reduced pressure, acetone recrystallization gets (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline magnesium salts 0.9g.Optical purity is 99.5%e.e.ESI-MS：358.1。

Embodiment 5:

With reference to embodiment 3, replace sodium hydroxide with potassium hydroxide, can prepare (R)-(+)-2-[[[4-(3-methoxy propoxy)-3-methyl-2-pyridyl] methyl] sulfinyl]-[1H]-benzoglyoxaline sylvite.Optical purity is 99.5%e.e.ESI-MS：357.9(M-K ⁺)。

Embodiment 6:

Can further specify the treatment advantage of this optical isomer by following pharmacological evaluation.

1. experiment modeling:

Fasting feedwater 24h before 135 rat modelings, etherization in the cover+beaker cotton balls nose appends anesthesia, the tincture of iodine, alcohol routine disinfection, the xiphoid-process lower abdomen hits exactly the 2～2.5cm that hits, and separates abdominal muscle, cuts off peritonaeum, gently move to stomach outside the abdomen, at the stomach facies ventralis, body of stomach and pyloric antrum intersection thrust 0.4～0.5mm under the serous coat with microsyringe is flat, inject 10 Glacial acetic acid 0.1mL, form papule, stomach is sent back to, sew up abdominal muscle, skin.

2. experimental technique:

135 rats are divided into 9 groups at random: blank model group, and 4 dosage groups of rabeprazole, 4 dosage groups of dextral-rabeprazole.Beginning administration in the 3rd day after the modeling, each group is all irritated stomach by 3mL/ (100g.d), blank model group is given equal-volume physiological saline, each organizes equal every day 1 time, totally 4 weeks. modeling 3d (before the administration), 17d (administration 14d), 31d (administration 28d) divides 3 batches to put to death rat, cut off the abdominal cavity along ventrimeson, take out stomach, cut off along greater gastric curvature, clean with the ice normal saline flushing. gastric mucosa is flattened on flat board, maximum major diameter and the wide footpath of vertical maximum with vernier caliper measurement ulcer. ulcer index (uI) is measured the major diameter and the wideest footpath of ulcer with vernier callipers, multiplying each other calculates the ulcer area as ulcer index, ulcer area: S=1/4 * DL * DS * towering, and DL refers to the ulcer major diameter in the formula, DS refers to the ulcer minor axis, the towering 3.14. that gets

3. experimental result:

Table 1 respectively organize rat ulcer index (mm2) and ulcer inhibition rate comparison (mean ± SD, n=15)

Claims

1. the optical isomer of a rabeprazole, its chemical structure is suc as formula shown in the I:

2. the pharmaceutically acceptable metal-salt of the described optical isomer of claim 1 or its hydrate, solvate.

3. the metal-salt of the described optical isomer of claim 2 is preferably by Li ⁺, Na ⁺, K ⁺, Mg ²⁺, Ca ²⁺, Ti ⁴⁺Salt Deng the positively charged ion formation.

4. the described optical isomer of claim 1 can pass through conventional chiral drug preparation method preparation such as chromatographic separation, asymmetric oxidation, fractionation and gets.

5. the described optical isomer of claim 1 is used for the treatment of digestive tract diseases.