CN1919847A - Novel hydrochloride compound and use thereof - Google Patents
Novel hydrochloride compound and use thereof Download PDFInfo
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- CN1919847A CN1919847A CN 200610116322 CN200610116322A CN1919847A CN 1919847 A CN1919847 A CN 1919847A CN 200610116322 CN200610116322 CN 200610116322 CN 200610116322 A CN200610116322 A CN 200610116322A CN 1919847 A CN1919847 A CN 1919847A
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- novel hydrochloride
- scopolamine
- novel
- hydrochloride
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Abstract
The invention discloses a new anti-halo compound in the medical technological domain, which is 3-[2-(diphenyl-mesyl)-acetoxylation]-2-phenylpropionic acid9-methyl-3oxa-9-aza-tricyclic [3.3.1.02,4]-n-7-grease hydrochlorate with chemical structure formulation as formulation I modified by scopolamine structure.
Description
Technical field
The present invention relates to medical technical field; be 3-[2-(phenylbenzene-methylsulfonyl)-acetoxyl group]-2-phenylpropionic acid-9-methyl-3-oxa--9-azepine-three ring [3.3.1.02,4] ninth of the ten Heavenly Stems-7-ester hydrochloride (abbreviation novel hydrochloride) and with the purposes of its preparation motion sickness resistant medicament.
Background technology
Motion sickness is meant takes the general malaise that the various vehicles produce.Mainly show as dizziness, feel sick, vomit, be in a cold sweat etc.By means of vehicles quick travel soldiers are one of characteristics of modern war.And the high rate of motion sickness will cause serious non-combat casualty or fighting capacity is descended.Particularly cross over the war of Jiang Hai, must solve the seasick problem that shortage is trained officers and men by ship.Equally, it is also significant in the non-military character activity to prevent and treat motion sickness.The prevention motion sickness medicine of Cai Yonging had central anticholinergic drugs such as antihistaminics such as diphenhydramine and Scopolamine in the past.Though these medicines have certain effect, side effect is many, and especially central inhibitory action makes the people drowsy after taking, and has a strong impact on fighting capacity or normal doings.In a word, still lack gratifying motion sickness drug at present.
Summary of the invention
The purpose of this invention is to provide a kind of drowsiness anti-kinetosis new compound 3-[2-(phenylbenzene-methylsulfonyl)-acetoxyl group that waits side effect that do not have]-2-phenylpropionic acid-9-methyl-3-oxa--9-azepine-three ring [3.3.1.0
2,4] ninth of the ten Heavenly Stems-7-ester hydrochloride (calling novel hydrochloride in the following text), chemical structural formula is as follows:
Novel hydrochloride is pale brown look oily liquids.Molecular formula C
32H
33NO
6S; Molecular weight: 559.6, fat-soluble, be soluble in organic solvents such as chloroform, ethyl acetate.
Its structure is through MS (ESI),
1HNMR and IR conclusive evidence data are as follows:
MS：m/z560.25(M
++H)，286 100％[(Ph)
2CHCOCH
2COOCH
2]+，
138(C
8H
12NO)+。
IR：(KBr，cm
-1)3028，2934，1713，1196，1060，1045，854，701。
1H-NMR: δ 1.58-1.83 (m, 4H, seven Yuans ring-CH
2* 2), 2.27 (s, 3H, NCH
3), 2.56-3.97 (m, 7H, seven Yuans ring-CH * 5, SOCH
2), 4.20-4.22 (m, 1H, PhCH), 4.64-4.89 (m, 2H, OCH
2), 5.11 (s, 1H, Ph
2CH), and 7.06-7.21 (m, 15H, ArH).
The compounds of this invention carries out structure of modification by Scopolamine and forms.
The preparation method is as follows:
1. be the feedstock production benzhydrol with benzophenone, sodium hydroxide, 95% ethanol.
2. prepare the diphenyl-methyl thioacetic acid with benzhydrol, Thiovanic acid, Hydrogen bromide.
3. prepare diphenyl-methyl sulfonyl acetate with diphenyl-methyl thioacetic acid and methyl alcohol.
4. being raw material with diphenyl-methyl sulfonyl acetate and Scopolamine, is catalyzer with the p-methyl benzene sulfonic chloride, gets ester condensates through esterification, and obtains target compound through column chromatography for separation repeatedly, again with hydrochloric acid with target compound acidifying salify.
Show that through experimentation on animals this new compound not only has stronger anti-halo effect, wait side effect but also overcome the drowsiness of Scopolamine effectively, thereby can be used for preparing the medicine of anti-kinetosis.
Embodiment
Now in conjunction with the embodiments the present invention is described in detail:
Embodiment one. the preparation novel hydrochloride compound
1), the preparation of benzhydrol
With benzophenone 60g, sodium hydroxide 60g, 95% ethanol 600ml drops in the 1000ml reaction flask, and vigorous stirring is divided three times and added zinc powder, adds 20g at every turn.TLC (sherwood oil: ethyl acetate=10: 1) follow the tracks of reaction process, reacted completely in about 2 hours.The filtering zinc powder in 3 liters of frozen water of filtrate impouring, filters and collects white solid, and dry back dissolve with ethanol filters once more, and filtrate adds the suitable quantity of water dilution, filters and collects the pure product 56.3g of white solid product, yield: 92.8%, and fusing point: 65.8～65.9 ℃.
2), the thiacetic preparation of diphenyl-methyl
Benzhydrol 31.3g, Thiovanic acid 15.7g, 40% Hydrogen bromide 160ml are dropped in the 250ml reaction flask, and mechanical stirring is heated to 95 ℃ of reactions 2 hours, and (chloroform: methyl alcohol: acetate=30: 1: 0.5) demonstration reacts completely TLC.Add an amount of frozen water to reaction system, cooling is filtered, filter cake with a large amount of cold water washings after, be dissolved in the sodium bicarbonate aqueous solution, once more filtration.Filtrate drips concentrated hydrochloric acid and transfers pH value to be about 3, separates out a large amount of white product, filters, and filter cake is dried after with a large amount of cold water washings, product weight 40.4g, and yield: 92.1%, fusing point: 128.2～128.8 ℃.
3), the preparation of diphenyl-methyl sulfonyl acetate
Diphenyl-methyl thioacetic acid 25.8g, methyl alcohol 600ml are dropped in the 1000ml reaction flask, dropping contains the aqueous solution 140ml of sodium periodate 23.54g, be warming up to 40～50 ℃ of reactions 6 hours, cooling, the filtering solid during filtrate concentrating fallen back, filters and collects the solid product of separating out, ethyl alcohol recrystallization, drying.Product is heavy: 25.5g, and yield: 93.1%, fusing point: 143.8～144.6 ℃.
4), the preparation of target compound
With diphenyl-methyl sulfonyl acetate 8.56g, Scopolamine 6.58g, Tosyl chloride 4.57g, pyridine 100ml, DMAP0.4g drops in the 250ml reaction flask, magnetic agitation, be warming up to back flow reaction, TLC (chloroform: methyl alcohol: tracking reaction process acetic acid 20: 1: 0.5), after reaction is finished, steam and remove pyridine, use the chloroform extraction product, alkali cleaning, washing, sodium chloride solution is washed after drying, separate through silica gel column chromatography repeatedly, carry out gradient elution with sherwood oil and ethyl acetate system and obtain target compound, again with hydrochloric acid with target compound acidifying salify, get product: 1.8g, yield: 16.1%.
The anti-kinetosis pharmacology experiment of novel hydrochloride is as follows:
Experiment one. the dizzy experiment of mouse anti
Laboratory animal: Kunming mouse, male, body weight 22～25g is provided by the The 2nd Army Medical College Animal House.
Be subjected to the reagent thing: novel hydrochloride, Scopolamine.
Experimental technique: get 54 of Kunming mouses, be divided into 6 groups at random: blank group, 4 dosage groups of novel hydrochloride (0.1,0.3,1,3mg/kg) and Scopolamine group (1mg/kg).It is 2mg/L that novel hydrochloride is mixed with concentration with 2% tween-80 solution, 6mg/L, 20mg/L, 60mg/L solution, it is 20mg/L solution that Scopolamine is mixed with concentration with 2% tween-80 solution, respectively to every mouse gastric infusion according to dosage, the mouse stomach volume is to give 0.5ml by the every 10g of body weight, the blank group is irritated stomach with equivalent 2% tween-80 solution, place the controlled three arm type gyroscope of WTD500A type to hang in the basket animal after 30 minutes, being rotated in the forward 40 minutes with 60 times/minute causes dizzy, after rotation finishes, animal is placed ground, observe the reaction in the animal 5 minutes immediately.Press table 1 standards of grading scoring back and calculate index of Response.
Table 1. standards of grading
| Index | Do not have | Have |
| Stool urine piloerection trembles | 0 minute 0 minute 0 minute 0 minute | Every 1 minute 1.2 minutes slight 0.6 minute, severe 1.2 minutes 1.2 minutes |
Experimental result: as shown in table 2, novel hydrochloride has significant anti-dizzy effect, and a certain amount of effect relationship is arranged.
The mouse anti halo effect of table 2. novel hydrochloride
| Group | Number of animals (only) | Dizzy index (X ± SD) |
| Contrast novel hydrochloride 0.1mg/kg novel hydrochloride 0.3mg/kg novel hydrochloride 1mg/kg novel hydrochloride 3mg/kg hyoscine 1mg/kg | 9 9 9 9 9 9 | 5.04±0.80 4.80±2.25 3.28±1.22 ** 2.12±0.70 ** 2.24±1.51 ** 2.90±0.53 ** |
*Each group compares P＜0.01 with the blank group
Experiment two. the dizzy experiment of rat anti:
Laboratory animal: Sprague-Dawley (SD) rat, male 200～250g.Provide by the The 2nd Army Medical College Animal House.
Be subjected to the reagent thing: novel hydrochloride, Scopolamine
Experimental technique: get 45 of SD rats, be divided into 5 groups at random: blank group, 3 dosage groups of novel hydrochloride (1mg/kg, 3mg/kg, 10mg/kg) and Scopolamine group (10mg/kg).It is 200mg/L, 600mg/L, 2000mg/L solution that novel hydrochloride is mixed with concentration with 2% tween-80 solution, it is 2000mg/L solution that Scopolamine is mixed with concentration with 2% tween-80 solution, to every rat gastric infusion according to dosage, the rat oral gavage volume is given 0.5ml by the every 100g of body weight respectively.The blank group is irritated stomach with equivalent 2% tween-80 solution, after 30 minutes animal placed the controlled three arm type gyroscope of WTD500A type to hang in the basket, dizzy to be rotated in the forward 40 minutes 60 times/minute and to cause, after rotation finishes, animal is placed ground, observe the reaction in the animal 5 minutes immediately.Press table 1 standards of grading scoring back and calculate index of Response.
Experimental result: as shown in table 3, novel hydrochloride has significant anti-dizzy effect, and a certain amount of effect relationship is arranged.
The rat anti halo effect of table 3. novel hydrochloride
| Group | Number of animals (only) | Dizzy index (X ± SD) |
| Contrast novel hydrochloride 1mg/kg novel hydrochloride 3mg/kg novel hydrochloride 10mg/kg Scopolamine 10mg/kg | 9 9 9 9 9 | 5.18±1.73 3.44±1.23 ** 3.17±1.64 ** 2.74±0.93 *** 3.71±0.90 ** |
*Each group compares P＜0.01 with the blank group
* *Each group compares P＜0.001 with the blank group
Experiment three. rat spontaneous activity experiment:
Laboratory animal: Sprague-Dawley (SD) rat, male 200～250g.Provide by the The 2nd Army Medical College Animal House.
Be subjected to the reagent thing: novel hydrochloride, Scopolamine
Experimental technique: get 18 of SD rats, be divided into 2 groups at random: novel hydrochloride 10mg/kg dosage group and Scopolamine 10mg/kg dosage group.Rat is put into before the administration general spontaneous activity video analytic system (Jiliang Software Sci-Tech Co., Ltd., Shanghai, model: 4 rat DigBehv-LM4) total range of motion, V-bar, the linear lag etc. in the record rat 5 minutes.Take out after record finishes, two groups of rats give 10mg/kg novel hydrochloride, the 10mg/kg Scopolamine of corresponding dosage respectively according to the method for experiment two.Administration after 30 minutes places animal the controlled three arm type gyroscope of WTD500A type to hang in the basket, and dizzy to be rotated in the forward 40 minutes 60 times/minute and to cause, rotation places ground with animal after finishing, and observes the reaction in the animal 5 minutes immediately.After finishing, observation is put into general spontaneous activity video analytic system immediately then with total range of motion, V-bar, the linear lag etc. in the same method record rat 5 minutes.The record back that finishes is taken out to wait (promptly to rotate back 30 minutes) after 25 minutes with same method again and is write down total range of motion, V-bar, the linear lag etc. in the rat 5 minutes.
Experimental result: shown in table 4, table 5, table 6, the scoring of novel hydrochloride group total range of motion, V-bar, the linear lag is higher than blank group and Scopolamine group far away, approaching with the scoring before the rotation, illustrate that the novel hydrochloride group does not obviously produce drowsiness side effect.
Table 4. novel hydrochloride to the influence of rat unit total range of motion in the time (n=9, X ± SD, m/5min)
| Group | Before the administration | Rotation back 5min | Rotation back 30min |
| Contrast Scopolamine 10mg/kg novel hydrochloride 10mg/kg | 21.4±3.1 24.2±3.2 24.7±4.8 | 5.2±1.9### 8.8±2.6### ** 22.2±4.4 ***+++ | 7.7±7.5### 5.2±2.3### ** 21.1±4.4 ***+++ |
**p＜0.01vs control
***p＜0.001vs control
###Before p＜0.001vs administration
+++P＜0.001vs positive drug
Table 5. novel hydrochloride to the influence of rat unit V-bar in the time (n=9, X ± SD, mm/s)
| Group | Before the administration | Rotation back 5min | Rotation back 30min |
| Contrast Scopolamine 10mg/kg novel hydrochloride 10mg/kg | 67.8±3.1 76.0±10.1 78.1±15.2 | 16.6±6.0### 28.0±8.4### ** 70.6±14.1 ***+++ | 24.4±23.7### 16.5±7.4### ** 66.9±14.0 ***+++ |
***p＜0.001vs control
**p＜0.01vs control
###Before p＜0.001vs administration
+++P＜0.001vs positive drug
Table 6. novel hydrochloride to the influence of the rat unit time linear lag (n=9, X ± SD, 5min)
| Group | Before the administration | Rotation back 5min | Rotation back 30min |
| Contrast Scopolamine 10mg/kg novel hydrochloride 10mg/kg | 0.63±0.03 0.64±0.02 0.60±0.03 | 0.34±0.09### 0.48±0.11### ** 0.65±0.05 *#+++ | 0.36±0.17### 0.34±0.13### 0.66±0.04 ***##+++ |
*p＜0.05vs control
***p＜0.001vs control
###Before p＜0.05vs administration
##Before p＜001vs administration
###Before p＜0.001vs administration
+++P＜0.001vs positive drug
More than experiment shows that each dosage group of novel hydrochloride all has significant anti-dizzy effect, and tangible dose-effect relationship is arranged.Novel hydrochloride not only has stronger anti-halo effect, but also overcome Scopolamine effectively drowsinessly wait side effect, thereby novel hydrochloride is a kind of anti-dizzy compound that has than the better pharmacological property of Scopolamine, the invention solves at present many anti-dizzy medicines side effects such as ubiquitous maincenter inhibition, thereby this compound can be used as the medicine for preparing anti-kinetosis.
Claims (2)
1. one kind has anti-dizzy active compound 3-[2-(phenylbenzene-methylsulfonyl)-acetoxyl group]-2-phenylpropionic acid-9-methyl-3-oxa--9-azepine-three ring [3.3.1.0
2,4] ninth of the ten Heavenly Stems-the 7-ester hydrochloride, chemical structural formula is as follows:
2. the application of the described compound of claim 1 in the preparation motion sickness resistant medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101163228A CN100415742C (en) | 2006-09-21 | 2006-09-21 | Novel hydrochloride compound and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101163228A CN100415742C (en) | 2006-09-21 | 2006-09-21 | Novel hydrochloride compound and use thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1919847A true CN1919847A (en) | 2007-02-28 |
| CN100415742C CN100415742C (en) | 2008-09-03 |
Family
ID=37777723
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101163228A Expired - Fee Related CN100415742C (en) | 2006-09-21 | 2006-09-21 | Novel hydrochloride compound and use thereof |
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|---|---|
| CN (1) | CN100415742C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230027B (en) * | 2008-02-22 | 2011-03-23 | 吉尔生化（上海）有限公司 | Method for preparing S-para methylbenzyl cysteine hydrochloride |
| CN101230028B (en) * | 2008-02-22 | 2011-04-27 | 吉尔生化（上海）有限公司 | Method for preparing S-para methoxylbenzyl cysteine hydrochloride |
| CN117510323A (en) * | 2024-01-08 | 2024-02-06 | 成都泰莱康科技有限公司 | Preparation method of Ramage Linker intermediate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1158078C (en) * | 2002-06-13 | 2004-07-21 | 中国人民解放军第二军医大学 | Compound scopolamine |
-
2006
- 2006-09-21 CN CNB2006101163228A patent/CN100415742C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230027B (en) * | 2008-02-22 | 2011-03-23 | 吉尔生化（上海）有限公司 | Method for preparing S-para methylbenzyl cysteine hydrochloride |
| CN101230028B (en) * | 2008-02-22 | 2011-04-27 | 吉尔生化（上海）有限公司 | Method for preparing S-para methoxylbenzyl cysteine hydrochloride |
| CN117510323A (en) * | 2024-01-08 | 2024-02-06 | 成都泰莱康科技有限公司 | Preparation method of Ramage Linker intermediate |
| CN117510323B (en) * | 2024-01-08 | 2024-04-05 | 成都泰莱康科技有限公司 | Preparation method of Ramage Linker intermediate |
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| Publication number | Publication date |
|---|---|
| CN100415742C (en) | 2008-09-03 |
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Granted publication date: 20080903 Termination date: 20110921 |