CN102603614B - 4-methoxymethyl-4- (N-substituted) aniline piperidine compound, preparation method and application - Google Patents
4-methoxymethyl-4- (N-substituted) aniline piperidine compound, preparation method and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 229960004134 propofol Drugs 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 propofol compound Chemical class 0.000 claims abstract description 13
- 230000000202 analgesic effect Effects 0.000 claims abstract description 12
- 229960003394 remifentanil Drugs 0.000 claims abstract description 9
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 230000002936 tranquilizing effect Effects 0.000 claims abstract description 4
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 206010002091 Anaesthesia Diseases 0.000 claims description 5
- 230000037005 anaesthesia Effects 0.000 claims description 5
- UKXZWEDNEGGXQX-UHFFFAOYSA-N aniline;piperidine Chemical class C1CCNCC1.NC1=CC=CC=C1 UKXZWEDNEGGXQX-UHFFFAOYSA-N 0.000 claims description 5
- 230000002557 soporific effect Effects 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 230000001624 sedative effect Effects 0.000 abstract description 5
- 230000036407 pain Effects 0.000 abstract description 3
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 5
- 230000003444 anaesthetic effect Effects 0.000 description 4
- 230000000146 antalgic effect Effects 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000003533 narcotic effect Effects 0.000 description 3
- 230000028527 righting reflex Effects 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 238000012449 Kunming mouse Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- ZTHRQJQJODGZHV-UHFFFAOYSA-N N-phenyl-propionamide Natural products CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
4-methoxymethyl-4- (N-substituted) aniline piperidine compounds, a preparation method and application thereof. The compound has a structure as shown in formula (I), wherein R is selected from free alkali or hydrochloride thereofWherein n =1 or 2. The compound can be dissolved in water, has analgesic and sedative effects, is suitable for relieving pain and tranquilizing a patient monitored after an operation, is particularly favorable for realizing the operation of the patient on an automatic control drug delivery system, and can reduce the operation of an anesthesiologist. The basic preparation method of the compound is that a propofol compound (III) reacts with a fatty diacid cyclic diol ester compound (IV) to obtain an intermediate, and then the intermediate is condensed with a compound (II) with a remifentanil mother nucleus structure to obtain the compound.
Description
Technical field
The present invention relates to a kind of compound with general anesthesia and analgesic effect, particularly 4-methoxyl methyl-4-(N-replacement) aniline piperidines, and the preparation method of this compound and pharmaceutical use.
Background technology
In the curative activity of clinical operation and postoperative care, combining of analgesia, calmness and anaesthetic used the operation conformability of having guaranteed patient.Current clinical anesthesia is all the monitoring anesthesia under doctor controls, and anaesthetist need to note at any time patient's vital sign and patient's pain is experienced and processed targetedly, use various antalgic and sedative medicines and realize main dependence of these processing.Conventional analgesic is opiates agonist at present, as fentanyl, and remifentanil etc.Remifentanil (Remifentanil, 3 [4 (methoxycarbonyl)-4-(N-Phenylpropionamide base) 1-piperidines] methyl propionate), structure suc as formula (II a) shown in.The common drug of compatibility has Midazolam, Disoprofol etc. with it.Disoprofol (Propofol, 2,6-Bis(1-methylethyl)phenol), structure is as shown in formula III.Remifentanil and Disoprofol all have that onset time is rapid, and metabolism is feature rapidly, and the drug regimen that these two kinds of medicines form can produce good antalgic and sedative effect, and patient's quick-recovery soon after drug withdrawal.But because its metabolism is all very rapid, in surgical procedure, Anesthetist need to regulate the dosage of two kinds of medicines at any time, the drug level of remaining valid, increased the complexity of operation, thereby many doctors are more prone to the alfentanil and the Midazolam etc. that use analgesia and calm time to grow clinically, result can make the postoperative recovery of patient slower, extend the residence time at Operation theatre, caused to a certain extent the waste of medical resource.In patient's postoperative care, because also needing to continue to use antalgic and sedative medicine, be widely used by patient-controlled analgesia pump at present, patient can be by simply touching button according to its wish, by relevant device, Pain relief agents is infused in patient body, produce analgesic effect, thereby reduced the situation of excessive administration or administration deficiency.But although Disoprofol can produce good sedation effect when lower than anesthetic concentration, because it is water-soluble low, making is all at present the form use with emulsion, and a large amount of high-fat emulsion is not suitable for the long-time administration to postoperative patient.Because the methyl esters structure in the upper substituting group of remifentanil piperidine ring N in vitro can not stable existence in solution, after solution preparation, need in 6 ~ 8 hours, use, otherwise medicine decomposes curative effect decline.
Summary of the invention
For above-mentioned situation, the invention provides a kind of 4-methoxyl methyl-4-(N-replacement) aniline piperidines of new texture, can effectively address the above problem.The present invention further also provides the preparation method of this compound, and the purposes in pharmacy of this compound.
The said 4-methoxyl methyl-4-of the present invention (N-replacement) aniline piperidines, the free alkali of structure form as shown in formula I, or its hydrochloride (I '):
R in formula is selected from
, n=1 wherein or 2.
In the compound of said structure of the present invention, a kind of preferred form is to be the hydrochloride shown in formula (I '), and n=1 in substituent R.
The one typical case preparation method of above-claimed cpd of the present invention is can be by C
3-4the Disoprofol monoester compound of fat diacid (III a) with compound (II) (U.S. chemical abstract (CAS) numbering 938184-95-3) condensation with remifentanil mother nucleus structure, obtain formula I structure product; Further pass into again after HCl gas salify, can obtain the hydrochloride product of formula (I ').Reaction process is as follows, the n=1 in formula or 2:
Wherein, the Disoprofol monoester compound of said fat diacid (III a), a kind of method be can be in the usual way again corresponding fat diacid acid anhydride react and obtain with Disoprofol.In addition, the another kind of method that can also adopt, is to be reacted and obtain with fat diacid ring diol ester compound (IV) by Disoprofol compound (III), the wherein n=1 in fat diacid ring diol ester compound (IV), R
1for dimethyl, reaction process is as follows:
Experimental result shows, the compound water soluble of the compound of the above-mentioned form of the present invention, particularly hydrochloride form, and there is satisfied tranquilizing soporific and/or anesthesia and analgesic activity.
Take above-claimed cpd of the present invention acceptable auxiliary material in active drug composition and pharmacy, by the usual manner of current relative medicine preparation, can prepare and can there is tranquilizing soporific and/or anesthesia and analgesic medicine for clinical, the preferably injection type medicine of administration outside vein or vein, be specially adapted to the patient of postoperative care to carry out antalgic and sedative, be particularly advantageous in and realize the operation of patient to automatic control drug delivery system, and can reduce Anesthetist's operation.
Below in conjunction with the embodiment of embodiment, foregoing of the present invention is described in further detail again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.Without departing from the idea case in the present invention described above, various replacements or the change made according to ordinary skill knowledge and customary means, all should comprise within the scope of the invention.
Embodiment
embodiment 1
Disoprofol (III) (1.00 g, 5.61mmol) and the sub-isopropyl ester (IV) of propanedioic acid ring (0.81 g, 5.61mmol) are mixed, in 40 ℃ ~ 90 ℃ stirring 5h, be then chilled to room temperature.Reaction solution is poured in water, with saturated sodium bicarbonate solution adjust pH to ~ 8, ethyl acetate extraction, point water-yielding stratum, then adjust pH after ~ 5 with 1N hydrochloric acid, ethyl acetate extracts.After the water washing of organic layer salt, separate anhydrous sodium sulfate drying.Filtrate decompression evaporate to dryness after filtering, (III is 1.00 ~ 1.13g a), productive rate 67 ~ 76% to obtain the propanedioic acid Disoprofol monoesters intermediate of yellow oil.Experiment demonstration, suitably improves temperature of reaction, and the productive rate that is conducive to improve intermediate (reacts to obtain intermediate 1.00g, productive rate 67% under 40 ℃ of conditions; 90 ℃ of reactions, can obtain intermediate 1.13g, productive rate 76%).
Compound (II) (CAS numbers 938184-95-3) (500 mg of fentanyl parent nucleus will be there are, 1.56mmol) be dissolved in (30 ml) in methylene dichloride with propanedioic acid Disoprofol monoesters intermediate, add N, N-cyclohexyl carbon imide (DCC, 490 mg, 2.34mmol), stirred overnight at room temperature.Reaction solution pours in water, dichloromethane extraction, organic layer after salt water washing, anhydrous sodium sulfate drying.Filter, filtrate evaporate to dryness, resistates obtains the formula I yellow oil product 210mg of free alkali form, productive rate 23% through silicagel column (developping agent: methylene chloride/methanol=10:1) purifying.
The formula I product (210 mg, 0.37 mmol) of free alkali form is dissolved in 20ml anhydrous diethyl ether, passes into hydrogen chloride gas in 0 ℃, and reaction 2h, filters and obtain its corresponding hydrochloride product 186mg, productive rate 83%.
Product structure detected result:
Nuclear magnetic resonance analyser: Bruker WH-300 (300 MHz) spectrometer, TMS is interior mark, δ unit is ppm.
Mass spectrograph: Agilent 1200 series 6130 mass spectrometer, ESI.
1HNMR（δ）（d-DMSO）：1.113~1.136(d,12H)，1.484~1.758(m,4H)，1.987~2.073 (t, 2H)， 2.301~2.348 (d, 2H)，2.740~2.888 (m, 4H)，3.048~3.374(m,4H)，3.441~3.479(d,2H)，3.625(s,2H)，3.733(s,3H)，4.145~4.245(s,broad,3H)，7.152 ~7.7 28(m, 8H)，10.923(d,H)。
Ms（M-HCl+H）：567.1。
embodiment 2
pharmacologically active experiment:
1. narcotic activity experiment:
15 body weight are divided into 3 groups at random at the male mouse of kunming of 20 ~ 30 grams, the compound of hydrochloride form of the present invention is configured to solution with physiological saline, and every group of 5 mouse, through tail vein injection administration, observe righting response and whether disappear, as the index whether with anaesthetic effect.The result of narcotic activity experiment is as shown in table 1.
The narcotic activity experimental result of table 1 the compounds of this invention
| Compound | Dosage (mg/kg) | Whether righting reflex disappears |
| Physiological saline | — | No |
| Disoprofol | 15 | Be |
 |
20 | Be |
Table 1 result shows, compound of the present invention has anaesthetic effect, can cause that mouse righting reflex reversibility disappears.
analgesic activities experiment:
In the time of 20 ℃ of room temperatures, body weight is placed on 55 ℃ of metal sheets at the female kunming mice of 20 ~ 30 grams, observe it from putting metal sheet to the reaction times of licking metapedes, get the reaction times more than 10 seconds the mouse below 30 seconds as suitable subjects.
The kunming mice that 15 warps is sieved in advance to stand the test is divided into 3 groups at random, compound described in patent of the present invention is configured to solution with physiological saline, every group of 5 mouse, test in 20 ℃ of room temperatures, through tail vein injection administration, observe its licking the sufficient reaction times on hot plate, if the reaction times extends one times or above person before compared with administration, there is the index of analgesic effect as this compound.Test-results sees the following form:
The analgesic experiment result of table 2 the compounds of this invention
| Compound | Dosage (mg/kg) | Whether there is analgesic activity |
| Physiological saline | — | No |
| Remifentanil | 1 | Have |
 |
3 | Have |
Table 2 result shows, the compounds of this invention has analgesic effect, can make the lick sufficient reacting generating time of mouse on hot plate obviously delay.
Claims (4)
1.4-methoxyl methyl-4-(N-replacement) aniline piperidines, structure is as the free alkali of formula I form or its hydrochloride (I '):
In formula, R is selected from
, wherein n=1.
2. the preparation method of compound described in claim 1, is characterized in that by C
3the Disoprofol monoester compound of fat diacid (III a) with compound (II) condensation with remifentanil mother nucleus structure, obtain formula I structure product, further pass into after HCl gas salify, obtain the hydrochloride product of formula (I '), reaction process is as follows, the n=1 in formula:
3. preparation method as claimed in claim 2, (III a) is reacted and is obtained with fat diacid ring diol ester compound (IV) by Disoprofol compound (III) to it is characterized in that the Disoprofol monoester compound of said fat diacid, the wherein n=1 in fat diacid ring diol ester compound (IV), R
1for dimethyl, reaction process is as follows:
4. described in claim 1, compound has the application in tranquilizing soporific and/or anesthesia and analgesic medicine in preparation.
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| CN201210065063.6A CN102603614B (en) | 2012-03-13 | 2012-03-13 | 4-methoxymethyl-4- (N-substituted) aniline piperidine compound, preparation method and application |
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| CN201210065063.6A CN102603614B (en) | 2012-03-13 | 2012-03-13 | 4-methoxymethyl-4- (N-substituted) aniline piperidine compound, preparation method and application |
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| CN102603614B true CN102603614B (en) | 2014-07-02 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007087164A2 (en) * | 2006-01-24 | 2007-08-02 | Mallinckrodt Inc. | Process for synthesizing remifentanil |
| CN101199480A (en) * | 2007-12-11 | 2008-06-18 | 西安力邦医药科技有限责任公司 | Compounded propofol fat emulsion injection containing analgesics and process for preparing same |
| US20080268071A1 (en) * | 2007-04-26 | 2008-10-30 | Auspex Pharmaceuticals, Inc. | Substituted cyclohexanones |
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxy acid ester compound of substituted phenol, preparation method and application in medicine |
| CN102020574A (en) * | 2009-09-14 | 2011-04-20 | 李勤耕 | diisopropylphenyl gamma-aminobutyrate derivatives and preparation methods thereof |
| CN102344408A (en) * | 2011-07-27 | 2012-02-08 | 中国人民解放军第四军医大学 | Double-effect anesthetic |
-
2012
- 2012-03-13 CN CN201210065063.6A patent/CN102603614B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007087164A2 (en) * | 2006-01-24 | 2007-08-02 | Mallinckrodt Inc. | Process for synthesizing remifentanil |
| US20080268071A1 (en) * | 2007-04-26 | 2008-10-30 | Auspex Pharmaceuticals, Inc. | Substituted cyclohexanones |
| CN101199480A (en) * | 2007-12-11 | 2008-06-18 | 西安力邦医药科技有限责任公司 | Compounded propofol fat emulsion injection containing analgesics and process for preparing same |
| CN102020574A (en) * | 2009-09-14 | 2011-04-20 | 李勤耕 | diisopropylphenyl gamma-aminobutyrate derivatives and preparation methods thereof |
| CN101906039A (en) * | 2010-06-23 | 2010-12-08 | 四川大学华西医院 | Hydroxy acid ester compound of substituted phenol, preparation method and application in medicine |
| CN102344408A (en) * | 2011-07-27 | 2012-02-08 | 中国人民解放军第四军医大学 | Double-effect anesthetic |
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| Title |
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| Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen a centre randomised, cross-over, open-label study in the Netherlands;F. Willem Rozendaal,等;《Intensive Care Medicine》;20090228;第35卷(第2期);第291-298页 * |
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