CN101786986A - (+)-meptazinol prodrug or salt thereof and preparation method thereof - Google Patents
(+)-meptazinol prodrug or salt thereof and preparation method thereof Download PDFInfo
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- CN101786986A CN101786986A CN 201010117129 CN201010117129A CN101786986A CN 101786986 A CN101786986 A CN 101786986A CN 201010117129 CN201010117129 CN 201010117129 CN 201010117129 A CN201010117129 A CN 201010117129A CN 101786986 A CN101786986 A CN 101786986A
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Abstract
The invention belongs to the pharmacy field and relates to a (+)-meptazinol prodrug or salt thereof and a preparation method thereof, in particular to (+)-meptazinol 2-(substituted) amino-6-alkyl-benzoate or salt thereof and a preparation method thereof. In the method, the structure of a raw (+)-meptazinol drug is modified and a phenolic hydroxy group in the original structure is enabled to combine with 2-(substituted) amino-6-alkyl-benzoic acid. Proved by experiments, the drug effect of the compound is stronger than that of (+)-meptazinol, and the pharmacodynamic duration time is longer than that of the (+)-meptazinol. Being prepared into enteric coated tablets or other enteric-coated preparations and corresponding slow-controlled release preparations for clinical purpose, the prodrug can obviously improve the analgesic activity, the pharmacodynamic duration time and the bioavailability of the raw drug (+)-meptazinol.
Description
Technical field
The invention belongs to pharmacy field, relate to (+)-meptazinol prodrug or its salt and preparation method thereof.
Background technology
Meptazinol (Meptazinol), chemical name 3-(3-ethyl-six hydrogen-1-methyl isophthalic acid H-azatropylidene-3-yl) phenol is the partial agonist of opioid receptor, and analgesic effect is remarkable, be usually used in moderate or severe pain that different reasons cause, as being used for operation back or analgesia in postpartum clinically.Its analgesic activities and pentazocine, pethidine, Dextropoxypheene is suitable with the Paracetamol compound, but than morphine slightly a little less than.Meptazinol is compared with other opioid analgesics, respiration inhibition and to give up side effect such as habituation less.Wy-22811 went on the market in 1986, trade(brand)name Meptid (Wyeth.UK) and Meptid (Ger) and Meptidol (Aust), and British Pharmacopoeia recorded in 98 years.
Similar on the meptazinol structure with the narcotic analgesic thing of most phenolic hydroxy groups, liver first-pass effect is serious, after the oral absorption phenolic hydroxyl group rapidly at the liver place by glucuronidation or sulfation, cause oral administration biaavailability to have only 8.69%, the oral dosage that treatment concentration needs is very big, mostly is drug administration by injection clinically.
Those skilled in the art considered that to generally acknowledging that effective medicine carries out the prodrug design be effective ways in the original new drug research, belong to present popular Me-too drug research type.Studies show that and utilize the prodrug design to reduce first pass effect, can improve bioavailability of medicament.As: the prodrug meptazinol of meptazinol (2-amino-6-methyl)-benzoic ether hydrochloride by rat in the local directly enteron aisle ligation administration of body, its bioavailability is 10 times of Wy-22811 rat oral gavage administration, similar to the bioavailability of Wy-22811 intravenously administrable, and good absorption (ZL 200410018366.8 meptazinol prodrugs or its esters and preparation method thereof) is all arranged at each section of enteron aisle.
At present, the meptazinol of external listing is the racemic modification medicine, does not still have optics active body listing report.For obtaining better efficacy, single enantiomer medicine that toxic side effect is littler, prior art splits meptazinol, obtains the optically active monomer of (+)-meptazinol and (-)-meptazinol configuration.Through the experimentation on animals gastric infusion, test (+)-and the anti-mouse vagusstoff of (-)-meptazinol hydrochloride writhing method activity, the result shows: gained ED
50Value is respectively 14.6 μ mol/kg and 33.3 μ mol/kg, and the activity of (+)-meptazinol is 3 times of (-)-meptazinol, thus, the research and development of its derivative is caused researchist's concern.
Summary of the invention
The purpose of this invention is to provide (+)-meptazinol prodrug or its salt and preparation method thereof.Relate in particular to (+)-2-(replacement) amino-6-alkyl-benzoic ether of meptazinol or its salt and preparation method thereof.
The invention provides the compound or its salt of formula (I),
R wherein
1Be selected from C
1-C
3Alkyl, R
2Be selected from H or C
1-C
3Alkyl.
Preferably, R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H, methyl, ethyl, n-propyl or sec.-propyl.
More preferably, R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H.
Most preferably, R
1Be selected from methyl, R
2Be selected from H.
The present invention also provides the preparation method of above-claimed cpd or its salt, and described method is selected from following method 1 or method 2,
Wherein,
Method 1 comprises the steps:
The condensation in the presence of condensing agent and catalyzer of (+)-meptazinol and formula (II) compound removes R then
3, reaction formula is:
R wherein
1Be selected from C
1-C
3Alkyl, R
2Be selected from H or C
1-C
3Alkyl.
Preferably, R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H, methyl, ethyl, n-propyl or sec.-propyl.
More preferably, R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H.
Most preferably, R
1Be selected from methyl, R
2Be selected from H.
R
3It is amino protecting group.
Described method 2 comprises the steps:
The reaction of (+)-meptazinol and formula (III) compound, reaction formula is
R wherein
1And R
2Definition the same.
Preferably, R
3Be selected from 9-fluorenes methoxycarbonyl base, uncle's fourth oxygen acyl group or trityl.
Preferably, wherein said condensing agent is selected from dicyclohexylcarbodiimide (DCC), 2-(7-azepine benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) or 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (EDCI) and 1-hydroxyl-benzo-triazole (HOBt), described catalyzer is selected from 4-Dimethylamino pyridine (DMAP).
Preferably, described method also comprises formula (I) compound and mineral acid or organic acid salify, and in alcohol, ether or the mixture of the two step of recrystallization.
Preferably, described mineral acid is selected from hydrochloric acid, Hydrogen bromide or hydroiodic acid HI or sulfuric acid, and described organic acid is selected from tartrate, toxilic acid or fumaric acid, and described alcohol is selected from methyl alcohol, ethanol or Virahol, and described ether is selected from ether, isopropyl ether or t-butyl methyl ether.
The present invention also provides the purposes of described compound or its salt in the preparation analgesic.
Compound provided by the present invention is (+)-meptazinol prodrug or its esters, specifically, is (+)-2-(replacement) amino-6-alkyl-benzoic ether of meptazinol.
The present invention carries out structural modification to the former medicine of (+) meptazinol, the phenolic hydroxyl group of original structure is combined with 2-(replacement) amino-6-alkyl-phenylformic acid, this prodrug can reduce liver first-pass effect: it is fat-soluble that its phenyl ring can increase medicine, make medicine enter the human body post-absorption and meet two-compartment model, increase drug absorption and action time; The amino tool power supply in its ortho position effect can form intramolecular hydrogen bond with ketonic oxygen; The sterically hindered hydrolysis that also can stop ester bond of its 6-alkyl, the further action time of prolong drug.
Most preferred of the present invention is (+)-meptazinol (2-amino-6-methyl)-benzoic ether or its esters, shown in following structural formula:
This compound is preparation by the following method preferably:
This method be (+)-meptazinol and amido protecting (2-amino-6-methyl)-phenylformic acid at Dcci (DCC) as condensing agent, 4-Dimethylamino pyridine (DMAP) is as condensation under the condition of catalyzer, and then the protecting group of deaminize obtains (+)-meptazinol (2-amino-6-methyl)-benzoic ether;
Perhaps use 6-methyl isatoic anhydride directly to prepare (+)-meptazinol (2-amino-6-methyl)-benzoic ether with (+)-meptazinol acidylate.
Wherein, (2-amino-6-the methyl)-phenylformic acid of amido protecting can make with amido protecting agent and (2-amino-6-methyl)-benzoic acid;
Described amido protecting agent can be that 9-fluorenes methoxycarbonyl chlorine is that Fmoc-Cl, tert-Butyl dicarbonate are Boc acid anhydrides or trityl chloride (R is Fmoc, Boc or trityl).
Above-mentioned (+)-meptazinol (2-amino-6-methyl)-benzoic ether and hydrochloric acid or Hydrogen bromide or hydroiodic acid HI or sulfuric acid or tartrate or toxilic acid salify are with alcohol, ether or the mixture recrystallization of the two.
The present invention carries out the experiment of animal gastric infusion with enteric coated preparation and (+)-meptazinol hydrochloride (hereinafter to be referred as former medicine) that (+)-meptazinol (2-amino-6-methyl)-benzoic ether hydrochloride (hereinafter to be referred as prodrug) and hydroxypropylcellulose are mixed and made into, and test is to the influence of rat radiation thermic pain.The result shows: threshold of pain rate elongation is the highest behind the prodrug 2h, is (synergy) more than 3 times of former medicine; Keep original threshold of pain rate elongation behind the prodrug 4h, and former medicine about 60% (prolongations of effect) have been reduced.
Experimental result shows: after 2 hours, the rat threshold of pain increment rate of administration prodrug enteric coated preparation is three times of former medicine, illustrates that the prodrug drug effect is stronger than former medicine; Compared with 1 hour, after 4 hours, the rat of administration prodrug enteric coated preparation keeps original threshold of pain increment rate, and that the threshold of pain increment rate of former medicine has reduced is about 60%, illustrates that the duration of efficacy of this prodrug is longer than former medicine.
Experimental result of the present invention confirms, (+)-meptazinol (2-amino-6-methyl)-benzoic ether or its esters are made ECT or other enteric coated preparation and corresponding controlled release agent type be used for clinically, can obviously improve analgesic activities, duration of efficacy and the bioavailability of former medicine meptazinol; The compound that also can fully predict simultaneously formula (I) also has the effect of the analgesic activities, duration of efficacy and the bioavailability that improve former medicine meptazinol.
For the ease of understanding, below will describe in detail of the present invention by specific embodiment.It needs to be noted, specific examples only is in order to illustrate, obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Embodiment
Embodiment 1 preparation (+)-meptazinol (2-amino-6-methyl)-benzoic ether hydrochloride
(1.00g 6.6mmol), is dissolved in 18ml 1, the 4-dioxane to 2-amino-6-tolyl acid.Add Na
2CO
3(1.40g 13.2mmol) is dissolved in the solution of 18ml water.Drip Fmoc-Cl (9-fluorenes methoxycarbonyl chlorine, 1.71g, 20ml 1 6.6mmol), 4-dioxane solution.Room temperature reaction 1 hour, stopped reaction.Reaction solution with in the 6N hydrochloric acid and after use ethyl acetate extraction.Organic layer merges, anhydrous Na
2SO
4Dry after-filtration, filtrate concentrates, and column chromatography for separation obtains N-Fmoc-2-amino-6-tolyl acid 1.57g, white solid, yield 64%, fusing point: 163-166 ℃.
In the 250ml there-necked flask, add N-Fmoc-2-amino-6-tolyl acid (6.22g, 16.7mmol) and (+)-meptazinol (3.85g, 16.5mmol), add the 80ml methylene dichloride, drip DCC (4.57g, 22.2mmol) and DMAP (0.25g, 12ml dichloromethane solution 2.0mmol).Be warming up to backflow, reacted 24 hours.Cooling, elimination solid (about 4g), steaming desolventizes, and gets the about 11g of yellow oil.Column chromatography for separation obtains light yellow oil 3.15g.With the anhydrous diethyl ether dissolving, add the HCl-diethyl ether solution, regulate pH to 6-7 and become hydrochloride, separate out white powder 2.89g, yield 43.5%, fusing point 108-111 ℃.
1HNMR (DMSO-d
6): δ 10.47 (brs, ≈ 1/2H, NH
+), 8.84 (brs, ≈ 1/2H, NH
+), (Ar-H), (Ar-H), 6.70 (Ar-H), 6.49 (Ar-H), (m, 6H contain Ar-NH to 3.99-3.09 to 7.35-7.08 to 7.47-7.40 for t, 1H for t, 1H for m, 4H for m, 1H
2, C
H 2-N-C
H 2), 2.82﹠amp; 2.80 (d, 3H, N-CH
3, J=4.69), 2.46 (s, 3H, Ar-CH
3), 2.44-2.35 (m, H, CH
2), 2.20-2.11 (m, H, CH
2), 1.94-1.41 (m, 6H, CH
2), 0.52﹠amp; 0.48 (t, 3H, CH
2C
H 3, J=7.43Hz);
MS(ESI)：367.3[M+H]
+；
It is 98.6% that HPLC measures content.
Embodiment 2 experimentation on animalies
(+)-meptazinol (2-amino-6-methyl)-benzoic ether hydrochloride (being called for short prodrug in this example) and (+)-meptazinol hydrochloride (being called for short former medicine in this example) are to the influence (per os filling stomach) of rat radiation thermic pain
1. animal
Strain: the SD big white mouse, sex: male, body weight: 200-210g
2. animal grouping
70 rats are divided into 7 groups by the random digit method, every group of 10 animals.
3. experimental technique
Each treated animal is irritated stomach by the soup difference per os that should give, and the administration capacity is the 0.3ml/100g body weight.Animal respectively at administration before and after the administration 1,2,4 hour with TF-photo-thermal pain threshold detector measure from pointolite begin irradiation apart from tail point 1.5-2.0cm place to whipping required time (pain territory: latent period), be limited to 30 seconds during measurement.
(judge with P＜0.05 for x ± SD) expression, data difference statistics employing one-way analysis of variance (ANOVA) check by group difference with mean+SD for data.
Table 1 is the experimental result that influences to rat radiation thermic pain.
Table 1
Claims (10)
1. (+)-meptazinol prodrug or its salt is characterized in that, have the structure of formula (I),
R wherein
1Be selected from C
1-C
3Alkyl, R
2Be selected from H or C
1-C
3Alkyl.
2. (+) as claimed in claim 1-meptazinol prodrug or its salt is characterized in that, wherein R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H, methyl, ethyl, n-propyl or sec.-propyl.
3. (+) as claimed in claim 1 or 2-meptazinol prodrug or its salt is characterized in that, wherein R
1Be selected from methyl, ethyl, n-propyl or sec.-propyl, R
2Be selected from H.
4. (+) as claimed in claim 3-meptazinol prodrug or its salt is characterized in that, wherein R
1Be selected from methyl, R
2Be selected from H.
5. as the preparation method of each described (+)-meptazinol prodrug of claim 1-4 or its salt, it is characterized in that, by following method:
The condensation in the presence of condensing agent and catalyzer of (+)-meptazinol and formula (II) compound removes R then
3, reaction formula is:
R wherein
1And R
2Definition identical with the claim of being quoted, R
3It is amino protecting group;
Or,
The reaction of (+)-meptazinol and formula (III) compound, reaction formula is:
R wherein
1And R
2Definition identical with the claim of being quoted.
6. method as claimed in claim 5, wherein R
3Be selected from 9-fluorenes methoxycarbonyl base, uncle's fourth oxygen acyl group or trityl.
7. as claim 5 or 6 described methods, wherein said condensing agent is selected from dicyclohexylcarbodiimide, 2-(7-azepine benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or 1-ethyl-3-(3-dimethylamine propyl) carbodiimide and 1-hydroxyl-benzo-triazole, described catalyzer is selected from the 4-Dimethylamino pyridine.
8. as any one described method of claim 5-7, it is characterized in that this method also comprises formula (I) compound and mineral acid or organic acid salify, and in alcohol, ether or the mixture of the two step of recrystallization.
9. method as claimed in claim 8, wherein said mineral acid is selected from hydrochloric acid, Hydrogen bromide or hydroiodic acid HI or sulfuric acid, described organic acid is selected from tartrate, toxilic acid or fumaric acid, and described alcohol is selected from methyl alcohol, ethanol or Virahol, and described ether is selected from ether, isopropyl ether or t-butyl methyl ether.
10. each described (+)-meptazinol prodrug of claim 1-4 or its salt are in the purposes of preparation in the analgesic.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420911A (en) * | 2012-05-25 | 2013-12-04 | 迪沙药业集团有限公司 | L-meptazinol phenyl carbamate-L-(+)-tartrate and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1569838A (en) * | 2004-05-14 | 2005-01-26 | 复旦大学 | Meptazinol ortho-propionyloxy-cis-benzyl acrylate and its salts and their production method |
| CN1569839A (en) * | 2004-05-14 | 2005-01-26 | 复旦大学 | Meptazinol prodrug and its salts and its production method |
| CN1850804A (en) * | 2006-03-31 | 2006-10-25 | 复旦大学 | Optical-purity meptazinol orits salts, and preparing method |
| CN101020661A (en) * | 2007-03-19 | 2007-08-22 | 复旦大学 | (-)-meptazinol carbamate derivative and/or its salt and their prepn and use |
-
2010
- 2010-03-03 CN CN 201010117129 patent/CN101786986A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1569838A (en) * | 2004-05-14 | 2005-01-26 | 复旦大学 | Meptazinol ortho-propionyloxy-cis-benzyl acrylate and its salts and their production method |
| CN1569839A (en) * | 2004-05-14 | 2005-01-26 | 复旦大学 | Meptazinol prodrug and its salts and its production method |
| CN1850804A (en) * | 2006-03-31 | 2006-10-25 | 复旦大学 | Optical-purity meptazinol orits salts, and preparing method |
| CN101020661A (en) * | 2007-03-19 | 2007-08-22 | 复旦大学 | (-)-meptazinol carbamate derivative and/or its salt and their prepn and use |
Non-Patent Citations (1)
| Title |
|---|
| 《Bioorganic & Medicinal Chemistry Letters》 20050409 Meiyan Lu等 Synthesis and relative bioavailability of meptazinol benzoyl esters as prodrugs 2607-2609，特别是2607页图1化合物1、2、3，2608页第一段 1-10 第15卷, 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420911A (en) * | 2012-05-25 | 2013-12-04 | 迪沙药业集团有限公司 | L-meptazinol phenyl carbamate-L-(+)-tartrate and preparation method thereof |
| CN103420911B (en) * | 2012-05-25 | 2016-06-08 | 迪沙药业集团有限公司 | A kind of left-handed meptazinol phenyl urethan-L-(+)-tartaric acid Salt And Preparation Method |
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Open date: 20100728 |