CN101786986A

CN101786986A - (+)-meptazinol prodrug or salt thereof and preparation method thereof

Info

Publication number: CN101786986A
Application number: CN 201010117129
Authority: CN
Inventors: 仇缀百; 卢美艳; 李炜; 谢琼; 章承继; 孙健; 晁博; 王小岳
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2010-03-03
Filing date: 2010-03-03
Publication date: 2010-07-28

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

(+) -meptazinol prodrug or salt thereof and preparation method thereof

Technical Field

The invention belongs to the field of pharmacy, and relates to a (+) -meptazinol prodrug or a salt thereof and a preparation method thereof.

Background

Meptazinol (Meptazinol), the chemical name of which is 3- (3-ethyl-hexahydro-1-methyl-1H-azepin-3-yl) phenol, is a partial agonist of opioid receptors, has a remarkable analgesic effect, and is commonly used for moderate or severe pain caused by different reasons, such as postoperative or postpartum analgesia in clinic. The analgesic activity of the compound is equivalent to that of pentazocine, meperidine, dexpropoxyphene and paracetamol, but is slightly weaker than that of morphine. Compared with other opioid analgesics, meptazinol has less side effects such as respiratory depression and addiction withdrawal. Meptazinol hydrochloride was marketed in 1986 under the trade names Meptid (wyeth. uk) and Meptid (ger) and meptidol (aust), in 98 years british pharmacopoeia.

The meptazinol is similar to most narcotic analgesic drugs containing phenolic hydroxyl in structure, the liver first-pass effect is serious, the phenolic hydroxyl is rapidly acidified or sulfated by glucurone in the liver after oral administration and absorption, the oral bioavailability is only 8.69 percent, the oral dosage required by the treatment concentration is very large, and the meptazinol is mainly administered by injection clinically.

The skilled artisan recognizes that prodrug design for a well-established drug is an effective approach in innovative drug research, and belongs to the current class of Me-to drug research. Studies have shown that the bioavailability of drugs can be improved by using prodrug design to reduce first-pass effect. Such as: the meptazinol (2-amino-6-methyl) -benzoate hydrochloride serving as a prodrug of meptazinol is administrated by directly ligating intestinal tracts of rats in vivo and locally, the bioavailability of the meptazinol hydrochloride is 10 times of that of meptazinol hydrochloride administered by intragastric administration, the bioavailability of the meptazinol hydrochloride is similar to that of meptazinol hydrochloride administered intravenously, and the meptazinol hydrochloride and meptazinol hydrochloride are well absorbed in all sections of intestinal tracts (ZL 200410018366.8 meptazinol prodrug or salt thereof and a preparation method thereof.

At present, meptazinol on the market abroad is a racemic drug, and no optically active body is reported on the market. In order to obtain single enantiomer medicaments with better curative effect and less toxic and side effect, meptazinol is split in the prior art to obtain optically active monomers with (+) -meptazinol and (-) -meptazinol configuration. The animal experiment shows that the medicine is administrated by gastric lavage and tested (+) -And (-) -meptazinol hydrochloride activity against mouse acetylcholine writhing method, the results show: the obtained ED₅₀Values of 14.6. mu. mol/kg and 33.3. mu. mol/kg, respectively, and the activity of (+) -meptazinol is 3 times that of (-) -meptazinol, and thus, research and development of derivatives thereof are drawing attention from researchers.

Disclosure of Invention

The object of the present invention is to provide a (+) -meptazinol prodrug or a salt thereof and a method for producing the same. In particular to 2- (substituted) amino-6-alkyl-benzoate of (+) -meptazinol or a salt thereof and a preparation method thereof.

The present invention provides a compound of formula (I) or a salt thereof,

wherein R is₁Is selected from C₁-C₃Alkyl radical, R₂Is selected from H or C₁-C₃An alkyl group.

Preferably, R₁Selected from methyl, ethyl, n-propyl or isopropyl, R₂Selected from H, methyl, ethyl, n-propyl or isopropyl.

More preferably, R₁Selected from methyl, ethyl, n-propyl or isopropyl, R₂Is selected from H.

Most preferably, R₁Selected from methyl, R₂Is selected from H.

The present invention also provides a process for producing the above-mentioned compound or a salt thereof, which is selected from the following process 1 or process 2,

wherein,

the method 1 comprises the following steps:

(+) -meptazinol and a compound of formula (II) in a condensing agent andcondensation in the presence of a catalyst, followed by R removal₃The reaction formula is as follows:

Most preferably, R₁Selected from methyl, R₂Is selected from H.

R₃Is an amino protecting group.

The method 2 comprises the following steps:

reaction of (+) -meptazinol with a compound of formula (III) in the formula

Wherein R is₁And R₂The definition of (A) is as above.

Preferably, R₃Selected from 9-fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl or trityl.

Preferably, wherein the condensing agent is selected from Dicyclohexylcarbodiimide (DCC), 2- (7-azabenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and 1-hydroxy-benzo-triazole (HOBt), and the catalyst is selected from 4-Dimethylaminopyridine (DMAP).

Preferably, the process further comprises the steps of salifying the compound of formula (I) with an inorganic or organic acid and recrystallizing in an alcohol, an ether or a mixture of both.

Preferably, the inorganic acid is selected from hydrochloric, hydrobromic or hydroiodic or sulfuric acid, the organic acid is selected from tartaric, maleic or fumaric acid, the alcohol is selected from methanol, ethanol or isopropanol, and the ether is selected from diethyl ether, isopropyl ether or tert-butyl methyl ether.

The invention also provides application of the compound or the salt thereof in preparing analgesic drugs.

The compounds provided by the present invention are (+) -meptazinol prodrugs or salts thereof, in particular, (+) -meptazinol 2- (substituted) amino-6-alkyl-benzoate.

The invention carries out structural modification on (+) meptazinol technical material, leads the phenolic hydroxyl of the original structure to be combined with 2- (substituted) amino-6-alkyl-benzoic acid, and the prodrug can reduce the first pass effect of liver: the benzene ring can increase the lipid solubility of the medicine, so that the medicine is absorbed after entering a human body and conforms to a two-chamber model, and the absorption and action time of the medicine is increased; the ortho-amino group has an electric supply effect and can form an intramolecular hydrogen bond with carbonyl oxygen; the steric hindrance of the 6-alkyl group can also prevent the hydrolysis of ester bonds, thereby further prolonging the action time of the medicament.

The most preferred compound of the invention is (+) -meptazinol (2-amino-6-methyl) -benzoate or a salt thereof, as shown in the following structural formula:

the compound is preferably prepared by the following method:

the method comprises the steps of condensing (+) -meptazinol and amino-protected (2-amino-6-methyl) -benzoic acid under the conditions that Dicyclohexylcarbodiimide (DCC) is used as a condensing agent and 4-Dimethylaminopyridine (DMAP) is used as a catalyst, and then removing amino protecting groups to obtain (+) -meptazinol (2-amino-6-methyl) -benzoate;

or 6-methylisatoic anhydride is directly acylated with (+) -meptazinol to prepare (+) -meptazinol (2-amino-6-methyl) -benzoate.

Wherein, the amino-protected (2-amino-6-methyl) -benzoic acid can be prepared by the reaction of an amino-protecting reagent and (2-amino-6-methyl) -benzoic acid;

the amino protecting reagent can be 9-fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), di-tert-butyl dicarbonate (Boc anhydride) or trityl chloride (R is Fmoc, Boc or trityl).

Salifying the (+) -meptazinol (2-amino-6-methyl) -benzoate with hydrochloric acid or hydrobromic acid or hydroiodic acid or sulfuric acid or tartaric acid or maleic acid, and recrystallizing with alcohol, ether or a mixture of the two.

According to the invention, an animal gavage administration experiment is carried out on an enteric preparation prepared by mixing (+) -meptazinol (2-amino-6-methyl) -benzoate hydrochloride (hereinafter referred to as prodrug) and hydroxypropyl cellulose, and the (+) -meptazinol hydrochloride (hereinafter referred to as original drug) to test the influence on the radiation-induced pain of rats. The results show that: the elongation rate of pain threshold of the prodrug is the highest after 2 hours, and is more than 3 times of that of the original drug (synergy); the prodrug keeps the original pain threshold elongation rate after 4 hours, and the original drug is reduced by about 60 percent (prolonged action).

The experimental results show that: after 2 hours, the pain threshold increasing rate of the rat which is fed with the prodrug enteric-coated preparation is three times of that of the original drug, which shows that the drug effect of the prodrug is stronger than that of the original drug; compared with 1 hour, after 4 hours, rats fed with the prodrug enteric-coated preparation keep the original pain threshold increasing rate, and the pain threshold increasing rate of the prodrug is reduced by about 60 percent, which indicates that the duration of the drug effect of the prodrug is longer than that of the prodrug.

The experimental results prove that the (+) -meptazinol (2-amino-6-methyl) -benzoate or salts thereof are prepared into enteric-coated tablets or other enteric-coated preparations and corresponding sustained-release preparations for clinical use, so that the analgesic activity, the duration time of the drug effect and the bioavailability of the original meptazinol can be obviously improved; at the same time, it can be fully predicted that the compound of formula (I) also has the effect of improving the analgesic activity, duration of drug effect and bioavailability of the original drug meptazinol.

For the sake of understanding, the present invention will be described in detail below by way of specific examples. It is specifically noted that the specific examples are given for illustrative purposes only, and it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention within the scope of the present invention based on the descriptions herein.

Detailed Description

EXAMPLE 1 preparation of (+) -meptazinol (2-amino-6-methyl) -benzoate hydrochloride

2-amino-6-methylbenzoic acid (1.00g, 6.6mmol) was dissolved in 18ml of 1, 4-dioxane. Adding Na₂CO₃(1.40g, 13.2mmol) in 18ml of water. A solution of Fmoc-Cl (9-fluorenylmethyloxycarbonyl chloride, 1.71g, 6.6mmol) in 20ml of 1, 4-dioxane was added dropwise. The reaction was stopped after 1 hour at room temperature. The reaction solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined and anhydrous Na₂SO₄Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain 1.57g of N-Fmoc-2-amino-6-methylbenzoic acid as a white solid, wherein the yield is 64%, and the melting point is as follows: 163 ℃ and 166 ℃.

N-Fmoc-2-amino-6-methylbenzoic acid (6.22g, 16.7mmol) and (+) -meptazinol (3.85g, 16.5mmol) were added to a 250ml three-necked flask, 80ml of dichloromethane was added, and a solution of DCC (4.57g, 22.2mmol) and DMAP (0.25g, 2.0mmol) in 12ml of dichloromethane was added dropwise. The reaction was heated to reflux and reacted for 24 hours. After cooling, the solid (about 4g) was filtered off and the solvent was evaporated to give about 11g of a yellow oil. Column chromatography gave 3.15g of a pale yellow oil. Dissolving with anhydrous ether, adding HCl-ether solution, adjusting pH to 6-7 to form hydrochloride, and separating out white powder 2.89g with yield of 43.5% and melting point of 108-.

¹HNMR(DMSO-d₆)：δ10.47(brs，≈1/2H，NH⁺)，8.84(brs，≈1/2H，NH⁺) 7.47-7.40(m, 1H, Ar-H), 7.35-7.08(m, 4H, Ar-H), 6.70(t, 1H, Ar-H), 6.49(t, 1H, Ar-H), 3.99-3.09(m, 6H, containing Ar-NH)₂，CH ₂-N-CH ₂)，2.82&2.80(d，3H，N-CH₃，J＝4.69)，2.46(s，3H，Ar-CH₃)，2.44-2.35(m，H，CH₂)，2.20-2.11(m，H，CH₂)，1.94-1.41(m，6H，CH₂)，0.52&0.48(t，3H，CH₂CH ₃，J＝7.43Hz)；

MS(ESI)：367.3[M+H]⁺；

The content was 98.6% by HPLC.

Example 2 animal experiments

The Effect of (+) -meptazinol (2-amino-6-methyl) -benzoate hydrochloride (in this example, abbreviated as prodrug) and (+) -meptazinol hydrochloride (in this example, abbreviated as prodrug) on radiation-induced pain in rats (oral gavage)

1. Animal(s) production

Strain: SD rat, sex: male, body weight: 200-210g

2. Grouping animals

70 rats were divided into 7 groups of 10 animals each by random number method.

3. Experimental methods

The animals of each group were each gavaged orally with the drug solution to be administered, and the administration volume was 0.3ml/100g body weight. The time (pain region: latency period) from the point light source to the point 1.5-2.0cm from the tail tip to the tail flick was measured with a TF-photothermal pain measuring instrument before and 1, 2, and 4 hours after administration, respectively, and the measurement time was 30 seconds.

Data are expressed as mean ± standard deviation (x ± SD), data variance statistics are tested using one-way analysis of variance (ANOVA), and differences between groups are judged as P < 0.05.

Table 1 shows the experimental results of the effect of radiation-induced thermal pain in rats.

TABLE 1

Claims

A (+) -meptazinol prodrug or a salt thereof, characterized by having a structure of formula (I),

wherein R is₁Is selected from C₁-C₃Alkyl radical, R₂Is selected from H or C₁-C₃An alkyl group.
2. The (+) -meptazinol prodrug or salt thereof of claim 1, wherein R is₁Selected from methyl, ethyl, n-propyl or isopropyl, R₂Selected from H, methyl, ethyl, n-propyl or isopropyl.
3. The (+) -meptazinol prodrug or salt thereof of claim 1 or 2, wherein R is₁Selected from methyl, ethyl, n-propyl or isopropyl, R₂Is selected from H.
4. The (+) -meptazinol prodrug or salt thereof of claim 3, wherein R is₁Selected from methyl, R₂Is selected from H.
5. The process for the preparation of (+) -meptazinol prodrug or salt thereof as claimed in any one of claims 1-4, wherein the prodrug is prepared by the following process:

condensing (+) -meptazinol and the compound of formula (II) in the presence of a condensing agent and a catalyst, and then removing R₃The reaction formula is as follows:

wherein R is₁And R₂As defined in the appended claims, R₃Is an amino protecting group;

or,

reacting (+) -meptazinol with a compound of formula (III) according to the formula:

wherein R is₁And R₂Are as defined in the appended claims.
6. The method of claim 5, wherein R₃Selected from 9-fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl or trityl.
7. The process of claim 5 or 6, wherein the condensing agent is selected from dicyclohexylcarbodiimide, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 1-hydroxy-benzo-triazole and the catalyst is selected from 4-dimethylaminopyridine.
8. The process according to any one of claims 5 to 7, further comprising the steps of salifying the compound of formula (I) with an inorganic or organic acid and recrystallising in an alcohol, an ether or a mixture of both.
9. The process of claim 8, wherein the inorganic acid is selected from hydrochloric, hydrobromic or hydroiodic or sulfuric acid, the organic acid is selected from tartaric, maleic or fumaric acid, the alcohol is selected from methanol, ethanol or isopropanol, and the ether is selected from diethyl ether, isopropyl ether or tert-butyl methyl ether.
10. Use of the (+) -meptazinol prodrug of any one of claims 1-4, or a salt thereof, for the preparation of an analgesic drug.